CN1312158C - Method for preparing cefixime - Google Patents
Method for preparing cefixime Download PDFInfo
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- CN1312158C CN1312158C CNB2005100135372A CN200510013537A CN1312158C CN 1312158 C CN1312158 C CN 1312158C CN B2005100135372 A CNB2005100135372 A CN B2005100135372A CN 200510013537 A CN200510013537 A CN 200510013537A CN 1312158 C CN1312158 C CN 1312158C
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Abstract
The present invention discloses a method for preparing cefixime from perhalate. The method comprises the following steps: a compound with a structural formula (III) reacts with perhalognic acid and organic protonic acid in organic solvent to prepare cefixime perhalate (I) by a protective-radical removing reaction, and then the compound with a structural formula (I) is refreed to obtain cefixime (II). The cefixime prepared by the present invention has the advantages of high purity, shallow appearance color and high yield. The present invention avoids inconvenience caused by using large amounts of alkali to extract the cefixime, is a cefixime preparing method having the advantages of low price and high efficiency, and is especially suitable for large-scale industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to the synthetic of cynnematin, in particular, is the preparation method of third generation oral cephalosporin Cefixime Micronized.
Background technology
Cefixime Micronized (II), chemical name: (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyl imino-) kharophen]-8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid trihydrate is semi-synthetic third generation oral cephalosporin, gram-positive microorganism and Gram-negative bacteria all there are stronger anti-microbial effect, highly stable to β-Nei Xiananmei.
According to bibliographical information, Cefixime Micronized generally makes by following synthetic method.
R wherein
1For hydrogen or carboxyl-protecting group to methoxybenzyl, diphenyl-methyl etc., R
2Be lower aliphatic alkyl such as carboxy protective ylmethyl, tertiary butyl, Z is chlorine or mercaptobenzothiazole etc.
Compound (III) is transformed into Cefixime Micronized (II) by deprotection base under alkalescence or acidic conditions.Because cynnematin is to the alkali instability, deprotection base under alkaline condition, yield low, of poor quality (DE19846449).In addition; carry out deprotection reaction at acidic conditions; as: with method [the Tetrahedron Lett. of aluminum chloride/methyl-phenoxide; 2793 (1979)], with the method (EP030630) of trifluoroacetic acid/methyl-phenoxide, with 99% formic acid be the method (WO98/31685) of deprotection agent and solvent, with the method [J.Org.Chem. of phenols; 56; 3633 (1991)] or the like; the method of these acidic conditions deprotection bases; because a large amount of protonic acids or the existence of strong lewis acid; side reactions such as cis-trans isomerization easily take place, and operation is loaded down with trivial details, yield is low, cost is high.Have among the WO98/31685 open again; during deprotection reaction (99% formic acid); add a large amount of vitriol oil formation Cefixime Micronized vitriol and separate out, because by product also becomes to salt out gained vitriol purity difference, low, the sad filter of yield, the easy moisture absorption, difficult dry with sulfuric acid.
Summary of the invention
The objective of the invention is to, overcome above-mentioned shortcoming of the prior art, a kind of preparation method of Cefixime Micronized is provided with not enough.
The present invention is achieved by following technical proposals: it comprises by structural formula (III) compound in organic solvent, with high hydracid and organic proton acid-respons, makes the deprotection reaction of Cefixime Micronized perhalide (I); The free again Cefixime Micronized (II) that obtains of structural formula (I) compound.
Wherein: R
1The expression hydrogen, to methoxybenzyl, diphenyl-methyl etc., R
2Lower aliphatic alkyl such as expression methyl, tertiary butyl.
Deprotection reaction by structural formula (III) compound generating structure formula (I) of the present invention carries out under 0-100 ℃ of temperature condition, preferred 5-50 ℃.
Structural formula of the present invention (I) compound is free again can adopt mineral alkali for example sodium hydroxide, ammoniacal liquor, saturated solution of sodium carbonate, saturated solution of sodium bicarbonate or the like dissociate, make Cefixime Micronized (II).
