Note: Descriptions are shown in the official language in which they were submitted.
1 ~3 ~ iG RAN 4008/315
The present invention relates to 3H-2-benzaæepines
oE the genexal Eormula
Rl
X ~ N~ >
wherein X is hydrogen, chloro or bromo, Y is hydrogen,
S fluoro or chloro, the broken line denotes an optional
bond, n i5 zero or 1 and R1 is hydrogen, bromo, chloro,
iodo, a radical of the formula
_ =
or a radical of the formula
R3
~
R3
wherein R2 is hydrogen, lower alkyl, hydroxy, amino,
monoalkylamino or dialkylamino and R3 is hydroxy or
amino with the proviso that
(i) X and Y cannot both be hydrogen, and
(ii) where R1 is other than hydrogen then the bond denoted
by the broken line must be present,
8t/16.4.81
8~
and to pharmaceutically acc~ptable salts thereo~.
3H-2-Benzazepines bu-t wherein R=Y=X~H have been disclo-
sed in the prior art, see Tetrahedron Letters, No. l, pp
33-36, 197~, Pergamon Press. These compounds in testing,
however, have proven to be inactive. The compounds of the
present invention, however, exhibit good psychotropic
activity although related in structure to the inactive
substance .
In accordance with the present invention, the compounds
of formula I and pharmaceutically acceptable salts thereof
can be prepared by
a) cyclizing a compound of the general formula
~ NH 2
X ~ O II
wherein X and Y have the significance given above
and the broken line denotes an optioE~ bond,
or
b) oxidizing a compound of the general formula
~11
~ ~ Ia
-- 2 --
~s~
wherein X and Y hava the signiflcance given above,
Rt1 is hydrogen, bromo, chloro or iodo and the broken
line denotes an optioE~ bond with the proviso that when
Rl1 is other than hydrogen, then the bond denoted by
the broken line must be present,
or
c) dehydrohalogcnating a compound of the general formula
~ .
wherein X and Y have the significance given above
and R12 is chloro, bromo or iodo,
or
d) reacting a compound of the general formula
Lb
~ n~
wherein X, Y, R12 and n have the significance given
above,
with a compound of the general formula
~C -- C-CH ~R~l IV
whe~ein R21 is hydrogen, lower alkyl, hydroxy, mono-
-- 3 --
7 ~
lower alkylamino oc di-lower alkylam.ino,
in the presence of a palladiurn salt, cuprou.s iodide, an
organophosphine ar.d a secondar-y or tertiary amine,
or
e) ren~ving the phthaloyl group (s) fran a ccmpo~d of the
general formula Phth ~
< Phth ~/ Phth
X~ ~ X~--~
~Y ~ y~OJ
V or VI
wherein X, Y and n have the significance given above
and Phth is phthalimido,
lo and, if desired;
f) converting a compound of formula I into a pharma-
ceutically acceptable salt.
The above process embodiments for the preparation of
the compounds of formula I and the preparation of starting
materials therefor are illustrated by the following Reaction
Schemes wherein X, Y, R12, n and Phth have the significance
given above and R22 is hydrogen, phthalimido, lower alkyl,
hydroxy, amino, monoalkylamino or dialkylamino, R31 is
hydroxy, phthalimido or amino and R4 is lower alkoxy:
.; ,
~ 4 -
Reactlor~ Schc~no I
X--~f X ~ ~j==C-t~i
~VI I e~/VI I I /~ I a
\~ ~ Ni12
XJ~- ~ Pl)tll~o ' X~;~
~f I c
I X / X
~-?
I a ~
X~
~ ,.
~:~s~
Reactii~n Scheme_II
X~r~> x~ ;X~
~Ia" ~III/ ~ ~Ib'
r~ X~ R'~
X~? ~'YX~
:~ ~r o
'7~.3t~i
R~3a~:tlor Sr.l~ o III
<R~2
~12 R~ R
X~, >~`~ X~ ~
~Ib [~ XIII
The compounds of ~ormulae II, III, V, VI, VIII and IX
also form art o~ the present inventlon.
The compounds of formulas VII and X do not form part
of the present invention but Examples 34 to 45 of the present
specification set forth methods for preparing these compounds.
The compound of formula VII may generally be prepared by
diazotizing the corresponding known aminobenzophenone using
sodium nitrite in sulfuric acid and isolating the salts by
precipitating the respective tetrafluoroborate salts which
are thereafter slurried in water and treated with aqueous
potassium iodide to give the iodobe~ophenone. These reactions
are carried out utilizing methods known in the art. Thereafter
the iodobenzophenone is treated with propargylphthalimide
in the presence of a mixture of palladium chloride, an organo-
phosphine, cuprous iodide and a secondary amine in a suitable
solvent to produce the phthalimidopropyne of formula VII.
~_= VIII
The compound of formula VII is hydrogenated utilizing a
transition metal catalyst, such as, Raney nick~l or platinum
oxide at from about atmospheric pressure to 50 pounds/square
inch with atmospheric pressure preferred. Solvents which may
be utilized include Cl to C6 alcohols, tetrahydrofuran,
dio~ane and -toluene.
VIII~ Ia' and IX~ Ia"
The compounds of formulas VIII and IX can be reacted
with an aqueous solution of a lower alkyl amine, e.g.,
methyl amine. A Cl to C~ alcohol can be utllized as the
solvent with ethanol as preferred. The reaction is most pre-
ferably carried out at about room temperature. The first
formed open.amine is not isolated but undergoes spontaneous
ring closure to the compound of formula Ia~ ardIa",r~ y.
An alternate method to produce the compounds of formulas
Ia' and Ia" consists of the reaction of the compounds of
formulas VIII and IX with hydrazine in an inert solvent, such
as, ethanol, tetrahydrofuran, aqueous ethanol ox a mixture
of ethanol and chloroform. The reaction temperature may vary
from about room temperature to about 100C with reflux tempera-
ture of the selected solvent as preferred. The product isextracted with dilute mineral acid and thereafter recovered
and neutralized.
, .
A third method which may be utili~ed to produce the com-
pounds of formulas Ia' and Ia" consists of a base followed
by an acid hydrolysis of the compounds of formulas VIII and
IX. For the base part of the hydrolysis an alkali metal hydro-
xide, such as, potassium or sodium hydroxide is utili2ed. For
the acid part of the h~drolysis, a 10% soluti.on of a mineral
acld, such as, hydrochloric, hydrobromic, sulfuric or phos-
phoric acid may be utilizecl. The hydrolyse~ are run at or
about room t~mp~rat.ure to reflux temperatures wi~h reflux
temperatures preferred. Orc~anic solvents, such as, Cl to
C4 alcohols or te-trahydrof~lran may be utilized to solubilize
the inqredients.
VII ~-~IX
The compol~nd of formula V~I i5 hydrogenated using a
Lindlar catalyst (prehydrogenated 10% palladium on barium sul-
fate) at about atmospheric pressure and about room temperature.
SoLvents suitable for the reaction include Cl to C6 alcohols,
tetrahydrofuran, dioxane or toluene.
VII~ X
The compound of formula VII can be reacted with a
primary lower alkyl amine, e.g., methyl or ethylamine, or
with hydra7ine in a water miscible solvent, such as, Cl to
C6 alcohols, ethers or dimethyl~ormamide. The reaction tempera-
ture may range from about 0C to 60aC with about room tempera-
ture as preferred.
Another method which may be utilized to produce the com-
pound of formula X consists of a base followed by an acid
hydrolysis of the compound of formula VII. For the base part
of the hydrolysis, an alkali metal hydroxide, such as, potas-
sium or sodium hydroxide is utilized. For the acid part of the
hydrolysis, a 10% solution of a mineral acid, such as, hydro-
chloric, hydrobromic, sulfuric or phosphoric acid may~be uti-
,
lized. The hydrolyses are run at or about room terDperature
to reflux temperatures ~ith reflux temperatureq preferred.
organic solvents, such as, C1 to C~ alcohols or tetrahydro-
furan may be utilized to solubilize the ingredients.
X ~ Ia"
The compound o~ formula X can be converted into a compound
of formula Ia" by u-tilizing the reactants and reaction para-
meters of step VII --~ IX. The first formed open amine is
not isolated but undergoes spontaneous ring closure to the
compound of formula Ia".
