Note: Descriptions are shown in the official language in which they were submitted.
66197-166D
- 1 - AHR Case 425 DI~. I
l~his is a divisional application of Application
Serial No. 478,110 filed April 2, 1985.
BA~KGROUND OF THE INVENTION
1. Field of Invention.
The parent application relates to a process for the
preparation of certain known pyrido[l,4]benzodiazepines and this
application relates to novel chemical intermediates useful for
preparing the pyrido[l,4]benzodiazepines.
An important aspect of the process is the utiliza-
! 10 tion of a strong non-nucleophilic base such as sodium hydride
to bring about condensation of an aminochloropyridine and an
aryl(aminophenyl)methanone in admixture with mobile inert liquid
carrier to produce the pyrido[l,4]benzodiazepines. Alternative-
ly, the condensation may be started with titanium tetrachloride
and finished with the non~nucleophilic base, in which case novel
intermediates are produced and used.
The present application provides a compound of the
formula:
,Ar
(IIIb)
alkl Q2
(wherein:
Ar is 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl
or phenyl substituted by 1 to 3 radicals which are the same or
different and are selected from the group consisting of halo,
loweralkyl, loweralkoxy, trifluoromethyl and nitro;
Z is hydrogen, halogen, loweralkyl, loweralkoxy,
hydroxy or nitro;
alkl is a straight or branched hydrocarbon chain
containing 1 to 8 carbon atoms;
- la - 66197-166D
Q is -NR R , -N=CH-OC2H5 or -0-CHCH2CH~CH2CH2; and
~ 1 and ~2 are each Cl 8alkyl or C(O)-O-Cl ~alkyl
or Rl and R2 -taken together with the adjacent atom form a hetero-
cyclic residue selected from the group consisting of l-piperi-
dinyl, l-phthalimido, l-pyrrolidinyl, 4-morpholino, l-piper-
azinyl and 4-substituted-1-piperazinyl, in which the substituen-t
in the 4-position is Cl ~alkyl or Cl galkoxy-carbonyl)r or an
acid addition salt thereof.
The present application also provides a process for
producing the compound of the formula (IIIb) as defined above
or an acid addition salt thereof, which comprises reacting a
compound of the formula:
~ ~ Ar
z ~ (IIIa)
NH2
(wherein Ar and Z are as defined above),
with a halide of the formula:
X-alkl-Q2
~wherein X is halogen, and
alkl and Q2 are as de~ined above),
in a reaction inert solvent, and
zO if desired, converting the thus-obtained product
into an acid addition salt thereof.
In the following description, the expression
"present inventlon" includes the subject matters of this appli-
cation and of the parent application.
9~
- lb - 661g7-166D
Some of the compounds of the formula (IIIb) are broadly krown.
The broadly known compounds are those in which alk1 i5 a
hydrocarbon chain con~aining 1 to 3 carbon atoms and Q2 is
-NR1R2 whexein R1 and R2 are each C1 8 alkyl or R1 and R2 taken
together with the adjacent nitrogen atom form a heterocyclic
residue selected from the group consisting of 1-piperidinyl,
1-pyrrolidinyl and 4-morpholino. However, the specific compound
produced in Preparation 1 described hereinafter is not known.
2. Information Disclosure Statement.
The aryl substituted pyrido[1,4]benzodiazepines
prepared by the process of this invention are disclosed in S.
African Patent 8:l/7866 and are the subject of a corresponding
commonly assigned United States Patent No. 4,447,361 :issued May
8, 1984. In the method of preparation disclosed in these
references, amino-halo pyridine and aminoarylphenones are
heated neat to give pyrido[1,4]benzodiazepines.
3~
ommonly asslgned U. S. Patent No. 4,480,110,
describes preparation
of C2-C(nitropyridinyl)amino]phenyl]arylmethanones, useful
in preparation of the pyrido~l,4~benzodiazepines, by
heating neat a halonitropyridine with an aminoarylphenone.
Heating and reaction of such mixtures as described
in the foregoing disclosures involves dïfficult handling
o viscous, sticky reactants and reaction products which
adhere to the reaction vessel. In contras~, in the present
invention the diazepine ring is formed by a strong non-
nucleophilic base such as sodium hydride in a solvent or
liquid carrier which provides high mobility, ease of
operation and increased yields and direct formation of the
sodium salts of the pyrido l,~-benzoidazepines.
Relating to the preparation o certain chemical
intermediates used in the process of the present invention,
yamamoto, M. and Yamamoto H. in chem. Pharm. Bullo 29(8) J
2135-2156 (1981) describe the reaction of 2-amino-4-
chlorobenzophenone and an amine in tha presence of titanium
tetrachloride a~ represen~ed by the following equation:
/C~Hs / ~H5
Cl ~ - O Ti Cl4 Cl ~ C - ~-Rl
wherein Rl-alkyl/ cycloalkyl, phenylalkyl, dialkylamino-
alkyl and 4-morpholinoalkyl.
Also relating to preparation o~ certain other
intermediates used in the process is a disclosure of phase-
transfer catalyzed ~-monoalkylation of 2-aminobenzophenones
o Mouzin, G., et al, in Synthesis Communications Georg.
Thieme Verlag 1981, p. 448-4~9. as represented by the
~ollowing e~uation:
425
~ ~ X2
~ C = o _alkylatinq a~ent/ _ ~ C = 0
,0 r ~aOH/THF/(n-C4Hg)4N Br
Xl~NH
R
wherein R=CH3, -CzH5 or allyl; Xl=Cl or Br; X2=H, Cl or F.
SUMMARY QF TB I~VENTI0~
Pyridobenzodiazepine compounds which are prepared
directly by the novel process o~ the present invention have
the fo3~ula:
Ar
Z~Y
R Formula I
wherein R is selectad from the group consisting of alkali-
metal cation ~M+),.hydrogen, ~alkl-Q wherein Q is selected
from hydrogen, halo, -NRlR2, -~=CH-O-Cz~5 or
. ~0
-0-CHCH2CH2CH2CH~;
- 25 Rl and R2 are selected from the group consisting of
loweralkyl, -c(0)0-loweralkyl or Rl and R2 taken together
with the adjacent nitrogen atom may form a heterocyclic
residue selected from the grol~p consisting of l-piperidinyl,
l-phthalimido, l-pyrrolidlnyl, 4-morpholinyl, l-piperazinyl,
and 4-substituted-piperaz.in-1-yl;
Ar is elected from the group consisting of 2, 3 and
4 pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted
by 1 to ~ radicals selected ~rom halo, loweralkyl, lower-
alksxy, trifluoromethyl or nitro and may be the same or
3~; different;
425
alkl i9 a straight or branched hydrocarbon chain
containing 1~8 carbon atoms;
Z is selected ~rom the group consisting of hydrogen,
halogen, loweralkyl, loweralkoxy, hydroxy or nitro;
Y is selected from the group consisting of hydrogen
or 1-2 radicals selected from loweralkyl, loweralkoxy or
hydroxy and may be the same or different, and the acid
addition salts thereof except when R=M~.
The compounds of Formula I have utility as anti-
depressant pharmaceuticals or as intermediates in ~he
preparation of other compounds of Formula I and of
Formula Ip described hereinbelow.
Additionally, the compounds of Formula I wherein R is
-alkl-O~CHCI~CH2CH~CH2 have been used to prepare compounds
f Formula I wherein R is -alkl-RlR2 via novel intermediates
wherein R is alkl-OH and.alkl-OS02W wherein W is as defined
hereinbelow.
In the ~urthPr definition of symbols in the formulas
hereon and where they appear elcewhere throughout this
specification and claim~, the terms have the following
significance.
The "alk" stxaight or branched connecting hydro~
carbon chain containing 1-8 car~ons is exemplified by
methy~ene (-CH2-), ethylene (-CHz-CI~-), propylene
(-CH2C~I2CH2-), ethylidene ~-CH-], 1,2-propylene
H CH3 CH9
CH-CH2- or -CH~ , isopropylidine ~-C- ~, or
CH3 CH3 c~3
1,~-butylene [-CH-CH2-CH2-~, and the like.
CH3
The term "loweralkyl" includes straig~t and branched
chain hydrocarbon radicals of up to eight carbon atoms
inclusive and is exemplifi2d by such groups as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tertiarv butyl,
~5 amyl, isoamyl, hexyl~ heptyl, octyl, and the like.
