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Synthetic method of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation

A sulfur-thymidine and microwave-assisted technology, which is applied in the field of pharmaceutical chemistry and pharmaceuticals, can solve the problems of unfavorable anti-cancer active drug research, time-consuming and energy-consuming, low yield, etc.

Inactive Publication Date: 2012-10-10
DALIAN UNIV
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  • Abstract
  • Description
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Problems solved by technology

[0005] There have been more than 40 years of research on the synthesis of sulfur-containing nucleosides and sulfur-containing nucleotides. Among them, the synthesis of thionucleosides, especially 4-sulfur thymidine compounds, is based on traditional heating Synthetic methods are often time-consuming and energy-consuming, and the yield is low, which is not conducive to the research on its anticancer active drugs

Method used

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  • Synthetic method of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation
  • Synthetic method of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation
  • Synthetic method of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: A method for synthesizing 4-thiothymidine, including the following steps:

[0035] (1) Synthesize 3',5'-O-dioxoacetylthymidine (Ⅲ) by acetylation to protect the hydroxyl group on the sugar ring.

[0036]

[0037] The compound thymidine (1.00g, 3.87mmol) (II) was dissolved in anhydrous pyridine (40.4ml, 502mmol), cooled to 0°C, and anhydrous acetic anhydride (8.3ml, 87.8mmol) was added at 0°C. Continue stirring for 5h (TLC tracking). After taking it out, the solvent was removed under reduced pressure and recrystallized from methanol to obtain white massive crystals (III) (2.41g, 9.33mmol), with a yield of 95%, mp 129-131°C. 1 H NMR(400MHz, DMSO-d 6 )δ: 11.39 (br s, 1H, NH), 7.50 (s, 1H, 6-H), 6.18 (t, J = 8.0 Hz, 1H, 1'-H), 5.18 (t, J = 4.0 Hz, 1H,3'-H), 4.25(d,J=4.0Hz,2H,5'-H), 4.14(d,J=4Hz,1H,4'-H,),2.25-2.48(m,2H, 2'-H),2.07(s,6H,2×-OC=OCH 3 ),1.80(s,3H,-CH 3 ).

[0038] (2) Synthesis of 3',5'-O-dioxoacetyl-4-thiothymidine (IV) by replacing oxygen with sulfur b...

Embodiment 2

[0044] Example 2: The effect of microwave reaction time on the thiosulfate yield in step B

[0045] (1) Synthesis of 3',5'-O-dioxoacetyl thymidine by acetylation of thymidine to protect the hydroxyl group on the sugar ring. For specific examples, refer to step (1) in Example 1.

[0046] (2) Synthesis of 3',5'-O-dioxoacetyl-4-thiothymidine by using the microwave method to substitute sulfur for oxygen.

[0047] The compound 3',5'-O-dioxoacetyl-4-thiothymidine (1.0g, 3.06mmol) was dissolved in anhydrous dioxane (55ml, 643mmol), and P was added 2 S 5 (1.02g, 4.59mmol), put into a microwave reactor, irradiate at 800W power for 5min (TLC tracking), repeat time, microwave reaction time are 8min, 10min, 15min, respectively, the yield under different microwave reaction time is shown in Table 1. It can be seen from the table that the microwave reaction time is 8-10min with the highest yield.

[0048] Table 1 The influence of microwave reaction time on product yield

[0049] Time / min

[0050]...

Embodiment 3

[0052] (1) Reacting thymidine with benzoyl chloride to protect the hydroxyl group on the sugar ring. For specific examples, refer to the literature Fox et al., JACS, 1959, vol. 81, p. 178-187. The 3',5'-O-dibenzoyl thymidine was obtained, the yield was 85%, and the NMR data was consistent with the literature value.

[0053] (2) Using microwave method to synthesize 3',5'-O-dibenzoyl-4-thiothymidine by replacing oxygen with sulfur.

[0054] The compound 3’,5’-O-dibenzoylthymidine (1.38g, 3.06mmol) was dissolved in anhydrous dioxane (55ml, 643mmol), and P 2 S 5 (1.02g, 4.59mmol), put into a microwave reactor, irradiate for 8min under 800W power (TLC tracking). After the reaction was stopped, the filtrate was collected and the solvent was removed under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol to obtain 1.20 g of a yellow solid with a yield of 83.9%. Melting point: 161-162°C. Anal.Calcd.for C 10 H 16 N 3 O 4 Cl:C,43.24;H,5.81;N,15.1...

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Abstract

The invention discloses a synthetic method of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation. Thymidine or a thymidine analogue ribothymidine are taken as raw materials; after hydroxyls on saccharide rings are protected, a reaction between reaction products of a previous step and phosphorus pentasulfide solid is carried out in a reactor; dioxane is taken as a solvent; microwave irradiation is carried out in microwaves of 80-100 watts for 7-10 minutes to obtain reaction products after a reaction of sulfur replacing oxygen is carried out; then methanol solution containing saturated ammonia gas is added into the reaction products of a previous step and stirring is carried out to remove protecting groups of hydroxyls at normal temperature; after recrystallization is carried out, the synthetic process of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation is realized. The invention is advantaged in that the method is with short reaction time, high yield and high product purity; a traditional time-consuming and energy-consuming synthetic method with low yield is avoided; and favorable conditions are provided for development of drugs containing sulfur nucleoside analogues.

Description

Technical field [0001] The invention relates to a preparation method of a compound, in particular, to a microwave-assisted synthesis method of 4-thiothymidine and its analogs, and the synthesized product is suitable for the field of medicinal chemistry and pharmacy. Background technique [0002] Under the promotion of the human gene research project, the information about the relationship between genes and diseases has been highly valued. Nucleosides are the most basic raw materials or elements of genes, and the development of nucleosides (including the bases of nucleosides) and nucleotides New drugs have become one of the important directions. These two types of drugs can be divided into natural nucleosides and nucleotides and non-natural nucleosides and nucleotides. By chemically modifying natural nucleosides and nucleotides, numerous nucleoside derivatives can be obtained, namely non-natural nucleosides and nucleosides. From the chemical structure point of view, they have man...

Claims

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Application Information

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IPC IPC(8): C07H19/067C07H19/073C07H1/00
CPCY02P20/55
Inventor 张晓辉王健翟红秀
Owner DALIAN UNIV
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