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Preparation method of ezetimibe chiral intermediate

A chiral catalyst and compound technology, which is applied in the field of preparation of ezetimibe chiral intermediates, can solve the problems of low yield, low atom economy, complicated post-processing and the like, and achieves low dosage and high application value. Effect

Active Publication Date: 2014-07-02
浙江瑞博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The disadvantages of (-)-DIP-Cl are, such as corrosiveness, easy to absorb moisture and become damp, sensitive to air, expensive, low atom economy, cumbersome post-processing, resulting in a large molar amount of chiral reducing reagent (at least 1.~ 1.8 equivalents), low yield (83%)

Method used

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  • Preparation method of ezetimibe chiral intermediate
  • Preparation method of ezetimibe chiral intermediate
  • Preparation method of ezetimibe chiral intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1: ( S Preparation of )-5-(4-fluorophenyl)-5-hydroxypentanoic acid

[0065] Weigh (5.0 mg, 0.005 mmol) chiral catalyst M (X is 3-methyl) and (30.3 g, 270 mmol) potassium tert-butoxide into the inner tube of the reaction, put the inner tube into the autoclave, Add 500 mL of ethanol and (52.6 g, 250 mmol) 5-(4-fluorophenyl)-5-oxopentanoic acid into the reaction inner tube, replace the gas in the kettle body with hydrogen, keep the hydrogen pressure at 0.2-10 MPa, and heat to The reaction was carried out at 50°C. After reacting for 10 hours, the reaction solution was concentrated. Add 300 mL of water and concentrated hydrochloric acid to the system to adjust pH=3~4. Add 300 mL of ethyl acetate, separate the layers, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Suction filtration, concentrated to light yellow solid ( S )-5-(4-fluorophenyl)-5-hydroxypentanoic acid 53.0 g, the yield was 100%, and the raw material 5-(4-fl...

Embodiment 2

[0074] Embodiment 2: ( S Preparation of )-5-(4-fluorophenyl)-5-hydroxypentanoic acid

[0075] Weigh (1.0 mg, 0.001 mmol) chiral catalyst M (X is H) and (606 mg, 5.4 mmol) potassium tert-butoxide into the reaction tube, put the reaction tube into the autoclave, Add 5 mL of ethanol and (1.05 g, 5 mmol) 5-(4-fluorophenyl)-5-oxopentanoic acid into the tube, replace the gas in the kettle with hydrogen, keep the hydrogen pressure at 0.2-10 MPa, and heat to 50°C react. After reacting for 20 hours, the reaction solution was concentrated. Add 10 mL of water and concentrated hydrochloric acid to the system to adjust pH=3~4. Add 10 mL of ethyl acetate, separate the layers, wash the organic phase with saturated brine once more, and dry over anhydrous sodium sulfate. Suction filtration, the solvent was concentrated to obtain a light yellow solid ( S )-5-(4-fluorophenyl)-5-hydroxypentanoic acid 1.06 g, the yield was 96.1%. According to the analysis by H NMR spectrum, the conversion o...

Embodiment 3

[0076] Embodiment 3: ( S Preparation of )-5-(4-fluorophenyl)-5-hydroxypentanoic acid

[0077] Weigh (1.0 mg, 0.001 mmol) chiral catalyst M (X is 4-methyl) and (40 mg, 1.0 mmol) potassium hydroxide into the reaction tube, put the reaction tube into the autoclave, Add 5 ml DMF and (10.5 g , 50 mmol) 5-(4-fluorophenyl)-5-oxopentanoic acid into the inner tube of the reaction, replace the gas in the kettle body with hydrogen, keep the hydrogen pressure at 0.2-10 MPa, and heat to The reaction was carried out at 50°C. After reacting for 20 hours, the reaction solution was concentrated. Add 10 mL of water and concentrated hydrochloric acid to the system to adjust pH=3~4. Add 10 mL of ethyl acetate, separate the layers, wash the organic phase with saturated brine once more, and dry over anhydrous sodium sulfate. Suction filtration, the solvent was concentrated to obtain a light yellow solid ( S )-5-(4-fluorophenyl)-5-hydroxypentanoic acid 10.3 g, the yield was 97.2%. According t...

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Abstract

The present invention relates to the field of pharmaceutical synthesis, and specifically, to a method for preparing an Ezetimibe chiral intermediate. The method is as follows: a method for preparing a compound with a formula (b) structure comprises the following steps: obtaining the compound with the formula (b) structure by using a compound with a formula (a) structure under the effects of a chiral catalyst, alkali and hydrogen, R is NR１R2, OR3 or OH, R１ and R2 are separate alkyl groups, and R3 is an C1-C6 alkyl group or a benzyl group. The chiral catalyst is a compound with a formula (M) structure: DTB is shown as a formula DTB. The yield of the compound with the formula (b) prepared by using the method can exceed 95%, and the optical purity can reach 100% at the maximum.

Description

[0001] technical field [0002] The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing a chiral intermediate of ezetimibe. [0003] Background technique [0004] Ezetimibe is a novel cholesterol absorption inhibitor for the treatment of hypercholesterolemia. Its chemical name is: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl) -2- and lactam. [0005] [0006] [0007] The key step in the synthesis of this compound is how to obtain the marked in the structural formula S structure, [0008] US20090047716 reported the chiral reduction of the corresponding ketone compound with ketoreductase, but the yield of this method is generally low, about 60%. [0009] US5618707 reported the chiral reduction of corresponding ketone compounds with microbial reductase, which can be resolved without resolving agent, but the reaction yield is low (68%), and the reductase culture time is long, about...

Claims

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Application Information

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IPC IPC(8): C07B53/00C07C59/56C07C51/367C07C69/732C07C67/31C07D295/182C07C235/34C07C231/12
CPCC07F15/0033C07B53/00C07C67/31C07C59/56C07C231/12C07C235/34C07C51/367C07D295/182C07C69/732C07F15/00C07B2200/07
Inventor 严普查车大庆李原强朱国良章向东屈晓广
Owner 浙江瑞博制药有限公司
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