X~ Ia'
The compound of formula X can be hydrogenated using Raney
nickel as a catalyst at from atmospheric pressure to 50
pounds/square inch with atmospheric pressure as preferred. The
reaction is run at about room temperature. Solvents suitable
for the reaction include C1 to C6 alcohols, tetrahydrofuran,
dioxane and toluene. The first formed open amine i9 not isola-
ted but undergoes spontaneous ring closure to the compound
of formula Ia'.
Ia'-__3 Ic and Ia" _-~ Id and Ib'~ Ib"
The compounds of formulas Ia' and Ia" and Ib' can be
reacted with a suitable oxidizing agent such as metachloro-
perbenzoic acid in an inert organic solvent such as methylene
chloride. The reaction may be run at between O~C to the reflux
25 temperature of the solvent with room temperature preferred.
Ia" III
The compound of formula Ia" can be halogenated utilizing
-- 10 --
a ha10genating aqent, such as, ~1emental chlorine, bromine or
iodine in a halogenated hydrocarbon, such as, methylene ~hlo-
ride or chloroform. The reaction i5 carried out at from about
0C to about room temperature with about room temperature as
preferred.
Ib'
The compound of the formula III can be dehydrohaloganated
utilizing an alkaLi metal, e.g., potassium or sodium, hydroxide,
carbonate or alkoxide. Suitable solvents include C1 to C6 alco-
hols, tetrahydrofuran, dioxane and dimethylformamide. When aC1 to C6 alcohol is used as a solvent in the above reaction an
end product mixture of compounds of the formulas Ib' and XI
is produced. The reaction temperature may vary from 0C to
reflux temperature of the chosen solvent with about room
temperature as preferred.
Ib--~ XII or XIII
The compounds of formulas Ib can be reacted with a mono-
substituted acetylene of the formula, HC-C-CH2-R22 whereir
R22 is hydrogen, phthalimido, lower alkyl, hydroxy, mono-
lower alkylamino or di-lower alkylamino. Examples of the
above vnclude propargyl alcohol, propargylphthalimide, N-
methylpropargylamine, propyne or N,N-dimethylpropargylamine.
The reaction is carried out in the presence of palladium
chloride, cuprous iodide, triphenylphosphine and a di- or
trialkylamine, such as, di- or triethylamine. Suitable solvents
include halogenated hydrocarbons, e.g., methylene chloride or
chloroform and dimethylformamide. The reaction temperature
may vary from about 0C to reflux te~perature with room
3 ~
temperat~re a.s p~ef~rred.
It was found that shorter reaction times and the use of
mano- or di-alkyl arnino substituted acetylenes tended to pro-
duce compounds of formula XII whereas longer reaction times
and the use of hydroxy and phthalimido substituted acetylenes
tended to ~orm compounds of formula XIII.
To arrive at R2 or R3 as amino, one can remove the
phthaloyl substituent at R22 or R31 by an acid or base
hydrolysisor by reaction with an aqueous monoalkyl amine or
hydrazine as in step VII ~ X.
As used herein the term "lower alkyl" or "alkyl" shall
mean a C1 to C7 with C1 to C~ as preferred, straight or bran-
ched chain hydrocarbon e.g., methyl, ethyl, propyl, etc.
A suitable pharmaceutical dosage unit can contain from
about 1 to about 500 mg of the benæa7epine end products with a
dosage range of from about 1 mg to about 100 mg baing the pre-
ferred oral administration and a dosage range of from about
1 mg to about 50 mg being preferred for parenteral administra-
tion. However, for any particular subject, the specific dosa-
ge regimen should be adjusted according to individual need and
the professional judgment of the person administering or
supervising the administration of the aforesaid compounds. It
i9 to be understood that the dosages set forth herein are
exemplary only and that they do not, to any extent, limit the
scope or practice of this inven-tion.
.
- 12 -
7i~
The term ~dosage unit~ as employed throughout this speci-
fication refers to pharmaceuticall~ disc~ete units suitable
as unitary dosages ~or mammalian subjec-t each containing a
predetermined quantity oE active material calculated to pro-
duce the desired therapeutic effect in association with therequired pharmaceutical dilllent, carrier or vehicle.
The 3~1-2-benzazepines of formula 1 are useful as pharma-
ceuticals and are characterized by activity especially as
sedative and anxiolytic agents. These compounds can be used
in the form of conventional pharmaceutical preparations; or
example, the aforesaid compounds can be mixed with conventional
organic or inorganic, inert pharmaceutical carriers suitable
for parenteral or enteral administration such as, for example,
water~gelatin, lactose, starch, magnesium stearate, talc,
vegetable oil, gums, polyalkylene glycols, Vaseline or the
like. They can be administered in conventional pharmaceutical
forms, e.g., solid forms, for examples, tablets, dragees,
capsules, suppositories or the like, or in liquid forms, for
example, solutions, suspensions or emulsions. Moreoverj the
pharmaceutical compositions containing compounds of this in-
vention can be subjected to conventional pharmaceutical expe-
dients such as sterili~ation, and can contain conventional pharma-
ceutical excipients such as preservatives, stabili~ing agents,
wet-ting agents, emulsifying agents, salts Eor the adjustment of
osmotic pressure, or buffers. The compositions can also contain
other therapeutically active matexials.
An example of the activities possessed by the compounds
of the present invontion is illustrated by the results of the
- 13 -
7~jtj
metrazol test of several species of the prese~t invention.
Periodically a metrazol standardization test precedes
the assay to ascertain the quantity o metrazol, administered
to control mice, suf~icie~-t to induce convulslve seizures in all
5 animals. This is usually 125 mg/kg. In the antimetrazol te~-t,
a compound is admini~tered orally to groups of four MiCe at
various dose levels. One hour later, metrazol (at a dose
level previously determined in the standardization test) is
administered subcutaneously and the animals are observed ~or
protection from convulsive seizures. Results are r~corded as
the number o~ animals protected against convulsions. The dose
at which 50% of the animals are protected ~rom convulsive sei-
zures is expressed as the ED50. On active compounds, 8 a~m~s are
employed per dose group. The ED50 is calculated by the
Miller-Tainter method (Proc. Soc. Exp. Med. and 8io., 57,
261, 194~).
8-chloro-S-(1-amino-2-propyn-3-yl)-1-phenyl-3H-2-benzazepine
dihydrochloride
Metrazol ED50 = 32 mg/kg (PO)
To~icity = 500 mg/kg (24 hr. LD50~ (PO)
8-chloro-5-(1-amino~2-propyn-3-yl)~1-(2-~luorophenyl)-3H-2-
benzazepine dihydrochloride
Metra~ol ED50 = 3 mg/kg (PO)
Toxicity = 500 mg~kg (24 hr. LD50) (PO)
8-chloro-l-phenyl-3H-2-benzazepine-2-oxide
Metrazol ED50 = 5.2 mg/kg (PO)
Toxicity = ~ 1000 mg/kg (24 hr. LD50) (PO)
- 14 -
.
~7~
8-chloro-5-(l~dimethylamino-2-propyn--3-yl)~ 2-fluor'o-
phenyl)-3H-2-benzazepi.ne dihydrochlorlcle
Metrazol ED50 = 19 mg/kg (Po)
Toxicity = ,>lOOO mg/kg (24 hr. LD50) (PO)
The compounds of the present invention wherein Rl is
hydrogen, bromo, chloro and iodo are also intermediates in the
production o other active benzazepines, for example, pyri-
midobenzazepines.
As preferred are compounds of the formula
X' ~ Ie
~ ~Y'
wherein X' is chloro, Y' is hydrogen, fluoro or chloro
and Rl3 is a radical of the formula
R23
-
or a radical or the formula
J ~
~ ~ 32
wherein R23 is amino, monoalkylamino or dialkylamino
and R32 i9 amino.
Especially preferred are compounds of the above formula
La wherein Rl3 is a radical of the formula
_ _ 23
_ 15 -
jl,, ~L sr;~ 8 j~
wherein R23 is amino, monoalkylamlno or dialkylamino.
Especially preferred compounds of the above formula
Ie are:
8-chloro-5-(1-amino-2-propyn-3-yl~-1-phenyl-3H-2-
benzazepine; and
8-chloro-5-(1-amino-2-propyn-3-yl)-1-~2-fluorophen~l)-
3H-2-benzazepine.
The above compounds of formula Ie exhibit antidepressant
activity as illustrated in the imipramine binding test as out-
lined below.
