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Crystalline form of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Disclosure Number: IPCOM000239380D
Publication Date: 2014-Nov-04
Document File: 4 page(s) / 414K

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Crystalline form of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-

    Described herein after are processes and solid state forms of (R)-3-(4- phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, referred to as a compound D.

Compound D can be an intermediate in the process for preparing R)-1-(3-(4-amino-3- (4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (referred to as Compound I)

Example a: Synthesis and recrystallization of Compound D

Step 1: Synthesis of crude tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-

pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (referred to as Compound C)

    A reactor of 250 mL was loaded with 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-amine (referred to as Compound A, 7 g, 0.023 mol), tert-butyl (S)-3- ((methylsulfonyl)oxy)piperidine-1-carboxylate (referred to as Compound B, 10.96 g,
0.04 mol), cesium carbonate (22.55 g, 0.07 mol) and DMF (81 mL). The suspension was heated to 100 °C (Tj). A portion of Compound B (5.5 g, 0.02 mol) was added at interval of ~23 h to the stirred reaction mixture at 100 °C (Tj). The stirring of the reaction mixture was continued at 100 °C for 27 h. After HPLC analysis had shown full consumption of Compound A (less than 0.5%), the mixture cooled to 60 °C (Tj).

Water (800 mL) and EtOAc (100 mL) were added to the reaction mixture and after vigorous stirring at 60 °C, the phases were separated. The aqueous phase was extracted with EtOAc (3x100 mL). The combined organic phase was washed with brine (50 mL), dried over MgSO4, filtrated and evaporated to give crude tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) piperidine-1-carboxylate (16.99 g, 80.5% purity based on assay, HPLC purity ~88%).

Step 2: Synthesis of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo [3,4-

d]pyrimidin-4-amine (referred to as Compound D)


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    Compound C (7.44 g, 53% assay, 8.1 mmol) was loaded into reaction vessel followed by addition of HCl/EtOH 7N mixture (70 mL). The resulting reaction mixture was stirred at rt for 17 h and then concentrated in vacuum. The obtained residue was extracted with water (150 mL)/EtOAc (2x90 mL). The aqueous phase was treated with sat. NaHCO3 (150 mL) followed by extraction with EtOAc (2x90 mL). The combined organic phase was washed with brine, dried over MgSO4, filtrated and evaporated to give Compound D (3.08 g, 91% based on assay, HPLC purity ~91%).

The obtained compound D was characterized by XRPD and found to be amorphous. The XRD pattern is presented in the following representative X-ray diffractogram):

Sample ID: Analyst: Uri, Sample name: IBR LB-1442-A+SI , Temp: 25.0°C
Date: 07/28/14 14:33 Step : 0.050° Integration Time: 1.000 sec
Range: 2.000 - 40.000° Cont. Scan Rate: 3.000 [°/min]

Vert. Scale Unit: [CPS]
Horz. Scale Unit: [deg]





                 10.0 14.0 18.0 22.0 26.0 30.0 34.0 38.0


Step 3:Recrystallization of (...