CN1594321A - Process for preparing cephazoline three-position intermediate - Google Patents
Process for preparing cephazoline three-position intermediate Download PDFInfo
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- CN1594321A CN1594321A CN 200410043639 CN200410043639A CN1594321A CN 1594321 A CN1594321 A CN 1594321A CN 200410043639 CN200410043639 CN 200410043639 CN 200410043639 A CN200410043639 A CN 200410043639A CN 1594321 A CN1594321 A CN 1594321A
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Abstract
Disclosed is a process for preparing cephazoline three-position intermediate which consists of, using a dissolvent as dissolvent, charging boron trifluoride to carry out complexation, charging complex compound, 7-ACA and MMT into the dissolvent, thus obtaining 3-(2-methyl-1,3,4-sulfurdiazole-5-group)sulfidomethyl-3-cephamalkene-4-carboxyl (TDA).
Description
Technical field: the present invention relates to a kind of new preparation method of three intermediates of a kind of antibacterials Kefzol, be specially three intermediates preparation of Kefzol.
Background technology: the Cephazolin chemical name is: 7-(1H-tetrazole-1-yl)-acetylaminohydroxyphenylarsonic acid 3-(2-methyl isophthalic acid .3.4-sulphur diazole-5-yl) thiomethyl-3-cephem-4-carboxylic acid is the first-generation cephalosporin for injections class antimicrobial drug of at present domestic and international wide clinical application.China claims Ancef, and this medicine goes on the market abroad in the seventies, and China has many producers also to produce.
It is starting raw material that the preparation of Kefzol is adopted with 7-amino-3-acetoxy-methyl-3-cephem-4-carboxylic acid (being called for short 7-ACA) usually, partly introduce 2-methyl isophthalic acid .3.4-thiadiazoles-5-sulfydryl (being called for short MMT) heterocycle by the acetoxyl group that replaces 3 (3-acetoxy-methyls) among the 7-ACA, this compound is again at C then
7-for carrying out the nitrogen acylation reaction on the side chain.C in the 7-ACA molecule
3Acetoxyl group on the-precedence methyl is the propylene ester, is replaced than being easier to nucleophilic substitution reaction takes place.Concrete introducing method bibliographical information is more, but has four kinds substantially: weak base catalysis method, boron trifluoride catalysis method, sulphuric acid catalysis method, trimethyl silicane catalysis of iodine method.The weak base catalysis method be organic or inorganic alkali as catalyzer, thereby reach the method for condensation purpose by the pH value of control in the reactive system.Because sulfydryl hydridization is at the C of 7-ACA
3The course that nucleophilic substitution reaction takes place on-precedence the methyl is S
N2 reaction mechanism, polar solvent carries out favourable to reaction, so be solvent usually with water, neutrality is carried out under alkaline condition.The technological process of the Kefzol of domestic manufacturer's production at present intermediate is used this method more.But use water as solvent, the beta-lactam nucleus ratio is easier to destroyed, and reacts extremely difficulty and carry out fully, and the 7-ACA transformation efficiency is generally 70～75%, and product purity is not high.In order to reduce the destruction of beta-lactam nucleus, reaction needed is ideal in the catalysis of nonaqueous phase.The boron trifluoride catalysis method has adopted this principle just.General be catalyzer with boron trifluoride complex (as complex compounds such as tetrahydrofuran (THF), ether), is solvent with acetonitrile or Glacial acetic acid, reacts under normal temperature or low-grade fever, can ten minutes smoothly at the C of 7-ACA
3Introducing sulfhydryl heterocycle on the side chain of-position, is that solvent is unfavorable for three wastes processing, contaminate environment but adopt acetonitrile, tetrahydrofuran (THF), ether.Many bibliographical informations are to cephalosporin this method, but also seldom are applied to this method in the synthesizing of Cephazolin intermediate.Because there is certain limitation in the boron trifluoride catalysis method, when the wetting ability that will introduce the sulfhydryl heterocycle compound very little (or polarity is minimum), then inapplicable this method.
