Note: Descriptions are shown in the official language in which they were submitted.
3937
RAN 4008/299
The present invention relates to compounds of the
general formula
,~,
X~N~
()n
[3
wherein X and ~ each are hydrogen, halogen having
an atomic number not greater than 35 or trifluoro-
methyl and n is 0 or 1.
These compounds are useful as intermediates in the
production of 2-benzazepines, compounds of pharmacological
activity.
More particularly, the present invention relates
to a novel process for preparing the compounds of
formula I, above, and to novel intermediates for their
production.
Bt/kn 28.12.1979
llZ89;~7
-- 2 --
In accordance with the process aspect of the
present invention, the compounds of ormula I, above,
are prepared by treating a compound of the general formula
~ ~ ==C -CH2--Z
r~ ~
X~=O I I
S wherein X and Y are as above and Z represents
a hydroxyamino, amino or protected amino group
with a mercuric salt under acidic conditions or with a
strong acid in the presence of water, if Z is a protected
amino group, splitting off the protecting group and, if a
compound of formula I wherein n is O is obtained, oxidizing
this compound, if desired, to a compound of formula I,
wherein n is 1.
In its main product aspect, the present invention
provides compounds of the general formula II, above, and
of the general formula
8937
-- 3
~C--CH;~ Z '
X~=O l l l
wherein X and ~ are as above and Z' represents
a hydroxy group or a leaving group.
The compounds of formulae II and III are useful
as intermediates in the production of 2-benzazepines,
compounds of pharmacological activity.
As used herein, the term "halogen" or "halo" means
the three forms chloro, bromo or fluoro. The term "protected
amino group" includes acylated amino groups such as phthal-
imido, carbobenzoxyamino, tert. butyloxycarbonylamino,formylamino, acetylamino, trifluoroacetylamino and the
like.
The term "leaving group" includes alkyl and aryl
sulfonyloxy groups such as methanesulfonyloxy and toluene-
sulfonyloxy, bromo, chloro and the like.
--4--
The present invention is illustrated in more detailby the following Reaction Schemes:
Scheme 1
X~
~ IV [~Illa
I
~NHOH ~ SO2CH3
XJ~ ~_ X~O
~ ila ~ b
X~> ~N`C H
~ lla ~ V
Z8937
Scheme 2
X ~ X~
IV I Ib
/ ~ O
I~ VI
~ 3--~
~J l,b
` ~lZ8937
S cheme 3
N~13 ~H2
IIb ¦ IIc
x~?
[3~ Ib
X~ ~ X~
~ ~ Ia ~ VII
`- ~128937
wherein X and Y are as above.
Scheme 1
IV ~IIIa
The compound of formula IIIa can be produced by
reacting the compound of formula IV with propargyl alcohol
in the presence of a palladium II salt such as palladium
chloride or acetate, an organophosphine, for example,
triphenylphosphine, cuprous iodide and a tertiary or,
preferably, secondary amine, such as, diethylamine or
diisopropylamine. The reaction solvent may be the amine
itself, e.g., diethylamine, a halogenated hydrocarbon,
e.g., methylene chloride, dimethylformamide or an ether
solvent. The reaction temperature may range from about
0 C to about 70 C with ambient temperatures as preferred.
The presence of cuprous iodide is mandatory if the reaction
is carried out at room temperature or below whilst this
is not the case if the reaction is carried out with heating.
The presence of the organophosphine is not absolutely
necessary but highly advantageous. Instead of the palladium
salt plus the organophosphine an appropriate complex such
as dichloro bis (triphenylphosphine) palladium II can also
be utilized.
'
The starting material of formula IV may be produced
; by diazotizing the corresponding known aminobenzophenone
~- using sodium nitrite in sulfuric acid and isolating the
llZ8937
-- 8 --
salts by precipitating the respective tetrafluoroborate
salts which are thereafter slurried in water and treated
with aqueous potassium iodide to give the iodobenzophenone.
These reactions are carried out utilizing methods known in
the art.
IIIa ~ IIIb
The compound of formula IIIa can be reacted with
methanesulfonyl chloride in the presence of a tertiary
amine, such as, triethylamine, and in the presence of an
organic solvent, such as, a halogenated hydrocarbon, e.g.,
methylene chloride or toluene or diethyl ether. The reaction
can be run between about -78 C and room temperature with
about 0 C as preferred. Compounds corresponding to those
of formula IIIb but which contain a suitable leaving group
other than mesyloxy can also be prepared starting from
compounds of formula IIIa by methods known per se, e.g.,
by means of toluenesulfonyl chloride, thionyl chloride,
phosphorus tribromide and the like.
