Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
RAN 4 0 0 3/ 3 19
1 ~ ~7:~63~
~'! The present invention relates to benzazepine deri-
¦ vatives. More particularly it relates to pyrimido[4,5-
d]~2]benzazepines of the general formula
~ N ~ 2
j ~ ~ X~R3
Y ~
wherein R1 is hydrogen~ lower alkyl, chloro, bromo,
; lower alkoxy, hydroxy, lower alkylthio or NR4R5 wherein
:R4 and R5 are hydrogen, lower alkyl or di-lower alkyl-
amino lower alkyl; R2 is hydrogen, lower alkyl or
:~Y,
amino; R3 is hydrogen, acyloxy or hydroxy; X is halogen
having an atomic number not greater than 35 and Y is
: hydrogen or halogen having an atomic number not greater
a
~ than 35 and the 6-oxides thereof when R3 is hydrogen
s~
~ and the pharmaceutically acceptable salts thereof~
., ,
As used herein, the terms "halo" or "halogen" refer to
the group chloro, bromo or fluoro.
~s Bt/ 3~.6.81
. ~
. - 1 -
-~i'7~3(~
By the term "lower alkyl" is meant a C1 to C7 hydro-
carbon radical which may be straight or branched chain, such .-
as, methyl, ethyl, propyl, isopropyl, butyl, etc.
By the term "acyloxy" is meant an organic radical
derlved from an organic acid by the removel of the hydrogen
~ group, such as, acetyloxy, benzoyloxy, etc.
In accordance with the present invention, compounds
¦ ~ ~ of formula I, N-oxides thereof when R3 is hydrogen and
pharmaceutically acceptable acid addition salts thereof
~ : can be prepared by
Y~ : a) dehydrogenating a compound of the general formula
^: :
i
s ~ ~R2
OD~ ~
VI
:: :
: ~ :
wherein R2, X and Y are as above,
or
¦ ~ bj 6-oxidizing a compound of formula I wherein R3 is
~;~ hydrogen and R1 is hydrogen, lower alkyl, chloro, bromo,
: lower alkoxy, hydroxy or NR4R5 wherein R~ and R5 are as
above,
j or
- - -. - ................ .
. - 2 -
7~;i3
,
c) treatlng a 6-oxlde of a compound of khe general formula
I wherein R3 is hydrogen with an acyla-ting agent
or
d) subjecting a compound of the genexal formula I wherein
R3 is acyloxy to an alkaline hydrolysis
or
e) chlorinating or brominating a compound of formula I
wherein R1 is hydroxy and R3 is hydrogen
or
f) treating a compound of formula I wherein R1 is chloro
or bromo or a 6-oxide thereof (in which case R3 is hydrogen)
with an agent providing a lower alkyl group, a lower alkyl-
mercapto group, a group of the formula NR4R5 or a lower
alkoxy group
. ~
~ or
, .
;~ g) reducing a compound of formula I wherein R1 is chloro
or bromo or a 6-oxide thereof (in which case R3 is hydrogen)
~:~ or
: ~
h) desulfuri~ating a compound of formula I wherein R1 is
lower alkylmercapto and R3 is hydrogen
: : ~
: or
:
i) treating a compound of formula I wherein R1 is lower
~ alkylmercapto and R3 is hydrogen with an amine of the formula
: :~ HNR4R5 wherein R4 and R5 are as above
or
j) converting a compound of formula I or a 6-oxide of a
- i
compound of formula I wherein R3 is hydrogen into a pharma-
ceutically acceptable acid addition salt.
These various process embodiments and the preparation
. . ..
. _ 3 _
d
i3(~
of stai^ting materials therefor are illustrated by the
~ollowing Reaction Schemes:
,~,
.,
~, .
'
;~
~:
_ ~ _
7~63~
O lower alkyl
=<0 lower alkyl
2 ~ J ~ r~-~> x~> x~ =~
I [~ lV I ~v
10 I ~R2 /R2
12 . ~Y ~ .
. I YII ; \~. VI .
16 Cl ~ ~ =~ ~7 ` .
~/ . ~= ~O
21 . ~ j ~ .
~ . , ~ Vlll ~ X
26 1~X~ ' ~ N/ ~OH
27 ~ X ~ Xl
.. ,, . , , .
- S -
1 - !
1~ ' 11'7Z~,30 1,
4 ~ X~
8 1I / Vlll \~ _
'_<~
7 111 ~ i xm
o~ ~ 3Y
D ~
28 ~XIV
30 ;~ erein R2, R3, ~ ~nd Y re ns 4bove ~nd R i~ rlcyl
`"~' .
117Z630
compoun~ of formula III may be prepared from an iodobenzophenone
~, appropria~ely substituted by ~ and Y. The iodobenzophenone is prepared by diazotizing
3il the ccrresponding known aminobenzophenone using sodium nitrite in sulfuric acid and
4 1 isolating the salts by precipitating the respective tetrafluoroborate salts which were
51~ the1eafter slurried in water and treated with aqueous potassiurn iodide to give the
6 !! iodobenzophenone. These reactions are carried out utilizing methods known in the art.
7!
8 l! The iodobenzophenone thereafter is reacted with propargyl phthalimide in the
g ~I presence of palladium chloride or acetate, cuprous iodide, an organophosphine, for;
10 ~1 example, triphenylphosphine, and a tertiary or secondary amine, such as, diethylamine or
diisopropylamine. The reaction solvent may be the amine itself, e.g., diethylamine, a
12 ¦! halogenated hydrocarbon, e.g., methylene chloride, dimethylformamide or ether solvents.
13 The reaction temperature may range from about 0 C to about 70 C with ambient
14 1 temperatures as preîerred.
16 1 The presence of cuprous iodide is mandatory if the reaction is carried out at room
17 ~ temperature or below while this is not the case if the reaction is carried out with heating.
18 11 The presence of the organophosphine is not absolutely necessary but highly advantageous.
19 i~ Instead of the palladium salt plus the organophosphine an appropriate complex such as
20 I dichloro bls (triphenylphosphine) palladium II can also be utilized.
21
22 The resultant product is hydrogenated using a Lindlar catalyst (prehydrogenated lOq6
23 ~I palladium on barium sulfate~ at about atmospheric pressure and about room temperature.
2~ Solvents suitable for the reaction include Cl to C6 alcohols, tetrahydrofuran, dioxane or
25 1 toluene.
.261
F ~7~ '
7Z63C~
¦ The resultant product is -thereafter reacted with an
I aqueous solution of a lower alkyl amine, e.g., methyl amine.
` A C1 to C4 alcohol is utilized as the solvent with ethanol
as preferred. The reaction is most preferably carried out
at about room temperature. The first formed open amine is
not isolated but undergoes spontaneous ring closure.
-
.~ Alternatively, the above reaction with an aqueous
solution of a lower alkylamine can be carried out before
¦ the hydrogenation using a Lindlar catalyst.
.
? .
The product is halogenated utilizing a halogenating
-
agent, such as, elemental chlorine, bromine or iodine in a
i:
halogenated hydrocarbon, such as, methylene chloride or
chloroform. The reaction is carried out at from about 0C
to about room temperature with about room temperature pre-
'1 :
ferred.
The product is dehydrohalogenated to produce the compound
~ `of formula III utilizing an alkali metal, e.g., potassium or
; ~ sodium, hydroxlde, carbonate or alkoxide. Suitable solvents
include C1 to C6 alcohols, tetrahydrofuran, dioxane and
dimethylformamide. The reaction temperature may vary from
0C to reflux temperature of the chosen solvent with about
room temperature as preferred.
'~ ;
IV ~ V
~i
The compound of formula III is reacted with carbon
i monoxide in the presence of a C1 to C6 alcohol, a tertiary
- 8 -
r
3~11
amine, e.g., triethylamine or tri-n-butyl amine, a palladium
catalyst, such as, palladium acetate or palladium bromide and
triphenylphosphine or dibromobis(triphenylphosphine) palladium
II and optionally cuprous iodide or hydrazine. The reaction
temperature may vary from about 60C to 120C with preferably
about 100C. The reaction may or may not be run under pressure
in order to shorten the reaction time.
