Title of Invention | A PROCESS FOR THE PREPARATION OF 3-METHYLCEPHAM DERIVATIVES |
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Abstract | A process for the preparation of 3-methylcepham-4-carboxylate of the formula (1), wherein R2 and R3 may be same or different and represent hydrogen, halogen, amino, alkyl, phenacetamido, substituted acetamido, phthalimido with a proviso that both R2 and R3 are not NHz, phenacetamido, phthalimido and the like; Rj represents a lower alkyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, 0- methoxybenzyl, o-chlorobenzyl or diphenylmethyl group, or a suitable ester residue which can be deprotected at a latter stage, L represents a leaving group; which comprises cyclizing dithioazetidinone compound of formula (III), wherein 'Het' represents a 5 or 6 membered -N- containing heterocyclic ring which may contain one or more heteroatoms selected from 0, S or N, using a cyclizing agent in the presence of organic or inorganic nitrites and a solvent at a temperature in the range of -40 to +60 °C to obtain compound of formula (1). |
Full Text | Field of the Invention The present invention relates to a process for the preparation of 3-methylcepham derivatives. More particularly, the present invention relates to a process for the preparation of 3-methylcepham-4-carboxylate of the formula (I). The 3-methylcepham-4-carboxylate of the formula (I) is a key intermediate in the preparation of 2ß-substituted methyl-2ot- methyl penicillin derivatives of the formula (II). where R1 represents hydrogen, carboxylic acid protecting group such as an ester or a pharmaceutically acceptable salt; R2 and R3 may be same or different and independently represent hydrogen, halogen, NH2, phenacetamido, substituted acetamido, phthalimido with a proviso that both R2 and R3 are not NH2> phenacetamido, phthalimido; Het represents a 5 or 6 membered NH containing heterocyclic ring system containing one or more heteroatoms selected from O, S, orN. Background of the Invention Several patents have disclosed various methods of producing 2ß-substituted methyl-2a- methyl penicillin derivatives of the formula (II), but none of the patents disclosed the process using the intermediate of formula (I). Tanaka et. al (Bull. Chem. Soc. Japan 62, 3046-3048 (1989)) describes a facile halogenative cyclization of 4-(2-benzothiazolyldithio)azetidinones and the susceptibility of 2-bromomethyl penams to isomerization to produce 3- bromocephams. The process reported that nitrosyl halide, generated from sodium nitrite and hydrogen halide in a biphasic water-dichloromethane medium, is shown to nitrosate the benzothiazolyl-nitrogen of the azetidinone derivative, thereby effecting the leaving of benzothiazolylthio group and forming the 2ß-halomethylpenam. The present invention is based on the mechanism that the protic acid itself directly reacts with the 4-(benzothiazolyldithio)azetidinone in a solvent to produce the cepham derivative, along with the by-product, 2-mercaptobenzothiazole. The 2-mercaptobenzothiazole was oxidized, by the addition of sodium nitrite, into 2,2'-dithiobis(benzothiazole), which is easier to remove from the reaction mixture owing to its less soluble nature and enable isolation of the cepham derivative. Objective of the Invention The main objective of the present invention is to provide a process for the preparation of 3-methylcepham-4-carboxylate of the formula (I). Yet another objective of the present invention is to develop a simple and commercially viable process for the preparation of 2ß-substituted methyl-2a-methyl penicillin derivatives of the formula (II) using the compound of formula (I). Summary of the Invention Accordingly, the present invention provides a process for the preparation of 3-methylcephan›4-carboxylate of the formula (I). wherein R2 and R3 may be same or different and represent hydrogen, halogen, amino, alkyl, phenacetamido, substituted acetamido, phthalimido with a proviso that both R2 and R3 are not NH2, phenacetamido, phthalimido and the like; Rl represents a lower alkyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, o-methoxybenzyl, o-chlorobenzyl or diphenylmethyl group, or a suitable ester residue which can be deprotected at a latter stage, L represents a leaving group such as halogen, tosylate, mesylate, triflate and the like, which comprises cyclizing the