High hydracid of the present invention is perchloric acid, hyperbromic acid, Periodic acid; Its consumption is a 0.5-5 times of equivalent with respect to compound (III).Preferred 1-2 times of equivalent.
The organic protonic acid that uses among the present invention, the weak acid of preferred pKa=3-5, as: formic acid, acetate, Mono Chloro Acetic Acid, trifluoroacetic acid etc. replace or unsubstituted low-grade alkyl carboxylic acid, replacement such as phenylformic acid, toluylic acid or unsubstituted aromatic carboxylic acid etc.The consumption of organic protonic acid is a 1-20 times of equivalent with respect to compound (III), preferred 3-10 times of equivalent.
Organic solvent of the present invention is ester class, nitrile, aromatic hydrocarbons, ketone, halogenated hydrocarbon.Nitriles such as acetonitrile, propionitrile, butyronitrile for example, aromatic hydrocarbons such as benzene, toluene, ester classes such as methyl-formiate, ethyl formate, butyl formate, methyl acetate, ethyl acetate, butylacetate, ketone such as acetone, methyl butyl ketone, halogenated hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin, preferred solvent is benzene, toluene, tetracol phenixin, chloroform, methylene dichloride, ethylene dichloride.The consumption of organic solvent, 1g is generally 2-100ml with respect to compound (III), preferred 5-50ml.
The preparation method's of Cefixime Micronized of the present invention concrete synthetic route is as follows:
Wherein: R
1The expression hydrogen, to methoxybenzyl, diphenyl-methyl etc., R
2Lower aliphatic alkyl such as expression methyl, tertiary butyl.
The preparation method of Cefixime Micronized of the present invention compares with prior preparation method has following significant positively effect:
The compound (III) of band protecting group is sloughed protecting group with high hydracid and organic protonic acid in organic solvent, form highly purified Cefixime Micronized perhalide (I) and separate out, and Cefixime Micronized perhalide (I) is again with the free Cefixime Micronized (II) that obtains of a spot of alkali.Cefixime Micronized purity height, appearance color that this method obtains are shallow, yield height, and the inconvenience of having avoided a large amount of alkaline extraction Cefixime Micronizeds of direct usefulness to bring.Be a cheapness, prepare the method for Cefixime Micronized efficiently, be particularly suitable for large-scale industrial production.
Embodiment
The present invention is further illustrated below in conjunction with embodiment, but the scope of protection of present invention is not limited in the following specific embodiment operation that provides.
Embodiment 1.
In the reaction flask of 500ml, add 7-[[(2-amino-4-thiazole)-[(tertiary butyl oxygen acetyl) oxime] acetyl] amino]-3-vinyl-8-oxygen-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxylic acid [III] 15g, methylene dichloride 150ml, formic acid 21ml, perchloric acid 12ml was warming up to 30 ℃ of insulated and stirred 2 hours.Be cooled to below 5 ℃, separate out solid, filter, the dry light yellow 7-[[(2-amino-4-thiazole that gets)-[(carboxymethyl) oxime] acetyl] amino]-3-vinyl-8-oxygen-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxylic acid perchlorate [I] 16.5g, yield 91.7%, HPLC 98%.
1H-NMR(DMSO)：3.6，3.8(ABq，2H)，4.69(s，2H)，5.20(d，1H)，5.31(d，1H)，5.59(d，1H)，5.79(dd，1H)，6.92(dd，1H)，6.99(s，1H)，9.71(d，1H)。
Embodiment 2
In the reaction flask of 500ml, add 7-[[(2-amino-4-thiazole)-[(tertiary butyl oxygen acetyl) oxime] acetyl] amino]-3-7 vinyl-8-oxygen-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxylic acid [III] 5g, ethyl acetate 100ml, formic acid 3ml, perchloric acid 2ml was warming up to 40 ℃ of insulated and stirred 1 hour.Be cooled to below 5 ℃, separate out solid, filter, the dry light yellow 7-[[(2-amino-4-thiazole that gets)-[(carboxymethyl) oxime] acetyl] amino]-3-vinyl-8-oxygen-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxylic acid perchlorate [I] 5.2g, yield 87%, HPLC 98.2%.
