Method for synthesizing dideoxynucleoside through glycosyl transfer reaction and application thereof

A technology of glycosyl transfer reaction and dideoxynucleoside, applied in chemical instruments and methods, sugar derivatives, sugar derivatives, etc., can solve the problems of low yield, many sugar ring restrictions, etc., to reduce production costs, operation simple method effect

Active Publication Date: 2015-03-04
SULI CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This reaction is an ideal method for preparing some unnatural nucleosides that are difficult to synthesize, but the current limitation is that the yield of the enzyme-catalyzed method is low, and the sugar ring of a given nucleoside is more restricted by other Lewis acid catalysis

Method used

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  • Method for synthesizing dideoxynucleoside through glycosyl transfer reaction and application thereof
  • Method for synthesizing dideoxynucleoside through glycosyl transfer reaction and application thereof
  • Method for synthesizing dideoxynucleoside through glycosyl transfer reaction and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Synthesis of ddA (2', 3'-dideoxyadenosine, 2', 3'-dideoxyadenosine)

[0058]

[0059] 1) Dissolve 21.2g of dideoxyuridine formula 1-1 compound (0.1mol) dried in vacuum in 100ml of THF which was dried beforehand, control the temperature between 0-10°C, add 20.7g K 2 CO 3 (0.15mol), stirred for 30min, slowly added dropwise 15.3g of acetic anhydride (0.15mol), the dropwise addition was completed within 20min, stirred at room temperature for 24h; 10ml of water was added to the system, the reaction was quenched, the THF was spin-dried, and the residue was washed with ethyl acetate The ester was recrystallized to obtain 24.1 g of 5′-acetyl protected dideoxyuridine (ie the compound of formula 1-2) (0.095 mol), with a yield of 95%;

[0060] 2) 25.4g 5'-acetyl protected dideoxyuridine formula 1-2 compound (0.1mol), adenine (27g, 0.2mol) and 1.78g palladium chloride (10mmol) were dissolved in pre-dried 150mlDMF , stir evenly, add 162g BSA (0.8mol) and 33.3gTMSOTf ...

Embodiment 2

[0061] Example 2: Synthesis of d4C (2', 3'-dideoxycytidine)

[0062]

[0063] 1) Dissolve 21g of the compound of dideoxyuridine formula 2-1 (0.1mol) dried in vacuum in 100ml of pre-dried pyridine, control the temperature between 0-10°C, add 1.23g of DMAP (0.01mol), and stir for 30min , slowly add 11g TMSCL (0.1mol) dropwise, the dropwise addition is completed within 30min, and stir at room temperature for 8h; add 5ml water to the system, quench the reaction, spin dry pyridine, and recrystallize the residue with dichloromethane to obtain 25.4g 5' -TMS-protected dideoxyuridine (compound of formula 2-2) (0.090mol), yield 90.2%;

[0064] 2) 28.2g 5′-TMS protected dideoxyuridine formula 2-2 compound (0.1mol), 27g cytosine (0.3mol) and 3.67g 1,1′-bis(diphenylphosphino)ferrocene Dissolve palladium chloride (5mmol) in 200ml of acetonitrile that has been dried beforehand, stir well, add 60.8g BSA (0.3mol) and 22.2g TMSOTf (0.1mol) to the system at room temperature, heat at 100°C fo...

Embodiment 3

[0065] Embodiment 3: the synthesis of ddI (dideoxyinosine)

[0066]

[0067] 1) For the synthesis method of 5′-acetyl protected dideoxyuridine (ie the compound of formula 2-2), see Example 1;

[0068] 2) 25.4g 5'-acetyl protected dideoxyuridine formula 2-2 compound (0.1mol), 27g hypoxanthine (0.2mol) and 8.6g tetrakis (triphenylphosphine) palladium (7.5mmol) dissolved In pre-dried 250ml dichloroethane, stir evenly, add 101g BSA (0.5mol) and 66.6g TMSOTf (0.3mol) to the system at room temperature, heat at 80°C for 12 hours, cool to room temperature, evaporate under reduced pressure Dichloromethane; add 500ml of aqueous sodium hydroxide solution (2mol / L) to the system, stir at room temperature for 0.5 hours, extract twice with 200ml of dichloromethane, combine the extracts, dry and concentrate, and the residue is washed with isopropyl The alcohol was recrystallized to obtain 23.3 g ddI (0.082 mol), with a yield of 81.6%.

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Abstract

The invention relates to a method for synthesizing dideoxynucleoside through a glycosyl transfer reaction and an application thereof. The method for synthesizing dideoxynucleoside comprises the following steps of: 1) performing a reaction between dideoxyuridine and a hydroxyl protecting agent to obtain a compound as shown in the formula 1-2 or a compound as shown in the formula 2-2; and 2) performing a reaction of the compound as shown in the formula 1-2 or the compound as shown in the formula 2-2 obtained from the step 1) under the action of a palladium catalyst so as to obtain dideoxynucleoside, namely a compound as shown in the formula 1-3 or a compound as shown in the formula 2-3. According to the preparation method for synthesizing dideoxynucleoside through the glycosyl transfer reaction, the operation method is simple, harsh reaction conditions and complex chemical reaction processes are not required, the disadvantage of low yield of the enzyme catalyzed glycosyl transfer reaction is solved, and the average yield is 80-95%.

Description

technical field [0001] The invention relates to a method for synthesizing dideoxynucleosides, in particular to a method for synthesizing dideoxynucleosides through a glycosyl transfer reaction and its application. Background technique [0002] In recent years, nucleoside antiviral drugs have developed gradually, and have become one of the remarkable and active varieties in the domestic and foreign pharmaceutical markets, especially the development of high-efficiency and low-toxicity antiviral drugs such as lamivudine and acyclovir Success has brought good news to the majority of patients. [0003] 2',3'-dideoxynucleoside is one of the important pharmaceutical intermediates and antiviral drugs, and it is one of the hot spots in the research of antiviral drugs in recent years. 2',3'-dideoxynucleoside antiviral drugs give the following examples: [0004] Didanosine (didanosine, ddI), as shown in formula I, also known as 2-deoxyinosine, didanosine, didanosine, BMY-40900, di-de...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/16C07H19/06C07H1/00
Inventor 刘迎春施章杰缪金凤刘建华焦德荣
Owner SULI CO LTD
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