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New synthetic method of fingolimod hydrochloride

A new synthesis technology of fingolimod hydrochloride, applied in the field of preparation of fingolimod hydrochloride, can solve the problems of harsh reaction conditions, excessively long reaction route, and difficulty in expanding production, and achieves mild synthesis conditions and easy synthesis of raw materials. The effect of obtaining and synthetic raw materials is cheap

Inactive Publication Date: 2015-01-21
YANTAI UNIV
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  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 1. The reaction route is too long and the reaction conditions are relatively harsh, involving low temperature, anhydrous and oxygen-free, high pressure and other reaction conditions, so it is not easy to expand production
[0009] 2. A large amount of expensive reagents are used in the reaction, such as lithium aluminum hydride, metal palladium, etc., and the production cost is relatively high
[0010] 3. Some raw materials are not easy to get, such as 3-nitro-1 (4-octylphenyl) propane-1,2-diol and 2-amino-2-hydroxymethyl-1,3-propanediol
[0011] 4. Some intermediates are less stable, such as 2-(4-n-octylbenzene)-chloroethane is unstable and difficult to store
Not suitable for industrial scale-up production

Method used

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  • New synthetic method of fingolimod hydrochloride
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  • New synthetic method of fingolimod hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 3-nitro-1-(4-octylphenyl)propan-1-one (2)

[0025] A mixture of 70 g (0.22 mol) of 3-bromo-1-(4-octylphenyl)propan-1-one (6) and 300 mL of dimethylformamide (DMF) was cooled on ice to below 20°C. 61 g (0.88 mol) of sodium nitrite was added to the above mixture, and the reaction was carried out at 20° C. for 2 h. After the reaction was completed, pour it into 1200mL of water under stirring, and a yellowish solid was precipitated, filtered, washed with water, and dried in vacuo. The crude product was decolorized with 450mL of n-hexane and 1g of activated carbon under reflux for 0.5h, filtered, and crystallized by cooling. Filtration and vacuum drying at room temperature gave 50 g of white solid, yield 80%, mp 54-56°C.

[0026] Compounding to 2 has the following NMR data:

[0027] 1 H MNR (CDCl 3 , δ): ppm7.89-7.91 (d, 2H, J=8.2Hz), 7.29-7.31 (d, 2H, J=8.2Hz), 4.81-4.84 (t, 2H, J=6.2Hz), 3.64- 3.67(t, 2H, J=6.2Hz), 2.66-2.69(t, 2H, J=7.6Hz), 1.61-1.65(m, 2H), 1.26-1.3...

Embodiment 2

[0029] 3-Bromo-1-(4-octylphenyl)propan-1-one (9)

[0030] Add 18.6ml of TFA and 7.92g (0.024mol) of 3-bromo-1-(4-octylphenyl)propan-1-one (6) into a 250ml single-necked bottle, stir magnetically, and add triethylsilane under ice-cooling 5.65g, stirred in the ice bath for 0.5h, removed the ice bath and continued to stir for 4h. After the reaction is detected by TLC, pour the reaction solution into an appropriate amount of ice water and stir, gradually add sodium bicarbonate solution, adjust to PH = 8, a slightly yellow oily substance appears on the liquid surface, extract with 100ml×3 petroleum ether, add anhydrous sodium sulfate Dry overnight, filter with suction, and rotary evaporate to obtain 14.29 g of a yellow liquid, which is passed through a column with petroleum ether as an eluent to obtain 7.46 g of a colorless liquid with a yield of 98.43%.

Embodiment 3

[0032] 1-(3-nitropropyl)-4-octylbenzene (3)

[0033] 9.59g (0.03mol) 3-bromo-1-(4-octylphenyl)propan-1-one (9) and 44ml DMF were added to a 250ml single-necked bottle, magnetically stirred, and 8.47g ( 0.12mol) sodium nitrite, the reaction solution changed from colorless to yellow, stirred in ice bath for 0.5h, then kept at 20°C for 6h, poured the reaction solution into an appropriate amount of ice water, stirred, and carried out with 100ml×3 petroleum ether Extraction, drying with anhydrous sodium sulfate overnight, suction filtration, and rotary evaporation to obtain 10.32 g of yellow liquid, which was passed through the column with PE:AE=20:1 as the eluent to obtain 7.20 g of yellow liquid, yield: 86.6%.

[0034] The combination of 3 has the following NMR data:

[0035] 1H MNR (CDCl3, δ): ppm7.08-7.16 (m, 4H), 4.34-4.37 (t, 2H, J = 6.9Hz), 2.66-2.70 (t, 2H, J = 7.5Hz), 2.55-2.57 (t, 2H, J=7.6Hz), 2.27-2.35(m, 2H), 1.55-1.61(m, 2H), 1.26-1.37(m, 10H), 0.86-0.89(t, 3H, J=7....

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Abstract

The invention provides a preparation method of fingolimod hydrochloride (1). The method comprises the following steps: carrying out a reducing reaction on 3-nitro-1(4-octylphenyl)propyl-1-one (2) to obtain a compound 1-(3-nitropropyl)-4-octylbenzene (3); reacting 1-(3-nitropropyl)-4-octylbenzene (3) with formaldehyde to generate 2-(4-octylphenylethyl)-2-nitro-propane-1,3-diol (4); and reducing the compound 4, and carrying out salt formation on the reduced compound 4 and hydrochloric acid to generate the 2-(4-octylphenylethyl)-2-amino-propane-1,3-diol hydrochloride (1) which is the fingolimod hydrochloride. The method has the advantages of short synthetic route, cheap and easily available synthetic raw materials, no obvious pollution in the synthetic process, and total yield reaching 40-45%, is a simple and economic method for preparing the fingolimod hydrochloride. The invention also provides a synthetic method of intermediates.

Description

technical field [0001] The invention relates to a preparation method of Fingolimod hydrochloride, which belongs to the technical field of medicine synthesis. technical background [0002] Fingol imod (1, Fingol imod) was the first natural amino acid structure extracted from Cordyceps sinensis by Tetsuro Fujita, a professor of pharmacology at Kyoto University. After SAR screening, the final structure was modified into the following molecular structure: [0003] [0004] The compound was initially studied as an immunosuppressant, but after further testing, Switzerland's Novartis dropped the idea of ​​an immunosuppressant drug for transplant patients because it did not outperform existing drugs. Interestingly, the company found that fingolimod had a strong effect in multiple sclerosis in trials of thousands of patients, reducing the number of relapses, although some patients may experience symptoms such as vision problems, fatigue and numbness . [0005] In April 2011, aft...

Claims

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Application Information

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IPC IPC(8): C07C215/28C07C213/02C07C213/08
Inventor 姚雷严宁曹阳郭鹏孙新凤张军风王新
Owner YANTAI UNIV
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