The term "halogen" includes chlorine, bromine)
fluorine, and iodinel pre~erably chlorine, bromine and
fluorine.
~ 3~ ~
- ' 425
The term "4-substituted-l-piperazinyl7' re~ers to
piperazine substitut~d in the 4~position by loweralk~l or
alkoxy-carbonyl blocking group which may subsequen~l~ be
removed to give the unsubstituted piperazine.
Pharmaceutically acceptable acid addition salts are
those salks formed by the pyridobenzodiazepines prepared
by the process of this invention with any acid which is
physiologically compatible in warm blooded animals, such
salts being formed either by strong or weak acids. Repre-
sentative of strong acids are hydrochloric, sulfuric and
phosphoric acids. Representative of weak acids are fumaric,
maleic,' succinic, oxalic, cyclohexamic and the lik~.
The 6-aryl-llH-pyrido~2~3-b]~l~4~benzodiazepines and
the 5,6-dihydxo derivatives thereof encompassed by
Formula I have the formula:
' Ar
Z ~ ~ Y
R ' Iw
l'he 6-ary~ H-pyrido~3~4-b]~lJ4]benzodiazepines and
the 5,6-dihydro derivatives thereof encompassed by Formula I
have the formula:
Z ~ I~
The ln-~r~ r~'~^r~,~-k~Ll,4J~ ~ -~r ' ~ ~
the 10,11 dihydro derivatives thereof encompassed by
Formula I have the formula:
"s~3
~25
Z ~ Y
R Iy
The 10-aryl-5H-pyrido~3,2-b~C1,4]benzodiazepines and
the 10,11-dihydro derivatives thereof encompass2d by
Formula I have the ormula:
Ar
~=~
Z ~ ~ ~ Y
R Iz
In all the formulas Iw to Iz, the symbols R, Ar, z
and Y have the definition given hereinabove under Formula I.
For the purpose of testing antidepressant activity
of the present invention compounds, the procedura given by
Englehardt, E. L., et al., J. Med. Chem. 11(2): ~25 (1968)
which has been indicative in the past of usefulness of
compounds for treating human depression was used as follows:
20 mg/kg of the compound to be tested was administered to
five adult female mice (ICR-DUB strain) intraperitoneally
30 minutes prior to the administration of a ptotic dose
(32 mg ~g IP) of tetrabenazine (as the methanesulfonate
salt). Thirty minutes later the presence or absence of
complete eyelid closure (ptosis) was assessed in each animal.
An EDso (Median Effective Dose) may be established for each
tested compound in blocking tetrabenazine-induced pto~i~ in
mice following the procedure given by Litchfield et al.
. Pharmacoi. ~xp. ~l~n~rap. ~: ~y~ 154y;.
~5 Compounds preparable by the process of the invention
or from the intermediates thereof which have antidepressant
activity in the foregoing antidepressant test procedure
have the Formula Ip
Ar
~N
z1~7~
R
Ip
wherein;
R is selected from the group consisting of hydrogen,
loweralXyl or -alk1~ R1R2;
Rl and R2 are selected from the group consisting of
hydroyen, loweralkyl or Rl and R2 taken together with the
adjacent nitrogen atom may form a heterocyclic residue
selected ~rom the group consisting of l-pyrrolidinyl,
4-morpholinyl, l-piperazinyl or 4-loweral~yl-1-piperazinyl;
Ar is selected from the group consisting of 2, 3 or
4-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted
by 1 to 3 radicals selected from halo, loweralkyl, lower-
alXoxy, trifluorome~hyl or nitro and may be the same or
different-
Alk1 is a straight or branched hydrocarbon chain
containing 1-8 carbon atoms;
Z is selected from the group consisting of hydrogen,
halogen, loweralkyl, loweralkoxy, hydroxy or nitro,
Y i9 qelected from the group consisting of hydrogen~
or 1-2 radicals selected from loweralkyl~ loweralXoxy or
hydroxy and may be the same or different,
and the pharmaceutically acceptable acid addition
salts.
The compounds of Formula Ip wherein R is -alkl-NRlR2
and ~L and RZ are loweralkyl or hydrogen have been shown
to have low incidence of antihistaminic~ anti-cholinergic
and cardiotoxic side effects when tested in animals.
425
The preferred pyridobenzodiazepines useful in the
method of treating depression are as follows:
dimethyl 6-phenyl-llH-pyrido~2,3-b~rl,4
benzodiazepine-ll-propanamine.
6-(4-fluorophenyl)-N,N-dimethyl-llH-pyrido
~2,3-b]~1~4]benzodiazepine-11-propanamine.
6-phenyl-lH-pyrido~2,3-b]C1,4]benzodiazepine-
ll-propanamine.
N-methyl-6-phenyl-llH-pyrido~2,3-b]~1,4
benzodiazepine-ll-propanamine.
6-(2-chlorophenyl)-N,~-aimethyl-lLH-pyrido
~2~3-b~ 4]benzodiazepine-ll-propanamine.
6-(2-fluorophenyl)~ -dimethyl-llH-pyrido -
~2~3-b][l~4]benzodiazepine-ll-propanamine .
The generalized schematic equation for the preparation
of pyridobenzodiazepines according to the process of the
invention is yiven in Chart I.
, ~Z~ ~ 3~ ~
425
CH~RT I
Z ~ ~ ~ ~ ~ Y
III rv
Strong non-nucleophi].ic
alkali-metal base and
Ar ~ liquid carrier
>=~
Z-~
When R3=alkali-metal ion 1 When R3=alkali-metal ion
a) Add Cl-alkl-Q ¦ Add aqueous proton donor
to reaction mixture ¦ to reaction mixture
b) **~*
\~
alkl_Q*** H
Ib Ic
*R=hydrogen, lowerOlkyl, -alkl-~RlR2, -alkl-~=CH-OC2H5
or alkl-O-CHCH2CH2CH2~H2 and Rl and RZ are as
defined under Fo~mula I
X=chlorine, bromine, fluorine or iodine.
**R3=alkali-matal ion, loweralkyl, -alk~ R2,
-alXl-~=CH-OC2H5 or -alkl-O-CHC~I2CHzCH2CH2 and
Rl and R2 are as defined under Formula I.
~**Q=hydrogen, halo, -alkl-~=CH-OC2H~, alkl-NRlR2
or -alkl-O-CHCHzCHzCH2CH2 and Rl and R2 are as
defined under Formula I.
****Add dimeth~lformamide to the reaction mixture when
Q i5 --C~CH2CHzCH2CH2 J hydrogen, halo and
-alk1~=CH-OCzH5.
Compounds of Formulas IaJ Ib and Ic are encompassed
by Formula I.
3~ ~
425
Additional procedures for converting compounds o~
Formu~as Ia or Ib wherein Q is -O-CHCH2CH2CH2CH2 which
have been separated from the reaction mixture (or which
have bs~n prepared by reacting isolated compounds wherein
R3 is H with godium hydride and reagent
Cl-alkl-CHCHzCH2CH2CH2) to useful antidepressant agents
~Formula VIII) are illustrated in the schematic equation of
Chart II.
C~RT II
Ar
>~
~ 1 ~o
Ie alkl-CHC~zCHzCH2CH2
1 Strong concentrated acid;
e.g., conc. HCl
Ar ~ ,protic solvent;e.g., ethanol
~ N
Z~Y
V /~ alkl-OH \ WS02Cl
~ Ar / \ (W=loweralkyl, phenyl
N ~ SO2Cl Ar ~ tolyl radicals)
llk~Cl
VI VII alklOSO2W
1H~R1R2 *
Z~N~
alkl-~RlR2 VI~I
*R~ and R2 are a defi~ed in Formula I + hydrogen.
Colll~OUfid~ OL rG;illUla ~e ~lid 'v~ drc æ.com~a-s~d ~y ~L'm~a
and Formula VIII is encompassed by Ip.
Csmpounds of Formula Ie~ V and VII are novel.
~2
11
Novel intermediates useful in the preparation of
pyridobenzodiazepines of Formula ~ have the formula:
N
z ~1 H X~--Y
.Formula II
wherein Ar, Y and z are the same as defined under Formula I;
X=halo (C1, Br, F, I) and R is selected from the group
consisting of hydrogen, loweralXyl, -alkl-NRlR2, -alkl-N=
CH OC2H5 or -alkl-O-CHOEI2CH2CH2CH2 wherein alkl, Rl and
R2 are the same as defined under Formula I and the acid
addition salts thereo~.
