A kind of preparation method of antineoplastic drug acalabrutinib key intermediate

A technology for antitumor drugs and intermediates, which is applied in chemical instruments and methods, compounds containing elements of Group 3/13 of the periodic table, organic chemistry, etc. Production, product purification difficulties and other problems, to achieve the effect of low cost, simple operation, simple post-processing

Active Publication Date: 2020-09-29
浙江合聚生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This method adopts expensive palladium catalyst and intermediate, and product purification is difficult, and yield is low, fails to solve the recycling problem of catalyst, is not suitable for large-scale industrial production

Method used

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  • A kind of preparation method of antineoplastic drug acalabrutinib key intermediate
  • A kind of preparation method of antineoplastic drug acalabrutinib key intermediate
  • A kind of preparation method of antineoplastic drug acalabrutinib key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] In the 500mL reaction flask, add p-bromotoluene (2.4g, 0.014mol), magnesium chips (3.7g, 0.15mol), THF16mL, iodine 10mg, heat up and reflux, after triggering, add dropwise the remaining THF 144mL and p-bromotoluene (21.6 g, 0.126mol) mixed solution, reacted at 70°C for 1 hour after dropping, then cooled to 0°C, added triisopropyl borate (52.6g, 0.28mol) dropwise, reacted for 1 hour after the dropwise addition, and then used 100mL saturated chlorinated The ammonium solution was quenched, separated, and the organic phase was washed with 100 mL of water, dried over anhydrous sodium sulfate, then distilled under reduced pressure, and vacuum-dried to obtain 17.3 g of white solid p-tolueneboronic acid, with a yield of 91%; EI-MSm / z: 137 [M+H]+.

[0040]In a 2L three-necked flask, add p-tolueneboronic acid (30g, 0.22mol), sodium hydroxide (30g, 0.75mol), tetrabutylammonium bromide (4.5g, 0.014mol), nickel chloride (1.8g, 0.014mol ) and 700 mL of water, after stirring evenly, ...

Embodiment 2

[0045] In the 500mL reaction flask, add p-bromotoluene (2.4g, 0.014mol), magnesium chips (5.8g, 0.147mol), THF16mL, iodine 10mg, heat up and reflux, after triggering, add dropwise the remaining THF 144mL and p-bromotoluene (21.6 g, 0.126mol) mixed solution, dropwise reacted at 40°C for 2 hours, then cooled to 0°C, added dropwise triisopropyl borate (63g, 0.21mol), reacted for 1 hour after the dropwise addition, and added 100mL saturated ammonium chloride The solution was quenched, separated, and the organic phase was washed with 100 mL of water, dried over anhydrous sodium sulfate, then distilled under reduced pressure, and vacuum-dried to obtain 15.2 g of p-tolueneboronic acid as a white solid, with a yield of 80%; EI-MSm / z: 137 [M+H]+.

[0046] In a 2L three-necked flask, add p-tolueneboronic acid (30g, 0.22mol), sodium hydroxide (18g, 0.44mol), tetrabutylammonium bromide (4.5g, 0.014mol), nickel chloride (1.8g, 0.014mol) ) and 700 mL of water, after stirring evenly, potass...

Embodiment 3

[0051] In the 500mL reaction flask, add p-bromotoluene (2.4g, 0.014mol), magnesium chips (3.7g, 0.15mol), THF16mL, iodine 10mg, heat up and reflux, after triggering, add dropwise the remaining THF 144mL and p-bromotoluene (21.6 g, 0.126mol) mixed solution, dropwise reacted at 70°C for 1 hour, then cooled to 0°C, added dropwise triisopropyl borate (29g, 0.154mol), reacted for 1 hour after the dropwise addition, and added 100mL saturated ammonium chloride The solution was quenched, separated, and the organic phase was washed with 100 mL of water, dried over anhydrous sodium sulfate, then distilled under reduced pressure, and vacuum-dried to obtain 15.6 g of p-tolueneboronic acid as a white solid, with a yield of 82%; EI-MSm / z: 137 [M+H]+.

[0052] In a 2L three-necked flask, add p-tolueneboronic acid (30g, 0.22mol), sodium hydroxide (35.2g, 0.88mol), tetrabutylammonium bromide (4.5g, 0.014mol), nickel chloride (1.8g, 0.014 mol) and 700 mL of water, after stirring evenly, potass...

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Abstract

The invention relates to a preparation method of an anti-tumor drug Acalabrutinib key intermediate. The preparation method comprises the following steps: with para-bromotoluene as a raw material, generating para-toluene boric acid through a Grignard reaction; performing oxidation through a nickel catalyst and then cyclization; finally, under the effect of DMAP catalysis and EDC hydrochloride, combining 2-aminopyridine to obtain a target product N-2-pyridyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide. According to the preparation method provided by the invention, in the preparation process of N-2-pyridyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide, the use of high-pollution and high-risk solvent or catalyst is avoided, the aftertreatment is simple, the product has high purity and can be directly applied to next reaction without purification; moreover, the operation is simple, the pollution is little, and the cost is low; through an oxidation process of a relatively cheap nickel catalyst efficiently catalyzing potassium permanganate, the yield is increased, and the cost is remarkably lowered.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a key intermediate N-2-pyridyl-4-(4,4,5,5-tetramethyl-1,3,2- The preparation method of dioxaborolan-2-yl)benzamide. Background technique [0002] N-2-pyridyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide is the key to the preparation of ACP-196 intermediate. Acalabrutinib, also known as ACP-196, is an oral inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity. BTK, one of the src sarcoma gene-associated BTK / Tec cytoplasmic tyrosine kinases, is overexpressed in B cell malignancies such that it plays an important role in B lymphocyte development, activation, signal transduction, proliferation and survival. After administration, ACP-196 inhibits the activity of BTK, prevents the activation of B cell antigen receptor (BCR) signaling pathway, prevents the activation of B cells and the activation of BTK-mediated downstream survival ...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07F5/02
CPCC07F5/02
Inventor杨勇杨铭沈超王栋
Owner浙江合聚生物医药有限公司