CN101817796A - Method for preparing cefotiam side chain - Google Patents
Method for preparing cefotiam side chain Download PDFInfo
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- CN101817796A CN101817796A CN201010185936A CN201010185936A CN101817796A CN 101817796 A CN101817796 A CN 101817796A CN 201010185936 A CN201010185936 A CN 201010185936A CN 201010185936 A CN201010185936 A CN 201010185936A CN 101817796 A CN101817796 A CN 101817796A
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Abstract
The invention discloses a method for preparing a cefotiam side chain 1-(2-dimethylaminoethyl)-5-mercapto tetrazole, which comprises the following steps of: (1) dissolving carbon disulfide into an organic solvent, dripping N,N-dimethyl ethylenediamine into the organic solvent at the temperature of between 0 and 30 DEG C, and filtering a product; and (2) adding the filtered product into the organic solvent, dripping hydrogen peroxide into the organic solvent at the temperature of between 0 and 40 DEG C to oxidize the filtered product, evaporating the organic solvent after the reaction is finished, dissolving the residual viscous liquid into methanol, dripping the solution into aqueous solution of sodium azide at the temperature of between 30 and 70 DEG C, decolorizing the solution and adjusting the acid to obtain the cefotiam side chain 1-(2-dimethylaminoethyl)-5-mercapto tetrazole. The method has the advantages of simple step, low cost and high product purity, and is favorable for industrialized production.
Description
Technical field
The invention belongs to medicine microbiotic intermediate field, particularly a kind of cefotiam side chain preparation method.。
Background technology
1-(2-dimethyl aminoethyl)-5-mercapto-tetrazole is 3 side chains of cefotiam, its synthetic method one with N, the N-dimethyl-ethylenediamine is a starting raw material, earlier with the dithiocarbonic anhydride addition, carries out methylation reaction again, gets in the sodiumazide cyclization at last.Its reaction principle is as follows:
Present method is made solvent with ether in the addition reaction process, increased the danger of operation.2-(N in the methylation reaction process, the N dimethylamine base) the ethylamino-dithionic acid needs to dissolve with alkali lye, and then the solution of dropping methylating reagent, after finishing, reaction also needs distillating recovering solvent, water is used organic solvent extraction again, through distillation, get 2-(N, N dimethylamine base) ethylamino-dithionic acid methyl esters behind the recrystallization.Methylate process operation complexity and yield has only 76%.Ring-closure reaction is used the mixed solvent of second alcohol and water, has increased the difficulty of solvent recuperation.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of cefotiam side chain, and step is simple, and cost is low, and the product purity height helps suitability for industrialized production.
The preparation method of a kind of cefotiam side chain 1-of the present invention (2-dimethyl aminoethyl)-5-mercapto-tetrazole is characterized in that:
Comprise the steps:
(1) drip N after dithiocarbonic anhydride is dissolved in organic solvent, the N-dimethyl-ethylenediamine, 0～30 ℃ of temperature, the reaction insulation that finishes, leach 2-(N, N dimethylamine base) ethylamino-dithionic acid;
(2) 2-(N, the N dimethylamine base) the ethylamino-dithionic acid adds water-insoluble organic solvent, and in 0～40 ℃ of dropping hydrogen peroxide, reaction finishes and tells water, steam and remove organic solvent, get the product thick substances, be dissolved in methyl alcohol, in the sodiumazide aqueous solution, drip, 30～70 ℃ of dropping temperatures, react the decolouring that finishes, regulate the pH value, leach product and get 1-(2-dimethyl aminoethyl)-5-mercapto-tetrazole to 4-6.
The present invention is with N, the N-dimethyl-ethylenediamine is a starting raw material, earlier with the dithiocarbonic anhydride addition, adduct adds and is dissolved in methyl alcohol and sodiumazide aqueous solution back flow reaction after dripping hydrogen peroxide oxidation behind the water-insoluble organic solvent, and the acid adjustment afterwards that finishes gets 1-(2-dimethyl aminoethyl)-5-mercapto-tetrazole.