IV + V ~VI
;~i The compounds of formulas IV and V are reacted with an
.~ .
amidine, such as, formamidine, acetamidine or guanidine in
S the presence of a base, such as, an alkali metal alkoxide,
e.g., sodium or potassium methoxide, ethoxide or butoxide.
Suitable solvents include Cl to C4 alcohols. The reaction
temperature may range from about room temperature to reflux
with the preferred temperature dependent on the amidine chosen
but not to exceed about 100C.
VI~ VII
: ~
The compound of formula VI is reacted with an oxidizing
agent, such as, manganese dioxide in a suitable solvent, e.g.,
~:
methylene chloride, tetrahydrofuran, or dimethylformamide.
d, . The reaction temperature may vary from about room temperature
~J
to 100C with about 60C as preferred.
The oxo compound of formula VII is a tautomeric form
, of the corresponding compound of formula I wherein Rl is
hydroxy. The same i5 true for the compounds of formulae X
,~
~7~63~ 1
and XI and similarly the oxo compollnd of formula IX is a
tautomeric orm of the 6~oxide o-f the corresponding compound
of formula I wherein R1 is hydroxy.
.,
~ VII -~ IX
. -,
The compound of formula VI is reacted with a peracid,
such as, m-chloroperbenzoic or pertrifluoroacetic acid in a
halogenated hydrocarbon solven-t such as methylene chloride.
- The reactlon temperature may vary from abou-t -20C to room
temperature with about 0C as preferred.
~ ' - ,
~'
IX __~ X
j ~
s The compound of formula VIII is reacted with an acid
anhydride derived from C1 to C5 carboxylic acids, such as,
~; acetic, propionic, etc. or trifluoroacetic anhydride. The
reactlon temperature may vary from about 40C to reflux
temperature with about reflux temperature as preferred. The
reaction temperature however should not exceed 125C.
: : ~
,
The compound of formula X is reacted with an aqueous
alkali metal carbonate, such as, sodium or potassium carbo-
..
;,'~ nate or an aqueous alkali metal hydroxide, such as, sodium
,
or potassium hydroxide. A co-solvent may be utilized, such
as, a C1 to C6 alcohol or tetrahydrofuran. The reaction
temperature may be varied from about 0C to 100C, pre-
ferably from about room temperature to 100C.
- 10 -
7~i3~
VII~ VIII
~,
The compound of formula VII is reacted with a phos-
phoryl halide, e.g., a chloride or bromide. A co-solvent,
such as, a chlorinated hydrocarbon, e.g., methylene chloride
~ or chloroform may be also utilized. The reaction temperature
`~ may be varied from about room temperature to reflux of the
selected solvent. About room temperature is preferred.
VIII ~ XII
: .
The compound of formula VIII or the corresponding
~s
1-bromo compound is reacted with an organo metalic reagen-t,
, such as, a lower alkyl lithium or a lower alkyl cuprate in
an ether solvent, such as, diethyl ether or tetrahydrofuran.
The reaction temperature may be varied from about -78C to
0C with about -78C as preferred.
:: :
~ VIII~ XIII
: ~
¦~ The compound of formula VIII ox the corresponding
~ ~ l-bromo compound is reacted with an alkali metal salt of a
,
-~ ~ lower alkyl mercaptan in a polar solvent, such as, dimethyl-
formamide or dimethyl sulfoxide. The reaction temperature
'. may be varied from about -78C to room temperature with
,
~ about room temperature as preferred.
i .
.
.
~ VIII~ XIV and XIII - ~XIV
~.
~ The compound of formula VIII or the correspondig
,~
- 11 -
i
3~
1-bromo compound is reacted with 3mmon]a Ol- a primary or se-
condary amine in a polar solvent, such as, dimethylformamide
or dimethyl sulfoxide. The reaction temperature may be
varied from about room temperature -to 100C with about
60C as preferred. Similarly a compound of formula XIII can
be used as starting material for producing a compound of
formula XIV.
,. .
VIII ~ XV
.~
~,
~ The compound of formula VIII or the corresponding
~ . .
~'~ 1-bromo compound is reacted with an alkali metal alkoxide
.
in the corresponding C1 to C6 alcohol. A co-solvent, such as,
an ether, e.g., tetrahydrofuran, dioxane, etc. or dimethyl-
formamide may also be utilized. The reaction temperature
.,
may vary from about 0C to room temperature with about 0C
as preferred.
The compound of formula VIII or the corresponding
1-bromo compound may be reacted in analogy to step VII ~ IX
in order to produce the 6-oxide of the chloro or bromo com-
pound and that compound may thereafter be reacted in analogy
to steps IX ~ X and X - ~ XI to form analogous compounds
to those of formulae X and XI. Thereafter these analogous
compounds ~ay undergo the further reactions set forth in
..~
r, : Scheme 1 wherein various R1 values are thereafter introduced
~ by replacement of the chloro or bromo substituent as descri-
bed in steps VIII ~ XII; VIII -~ XIII; VIII ~XVI;
VIII - `~ XV and VIII ~XIV.
i
- 12 -
.
1 Furthermore, compounds of formulae XII, XIV, XV and XVI can
2 be reacted in analogy to step VII~ IX and similarly 6-oxides
3 of compounds of formulae XII, XIII, XIV, XV and XVI can be reacted
4 ,n analogy to steps IX ~ X and X--~ XI to form analogous com-
pounds to those of formulae X and XI.
6 VIII ~ XVI
_
7 A compound of the formula VIII is reacted with a reducing
8 agent, such as, hydrogen, at atmospheric pressure using Raney
9 nickel as catalyst in a Cl to C4 alcohol or zinc and ammonium
chloride in a mixture of water and tetrahydrofuran or water and
11 dioxane. The reaction temperature ~aries from 0C to the reflux
12 temperature of the solvent chosen with room temperature preferred.
13 XIII > XVI
_
14 A compound of the formula X~II is reacted with Raney nickel
in a Cl to C4 alcohol. The reaction temperature varies from 0C
16 to the reflux temperature of the chosen solvent with about reflux
17 temperature preferred. This reaction constitutes a desulfuriza-
18 tion w~ich is a well-known process in the art.
19 The expression "pharmaceutically acceptable salts" is used
to include salts with both inorganic and organic pharmaceutically
21 acceptable strong acids, such as, sulfuric acid, hydrochloric
22 acid~ nitric acid, methanesulfonic acid and p-toluenesulfonic
23 acid. Such salts can be formed quite readily by those skilled in
24 the art with the prior art and the nature of the compound to be
placed i~ salt form in view.
26 The pyrimido[4,5-d][2]benzazepines of the present invention
27 are useful as pharmaceuticals and are characterized by activity
28 as sedatives and anxiolytic agents. These compounds can be used
29 in the form of conventional pharmaceutical preparations; for
example, the aforesaid compounds can be mixed with conventional
31 organic or inorganic, inert pharmaceutical carriers suitable for
-13
~1 ~ Z~3C~
1 parenteral or enteral administration such as for example, water
2 gelatin, lactose, starch, magnesium stearate, talc, vegetable
3 oil, gums, polyalkylene glycols, Vaseline or the like~ Th~y can
4 be administered in conventional pharmaceutical forms, e.g.,
solid forms, for Pxample, tablets, dragees, capsules, suppositories
6 or the like, or in liquid forms, for example, solutions,
7 suspensions or emulsions. Moreover, the pharmaceutical compositi-
8 tions containing compounds of this invention can be subjected to
g con~entional pharmaceutical expedients such as sterilization, and
can contain conventional pharmaceutical excipients such as
11 preservatives, stabilizing agents, wetting agents, emulsifying
12 ag~nts, salts for the adjustment of osmotic pressure, or buffers.
