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A process for preparing crystalline 4-Amino-3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidine

IP.com Disclosure Number: IPCOM000237637D
Publication Date: 2014-Jun-30
Document File: 3 page(s) / 24K

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A process for preparing crystalline 4-Amino-3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidine

     Provided herein is a process for preparing crystalline 4-Amino-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine, referred herein as Compound I. The process is described in Example 1. The isolated samples were analyzed by X-ray powder diffraction ("XRPD"), which indicated a formation of a crystalline form of Compound I. Figure 1 depicts the XRPD of the obtained crystalline form.

    Compound I may be used for preparing (S)-1-(3-(4-amino-3-(4- phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.

Figure 1: XRPD of a crystalline form of Compound I

Si

    According to Figure 1, the crystalline form of Compound I is characterized by XRPD peaks at: 5.4, 9.1, 10.8, 13.0, 14.6, 15.6, 16.2, 16.9, 19.0, 19.3, 20.1, 21.1,
22.5, 24.3, 25.6, 26.6, 27.9 and 29.5 degrees 2-theta ± 0.2 degrees 2-theta.

XRPD method:

    XRPD 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.

The peak at 28.5° is attributed to silicon powder added as internal standard.

°2 theta


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Example 1: A process for preparing 4-Amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidine
Step A: Preparation of 1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene

Phenoxybenzoic acid (12 g) was mixed with thionyl chloride (24.4 mL) and the mixture was stirred at reflux for 1h. Thionyl chloride was removed by distillation. The residue was dissolved in a mixture of toluene (48 mL) and THF (8.4 mL). Malononitrile (3.53 mL) was added. The mixture was cooled to -5 C and solution of DIPEA (19.5 mL) in Toluene (36 mL) was added slowly, maintaining the temperature below 0C. After stirring for 1h, the mixture was stirred at 20 C for 16 h.

The resulting mixture was diluted with H2SO4 (1M, 35 mL) and water (25 mL). The product was extracted with EtOAc (25 mL). The organic solution was w...