Note: Descriptions are shown in the official language in which they were submitted.
51~7
~ - 1 - 6197-169
', ~
s
J ~ V` '
This application is closely related to Serial NO . 438,362,
filed September 30J 1983.
BACKGROUND OF THE INV~NTION
1. Field of Invention
The present invention relates to novel aromatic oxazepinones~
thiazeplnones and diazepinones and sulfur analogs thereof and is
particularly concerned with aromatic 1,4-oxazepinones, thiazepinones,
diazepinones and thiones of all, which have the aromatic component
fused into the oxazepine, thiazepine or diazepine component, each com-
ponent thereby having two commonly shared carbon atoms and the oxaze-
'I pine, thiazepine or diazepine ring having an oxo ~or thioxo) function on
the carbon atom adjacent to one of the shared carbon atoms and a short
, chain aminoalkyl, alkylaminoalkyl or heterocyclicaminoalkyl radical
attached to the carbon atom two positions away from the other shared
: carbon atom, the compounds having antihistaminic and anti-allergy
:~ utility, and a novel process and novel intermediates or the prepara-
,: . tion thereof.
2. Information Disclosure Statement.
3-Aryl-1,4-benzoxazepin-5(4H)-ones substituted on the oxaze-
pine nitrogen by an aminoalkyl radical have been disclosed by Schenker~ K.
in Swiss Patent 5U5,850 ~C.A. 75 986005).
.
,. .
419A-CIP-
~L2~L5647
Conversion of flavanones into benzoxazepinones
~ub~tituted in the 2-position by a phenyl radical has been
disclosed by Levai, A. and Bognar~ R., Top. Flavanoid
Chem. Biochem. Proc. Hung. Bioflavonoid Symp. 4th Ed. 1973
(Pub. 1975) 119-2~ ~C.A. 85, 79098n). Thione derivatives
were obtained by treating with phosphorus pentasulfide.
Certain chemical intermediates~ the l-substituted-
3-substituted phenoxypyrrolidines illustrated ~y
l-methyl-3-(2-carbamoylphenoxy)pyrrolidine~
1-benzyl-3-(2-carbamoylphenoxy)pyrrolidine, and
l-methyl-3-(2-carboxyphenoxy)pyrrolidine,
in an otherwise novel class are disclosed in U. S. Patent
3,577,415.
OBJECTS AND SUMM~RY OF THE INVE~TIO~
The oxazepine, thiazepine and diazepine derivatives of
the pre~ent invention which exhibit antihistaminic activity
have the formula:
R4 R
E~(CE~)n Z
~ A` ~ )
~ `-- B Formula I
wherein;
A represents an aromatic ring having two of its ~arbon
atoms held mutually with the oxazepine, thiazepine or
diazepine moiety ~elected from the group consisting of
benzeneJ naphthalene, a ~uinoline, or a pyridine in any of
its four positions, any of the rings optionally substituted
by one or two Y radicals selected from the group consisting
~ 30 of halo, loweralkyl, loweralkoxy, diloweralkylamino, nitro
j~ or trifluoromethyl;
E is ~elected from oxygen, sulfur or loweralkyl
~ubstituted nitrogen,
B i5 6elected from oxygen or sulfur;
R is selected from the group consisting of hydrogen,
~5 loweralkyl, cyclo~lkyl or phenyl-loweralkyl, o~ which phenyl
may be optionall~ ~u~s~-tu.od by one or two radicals
419A CIP-
~Z4~;64'7
selected from halo, loweralkyl, loweralkoxy, nitro or
trifluoromethyl;
n is 1, 2 or ~;
R~ and R5 are selected from hydrogen or loweralkyl
5 (1-5 C);
z is selected from the group consisting of -~RlR2,
lH-pyrazol-l-yl, lH-imidazol-l-yl, lH-imidazol-2-yl,
4,5-dihydro-lH-imidazol-2-yl;
Rl and R~ are selected from the group consisting of
hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl, of
which phenyl may be otpionally 6ubstituted by 1 or 2
radicals ~elected from halo, loweralkylJ loweralkoxy, nitro,
trifluoromethyl or cyano, or Rl and ~2 taken together with
the adjacent nitro~en atom may form a heterocyclic residue
6elected from the group consisting of l-azetidinylg
1 pyrrolidinyl, 2,~-dimethylpyrrolidin-1-yl, 2-methyl-
pyrrolidin~l~yl, l-piperidinyl, 4-substituted piperidin-l-
yl, 4-~bis(4-fluorophenyl)methyl]-piperidin-1-yl, 4-
morpholinyl, l-piperzzinyl, 4-substituted piperazin-l-yl,
1,2,3~6-tetrahydropyridin-1-yl, l~-pyrr~l-l-yl or
2,5-dihydro-lH-pyrrol-l-yl, and the pharma~eutically
acceptable ~alts thereof with the proviso that when R - H,
Z is never a primary or secondary amine, and a further
: proviso that when n = 3, z is not pyrazolyl, or imidazolyl.
The novel oxazepine, thiazepine and diazepine
precursors leading to compounds of Formula I have the
formula:
R4 ~R5
~E ~ ( CH ) n~X
( ~-2 ~ R Formula II
wherein A, B, E, R, ~4, R5 and Y are as defined under
Formula I above, except R is not hydrogeng n i~ 1 or 2, and
X i6 chlori~e, bromine, cyano, or l-~hthalimido, and the
a~id addition salts thereof.
.
; 419A-CIP-2
$64~7
other che~5ical intermediates in the preparation of
compounds of Formsula II are novel and have the formula:
Lo 2 ~ ~ O~-X R ]
Foxmsula III
wherein A~ E, R, R4, R5, n and Y are as defined under
Formula II above and X is chlorine or bromine.
Other chemical intermsediates leading to compounds of
Formula III have the formula:
R~ R5
. ~ ~E ~ ~H ) n
Formsula IVa
wherein A~ E~ R, R4, R5, n and Y are as de~ined und8r
Formula II, and Q is selected ~rom C NHz ~CN or C oR3
where R3 is H, alkali metal ion or an esterifying radical~
~ Compounds of Formula IVa are novel except wherein A i5 phenyl
¦: 25 or substituted phenyl and E is oxygen.
Other chsmical intermediates used in alternate
; procedures ~or preparing compounds of Fonmula I and which
are not precursors of Formula III type compounds have th~
formulas V and VI.
o- C\-(CH)n-NRlR2
'o~C~R9
~; 35 Formula V
`:
i:
i
419A-C:
~L~4564L7
R~ R5
HO-t -(CH)n-NRlR2
~_ , ,C ~R
o Formula VI
wherein A, Rl, R2, R4 and R5 have the values assigned under
Formula I, and R3 is H or alXali metal ion. Compounds of
Formulas V and VI are-not part of the present invention but
are intended to be the subject of a separate application.
In the further definition of symbols in the formulas
hereof and where they appear elsewhere throughout this
15 specification and the claims, the terms have the following
significance.
The term "loweralkyl'~ as used herein, unless otherwise
I specified, includes ~traight and branched chain radicals of
up to eight carbons inclusive and is exemplified by such
groups as methyl, ethyl, propyl, isopropyl, butyl, sec.
, butylj tert. butyl, amyl, isoamyl, hexyl, heptyl and octyl
radicals and the like. The term "loweralkoxy" has the
formula -0-loweralkyl.
The texm "cycloalkyl" as used herein includes primarily
cyclic alkyl radicals containing 3-9 car~on atoms inclusive
and includes such groups as cyclopropyl, cyclobutyl, cyclo-
pentylJ cyclohexyl, methylcyclohexyl, cycloheptyl and the
like.
- The t~rms "halo" or "halogen" when referred to herein
include fluorine; chlorine, bromine and iodine unless other-
wise stated.
"Pha~naceutically a~ceptable salts" include acid
~ddition salts, hydrates, alcoholates and ~uat~rnary salts
` o~ the compounds of Formula I, which are physiologically
~ ~ ~5 compatible in warm-blo~ded animals. The acid addition salts
'i$ ~: may be formed by either strong or weak ~oids. ~epresentative
of strong acids are hydroohloric, sulfuric ~nd phosphoric
aoids. Represent~tive or weak ~cida are ~umaric, maleic,
A
~'
419A-CI~
~2~56~7
' succinic, oxalic, citric, tartarlc~ hexamic, and the like.
2 Suitable cuaternary salts include the loweralkyl
2 halides and loweralkyl sulfates.
2 By "sulfurizing ~gent" is meant any agent or mixture
5 of agents which will convert diazepinones, ox- and
thiazepinones to diazepine-thiones, ox- and thiazepine-
thiones, such as 2,4-bis(4-methoxyphenyl)-1,3,2J4-dithia-
diphosphetane-2,4-disulfide (Lawesson) reagent or a mixture
of phosphorus pentasulfide and alkalimetal sulfide or
2 10 mixture of phosphorus pentasulfide in a suitable solvent
such as acetonitrileJ toluene or pyridine. By the use of
';sulfurizing agent" the azepinones are thereby "sulfurized"
to azepine-thiones.
The compounds of the present invention exhibit anti-
! 15 histaminic activity in guinea pigs. The method of testing
is a modification of the procedure of Tozzi et al (Agents
and ActionsJ Vol. 4/4, 264-270, 1974) as follows: Guinea
; pigs are fasted 18-24 hrs in individual cages. Water is
~ available ad libitum. On the test dayJ animals in groups
f ~` 20 of 3 are injected intraperitoneally with 30 mg~ g of the
test compound prepared in an appropriate vehicle. Thirty
minutes later hi~tamine at a dosage level of 1.2 mg/kg
(= 2 x the LDg9) i8 injected into a marginal ear vein.
Survival of the guinea pigs for 24 hrs is positive evidence
25 of antihistaminic activity. If the vehicle used for the
test compound is other than water, its effect is established
2, by testing an equal amount as a control. The dose pro~ecting
50% of the animals (PD50) from death may be established
from dose-response curves. The non-sedative nature of the
30 compounds is discussed hereinbelow under "Additional
~ Pharmacolo~y."
2 The novel process of this invention comprises the
1 following steps:
s Step 1) Halogenating a compound of the formula
~F~)
R IVb
419A-CII
~2gL5~
wherein;
A represents an aromatie ring selected from benzene,
naphthalene, a quinoline, or a pyridine in any one of its
i four positions, any of the rings optionally substituted by
one or two Y-radicals 6elected from halo, loweralkyl,
loweralkoxy, diloweralkylamino, nitro, or trifluoromethyl:
E is oxygen, sulfur, or loweralkyl substituted
nitrog~en,
R is selected fr~m the group consisting of loweralkyl,
cycloalkyl or phenyl-loweralkyl, of which phenyl may be
optionally substituted by one or two radicals selected rom
halo~ loweralkyl, loweralkoxy, nitro or trifluoromethyl;
R3 is hydrogen or an acid neutralizing ion;
R4 and R5 are hydrogen or loweralkyl (1-5 C); and
n is one or two,
1~ to give a compound of the formula
LY~ Ç ~ ] X
or its free base wherein X is chlorine or bromine and
A, E, R, R~, R5, Y ~nd n are the same as the starting
values. Among 6uitable halogenating agents are
a~ thionyl halides
b) triphenylpho~phine and a carbon tetrahalide
c) phosphorus pentahalides
- d) phosphorus trihalides, and
e) triphenylphosphine dihalide.
Step 2) ~eutralizing, i~ nlecessary, and fusing the
carboxylic acid halide derivative prepared in ~tep 1 to
give an oxazepinone, thia7.epinone ox diazepinone of the
ormula
419A-CIP-2
R IIa
wherein A, E, R, R~, R5, X, Y and n are as defined above in
l~ step l, and A now has two of its carbon atoms held mutually
with the oxazepine, thiazepine, or diazepine moiety;
Step 3) Optionally reacting the compound prepared in
step 2 with a sulfurizing agent to obtain an oxazepine-
:~ thione, thiazepinethione, or diazepinethione of the formula
~: R4
(Y ~ ~~" ~ ~C~)n-x
wherein A, E, R, R4, Rs, X, Y and n are as defined above
in step 2.
: 25 Step 4) When required, reacting a compound prepared
in step 2 with an alkali-metal cyanide to obtain a compound
of the foxmula
: R4 R
~ 2
~ ~ 6 R Ilc
.
wherein ~, E, ~, R, ~ and R5 are as de~ined in step 2,
. 419A-CI:
124S64L~
Step 5) Reacting a halogen compound prepared in
tep 2 c:~r 3 with a compound of tha formula
ZH
wherein z is selected from -NRlR2, lH~pyrazol-l-yl,
lH-Lmidazol-l-yl, lH-imidazol-2-yl, or 4,5-dihydro-lH-
-~ imidazol-2-yl, and wherein Rl and R2 are selected from
: hydrogen, loweralkyl, cycloalkyl and phenyl-loweralkyl, of
which phenyl may be optionally substituted with 1 or 2
:~ radical~ selected from halo, loweralkyl, loweralkoxy, nitro,
trifluoromethyl or cyano, or Rl and RZ taken together wi~h
the adjacent nitrogen atom may form a heterocyclic residue
selected from the group consisting of l-azetidinyl,
l-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methyl-
pyrrolidin-l-yl, l-piperidinyl, 4-substituted-piperidine-
l-yl, 4-~bis(4-fluorophenyl)methyl]piperidin-1-yl,
4-morpholinyl, l-piperazinyl, 4-substituted-piperazin-1-yl
1,2,~,6-tetrahydropyridine-1-yl, 2,5-dihydro-lH-pyrrol-l-yl,
lH-pyrrol-l-yl, or l-phth~limidyl to give the compound of
the formula
(C~)n~z
(Y~
Ia
wherein A, E, R, R4, R5, n and Y are a~ defined above in
step 2, Z is the same as in the ZH compound, and B is an
oxygen or sulfur atom,
Step 6) Optionally reacting a compound prepared in
step 5 wherein B i6 an oxygen atom with a sulfurizing
agent, preferably phosphorus pentasulfide in pyridine to
, ~ obtain a compound of the formula
R4 l5
~ 35 "~ ~ E ~ (~ z
I ' A I
~ ~ ~ R Ib
419A-CIP-2
5~i~7
wherein ~, E~ RJ R4~ R5~ n, Y and Z are as defined in
step 5.
Step 7) Reducing a ~yano compound (Formula IIc~
prepared in step 4, or reacting a phthalimido compound
prepared in step 4 with hydrazine-hydrate to give a
primary amine of the formula
.. R4
"~ E ~ (C~)2-
(y) ~ ,' ~ N
R Ic-la
wherein A, E, Y, R, R4 and R5 are defined in steps 2 and 4.
Step 8) When required, reacting a primary amine
prepared in steps 5 or 7 of the formula
R4 R5
, ~ / E ~ (CH)l-~H2
~--R Ic-l
wherein A, E, Y, ~, R~ and R5 are as defined in step 2
- 25 with one of the following reactants or sets of
reactants:
a) formaldehyde and formic acid to give a
;tertiary dimethylamineJ
b) a dihalide or alkenedihalide to give a
heterocyclic amine,
c) a dialdehyde and sodium cyanoborohydride
.~ to give a heterocyclic amine,
;; d) equal molar ~mounts of aldehyde or ketone,
sodium cyanoborohydride with large exces~
~5 of above primary amine to give a secondary
amine,
419A-CIP-
56~7
11
e) equal molar amounts of the primary amine
and sodium cyanoborohydride with at least
two equivalents of aldehyde or ketone,
f) in sequence: trifluoroacetyl chloride, alkyl
or phenyl-alkyl halide, potassium hydride
and potassium hydroxide to give a secondary amine,
- all products being encompassed by the formula
R5
~ (CH) -Z
(Y~
R Id
wherein ~, E, Y, R, R4 and R5 are as defined in step 2
and z i8 -NRlR~ wherein Rl and R2
are loweralkyl J cycloalkyl and phenyl-loweralkyl with
phenyl being optionally substituted by halo, loweralkyl,
loweralkoxy, nitro, trifluoromethyl or cyano or Rl and R2
taken together with the adjacent nitrogçn may form a
heterocyclic residue selected from l-azetidinyl, l-pyrroli-
dinyl, l-piperidinyl, 4-substituted-piperidin-l~yl,
4-~bis(4-fluorophenyl)methyl~piperidin-1-yl, 4-morpholinyl,
l-piperazinyll 4-substituted-piperazin-1-yl, 1,2,3,6-
tetrahydropyridin-l-Yl, lH-pyrrol-l-yl
or 2-methylpyrrolidin-1-yl, and optionally sulfurizing the
diazepinone, azepinone or thiaz~pinone to give the
corresponding thione as in step 6.
Step 9) When required, reacting a benzyl or substituted
:~: 30 benzyl compound obtained in ~teps 5, 6, or 8 wherein Z is
tertiary amino, or non-reactive heterocycle radical such as
pyrazolyl or ~midazolyl of the formula
4 l5
~5 " ~ ~ (CH)l -3Z
C~4 Ie
phenyl
419A-~
~2~5~
12
wherein A, E, ~, R4 and R5 are as defined in ~tep 2, and z
is a radical taken from the definition of z under Formula I,
subject to the same pxovisos given thereunder, with sodium
and ammonia to give a compound of the formula
R4
~ /E ~ ( )1-~
H ~f
wherein A, E, ~, R4 and R5 are as defined in step 2, n is 1
to 3 and z is the same as the starting compound in this
step,
Step 10) Optionally reacting the free base of any
compound prepared in steps 5 to 9 with a pharmaceutically
acceptable acid or quaternary forming halide or sulfate to
form a pharmaceutically acceptable salt thereof.
The compounds of Formula I wherein n is 2 are preferred
for their antihistaminic activity. The process which
includes steps 1 to ~, 5, 6 and 10 wherein compounds prepared
have a methyl or ethyl side chain (n = 1 or 2) represents
a preferr~d process corresponding to a succession of steps
designated A to F as explained hereinbelow.
The compounds of Formulas Ia, Ib. Ic-l to IC_7~ Ic~la~
Id, IeJ If are all encompassed by Formula I and the compounds
of Formulas IIa, IIb, IIC, IId and II~ are all encompassed
by Formula II.
Step~ 1 to 4 also repre~ent a novel process for
3~ preparing compounds of Formula IIa, II~, IIC, all encompassed
by Formula II.
It is therefore an object of the pr0sent invention to
provide certain novel aromatic 1,4-oxazepinones, thiazepinones
and diazepinones and sulfur analogs thereof as described
hereinabove under ~fiald of invention" and as defined by
Formula I which have antihistaminic activity.
419A-CIP-2
456~7
13
Another object is to provide certain novel aromatic
1,4-oxazepinones, thiazepinones and diazepinones (and sulfur
analogs thereof) substituted with haloalkyl or cyanoalkyl
and phthalimidoalkyl radicals which are chemical intermediates
as defined by Formula I.
Still another object is to provide a novel route and
proc~ss for preparation of aromatic 1,4-oxazepinonesJ
thiazepinones, diazepinones and sulfur analogs thereof
substituted with short chain haloalkyl~ cyanoalXyl or amino-
alkyl radicals.
Additional objects and advantages of the presentinvention will be apparent to one skilled in the art and
others will become apparent from the following description
of the best mode of carrying out the present invention and
fr~m the appended claims.
DETAILED DESCRIPTIO~ OF THE INVENTION
The present invention encompasses the novel dia7epine,
oxazepine and thiazepine derivatives set forth in Formulas
I and II and certain novel compounds of Formulas III, IVa
and IVb as c~mposition of matter and a process for the
preparation of compounds of Formulas I, II and III.
Charts I and II illustrate the preparation of all
intermediates. R is never hydrogen.
Chart III illustrates reaction sequence for preparing
end-products wherein R is other than hydrogen and n is
1 or 2.
Chart IV illustrates preparation of compounds having
ethyl and propyl radicals-omega substituted by primary amine
NH2). R is never hydroqen.
3 Chart V illustrates methods of converting the omeg~
~ NH~-substituted ethyl and propyl compounds to ~econdary
¦ ~ and tertiary amines. This is an alternate method for
prepariny the ethyl-secondary and tertiary amines. ~ is
never hydrogen.
Chart VI illustrates preparation of compounds wherein
R is hydrogenc
Preparati~ns 1-40 illustrate ~yntheses of compounds of
Formulas IVa, IYb or provide certain starting materials
,
Ill9A-CI~
S1~47
therefor. Preparation 41 provides a starting material for an
alternate process. See Chart VIII, Formula VI. Inter-
mediates 1-64 (see also Table 1) illustrate preparation of
compounds encompassed by Formula II, which are chemical
intermediates substituted with haloalkyl, cyanoalkyl, or
phthalimidoalkyl radicals. The compounds of Formula II are
formed in the reaction mixture usually without isolation.
Charts VII and VIII illustrate the preparation of
compounds of Formula I by novel alternate methods illustrated
10 further in Examples 68b~ 90 and 107 to 109, which process
methods thereof are not part of the present invention but
which process methods are intended to be the subject of a
separate application~
Examples 1-123 (see also Table 2) illustrate preparation
of compounds encompassed by Formula I. The scope of the
invention is not limited by the preparations, intermediates
and examples, however.
419A-CI~
L5~47
C~ RT I
Preparation of Intermediates
' ~ ~ + ~ n ~ CK)n
E=O or S Rs
See footnotes , , ~ E ~ (CH)n
c) and d) fos ~A ~ L
10 other E values ( a-2 R
IVa
*Hydrolyze
H)n
~ A I ~N
(Y)O 2 ~ ~OR9 R IVb
~ ¦ R3 = H or M
~ Halogenate
( ~
\~*
RS \ Heat and/or
R4 l \neutralize when required
".~ E ~ (CH3n~halo ~ R~ R5
2~ ; A r \ Optional ,v-~ / ~ (CH)n-halo
( ~-2 S R IIb url lng ' A ~ )
Optional to
lengthen chain
~ _~ _
R~ I
( CH) n-CN
R IIc
(cont,)
~2~56~7
- 16 - 66197-169
Footnotes (Chart I):
a) R i.s never hydrogen.
b) n = 1 or 2.
X = Halogen ~Cl, Br)
W = Aryl sulfonate, alkyl
sulfonate or X.
M = Acid neutralizing ion,
: e.g. alkali-metal.
O O
~ Q is -C-NH2, -CN~ -C-oR3
; where R3 is H, M or
esterifying radical.
*Hydroly~e when Q is other
O ,0
than -C-OH or C-OM.
**Diagram illustrating the
suggested formation and
:~ cleavage of bonds to
effect rearrangement.
R4 R5
~O ~ J CH) 1 or 0
o R
-~ loweralkyl R4 R5
c) Illustrates ~-- IH
When E = lowera.lkyl I A r +Br- - (CH)n
: ~N~ ~_,'l base ~N /
and ~ R
A = phenyl, naphthyl loweralkyl
or ~ -E ~ ,N n-butyl
~ CO2
loweralkyl
R4 R5
~N--~ ( CH)
~i
s~
- 16a - 66197-169
d) Illustrates
When E = loweralkyl loweralkyl
,~ N ~ '~~ ~ Cl ¦ R4 R5
and `~ ' ~ COOH ~ t ~I)n
A = pyrido N
or R
or ~ E loveralkyl
~N ~ ~C/l)n
: ~ A N
~ _~ CoO~/ R
~2~56~7 41 9A-~
C~
Alternate Method of Preparing Pyrido Ring -
R5Halogenated Intermediate~a) R5
( )1-2 fl ~ ~ ~ (CH)1 ~-X
5R IId + S0zCl2 ~ Cl ~ ~
dimethylformamide R
Footnotes:
X = Cl, Br, CN
E and R are as defined in Formula I
a) n = l or 2
15CH~RT III
Preparation of End Products
(n = l or 2; R = other than H)
,~ (CH)n-ha10 , ~ ~ ~ (CH)n-ha10
t )o-z S' R IIb 0-2 o R IIa
Iz~ 5 ¦ ZH
" ~ ~ ~ (CH)n-z ,_ ~ E ~ (CH) -z
(Y)o_æ S R Sulfurizing (y) ~ ~ ~ N
Ib Ia
Footnote:
Z i5 as defined for n - l or 2
under ~ormula I.
419A-CIE
56~7
~H~R~ IV
Preparation of Primary Ethyl and Propyl Amino
Compounds wherein R i~ other than Hydrogen
from Cyano Intexmediate
" ~ E ~ (CH)l 2 CN , ~ ~ ~ (CH)2_3-
(Y)0-2 Ilc (Y)0-2 o X la
CH~RT VI
Preparation of Compounds Having
Unsubstituted Azepine Nitrogen (R=H)
~ H ~
(Y)0_2 o' 1 3 (Y)o ~ H
2~ C3H~ Ie ' If
R - Benzyl R = H
Footnote:
*Z ~annot be a prLmary or secondary amine.
3o
51~7
~19~ 66197-169
CfT.~RT V
Additional Preparations of Secondary and
Tertiary Amino-alkyl Compounds within
R is other than H (a)
~ E- ~ (CH2)1 3 NH2 _ ~ ~ E ~ (CH2)nN(CH3)2
( ~~ ~ ~ c 1 ~ ~0-2 0 ~
, - ~ ~ E ~ (G'-I ) -N Hetl
* HC-(CEI2) -CH ~ N
R-3
2 NaBH3CN 0-2 0 R Ic-3
CH30H(pH 6-8)
H
*1 mole aldehyde or ketone ,- ~ ~ ~ E ~ (~2)n-N-R
1 mole NaBH3CN ~ A I )
MeaH (pH 6-8) ~ ' ~ N
: Ic 1 in excess (Y)o_2 R Ic_4
: :
. 1 mole same or different
aldehyde or ketone; 1 mole
: NaBH~CN;
I ~ MeOHrpH 6-8)
2 mole aldehyde or ketoQe~ / E ~ (CH2)n-NRlR2
2 mole NaBH3CN I A I )
. ~ .. -~
: MeOH (pH 6-8) (Y)` ~ ~ ~ N
O- O Ic-5
React in sequence 1-4**
1) Trifluoroacetyl chloride; . I
~` 2) Alkyl or phenylalkyl- ~ ~ E ~ (C~I2)n-N-R
halide; ~ ~ A ,¦ )
3) KH; ~ _ ~ ~ N
4) Me~al hydroxide (Y) 2 R I -6
sultable solven~ 0- c
Rl= alkyl or 0 -alkyl-
~2'~56~7
-20- 66197-169
IC-1) Optional to produce ' `~ ~ E ~ (CH2)n-z
to 3 thione; ~ > N
Ic 6) Sulfurizing agent( ~0-2
Footnotes:
(a)
Illustrated for R a~d R = H and
is applicable for R and/or R5 =
loweralkyl (1-5c).
n = 1-3
*Method described by R.F. Borch, et al.
J. Amer. Chem. Soc. 93 2897 (1971).
Footnote Chart V continued under *.
Illustration of reaction of a compound of Fo D la I
wherein Z is NH2 with aldehydes and ketones c-l
follows:
Reactant Z-Radical Produced
1) 1 mole acetaldehyde -NHC H
1 mole NaBH3CN 2 5
excess primary amine
(Z----NH2)
2) 1 mole acetone -NHCH(CH )
1 mole NaBH3CN 3 2
3) 1 mole benzaldehyde NHCH2C6H5
1 mole NaBH3CN
eXC(eSNHPr)imary amine
4) 1 mole cyclohexanone -NHC6H
1 mole NaBH3CN
5) 2 mole acetaldehyde -N(C2H5)2
2 mole NaBH3CN
6) 1 mole acetaldehyde )
1 mole NaBH3CN
excess primary amine)
(Z--H)
followed by
1 mole formaldehyde ) N(C~l3)C2H5
1 mole NaBH3CN
J.E. Norlander et al., Tetrahedron
Letters 1978(50)pp 4987-4990.
''
419A-(
5~
21
CHART VII
Altexnative Method of Preparing Oxazepinones
HO ~ T -(C~ )n~Z ~ KH ~ ) H T
I ~CH2 1 ,CH2
R R
,~ Cl
~ ~ ~ ~ C-oR3
O
" ~[~o~R ~5
O~ `R
O~
la ~ metal
: hydride
~4 R5
(CH)n~Z
'` A ~ N
O
419A-CIP-2
L5~7
22
CH~RT VIII
Further Alternate Method of Preparing
Oxazepinones
R9~ + ~ ~CRz
QN=C=N~
or
MeSO2Cl/Et3N
.
15R~ jRJ HoR4 R5
~: " ~ ~ "_~ ~ C~ (cH)n~z
A ~ N Select from ~ F ~ VI
R ~aH, KH, O R
NaNH~ or K-o-t-Bu
*R3 = H, alkali-metal.
419A-CI
56~7
23
In reference to the processes and the process steps
of the invention summarized above as they apply to the
preparation of compounds of Formulas I, II and III, the
f~llowing further description is applicable.
In step 1, starting compounds of Formula IVb ~See
Chart I) bearing a carboxylic acid or an acid neutrali2ing
ion such as an alkali-metal salt thereof on the A ring
ortho to the ether linkage as a substantially pure entity
or preferably derived in a reaction mixture resulting from
hydrolysis of precursors bearing in the same ortho
position, carbamoyl, cyano or carboxylic acid ester
functions without substantial isolation of the carboxylic
acid (or salt) compound from the reaction mixture, are
treated with any suitable halogenating agent such as are
described above, preferably thionyl chloride or triphenyl
phosphine and carbon tetrachloride. The haloyenation i5
conducted in any suitable organic solvent, preferably a
refluxing organic solvent or a refluxing halogenating
agent such ac the preferred thionyl chloride. Temperatur~s
; ~ 20 for the c~lorination over a wide range may be employed,
for example, from room temperature to 100C. or above;
however~ temperatures of ~o-80c. are preferredJ which
temperatures encompass that of refluxing chloroform or
thionyl chloride. When excess haloqenating agent such as
thionyl chloride has been used as carrier, it is advanta-
geously evsporated. When solvent such as chloroform is
used, it may, but not necessarily, be evaporated away. In
any event a solution comprising a solvent and compounds of
Formula III or a residue compri~ed of Formula III compounds,
all of which are confirmed by infra-red analysis is
available for use in the next step.
In step 2, the halogenated compounds of Formula III,
prepared in 6tep 1, if not already in a solvent, are
~olubilized with organic solvent, preferably chloroform
35 and usually neutr~lized or basified preferably wi~h a
tertiaxy amine such as triethyl amine, and then heated at
temperature and for a time ~ufficient to effect ~ fusion
.~, ,
419A-(
~2~S~
24
of the carbonyl with the basic nitrogen and cleavage of the
cyclic amine and formation o~ the chloro or bromoalkyl-
oxazepinone, thiazepinone or diaæepinone compounds of
Formula IIa. If the tendency to fuse is sufficiently great,
S the neutralization of basification may be eliminated. The
Formula IIa compounds may be isolated by conventional means,
Eor example, by partitioning between a suitable organic
solvent or mixture of solvents and aqueous acid or base
followed by drying and evaporating the organic layer and
recrystallizing the residue from a suitable solvent.
In step 3, the compounds of Formula lIa may optionally
be converted to the oxazepinethione, thia~epinethione or
diazepinethione (IIb) by heating together with sulfurizing
agent in a suitable organic solvent such as toluene
acetonitrile. The thione (IIb) may be isolated by conven-
tional means, preferably by partitioning between an organic
solvent and dilute alkali metal base and crystalliæing from
a suitable solvent such as ethanol.
In step 4, an oxazepinone) thiazepinone or diazepinone
~; 20 (IIa) is reacted with potassium cyanide in a hot protic
solvent using a phase transfer catalyst such as tetrabutyl
ammonium bromide. The resulting cyano compound is then
extracted into a suitable solvent such as ethyl acetate, and
the solution dried and evaporated. The residue is then
recrystallized from suitable ~olvent uch as a mixture of
ethyl acetate and isopropyl ether ox ethyl acetate alone.
As will be realized, the compounds produced have cyano-
methyl and cyano-ethyl side chains tn = 1 or 2) which lead
to side chain lengthening to amino propyl n - 3 or as an
30 ~lternate 6tarting material for lengthening of a methyl
chain to amino ethyl.
In ~tep 5, the oxazepinone, thiazepinone (IIa) or
diazepinone obtained in step 2 or the oxazepinethione and
thiazepinethione (IIb) or diazepinethione obtained in step
~re reacted with pyrazole, imidazole or with ~n ~mine of the
formula NHRlR2 wherein Rl ~nd R2 have the value given under
419A-CIP-c
~L2~56~
Formula I above to give compounds of Formulas Ia and Ib)
respectively. The latter reaction is preferably conducted
in excess amine as in the instance of volatile methylamines.
The free bases of products of Formula Ia and Ib are isolated
by conventional means by removing volatiles and partitioning
between dilute aqueous alkali metal base and a solvent such
as chloroform or methylene chloride followed by evaporation.
The free base may be converted to a pharmaceutically
accepta~le salt with an appropriate acid and in the case of
a quaternary salt with a loweralkyl halide or ~ulfate and
recrystallized by conventional means. The free bases may
be recovered from the acid addition salts, usually in a
purer form~ by again partitioning the salt between aqueous
base and a suitable solvent followed by evaporation. As
will be realized and as shown in Chart I, the side chain of
the intermediate produced is limited to aminomethyl and
aminoethyl (n = 2).
In step 6, when it i~ desirable, a compound prepared in
step 5 wherein B is oxygen is sulfurized, preferably by
refluxing in dry pyridine with phosphoxus pentasulfide for
several hours. The resulting thione is isolated by cooling
~` the solution and partitioning between a suitable solvent
such as chloroform and an aqueous base and evaporating
the organic phase and isolating by conventional means.
In step 7, a cyano compound (IIc) prepared in step 4
which is a diazepinone, an oxazepinone or a thiazepinone
is reduced~ preferably with hydrogen using Raney nickel
catalyst at about 60C. The primary aminoethyl or amino-
propyl compound (n = 2 or 3) produced is isolated by
conventional means, preferably as an acid addition salt
which may be converted back to the free base by partitioning
between a suitable solvent and aqueous base and ther~after
drying and evaporating the organic layer.
In ~tep 8 (see Chart V), a primary amine i8 converted
to a secondary or tertiary amine by ~ choioe of reactants-
~he method prov.ides a route to secondary and tertiary amino
~`
419~-CIP
~L24S6~ .
26
compounds of Formula I having n = 3 not afforded by step 5
and, in addition, provides an alternate route to secondary
and tertiary amino compounds of Formula I wherein n = 1 or 2.
~he preparation of dimethylamino deriva~ives by reaction
of primary amine with formaldehyde and formic acid is a
conventional method for preparing tertiary dimethyl amines
as is reaction of a dihalide to give a heterocyclic amine
such as l-pyrrolidino, piperidino or 4-morpholino. The
alternatives employing sodium cyanoborohydride follow the
procedures described by R. F. Borch et al, J. Amer. Chem.
Soc. 9~, 2897 (1971). The procedure which employs conversion
to a trifluoroacetamide is described by ~. E. ~orlander
et al, Tetrahedron Letters, 1978 (50) pp 4987-4990.
In step 9) a 4-benzyloxazepinone, 4-benzyl-thiazepinone
or 4-benzyldiazepinone derivative (R = Benzyl) under
Formula I excluding primary or secondary amines is converted
to the corresponding ~-unsubstituted (R = H) oxazepinone,
thiazepinone or diazepinone by reaction with sodium and
ammonia and may be isolated as illustrated in Ex~mple 68.
Step 10 is optional depending on whether the compound
of Formula I is already in the form of a pharmaceutically
acceptable salt or whether it is desirable to convert to
another salt or whether the free base is desiredO To obtain
~he free base from any addition salt of Formula I, the salt
is partitioned between a suitable organic solvent such as
chloroform and a dilute aqueous baseO The organic layer
is dried and condensed to give the free base which is then,
if desired, reac.ed with an acid described above to give
the desired salt.
As mentioned above, the preferred steps for reaching
the preferred compounds having an ethyl side chain in the
2-p~sition include steps 1 to 39 5, 6 and 10 of the general
process for preparing all the compounds of Formula 1.
Inasmuch as the compounds having a methyl side ehain can
be made by the same process, compounds wherein n = 1 are
included in the preferred process. These ~teps of a
4l9A-c
56~7
~ 27
preferred process are designated A to F corresponding to
the numbered steps of the general process with the limitation
that n = 1 or 2 and R is other than hydrogen a~ follows:
corresponding General
Step Number with
Preferred Process DescriptiOn Pertaining
SteP Desianation to n - 1 or 2
B 2
C 3
D
E 6
F 10
Compounds of Formula I wherein E is O or S are
1~ preferred because of their potency as antihistamines based
on test comparisons made.
4lgA -CII
lL2~6~7
28
Pre aration 1
2~ Benzyl-~-pvrrolidinyloxy~benzamide.
To a ~u6pe~sion of 4.~ g ~0.11 mole) of sodium amide
in 60 ml of dry toluene was added 19.3 9 (0.11 mole) o~
l-benzyl-3-pyrrolidinol at a rate to maintain ~ temperature
of 35C. Stirring was continued at room temperature for
3 hours. To the mixture wa ~dded at rapid drop 19 g
(0.1 mole) of o-toluenesulfonyl chloride with ice bath
cooling to maintain a temperature of 20-~0C. Stirring
was continued at room t~mperature for 2.5 hours and the
mixtuxe allowed to ~tand overnight. The toluene was
washed twi~e with water, dried with sodium ~ulfate and
concentrated.
To a suspension of 5.4 g (0.1 mole) of xodium
methoxide in 50 ml of dimethylformamide in another vessel
was added 1~ . 6 g ( 0 .1 mole) of Ral icylamide in 75 ml of
dimethylformamide at a rate to maintain a temperature of
50~C. After 6tirring 15 minutes, the above prepared
~ulfonate in 25 ml of dimethylformamide wa added drop-
wise and the ~olution refluxed 5 hour~. The material
was partitioned between 500 ml of ethyl acetate and 500 ml
of water. The ethyl acetate was extxacted with dilute
hydrochloric acid, the acid basified with dilute ~odium
hydroxide and extracted with ethyl acetate. The organic
layer was dried, ~oncentrated, and the residue ~ry~tal-
lized twice from isopropyl ether-ethyl acetate. Yield of
product was 12.5 g (42%), m.p. 120.5-122C.
Analysis: Calculated for C1BH~ON202 C,72.95; H,6.80;
N,9.46
Found : CJ73.~3: H~6~78;
.9.56
~0 ~paration 2
2~ Methyl-3-pYrxolidinylox~ benzamide.
To 85.6 9 (2.2 moles) of sodium ~mide in 1.5 liter of
dry toluene was ~dded 202 g (2 moles) of 1-methyl-3-
pyrrolidinol ~o ~ not to exceed a temp~rature o~ 50 C.
The mixture W~8 then heated to 70C. for 4.5 hours. The
mixture was cooled ~nd ~81 q (2 mol2s) ~f o-toluene-
~ul~onylchloride w~ add~d ~t a rapid drop while maintaining
419A-CI~
~Z~
29
a temperature of 20-30~C. with an iee bath. The mixture
wa ~tirred at room ~emperature for 2.5 hours and washed
with water. The toluene solution was dried with sodium
6ulfate and concentr~ted. The residue, dissolved in 500
ml of dLmethylformamide, wa~ added to a reaction mixture
prepared by adding 119 g (2.2 moles) of Rodium methoxide
and 274 g (2.0 moles) of ~alicylamide to one liter of
dimethylformamide and the mixture was worked up ~s in
preparation 1. Yield of product was 170 g (38%), m.pO
116-118C.
Analysis: Calculated for C12Hl~N202: CJ65.43; H~7.32;
~1~ 12 .72
Found : C,65.?8; ~7.28
~,12.77
Preparation ~
2-r~ Benzyl)pyrrolidinyloxylbenzoic acid.
To a solution Of 20.3 g (0.52 mole) of sodium
hydroxide in 600 ml of ethanol and 400 ml of water was
added 150 g (0.51 mole) of 2-[3-(l-benzyl)pyrrolidin
benzamide and the mixture was stirred at reflux ~or 48
hours. The mixture was concentrated on the rotary
evaporator to one-half volume and the residue wa~ extracted
with ethyl acetate to remove unreacted amide. The water
layer was filtered and the pH of the filtrate ~dju~ted to
6.5 with hydrochloric acid. The filtrate was concentrated
~n the rotary ev~porator. ~he re6idue was dissolved in
isopropyl alcohol. The re&ulting mixture was filtQred and
the filtrate concentrated. $he residue 85.7 9 was comprised
substantially of the title compound.
Preparation 4
~-~(1-Methyl-3-pyrrolidinyl)oxyl-2-naphthalene-
carboxamide.
To a c~oled solution of 68 g (0.67 ~ole) of l-methyl-
3-pyrrolidinol and 74 g (0.73 mole) triethylamine in 700 ml
of dry benzene wa~ ~dded dropwi3e 74 g ~o.6~ ~ole) of
methane~ulfonyl chloride. ~fter ~tirring ~ room temperature
`~ ~or 45 min, the mixture wa~ filtered and the filtrate
concentrat~d under reduced pre3sure and di~olved in 100 ml
419A-CIP-
~Z~S6~7
~o
of dimethylf~rmamide.
To ~ cooled ~uspension of 10.8 g (0.45 mole~ of
sodium hydride in 75 ml of dimethylformamide in another
veRYel, 84 g to-45 mole) of 3-hydroxy-2-naphth~lene-
5 carboxamide disÆolved in 400 ml of dimethylformamide wasadded dropwise. The above prepared ~ulfonate 001ution
was added dropwise and the reaction mixture Etirred and
heated at reflux for 16 hr. The cooled solution was
diluted with 1000 ml of water and extracted twice with
500 ml portion~ of chloroform. The chloroform was waæhed
with water and extracted twice with 500 ml portions of
~N hydrochloric acid. The a~ueous extract6 were made
alkaline with 50~ sodium hydroxide and extracted thrice
: with 500 ml portionq of chloroform . After drying over
magnesium ~ulfate, the chloroform was evaporated under
reduced preRsure affording 27.4 g (22 0 of a pale yellow
~olid. Recrystallized from ethyl acetate, m.p. =
128-130C.
Analysi-q: Calculated for Cl~Bl~Nz02: C,71.09: H,6.71;
~,10.~6
~ound : C,70.88; H,6.68;
~,10.37
Preparation 5
3-[(1-Methyl-3-pyrrolidinyl)oxy~-2-naphthalene-
carboxylic acid oxalate t2~
To a 601ution of 21.6 g to-54 mole) of scdium
hydroxide in 500 ml of water was added 74 g (0.27 mole) of
3-tl-methyl-3-pyrrolinyl)oxy~-2-naphthalenecarboxamide.
The solution was heated at reflux for 16 hrs and on cooling,
~he pH was adjuRted to 6.8 with concentrated hydrochloric
~0 acid. The resultant ~olid was separAted by filtration and
the pH of the filtrate was adjusted to 6.02. The filtrate
wa~ concentrated under reduced pre~sure and the residue
boiled in 200 ml o~ i~opropyl ~lcohol and filtered. The
filtrate was ~gain concentrated under r~duced pre~sure to
give 69 g (94%) of an amorphou~ ~olid. An ali~uot was
dissolved in isopropanol ~nd treated with oxalic acid.