Male rats (180 g) are decapitated and the ~rains imme-
diately placed on ice. The cortex is dissected and homo-
genized in 8 volumes of 0.25 M sucrose. The homogenate is
centrifuged at 2900 rpm (1000 x g). The supernatant is de-
canted and polytronized for 60 seconds. Dilutions of imi-
pramine hydrochloride are made in ethanol (1:5). Each assay
sample contains~ 3 ml of Krebs Ringer Buffer, 20 ~l of imi-
pramine or other drugs and 20 ~l of H-imipramine ~0.1 mM).
Imipramine (10 M) is used to define nonspecific binding.
Incubation is for 15 minutes at room temperature. Samples are
then put in an ice bath for 5 minutes. Each sample is filte-
red. The filter papers are placed in 13 ml of aquasol and
shaken for 2 hours, then the radioactivity trapped on the
filter is determined by liquid scintillation spectrometry.
- 16 -
Compound H-Imipramine Binding
IC50 (~M)
Imipramine 7.l
8-Chloro-5-(l-amino-2-propyn-3-yl)-l-
phenyl-3H-2-benzazepine dihydrochloride 1l.0
8-Chloro-5-~1-amino-2-propyn-3-yl)-1-
(2-fluorophenyl)-3~1~2-benza~epine dihy~ro-
chloride 20.0
The expression "pharmaceutically acceptable salts" is used
to include salts with both inorganlc and organic pharma-
ceutically acceptable acids, such as, hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid, phosphoric
acid, citric acid, formic acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methanesulfonic acid, para-
toluenesulfonic acid and the like. Such salts can be formedquite readily by those skilled in the art, with the prior
art and the nature of the compound to be placedin salt form,
in view.
The following examples are illustrative, ~ut not limi-
tative of this invention. All temperatures given are in
degrees centigrade, unless indicated otherwise.
'E,xçam~le ~
Chloro-2-benzoyl~henyl~ -3-~hthal:Lmido~ropane
_ _ __ ._ . ___ _ _ , . . _ _ . . _ . . __ ..,. __ _ .._ ., _ ,__
A mixture of 2 ~ (5 mmo~e) of 1-C4-chloro-2-benzoylphenyl~
-3-phthalimidopropyne and 1/2 teaspoonful of Raney nickel in 25 ml
of tetrahydrofuran was hydrogenated at room temperature and atmos-
pheric pressure. When 240 ml o~ hydrogen was absorbed, the catalyst
was separated by filtration and the Eil-trate concentrated at re-
duced pressure to dryness The residue was crystallized from a
mixture of ether and petroleum to gi~e crude produck as a tan
solid, mp 94-97C. Recrystallization from ether gave pale yellow
prisms, mp 98-99C.
Exa'mple 2
_.
l- ~-Chloro-2-(2-~luorohen'zo'yl')pheny~ -3-ph'tha'limi'dopropane
A mixture of 9.6 g (23 mmole) of 1-L4-chloro-2-(2-f`luoro-
benzoyl)phenyl~ -3-phthalimidopropyne and l teaspoonful of Raney
nickel in 70 ml of tetrahydrofuran was hydrogenated at room tem-
perature and atmospheric pressure. When 1.05 L of hydrogen was
absorbed the catalyst was separated by filtration and the filtrate
was concentrated at xeduced pressure to dryness. The residue
crystallized from a mixture of ether and petroleum ether to give
the product as a tan solid, mp 98-99C.
_ample 3
8-Chloro-4,'5-dihvdro-1-phenyl-3H-2-benzazepine hydro'chloride
_ .
A solution of 5.1 g (12.6 mmole) of 1-~4 chloro-2-benz-
oylphenyl~ -3-phthalimidopropane in 100 ml of ethanol and 20 ml
of 3N sodium hydroxide was refluxed for 2 hr. The solution was
diluted with 60 ml of 3 N hydrochloric acid and refluxed for
12 hr. The mixture was diluted with water and extracted with
ether. The aqueous layer was separated, made alkaline with
dilute sodium hydroxide, and extracted with methylene chloride.
The methylene chloride extract was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to dryness.
-18-
The residue ~as purified by plug fil-tration (sillca gel,10 y;
eluent, methylene chlorLde) and the eluent was acidified with
methanolic hyclrocJen chloride. The solution wa5 concentra-ted
at reduced pressure to dryness and the residue was crystallized
from a mixture of lsopropanol and e-ther to ~ive a colorless
solid, mp 234-235C. Recrystalliza-tion Erom a mixture of meth-
ylene chloride and ether ~ave colorless needles, mp 234-235C
dec.
Ex_mple 4
3-Chloro-4_ -dihyd'ro'~ '2~f uorophe_yl)-'3H-2 benz'aze'pine h~
chlor'ide
Meth'ocl A. A mLxture of 2.9 g (10 mmole) oE 3-amino-1
-~4-chloro-2(2-fluoroben~oyl )phenyl propyne and 1/4 teaspoonful
of Raney nickel in 50 ml of tetrahydrofuran was hydrogenated at
room temperature and atmospheric pressure. When 430 ml of hydrogen
was absorbed the catal~st was removed by filtration and the fil-
trate was concentrated at reduced pressure to dryness. ~ solu-
tion of the residue in an ~xcess of methanolic hydrogen chloride
was diluted with ether and end product, mp 176-177C dec was
collected by filtration. Recrystallization from a mixture of
methanol and ether gave pale yellow plates, mp 209-215C dec.
Method B A solution of 5.9 g (14 mmole) of 1--{4-chloro-
2-(2-fluorobenzoyl)phenyl-3-phthalimidopropane in a mixture of
100 ml of ethanol and 20 ml of 3N sodium hydroxide was refluxed
for 2 hrr diluted with 60 ml of 3N hydrochloric acid and refluxed
for 12 hr. The reaction mixture was poured into water and
extracted wi-th ether~ The aqueous acid layer was separated,
made alka]ine with dilute sodium hydroxide and extracted with
methylene chloride. The methylene chloride solution was dried
over anhydrous sodium sulfate and concentrated at reduced
pressure to dryness. Purification by plug filtration (alumina
Woelm 1,50 g, eluent, methylene chloride) gave an oil which was
diluted with an excess of methanolic hydrogen chloride and
concentrated at reduced pressure to dryness. The residue was
crystallized from a mixture of methanol and ether to ~i~e p~ct
which was identical in every respect to an authentic sample.
.~q
1 9 -
- .~
4~ 7~
Exa~ple 5
l-L4-Chloro-2-benzo~lehe~y.l~-3-ph-thallmldopro~ne
A m:Lxture o:~ 2.0 g (5 mmole) of 1-c4-chloro-2-benzoy~-
pheny~ -3-phthalimidopropyne and 0.1 g of prehydrogenated 10%
palladium on barium sul:~-te .in 50 ml of tetrahydrofuran was
hydrogena-ted at room temperature and atmospheric pressure until
85 ml of hydroyen was absorbed. The catalyst was removed
by filtration and the Eil-trate was concentrated at reduced
pressure to dryness.. The residue was crystallized from e-ther
to give a wh:Lte solid, mp 70-72C. RecrystaLlization from ether
gave colorless prisms, mp 70-72C.
Example 6
l-L4-chlo _-2-(2-~ robenzoyl.)phe~ ^u3e~ ~ r~pene
The preparation of 1-~4-chloro-2-(2-Eluorobenzoyl)phenyl~
-3-phthalimidopropene was conduc-ted in the same manner as the
preparation of l-~4~-chloro-2-benzo~lphenyi~ -3-phthalimidopropene
to give colorless needles, mp 117 C.
_ample 7
8-Chloro-l-phenyl-3H-2-ben~az.epine hydrochloride
. _ __ . .. _ . .. ... _
Method A. A mixture oE 0.1 g of prehydrogenated 10%
paLladium on barium sulfate and 27 g (0~1 mole) of 3-amino
-1-~2-benzoyl-4-chlorophenyl propyne in 100 ml of tetrahydrofuran
was hydrogenated at room temperature and atmospheric pressure until 2.4 L Ica
0.1 mole) of hydrogen was absorbed. The catalyst was removed
by filtration. The filtrate was diluted with an excess oE
methanolic hydrogen chloride and 100 ml of isopropanol and
concentrated at reduced pressure to a crystalline residue.
Trituration with a mixture of ether and methanol gave a tan
solid, mp 224-226 C dec. Recxystallization from a mixture of
methanol and ether ga~e cream colored prisms, mp 227-228 C dec.
