Preparation method of ticagrelor intermediate

By using a low-toxicity, low-cost reagent route to prepare ticagrelor intermediates, the problem of large-scale production of ticagrelor intermediates has been solved, enabling low-cost and environmentally friendly industrial production.

CN119371395APending Publication Date: 2025-01-28JIANGSU CAREFREE PHARM CO LTD
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Patent Information

Application Number
CN202310931160.7
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2023-07-27
Publication Date
2025-01-28

AI Technical Summary

Technical Problem

Existing technologies make it difficult to achieve large-scale production of ticagrelor intermediates, and key reagents are expensive and environmentally unfriendly.

Method used

Using low-toxicity and low-cost reagents, ticagrelor is synthesized by preparing key intermediates such as 2-(((3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo-4-yl)oxy)-ethanol(2R,3R)-2,3-dihydroxysuccinate. The key reagents can be recycled and reused.

Benefits of technology

This enables low-cost, environmentally friendly, large-scale production of ticagrelor intermediates, making it suitable for industrial production.

✦ Generated by Eureka AI based on patent content.

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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of a ticagrelor intermediate, which comprises the following steps: preparing 2-(((3aR, 4S, 6R, 6aS)-6-aminotetrahydro-2, 2-dimethyl-4H-cyclopentyl-1, 3-dioxolane-4-yl) oxy)-ethanol (2R, 3R)-2, 3-dihydroxysuccinic acid salt; and a step of preparing 4, 6-dichloro-2-(propylthio)-5-aminopyrimidine. Reagents used in the method are non-toxic, harmless and low in price, the key reagents can be recycled, and the method is suitable for industrial production.
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Description

Technical Field

[0001] The present invention belongs to the technical field of biopharmaceuticals, and in particular relates to a method for preparing a ticagrelor intermediate. Background Art

[0002] Ticagrelor is a new, selective small molecule anticoagulant drug. It belongs to the new cyclopentyl triazole (CPTP) reversible P2Y12-receptor antagonist. It activates P2Y12-receptors, reversibly blocks ADP-mediated platelet activation and aggregation, and effectively inhibits the formation of atherosclerotic thrombi. It is clinically used for patients with acute coronary syndromes (ACS), including those receiving drug therapy and percutaneous coronary intervention (PCI), to reduce the incidence of thrombotic cardiovascular events. Summary of the invention

[0003] The object of the present invention is to provide a method for preparing a ticagrelor intermediate, which is conducive to large-scale mass production.

[0004] To achieve the above object, the present invention provides the following technical solutions:

[0005] A method for preparing a ticagrelor intermediate comprises the following steps:

[0006] Step of preparing 2-(((3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)-ethanol (2R,3R)-2,3-dihydroxysuccinate;

[0007] Procedure for the preparation of 4,6-dichloro-2-(propylthio)-5-aminopyrimidine.

[0008] Also included is a step of preparing 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl)amino)tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)ethanol.

[0009] The method also includes a step of preparing (1R, 2S)-rel-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride.

[0010] The method also includes the step of preparing 1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine (R)-mandelate salt.

[0011] The molecular formula of ticagrelor is C23 H 28 F2N6O4S, chemical formula is

[0012]

[0013] The molecular formula of the 2-(((3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolane-4-yl)oxy)-ethanol (2R,3R)-2,3-dihydroxysuccinate is C 16 H 29 NO 12 , the chemical formula is

[0014]

[0015] The molecular formula of the 4,6-dichloro-2-(propylthio)-5-aminopyrimidine is C7H9C l2 N3S, chemical formula is

[0016]

[0017] The molecular formula of the 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl)amino)tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)ethanol is C 17 H 27 C1N 4O4 S, chemical formula is

[0018]

[0019] The molecular formula of the (1R, 2S)-rel-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride is C9H9F2N.HCl, and the chemical formula is

[0020]

[0021] The molecular formula of the 1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (R)-mandelate salt is C 17 H 17 F2NO3, chemical formula is

[0022]

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The reagents used in the present invention are non-toxic and harmless, and are relatively cheap. The key reagents used can be recycled and reused, and are suitable for industrial production. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] Example.

[0027] A method for preparing a ticagrelor intermediate comprises the following steps:

[0028] Step of preparing 2-(((3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)-ethanol (2R,3R)-2,3-dihydroxysuccinate;

[0029] Procedure for the preparation of 4,6-dichloro-2-(propylthio)-5-aminopyrimidine.

[0030] Also included is a step of preparing 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl)amino)tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)ethanol.

[0031] The method also includes a step of preparing (1R, 2S)-rel-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride.

[0032] The method also includes the step of preparing 1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine (R)-mandelate salt.

[0033] The molecular formula of ticagrelor is C 23 H 28 F2N6O4S, chemical formula is

[0034]

[0035] The molecular formula of the 2-(((3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolane-4-yl)oxy)-ethanol (2R,3R)-2,3-dihydroxysuccinate is C 16 H 29 NO 12 , the chemical formula is

[0036]

[0037] The molecular formula of the 4,6-dichloro-2-(propylthio)-5-aminopyrimidine is C7H9C l2 N3S, chemical formula is

[0038]

[0040] The molecular formula of the 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl)amino)tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)ethanol is C 17 H 27 C1N 4O4 S, chemical formula is

[0041]

[0042] The molecular formula of the (1R, 2S)-rel-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride is C9H9F2N.HCl, and the chemical formula is

[0043]

[0044] The molecular formula of the 1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (R)-mandelate salt is C 17 H 17 F2NO3, chemical formula is

[0045]

Claims

1. A method for preparing a ticagrelor intermediate, characterized in that The steps include: Step of preparing 2-(((3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)-ethanol (2R,3R)-2,3-dihydroxysuccinate; Procedure for the preparation of 4,6-dichloro-2-(propylthio)-5-aminopyrimidine.

2. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that Also included is a step of preparing 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl)amino)tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)ethanol.

3. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that The method also includes a step of preparing (1R, 2S)-rel-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride.

4. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that The method also includes the step of preparing 1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine (R)-mandelate salt.

5. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that The molecular formula of ticagrelor is C 23 H 28 F2N6O4S, chemical formula is 6. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that The molecular formula of the 2-(((3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolane-4-yl)oxy)-ethanol (2R,3R)-2,3-dihydroxysuccinate is C 16 H 29 NO 12 , the chemical formula is 7. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that The molecular formula of the 4,6-dichloro-2-(propylthio)-5-aminopyrimidine is C7H9C l2 N3S, chemical formula is 8. The method for preparing a ticagrelor intermediate according to claim 2, characterized in that The molecular formula of the 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl)amino)tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy)ethanol is C 17 H 27 C1N 4O4 S, chemical formula is 9. The method for preparing a ticagrelor intermediate according to claim 3, characterized in that The molecular formula of the (1R, 2S)-rel-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride is C9H9F2N.HCl, and the chemical formula is 10. The method for preparing a ticagrelor intermediate according to claim 4, characterized in that The molecular formula of the 1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (R)-mandelate salt is C 17 H 17 F2NO3, chemical formula is