CN102285907A - Method for preparing aztreonam monocyclic parent nucleus - Google Patents
Method for preparing aztreonam monocyclic parent nucleus Download PDFInfo
- Publication number
- CN102285907A CN102285907A CN2011102801829A CN201110280182A CN102285907A CN 102285907 A CN102285907 A CN 102285907A CN 2011102801829 A CN2011102801829 A CN 2011102801829A CN 201110280182 A CN201110280182 A CN 201110280182A CN 102285907 A CN102285907 A CN 102285907A
- Authority
- CN
- China
- Prior art keywords
- weight parts
- aztreonam
- monocycle
- parent nucleus
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing aztreonam monocyclic parent nucleus. The method is performed under the protection of benzyl chloroformate under a strong acid condition; and closed loop reaction is performed by using sodium carbonate. The method has the advantages of greatly improving the yield, along with overall effectiveness of 48 percent.
Description
Technical field
The present invention relates to a kind of synthetic method of medicine, particularly a kind of preparation method of aztreonam monocycle parent nucleus.
Background technology
Aztreonam (claiming ammonia thiophene acid monoamine rhzomorph again, aztreonam, Aztreonam) is complete synthesis monocycle beta-lactam antibiotic.Its antimicrobial spectrum mainly comprises Gram-negative bacteria, as intestinal bacteria, klebsiella bacillus, serratia marcecens, Proteus mirabilis, hemophilus influenzae, citrobacter, Pseudomonas aeruginosa, gonococcus etc.Clinical medicinal 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 it can enter cerebrospinal fluid, can be used for meningitis.Because the anti-enzyme of aztreonam is strong, other medicines when insensitive, are used and medicine Chang Youxiao.
The chemical name of aztreonam is: [2S-[2a, 3b (Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo group-3-azetidinyl) amino]-2-oxidation ethylidene] amino] oxo]-2 Methylpropionic acid, English name: Aztreonam, molecular formula: C13H17N5O8S2, molecular weight: 435.43.
Aztreonam is that first is applied to clinical monocycle β one lactam antibiotics medicine, and this product few side effects is first chemosynthesis penicillin medicine.
Aztreonam monocycle parent nucleus is an indispensable intermediate of producing aztreonam.At present, domestic synthetic aztreonam monocycle parent nucleus route mainly contains two:
Synthetic route 1.
Threonine is a basic material; carry out esterification through methyl alcohol and sulfur oxychloride, carry out the BOC protective reaction, carry out ammonolysis reaction with tert-Butyl dicarbonate; carrying out the Ma Shi reaction with methane sulfonyl chloride; through extracting secondary, add methylene dichloride again and carry out carrying out chlorosulfonation, again with butyl hydrogen sulfate amine with chlorsulfonic acid again through solvent recuperation; carry out ring-closure reaction; carry out the deprotection base with formic acid, get product through recrystallization again, total recovery 24%.This process recovery ratio is low, and when its reason was the Boc protective reaction, Boc very easily took off under acidic conditions, and under strong acid subsequently, by product is many when causing sulfonation, and yield is low, poor product quality.
Synthetic route 2
With the Threonine is that basic material and methyl alcohol sulfur oxychloride carry out esterification.This method is: at NH
3Carry out ammonolysis reaction in the environment, carry out CBZ reaction with chloroformic acid benzyl ester again, carry out the Ma Shi reaction, carry out chlorosulphonation, carry out ring-closure reaction, carry out hydrogenation with 10% palladium charcoal with tetrabutyl hydrogen sulfate amine with chlorsulfonic acid through methanesulfonic chlorine, make with extra care again product.This technology shortcoming, when the CBZ protective reaction, reaction is incomplete, and because of poorly water-soluble, raw material forms parcel, influences yield and quality product, and production cost is higher, and yield is low.
Above-mentioned two kinds of preparation methods are owing to ring-closure reaction the time, and operational path adopts 4-butyl ammonium hydrogen sulfate to carry out ring-closure reaction, and because of tetrabutyl hydrogen sulfate amine value lattice height, yield is low, and the production cost height.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method of aztreonam monocycle parent nucleus, this method has stable reaction, and yield is imitated high, the advantage of transformation efficiency more than 98%.
