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Preparation method of siponimod intermediate

A technology of inert gases and compounds, applied in the field of preparation of siponimod intermediates, can solve the problem of high cost, achieve the effects of reducing three wastes, reducing costs, and removing impurities efficiently and conveniently

Pending Publication Date: 2021-05-04
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since this method requires the use of relatively expensive ethynyl TMS as a reagent, its cost is relatively high

Method used

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  • Preparation method of siponimod intermediate
  • Preparation method of siponimod intermediate
  • Preparation method of siponimod intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] The preparation of embodiment 1 compound (B)

[0069] Add compound (A) (15.00g), 2-methyl-3-butyn-2-alcohol (7.16g), Pd(dppf)Cl in the reaction flask 2 (0.96g), cuprous iodide (0.62g), and TEA (150mL), the air in the reaction flask was replaced with nitrogen 3 times, and the temperature was raised to 80°C under stirring, and the reaction was continued until the reaction was detected by HPLC. Cool the reaction solution to room temperature, filter with suction, spin dry the filtrate, add 45ml of water to the spin-dried product, extract 30ml*3 times with EA, combine the organic layers and spin dry, and recrystallize the spin-dried product in toluene to obtain compound (B): 13.42g The yield is 88%, detection: purity 98%, MS: [M+1]=233.1, NMR: 1H NMR (400MHz, DMSO-d6): δ1.50 (6H, s), 2.58 (3H, s) 4.67~4.69(2H,d), 5.45~5.48(1H,t), 5.52(1H,s), 7.65~7.67(1H,d), 7.86(1H,s), 7.86~7.93(1H,d).

Embodiment 2

[0070] The preparation of embodiment 2 compound (B)

[0071] Add compound (A) (15.00g), 2-methyl-3-butyn-2-alcohol (7.16g), Pd(dppf)Cl in the reaction flask 2 (0.96g), cuprous iodide (1.24g), and DIPEA (150mL), the air in the reaction flask was replaced with nitrogen 3 times, the temperature was raised to 80°C under stirring, and the reaction was continued until the reaction was detected by HPLC. Cool the reaction solution to room temperature, filter with suction, spin dry the filtrate, add 45ml of water to the spin-dried product, extract 30ml*3 times with EA, combine the organic layers and spin dry, and recrystallize the spin-dried product in toluene to obtain compound (B): 11.44g ; Yield is 75%, detection: purity 96%.

Embodiment 3

[0072] The preparation of embodiment 3 compound (B)

[0073]Add compound (A) (15.00g), 2-methyl-3-butyn-2-alcohol (7.16g), dichloroditriphenylphosphine palladium (0.92g), cuprous iodide ( 0.93g), and TEA (150mL), the air in the reaction flask was replaced with nitrogen for 3 times, the temperature was raised to 80°C under stirring, and the reaction was continued until the reaction was detected by HPLC. Cool the reaction solution to room temperature, filter with suction, spin dry the filtrate, add 45ml of water to the spin-dried product, extract 30ml*3 times with EA, combine the organic layer and spin-dry, and recrystallize the spin-dried product in toluene to obtain compound (B): 12.35g ; Yield is 81%, detection: purity 94%.

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Abstract

The invention relates to a preparation method of a siponimod intermediate, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: carrying out substitution coupling and deprotection on a substrate of an intermediate, so as to realize an intermediate synthesis reaction with cheap and easily available raw materials and simple impurity removal; and carrying out reduction and other steps on the obtained intermediate compound 1-(3-ethyl-4-(hydroxymethyl) phenyl) ethyl ketone to obtain siponimod. According to the method, the cost is reduced, impurity removal is efficient and convenient, multi-step post-treatment processes are saved, energy consumption is low, three wastes are reduced, environment friendliness is achieved, and large-scale industrial production is facilitated.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a siponimod intermediate. Background technique [0002] SiponiMod (SiponiMod) its chemical name is: 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl-benzyl (benxyl)}- Azetidine-3-carboxylic acid. The chemical structural formula is shown in formula (I). Siponimod is an oral sphingosine-1-phosphate receptor modulator used in the treatment of multiple sclerosis. [0003] The structure of Siponimod is shown in formula (I): [0004] [0005] The compound 1-(3-ethyl-4-(hydroxymethyl)phenyl) ethyl ketone is a commonly used intermediate in the synthesis of siponimod, and its chemical structure is shown in formula (II). [0006] [0007] Patent WO2004103306A2 discloses a synthetic route for preparing 1-(3-ethyl-4-(hydroxymethyl)phenyl) ethyl ketone: the compound 1-(3-ethyl-4-(hydroxymethyl)benzene Base) ethyl ketone is prepared from 4-amin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/68C07C45/67C07C49/835
CPCC07C45/68C07C45/673C07C49/835
Inventor 王仲清林碧悦刘诗雨寇景平刘震李建兵徐军罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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