Chemical equation of the present invention is as follows:
The solvent of described step (1) can be used methylene dichloride, trichloromethane, ethylene dichloride, methyl alcohol, ethanol, acetonitrile equal solvent, and these solvents can be used alone or as a mixture;
The consumption of dithiocarbonic anhydride is N in the described step (1), 1～1.2 times of the mole number of N-dimethyl-ethylenediamine;
Temperature of reaction is preferably 0～20 ℃ in the described step (1);
Organic solvent in the described step (2) can be used methylene dichloride, trichloromethane, ethylene dichloride, ethyl acetate equal solvent, and these solvents can be used alone or as a mixture;
The consumption of the hydrogen peroxide in the described step (2) is 2～4 times of 2-(N, N dimethylamine base) ethylamino-dithionic acid mole number.
The temperature of the dropping hydrogen peroxide in the described step (2) is 0～30 ℃
The consumption of the sodiumazide in the described step (2) is 1～1.2 times of 2-(N, N dimethylamine base) ethylamino-dithionic acid mole number.
Advantage of the present invention:
This method steps is simple, and cost is low, and the product purity height helps suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.These embodiment only are used to the present invention is described and are not used in the restriction scope of the invention.
Embodiment one
79.8g (1.05mol) dithiocarbonic anhydride is dissolved in 450mL methyl alcohol, drips 88gN under 15 ℃, N-dimethyl-ethylenediamine (1.0mol), and dropping time control 1h, insulation 3h, suction filtration, 40 ℃ of vacuum dryings get 156g2-(N, N dimethylamine base) ethylamino-dithionic acid.
49.2g (0.3mol) add the 250mL methylene dichloride, drip hydrogen peroxide 136mL (1.2mol) below 20 ℃, react the separatory that finishes, dichloromethane layer vacuum distilling gets the thickness solidliquid mixture, adds 50mL methyl alcohol.21g (0.32mol) sodiumazide is dissolved in the 80mL water, is warming up to 60 ℃, drips above-mentioned methanol solution, drips time 1h, drip off back insulation 1h, activated carbon decolorizing 30min adds 50mL dichloromethane extraction separatory, water is adjusted to pH=4 with concentrated hydrochloric acid, and suction filtration gets cefotiam side chain crude product 42g.The crude product heating is water-soluble, the activated carbon decolorizing filter, and mother liquor cooling crystallization, suction filtration gets 33g cefotiam side chain 1-(2-dimethyl aminoethyl)-5-mercapto-tetrazole elaboration, purity＞99.3%, total recovery 60% (with N, N-dimethyl-ethylenediamine meter).
Embodiment two
79.8g (1.05mol) dithiocarbonic anhydride is dissolved in the 450mL chloroform, drips 88gN under 15 ℃, N-dimethyl-ethylenediamine (1.0mol), and dropping time control 1h, insulation 3h, suction filtration, 40 ℃ of vacuum dryings get 154g2-(N, N dimethylamine base) ethylamino-dithionic acid.
49.2g (0.3mol) add the 250mL methylene dichloride, drip hydrogen peroxide 102mL (0.9mol) below 20 ℃, react the separatory that finishes, dichloromethane layer vacuum distilling gets the thickness solidliquid mixture, adds 50mL methyl alcohol.21g (0.32mol) sodiumazide is dissolved in the 80mL water, is warming up to 60 ℃, drips above-mentioned methanol solution, drips time 1h, drip off back insulation 1h, activated carbon decolorizing 30min adds 50mL dichloromethane extraction separatory, water is adjusted to pH=4 with concentrated hydrochloric acid, and suction filtration gets cefotiam side chain crude product 43.2g.The crude product heating is water-soluble, and activated carbon decolorizing filters, mother liquor cooling crystallization, and suction filtration gets 33.8g cefotiam side chain 1-(2-dimethyl aminoethyl)-5-mercapto-tetrazole elaboration, purity＞99.3%, total recovery 61.4% (with N, N-dimethyl-ethylenediamine meter).
