CN105061508A - Synthesis method of carbapenem antibiotic parent nucleus MAP - Google Patents
Synthesis method of carbapenem antibiotic parent nucleus MAP Download PDFInfo
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- CN105061508A CN105061508A CN201510559130.3A CN201510559130A CN105061508A CN 105061508 A CN105061508 A CN 105061508A CN 201510559130 A CN201510559130 A CN 201510559130A CN 105061508 A CN105061508 A CN 105061508A
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Abstract
The invention discloses a synthesis method of carbapenem antibiotic parent nucleus MAP. Compared with the prior art, the method redesigns an MAP synthesis route, enhances the synthesis efficiency, has the advantages of lower reaction raw material price, low reaction conditions and lower three wastes, lowers the energy consumption and cost, and satisfies the environment-friendly requirement.
Description
Technical field
The invention belongs to medicine intermediate field, be specifically related to the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP.
Background technology
Carbapenem antibiotic is the β-lactam antibitics that 20 century 70s start to research and develop the class brand new probed into.Such medicine has the advantages such as anti-microbial activity is extremely strong, antimicrobial spectrum is extremely wide and highly stable to β-lactamase, toxicity is lower, based on the quality that these are rare, nowadays it has been clinical treatment bacterium mixed infection, especially the very effective antibacterials of a class of severe and postoperative bacterium severe infections, and the critical role that cannot replace has been occupied on global microbiotic market.
1976, the Merck & Co., Inc. investigator of the U.S. extracted sulfomycin from livestock streptomycete fermentation liquid, and this is first historically carbapenem antibiotic, and found that it can make the bacterium of human disease have certain antagonistic action to multiple.
In the middle of microbiotic known now, carbapenem antibiotic is the class antibacterials that anti-microbial effect is extremely strong, antimicrobial spectrum is extremely wide.From the clinical application of several carbapenems medicines gone on the market, its good curative effect had has obtained society and clinical affirmative.But it is not long that such medicine enters China's time, domestic clinical application be import medicine substantially, major cause be its parent nucleus be difficult to synthesis.Meropenem has uniquely dropped into production at home, and have 4 domestic medicine enterprises by the examination & approval of National Drug Administration, can carry out the related products producing meropenem.Nowadays the market growth of this type of medicine obtains very swift and violent.Wherein the worldwide sales of carbapenem antibiotic in 2009 accounts for 10% share in microbiotic market in the world, reaches 3,000,000,000 dollars.2005 ~ 2008 years carbapenem antibiotic market continues to rise at home, and wherein such drug product amount of money in 2008 reaches 22.64 hundred million yuan, but also in continuation increases.In recent years, along with China uses in a large number to microbiotic without stint, pathogenic bacterium resistance is constantly increased, the infection of multi-drug resistant bacteria and the generation of complete Resistant strain even occur, and are a kind of acid tests for clinical anti-infective therapy.But ask not long during the use of carbapenem antibiotic clinical treatment at home, also be not enough to manifest obvious resistance, add that this type of medicine has and all has very high activity and has a broad antifungal spectrum to multiple drug-resistant bacteria, the distinguishing features such as bad toxic side effects is few and light, become the weapon that clinical antagonism Resistant strain is strong.
Along with China's microbiotic industrial expansion, and the clinical drug-resistant bacterium problem of serious existence instantly, carbapenem antibiotic is the highly effective medicine of a kind for the treatment of for severe infection beyond doubt.And the preparation of synthesizing such antibiotic key intermediate parent nucleus MAP just seems and is even more important, the optimization improvement of its production method will produce huge economic results in society.
The three wastes of MAP synthetic method of the prior art are more, can not meet the requirement to environmental protection.
Summary of the invention
The technical problem to be solved in the present invention is to provide the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP.
