WO2004083217A1 - An improved process for the preparation of cefoxitin - Google Patents
An improved process for the preparation of cefoxitin Download PDFInfo
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- WO2004083217A1 WO2004083217A1 PCT/IB2003/006239 IB0306239W WO2004083217A1 WO 2004083217 A1 WO2004083217 A1 WO 2004083217A1 IB 0306239 W IB0306239 W IB 0306239W WO 2004083217 A1 WO2004083217 A1 WO 2004083217A1
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- cefoxitin
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- 0 CO[C@](C1SCC(CO)=C([*-])N11)(C1=O)NC(Cc1ccc[s]1)=O Chemical compound CO[C@](C1SCC(CO)=C([*-])N11)(C1=O)NC(Cc1ccc[s]1)=O 0.000 description 1
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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
Definitions
- the present invention relates to an improved process for the preparation of cefoxitin of formula (I).
- US patent 4,210,750 and 4,292,750 disclose a process for the preparation cefoxitin, which involve the usage of an isocyanate wherein the labile substituent is hydrocarbyl or substituted hydrocarbyl group.
- the main objective of the present invention is to provide a process for preparation of cefoxitin of the formula (I).
- Another objective of the present invention is to provide novel intermediates of formulae (III) and (IN) their use in the preparation of cefoxitin of the formula (I).
- Yet another objective of the present invention is to provide the process for the preparation of cefoxitin, which is easy to implement on commercial scales.
- Another objective of the present invention is to provide novel intermediates of formula (III) & (IV) for the preparation of cefoxitin.
- Still another objective of the present invention is to provide a high-yielding method of producing cefoxitin of the formula (I).
- the present invention provides an improved process for the preparation of cefoxitin of the formula (I),
- the said process comprising the steps of: (i) treating the compound of formula (II) with a halogenating agent in an organic solvent, followed by treatment with alkali/alkaline earth metal methoxides at a temperature in the range of -100°C to 0°C, isolating the product formed as an organic amine salt of the formula (III), where M represents an organic counter ion (ii) treating the salt of formula (III) with a base in the presence of solvent at a temperature in the range of -75 to 10°C, isolating the product formed as an organic amine salt of the formula (IN), where M + represents an organic counter ion, (iii) carbamoylating the compound of formula (IV) with isocyanate of formula (V) wherein R is a labile group in the presence of a solvent at a temperature in the range of -60°C to 10°C, and isolating to get cefoxitin of the formula (I), and
- cefoxitin if required converting cefoxitin into cefoxitin sodium using source of sodium ion in the presence of solvent at a temperature in the range of -60°C to 0°C.
- the synthesis of cefoxitin of the formula (I) is as shown in Scheme-I:
- the halogenating agent used in step (i) is selected form t-butoxy chloride, N-chlorosuccinimide, N- bromosuccinimide, bromine or chlorine.
- the organic solvent used in step (i) is selected from dichloromethane, methanol, chloroform, THF or ethylene chloride and the like or mixtures thereof.
- the organic amine used in step (i) is selected from diethylamine, methylethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'- diphenylethylenediamine, l,4-diazabicyclo(2.2.2)octane, N,N- diisopropylethylamine, N,N-diisopropylamine, octylamine, and the like, more particularly cyclohexyl
- the alkali/alkaline earth metal methoxides employed in step (i) is selected from lithium methoxide, sodium methoxide, magnesium methoxide, and the like.
- the solvent employed in step (ii) is selected from methanol, acetone, water, THF, ethyl acetate and the like or mixtures thereof; and the base employed in step (ii) is selected from sodium hydroxide, potassium hydroxide and the like, more particularly sodium hydroxide.
- the organic amine used in step (ii) is selected from cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene, N,N' -diphenylethylenediamine, 1 ,4- diazabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine, octylamine, more particularly benzathine salt (N,N'-dibenzylethylenediamine).
- the solvent employed in step (iii) is selected from THF, methanol, dichloromethane, acetone, ethyl acetate, methyl acetate or mixtures thereof.
- the labile group represented by R in step (iii) is selected from chlorosulphonyl, mono, di or trichloroacetyl, bromosulphonyl, trichloroethoxycarbonyl, trimethylsilyl or chlorobenzene sulphonyl group.
- the starting material of formula (II) is prepared according to the procedures available in the prior art.
- the sodium ion source used in step (iv) is such as sodium 2-ethyl hexonate, sodium acetate, sodium lactate and the like.
