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Preparation method and preparation intermediate of fingolimod hydrochloride

A technology for fingolimod hydrochloride and an intermediate, which is applied in the field of pharmaceutical synthesis, can solve the problems of column purification, complicated operation, low yield and the like, and achieves the effects of easy industrial production, advanced preparation technology and cost reduction.

Inactive Publication Date: 2015-04-22
湖北金赛药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 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 steps such as nitrosation and reduction to obtain FTY-720, the total yield is relatively high (about 28%), but the overall reaction steps are still too long, and the intermediate needs to be purified by column
[0008] 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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  • Preparation method and preparation intermediate of fingolimod hydrochloride
  • Preparation method and preparation intermediate of fingolimod hydrochloride
  • Preparation method and preparation intermediate of fingolimod hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] step 1

[0034] In a 250mL three-necked flask, add 19g (0.1mol) of n-octylbenzene, 13.3g (0.1mol) of aluminum trichloride, and 35mL of dichloromethane, cool to -10°C, add dropwise 11.3g (0.1mol) of chloroacetyl chloride in 30mL of dichloromethane solution, the dropwise addition temperature is between 0°C, after the dropwise addition is completed, stir at room temperature for 2 hours. Pour the reaction solution into 200 mL of ice water with stirring, separate the organic phase, extract the water phase with 50 mL of dichloromethane, combine the organic phases, wash twice with water, dry over anhydrous magnesium sulfate, filter and concentrate, add 30 mL of petroleum ether to the residue , placed in the refrigerator overnight, and the precipitated solid was suction-filtered to obtain 17 g of a white solid (Compound A).

[0035] step 2

[0036] In a 500mL three-neck flask, add 200mL of absolute ethanol, cut 4.6 (0.2mol) g of sodium metal into small pieces and slowly add t...

Embodiment 2

[0049] step 1

[0050] In a 250mL three-necked flask, add 19g (0.1mol) of n-octylbenzene, 13.3g (0.1mol) of aluminum trichloride, and 35mL of dichloromethane, cool to -10°C, add dropwise 11.3g (0.1mol) of chloroacetyl chloride in 30mL of dichloromethane solution, the dropwise addition temperature is between -5-0°C, after the dropwise addition is completed, stir at room temperature for 2 hours. Pour the reaction solution into 200 mL of ice water with stirring, separate the organic phase, extract the water phase with 50 mL of dichloromethane, combine the organic phases, wash twice with water, dry over anhydrous magnesium sulfate, filter and concentrate, add 30 mL of petroleum ether to the residue , placed in the refrigerator overnight, and the precipitated solid was suction-filtered to obtain 17.2 g of a white solid (Compound A).

[0051] step 2

[0052] In a 500mL three-neck flask, add 200mL of absolute ethanol, cut 4.6 (0.2mol) g of sodium metal into small pieces and slowly ...

Embodiment 3

[0065] step 1

[0066] In a 250mL three-necked flask, add 19g (0.1mol) of n-octylbenzene, 13.3g (0.1mol) of aluminum trichloride, and 35mL of dichloromethane, cool to -10°C, add dropwise 11.3g (0.1mol) of chloroacetyl chloride in For a solution of 30 mL of dichloromethane, the dropwise addition temperature is between -10°C and 5°C. After the dropwise addition is complete, stir at room temperature for 2 hours. Pour the reaction solution into 200 mL of ice water with stirring, separate the organic phase, extract the water phase with 50 mL of dichloromethane, combine the organic phases, wash twice with water, dry over anhydrous magnesium sulfate, filter and concentrate, add 30 mL of petroleum ether to the residue , placed in the refrigerator overnight, and the precipitated solid was suction-filtered to obtain 17.3 g of a white solid (Compound A).

[0067] step 2

[0068] Add 200mL of absolute ethanol to a 500mL three-necked flask, cut 4.6 (0.2mol) g of sodium metal into small p...

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Abstract

The invention relates to the field of drug synthesis, and specifically relates to a preparation method and a preparation intermediate of fingolimod hydrochloride. The method provides a completely novel synthesis route. According to the method, n-octyl benzene and chloroacetyl chloride are adopted as initial raw materials; and fingolimod hydrochloride is prepared through the steps of Friedel-Crafts acylation, coupling, ketone carbonyl reduction, ester group reduction, amide hydrolysis, hydrochloride formation, and the like. The preparation method is completely novel; preparation process is advanced; yield is high; the method is stable; and cost can be effectively reduced.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation 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. FTY-720 is an immunosuppressant, mainly For the treatment of relapsing-remitting multiple sclerosis (MS), it was approved by the US FDA on September 21, 2010, becoming the first oral drug for the treatment of relapsing-remitting multiple sclerosis (MS) new immunosuppressant. [0003] 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 am...

Claims

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Application Information

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IPC IPC(8): C07C49/80C07C215/28C07C213/02
Inventor 熊开文赵继舒
Owner 湖北金赛药业有限公司
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