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Preparation method of Bcl-2 inhibitor venetoclax and intermediate

A technology of inhibitors and intermediates, applied in the field of drug synthesis, achieves the effects of simple reaction operation, simplified preparation process and reduced synthesis cost

Active Publication Date: 2017-12-22
THE FIRST AFFILIATED HOSPITAL OF ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The purpose of the present invention is to overcome the defects of the existing synthetic routes and provide a novel preparation method of the Bc1-2 inhibitor venetoclax and its intermediates. The preparation method has mild reaction conditions, simple and convenient operation, environmental protection, high efficiency and low cost, and is easy for large-scale production

Method used

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  • Preparation method of Bcl-2 inhibitor venetoclax and intermediate
  • Preparation method of Bcl-2 inhibitor venetoclax and intermediate
  • Preparation method of Bcl-2 inhibitor venetoclax and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Preparation of methyl 4-fluorosalicylate (compound II)

[0031]

[0032] The preparation of methyl 4-fluorosalicylate (II) involves two steps.

[0033] Step 1: Preparation of 4-fluorosalicylic acid

[0034]Dimethylsulfoxide (DMSO, 4L) was added to a dry 10L four-necked flask, 2,4-difluorobenzoic acid (500g, 3.16mol) and NaOH (253g, 6.32mol) were added under stirring, and the temperature was raised to 130°C, reacted for about 8 hours, and detected by TLC. After the reaction was complete, the reaction system dropped to room temperature, and the reaction solution was slowly poured into 40L of ice water, and the pH was adjusted to 2-3 with concentrated hydrochloric acid (the temperature during the pH adjustment process should not be higher than 20°C), a large amount of solids were precipitated, continued to stir for 2h and then suction filtered, the filter cake was washed with an appropriate amount of water to obtain a white solid, and dried under reduced pre...

Embodiment 2

[0037] Embodiment two: the preparation of compound III

[0038]

[0039] Add DMSO (5L) into a dry 10L four-neck flask, add compound II (400g, 2.35mol) under stirring, slowly add piperazine (607g, 7.05mol), react at room temperature for 5h, and detect by TLC. After the reaction is complete, the The reaction solution was slowly poured into 40L of ice water, extracted with ethyl acetate (20L×3), the ethyl acetate was combined, and the organic phase was washed three times with saturated brine (10L×3), dried and concentrated under reduced pressure to obtain 500g of compound III , The crude yield is 90%. It was directly used in the next reaction without purification.

Embodiment 3

[0040] Embodiment three: the preparation of compound V

[0041]

[0042] Add dichloromethane (7L) into a 10L four-neck flask, add compound III (500g, 2.11mol) and raw material IV (577g, 2.32mol) under stirring, and slowly add sodium triacetoxyborohydride (352g, 1.67 mol), temperature control is not higher than 30 °C, after addition, react at room temperature for 5 hours, TLC monitoring, after the reaction is complete, add saturated saline (1.5L×2) to wash twice, the organic phase is dried with anhydrous magnesium sulfate, and suction filtered , concentrated under reduced pressure, dissolved the concentrate in ethyl acetate (1L), and heated to 50°C to dissolve, then slowly added n-hexane (5L) dropwise, solids gradually precipitated, kept at 10-15°C and stirred for 2h, then suction filtered , the filter cake was washed with a mixed solvent (0.5 L) of ethyl acetate and n-hexane (volume ratio 1:3), and air-dried at 50° C. to obtain 794 g of an off-white solid, with a yield of 8...

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Abstract

The invention relates to a preparation method of an intermediate needed for preparing a Bcl-2 inhibitor venetoclax. The synthetic route is represented as follows, and specifically comprises the following steps: using a compound I 2,4-difluorobenzoic acid as a raw material, performing hydroxylation and methyl esterification reactions to obtain a compound II methyl 4-fluoro-2-hydroxybenzoate; performing coupling on the compound II and piperazine to obtain a compound III; performing a reaction on the compound III with a raw material IV to obtain a compound V; and performing C-O coupling on the compound V and a compound VI 5-bromo-7-azaindole to obtain a compound VII, which is the intermediate. The preparation method provided by the invention has a mild reaction condition, has simple operation, is environmental friendly and high efficient, has low cost and is easy for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a novel synthesis method of a Bcl-2 inhibitor venetoclax and an intermediate. Background technique [0002] Venetoclax is a B-cell lymphoma-2 gene (B-ce111ymphoma-2, referred to as Bcl-2) inhibitor jointly developed by AbbVie and Roche. In its phase I clinical trial (NCT01328626), for the enrolled patients In 84 patients with relapsed / refractory CLL / SLL, the response rate of venetoclax to CLL / SLL was 79% (complete response rate was 22%), and the median duration of response was 20.5 months; for 44 patients with relapsed / refractory In patients with curative non-Hodgkin's lymphoma, the response rate to venetoclax was 48% (complete response rate was 7.5%). Subsequent studies have confirmed that venetoclax is as effective as obinutuzumab, idelalisib, ibrutinib and other anti-tumor drugs, and has received FDA breakthrough drug certification. In June 2016, venetocla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 程伟彦田鑫张晓坚杨志衡杜玥袁永亮
Owner THE FIRST AFFILIATED HOSPITAL OF ZHENGZHOU UNIV
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