Method for preparing key intermediate of limaprost

A technology of limatoprost and branched chain alkyl, which is applied in the field of preparation of chiral compounds, can solve problems such as low production efficiency, large solvent, and difficulty in scaling up

Inactive Publication Date: 2013-01-16
SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation process must go through multiple separations and purifications to obtain the high-purity limatoprost intermediate, which leads to the consumption of a large a...

Method used

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  • Method for preparing key intermediate of limaprost
  • Method for preparing key intermediate of limaprost
  • Method for preparing key intermediate of limaprost

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preparation example Construction

[0098] The preparation of formula 1 intermediate and formula 2 intermediate

[0099] The formula 1 intermediate and the formula 2 intermediate of the present invention can be prepared by the following method, but the conditions of the method, such as the amount of reactant, solvent, base, compound used, reaction temperature, reaction time required, etc. are not limited to the following Explanation. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.

[0100] In the preparation method of the present invention, each reaction is usually carried out in an inert solvent, and the reaction time is usually 0.1-48 hours, preferably 0.5-24 hours.

[0101] Taking the intermediate of formula 2 as an example, a preferred method includes:

[0102] (1) under ac...

Embodiment 1

[0145] Preparation of starting material formula 8a compound

[0146] The commercially available Corey lactone is used as a starting material, and it is prepared by referring to the methods reported in documents GB1579464A1 and US3992439A1.

Embodiment 3

[0154] Preparation of formula 1a compound

[0155]

[0156] The compound of formula 3 (8.23g), the compound of formula 4a (6.6g), concentrated sulfuric acid (0.2ml) and toluene (40ml) were stirred evenly, heated to reflux for dehydration reaction for 5h, followed by TLC. After complete reaction, lower the reaction temperature and add 10% Na 2 CO 3 (4ml) to quench the reaction, extract the aqueous layer with n-hexane (20ml*4), combine the organic layers and wash with saturated sodium chloride solution (50ml), dry over anhydrous sodium sulfate and distill under reduced pressure to collect fractions at 120-126°C , to obtain the compound of formula 5a (13.9 g).

[0157] Under the protection of nitrogen, the compound of formula 6a (14.2g) and tetrahydrofuran (83ml) were mixed, stirred and cooled to below -70°C, and n-hexane solution of n-Butyl lithium (n-Butyl lithium) (45.7ml, 2.5M ), the dropwise addition process controlled the temperature below -70°C, and after the dropwis...

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Abstract

The invention discloses a method for preparing the key intermediate of limaprost, particularly provides a chiral compound of formula I and a preparation method thereof. The method comprises the following steps: (1) reacting a compound of formula 3 with a compound of formula 4 to obtain a compound of formula 5; (2) reacting a compound of formula 6 with the compound of formula 5 to obtain a compound of formula 7; (3) mixing the compound of formula 7 with a compound of formula 8 to obtain the compound of formula 1; (4) reacting the compound of formula 1 with a reducing agent to obtain a raw product, separating and purifying the raw product by column chromatography to obtain a compound of formula 2; (5) reacting the compound of formula 2 with a protector reduction agent to obtain a compound of formula 9, wherein each structural formula and substituent are defined as the specification. According to the invention, the method has mild reaction conditions, and the high-purity chiral compound can be conveniently and efficiently prepared.

Description

technical field [0001] The invention relates to a preparation method of a chiral compound, in particular to a preparation method of a limatoprost intermediate. Background technique [0002] The chemical name of limaprost is: (E)-7-[(1R,2R,3R)-3-hydroxy-2-[(3S,5S)-(E)-3-hydroxy-5-methyl-1 -Nonenyl]-5-oxocyclopentyl]-2-heptanoic acid ((E)-7-[(1R,2R,3R)-3-hydroxy-2-[(3S,5S,E)- 3-hydroxy-5-methylnon-1-enyl]-5-oxocyclopentyl]hept-2-enoic acid), the structure of which is shown in the compound of formula 10. [0003] [0004] Limaprost has the effects of dilating blood vessels, increasing blood flow and anti-platelet aggregation, and is clinically used to improve various ischemic symptoms caused by thromboangiitis obliterans, such as ulcers, pain, and coldness; and to improve acquired Subjective symptoms and walking ability in lumbar spinal stenosis. Limatoprost has broad application prospects because of its effective oral administration, good drug effect and convenient medic...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07D309/12C07C405/00
Inventor 刘毓彬何兵明唐志军季晓铭
Owner SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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