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Preparation and medicine purpose of nucleoside alkoxide benzyl phosphoramidic acid/phosphonate derivative

A technology of alkoxybenzyl phosphoramidate and phosphonate, which is applied in the field of medicine and can solve problems such as the inability to use antiviral drugs

Inactive Publication Date: 2017-10-24
刘沛
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Nucleoside triphosphate itself has multiple negative charges and very high polarity, so it is difficult to pass through the cell wall and enter the interior of the cell, so it cannot be used directly as an antiviral drug

Method used

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  • Preparation and medicine purpose of nucleoside alkoxide benzyl phosphoramidic acid/phosphonate derivative
  • Preparation and medicine purpose of nucleoside alkoxide benzyl phosphoramidic acid/phosphonate derivative
  • Preparation and medicine purpose of nucleoside alkoxide benzyl phosphoramidic acid/phosphonate derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088]

[0089] Compound 1 (12.8g, 50mmol) was dissolved in dichloromethane (100mL) and cooled to -78°C, and 2-acetoxybenzyl alcohol (8.3g, 50mmol) and triethylamine ( 7.7 mL, 55 mmol) in dichloromethane (100 mL). The reaction solution was stirred at -78°C for 30 minutes, then warmed up to 0°C, and a solution of dry D-alanine isopropyl ester hydrochloride (7.68g, 50mmol) in dichloromethane (100mL) was slowly added, followed by the above Triethylamine (14.7 mL, 105 mmol) was slowly added dropwise into the reaction solution, and the dropwise addition was completed in 90 minutes, and the reaction solution was continuously stirred at zero temperature for 3 hours. The solvent was removed by rotary evaporation, ethyl acetate was added to grind powder, filtered, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:3) to obtain a colorless oily product 3 (17.7g, 84%), can slowly solidify a...

Embodiment 2

[0091]

[0092] benzyl alcohol 4 (152mg, 1mmol) and POCl3 (95μL, 1mmol) in anhydrous ether (5mL) was cooled to -78°C, triethylamine (140μL, 1mmol) was slowly added dropwise, and stirring was continued for 2 hours after the addition was complete. Add L-alanine isopropyl ester hydrochloride (168mg, 1mmol) and triethylamine (280μL, 2mmol) in dichloromethane (1mL) dropwise to the reaction solution at -78°C, and react for 60 minutes The temperature of the reaction solution was slowly raised to 0°C over 1.5 hours.

[0093] A solution of pentafluorophenol (184 mg, 1 mmol) in dichloromethane (1 mL) was added to the reaction vial, followed by slowly adding triethylamine (140 μL, 1 mmol) dropwise within 1 hour, and the reaction solution was slowly raised to room temperature and stirred overnight. Remove triethylamine hydrochloride by filtration, wash the filter cake with a small amount of dichloromethane, wash the combined organic phase with water and dry (Na2SO4), concentrate the r...

Embodiment 3

[0097]

[0098] Adopt the synthetic method identical with embodiment 2, by benzyl alcohol 6 Prepared compound 7 , 7a and 7b . mixed product 7 : 1HNMR (CDCl3, 400MHz) δ7.01-7.31 (m, 3H), 5.03-5.09 (m, 1H), 4.72 (s, 1H), 4.64 (s, 1H), 4.02-4.08 (m, 1H), 3.84-3.91(m, 1H), 2.33(s, 1.5H), 2.30(s, 1.5H), 1.36-1.46(m, 3H), 1.22-1.34(m, 6H); MS(m / z) 516 (M+H).

[0099] 7a : 1H NMR (CDCl3, 400MHz) δ7.01-7.28 (m, 3H), 5.03-5.09 (m, 1H), 4.64 (s, 2H), 4.02-4.08 (m, 1H), 3.84-3.90 (m, 1H), 2.30 (s, 3H), 1.41-1.46 (m, 3H), 1.24-1.28 (m, 6H); MS (m / z) 516 (M+H).

[0100] 7b : 1H NMR (CDCl3, 400MHz) δ7.10-7.32 (m, 3H), 5.06-5.12 (m, 1H), 4.71 (s, 2H), 4.07-4.11 (m, 1H), 3.77-3.81 (M, 1H), 2.33 (s, 3H), 1.45-1.49 (m, 3H), 1.24-1.30 (m, 6H); MS (m / z) 516 (M+H).

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Abstract

The invention relates to a preparation method and a purpose of a novel nucleoside phosphoramidic acid / phosphonate prodrug simultaneously formed by alkoxide benzyl alcohol and D or L-amino-acid ester. The novel nucleoside phosphoramidic acid / phosphonate prodrug containing alkoxide benzyl is a compound shown by the formula (I) or an isomer or a medicinal salt of the compound. The compound can be used as prodrug of various nucleoside analogs such as acyclic nucleoside, carbocyclic nucleoside and furan ring nucleoside; the bioactivity of the nucleoside compounds are enhanced, so that the application of the compound in the fields of virus infection and cancer treatment is optimized. The formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a novel nucleoside phosphoramidate / phosphonate prodrug composed of D- or L-amino acid ester and alkoxy-substituted benzyl alcohol, as well as its preparation method and application. Background of the invention [0002] Nucleoside compounds are deoxyribonucleic acid and ribonucleic acid, that is, the structural monomers of biological genetic genes DNA and RNA. They have important functions in all living organisms and are widely used in the treatment of viral infections and cancer. Since the 1960s, many biologically active nucleoside analogs have been used to treat various viral infections such as herpes, AIDS, and hepatitis B and C. These artificially synthesized nucleoside analogs can block the growth of viral nucleic acid chains, destroy the replication of viral genes, and become antiviral drugs ( figure 1 ). [0003] Such as figure 1 As shown, nucleosides must fi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/24C07F9/6558C07F9/6561C07H1/00C07H19/10C07H19/12A61K31/675A61K31/7076A61K31/7072A61K31/706A61K31/7068A61P31/18A61P31/14A61P31/20A61P35/00
CPCC07B2200/05C07F9/2429C07F9/2458C07F9/65586C07F9/65616C07H1/00C07H19/10C07H19/12Y02A50/30
Inventor 刘沛
Owner 刘沛
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