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Preparation of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, its salt and intermediates thereof

IP.com Disclosure Number: IPCOM000238881D
Publication Date: 2014-Sep-23
Document File: 5 page(s) / 108K

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Preparation of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, its salt and intermediates thereof

            Provided herein below are intermediate in the synthesis of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one,  and amorphous form thereof. Also described amorphous form of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one and crystalline form of its hydrochloride salt.

tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate

            Synthesis of the above listed compound is described in the following example 1:

Example 1: A process for preparing tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate    

            A flask equipped with overhead stirrer and reflux condenser was charged with 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1 g, 3.3 mmol), Cs2CO3 (3.2 g, 9.9 mmol), 10 ml of DMF and 1eq of activated form of tert-butyl (S)-3-hydroxypiperidine-1-carboxylate. The activated form of tert-butyl (S)-3-hydroxypiperidine-1-carboxylate can be: mesylate /tosylate /nosylate /acetate /trifluoroacetate/triflate.
The reaction was heated up to 100 °C and stirred at this temperature for 24-48h followed by extraction with EtOAc and water and evaporation of the organic phase.

            Amorphous form of this compound, as well as its synthesis is described below:

Amorphous tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate


Figure 1:

The process is described in Example 2.

Example 2: A process for preparing amorphous tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate    

            Into 250ml reactor were loaded under  stream of nitrogen: (4-phenoxyphenyl)boronic acid (14.45g), tert-butyl (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (10g) , K2CO3 (9.33g) and DMF (100ml). The mixture was degassed for 10 min then heated to 150 oC and stirred for 3h.  The reaction was cooled to 80 oC followed by addition of EtOAc (100ml) and filtered on Hyflo. The cake was washed with hot EtOAc (80 ml) and the filtrate was extracted with water and brine. The concentrated residue was purified by column chromatography (EtOAc/Hexane) to obtain 5.75g of a yellow solid which was analyzed by XRPD and found to be amorphous (Figure 1).

             (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one prepared according to the above described procedures, can be used to prepare (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one and salts thereof.

(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazo...