CN110003243A - A kind of preparation method of oxacephem parent nucleus - Google Patents
A kind of preparation method of oxacephem parent nucleus Download PDFInfo
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- CN110003243A CN110003243A CN201910325931.1A CN201910325931A CN110003243A CN 110003243 A CN110003243 A CN 110003243A CN 201910325931 A CN201910325931 A CN 201910325931A CN 110003243 A CN110003243 A CN 110003243A
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- reaction
- parent nucleus
- oxacephem
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/02—Preparation
- C07D505/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
- C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
- C07D505/16—Nitrogen atoms
- C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of preparation methods of oxacephem parent nucleus, this method is with compound (I) for raw material, in organic solvent, after oxidation reaction first occurs with peroxide, it is reacted again with sodium thiosulfate, after completion of the reaction, extracts methylene chloride phase, after vacuum distillation, recrystallisation solvent is added and obtains final product oxacephem parent nucleus.The preparation method preparation manipulation of oxacephem parent nucleus of the present invention is simple, prepares that raw material is cheap and easy to get, and preparation cost is low, and reaction route is short, and molar yield is high, and the finished product purity (HPLC) for being easy to industrialize, and preparing is up to 99%.
Description
Technical field
The present invention relates to chemicals synthesis technical fields, and in particular to a kind of preparation method of oxacephem parent nucleus.
Background technique
Oxacephem has been the sulphur of the cephem former heterocyclic system being substituted with an oxygen, i.e. 1 one azabicyclo of 5_ oxa- } 4,3,
D] pungent 2_ alkene, the antibiotic containing this heterocycle is known as oxygen head and embraces carbapenem antibiotic, belong to third generation head and steep rhzomorph, correlative study refers to
Out: the resisting gram-positive angle of the more corresponding cephem of oxacephem and the activity of negative bacterium have enhancing, and current oxygen head is embraced
Carbapenem antibiotic has: latamoxef and Flomoxef etc., such antibiotic has has a broad antifungal spectrum, especially right to G+ bacterium, G- bacterium
The S. aureus L-forms (MRSA) of methicillin resistance have very strong antibacterial activity, and existing oxacephem parent nucleus preparation process operating procedure is multiple
Miscellaneous, conversion process is unstable, and the finished product purity of preparation is not high.
Summary of the invention
The purpose of the present invention is to solve the above-mentioned problems, provides a kind of preparation method of oxacephem parent nucleus.
Term explanation:
Oxacephem parent nucleus, i.e. (6R, 7R) -7- [(4- toluyl) amido] -3- chloromethyl -8- oxo -5- oxa- -
1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid benzhydryl ester, chemical structural formula are as follows:
Compound (I), chemical structural formula is as follows:
To achieve the goals above, the present invention adopts the following technical scheme:
A kind of preparation method of oxacephem parent nucleus, including following preparation step:
(1), compound (I) and organic solvent are added into reaction vessel, temperature is controlled at 0~10 DEG C, stirred to complete
Dissolution, reaction material liquid are transparent；
(2), the dichloromethane solution of peroxide is added into reaction material liquid, reaction temperature controls the reaction at 0~10 DEG C
Time is 1~4h；
(3), step (2) after completion of the reaction, it is water-soluble that the sodium thiosulfate that mass fraction is 15% is added into reaction material liquid
Liquid, reaction temperature control is at 0~30 DEG C, reaction time 4h；
(4), after completion of the reaction, stratification extracts to obtain methylene chloride phase to step (3), and after vacuum distillation, it is molten that crystallization is added
Agent obtains crystal, crystal is washed with recrystallisation solvent, oxacephem parent nucleus is obtained after drying after filtering.
Further, the molar ratio of the compound (I), peroxide and sodium thiosulfate is 1:(1.3~3): (1.5
~5), preferably 1:1.5:3.
Further, the organic solvent is methylene chloride, the one or two in chloroform.
Further, the recrystallisation solvent is one or both of methanol, ethyl alcohol.
Further, the peroxide is one of Peracetic acid, metachloroperbenzoic acid.
The preparation route of the method for the invention is as follows:
The beneficial effects of the present invention are: the preparation method preparation manipulation of oxacephem parent nucleus of the present invention is simple, system
Standby raw material is cheap and easy to get, and preparation cost is low, and reaction route is short, and molar yield is high, the finished product purity for being easy to industrialize, and preparing
(HPLC) up to 99%.
Specific embodiment
The following examples can make those skilled in the art that the present invention be more fully understood, but not limit in any way
The present invention.
A kind of preparation method of oxacephem parent nucleus, including following preparation step:
(1), it is added into reaction vessel and organic solvent, temperature is controlled at 0~10 DEG C, stirring is reacted to being completely dissolved
Feed liquid is transparent；
(2), the dichloromethane solution of peroxide is added into reaction material liquid, reaction temperature controls the reaction at 0~10 DEG C
Time is 1~4h；
(3), step (2) after completion of the reaction, it is water-soluble that the sodium thiosulfate that mass fraction is 15% is added into reaction material liquid
Liquid, reaction temperature control is at 0~30 DEG C, reaction time 4h；
(4), after completion of the reaction, stratification extracts to obtain methylene chloride phase to step (3), and after vacuum distillation, it is molten that crystallization is added
Agent obtains crystal, crystal is washed with recrystallisation solvent, oxacephem parent nucleus is obtained after drying after filtering.
In this preferred embodiment, the molar ratio of the compound (I), peroxide and sodium thiosulfate be 1:(1.3~
3): (1.5~5), preferably 1:1.5:3.