IIIb ~ IIa ---~Ia
The compound of formula IIIb or an analog thereof
containing a suitable leaving group other than mesyloxy
is reacted with hydroxylamine. This is conveniently
effected in a Cl to C4 alcohol solvent at a reaction tem-
perature of from about 0 C to room temperature, with
~128937
about room temperature as preferred. The isolated inter-
mediate compound IIa can thereafter be reacted with a
mercuric salt, such as the sulfate, chloride, acetate,
trifluoroacetate, a sulfonate (including salts with sul-
fonic acid groups containing ion exchangers) in the presenceof an acid such as carboxylic acids or dilute or concen-
trated mineral acid and expediently in the presence of an
inert organic solvent. Thus, the compound of formula IIa
can be reacted with a mixture of mercuric sulfate and a
Cl to C5 carboxylic acid, e.g., formic or acetic acid in
an inert solvent, such as, a halogenated hydrocarbon, e.g.,
methylene chloride. The reaction temperature ranges from
about -10 C to room temperature with about 0 C to 5 C
as preferred. Alternatively, the compound of formula IIa can
be treated with a strong acid in the presence of water,
e.g., with concentrated sulfuric acid at from about -10 C
to room temperature with about 0 C being preferred.
Ia ~ V
The compound of formula Ia can then be reacted with
dimethylformamide dimethylacetal in an inert solvent, such
; as, a halogenated hydrocarbon, e.g., methylene chloride,
or dimethylformamide or high boiling ethers. The reaction
temperature may range from about 0 C to 100 C with room
temperature as preferred.
-` 1128937
-- 10 --
Scheme 2
. .
IV ~IIb
The compound of formula IV can be reacted with
propargyl phthalimide in the presence of palladium chloride,
cuprous iodide, an organophosphine, e.g., triphenylphosphine
and a secondary amine, such as, diethylamine or diisopropyl-
amine. The solvents and reaction conditions are as
previously disclosed for step IV ~IIIa. Compounds
corresponding to those of formula IIb but which contain a
suitable protected amino group other than phthalimido can
also be prepared in a similar manner starting from compounds
- of formula IV by means of e.g. N-carbobenzoxy propargylamine
or corresponding N-formyl, N-tert.butoxycarbonyl, N-acetyl or
N-trifluoroacetyl compounds.
IIb ) VI
The compound of formula IIb or an analog thereof
: containing a suitable protected amino group other than
phthalimido can then be subjected to reaction conditions
as described for step IIa ~ Ia, above. Thus it can be reacted
with a mixture of mercuric sulfate and a Cl to C5 carboxylic
acid, e.g., formic or acetic acid, in the presence of a
halogenated hydrocarbon solvent, e.g., methylene chloride,
or an inert ether. The reaction temperature may range from
about o C to room temperature with about 0 C as preferred.
;
1128937
-- 11 --
Alternatively, the compound of formula IIb or an analog
thereof containing a suitable protected amino group other
than phthalimido can be treated with concentrated sulfuric
acid at from about -10 C to room temperature with about
0 C being preferred. The compounds of formula VI and
analogs thereof containing a suitable protected amino group
other than phthalimido also form part of the present invent-
ion. They are useful as intermediates in the production
of 2-benzazepines, compounds of pharmacological activity.
VI ~ Ib
In order to obtain a compound of formula Ib, the
protecting group is split off from a compound of formula VI
or an analog thereof containing a suitable protected amino
group other than phthalimido.
A compound of formula VI is expediently reacted
; with a primary alkyl amine, e.g., methyl or ethylamine in
a Cl to C4 alcohol solvent. The reaction temperature may
range from about 0 C to room temperature with room
- temperature as preferred.
An alternate method to produce the compound of -
formula Ib consists of the reaction of the compound of
formula VI with hydrazine in an inert solvent, such as,
ethanol, a mixture of ethanol and chloroform, tetrahydro-
furan or aqùeous ethanol. The reaction temperature may
vary from about room temperature to about 100 C with
reflux temperature of the selected solvent as preferred.
The product is extracted with dilute mineral acid and
thereafter recovered by neutralization.
Z8937
- 12 -
A third method which may be utilized to produce
the compound of formula Ib consists of an acid or base
hydrolysis of the compound of formula VI. For an acid
hydrolysis, a 30% solution of a mineral acid, such as,
hydrochloric, hydrobromic, sulfuric or phosphoric acid may
be utilized. The reaction is run at or about reflux tempera-
ture. For a base hydrolysis, an alkali metal hydroxide,
such as, potassium or sodium hydroxide is utilized.
Inert organic solvents, such as those set forth above may
be utilized to solubilize the ingredients. The reaction
is run at or above reflux temperature of the selected
solvent.
Methods for splitting off the protecting group from
compounds corresponding to those of formula VI but contain-
ing a suitable protected amino group other than phthalimidoare readily available to those skilled in the art.