Technical scheme of the present invention is: the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP, is characterized in that, comprise the following steps:
1) in the reaction vessel of nitrogen protection, add propanedioic acid to nitrobenzyl alcohol monoesters, methylene dichloride, Magnesium Chloride Anhydrous, and at room temperature drip triethylamine, reaction 2 ~ 3h, obtains anhydrous magnesium salts;
2) in the reaction vessel of nitrogen protection, 4-MBA, methylene dichloride, N is added, N-carbonyl-diimidazole (CDI) and anhydrous magnesium salts, 7 ~ 8h is incubated at 20 ~ 30 DEG C, hydrochloric acid is added after being cooled to 20 ~ 30 DEG C, stir 20 ~ 30min, stratification is also separated the organic solution that organic layer obtains intermediate A;
3) in the organic solution of intermediate A, tolylsulfonyl nitrine is added, be warming up to 50 DEG C of reaction 1 ~ 2h, carry out concentrated obtaining pale tan oil at 40 ~ 45 DEG C, then in pale tan oil, add Virahol, be cooled to 5 ~ 10 DEG C and carry out crystallization, solid-liquid separation obtains intermediate B;
4) intermediate B be added in acetone and water, heat to 40 ~ 50 DEG C, reaction 10 ~ 11h, then add sodium hydroxide solution and regulate pH to neutral, underpressure distillation is also filtered and obtained filter cake is intermediate C;
5) in reaction vessel, add intermediate C, ethyl acetate, rhodium caprylate catalyzer temperature-elevating to 70 ~ 75 DEG C insulation 20 ~ 30min, be cooled to-5 DEG C, and diphenyl phosphoryl chlorine and diisopropylethylamine is dripped below-5 DEG C, after stirring 30 ~ 50min, carry out layering, in organic layer, add diphenyl phosphoryl chlorine, after reaction terminates, organic layer be separated and carry out crystallization, after filtration, obtaining MAP.
Further, step 1) in propanedioic acid to nitrobenzyl alcohol monoesters 7 ~ 8 weight part, methylene dichloride 10 ~ 15 weight part, Magnesium Chloride Anhydrous 1 ~ 2 weight part, triethylamine 1 ~ 2 weight part.
Further, step 2) in 4-MBA10 ~ 15 weight parts, methylene dichloride 20 ~ 30 weight part, CDI5 ~ 6 weight part.
Further, step 3) middle tolylsulfonyl nitrine 5 ~ 10 weight part.
Further, step 5) middle ethyl acetate 40 ~ 50 weight part, rhodium caprylate catalyzer 0.1 ~ 0.2 weight part, diphenyl phosphoryl chlorine 5 ~ 10 weight part, diisopropylethylamine 2 ~ 5 weight part.
Further, the structural formula of intermediate A is
Further, the structural formula of intermediate B is
Further, the structural formula of intermediate C is
Synthetic route of the present invention is:
Compared with prior art, the present invention has redesigned the synthetic route of a MAP, improves combined coefficient, and reaction raw materials price is lower, and reaction conditions is not harsh, relatively reduce energy consumption and cost, and the three wastes is relatively low, meets the requirement to environmental protection.
Embodiment
Embodiment 1
A synthetic method of carbapenem antibiotic parent nucleus MAP, is characterized in that, comprises the following steps:
1) in the reaction vessel of nitrogen protection, add propanedioic acid to nitrobenzyl alcohol monoesters, methylene dichloride, Magnesium Chloride Anhydrous, and at room temperature drip triethylamine, reaction 3h, obtains anhydrous magnesium salts;
2) in the reaction vessel of nitrogen protection, add 4-MBA, methylene dichloride, CDI and anhydrous magnesium salts, be incubated 7 ~ 8h, add hydrochloric acid after being cooled to 25 DEG C at 30 DEG C, stir 30min, stratification is also separated the organic solution that organic layer obtains intermediate A;
3) in the organic solution of intermediate A, tolylsulfonyl nitrine is added, be warming up to 50 DEG C of reaction 2h, carry out concentrated obtaining pale tan oil at 40 DEG C, then in pale tan oil, add Virahol, be cooled to 5 ~ 10 DEG C and carry out crystallization, solid-liquid separation obtains intermediate B;
4) intermediate B be added in acetone and water, heat to 45 DEG C, reaction 11h, then add sodium hydroxide solution and regulate pH to neutral, underpressure distillation is also filtered and obtained filter cake is intermediate C;
5) in reaction vessel, add intermediate C, ethyl acetate, rhodium caprylate catalyzer temperature-elevating to 75 DEG C insulation 20min, be cooled to-5 DEG C, and diphenyl phosphoryl chlorine and diisopropylethylamine is dripped below-5 DEG C, after stirring 30 ~ 50min, carry out layering, in organic layer, add diphenyl phosphoryl chlorine, after reaction terminates, organic layer be separated and carry out crystallization, after filtration, obtaining MAP.
