CN108299471A - A kind of improvement preparation process of cefmetazole intermediate - Google Patents
A kind of improvement preparation process of cefmetazole intermediate Download PDFInfo
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- CN108299471A CN108299471A CN201710020527.4A CN201710020527A CN108299471A CN 108299471 A CN108299471 A CN 108299471A CN 201710020527 A CN201710020527 A CN 201710020527A CN 108299471 A CN108299471 A CN 108299471A
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- intermediate compound
- cefmetazole
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- bronsted acid
- ethyl acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—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
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to a kind of cefmetazole intermediates（Intermediate compound IV）Improvement preparation process.This method replaces silylating reagent in the prior art in suitable solvent using Bronsted acid, prepares intermediate compound IV by intermediate III, conversion ratio is increased to 98%, and single step yield is 90 ~ 95%.Improvement preparation process disclosed by the invention avoids harm of the silylating reagent smoke to technical staff and the pollution to environment；And the Bronsted acid that the present invention uses is cheap and easy to get, reaction condition is mild, and single step cost is greatly lowered；The intermediate compound IV of preparation can not post-treated purifying, be directly used in and react in next step, or intermediate compound IV is prepared into salt for industry application at salt technology according to existing.
Description
Technical field
The invention belongs to pharmaceutical synthesis preparation fields, more particularly to the improvement preparation process of cephalosporin compound intermediate.
Background technology
Cefmetazole sodium, chemistry are entitled：(6R, 7S) -7- [[2- (cyanogen methyl sulphur) acetyl] amino] -7- methoxyl groups -3-
[(1- methyl tetrazolium -5- bases) sulfidomethyl] -8- oxos -5- thia -1- azabicyclos [4.2.0] oct-2-ene -2- formic acid sodium salts,
Molecular formula is：C15H16N7NaO5S3, structural formula is as follows：
Cefmetazole sodium is second generation cephalosporin, is by the semi-synthetic cephalosporins antibiosis that company formulates altogether of Japan three
Element, the wide spectrum beta-lactamase generated to negative bacillus have preferable stability.It is Escherichia coli, klebostiella pneumoniae, unusual
Proteus, Shigella, Salmonella, S. aureus L-forms, A groups hemolytic streptococcus, Bramhamella Catarrhalis have preferably this product
Sensitivity.Clinically it is mainly used for infection in respiratory system, pneumonia, branch gas caused by treating purulent meningitis and sensitive bacteria
Guan Yan, infection of biliary tract, peritonitis, infection of biliary tract, urinary infection, gynemetrics's bacterium infection, skin soft-tissue infection and operation
Prevent infection etc. afterwards.
The most frequently used technique of domestic large-scale production cefmetazole sodium is to use 7-MAC for starting material, or adopt at present
With 7-ACA it is that starting material first prepares 7-MAC, but that there are costs of material is high, agents useful for same toxicity is big, environmental pollution for the route
The defects such as weight, complex process, total recovery be low, maximum defect are cefmetazole sodium finished product purity prepared by the route
Low, impurity content is high, and current process for refining is bad to the refining effect of impurity, results in the need for refining repeatedly and repeatedly can be only achieved
Bulk pharmaceutical chemicals standard, and then total recovery is low, it is of high cost.
Develop new total recovery is high, environmental pollution is small, purity is high, the cefmetazole sodium new process with cost advantage always
It is the technical issues of current this field is badly in need of solving.The prior art discloses a large amount of new or optimization suitable industrialized production
Technical study it is all underway always.
Patent of invention US3960845, CN103709179A disclose the new cefmetazole preparation process techniques
Using compound I as starting material, cefmetazole acid crude is prepared by silanization/halogenated, methoxylation, secondary silanization, condensation.
Its synthetic route is as follows：
The advantages of synthetic route, is that total recovery is up to 55 ~ 65%, at low cost, environmental pollution is small, good product purity（>
99%）, be suitble to industrialized production.
It is prepared by wherein key intermediate IV（Secondary silylation step）Using trim,ethylchlorosilane, bromotrimethylsilane, three
Methyl iodide silane, the bis- pivaloyl amine of N, O-, the mixing of one or more of hexamethyldisilazane.Its dosage is
Intermediate compound I is 1 with secondary silylating reagent molar ratio:5~8.
