This invention pertains to an improved process for the preparation of 3-hydroxy benzodiazepines. More particularly the present invention relates to an improved process for the preparation of 7-chloro-3-hydroxy-5-phenyI-l, 3-dihydro-2H-1, 4-benzodiazepin-2-ones represented by formula I which are useful as anxiolytic and muscle relaxant agents*

where R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like,
• Prior art
It is known in the prior art that compounds of formula II,


where R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like, and R2 represents an acyl moiety such as acetyl, propionyl, benzoyl, toluyl and the like, may be hydrolyzed to compounds of formula I under acidic or basic conditions.
Thus, US Patent 3,296,249 discloses hydrolysis of 7-chloro-3-acyloxy-5-phenyH,3-dihydro-2H-1,4-benzodiazepin-2-ones of formula II using alkali metal hydroxides to yield the corresponding 3-hydroxy benzodiazepine-2-ones of formula I.
Bell etal. [J.Org.Chem. 27, 1691-1695 (1962)] have reported the hydrolysis of 7-chloro-3-acetoxy~5-phenyl-1, 3-dihydro-2H-l, 4-benzodiazepin-2-ones of formula II (Rl = H, CH3; R2 = COCH3) to the corresponding 3-hydroxy compounds of formula I (R,=H, CH3) using sodium hydroxide. They also reported [XOrg.Chem. TL 1691-1695 (1962)] that the hydrolysis of 7-chloro-l-methyl-3-acetoxy-5-phenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-ones of formula II (RlssCH3; R2=COCH3) using sodium hydroxide gave another product, 7-chloro-l-methyl-5-phenyl-4,5-dihydro-2H-l,4-benzodiazepine-2,3(lH)-diones of formula III (R= CH3) which is isomeric with the corresponding compound of formula I (R1= CH3).

where R represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like.
Compounds of formula I (R,=H, CH3) have been rearranged to compounds of formula III (R=H, CH3) on treatment with sodium hydroxide [J.Org.Chem. 27, 1691-1695 (1962)].

Thus, the alkaline hydrolysis of compound of formula II to form compound of formula I using alkali metal hydroxides, as described above, suffers due to the possible formation of a by-product, dione, of formula III.
Thus, the drawback of the above process is the formation of by-products such as dione of formula III during the course of hydrolysis of 3-acyloxy benodiazepinones of formula II in the preparation of 3-hydroxy benzodiazepinones of formula I using strong alkalis such as alkali metal hydroxides.
U.S.Patent number 4,412,952 discloses that particular reaction conditions employed in the hydrolysis of compound II using sodium hydroxide significantly affect the quality and yield of compound I. The said patent further discloses a process requiring catalytic amounts of potassium alkoxide or potassium hydroxide for the conversion of compound II to compound L
The most critical aspect of the said invention is the pH of the reaction medium from 11 to 11,5, preferably 11.2 to 11.4, most preferably 11.3 is essential for obtaining the desired results.
Whereas it is possible to maintain a pH of 11.3 using sophisticated instrumentation in the laboratory which is most critical for the success of this process, maintenance of the pH in a very close range on a commercial scale poses operational problems and requires sophisticated and expensive instrumentation for online control of pH as well as for regulating addition of potassium hydroxide or potassium alkoxide simultaneously. Even then, any minor variation in the control of the most critical parameter such as pH at 11,3 will adversely affect the quality and yield of the desired compound.
Thus, the drawbacks of the above mentioned process are the operational difficulties faced in maintaining specific pH at 11.3 which is the most critical aspect of the success of the above mentioned process in the commercial scale production and

simultaneous regulation of addition of potassium hydroxide or potassium alkoxide for maintaining the pH precisely at 113.
Thus a need was felt to develop an operationally feasible and simpler process for the commercial production of 3-hydroxy benzodiazepinones of formula I which should give the desired product devoid of any by-product without requiring online pH controls or other instrumental controls for regulating the addition of alkali.
• Objectives of the invention
■
Accordingly the main objective of the present invention is to provide an improved process for the preparation of 3-hydroxy benzodiazepinones of formula I avoiding the drawbacks of the hitherto known processes.
Another objective of the present invention is to provide an improved process for the preparation of 3-hydroxy benzodiazepinones of formula I which is operationally simpler and safer.
Yet another objective of the present invention is to provide an improved process for the preparation of 3-hydroxy benzodiazepinones of formula I by the hydrolysis of the compound of the formula II using mild alkali.
Still another objective of the present invention is to provide an improved process for the preparation of 3-hydroxy benzodiazepinones of formula I by the hydrolysis of the compound of the formula II using mild alkali which facilitates the control of pH in the reaction medium of its own without resorting to use of pH meter or any other instrumentation during alkali addition.
Another objective of the present invention is to provide an improved process for the preparation of 3-hydroxy benzodiazepinones of formula I by the hydrolysis of the compound of the formula II using mild alkali, as a catalyst, which inhibits the formation of by-products of compounds such as dione of formula III

