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process for preparing crystalline methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate Disclosure Number: IPCOM000240207D
Publication Date: 2015-Jan-13
Document File: 2 page(s) / 151K

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process for preparing crystalline methyl 3-(benzyloxy)-5-((2,4-



Provided herein is a process for preparing crystalline 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 in the preparation of (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.

Figure 1: XRPD of a crystalline form of Compound I

XRPD peaks: 9.5, 11.8, 14.2, 16.1, 18.3, 20.8, 22.8, 25.8, 26.7, and 27.3 ± 0.2 degrees 2-theta.

XRPD method:

The analysis was performed on ARL (SCINTAG) powder X-Ray diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 Å was used. Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05°, and a rate of 3 deg/min.

Example 1:

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80 g oil of compound I-crude was suspended in 100 ml dichloromethane (DCM). The solids which weren't dissolved were filtrated. DCM was evaporated to give 70 g of an orange oil. 60 g of this crude were dissolved in 130 ml DCM, clear solution was obtained. Flash Column chromatography purification was performed (30:70 Hexane:Ethyl acetate gradient) and 33 g crude compound I-A as an orange oil was obtained.