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Preparation of (R)-8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1- (4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione

IP.com Disclosure Number: IPCOM000238270D
Publication Date: 2014-Aug-13
Document File: 5 page(s) / 49K

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The IP.com Prior Art Database

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Page 01 of 5

Preparation of (R)-8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1- (4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione


(R)-8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2- ylmethyl)-3,7-dihydro-purine-2,6-dione, referred herein as Compound I, has the following chemical structure:

N

O

N

N

N

O N

N N

NH2

(I)

A process for the preparation of compound I was described in IPCOM000215450D. Several process related impurities may be obtained by the process referred above.

Described herein after is compound I having low levels of less than 0.1% of the impurities described below. The impurities can be obtained, for example, by controlling the reaction temperature, water content and by shortening time of the reaction mixture exposing to extreme pH values.

The following process impurities were identified during the preparation of Compound I:

1) (R)-N-(2-acetylphenyl)-2-(8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3- methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide, referred herein as Compound II, having the following structure:

HN

O

N

O

N

O N

N N

(II)

Provided is a process for the preparation of Compound II:

O

NH2


Page 02 of 5


(R)-3-N-tert-butoxycarbonylaminopiperidine was reacted with N-(2-acetylphenyl)-2- (8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl) acetamide in the presence of base and using an alcohol as the reaction solvent. The reaction was performed under heating during overnight. The reaction mixture having about 90% of tert-butyl (R)-(1-(1-(2-((2-acetylphenyl)amino)-2-oxoethyl)-7-(but-2- yn-1-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3- yl)carbamate (intermediate organic solution) was washed several times with water and separated.

An excess of aqueous HCl solution was added to the previously obtained intermediate organic solution. The reaction was stirred under heating until complete conversion was observed. The resulting mixture was separated. The organic phase was washed additionally with diluted aqueous solution of base and separated. The washed organic solution was evaporated to dryness. The residue was re-crystallized from alcohol, filtered and dried in vacuum oven under heating to afford crude material having about 87% of Compound II and about 12% of N-(2-acetylphenyl)-2-(8-((R)-3-(((Z)-1-(2-(2- (8-((R)-3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3,6,7- tetrahydr...