CN101591282A - The synthetic method of aztreonam intermediate 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid - Google Patents
The synthetic method of aztreonam intermediate 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid Download PDFInfo
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Abstract
The present invention relates to organic chemistry filed, be a kind of synthetic method of aztreonam main ring, especially a kind of synthetic method by [2+2] prepared in reaction aztreonam intermediate 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid.With (R; E)-the phthalic imidine Acetyl Chloride 98Min. (I) of tertiary butyl sulfonamido ethyl imines (II) and equimolar amount is initial step under organic base catalytic; [2+2] reaction with chiral substrates control obtains key intermediate 3-amino-2-methyl-4-oxo-1-azetidinyl sulfonic acid through removing with sulfonylation of overprotection then.Committed step is a step to have produced needed two chiral centres, and step is few, the total yield height, and total yield can reach 27%, and the yield of the rapid reaction of more former multistep is doubled many.This route is suitable for suitability for industrialized production.
Description
Technical field
The present invention relates to organic chemistry filed, be a kind of synthetic method of aztreonam main ring, especially a kind of synthetic method by [2+2] prepared in reaction aztreonam intermediate 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid.
Background technology
Aztreonam is first synthetic monocycle antibiotic of U.S. Bristol-Myers Squibb Co. (Bristol-Myers Squibb Co) research and development.Its synthetic method is at patent US4, report all arranged in 533,670, US4,775,670 and US5,194,604.Shown in synthetic route 1,, obtained 3-amino-2-methyl-4-oxo-1-azetidinyl sulfonic acid through the reaction of 7 steps from the L-Threonine.
Synthetic route 1:
Above-mentioned intermediate 3-amino-2-methyl-4-oxo-1-azetidinyl sulfonic acid (VI) obtains aztreonam through further transforming again, and reaction formula is as follows:
The present invention aims to provide a kind of new synthetic route, in the hope of shortening reaction scheme, improves reaction yield.
Summary of the invention
Technical problem to be solved by this invention is to provide the synthetic method of a kind of aztreonam main ring 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, and this method has shortened reaction scheme, obtains cheap and good-quality product.
The present invention solves the problems of the technologies described above the technical scheme of being taked: the synthetic method of a kind of aztreonam intermediate 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid comprises the steps:
The first step: with (R, E)-the phthalic imidine Acetyl Chloride 98Min. (I) of tertiary butyl sulfonamido ethyl imines (II) and equimolar amount is under organic base catalytic, carry out [2+2] reaction and generate 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo-1-azelidinyl]-3-isoindole-1,3-diketone (III), wherein, described organic bases is NR
3, R is for being C
1～C
8A kind of in alkyl, alkyl morphine quinoline, Alkylpiperidine, the pyridine, reaction formula is:
Second step: with 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo-1-azelidinyl]-3-isoindole-1,3-diketone (III) is oxidized to tertiary butyl sulfoamido with oxygenant with tertiary butyl sulfonamido, remove tertiary butyl sulfoamido with acid again, make 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1,3-diketone (IV), wherein, described oxygenant is a clorox, sodium chlorate, hydrogen peroxide, a kind of in the peroxycarboxylic acid, described acid is hydrochloric acid, sulfuric acid, nitric acid, a kind of in the alkyl carboxylic acid, reaction formula is:
The 3rd step: at 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1, add the sulphur trioxide pyridine in the 3-diketone (IV), sulfonation reaction makes (2S, 3S)-and 3-(1,3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V), wherein, compound (IV) is 1: 1～5 with the mol ratio of sulphur trioxide pyridine, and reaction formula is:
The 4th step: at (2S, 3S)-3-(1, add the N-methyl hydrazine in 3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V) and remove 1,3-dioxy-pseudoindoyl, make 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (VI), wherein, compound (V) is 1: 1～3 with the mol ratio of N-methyl hydrazine, and reaction formula is:
Concrete, compound (IV) can be 1: 1,1.5,2,2.5,3,3.5,4,4.5 or 5 with the mol ratio of sulphur trioxide pyridine;
Compound (V) can be 1: 1,1.5,2,2.5 or 3 with the mol ratio of N-methyl hydrazine.
On the basis of such scheme, in the first step, with (R, E)-tertiary butyl sulfonamido ethyl imines (II) is dissolved in the organic solvent, add organic bases, be cooled to freezing point, phthalic imidine Acetyl Chloride 98Min. (I) is dissolved in wiring solution-forming in the organic solvent, drip the organic solution of phthalic imidine Acetyl Chloride 98Min. (I), be warming up to room temperature reaction 1～2 hour, make 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo aza ring butyl]-3-isoindole-1,3-diketone (III).
On the basis of such scheme, in the first step, described organic bases is preferably triethylamine.
On the basis of such scheme, in second step, with 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo-1-azelidinyl]-3-isoindole-1,3-diketone (III) is dissolved in the organic solvent, adds oxygenant in freezing point, stirs 2～4 hours, separatory, the organic phase washing adds organic solvent and acid, is heated to 40～100 ℃ and refluxes 1～3 hour, separatory, water extraction, organic phase merge the back and concentrate, and make 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1,3-diketone (IV).