~............................. -20-
Method B. A.mi~tu.re of 6 g (15 mmole) of 1-C4-chloro-2-
~enzoyLphenyl~-3-phthal,imidoproperle, 0.~ g (18 mmole) of 85%
hydrazine hydra-te and 70 ml of 95% ethanol was refluxed fox 2.5
hr. The insoluble precipitate :formed was separated by fil-tration.
The filtra-te was aciclified with ice cold dilu-te hydroehlorie
acid and extracted with ethe.r. The a~ueous layer was separated,
made alkali.ne with dilute sodium hydroxide and extracted with
methylene chloricle. The methy~len.e chloride solution was dried
over anhydrous sodium sulfate, aciclified with methanolic hydroyen
ehloride, diluted with isopropanol and eoncentrated at redueed
pressure to a small ~olume. The crude product was colleeted by
filtration to gi~e tan prisms, mp 223-22SC dec whieh was
iden-tieal in every respee-t to an authen-tie sample.
E ~ e 8
8-Chloro-1-'(2-E'lour~ nyl)-3H-2-benzaziepine hyd.roehloride
The preparation of 8-chloro-1-(2-fluorophenyl3-3H-2-
benza~;epine hydroehloride wa,s eonducted in the same manner as the
preparation of 8-chloro-1-phenyl-3H-2-benzazepine hydrochloride
to gi~e product (Method A) and (Method B) as of'f-white prisms,
mp 210-212C dee.
Example 9
8-Chloro-l-t2-chlor:ophenyl)-:3H-2-;benz.azepine
A mixture of 4.6 (15 mmole) of 3-amino-1-L2-(2-ehloroben-
zoyl)-4-ehlorophenyl~ propyne and 0.1 g of prehydrogenated palla-
dium on barium sulfate in 30 ml of tetrahydrofuran was hydrogen-
ated at room temperature and atmospherie pressure until 335 ml
of hydrogen was absorbed. The eatalyst was removed by filtration
and the filtrate eoneentrated at redueed pressure. The residue
was erystallized from ether to give a cream eolored solid, mp
113-115C. Reerystallization from ether gave cream eolored
prisms, mp 117-118C.
-21-
,
. ~.. .
I The tnethanesulfonate sQlt of 8-chlor~1-(2--chlorophenyl)-3H-2-benzazepine was
2 prepared by the ~dditlon ot an excess of a IM methanol solution of methanesulfonic acid to
3 a methanol solution of thc abov~ compound and isolQted by precipitating the sult with the
4 addition of ether. Recrystallization from a rnixture of methanol arld ether gave the
5 methanesulfonate salt us colorless plates, mp X01-202C.
7Example 10
8~ ochloride
__
9The preparat2On of 1-(2-cMorophenyl)-3H-2-benzazepine hydrochloride was con-
10 ducted in the same manner (Method A) ~s the preparation of 8-chlor~l-phenyl-3EI-2-
11 benzazepine hydrochloride to give tan needles, mp 201-202 C dec.
12
13Exame~ 11
148-Chloro-4,5-dihydro-1-phen~1-3H-2-benzazepine -ox de
A solution of 1.4 g (5.5 mmole) of 8-chioro-4,5-dihydro-1-phenyl-3H-2-benzazepine
16 and 1.4 g (7 mmole) of 85% m-chloroperbenzoic aoid in 50 ml of methylene chloride was
17 stirred at room temperat tre for 18 hr. The reaction mixture was washed with dilute
18 aqueous sodium hydroxide and the organic layer was separated, dried over anhydrous
19 sodium sulfate and concentrated In vacuo to dryness. The residue was crysta]lized from
20 ether to give a colorless solid, mp 120-125 C. Recrystallization from ether gave colorless
z I prlsnr, p l42-14ao C
22275
.
ll - 22 -
r s ~
~7~>
1 Ex~mple 12
2 8-Chlo~ ehenyl-3H-?-benzazee~ne-2-oxide
3 A mixture of 10.7 g (42 rnmole) of 8-chloro-1-phenyl-3H-2-benzuzepine, 10.7 g (53
4 mmole) of 85% metachloroperbenzoic Qcid and 100 rnl o~ methylene chloride w~ stirred Qt
room ternperature or IG hr. The mixture w~s w~shed with aold dilute ~queous sodiuml
6 hydroxide and brine. The methylene chloride solution was dried over Qnhydrous sodium¦
7 sulfate and concentrated nt reduced pressure to dryness. The residue WQS crystallize
8 wlth ether to give crude product, mp 130-131 C. Recry~tallizution from ether gave tAn .
9 prisms, mp 122-123 C.
Il ~e~
12 8-Chloro-l-r2-fluorophenpll -3H-2-b~n7~zepin~2-oxlde
13 l~le praparation of 8-chloro-1-(2-~luorophenyl)-3El-2-benzazepine-2-oxide was con-
14 ducted In the same manner as the prep~ration of 8~chloro-1-phenyl-3H~2-benzazepin~2-
15 oxide to give colorless prisms, mp 138-139 C.
16
17 . ~?~
18 8-Chloro-1-(2-chlorophen~TI?-3H-2-benzazepine-2.-oxide
19 The preparation of 8-chloro-1-(2-chlorophenyl)-3H-2-benzazepine-2--oxide was con-
20 ducted in the same manner as the preparation of 8-chlo~o-1-phenyl-3H-2-benzazepine-2-¦
21 oxide ~o give cream colored prisms, mp 196-197 C.
2Z
23 Example 15
24 1~2-Chlorophenyl)-3H-2-bsngazepine-2-oxide
25 The preparation o~ 1-(2-chlorophenyl)-3H-2-benzazepin~2-oxide was conducted in .
26 the same manner as the preparation of 8-chloro-1-phenyl-3H-2-benzagepine-2 oxide to
27 give OreRm colored rods, mp 115-116 C.
r~7~ Il!
l ~ !~6
2 ¦ ~:~!~mo-4~ dihydro- -~en~1-3 H-2-3enzazepin_
3 ¦ Dropwise 200 ml (0.18 mole) of Q 5% bromine solution in methylene chloride was
4 ¦ added to 26.5 g (0.1 mole) of 8-chloro-1-phenyl-3H-2-benzazepine in 300 ml of methylene
5 ¦ chloride. The mixture was stirred at roorn temperature for I hr, diluted with an excess Or
6 ¦saturated aqueous sodium carbonat~ and stirred at room temperature for 15 min. ~he
7 ¦ methylene cllloride solution was separated, dried over anhydrous sodium sulfate, and
8 ¦diluted with an exceas of methanolic hydrogen chloride. Th~ acid solution wss
9 ¦ concentrated to a small volume at reduced pressure and th~ salt WRS precipitated by the
10 ¦ addition of ether to give the salt as a colorless solld, mp 164-165C. Recryst~lIlzation
Il l from methylene chloride gave colorless crystals, mp 164-165C dec. The compound has
12 ¦ been found to have a second melting point of 172-173 C dec.
13 1
14 ¦ A methanol solution of the salt was neutralized with dilute aqueous sodium
15 ¦ hydroxide and the resulting cryst Is colleoted by filtration. Recrystalllzation from
ZC mrthenol gav. the en rodr~t ao colorless prismt, mp 113-115 C.
22
26
.
~-~75' 11 ~
" ~
Il ..~
1 . .
2 ~romo- 1,5-dihyclro-1-(2-fluoro"otlcr!yl?-3 H-2-benzazepine
3 The preparatloll of 8-chlor~4,5-dibromo-4~5-dihydro-1-(2-fluorophenyl)-3H-2-ben-
4 zazepine was conducted in the same manner a~s the preparation of 8-chloro~,5-dibromo-
4,5-dihydro-1-phenyl-3~-2-benzazepine to give the hydrochloride salt as a colorless solid,
6 mp 158-159 C dec. and the end product as colorles3 prisms, mp 102 10~ C.
8 Example 18
9 8-Chloro-4,5-dibromo-4,5-dihydro-1-(2-chlorophenyl)-3H-2-benzazepine
The prcparation of 8-chloro-4,5-dibromo-4,5-dihydro-1-(2-chlorophenyl)-3H-2-ben-11 zazepine was conducted in the same manner QS the praparation of 8-chloro-4,5-dibromo-
12 4,$-dihydro-1-phenyl-3H-2-benzazepine to give pale yellow prisms, mp 139 C dec.
