Preparation of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate
Publication Date: 2014-Jun-25
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Preparation of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-
Provided herein is a process for preparing methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)- 1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate, referred herein as Compound I. The process is described in Example 1.
Compound I may be used for preparing (4R,12aS)-9-((2,4-difluorobenzyl)-carbamoyl)-4-methyl-6,8- dioxo-3,4,6,8,12,12a-hexahydro-2Hpyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate and salts thereof.
Preparation of 4-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-oxobutanamide
Step 1: Ethyl 4-(benzyloxy)-3-oxobutanoate (15 g) was dissolved in toluene (150 ml) followed by addition of ethylene glycol (24 ml) and p-toluenesulfonic acid (PTSA) (0.97 g). To the reaction vessel was connected Dean-Stark distillation system and the reaction mixture was refluxed till full consumption of the starting material. The reaction was cooled to RT, washed with aqueous K2CO3
and evaporated to give ethyl 2-(2-((benzyloxy)methyl)-1,3-dioxolan-2-yl)acetate as brown oil which was introduced to the next step without purification.
Step 2: The oily residue (16 g) was dissolved in EtOH (160 ml) followed by addition of 16% aqueous NaOH (27 ml). The reaction mixture was stirred at RT for 16h. Then EtOH was removed by evaporation and the obtained residue was dissolved in EtOAc, washed with 5% aqueous citric acid and evaporated to give 2-(2-((benzyloxy)methyl)-1,3-dioxolan-2-yl)acetic acid as an oil which was introduced to the next step without purification.
Step 3: The oily residue (12.4 g) was dissolved in DCM (125 ml) followed by addition of hydroxybenzotriazole (HOBT) (8.28 g) and DCC (11.2 g). The reaction mass was mixed at RT for 30 minutes followed by addition of 2,4-difluorobenzylamine (8.5 g). The reactio...