Ibrutinib synthesis method

A synthesis method, the technology of ibrutinib, applied in the field of drug synthesis, can solve the problems of ibrutinib quality research and quality control, increase the difficulty of ibrutinib purification, unstable chemical properties, etc., and achieve quality Easy to control, quality controllable, mild reaction conditions

Active Publication Date: 2018-02-09
HEILONGJIANG ZBD PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The last step of the synthesis method uses acryloyl chloride as the acryloylating reagent. Although the structure of the reagent itself is relatively simple, its chemical properties are unstable and prone to side reactions such as decomposition, addition and polymerization, so it contains many types of impurities. , and most of these impurities can participate in the reaction, and the resulting product has a similar structure to ibrutinib and is difficult to separate, which greatly increases the difficulty of purification of ibrutinib
In addition, acryloyl chloride is a liquid substance, and it is difficult to conduct quality research and quality control of ibrutinib

Method used

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  • Ibrutinib synthesis method

Examples

Experimental program
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preparation example Construction

[0016] This embodiment provides a synthetic method of ibrutinib, which includes:

[0017] Compound M and the compound of formula I undergo an acylation reaction in the presence of a base, and its reaction formula is as follows:

[0018]

[0019] Wherein, compound M can be bought, also can choose to adopt following route synthetically to obtain:

[0020]

[0021] The general structural formula of formula I compound is:

[0022]

[0023] Wherein, R is selected from:

[0024]

[0025] Optionally, compounds of formula I include the following compounds:

[0026]

[0027] Further, the base added in the above-mentioned acylation reaction includes N,N-diisopropylethylamine, triethylamine, N-methylmorpholine and 1,8-diazabicycloundec-7 -at least one of alkenes. Optionally, the equivalent of the base added is 2-5eq., or 2.5-3.5eq., or 3eq.

[0028] Further, the temperature of the reaction liquid when the base is added in the above acylation reaction is -5-10°C, or 0-...

Embodiment 1-1

[0044] This embodiment provides a synthetic method of ibrutinib, which includes:

[0045] Step S1: the synthesis of formula (I-a) compound, synthetic route is as follows:

[0046]

[0047] Add acrylic acid (100g, 1.39mol, 1.00eq.) to a 2L reaction flask containing 1L of dichloromethane, add carbonyldiimidazole (292.53g, 1.81mol, 1.30eq.) in batches, and stir at 20-30°C for 2 hours , Gas chromatography (GC) detects that the acrylic acid has basically reacted completely. Add 0.5L water to the reaction system to stir and separate the liquid, separate the water phase, repeat 3 times, dichloromethane solution is concentrated under reduced pressure, and the obtained solid is recrystallized with methyl tert-butyl ether After drying, off-white solid 1-(1H-imidazol-1-yl)prop-2-en-1-one (151.07g, 1.23mol) was obtained, which was the compound of formula (I-a), with a yield of 88.50%, HPLC purity 99.55%.

[0048] Step S2: Synthesis of ibrutinib, the synthetic route is as follows:

...

Embodiment 1-2

[0052] This example provides a synthetic method of ibrutinib, the synthetic route of which is consistent with that of Example 1, except that step S2:

[0053]

[0054](R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazol[3,4-d]pyrimidin-4-amine (200g, 0.52mol, 1.00eq.) and 1-(1H-imidazol-1-yl)prop-2-en-1-one (76.20g, 0.62mol, 1.20eq.) were added to a 5L reaction flask containing 3L dichloromethane, Add 1,8-diazabicycloundec-7-ene (197.77g, 1.30mol, 2.50eq.) dropwise at -5-0°C, raise the temperature to 15-25°C and stir for 1 hour, HPLC detects that the reaction is complete, Add 1L of dichloromethane, wash the organic phase twice with 2L of dilute phosphoric acid aqueous solution, wash with 2L of dilute sodium carbonate aqueous solution, wash with 2L of purified water, and concentrate under reduced pressure. The mixed solvent was crystallized, and after drying, ibrutinib (167.39 g, 0.38 mol) was obtained with a yield of 78.85%, a HPLC purity of 99.81%, and a maximum of 0.03%...

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Abstract

The invention provides an ibrutinib synthesis method and belongs to the field of medicine synthesis. The synthesis method includes the step that a compound M and a compound of formula I undergo acylation reaction in the presence of alkaline. The synthesis method is mild in reaction conditions, side reaction is less, obtained ibrutinib is high in yield, and the purity is 99.50 or above. A syntheticroute of the synthesis method is described as follows.

Description

technical field [0001] The present invention relates to the field of drug synthesis, in particular to a synthetic method of ibrutinib. Background technique [0002] Ibrutinib (trade name: IMBRUVICA) is jointly developed by Drug Circulation Company and Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It is the first oral Bruton's Tyrosine Kinase (Bruton's Tyrosine Kinase, BTK) inhibitors. Indications for ibrutinib include mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and CLL with deletion of chromosome 17. In January 2015, the FDA approved the expansion of the indication of ibrutinib to a rare type of non-Hodgkin's lymphoma— The treatment of macroglobulinemia (WM), becoming the first drug to treat the disease. [0003] At present, the synthetic method of ibrutinib mainly uses 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-4-amine as raw material, and carries out Mitsunobu reaction with chiral alcohol , removal of Boc protecting group and acyl...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 方同华陈玉玲江敏张巍孙科陈鑫
Owner HEILONGJIANG ZBD PHARMA
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