13
14 ample 19
lS 8-Chloro-5-bromo-1-phen~1-3H-2-benzazepine hydrochloride and
16 8-Chloro-3-methoxy~ henyl-3H-2-benza~eine methanesulfonate
17 A solution of 24 g (53 mmole) of 8-chloro-4,5-dibromo-4,5-dihydro-1-phenyl-3H-2-
18 benzazepine hydrochloride in 1 L of methanol and 180 ml of 10% aqueous sodium hydroxid~
19 was stirred at room temperature for 45 hr. The mixture was concentrated in vacllo to a
small volume and the residue was extracted with methylena chloride. The methylene
21 chloride solution was dried over anhydrous sodium sulfate, diluted with an excess of
22 methanolic hydrogen chloride and concentrated in vacuo to dryness. The residue
23 crystallized from a mixture of isopropanol and ether to give an off-white solid, mp 229-
24 230C. Recrystallization from methylene chloride gave the hydrochloride of the bromo
26 ~ ~ compound aa aolorless rlsms, mp 330-235C dec.
v~."
I l`hc ~rudc motllcr li~llors ~vcrc bnsiricl t~ilh cl~l~te aqucous sodium l)~dro.~;idc and
2 ¦ e.~rnc~c~l ~viLI~ mclllylcnc cllloricle. Thc rmctlly~cne cllloridc solulion was dricd ovcr~
3 I nnhydrous sodium sulfnte nnd conccntrntccl In vncllo. Purificntioll by column chrornato-
4 ! ~r~phy (silic~ ~cl; elucnts mcthylcne ctlloridc, then cthcl) gnve after conccntrntion of thr !
S I cthcr ~ractiolls a colorlcss oil. The oil was dissolYed in a mcthanol solution of !
6 ! mctharlesulfonic ncid and thc salt wus precipitated by the addition of ether. Reclystnl
7 li~ation from Q mixturc o~ mctllanol and cthcr gave off-white prisms, mp 139~ 0 C.
9 x~e~_ 2 o
8_loro-5-brorno-1-(2:rluo. o?honyl?-3H-2-benzazepine h!. droehlol ide
11 A mixture of 21 g (~5 mmole) of 8-chlor~,5-dibromo-4,5-dihydro-1-(2-fluoro-
12 phenyl)-3H-2-bcnæazcpine hydrochloride, 40 ml of dioxane, 3ûO ml of methanol and 40 ml!
13 of 10% aqueous sodium hydroxide was stirred at room temperature for 5 hr and then !
14 concentrated Qt reduced prcssure to a small volume. The eoncentrate was diluted with
water and extrneted with methylene chloride. The methylene ehloride solution was dried I
i6 -over anhydrous sodium sulfate, diluted with isopropanol and an exeess of methanolie
17 -hydrogen ehloride. The mixture was eoncentrated At reduced pressure to ~ small volume
18 to give the hydrochloride salt as a eolorless solid, mp 231-232~ C. Recrystallization from a
19 mixture of methylene ehlorids and ether gave the salt as colorless crystals, mp 233-23~ C
dec. The methanesulfonate salt of the by-produet (8-chloro-3-methoxy-1-(2-fluorophenyl)-
22 3H-~ benzaz~i,e) was not isolated.
2g
27 -
'
r ~,7~ . ¦ . I
1 ~
2 18 Chloro-5-bromo-1-(2-chlorophenyl)--3 11-2-benzazeplne and
3 ¦ 8-Chloro-3-me thoxy-1-(2 chlorophenyl)-3 H-2-benza~epine
4 ¦ A solution of 60.0 g (0.13~ mole) of 8-chloro-4,5-dibromo-4,5-dihydro-1-(2
S ¦ chlorophenyl)-3H-~-bcn~a~epine and 75 rnl of 40% aqueous sodium hydroxide in a mixtur
6 ¦ f 300 ml of dioxans and 900 ml of methanol wrls stirred at room temperature for 4 hr.
7 ¦ The mixture was concentrated in vacuo to a small volume and the residue was extracted
8 ¦ with methylene chloride. The methylene chloride solution was dried over anhydrous
9 ¦ sodium sulfate, diluted with an excess of methanolic hydrogen chloride and isopropano
10 ¦ and concentrated in vacuo to dryness. The residue crystallized from a mixture o
11 ¦ isoprop'anol and ether to give a whitc solid. The white solid was partitioned betwee
12 ¦ methylene chloride and aqueous sodium bicarbonate. The methylene chloride solution wa
13 ¦ dried over anhydrous sodium sulfate and concentrated at reduced pressure to give
14 ¦ amber oil Purification by column chromatography (silica gel, 250 g; eluent, methylen
15 ¦ chloride~ gave the bromo compound as colorless prisms, mp 125-127C.
161
17 ¦ The crude mother liquors were partitioned between methylene ¢hloride and aqueo
18 ¦ ammonium hydroxide. The methylene chloride solution was dried over anhydrous sodiu
19 ¦ sulfate and concentrated at reduced pressure. Trituration with a mixture of ether an
20 ¦ petroleum ether gave the methoxy compound as a tan solid. Recrystalli~ation from
21 ¦ mixture of ether and pertroleum ether gave cream colored prisms, mp 83-85 C.
26 I
r~l7~
__ . _ _
3'7~
l~xnmple 2 2
28-Chloro-5-~romo-1-phenyl-3 H-2-benzazepine-2-ox1de
3A solution of 6.9 g ~20.7 mmole) of 8-chloro-5-brom~l-pheny1-3H-2-benzazepine
and 6 g (29 mmole) of 85% m^chloroperbenzoic acid in 100 ml of methylene chloride was
S stirrred at room temperutur~ for I hr. l`he mixture was washed with cold dilute sodlum
6 hdyroxide, dried over anhydrous sodium sulfate and concentrated ~t reduced pressure to
7dryness. The residue wa~ crystallized from ether to give ~ whlte solid, mp 184-185~C.
8 ~ecrystQllizQtion Irom ether gave colorle~;s prisms, mp 185-18~ C dec.
Example 2 3
11 8-Chloro-5-~1-dimethylamino-2-propyn-3-yl)-1-phenyl-3H-2-benzazepine dih~ rochloride
12 1/4 molar hydrate
13 A mlxture of 120 ml of 98% diethylamine, 88.~ mg (O.S mmole) of pallQdium
14 chloride, 262.4 mg (1 mmole) of triphenylphosphine, 95.2 mg (O.S mmole) of cuprous iodide,
8.7 g (26 mmole) oi 8-chloro-5-bromo-1-phenyl-3H-~-benzazepine and 25 g (0.3 mole) of 1-
16 dimethylamino-2-propyne was stirred under argon for 24 hr. The mixture w~s17 concentrated at reduced pressure to dryness. The residue was dissolved in methylene
12 chloride and washed with water. The methylene chloride solution was dried over
19 anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification
by column chrom~tography (silica gel, S0 g; eluent, methyIene chloride then ether) gave an
21 oil. The oil was dissolved in ethanol and diluted with an excess of ethanolic hydrogen
22 ohloride to give the dihydrochloride salt as a colorless solid, mp 193-195 C dec.
23 Recrystallization from methylene chloride gave the salt as colorless crystals, mp 198-
24 199 C dec.
2S
26
27
~ _ 28 --
~ '`7~
2 8-Chloro-J~ dimethy~Qmino-2-propyn~1-~2-tluorophen~ 2-benzazepine dih~dr~
3 chloride
4 A mixture of 40 ml of 98~6 diethylAmirle, 44.3 mg (O.Z5 mmole) p~l~diurn chloride,
131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of cuprous iodide, 3.5
6 ~9.4 mmole) of 8-chloro-5~bromo-1~2-fluorophenyl)-3H-2-benz~zepine and 1~ ml Or 1-
7 dimethylamin~2-propyne was stirrecl under nitrogen at room temperature ~or 23 hr. The
8 mixture W~a concentrated at reduced pressure to dryness. The residue was dissolved in
9 methylene chlorkle, washed with water and dried over flnhydrous sodium sulfate. The
methylene chloride solution was diluted with an excess of methanolic hydrogen chloride
11 and concentrated In vacuo to dryness. The residue crJstallized from a mixture of ethanol
12 and isopropanol to give the dihydrochloride aa a yellow solid, mp 15S-1S6 C. Recrystall-
13 ization from a mixture of ethanol and ether gave the salt as pale yel1ow rods, mp 194-
14 195 C dec.
