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Synthesis method of cangrelor intermediate

A synthesis method and intermediate technology, applied in the field of pharmaceutical chemical synthesis, can solve problems such as unfavorable industrial production, phosphorus oxychloride is highly toxic, and increase reaction cost, so as to be beneficial to industrial production, improve utilization rate, and reduce reaction cost effect

Active Publication Date: 2016-09-21
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The utilization rate of compound (VII) used in the above-mentioned route has only 50%, and its charging amount is 6 times of compound (III), namely compound (VII) consumption is big and utilization rate is low, because the raw material of preparation compound (VII) Trifluoroiodopropane is a kind of very expensive reagent, under the situation that compound (VII) consumption is large and utilization rate is low, has increased reaction cost greatly, is unfavorable for industrialized production; In addition, the trichloro used in reaction process Phosphorus is highly toxic and unsafe to handle

Method used

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  • Synthesis method of cangrelor intermediate
  • Synthesis method of cangrelor intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0044]

[0045] Add compound 2 (50 g, 0.167 mol) and 0.5 mol / L NaOH solution (840 mL) into a 2 L three-necked flask, and stir for 10 min. Add trifluoroiodopropane (45 g, 0.2 mol) and stir the reaction at room temperature for 4-5 hours. 500 mL of ethyl acetate was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 55.5 g of a yellow solid with a yield of 84%.

Embodiment 2

[0047]

[0048] Add compound 3 (25.3g, 0.064mol), 100mL of acetonitrile, 26g of triethylamine, 0.6g of DMAP into a 500mL three-neck flask, and slowly add 23g of acetic anhydride dropwise under stirring. After the addition, control the temperature within the range of 20-25°C Reaction 0.5h. Add 25 mL of methanol, stir for 30 min, evaporate the solvent under reduced pressure, add 100 mL of isopropanol for slurry, and filter to obtain 31.0 g of compound 4a as a white solid with a yield of 93%.

[0049] The NMR data of compound 4a are: 1H NMR (400MHz, DMSO) δ8.24(s,1H),7.53(s,2H),6.17(d,J=5.1Hz,1H),6.04–5.97(m,1H),5.54(t,J= 5.5Hz, 1H), 4.42–4.34(m, 2H), 4.24(td, J=6.9, 2.8Hz, 1H), 3.29–3.24(m, 2H), 2.79–2.64(m, 2H), 2.11(s ,3H), 2.04(s,3H), 2.00(s,3H).

Embodiment 3

[0051] Prepare compound 4a according to the method for embodiment 2, the charging amount of compound 3 is by 0.064mol, add different bases respectively, adjust the scope of temperature, and real-time monitoring reaction situation; With triethylamine in embodiment 2 as base, temperature is 20-25°C as a control, the results are shown in the following table: when a strong base is used or the reaction temperature is too high, the yield of the target product is reduced due to the formation of by-product 4a'; when the temperature is too low, the reaction time is prolonged, and The reaction is difficult to complete.

[0052]

[0053]

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Abstract

Belonging to the field of chemical synthesis of drugs, the invention in particular relates to a synthesis method of a compound cangrelor intermediate shown as formula (6). The invention provides a new synthesis method of the cangrelor intermediate (compound 6). The method includes: taking thioadenosine as the raw material, firstly carrying out reaction with a diazotization reagent and a halogenated reagent, then carrying out reaction with 2-(methylthio)ethylamine, and finally conducting hydrolysis to obtain a compound 6. The method has the advantages of cheap raw materials, efficient reaction, safety and easy operation, and is conducive to industrial production. (formula 6).

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of a cangrelor intermediate. Background technique [0002] Platelets play an important role in the process of thrombus formation. Adenosine diphosphate (ADP) exists in high-density granules in platelet cells and is released when platelets undergo aggregation reactions. ADP acts on platelets through the ADP receptor on the platelet membrane. The shape and biological behavior of platelets are affected, and the aggregation process of platelets is further accelerated. P2Y12 receptor antagonists can inhibit platelet aggregation without affecting ADP-mediated vascular response. P2Y12 receptor antagonists are divided into thienopyridines and non-thienopyridines according to their chemical structures. ) and non-thienopyridines (such as nogrelor, ticagrelor, and cangrelor). [0003] The structure of cangrelor contains triphosphate side chai...

Claims

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Application Information

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IPC IPC(8): C07H19/167C07H1/00
CPCC07H1/00C07H19/167
Inventor 叶天健陆修伟郁光亮何思潘鹏田嘉慧
Owner ZHEJIANG YONGNING PHARMA
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