Further, step 1) in propanedioic acid to nitrobenzyl alcohol monoesters 8 weight part, methylene dichloride 15 weight part, Magnesium Chloride Anhydrous 1 weight part, triethylamine 1 weight part.
Further, step 2) middle 4-MBA15 weight part, methylene dichloride 30 weight part, CDI5 weight part.
Further, step 3) middle tolylsulfonyl nitrine 5 weight part.
Further, step 5) middle ethyl acetate 40 weight part, rhodium caprylate catalyzer 0.1 weight part, diphenyl phosphoryl chlorine 10 weight part, diisopropylethylamine 5 weight part.
Embodiment 2
A synthetic method of carbapenem antibiotic parent nucleus MAP, is characterized in that, comprises the following steps:
1) in the reaction vessel of nitrogen protection, add propanedioic acid to nitrobenzyl alcohol monoesters, methylene dichloride, Magnesium Chloride Anhydrous, and at room temperature drip triethylamine, reaction 2h, obtains anhydrous magnesium salts;
2) in the reaction vessel of nitrogen protection, add 4-MBA, methylene dichloride, CDI and anhydrous magnesium salts, at 20 DEG C, be incubated 7h, add hydrochloric acid after being cooled to 20 DEG C, stir 20min, stratification is also separated the organic solution that organic layer obtains intermediate A;
3) in the organic solution of intermediate A, tolylsulfonyl nitrine is added, be warming up to 50 DEG C of reaction 1h, carry out concentrated obtaining pale tan oil at 40 DEG C, then in pale tan oil, add Virahol, be cooled to 5 DEG C and carry out crystallization, solid-liquid separation obtains intermediate B;
4) intermediate B be added in acetone and water, heat to 40 ~ 50 DEG C, reaction 10h, then add sodium hydroxide solution and regulate pH to neutral, underpressure distillation is also filtered and obtained filter cake is intermediate C;
5) in reaction vessel, add intermediate C, ethyl acetate, rhodium caprylate catalyzer temperature-elevating to 70 DEG C insulation 20min, be cooled to-5 DEG C, and diphenyl phosphoryl chlorine and diisopropylethylamine is dripped below-5 DEG C, after stirring 30min, carry out layering, in organic layer, add diphenyl phosphoryl chlorine, after reaction terminates, organic layer be separated and carry out crystallization, after filtration, obtaining MAP.
Further, step 1) in propanedioic acid to nitrobenzyl alcohol monoesters 7 weight part, methylene dichloride 10 weight part, Magnesium Chloride Anhydrous 1 weight part, triethylamine 1 weight part.
Further, step 2) middle 4-MBA10 weight part, methylene dichloride 20 weight part, CDI5 weight part.
Further, step 3) middle tolylsulfonyl nitrine 5 weight part.
Further, step 5) middle ethyl acetate 40 weight part, rhodium caprylate catalyzer 0.1 weight part, diphenyl phosphoryl chlorine 5 weight part, diisopropylethylamine 2 weight part.
Embodiment 3
A synthetic method of carbapenem antibiotic parent nucleus MAP, is characterized in that, comprises the following steps:
1) in the reaction vessel of nitrogen protection, add propanedioic acid to nitrobenzyl alcohol monoesters, methylene dichloride, Magnesium Chloride Anhydrous, and at room temperature drip triethylamine, reaction 3h, obtains anhydrous magnesium salts;
2) in the reaction vessel of nitrogen protection, add 4-MBA, methylene dichloride, CDI and anhydrous magnesium salts, at 30 DEG C, be incubated 8h, add hydrochloric acid after being cooled to 30 DEG C, stir 30min, stratification is also separated the organic solution that organic layer obtains intermediate A;
3) in the organic solution of intermediate A, tolylsulfonyl nitrine is added, be warming up to 50 DEG C of reaction 2h, carry out concentrated obtaining pale tan oil at 45 DEG C, then in pale tan oil, add Virahol, be cooled to 10 DEG C and carry out crystallization, solid-liquid separation obtains intermediate B;
4) intermediate B be added in acetone and water, heat to 50 DEG C, reaction 11h, then add sodium hydroxide solution and regulate pH to neutral, underpressure distillation is also filtered and obtained filter cake is intermediate C;
5) in reaction vessel, add intermediate C, ethyl acetate, rhodium caprylate catalyzer temperature-elevating to 75 DEG C insulation 30min, be cooled to-5 DEG C, and diphenyl phosphoryl chlorine and diisopropylethylamine is dripped below-5 DEG C, after stirring 50min, carry out layering, in organic layer, add diphenyl phosphoryl chlorine, after reaction terminates, organic layer be separated and carry out crystallization, after filtration, obtaining MAP.
