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4 6 6 1 isobutoxy vinyl 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: IPCOM000244148D
Publication Date: 2015-Nov-15
Document File: 2 page(s) / 308K

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Page 01 of 2

4-{6-[6-(1-isobutoxy-vinyl)-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 a crystalline form of 4-{6-[6-(1-isobutoxy-vinyl)-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 B).

Compound B

Preparation of crystalline4-{6-[6-(1-isobutoxy-vinyl)-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 (compound B)

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, designated herein Compound A, can be prepared, for example, according to processes described in US 6936612, example 34.

Compound A, isobutyl-vinyl ether (2.0 - 3.0 eq) and a base (2.0 - 3.0 eq), for example TEA or DIPEA (N,N-diisopropylethylamine) were suspended in 1-butanol (5 to 10
v./w.). Palladium acetate (0.75 mol% to 4 mol%) and DPEPhos (0.75 mol% to 4 mol%),
i.e. bis[(2-diphenylphosphino)phenyl] ether, were added to the suspension and the mixture was heated at 90 - 95 °C for 24 h.


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After cooling the reaction was quenched by addition of water (1.0 - 1.5 v./w.) and filtered through a dicalite pad. The pad was washed with hot 1-butanol. After cooling to 0 °C, the resulting suspension was...