US 2016/0102057 A1Published application

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

AssigneeUnichem Laboratories Ltd

InventorsDhananjay G. SATHE, Arijit DAS, Yogesh Subhash PATIL, Nilesh L. BONDE, Ankush Sampat KEKAN

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Abstract

The present invention 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 invention is also related to novel intermediates: wherein R, R′ and X are as described in the specification.

Claims17

Dependent claims

A process for the preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine (Formula IIa) comprising:

(i) N-acylation of 3-Amino-4-methyl pyridine (Formula III) with alkyl, aryl or substituted aryl acid chloride or acid anhydride to prepare a compound of the Formula IVa and optionally isolating it;
(ii) quarternization of Nitrogen of the Pyridine system in a compound of the Formula IVa, using benzyl or substituted aryl benzyl halide in an organic solvent to prepare a compound of the Formula Va and optionally isolating it;
(iii) partial reduction of a compound of the Formula Va to produce 1,2,5,6-Tetrahydropyridine system of a compound of the Formula VIa in presence of a reducing agent or any alkali metal borohydride agent in a suitable solvent, at an ambient temperature;
(iv) hydrolysis of 1,2,5,6-Tetrahydropyridine system of a compound of the Formula VIa in presence of an acid or mixture of acids to prepare a compound of the Formula VIIa at an ambient temperature;
(v) reductive amination of a compound of the Formula VIIa using Methylamine in presence of any Lewis acid in an organic solvent or an aqueous solvent or mixture(s) thereof followed by reduction using any reducing agent or any alkali metal borohydride derivatives to prepare a compound of the Formula VIIIa at an ambient temperature;
and
(vi) further resolution of a compound of the formula VIIIa in presence of any resoluting agent in an organic solvent or an aqueous solvent or mixture(s) thereof to prepare the compound of Formula IIa.

4 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/891,028Filed 2 Dec 2014
Priority: IN 3843/MUM/20139 Dec 2013
Published: 14 Apr 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 211/02
Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings: preparation by ring-closure or hydrogenation
C07D 211/56
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 211/72
Having one double bond between ring members or between a ring member and a non-ring member: with hetero atoms or with carbon atoms having three…
C07D 211/98
With a hetero atom directly attached to the ring nitrogen atom: nitrogen atom