Title of Invention	A NOVEL ENZYME MEDIATED PROCESS FOR THE PREPARATION OF 2-AMINOBENZOPHENONES
Abstract	The present invention provides a simple and inexpensive process for the reductive cleavage of N—-O bond of 2,1-benzisoxazolium salts and 2,1-benzisoxazoles with bakers" yeast. The procedure gives excellent yields of 2-alkylamino and 2-aminobenzophenones.

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A NOVEL ENZYME MEDIATED PROCESS FOR THE PREPARATION OF 2-AMINOBENZOPHENONES. This invention relates to a new process for the preparation of substituted amino benzophenones and more particularly 2-aminobenzophenones of the following general formula The 2-aminobenzophenones are important industrial chemicals as intermediates leading to numerous CNS drugs of the 1,4-benzodiazepine class which are used clinically for example Valium, Librium, Nitrazepam, Flurazepam Oxazepam, Alprozalam amd Triazolam. The key factor in synthesis of these substances is the construction of 2-aminobenzophenones and suitably substituted 2- aminobenzophenone moiety. Reference may be made to L. H Sternbach. R. I. Fryer, W. Metlesics. G. Sach, A. Stempel, J. Ore. Chem.. 1962, 27, 3781 wherein 2-aminobenzophenone leads to numerous CNS drugs of the benzodiazepine group. Another reference may be made to Coombs, R. V., Danna, R. P., Denzer, M.. Hardtmann. G.E.. Huesi. B., Koletar. G.. On. H.. Jukniewicz. E. J. Med. Chem. 1973. 16. 1237 wherein chlorodiazepoxide, proquazone, amfemac amd nitrazepam, which are drugs in the market are prepared from 2-aminobenzophnones Still another,reference may be made to Walesh. D. A. Synthesis. 1980. 677 wherein the key factor in the synthesis of these drug molecule is the construction of a suitably substituted 2-aminobenzophenone moiety is described. The compounds of formula 1 of most interest in the invention bear either a chloro or bromo radical at the 5-position and an alkyl (e.g. methyl, ethyl) radical on the nitrogen atom of the amino group on the 2-position of the benzophenone molecule. Such a compound is 2-methylamino-5-chloro-benzophenone. The methods hitherto employed for the manufacture of ortho alkylamino benzophenones almost invariably use 2-amino benzophenones as the starting material. In one of the known methods the 2-amino group is protected by reaction with benzene sulfonyl chloride or p-toluene sulfonyl chloride (PTS) and the sulfonamide obtained is alkylated with an alkylating agent. Removal of the protective group from the protected 2- alkylamino group by hydrolysis gives 2-alkylamino benzophenones. This method may be represented by the following reaction scheme. The above method suffers from two major drawbacks, i.e. it involves isolation of several intermediates, which is both cumbersome and expensive, and the yield of the final product is very poor. Reference may be made to Sternbach, L. H., Reeder, E.. Keller, P., and Metlesics. W. J Org Chem, 1961. 26. 4488 wherein synthesis of 2-aminobenzophenones from substituted anilines under high temperature condition is described. Another reference may be made to Walder, G. N. J. Org. Chem. 1962, 27. 1929 wherein expensive palladium is used for the reduction of 2,1-benzisoxazoles. Still another reference may be made to Ning, R. Y., Madan, P. B. and Sternbach, L. H. J. Heterocyclic Chem., 1974, 11, 107 wherein functional groups susceptable to reduction cannot be tolerated. Still another reference may be made to Boruah. R. C., Sandhu. J. S.. Thvaearajan. G. J. Heterocyclic Chem., 1979, 16. 1087 wherein halogen enters in the carbocyclic ring, by cleaving 2,1-benzisoxazoles with thionyl chloride. Another known method employs direct alkylation of 2-aminobenzophenones by methyl p-toluene sulphonate. In this case the yields and purity of the product are far from satisfactory. Moreover, catalytic hydrogenation of 2,1-benzisoxazoles involves expensive paltinum or supported palladium. Thionylchloride catalysed cleavage of 2,1-benzisoxazoles gave 2-aminobenzophenone with the entry of halogen atom in to the carbocyclic ring and the corresponding 1,4-benzodiazepines are pharmologically less active due to a chloro substituent in the 9 position. The present method appears to be superior as well as novel for the production of 2-aminobenzophenones from easily available Baker's yeast which shows high selectivity and conversions are also high. Object of the invention: The main object of the present invention is to provide a process for the preparation of substiutted amino benzophenones. Another object of the present invention is to provide a process for the production of 2-aminobenzophenones from easily available Baker's yeast which shows high selectivity and conversions are also high. Wherein R is an alkyl group, or an alkyl radical or a hydrogen and X is