13 The compositions can also contain other therapeutically active
14 materials.
A suitable pharmaceuticai dosage unit can contain from about
16 1 to about 500 mg. of the benzazepine end products with a dosage
19 range of fxom about 1 mg to about lOOmg being the preferred oral
18 administration and a dosage range of from about 1 mg to about
19 50 mg being preferred for pdrenteral administration. However,
for an~ particular subject, the specific dosage regimen should
21 be adjusted according to individual need and the professional
.:
22 judgment of the person administering or supervising the
23 a~ministxation o~ the aforesaid compounds. It is to be
24 understood that the dosages set forth herein are exemplary only
and that they do not, to any extent, limit the scope or
26 practice of this invention.
27 The term "dosage unit" as employed throughout this
28 specification refers to pharmaceutically discrete units suitable
29 as unitary dosages for mammalian subject each containing a
predetermined quantity of active material calculated to produce
31 the desired therapeutic effect in association with the required
32 pharmaecutical diluent, carrier or vehicle.
-14-
26~
1 Preferred are compounds of formula I wherein Rl is as above,
2 R3 is hydrogen and R2 is hydrogen or lower alkyl.
3 Especially preferred compounds of formula I include the
4 following:
A. 9-chloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepin-1
6 (2H) one
7 B. 9-chloro-7-(2-fluorophenyl)-3-methyl-5H-pyrimido[4,5-d]L2]
8 benzazepin 1)2H)-one
~ C. 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]~enzazepine
lQ~ D. ~-chloro-1,3-dimethyl-7-phenyl-SH-pYrimido[4,5-d][2]
11 benzazepine
12 E. 9-chloro-7-(2-fluorophenyl)-3-methyl-1-methoxy-5H-pyrimido
13 ~4,5-d][2]benzazepine
14 The pharmaceutical activities of the instantly claimed
compounds are indicated by the pharmacological data set forth
16 below for one of the compounds of the inventlon.
17 Tests
18 Inclined Unanesthetized
19 Compounds Footshock Screen Cat
20 1,9-dichloro-3-methyl- 10 mg/kg 400 mg/kg 10 mg/kg
21 7-phenyl-5H-pyrimido-
22 4,5-D-2-benzazepine
23 Toxicity (LD50) = greater than 1000 mg/kg (PO)
24 A summary of the pharmacological tests which are known in
the art is as follows:
26 Footshock
27 A pair of mice is confined under a one liter beaker placed
28 on a grid which presents shock to the feet. At least 5 fighting
29 epi-sodes-are elicited in a two-minute period. Pairs of mice are
marked and pretreated 1 hour prior to a second shocking. Logari-
31 thmic dose intervals are utilized up to a maximum of 100 mg/kg.
32 At the 100% blocking dose, 3 out of 3 pairs must be blocked from
33 fighting.
- 15 -
3~
1 nclined Screen
2 Groups o~ 6 male mice are given the test drug (maximum dose
3 of 500 mg/kg~ and then are left sn the inclined screen at
4 least 4 hours for observation of paralyzing effects severe
enough to cause them to slide off the screen. If ac~ivity is
6 obser~ed, additional doses are taken until at least two are
7 reached at which some, but not all of the animals slide off the
8 screen. Doses at which mice fall off the screen due to
9 toxicity ox excitation are not included in the calculation of
PD50-
11 Unanesthetized Cat
12 Cats are treated orally and observed ~or minimum
13 symptom~ usually ataxia. One cat is used at a dose of 50 mg/kg.
14 If actl~ity is present, up to three cats/dose are used. Results
are giYen as minimum effective dose.
16 The following examples are illustrative, but not limitative
17 of this in~ention. All temperatures given are in degrees
18 centigrade, unless indicated otherwise.
- 16 -
63~
1 Example 1
2 8-Chloro-l-phenyl-5H-2-benzaz'epine-5-c'arb _y ic acid butyl
3 ester and 8-Chloro-l-phenyl-'3H-2-benzazepine-5-carboxylic acid
4 butyl ester
A 12 oz Fisher-Porter pressure bottle containing 12.5 g
6 (33.8 mmol) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine
7 hydrochloride, 175 mg (0.2 mmol) of dibromobis (triphenyl-
8 phosphine) palladium II and 250 mg (1.3 mmol) of cuprous
g iodide was flushed with argon. To the pressure bot~le was
then added 17 mL of tri-n-butylamine and 6.2 mL of n-butanol
11 and the mixture was heated at 110 under 40 psi of carbon
12 monoxide for lB hr. The reaction was cooled, diluted with
13 ether, and ~ashed ~ith water. The ether solution was dried
14 o~er anhydrous s~dium sulfate ~nd concentrated at reduced
pressure to ~ield 13.0 g o~ a mixture of the end products as
16 a xed oil. Purification of 4.0 g of the mixture by column
17 chxomato~raphy (silica gel, 40 g, methylene chloride, as
18 eluent~ gave the 5-H compound as a yeliow oil.
19 Further elution with methylene chioride yielded the 3-H
compound as a yellow oil.
21 'Ex'ampl'e 2
22 8-Chloro~ (2-fluorophenyl)-5H-2-benzazepine-5-carboxylic acid
23 bu*yl ester and 8-Chloro-I' (2-fluorophenyl)-3H-2-benzazepine-
24 5'-carboxylic 'acid butyl ester
A 12 oz Fisher-Porter pressure bottle containing 12.8 g
26 -(33 mmol) of B-chloro-5-bromo-1-(2-fluorophenyl)-3H-2-
27 benzazepine hydrochloride~ 175 mg (0.2 mmol) of dibromo-
28 bis(triphenylphosphine) palladium II and 250 mg (1.3 mmol) of
29 cuprous iodide was flushed with argon. To the pressure bottle
was then added 17 mL of tri-n-butylamine and 6.2 mL of
31 n-butanol and the mixture was heated at 110 under 40 psi
-17-
7~3~3
1 of carbon monoxide for 18 hr. The redction mixture was
2 cooled, diluted with ether and washed with water. The ether
3 solution was dried over anhydrous sodium sulfate and concen-
4 trated at reduced pressure to give a mixtuxe of the end
product as a red oil. The oil was used without further
6 purification.
7 Exa'mple 3
8 8-chloro-l-(2-chlorophenyl)-5H-2-benzazepine-5-carboxylic ac_d
g butyl e'ster and 8-Chloro-1-'~2-'chloroph'enyl)-3H-2-benzazepine-
'5-carboxylic acid butyl es'ter
11 A 3 02 Fisher-Porter pressure bottle containing 3.5 g
12 '(9O5 ~ol) of 8-chloro--5-bromo-1 t2-fluorophenyl)-3H-2-
13 benzazepine and 70 mg (0.09 mmol) o~ dibromobis (triphenyl-
14 phosphine) palladium II was flushed with argon. To the
pressu~e bottle was then added 1.8 mL of n-butanol and 2.6 mL
16 of txi butylamine and the mixture was heated to 100 under
17 40 psi of carbon monoxide for 24 hr. The mixture was cooled,
18 diluted with ether and washed with water. The ether solution
19 was dried o~er anhydrous ~odium sulfate and concentrated at
reduced pressuxe to gi~e a mixture of the end products as a
21 red oil. The oil was u~ed without further purification. --
22 ' Ex'ample 4
23 8-Chlor _ 1-(2-fluorophenyl)-SH-2-benzazepine-5-carboxylic acld
24 ' methyl ester `and 8-chloro~ 2--fluoroph-nyl(-3H-2-benzazepine
' 5'-c'arboxylic ac'id'methyl ester
. ~
26 A 3 oz Fisher-Porter pressure bottle containing 2.0 g (5.1
27 mmol) of 8-chloro-5-bromo-l-(2-fluorophenyl)-3H-2-benzazepine
28 hydrochloride, 50 mg (0.06 mmol) of dibromobis (triphenylphosphine)
29 palladium II and 60 mg ~0.3 mmol) of cuprous iodide was flushed
with argon. To the pressure bottle was then added 2.6 mL of
31 tri-n-butylamine and ~.O mL of methanol and the mixture was
32 heated to 100 under 40 psi of carbon monoxide for 18 hr. me
-18-
~1~7~63~;9
1 reaction was cooled, diluted with ether and washed with water.
