CN105153215A - Refining method for improving quality of imipenem key intermediate - Google Patents
Refining method for improving quality of imipenem key intermediate Download PDFInfo
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- CN105153215A CN105153215A CN201510452781.2A CN201510452781A CN105153215A CN 105153215 A CN105153215 A CN 105153215A CN 201510452781 A CN201510452781 A CN 201510452781A CN 105153215 A CN105153215 A CN 105153215A
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Abstract
The invention discloses a refining method for improving the quality of an imipenem key intermediate. The method comprises the following steps of adding raw materials N-(4-methoxyphenyl)-4-acetyl-3-[1-(tert-butyl dimethyl-siloxy) ethyl] azetidinone and sodium acetate into a reaction bottle, and controlling the temperature to be within 0-10 DEG C, dropwise adding an oxidant for 3 hours; then, conducting a reaction for 16 hours at 20-25 DEG C, and controlling the reaction endpoint by high-performance liquid chromatography; and dropwise adding the sodium sulfite to neutralize excessive oxidant until the color of starch potassium iodide does not change after the reaction is finished, adding hexane to conduct extraction for 5 times, drying the mixed hexane with anhydrous sodium sulfate, reclaiming the hexane at a reduced pressure until the residue is dry, adding absolute methanol to conduct heating and dissolving, adding activated carbon, coudcting refluxing and insulating for 30 minutes, conducting filtering when the mixture is hot, cooling the filtrate to 5 DEG C below zero, filtering the filtrate, and baking the filter cake at 40 DEG C at a reduced pressure until the filter cake is dry so as to obtain a dried product. The method can be used for remarkably improving the product quality and has a remarkable economic benefit.
Description
Technical field
The invention belongs to basic chemical industry field, particularly relate to a kind of process for purification improving imipenum key intermediate N-(4-p-methoxy-phenyl)-4-acetoxy-3-{ 1-(tertiary butyl dimethyl Si base) ethyl } azetidinone quality.
Background technology
Imipenum key intermediate N-(4-p-methoxy-phenyl)-4-acetoxy-3-{ 1-(tertiary butyl dimethyl Si base) ethyl } azetidinone adopted hexane to make reaction, extraction solvent in the past, obtained N-(4-p-methoxy-phenyl)-4-acetoxy-3-{ 1-(tertiary butyl dimethyl Si base) ethyl } azetidinone through extraction liquid concentrating under reduced pressure.The problems such as it is low that the method mainly exists purity, and product by product is many, of poor quality, these ropy factors will directly have influence on the quality of the finished product imipenum.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of process for purification improving the quality of imipenum key intermediate, not only can improve purity on the one hand, improve the quality of products; Can increase economic efficiency on the other hand.
For solving the problems of the technologies described above, the invention provides a kind of process for purification improving the quality of imipenum key intermediate, comprising the following steps:
(1) in reaction flask, add raw material N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } azetidinone and sodium-acetate, temperature is controlled in 0-10 DEG C, drip oxygenant, time for adding is 3 hours, then react 16 hours at 20-25 DEG C, control reaction end by high performance liquid chromatography;
(2), after reaction terminates, drip oxygenant in S-WAT and excessive to starch potassium iodide nondiscoloration, add hexane and extract 5 times, solvent hexane remaining after merging 5 extractions, with anhydrous sodium sulfate drying, after reclaim under reduced pressure hexane is extremely dry, must residuum be distilled, add the anhydrous methanol heating for dissolving of described distillation residuum 6-8 times amount, then add gac, backflow insulation 30 minutes, filtered while hot, is chilled to-5 DEG C by filtrate, filters, filter cake 40 DEG C of decompression dryings, to dry, obtain dry product.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, N-described in described step (1) (4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } mol ratio of azetidinone, sodium-acetate and oxygenant is 1:0.8:1.05.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, described in described step (1), oxygenant is hydrogen peroxide.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, described in described step (1), the weight percent of hydrogen peroxide is 50%.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, the weight percent of S-WAT described in described step (2) is 10%.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, described in described step (2), the addition of hexane is 200ml/ time.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, described in described step (2), the addition of anhydrous sodium sulphate is 20g.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, described in described step (2), the pressure of reclaim under reduced pressure hexane is vacuum tightness-0.09mpa.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, described in described step (2), the weight percent of gac is 2%.
