Method for preparing tazarotene without copper iodide

A technology of tazarotene and cuprous iodide, applied in the field of drug synthesis, can solve the problems of harsh reaction conditions, high recovery cost, difficult to remove, etc., and achieves the effects of short reaction time, high product yield and easy recovery

Active Publication Date: 2018-12-25
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because both methods use palladium complexes as catalysts, not only the price is expensive, but also the recovery of heavy metals is very cumbersome and the recovery cost is high
In addition, due to the use of n-butyllithium in the reaction system, anhydrous reaction is required, and the reaction conditions are relatively harsh.
[0006] In the synthesis of tazarotene reported in U.S. Patent No. 7,273,937 in 2006, the operation method of the last step of synthesis requires low temperature and column passing. These complicated means are not conducive to industrial scale production
[0016] Cuprous iodide is easy to form a complex with the produc...

Method used

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  • Method for preparing tazarotene without copper iodide
  • Method for preparing tazarotene without copper iodide
  • Method for preparing tazarotene without copper iodide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Add 62g of DMF, 0.81g of 10% palladium carbon, and 0.40g of triphenylphosphine into a clean 250mL three-necked flask, stir, and replace with nitrogen. Maintain a weak nitrogen flow and stir for 10-20 minutes. 15.0 g of 4, 4-dimethylbenzothiopyran-6-yl-acetylene, 16.5 g of ethyl 6-chloronicotinate, 12.5 g of potassium acetate, 2.43 g of purified water, and 25 g of DMF were sequentially added. Raise the temperature to 85°C, react for 4 hours, and then monitor by TLC until the spots of 4,4-dimethylbenzothiopyran-6-yl-acetylene disappear (developer dichloromethane:n-hexane=1:6).

[0059]Cool down to room temperature, filter with suction, add 55g of dichloromethane and 470g of drinking water to the filtrate, stir, let stand, and separate the liquids. The combined organic phases were washed twice with 250 g of saturated sodium bicarbonate solution. Separate the liquids, combine the organic phases, and wash in twice with 250 g of saturated sodium chloride solution. Separate...

Embodiment 2

[0061] Add 100 g of N-methylpyrrolidone, 0.81 g of 10% palladium carbon, and 0.80 g of triphenylphosphine into a clean 250 mL three-necked flask, stir, and replace with nitrogen. Maintain a weak nitrogen flow and stir for 10-20 minutes. 15.0 g of 4, 4-dimethylbenzothiopyran-6-yl-acetylene, 18.0 g of ethyl 6-chloronicotinate, 12.5 g of potassium carbonate, and 2.43 g of purified water were sequentially added. Raise the temperature to 90°C, react for 5 hours, and then monitor by TLC until the spots of 4,4-dimethylbenzothiopyran-6-yl-acetylene disappear (developing solvent: dichloromethane:n-hexane=1:6).

[0062] Cool down to room temperature, filter with suction, add 55g of dichloromethane and 470g of drinking water to the filtrate, stir, let stand, and separate the liquids. The combined organic phases were washed twice with 250 g of 10% sodium carbonate solution. Separate the layers, combine the organic phases, and wash twice with 250 g of saturated sodium chloride solution. ...

Embodiment 3

[0064] Add 100 g of toluene, 0.81 g of 10% palladium carbon, and 0.40 g of triphenylphosphine into a clean 250 mL three-necked flask, stir, and replace with nitrogen. Maintain a weak nitrogen flow and stir for 10-20 minutes. 15.0 g of 4, 4-dimethylbenzothiopyran-6-yl-acetylene, 15.0 g of ethyl 6-chloronicotinate, 15.0 g of potassium acetate, and 1.62 g of purified water were sequentially added. Raise the temperature to 95°C, react for 6 hours, and then monitor by TLC until the spots of 4,4-dimethylbenzothiopyran-6-yl-acetylene disappear (developing agent: dichloromethane: n-hexane = 1:6).

[0065] Cool down to room temperature, filter with suction, add 55g of dichloromethane and 470g of drinking water to the filtrate, stir, let stand, and separate the liquids. The combined organic phases were washed twice with 250 g of 10% sodium carbonate solution. Separate the layers, combine the organic phases, and wash twice with 250 g of saturated sodium chloride solution. Separate the...

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PUM

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Abstract

The invention provides a method for preparing tazarotene without copper iodide. Palladium catalysts and triphenylphosphine are added into specific organic solvents and stirred, replacement in nitrogenis performed, 4, 4-dimethyl thiochroman-6-radical-acetylene, 6-chloro-ethyl nicotinate and acid-binding agents are added to perform reaction. The method is environmentally friendly, the catalysts areeasily recycled, and waste water containing heavy metal is not generated. Compared with the prior art, the method is short in reaction time and reaction temperature. A product prepared by the methodis high in yield and purity and stable in quality.

Description

Technical field: [0001] The invention relates to a drug synthesis method, in particular to a preparation method of tazarotene without using cuprous iodide. Background technique: [0002] Tazarotene (I) is the first receptor-selective, third-generation aromatic retinoid drug that selectively binds to two retinoic acid receptors (RAR-β; RAR-γ), but not Binds to retinoic acid X receptor (RXR). It is clinically safe and effective for the treatment of psoriasis, acne, abnormal keratosis, pilosebaceous gland disease, and precancerous lesions of the skin. [0003] [0004] There are many reports on the synthesis methods of tazarotene, but each has some disadvantages and is not suitable for industrial production. [0005] For example, US Patent No. 5,089,509 in 1992 and US No. 5,602,130 in 1997 all disclose different synthesis methods of tazarotene. The last step synthesis of above-mentioned two kinds of methods all is to use 4,4-dimethylbenzothiopyran-6-yl-acetylene and ethyl...

Claims

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Application Information

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IPC IPC(8): C07D409/06
CPCC07D409/06
Inventor 陈磊陈永流谭涛邹华安
Owner CHONGQING HUABANGSHENGKAI PHARM
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