CN110372728A - A kind of preparation method of oxacephem parent nucleus intermediate - Google Patents
A kind of preparation method of oxacephem parent nucleus intermediate Download PDFInfo
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- CN110372728A CN110372728A CN201910748576.9A CN201910748576A CN110372728A CN 110372728 A CN110372728 A CN 110372728A CN 201910748576 A CN201910748576 A CN 201910748576A CN 110372728 A CN110372728 A CN 110372728A
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- reaction
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- parent nucleus
- boron trifluoride
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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
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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
- C07D505/10—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)
Abstract
The invention discloses a kind of preparation methods of oxacephem parent nucleus intermediate, including following preparation step: (1), methylene chloride being added into reaction vessel, it is put into the reaction vessel after compound OXAOH(001) is concentrated and dried, stirring is dissolved completely in methylene chloride to (001), obtains mixed solution A；(2), boron trifluoride ether is added in the mixed solution A obtained to step (1), boron trifluoride ether obtains (2R after reacting with (001) in the mixed solution A, 6R, 7R) -3- methylene -7- [(4- toluyl) amino] -8- oxo -5- oxa- -1- azabicyclo [4.2.0] octane -2- diphenylmethyl carboxylate.The preparation method of oxacephem parent nucleus intermediate disclosed by the invention is precipitated without solid during the reaction, reactive liquid solution is become by pervious solid-liquid reaction, accelerate reaction time and reaction rate, improve the accuracy of reaction solution detection, improve the quality of product, avoid sampling error, it is ensured that the qualification rate of product has more accurate guidance to production.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical fields, and in particular to a kind of preparation method of oxacephem parent nucleus intermediate.
Background technique
In the preparation process of existing oxacephem parent nucleus intermediate, uses ethyl acetate as reaction dissolvent, reacted
Solid precipitation is easy in journey, causing reaction process is solid-liquid reaction, and reaction solution sample detection cannot be truly reflected instead completely
Process is answered, and if raw material peak is lower when the solid accounting in the sample of sampling is larger, reacting the testing result provided is reaction
Completely, the conversion ratio for resulting in this to walk in this way at blind area, can also quality to product and yield affect.
Summary of the invention
The purpose of the present invention is to solve the above-mentioned problems, provides a kind of preparation side of oxacephem parent nucleus intermediate
Method.
To achieve the goals above, the present invention adopts the following technical scheme:
A kind of preparation method of oxacephem parent nucleus intermediate, including following preparation step:
(1), methylene chloride is added into reaction vessel, compound OXAOH (001) is concentrated and dried to moisture content and is lower than
It is put into after 0.05% in the reaction vessel, solution temperature is controlled at 10~15 DEG C, and stirring is dissolved completely in dichloromethane to (001)
In alkane, mixed solution A is obtained；
(2), boron trifluoride ether is added in the mixed solution A obtained to step (1), reaction temperature control is 10~15
DEG C, boron trifluoride ether obtains (2R, 6R, 7R) -3- methylene -7- [(4- first after reacting with (001) in the mixed solution A
Base benzoyl) amino] -8- oxo -5- oxa- -1- azabicyclo [4.2.0] octane -2- diphenylmethyl carboxylate (002).
Further, the volume ratio of (001) and methylene chloride is 1: 10 in the step (1).
Further, boron trifluoride ether and the molar ratio of (001) are (3~5) in the step (2): 100.
The beneficial effects of the present invention are: the preparation method of oxacephem parent nucleus intermediate disclosed by the invention is in reaction process
In there is no solid precipitation, reactive liquid solution is become by pervious solid-liquid reaction, reaction time and reaction rate is accelerated, improves
The accuracy of reaction solution detection, improves the quality of product, avoids sampling error, it is ensured that the qualification rate of product, to production
There is more accurate guidance, obtained product purity is high, and high income, color is good, reaction rate is improved, when reducing reaction
Between, it is easy to operate, reduce the investment of equipment, low energy consumption.
Detailed description of the invention
Fig. 1 is the chemical structural formula of compound OXAOH (001).
Fig. 2 is compound (2R, 6R, 7R) -3- methylene -7- [(4- toluyl) amino] -8- oxo -5- oxa- -
The chemical structural formula of 1- azabicyclo [4.2.0] octane -2- diphenylmethyl carboxylate (002).
Fig. 3 is the chemical equation of oxacephem parent nucleus intermediate preparation.
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 intermediate, including following preparation step:
(1), methylene chloride is added into reaction vessel, compound OXAOH (001) is concentrated and dried to moisture content and is lower than
It is put into after 0.05% in the reaction vessel, solution temperature is controlled at 10~15 DEG C, and stirring is dissolved completely in dichloromethane to (001)
In alkane, mixed solution A is obtained；
(2), boron trifluoride ether is added in the mixed solution A obtained to step (1), reaction temperature control is 10~15
DEG C, boron trifluoride ether obtains (2R, 6R, 7R) -3- methylene -7- [(4- first after reacting with (001) in the mixed solution A
Base benzoyl) amino] -8- oxo -5- oxa- -1- azabicyclo [4.2.0] octane -2- diphenylmethyl carboxylate (002).
In this preferred embodiment, the volume ratio of (001) and methylene chloride is 1: 10 in the step (1).
In this preferred embodiment, boron trifluoride ether and the molar ratio of (001) are (3~5) in the step (2): 100.
