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Synthesis of 1-[carbobenzoxy-amion]-2-methyl-4-oxo-3-tert butyl sulfonyl-3-aminoheterocycobutane

A technology of tert-butanesulfonyl and hexacyclobutane, applied in the direction of organic chemistry and the like, can solve the problems of less than 50% total yield, low yield in the ring-closing process, large waste water and waste residue, etc., and achieves stable product quality, The effect of high product yield and increased production capacity

Inactive Publication Date: 2019-01-18
SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The above patents have the following disadvantages: different solvents are used in the hydroxyl protection process and the sulfonation ring closure, and there are many types of solvents, the post-treatment is cumbersome, and the highly toxic chemical chlorosulfonic acid is used in the sulfonation process. Waste residue, the production cycle is long, the yield of the ring closure process is low, and the product contains impurities of intermolecular reactions, the total yield is less than 50%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 50 g of N-benzyloxycarbonyl-L-threonine amide solid into a 500 mL reaction flask, add 500 mL of butyl acetate, cool to -5°C, add 23 g of methanesulfonyl chloride and 22.5 g of triethylamine to obtain a mixed reaction solution, Add 82g of sulfur trioxide-triethylamine complex, raise the temperature to 70°C, distill 250ml of butyl acetate under reduced pressure during the heating process, and then keep the reaction under normal pressure for 5h. After the reaction is completed, distill the solvent under reduced pressure to obtain a dry product, add water Dissolve to obtain a solution, add the solution dropwise to 40°C sodium hydroxide aqueous solution, adjust the reaction pH to 6.5, cool down to crystallize, and filter with suction to obtain 1-[benzyloxycarbonyl-amino]-2-methyl-4-oxo Dai-3-tert-butanesulfonyl-3-aminobutane 60.4g, purity 98.6%, yield: 90.4%, hydrogenation verification 1h 40min reaction completed.

Embodiment 2

[0032] Add 50g of N-benzyloxycarbonyl-L-threonine amide solid into a 500mL reaction flask, add 750mL of dichloroethane, cool down to -5°C, add 23g of methanesulfonyl chloride and 22.5g of pyridine to obtain a mixed reaction solution, add Sulfur trioxide-pyridine complex 72g, heated up to 80°C, distilled 350ml of dichloroethane under reduced pressure during the heating process, and then reacted at normal pressure for 6 hours. Solution, add the solution dropwise to 38°C sodium hydroxide aqueous solution, adjust the reaction pH to 6.5, cool down and crystallize, filter with suction to obtain 1-[benzyloxycarbonyl-amino]-2-methyl-4-oxo- 61.1 g of 3-tert-butanesulfonyl-3-aminobutane, with a purity of 97.9%, a yield of 91.6%, and the reaction was completed after 2 hours of hydrogenation verification.

Embodiment 3

[0034] Add 50g of N-benzyloxycarbonyl-L-threonine amide solid to a 500mL reaction flask, add 400mL of carbon tetrachloride, cool down to -5°C, add 23g of methanesulfonyl chloride and 22.5g of 2-picoline to obtain a mixed Add 78.4g of sulfur trioxide-2-picoline complex to the reaction solution, raise the temperature to 80°C, distill 160ml of carbon tetrachloride under reduced pressure during the heating process, and then keep the reaction under normal pressure for 8 hours. After the detection reaction is completed, reduce the pressure Distill the solvent to obtain a dry product, add water to dissolve to obtain a solution, add the solution dropwise to an aqueous sodium hydroxide solution at 42°C, adjust the reaction pH to 6.5, cool down to crystallize, and filter with suction to obtain 1-[benzyloxycarbonyl-amino]-2 - Methyl-4-oxo-3-tert-butanesulfonyl-3-aminobutane 60.1g, purity 98.4%, yield: 90.2%, hydrogenation verification 2h reaction completed.

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Abstract

The invention belongs to the technical field of medicine synthesis and in particular relates to synthesis of 1-[carbobenzoxy-amion]-2-methyl-4-oxo-3-tert butyl sulfonyl-3-aminoheterocycobutane. The synthesis comprises the following steps: adding solid N-carbobenzoxy-L-threonine amide to a reaction kettle, adding an organic solvent, stirring and cooling, and adding methylsufonyl chloride and an acid-binding agent to obtain a mixed reaction solution; adding a sulfur trioxide-organic alkaline complex, raising the temperature to react, evaporating the solvent in the temperature rise process, and after reaction, evaporating the solvent to obtain N-sulfo-N-carbobenzoxy-O-methane sodium sulfo-L-threonine amide; and dissolving with water, adding an aqueous solution into a hot sodium hydroxide solution, carrying out the temperature-reduced suction filtration to obtain 1-[carbobenzoxy-amion]-2-methyl-4-oxo-3-tert butyl sulfonyl-3-aminoheterocycobutane, wherein a hydrogenating test is reacted within 2 hours. The method is short in reaction time, green and environment-friendly, simple in process, relatively low in cost and high in total recovery.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to the synthesis of 1-[benzyloxycarbonyl-amino]-2-methyl-4-oxo-3-tert-butanesulfonyl-3-ametidine. Background technique [0002] Aztreonam is a monocyclic β-lactam antibiotic that has a good therapeutic effect on Gram-negative bacterial infections. The main ring of aztreonam is an important intermediate for the synthesis of aztreonam. The production process of the main ring, especially the mesylation and sulfonation process, produces a large amount of waste water, waste gas and waste residue, which is harmful to the environment; in addition, the ring closure process The ring opening of the material and the generation of impurities by intermolecular reactions affect the yield of 1-[benzyloxycarbonyl-amino]-2-methyl-4-oxo-3-tert-butanesulfonyl-3-aminobutane And quality, also may lead to catalyst palladium poisoning of next step hydrogenation reaction, hydr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/085
CPCC07D205/085
Inventor 马永祥孟宪强蔡会敏代建建
Owner SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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