Eisai Company, Limited

Eisai Chemical Co., Ltd.

Agency of Industrial Science and Technology

Eisai Chemical

Tomio Tsurugi

Toshikazu Shimizu

Yoshio Urawa

Ken Furukawa

Yoji Yamagishi

Tomio Ichino

Shizumasa Kijima

Yuichi Inai

Yoshimasa Takahara

Kenji Nakajima

Akio Sato

Yoshiyuki Kawakami

Yoshiyuki Kohara

Hiroshi Kuroda

Yoshihiko Hisatake

Akio Imai

Makoto Uemura

Takashi Endo

Takuo Tanaka

Toshiyuki Ichinohe

The present invention provides a novel industrially excellent and ecological process for producing methylcobalamin which is useful as a medicament etc. More specifically, it provides a process for producing methylcobalamin by reducing cyanocobalamin or hydroxocobalamin in the presence of a reducing agent, and then methylating the reductant by adding a water-soluble methylating agent.

Process for producing methylcobalamin

The present invention provides novel polymorphic crystals (A) to (C) having excellent handling properties and an extremely low content of residual solvent of donepezil used as a precursor for production of donepezil hydrochloride having an excellent action as a medicament, and an industrial process for producing the same. Further, the novel polymorphic crystals (A) to (C) according to the present invention are characterized by the powder X-ray diffraction pattern and/or IR absorption peaks of donepezil represented by the following formula:

Donepezil polycrystals and process for producing the same

The present invention provides an industrially advantageous process for preparing a 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo�4,5-b!pyridine derivative represented by the following formula (II) which is a precursor of an antagonist against an angiotensin II receptor useful as an antihypertensive drug, a biphenyl derivative which is a precursor of the substituent of the pyridine derivative, a process for the preparation thereof, and an intermediate useful for the preparation of the biphenyl derivative: ##STR1## The 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo�4,5-b!pyridine derivative can be prepared in a high yield according to the present invention from a 2-amino-5-halogeno-3-nitropyridine derivative through amidation, N-alkylation and reductive cyclization. The halogen atom introduced at the 5-position as a protective group against nitration can be eliminated simultaneously in the step which is conducted thereafter. Thus, this process is industrially advantageous. Further, the biphenyl derivative of the present invention is excellent in reactivity and purity of the product, thus being an intermediate suitable for the industrial production.

Intermediates for imidazopyridine derivatives

The present invention provides an industrially advantageous process for preparing a 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative represented by the following formula (II) which is a precursor of an antagonist against an angiotensin II receptor useful as an antihypertensive drug, a biphenyl derivative which is a precursor of the substituent of the pyridine derivative, a process for the preparation thereof, and an intermediate useful for the preparation of the biphenyl derivative: ##STR1##

Intermediates for imidazopyridines

The present invention provides an industrially advantageous process for preparing a 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative represented by the following formula (II) which is a precursor of an antagonist against an angiotensin II receptor useful as an antihypertensive drug, a biphenyl derivative which is a precursor of the substituent of the pyridine derivative, a process for the preparation thereof, and an intermediate useful for the preparation of the biphenyl derivative: ##STR1## The 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo-[4,5-b]pyridine derivative can be prepared in a high yield according to the present invention from a 2-amino-5-halogeno-3-nitropyridine derivative through amidation, N-alkylation and reductive cyclization. The halogen atom introduced at the 5-position as a protective group against nitration can be eliminated simultaneously in the step which is conducted thereafter. Thus, this process is industrially advantageous. Further, the biphenyl derivative of the present invention is excellent in reactivity and purity of the product, thus being an intermediate suitable for the industrial production.

Process for the preparation of imidazopyridine derivatives and

The present invention provides an industrially advantageous process for preparing a 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative represented by the following formula (II) which is a precursor of an antagonist against an angiotensin II receptor useful as an antihypertensive drug, a biphenyl derivative which is a precursor of the substituent of the pyridine derivative, a process for the preparation thereof, and an intermediate useful for the preparation of the biphenyl derivative: ##STR1## The 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative can be prepared in a high yield according to the present invention from a 2-amino-5-halogeno-3-nitropyridine derivative through amidation, N-alkylation and reductive cyclization.

Sulfonyloxy-biphenylcarboxylic ester derivatives which are intermediates

Process for the preparation of imidazopyridine derivatives

Intermediates for substituted biphenylmethylmidazopyridine angiotensin

The present invention provides an industrially advantageous process for preparing a 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative represented by the following formula (II) which is a precursor of an antagonist against an angiotensin II receptor useful as an antihypertensive drug, a biphenyl derivative which is a precursor of the substituent of the pyridine derivative, a process for the preparation thereof, and an intermediate useful for the preparation of the biphenyl derivative: ##STR1## The 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative can be prepared in a high yield according to the present invention from a 2-amino-5-halogeno-3-nitropyridine derivative through amidation, N-alkylation and reductive cyclization. The halogen atom introduced at the 5-position as a protective group against nitration can be eliminated simultaneously in the step which is conducted thereafter. Thus, this process is industrially advantageous. Further, the biphenyl derivative of the present invention is excellent in reactivity and purity of the product, thus being an intermediate suitable for the industrial production.

Process for the preparation of biphenyl containing intermediates useful

Process for the preparation of imidazopyridine derivatives, and

Polyprenyl carboxylic acid derivatives having the general formula (I): ##STR1## in which n is an integer of from 2 to 4, R.sub.1 represents the hydrogen atom or a protecting group for the carboxylic acid group, and R.sub.2 represents a hydroxymethyl, formyl or carboxyl group, are disclosed. A process for the preparation of the polyprenyl carboxylic acid derivative involving microbiological oxidation using a strain belonging to the genus Nocardia is disclosed. The compounds have anti-ulcer activity and hypotensive activity. The compounds also are useful as intermediates for preparing polyprenyl carboxylic acids of the formula ##STR2## and esters thereof, wherein l is an integer of from 4 to 11. The polyprenyl carboxylic acids and esters thereof have hypotensive activity and anti-ulcer activity.

Polyprenyl carboxylic acid derivatives

A process is disclosed for the preparation of a compound having the general formula: ##STR1## wherein n is an integer of from 2 to 4, R.sub.1 is an ester-forming moiety effective as a protecting group for a carboxyl group, and R.sub.2 is hydroxymethyl, formyl or carboxyl. The compounds (I) are useful as intermediates for the preparation of polyprenyl compounds having hypotensive and anti-ulcer activity. The process of the invention includes cultivating a microorganism selected from a strain of the genus Nocardia called BPM 1613, FERM-P No. 1609, Corynebacterium equi IAM 1038, Candida lipolytica IFO 0746, and Mycobacterium smegmatis IFO 3083, in a nutritive culture medium, in the presence of a compound having the general formula: ##STR2## wherein R.sub.3 is an ester-forming moiety effective as a protecting group for a carboxyl group, whereby the microorganism utilizes the compound (II) as a carbon source and oxidizes the compound (II), thereby converting the compound (II) into the compound (I).

Process for preparing polyprenyl carboxylic acid derivatives

Growing community of inventors

Chiba, Japan

Tomio Tsurugi