Embodiment: (1) it, into reaction vessel is added methylene chloride 100g, compound OXAOH (001) is concentrated and dried extremely
Moisture content is put into the reaction vessel after being lower than 0.05%, and solution temperature is controlled at 10 DEG C, and stirring is completely dissolved to (001)
In methylene chloride, mixed solution A is obtained；
(2), boron trifluoride ether 0.51g is added in the mixed solution A obtained to step (1), reaction temperature control is 10
~15 DEG C, reaction time 3h, boron trifluoride ether obtains (2R, 6R, 7R)-after reacting with (001) in the mixed solution A
3- methylene -7- [(4- toluyl) amino] -8- oxo -5- oxa- -1- azabicyclo [4.2.0] octane -2- carboxylic acid two
Benzene methyl (002).
After changing the reaction dissolvent in step (1) into ethyl acetate by methylene chloride, reaction process comparison is as follows:
Reaction solution does not have rule that can follow when can be seen that from the data in table using ethyl acetate as reaction dissolvent, cannot
Reflect the reaction process of this step process, and when using methylene chloride as reaction dissolvent, raw material peak be constantly reduce, and turn
Conversion ratio when rate will be significantly larger than using ethyl acetate as reaction dissolvent.
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 (3)
1. a kind of preparation method of oxacephem parent nucleus intermediate, which is characterized in that including following preparation step:
(1), methylene chloride is added into reaction vessel, compound OXAOH(001) is concentrated and dried to moisture content and is lower than
It is put into after 0.05% in the reaction vessel, solution temperature is controlled at 10~15 DEG C, and stirring is dissolved completely in dichloromethane to (001)
In alkane, mixed solution A is obtained；
(2), it is added boron trifluoride ether in the mixed solution A obtained to step (1), reaction temperature control is 10~15 DEG C, three
Fluorination borate ether obtains (2R, 6R, 7R) -3- methylene -7- [(4- methylbenzene after reacting with (001) in the mixed solution A
Formyl) amino] -8- oxo -5- oxa- -1- azabicyclo [4.2.0] octane -2- diphenylmethyl carboxylate (002).
2. a kind of preparation method of oxacephem parent nucleus intermediate according to claim 1, which is characterized in that the step
(1) volume ratio of (001) and methylene chloride is 1: 10 in.
3. a kind of preparation method of oxacephem parent nucleus intermediate according to claim 1, which is characterized in that the step
(2) boron trifluoride ether and the molar ratio of (001) are (3~5) in: 100.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548358A (en) * | 2020-06-18 | 2020-08-18 | 山西千岫制药有限公司 | Synthesis and preparation method of cefepime side chain intermediate |
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| US3905979A (en) * | 1974-05-09 | 1975-09-16 | Stanford Research Inst | Diazabicyclooctanes and diazabicycloheptanes |
| US20060189830A1 (en) * | 2005-01-18 | 2006-08-24 | California Institute Of Technology | Enantioselective alpha-fluorination of aldehydes using chiral organic catalysts |
| CN101096373A (en) * | 2006-06-28 | 2008-01-02 | 哈药集团制药总厂 | Method for preparing cefotiam dihydrate dihydrochloride |
| CN102875571A (en) * | 2012-10-30 | 2013-01-16 | 陕西思尔生物科技有限公司 | Latamoxef Sodium midbody synthetic method |
| CN107325115A (en) * | 2017-07-31 | 2017-11-07 | 山西千岫制药有限公司 | A kind of preparation method of oxygen cephalosporin intermediate |
| CN107383066A (en) * | 2017-07-31 | 2017-11-24 | 山西千岫制药有限公司 | A kind of method of latamoxef acid deprotection base |
| CN108395444A (en) * | 2018-04-04 | 2018-08-14 | 梯尔希（南京）药物研发有限公司 | A kind of preparation method of 3- ethyls cefadroxil |
-
2019
- 2019-08-14 CN CN201910748576.9A patent/CN110372728A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3905979A (en) * | 1974-05-09 | 1975-09-16 | Stanford Research Inst | Diazabicyclooctanes and diazabicycloheptanes |
| US20060189830A1 (en) * | 2005-01-18 | 2006-08-24 | California Institute Of Technology | Enantioselective alpha-fluorination of aldehydes using chiral organic catalysts |
| CN101096373A (en) * | 2006-06-28 | 2008-01-02 | 哈药集团制药总厂 | Method for preparing cefotiam dihydrate dihydrochloride |
| CN102875571A (en) * | 2012-10-30 | 2013-01-16 | 陕西思尔生物科技有限公司 | Latamoxef Sodium midbody synthetic method |
| CN107325115A (en) * | 2017-07-31 | 2017-11-07 | 山西千岫制药有限公司 | A kind of preparation method of oxygen cephalosporin intermediate |
| CN107383066A (en) * | 2017-07-31 | 2017-11-24 | 山西千岫制药有限公司 | A kind of method of latamoxef acid deprotection base |
| CN108395444A (en) * | 2018-04-04 | 2018-08-14 | 梯尔希（南京）药物研发有限公司 | A kind of preparation method of 3- ethyls cefadroxil |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548358A (en) * | 2020-06-18 | 2020-08-18 | 山西千岫制药有限公司 | Synthesis and preparation method of cefepime side chain intermediate |
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