Embodiment three
83.6g (1.1mol) dithiocarbonic anhydride is dissolved in 450mL methyl alcohol, drips 88gN under 15 ℃, N-dimethyl-ethylenediamine (10mol), and dropping time control 1h, insulation 3h, suction filtration, 40 ℃ of vacuum dryings get 158g2-(N, N dimethylamine base) ethylamino-dithionic acid.
49.2g (0.3mol) add the 250mL ethyl acetate, drip hydrogen peroxide 136mL (1.2mol) below 40 ℃, react the separatory that finishes, ethyl acetate layer vacuum distilling gets the thickness solidliquid mixture, adds 50mL methyl alcohol.21g (0.32mol) sodiumazide is dissolved in the 80mL water, is warming up to 60 ℃, and above-mentioned methanol solution drips time 1h, drip off back insulation 1h, activated carbon decolorizing 30min adds 50mL ethyl acetate extraction separatory, water is adjusted to pH=4 with concentrated hydrochloric acid, and suction filtration gets cefotiam side chain crude product 45g.The crude product heating is water-soluble, and activated carbon decolorizing filters, mother liquor cooling crystallization, and suction filtration gets 34.1g cefotiam side chain 1-(2-dimethyl aminoethyl)-5-mercapto-tetrazole elaboration, purity＞99.3%, total recovery 64% (with N, N-dimethyl-ethylenediamine meter).
Embodiment four
83.6g (1.1mol) dithiocarbonic anhydride is dissolved in 450mL methyl alcohol, drips 88gN under 15 ℃, N-dimethyl-ethylenediamine (1.0mol), and dropping time control 1h, insulation 3h, suction filtration, 40 ℃ of vacuum dryings get 158g2-(N, N dimethylamine base) ethylamino-dithionic acid.
49.2g (0.3mol) add the 250mL ethyl acetate, drip hydrogen peroxide 102mL (0.9mol) below 40 ℃, react the separatory that finishes, ethyl acetate layer vacuum distilling gets the thickness solidliquid mixture, adds 50mL methyl alcohol.19.5g (0.3mol) sodiumazide is dissolved in the 80mL water, is warming up to 60 ℃, above-mentioned methanol solution drips time 1h, drip off back insulation 1h, activated carbon decolorizing 30min adds 50mL ethyl acetate extraction separatory, water is adjusted to pH=4 with concentrated hydrochloric acid, and suction filtration gets cefotiam side chain crude product 43.6g.The crude product heating is water-soluble, and activated carbon decolorizing filters, mother liquor cooling crystallization, and suction filtration gets 33.6g cefotiam side chain 1-(2-dimethyl aminoethyl)-5-mercapto-tetrazole elaboration, purity＞99.3%, total recovery 63% (with N, N-dimethyl-ethylenediamine meter).
Claims (8)
1. the preparation method of a cefotiam side chain is characterized in that: comprise the steps:
(1) drip N after dithiocarbonic anhydride is dissolved in organic solvent, the N-dimethyl-ethylenediamine, 0～30 ℃ of temperature, the reaction insulation that finishes, leach 2-(N, N dimethylamine base) ethylamino-dithionic acid;
(2) 2-(N, the N dimethylamine base) the ethylamino-dithionic acid adds water-insoluble organic solvent, and in 0～40 ℃ of dropping hydrogen peroxide, reaction finishes and tells water, steam and remove organic solvent, get the product thick substances, be dissolved in methyl alcohol, in the sodiumazide aqueous solution, drip, 30～70 ℃ of dropping temperatures, react the decolouring that finishes, regulate the pH value, leach product and get 1-(2-dimethyl aminoethyl)-5-mercapto-tetrazole to 4-6.
