Method for preparing all-trans tretinoin

A technology of all-trans retinoic acid and retinoic acid, applied in the field of preparation of all-trans retinoic acid, can solve the problems of low yield of all-trans retinoic acid, high cost, difficult operation and the like

Active Publication Date: 2010-07-14
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Like this, remaining all-trans retinoic acid yield is low, and cost is high, and difficult to operate

Method used

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  • Method for preparing all-trans tretinoin
  • Method for preparing all-trans tretinoin

Examples

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Effect test

Embodiment 1

[0038] The preparation of the mixture of embodiment 1 all-trans retinoic acid (I) and 11-cis-retinoic acid (VI)

[0039] Under nitrogen conditions, 500.4g of [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadiene]-triphenyl Phosphine chloride salt (WITTIG salt) and 187g of β-formyl butyl crotonate were dissolved in 1947ml of isopropanol, cooled to -10°C, 1250ml of 2N potassium hydroxide isopropanol solution was added dropwise, and When the temperature was kept between -10 and 0°C, the addition was completed and reacted for 1 hour. The reaction solution was added to water, extracted with 2×1000ml of petroleum ether, the organic layers were combined, washed with 2×300ml of water, and evaporated under reduced pressure. The solvent was removed to obtain 325 g (yield 99.0%) of a brown oily liquid, which contained 61% all-trans butyl retinoate and 36.1% 11-cis-butyl retinoate as detected by HPLC.

[0040] Under the condition of blowing nitrogen, 325 g of the mixture of all-...

Embodiment 211

[0041] Example 211 - Transformation of cis-retinoic acid into all-trans retinoic acid (1)

[0042] Under the condition of nitrogen flow, the mixed acid solution prepared in Example 1 was heated to 50° C., then a mixture of 330 mg palladium nitrate, 2160 mg triphenylphosphine, 1600 mg triethylamine and 250 ml acetonitrile was added, and the mixture was reacted for 1 hour and detected by HPLC The result was 95.3% all-trans retinoic acid and 1.1% 11-cis-retinoic acid, 600-700g of solvent was evaporated under reduced pressure, cooled to 0°C, kept for 2 hours, filtered to obtain 226.2g of all-trans retinoic acid, detected by HPLC The content is 99.6%.

Embodiment 311

[0043] Example 311-Transformation of cis-retinoic acid to all-trans retinoic acid (2)

[0044] Under the condition of nitrogen flow, the mixed acid solution prepared in Example 1 was heated to 50° C., then a mixture of 116 mg of palladium nitrate, 796 mg of triphenylphosphine, 528 mg of triethylamine and 132 ml of acetonitrile was added, reacted for 2 hours, and detected by HPLC The result was 93.3% all-trans retinoic acid and 3.1% 11-cis-retinoic acid, 600-700g of solvent was evaporated under reduced pressure, cooled to 0°C, kept for 2 hours, filtered to obtain 214.2g of all-trans retinoic acid, detected by HPLC The content is 99.6%.

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Abstract

The invention provides a method for transforming 11-cis-tretinoin into all-trans tretinoin, which is characterized by using a palladium nitrate composite catalyst. The invention also provides a method for synthesizing the all-trans tretinoin, which comprises the following steps of: using compounds (II) and (III) as raw materials to perform WITTIG reaction under the action of alkali so as to obtain a mixture of all-trans retinoic acid ester and 11-cis-retinoic acid ester; performing hydrolysis and acidification to obtain a mixture of the all-trans tretinoin and an isomer 11-cis-tretinoin; and transforming the isomer to obtain the target product namely the all-trans tretinoin. The method can be finished by two steps and has the advantages of complete reaction, high yield, less isomer content in the finished product and low cost, and is suitable for industrial production.

Description

Technical field: [0001] The invention relates to a preparation method of all-trans retinoic acid, in particular to a method for transforming 11-cis-retinoic acid into all-trans retinoic acid. Background technique: [0002] All-trans retinoic acid is a metabolic intermediate product of vitamin A and has various pharmacological effects. Its Chinese name is 3,7-dimethyl-9-(2,6,6-trimethylcyclohexene)-2, 4,6,8 all-trans nonatraenoic acid, the structural formula is as formula I: [0003] [0004] The preparation of currently disclosed all-trans retinoic acid mainly contains the following methods: [0005] US3746730 discloses using retinoic acid acetate as a raw material, hydrolyzing it, and then oxidizing it with silver oxide to directly obtain all-trans retinoic acid. This method has low yield, high cost, serious waste, and is not suitable for industrial production. [0006] European patent EP0563825 improves the above-mentioned process of US3746730, using vitamin A acetate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C403/20B01J31/24B01J31/28
Inventor 邓青均
Owner CHONGQING HUABANGSHENGKAI PHARM
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