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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

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Problems solved by technology

[0015] In this route, Mitsunobu reaction occurs with 3-iodo-4-aminopyrazolo[3,4-d]pyrimidine as a raw material, and the raw material cost of the iodide is high, and the yield of Mitsunobu reaction step is only 25%

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

Embodiment 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 a light brown suspension The turbid solution was lowered to 0°C, and DIAD (198.4g, 0.98mol) was added dropwise. During the dropwise addition, the temperature was kept below 5°C, and the solution gradually turned into light yellow and clear. After dropping, it gradually rose to 20°C and stirred for 3 hours. Then, concentrated hydrochloric acid was added. (10eq), raised to 50°C and stirred for 2h, cooled to room temperature, filtered, the filter cake was washed with a small amount of THF, vacuum concentrated to dryness to constant weight to obtain 74.0g of off-white solid, yield 71.0%, chemical purity 98.5%. Take 30g and dissociate with aqueous sodium bicarbonate to obtain 22.9g of free base, with a dissociation rate of 95.1% and a chemical purity of 98.5%. m / z(MH...

Embodiment 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 a light brown suspension The turbid liquid was lowered to 0°C, and DEAD (170.8g, 0.98mol) was added dropwise. During the dropping process, the temperature was kept below 5°C, and the solution gradually turned into light yellow and clear. After the drop, it gradually rose to 20°C and stirred for 3 hours. Then, concentrated hydrochloric acid was added. (10eq), raised 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 constant weight to obtain 70.3g of off-white solid with a yield of 67.8% and a chemical purity of 98.3%.

Embodiment 3

[0056]

[0057] 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 dropped into 1,4-dioxane ( 200mL) and water (80mL) mixed solvent, pass through nitrogen to carry out bubbling 20min, add Pd(PPh 3 ) 4 (0.62g, 5.4×10 -4 mol), continue to feed nitrogen bubbles for 5 min, heat to reflux and stir for 5 h, the reaction solution is concentrated, ethyl acetate (100 mL) and water (100 mL) are added, the pH is adjusted to 2-3 with hydrochloric acid, liquid separation, and the aqueous phase Add ethyl acetate (100mL) for extraction 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 the layers, and dry the organic layer with anhydrous sodium sulfate. Evaporate to dryness to obtain 18.8 g of off-white solid, which is the free base of compound 6, with a yield of 90.0% and a chemic...

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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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