All positions of the pyridinyl nitrogen encompassed
by Formula II are illustrated as follows:
X~ Y Z
R R
IIa IIb
R R
IIc IId
Compounds of Formula II are novelly prepared according
to '~.;e rO; o~ g y~r.era;l~d Sc;~e.~la~ic equation:
~2
12
T~l Dtert amine, z ~ ~ ~ y
aprotic solvent; I X
e.g., methylene R
chloride (Room Temp.~ II
X=halo,
R=H or -alkl-Q, wherein Q = H or -~RlRZ.
Compounds of Formula II are novel.
'~ Compounds of Formula IV are available commercially
or can he,readily pr,epared by known methods.
Compound~ of Formula III wherein R is H and corre-
~ponding to the Formula IIIa
O~
IIIa
are available commercially or may be prepared by known
methods.
~ovel compounds of Formula III wherein R is -alkl-Q
and Q is H or -~RlRZ are prepared according to the
following generalized schematic equation from compounds
of Formula IIIa
O Ar
25Ar THF - "C'
z ~ + x-alk-Q ~aOH III~
~H2 alkylating agent;
e.g., tert-n-butyl-
IIIa ammonium bromide
wherein X is halo, R is selected from -alkl~RlRZ,
alkl-N=CH-OCzH5 or alkl-O-CHCH2CH2CH2CH2 and Ar, z and
Rl~R~ are ~s dccir.ad ur.daL- rormula I,and tha acid addition
salts thereof.
s~
4~5
It is therefore an object of the present invention to
provide a novel process for the preparation of aryl-llH-
pyrido~ll4]benzodiazepines which are either antidepressant
pharmaceutical agents or useful in the preparation of other
aryl~ -pyridoC1,4~benzodiazepine agents wlnich have
antidepressant activity which utilizes a strong nucleophilic
base in the condensation of (aminophenyl)arylmethanones and
an amino-chloropyridine or partially condensed intermediates
from those reactants all in stirrable admixture with inert
liquid carrier.
Another object is to provide novel chemical inter-
mediates and process therefor, such intermediates being
useful in the preparatlon of arylpyridobenzodiazepines,
which intermediates in general terms are phenylamines linked
adjacent to the amine function via phenyl-substituted
iminomethylene bridge to halopyridine and process therefor.
Still another object is to provide certain no~el
(aminophenyl) arylmethanones useful as intermediates in the
process of the invention.
DETA:I:LED DESCRIPTIO~ OF TEIE I~ TIO~
The novel process of the invention for preparing
compounds of Formula I is comprised of the following four
steps 1 to 4 with an optional preliminary step A.
Step 1, reacting a compound of the formula
Ar
>~
X~Y
or a mixture of compounds of the formulas
o~ /Ar
~,C H2 ~7
III R IV
425
14
w~erein Ar, Y and z are as defined under Formula I, X i3
halo (chlorine, bromine, fluorine or iodine), R is hydrogen
or alkl~Q wherein alXl is as defined above and Q is selected
~rom hydroge~, -~RlR2, -N=cH-oc2Hs~ or -o-c~cH2cH2cH2cHz and
~1 and R2 are selected from loweralkyl, -C(0)0-loweralkyl
or Rl and R2 taken -together with the adjacent nitrogen atom
may form a heterocyclic residue selected from the group
consisting of l-piperidinyl, l-phthalimido, l-pyrrolidinyl,
4-morpholinyl, l-piperazinyl and 4-substituted-piperazin-1-
yl ~ogether with at least a stoichiometric amount of astrong non-nucleophilic alkali-metal base in stirrable
admixture with inert liquid carrier to give a compound of
the ~ormula
Ar
z " ~
in stirrable admixture with inert liquid carrier, wherein Ar,
Y and Z are as defined above and R3 is an alkali-metal ion
selected from sodium, potassium or lithium or -alkl-Q,
whereln alkl is as defined above and Q is the same as in
the starting compound~
Step 2, optionally when desired, r~acting a compound
as prepared in step 1 in admixture with said liquid carrier
wherein R3 is an alkali-metal ion with a proton source to
give a compound of the foxmula
Ar
~Y
H
J
425
15
in admixture with inert liquid carrier wherein Ar, Z and Y
axe as defined above.
Step ~, when desired, reacting a compound as prepared
i~ admi:xture with liquid carrier in step 1 wherein R3 is an
alkali-metal ion with a reagent having the formula
halo-alX l~
wherein Q is selected ~rom hydrogen, -NRlR2, ~N=CH-0-C2EI5,
~0
or -0-CHCH2CH~CH2CH2 and Rl and R2 are selected from the
group consisting of loweralkyl, -C(0)0-loweralkyl or Rl and
R2 taken together with the adjacent nitrogen atom may form
a heterocyclic residue selected from the group consisting
of l-piperidinyl, 1-phthalimido, l-pyrrolidinyl,
4-morpholinyl, l-piperazinyl and 4-substituted-piperazin-
1-yl, to give a compound of the formula
Ar
. ~7~Y
alkl-Q
in admixture with liquid carrier wherein Q has the startin~
value of the reagent and Ar~ Y, Z and -alkl are as defined
above.
Step 4, separating a compound prepared in step 1 oth~r
than a compound whPrein R9 is an alkali-metal cation, and
in steps 2 and 3 by conventional means from the carrier
and the reaction mixture to give a compound of the formula
Ar
Z
3 ~ 425
16
wherein Ar, Y, Z and R are as defined above, except R is
not alkali-metal cation, and the acid addition salts
thereof.
In another novel variation of the process in a
preliminary Step A, compounds of Formula II, when used
in step 1, see Chart 1, are prepared as follows.
Step A, reacting a mixture of a compound of the
formula
O~ ~Ar
~[~
I III
R
wherein Ar, Z and R are as defined in step 1 of the rormula
H2 ~ ~
IV
wherein X is halogen and Y is as defined under Formula Ig
together with titanium tetrachloride and an excess of a
tertiary organic amine in an inert liquid carrier and
separating the product from the reaction mixture.
Obviously, Step A also serves as a single process
step for preparing compounds of Formula II, see Chart I,
which, as stated above~ are novel chemical intermediates.
The following description iq applicable to the
foregoing process:
In step 1, ~uitable liquid carriers must be non-
reactive with the strong non-nucleophilic base; e.g.,
sodium hydride and other reactants free of moisture and
stable enough to prevent development of alkaline metal
hydroxides which lead to impurities which are difficult to
remove. Carrierq generally classified as strictly protic
are not suitable. Suitable liquid carriers may or may not
solubilize the reactants or products but some solubility
o~ organic reactants and products in the carrier is usually
~ 3~ 3 ~25
desirable. Examples of aprotic aromatic non-polar qolvents
which are suitable as carriers are toluene7 xylene and
benzene. Examples of aprotic non-polar ether solvents
which are suitable carriers are tetrahydrofuran, dioxane,
and ethyleneglycol dimethyl etherO Examples of aprotic
polar solvents which are suitable as carriers are dimethyl-
formamide, morpholinoformamide, alkyl-~-pyrrolidinones,
pyridine and dimethylsulfoxide. A preferred carrier is
toluene. Use of mixtures of these carriers have been demon-
strated to have advantage and such advantage will depend onthe specific reactants or products involved, particularly
when solubility is a factor. One such preferred mixture
involves toluene and tetrahydrofuran. Another preferred
combination is toluene and dimethyl~ormamide as in the
case when the radical -alkl-O-CHCH2CHzCH2CH2 is involved.
The amount of carrier may vary widely ranging from as
little as about 5 part per 100 parts by weight of
reactants to as much as 100 parts or more per 100 parts
by weight of reactants. Generally, the minimum amount of
carrier which can be used is that amount of carrier which
will provide sufficient mobility for the reaction mixture
to become stirrable and to provide flowability to the mix.
When toluene is used, about 8 12 parts by weight of carrier
to reaction mixture is a preferred range. A wide range of
25 temperatures in step 1 may be employed, suitably about
20Co to 150C., about 40C. to 120C. being preferred.