Summary of the invention: the object of the present invention is to provide a kind of, cost is low, the solvent in the mother liquor can reclaim, significantly reduce environmental protection pressure, the written or printed documents reaction is very easily carried out, this solvent is easy to reclaim, easily degraded in air, three intermediates preparation of a kind of Kefzol that environmental pollution is little.The object of the present invention is achieved like this: a kind of solvent is made solvent, adds boron trifluoride and carries out complexing.Do in the solvent at solvent, add complex compound, 7-ACA and MMT, the 3-of system (2-methyl isophthalic acid .3.4-sulphur diazole-5-yl) thiomethyl-3-cephem-4-carboxylic acid (being called for short TDA).
Chemical equation is:
Two-step reaction has synthesized three intermediates of Kefzol (TDA).Vehicle compounds (I) and boron trifluoride react at a certain temperature and obtain compound (II), are doing with solvent under the situation of solvent, add compound (II), compound (III) MMT and compound (IV) 7-ACA,
Carry out condensation at a certain temperature and obtain compound (V) TDA, through dripping alkali, separate out product, aftertreatment promptly gets 3-(2-methyl isophthalic acid .3.4-sulphur diazole-5-yl) thiomethyl-3-cephem-4-carboxylic acid (being called for short TDA) and is products therefrom after the drying.
Among the present invention, compound (I) changes in the reaction of (II) compound, the organic solvent compound has acetonitrile, acetate, ether, formic acid, tetrahydrofuran (THF), ethyl acetate, methylcarbonate, common 0 ℃-40 ℃ of diethyl carbonate, oxalic acid, this step temperature of reaction, reaction times 20min-90min, this compound (I) changes into the material proportion of (II) compound, for every mole compound (I), the common consumption 0.1-0.4 of palpus boron trifluoride mole, compound (II) is separated out with solid state, does not need to make with extra care to be directly used in next step reaction.Exist under the catalysis at compound (II), compound (III) MMT and compound (IV) 7-ACA reaction make compound (V) TDA, and this step reaction is used organic solvent acetonitrile, acetate, ether, ethanol, tetrahydrofuran (THF), methylcarbonate, ethyl acetate, diethyl carbonate, formic acid and oxalic acid as solvent; For every mole compound (IV) 7-ACA; the consumption of compound (III) MMT is generally the 1.0-2.0 mole; the consumption of compound (II) is generally the 3-8 mole; this step needs nitrogen protection; reaction is normally carried out under a normal atmosphere; or carry out adding to depress; the typical temperature of this step reaction is 0 ℃-60 ℃; reaction times is 10min-80min normally; after reaction is finished; need transfer PH with alkali lye, the alkali lye of this step reaction usefulness is alkali-metal supercarbonate; carbonate; oxyhydroxide and organic bases are as sodium bicarbonate; saleratus; yellow soda ash; salt of wormwood; sodium hydroxide; potassium hydroxide; ammoniacal liquor; triethylamine; diethylamine; tetramethyl guanidine etc.; the pH value scope of reaction is 3.0-5.0; ooze crystallization, product is separated out, and filters; water; the solvent washing; used solvent washing is acetone; methylene dichloride; methylcarbonate; ethyl acetate; b propanol; ethanol, vacuum-drying obtains the highly purified compound of high yield (V) TDA.
Embodiment: example 1: under the room temperature, add the 200ml methylcarbonate, controlled temperature is at 15 ± 5 ℃, logical boron triflouride gas 80g in 35 ± 5min in, and the product filtration is with 50ml methylcarbonate solution, 200ml washing with acetone, drain.In temperature is 50 ℃, and drying is 10 hours under vacuum condition.Obtain solid chemical compound (II) 150g.
