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Method for combining Fingolimod intermediate

A technology of intermediates and compounds, applied in the field of compound preparation, can solve the problems of high cost of synthetic routes, expensive raw materials, difficult industrialization, etc., and achieve the effect of simple operation, short synthetic route and easy control of conditions

Active Publication Date: 2013-06-12
NANJING JIEYUN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this route is that some raw materials are expensive, making the total cost higher
In the process of synthesizing compound 20, relatively expensive (2-oxopropyl) phosphonic acid dimethyl ester and p-toluenesulfonyl azide reagent are used, so the synthetic route cost is higher, is difficult to industrialization

Method used

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  • Method for combining Fingolimod intermediate
  • Method for combining Fingolimod intermediate
  • Method for combining Fingolimod intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 1.1 Compounds 3 preparation of

[0036] Under nitrogen protection, the compound 2 (9.9g, 38.18mmol), compound 1 (21.9g, 45.82mmol) and anhydrous K 2 CO 3 (14.8g, 106.9mmol) was added to a 500mL three-necked flask, and then a mixed solvent composed of 150mL anhydrous THF and 50mL anhydrous DMF was added, slowly heated to 80°C, and reacted for 5h. After cooling, add water, extract with ethyl acetate (100 mL×3), combine the organic phases, wash with water successively, wash with saturated brine, anhydrous Na 2 SO 4 Drying, column chromatography obtains 12.3g corresponding alkene compound 3 ; compound 3 It is a mixture with a cis-trans structure, and the yield is 85.1%.

[0037] 1.2 Compounds 3 preparation of

[0038] Under nitrogen protection, the compound 2 (9.9g, 38.18mmol), compound 1 (21.9g, 45.82mmol) and anhydrous Na 2 CO 3(11.3g, 106.9mmol) was added to a 500mL three-necked flask, and then a mixed solvent composed of 150mL anhydrous THF and 50mL an...

Embodiment 2

[0040] 2.1 Compounds 4 preparation of

[0041] compound 3 (12.0 g, 31.71 mmol) was dissolved in 150 mL of methanol, 1.2 g of Pd / C ((10 wt%) was added, and reacted at room temperature under hydrogen for 12 h. Suction filtration, evaporation of the solvent under reduced pressure gave 10.3 g of white solid product 4 , and the yield was 92.7%.

[0042] Mp: 160-163 oC; 1 H NMR (500MHz, CDCl 3 ): δ 1.41 (s, 3 H), 1.43 (s, 3 H), 1.47 (s, 9 H), 1.92 (t, 2 H), 2.44-2.48 (m, 2 H), 3.55 (s, 2 H), 3.66 (d, J = 12 Hz, 2 H), 3.88 (d, J = 11 Hz, 2 H), 4.98 (s, 1 H), 6.61 (d, J = 8 Hz, 2 H), 6.96 (d, J = 8 Hz, 2 H); HRMS (EI): m / z calcd for C 19 h 30 N 2 o 4 [M] + : 350.2206, found: 350.2203.

[0043] 2.2 Compounds 4 preparation of

[0044] compound 3 (12.0 g, 31.71 mmol) was dissolved in 150 mL of ethanol, 1.2 g of Pd / C ((10 wt%) was added, and the reaction was carried out at room temperature under hydrogen for 12 h. Suction filtration, and the solvent was evapora...

Embodiment 3

[0050] 3.1 Compounds 5 preparation of

[0051] Dissolve pinacol diboronate (7.25g, 28.53mmol) and benzoyl peroxide (0.14g, 0.57mmol) in 150mL CH 3 CN, followed by adding compounds 4 (10.0g, 28.53mmol) and tert-butyl nitrite (4.42g, 42.80mmol), react at room temperature for 6h after addition. Add water to terminate the reaction, extract with ethyl acetate (100 mL×3), combine the organic phases, wash with water successively, wash with saturated brine, anhydrous Na 2 SO 4 dry. Suction filtration, evaporation of the solvent under reduced pressure, and column chromatography yielded 7.76 g of a white solid product with a yield of 60%.

[0052] Mp: 145-148 oC; 1 H NMR (500MHz, CDCl 3 ): δ 1.33 (s, 12 H), 1.41 (s, 3 H), 1.43 (s, 3 H), 1.47 (s, 9 H), 1.98 (t, 2 H), 2.56-2.60 (m, 2 H), 3.66 (d, J = 12 Hz, 2 H), 3.88 (d, J = 11 Hz, 2 H), 4.98 (s, 1 H), 7.19 (d, J = 8 Hz, 2 H), 7.71 (d, J = 8 Hz, 2 H); HRMS (EI): m / z calcd for C 25 h 40 BNO 6 [M] + : 461.2949, f...

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Abstract

The invention provides a method for combining a Fingolimod intermediate. The method includes that: a. compound 1 and a compound 2 conduct Wittig reaction to produce a compound 3; b. the compound 3 conducts hydrogenation reaction under a condition that catalyst Pd / C exists to produce a compound 4; c. the compound 4 reacts with bisdiboron, benzoyl peroxide and t-BuONO to produce a compound 5; d. the compound 5 and a iodo-object 6 conduct Suzuki reaction to produce a compound 7; and e. the compound 7 conducts hydrogenation reaction under the catalysis of Pd / C to produce a compound 8. The method for combining the Fingolimod intermediate is simple and short in synthetic route, easy and convenient to operate, low in cost, high in rate of production and easy for industrialized production.

Description

technical field [0001] The present invention relates to the technical field of compound preparation, in particular to the technical field of preparation of key intermediates of fingolimod, and more specifically to a new method for synthesizing key intermediates of fingolimod. Background technique [0002] Fingolimod was originally developed by Japan's Mitsubishi Pharmaceutical Company, and later transferred the global management rights to Switzerland's Novartis Pharmaceutical Company. It was the first to be approved by the US FDA on September 21, 2010, becoming the first drug that can be administered orally for the treatment of relapse A novel immunosuppressant for remitting multiple sclerosis, primarily for the treatment of relapsing multiple sclerosis, reducing the frequency of clinical exacerbations and delaying the accumulation of physical disability. [0003] [0004] [0005] compound 8 It is a key intermediate in the synthesis of fingolimod. Currently, compounds...

Claims

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Application Information

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IPC IPC(8): C07D319/06
Inventor 梅铁文于秀华史培忠刘雅倩罗宇吕伟
Owner NANJING JIEYUN PHARMA TECH CO LTD
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