Scheme 3
IIb ~IIc
In order to obtain a compound of formula IIc, the
protecting group is split off from a compound of formula IIb
or an analog thereof containing a suitable protected amino
group other than phthalimido under conditions as described
for step VI ~ Ib, above. Thus, a compound of formula IIb
can be reacted with a primary alkyl amine, e.g., methyl
or ethylamine in a water miscible solvent, such as, Cl to
C4 alcohols or ethers or dimethylformamide. The reaction
l~Z8937
- 13 -
temperature may range from about 0 C to 60 C with about
room temperature as preferred.
- IIc ~Ib
The compound of formula IIc can then be subjected
to reaction conditions as described for step IIa --~Ia,
above. Thus, it may be reacted with a mixture of mercuric
sulfate and a C1 to C5 carboxylic acid in the presence of
a halogenated hydrocarbon solvent or may be reacted with
concentrated sulfuric acid at from about -10 C to room
temperature with about 0 C as preferred.
Ib ~ Ia and VII
The compound of formula Ib can be reacted with a
peracid, such as, metachloroperbenzoic acid in an inert
organic solvent such as a halogenated hydrocarbon, e.g.,
methylene chloride or an ether. The reaction may be carried
out from about 0 C to 40 C with about room temperature
as preferred. The mixture of products may thereafter be
separated from one another by fractional crystallization.
Analysis by thin-layer chromatography indicates the
presence o both products.
1128g37
- 14 -
In the above scheme it should be noted that where
the term "lower alkyl" or "alkyl" is utilized, there is
meant a Cl to C7 (Cl to C4 preferred) straight or branched
aliphatic hydrocarbon chain.
The compound of formula Ib is a known intermediate
in the art and is useful in the produc~ion of various
benzazepines which are compounds of pharmacological
utility, i.e., as anxiolytics, see, for example,
U.S. Patents Nos. 4.028.381; 4.022.800 and 4.022.801.
- 10 The present process to produce Ib offers an advantage over
the prior art in that it involves fewer steps, is cheaper
and affords better yields. In a similar way as the compounds
of formula Ia, also the compounds of formula Ib can be
reacted with dimethylformamide dimethylacetal as described
for step Ia ~V.
The compound of formula V which can be prepared from
the compound of formula Ia is also a useful intermediate
for the production of 2-benzazepines, e.g., pyrimido-2-
benzazepines of the formula
~12~3937
-- 15 --
H2N
N~
,~ Vlll
¢~Y
whe~ein X and Y are as above.
The above compounds of formula VIII can be
produced by the reaction of the compound of formula V with
a compound of the formula
~ NH
NH2 ~ C IX
NH2
Any inert organic solvent such as methylene chloride,
alcohols such as methanol, ethers such as dioxane, tetra-
hydrofuran or dimethylformamide may be utilized with a
reaction temperature ranging from about room temperature
to reflux temperature of the chosen solvent with about
room temperature as preferred.
The above reaction of V with IX to give VIII does
not form a part of the present invention, but is presented
for completenesss of disclosure relating to the utility
of the compounds of formula Ia. The pyrimido-2-benzazepines
of formula VIII exhibit anxiolytic and sedative activities.
~289~7
- 16 -
The following Examples illustrate the present
invention. All temperatures are indicated in degrees
centigrade.
``~128937
-- 17 --
Example 1
5-Chloro-2-iodobenzophenone
A mixture of 76 g (1.1 mole) of sodium nitrite and 450 ml of sulfuric acid
was heated on a steam bath to ca 80 C until complete solution was achieved
5The solution was cooled to 30 C and 232 g (1.0 mole) of 2-amino-5-
chlorobenzophenone was added in portions keeping the temperature between
30 C and 40 C. The mixture was stirred for I hr and then slowly poured into 3
1. of an ice and water mixture. The solution was filtered through Hy-Flo and to
the stirred filtrate waæ added slowly a solution of 200 g (1.83 mole) of sodium
10fluoborate 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-benzoyl-4-chlorobenzenediazonium fluoborate was slurried
in 3 1. of water, and a solution of 332 g (2 moles) of potassium iodide in 1 1. of
water was added dropwise. The mixture was stirred at room temperature for 4
15hr and the resulting precipitate was collected by filtration. The crude product
was added to 1 1. of boiling ether, filtered, and dried with anhydrous sodium
sulfate. The ether solution was concentrated to 500 ml and the addition of 100
ml of petroleum ether gave the product. A small amount of the material was
recrystallized from a mixture of ether and petroleum ether to give fine yellow
20 prisms, mp 80-82 C.
Example 2
5-Chlor~2'-nuoro-2-iodobenzophenone
The preparation of 5-chloro-2'-fluoro-2iodobenzophenone waæ con-
ducted in the same manner as the preparation of 5-chloro-2-iodobenzophenone
25 to give light yellow prisms, mp 78-81 C.
:'
,, ' ' ~ ', .
