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Preparation method of tipiracil intermediate

A technology of pyrimidinedione and chloromethyl is applied in the field of preparation of tippyrimidine intermediates, which can solve the problems of high synthesis and preparation cost, complicated post-processing process, inconvenient product purification and the like, and achieves simplified operation, stable process and production cost. reduced effect

Inactive Publication Date: 2016-08-31
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the above synthetic route, compound V and compound IV have poor solubility in most organic solvents, resulting in inconvenient product purification and complicated post-treatment process, resulting in an overall yield of only 18%, which in turn results in high synthesis and preparation costs. Especially prominent in industrial scale-up production

Method used

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  • Preparation method of tipiracil intermediate
  • Preparation method of tipiracil intermediate
  • Preparation method of tipiracil intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] At room temperature, 1000 mL of glacial acetic acid and 150 g of selenium dioxide were successively added into a three-neck flask, and 125 g of compound VII was added into the three-necked flask under stirring, and then the temperature was controlled to 115° C. for reflux reaction for 5 h. After the reaction is completed, filter with suction, add 400 mL of purified water to the filter cake, reflux at 95 ° C for 1 hour, concentrate to dryness after suction filtration, add 400 mL of purified water to it again, make slurry for 1 hour at room temperature, and then filter with suction. After washing with water and absolute ethanol, 90 g of a light yellow solid (compound VI) was obtained after air-drying, with a yield of 68%.

[0030] Step 2:

[0031]

Embodiment 2

[0033] At room temperature, 80 g of compound VI and 500 mL of glacial acetic acid were successively added into a three-necked flask, and 358 g of potassium iodide / potassium iodate (molar ratio 5:1) was slowly added, and the reaction was stirred gently for 4 hours. After the reaction was completed, it was suction-filtered, and the filter cake was washed with purified water and diethyl ether for at least 3 times in sequence, and after air-drying, 132 g of a yellow solid, namely compound VI', was obtained with a yield of 87%.

[0034] Step 3:

[0035]

Embodiment 3

[0037] At room temperature, add 1000mL of ethanol and 100g of compound VI' into the three-necked flask successively, control the temperature in the range of 5-10°C with a low-temperature water bath, add 50g of sodium borohydride into the three-necked flask at a uniform speed, and slowly raise the temperature to room temperature for 1h Then continue to react for 2h. After the reaction was completed, hydrochloric acid was added dropwise to the reaction mixture, the pH was adjusted to about 2, and the solvent was distilled off under reduced pressure. After the solvent was removed, an appropriate amount of purified water was added to stir for beating for 1 hour, and then suction filtered. The filter cake was washed with purified water and ether in turn, and after blast drying, 84 g of a yellow-white solid was obtained, namely compound V', with a yield of 84%.

[0038] Step 4:

[0039]

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PUM

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Abstract

The invention provides a preparation method of a tipiracil intermediate which is 6-(chloromethyl)-2, 4-(1H, 3H)-pyrimidinedione. 6-methyl-2, 4-(1H, 3H)-pyrimidinedione as an initial raw material undergoes an iodine replacement reaction at the 5th site of a compound and then the product undergoes reduction and chlorination reactions at the 6th site to produce a desired product. The preparation method has the advantages of stable processes, high yield and low cost and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing a tipiracil intermediate. Background technique [0002] Formula I compound 5-chloro-6-(2-iminopyrrolidinyl-1-yl)methyl-2,4-(1H,3H)-pyrimidinedione, whose common name is tipiracil (Tipiracil), is a A thymidine phosphorylase inhibitor. The compound preparation composed of tipiracil hydrochloride and trifluridine (Trifluridine) was researched and developed by the Japanese company Taiho Pharma, and has been approved by the Japanese Ministry of Health, Labor and Welfare and the US FDA for the treatment of refractory metastatic metastatic disease. Rectal cancer, traded under the trade name Lonsurf, has been under clinical investigation for its application in the treatment of various other solid tumors such as gastric cancer. [0003] [0004] The PCT patent application WO9630346 for the compound of tipiracil was proposed by Dapeng Pharmaceuticals in 1996. Curre...

Claims

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Application Information

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IPC IPC(8): C07D239/54
CPCC07D239/54
Inventor 袁金桥田文宇王玲刘芳洁
Owner HARVEST PHARMA HUNAN CO LTD
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