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Intermediate compounds and process for the preparation of fingolimod

A technology of compounds and catalysts, applied in the field of intermediate compounds and methods for the preparation of fingolimod, capable of solving problems such as difficult operation and low total yield

Inactive Publication Date: 2013-09-18
MAPI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Other practical problems related to the teaching of CN1765872 are: formation of 3-nitro-1-(p-octylphenyl)propan-1-ol as an oil which is difficult to handle at the production stage, formylation (56%) and hydrogenation (66%) steps in moderate yields, and low overall yields (about 20%)

Method used

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  • Intermediate compounds and process for the preparation of fingolimod
  • Intermediate compounds and process for the preparation of fingolimod
  • Intermediate compounds and process for the preparation of fingolimod

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] Example 1 : Preparation of 3-nitro-1-(4-octylphenyl)propan-1-one (12)

[0197] In a dry flask, 3-nitropropionic acid [commercially available or prepared according to Silva, P.C.; Costa, J.S.; Pereira, V.L.P. Synth. Commun. 2001, 31, 595, (10.0 g, 85.0 mmol)] was mixed with SOCl 2 (100ml) was stirred overnight. After addition of anhydrous toluene, the solution was azeotropically distilled to remove excess SOCl 2 . The residue can be used directly for acylation or distillation (80-83°C / 0.1-0.2mbar [SYNTHESIS 2009, No.5, p.715]) to provide pure 3-nitropropionyl chloride as a clear liquid.

[0198] AlCl 3 (12.0 g, 89.0 mmol) was added to 15 ml of methylene chloride and cooled to 0-5°C, followed by the addition of 3-nitropropionyl chloride (11 g, 80 mmol). Octylbenzene (17.10 g, 89.0 mmol) was added dropwise to 40 ml of CH 2 Cl 2 and the solution was stirred at room temperature under TLC monitoring. After the reaction was complete, the mixture was poured onto ice, a...

Embodiment 2

[0199] Example 2 : Preparation of 3-nitro-1-(4-octylphenyl)propyl acetate (13)

[0200] To a solution of 3-nitro-1-(4-octylphenyl)propan-1-one (12) (5.00 g) in methanol (25 ml) was added sodium borohydride (0.8 g) at 0°C , and the mixture was left to stand at room temperature for 4.5 hr. The suspension was diluted with ethyl acetate and washed successively with 1N HCl, sodium bicarbonate solution and brine. The ethyl acetate layer was passed through anhydrous Na 2 SO 4 Dried and concentrated. Pyridine (1.5eq), dichloromethane (10v) and acetic anhydride (10eq) were added to the residue, and the mixture was allowed to stand at room temperature overnight. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed successively with 1N HCl, sodium bicarbonate solution and brine. The ethyl acetate solution was dried over sodium sulfate and concentrated. The residue is pure enough for the next transformation or can be purified by ...

Embodiment 3

[0201] Example 3 : Preparation of 2-nitro-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol (14)

[0202] To a mixture of paraformaldehyde (0.13 mol, 9 eq) was added dropwise 4 ml (1.5 eq) of triethylamine in 40 ml of 1,4-dioxane at room temperature and with stirring, in 50 ml of 1, 3-nitro-1-(4-octylphenyl)propyl acetate (13) (5 g, 0.015 mol) in 4-dioxane, the mixture was slowly heated to 70 °C and controlled on TLC Stir at this temperature for 24 h. Water was added to the reaction mixture, and the pH of the mixture was adjusted to about 9-10, and stirred at 40° C. for 16 h for deprotection (monitored by TLC and HPLC). After the reaction was complete (about 2-3 h), the mixture was extracted with ethyl acetate and washed successively with 1N HCl, sodium bicarbonate solution and brine. The ethyl acetate solution was dried over sodium sulfate and concentrated. The residue is pure enough for the next transformation or can be purified by crystallization or silica gel column chromatog...

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Abstract

The present invention relates to processes for the preparation of (2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (Fingolimod) and pharmaceutically acceptable salts thereof, and intermediates formed in such processes.

Description

technical field [0001] The present invention relates to a process for the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (fingolimod) and pharmaceutically acceptable salts thereof, and in Intermediates formed in such processes. Background technique [0002] Fingolimod, also known as 2-amino-2-[2-(4-octylphenyl)ethyl]-l,3-propanediol, is marketed as its hydrochloride salt and is a sphingosine Alcohol-1-phosphate receptor (S1P-R) modulators that act as immunomodulators by causing lymphopenia through sequestration of circulating lymphocytes into secondary lymphoid tissues, thereby preventing lymphocyte transfer to transplanted or other infected tissues. Fingolimod (FTY720) is an innovative oral treatment for relapsing-remitting multiple sclerosis (RRMS). Patients with MS display a spectrum of symptoms caused by demyelination of the central nervous system (CNS), including the brain, spinal cord and optic nerves. The destruction of the protective myelin she...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/27
CPCC07C201/12C07C205/40C07C205/45C07C231/02C07D319/06C07F9/4056C07F9/5456A61P25/00A61P43/00C07C215/28C07C205/16C07C205/02C07C205/31C07C213/02C07F9/4021C07F9/5442
Inventor 埃胡德·马罗姆迈克尔·米治里特斯基塞·鲁比诺夫
Owner MAPI PHARMA
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