Note: Descriptions are shown in the official language in which they were submitted.
1~55g~9~
The present invention relates to an improved process for
the manufacture of benzodiazepine derivatives of the general
formula
~ ~ - CO
Rl N
R2
wherein R signifies hydrogen or alkyl with up to 7 carbon atoms,
Rl s;.gnifies hydrogen, halogen or
trifluoromethyl and R2 signifies phenyl, and 4-oxides thereof.
The expression "halogen" includes the four halogens fluorine,
chlorine, bromine and iodine.
In a preferred embodiment of the process in accordance
with the invention, Rl signifies halcgen, preferably chlorin~,
.,
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.
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Especially preferred is the manufacture of 7-chloro-1,3-dihydro- - -
l-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
This invention relates to an improved process for the
manufacture of benzodiazepine derivatives of the general formula
R
~ N - C ~ I :
Rl C = N
R2
wherein R signi~ies hydrogen or alkyl with up to 7 carbon atoms, R
signifies hydrogen, halogen or trifluoromethyl and R2 signifies
phenyl, and 4-oxides thereof by cyclization a compound of the general
formula
R
~/N-co-cH2-NH-R3 ' '
l C=O IV
R2 :1
wherein R, Rl and R2 are as defined above and R3 signifies hydrogen or :~.
hydroxy the improvement which comprises preparing the compound of
formula IV by reacting a benzophenone of the general formula
R
NH
Rl ~ C=O II
R2 ~. .
wherein R, Rl and R2 are as definad above with a nitroacetic acid halide
and reducing the obtained nitroacetyl compound of the general formula
~ r - 3 - ~
,, : .
l~S5491
CO-CH2 -N02
Rl ~ C=O III
R2
wherein R, Rl and R2 are as defined above, either
a) wi~h about 6 g. atom of zinc per mol. of compound III in order
to obtain a compound of ~ormula IV, wherein R3 is hydroxy, or
b) with about 10 g. atom of zinc per mol. of compound III or
catalytically in order to obtain a compound of formula IV, wherein R3 is
hydrogen.
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The reaction Or a compound o~ the general fQrmula II
with the acid halide is preferably carried out in an inert
organic solvent(such as hydrocarbons, e.g. benzene, toluene
and the liken chlorinated hydrocarbons such as chloroform,
methylene chloride and the like, ethers such as dioxane and
the like)and at temperatures from -5 to 50C.
It is expedient to use nitroacetyl chloride as the
nitroacetic acid hali~e. ~his nikroacetyl chloride can be
obtained expediently by the reaction of nitroacetic acid with
phosphoru~ pentachloride~ whereby the mixture o~ nitroacetyl
chloride and phosphorus oxyehloride can be used directly for
the acylation.
~he reduction of a compound of the form~la III can be
carried out~ e.g~ with zinc9 expedien~ly in acidic or neutral
medium and at temperatureR rrom -20~ to 100C. Depending on
the reaction condition~, i.e, the reaction time or the amount
of acid and zinc used, there is obtained a hydro~lamine
deri~ativ~ of the general formula
0-CH2-NH~H
Rl ~ ~ IV~
R2
wherein R~ Rl and R2 are as de~ined above
,:
or an amine of the general formula
...
. .
i;S4~l
H2-NH4~ ~Vb
wherein R, Rl and R2 are as defined above.
Ilfq
Amines of the formula ~ can also be obtained from the corres-
ponding nitro derivatives o~ the ~ormula III by catalytic
reduction, e.g. with palladiumJ platinum and the like.
The reduction of a compound of the formula III to a
hydroxylamine or amine derivative is expediently effected in
a solvent such as hydrocarbons, e.g. benzene, toluene,
chlorinated hydrocarbons, e.g. methylene chloride, alcohols
such as methanol, ethanol, ethers, glacial acetic acid,
aqueous acetic acid (either alone or in admixture with other
solvents, e.g. the solvents ~ust mentioned).
rme cyclisation of a hydroxylamine or amlne derivative
can be ef~ecked in acidic or alkaline medium in a known manner.
~:
Compounds of the formula I~ and N~can be cyclised
without isolation o~ same ~rom the reaction mixture.
~ .
Benzodiazepines of formula I and l~-oxides thereof are
known compounds which are known to be userul as sedatlves,
anticonvulsants and muscle relaxants.