2 The ether solution was dried over anhydrous sodium sulfate and
3 concentrated at reduced pressure. Purification of the residue
4 by column chromatography (silica gel, 30 g; eluent, methylene
chloride) gave as the first product band the 3~H compound as
6 off-white needlesJ mp 106-107.
7 Further, elution with 20~ (v/v) of methylene chloride gave
8 the second product band the 5H compound as pale yellow needles,
g mp 125-126.
10'Example 5
11 9-Chl'oro- 11~' d'ih'ydro'-3-me'th'yl-7-'phenyL-'5'H-pyrimido-[4,5-d]
12 [2 benzazepin-1_2H)-one
13 In one portion, 11.5 mL l49 mmol) of a 4~34 M methanol
14 solution of sodium methoxide was added to a solution of 11.0
g ~31 ~mol) of a mixture of 8-chloro-1-phenyl~5H-2-benzazepi~5-
16 carboxylic acid butyl ester and 8-chloro-1-phenyl-3H-2-
17 benzazepine-5-carboxylic acid butyl ester and 5.7 g (60 mmol)
18 o~ aceta~idine hydrochloride in 200 mL of ethanol. The mixture
19 was re~luxed for 18 hr~ cooled and poured into 800 mL of water.
The resulting precipitate was collected by filtration and washed
21 ~ith ether to yield a yellow solid. Recrystallization from
22tetrahydrofuran gave off-white prisms, mp 155-160.
23'Ex'a'mpl'e' 6
249-Chloro-4a,11b-dih~dro-3-methyl-7-(2-fluorophenyi)-5H-@yrimido
.~
25' [4,5'-d~2]benzazepin-1(2H)-one
26In one portion 14.0 mL of a 4.34 M methanol solution of
27sodium methoxide was added to a solution of 14.0 g (37.7 mmol) of
2B a mixture of 8-chloro-l-~2-fluorophenyl)-5H-2-benzazepine-5~
29 carboxylic acid butyl ester and 8-chloro-1-(2-fluorophenyl)-3H-
2-benzazepine-5~carboxylic acid butyl ester and 7.0 g (74 mmol)
31 of acetamidine hydrochloride in 250 mL of ethanol. The mixture
32 was refluxed ~or 17 hr. cooled and poured into 1 L of ~ater.
-19-
~ ~ 7~2~30
1 The resulting precipitate was collected by flltration and
2 washed with ether to yield an off-white solid, mp 150-165.
3 Alternatively, any of the methyl esters obtained in
4 Example 4 or a mixture thereof can be used as starting material
instead of the butyl ester mixture.
'
:
~ .
-20-
~ ..
ll (~
I ~.11'7~
l I
Example 7
2 ~ ~ ~ ~molar
3 hydrQtc
Drop~ise 9.5 mL (41 mmol) of a 4.3 M methanol solution of sodium methoxide was
S added to a solution of 8.0 g ~22.6 mmol) of a mixture of 8 chloro-1-pher.yl-5H-2-,
6 benzazepine-5-carboxyl;c acid butyl ester and 8-chloro-1-pllenyl-3H-2-benzazepine-5-,
7 carboxylic acid butyl ester and 6.5 g ~62.4 mmol) of formamidine acetate in 70 mL of '
8 ethanol. When the addition was complete stirring at room temperature W8 continued for,
9 30 min. The reaction was diluted with water and extracted with methylene chloride. The
10 methylene chloride solution was washed with water, dried over anhydrous sodium sulfate '
Il and concentrated at reduced pressure. The residue was crystallized from a mixture of
12 ether and petroleum ether to give a yellow soLid. Recrystallization from a mixture of
13 ether and methylene chloride gave pale yellow prisms, mp 150-155.
~4
The filtrate from the crystallization of the end product was concentrated at reduced
16 pressure. The residue was purif~ed by plug filtration ~silica gel, eluent methylene chloride) i
l7 to give the 5 H starting material as a yellow oil, whose TLC Rf va1ue was identical to an;
18 authentic sample.
19 .
Example 8
21 9-Chloro-3-methyl-7-phenyl-sH~yrimido~4?5-d] ~2] benzazeDin-1(2H3-one
22 A mixture of 2D.0 g (230 mmol) of activated manganese dioxide and 5.3 g (14.8 mmol)
23 of 9-chloro 4a,11b-dihydro-3-methyl-7-phenyl-SH-pyrimido[4,5-dl 12]benzazepin-(2H)-one
24 in 500 mL of tetrahydrofuran was refluxed for 2 hr. The manganese dioxide was removed
by îiltration through ~elite and the filtrate was concentrated at reduced pressure to give a !
26 pale yellow solid, mp 245-248. Recrystallization from a mixture of methylene chloride
27 and ether gave ~olorless crystals, mp 248-24g.
...
* Trade Mark.
- 21 -
~,'
..
` U7Z630
. .~
2 9-Chloro-3-mcthyl-7-(2-fluorophenvl)-5~-pyrimido[1,~-c] ~2] benæazeDin 1(2H)-one
3 The prcparation of 9-chlor~3-methyl-7-(2-fluoropheny1)-SH-pyrimido[4,5-d] ~2] ben~a-
4 zepin-I(2H)-one was conducted ;n the same manner as the preparation of 9-chloro-3-
methyl-7-phcnyl-5H-pyrimido~4,5-d] [2] benzazepin-1(2H)-one to give pale yellow prisms,
6 mp 262-264.
7 .
8 Exam~le 10
9 9-Chloro-3-methvl-7-(2-chlorophenyl)-5H-pyrimido[4,5-d] [2] benzazepin-1(2H)-one
In one portion 6.0 mL (24 mmol) of a 4.0 M methanol solution of sodium methoxideIl was added to 4.35 g tll.2 mmol~ of a mixture of 8-chloro-1-(2-chlorophenyl)-5H-2-
12 benza~epine-5-carboxylic acid butyl ester and 8-chloro-1-(2-chlorophenyl)-3H-2-benzaze-
13 pine-5-carboxylic acid butyl ester and 2.5 g (26 mmol) of acetamidine hydrochloride in 50
14 mL of ethanol. The mixture was refluxed for 6 hr and diluted with water. The resulting
precipitate was collected by filtration and washed with ether to give an amorphous tan
16 solid.
17
18 A mixture of the tan solid and 6.0 g of activated manganese dioxide in 100 mL of
tetrahydrofuran was refluxed for 4 hr~ The manganese dioxide was removed by filtration
over celite and the filtrate was concentrated at reduced pressure to give a cream colored;
21 ~ solid. Recr tnl~izatlon from ethy~ acetn~e gnve cclorless crystnls mp 277-279.
~5
26
27
.'
-22-
~Z630
xample ~
2 ~ . .
9-C!lloro-7-e~enyl-5H~pyrimido[4~5-d] [2] benzuzepin-1(2H)-one
3 A mixturc of 2.2 g (6.8 mmol) of 9-chloro-4a,11b-dihydr~l-phenyl-SH-pyrimidol~,5-
4 dl ~2] b~nzazcpin-1(2H)-one and 10 g (110 mmol) of activated manganese dioxide in 100 mL of
5 tetrahydrofuran was refluxed for 18 hr. The mixture was cooled, the manganese dioxide
6 was removed by filtration over celite and the filtrate was concentrated at reduced .
