CN102690220A - Preparation method for synthesizing intermediate of carbapenem compound - Google Patents
Preparation method for synthesizing intermediate of carbapenem compound Download PDFInfo
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- CN102690220A CN102690220A CN2012101024540A CN201210102454A CN102690220A CN 102690220 A CN102690220 A CN 102690220A CN 2012101024540 A CN2012101024540 A CN 2012101024540A CN 201210102454 A CN201210102454 A CN 201210102454A CN 102690220 A CN102690220 A CN 102690220A
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Abstract
The invention relates to a preparation method of (3S,4R)-4-(3-[(R)-1'-hydroxyethyl]-4-azetidine-2-ketone)-3-diazo-2-oxo-p-nitrobenzyl butyrate. In the preparation steps of a compound II, expensive iodine salts such as sodium iodide and potassium iodide are used as catalysts in the patent US5340927 and the patent EP0414904, which makes the cost of a compound IV be relatively high. A cheap zinc salt is adopted as a catalyst in the invention, so the cost of the compound IV is greatly reduced, wherein the zinc salt is one selected from zinc acetate, zinc chloride, zinc sulfate and zinc bromide. In the invention, the catalytic mechanism of the zinc salts is to prepare a complex from the zinc salts and a compound I so as to form an onium salt, thereby reducing reactive activation energy and improving the activity of the compound I. A post-treatment of the compound II is not required after preparing the compound II, thereby simplifying the operation processes by entering a next reaction directly.
Description
Technical field
The present invention relates to a kind of (3S, 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the preparation method of nitrobenzyl ester.
Background technology
(3S, 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is the key intermediate that synthesizing imine is trained carbapenem compounds such as south to the nitrobenzyl ester.At present; Document about the imipenum preparation is many; (3S, 4R)-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is fewer to the document of nitrobenzyl ester for 4-, US 5340927 and EP0414904 have reported the synthetic of it but about preparation.
The synthetic route of US 5340927 reports is that silyl enol ether reacting generating compound II takes place under the catalysis of salt compounded of iodine chemical compounds I, and compound ii will pass through and remove solvent under reduced pressure, after the no water filtration, at ZnBr
2Catalysis down with 4-AA condensation reaction to take place generate the compound III, the compound III is through methylsulfonic acid alcoholysis generation compound IV.
Concrete chemical formula is following:
The synthetic route of EP0414904 report also is that silyl enol ether reacting generating compound II takes place under the catalysis of salt compounded of iodine chemical compounds I, and compound ii will pass through and remove solvent under reduced pressure, after the no water filtration, at ZnBr
2Catalysis down with 4-AA condensation reaction to take place generate the compound III, the compound III is through hydrochloric acid hydrolysis generation compound IV.
Concrete chemical formula is following:
The shortcoming of US 5340927 and EP 0414904 operational path is: 1. in the preparation process of compound ii, used expensive salt compounded of iodine to make catalyzer, chemical compounds I and salt compounded of iodine mol ratio are 1:1.17～1.4, have increased the cost of compound IV.2. after the compound ii preparation finishes, pass through removing solvent under reduced pressure, nitrogen protection is filtered down, and these operate in to produce goes up more complicated, and operational condition is difficult for reaching.
Summary of the invention
The objective of the invention is to customer service deficiency of the prior art and provide a kind of easy and simple to handle, with low cost (3S, 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the preparation method of nitrobenzyl ester.
The objective of the invention is to realize like this: a kind of (3S; 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the preparation method of nitrobenzyl ester; Be by following three-step reaction make (3S, 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the nitrobenzyl ester:
The temperature of the first step reaction is 10-30 ℃, and reaction times 1-3h, zinc salt catalyzer are zinc acetate, zinc chloride, zinc sulfate, zinc bromide a kind of, reaction solvent M
eCN is an acetonitrile, methylene dichloride, THF; N, dinethylformamide, a kind of in the dioxane; The mol ratio of zinc salt catalyzer and chemical compounds I is 0.2-2:1; The mol ratio of triethylamine TEA and chemical compounds I is 1.2-1.8:1, and the mol ratio of trimethylchlorosilane TMSI and chemical compounds I is 1.2-1.8:1, reaction solvent M
eThe volume/weight ratio of CN and chemical compounds I is 1～5:1, and the first step reaction finishes the back and directly gets into the reaction of second step.
