Preparation method of prostaglandin derivative

A technology for preparation steps and compounds, which is applied in the field of preparation of prostaglandin derivatives, can solve problems such as high requirements for reaction equipment and threats to production safety, and achieve the effects of simplifying reaction conditions, reducing requirements, and reducing pressure

Inactive Publication Date: 2012-07-11
WUHAN QR PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, it was found in the preparation that according to the technical scheme in the previous application of the applicant, when implementing the last step reaction, the pressure of the hydrogenation reaction needs to be above 60psi (0.42MPa, approximately equivalent to 4 atmospheric pressures), so during production, the reaction The equipment has high requirements and poses a certain threat to safe production

Method used

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  • Preparation method of prostaglandin derivative
  • Preparation method of prostaglandin derivative
  • Preparation method of prostaglandin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]

[0045] In a 250mL dry three-necked flask, add 3 (4.06g, 1eq.) and 50mL of anhydrous toluene, lower the temperature to -70°C under the protection of nitrogen, add 34mL DIBAL-H (2.0eq., 1M) dropwise, and drop it for 1.5 hours. . And stirred at this temperature for 1 hour, TLC detected that the reaction was completed, 2 g of isopropanol (4 eq.) was added dropwise to quench the reaction, the temperature was raised to room temperature, and stirring was continued for 1 hour. 40 mL of saturated sodium potassium tartrate solution and 40 mL of diethyl ether were added dropwise, stirred for 5 minutes, allowed to stand to separate layers, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to obtain 4.08 g of crude compound 5. It was directly used for the next reaction without purification.

Embodiment 2

[0047]

[0048] Add compound 4 (15g, 2.5eq.) and 50mL of anhydrous THF into a 250mL three-neck flask, stir in an ice bath, slowly add LiHMDS (66.5mL, 1M) THF solution dropwise to obtain a brick-red solution, stir at 20°C for 1 hour . 5g (1.0eq.) of compound 5 was added to the reaction solution, and stirred at 20°C for 3 hours. TLC detected the end of the reaction, quenched the reaction with 40 mL of ice water, concentrated under reduced pressure to remove THF, extracted the aqueous phase with methyl tert-butyl ether (50 mL×3), washed once with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and Concentration gave 6.1 g of crude compound 6. Purification by column chromatography yielded 4.6 g of compound 6.

Embodiment 3

[0050]

[0051] Add 10 mL of acetonitrile to compound 6 (4.6 g), stir to dissolve, add diisopropylethylamine (2.66 mL), 4-methoxybenzyl bromide (1.8 mL), and stir at room temperature for 16 hours. The completion of the reaction was detected by TLC, and the reaction solution was concentrated under reduced pressure and purified by column to obtain compound 7 (4.9 g).

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Abstract

The invention discloses a preparation method of a prostaglandin derivative. The method comprises the following steps: protecting corresponding hydroxyl in a prostaglandin intermediate body with alkoxy benzyl; and performing a hydrogenation reaction under a normal pressure to prepare a corresponding prostaglandin derivative. According to the method, the reaction condition is reduced, and the yield is improved. The method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a preparation method of prostaglandin derivatives. Background technique [0002] Many prostaglandin derivatives have multiple therapeutic effects. Lubiprostone is a kind of prostaglandin derivatives. It is a selective chloride ion channel activator and has a novel mechanism of action. It relieves constipation by increasing intestinal fluid secretion and enhancing intestinal motility symptom. Its English name: Lubiprostone, chemical name: (-)-7-[(2R, 4aR, 5R, 7aR)-2-(1,1-difluoro-n-pentyl)-2-dihydroxy-6-oxoocta Hydrocyclopentapyran-5-yl] n-heptanoic acid. [0003] The structural formula of lubiprostone is shown below: [0004] [0005] Experiments have proved that the compound exists in the form of dynamic equilibrium of two structures under normal conditions, as shown below, [0006] [0007] The main method of preparing lubiprostone or other prostaglandin compoun...

Claims

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Application Information

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IPC IPC(8): C07C405/00
Inventor 邓宇许全胜廖文胜陈蔚江王朝东
Owner WUHAN QR PHARMA CO LTD
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