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Preparation and characterization of Sorafenib Hemitosylate Monohydrate

IP.com Disclosure Number: IPCOM000246815D
Publication Date: 2016-Jul-04
Document File: 11 page(s) / 3M

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The IP.com Prior Art Database

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Preparation and characterization of Sorafenib Hemitosylate Monohydrate

Sorafenib Hemitosylate Monohydrate C21H16ClF3N403 (C7H803S) 0.5·H20

Mol. Wt.: 568.35

Experimental preparation procedure

Procedure 1

A suspension of Sorafenib free base (5 g, 10.75 mmol) in 1-propanol (65 mL) was heated to 50 °C in a 250 mL flask equipped with mechanical stirring. The resulting slightly turbid mixture was cooled to room temperature before adding dropwise, during 30 minutes, a solution of pTsOH.H2O (1,43 g, 7.52 mmol, 0.7 eq.) in H2O (6.5 mL). The resulting suspension was allowed to crystallize 4 h at RT and 2 h at 0-5 °C. The solid was filtered off with a sinter funnel n°3, washed with cold 1-propanol:H2O 9:1 (2x10 mL) and dried under high vacuum at room temperature for 15 h affording pure Sorafenib hemitosylate monohydrate
(5.51 g, 90%) as a slightly yellow crystalline solid.

Procedure 2

A suspension of Sorafenib free base (80 g, 0.1721 mol) in ethanol (800 mL) was stirred at RT (approx.20°C). Then, a solution of pTsOH.H2O (22.92 g, 0.7 eq.) in H2O (104 mL) was slowly added in at least 30 minutes.

The resulting suspension was allowed to crystallize for 4 h at 20°C and 2 h at -5/+5 °C. The solid was filtered off, washed with cold ethanol:H2O 9:1 (2x160 mL) and dried under high vacuum at room temperature (approx. 20°C) for 15 h affording pure Sorafenib hemitosylate monohydrate (90 g, 92%) as a slightly yellow solid.

Procedure 3

In a 3-necked 500 mL round bottom flask equipped with mechanical stirring, sorafenib free base (20.01 g, 43 mmol) was suspended in a solvent mixture EtOH:H20 91:9 (v/v) (160 mL, 8 vol.). To the resulting suspension, a solution of pTsOH.H20 (8.95 g, 47 mmol, 1.1 eq) in EtOH:H20 91:9 (v/v) (35 mL, 1.75 voL) was added dropwise at RT (rate of 12 mL/h). The crude was seeded with Sorafenib hemitosylate at the beginning of the addition and then each hour. At the end of the addition XRPD showed total conversion into Sorafenib hemitosylate monohydrate. The yellow suspension was stirred for one additional hour before filtering through a sintered glass funnel n2. The resulting solid was washed twice with EtOH:H20 91:9 (2x40 mL, 2x2v) and dried under vacuum at room temperature to constant weight. 22.09 g of Sorafenib hemitosylate monohydrate were obtained as a pale yellow solid (Yield 90%).

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1H NMR

Proton nuclear magnetic resonance analyses were recorded with a Varian Mercury 400 spectrometer, equipped with a broadband probe ATB 1H/19F/X of 5 mm. Spectra were acquired dissolving 5-10 mg of sample in 0.6 mL of deuterated dimethyl sulfoxide (DMSO-d6).

1H-NMR (DMSO-d6, 400 MHz): δ = 9.25 (s, 2H); 9.04 (s, 2H); 8.81 (d, J = 4.0 Hz, 2H); 8.52 (d, J = 6.0 Hz, 2H);
8.12 (d, J = 2.4 Hz, 2H); 7.68-7.58 (m, 8H); 7.49 (d, J = 8.0 Hz, 2H); 7.43 (s, 2H); 7.20-7.16 (m, 6H); 7.12 (d, J =
8.4 Hz, 2H); 2.79 (d, J = 8.4 Hz, 6H); 2.29 (s, 3H) (see Figure 1).

Figure 1

1H NMR Sorafenib Hemitosylate Monohydrate

KARL-FISCHER

Karl-F...