. ,
'
1~289~7
-- 18 --
Example 3
2',5-Dichloro-2-iodobenzophenone
Method A. The preparation of 2', 5-dichloro-2-iodobenzophenone was
conducted in the same manner as the preparation of S-chloro-2-iodobenzo-
5 phenone to give light yellow prisms, mp 64-66 C.
Method B. A solution of 9.0 g (0.13 mole) of sodium nitrite in 30 ml of
water was added dropwise to a solution of 27 g (0.1 mole) of 2-amino-2',5-
dichlorobenzophenone in 50 ml of acetic acid and 30 ml of sulfuric acid which
was cooled to 0 C. Stirring at 0 C was continued for 1.5 hr followed by the
dropwise addition of 33 g (0.2 mole) of potassium iodide in 40 ml of water. The
mixture was stirred at 0 C for 2 hr. The mixture was diluted with water, and
extracted with ether. The ether solution was washed with 5% aqueous sodium
thiosulfate, dried over anhydrous sodium sulfate and concentrated at reduced
pressure to a brown oil. Crystallization from cold ether gave the product, mp
15 63-65 C which was identical in every respect to an authentic sample.
Example 4
2'-Chloro-2-iodobenzophenone
The preparation of 2'-chloro-2-iodobenzophenone was conducted in the
same manner as 5-chloro-2-iodobenzophenone to give pale yellow prisms, mp
20 62-64 C.
Example 5
2-Iodobenzophenone
The preparation of 2-iodobenzophenone was conducted in the same
manner as the preparation of 5~hloro-2-iodobenzophenone to give a brown oil.
25 A small amount was purified by column chromatography to give white prisms,
mp 29-31 C.
~lZ8937
-- 19 --
Example 6
1-[4-Chloro-2-benzoylphenyll -3-phthalimidopropyne
A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole)
of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide~ 68.8 g (0.21 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-propargyl-phthalimide was
added to the solution and the resulting mixture stirred for 20 hr. The volatileswere removed at reduced pressure and the residue was triturated with 200 ml of
isopropanol. The resulting precipitate was collected by filtration to give the
crude product mp 130-133 C. Recrystallization from acetone gave cream
colored prisms, mp 148-150 C.
Example 7
1-[4-Chloro-2~2-fluorobenzoyl)phenyll -3-phthalimidopropyne
The preparation of 1-[4-chloro-2~2-fluorobenzoyl)phenyl~-3-phthalimi-
dopyrowne was conducted in the same manner as the preparation of 1-[4-chloro-
2-benzoylphenyll-3-phthalimidopropyne to give cream colored prisms, mp 158-
161 C.
Example 8
1-[4-Chloro-2-(2-chlorobenzoyl)Phenyll-3-PhthalimidoproPYne
The preparation of 1-[4-chloro-2~2-chlorobenzoyl)phenyl~-3-phthalimi-
dopropyne was conducted in the same manner as the preparation of 1-[4-chloro-
2-benzoylphenyll-3-phthalimidopropyne to give cream colored prisms, mp 144-
145 C.
~28937
-- 20 --
Example 9
1-[2-~2-Chlorobenzoyl)phenyll -3-phthalimidopropyne
The preparation of 1-[2-(2-chlorobenzoyl)phenyll-3-phthalimidopro w ne
was - conducted in the same manner as the preparation of 1-[4-chloro-2-
S benzoylphenyll-3-phthalimidopropyne to give cream colored prisms, mp 149-
150 C.
Example 10
1-[2-Benzoylphenyll -3-phthalimidopropyne
The preparation of 1-[2-benzoylphenyll-3-phthalimidopropyne was con-
10 ducted in the same manner as the preparation of 1-[4-chloro-2-benzoylphenyll-
3-phthalimidopropyne to give cream colored prisms, mp 164-16S C.
Example 11
3-Hydroxy-1-[4-chloro-2-benzoylphenyll propyne
A mixture of 0.17 g (1.0 mmole) of palladium chloride, 0.5 g (2.0 mmole)
of triphenylphosphine, 0.1 g (0.5 mmole) of cuprous iodide, 15 g (43 mmole) of 5-
chloro-2-iodobenzophenone and 60 ml of diethylamine was stirred at room
temperature for 20 min. In one portion 6.0 g (107 mmole) of propargyl alcohol
was added, and the resulting mixture was stirred for 24 hr. The solvent was
removed at reduced pressure and the residue was dissolved in ether. The ether
20 solution was washed with water, dried with anhydrous sodium sulfate, and
concentrated at reduced pressure to give the product as a red oil.
Example 12
3-Hydroxy-1-[4-chloro-2-(2-fluorobenzoyl)phenyll propyne
A mixture of 0.37 g (O.S mmole) of dichlorobis (triphenylphosphine)
llZ8937
-- 21 --
palladium II, 70 mg (0.35 mmole) of cuprous iodide, 36.1 g (0.1 mole) o~ S-chloro-
2'-fluoro-2-iodobenzophenone and 12 ml (0.2 mole) of propargyl alcohol in 200 ml
of diethylamine was stirred at room temperature for 4 days. The mixture was
concentrated at reduced pressure and the residue was partitioned between ether
S and water. The ether layer was washed with water, dried over anhydrous
sodium sulfate and concentrated at reduced pressure to give the product as an
amber oil.
