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Acalabrutinib and synthesizing method for intermediate thereof

A synthesis method and technology for intermediates, which are applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of high cost of enlarged production routes, cumbersome processes, and excessively long linear steps, and achieve the reduction of heavy metal residues, high product purity, and reduced The effect of process cost

Active Publication Date: 2018-07-06
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The linear steps of this route are too long, the process is relatively cumbersome, and the cost of enlarging the production route is relatively high

Method used

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  • Acalabrutinib and synthesizing method for intermediate thereof
  • Acalabrutinib and synthesizing method for intermediate thereof
  • Acalabrutinib and synthesizing method for intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046]

[0047] Add compound 1a (21.33g, 100mmol), 2-chloro-2-formyl acetonitrile (10.35, 100mmol) and acetonitrile (106mL) into the three-necked flask, add triethylamine (20.23g, 200mmol), stir well and heat to reflux React overnight. At the end of the reaction, some isopropanol was spun off, and water (213 mL) was added to precipitate a large amount of solid, which was filtered, and the crude product was slurried with a mixed solvent of isopropanol and petroleum ether, filtered and dried to obtain compound 2a (21.77 g, 83%). MS(ESI)m / z=263.2[M+H] + .

Embodiment 2

[0049]

[0050] Add compound 1b (24.73g, 100mmol), 2-chloro-2-formyl acetonitrile (10.35, 100mmol) and DMAC (124mL) into the three-necked flask, add potassium carbonate (27.64g, 200mmol), stir well and heat to 75~ React overnight at 80°C. After the reaction was completed, water (247 mL) was added, and a large amount of solid precipitated out, which was filtered, and the crude product was slurried with a mixed solvent of isopropanol and petroleum ether, filtered and dried to obtain compound 2b (23.11 g, 78%). MS(ESI)m / z=297.1[M+H] + .

Embodiment 3

[0052]

[0053] Compound 2a (26.23g, 100mmol) and acetonitrile (131mL) were added into a three-neck flask, stirred evenly, NBS (19.58g, 110mmol) was added, and reacted at 25-30°C for 4-6 hours. At the end of the reaction, part of the acetonitrile was spun off, and 5% sodium bisulfite solution (262 mL) was added to precipitate a large amount of solid, which was filtered, and the crude product was slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered and dried to obtain compound 3a (29.68 g, 87%) . MS(ESI)m / z=341.0[M+H] +1 HNMR(400MHz,DMSO-d6)δ12.72(br,1H),4.66-4.85(m,1H),3.18-3.40(m,2H),1.71-2.30(m,4H),1.14-1.45(m, 9H).

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Abstract

The invention discloses an Acalabrutinib synthesizing method which comprises the steps: utilizing L-proline derivative compound shown in a formula 1 and 2-chloro-2-formyl acetonitrile as beginning rawmaterials to directly condense and cyclize to obtain a compound in a formula 2; after bromination, reacting with cheap chloroacetaldehyde dimethyl acetal to obtain intermediate compound in a formula3; obtaining key intermediate compound shown in a formula 6 through hydrolysis and cyclization reaction; then performing Suzuki coupling with borate intermediate compound shown in a formula 8; then de-protecting and salifying to obtain compound shown in a formula 10; finally, performing condensation with tetrolic acid to obtain a final product Acalabrutinib shown in a formula 11. The path has theadvantages of simpleness in operation, higher total yield and suitability for enlarged production, and a purity of the obtained product is also higher.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a chemical synthesis method of an Acalabrutinib intermediate and a raw material medicine for treating malignant tumors. Background technique [0002] Acalabrutinib (ACP-196) is a second-generation Bruton's tyrosine kinase (BTK) inhibitor developed by AstraZeneca for the treatment of chronic lymphocytic leukemia. Compared with the first-generation BTK inhibitor ibrutinib, it has higher drug selectivity and lower side effects. On October 31, 2017, Acalabrutinib was approved for marketing by the FDA in an ultra-fast manner. The approved indications are for patients with mantle cell lymphoma who have failed at least one line of treatment in the past. At present, clinical trials for other indications are also progressing smoothly. market expectation. [0003] The chemical name of Acalabrutinib is: (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]piperidin-1-...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D487/04
CPCC07D403/04C07D487/04Y02P20/55
Inventor 郑旭春张一平付晨晨
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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