Ranbaxy Laboratories, Inc.

Jag Mohan Khanna

Yatendra Kumar

Naresh Kumar

Rajesh Kumar Thaper

S M Kumar

Ramesh Dandala

Pankaj Sharma

Vijay Kumar Handa

Mukesh Kumar Sharma

Rakesh Kumar Arora

Neera Tiwari

Satyananda Misra

Brij Khera

Arun Malhotra

Chandrahas Khanduri

Swargam Sathyanarayan

Girij Pal Singh

Mahavir Singh Khanna

Ram Chander Aryan

Kiran Bala

Purna Chandra Ray

Shailendra Kumar Singh

Mashkoor Husain

There is described a process for the preparation of cefuroxime from predominantly S-cefuroxime axetil, R, S mixture of cefuroxime axetil or R-cefuroxime axetil not meeting the purity criteria. This comprises treating cefuroxime axetil with alkoxides in the presence of a suitable solvent or solvent mixture and isolating cefuroxime from the reaction mixture.

Process for the preparation of cefuroxime

A novel process of lactonizaton in the preparation of statins (e.g., the HMG--CoA reductase inhibitors lovastatin and simvastatin) employs very mild reaction conditions. The improved process comprises dissolving the open ring hydroxy acid form of the statins in an organic solvent by heating at a temperature, which ranges from ambient to reflux of the solvent, under anhydrous conditions to produce a solution, treating the solution with a mild catalyst at a temperature from about ambient to 50.degree. C., and adding water to the solution to cause the statins in lactone form to crystalize from the reaction mixture. The mild catalyst used in the reaction is a salt of an organic base with an organic or inorganic acid, such as pyridine hydrobromide, pyridine hydrochloride, or pyridinium, p-toluene sulfonate. The organic solvent comprises a lower alkanol, a non-alcoholic polar solvent, or a mixture of the two.

Process of lactonization in the preparation of statins

An improved process of lactonization in the preparation of statins (e.g., the HMG--CoA reductase inhibitors lovastatin and simvastatin) employs very mild reaction conditions. The improved process comprises treating the open ring hydroxy acid form of the statins with an excess of acetic acid and in the absence of a strong acid catalyst under mild heating conditions (e.g., ambient to 55.degree. C.), and adding an anti-solvent to the reaction mixture, thereby causing the statins in lactone form to crystalize from the reaction mixture. The acetic acid serves as both a solvent and a catalyst for the lactonization reaction.

A process for preparing certain cephalosporin antibiotics, namely, cefotaxime, cefetemet, and ceftriaxone sodium comprising acylation of 7-amino-3-cephem-4-carboxylic acid derivatives with 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-metho xyiminoacetate having the formula: ##STR1##

Process for producing cephalosporin antibiotics

A multistep process for producing 8-chloro-6-(2-fluorophenyl)-1-methyl-4-H-imidazo�1,5a!�1,4!benzodiazepine (midazolam) comprises treating a compound of Formula II with a lower alkyl dithiol to produce a compound of Formula III, wherein n=2 or 3, converting the compound of Formula III to a compound of Formula VII, and then treating the compound of Formula VII with a deprotecting agent, thereby producing midazolam. Novel intermediate compounds are also disclosed.

Process for the manufacture of

A process for preparing simvastatin from lovastatin or mevinolinic acid in salt form comprises treating either starting material with cyclopropyl or butyl amine, the pyranone ring thereby being opened when lovastatin is the starting material, adding a methyl group to the 2-methylbutyrate side chain, and thereafter closing the open pyranone ring to produce simvastatin. The process is performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring. In a preferred embodiment, the starting material is treated with cyclopropyl amine which produces simvastatin via the novel intermediate lovastatin cyclopropyl amide.

Key intermediates in the manufacture of simvastatin

Process for manufacturing simvastatin from lovastatin or mevinolinic acid

A multistep process for producing 8-chloro-6-(2-fluorophenyl)-1-methyl-4-H-imidazo�1,5a!�1,4! benzodiazepine (midazolam) comprises treating a compound of Formula II with a lower alkyl dithiol to produce a compound of Formula III, wherein n=2 or 3, converting the compound of Formula III to a compound of Formula VII, and then treating the compound of Formula VII with a deprotecting agent, thereby producing midazolam. Novel intermediate compounds are also disclosed.