Cl or Br. which comprises reacting a compound of the formula (II). According to the present investigation a process for the preparation of substituted amino benzophenones of general formula (I). Wherein X is Cl or Br, with alkylating agent in a non-polar solvent to produce a quarternary salt of the following formula (III). Wherein R and X are as defined above in formula I and R' is an alkyl group, reacting the compound of formulaIII obtained above with yeast is an alcoholic solution is presence of alkali hydroxide at a temperature in the range of 55 to 80 °C , isolating the desired compound of formula I by convational methods . In an embodiment of the present invention, the products can be prepared in high yields. In another embodiment of the present invention, since the intermediate quaternary salt (III) is virtually insoluble in non-polar organic solvents, it separates without much difficulty from the reaction mixture in very pure form, uncontaminated with the starting materials and reduction of (III) leads to the desired products having a very high degree of purity. Still in another embodiment of the present invention, the process avoids the need for isolation of intermediates, thereby avoiding any losses during such isolation. Still in another embodiment of the process, the yeast species is very cheap and the method is eco friendly. Another embodiment of the present invention the puarternary salt is reduced by catalytic hydrogenation using a supported palladium or platinum catalyst or Raney nickel. Detailed description. The process according to the invention uses substituted anthranils (II) as the starting material and these may readily be prepared by reaction of aromatic nitro compounds optionally substituted with Cl & Br atoms, with benzyl cyanide in strongly basic alcoholic (e.g. methanolic) solution. The anthranils (II), by reaction with alkylating agents e.g. dialkyl sulphates can be converted in the quarternary salts (III) in almost quantitative yields. The optimum reaction conditions very with the measure of the alkylating agent used. The alkylation of the anthranil derivatives (II) is found to proceed satisfactorily between 30° and 110°C. The quarternary salts (III) thus obtained are usually coloured, crystalline solids and insoluble in non-polar solvents like benzene or toluene. These salts owing to their insolubility separate form the reaction mixture in almost pure condition. Chloroform may also be used as solvent during the alkylation. The quarternary salts (III) may be reduced, by techniques well known in the art, to produce aminobenzophenones (I) in high yield and purity. Reduction of the quarternary salts may be effected by the use of enzymes, such as, for example, bakers' yeast. The above sequence of reactions may be schematically represented as follows :- Where R is as defined above. The compounds (I) are very important, and are particularly useful in the manufacture of a number of pharmaceutical products including "Diazepam" and related benzodiazepine derivatives. The details of the method disclosed in this invention have been described in the following specific which are provided to illustrate the invention only and these should not be construed to limit the scope of the present investigation. EXAMPLE 1 a) Preparation of N-methyl-3-phenyl-5-chloro anthranil methosulfate. A mixture of 3-phenyl-5-chloroanthranil (1,15 gm), dimethyl sulphate (1.26 gm) and toluene (200 ml) was heated together with stirring at 110°C for two hours. After almost one hour the separation of the quarternary salt started. The mixture after reaction was cooled to 10°C and the separated solid was filtered off. The pure yellow crystalline solid (1.54 gm) which crystallised out had M.P. 173-174°C. b) Preparation of 2-methyl amino-5-chlorobenzophenone. To a well stirred suspension of bakers' yeast (30gms) in distilled water (80ml), heated to 70 °C for 5 min, added a solution of N-methyl-3-phenyl-5-chloro anthranil methosulphate (0.5 gm) in methanol (40 ml) and sodium hydroxide solution (40%, 10ml). The resulting mixture was heated to 70 °C with stirring for one hour (monitored by TLC) and filtered in a sintered glass funnel using celite. The filtrate was extracted with dichloromethane (30 ml x 2) and dried over anhydrous sodium sulphate and concentrated. The yield of the dry 2-methylamino-5-chloro benzophenone was 300mg. The product obtained as a bright yellow powder mp. 91-92°C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase) EXAMPLE - 2 c) Preparation of 2-methyl amino-5-bromobenzophenone. To a well stirred suspension of bakers' yeast (30gms) in distilled water (80ml), heated to 70 °C for 5 min, added a solution of N-methyl-3-phenyl-5-bromo anthranil methosulphate (0.5 gm) in methanol (40 ml) and sodium