Preparation method of ticagrelor midbody

A technology for ticagrelor and an intermediate, which is applied in the field of chemical synthesis, can solve the problems of being unsuitable for industrial production, high energy consumption for solvent recovery, and high equipment requirements, and achieves the effects of not easy to catch fire, low production cost, and good product purity.

Active Publication Date: 2013-09-04
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has low reaction temperature, high requirements on equipment, high boiling point of the solvent used, high energy consumption for solvent recovery, and the use of aluminum tetrahydrogen lithium in the production process, which has great safety hazards in production and is not suitable for industrial production.

Method used

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  • Preparation method of ticagrelor midbody
  • Preparation method of ticagrelor midbody
  • Preparation method of ticagrelor midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051]

[0052] Under nitrogen protection, 6.3g NaH (60% content) was suspended in 120mL tetrahydrofuran. 35.0 g of compound II was slowly added dropwise to the above suspension. 24.6 g of ethyl chloroacetate was added dropwise to the reaction solution, TLC detected that the reaction was complete, extracted with ethyl acetate, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain 43 g of crude product of light yellow viscous liquid compound IV, The yield is 96% (based on compound I). 1 H NMR (500MHz, CDCl 3 )δ1.21-1.29 (m, 6H), 1.40 (s, 3H), 1.82 (d, J=14.5Hz, 1H), 2.18-2.23 (m, 1H), 3.91 (d, J=4.2Hz, 1H ),4.08(d,J=5.6Hz,1H),4.14-4.24(m,4H),4.57(s,2H),5.10(dd,J 1 =12.5Hz,J 2 =2.7Hz,2H),6.00(d,J=8.7Hz,1H),7.28-7.36(m,5H).

Embodiment 2

[0054]

[0055] 45g of compound IV was dissolved in tetrahydrofuran, 5g of sodium borohydride was added at room temperature, 10mL of methanol was slowly added dropwise to the above solution, and stirred overnight at room temperature. TLC showed that the reaction was complete, 150 mL of water was added, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was directly used for the next reaction.

Embodiment 3

[0057]

[0058] Dissolve 38.7g of compound V in ethanol, weigh 2.0g of 5% palladium carbon, and react in a hydrogen environment for 5 hours, and TLC detects that the reaction is complete. The palladium carbon was suction-filtered and concentrated, and the crude product was subjected to silica gel column chromatography to obtain 22.8 g of ticagrelor intermediate I, with a yield of 95%, an HPLC purity of over 98%, and a retention time consistent with that of the standard product. 1 H NMR (500MHz, CDCl 3 )δ1.27(s,3H),1.39(s,3H),1.95(d,J=12.0Hz,2H),2.10-2.14(m,1H),3.43(d,J=6.0Hz,1H), 3.55-3.63(m,2H),3.65-3.70(m,2H),3.90(s,J=4.2Hz,1H),4.57(d,J=5.4Hz,1H),4.66(d,J=5.0Hz ,1H).

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Abstract

The invention discloses a of a ticagrelor midbody. The preparation method comprises the following steps of: by taking chiral cyclopentanol protected by N-Cbz under an alkaline condition as a starting material, converting the starting material to a compound IV by utilizing an etherification reaction, then reducing under a system of a reducing agent and alcohol to obtain a compound V, and at last, removing protecting groups to obtain a icagrelor midbody I. The whole reaction process is short in time; the purity of the product is high; the yield is high; and each midbody is easily purified. The needed materials are cheap and easily-available, so that the preparation preparation saves time and production cost, is favorable for large-scale industry production and has important significance.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to the key intermediate 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- Synthetic method of cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol. Background technique [0002] Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, and it is also the first reversible binding P 2 Y 12 An adenosine diphosphate receptor (ADP) antagonist that reversibly acts on the purine 2 receptor subtype P on vascular smooth muscle cells (VSMC) 2 Y 12 , has obvious inhibitory effect on platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. Because the antiplatelet effect of ticagrelor is reversible, it is especially suitable for patients who need anticoagulant therapy before surgery. The world's second best-selling drug, clopidogrel, is an irreversible thienopyridine ADP P 2 Y 12 Re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/44
CPCY02P20/55
Inventor 张兴贤柳英帅周敦峰刘良肖美良何昆仑胡庆余盛刚倪建昆
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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