The more specific prefexred temperature is that obtained
with boiling tetrahydrofuran and refluxing ~oluene; i.e
65C. to 110C. While it is possible to conduct the
reaction using a stoi~hiometric amount of sodium hydride,
more complete reaction is ob~ained by using at least one
molar excess of base. Two molar equivalents of strong
alkali-metal non-nucleophilic base; e.g., sodium hydride~
is therefore preferxed. One preferred mode of conducting
the reaction in step 1 i~ to slurrv or di~solve the amino-
halopyridine in a suitable aprotic carrier, pre~erably
toluen~, and simultaneouqly add a slurry of the non-
nucleophilic alkali-metal base in the same carrier and a
425
18
solution of the amino~enzophenone in a suitable aprotic
non-polar solvent, pref~rably tetrahydrofuran or dioxane,
at a temperature such that the tetrahydrofuran boils off
during the addition as the aminobenzophenone is reacted.
As indicated above, sodium, potassium or lithium hydrides
are suitable strong non-nucleophilic bases which facilitate
the reaction, making possible the use of the solvent
carriers and are preferredJ sodium hydride being especially
preferred. Among other strong, non-nucleophilic bases
which may be used are potassium tertiary butoxide, sodium
triphenylmethane, sodium dimethylsulfoxide, ~nd alkali-
metal amides.
The following illustrates the balanced equation
involved in step 1 for each type of reactants when the
strong non-nucleophilic alkali-metal base is sodium hydride.
P,r
z ~NH2 ~-- + 2~aH aprotic solvent
~,>=N~ ~ ~ NaCl + 2H2
Z~Y
. Ar ~a
C=N
~ ~ ~+ ~aH aprotic solvent
z ~ NH ~~Y Ar
llk l-Q __~NaC1 + Hz
0~ /Ar alkl_Q
z _~NH2 C~ 3NaH aprot ic solvent
Ar
~>=~ + ~oH~acl*H2
Z~I~Y
Na
0~ Ar E N y~ 2~aHaprotic solv>nt
alk 1 _Q
Ar
>=~+ ~aoH~acl+2H2
Z ~ I ~ Y
alkl~
In each instance it is pre:Eerable to use an excess
o sodium hydride.
~ 3~ ~ 425
.
In ~tep 2, an alXali-mPtal salt of compounds as
prepared in step 1 still in the liquid carrier are
converted to the \N~ compounds by reacting with any reagent
H
capable o providing a proton source. Examples of suitable
agents are water~ weak or strong acids~ and water containing
bufering salts. The latter agent is preferred and the
preferred buffexing salt is ammonium chloride. Blueish
green color of the solution present initially in this step
is indicative of the sodium salt of the pyridobenzo-
diazepine and as the proton source is added such as aqueousammonium chloride solution, a golden yellow solid precipi-
tates.
In step ~, the halo-alkl-Q reagent in a suitable
organic solvent i5 added to the reaction mixture containing
a metal salt, i.e., R3=alkali-metal ion,and the reaction
mixture is heated until reaction is complete. Solvents
used to dissolve the reagent are generally the same as used
for the carrier in step 1, except when Q is pyranoyloxy =
-0-CHCEI2C~2CH2CH2, halo or -N=CH~OC2H5, dimethylformamide
is used. The reaction mixture is filtered to remove halo
salt by-product.
In step 4, the products may be isoLated, a) by
extraction, preferably by partitioning between water and
methylene chloride; b) by chromatographic separation,
c) by conversion to acid addition salts and recrystallizing
from suitable solvent or solvent combinations; d) by
dissolving the strong acid salts such as the hydrochlorlde
in water and extracting out impurities with a solvent such
as toluene.
~0 In preliminary step A, compounds of Formula II are
substantially separated from li~uid carrier by conventional
means such as evaporating solvents and par~itioning between
water and organic solvent, iltering to remove titanium
oxide, washing,drying and evaporating the solvent layer to
~5 give the product as residue which can be used directly in
step 1. The product may be further purified by chroma-
tography or recrystallization from organic solvents.
~ 3 ~25
A preferred procedure for conducting the combination
of step~ 1 and 3 (i.e., when step 2 is not involved) iq to
simultaneously add a tetrahydrofuran o~ dioxane solution
of a compound of the formula
o~ ~ r
Z~
R
wherein Ar, R and z are as defined in step 1 and a slurry
of sodium hydride in toluene to a hot toluene solution
o.f a pyridine compound of the formula
H2N~ " ^~
~ ~ Y
wherein X and Y are as defined in step 1 at a rate such
that the tetrahydrofuran or dioxane i5 distilled away at
about the same rate it is being added and thereafter adding0 a toluene solution containing a reagent having the formula
halo-alkl-Q
wherein alkl and Q are as defined in step 3, except in the
in the instance w~ere Q is -O-CHCH2CH2CH~CH2, halo or
-N=OEI-OC2Hs in which case the solvent for the halo-alkl-Q
reagent preferred is dimethylformamide.
A preferred embodiment is the use in s~ep 1 of a
mixture of compounds of said formula~
o~ Ar
~ C and H2~ ~
III . IV
Another preerred embodiment is the use in step 1 of
a mixture of compound~ of formulas III and IV and a strong
base consisting of sodium hydride.
~6 ~ 3~ ~ 425
22
A furthex preferred embodiment is the use in step 1
of a mixture of compounds of formulas III and IV wherein
R is H.
A still further preferred embodiment is the use in
step 1 of a mixture of compounds o formulas III and IV
wherein R is H and the strong base is sodium hydride.
~ nother preferred embodiment is the use in step 1 of
a mixture of compounds of formulas III and IV consisting
o 2-aminob~nzophenone and ~-amino-2-chloropyridine and
a strong base cons isting of sodium hydride in step 1 to
produce the sodium salt of 6-phenyl-llH-pyrido~2,3-b]
~1,4~benzodiazepine in step Z.
As an extension of the process outlined in steps 1-4
above with or without optional step A, the following
further optional steps (see Chart II) are novelly employed
to obtain certain compounds of Formulas I and Ip in
steps 5 to 8. As will be recognized, the generic sccpe
of compounds preparable is extended to include R=OH,
-alkl-oSO2-alkyl, alk1-OSO2-phenyl and one or both of
Rl and R2 are H.
Step 5, reacting a novel compound obtained in step 4
of the formula
Ar
>~
~ ~ ~
Ie alkl-O-CHCH2CH~CH~CH2
wherein Ar~ Y, z and alkl are as defined under Formula I
~0 with a strong concentrated acid in protic solvent,
pre~erabLy e~hanol, to give a novel compound of the formula
Ar
alklOEI
I~
353 ~2
23
w~erein Ar, Y~ z and alkl are as defined above.
Step 6, reacting a compound prepared in step 5 with
thionyl chloride to obtain a compound of the formula
Ar
Z ~ y
Ib alkL-chloride
wherein Ar, Y, Z and alkl are as defined above.
Step 7, reacting a compound prepared in step 5 with
a reagent
WSO2Cl
wherein W i~ loweralkyl, phenyl or tolyl to give a
compound of the formula
Ar
~ N
Z-~Y
Ig alkl-OS0zW
wherein Ar, Y, Z, alkl and W are as defined above.
Step 8, reacting a compound prepared in steps 6 or 7
with a secondary or primary amine of the formula
HNRlR2
wherein Rl and R2 are selected ~rom hydrogen, loweralkylg
and -NRlR2 may be a heterocyclic radical as defined under
Formula I, to give a compound of the formula
~ Ar
Z- ~ ~ ~N
alklNRlR2
~5 w~erein Ar, Y, Z, alkl and Rl, R2 and -NRlR2 are as deined
above.
- ~ f
~25
24
Primary amines may be prepared by reacting compounds
wherein ~NRlR~ is phthalimido with hydrazine hydrate and
acid
~r
~ N
alkl ~H2
Compounds prepared by the process wherein Q is
~MHC(O)O-loweralkyl may be reacted with lithium aluminum
hydride to prepare secondary amines of the formula
Ar
~ N
Z~l~
alklN-CE9
Compounds wherein Q is -~=CH-OCzH5 may also be reacted
with sodium borohydride to prepare secondary amines.
425
3~ 3
The following preparations 1 and 2 illustrate the
method for preparing ary,-(2-amino-substituted-phenyl)
methanone of Formula ~II wherein R is other than hyarogen
(see Chart II) and are not to be construed as being
limiting in nature.