Example 13
3-Hydroxy-1-[4-chloro-2-(2-fluorobenzoyl)phenyl~ propyne methanesulfonate
Dropwise 13 ml (0.17 mole) of methanesulfonyl chloride was added to a
solution of 28.9 g (0.1 mole) of 3-hydroxy-1-[4-chloro-2-(2-fluorobenzoyl~
phenyll propyne and 24.4 ml (0.175 mole) of triethylamine in 300 ml of
methylene chloride which was cooled to 0 C. The mixture was washed with ice
water, cold lN hydrochloric acid, cold saturated aqueous sodium bicarbonate and
lS dried over anhydrous sodium sulfate. Concentration of the methylene chloride
solution gave a brown oil which was crystallized from ether to give a yellow
solid. Recrystallization from a mixture of ether and petroleum ether gave off-
white prisms, mp 95-96 C.
Example 14
20 1-[4-Chloro-2-benzoylphenyll-3-pmhalimidoProPan-l-one
A mixture of 20 g (50 mmole) of 1-[4-chloro-2-benzoylphenyll-3-
phthalimidopropyne, 1.0 g (3 mmole) of mercuric sulfate and 55 ml of formic
acid in 50 ml of methylene chloride was stirred at room temperature for 30 min.
The mixture was poured over ice and extracted with ethyl acetate. The ethyl
25 acetate solution was dried over anhydrous sodium sulfate and concentrated at
reduced pressure to dryness. The residue was crystallized from a mixture of
.
' ' .
~ : .
- ' ~
llZ8937
-- 22 --
ethyl acetate ~nd ether to give a colorless solld. Recrystalllzation from
acetone gave colorless prisms, mp 163-164 C.
Example 15
3-Amino-1-[4-chloro-2-benzoylPhenyll propyne
5Method A. A mixture of 72 g (0.18 mole) of 1-[4-chloro-2-benzoyl-
phenyll-3-phthalimidopropyne, 90 ml of 40% aqueous methylamine, and 300 ml
of ethanol was stirred at room temperature for 90 min. The mixture was
diluted with 300 ml of ether, and the precipitate was removed by filtration.
The filtrate was further diluted with 300 ml of ether, washed with water and
10 dried over anhydrous sodium sulfate. Concentration of the ether solution at
reduced pressure gave a brown oil, which when triturated with ether gave a
yellow solid. Recrystallization from ether gave pale yellow prisms, mp 68-
69 C
Method B. A mixture of 4 g (10 mmole) of 1-t4-chloro-2-benzoylphenyll-
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 was 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
20 chloride. The methylene chloride solution was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to dryness. The residue was
crystallized from a mixture of ether and petroleum ether to give a pale yellow
solid, mp 68-69 C which was identical in every respect to an authentic sample.
The hydrochloride salt of 3-amino-1-[4-chloro-2-benzoylphenyl~ propyne
25 was prepared by the addition of an excess of 6% methanolic hydrogen chloride
1128937
-- 23 --
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 173-174C.
Example 16
5 3-Amino-1-[4-chloro-2~?-fluorobenzoyl)phenyl] propyne
Method A. The preparation of 3-amino-1-[4-chloro-2~2-~luorobenzoyl)-
pheny~ propyne was conducted in the same manner (Method A) as the
preparation of 3-amino-1-[4-chloro-2-benzoylphenyll propyne to give yellow
prisms, mp 89-91 C.
Method B. A mixture of 50 g of 1-[4-chloro-2-(2-fluorobenzoyl)phenyll-
3-phthalimidoprowne, 50 ml of 40% aqueous methylamine and 150 ml of
dimethylformamide was stirred at room temperature for 25 min. Dropwise 500
ml of water was added, and the resulting precipitate was collected by filtration.
The precipitate was dissolved in methylene chloride, dried over anhydrous
15 sodium sulfate, and concentrated at reduced pressure to give a pale yellow
solid. Recrystallization from ether gave pale yellow prisms, mp 89-91 C which
was identical in every respect to an authentic sample.
Method C. A mixture of 400 g (0.96 mole) of 1-[4-chloro-2~2-
fluorobenzoyl)phenyll-3-phthalimidopropyne, 1.31 of ethanol and 300 ml of 40%
20 aqueous methyl~mine was stirred at room temperature for 2 hr. Dropwise 2.81
of water was added, and the resulting precipitate was collected by filtration to
give a pale yellow solid, mp 79-80C. Recrystallization from ether gave pale
yellow prisms, mp 89-91 C which was identical in every respect to an authentic
sample.
