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Amorphous form of (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

IP.com Disclosure Number: IPCOM000235513D
Publication Date: 2014-Mar-05
Document File: 4 page(s) / 288K

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The IP.com Prior Art Database

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   Amorphous form of (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

    N-[[P(S),2'R]-2'-deoxy-2'-fluoro-2'-methyl-P-phenyl-5'-uridylyl]-, 1-methylethyl ester, or (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 formula:

OPr-i

Me

OH

   F O

O

RR R

R

N

H

    O N

O P N

S S

H

O

O

PhO

Me

    Provided herein are processes for preparing amorphous form of Compound I. Samples were prepared by the processes described in examples 1-8 and were analyzed by X-ray powder diffraction ("XRPD") to provide an amorphous form of Compound I. Figure 1 presents the XRPD of the obtained amorphous form.

Figure 1: XRPD of amorphous form of Compound I

1


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XRPD method

    The samples were measured on a D8 Advance powder X-ray diffractometer (Bruker AXS, Karlsruhe, Germany) in a rotating PMMA sample holder (diameter: 25 mm; depth: 1 mm) in reflection mode (Bragg-Brentano geometry). Conditions of the measurements are summarized in the table below. Raw data were analyzed with the program EVA (Bruker AXS, Karlsruhe, Germany). Background subtraction and Kα2 stripping were not performed.

radiation Cu Kα1/α2

source
34 kV / 40 mA

Vantec-1 (electronic window: 3°)

Ni (diffracted beam) 435 mm 12 mm 8 mm divergence slit

v6.00 (variable)

Soller slit (incident /diffracted beam) 2.5°
2θ range

2° ≤ 2θ ≤ 55° step size step time

detector Kβ filter

measuring circle diameter detector window slit

anti-scatter slit (diffracted beam)


0.016


0.2 s

Examples

Reference example: Preparation of the starting material

Form 1 of Compound I was prepared according to B. S. Ross, P. G. Reddy, H.-R. Zhang, S. Rachakonda, M. J. Sofia, J. Org. Chem. 2011, 76, 8311 using the pentafluorophenyl reagent. Form 1 of Compound 1 may be characterized according to WO2010/135569.

Example 1: Preparation of amorphous form of Compound I

Form 1 of Compound I (approx. 200mg) was stirred at 500 rpm in a mixture of acetone and cyclohexane (1:1) (2mL) for 72h, at room temperature. After isolation and filtration, the sample was analyzed by XRPD to give amorphous form of Compound I.

Example 2: Preparation of amorphous form of Compound I

2


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