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A process for the preparation of an intermediate for a triazolopyrimidine carbonucleoside

A compound and a selected technology, applied in the field of solvates and compounds of the formula for preparing ticagrelor, can solve problems such as difficulties in industrial scale expansion

Inactive Publication Date: 2015-04-15
ENANTIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The industrial scale-up of these methods creates considerable difficulties

Method used

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  • A process for the preparation of an intermediate for a triazolopyrimidine carbonucleoside
  • A process for the preparation of an intermediate for a triazolopyrimidine carbonucleoside
  • A process for the preparation of an intermediate for a triazolopyrimidine carbonucleoside

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0187] Example 1. Preparation of N-(4,6-dihydroxy-2-mercaptopyrimidin-5-yl)acetamide (compound of formula VA, wherein R 1 is methyl).

[0188]

[0189] Procedure for the separation of sodium salts.

[0190] Diethyl acetamidomalonate (5 g, 23.01 mmol) and thiourea (2.45 g, 32.2 mmol, 1.4 eq) were added to sodium ethoxide (21% w / w, 20 ml, 52.9 mmol, 2.3 eq) in EtOH (65 mL ) solution. The reaction mixture was heated to reflux temperature for 4h. The resulting suspension was cooled to RT, then to 0 °C, filtered, and the sodium solid salt was washed with EtOH (10 mL).

[0191] The sodium salt was dissolved in a minimum amount of water (25 mL), and the solution was acidified to pH 1 with concentrated HCl (4 mL). The resulting precipitate was filtered and washed with cold EtOH (5 mL) and cold EtOH 2 O (5 mL) wash. The solid was dried under vacuum to afford N-(4,6-dihydroxy-2-mercaptopyrimidin-5-yl)acetamide (3.24 g, 70% yield, 100% HPLC-MS) as a pale yellow solid.

[0192...

Embodiment 2

[0195] Example 2. Preparation of N-(4,6-dihydroxy-2-(propylthio)pyrimidin-5-yl)acetamide (compound of formula IVA, wherein R 1 is methyl).

[0196]

[0197] NaOH (50% w / w, 2.6mL, 50mmol, 5eq) aqueous solution was slowly added to N-(4,6-dihydroxy-2-mercaptopyrimidin-5-yl)acetamide (2g , 9.95 mmol) in MeOH (10 mL). The reaction mixture was stirred at RT for 30 min, and 1-bromopropane (2.6 mL, 30 mmol, 3 eq) was added dropwise, the resulting solution was stirred at RT overnight, and a solid precipitated. The solvent was evaporated and water (7 mL) was added to obtain a clear solution. Concentrated HCl (2.4 mL) was added and the resulting solid was filtered, washed with cold water (2 mL), and dried in vacuo to afford N-(4,6-dihydroxy-2-(propylthio)pyrimidin-5-yl) Acetamide (1.96 g, 82% yield, 97.8% HPLC-MS), as an off-white solid.

[0198] 1 H-NMR (DMSO-d6, 400MHz, ppm): 12.54(s, 1H, OH), 11.44(s, 1H, OH), 8.87(s, 1H, NH), 3.06(t, J=6.8Hz, 3H , CH 2 ), 1.94 (s, 3H, CH 3...

Embodiment 3

[0199] Example 3. Preparation of 5-amino-2-(propylthio)pyrimidine-4,6-diol hydrochloride (compound IIIA-HCl).

[0200]

[0201] 6M HCl (5 mL) was added to a suspension of N-(4,6-dihydroxy-2-(propylthio)pyrimidin-5-yl)acetamide (5 g, 20.55 mmol) in MeOH (20 mL) from Example 2 . The resulting suspension was stirred at 50 °C for 18 h and evaporated to dryness. Toluene was added to the residue, and the mixture was concentrated to dryness (3 x 20 mL) to give 5-amino-2-(propylthio)pyrimidine-4,6-diol (III-HCl) (5 g, quantitative yield Yield, 93.5% HPLC-MS), as a pale yellow solid.

[0202] 1 H-NMR (DMSO-d6, 400MHz, ppm): 3.10(t, J=6.8Hz, 3H, CH 2 ), 1.65 (sex, J=6.8, 7.6Hz, 2H, CH 2 ), 0.95(t, J=7.6Hz, 3H, CH 3 ).

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Abstract

A process for the preparation of 4,6-dihalopyrimidin-5-aminesof formula (II), or salts thereof, which comprises reacting 5-aminopyrimidin-4,6-diols of formula (III), or salts thereof, or a solvate either of the compound of formula (III) or of a salt thereof, with a halogenating agent, new intermediates useful in the preparation of the compound of formula (II) and processes for the preparation of these intermediates. The invention also refers to a process for the preparation of ticagrelor or a pharmaceutically acceptable saltthereoffrom 4,6-dihalo-2- (propylthio)pyrimidin-5-amine of formula (IIA).

Description

[0001] The present invention relates to processes for the preparation of compounds of formula (II), novel intermediates useful in their preparation and processes for the preparation of these intermediates. The present invention also relates to the preparation of a compound of formula (I) and a pharmaceutically acceptable salt thereof or a solvate thereof or a solvate of a salt thereof by a process comprising the preparation of a compound of formula (II). Background technique [0002] Ticagrelor is a compound of formula (IA) (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl Amino]-5-(propylthio)-3H-(1,2,3)triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopenta - The name of 1,2-diol, whose chemical structure is as follows. [0003] [0004] Ticagrelor is an inhibitor of platelet aggregation, specifically the CYP3A4 receptor, and is indicated to prevent thrombotic events in patients with acute coronary syndrome or myocardial infarction. Ticagrelor is rapidl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47A61K31/505
CPCC07D239/47C07D239/42C07D239/52C07D487/04
Inventor M·帕斯托安圭拉A·C·康莉
Owner ENANTIA
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