On the basis of such scheme, in second step, described oxygenant is preferably clorox, and acid is hydrochloric acid.
On the basis of such scheme, in the 3rd step, with 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1,3-diketone (IV) is dissolved in the organic solvent, adds the sulphur trioxide pyridine, is heated to 65～75 ℃ of reactions 2.5～4 hours, pour frozen water after the cooling into, extraction, recrystallization makes (2S, 3S)-and 3-(1,3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V).
On the basis of such scheme, in the 4th step, with (2S, 3S)-3-(1,3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V) is dissolved in the organic solvent, adds the N-methyl hydrazine, is heated to 40～100 ℃ and refluxes 4～6 hours, cold filtration, solids wash, filtrate and washings merge, and add acid, separate out solid, make 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (VI).
On the basis of such scheme, in the 4th step, described acid is a kind of in formic acid, acetate, hydrochloric acid, sulfuric acid, the phosphoric acid.
On the basis of such scheme, described organic solvent is a kind of in methylene dichloride, ethylene dichloride, methyl alcohol, ethanol, dimethyl formamide (DMF), tetrahydrofuran (THF), benzene, the toluene.
The invention has the beneficial effects as follows:
Synthesis step of the present invention is few, and route is short, and committed step has produced needed two chiral centres with chiral substrates control [2+2] reaction a, step.Obtain key intermediate 3-amino-2-methyl-4-oxo-1-azetidinyl sulfonic acid through removing of overprotection then with sulfonylation.This route is suitable for suitability for industrialized production.
Embodiment
The synthetic method of a kind of aztreonam intermediate 3-amino-2-methyl-4-oxo-1-azetidinyl sulfonic acid comprises the steps:
The first step: with (R, E)-tertiary butyl sulfonamido ethyl imines (II) (0.2mol) is dissolved in the 500ml methylene dichloride, add triethylamine (0.24mol), be cooled to 0 ℃, drip phthalic imidine Acetyl Chloride 98Min. (I) dichloromethane solution (0.2mol), rise to room temperature then and carry out [2+2] reaction 1 hour, get 2-[(2S after the conventional processing, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo aza ring butyl]-3-isoindole-1,3-diketone (III) reaction formula is:
Second step: with 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo aza ring butyl]-3-isoindole-1,3-diketone (III) (0.18mol) is dissolved in the 500ml methylene dichloride, and 0 ℃ adds aqueous sodium hypochlorite solution 200ml, stirred 3 hours, separatory, organic phase is washed with aqueous solution of sodium bisulfite, adds ethanol 200ml and hydrochloric acid 50ml then, being heated to 70 ℃ refluxed 2 hours, separatory, water dichloromethane extraction, concentrated making after organic phase merges
2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1,3-diketone (IV) reaction formula is:
The 3rd step: with 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1,3-diketone (IV) (0.2mol) is dissolved among the DMF (200ml), add sulphur trioxide pyridine (0.4mol), be heated to 70 ℃ of reactions 3 hours, after the cooling, pour frozen water into, ethyl acetate extraction gets thick product, makes with ethyl alcohol recrystallization
(2S, 3S)-3-(1,3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V), reaction formula is:
The 4th step: with (2S, 3S)-(1,3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V) (0.15mol) is dissolved in the ethanol (500ml) 3-, adds N-methyl hydrazine (0.18mol), being heated to 65 ℃ refluxed 5 hours, cooled and filtered, the solid washing with alcohol, filtrate and washings merge, add formic acid (0.2mol), have solid to separate out, make product 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (VI) after the filtration, reaction formula is:
Total yield reaches 27%, is doubled many than the rapid yield of reacting of existing multistep.
