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Process of synthesizing (2S-trans)-3-methyl-4-oxo-1-azacyclo butyl sulfonic acid

A technology of azetidine sulfonic acid and sulfamic acid, applied in directions such as organic chemistry, can solve problems such as low yield and difficult operation, and achieve the effects of improved yield, low cost and mild reaction conditions

Active Publication Date: 2009-05-13
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The operational route of synthetic (2S-trans)-3-amino-2-methyl-4-oxo-1-azetidinesulfonic acid all involves the step of sulfonation on the amino group, and the yield of this step is relatively low, And use extremely toxic chlorosulfonic acid, it is not easy to operate in industrialization

Method used

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  • Process of synthesizing (2S-trans)-3-methyl-4-oxo-1-azacyclo butyl sulfonic acid
  • Process of synthesizing (2S-trans)-3-methyl-4-oxo-1-azacyclo butyl sulfonic acid
  • Process of synthesizing (2S-trans)-3-methyl-4-oxo-1-azacyclo butyl sulfonic acid

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Embodiment 1

[0059] Step A:

[0060] In a 2L three-necked flask, add 350ml of water and 350ml of 1,4-dioxane, stir evenly, add 67.3g of L-threonine, 94.5ml of triethylamine, 181g of di-tert-butyl dicarbonate, and react at room temperature overnight. After the plate reaction is complete, add 500ml ethyl acetate, stir for 30 minutes, separate the organic layer, adjust the pH of the aqueous layer to 2~3 with hydrochloric acid, extract with ethyl acetate 300×3, combine the organic layers, and dry with anhydrous sodium sulfate. It was filtered and concentrated to obtain 115 g of colorless oil with a yield of 93%.

[0061] Step B

[0062] Take 11.2g of the product of step A, dissolve it in a 250ml three-necked flask with 100ml tetrahydrofuran, cool to -5℃ with an ice salt bath, add 7.2g 1-hydroxybenzotriazole, and add 11.7g N,N-dicyclohexylcarbodiimide After stirring for 30 minutes, add 5.5g sulfamic acid and 5.7g triethylamine. After reacting at low temperature for 1 hour, remove the ice bath, reac...

Embodiment 2

[0070] Step A:

[0071] In a 2L three-necked flask, add 350ml water and 350ml 1,4-dioxane, stir well, add 67.3g L-threonine, 94.5ml triethylamine, drop 144g benzyl chloroformate, the addition is complete After that, react overnight at room temperature. After the spotting reaction is complete, add 500 ml of ethyl acetate, stir for 30 minutes, separate the organic layer, adjust the pH of the aqueous layer to 2 to 3 with hydrochloric acid, extract with ethyl acetate 300×3, and combine the organic layers. It was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 136 g of a colorless oil with a yield of 95%.

[0072] Step B

[0073] Take 13g of the product of step A and dissolve it in a 250ml three-necked flask with 100ml of tetrahydrofuran, cool to -5°C in an ice-salt bath, add 7.2g of 1-hydroxybenzotriazole, and add 11.7g of N,N-dicyclohexylcarbodiimide, Stir for 30 minutes, add 5.5g sulfamic acid and 5.7g triethylamine, react at low temperature for 1 hour, rem...

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Abstract

The present invention relates to process of synthesizing (2S-trans)-3-amino-2-methyl-4-oxo-1-azacyclo butyl sulfonic acid. The process includes the following steps: 1. reaction of L-threonine and matter to protect its amino group; 2 condensation of L-threonine with protected amino group and aminosulfonic acid to obtain threonyl aminosulfonic acid with protected amino group; 3. reaction of threonyl aminosulfonic acid with protected amino group and methylsulfnyl chloride to protect hydroxyl radicap in threonine segment; 4. cyclization reaction to form protected quaternary ammonium salt of azacyclo butyl sulfonic acid; and 5. deprotection to obtain (2S-trans)-3-amino-2-methyl-4-oxo-1-azacyclo butyl sulfonic acid.

Description

Technical field: [0001] The invention relates to a new method for synthesizing (2S-trans)-3-amino-2-methyl-4-oxo-1-azetidine sulfonic acid. Background technique: [0002] (2S-trans)-3-amino-2-methyl-4-oxo-1-azetidine sulfonic acid is a key intermediate for the synthesis of aztreonam. Aztreonam is an antibacterial drug developed by Bristol-Myers Squibb in the United States. It was launched in Italy in 1984. It is a synthetic monocyclic β-lactam antibiotic. The antibacterial spectrum mainly includes Gram-negative bacteria, such as Escherichia coli, Klebsiella, Serratia, Proteus mirabilis, Haemophilus influenzae, Citrobacter, Pseudomonas aeruginosa, Neisseria gonorrhoeae, etc. Clinically, it is mainly used for respiratory tract, lung infection, urinary tract infection, abdominal cavity infection, bone and joint infection, skin and soft tissue inflammation, gynecological infection, and gonorrhea caused by sensitive Gram-negative bacteria. Because this product can enter the cerebrospi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/085
Inventor 杨琰刘亚杰
Owner CHINA RESOURCES SAIKE PHARMA
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