16 Example 25
17 8-Chloro-5~ dimethylamlno-2-propyn-3-yl)-1-phen~1-3H-2-benzazepine-2-oxide
1~ A mixture of 3.5 g (10 mmole) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine-2
19 oxide, 40 ml of 9896 diethylamine, 40 ml of dimethylformamide, 44.3 mg (0.25 mmole) of
20 palladium chloride, 131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of
~1 cuprous iodide and 16 ml of 1-dimethylamino-2-propyne was stirred at room temperature
22 under nitrogen for 24 hr. The m~xture was concentrated at reduced pressure to dryness
23 An ether solution of the residue containing petroleum ether was washed with water
24 followed by dilute cold hydrochloric acid. The aqueous solution was separa~ed, made
2S alkaline with dilute cold sodium hydroxide and extracted with methylene chloride. The
26 methylene chloride solution was dried over anhydrous sodium sul~ate and concentrated at
27 reduced pressure to dryness. The residue crystalli~ed from ~ mixture of ether and
28 petroleum ether to give a tan solid, mp 121-123 C. Recrystallization frorn ether gave tan
29 prisms, mpl2~-125C.
r ~1711 ' ~ - 29 -
~ it;~ I
mple ~6
2 8-Chloro-5~ hyc3ro~-~propyn-3-yl)-1-~hcnyl-3 H-2-benz~zeplne hydrochioricle
3 A mixture of 40 ml oE 98~6 dicthylnmine, 44.3 rn~ (0.25 mmole) of p~lladium
4 chloride, 131.Z mg ~0.5 mmole) of triphenylphosphirle, 47.6 mg ~0.25 mmole) of cuprous
S iodlde, 3.5 g ~10.5 mmole) of ~-chloro-5-brom~l-phenyl-3H-2-benzazepine und 5 rnl of
6 propargyl alcohol was stirred ~t room t~mperature under nitrogen for 7 hr. The mixture
7 W85 concentr~ted at reduced pressure to dryness. The r esldue was dissolved in methylene
8 chloride, and washed with wRter. The methylen0 chlorid~ solution was dried over
9 snhydrous sodium sulfate and concentrated at reduced pressur~ to dryness. Purlficatlon
by column chromatography (silica gel, 20 g; eluent 20% ether in methylene c hloride) gave
Il ¦ a ~olor~ess oil. The oil was dissolved in an excess of methanolic hydrogen chloride and
12 concentrat~d at reduced pressure to dryness. The residue crystallized from a mixture of
13 ¦ methanol and ether to give a tan solid, mp 228-229 C dec.
14
~5 1 ~m~L~
16 ¦ 8-Chloro-5~ dihydroxy-2-hexen-4-yn-3-yl)-1-phenyl-3H-2-benza~epine
17 1 A mixture of 40 ml of 9896 diethylamine, 44.3 mg (0.25 mmole) of pslladium
18 ¦ chloride, 131 mg (0.5 mmole) of triphenyl phosphine, 47.6 mg (0.25 mmole) of cuprous
19 ¦ iodide, 3.5 g (10.5 mmole) of 8-chloro-5-bromo-1-phenyl-3H^2-benzazepine and 5 ml of
20 1 propsrgyl alcohol was stirred at ~oom temperature under nitrogen ~or 24 hr. The mixture
21 ¦ was concentrated ~t reduced pressure to dryness Th~ residue was dissolved in methylene
22 chloride, and washed with water. The methylene chloride solution was dried over
~3 ¦ anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification
21~ by column chromatography (20 g silica gel; eluent, 23% ether in methylene chloride) gave
2S an oil which crystallized from a mixture of tetrahydrofuran and ether to give tsn prism,
26 mp 210-211 C deG
27
_30_
~..".
~.,, . ~
o~
I The hydrochloriflc snlt was preparod by clissolving the end product in an excess of
2 methanolic hydrogen chloride and isolated by precipitating the ~alt by the addition of
ether. Recrystallization from a mixture of methanol and ether gave the hydrochloride
4 salt as cre~m colored plates, mp 290 C.
6 Example 28
7 8 Chloro-S~ propyny~ -phenyl-3H-2-belnzazepine hydrochloride
8 A stirred mixture of 180 ml of '38% diethylflmine (degnssed with nitro~en), 7.2 g
9 (21.B mmole) of 8-chloro-5~bromo-1-phenyl-3H-2-benzazepine, 0.4 g (0.6 mmole) of
dichlorobis(triphenylphosphine)palladium ~), 0.1 g tO.5 mmole) of cuprous iodide w~s
11 saturated with propyne nnd stirred under an atmosphere of propyne for 23 hr. The mixture
12 was concentrated at reduced pressure to dryness. The residue was dissolved in methylene
13 chloride and washed successively with dilute sodium carbonate and water. The methylene
14 chloride solution was dried over anhydrous sodium sulPate and concentrated at reducst
pressure to dryness to give an oil. A methylene chloride solution oP the oil WQS dilutec
1~ with an excess ethanolic hydrogen ,chloride, concentrated at reduced pressure an
17 crystallized from a mixture of ethanol and isopropanol to give the hydrochloride salt as
18 yellow solid, mp 206-207C dec. Recrystallization from Q mixture oP ethanol and ethe
ZO gave the salt as pale yellow prisms, mp 210-211 C dec.
23 .
2S
26
27
P ~175 -
I ~zs
2 8-Chloro-S~ phthalimido-2-pro
3 ~_ ~--y!-3H-2-benzazee~
4 A mixture of 600 ml of 98~6 diethylamine, 600 ml of methylene chloride, 24 g (65
mmole) of 8-chlor~5-bromo-1-phenyl-3H-2-benzazepine hydrochloride, 7.2 g (10 rnmole) of
6 dichlorobis(triphenylphosphine)palladium (Il), 1.8 g (9.5 mmole) of cuprous iodide and 20 g
7 (0.11 mole) of propargyl phthalimide was stirred at room temperature und0r nitrogen for
8 5.5 hr. The mixture was conoentrated at reduced pressure to dryne~s and the residue w~
9 dissolved in methylene chloride. The methylene chloride solutlon was washed with water,
10 dried over ~nhydrous sodium sulfate and concentrated at reduced pressure to dryness.
I l Purification by column chrom~tography (sil~ca gel, 450 g; eluene~ methylene chloride
12 gradient to 10% ether in methylene chloride) gave as the first product band the propyn-3-
13 yl compound as a tan solid, mp 177-178 C. Recrystallization from a mixture Or methylene
14 chloride and ether gave tan prisms, mp 185-186 C.
16 A second product hand gave the hexen-4-yn-3-yl compound as an off-white solidJ
2 mp 185-190 C. 9 ecryl~t /~tion ~rom .cetonitrile gave grey needle:, mp 19S-199 C.
21
24
26 .
27
r ~173 ' ~ -- 32 -
~ ~ '7~
l~xample 3 0
2 8-Chloro-1-(2-fluor?~h~nvl)-S-(I-phthalimido-2=~roDyn-3-yl)-3H-2-benzazepine
3 A mi:~ture of 40 ml of 98% diethylamine, 50 rnl of methylen~ chloride, 0.6 g (0.9
4 mmole) dichlorobis(triphenylphosphine)pall~dium (Il), O.lS g (0.8 mmole) cuprous iodide, 3.B
g (10.8 mmole) of 8-chlor~5-brorno-1-(2-fluorophenyl)-3H-2-ben~zepine and 3 g (16
6 mmole) of propargyl phthalimide w~s stirred under nitrogen at roorn tempernturc for 24
7 hr. The mixture was concentrated at reduced pressure to dryness. Thc residue was
8 dissolved in methylene chloride and waslhed with water. The methylene chlorid~ solutio
9 wns dried over anhydrous sodlum sulfate und concentrated at reduced pressure to dryness~
Purification of the residue by column chromatography (sillca gel, 50 g; eluent, methylena
11 chloride gradient to 5% ether in methylene chlorlde) gave as the ma~or fraetion a colorles
12 solld. RecrystalllzRtion from ether gave colorless needles, mp 164-16$~C.