As a kind of a kind of preferred version improving the process for purification of the quality of imipenum key intermediate of the present invention, the pressure of filter cake 40 DEG C of decompression dryings described in described step (2) is for being vacuum tightness-0.09mpa.
The invention discloses a kind of process for purification improving imipenum key intermediate N-(4-p-methoxy-phenyl)-4-acetoxy-3-{ 1-(tertiary butyl dimethyl Si base) ethyl } azetidinone quality, this compound purity is made to bring up to about 99.75% from original 85.23%, quality product significantly improves, and has significant economic benefit.
Embodiment
The invention provides a kind of process for purification improving the quality of imipenum key intermediate, comprise the following steps:
(1) in reaction flask, add raw material N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } azetidinone and sodium-acetate, temperature is controlled in 0-10 DEG C, drip oxygenant, time for adding is 3 hours, then react 16 hours at 20-25 DEG C, control reaction end by high performance liquid chromatography;
(2), after reaction terminates, drip oxygenant in S-WAT and excessive to starch potassium iodide nondiscoloration, add hexane and extract 5 times, solvent hexane remaining after merging 5 extractions, with anhydrous sodium sulfate drying, after reclaim under reduced pressure hexane is extremely dry, must residuum be distilled, add the anhydrous methanol heating for dissolving of described distillation residuum 6-8 times amount, then add gac, backflow insulation 30 minutes, filtered while hot, is chilled to-5 DEG C by filtrate, filters, filter cake 40 DEG C of decompression dryings, to dry, obtain dry product.
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, and below in conjunction with embodiment, the present invention is further detailed explanation.
Improve a process for purification for the quality of imipenum key intermediate, comprising:
Step one: add raw material N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl in reaction flask } azetidinone and sodium-acetate, temperature is controlled in 0-10 DEG C, drip oxygenant, time for adding is 3 hours, then react 16 hours at 20-25 DEG C, control reaction end by high performance liquid chromatography; With
In one embodiment, this step can specific as followsly perform: in reaction flask, add raw material N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } azetidinone and sodium-acetate, temperature is controlled in 0-10 DEG C, drip oxygenant, described oxygenant be weight percentage 50% hydrogen peroxide time for adding be 3 hours, then react 16 hours at 20-25 DEG C, reaction end is controlled by high performance liquid chromatography, wherein, described N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } azetidinone, the mol ratio of sodium-acetate and oxygenant is 1:0.8:1.05.
Step 2: after reaction terminates, drips oxygenant in S-WAT and excessive to starch potassium iodide nondiscoloration, adds hexane and extract 5 times, solvent hexane remaining after merging 5 extractions, with anhydrous sodium sulfate drying, after reclaim under reduced pressure hexane is extremely dry, must residuum be distilled, add the anhydrous methanol heating for dissolving of described distillation residuum 6-8 times amount, then add gac, backflow insulation 30 minutes, filtered while hot, is chilled to-5 DEG C by filtrate, filters, filter cake 40 DEG C of decompression dryings, to dry, obtain dry product.
In one embodiment, this step can specific as followsly perform: after reaction terminates, dripping weight percent is that in the S-WAT of 10% He excessive oxygenant is to starch potassium iodide nondiscoloration, add 200ml/ hexane and extract 5 times, solvent hexane 20g anhydrous sodium sulfate drying remaining after merging 5 extractions, be decompressed to vacuum tightness-0.09mpa and reclaim hexane to after dry, residuum must be distilled, add the anhydrous methanol heating for dissolving of described distillation residuum 6-8 times amount, add the gac that weight percent is 2% again, backflow insulation 30 minutes, filtered while hot, filtrate is chilled to-5 DEG C, filter, filter cake 40 DEG C is decompressed to vacuum tightness-0.09mpa dries to dry, obtain dry product.
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, further illustrate technical scheme of the present invention below in conjunction with embodiment.But the invention is not restricted to listed embodiment, also should be included in other any known changes in interest field of the presently claimed invention.
First, alleged herein " embodiment " or " embodiment " refers to special characteristic, structure or the characteristic that can be contained at least one implementation of the present invention.Different local in this manual " in one embodiment " occurred not all refers to same embodiment, neither be independent or optionally mutually exclusive with other embodiments embodiment.
Secondly, that says in the present invention is all weight percentage to per-cent, and the per-cent of the content of the something in certain step described is ratio shared for reaction solution in this step.
