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Preparation method of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one as meropenem intermediate

A technology of chloropropionylspirobenzoxazine and meropenem, which is applied in the field of drug synthesis, can solve the problems of low yield and purity of bromopropionylspirobenzoxazine cyclohexane, high price, complicated production process, etc. Achieve the effects of cheap and easy-to-obtain raw materials and catalysts, suitable for industrial production, and increased reaction yield

Active Publication Date: 2017-02-22
XINXIANG HAIBIN PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The bromopropionylspirobenzoxazine cyclohexane yield and purity that this method makes are lower, simultaneously, need to adopt the magnetic solid base catalyst with complex production process and expensive price in the preparation, complex reaction process, reaction dangerous system High, complex post-processing, serious environmental pollution, high cost

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  • Preparation method of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one as meropenem intermediate
  • Preparation method of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one as meropenem intermediate
  • Preparation method of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one as meropenem intermediate

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preparation example Construction

[0020] The invention provides a method for preparing meropenem intermediate chloropropionylspirobenzoxazine cyclohexane, comprising the following steps:

[0021] Spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one and α-chloropropionyl chloride were mixed in an aprotic solvent under the action of an acid-binding agent Condensation reaction was carried out to obtain chloropropionyl spirobenzoxazine cyclohexane.

[0022] Preferably, specifically: in the presence of protective gas, spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, α- Chloropropionyl chloride, acid binding agent and aprotic solvent are mixed for condensation reaction to obtain chloropropionyl spirobenzoxazine cyclohexane.

[0023] The present invention has no special limitation on the protective gas, and the protective gas well-known to those skilled in the art can be used. Nitrogen is preferably used in the present invention.

[0024] The spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-...

Embodiment 1

[0047] According to the molar ratio of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, α-chloropropionyl chloride and triethylamine is 1:1.4 : 1.2, respectively weigh 80g of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, 65g of α-chloropropionyl chloride and 45g triethylamine; according to the mass ratio of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one to toluene as 1:3.1, weigh 250g toluene; according to the mass ratio of [2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one to isopropanol is 1:1, weigh 80g isopropanol.

[0048] Under nitrogen protection, toluene, spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, α-chloropropionyl chloride and triethylamine Put it into a four-neck flask for reaction, the reaction temperature is 80°C, and the reaction time is 5h. After the reaction, cool down to room temperature, wash three times with 200g water, three times with 200g 8% sodium hydroxide solution, three times with 200g wa...

Embodiment 2

[0050] According to the molar ratio of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, α-chloropropionyl chloride and 4-dimethylaminopyridine is 1:1.5:0.8, weigh 80g of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one and 70g of α-chloropropane Acyl chloride and 38g of 4-dimethylaminopyridine; according to the mass ratio of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one to xylene 1:3.7, weigh 300g xylene; according to the mass ratio of [2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one and n-butanol 1:1, weigh 80g of n-butanol.

[0051] Under nitrogen protection, xylene, spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, α-chloropropionyl chloride and 4- Dimethylaminopyridine was added into a four-necked flask for reaction, the reaction temperature was 90° C., and the reaction time was 4.5 hours. After the reaction was completed, it was lowered to room temperature, washed three times with 200 g of water, three times with 25...

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Abstract

The invention provides a preparation method of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one as a meropenem intermediate. According to the preparation method, alpha-chloropropionyl chloride with lower reaction activity is adopted and cooperates with specific raw materials to play a role together, so that the reaction yield is greatly increased instead of being reduced; meanwhile, due to the lower activity of alpha-chloropropionyl chloride, fewer side reactions participate in the reaction, an obtained product contains fewer impurities, and 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one with higher yield and purity is obtained and can replace 3-(2-bromo-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one for preparing meropenem. Besides, a synthetic process of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one requires no magnetic solid base catalysts, so that the reaction conditions are safer, the reaction path is simple, aftertreatment is convenient, the raw materials and the catalyst are inexpensive and available, and the preparation method is safe, environment-friendly, lower in preparation cost and more suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of chlorpropionylspirobenzoxazine cyclohexane, an intermediate of meropenem. Background technique [0002] Meropenem, also known as Meropenem, English name: Meropenem, chemical name: (4R,5S,6S)-3-[[(3S,5S)-5-(dimethylcarbamoyl)-3-pyrrole Alkyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-nitrobicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate , was first developed by Dainippon Sumitomo Pharma and AstraZeneca, and was first listed in Italy in 1995, and then gradually applied to the market around the world, with broad market prospects. As a second-generation carbapenem antibiotic, compared with other similar antibiotics, it has the advantages of broad antibacterial spectrum, strong antibacterial effect, and stability to DHP-1 enzyme. It is mainly used for the treatment of respiratory tract infection, abdominal infection, urinary tract infection, et...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/22
CPCC07D265/22
Inventor 路生辉李国祥布文安袁小二申友明任伟段振晓李瑞华卢现李延龙
Owner XINXIANG HAIBIN PHARMA