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Synthetic method of aztreonam intermediate

An intermediate, aztreonam main ring technology, applied in the field of synthesis of aztreonam intermediates, can solve the problems of expensive palladium carbon, strong corrosion of instruments, and high industrialization costs

Active Publication Date: 2013-02-13
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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Problems solved by technology

tert-butoxycarbonyl can be removed under acidic conditions (WO2004 / 13133 A1; GB 2071650), but the four-member core structure is prone to side reactions in acidic environments
Benzyloxycarbonyl is mainly used in the case of palladium as a catalyst to remove benzyl by hydrogenation (US5194604A1, US5254681A1, EP411541A2, WO2007 / 65288A2), but palladium carbon is more expensive and the cost of industrialization is high
Some data use phenylacetyl group as amino protecting group and phosgene as deprotection reagent (Journal of Organic Chemistry 1982, 47, 176-178). The disadvantage of this method is that phosgene is highly toxic and corrosive to instruments, and easy to cause pollution

Method used

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  • Synthetic method of aztreonam intermediate

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Embodiment Construction

[0014] A, the preparation of phenylacetyl-L-threonine amide

[0015] Add 1000 mL of methanol to the flask, cool to 0 °C, add 130 mL of thionyl chloride at 0-10 °C, then cool to 0 °C, add 59.5 g (0.5 mol) of L-threonine, then slowly rise to room temperature , stirred for 6 hours, the mixture was concentrated and distilled under reduced pressure for 0.5 hours to obtain a colorless viscous oil. Dissolve the substance in 3000 mL of methanol, cool to -5 °C, saturate the solution with ammonia gas, then remove the cooling, and the sealed flask can stand for 3 days until the basic reaction of L-threonamide methyl ester is completely detected by TLC . Then the solution was concentrated to about 1000mL, 250 mL of 3M potassium hydroxide solution was added, and the reaction solution was concentrated into a viscous solution, diluted with 500 mL of water, 73.3 mL (0.55 mol) of phenylacetyl chloride, and the resulting mixture was cooled at room temperature Stir overnight, saturate the reac...

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Abstract

The invention relates to a synthetic method of an aztreonam intermediate, and particularly relates to a method for removing a phenylacetyl protective group at a 3-amino position of an aztreonam main ring intermediate. The invention comprises the following steps: preparing phenylacetyl-L-threoninamide from L-threonine, performing sulfonylation of a beta-position hydroxyl, and sulfonation of an end amino, then preparing the aztreonam main ring intermediate with the amino protected by the phenylacetyl protective group through cyclization, performing hydrolysis in the presence of penicillin G acylase, and removing the protective group on the amino to obtain the aztreonam main ring intermediate. The method of the invention has the advantages of mild process conditions, simple post-treatment, high finished product purity, and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of an aztreonam intermediate, and mainly relates to a deprotection method of an amino-protected aztreonam main ring intermediate. Background technique [0002] The main ring intermediate of aztreonam, (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid, is an important part of the production of anti-infective drug aztreonam Intermediates, the structure of which is shown in the figure below: [0003] [0004] For the amino group at the 3-position of the intermediate, tert-butoxycarbonyl and benzyloxycarbonyl are mainly used as protecting groups. The tert-butoxycarbonyl group can be removed under acidic conditions (WO2004 / 13133 A1; GB 2071650), but the quaternary core structure is prone to side reactions in acidic environments. Benzyloxycarbonyl is mainly used in the case of palladium as a catalyst to remove benzyl by hydrogenation (US5194604A1, US5254681A1, EP411541A2, WO2007 / 65288A2), but palladi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/10
Inventor 姜维平何亮王庆
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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