The oxalate ~alt w~8 recrystallized ~rom ethanol ~ater,
419ArCIP
i24S~i47
31
m.p. 209-212~C.
Analy~is: c~lculated for C17Hl~N05: C,64.55; H,5.74;
N,4.43
~ound : C,63.86; H,5.68;
~,4-37
5Pre~aration 6
Sodium 2-r(l-methvl-3-pvrrolidinyl~oxy]-3-pyridine
carb~xylate.
To a 6tirred suspension of 6.4 g (0.13 mole~ of 50%
odium hydride (mineral oil) in 50 ml of dimethyl-
sulfoxide was added dropwise 6.4 g (o.o6~ mole) of
l-methyl-3-pyrrolidinol. During addition~ the temperatuxe
rose from 25C. to 31C. After 10 minutes, a ~olution
of 10 g (0.063 mole) of 2-chloronicotinio ~cid in 50 ml
of dLm~thy~sulfoxide was added dropwise causing the
temperature to rise. When the temperature reached 55 C.,
it was maintained there by the intermittent u~e of an ice
bath until addition was complete. The mixture was then
heated to 55-60 C. for 1.5 hr., cooled and iltered. The
~ilter cake was ~u6pended in 100 ml o~ ethyl acet~te and
filtered. The solid was recryst~llized ~rom ethyl acetate-
methanol. Yield of product was 5 g., dec. 240C. The
NMR analysi~ showed that the compound contained 1 h mole
of sodium acetate as impurity.
Analysis: Calculated for CllHl3N203Na-l/3C2HgO2Na:
C,51.62; H,5.20; N,10.32
25Found : C,51.81; ~5.15; N,10.39
Prepar3tion 7
4-Chloro-2-[ ( 1-methyl-3-pyrrolidinyl )o~
To ~ ~olution of 55.5 g (0.55 mole) of triethyl~mine
i~ 500 ml of dry b~nzene was ~dded dropwise 50.5 g (0.50
30 mole) of 1-methyl-3-pyrrolidinol ~t ~uch a rate a8 to
maintain a temper~ture of 25-~5 C. To the mixture,
maintained ~t 20-50C., was added dropwi~e, 57 g (0.50
mole~ of methanesulfonyl chloride. After ~tirring for
1 hr at room temper~ture, the miKture W2~ ~ilter~d an~
the precipitat~ w~hed with 250 ml of hot benzene. ~he
~iltrate ~nd wa~h were cQ~bined ~nd ~on~entrated under
419A_~
~L2~5~4'7
reduced pre.qsure and the re~idue digsolved in 200 ml
dimethylformamide.
To a cooled ~uspension of lg.6 g tO.41 mole) of
6~di~m hydride in 100 ml of dimethyl~ormamide in ~nother
ve.csel was added dropwi~e a solution of 70 g (0.41 mole)
of 4-chlorosalicylamide in 200 ml dim~thylfonmamide at a
rate such as to main~ain a temperature of 20~C. To the
resulting reaction mixture was added dropwise the ~ove-
prepared ~ulfonate ~alt and the mixture was heated at
reflux f~r 19 hrs. The reaction mixture was cooled and
diluted with one liter of water. The diluted mixture was
extract~d three times with ~00 ml portions o~ ~loroform.
The chloroform extracts were combined and extracted with
two 500 ml portions of 3N hydrochloric acid. The ccmbined
aqueous extract was made alkaline with 50~ sodium hydroxide
and extracted three times with 500 ml portion~ of ethyl
acetate. The combined ethyl acetate extract was dried
over magnesium ~ulfate and concentrated under reduced
pressure to give 46.5 g (45%) beiqe solid. The ~olid was
recrystallized from ethyl acetate, m.p. 122-12~C.
Analysis: Calculated for Cl2~l5N2ClOz: C,56.58; H,5.94:
N,10.99
Found : C,56.48; H,5.96:
N,10.84
Preparation 8
5-Bromo-?-r(l-methyl-3-pyrrolidinyl)oxylbenzamide.
To a cooled solution o~ 101 g (1.0 mole) 1-methyl-3-
pyrro~idinol, 111 g (1.1 mole) triethylamine in 1030 ml
of dry benzene was ~dded dropwise 114 g (1.0 mole) of
methane~ulfonyl chloride. The reaction mixture w~s stirr~d
at room temperature for 1 hour and filtexed. The filtrate
wa~ concentrated undcr reduced pre~sure and dissolved in
100 ml dimethylformamid~.
To a ~ooled su~pension of 30 ~ (0.6~ mole) ~odium
hydride in 100 ml dimethylformamide in another ves~el was
~ddea dropwiae ~-bromosalicylamide (137 93 0.63 mole)
dissolved in 750 ml of dim~thylformamide. Th~ abc~ve
prepared eulfonate was ~dded dropwi~e ~nd the reaction
419A-CI
mixture heated at reflux for 18 hr~. The cooled solution
was diluted with 1000 ml o~ water and extracted thrice
with 500 ml porti~n~ of chloroform. The chl~roform
extract~ were washed with wa~er ~nd ~xtracted four times
with 500 m~ portion~ of 3N hydrochl~ric acid. The aqueous
layer wa~ made alkaline with 50~ sodium hydroxide and
extracted with chloroform. The chloroform extract~ were
washed with water, dried over m~gnesium ~ulfate and
evapo~ated under reduced pressure to give 52 ~ (280 of a
yellow solid. The solid was recrystallized from ethyl
acetate/chlor~form, m.p. 160-162C.
Analysis: Calculated for Cl2HlsN2BrO2: C,48.18; H,5.05;
N,9.36
Found : C,48.02; H,5.01;
N,9.22
Preparation ~
5~-Chloro-2-r(l-methyl-~S-pyrrolidinyl?oxy~benzamide
hemihvdxate.
To a cooled ~u6pension of 2.4 g (0.41 mole) sodium
hydride in 50 ml of dimethylformamide was added dropwise
17 g tO.l mole) of 5-chlorosalicylamide dissolved in 50 ml
of dimethylformamide at a rate ~uch that the temperature
did not exceed 20C. After addition of the sali~ylamide
was complete, 16.7 g (0.1 mole) of 3-bromo-1-methyl-
pyrrolidine dis~olved in 50 ml of dLmethylformamide was
added dropwise. ~he reaction mixture was stirred ~nd
heated at reflux for 19 hr. The cooled solution was
diluted with 250 ml of water ~nd extr~cted twice wi~h
250 ml portionR o~ chloroform. The ~hloroform was
extracted thrice with 500 ml portion~ of 3~ hydroch~oric
acid. The aqueous extracts were made alkaline with 50~
~odium hydroxide and extracted with ethyl ~cetate. Drying
over magne~ium sulfate ~nd ev~poration of the e~hyl ac~tate
under reduced pressure gave 6 g (230 Of product aa a
beige solid. ~he solid was recry~tallized ~rom ethyl
acetate, m.p. 126-128C.
Analy~ia: Calculated for C2~H92~4Cl205: Cl54.65; ~,6.11;
N,10.62
Found : C,54.87; H,6.12;
N,10.69
419A-CIP
~2~S6~7
34
~ Methyl-3-pyrrolidinyl)oxyl-2-naphthalene
carboxamide.
A solution of 118 g (o.6~ mole) of 1-hydroxy-2-
naphthalenecarboxamide in 250 ml of dimethylsulfoxide
5 was added dropwise to a ~uRpension of 27.6 g (o.69 mole)
o~ 50% sodium hydride (mineral oil) in 250 ml of dimethyl-
sulfoxide. The reaction was exothermic and the
temperature ro-~ to 60C.
In another ves~el, 79 g (0.69 mole) of methane-
sulfonylchloride W~8 addea dropwi~e to a ~olution of69.7 g (o.69 mole) of 1-methyl-3-pyrrolidinol ~nd 77 g
(0.76 mole) of tri~thylamine in 500 ml of dry benzene
while cooling with an ice bath. The mixture was stirred
15 minutes and filtered. The filt~r cake was wa~hed with
500 ml o~ benzene and the benzene ~iltrates were combined
and concentrated on the rotary evaporator to ab~ut 200 ml.
The residue was added dropwise to the a~ove prepared
dimethylsulfoxide solution containing the ~odium ~alt of
l-hydroxy-~-naphthalenecarboxamide whil~ stirring at 75C.
The temperature was maintained at 75C. ~or 18 hr with
external heat. The resulting solution was cooled and ~n
equal volume of water was added. The mixtur~ was extracted
with three portions of chloroform. The washes were combined
and concentrated. The residue was partitioned between ethyl
acetate and dilute hydrochloric ~cid. The acid l~yer w~s
made basic with sodium hydroxide and extracted twice with
ethyl ~cetate. The ethyl ~cetate washes were combined,
dried over sodium ~ulfate and ~o~centrated. The residue
was crystallized from ethyl acet~te-i~ooctane. Yield of
~olid was 55 g (32 O . A portion wa~ recrystallized twi~e
from ethyl acetate-i60~ctane, m.p. 122-129~C.
Analysis: Calculated for Cl~Hl~20~: .C,71.11; H,6.71:
~,10.36
Found : C,70.96: ~,6.71;
N,10.31
419A-CIP-~
~LZ~S6~7
Preparation 11
~-Methoxy-2 ~ methvl-3~pvrro1idinyl3Oxylbenzamide.
To a 801utio~ of 151 g (1.5 mole) 1-methyl-3-
pyrrolidinol and 166 g (1.6 mole) triethyl~mi~e in 1500 ml
of dry benzene was added dropwise 171 g (1.5 ~ole~ of
methanesulfonyl chloride with cooling. The reacti~n
mixture was stirred at room temperature for ~ne houx and
filtered. The filtrate was concentrated under reduced
pressure to give an orange-co1ored oil.
In another vessel, to a 3uspension of 50~ sodium hydride~
mineral oil (72 g; 1.5 mole~ in 1~0 ml dimethylformamide
the sul~onate prepare~ ~ove and 139 g (0.93 mole) of 5-me~ho~
salicylamide dissolved in 600 ml dLmethylformamide were
~dded dropwise with cooling. The reaction mixture was
heated at reflux for 14 hr. ~fter c~oling, the r2action
was diluted with lO00 ml of water ~nd extracted three
times with 700 ml portions of chloroform. The combined
chloroform extracts were washed thrice with water and
extracted thrice with 500 ml portions of 3N hydrochloric
acid. The ~queous layer was made ~lkaline and extracted
with chloroform. The chloroform extracts were washed
thrice with water, dried over magnesium sulf~te ~nd
evaporated under reduced pressure to give a viscous brown
oil. Vacuum distillation of this material yielded a
vi~cous orhnge oil which was dissolved in chloroform,
extractea in acid; made alkaline and ~xtr~cted int~ chloro~
~orm ~gain. Evaporation of the solvent gave a dark brown
: oil which solidified under reduced pre~sure. Three
recrystallizations from ethyl acet~te gave 10 g of white
cryst~ls (4~), m.p. 85-87~C.
~0 ~nalysi~: calculated fox ClgHl8N20~: C,62.~; H,7.25,
~ 1 11 . 19
~ound : C,62.47; H,7.26;
~ 7 ~ 0
~ S6~7 i 4l9A-cIp-~
36
Preparation 12
3- r ( 1 -Me thyl -3-pyr rol id i nyl ) oxy 1-4 -pyr i d i ne -
~'~
A 801ut i~n of 55 g ( Q.55 mole) of 1 methyl-3-
pyrrolidinal in 55 ml of dry dimethylformamide was added
dropwise to a suspension of 22 ~ (o.58 mole) of 60~
sodium hydride/40% mineral oil in 300 ml of dimethyl-
formamide. The mixture was ~tirred at room temperature
for one hour and 7~ g (0.5~ mole) of 3-chloro-4-cyano-
pyridine in 200 ml of dimethylformamide was added dropwise
with mild cooling to maintain a temperature of 30-40 C.
The solution wa~ stirred ~ hours ~nd an eaual volume of
water ~dded. The solution was made acidic with dilute
~ydrochloric acid and extracted with i60propyl ether.
The aqueous layer was made basic with sodium hydroxide
and extracted 5 times with chloroform. The ~xtracts were
combined, dried ~ver ~odium sulfate ~nd concentrated.
The residue was treated with 50 g of fumaric acid in
400 ml of isopropyl alcohol and 40 ml o~ water. The
resulting crystals (51 g; 21%) were collected. A 2 g
; 20 6ample was recrystallized from methyl isobutyl ketone.
~ield of product was 1.5 y, m.p. 172-174C.
Analysis: calculated for Cl~H2lN30~ : C,52.42; H,4.86;
N,9.65
Found : C,52.40; H34.90,
~,9.68
Preparation 13
~ Methyl-~-pyrrolidinyl)oxy~-2~naphthalene-
carbonitrile oxal~te.
A ~olution o~ 29 g (0.11 mole) of l~ methyl-
pyrrolidinyl)oxy-2-naphthalenecarboxamide and ~8 g (0.32
;~ 30 mole) of thionyl chloride in 150 ml of chloroform was
heated to reflux for 6 hr. The solution was poured into
ice and made basic with ~odium hydroxide. ~he chloroform
l~yer wa~ separated, dried over sodi~m ~ulfate and
concentrated, The r~idue wns dis~olved in hot iaoocta~e.
35 The solution was treate~ with charcoal, filt~red nnd
concentrated. The residue was di~601ved in i~opropyl
! 419A-CI~2
~S6~L7
37
alcohol and oxalic acid was added. The precipitate was
recrystallized from isopropyl alcohol-water mixture.
Yield of product was 11.5 g (31O , m.p. 176-184C.
Analysis: Calculated for Cl~Hl~NzO5: C,63.15; H,5 30;
Found : CJ63.00; H,5.29;
~,~-15
Preparation 14
5-Diiodo-methylsal~cilate.
To one liter of absolute methanol was added 150 g
(0.39 mole) of 3,5-diiodosalicylic acid. Hydrogen chloride
was bubbled through the reaction mixture under agitation
and refluxed for 3 hrs. The reaction mixture turned
cloudy and suddenly a large volume of white crystals
precipitated. The mixture was filtered to give, after
drying, 136 g (83~) of product, m.p. 198-202C.
PreParation 15
2=Hydroxy-3,~-diio benzamide.
A stainless steel homb, cooled with dry ice acetone,
was charged with excess liquid ammonia, 3,5-diiodomethyl-
salicylate and a catalytic ~mount of sodium hydride. The
bomb was sealed and shaken at room temperature for 16 hrs.
On cooling again~ the contents of the bomb were poured
out and excess ammonia allowed to evaporate at room
temperature. The product melted 190-195C. with
decomposltion. Mass spec analysis confirmed molecular
weight of the title compound.
Preparation 16
~5,5-Diiodo ? -r(l-methyl-3-pyrrolidinyl1oxylbenzamide.
Following the procedure of preparation 1, substituting
2-hydroxy-3,5-diiodobenzamide for salicylamide, the title
compound is prepared.
41~A -CX~
56~7
38
~C
Sodium-2-t(l-methyl-3-~zetidinyl)oxy~-3-pyridine
The title compound i~ prepared by following the
procedure of preparation 6 but eubstituting l-methyl-~-
5 azetidinol ~or 1 methyl-3-pyrrolidinol.
PreDaration 18
4 - ~ ( 1-Methyl-3 -pyrrolidinyl~oxy~-3-pyridine carboxylic
acid sodium ~alt
4-Chloropyridine i5 reacted with diisopropyl lithium
10 amide and carbon dioxide to give the lithium ~alt of
~-carboxy-4-chloropyridine which i~ th~n reacted with
l-methyl-3-pyrrolidinol as in Preparation 6.
Pr~paxation 1~
~-r(l-Meth~ -pyrrolidinyl)oxyl-2~e~ridinecarbonitrile
fumarate.
Cl 2~carboxamido-3-hydroxypyridine i8 reacted with
: ~-P_o to give 2-cyano-3-chloropyridine which i8 then
~1
r~acted with l-methyl-3-pyrrolidinol ~5 in preparation 12
to give the title compound.
Preparation 20
l Meth~1 7-P~rrolidinethiol ~cetate (ester~ ethane-
dioate.
To a solution of 101 g (1 mole~ of l-methyl-~-
pyrrolidinol ~nd 110 q (1.1 mole) of tri*t~ylamine in 700
ml of dry benzene wa~ a~ded dropwi~e 115 g (1 mole) of
methane~ulfonyl chloride whil~ stirring ~nd cooling with
an ice bath. The resulting mixture wa~ ~tirred for 0.5 hr.
and filtered. Th~ ~iltrate was concentrated on the rot~ry
evaporator to about 200 ml being careful not to overheat.
~0 ~he re~idue was di~solv~d in about 150 ml ~f ~thanol.
In a ~eparate v~sel, 25.3 g (1.1 mole) ~ ~odium
wa6 dis~olved in 800 ml of 200 proo eth~nol under
~: nitrogen ga~ swe~p. After æissolution wa* cDmplete,
83.6 g (1.1 mole) o~ thislacetic acid w~ d~d ~lowly ~nd
the r~ulting ~olution wa~ ~tirr~d ~n additional 10 min.
419A-clP-2
~5E;~7
39
The above prepared ethanolic solution of methane3ulfonate
was ~dded and the resulting ~olution was heated to 60~C.
f~r 20 hrs. The mixture was cooled to 2~C. and filtered
and the filtrate was concentra~ed on a rotary evaporat~r.
The residue was dissolved in i60propyl ether ~nd the
mi~ture filtered to remove a small am~unt of ~olid. The
filtrate wa~ c~ncentrated and the re~idue di~tilled to
yield 70 g of the free base title ester, b.p. 95~105/15 mm.
A 7 g portion of the fr~e base was treated with 4 g
of oxalic acid in isopropyl alcohol a~d the ~alt obtained
was recrystallized from isopropyl alcohol to give 8.4 g
of title product, m.p. 108-111C.
Preparation 21
l_Methyl ~_pYrrolidinethiol oxalate.
A solution of 62 g (0.39 mole) of 1-methyl-3-
pyrrolidinethiol acetate (este~r) in 200 ~1 of absolute
methanol was treated with a 2 mm sphere of 60dium and
the resulting ~olution was distilled at 1 atm. pressure
to a pot temperature of 100C. Vacuum was applied and
the pressure was 810wly decreased to 100 mm. The residue
was di~tilled to a pot temperature of 130C., yielding
25 g (56%) of distillate with a boiling point of 95-100C./
100 mm which was the free base of the title cornpound.~ A
4 g sample was treated with oxalic and in isopropyl alcohol
to give 5.5 g of oxalate salt, m.p, 80-~2C.
Preparation 22
2-r (l-~lethyl-3-pyrrolidiny~l~thiol-3-pyrldine
carboxvl~c acid.
To a ~tirred suspension of 80 g (2 mole) of 60% sodium
hydride (in mineral oil) in 800 ml of dry dimethylformamide,
all heated to 60 C. and using nitrogen gas ~low wa~ added
dropwise, a ~olution of 15~.0 g ( 1 mole) of 2-chloro-
ni~otinic acid and 117 g ( 1 mole) of 1-methyl-3-
pyrrolidinethiol in 300 ml ~f dimethylformamide at a rate
which m~intained ~ temperature of 60-67C. The ~ixture
wns heated to 65C. for 6 hr and allowed to ~t~nd overnight
~t room temperature and then ~iltered. The ~ollected
419A-CI~2
~LZ~5647
~o
~olid was ~uspended in one liter ~f isopropyl alcohol
and hydrogen chloride was bubbled into the ~uspension
until ~ pH o~ 6.2 was reached. The mixture was brought to a
boil and filtered. The ~olid w~s dissol~ed in 2 liters
5 of water and extracted with i~opropyl ether. The pH was
adjusted to 6.0 ~nd the 801uti~n was concentrated to a
v~lume of 800 ml znd pla~ed in a refrigerator. The
resulting ~olid (85 g) collec~ed by filtration, was a
mixture consi~ting of about 85~ of the title compound and
15~ sodium chloride. A sample portion of thi~ was
crystallized once from ethanol and ~wice from isopropyl
alcohol-water. Ihe recrystallized product decomposed at
about 225C.
Preparation 23
Sodium 2-r(l-Cyclohexyl-~-azetidinyl)oxy]-3-pyridine
carboxylate.
A solution of 105 g (0.68 mole) of 1-cyclohexyl-3-
azetidinol and 106 g (o.68 mole) of 2-chloronic~tinic acid
in 400 ml of dry dimethylformamide was added at a rapid
drop to 52 g (1.~5 mole) of 60% sodium hydride/mineral oil
suspended in 400 ml of dry dimethylformamide at 60C.
Mild exothermic reacti~n was noted. Aftex stirring for
2 hr at 60C~,the mixture was filtered. The filter cake
was washed with ethylacetate and dried at 80C./2 n~ to
give 174 g (86%) of crude title compound.
Prepara tion ? 4
2-rN-Methyl~ N~ (l-ethylpyrrolidiny~ benzoic acid
lithium salt.
A mixture of 1068 g (6 mole) of 3-bromo-1-ethyl-
~0 pyrrolidine, 828 g (6 mole) of potassium carbonate and1700 ml of N-methylaniline was ~tirred at reflux for 2 hr,
cooled and filtered. The filtra~e Wa8 extracted with
dilute aqueous sodium hydroxide, dried over anhydxous
~odium sulfate and distilled. Yield of l-ethyl-3-tN-
~5 methyl, N-phenylamino~pyrr~lidine was 452 g (37-50 ) b.p.
100-105/0.1 m~.
The above prepared ~ompound, 20.5 g (0~1 mole) and
46.5 g of 15.1~ butyllithium ~nd 20 ml of diethyl ether
we-e heated at reflux for 2 hr. The reaction mixture was
419A-C:
~IL;~4S~
then poured onto a slurry of dry ice in diethyl ether. The
excess carbon dioxide was allowed to evaporate sver a
period ~f time and the residue was stirred in diethyl ether
and filtered. The filter cake was dried in vacuo to give
15 g of the title product.
Preparation 2~
2 -Chloro-~qu inolinecarboxylic acid.
To a solution of 21.3 ml (0.15 mole) of diisopropyl
amine in 300 ml of dry tetrahydrofuran under a continuous
nitrogen blanket, at -70C., was added 61.6 ml of 2.7 M
n-butyllithium in hexane tO.165 mole) while maintaining
the temperature at -60 to -70C. Subsequent to this
addition, the temperature was maintained at -65C. for
approximately 20 minutes. A solution of 20 g (0.12 mole)
o 2-chloroquinoline in 60 ml of tetrahydrofuran was added
dropwise while maintaining the tempexature at -60 to -70 C.
A ter holding the temperature at -65C. for 20 minutes
subsequent to this addition, the entire reaction mixture was
poured onto a large excess of dry ice. Most of the solvent
was evaporated in a stream of air; the residual solvent was
removed by rotary evaporation. The rçsidue was taken up in
300 ml water, made basic with dil aq. sodium hydroxide and
washed with ~ x 50 ml of isopropyl ether. The aqueous
layer was filtered and made acidic ( 4 to 5 pH) with dilute
aqueous hydrochloric acid. The precipitate was collected,
washed with water, isopropyl alcohol, and isopropyl ether,
and dried, giving 15.4 g (62%) of white crystals, m.p.
190-210C. (decomp.). A sample was recrystallized from
isopropyl alcohol giving an analytical sample, m.p. 190-
3 21QC. (decomp.).Analysis: calculated for CloH~N02: C,57.85; H,2.91; ~,6.75
Fou~d : C,57.80; H,2.96; ~,6.6
419A-CI~
S6~L7
42
Preparation 26
4-Chloro-7-(trlfluoromethy~ uinolineca-rboxylic
acid.
-
To a c~oled solution of 15.8 ml (0.11 mole) of
diisopropyl amine in 250 ml of tetrahydrofuran under a
blanket of dry nitrog~n at -70C. was added 44 ml of 2.7 M
n-butyllithium in hexane at -60 to -70C. The ~olution was
stirred for 20 minutes at -70C. and a solution/suspension
of 25 g (0.11 mole) of 3-chloro-7-trifluoromethyl cuinoline
in 125 ml of tetrahydrofuran was added dropwise while
maintaining the temperature between -60 and -70C. The
temperature was held at -70C. for 20 minutes subsequent
to the addition of the quinoline. The ~olution ~deep red)
was poured onto a large excess of dry ice and the solvent
allowed to evaporate overnight at ro~m temperature. The
residual solvent was removed by rotary evaporation (60 C.,
30 mm) and the residue taken up in 800 ml of dil sodium
hydroxide. An attempted wash with 75 ml of chloroform
caused the sodium salt of the product acid to precipitate
out. This precipitate was collected and washed with 1
liter of chloroform and suspended in 500 ml of water. The
suspension was stirred while acidifying with 6N hydro-
chloric acid to pH 2. The solid was collected and washed
with 500 ml of water. After drying, 16.2 g (53O of white
solid was eollected, m.p. 310C.
Analysis: Calculated for CllH~NO2ClF9: C,47.94; H,1.83;
~,5.08
Found : C~47.56; H,1.79;
N,4.99
Prep~ ation 27
3,~-Dichloro-4-pvridinecarboxylic acid.
To a solution of 4.96 ml (0.036 mole) of dii~opropyl-
amine in 200 ml of t~trahydrofuran at -65C~ under a
nitrogen blanket was added dropwi~e 14.9 ml of 2.5 M
n-butyllithium in hexane while maintaining the above
temperature. Twenty minutes subsequent to that ~ddition
a solution 5.0 g (0.034 mole) of 3,5-dichloropyridine in
30 ml tetrahydrofuran at -60 to -70 C. was added. The
reaction mixture was gtirred at -70 C. for 1~2 hrJ poured
419A-CIP-
5~i~7
4~
onto a large excess of dry ice and allowed to evaporate
overnight at room temperature. The residue was taken up
in 100 ml of dilute aqueous sodium hydroxide, washed with
3 x 30 ml of methylenechloride and filtered. The filtrate
was acidified to~ pH 2 with dilute hydrochloric acid to
precipitate out the product. After cooling, the precipitate
was collected and recrystallized from ethyl acetate/hex~ne
giving 1.9 g (29%) of white analytically pure crystals,
m.p. 2~1-35c.(decomp.).
Analysis: Calculated for C6H3NO2Cl2: C,~7.53; H,1.57;
N,7.30
Found : C,37.33; H,1.56;
N,7.21
Preparation 28
~-Hydroxy-6-isoquinolinecarboxamide.
5-Hydroxy-6-isoquinolinecarboxylic acid methyl ester
as reported by Dyke, S. F. et al., in Tetrahedron 197~,
29(6), 857-62, is reacted with excess ammonia in a steel
bomb for 12-18 hr. The excess ammonia is allowed to
evaporate and the residue is crystallized from a suitable
solvent mix such as ethyl acetate-toluene to give the
title compound.
PreParation 2~
5-~(1-Methyl-3-pyrrolidinyl)oxy~-6-isoquinoline-
carboxamide.
Following the procedure of Preparation 10, but
substituting 5-hydxoxy-6-isoquinolinecarboxamide ~or
~ l~hydroxy-2-naphthalenecarboxamide, the title compound
- is prepared.
Preparation ~0
7-Hydroxy~6-iso~uinoline rboxamide.
7-Hydroxy-5-isopuinolinecarboxylic acid methyl ester
as reported by Dyke (see ref. given in Prep. 28) i8
reacted with excess ammonia in a steel bomb ~or 12-18 hr.
The excess ammonia is allowed to evaporate and the residue
; ~5 is crystallized from a su~table solvent mix auch as ethyl
acetate-toluene to give the title compound.
419A-CIE
~56~7
44
Preparation 31
7-~(l-Methyl-3-pyrrolidinyl)oxy~6-isoauinoline-
carboxamide.
~ ollowin~ the procedure of Preparation 10, but
substituting 5-hydroxy-6-isoquinolinecarboxamide for
1-hydroxy-2-naphthalenecarboxamide, the t.itle compound
is prepared.
- Preparation 32
5-Methyl-8- r ( 1-methyl-3-pyrrolidinYl~oxyl-7-quinoline-
carboxamide.
Following the procedure of Preparation 10, but
substituting 8-hydroxy-5-methyl-7-quinolinecarboxamide
~as reported by V-Kapoor et alJ Indian J. Chem. 4(10),
4~8-51 (1966): (C.A. 66, 7~802p)] for 1 hydroxy-2-
naphthalenecarboxamide, the title compound is prepared.
PreParation 33
8-HYdroxY-2-methY1-7-quinolinecarboxvlic acid methyl
ester.
8-Hydroxy-2-methyl-7-quinolinecarboxylic acid (as
reported by Meek, W. H. et al., in J. ~hem. Eng. Data l9og,
14(3), ~88-91) is reacted with methanolic boron trifluoride
solution for several hours. The resulting mixture is
added to an a~ueous solution of sodium bicarbonate to give
finally a basic solution. The solution is extracted with
chloroform. The chloroform extract is dried over anhydrous
sodium sulfate and concentrated and the residue is crystal-
lized from a suitable solvent such as isooctane to give
`~ the title compound.
Preparation ~4
8-Hydroxy-2-met~yl-7-quinolinecarboxamide.
~ Hydroxy-2-methyl-7-~uinolinecarboxylic acid methyl
ester is reacted with excess ammonia in a ~teel bomb for
12-18 hr. The excess ammonia is allowed to evapora~e and
; the re~idue i8 crystallized from a suitable ~olvent to ~ive
~ the title compound.
j.
419A-CI}
:~L2~L56~7
Preparation
2-Methvl-8-~ methyl-~=pyrrolidinyl)oxyl-7-quinoline
carboxamide.
Following the procedure of Preparation 10, but
substituting 8-hydroxy-2-methyl-7-quinolinecarboxamide for
1-hydroxy-2-naphthalenecarboxamide, the title compound is
prepared.
PreParation 76
6-Hydroxv-5-quinolinecarboxvlic acid methvl ester.
6-Rydroxy-5-quinolinecarboxylic acid tas reported by
0 Da Re, P. et al. in Ann. Chem. (Rome) 1970~ 60(3), 215-24
(C.A. ~, 253~8m)~ is reacted with methanolic boron
trifluoride solution for several hours. The resulting
mixture is added to an aqueous solution of sodium bicarbon-
ate to give finally a basic solution. The solution is
extracted with chloroform. The chloroform extract is
dried over anhydrous sodium sulfate and concentrated and
the residue is crystallized from a suitable solventO
Preparation ~7
6-Hydroxy-5-quinolinecarboxamide.
6-Hydroxy-5-quinolinecarboxylic acid methyl ester is
reacted with excess ammonia in a steel bomb for 12-18 hr.
The excess ammon~ is allowed to evaporate and the residue
is crystallized from a suitable solvent to give the title
compound.
Preparation ~8
6-r(l-Methyl-3-pYrrolidinYl)oxYl-5-quinolinecarobxamide
Following the procedure of Preparation 10, but
substituting 6-hydroxy-5-quinolinecarboxamide for l-hydroxy-
2-naphthalenecarboxamide, the title compound i9 prepared.
Preparation ~q
8-Hydroxy-7-~uinolinecarboxamide~
8-Hydroxy-7-q~inoli~ecarboxylic acid methyl ester ~as
reported by EcXst~in, Z. et al. in Psl. J. Chem. 1979~
53(11), 2373-7 (C.A. 9?, 21524~s)3 is reacted with excess
ammonia in a steel bomb for 12-18 hr. The exces~ ammonia
is allowed to evaporate and the residue is crystallized
from a ~uitable ~olv0nt to give the title compound.
419A-CIP-2
L5~i~7
46
Preparation 40
8-[tl- ethyl-~-pyrrolidinyl)oxy~-7-quinolinecarboxamide.
Folling the procedure of Preparation 10, but
substituting 8-hydroxy-7-quinolinecarboxamide for l-hydroxy-
2-naphthalenecarboxamide, the title compound is prepared.
Preparation 41 (Refer to chart VIII)
2-Chloro-N-~ -(dimethylamino)-2-hydroxybutYl~-3-
pyridinecarboxamide monohydrochloride.
To a suspension of 11.9 g (0.076 mole) of 2-chloro-
nicotinic in 200 ml of methylene chloride was added 10.2 g
(0.076 mole) of l-hydroxybenzotriazole, 10 g (0.076 mole)
of l-amino-4-(dimethylamino)-2-butanol, and 15.6 g (0.076
mole) of dicyclohexylcarbodiimide. The resulting solution
was stirred at room temperature for 6 hr and allowed to
stand for 66 hr. The resulting mixture was filtered and
the filtrate concentrated on the rotary evaporator. The
residue was shaken with a mixture of dilute hudrochloric
acid and isopropyl ether. The resulting 3 phase system
(1 solid, 2 liquid) was filtered and the solid discarded.
The aaueous layer was separated, made basic with sodium
hydroxide and extracted ~ times with chloroform. The
combined chloro~orm extracts were combined, dried over
~ anhydrous sodium sulfate and concentrated. The residue
; was dissolved in isopropyl alcohol and acidified with
ethereal hydrogen chloride. The resulting precipitate
2~ was dissolved by heating and adding methanol. The crystals
obtained on cooling were recrystallized from ethanol to
give 9.6 g (41%), m.p. 182 192C.
Analysis: Calculated for Cl2HlgN302Cl2: C,46.77; H,6.21;
N,1~.6
Found : C,46.67; H,6.42,
N,13.91
:
::
41yA-cI
5~;~7
47
Intermediate 1
2~(2~ChlOrne-hVI¦-3L_2~aL~y~o-~-methyl-114 benzox_
azepin-St4H)-one.
To 54 g (1.35 mole) of s~dium hydroxide in 800 ml of
water was Ddded 148 g (0.67 mole) of 2-~(1-methyl-3-
pyrrolidinyl)oxy]benzamide and the mixture brought toreflux for lB hx. The pH was adju3ted to 7 with hydro-
chloric acid a~d the ~olutio~ filtered and ~oncentrated.
The residue was boiled with 400 ml of i.~opropanol and
filtered. The filtrate was concentrated and the residue
(which crystallized) was refluxed wit~ 300 ml of thionyl
chloride for 0.5 hr. nnd ~oncentr~ted in vacuo. The
residue was dissolved in 300 ml of chloroform ~nd the
solvent boiled off in vacuo. The residue was redissol~ed
: in chloroform, 1~0 ml of triethyl amine ~dded and the
mixture refluxed 1 hr. The ~olution was concentrated in
vacu~ and the residue partitioned ~etween 400 ml of ethyl
acetate, 400 ml of isopropyl ether and 500 ml of dilute
hydrochloric acid. The organic layex was washed twice
with water and once with dilute sodium ~ydroxide, dried
with Rodium sulfate and concentrated. The re~idue was
: crystallized from isopropanol-watex. Yield of product
was 75 g (47O , m~p. 97-107C.
Analysis: calculated for Cl2~l~N02Cl: C,60.13; HJ5~89;
~,5.84
Found : C,60.35; H,5.91;
N~5.65
ntermediate 2
4-Benzyl-2-~ -chloroethyl)-2~-dihvdro-1~4-benzox-
a~epin-S~)-one.
To 85.7 g (0.29 mole)of 2~ benzyl-3-pyrrolidinyl)
oxy~-benzoic ~cid w~s ~dded 150 ~1 of thio~yl ~hloride.
The 601ution stood for 15 min and was then r~luxed 30 min.
and concentrated in ~cuo. The residue wa~ twi~e treated
with 250 ml of chloroform and concentrat~d in vn~uo. The
re6idue was di0solved in 5Q0 ml of chloroform ~nd 101 g
(1 mole) of ~riethylamine ~dded ~lowly with ~tirring. Th~
solution was r~fluxed 1 hr. ~nd c~nc~ntrate~ an v~cuo.
~ 419A-CIP.
~Zg~ 7
48
The re~idue wa~ partitioned b~tween 50% ethyl ~cetate-
50~ isopropyl ether and dilu~e hydrochloric acid. The
organic l~yer was washed with dilute ~odium hydroxide
and coneentrated. The re6idue was ~rystallized 5 times
from isopropyl ether-ethyl ~cetate. Yield of product was
23.8 g (26%), m.p. 145.0-147C.
Analysis: Calculated for CleHleN~ZCl: C,68.46; ~,~.74;
N,4.44
Found : C,68.47; H,5.89,
~,4.32
Intermediate
?-~2-(Chloroethyl)-2.3-dihydro-4-methylna~th~2~-f
tl,4~oxazepin-5(4H)-one.
. . . _
To a solution of 21.6 g (0.54 mole) ~odium hydroxide
in 500 ml of water was added 74 g (0.27 mole) of 3-
r 1-methyl-~-pyrrolidinyl)oxy]-2-naphthalenecarboxamide
and the mixture heated at reflux for 16 hr. The pH was
adjusted to 6.8 with concentrated hydrochloric acid, the
solution was filtered and concentrated. The residue was
boiled with 200 ml of isopropyl alcohol and filtered. The
filtrate was concentrated under reduced pressure and the
residue dissolved in chloroform. Thionyl chloride (59 g,
0.50 mole) was added and the reaction mixture heated at
reflux for 4 hr. After cooling (67 g, 0.67 mole) tri-
ethylamine was added dropwise. The mixture was
washed ~e~uentially: twice with ~N hydrochloric acid,
twice with water~ twice with 10% sodium hydroxide, twice
with water and dried over magnesium ~ulfate. Evaporation
of the chloroform under reduced pressure gave 44 g (58%)
of a vi~cous dark brown oil. The material was purified by
high pressure liquid ~hromatography (50/50 ethyl ~cetate/
hexane) ~nd recrystalli~ed from i~opropyl ~lcohol to yield
brown ~rystals, m.p. - 101-102C.
Analysis: Calculated for Cl~,H~ Cl~ C,66.32; BJ5.57;
~,4 .83
E'ound ~ C,66.19, ~,5.63;
N~ 4 .77
; 4l9A-cIp-2
S~
49
Xntermediate 4
2-(2-Chloroe~hyl)-2,3-dihydro-4-me~hylpyrido~3,2-f~
~1,4]-oxazepin-5(4H)-one hydrochloride.
.
~ ydrogen chloride gas WDS bubbled into a 6uspension
o~ 150 g (0.61 mole) of &odium 2-~(1-methyl-3-pyrrolidinyl)
oxy]-3-pyridinecarboxylate in 1 liter of chloroform until
a pH of 6 was reached. To the 6tirred mixture was ~dded
350 g (1.34 mole) of triphenylphosphine and 350 g (2.3
mole) of carbon tetrachloride and ~he resulting cloudy
solution was ~tirred at reflux for 1.5 hr. About 100 ml
of ethanol was added and the heat removed. The solution
was stirred for 1 hour while cooling and 200 ml of
isooctane was added. The golution was extracted 4 times
with a total of 800 ml of dilute hydrochl~ric acid. The
acid extracts were combined, made basic with sodium
hydroxide and extracted with chloroform. The chloroform
layer was separated and dried over Rodium sulfate and
concentrated. The residue was dissolved in a mixture of
~` 500 ml each of isopropyl alcohol and iqopropyl ether and
acidified with ethereal hydrogen chloride. ~he resulting
; 20 crystals weighed 82 g (49%). A portion was recrystallized
~rom i~opropyl alcohol, m.p. 149-153C.
Analysis: Calculated for CllHl~N202Cl2: C,47.67; H,5.09;
N,10.11
F~und : C,47.57; H,5.18:
N,10.00
Intermediate 5
8-Chloro-2-(2-chloroethyl~-2.3-dihydro-4-methyl-1.4-
, enzoxa~ePin-5(4H)-one._
To a solution of 10.4 g (0.26 mole) of ~odium hydroxide
in 150 ml of water was added ~2 g tO.13 mole) o~ 4-chloro-
2~ methyl-3-pyrrolidinyl)oxy~benzamide and the mixture
was heated at reflux for 24 hr. The reaction mixture was
adjusted to p~ 6 with concentrated hydro~hloric ~cid and
filtered and the filtrate ~oncentrated. The residue was
boiled with 100 ml of i~opropyl ~lcohol and the mixture
- 35 filtered. The ~iltrate w~ concentrated and heated at
reflux with g8 g to.~ mole~ of thionyl chloride for 1 hr.
.~ 419A-CIP-c
~Z~LSi69~'7
~o
The excess thionyl chloride was evaporated under reduced
pre~sure~ The residue w~s ~i8solved in 70 ml of chloro-
form and the solvent svaporated under reduced pressure.
The residue was redigsolved in 75 ml of chloroform and
40 ml of triethylamine was added gradually. The mixture
was heated at reflux for 1 hr. The ~olvent wa~ evaporated
under reduced pres~ure to give a dark-brown ~olid. The
solid was dissolved in ethyl acetate nnd the resulting
solution washed twice with 200 ml of water and twice with
250 ml of 20~ sodium hydroxide. ~he organic layer was
dried over magnesium sulfate and concentrated under reduced
pressure to give 21 g t59~) of dark-brown 601id. The
solid was recrystallized from isopropyl alcohol to give
the title compound, m.p. 85-87 C.
Analysis: Calculated for Cl2~lgNCl202: C,52.57; H,4.78;
N,5.11
Yound : C,52.57; H,4.77:
N,s.o4
Intermediate 6
7-Bromo-2-~2-chloroethYl~-2 3-dlhydro-4-methyl-1,4-
benzoxaz4pine-~(4H~-one.
To a solution of 9.6 g (o.24 mole) of ~odium hydroxide
in 200 ml of water was added ~7 g (0.12 mole) of 5-bromo-
2-~ methyl-~-pyrrolidinyl)oxy~-benzamide and the mixture
was heated at reflux for 18 hr. The pH of the mixture
wa~ adjuRted to 6.7 with concentr~ted hydrochloric acid
solution. The ~olution w~ concentrated under reduced
pressure and the residue was boiled in 250 ml of isopxopyl
alcohol for 1 hr. The mixture was filtered and the
filtrate wa~ concentrated. The residue was dissolved in
chloroform and to the solution was ~dded 28.3 g (0.24 mole)
o~ thionyl chloride. The ~ixture wa heated at reflux for
0.5 hr and cooled to 15 C. with an ice bath. To the
mixture w~s added dropwise 26.6 9 (0.26 mole) of triethyl-
~mine at ~uch ~ rate that the temperature did not exceed
~5 25C. The reaction ~ixture w~s stirred ~t room temperature
for 1 hr, then wa~hed con~ecutively with 3N hyarochloric
acid, 15~ ~queou~ ~odium hydroxide and water. The
419A-CIP~2
~LZgL-5~7
chloroform layex was dried ov~r magnesium sulfa~e and
concentrated under reduced pressure to ~ive 23 g (60~) of
brown aolid. A portion o~ the golid was recxystallized
from ethyl acetate isopropyl ether, m.p. 92-94 C.
Analysis: Calculated for Cl2Hl3NBrC10z: C,45.24; H,4 11
Pound : C,45.61; H,4.17;
~,4.42
Intermediate 7
7-Chloro-2 12-chloroethyl~-2 ~ dihydro-4-methvl-1,4-
benzoxazepin-~(4H)-one.
