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Industrial process for preparing beta-thymidine

A thymidine and industrial technology, applied in the field of industrial preparation of beta-thymidine, can solve the problems of difficult recovery, equipment corrosion, long route and the like, and achieve the effects of simple and easy production process, reduced production cost and shortened synthesis route.

Inactive Publication Date: 2005-07-06
SHAXING CHEM TAIZHOU CITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, those who use chemical synthesis methods are: US4914233 (application date: March 1, 1988) discloses a method for converting α, β tetra-O-acyl ribose into β-thymidine. The starting material of this method is not easy obtained, and the α, β configuration ratio of raw materials is not easy to grasp, and the stereoselectivity is poor; CN1055293 (application date: October 6, 1998) describes a kind of protected thymine and α, β-tetraacetyl-D- Ribose is catalyzed by Lewis acid in a five-step synthesis method of condensation, alcoholysis, halo-acylation, catalytic hydrogenation and alcoholysis. To prepare 5-methyluridine, the process is complicated, and the condensation reaction catalyst adopts expensive and difficult-to-recover Lewis acid, the route is long, the yield is low, and the cost is high; US5596087 (application date: May 30, 1994) involves a A method for preparing β-thymidine from unprotected xylidene thymidine, using propionyl bromide in the halogenation-acylation process, the yield is low, and the equipment is severely corroded

Method used

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  • Industrial process for preparing beta-thymidine
  • Industrial process for preparing beta-thymidine

Examples

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example 1

[0011] Add 15g (0.1mol) of D-ribose and 150ml of dichloromethane into a 250ml three-neck flask equipped with a stirrer, a thermometer, and a dropping funnel, stir until dissolved, then add 12.5g of thymine (0.1mol), and cool to 10 Below ℃, add 12ml of 98.5% concentrated sulfuric acid dropwise, after the addition is complete, naturally raise the temperature to 20-25℃, stir and react for 10 hours, add water, stir and separate layers, extract the aqueous layer with dichloromethane, combine the organic layers, and distill off dichloromethane Recrystallized from methane and ethanol to obtain 23 g of off-white 5-methyluridine, content (HPLC): 99.2%, melting point: 181-185°C: yield: 89.14%.

example 2

[0013] Add 150ml of acetonitrile and 30g (0.42mol) of propionyl chloride to a 500ml three-necked flask equipped with a stirrer and a thermometer, raise the temperature to 50°C, add 20g (0.077mol) of 5-methyluridine in batches, and keep stirring at 60°C for reaction For 3 hours, distill acetonitrile, cool, add 200ml of water, cool to below 5°C, keep stirring for 2 hours, filter with suction, wash with water, dry to obtain light yellow solid 2′-chloro-2′-deoxy-5-methyl-3 ', 5'-O-alkanoyl-β-D-riburidine 28g, melting point: 132-134°C, content (HPLC): 97.3%, yield: 93%.

example 3

[0015] Add 2'-chloro-2'-deoxy-5-methyl 4-3', 5'-O-alkanoyl-β-D-riburidine 39g (0.1mol) in the autoclave, add methanol / Water (1:0.3) 400ml, sodium acetate 12.5g (0.15mol), stir to dissolve, add Pd / C 40g, pass hydrogen to 3×10 5 Pa, react at 25--30°C for 4 hours, filter off the catalyst, concentrate under reduced pressure to obtain a viscous substance, which is directly used in the next reaction.

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Abstract

The invention belongs to medical intermediate field, and relates to a four-step synthesis method for industrial preparation of a beta thymidine. The invention is characterized in that a D-ribose is used as initial raw material. The D-ribose is transformed into the beta thymidine after direct condensation with thymine, halogenation-acylation reaction with propionyl chloride, catalytic hydrogenation reduction and catalyzed alcoholysis with total yield greater than 65%.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates and relates to an industrial preparation method of β-thymidine. Background technique [0002] β-Thymidine, also known as Deoxythymidine, is a key intermediate of Zidovodine, a drug for the treatment of AIDS. At present, the preparation methods of β-thymidine mainly include four methods: chemical synthesis, DNA enzymatic hydrolysis, fermentation and enzymatic method. At present, those who use chemical synthesis methods are: US4914233 (application date: March 1, 1988) discloses a method for converting α, β tetra-O-acyl ribose into β-thymidine. The starting material of this method is not easy obtained, and the α, β configuration ratio of raw materials is not easy to grasp, and the stereoselectivity is poor; CN1055293 (application date: October 6, 1998) describes a kind of protected thymine and α, β-tetraacetyl-D- Ribose is catalyzed by Lewis acid in a five-step synthesis method of conden...

Claims

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Application Information

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IPC IPC(8): C07H19/067
Inventor 吴发明宁向阳
Owner SHAXING CHEM TAIZHOU CITY
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