PreParation 1
~ 2-~3-(Dimethylamino)propyl]aminO]phenyl]phenyl-
methanone monohydrochloride.
- To a mixture of 78.8 g (004 mole) of 2-aminoben~o-
phenone, 160 g (4.0 mole) of crushed sodium hydroxide and
8 g of tetra-n-butyl ammonium bromide was added a dry
solution of 145.8 g (1.2 mole) of 3-dimethylaminpropyl
chloride in 700 ml of tetrahydrofuran. The mixture was
stirred mechanically and was maintained at reflux overnight.
The tetrahydrofuran solution was decanted and concentrated.
The concentrate was dissolved in toluene. The solid from
which the tetrahydrofuran was decanted was dissolved in
water and extracted with the toluene solution. The
resulting toluene layer was separated and washed twice
with water and th~n extracted three times with portions of
20% acetic acid totaling 600 ml. The combined acetic acid
solution was washed once with tol~ene and then made basic
with 50~ sodiu-m hydroxide in the presence of toluene. Th~
a~ueous layer was separated and extracted once with toluene.
The toluene layers were combined and washed with water,
dried over sodium sulfate and evaporated to give 112.8 g
(100~) of nearly pure ~ee base o the title compound. A
20 g sample was dissolved in 75 ml of isopropyl alcohol
to which was added o.o76 mole of hydrogen chloride dissolved
in about 35 ml isopropyl alcohol. Additional isopropyl
alcohol and isopropyl eth,r (about 1:1 ratio) were added
to make a total volume of about 200 ml. The mixture was
stirred overnightO The yellow solid was collected by
filtration, washed once with 1:1 isopropyl alcohol/
isopropyl ether and twice with isopropyl ether. Weight
of product obtained from the 20 g samrle was 16.4 a.
m.p. 182-183C.
353 ~25
26
Analysis: Calculated for Cl8H23~zOCl C,67.81; H,7.27;
~,8.79
Found : C,67.68; ~,7.29;
N,8.70
PreParation ?
Following the procedure of Preparation 1 but substi-
~uting the following for 3-dimethylaminopropyl chloride,
3-(1-pyrrolidinyl)propylamine,
~ -(l-piparidinyl)propylamine, and
3-(4-morpholinyl)propylamine,
there are obtained:
[2-~3-(l-pyrrolidinyl)pxopyl]amino]ph2nyl]phen
methanone,
~2-~3~ piperidinyl)propyl~amino]phenyl]phenyl-
methanone, and
~2-~C3-(4-morpholinyl)propyl]amino]phenyl]phenyl-
methanone.
27
The following examples are provided merely by way of
illustration and are not to be construed as being limiting
in nature.
~-c(2-Aminophenyl)phenylmethylene]-2-chloro-3
pyridinamine.
To a stirred suspension o ~.94 g (0.02 mole) of
2-aminoben~ophenone and 2.58 g (0~02 mole) of 3-amino-2-
chloropyridine in 20 ml of toluene and 6.2 ml (o.o48
mole) of triethylamine under a nitrogen blanket in an ice
bath was added a solution of 2.28 g (0.012 mole) of
titanium tetrachloride in 10 ml of toluene over a 5 min
period. After the addition was complete, the ice bath was
removed. The mixture became dark red in color and solid
material was in evidence. About 15 ml of toluene was
added followed by 15 ml o methylene chloride. After 1 hr
total time, TLC showed starting material and product were
present. Ater ~ hr total time, additional titanium
chlorideg1.52 g (o.o8 mole), in 4.15 ml (0.032 mole~ of
triethylamine and methylene chloride was added to the
reaction mixture which was th~n stirred overnight. The
mixture was evaporated. The residue was partitioned
between water and methylene chloride. Solid precipitate
was removed by filtration. The aaueous layer was separated
and extracted again wikh methylene chloride. The methylene
chloride layers were combined and back washed with sodium
chloride solution, dried over sodium sulate and evaporated
to give 6.2 g of orange oil. The chemical ionization
mass spectrometer gave product peak at m/e 308 and
starting materials peaks at m/e 198 and m/e 1290 NMR
analysis as follows indicated the product was composed of
about 75% of the title compound. The lH~MR spectrum of
the crude subject product was obtained in CDC13 containing
1~ tetramethylsilane (T~1~). The chemical shifts, multi-
~5 plicities and assianments are ~i~ten belo~.
3~ 3 425
28
Mixture C~H5
and
A B C
Chemical Shifts
~muLtiplici~ie~)
at_ppm Assignments
7.50 (multiplet) Ha in Compound A
7.~5 (multiplet) Hb in Compound B
7.30-5.95 (multiplet) signals from other
protons attached to
carbons on Compounds
A, B and C
5 ~ (broad singlet) -~H signals
4.83 (singlet) CH2C12 (methylene
= chloride)
Ratio o~ the integrations at 7.50 ppm to ~hat at 7.35 ppm
is roughly 3:1, thus the product iq about 75% A.
Example 2
N-r(2-Aminophenyl
pyridinamine.
To a stirred suspension of 7.88 g (0.04 mole) of
2-aminobenzophenone and 5.14 g (0.0~ mole) of ~-amino-2-
chloropyridine in 100 ml of methylene chloride and
27.2 ml (0.2 mole) of triethylamine undex nitrogen blanket
was added a solution of 5.28 ml of titanium tetrachlo~ide
in 20 ml of methylene chloride dropwise over a 10 min
period. The reaction mixture was stirred at room temperatur2
for 22 hr. Water was added slowly to the reaction mixture
until a thick suspension was formed. The suspension was
poured into 150 ml of water and the resulting mixture was
stirr~d ror ;7 min. ~he mixtur~ was filtered to remove
ti~anium dioxide. The filter cake was rinsed with
~5 methylene chloride. The organic layer of the filtrate was
3 42
29
separated. The aqueous layer was extracted once with
methylene chlorîde. The methylene chloride layers were
combined, washed with dilute sodium bicarbonate solution,
dried and evaporated to give 12.6 g of brown syrup. MMR
analysis as follows indicated the product was composed
mainly of title compound with about 15~ 3-amino-2-chloro-
pyridine starting material contaminant. The lHNMR spectrum
of the crude subject product was obtained in CDC13
containing 1~ ketramethylsilane (TMS). The chemical shifts,
multiplicities and assignments are given below.
Mixtu~e of CBH5
~ ~ , Hb ~ H
Ha
A B C
Chemical Shi~ts
~multiplicities) Assiqnments
at Ppm
7.70 (multiplet) Ha in compound A
7.55 (multiplet) Hb in Compound B
5.55 (broad singlet) ~H 3ignals
5.00 (singlet) CH2Cl2 (methylene
~ chloride)
7.40-610 (multiplet) signals from remaind~r
of protons on Compounds
A, B and C.
Ratio of the integrations at 7.70 ppm to that at 7.55 ppm
is roughly 13 to 2; thus the product is about 85% A.
Example ~
3a Following the procedure of Example 2 but substituting
the following for 3-amino-2-chloropyridine,
4-amino-3-chloropyridine,
3-amino-4-chloropyridine, and
2-amino-5 chloropyridine
there are obtained:
. 42
a~ (2-aminophenyl)phenylmethylene~-3-chloro-4-
pyridineamine,
b) N-C(2-aminophenyl)phenylmethylene]-4-chloro-3-
pyridinamine, and
c) N-~(2-ami.nophenyl)phenylmethylene]-3-chloro-2-
pyridinamine .
Exam~e 4
Following the procedure of Example 2 but substituting
the ollowing for 2-aminob~nzophenone,
2-amino-4-chlorobenzophenone~
2-amino-4-methylbenzophenone,
2-amino-4-methoxybenzophenone,
2-amino-4~hydroxybenzophenone,
2-amino-4-nitrobenzophenone J
2-amino-5-chlorobenzophenone,
2-amino-4l-chlorobenzophenone, and
2-amino-4'-methylbenzophenone,
there are obtained:
a) ~-~t2-amino-4-chlorophenyl~phenylmethylene]-2-chloro-
3-pyridinamine,
b) ~-[(2-amino-4-methylphenyl)phenylmethylane]-2-chloro-
3-pyridineamine,
c) ~-~(2-amino-4-methoxyphenyl)phenylmethylene]-2-chloro-
3-pyridinamine,
d) ~-[(2-amino-4-hydroxyphenyl)phenylmethylene~-2-chloro-
3-pyridinamine,
e) ~-~t2-amino-4-nitrophenyl)phenylmethylene]-2-chloro-
3-pyridinamine,
f) N-~(2-amino-5-chlorophenyl)phenylmethylene]-2-chloro-
pyridinamine,
g) ~-~(2-aminophenyl)-4-chlorophenylmethylene]-2-chloro-
3-pyridinamine, and
h) ~ C(2-aminophenyl)-4-methylphenylmethylene]-2-chloro-
3-pyridinamine.