Patent of invention CN10130226《The preparation method of Cephamycin intermediate compound》, disclose similar to compound IV
Cefmetazole midbody compound and its optimization preparation method.The difference is that starting material I using bromo-derivative rather than
Chloro thing, intermediate II is halogenated to use dimethyl sulfoxide.
Patent of invention CN103193796《A kind of Cephamycin intermediate compound and preparation method thereof》, disclose in route 1
The purification process of key intermediate IV.Intermediate compound IV in solvent acetone or ethyl acetate with suitable organic amine dicyclohexylamine
At solid is salted out, intermediate leads to IV by that can reach good refining effect at salt, and can realize the solidification of intermediate compound IV, has
Conducive to the long term storage of intermediate compound IV.
Key intermediate IV in route 1 is widely used, not only can be used as synthesis cefmetazole sodium key intermediate, simultaneously
Also it can be used as the key intermediate of cefminox sodium, Cefotetan Disodium and cefoxitin sodium.
The preparation of key intermediate IV and its bromo analogue that currently available technology discloses are intermediate III in solvent
It is middle that a certain amount of silylating reagent is added（Such as trim,ethylchlorosilane, bromotrimethylsilane, Iodotrimethylsilane, N, O- bis- three
Methylacetamide, hexamethyldisilazane）It prepares, silylating reagent dosage is 5 ~ 8 equivalents.
The defect of the existing technology of preparing is that silylating reagent is smokiness reagent, is more toxic, environmental pollution is heavier.
And silylating reagent dosage is big, considerably beyond theoretical amount, single step cost is higher.
Key intermediate IV is widely used, existing technology of preparing using silylating reagent there are toxicity big, environmental pollution weight,
The defects of dosage is more, and single step is of high cost improve and optimizate step preparation process and have become the technology that current this field is badly in need of solving and ask
Topic.
Invention content
The environmental-friendly of cephalo antibiotics key intermediate IV is prepared the object of the present invention is to provide a kind of, it is at low cost
Improve synthesis technology.
Improvement synthesis technology disclosed by the invention is as follows:
As shown in above-mentioned route, by intermediate III in suitable solvent, Bronsted acid is added, in a constant temperature in intermediate compound IV
It is prepared by the lower reaction of degree.
Wherein Bronsted acid is selected from the mixing of one or both of hydrochloric acid, hydrobromic acid, sulfuric acid in any proportion.
Wherein the dosage of Bronsted acid is intermediate III:Bronsted acid (molar ratio) is 1:2 ~ 9, preferably 1:5~9.
Reaction dissolvent in ethyl acetate, acetone, DMF, chloroform, the dichloromethane it is one or more in any proportion
Mixing.
Reaction temperature is -30 ~ 50 DEG C, preferably 30 ~ 50 DEG C.
The aqueous solution of Bronsted acid and non-generic Bronsted acid that the present invention uses, but use proton acid gas or Bronsted acid
Organic solvent solution, find whether moisture content can be fully converted to the reaction process intermediate state in reaction system in early-stage study
Product key intermediate IV has played key effect, and excessively reaction largely rests on intermediate state to moisture content, and conversion ratio 50% passes through
Analysis to reaction mechanism, our pleasantly surprised discoveries change protonic acid aqueous solution into proton acid gas or Bronsted acid organic solvent
After solution, reaction is thorough, and conversion ratio reaches 98%, is almost completely converted into product.
The wherein Bronsted acid organic solvent solution preferably identical solvent with reaction dissolvent.
The present invention is to disclose patent of invention CN10130226 and CN103709179A the skill of key intermediate IV in route
Art is improved.Silylating reagent disclosed in the prior art is replaced using Bronsted acid, reduces environmental pollution, selected Bronsted acid
Cheap and easy to get, cost is well below silylating reagent, and high conversion rate is up to 98%, single step product yield 90 ~ 95%, yield and purity
Increased substantially compared with the prior art, can be directly used in without further purification in next step react, or according to it is existing will be in key at salt technology
Mesosome IV is prepared into salt for commercial applications.
Key intermediate IV disclosed by the invention compared with prior art, it is advantageous that：
（1）The present invention replaces the silylating reagent of the prior art using Bronsted acid（Trim,ethylchlorosilane, bromotrimethylsilane, three
Methyl iodide silane, the bis- pivaloyl amine of N, O-, hexamethyldisilazane）Key intermediate IV is prepared, silanization examination is avoided
Harm of the agent smoke to technical staff, and greatly reduce the pollution to environment；
（2）The Bronsted acid that the present invention uses is cheap and easy to get, and reaction condition is mild, and single step cost is greatly lowered；
（3）The present invention replaces silylating reagent, conversion ratio to be increased to 98% using Bronsted acid, and single step yield is 90 ~ 95%, yield and
Purity is significantly improved compared with the prior art.
Specific implementation mode
Only the present invention is described further for embodiment below, should not be understood as the limit to the scope of the present invention
System.The adjustment and modification for some non-intrinsically safes that those skilled in the art makes invention content still fall within the guarantor of the present invention
Protect range.
The preparation of 1 intermediate III of test example
Intermediate III provides present invention experiment and uses after being prepared with reference to CN103709179 embodiments 1.
Embodiment 1
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）It is dissolved in ethyl acetate
Among 400ml, it is passed through dry HCl gases into reaction solution, is to slowly warm up to 40 DEG C, keeps 40 DEG C of reactions to the reaction was complete
（1.5~2h）, stop reaction, ice water 300ml, ethyl acetate 100ml is added to -20 DEG C in cooling reaction, in 8-10 DEG C of stirring
30min, layering, aqueous layer with ethyl acetate are extracted to no product, merge organic layer, dry with saturated common salt water washing, filter,
Filter cake is washed with ethyl acetate, and filtrate is concentrated to dryness in 5 ~ 10 DEG C, obtains oily intermediate compound IV, yield 94%, purity 96%.
Embodiment 2
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）It is dissolved in ethyl acetate
Among 400ml, the HCl ethyl acetate solutions 46ml of dry 2N is passed through into reaction solution（Compared to intermediate III molar equivalent
For 2.0eq）, 40 DEG C are to slowly warm up to, keeps 40 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, cooling reaction to -20
DEG C, ice water 300ml, ethyl acetate 100ml is added, 30min, layering are stirred in 8-10 DEG C, aqueous layer with ethyl acetate is extracted to nothing
Product merges organic layer, dry with saturated common salt water washing, filters, filter cake is washed with ethyl acetate, and filtrate is dense in 5 ~ 10 DEG C
It is reduced to dry, obtains oily intermediate compound IV, yield 95%, purity 95.5%.
Embodiment 3
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）It is dissolved in ethyl acetate
Among 400ml, the HCl ethyl acetate solutions 207ml of dry 2N is passed through into reaction solution（Work as compared to intermediate III mole
Amount is 9.0eq）, 40 DEG C are to slowly warm up to, keeps 40 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, cooling reaction to-
20 DEG C, ice water 300ml, ethyl acetate 100ml is added, 30min, layering are stirred in 8-10 DEG C, aqueous layer with ethyl acetate is extracted to
Without product, merge organic layer, it is dry with saturated common salt water washing, it filters, filter cake is washed with ethyl acetate, and filtrate is in 5 ~ 10 DEG C
It is concentrated to dryness, obtains oily intermediate compound IV, yield 93.7%, purity 96.5%.
Embodiment 4
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）It is dissolved in ethyl acetate
Among 400ml, the HCl ethyl acetate solutions 115ml of dry 2N is passed through into reaction solution（Work as compared to intermediate III mole
Amount is 5.0eq）, 40 DEG C are to slowly warm up to, keeps 40 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, cooling reaction to-
20 DEG C, ice water 300ml, ethyl acetate 100ml is added, 30min, layering are stirred in 8-10 DEG C, aqueous layer with ethyl acetate is extracted to
Without product, merge organic layer, it is dry with saturated common salt water washing, it filters, filter cake is washed with ethyl acetate, and filtrate is in 5 ~ 10 DEG C
It is concentrated to dryness, obtains oily intermediate compound IV, yield 94%, purity 95.3%.
