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Preparation method of 5-chloro-6-(chloromethyl)-2,4-(1H,3H)-pyrimidinedione

A technology of pyrimidinedione and chloromethyl, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of unavailable raw materials and high prices, and achieve the effects of low price, low production cost and good solubility

Pending Publication Date: 2017-09-01
卡硼瑞(北京)科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As we all know, selenium dioxide is acutely toxic, highly toxic, and has an irritating effect on the skin and mucous membranes similar to sulfur dioxide. Rats inhale selenium dioxide vapor at 150-600mg / m 3 Animals die immediately. This product is controlled by the public security department according to the Regulations on the Safety Management of Hazardous Chemicals. The raw materials are not easy to obtain and the price is expensive.

Method used

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  • Preparation method of 5-chloro-6-(chloromethyl)-2,4-(1H,3H)-pyrimidinedione
  • Preparation method of 5-chloro-6-(chloromethyl)-2,4-(1H,3H)-pyrimidinedione
  • Preparation method of 5-chloro-6-(chloromethyl)-2,4-(1H,3H)-pyrimidinedione

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 78g (0.50mol) orotic acid (B 0 ) into 700ml of acetic acid, 25ml of acetic anhydride and a catalytic amount of ferric chloride, heated to 90-95°C, and 108g (0.80mol) of sulfonyl chloride (FW135) was added dropwise. Methyl ester was completely chlorinated (TLC detection) to stop the reaction, the reaction solution was cooled to 10°C, filtered to obtain a solid, rinsed with acetic acid and water in turn, and dried with hot air to obtain a yellow solid. Melting point: mp: 288°C, 88.0g was obtained (0.46mol) α-chloroorotic acid (B 1 ), the molar yield is 92%.

[0044] 1 HNMR (400MHz, DMSO-d6) δH11.82 (1H, s), 11.61 (1H, s), 3.82 (3H, s)

Embodiment 2

[0046] Add 67g (0.35mol) of orotic acid into 500ml aqueous solution containing % NaOH, heat to 30-45°C to dissolve completely, add 70g (0.45mol) of N-chlorosuccinimide, and heat overnight until the orotic acid is completely chlorinated Generation (TLC detection) to stop the reaction, the reaction solution was cooled to 10 ° C, slowly added 5% HCl solution, adjusted to pH = 1.0, filtered to obtain a solid, recrystallized with ethanol, and dried with hot air to obtain a light yellow solid. Melting point: mp : 285 ℃, obtain 57.0g (0.30mol) α-chloroorotic acid (B 1 ), a molar yield of 86%.

[0047] 1H NMR (400MHz, DMSO-d6) δH11.80(1H, s), 11.60(1H, s)

[0048] Step b reaction formula:

[0049]

Embodiment 3

[0051] 46g (0.24mol) α-chloroorotic acid (B 1 ) and 38g (1.0mol) sodium borohydride powder were dispersed in 200ml tetrahydrofuran solution, stirred vigorously, slowly added 25ml methanol, refluxed for 14 hours, TLC detected the reaction, cooled to room temperature, added 300mlNH 4 Cl aqueous solution, continue stirring for 10 h, separate the organic layer, extract the aqueous phase three times with 300 ml of ethyl acetate, combine the organic phases, dry with magnesium sulfate and remove by filtration to obtain a light yellow organic phase, concentrate to dryness, and recrystallize with ethanol to obtain As a pale yellow solid, 40 g (0.22 mol) of 5-chloro-6-(hydroxymethyl)-2,4-(1H,3H)-pyrimidinedione (B 2 ), the molar yield is 90%. .

[0052] 1 HNMR (400MHz, DMSO-d 6 )δH11.30 (1H, s), 11.40 (1H, s), 4.65 (2H, s)

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Abstract

The patent provides a preparation method of 5-chloro-6-(chloromethyl)-2,4-(1H,3H)-pyrimidinedione. Orotic acid, which is used as a starting material, undergoes alpha-hydrogen chlorination; then, carboxyl is directly reduced to hydroxymethyl; and a chlorination replacement reaction is carried out. Through the three-step reactions, the target product is obtained. The preparation method of the invention is simple to operate, has stable process, has high yield, is low-cost, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemical synthesis, in particular to a preparation method of drug precursor 5-chloro-6-(chloromethyl)-2,4-(1H,3H)-pyrimidinedione. Background technique [0002] Important synthesis of 5-chloro-6-(chloromethyl)-2,4-(1H,3H)-pyrimidinedione for the preparation of nucleoside uracil or its salt analogue tipiracil hydrochloride (TPI) precursor, whose structure is as follows: [0003] [0004] A new type of anti-metabolism compound drug TAS-102 tablet developed by Japan Dapeng (Tahoe Oncology) company, FDA approved listing. It is an anti-tumor nucleoside analog trifluorothymidine (trifluridine, Trifluridine, referred to as FID) and thymidine phosphorylase inhibitor tipiracil (Tipiracil, tipiracil hydrochloride, referred to as TPI) The compound drug composed of it is used for the treatment of patients with refractory metastatic colorectal cancer who no longer respond to chemotherapy and biological therapy. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/553
CPCC07D239/553
Inventor 陈功谢素琼宋雪
Owner 卡硼瑞(北京)科技有限公司