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Intermediate of synthetic imipenem medicine as well as preparation method and application thereof

A technology of penems and intermediates, which is applied to the preparation of sulfonamides, chemical instruments and methods, and compounds of elements in group 4/14 of the periodic table, etc., which can solve problems such as high cost, poor availability, and complicated preparation process , to achieve the effects of low cost, easy preparation and good product yield

Active Publication Date: 2011-02-16
山东安弘制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the poor availability of the precursor compounds and the complicated preparation process, the cost of preparing target products from ring-structured compounds with such auxiliary groups is very expensive

Method used

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  • Intermediate of synthetic imipenem medicine as well as preparation method and application thereof
  • Intermediate of synthetic imipenem medicine as well as preparation method and application thereof
  • Intermediate of synthetic imipenem medicine as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1) Preparation of (R)-4-methyl-N-(1-phenylethyl)benzenesulfonamide

[0044]

[0045]Add 121g (1mol) (R)-methylbenzylamine, 500ml of dichloromethane and 101g (1mol) of triethylamine into the there-necked flask, stir and cool down to 0°C, add 190g (1mol) of TSCl dropwise, and keep the temperature constant Above 10°C, stir the reaction at 0-10°C for 30 minutes. 300 ml of 1N hydrochloric acid, 300 ml of 5% sodium bicarbonate and 300 ml of water were added to wash the organic phase. A large number of crystals appeared after rotary evaporation and concentration, and then 300ml of methanol was added to the concentrate, stirred and heated to dissolve most of them. Stir intermittently and cool down to 0°C, and put in the freezer (or refrigerator) at -15°C for 24 hours. Filter, wash with a small amount of methanol, and dry in vacuo. 240 g (87% yield) of (R)-4-methyl-N-(1-phenylethyl)benzenesulfonamide were obtained.

[0046] Mp 97~99℃,

[0047] [α]=+72° (c=0.4, EtOH)

[...

Embodiment 2

[0050] 2) Preparation of 2-bromo-N-((R)-1-phenylethyl)-N-p-toluenesulfonyl propionamide

[0051]

[0052] In the there-necked flask, add 50g (0.182mol) (R)-4-methyl-N-(1-phenylethyl) benzenesulfonamide, 200ml of dichloromethane and 31.2g (0.3mol) of triethylamine and stir , keeping the temperature at 5-10°C, 58.8g (0.273mol) of 2-bromopropionyl bromide was added dropwise, stirred and reacted at 5-10°C for 30 minutes, and then reacted at room temperature for 17h. The organic layer was washed with saturated sodium bicarbonate solution (150ml) and brine (100ml), dried over anhydrous magnesium sulfate, and concentrated to obtain 60.3g (yield 81%) of 2-bromo-N-((R)- 1-phenylethyl)-N-p-toluenesulfonylpropionamide. The infrared spectrum and nuclear magnetic spectrum of the product are as follows figure 1 and figure 2 shown.

[0053] IR (KBr, cm -1 ): 3062, 2979, 2924, 1703, 1596, 1496, 1447, 1357, 1147, 1121, 966.

[0054] 1 H-NMR (200MHz, CDCl3): 1.58 (3H, m), 1.97 (3H, m...

Embodiment 3

[0056] 3) Preparation of 2-bromo-N-(4-chlorobenzenesulfonyl)-N-((R)-1-m-tolylethyl)propionamide

[0057]

[0058] The same as the operation process of Example 1 and Example 2, the difference is to use 13.5g (0.10mol) of 4-chlorobenzenesulfonyl chloride and 22.1g (0.105mol) of R-1-m-tolylethylamine to obtain white powder 34.6 g (yield 78.2%) 2-bromo-N-(4-chlorobenzenesulfonyl)-N-((R)-1-m-tolylethyl)propanamide.

[0059] Mp: 112~113℃

[0060] 1 H-NMR (200MHz, CDCl3): 1.58 (3H, m), 1.97 (3H, d), 2.35 (3H, s), 4.55 (1H, dd), 5.06 (1H, dd), 6.88-6.93 (3H, m), 7.09(1H,m), 7.61(2H,d), 7.74(2H,d)

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Abstract

The invention relates to an intermediate of a synthetic imipenem medicine as well as a preparation method and application thereof. The intermediate has a structural formula disclosed by the following formula (I), wherein R1 stands for low-carbon alkyl, nitryl, halogen or hydrogen of substituted C1-C3 in arbitrary positions; and R2 stands for aryl, alkyl or aralkyl with or without substituents. The preparation process of the intermediate comprises the following steps of: firstly reacting sulfonyl chloride compounds with aniline compounds; and then, reacting the obtained product with 2-bromopropionyl bromide under the existence of organic base. The intermediate can be used for synthesizing carbapenem antibiotics, namely an imipenem key intermediate as beta-methylazacyclo-2-ketone (shortenedfor 4-BMA). The invention has the advantages of simple synthesis, low cost, high reaction stereoselectivity and good product yield, raw materials are cheap and easy to be obtained, and a compound precursor can be repeatedly used after being recovered.

Description

technical field [0001] The invention relates to an intermediate for synthesizing penem drugs, a preparation method and application thereof. Background technique [0002] Carbapenem antibiotics (namely, penems) are a new type of β-lactam antibiotics, known for their broad antibacterial spectrum and strong antibacterial effect. The key intermediate used in the synthesis of the main ring of penem drugs is β-methylazetidin-2-one (abbreviated as 4-BMA). The introduction of the methyl group at the C-1β position of 4-BMA greatly improves the stability of the final product penem drugs against renal dehydropeptidase (DHP-I), and no longer needs to be combined with DHP-I inhibitors Medication without affecting its antibacterial activity. Synthesizing the intermediate 4-BMA from the intermediate 4-acetoxyazetidinone (abbreviated as 4AA), and then introducing the C-1β methyl structure through the intermediate 4-BMA is the most effective and most effective way to synthesize penems. Fe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/38C07C303/40C07D477/04C07C311/51C07F7/18
CPCC07C311/51C07D205/08
Inventor 张工张艳丽
Owner 山东安弘制药有限公司
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