compound of formula (III) using a cyclizing agent in the presence of organic or inorganic nitrites and a solvent at a temperature in the range of -40 °C to +60 °C to obtain compound of formula (I). Detailed Description of the Invention In yet another embodiment of the present invention the cyclizing agent is selected from HC1, HBr, p-toluenesulfonic acid, methanesulfonic acid, and/or halogenating agents such as bromine, chlorine, IBr, BrCl and the like or mixture thereof in the presence of inorganic nitrites such as sodium nitrite, potassium nitrite, or organic nitrites such as amyl nitrite, isoamyl nitrite, nitrosonium tetrafluoroborate, and the like and solvent selected from DMF, acetonitrile, N,N-dimethylacetamide, ethyl acetate, N-methyl-2-pyrrolidin-2-one, dioxane, THF, methylene dichloride, diethyleneglycol dimethyl ether, ethylene dichloride, toluene and the like or mixture thereof. The reaction is carried out at a temperature in the range of-30 °C to +60 °C. The purpose of using nitrite is to eliminate the mercaptobenzothiazole formed in the reaction and it does not have any role in the reaction per se. The elimination of mercaptobenzothiazole is necessary in order to avoid the formation of impurities in the final product. In yet another embodiment of the present invention, there is provided a process for the preparation of 2ß-substituted methyl-2ct- methyl penicillin derivatives of the formula (II) where R1 represents hydrogen, carboxylic acid protecting group such as an ester or a pharmaceutically acceptable salt; R and R may be same or different and independently represent hydrogen, halogen, N¾ phenacetamido, phthalimido with a proviso that both R" and R are not NH2, phenacetamido, phthalimido; Het represents a 5 or 6 membered NH containing heterocycle ring system containing one or more heteroatoms selected from O, S, or N from 3-methylcepham-4-carboxylate of the formula (I) wherein all symbols are as defined above. The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention. Example 1 Preparation of p-nitrobenzyl-3-bromo-3-methylcepham-4-carboxylate p-Nitrobenzyl 2-oxo-4-(benzothiazol-2-yl)dithio-a-isopropenyl-l-azetidine acetate (200 g) was added to A^-dimethylformamide (1000 mL) at 25-30 °C under stirring. To the clear solution obtained, hydrobromic acid (48% w/w, 150 mL) was added over a period of 40 min at 25-30 °C and stirred for 30 min. A solution of sodium nitrite (27.5 g in 120 mL water) was added over 30 min and stirring continued for 120 min. After the reaction was over, the reaction mixture was filtered and sucked well. The filtrate was charged slowly into a stirred mixture of ethyl acetate and water over a period of 30 min at 0-5 °C. The pH was set to 5.0-5.5 with sodium bicarbonate solution and the aqueous layer extracted with ethyl acetate three times. The organic layers were combined, washed with water, and charcoalized. The solvent was distilled off under vacuum until a thick slurry was obtained. Ethyl acetate and diisopropyl ether were added, stirred well at 25-30 °C, filtered, and washed with ethyl acetate-diisopropyl ether mixture. Drying under vacuum for 6-8 hrs at 25-30 °C afforded the pure title compound (107-125 g). Example 2 Preparation of p-nitrobenzyl-3-bromo-3-methylcepham-4-carboxylate p-Nitrobenzyl 2-oxo-4-(benzothiazol-2-yl)dithio-a-isopropenyl-l-azetidine acetate (200 g) was added to ^7V-dimethylformamide (1000 mL) at 25-30 °C under stirring. To the clear solution obtained, hydrobromic acid (48% w/w, 150 mL) was added over a period of 40 min at 25-30 °C. A solution of sodium nitrite (27.5 g in 120 mL water) was added over 40 min and stirring continued for 120 min. After completion of the reaction, the reaction mixture was cooled to 0-5 °C and sodium bicarbonate added until pH was in the range 4.0-4.5. The reaction mixture was cooled to -5 °C, water (550 mL) added under stirring and filtered. The wet cake was charged into ethyl acetate (1000 mL), stirred well and filtered. The filtrate was washed with water twice and charcoalized. Solvent was distilled off under vacuum until a thick slurry was obtained. Ethyl acetate and diisopropyl ether were added, stirred well at 25-30 °C, filtered, and washed with ethyl acetate-diisopropyl ether mixture. Drying under vacuum for 6-8 hrs at 25-30 °C afforded the pure title compound (110-130 g). Example 3 Preparation of