7 pressure. Purification of the residue by column chromatography (silica gel 10 g; eluents,
8 20% ether in methylene chloride followed by 50~6 ethyl acetate in methylene chloride)
9 gave pale yellow prisms, mp 226-229o
~33; io
Il. ~ '.
12 3-Amino-9-chloro-7-(2-fluorophenyl)-5H-pyrimidor4,5-d] [2] benzazepin-1(2H_-one
13 In one portion 5.0 mL (22 mmol) of a 4.34 M methanol solution of sodium methoxide
14 was added to a mixture of 5.0 g (13.5 mmol) of a miacture of 8-chloro-1-(2-fluorophenyl)-
SH-2-benzazepine-5-cflrboxylic acid butyl ester and 8-chloro-1-(2-fluorophenyl)-3H-2-
16 benzazepine-5-carboxylic acid butyl ester and 5.0 g (27.7 mmol) of guanidine carbonate in
100 mL of ethanol. The mixture was refluxed for 1 hr and diluted with water. The j
; 18 resulting precipitate was collected by filtration and washed with ether to give a brown i
t ~ 19 solid.
21 A mixture of the brown solid and 5.0 g of activated manganese dioxide in 175 mL of
22 dimethylformamide was heated~to ioo for 2 hr~ The manganese dioxide was removed by
23 filtration over celite and the filtrate was partititoned between a mixture of methylene,
24 chloride and water. The methylene chloride solution was dried oYer anhydrous sodium;
sulfate and concentrated at reduced pressure to give a tan solid~ Recrystallization from a
~6 mixture of methanol and tetrahydrofuran gave off-white prisms, mp 331-332.
27
, . ' ' ., , ' .,
~ _ 23 - ` ~` ` -
. .
7~6a~
.Exa m~ 13
2 1,9-Dichloro-3-methvl-7-phenyl-5H-pvrimido[i.~-d] [~) benznz2pine
3 A solution of 3.5 g ~10.4 mmol) of 9-chlGro-3-methyl-7-pheny1-5H-pyrimido[4,5-
4 dl [2~ benzazepin-1(2H)-one and 22 mL of phosphorous o.Yychloride in 100 mL of methylene
chloride was stirred at room temperature for 18 hrO The reaction mixture was
6 concentrated at reduced pressure to a solid residue. The residue was partitioned between
7 ice cold saturated aqueous sodium bicarbonate and methylene chloride. The methylene
8 chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced
9 pressure to a yellow residue Purification by column chromatograplly (silica gel, 40.0 g;
eluent: methylene chloride ether, 10:1) gave a pale yellow solid, mp 190-192. A portion
11 was recrystallized from a mixture of ether and petroleum ether to yield colorless prisms,
12 mp 191-193.
13
14 Example 14
1,9-Dichloro-3-metllyl-7-(2-fluoro~hen~1)-5E~-pyrim o[4,5-d] [2] benzazepine hydrochloride
16 A mixture of 3.3 g (9.3 rnmol) of 9-chloro-3-methyl-7-~2-fluorophenyl)-5H-pyrimido-
17 E4,5-d] 12~ benzazepin-1(2H)-one and 20 mL of phosphorous oxychloride in 90 mL of
18 methylene chloride was stirred at room temperature for 18 hr. The reaction was
concentrated at reduced pressure and the residue partitioned between aqueous sodium
bicarbonate and methylene chloride. The methylene chloride solution was dri~d over
21 anhydrous sodium sulfate and concentrated at reduced pressure. Purification of the
22 residue by column chromatography (silica gel, 40 g; eluent, 10% ether in methylene
23 chloride) gave the free base of the end products as a yellow oil.
24
The hydrochloride salt was prepared by the additlon of one molar equivalent of a 1.4
26 M methanol solution of hydrogen chloride to an ether solution of end product and wus
27 isolated by filtration. Recrystallization of the hydrochloride salt from a mi:cture Of
28 methylene chloride and ether gnve the salt ns pale yellow prisms, r~p 178-182.
.. . .
~ 3~
Example ls -
2 9-Chloro-l-methoxy-3-methyl-?-phenyl-5H-pyl~imido[~,5-rl] [~] benznzepine3 A solution of 1.0 g (2.8 mmol) of 1,~-dichloro-3-methyl-7-phen~1-5H-pyrimido[4,5-
4 d~ [2] benzazepine and 1.0 mL of a 4.2 M methanol solution of sodium methoxide in 20 mL
of a 1:1 mixture of methanol and tetrahydrofuran was stirred at room temperature for I hr.
6 I The solvent was removed at reduced pressure and the residue was triturated with water to
7 give an off-white solid. Recrystallization from a mixture of ether and petroleum ether
8 gave colorless prisms, mp 185-187.
9 . , ,' .
Example 16 -
11 9-Chloro-7-(2-fluorophenyl)-1-methoxy-3-methyl-5H-pyrimido[4,5-d] [21 benzazepine
12 The preparation of 9-chloro-7-~2-fluorophenyl)-1-methoxy-3-methyl-5H-pyrimido[4,5-
13 dl [2~ benzazepine was conducted in the same manner as the preparation of 9-chloro-1-
14 methoxy-3-methyl-7-phenyl-5H-pyrimido[4,5-d] [2] benzazepine to give pale yellow prisms,
mp 188-189.
1~ . ', .
17 Example 17
18 9-Chloro-3-meth~l-1-(meth~lthio)-7-phen~Tl-5H-pyrimido[415-d] [2] benzazepine
In one portion 1.0 g (2.8 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido~4,5-;
2~ d] ~2] benzazepine was added to a solution of 150 mg (3.1 mmol) of 50% mineral oil
dispersion of sodium hydride and an excess of methyl mercaptan (~3.1 mmol~ in 25 mL of
22 dimethylformamide. The mixture was stirred a~ room temperature for 30 min and diluted
with water. The resulting precipitate was collected by filtration to give a yellow solid.
24 Recrystallization from a mixture of ether and methylene chloride gave pale yellow prisms,
26 mp 181-183''
, ,' ' , ' '' " . .
., , ~ .
. , . " ., ,. .
- 25 - :
. , ''''. ,~.
63~ .
Example 18
2 N-(9-Ch!or~3-methyl-7-phenyl-S~I-pyrimido~-~,S-d~ [21 benzazepin-lyl)-N',N'-dimethyl-
3 ]?3-propanedinmine 1/3 molar hvdrnte
4 A solution of 1.0 g (2.8 mmol) of 1,9-dichloro-3-methyl-7-phenyl-SH-pyrimido[4,5-
S ~ [2] benzazepine and 1 mL of dimethylaminopropylamine in 25 mL of dimethyformamide
6 was heated to 65 for 16 hr~ The mixture was poured into ice water and the resulting
7 precipitate was collected by filtration to give a tan solid. Recrystallization from a
8 mixture of ether and petroleum ether gave colorless needles, mp 124-127.
io The hydrochloride salt was prepared by the addition of one molar equivalent of a 1.4
11 M methanol solution of hydrogen chloride to a methanol solution of the end product and
12 isolated by precipitating the salt with the addition of ether. Recrystallization from a
13 mixture of methanol and ether gave the hydrochloride salt as off-white prisms, mp 190-
194.
16 . Example 19
17 9-Chloro-1,3-dimethyl-7-~henyl-5H-pyrimido~4,5-d] [2] benzazepine l!4 molar etherate
18 Dropwise 13.2 ml (18.5 mmol) of a 1.4 M ether solution of methyl lithium was added to
1 a suspension of 1.7 g (8.9 mmol) of cuprous iodide in 50 mL of ether which was cooied to
0. A solution of 0.8 g (2.2 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido~4,5-
21 dl 12] benzazepine in 30 mL of ether was added dropwise to the ether solution of lithium
22 dimethylcuprate which was further cooled to -25. The mixture was stirred at -25 for I
23 hr, warmed to room temperature, diluted with water nnd saturated with hydrogen sulfide.
