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Novel intermediate of ticagrelor and preparation method thereof

A technology of ticagrelor and a compound is applied in the field of novel intermediates of antiplatelet aggregation drug ticagrelor and its preparation, which can solve the problems of unfavorable industrialized production, lengthy process operation, long reaction time and the like, and achieves short reaction time and high purity. High, easy post-processing results

Active Publication Date: 2014-03-12
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method for preparing ticagrelor with this novel intermediate involves substitution reactions, cyclization reactions, coupling reactions and deprotection reactions. The described reaction time is long, and the process operation is lengthy and cumbersome, which is not conducive to industrial production

Method used

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  • Novel intermediate of ticagrelor and preparation method thereof
  • Novel intermediate of ticagrelor and preparation method thereof
  • Novel intermediate of ticagrelor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 2-[(3aR,4S,6R,6aS)-6-Benzyl carbamate-2,2-dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]-dioxane Pent-4-ol

[0037]

[0038] Add (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]-dioxane to a 250ml reaction flask Pent-4-ol (3.0g), ethyl acetate 60ml, potassium carbonate (4.84g). Cool to 0°C, add 20ml of water, dissolve and clarify. Benzyl chloroformate (3.6 g) was added dropwise while maintaining 0°C. After the dropwise addition, keep warm for 20 minutes, rise to room temperature and stir for 3 hours, extract with ethyl acetate, and wash the organic layer once with 20 ml of water. The organic layer was concentrated under reduced pressure to obtain compound a: 2.68 g.

Embodiment 2

[0040] 2-{[(3aR,4S,6R,6aS)-6-Benzyl carbamate-2,2-dimethyltetrahydro-3aH-cyclopentadieno[d[1,3]-dioxane Pent-4-yl]oxy}-1-benzoic acid ethyl ester

[0041]

[0042] Compound a (2.68g) was dissolved in 30ml of tetrahydrofuran, then potassium tert-butoxide (1.5g) was added and cooled to -10°C. A tetrahydrofuran solution of ethyl 2-bromobenzoate (3.0 g) was slowly added, reacted at -10°C for 2 hours, and the organic phase was washed twice with 50 ml of water respectively. Concentrate through a silica gel column (EA:PE=1:6) to obtain compound b, 2.14g.

Embodiment 3

[0044] 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopentadieno[d[1,3]-dioxol-4 -yl]oxy}-1-ethyl benzoate

[0045]

[0046] Compound b (2.0 g) was dissolved in 25 ml of methanol, and then 0.22 g of palladium carbon was added, then hydrogen gas was introduced at room temperature and pressure, stirred overnight and concentrated by filtration to obtain compound c, 1.2 g.

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Abstract

The invention discloses a novel intermediate of ticagrelor, i.e., a compound represented by a formula (I), and a preparation method thereof. The preparation method for the compound represented by the formula (I) comprises a step of subjecting a compound represented by a formula (II) or a proper salt of the compound represented by the formula (II) and a compound represented by a formula (III) to a substitution reaction, wherein R in the formulas represents substituted or unsubstituted benzyl and benzoyl groups. The invention further discloses a preparation method for a ticagrelor compound represented by a formula (A) from the novel intermediate, i.e., the compound represented by the formula (I). The method for preparing ticagrelor from the novel intermediate has the advantages of short reaction time, easy and convenient post-treatment, high yield and high product purity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a novel intermediate of an anti-platelet aggregation drug ticagrelor and a preparation method thereof. Background technique [0002] US patents US6251910 and US6525060 disclose a series of new triazolo (4,5-D) pyrimidine compounds, among which ticagrelor is a new type of selective small molecule anticoagulant drug. The drug can reversibly act on the purine 2 receptor subtype P2Y12 on vascular smooth muscle cells, has obvious inhibitory effect on platelet aggregation caused by ADP, and takes effect quickly after oral administration, so it can effectively improve the health of patients with acute coronary heart disease. symptom. [0003] The chemical name of ticagrelor is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(thiopropane Base)-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, which The chemical structure is shown...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D317/44C07D487/04
CPCC07D317/44C07D405/12C07D487/04
Inventor 王海龙曾磊王仲清
Owner SUNSHINE LAKE PHARM CO LTD
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