CN1803807A - 4AA oxidizing synthesis method - Google Patents
4AA oxidizing synthesis method Download PDFInfo
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- CN1803807A CN1803807A CN 200610023223 CN200610023223A CN1803807A CN 1803807 A CN1803807 A CN 1803807A CN 200610023223 CN200610023223 CN 200610023223 CN 200610023223 A CN200610023223 A CN 200610023223A CN 1803807 A CN1803807 A CN 1803807A
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Abstract
The related oxo-synthesis method for 4AA comprises: with RuCl3 as the catalyst, dissolving (S)-3-((R)-1-(tert-butyldimethylsilyloxy)ethyl)azetidin-2-one into solvent to prepare the product on action of PAA and anhydrous NaA. The advantages of this invention include: reducing catalyst dosage and cost greatly for same yield as well as the environmental pollution with much less heavy metal sewage.
Description
Technical field
That the present invention relates to is a kind of preparation method of chemical technology field, specifically is the oxidation preparation method of a kind of synthetic 4AA.
Technical background
4AA is the key intermediate of synthetic 1-beta-methyl carbapenem compound, promptly (3R, 4R)-4-acetoxy-3-[(R)-1 '-((t-butyldimethylsilyl) oxy) ethyl]-2-azetidinone.Carbapenem is one group of novel complete synthesis β-Nei Xiananleikangshengsu.Gram-positive microorganism and negative bacterium, aerophil, anerobe all there is very strong anti-microbial activity.Since finding sulfomycin in 1976, the research of carbapenem antibiotic has had very big development, in China's kind of having gone on the market imipenum, panipenem and Meropenem is arranged, and also has the kinds of much carrying out clinical trial.Therefore, synthetic the having great importance of research carbapenem antibiotics intermediate.From (I ' R, 3S)-important method that 3-[1 '-[(t-butyldimethylsilyl) oxy]-ethyllazetidin-2-one prepares 4AA is an oxidation style.
Find through literature search prior art, " Ruthenium-Catalyzed Oxidation of Amides and Lactams with Peroxides " (the superoxide ruthenium catalyzed oxidation of amine and lactan) that Murahashi etc. delivered on the 7820th page of " Journal of AmericanChemiscal Society " (JACS) the 112nd phase, propose to use 5mol%Ru/C catalysis in this article, concrete grammar is: to substrate is housed, the reaction flask of 5mol%Ru/C and sodium acetate, anhydrous drips 30% Peracetic Acid, stirring at room 2 and a half hours, after-filtration is finished in reaction, it is dropped in the water, use n-hexane extraction.Its deficiency is: catalyzer heavy metal Ru consumption is higher, and is too high from seeing cost economically, and a large amount of heavy metals also can bring serious environmental to pollute in aftertreatment.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, the oxidation synthesis method of a kind of 4AA is provided, make it when keeping yield, reduce the heavy metal catalyst consumption as far as possible, reduce cost, reduce the environmental pollution that heavy metal brings in the aftertreatment.
The present invention is achieved by the following technical solutions, and the present invention adopts (S)-3-((R)-1-(tert-butyl-dimethylsilyloxy) ethyl) azetidin-2-one with RuCl
3For catalyzer and be dissolved in solvent, under Peracetic Acid and sodium acetate, anhydrous effect, oxidation makes 4AA.
Described solvent is acetonitrile, THF, 1, and a kind of in the 4-dioxane is preferably acetonitrile.
Described RuCl
3Consumption be the 1-2mol% of substrate, be preferably 1.5mol%.
Described sodium acetate, anhydrous, its consumption is 1～1.05equiv. of substrate, is preferably 1.0equiv..
Described Peracetic Acid oxidation, its consumption is: the 1mmol substrate is with the oxidation of 8.5ml40% Peracetic Acid.
Among the present invention, the temperature of reaction after the adding Peracetic Acid is preferably 10 ℃ between 5-10 ℃.
