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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  • Abstract
  • Description
  • Claims
  • 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.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0023] Example 1

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

[0025] 70 grams (0.22 mol) of a mixture of 3-bromo-1-(4-octylphenyl)propan-1-one (6) and 300 mL of dimethylformamide (DMF), cooled to below 20°C on ice. 61g (0.88mol) sodium nitrite was added to the above mixture, and the reaction was kept at 20°C for 2h. After the reaction was completed, it was poured into 1200mL water with stirring to precipitate a yellowish solid, filtered, washed with water, and dried in vacuum. The crude product was decolorized with 450mL n-hexane and 1g activated carbon by heating and refluxing for 0.5h, filtered, and cooled to crystallize. Filter and vacuum dry at room temperature to obtain 50 grams of white solid, yield 80%, mp 54-56°C.

[0026] Compound 2 has the following nuclear magnetic data:

[0027] 1 H MNR(CDCl 3 , Δ): ppm 7.89-7.91 (d, 2H, J = 8.2 Hz), 7.29-7.31 (d, 2H, J = 8.2 Hz), 4.81-4.84 (t, 2H, J = 6.2 Hz), 3.64- 3.67 (t, 2H, J = 6.2 Hz), 2.66-2.69 (t, 2H, J = 7.6 Hz), 1.61-...

Example Embodiment

[0028] Example 2

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

[0030] Add 18.6ml TFA and 7.92g (0.024mol) 3-bromo-1-(4-octylphenyl)propan-1-one (6) into a 250ml single-necked flask, stir magnetically, and add triethylsilane under ice bath 5.65g, stir under ice bath for 0.5h, remove ice bath and continue stirring for 4h. After the reaction was detected by TLC, the reaction solution was poured into an appropriate amount of ice water and stirred, and sodium bicarbonate solution was gradually added to adjust to PH=8. A yellowish oil appeared on the liquid surface. Extract with 100ml×3 petroleum ether and add anhydrous sodium sulfate After drying overnight, suction filtration, and rotary evaporation, 14.29 g of yellow liquid was obtained, which was passed through the column with petroleum ether as the eluent to obtain 7.46 g of colorless liquid, and the yield was 98.43%.

Example Embodiment

[0031] Example 3 :

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

[0033] Add 9.59g (0.03mol) 3-bromo-1-(4-octylphenyl)propan-1-one (9) and 44ml DMF into a 250ml single-necked flask, stir magnetically, and add 8.47g( 0.12mol) Sodium nitrite, the reaction solution changes from colorless to yellow. Stir for 0.5h in an ice bath, then keep the reaction at 20℃ for 6h. Pour the reaction solution into an appropriate amount of ice water, stir, and use 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. The yield was 86.6%.

[0034] Compound 3 has the following nuclear magnetic 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 = 7.6 Hz), 2.27-2.35 (m, 2H), 1.55-1.61 (m, 2H), 1.26-1.37 (m, 10H), 0.86-0...

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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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