Further, step 1) in propanedioic acid to nitrobenzyl alcohol monoesters 8 weight part, methylene dichloride 15 weight part, Magnesium Chloride Anhydrous 2 weight part, triethylamine 2 weight part.
Further, step 2) middle 4-MBA15 weight part, methylene dichloride 30 weight part, CDI6 weight part.
Further, step 3) middle tolylsulfonyl nitrine 10 weight part.
Further, step 5) middle ethyl acetate 0 weight part, rhodium caprylate catalyzer 0.2 weight part, diphenyl phosphoryl chlorine 10 weight part, diisopropylethylamine 5 weight part.
Embodiment 4
A synthetic method of carbapenem antibiotic parent nucleus MAP, is characterized in that, comprises the following steps:
1) in the reaction vessel of nitrogen protection, add propanedioic acid to nitrobenzyl alcohol monoesters, methylene dichloride, Magnesium Chloride Anhydrous, and at room temperature drip triethylamine, reaction 3h, obtains anhydrous magnesium salts;
2) in the reaction vessel of nitrogen protection, add 4-MBA, methylene dichloride, CDI and anhydrous magnesium salts, at 0 DEG C, be incubated 8h, add hydrochloric acid after being cooled to 20 ~ 30 DEG C, stir 30min, stratification is also separated the organic solution that organic layer obtains intermediate A;
3) in the organic solution of intermediate A, tolylsulfonyl nitrine is added, be warming up to 50 DEG C of reaction 2h, carry out concentrated obtaining pale tan oil at 45 DEG C, then in pale tan oil, add Virahol, be cooled to 5 DEG C and carry out crystallization, solid-liquid separation obtains intermediate B;
4) intermediate B be added in acetone and water, heat to 50 DEG C, reaction 11h, then add sodium hydroxide solution and regulate pH to neutral, underpressure distillation is also filtered and obtained filter cake is intermediate C;
5) in reaction vessel, add intermediate C, ethyl acetate, rhodium caprylate catalyzer temperature-elevating to 75 DEG C insulation 20min, be cooled to-5 DEG C, and diphenyl phosphoryl chlorine and diisopropylethylamine is dripped below-5 DEG C, after stirring 30min, carry out layering, in organic layer, add diphenyl phosphoryl chlorine, after reaction terminates, organic layer be separated and carry out crystallization, after filtration, obtaining MAP.
Further, step 1) in propanedioic acid to nitrobenzyl alcohol monoesters 8 weight part, methylene dichloride 15 weight part, Magnesium Chloride Anhydrous 2 weight part, triethylamine 2 weight part.
Further, step 2) middle 4-MBA15 weight part, methylene dichloride 30 weight part, CDI6 weight part.
Further, step 3) middle tolylsulfonyl nitrine 10 weight part.
Further, step 5) middle ethyl acetate 40 weight part, rhodium caprylate catalyzer 0.2 weight part, diphenyl phosphoryl chlorine 5 weight part, diisopropylethylamine 2 weight part.
