Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF AZETIDINONE DERIVATIVES

Abstract

The present invention provides an improved process for tHe preparation of cpioxazolino asetidinone compounds of the formula (I) wherein R<sub>1</sub> is a carboxy-protecting group; R<sub>2</sub> is aryl, arylmethyl or aryloxymethyl; which comprises reacting 6-epipenicillanic acid sulfoxides with trivalent phosphorous compound in an organic solvent in the presence of catalytic quantities of sulfonic acid derivatives of formula (II) wherein R<sub>3</sub>, R<sub>3a</sub>, R<sub>3b</sub> are same or different and represents hydroacn, hydroxy, methyl or halogen and R<sub>4</sub> in hydrogen or alkali/alkaline earth metal; n may vary fronn 1 to 3; Etlkyl represents (C<sub>1</sub>-C<sub>6</sub>) linear or branched chain alkyl group and aryl represents phenyl or benzyl group.

Full Text

Field of the Invention The present invention provides an improved process for the preparation of epioxazohno azetidinone compounds of the formula (I) wherein R5 is hydrogen or a counter-ion which forms a salt or esters which forms a prodrug. The oxacephalosporins of the formula (III) exhibit wide biological activity. Background of the Invention In view of the importance of the epioxazolino azetidinone compounds of the formula (I), as key intermediates for the synthesis of a wide variety of , oxacephalosporin drugs, various methods of preparation were reported. US Patent 4,271,296 reported the preparation of the epioxazolino azetidinone compounds of the formula (I) by refluxing the 6-epipenicillanic acid sulfoxide and triphenylphosphine in a mixture of 1,2-dichloroethane and toluene in a Dean-Stark in the presence of molecular sieves 5 A. After completion of reaction the product was obtained by performing column chromatography over silica gel using benzene/ethyl acetate mixture. S.Yamamoto et al. (Tetrahedron Lett. 1981, 3089) reported the additional formation of thiazolidine compounds of the formula (V), when the reaction is performed in the absence of any added catalysts. While the addition of carboxylic acids led to (i) suppression of the formation of the thiazolidine compounds of the formula (V), and (ii) favor the formation of the compounds of the formula (I), competitive formation of azetidinone derivatives of the formula (VI) was observed. At this juncture, use of squaric acid has been found to favor the formation of product, while the formation of the unwanted side products (V) and (VI), wherein R6 is acyl group, was suppressed. However, the cost of squaric acid is so high that it makes the process less attractive. On the other hand, preparation of the same in lab is not straightforward. The processes as described above is as shown in scheme -1 Thus we were in search of a simple, and cost-effective catalyst which could lead to efficient conversion of 6-epipenicillanic acid sulfoxides of the formula (IV) into the epioxazolino azetidinones of the formula (I). The ideal catalyst also has to simultaneously suppress formation of the thiazolines of the formula (V) and the 4-acetoxy compounds of the formula (VI). Thus, we have employed a wide variety of acids ranging from aromatic mono- and di-carboxylic acids, aliphatic carboxylic acids, phenolic acids containing electron-donating and electron withdrawing groups, phosphorous-acids, sulfur-acids, and so on. With our continued search and intense investigation, we finally achieved identifying good catalytic system, which affords clean conversion of the penicillin 'sulfoxides of the formula (IV) to epioxazolino-azetidinone compounds of the formula (I). Objectives of the Invention The objective of the invention is to provide a simple and efficient process for producing epioxazolino azetidinone compounds of the formula (I). Another objective of the present invention is to provide a good catalytic system for manufacturing epioxazolino-azetidinone compounds of the formula (I). Yet another objective of the present invention is to provide low cost catalytic system to ensure selective preparation of epioxazolino-azetidinone compounds of the formula (I). Yet another objective of the invention is to provide a catalytic reaction system which suppresses the formation of competitive side-products of the formula (V) and (VI), while favoring the formation of the compounds of the formula (I). wherein R3, Rsa, Rsb are same or different and represents hydrogen, hydroxy, methyl or halogen and R4 is hydrogen or alkali/alkaline earth metal; n may vary from 1 to 3; alkyl represents (Ci-Ce) linear or branched chain alkyl group and aryl represents phenyl or benzyl group; which comprises reacting 6-epipenicillanic acid sulfoxides of the formula (IV) with trivalent phosphorous compound in an organic solvent in the presence of catalytic quantities of sulfonic acid derivatives of formula (II) at a temperature in the range of 30 °C to 160 °C, over a period of 30 min to 4 hrs, to get the epioxazolino azetidinone compounds of the formula (I). Description of the Invention In an embodiment of the present invention, the substituent represented R\ is a carboxy-protecting group selected from diphenylmethyl, 4-methoxybenzyl, 2-methoxybenzyl, 2-chlorobenzyl, 4-nitrobenzyl or benzyl. In another embodiment of the present invention, the substituent represented by R2 is selected from aryl such as phenyl; arylmethyl