AHR-425
31
'-~2 r (2-Chloro-3-pyridinyl mino)phenylmethyl~phenyl~-
N,~-dimethyl lj~-propanediamine.
To a mixture of 2.82 g (0.01 mole) of i2-C~-(dimethyl-
amino)propyl~amino~phenyl]phenylmethanone and 1.29 g (0.01
mole) of 3-amino-2-chloropyridine, 6.2 ml (o.o48 mole) of
triethylamine and 20 ml of methyl~ne chloride stirred in an
ice bath under nitrogen atmosphere was added 2.28 g (0.012
mole) of titanium tetrachloride in 10 ml of methylene
chloride during a 5 minute period. The mixture was then
stirred at room temperature for 2 days during which time
mass spec-CI showed little change in relative intensity
of M.W. 129 (starting pyridine) and M.W. 393 (title product~.
Water was added to the reaction mixture and ~tirring was
continued for 1.5 hr. The mLxture was filterad to remove
solid and the filter cake was rinsed with methylene
chloride. Saturated sodium chloride solution was added to
facilitate separation of layers. The methylene chloride
layer was washed once with more sodium chloride solution.
The aqueous layer having a p~ of about 6 was basified to
about pH 8-9 with potassium carbonate and then extracted
twice with methylene chloride. The latter methylene
chloride layers were washed with sodium chloriae solution.
All the methylene chloride extracts were combined, dried
and evaporated to give 4.8 g o~ semi-solid product. TLC
o~ the product showed it contained very little starting
3-amino-2-chloropyridine. Mass SpecO analysis showed the
presence of compounds with molecular weight corresponding
to title product (39~), 3-amino-2-chloropyridine ~129) and
triethylamine (102) but no r2-C~3-(dimethylamino)propyl~
amino]phenyl]phenylmethanone~ l~NMR ~pectrum in CDC13
containing l$ TMS indicated the product was mostly title
compound and some triethylamine. ~o 3-amino-2-chloro-
pyridine was seen. The chemical shi~ts, multiplicities
and assignments are given below.
~ 3 4~5
32
A mixture of ~ 6H5 (C2Hs)3 ~T HCl
Ha C~2CH2C~z-~(CH3~ 2
Chemical Shifts-
(multiplicities)
at ppm Assiqnments
9.85-9.40 (multiplet) ~H on A as well as
TEt)3~.H
7.85 (multiplet) Ha
7.50-6.23 (multiplet) protons attached to
aromatic rings
5.25 ( 9 inglet) CH2Cl2 (methylene
= chloride)
2.25 (singlet) N(Me)2 (methyl group
signal)
3.70-1.70 (multiplat) signals ~rom alkylene
groups (-CH2-) on
compound A as well as
triethylamine
1.35 (triplet) methyl group signals
on triethylamine
Exam~le 6
2-L (2-Chloro-3-pyridinyl~mino)phenyl_ethyllphenyl~-
~,M-dimethyl-1,3-propanediamine.
To a mixture of 6.~7 g (0.02 mole) of ~2 ~3-(dimethyl-
amino)propyl~amino]phenyl]phenylmethanone and 2.57 g
(0.02 mole) o~ 3-amino-2-chloropyridine, 16.8 ml (0.12 mole)
of triethylamine in 80 ml of methylene chloride
stirred in an ice bath under nitrogen atmosphere was added
dropwise 2.64 ml (0.024 mole) of titanium tetrachloride in
20 ml of methylene chloride over a 10 min period. The
mixture was allowed to cool to room temperature with
concinue~ agica~ion~ l~ne roLlowing day cnemlcal ionization
mass spectrometry showed that the reaction had
essentially gone to completion with no starting methanone
3~ 3 ~25
33
compound present. ~LC showed little of the s~arting
pyridine was present. The mixture was stirred over the
weekend. Water was added to the reaction mixture and
stirring was continued for 1.5 hrO The mixture was
filtered to remove solid and filter cake was rinsed with
methylene chloride. Saturated sodium bicarbonate solution
was added to facilitate separation of layers. The methylene
chloride layer was washed once with more bicarbonate
solution. The a~ueous layer was washed with methylene
chloride and all the methylene chloride extracts were
combined, dried and evaporated to give 7.35 g (93.5%) of
brown oil. The chemical ionization mass spectrometer gave
a signal corresponding to a molecular weight of the title
compound at m/e ~9~.5 and showed a trace of compound at
m/e 282 (starting methanone ~ree base) and some compound at
m/e 102 (triethylamine) and some compound at m/e 129.5
(staxting amino-chloropyridine). ~he lHNMR spectrum of the
subject product was obtained in CDCl~ containing 1% tetra-
methylsilane (TMS) and is consistent with the proposed
structure and with methylene chloride as minor impurity.
~o signal from starting materials were detected~ The
chemical shifts, multiplicities and assignments are given
below.
arom. C H arom.
C~
\ CH2-C~2-CH~-~(CH~)2
c d e f
~5
34
Image
Example 7
6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-
pyranoyloxypropyl.
To a solution of 10.82 g (0.04 mole) of 6-phenyl-11H-
pyrido[2,3-b][1,4]benzodiazepine in 60 ml of dimethyl-
formamide was added 3.2 g (0.08 mole) of sodium hydride
as 60% suspension in mineral oil followed by 13.2 ml
(0.08 mole) of 1-chloro-3-pyranoyloxypropane. Progress of
the reaction was followed via TLC and an additional 0.7 g
of 60% sodium hydride was added. After the reaction had
stirred for about 3 days, a trace of starting pyrido-
benzodiazepine remained. The reaction mixture was treated
with aqueous ammonium chloride and extracted three times with
toluene. The toluene layer was back-washed with water,
dried) treated with activated charcoal and filtered. The
filtrate was evaporated to give 22.8 g of black oil. The
oil was passed through a short column of 45 g silica gel,
eluting first with toluene and then toluene-ethyl acetate,
Fraction A was concentrated to give 16.3 g of a mixture
consisting of 85% title product and 15% 1-chloro-3-
pranoyloxy propane + mineral oil + toluene. Fraction B
was concentrated to give 2,4 g residue. Mass spectra of
Fraction A showed the following:
m/e 179 which is starting 1-chloro-3-pyranoyloxy
propane used in excess,
m/e 330 which is a fragment from the product, and
m/e 414 which is the title product.
~2~ 2 ~ ~ 425
The lHNMR spectrum of the subject crude product was obtained
and is consistent with the proposed structure and with
toluene and l-chloro-3-pyranoyloxypropane. The chemical
shifts, multiplicities and assignments are given below.
C~Hs f
+ Cl-CH2 -Cf 2 -Cd2 ~
CHz - CH2 - CH2-0 ~ d
d f d H c + ~CeH3
Chemical Shifts
(multiplicities)
at ppm ~ E~
8.15 (multiplet) Ha
7.95-6.90 (multiplet) remainder of aromatic
protons
4.58 (broad singlet) Hb
4.48 (broad singlet) ~Ic
4.25 (multiplet) d protons
2.35 (singlet) e protons
2.25-1.15 (multiplet) f protons
Example 8
6-Phenyl llH-pyrido ~ ne-ll-
A mixture of 3.6 g (o.oo88 mole) of 6-phenyl-llH-
pyrido~2,3-b][1,4]benzodiazepine-11-pyranoyloxypropyl,
3.6 ml of 37~ aqueous hydrochloric acid and 15 ml of 190
proof ethanol was stirred overnight. Sodium hydroxide
pellets, 1.7 g, was added and the mixture stirred until
the pellets had disintegrated. The solvent was evaporated
and ~he residue was partitioned between methylene chloride
and water. The aqueous layer was extracted once more with
methylene chloride. The combined methylene chloride layers
were washed with water, dried and evaporated to give 2.93 g
of brown oil which crystalliæed. The crystals were
separated by filtration and washed with isopropyl ether-
~25
36
petroleum ether. On drying, the yellow crystals weighed1.91 g, m.p. 131-13~C. Mass spectra of the product
showed the following:
m/e 10~ which is isopropyl ether which was used
as cry~talliæation solventg
m/e 414 which is starting material, trace amount, and
m/e 330 which is title product.
