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Preparation method of meropenem intermediate 4-BMA

A technology of meropenem and 4-BMA, applied in the field of preparation of meropenem intermediate 4-BMA, can solve the problems of unsatisfactory purity and yield, affecting the quality and cost of meropenem

Active Publication Date: 2017-02-15
XINXIANG HAIBIN PHARMA
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Problems solved by technology

And in the above-mentioned method, because the activity of bromopropionyl spirobenzoxazine cyclohexane is higher, thereby, improved (3S, 4S)-4-[(R)-1-carboxyethyl]-3 -[(R)-1-isobutyldimethylsilyloxyethyl]-2-azetidinone (4-BMA) purity and yield, but used in actual production, its purity and yield The rate is not very satisfactory, which affects the quality and cost of the final product meropenem

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  • Preparation method of meropenem intermediate 4-BMA
  • Preparation method of meropenem intermediate 4-BMA
  • Preparation method of meropenem intermediate 4-BMA

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[0023] The present invention provides a preparation method of meropenem intermediate 4-BMA, comprising the following steps:

[0024] A) mixing 4-acetoxyazetidinone, an aprotic solvent and an activated metal to carry out a first reaction;

[0025] B) mixing the product of the first reaction with chloropropionyl spirobenzoxazine cyclohexane to carry out the second reaction;

[0026] C) hydrolyzing the product of the second reaction under hydrogen peroxide and alkaline conditions to obtain 4-BMA.

[0027] The 4-acetoxyazetidinone has a structure as shown in formula (I):

[0028]

[0029] The aprotic solvent is preferably one or more of tetrahydrofuran, ethyl acetate, isopropyl ether, benzene, toluene, xylene, chlorobenzene, N,N-dimethylformamide, and dimethyl sulfoxide.

[0030] The activated metal is preferably one or both of magnesium powder and zinc powder.

[0031] In the present invention, the mass ratio of the 4-acetoxyazetidinone to the aprotic solvent is preferably ...

Embodiment 1

[0080] 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.

[0081] 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

[0083] According to the molar ratio of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, α-chloropropionyl chloride and pyridine is 1:1.6:1.4 , weigh 80g of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, 75g of α-chloropropionyl chloride and 40g of pyridine ;According to the mass ratio of spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one to chlorobenzene is 1:4.4, weigh 350g chlorobenzene ; According to the mass ratio of [2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one to ethanol is 1:1, weigh 80g of ethanol.

[0084] Under nitrogen protection, chlorobenzene, spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane]-4-one, α-chloropropionyl chloride and pyridine were added The reaction was carried out in a four-neck flask, the temperature of the reaction was 50° C., and the reaction time was 8 h. After the reaction, cool down to room temperature, wash three times with 200g water, three times with 200g 10% potassium hydroxide solution, thr...

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Abstract

The invention provides a preparation method of a meropenem intermediate 4-BMA. Low-reaction-activity propionyl spirobenzoxazine cyclohexane is adopted, the meropenem intermediate 4-BMA is prepared through Reformatsky reaction and hydrolysis reaction in sequence, and in the preparation process, side reactions participating in reaction are few, further obtained product impurities are less, and the prepared 4-BMA is high in purity. In addition, the propionyl spirobenzoxazine cyclohexane is adopted as a raw material, the reaction yield is not affected, on the contrary, the reaction yield is greatly improved, and high reaction yield is obtained. Further, the adopted synthetic process is simple, post-treatment is convenient and easy to operate, the raw material and a catalyst are cheap and easy to obtain, safe and environmentally friendly, and the preparation cost is low. An experimental result shows that the mole yield of the prepared meropenem intermediate 4-BMA is 90.0% or above, and the purity is 98.5% or above.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of meropenem intermediate 4-BMA. 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. As one of the important members of carbapenem antibiotics, meropenem not only has good chemical stability, stability to β-lactamase and renal dehydropeptidase, but also is effective against severe and multidrug-resistant bacterial infections such as respiratory tract The treatment effect of infection, abdominal infection, urinary tract infection, etc. is excellent, and it is widely used in the world at present, and the market prospect is broad. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1804C07F7/1892
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
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