Hydrogen chloride was bubbled through a olution of
113 q ( O r 44 mole) 5-chloro-2-t(l-methyl-3-pyrrolidinyl)oxy~
benzamide diQsolved in 500 ml o~ glacial acetic acid for
15 min while the reaction was cooled with an ice bath.
Butylnitrit.e (142 g, 1.~8 mole) was then added in one
portion; the reaction was ~tirred at room temperature fox
16 hr and heated at reflux for an additional 6 hr. The
acetic acid was evaporated under reduced pressure, tetra-
chloroethane was added twice to the residue and evaporated.
The residue was di~solved in chloroform, treated with
163 g (1.~8 mole) of thionyl chloride and heated at reflux
for 22 hr. The reaction mixture was cooled with an ice
bath and 152 g tl.5 mole~ of triethylamine was added drop-
; wise at ~uch a rate that the temperature was kept at
25-30C. The reaction mixture was diluted with 200 ml of
chloro~orm a~d washed consecutively with 3N hydrochloric
acid, water, 10~ sodium hydroxide and water. The chloro-
form was evaporated under reduced pre~sure to give 40 g of
~ . a black, t~r-like residue (33%).
:~ 30 An aliquot of this residue wa~ purified on a silica
: gel column u~ing ethyl ~cetate as the eluting solvent.
Recrystallization from isopropyl alcohol gave beige
cry8tal5, m.p. 101-10~C.
Analysis: Calculated ~or Cl2Hl~NCl202: C,52.57; ~,4.78;
~5 Found : C,52.63, H,~ 8~,
~,5 5
4l9p~-cIp-2
~2~S~ 7
52
Intermediæte 8
rl,41XaZePin-5(4H)-c>ne .
~ Hydrogen chloride gas was bubbled into a ~olution of
¦'~8 g (0.03 mole~ of 1-r(l-methyl-3-pyrrolidinyl)oxy]-2-
5 naphthalenecarboxamide in 40 ml of acetic ~cid for about
2 min. The solution was cooled with an ice b~th and 6.1 g
(o.o6 mole) of n-butyl nitrite was udded slowly beneath
the surface of the liquid at 12~15C. (about 10 minutes
recuired). ~he solution was stirred at 25C. for 18 hr
and heated on the ~team bath for 3 hr. ~he solution was
concentrated on the rotary evaporator. The residue was
di~olved in 60 ml of 1,1,2,2-tetrachloroethane which was
removed on the rotary evaporator at 0.5 mm/steam tempera-
~ure.
: 15 The re~idue was dissolved in 75 ml of chloroform and
treated with 7 g (0.06 mole) of thionyl chloride and
brought to reflux ~or 12 hr. The ~olution was extracted
with water (tested acidic) followed by dilute sodium
hydroxide, dried over sodium æulfate and concentrated.
The residue was ~rystallized twice ~rom isopropyl ether~
ethyl acetate. Yield of product was 3.2 g (37%), m.p.
lO9-111C . ..
Analysis: Cal~ulated for Cl~Hl~N02Cl: C,66.32; H,5.57;
N,4.84
Found : C,66.15; H,5.56:
~,4.76
Intermediate 9
?-(2-ChloroethYl~-2.~-aihydro-7-methoxY-4-methyl-1!4-
benzoxazePi~ 4H?-one.
To a ~olution of 19.2 g (o.48 mole) of sodium hydroxide
in 500 ml of water was added 60 g ~0.24 mole) of 5-methoxy-
2-~ methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture
was he~ted at re~lux for 24 hr. The reacti~n mixture was
cooled and the p~ adju~ted to 6.8 with concentr~ted hydro-
chloric acid. The mixture waæ c~ncentrated under reduced
35 pressure and the residue wa~ boiled in iGopropyl alcohol
for 1 hour. The mixtur~ was filtered and the filtrate was
419A-CIP-2
~2~LS~
c~ncentrated. The residue was dis~olved in 500 ml of
chloroform ~nd to this sclution was added 11~ g (o.96 m~le)
of thionyl chloride. The mixture was heated at reflux f~r
48 hr, then cooled with an ice/acetone bath. To the
mixture was added dropwise 97 g (o.96 mole) of triethyl-
amine at ~uch a rate that the temperature did not exceed
25C. The reaction ~olution was w~shed in ~equence with
water, 3N hydrochloric acid ~olution, water, 15~ a~ueous
~odium hydroxide and water and ~inally dried over magnesium
sulfate. The ~olvent was evaporated under reduced
pres~ure to give a bla-k ~olid. The ~olid was purified
on a silica gel column using ethyl acetate as the eluting
~olvent to give on i~olation 15 g ~23%) of beige c~lored
product~ m.p. 98-100C.
Analysis: cal~ulated fox C13Hl~N~103: C,57.89; ~,5.98;
N,5.19
Found : C,57.53; H,6.oo;
N,5.16
Intermediate 10
2 (2-Chloroethvl)-2,~-dihydro-4-meth~l-1 ~-benz~x=
azeE~ne-5(4H~-thione.
A mixture of 18.5 g ~o.0834 mole) of phosphorus
pentasulfitie and 18.5 g potassium 6ulfide was ground
together and added to a solution of 100 g ~0.417 mole) of
2-(2-ehl~roethyl)-2,3-dihydro-4-methyl~1,4-benzoxazepin-
5(4H)-one in dry toluene, the ~ixture refluxed 24 hr . and
filtered. ~he filtrate was concentrated and partitioned
between chloro~orm and dilute sodium hydroxide. The
chloroform layer wa~ concentrated ~nd the residu~ was
crystalliz~d eeveral time~ from ethanol. Yield of product
w~ 55 g ( 52 %), m ~ p . 1o5-lo8oc.
; Analusis: C~l~ul~ted for C~2Hl~SOCl: C,56.35, ~5.52;
N,5.48; S,12~54
Found : C,56.55; H,5.47;
N,5.~9; S,12.55
l~l9A-CIP _~
~56~7
54
Intermediate 11
2-(2-Chloroethyl)-2,~-dihydro-4-methylpyrid~t3,2-f
t 19 4 ~ -oxazepine-5 ( 4H~ -thione .
To a solution of 59 g (0.25 mole) of 2-(2-chloroethyl)-
2, ~i-dihydro-4-methylpyrido~3,2-f]~1,4]oxazepin-5(4EI)one
hydrochloride in 1500 ml of chloroform was ~dded 41.5 g
(0.19 mole) of phosphorus pentasulfide ~nd 'che mixture was
heated ts reflux for 18 hr . The mixture was f iltered and
the filtrate was extracted with dilute aodium hydr~xide.
The chloroform layer was concentrated and the residue was
dissolved in 250 ml of boil ing isopropyl alcohol . On
coolirlg, 28 g (440 of yellow solid precipitated. A
portion was recrystallized from isc>propyl alcohol, m.p.
134 -136C .
Analysis: calculated for Cl1Hl3N2ClOS: C,51.46; H,5.10;
N, 10 . 81
Found: C,51.35, H,~.21;
~,10 .72
Int ermed ia t e 12
2 - ( 2 -Chloroethyl)-2, 3-d ihydro-4 -methylnaphthr 2, 3-~
~1l 4]oxa~epine-5( 4H) -thione .
To a solution of 16.6 g (o.o6 mole) of 2-(2-chloro-
ethyl)-2,3-dihydro-4-methylnaphtht2 ,3-f]~1,4~oxazepin-
5 ( 4H) -one in 150 ml of dry toluene was added a mixture of
8.6 g (0.045 mole~ of phosphorus pent~sul~ide and 8.6 g
of potas~ium ~ulfide which had been ground together. The
25 reactic~n mixture was ~tirred and heated at reflux for
~: ?4 hr. Tl e mixture was filtered hot ~nd the filtrate
eoncentrated under reduced pressure. Yellow solid, 6.5 g
- (~5,¢) was obtained which was recrystallized from ethanol,
m.p. 166-168C.
30 ~naly~is: Calculated ~or Cl,3Hl~NClOS: C,62.84; H,5.27;
~1,4 .58
Found . C,62.29; EI,5.118;
~, 4 .47
~'
~2456~7 ` 4l9A-CIP-2
Intermediate 1~
8-Chloro? -~2 chloroethYl~-2,~-dihydro-4-met~yl-1,4-
b_L}
; To a ~olution of 4~ g (0.16 mole) of 8-chloro-2-(2-~hloroethyl)-2,~-dihydro-4-methyl-1~4-benzoxazepin-5(4~)-
one in 400 ml ~f dry toluene was ~dded a mixture of 23 g
(0.12 mole) of phcsphorus pentasulfide and 23 g of potassium
~ulfide which had been ground together. The reaction
mixture was stirred and heated ~t reflux for 24 hr. The
mixture was filtered hot and the filtrate coneentrated
under reduced pressure to give 25.5 g (55%) of orange oil
which solidified on ~tanding at room temperature. The
601id was recrystallized from ethanol, m.p. 105-106 C.
Analysis: Calculated for C12Hl3NC120S: C,49.66; H,4.52;
~,4.8~
Found : C,49.63: H~4.53;
N,4.75
Intermediate 14
7-~romo-2-(2-chloroethYl)-2,~-dihydro-4-methyl-1 ~-
benzoxazePine-~(4H~-thione.
To a 801ut ion of 11.0 g (0.035 mole) of 7-~romo-2-
(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-
one in 150 ml of dry toluene was added a mixture of 13.4 g
~0.07 mole) of phosphoru~ pentasulfide and 13.4 g of
potassium sulfide which h~d been ground together. The
reaction mixture was heated at reflux for 5 hr under a
nitrogen atmosphere. The m;xture was filtered hot and the
filtrate concentrated under reduced pressure. The residue
was dis601ved in chlorofoYm. The chloroform solution w~s
washed twice with dilute aoueous ~odium hydroxide, dried over
magne~ium ~ulfate and concentrated under reduced pressure
to give 8.5 g (72 0 of yellow ~olid. ~he ~olid was
recrystallized from ethanol, m.p. 118-120C.
Analysis: Calculated for Cl2Hl9~BrClOS: C,43.07, ~,~.92;
~,4.~8
Found : C,43.08: ~,3.88;
~,4.12
419A-CIP
5~;~7
56
I ermediate 1
2-(2-Chlc)roethyl~-2~-dihvdro-4=methylnaphthr2 Ll-
r 1,4 ~ H)-thione.
A mixture of 9.55 g of phosphorus pent~6ulfide and
9.5 g of potassium ~ulfide were ground together ~nd added
to a ~olution of 20.2 g (0.07 mole) of ~-(2-chloroethyl)-
2,~-dihydro-4-methylnaphth~2,1-$]~1,4]oxazepin-5(4H)-one
-in 200 ml of dry toluene. The mixture was 3tirred and
heated at reflux for 7 hr. The hot reaction mixture was
filtered and the product ~rystallized from the ~ooled
~iltrate. Re~rystallization from chloroform gave 18 5
(84~) of yellow ~rystal6, m.p. 167-170C.
Analysi~: calculated for Cl~Hl~ClOS: CJ62~84; H,5.27;
~,4.5~
Found CJ62.85; H~5.20;
~,4-55
Intermediate 16
2-(2-chloroethyl)-2,3-dihydro- ~ ~4,~-fl
rl~4l-oxazepin-5(4H)-one hydrochloride.
A 4~ g (0.11 mole~ ~ampl~ of ~-t(l-methyl-~-
pyrrolidinyl)oxy~-4-pyridinecarbonitrile fumarate ~1:2~
was partitioned between chloroform and a saturated solution
of potassium carbonate. The aqueous layer was extracted
twice with chloroform. All chloroform extracts were
combined~ dried and con~entrated. The residue was
di~solved in 125 ml of t-butanol a~d added to 34 9 ~0.6
~ 25 mole~ of potassium hydroxide pellets. The mixture was
; stirred at room temperature for 88 hr. and then diluted
. with 150 ml of toluene. Thi~ mixture was filtered and the
~iltrate conc~ntrated. ~he residue was di6solv~a in
chloroform, with cooling, ~nd the p~ ~djusted to 6.o with
~ ~0 hydrogen chloride gas. ~he resulting mixture was concen-
; trated and 400 ml o~ dry toluene was ~dd~d to the residue.
The toluene was removed on the rotaxy evaporator (~team
heat/redu~ed pre~sure) to remove any water. The residue
was di~solved in 400 ml o chloroform ~nd 63 9 of triphenyl-
pho~phine wa3 added followed by 70 g of carbon tetra-
chloride. The ~olution wa~ ~tirred ~t reflux for 2 hr and
., . 4l9A-CIP-2
~2~5647
57
another ~0 g of triphenylphosphine added. Af~er an
additional hour reflux, 70 9 mor~ carbon tetrachloride
and 63 g more of triphenylpho~phine were added and reflux
was continued for 4 hr. The solution was extracted with
dilute s~dium hydroxide, then concentrated. The residue
was partitioned hetw~en toluene and dilute hydrochloric
acid. The t~luene layer was extracted five times with
dilute hydrochloric acid. The acid extracts were combined,
basified with ~odium hydroxide and extracted with chloro-
form. The ~hloroform layer was dried over ~odium sulfate~nd concentrated. The residue was chromatographed on a
7 x 25 cm column of ~ilica gel with acetone liquid phase.
Free base of the title compound i~olated after evaporation
amounted to 5.8 g ~20%). To a portion of the free base
di~solved in isopropyl alcohol was added ethereal hydrogen
chloride and i~pxopyl ether. The resulting crystals
were collected and dried, m.p. 188-190C.
Analysiq: Calculated for CllHl4N202C12: C,47.67; H,5.09;
N,10.11
Found: C,48.33; H,5.22;
N,9.73
Intermediate~
2-(2-chloroethyl)-2,3-dihydro-4-methylpyrldo ~ 4-f
C1,4~oxazepin-5(4H)-one hydrochloride.
~n the procedure of Intermediate 4, equal molar
amounts o~ sodium 4-t(l-methyl-3-pyrrolidinyl)oxy~-3-
pyridinecarboxylatewas substituted for 2~ methyl-3-
pyrrolidinyl)oxy]-3-pyridinecarboxylic acid ~nd the title
compound was obtained.
3 2-(2-Chloroethyl) -2 ,3-dihydro-4-methylpyridor2 ,3-f
~1, 4 ] ox azep in-5 ( 4H ) -one hydrochloride.
the procedure of Intermediate 16, 3-t(l-methyl-
3-pyrrolidinyl)oxy~-~-pyridine~arbonitrile fumarate is
su~st ituted for 3~ methyl-3-pyrrol idinyl ) ~xy ~ -4 -
~5 pyridinecarbon trile fumarate~ the title c~mpound i~
obtained.
~ ~24S6~7 ; 4l9A-cIp-2
58
~L~2
7-Chlox~2-(2-chlor~ethyl~-2,~-dihydro-4-methyl-1,4-
benzoxazepine-5~H)-thione.
To a solution of 20 g (0.07 mole~ of 7~rchloro-2-(2-
chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-
one in 200 ml of toluene was added a mixture sf 9.55 g
to-o5 mole) of phosphorus pentaqulfide and 9.5 g of
potassium sulfide which had been ground together. The
reaction mixture was filtered ~nd the filtrate concentrated
under reduced pressure to give a yellow ~olid. Recrystal-
lization from absolute ethanol gave 12.5 g (68O of the
product, m.p. 102-104C.
Analysis: Calculated for Cl2Hl9NC120S: C,49.66; H,4.52;
~,4.8~
Found . : C,49.62; H,4.55;
N,4.76
Intermed ate 20
2-(2-Chloroethyl~-7,9-diiodo-2~3-dihydro-4-methYl-
1,4-benzoxazepin-5(4H~-one.
When in t~e procedure of Intermediate 1~ 3,5-diido- :
2~ methyl-3-pyrrolidinyl)oxy~-benzamide is ~ubstituted
~or 2-~(1-methyl-3-pyrrolidinyl)oxy~benzamide, the title
compound is prepared.
Intermediate ?l
2-Chloromethyl-2,3-dihydro-4-methylpyrido~,2-f~1,4
oxazepin-5(4H)-hydrochloride.
When in the proeedure of Intermediate 4~ an equal molar
amount of sodium 2-~(1-methyl-~-azetidinyl)oxy]-3-pyridine-
carboxylate sodium ~cetate is ~ubstitut~d ~or sodium 2-
~(l-methyl-3-pyrrolidinyl)oxy~-3-pyridin~carboxylate~
the title ~ompound is prepared.
Intermediate 2_
~o 2-(2-Chloroethyl)-2J3-dihydro-4-methylpyridor4,3-f~
rl,4~
A ~olution of 5 g (0.021 mole) of 2-(2-~hlorc~thyl)-
2,~-dihydro-4-methylpyridoC4,3-f~ 4J-oxazepin-5(4H)-one
and 5.1 g (0.0126 mole~ of 2,4-bi~(4-methoxyphenyl)-1,3,2,4-
dithiodiphosphetane-294-di~ulfide in 100 ml ~ dry
~2456~7 ) 4l9A-cIp-2
59
toluene was stirred at reflux for 2.5 hr. The 601ution
was ~ooled and extracted three t~mes with sodium
bicarbona~e solution. The toluene layer was dried over
odium sulfate and ~o~centrated. The residue was chromato-
graphed thigh pressure liquid chromatograph) using asilica column and ethyl acetate liquid phase. The
fraction containing the product was concentrated by
evaporation and the re~idue was crystallized from ethyl
alcohol to give 0.6 g (llO of the title compound.
Intermedia~e 23
: 2~(2-Chloroethyl~-2,3-dihydro-7-methox~-4-methyl 1,4-
benzoxazepine-5(4H~-thione.
To a solution of 10.3 g (0.04 mole) of 2~(2 chloro-
ethyl)-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-
: 15 5(4H)-one in 200 ml of chloroform was added a mlxture of
5.7 g ~0.03 mole) of phosphoru~ pentasulfide and 5.7 g of
potassium ~ulfide which had been ground together. The
reaction mixture was ~tirred ~nd heated at reflux under
nitro~en atmo~phere for 5 hr. The mixture was filtered
; 20 hot and the ~iltrate concentrated under reduced pressure.
~he reqidue, an orange solid, was recrystallized from
ethanol to give 7.4 g (65 O o~ product, m.p. 98-100 C.
Analysis: Calculated ~or Cl3Hl~Cl02S: C,54.64; H,5.65;
~,4.90
Found : C,54.57; H,5.67;
~,4.85
Intermediate 24
When in the procedure o~ Intermediste 2, e~ual molar
amounts of the ~ollowing are substituted for 2-~1 benzyl-~-
pyrrolidinyloxy)benzoic acid:
; ~0 2-~(1-cyclohexyl-3-pyrrolidinyl)oxy~b~nzoic acid,
2-~(1-ethyl-3-pyrroliainyl)oxy3benzoic: BCi~l,
2-t(l-i~spropyl-3-pyrrolidinyl)oxy]benzoic acid,
2-~ (4-~lGrobenzy~ )-3-pyrrolidinyl~oxy~benzoic acid,
2-~ (4-methylbenzyl)-3-pyrrolidinyl]c~xy~benzoic hCid,
2-~ ,5-dimethoxyb~nzyl)-3-pyrrolidinyl~oxy~benzoic
~cid,
2-~tl-(trifluoromethylb~nzy~ pyrrolidinylJ
benzoic ~id, ~nd
12456~7 i 419A-CIP-2
2~ (4-nitr~benzyl)-~-pyrrolidinyl]oxy~benzoic
~cid, and
there are obtained:
a) 2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydro-lJ4-
. benzoxazepin-5(4H)-one,
b) 2-(2-chlor~ethyl)-2,3-dihydro-4-ethyl-1,4-benæox-
AZ epin-5(4H)-one,
c) 2-(2-chloroethyl)-2,~-dihydro-4-isopropyl-1,4-
~enzoxazepin-5(4H)-one,
d~ 2-(2-chloroethyl)-4-(4-chlorobenzyl)-2,~-dihydro
1,4-benzoxazepin-5(4H)-one,
e) 2-(2-chloxoethyl)-2,3-dihydro-4-(4-methylbenzyl)-
1,4-benzoxazepin-5(4H)-one,
f) 2-(2-chloroethyl)-2,~-dihydro-4-(3,5-dimethoxybenzyl)-
1,4-benzoxazepin-5(4H)-one,
~ g) 2-(2-chl~roethyl)-2,3-dihydro-4-(3 trifluor~methyl-
: benzyl)-1,4-benzoxazepin-5(4H)-one,
h) 2-(2-chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)e
1,4-benzoxazepin-5(4H)-one.
Intermediate_2~
When in the procedure of Intermediate 4, equal molar
amounts of the f~llowing are ~ubstituted for ~odium 2-
r ( I-methyl-3-pyrrolidinyl)oxy~-3-pyridine carboxylate:
2-C(l-cyclohexyl-3-pyrrolidinyl)oxy]-3-pyridine
carboxylate,
~ 3o 2-tll-ethyl-3-pyrrolidinyl)oxy~-3-pyri~ine carboxylate
:~ 2-[l-isopropyl-3-pyrrolidinyl)oxy~-3-~yridine
;~ carboxylate,
~ 2-~E 1-(4-chlorobenzyl)-3-pyrr~lidinyl~oxy~-3 pyridine
.~ c~rboxylatQ,
2-~tl-(4-methylbenzyl)-3-pyrrolidinyl~oxy~-3-pyridine
carboxylate,
4l9A-cIp-2
S~i~7
61
2-~tl-(4-methoxybenzyl)-3-pyrrolidinyl]~xy~-3-
pyridine carboxylate,
2-r[l-(3-trifluoromethylbenzyl)-3-pyrrolidinyl]oxy]
: ~-pyridine carboxylate, ~nd
52-~1-(4-nitrobenzyl)-3-pyrrolidiny~oxy~-3-pyridine
carboxylate
there are obtained:
10a) 2-(2-chloroethyl)-4-cyclohexyl-2,3-dihydro-pyrido
r3,2-f]~1~4]sxazepin-5(4H~-one hydrochlsride,
b) 2-(2-chloroethyl)-2,3-d~hydro-4-ethylpyrido~J2-f]
~1,4]-oxazepin-5~4H)one hydrochloride,
c) 2-(2-chloroethyl)-2, ~ ihydro-4-isopropylpyridc:~3J2-f]
15~1,4~-oxazepin-5(4H)-one hydrochloride,
d) 2-(2-chloroethyl)-4-(4-chlorobenzyl)-2,3-dihydro-
pyrido~3p2-f~1,4]-ox~zepin-5(4H)-one hydrochloride,
e) 2-(2-chloroethyl)-2,3-dihydro-4-(4-methylbenzyl)
pyridot~,2-f~1,4~-oxazepin-5(4H)-one hydrochloride,
20f) 2-(2-chloroethyl)-2,~-dihydro-4-(4-methoxybenzyl)
pyrido~,2~f~1,4~-oxazepin-5(4H)-one hydrochloride,
g) 2-(2-chloroethyl)-2,~-dihydro-4-(~-tri~luoromethyl-
benzyl)pyrido~,2-f~1,4~-5(4H)-one hydrochloride,and
h) 2 (2-chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)-
: 25pyrido)t3,2-f~1,4]-oxazepin-5(4H)-one hydro-
chloride.
.
Intermediate 26
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyridoC3,2-f~
r 1 ~ 4~-thia~epin-5(4H)-one.
~ mixture of 80.75 g (0.34 mole) of 2-~ methyl-~-
pyrrolidinyl)thiQJ-3-pyridinec~rboxylic ~cid, 500 ml of
chloroform, 200 g of carbon tetrachloride ~nd 178 g (o.68
~ole) of trip~2nylpho~phine Wa3 stirred ~t reflux ~or 2.5 hr.
~he re~ulting ~olution was extracted with one 500 ml ~nd
three 125 ml p~rtivn~ of lN hydxochloric a~id. The acid
419A-CI
56~L7
62
extracts were combined and extracted with isopropyl ether.
The aqueous layer was basified with sodium hydroxide and
extracted three times with chloroform. The combined chloro-
form extract was dried over sodium sulfate and concentrated.
A portion of the residue was chromatographed on the high
pressure liquid chromatograph using a eilica column and
ethyl acetate. The compound obtained was crystallized from
isopropyl ether-isopropyl alcohol, m.p. 97-100C.
Analysis: calculated for CllHl3N20SCl: C,51.46; H,5.10,
N,10.91
Found : C,51.63; H,5.12:
N,10.85
Intermediate 27
2-(2-Chloroethyl)-2, ~-dihydro-4-methylpyrido~ ~,2-fl
~1,4~-thiazepine-5(4H)-thione.
15 A mixture of 4.~ g (0.017 mole) of 2-(2-chloroethyl)-
2,3-dihydro-4-methylpyrido[~,2-f]~1,4]thiazepin-5(4H~-one,
100 ml of toluene and 4.8 g (0.012 mole) of 2,4-bis(4-
methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide
was refluxed for ~ hr and then extracted twice with dilute
sodium hydroxide. The organic layer was concentrated and
the residue chromatographed on the high pressure liquid
chromatograph using a silica column and 50% ethyl acetate-
50% hexane. The yield of title compound was 2 g, m.p.
160-162C.
25 Analysis: Calculated for C~ 3~2S2Cl: C,48.43; H,4.80,
~,10.27
Found: C,48.46; H,4.81,
N,10.51
Intermediate 28
- 2-~2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,4 f
; ~0 ~1,4~oxazepin-5~4H)-one.
i
A solution of 78 g (0.5 mole) of 4-chloronicotinic
acid and 52 g (0.52 mole) of l-methylpyrrolidinol in 150 ml
of dimethylformamide was added to a suspension of 44 g
(1.1 mole) of 60% ~odium hydride/mineral oil in 800 ml of
dimethylformamide at a rate so as to maintain a temperature
of 55-70 C. (preheated to 55C.). ~he resulting mixture was
heated to 60~C. ~or 4 hr and filtered while hot. The
filtrate was concentrated on the rotary ~vaporator ~5 mm/steam
419A-CI
56
6~
bath). ~he re~idue was diGsolved in 600 ml of water and
extracted with ~sopropyl e~her. The pR of the aaueous layer
was ~djusted to 6 with hydrochloric ~cid and ~he ~olution
was concentrated on the rotary e~aporator (5 mm/steam bath)
The re~idue wa6 ~uspended in 800 ml of chloroform ~nd 188 g
(1.1 mole~ of triphenylphosphine added followed by 250 ml
of carbon tetrachloride. The mixture W25 gently heated to
60C. whereupon the reaction becam~ exothermic ~nd an ice
bath was u~ed to maintain n temperature of 60-65C. for
about 20 minutes. ~he ice bath wa~ removed and the mixture
was heated to reflux ~or ~.5 hr ~nd coole~. The ~olution
w~s extracted with 600 ml of water Pollowed by two 200 ml
portions of 1~ hydrochloric ~cid. The ucid layer was made
basic with ~odium hydroxide and extracted three times with
chloro~orm. The chloroform was concentrated and th~ residue
was chromatographed by high pressure liquid chromatography
using 6ilica gel and eluting with ethyl acetate. Yield of
product was 30 g (25%). The ma88 spectra and NMR ~re in
agreement with the ~tructure of the title compourld.
Intennediate 29
2-~?-chloroethyl? -? .3-dihYdro-4-methvlPyrid~ 4-f~ 4
oxazepine-~(4H)-thione monohydrochloride.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,4-f~
~1,4]ox~zepin-~(4~)-one, 15 ~ (o.o6 mole~, was dissolved in
200 ml of dry tolu~ne and 15 g (0.037 mole) o~ t2,4-bis
(4-methoxyphenyl)~ ,2,4-dithi~pho~ph~tane~2,4 di~ulfide
wa~ added. The mixture W~6 refluxed for 2.5 hr and the
toluene solution decanted. The re~idue w~ partitioned
between dilute ~odium hydroxide ~nd chloroform. The chloro-
form was dried and concentrated. The res~due wa~ chroma-
togr~phed Qn a high pr~ssure liquid chromatograph (Waters 500)
u~ing ~ ~ilica column and eluting with ethyl ac~t~te. The
fraction containing materi~l of ~lecular weight 257 was
cQncen~rated. ~he X~8idUR ~n i~opr~pyl al~ohol w~ treated
with hydrogen chlori~e and the r~sulting cry~t~l~ were
collected. Yield of ~ydrochlorid~ ~lt Wa8 0.1 g (o.6%) J
m.p. 168-171C.
419A-CIP-2
.2~ 7
64
Analysis: Calculated for CllHl~N2OSCl2: C,45.06; H,4.81,
N,9-55
Found : C,45.15: H,4.98;
N,9.26
Intermediate ~0
2,3,4,5-Tetrah dro-4-methyl-5-oxopyrid
oxazeplne-2-propanenitrile.
2-~2-chloroethyl)-2,3-dihydro-4-methylpyrido~,2-f]
~1,4]oxazepin-5(4H)-one hydrochloride, 100 g (0.415 mole)
was partitioned between dilute aqueous sodium hydroxide
(200 ml) and chloroform (200 ml). The organic layer was
saved and the aqueous layer extracted with chloroform
(3 X 50 ml). The organic layer were combined, dried over
sodium sulfate and concentrated by rotary evaporation
(70 C.~ water a~pirator). The residue, the free base of
the starting hydrochloridel 89 g (0.37 mole) was dissolved
in 150 ml of toluene and to the solution was added tetra-
butyl ammonium bromide, 9 g (0.027 mole); Saturated aaueous
potassium cyanide (100 ml) was then added and the mixture
stirred mechanically at reflux. After 2 hr, additional
tetrabutyl ammonium bromide, 3 g (0.009 mole) and saturated
aqueous potassium cyanide (20 ml) were added and the mixture
stirred for 0.75 hr at reflux. The contents of the reaction
vessel were extracted with ethyl acetate (3 X 50 ml~. (Note:
chloroform should be used instead~. The organic layer
dried over sodium sulfate and concentrated by rotary
evaporation (70C. 3 water aspirator) to 1 ~ the original
volume. Upon cooling, crystallization ensued. The crystals
were filtered and washed with several portions of ethyl
acetate and isopropyl ether. Thirty 9 (~5O of off-white
crystals were collected, m.p. 104-105 C. A sample was
recrystallized from ethyl acetate, m.p. 104-105 C.
Analysis: calculated for C~2H13~30z: C,62.33; H,5.67;
N,18.17
Fo~nd : c,62.06; H,5.65
~,17.97
419A-CIP-
~56~7
Intermediate 31
2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyridor3,2-f
~1,4 1oxazepin-5(4H)-one hydrochloride.
To a stirred suspension of sodium hydride mineral oil
(8l.45 g Ol' 60% dispersion 2.036 mole) in dimethyl-
sulfoxide (500 ml) heated to 50C. was added dropwise a
solution of 2-chloronicotinic acid (142 g, 0.905 mole)
and N-ethyl-2-pyrrolidinol (99 g, o.86 mole) in dimethyl-
sulfoxide (500 ml) at a rate to maintain 55 -60C.
(occasior-al cooling was necessary~. After the addition
was complete, the mixture was stirred at 50-60C. for
1.5 hr and allowed to cool. The solid which precipitated
was filtered, washed with ethyl acetate and dried.
The dry sodium salt (172.53 gj 0.62 mole) was
suspended in chloroform (1 liter)- Hydrogen chloride ~as was
bubbled through the suspension until the pH meter read
5.76. Triphenylphosphine (365.5 g, 1.395 mole) and CC14
(365.5 g) were added and the mixture stirred at reflux.
After 45 minutes, IR showed 95% reaction. Additional
triphenylpho~phine (100 g, o.~8 mole) and CCl4 (100 g)
were added and the solution stirred at reflux an additional
45 min. IR showed ~995~ reaction. After cooling, the
solution was extracted several times with dilute hydro-
chloric acid (1.5 liter total) The a~ueous layer was then
made basic with concentrated sodium hydroxide solution
and extracted into chloroform (3 x 250 ml). The organic
layer was dried over sodium sulfate and concentrated by
rotary evaporation ~70C, water aspirator~. The residuel
oil was dissolved in isopropyl alcohol (500 ml) and
acidified with hydrogen chloride gas. Upon cooling, an oil
was noted and the volume reduced to 1/3 the original volume.
Upon cooling, 70 g (.241 mole, 28%) of pale brown crystals
were collected, m.p. 15~-155C~C.
Analysis: Calculated for Cl~H~ 202Cl;~: C,49.50; H,5.5~,
~,9.62
Found : C,49.64; H,5.62;
~,9-32
419A-CI
~2g~56~L7
66
I _ rmediate 32
2-(2-Chloroethyl)-4-ethyl-2)~-dihydropyr~doC~,2-f
~,4~oxazepin-5(4H)-thione hydrochloride.
2-(2-chloroethyl)-4-ethyl-2~3-dihydropyridoc3~2-f~
tl,4~oxazepin-5(4H~-one hydrochloride, approximately
5 50 g, was partitioned between dilute aqueous sodium
hydroxide (50 ml) and chloroform (50 ml). The organic
layer was saved and the aqueous layer extracted with
additional methylene chloride (2 x 50 ml). The organic
layers were combined, dried over sodium ~ulfate, filtered
and concentrated by rotary evaporation (70~C, water
aspirator) yielding 39 g (0.15~ mole) of the free base.
The free base thus obtained was dissolved in chloroform
(1.2 1) J and phosphorus pentasulfide (33.9 g, 0.153 mole)
was added while stirring. The xesulting mixture was
heated to reflux for 16 hr. After cooling, the reaction
mixture was filtered, washed with dilute a~ueous sodium
hydroxide (~ x 300 ml), dried over sodium sulfate and
concentrated by rotary evaporation (70C, water aspirator)
to a yellow viscous oil. The oil was taken up in isopropyl
alcohol (~200 ml) and made acidic with hydrogen chloride
gas. Upon cooling, 20 ~ (4~ O of crystals were collected,
m.p. 13~-135C.
Analysis: Calculated for C~2Hl~N20SCl2: C~46.91; H,5.25;
N,9.12
Found : C,47.33; H,5.38;
N,9.10
Intermediat~
l~hloro-2-(2-chloroethyl)-2,~-dihydro-4-m_thylpyrido
L~ !2 -f~ 4~oxazepin-~(4H)-one.
A sample of 2-(2-chloroethyl)-2, ~-dihydro-4-methyl-
pyrido[~,2-f]~1,4]-oxazepin-5-(4~)-one hydrochloride (10 g~
~0 136 mole) was dissolved in dimethylformamide (150 ml) and
heated to reflux. Sulfuryl chloride (20 g, 0.148 mole) was
then added dropwise over a period of 40-50 minutes. The
reaction was allowed to ~tir at reflux for ~0 minutes
followin~ the addition of SO2CL;~. After cooling, the
419A-C
56~7
contents o~ the flask w~r~ partitioned between watex
(150 ml) and benzene (150 ml). The benzene layer was
saved and the water layer extracted with an additional
amount of benzene (2 X 50 mI)0 The benzene extracts were
combined and washed with dilute a~ueous potassium hydroxide
(2 X 50 ml) followed by dilute aaueous hydrochloric acid
(2 X 50 ml). The benzene layer was dried over sodium
sulfate and concentrated by rotary evaporation (~70C.,
water aspirator) yielding 2.61 g of crude material. The
crude material was recrystallized from isopropyl ether
giving 1.25 g (12.6%) of of~-white crystalsl m.p. 78-79 C.
Analysis: Calculated for CllH~2NzO2Cl2: C,48.02; H,4.40;
N,10.18
Found : C,48.07; H,4.53,
N,10.10
Intermediate 34
7-Chloro~2-(2-chloroethyl) -? ,3-dihydro-4-methylpyrido
[ 5,2-fl~1,41oxazepine-5(4H)thione.
7-Chloro-2-(2-chloroethyl)-2,~-dihydro-4-methylpyrido
. ~3,2-f]~1,4]oxazepin~-5(4H)-one, 6.o g (0.022 mole) was
suspended in 200 ml of toluene. To this suspension was
added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-
2,4-dilsulfide. The mixture was heated to reflux with
vigorous stirring for 2 hours. Because the reaction was not
complete, an additional amount (3.0 g) of 2,4-bis(4-methoxy-
phenyl)-1,~-dithia-~,4-diphosphetane-2,4-disulfide was added
and the mixture stirred at reflux for 2 hr and left Etanding
for 56 hr at room temperature. The toluene layer was
decanted and washed with 50 ml of dilute a~ueous sodium
hydroxide and 50 ml o~ dilute hydrochloric acid. Toluene
was removed by rotary evaporation (~80C., water aspirator).
The ~rude oil was recrystallized from isopropyl alcohol
giving 3.5 g (54%) of pale yellow crystals, m.p. 125-127C.
Analysis: Calculated for CllHl2~2OSCl2: C,45.~7; H,4.15;
~,9.62
Found : C,45.40; H,4.20;
~5 N,9.71
419A-CI~
~2~56
68
Intermediate
2-(chloromethyl)-4-cyclohexyl-2J~s-dihydropy~idor3 2-f
Ll~4~oxazepin-5~4H~-one.
A 15 g ~0.05 mole) sample of sodium 2-[(1 cyclohexyl-
3-azetidinyl)oxy]-3-pyridine carboxylate obtained in
Preparation 23 was suspended in 100 ml of chloroform and
hydrogen chloride passed in until a pH of 5.8 r~mained
steady. To the stirred mixture was added 18 g of thionyl
chloride. The resulting solution was stirred at room
temperature for ~ hr. An I.R. spectrum showed a peak
at 1770 cml which is characteristic of acid chloride.
Forty milliliters of triethylamine was added dropwise
while cooling to about 25C. with an ice ~ath. The chloro-
form solution was stirred an additional 0.5 hr and was
extracted with water, dried over sodium sulfate and
concentrated. The residue was chromatographed on a 7 x 20
cm silica column using ethanol as the eluent. The desired
material was the first to be removed from the column.
The ethanolic solution was concentrated and the residue
crystallized once from ethyl acetate-isopropyl ether and
once from isopropyl alcohol. Yield of title compound was
1 g (7%), m.p. 120-122~C.
Analysis: Calculated for Cl5HlgN202C1: C,61.12; Hl6.50,
N,9.50
Found : C,61.11; H,6.62;
N,9.32
Intermediate ~
2-t2-chloroethyl~-?~-dihydro-4-(phenylmeth~l)pyrido
L3,2-~1,41oxazepin-5(4H~one.
; The title compound was prepared in crude form in the
first part of Example 67.
;
419A-CIP-c
69
Intermediate ~l
2,3-Dihydro-2~ dihydro-1,3-dioxo-2H-isoindol-2-yl)
ethyl-4-methylpyrido~3,2-flrl,4~oxazepin-5(4H)-one.
~o a solution of 4.92 g (0.02 mole) of 2-(2-chloroethyl)-
2,3-dihydro-4-methylpyrido~3,2-f~ -lJ4-oxazepin-5-(4H)one
in ~5 ml of dimethylformamide was add0d 7.55 g (0.041 mole)
of potassium phthalimide. The mixture was stirred for 5 hr
at 100C. and left standing at room temperature overnight.
Dimethylformamide was removed by rotary ~vaporation (80C.
vacuum pump). The residue was taken up in 100 ml of chloro-
form and washed with water (2 x ~0 ml) and 2M pota-sium
hydroxide (2 x 3 ml). The organic layer was dried over
anhydrous sodium sulfate, filtered and concentrated by
rotary evap~ration (70 C., water aspirator). The 6.26 g of
crude product was recrystallized from isopropyl alcohol to
give 2.60 g (36%) white cyrstalline powder, m.p. 146-47 C.
Analysis: calculated for Cl9Hl7N304: C,64.95, H,4.88; ~,11.95
Found : C,65.18; H,4.91; N,12.09
Intermediate_~8
2 -r 2-(2~3-Dihydro-4~methyl-5(4H)-thioxopyrldor3,2-f
rl,4-oxazepin-2-yl)-ethyll-lH-isoindole-1,3(2H~-dione.
To a solution of 1.0 g (o.oo~8 mole) of 2-(2-chloroethyl)-
2,3-dihydro-4 methylpyrido~,2-f]-lJ4-oxazepine-5(4H)-thione
in 20 ml dimethylformamide was added 1.43 g (o.0078 mole) of
potassium phthalimide. The mixturP was heated to 100 C.
for 6 hr with stirring.
The dimethylformamide was removed by rotary evaporation
(70, vacuum pump) and th~ residue taken up in chloroform
(100 ml). The organic layer was washed with 2N potassium
hydroxide (2 x 3û ml), dried over anhydrous ~odium sulfate,
~50 filtered, and concentrated by rotary e-,raporation (~70C.,
water aspirator). The crude oil (1.2 g) was recrystallized
from isopropyl alcohol giving 0.95 g (68O o~ pale white
crystals, m.p. 172-73C.
Analysis: Calculated for Cl~Hl7~9O3S: C,62.117 ~94.66;
~ 4
~ound : C,61.85; ~,4.70;
N,11.5
419A-CI~
~2~56~7
Intermediate ~
2,~5,4,5-Tetrahydro-4-methyl-5-thioxopyrido~3,2-fl~,1,41-
To a solution of 11.0 g (0.04 mole) of 2,3,4~5-tetrahydro-
4-methyl-5-oxopyrido~3,2-f~1,4~-oxazepine-2-propanenitrile
in 175 ml toluene was added 10.5 g (0.026 mole) of 2,4-bis
(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide.
The reacti~n mixture was heated ~o reflux for 2 hr with
vigorous mechanical stirring. Another ~.0 g (0.007 mole)
of 2,4 bis (4-methoxyphenyl)-1,3-dithia-2~4-aiphosphetane
2,4-disulfide was added and heating continued f~r 1 hr
additional. The reaction mixture was allowed to cool and
stand overnight at room temperature. Toluene was removed by
rotary evap~ration (90C., water aspirator) and the residue
taken up in 200 ml chloroform. This was washed with 2 x 50
1~ ml 2M aqueous potassium hydroxide and c~ncentrated by
rotary evaporator (90C., water aspirator). Crystallization
ensued upon cooling. Recrystallization from isopropyl
alcohol afforded 1.60 g tl3.8%) product, m.p. 155-56 C.
Analysis: calculated for Cl2RI9~3OS: C,58.28; H,5.30;
N,16.99
Found : C,58.00; H,5.26;
N,17.13
Intermediate 40
2~?-chloro-1-methylethYl~-2,~-dih~dro-4-methylpyrido
2-flLl,4~-oxazepin-5(4H~-one hydrochloride.
To a su~pension of 59~6 g (60%) in oil, 1.49 mole) of
sodium hydride in 400 ml of tetrahydrofuran heated to reflux
wa~ added a solution ~f 110 g (0.71 mole) of 2-chloro-
nicotinic acid and 81~3 g (0.71 mole) of 1,4-dimethyl-3-
pyrrolidinol in 400 ml of tetrahydrofuran at a rate such
that good reflux was maintained (20-~5 minutes). Heating at
reflux was continued for 2 hr ubsequent to the completion
o~ the additi~n. Because mass spectra showed 30~ ~tarting
material at this point, 25.0 g (0.6~ mole) addition~l sodium
hydride was added ~nd rç~lux continued for 4 hr. Th~
reactisn ~ixture was left ~tanding overnight.