The preparation method of aztreonam monocycle parent nucleus of the present invention has following steps:
1) gets 99.5% methyl alcohol 200 weight parts, Threonine 50 weight parts of adding 99.6%, be cooled to 3-5 ℃, sulfur oxychloride 50 weight parts of dropping 99.2%, the temperature that is heated to solution is 35-45 ℃, reacts 15-17 hour, after the underpressure distillation, add 99.5% methyl alcohol 125 weight parts, drip saturated solution of sodium carbonate, the pH value of adjusting solution is 7-8; Drip chloroformic acid benzyl ester 50 weight parts, reaction 3-5h filters, and gets the beta-hydroxy N-formyl benzyl ester Threonine methyl esters of 105 weight parts;
2) the beta-hydroxy N-formyl benzyl ester Threonine methyl esters that obtains in the step 1) is joined in the retort, add methyl alcohol 200 weight parts, slowly logical ammonia 50 weight parts, reaction 29-31h, underpressure distillation;
3) underpressure distillation finishes toluene 60 weight parts of back adding 99.4%, dissolving, and crystallisation by cooling, filtration drying get 75 weight part Threonine acid amides xln;
4) get threonyl amine crystal 50 weight part that obtains in the step 3), methylene dichloride 300 weight parts of adding 99.5%, 99.3% 2-picoline 100 weight parts, methane sulfonyl chloride 30 weight parts of dropping 99.6%, reaction 5-7h, slowly drip 98.6% chlorsulfonic acid 50 weight parts, 6 hours dropping time, reaction 23-25h, be transferred in the frozen water, the PH=8.25-8.35 that adjusts solution with sodium carbonate solution reacts 5-7h, is cooled to the 4-6 degree subsequently, filter, get 200 weight part aztreonam monocycle parent nucleus crude products;
5) get the aztreonam monocycle parent nucleus crude product of step 4) gained, add water 600 weight parts, stirring and dissolving, be heated to 50 ℃, filter, be cooled to 15 ℃, centrifuge dehydration, must make with extra care aztreonam monocycle parent nucleus 50 weight parts, behind the hydrogenation, add 31% refining hydrochloric acid 20 weight parts, dropping is in reaction solution, be cooled to 0 ℃, reacted 6 hours, filtration, the dry aztreonam monocycle parent nucleus finished product that gets.
The method of the described hydrogenation of step 5) is: refining aztreonam monocycle parent nucleus 50 weight parts of getting the step 5) gained, add methyl alcohol 200 weight parts, suction filtration is to the hydrogenation axe, be cooled to 15 ℃, palladium carbon 2 weight parts of adding 5%, nitrogen are caught up with sky twice, feed hydrogen again, logical H-H reaction 4 hours, the nitrogen press filtration of row's hydrogen.
Weight part of the present invention adopts gram or kilogram.
Reagent of the present invention all adopts commercially available conventional reagent.
Percentage concentration of the present invention is weight percent concentration.
Technique effect of the present invention is:
1. adopt from esterification intact after, add methyl alcohol, increase water-solublely, carry out the CBZ protective reaction, thereby improved quality product, its transformation efficiency can reach more than 98%, raising total recovery height.
2. this process using yellow soda ash carries out ring-closure reaction, the yield height, and production cost is low, and the total recovery of product is about 48%.
Adopt the aztreonam monocycle parent nucleus of the inventive method preparation, in May, 2011 through the check of Chongqing City's food and medicine check (report number is: 2011T0232), its result is an aztreonam monocycle parent nucleus for products obtained therefrom, and specifically detection thes contents are as follows:
Embodiment
The method for preparing aztreonam monocycle parent nucleus is as follows:
1) getting weight percent concentration is 200 kilograms of 99.5% methyl alcohol, add weight percent concentration and be 50 kilograms of 99.6% Threonines, be cooled to 3-5 ℃, drip weight percent concentration and be 50 kilograms of 99.2% sulfur oxychlorides, the temperature that is heated to solution is 35-45 ℃, reacts 15-17 hour, after the underpressure distillation, add 125 kilograms of 99.5% methyl alcohol, drip saturated solution of sodium carbonate, the pH value of adjusting solution is 7-8; Drip 50 kilograms of chloroformic acid benzyl esters, reaction 3-5h filters, and gets 105 kilograms beta-hydroxy N-formyl benzyl ester Threonine methyl esters;
2) the beta-hydroxy N-formyl benzyl ester Threonine methyl esters that obtains in the step 1) is joined in the retort, add 200 kilograms of methyl alcohol, 50 kilograms of slowly logical ammonia, reaction 29-31h, underpressure distillation;
60 kilograms of the toluene of adding 99.4% after 3) underpressure distillation finishes, dissolving, crystallisation by cooling, filtration drying get 75 kilograms of Threonine acid amides xln;
4) get 0 kilogram of the threonyl amine crystal 5 that obtains in the step 3), add 300 kilograms of 99.5% methylene dichloride, 99.3% 2-picoline double centner, 30 kilograms of the methane sulfonyl chlorides of dropping 99.6%, reaction 5-7h slowly drips 50 kilograms of 98.6% chlorsulfonic acids, 6 hours dropping time, reaction 23-25h, be transferred in the frozen water, the PH=8.25-8.35 that adjusts solution with sodium carbonate solution reacts 5-7h, is cooled to the 4-6 degree subsequently, filter, get 200 kilograms of aztreonam monocycle parent nucleus crude products;
5) get 200 kilograms of the aztreonam monocycle parent nucleus crude products of step 4) gained, add 600 kilograms in water, stirring and dissolving, be heated to 50 ℃, filter, be cooled to 15 ℃, centrifuge dehydration must be made with extra care 50 kilograms of aztreonam monocycle parent nucleus, hydrogenation: get 50 kilograms of refining aztreonam monocycle parent nucleus, add the weight percentage concentration and be 200 kilograms of 99.5% methyl alcohol, suction filtration is cooled to 15 ℃ to the hydrogenation axe, 2 kilograms in the palladium carbon of adding 5%, nitrogen are caught up with sky twice, feed hydrogen again, logical H-H reaction 4 hours, the nitrogen press filtration of row's hydrogen.20 kilograms of the refining hydrochloric acid of adding 31% drip in reaction solution, are cooled to 0 ℃, reacted 6 hours, and filtration, the dry aztreonam monocycle parent nucleus finished product that gets, the total recovery of aztreonam monocycle parent nucleus finished product is about 48%.