Example 2:
Under the room temperature condition, add the 150ml acetonitrile and make solvent, the experiment 1 solid 53g that obtains, agitation condition adds 7ACA 20g, MMT 9.6g down and reacts about 60min down in 40 ± 5 ℃, detect condensated liquid content at high-pressure liquid phase, the 7ACA residual quantity reacted completely less than 1.0% o'clock, dripped water 200ml in 30min, stir 60min, add to PH=3.5 with the 20%NaOH drips of solution.Suction filtration, use the 100ml water washing, drain, with the washing of 200ml methylcarbonate.Drain.In temperature is under 50 ℃ of vacuum conditions dry 10 hours.Get solid chemical compound TDA (V) 22.0g.K.F:0.86%; High performance liquid phase detects purity: 97.6%
Example 3:
Under the room temperature condition, add the 150ml tetrahydrofuran (THF), the experiment 1 solid 48g that obtains, agitation condition adds 7-ACA 20g, MMT9.6g down, reacts 60min down, high performance liquid phase detection condensated liquid content in 40 ± 4 ℃, the 7-ACA residual quantity was less than 1.0% o'clock, drip 200ml water in the 30min, stir 60min, drop to PH=3.85 with triethylamine solution.Suction filtration, wash with about 100ml water, 200ml acetone.Drain.Drying is 10 hours under 50 ℃ of vacuum conditions of temperature.Get solid TDA 20.7g.K.F=0.64%, high performance liquid phase detection level (dry basis): 96.5%
Example 4:
Under the room temperature condition, add the 200ml acetonitrile, (30～45 ℃) min feeds boron triflouride gas 35g under (20～40) ℃, after reacting completely, add acetate 40ml, 7-ACA 20g, MMT10g, reaction 60min under 40 ± 2 ℃, high performance liquid phase detects condensated liquid content, and the 7-ACA residual quantity was less than 1.0% o'clock, after reacting completely, in 30min, drip 200ml water, stir 60min, drop to PH=4.0 with 20%NaOH.Suction filtration, wash with 100ml washing, 200ml acetone.Suction filtration, drying.Drying is 10 hours under 50 ℃ of vacuum conditions of temperature.Get solid TDA 20.5g.K.F=0.56%, high performance liquid phase detection level (dry basis): 94.2%
Example 5:
Under the room temperature condition, add the 100ml ether, feed boron triflouride gas 45g in 7 ± 2 ℃ of following 30min, agitation condition adds formic acid 10ml, 7-ACA 20g, MMT 10.5g down, reaction 60min under 30 ± 2 ℃, high performance liquid phase detects condensated liquid content, the 7-ACA residual quantity reacted completely less than 1.0% o'clock, dripped 200ml water in 30min, stir 60min, drop to PH=3.9 with 20%KOH.Suction filtration, wash with 100ml water, 200ml acetone.Suction filtration, drying.Drying is 10 hours under 50 ℃ of vacuum conditions of temperature.Get solid TDA 21.8g, K.F=0.75%, high performance liquid phase detection level (dry basis): 97.8%
Example 6:
Under the room temperature condition, add the 100ml methylcarbonate, under 20 ± 2 ℃, feed boron triflouride gas 40g in 60min, agitation condition adds oxalic acid 25g, 7-ACA 20g, MMT10g reaction 60min under 45 ± 2 ℃ down, and high performance liquid phase detects condensated liquid content, the 7ACA residual quantity was less than 1.0% o'clock, 30min drips 200ml water, stirs 60min, drops to PH=4.1 with 15% ammoniacal liquor.Suction filtration, wash with 100ml water, 200ml acetone.Suction filtration, drying.Drying is 10 hours under 50 ℃ of vacuum conditions of temperature.Get solid TDA 20.7g, K.F=0.82%, high performance liquid phase detection level (dry basis): 95.8%
Example 7:
Under the room temperature condition, add the 100ml diethyl carbonate, under 30 ± 5 ℃, in 70min, feed boron triflouride gas 40g, agitation condition adds acetate 40ml, 7ACA 20g, MMT 10.5g down, reaction 70min under 50 ± 2 ℃, high performance liquid phase detects condensated liquid content, during 7ACA 1.0%, react completely, in 30min, drip 200ml water, stir 60min, drop to PH=4.1 with 20% sodium carbonate solution.Suction filtration, wash with 100ml water, 200ml acetone.Suction filtration, drying.Drying is 10 hours under temperature 50 vacuum conditions.Get solid TDA 22.2g, K.F=0.45%, high performance liquid phase detection level (dry basis): 97.6%
Example 8:
Under the room temperature condition, add the 100ml methylcarbonate, under 20 ± 5 ℃, in 60min, feed boron triflouride gas 40g, agitation condition adds 7-ACA 20g, MMT 9.6g down, reaction 60min under 30 ± 2 ℃, high-pressure liquid phase detects condensated liquid content, and the 7-ACA residual quantity was less than 1.0% o'clock, react completely, 30min drips 200ml water, stirs 60min, drops to PH=3.8 with tetramethyl guanidine.Suction filtration, 100ml washing, 200ml ethanol are washed.Suction filtration, drying.Drying is 10 hours under 50 ℃ of vacuum conditions of temperature.Get solid TDA 22.2g, K.F=0.64%, high performance liquid phase detection level (dry basis): 98.2%
Example 9:
Under the room temperature condition, add the 200ml acetic acid solution, under 20 ± 2 ℃, in 50min, feed boron triflouride gas 40g, agitation condition adds acetonitrile 110ml, 7-ACA 20g, MMT9.6g down, reaction 60min under 35 ± 2 ℃, high performance liquid phase detects condensated liquid content, and the 7ACA residual quantity was less than 1.0% o'clock, react completely, in 30min, drip 200ml water, stir 60min, add to PH=3.9 with the 20%NaOH drips of solution.Suction filtration, wash with 100ml water, 200ml acetonitrile.Drain.Drying is 10 hours under temperature 50 vacuum conditions.Get solid TDA 20.1g, K.F=0.72%, high performance liquid phase detection level (dry basis): 95.2%
Example 10:
Under the room temperature condition, add 100ml acetonitrile, 100ml acetate, agitation condition adds 7-ACA 20g, MMT 9.6g down, under 30 ± 2 ℃, feed boron triflouride gas 40g, reaction 60min, high-pressure liquid phase detects condensated liquid content, and the 7-ACA residual quantity was less than 1.0% o'clock, react completely, 30min drips 200ml water, stirs 60min, the NaHCO with 10%
3Drips of solution adds to PH=3.8.Suction filtration, 100ml washing, 200ml acetonitrile are washed.Suction filtration, drying.Drying is 10 hours under 50 ℃ of vacuum conditions of temperature.Get solid TDA 20.2g, K.F=0.64%, high performance liquid phase detection level (dry basis): 95.2%
Claims (6)
1, three intermediates preparation of a kind of Kefzol, it is characterized in that: a kind of solvent is made solvent, adds boron trifluoride and carries out complexing.
2, three intermediates preparation of a kind of Kefzol according to claim 1 is characterized in that:
Do in the solvent at solvent, add complex compound, 7-ACA and MMT, the 3-of system (2-methyl isophthalic acid .3.4-
Sulphur diazole-5-yl) thiomethyl-3-cephem-4-carboxylic acid (being called for short TDA).
3, three intermediates preparation of a kind of Kefzol according to claim 1, it is characterized in that: chemical equation is:
Two-step reaction has synthesized three intermediates of Kefzol (TDA).
4, three intermediates preparation of a kind of Kefzol according to claim 1, it is characterized in that: vehicle compounds (I) and boron trifluoride, react at a certain temperature and obtain compound (II), doing with solvent under the situation of solvent, add compound (II), compound (III) MMT and compound (IV) 7-ACA
Carry out condensation at a certain temperature and obtain compound (V) TDA, through dripping alkali, separate out product, aftertreatment promptly gets 3-(2-methyl isophthalic acid .3.4-sulphur diazole-5-yl) thiomethyl-3-cephem-4-carboxylic acid (being called for short TDA) and is products therefrom after the drying.
5, three intermediates preparation of a kind of Kefzol according to claim 1, it is characterized in that: among this preparation method, compound (I) changes in the reaction of (II) compound, the organic solvent compound has acetonitrile, acetate, ether, formic acid, tetrahydrofuran (THF), ethyl acetate, methylcarbonate, diethyl carbonate, oxalic acid, common 0 ℃-40 ℃ of this step temperature of reaction, reaction times 20min-90min, this compound (I) changes into the material proportion of (II) compound, for every mole compound (I), the common consumption 0.1-0.4 of palpus boron trifluoride mole, compound (II) is separated out with solid state, does not need to make with extra care to be directly used in next step reaction.