4l9A-cIp-c
lZ45S47
The mixture was auenched with isopropyl alcohol and
filtration attemp~d. However, when filtration failed, the
solvent was stripped off by rotary evaporation.
This crude Qalt was suspended in 1 liter of chlor~form
and hydrogen chloride gas was bubbled in until a pH of 6 was
reached. To this suspension was added 372 g (1.42 mole) of
triphenylphosphine and 372 g carbon tetrachloxide and the
entire mixture heated at reflux for 1.5 hr. However, reaction
was not complete as evidenced by I. R. An additional
o loo g (o.~8 mole) of triphenyl phosphine and 100 g of carbon
tetrachloride was added and reflux continued overnight.
After cooling the reaction, lOQ g of triethylamine was added.
The reaction mixture was extracted with 4 x 200 ml of
dil aqueous hydrochloric acid. The hydrochloric acid
extracts were made basic with conc. sodium hydroxide and
extracted into a total of 1 liter of chloroform. The
- chloroform was removed by rotary evaporation (70 C; 3 mm)
and the residue taken up in 300 ml toluene.
The toluene was extracted with 4 x 125 ml of dil
a~ueous hydrochloric acid. The hydrochloric acid extracts
were combined and washed with 4 x 200 ml of methylene
chloride. The hydrochloric acid layer was basified with
conc. sodium hydroxide and extracted with methylene chl~ride.
The organic extracts were combined, dried over sodium
ulfate, filtered and concentrated by rotary evaporation.
The residue was taXen up in isopropyl alcohol and treated
with hydrogen chloride gas. Approximately 34 g (16~) of
white crystals were collected. Recrystallization in
isopropyl alcohol gave an analytical sample, m.p. 178-81 C.
Analysis: calculated for ClzHl~N202Cl2: C, 49.50; H,5.54;
~,9.62
Found C, 49.46; H,5.54;
~9-50
.
419A-CIP-2
~Z~56~7
Intermediate 41
2-(2-chloroethyl)-2,3-dihydro-2~4-dimethylpyrido~3,2-fl-
1 4-oxaze~ n-5(4H~-one hvdrochloride.
To a suspension of 60 g (60% in oil, 1.5 mole) of sodium
hydride in 400 ml of tetrahydrofuran heated to reflux was
added a solution of 110 g (0.70 mole) of 2-chloronicotinic
~cid and 80 g (0.70 mole~ of 1,3-dimethyl-3-pyrrolidinol so
as to maintain good reflux. ~eating at reflux was continued
overnight. The mass spectra showed very little product at
this point, therefore, 400 ml of dimethylformamide was added
and heating at 77C. was continued overnight. Approximately
10~ of the desired product was then observed by mass spectra.
The tetrahydrofuran was evaporated by passing nitrogen gas
over the reaction mixture while at the same time being
replaced with dimethylformamide. The temperature was
concomitantly increased to 100C. The mixture was stirred
overnight at 100C. After cooling, no salt precipitated
out; therefore, dimethylformamide was removed by rotary
evaporation (90C.7 5 mm). Approximately 250 g of crude
salt was collected.
Into a suspension of 230 g (~o.88 mole) of this crude
salt in 1 lit0r of chloroform was bubbled hydrogen chloride
gas to pH 6. To this suspension was added 46~ 9 (1.77 mole)
of triphenyl phosphine and 463 g of carbon tetrachloride.
The mixture was then heated to reflux. After 8 minutes a
vigorous exotherm ensued which 6ubsided in 30 minutes.
Reflux was continued for 2.5 hr. According to infrared
analysis, the reaction was near completion. Approximately
40 ml of triethylamine was added to drive the reaction to
completion. The mixture was left standing overnigXt at
room temperature.
; The reaction mixture was extracted with 700 ml dil. aq.
hydrochloric acid. The hydrochloric acid extracts were
;~ combined and washed with 4 x 100 ml of chloroform. The
combined agueous hydrochloric acid extracts were then made
basic with conc. sodium hydroxide and extracted with
5 x 200 ml of methylene chloride. The organic extracts were
combined, dried ov~r anhydrous ~odium ~ulfateJ filtered and
concentrated by rotary evapoxation (70C.; ~0 mm). The
419A-CIF
~L;2456~7
residue was taken up in 600 ml of toluene and treated with
activated charcoal 4 times. The toluene was then removed
by rotary evaporation and the residue treated with hydrogen
chloride in isopropyl alcohol whic~ afforded 53 g (21%).
Recrystallization from isopropyl alcohol afforded an
analytically pure sample, m.p. 155-158C.).
Analysis: Calculated for Cl2Hl~NzO2Cl2: C,49.50; H,5.54;
N,9.62
Found : C,49.49; H,5.61
N,9-75
Intermediate 42
2-(2-Chloroethyl~-2,3-dihvdro-2,4-dimethylPyridor~2-f]
1,4-oxazepine-5(4H?-thione.
To a suspension of 4.6 g (0.04 mole) of phosphorus
; pentasulfide in 50 ml of acetonitrile was added, all at
once, a solution of 20 g (0.0?9 mole) of 2-(2-chloroethyl)-
2,3-dihydro-2,4-dimethylpyrido~3,2-f]-1,4-oxazepin-5(4H)-
one in 50 ml of acetonitrile. The mixture was heated to
reflux for 4 hr with stirring, at which time the mass
spe_tra showed no starting material. The reaction was left
standing overnight at room temperature.
To the reaction mixture was added 100 ml of toluene
followed by stirring for 15 minutes. Some tar-like material
collected on the sides of the reaction vessel. The solution
was filtered with much difficulty. The filtrate was saved
and washed s~ Y with 3 x 50 ml of saturate~l aqueous
sodium bicarbonate. The organic phase was dried over
anhydrous sodium sulfate, treat~d with activated charcoal,
filtered, dried again over anhydrous sodium sulfate~ filtered,
and concentrated by rotary evaporation (80C.; 30 mm). The
crude oil (9.2 g) was crystallized from isopropyl alcohol,
giving 6.o g (28O of yellow crystals, m.~. 119-121~C.
Analysis: calculated for ClzHl5N20SCl: C,53.23; H,5.58;
N.lo-35
Found : Cj53.05, H,5.60;
N,10.34
~ . j
419A-CIP
~Z~56~7
74
Intermediate 4
2~(2-Chloropropyl)-2,3-dihydro-4=methylpyridot~,2-f~
1,4-oxazepin-5(4H)-one hydrochloride.
To a suspension of ~6.I g of 60~ sodium hydride in oil
(0.90 mole) in 300 ml of tetrahydrofuran heated to reflux
and under a nitrogen blanket was added a solution of 68.~ g
(0.43 mole) o~ 2-chloronicotinic acid and 50 g to-43 mole)
of 1,2-dimethyl-4-pyrrolidinol in 300 ml of tetrahydrofuran
atia rate such that good reflux was maintained (20 min).
Subseguent to this addition, heating at reflux was maintained
for 2.5 hr at which time the reaction appeared to be complete
(by mass spec.). The crude sodium salt was filtered and
washed with ethyl acetate affording 135 g of the crude
sodium salt.
To a suspension of 115 g (~0.44 mole) of the above
sodium salt in 650 ml of chloroform was added hydrogen
chloride to reach a pH of 6. To this mixture was added
231.8 g (o.88 mole) of triphenylphosphine and 231.8 g of
carbon tetrachloride and the entire reaction mixture heated
to reflux or 3 hr. After cooling, the reaction mixture
was extracted with 4 x 250 ml of di hydrochloric acid.
The agueous layer was washed with 4 x 125 ml of chloroform
and made basic with concentrated sodium hydroxide. The
a~ueous layer was then extracted with 3 x 250 ml of
chloroform. The organic extracts were combined, dried over
~nhydrous sodium sulfate, filtered and concentrated by
rotary evaporation. To the residue was added 800 ml of
toluene and the resulting solution decolorized 3 times with
activated charcoal. ~he solvent was removed by rotary
evaporation (90C., 30 mm). The residue was taken up in
300 ml of isopropyl alcohol and the solution was saturated
with hydrogen chlorideJ ~eeded, and left standing overnight
at xoom temperature. Approximately 30 g (~23%) of salt was
collected. An analytical sample was prepared by r~crystal-
lizating the salt ~ times from isopropyl alcohol, m.p.
14~-49C.
Analy~is: calculated ~or Cl2Hl~202C12: CJ49.50, ~,5.54
N,9.62
Found : C,49.85; H,5.62
N,9.84
.
~L245647 419A-CIP-2
Intermediate 44
2-(2-Chloropropyl)-2,3-dihydro-3-methylpyrido~3,2-f~-
; 1,4-oxazepine-5(4H)-thione.
To a suspension of 4.90 g (0.022 mo~e) of phosphorus
pentasulfide in 30 ml of acetonitrile was added a solution
of 10 g (0.039 mole) of 2-(2-chloropropyl)-2,3-dihydro-4-
methylpyrido~3~2-f]-l~4-oxazepin-5(4H)-one in 25 ml of
acetonitrile. The mixture was heated to reflux, with
stirring, for 5.5 hours and left standing at room temperature
overnight. To the reaction mixture was added 50 ml of
toluene, followed by stirring for a few minutes. The mixture
was filtered and the residue washed with 25 ml of toluene/
acetonitrile. The filtrate was washed cautiouslY with
3 x 75 ml of saturated aqueous sodium bicarbonate, dried
~` over anhydrous sodium sulfata, filtered, treated with
activated charcoal~ filtered and concentrated by rotary
evaporation (90 C., 30 mm). The crude syrup (10.0 g) was
crystallized from isopropyl ether/isopropyl alcohol, giving
5 g of yellow crystals, m.p. 95-97 C. A second crop was
collected, bringing the total to 6 g (57%).
Analysis: calculated for Cl2HlsN20SCl- C,53.28, H,5.58;
N,10.35
Found : C,53.13, H,5.58;
~,10.35
Intermediate 45
?-(2-Chloro-l-methylethyl)-2,3-dihydro-4-methylpyrido
~3,2-fl-1,4-oxazepine-5(4H)-thione hydrochloride.
To a suspension of 5.35 g (0.024 mole) of phosphorus
pentasulfide in 25 ml of acetonitrile was added à solution
of 10.9 g (0.043 mole) of 2~(2-chloro-1-methylethyl)-2,3-
dihydro-4-methylpyrido~3,2-f]-1,4-oxazepin-5(4H)~one in
25 ml of acetonitrile. The mixture was heated to reflux for
2.75 hr and left standing at room temperature overnight.
To the cooled reaction mixture was added 50 ml of toluene,
followed by filtration. The residue was washed with 45 ml
;~ of 3/1, vhl toluen~/acetonitrile. The filtrate was washed
cautiously with 3 x 75 ml of saturated sodium bicarbonate,
dried over anhydrous sodium sulfate, filtered, treated with
activated charcoal, filtered,and concentrated by rotary
419A-CIE
~IL2~56~7
76
evaporation. The residue was treated wi~h hydrogen chloride
in isopropyl alcohol/isopropyl ether which yielded one crop
of 4.5 g of yellow crystals, m.p. 148 51 C. t(Note: a second
crop of 1.5 g was collected, bringing the total yield to
6.o g (45.40].
Analysis: Calculated for Cl2Hl6N20SC12: C,46.91; H,5.25;
N,9.12
Found : C,48.86; H,5.34,
N,9.o5
Intermediate 46
2-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino
r 6,7-b]-~inolin-~(4H)-one.
To 21.3 ml (0.15 mole) of diisopropylamine in 300 ml
of tetrahydrofuran at -70C. was added dropwiRe, at a rate
to keep the temperature between -70 and -60C., 61.1 ml of
2.7 M n-butyllithium (0.16 mole). The temperature was
maint~ined at -70 C. + 3 C. for 20 minutes. A solution of
2-chloroquinoline in 60 ml of tetrahydrofuran was added
dropwise at a rate such that temperatuxe remained between
-70 and -60C. After 20 minutes, the darkened reaction
solution was poured onto a large excess of dry ice. The
solvent was evaporated with a stream of air.
The residue was taken up in 300 ml of water, made basic
with dilute aqueous sodium hydroxide and washed with 3 x 50
ml of isopropyl ether. The aqueous phase was filtered and
treated with dilute hydrochloric acid to ~pH 4-5, at which
time a copious precipitate formed. The precipitate was
collected and the filtrate reacidified yielding more
precipitate. The precipitates were combined and washed with
- water, isopropyl alcohol, and isopropyl ether. Approximately
15.4 g (61.5 0 of off-white crystals were collected.
To a suspension of 4.0 g of 60% sodium hydride in oil
(0.10 mole) in 100 ml tetrahydrofuran heated to reflux was
added a so~ution of 5.5 g (o.o48 mole) of N-methyl-3-
pyxrolidinol and lO g (o.o48 mole) of the above prepared
~5 2-chloro-~-auinolinecarboxylic and in 50 ml of tetrahydrofuran
at such rate as to maintain good reflux. Reflux was
maintained for 1 5 hr and the reaction mixture cooled. The
~ol~ent was removed by rotary evaporation yielding 26 g
419A-CIP-2
56~7
77
crude product.
The entire crude pr~duct from above was suspended in
150 ml chloroform and hydrogen chloride bubbled in until pH
of 5.76 was reached (note: a~ter hydrogen chloride addition
ceased, ~he pH continued to lower to 1.7). To this
suspension was added 25.0 g (o.og6 mole) of triphenylphosphine
and 25 g of car~on tetrachloride. After 45 min, an additional
10 g (0.0~ mole) of triphenylphosphine and 10 g of carbon
tetrachloride was added. After 30 minutes, the heat was
removed and the reaction driven to completion by dropwise
addition of 20 ml of triethylamine.
The reaction mixture was extracted with 3 x 50 ml of
~N hydrochloric acid. The a~ueous extracts were combined,
washed with 2 x 50 ml chloroform, made basic with concen-
trated sodium hydroxide and extracted with 3 x ~0 ml ofchloroform. The organic extracts were combined and concen-
trated by rotary evaporation. The syrupy residue was taken
up in 100 ml of toluene and treated with activated charcoal.
The toluene was removed by rotary evaporation and the syrupy
residue crystallized from isopropyl alcohol, giving 1.5 g
(11%) of white crystals, m.p. 133-1~4C.
Analysis: Calculated for ClsHl5N20zCl: C,61.97; H,5.20;
N,9.63
Found : C,61.7~; H,5.1
N,9.54
Intermediate 47
2-(2-Chloroethyl)-2,3-d~ydro-4-methYl-1,4-oxazepino
f 6, 7-b1quinoline-~(4H) -thione .
To 3.0 g (0.01 mole) of 2-(2 chloroethyl)-2,3-dihydro-
4-methyl-1,4-oxazepinot6,7-bJ-q~inolin-5(4H)-one in 30 ml
of acetonitrile was added 1.3 g (o.oo6 mole~ of phosphorus
pentasulfide. The mixture was stirred vigorously at refllx
~or 2 hr. After cooling3 the reaction mixture was diluted
with 60 ml of toluene and fil'ere~. Tne re~idue on the
filter paper waQ washed with 50 ml of additional toluene/
acetonitrile, ~/1, V~V. The filtrate was wa~hed with
~ x 50 ml aturated sodium earbonate (caution: gas evolved! .
dried over anhydr~us ~odium ~ulfate, filtered, treated with
activated char~oal, filtered again and concentrated by
rotary evaporation (90C., 30 ~m). The residual %yrup was
419A-CIP-2
~2~L5647
78
crystallized from isopropyl alcohol, yielding 1.6 9 (52 O
of yellow crystals, m.p. 1l4-ll6oc.
Analysis: Calculated for Cl5Hl5N2OClS: C,58.72; H,4.93;
N,9.13
Found : C,~8.38; H,4.92;
N,9.07
Intermediate 48
?-(2-Chloroethyl~-2,, 5-dihydro-4-methvl-~-ttrifluoro-
methyl~ 4-oxazepinor6 7-c]quininolin~4H)-one hydro-
chloride.
To a suspension of 3.16 g (60~ in oil, o.o8 mole) of
sodium hydride in 250 ml of tetrahydrofuran under dry
nitrogen atmosphere heated to reflux was added a ~olution
` of 10.42 g (o.o~8 mole) of 4-chloro-7-(trifluoromethyl)-3
quinolinecarboxylic acid and 3.81 g (o.o~B mole) of N-methyl-
3-pyrrolidinol in 50 ml of tetrahydrouran at such a rate
as to maintain good reflux. Heating at reflux was continued
~; for ~ hr. The solvent was removed by rotary evaporation
(80C., 30 mm), and the crude sodium salt (12 g) was dried
; overnight.
The entire amount of crude sodium salt was suspended
in 250 ml of methylene chloride. Hydrogen chloride was
added to a pH of 2. To this suspension was added 19.4 g
(0.074 mole) of triphenyl phosphine and 19.4 g of car~on
tetrachloride. The extire mixture was heated to reflux for
3 hrs. IR indicated presence of acid chloride7 therefore~
the reaction was driven to completion by the addition of
15 ml of tri~thylamine. After cooling, the reaction mixture
was ex~racted with 2 x 75 ml of 3N hydrochloric acid~ The
acid washings were combined and washed with 75 ml of
~o methylene chloride. The water layer wa~ made ~a~ic (after
cooling with ice) and extracted with 3 x 75 ml methylene
chloride. Th~ methylene chloride was removed by rotary
evaporation and the re~idue taken up in 100 ml of toluene.
The solution was treated with acti~ated charcoal, filtered,
and concentrated by rotary evaporation (90~ 0 mm~. The
residue was dissolved in isopropyl alcohol and acidified
with ethereal hydrogen chloride. Appr~ximately 1.1 g (7.~)
of white needles were collected, m~p. 17~-174 C.
419A-CIP-
~Z4~i6~7
79
Analysis: calculated for Cl~Hl5N202C12F~: C,48.63; H,3.83;
N, 7.og
Found : C~48.78; HJ~.84;
N,7.04
Intermediate 49
2-(2-Chlorophenyl)-2,3-dih~dro-4-methyl-9-(trifluoro-
meth~ 1,4-oxazepinor~i,7-c]quinoline-C,(4H)-thione.
To a suspension of 0.85 g (.004 mole) of phosph~rus
pentasulfide in 25 ml of acetonitrile was added to a solution
of 2.3 g (o.oo64 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-
methyl-9-(trifluoromethyl)-1,4-oxazepino~6,7-c~quinolin-
5(4H)-one and the mixture heated tQ reflux. TLC in ethyl
acetate showed only 50% conversion; therefore, 0.5 g
(0.0022 mole) of phosphoruspentasul~ide was added. Ater
an additional 2 hr, no change was seen in starting material/
product. ~eat was removed and the reaction mixture left
standing overnight. The mixture was diluted with 75 ml
of toluene and washed cautiously (gas evolved) with 3 x 50 ml
of saturated sodium bicarbonate. The 601vent was removed
by rotary evaporation and the residue combined with a
20 previous run of the same material. The combined products
were purified by column chromatography over silica gel
eluting with ethyl acetate. The solvent was removed frQm
the fractions containing the product giving O.g y of yellow
oil. The oil was recrystallized from isopropyl ether
giving 0.55 g of yellow crystals, m.p. 1~5-37C.
Analysis: Calculated for Cl~Hl4N20SF3Cl: CJ51.27; H,3.77;
N,7.47
Found : C,51.41; H~o83
N,7.4
Intermediate ~0
302 -ChloromethYl~ ,4-tetrahyd o~ y~_4-(1-methYl-
ethyl)-5~ 4-benzcdiazepin-5-one_.
To a stirring solution of 266 ml (o.64 mole) of ~.4 m
butyllithium solution in hexane, was slowly added 117.5 g
(o.58 mole) of ~-methyl-~-phenyl-l-(l-methylethyl~
~5 azetidineami~e. The temperature of the mixture xose to
55C. which was then allowed to reflux for 5.5 hours.
When co~led, the solution was poured slowly with ~igorous
419A-CIP-
~.2~5~47
stirring onto a slurry of dry ice in hexane and allowed to
stand overnight. The residue was di~solved in chloroform
and 117~0 g (1.16 mole) of phosphorous oxychloride was added
dropwise while stirring. The solution was refluxed for two
hours. Upon cooling, the solution was washed, first with a
dilute hydrochloric acid solution, then with a dilute sodium
hydroxide solution. The hexane l~ycr was dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo.
The residue was dissolved in hot isopropyl ether. The
crystals obtained on cooling were recrystallized from the
same solvent. The white solid weighed 45.0 g ~29%)~ The
solid was recrystallized twice more to give an analytical
sample, m.p. 90 92C.
Analysis: calculated for Cl4~l~CllN20: c,6~.o3, H,7.18;
N,10.50
Found : C,62.59; H,7.09,
N,10.40
Intermediate ~1
2-(2-ChloroethYl)-4-ethyl-1-methvl-1.2,3,4-tetrahvdro-
5H-1 4-benzodiazepin-5-one
To 206 g (1 mole) of 1-ethyl-3-methylanilinopyrrolidine
was added 660 ml (1.05 moles3 of 14.98~ butyllithium in
hexane and the solution refluxed for 2 hours and poured on
solid carbon dioxide. The carbon dioxide hexane mixture was
allowed to evaporate overnight, leaving a dry yellow solid.
The solid was dissolved in chloroform. To this solution was
added dropwise with stirring 1 mole of phosphorous tri-
chloride. The temperature rose to reflux during addition
and remained there throughout most of the addition. when the
` addition was completeJ the mixture was stirred one hour and
water was added cautiously. The resulting mixture was made
basic with sodium hydroxide. The chloroform layer was
separated, dried over anhydrous ~odium sulfate and concen-
trated. The residue was crystallized from isopropyl ether
to yield 112 g (42 O J m p. 75-79 C. A 25 g sample was
~5 recrystallized from isopropyl ether to give 18 g of product,
m.p. 78-80C.
Analysis: Calculated for Cl~Hl3N~OlCl: c,63.o3; H,7.18;
~ ,10.50
Found : C,63.27; ~,7.22;
N/10.55
~L245647 419A-CIP
81
Intermediate ~2
6-Chloro-2-(2-chloroethyl~-2.'3-dihydro-4-methYlPYrido
C4,~-f;L-1.4-oxazePin-5(4H-one.
To a suspension of 2.1g (60% in oil, 0.052 mole) of
sodium hydride in 125 ml of dimethylformamide heated to 60 C.
under a nitrogen gas blanket was added a solution of 2.65 g
(0.026 mole) of N-methyl-~-pyrrolidinol and 5.0 g (0.026
mole) of 3,5-dichloropyridine-4-carboxylic acid in 40 ml of
dimethylformamide dropwise at such a rate as to maintain
60C. Subse~uent to this addition, the mixture was heated
to 75 C. for 3 hr. The solvent was then removed by rotary
evaporation (60C., 5 mm). The entire solid residue was
suspended in 150 ml methylene chloride and hydrogen chloride
added until ~ pH of 3 was reached. To the resulting mixture
was added 15 g (0.057 mole) of triphenylphosphine and 15 g
carbon tetrachloride and the entire mixture heated to reflux.
After 1 hr, 7.5 g (0.029 mole) of triphenylphosphine and
7.5 g carbon tetrachloride were added, followed by the same
increments 1 hr later. The reaction was driven to completion
by adding 20 ml of triethyla~ine. The reaction mixture was
washed with 6 x 50 ml of 3N hydrochloric acidJ dried o~er
sodium sulfate, filtered and concentrated by rotary
evaporation. To the residue was added ethyl acetate, which
caused much tarry material to fall out of solution, leaving
the desired product and triphenylphosphine oxide in ~olution.
; 25 The mixture was chromatographe~ by column chromatography
using silica gel as the stationary phase and ethyl acetate
as eluent. Similar fractions were combined and ethyl
acetate removed by rota~y evaporation, yielding o.6 g (7%),
; of white crystals, m.p. 134-~8C.
Analysis: Calculated for CllHl2N202Cl2: C,48.02; H,4.40
~ ,10.18
Found : C,47.89, H,4.38;
N,10.12
~7 419A-CI
82
Intermediate ~
2-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino
L7 6-f~isoquinolin-5(4H)-one.
~ ollowing the procedure of Intermediate 8, 5-~(1-methyl-
~-pyrrolidinyl)oxy~-6-isoquinolinecarboxamide is converted
to the title compound.
Intermediate ~4
2-(2-chloroethyl)-2,3-dihydro-4-m~thyl-1l4-oxazepino
r7.6-f~isoq_1noline-~(4H)-thione.
Following the procedure of Intermediate 47, 2-(2-
chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino~7,6-f]
isoquinoline-5(4H)-one is sulfurized to give the title
compound.
Intermediate ~
2 (2-Chloroethvl)-2,3-dihvdro-4-methyl-1,4-oxazepino
r 6.7-qlisoquinolin-5(4H)-one.
~ollowing the procedure of Intermediate 8, 7~
methyl-~-pyrrolidinyl)oxy~-6-isoauinolinecarboxamide is
converted to the title compound.
Intermediate ~6
? -(2-ChloroethY1)-2~-dihydro-4-methYl-1 4-oxazepino
E6~7-q~isoquinoline-5(4H)-thione.
Following the prscedure of Intermediate 47, 2-(2-chloro-
ethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-g~iso~uinolin-
5(4H)-one is sulfurized to give the title compound.
Intermediate ~7
2-(2-chloroethvl)-2~-dihydro-4.7-dimeth~ 4-oxazepino
r6l7 h]quinolin-5(4H)-on~.
Followins the procedure of Intermediate 8, 5-methyl-
8-~(1-methyl-3-pyrrolidinyl)oxy~-7-quinolinecarboxamide is
converted to the title compound.
Intermediate 58
2-(2-ChloroethY1)-2~ -dihydro-4.7-dimethyl-1~4-oxaze~
L6,7-h~quinol~ne-5(4H)-thione.
Following the procedure of Intermedi~te 47, 2-(2-chloro~
ethyl) -2 ,~-dihydro-4,7-dimethyl-1,4-oxazepinot6,7-h~ouinoline-
5(4H)-one i~ sulfurized to give the titl~ compouna.
419A-CIP-
564~'7
8~
Intermediate
2-t? -Chloroethvl)-2 3-dihy~ro-4~10-dimethy~ 4
oxazeRinor6~7-h]quinolin-5(4H~-one.
Followinq the ~rocedure of Intermediate 8, 2-methyl-
8[(1-methyl-3- pyrrolidinyl)oxy]-7-quinolinecarboxamide is
converted to the title compound.
Intermediate 60
? - (2-Chloroethyl)-2~3-dihydro-4l10-dimethyl-1,4-
oxzaepino[6,7-hlquinoline(5-4H)-thione.
. . _
Following the procedure of Intermediate 47J 2-(2-chloro-
ethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino~6,7 h~
~uinoline-5(4H)-one is sulfurized to give the title compound.
Intermediate 61
2-(2-chloroethyl)-3~=dihydro-2-methyl 1,4~ oxazepino
r6,7~flqUinOlin-1(2H)-one
Following the procedure of Intermediate 8, 6-~(1-
methyl-3-pyrrolidinyl)-oxy]-5-quinolinesarboxamide is
converted to the title compound.
Intermediate 6?
4-(2-Chloroethyl)-31~-dihydro-2-methYl r 1~ 4-oxazepino
L6,7-f~quinoline-1(2H)-thione.
Following the procedure of Intermediate 47, 2-(2-
chloroethyl)-~,4-dihydro-2-methylrl,4~-oxazepino~6,7-f]
quinolin-1(2H)one is sulfurized to give the title compound.
Intermediate 6~
2-(2-chloroethYlJ-2,3-dihydro-4-methyl-1~4-oxa epino
t6,7-h~uinolin-~(4H)-one.
Following the procedure of Intermediate 8, 8-r(l-methyl-
3-pyrrolidinyl)oxy~-7-quinolinecarboxamide i~ converted to
the title compound.
Intermediate 64
2-(2-chloroethyl~-2,3-dihydro-4-methyl-1,4-oxazepino
,7-h]quinoline-5(4H)-thione.
Following the procedure of Intermediate 47, 2-(2-chloro-
ethylJ 2,3-dihydro-4-methyl-l,4-oxazepino~6J7-h]quinolin
5(4H)-one is ~ulfurized to ~ive the title compound.
419A-CIP-2
56~7
84
Tabl~ 1
R
.,~ (E ~ (CH)n-X
B
~nter- Rs
, A(Y)0-2 ~ R R4 E X ~(CH)n~ Salt
1 benz O -CR~ ~ O Cl -~CE2 2-
2 benz O -CHz-C~H~ ~ Cl -sCH2 2- -
n~phtht2,3-f~ O -CH3 H O Cl _ CH2 2 -
4 Dyrido[~,2-~] O -CH~ H O Cl ~ CHz 2- HCl
B-cl-benz O -CH~ ~ O Cl _ CH2 z_
7-Br-benz O -CH9 ~ O Cl ~ CH2 2-
7 7-Cl-benz O -CH9 ~ O Cl _ CH2 2-
8 naphth~2,1-f~ O -CH9 ~ Cl ~ CH2 2 -
9 7-OCB9-benz O -CH9 H O Cl - CH2 2-
10 benz S -CH3 H O Cl ~ CH2 2-
11 pyridot~,2-f~ S -CH9 H O C1 _ CH2~2-
12 naphth~2,3-f~ 5 -CH3 ~ Cl _ CH2~2 -
13 8-Cl-benz S -CH9 ~ O Cl CH2~z-
: 14 7-Br-benz S -CH9 ~ Cl _ CH2~2-
naphthE2,1_f~ S -CH9 ~ O Cl _ CH2~2- HCl
lB pyridot2,~-f~ O -CH3 H O Cl -5CH2 2- HC1
19 7-Cl-benz S -CH9 H O Cl -~CH2 2-
20 7,9-diiodo-benz O -CH3 ~ Cl -~CH2 2-
~ 21 pyrido~3,2-~] S -CH~ H O Cl - CH4- HCl
.~ ~2 pyridor4,3-~ S -CH9 H O Cl _ CHz)2-
23 7-OCH3-benz S -CH~ H O Cl ~ CH2 2- -
~24~ benz O -C~Xll ~ O C1 _ CH2 2 -
:~b benz O -C2HS ~ O C1 ~ C~2 2-
~ benz O -CH(CH9)2 ~ O Cl - c~2 2-
d benz O 4-Cl-Co~-CH~- ~ O Cl ~ CH2 Z~
e benz 0 4-CH~-C~H~-C~2- ~ O Cl _ CH2 2- ~
benz ~ 3,5-~OC~s)2~ ~ O Cl _ CH2 2- -
CO~ -CH2-
g) benz O 3-CF~-C~H~-CH~- ~ O Cl -5CH2~2- -
~) ~enz O 4-~2-CeH~-C~a- H O Cl -~CH2 ~2-
25a) pyrid~t3,2-~ 0 ~Ca~ Cl -~CHk 2- HCl
b pyrido~3,2-f ~ O -C2~g E~ O Cl ~ CH2 ;~~ HCL
pyridot3,2-f] 0 -CH(CH9)2 ~ Cl CH2 2- ~Cl
. d pyridot3,2-f~ O 4-Cl-C~H4-C~2- R O Cl ~ CH2 2- HCl
: ~ pyridot3,2-~] 0 4-CH -CoH~-CH~- ~ O Cl ~ CH2 2- HCl
f pyridot3,2-f~ 0 3,5-~OCH~)2- R O Cl _ C~2 2- HCl
C ~,H ~C}~2 -
g) pyridot3,2-f] O 3-CF~-C~H4-C~2- ~ O Cl -(CH212- HCl ;:
h) pyridot3,2-f] O 4-No2-CoH~-CH2- ~ O Cl -~C~)2- HCl
26 ~yri~ot3,2-~ 0 -CR~ H S Cl -~C~
27 pyri~o~,2-~ S -C~ Cl -~CH2)2-
( cont . )
419A-CIP-~
S6~7
Table l_( ccnt .l
Inter- ~5
mediate 4 ~
No. A(Y~0-2 B R R E X ~~CH)n- 5alt
28 pyrido~3,4-f] 0 -CH3 H O cl _ CH2~2
29 pyrido~3,4-f] S -CH3 H O Cl _ CH2 )2 - HCl
pyrido~3,2-f~ 0 -CH3 H O --CN _ CH2 )2-
31 pyrido~3,2-f~ 0 -C2Hs H O cl _ CH2)2- HCl
32 pyridor3,2~f] S C2Hs H O cl _ CH2~2- HCl
33 7-Cl-pyrido O -CH3 H O cl -~CH2 )2-
34 7r-3Cl-pyrido S -CH3 H O Cl ,-(CH2)2-
pyridor3,2-f~ 0 -C~Hll H O cl -CH2-
36 pyrido~3,2-f~ 0 ~CH2C9Hej H O Cl -(CH2 )2-
37 pyridot3,2-f~ 0 -CH3 B O l-phtha-
limido - CH2)2-
38 pyridor3,2_f~ S -CH3 H O ., _ CH2~2- ~
39 pyridot3,2-f~ S -CH3 H O CN _ `H3
pyrido~3,2-~ 0 -CH3 H O Cl -C-CHz- HCl
41 pyrido~3,2-f~ 0 -CH3 -CH3 0 Cl _ CH2~2- HCl
42 pyridot3,2-f~ 0 -CH3 -CH3 0 Cl _ CH2)z-
43 pyrido~3,2-f~ 0 -CH3 H O Cl -CH2-C-Cl HCl
cHH3
44 pyrido~3,2-f~ S -CH3 H O Cl -CH2-C-Cl HCl
C~H3 H
pyrido~3,2-f~ 5 -CH3 H O Cl -C-CH2- HCl
~ O -CH3 H O cl -(CH2 )2-
47 ~ S -CH3 H Cl -(CH2 )2 - - -
48 ~ O -CH3 H O Cl -(CH2 )2- HCl
CF3 E
49 ~ S -CH9 H O Cl -(CHz )2
CF9 N CH3
benz O -CB(CH3)2 H ~N~ Cl -C~2-
51 benz O -C2H~; H ~ Cl -(CH2 )2 -
52 6-Cl-pyrido O CH3 H O Cl -(C~2 )2-
t 4~3~f~E
53 N~ O -CH3 H O Cl -~CH2)2-
54 ~ ~ S -CH3 H O Cl -(CH2)2-
(cont.
419~-CIP-2
~Z~5~7
86
Table l (cont.
~nter-
mediate R5
No. _ A(Y~o-2 B R R4 ~ X ~(CH)n~ Salt
~ O -CH3 H O Cl -(C~b)2- ~
N ~ S -CH3 H 0 cl -(C~2)2- ~
57 ~ o -CH3 H 0 Cl -(CH2)2
,
58~ S -CH3 H . 0 Cl -(CH2)2- ~
CH3
59~ 0 -CH3 H 0 Cl -(CH2)2-
60C~ ~ S -C~3 ~ ~ cl -(C~: ~2
61~ E 0 -CH3 H 0 Cl -(CH2)2
6~~ S -CH3 H 0 Cl -(CH2)2
6~~ o - CH3 H 0 Cl -(CHZ)2
64~ s - CH3 H 0 Cl -(CHz~2
) 4lgA -cI~
i6~7
87
2-r2-(DLmethylam no~ethyll-2,3-dihydro-4-methyl-1,4-
benzoxaz~ n- ~ e hydrochloride.
A ~olution of 9 9 (0.2 mole) of dimethylz~mine in 250 ml
of ethanol was added to 24 9 (0.1 mole) of 2-~2-chlorG-
ethyl)-2,~-dihydro-4-methyl-1,4-benzoxazepin-5(4~)one in
a steel bomb. ~he mixture wa~ heated ~t 100C. for 18 hrs.
The solution was concentr~ted 'n vacuo and the re~idue
partitioned between ethyl acetate and dilute ~odium
hydroxide. The ethyl acetate layer wa~ concentrated and
the re~idue cQmprised ~ub~t~ntially of the free base of
the title compound was dissolved in methyl i~obutyl ketone-
isopropanol mixture. The ~olution was acidified with
hydrogen chloride gas to give the title compound, m.p.
188-197C.
Example 2
2-~2-(Dimethylamine)ethyll-2 ,3-dihydro-4-methyl-1,4-
benzoxaze~ine-5(4H)-one.
All of the hydrochloride ~alt obtained in Example 1
was partitioned between chloroform ~nd dilute ~odium
hydroxide ~nd the chloroform layer concentrated. The
r~sidue was crystallized several time6 from isopropyl ether
to give 6 g (21%) of the ~ree ba~eJ m.p. ~6-76C.
Analysis: Calculated for C~H2o~202: C,67.72; H,8il2,
Found : C,67.35; H~B.l6;
~,11.~9
Exampl~ ~
?,3-D_ ydro-4-methyl ~ 2-(4-morpholino)ethyl~-1,4-
benzox~zepin-5(4~)-one fumar~te tl~
~ o 50 ml o~ morpholine W~B ~dded 20 g (o.o84 mole) of
~0 2~(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-benzoxazepine-
5(4H)-one. The ~olution W~8 refluxed for 5 hr~ and then
concentr~ted in vacuo. ~he re idue w~s dissolved in
~hloroform, ~nd the ~olution w~ washed with ~ilute ~odium
hydroxide, ~ried over ~odium ~ulf~te and concentr~ted in
~5 va~uo. $he residue comprised 0ub~tantiAlly ~f the free
~2~56~ 4l9A-cI~2
88
base ~f the title compound was reacted with 10.5 g
(0.09 mole) of fumaric acid in i~opropanol-water. The
resulting ~olid wa~ recrystallized from i~opropanol-water
to give 21.5 g (64%), m.p. 199-201C.
Analysis: calculated for CzoHz~N207: C,59.10; ~,6.45,
N,6.89
Found : C,~8.95; ~,6.52;
N,6.88
ExamPle 4
4-Benzyl-2,~-dihydro-2-r2-(4-morpholino~ethyll-1,4-
benzoxazepin-5(4H~-one.
To 200 ml of morpholine was added ~0 g (0.095 mole)
of 4-benzyl-2-(2-chloroethyl)-2,3-dihydro-1,4~benzoxazepin-
5-t4~)-one. The solution was refluxed for 3 hrs and then
concentrated ~n vacuo. The residue was partitioned between
dilute sodium hydroxide and chloroform. The chloroform
layer was dried over ~odium 6ulfate and concentrated in
vacuo. The ~olid obtained was recrystallized Xrom i~opropyl
; ether-ethyl acetate three times to give 15.2 g of solid
; (4~ 0, m.p. 97-99C
Analysis: Calculated for C~2H4~NZ0~: C,72.10; H,7.15,
N,7.64
Found : C,72.25; H,7.22,
N,7.64
Example ~
4-Benzyl-2,3-dihydro-2-r2-(methylamino~-3-ethyll-
lJ4-benzoxazep_n-5(4~)- ne_fumarate rl:ll.
A solution of 5.95 g (0.19 mole) o~ monomethylamine
in 200 ml of ethanol wa~ ~dded to 30 g (0.095 mole) of
4-benzyl-2-(2-chloroethyl~-2,3-dihydro-1,4-benzoxaz~pin-
5(4~ ne in a Gteel bomb. The mixture w~s heated at
~0 100 C. for 16 hr. The solution was concentrated in acuo
and the re~idue partitioned between chloroform ænd dilute
; aodium hydroxide. The chloroform layer was concentrated
and the residue comprised 0ub~t~ntially of ~he free base
of the ti~le comp~und was dissolved in isopropanol and
reacted with fumaric acid to giv~ the fumar~te. The salt
wa~ dried under vacuum ~t lO0 C0 until entrapped isopropyl
. ` ~Z~56~7 , 419A-CIP~2
8~
alcohol was removed, m.~. 178-81 C.
Analysis: Calculated fvr C23H2~N2O~: C,64.77; H,6.15;
~,6.57
Found : C,64.87; H,6.20;
M~6.62
Example 6
2-~ -(DimethYlamino)ethyl~-2~3-dihy~ro-4-methv~ 4
benzoxazePine-5(~H)thione hydrochloride r ~
~o a solution of 7.2 g (0.16 mole) of dimethylamine
in 350 ml of absolute ethanol was added 20.4 g (o.08 mole)
~f 2-(2-chloroethyl)-2J3-dihydro-4-methyl-1,4 b~nzoxazepine-
5(4H)thione. The solu ion was heated in a steel bomb for
18 hr at 10~ C. and then concentrated. The reqidue was
partitioned between ehloroform and dilute sodium hydroxide.
The chloroform layer was dried over ~odium sulfate and
~oncentrated. The ~olid comprised ~ubstantially of the
free ~ase of the title compound was reacted with hydrogen
chloride gas in ethanol to give the hydxochloride salt.
The salt was recryst~llized from ethanol ~nd dimet~yl-
formamide followed by three recrystallizations from ethanol
20 to give 7.5 g (280 , m.p. 2~-2~6C.
'~ Analysis: Calculated for Cl~H2lN2SOC1: C,55.90; H,7.o4;
N,9.~2
Found : C,55.72, H,7.26;
~,8.94
` Example 7
4-Benzyl -2 I2-~ imethylamino~ethyll-?,~-dihydro-
1,4-benzoxazepin-~ )-one monohydrate.
Following the procedure of Example 1, 4-benzyl-2-
:' (2-chloroethyl)-215-dihydro-1,4-benzoxazepin-5(4H)-one
and dimethylamine were reacted and the free base of the
title compound was ~btained in t~e concentrated residue.
Recrystallization from ethanol-water gave the product, m.p.
75-77C.
Analysis: Calculated for C~OHZO~O3 CJ7O.1~; RJ7.65; ~,8.21
Found ~ C~70.02; ~J7~5~; N~8-25
.
419A-CI~2
56~ ~
~ .
2,3-Dihydro-4-methyl-2-r2-(4-morpholino)ethyll-1,4-
benzoxazepin~(4H)-thione hydrochloride ~1.1~.
A solution of 20.4 g (o.o8 mole) of 2,3-dihydro-4-
methyl-2-(2-chloroethyl)-1,4-benzoxazepin-5(4H)-thione
in 60 ml of morpholine was refluxed for 5 hr. then
concentrated. The residue was partitioned between dilute
sodium hydroxide and chloroform. The chloroform layer was
dried over ~odium sulfate an~ concentrated to give a
residue ~omprised ~ubstantially of the ~ree base of the
title compound. The hydrochloride ~alt was prepared in
methyl isobutyl ketone-dimethylformamide ~olution with
hydrogen chloride gas. The salt was recrystallized from
ethanol-dimethyl~ormamide to give 14 9 solid (51 0 ,
m.p. 253-256C.