Embodiment 1
In reaction flask, add N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } azetidinone, sodium-acetate; 50% hydrogen peroxide is dripped in control 0-10 DEG C; time for adding about 3 hours; react 16 hours at 20-25 DEG C, control reaction end by high performance liquid chromatography.After reaction terminates, drip oxygenant in the S-WAT of 10% and excessive to starch potassium iodide nondiscoloration, add hexane and extract 5 times, merge hexane layer anhydrous sodium sulfate drying, after reclaim under reduced pressure hexane is extremely dry, add 6 times amount anhydrous methanol heating for dissolving, add the gac of theoretical amount 2% again, backflow insulation 30 minutes, filtered while hot, is chilled to-5 DEG C by filtrate, filter, filter cake 40 DEG C of decompression dryings are to dry, and lower batch of filtrate is applied mechanically, dry product purity 98.75%.
Embodiment 2
In reaction flask, add N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } azetidinone, sodium-acetate; 50% hydrogen peroxide is dripped in control 0-10 DEG C; time for adding about 3 hours; react 16 hours at 20-25 DEG C, control reaction end by high performance liquid chromatography.After reaction terminates, drip oxygenant in the S-WAT of 10% and excessive to starch potassium iodide nondiscoloration, add hexane and extract 5 times, merge hexane layer anhydrous sodium sulfate drying, after reclaim under reduced pressure hexane is extremely dry, add 7 times amount anhydrous methanol heating for dissolving, add the gac of theoretical amount 2% again, backflow insulation 30 minutes, filtered while hot, is chilled to-5 DEG C by filtrate, filter, filter cake 40 DEG C of decompression dryings are to dry, and lower batch of filtrate is applied mechanically, dry product purity 99.15%.
Embodiment 3
In reaction flask, add N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } azetidinone, sodium-acetate; 50% hydrogen peroxide is dripped in control 0-10 DEG C; time for adding about 3 hours; react 16 hours at 20-25 DEG C, control reaction end by high performance liquid chromatography.After reaction terminates, drip oxygenant in the S-WAT of 10% and excessive to starch potassium iodide nondiscoloration, add hexane and extract 5 times, merge hexane layer anhydrous sodium sulfate drying, after reclaim under reduced pressure hexane is extremely dry, add 8 times amount anhydrous methanol heating for dissolving, add the gac of theoretical amount 2% again, backflow insulation 30 minutes, filtered while hot, is chilled to-5 DEG C by filtrate, filter, filter cake 40 DEG C of decompression dryings are to dry, and lower batch of filtrate is applied mechanically, dry product purity 99.75%.
Imipenum key intermediate N-(4-the p-methoxy-phenyl)-4-acetoxy-3 that embodiment 1 ~ 3 obtains-{ 1-(tertiary butyl dimethyl Si base) ethyl } azetidinone quality meets inner controlling standard of enterprise.
In sum, the invention discloses a kind of process for purification improving imipenum key intermediate N-(4-p-methoxy-phenyl)-4-acetoxy-3-{ 1-(tertiary butyl dimethyl Si base) ethyl } azetidinone quality, remarkable advantage of the present invention:
The purity of 1, imipenum key intermediate N-(4-p-methoxy-phenyl)-4-acetoxy-3 described in present method-{ 1-(tertiary butyl dimethyl Si base) ethyl } azetidinone brings up to 99.75% by original 85.23%;
2, present method is owing to improve imipenum key intermediate N-(4-p-methoxy-phenyl)-4-acetoxy-3-{ 1-(tertiary butyl dimethyl Si base) ethyl } azetidinone quality, so make imipenum subsequent reactions yield and quality have also been obtained raising.
It should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to technical scheme of the present invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (10)
1. improve a process for purification for the quality of imipenum key intermediate, it comprises:
(1) in reaction flask, add raw material N-(4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } azetidinone and sodium-acetate, temperature is controlled in 0-10 DEG C, drip oxygenant, time for adding is 3 hours, then react 16 hours at 20-25 DEG C, control reaction end by high performance liquid chromatography;
(2), after reaction terminates, drip oxygenant in S-WAT and excessive to starch potassium iodide nondiscoloration, add hexane and extract 5 times, solvent hexane remaining after merging 5 extractions, with anhydrous sodium sulfate drying, after reclaim under reduced pressure hexane is extremely dry, must residuum be distilled, add the anhydrous methanol heating for dissolving of described distillation residuum 6-8 times amount, then add gac, backflow insulation 30 minutes, filtered while hot, is chilled to-5 DEG C by filtrate, filters, filter cake 40 DEG C of decompression dryings, to dry, obtain dry product.
