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Trifluridine intermediate and preparation method of trifluridine

A technology for trifluridine and intermediates, applied in the field of drug synthesis, can solve problems such as being difficult to be applied in industrial production, and achieve the effects of controllable product quality, high purity and improved production process

Active Publication Date: 2016-04-06
SINOPHARM A THINK PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The process can use other Lewis acids such as copper fluoride in the condensation step. Although the use of other Lewis acids can avoid the use of fluorinated reagents, due to the use of a large amount of difficult-to-handle metal reagents, such as zinc dichloride, etc., there will be It causes many problems in post-processing, and it is difficult to apply in industrial production

Method used

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  • Trifluridine intermediate and preparation method of trifluridine
  • Trifluridine intermediate and preparation method of trifluridine
  • Trifluridine intermediate and preparation method of trifluridine

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preparation example Construction

[0037] The invention provides a kind of preparation method of trifluridine intermediate, comprising the following steps:

[0038] A) under the effect of acidic resin catalyst, 1-chloro-2-deoxy-3,5-two-O-p-chlorobenzoyl-D-ribose and 5-trifluoromethyl-2,4-bis( After the condensation reaction of trimethylsilyloxy)pyrimidine, the trifluridine intermediate is obtained.

[0039] Described acidic resin is preferably one or more in Amberjet1500H cationic resin, Dowex50W-X2 resin and strongly acidic styrenic cation exchange resin, more preferably Amberjet1500H cationic resin, Dowex50W-X2 resin or strongly acidic styrenic cation exchange resin Resin, most preferably Dowex50W-X2 resin; The mass ratio of described 1-chloro-2-deoxy-3,5-two-O-p-chlorobenzoyl-D-ribose and acidic resin catalyst is preferably 1:(0.008 ~0.02), more preferably 1:(0.01~0.018), more preferably 1:(0.012~0.016), most preferably 1:(0.013~0.015); the 1-chloro-2-deoxy-3,5 The mass ratio of -di-O-p-chlorobenzoyl-D-rib...

Embodiment 1

[0061] 1. Preparation of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine

[0062] Weigh 2.40 kg of 5-trifluoromethyluracil into a 50 L reaction flask, add 14.8 L of HMDS, drop in 60 ml of TMSCl, and react at a temperature of 110° C. for 3 h. Distill under reduced pressure, collect the product of stable fraction (130 ℃, vacuum: 0.090mpa), obtain 3.66kg of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine, calculate the reaction yield The rate is 85.0%.

[0063] 2. Preparation of 1-(2'-deoxy-3,5-di-O-p-chlorobenzoyl-β-D-furanosyl)-5-trifluoromethyluracil

[0064]Add 3.66g of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine prepared in the above steps, 36.6mg of Dowex50W-X2 resin and 50mL of chloroform into a 100mL enamel reaction bottle, at 25°C Stir at a temperature of 10 min, and after the solid is basically dissolved, add 3.72 g of 1-chloro-2-deoxy-3,5-di-O-p-chlorobenzoyl-D-ribose to the mixed system, and stir for another 12 h. filter.

[0065] After th...

Embodiment 2

[0081] Preparation of 1-(2'-deoxy-3,5-di-O-p-chlorobenzoyl-β-D-furanosyl)-5-trifluoromethyluracil

[0082] Add 3.66 g of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine, 36.6 mg of Amberjet 1500H cationic resin and 50 mL of chloroform into a 100 mL enamel reaction bottle and stir at a temperature of 25°C After 10 minutes, after the solid was dissolved, 3.72 g of 1-chloro-2-deoxy-3,5-di-O-p-chlorobenzoyl-D-ribose was added to the mixed system, stirred for another 12 hours, and filtered.

[0083] After the reaction was completed, 20 mL of hydrochloric acid with a concentration of 1 mol / L was added to the system, stirred for 15 min, and 20 mL of water was added to the system again, after stirring for 15 min, the liquid was separated. Add 10 mL of saturated brine to the organic phase to wash once, add 2 g of anhydrous sodium sulfate to dry, filter, and then concentrate the organic solvent under reduced pressure, and add anhydrous ethanol (12 mL)-n-hexane (30 mL) mixed solut...

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Abstract

The invention provides a preparation method of a trifluridine intermediate. Under the action of an acidic resin catalyst, 1-chloro-2-deoxy-3,5-di-O-p-chlorobenzoyl-D-ribose and 5-trifluoromethyl-2,4-bis(trimethylsilaneoxy)pyrimidine undergo a condensation reaction so as to obtain the trifluridine intermediate. According to the invention, a heterogeneous catalysis technology is utilized, acidic resin is used as a catalyst, and a traditional Lewis acid catalyst is replaced. Under the precondition of guaranteeing that product quality is controllable, a production technology is greatly improved. Catalytic efficiency is high, and conditions are mild. Purity of the prepared 1-(2'-deoxy-3,5-di-O-p-chlorobenzoyl-beta-D-furanose)-5-trifluoromethyluracil is greatly raised, and the problem that the use of the Lewis acid catalyst leads to severe post-treatment emulsification and environmental pollution and is not beneficial to industrial production is also effectively solved.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a trifluridine intermediate and a preparation method of trifluridine. Background technique [0002] Trifluridine, also known as trifluridine, trifluridine, trifluorothymidine, trifluridine, trifluridine, trifluorothymidine or 5-trifluoromethyl-2-deoxyuridine Glycosides, etc., the molecular formula is C 10 h 11 f 3 N 2 o 5 , is a class of antiviral drugs used to prevent and treat viral infections, mainly for herpetic keratitis and conjunctivitis. Existing medical research shows that the drug with trifluridine as the main active ingredient can also be used as an anti-cancer nucleoside drug, which is mainly used for the treatment of colorectal cancer, especially for the early treatment of patients with colon cancer. Fluoxiridine can directly interact with the DNA of cancer, making the DNA unable to function normally. Its mechanism of action is different ...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00
CPCC07H1/00C07H19/073
Inventor 郑亚东和龙张华徐昊
Owner SINOPHARM A THINK PHARMA
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