Preparation method for ibrutinib

A technology of ibrutinib and its compound, which is applied in the field of preparation of ibrutinib, can solve the problems of high cost of iodide raw materials, the yield of Mitsunobu reaction step is only 25%, and achieve the effect of high product yield and purity

Inactive Publication Date: 2016-10-05
SHANGHAI DUDE MEDICAL SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In this route, Mitsunobu reaction occurs with 3-iodo-4-aminopyrazolo[3,4-d]pyrimidine as a raw mate

Method used

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  • Preparation method for ibrutinib
  • Preparation method for ibrutinib
  • Preparation method for ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0049] Example 1

[0050]

[0051] Under nitrogen protection, the compound of formula 1 (60g, 0.28mol), the compound of formula 2 (84.6g, 0.42mol) and triphenylphosphine (257.4g, 0.98mol) were added to anhydrous THF (10eq volume), and the suspension was light brown Turbid liquid, drop to 0°C, add DIAD (198.4g, 0.98mol) dropwise, keep the temperature below 5°C during the dropping process, the solution gradually turns into pale yellow and clear, and gradually rise to 20°C after dropping and stir for 3h, add concentrated hydrochloric acid (10eq), heated to 50°C and stirred for 2h, cooled to room temperature, filtered, the filter cake was washed with a small amount of THF, and concentrated in vacuo to dryness to a constant weight to obtain 74.0g of off-white solid with a yield of 71.0% and a chemical purity of 98.5%. Take 30 g and free it with sodium bicarbonate aqueous solution to obtain 22.9 g of free alkali with a free rate of 95.1% and a chemical purity of 98.5%. m / z(MH+)297,1H ...

Example Embodiment

[0052] Example 2

[0053]

[0054] Under nitrogen protection, the compound of formula 1 (60g, 0.28mol), the compound of formula 2 (84.6g, 0.42mol) and triphenylphosphine (257.4g, 0.98mol) were added to anhydrous THF (10eq volume), and the suspension was light brown Turbid liquid, drop to 0°C, add DEAD (170.8g, 0.98mol) dropwise, keep the temperature below 5°C during the dropping process, the solution gradually turns to pale yellow and clear, and gradually rise to 20°C after dropping and stir for 3h, add concentrated hydrochloric acid (10eq), heated to 50°C and stirred for 2h, cooled to room temperature, filtered, the filter cake was washed with a small amount of THF, concentrated in vacuo to dryness to constant weight to obtain 70.3g of off-white solid, yield 67.8%, chemical purity 98.3%.

Example Embodiment

[0055] Example 3

[0056]

[0057] The dihydrochloride (20g, 0.054mol) of the compound of formula 4, 4-phenoxyphenylboronic acid (17.35g, 0.081mol) and potassium phosphate (40.15g, 0.19mol) were put into 1,4-dioxane ( 200mL) and water (80mL) mixed solvent, bubbling with nitrogen for 20min, adding Pd(PPh 3 ) 4 (0.62g, 5.4×10 -4 mol), bubbling with nitrogen for 5 minutes, heating to reflux and stirring for 5 hours, the reaction solution is concentrated, ethyl acetate (100mL) and water (100mL) are added, the pH is adjusted to 2-3 with hydrochloric acid, and the solution is separated into the water phase Add ethyl acetate (100mL) to extract once, add dichloromethane (200mL) to the aqueous phase after liquid separation, adjust the pH to 9-10 with 6N sodium hydroxide solution, stir and separate, and dry the organic layer with anhydrous sodium sulfate. It was evaporated to dryness to obtain 18.8 g of off-white solid, which was compound 6 free base, with a yield of 90.0% and a chemical p...

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Abstract

The invention specifically relates to a preparation method for ibrutinib, belonging to the field of pharmaceutical chemistry. The preparation method comprises the following steps: reacting a compound as shown in a formula 1 which is described in the specification with a compound as shown in a formula 2 which is described in the specification in the presence of a Mitsunobu reaction reagent so as to obtain a compound as shown in a formula 3 which is described in the specification, and removing protective groups of the compound as shown in the formula 3 in the presence of acid so as to produce a compound as shown in a formula 4 which is described in the specification; subjecting the compound as shown in the formula 4 and a compound as shown in a formula 5 which is described in the specification to a Suzuki coupling reaction in the presence of a catalyst so as to produce a compound as shown in a formula 6 which is described in the specification; and reacting the compound as shown in the formula 6 with acryloyl chloride in the presence of alkali so as to produce ibrutinib. The method has the advantages of high yield of each step, easy purification of the product, high product purity and good industrial production prospects.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, specifically, the present invention relates to the preparation method of Ibrutinib (Ibrutinib, trade name: Imbruvica) and the intermediate used. Background technique [0002] Bruton's tyrosine kinase is a key signaling molecule in the B cell receptor signaling complex, which plays an important role in the survival and spread of malignant B cells. Ibrutinib is a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor jointly developed by Pharmacyclics Inc and Janssen Biotech. Ibrutinib can block the uncontrolled proliferation and spread of malignant B cells signaling pathway, induces apoptosis and inhibits cell migration and adhesion of malignant B cells. The drug was first launched in the United States in November 2013. The indication is mantle cell lymphoma (MCL) that has received previous treatment. Recently, it has also been approved for chronic lymphocytic leukemia and patient...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 张喜全孔锐刘新陈姗陈晓萍杨雷雷张爱明程兴栋
Owner SHANGHAI DUDE MEDICAL SCI & TECH CO LTD
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