Check patentability & draft patents in minutes with Patsnap Eureka AI!

Synthetic method of telbivudine and intermediate thereof

A technology for tibivudine and its intermediates, which is applied in the field of synthesis of tibivudine and its intermediates, can solve the problems of cumbersome operation, difficulty in scale-up production, unstable compounds, etc., and achieve high yield, high purity, and easy operation simple effect

Inactive Publication Date: 2008-11-12
SHANGHAI INST OF PHARMA IND CO LTD +1
View PDF1 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In this method, the chlorinated compound is extremely unstable, and it is easy to decompose and turn black during the filtration process, and must be condensed with thymine immediately, the operation is cumbersome, and it is not easy to scale up production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthetic method of telbivudine and intermediate thereof
  • Synthetic method of telbivudine and intermediate thereof
  • Synthetic method of telbivudine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023]

[0024] With 20g (81mmol) of 3,4-di-O-acetyl-β-methyl-2-deoxy-L-nucleoside furanoside (compound of formula I, R is Ac), add 11g (86mmol) thymine, add 19ml (91mmol) of hexamethyldisilazane (HMDS) in 600ml of dichloromethane, 13ml (30g, 101mmol) of trimethylchlorosilane, 10ml (84mmol) of tin tetrachloride (21.8g). React at 30°C for 24 hours, remove the solvent by rotary evaporation, add 1200ml ethyl acetate and 900ml saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with ethyl acetate 1200ml×2, combine the organic phases, and use 1200ml saturated chlorinated Washed with sodium solution, dried, filtered, and rotary evaporated to obtain 22 g of crude product. Add 200ml×2 n-hexane to the solid, stir for 2h, and obtain 20g of compound 2. Recrystallization from methanol gave 16 g of β isomer (yield: 58%, purity: 96.0%).

Embodiment 2

[0026]

[0027] With 20g (53mmol) of 3,4-di-O-p-toluyl-α,β-methyl-2-deoxy-L-nucleoside (compound of formula I, R is 4-CH 3 PhCO), add 7g (55mmol) thymine, add 400ml ethyl acetate containing 12ml (58mmol) hexamethyldisilazane (HMDS), dichloromethane 100ml, 8ml (62mmol) trimethylchlorosilane, 9.5ml (80 mmol) tin tetrachloride (21 g). React at 40°C for 20 hours, add 500ml of ethyl acetate and 600ml of saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with 900ml of ethyl acetate x 2, combine the organic phases, wash with 900ml of saturated sodium chloride solution, and dry , filtered, and rotary evaporated to obtain 24 g of crude product. Add 200ml×2 n-hexane to the solid and stir for 2h to obtain 22g of compound 4. Recrystallized with ethanol to obtain β-isomer 19g (yield: 69%, purity: 97.5%, m.p 227-229°C (document: 225-227°C))

Embodiment 3

[0029]

[0030] With 20g (56mmol) of 3,4-di-O-benzoyl-β-methyl-2-deoxy-L-nucleoside furanoside (compound of formula I, R is PhCO), add 8g (63mmol) pyrimidine, add Contain 25ml (125mmol) of hexamethyldisilazane (HMDS) in 450ml of ether, 16ml (84mmol) of titanium tetrachloride (16g). React at 50°C for 15 hours, remove the solvent by rotary evaporation, add 900ml ethyl acetate and 600ml saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with ethyl acetate 900ml×2, combine the organic phases, and use 900ml saturated chlorinated Washed with sodium solution, dried, filtered, and rotary evaporated to obtain 20 g of crude product. Add 200ml×2 n-hexane to the solid and stir for 2h to obtain 16g of compound 6. Recrystallized with methanol to obtain β-isomer 15g (yield: 60%, purity: 97.0%, m.p 223-225°C (document: 224-225°C))

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a method for making telbivudine and the intermediate of the same. The method comprises the following steps that: Lewis acid is taken as catalyst, and trialkyl silicon halide and compounds as shown in formula I and formula II are added in organic solvent so as to carry out reaction, thereby obtaining the compound as shown in formula I and the thymine as shown in formula II; the obtained compounds are reacted to obtain the mixture of the compounds of alpha isomer and beta isomer and shown in formula III, and then the mixture is separated to extract the beta isomer; the beta isomer is reacted with hydrogen donor in the organic solvent in the presence of organic base so as to obtain telbivudine as shown in formula IV; moreover, R is substitutional benzyl group or acyl on benzyl group and benzene ring, and R' is CH3. The method has simple operation and does not need column chromatography and special equipment; moreover, the obtained product has higher yield and high purity and is suitable to be used in industrialized production.

Description

technical field [0001] The invention relates to a synthetic method of a compound and an intermediate thereof, in particular to a synthetic method of tibivudine and an intermediate thereof. Background technique [0002] Tabivudine is a new nucleoside anti-HBV compound, which has completed phase III clinical trials and is in the pre-registration stage. Its chemical name is: 2'-deoxy-β-L-thymidine. Tibivudine has the pharmacological activity of general nucleoside anti-HBV drugs. [0003] At present, the preparation of tibivudine adopts the method disclosed in the patent document WO2005003374, and the steps are as follows: [0004] (1) Use acetic acid as a solvent, feed HCl gas or drop into saturated HCl acetic acid solution and acetyl chloride to chlorinate the compound (Formula I), and collect the chlorinated product (Formula V) as a white solid by filtration; [0005] (2) reacting thymine (formula II) with a trialkyl silicon halide to obtain a compound (formula VI); [00...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073
Inventor 李春燕袁哲东朱雪炎刘向奎张秀平俞雄
Owner SHANGHAI INST OF PHARMA IND CO LTD
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com