Embodiment 5
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）Be dissolved in acetone 400ml it
In, the HCl acetone solns 115ml of dry 2N is passed through into reaction solution（Compared to intermediate III molar equivalent be 5.0eq）,
40 DEG C are to slowly warm up to, keeps 40 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, ice is added to -20 DEG C in cooling reaction
Water 300ml, ethyl acetate 100ml stir 30min, layering in 8-10 DEG C, and aqueous layer with ethyl acetate is extracted to no product, merges
Organic layer, it is dry with saturated common salt water washing, it filters, filter cake is washed with ethyl acetate, and filtrate is concentrated to dryness in 5 ~ 10 DEG C, obtains
To oily intermediate compound IV, yield 95.2%, purity 94.6%.
Embodiment 6
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）Be dissolved in chloroform 400ml it
In, the HCl chloroformic solutions 115ml of dry 2N is passed through into reaction solution（Compared to intermediate III molar equivalent be 5.0eq）,
40 DEG C are to slowly warm up to, keeps 40 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, ice is added to -20 DEG C in cooling reaction
Water 300ml, chloroform 100ml stir 30min, layering in 8-10 DEG C, and water layer is extracted to no product with chloroform, merges organic layer, uses
Saturated common salt water washing, it is dry, it filters, filter cake chloroform, filtrate is concentrated to dryness in 5 ~ 10 DEG C, obtains oily intermediate
IV, yield 94.1%, purity 95.8%.
Embodiment 7
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）Be dissolved in DMF400ml it
In, the HCl DMF solutions 115ml of dry 2N is passed through into reaction solution（Compared to intermediate III molar equivalent be 5.0eq）,
40 DEG C are to slowly warm up to, keeps 40 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, ice is added to -20 DEG C in cooling reaction
Water 300ml, ethyl acetate 500ml stir 30min, layering in 8-10 DEG C, and aqueous layer with ethyl acetate is extracted to no product, merges
Organic layer, it is dry with saturated common salt water washing, it filters, filter cake is washed with ethyl acetate, and filtrate is concentrated to dryness in 5 ~ 10 DEG C, obtains
To oily intermediate compound IV, yield 93.2%, purity 94.8%.
Embodiment 8
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）It is dissolved in ethyl acetate
Among 400ml, the HCl ethyl acetate solutions 115ml of dry 2N is passed through into reaction solution（Work as compared to intermediate III mole
Amount is 5.0eq）, -30 DEG C are to slowly warm up to, keeps -30 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, ice water be added
300ml, ethyl acetate 100ml, 30min, layering are stirred in 8-10 DEG C, and aqueous layer with ethyl acetate is extracted to no product, is associated with
Machine layer, it is dry with saturated common salt water washing, it filters, filter cake is washed with ethyl acetate, and filtrate is concentrated to dryness in 5 ~ 10 DEG C, obtains
Oily intermediate compound IV, yield 85%, purity 90.4%.
Embodiment 9
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）It is dissolved in ethyl acetate
Among 400ml, the HCl ethyl acetate solutions 115ml of dry 2N is passed through into reaction solution（Work as compared to intermediate III mole
Amount is 5.0eq）, 50 DEG C are to slowly warm up to, keeps 50 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, cooling reaction to-
20 DEG C, ice water 300ml, ethyl acetate 100ml is added, 30min, layering are stirred in 8-10 DEG C, aqueous layer with ethyl acetate is extracted to
Without product, merge organic layer, it is dry with saturated common salt water washing, it filters, filter cake is washed with ethyl acetate, and filtrate is in 5 ~ 10 DEG C
It is concentrated to dryness, obtains oily intermediate compound IV, yield 90.5%, purity 94.3%.
