CN1974568A - Prepn process of aztreonam - Google Patents
Prepn process of aztreonam Download PDFInfo
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- CN1974568A CN1974568A CN 200610165272 CN200610165272A CN1974568A CN 1974568 A CN1974568 A CN 1974568A CN 200610165272 CN200610165272 CN 200610165272 CN 200610165272 A CN200610165272 A CN 200610165272A CN 1974568 A CN1974568 A CN 1974568A
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Abstract
The present invention relates to the preparation process of Aztreonam as one kind of antibacterial medicine. The preparation process includes the reaction of Aztreonam with protected side chain and formic acid or its water solution to obtain Aztreonam.
Description
Technical field:
The present invention relates to a kind of synthetic method of antibacterials aztreonam, this method comprises the aztreonam of side chain protected and the reactant aqueous solution of formic acid or formic acid, obtains the step of aztreonam.
Background technology:
Aztreonam is a kind of antibacterials of U.S. Shi Guibao company exploitation, and 1984 in Italy's listing, and it is a kind of monocycle beta-lactam microbiotic that can synthetic.Antimicrobial spectrum mainly comprises Gram-negative bacteria, as intestinal bacteria, klebsiella bacillus, serratia marcecens, Proteus mirabilis, hemophilus influenzae, citrobacter, Pseudomonas aeruginosa, gonococcus etc.Clinical respiratory tract due to the responsive Gram-negative bacteria, pulmonary infection, urinary tract infections, abdominal cavity infection, bone and the infection of joint, skin and soft tissue inflammation and gynecological infection, and the gonorrhoea etc. of being mainly used in.Because of aztreonam can enter cerebrospinal fluid, can be used for meningitis.The anti-enzyme of aztreonam is strong, and when insensitive, it is also effective to use aztreonam to other medicines.Aztreonam has following chemical structure:
Aztreonam is known multi-crystalline compounds, and α, β, four kinds of crystal formations of γ, δ are arranged.
Document US 4775670 has been reported a kind of preparation method of aztreonam; relate to 2-(2-amino-4-thiazolyl)-2-(1-phenylbenzene methoxy carbonyl-1-methyl ethoxy) acetimidic acid hydrochloride and (2S-is trans)-3-amino-2-methyl-4-oxo-1-azetidinyl sulfonic acid and carry out dehydration reaction, take off that diphenyl-methyl is protected and the method that makes aztreonam with trifluoroacetic acid and phenylmethylether then with dicyclohexylcarbodiimide.
Document CN1681812A has reported that employing mineral acid (hydrochloric acid, sulfuric acid, trifluoroacetic acid) and t-bu aztreonam reaction take off the method that tertiary butyl protection obtains aztreonam.
It is that reaction adopts the trifluoroacetic acid cost higher that there is commonplace problem in the above method, and can't reclaim, and adopts that hydrochloric acid or sulfuric acid productive rate are low to have open-loop products to generate, and can't recovery set usefulness, and environment is produced harm.
Summary of the invention:
For overcoming the defective of prior art, the invention provides a kind of novel method of synthetic aztreonam.
Method of the present invention is the aztreonam deprotection base with protection, and the method for employing is, with the aztreonam and the formic acid reaction of protection.
Method of the present invention; preferably with t-bu aztreonam; with diphenyl-methyl aztreonam deprotection base; the t-bu aztreonam chemical name is: [3S-[3 α (Z), 4 β]]-3-[[(2-amino-4-thiazolyl) [(1-tertbutyloxycarbonyl-1-methyl ethoxy) imino-] ethanoyl] amino]-4-methyl-2-oxo-1-azetidin alkyl sulfonic acid.
Diphenyl-methyl aztreonam chemical name is: [3S-[3 α (Z), 4 β]]-3-[[(2-amino-4-thiazolyl) [(1-phenylbenzene methoxy carbonyl-1-methyl ethoxy) imino-] ethanoyl] amino]-4-methyl-2-oxo-1-azetidin alkyl sulfonic acid.
Preferred reaction scheme is as follows:
Route one: t-bu aztreonam and formic acid reaction
Route two: diphenyl-methyl aztreonam and formic acid reaction
In the above synthetic method, starting raw material t-bu aztreonam and diphenyl-methyl aztreonam are prior aries, and its intermediate as synthetic aztreonam can have been bought from the market, also can be synthetic by literature method.
Starting raw material formic acid can adopt pure formic acid, also can adopt aqueous formic acid, formic acid concn between 30%～100%, preferred 40-60%.Other solution of formic acid according to circumstances also can adopt.
More than reaction can be carried out under 0 ℃～80 ℃ conditions, preferred room temperature condition, and the reaction times is 1-5 hour, preferred 1-3 hour, after reaction finishes, reclaim formic acid, obtain aztreonam.
The gained aztreonam can further be made with extra care, and obtains being fit to medicinal aztreonam raw material, makes with extra care and can adopt methods such as washing, recrystallization.
Method of the present invention is compared with prior art, and advantage is, reaction conditions relaxes, and the formic acid of employing or aqueous formic acid can recovery set usefulness, and be simple to operate, the productive rate height, and the purity height, cost is low, is fit to scale operation.
Embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1: the t-bu aztreonam deprotection prepares aztreonam
In the 250ml flask, add t-bu aztreonam 20g and 100ml anhydrous formic acid, stirring at room reaction 3 hours, reaction finishes, reclaim under reduced pressure formic acid adds the 100ml deionized water in the oily matter that obtains, with 0 ℃～5 ℃ stir half an hour, the adularescent solid generates, filter, filter cake washs with cold water and cold acetone, and drying obtains the 13.3g product.Productive rate 75%.
