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Crystalline form of isopropyl ((S)-(((2R,3R,4R,5R)-5-(4-benzamido-2- oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

IP.com Disclosure Number: IPCOM000248453D
Publication Date: 2016-Dec-01
Document File: 5 page(s) / 296K

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The IP.com Prior Art Database

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Crystalline form of isopropyl ((S)-(((2R,3R,4R,5R)-5-(4-benzamido-2- oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

     (2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (referred to as Compound I) has the following structure:

Compound I

    Described herein below, is a crystalline form of isopropyl ((S)-(((2R,3R,4R,5R)- 5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran- 2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (referred to as compound A), which may be an intermediate in the preparation of compound I.

Compound A

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Preparation of crystallineisopropyl ((S)-(((2R,3R,4R,5R)-5-(4-benzamido-2- oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (compound A)

To a 3-neck RBF was added N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5- (hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4- yl)benzamide (5 g, 0.013 mol), 3,5-dibromo-4-(((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy) phosphoryl)oxy)methyl benzoate (14.4 g, 0.0249 mol), and THF (75 mL). This mixture was cooled to -30°C, followed by slow addition of 1.35M t-BuMgCl (17 mL, 0.022 mol) in 1-2 hours. The reaction mixture was slowly warmed to 22-25°C over 5-6 hours and stirred at that temperature overnight. The reaction mixture was quenched by addition of acetic acid (6 mL) and stirred at 22-25°C for 1-3 hours. Water (10 mL) was added and stirred for another 30 min and the aqueous layer was separated. THF layer was distilled under vacuum up to 3.5-4.5 vol of the reaction mass and ethyl acetate (60 mL) and stirred for another 1-2 hour at 22-25°C. The reaction mass was filtered to give an off-white solid (6.5 g).

This off-white solid was dissolved in MDC (50 mL) and washed with water (10 mL), aq. Sodium bicarbonate (10 mL), and brine solution (10 mL). Further concentration to 25 mL, THF (4.2 mL) was added. Moisture content of the MDC layer before addition of THF is 1.3%. MTBE (85 mL) was then added and the desired product was isolated by filtration to give an off-white solid (5 g).

The obtained product (compound A) was characterized by XRPD pattern. The XRPD pattern is of compound A is presented in the following representative X-ray diffractogram:

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Main XRD peaks of compound A are: 6.0, 7.2, 9.5, 11.4, 13.1, 14.3, 15.4; 16.8, 17.6,
19.1, 21.1 and 24.1 deg-2-theta ± 0.2 deg 2-theta.

N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran- 2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide

And 3,5-dibromo-4-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy) phosphoryl)oxy)methyl benzoate may be prepared according to the following examples.

Preparation of N-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3- methyltetrahydrofuran-2-yl...