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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

IP.com Disclosure Number: IPCOM000239114D
Publication Date: 2014-Oct-13
Document File: 1 page(s) / 49K

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Preparation of (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-



Provided herein 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 for preparing (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 thereof.

Example 1:

Methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dihydroxyethyl)-4-oxo-1,4- dihydropyridine-2-carboxylate (1 gr) was slurried in Toluene(6 ml), followed by addition of (R)-3- aminobutan-1-ol (0.23gr) and 4.7 eq of C1-C10 linear or branched carboxylic acid*. The reaction mixture was heated to 100 oCfor 2hr to form (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.

(*) C1-C10 linear or branched carboxylic acid can be selected from: formic acid, acetic acid, propionic acid, 2-ethyl butyric acid, isobutyric acid, pivalic acid, butyric acid, 2-methyl butyric, 2,2- dimethyl butyric, 2-methyl pentanoic acid, pentanoic acid, hexanoic acid, octanoic acid, decanoic acid.