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Method for preparation of antiviral composition and application of intermediate thereof

A technology for intermediates and compounds is applied in the application field of preparing antiviral compositions and intermediates thereof, and can solve the problems of poor selectivity, large reaction volume ratio, and high cost of triphenylphosphine

Inactive Publication Date: 2012-05-09
康卓维尔制药公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the cost of resin-bound triphenylphosphine is high and the reaction volume ratio is large
Therefore, this preparation method is not suitable for scale-up production
In addition, due to the poor selectivity for primary and secondary hydroxyl groups, the by-product of double valine substitution was significantly present, in this case, purification by column chromatography was required to obtain sufficiently pure compound FV100

Method used

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  • Method for preparation of antiviral composition and application of intermediate thereof
  • Method for preparation of antiviral composition and application of intermediate thereof
  • Method for preparation of antiviral composition and application of intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0256] 3-((2R,4S,5R)-5-(triphenylmethoxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)-6-(4-pentylphenyl)furan[2 ,3-d]pyrimidin-2(3H)-one

[0257]

[0258] 500 grams (1.25 moles) of 3- ((2R, 4S, 5R) -(4-Hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-6-(4-pentylphenyl)furan[2,3-d]pyrimidin-2(3H)-one and 2500 Milliliters of pyridine was added to a 5-liter three-necked flask. The mixture was stirred, and 508 g (1.5 mmol) of trityl chloride dissolved in 120 ml of dichloromethane solution was added dropwise thereto at room temperature. After completion of the dropwise addition, the mixture was stirred at room temperature for 3-5 hours. The reaction was then quenched with 50 mL of water. The reaction solution was concentrated to dryness. The residue was dried three times with 500 ml of toluene. The residue was redissolved in 5000 ml of dichloromethane. The organic solution was washed three times with 2500 ml of concentrated brine. The organic layer was dried with 273 g of anhydrous...

Embodiment 2

[0260] 3-((2R,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)-6- Preparation of (4-pentylphenyl)furan[2,3-d]pyrimidin-2(3H)-one

[0261]

[0262] Add 2.8 kg (7.03 moles) of 3-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-6-(4-pentane) to a 50-liter reactor Phenyl)furan [2,3-d]pyrimidin-2(3H)-one, 2.8 kg (35.4 moles) of pyridine and 22.4 kg of methylene chloride. 2.86 kg (8.44 mol) of 4,4'-dimethoxytrityl chloride (DMT-Cl) was dissolved in 14.9 kg of dichloromethane and dropped into the above mixture while stirring at room temperature. After dripping, the mixture was stirred at room temperature for 0.5 hour. The reaction solution was filtered and the filter cake was washed with 2.5 kg of dichloromethane. The filtrate was washed with 28 kg of 5% sodium bicarbonate aqueous solution. The aqueous layer was extracted with 3.7 kg of dichloromethane. The organic layers were combined and washed with brine. The organic layer was...

Embodiment 3

[0266] 3-((2R,4S,5R)-(5-((tert-butyldimethylsiloxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)-6-(4-pentylphenyl ) Preparation of furan[2,3-d]pyrimidin-2(3H)-one

[0267]

[0268] Add 398 mg (1.0 mmol) of 3- ((2R, 4S, 5R) (4-Hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-6-(4-pentylphenyl)furan[2,3-d]pyrimidin-2(3H)-one, 450 mg (3.0 mmol) tert-butyldimethylchlorosilane, 204 mg (3.0 mmol) imidazole, and 5 mL dimethylformamide (DMF). The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography (TLC).

[0269] TLC: eluent: petroleum ether / ethyl acetate=1:1;

[0270] 3-((2R,4S,5R)-(4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-6-(4-pentylphenyl)furan[2,3-d]pyrimidine -2(3H)-ketone:

[0271] R f =0;

[0272] 3-((2R,4S,5R)-(5-((tert-butyldimethylsiloxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)-6-(4-pentylphenyl )Furan[2,3-d]pyrimidin-2(3H)-one:

[0273] R f =0.25

[0274] Pour the mixture into water. Extract with ethyl acetate. The organic ...

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Abstract

The invention relates to a method for synthesis of a bicyclic nucleoside antiviral compound and a method for synthesis of an intermediate used in the method. The invention also relates to a novel intermediate compound used in the method. The antiviral compound can be effectively used in treatment of herpes zoster (i.e. varicella zoster virus VZV and herpes zoster shingles) or in prevention of postherpetic neuralgia (PHN) caused by the virus.

Description

Technical field [0001] The present invention relates to the preparation of synthetic active pharmaceutical ingredient FV100, (R)-((2R,3S,5R)-(3-hydroxy-5-(2-oxo-6-(4-pentylphenyl)furan [2, 3-d]pyrimidine-3(2H)-yl)-tetrahydrofuran-2-yl)methyl 2-amino-3-methylbutyl ester hydrochloride, a method of bicyclic nucleoside compounds, this compound can Effective for the treatment of herpes zoster (ie varicella-zoster virus, VZV, shingles), and for the prevention of herpes zoster neuralgia (PHN) caused by this virus infection The invention also relates to a novel compound that can be used as an intermediate in the preparation process of the active drug molecule. Background technique [0002] Herpes zoster, also called shingles, is caused by the resurrection of the virus that causes chickenpox (varicella zoster virus). The virus can spread from one or more ganglia along the infected part, infect the corresponding dermatome (the area of ​​the skin innervated by the spinal segmental nerves)...

Claims

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Application Information

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IPC IPC(8): C07H19/24C07H1/00
CPCY02P20/55
Inventor 王延龄何训贵刘传军李杰王元
Owner 康卓维尔制药公司
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