Preparation method of remdesivir intermediate 2-ethyl-1-butanol

A technology for remdesivir and intermediates, which is applied in the field of preparation of remdesivir intermediate remdesivir intermediate 2-ethyl-1-butanol, can solve the problem that there is no effective method for compounds and is not suitable for industrial production , the reaction conditions are difficult to control and other problems, to achieve the effect of convenient access, promotion of development, and simple raw materials

Active Publication Date: 2020-07-31
苏州特瑞药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Recently, there have also been reports on the preparation of target compounds by high temperature and high pressure polymerization between carbon monoxide and methanol, formaldehyde and 2-pentanol, etc., but this method has more complex components, difficult control of reaction conditions, and difficult separation of products Industrial production
[0007] It can be seen from this that the structure of 2-ethyl-1-butanol does not seem to be complicated, but there are currently no more effective methods for preparing this compound

Method used

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  • Preparation method of remdesivir intermediate 2-ethyl-1-butanol
  • Preparation method of remdesivir intermediate 2-ethyl-1-butanol
  • Preparation method of remdesivir intermediate 2-ethyl-1-butanol

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Under a nitrogen atmosphere, add methyl acetoacetate (II) (11.6g, 100mmol) and 80mL of dry methanol to a dry reaction flask, cool down to -10°C, and slowly add 80mL of a methanol solution of sodium methoxide (8.1g, 150mmol) dropwise . After the dropwise addition was completed, ethyl iodide (18.7 g, 120 mmol) was added at -5-5°C and stirred for 2 hours. Raise the temperature to 5-10°C, and continue stirring for 3-4 hours. The reaction was quenched with 25 mL of saturated ammonium chloride, extracted three times with dichloromethane, the organic phases were combined, washed successively with 5% sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. Concentration gave 13.4 g of light yellow liquid 2-ethyl-3-oxo-butyric acid methyl ester (III), yield 93.1%, EI-MS m / z: 145[M+H] + .

Embodiment 2

[0048] Under nitrogen atmosphere and at -5~0°C, add 2-ethyl-3-oxo-butyric acid methyl ester (III) (7.2g, 50mmol), sodium hydride (1.32g, 55mmol) and Solvent hexamethylphosphoric triamide (HMPA) 100mL. After rising to room temperature and stirring for 1 hour, chloromethyl methyl ether (4.4 g, 55 mmol) was added, and stirring was continued at room temperature for 2 to 3 hours. The reaction was quenched with saturated sodium bicarbonate solution under ice-cooling, and extracted three times with ether, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was transferred to a dry reaction flask, and 200 mL of diethyl ether was added to dissolve it. Under a nitrogen atmosphere, add a liquid ammonia solution containing lithium (0.35g, 50mmol), keep the reaction temperature at -35~-25°C and stir the reaction for 1 hour, slowly rise to room temperature, quench the reaction with saturated ammoni...

Embodiment 3

[0050] In a dry three-necked reaction flask under a nitrogen atmosphere, lithium aluminum hydride (3.8 g, 100 mmol) and ether 100 mL were added. The temperature was lowered to -5-0°C, and a diethyl ether solution of methyl 2-ethylbutyrate (IV) (13.0 g, 100 mmol) was added dropwise with stirring, and the addition was completed in about 1 hour. Continue the reaction at 0-5°C for 2 hours, quench the reaction with saturated ammonium chloride aqueous solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 2-Ethyl-1-butanol (I) 9.1g, yield 89.2%, EI-MS m / z: 103[M+H] + .

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Abstract

The invention relates to a preparation method of a remdesivir intermediate 2-ethyl-1-butanol. The preparation method comprises a step of substitution reaction, namely a step of carrying out a substitution reaction on alkyl acetoacetate and halogenated ethane under an alkaline condition to obtain alkyl 2-ethyl-3-oxo-butyrate; a step of addition reduction, namely a step of carrying out an addition reduction reaction on the alkyl 2-ethyl-3-oxo-butyate to obtain alkyl 2-ethylbutyrate; a step of reduction, namely a step of subjecting the alkyl 2-ethylbutyrate to a reduction reaction to prepare 2-ethyl-1-butanol (I). According to the preparation method of the remdesivir intermediate 2-ethyl-1-butanol, the alkyl acetoacetate and halogenated ethane serve as main raw materials, the raw materials are simple and easy to obtain, the 2-ethyl-1-butanol (I) is prepared through substitution reaction, addition reduction and reduction reaction, the process is simple, economical and environmentally friendly, the product is convenient to obtain, and industrial production of remdesivir bulk drugs is facilitated.

Description

technical field [0001] The present invention relates to a preparation method of an intermediate, in particular to a preparation method of a remdesivir intermediate remdesivir intermediate 2-ethyl-1-butanol. Background technique [0002] Remdesivir is a nucleotide analog prodrug developed by Gilead that inhibits RNA-dependent RNA synthetase. According to Gilead's report, the drug has not been approved for marketing in any country, and its safety and effectiveness have not been confirmed. However, in vitro and in animal models, Remdesivir has demonstrated activity against viral pathogens of atypical pneumonia (SARS) and Middle East Respiratory Syndrome (MERS), which are also coronaviruses and are related to 2019-nCoV are very similar in structure. At present, Gilead is advancing the use of 2019-nCoV virus samples to conduct appropriate laboratory tests on Remdesivir, and then carry out corresponding clinical research. [0003] The structural formula of Remdesivir is: [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C31/125C07C29/147
CPCC07C29/147C07C67/317C07C67/343C07C31/125C07C69/24C07C69/72
Inventor 许学农赵德成包志坚王喆苏健顾新禹薛佳
Owner 苏州特瑞药业股份有限公司
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