Structure and synthesis of novel benzyl amido phosphate prodrug of nucleoside compound

A technology of benzyl phosphoramidate and compounds, applied in the fields of compounds of elements of group 5/15 of the periodic table, organic chemistry, antineoplastic drugs, etc., which can solve the problems of carcinogenic toxicity and lower bioavailability

Active Publication Date: 2012-07-04
刘沛
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the phenols produced by the metabolism of McGuigan prodrugs have potential carcinogenic toxicity, and their li...

Method used

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  • Structure and synthesis of novel benzyl amido phosphate prodrug of nucleoside compound
  • Structure and synthesis of novel benzyl amido phosphate prodrug of nucleoside compound
  • Structure and synthesis of novel benzyl amido phosphate prodrug of nucleoside compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062]

[0063] A solution of 30 mmoles of appropriately substituted benzyl alcohol and triethylamine (4.25 mL, 30.5 mmol) in dry benzene (125 mL) was slowly added dropwise to freshly distilled phosphorus oxychloride (10 mL, 107 mmol) at 0-10 °C In dry benzene (50 mL), the reaction solution was slowly warmed up and stirred at room temperature overnight. The reaction mixture was filtered under dry conditions, and the filtrate was concentrated to give substituted benzyl phosphoryl dichloride (12).

Embodiment 2

[0065]

[0066] Dissolve substituted benzylphosphoryl dichloride (12) (4mmol) and appropriately substituted benzylamine (13, 4mmol) into dry dichloromethane (50mL), slowly add three Ethylamine (0.6 mL, 4.3 mmol) in dichloromethane (10 mL). The reaction solution was stirred and reacted at room temperature for 5 hours, the solvent was evaporated, dry diethyl ether (25 mL) was added to the residue, filtered under nitrogen protection, and the N, O-disubstituted benzylphosphoryl chloride (14) obtained after the filtrate was concentrated could be directly For the next reaction without purification.

[0067] The obtained N,O-disubstituted benzyl phosphoryl chloride (14) can also be dissolved in dry tetrahydrofuran (4 mL) to prepare a 1 mol / L solution for use.

Embodiment 3

[0069]

[0070] At room temperature, N-methylimidazole (410 mg, 5 mmol) was slowly added dropwise to a suspension of uracil (244 mg, 1 mmol) in anhydrous THF (5 mL), and stirred at room temperature for 30 minutes. Then, a solution of N, O-dibenzylphosphoryl chloride (14b, 618 mg, 2 mmol) in THF (2 mL) was slowly added to the above reaction mixture, and the reaction was stirred overnight at room temperature. The reaction solution was concentrated by rotary evaporation, the residue was dissolved in chloroform (10 mL), the organic phase was washed with dilute hydrochloric acid (1M, 10 mL), saturated sodium bicarbonate (10 mL), water (15 mL), and dried (Na 2 SO 4 ), concentrated, and the synthesized uracil benzyl phosphoramidate was purified by silica gel column chromatography (dichloromethane:methanol=10:1). MS(m / e)518(M+H). 1 H NMR (CD 3 OD, 400MHz) δ7.66(d, J=6.8Hz, 0.5H), 7.58(d, J=8.4Hz, 0.5H), 6.98-7.32(m, 9H), 5.72(d, J=5.6Hz, 0.5H), 5.70(d, J=5.2Hz, 0.5H), 5.47(, d,...

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Abstract

The invention discloses a novel benzyl amido phosphate structure shown as a formula (I). The novel benzyl amido phosphate ester structure can be taken as a prodrug of various nucleoside compounds (including acyclic nucleoside, carbocycle nucleoside, furan ring nucleoside and the like) for enhancing the bioactivity of the nucleoside compounds, so that the novel benzyl amido phosphate ester structure is applied to treatment of virus infection and cancers.

Description

[0001] Rights request [0002] 1. a novel benzyl phosphoramidate prodrug of nucleoside compound, it is characterized in that following molecular structure: [0003] [0004] Among them, the phosphoramidate functional group contains [0005] A phosphoester bond formed by a suitably substituted benzyl alcohol; a phosphoramide bond formed by a suitably substituted benzylamino or α-amino acid ester; a nucleoside (including acyclic nucleoside, carbocyclic nucleoside, and The 5'-hydroxyl of the furan ring nucleoside, etc.) participates in the phosphoester bond formed. [0006] 2. benzyl phosphoramidate derivatives as claimed in claim 1, [0007] R 1 with R 2 Each independently, can be hydrogen, halogen, carbonyl, carboxyl, nitro, ester, amido, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxyl, C 1 -C 8 Amino group, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 2 -C 8 the acyl group. [0008] R 3 , R 4 , R 5 is hydrogen, halogen, benzene ring or C 1 -C 4 of alkyl. [0009] R 6 is ben...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K47/48A61K31/7076A61P31/12A61P35/00A61K47/54
Inventor 刘沛
Owner 刘沛
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