PREPARATION FOR 1,4-BENZODIAZEPINES

BENZODIAZEPINES-1,4

English Abstract

ABSTRACT OF THE DISCLOSURE
A novel process for producing 1,4-benzodiazepine
derivatives of the formula (I),
<IMG> (I)
wherein X is halogen, R1 is C1-C5 alkyl, and R2 is C1-C5 alkyl,
and their pharmaceutically acceptable salts, which are useful as
medicaments. These compounds (I) may be obtained by reacting a
compound of the formula (II),
<IMG> (II)
wherein X, R1 and R2 are as defined above, with a halogen or a
hypohalogenous acid salt in the presence of a base.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing 1,4-benzodiazepine
derivatives of the formula (I)
<IMG> (I)
wherein X is a halogen atom, R1 is a C1-C5 alkyl group, and R2
is a C1-C5 alkyl group, and their pharmaceutically acceptable
salts, which comprises reacting a compound of the formula (II),
<IMG> (II)
wherein X, Y, R1 and R2 are as defined above, with a halogen or
a hypohalic acid salt in the presence of a base in a suitable
solvent.
2. A process according to claim 1, wherein the said
base is an alkali metal hydroxide, an alkali metal carbonate or
an alkali metal alcoholate.
3. A process according to claim 1, wherein the
reaction is carried out under cooling.
4. A process according to claim 1, 2 or 3, wherein
said solvent is an alcohol, water, chloroform, dioxane, tetra-
hydrofuran or a mixture thereof.
5. A process as claimed in claim 1, 2 or 3, in which
in the reactants X is chlorine in the 7-position, R2 is methyl,
ethyl n-propyl or n-butyl and R1 is methyl.

6. A process as claimed in claim 1, 2 or 3, in which
in the reactants R1 is methyl, R2 is methyl and X is chlorine.
7. A process as claimed in claim 1, 2 or 3, in which
in the reactants R1 is methyl, R2 is methyl and X is chlorine
in the 7-position.

Description

The present invention relates to a process ~or
producing 1,4-benzodiazepine dexivatives and their salts. More
particularly, the present in~ention relates to a process for
producing 1,4-benzodiazepine derivati~es of the formula (I),
D~, C = W~ '
~ ~ 2
X Rl
wherein X is a halogen atom, Rl is a Cl-C5 alkyl group and R~ is
a Cl-C5 alkyl group and their pharmaceutically acceptable salts.
Examples of the "halogen atom" include chlorine, bro-
mine, fluorine and iodine. Examples of Cl-C5 alkyl include
methyl, ethyl, propyl and butyl.
The above mentioned compound (I) have been already
known as useful medicaments such as sedatives, antispasmodics,
muscle-relaxants and sleep inducing agents.
As the result of a study for seeking an advantageous
process for producing 1,4-benzodiazepine derivatives (I), the
inventors of the present invention have found a novel advantageous
process thereof.
Accordingly, the present invention provides an advan-
tageous process for producing 1,4-benzodiazepine derivatives (I).
The present invention also provides novel compounds
(II) as defined below.
According to the present invention there is provided a
process for producing 1,4-benzodiazepine derivatives of the
formula (I),
~ N - C (I)
X I \\ ~,
R1 O
- . '' , . : . .

5~L~
wherein X, Rl and R2 are a~ defined above, and their salts which
comprises reacting a c~mpound of the for~ula (II)I
Il ~
(II)
N COfHCONH2
Rl R2
wherein X, Rl and R2 are as defined above, with a halogen or a
hypohalogenous acid salt in the presence of a base, and further
provides a novel compound of the formula (II) as defined above,
which are useful as the intermediate for the preparation of the
compound (I~.
According to the invention, the reaction may be carried
out preferably in a suitable solvent, for example, an alcohol such
as methanol, ethanol, isopropanol, etc. water, chloroform, dioxane,
tetrahydrofuran or a mixture thereof. The reaction is preferably
carried out under cooling, however it also may be carried out at
a boiling point o~ the solvent used.
Preferable examples of the halogen are bromine and
chlorine. The said hypohalogenous acid salt may preferably be
hypochlorite (for example, potassium hypochlorite, sodium hypo-
chlorite) and hypobromite (for example, potassium hypobromite,
sodium hypobromite).
The said base includes an alkali metal hydroxide (such ;
as sodium hydroxide; potassium hydroxide, etc) an a~kali metal
carbonate (such as sodium carbonate, potassium carbonate, etc)
or an alkali metal alcoholate (such as sodium alcoholate,
potassium alcoholate).
Thus obtained 1,4-benzodiazepine derivatives may be
converted into the acid addition salts thereof by treating with a
mineral acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric
. ~'
~ :
,., . . . . ., . . : .
- .:
:. :

