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Synthesizing nucleoside analog for antivirus

A synthesis method and product technology, applied in antiviral agents, bulk chemical production, organic chemistry, etc., can solve problems such as ordinary silica gel column separation

Inactive Publication Date: 2006-03-29
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The Baschang group improved this route (Scheme 2, Tetrahedron: Asymmetry, 1992, 193-196). They used compound 5' as a raw material, but the isomers 6' and 7' of the obtained epoxy compound still cannot be used for ordinary silica gel. Column separation, must still be separated with a preparative HPLC column

Method used

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  • Synthesizing nucleoside analog for antivirus
  • Synthesizing nucleoside analog for antivirus
  • Synthesizing nucleoside analog for antivirus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of compound 9:

[0025] 0.5 g (4 mmol) of raw materials were dissolved in 10 ml of pyridine (potassium hydroxide dried), stirred, and 1.6 g (4.7 mol) of 4,4'-dimethoxytrityl chloride was added. After stirring at room temperature for 3 hours, evaporate the pyridine to dryness, add 30ml of water, and extract with ethyl acetate (25ml×3). The organic phases were combined, washed with saturated brine (25ml×3), and dried over anhydrous sodium sulfate. After filtering and evaporating the solvent, the obtained crude product was subjected to column chromatography (eluent: n-hexane: ethyl acetate = 20:1) to obtain 1.4 g of the product (yield: 94%). 1 HNMR (CDCl 3 ): δ7.44-7.20(m, 9H); 6.85-6.82(m, 4H); 4.74-4.22(m, 1H); 3.79(s, 6H); 3.12-3.15(m, 2H); 2.60-3.00 (m, 2H), 2.05-2.45 (m, 3H).

Embodiment 2

[0027] Preparation of Compound 10:

[0028] Under the protection of argon, add 0.824 g of potassium tert-butoxide into a dry 25 ml three-necked flask, add dry 5 ml of dimethyl sulfoxide, stir, and dropwise add 1.36 g of compound 9 dissolved in 5 ml of dimethyl sulfoxide. Stir overnight. Then the reaction solution was poured into 20ml ice water, the pH value was adjusted to neutral with 5% hydrochloric acid, sodium chloride was added to saturation, extracted with ether (20ml×3), the organic phases were combined, and washed with water (20ml×3) , dried over anhydrous sodium sulfate. After filtering and evaporating the solvent to dryness, the obtained crude product was subjected to column chromatography (eluent: n-hexane:ethyl acetate=20:1), and 1.23 g of the product was obtained (yield: 98%). 1 HNMR (CDCl 3 ): δ7.47-7.20(m, 9H); 6.85-6.80(m, 4H); 6.14-6.01(m, 2H); 3.8(s, 6H); 3.12-3.10(m, 3H); 2.63-2.62 (m, 1H); 2.18-2.13(m, 1H).

Embodiment 3

[0030] Preparation of compound 11:

[0031] Dissolve 44 grams (0.114mol) of compound 10 in 600ml of dichloromethane, add 19.15 grams (0.228mol) of sodium bicarbonate 19.15 grams (0.228mol) dissolved in 100ml of water, stir vigorously, and cool the reaction to 0 with an ice-water bath °C, add 41 g (0.171 mol) m-chloroperoxybenzoic acid in batches, and stir overnight at room temperature. Then slowly add an aqueous solution of 17.8 grams (0.171mol) of sodium bisulfite, continue to stir for 1 hour, carefully add 300ml of 10% potassium carbonate aqueous solution, separate the liquids, and wash the organic phase once with 300ml of 10% potassium carbonate aqueous solution, and then use Wash with saturated brine (300ml×3), and dry over anhydrous sodium sulfate. After filtering and evaporating the solvent to dryness, the obtained crude product was subjected to column chromatography (eluent: n-hexane:ethyl acetate=30:1), and 34 g of the product was obtained (yie...

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Abstract

Compound 3 is dissolved in dry pyridine, reacting with 4,4-dimethoxy trityl chloride to obtain compound 9. Said compound 9 is then removed its hydrogen chloride by reacting with 5-butanol potassium to obtain compound 10, then reacting with m-chloro peroxy benzoic acid to obtain compound 11. Compound 11 and compound 12 have obvious different of Rf values on silca-gel plate, so they are separated by silica column. Compound 11 and compound 12 have obvious difference of Rf values on silia-gel plate, so they are separated by silica column. Compound 11 and compound 12 react with alkali base respectively to obtain compound 13 or compound 15, then being reacted with acetic acid to remove its 4,4-dimethoxy triphenmethyl to obtain final invented products: compound 1, compound 2, compound 14 or compound 16. advantages are: simple operation, single raw material more kinds of final products, with spectrum anti-virus activity.

Description

technical field [0001] The present invention provides a new synthetic method for synthesizing compounds 1 and 2 and their analogues with broad-spectrum antiviral activity. technical background [0002] The Slasarchyk group reported in 1992 that compounds 1 and 2 had broad-spectrum antiviral effects against hepatitis viruses (HSV-1, HSV-2), varicella herpes virus (VZV), and human cytomegalovirus (HCMV). Very good inhibitory effect (US, Patent, 4918075, 1990; J. Med. Chem., 1992, 35, 1799-1802). They reported their synthesis method as early as 1989 (Schemel, Tetrahed. Lett., 1989, 50, 6955-6958). In this synthetic route, the key intermediate 6 cannot be separated from its isomer 7 by an ordinary silica gel column, and must be separated by a preparative HPLC column, which makes the synthesis cost extremely expensive and cannot be prepared on a large scale. [0003] [0004] The Baschang group improved this route (Scheme 2, Tetrahedron: Asymmetry, 1992, 193-196). They used ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/00C07D473/18C07D239/46A61P31/12
CPCY02P20/55
Inventor 蒋昌盛何皓徐亮林国强
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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