The lE NMR spectrum o the subject crystaLline product was
obtained and is consistent with the proposed structure
C~5~ and (cH3)2cHocH(cH3)2
CH2CH2CH2-OH
b c a d
The chemical shifts, multiplicities and assignments are
given below~
Chemical Shifts
(multiplicities)
at Ppm Assiqnments
8.20-6.80 (multiplet) all aromatic protons
4.45-3.50 (multiplet) a protons
~.65 (where triplet centered) b protons
2.65 (singlet) d protons
2.15-1.65 (multiplet) c protons
1.10 (doublet) e protons
Example 9
Nl-r 2-c~loro-6-L-(3-chloro-4-pyridinylimino)phenylmethylJ
phenyl~-M,~-dimethyl-1,3-propanediamine.
Following the procedure of Example 6 and substituting
~2-C~3-(dimethylamirlo)prop~,rl]amino]-6-chlorophenyl~phenyl-
methanone, the title compound is prepared.
~2~
~Z3~3
~7
Example 10
6-Phe~y~-llH-pyridoC?,3-bJ~l ~ nzodiazepine sodium
Salt (Crude Mixture).
To a solution of 516 g (4 mole3 of 3-amino-2-chloro-
pyridine in ~.8 liters of toluene were added simultaneously
in batches a solution o~ 830 g (4.2 mole~ of 2-amino-
benzophenone in 2~2 liters of pyridine and a slurry of
290 g ~12 mole) (as 60~ in mineral oil) of sodium hydride
slurried in 500 ml of toluene over a 2 hr period at reflux.
Re~lux continued for 3 hr additional. Evolution of
hydrogen was vigorous. After stirring overnight at ambient
temperature, the mixture was heated to remove a volume of
distillate o~ 3.8 liters which ~MR indicated to be 65
toluene and 35~ pyridine.
Example 11
6-Phenyl-llH-pyrido ~ ~-b~,4Lbenzodiazepine.
To the residual mixture in Example 10 was added
cautiously a solution of 440 g (8 mole) of ammonium chloride
in 700 ml of water (much foaming). The mixture was heated
to remove 1.5 litsrs of distillate comprised of water,
pyridine and toluene. To the residual solution was added
500 ml of toluene and the mixture heated a second time to
remove 900 ml of distillate. To the residual solution
500 ml more toluene was added and the mixture was again
heated to remove 500 ml of distillate. The orange residual
slurry was diluted with 7.2 liters of tetrahydrofuran.
The mixture was filtered~ The cake was washed by slurrying
in 3 liters of hot tetrahydrofuran and the slurry filtered.
The Xiltrates were combined and passed through a silica gel
column. The eluent was concentrated and the residue
~0 slurried in isopropyl ether-toluene i3:1~. Brown-orange
solid was collected by filtrationO The filtrate was
concentrated and azeotroped with toluene to remove pyridine
The xesidual solution was diluted with i~opropyl ether-
t~ r.~ 1J ^r.~ V~ Vr1 -n-a;, I ~ CrC~G~ ~V Vb~airl
yellow crystals. The combined yield of the title compound
was 813 g (75~ based on starting materials in Example 10.
~ 3~ ~ 425
38
TLC analysis o the product gave a good comparative result
with known title product.
ExamPle l?
~ -Dimethyl-6-phenyl-llH-pyrido~2,3-b~1,4~benzo-
~
~ mixture of 920 g (3.4 mole) of 6-phenyl-llH-pyrido
[2,3-b]~1,4~benzodiazepine prepared in Example 11 (and
. another small run~ in 2 liters of toluene and 1.5 liter of
tetrahydrofuran and 84 g (~.5 mole) of sodium hydride (as
60~ in mineral oil) was heated at reflux with vigorous
evolution of hydrogen. The mixture became black-green in
color. To the mixture was added a solution of 7.6 mole of
3-dimethylaminopropyl chloride in 2 liters of toluene and
the reaction mixture was heated at reflux for 5 hr and then
cooled overnight. The black-yellow mixture was filtered
with difficulty mainly to remove sodium chloride. The
~iltrate was concentrated to remove all but about 1.5-2
liters of toluene. The residual toluene concentrate was
diluted with 2 liters of methylene chloride and the solution
washed with water. The washed solution was concentrated on
a rotary evaporator at 80C. bath temperature. The
remaining black syrup weighed 1400 g. The syrup was poured
910wly into a hot solution of 394 g (3.4 mole) of fumaric
acid in 4 liters of isopropyl alcohol. The solution was
treated with activated charcoal and filtered. The filtrate
was seeded and refrigerated overnight. The yellow precipitate
was collected by filtration and washed with a small amount
of isopropyl e~her and dried to give 1491 g (93%) of the
fumarate salt. The salt was dissolved in 17.2 liters of
isopropyl alcohol and the solution was treated with 75 g
of charcoal heated at reflux for 15 min and filtered
through a column containiny 100 g of Celite which had been
wetted with 200 ml of isop~opyl alcohol. Th~ filtrate was
then stirred for 20 hr. The precipitate was collected ~y
~5 ~iltratjon wach~ng t~e f;lter C~ke ~?'th COld isopropyl
alcohol followed by 3 liters of isopropyl ether and dried
to give 1255 g (85%) of crystalline product. The crystals
2 3~ ~ 425
39
were triturated with 1 l1ter of isopropyl ether-methylene
chloride (~:1 by vol.) and the mixture subjected to
filtration. Tha cake was vacuum dried at 60C. overnight
under high vacuum, m.p. 174-175C., uncorrected.
Ana1YSi5: Calculated for C27H28~04: CJ68~63~ H~5~97;
N, 11 .86
Found : C,60.48; H,6.00;
~911.80
Example 13
N,N~Dimethyl-6-phenyl-llH-pyridor2,3-b~l,4lbenzo-
diazepine~ll-propanemine Fumarate ~
Preparation of Crude Free Base of Title Compound.
To a solution of 780 g (6 mole) of 3-amino-2-chloro-
pyridine in 2 liters of toluene at re1ux was added
simultaneously a solution of 1,320 g (6.6 mole) of 2-amino-
15 benzophenone in 3 liters of tetrahydrofuran and a slurry
o~ 444.0 g (18.5 mole) of sodium hydride in 1.2 liters of
toluene over a 3 hr period. (During the addition at reflux,
the tetrahydrofuran distilled out at about the same rate
it was being added). To the reaction mixture was added
12 moles of 3-dimethylaminopropyl chloride in 3.5 liters
of toluene. The mixture was heated at reflux for 5 hr
then was allowed to COO1J standing overnight at ambient
temperature. TLC indicated some 6-phenyl-llH-pyrido~2,3-b~
rlg4]benzodiazepine was present; ~herefore, 12 g more
sodium hydride was added and the mixture was heated at
re~lux to complete the reaction. The mixture wa~ allowed
to cool somewhat and 2 liters of saturated ammonium
chloride and 3 liters of water were added. The aaueous
layer was discarded and the toluene layer was washed four
times with 2 liters of water ~ach time. The toluene layer
was con~entrated on a rotary evaporator and finally
subjected to high vacuum distillation to remove unreacted
3-dimethylaminopropyl chloride. Yield of crude syrup
containing primarily the free base of the title compound
was 2.680 g.
3 42
Conversion to Fumarate Salt and Purification Thereof
. _ ,
The crude syrup was mixed with 6 moles of fumaric acid
in 10 liters of isopropyl alcohol. The precipitate was
collected and washed with 3 liters of isopropyl alcohol and
recrystalli2ed twice to give 2,200 g of yellow crystals. A
sample triturate~ with a mixture of hot isopropyl ether-
methylene chloride ~3:1 by volume~ gave the following
analysis:
Analysis: calculated for C27H2aN~0~: C,68.63; H,5.97;
N,11.86
Found C,68.23; H,5.99;
N,11.87
Example 14
~ imethyl-6-phenyl-llH-pyridor2,3-b1 r 1,4~benzo-
diazepine~ propanamine Fumarate r 1 1] .