15 Analysis: Calculated for C1BH23N2SO2C1: C,56.04; H,6.76,
N, 8.17
Found : C,55.7~; H,6.63;
N,7-97
ExamPle 9
; 2-~2-(Dimethylamino)ethyl 1-? 3-dihydro-4-methylnaphth
20 ~2,3-f 1r 1,41-oxazepin-5(4H)-one oxalate r ~
A steel bomb was charged with 5.0 g (0.017 mole) of
2-(2-chloroethyl)-2,3-dihydro-4 methylnaphth~2,3-f~c1,4~
oxazepin-5(4H)-one, 50 ml of absolute ethanol and 3.78 g
(0.034 mole) of dimethylamine 8S 40% aaueous ~olution. The
25 bomb was he~ted at 100C. ~or 16 hr. Volatiles were removed
under reduced pre~su~e ~nd the residue partitioned between
chlorofo~m and 15% aaueous sodium hydroxide. The chloroform
layer was w~shed twice with water9 dried over magnesium
~u}fate and concentrated under reduced pressure to give 2.7 9
~; ~0 (54,~) of vi~cous yellow oil compri~ed subst~ntially of
the ~ree ba~e of the title compound. The oil was dissolved
in isopropyl alcohol ~nd reacted with oxalic ~cid. The
~xalate s~lt Wa8 recrystallized from ethanol-w~ter, m.p.
~ l~e-19~C.
: 35 Analysis: Calculated for C20H2~N20~: C,61.84; ~,6.23; N,7.21
Found : CJ61.4~ 6.27; ~J7.09
~2456~7 i 419A-CIp-~
91
ExamPle 10
2-r2-(Dimethylamino~ethyl~-2,3-dihydro-4-methylpyrido
t3,2-f~1,43-oxazepin-5(4H?-one fumarate ~2:3~.
To 90 g (o.8 mole) of 40% a~ueou~ dimethylamine in a steel
bomb waC added 25 g (0.09 mole~ of 2-(2-chloroethyl)-2,3-
dihydro-4-methylpyrido~,2-f]~1,4]-oxazepin-5(4~)-one
hydrochloride. The mixture was heated to 100C. for 15 hr
under mild ~gitation. The mixture was partitioned using
dilute sodium hydroxide and two chloroform extractions.
~he chloroform layexs were combined and concentrated. The
residue comprised substantially of the free ~ase of the
title ~ompound was dissolved in 200 ml of isopropyl alcohol
and 9 g of oxalic acid added. The oxalate salt was
recry~tallized from 95~ ethanol to give 18 g. The oxalate
salt was then converted to the free base by partitioning
between chloroform and dilute sodium hydroxide and
evaporating the chloroform layer. The re~idue, the free
base of the title compound, was dissolved in isopxopyl
alcohol and reacted with fumaric acid to give 13 g of white
solid (34%), m.p. 146-148C.
20 Analysis: calculated for ClaH25N30~: C,53.90; HJ5.9O,
N,9.92
Found : C,53.76; H,6.o2, -
N,9.96
ExamPle 11
2 -r2 - ( Dimethylamino)ethyll-2,3-dihydro-4-methylpyrido
~- 25 r~J2-f~l,4~-0XazePin~-5(4H)-thiOne fuma_ate Compound with
ethanol ~ :0.5]
To a 301ution of 32.8 g (0.29 mole) of 40~ aqueous
dimethylamine and 100 ml of ethanol in ~teel bomb was added
15 g ~0.058 mole) of 2-(2-chloroethyl~-2,~-dihydro-4_
methylpyridot3,2-f~tl,4~-ox~zepine-5(4~)-thione. The
~` ~ixture was heated to 100 C. for 18 hr under mild agitation.
The ~olution was cooled and partitioned between chloform
and dilute ~odium hydroxide. ~he chloroform layex was
~ried over ~odium ~ulfate and concentrated. The residue
comprised ~ubqtantially of the free base o~ the title
compound wa6 dis~olved in isopropyl alcohol and re~cted
419A -CIP-2
~Z~56~7
92
with 7 g of fumaric ~cid. The fumarate ~alt was recrystal-
lized from ifiopropyl ~lcohol to give 19 g (86~), m.p.
105-129 C. A 14 g sample ~f the ~alt was recry tallized
from ethanol to give 10.5 g yellow solid, m.p. 103-118 C.
The ~MR spectra indicates th~ crystals contain 1~ mole
ethanol.
Analysis: Calculated for C3~H52N~0ll52: C,53.45; H,6.48:
N,10.39
Found : C,53.07: H,6.53;
N,10.23
Example 12
2-~2-(Dimethylamino?ethyll-2,3-dihydro-4-methylpyrido
r3,2-f][1,49-oxazepine-5(4H)-thione fumarate ~
To a solution of 113 ml (1.0 mole) of 40~ aqueous
dimethylamine and 326 ml of ethanol in a ~teel bomb was
added 48.4 g (0.189 mole) of 2-(2-chloroethyl)-2/~-
dihydro-4-methylpyridoC3,2-f~lJ4~-oxazepine-5( 4H)-thione .
The mixture was heated at 100C. for 14 hr. The ethanol
was removed in a rotary ev~porator leaving some water in
the residue. Th~ residue wa~ dissolved in 200 ml of
methylene chloride and washed with three 100 ml portions
of 20% aqueous potassium carbonate solution. The combined
aqueous layers were extracted with three 150 ml portions of
methylene chloride. Methylene chloride ~olutions were
combined and treated with charcoal. Charcoal was filtered
2~ off and the ~iltrate wa~ ~vaporated to give an oil. The
oil was di~solved in 215 ml isopropyl alcohol and the
solution was heated to n ~low boil. A solution of 21.9 g
(0.19 mole) of fumaric acid in 150 ml of boiling methanol
was added to the isopropyl alcohol ~olution. Cry~talline
~olid was obtained weighing 6~.4 g (880 . The solid was
recrystallized rom hot 200 proof ethyl ~lcohol. The
~rystal~ were filtered off and triturated in i~opropyl ether
at room temperature and again separated by filtering.
After ~rying in a ~a~uum oven overnight at ~ ~C., crys~als
~5 in the ~mount of 72.45 g (790 , m.p. 1~0~133c.,were
obtained.
~naly~ Calcul~ted for Cl7H~gN30sS: c,53.s3; ~,6.o8; N,11.02
Found : C,53.23; H,6.11; N,10.64
5 ~ ~ ! 4l9~-cIp-2
~3
~xample 17
4-Benzyl-2,~-dihydro-2-t2-(4-morpholino)0thyll-1,4-
benzoxaze~_ne-~ 4H)-thione.
To a 3u~pension of a finely ground mixture of 2.9 g
(0.013 mole) of pho~phorus pentasulfide ~nd 2~9 g of
5 potassium ~ulfide in 75 ml of dry toluene was added 12 g
(0.033 mole) of 4-benzyl-2~3-dihydro-2-[2-(4 morpholino)
ethyl~ 4-benzoxazepine-5(4H)-one. The mixture was
stirred at r~flux for 10 hr. and filtered. The filtrat~
was concentrat~d and the re~idue crys~allized from
isopropyl ~ther-toluene to give 2.54g (20%), m.p. 236-
238C.
Analysis: Calculated for C22H2~N202S: C,69.08; H,6.85;
N,7.~2
F~und : C,69.60; H,6.96;
N,7-15
ExamPle 14
2,3-Dihydro-4-methyl-2-~2-(methylamino)ethyl~-1,4-
benzoxazepin-5(4H)-one fumarate tl~
Following the procedure of Example 5, 50 g (0.21 mole)
of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1 J 4-benzoxazepin-
5(4H)-one and 13.0 g (0.42 mole) of monomethylamine (in
400 ml ethanol) were reacted to give the free base of the
title comp~und which was reacted with fumaric acid to give,
nfter i~olation and recrystallization from ethyl alcohol,
17 g (23%) of the title compound, m.p. 154-156C.5 ~nalysi6: Calculated for C~7H22N2O~: C,58.27; H,6.~,
N,8.oo
Found ~ cJ58~34î H,6.52;
N,7.~2
2,~-Dihydro-4-methyl-2-r2-~methylamino~ethyll-1,4-
0 benzoxazepin-5(4~)-one.
2"3-Dihydro-4-methyl-2-r2-(me'chylamino)ethyl~-lJ4-
benzoxazepin-5(4~)-one fumarate was converted back to the
free base by partitioning in dilute ~odium hydroxide ~nd
chloroform. Evaporation of the chloroform layer ~nd
di~tiliing, b.p. 182/0,2 ~m, gave 4.3 g of the product.
Analysi~: Calcul~t~d for C35~eN~2: C~66.64; ~7.74; NJ11.96
Found : C,66.48; H!7~69; N,11.88
415~cIP-c
;6~7
94
Exam~e 16
2~3-Dihydro-2-L2-(4-hydroxy~4-phenyl)-piperidin
ethyl~-4-methyl l~4-benzoxazepine-s(4H)-th~one (and
hydrochloride salt.)
A suspension of 10.7 g (0.078 mole) of potBssium
carbonate, 13.7 g (0.078 mole) of 4-hydroxy-4-phenyl-
piperidine and 19.8 g (0.078 mole) of 2-(2-chloroethyl)-
2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in
200 ml of n-butanol was refluxed overnight. The mixture
was filtered and ~he filtrate concentrated in vacuo.
The residue was d~solved in ethanol-ligroin and reacted
with hydrogen chloride gas to give the hydrochloride
salt which was recrystallized from ethanol-dimethyl-
~ormamide. The hydrochloride salt was converted back to
the free base by partitioning in chloroform and dilute
sodium hydroxide and evaporating the chloroform. Recry~tal-
lization twice rom isopropyl alcohol gave 9.27 g (30~)
product free base, m.p. 142-148C.
Analysis: calculated for C23N2BN2OzS: C,69.66; H,7.12;
N,7.07
Found : C,69.78, H,7.18;
N,7.00
Example 17
2,3-Dihydro-4-methyl-2-r2-rl-(4-phenyl-1,2,3,6-
tetrahydro)pyridinyl lethyl ]-1, 4-benzoxazepine-5( 4H) thione .
A su~pen~ion of 24.~ g (0.176 mole) of potassium
carbonate, 11.5 g (0.059 mole) of 4-phenyl-1J2,3,~-tetrahy~ro-
pyridine and 15 g (0.059 mole) of 2-(2-chloroethyl)-2,3
dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione and enough
n-butanol to form a slurry were refluxed for 72 hr. The
reaction mixture was filtered hot and the filtrate cooled
to room temperature and refiltered. The last filtrate ~as
concentrated and the re5idue dissolved in ethyl ~cetate.
The crystals obtained on cooling were recry~tallized fr~m
ethyl ~cetate to give 7 g of product (31O , ~.p. 153-155 C.
Analysi~: Calcul~ted fo~ CzsH2~N2S: C,72.98; H,6.92, N,7.40
Found : CJ73.~6: ~,7.01: N,7.47
5~ 9A-Cl~-2
9~
Example 1 8
methy~ 4-benzoxaze~-ne-~4H~-thione hydr~chloride tl~
A solution of 9.8 g (0.04 mole) of 8-chloro-2-
(2-chloroethyl)-2,~-dihydro-4-methyl-1,4-benzox~zepine-5
(4H)-thione in 50 ml of absolute ethanol and 10 ml of a
40% aqueous ~olution of dimethylamine were mixed and heated
in a ~teel bom~ ~t 100C. ~or 16 hr. The ethanol was
evaporated under reduced pressure and the residu~ dissolved
in chloroform and partitioned with 10~ ~odium hydroxide
10 ~olution. The chloroform layer was evaporated under
reduced pressure to give an amorphous ~olid. The solid
was dissolved in 6N hydrochloric acid and the solution
washed with ethyl acetate. The a~ueous layer was baqified
with 50% ~odium hydroxide and extracted with ethyl acetate.
15 The ethyl acetate layer was evaporated under reduced
pressure to give a viscous oil compri~ed substantially of
the free base of the title compound whi~h was di~s~lved
in absolute ethanol and rea~ted with ethereal hydrogen
chloride. The hydrochloride salt was recrystallized from
ethanol to give 30 9 (25 O product, m.p. 196-199 C.
Analysis: Calculated for C 1 4H2 0~2 C12 OS: C,50.15; ~,6.01,
~,8~35
Found : C~50.15; H,6.18;
N,8.07
Example 1
8-Chloro-2-r2-(dimethylamino)ethyll-2J3-dihydro-4
L _ _ , _ _
methyl-1,4~benzoxæzepin-5(4H~-one oxalate rl:ll.
A solution of 10 g (0.0~7 mole) of 8-chloro-2-(2-
chloroethyl)-2~3-dihydro-4-methy~ 4-b~nzoxazepin-5~4H)
one in 50 ml of ab~olute ethanol and 10 ml of 40~ a~ueous
~olution of dimethylamine were mixed ~nd heated in a 3teel
bomb at 100C. ~or 16 hr. The 801ution wa~ concentrated
under reduced pressure and the residue di~olved in ~hloro-
form and partitioned with 15~ sodium hydroxide (2 washes).
The chloroform layer was dried over magne~ium ~ulfate and
~5 evaporated under r~duced pressure to give ~n oil, ~omprised
~ubstantially of the ree b~ of th~ title ~ompound.
419A-CIP-2
~2~S~7
96
The oil was dissolved in ~bsolute ethanol and reacted with
oxalic ~cid. The oxala~e ~alt was recrystalliz~d from
ethanol in the ~mount of 4 g (38~), m.p. 198-201C.
~nalysis: Calculated for Cl8H2lN2ClG8: C,~1.55; H,5.68;
N,7-51
Found : C,51.07; H,5.69;
N,7.4
Example 20
7-Bromo-2-~2-(dimethylamino)ethyl~--2,3-dihydro-4-
methyl-1,4-benzoxazepin-5(4H)-one oxalate ~
To a ~olution of ~.~ g (0.01 mole)of 7-bromo-2-
(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin
5(4H)-one in 50 ml of ~b~olute ethanol was added 2;2 ml
of a 40~ aqueous eolution o~ dimethylamine. The reaction
mixture was heated in ~ ~tainle~s ~teel bomb at 100C.
~or 16 hr and concentrated under reduced pressure. The
residue was partitioned betwe~n chloroform and 15~ sodium
hydroxide solution. The chloroform layer wa~ ~eparated
and extracted with 3N aqueous hydrochloric acid. The acid
layer was basified with 50~ aqueous sodium hydroxide and
extra~ted with chloroform. The chloroform was evaporated under
reduced pre~sure to give 2.4 g (73%) viscous brown oil,
the free base of the title ~ompound. The oil was dissolved
in i~opropyl alcohol and reacted with oxalic acid. The
oxalate salt was recrystallized from i opropyl alcohol/
~5 water to give the title ~alt, m.p. 192-194 C.
Analy~is: Cal~ulated for Cl~H2l08BrN2: c,46.o6; H,5.07;
N,6.71
Found : c,46.oo; ~,5.10;
~,6.68
Exam~e 21
2-~?-(Dimethylamino~eth~11-2L3-dihydro-4-methylnaphth
A ~olution of 8 g (0.028 mole) o 2-~2-chloroethyl)-
2,3-dihydro-4-methylnapl~th~2,1-f~1,4~oxazepin-5(4~ one
~nd 6.2 g of 40~ dimethylamine (0.055 mole) in 100 ml of
3~ ethanol was heat2d in a ~teel bomb to 100 C. for 18 hr.
The re~ulting ~olution wa3 partitioned betw~en methylene
chloride ~nd dilute ~odium hydroxide solut on. The
methylene chloride lay~r wa~ dried over ~odium ~ulfæte ~nd
419A,CIP-~
LZ~5~7
97
concentr~ted. ~he residue compri~ed ~ubstantially of the
free base of the title compound wa~ di solved in isopropyl
alcohol and reacted with 2.6 g oxalic acid. The oxalate
oalt obtained was recrystallized from i~opropyl alc~hc)l
5in water, m.p. 206-209~C.
Analysis: Calcula~ed for C20P2~,N20~3: C,61.85; H,6.23;
~,7 .21
Found : C,61.61; ~1,6.26;
. ~,7-13
Example 22
When in the pr~cedure of Example 10 eaual molar amounts
of the following are substituted for 2-(2-chloroethyl)-
2~-dihydro-4-methylpyrido~3~2-f~[l~4~-oxazepin -5(4H)-one
hydrochloride:
2-(2-chloroethyl)-2,~-dihydro-4-methylpyrido~4,3-f]
tl,4~-oxazepin-5(4H)-one hydrochloride,
2 -(2 -chloroethyl ) -2 ~ 3-dihydro-4-methylpyrido[3,4-f~
tl,4~-oxazepin-5(4H)-one hydrochloride, and
2-(2-chloroethyl)-2~3-dihydro-4-methylpyrido~2~3-f]
~1,4~-oxazepi~-5(4H)-one hydrochloride,
there are obtained:
2-~2-(dimethylamino)ethyl]-2,~-dihydro-4-methylpyrido
~4J3-f~1,4~-oxazepin-5(4H)-one fumarate,
2-~2-(dimethylamino)ethyl]-2,3-dihydro-4-rnethylpyrido
t~4-f~ 4]-oxazepin-5(4~)-one fumarate, and
2~ 2-~2-(dimethylamino)ethyl~-2,~-dihydro-4-methylpyrido
t2,3-f~1,41-oxazepin-5(4H)-one fumarate.
Example 2~
2-~2-(Dimethyl~mino)ethyl~-2,3-dihydro-4-methylpyrido
4,3-f~1,4~-oxazepine-5(4~-thione hydrochlorid ~ ~
To n solution of 0.5 g (0.002 mole) of 2-(2-chloro-
ethyl)-2,3-dihydro-4-methylpyrido~4,~i-f]El,4~-oxazepine-
5(4H)-thione in 20 ml of ethyl alcohol was ~dded 2 ml ~f
40~ a~ueou~ dlmethylamine. The ~ixture was heated in a
~teei bomb to 100 C. for 14 hr. ~he resulting ~olution
wafi filtered and ~oncontrated. The residue wa8 dis~olved
in isopropyl alcohol nnd a few drop~ of ethsreal hydrogen
~hloride were add~d. The hydrochloride ~alt cry~tals were
419A-CIP-2
5~;~7
~8
r~crystallized by di~solving in ~thyl alcohol ~nd boiling
while replacing ~he ethyl alcohol with i~opropyl alcohol.
The yield of pr~duct was 0.3 g (47%), m.p.: decomp. above
200C.
Analysi~: calculated for C2~H~ O2S2Cl~: C,48.78; H,6.46;
Found : C,49~4; H,6.47,
. 0
Ex ampl e 2 4
2-r2-(Diethylamino)ethyl]-2,3 dihydro-4-methylpyrido
10 ~3~2-f~ 4]oxazepin~-5(4E~)-thione.
.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]
~ 1 J 4~-oxazepine-5~4H)-thione and diethylamine in ethanol
are heats~ together to obtain the title comp~und.
Example 2~
2-~2-(DimethYlamino~ethvl1-2,~-dihydro-4-methylnaphth
t2,3-f~1,4~-oxaz~pine-5(4H)thione oxalate ~1:1] hemihydrate.
To a solution of 15 g (0.05 mole~ of 2-(2-chloroethyl)-
2,3-dihydro-4-methylnaphth~2,3-f~1,4]-oxazepine-5(4H)-
thione in 50 ml of absolute ethanol was added 10 ml of a
45% aqueous 801ution of dim~thylamine. The ~olution was
heated in a ~teel bomb for 16 hr. The ethanol was
evaporated under reduced pressure and the re~idue par-
titioned between chlor~orm and 15~ ~ueous ~odium hydroxide.
~he chloroform layer was sepaxated and extracted with 3N
a~ueous hydrochloric acid. The acid layer was basified
with 50% a~ueous ~odium hydroxlde and extracted with
chloroform. The chloroform solution wa~ concentrated under
reduced pressure ~nd the residue was di~olved in isopropyl
alcohol and reacted with oxalic acid. The salt was
recrystallized fxom i~opropyl ~lcohol and water to give
the title compound, m.p. 115-118C.
Analy3ia: Calculated for C~oH~oN4olls2: C,58.09; H,6.o9;
~,6.77
Found : C,58.42; ~,5.85,
~,6.70
419A-CIP-2
99
ExamPle ?6
2-~2-(Dimethylamino~ethyl~-2J3-dihydro-7J9-diiodo-4
methyl-1,4-benzoxazepin-5(4H~-one.
Utilizing the pxocedures of Ex~mple 1 ~nd 2 and
substituting 2-(2-chloroethyl)-7,9-dii~do-4-methyl-2,3--
dihydro-4-methyl-1,4-benzoxa~epin 5(4~)-one for 2-(chloro-
ethyl)-4-methyl-2,3-~ihydro-1,4-benæoxazepin-5(4H~-one,
the title comp~und i8 obtained.
ExamPle ?7
7-Chloro-2I 2-(dimethylamino)ethyl~-2~-dihydro-4-
methyl-1,4-benzoxazepin-5(4H)-one oxalate~
To a solution of 9.0 g (0.03~ ~ole) of 7-chloro-2-
(2-chloroethyl)-2J3-dihydro-4-m~thyl-1,4-benzoxazepin-5(4H3-
one in 50 ml absolute ethanol was ~dded 7 g to.o66 mole)
of a 45~ ~ueous ~olution of dimethyl~mine. The ~olution
was heated in ~ ~tainle~s ~teel bomb at 100~C. for 14 hr.
:~ The reaction mixture wa~ ~oncentrated under reduced
pres~ure ~nd the residue was partitioned between chl~ro-
~orm and 15% a~ueou3 ~odium hydroxide. The chloroform
layer was 3eparated and evaporated under reduced pre~sure
to give a viscou~ brown oil. The~ ~il was dissolved in
iqopropyl alcohol and oxalic acid added. Recrystallization
from i~opropyl alcohol~water gave 7.0 g (57~) oxalate
~alt, m.p. 199-200~C.
Analy~i6: Calculated ~or Cl~H~lN20eCl: Cl51.55; ,5.68:
~N,7-51
Found : C~51.~2; ~,5.72;
~-7.44
2-~Dimethylamino)methyl-?,3-dihydro-4-methylpyrido
~ ~.
3o When in the procedure o~ Example 10, 2-chloromethyl-
2,3-dihydro-4-m~thylpyridot3,2-f~1,4~-OXazepin-5(4H)-one
a~ ~ub~tituted ~or 2~(2-chloroethyl)-2,3-dihydro-4-methyl-
pyrido~,2-f~tl,4~-oxazepin-5(4H)-one, the title compound
i~ prepared and i~ isolated i de~ired ~ a pharm~ceuti-
c~lly acceptable ~alt.
~ 5~7 ~1 9A-CIP-2
100
Example 29
2-r2-(Dimethylamino)ethyll~2,3-dihydro-4-methylpyrido
~3J2-f~ 4~-oxazepine-5(4H~-thione methiodide.
2 ~2-~Dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido
~3~2-f][~,4]-oxazepine-5(4H)-thione ~umarate ~
ethanol r2:1~, 3.8 g (0.01 mole) was partitioned between
chloroform and dilute sodium hydroxide. The chlorofoxm
extract was dried over sodium ~ulfate and concentrated.
The residue was dissolved in 15 ml of methyl isobutyl
ketone and added to a solution of 1.4 g (0.01 mole) of
methyl iodide in 15 ml of isobutyl ketone. Recrystal-
lization from 50~ ethanol - 50% methyl isobutyl ketone
gave 2.5 g (78%) of the product, m.p. 221-225C.
Analysis: Calculated for Cl~H2~N30SI: C,41.28; H,5.44;
~, 10 .31
Found : C,41.29; H,5.51;
N,10.3G
Example 30
7-Chloro- ~ 2-(dLmethylamino)ethyl~-2 ,3-dihydro-4-
methyl-1,4-benzoxazepine-5(4H)-thione oxalate rl~
hemihydrate.
To a solution of 8.o g (0.027 mole) of 7-chloro-2-
(2-chloroethyl~2~3-dihydro-4-m~thy~ 4-benzoxazepine-5(4H)
thione in 50 ml of absolute ethanol was added 6 ml
(0.054 mole) of 40~ a~ueous solution o~ dimethylamine. The
solution wa~ heated in a steel bomb at 90C. for 14 hr.
The ethanol was removed under reduced pressure and the
residue was partitioned between chloroform nnd aqu~ouS
sodium hydroxideO The chloroform layer was concentrated to
give a viscou~ yellow oil. The oil was dissolved in
isopropyl ~lcohol ~nd rea~ted with oxalic acid. The oxalate
~alt immediately precipita~ed. The mixtuxe was heated and
a small amount o~ water wa~ added to dis301ve the salt. A
white crystallin~ powder W~8 o~tainedJ m.p. 150-151~C.
Analysi~: Calculated for C32H44N4C120ll52: C,48.30; 8,5~57;
N,7.o4
Found : C,48.74; H,5.34;
~,6.95
419~CIP-2
iL564
101
ExamPle ~1
2-~2-(Dimethylamino)ethyl~-2,~-dihydro-4-methyln2phth
To a ~olution of 15.0 g (0.05 mole) of 2-(2-chloro-
ethyl)-2,3-dihydro-4~methylnaphth~2,1-f]C1,43-oxazepine-
5(4H)-thione in 50 ml of absolut~ ethanol w~a a~ded 10 g
of a 40~ aqueous solution of dimethylamine. The resulting
801ution was heated in ~ ~teel bomb ~t 100C. for 40 hr
and concentrated under redu~ed pressure. The residue was
partitioned between 15~ aqueous Rodium hydroxide and
chloroform. The ~hloroform layer was evapor~ted and the
re~idue partitioned b~tween ~N hydrochloric acid and
chloroform. ~he aqueous layer was made alkaline with 50%
sodium hydroxide and extracted with chloroform. The
chloroform extract wa~ concentrated and the residue
di~solved in i~opropyl alc~hol. Ethereal hydrogen chloride
was added. Recry6tallization of the precipitate from
isopropyl alcohol/water gave 3.0 g t20%) of the product,
m.p. 2~8-240C.
~; Analysis: calculated for Cl~H29N2ClOS: C,61.61; H,6.61;
N,7.98
~ound : CJ61.8O; H,6.61,
N , 7 . 91
ExamPle ~?
When in th~ procedure of Example 11 equal molar
~mounts of the following are ~ubstituted for 2-(2-chloro-
25 ethyl)-2,3-dihydro~4-methylpyrido~,2-f~1,4~-oxazepine-
5(4H) thione:
2-~2-chloroethyl)-2~3-dihydro-4-methylpyrido~3,4-f]
r 1,4~-oxazepine-5(4H)-thione, and
2-(2-chlorGethyl-2,3-dihydro-4-methylpyrido~2,3_f]
tl,4~-~xazepine-5(4H~-thione,
there ~re obtained:
~) 2-~2 (dim~thyl~mino)ethyl~-2,3-dihydro-4-methylpyrido
r~,4-f]~l~43-oxazepine-5(4H)-thione fumarate, and
b) 2-r2-(dimethylamino)ethyl~-2,3-dihydro-4-m~thylpyrido
35 ~2~3-f~ 4]-oxa~epine-5(4H)-thlone ~umarnte.
419A_CIP-~
~Z~5G~7
102
Exam~le 33
m
hemihydrate.
__
To a solution of ~.0 g (0.011 mole) of 2-(2-chloro-
ethyl)-2,3-dihydro 7-methoxy-4-methyl-1,4-benzox~zepin-
5(4H)-one in 50 ml of ab601ute ethanol was added 3.0 g of
a 40% aqueous ~olution of dimethylamine. The reaction
mixture was heated in a ~tainless steel bo~b at 100C. for
16 hr, cooled and evaporated under reduced pressure. The
xesidue wa~ partitioned between chloroform and 15~ sodium
hydroxide solution. The chloroform layer was concentrated
and the residue, the free baseJ was dissolved in i~opropyl
alcohol and reacted with oxalic ncid. The resulting
oxalate salt was recrystallized from isopropyl alcohol~H2o
to give 1.9 g (45%) of the title salt, m.p. 176-178 C.
Anslysis: Calculated for C3~H50N415: CJ54.10; H,6.67,
N,7.42
FOUnd : C,54.2~; H,6.59;
N,7 5~
7-Bromo-2-L2 (dimethylamino)ethyll-2,3-dihydro-4-
methyl-1,4-benzoxazepine -5 ( 4H ) -thiOne oxalate rl:l~
monohydrate.
To a solution of 13 g (0.04 mole) of 7 bromo 2-(2
chloroethyl)-2,~-dihydro-4 methyl-l, 4-benzoxazepine-5~4H)-
thione in 50 ml of absolute ethanol was added 8 ml of a
45% a~ueous ~olution of dimethyiamine. The solution was
heated at 100C. in a steel bomb for 16 hr. ~he ethanol
was evapora~ed under reduced pre~sure and the residue
partitioned between ethyl ~cet~te and 3N aqueous hydro-
chloric acid. The aaueou~ extr~ct was basified with 50
agueou~ sodium hydroxide and extracted with chloroform.
The chloroform was concentrated under reduced pressure.
The rPsidue~ the free ba~e of the title compound, was
di~olved in i~opropyl ~lcohol ~nd reacted with oxalic
acid. The oxalate salt was r~crys~allized ~rom 95~ ethanol
~5 to give the title salt, m.p. 155-157C.
419A-CIP-2
56~7
103
Analysi~: Calculated fvr C~2H4~N~Br2Ol2Sz C,42.58; H,5.14,
N,6.12
Found : C,42.9~; H,4.79
N,6.19
Examele ~a to h
When in the procedure of Example 27, equal molar
~mounts of the fQllowing ~re ~ub tituted ~or 7-chloro-2-
t2-chloroethyl)-2,~-dihydro-4-methyl-1,4-benzoxazepin-
~(4H)-one,
2-~2-chl~roethyl)-4-cyclohexyl-2,3-dihydro-1,4-
benzoxazepin-5(4H)-one,
2-(2-chloroethyl)-2,3 dihydro-4-e~hyl-1,4-benz-
oxazepin-5(4H)-one~
2-(2-chloroethyl)-2,3-dihydro-4-isopropyl-1,4-benz-
oxazepin-5(4H)-one,
2-(2-chloroethyl)-4-(4-chloro~enzyl)-2,~-dihydro-
1, 4-benzoxazep in-5(4H)-one,
2-(2-chloroethyl)-2,3-dihydro-4-(4-methylbenzyl)-
1,4-benzoxazepin-5(4H)-one,
2-(3-~hloroethyl)-2,3-dihydro-4-(3,5-d~methoxybenzyl)-
1,4 benzoxazepin-5(4H)-one,
2-~2-chloroethyl)-2,3-dihydro-4-(~-trifluoromethyl-
benzyl)-l t 4-benzox~zepin-5 ( 4~) -one, ~nd
2-(~-chloroethyl)-2,3-dihydro-4-(4-nitrobenzyl)--
1,4-benzoxazepin-5(4H)-one,
~5
there are obtained:
a) ~-cyclohexyl-2-~2-(dimethylamino)ethyl~-2,3-dihydro-
1,4-benzox~z~pin-5(4H)-one oxalate,
b) 2-t2-(d~methylamino)ethyl~-2J3-dihydro-4-ethyl-1~4-
benzoxazepin-5(4H)-one oxalateJ
~) 2-[2-(dimethylamino~ethyl~-2,~dihydro-4-i~opropyl~
1,4-benzoxazepin-5(4H)-one ox~late,
d3 4-(4-chlorobenzyl)-2-~2-(dLmethyl~mino)ethylJ-2,3-
dihydro~l"4-benzoxazepin-5(4EI~-one o~al~te,
2-~dimethylamino~;~thyl~-2,3-dihydro-~ -m~thyl-
b~nzyl)~lJ4~benzoxazepin-5(4EI)-one oxal~te,
419A -CIP-2
~L~47
104
f) 2-C2-(dimethylamino)ethyl]-2,3-dihydro-4-(3,5-
dimethoxybenzyl)-1,4-benzoxazepin-5(4H)-one
oxalate,
g) 2-C2-(dimethylamino)~thyl~-2,3-dihydro-4~
(trifluoromethyl)benzyl]-1,4-ben20xazepin-5(4H)-
one oxalate, and
h) 2-~2-(dLmethylaminc)ethyl]-2,3-dihydro-4-t4-nitro-
benzyl)-1,4-benzoxazepin-5~4H)-one oxalate.
ExamPle 36a to h
When in the procedure of Example 10, equal molar
~mounts of the following are ~ubstituted for 2-(2-chloro-
ethyl)-2,3-dihydro-4-methylpyrido~,2-f]~1,4~-oxazepin-
5(4H)-one hydrochloride,
2-(2-chloroethyl)-4-cyclohexyl 2~3-dihydropyrido
t3,2-f~rl,4~-oxazepin-5(4H)-one hydrochloride,
2-(2-chloroethyl)-2,3-dihydro-4-ethylpyrido
r3,2-~rl,43-oxazepin-5(4H)-one hydrochloride,
2-(2-chloroethyl)-2,3-dihydro-4-i~opropylpyrido
t3,2-f~tlJ4~-oxazepin-5(4H)-one hydrochloride,
2-(2-chloroethyl)-4-(4-chlorobenzoyl)-2,3-dihydro-
pyrido~3,2-f~1,4~-oxazepin-5(4H)-one hydrochloride,
2-(2-chloroethyl)-2,3-dihydro-4-(4-methylbenzyl)-
pyridot3,2-f]~1,4]-oxaz~pin-5(4H)-one hydrochloride~
2-(2-chloroethyl)~2,3-dihydro-4-(4-methoxybenzyl)-
pyridot3,2-f~1,4~-oxazepin-~(4H)-one hydrochloride~
2-(2-chloroethyl~-2,~-dihydro-4-(3-trifluoromethyl-
benzyl~pyrido~ 5~2-f]cl,4]-oxazepin-5~4H)-one
hydrochloride" and
2-(2-chloroethyl)-2,3-dihydro-4~( 4-nitrobenzyl) -pyrido
r3,2-f]~1,4~ oxazepin-5(4H)-one hydrochloride~
there are obtained:
~ 3 4 -ey~l~hexyl-2-~?-(dimethylamino)ethyl~-2,3-dihydro-
pyrido~3~2-f]rl~4~-oxazepin-5(4h)-one fumarateJ
r ~
105- 66197-169
b) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-ethyl-
pyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate,
c) 2-[2 (dimethylamino)ethyl]-2,3-dihydro-4-isopropyl-
pyrido[3,2-f][1,4]-oxazepin-5(4H)-one fumarate,
d) 4-(4-chlorobenzyl)-2-[2-(dimethylamino)ethyl]-
2,3-dihydro-pyrido[3,2-f][1,4]-oxazepin-5(4H)-
one fumarate,
e) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-~4-methyl-
benzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)--one
fumarate,
f) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-
methoxybenzyl)-pyrido[3,2-f][1,4]-oxazepln-5
(4H)-one fumarate,
g) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(3-tri-
fluoromethylbenzyl)-pyrido[3,2-f][1,4]-oxazepin-
5(4H)-one fumarate, and
h) 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-(4-nitro-
benzyl)-pyrido[3,2-f][1,4]-oxazepin-5(4H)-one
fumarate.
Example 37a to d
When in the procedure of Example 3, equal molar
amounts of the following are substituted Eor morpholine:
pyrrolidine,
piperidine,
piperazine, and
4-methyl-piperazine,
there are obtained:
a) 2,3-dihydro-4-me-thyl-2-[2 (l-pyrrolidino)ethyl]-
~6~'7
-105a- 66197-169
1,4-benzoxazepin-5(4H)-one fumarate
b) 2,3-dihydro-4-methyl-2-[2-(1-piperidino)ethyl]-
1,4-benzoxazepin-5(4H)-one fumarate.
c) 2,3-dihydro-4-methyl-2-[2-(1-piperazino)ethyl]-
1,4-benzoxazepin-4(4H)-one fumarate, and
d) 2,3-dihydro-4-methyl-2-[2-(4-methylpiperazin-1-yl)
ethyl]-1,4-benzoxazepin-5(4H)-one fumarate.
:~;
419~CI~2
~.1~56~
106
2-r2-(Dimethylamino)ethyl~-2 ,3-dihydro-4-methylpyrido
A ~olution of 1.5 g (o.0058 mole) of 2-(2-chloroethyl)-
2,3-dihydro-4-methylpyrido~3,2-f~1,4~-thiazepin-5(4H)-one
in 20 ml of dimethylamine was stirred at 25~C. in ~ sealed
container for 72 hr. The excess dimethylamine waQ allowed
to evaporate and the residue was partitioned between
chloroform ~nd dilute sodium hydroxide. The chloroform
layer was concentrated ~nd the re~idue, the free base of
the title compound, wa~ dissolved in i opropyl alcohol and
reacted with hydrogen chlorid0. The reRulting hydro-
chloride salt weighed 1.5 g (77%), m.p.9 250 C.
Analysi~: calculated for Cl3H2lN30SCl2: C,46.16; H,6.27
N,12.42
Found : C,45.68; H,6.18;
N.12-~5
ExamPle 39
2-C2-(Dimethylamino~ethyl~-2,3-dihydro-4-methylpyrido
~3,2-f~1,4~-thiazepine-5(4H)-thione oxalate.
A ~olution of 1.5 g (0.00~ mole) of 2-(2-chloroethyl)-
2,3-dihydro-4-methylpyrido~,2-f~1,4~-thiazepine-5(4H)-
thione in 40 ml of dimethylamine was ~tirred at 25C. in a
sealed container f~x 96 hr. The dimethylamine was allowed
20 to evaporate and the residue wa~ partitioned between
methylene chloride and dilute sodium hydroxide. The chloro-
form layer was concentrated and the residue, the free base
of the titl~ compound, was reacted with 0.4 g oxalic acid
in a ~olution of 30 ml of 90-100 isopropyl alcohol water.
Th~ resultiag crystal~ were recryst~llized from the same
~olvent to give 1 g of the product, m.p. 191-19~C.
Analysi~: Calculat~d for ClsH2lN3520~: C,48.50; ~,5.70;
Found ~ C,48.49; ~1,5.84
N,10.99
419A-CIP-2
L5~
107
Example 40
2 -r2 -( Dimethvlamino~ethyl~-2 9 3-dihydro-4~methylpyrido
[~,4-f~rl,4]oxazepin-5(4H)-one oxalate (1:2) hemihydrate.
A solution of 5 g (0.02 mole) of 2-(2 chloroethyl)~
2,~-dihydro-4-methy~pyrido~3,4-f]~1,4~oxazepin-5(4H)-one,
in 25 ml of dimethylamine was placed in a sealed vessel
and stirred for 72 hr. The vessel was opened and the excess
dimethylamine allowed to evaporate. The residue was
dissolved in chlorofoxm and the solvent was stripped off in
vacuo to remove ~xcess dimethylamine. The residue was
partitioned between dilute sodium hydroxide and ethyl
acetate. The ethyl acetate solution was concentrated and
the residue was treated with 3 g (0.0~3 mole) of oxalic acid
in 50 ml of isopropyl alcohol and enough water to dissolve
the salt while boiling. The resulting crystals were
recrystallized from the same solvent. Yield of product WAS
5.3 g (60~), m.p. 179-181C.
Analysis: Calculated for C34H4~N~02l: C,46.48; H,5.52;
N,9~58
Found : C,46.58; H,5.70
N,9~61
20Example 41
2-~2-(Dimethylamino~ethyl~-2,3-dihYdro-4-methylPyrido
L~,4-fl~1,4~oxazepine=5(4H)-thione oxalate ~1:2~.
A 4 g (0.009 mole) sample of 2-~2-(dimethylamino)ethyl]--
2, 3-dihydro-4 -methylpyrido~ ~, 4 -f]~1,4~oxazepin-5(4~)-one
oxalate (1:2) hemihydrate was partitioned hetween dilute
sodium hydroxide and chloroform. The aqueous layer was
extracted three times and the combined chloroform extracts
were dried over ~odium sulfate and concentrated. The residue
was dissolved in 200 ml of dry toluene and again concentrated
in vacuo to effect drying. The residue was dissolved in dry
pyridine (10 ml ) a~d treated with 2.8 g (0.01 mole) of
phosporus pentasulfide. The mixture was ~tirred at reflux
for 20 hr. The cooled mixture w~ partitioned between dilute
~odium hydroxide and chloroform. The aqueous layer was
~5 extracted three times with chloroform. The combi~ed chloro-
form extract~ were dried over sodium ~ulfate and concentratedO
4 l9A~clp-2
108
One gram of the residue was treated with o.6 g of oxalic
acid in isopropyl alcohol/10% water. The resulting crystals
were collected by filtration. Yield of oxalate salt was
0.37 g., m.p. 111-114C.
Analysis: calculated for Cl7H29N3S08: C,45.84; H,5.20;
~,9-43
Found : C,45.46; H,5.38
N,9.28
ExamPle 42
2-(2-Aminopropyl)-2,3-dihydro-4-methyl-pyrido~3,2 fl
10 rl,41-oxazepin-5(4H)-one, oxalate ~1.1~.
2,3-Dihydro-4-methyl-5(4H)-oxopyrido~3,2-f]~1,4]
oxazepine-2-propanenitrile, 5 g (0.22 mole, in 150 ml of
ethanol was treated with about 1.5 g of wet Raney nickel.
The mixture was hydrogenated in a Parr apparatus at 60C.
15 and 40 psi. The mixture was cooled and filtered and the
filtrate concentrated. The residue was treated with 3.9 g
of oxalic acid in 130 ml of boiling isopropyl alcohol
containing 2 ml of water. The hot solution was filtered
and allowed to cool. The resulting solid was recrystal-
20 lized from ethanol. Yield of oxalate hemihydrate was3 g (4~%), m.p. 126-134C.
Analysis:Calculatedfor C2~H4ON607: ,50.30; H,6.o3
N,12 .57
Found : C,50.46, H,5.71;
~1,12.21
Example 43
2,~-Di dro-4-methyl-~-r2-(4 morpholl l~ethyl~-
pyridor3J2-flrl94loxazepin-5(4H)-one maleate rl:ll.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]
~1,4]oxazepin-5(4H)-one hydrochloride~ 16 g (058 mole) was
30 dissolved in morpholine (30 ml) and stirred overnight at
room temperature. Tc> the solution was added dilute sodium
hydrs~xide solution (50 ml) and the resulting mixture
extracted with chloroform (3 X 30 ml). The chloroforrn was
removed on the rotary evaporator with aspiration. The
35 residual morpholine was removed in vacuo at 50C. (rotary
evaporatc~r3. To the residual free base (15.5 g, .053 mole)
419A-CIP-2
~2~S~7
109
was ~dded i~opropyl alcohol (1 liter) and maleic acid
(9.24 g g, .o80 mole). The mixture was heated to boiling
and the clear solution cooled at 20C. :for ~everal hGurs.
The resulting crystals, 16 g (68.1%), were recrystallized
from isopropyl alcohol, m.p. 163-165 C.
