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Synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and intermediate

A technology of dioxole and cyclopropanecarboxylic acid is applied in the field of medicinal chemistry synthesis, and can solve the problems of residual palladium in the product, danger of sodium cyanide reagent, low overall yield, etc., so as to improve yield, ensure safety, reduce cost effect

Active Publication Date: 2015-12-16
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 material is 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 is not suitable for industrialization 4. The overall yield of reaction is very low

Method used

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  • Synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and intermediate
  • Synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and intermediate
  • Synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: the synthesis of compound 6a

[0069]

[0070] Add compound 7a (50g, 0.255mol) and 250ml of dichloromethane into a 1L three-necked flask, stir at room temperature, add carbonyldiimidazole (62g, 0.382mol) in batches, react at room temperature for 1h, add 50ml of methanol, stir for 1h, and The reaction solution was poured into a separatory funnel, 200ml of water was added for extraction, the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain 50g of compound 6a, with a yield of 93.3%.

Embodiment 2

[0071] Embodiment 2: the synthesis of compound 5a

[0072]

[0073] Into a 250mL three-neck flask, add compound 6a (10g, 0.048mol), 80ml tetrahydrofuran, add paraformaldehyde (15g, 0.48mol), potassium carbonate (20g, 0.144mol) in sequence, and react at 40°C for 2h. After the reaction was complete, pour the reaction solution into a separatory funnel, add 100ml of water and 150ml of tetrahydrofuran for extraction, collect the organic layer, dry over anhydrous sodium sulfate, filter, and spin the filtrate under reduced pressure to obtain 9.6g of compound 5a, with a yield of 90.0 %.

Embodiment 3

[0074] Embodiment 3: the synthesis of compound 4a

[0075]

[0076] Under the protection of nitrogen, trimethylsulfoxide iodide (44.0 g, 0.2 mol), 100 ml of DMF, and potassium tert-butoxide (22.3 g, 0.2 mol) were added to a 250 ml round bottom flask, and stirred at room temperature for 45 min. Compound 5a (22.2 g, 0.1 mol) was dissolved in 70 ml of DMF, and slowly added to the above solution, and the temperature of the reaction system was raised to 35°C. Heat to 45°C, react for 1 hour, cool the reaction system to 0-5°C, add 80ml of 2N hydrochloric acid solution dropwise, add 250ml of ethyl acetate to extract the water layer, dry over anhydrous sodium sulfate, filter, and spin dry the filtrate under reduced pressure to obtain 20.8g Compound 4a, yield 88.1%. 1H NMR (400MHz, DMSO) 6.90 (d, J=1.7Hz, H), 6.87–6.82 (m, 2H), 3.74 (s, 3H), 3.74 (s, 3H), 3.54 (s, 3H), 1.45 ( q,J=3.8Hz,2H),1.17(q,J=4.0Hz,2H).

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Abstract

The invention belongs to the field of chemical synthesis of drugs, particularly relates to a synthetic method of 1-(2,2-difluoro-benzo[d][1,3]) dioxole-5-yl) cyclopropanecarboxylic acid and an intermediate and aims to provide a synthesis method of a compound (1). The method comprises steps as follows: a, a compound (4) and boron tribromide react, and a compound (3) is synthesized; b, the compound (3) and difluorodibromomethane have a ring closing reaction in the presence of a phase-transfer catalyst, and a compound (2) is synthesized; c, the compound (2) is hydrolyzed, and the compound (1) is synthesized. According to the synthetic method and the intermediate, one novel compound (4) is provided, one novel preparation method of the compound (1) is obtained, with the adoption of the method, not only can the overall yield of the reaction be increased, but also expensive reaction raw materials can be avoided, and the reaction cost is reduced to the great extent; besides, according to the method, utilization of a palladium catalyst and a dangerous sodium cyanide reagent can further be avoided, the safety of pharmaceutical production is guaranteed, 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 synthesis method of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid and the method thereof intermediate. Background technique [0002] Cystic fibrosis (CF) is a serious, life-threatening genetic disease caused by defects in the CF transmembrane conductance regulator (CFTR). Normal CFTR is a chloride ion channel protein present on the cell membrane, through which chloride ions can freely enter and exit cells, and cells can also secrete a thin layer of mucus to protect the airway epithelium. In 90% of CF patients, the F508del mutation (deletion of phenylalanine at position 508 in CFTR) will appear in the CFTR gene of 90% of CF patients. When this mutation occurs, CFTR cannot be folded normally, and it is easily degraded after synthesis, resulting in cell damage. The number of CFTR is greatly reduced, so that chloride ions cannot f...

Claims

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Application Information

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IPC IPC(8): C07D317/46C07C69/757
CPCC07C69/757C07D317/46
Inventor 叶天健陆修伟郁光亮何思
Owner ZHEJIANG YONGNING PHARMA
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