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Preparation method of 1,2,4-thiadiazole oximido acetic acid compound

A technology for thiadiazoloxime and acetic acid, which is applied in the field of preparation of 1,2,4-thiadiazoloxime acetic acid series compounds, can solve the problem of shortening the operation steps of thiadiazoloxime acetic acid series compounds, many process steps, Complicated operation and other problems, to achieve the effect of unique method and principle, shortened operation steps, and high reaction yield

Active Publication Date: 2013-05-08
HEBEI BOLUNTE PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] The object of the present invention is to provide a kind of 1,2,4-thiadiazoloximinoacetic acid series compound (or be referred to as 1,2,4-thiadiazoloximinoacetic acid, itself is a series of compounds, hereinafter the same) The preparation method solves the problems of many process steps and complicated operation in the prior art. Its method and principle are unique, and the product purification process and operation process are simple and convenient, which greatly shortens the operation steps for manufacturing thiadiazoloximinoacetic acid series compounds ; and the reaction yield and product purity are high; especially suitable for industrial production

Method used

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  • Preparation method of 1,2,4-thiadiazole oximido acetic acid compound

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Experimental program
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Embodiment 1

[0054]

[0055] Synthesis of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazole-3)-acetic acid: 2-methoxyimino-2-(5-formylamino-1 , 2,4-thiadiazole-3)-methyl acetate (265g, 97%, 1.0mol) was added to a 5L there-necked flask, and then 3L (3.0mol) of 1.0M LiOH aqueous solution was added to the reaction flask, and the temperature was raised to React at 50-60°C for 12 hours. TLC tracking analysis, after the reaction is completed, lower to room temperature, adjust the pH to 5 with concentrated hydrochloric acid, add 50g of activated carbon to decolorize, then adjust the pH to 1 with concentrated hydrochloric acid, a large number of white crystals precipitate, filter and wash with a small amount of cold methanol, and dry to obtain white Solid 153g, yield 80%, content (HPLC) 97%, H 1 NMR (500Hz, DMSO-d e ), δ3.93 (3H, s), 8.21 (2H, s), mp.175~178°C (dec).

Embodiment 2

[0057]

[0058] Synthesis of 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazole-3)-acetic acid: 2-ethoxyimino-2-(5-formylamino-1 , 2,4-thiadiazole-3)-acetonitrile (520g, 95%, 2.1mol), 3.5L of water was added in a 5L four-necked flask, and 383g (4.60mol) of 48% aqueous sodium hydroxide solution was added under stirring, and the temperature was raised to Reaction at 50-60°C. TLC tracking analysis, after the reaction (about 12 hours), cool down, adjust the pH to 4 with concentrated hydrochloric acid, add 50 g of activated carbon for decolorization, then adjust the pH to 1 with concentrated hydrochloric acid, extract with ethyl acetate (2LX2), and evaporate the solvent to dryness under reduced pressure After adding 1.5L acetonitrile for recrystallization, 178g of light yellow solid powder product was obtained, yield 39%, content (HPLC) 92%, H 1 NMR (500Hz, DMSO-d e ), δ1.22 (3H, t, J=7Hz,), 4.17 (2H, q, J=7Hz), 8.17 (NH2, 2H, bs), mp.160~162°C (dec).

Embodiment 3

[0060]

[0061] Synthesis of 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazole-3)-acetic acid: 2-ethoxyimino-2-(5-formylamino- 1,2,4-thiadiazole-3)-acetonitrile (258g, 95%, 1mol) was added to a 5L three-necked flask, then 3.5L LiOH (1.2M) aqueous solution was added to the reaction flask, and hexadecyl Trimethylammonium chloride (7.8g), 120g 30% H 2 o 2 Add 120g 30% H 2 o 2 , 30°C-35°C stirring reaction for 6 hours. The temperature was raised to 70°C-75°C for 12 hours, followed by TLC. After cooling down to 5°C, the reaction liquid was acidified with concentrated hydrochloric acid to pH 1.5, and a large amount of white crystals were precipitated. The solid was filtered and washed with a small amount of cold methanol, and the product was vacuum-dried to obtain 171 g of a white solid product with a content (HPLC) of 97%. Yield 81%, H 1 NMR (500Hz, DMSO-d e ), δ1.22(3H, t, J=7Hz,), 4.17(2H, q, J=7Hz), 8.17(NH 2 , 2H, bs), mp.163~165℃(dec)

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Abstract

The invention provides a preparation method of a 1,2,4-thiadiazole oximido acetic acid compound, relating to the technical field of preparation technology of 7-site side chain 1,2,4-thiadiazole oximido acetic acid compound of fourth-generation cephalosporin and fifth-generation cephalosporin. The product is obtained by alkali hydrolysis reaction of the derivative of the 1,2,4-thiadiazole oximido acetic acid compound, and the temperature of the hydrolysis reaction system is controlled to be below 150 DEG C. The method of the invention has peculiar principle, and solves the problems of various technical steps, complex operation and the like in the prior art; in addition, product purification technology and operation technology are simple, the operation steps for manufacturing the thiadiazole oximido acetic acid compound are greatly shortened and reaction yield and product purity are higher. A byproduct which can be detected in a reaction mixture can be lower than 5%, reaction yield can be improved to 75-85%, and purity can be more than 97%. The method of the invention is especially suitable for producing the thiadiazole oximido acetic acid compound products with high purity.

Description

technical field [0001] The invention relates to the technical field of preparation technology of the 7-position side chain 1,2,4-thiadiazoxime acetic acid series compounds of the fourth-generation cephalosporin and the fifth-generation cephalosporin. Background technique [0002] Anti-infective drugs account for 13% of the total share in the medicines used in the world, and cephalosporins, as a class of anti-infective drugs, have always ranked first in the amount of anti-infective drugs. There are many kinds of cephalosporin antibiotics, and they are widely used, and they have already occupied nearly half of the market share of antibiotics. With the continuous update of the structure of cephalosporin compounds and the continuous optimization of drug efficacy, human beings have entered the era of the fourth generation, or even the fifth generation of cephalosporins, and are solving the problem of the use of the first three generations of cephalosporin antibiotics in resisting...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D285/08
Inventor 李玮依恒萍李璟陈莹
Owner HEBEI BOLUNTE PHARMA
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