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Siponimod intermediate and preparation method thereof

A compound and reaction solvent technology, applied in the field of siponimod intermediate and its preparation, can solve the problems of limited industrial application, high cost, and low reaction safety factor

Pending Publication Date: 2021-10-22
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because this method requires the use of explosive diazonium salts and highly active Grignard reagents, the reaction safety factor is low
And the cost of substrate 4-amino-3-ethylbenzonitrile is relatively high, which limits the industrial application of this route

Method used

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  • Siponimod intermediate and preparation method thereof
  • Siponimod intermediate and preparation method thereof
  • Siponimod intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] The preparation of embodiment 1 compound (10)

[0075]

[0076] Add compound (9) (60.59g), dichloromethane (480mL), 4-dimethylaminopyridine (134.39g), di-tert-butyl dicarbonate (272.81g) into a 1000mL three-necked reaction flask, and heat up to 40°C After stirring for 4h, water (240mL) was added after the reaction was completed, and the organic phase was concentrated under reduced pressure after liquid separation to obtain compound (10) (160.71g). The crude product yield was 100%, and the purity: 95.2%; .

Embodiment 2

[0077] The preparation of embodiment 2 compound (12)

[0078]

[0079] Add dichloromethane (200mL) into a 1000mL three-necked reaction flask, cool down to 0°C, add aluminum trichloride (29.33g), dropwise add acetyl chloride (15.70g), and dropwise add compound (10) (64.28g ) in dichloromethane (200mL). After the dropwise addition, control the temperature and react at 25°C for 3 hours. After the reaction, drop the reaction solution into dilute hydrochloric acid (2mol / L, 300mL). After the dropwise addition, control the temperature and react at 25°C for 2h. After the reaction, add hydrogen The sodium oxide aqueous solution was adjusted to pH ≈ 9-12, and the aqueous phase was extracted once with dichloromethane (200mL) after separation, the combined organic phase was washed with water (200mL), the organic phase was concentrated under reduced pressure to obtain a yellow oil, and then washed with ethanol Recrystallization (10vol absolute ethanol, heated to 70°C for dissolution, c...

Embodiment 3

[0081] The preparation of embodiment 3 compound (13)

[0082]

[0083] Add 48% hydrobromic acid aqueous solution (50mL) and compound (12) (16.32g) into a 500mL three-necked reaction flask, cool down to 0°C, control the temperature at 0-5°C and slowly add sodium nitrite (6.90g). Add the above reaction solution to 20% hydrobromic acid solution (20mL) containing cuprous bromide (20.08g), heat up to reflux temperature after addition, react for 5h, cool down to room temperature after the reaction, and dichloromethane Methane (100mL) was extracted three times, the combined organic phase was washed with water (150mL), the organic phase was concentrated under reduced pressure to obtain a yellow oil, and then column chromatography (gradient elution, n-hexane:ethyl acetate=10:1 to 4 :1) A light yellow solid (18.64g) was obtained, yield 82.1%, purity: 96.8%; MS: [M+1]=227.0.

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PUM

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Abstract

The invention relates to a siponimod intermediate and a preparation method thereof, and belongs to the field of medicinal chemistry. According to the preparation method, by taking 2-ethylaniline as a starting material, 1-(3-ethyl-4-hydroxymethyl) acetophenone is obtained through multi-step reaction. The method has the advantages of high yield, simple and easily available raw materials, low cost and controllable reaction conditions and temperature, and is suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a siponimod intermediate and a preparation method thereof. Background technique [0002] SiponiMod (SiponiMod) its chemical name is: 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl-benzyl (benxyl)}- Azetidine-3-carboxylic acid has a chemical structural formula as shown in formula (I). Siponimod is an oral sphingosine-1-phosphate receptor modulator used in the treatment of multiple sclerosis. [0003] [0004] 1-(3-ethyl-4 hydroxymethyl)acetophenone is a common intermediate for the synthesis of Siponimod, and its chemical structural formula is as shown in formula (09): [0005] [0006] Patent WO2004103306A2 discloses a synthetic route for the preparation of 1-(3-ethyl-4-hydroxymethyl)acetophenone: using 4-amino-3-ethylbenzonitrile as raw material, through diazotization reaction, formyl Chemicalization, sodium borohydride reduction, Grignard reaction in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/26C07D317/20C07D317/16C07C271/28C07C49/82C07C45/00
CPCC07C49/82C07D317/26C07D317/20C07D317/16C07C271/28
Inventor 林碧悦王仲清寇景平李建兵胡吉安黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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