• Principle based on which the present invention has been developed
The present invention has been developed based on our findings on sustained R&D experimentation that the hydrolysis of the 7-chloro-3-acyloxy-5-phenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-ones of formula II can be performed easily and efficiently using catalytic amounts of mild alkali such as alkali metal bicarbonates. Use of catalytic amounts of alkali metal bicarbonates such as sodium bicarbonate facilitates the control of pH in the reaction medium of its own without resorting to controls using pH meters and not requiring regulation of addition of sodium bicarbonate during the course of the reaction. Thus formation of by-products of compounds such as dione of formula III can easily be inhibited*
As explained above, while hydrolyzing compounds of the formula II, the prior art used strong alkali such as sodium hydroxide or potassium hydroxide or potassium alkoxides. The use of strong alkali has the drawback of the formation of the unwanted by product namely the dione of the formula III. In addition, it is also essential to maintain the pH of the reaction medium from 11 to 11.5, preferably 1 1.2 to 11.4, most preferably 11.3. Any minor variation in the control of the most critical parameter such as pH at 11.3 will adversely affect the quality and yield of the desired product. It may be possible to maintain such a precise pH using sophisticated instrumentation in the laboratory, but maintenance of such a specific pH in a process used for commercial production would not be feasible. Further addition of potassium hydroxide or potassium alkoxide to the reaction medium to regulate the specific pH would also be difficult.
It is pertinent to note that in none of the prior art processes the use of mild alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate for the hydrolysis of the compound of the formula II has been disclosed. The use of mild alkali facilitates the control of pH in the reaction medium of its own without resorting to controls using pH meters and not requiring regulation of addition of mild alkali during the course of the reaction. In a commercial process also such a condition can be employed. The use of mild alkali further inhibits the formation of the unwanted by product such as dione of formula III.

• Summary of the invention
Accordingly the present invention provides an improved process for the preparation of 3-hydroxy benzodiazepines of formula I,

where R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl , which comprises hydrolyzing 3-acyloxy benzodiazepinones of the formula II,

where R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and R2 represents an acyl moiety such as acetyl, propionyl, benzoyl, toluyl and the like, using catalytic amounts of mild alkali such as alkali metal

bicarbonates in the presence of lower alcohols containing up to three carbons as solvent at a temperature in the range of the room temperature to the reflux temperatures of the solvent used and isolating the compound of the formula I formed by conventional methods
In an embodiment of the present invention the catalytic amounts of alkali metal bicarbonates used range from 1 to 10 molar percent and preferably 1.5 to 2%, It is possible to use higher amounts of the catalyst which does not affect the success of the reaction.
Another embodiment of the present invention is the use of lower alcohols as reaction medium selected from methanol, ethanol or isopropanol, the preferred solvent being methanol
The temperature of the reaction is not critical which can vary from room temperature to reflux temperature of the solvent used.
The reaction time varies depending upon the reaction temperature used and the quantity of alkali metal carbonate employed. For example with a catalyst amount of 1.8 molar percent, the hydrolysis of 7-chloro-l-methyl-3-acetoxy-5-phenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one of formula II (R1=CH3; R2=COCH3) is complete in two hours at 65°C using methanol as a solvent, where as with the same amount of the catalyst and the same solvent, it takes nearly three hours for the completion of the reaction at 53-55°C.
The product of the reaction may be isolated by conventional techniques, e.g+, neutralization, precipitation, filtration and crystallization. Although neutralization of bicarbonate is preferred but it is not critical.
The following example describes the invention, in general, as an illustration and should not be construed to limit the scope of the invention in any way. The temperatures are uncorrected.

V
Example I
To a suspension of 50 gm of 7-chloro-l-methyl-3-acetoxy-5-phenyl-benzodiazepin-2-one in 200 ml of methanol is added 250 mg of sodium bicarbonate and heated to reflux. In the end of two hours of reflux, the suspension becomes essentially clear. TLC on silica gel chromatoplate revealed the completion of the reaction. The reaction mass was neutralized with acetic acid at reflux temperature. Water was added and the reaction mass cooled. The reaction product separated as a crystalline white mass, was filtered on a buchner funnel, washed with water and dried to yield 43.2 gm of the product which was homogeneous on TLC. It was crystallized from isopropanol to give pure 7-chloro-5-phenyl-3-hydroxybenzodiazepine-2-one as a crystalline product melting at 157-159°C.
• Advantages of the invention
1. The process does not require maintaining specific pH of the reaction medium which makes the process operationally simpler,
2. The process is applicable for the production of hydroxy 1 benzodiazpinones on a commercial scale, and
3. The process does not produce the unwanted by product such as dione of the formula III.
4. The yield of hydroxyl benzodiazpinones produced by the process is more than that obtained by the prior art processes

We Claim
1. An improved process for the preparation of 3-hydroxy benzodiazepines of formula I,

where R1 represents hydrogen or C\ to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like, which comprises hydrolyzing 3-acyloxy benzodiazepinones of formula II,

where R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl, and R2 represents an acyl moiety such as acetyl, propionyl, benzoyl, toluyl, using catalytic amounts of alkali metal bicarbonates in the presence in lower alkanol containing up to three carbons as a solvent at a temperature in the range of the room temperature to reflux temperatures of the solvent used and isolating the compound of the formula I formed by conventional methods

2. An improved process as claimed in claim 1, wherein the amount of the catalyst
used ranges between 1 and 10 molar percent, preferably between 1.5 and 2
molar percent.
3. An improved process as claimed in claims 1 and 2 wherein lower alkanol used as a
solvent is methanol
4. An improved process as claimed in claims 1 to 3 wherein the temperature of the reaction ranges from room temperatures to reflux temperatures of the solvent used.
5. An improved process as claimed in claims 1 to 4 wherein the reaction product is
isolated by neutralization, precipitation, filtration and crystallization, by conventional methods
6. An improved process for the preparation of 3-hydrxy-benzodiazepinones of
formula I as defined above substantially as herein described with reference to the
Example,