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Preparation method of benzo[1,3-d]dioxole and its intermediate

A dioxole, 3-d technology, applied in the direction of organic chemistry, bulk chemical production, etc., can solve the problems of low overall yield, unsuitable for industrial production, dangerous sodium cyanide reagent, etc., and shorten the reaction route. , the effect of improving the overall yield of the reaction

Active Publication Date: 2020-04-10
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are following defects in this route: 1. the reaction raw materials are expensive, which is unfavorable for cost control; 2. palladium catalyst is used in the reaction process, and there are palladium residues in the product easily; 3. the sodium cyanide reagent used in the reaction is more dangerous and unsuitable 4. The overall reaction yield is very low, only 1.2%

Method used

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  • Preparation method of benzo[1,3-d]dioxole and its intermediate
  • Preparation method of benzo[1,3-d]dioxole and its intermediate
  • Preparation method of benzo[1,3-d]dioxole and its intermediate

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Effect test

Embodiment 1

[0047]

[0048] Add compound 5 (20g, 1.0eq) and methanol (90ml) to the reaction kettle, add thionyl chloride (11ml, 1.5eq) dropwise while maintaining the temperature below 0°C, move to room temperature and stir until the reaction is complete, then evaporate to dryness The solvent was diluted with ethyl acetate (250ml) successively, washed with water (100ml), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 19.59g of a brown solid (91.8% yield).

Embodiment 2

[0050]

[0051] Add compound 4a (3.00g, 1 equivalent), toluene (25ml) and PCl in the reaction kettle 5 (8.52g, 3 equivalents), the system was 80°C until the reaction was complete, cooled to room temperature, quickly washed with water to remove acidic by-products, evaporated toluene to obtain a yellow oil, and the oil was separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1) A total of 3.50 g (yield 88.8%) of off-white solid compound 3a was obtained (it can also be directly used in the next step without purification by column chromatography).

[0052] 1 H NMR (400MHz, DMSO) δ7.51(d, J=1.5Hz, 1H), 7.40(d, J=8.3Hz, 1H), 7.27(dd, J=8.3, 1.8Hz, 1H), 3.55(s ,3H),1.52(q,J=4.1Hz,2H),1.24(q,J=4.1Hz,2H); figure 1 shown.

Embodiment 3

[0054]

[0055]Add compound 3a (3.50g, 1 equivalent) into the reaction kettle, add TEA*3HF (6.7ml, 3 equivalents) dropwise under stirring, stir at room temperature for 48 hours, add ethyl acetate (50ml) and water (50ml) to the system successively liquid, and the organic phase was evaporated to dryness to obtain 3.00 g of compound 2a (yield 96.7%).

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Abstract

The invention relates to the field of medicinal chemical synthesis, and discloses a method for preparing benzo[1,3-d] dioxole and an intermediate of benzo[1,3-d] dioxole. The method comprises the following steps: performing three steps of reactions of chloro-substitution, fluorination and deprotection on a compound of formula (4) as shown in the specification so as to prepare a compound of formula (1) as shown in the specification, and in the formulae, R is a carboxyl protection group. By adopting the method, the problems that in the prior art, the yield of benzo[1,3-d] dioxole is low and the reaction operation is not safe can be solved, the compound of the formula (4) is adopted as a raw material which is directly introduced into a three-membered ring structure, so that a dangerous sodium cyanide reagent is not used, and moreover, a reaction route is shortened, the overall yield of the reaction can be greatly increased, and the method is applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of benzo[1,3-d]dioxole and an intermediate thereof. Background technique [0002] Lumacaftor is a CFTR modulator developed by Vertex Pharmaceuticals and approved for the treatment of cystic fibrosis. Its structural formula is as follows: [0003] [0004] In the preparation process of a series of CFTR modulators such as lumacaftor, benzo[1,3-d]dioxole represented by formula (1) is a key intermediate: [0005] [0006] Patent CN101356170 discloses the preparation of benzo[1,3- d] the method of dioxole, concrete route is as follows: [0007] [0008] There are following defects in this route: 1. the reaction raw materials are expensive, which is unfavorable for cost control; 2. palladium catalyst is used in the reaction process, and palladium residues are easily arranged in the product; 3. the sodium cyanide reagent used ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/46C07D317/60
CPCC07D317/46C07D317/60Y02P20/55
Inventor 叶天健陆修伟郁光亮刘婷
Owner ZHEJIANG YONGNING PHARMA
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