Analysis: Calculated for Cl~H25N307: C,56.01; ~I,6.18;
~1, 10 .31
Found : CJ55.71; H,6.21;
N,10.18
Example 44
2,3-Dihydro-4-methyl-2-r2-(1-E~yrrolidinyl~ethyllpyrido
~2-f~ 4]-oxazepin-5(4H~-one fumarate rl 11-
A sample of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-
pyridot3,2-f~ 4]-oxazepine-5(4H)-one hy~rochloride, 16 g
t0.058 mole), wa3 dissolved in 65 ml of pyrrolidine. The
stirred solution wa heated to 80C. for 3 hr. The solution
was cooled to room temperature and dilute sodium hydroxide
solutio~ (50 ml) was added. The resulting solution was
extracted with chloroform (3 X 30 ml) and concentrated in
vacuo. The residue was taken up in boiling isopropyl
alcohol (500 ml/ and fumaric acid (9.2 g, .079 mole) was
added. The solution was filtered hot and the filtrate
cooled to 20 C. for several hours. The resulting crystals,
14 g (47.80 were collected and recrystallized from
isopropyl alcohol, m.p. l47-l4goc.5 ~nalysis: calculated for C23OloN3H2~: C,54.4~; H,5.76;
N,8.28
Found : C,54.~8; ~J5.83
N,B.27
Example 45
2-t2-(Dibutylamino)ethyll-2,~-dihydro-4-methyl-pyrido
r3,2-flrl,41oxazepin-5(4H~-one maleate rl~
-(2-chloroethyl)-2,~-dihydro-4-methylpyrido~3,2-f]
~1,4]oxazepine-5(4H)-one hydrochloride, 16 g (0.058 mole)
was dissolved in dimethylformamide (30 ml) and di-n-butyl-
amine (30 ml). The ~olution was stirred at 90 C. fvr 3 hr
at 100C. for 2.5 hr. The solution was cooled and to it was
added 50 ml o~ dilut~ sodium hydroxide 301ution. The
re ulting mixture was extracted with chloroorm (3 X 50 ml).
~Z~56 47 419A-CI~2
110
The chloroform was removed on the rotary evaporator with
water aspiration at 50C. Residual dimethylformamide and
di-n-butylamine were removed at low vacuum a~d 50C. (rotary
evaporator). To the residual free base, 13.8 g (0.041 mole)
was added isopropyl alcohol (900 ml) and oxalic acid, 5.6 g
(0.062 mole) and the solution heated to boiling. The clear
solution was cooled overnight at 20C. and filtered to
gi~e 13.6 g (56.5%) of crystals which were recrystallized
from isopropyl alcohol, m.p. 195-1~6C.
10 Analysis: Calculated for C2 ~H33N30~: CJ59O59; H,7.85;
N J 9 72
Found : C,59.37; H,7.91;
N,9.86
Example 46
2 -r2 - (Diethylamino)ethYl-l-2~3-dihydro-4-methylpyrido
~3 2-f]~l~4~oxazepin-s(4H)-one oxalate rl:l~.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f]
~1,4]oxazepin-5(4H)-one hydrochloride, 16 g (0.058 mole)
was suspended in diethylamine (30 ml). The suspension was
stirred for 72 hr at room temperature. The mass spectrum
indicated that the reaction had progressed 33~ at this
point. The mixture was then heated to reflux for 6 hr.
Diethylamine was removed by rotary evaporation (70 C. water
aspirator). The residue was taken up in chloroform (100 ml)
and washed with dilute aqueous sodium hydroxide (2 X 30 ml).
The organic layer was concentrated by rotary evaporation
(70 C, water aspirator~. The residue was dissolved in
boiling isopropyl alcohol and treated with oxalic acid.
Upon cooling, 18 .6 g (87.7%) of light brown crystals were
collected (m.p. 150 -155 C.). A sample was recrystallized
30 three more times froM isopropyl alcohol~ m.p. 156-157C.
Analysis: Calculated for Cl7H25N30~: C,55.57; HJ6~86~
N,11.43
Found : C,55.28, H,6.85
~,11.~7
4la~-cI~2
~2~6~
111
Example 47
? ,3-Dihydro-4-methyl-2-[2-(1-piperidinyl~ethyl]pyrido
~3~2-f~[l~4l-oxazepin-5(4H)-one oxalate
2-(2-Chl~roethyl)-2,3 dihydro-4-methylpyrido[3,2-f~
t 1,4]oxazepin-5(4H~-one hydrochloride, 4 g (0.015 mole)
was dissolved in piperidine (30 ml) and heated to 80 C.
with stirring for 20 minutes. The piperidine was removed
by rotary evaporation (85C, vacuum pump) and the residue
taken up in chloroform (50 ml). The organic layer was
washed with dilute aqueous sodium hydroxide (2 x 20 ml)
and concentrated by rotary evaporation ~80C, water
aspirator). The resulting oil was taken up in hot
isopropyl alcohol and treated with oxalic acid. Upon
cooling, crystals of the oxalate salt were collected and
recrystallized from isopropyl alcohol, to give 3.4 g (62~)
f pale brown crystals m p 133-136 C
Analysis: Calculated for Cl~H25N30~: C,56.98; H,6.64;
~,11.07
Found : C,s6.95; H,6.87;
N,10.79
Example 48
2,3-Dihydro-4-methyl-2-~2~methyl(phenylmethyl~amino
ethyllpyrido[3,2-f~1,41~xazepin-5(~H)-one maleate ~
2-(2-Chloroethyl)-2,~-dihydro-4-methylpyrido~3,2-fl
~1,4~oxazepin-5(4~)-one hydrochloride, 4 g (0.015 mole)
was dissolved in methyl benzyl amine (30 ml) and heated to
80 C. with stirring. After three hours, the excess amine
was removed by rotary evaporation (90 C, vacuum pump). The
residual oil was taken up in chloroform (40 ml) and washed
with dilute aqueous sodium hydroxide (30 ml). The chloro-
form layer was concentrated by rotary evaporation (90C,
water aspirator). T~e residual oil was dissolved in hot
isopropyl alcohol and treated with maleic acid. Upon
cooling, 4.23 g (66%) of pale brown crystals were collected,
m.p. 167-169C.
Analysis: calculated for C~9H47N30~: C~62.57; H,6.16:
Found : C,62.28; H,6 16:
N,9.24
~2~S6g~
112
xample 4
- 2,3-Dihydro-4-methyl-2-~2-(methylphenylamino)ethyl~
pyrido~3J2-f]tl~4]oxazepin-5(4H~-one.
2-(2-Chloroethyl)-2,~-dihydro-4-methylpyrido[3,2-f~
~l~4]oxazepin-5 (4H)-one hydrochloride, 4.00 g (0.015 mole)
was dissolved in N-methylaniline (~0 ml~ and heated to
95 C. with stirring for 2 days. Excess ~-methylaniline was
removed by rotary evaporation (95C, vacuum pump). The
residue was taken up irl chloroform (80 ml)and washed with
dilute a~ueous sodium hydroxide (~0 ml) The chloroform
layer was decolorized with activated carbon and dried over
sodium sulfate, filtexed and concentrated by rotary
evaporation. The remaining residue was dissolved in ethyl
acetate (50 ml) and purified by high pressure liauid
chromatography using a silica gel column and ethyl acetate
as the eluent. After purification, crystals formed from
ethyl acetate. These crystals were recrystallized from
ethyl acetate, giving 1.40 g (~1%) of pale brown crystals.
Analysis: caleulated for Cl~H2lN302: C,69.4~; ~,6.79;
~,13.49
Found : C,69.31, H,6.77;
~,13.54
2-~2-(2,5-Dimethyl-l-pyrrolidinyl)ethyll-2?~-dihydr
4-methylpyr do ~3,2-flrl,4loxazepin-5(4H)-one fwnarate
r ~
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyridor~i,2-f]
~l34]oxazepin-5 (4H)-one, 5.0 g (0.021 mole), was dissolved
in 25 ml of absolute ethanol and ~ g (0.0~ mole) of 2,5-
dimethylpyrrolidine was added. The solution wa~ heated to
75 C. for 48 hrs with stirring. Becau~e the reaction was
incomplete ~t this time, an additional amount of 2,5-
dimethylpyrrolidine (1.00 g, 0.01 mole) was added and the
reaction continued. After 5 days, the reaction was still
incomplete and more ~75-dimethylpyrrolidine (1.00 g, 0.01
mole) was added. The reaction appeared complete 2 days
later. Solvent was removed by rotary evaporation (80C.,
water aspirator~. Excess 2,5-dimethylpyrrolidine was
113
removed by rotary evaporation (80C, vacuum pump). The
residue was taken up in chloroform (200 ml) and washed
with dilute aoueous ~odium hydroxide (2 x 75 ml). The
organic layer was dried over sodium sulfate, filtered, and
concentrated by rotary evaporation (70C, water aspirator).
The resulting oil wa~ dissolved in hot isopropyl alcohol
and treated with fumaric acid. Upon coolingJ 2.38 g
(27.~ O of pale brown crystals was collected, m.p. 161
162C.
10Analysis- Calculated for CZlH2eN3o6: C,60.13; H,6.96;
N,10.02
Found : C,59.79; H,6.93;
~ ,9.76
Example ~1
2,3-Dihydro-4-methyl-2-~2-(2-methyl-1-pyrrolidinyl)
15ethylJpyrido ~ J 2 -f]~1,41oxazepin-5(4H)-one.
To a solution of 3.5 g (0.0145 mole) of 2-(2-chloro-
ethyl~-2,3-dihydro-4-methylpyrido t3,2-f]~1,4~oxazepine-
5(4H)-one in ethanol (15 ml) was added 2-methyl pyrrolidine
(5.0 g, o.o63 mole). The solution was heated to reflux
for ~ hours with stirriny. The ethanol was removed by
rotary evaporation (water aspirator, 80 C.). The residual
oil was partitioned between dilute aoueous sodium hydroxide
(50 ml) and chloroform (50 ml). The organic layer was
saved and the aqueous layer extracted with chloroform
(2 x 30 ml). All the chloroform layers were combined,
dried over anhydrous sodium sulfate and concentrated by
rotary evaporation (water aspirator, 70 C.). The residual
oil was then distilled at 200 C. and low vacuum (vacuum
pump~ giving 1.5 g (35-7O of a clear oil.
30Analysis: Calculated for Cl~H23N3O2: C,65.41; H,8.01;
N,14.52
Found : C,65.83; HJ 8 . o6,
NJl4-39
419A_CIp-2
114
2,3-Dihydro-4-methyl-2-[2-(lH-pyrazol=l-yl)ethyl~
pyrido r3,2-flLl,4]oxazepin-5(4H) one.
rnO a suspension of sodium hydride (1.2 g active,
0.05 mole) in dimethylformamide (15 ml) was added dropwise
a solution of pyrazole (3.10 g, 0.045 mole) in dimethyl-
formamide (15 ml). The resulting solution was then added
to a solution of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-
pyrido~3,2-f~1,4~ oxazepine-5(4H)-one ~9.12 g, 0.038 mole)
in ~0 ml of dimethylformamide. The flask was sealed and
stirred overnight. Because the reaction had not yet gone
to completion at this point, pyrazole (3.12 g, 0.045 mole)
was added to the reaction solution and stirred overnight.
The reaction was still not complete and another suspension
of sodium hydride (0.5 g active, 0.021 mole) and pyrazole
(1.5 g, 0.022 mole) in dimethylformamide (10 ml) was added
and the reaction stirred overnight. The reaction appeared
to be complete. Dimethylformamide was removed by rOtary
evaporation (80 C, vacuum pump), and the residue taken up
in chloroform (100 ml) which was washed with dilute aqueous
sodium hydroxide (1 x 50 ml~, dried over anhydrous ~odium
sulfate and concentrated by rotary evaporation (70 C,
water aspirator). The material was purified by high
pressure liquid chromatography, 95:5 by volume ethanol:
methanol on a silica gel column. q'he fractions containing
the desired product were concentrated by rotary evaporation
(70 C, water aspirator). Crystallization ensu2d upon
cooling. The crystals were collected and recrystallized
from ethanol. The yield was 1.5 (14.5%), m.p. 1~2-134 C.
~nalysis: calculated for C14Hl~N~Oz: C,61.75; H,5.92,
N,20.58
Found : C J 61.35; H,5.89;
N,20.67
1~lgA~CIP-2
115
xampl~
2,3-Dihydro-?-~2-(l~imidazol-1-yl)ethy ~ -methyl-
yrido[3,2-f~rl,4~oxazepin-5(4H)-one.
To a solution of 2~ chloroethyl)-2,3-dihyaro-4-
methylpyrids ~3,2-f~1,4~-oxazepine-5(4H)-one, 9.12 g
5 (O.038 mole) in dimethylformamide (30 ml) wa~ added
imidazole, 5.66 g (o.o83 mole). The ~olution was heated
to 130C. for 18 hx. Dimethylformamide ~tas removed by
rotary evaporation (80C, vacuum pump) and the residue
taken up in chloroform (100 ml). The chloroform was washed
witl, dilute ~ueous sodium hydroxide (30 ml), ~ried over
sodium sulfate ~nd concentrated by rotary evaporation
(70C, water aspirator) to an oil. Cry~tallization was
induced with ethanol. White crystals, 1.5 g (14.5O were
collected, m.p. 150-152C.
Analysis: Calculated for Cl4HlaN402: C,61.75; H~5.92,
N,20.58
Found : C,61.36; H,5.92;
N,20.60
Example ~4
2-r2-(Dimethylamino)ethyll-4-ethyl-2,3-dihydropyrido
L3,2-f~rl,41oxazepin-5(4H)-one oxalate rl~
To 30 ml of dimethylamine collected at 0C. was added
6 g (0.021 mole) 2-(2 chloroethyl)-4-ethyl-2,3-dihydropyrido
~3,2-f~1,4]oxa~epin-5(4H)-one, hydrochloride. The flask
was sealed tightly and 3tirred 70 hr at room ~emperature.
The solution was then cooled to 0C. and the stopper of the
flask removed. DLmethylamine was allowed to evaporate. The
residue was t~cen up in chloroform (1 x 150 ml) and washed
with dilute aqueous sodium hydroxide (1 ~ 50 rnl). The
organic layer was dried over ~odium sulfate~ filtered and
concentrated by rotary evaporation (70 C, water aspirator).
The residue was dissolved in hot isopropyl ~lcohol and
treated with oxalic acid. Upon coolingl 4.5 ~61.50 was
collected, m.p. 208 c.
Analysis: Calculated for Cl~H23N90~- C,54.38; H,5.56,
~,11.89
Found : C~54.26, H,6.61,
~,11.81
419A-CIP-2
116
Example ~
2,3-Dihydro-4-ethyl-2- ~ (l-pyrrolidinyl)ethyl~pyrido
~ L~ .
2~(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido~,2-f~
~lJ4]oxazepin-5(4H)-one hydrochloride, 3 g (0.01 mole)
was dissolved in pyrrolidine (30 ml) and heated to 70 C. for
70 minutes with stlrrlng. After cooling, the contents of
the reaction flask were diluted with diiute aqueous sodium
hydroxide (40 ml) and extracted with chloroform (2 x ~0 ml).
The chloroform layer was dried over sodium sulfate, filtered
and concentrated to a viscous brown oil by rotary evaporation
(70 C, water aspirator). The oil was taken up in hot
isopropyl alcohol and treated with oxalic acid. Upon cooling,
the resulting solid was recrystallized from isopropyl
alcohol5 giving pale brown crystals, 1.80 g (45.4~), m.p.
185-188C.
Analysis: Calculated for Cl8H~5N306: C,56.98; H,6.64;
N,11.07
Found : C,56.90; H,6.67;
N,10.90
Example ~6
2,3~-Dihydro-4-methyl-2-r2-(4-morpholinyl)ethyllpyrido
~3,2-fl~l ~ oxazepin-5(4H)-thione.
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido~,2-f]
~1,4~oxazepine-5(4H)-thione, 4.5 g (0.018 mole) was
dissolved in morpholine (30 ml). The solution was heated
with stirring to 50 -60C. for 6 hr. The morpholine was
then removed by rotary evaporation ( goC. vacuum pump).
The residue was taken up in chloroform (100 ml) and washed
with dilute aqueous sodium hydroxide (2 x ~0 ml). The
organic layer was concentrated b~ rotary evaporation (60C,
water aspirator). The residue was recrv~tallized from
ethanol giving 3.26 g (60~) of light yellow crystals,
m.p. 152-153C.
~nalysis: Calculated for ClsH2lN302S: C,58.61; H,6.89
N~13.66
Found : C,58.48; H,6.92;
~,13.6
419A-CIP-~
2~5 6
117
xample 57
2-~ -(Dibutylamino)ethyl~-2,3-dihydro-4-methylpyrido
[3,2-f~1,4~oxazepine-5(4~)-thione oxalate [1~
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido t3,2-f]
~l~4]-oxazepine-5(4H)-thione~ 4 g (O.C16 mole) was
suspended in di-n-butylamine (30 ml). Dimethylformamide
(ca. lQ ml) was added to the stirred mixture until
dissolution occurred. The solution was heated to 140 C.
for }.5 hr with stirring. Di-n-butylamine and dimethyl-
formamide were removed by rotary evaporation (80 C. vacuum
pump). The residue was then diluted with dilute aqueous
sodium hydroxide (50 ml) and extracted with chloroform
(~ x 40 ml). Chloroform was removed by rotary evaporation
(70 C, water aspirator). The residue was dissolved in
boiling isopropyl alcohol and treated with oxalic acid.
Upon cooling, the resulting oxalate salt was filtered
and recrystallized from isopropyl alcohol to give 3.2 g
(47%) of yellow crystals, m.p. 208C.
A~lysis: Calculated for C21H33N3O5S: C,57.38; H,7.57,
N,9.56
Found : C,57.04; H,7.63;
N,9.~1
Example 58
2-r2-~Diethylamino)ethyl]-2,~-dihYdro-4-methylpyrido
~3~2-f~,4]oxazepine-~4H~thione oxalate ~1:11.
2-(2-Chloroethyl)-2,3-dihydro-4-methyl[3,2-f~[1,4]
oxazepine-5(4H)-thione, 4 g (0.016 mole) was suspended in
diethylamine (30 ml). Dimethylformamide was added to the
~irred suspension until dissolution occurred (10 ml). The
~tirred solution was heated to 65 C. for 8 hr. Diethylamine
was removed by rotary evaporation (70 C, water aspirator);
~ 30 the remaining dimethylformamide was removed at low pressure
: (vacuum pump) and 90 C. The residue was taken up in
chloroform (100 ml) and washed with dilute a~ueous sodium
hydroxide ~2 x ~0 ml). The organic layer was concentrated
by rotary evaporation (70 C, water aspirator). 'rhe residue
~5 was dissolved in boiling isopropyl alcohol and treated with
oxalic acid. Upon cooling, the oxalate ~alt, 1.7 g ~28.5O
was obtained, m.p. 142-144C.
419.~~CIP-2
118
Analysis calculated for Cl7H25N3O5S- C,5~._5; H,6.57;
~,10.95
Found : C,53.14; H, b .60;
N,10.72
Examele ~
2,~~Dihydro-4-methyl-2- ~-(l-pyrrolidin~l)ethyl]
pyrido~3~2-f][l~4loxazepine-5(4H)-thione oxalate ~1:1~.
2-(2-Chloroethyl)-2,3-dihydro-4-me~hylpyrido[3,2 :f]
[1,4]oxazepine-5(4H)-thione, 5 g (0.02 m~le) wa~;
dissolved in 30 ml of pyrrolidine. The solution was heated
10 to 60 -80C. for 35 minutes with stirring. AFter cooling
to room temperature, the reaction mixture was diluted with
dilute aqueous ~odium hydroxide (50 ml) and extracted with
chloroform (? x 50 ml). The organic layer Wa5 concentrated
by rotary evaporation (70C, water aspirator). Residual
pyxrolidine was removed at 90C. and vacuum pump. The
residue was dissolved in hot ethanol and treated with
` oxalic acid. Upon cooling, the oxalate salt was collected
and recrystallized twice from ethanol to give 3.35 g, (45%)
of product, m.p. 141 C.
20 Analysis: calculated for C-7H23~205S: C,53.53; H,6.o8,
N,11.02
Found : ~,53.39; H~6.11;
N,10.91 -
2,3-Dihydro-2 i 2-(lH-imidazol-l-yl)ethyl~-4~methyl-
pyrido-~3,2 ~ tl,4~oxazepine-5(4H)-thione o~:alate r2 ~.
To a solution of 2-~2-chloroethyl)-2J~-dihydro-4-
me~hylpyrido~,2-f~lJ4~oxazepine-5(4H)-thione, 4.5 g
(0.018 mol~) in dimethylformamide (35 ml) was added
imidazole (2.20 g, o.o38 mole). The resulting solution
was heated to 1~0 C. for 15 hrs. DimetllylEormamide was
removed by rotary evaporation (80 C, vacuurn pump) 9 and the
residue diluted with dilute aaueous sodium hydroxide
~50 ml). The aqueous ~olution was extracted with chloro-
form (1 x 50 ml~, dried o~er anhydrous sodium ~ul~ate and
~5 concentrated by rotary evaporation ~water ~spirator, 70C).
The resulting oil wa3 treat~d with oxalic ~cîd in ethanol.
~our grams ~54%) of pale yellow crystals w~re collected and
419A-CIP-2
5~ 7
119
recrystallized again with ethanol, m.p. 163-167C.
Analysis: Calculated for C17H1907N~S: CJ48.22; H~4.52;
N,13-23
Found : C,48.0ll; H,4.62;
N,13.18
Example 61
2-~2-(Dimethylamlno)ethyll-4-ethyl-2,3-dihydropyrido
~3J2-flElJ4loxaze~in-~(4H)-thione.
.
2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido~3,2-f]
~1,4~ oxazepin-5(4H)-thione hydrochloride~ 5.00 g (0.016
mole) was added to 20 ml of anhydrous dimethylamine. The
reaction flask was sealed tightly and stirred at room
temperature ~or 6 days. The flask was opened after cooling
to 0C. and dimethylamine allowed to evaporate at room
temperature. The residue was taken up in chloroform
(100 ml) and washed with dilute aqueous sodium hydroxide
(1 x 30 ml). The chlorofonn layer was dried over sodium
sulfate9 filtered and concentrated by rotary evaporation.
The residual oil was dissolved in hot cyclohexane. Upon
cooling, 1.76 g (39.4%~ of light yellow crystals were
collected, m.p. 7~C.
Analysis: Calculated for Cl4H2lN30S: C,60.18; H,7.58,
N,15.03
Found : C,60.32; H,7.70;
N,15-13
Exam-ple 6?
2,3-Dihydro-4-methyl-2-~2-~methyl(phenylmethyl)amino]
~thyl~pyrido~3,2-f~1,41oxazepine-5(4H)-thione oxalate
_ _ . _ ~
C l ~
To a solution of 4 g (0.0155 mole) of 2-(2-chloro-
ethyl)-2J3-dihydro-4-methylpyrido~3,2-f~1,4~oxazepine-
5(4H)-thione in 70 ml of chlorofonn was added 10.0 g (0.036
mole) of benzylmethylamine. The ~olution was stirred at
reflux for 24 hr. The reaction solution was washed with
water (2 x 50 ml) and concentrated by rotary evaporation
(~70CJ water aspirator). The residue was distilled on a
molecular still at 165 C./0.1 ~n. The residue wa~ treated
with oxalic acid in hot igopropyl ~lcohol. Upon cooling,
419A-CIP-2
120
two crops of crystals were collected. Th~ purity of each
crop was checked. The two crops were combined and
recrystallized together in hot isopropyl alcohol. Upon
cooling, 3.69 g (55%) of pale yellow crystals, m.p.
5 163-166C were collected.
Analysis: calculated for C2lH25N30ss: C,58-45; H~5-84;
N,9-74
Found : C,58.24; ~,5.92;
N,9.61
ExamPle 63
2,~-Dihydro-2- ~ (methylamino)ethyl)-4-methylpyrido
r3,2-flrl,41oxazepine-5(4H)-thione oxalate ~1:1.51.
2-(2-Chloroethyl)-2~3-dihydro-4-methylpyrido~3,2-f]
[l~4~oxazepine-5(4H)-thioneJ 4-0 g (0-016 mole~ was
suspended in a 30~ solution of methylamine in 70 ml of
ethanol and allowed to stir for 56 hr at room temperature.
Because of incomplete reaction, the reaction solution was
heated slowly vver a 2 hr period to 55C. and stirred at
that temperature for 24 hr. Methylamine was removed by
water aspiration for 1.5 hr. The resulting ~olution was
concentrated by rotary evaporation (70CJ water aspirator).
The residual oil was taken up in chloroform (150 ml~ and
washed with 2 M aqueous potassium hydroxide (2 x 50 ml).
The chloroform layer was dried over sodium sulfate and
concentrated by rotary evaporation (70 C, water aspirator).
The residue was dissolved in hot ethanol and treated with
oxalic acid. Upon cooling, 2.0 g (~7.5O Of yellow
crystals were collected, m.p. 137-1~8C.
Analysis: Calculated for Cl5H20N3O7S: C,46.63; H,5.22;
~,10.67
Found : C,46.47, H,5.35,
N,10.85
~
7-Chloro-2,3-dihydro-4-methyl-2 -r2 -r l-pyrrolidino)
ethyl~pyridot3,2-f~1,4~oxazepin-5(4H)-one fumarate_ ~ 5~k
7-Chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido
t332-f]~l94]oxazepin-5(4H)-one ~2.5 g, 0.009 mole~ w~s
~5 dissolved in 50 ml pyrrolidine and the solution was heated
tv 80C. for 1 hr. The pyrrolidine was xemoved by rotary
4 19A-CIP~
~Z~51~7
121
evaporation (80C., water aspirator) and the residue
dissolved in 100 ml of chloroform. The organic layer was
washed with water (2 X 50 ml~, dried over sodium sulfate
and concentrated by rotary evaporation (~80C., water
aspirator). The residue was treated with fumaric acid and
allowed to stand o~ernight. The resulting crystals were
collected, 1.25 g (23.2~), m~p. 164-166C.
Analysis: Calculated for C25H30N3ol2cl: C,50-05; H,5.o4;
N,7.00
Found : C,50.22; H,5.14;
N,7.02
~
7-Chloro-2-~2-(dimethylamino)ethyll-~,3-dihydro-4-
methylpyrido~3,2-f][1,41oxazepin-5(4H)-one oxalate Ll:ll.
A 2.8 g (0.01 mole) sample of 7-chloro-2-(2-chloro-
ethyl)-2,3-dihydro-4-methylpyrido[3,2-f]~1,4]oxazepin-5(4H)-
one was added to 25 ml of dimethylamine and stirred for96 hr in a sealed flask. The excess amine was allowed to
evaporate and the residue was partitioned between chloroform
and dilute sodium hydroxide. The chloroform was dried over
sodium sulfate and concentrated. The residue was treated
with 0-7 g of oxalic acid in isopropyl alcohol. The
resulting crystals were recrystallized from the same solvent.
Yield was 1.5 g of oxalate salt (40%), m.p. 150-156 C.
Analysis: calculated for Cl5H20N30~Cl: C,48.20; H,5.39;
N,11.24
Found : c,48.og; H~5.47
N,11.12
ExamPle 66
4-Cyclohexyl-2 -r_ dlmethylamino)methyll-2,~-dihydro-
pyrido[~,2-1 r 1,41oxazepin-5(4H)-one oxalate.
Utilizing the procedure of Example 10, 2-(chloro-
methyl)-4-cyclohexyl-2,3-dihydropyridot3,2-f][1,4]oxazepin-
5(4H)-one (Intermediate ~5) is reacted with 40~ aqueous
dimethylamine and reacted with oxalic acid in isopropyl
alcohol.
4l9A-cIp-2
~2f~6~'~
122
Example 67
2-~Dimethylamino)ethyll-2,3-dihydro-4-phenylmethyl-
pyrido~3,2-f~ ~ 4 ~ azepin-5(4H)-one oxalate [1:1.5
hemihydrate.
A solution containing 94.2 g (o.6 mole) o 2 chloro-
5 nicotinic acid and 100 9 (0.54 mole) of 1-benzyl-3-
pyrrolidinol in 800 ml of dry tetrahydrofuran was added at
a rapid drop to a stirred suspension of 52 g (1.3 mole) of
60~ sodium hydride/mineral oil in 500 ml of dry tetrahydro-
furan at reflux temperature (addition tlme was about 1 hr).
The mixture was heated to reflux for an additional 1.5 hr
and then cooled to room temperature. Approximately 1 liter
of ethyl acetate was added and filtration attempted
unsuccessfully. The mixture was allowed to stand overnight
at room temperature and then was concentrated on the rotary
15 evaporator at 100C. and 50 mm pressure. The residue was
dissolved in 1 liter of chloroform and the pH of the
solution was adjusted to 6.15 with hydrogen chloride gas.
To the solution was added, with stirring, 383 g (1.0 mole)
of triphenylphosphine and 383 g (2.48 mole) of carbon
tetrachloride. The mixture was refluxed for 1 hr and 50 ml
o~ ethanol was added. The solution was cooled to room
temperature and extracted three times with ~00 ml portions
of dilute hydrochloric acid. The chloroform layer was
extracted with dilute sGdium hydroxide, dried over sodium
sulfate and concentrated. The mass spectra indicated the
presence of 2-(2-chloroethyl)-2,3-dihydro-4-(phenylmethyl)
pyrido~3,2-f~1,4~oxazepin-5(4H)-one (mass 316), triphenyl-
phosphine (mass 26~) and triphenylphosphine oxide (mass 278).
one-third of the residue was chromatographed on a high
pressure liquid chromatopraph in an unsuccessful attempt to
purify the compound. The other 2/3 of the residue was
dissolved in 30 ml of chloroform and added to a ~olution
of 30 g of dimethyl amine in ethanol. The solution was
heated to reflux for 4 hr and concentrated on the rotary
evaporator. The residue was partitioned between chloroform
and 1 ~ hydrochloric acid. The acid layer was made basic
4~9A CIP-2
i6~7
123
with sodium hydroxide and extracted with chloroform. The
chloroform layer was dxied over sodium sulfate and concen-
trated. ~he residue (10 g) was treated with an eguivalent
amount of oxalic acid in a mixture of isopropyl alcohol-
ethanol-isopropyl ether. The resulting crystals in the
amount of 9 g (5%) were recrystallized from the same solvent
mixture, m.p. 95-98 C.
Analysis: Calculated for C44H54N60l7: C,56-28; H,5-79;
N,8-95
Found : C,56.61; H,5.76;
N,8-77
Example 68-a
2-~2-(Dimethylamino)ethyl]-2,3-dihydropyrido[3,2-f
~1,41oxazepin-5(4H)-one.
A solution of 3.0 g (0.006 mole) of 2-~2-(dimethyl-
amino ethyl]-2,3-dihydro-4-phenylmethylpyrldo~3,2-f][1,4]
oxazepin-5(4H)-one oxalate rl:l.5]-hemihydrate in about
50 ml of water was made basic with dilute aqueous sodium
hydroxide solution and then extracted with three 50 ml
portions of benzene. The combined benzene extract was
dried over anhydrous sodium sulfate and concentrated on
the rotary evaporator (steam bath/50 mm). The residue was
dried further by azeotroping 2 times with about 50 ml of
dry benzene, evaporating to dryness each time. The ~inal
residue was dissolved in 40 ml of liquid ammonia and
small spheres of sodium were added with stirring to the
solution until a blue color persisted for 20 minutes.
(Addition time was about 1 hr). Three grams of ammonium
chloride was added slowly and the ammonia was allowed to
evaporate. The residue was suspended in chloroform and
the mixture was filtered. The filtrate was concentrated
and the residue chromatographed on preparative high pressure
liquid chromatograph using a silica gel column and eluting
with 75% ~thyl acetate/25% dimethylformamide. The yield
of product was 0.1 g (7~. The chemical ionizativn
mass spectrophotometer gave a peak at 236 corresponding to
a molecular weight of 2~5. The lH NMR spectrum of the
', 1 ~A -c I ~-2
6 ~ 7
124
subject compound was obtained in CDC13 containing
1% tetramethylsilane (TMS) and is consistent with the
proposed structure and dimethylformamide (DMF) and mineral
oil as minor impurities. The chemical shifts, multi-
plicitiesJ and assignments are given below:
~ CH2 CHz N ( CH3 ) 2
~3 o ~
Chemical Shifts (multiplicities) Assiqnments
8.45 (multiplet) H(8) and H(6)
8.oo (singlet) C-H (DMF)
7-85 broad singlet) N-H
1 7.20 doublet of doublets) H(7)
4-65 pentet) ~(2)
4.05 broad singlet) unknown impurity
3 50 triplet? H2(3)
2.95 ~sin~let~ CH3 DMF )
2.90 ~singlet~ CH3 DMF )
2.60 (triplet) H2t !to amino nitrogen
2.25 (single~) N(CH3)2
2.05 (multiplet) H2-~ to amino nitrogen
0.7-1.7 (multiplet) mineral oil
ExamPle 68-b (Refer to Chart VIII)
2-~2-(Dimethylamino)ethyl)-2,3-dihydropyrido~3,2-f]-
1,4-oxazepin-5(4H)-one fumarate Cl ll.
An 8 g (0.026 mole) sample of 2-chloro-N-~4-(dimethyl-
amino)-2-hydroxybutyl~ 3-pyridinecarboxamide monohydro-
chloride was partitioned between chloroform and dilute sodium
hydroxide. The chloroform was dried over anhydrous #odium
6ulfate and concentrated. The residue was dissolved in 80 ml
of dry benzene which was removed on the rotary evaporator
~ (100C./~0 min~. The residue in 20 ml of dry tetrahydrofuran
was added ~lowly to a stirred su~pension of 8.~ g (0.052
mole) of potassium hydride/mineral oil in 80 ml of dry
tatrahydrofuran. The mixtur~ was stirr~d at reflux for ~ hr,
~ooled and treated with 10 ml of isopropyl alcohol. The
solution was partitioned between isopropyl ether and dilute
hydrochloric acid. The acid layer was made ~asic with
sodium hydroxide and extracted 4 tim~s with chloroform. The
chloroform was concentrated and the re~idue w~s chromato
graphed on HPLC (Eilica; 90% ethanol-10% triethylamine. ~he
419A-CIP-2
~S~4~7
125
desired fractions were concen~rated and th~ residue (1.3 g)
treated with 0.7 g of fumaric acid in 25 ml of isopropyl
alcohol The resulting crystals weighed 1.2 g (13~)
and melted at 160-164C.
Analysis: Calculated for Cl6H2lN~O~: C,54.69; H,6.o2;
N,11.96
Found : C,54.29; H,6.o2;
N,11.54
- ExamPle 69
2-~ ~-(Dimethylamino~propyll -2 ,3-dihydro-4-methylpyrldo
L3,2-fl~1,41oxazepin-5(4H)-one fumarate Ll:1.5~ hemihydrate.
To 5.0 g (0.21 mole) of 2-(3-aminopropyl)-2,3-dihydro-
4-methylpyrido~3,2-f]~1,4~-oxazepin-5(4H)-one was added,
while cooling in a watex bath, an 88~ a~ueous solution of
formic acid, 20 g (0.38 mole). To the resulting solution
was added a solution of 37~ aoueous formaldehyde (inhibited
with 13~ methanol), 10.7 g (0.13 mole). The resulting
solution was heated on a steam bath for 5.5 hr. The mixture
was cooled and 100 ml of dilute aaueous hydrochloric acid
was added. The solution was evaporated to dryness and the
residue was dissolved in 50 ml of water. The solution was
neutralized with dilute aaueous potassium hydroxide and
extracted with four 50 ml portions of chloroform. The
combined chloroform extracts was dried over sodium sulfate
and concentrated by rotary evaporation. The residue was
reacted with fumaric acid in hot isopropyl alcohol. The
collected product, 3.0 g (31.8O was recrystallized twice
from isopropyl alcohol, m.p. 108-110C.
Analysis: Calculated for C~oH5~N~0l7: C,53.81, H,6.32;
N,9.41
Found : C,53.69; H,6.33,
N,9.41
419A-CIP-2
i6~7
126
Example 70
2-~3-(Dimethylamino)propyll-?,3-dihydro_4-meth~lpyrido
-f lr l 4loxazePine-~(4H)-thione oxalate [1.2l.
To a solution of ll.0 g (0.042 mole) of 2-[3-(dimethyl-
amino)propyl]-2, 5-dihydro-4-methylpyrido[3,2 ~:E] ~1, 4 ~-
oxazepin-5(4H)-one in 125 ml of pyri~ine was added 9.25 g
(0.042 mole) of pho~phorus pentasulfide. The mixture was
heated to reflux for ~.5 hr while stirring. After cooling
to room temperature, the reaction solution was added to an
equal volume of 2 molar potassium hydroxide. The mixture was
extract~d with 800 ml of methylene chloride in several
portions. The organic phase was washed with three lO0 ml
portions of dilute potassium hydroxide, dried over sodium
sulfate, filtered and concentrated by rotary evaporator
(water-aspirator, 70C.)c The residual oil was subjected
to reduced pressure of the vacuum pump for 2 hr at 90C.
and then cooled and reacted with oxalic acid in isopropyl
alcohol. Two crops, 4.5 and 3.1 g were collected, combined
and recrystallized from isopropyl alcohol to give 6.5 g
(~4%) of yellow crystals, m.p. 136-138C.
Analysis: Calculated for Cl8H25N3OgS: CJ47.05; H~5.42
~J9.16
Found : C,46.76; HJ5.75;
N J 9 . 04
Example 71
7-Chloro-2-~2-(dimethylamino)ethyl]-2,3-dihydro-4-
methylpyrido~3,2- ~ ~l4loxazepine-5(4H)-thione fumarate
hemihydrate, hemiisopropyl _lcoholate.
To 55 ml of a methanolic solution containing 57% by
volum~ dimethylamine was added 2.50 g (0.009 mole) of
7-chloro-2-(2-chloroethyl)-2,~-dihydro-4-methylpyrido
t3J2-f]tlJ4~-oxazepine-5(4H)-thione. The reaction vessel
was ~ealed and allowed to stand ~or 16 hr. Thin-layer
chromatography indicated the reaction was about 60%
complete. The solution was heated gradually to 45C.
(heating time about 5 hr). Methanol and unreacted dimethyl-
amine were removed by rotary evaporator (water aspirator,
60 C.~. The residue was taken up in lO0 ml of chloroform
and the ~olution was washed with two 40 ml portions of
419A-CIP-2
~2~56~
127
water. The organic layer was dried over sodium sulfate,
filtered and concentrated by rotar~ evaporator. The residue
was reacted with fumaric acid in isopropyl alcohol. The
xesulting crystals, 1.4~ g (36.5~) were recrystallized from
5 isopropyl alcohol and dried thoroughly in a drying pistol,
m.p. 98-104C.
Analysis: Calculated for C37H~N60l2ClzS2: C,48.84; H,5.98;
~,9.23
Found : C,48.82: H,5.80,
N,9.37
Example 72
2,~-Dihydro-4-methyl-2-r2-(methylamino)ethyllpyrldo-
L3,2-flrl,4~-oxazepin-5(4H)-one oxalate rl:l~.
To 90 ml of a solution of 30~ monomethylamine in ethanol
was added 11.0 g (0.04 mole) of 2-(2-chloroethyl)-2,3-dihydro-
4-methylpyrido~3,2-f~-1,4-oxazepin-5(4H)-one hydrochloride.
The solution ~as heated gradually over a period of 2 hr to
55 C0 and held at that temperature overnight.
Monomethylamine and ethanol were removed by rotary
evap~ration (water aspirator, 70C.) and the residue was
taken up in 100 ml of chloroform. The organic layer was
washed with dilute aqueous sodium hydroxide (2 x ~0 ml),dried
over anhydrous sodium sulfate, filtered, and concentrated by
rotary evaporation (70C, water aspirator). The 9.0 g of
crude oil was treated with oxalic acid in isopropyl alcohol.
The resulting crystals weighed 8.77 g (67.80 3 m.p.
148-50C.
Analysis: calculated for Cl4Hl~N306: C,51.69, H,5.89;
~,12.92
Found : C,51.88, H,5.97;
N,12.96
Example 73
?-~AminoethYl~ -2 ,3-dihYdro-4-methvlpYrido~3,,2-f][1,4
3 oxazepin-5(4H)-one, fumarate ~
To a suspension of 17.0 g (o.o48 mole) of 2,3-dihydro-
2-~1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-4-methyl-
pyridot3,2-f~oxazepin-5(4H)-one in 100 ml of absclu~e
ethanol was added 3.0 g ~0.051 mole) of 85% hydrazine hydrate
in water and the mixture heated to reflux with stirring. In
15 minutes the reaction mixture became clear. After 40 min
419A-CIP-2
~2,~5~7
128
a copious precipitate of presumably ph~haly hydrazide had
~Grmed. Another 100 ml of absolute ethanol was added to
ensure good mixing. After 2 hr at reflux, the cooled mixture
was filtered. The filtrate was concentrated on the rotary
evaporator (water aspirator, 80C.) and the residue taken up
in 75 ml of chloroform. The organic layer was washed with
dilute aqueous sodium hydroxide (2 x 3 ml~, dried over
anhydrous sodium sulfate, filtexed, and the filtrate concen-
trated by rotary evaporati~n (water aspirator, 75C.). The
residue was treated with fumaric acid in isopropyl alcohol
and yielded 7.0 g (4~0 of pale white crystals, m.p.
196-197C.
~nalysis: Calculated for Cl5HlaN30~: C,53.41, H,5.68:
N,12.46
Found : C,5~.63; H~5.78
NJ12~33
Example 74
2-(2-Aminoethyl)-2,3-dihydro-4-methylpyrido~,2-fl~1,4
oxazepin-5(4H)-thione, fumarate ~2:1].
To a suspension of 12.15 (0.03~ mole) of 2-~2-(2,~-
dihydro-5(4H)- thioxopyrido~3,2-f]~1,4~oxazepin-2-yl)ethyl]-
20 lH-isoindole-1J3(2H)dione in 150 ml of absolute ethanol was
added 2.08 g (0.035 mole) of an 85~ solution of hydrazine
hydrate in water. The mixture was heated to reflux for 2 hrs.
After cooling, solid phthalylhydrazide w~s filterad off.
Ethanol was removed by rotary evapoxation (85 C.,water aspirator)
and the residue partitioned between 180 ml chloroform and
50 ml dilute aqueous sodium hydroxide. The organic layer was
washed further with dilute aqueous sodium hydroxide (3 x 30
ml), dried ov~r anhydrous sodium sulfate, filtered and conce~-
trated by rotary evaporation (water aspirator, 7UC.~. The
crude oil was treated with fumaric acid in isopropyl alcohol
which yielded 6.70 g (68.7~) o~ pale yellow crystals,
m.p. 2Q8-o9C.
Analysis: calculated for Cl~Hl7N303S: C,52.87; H,5.80:
~,14.~3
Found C,52.72; H,5.81,
N,14.16
419A-CIP-~
~2~S~
129
Example 75
2,~5-Dihydro 4-methyl-2[2-L(l-methylethyl)amlnolethyl
pyrido~3~2-f~[l,4]oxazepin-5(4H)-one~ fumarate ~1:21.
