3'-thionucleoside synthesis method

A compound and mixture technology, which is applied in the production of bulk chemicals, sugar derivatives, organic chemistry, etc., can solve the problems of low purity, low yield of target products, lengthy synthetic routes, etc., and achieve the effect of increasing yield

Inactive Publication Date: 2012-10-03
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] So far, many documents have reported the synthetic method of 3'-thionucleosides (Matulic-Adamic, J.; et al., Helv.Chim.Acta., 1999, 82 (12), 2141-2150; Lu, J.; et al., Biorg.Med.Chem., 2008, 16(10), 5754-5760.), but the existing method for synthesizing 3'-thionucleosides has a long synthetic route (generally requires seven steps reaction), the yield of the target product is low (total yield is only about 10%) and the defects such as the purity is not high

Method used

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  • 3'-thionucleoside synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation of compound shown in formula Ia:

[0038]

[0039] Dissolve 2'-deoxyinosine (0.2520g, 1.0mmol) in 10mL of treated anhydrous DBU, start stirring, and slowly add DMTCl (0.4060g, 1.2mmol) to the two-necked flask, and the reaction solution continues to be heated at room temperature. The reaction was stirred for 19h. Pass through a silica gel column, first remove pyridine with an eluent (DCM:EtOH=20:1, V / V), and then increase the polarity to obtain the product. The product is a white solid 0.5483g (5'-DMT-2'- Deoxyinosine, compound IIIa), the yield was 98.97%.

[0040] Dissolve Sareite reagent (0.6400g, 1.5mmol) in 8mL of treated anhydrous dichloromethane, start stirring, then cool in ice bath for 10min, slowly add compound 5′-DMT-2′-deoxyinosine (0.5440 g, 1.0mmol), then react in ice bath for 1h, remove the ice bath, slowly rise to room temperature and continue the reaction for 4h, add 8mL of anhydrous isopropanol dropwise to the reaction solution, add ...

Embodiment 2

[0048] The preparation of compound shown in formula I b:

[0049]

[0050] Except that 2-acetamide-2'-deoxyadenosine was substituted for 2'-deoxyinosine in Example 1, other conditions were the same as in Example 1 to obtain the title compound. The purity of the title compound was 98%, and its overall yield was about 45%.

[0051] 1 H NMR (400MHz, CDCl 3 ): δ10.32(s, 1H), 8.30(s, 1H), 6.97(s, 2H), 7.43-6.84(m, 13H), 5.94(dd, 1H, J 1 = 4.0Hz,J 2 =8Hz), 4.38(m, 1H), 3.83(s, 6H), 3.63(dd, 1H, J 1 = 4.0Hz,J 2 =8Hz), 3.38(dd,1H,J 1 = 4.0Hz,J 2 =8Hz), 2.90(m, 1H), 2.68(m, 1H), 2.43(m, 1H), 2.04(s, 3H), 1.58(d, 1H, J=8Hz).

[0052] MS(ESI): m / z calcd for C 33 h 34 N 6 o 5 S: [M+H + ]: 627.2; found: 627.3.

Embodiment 3

[0054] The preparation of compound shown in formula Ic:

[0055]

[0056] According to the method described in Example 1, only changing the raw material 2′-deoxyinosine to 2-acetamide-6-benzamide-2′-deoxyadenosine, and DMTCl to TBSCl can successfully obtain the title compound. The purity of the title compound was 98%, and its overall yield was about 49%.

[0057] 1 H NMR (400MHz, CDCl 3 ): δ11.34(s, 1H), 10.32(s, 1H), 8.36(s, 1H), 8.05-6.84(m, 5H), 5.94(dd, 1H, J 1 = 4.0Hz,J 2 =8Hz), 4.38(m, 1H), 4.20(m, 1H), 3.73(s, 1H), 2.93(dd, 1H, J 1 = 4.0Hz,J 2 =8Hz), 2.68(dd,1H,J 1 = 4.0Hz,J 2 =8Hz), 2.40(m, 1H), 2.08(s, 3H), 1.60(d, 1H, J=8Hz), 0.21(s, 9H).

[0058] MS(ESI): m / z calcd for C 22 h 28 N 6 o 4 SSi: [M+H + ]: 501.2; found: 502.3.

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Abstract

The invention relates to a 3'-thionucleoside synthesis method. According to the method, oxonucleotide which is easy to obtain is used as initial raw materials, firstly, primary hydroxyl groups of furan ring is subjected to selective protection, then, twice turning is carried out, and -SH is successfully introduced at the No.3 bit of the furan ring. The synthesis method has the advantages that the synthesis path of 3'-thionucleoside is optimized, and target products can be obtained from the initial raw materials through five-step reaction, so the yield (the yield is 4 to 5 times that in the prior art) and the purity of the target products are improved.

Description

technical field [0001] The present invention relates to a kind of synthetic method of 3'-thionucleoside Background technique [0002] Nucleoside is a glycoside formed by ribose or deoxyribose and a base (such as adenine, thymine, guanine, oxamidine or uracil), and is an important part of DNA and RNA. In addition, some nucleosides or their derivatives have medicinal value (such as inosine (inosine) can treat acute and chronic hepatitis and rheumatic heart disease, and have the effect of increasing white blood cells; 5'-fluorouracil deoxynucleoside Glycosides can resist tumors (lower toxicity than 5′-fluorouracil), and have certain curative effects on liver cancer, gastric cancer, rectal cancer, ovarian cancer, and bladder cancer; cytosine arabinoside has a significant effect on alleviating leukemia; 5′-deoxy-5′- Iodouridine is a specific drug for the treatment of viral keratitis) Therefore, the research on the synthesis of nucleosides has aroused great interest. [0003] 3'...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H19/16
CPCY02P20/55
Inventor 罗千福程仁军鲍书敏王秋
Owner EAST CHINA UNIV OF SCI & TECH
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