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A kind of chiral synthesis method of ivosidenib and its intermediate

A technology for chiral synthesis and intermediates, which is applied in the field of medicine and chemical industry, can solve the problems of high solvent cost, unknown toxicity of trifluoroethanol, and the process cannot be industrialized on a large scale, and achieves the effect of improving safety.

Active Publication Date: 2021-01-15
BEIJING MEDIKING BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] However, the disadvantages of the above-mentioned process are: 1. The product needs to be separated by a chiral column, and the process cannot be industrialized on a large scale; It should be classified as a Class 4 solvent in the ICH solvent classification, that is, a solvent that has no toxicological data and should be used with caution, and may have drug safety risks

Method used

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  • A kind of chiral synthesis method of ivosidenib and its intermediate
  • A kind of chiral synthesis method of ivosidenib and its intermediate
  • A kind of chiral synthesis method of ivosidenib and its intermediate

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preparation example Construction

[0024] The references for catalyst preparation refer to "Journal of the American Chemical Society" 2018, 140, 10374-10381, 2019, 141, 8, 3414-3418 and their reference reports. The raw material N-(4-cyanopyridin-2-yl)L-pyroglutamic acid is synthesized by the Buchwald-Hartwig reaction step in the reference compound patent US2013190249A1.

[0025] Liquid chromatographic testing conditions for the de value of the product:

[0026] Instrument: Waters E2695 liquid chromatograph

[0027] Chromatographic column: CHIRALCEL ID 4.6mm×250mm×5μm

[0028] Mobile phase: n-hexane / isopropanol 80 / 20

[0029] Detection wavelength: 254nm

[0030] Column temperature: 35°C

[0031] Flow rate: 1.0mL / min

Embodiment 1

[0032] The synthesis of embodiment 1 Ivosidenib intermediate A

[0033]

[0034] Add L-pyroglutamic acid (0.1mol, 12.91g), o-chlorobenzaldehyde (0.1mol, 14.06g), 3-amino-5-fluoropyridine (0.1mol, 11.21g) into a dry nitrogen-protected reaction flask , chiral protonic acid catalyst (5mmol, 1.57g) and acetonitrile (10mL), stirred at about 20°C for 30 minutes, raised the temperature to about 80°C, and slowly added 1,1-difluoro-3-isocyclobutyronitrile ( 0.1mol, 11.71g), the dropwise addition was completed, and the reaction was carried out overnight. Spin-dry the solvent, add dichloromethane (20mL) to dissolve, wash the organic phase twice with 5% ice sodium carbonate solution (30mL), dry over anhydrous sodium sulfate, spin-dry, wash with dichloromethane / n-hexane (1:3 ) after recrystallization and purification to obtain optically pure Ivosidenib intermediate A, the yield was 49%, and the de value detected by liquid phase was 12%.

Embodiment 2

[0035] The synthesis of embodiment 2 Ivosidenib intermediate A

[0036]

[0037] Add L-pyroglutamic acid (0.1mol, 12.91g), o-chlorobenzaldehyde (0.1mol, 14.06g), 3-amino-5-fluoropyridine (0.1mol, 11.21g) into a dry nitrogen-protected reaction flask , chiral protonic acid catalyst (5mmol, 2.33g) and ethyl acetate (10mL), stirred at about 20°C for 30 minutes, cooled down to about -80°C internal temperature, and slowly added dropwise 1,1-difluoro-3-heterocyclic Butyronitrile (0.1mol, 11.71g), the dropwise addition was completed, and the reaction was carried out overnight. The reaction solution was washed twice with 5% ice sodium carbonate solution (30mL), dried over anhydrous sodium sulfate, spin-dried, purified by recrystallization from dichloromethane / n-hexane (1:3) to obtain optically pure Ivosidenib intermediate A , the yield was 57%, and the de value detected by liquid phase was 19%.

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Abstract

The invention discloses a chiral synthesis method of Ivosidenib and an intermediate thereof. The method comprises the steps: adding an L-pyroglutamic acid derivative, o-chlorobenzaldehyde, 3-amino-5-fluoropyridine, a chiral protonic acid catalyst and a solvent, stirring, adding 1,1-difluoro-3-isocyclic butyronitrile, carrying out a reaction, and purifying the reaction solution to obtain Ivosidenibor the intermediate thereof. According to the synthesis method, chiral column purification is avoided in reaction, the synthetic method is suitable for industrial large-scale production, a solvent with doubted safety is removed, and the prepared medicine is high in safety and has important application significance in medicine production.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a chiral synthesis method of Ivosidenib and its intermediates. Background technique [0002] Ivosidenib is a mutation-targeted isocitrate dehydrogenase-1 (IDH1) inhibitor developed by Agios Pharms, chemical name: (2S)-N-[(1S)-1-(2-chlorophenyl )-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-N-(5-fluoropyridin-3-yl)-1-(4-cyanopyridine-2 -yl)-5-oxopyrrolidine-2-carboxamide. The drug was approved for marketing in the United States in July 2018 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with susceptible IDH1 mutations. [0003] Ivosidenib has been on the market not long ago, and its synthesis method is rarely reported in the literature, and the key steps are exactly the same as those reported in the compound patent US2013190249A1 (see also the literature "Chinese Journal of Medicinal Chemistry" 2019, 29(2), 163 and "Chi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D401/14C07B53/00
CPCC07B53/00C07B2200/07C07D401/12C07D401/14
Inventor 赵胜贤张晶宁王正悫
Owner BEIJING MEDIKING BIOPHARM