Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine

An aminopyrimidine and propylthio technology, which is applied in the field of preparation of 2-propylthio-4,6-dichloro-5-aminopyrimidine, can solve the high pressure of hydrogenation reduction of azo compounds and increase the industrial production cost of cargreol , the problem of expensive starting materials, etc., to achieve the effect of reducing production costs, developing a large market, and improving productivity

Inactive Publication Date: 2014-07-16
CHAMBROAD CHEM IND RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The disadvantage of this route is that the starting materials are expensive, the cost is higher, the hydrogenation reduction of azo compounds requires higher pressure, the reaction conditions are harsh, and the post-treatment of the product is complicated, which is not conducive to industrial scale-up, thereby increasing the industrial production of ticagrelor cost

Method used

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  • Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine
  • Preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine

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Embodiment 1

[0038] (1) Synthesis of Compound V

[0039]

[0040] Weigh 20g of diethyl malonate and put it into a 250ml round bottom flask, slowly add 20ml of fuming nitric acid dropwise under ice bath, and control the temperature below 15°C. After stirring at room temperature for 2 hours, the mixture was poured into ice water, then extracted twice with dichloromethane, and the organic layers were combined; the organic layers were washed with water and 5% aqueous urea solution until the starch potassium iodide test paper did not develop color. The dichloromethane solution was extracted with 10% sodium carbonate solution, the combined aqueous layers were acidified to pH ~ 4 with concentrated hydrochloric acid, then extracted with dichloromethane, the combined extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. 24g of product compound V was obtained, yield: 93.75%. 1 H-NMR (400MHz, CDCl3) δ: 5.83(s, 1H), 4.46(q, J=4.0Hz, 4H), 1....

Embodiment 2

[0054] (1) Synthesis of compound V

[0055]

[0056] Take 20g of diethyl malonate and put it into a 250ml round bottom flask, slowly add 5ml of fuming nitric acid dropwise under ice bath, and control the temperature below 15°C. Stir at room temperature for 2 hours, pour the mixture into ice water, then extract twice with dichloromethane, and combine the organic layers; the organic layers were washed with water and 5% urea aqueous solution, respectively, until the starch potassium iodide test paper did not develop color. The dichloromethane solution was extracted with 10% sodium carbonate solution, the combined aqueous layers were acidified to pH 2 with concentrated hydrochloric acid, then extracted with dichloromethane, the combined extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 24g Product compound V, yield: 93.75%. 1 H-NMR (400MHz, CDCl3) δ: 5.83(s, 1H), 4.46(q, J=4.0Hz, 4H), 1.38(t, J=4.0Hz, 6H). ...

Embodiment 3

[0070] (1) Synthesis of compound V

[0071]

[0072] Weigh 20g of diethyl malonate and put it into a 250ml round bottom flask, slowly add 80ml of fuming nitric acid dropwise under ice bath, and control the temperature below 15°C. After stirring at room temperature for 2 hours, the mixture was poured into ice water, then extracted twice with dichloromethane, and the organic layers were combined; the organic layers were washed with water and 5% aqueous urea solution until the starch potassium iodide test paper did not develop color. The dichloromethane solution was extracted with 10% sodium carbonate solution, the combined aqueous layers were acidified to pH 2 with concentrated hydrochloric acid, then extracted with dichloromethane, the combined extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 24g Product compound V, yield: 93.75%. 1 H-NMR (400MHz, CDCl3) δ: 5.83(s, 1H), 4.46(q, J=4.0Hz, 4H), 1.38(t, J=4...

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Abstract

The invention provides a preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine, which comprises the following steps: reacting diethyl malonate and fuming nitric acid at 0-15 DEG C, carrying out acid washing and alkali washing to obtain a compound V, dissolving the compound V in ethanol, adding sodium ethylate and thiocarbamide, and reacting to obtain a compound IV; reacting the compound IV with halogenated n-butane in an alkaline solution to obtain a compound III; chlorinating hydroxy group of the compound III in phosphorus oxychloride containing N,N- dimethylaniline to produce a compound II; and finally, reducing the compound II by using hydrogen in alcohol under the catalytic action of palladium on carbon to obtain the 2-propylthio-4,6-dichloro-5-aminopyrimidine. The method optimizes the technique, lowers the production cost, and enhances the reaction yield.

Description

technical field [0001] The invention belongs to the technical field of chemical industry, and particularly relates to a preparation method of 2-propylthio-4,6-dichloro-5-aminopyrimidine. Background technique [0002] Ticagrelor (Brilinta) is a new type of small molecule anticoagulant drug developed by AstraZeneca. It was approved by the European Union in December 2010 and approved by the US FDA in July 2011. Clinical trials have confirmed that this drug, unlike the thienopyridine anticoagulant drugs clopidogrel and prasugrel, can reversibly act on the adenosine diphosphate (ADP) receptor subtype P2Y12, and has a significant effect on ADP-induced platelet aggregation. Inhibitory effect, and rapid onset of oral administration, can effectively improve the symptoms of patients with acute coronary syndrome (ACS), especially for patients who need coronary artery bypass grafting (CABG). [0003] 2-Propylthio-4,6-dichloro-5-aminopyrimidine is an important intermediate of ticagrelor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 王军政吴文雷张建林孙智华成鲁南
Owner CHAMBROAD CHEM IND RES INST CO LTD
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