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A kind of preparation method of abt-199 intermediate

A technology of ABT-199 and intermediates, applied in the field of organic synthesis, can solve the problems of easy volatilization of boron tribromide, large amount of sodium methoxide, expensive raw materials, etc., and achieve the effect of low cost, high yield and no selectivity

Active Publication Date: 2019-05-21
PHARMA SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] However, this route also has expensive starting materials; the amount of sodium methoxide is too large, and post-treatment produces a lot of waste water; in addition, boron tribromide is easy to volatilize and has high toxicity, which is not convenient for industrial scale-up operation

Method used

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  • A kind of preparation method of abt-199 intermediate
  • A kind of preparation method of abt-199 intermediate
  • A kind of preparation method of abt-199 intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0070] Step 1: Preparation of methyl 2-(2,2-diethoxyethoxy)-4-fluorobenzoate (Ⅲ)

[0071]

[0072] At room temperature, add 150ml of N,N-dimethylacetamide DMAC to a 250ml three-necked flask and start stirring. Add methyl 4-fluorosalicylate (17g, 0.1mol), anhydrous potassium carbonate (27.54g, 0.2mol), 2-bromo-1,1-diethoxyethane (21.76g, 0.11mol), turn on condensed water and heating, the internal temperature is 130-140°C, and keep warm for reaction. The reaction started out as clear and colorless and gradually became dark.

[0073] After 2 hours of reaction, the TLC was controlled, and the reaction was completed. Stop heating and cool down to room temperature (20-30°C). Under the condition of stirring, the reaction solution was slowly poured into 300ml of water, and stirred for 30 minutes. Extract with EA (200ml*3 times), combine the organic phases, wash once with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter with suction, and concentrate t...

Embodiment 2

[0117] Step 1: Preparation of methyl 2-(2,2-diethoxyethoxy)-4-fluorobenzoate (Ⅲ)

[0118]

[0119] At room temperature, add 1500ml of N,N-dimethylacetamide DMAC to a 3000ml three-necked flask and start stirring. Add methyl 4-fluorosalicylate (170g, 1mol), anhydrous potassium carbonate (275.4g, 2mol), 2-bromo-1,1-diethoxyethane (217.6g, 1.1mol) into the reaction flask ), turn on condensed water and heating, the inner temperature is 130-140°C, and keep warm for reaction. The reaction started out as clear and colorless and gradually became dark.

[0120] After 2 hours of reaction, the TLC was controlled, and the reaction was completed. Stop heating and cool down to room temperature (20-30°C). Under the condition of stirring, the reaction solution was slowly poured into 3000ml of water, and stirred for 30 minutes. Extract with EA (2000ml*3 times), combine the organic phases, wash once with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter...

Embodiment 6

[0149] Example 6: Preparation of 2-(1H-pyrrole[2,3-b]pyridine-5-oxyl)-4-fluorobenzoic acid (X)

[0150]

[0151] At room temperature, in a 50ml three-necked flask, add the compound of formula IX (40g, 0.13mmol), 60wt% sulfuric acid (400ml), the volume-to-mass ratio of sulfuric acid to the compound of formula IX is 10:1, stir, heat up to 80°C, keep Temperature reaction for 1.5-2 hours. Sampling LC-MS control, the reaction of raw materials is completed, add water to dilute sulfuric acid to 30wt%, heat up to reflux (100°C) for reaction, and the intermediate is less than 1% after 24-30 hours.

[0152] Stop heating and cool down to room temperature (20-30°C) naturally. Adjust the pH to 2-3 with aqueous sodium hydroxide solution, extract with EA, concentrate the solvent to obtain a solid, and dry to obtain the compound of formula X.

[0153] Yield: 32.3 g, yield: 92.3%.

[0154] MS (M+1): 273.

[0155] 1 H NMR (400MHz, DMSO-d6) δ12.818(s, 1H), 11.760(s, 1H), 8.063(d, J=2.4Hz...

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Abstract

The invention discloses a preparation method of an ABT-199 intermediate. The structure of the intermediate corresponds to a formula XI (shown in the description). The preparation method comprises the steps of carrying out seven reaction steps of condensation, elimination, addition, cyclization, deprotection, hydrolysis and reesterification on a compound of formula I, namely 4-methyl fluorosalicylate, so as to finally obtain the ABT-199 intermediate of the formula XI. The preparation method has the beneficial effects that the raw materials are cheap and easily available, reaction conditions are mild, the selective problem is avoided, and the yield is relatively high; and the preparation method is more applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of an ABT-199 intermediate. Background technique [0002] ABT-199 (Venetoclax), chemical name 2-[(1H-pyrrolo[2,3-B]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl) -4,4-Dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]-nitrogen-[3-nitro-4-[[(tetrahydropyran-4-yl)methyl Base]amino]benzenesulfonamide]methylbenzoate is an experimental B-cell lymphoma factor-2 (BCL-2) inhibitor jointly developed by AbbVie and Roche. BCL-2 is a protein that prevents apoptosis in some cells, including lymphocytes. ABT-199 is designed to selectively inhibit the function of BCL-2 factors, restore the cell communication system, and allow cancer cells to self-destruct, so as to achieve the effect of treating tumors. [0003] [0004] FDA believes that this drug has a significant effect in the treatment of chronic myelogenous leukemia patients with 17p gene deletion ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 彭少平庄银枪江辉
Owner PHARMA SHANGHAI