1H-NMR(DMSO)：3.6，3.8(ABq，2H)，4.69(s，2H)，5.20(d，1H)，5.31(d，1H)，5.59(d，1H)，5.79(dd，1H)，6.92(dd，1H)，6.99(s，1H)，9.71(d，1H)。
Embodiment 3
In the reaction flask of 500ml, with 7-[[(2-amino-4-thiazole)-[(carboxymethyl) oxime] acetyl] amino]-3-vinyl-8-oxygen-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxylic acid perchlorate [I] 16g is suspended in the water of 150ml, be cooled to below 5 ℃, drip saturated solution of sodium carbonate, after the solid stirring and dissolving, add carbon decolouring 1 hour.Filter, filtrate transfers to pH2.5 with the hydrochloric acid of 4N, and 5 ℃ were stirred 0.5 hour, and leached solid, the dry 7-[[(2-amino-4-thiazole that gets)-and [(carboxymethyl) oxime] acetyl] amino]-3-vinyl-8-oxygen-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxylic acid (II, Cefixime Micronized) 12g.HPLC?98.3％
1H-NMR(DMSO-D6)：3.54，3.8(ABq，2H)，4.58(s，2H)，5.20(d，1H)，5.31(d，1H)，5.59(d，1H)，5.80(dd，1H)，6.80(s，2H)，6.86(dd，2H)，7.24(s，2H)，9.54(d，1H)。
IR：3536cm
-1，3297cm
-1，2948cm
-1，3300-2500cm
-1，1771cm
-1，1668cm
-1，1096cm
-1。
Claims (6)
1, a kind of preparation method of Cefixime Micronized is characterized in that, comprises by structural formula (III) compound in organic solvent, with high hydracid and organic proton acid-respons, makes the deprotection reaction of Cefixime Micronized perhalide (I); The free again Cefixime Micronized (II) that obtains of structural formula (I) compound;
Wherein: R
1The expression hydrogen, to methoxybenzyl, diphenyl-methyl, R
2Expression methyl, tertiary butyl lower aliphatic alkyl.
2, preparation method as claimed in claim 1 is characterized in that, described deprotection reaction by structural formula (III) compound generating structure formula (I) carries out under 0-100 ℃ of temperature condition.
3, preparation method as claimed in claim 1 is characterized in that, the free more free Cefixime Micronized (II) that makes of mineral alkali that adopts of described structural formula (I) compound.
4, preparation method as claimed in claim 1 is characterized in that, described high hydracid is perchloric acid, hyperbromic acid, Periodic acid; Its consumption is a 0.5-5 times of equivalent with respect to compound (III).
5, preparation method as claimed in claim 1 is characterized in that, described organic protonic acid is formic acid, acetate, Mono Chloro Acetic Acid, trifluoroacetic acid or phenylformic acid, toluylic acid; Its consumption is a 1-20 times of equivalent with respect to compound (III).