Tc a solution of 2.52 g (0.011 mole) of 2-(2-aminoethyl)-
2,3-dihydro-4-methylpyrido~3~2-f]~l~4]oxazepin-5(4H)-one in
5 50 ml dry methanol was added methanolic hydrogen chloride
until pEI 6 was reached. To this solution was added 3.29 g
(0.057 mole) of acetone, 1.79 g (0.029 mole) of sodium
cyanoborohydride and 5 g 3A molecular sieves. The pH was
checked and readjusted to pH 7-8 with methanolic hydrogen
10 chloride and stirr~?d 24 hr at room temperature. The reaction
mixture was filtered, and concentrated by rotary evaporation
(7() C., water aspirator). The residue was taken up in
100 ml of chloroform, washed with dilute aqueous sodium
hydroxide, dried over anhydrous sodium sulfate, filtered,
15 and concentrated }~y rotary evaporation (water aspirator,
70 C.). The residue was treated with fumaric acid in
isopropyl alcohol which gave 1.58 g (295b) of white crystals~
m.p. 152-153C.
Analysis: Calculated for C22H2gN3Olo: C,53.33, H,5.89;
N,8.48
Found : C,53.43; H,5.94,
N,8.54
Example 76
2-~2-~is(phenylmethyl)aminolethyll-2,~i-dihydro~4-
methylpyrido~3,2-f~tl,41oxazepine-~(4H)-thione, fumarate rl~
To a solution of 3.15 g (0.013 mole) of 2-(2-aminoethyl)-
2,3-dihydro-4-methylpyrido~3,2-E]~1,4]oxazepine-5(4E~)thione
in ~25 ml dry methanol was added methanc>lic hydro~en chloride
to pH 5-6, followed byP~ 2-3 g 3A molecular sieves, 6.89 g
(0.065 mole) benzaldehyde and 2.04 g (0.0325 g)sodium cyano-
borohydride. The pH was again adjusted to pH 7 with methanolic
hydrogen chloride. A~ter 6 hr of stirring at room temperature,
TL{ (eluting with 6~ triethylamine in methanol) ~howed what
appeared to be exclusively monoalkylated product with very
ittle starting material. To the reaction mixture was then
~i5 added 1.0 g to.oog mole) of benzaldehyde and the mixture
~;tirred overnight at room temperature. The reaction mixture
was filtered and concentrated by rc)tary evaporation (70 C.,
4 l9A-cIp-2
;6~7
130
water aspirator). The residue wa~ taken up in 100 ml of
chloro orm and wash2d with 2 x 30 ml dilute aque~us sodium
hydroxide. The chloroform was removed by rotary evaporation
(70 C., water aspirator~. The xesidue was dissolved in
100 ml dilute hydrochloric acid which was sub3equently washed
with 2 x 30 ml ethyl acetate, made basic with dilute aqueous
sodium hydroxideJ extracted with 4 x 30 ml chloroform. The
chloroform was dried over anhydrous sodium sulfate, filtered
and concentrated ~y rotary evaporation (70C, water
aspirator. The residue showed both the mono- and di-alXylated
product by TLC (6~ triethylamine/94 methanol) and NMR.
To a solution of the 3.0 g crude material dissolved
in 30 ml dry methanol was added methanolic hydrogen chloride
to pH 4-5, 10.0 g (10.094 mole) of benæaldehyde and 2.00 g
(0.0319 mole) of sodium cyanoborohydride. The pH was neutral.
To the reaction mixture was added -1 g of 3A molecular
sieves~ The reactio~ mixture was stirred for 6 days at
room temperature.
The methanol was removed by rotary evaporation (70C,
water aspirator) after filtration. The residue was diss~lved
in ~100 ml chloroform and washed with 2 x 50 ml dilute
aqueous sodium hydroxide. The chloroform was xemoved by
rotary evaporation (70J water aspirator) and the residue
dissolved in 100 ml of dilute aqueous hydrochloric acid.
The aqueous layer was washed with 2 x 50 ml of ethyl acetate
(the ethyl acetate was extracted with 2 x 30 ml of dilute
hydrochloric acid and all acid layers combined; this was
done because the product appeared to be somewhat soluble
in ethyl acetate). The hydrochloric acid layer was made
~0 basic with concentrated sodium hydroxide solution and
extracted with 2 x 50 ml of chloroform. The chloroform
layer was dried over ~nhydrou5 xodium ~ulfate, filtered and
concentrated by rotary ~vaporation (70~C, water asplrator. The
3.0 g of crude product obtain~d was di6solved in ho~ isopropyl
35 ~lcohol)~nd treated with fumaric acid. The resulting
crystals, 1.40 g (20.2 O , melted at 123-126 C. with sli~ht
~hrinkage occurring at 118C.
Analysis: Calculated for C~31N305S: CJ65.27; H,5.86~ ~7.87
Found : C,65.11: H,5.87; ~,8.05
~l9~-CIP~2
~2g~6~7
131
Æxample 77
2,~-Dihydro-4-methyl-2 r2-(~-methyl-1-pip~razinyl~ethyl
pyrido[3,2-~1rl,41oxaze~in-5(4~)-one fumarate rl:2~mono-
hydrate.
To a solution of 10.45 g (0.043 mole) of 2-(2-chloro-
ethyl)-2,3-dihydro-4-methylpyrido~,2-f]-1,4-oxazepine-5(4H)-
one in 80 ml of absolute ethanol was added 10.84 g (0.1084 mole)
o~ N-methyl piperazine and the resulting solution heated to
reflux for 4 hr. .~t ~ha~ time, because ~25$ starting material
was present by mass spec, an additional 5.0 g (0.05 mole) of
N-methyl piperazine was added and heating to reflux was
continued for 2 hr. Ethanol was removed by rotary evaporation
(70, water aspirator) and the residue diluted with 150 ml
of water. The water was extracted with 4 x 50 ml of chloro-
form and the oryanic layer was washed with 2 x 50 ml of water,
dried over anhydrous sodium sulfate, filtered and concentrated
by rotary evaporation (70C, water aspirator). The residue
was concentrated (vacuum pump/95-100 C.) for 3.5 hr. Treat-
ment of the residue with fumaric acid in isopropyl alcohol
yielded 8.45 g (35.4~) of pale white crystals, m.p. 162-
167C.
Analysis: calculated for C24H34~40ll: C,51-98: H,6-17
N,10.10
~ound : C,52.0~; H,6.oo:
N,10.17
ExamDle 78
2.3-Dih~dro-4-methyl-2-r2-~4-methYl-l-piperazinYl)ethyl]
pyridor3,2-f~1,4~oxazepine--~(4HL-thione rumarate r~
hemihydrate.
To 8.o g (0.0~1) mole of 2-(2-chloroethyl)-2~3-dihydr
4-methylpyrido[3,2-f]-1,4-oxazepine-5-(4H)-thione in 80 ml
of absolute ethanol was added 9.30 g (0.093 mole) of ~-methyl
piperazine. The mixture was heated to reflux for 2 hr and
an additional 5.0 g (0.05 mole) N~methyl piperazine was
added. Reflux was continued or an ~dditional 5 hr.
Ethanol was removed by rotary evaporation (90C, water
aspirator). Residual N-methyl piperazine was r~moved at
90 C. with vacuum pump for 2 hr. The residue was taken up
in 150 ml of chloroform and washed with 2 x 50 ml of water.
The organic layer wa~ dried over anhydrous sodium ulfate,
filtered and concentr~ted by rotary evaporation (90C, water
419-CIP-2
2 ~ 7
132
aspirator). The residue was concentrated further with a
vacuum pump at 90C. The 10.0 g of crude material was
treated with fumaric acid in isopropyl alcohol which yielded
10.0 g (57.4%) of light yellow crystals, m.p. 184-185 C.
Analysis: Calculated for C24H33N403.5S:C,51.32; H,5.92;
~,9.98
Found :C,51.56; H,5.89,
N,9.8
Example 79
2-r2-t4-~Bis(4-fluorophenyl)methyl~ piperidinyl
10 ethyll-2,~-dihydro-4-methylpyridot~,2-f ~ ,41-oxazepin-5(4H)
one dihydrochloride he hydrate.
Ten grams (o.036 mole) of 2-(2-chloroethyl)-2,3-
dihydro-4-methylpyrido~3,2-f]-1,4-oxazepin-5-(4H)-one
hydrochloride were partitioned between dilute sodium hydroxide
and chloroform. The chloroform was dried over Rodium sulfate
and concentrated on the rotary evaporator. The residue was
dissolved in 50 ml of ethanol and 10.3 g (o.036 mole) of
4-tbis(4-fluorophenyl)-methyl~piperidine was added. The
solution was heated to reflux for 18 ~r and concentrated
on the rotary evaporator. The residue was partitioned
between dilute sodium hydroxide and chloroform. The
chloroform was dried over anhydrous sodium sulfate and
concentrated. The residue was chromatograph~d on a Waters
500 HPlC (silica/92~ ethyl acetate-8% triethyla~ine~. After
concentration of the desired product, the residue was
dissolved in isopropyl alcohol and treated with ethereal
hydrogen chloride. The re ulting crystals weighed 3 g (14~)
and melted at 150-180C.
Analysis: Calculated for C5sH~gN6o5cl4F~: C,60.73; H,5.98
N,7~33
Found : C,60.~0; H,6.o4
N,7.12
ExamPle 80
2-r2-(4,5-Dihydro-lH-imidazol-2-yl~eth~11-2,~-dihydro-
4-methylpyridor~,2-flrl,4 ~oxazepin-~(4H)-one oxalate ~
Into a cooled (water bath) solution of 10 g (0.043 mole)
of 2,3,4,5-tetrahydro-4-mPthyl-5-oxopyrido~3,2~ 1,4]
oxazepine-2-propane-nitrile in 50 ml of ethylenediamine was
bubbled hydrogen sulfide gas for 10 min. The reaction flask
419A-CIP-2
6~7
1~
was tightly stoppered and left standing at room temperature
for 5 days. The reaction solution (now partially solidified)
was diluted with 100 ml of dilute sodium hydroxide and
extracted with 5 x 30 ml of chloroform. The organic extracts
were dried over anhydrous sodium sulfate, filtered, and
concentrated by rotary evaporation (70C. water aspirator).
The entire residue was dissolved in 50 ml of ethylenediamine
and saturated with hydrogen sulfide for 10 minutes while
cooling in a water bath. The flask was tightly stoppered
and left standing at room temperature for 5 days. The
contents of the reaction flask were diluted with 200 ml of 2N
aqueous potassium hydroxide a~d extracted with 3 x 125 ml
of chloroform. The organic extracts were washed with 3 x 50
ml 2N aqueous potassium hydroxide and extracted into 3 x
5 ml of dilute aqueous hydrochloric acid. The acid extxacts
were basified with concentrated sodium hydroxide and extracted
into 3 x 40 ml of chlofoform. The organic extracts were
dried over sodium sulfate, filtered and concentrated by rotary
evaporation. The syrupy residue was treated with oxalic acid
in isopropyl alcohol to give 3.5 g (22%) of white crystals.
One recrystallization from isopropyl alcohol afforded an
analytical sample, m.p. 198 C. with decomposition.
Analysis: Calculated for Cl~H2lN406: C,52.74, H,5.53;
N715-~8
Found : C,52.76; H,5.58;
N,15-51
Example 81
2,3-Dihydro-4-methyl-2-[2-(methylphenyl~mino~ethyl
pyrido~3,2-f~1,41oxazepine-5(4~-thione.
To a suspension of 2-(2-chloroethyl)-2,~-dihydro-4-
methylpyrido~3,2-f]~1~4]oxazepine-5(4H)-thione in 100 ml of
toluene was added 11.49 g (0.11 mole) N-methylaniline and
the mixture heated to re~lux with stirring for 2 days (after
approx. 6 hr, ~3.0 g (0.22 mole) additional N-methyl~niline
was added). Toluene was remvved by rotary evaporation
(90 C., water aspirator). The N-methylaniline was removed
also by rotary evaporation (90 C., vacuum pump~. The residue
was taken up in 100 ml of chloroform and washed with 3 x 30
ml dilute aqueous sodium hydroxide. The organic layer was
dried over ~nhydrou8 sodium sulfate, filtered and concentrated
419A-CIP-2
56~7
1~4
by rotary evaporation (80C., water aspirator). ~ore
N-methylaniline was removed with the vacuum pump at 90 C.
for several hours. To the residue was added 150 ml of ethyl
acetate at which point some product crystallized out.
However, since much remained in solution, preparative HPLC
on a silica gel column eluting with 60~ hexane/40~ ethyl
acetate was effected. After concentrating the flasks
containing the product, crystallization was effected induced
by seeding. The chromatographed product was recrystallized
from ethyl acetate/isopropyl alcohol and amounted to 1.1 g
m.p. 164-5C. Approximately 2 g additional was collected
by recrystallization of crude product, m.p. 163-4 C. The
combined yield was 3.1 g (26%).
Analysis: calculated for Cl8H~lN30S: c,66.o3; H,6046;
N,12.83
Found : C,65.72; H,6.51
N,13.1
Example 82
2-(3-Aminopropyl)-2~3-dihydro-4-methylpyrldor~2-f~rl~4
oxazepine-~(4H)-thione ~umarate tl~
A sample of 15.0 g (0.064 mole) of 2-(3-aminopropyl)-
2,3-dihydro-4-methylpyrido~3,2-:E]!1,4]-oxazepin-5(4H)-one
was di~solved in 50 ml methylene chloride and to it was
added 15.24 g (0.07 mole) of di-tertbutyl dicarbonate. ~he
solution was stirred for 30 minutes at room temperature. The
protected amine was purified by HPLC on a silica gel column,
eluting with ethyl acetate. Approximately 15 g (0.045 mole
70-30 of the protected amine was collected as an oil. To
a solution of 1~.5 g (0.04 mole) of this oil in dry toluene
was added 8.16 g (0.02 mole) of 2,4-bis(4-methoxyphenyl)-
1,3-dithia-2,4-diphosphetane-2,4--disulfide. The reaction
mixture was heated to 80 C. for 2 hr. An additional amount
(2.0 g, 0.005 mole) of 2,4-bis(4-methoxyphenyl3-1,~-dithia-
2,4-diphosphetane-2,4-disulfide was added and heating
continued ~or 1 hr. Another 4.0 g (0.01 mole) of 2,4-bis-
~5 (4-methoxyphenyl)-1,3-dithia-2J4-diphosphetane-2,4-disulfide
was added and the heating continued for 5 hr. After cooling,
the toluene was decanted off, washed with 5 x 30 ml dilute
aqueous sodium hydroxide, dried over sodium sulfate, filtered
and concentrated by rotary avaporation. Isopropyl alcohol
419~-CIP-2
~2~LS~4~7
was added to the residue, resulting in pxecipitation of an
impurity (possi~ly spent Lawesson's Reagent). Isopr~pyl
alcohol was removed by rotary evapora~ion and the residue
purified by HPLC on a silica qel column, eluting with 1%
methanolj99~ ~hloroform. Approximately 6 g (0.017 mole,
42.6~) of material was collected and treated with 100 ml of
a solution of trifluoro acetic acid~anisole/methylene
chloride, 40/10/50, v/v/v for 30 minutes. The solvent blend
was removed by rotary evaporation (70C, water aspirator)
and the residue taken up in 150 ml ~f methylene chl~ride.
This layer was washed with 3 x 4b ml dilute a~ueous sodi~m
hydroxide, dried over anhydrou~ qodium sulfate, filtered and
concentrated by rotary evaporation. The residue was treated
with fumaric acid in isopr~pyl alcohol, which yielded 4.0 g
(0.011 mole, 64%) of the salt. Recrystallization from
isopropyl alcohol afforded an analytical Qample~ m.p.
154-166C.
Analysis: Calculated for Cl~H2lN2os: C,52-30; H,5~76;
N,11.43
Found : C,52.4~; H,5.83;
N,11.51
Exampl ~
2-r2-~DimethYlamino~ethyl) 2~-dihydropyridor~ 2-f~ r 1 ~41
oxazepine- ~4~ thione dihydrochloride monohydrate.
To 5 g (0.021 mole of 2-L2-(dimethylamino)ethyl~-2,3-
dihydropyridot3,2-f~-1,4-oxazepin-5(4H)-one in 50 ml of
2~ pyridine was added 5.1 g (0.o46 mole) of phosphorus penta-
sulfide. An exothermic reaction insu~d. When the temperature
dropped, the mixture was heated to 70 C. ~or 3.5 hr and
allowed to cool. The mixture was partitioned between dilute
sodium hydroxide and chloroform while cooling by addition
f ice. The a~ueous layer was extracted 3 more times with
chloroform. The ~ombined chlofoform extracts were dried over
anhydrous sodium sulfate and concentrated. The residue was
dissolved in 40 ml of ethanol and made acidic with ethereal
hydrogen chloride. The resulting crystals were recrystal-
lized from 95% ethanol. Yield was 1.4 g ~19%), m.p. 172-
175C.
419~-CIP-2
SEi~L7
1~6
Analysis: Calculated for Cl2H2lN3SO2C12: C,42.10; H,6.1~
N,12.23
Found : CJ42~6; HJ5.74;
N,12.34
ExamPle 84
2-~2-~4-~Bis(4 flu~rophenyl)methyl1-1-piperldinyl~ethyl~
2 ~ 3-dihydro-4-methyipyrido~3~2-fl[l~4]oxazepine-5(4H)-thione
oxalate hydrate ~1:1 1~.
A solution of 4 g (0.016 mole) of 2-(2-c~loroethyl)-
2,3-dihydro~4-methylpyrido~3~2-f]tl~4]-o~azepine-5(4H) -
thlone and 4 5 g (o.01G mole) of 4-~bis(4-fluorophenyl)-
methyl]piperidine in 100 ml of ethanol was refluxed for 48 hr.
One gram of K2CO3 was added and this mixture stirred at
reflux for 144 hr. The mixture was concentrated and the
residue partitioned between chloroform and dilute sodium
hydroxide. The chloroform was dried over anhydrous sodium
sulfate and concentrated. The residue wa~ chromatographed
on a Waters~ 500 HPLC using a silica column and elutiny with
absolute ethanol. The material with mass 507 was collected
and concentrated. The residue t6 9) was reacted with 1.2 g
of oxalic acid in etha~ol. Yield was 5 g, m.p. 125-138 C.
Analysis: Calculated for C3lH35N3O~SF2: C,60.47; H,5.72;
N,6.82
Found : C,60.62; H,5.60,
N,6.58
Example 8~
2J3-Dihydro-4-methyl-2-r2-(lH-pyr~Q~ yl~ethyl]p~rido
_
To a suspension of 2.16 g (0.054 mole) of sodium hydride
in 20 ml of dimethylformamide was added dropwise a solution
of 2.92 g (0.04~ mole~of pyraæole in 10 ml of dimethyl-
formamide. There was a ~light exotherm at this point with
60me evolution of hydrogen gas. The resulting solution was
then added dropwise to a solution of 10.0 9 (0.039 mole) of
2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~3,2-f~-1,4-
oxazepine-~(4H)-thione in 30 ml of dimethylformamide. The
~5 reaction ~ask was ~ealed and stirred overnight a~ room
temperature.
The solvent ~imethylformamide was removed by rotary
~vapoxatiGn (90C; 30 mm). The residue was taken up in 200 ml
of ohloroform which wa~ subsequently washed with 2 x 50 ml
~2,456~7 419A-CIP-2
37
of water followed by 50 ml dil. aaueous sodium hydroxide.
The organic layer was then dried over sodium sulfate,
filtered and concentrated by rotary evaporation (70 C.; 30 mm).
Isopropyl alcohol was added to th~ residue and crystallization
ensued after cooling. The crude crystals (4.5 g) were
recrystallized from isopropyl alcohGl giving 3.45 g (31~)
of yellow crystals, m.p. 119-121C.
Analysis: Calculated for Cl4HlaN40S: C,58.31; H,5.59;
N,19.43
Found : C,58.01; H,5.59;
N,19.~7
Exam~le 86
? -L2-~Dimethylamino)-l-methylethyll-2~3-dihydro-4-
methvl~vridor~ 2-flrl 41-oxaze~in-~r4H)-one oxalate ~
To 4.5 g (0.018 mole of 2-(2-chloro-1-methylethyl)-
2,3-dihydro-4-methylpyrido~3,2-f]-1,4-oxazepin-5(4H)-one
was added 20 ml of methanol and 40 ml of dimethylamine.
The reaction flask was tightly sealed and left standing at
room temperature for 72 hr. The flask was opened after
cooling and the methanol and dimethylamine evaporated.
Another 15 ml of methanol and 40 ml of dimethylamine were
added, the flask sealed tightly and left standing at room
temperature for 7 days. The methanol and dimethylamine
were evaporated and the residue taken up in 100 ml of
chloroform. The chloroform layer was washed with 2 x 50 ml
dil sodium hydroxide and 50 ml of water, dried over anhydrous
sodium sulfate, filtered and concentrated by rotary
evaporation. The crude material which was coliected was
treated with oxalic acid in isopropyl alcohol which afforded
3.5 g (55%) white crystals, m.p. 204-05C.
~0 Analysis: Calculated for Ci~H23N3O~: C,54.38; H,o.56
N,11.89
Found : C,54.32 H,5.61;
N,11.86
~Z~ 7
38
Example 8
2 ~-Dihydro-2-L2-~4,~dihydro-lH-imidazol-2-yl)ethyl]
4-methylpyridor3l2-flrl 41-oxaz~pine-5(4H~-~hione oxalate
.. . _ -- -~_ .
~2~
Into a suspension of 2,3,4,5-tetrahydro-4-methyl-5-
thioxopyridot3,2-f]~1,4]-oxazepine-2-propanenitrile in 30 ml
of ethylene diamine was bubbled hydrogen sulfide gas for
15 min while cooling in a water bath. The flask was then
sealed and stirred at room temperatuxe for 5 days. Mass
~pectra showed much starting material. An additional 15 ml
of methylene diamine was added and the mixture saturated
again with hydrog0n sulfide. The flask was resealed and
left standing for 8 days. The reaction mixture was diluted
with 100 ml dil aqueous sodium hydroxide and extracted
into 3 x 60 ml of chloroform. The chloroform extracts were
combined and washed with 50 ml of water. Some crystal-
lization occurred in the separatory funnel but complete
crystallization could not be effected. The organic layer
was concentrated by rotary evaporation and the resid~e
treated with oxalic acid in isopropyl alcohol. The crude
crystals, 7.0 g, (55 0 were recrystallized from methanol/
etha~ol yielding an analytical sample, m.p. 198-200C.
Analysis: calculated for Cl7HzlN407S: C,47.99; H,4097;
N,1~.16
Found : C~47.63; H,5.09;
N,13.04
Example 88
2-r2-(Dlmethylamino)ethyll-2,3-dihydro-2,4-dimethyl-
pyrido[~,2-flrl,410xazepin-5(4H)-one dihydrochloride.
To 4.5 g (0.015 mole) of 2-(2-chloroethyl)-2,3-dihydro-
2,4-dimethylpyrido[3,2-f~-1,4-oxazepin-5(4H)-one hydro-
chloride in 15 ml of methanol was added 40 ml of
dimethylamine. The flasX was ~ealed tightly and left
standing at room temper~ture for 8 days. The methanol and
dimethylamine were removed by rotary evaporation (70 C; 30
~m). The residue wa- taXen up i~ 150 ml of chloroform,
washed with 2 x 50 ml dil aqueous sodium hydroxi~de, dried
over anhydrous ~odium ~ulfate~ filtered and concentrated by
rotary evaporætion (70 C; ~0 mm). The syrupy residue was
,. . ~ ,
419A~CIP-2
~5~
139
treated with hydrogen ohloride in isopropyl alcohol, which
afforded ~.5 g (67%) of white crystals, m.p. 188-90 C.
Analysis: Calculated for Cl4H2~N302C12: C,50.~1; H,6.89;
~,12.50
Found : C,50.00; H,6.98
~,12.49
5Example 89
2- ~ Dimethylamino)ethyll-2,3-dihy~ro-2~4-dimethyl-
pyrldor3~2-~ ~ 41~azepine-5(4H)-thione monohydrochloride.
To a suspension o~ 4.5 g (0.017 mole) of 2-(2-chloro-
ethyl)-2,3-dihydro-2,4-dimethylpyrido~3,2-~-1,4-oxazepine-
5(4H)-thione in 20 ml of metha~ol, cooled in an ice hath,
wa3 added 40 ml of dimethylamine. The flask was sealed
tightly and left standing at room temperature for 10 days.
The dimethylamine and methanol were removed by rotary
evaporation (60C; 30 mm). The residue was taken up in
15150 ml of chloroform, washed with ~ x 50 ml dil sodium
hydroxide, dried over anhydrous sodium sul~ate, filtexed
and concentrated by r~tary evaporation (70C; 30 mm). The
crude oil wa~ dissolved in isopropyl alcohol and tre~ed
with ethereal hydrogen chloride, which yielded 4.0 g (76%)
of yellow crystals3 m.p. 255 C. with decomposition.
Analysis: Calculated for Cl4H~2~30SCl: C,53.~3; H,7.02;
~,13.~0
Fou~d : C,53.21; H,7.15;
~,13.19
Example ~ (Refer to Ch~rt VII)
25?-t2-(Dimethylamino)ethyll-2,3-dihydro-4-methyl~1,4~-
xazepinot6,7-c~quinol n 5(4~-one oxalate ~
To a suspension of 19.4 g (35% in oil, 0.172 mole) of
KH in 150 ml tetrahydrofuran was added at a rapid drop 12.4 g
; ~o.o85 mol~) of 1-di~ethylamino-4-methylamino-2-~utanol.
30After 10 minute~, 20 g (o.o85 mole~ of 3-~arboxyethyl 4-
chloroquinvline was added by a powder dropping ~unnel over
a period ~f 30 min. The mixture was 3~irred at room
temperature overnight.
Approxim~tely 50 ml ~f water was add~d to quench the
reaction ~nd the mixture partitioned between i~opropyl ether
and water. ~he aqu~ous layer was extractea again with
2 x 70.ml of isopropyl ether~ The a~ueou~ layer was then
419A-CIP-2
~LZ~S6~7
continuously extracted for 15 hr with chloroform. The chloro-
form layer was collected, filtered and concentrated by rotary
evaporation (80C, 30 mm). The crude material (18 g) was
purified by HPLC using silica gel as the stationary phase
and 3% triethylamine/ethanol as the eluent. Approximately
4 g ( 15.6%) of reasonably pure free base of the title compound
was collected. A 1.5 g sample of the free base was reacted
with 0.5 g oxalic acid in 10 ml of ethanol. The resulting
cyrstals weighed ~ g and melted at 214-218C.
Analysis: Calculated for Cl~H23N306: C,58-60~ H~5-95; NJ1O-79
Found : C,58.46, H,6.10; N,10.75
Example ~1
2-~2-(Dimethylamino)-l-methylethyll-2,3-dihydro-4-
methylpyridor3,2-fl~1,4~-oxazepine-5(4H~-thione oxalate
[1 11-
To a suspension of 4.0 g (0.013 mole) of 2-(2-chloro-1-
methylethyl)-2,3-dihydro-4-methylpyrido~3,2~f~[1,4]oxazepine-
5(4H)-thione hydrochloride in 20 ml of methanol cooled in an
ice bath was added 35 ml o~ dimethylamine previously collected
at C. The reaction flask was sealed tightly and left
standing at room temperature for 10 days. The solvent was
removed by rotary evaporation (80 C, water aspirator) and
the residue taken up in 150 ml of chloroform. The organrc
layer was washed with 2 x 50 ml of dilute aaueous sodium
hydroxide, dried over anhydrous sodium sulate, filtered, and
concentrated by rotary evaporation. The crude residue was
treated with oxalic acid in isopropyl alcohol and left
standing overnight at room temperature, yielding 3.1 g (65~)
of yellow crystalsJ m.p. 211-213C.
Analysis: Calculated for C1~H2305N3S: C,52.02; H,6.18; N,11.37
Found : C,51.79; H,6.34, N,11.24
Example ~
2-r2-(Dimethylamino)propyl~-2,3-dihydro-4-methylpyrido
3 2-flrl 410xazepin-5(4H)-one dihydrochloride.
L, I. . .
Into a stainless ~teel bomb was placed 1.0 g sodium
iodide, 5.0 g (0 ~017 mole) of 2-(2-chloropropyl)-2 ,3-
dihydro-4-methylpyrido[3,2-f~1,4]oxazepin-5(4H)-one and
40 ml of dimethylamine. The bomb w~s ~ealed tightly, pl~ced
~2~5647 41 9A -C I P -2
llJl
in the oven at 60C. and rolled continuously for 7 days.
The bomb was allowed to stand at room temperature for several
days. The residue was combined with that of a previous run
of equal size and separated via column chromatography using
silica gel and eluting with ethanol and then with 3~ tri-
ethylamine/ethanol. The fractions containing the desired
product were co~bined and concentrated by rotary evaporation
(80C, 30 mm). The residue was taken up in 150 ml of
chloroform and washed with 2 x 50 ml diluted sodium hydroxide.
The chloroform was removed by rotary evaporation (70 C.,
30 mm) and the residue treated with ethereal hydrogen
chloride and hydrogen chloride in isopropyl alcohol. The
white crystals which were collected weighed 3 g (28%),
m.p. 173-76C.
Analysis: Calculated for Cl4H~3N202Cl2: C,50.01; H,6.89;
N,12.50
Found : C,50.40, H,7.o4
N,12.36
Example 93
2,~Dihydro-4-met y~ r2-(2-methyl~l-pyrrolidiny
ethyllpyridor3 2-flL1 ~ oxazepine-5(4H)-thione fumarate
compound with 2-propanol ~
To a suspension of 5.0 g (0.019 mole) of 2-(chloroethyl)-
2,3-dihydro-4-methylpyrido~3,2-f]-1,4-oxa2epine-5(4H)-
thione in 25 ml of absolute ethanol was added 3.5 g to-o4
mole) of 2-methylpyrrolidine. The mixture was heated to
reflux for 6.5 hr and left standing at room temperature
overnight. Mass ~pec and TLC showed presence of starting
materials. Approximately 5 g of potassium carbonate was
added and heating at reflux was continued for 24 hr.
Ethanol was removed by rotary evaporation (70 C, ~0 mm). The
residue was taXen up in 100 ml of methylena chloride and
washed with 2 x 50 ml dil. aqueous sodium hydroxide. The
; organic layer was dried over anhydrous sodium aulfate,
filtered, and concentrated by rotary evaporation (70C9
~0 mm). The residual syrup was dissolved in isopropyl
aocohol and treated with fumaric acid ~ffording 4.5 g (0.01
mvle, 49.2 O Of crude crystalsO Two recrystallization5
~rom isopropyl a~orded 1.5 ~ (16.4%) of yellow crystals,
419A-CIP-2
516~7
142
m.p., 92-95C~
Analysis: calculated for C23H35N30~S: C,57.~6; H,7.~3,
N,8.72
Found : C,57.12, H,7.30;
N,8.70
~
2- ~ (Dimethylamino)ethyl~-2,3-dihydro-4-methyl-9-
(trifluormethyl)-~1,4~oxazepino~6,7-c~quinolin-5(4H)-one
fumarate ~
To 55 ml of dimethylamine collected over an ice/methanol
bath was added 2.2 g (0.005 mole) of 2-(2-chloroethyl)-2,3-
dihydro-4-methyl-9-(trifluoromethyl)-1,4-oxazepino~6,7-c~
quinolin-5(4H)-one hydrochloride. The flask was sealed
tightly and left standing at room temperature for 6 days.
After cooling to 0C., the flask was opened and the solvent
allowed to evaporate at room temperature overnight. The
residue was taken up in 100 ml of chloroform, washed with
x ~0 ml of dil sodium hydroxide, dried over anhydrous
sodium sulfate and concentrated to rotary evaporation (70 C,
~0 mm). The residual oil was treated with fumaric acid in
isopropyl alcohol and dried, giving 2.2 g (81%) of white
crystals, m.p. 204-05C.
Analysis: Calculated for C22H24N306F3: C,54.66; H,5.00;
N,~.69
Found : C,54.74; H,5.12;
~,~-55
Example
2-~2-(Dimethylamino)ethvll-2?3-dihy~o-4-m
oxazepino~6.7-b~quinolin-~(4~)-one fumarat hYdrate ~l~
To 40 ml uf dimethylamine cooled to ~0 C. in an ice
water bath was added 3.85 g (0.01~ mole) of 2-(2-chloro-
~0 ethyl)-2,~-dihydro-4-methyl-1,4-oxazepino~6,7-b~-quinoline~
5(4H)-one in 25 ml of methanol. The reaction flask was
sealed tightly and le~t standing at room temperature for
5 day~. After cooling, the reaction flask was opened and
the ~olvent allowed to evaporate in a stream o~ air. The
residue was taken up in 100 ml of chloroform and waQhed with
2 x 50 ml of dilute aqueous sodium hydroxide. The organic
layer was dried over anhydrous 60dium sulfate, filteredJ and
conc~ntr~ted by rotary evaporation (70, 30 mm~. The
419A-CIP-~
143
residual oil was treated with fumaric acid in isopropyl
alcohol which afforded ~.7 g (67~) of white crys.als,
m~p. 125-130C.
Analysis: Calculated for C2lH28N30~.5: C,59.43; H, 17;
~,9.90
Found : C,59~59; H,6.35;
N,9.60
Exam~le 95
2-r2-(Dime'hylamino?ethyl~-2~-dihydro-4-methylrl,4]
oxazepinoL5,7-blquinoline-5(4H~-thione fumar~te compound
with isopropanol hydrate ~1:1:0.5:0.5~.
To 45 ml of dimethylamine was added 0.95 g (0.003 mole)
of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxaæepino
~6,7-b]quinoline-5(4H)-thione. The reaction flask was s~aled
tightly and left standing at room temperature for 6 days.
After cooling to 0C., the flask was opened and the solvent
allowed to evaporate at room temperature. The residue was
taken up in 50 ml of chloroform and washed with 3 x 30 ml
of dilute aqueous sodium hydroxide. The organic layer was
dried over anhydrous sodium sulfate, filtered, and concen-
trated by rotary evaporation, yielding 0.94 g of syrup (99
This was combined with 1.0 g of the same product from a
previous run* and treated with fumaric acid in isopropyl
alcohol afording 1.5 9 of yellow crystals~ m.p.l23-26c.
*The previous run was made in the same manner as above
except that hydrochloride salt was collected. However, the
hydrochloride salt partially decomposed upon drying in a
drying pistol at 82.5C. Caution should be ex~rcised not to
; heat the product above the boiling point of acetone (56-57C)
while drying.
Analy-~is: calculated for C22.3~3oN3o~s:c~57.43; H,6.43;
~,8.92
Found :C~57.60; H,6.21;
N,9.02
419A-CIP-2
~2g~56~7
144
ExamplP 97
4-Ethy~ 2~3~4-tetrahydro-2-~2-~4-hydroxy-4-~hen
piperidin~-ethyl~-l-methvl-~H-1 4-benzodiazepin-~one
fumarate compound with 2-proDanol rl~
A mixture of 13.4 g (0.05 mole) of 2-(2-chloroethyl)-
4-ethyl-1-methyl-1,2,~,4-tetrahydro-5H-1,4-benzodiazepin-5-
one, 8.85 g (0.05 mole) of 4-hydroxy-4-phenylpiperidine, and
14 g (0.1 mole) of potassium carbonate in 100 ml of n-butanol
was refluxed for 18 hr and filtered. The filtrate was
concentrated and the residue partitioned between chloroform
and dilute sodium hydroxide. The organic layer was dried
over anhydrous sodium sulfate and concentrated. The residue
was chromatographed on a 4.5 x 45 cm Florisil~ column
eluting with chloroform-methanol mixture with a gradation
from 100~ to 84~ chloroform. The fractions containing the
pure product (as seen on tlc using 95% chloroform-5~ methanol
on Florisil~) were combined and concentrated. The residue
was molecularly distilled at 250C. and 0.02 mm Hg. The
fumarate salt was prepared in isopropyl alcohol and
recrystallized from isopropyl alcohol-water. Yield 5.8 g.
20 (20%) m.p. 128-139C.
Analysis: Calculated for C32H~5N307: C,65.85; H,7.77
N J 7.20
Found : C,64.85; H,7.49
~ , 7 . o6
Example 98
4-Ethyl-l-methyl-2-~?-morPhol_noethyl)-1,2 ~L4-tetra-
hydro-~H-1~4-benzodiazepin-~-one.
A solution of ~0 g (0.112 mole) of 2-(2-chloroethyl)-
4-ethyl-1-methyl-1,2,~,4-tetrahydro-5H-1,4-benzodiazepin-5-
one in 70 ml of morpholine was refluxed for 3 hrs, concen-
trated on the rotary e~aporator and the residue partitioned
between chloroform and dilute sodium hydroxide. The chloro-
fonm was dried over anhydrous sodium sulfate and concentrated
on the rotary evaporator. The residue was crystallized
twice from isopropyl ether containing a small amount of
~5 ethanol, m.p. 128-148 C. Recrystallization from toluene
gave 19.5 g (61%) of product, m.p. 128-148C.
Analysis: Calculated for Cl~H~r~o2:c~68.~ ,8.57; N,13.24
~ou~d -:C,68.29; H 8.57; N,13.26
419A-CIP-2
~2~56~
145
Example 99
4~ methylethyl~-5H-1,4-benzodiazepin-5-one.
A mixture of 5.0 g (0.02 mole) of 2-chloromethyl-
1,2,3,4-tetrahydro-1-methyl-4-(1-methylethyl)-5H-1,4-
benzodiazepin-5-one, and 15.0 g (0.45 mole) of dimethyl-
amine, and 200 ml of methanol were placed in a steel bomb
and heated and stirred at 100C~ for 15 hr. Af~er concen-
trating in vacuo, the residue partitioned between dilute
sodium hydroxide ~olution and chloroform. The chloroform
layer was dried over anhydrous sodium sulfate, filtered and
concentrated ln vacuo. The residue crystallized in isopropyl
ether and was re~rystallized twice from the same. It
weighed 29.0 g (68O J m.p. 93-95C.
Analysiso calculat~d for Cl~H~sN30: C,69.78; H,9.15; N,15.26
Found : CJ69.81; H,9.01, N,15.73
ExamPle 100
?-(2-DimethylaminoethYl)-4-ethYl-l-methYl-1,2,~,4-
tetrahydro-~H-1,4-benzodiazepin-5-one.
A ~olution of 30 g (0.112 mole) of 2-(2-chloroethyl)-
4-ethyl-1-methyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-
one and 10 ~ (0.224 mole) of dimethylamine in 300 ml of
ethanol was heated at 125C. for 8 hrs and concentrated.
The residue was partitioned between chloroform and dilute
sodium hydroxide. The chloroform was dried over anhydrous
sodium sulfate, concentrated and distilled. Yield of
product was 20.5 g (66.5%) J b.p. 175-178/0.1 mm.
Analysis: calculated for C1~H~5N90 CJ69.78; H~9~15; N,15.25
Found : C,69.60; H,9.17: N,15.20
ExamPle 101
2.3-Dihydro _ -methyl-2-C2~ piperidinyl)ethyl]~rido-
t~l2-f ~114]oxazepine-5(4H~-thione f a ~ e comPound
with iso2ro~yl alcohol rl:lØ5:0.5~._
~o a suspension o~ 5.0 g (0.019 mole) of 2-(2 chloro-
ethyl)-2,3-dihydro-4-methylpyrido~3J2-f3-1,4-oxazepine-5(4H)-
thione in 75 ml of ab~olute ethanol was added 10 ml of
pyridins and the mixture heated to 50C. for 4 days. Ethanol
419A-CIP-2
2~5
146
was removed by rotary evaporation (70C, 30 mm Hg).
Piperidine was removed by rotary evaporation (80C, 5 mm Hg)
followed by azeotroping with 2 x 100 ml of toluene. ~he
syrupy residue was taken up in 200 ml of isopropyl alcohol
and heated with fumaric acid which afforded 5.2 g (57O
yellow crystals, m.p. 13~-40~C.
Analysis: calculated for C2l.sH32N30~S: C,56.07; H,7.00
N J 9 . 12
Found : C,55.90; H,6.85,
~,9-17
xample 102
6-Chloro-2.3-dih~dro-4-methyl-2-f2-(dimethylamino)ethyll-
4-methvlpYrldor~=fl~1.4~-oxazePin~5(4H)-one fumarate.
r1 O.~.
To 40 ml of freshly collected dimethylamine at -10C
was added 4.0 g (0.015 mole) of 6-chloro-2-(2-chloroethyl)-
2,3-dihydro-4-methylpyrido~4,3-f~-1,4-oxazepin-5(4H)-one.
~he reaction ~lask was sealed tightly and left standing at
room temperatur2 for 5 days. After cooling to -10C., the
flask was opened and the dimethylamine allowed to evaporate
overnight. The residue was taken up in 100 ml of chloroform,
washed with 2 x 30 ml of dilute sodium hydroxide, dried
over anhydrous sodium sulfate, filtered and concentrated by
rotary evaporation (70C, 30 mm Hg). The residue was
treated with fumaric acid in isopropyl alcohol which upon
crystallization afforded 3.8 g (76~7 O of yel~ow crystals.
Analysis: Calculated for C15H2oN304Cl: C,52,70; H,5.90,
N,12~29
Found : C,52.67; H,5.96;
N,12.01
Example lO3
2,3-Dihydro-4-methyl-6-dimethylamino-2-~2-tdimethyl-
amino)ethyll~4 methylpyrido~4,3-f~tl,4~oxazepin-5(4~)-one
fumarate [1:1.5~.
To 100 ml o freshly collected dimethylamine in a
~tainless steel bomb was added 4.5 g t0.016 mole) o~ 6-chloro-
~5 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido~4,3-f]-1,4-
oxaæepin-5(4H)-one. The bomb was s~aled tightly and placed
in an oven at 100C. for 18 hr. After c~oling, the bomb was
419A-CIP-2
~6
147
opened and the dimethylamine allowed to evaporate at room
temperature. The residue was taken up in 150 ml of
chloroform, washed with 2 x 40 ml of dilute aqueous sodium
hydroxide, dried over anhydrous sodium sulfat~, filtered
and concentrated by rotary evaporation (70 C, 30 mm Hg).
~he residue was treated with fumaric acid in i~opropyl
alcohol. The resulting crystals were collected, dried
overnight at room temperature, 0.5 mm Hg. The white
crystals were collected and afforded 4.2 g (56.3O of the
title compound, m.p. 172-75C.
Analysis: Calculat~d for C2lH30~4oe: C,54.07; H,6.48; N,12.01
Found : C,54.01; H,6.58; N,12.00
Example 104
2,3-Dihydro-?-L2-(2,5-dihydro-lH-pYrrol~ ethyl~-4-
methylpyridor3~?-fl-1,4-oxazepin ~ H)-one fumarate rl:?L~
To a solution of 10.0 g (0.041 mole) of 2-(2-chloro-
ethyl~-2~3-dihydro-4-methylpyrido~2-f]-lJ4-oxazepin-
; 5(4H)-one in 50 ml of dimethylformamide was added 9.0 g
(0.14 mole) of a mixture of 3-pyrroline:pyrrolidine*, ~
v/v. The solution was heated to 65C. under an ~2 blanket
overnight. The solvent was removed by rotary evaporation
(70 C., 0.5 mm Hg). The syrupy residue was taXen up in
100 ml of chloroform, washed with 2 x 30 ml of dil. a~ueous
sodium hydroxide, dried over anhydrous sodium sulfate,
filtered and concentrated by rotary evaporation (60C, ~0 mm).