- the solvent used in used in step (iv) is selected from methanol, acetone, THF, ethyl acetate, acetonitrle, isobutyl methyl ketone, ethyl methyl ketone, water and the like or mixtures thereof more particularly, acetone/methanol.
- cefoxitin sodium may be washed with solvents like methanol, acetone, IPE, ethyl acetate, hexane, toluene and the like or mixtures thereof.
- Step i Preparation of 7-oc-methoxy-7-(2-thienyl)acetamidocephalosporanic acid cyclohexy ⁇ amine salt
- Step ii Preparation of 3-hydroxymethyl-7-oc-methoxy-7-[(2-thienyl) acetamido]-3-cephem-4-carboxylic acid N,N'-bis(phenylmethyl)-l,2- ethanediamine salt
- step (ii) 7-oc-methoxy cephalothin (100 gm) obtained from step (ii) was added at 1 °C and cooled to -45 °C.
- sodium hydroxide solution 28 gm in 167 ml water
- pH was adjusted to 7.0 using aqueous acetic acid at -45°C.
- the temperature of the reaction mass was raised to 28°C and distilled of approximately 400 ml reaction mass.
- Step iii Preparation of 7-oc-methoxy-7-[(2-thienyl)acetamido]-3- caramoyloxymethyl-3-cephem-4-carboxylic acid
- decarbomoyl cefoxitin benzathine salt 50 gm obtained from step (iii) was added, and cooled to -55°C, followed by slow addition of precooled solution of chloro sulphonyl isocynate (35.0 gm) in THF (50 ml) at -55 °C. Reaction mass was stirred till completion of the reaction. After completion of the reaction, the reaction mass was added into cold DM water and stirred for 2 hours.
- reaction mass was adjusted to 6.0 with sodium carbonate solution (83 ml) and degassed for 30 minutes. Acetic acid was added to adjust the pH to 5.4-5.6, and activated carbon (3.5 gm) was added and stirred for 10 minutes. Carbon was filtered and washed the bed with water. To the filtrate ethyl acetate (9 ml) was added and pH of filtrate adjusted to 2.0 with 1:1 HC1 (14 ml). The reaction mass cooled to 10 °C, the solid obtained was filtered, washed with water, and dried to yield title compound in pure form.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to an improved process for the preparation of cefoxitin of formula (I).
Description
AN IMPROVED PROCESS FORTHE PREPARATION OF
CEFOXITIN
Field of the Invention The present invention relates to an improved process for the preparation of cefoxitin of formula (I).
Background of the Invention US patent 4,297,488 discloses different processes for the preparation of cefoxitin, which uses ester protected cephem nucleus. These processes involve deprotection after carbamoylation because of which, yield of the product is less.
US patent 4,210,750 and 4,292,750 disclose a process for the preparation cefoxitin, which involve the usage of an isocyanate wherein the labile substituent is hydrocarbyl or substituted hydrocarbyl group.
The above said prior art processes always yield cefoxitin with poor quality, and color.
We have now found an improved process for the preparation of the compound of formula (I), which process has advantages over the processes described in the above-mentioned prior art documents.
Objectives of the Invention
The main objective of the present invention is to provide a process for preparation of cefoxitin of the formula (I).
Another objective of the present invention is to provide novel intermediates of formulae (III) and (IN) their use in the preparation of cefoxitin of the formula (I).
Yet another objective of the present invention is to provide the process for the preparation of cefoxitin, which is easy to implement on commercial scales. Another objective of the present invention is to provide novel intermediates of formula (III) & (IV) for the preparation of cefoxitin.
Still another objective of the present invention is to provide a high-yielding method of producing cefoxitin of the formula (I).
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of cefoxitin of the formula (I),
(iv) if required converting cefoxitin into cefoxitin sodium using source of sodium ion in the presence of solvent at a temperature in the range of -60°C to 0°C. The synthesis of cefoxitin of the formula (I) is as shown in Scheme-I:
Detailed Description of the Invention
In an embodiment of the present invention, the halogenating agent used in step (i) is selected form t-butoxy chloride, N-chlorosuccinimide, N- bromosuccinimide, bromine or chlorine.
In another embodiment of the present invention, the organic solvent used in step (i) is selected from dichloromethane, methanol, chloroform, THF or ethylene chloride and the like or mixtures thereof.
In another embodiment of the present invention, the organic amine used in step (i) is selected from diethylamine, methylethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'- diphenylethylenediamine, l,4-diazabicyclo(2.2.2)octane, N,N- diisopropylethylamine, N,N-diisopropylamine, octylamine, and the like, more particularly cyclohexyl amine salt.