6, three intermediates preparation of a kind of Kefzol according to claim 1 is characterized in that:
Exist under the catalysis at compound (II), compound (III) MMT and compound (IV) 7-ACA reaction make compound (V) TDA, and this step reaction is used organic solvent acetonitrile, acetate, ether, ethanol, tetrahydrofuran (THF), methylcarbonate, ethyl acetate, diethyl carbonate, formic acid and oxalic acid as solvent; For every mole compound (IV) 7-ACA; the consumption of compound (III) MMT is generally the 1.0-2.0 mole; the consumption of compound (II) is generally the 3-8 mole; this step needs nitrogen protection; reaction is normally carried out under a normal atmosphere; or carry out adding to depress; the typical temperature of this step reaction is 0 ℃-60 ℃; reaction times is 10min-80min normally; after reaction is finished; need transfer PH with alkali lye, the alkali lye of this step reaction usefulness is alkali-metal supercarbonate; carbonate; oxyhydroxide and organic bases are as sodium bicarbonate; saleratus; yellow soda ash; salt of wormwood; sodium hydroxide; potassium hydroxide; ammoniacal liquor; triethylamine; diethylamine; tetramethyl guanidine etc.; the pH value scope of reaction is 3.0-5.0; ooze crystallization, product is separated out, and filters; water; the solvent washing; used solvent washing is acetone; methylene dichloride; methylcarbonate; ethyl acetate; b propanol; ethanol, vacuum-drying obtains the highly purified compound of high yield (V) TDA.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100355761C (en) * | 2006-03-22 | 2007-12-19 | 黑龙江豪运经贸有限公司 | Production of boric carbonic acid dimethyl ester complex trifluoride |
| CN100506210C (en) * | 2008-01-18 | 2009-07-01 | 山东罗欣药业股份有限公司 | Ceftezole sodium powder injection and synthesizing method thereof |
| CN102321101A (en) * | 2011-07-28 | 2012-01-18 | 哈药集团制药总厂 | Preparation method of cefazolin sodium |
| CN102617607A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing cefazolin compounds |
| CN102633813A (en) * | 2012-04-17 | 2012-08-15 | 黑龙江豪运精细化工有限公司 | Preparation method of cefazolin sodium intermediate TDA (tolylenediamine) |
| CN109336905A (en) * | 2018-12-24 | 2019-02-15 | 淄博鑫泉医药技术服务有限公司 | The synthetic method of Cefazolin Intermediate TDA |
-
2004
- 2004-06-23 CN CN 200410043639 patent/CN1594321A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100355761C (en) * | 2006-03-22 | 2007-12-19 | 黑龙江豪运经贸有限公司 | Production of boric carbonic acid dimethyl ester complex trifluoride |
| CN100506210C (en) * | 2008-01-18 | 2009-07-01 | 山东罗欣药业股份有限公司 | Ceftezole sodium powder injection and synthesizing method thereof |
| CN102321101A (en) * | 2011-07-28 | 2012-01-18 | 哈药集团制药总厂 | Preparation method of cefazolin sodium |
| CN102321101B (en) * | 2011-07-28 | 2015-07-15 | 哈药集团制药总厂 | Preparation method of cefazolin sodium |
| CN102617607A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing cefazolin compounds |
| CN102617607B (en) * | 2012-03-31 | 2014-04-16 | 哈药集团制药总厂 | Method for preparing cefazolin compounds |
| CN102633813A (en) * | 2012-04-17 | 2012-08-15 | 黑龙江豪运精细化工有限公司 | Preparation method of cefazolin sodium intermediate TDA (tolylenediamine) |
| CN109336905A (en) * | 2018-12-24 | 2019-02-15 | 淄博鑫泉医药技术服务有限公司 | The synthetic method of Cefazolin Intermediate TDA |
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