Synthesis of bcl-2 inhibitor abt-199

A technology of ABT-199 and bcl-2, applied in the field of drug synthesis, can solve the problems of inability to purify, low yield, low yield of compound 5, etc., and achieve the effects of simple steps and cheap raw materials

Active Publication Date: 2016-06-01
南京正济医药销售有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] When this method is preparing compound 5, since compound 4 has two Fs, both can participate in the reaction, resulting in a very low yield of compound 5, and it cannot be purified, and the reaction is carried out to generate a mixture of 2-position substitution and 4-position substitution; During the reaction, the TIPS protecting group is removed, resulting in the reaction of -OH in the substrate with another molecule of N itself, resulting in a very low yield

Method used

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  • Synthesis of bcl-2 inhibitor abt-199
  • Synthesis of bcl-2 inhibitor abt-199
  • Synthesis of bcl-2 inhibitor abt-199

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] The preparation of embodiment one compound (F)

[0020]

[0021] Step 1: Synthesis of compound (C)

[0022] Add 50.0g of methyl 2-fluoro-4-nitrobenzoate into a 1L three-necked flask, dissolve it in 250ml of N'N-dimethylformamide, add 33.6g of 5-hydroxy-7-azaindole in sequence, Potassium carbonate was 34.7g, and the reaction liquid was heated at 50°C for 2 hours under the protection of nitrogen gas, then poured into 2L of ice water, extracted three times with ethyl acetate, and the organic phase was dried with saturated sodium chloride and then spin-dried to obtain the crude product of compound (C) 82.0 g, the crude product was directly put into the next reaction without purification.

[0023] The second step: synthetic compound (D)

[0024] Dissolve the crude product of the compound (C) in the previous step with 400ml of methanol, add 4.0g of 10% palladium carbon, and react with hydrogen gas under normal pressure. Purification directly into the next reaction.

[...

Embodiment 2

[0027] The preparation of embodiment two compound (H)

[0028]

[0029] Take 5.0 g of compound (G) (prepared according to the method in WO2012058392), dissolve it in 50 ml of dichloromethane, add 5.6 ml of triethylamine, stir and cool the reaction solution to 0-5 degrees, add 2.7 g of methanesulfonyl chloride dropwise, and complete the addition The reaction solution was raised to room temperature and reacted overnight. After the reaction was detected by TLC, water was added to quench the reaction. The organic phase was dried over anhydrous sodium sulfate and the solvent was spun off. Purification by silica gel column chromatography gave 6.5 g of compound (H), with a yield of 99%.

Embodiment 3

[0030] The preparation of embodiment three ABT-199

[0031]

[0032] The first step: synthesis of compound (I)

[0033] Add 2.5g of compound (F), 2.3g of compound (H), 1.9g of potassium carbonate, and 15ml of N'N-dimethylformamide in a 100ml three-necked flask, and react at 50 degrees under nitrogen protection. After the reaction is detected by TLC The reaction solution was poured into ice water, extracted twice by adding ethyl acetate, the ethyl acetate phase was dried over anhydrous sodium sulfate and then spin-dried, purified by silica gel column chromatography to obtain 3.6 g of compound (I), with a yield of 88%.

[0034] The second step: synthesis of compound (J)

[0035] Add 1.0 g of compound (I) to a 10 ml single-necked bottle, followed by adding 5 ml of water, 5 ml of ethanol, 5 ml of tetrahydrofuran, and 136 mg of sodium hydroxide. pH4-5, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate and then spin-dried to obtain 907 mg of compound...

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Abstract

The invention discloses a synthesis method of a Bcl-2 inhibitor ABT-199. The method comprises the following steps: by using methyl 2-fluoro-4-nitrobenzoate and 5-hydroxy-7-azaindole as raw materials, carrying out substitution, reduction, cyclization, substitution, hydrolysis, condensation and the like to synthesize the ABT-199. The method has the characteristics of mild reaction conditions, simple operating technique, low cost and high yield.

Description

(1) Technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular, the invention relates to a synthesis method of Bcl-2 inhibitor ABT-199. (2) Technical background [0002] The B-lymphoma-2 gene is referred to as bcl-2 (B-celllymphoma-2), which is one of the most important oncogenes in cell apoptosis research. Bcl-2 gene (namely B-cell lymphoma / leukemia-2 gene) is a proto-oncogene, which can inhibit apoptosis, and some studies in recent years have begun to reveal the mechanism of this effect. The Bcl-2 protein family that has been discovered so far can be divided into two categories according to their functions. One category has the same anti-apoptotic effect as Bcl-2, such as mammalian Bcl-XL, Bcl-W, Mcl-1, A1, nematode Ced-9, vaccinia virus E1B119kD, etc., while another type has the effect of promoting apoptosis, such as Bax, Bcl-Xs, Bax, Bak, Bik / Nbk, Bid and Harakiri. In the animal kingdom, most cell death is achieved by apopt...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 葛敏许云雷
Owner 南京正济医药销售有限公司
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