Claims (9)
1, the synthetic method of a kind of aztreonam intermediate 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid is characterized in that comprising the steps:
The first step: with (R, E)-the phthalic imidine Acetyl Chloride 98Min. (I) of tertiary butyl sulfonamido ethyl imines (II) and equimolar amount is under organic base catalytic, reaction generates 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo-1-azelidinyl]-3-isoindole-1,3-diketone (III), wherein, described organic bases is NR
3, R is for being C
1～C
8A kind of in alkyl, alkyl morphine quinoline, Alkylpiperidine, the pyridine, reaction formula is:
Second step: with 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo-1-azelidinyl]-3-isoindole-1,3-diketone (III) is oxidized to tertiary butyl sulfoamido with oxygenant with tertiary butyl sulfonamido, remove tertiary butyl sulfoamido with acid again, make 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1,3-diketone (IV), wherein, described oxygenant is a clorox, sodium chlorate, hydrogen peroxide, a kind of in the peroxycarboxylic acid, described acid is hydrochloric acid, sulfuric acid, nitric acid, a kind of in the alkyl carboxylic acid, reaction formula is:
The 3rd step: at 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1, add the sulphur trioxide pyridine in the 3-diketone (IV), sulfonation reaction makes (2S, 3S)-and 3-(1,3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-ammonia heterocycle butyl sulfonic acid (V), wherein, compound (IV) is 1: 1～5 with the mol ratio of sulphur trioxide pyridine, and reaction formula is:
The 4th step: at (2S, 3S)-3-(1, add the N-methyl hydrazine in 3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V) and remove 1,3-dioxy-pseudoindoyl, make 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (VI), wherein, compound (V) is 1: 1～3 with the mol ratio of N-methyl hydrazine, and reaction formula is:
2, the synthetic method of aztreonam intermediate 3-amino-2-methyl according to claim 1-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, it is characterized in that: in the first step, with (R, E)-tertiary butyl sulfonamido ethyl imines (II) is dissolved in the organic solvent, add organic bases, be cooled to freezing point, phthalic imidine Acetyl Chloride 98Min. (I) is dissolved in wiring solution-forming in the organic solvent, drip the organic solution of phthalic imidine Acetyl Chloride 98Min. (I), drip the organic solvent solution of phthalic imidine Acetyl Chloride 98Min. (I), be warming up to room temperature reaction 1～2 hour, make 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo aza ring butyl]-3-isoindole-1,3-diketone (III).
3, the synthetic method of aztreonam intermediate 3-amino-2-methyl according to claim 2-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, it is characterized in that: described organic bases is a triethylamine.
4, the synthetic method of aztreonam intermediate 3-amino-2-methyl according to claim 1-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, it is characterized in that: in second step, with 2-[(2S, 3S)-2-methyl isophthalic acid-((R)-tertiary butyl sulfonamido)-4-oxo-1-azelidinyl]-3-isoindole-1,3-diketone (III) is dissolved in the organic solvent, adds oxygenant in freezing point, stirs 2～4 hours, separatory, the organic phase washing adds organic solvent and acid, reflux 1～3 hour, separatory, water extraction, organic phase merge the back and concentrate, and make 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1,3-diketone (IV).
5, the synthetic method of aztreonam intermediate 3-amino-2-methyl according to claim 4-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, it is characterized in that: described oxygenant is a clorox, acid is hydrochloric acid.
6, the synthetic method of aztreonam intermediate 3-amino-2-methyl according to claim 1-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, it is characterized in that: in the 3rd step, with 2-[(2S, 3S)-the 2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl]-3-isoindole-1,3-diketone (IV) is dissolved in the organic solvent, add the sulphur trioxide pyridine, be heated to 65～75 ℃ of reactions 2.5～4 hours, pour frozen water after the cooling into, extraction, recrystallization makes (2S, 3S)-and 3-(1,3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V).
7, the synthetic method of aztreonam intermediate 3-amino-2-methyl according to claim 1-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, it is characterized in that: in the 4th step, with (2S, 3S)-3-(1,3-dioxy-pseudoindoyl-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (V) is dissolved in the organic solvent, add the N-methyl hydrazine, be heated to and refluxed 4～6 hours, cold filtration, solids wash, filtrate and washings merge, and add acid, separate out solid, make 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid (VI).
8, the synthetic method of aztreonam intermediate 3-amino-2-methyl according to claim 7-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid is characterized in that: described acid is a kind of in formic acid, acetate, hydrochloric acid, sulfuric acid, the phosphoric acid.
9, according to the synthetic method of the described aztreonam intermediate of one of claim 2 to 8 3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, it is characterized in that: described organic solvent is a kind of in methylene dichloride, ethylene dichloride, methyl alcohol, ethanol, dimethyl formamide, tetrahydrofuran (THF), benzene, the toluene.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382026A (en) * | 2011-10-17 | 2012-03-21 | 重庆南松医药科技股份有限公司 | Environmentally-friendly synthesis process of Aztreonam main ring (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid |
| CN102925510A (en) * | 2011-08-09 | 2013-02-13 | 重庆圣华曦药业股份有限公司 | Synthetic method of aztreonam intermediate |
| CN104592081A (en) * | 2015-02-06 | 2015-05-06 | 石家庄万业化工科技有限公司 | Synthesis method of aztreonam main ring |
-
2009
- 2009-06-26 CN CNA2009100539891A patent/CN101591282A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102925510A (en) * | 2011-08-09 | 2013-02-13 | 重庆圣华曦药业股份有限公司 | Synthetic method of aztreonam intermediate |
| CN102382026A (en) * | 2011-10-17 | 2012-03-21 | 重庆南松医药科技股份有限公司 | Environmentally-friendly synthesis process of Aztreonam main ring (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid |
| CN104592081A (en) * | 2015-02-06 | 2015-05-06 | 石家庄万业化工科技有限公司 | Synthesis method of aztreonam main ring |
| CN104592081B (en) * | 2015-02-06 | 2017-03-08 | 石家庄万业化工科技有限公司 | A kind of synthetic method of aztreonam main ring |
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