Method for synthesizing Vibativ intermediate

A synthesis method and telavancin technology, applied in the field of medicine, can solve problems such as high cost, and achieve the effects of reduced synthesis cost, less side reactions, and easy control of reaction conditions

Inactive Publication Date: 2020-06-05
福建康鸿生物科技有限公司
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  • Claims
  • Application Information

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Problems solved by technology

[0005] Another researcher, Cao Shenghua et al., used decylamine and aminoacetaldehyde dimethyl acetal as starting materials, and obtained N-(9-fluorenylmethoxycarbonyl)decylaminoethyl through reductive amin

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  • Method for synthesizing Vibativ intermediate

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[0026] Such as figure 1 Shown, a kind of telavancin intermediate synthetic method of the present embodiment, the purpose is to provide the method for synthesizing telavancin intermediate N-(9-fluorenylmethoxycarbonyl) decyl amino acetaldehyde: with n-decyl Alcohol and aminoethanol are starting materials, through condensation, Fmoc-Cl amino protection, oxidation to obtain N-(9-fluorenylmethoxycarbonyl)decylaminoacetaldehyde, the present invention selects 2,2,6,6-tetra Methyl piperidine oxide (TEMPO) is an oxidizing agent, the reaction temperature is below 0°C, and dichloromethane is a solvent to selectively control the oxidation of primary alcohols into aldehydes, including the following steps:

[0027] (1) At room temperature, dissolve n-decyl alcohol with dichloromethane, add organic base 1, add dropwise methanesulfonyl chloride, and react for 12 hours;

[0028] (2) adding the reaction solution after reacting for 12 hours into ice water, layering, and concentrating to obtain...

Embodiment 1

[0039] The synthesis of embodiment 1N-n-decylaminoethanol:

[0040] Take 8g (50mmol) of n-decyl alcohol and add it to a three-necked flask, stir and dilute with 25ml of dichloromethane, add 4g (59mmol) of triethylamine, control the reaction temperature at 0°C, add 8g (70mmol) of methanesulfonyl chloride dropwise, and the dropwise addition is completed. Warm up to room temperature and react for 12h. TLC (iodine fumigation) detected the completion of the reaction, added ice water, separated layers, collected the organic layer, dried over sodium sulfate, and concentrated to obtain concentrated solution 1, which can be carried out in the next step without purification. Concentrate 1 was dissolved in 30ml of absolute ethanol, transferred to a three-necked flask, added with 30g (0.5mol) of aminoethanol, slowly raised to 90°C, and reacted for 12h. Add 100ml dichloromethane and 100ml water, separate layers, the organic layer is dried over sodium sulfate, concentrates, obtains concent...

Embodiment 2

[0041] The synthesis of embodiment 2N-n-decylaminoethanol:

[0042] Take 8g (50mmol) of n-decyl alcohol and add it to a three-necked flask, stir and dilute with 25ml of dichloromethane, add 4g (59mmol) of triethylamine, control the reaction temperature at 0°C, add 8g (70mmol) of methanesulfonyl chloride dropwise, and the dropwise addition is completed. Warm up to room temperature and react for 12h. TLC (iodine fumigation) detected the completion of the reaction, added ice water, separated layers, collected the organic layer, dried over sodium sulfate, and concentrated to obtain concentrated solution 1, which can be carried out in the next step without purification. Concentrate 1 was dissolved in 30ml of absolute ethanol, transferred to a three-necked flask, 60g (1mol) of aminoethanol was added, the temperature was slowly raised to 90°C, and reacted for 12h. Add 100ml dichloromethane and 100ml water, layering is difficult, do not carry out next step reaction.

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Abstract

The invention discloses a method for synthesizing a Vibativ intermediate. The method comprises the following steps: taking n-decanol and aminoethanol as starting materials, carrying out condensation and Fmoc-Cl amino protection, and performing oxidation to obtain N-(9-fluorenylmethoxycarbonyl)decylaminoacetaldehyde. 2, 2, 6, 6-tetramethylpiperidine oxide (TEMPO) is used as an oxidizing agent, a reaction temperature is below 0 DEG C, dichloromethane is used as a solvent, the primary alcohol is selectively controlled to be oxidized into aldehyde, materials involved in synthesis are low in price,the synthesis cost is greatly reduced, the synthesis yield is high, side reactions are few, all synthesis steps are easy to operate, follow-up treatment is simple and environmentally friendly, TEMPOoxidation conditions are mild, the pH value and the reaction temperature of a reaction liquid are controlled, aldehyde is obtained by selective oxidation, the reaction conditions are easy to control,and follow-up treatment is simple.

Description

Technical field: [0001] The invention belongs to the technical field of medicines, in particular to a method for synthesizing telavancin intermediates. Background technique: [0002] Telavancin is a new type of lipoglycopeptide antibiotic, a new drug jointly developed by Theravance of the United States and Astellas of Japan. In 2009, the US FDA approved it for the treatment of skin infections caused by Gram-positive bacteria, and in 2011, the EMA approved it for the treatment of adult hospital-acquired pneumonia caused by MRSA. Telavancin is more active than vancomycin on MRSA, MRSE, etc., and has a longer half-life than vancomycin, and it is clinically administered once a day. The abuse of antibiotics by humans leads to the emergence of superbugs, which are multi-drug resistant bacteria. Antibiotics on the market have no therapeutic effect on superbugs, but telavancin has anti-drug resistance and has been used for infections caused by sensitive bacteria for a long time. T...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/18
CPCC07C213/08C07C269/04C07C269/06C07C303/28C07C2603/18C07C309/66C07C215/08C07C271/16C07C271/18
Inventor 张茂华蒋永飞苏专专孙万树詹立都
Owner 福建康鸿生物科技有限公司
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