In this preferred embodiment, the organic solvent is methylene chloride, the one or two in chloroform
In this preferred embodiment, the recrystallisation solvent is one or both of methanol, ethyl alcohol.
In this preferred embodiment, the peroxide is Peracetic acid, metachloroperbenzoic acid
One of.
Embodiment: methylene chloride 100mL, compound (I) 10.0g (0.0159mol), temperature are added into reaction vessel
Control is at 0~10 DEG C, and stirring is completely dissolved to compound (I), and reaction material liquid is transparent, and quality point is added dropwise into reaction material liquid
Used time 30min is added dropwise, after dripping in the dichloromethane solution 41.2g (0.0239mol) for the metachloroperbenzoic acid that number is 10%
Controlling reaction temperature is 0~10 DEG C, reaction time 2h, and after the reaction was completed, it is 15% that mass fraction is added into reaction material liquid
Sodium thiosulfate solution 50ml (0.0475mol), control reaction temperature are 0~10 DEG C, reaction time 4h, stratification,
Methylene chloride phase is extracted to obtain, vacuum distillation is dry, and 50ml methanol stirred crystallization is added, and crystal is obtained after filtering, crystal is used
The washing of 30ml methanol, obtains oxacephem parent nucleus after drying.
The purity of oxacephem parent nucleus made from preparation method with high performance liquid chromatography (HPLC) detection embodiment is high
The specific testing conditions of effect liquid phase chromatogram method (HPLC) are as follows:
Liquid chromatograph: Shimadzu LC-10AT VP；
Pillar: Shimadzu C-18 chromatographic column；
Flow velocity: 1.0ml/min；
Column temperature: 15~25 DEG C；
Mobile phase: 400ml purified water is mixed with 600ml acetonitrile, obtains mobile phase.
Detection wavelength: 254nm.
Testing result are as follows: the purity of oxacephem parent nucleus is 99.7006%.
It will be understood by those skilled in the art that above embodiments are only exemplary embodiments, without departing substantially from spirit of the invention
In the case where range, a variety of variations can be carried out, replaced and changed.
Claims (5)
1. a kind of preparation method of oxacephem parent nucleus, which is characterized in that including following preparation step:
(1), compound (I) and organic solvent are added into reaction vessel, temperature is controlled at 0 ~ 10 DEG C, stirring to being completely dissolved,
Reaction material liquid is transparent；
(2), the dichloromethane solution of peroxide is added into reaction material liquid, reaction temperature control is at 0 ~ 10 DEG C, the reaction time
For 1 ~ 4h;
(3), step (2) after completion of the reaction, the sodium thiosulfate solution that mass fraction is 15% is added into reaction material liquid, instead
Answer temperature control at 0 ~ 30 DEG C, reaction time 4h；
(4), after completion of the reaction, stratification extracts to obtain methylene chloride phase to step (3), and after vacuum distillation, recrystallisation solvent is added,
Crystal is obtained after filtering, and crystal is washed with recrystallisation solvent, oxacephem parent nucleus is obtained after drying.
2. a kind of preparation method of oxacephem parent nucleus according to claim 1, which is characterized in that the compound (I),
The molar ratio of peroxide and sodium thiosulfate is 1:(1.3 ~ 3): (1.5 ~ 5), preferably 1:1.5:3.
3. a kind of preparation method of oxacephem parent nucleus according to claim 1, which is characterized in that the organic solvent is
One or two in methylene chloride, chloroform.
4. a kind of preparation method of oxacephem parent nucleus according to claim 1, which is characterized in that the recrystallisation solvent is
One or both of methanol, ethyl alcohol.
5. a kind of preparation method of oxacephem parent nucleus according to claim 1, which is characterized in that the peroxide is
One of Peracetic acid, metachloroperbenzoic acid.
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| CN201910325931.1A CN110003243A (en) | 2019-04-23 | 2019-04-23 | A kind of preparation method of oxacephem parent nucleus |
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| CN201910325931.1A CN110003243A (en) | 2019-04-23 | 2019-04-23 | A kind of preparation method of oxacephem parent nucleus |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS543088A (en) * | 1977-06-06 | 1979-01-11 | Shionogi & Co Ltd | Preparation of 1-oxadethiacephalosporin |
| US4478997A (en) * | 1977-02-15 | 1984-10-23 | Shionogi & Co., Ltd. | 1-Oxadethiacepham compounds |
| CN103254215A (en) * | 2013-05-24 | 2013-08-21 | 浙江东邦药业有限公司 | Preparation method of allyl chlorooxyl cephalosporin compound |
| CN106749335A (en) * | 2016-11-29 | 2017-05-31 | 浙江新和成股份有限公司 | A kind of preparation method and application of halo oxygen cephalo-type intermediate |
-
2019
- 2019-04-23 CN CN201910325931.1A patent/CN110003243A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4478997A (en) * | 1977-02-15 | 1984-10-23 | Shionogi & Co., Ltd. | 1-Oxadethiacepham compounds |
| JPS543088A (en) * | 1977-06-06 | 1979-01-11 | Shionogi & Co Ltd | Preparation of 1-oxadethiacephalosporin |
| CN103254215A (en) * | 2013-05-24 | 2013-08-21 | 浙江东邦药业有限公司 | Preparation method of allyl chlorooxyl cephalosporin compound |
| CN106749335A (en) * | 2016-11-29 | 2017-05-31 | 浙江新和成股份有限公司 | A kind of preparation method and application of halo oxygen cephalo-type intermediate |
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