2. the as claimed in claim 1 process for purification improving the quality of imipenum key intermediate, is characterized in that: N-described in described step (1) (4-p-methoxy-phenyl)-4-ethanoyl-3-{1-(tertiary butyl dimethyl Si base) ethyl } mol ratio of azetidinone, sodium-acetate and oxygenant is 1:0.8:1.05.
3. the process for purification improving the quality of imipenum key intermediate as claimed in claim 1, is characterized in that: described in described step (1), oxygenant is hydrogen peroxide.
4. the process for purification improving the quality of imipenum key intermediate as claimed in claim 3, is characterized in that: described in described step (1), the weight percent of hydrogen peroxide is 50%.
5. the process for purification improving the quality of imipenum key intermediate as claimed in claim 1, is characterized in that: described in described step (2), the weight percent of S-WAT is 10%.
6. the process for purification improving the quality of imipenum key intermediate as claimed in claim 1, is characterized in that: described in described step (2), the addition of hexane is 200ml/ time.
7. the process for purification improving the quality of imipenum key intermediate as claimed in claim 1, is characterized in that: described in described step (2), the addition of anhydrous sodium sulphate is 20g.
8. the process for purification improving the quality of imipenum key intermediate as claimed in claim 1, is characterized in that: described in described step (2), the pressure of reclaim under reduced pressure hexane is vacuum tightness-0.09mpa.
9. the process for purification improving the quality of imipenum key intermediate as claimed in claim 1, is characterized in that: described in described step (2), the weight percent of gac is 2%.
10. the process for purification improving the quality of imipenum key intermediate as claimed in claim 1, is characterized in that: described in described step (2), the pressure of filter cake 40 DEG C of decompression dryings is vacuum tightness-0.09mpa.
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| CN201510452781.2A CN105153215A (en) | 2015-07-28 | 2015-07-28 | Refining method for improving quality of imipenem key intermediate |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007836A1 (en) * | 2006-07-13 | 2008-01-17 | Choongwae Pharma Corporation | Method for preparing 4-acetoxyazetidinone and derivatives thereof |
| CN101747250A (en) * | 2008-12-16 | 2010-06-23 | 上海医药工业研究院 | Method for preparing 4 - acyloxo heterocyclic ketone compounds |
| CN102002066A (en) * | 2010-11-01 | 2011-04-06 | 山东鑫泉医药中间体有限公司 | Synthesis method of 4-acetoxyl-2-azetidinone |
| CN102936262A (en) * | 2012-11-07 | 2013-02-20 | 凯莱英医药集团（天津）股份有限公司 | Preparation method for imipenem medicine intermediate 4AA |
| CN103665021A (en) * | 2013-12-03 | 2014-03-26 | 西安赛美科医药研发有限公司 | Synthetic method of biapenem drug intermediate 4-AA |
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2015
- 2015-07-28 CN CN201510452781.2A patent/CN105153215A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007836A1 (en) * | 2006-07-13 | 2008-01-17 | Choongwae Pharma Corporation | Method for preparing 4-acetoxyazetidinone and derivatives thereof |
| CN101747250A (en) * | 2008-12-16 | 2010-06-23 | 上海医药工业研究院 | Method for preparing 4 - acyloxo heterocyclic ketone compounds |
| CN102002066A (en) * | 2010-11-01 | 2011-04-06 | 山东鑫泉医药中间体有限公司 | Synthesis method of 4-acetoxyl-2-azetidinone |
| CN102936262A (en) * | 2012-11-07 | 2013-02-20 | 凯莱英医药集团（天津）股份有限公司 | Preparation method for imipenem medicine intermediate 4AA |
| CN103665021A (en) * | 2013-12-03 | 2014-03-26 | 西安赛美科医药研发有限公司 | Synthetic method of biapenem drug intermediate 4-AA |
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Address after: 224100 Yancheng City Dafeng marine biological medicine industrial park Applicant after: Jiangsu Ruike medicine science and Technology Co Ltd Address before: 224145 Yancheng City marine biological medicine industry park, Jiangsu Province Applicant before: JIANGSU RUIKE PHARMACEUTICAL CO., LTD. |
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