Claims (2)
1. the preparation method of an aztreonam monocycle parent nucleus is characterized in that following steps are arranged:
1) gets 99.5% methyl alcohol 200 weight parts, Threonine 50 weight parts of adding 99.6%, be cooled to 3-5 ℃, sulfur oxychloride 50 weight parts of dropping 99.2%, the temperature that is heated to solution is 35-45 ℃, reacts 15-17 hour, after the underpressure distillation, add 99.5% methyl alcohol 125 weight parts, drip saturated solution of sodium carbonate, the pH value of adjusting solution is 7-8; Drip chloroformic acid benzyl ester 50 weight parts, reaction 3-5h filters, and gets the beta-hydroxy N-formyl benzyl ester Threonine methyl esters of 105 weight parts;
2) the beta-hydroxy N-formyl benzyl ester Threonine methyl esters that obtains in the step 1) is joined in the retort, add methyl alcohol 200 weight parts, slowly logical ammonia 50 weight parts, reaction 29-31h, underpressure distillation;
3) underpressure distillation finishes toluene 60 weight parts of back adding 99.4%, dissolving, and crystallisation by cooling, filtration drying get 75 weight part Threonine acid amides xln;
4) get threonyl amine crystal 50 weight part that obtains in the step 3), methylene dichloride 300 weight parts of adding 99.5%, 99.3% 2-picoline 100 weight parts, methane sulfonyl chloride 30 weight parts of dropping 99.6%, reaction 5-7h, slowly drip 98.6% chlorsulfonic acid 50 weight parts, 6 hours dropping time, reaction 23-25h, be transferred in the frozen water, the PH=8.25-8.35 that adjusts solution with sodium carbonate solution reacts 5-7h, is cooled to the 4-6 degree subsequently, filter, get 200 weight part aztreonam monocycle parent nucleus crude products;
5) get the aztreonam monocycle parent nucleus crude product of step 4) gained, add water 600 weight parts, stirring and dissolving, be heated to 50 ℃, filter, be cooled to 15 ℃, centrifuge dehydration, must make with extra care aztreonam monocycle parent nucleus 50 weight parts, behind the hydrogenation, add 31% refining hydrochloric acid 20 weight parts, dropping is in reaction solution, be cooled to 0 ℃, reacted 6 hours, filtration, the dry aztreonam monocycle parent nucleus finished product that gets.
