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Continuous low-cost preparation method of ibrutinib

A low-cost, phenoxyphenyl technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of high cost, excessive use of triphenylphosphine, and large residual amount of raw materials, etc., to achieve low production cost, Solvent recovery is easy to apply, and the effect of high comprehensive yield

Active Publication Date: 2020-05-08
河北合佳医药科技集团股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Aiming at the technical problems existing in the prior art, the technical problem to be solved by the present invention is to overcome the defects in the prior art such as large residual amount of raw materials, excessive use of triphenylphosphine, and high cost; Low cost, environmentally friendly and continuous preparation method of ibrutinib, the obtained ibrutinib HPLC purity ≥ 99%, suitable for industrial production

Method used

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  • Continuous low-cost preparation method of ibrutinib
  • Continuous low-cost preparation method of ibrutinib
  • Continuous low-cost preparation method of ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Add 40ml of dichloromethane to a 100ml reaction flask, and add (2.875g, 0.0095mol) 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidine-4- Amine, (2.479 g, 0.0123 mol) (s)-1-tert-butoxycarbonyl-3-hydroxypiperidine, (2.479 g, 0.0123 mol) triphenylphosphine. Under temperature control at 25°C, diisopropyl azodicarboxylate dichloromethane solution (dissolve 2.492g, 0.0123mol DIAD in 15ml dichloromethane) was added dropwise, and the dripping was completed in 35min, and the reaction was kept for 5h.

[0039]Control the temperature at 0°C, add HCl gas into the reaction solution under stirring, continue for 4 hours, then add sodium chloride aqueous solution for extraction after 3 hours of heat preservation, and add 30ml concentrated hydrochloric acid under stirring for the dichloro phase (organic phase obtained after extraction), and stir After 30 min, the aqueous phase was separated and the two aqueous phases were combined, and the pH was adjusted to 2.8 with 10% aqueous sodium hyd...

Embodiment 2

[0043] Add 40ml of dichloromethane into a 100ml reaction flask, and add (2.875g, 0.0095mol) compound formula II (including 0.358g of compound formula II recovered in Example 1), (1.907g, 0.0095mol) compound formula V, (1.989g, 0.0076mol) compound of formula III. Under temperature control at 25°C, dichloromethane solution of compound formula IV (dissolve 1.533 g, 0.0076 mol of DIAD in 15 ml of dichloromethane) was added dropwise, the dripping was completed in 35 minutes, and the reaction was kept for 5 hours.

[0044] The temperature was controlled at 0°C, and HCl gas was passed into the reaction solution under stirring for 4 hours. Insulation reaction 3h. Add aqueous sodium chloride for extraction. Add 30ml of concentrated hydrochloric acid to the dichloro phase while stirring, stir for 30min, separate the water phase and combine the two water phases, adjust the pH to 3.1 with 10% aqueous sodium hydroxide solution while stirring, add 60ml of ethyl acetate, and extract compou...

Embodiment 3

[0048] Add 40ml of dichloromethane into a 100ml reaction flask, and add (2.875g, 0.0095mol) compound formula II (including 1.014g of compound formula II recovered in Example 2), (2.479g, 0.0123mol) compound formula V, (3.232g, 0.0123mol) compound of formula III. Under temperature control at 20°C, dichloromethane solution of compound formula IV (dissolve 2.492 g, 0.0123 mol of DIAD in 15 ml of dichloromethane) was added dropwise, the dripping was completed in 35 minutes, and the reaction was kept for 5 hours.

[0049] The temperature was controlled at 0°C, and HCl gas was passed into the reaction solution under stirring for 4 hours. Insulation reaction 3h. Add sodium chloride aqueous solution for extraction, add 30ml of concentrated hydrochloric acid while stirring the dichloro phase, separate the water phase after stirring for 30min and combine the two water phases, adjust the pH to 2.5 with 10% sodium hydroxide aqueous solution while stirring, add 60ml of ethyl acetate Este...

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Abstract

The invention discloses a continuous low-cost preparation method of ibrutinib, belonging to the technical field of medicine synthesis. The method comprises the following steps: 1) carrying out a Mitsunobu reaction on a raw material, DIAD and triphenylphosphine to obtain an intermediate; 2) removing a Boc protecting group from a reaction solution, extracting unreacted 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, and feeding and applying the unreacted 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine indiscriminately; 3) adding dichloromethane into a water phase obtained afterraw material extraction in the step 2), adjusting a pH value by using an aqueous sodium hydroxide solution, separating out an organic phase, carrying out drying by using anhydrous sodium sulfate, anddirectly adding triethylamine and acryloyl chloride for an acylation reaction; and 4) conducting washing, removing impurities, and performing evaporating to remove solvents to obtain ibrutinib. The preparation method of the invention overcomes the defects of large residual quantity of raw materials, excessive use of triphenylphosphine oxide, high cost and the like in the prior art, has the advantages of high comprehensive yield, low production cost, environment friendliness and continuity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of ibrutinib, belonging to the technical field of pharmaceutical synthesis. Background technique [0002] Ibrutinib, also known as Ibrutinib chemical name (R)-1-(3-(4-aMino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyriMidin- 1-yl)piperidin-1-yl)prop-2-en-1-one, CAS number: 936563-96-1, molecular weight 440.5, belongs to small molecule targeted drugs. Jointly developed by Pharmacyclics of the United States and Johnson & Johnson, it is an oral first-in-class drug called Bruton's tyrosine kinase (BTK) inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) ) and other diseases, and was approved by the U.S. Food and Drug Administration (FDA) for marketing on November 13, 2013. Due to its unique and significant therapeutic effect on many diseases, the international sales of this drug have grown rapidly in recent years, and the demand is increasing. increase. Its structura...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 刘振强郑祥樟刘新元刘东娜梁丙辰王宇栋刘艳君
Owner 河北合佳医药科技集团股份有限公司
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