Process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine

a technology of piperidin and methylamine, which is applied in the field of process for the preparation of (3r, 4r)(1benzyl-4-methylpiperidin3yl)methylamine, can solve the problems of high cost of reagents, difficult commercial use, and complicated synthesis, and achieves improved and efficient results. , the effect of improving the yield over all

a technology of piperidin and methylamine, which is applied in the field of process for the preparation of (3r, 4r)(1benzyl-4-methylpiperidin3yl)methylamine, can solve the problems of high cost of reagents, difficult commercial use, and complicated synthesis, and achieves improved and efficient results. , the effect of improving the yield over all

US20170240510A1Inactive Publication Date: 2017-08-24UNICHEM LAB LTD
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  • Process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine
  • Process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine
  • Process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine

Examples

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example-1

Preparation of N-(4-methylpyridin-3-yl)-acetamide from 3-Amino-4-methyl pyridine

[0073]3-Amino-4-methyl pyridine (200 gm) and Acetic acid (600 mL) were charged in a 2 L 4-neck round bottom flask with an overhead stirrer and stirred for 15 minutes at RT. Acetic anhydride (284 gm / 263 mL) or Acetyl chloride (174 gm) was added drop wise within 1-2 h at that temperature. The reaction mass was then stirred at RT for 8-10 h. After the completion of the reaction as monitored by TLC, HPLC; acetic acid was distilled out under vacuum. Methanol (1 L) was then added to the reaction mixture and the pH of the reaction mixture was maintained around 10-12 by liq. Ammonia. Methanol was distilled out completely under vacuum at 50° C. to 55° C. The product was then extracted with MDC (1 L) to get the pure product. Yield: 98% w / w; HPLC Purity: 98%.

example-2

Preparation of N-(4-methylpyridin-3-yl)-acetamide from 3-Amino-4-methyl pyridine

[0074]3-Amino-4-methyl pyridine (200 gm) and Acetic anhydride (284 gm / 263 mL) in a 2 L 4-neck round bottom flask with an overhead stirrer were stirred for 15 minutes at RT. The stirring was continued at RT for 1-3 h. After the completion of the reaction as monitored by TLC, Methanol (1 L) was added to the reaction mixture and the pH of the reaction mixture was maintained around 10-12 by liq. Ammonia. Methanol was distilled out completely under vacuum at 50° C. to 55° C. Extraction with MDC (1 L) gave pure product. Yield: 98% w / w; HPLC Purity: 98%.

example-3

Preparation of N-(4-methylpyridinium-3-yl)-acetamide acetate from 3-amino-4-methyl pyridine

[0075]3-Amino-4-methyl pyridine (200 gm), Acetic anhydride (284 gm / 263 mL) or Acetyl chloride (174 gm) and MDC (1 L) in a 2 L 4-neck round bottom flask with an overhead stirrer were stirred for 15 minuets at RT. The reaction mass was stirred at RT for 8-10 h. Completion of the reaction was monitored by TLC, HPLC. Extraction with MDC (1 L) gave pure product. Yield: 98% w / w; HPLC Purity: 98%.

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Abstract

The present disclosure is related to an improved and efficient process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine which comprises:(a) N-acylation of 3-Amino-4-methyl pyridine; (b) Quarternization of 3-Acetylamino-4-methyl pyridine using benzyl halide; (c) Partial reduction of quarternized 3-Acetylamino-4-methyl pyridine by Sodium borohydride in Methanol or water; (d) Hydrolysis of partially reduced product to 1-Benzyl-4-methylpiperidin-3-one in presence of acid; (e) Reductive amination of 1-Benzyl-4-methylpiperidin-3-one using Methanolic methylamine in presence of Titanium(IV) isopropoxide in Methanol; (f) Resolution of 1-Benzyl-4-methylpiperidin-3-yl)-methylamine using Ditoluoyl (L) tartaric acid to get (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine. The disclosure is also related to novel intermediates:wherein R, R′ and X are as described in the specification.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a divisional of U.S. patent application Ser. No. 14 / 891,028, filed on Nov. 13, 2015, which is U.S. National Phase filing of International Application No. PCT / IB2014 / 066510, filed on Dec. 2, 2014, designating the United States of America and claiming priority to Indian Patent Application No. 3843 / MUM / 2013, filed Dec. 9, 2013, and this application claims priority to and the benefit of the above-identified applications, which are all incorporated by reference herein in their entireties.TECHNICAL FIELD[0002]The present invention provides an efficient and improved process for the preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine; a key starting material for the synthesis of 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile.BACKGROUND OF THE INVENTION[0003]3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo...

Claims

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Application Information

Patent Timeline
24 Aug 2017
Publication
US20170240510A1
IPC
C07D213/75; C07D213/74; C07D211/98; C07D211/56
CPC
C07D213/75; C07D211/98; C07D213/74; C07D211/56; C07D211/02; C07D211/72
Inventors
SATHE, DHANANJAY G.; DAS, ARIJIT