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Preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof

A technology of pyrimidine diketone and methylpyrimidine, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of affecting the quality of the target product and production cost, increasing the preparation cost, poor solubility, etc., and achieving the effects of reduced production cost, stable process and high quality

Active Publication Date: 2015-09-30
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this synthetic route, 6-methylpyrimidine-2,4(1H,3H)-dione is used as the starting material to obtain compound 4. The total yield reported in the literature is only 18%, and the solubility of compound 5 and compound 6 is extremely poor. , is almost insoluble in most organic solvents, and its purification is quite difficult, which greatly increases its preparation cost (the cost of compound 6 reaches more than 100,000 / kg), and further affects the quality and production cost of the target product

Method used

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  • Preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof
  • Preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof
  • Preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0037] At room temperature, glacial acetic acid (1500ml) and selenium dioxide (200g) were successively added into a three-necked flask, and 6-methyluracil (189g) was added to the above reaction mixture under stirring. Add complete, reflux reaction 7h. After the reaction is completed, filter with suction, add the filter cake and an appropriate amount of purified water into a three-necked flask, heat up and reflux for at least half an hour while stirring, filter with suction, combine the filter cake and concentrate to dryness. Add water to the fraction and beat at room temperature. Suction filtration, and the filter cake was sequentially rinsed with appropriate amount of water and absolute ethanol. The resulting filter cake was air-dried to obtain 130 g of a yellow-white solid, namely compound 1, with a yield of 65%.

[0038] Step b:

[0039]

Embodiment 2

[0041] Under water bath conditions, add compound 1 (100g) and glacial acetic acid (500ml) into a three-necked reaction flask, control the temperature below 30 degrees, add sulfuryl chloride (144.5g) dropwise, and continue the reaction for at least 2h after the dropwise addition. After the reaction was completed, an appropriate amount of isopropyl ether was added to the reaction solution, stirred for at least 20 minutes, filtered with suction, the filter cake was beaten with isopropyl ether, and dried by blasting to obtain 95 g of yellow solid, namely compound 2, with a yield of 95%.

[0042] stepc:

[0043]

Embodiment 3

[0045] Under the ice-salt bath, add anhydrous methanol (850ml) and compound 2 (85g) into the three-necked flask in turn, stir and control the temperature at 0-20°C, add sodium borohydride (45.6g,) to the above reaction in batches in the liquid. After the addition, return to room temperature and continue the reaction for at least 2h. After the reaction is completed, hydrochloric acid is added dropwise to the above reaction mixture to adjust the pH to 2-3 under the condition of a water bath. Then concentrated under reduced pressure to distill off methanol. After cooling, add water to the distillate for at least 20 minutes, filter with suction, and rinse the filter cake with water and ethanol in turn. Blast drying gave 76.5 g of a yellow-white solid, that is, compound 3, with a yield of 90%.

[0046] Step d:

[0047]

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Abstract

The invention provides a preparation method of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidine dione or salts thereof, which comprises the following steps: by using 6-methylpyrimidyl-2,4(1H,3H)-dione as an initial raw material, carrying out 6- site methyl oxidation and 5- site hydrogen chlorination, reducing the 6- site formyl group, carrying out condensation with 2-aminopyrrolidine or corresponding salts to obtain the target product. The method is simple to operate and stable in technique, is suitable for industrial production, and has the advantages of high yield, high purity and low cost.

Description

technical field [0001] The present invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation of 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidinedione or its salt Preparation. Background technique [0002] TIP hydrochloride, full name: 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride. TAS-102, developed by Taiho (subsidiary of Otsuka Pharmaceutical Co., Ltd.), is a compound of nucleoside analog trifluridine and thymidine phosphorylase inhibitor (TIP hydrochloride) Tipracilhydrochloride (MUP-98156). For the treatment of cancers including colorectal cancer. In February 2013, Taiho submitted an application for TAS-102 in Japan for the treatment of unresectable advanced recurrent colorectal cancer. In terms of market, this product is not yet on the market. [0003] According to statistics from the American Cancer Society, from 2005 to 2009, the incidence rate of colorectal cancer in t...

Claims

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Application Information

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IPC IPC(8): C07D403/06
CPCC07D403/06
Inventor 孙平李赛杜祖银赵军军李孝壁
Owner JIANGSU HANSOH PHARMA CO LTD
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