The synthetic route of the inventive method is as follows:
The present invention uses (S)-3-((R)-1-(tert-butyldimethylsilyloxy) ethyl) azetidin-2-one to be substrate, reduces catalyst levels and suitably increases oxidant content; Used oxygenant is the acetic acid solution of Peracetic Acid, and convenient recovery and acetate still can be oxidized to Peracetic Acid, help cyclic production.
The present invention has following advantage: 1) when keeping yield, significantly reduced catalyst consumption;
2) minimizing of catalyst levels has reduced the cost that reacts to a great extent, and is more outstanding aspect economy;
3) discharging of heavy metal waste liquid greatly reduces, and the pollution level of environment is reduced greatly.
Embodiment
Embodiment 1:
Under the nitrogen atmosphere, with (S)-3-((R)-1-(tert-butyldimethylsilyloxy) ethyl) azetidin-2-one (385.4mg, 1.68mmol), sodium-acetate (137.8mg, 1.68mmol) dissolve with the 5ml acetonitrile, and dissolve the 1.5%mol RuCl of substrate with the 5ml acetonitrile
3, 99% (5.3mg) injects reaction system in-5 ℃.Afterwards, slowly add 14.0ml 40% Peracetic Acid at-5 ℃, 10 ℃ of reactions.TLC monitoring, reaction finish the back and concentrate, and column chromatography separated product 4AA (385mg, Yield=80%).
Embodiment 2:
Under the nitrogen atmosphere, with (S)-3-((R)-1-(tert-butyldimethylsilyloxy) ethyl) azetidin-2-one (358.0mg, 1.56mmol), sodium-acetate (128.0mg, 1.56mmol) dissolve with the 5ml acetonitrile, and dissolve the 1%mol RuCl of substrate with the 5ml acetonitrile
3, 99% (3.3mg) injects reaction system in-5 ℃.Afterwards, in-5 ℃ of slow 13.0ml 40% Peracetic Acid that add, 10 ℃ of reactions.TLC monitoring, reaction finish the back and concentrate, and column chromatography separated product 4AA (354.2mg, Yield=79%).
Embodiment 3:
Under the nitrogen atmosphere, with (S)-3-((R)-1-(tert-butyldimethylsilyloxy) ethyl) azetidin-2-one (293.6mg, 1.28mmol), sodium-acetate (110.2mg, 1.34mmol) dissolve with the 5ml acetonitrile, and dissolve the 1.5%mol RuCl of substrate with the 5ml acetonitrile
3, 99% (4.1mg) injects reaction system in-5 ℃.Afterwards, in-5 ℃ of slow 11.0ml 40% Peracetic Acid that add, 10 ℃ of reactions.TLC monitoring, reaction finish the back and concentrate, and column chromatography separated product 4AA (287.0mg, Yield=78%).
Embodiment 4:
Under the nitrogen atmosphere, with (S)-3-((R)-1-(tert-butyldimethylsilyloxy) ethyl) azetidin-2-one (401.4mg, 1.75mmol), sodium-acetate (143.6mg, 1.75mmol) dissolve with 5.5mlTHF, and dissolve the 1.5%mol RuCl of substrate with 5.5mlTHF
3, 99% (5.5mg) injects reaction system in-5 ℃.Afterwards, in-5 ℃ of slow 15.0ml 40% Peracetic Acid that add, 10 ℃ of reactions.TLC monitoring, reaction finish the back and concentrate, and column chromatography separated product 4AA (377.3mg, Yield=75%).
Embodiment 5:
Under the nitrogen atmosphere, with (S)-3-((R)-1-(tert-butyldimethylsilyloxy) ethyl) azetidin-2-one (236.3mg, 1.03mmol), sodium-acetate (84.5mg, 1.03mmol) dissolve with the 5ml acetonitrile, and dissolve the 1.5%mol RuCl of substrate with the 5ml acetonitrile
3, 99% (3.2mg) injects reaction system in-5 ℃.Afterwards, slowly add 9.0ml 40% Peracetic Acid at-5 ℃, 5 ℃ of reactions.TLC monitoring, reaction finish the back and concentrate, and column chromatography separated product 4AA (210.2mg, Yield=71%).