- 5 -
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.
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The following Examples illustrate the process in accor-
dance with the invention. All temperatures are given in C.
Example
10.5 g (0.1 mol) of nitroacetic acid are suspended in
50 ml of dry chloroform and 23 g (0.11 mol) of phosphorus
pentachloride are added at -20. The reaction mixture is
stirred for 30 minutes at -20 to -10. The clear solution
so-obtained~ together with 200 ml of a 15 ~ sodium carbonate
solution is added dropwise at 2-5 to a strongly stirred
solution of 11.6 g (0.05 mol) of 2-amino-5-chlorobenzophenone
in 100 ml of chloroform. By a rapid addition of the acid
chloride mixture, it is achieved that at no point in time does
the reaction mixture react alkaline. After effecting the
addition, the mixture is stirred at 5-10 for a further 15
~5 minuteæ. The chloroform phase is then separated, washed with
water, drled over sodium sulphate and thoroughly evaporated
(~ 30 ). The orystalline residue is suspended in ether and
filtered off under suction to give 2'-benzoyl-4'-chloro-2-
nitroa¢etanllide of meltlng point 163-166 (decomp. and
conversion into 6-chloro-~-nitro-4-phenylcarbostyril).
4 g of zinc dust are introduced in one portion into a
solution of 3.2 g (0.01 mol) of 2'-benzoyl-4'-chloro-2-nitro-
acetanillde in 100 ml of methylene chloride and 4 ml of
.
.. ...
.. . . . .. . . . . .
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glacial acetic acid with stirring under nitrogen. The
temperature increase results in a vigorous reflux of the
solvent. After cessation of the exothermal reaction, the
mixture is stirred for a further 10 minutes and made alkaline
with dilute ammonia. The methylene chloride phase is dried
over anhydrous sodium sulphate, filtered and evaporated in
vacuo. The residue is taken up in ether and there crystallises
2'-benzoyl-4'-chloro-2-hydroxylaminoace~anilide which, after
recrystallisation from alcohol, melts at 125-128. This product
can be converted, for example by t~eatment with alcoholic hydro-
chloric acid, into 7-chloro-1,3-dihydro-5-phenyl-2H-l,~-benzo-
diazepin-2-one 4-oxide of melting point 231-233.
Example 2
. .
The nitroacetic acid chloride is prepared from 10.5 g
of nitroacetic acid and 23 g of phosphorus pentachloride accord-
ing to the proceduro described in Example 1. This acid chloride
is added dropwise at 5-10, together with 200 ml of a 15 % soda
solution, ~o a strongly stirred solution o~ 12.3 g ~0.05 mol)
of 5-chloro-2-methylaminobenzophenone in 50 ml of chloro~orm.
At the end of the addition, the mixture is stirred for a ~urther
20 minutes at 5-10. The chloroform phase is separated, washed
with water, dried over sodium sulphate and evaporated in vacuo
at 30. The residue is crystallized from ether. After
recrystallisation from methylene chloride/hexane,
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. .. ... , ., . , . : .
. . . . .. .. .
~La35549~
there is obtained 2'-benzoyl-4'-chloro-N-methyl-2 nitro
acetanilide of melting point 120-123 (decomp. and conversion
into 6-chloro-1-methyl-3-nitro-4-phenylcarbostyril of mel~ing
point 212-214).
1 ml of glacial acetic acid and 2 g of zinc dust are
added to a solution of lg of 2'-benzoyl-4'-chloro-N-methyl-
2-nitroacetanilide in 15 ml of me~hylene chloride. After the
exothermal reaction, the mixture is stirred at room temperature
for a further 15 minutes. After the addition of 5 ml of conc.
ammonia, the reaction mixture is partitioned between Nater and
ether. The ether phase is extracted 3 x with 2-n hydrochloric
acid. The ~xtracts are washed with ether and are made alkaline
by addition of ammonia. The liberated bases are extracted with
methylene chlorid0. The extracts are dried over sodium sulphate
and evaporated to yield a crude product~ By chromatography on
15 g of silica gel with 10 % ethyl acetate in methylene chloride -
and crystallisation from ether/hexane, there is obtained 7-chloro-
1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one of m.p.
130-13~.
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