1128937
-- 24 --
Example 17
3-Amino-1-[4-chloro-2-(2-chlorobenzoyl)phenyll propyne
The preparation of 3-amino-1-14-chloro-2-(2-chlorobenzoyl)phenylJ-
propyne was conducted in the same manner as the preparation of 3-amino-1-[4-
5 chloro-2-benzoylphenyll propyne ~Method A] to give pale yellow prisms, mp 81-
82 C.
Example 18
3-Amino-1-~2-(2-chlorobenzoyl)phenyl~ propyne
The preparation of 3-amino-1-[2~2-chlorobenzoyl)phenyll propyne was
conducted in the same manner as the preparation of 3-amino-1-14-chloro-2-
benzoylphenyl~ propyne [Method A] to give an amber oil.
The hydrochloride salt of 3-amino-1-[2-(2-chlorobenzoyl)phenyll 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
15 the addition of ether. Recrystallization from a mixture of methanol and ether
gave the salt as white needles, mp 160-162 C.
ExamPle 19
3-Amino-1-[2-benzoylPhenyll propyne
The preparation of 3-amino-1-[2-benzoylphenyll propyne was conducted
20 in the same manner as the preparation of 3-amino-1-[4-chloro-2-benzoylphenyll-
propyne [Method A] to give an amber oil.
The hydrochloride salt of 3-amino-1-[2-benzoylphenyll propyne was
prepared by the addition of an excess of 6% methanolic hydrogen chloride to a
methanol solution of the product and was isolated by precipitating the salt with
llZ8937
-- 25 --
the addition of ether. Recrystallization from a mixture of methanol and ether
gave the salt as white needles, mp 157-158 C.
Example 20
8-Chloro-1~2-fluorophenyl)-3 ,4-dihydro-5 H-2-benzazepin-5-one
Method A. A solution of 14.4 g (50 mmole) of 3-amino-1-[4-chloro-2-(2-
fluorobenzoyl)phenyll propyne in 50 ml of methylene chloride was added to a
solution of 3.0 g (10 mmole) of mercuric sulfate in 50 ml of formic acid, which
was cooled to 0 C. The mixture was stirred at 0 C for 3 hr, poured over ice,
basified with ammonium hydroxide and extracted with methylene chloride. The
methylene chloride solution was dried over anhydrous sodium sulfate and
concentrated at reduced pressure to give a brown oil. The oil was dissolved in 25
ml of isopropanol and 4.8 g (S0 mmole) of methanesulfonic acid was added. The
resulting precipitate was collected by filtration to give the methanesulfonate
salt of the product as off-white crystals. Recrystallization from a mixture of
methylene chloride and isopropanol gave the methanesulfonate salt of the
product as pale yellow rods, mp 176-177 C.
A sample of the methanesulfonate salt was partitioned between
methylene chloride and aqueous saturated sodium bicarbonate. The methylene
chloride solution was dried over anhydrous sodium sulfate, concentrated at
reduced pressure and the residue was crystallized with ether. Recrystallization
from ether gave off-white prisms, mp 109-110 C.
Method B. A solution of 200 g (0.69 mole) of 3-amino-1-[4-chloro-2-(2-
fluorobenzoyl)phenyll propyne in 500 ml of methylene chloride was added
dropwise to 400 ml of concentrated sulfuric acid, which was cooled to 5 C. The
mixture was stirred at 5 C for 3 hr, poured over ice, basified with ammonium
1128937
-- 26 --
hydroxide and extracted with methylene chloride. The methylene chloride
solution was dried over anhydrous sodium sulfate and concentrated at reduced
pressure to give a brown oil. The brown oil was dissolved in 350 ml of a 2M
methanol solution of methanesulfonic acid and the salt of the product was
S precipitated by the addition of ether to give the salt as off-white rods.
Recrystallization from a mixture of methylene chloride and isopropanol gave
the methanesulfonate salt as off-white rods, mp 176-177 C which were identical
in every respect to an authentic sample.
Example 21
8-Chloro-l-phenyl-3,4-dihydro-5H-2-benzazepin-S-one
The preparation of 8-chloro-1-phenyl-3,4-dihydro-5H-2-benzazepin-S-
one was conducted in the same manner as the preparation of 8-chloro-1~2-
fluorophenyl)-3,4-dihydro-SH-2-benzazepin-S-one (Method A) to give the meth-
anesulfonate salt as off-white prisms, mp 187-190 C.
lS Example 22
8-Chloro-1-(2-chlorophenyl)-3,4-dihydro-SH-2-benzazepin-5-one
The preparation of 8-chloro-1~2-chlorophenyl)-3,4-dihydro-5H-2-benza-
zepin-5-one was conducted in the same manner as the preparation of 8-chloro-1-
(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one (Method A) to give the
20 methanesulfonate salt as colorless needles, mp 180-181 C.