In yet another embodiment of the present invention the alkali/alkaline earth metal methoxides employed in step (i) is selected from lithium methoxide, sodium methoxide, magnesium methoxide, and the like.
In still another embodiment of the present invention, the solvent employed in step (ii) is selected from methanol, acetone, water, THF, ethyl acetate and the like or mixtures thereof; and the base employed in step (ii) is selected from sodium hydroxide, potassium hydroxide and the like, more particularly sodium hydroxide. In another embodiment of the present invention, the organic amine used in step (ii) is selected from cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene, N,N' -diphenylethylenediamine, 1 ,4- diazabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine, octylamine, more particularly benzathine salt (N,N'-dibenzylethylenediamine).
In another embodiment of the present invention, the solvent employed in step (iii) is selected from THF, methanol, dichloromethane, acetone, ethyl acetate, methyl acetate or mixtures thereof.
In still another embodiment of the present invention, the labile group represented by R in step (iii) is selected from chlorosulphonyl, mono, di or trichloroacetyl, bromosulphonyl, trichloroethoxycarbonyl, trimethylsilyl or chlorobenzene sulphonyl group.
In yet another embodiment of the present invention, the starting material of formula (II) is prepared according to the procedures available in the prior art.
In an embodiment of the present invention, the sodium ion source used in step (iv) is such as sodium 2-ethyl hexonate, sodium acetate, sodium lactate and the like.
In an embodiment of the present invention, the solvent used in used in step (iv) is selected from methanol, acetone, THF, ethyl acetate, acetonitrle, isobutyl methyl ketone, ethyl methyl ketone, water and the like or mixtures thereof more particularly, acetone/methanol. In still another embodiment of the present invention cefoxitin sodium may be washed with solvents like methanol, acetone, IPE, ethyl acetate, hexane, toluene and the like or mixtures thereof.
The foregoing technique has been found to be markedly attractive, both from commercial point of view and affords good quality of cefoxitin of formula (I). The present invention is illustrated with the following examples, which should not be construed as limiting the scope of the invention.
Example I
Step i: Preparation of 7-oc-methoxy-7-(2-thienyl)acetamidocephalosporanic acid cyclohexyϊ amine salt
To dichloromethane (806 ml) and methanol (83.0 ml), 7-(2-thienyl) acetamidocephalosporanic acid sodium salt (100 gm) was added and cooled to -20 °C. Methane sulfonic acid (25.3 gm) was added and cooled to -90°C. N- Chlorosuccinimide (60.8 gm) was added followed by sodium methoxide solution (337.3 gm) in methanol (160 ml) was added slowly at -90°C. The reaction mass was stirred till completion of reaction, after completion of reaction sodium
metabisulphite (20.6 gm), aqueous acetic acid (150 ml) and sodium chloride solution (189 gm in 1164 ml water) were added at -90°C. After addition, 1:1 HC1 (23.5 ml) was added at 0°C, then the layers were separated, organic layer was washed with water and distilled of organic layer until final volume becomes (500 ml). To this mass cyclohexyl amine in acetone was added dropwise till pH becomes 6.5. IPE was added and stirred the reaction mass for 2 hours at 0°C. The solid obtained was filtered, washed with acetone and dried to get the title compound (101.0 gm).
Step ii; Preparation of 3-hydroxymethyl-7-oc-methoxy-7-[(2-thienyl) acetamido]-3-cephem-4-carboxylic acid N,N'-bis(phenylmethyl)-l,2- ethanediamine salt
To a mixture of DM water (326 ml) and methanol (366 ml), 7-oc-methoxy cephalothin (100 gm) obtained from step (ii) was added at 1 °C and cooled to -45 °C. To the reaction mixture, sodium hydroxide solution (28 gm in 167 ml water) was added slowly at 5 °C and stirred at -45 °C till completion of reaction. After completion of reaction, pH was adjusted to 7.0 using aqueous acetic acid at -45°C. The temperature of the reaction mass was raised to 28°C and distilled of approximately 400 ml reaction mass. Ethyl acetate (52 ml), benzathine diacetate (40 gm) were added and stirred the reaction mixture for 2 hour at 20°C. The reaction mass was cooled and the solid obtained was filtered, washed with water followed by ethyl acetate and dried to get the title compound (72 gm).