Claims (8)
1. a synthetic method of carbapenem antibiotic parent nucleus MAP, is characterized in that, comprises the following steps:
1) in the reaction vessel of nitrogen protection, add propanedioic acid to nitrobenzyl alcohol monoesters, methylene dichloride, Magnesium Chloride Anhydrous, and at room temperature drip triethylamine, reaction 2 ~ 3h, obtains anhydrous magnesium salts;
2) in the reaction vessel of nitrogen protection, 4-MBA, methylene dichloride, CDI and anhydrous magnesium salts is added, 7 ~ 8h is incubated at 20 ~ 30 DEG C, add hydrochloric acid after being cooled to 20 ~ 30 DEG C, stir 20 ~ 30min, stratification is also separated the organic solution that organic layer obtains intermediate A;
3) in the organic solution of intermediate A, tolylsulfonyl nitrine is added, be warming up to 50 DEG C of reaction 1 ~ 2h, carry out concentrated obtaining pale tan oil at 40 ~ 45 DEG C, then in pale tan oil, add Virahol, be cooled to 5 ~ 10 DEG C and carry out crystallization, solid-liquid separation obtains intermediate B;
4) intermediate B be added in acetone and water, heat to 40 ~ 50 DEG C, reaction 10 ~ 11h, then add sodium hydroxide solution and regulate pH to neutral, underpressure distillation is also filtered and obtained filter cake is intermediate C;
5) in reaction vessel, add intermediate C, ethyl acetate, rhodium caprylate catalyzer temperature-elevating to 70 ~ 75 DEG C insulation 20 ~ 30min, be cooled to-5 DEG C, and drip diphenyl phosphoryl chlorine and diisopropylethylamine once at-5 DEG C, after stirring 30 ~ 50min, carry out layering, in organic layer, add diphenyl phosphoryl chlorine, after reaction terminates, organic layer be separated and carry out crystallization, after filtration, obtaining MAP.
2. the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP according to claim 1, it is characterized in that, step 1) in propanedioic acid to nitrobenzyl alcohol monoesters 7 ~ 8 weight part, methylene dichloride 10 ~ 15 weight part, Magnesium Chloride Anhydrous 1 ~ 2 weight part, triethylamine 1 ~ 2 weight part.
3. the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP according to claim 1, is characterized in that, step 2) in 4-MBA10 ~ 15 weight parts, methylene dichloride 20 ~ 30 weight part, CDI5 ~ 6 weight part.
4. the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP according to claim 1, is characterized in that, step 3) middle tolylsulfonyl nitrine 5 ~ 10 weight part.
5. the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP according to claim 1, it is characterized in that, step 5) middle ethyl acetate 40 ~ 50 weight part, rhodium caprylate catalyzer 0.1 ~ 0.2 weight part, diphenyl phosphoryl chlorine 5 ~ 10 weight part, diisopropylethylamine 2 ~ 5 weight part.
6. the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP according to claim 1, is characterized in that, the structural formula of intermediate A is
7. the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP according to claim 1, is characterized in that, the structural formula of intermediate B is
8. the synthetic method of a kind of carbapenem antibiotic parent nucleus MAP according to claim 1, is characterized in that, the structural formula of intermediate C is
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108948086A (en) * | 2018-08-22 | 2018-12-07 | 浙江海翔川南药业有限公司 | Train the synthesis technology and process system of southern class antibiotic parent nucleus MAP |
| CN115521338A (en) * | 2022-11-04 | 2022-12-27 | 山东金城医药化工有限公司 | Preparation method of meropenem intermediate MAP |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06321946A (en) * | 1992-07-08 | 1994-11-22 | Takeda Chem Ind Ltd | Production of carbapenems |
| CN101560219A (en) * | 2008-04-14 | 2009-10-21 | 深圳市海滨制药有限公司 | Synthetic method of 1 beta methyl carbapenem antibiotic midbody |
| CN103214507A (en) * | 2013-04-10 | 2013-07-24 | 浙江九洲药业股份有限公司 | Preparation method of nitrogen heterocyclic compound |
-
2015
- 2015-09-06 CN CN201510559130.3A patent/CN105061508A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06321946A (en) * | 1992-07-08 | 1994-11-22 | Takeda Chem Ind Ltd | Production of carbapenems |
| CN101560219A (en) * | 2008-04-14 | 2009-10-21 | 深圳市海滨制药有限公司 | Synthetic method of 1 beta methyl carbapenem antibiotic midbody |
| CN103214507A (en) * | 2013-04-10 | 2013-07-24 | 浙江九洲药业股份有限公司 | Preparation method of nitrogen heterocyclic compound |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108948086A (en) * | 2018-08-22 | 2018-12-07 | 浙江海翔川南药业有限公司 | Train the synthesis technology and process system of southern class antibiotic parent nucleus MAP |
| CN108948086B (en) * | 2018-08-22 | 2020-12-01 | 浙江海翔川南药业有限公司 | Synthetic process and process system of mother nucleus MAP of penem antibiotics |
| CN115521338A (en) * | 2022-11-04 | 2022-12-27 | 山东金城医药化工有限公司 | Preparation method of meropenem intermediate MAP |
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