Embodiment 10
Intermediate III（It feeds intake 25g by intermediate compound I, intermediate III prepared by 1 the method for test example）It is dissolved in ethyl acetate
Among 400ml, the HBr ethyl acetate solutions 115ml of dry 2N is passed through into reaction solution（Work as compared to intermediate III mole
Amount is 5.0eq）, 50 DEG C are to slowly warm up to, keeps 50 DEG C of reactions to the reaction was complete（1.5~2h）, stop reaction, cooling reaction to-
20 DEG C, ice water 300ml, ethyl acetate 100ml is added, 30min, layering are stirred in 8-10 DEG C, aqueous layer with ethyl acetate is extracted to
Without product, merge organic layer, it is dry with saturated common salt water washing, it filters, filter cake is washed with ethyl acetate, and filtrate is in 5 ~ 10 DEG C
It is concentrated to dryness, obtains oily intermediate compound IV, yield 94.2%, purity 95%.
Claims (10)
1. a kind of improvement preparation process of cefmetazole intermediate compound IV, this method chemical equation are as follows：
。
2. cefmetazole intermediate compound IV described in claim 1 improves preparation process, it is characterised in that Bronsted acid used be HCl,
HBr、H2SO4In one or more mixing in any proportion.
3. cefmetazole intermediate compound IV described in claim 1 improves preparation process, it is characterised in that Bronsted acid used is preferred
The mixing of one or both of HCl, HBr in any proportion.
4. cefmetazole intermediate compound IV described in claim 1 improves preparation process, it is characterised in that Bronsted acid used is gas
Or the organic solvent solution of Bronsted acid.
5. cefmetazole intermediate compound IV described in claim 1 improves preparation process, it is characterised in that Bronsted acid amount ratio used
Intermediate III molar ratio is 1:2~9.
6. cefmetazole intermediate compound IV described in claim 1 improves preparation process, it is characterised in that Bronsted acid amount ratio used
Intermediate III molar ratio is preferably 1:5~9.
7. cefmetazole intermediate compound IV described in claim 1 improves preparation process, it is characterised in that reaction dissolvent is acetic acid second
One or more mixing in any proportion in ester, acetone, chloroform, dichloromethane, DMF.
8. cefmetazole intermediate compound IV described in claim 1 improves preparation process, it is characterised in that reaction temperature is -30~50
℃。
9. cefmetazole intermediate compound IV described in claim 1 improves preparation process, it is characterised in that reaction temperature preferably 30~
50℃。
10. Bronsted acid organic solvent solution as claimed in claim 4, organic solvent is ethyl acetate, acetone, chloroform, dichloro
One or more mixing in any proportion in methane, DMF.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111138456A (en) * | 2019-12-27 | 2020-05-12 | 山东安弘制药有限公司 | Preparation method of cephamycin intermediate compound |
| CN111393455A (en) * | 2020-04-28 | 2020-07-10 | 福建省福抗药业股份有限公司 | Preparation method of cefmetazole impurity |
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|---|---|---|---|---|
| US3960845A (en) * | 1974-03-22 | 1976-06-01 | Sankyo Company Limited | Process for preparing 7β-acylamino-7α-alkoxycephalosporins or 6β-acylamino-6α-alkoxypenicillins |
| CN103193796A (en) * | 2013-04-01 | 2013-07-10 | 齐鲁安替（临邑）制药有限公司 | Cephamycin intermediate compound and preparation method thereof |
| CN103709179A (en) * | 2013-12-17 | 2014-04-09 | 福建省福抗药业股份有限公司 | Synthesis and purification method of cefmetazole sodium |
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2017
- 2017-01-12 CN CN201710020527.4A patent/CN108299471B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3960845A (en) * | 1974-03-22 | 1976-06-01 | Sankyo Company Limited | Process for preparing 7β-acylamino-7α-alkoxycephalosporins or 6β-acylamino-6α-alkoxypenicillins |
| CN103193796A (en) * | 2013-04-01 | 2013-07-10 | 齐鲁安替（临邑）制药有限公司 | Cephamycin intermediate compound and preparation method thereof |
| CN103709179A (en) * | 2013-12-17 | 2014-04-09 | 福建省福抗药业股份有限公司 | Synthesis and purification method of cefmetazole sodium |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111138456A (en) * | 2019-12-27 | 2020-05-12 | 山东安弘制药有限公司 | Preparation method of cephamycin intermediate compound |
| CN111393455A (en) * | 2020-04-28 | 2020-07-10 | 福建省福抗药业股份有限公司 | Preparation method of cefmetazole impurity |
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