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Method and intermediate for synthesizing Fingolimod hydrochloride

A Chinese-style fingolimod hydrochloride technology, applied in the field of drug synthesis, can solve the problems of product purity not clearly stated, too long reaction steps, long reaction routes, etc., and achieve easy industrial scale-up production, short reaction steps, and simplified operation Effect

Active Publication Date: 2014-05-21
四川弘远药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN1483721A then adopts a kind of method of newly constructing the structure of aminopropanediol on the basis of this thinking, after it obtains 4-(2-halogenated ethyl) octylbenzene, it and malonic acid ester under alkaline condition Condensation, followed by nitrosation, reduction and other steps to obtain FTY-720, the total yield is high (about 28%), but the overall reaction steps are still too long, and the intermediate needs to be purified by column
[0009] Although the above documents have provided different methods for preparing FTY-720, there are certain problems, such as long reaction route, low yield or complicated operation, and the need for column purification; The key parameter, that is, the purity of the product is not clearly stated

Method used

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  • Method and intermediate for synthesizing Fingolimod hydrochloride
  • Method and intermediate for synthesizing Fingolimod hydrochloride
  • Method and intermediate for synthesizing Fingolimod hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0067] The preparation of embodiment pair octanoyl bromide propyl benzene (compound III)

[0068] Add aluminum trichloride (160g, 1.2mol, 2eq) into a 500ml three-necked flask, keep the temperature of the reaction solution not higher than -15°C, and add the pre-mixed 3-bromophenylpropane (121g, 0.6mol, 1eq), and n-octanoyl chloride (116g, 0.72mol, 1.2eq). After the dropwise addition, stir at -5°C until the reaction is complete [reaction takes about 4 hours, HPLC detection: raw material 3-bromophenylpropane ≤ 0.5%]. When the mixed solution is kept at 0°C-10°C, slowly pour the reaction solution into 1200ml of 5% hydrochloric acid water, extract with ethyl acetate (200ml×3 times), combine the organic layers, wash the organic layer with saturated brine, anhydrous sodium sulfate (50g ), dried, filtered, and the filtrate was concentrated by rotary evaporation at no higher than 40°C to obtain p-octanoyl bromide propylbenzene (190 g, HPLC purity 96.93%, yield 97%) as a yellow oil. h ...

Embodiment 2

[0069] The preparation of embodiment two p-octanoyl bromide propyl benzene (compound III)

[0070] Add aluminum trichloride (160g, 1.2mol, 2eq) into a 500ml three-neck flask, keep the temperature of the reaction solution not higher than -15°C and add 3-bromophenylpropane (121g, 0.6mol, 1eq) dropwise with stirring, then Keep the reaction temperature below -20°C and add n-octanoyl chloride (116g, 0.72mol, 1.2eq) dropwise. After the dropwise addition, stir at below -5°C until the reaction is complete [reaction takes about 4 hours, HPLC detection: raw material 3-bromo Phenylpropane≤0.5%]. When the mixed solution is kept at 0°C-10°C, slowly pour the reaction solution into 1200ml of 5% hydrochloric acid water, extract with ethyl acetate (200ml×3 times), combine the organic layers, wash the organic layer with saturated brine, anhydrous sodium sulfate (50g ), dried, filtered, and the filtrate was concentrated by rotary evaporation at no higher than 40°C to obtain p-octanoyl bromide p...

Embodiment 3

[0071] The preparation of embodiment three p-octanoyl iodopropylbenzene (compound III)

[0072] Add aluminum trichloride (5.3g, 0.04mol, 2eq) into a 50ml three-necked flask, keep the temperature of the reaction solution not higher than -15°C and add 3-iodophenylpropane (5g, 0.02mol , 1 eq) and n-octanoyl chloride (3.9 g, 0.024 mol, 1.2 eq). After the dropwise addition, stir at -5°C until the reaction is complete [the reaction takes about 2-4 hours, HPLC detection: raw material 3-iodophenylpropane ≤ 0.5%,]. Keep the mixed solution at 0°C-10°C, slowly pour the reaction solution into 50ml of 5% hydrochloric acid water, extract with ethyl acetate (20ml×3 times), combine the organic layer, wash the organic layer with saturated brine, anhydrous sodium sulfate (3g) After drying and filtering, the filtrate was concentrated by rotary evaporation at no higher than 40°C to obtain p-octanoyl iodopropylbenzene (6.8 g, HPLC purity 96.26%, yield 92%).

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Abstract

The invention provides a method and an intermediate for synthesizing Fingolimod hydrochloride. The method comprises the following steps: performing nitro-substitution, formaldehyde condensation, reduction and salification on octyl halogenated propylbenzene by using a novel intermediate, thereby obtaining the Fingolimod hydrochloride. The synthetic method is short in route, high in yield, low in cost, mild in reaction conditions, simple and convenient in operation and high in product purity and has high application value in large-scale industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis method of fingolimod hydrochloride and an intermediate thereof. Background technique [0002] Fingolimod hydrochloride is referred to as FTY-720 for short, and its chemical name is 2-(4-octylphenyl)ethyl-2-amino-1,3-propanediol hydrochloride. Its structure is shown in Formula 1: [0003] Formula 1: [0004] [0005] FTY-720 is an immunosuppressant mainly used to treat relapsing-remitting multiple sclerosis (MS). Novel immunosuppressants for relapsing-remitting multiple sclerosis (MS). [0006] At present, there are several methods for synthesizing FTY-720 in the literature: the earliest FTY-720 compound patent US5604229 uses phenethyl acetate as a raw material, first constructs an octyl substituent through Friedel-Crafts acylation, and then converts The ester group is converted into a more active iodine substituent, and the aminopropanediol structure is constructed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C22/04C07C17/35C07C215/28C07C213/02C07C49/80C07C45/46
Inventor 柯潇常和西叶勇
Owner 四川弘远药业有限公司
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