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New synthetic method for 6-benzyl-1-ethoxymethyl-5-isopropyluracil (Emivirine) and analogues thereof

A methyl, C1-C4 technology, applied in the field of preparation of pharmaceutical active ingredients, can solve the problems of high toxicity, etc., and achieve the effect of simple operation and easy mass production

Inactive Publication Date: 2013-01-02
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the Grignard reaction, transition elements and monovalent copper salts are used as catalysts, which are more poisonous

Method used

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  • New synthetic method for 6-benzyl-1-ethoxymethyl-5-isopropyluracil (Emivirine) and analogues thereof
  • New synthetic method for 6-benzyl-1-ethoxymethyl-5-isopropyluracil (Emivirine) and analogues thereof
  • New synthetic method for 6-benzyl-1-ethoxymethyl-5-isopropyluracil (Emivirine) and analogues thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1 Preparation of 3-oxo-4-phenylbutyric acid ethyl ester (compound of formula I)

[0031]Cycloisopropyl malonate (23.75g, 0.165mol) and anhydrous pyridine (32.5mL, 0.4mol) were dissolved in 100mL of dichloromethane, and then slowly dropped into phenylacetyl chloride (25.50g, 0.165mol ), continue to react at 0°C for 1 hour, and react at room temperature for 1 hour. The reaction solution was diluted with 50 mL of dichloromethane and 100 mL of 2N hydrochloric acid was added, the organic phase was separated, the aqueous layer was extracted twice with dichloromethane (50 mL), the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain a light orange solid. Rinse with a small amount of ethanol to obtain white crystals. After suction filtration, directly reflux in 250 mL of absolute ethanol for 2.5 hours. After evaporating the solvent under reduced pressure, a light yellow liquid is obtained, which can be used in the next reac...

Embodiment 2

[0034] Example 2 Preparation of ethyl 3-oxo-4-cyclohexylbutanoate (compound of formula I)

[0035] Cycloisopropyl malonate (23.75g, 0.165mol) and anhydrous pyridine (32.5mL, 0.4mol) were dissolved in 100mL of dichloromethane, and then cyclohexylacetyl chloride (26.40g, 0.165 mol), continue to react at 0°C for 1 hour, and react at room temperature for 1 hour. The reaction solution was diluted with 50 mL of dichloromethane, and 100 mL of 2N hydrochloric acid was added, the organic phase was separated, the aqueous layer was extracted twice with dichloromethane (50 mL), the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain a light orange solid. After suction filtration, directly reflux in 250 mL of absolute ethanol for 2.5 hours, evaporate the solvent under reduced pressure to obtain a light yellow liquid, which can be used in the next reaction without purification. Purification by silica gel column chromatography (50:1 petroleum ether / ...

Embodiment 3

[0038] Example 3 Preparation of ethyl 2-isopropyl-3-oxo-4-phenylbutyrate (compound of formula II)

[0039] Ethyl 3-oxo-4-phenylbutyrate (16.5g, 0.080mol), 2-bromopropane (11.8g, 0.096mol), anhydrous potassium carbonate (26.2g, 0.24mol) and dry DMF (25mL ) were mixed and stirred at room temperature for 12 hours. Add ethyl acetate (50 mL) to dilute, wash with water, wash with saturated brine, and dry over sodium sulfate. The solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (80:1 petroleum ether / ethyl acetate) to obtain 14.2 g of light yellow liquid with a yield of 71.3%.

[0040] ESI-MS: m / z=249.1[M+H] +

[0041] 1 H NMR (300MHz, CDCl 3 )δ: 7.38~7.22 (5H, m, ArH), 5.07 (1H, s, COCHCO), 4.42~4.36 (1H, m, CHMe 2 ), 4.21~4.16 (2H, q, OCH 2 CH 3 ), 4.11 (2H, s, CH 2 Ph), 1.32~1.29 (3H, t, OCH 2 CH 3 )1.26~1.24 (6H, d, CHMe 2 ).

[0042] 13 C NMR (75MHz, CDCl 3 )δ: 172.01 (C-3), 167.84 (C-1), 138.14, 129.18, 128.14, 126...

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Abstract

The invention relates to a new synthetic method for a compound which is represented by the general formula (IV), n thereof is 1, 2 or 3, R1 is selected from phenyl, naphthyl, cyclopentyl and cyclohexyl, R2 is selected from C1 to C4 alkyl, vinyl and formoxyl, and R3 is selected from methyl, vinyl, cyclohexyl and phenyl. The invention provides the new synthetic method which treats isopropyl cyclomalonate as a raw material. The method has the advantages of easily obtained raw materials and reagents and simple operation, and allows multi sites to be reconstructed simultaneously and easily, a large selection space in new drug molecule designation to be achieved and the officinal possibility of such compound to be increased.

Description

Technical field: [0001] The present invention relates to a kind of preparation method of active ingredient of medicine, more specifically a kind of compound 6-benzyl-1-ethoxymethyl-5 isopropyluracil (Emivirine) with anti-HIV-1 type AIDS activity and preparation methods of analogues thereof. Background technique: [0002] Emivirine is a non-nucleoside reverse transcriptase inhibitor, which produces non-competitive inhibition with the reverse transcriptase of HIV-1 virus and has potent anti-HIV activity in vitro. It is compatible with AZT (zidovudine), d4T (stata Vudine) and 3TC (lamivudine) and many other major anti-HIV-1 drugs can produce a synergistic effect in combination, and there is no cross-resistance with nucleoside reverse transcriptase inhibitors. Virus strains resistant to AZT and 3TC can still fully maintain the sensitivity to the drug. The drug has excellent preclinical toxicological properties. Animal test results show that the drug does not produce long-term...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/54
Inventor 李立高宇王孝伟刘俊义
Owner PEKING UNIV