Claims (10)
1, the oxidation synthesis method of a kind of 4AA is characterized in that, adopts (S)-3-((R)-1-(tert-butyl-dimethylsilyloxy) ethyl) azetidin-2-one with RuCl
3For catalyzer and be dissolved in solvent, under Peracetic Acid and sodium acetate, anhydrous effect, oxidation makes 4AA.
2, the oxidation synthesis method of 4AA according to claim 1 is characterized in that, described solvent is acetonitrile, THF, 1, a kind of in the 4-dioxane.
According to the oxidation synthesis method of claim 1 or 2 described 4AA, it is characterized in that 3, described solvent is acetonitrile.
4, the oxidation synthesis method of 4AA according to claim 1 is characterized in that, described RuCl
3Consumption be the 1-2mol% of substrate.
5, according to the oxidation synthesis method of claim 1 or 4 described 4AA, it is characterized in that described RuCl
3Consumption be the 1.5mol% of substrate.
6, the oxidation synthesis method of 4AA according to claim 1 is characterized in that, described sodium acetate, anhydrous, its consumption are 1～1.05equiv. of substrate.
According to the oxidation synthesis method of claim 1 or 6 described 4AA, it is characterized in that 7, described sodium acetate, anhydrous, its consumption are the 1.0equiv. of substrate.
8, the oxidation synthesis method of 4AA according to claim 1 is characterized in that, described Peracetic Acid oxidation, and its consumption is: the 1mmol substrate is with the oxidation of 8.5ml40% Peracetic Acid.
According to the oxidation synthesis method of claim 1 or 8 described 4AA, it is characterized in that 9, the temperature of reaction after the adding Peracetic Acid is between 5-10 ℃.
According to the oxidation synthesis method of claim 1 or 8 described 4AA, it is characterized in that 10, the temperature of reaction after the adding Peracetic Acid is 10 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100232235A CN100494204C (en) | 2006-01-12 | 2006-01-12 | (1'R,3R, 4R)-4-acetoxy-3-(1-tert-butyldimethylsiloxyethyl) azetidin-2-one oxidation synthesis method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100232235A CN100494204C (en) | 2006-01-12 | 2006-01-12 | (1'R,3R, 4R)-4-acetoxy-3-(1-tert-butyldimethylsiloxyethyl) azetidin-2-one oxidation synthesis method |
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| Publication Number | Publication Date |
|---|---|
| CN1803807A true CN1803807A (en) | 2006-07-19 |
| CN100494204C CN100494204C (en) | 2009-06-03 |
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| CNB2006100232235A Active CN100494204C (en) | 2006-01-12 | 2006-01-12 | (1'R,3R, 4R)-4-acetoxy-3-(1-tert-butyldimethylsiloxyethyl) azetidin-2-one oxidation synthesis method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114933611A (en) * | 2022-04-12 | 2022-08-23 | 中国科学院大连化学物理研究所 | Method for continuously preparing penem antibiotic intermediate 4-acetoxy azetidinone |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0371875B1 (en) * | 1988-11-29 | 1994-12-28 | Takasago International Corporation | Process for preparing 4-acetoxyazetidinones |
| JP2787248B2 (en) * | 1990-11-30 | 1998-08-13 | 高砂香料工業株式会社 | Method for producing 4-acetoxyazetidinones |
| JP4142444B2 (en) * | 2001-03-07 | 2008-09-03 | 第一三共株式会社 | Method for producing 2-azetidinone derivative |
| JP4552231B2 (en) * | 2003-07-11 | 2010-09-29 | 日本曹達株式会社 | Method for producing carbapenem intermediate |
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2006
- 2006-01-12 CN CNB2006100232235A patent/CN100494204C/en active Active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114933611A (en) * | 2022-04-12 | 2022-08-23 | 中国科学院大连化学物理研究所 | Method for continuously preparing penem antibiotic intermediate 4-acetoxy azetidinone |
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