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Process for preparation of 4 6 6 Bromo 8 cyclopentyl 5 methyl 7 oxo 7 8 dihydro pyrido 2 3 d pyrimidin 2 ylamino pyridin 3 yl piperazine 1 carboxylic acid tert butyl ester

IP.com Disclosure Number: IPCOM000244149D
Publication Date: 2015-Nov-15
Document File: 4 page(s) / 419K

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The IP.com Prior Art Database

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Page 01 of 4

Process for preparation of 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7- oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]- piperazine-1-carboxylic acid tert-butyl ester

    Described herein below, is an improved process for preparation of 4-[6-(6- Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2- ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (referred to as compound C).

Br

N O

    Compound C may be used for the preparation of (2-(5-(piperazin-1-yl)pyridin- 2-ylamino)-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one).

    The process provides a route for preparation of compound C comprising reacting 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]-pyrimidin-7- one, designated herein compound A, with 4-(6-amino-3-pyridyl)-1-Boc-piperazine, designated herein compound B, in the presence of a base. The base may be iPrMgCl, LiHMDS, HMDS-MgCl (prepared by mixing hexamethyldisilazane with e.g. MeMgCl or iPrMgCl), (iPr)2N-MgCl or TMPMgCl*LiCl (TMP = 2,2,6,6- tetramethylpiperidine). Such conditions are considered suitable for industrial scale production.

    Compound C may be produced with controlled levels of up to 0.05% of tert- butyl 4-(6-(8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2- ylamino)pyridin-3-yl)piperazine-1-carboxylate, referred to herein as compound D.

N

HN N

N

Boc

N

Compound C

N


Page 02 of 4

N N

Compound D

Experimental procedure:

Compound A (6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]-pyrimidin-7-one) and compound B (4-(6-amino-3-pyridyl)-1-Boc-piperazine) were suspended in THF or toluene (5 - 40 v./w. ). Base (2 - 3 eq) was added under stirring at a temperature of 15 to 50 °C. After the addition was complete, the mixture was stirred for another 2 - 16 h. The reaction was quenched by addition of acetic acid (0.6 - 1.2 molEq). Upon precipitation of the product, the suspension was stirred for 16 h and filtered. The solid was washed with THF and dried under vacuum...