CN101993450A - Preparation method of cefoselis sulfate - Google Patents
Preparation method of cefoselis sulfate Download PDFInfo
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- CN101993450A CN101993450A CN2010105288924A CN201010528892A CN101993450A CN 101993450 A CN101993450 A CN 101993450A CN 2010105288924 A CN2010105288924 A CN 2010105288924A CN 201010528892 A CN201010528892 A CN 201010528892A CN 101993450 A CN101993450 A CN 101993450A
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- ethyl acetate
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- 0 *CC[n]1c(C#C)ccc1* Chemical compound *CC[n]1c(C#C)ccc1* 0.000 description 1
- FMLHDGQGNPAMRR-UHFFFAOYSA-N CC(C)(C)OC(NC(C1SCC(CCl)=C(C(O)=O)N11)C1=O)=O Chemical compound CC(C)(C)OC(NC(C1SCC(CCl)=C(C(O)=O)N11)C1=O)=O FMLHDGQGNPAMRR-UHFFFAOYSA-N 0.000 description 1
- LKNCYHNQBFPTTF-UHFFFAOYSA-N CCC(CSC1C2C)=C(C(OC)=O)N1C2=O Chemical compound CCC(CSC1C2C)=C(C(OC)=O)N1C2=O LKNCYHNQBFPTTF-UHFFFAOYSA-N 0.000 description 1
- CECZTOUVIJWFJE-SSDOTTSWSA-N NNC(SC1)=N[C@H]1C(C(Sc1nc(cccc2)c2[s]1)=O)=N Chemical compound NNC(SC1)=N[C@H]1C(C(Sc1nc(cccc2)c2[s]1)=O)=N CECZTOUVIJWFJE-SSDOTTSWSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of cefoselis sulfate and also discloses an important intermediate of 7beta-butyloxyacylamino-3-[3-formylamino-2-(formyloxyethyl)-1-pyrazolonium] methyl-3-cephem-4-formate (V) and a preparation method thereof. Meanwhile, the invention discloses a synthesis method of the cefoselis sulfate through the steps of taking the V as raw material and reacting the V with 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid benzothiazole ester and then salifying with sulfuric acid. The synthesis method has mild reaction conditions, available raw materials and higher yield and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic field of cephalosporin analog antibiotic, be specifically related to a kind of preparation method of cefoselis sulfate.
Background technology
Cefoselis sulfate (Cefoselis Sulfate) is developed jointly by Japanese rattan pool drug company and U.S. Johnson company, went on the market in Japan first in 1998, its chemical name is: 6R, 7R)-and 3-{[2,3-dihydro-3-imino--2-(2-hydroxyethyl)-2H-pyrazol-1-yl] methyl }-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-3-formic acid vitriol.As the 4th generation cephalosporin analog antibiotic typical case representative, cefoselis sulfate is compared with third generation cephalosporin, it has strengthened anti-G
+Bacterium, G
-Bacterium, the activity of anerobe reaches the stability to β-Nei Xiananmei, has significantly improved staphylococcus aureus nuclear green pus liver bacterium isoreactivity.Clinical study shows, behind the intravenous injection cefoselis sulfate, and the Plasma Concentration height, long half time, widely distributed in human body, adverse reaction rate is low, shows that cefoselis sulfate is being an antimicrobial drug very effectively aspect the treatment systemic infection.
The preparation method of cefoselis sulfate mainly contains following four synthetic routes:
Route one [Ohki H etal, Journal of Antibiotics, 1993,46 (2): 359]
Route two [Pandurang B D etal, US20040132995A1,2004-09-08]
Route three: [Takaya T etal, EP 0261615,1988-03-20]
Route four [Meng Hong, etal, CN1616860A, 2005-05-11]
Route one raw material needs to be obtained through the reaction of five steps by 7-ACA, increased reactions steps, the intermediate that the first step reaction obtains is very unstable at TFA deprotection based products, need carry out next step operation immediately, and use resin HP-20 to cross post step trouble, the product loss is bigger; Wherein a step is used PCl to route two
5When removing protecting group, use temperature is-25 ℃, and severe reaction conditions is not suitable for amplifying and produces; 37 side chains of route are not directly to connect thiazole, carry out in two steps, and have used the very big PCl of pungency
5Though route four has been done very big improvement, used trifluoroacetic acid to remove one of them protecting group, trifluoroacetic acid is a kind of fuming liquid of strong and stimulating.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, provide a yield height, the preparation method of a kind of cefoselis sulfate of environmental protection.
One aspect of the present invention provides 7 β-uncle's fourth oxygen amido-3-[3-formamido group-2-(methanoyl ethyl)-1-pyrazoles drone base] preparation method of methyl-3-cephem-4-formate, specific as follows:
A kind of preparation method of cefoselis sulfate may further comprise the steps:
(1). with compound
Join in the solution of tetrahydrofuran (THF) and triethylamine, the ice-water bath cooling drips Boc down
2O dropwises, the stirring at room reaction, after reacting completely, steam and remove most of tetrahydrofuran (THF), use ethyl acetate extraction, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated aqueous common salt washs successively, and the organic layer anhydrous sodium sulfate drying filters, after organic layer concentrates, add the sherwood oil crystallisation by cooling and obtain compound
Described compound
With Boc
2The mol ratio of O is preferably 1.00: 1.05--1.00: 1.10;
(2) with compound
In methyl alcohol and the ethyl acetate mixed solvent, use Pd/C catalysis, remove 4-position protecting group, after reaction finished, in the reaction solution impouring isopropyl ether, crystallization obtained compound
Described compound
(II) mass volume ratio with ethyl acetate is preferably 1.0: 8.0-1.0: 10.0, and the mass volume ratio of Pd/C and ethyl acetate is preferably 3%-5%;
(3) with compound
Add in the tetrahydrofuran (THF), add the Tetrabutyl amonium bromide (TBAB) of sodium bicarbonate and catalytic amount then,, after reaction solution is concentrated into certain volume, add methylene dichloride, separate out solid, obtain intermediate with the reaction of 5-formamido group-1-(2-methanoyl ethyl) pyrazoles
Described compound
Be preferably 20.0 with the mol ratio of Tetrabutyl amonium bromide: 1.0-25.0: 1.0;
(4) compound
In the hydrochloric acid soln of methyl alcohol, remove C-7 bit amino and C-3 position Side chain protective group simultaneously, obtain intermediate
(5) compound
And compound
Filtrate is regulated PH=1 with sulfuric acid in .MeOH solution, and with in the reaction solution impouring 2000ml ice acetone, the off-white color solid is separated out, and filters then, and filter cake is iced washing with acetone with 300ml, drying, and gained crude product water and Virahol recrystallization obtain compound
Be cefoselis sulfate;
In the present invention, its preparation method is expressed as with chemical equation:
Beneficial effect:
The compound yield is than prior art height among the present invention, and the present invention compared with prior art it is advantageous that: the technology yield improves before comparing; Synthesize and adopted the catalytic method of Pd/C, avoided using strong volatile trifluoroacetic acid, environmental protection, yield is up to 94%, and catalyzer can recycle.
Embodiment
In order to make technique means of the present invention, creation characteristic, workflow, using method reach purpose and effect is easy to understand,, further set forth the present invention below in conjunction with concrete diagram.
Compound I I's is synthetic:
In the reaction flask, add Compound I 81.0 grams (0.20mol), tetrahydrofuran (THF) 400ml, triethylamine 24.3 grams are cooled to 0-5 ℃, drip Boc
2O48.0 restrains (0.22mol), dropwises, and returns to stirring at room reaction 8 hours, reaction solution is concentrated into 150ml, adds ethyl acetate 500ml to resistates, uses 1M hydrochloric acid 20ml successively, saturated aqueous common salt 200ml washing, the ethyl acetate layer anhydrous sodium sulfate drying; Filter, filtrate is concentrated into dried, adds sherwood oil (60-90 ℃) freezing and crystallizing, obtains white solid 81.8 grams, yield 87.21% (calculating with Compound I).
1HNMR(300MHz，CDCl
3)：δ1.46(s，9H)，3.48(d，1H)，3.68(d，1H)，3.80(s，3H)，
4.45(d，1H)，4.55(d，1H)，4.97(d，1H)，5.23(s，2H)，5.62(q，1H)，6.88-6.93(m，2H)，
7.35-7.40(m，2H)。
Synthesizing of compound III:
In the reaction flask, add Compound I I46.9 gram (0.10mol), ethyl acetate 450ml, methyl alcohol 30ml, stir adding 10%Pd/C13.5 gram down, temperature rising reflux reaction 4 hours, the TLC monitoring reaction is complete, filtered and recycled Pd/C, in the cold isopropyl ether of filtrate impouring 1200ml, stirred crystallization, off-white color solid 32.7 grams, yield 93.69% (molar yield calculates with Compound I I);
1HNMR(300MHz，CDCl
3)：δ1.43(s，9H)，3.07(d，1H)，3.19(s，1H)，4.02(s，2H)，
5.01(d，1H)，5.48(d，1H)，11.06(b，1H)。
Synthesizing of compound IV:
In the reaction flask, add compound III 20.9 grams (0.06mol), tetrahydrofuran (THF) 300ml, stirring and dissolving adds Tetrabutyl amonium bromide 1.0 grams (3mmol), sodium bicarbonate 10.1 grams (0.12mol), 5-formamido group-1-(2-methanoyl ethyl) pyrazoles 16.5 grams (0.09mmol), stirring at room reaction 2 hours is filtered, filtrate is concentrated into about 100ml, in the impouring 500ml methylene dichloride, has yellow solid to separate out, filter, drying, 31.2 grams (yield: 97.9%, calculate) with compound III;
Compound V's is synthetic:
In the reaction flask, add compound IV 31.2 grams, methyl alcohol 100ml, stir, add 37% hydrochloric acid 20ml, stirring at room reaction 4 hours is in reaction solution impouring 500ml cold acetone, stirring at low speed, obtain light yellow solid, filter, filter cake washs with the 100ml cold acetone, drying gets light yellow solid 20.7 grams (yield 92.0%).
Synthesizing of compound VI:
In the reaction flask, add compound V20 gram, water 80ml, methyl alcohol 100ml stirs down, adds AE active ester 18.7 grams, room temperature reaction 4 hours is neutral with sodium bicarbonate conditioned reaction liquid in the reaction process, after reacting completely, filter, filtrate is regulated PH=1 with 2M sulfuric acid, then with in the reaction solution impouring 2000ml ice acetone, the off-white color solid is separated out, filter, filter cake is iced washing with acetone with 300ml, drying; Gained crude product water and Virahol recrystallization obtain white crystalline powder 26.4 gram (yields: 80.7%)
Total recovery: 59.39% (calculating) with Compound I.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (3)
1. the preparation method of a cefoselis sulfate is characterized in that, may further comprise the steps:
(1). with compound
Join in the solution of tetrahydrofuran (THF) and triethylamine, the ice-water bath cooling drips Boc down
2O dropwises, the stirring at room reaction, after reacting completely, steam and remove most of tetrahydrofuran (THF), use ethyl acetate extraction, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated aqueous common salt washs successively, and the organic layer anhydrous sodium sulfate drying filters, after organic layer concentrates, add the sherwood oil crystallisation by cooling and obtain compound
(2) with compound
In methyl alcohol and the ethyl acetate mixed solvent, use Pd/C catalysis, remove 4-position protecting group, after reaction finished, in the reaction solution impouring isopropyl ether, crystallization obtained compound
Described compound
(II) mass volume ratio with ethyl acetate is preferably 1.0: 8.0-1.0: 10.0, and the mass volume ratio of Pd/C and ethyl acetate is preferably 3%-5%;
(3) with compound
Add in the tetrahydrofuran (THF), add the Tetrabutyl amonium bromide (TBAB) of sodium bicarbonate and catalytic amount then,, after reaction solution is concentrated into certain volume, add methylene dichloride, separate out solid, obtain intermediate with the reaction of 5-formamido group-1-(2-methanoyl ethyl) pyrazoles
(4) compound
In the hydrochloric acid soln of methyl alcohol, remove C-7 bit amino and C-3 position Side chain protective group simultaneously, obtain intermediate
(5) compound
And compound
Filtrate is regulated PH=1 with sulfuric acid in .MeOH solution, and with in the reaction solution impouring 2000ml ice acetone, the off-white color solid is separated out, and filters then, and filter cake is iced washing with acetone with 300ml, drying, and gained crude product water and Virahol recrystallization obtain compound
Be cefoselis sulfate.
2. the preparation method of a kind of cefoselis sulfate according to claim 1 is characterized in that, described compound
With Boc
2The mol ratio of O is preferably 1.00: 1.05--1.00: 1.10.
3. the preparation method of a kind of cefoselis sulfate according to claim 1 is characterized in that, described compound
Be preferably 20.0 with the mol ratio of Tetrabutyl amonium bromide: 1.0-25.0: 1.0.
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| CN201010528892A CN101993450B (en) | 2010-11-03 | 2010-11-03 | Preparation method of cefoselis sulfate |
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| CN101993450B CN101993450B (en) | 2011-11-30 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827190A (en) * | 2011-06-14 | 2012-12-19 | 江苏豪森医药集团连云港宏创医药有限公司 | Cefoselis sulfate intermediate and preparation method thereof |
| CN103044454A (en) * | 2011-10-14 | 2013-04-17 | 四川科伦药业股份有限公司 | Method for synthesizing cefoselis sulfate |
| CN103896964A (en) * | 2014-03-31 | 2014-07-02 | 南京工业大学 | Method for preparing cephalosporin intermediates |
| CN106317077A (en) * | 2015-06-24 | 2017-01-11 | 连云港恒运医药科技有限公司 | Novel efficient preparation method of ceftiofur sulfate intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1032540A (en) * | 1987-09-14 | 1989-04-26 | 藤泽药品工业株式会社 | Cephem compound and preparation method thereof |
| CN1613860A (en) * | 2003-11-07 | 2005-05-11 | 天津药物研究院 | Cephaene onium salt compound and its preparation, and synthesis of cephapyrazde sulfate therefrom |
-
2010
- 2010-11-03 CN CN201010528892A patent/CN101993450B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1032540A (en) * | 1987-09-14 | 1989-04-26 | 藤泽药品工业株式会社 | Cephem compound and preparation method thereof |
| CN1613860A (en) * | 2003-11-07 | 2005-05-11 | 天津药物研究院 | Cephaene onium salt compound and its preparation, and synthesis of cephapyrazde sulfate therefrom |
Non-Patent Citations (1)
| Title |
|---|
| 《精细化工中间体》 20070228 黄朋勉 硫酸头孢噻利的合成研究进展 15-18 1-3 第37卷, 第1期 2 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827190A (en) * | 2011-06-14 | 2012-12-19 | 江苏豪森医药集团连云港宏创医药有限公司 | Cefoselis sulfate intermediate and preparation method thereof |
| CN103044454A (en) * | 2011-10-14 | 2013-04-17 | 四川科伦药业股份有限公司 | Method for synthesizing cefoselis sulfate |
| CN103044454B (en) * | 2011-10-14 | 2016-04-13 | 四川科伦药业股份有限公司 | A kind of synthetic method of cefoselis sulfate |
| CN103896964A (en) * | 2014-03-31 | 2014-07-02 | 南京工业大学 | Method for preparing cephalosporin intermediates |
| CN103896964B (en) * | 2014-03-31 | 2016-04-13 | 南京工业大学 | The preparation method of cepham intermediate |
| CN106317077A (en) * | 2015-06-24 | 2017-01-11 | 连云港恒运医药科技有限公司 | Novel efficient preparation method of ceftiofur sulfate intermediate |
| CN106317077B (en) * | 2015-06-24 | 2020-07-17 | 连云港恒运药业有限公司 | Novel efficient preparation method of cefoselis sulfate intermediate |
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| CN101993450B (en) | 2011-11-30 |
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Address after: 410000, Liuyang Liuyang Hunan biological medicine Park Mountain Street Patentee after: Hunan Eurasia Pharmaceutical Co., Ltd. Address before: 410000, Liuyang Liuyang Hunan biological medicine Park Mountain Street Patentee before: Hunan Ouya Biological Co., Ltd. |
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Denomination of invention: A preparation method of cefoselide sulfate Effective date of registration: 20210430 Granted publication date: 20111130 Pledgee: Bank of Changsha Limited by Share Ltd. Liuyang branch Pledgor: Hunan Eurasia pharmaceutcal Corp.,Ltd. Registration number: Y2021430000009 |
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