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A kind of method for preparing Alitretinoin

A technology of a compound, a palladium compound, applied in the field of preparation of alitretinoic acid, can solve the problems of effective control, difficult light conditions, high cost, etc., and achieve the effect of convenient industrial production, high application value, and easy operation

Active Publication Date: 2015-10-28
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 1. The cost is high, using chromatographically pure acetonitrile as the solvent, the cost is high;
[0008] 2. The operation is complicated, and it is difficult to effectively control the lighting conditions, which limits its application in industrial production;
[0009] 3. The yield is low and the product purity is low: the product purity obtained by this method is 97.8%, and the yield is only 5%

Method used

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  • A kind of method for preparing Alitretinoin
  • A kind of method for preparing Alitretinoin
  • A kind of method for preparing Alitretinoin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation of embodiment 1 formula I compound (one)

[0031] Under the protection of nitrogen, add 2L of ethanol and 100g of all-trans retinoic acid into the reaction bottle, stir, then raise the temperature to 50-55°C, and add 89mg of PdCl2. After reacting for 1.5 h, the purity of the product was detected by HPLC to be 21%. The reaction solution was slowly cooled to 0-5°C, kept warm for 180 minutes, and filtered with suction; the filtrate was added to another clean reaction bottle, continued to cool down to -10-6°C, kept warm for 20 minutes, and filtered with suction to obtain 12.1 g of the product. Yield 12.1%, HPLC purity 99.60%.

Embodiment 2

[0032] The preparation of embodiment 2 formula I compound (two)

[0033] Under the protection of nitrogen, add 3.5 L of propyl propionate and 100 g of all-trans retinoic acid to the reaction flask, stir, then raise the temperature to 30-35 °C, add (Et3P)4Pd(0) 80 mg, react for 2 hours, and pass through HPLC The purity of the product was detected to be 20.3%. The reaction solution was slowly cooled to 2-5°C, kept warm for 10 minutes, and filtered with suction. The filtrate was added to another clean reaction bottle, continued to cool down to -20--16°C, kept warm for 60 minutes, and filtered with suction to obtain 11.0 g of the product. The yield was 11.0%, and the HPLC purity was 99.49%.

Embodiment 3

[0034] The preparation of embodiment 3 formula I compound (three)

[0035] Under the protection of nitrogen, add 2L of ethyl formate and 100g of all-trans retinoic acid into the reaction flask, stir, then raise the temperature to 75-80°C, add K2PdCl6300mg, react for 1.5h, and the purity of the product is 20.1% by HPLC. The reaction solution was slowly cooled to 15-20°C, kept warm for 50 minutes, and filtered with suction. The filtrate was added to another clean reaction bottle, continued to cool down to -5-9°C, kept warm for 360 minutes, and filtered with suction to obtain 11.3 g of the product. The yield was 11.3%, and the HPLC purity was 99.38%.

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Abstract

The invention provides a method for preparing a compound disclosed as Formula I. Under the catalytic action of a palladium compound, a compound disclosed as Formula is subjected to isomerization reaction in an organic solvent to obtain the compound disclosed as Formula I. The method is simple to operate, has the advantages of low cost and controllable conditions, and is convenient for industrial production. After the after-treatment steps, the alitretinoin with the purity of higher than 99% can be obtained, and the product yield is up to higher than 12%.

Description

technical field [0001] The invention relates to a method for preparing alitretinoic acid, in particular to a method for preparing alitretinoic acid by using all-trans retinoic acid as a raw material through isomerization reaction. Background technique [0002] Alitretinoin (formula I) is an important drug in the field of skin diseases, and its chemical name is: 3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)- 2E, 4E, 6Z, 8E-nonatetonic acid, is all-trans retinoic acid (formula II, chemical name: 3,7-dimethyl-9-(2,6,6-trimethylcyclohexene- 1-yl)-9-cis isomer of 2E, 4E, 6E, 8E-all-trans-nonadrenoic acid). [0003] [0004] Since alitretinoic acid (formula I) differs from all-trans retinoic acid (formula II) only in steric configuration, the compound of formula II can be used as a raw material to synthesize alitretinoic acid. [0005] In the prior art (Bioorganic & Medicinal Chemistry Letter, vol.4, No.2, p349-350, 1994), adopt photochemical reaction, under the condition o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C57/26C07C51/353
Inventor 邓青均王绍辉
Owner CHONGQING HUABANGSHENGKAI PHARM