Embodiment 2: the t-bu aztreonam deprotection prepares aztreonam
In the 250ml flask, add t-bu aztreonam 20g and 100ml50% aqueous formic acid, stirring at room reaction 3 hours, reaction finishes, being chilled to 0 ℃～5 ℃ stirred 1 hour, the adularescent solid generates, and filters, and the aqueous formic acid that obtains is collected and applied mechanically, filter cake washs with cold water and cold acetone, and drying obtains 11.3g aztreonam product.Productive rate 63.8%.
Embodiment 3: diphenyl-methyl aztreonam deprotection prepares aztreonam
In the 250ml flask, add diphenyl-methyl aztreonam 20g and 100ml anhydrous formic acid, stirring at room reaction 3 hours, reaction finishes, reclaim under reduced pressure formic acid adds the 100ml deionized water in the oily matter that obtains, with 0 ℃～5 ℃ stir half an hour, the adularescent solid generates, filter, filter cake washs with cold water and cold acetone, and drying obtains the 9.8g product.Productive rate 68%.
Embodiment 4: diphenyl-methyl aztreonam deprotection prepares aztreonam
In the 250ml flask, add diphenyl-methyl aztreonam 20g and 100ml50% aqueous formic acid, stirring at room reaction 3 hours, reaction finishes, being chilled to 0 ℃～5 ℃ stirred 1 hour, the adularescent solid generates, and filters, and the aqueous formic acid that obtains is collected and applied mechanically, filter cake washs with cold water and cold acetone, and drying obtains the 10.1g product.Productive rate 70%.
Embodiment 5: the t-bu aztreonam deprotection prepares aztreonam
In the 250ml flask, add t-bu aztreonam 20g and 100ml50% aqueous formic acid, in 50 ℃ of stirring reactions 1 hour, reaction finishes, being chilled to 0 ℃～5 ℃ stirred 1 hour, the adularescent solid generates, and filters, and the aqueous formic acid that obtains is collected and applied mechanically, filter cake washs with cold water and cold acetone, and drying obtains 12g aztreonam product.Productive rate 67.7%.
Claims (10)
1. a method for preparing aztreonam is characterized in that, the process following steps: with the aztreonam and the formic acid reaction of protection.
2. the method for claim 1 is characterized in that, the aztreonam of described protection is selected from: t-bu aztreonam and diphenyl-methyl aztreonam.
3. the method for claim 1 is characterized in that, described formic acid is selected from the aqueous solution of pure formic acid and formic acid.
4. the method for claim 1 is characterized in that, the concentration of aqueous solution scope of described formic acid is 30%～100%.
5. method as claimed in claim 4 is characterized in that, the concentration of aqueous solution scope of described formic acid is 50%.
6. the method for claim 1 is characterized in that, range of reaction temperature is 0 ℃～80 ℃.
7. method as claimed in claim 6 is characterized in that, temperature of reaction is a room temperature.
8. the method for claim 1 is characterized in that, the reaction times is 1-5 hour.
9. method as claimed in claim 8 is characterized in that, the reaction times is 1-3 hour.
10. the method for claim 1 is characterized in that, also comprises, after described reaction finishes, reclaims formic acid, obtains reactant, and after filtration, with cold water and cold acetone washing, drying obtains aztreonam.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101652722A CN100469777C (en) | 2006-12-15 | 2006-12-15 | Prepn process of aztreonam |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101652722A CN100469777C (en) | 2006-12-15 | 2006-12-15 | Prepn process of aztreonam |
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| CN1974568A true CN1974568A (en) | 2007-06-06 |
| CN100469777C CN100469777C (en) | 2009-03-18 |
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| CNB2006101652722A Active CN100469777C (en) | 2006-12-15 | 2006-12-15 | Prepn process of aztreonam |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351855A (en) * | 2011-08-12 | 2012-02-15 | 山西仟源制药股份有限公司 | Production method of beta-crystal form aztreonam aseptic raw drug |
| CN103570707A (en) * | 2012-07-21 | 2014-02-12 | 重庆圣华曦药业股份有限公司 | Improved synthetic method of aztreonam |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4775670A (en) * | 1980-09-29 | 1988-10-04 | E. R. Squibb & Sons, Inc. | 2-oxo-1-azetidinesulfonic acid salts |
| US4946838A (en) * | 1981-07-13 | 1990-08-07 | E. R. Squibb & Sons, Inc. | Crystalline anhydrous aztreonam |
| US4826973A (en) * | 1984-07-20 | 1989-05-02 | E. R. Squibb & Sons, Inc. | Delta form of aztreonam and preparation thereof |
-
2006
- 2006-12-15 CN CNB2006101652722A patent/CN100469777C/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351855A (en) * | 2011-08-12 | 2012-02-15 | 山西仟源制药股份有限公司 | Production method of beta-crystal form aztreonam aseptic raw drug |
| CN103570707A (en) * | 2012-07-21 | 2014-02-12 | 重庆圣华曦药业股份有限公司 | Improved synthetic method of aztreonam |
| CN103570707B (en) * | 2012-07-21 | 2016-03-09 | 重庆圣华曦药业股份有限公司 | A kind of synthetic method of aztreonam of improvement |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100469777C (en) | 2009-03-18 |
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Owner name: HUARUN SAIKE PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: SAIKE PHARMACEUTICAL CO., LTD., BEIJING |
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Address after: 100021 Beijing city Chaoyang District Jinsong three District No. 302 Huateng building room 1101 Patentee after: China Resources Saike Pharmaceutical Co., Ltd. Address before: 100021 Beijing city Chaoyang District Jinsong three District No. 302 Huateng building room 1101 Patentee before: Saike Pharmaceutical Co., Ltd., Beijing |