Novel synthesis method of fingolimod hydrochloride

A technology of fingolimod hydrochloride and a new method, applied in the new synthesis field of multiple sclerosis treatment drug fingolimod hydrochloride, can solve the problems of instability, difficult post-processing, long reaction route and the like, and achieve mild reaction conditions , Good use value, easy post-processing effect

Active Publication Date: 2011-07-13
安庆润科生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 1. The reaction route is long, and the Friedel-Crafts reaction is required, the post-processing is difficult, and the pollution is serious
[0009] 2. When synthesizing some intermediates, it is necessary to use the reducing agent LiAlH 4 , the raw material cost is high, and LiAlH 4 There are great safety hazards in production
[0010] 3. Th

Method used

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  • Novel synthesis method of fingolimod hydrochloride
  • Novel synthesis method of fingolimod hydrochloride
  • Novel synthesis method of fingolimod hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Dissolve p-4-n-octylbenzyl bromide (10.0g, 35.5mmol), 2-mercaptobenzothiazole (6.5g, 39mmol) and anhydrous potassium carbonate (5.4g, 39mmol) in 100ml of DMF, heat to reflux for 3 hours, When the reaction is complete, stop the reaction. After cooling, 100ml of water was added and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 13.0 g of compound (6), a pale yellow solid, Mp: 52-54° C.; yield: 99%.

[0030] 1 H NMR (500HMz, CDCl3): 0.87(t, 3H), 1.26-1.29(m, 10H), 1.57-1.59(m, 2H), 2.57(t, 2H), 4.58(s, 2H), 7.14(d , J=8Hz, 2H), 7.25-7.31(m, 1H), 7.35(d, J=8Hz, 2H), 7.40-7.43(m, 1H), 7.74(d, J=8Hz, 1H), 7.89( d, J = 8 Hz, 1H).

[0031] Two, the synthesis of compound (7)

Embodiment 2

[0033] Compound (6) (7.4g, 20mmol) was dissolved in 150ml of chloroform, and m-chloroperoxybenzoic acid (14.8g, 60mmol) was added in 3 batches under ice-cooling conditions. After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 4 hours, and the reaction was completed. Sequentially wash with saturated sodium bicarbonate, saturated sodium thiosulfate, water, saturated brine, and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained light yellow solid was recrystallized from ethyl acetate to obtain 6.8 g of the product, compound (7), as a light yellow solid, yield: 85%.

Embodiment 3

[0035] Compound (6) (7.4 g, 20 mmol) was dissolved in 30 ml of acetic acid, and 30% hydrogen peroxide (5.0 g, 42 mmol) was added dropwise under ice-cooling conditions. Then remove the ice bath, stir at room temperature for 20 hours, pour into 100ml of water after the reaction, extract with ethyl acetate (30ml*3), combine the organic layers, wash with saturated sodium bicarbonate, saturated sodium thiosulfate, water, and saturated salt Washed with water, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained light yellow solid was recrystallized from ethyl acetate to obtain the product, compound (7), 6.0 g, light yellow solid, yield: 75%.

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Abstract

The invention discloses a novel synthesis method of fingolimod hydrochloride. The method comprises the following steps of: 1, reacting a compound (5) with a sulfhydryl compound under alkaline conditions to generate a key intermediate product (6); 2, performing oxidation reaction on the product (6) to generate a sulfonyl compound (7); 3, performing Knoevenagel condensation reaction on the sulfonylcompound (7) and a raw material aldehyde group compound (8) under the alkaline conditions to obtain a key intermediate (9); and 4, performing hydrogenation reduction reaction on the intermediate (9) and performing amino group deprotection simultaneously to prepare 5-amino-5-[2-(4-n-octylphenyl)ethyl]-2,2-dimethyl-1,3-dioxane; and performing acetonylidene deprotection in diluted hydrochloric acid and salifying simultaneously to obtain a target compound fingolimod hydrochloride (1). In the method, raw materials are readily available, reaction conditions are mild, aftertreatment is convenient, and the method is high in yield, low in cost, environmentally-friendly, and high in utilization value in industrial production.

Description

technical field [0001] The invention relates to a new synthesis method of Fingolimod hydrochloride (Fingolimod, FTY720), a drug for treating multiple sclerosis. Background technique [0002] Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, which is more common in young and middle-aged people. The disease involves lesions in the brain or spinal cord. Nerve cells have many dendritic nerve fibers, which are like intricate wires. Multiple sclerosis is caused by the demyelination of various sizes in the central nervous system. By "sclerosis" is meant that these demyelinated areas have hardened due to scar tissue produced during tissue repair. There may be several of these lumps, and as time progresses, new lumps may also appear, so it is called "multiple." Multiple sclerosis is a peculiar nervous system disease, which mostly occurs in young and middle-aged people aged 20 to 40, and its etiology is still unknown. There are many different theor...

Claims

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Application Information

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IPC IPC(8): C07C215/28C07C213/00
CPCC07D319/06C07D277/70C07C213/00C07D277/76C07C215/28
Inventor 肖锋胡峰
Owner 安庆润科生物医药科技有限公司
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