2~ The resulting precipitate was removed by filtration over celite and the filtrate was
concentrated at reduced pressure. Purification of the residue by column chromatography
~6 (silica gel, 10 g; eluent, 20~6 ether in methylene chloride) gave an oil which was
27 crystallized from 6 mixture of ether and petroleum ether to give off-white needles, mp
2B 121-124 .
., ' ' , '' "~''''',,' ' ' " .
. , ~ '' ` . , , . . ' i ' , i ~ ;~''~;'-
_ 26 - -.
-. . , . -- ,
: . .
O
1 ~ E~e~
2 1-[4-Chioro-2-benzoylphei-~yl]-3-phtha~ idoproPene
I . . _.... . _. .
3 I A mixture of 2.0 g of (S mr~olc) of l-i4-chloro-2-benzoylphenyll-3-phthalimido-
4 11 propyne and 0.1 g of prehydrogenated 10~6 palladium on barium sulfate in 50 ml of
5 ~I tetrahydrofuran was hdyrogenated at room temperature and atmospheric pressure until 85
6 1 ml of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate was
7 1l concentrated at reduced pressure to dryness. The residue was crystallized from ether to
8 1 give a white solid, mp 70-72~ C. Recrystalli~ation from ether gave colorless prisms, mp
9 11 70-72C.
~;' 10 1' .
11 Example 21
I
12 ¦ 8-Chloro-l-phenyl-311-2-benza_e~ine h~vdrochloride
13 11 A mixture of 6 g (15 mmole) o~ 4-chloro-2-ben~oylphenyll-3-phthalimidopropene,
14 I 0.9 g (18 mmole) of ~5% hydrazine hydrate and 70 ml of 95% ethanol was refluxed for 2.5
15 ¦ hr. The insoluble precipitate formed was separated by filtration. The filtrate was
16 I acidified with ice cold dilute hydrochloric acid and extracted with ether. The aqueous
-I 17 layer was separated, made alkaline with dilute sodium hydroxide and extracted with
I .
18 I methylene chloride. The methylene chloride solution was dried over anhydrous sodium
19 I sulfate, acidified with methanolic hydrogen chloride, diluted with isopropanol and~
20 I concentrated at reduced pressure to a small volllme. The crude product was collected by
74 filtration to give trn prisms, mp 223-225 C deo.
27 1
~ ' I
-27-
F ~ 1 7~ '
7~3~3
1xam~le 22
29-chloro-3-methyl-7-phenyl-5H-pyrimido--[4~`5-d~[;23~enzazepin-l(2H)
. . _.
3one 6'-oxide
4A solution of 2.8 g (8.3 mmol) of 9-chloro-3-methyl-J-
5phenyl-5H-pyrimido[4,5 d][2]ben~azepin-1(2Hj-one and 2.5 g(ll.5
6 mmol) of B5~ m chloroperbenzoic acid in 110 mL of methylene
7 chloride was stirred at room temperature for 2.5 hr. The
8 xeaction mixture was washed with saturated aqueous sodium bicar-
g bonate, dried over anhydrous sodium sulfate and concentrated at
reduced pressure to give a yellow solid. Recrystallization from
11methanol ga~e pale yellow prisms, mp 219-221.
12Ex'ample `23
135-(Ac'et'yloxy)-'9-'ch1oro~'3-methyl-7-phe'nyl-5H-py mido[4,5-d]_[2]
14 benzazepin-'I('2H)-one
15A mixture of 0.5 g jl.4 m~ol) of 9-chloro-3-methyl-7-
16phenyl-5H-pyrimido[4~5-d][23benzazepin-l(2H~-one 6-oxide and 10 mL
17 of acetic anhydride was heated on a steam bath for 3 hr. The
18 reaction mixture was concentrated at reduced pressure and the
19 cxystalline product separated. ~ecrystallization from methylene
chloride ga~e the product as cream colored crystals, mp ~320.
21' Example''24
22` 9-chloxo-5-h~droxy-3-mer-hyl-7-phenyl-5H-pyrimido[4~5-d][2]
23 ' be~z epin-'1(2H)-one
24A mixture of 2.1 g (5.3 mmol) of 5-(acetyloxy)-9-chloro-3-
25methyl-7-phenyl-5H-pyrimido[4,5-d~[2]~enzazepin-1(2H)-one and 50
26 mL of 3N sodium hydroxide was heated on a steam bath for 5 min.
27The reaction ~ixture ~as diluted ~ith 200 mL of ice water and 50
28 mL of ether. The sodium hydroxide was neutralized with acetic
29 acid and the resulting mixture stirred at room temperatuxe for
30 min. The resuIting precipitate was collected by filtration
31 to gi~e off-white solid. Recrystallization from tetrahydrofuran
32ga~e the product as colorless crystals, mp 253-255 (dec.).
- 28 -
~.:1'7~63(~
1 Ex'a'~pl'e'25
2 8-Chloro-1-(2-chloroph'enyl')-3H-2-b'enza'zepi'ne
3 A mixture of 4.6 g (15 mmole) of 3-amino-1-[2-(2-
4 chlorobenzoyl)-4-chlorophenyl~-propyne and 0.1 g of
prehydrogenated palladium on barium sulfate in 30 ml of
6 tetrahydrofuran was hydrogenated at room temperature and
7 atmospheric pressure until 355 ml of hydrogen was absorbed.
8 The catalyst was removed by filtration and the filtrate
9 concentrated at reduced pressure. The residue was crystallized
fro~ ether to give a cream colored solid, mp 113-115C.
11 Rec~ystallization from ether gave cream colored prisms, mp
12 117-118C.
13 The methanesu~lfonate salt of 8-chloro-1-(2-chlorophenyl)-
14 3H-2-benzazepine was prepared by the addition of an excess of a
'-1~ methanol solution of methanesulfonic acid to a methanol
16 solution of the above compound and isolated by precipitating
17 the salt with the addition of ether. Recrystallization from a
13 mixtuxe of methanol and ether gaye the methanesulfonate salt
19 as colorless plates~ mp 201-202C.
. . . . . .
Exa'mple 26
21 ''8'-Chl'o o-1~ 2-fluorophenyl)-3H-2-benzazepine
22 The preparation o~ 8-chloro-1-(2-fluorophenyl~-3H-2-
23 benzazepine hydrochloride was conducted in the same manner as
24 the preparation o~ 8-chloro-1-(2-chlorophenyl)-3H-2-benzazepine.
The hydrochloride was obtained as off-white prisms, mp 210-212C dec.
-29-
3~
1 ' ~xample 27
2 8-Chloro'-4,'5`-dibromo-4,'5-dihyd_o'-'1'-phe'nyl'-3H-'2-benzazepine
3 Dropwise 200 ml (0.18 mole) of a 5% bromine solution in
4 methylene chloride was added to 26.5 g (0.1 mole) of 8-chloro-1-
phenyl-3H 2-benzazepine in 300 ml sf methylene chloride. The
6 mixture was stirred at room temperature for 1 hr, diluted with
7 an excess of saturated aqueous sodium carbonate and stirred at
8 room temperature for 15 min. The methylene chloride solution
9 was separated, dried over anhydrous sodium sulfate, and diluted
with an excess of methanolic hydrogen chloride. The acid
Il solution was concentrated to a small volume at reduced pres~re
12 and the salt ~as precipitated by the addition of ether to give
13 the salt as a colorless solid, mp 164-165C. Recrystalli~ation
14 from methylene chloride gave colorless crystals, mp 164-165C
dec. The compound has been found to have a second melting
16 point of 172-173C dec.
17 A methanol solution of the salt was neutralized with
18 dilute aqueous sodium hydroxide and the resulting crystals
19 collected by filtration. Recrystallization from methanol
gave the end product as colorless prisms, mp 113-115C.
