PROCESSES FOR PREPARING OXAZINOBENZODIAZEPINES

SYNTHESE D'OXAZINOBENZODIAZEPINES

English Abstract

TITLE
PROCESSES FOR PREPARING
OXAZINOBENZODIAZEPINES
INVENTOR
VLADIMIR HACH
ABSTRACT OF THE DISCLOSURE
The present invention relates to a novel
process for the preparation of certain known oxazino-
benzodiazepine compounds, which comprises reacting a
5-phenyl-3H-1,4-benzodiazepine-2(1H)-one with a diketene
in an inert organic solvent, the reaction being conducted
at a temperature of between -10°C and +30°C in the presence
of a basic condensation catalyst and wherein the molar
ratio of the benzodiazepine to the diketene reactant is
preferably in the range of between 1:1 to 1:5, advantageously
from 1:1 to 1:2.

Claims

WHAT IS CLAIMED IS:
1. A process for making an oxazinobenzodiazepine
of the following general formula:
<IMG> .......(I)
wherein R1, R2, R3 and R4 independently represent hydrogen,
lower alkyl, lower alkoxy, halogen, -CF3, -NO2 or -CN,
R5 represents hydrogen, lower alkyl or benzyl,
R6 represents oxygen or sulphur, R7 represents hydrogen,
lower alkyl or lower alkoxy and R8 represents hydrogen,
lower alkyl or phenyl, which comprises reacting together,
in an inert organic solvent, at a temperature of between
-10°C and +30°C and in the presence of a base which acts as a
catalyst, a 5-phenyl-3H-1,4-benzodiazepine-2(1H)-one of the
following general formula:
<IMG> .......(II)

and a diketene of the formula:
(R8-CR=C-O)2 ....(III)
wherein in the foregoing formulae II and III, R1, R2, R3,
R4, R5, R6, R7 and R8 have the same significance as in
formula I.
2. Process for the production of an oxazinobenzodiaze-
pine of the general formula:
<IMG> .....(I')
wherein R8 represents hydrogen, lower alkyl or phenyl,
which comprises reacting 7-chloro-1-methyl-5-phenyl-3H-1,4-
benzo-diazepine-2(1H)-one with a diketene of formula:
(R8-CH=C=O)2 .....(III)
wherein R8 has the same significance as in formula I',
in an inert organic solvent, at a temperature of from
-10°C to +30°C and in the presence of a base which acts as a
catalyst.
3. Process for the production
of 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]
oxazino[3,2-d][1,4] benzodiazepine-4,7(6H)-dione comprising
reacting 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepine-
2(1H)-one with a diketene of formula
(R8-CH=C=O)2 ....(III)

wherein R8 represents hydrogen, in an inert organic
solvent, at a temperature of from -10°C to +30°C and in
the presence of a base which acts as a catalyst.
4. The process as claimed in Claim 1, 2 or 3 wherein
the solvent is acetone.
5. The process as claimed in Claim 1, 2 or 3 wherein
the solvent is a liquid aliphatic carboxylic acid.
6. The process as claimed in Claim 1, 2 or 3 wherein the
solvent is acetic acid.
7. The process as claimed in Claim 1, 2 or 3 wherein
the base which acts as a catalyst is soluble in the solvent.
8. The process according to Claim 1, 2 or 3 wherein
the base which acts as a catalyst is a tertiary amine.
9. The process according to Claim 1, 2 or 3 wherein
the base which acts as a catalyst is pyridine.
10. The process as claimed in Claim 1, 2 or 3 wherein
the base which acts as a catalyst is present in amounts of
from 0.1 to 10 molar equivalents based on the
benzodiazepine reactant.
11. The process as claimed in Claim 1, 2 or 3 wherein
the base which acts as a catalyst is present in amounts of
from 0.1 to 2 molar equivalents, based on the benzodiazepine
reactant.
12. The process as claimed in Claim 1, 2 or 3 wherein
the molar ratio of the benzodiazepine to the diketene
reactant is in the range of between 1:1 to 1:5.
13. The process as claimed in Claim 1, 2 or 3 wherein
the molar ratio of the benzodiazepine to the diketene
reactant is from 1:1 to 1:2.