2. the preparation method of aztreonam monocycle parent nucleus according to claim 1, it is characterized in that: the method for the described hydrogenation of step 5) is: refining aztreonam monocycle parent nucleus 50 weight parts of getting the step 5) gained, add methyl alcohol 200 weight parts, suction filtration is cooled to 15 ℃ to the hydrogenation axe, adds 5% palladium carbon 2 weight parts, nitrogen is caught up with empty twice, feed hydrogen again, logical H-H reaction 4 hours, the nitrogen press filtration of row's hydrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110280182.9A CN102285907B (en) | 2011-09-20 | 2011-09-20 | The preparation method of aztreonam monocycle parent nucleus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110280182.9A CN102285907B (en) | 2011-09-20 | 2011-09-20 | The preparation method of aztreonam monocycle parent nucleus |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102285907A true CN102285907A (en) | 2011-12-21 |
| CN102285907B CN102285907B (en) | 2016-03-16 |
Family
ID=45332686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110280182.9A Active CN102285907B (en) | 2011-09-20 | 2011-09-20 | The preparation method of aztreonam monocycle parent nucleus |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102285907B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102807519A (en) * | 2012-08-14 | 2012-12-05 | 济南瑞丰医药科技有限公司 | Preparation method of aztreonam side-chain small ring |
| CN105418474A (en) * | 2015-12-21 | 2016-03-23 | 山东金城医药化工股份有限公司 | Refining method for main ring of aztreonam |
| CN105481731A (en) * | 2015-12-21 | 2016-04-13 | 山东金城医药化工股份有限公司 | Preparation method of N-sulpho-N-carbobenzoxy-O-methane sulfonyl-L-threonine chlorseptol |
| CN108341764A (en) * | 2017-01-25 | 2018-07-31 | 重庆常捷医药有限公司 | A kind of synthetic method of aztreonam parent nucleus |
| CN111533674A (en) * | 2020-04-09 | 2020-08-14 | 北京世纪迈劲生物科技有限公司 | Preparation method of aztreonam main ring intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362713A (en) * | 2008-09-17 | 2009-02-11 | 重庆莱美药业股份有限公司 | Preparation method of (3S-trans)-3-amido-4-methyl-2-oxo-1-sulfoazetidine |
-
2011
- 2011-09-20 CN CN201110280182.9A patent/CN102285907B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362713A (en) * | 2008-09-17 | 2009-02-11 | 重庆莱美药业股份有限公司 | Preparation method of (3S-trans)-3-amido-4-methyl-2-oxo-1-sulfoazetidine |
Non-Patent Citations (1)
| Title |
|---|
| 张宏等: "氨曲南小单环的合成工艺研究", 《化学世界》, vol. 50, no. 9, 25 September 2009 (2009-09-25), pages 547 - 548 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102807519A (en) * | 2012-08-14 | 2012-12-05 | 济南瑞丰医药科技有限公司 | Preparation method of aztreonam side-chain small ring |
| CN105418474A (en) * | 2015-12-21 | 2016-03-23 | 山东金城医药化工股份有限公司 | Refining method for main ring of aztreonam |
| CN105481731A (en) * | 2015-12-21 | 2016-04-13 | 山东金城医药化工股份有限公司 | Preparation method of N-sulpho-N-carbobenzoxy-O-methane sulfonyl-L-threonine chlorseptol |
| CN108341764A (en) * | 2017-01-25 | 2018-07-31 | 重庆常捷医药有限公司 | A kind of synthetic method of aztreonam parent nucleus |
| CN108341764B (en) * | 2017-01-25 | 2021-02-09 | 重庆常捷医药有限公司 | Synthetic method of aztreonam mother nucleus |
| CN111533674A (en) * | 2020-04-09 | 2020-08-14 | 北京世纪迈劲生物科技有限公司 | Preparation method of aztreonam main ring intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102285907B (en) | 2016-03-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10919887B2 (en) | Salts and solid forms of a monobactam antibiotic | |
| CN102285907A (en) | Method for preparing aztreonam monocyclic parent nucleus | |
| CN102199111B (en) | Process and intermediates for the preparation of hepatitis C virus protease inhibitor | |
| CN1227542A (en) | N-substituted indol-3-glyoxylamid with antiasthmatic, antiallergic and immunosuppressive/immunomodulating effect | |
| CN104961672A (en) | Synthetic method of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidine-4-yl)-N'-(4-isobutoxybenzyl)urea | |
| US20040242556A1 (en) | Novel crystalline form of cefdinir | |
| CN103319502B (en) | Sulbenicillin sodium preparation method | |
| CN107501268B (en) | Preparation method of tebipenem pivoxil and intermediate thereof | |
| WO2019026014A1 (en) | Processes for preparation of lifitegrast and intermediates thereof | |
| CN103242305A (en) | Azilsartan preparation method | |
| US20130005974A1 (en) | Synthesis of a neurostimulative piperazine | |
| CN102127068B (en) | Method for synthesizing aztreonam compound | |
| CN104193765A (en) | Method for synthesizing cefixime | |
| CN107445950B (en) | Refining method of tebipenem pivoxil side chain | |
| CN101941982B (en) | Novel preparation method of pharmaceutical ceforanide | |
| CN103044416A (en) | Synthetic method of Carumonam sodium | |
| CN111253315A (en) | Imidapril hydrochloride organic impurity and preparation method thereof | |
| US9382207B2 (en) | Process for the preparation of atazanavir bisulfate | |
| CN106222230A (en) | A kind of method of green enzymatic clarification cefaclor | |
| CN114409677A (en) | Preparation method of high-purity cefotaxime acid | |
| CN114591299A (en) | Paroviride intermediate and preparation and application thereof | |
| US20230271921A1 (en) | Synthesis of (2s,5r)-5-(2-chlorophenyl)-1-(2'-methoxy-[1,1'-biphenyl]-4- carbonyl)pyrrolidine-2-carboxylic acid | |
| CN110804635A (en) | Synthesis method of latamoxef sodium | |
| CN102858739A (en) | A process for amidation of pyrrole carboxylate compounds | |
| CN102443014B (en) | 3-cefaclor derivative as well as synthesis method and application thereof in preparation of cefaclor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |