CN105646542B - The method that microwave method synthesizes Cefpirome Sulfate - Google Patents
The method that microwave method synthesizes Cefpirome Sulfate Download PDFInfo
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- CN105646542B CN105646542B CN201610134446.2A CN201610134446A CN105646542B CN 105646542 B CN105646542 B CN 105646542B CN 201610134446 A CN201610134446 A CN 201610134446A CN 105646542 B CN105646542 B CN 105646542B
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- microwave
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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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- 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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses the methods of microwave method synthesis Cefpirome Sulfate, which is characterized in that including step：(1) 7 amino-cephalo-alkanoic acids and AE active esters are weighed, is ground uniformly after mixing, adds in 2,3 cyclopenta pyridines and the concentrated sulfuric acid afterwards；(2) 300W microwave reactions 1~2 minute, 450W microwave reactions 1~2 minute, 750W microwave reactions 2~3 minutes；(3) after reaction, reaction residue is added in deionized water, is filtered after stirring and evenly mixing, take filtrate, removed solvent, obtain white solid, i.e. Cefpirome Sulfate.It uses microwave method, and is one pot process, and preparation process is simple, without using reaction dissolvent also without expensive catalyst, you can obtain the product of high-purity in high yield.
Description
Technical field
The present invention relates to a kind of synthetic methods, and in particular to a kind of method of microwave method synthesis Cefpirome Sulfate.Belong to
Pharmaceutical technology field.
Background technology
The new super broad-spectrum cephalosporin of Cefpirome system forth generation is to be developed by German Hoechst companies, in 1992
It is listed first in Sweden.Clinically Cefpirome is normally manufactured as the form of sulfate, i.e. Cefpirome Sulfate, can be well
It is absorbed in stomach., with broad spectrum antibiotic activity, pneumococcus and enterococcus to staphylococcus, penicillin resistant have for it
Effect.It is similar to cefotaxime to the effect of Pseudomonas aeruginosa, there is good efficacy to the pathogen of many antibiotic-resistants.It is clinical main
For infection such as serious respiratory tract, urinary tract infection and skin and soft tissues.Cefpirome adverse reaction is less, tolerance compared with
It is good, the gastrointestinal dysfunctions such as allergic reactions, the diarrhea such as adverse reaction such as fash, slight reversible chemical examination change etc. and first generation head
Spore rhzomorph is similar.
Synthesis Cefpirome is all as original with 7-amino-cephalosporanic acid (7-ACA, i.e., I in following reaction equation) at present
Material, mainly there is two lines：1. first with the reactive derivative of ainothiazoly loximate acylation reaction occurs for 7-ACA, cefotaxime acid is generated,
Then substitution reaction generation Cefpirome occurs with 2,3- cyclopenta pyridines again；2. it is first taken with 2,3- cyclopenta pyridines
Generation reaction, then acylation reaction is carried out, obtain target product.
The route 1. following (R therein of reaction equation1For halogen ,-O- or-S-)：
1. middle acylation reaction prepares the technique that cefotaxime acid is comparative maturity to route, and key is that the substitution of next step is anti-
Should, the synthetic method disclosed in existing literature has the following problems：Reaction yield is low, it is necessary to the unsuitable industrial metaplasia such as column chromatography
The separation means of production, catalyst require reaction condition high costly or to water sensitive, and production difficulty is big etc..
The route 2. following (R therein of reaction equation1For halogen ,-O- or-S-)：
Route 2. with route 1. compared with, yield slightly improves, but it relys more on some catalyst costly, reaction
Of high cost, nonetheless, reaction yield still cannot meet the basic demand of industrialized production.
The content of the invention
The purpose of the present invention is to overcome above-mentioned the deficiencies in the prior art, provide a kind of microwave method synthesis Cefpirome Sulfate
Method, use microwave method, and be one pot process, preparation process is simple, without using reaction dissolvent also without expensive
Catalyst, you can obtain the product of high-purity in high yield.
To achieve the above object, the present invention uses following technical proposals：
The method that microwave method synthesizes Cefpirome Sulfate, including step：
(1) 7-amino-cephalosporanic acid (7-ACA, chemical compounds I) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester (AEMA, compound VII) are weighed, after mixing
Grinding is uniform, adds in 2,3-cyclopentenopyridine (compounds Ⅳ) and the concentrated sulfuric acid (98w.t.%) afterwards；
(2) 300W microwave reactions 1~2 minute, 450W microwave reactions 1~2 minute, 750W microwave reactions 2~3 minutes；
(3) after reaction, reaction residue is added in deionized water, is filtered after stirring and evenly mixing, take filtrate, removed molten
Agent obtains white solid, i.e. Cefpirome Sulfate；
Wherein, the ratio between amount of substance of 7-amino-cephalosporanic acid, AE active ester and 2,3-cyclopentenopyridine is 1：1~
1.2：1~1.2, the mass ratio of 7-amino-cephalosporanic acid, the concentrated sulfuric acid and deionized water is 1：3~5：10~12.
Its reaction equation is as follows：
Preferably, the ratio between amount of substance of 7-amino-cephalosporanic acid, AE active ester and 2,3-cyclopentenopyridine is 1：
1.1：1.1, the mass ratio of 7-amino-cephalosporanic acid, the concentrated sulfuric acid and deionized water is 1：4：11.
Preferably, step (2) is 300W microwave reactions 1 minute, and 450W microwave reactions 1 minute, 750W microwave reactions 2 divide
Clock.
Preferably, in step (3), remove the white solid that solvent obtains and be dried in vacuo under the conditions of 40~50 DEG C.
It is further preferred that when drying time is 4~6 small.
Beneficial effects of the present invention：
The present invention is added without reaction dissolvent, is added without catalyst using microwave one pot reaction, easy to operate, during reaction
Between it is short, the Cefpirome Sulfate of high-purity can be obtained in high yield.Reaction cost is cheap, and post processing is simple, and expands reaction
Higher reaction yield and purity are still ensured that afterwards, are suitable for industrialized production.
Specific embodiment
With reference to embodiment, the present invention will be further elaborated, it should explanation, the description below merely to
It explains the present invention, its content is not defined.
The reaction scheme of the present invention is as follows：
Embodiment 1：
The method of the microwave method synthesis Cefpirome Sulfate of the present invention, including step：
(1) 7-amino-cephalosporanic acid 2.72g (7-ACA, chemical compounds I, MW272,0.01mol) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester are weighed
It is ground after 3.5g (AEMA, compound VII, MW350,0.01mol) mixing uniformly, adds in 2,3-cyclopentenopyridine 1.19g afterwards
(compounds Ⅳ, MW119,0.01mol) and concentrated sulfuric acid 8.16g (98wt%)；
(2) 300W microwave reactions 2 minutes, 450W microwave reactions 1 minute, 750W microwave reactions 2 minutes；
(3) after reaction, reaction residue is added in 27.2g deionized waters, is filtered after stirring and evenly mixing, take filtrate,
Solvent is removed, obtains white solid, to get Cefpirome Sulfate 5.03g (MW514), yield when vacuum drying 4 is small under the conditions of 40 DEG C
97.8%, purity more than 99.9%.
1H NMR(D2O,500MHz)δ:2.10 (t, J=7.5Hz, 2H), 3.00 (t, J=7.5Hz, 2H), 3.14 (t, J=
7.5Hz, 2H), 3.32 (s, 2H), 3.84 (s, 3H), 5.05 (d, J=8Hz, 1H), 5.20 (t, J=7.5Hz, 1H), 5.64 (s,
2H), 6.90 (t, J=7.5Hz, 1H), 7.56 (s, 1H), 8.09 (d, 1H), 8.32 (d, J=8Hz, 1H).
Embodiment 2：
The method of the microwave method synthesis Cefpirome Sulfate of the present invention, including step：
(1) 7-amino-cephalosporanic acid 2.72g (7-ACA, chemical compounds I, MW272,0.01mol) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester are weighed
It is ground uniformly after 4.2g (AEMA, compound VII, MW350,0.012mol) mixing, adds in 2,3-cyclopentenopyridine afterwards
1.428g (compounds Ⅳ, MW119,0.012mol) and concentrated sulfuric acid 13.6g (98wt%)；
(2) 300W microwave reactions 1 minute, 450W microwave reactions 2 minutes, 750W microwave reactions 3 minutes；
(3) after reaction, reaction residue is added in 32.64g deionized waters, is filtered after stirring and evenly mixing, take filtrate,
Solvent is removed, obtains white solid, to get Cefpirome Sulfate 5.03g (MW514), yield when vacuum drying 6 is small under the conditions of 50 DEG C
97.8%, purity more than 99.9%.
1H NMR(D2O,500MHz)δ:2.10 (t, J=7.5Hz, 2H), 3.00 (t, J=7.5Hz, 2H), 3.14 (t, J=
7.5Hz, 2H), 3.32 (s, 2H), 3.84 (s, 3H), 5.05 (d, J=8Hz, 1H), 5.20 (t, J=7.5Hz, 1H), 5.64 (s,
2H), 6.90 (t, J=7.5Hz, 1H), 7.56 (s, 1H), 8.09 (d, 1H), 8.32 (d, J=8Hz, 1H).
Embodiment 3：
The method of the microwave method synthesis Cefpirome Sulfate of the present invention, including step：
(1) 7-amino-cephalosporanic acid 2.72g (7-ACA, chemical compounds I, MW272,0.01mol) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester are weighed
It is ground uniformly after 3.85g (AEMA, compound VII, MW350,0.011mol) mixing, adds in 2,3-cyclopentenopyridine afterwards
1.309g (compounds Ⅳ, MW119,0.011mol) and concentrated sulfuric acid 10.88g (98wt%)；
(2) 300W microwave reactions 1 minute, 450W microwave reactions 1 minute, 750W microwave reactions 2 minutes；
(3) after reaction, reaction residue is added in 29.92g deionized waters, is filtered after stirring and evenly mixing, take filtrate,
Solvent is removed, obtains white solid, to get Cefpirome Sulfate 5.09g (MW514), yield when vacuum drying 4 is small under the conditions of 50 DEG C
99.0%, purity more than 99.9%.
1H NMR(D2O,500MHz)δ:2.10 (t, J=7.5Hz, 2H), 3.00 (t, J=7.5Hz, 2H), 3.14 (t, J=
7.5Hz, 2H), 3.32 (s, 2H), 3.84 (s, 3H), 5.05 (d, J=8Hz, 1H), 5.20 (t, J=7.5Hz, 1H), 5.64 (s,
2H), 6.90 (t, J=7.5Hz, 1H), 7.56 (s, 1H), 8.09 (d, 1H), 8.32 (d, J=8Hz, 1H).
Embodiment 4：
The method of the microwave method synthesis Cefpirome Sulfate of the present invention, including step：
(1) 7-amino-cephalosporanic acid 27.2g (7-ACA, chemical compounds I, MW272,0.1mol) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester are weighed
It is ground uniformly after 38.5g (AEMA, compound VII, MW350,0.11mol) mixing, adds in 2,3-cyclopentenopyridine afterwards
13.09g (compounds Ⅳ, MW119,0.11mol) and concentrated sulfuric acid 108.8g (98wt%)；
(2) 300W microwave reactions 1 minute, 450W microwave reactions 1 minute, 750W microwave reactions 2 minutes；
(3) after reaction, reaction residue is added in 299.2g deionized waters, is filtered after stirring and evenly mixing, take filtrate,
Solvent is removed, obtains white solid, to get Cefpirome Sulfate 50.9g (MW514), yield when vacuum drying 4 is small under the conditions of 50 DEG C
99.0%, purity more than 99.9%.
Embodiment 5：
The method of the microwave method synthesis Cefpirome Sulfate of the present invention, including step：
(1) 7-amino-cephalosporanic acid 272g (7-ACA, chemical compounds I, MW272,1mol) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester 385g is weighed
Uniform, addition 2,3-cyclopentenopyridine 130.9g (changes afterwards are ground after (AEMA, compound VII, MW350,1.1mol) mixing
Close object IV, MW119,1.1mol) and concentrated sulfuric acid 1088g (98wt%)；
(2) 300W microwave reactions 1 minute, 450W microwave reactions 1 minute, 750W microwave reactions 2 minutes；
(3) after reaction, reaction residue is added in 2992g deionized waters, is filtered after stirring and evenly mixing, take filtrate,
Solvent is removed, obtains white solid, to get Cefpirome Sulfate 505g (MW514), yield when vacuum drying 4 is small under the conditions of 50 DEG C
98.2%, purity more than 99.9%.
Embodiment 6：
The method of the microwave method synthesis Cefpirome Sulfate of the present invention, including step：
(1) 7-amino-cephalosporanic acid 2.72kg (7-ACA, chemical compounds I, MW272,10mol) and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester are weighed
It is ground uniformly after 3.85kg (AEMA, compound VII, MW350,11mol) mixing, adds in 2,3-cyclopentenopyridine afterwards
1.309kg (compounds Ⅳ, MW119,11mol) and concentrated sulfuric acid 10.88kg (98wt%)；
(2) 300W microwave reactions 1 minute, 450W microwave reactions 1 minute, 750W microwave reactions 2 minutes；
(3) after reaction, reaction residue is added in 29.92kg deionized waters, is filtered after stirring and evenly mixing, take filter
Liquid removes solvent, obtains white solid, to get Cefpirome Sulfate 5.07kg (MW514) when vacuum drying 4 is small under the conditions of 50 DEG C,
Yield 98.6%, purity more than 99.9%.
From embodiment 4~6 as can be seen that after iodine, the yield and purity of product are still more stable, suitable for industry
Metaplasia is produced.
Although the above-mentioned specific embodiment to the present invention is described, not to the limit of the scope of the present invention
System, based on the technical solutions of the present invention, those skilled in the art need not make the creative labor can make it is each
Kind modification is deformed still within protection scope of the present invention.
Claims (5)
1. the method that microwave method synthesizes Cefpirome Sulfate, which is characterized in that including step：
(1) 7-amino-cephalosporanic acid and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester are weighed, is ground uniformly after mixing, adds in 2,3-cyclopentenopyridine afterwards
And the concentrated sulfuric acid；
(2) 300W microwave reactions 1~2 minute, 450W microwave reactions 1~2 minute, 750W microwave reactions 2~3 minutes；
(3) after reaction, reaction residue is added in deionized water, is filtered after stirring and evenly mixing, take filtrate, remove solvent,
Obtain white solid, i.e. Cefpirome Sulfate；
Wherein, the ratio between amount of substance of 7-amino-cephalosporanic acid, AE active ester and 2,3-cyclopentenopyridine is 1：1~1.2：1
~1.2, the mass ratio of 7-amino-cephalosporanic acid, the concentrated sulfuric acid and deionized water is 1：3~5：10~12.
2. the method for microwave method synthesis Cefpirome Sulfate as described in claim 1, which is characterized in that 7- amino cephalo alkane
The ratio between amount of substance of acid, AE active ester and 2,3- cyclopenta pyridines is 1：1.1：1.1,7-amino-cephalosporanic acid, the concentrated sulfuric acid
Mass ratio with deionized water is 1：4：11.
3. the method for microwave method synthesis Cefpirome Sulfate as described in claim 1, which is characterized in that step (2) is 300W
Microwave reaction 1 minute, 450W microwave reactions 1 minute, 750W microwave reactions 2 minutes.
4. the method for microwave method synthesis Cefpirome Sulfate as described in claim 1, which is characterized in that in step (3), remove
The white solid that solvent obtains is dried in vacuo under the conditions of 40~50 DEG C.
5. the method for microwave method synthesis Cefpirome Sulfate as claimed in claim 4, which is characterized in that drying time is 4~6
Hour.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1533530A (en) * | 1976-03-04 | 1978-11-29 | Toyo Jozo Kk | Cephalosporins |
| CN101456870A (en) * | 2007-12-11 | 2009-06-17 | 北京琥珀光华医药科技开发有限公司 | Novel process for synthesizing cefpirome sulfate |
| CN102584856A (en) * | 2011-12-27 | 2012-07-18 | 开封豫港制药有限公司 | Method for preparing cefpirome sulfate |
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2016
- 2016-03-09 CN CN201610134446.2A patent/CN105646542B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1533530A (en) * | 1976-03-04 | 1978-11-29 | Toyo Jozo Kk | Cephalosporins |
| CN101456870A (en) * | 2007-12-11 | 2009-06-17 | 北京琥珀光华医药科技开发有限公司 | Novel process for synthesizing cefpirome sulfate |
| CN102584856A (en) * | 2011-12-27 | 2012-07-18 | 开封豫港制药有限公司 | Method for preparing cefpirome sulfate |
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