Step iii; Preparation of 7-oc-methoxy-7-[(2-thienyl)acetamido]-3- caramoyloxymethyl-3-cephem-4-carboxylic acid
To THF (400 ml) decarbomoyl cefoxitin benzathine salt (50 gm) obtained from step (iii) was added, and cooled to -55°C, followed by slow addition of precooled solution of chloro sulphonyl isocynate (35.0 gm) in THF (50 ml) at -55 °C. Reaction mass was stirred till completion of the reaction. After completion of the reaction, the reaction mass was added into cold DM water and stirred for 2 hours. Ethyl acetate (1277.0 ml) was added; the byproduct obtained was filtered and washed with ethyl acetate/water mixture. To the filtrate 10% sodium chloride solution (225 ml) was added, stirred 10 minutes, then the layer were separated. The organic layer was washed with 10% sodium chloride solution. The product was extracted with mixture of sodium bicarbonate solution and sodium chloride solution. The pH of aqueous solution was adjusted to 2.0 with 1 :1 HC1 and cooled to 10 °C. The solid obtained was filtered, washed, and dried. The dried solid was added to DM water (462 ml) at 25°C. pH of reaction mass was adjusted to 6.0 with sodium carbonate solution (83 ml) and degassed for 30 minutes. Acetic acid was added to adjust the pH to 5.4-5.6, and activated carbon (3.5 gm) was added and stirred for 10 minutes. Carbon was filtered and washed the bed with water. To the filtrate ethyl acetate (9 ml) was added and pH of filtrate adjusted to 2.0 with 1:1 HC1 (14 ml). The reaction mass cooled to 10 °C, the solid obtained was filtered, washed with water, and dried to yield title compound in pure form.
Example II
Preparation of Cefoxitin Sodium;
To cefoxitin acid (11 g) in 12% aqueous acetone (88 ml), 60% aqueous sodium lactate (4.7 g) solution was added at 30°C and stirred for 10 minutes, excess acetone was added (275 ml) to precipitate the product. The solid was filtered and dried under vacuum to yield the title compound in pure form (10 g)
Example III
Preparation of Cefoxitin Sodium;
To cefoxitin acid (25 g) in a mixture of acetone (350 ml) and methanol (87 ml), sodium 2-ethyl hexonate (10.7 g) in acetone (60 ml) was added at 20°C and stirred for 30 minutes. The reaction mass was cooled to 10°C to precipitate the product. The solid was filtered and dried under vacuum to yield the title compound in pure form.
Claims
We claim:
1) A process for the preparation of cefoxitin of formula (I)
(i) treating the compound of formula (II) with a halogenating agent in an organic solvent, followed by treatment with alkali/alkaline earth metal methoxide at a temperature in the range of -100°C to 0°C, isolating the product formed as an organic amine salt of the formula (III), where M+ represents an organic counter ion
(ii) treating the salt of formula (III) with a base in the presence of solvent at a temperature in the range of -75 to 10°C, isolating the product formed as an organic amine salt of the formula (IV),where M+ represents an organic counter ion,
(iii) carbamoylating the compound of formula (IV) with isocyanate of formula (V) wherein R is a labile group in the presence of a solvent at a temperature in the range of -60°C to 10°C, and isolating to get cefoxitin of the formula (I), and
(iv) if required converting cefoxitin into cefoxitin sodium using source of sodium ion in the presence of solvent at a temperature in the range of -60°C to 0°C.
2) The process as claimed in claim 1, wherein the halogenting agent used in step (i) is selected form t-butoxy chloride, N-chlorosuccinimide, N- bromosuccinimide, bromine or chlorine.
3) The process as claimed in claim 1, wherein the organic solvent used in step (i) is selected from dichloromethane, methanol chloroform, THF or ethylene chloride and the like or mixtures thereof.
4) The process as claimed in claim 1, wherein the organic amine used in step (i) is selected from diethylamine, methylethylamme, triethylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 1 ,8-diazabicyclo(5.4.0)undec- 7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, l,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine or octylamine.
5) The process as claimed in claim 1, wherein alkali/alkaline earth metal methoxides employed in step (i) is selected from lithium methoxide, sodium methoxide or magnesium methoxide. 6) The process as claimed in claim 1, wherein the solvent employed in step (ii) is selected from methanol, acetone, water, THF, ethyl acetate or mixtures thereof.
7) The process as claimed in claim 1, wherein and the base employed in step (ii) is selected from sodium hydroxide, or potassium hydroxide.
8) The process as claimed in claim 1, wherein the organic amine used in step (ii) is selected from cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, 1 ,4-
dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine, octylamine.