Example 23
1-(2-Chlorophenyl)-3,4-dihydro-5H-2-benzazepin-S-one
The preparation of 1-(2-chlorophenyl)-3,4-dihydro-SH-2-benzazepin-5-
one was conducted in the same manner as the preparation of 8-chloro-1-(2-
25 fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one (Method A) to give a pale
~.~ Z~3937
-- 27 --
yellow solid, mp 135-137 C.
Example 24
l-Phenyl-3 24-dihydro-5 H-2-benzazepin-5 -one
The preparation of l-phenyl-3,4-dihydro-5H-2-benzazepin-5-one was
5 conducted in the same manner as the preparation of 8-chlor~1~2-fluorophenyl)-
3,4-dihydro-5H-2-benzazepin-5-one (Method A) to give the methanesulfon~te
salt as off-white prisms, mp 196-198 C.
Example 25
8-Chloro-1~2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene] -5H-
10 2-benzazepin-5-one
Method A. A mixture of 7.2 g (25 mmole) of 8-cMoro-1~2-
fluorophenyl~3,4-dihydro-SH-2-benzazepin-5-one and 50 ml of dimethyl-
formamide dimethyl acetal was refluxed for 1 hr. The mixture was-
concentrated at reduced pressure to give tan crystals. Recrystallization from
15 ether gave yellow prisms, mp 228-233 C.
Method B. A mixture of 10 g (35 mmole) of crude 8-chloro-3,4-dihydro-
1~2-fluorophenyl)-SH-2-benzazepin-5-one and 10 g (84 mmole) of dimethyl-
formamide dimethyl acetal in 10 ml of dimethylformamide was stirred at room
temperature for 12 hr. The resulting precipitate was collected by filtration, and
20 washed successively with ethanol and ether to give tan crystals which were
identical in every respect to an authentic sample.
Method C. A solution of 100 g (0.35 mole) of 3-amino-1- [4-chloro-2-(2-
fluorobenzoyl)phenyll propyne in 200 ml of methylene chloride was added
dropwise to 210 ml of 95% sulfuric acid, which was cooled to 5 C. The mixture
llZ8937
-- 28 --
was stirred at 5C for 3.5 hr. The dark, syrupy mixture was poured over 2.5 1 otcrushed ice, basified with 525 ml of concentrated ammonium hydroxide and
extracted with methylene chloride. The methylene chloride solution was
washed with water, dried over anhydrous sodium sulfate and concentrated at
reduced pressure to give a brown ~il containing 8-chloro-1~2-fluorophenyl)-3,4-
dihydro-5 H-2-benzazepin-5-one.
The oil was dissolved in 200 ml of dimethylformamide dimethyl acetal
and heated on a steam bath for 15 min. The mixture was cooled and the
resulting precipitate was collected by filtration and washed successively with
ethanol and ether. The product was air dried to give light tan crystals which
were identical in every respect to an authentic sample.
Example 26
8-Chloro-l-phenyl-3,4-dihydro~-[(dimethylamino)methylene] -5H-2-benzazepin-
5-one
The preparation of 8-chlor~l-phenyl-3,4-dihydro-4-[(dimethylamino)-
methylene]-5H-2-benzazepin-5-one was conducted in the same maMer as the
preparation of 8-chloro-1~2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)-
methylene]-5H-2-benzazepin-S-one (Method A) to give yellow prisms, mp 180-
183 C
Example 27
8-Chloro-1~2-chlorophenyl)-3,4-dihydro~-[(dimethylamino)methylene] -5H-
2-benzazepin-5-one
A mixture of 18.6 g (61 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-
dihydro-SH-2-benzazepin-5-one and 149 ml of dimethylformamide dimethyl
acetal was gently heated (ca 50 C) for 12 hr. The mixture was concentrated at
~128937
-- 29 --
reduced pressure to dryness. The residue was crystalllzed ~rom a mixture o~
ether and methylene chloride to give a yellow solid, mp 170-171C. Recrystal-
lization from ether gave yellow prisms, mp 170-171 C.
Example 28
1-(2-Chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-SH-2-benzazepin-
5-one
A mixture of 3.4 g (12.5 mmole) of 1-(2-chlorophenyl)-3,4-dihydro-5H-2-
benzazepin-5-one and 28 ml of dimethylformamide dimethyl acetal was refluxed
for 2 hr. The mixture was concentrated at reduced pressure and the resulting
solid was triturated with ether to give a tan solid, mp 155-157 C. Recyrstalliza-
tion from a mixture of methylene chloride and ether gave yellow prisms, mp
158-159 C.
Example 29
3,4-Dihydro-4-[(dimethylamino)methylene] -5H-2-benzazepin-5-one
A mixture of 5.2 g (22 mmole) of 3,4-dihydro-1-phenyl-SH-2-benzazepin-
5-one and 43 ml of dimethylformamide dimethyl acetal was refluxed for 4 hr.