-30-
~263~3
1 'Example 28
2 8-Chloro-4,5-dibromo-4',5-dihyd'r'o'~ '('2'-'f'lu'or'ophenyl)-3H-2-
3 benza'zepine
4 The preparation of 8-chloro-4,5-dibromo-4,5-dihydro-1-
(2 fluorophenyl)-3H-2-benzazepine was conducted in the same
6 manner as the preparation of 8-chloxo-4,5-dibromo-4,5-dihydro-
7 1-phenyl-3H-2-benzazepine to give the hydrochloride salt as a
8 colorless solid, mp 158 I59C decO and the end product as
9 colorless prisms, mp 102-I03~C.
' Exa'mple 29
11 '8-Chloxo-4,'5-dibr'omo-4,5-dih'y'dr'o'-1~'(2-chlorophenyl~-3H-2-benzazepme
12 The preparation of 8-chloro-4,5-dibromo-4,5-dihydro-1-(2
13 -chlo~ophenyl)-3H-2-benzazepine was conducted in the same manner
14 as the preparation of 8-chloro-4,5-dibromo-4,5-dihydro-1-phenyl
-3H-2-benzazepine to give pale yellow prisms, mp 139C dec.
16 'Exampl'e'30
17 8-'Chior'o-5-b'romo-1-phenyl'-'3H-2'-ben'zaz ne'hy'drochloride and
.
18 `8-Chlor'o-3`-methoxy-1'-phenyI-3~H-2-benzaze~_e methanesulfonate
19 A solution of 24 g (53 mmole) of 8-chloro-4,
5-dibromo-4,5-dihydro-1-phenyl-3~-2-benzazepine hydrochloride
21 in 1 L of methanol and 180 ml o~ 10% aqueous sodium hydroxide
22 was stirred at room emperature for 45 hr. The mixture was
23 concentrated'in vacuo to a small volume and the residue was
_ __
24 extracted with methylene chloride. The methylene chloride
solution was dried over anhydrous sodium sulfate, diluted with
26 an excess of methanolic hydrogen chloride and concentrated in
27 ' vacuo to dryness. The residue crystallized from a mixture of
28 isopropanol and ether to gi~e an off-white solid, mp 229-230C.
29 Recxystallization from methylene chloride gave the hydrochloride
of the bromo compound as colorless prisms, mp 230-235C dec.
-31-
i3~
1 The crude mother liquors were basifled with dilute
2 aqueous sodium hydroxide and extracted with methylene chloride.
3 The methylene chloride solution was dried over anhydrous sodium
.
4 sulEate and concentrated`'in 'vacuo. Purification by column
chromatoqraphy (silica gel; eluents methylene chloride, then
6 ether) gave after concentration of the ether fractions a
7 colorless oil. The oil was dissolved in a methanol solution of
8 methanesulfonic acid and the salt was precipitated by the
9 addition of ether. Recrystalli~ation from a mixture of methanol
and ether gaYe off-~hite prisms, mp 139-140C.
11 . .. .. .
'Example''31
. .
12 8-Chloxo-5-bromo-1-(2-fluoroph'en~ 3~-2-benza~epine hydxx~loride
13 'A mixture of 21 g (45 mmole) of 8~chloro-4,5-dibromo-4,5
14 -dihydro-1-(2-fluoro-phenyl)-3H-2-benzazepine hydrochloride, 40
ml of dioxane, 360 ml of methanol and 40 ml of 10% aqueous
16 sodium hydroxide was stirred at room temperature for 5 hr and
17 then concentrated at reduced pressure to a small volume. The
18 concentrate was diluted with water and extracted with methylene
19 chloride. The methylene chloride solution was dried over
Z0 anhydrous sodium sulfate, diluted with isopropanol and an
21 excess o methanolic hydrogen chloride. The mixture was concen-
22 trated at reduced pressure to a small volume to qive the
23 hydrochloride salt as a colorless solidr mp 231-232C.
24 ~ecrystalli ation from a mixture of methylene chloride and ether
ga~e the salt as colorless crystals, mp 233-234C dec. The
26 methanesulfonate salt of the by-product was not isolated.
-32-
7~6;3~
1 Example 32
2 8-Chloro-5-b'romo~ 2'-chl'or'oph'e'n'y'1'j'-3H'-2-b'enz'a'zepine and
3 8-Chloro-3-methoxy-1-'(2-chlor'o~'h'e'nyl)-3H'-'2-b-en2'azepine
4 ~ solution of 60.0 g ~0.134 mole) of 8-chloro-4,5-
dibromo-4,5-dihydro-I-(2-chlorophenyl)-3H-2-benzazepine and
6 75 ml of 40% aqueous sodium hydroxide in a mixture of 300 ml of
7 dioxane and 900 ml of methanol was stirred at room temperature
8 for 4 hr. The mixture was concentrated in 'vacuo to a small
9 ~olume and the residue was extracted with methylene chloride.
The methylene chloride solution was dried over anhydrous sodium
11 sulfate, diluted with an excess of methanolic hydrogen chloride
12 and isopropanol and concentrated'in vacuo to dryness. The
13 residue crystallized from a mixture of isopropanol ar.d ether to
14 gi~e a w~ite solid. The white solid was partitioned between
~ethylene chloride and aqueous sodium bicarbonate. The
16 methylene chloride solution was dried over anhydrous sodium
17 sul~ate and concentrated at reduced pressure to give an amber
18 oil. Purification by column chromatography (silica gel, 250 g;
19 eluent, methylene chloride) ga~e the bxomo compound as colorless
pris~s, mp 125-127C.
21 The crude mothex liquors were partitioned between
22 methylene chloride and aqueous ammonium hydroxide. The
23 methylene chloride solution was dried o~er anhydrous sodium
24 sulate and concentrated at reduced pressure. Trituration with
a mixture of ether and petroleum ether gave the methoxy com-
26 pound as a tan solid. Recrystalli%ation from a mixture of
27 ether and pertroleum ether ga~e cream colored prisms, mp 83-85~C.
7~63~
1 'Ex`amp'l'e 33
2 S~Chlo'ro-'2-iodobenzophenone
3 A mixture of 76 g (1.1 mole) of sodium nitrite and 450
4 ml of sulfuric acid was heated on a steam bath to ca 80~ until
complete solution was achieved. The solution was cooled to 30
6 and 232 g 11.0 mole) of 2-am~no-S-chlorobenzophenone was added
7 in portions keeping the temperature between'30~ and 40. The
8 ~ixture was stirred for 1 hr and then slowly poured into 3 L of
g an ice and water mixture. The solution was filtered through
Hy-Flo and to the stir~ed filtrate was added slo~ly a solution
11 of 200 g (1.83 mole) of sodium fluoborate in 800 ml of water.
12 The resulting precipitate was collected by filtration and
13 ,washed ~ith water (2xlO0 ml) to give a moist white solid.
14
The moist 2-benzoyl-4-chlorobenzenediazonium fluoborate
was slurried in 3L of water, and a solution of 332 g (2 moles)
16 of,potassium iodide in 1 h of water was added dropwise. The
17 mi~ture was stirred at room temperature for 4 hr and the
18 resulting precipitate was collected by iltra~ion. The crude
19 product was added to lL of boiling ether, filtered, and dried
~ith anhydrous sodium sulfate. The ether solution was
21 concentrated to 500 ml and the addition of 100 ml of petroleum
22 ether gave end product. A small amount o end product was
23 recrystallized from a mixture of ether and petroleum ether to
24 gi~e light yellow prisms, mp 80-82.
* Trademark
26
-34-
~i726~
l ''Ex'a'mple '34
2 5-Chloro-2'-fluoro-2-iodobenzo'ph'enone
-
3 The preparation of 5-chloro-2'-fluoro-2-iodobenzophenone
4 was conducted in the same manner as the preparation of 5-chloro-
2-iodobenzophenone LO give the end product as light yellow
6 prisms, mp 78-81.
