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New synthesis method of optically pure lactone

A technology of compounds and hydroxy esters, which is applied in the preparation of chiral drug sertraline chiral intermediates and ezetimibe chiral intermediates, and in the field of preparation of chiral lactones, which can solve the problem of large environmental pollution, high price and difficult availability , high toxicity and other issues

Inactive Publication Date: 2011-07-20
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The chiral resolving agent ephedrine used has many problems such as high toxicity, large environmental pollution, and high price and difficulty in obtaining

Method used

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  • New synthesis method of optically pure lactone
  • New synthesis method of optically pure lactone
  • New synthesis method of optically pure lactone

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Experimental program
Comparison scheme
Effect test

Embodiment 1-15

[0047] [RhCl 2 Cp*] 2 1.3 mg (0.002 mmol) of the chiral ligand L* (0.0044 mmol) was reacted with 1 ml of degassed water at 40° C. for 1 hour under the protection of argon. Add 95.2 mg (0.4 mmol) of ethyl 5-(4-fluorophenyl)-5-carbonyl butyrate and 208 mg (2 mmol) of sodium formate dihydrate, and react at 40°C for 4 hours under the protection of argon. Extract with diethyl ether 3x3 ml, dry over anhydrous sodium sulfate, remove the metal complex with a silica gel layer, and remove the solvent under reduced pressure to obtain a light brown oil. NMR determined the content of each component. The product represents ethyl 5-(4-fluorophenyl)-5-hydroxybutyrate and the substrate represents ethyl 5-(4-fluorophenyl)-5-oxobutyrate. e.e value determination method: chiral OD column, mobile phase: n-hexane / isopropanol=98 / 2, flow rate: 1mL / min -1 , detection wavelength: 254nm, t R =29.5,t S = 31.1. The e.e value of the product / substrate <50% on NMR was not measured.

[0048] Results of...

Embodiment 16

[0055] [RhCl 2 Cp*] 2 1.3 mg (0.002 mmol), 1.9 mg (0.0044 mmol) of (S,S,R)-Cs-DPEN and 1 ml of degassed water were reacted at 40°C for 1 hour under the protection of argon. Add 89.6 mg (0.4 mmol) of methyl 4-(4-fluorobenzoyl)butyrate and 208 mg (2 mmol) of sodium formate dihydrate, and react at 40° C. for 4 hours under the protection of argon. Add 0.5 ml of 6N sodium hydroxide solution, stir for 0.5 hours, add 1N hydrochloric acid at room temperature to adjust the pH value to about 2, extract with ethyl acetate 3x10 ml, dry over anhydrous sodium sulfate, remove metal complexes with silica gel layer, and reduce pressure Remove solvent. Then 1 ml of 1N hydrochloric acid and 5 ml of dichloromethane were added and stirred at 25°C for 10 hours, monitored by TLC (ethyl acetate:petroleum ether=1:1) until the reaction was complete. The organic layer was separated, and the aqueous phase was extracted with 3×5 milliliters of dichloromethane, the organic layers were combined, dried ov...

Embodiment 17

[0057] [RhCl 2 Cp*] 2 1.3 mg (0.002 mmol), 1.9 mg (0.0044 mmol) of (S,S,R)-Cs-DPEN and 1 ml of degassed water were reacted at 40°C for 1 hour under the protection of argon. Add 95.2 mg (0.4 mmol) of ethyl 4-(4-fluorobenzoyl)butyrate and 208 mg (2 mmol) of sodium formate dihydrate, and react at 40° C. for 4 hours under the protection of argon. Add 0.5 ml of 6N sodium hydroxide solution, stir for 0.5 hours, add 1N hydrochloric acid at room temperature to adjust the pH value to about 2, extract with ethyl acetate 3x10 ml, dry over anhydrous sodium sulfate, remove metal complexes with silica gel layer, and reduce pressure Remove solvent. Then 1 ml of 1N hydrochloric acid and 5 ml of dichloromethane were added and stirred at 25°C for 10 hours, monitored by TLC (ethyl acetate:petroleum ether=1:1) until the reaction was complete. The organic layer was separated, and the aqueous phase was extracted with 3×5 milliliters of dichloromethane, the organic layers were combined, dried ove...

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Abstract

The invention provides a new preparation method of chiral hydroxy ester (II) and optically pure lactone (IV). The preparation method comprises the following steps: the ketonic ester shown in the general formula (I) performs aqueous-phase asymmetric reduction reaction and obtain chiral hydroxy ester (II), chiral hydroxy ester (II) is hydrolyzed and then cyclized in solvent in the presence of acid to obtain the chiral lactone compound shown in the general formula IV, wherein R1 and R2 are the same or different and do not represent hydrogen or halogen; and n is 1 or 2, and R3 is CH3, CH2CH3, or CH(CH3)2. When R1 is Cl, R2 is Cl and n is 1, the compound (IV) is the chiral intermediate of the antidepressant chiral medicine sertraline; and when R1 is F, R2 is H and n is 2, the compound (IV) is the chiral intermediate of the antilipemic chiral medicine ezetimibe.

Description

technical field [0001] The invention belongs to the fields of medicinal chemistry and organic chemistry. Specifically, the invention relates to the synthesis of a chiral hydroxy ester compound and a method for preparing a chiral lactone using the compound as a raw material. The method is particularly suitable for the preparation of chiral drug sertraline chiral intermediates and ezetimibe chiral intermediates. Background technique [0002] Sertraline is a selective serotonin reuptake inhibitor, which can help improve the body's ability to effectively relieve patients' depressive symptoms, including irritability, and reduce persistent fatigue symptoms and anxiety states . It has been widely used in the treatment of depressive and obsessive-compulsive disorders in the world. It has the characteristics of long-acting, low toxicity to liver cells, fast digestion in the body, and is suitable for the elderly, so it has the most promising development among SSRI drugs for the trea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/732C07C67/31B01J31/22C07F15/00C07D307/20C07D309/10
Inventor 邓金根车国勇唐远富朱槿陈永正廖建
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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