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Crystallization of (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5- trifluorophenyl)butan-1-one phosphate

IP.com Disclosure Number: IPCOM000174452D
Publication Date: 2008-Sep-09
Document File: 4 page(s) / 47K

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The IP.com Prior Art Database

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     Crystallization of (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8- tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5- trifluorophenyl)butan-1-one phosphate

(3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4- (2,4,5- trifluorophenyl)butan-1-one, has the following chemical structure:

F

F

Sitagliptin

The phosphate salt of (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8- tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5- trifluorophenyl)butan-1-one is a glucagon-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor.

Provided is a process for crystallizing (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8- tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5- trifluorophenyl)butan-1-one phosphate.

In one example, phosphoric acid was added to a solution of (3R)-3-amino-1-[9- (trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5- trifluorophenyl)butan-1-one in a mixture of ethanol and water; the solution was heated to a temperature of about 65°C, and then cooled to a room temperature to allow precipitating. The obtained precipitated was analyzed by XRD. The X ray diffraction of

F

NH2 O

N

N

N N

CF

3

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the obtained (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8- dien-4-yl]-4-(2,4,5- trifluorophenyl)butan-1-one phosphate is provided the following Figure:

The characteristic XRD peaks of this form are 4.7, 13.5, 14.0, 14.4, 15.5, 18.3, 19.2, 19.5 and 23.7 degrees two theta.

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The obtained precipitate was further maintained under vapor of tert-butyl ether for about 40 days, and then was analyzed by the by XRD and found to have the same form with higher crystallinity. The X ray diffraction obtaining after this period of time is provided the following Figure:

The characteristic XRD peaks of this form are 4.7, 13.5, 14.0, 1...