CN1424316A - Preparation of cephalosporin compound - Google Patents
Preparation of cephalosporin compound Download PDFInfo
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- CN1424316A CN1424316A CN 01142350 CN01142350A CN1424316A CN 1424316 A CN1424316 A CN 1424316A CN 01142350 CN01142350 CN 01142350 CN 01142350 A CN01142350 A CN 01142350A CN 1424316 A CN1424316 A CN 1424316A
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- compound
- ethanoyl
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Abstract
A cephalo-type compound is prepared by the chemical reaction on site 3 of the mother kernel of 7-ACA or its derivative in the dialkyl carbonate as sovlent under existance of low-class fatty acid and BF3 complex as catalyst.
Description
The present invention relates to prepare a kind of method of cephalosporin compound, specifically, is by the chemical reaction on 3 of the cephalo parent nucleus, prepares cephalosporin compound.
Cephalosporin compound is the important antibiotic medicine of a class, and the prepared cephalosporin compound of chemical reaction on 3 of the cephalo parent nucleus is important pharmaceutical intermediate, as 7-amino-3-[(2-furans carbonyl) mercapto methyl] Cephalosporanic acid (A).
Set forth its preparation method at patent WO87/01117 (US86/01635).This method be with usefulness 7-ACA (B) and 2-furans mercapto acid sodium (C) in water, pH is 6.4 ± 0.1, temperature is 50 to 65 ℃, reacts to make in 5 hours.
But the product purity that this method obtains is low, because contain the yield and the quality of the following preparation of unreacted 7-ACA influence ceftiofur.
Now, we find that 7-ACA or its derivative and the acid of 2-furans mercapto are in the dialkyl carbonate non-aqueous solvent, in the presence of lower fatty acid, with BF
3Complex compound is as catalyst reaction, and high yield obtains 7-amino-3-[(2-furans carbonyl) mercapto methyl] Cephalosporanic acid, and the product that makes directly can be used as intermediate and uses without purifying.
The present invention is except having above-mentioned advantage, owing to used dialkyl carbonate as reaction medium in the reaction, it is useful to environmental health and environment protection.
The object of the invention has provided a kind of high yield, prepared in high purity 7-amino-3-[(2-furans carbonyl) mercapto methyl] method of Cephalosporanic acid and derivative thereof.
The detailed description of the invention is as follows:
The present invention is the method for the cephalosporin compound shown in the preparation general formula (I).General formula (I) is:
R wherein
1, R
2Be hydrogen atom, perhaps R
1Be hydrogen atom, R
2Be ethanoyl; 2-(thiazolamine-4-yl) ethanoyl; phenylacetyl; the alpha-amino group phenylacetyl; alpha-amino group para hydroxybenzene ethanoyl; 2-(thiazolamine-4-yl)-2-(methoxy imino) ethanoyl; 2-[(4-ethyl-2; 3--oxygen-piperazine-1 base)-formamido group]-2-is to hydroxyphenyl-ethanoyl; (2-methylamino-phenyl) ethanoyl; 2-(1-methyl-4-hydroxyl-pyridine-5 bases-formamido group)-2-is to hydroxyphenyl-ethanoyl; 2-tetrazole-1 base-ethanoyl; 2 chloracetyl; phthaloyl; benzenesulfonyl
This preparation method is compound (II) and compound (III) reacting generating compound (I),
R wherein
1And R
2Same compound (I),
Its reaction conditions is; (1) at a kind of C
1-3Aliphatic carboxylic acid carry out under existing; (2) be catalyzer with compound (IV) and/or compound (V),
BF
3·A (IV)
Wherein A is tetrahydrofuran (THF), methyl alcohol, acetate or ether, described BF
3A is a kind of BF
3Complex compound, it can prepare separately and add in the reaction vessel, also can be with BF in reaction process
3Feeding contains that preparation produces in the material of solvent orange 2 A;
R
3Or R
4Be a C
1-4Alkyl, perhaps R
3And R
4Be a C altogether
2-4Alkylidene chain, described
Be a kind of BF
3Complex compound, it can prepare separately and add in the reaction vessel, also can be with BF in reaction process
3Feeding contains solvent
Material in preparation produce; (3) in non-aqueous solvent (VI), carry out,
R wherein
3, R
4Define same compound (V);
(4) temperature of reaction is 0～60 ℃, about 30 minutes to 8 hours of reaction times.In above-mentioned reaction, this lipid acid of adding can be selected formic acid, acetate, propionic acid, and preferable formic acid and acetate are preferably formic acid especially.
The consumption of this lipid acid in reaction system is the 5-20% of weight of solvent.
Compound (IV) or compound (V) are a kind of complex compounds.This complex compound can be used commercially available product, also can prepare temporarily, and the method for preparing complex compound is very simple, as long as with BF
3In the solvent of feeding A or described dialkyl carbonate, need not extract during use, refining, directly use.The present invention has also comprised the direct BF of feeding in reaction system
3Compound (IV) that produces or compound (V) and their mixture are used for catalyzed reaction.
A in the compound (IV) is preferably methyl alcohol or ether, is preferably methyl alcohol especially.
Optional methylcarbonate, diethyl carbonate, dipropyl carbonate, the Methyl ethyl carbonate selected of dialkyl carbonate ester moiety in the compound (V).
Be preferably methylcarbonate, diethyl carbonate.
Preferred especially methylcarbonate.
The protecting group that carboxyl is suitable has: trichloromethyl, to chloro acetyl, pivaloyl oxygen methyl, diphenyl-methyl, to nitrobenzyl.
Amino suitable protecting group has: 2-chloracetyl, aryl methylene, phthaloyl etc.
Reaction solvent compound (VI) can be selected diethyl carbonate, methylcarbonate, Texacar PC and ethylene carbonate, is preferably methylcarbonate.
Described solvent can be same with complex compound bonded solvent phase, also can be different.
Optimal reaction temperature is chosen as 40-50 ℃, and optimum reacting time is chosen as 30 minutes and finished by 4 hours.
Protecting group is sloughed with known method and is finished.
Be the embodiment of the invention below, described embodiment just is used for having illustrated the present invention, rather than is used for limiting the present invention.
Embodiment 1
With BF
320.4g (0.3002mol) feed in 50ml methylcarbonate and the 12.5ml formic acid mixing solutions, and stirred 45 minutes, obtain solution 1 at 25 ℃.
(HPLC 95% with 23.6g 7-ACA, 0.0825mol) and the acid of 29.49g 2-furans mercapto be added to respectively in the 75ml methylcarbonate, then solution 1 is added in the above-mentioned suspension, mixture kept 3.5 hours at 45 ℃, be cooled to 20 ℃ then, with 25ml 20% salt acid treatment, stirred 1.5 hours at 5 ℃.
The precipitation that filter to collect forms, and wash with the 75ml methylcarbonate joins the precipitation of gained in the acetone of 5 ℃ of 115ml.The acetone mixed solution of 200ml water and 75ml is added in the above-mentioned suspension, regulating the pH value with strong aqua again is 2.7, stirred 30 minutes, filter, with 100ml water and 150ml washing with acetone, 40 ℃ of following vacuum-drying filter cakes obtain 22.9g 7-amino-3-[(2-furans carbonyl) thiopurine methyltransferase] Cephalosporanic acid (98%HPLC) (yield is 80.0%).
Embodiment 2
(95%HPLC 0.1397mol), the mercapto acid of 28.2g 2-furans and 20ml formic acid adds in the 130ml methylcarbonate solution, stirred 45 minutes at 25 ℃ with 40.0g 7-ACA.The gradation in 1 hour of 134.3g boric carbonic acid dimethyl ester complex trifluoride is added in the above-mentioned aaerosol solution, kept 2.5 hours at 45 ℃, be chilled to 20 ℃, with 42ml 20% salt acid treatment, handle with embodiment 1 below, obtain 37.0g 7-amino-3-[(2-furans carbonyl) thiopurine methyltransferase] Cephalosporanic acid (98%HPLC) (yield is 76.3%).
Embodiment 3
(95%HPLC 0.1397mol), the mercapto acid of 28.2g 2-furans and 50ml glacial acetic acid add in the 100ml diethyl carbonate solution, stirred 45 minutes at 25 ℃ with 40.0g 7-ACA.The gradation in 1 hour of 175.0g boric carbonic acid dimethyl ester complex trifluoride is added in the above-mentioned aaerosol solution, kept 3.5 hours at 40 ℃, be chilled to 20 ℃, with 42ml 20% salt acid treatment, handle with embodiment 1 below, obtain 35.9g 7-amino-3-[(2-furans carbonyl) thiopurine methyltransferase] Cephalosporanic acid (96%HPLC) (yield is 72.6%).
Embodiment 4
With 38.8g 7-ACA (95%HPLC, 0.1355mol), 24.1g acid of 2-furans mercapto and 20g formic acid add in the 130ml methylcarbonate solution, in 1 hour, add the 123.3g boron trifluoride ethyl ether complex, kept 3.5 hours at 45 ℃, be chilled to 0 ℃, add 0 ℃ of about 350ml of frozen water, dripping 20% sodium hydroxide solution adjusting pH down at 0 ℃ is 0.5, after stirring 1 hour with 0-5 ℃, filter crystallization, with 200ml water and 200ml washing with acetone, 40 ℃ of vacuum-drying filter cakes, obtain 32.9g 7-amino-3-[(2-furans carbonyl) thiopurine methyltransferase] Cephalosporanic acid (94.0%HPLC) (yield is 67.2%).
Embodiment 5
With 38.8g 7-ACA (95%HPLC, 0.1355mol) and 24.1g 2-furans mercapto is sour and 20g formic acid adds in the 130ml methylcarbonate solution, in 1 hour, add the 123.3g boron trifluoride ethyl ether complex, 30 ℃ of reactions 4 hours, below handle, obtain 17.4g 7-amino-3-[(2-furans carbonyl with embodiment 4) thiopurine methyltransferase] Cephalosporanic acid (90.0%HPLC) (yield is 42.5%).
Claims (6)
1. method for preparing the cephalosporin compound shown in the general formula (I),
R wherein
1Be hydrogen atom, R
2Optional is hydrogen atom; ethanoyl; 2-(thiazolamine-4-yl) ethanoyl; phenylacetyl; the alpha-amino group phenylacetyl; alpha-amino group para hydroxybenzene ethanoyl; 2-(thiazolamine-4-yl)-2-(methoxy imino) ethanoyl; 2-[(4-ethyl-2; 3-dioxy-piperazine-1 base)-formamido group]-2-is to hydroxyphenyl-ethanoyl; (2-methylamino-phenyl) ethanoyl; 2-(1-methyl-4-hydroxyl-pyridine-5 bases-formamido group)-2-is to hydroxyphenyl-ethanoyl; 2-tetrazole-1 base-ethanoyl; 2 chloracetyl; phthaloyl; benzenesulfonyl
This preparation method is: compound (II) and compound (III) reacting generating compound (I),
R wherein
1And R
2Same compound (I)
It is characterized in that:
(1) at a kind of C
1-3Aliphatic carboxylic acid exist down;
(2) be catalyzer with compound (IV) and/or compound (V),
BF
3·A (IV)
Wherein A is tetrahydrofuran (THF), methyl alcohol, acetate or ether, described BF
3A is a kind of BF
3Complex compound,
It is included in the reaction process BF
3Feeding contains that preparation produces in the material of solvent orange 2 A,
R wherein
3Or R
4Be a C
1-4Alkyl, perhaps R
3And R
4Be a C altogether
2-4Alkylidene chain, described
Be a kind of BF
3Complex compound, it is included in the reaction process BF
3Feeding contains solvent
Material in preparation produce; (3) in non-aqueous solvent (VI), carry out,
R wherein
3, R
4Define same compound (V);
(4) temperature of reaction is at 0～60 ℃, about 30 minutes to 8 hours of reaction times.
2. according to the method for claim 1, it is characterized in that compound (VI) is methylcarbonate, diethyl carbonate, carbonic acid ethylidene ester or propylene carbonate.
3. according to the method for claim 2, it is characterized in that compound (VI) is a methylcarbonate.
4. according to the method for claim 1, it is characterized in that C
1-3Aliphatic carboxylic acid be formic acid, its consumption in reaction system is 5% to 20% of a solvent weight.
5. according to claim 1 method, it is characterized in that temperature of reaction is 40-50 ℃, the reaction times is 30 minutes to 4 hours.
6. according to the method for claim 1, the compound shown in the general formula (I) that it is characterized in that preparing is 7-amino-3-[(2-furans carbonyl) thiopurine methyltransferase] Cephalosporanic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011423501A CN1176089C (en) | 2001-12-11 | 2001-12-11 | Preparation of cephalosporin compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011423501A CN1176089C (en) | 2001-12-11 | 2001-12-11 | Preparation of cephalosporin compound |
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| Publication Number | Publication Date |
|---|---|
| CN1424316A true CN1424316A (en) | 2003-06-18 |
| CN1176089C CN1176089C (en) | 2004-11-17 |
Family
ID=4676781
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011423501A Expired - Fee Related CN1176089C (en) | 2001-12-11 | 2001-12-11 | Preparation of cephalosporin compound |
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| Country | Link |
|---|---|
| CN (1) | CN1176089C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100364998C (en) * | 2006-07-12 | 2008-01-30 | 黑龙江豪运经贸有限公司 | Complexing method of boron trifluoride methylcarbonate complex |
| CN102234289A (en) * | 2010-05-02 | 2011-11-09 | 青岛科技大学 | Novel method for preparing ceftiofur intermediate |
| CN103641846A (en) * | 2013-11-28 | 2014-03-19 | 山东鑫泉医药有限公司 | Preparation method of 7-amino ceftriaxone sodium |
| CN104130273A (en) * | 2014-08-18 | 2014-11-05 | 哈药集团制药总厂 | Method for synthesizing ceftriaxone sodium |
| CN114409676A (en) * | 2021-12-24 | 2022-04-29 | 河南立诺制药有限公司 | Preparation method of 7-ACF |
-
2001
- 2001-12-11 CN CNB011423501A patent/CN1176089C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100364998C (en) * | 2006-07-12 | 2008-01-30 | 黑龙江豪运经贸有限公司 | Complexing method of boron trifluoride methylcarbonate complex |
| CN102234289A (en) * | 2010-05-02 | 2011-11-09 | 青岛科技大学 | Novel method for preparing ceftiofur intermediate |
| CN102234289B (en) * | 2010-05-02 | 2013-07-10 | 青岛科技大学 | Novel method for preparing ceftiofur intermediate |
| CN103641846A (en) * | 2013-11-28 | 2014-03-19 | 山东鑫泉医药有限公司 | Preparation method of 7-amino ceftriaxone sodium |
| CN103641846B (en) * | 2013-11-28 | 2015-08-19 | 山东鑫泉医药有限公司 | The preparation method of the amino rocephin of 7- |
| CN104130273A (en) * | 2014-08-18 | 2014-11-05 | 哈药集团制药总厂 | Method for synthesizing ceftriaxone sodium |
| CN104130273B (en) * | 2014-08-18 | 2016-10-26 | 哈药集团制药总厂 | A kind of synthetic method of ceftriaxone sodium |
| CN114409676A (en) * | 2021-12-24 | 2022-04-29 | 河南立诺制药有限公司 | Preparation method of 7-ACF |
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| Publication number | Publication date |
|---|---|
| CN1176089C (en) | 2004-11-17 |
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Granted publication date: 20041117 Termination date: 20191211 |