The mixture was concentrated at reduced pressure to dryness. The residue was
crystallized with ether to give a yellow solid, mp 131-133 C. Recrystallization
from ether gave yellow prisms, mp 131-132 C.
Example 30
8-Chloro-1~2-nuorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide
Method A. A mixture of 6.4 g (22 mmole) of 8-chloro-1-(2-
fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmole) of m-
chloroperbenzoic acid in 350 ml of methylene chloride was stirred at room
25 temperature for 2 hr. The methylene chloride solution was washed with
,.' ,. ' '
. . . ~ - .
,
llZ8937
-- 30 --
saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium
sulfate and concentrated at reduced pressure to give a yellow oil. The oil was
crystallized from Q mixture of ether and petroleum ether to give of~-white
prisms, mp 166-168 C. Recrystallization Irom a mixture of ether and methylene
cMoride gave colorless prisms, mp 168-170 C.
Method B. A mixture of 5.8 g (16 mmole) of 3-hydroxy-1-[4-chloro-2~2-
fluorobenzoyl)phenyll prowne methanesulfonate and 50 ml of methanolic solu-
tion of hydroxylamine (from 6.1 g, 88 mmole of hydroxylamine hydrochloride) in
50 ml of tetrahydrofuran was stirred at room temperature for 13 hr. The
10 mixture was concentrated at reduced pressure and the residue was partitioned
between methylene chloride and wster. The methylene chloride solution was
dried over anhydrous sodium sulfate and concentrated at reduced pressure to
give an amber oil containing 3-hydroxyamino-1-14-chloro-2-(2-fluorobenzoyl~
phenyll propyne.
A solution of 3.4 g of the amber oil in 70 ml of methylene cMoride was
added dropwise to a mixture of 0.7 g (2.3 mmole) of mercuric sulfate and 17 ml
- of formic acid which was cooled to 0 C. The resulting mixture was stirred at
room temperature overnight, poured over ice and basified with ammonium
hydroxide. The methylene chloride solution was washed with water, dried over
ao anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow
oil. Purification by column chromatography (silica gel, 50 g; 3:1 methylene
chloride and ether, eluent) gave tan crystals, mp 165-167 C. Recrystallization
from a mixture of ether and methylene cMoride gave pale yellow prisms, mp
167-170 C which were identical in every respect to an authentic sample.
llZB937
ExamPle 31
8-Chloro-1~2-ahlorophenyl)-3,4-dihydro-5H-2-benzazePin-5-one-2-oxide
The preparation of 8-chloro-1~2-chlorophenyl)-3,4-dihydro-5H-2-benza-
zepin-5-one-2-oxide was conducted in the same manner as the preparation of 8-
chloro-1-(2-fluorophenyl)-3,4-dihydro-SH-2-benzazepin-S-one-2-oxide (Method
A) to give yellow prisms, mp 184-187 C.
Example 32
8-Chloro-1~2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene] -SH-
2-benzazepin-5-one-2-oxide
A mixture of 3.4 g (11 mmole) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-
SH-2-benzazepin-S-one-2-oxide and 26 ml of dimethylformamide dimethyl
acetal was stirred at room temperature for 12 hr. The mixture was diluted with
ether snd the precipitate collected to give a yellow solid, mp 175-178 C.
Recrystallization from a mixture of ether and ethyl acetate gave yellow
lS needles, mp 193-194 C.
~:,
Example 33
8-Chloro-1-(2-chlorophen~rl)-3,4-dihydro-4-[(dimethylamino)methylene]-SH-
2-benzazepin-S-one-2-oxide
The preparation of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(di-
methylaminc)methylene]-SH-2-benzazepin-S-one-2-oxide was prepared in the
same manner as the preparation of 8-chloro-1~2-fluorophenyl)-3,4-dihydro-4-
~(dimethylamino)methylene]-SH-2-benzazepin-S-one-2-oxide to give yellow
prisms, mp 196-198 C.
Example 34
8-Chloro-l-phenyl-3,4-dihydro-5H-2-benzazepin-S-one
~ ~'
.. ..
,
:. . . .
,, ,
llZ8~37
-- 32 --
A mixture of 2.1 g (5 mmole) of 1-[4-chloro-2-benzoylphenyll-3-
phthalimidopropan-l-one and 10 ml ot 40% aqueous methylamine in 25 ml of
ethanol was stirred at room temperature for 45 min. The mixture was poured
into water and extracted with ether. The ether layer was dried over snhydrous
sodium sulfate and concentrated at reduced pressure to dryness. The residue
~1.4 g) was purified by plug filtration (silica gel; eluent, methylene chloride).
The resulting oil was treated with a lM solution of methanolic methanesulfonic
acid to give the methanesulfonate salt of the product, mp 187-190 C., which was
identical in every respect to an authentic sample.
