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Process for making fingolimod

A technology for compound and acid addition salt, applied in the field of preparation of fingolimod, can solve the problems of uneconomical, slow sequential or parallel reduction/hydrogenolysis, etc.

Inactive Publication Date: 2013-07-03
SYNTHON BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the OH- and NO of intermediate (8) 2 - Sequential or parallel reduction / hydrogenolysis of groups is extremely slow and therefore less economical
[0016] Therefore, although many methods of preparing fingolimod are known, improvements in the methods of preparing fingolimod are still desirable

Method used

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  • Process for making fingolimod
  • Process for making fingolimod

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] 3-nitro-1-(4-octylphenyl)propan-1-ol

[0074] A solution of 11.0 g 3-nitro-1-(4-octylphenyl)propan-1-one (37.8 mmol) in 48 g THF, 3.6 g water and 1.2 g methanol was cooled to 0°C. To this solution was added 0.6 g NaBH 4 (15.9 mmol), and the solution was stirred at the same temperature. After 2 hours, the reaction mixture was quenched with 65 g of water. Then 80 g EtOAc was added and the aqueous phase was extracted with 2 x 20 g EtOAc. The combined organic phases were washed with 2 x 15 g of water. Carbon filtration of the yellow organic phase with 0.4 g activated charcoal followed by removal of the solvent by rotary evaporation afforded 9.72 g of the title compound (33.1 mmol, 88%) as a colorless oily residue. Impurity (13) content: 1.34% (HPLC).

Embodiment 2

[0076] 3-nitro-1-(4-octylphenyl)propan-1-ol

[0077] 3-Nitro-1-(4-octylphenyl)propan-1-one (5 g, 17.16 mmol) was dissolved in anhydrous THF (75 mL) under nitrogen atmosphere. The solution was cooled to 0 °C and a 4M solution of lithium borohydride in THF (2.145 mL, 8.58 mmol) was added over a period of 12 minutes. Stirring was continued at 0°C, then monitored by HPLC. After 25 minutes, HPLC showed no more starting material. The reaction mixture was poured into ice-water and 4M aqueous hydrochloric acid was added (gas evolved!) until pH<6. The mixture was extracted with diethyl ether (3x100ml), washed with brine (100ml), dried (sodium sulfate), filtered and evaporated to dryness to give 3-nitro-1-(4-octylphenyl)propan-1-ol, Yield 4.72 g (94%) as a yellow oil.

Embodiment 3

[0079] 3-(Hydroxymethyl)-3-nitro-1-(4-octylphenyl)butan-1,4-diol

[0080] 3-Nitro-1-(4-octylphenyl)propan-1-ol (3.27g, 11.15mmol) was dissolved in methanol (11.15ml) to give a cloudy orange solution. To the resulting solution was added triethylamine (1.553ml, 11.15mmol) followed by formalin (37% in water, stabilized with 12% methanol) (5.02ml, 66.9mmol). The mixture was heated to 40 °C and the reaction was monitored by HPLC. After 120 minutes, HPLC showed complete conversion of starting material. Water (100 mL) was added to give a white emulsion. 1M aqueous hydrochloric acid was added until pH<6. The mixture was extracted with ethyl acetate (2x100ml), washed with brine (25ml), dried (sodium sulfate), filtered and evaporated to dryness to give product 2 as a brown solid / oil in 3.54g (97%) yield .

[0081] The crude product was recrystallized from a mixture of heptane and ethyl acetate to afford a white solid in 2.06 g (52%) yield, >99% purity.

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Abstract

The invention relates to a process of making fingolimod of formula (1), or an acid addition salt thereof comprising a step of reacting the compound of formula (11) and / or a compound of formula (14) or an acid addition salt thereof, in a solvent with hydrogen in a presence of a hydrogenation catalyst, preferably palladium catalyst, and optionally converting fingolimod of formula (1) into an acid addition salt, to compounds of formula (11) and (14), processes of making them and to their use in making fingolimod.

Description

Background of the invention [0001] Fingolimod (commonly coded as FTY720) is chemically 2-amino-2-[2-(4-octylphenyl)ethyl]-propan-1,3-diol of the following formula (1), [0002] [0003] is a pharmaceutically active compound currently being tested as an immunosuppressant and as an active agent in the treatment of multiple sclerosis. It can form stable acid addition salts, of which fingolimod hydrochloride is the most commonly used salt. [0004] Fingolimod was first disclosed in Yoshitomi's EP627406, which also describes two basic routes for its preparation. [0005] In the first route (Example 28 of EP'406), the final synthetic step involves deacetylation of the protected diol-amine (2) by base hydrolysis: [0006] [0007] In the second route (Example 234 of EP'406), the final synthetic step involves reduction of the diester-amine (4): [0008] [0009] Subsequently, several alternative routes for the preparation of fingolimod were developed. Of these, the method...

Claims

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Application Information

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IPC IPC(8): C07C205/16C07C209/34C07C209/70C07C215/28
CPCC07C205/16C07C201/12C07C213/02C07C213/08C07C215/28C07C215/20
Inventor R·G·吉灵
Owner SYNTHON BV
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