The temperature of second step reaction is 10-25 ℃; Reaction times is 12-18h, and reaction solvent is a kind of in methylene dichloride, ETHYLE ACETATE, the toluene, and Lewis acid is a kind of in zinc chloride, zinc bromide, the iron trichloride; The volume/weight ratio of reaction solvent and chemical compounds I is 5-10:1; Lewis acid is 0.1-0.5:1 with the mol ratio of chemical compounds I, and the mol ratio of 4-AA and chemical compounds I is 0.75-0.8:1, and the reaction of second step finishes the back and directly got into for the 3rd step.
The temperature of three-step reaction is 15-25 ℃, and the time of reaction is 24-36h, and the mol ratio of methylsulfonic acid MSA and chemical compounds I is 0.1-0.4, and the volume/weight ratio of methyl alcohol and chemical compounds I is 2-4:1.
Behind the 3rd EOS, filtering, is vacuum-drying under 45 ℃ of conditions in temperature, weigh the compound IV.
Wherein in the preparation process of compound ii, patent US 5340927 and patent EP 0414904 have adopted expensive Soiodin, and salt compounded of iodine such as potassiumiodide are made catalyzer; Cause the cost of compound IV higher, we have found a kind of zinc salt of cheapness to make catalyzer, and the zinc salt catalyzer can be a zinc acetate; Zinc chloride; Zinc sulfate, a kind of in the zinc bromide greatly reduces the cost of compound IV.
In the preparation of compound ii; The catalytic catalytic mechanism of used zinc salt is different fully with the catalytic catalytic mechanism of salt compounded of iodine with patent US 5340927 and patent EP 0414904 report; The catalytic mechanism of the used zinc salt of the present invention is zinc salt and chemical compounds I complexing; Form a kind of salt transition state, reduced reaction activity, improved the activity of chemical compounds I.The catalytic mechanism of the patent US 5340927 and the salt compounded of iodine of patent EP 0414904 report is trimethylchlorosilane and salt compounded of iodine reaction, generates Iodotrimethylsilane, has reduced the activity of reaction reagent.
After the compound ii preparation finishes, needn't carry out aftertreatment to compound ii, directly get into step reaction down, simplified operating process.
Embodiment
Below in conjunction with concrete embodiment the present invention is done further description.
Embodiment 1: under the nitrogen protection, add 4.1g Zinc Chloride Anhydrous, 30mL acetonitrile in the 10g chemical compounds I.5 ℃ of mixed solutions that add 6.2g trimethylchlorosilane and 5.8g triethylamine of temperature control.After adding, 5 ℃ of reactions of temperature control, 1～2h.Reaction adds 80ml ETHYLE ACETATE to terminal, adds the 1g Zinc Chloride Anhydrous, 9g 4-AA, and 20 ℃ of reactions of temperature control are to terminal.Add 20mL methyl alcohol, the 0.7g methylsulfonic acid, 18 ℃ of reactions of temperature control are to terminal.Filter, 45 ℃ of vacuum-dryings, weigh 9.2g, content 98.3%.
Embodiment 2: under the nitrogen protection, add 4.1g Zinc Bromide Anhydrous, 30mL methylene dichloride in the 10g chemical compounds I.5 ℃ of mixed solutions that add 6.2g trimethylchlorosilane and 5.8g triethylamine of temperature control.After adding, 5 ℃ of reactions of temperature control, 1～2h.Reaction adds the 60ml methylene dichloride to terminal, adds the 1g Zinc Bromide Anhydrous, 9g 4-AA, and 20 ℃ of reactions of temperature control are to terminal.Add 20mL methyl alcohol, the 0.7g methylsulfonic acid, 18 ℃ of reactions of temperature control are to terminal.Filter, 45 ℃ of vacuum-dryings, weigh 9.0g, content 98.5%.
Embodiment 3: under the nitrogen protection, add 5.5g Zinc Chloride Anhydrous, 20mL acetonitrile in the 10g chemical compounds I.5 ℃ of mixed solutions that add 6.2g trimethylchlorosilane and 5.8g triethylamine of temperature control.After adding, 5 ℃ of reactions of temperature control, 1～2h.Reaction adds 60ml toluene to terminal, adds the 1g Zinc Chloride Anhydrous, 9g 4-AA, and 20 ℃ of reactions of temperature control are to terminal.Add 20mL methyl alcohol, the 0.7g methylsulfonic acid, 18 ℃ of reactions of temperature control are to terminal.Filter, 45 ℃ of vacuum-dryings, weigh 9.2g, content 98%.
