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Synthetic method of all-trans retinoic acid

A technology of reaction and methylation, which is applied in the field of synthesis of all-trans retinoic acid, can solve problems such as multi-hours, many steps, and complicated operations

Active Publication Date: 2016-09-21
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method has many steps, there is an intermediate separation step, the operation is more complicated, more man-hours are required, and the loss of the product is caused.
Especially in the hydrolysis step, it is time-consuming and incomplete, so the cost is higher, and the total yield can only reach 75% at the highest

Method used

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  • Synthetic method of all-trans retinoic acid
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  • Synthetic method of all-trans retinoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0042] Example 13, the preparation of 7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)-2,4,6,8 all-trans nonatraenoic acid

[0043] 186g of [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadiene]-triphenylphosphine chloride was dissolved in 500ml of isopropanol Add 42.3g of β-formyl crotonic acid under nitrogen gas, stir until the solution is clear, cool down to -5°C, add dropwise 571ml of 2N KOH isopropanol solution, keep the temperature at -5°C, and react for 2 hours. Then adjust the pH value to 7-8 with hydrochloric acid, add 86 mg palladium acetate, heat up to 50 ° C, and detect the reaction result by high performance liquid chromatography (HPLC). After the isomerization reaction is completed, pour it into water, add concentrated hydrochloric acid to neutralize, The crude product was obtained by suction filtration, and 95.2 g of the product was obtained by crystallization with ethyl acetate, with a purity of 99.7% and a yield of 85.3%.

Embodiment 2、3 and comparative test example 1、2

[0044] Embodiment 2, 3 and comparative test example 1, 2 - different isomerization pH conditions

[0045] Change the pH value regulated by hydrochloric acid, and others are carried out according to the conditions and methods of Example 1, and the obtained results are as follows:

[0046] Hydrochloric acid neutralizes pH

[0047] Conclusion: The pH value of the isomerization reaction is 5-10, the product has good purity and high yield.

Embodiment 4～7

[0048] Embodiment 4~7——different isomerization catalysts

[0049] Carry out according to the condition of embodiment 1, just change the kind of catalyst, obtained result is as follows:

[0050] Example

[0051] Conclusion: Several isomerization catalysts have good effect, and the obtained product has good purity and high yield.

[0052] Embodiment 8-10 and comparative test example 4——different isomerization temperature

[0053] Carry out according to the condition of embodiment 1, just change the temperature of isomerization reaction, gained result is as following table:

[0054] temperature(℃)

[0055] Conclusion: The suitable temperature for isomerization reaction is 50~70℃.

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Abstract

The synthetic method of all-trans retinoic acid, with [3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-2,4-pentadiene]-triphenylphosphine Salt and β-formyl crotonic acid are used as raw materials, WITTIG reaction occurs under the action of alkali, and then palladium compound or rhodium compound is added to directly carry out isomerization reaction to obtain the desired all-trans configuration product. The reaction intermediate product of the method does not need to be separated, and the two-step reaction of the WITTIG reaction and the isomerization reaction is continuously carried out in one container, the operation is simple and convenient, the production cost is saved, and the method is suitable for industrial production.

Description

Technical field: [0001] The invention relates to a synthetic method of all-trans retinoic acid, in particular to 3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)-2,4,6 , A preparation method of 8 all-trans-nonatetonic acid. Background of the invention: [0002] 3,7-Dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)-2,4,6,8 all-trans-nonatetronic acid (compound of formula I) is a vitamin The metabolic intermediate product of A is widely used in the treatment of psoriasis and acne; at present, it is the drug of choice for the treatment of acute promyelocytic leukemia and bone marrow dysplasia. [0003] [0004] Because the nonatetonic acid in the compound of formula I is in the all-trans configuration, it is easy to produce multiple isomers during preparation, such as the cis isomer of formula IV, so in the synthetic method of the compound of formula I, it is very easy to The important thing is to control the configuration of the product, and effectively convert the obtained cis-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C403/20
CPCC07C403/20C07C51/353C07C2601/16C07C59/64C07C51/00
Inventor 邓青均王绍辉朱强杨玉金
Owner CHONGQING HUABANGSHENGKAI PHARM
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