p-nitrobenzyl-3-bromo-3-methylcepham-4-carboxylate p-Nitrobenzyl 2-oxo-4-(benzothiazol-2-yl)dithio-a-isopropenyl-l-azetidine acetate (200 g) was added to Af Af-dimethylformamide (1000 mL) at 25-30 °C under stirring. To the clear solution obtained, hydrobromic acid (48% w/w, 150 mL) was added over a period of 40 min at 25-30 °C. A solution of sodium nitrite (27.5 g in 120 mL water) was added over 40 min and stirring continued for 120 min. After completion of the reaction, the reaction mixture was cooled to 0-5 °C and sodium bicarbonate added until pH was in the range 4.0-4.5. The reaction mixture was cooled to -5 °C, water (550 mL) added under stirring and filtered. The wet cake was charged into ethyl acetate (1000 mL), stirred well and filtered. The filtrate was washed with water twice and charcoalized. The solvent was distilled off under vacuum until a thick slurry was obtained. Diethyl ether was added, stirred well at 25-30 °C, filtered, and dried under vacuum for 30 min to afford pure title compound (110-130 g). We claim: 1. A process for the preparation of 3-methylcepham-4-carboxylate of the formula (I). wherein R and R are same or different and represent hydrogen, halogen, amino, alkyl, phenacetamido, substituted acetamido, phthalimido with a proviso that both R and R are not NH2, phenacetamido, phthalimido; R represents a lower alkyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, o-methoxybenzyl, o-chlorobenzyl or diphenylmethyl group, or a suitable ester residue which can be deprotected at a latter stage, L represents a leaving group, which comprises cyclizing the compound of formula (III) using a cyclizing agent in the presence of organic or inorganic nitrites and a solvent at a temperature in the range of-40 °C to +60 °C to obtain compound of formula (I). 2. The process as claimed in claim 1, wherein the leaving group represented by L is halogen, tosylate, mesylate or triflate. 3. The process as claimed in claim 1, wherein the cyclizing agent is selected from HC1, HBr, p-toluenesulfonic acid, methanesulfonic acid, bromine, chlorine, IBr, BrCl or mixture thereof. 4. The process as claimed in claim 1, wherein the inorganic nitrites used is selected from sodium nitrite or potassium nitrite. 5. The process as claimed in claim 1, wherein the organic nitrites used is selected from amyl nitrite, isoamyl nitrite or nitrosonium tetrafluoroborate. 6. The process as claimed in cliam 1, wherein the solvent used is selected from DMF, acetonitrile, A^A^-dimethylacetamide, ethyl acetate, N-methyl-2-pyrrolidin-2-one, dioxane, THF, methylene dichloride, diethyleneglycol dimethyl ether, ethylene dichloride, toluene or mixture thereof. 7. A process for the preparation of 2ß-substituted methyl-2a- methyl penicillin derivatives of the formula (II) where Rl represents hydrogen, carboxylic acid protecting group such as an ester or a pharmaceutically acceptable salt; R and R may be same or different and independently represent hydrogen, halogen, N¾, phenacetamido, phthalimido with a proviso that both R" and R are not N¾, phenacetamido, phthalimido; Het represents a 5 or 6 membered NH containing heterocycle ring system containing one or more heteroatoms selected from 0, S, or N from 3-methylcepham-4-carboxylate of the formula (I) prepared by a process claimed in claim 1. Dated this twentieth (20th) day of August 2003 |
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670-che-2003-claims granted.pdf
670-che-2003-correspondnece-others.pdf
670-che-2003-correspondnece-po.pdf
670-che-2003-description(complete)filed.pdf
670-che-2003-description(complete)granted.pdf
Patent Number | 212399 | |||||||||||||||
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Indian Patent Application Number | 670/CHE/2003 | |||||||||||||||
PG Journal Number | 07/2008 | |||||||||||||||
Publication Date | 15-Feb-2008 | |||||||||||||||
Grant Date | 03-Dec-2007 | |||||||||||||||
Date of Filing | 21-Aug-2003 | |||||||||||||||
Name of Patentee | M/S. ORCHID CHEMICALS & PHARMACEUTICALS LTD | |||||||||||||||
Applicant Address | ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI 600 034 | |||||||||||||||
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PCT International Classification Number | C07D 501/00 | |||||||||||||||
PCT International Application Number | N/A | |||||||||||||||
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