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Tipiracil hydrochloride and synthesis method of intermediate 6-(chloromethyl)uracil

A technology of chloromethyluracil and methyluracil, which is applied in the field of synthesis of tipiracil hydrochloride and its intermediate 6-chloromethyluracil, which can solve the problem of high toxicity, unfavorable environmental friendliness, and increase drug safety Hidden dangers and other problems, to achieve the effect of improving yield and purity, increasing environmental friendliness

Inactive Publication Date: 2017-06-27
SINOPHARM A THINK PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, selenium dioxide has high toxicity, which increases the safety hazard of the drug itself and is not conducive to environmental friendliness.

Method used

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  • Tipiracil hydrochloride and synthesis method of intermediate 6-(chloromethyl)uracil
  • Tipiracil hydrochloride and synthesis method of intermediate 6-(chloromethyl)uracil
  • Tipiracil hydrochloride and synthesis method of intermediate 6-(chloromethyl)uracil

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preparation example Construction

[0039] The invention provides a kind of synthetic method of 6-chloromethyluracil, comprising the following steps:

[0040] oxidizing 6-methyluracil and copper oxide in a solvent to obtain 6-formyluracil;

[0041] Reduction of 6-formyluracil to obtain 6-hydroxymethyluracil;

[0042] Chlorination of 6-hydroxymethyluracil gives 6-chloromethyluracil.

[0043] The synthesis method of 6-chloromethyluracil provided by the present application is environmentally friendly, and the product yield and purity are high, and is more suitable for application in the pharmaceutical industry.

[0044] In the embodiment of the present application, 6-methyluracil, a solvent and copper oxide were mixed in a reaction kettle, and air was introduced into the system at normal pressure, and heated for oxidation reaction to obtain 6-formyluracil.

[0045] The present application uses 6-methyluracil as a raw material and copper oxide as an oxidant to realize the oxidation of methyl in 6-methyluracil to f...

Embodiment 1

[0081] Synthesis of 6-Formyluracil by Copper Oxide Oxidation

[0082] In a 500L reactor, add 6-methyluracil (20.0kg, 158.59mol) into 150L of acetic acid, add 200g of copper oxide under stirring, and feed air into the system at normal pressure. Heating to 110°C, the color of the reaction solution changed from white turbidity to green turbidity, and the reaction was continued for 5 hours. TLC traced the reaction of the raw material point and disappeared (dichloromethane:methanol=5:1), and the reaction was completed.

[0083] After the reaction was completed, the solvent acetic acid was evaporated under reduced pressure (55°C, 0.09MPa), filtered with diatomaceous earth, the filtrate was cooled to room temperature, adjusted to pH ≈ 1 with concentrated hydrochloric acid, allowed to stand for 8 hours, filtered with suction, and the filter cake was washed with 10L ethanol. Air-dried at 60° C. for 7 hours to obtain light yellow solid compound 1 (8.2 kg, yield 37%).

[0084] The resul...

Embodiment 2

[0095] Synthesis of 6-Hydroxymethyluracil

[0096] In a 500L reactor, add compound 1 (8.2kg, 58.53mol) into 82L tetrahydrofuran, start stirring, add sodium borohydride (2.38kg, 64.38mol), stir at room temperature (20°C) for 20min, and slowly add 100mL Water, there are bubbles, keep the temperature (20°C) and stir for 3 hours, TLC tracking compound 1 point reaction disappears (dichloromethane:methanol=5:1), the reaction is complete.

[0097] Slowly add 42L of water to the reaction solution, evaporate tetrahydrofuran under reduced pressure, the reaction solution is clarified, cooled to room temperature, adjusted to pH ≈ 1 with concentrated hydrochloric acid, left to stand for 3 hours, centrifuged to obtain a filter cake; the filtrate is evaporated to dryness under reduced pressure to obtain a solid, add Stir with 10 L of water for 30 min, filter with suction, combine the filter cakes, and dry under reduced pressure at 60°C for 8 hours to obtain Compound 2 as an off-white solid (...

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Abstract

The invention provides a synthesis method of 6-(chloromethyl)uracil. The synthesis method comprises the steps that 6-(methyl)uracil and copper oxide perform oxidizing reaction in a solvent to obtain 6-(formyl)uracil; the 6-(formyl)uracil is reduced to obtain 6-(hydroxymethyl)uracil; the 6-(hydroxymethyl)uracil is subjected to chlorination to obtain the 6-(chloromethyl)uracil, wherein the purity of the 6-(chloromethyl)uracil is high than 99.0%. The synthesis method of the 6-(chloromethyl)uracil is optimized, selenium dioxide is replaced by low-toxicity metal oxide to achieve a 6-(formyl)uracil oxidation process, environmental friendliness is improved, and meanwhile the yield and purity of the 6-(chloromethyl)uracil are improved. The invention further provides a synthesis method of tipiracil hydrochloride. The obtained 6-(chloromethyl)uracil obtained by adopting the process is an intermediate, the tipiracil hydrochloride is directly prepared through three steps of chloro, condensing and salifying reaction, the obtained raw material drug does not need any purifying process, and the purity ishigher than 99.0%.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a synthesis method of tipiracil hydrochloride and its intermediate 6-chloromethyluracil. Background technique [0002] Trifluridine Hydrochloride Tipiracil Tablets (TAS-102), developed by Taiho Pharma and approved by MHLW in Japan in 2014, is an anti-tumor drug for the treatment of unresectable or recurrent advanced colorectal cancer Compound drugs. Wherein, tipiracil hydrochloride (or tipiracil hydrochloride) is the main component of the antineoplastic drug trifluridine tablet. Tipimidine hydrochloride is a thymidine phosphorylase inhibitor, which can effectively reduce the degradation of trifluridine during drug metabolism. [0003] At present, the main synthetic strategies of tipiracil hydrochloride include: [0004] 1. Using 5-chloro-6-methylpyrimidine as the starting material, first use NCS (N-chlorosuccinimide) to chlorinate the methyl group, and then condense with 2-a...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D239/54
CPCC07D403/06C07D239/54
Inventor 王淑娟徐昊康威
Owner SINOPHARM A THINK PHARMA
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