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Method for preparing ticagrelor key intermediate

A technology of ticagrelor and intermediates, which is applied in the new synthesis field of key intermediates of anticoagulant ticagrelor, can solve the problems of complex post-processing, high energy consumption of reduction reaction, high risk, etc. Friendly, mild reaction conditions, cheap and easy-to-obtain raw materials

Active Publication Date: 2015-04-08
KAIYUAN HENGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Adopting this method to prepare the reduction reaction of the intermediate consumes a lot of energy, and the post-treatment is complicated and dangerous.

Method used

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  • Method for preparing ticagrelor key intermediate
  • Method for preparing ticagrelor key intermediate
  • Method for preparing ticagrelor key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 [3aS-(3aα,4α,6α,6aα)]-[2,2-Dimethyl-6-(hydroxyethyl)-tetrahydro-4H-cyclopenta-1,3-dioxolane Preparation of -4-yl-carbamic acid-benzyl methyl ester

[0035]

[0036] Add compound 2 (1 g, 3.25 mmol, 1 eq.) and anhydrous tetrahydrofuran (20 mL) into a dry three-necked flask. Cool to 0 °C, add potassium tert-butoxide (0.73 g, 6.51 mmol, 2 eq.) under nitrogen protection, and stir at this temperature for 2 hours, then add 1,3,2-dioxazolethiophene-2,2 - Dioxide (IIIa), stirred at room temperature for 1 hour. After the reaction was complete, concentrated sulfuric acid (2 mL) was added to the reaction solution, stirred for 5 minutes, and intermediate 4 was completely reacted. The reaction solution was concentrated to dryness to remove the solvent, and recrystallized from absolute ethanol to obtain 3 as a white solid. Yield: 0.45 g, Yield: 39%.

[0037] 1 HNMR (400MHz, CDCl 3 ), δ7.31(m,5H), 5.74(d,1H), 5.11(d,2H), 4.55(m,2H), 4.17(m,1H), 3.88(m,1H), 3.72(m, ...

Embodiment 2

[0038] Example 2 [3aR-(3aα, 4α, 6α, 6aα)]-2-[[6-amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolane- Preparation of 4-yl]oxo]-ethanol

[0039]

[0040] Compound 3 (4g, 5.7mmol) was dissolved in absolute ethanol (20mL), and a catalytic amount of 10% palladium carbon was added, and stirred overnight under a hydrogen atmosphere. After the reaction was detected by TLC, it was filtered, and the filter cake was washed three times with anhydrous methanol. The filtrate was concentrated to obtain compound 10 as a light yellow oil (TLC: DCM : MeOH = 8:1). Yield: 2.2 g, Yield: 93%.

[0041] 1 H NMR (400 MHz, CDCl 3 ) δ 4.57 (d, 1H), 4.37 (d, 1H), 3.79 (d, 1H), 3.61 – 3.46 (m, 4H), 3.26 (d, 1H), 3.02 (s, 3H), 2.10 - 2.01 ( m, 1H), 1.73 (d, 1H), 1.33 (s, 3H), 1.20 (s, 3H).

Embodiment 3

[0042] Example 3 2-[(3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxolane-4- Preparation of alcohol]isoindoline-1,3-dione

[0043]

[0044] Add 1 (3 g, 17.3 mmol, 1 eq.), phthalic anhydride (2.6 g, 17.3 mmol, 1 eq.) and DIPEA (3.7 mL, 22.5 mmol, 1.3 eq.) in a stuffy jar, and Sealed reaction at ℃ for 5 hours. Cool to room temperature, add dichloromethane and water to the reaction liquid, separate layers, collect the organic phase, dry and filter, concentrate to obtain the crude product, and column chromatography obtains 2 g of solid, yield: 40%.

[0045] 1 HNMR (400MHz, CDCl 3 ):7.89(m, 2H), 7.78(m, 2H), 5.11(m, 1H), 4.73(m, 2H), 4.32(m, 1H), 3.75(d, 1H), 2.67(m, 1H) , 2.01(m, 1H), 1.52(s, 3H), 1.27(s, 3H).

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PUM

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Abstract

The invention discloses a new method for preparing a ticagrelor key intermediate I. The method comprises the steps of performing O-alkylation on an intermediate II by using ethylene sulfate and glycol sulfite, and then depriving the amino protecting group to obtain the ticagrelor key intermediate I. Raw materials involved with the method are cheap and easily available; the method is mild in reaction conditions and friendly to the environment, and has good industrial production prospect.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis. Specifically, it is a new synthesis method of a key intermediate of the anticoagulant drug ticagrelor. Background technique [0002] Ticagrelor, English name: Ticagrelor; used code: ADZ6140, AR-C126532, belongs to cyclopentyl triazolopyrimidine compounds, chemical name (1S,2S,3R,5S)-3-[7-[ (1R,2S)-2-(3,4-Dichlorophenyl)cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3]triazol[4,5-d]pyrimidine -3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The drug is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor (purinoceptor2, P2) subtype P2Y12 on vascular smooth muscle cells (VSMC), and has obvious inhibitory effect on platelet aggregation caused by ADP, and the effect is rapid after oral administration, so Can effectively improve the symptoms of patients with acute coronary heart disease. The antiplatelet effec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/44C07D405/04
CPCY02P20/55
Inventor 安荣昌董学军王伟华
Owner KAIYUAN HENGTAI PHARMA
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