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Ibrutinib preparation method, ibrutinib intermediate, and ibrutinib intermediate preparation method

A technology of ibrutinib and intermediates, applied in the field of small molecule drugs, can solve problems such as difficult methylation reactions, hidden dangers of heavy metal residues, and reduced market competitiveness, to achieve low prices, increase reaction yields, and reduce production costs Effect

Inactive Publication Date: 2016-12-07
SUZHOU PENGXU PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Chinese patent CN 10362677 and world patents WO 201482598 and WO 201468527 report a method for preparing Ibrutinib using dimethyl sulfate as a methylation reagent, wherein the methylation reaction is relatively difficult and the yield is not high
[0009] In this method, the coupling reaction of the intermediate preparation process uses a heavy metal Pd catalyst, which brings hidden dangers of heavy metal residues, resulting in high costs, reducing market competitiveness, and is not conducive to large-scale production.

Method used

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Experimental program
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Effect test

Embodiment 1

[0053] Synthetic compound (2)

[0054]

[0055]Measure toluene (4 Vol, volume multiple relative to the mass of compound 1) into the reaction kettle, and weigh 1 eq of compound (1) into the above reaction kettle. Thionyl chloride (1.5eq) was added, and the reaction was heated at 110°C until the conversion of the raw material was complete. The solvent was removed by rotary evaporation to obtain a crude product, which was directly used in the next reaction.

Embodiment 2

[0057] Synthetic compound (3)

[0058]

[0059] Prepare a solution of malononitrile (1.1eq) in Me-THF (1Vol), dropwise add it to a solution of NaH (2eq) in Me-THF (2Vol), and continue stirring for 30min after the addition of malononitrile is complete. 1eq of compound (2) was dissolved in Me-THF (2Vol) to form a solution, which was added dropwise to the above reaction solution. After the dropwise addition was completed, stirring was continued until the reaction was completed. Add 1N hydrochloric acid to the reaction solution to pH = 2-3, add water (4 Vol) for separation. The aqueous phase was extracted twice with EA (3 Vol), and the organic phases were combined and spin-dried to obtain a crude product. The crude product was purified by recrystallization with a yield of 95%.

[0060] The NMR data of the product are as follows:

[0061] 1 H NMR (400MHz, DMSO) δ7.67–7.59(m,2H),7.48–7.37(m,2H),7.19(t,J=7.4Hz,1H),7.09–7.02(m,2H),6.99– 6.91 (m,2H).

Embodiment 3

[0063] Synthetic compound (4)

[0064]

[0065] Weigh compound 3 (1eq), add 1,4-Dioxane (5vol), and stir to dissolve. Weigh NaHCO 3 (1.5eq), was added to the reaction kettle. The system was heated to 70°C, and Et was added dropwise 2 SO 4 (2eq). HPLC monitors that the reaction is completed, and the temperature is cooled. EA (4vol) was extracted and washed with saturated brine (4vol). Dried and spin-dried to obtain the crude product, which was directly used in the next reaction.

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Abstract

The present invention provides an ibrutinib preparation method, which comprises that (a) a compound (3) reacts with diethyl sulfate to obtain a compound (4); (b) the compound (4) reacts with a hydrazine dihydrochloride to obtain a compound (5); (c) the compound (5) reacts with formamide to obtain a compound (6); (d) after the compound (6) reacts with (R)-1-Boc-3-hydroxypiperidine, an acid is added to make a compound (7) be subjected to a deprotection reaction to obtain a compound (8); and (e) the compound (8) reacts with acryloyl chloride to obtain a compound (9) ibrutinib. The present invention further provides an ibrutinib intermediate represented by a formula (4) and a preparation method of the intermediate compound (8). According to the present invention, the method has advantages of low cost, good safety and high yield, and is suitable for large-scale production. The reaction route is defined in the specification.

Description

technical field [0001] The present invention relates to the field of small molecule drugs, more particularly to a preparation method of ibrutinib, an intermediate of ibrutinib and a preparation method of the intermediate. Background technique [0002] Cancer is a major disease facing mankind at present, and a large number of patients die of cancer every year. Ibrutinib is an oral heavyweight new anticancer drug called Bruton's tyrosine kinase (BTK) inhibitor. The drug irreversibly inhibits BTK by selectively covalently binding to the cysteine ​​residue (Cys-481) in the active site of the target protein BTK, thereby effectively preventing the tumor from migrating from B cells to cells suitable for the tumor growth environment. lymphatic tissue. In addition to the treatment of mantle cell lymphoma, the drug is also used to treat chronic lymphocytic leukemia and small lymphocytic lymphoma. [0003] Patent US 20080108636 reports the synthesis of Ibrutinib. The synthetic rout...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C253/30C07C255/37
Inventor 王鹏李丕旭谷向永
Owner SUZHOU PENGXU PHARM TECH CO LTD
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