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Novel method for asymmetric synthesis of (1S,2S)-2-fluorocyclopropanecarboxylic acid under catalysis of chiral rhodium catalyst

A technology of rhodium catalyst and fluorocyclopropane, which is applied in the field of asymmetric synthesis of 2-fluorocyclopropanecarboxylic acid catalyzed by chiral rhodium catalyst, which can solve the problems of high Trans/Cis ratio and no absolute configuration stereoselectivity

Active Publication Date: 2019-11-22
CHEN STONE GUANGZHOU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] 2) The method reported in the literature uses dipolytriphenylacetic acid rhodium acetate catalyst to catalyze the cyclopropanation reaction, the Trans / Cis ratio is high, and it has good cis / trans stereoselectivity, but there is no stereoselectivity of absolute configuration

Method used

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  • Novel method for asymmetric synthesis of (1S,2S)-2-fluorocyclopropanecarboxylic acid under catalysis of chiral rhodium catalyst
  • Novel method for asymmetric synthesis of (1S,2S)-2-fluorocyclopropanecarboxylic acid under catalysis of chiral rhodium catalyst
  • Novel method for asymmetric synthesis of (1S,2S)-2-fluorocyclopropanecarboxylic acid under catalysis of chiral rhodium catalyst

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1: Rh 2 {(s)-nta} 4 Synthesis

[0094]

[0095] Take a 500mL three-neck flask, add DMF (300mL), 1,8-naphthalene dicarboxylic anhydride (30 g, 151.4mmol), L-alanine (13.5g, 151.4mmol) in turn under stirring; heat up to 145°C-150°C The reaction was continued for 5 hours; the reaction solution was concentrated to obtain the crude compound 1-2; the crude product was purified by silica gel column to obtain 26.5 g of compound 1-2.

[0096] Take a 250mL three-neck flask, add chlorobenzene (150mL), compound 1-2 (12.2g, 45.2mmol) and dimeric rhodium acetate (5g, 11.3mmol) sequentially under stirring; heat up to 130°C-135°C, and reflux for 3 hours ; The there-necked flask is equipped with a vacuum distillation device, and the solvent is distilled while stirring the reaction until it does not drop; add n-hexane (60mL), make a slurry, filter, and dry the solid to obtain 14g Rh 2 {(s)-nta} 4 .

[0097] Compound 1-2, 1 HNMR (DMSO-d 6 ,400MHz):δ12.3(br,1H),8.49~8.53(...

Embodiment 2

[0098] Example 2: Rh 2 {(s)-nttl} 4 Synthesis

[0099]

[0100] Take a 500mL three-neck flask, add DMF (300mL), 1,8-naphthalene dicarboxylic anhydride (30 g, 151.4mmol), L-tert-leucine (19.9g, 151.4mmol) in turn under stirring; The reaction was continued at °C for 5 hours; the reaction solution was concentrated to obtain a crude compound 2-2; the crude product was purified by a silica gel column to obtain 28 g of compound 2-2.

[0101] Take a 250mL three-neck flask, add chlorobenzene (150mL), compound 2-2 (14.1g, 45.2mmol) and dimerized rhodium acetate (5g, 11.3mmol) in sequence under stirring; heat up to 130°C-135°C, and reflux for 3 hours ; The vacuum distillation device is configured on the three-necked flask, and the solvent is distilled while stirring the reaction until it does not drop; Add n-hexane (60mL), make a slurry, filter, and dry the solid to obtain 16g Rh 2 {(s)-nttl} 4 .

[0102] Compound 2-2, 1 HNMR (CDCl 3 ,400MHz):δ12.1(br,1H),8.58~8.62(m,2H), 8.20...

Embodiment 3

[0103] Example 3: Rh 2 {(s)-bpttl} 4 Synthesis

[0104]

[0105] Take a 500mL three-neck flask, add DMF (300mL), 2,3-naphthalene dianhydride (30g, 151.4mmol) and L-tert-leucine (19.9g, 151.4mmol) in turn under stirring; heat up to 145°C-150°C The reaction was continued for 5 hours; the reaction solution was concentrated to obtain a crude compound 3-2; the crude product was purified by a silica gel column to obtain 27 g of compound 3-2.

[0106] Take a 250mL three-neck flask, add chlorobenzene (150mL), compound 3-2 (14.1g, 45.2mmol) and dimeric rhodium acetate (5g, 11.3mmol) in sequence under stirring; heat up to 130°C-135°C, and reflux for 3 hours ; The there-necked flask is equipped with a vacuum distillation device, and the solvent is distilled while stirring the reaction, and distilled until it does not drop; add n-hexane (60mL), make a slurry, filter, and dry the solid to obtain 15g Rh 2 {(s)-bpttl} 4 .

[0107] Compound 3-2, 1 HNMR (CDCl 3 ,400MHz):δ12.7(br,1H),...

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Abstract

The invention provides a novel method for asymmetric synthesis of (1S, 2S)-2-fluorocyclopropanecarboxylic acid under catalysis of a chiral rhodium catalyst. The chiral rhodium catalyst not only can catalyze 1-fluoro-1-benzenesulfonyl ethylene and ethyl diazoacetate to carry out asymmetric cyclization reaction, but also can catalyze 1-fluoro-1-chloroethylene and ethyl diazoacetate to carry out asymmetric cyclization reaction. The method provided by the invention has the advantages that the universality is good, and the reaction yield is high, wherein the SS / RR value of (1S, 2S)-2-fluorocyclopropanecarboxylic acid is as high as 98%, so that the preparation cost is greatly reduced, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a novel method for asymmetrically synthesizing (1S, 2S)-2-fluorocyclopropanecarboxylic acid catalyzed by a chiral rhodium catalyst. Background technique [0002] Sitafloxacin is a broad-spectrum quinolone antibacterial drug developed by Daiichi Sankyo, and its monohydrate is used clinically. It not only has antibacterial activity against Gram-negative bacteria, but also has strong antibacterial activity against Gram-positive bacteria, anaerobic bacteria, mycoplasma, chlamydia, etc. It also has good bactericidal effect on many common clinical fluoroquinolone-resistant strains. [0003] Sitafloxacin was listed in Japan for the first time in June 2008, and will be listed in China, South Korea and other countries in the next few years, and has a very broad market prospect. The compound structure of sitafloxacin contains a key fragment - chiral fluorocyclopropylamine group, which has good pharmacokinetic properties and can reduce a...

Claims

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Application Information

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IPC IPC(8): C07C51/09C07C61/15B01J31/22
CPCC07C51/09C07C315/04B01J31/2208B01J31/2213C07C2601/02C07B2200/07B01J2531/822B01J2531/0208B01J2531/0213B01J2531/0238C07C61/15C07C317/44Y02P20/584
Inventor 赖英杰王绪炎梁龙夏学良
Owner CHEN STONE GUANGZHOU CO LTD
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