Description

24Z9
BAC~GROUND OF T~E INVENTION
(a) Field of Invention
The present invention relates generally to processes
for manufacturing oxazinobenzodiazepine compounds. More
particularly, this invention is concerned with an improved
process for preparing oxazinobenzodiazepines of the following
general formula:
Rl ~
R~ O .,..... ~I)
R4 1 2 R8
~a
wherein Rl , R~, R~ and R4 independently represent hydrogen,
lower alkyl, lower alkoxy, halogen, -CF3, -NO2 or -CN, R5
represents hydrogen, lower alkyl or benzyl, R6 represents
oxygen or sulphur, R~ represènts hydrogen, lower alkyl or
lower alkoxy and Ra represents hydrogen, lower alkyl or
phenyl.
Compounds of the class defined by the foregoing
general formula I are known, and are the subject of
U.S.P. 3,573,282. Such compounds have been described as
possessing useful pharmacological properties in that they
exhibit tranquilizer, sedative and anti-convulsant effects.
Illustrative of such compounds is ll-chloro-8,12b-dihydro-
2,8 dimethyl-12b-phenyl-4H-[1,3]oxazino~3,2-d]~1,4]benzodiaze-
pine-4,7(6~)-dione, known generally as ketazolam.
Several processes have been described for preparing
these oxazinoben20diazepine compounds. For instance, in
- 2 -

Z429
the aforementioned United States patent, the compounds are
prepared by treating a selected 5-phenyl-3H-1,4-benzodiazepine-
2(lH)-one with a diketene,either hy direct addition or
produced in situ, i.e., by the addition of acyl halides and
a strong base. The direct addition procedure is effected by
refluxing the benzodiazepine :in an inert organic solvent with
a large excess (5 to 15 molar equivalents) of the diketene
over a period of 1 to 10 hours. For instance, ll-chloro-
8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d]-
benzodiazepine-4,7(6H)-dione is obtained following the
procedure of Example 2 in said patent in 64% overall yield
by refluxing for 18 hours a mixture of 7-chloro-1-methyl-5-
phenyl-3H-1,4-benzodiazepine-2(lH)-one and a 50~ by weight
solution of diketene in acetone. At the high temperature at
which this reaction is effected there is a tendency toward
polymer formationfrom the reactants. Accordingly, in many
instances the product resulting from this prior art process has
been contaminated with impurities. Since the compounds are
intended for use as medicaments which often must be
continuously used by chronically ill patients, objectionable
impurities cannot be tolerated. These impurities, therefore,
need to be removed using costly and tedious procedures in
order to provide a drug product which is acceptable for
administration.
With the foregoing points in mind, it is a
principal object of this invention to provide an improved
process for making such oxazinobenzodiazepines which avoids
the need for elevated reaction temperatures and elaborate,
costly equipment and which affords the compounds in good
yield and in a relatively pure state so that extensive
-- 3 --

1~4 ~2~
puriication is not usually rcquired.
SUMM~.RY_OF THE INVENTION
The improved process of this i~vention comprises
reacting together, in an inert organic solvent, a
S-phenyl-~H-1,4-benzodiazepine-2(1H)-one of the following
general ~ormula:
Rs
~,1~ c~R6
Rl ~ ll CHR7
~ N
R2 1 ~..... (II)
~3
~ 1~
with a diketene of the formula:
~R8-C~=C=O)2 ...... (III)
wnerein in the foregoing formulae II and III,Rl, R2, R3,
R4, R5, ~6, R7 and R3 have the same significance as herein
be~ore, characterized in that, the reaction is conducted at
a temperature of between about -10C and +30C in the presence
of a base which acts as a catalyst hereinafter referred to as
a basic condensation catalyst. -
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A highly preferred embodiment of tnis i~vention
is directed to the preparation of the compound, ll-chloro-
8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino-
l3~2-d][l~4]-benzodiazepine-4~7~6H)-dione (ketazolam) by
reacting 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepine-
2(1~)-one with diketene.
The reaction is carried out in an inert organic

