Teva Pharmaceutical Industries Limited

Ilya Avrutov

Igor Lifshitz

Edi Schwartz

Basem Masarwa

Neomi Gershon

Judith Aronhime

Marioara Mendelovici

Anita Liberman

Gideon Pilarski

Valerie Niddam

Elizabeth Lewiner

Ronen Borochovitz

Improved processes for preparing substituted 2-(2-pyridylmethyl)sulfinyl-1H-benzimidazoles are disclosed.

Processes for the production of substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles

The present invention relates to processes for preparing protected silylated clarithromycin oxime, preferably 6-O-methyl-2',4&#x2033;-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime ('S-MOP oxime'), and for converting protected silylated clarithromycin oxime, preferably S-MOP oxime, to clarithromycin. Processes for preparing protected silylated clarithromycin oxime according to the present invention, include reacting a silyl oxime derivative with methylating agent in the presence of at least one solvent and a base, where the solvent comprises methyl tertbutyl ether. Processes for converting protected silylated clarithromycin oxime to clarithromycin according to the present invention, include reacting protected silylated clarithromycin oxime with ethanol and water at an ethanol to water ratio of about 1:1, in the presence of an acid and a deoximating agent and cooling the reaction mixture prior to adding sodium hydroxide, where the process takes place without any additional water addition. Further processes for converting protected silylated clarithromycin oxime to clarithromycin, include heating a mixture of protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of deoximating agent to produce essentially oxime-free clarithromycin.

Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same

The present invention relates to processes for converting clarithromycin Form I to clarithromycin Form II, which include slurrying clarithromycin the Form I in water. The present invention also relates to processes for the preparation of clarithromycin Form II by converting erythromycin A to clarithromycin and thereafter converting clarithromycin Form I to clarithromycin Form II by slurrying.

Processes for preparing clarithromycin polymorphs

Disclosed are processes for preparing novel carbamate intermediates of paroxetine comprising dealkylating N-alkylparoxetine by reaction thereof with a haloalkyl ester of a haloformic acid, in a suitable organic solvent. Also disclosed are processes for preparing paroxetine comprising hydrolyzing the novel carbamate intermediates in a suitable solvent. Paroxetine prepared by the above processes can be neutralized with hydrogen chloride and crystallized as paroxetine hydrochloride anhydrous, hemihydrate or as a solvate of isopropanol. The invention is further directed to the novel carbamate intermediates formed by the disclosed processes.

Preparation of paroxetine involving novel intermediates

The present invention is directed to methods for preparing intermediates useful in the synthesis of paroxetine wherein the intermediates are substantially free of alkoxy impurities as well as to methods for preparing paroxetine and pharmaceutically acceptable salts thereof substantially free of alkoxy impurities. The alkoxy impurity is reacted with an ether cleaving agent to generate the corresponding phenol, which is separated, yielding the desired product substantially free of alkoxy impurities. Paroxetine intermediates such as PMA, paroxetine, and pharmaceutically acceptable salts thereof substantially free of alkoxy impurities also form part of the present invention.

Process for the preparation of paroxetine substantially free of alkoxy impurities

A process for synthesizing leflunomide from 5-methylisoxazole-4-carboxylic acid and 4-trifluoromethylaniline is provided in which the carboxylic acid group of 5-methylisoxazole-4-carboxylic acid is chlorinated, forming 5-methylisoxazole-4-carboxylic acid chloride. The acid chloride is then reacted without intermediate distillation with 4-trifluoromethylaniline in the presence of an alkali metal or alkaline-earth metal bicarbonate acid scavenger.

Method for synthesizing leflunomide

New leflunomide Form III is disclosed, along with processes for preparing it. The present invention also provides an economic process for preparing leflunomide Form II and a process for preparing leflunomide Form I from leflunomide Form III. Pharmaceutical compositions and dosage forms containing the new form and methods of using them for the treatment of rheumatoid arthritis are also disclosed.

Processes for making- and a new crystalline form of- leflunomide

The present invention relates to processes for converting clarithromycin Form 0 to clarithromycin Form II, which include slurrying clarithromycin the Form 0 in water. The present invention also relates to processes for the preparation of clarithromycin Form II by converting erythromycin A to clarithromycin and thereafter converting clarithromycin Form 0 to clarithromycin Form II by slurrying. The present invention further relates to the novel clarithromycin polymorph Form IV, a process for its preparation, pharmaceutical compositions comprising the compound, and methods of using the compound as a therapeutic agent.

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Bat Hefer, Israel

Ilya Avrutov