Owing to described the present invention with specific embodiment, to be proficient in this technological technician and can to revise and the equivalence change it, this is understood to include within scope of the present invention.
Claims (5)
1. (3S; 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the preparation method of nitrobenzyl ester; It is characterized in that: be by following three-step reaction make (3S, 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the nitrobenzyl ester:
2. according to claim 1 a kind of (3S, 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the preparation method of nitrobenzyl ester, it is characterized in that: the temperature of the first step reaction is 10-30 ℃; Reaction times 1-3h; The zinc salt catalyzer is a zinc acetate, zinc chloride, zinc sulfate; Zinc bromide a kind of, reaction solvent M
eCN is an acetonitrile, methylene dichloride, THF; N, dinethylformamide, a kind of in the dioxane; The mol ratio of zinc salt catalyzer and chemical compounds I is 0.2-2:1; The mol ratio of triethylamine TEA and chemical compounds I is 1.2-1.8:1, and the mol ratio of trimethylchlorosilane TMSI and chemical compounds I is 1.2-1.8:1, reaction solvent M
eThe volume/weight ratio of CN and chemical compounds I is 1～5:1, and the first step reaction finishes the back and directly gets into the reaction of second step.
3. a kind of (3S according to claim 2; 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the preparation method of nitrobenzyl ester; It is characterized in that: the temperature of second step reaction is 10-25 ℃; Reaction times is 12-18h, and reaction solvent is a kind of in methylene dichloride, ETHYLE ACETATE, the toluene, and Lewis acid is a kind of in zinc chloride, zinc bromide, the iron trichloride; The volume/weight ratio of reaction solvent and chemical compounds I is 5-10:1; Lewis acid is 0.1-0.5:1 with the mol ratio of chemical compounds I, and the mol ratio of 4-AA and chemical compounds I is 0.75-0.8:1, and the reaction of second step finishes the back and directly got into for the 3rd step.
4. a kind of (3S according to claim 3; 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the preparation method of nitrobenzyl ester; It is characterized in that: the temperature of three-step reaction is 15-25 ℃; The time of reaction is 24-36h, and the mol ratio of methylsulfonic acid MSA and chemical compounds I is 0.1-0.4, and the volume/weight ratio of methyl alcohol and chemical compounds I is 2-4:1.
5. a kind of (3S according to claim 4; 4R)-4-(3-[(R)-1 '-hydroxyethyl]-4-azetidine-2-ketone)-3-diazonium-2-oxo-butyric acid is to the preparation method of nitrobenzyl ester; It is characterized in that: behind the 3rd EOS; Filtering, is vacuum-drying under 45 ℃ of conditions in temperature, weigh the compound IV.
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| CN2012101024540A CN102690220A (en) | 2012-04-10 | 2012-04-10 | Preparation method for synthesizing intermediate of carbapenem compound |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0414904A1 (en) * | 1989-01-12 | 1991-03-06 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Preparation of enol silyl ether compounds |
| US5340927A (en) * | 1989-07-18 | 1994-08-23 | Merck & Co., Inc. | Process for the preparation of 2-diazo-3-trisubstituted silyloxy 3-butenoates |
-
2012
- 2012-04-10 CN CN2012101024540A patent/CN102690220A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0414904A1 (en) * | 1989-01-12 | 1991-03-06 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Preparation of enol silyl ether compounds |
| US5340927A (en) * | 1989-07-18 | 1994-08-23 | Merck & Co., Inc. | Process for the preparation of 2-diazo-3-trisubstituted silyloxy 3-butenoates |
Non-Patent Citations (1)
| Title |
|---|
| CALVIN S. K. WAN ET AL.: "Stereoselective and Regioselective Thermal and Photochemical Preparation of Siloxy Dienes", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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Inventor after: Li Lingling Inventor after: Zhou Chengkun Inventor after: Cheng Jinhua Inventor after: Guo Jinghong Inventor after: Hou Yongtao Inventor after: Li Guoqiang Inventor before: Zhou Chengkun Inventor before: Cheng Jinhua Inventor before: Guo Jinghong Inventor before: Hou Yongtao Inventor before: Li Guoqiang |
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Free format text: CORRECT: INVENTOR; FROM: ZHOU CHENGKUN CHENG JINHUA GUO JINGHONG HOU YONGTAO LI GUOQIANG TO: LI LINGLING ZHOU CHENGKUN CHENG JINHUA GUO JINGHONG HOU YONGTAO LI GUOQIANG |
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Application publication date: 20120926 |