Example'35
9 ''2','5-pich'lo'ro-2-'iod'oben ophe'no'ne
The preparation o~ 2'-5-dichloro-2-iodobenzophenone was
11 conducted in the same manner as the preparation of 5-chloro-2-
12 iodobenzophenone to give the end product as light yellow prisms,
13 ~p 64-6,6.
::
-35-
7~t~3~
1 Ex'ampl'e 36
2 l-[4'-Chloro-2'-benzoylphenylj'-3-phthalimidopropyne
3 A mixture of 0.71 g t4.0 mmole) of palladium chloride,
4 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of
; 5 cuprous iodide, 68.8 g (0.20 mole) of 5-chloro-2-iodobenzo-
6 phenone, 200 ml of diethylamine, and 400 ml o methylene
7 chloxide ~as stirred at room temperature under argon until
8 co~plete solution was obtained. In one portion, 40.0 g
9 (0.22 mole) of N-propargylphthalimide was added to thesolution
and the resulting mixture stirred for 20 hr. The Yolatiles
ll were remo~ed at reduced pressure and the residue was
txiturated with 200 ml of iospropanol. The resulting precipitate
' 13 was collected by ~iltration to giye crude end product.
14 Recr~stallization from acetone gave cream cDlored prism~s, ~p 148-150C.
. ~ .......
''Exampl`e' 37
.
16 l-~:4-Chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropyne
17 The preparation of l~ chloro-2-(2-fluorobenzoyl)
18 phenyl~-3-phthalimidopyropyne was conducted in a similar manner
l9 as the preparation o~ l-[4-chloro-2-benzoylphenyl]-3-
phthallmldopropyne to give creem colore~ prismq, mp 158-161C.
.
-36-
~;,;
;~L7~1~3~3
1 `Ex'a'mp'le `38
2 1-[4-Chloro-2-~'2-chlbrobenzoyl)phen`yl]-3-phthal'imidopropyne
3 The preparation of 1-[4-chloro-2 (2-chlorobenzoyl)
4 phenyl]-3-phthalimidopropyne was conducted in the same manner as
the preparation of 1-[4-chloro-2 benzoylphenyl]-3-
6 phthalimidopropyne to give cream colored prisms, mp 144-145C.
:: .
-37-
1J~7~Li3~
I Example 39
2 3-Amino-1-~4-chlor~2-(?-fluorobenzoyl)phenyl~ pro~yne
l __
3 Method A A mixture of 50 g of 1-[4-chloro--2-(2-fluorobenzoyl)phenyl~3-
4 1 phthalimidopropyne, S0 ml of 40% aqueous methylamine and 150 ml of dimethylformamide
5 jl was stirred at room temperature for 25 min. Dropwise 500 ml of water was added, and
6 the resulting precipitate was collected by filtration. The precipitate was dissolved in
? methylene chloride dried over anhydrous sodium sulfate, and concentrated at reduced
8 j pressure to give a pale yellow solid. Recrystallization from ether gave pale yellow prisms,
9 ll mp 89-91 C. - i
~' 101 1
11 I Method B A mixture of 400 g (0.96 mole) of 1 [4-chloro-2-(2-fluorobenzoyl)phenyl] -
12 1l 3-phthalimidopropyne, 1.3L of ethanol and 300 ml of 40% aqueous methylamine was stirred
13 ,l at room temperature for 2 hr. Dropwise 2.8 1 of water was added, and the resulting
14 ~ precipitate was collected by filtration to give a pale yellow solid, mp 70-80 C.
15 I Recrystallization from ether gave pale yellow prisms, mp 80-91 C ..
16
17
18 Example 40
3-Amino-1-[4-chloro-2-(2-chlorobenzo~ henyll ~roE~
20 ¦ The preparation of 3-amino~ 4-chloro-2-(2-chlorobenzoyl)phenyllpropyne was
21 i conducted in the same manner as the preparation of 3-amino-1-~4-chloro-2-(2-
22 ~ fluorbenzoyl)phenyll propyne to give pale yellow prisms, mp 81-82~ C.
231
24 1
-38-
I I
~ 7
Example 41
2 TABLE,l' FOR~ 1UL~TION ~Direct com,oression)
3 Item 1n~redients m~/tablet m~tablet~/tablet m~/tablet
4 1. 9-chloro-7-(2-fluorophenyl)- 1 S lO 2S
3~methyl-SH-pyrimido~,5-q7_
S ~2~benzazepin- l (2H)-one
6 1,9-dichlor~methyl-7-
phenyl-5H-pyrimido~4,5-c¦7-
7 ~7benzazepine,
8 2. Lactose ~21 217 212 Igl
g 3. Avicel * 4S 45 45 S5
4. Direct Compression Starch 30 30 30 35
ll S. Magnesium Stearate 3 3 3 4
_ ~ _
13 - Weight of ~ablet 300 mg 300 mg 300 mg 300 m~
1~ .
15 Procedure:
16 l. Mix Item 1 with an equal amount of lactosec Mix well.
17 2. Mix with Items ~ and 4, and the remaining amount of Item 2. Mix well.
: ~: 3. Add magnesium stearate and mix ior 3 minutes,
19 4. Compress on a suitable press equipped with appropriate punches.
2n
21 .
' ~22
23
24
2S * ,Trade Mark.
~6
27 . .
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~xample 42
2 TABLET FORMUI,ATION (Wet granula~ion) , ' ¦,
3 Item !n~redients m~/tablet ~blet m~Jtablet m,E~/tablet
4 1. 9-chloro-7-(2-fluorophenyl~1 S 10 25 '
~methyl-5H-pyrimido~,5-~7-
S ~benzazepin-1(2H~-one
S 1,9-dichloro-3-methyl-7-
phenyl-5H-pyrimidoL4,5-d]- '
7 C~7benzazepine
8 2. Lactose 202 232 261 280
9 3. Modified Starch 25 35 45 55
4. Pregelatinized Starch 20 25 30 35 .
11 5. Distilled Water q.s.
12 6. Magnesium Stearate 2 3 4 5
13 ,~
14 Weight of table~ 2S0 mg 300 mg 350 mg 400 mg
' "
16 Procedure-
. .
17 1. M~x Items 1-4 in a suitable mixer.
18 2. Granulate with sufficient distilled water to proper consistency. Mill.
19 3. Dry in a suitable oven.
4. Mill and mix with magnesium stearate for 3 minutes. -
2 5. Comp s on ~ ~it.ble pre~ quil e~ with ap~ropriate punches.
26 ~ ' ~ '
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, . . . , ' '.' . .'
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2 ¦ ~:APSULE FORMULATION .
3 ¦ 3tem In~redients m~/tablet m~/tablet T:~ m~/tablet
4 ¦ 1. 9-chloro-7-(2-~luorophenyl~1 S 10 23 .
I . ~methyl-5H-pyrirnido[4,~d~-
S ¦ . ~7benzazepin- 1 (2H~one
6 ¦ l,9-dichloro-3-methyl-7- .
l phenyl-5H-pyrimido~4,5-d7-
- 7 . 1 ~2~benzazepine
8 ¦ 2. Lactose 203 293.S 328 372.5
9 ¦ 3. Starch 30 3S 40 30
10 ¦ 4. Talc 15 lS 20 20
Il ¦ 5. Aerosol OT i 1.5 2 2.5
12 l
I _ _ _
13 ¦ Capsulefill welght 2S0mg 350 mg400 mg 450 mg
14 I .
lS ¦ Procedure: -
16 ¦ 1. Mill Items 1, 29 3 and 5 in a suitable mixer. Mill.
17 ¦ ~. Add talc and mix well.
18 ¦ 3~ Encapsulate on suitable equipment.
19 l
20 I .
21 I . .
22 I .
2~ ¦ * Trade Mark. .
24 I . . .
2S I .
26 l
27 I . . .
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I . - 41 - . .~
: 1 ~31 ''
