Intermediate compounds for thiophane nucleoside analogues and preparation method thereof

A technology of thiophene nucleosides and thiophene nucleosides, which is applied in the fields of silicon organic compounds and organic chemistry, and can solve problems such as high cost, harsh conditions, and long reaction routes

Inactive Publication Date: 2010-11-10
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Therefore, the technical problem to be solved in the present invention is to provide a new class of tetrahydrothiophene nucleoside analogues for the synthesis of existing tetrahydrothiophene nucleoside compounds with long reaction routes, high cost and harsh conditions. Intermediate compound and preparation method thereof

Method used

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  • Intermediate compounds for thiophane nucleoside analogues and preparation method thereof
  • Intermediate compounds for thiophane nucleoside analogues and preparation method thereof
  • Intermediate compounds for thiophane nucleoside analogues and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: (2S, 3S, 4R)-2-tert-butyldimethylsiloxymethyl-3,4-O-isopropylidene-tetrahydrothiophene (compound 12)

[0034] Compound 11 (32.1 g, 0.07 mol) was dissolved in 700 mL of dimethyl sulfoxide, sodium sulfide hydrate (20 g, 0.08 mol) was added at room temperature, mechanically stirred at 100°C, and monitored by TLC until the disappearance of the raw material. After cooling down to room temperature, the reaction system was poured into ice water, stirred for 5 minutes, and extracted with ether five times (200 mL / time). The organic layers were combined, washed with water 3 times (200 mL / time), dried over anhydrous magnesium sulfate and concentrated to obtain a crude yellow oil. The crude product was purified by column chromatography (petroleum ether / ethyl acetate 20 / 1) to obtain 13.8 g of a yellow oil with a yield of 65%.

[0035] [α] D 20 =194°C=1.0, Methanol.

[0036] MS m / z: 305 (M + +1). 1 HNMR (CDCl 3 )δ (ppm): 0.89 (s, 9H); 0.08 (s, 6H); 1.29 (s, 3H); 1.4...

Embodiment 2

[0037] Example 2: (2S, 3S, 4R)-1-oxo-2-tert-butyldimethylsiloxymethyl-3,4-O-isopropylidene-tetrahydrothiophene (compound 13)

[0038] Compound 12 (7.4 g, 24.3 mmol) was dissolved in 150 mL of dichloromethane. At -78°C, 0.49mol / L m-chloroperoxybenzoic acid in dichloromethane (50mL, 24.5mmol) was added dropwise, reacted for 1 hour, then warmed up to room temperature, added saturated aqueous sodium bicarbonate, and stirred for 5 minutes. The layers were separated, the aqueous layer was extracted three times with dichloromethane (30 mL / time), the organic layers were combined, and the organic layer was washed with saturated brine. Dry over anhydrous magnesium sulfate and concentrate to give a white solid. After purification by column chromatography (petroleum ether / ethyl acetate 3 / 1), 3.97 g of a white solid was obtained, with a yield of 51%.

[0039] [α] D 20 =153°C=1.0, Methanol.

[0040] MS m / z: 343 (M + +23). 1 HNMR (CDCl 3 )δ (ppm): 0.93 (s, 9H); 0.12 (S, 6H); 1.30 (S,...

Embodiment 3

[0041] Example 3: (2S, 3S, 4R)-1-oxo-2-tert-butyldimethylsiloxymethyl-3,4-O-isopropylidene-tetrahydrothiophene (compound 13)

[0042] Compound 12 (7.4 g, 24.3 mmol) was dissolved in 150 mL of dichloromethane. At -10°C, 0.49 mol / L m-chloroperbenzoic acid-added dichloromethane solution (50 mL, 24.5 mmol) was added dropwise. After reacting for 1 hour, it was raised to room temperature, and saturated aqueous sodium bicarbonate solution was added, and stirred for 5 minutes. The layers were separated, and the aqueous layer was extracted three times with dichloromethane (30 mL / time). The organic layers were combined and washed with saturated brine. Dry over anhydrous magnesium sulfate, filter and concentrate to obtain a white solid. Purified by column chromatography (petroleum ether / ethyl acetate 3 / 1) to obtain a white solid with a yield of 48%.

[0043] [α] D 20 =153°C=1.0, Methanol.

[0044] MS m / z: 343 (M + +23). 1 HNMR (CDCl 3 )δ (ppm): 0.93 (s, 9H); 0.12 (S, 6H); 1.30 (S, ...

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Abstract

The invention discloses intermediate compounds expressed as a general formula 1 for synthesizing thiophane nucleoside analogues and a preparation method thereof. In the general formula, Ac represents acetyl. The intermediate compounds can be used for synthesizing new thiophane nucleoside analogues. The thiophane nucleoside compounds or pharmaceutically acceptable salts, solvates, optical isomers or polymorphic substances thereof have good anti-tumor effect.

Description

technical field [0001] The invention relates to a class of intermediate compounds, in particular to an intermediate compound for synthesizing a new class of tetrahydrothiophene nucleoside analogs and a preparation method thereof. Background technique [0002] Malignant tumor is a common disease that seriously threatens human health. Although there is no cure drug found so far, considerable progress has been made in anticancer chemotherapy over the past few decades, and anticancer drugs have emerged in an endless stream. Nucleoside compounds are one of the important antitumor chemotherapeutic drugs. [0003] Nucleoside antineoplastic drugs include derivatives of various purine and pyrimidine nucleosides. These compounds, as anti-metabolites, produce cytotoxic effects from three aspects: 1) nucleoside compounds are used as pseudo-substrates in biochemical reactions, inhibiting the related enzymes of nucleotide de novo synthesis, interfering with deoxyribonucleoside triphospha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07F7/08
Inventor 丛立庆金东哲孙桂芳周伟澄
Owner SHANGHAI INST OF PHARMA IND
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