6, preparation method as claimed in claim 1 is characterized in that, described organic solvent is ester class, nitrile, aromatic hydrocarbons, ketone, halogenated hydrocarbon.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100135372A CN1312158C (en) | 2005-05-20 | 2005-05-20 | Method for preparing cefixime |
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| CNB2005100135372A CN1312158C (en) | 2005-05-20 | 2005-05-20 | Method for preparing cefixime |
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| CN1696134A CN1696134A (en) | 2005-11-16 |
| CN1312158C true CN1312158C (en) | 2007-04-25 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731529A (en) * | 2012-06-28 | 2012-10-17 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Refining method for cefixime |
| CN104004003B (en) * | 2013-02-22 | 2016-05-25 | 广州白云山医药集团股份有限公司白云山制药总厂 | Cefixime derivative and its production and use |
| CN103980293B (en) * | 2014-05-21 | 2016-08-17 | 广州白云山医药集团股份有限公司白云山化学制药厂 | 3-vinyl-7-(thiazole methoxyimino) preparation method of Cephalosporanic acid |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4258041A (en) * | 1978-05-26 | 1981-03-24 | Glaxo Group Limited | (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylate and salts thereof |
| WO1995033753A1 (en) * | 1994-06-03 | 1995-12-14 | Marcham Trading & Investment Ltd. | Process for the preparation of trihydrated cefixime |
| CN1295576A (en) * | 1998-04-02 | 2001-05-16 | 生物化学有限公司 | Process for purification of cephalosporin derivative |
| US6277996B1 (en) * | 2000-03-06 | 2001-08-21 | Hanmi Fine Chemicals Co., Ltd. | Thiazole compound and a process thereof |
| US6313289B1 (en) * | 1997-01-16 | 2001-11-06 | Biochemie Gesellschaft M.B.H. | Purification process |
| US6384212B1 (en) * | 2000-03-20 | 2002-05-07 | Hanmi Fine Chemicals Co., Ltd. | Process for preparing cephalosporin antibiotics using new thiazole compound |
| US20040082560A1 (en) * | 2002-10-24 | 2004-04-29 | Orchid Chemicals And Pharmaceuticals Limited | Process for the preparation of cefixime |
| US20050032771A1 (en) * | 2001-11-09 | 2005-02-10 | Walter Cabri | Process for the preparation of cefixime via alkyl-or aryl-sulfonates |
-
2005
- 2005-05-20 CN CNB2005100135372A patent/CN1312158C/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4258041A (en) * | 1978-05-26 | 1981-03-24 | Glaxo Group Limited | (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylate and salts thereof |
| WO1995033753A1 (en) * | 1994-06-03 | 1995-12-14 | Marcham Trading & Investment Ltd. | Process for the preparation of trihydrated cefixime |
| US6313289B1 (en) * | 1997-01-16 | 2001-11-06 | Biochemie Gesellschaft M.B.H. | Purification process |
| CN1295576A (en) * | 1998-04-02 | 2001-05-16 | 生物化学有限公司 | Process for purification of cephalosporin derivative |
| US6277996B1 (en) * | 2000-03-06 | 2001-08-21 | Hanmi Fine Chemicals Co., Ltd. | Thiazole compound and a process thereof |
| US6384212B1 (en) * | 2000-03-20 | 2002-05-07 | Hanmi Fine Chemicals Co., Ltd. | Process for preparing cephalosporin antibiotics using new thiazole compound |
| US20050032771A1 (en) * | 2001-11-09 | 2005-02-10 | Walter Cabri | Process for the preparation of cefixime via alkyl-or aryl-sulfonates |
| US20040082560A1 (en) * | 2002-10-24 | 2004-04-29 | Orchid Chemicals And Pharmaceuticals Limited | Process for the preparation of cefixime |
| US6800755B2 (en) * | 2002-10-24 | 2004-10-05 | Orchid Chemicals And Pharmaceuticals Limited | Process for the preparation of cefixime |
Non-Patent Citations (1)
| Title |
|---|
| 头孢克肟的合成 胡艾希等，中国医药工业杂志，第35卷第1期 2004 * |
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Assignee: Tianjin Pharmaceutical Group Gencom Pharmaceutical Co., Ltd. Assignor: Tianjin Pharmaceutical Group Technology Development Co., Ltd. Contract fulfillment period: 2009.3.5 to 2014.3.5 contract change Contract record no.: 2009120000099 Denomination of invention: Method for preparing cefixime Granted publication date: 20070425 License type: Exclusive license Record date: 2009.7.9 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.3.5 TO 2014.3.5; CHANGE OF CONTRACT Name of requester: TIANJIN MEDICINE GROUP JINKANG PHARMACEUTICAL CO., Effective date: 20090709 |