The residue was azetroped with 3 x 100 ml of toluene. The
residue was purified by HPLC to separate out the pyrrolidine
derivative,eluting with 2% triethylamine in methylene
chloride (v/v). Fractions with similax TLC's were combined
and concentrated by rotary ~vaporation. To the residue was
added~100 ml of toluene and the mixture heated to 70C.
and filtesed hot. Approximately 0.2-0.3 g of hygroscopic
crystals were collect~d~ The toluene was removed by rotary
evapor~tion (70~C, ~0 mm Hg). ~he re~idual ~yrup wa~ treated
wi~h fumaric acid in isopropyl alcohol. Two ~rops of
cry~tals were collected, combined and recrystallized to~ether
giving 4.6 9 (22.1O of white crystals, m.p. 158 159 C.
~ ~ 5 ~ ~ 419~-CIP-2
148
Analysis: calculated for C29H27N3O~o: C~54~55; H~5.3
N,8.~1
Found : C,54.58: H,5.49;
N,8.30
*Pyrroline contains pyrrolidine as Lmpurity.
Exam~le 105
2,3-Dihydro-2-(2,5-dihydro-lH-pyrrol-l-yl)~thyl~-4-
ethylpyrido~3,2-f~ -oxazepine-5(4H~-thione fumarate
To a solution o~ 9.0 g (0.035 mole) of 2-(2-chloro-
ethyl)-2,~-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H~-
thione in 50 ml of dry dimethylfor~amide was added lOoO g
10 (0.141 mole)of3-~yrroline/pyrrolidine*, 3:1, v/v, and the
mixture heated to 60C. for 18 hr. The solvent was removed
by rotary evaporation (70C, 0.5 mm Hg) and the syrupy
residue purified by HPLC separating out the pyrrolidine
derivative eluting with 2% triethylamine in methylene
chloride (v/v) over silica gel. Fractions having similar
TLC's were combined and concentrated by rotary evaporation.
The syrupy residue was treated with fumaric acid in
isopropyl alcohol which afforded 4.0 g (28.1~) of crystals.
One recrystallization from isopropyl alcohol af~orded an
20 analytical sarnple, m.p. 143-45C.
Analysis: Calculated for ClgH~3N3O5S: C,56.28; H,5.72,
N,10.36
Found : C,56.03; H,5-23,
*Pyrroline contains pyrrolidine as impurity.
Exam~le 106
2-r2-(1-A~etidinyl)ethYl~ -dihYdro-4-methylPyrido
r3,?-frrl,4~oxazepin 5(4H)-one oxalate hydrate rl l:0.5~.
To a solution of 4-1 g (0-017 mol4) of 2-(2-chloro-
ethyl)-2,3-dihydro-4-methylpyrido~3~2-f]-l~4-oxazepin-5(4~)
one in 50 ml of dimethylformamide under nitrogen was
~0 added a solution/suspension of 0-7 g (60~ in oil, 0.017 mole)
of sodium hydride in .10 ml of dimethylformamide to which
1.0 g (0.017 mole) of azetidine in 20 ml of dimethylformamide
had been added and allowed to stir under nitrogen atmosphere
until hydrogen evolution ceased ( 15 min). The reaction
~5 mixture was stirred for 18 hr under nitrogen at room
temperature. The ~olvent was removed by rotary evaporation
(70C, 0.5 rnm Hg) and the residue taken up in 100 ml of
chloroform, washed with 3 x 30 ml dil. aqueous sodiurn
419A-CIP-2
~2g~5 E;~7
49
hydroxide, dried over anhydrous sodium sulfate, filtered and
concentrated by rotary evaporation. The residue was treated
with oxalic acid in isopropyl alcohol which afforded 1.3 g
(21.2%~ of white crystals, m.p. 172-17~C. with ~light
decomposition.
Analysis: Calculated for C16Hz2N306.s: C,5~-33; H~6-15;
N,11.65
Found : C,53.73; H,6.11,
N,11.67
Exam~le 107 (Refer to Chart VIII~
2-~(Dimethylamino ~ethyl]-2,~-dihydro-4-methylpyrido
~3,~ ~ ~1,4]oxazepin-5(4H)-one fumarate ~
Dimethylamine 22.6 gJ 40% solution (0.2 mole) was
added dropwise to a solution of 16 ml of epichlorohydrin
(0.2 mole) in 100 ml of methanol at 5C. stirring in an
ice bath. After two hours at 5C. a chilled solution of
85 ml methylamine of 40% solution (1 mole) was poured into
the reaction mixture. Stirring was continued in ice bath
for one hour and then room temperature o~ernight. The
solvents were evaporated and the clear oil was pumped under
vacuum at 75 C. for 1.5 hr to give 28.23 g (~84% yield) of
l-dimethylamino~3-methylamino-2-propanol hydrochloride (I)
as the main product.
Compound I, 21.4 g (0.143 mole) and 22.6 g o~ 2-chloro-
nicotinic acid tO.143 mole) were stirred in 150 ml acetoni-
trile and 60 ml water as a two-layer ~ystem. Dicyclohexyl-
carbodilmide, ~ g (0.16 mole~ disæolved in 90 ml of
acetonitrile was added in four portions. After the addition
of the second portion, an ice bath was necessary for
controlling the temperature at around 25 C. Two and a half
hours later, 10 g of 2-chloronicotinic acid was added to
the reaction mixture and 15 g of dicyclohexylcarbodiLmide
in 200 ml of acetonitrile was added in another hour. The
reaction was stirred at room temperature overnight. Concen-
trated hydrochloric acid was added to the reaction mixture
to pH 2 in order to convert the excess carbodiimide to urea.
The white ~olid was removed by filtration and rin~ed with
aqueous acetonitrile. The filtrate and washings were
evaporated to a paste which was partitioned between methylene
419A-CIP-2
150
chloride and potassium carbonate solution. The aqueous
layer was extracted two more times with methylene chloride.
The methylene chloride soluticns were back washed with
sodium chloride solution, dried over anhydrous sodiu~
sulfate and evaporated to give 56 9 of oil. This oil was
chromato~raphed on 250 g of silica gel eluting with
methanol to give 26.97 g of light brown oil containing
mainly the 2-chloronicotinamide of compound I.
The 26.97 g of compound obtained from chromatography
was dissolved in 200 ml of toluene and heated to dis ill out
about 40 ml solvent and then refluxed under a Dean-Stark
trap for one half hour. Sodium hydride, 15 g (50% suspension
in mineral oil, 0.3 mole) was added portionwise to the
toluene solution at room temperature. The mixture was then
heated to reflux for 20 min. The cooled mixture was
treated with isopropanol and celite and then filtered. The
filtrate was acidified with hydrogen chloride solution in
isopropanol. The white solid thus formed was collected by
filtration, rinsed with isopropyl alcohol-isopropyl ether
and dried under nitrogen. This material weighed 11 g and
absorbed moisture from air readily. Some second and third
crop materials were obtained from the mother liauor and
washings. All three crops were combined and dissolved in
water, the solution was made basic with excess amount of
potassium carbonate and then extracted three times with
methylene chloride; the methylene chloride solutions were
back washed with saturated sodium chloride solution, dried
over magnesium sulfate and treated with activated charcoal,
filtered and evaporated to give 8.8 g of brown oil, the
free base of the title compound.
A 1.9 g sample of the brown oil was dissolved in
methanol and kept warm on ~team bath. Fumaric acid was
added and the solution was concentrated to a small volume.
Excess amount of acetone was added to crystallize out the
fumarate salt. The salt was recrystallized once to 1.4 y
of white solid, m.p. 150-151C.
Analysis: calculat~d for C~ N30~,: C,54.70; H,6.o2; N,11.96
Found : C,54.69; H,6.o7; N,11.88
419A-ClP-2
~S~
151
Example 108
2-~(Dimethylamino)methyll-2~3-dihydro-4-methylpyrido
2-fl~1,4 ~xazepine-5(4H)-thione fumarate L2~
2-~(Dimethylamino)methyl~-2,~-dihydro-4-methylpyrido
~,2-f]~1~4]oxazepine-5(4H)-one, 4.8 g, was dried azotropi-
cally in about 50 ml of toluene. To the warm 801ution was
added Lawesson reagent (Aldrich ~22, 743-9, 4.9 g) and the
reduction mixture was kept at reflux fox two hours. On
contact with concentrated potassium carbonate solution,
the reaction mixture became a three-layer system; both the
aqueous layer a~d the toluene layer contained product but
not the third gummy layer. The layers were separated and
the a~ueous layer was extracted three times with methylene
chloride which was back washed with saturated sodium
chloride solution, combined with the toluene layer, dried
over sodium sulfate and evaporated to 5.25 g oil. This oil
was dissolved in methanol and 2.45 g fumaric acid was added.
With heating and stirring, isopropanol was added to the
poi~t of cloudiness and then left stirring overnight. The
mixture first deposited out a layer of brown gummy m~terial
and then crystallized to a yellow powder. The yellow
powder, 2.85 g, was collected and recrystallized from
methanol, m.p. 178-179 C.
Analysis: Calculated for Cl~HlgN3O3S: C,54.35; H,6.19;
NJ13-58
Found : C~54.21; H,6.20;
~,13.53
Exam2~_109 (Refer to Chart VIII)
2-[2-(DimethYlamino1ethvl~2 ,3-dlhYdro-4-meth~vrido
r3~2-flr 1 . 4~oxazepin-~(4H)-one.
To a cold (ice bath) solution of 3.2 g (0.02 mole) of
2-chloronicotinic acid and 3 g (0.02 mole) of l-dimethylamino-
4-methylamino-~-butanol in 25 ml of methylene chloride was
added 4.55 g (0.022 mole) of dicyclohexyl carbodiimide.
~ethanesulfonic acid, 1.8 ml, was added to bring the pH to
6. White solid ap~eared in the reaction mixture. The ice
bath was removed after 1 hr a~d the mixture was allowed to
~t~nd at room temperature overnight. The white solid was
removed by filtration and the filter cake rinsed with
419A-CIP-2
56~7
1~2
methylene chloride. The combined filtrate and wash was
extracted twice with o.6 N hydrochloric acid (15 ml and
10 ml). To the combined acidic aqueous extracts was added
6 g of potassium bicarbonate and methylene chloride with
stirring. The layers were separated and the aaueous basic
layer was extracted with methylene chloride. The methylene
chloride layers were combined, dried over anhydrous sodium
sulfate and evaporated to give 4.5 g brown oil which was
predominantly 2-chloro-N-~4-(dimethylamino)-2-hydroxybutyl~-
10 N-methyl-3-pyridinecarboxamide.
The 4.26 g (0.0149 mole) of the foregoing prepared
3-pyridinecarboxamide was mixed with 50 ml of toluene and
the mixture was heated to distill off about 20 ml of solvent
and then kept at reflux using a Dean-Stark trap to collect
moisture. The temperature of the solution was lowered
; somewhat and o.864 g (0.018 mole) of sodium hydride in mineral
oil was added to produce qentle reflux. After a total of
45 min, the mixture was cooled and to it was added 0.5 ml of
isopropyl alcohol and 0.5 ml of water. Carbon dioxide was
bubbled in to convert the sodium hydroxide produced to
~odium bicarbonate. The mixture was then a~eotroped to
dryness using a Dean-Stark trap. Some acetonitrile was
added to the hot mixture. After coolingJ the mixture was
filtered through celite rinsing with acetonitxile. The
filtrate was evaporated to give a mixture of the title
pxoduct and a trace of mineral oil. The amount of titl~
product obtained was 3.45 g (33~ yield). The ~MR and Mass
Spec agreed with that of the free base of the compound
prepared in Example 10.
419A-CIP-2
~2~5~7
153
Example 110
?-~2-(Dimethylamino)ethyl]-2,~-dihydro-4-methYl-1,4-
oxazepinor7,6-f~isoquinolin-5(4H)-one oxalate.
Following the procedure of Example 21, 2-(2-chl~roethyl)-
2,3-dihydro-4-methyl-134-oxazepino~7,6-f~isoquinolin-5(4H)-
one is reacted with dimet~ylamine to give the title compound.
Example 111
?-~2-(Dimethylamino)ethyll~,3-dihydro-4-methyl-1,4-
-
oxazepino~7,6-flisoauinoline-5(4H)-thione hydrochloride.
Following the procedure of Example 31, 2-(2-chloroethyl)-
2,~-dihydro-4-methyl-1~4-oxazepino[7,6-f~isoquinoline-5(4H)-
thione is reacted with dimethylamine to give the title
compound.
Examp le 1 l?
?-r2-(Dimethylamino)ethyll-2~3-dihydro-4-methyl-l~4
oxazepino~6,7-q]isoquinolin-~(4H~-one oxalate.
Following the procedure of Example 21, 2-(2-chloroethyl)-
2,3-dihydro-4-methyl-1,4-oxazepinot6,7-g~isoquinolin-5(4H)~
one is reacted with dimethylamine to give the title compound.
Example 11~
2-~2-(Dimeth~lamino)ethyl~-2 7-dihydro-4-methyl-1,4-
oxazePiner6.7-qlisoquinoline-5(4H)-thione hydrochloride
Following the procedure of Example 31, 2-(2-chloroethyl)-
2,3-dihydro-4-methyl-1,4-oxazepino~6,7-g~isoquinoline-5(4H)-
thione is reacted with dimethylamine to give the title
compound~
Example 114
2-~-(Dimethylamino)ethYll-2 3-dihydro-~ 7-dimethyl=
1,4-oxaz pinor6,7-bl~uinolin-5(4H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloroethyl)-
3o 2~3-dihydro-4,7-dimethyl-1,4-oxa2epino~6,7-h]a-linolin-5t4H)-
one is reacted with dimethylamine to give the title compound.
419A-CIP-2
5~7
154
Example 11~
2-~2-~Dimethylamino)ethyl~-2,3-dihydro-4,7-dimethyl-
~4-oxazepino~6J7-h]quinoline-5(4H)-thione hydrochloride.
Pollowing the procedure of Example 31, 2-(2-chloroethyl)-
2,3-dihydro-4,7-dimethyl-1,4-oxazepino~6,7-h~guinoline-
5(4H)-thione is reacted with dimethylamine to give the title
compound.
Exam~le ll6
2-~2-(Dlmethylamino)ethyll-2 ,3-dihydro-4!10-dimethyl-
1,4-oxazepino~6,7-hlquinolin-5(4H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloro-
ethyl)-2~3-dihydrc-4~lo-dimethyl-ll4-oxazepino[6~7-h~-
quinolin-5(4H)-one is reacted with dimethylamine to give
the title compound.
Exam~le 117
2-~2-(Dimethylamino~ethyll-2,3-dihydro-4~10-dimethyl-
1,4-oxazepino~6,7-hl~uinollne-5(4H)-thione hydrochloride.
Following the procedure of Example 31, 2-(2-chloro-
ethyl)-2~5-dihydro-4,10-dimethyl-1,4-oxazepino[6~7-h)
quinoline-5(4H)-thione is reacted with dimethylamine to
give the title compound.
Example 118
4-r2-(Dimethylamino)ethyll-3,4-dihydro-2-methyl-rl,4~-
oxazepino~6,7-f1quinolin-1(2H~-one oxalate.
Following the procedure of Example 21, 2-(2-chloro-
ethyl)-3,4-dihydro-2-methyl~1,4]-oxazepino[6,7-f]quinolin-
1(2H)-one is reacted with dimethylamine to give the title
compoundO
Example 11~
4-r2-(DimethylaminO)ethyll-3~4-dihydro-2-methylrl,41-
_ . . .
oxazepinor6,7-flquinoline-l~2H)-thione hydrochloride.
__~ .
Following the procedure of Example 31, 4-(2-chloro-
ethyl)-3,4-dihydro-2-methyl-[1,4~-oxazepino~6,7-f~quinoline-
1(2H)-thione is reacted with dimethylamine to give the
title compound.
419A-CIP-2
5 ~ ~7
155
Example 120
2-~2-(Dimethylamino)ethyll-2,3-dihydro-4-methyl-1,4-
oxazeplno[6,7-h ~ lnolin-5(4H)-one oxalate.
Following the procedure of Example 21, 2-(2-chloro-
ethyl)-2,3-dihydro-4~methyl-1,4-oxazepinot6,7-h]quinolin-
5(4H~-one is reacted with dimethylamine to give the title
compound.
Example 121
?-r?-(Dimethylamino)ethyl~-2,~-dihydro-4-methvl-1,4-
oxazepinor6~l~h~inoline ~ -thione hydrochloride.
Following the procedure of Example 31, 2-(2-chloro-
ethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-h]quinoline-
5(4H)-thione is reacted with dimethylamine to give the
title compound.
ExamPle 122
2-~2-(1-Azetidinyl)ethyll-2,3-dihydro-4-methylpyrido
t3,2-fl~1,41oxazepin-5(4H)-one oxalate hydrate Ll:1:0.51.
To a solution of 5.0 g (0.021 mole) of 2-(2-chloro-
ethyl)-2,3-dihydro-4-methylpyrido~,2-f~-1,4 oxazepin-5(4~)-
one dissolved in 40 ml of dimethylsulfoxide was added 8.7 g
20 (0.063 mole) of potassium carbonate followed by 1.40 g
(0.025 mole) of azetidine. The mixture was stirred for
4 days at room temperature*. Another 0.5 g (0.009 m~le) of
azetidine was added and stirring continued for 2~ hx.
Another 0.7 g (0.012 mole) of azetidine was added and the
mixture was stirred for 24 hr. The potassium carbonate was
$iltered off and the dimethyl sulfoxide was removed from
the filtrate by rotary evaporation at 90 C., 0.5 mm Hg.
The residue was taken up in 100 ml of methylene chloride
and the solution was washed with two ~0 ml portions of
~0 water followed by 30 ml of dilute aueous sodium hydroxide.
The organic layer was dried over magnesium sulfate, filtered
and concentrated ~y rotary evaporation. The residual syrup
was reacted with ox-alic acid in isopropyl alcohol giving
3.3 g (44~) of white crystals, m.p. 170-172C. lHNMR analysis
was essentially the ~ame as for the ~ame compound obtained
in Example 106.
*Stirrer had mal~unctioned causing need ~or a longer
419A~CIP-2
~ ~ ~ S 6 ~ 7
156
stirring period than an estimated 1-2 days that should be
reauired.
Example 123
2~ Azetidinyl)ethyll-2,3-dihydro-4-methylpyrido
r 3,2-f ]Ll J 4~oxazepine-5(4H)-thione fumarate.
To 5.0 g (0.0914 mole) of 2-(2-chloroethyl)-2,5-
dihydro-4-methylpyrido~3,2-f]-lJ4-oxazepine-5(4~H)-thione
dissolved in 50 ml of dimethylsulfoxide was added 8.o4 g
(o.o58 mole) of potassium carbonate and 1.21 g (0.021 mole)
of azetidine. The reaction mixture was stirred at room
temperature for 8 hr after which was added 0.5 g (0.009
mole~ of azetidine and the mixture was stirred overnight
at room ~emperature. An additional 0.3 g (0.005 mole of
azetidine was added and stirring was continued for 24 hr.
The mixture was filtered and solvent removed by rotary
evaporator at 80C., 0.5 mm Hg. The residue was taken up
in 100 ml of chloroform and the solution was washed with
two 30 ml portions of dilute aaueous sodium hydroxide.
The organic layer was dried over magnesium sulfateJ
filtered and concentrated by rotary evaporator. The
residue was reacted with fumaric acid in isopropyl alcohol
to give 2.5 g (310 of pale yellow crystals, m.p. 122-126 C.
157 ~ S6g~7 66l97-l69
Table 2
R4 R5
~E ~ (CH)n Z
( Y ) ~ ,;~
0-2 B R
Ex. 4 I5
No. A(Y)0-2 _ R R E Z -(CHn)- Salt_ _ _ _
1 benz O -CH3 H O -N(CH3)2 -(CH2)2- HCl
2 benz O -CH3 H O -N(CH3)2 !'
3 benz 3 ~ fumarate
4 benz O -CH2~ H O -~ ~
/
benz O -CH20 H O -NHCH3 " Eumarate
6 benz S -CH3 H O -N(CH3)2 " HCl
7 benz O -CH20 H O -N(CH3)2 " H20
8 benz S -CH3 H O - ~ " HCl
9 naphth[2,3-f] 0 -CH3 H O -N(CH3)2 " oxalate
pyrido[3,2-f] 0 -CH3 H O -N(CH3)2 " 1.5 fumura-te
ll pyrido[3,2-f] S -CH3 H O -N(CH3)2 " fumarate,
O.5 ethanol
12 pyrido[3,2-f] S -CH3 H -N~CH3)2 " fumarate
13 benz S -CH20 H O -N~__/O ~ _
14 benz O -CH3 H O -NHCH3 " Eumara-te
15 benz O -CH3 H O -NHCH3 "
16 benz 3 ~ OH
17 benz S -CH3 H O ~
18 8-Cl-benz S -CH3 H O -N(CH3)2 " HCl
~56~7
R5
No A(Y)O_ B R R E Z ~ n) 5aIt_
19 8-Cl-benz O -CH3 H O -N(CH3)2 " oxalate
20 7-Br-benæ O -CH3 H o -N(CH3)2 " oxalate
21 naph[2,1-f] O -CH3 H O -N(CH3)2 " oxalate
22 a) pyrido[4,3-f] O -CH3 H O --N(CH3)2 ' fumarate
b) pyrido[3,4-f] O -CH3 H o -N)CH3)2 fumarate
c) pyrido[2,3-f] O -CH3 H O -N(CH3)2 fumarate
23pyrido[4,3-f] S -CH3 H O -N(CH3)2 1.5 HCl
24pyrido[3,2-f] S -CH3 H O -(C2H5)2 "
25naphth[2,3-f] S -CH3 H O -N(CH3)2 " oxalate,
267,9 diiodobenz O -CH3 H O -N(CH3)2 "
27 7-Cl-benz O -CH3 H O -N(CH3)2 " oxalate
28 pyrido[3,2-f] O -CH3 H O -N(CH3)2 -CH2-
29 pyrido[3,2-f] 9 -CH3 H O -N(CH3)2 -(CH2)?- methiodide
30 7-Cl-benz S -CH3 H O -N(CH3)2 " oxalate.
31 naphth[2,1-f] S -CH3 H O -N(CH3)2 " HCl
32 a) pyrido[3,4-f] S -CH3 H O -N(CH3)2 " fumarate
b) pyrido[2,3-f] S -CH3 H O -N(CH3)2 " fumarate
33 7-OCH3-benz O -CH3 H O -N(CH3)2 " oxalate.
34 7-Br-benz S -CH3 H O -N(CH3)2 " oxalate
H20
35 a) benz C6 12 H -N(CH3)2 " oxala-te
b) benz C2 5 -N(CH3)2 " oxalate
c) benz O -CH(CH2)2H O -N(CEl3)2 " oxalate
d) benz O 4-Cl- H O -N(CH3)2 " oxalate
C 6 H 4CH2
e) benz 4-CH3-H O -N(CH3)2 -(CH2)2- oxalate
C6H4 CH2
f) benz O 3,5- H O -N(CH3)2 " oxalate
(OCH~)2-
C H CH
. ~ ,
~ 6~ 66197-169
No. A(Y)0-2 B R R E z -(CHn)- salt
g) benz 0 3-CF3- H O -N(CH ) " oxalate
C~12~
h) benz 0 4-N02- H O -N(CH3)2 " oxala-te
36a) pyrido[3,2-f] 0 C6Hll H O -N(CH3)2 " Eumarate
b) pyrido[3,2-f] 0 C2H5 H O -N(CH3)2 " fumarate
(CH3)2 3 fumarate
d) pyrido[3,2-f] 0 4-Cl- H O -N(CH3)2 " fumarate
C6H4CH2-
e) pyrido[3,2-f] 0 4-CH3- H O -N(CH3)2 " fumarate
; 6 4C 2
f) pyrido[3,2-f] 0 4-OCH3-H O -N(CH3)2 " fumarate
6 4 2
g) pyrido[3,2-f] 0 3-CF3- H O -N(:ÇH3)2 " fumarate
6 4 2
h) pyrido[3,2-f] 0 4-N02-C6-H O -N(CH )2 " fumarate
4CH2
: 37a) ben~- O CH3 H O l-pyrro- " fumarate
lidinyl
:b) benz O -CH3 H O l-piperi- " fumarate
dinyl
`:
c) benz O -CH3 H O l-pipera- " :fumarate
;d) benz O -CH3 H 0 4-CH -piper- " fumarate
aziny~
38 pyrido[3r2-f] 0 -CH H S -N(CH3)2 " 2.HCl
39 pyrido[3,2-f] S -CH3 H S -N(CH3~2 " oxalate
pyrido[3,4-f] 0 -CH3 H O -N(CH3)2 " 1/2 H20
~- 2 oxalate
;",
~'~
-160- ~ 2~56~7 66197-169
RS
No A(Y)0-2 B R R E Z -(CHn)- salt
-
41 pyrido[3,4-f] S -CH3 H 0 -N(CH3)2 " late
42 pyrido[3,2-f] 0 -CH3 H 0 -NH2 -(CH2)3- 1/2 -
oxolate
43 pyrido[3,2-f] 0 -CH3 H o -N\_ /0 -(CH2)2- maleate
44 pyrido[3,2-f] 0 -CH3 H 0 l-pyrroli- " 2 fuma-
dinyl rate
pyrido[3,2-f] 0 -CH3 H 0 N-(n-butyl)2 " maleate
46 pyrido[3,2-E] 0 -CH3 H 0 -N(C2H5)2 " oxalate
47 pyrido[3,2-f] 0 -CH3 H 0 l-piperidinyl " oxalate
48 pyrido[3,2-f] 0 -CH3 H 0 -N(CH3)(benzyl)" maleate
49 pyrido[3,2-f] 0 -CH3 H -N(CH3)-c6Hs
pyrido[3,2-f] 0 -CH3 H ~ ~ fumarate
C
51 pyrido[3/2-f] 0 -CH3 EI 0 _ ~ " :
CH3
pyrido[3,2-f] 0 -CH3 H 0 r j "
53 pyrido[3,2-f] 0 -CH3 H -N ~
54 pyrido[3,2-f] 0 -C2Hs H 0 -N(CH3)2 " oxalate
pyrido[3,2-f] 0 -C2H5 H dinyl oxalate
56 pyrido~3/2-f] S -CH3 H 0 -N ~ " ~ ~
57 pyrido[3/2-f] S -C~13 H butyl)2 oxalate
~ ,.
-160a- ~2~56~7 66197-169
rl 5
No. A(Y)0-2 B r~ R E Z -(CHn)- Sc~lt
58 pyrido[3,2-f] S -CH3 H o -N(C2 H5)2 ll oxalate
59 pyrido[3,2-f] S -CH3 H O l-pyrroli- oxalate
dinyl
pyrido[3,2-f] S -CH H O ~ " 1.5 oxo-
3 -N ~ N late
61 pyrido[3,2-f] S -C2Hs H O -N(CH3)2 -(CH2)2
62 pyrido[3,2-f] S -CH3 H O -N(CH3)- " oxalate
(benzyl)
63 pyrido[3,2-f] S -CH3 H O -NHCH3 " 1.5 -
oxolate
64 7~Cl-pyrido O -CH3 H O -l-pyrroli- " 2.5 -
1 [3,2-f] dinyl fumarate
7-Cl-pyrido 0 -CH3 H O -N(CH3)2 " oxalate
66 pyrido[3,2-f] 0 -C6HllH -N(CH3)2 -CH2- oxalate
67 pyrido[3~2~f] CcH2 0 -N(CH3)2 late,
6 5 1/2 H20
68a) pyrido[3,2-f] 0 H H O -N(CH3)2 "
68b) pyrido[3,2-f] 0 H H O -N(CH3)2 -(CH2)2- fumarate
69 pyridol3,2-f] 0 -CH3 H O -N(CH3)2 ( 2)3
fumarate
., O.S H20
pyridol3,2-f] S -CH3 H 0 -N(CH3)2 -(CH2)321/x2~1Ha~2e'
71 E3,2-f] S -CH3 H O -N(CH3)2 -(CH2)2-1/2 H~O,
HOH
72 pyrido[3,2-f] 0 -CH3 H O -NHCH3 " oxalate
73 pyrido[3,2-f] 0 -CH3 H O -NH2 " fumarate
.
74 pyrido[3,2-f] S -CH3 H 2 0.5
fumarate.
pyrido[3,2-f] 0 -CH3 H -N-CH(CH3)2 fwnarate
,~ :
- 160b- ~z~5~7 66197-169
R5
Ex
No. A(Y)0-2 B R R E Z -(CHn)- s~].t
76 pyrido[3,2-f] S -CH3 H 5)2 fumurate
77 pyrido[3,2-f] 0 -CH3 H 0 4-methyl- " 2.0
piperazin- fumarate,
_. l-yl hydrate
78 pyrido[3,2-f] S -CH3 H 0 4-methyl- " 2.0
piperazin- fumarate,
l-yl 1/2 H20
79 pyrido[3,2-f~ 0 -C~3 H 0 (a) " 2.0
fumarate,
1/2 H20
~ 80 pyrido[3,2-f] 0 -CH3 H 0 -~ ~ " oxalate
81 pyrido[3,2-f] S -CH3 H 0 -N(CH3)- "
(C5H5)
82 pyrido[3,2-f] S -CH3 H 0 -NH2 -(CH2)3- fumarate
83 pyrido[3,2-f] S H H 0 -N(CH3)2- -(CH2)2 2 HCl,
84 pyrido[3l2-f] S -CH3 H 0 (a) " oxalate,
H20
pyrido[3,2-E] S -CH3 H 0 - ~ " -
F~3
86 pyrido[3,2-f] 0 -CH3 H 0 -N(CH3)2 -OEl-CH2- oxalate
87 pyrido[3,2-f] S -CH3 H o ~ ~ -(CH2)2-1.5
oxalate
,:
88 pyrido[3,2-f] 0 -CH3 -CH3 0 -N(CH3)2 " 2 HCl
89 pyrido[3,2-f] S -CH3 -CH30 -N(CH3)2 " HCl
E
90 ~ 0 -CH3 H -N(CH3)2 oxalate
ICH3
91 pyrido[3,2-f] S -CH3 H 0 -N(CH3)2 -CH-CH2- o~alate
~1
~S6~7 661~7-16')
No. ~(Y)0-2 B R R4 E r~ 11 t
~,H3
92 pyrido[3,2-f] 0 -CH3 H O -N(CH3)2 -CH2-C- HCl
93 pyrido[3,2-f] S -CH3 H -N~ -(CH2)2 (fumarate
\ J (isopropyl
E (alcoh
94 ~ OCH3 H ON(CH2)2 (C 2)2
CF3
~ O-CH3 H O -N(CH3)2 -(CH2)2- fumarate,
96 ~ SCH3 H O N(CH3)2 (CH2,)2 iF.umarate,
: alcohol,
H20
CH3 OH
97 benz C2 5 N -N ~ -(CH3)2- fumarate
. alcohol
Cl 3 ~_~
98 benz o C2H5 H -N~ -N~_O (CH2)2
99 benz O -CH- H ~N` -N ( CH3)2 -CH2-
(CH3 ) 2 CIH3
100 benz C2H5 H ,N~ -N(CH3)2 -(CH2)2- -
101 pyrido[3,2-f] S -CH3 H o -N ~ -(CH2)2-(fumarate,
(0.5 iso-
(propyl
(alcohol
102 6-Cl-pyrido O-CH3 H O -N(CH3)2 r,ate
5~;~7
-160d- 661')7
No. A(Y)O-2 B ~ R ~ Z
: l 103 6-[N(CH3)2]- O -CH3 H O -N(CH3)2 -(CH2)2- 1.5 fuma-
pyrido[4,3-f] rate
104 pyrido[3,2-f] O -CH3 H O -N~ -(CH2)2- 2 0 fuma-
105 pyrido~3,2-f] S -CH3 H O -N~ -(cH2)2- fumarate
106 pyrido[3,2-f] O -CH3 H O -N ~ -(CH2)2- oxalate,
107 pyrido[3,2-f] O -CH3 H O -N(CH3)2 -CH2- fumarate
108 pyrido[3,2-f] S -CH3 H O -N(CH3)2 -CH2- rate
109 pyrido[3,2-f] O -CH3 H O -N(CH3)2 -(CH2)2
110 N~ O -CH3 H O -N(CH3)2 -(CH2)2- oxalate
E
:111 ~ S -CH3 H O -N(CH3)2 -(CH2)2
112 ~ ~ CH3 H O N(CH3)2(CH2)2 x a
113 N ~ S -CH3 H O -N(CH3)2-(CH2)2- HCl
114 ~ ~ O-CH3 H O -N(CH3)2 -(CH2)2
5~ 7 41 9A - C I P -2
161
Table ~ ( cont . )
Ex. R5
Nc).A(Y)Q-2 ~3 R R4 ~ Z ~~C~n~ Salt
N ~
~ S -CH3 H O -N(CH3)2 -(CHz)2- HCl
CH3
CH ~ -CH9 H O -N(CH3)2 -(CH2)2- oxalate
CH ~ S -CH3 R O -N(CH3)2 -(C~2)~- HCl
O -cHs ~ O -N(CH3)2 -(CH2)2- oxalate
119 ~ S -CH3 H O -N(CH3)2 -(CH2)2- HCl
120 ~ -CH9 H O -N(CH3)2 -(CH2)2- oxalate
N
121 ~ S -CH3 H O -N(CH3)2 -(CH2)2- ~Cl
122 pyridot3,2-~ 0 -CH9 ~ o -N ~ -(CF4 )2 - oxal~te,
0.5 H20
123 pyridot3,2-~ S -CH9 H O -N ~ -(CH2)2- ~umarate
Pootnote:
( -N 3 CH-(4F-c~H~) 2
3~2~56gl7
162
Additional Pharmacoloqy
Experiments were conducted to determine whether
sedation was present as a result of administration of the
compounds of the invention as antihistaminics and the results
on compounds tested suggests they are non-sedative anti-
histaminics. The comparative antihistaminic agent used was
diphenhydramine which does cause sedation. See Douglas, W. C.
(1980), "~listamine and 5-hydroxytryptamine (serotonin) and
their antagonists" in The Pharmacoloqical Basis of Thera-
peutlcs (ed: A. G. Gilman9 L. S. Goodman, A. Gilman, 6th
edition, Macmillan, New York, pp 609-641. In the present
tests, sedation is defined as a change in the electro-
encephalograms (EEGs) from the normal pattern of low voltage,
fast (~) cerebral cortical waves (1?-25 Hz, <50 mV
amplitude) to synchronized high voltage, slow(~, D) cerebral
cortical waves (1-3, 4-7 ~z, > 50 m V amplitude) with
frequent periods of sleep spindles predominating.
Experimental Method
for Sedat_ve ActivitY
Ten cats of both sexes were anesthetized with halothane
and cannulae placed in the trachea, the left cephalic vein,
and the right femoral artery for artificial ventilation, drug
administration, and blood pressure recording, respectively.
The head was fixed in a Xopf stereotaxic unit and the
calvarium was widely exposed. Stainless steel screw electrodes
(1/4") were placed through the calvarium so that the tips
rested on the dura over the frontal, parietal, and occipital
areas, bilaterally. An electrode of the same type was placed
in the right frontal sinus and served as the reference
; electrode ~or monopolar EEG recordings. After completion of
i 30 the surgery, the animal was given gallamine triethiodide
t20 mg, IV; supplemented as necessary) and the halothane
withdrawn. Artificial respiration was instituted (10 ml room
air/k~ ~ sec).
EEGs were made on a Grass, Model 5, electroencephalograph
along with (lead II) EKG. Typically, EEGs were recorded for
2-3 min every 10 min. ~rterial blood pressure was continuously
monitored on a Grass, Model 79, poly~raph.
4 1 yA -C I P - ''
~2~56~7
6~
In most experiments, histamine (0.5 ~g ~ g, IV) was
given to produce a transient (~ 30 sec) hypotensive effect.
It was normally given 10, 20 and ~0 min prior to the first
dose of the test drug and then 5, 10 and 20 min after each
dose of the test drug. In this way an ~ndication of the
antihistaminic activity of test drug could be quantified.
Concomitant with the antihistaminic ~uantification
was the efect of test drug on EEG. Test drug was usually
given in increasing doses of 0.1, 0.3, 0.5, 1, 3, 5, 10 and
20 mg ~ g, IV.
Experimental Results
on Sedative Potential
Illustratively of the compounds tested (Examples 12J 65
and 71) the compound of Example 12 produced a 50% reduction
of the histamine-induced depressor effect on blood pressure
at 0.~ mg~kg, IV and a 100% suppression at 1-~ mg ~ g, IV.
There were no signs of sedation in these animals at any
dose up to 20 mg~ g, IV.
On the other hand, the comparative drug, diphen-
hydramine, kno~n to produce sedation (tested here in 6 cats)prod~ced a 50~ sup~~ession of the histamine-inducer3 depre~so-
effect on blood pressure at 0.5 mg~kg, IV and a 100~
suppression at 3-5 mg ~ g, IV. Signs of sedation with
aiphenhydramine occurred in the EEG tracings as low as
0.5 mg ~g, IV with mar~ed slowing, synchronized waves, and
sleep spindles at 1-3 mg~kg, lV. In summary, diph2~hydramine
produced an antihistaminic effect in doses which also
produced a sedativ2 effect. This is similar to what is seen
in man with diphenhydramine.
In contrast to the effects of diphenhydramine, compounds
such as that of Exa.nple 12 do not produce sedation at any
dose up to 20 mg ~g, even though the antihistaminic cffects
occurre~ at much lower doses. These data, therefore, suggest
the nonsedative nature of compound3 of the invention.
4l9A-cIp-2
~Z:~56~7
64
Pharmaceutical ComPosition
.
The invention further provides pharmaceutical
compositions for administration to a living animal body
comprising, as active ingredients, at least one of the
compounds of Formula I according to the invention in
association with a pharmaceutical carrier or excipient.
The compounds are thus pre~ented in a therapeutic
composition suitable for oral, rectal, parenteral,
subcutaneous, intramuscular, intraperitoneal, intravenOuS,
or intranasal ~dministration. ~hus, for example,
compositions for oral ~dministration can taXe the form of
elixirs, capsules, tablets or coated tablets containing
carriers conveniently used in the pharmaceutical art.
Suitable tableting excipients include lactose, potato
and maize starches, talc, gelatin and 6tearic and silicic
acids, mAgnesium ~tearate and polyvinyl pyrrolidone.
For parenteral administration, the carrier or
excipient can be comprised of a sterile parenterally
acceptable liquid; e.g., water or arachis oil contained
in ampoules.
In c~mpositions for rectal administrationJ the carrier
can be comprised of a ~uppository ba~e; e.g., cocoa butter
or a glyceride.
Application to the nose, throat or bronchial region
can be in the form ~f gargle or an aerosol spray containing
small particles of the ~gent ~f Formula I in a spray or
dry powder form.
Advantageously, the compo6itions ~re formulated as
dosage unit6, ~ach unit be ing adapted to supply a fixed
dose of nctive ingredients. Tablet~, coated tablets,
capsules, ampoules and 8uppo8itories are examples of
preferred dosage ~orms ~ccording to the inventio~, It is
only nece~8ary that the active ingredient constitute an
effective amount; i.e., such that a suitable effective
dosage will be consistent with the dosage form employed.
The exact individual dosages, a~ well as daily dos~ges,
4l9A-cIp -2
56~7
will of course be determined acco~ding to ~tandard medical
principles under the directiDn of a physician or veteri-
narian. ~enerally, the pharmacology tests on guinea pigs
in ~omparison to certain other antihiRtaminic drugs
suggests an ~ffective do~e for an adult will be in the
range of 2 ~o 8 mg ~or the more active compounds.
Based on the animal data, unit dosage~ containing an
amount of compound equivalent to abou~ 0.03 to 0.10 mg
of active drug per kilogxam of body weight are contemplated.
Daily dosages of about 0.2 to o.6 mg~kq of body weight
are contemplated for humans ~nd obviously several small
unit dosage forms may be ~dministered ~t one time. Howe~er,
the ~cope of the invention i5 not to be limited by these
contemplations due to uncertainty in transposing from
animal data to humans.
Ex~mples of unit dosage compositions are as follows:
Capsule~:
~nqredients Per capsule
1. Active ingredient 4 mg.
2. Lactose 150 mg.
3. Magnesium stearate 4 mg.
Tablets:
Inqredients
1. Active ingredient 4 mg.
2 2. Corn ~tarch 20 mg.
3. Xelacid 20 mg.
4. Kelto~e 20 mg.
5. Magnesium stearate 1.3 mg.
Procedure for tablets:
1. a1end 1J 2 9 3~ 4 in larger ~mount~.
; 30 2. Add ~uf~icaent water portionwise to blend to
the blend from ~tep 1 with careful stirring after each
~ddition. Su~h additions of water and 5tirring continue
until the mass i5 of a constituency to permit its
conversion to wet granules~
3. ~he wet mass i~ converted to granules ~y passing
it throllgh the ~illating granulator u~ing 8 me~h ~creen.
4. The wet granules are then dried in ~n oven at
I40F.
419A-CIP2
3 ;2~5~7
166
5. The dry granules are lubricated with the
magnesium ~tearate.
6. The lubricated granules are compressed on a
~uitable tablet press.
~ntramuscular Iniection
Per ml.
1. Active ingredients 10.0 mg.
2. Isotonic buffer solution 4.0 q.~ to 1.0 ml.
Proc~dure:
1. Dissolve the active ingredient in the buffer
801u tion.
2. A~eptically filter the ~olution from step 1.
3. The aterile ~olution is now aseptically filled
into 6terile ampuls.
4. The ampuls are sealed under aseptic condition.
Suppositorie~:
In~redient~ Per Su Pp .
1. Active ingredient 10.0 mg.
2. Polyethylene Glycol 10001~50.0 mg.
~. Polyethylene Glycol 4000450.0 mg.
Procedure:
1. Melt 2 ~nd 3 together and stir until uniform.
2. Dissolve No. 1 in the molten mass from step 1
and stir until uniform.
3. Pour the molten mass from step 2 into suppository
molds and chill.
4. RemoYe the suppositories from molds and wrap.
Therapeutic cGmpositions for combatting hi~tamine in
unit do6age form, comprising a pharmaceutical carrier
and an effective ~mount of a compound of Formula X or a
~0 phanmaceutically acceptable acid addition salt thereof
are therefore an embodiment of 'chi~ invention.
.
4l9~cI~2
167
Various modifi~ation~ ~nd eauivalent~ will be
apparent to one skilled in the art and may be made in the
compounds, methods, processes and pharmaceutical
compositions of the present invention without departing
~rom the ~piri~ and ~cope thereof, and it i8 therefore
to be under~tood that the invention i5 to be limited only
by the scope of the appended claims.