Process for the manufacture of 8-chloro-6 (2-fluorophenyl)-1

A process for the manufacture of pharmaceutical grade ranitidine base(N-�2-���5-(Dimethylamino)methyl!-2-furanyl!methyl!thio!ethyl-N'-methy l-2-nitro-1, 1-ethenediamine), is described. In-vitro and in-vivo pharmacological studies and acute toxicity studies indicate that it is as active and as safe as Form 2 ranitidine hydrochloride.

Process for the manufacture of pharmaceutical grade ranitidine base

A process for the manufacture of Form 1 ranitidine hydrochloride (N-[2-[[[5-(Dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl-N'-methyl-2- nitro-1,1-ethenediamine) hydrochloride, is described. A process to convert ranitidine hydrochloride Form 2 to Form 1 is also described.

Process for the manufacture of form 1 ranitidine hydrochloride

A process for converting cephalosporin p-nitrobenzyl ester (Formula I) to the corresponding cephalosporin free acid (Formula II) comprising treating the cephalosporin p-nitrobenzyl ester with a metal selected from the group consisting of iron, magnesium, aluminum, and tin, and with hydrochloric acid in a mixture of water and a water-miscible organic solvent. Preferably, the metal is iron in the form of a fine powder, and the reaction is carried out at a temperature in the range of 30.degree.-50.degree. C.

Process for P-nitrobenzyl ester cleavage in cephalosporin

A process for the manufacture of 7-acylamino-3-hydroxycephem-4-carboxylate-1-oxide in E-rotamer form (Formula III), comprises reacting a 7-acylamino-3-exomethylenecepham-4-carboxylate-1-oxide with ozone in an inert organic solvent in the presence of a catalytic amount of an organic or inorganic base at a temperature ranging from about -80.degree. C. to about +20.degree. C. The E-rotamer (wherein the 3-hydroxy group is strongly hydrogen bonded to the carbonyl of the 4-ester group) exhibits different chemical and physical properties from and is more thermodynamically stable than, the Z-rotamer (wherein there is no hydrogen bonding between the 3-hydroxy group and the carbonyl of the 4-ester group).

Process for preparing Z and E-rotamers of 3-hydroxy cephem derivatives

A process for preparing a 2-chlorosulfinylazetidinone comprises heating in an inert organic solvent a penicillin sulfoxide ester, at a temperature between about 75.degree. C. and 140.degree. C., with an N-chlorohalogenating agent in the presence of a weakly basic N-alkali metal salt of a cyclic imide. The weakly basic N-alkali metal salt of a cyclic imide acts as an acid scavenger to bind the hydrogen chloride which is produced as a byproduct of the reaction. Preferably, the N-chlorohalogenating agent is N-chlorosuccinimide or N-chlorophthalimide, and the weakly basic N-alkali metal salt of a cyclic imide is the sodium or potassium salt of succinimide or phthalimide.

Process for the preparation of 2-chlorosulfinylazetidinone

A one-pot process for preparing 7-amino-3-exomethylene-3-cepham-4-carboxylic acid ester (II) comprises: (a) reacting 7-acylamino-3-exomethylene-3-cepham-1-oxide-4-carboxylic acid ester (I) with a silylating agent in an inert solvent and in the presence of a base, (b) adding a phosphorous halide to produce an iminohalide, and (c) adding an anhydrous alcohol. In a preferred embodiment, the silylating agent comprises trimethylchlorosilane, and the phosphorous halide comprises phosphorous pentachloride.

An improved method for preparing 2-chlorosulfinyl azetidine-4-one comprises heating a penicillin sulfoxide ester with an N-chlorohalogenating agent at a temperature of about 75.degree. C. to about 140.degree. in an inert organic solvent, and in the presence of an organic solvent insoluble, strongly basic ion exchange resin. Desirably, the ion exchange resin comprises a styrene-divinyl benzane copolymer which is about 2 to 16% cross-linked and incorporates a quaternary ammonium functionality. Such ion exchange resins are commercially available. The 2-chlorosulfinyl azetidine-4-one which is produced by this method can be cyclized in the presence of a Friedel-Crafts catalysts to afford the 3-exomethylene cepham sulfoxide ester in yields of 80-90%.

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New Delhi, India

Jag Mohan Khanna