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Preparation of (4R,12aS)-7(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo- 3,4,6,8,12,12a-hexahydro-2H pyrido [1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide Disclosure Number: IPCOM000240117D
Publication Date: 2015-Jan-04
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  Preparation of (4R,12aS)-7(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo- 3,4,6,8,12,12a-hexahydro-2H pyrido [1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide

Disclosed herein after is a process for preparing (4R,12aS)-7(benzyloxy)-N-(2,4- difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H pyrido [1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, referred herein as compound I.The process is described in Example 1.

Compound I may be used in the preparation of (4R,12aS)-N-(2,4-difluorobenzyl)- 7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide and salts

Example 1:

Methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4- dihydropyridine-2-carboxylate (may be prepared according to the process disclosed in IP.COM 000239636) (70 g) was dissolved in acetonitrile (410 mL) and the mixture was heated to reflux. Acetic acid (40.7 gr) and methanesulfonic acid (3.91 gr) were added and the reaction mixture was stirred at reflux for 6.5 hr. The mixture was cooled to room temperature and a solution of (R)- 3-amino butan-1-ol (14.49 gr) in acetonitrile (60 mL) was added. The reaction mixture was heated to reflux and stirred overnight. (4R,12aS)- 7(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H pyrido [1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide was obtained.