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Method for preparing 13-cis isotretinoin

A technology of formic acid and cis-retinoic acid, applied in the field of preparation of 13-cis-retinoic acid, which can solve the problems of cumbersome operation and difficult industrial scale production

Inactive Publication Date: 2014-10-08
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above-mentioned methods all involve hydrolysis, extraction, distillation and other steps to carry out isomerization reaction after the WITTIG reaction is completed, the operation is cumbersome, and it is not easy to realize industrial scale production

Method used

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  • Method for preparing 13-cis isotretinoin
  • Method for preparing 13-cis isotretinoin
  • Method for preparing 13-cis isotretinoin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] 372g of [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadiene]-triphenylphosphine chloride was dissolved in 1000ml of ethanol, Add 84.6g of 5-hydroxy-4-methyl-2-5[H]-furanone under nitrogen, stir until the solution is clear, cool down to -20°C, add 1200ml of 2NKOH ethanol solution dropwise, and keep the temperature at -20± 5°C, react for 2 hours, then adjust the pH value to 7-8 with hydrochloric acid, add 250mg palladium nitrate dissolved in 150ml acetonitrile, heat up to 35°C, detect the reaction result by high performance liquid chromatography (HPLC), and the isomerization reaction is complete Afterwards, pour it into water, add acid to neutralize to pH 2-3, and suction filter to obtain the crude product, which is crystallized with ethyl acetate to obtain 200.2 g of the product, with a purity of 99.7% and a yield of 89.9%.

Embodiment 2

[0066] 372g of [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadiene]-triphenylphosphine chloride was dissolved in 1000ml of ethanol, Add 84.6g of 5-hydroxy-4-methyl-2-5[H]-furanone under nitrogen, stir until the solution is clear, cool down to -40°C, add 1200ml of 2NKOH ethanol solution dropwise, and keep the temperature at -40± 5°C, react for 2 hours, then adjust the pH value to 7-8 with hydrochloric acid, add 250mg palladium nitrate dissolved in 150ml acetonitrile, raise the temperature to 60°C, detect the reaction result by high performance liquid chromatography (HPLC), and the isomerization reaction is completed Finally, pour it into water, add acid to neutralize to pH2-3, and suction filter to obtain the crude product, which is crystallized with ethyl acetate to obtain 204.7g of the product, with a purity of 99.7% and a yield of 92.1%.

Embodiment 3

[0068] 372g of [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadiene]-triphenylphosphine chloride was dissolved in 1000ml of ethanol, Add 84.6g of 5-hydroxy-4-methyl-2-5[H]-furanone under nitrogen, stir until the solution is clear, cool down to 15°C, add 1200ml of 2NKOH ethanol solution dropwise, and keep the temperature at 15±5°C , react for 2 hours, then adjust the pH value to 7-8 with hydrochloric acid, add 250 mg of palladium nitrate dissolved in 150 ml of acetonitrile, heat up to 70 ° C, and detect the reaction result by high performance liquid chromatography (HPLC). After the isomerization reaction is completed, Pour it into water, add acid to neutralize to pH 2-3, and filter with suction to obtain the crude product. Crystallize with ethyl acetate to obtain 198.4 g of the product, with a purity of 99.5% and a yield of 88.7%.

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Abstract

The invention discloses a method for preparing 13-cis isotretinoin. The method comprises the following steps: directly adding an acid to a solution containing a compound represented by formula I and a compound represented by formula IV and generated through a WITTIG reaction to adjust the pH value to 5-10, adding a palladium compound or a rhodium compound, and carrying out an isomerization reaction to obtain a product with the configuration represented by formula I. The 13-cis isotretinoin preparation is completed in a one step mode through a series of reactions comprising the WITTIG reaction and the isomerization reaction without hydrolysis, extraction or distillation after the WITTIG reaction, so the method has the advantages of step simplification, yield increase, total yield reaching 90%, low cost, and suitableness for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for preparing 13-cis-retinoic acid. Background technique [0002] 13-cis retinoic acid is also known as 13-cis retinoic acid and isotretinoin. Its structural formula is shown in formula Ⅰ. It is an intermediate product of vitamin A (retinol) metabolism, and it can strongly and rapidly inhibit the proliferation of skin gland cells. It belongs to retinoic acid drugs and is clinically used for severe acne, cystic acne, and acne conglomerates that are ineffective in the treatment of other drugs, especially for severe refractory nodular acne (nodular acne, namely Inflammatory lesions with a diameter ≥ 5mm, nodules may purulent or hemorrhage), and can also be used for pityriasis rubra, acne, pityriasis rubella, dermatology and other diseases. [0003] [0004] Structurally, 13-cis-retinoic acid (such as formula I) is a highly conjugated molecule cons...

Claims

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Application Information

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