9) The process as claimed in claim 1, wherein the the solvent employed in step (iii) is selected from THF, methanol dichloromethane, acetone, ethyl acetate, methyl acetate or mixtures thereof.
10) The process claimed in claim 1, wherein the labile group represented by R in step (iii) is selected from chlorosulphonyl, mono, di or trichloroacetyl, bromosulphonyl, trichloroethoxycarbonyl, trimethylsilyl or chlorobenzene sulphonyl group. 11) A compound of formula (III)
13) A process for the preparation of cefoxitin sodium which comprises treating cefoxitin acid of formula (I) with sodium ion source in the presence of solvent at a temperature in the range of 0 to 40°C.
14) A process according to claim 1 or 13, wherein the sodium ion source is selected from sodium 2-ethyl hexonate, sodium acetate, or sodium lactate.
15) A process according to claim 1 or 13, wherein the solvent used is selected from methanol, acetone, THF, ethyl acetate, acetonitrle, isobutyl methyl ketone, ethyl methyl ketone, IPE, hexane, toluene or water.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/548,888 US7662955B2 (en) | 2003-03-20 | 2003-12-31 | Process for the preparation of cefoxitin |
| AU2003294161A AU2003294161A1 (en) | 2003-03-20 | 2003-12-31 | An improved process for the preparation of cefoxitin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN236CH2003 | 2003-03-20 | ||
| IN236/MAS/2003 | 2003-03-20 |
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| WO2004083217A1 true WO2004083217A1 (en) | 2004-09-30 |
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| PCT/IB2003/006239 WO2004083217A1 (en) | 2003-03-20 | 2003-12-31 | An improved process for the preparation of cefoxitin |
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| WO (1) | WO2004083217A1 (en) |
Cited By (23)
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|---|---|---|---|---|
| EP1748049A2 (en) * | 2005-07-27 | 2007-01-31 | ACS DOBFAR S.p.A. | Process for preparing cefoxitin |
| EP2048240A2 (en) | 2007-10-09 | 2009-04-15 | ACS DOBFAR S.p.A. | Process for producing 7-methoxy-3-desacetylcefalotin |
| CN101941983A (en) * | 2010-09-25 | 2011-01-12 | 海南天煌制药有限公司 | Preparation method of high-purity cefoxitin sodium |
| CN101607967B (en) * | 2009-07-23 | 2011-06-15 | 河北九派制药有限公司 | Cefoxitin acid preparation method |
| CN102358744A (en) * | 2011-09-02 | 2012-02-22 | 山东罗欣药业股份有限公司 | Cefoxitin sodium crystal compound and cefoxitin sodium composition powder injection |
| CN102399234A (en) * | 2011-12-06 | 2012-04-04 | 苏州中联化学制药有限公司 | Preparation method for Cefoxintin sodium |
| CN102633819A (en) * | 2012-04-24 | 2012-08-15 | 齐鲁安替（临邑）制药有限公司 | Preparation method of cefoxitin |
| CN102942577A (en) * | 2012-12-04 | 2013-02-27 | 罗诚 | Cefoxitin sodium compound-containing pharmaceutical composition |
| CN103012437A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing cefoxitin acid as antibacterial medicament |
| CN103304582A (en) * | 2013-06-28 | 2013-09-18 | 四川省惠达药业有限公司 | Cefoxitin sodium compound, preparation method and pharmaceutical composition thereof |
| CN103450225A (en) * | 2013-08-22 | 2013-12-18 | 海南葫芦娃制药有限公司 | Preparation method of cefoxitin sodium |
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| CN104230956A (en) * | 2012-04-24 | 2014-12-24 | 齐鲁安替（临邑）制药有限公司 | Method for preparing cefoxitin |
| CN104402908A (en) * | 2014-10-23 | 2015-03-11 | 胡梨芳 | Cefoxitin sodium compound entity and composition and uses thereof |
| CN104622695A (en) * | 2015-03-10 | 2015-05-20 | 华北制药河北华民药业有限责任公司 | Cefoxitin sodium powder preparation for injection |
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| CN110396105A (en) * | 2018-09-10 | 2019-11-01 | 广东金城金素制药有限公司 | Mei Fu elder generation cefoxitin sodium pharmaceutical preparation prevents infection application in gastrointestinal surgery |
| CN111217836A (en) * | 2020-03-20 | 2020-06-02 | 侯二美 | Preparation method of cefoxitin |
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