hydroxide solution (40%, 10ml). The resulting mixture was heated to 70 °C with stirring for one hour (monitored by TLC) and filtered in a sintered glass funnel using celite. The filtrate was extracted with dichloromethane (30 ml x 2) and dried over anhydrous sodium sulphate and concentrated. The yield of the dry 2-methylamino-5-bromo benzophenone was 300mg. The product obtained as a bright yellow crystalline solid mp 91-93 °C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase) EXAMPLE-3 d) Preparation of N-ethyl-3-phenyl-5-chloro anthranil ethosulfate. Anthranil ethosulphate was prepared similarly as anthranil methosulphate from 3-phenyl-5-chloroanthranil and di ethyl sulphate e) Preparation of 2-ethylamino-5-chlorobenzophenone. To a well stirred suspension of bakers' yeast (30gms) in distilled water (80ml), heated to 70 °C for 5 min, added a solution of N-ethyl-3-phenyl-5-chloro anthranil ethosulphate (0.5 gm) in methanol (40 ml) and sodium hydroxide solution (40%, 10ml). The resulting mixture was heated to 70 °C with stirring for one hour (monitored by TLC) and filtered in a sintered glass funnel using celite. The filtrate was extracted with dichloromethane (30 ml x 2) and dried over anhydrous sodium sulphate and concentrated. The yield of the dry 2-ethylamino-5-chloro benzophenone was 300 mg. The product obtained as a yellow crystals mp. 74-75 °C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase). EXAMPLE-4 f) Preparation of 5-chloro-7-phenyl anthranil. A suspension of sodium hydroxide (33gm) in methanol (160ml) was stirred well to dissolve the sodium hydroxide and the mixture was cooled to 10°C. To this benzylcyanide (4.84gm) and p-chloro nitrobenzene dissolved in methanol (80ml) was added dropwise for 3 hours maintaining the temperature at 10°C. The resulting mixture was further stirred for 10 min (monitored by TLC). The reaction mixture was then poured into water (400 ml) containing ice with stirring. The precipitated 5-chloro-7-phenyl anthranil was filtered off, washed with cooled water and dried. The product thus obtained was recrystallised from methanol. g) Preparation of 2-Amino-5-chlorobenzophenone. To a well stirred suspension of bakers' yeast (30gms) in distilled water (80 ml), heated to 70 °C for 5 min, added a solution of 3-phenyl-5-chloro anthranil (0.5 gm) in methanol (40 ml) and sodium hydroxide solution (40%, 10 ml). The resulting mixture was heated to 70°C with stirring for one hour (monitored by TLC) and filtered in a sintered glass funnel using celite. The filtrate was extracted with dichloromethane (30 ml x 2) and dried over anhydrous sodium sulphate and concentrated. The yield of the dry 2-amino-5-chloro benzophenone was 310mg. The product obtained as a bright yellow powder mp. 91-92°C. The product gave a single spot on TLC (silica gel plates with benzene as mobile phase) EXAMPLE- 5 h) Preparation of 2-Amino-5-bromobenzophenone. 2-Amino-5-bromobenzophenone was prepared similarly by following the procedure for the preparation of 2-amino-5-chlorobenzophenone using bakers' yeast. ADVANTAGE. The main advantage of the present invention is to provide a process for the production of 2-aminobenzophenones from easily available Baker's yeast which shows high selectivity and conversions are also high. We Claim:- 1. A process for the preparation of substituted amino benzophenones of general formula (I). (Figure Removed) Wherein R is an alkyl group, or an alkyl radical or a hydrogen and X is Cl or Br. which comprises reacting a compound of the formula (II). Wherein X is Cl or Br, with alkylating agent in a non-polar solvent to produce a quarternary salt of the following formula (III). R and X are as defined above in formula I and R' is an alkyl group, reacting the compound of formulalll obtained above with yeast in an alcoholic solution in presence of alkali hydroxide at a temperature in the range of 55 to 80 °C , isolating the desired compound of formula I by convational methods . 2 A process as claimed in the claim 1, wherein the compound of formula II is reacted with an alkylating agent selected from methyl iodide or dimethyl sulphate . 3. A process as claimed in claim 1, wherein the non polar solvent is sleeted from benzene , toluene, chloroform or mixture thereof. 4. A process as claimed in any preceding claim, wherein the reaction with the alkylating or alkylating agent is carried out at a temperature of between 30°C and 110° 5. A process as claimed in any proceding claim, wherein the compound of formula I is produced by reacting the salt with Baker's yeast. 6.. A process for the preparation of substituted amino benzophenones, substantially as herein described with reference to the examples, accompanying this specification.

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