~09~5~L~
acid, phosphoric acid) or an organic acid (e.g. maleic acid,
fumaric acid, succinic acid, formic acid, acetic acid).
The compo~ld (II) may be prepared easily by convention-
al methods in the art, for example, the compound ~II) can be
obtained by reacting the corresponding 2 amino-benzophenone
derivative with the corresponding malonyl halide and then treating
the thus obtained malonamyl halide derivative with ammonia.
This reaction may be carried out in the presence or
absence of a suitable solventO This reaction may preferably be
carried out below room temperature but it is not limitative.
According to the process of the invention, the
following 1,4-benzodiazepine derivatives may be obtained.
3-Methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-
2-one
3-Methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-
benzodiazepin-2-one
3-Methyl-5-phenyl-7-bromo-1,3-dihydro-2H-1,4-
benzodiazepin-2-one
3-Ethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-
benzodiazepin-2-one
3~Propyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-
benzodiazepin-2-one
3-Butyl-5-phenyl~7-chloro-1,3-dihydro-2H-1,4-
benzodiazepin-2 one, and
1,3-Dimethyl-5-pheny1-7-chloro-1,3-dihydro-2H-1,4-
benzodiaæepin-2-one.
The present invention is illustrated more particularly
by the following example, but it is not intended to limit the
scope of the present invention.
Example
(~) Preparation o~ N-(2-benzoyl-4-chlorophenyl)-2,N-
dimethy~malonamide.
-- 3 --
.
.. ' , . ' ,
'~ ' ' , ~ ' . . ' ' ' '

3LC)4~5 ~
One ~ram of methylmalonyl chloride was added to the
solution of 1~ g of 2-methylamino-5-chloro-benzophenone in 20
ml of ether and the mixture was stirred ~or 30 minutes at a room
temperature. Then, the yellow color of the reaction mixture
turned pale. Ammonia was introduced into the ether solution of
the malonamyl chloride derivati~e thus obtained, under cooling.
The precipitated crystals were filtrated off and
washed with tetrahydrofuran. The filtrate and the tetrahydrofuran
layer were collected and distilled off under reduced pressure.
The resi~ue was treated with ether to give crystals of N-(2-
benzoyl-4-chlorophenyl)-2,N-dimethylmalonylamide, m.p. 148 -
149C. These crude crystals were recrystallized from a mixture
of tetrahydrofuran and ether to give the pure crystals, m.p.
152 - 153~C.
(B) Preparation of 1,3-dimethyl-5-phenyl-7 chloro-1,3-
dihydro-2H~1,4-benzodiazepin-2-one.
To a solution of 0,48 g of sodium hydroxide in 4 ml of
water was added dropwise 0.38 g of bromine below OC and the ~ -
mixture was cooled to -7C. The cooled solution of 0.2 g of
N-(2-benzoyl-4-chlorophenyl)2,N-dimethylmalonamide in 4 ml of
tetrahydrofuran was added dropwise thereto, while stirring was
continued. After addition stirring for one hour at -5 to -3~C,
the tetrahydrofuran Iayer was separated and the aqueous layer was
extracted with ether.
These collected organic layers were dried over anhydrous
sodium sulfate, and distilled off under reduced pressure to give
1,3-dimethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-
2-one. The hydrochloride was obtained by treating it with hydrogen
chloride-isopropanol.
IR (Nujal) 1695, 1620, 1595 cm
`-1`'~ i
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. ' ' ' . . ' '' '; .