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Method for the preparation of pure nilotinib and its salt

A technology for forming salts and compounds, which is applied in the field of preparing pure nilotinib and its salts, and can solve problems such as low yield values

Pending Publication Date: 2018-11-23
F I S FAB ILTALIANA SINTETICI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, the disclosed process provided nilotinib dihydrochloride dihydrate in a molar yield of 67.27%, which is a rather low yield value

Method used

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  • Method for the preparation of pure nilotinib and its salt
  • Method for the preparation of pure nilotinib and its salt
  • Method for the preparation of pure nilotinib and its salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Example 1: Standard synthesis of compounds of formula (I)

[0139]

[0140] A mixture of compound 5 (530 g, 1.73 mol) in N-methyl-2-pyrrolidone (abbreviated as NMP) (3710 mL) was heated at 60° C., and then thionyl chloride (159 g, 1.34 mol) was added within about 30 min. ). The reaction was then stirred at the same temperature for 1 hour. A solution of compound 6 (417.3 g, 1.73 mol) in NMP (1590 mL) was then added to the reaction mixture. The resulting reaction mixture was heated at 90°C, and the reaction was stirred at the same temperature for 2 hours. The reaction mixture was then cooled to 80 °C and water (4770 mL) was added. The pH was adjusted to pH=11 with 30% sodium hydroxide solution (988.6 mL). The resulting mixture was then cooled to T=40°C and stirred for 3 hours. The mixture was then filtered and the filtrate containing compound (I) was washed with water. The resulting solid was dried in vacuo to give Compound (I) as a white solid (824.6 g, 86% yiel...

Embodiment 2

[0141] Example 2: Synthesis of compounds of formula (I)

[0142]

[0143] To a mixture of compound (I) (800 g, 1.51 mol) in methanol (12000 mL) was added 32% aqueous hydrochloric acid until the pH was 2.5-3.5 (indicative amount 148 mL). The resulting mixture was then heated at 60-65°C and stirred at the same temperature for 1 hour until completely dissolved. To the resulting solution was then added 15% aqueous sodium hydroxide until pH 9 (indicative amount 307 mL). The resulting mixture was then cooled to T=40° C. within 1 hour and then filtered at the same temperature. The obtained filtrate containing Compound (I) was washed with methanol (800 mL). The resulting solid was dried under vacuum to give Compound (I) as a white solid (738.4 g, 92% yield, HPLC purity 99.7%, acid (IV) impurity <0.05%).

Embodiment 3

[0144] Example 3: Synthesis of compounds of formula (I)

[0145]

[0146] To a mixture of compound (I) (10 g, 18.88 mmol), acid 5 (1 g, 3.26 mmol) and aniline 6 (1 g, 4.156 mmol) in methanol (150 mL) was added 32% aqueous hydrochloric acid until the pH was 2.5-3.5 ( Indicative volume is 1.8 mL). The resulting mixture was then heated at 60-65°C and stirred at the same temperature for 1 hour until completely dissolved. To the resulting solution was then added 30% aqueous sodium hydroxide until pH 9 (indicative amount 2.1 mL). The resulting mixture was then cooled to T=40°C within 1 hour and then filtered at the same temperature. The obtained filtrate containing Compound (I) was washed with methanol (10 mL). The resulting solid was dried in vacuo to give Compound (I) as a white solid (8.89 g, 89.9% yield, HPLC purity 99.90%, acid 5 impurity 0.02%, aniline 6 impurity 0.00%).

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Abstract

The present invention discloses a method for the preparation of pure nilotinib and its salt. The method comprises the following steps: (a) providing the solution of free alkali raw material of a chemical compound of the formula (I) in the mixture of C1-C4 alcohol and mineral acid; (b) adding alkali into the solution in the step (a) in order to acquire pH value of being more than 8, inoculating thesolution in the step (b); (c) inoculating the solution in the step (b) if appropriate; (d) acquiring a suspension solution of the chemical compound of the formula (I); (e) separating a product of theformula (I). The invention aims to the method to prepare pharmaceutical active ingredient Nilotinib free base or Nilotinib dihydrochloride dihydrate by means of an improved crystallization procedure.

Description

technical field [0001] The invention relates to a method for preparing pure nilotinib and salts thereof. Background technique [0002] The drug compound named Nilotinib has the chemical name 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl ]-3-[[4-(3-pyridyl)-2-pyrimidinyl] amino]-benzamide, and structurally represented by formula (I): [0003] [0004] Nilotinib is a small molecule tyrosine kinase inhibitor approved for the treatment of imatinib-resistant chronic myeloid leukemia. It is structurally related to imatinib and developed on the basis of the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. [0005] Nilotinib is a selective Bcr-Abl kinase inhibitor that is 10-30 times more potent than imatinib. In Europe, since September 2009, it has been available under the trade name The following is commercially available as the monohydrochloride monohydrate salt Form B. [0006] US Patent Application No. 10 / 520,3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14C07D233/61A61P35/00C07B2200/13
Inventor 施金普罗伯托·普罗费塔
Owner F I S FAB ILTALIANA SINTETICI SPA
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