Synthesis and purification process of ibrutinib intermediates

A technology for ibrutinib and intermediates, applied in the field of ibrutinib intermediates and its recrystallization, can solve the problems of difficult control of the reaction process, high price, high cost, etc., achieve mild reaction conditions, simple experimental process, reduce cost effect

Inactive Publication Date: 2016-11-09
AMICOGEN CHINA BIOPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Both of the above two methods of synthesizing ibrutinib have gone through intermediate B, and the original research patent US7514444 uses the method of column chromatography to purify the intermediate, which is time-consuming and not suitable for large-scale production; pa

Method used

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  • Synthesis and purification process of ibrutinib intermediates
  • Synthesis and purification process of ibrutinib intermediates
  • Synthesis and purification process of ibrutinib intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Dissolve 10.0g (38.2mmol 1.0eq) of triphenylphosphine in 100ml of THF, cool at 0°C, add 7.67g (38.2mmol 1.0eq) of (s)-1-tert-butoxycarbonyl-3-hydroxypiperidine and 11.5g (38.2mmol 1.0eq) 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-4-amine, after stirring for 20 minutes, 7.67g (38.2mmol 1.0eq ) DIAD was added dropwise to the reaction liquid system, and kept at 0° C. for 20 hours. Then concentrate the feed solution to a viscous shape, add 380ml 0.5M dioxane hydrochloride solution, react at 20°C for 4 hours, concentrate, add 100ml water and 100ml ethyl acetate, separate layers, add 20ml methanol in the water phase, and then Adjust the pH to 10-11 with 10% aqueous sodium hydroxide solution, grow crystals for 30 minutes, and filter to obtain 8.85 g of crude product, with a yield of 60%.

[0030] Suspend 8.0 g of the crude product in 80 ml of a mixed solvent (methanol: ethyl acetate = 1:3), heat to reflux until dissolved, naturally cool at 20°C and stir for 12 hours, and ...

Embodiment 2

[0032] Dissolve 10.0g (38.2mmol 1.0eq) of triphenylphosphine in 100ml of THF, cool at 0°C, add 7.67g (38.2mmol 1.0eq) of (s)-1-tert-butoxycarbonyl-3-hydroxypiperidine and 11.5g (38.2mmol 1.0eq) 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-4-amine, after stirring for 20 minutes, 7.67g (38.2mmol 1.0eq ) DIAD was added dropwise to the reaction liquid system, and kept at 0° C. for 20 hours. Then concentrate the feed solution to a viscous shape, add 380ml 0.5M dioxane hydrochloride solution, react at 20°C for 4 hours, concentrate, add 100ml water and 100ml ethyl acetate, separate layers, add 10ml ethanol in the water phase, and then Adjust the pH to 10-11 with 20% aqueous sodium hydroxide solution, grow crystals for 30 minutes, and filter to obtain 9.13 g of crude product, with a yield of 61.9%.

[0033] Suspend 8.0 g of the crude product in 64 ml of a mixed solvent (methanol: acetonitrile = 1:2), heat to reflux until dissolved, naturally cool at 20°C and stir for 12 hours, and ...

Embodiment 3

[0035] Dissolve 10.0g (38.2mmol 1.0eq) of triphenylphosphine in 100ml of THF, cool at 0°C, add 7.67g (38.2mmol 1.0eq) of (s)-1-tert-butoxycarbonyl-3-hydroxypiperidine and 11.5g (38.2mmol 1.0eq) 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-4-amine, after stirring for 20 minutes, 7.67g (38.2mmol 1.0eq ) DIAD was added dropwise to the reaction liquid system, and kept at 0° C. for 20 hours. Then concentrate the feed solution to a viscous shape, add 380ml 0.5M dioxane hydrochloride solution, react at 20°C for 4 hours, concentrate, add 100ml water and 100ml ethyl acetate, separate layers, add 15ml acetone in the water phase, and then Adjust the pH to 10-11 with 15% potassium hydroxide aqueous solution, grow crystals for 30 minutes, and filter to obtain 8.66 g of crude product, with a yield of 58.7%.

[0036] Suspend 8.0 g of the crude product in 56 ml of mixed solvent (methanol: ethanol = 1:1), heat to reflux until dissolved, naturally cool at 20°C and stir for 12 hours, and filt...

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Abstract

The invention relates to a synthesis and purification process of ibrutinib intermediates, in particular to a process to obtain ibrutinib intermediates with the purity being greater than 97 percent by performing Mitsunobu reaction and Boc removal processes on 3-(4-phenoxyl phenyl)-1H-pyrazole[3,4-d]pyridine-4-amine and (s)-1-t-butyloxycarboryl-3-hydroxypiperidine, triphenylphosphine and DIAD to obtain intermediate mixing samples, using solvents for crystallization to obtain intermediate coarse products, and then recrystallizing the coarse products by a mixed solvent method. According to the process, a one-pot method is used for obtaining the ibrutinib intermediates; the reaction process is simple; the yield is high; meanwhile, an efficient refining method is also provided.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, specifically 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-4-amine and (s)-1-tert-butoxycarbonyl -3-Hydroxypiperidine, triphenylphosphine, and DIAD are obtained through the Mitsunobu reaction and de-Boc process to obtain ibrutinib intermediates and their recrystallization processes. Background technique [0002] Ibrutinib is a drug for the treatment of mantle cell lymphoma (MCL) jointly developed by pharmacyclics and Johnson & Johnson. The trade name is Imbruvica, which was approved by the FDA in October 2013. The specific structure is as follows: [0003] [0004] The original research patent US7514444 discloses a synthesis method of ibrutinib, the specific synthesis route is as follows: [0005] [0006] Patent CN104557945A discloses another synthesis method of ibrutinib, the specific synthesis route is as follows: [0007] [0008] Both of the above two methods for synthesi...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 陈伟陈强公文涛李建国王玲
Owner AMICOGEN CHINA BIOPHARM CO LTD
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