Synthetic method for 5-chloro-6-(2-iminopyrrolidinyl-1-yl)methyl-2,4-(1H,3H)pyrimidinedione hydrochloride

A technology of iminopyrrolidine hydrochloride and iminopyrrolidinyl, which is applied in the field of synthesis of 5-chloro-6-methyl-2,4-pyrimidinedione hydrochloride, can solve unfavorable industrial scale-up production, Adverse effects on the water environment, difficulties in post-processing, etc., to achieve low price, short time, and environmental friendliness

Active Publication Date: 2014-08-13
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008]In the first step of the route, selenium dioxide, which is highly toxic, is used in the oxidation reaction, which is highly irritating to the skin and mucous membranes, and may also be harmful to the water environment. produce long-term adverse effects; 6-(chloromethyl)-2-(methylthio)pyrimidin-4(3H)-one I', 6-(chloromethyl)-2-(methylthio)pyrimidine-4( 3H)-ketone' has good water solubility and is difficult to purify by conventional methods, causing great difficulties to the post-treatment of the reaction, which is not conducive to industrial scale-up production

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0039] Embodiment 1: the preparation method 1 of compound VI

[0040] Dissolve 129.3 g of sodium carbonate (1.22 mol) in 1 L of water, then add 96.3 g of compound VII (0.69 mol), add dropwise 113.6 g of ethyl 4-chloroacetoacetate (0.69 mol), control the temperature at 25±5°C, and react 12 hours. After the reaction was completed, the stirring was stopped, the pH value was adjusted to neutral with 6M hydrochloric acid, filtered, and the obtained product was placed in a blast drying oven and dried at 50°C for 2 hours to obtain 80 g of the target product VI as an off-white solid, yield: 61%.

[0041] HNMR qualitative analysis:

[0042] 1 HNMR (400MHz, DMSO- d6), ppm: 12.75(1H,s,NH), 6.25(1H,s,C=CH), 4.49(2H,s,CH 2 ), 2.49 (3H, s, SCH 3 ).

Embodiment 2

[0043] Embodiment 2: the preparation method 2 of compound VI

[0044] Dissolve 219.4 g of sodium carbonate (2.07 mol) in 1 L of water, then add 96.3 g of compound VII (0.69 mol), add dropwise 227.1 g of ethyl 4-chloroacetoacetate (1.38 mol), control the temperature at 25±5°C, and react 10 hours. After the reaction is complete, stop stirring, adjust the pH value to neutral with 6M hydrochloric acid, filter, and place the obtained product in a blast drying oven, and dry at 50±5°C for 6-8 hours to obtain 70 g of the off-white solid target product VI, the yield : 53.4%.

Embodiment 3

[0045] Embodiment 3: the preparation method 3 of compound VI

[0046] Dissolve 129.3 g of sodium carbonate (1.22 mol) in 1 L of methanol, then add 96.3 g of compound VII (0.69 mol), add 113.6 g of ethyl 4-chloroacetoacetate (0.69 mol) dropwise, and control the temperature at 50±5°C. React for 5 hours. After the reaction is completed, stop stirring, adjust the pH value to neutral with 6M hydrochloric acid, filter, and place the obtained product in a blast drying oven, and dry at 50±5°C for 6-8 hours to obtain 68 g of off-white solid target product VI, the yield : 51.9%.

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Abstract

The invention relates to a synthetic method for 5-chloro-6-(2-iminopyrrolidinyl-1-yl)methyl-2,4-(1H,3H)pyrimidinedione hydrochloride. The synthetic method comprises the following steps: with S-methylisothiourea sulfate as a starting raw material, subjecting S-methylisothiourea sulfate and ethyl chloroacetoacetate to a cyclization reaction under an alkaline condition so as to obtain 6-(chloromethyl)-2-(methylthio)pyrimidine-4(3H)-one; carrying out a chlorination reaction on a pyrimidine ring so as to obtain 5-chloro-6-(chloromethyl)-2-(methylthio)pyrimidine-4(3H)-one; then carrying out a hydrolysis reaction under an acidic condition so as to obtain 5-chloro-6-(chloromethyl)pyrimidine-2,4-(1H,3H)-dione; and reacting 5-chloro-6-(chloromethyl)pyrimidine-2,4-(1H,3H)-dione with 2-iminopyrrolidinyl hydrochloride so as to obtain 5-chloro-6-(2-iminopyrrolidinyl-1-yl)methyl-2,4-(1H,3H)pyrimidinedione hydrochloride, i.e., a finished product of hydrochloride. The synthetic method has the advantages of simple operation, a stable intermediate, easy availability, high yield and easy realization of industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to the synthesis of 5-chloro-6-(2-iminopyrrolidinyl-1-yl)methyl-2,4-(1H,3H)pyrimidinedione hydrochloride method. Background technique [0002] Formula I compound 5-chloro-6-(2-iminopyrrolidinyl-1-yl)methyl-2,4-(1H, 3H)pyrimidinedione hydrochloride (INN: Tipiracil Hydrochloride) is a chest Glycoside phosphorylase inhibitors, combined with trifluridine, are being developed for the treatment of advanced colorectal cancer, gastric cancer, etc. [0003] [0004] Its compound patent (EP0763529, US5744475) was applied in 1996, and the route mentioned in the article is: [0005] [0006] In addition, the literature (Nucleosides, Nucleotides, and Nucleic Acids, 24 (5-7): 367–373, (2005)) reported a more detailed synthetic route of the compound. The routes mentioned in it are: [0007] [0008] The highly toxic selenium dioxide is used in the first oxidation reaction of this...

Claims

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Application Information

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IPC IPC(8): C07D403/06
CPCC07D403/06
Inventor 甄宜战张志强郑志旭李娜娜
Owner SHANDONG BESTCOMM PHARMA CO LTD
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