Method for preparing azetidinone derivatives

A technology of epoxy butyric acid and epoxy butyramide, applied in the direction of organic chemistry and the like, can solve problems such as unfavorable industrial production, high cost of acid binding agent, low reaction temperature, etc., and achieves simplified operation, reduced cost, and increased reaction temperature. Effect

Active Publication Date: 2010-03-31
浙江瑞博制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] But this synthetic route has the following problems: the yield is not high; the reaction temperature is low (-30° C.), which is not conducive to the carrying out of

Method used

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  • Method for preparing azetidinone derivatives
  • Method for preparing azetidinone derivatives
  • Method for preparing azetidinone derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Example 1. (2R, 3S)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-epoxybutanamide

[0020] In a 500 ml four-necked flask, 10.2 g (0.1 mol) of (2R, 3S)-epoxybutyric acid was added and dissolved in 200 ml of ethyl acetate. Cool to 0°C-5°C, add 12.5g (0.134mol) of 4-methylpyridine dropwise at this temperature, then add 12.5g (0.104mol) of pivaloyl chloride dropwise, and keep warm for 2.5hr after dropping. Then, 18.5 g (0.089 mol) of ethyl N-(4-methoxyphenyl) acetate was charged and reacted at this temperature for 1 hr. Then the temperature was raised to 20° C. to 25° C., and the reaction was carried out for 16 hours, and the reaction progress was detected by HPLC. After the reaction, the mixture was washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. Then recrystallized from diethyl ether to obtain 23.5 g of the title compo...

Embodiment 2

[0021] Example 2. (2R, 3S)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-epoxybutanamide

[0022] In a 500 ml four-necked flask, 10.2 g (0.1 mol) of (2R, 3S)-epoxybutyric acid was added and dissolved in 200 ml of ethyl acetate. Cool to 0°C-5°C, add 15g (0.148mol) triethylamine dropwise at this temperature, and then add 12.5g (0.104mol) pivaloyl chloride dropwise, and keep warm for 1hr after dropping. Then, 18.5 g (0.089 mol) of ethyl N-(4-methoxyphenyl) acetate was charged and reacted at this temperature for 1 hr. Then the temperature was raised to 20° C. to 25° C., and the reaction was carried out for 14 hours, and the reaction progress was detected by HPLC. After the reaction, the mixture was washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. Then recrystallized from diethyl ether to obtain 23 g of the title compound. (Yiel...

Embodiment 3

[0023] Example 3. (2R, 3S)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-epoxybutanamide

[0024] In a 500 ml four-neck flask, 10.2 g (0.1 mol) of (2R,3S)-epoxybutyric acid was added and dissolved in 200 ml of chloroform. Add 10.6 g (0.134 mol) of pyridine dropwise at a temperature of 20° C. to 25° C., and then add 12.5 g (0.104 mol) of pivaloyl chloride dropwise, and keep warm for 0.5 hr after dropping. Then, 18.5 g (0.089 mol) of ethyl N-(4-methoxyphenyl) acetate was added and reacted at this temperature for 1.5 hr. Then the temperature was raised to 30° C. to 35° C., and the reaction was carried out for 16 hours, and the reaction progress was detected by HPLC. After the reaction was completed, the mixture was washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain an oil. Then, it was recrystallized from hexane to obtain 23.3 g of th...

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Abstract

The invention discloses a method for preparing azetidinone derivatives represented by the formula (I), wherein, in a reaction solvent, the (2R, 3R)- epoxybutyric acid represented by the formula (II) and an active agent are reacted for generating mixed anhydride, in exist of an acid binding agent, the mixed anhydride is reacted with aryl alkyl acetate represented by the formula (III), and the target compound (I) is obtained by posttreating the reaction liquid after the reaction. The active agent is pivaloyl chloride, and the acid binding agent is one or two of the following in any proportions:triethylamine, 4-picoline, pyridine, N, N-dimethylamino pyridine, N-methyl morpholines, sodium carbonate and potassium carbonate, wherein the reaction temperature is from 25 DEG C to 60 DEG C. The method of the invention has advantages of milder reaction condition, easy and simple operation, low cost and high yield, and is suitable for the industrial production.

Description

(1) Technical field [0001] The invention relates to a chemical preparation method of azetidinone derivatives, specifically (2R,3S)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-ring The preparation method of oxybutyramide. (2) Background technology [0002] The chemical substance (2R, 3S)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-epoxybutanamide involved in the present invention is a key intermediate in the synthesis of penem antibacterial drugs Body, all has very big application value in chemical and pharmaceutical industry, and its structural formula is as shown in formula (I): [0003] [0004] The synthetic preparation of this compound is disclosed in the patent WO 9807691 (CHOONGWAEPHARMACEUTICAL CO., LTD, 1998.2.26), and the specific synthetic route is as follows: [0005] [0006] But this synthetic route has the following problems: the yield is not high; the reaction temperature is low (-30° C.), which is not conducive to the carrying out of the reactio...

Claims

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Application Information

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IPC IPC(8): C07D303/48
Inventor 陈士明陶丙胜杨素清邓飞彪
Owner 浙江瑞博制药有限公司
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