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Nitrogen heterocyclic butanone as well as synthesis method and application thereof

A technology of azetidinone and synthesis method, applied in the direction of organic chemistry, etc., can solve the problems of unstable reaction, affecting yield, low yield, etc., and achieve the effects of high reaction yield, reduced emissions, and reduced costs

Active Publication Date: 2014-07-16
HEBEI WORLDSTAR CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The prior art prepares 4-AA key intermediates to form epoxides during the reaction process, and the three-membered ring is unstable. In case of an acidic environment, it is easy to open and decompose, which seriously affects the yield; some existing technical conditions are not easy to control, and the reaction is unstable. , low yield

Method used

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  • Nitrogen heterocyclic butanone as well as synthesis method and application thereof
  • Nitrogen heterocyclic butanone as well as synthesis method and application thereof
  • Nitrogen heterocyclic butanone as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] An azetidinone, the chemical name is: (3S,4S)-3-[(1R)-hydroxyethyl]-4-phenylacetyl-1-p-methoxyphenyl-2-azacyclic ring Butanone (compound Ⅰ), the structure is as follows,

[0038]

[0039] Compound I.

[0040] The synthesis method comprises the following steps: (1) Synthesis of (2S,3R)-2-amino-3-hydroxyl-N-(4-methoxyphenyl)butylamine (compound II): ethyl acetate is a solvent, L-threonine reacts with p-aminoanisole under the action of CDI to generate compound Ⅱ;

[0041] In a dry and clean reaction bottle, add 540 g of ethyl acetate under temperature control at 25°C, turn on electric stirring and add 146 g of N,N-carbonyldiimidazole, add 100 g (0.84 mol) of L-threonine in batches, and add in ten batches, After adding one batch, add the next batch when there are no more bubbles in the system, then keep stirring at 25°C for 1 h under nitrogen protection, add 98.5 g (0.8 mol) of p-aminoanisole, raise the temperature to 45°C, and Insulate and stir the reaction for 3-5 h...

Embodiment 2

[0049] A kind of azetidinone, structure is the same as embodiment 1.

[0050] The synthesis method comprises the following steps: (1) Synthesis of (2S,3R)-2-amino-3-hydroxyl-N-(4-methoxyphenyl)butylamine (compound II): ethyl acetate is a solvent, L-threonine reacts with p-aminoanisole under the action of CDI to generate compound Ⅱ;

[0051] In a dry and clean reaction bottle, add 540 g of ethyl acetate under temperature control at 27°C, turn on electric stirring and add 146 g of N,N-carbonyldiimidazole, add 100 g (0.84 mol) of L-threonine in batches, and add in ten batches, After adding one batch, add the next batch when there are no more bubbles in the system, then keep stirring at 25°C for 1 h under nitrogen protection, add 98.5 g (0.8 mol) of p-aminoanisole, raise the temperature to 55°C, and Insulate and stir the reaction for 3-5 h, monitor the reaction to the end point by TLC, and wash the organic phase with 85 ml 2 mol / L hydrochloric acid, 230 ml 10% NaHCO 3 The aqueou...

Embodiment 3

[0059] A kind of azetidinone, structure is the same as embodiment 1.

[0060] The synthesis method comprises the following steps: (1) Synthesis of (2S,3R)-2-amino-3-hydroxyl-N-(4-methoxyphenyl)butylamine (compound II): ethyl acetate is a solvent, L-threonine reacts with p-aminoanisole under the action of CDI to generate compound Ⅱ;

[0061] In a dry and clean reaction bottle, add 540 g of ethyl acetate under temperature control at 23°C, turn on electric stirring and add 146 g of N,N-carbonyldiimidazole, add 100 g (0.84 mol) of L-threonine in batches, and add in ten batches, After adding one batch, add the next batch when there are no more bubbles in the system, then keep stirring at 25°C for 1 h under nitrogen protection, add 98.5 g (0.8 mol) of p-aminoanisole, raise the temperature to 45°C, and Insulate and stir the reaction for 3-5 h, monitor the reaction to the end point by TLC, and wash the organic phase with 85 ml 2 mol / L hydrochloric acid, 230 ml 10% NaHCO 3 The aqueou...

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PUM

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Abstract

The invention discloses a nitrogen heterocyclic butanone and belongs to the technical field of heterocyclic compounds. The nitrogen heterocyclic butanone is chemically named as (3S,4S)-3-[(1R)-hydroxy ethyl]-4-benzene acetyl-1-p-methoxyphenyl-2-nitrogen heterocyclic butanone (compound I). A synthesis method comprises the following steps: (1) the synthesis of a compound II, namely performing a reaction on L-threonine and p-anisidine under the action of CDI (Carbon Dioxide Ice) by taking ethyl acetate as a solvent; (2) the synthesis of a compound III, namely performing an epoxidation reaction on the compound II with HCl, NaNO2 and NaOH; (3) the synthesis of a compound IV, namely performing the reaction on the compound III and 2-chloroethene benzophenone so as to synthesize the compound IV; (4) the synthesis of the compound I, namely performing a cyclization reaction on the compound IV under the action of zinc chloride and piperidine so as to synthesize the compound I. The method is high in reaction yield; the selectivity of the reactions is improved and the epoxide butyrylamide is almost all converted into a target product by taking the zinc chloride as a lewis acid.

Description

technical field [0001] The present invention relates to the technical field of heterocyclic compounds. Background technique [0002] Penem antibiotics are similar to vancomycin and are currently the most effective antibiotic products. At present, many germs are extremely resistant to macrocyclic drugs such as cephalosporins, and penem drugs are safer than vancomycin (known as the antibiotic of last resort), which is the last line of defense for human health , has a wider range of applications, and is clinically used as an antibiotic defense line for humans second only to vancomycin. The key factor for the success of penem products is that their cost is comparable to other antibiotics, and they have great advantages in terms of process technology and cost control. And 4-AA is the key intermediate in the synthesis of all penem drugs. There are many methods for synthesizing 4-AA at present, among which the production method using L-threonine as the starting material has attr...

Claims

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Application Information

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IPC IPC(8): C07D205/08
CPCC07D205/08
Inventor 郝金恒王光远钟少雄王金龙杜静纪爱民
Owner HEBEI WORLDSTAR CHEM
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