13
14 Example 31
8-Chlor~5-(N-me~ ~ ~ ~drochloride
16 A mixture of 3.7 g (10 mmole) of 8-chlor~5-bromo-1-phenyl-3H-2-benzazepine¦
17 hydrochloride, 0.4 g (0.~ mmole) of dichlorobis(triphenylphosphine)palladium (Il), 0.2 g (1¦
18 mmole) cuprous iodide and 2 ml (excess) of 97% N-methylpropargylamine in S0 ml of 98~o
19 diethylamine and 100 ml OI methylene chloride was stirred at room temperature under
nitrogen for 24 hr. The reaction was concentrated at reduced pressure to dryness. The
21 residue w~s dissolved in methylene chloride and extrflcted with dilute ice cold
22 hydrochloric acid. The acid extract was made alkaline with dilute ice cold sodium
23 carbonate and extracted with ether. The ether solution was dried over anhydrous sodium
24 sul~ate and concentrated at reduced pressure to dryness. Purification of the residue by
2S column chromatography (silica gel, 20 g; eluent, 20% ether in methylene chloride followed
2~ by 10% meth~nol in methylene chloride) gave from the latter eluent an amber oil. The oil
27 was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduce
28 pressure to dryness. The residue crys$allized from isopropanol to ~ve end product whic~
29 when recrystaUized from isopropanol gave tan crystals, mp 169-175~C dec.
r ~17a 1~
~-,~r
~ 7~
Exam ple 3 2
2 8-Chloro-5~ amino-?-proD!Jn-3yl)-l-ph~nyl-3H-2-benzazepine dihydrochlor~de
3 A mixture of 5 g (11.1 mmole) of 8-chloro-S-(I-phthalimido-2-propyn-3~yl)-1-phenyl-
4 3H-2-benzazepine, 100 ml of ethnnol and 20 ml of ~0% aqueous methylamine was stirred at
5 room temperature for I hr, poured into icc water and extracted with ether. The ether
6 solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure t
7 dryness. The residue was dissolved in an excess of methanolic hydrogen chloride an
8 concentrated at reduced pressure to dryness. The residue crystalllzed from a mixture of
9 ethanol and isopropanol to give a tan solid, mp 2~7-243C. Recrystallization from a
mixture of ethanol and ether gave tfln prisms, mp 247-248 C.
11 .
12 Exnmple 3 3
13 8-Chloro-S~ amino-2-propyn-3-yl)-1-(2-fluorophellyl)-3H-2-benzazepine dihydrochloride
14 A mixture of 1.3 g (2.9 mmoles) of 8-chloro-5~1-phthalimido-2-propyn-3-yl)-1~2-
~luorophenyl)-3H-2-benzazepine, S0 ml of ethanol and 10 ml of 40% aqueous methylamin
16 was stirred at room temperature for 1 hr. The mi2~ture was poured into ice water and
17 extracted with ether. The ether solution was clried over anhydraus sodium sulfate and
18 concentrated at reduced pressure to dryness. The residue was dissolved in an excess o
19 ethanolic hydrogen chloride and the resu}ting salt precipitated by the addition of ether tc
give an off-white solid, mp 211-216 C. Recrystallization from a mixture of methanol and
23 ~ ~ ether 6cve gr6Y needl , mp 216-218 C deo.
24
26
27
~ 7~'
~ ~
.7~
Exatnple 34
, ... _ . .... .... .
5-Chloro-2-iodobe~zo~he~one
A mix~ure of 76 g (1.1 mole) of soclium ni-tri-te and 450 ml
of sulfuric acid was hea-ted on a s-tea;~n bath to _a 80 until
complete solution was achieved. The solution was cooled to 30
and 232 g (1.0 mole) of 2-amino-5-chlorobenzophenone was added
in por-tions keeping the temperature between 30 and 40. The
mixture was stirred for l hr and then slowly poured into 3 L of an
ice and water mixture. The solution was filtered through Hy-Flo
and to the stirred filtrate was added slowly a solution oE 200 g
(1.83 mole) of sodium fluoborate in 800 ml of water. The resulting
precipitate was collected by filtration and washed with water
(2xlO0 ml) to give a moist white solid.
The moist 2-benzo~1-4-chlorobenzenediazonium fluoborate
was slurried in 3 L of water, and a solution of 332 g (2 moles) of
potassium iodide in l L of water was added dropwise. The mixture
was s-tirred at room temperature for 4 hr and the resulting precipi~
tate was collected by filtra-tion. The crude product was added to
1 L of boiling ether, filteredt and dried with anhydrous sodium
sulfate. The ether solution was concentrated to 500 ml and
the addition of lO0 ml of petroleum ether gave end product. A
small amount of end product was recrystallized from a mixture of
ether and petroleum ether to gi~e light yellow prisms, mp 80~82.
-35-
-~..~'
hxa~ple 35
S-Chloro-2~-f luoro-2-ioclobenzoph.enone
_ _ _ _ _ . .. __ _.. _ .. _ _. . . .. _ .. ... . _. . _.. ..
The p~eparation of 5-ch,loro-2~-fluoro-2-iodobenzophenone
was conducted in the same manner as the preparation o~ 5-chlo.ro-
2-iodobenzophenone to give the end product as light yellow prlsms,
mp 78-81.
Exam~l'e 36
2', 5-D_ch or -2_10~obenzoph none
The preparation o:E 2'-5-dichloro-2-iodobenzophenon.e was
conducted in the same manner a.s the prepara-ti.on of 5-chloro-2-
iodobenzophenone to give the end produc-t as liyht yellow prisms.,
mp 64-66.
Ex'ample 37
2'-Chloro-:2-iodobenzophenone
. _ ___ . .. ..
The preparation,o~ 2l-chloro-2-iodobenzophenone was con-
ducted in the same manner as 5-chloro-2-iodobenzQphenone to gi~e
th.e end product as pale yellow pr,isms, mp 62-64.
'~ ~ 36-
J~i
Example 38
1 ~ Chloro-2-benzo~l~henyl~l-3-~lthali~ldo~ro~ne
_ _._._ ___._ ____ .. ~__ _. _. __ ._ ._ .. _ _. ~ . __. _ _ . __ .. _ .. . __ . _ .. ,_ _. _~ _, .. _, _ _._._ _ _ ._ . _, .. __ . __
A mixture of 0.71 g (4.0 ~mole) of paLl~dium chloride,
2.1 g (8.0 ~mole) of triphenylphosphine, 0.80 g (4.2 mmole) oE
cuprous iodide, 68.8 g (0.20 mole~ of 5-chloro-2-iodobenzophenone,
200 ml of diethylamine, and 400 ml of methylene chloride was stirred
at room temperature under argon until complete solution was obtained.
In one portion, 40.0 g (0.22 mole) of N-propargylphthalimide was
added to the solution and the resulting mixture stirred for 20 hr.
The ~olatiles were re~oved at reduced pre~sure and -the residue
was tritura-ted with 200 ml of iospropanol. The resulting Precipi-
trate was collected by filtra-tion to gi~e crude end product. Recry-
stallization from acetone gave cream colored prisms, mp 148-150C.
Example 39
___
1~~4-Chloro-2`-(2-flourobenzoyl)phenyl~ -3-phthalimidopropyne
.. . .. _ . . _ . ~
The preparation of 1-[4-chloro-2-(2-fluorobenzoyl)
phenyl~- 3-phthalimiaopy~px~e was conducted in a similar manner
as the preparation of l-t4-chloro-2-benzoylphenyl3-3-phthalimido~
propyne to give cream colored prisms, mp 158-I61C.
-37-
7~
~ Le 40
1-~4-Ch oro-2-(2--chlorobe~zoyl)~he~y-~J -3-phthaL imid p~ap~e
The prepara.~io~ of l-L4-chloro-2-~2-chlorobe~zoyl)
phenyl3-3-phthalimidopropyne was cond~lc-ted in the same manner as the
prepara-tion of l-~4-chlo~o-2-benz.oylphen.yl~-3-phthalimidopropyne
to give cream colored prisms, mp 144-'L45C.
Example 4.l
l-r2-(2-chlorobenzoyl)phen ~ -3 phthal:1 _ o-.r_ yne
The preparation of 1-~2-(2-chlorobenz.oyl)phenyl
-3-phthallmidopropyne was conducted in the same manner as the prep-
aration.of l-C4-chloro-2-ben,zoylphen~lJ-3-phthalimidQpropyne to
gi~e cream colored prisms, mp 149-150C.