1~4~429
solvent. Suitable sol~ents include, for example, acetone,
benzene, chloroform, diethylether, tetrahydrofuran and any
other organic solvent that does not react substantially or
otherwise interfere with the reactants. Acetone is often the
solvent of choice. In addition, liquid organic acids, such
as formic, acetic, or propionic acids, may also be used as
solvents.
The basic catalyst should preferably be soluble in
the selected solvent. Suitable basic catalysts include organic
bases such, for example, as triethylamine, trimethylamine,
tributylamine, dimethylaniline, pyridine and quinoline.
Inorganic bases such a zinc oxide and barium oxide or basic
ion exchange resins may also be used in suspension. The
preferred basic catalysts are the tertiary amines such as,
for example, pyridine, which is a weak base with a basic
dissociation constant of around 10 9. Conveniently, the base
is present in amounts of between about 0.1 and about 10 molar
equivalents, preferably between 0.1 and 2 molar equivalents,
based on the benzodiazepine reactant.
The condensation reaction between the benzodiazepine
and the diketene is noteworthy as proceeding rapidly at around
or even below ambient temperature, (24 to 26C.), and,
surprisingly, the reaction proceeds smoothly to give good yields
of the desired oxazinobenzodiazepines when conducted at a
temperature between -10C and +30C. Usually the reaction is
substantially complete in an hour or less. However, heat may
be applied if desired.
In a preferred embodiment of this invention, to achieve
best yields, the molar ratio of the 5-phenyl-3H-benzodiazepin-
2(lH)-one to diketene is in the range of 1:1 to 1:5,
advantageously around 1:1 to 1:2.

~Q4'Z42~
The product so-obtained is isolated and purified by
conventional procedures such as extraction, chromatography,
trituration, crystallization and recrystallization.
The following exampleSdirected to the p~eparation of
a preferred compound, ketazolam, a~ illustrative of the
improved process of this invention.
Exa~ A five litre flask was charged with 42 gms. ~0.14
mOles) of 7-chloro-1-methyl-5-phenyl-3~-1,4-benzodia~epin-
2(lH)-one, 360 mls. acetone as solvent and 90 mls. ~1.11
moles) pyridine as the basic condensation catalyst. The
resulting solution was cooled to 5C., whereupon 30 mls.
(0.39 moles) of diketene were added over a one hour period,
during which time the contents of the flask were stirred.
After completion of the addition, the solution wa~ stirred
for 1 hour at 5C. to 10C. Thereafter 3800 mls. of ice
cold water were added over a 30 minute period, and a solid
precipitated out. With the contents of the flask held at
room temperature, the stirring was continued for a further
30 minutes. Tren, the solid material was recovered by
filtration, washed with water and dried at room temperature
20- to give 54.4 gms. (yield 94.7%) of the desired ll-chloro-
8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]o~azino
[3,2-d]11,4]-benzodiazepine-4,7(6H)-dione. A 51 gm. portion
of this material was titrated with 75 mls. of acetone at
5C., filtered, washed with acetone and dried at room
temperature. Thereafter 50 gms. of this acetone-washed
product were dissolved in 1250 mls. of acetone, slurried
with 5 g. Norit and the slurry stirred for 10 minutes,
filtered through a filter aid and rur. into 3250 mls. water,
stirred 1 hour at room temperature, filtered and dried in
high vacuum over night to give 42.87 gms. (overall yie~d _

i~)42429
79~) of a ~lite crystalline pow~e~ nalysis of this prc~uct by
IR, ~ and chromatcgr~phic methccls shc~ecl it was highly ~ure so that
the stability of the cxmpound t~oulcl be es~?cially goad.
rxample 2:
0.7 gm (0.023 moles) of 7-chloro-1-methyl-5-phenyl~3H-1,4-
benzodiazepin-2(~1)-one was dissolved in :L0 ml of acetic acid in a
50 ml flask. 1 ~L (0.012 moles) of pyridine c~nd 0.6 nL (0.0078 moles)
of diketene were then aclded and the reaction muxture was kept at
betwe~n o& and 5C temperature for ~ hours, with occasional stirring.
The temperature was then raised to rocm-temperature (between 20C
and 25C) and kept for an additionaL t~o hours, with occasional agitation.
The entire reaction muxture was then poured into 225 ml of
cold water, stirred for five munutes, the precipitated white crystalline
solid filtered off, washed wi~h water and dried at room temperature to
give 0.75 gm ( yield _ 78.9~) of the desired 11-chlorcr~8,12b-dlhydro-
2,8-dimethyl-12b-phenyl-4H- [1,~ oxazino- ~,2-~ -1,4-benzodiazepine-
4,7(6}1)-dione.