such as benzyl or aryloxy methyl. In still another embodiment, the catalyst of the formula (II) used in the process is selected from 4,6-dihydroxy-l,3-benzenedisulfonic acid, 4,5-dihydroxy-1,3-benzenedisulfonic acid, 2-hydroxy-l,3,5-benzenetrisulfonic acid, 1,3-butanedisulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzene sulfonic acid and the like; or their salts of the corresponding alkali/alkaline earth metals such as potassium, lithium, sodium, calcium, barium or magnesium. In yet another embodiment of the present invention, the solvent used in the process is selected from toluene, xylene, tetrachloroethylene, trichloroethylene, dichloroethane or dioxane. In yet another embodiment, the trivalent phosphorous compound used in the process is selected from triphenylphosphine, or tri-n-butylphosphine or tri(o-tolyl)phosphine. In one more embodiment of the present invention, the preferable temperature of the reaction is 80 °C to 120 °C. The foregoing technique has been found to be atfractive from commercial, technological and ecological views, and affords epioxazolino azetidinones of the compound of formula (I). The starting materials of the present invention, the 6-epipenicillanic acid sulfoxides of the general formula (IV) can be prepared by the procedures well known in the art. The catalysts of the invention, namely sulfonic acid or their derivatives of the formula (III) can be prepared by the procedure known in the art. Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention. Example 1: Preparation of Epioxazolino-azetidinone compound of the formula (I; Ri = diphenylmethyl; R2 = phenyl) Diphenylmethyl 6a-benzamidopenicillanate-l-oxide (5 gm) was added to toluene (100 ml) at 27-30 °C under stirring in a Dean-Stark water separator. Triphenylphosphine (2.87 gm) and disodiura 4,6-dihydroxy-1,3-benzene disulfonate (75 mg) was added and the resulting mixture was heated to 100-110 °C over 30-60 min. The reaction mixture was maintained at this temperature for 3-4 hrs and the progress of the reaction was monitored. After the completion of reaction, the reaction mixture was cooled and washed with water. The solvent was distilled off under vacuum and the residue obtained was treated with acetonitrile. The hetereogeneous mixture was filtered, concentrated to remove the solvent. The residue was treated with isopropyl ether and isopropyl alcohol to get pure epioxazolino azetidinone of the formula (I; Ri = diphenylmethyl; R2 = phenyl) in 75-90% yield. Example 2: Preparation of Epioxazolino-azetidinone compound of the formula (I; Ri = diphenylmethyl; R2 = phenyl) Diphenylmethyl 6a-benzamidopenicillanate-l-oxide (10 gm) was added to toluene (200 ml) at 27-30 °C under stirring in a Dean-Stark water separator. Triphenylphosphine (5.8 gm) and sodium p-toluene benzene sulfonate (100 mg) was added and the resulting mixture was heated to 100-110 °C over 30-60 min. The reaction mixture was maintained at this temperature for 3-4 hrs and the progress of the reaction was monitored. After the completion of reaction, the reaction mixture was cooled and washed with water. The solvent was distilled off under vacuum and the residue obtained was treated with acetonitrile. The hetereogeneous mixture was filtered, concentrated to remove the solvent. The residue was treated with isopropyl ether and isopropyl alcohol to get pure epioxazolino azetidinone of the formula (I; Ri = diphenylmethyl; R2 = phenyl) in 75-90% yield. We Claim: 1. An improved process for the preparation of the compound of formula (I), wherein R3, are same or different and represents hydrogen, hydroxy, methyl or halogen and R4 is hydrogen or alkali/alkaline earth metal; n may vary from 1 to 3; alkyl represents linear or branched chain alkyl group and aryl represents phenyl or benzyl group; at a temperature in the range ot 3U "U to lou "C, over a period of 30 min to 4 hrs, to get the epioxazolino azetidinone compounds of the formula (I). 2. The process as claimed in claim 1, wherein the carboxy-protecting group is selected from diphenylmethyl, 4-methoxybenzyl, 2-methoxybenzyl, 2-chloro benzyl, 4-nitrobenzyl or benzyl. 3. The process as claimed in claim 1, wherein the sulfonic acids selected from 4,6-dihydroxy-l,3-benzenedisulfonic acid, 4,5-dihydroxy-l,3-benzenedisulfonic acid, 2-hydroxy-l,3,5-benzenetrisulfonic acid, 1,3-butanedisulfonic acid, ' methanesulfonic acid, p-toluenesulfonic acid, benzene sulfonic acid and the like; or their salts of the corresponding alkali/alkaline earth metals such as potassium, lithium, sodium, calcium, barium or magnesiirai. 4. • The process as claimed in claim 1, wherein the solvent used in the process is selected from toluene, xylene, tetrachloroethylene, trichloroethylene, dichloroethane or dioxane. 5. The process as claimed in claim 1, wherein the trivalent phosphorous compound used in the process is selected from triphenylphosphine, tri(o- tolyl)phosphine or tri-n-butylphosphine. 6. The process as claimed in claim 1, wherein the preferable temperature for the reaction is 80 °C to 130 "C.

Documents:

0851-mas-2002 abstract.pdf

0851-mas-2002 claims.pdf

0851-mas-2002 correspondence-others.pdf

0851-mas-2002 correspondence-po.pdf

0851-mas-2002 description (complete).pdf

0851-mas-2002 form-1.pdf

0851-mas-2002 form-13.pdf

0851-mas-2002 form-19.pdf

0851-mas-2002 form-3.pdf

0851-mas-2002 form-5.pdf