-38-
Exa~ple ~2
, .. , . . .. . ~
3-Amino-L-r2-benzoyl-4-c~loro~hen~ ro~yne
Method A. A mixture of 72 ~ (0.18 mole) of 1- L 4-chloro-
2-benzoylphenyl7 -3-phthalimidopropyne, 90 ml of 40% aqueous meth-
ylamine, and 300 mL o~ ethanol was .stirred at room temperature ~or
90 min. The mixture was diluted with 30~ ml of ether, and the
precipitate was remo~ed by filtration. The filtrate was further
diluted with 300 ml of ether, washed wi-th water and dried over
anhydrQus sodium sulfate. Concentration of -the ether solution at
reduced pressure ya~e a brown oil, which when tri-turated with
ether gave a yellow solid. Recrystallization from ether gave pale
yellow prisms, mp 68- 69C.
Method B. A mixture of 4 g (10 mmole) of 1-L4-chloro-
2-benzoylphenyl~-3-phthalimidopropyne and 0.6 g (16 mmole) of 85%
hydrazine hydrate in 150 ml of 95% ethanol was refluxed for 5.5
hr. The mixture ~as cooled and the insoluble precipitate removed
by filtration. The filtrate was diluted with water, acidified with
hydrochloric acid and extracted with ether. The aqueous solution
was basified with dilute sodium carbonate and extracted with
methylene chloride. The methylene chloride solution was dried
o~er anhydrous sodium sulfate and concentrated at reduced pressure
to dryness. The residue was crystallized from a mixture of ether
and petroleum ether to gi~e a pale yellow solid, mp 68-69 C which
was identical in every respect to an authentic sample.
The hydrochloride salt of 3-amino~ chloro-2-benzoy-
lphenyl~propyne was prepared by the addition of an excess of 6%
methanolic hydrogen chloxide to a methanol solution of the product
and isolated by precipitating the salt with the addition of ether.
Recrystallization from a mixture of methanol and ether gave the
hydrochloride as white needles, mp 173-174 C.
- -39-
~ 3
E~ka,mple 43
_ ~ 4- ~Loro-2_2=~.luoroben oyl)pheny1 ~ p~`ne
~ ethod A.. The preparation of 3-amino-1- C~-chloro-2-(2-
fluorobenzoyl)phenyl~ -propyne was conducted in the same manner
(~ethod A) as the prepa.ration of 3-amino-1-~4-c~loro--2-b0nzoylphenyl]
propyne to give yellow prisms, mp 89-91C.
eth'od B. A mixture of 50 g of 1-~4-chloro-2(2-fluoro-
benzoyl)phenylJ ~3-ph-tha,limidopropyne, 50 ml of 40~ aqueous methyla-
mine and 150 ml of dimethylformamide was stirred at room -temper-
ature for 25 min. Dropwise 500 ml oE water was added, and the
resulting precipita-te was collected by filtration~ The precipitate
was dissol~ed in methylene ch.loride, dried over anhydrous sodium
sulf`ate, and concentrated at reduced pressure to give a pale yellow
solid. Recrystallization from ether gave pale yellow prisms, mp
89-91C which was identical in.every respect to an authentic
sample.
Method' C. A m,ixture of 400 g (0.96 mole) o~ 4-chloro-
2-(2-flùoroben,zoyl)-phenyl~ --3-phthalimidopropyne, 1.3 L of ethanol
and 300 ml of 40% aqueous methylamine was stirred at room tempera-
ture for 2 hr. Dropwise 2.8 1 of water was added, and the
resulting precipitate was collected by filtration to give a pale
yellow soli.d, mp 79-80C. Recrystallization from ether gave
pale yellow prism.s, mp 89-9leC which wa.s identical in every respect
to an authentic sampl,e~
a~
- -40-
Exa~ple 4 4
3-Amino~ (l.-chloro-2~(2-chlorobenzQyl)phenyl) p~ ne
The prep~ation of 3-amino-1-Z4-chloro-2-(2-chlorohen-
zoyl)pheny~ propyne was conducted in the same manner as the prep-
aration of 3 amino~ 4~chloro-2-berlzoylphenyl~ propyne LMethod
to give pale yellow prisms, mp 81-82~C.
Ex ~ l5
3-Amino-1-:~2'~(2 'chloroben'z'o'y_ ~heny ~ propyne
The prepa.ration of 3-amino-1-~2-(2-chlorohenzoyl)
phenyl~ propyne was conducted in the same manner as the preparation
of 3-amino-1~4-chloro-2-benz.oylphenylJ propyne LMethod A3to give
an amber oil..
The hydroch,loride salt o~ 3-amino~ (2-chloroben~oyl~
phenylJ propyne was prepared by the addition of an excess of 6~
methanolic hydrogen chloride to a methanol solution of the product
and isolated by precipitating the salt by the addition of ether.
Recrystallization from.a mixture o~ methanol and ether gave the
salt as while needles, mp 160-162 C.
-41-
ll A~ 7 ~3 ~ ~
¦ F.~am~e 4 6
2 ¦ TABLET FORMULATION (Wet granulation)
3 ¦ Item In~redientsm~/tablet ~m~/tablet
4 ¦ 1. 8-chloro-1-phenyl-3H- 1 S 10 50
S ¦ 2-benzazepine-2-oxide or
6 ¦ 3-L^8-chloro- 1-(2-fluor~
I phenyl)-3H-2-benzazepin-
7 1 5-yl7-~-propyn- l-amine
8 ¦ 2. Lactose l9S 230 264 263
9 13. Modified Starch 12.5 lS 17.520
10 ¦ 4. Pregelatinized Starch 12.S IS 17.S 20
I l l 5. Cornstarch 25 30 3S 40
12 ¦ 6. Magnesium Stearate 4 S 6 7
13 ¦ 7. Distilled Water q.s. _ _ __
141 _ _ .
¦ Weight of tablet2S0 mg 300 mg 3S0 mg400 mg
16 1
17 ¦ Procedure:
18 1. Mix items 1-5 in a suitable mixer.
19 2. Granulate with sufficient distiiled water to proper consistency. hlill.
20 3. Dry in a suitable oven.
21 4. Mill and mix with magnesium stearate.
23 5. Compress on a suitable press equipped with appropriate punches.
2S
26
27
.
r~l7~-
1 ¦ Exarn~7
'2 ¦ TA~LET FORhlULATlON (Direct cornpression)
3 ¦ Item ln~!edients ~ablet ~ ~ m~/tablet
4 1 l. 8-chlor~l-phenyl-3H- 1 S 10 S0
5 ¦ 2-benza~epjne-2-oxide or
6 ¦ 3-Q~-chloro- 1-(2-fluoro-
l phenyl~3H-2-benza~epin-
7 1 S-y~-2-propyn-l-amine
8 ¦ 2. Lactose 127 155 . S 182 206
9 ¦ 3. Microcrystalline Cellulose40 50 60 80
¦ 4. Direct Compression Starch 10 12 IS 20
I ll S. ~ornstarch 20 2S 30 40
13 6. Magnesium Stearate 2 2.S 3
14 Weight of tablet 200 m~2S0 m~ 300 n8 400 rn8
lS
l 6 Procedure:
_ .
17 1. Mix items l-S in a suitable mixer for I to lS minutes.
18 . 2. Add magnesium stearate and mix for S minutes.
l9 3. Compress on a suitable press equipped wi~h appropriate punches.
21
- ~3 _
~..,.. .
E~xample - 4 8
2 CAPSULE FORMULATION
3 Item In~redients~let ~ ~8~ m~/tablet
_
4 I . 8^chloro- 1-phenyl-3H-1 5 l0 50
2-ben~azepine-2-oxide or
6 ~B-chloro- 1-~2-fluoro-
phenyl)-3H-2-benzazepin-
7 5-yJ7-2-propyn- l-amine
8 7. Lactose 149 182.5215 2S0
9 3. Cornstarch 40 50 60 80
10 4. Talc 8 l0 12 16
Il 5. Magnesil~m Stearate 2 2.5 3 4
12 . . _ _ .
Capsule fill welght 200 mg250 m8 300 mg 400 mg
14
15 Procedure:
16 1. Mill items 1, 2 and 3 in a suitable mixer. Mill.
17 2. Add 4 and S and mix well.
Z0 3. Encapsulate on sl able equipmene.
2223 ''
225
26 .
27
l .
r~l7~
.
