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Process for preparation of Tert-Butyl 4-(6-(7-cyclopentyl-6- (dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)pyridin-3-yl)piperazine-1-carboxylate

IP.com Disclosure Number: IPCOM000250224D
Publication Date: 2017-Jun-13
Document File: 5 page(s) / 462K

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The IP.com Prior Art Database

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Process for preparation of Tert-Butyl 4-(6-(7-cyclopentyl-6-

(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-

ylamino)pyridin-3-yl)piperazine-1-carboxylate

Described herein below, is an improved process for preparation of Tert-Butyl

4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-

ylamino)pyridin-3-yl)piperazine-1-carboxylate (referred to as compound C).

Compound C

Compound C may be used for the preparation of 7-cyclopentyl-N,N-dimethyl-

2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-

carboxamide.

The process provides a route for preparation of compound C comprising

reacting 2-Chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-

carboxamide, designated herein compound A, with Tert-butyl 4-(6-aminopyridin-3-

yl)piperazine-1-carboxylate, designated herein compound B.

N

NCl N N

O

N

NH2

N

N

Boc

+

N

NN H

N N

O

N

N

N Boc

Compound A Compound B Compound C

The process may be performed using solvents such as, but not limited to,

water, dichloromethane, dimethylformamide (DMF), dimethylacetamide (DMA),

acetonitrile, 2-butanol, diglyme, N-methylpyrrolidinone (NMP), toluene, MIBK

(methyl isobutyl ketone), anisole. The process may be performed in the absence or in

presence of an inorganic or organic base such as, but not limited to, trimethylamine

(TEA), diisopropylethylamine (DIPEA), potassium carbonate, sodium carbonate,

potassium acetate, sodium acetate, potassium hydroxide, potassium phosphate, cesium

carbonate, pyridine, sodium tert-butoxide, potassium tert-butoxide, potassium tert-

amyloxide.

The process may be performed in the presence of a palladium source such as,

but not limited to, palladium acetate, Pd2(dba)3, Pd(dba)2, PdCl2(PhCN)2,

PdCl2(dppf), Pd(acac)2, [AllylPdCl]2, Pd(MeCN)2Cl2, and in the presence of a ligand

such as, but not limited to, BINAP, i.e. (±)2,2’-bis(diphenylphosphino)-1,1’-

binaphthalene, DPEPhos, i.e. bis[(2-diphenylphosphino)phenyl]ether, XantPhos, i.e.

4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, DPPF, i.e. 1,1’-

bis(diphenylphosphino)-ferrocene, DPPP, i.e. 1,3-bis(diphenylphosphino)propane.

Compound A can be prepared, for example, according to processes described

in WO 2010/020675, General procedure F, or WO 2012/064805, example 1.

Compound B can be prepared, for example, according to processes described

in WO 2010/020675, example B or WO 2012/064805, example 2.

Experimental procedure:

Procedure 1

Compound A (4.00 g, 1.0 eq.), compound B (4.18 g, 1.1 eq), palladium acetate

(0.046 g, 1.5 mol%), ±BINAP, (0.13 g, 1.5 mol%) were suspended in MIBK (8.0

v/w). The suspension was heated to 40 °C. Upon 30 min stirring, K3PO4 (4.35 g, 1.5

eq) was added portion wise over 20 minutes. The suspension was heated to 100 °C

and stirred for 5 h. The mixture was cooled to 70 °C. After cooling the suspension

was diluted by dropwise addition of water...