Preparation of Crude Free Base of Title Com~und
To a solution of 129 g (1 mole) of 3-amino-2-chloro-
pyridine in 350 ml of toluene at reflux was added simul-
taneously a solution of 217 g (1.1 mole) of 2-aminobenzo-
phenone in 500 ml of tetrahydrofuran and a slurry of 74.5 g
(3.1 mole) of sodium hydride in 250 ml of toluene over a
1.5 hr period. (During the addition at reflux the tetra-
hydrofuran distilled out at about the same rate it was
being added). To the reaction mixture was added 2 moles
o~ 3-dimethylaminopropyl chloride in 600 ml of tolusne.
The mixture was heated at reflux for 5 hr.
To the black slurry comprised of free base of the title
compound and some unreacted sodium hydride and 3-dimethyl-
aminopropyl chloride in toluene (shown by TLC to be free
of any 6-phenyl-llH-pyrido~2,3-b]~1,4~benzodiazepine~ was
~0 added 1 mole of ammonium chloride in 800 ml of water. The
organic layer was separated and washed with four 500 ml
portions of water. The organic layer was concentrated on a
rotoevaporator to remove solvent and under high vacuum to
remove unreacted 3-dimethylaminopropyl chloride. Yield `
~5 of dark brown-yellow syrup comprised principally of free
base of the title compound was 433 g.
. , . , 425
353
41
Conversion to Fumarate Salt
The syrup was dissolved in 800 ml of isopropyl alcohol
and to the solution wa~ added 1 mole of fumaric acid in
1.5 liter3 of isopropyl alcohol. The salt crystallized by
seeding and separated by filtration.
Example 15
6-(2-Thien~l~-llH-p~idor2,~-b~1,4]benzodiazepine.
Following the procedurss of Examples 10 and 11 but
substituting 2-aminophenyl-(2-thienyl)methanone in
Example 10 for 2-aminobenzophenone, the title compound is
obtained.
Example 16
6-~-Thienyl)-llH-pyrido[2~3-b1rl,41benzo_iazepine.
Following the procedures of Examples 10 and 11 but
substituting 2-aminophenyl-(~-thienyl)methanone in
Example 10 for 2-aminobenzophenone, the title compound is
obtained.
Example 17
6-t2-PYridiny~l)-llH-pyrido~2~3-b~ 4lbenzodiazepine.
Following the procedures of Examples 10 and 11 but
substituting 2-aminophenyl-(2 pyridinyl)methanone for
2-aminobenzophenone in Example 10, the title compound is
obtained.
a~E~ 8
6-(3-pyridinyl?-llH-pyrido~2~3-b]~l~4lbenzodiazepine .
Following the procedures of Examples 10 and 11 but
substituting 2-aminophenyl-(~-pyridinyl)methanone for
2-aminobenzophenone in Example ~0, th~ title compound is
obtained.
Example 19
~0 6-(4-Pyridinyl)~ -pyrido~2,~5-bl~1,41benzodia7.epine.
Following the procedure3 of Examples 10 and 11 but
substituting 2-aminophenyl-( -pyridinyl)methanone for
2-aminobenzophenone in Example 10, the ~itle compound is
obtained.
425
42
~xample 20
Following the procedure of Example 12 but substi-
tuting the following for 6-phenyl-llH-pyridoC2,3-b]~1,4]
benzodiazepine:
6-(2-thienyl)-lH-pyrido~2,3-b~1,4]benzodiazepine,
6-(3-thienyl)-llH-pyrido~2,3-b]~1,4~benzodiazepine,
6-(2-pyridinyl)-llH-pyridoc2,3-b][1,4~benzodiazepine,
6-(3-pyridinyl)~ -pyridoC2,3-b~1,4]benzodiazepine,
and, 6-(4-pyridinyl)-llH-pyr~do[2,3-b]~1,4~benzodiazepine,
there are obtained:
a) ~ dime~hyl-~-(2-thienyl)-llH-pyrido~2,3-b~[1,4]
benzodia~epine-ll-propanamine fumarate,
b) N,N-dimethyl-6-(3-thienyl)-llH-pyrido~2,3-b][1,4]
benzodia~epine-ll-propanamine fumarate,
c~ ~,N-dimethyl-6-(2-pyridinyl)-llH-pyrido~2,3-b][1,4]
benzodiazepine-ll-propanamine fumarate,
d) ~,~-dimethyl-6-(3-pyridinyl)-llH-pyridor2,3-b]rl,4]
benzodiazepine-ll-propanamina fumarate, and
e) N,N dimethyl-6-(4-pyridiny~ lH-pyrido~2~3-b]~l~4]
ben~odiazepine-ll-propanamine fumarate.
Following the procedure o Example 5 but substituting
the ~ollowing for ~2-~c3-(dimethylamino)propyl]amino]
phenyl~phenylmethanone:
~2-~3~ pyrrolidinyl)propyl~amino~phenyllphenyl-
methanone,
~2-~3-(1-piperidinyl)propyl]amino]phenyl]phenyl-
methanone, and
c2-~C3-(4-morpholinyl)propyl~amino]phenyl]phenyl-
methanone,
there are obtained:
~-~2-~(2-chloro-3-pyridinylimino)-3-(1-pyrrolidinyl)
propanamine,
N-~2-~(2-chloro-3-pyridinylimino)-3-(1-piperidinyl)
propanamine, and
N-~2-~(2-chloro-3-pyridinylamino]-3-(4-morpholinyl)
propanamine,
3~ 425
~3
Example 2?
M,~-Dimethyl-6-phenyl-llH-pyrid~I2,3-b~[1,41benzo-
diazepine~ propanamine Fumarate r 1 11
To a solution of 2.5 g t0.00637 mole) of ~ 2-~(2-
chloro-3-pyridinylimino)phenylmethyl]phenyl]-N,N-dimethyl-
1,3-propanediamine obtained in Example 5 in 20 ml of
toluene (solution was dried by azeotroping using a Dean
Stark trap and cooled) was added 0.62 g (0.0128 mole) of
sodium hydride as 50% mineral oil suspension added to a
small amount of toluene. The mixture was heated at reflux
for 3 hr. Water was added cautiously. The toluene layer
was washed twice with water and extracted twice with 1 N
aqueous hydrochloric acid solution. The aqueous acidic
layer was washed with toluene. The aqueous layer was then
basified with 50~ sodium hydroxide solution in the presence
O~ toluene. The aqueous layer was extxacted twice with
toluene. The toluene layers were combined, charcoaled,
filtered and evaporated to give 2.03 g o~ brown oil, the
free base of the title compound (89.5% yield). The oiL
was dissolved in isopropyl alcohol and 0.7 g fumaric acid
was added with warming. The solution was seeded with known
title compound and allowed to stand about 15 hr at room
temperature. Isopropyl ether was added with stirring for
15 min9 The solid was collected by filtration and washed
once with isopropyl alcohol-isopropyl ether mix and once
with isopropyl ether. On air drying, 2.4 g (80O , m.p.
168-170C. was obtained. Th~ melting point, ~MR analysis
and Mass Spec. analysis were comparable to known title
compound.
Example ? 3
Following the procedure of Example 22 but substituting
the following for ~ 2-~(2-chloro-3-pyridinylimino)phenyl-
methyl~phenyl]~ -dimethy~ 3-propanamine:
~-~2-C(2-chloro-3-pyridinylimino)-3~ pyrrolidinyl)
propanamine,
M-~2-~(2-chloro-3~pyridinylimino~-3-(1-piperidinyl)
propanamine, and
2~;~ 3~ ~ 425
44
M-~2-C(2-chloro-3~pyxidinylimino)-3-(4-morpholinyl3
propanamine,
there are obtained:
6-phenyl-11-C3~ pyrrolidinyl)propyl]-llH-pyrido-
5~2,3-b~1,4]benzodiazepine fumarat2,
6-phenyl-11-C~-(l-piperidinyl)propyl]-llH-pyrido
~2~3-b]~l~4~benzodiazepine fumarate, and
6-phenyl-11-~3-(4-morpholinyl)propyl]-llH-pyrido
~2~3-b]~l~4]benzodiazepine fumarate, using
ethanol-e~hyl acetate recrystallizing solvent in the
latter.
. ~