2. the preparation method of a kind of cefotiam side chain according to claim 1, it is characterized in that: the organic solvent in the step (1) is selected from one or more in methylene dichloride, trichloromethane, ethylene dichloride, methyl alcohol, ethanol, the acetonitrile.
3. the preparation method of a kind of cefotiam side chain according to claim 1 is characterized in that: the consumption of dithiocarbonic anhydride is N in the step (1), 1～1.5 times of the mole number of N-dimethyl-ethylenediamine.
4. the preparation method of a kind of cefotiam side chain according to claim 1 is characterized in that: temperature of reaction is 0～20 ℃ in the step (1).
5. the preparation method of a kind of cefotiam side chain according to claim 1, it is characterized in that: the organic solvent in the step (2) is selected from one or more in methylene dichloride, trichloromethane, ethylene dichloride, the ethyl acetate.
6. the preparation method of a kind of cefotiam side chain according to claim 1, it is characterized in that: the hydrogen peroxide dropping temperature in the step (2) is 0～30 ℃.
7. the preparation method of a kind of cefotiam side chain according to claim 1, it is characterized in that: the consumption of the hydrogen peroxide in the step (2) is 2～4 times of 2-(N, N dimethylamine base) ethylamino-dithionic acid mole number.
8. the preparation method of a kind of cefotiam side chain according to claim 1 is characterized in that: the consumption of sodiumazide is 1～1.2 times of 2-(N, N dimethylamine base) ethylamino-dithionic acid mole number in the step (2).
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| CN201010185936A CN101817796A (en) | 2010-05-28 | 2010-05-28 | Method for preparing cefotiam side chain |
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| CN201010185936A CN101817796A (en) | 2010-05-28 | 2010-05-28 | Method for preparing cefotiam side chain |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850287A (en) * | 2012-10-10 | 2013-01-02 | 山东金城医药化工股份有限公司 | Method for refining metronidazole (MTZ) |
| CN110950816A (en) * | 2019-12-13 | 2020-04-03 | 山东金城医药化工有限公司 | Synthesis method of 1- (2-dimethylaminoethyl) -5-mercaptotetrazole |
| CN112010815A (en) * | 2020-09-18 | 2020-12-01 | 河北凯力昂生物科技有限公司 | Synthesis method of 1- (2-dimethylaminoethyl) -1H-5-mercapto-tetrazole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4508816A (en) * | 1982-10-21 | 1985-04-02 | Fuji Photo Film Co., Ltd. | Method for bleaching color photosensitive material |
| US4933265A (en) * | 1986-09-01 | 1990-06-12 | Fuji Photo Film Co., Ltd. | Process for forming direct positive color image |
| CN101045733A (en) * | 2007-01-26 | 2007-10-03 | 上海宁瑞生化技术有限公司 | Preparation method of cefotiam chloride |
-
2010
- 2010-05-28 CN CN201010185936A patent/CN101817796A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4508816A (en) * | 1982-10-21 | 1985-04-02 | Fuji Photo Film Co., Ltd. | Method for bleaching color photosensitive material |
| US4933265A (en) * | 1986-09-01 | 1990-06-12 | Fuji Photo Film Co., Ltd. | Process for forming direct positive color image |
| CN101045733A (en) * | 2007-01-26 | 2007-10-03 | 上海宁瑞生化技术有限公司 | Preparation method of cefotiam chloride |
Non-Patent Citations (1)
| Title |
|---|
| 刘丽秀等: "甲基巯基四唑合成工艺研究", 《四川化工》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850287A (en) * | 2012-10-10 | 2013-01-02 | 山东金城医药化工股份有限公司 | Method for refining metronidazole (MTZ) |
| CN102850287B (en) * | 2012-10-10 | 2015-02-18 | 山东金城医药化工股份有限公司 | Method for refining metronidazole (MTZ) |
| CN110950816A (en) * | 2019-12-13 | 2020-04-03 | 山东金城医药化工有限公司 | Synthesis method of 1- (2-dimethylaminoethyl) -5-mercaptotetrazole |
| CN112010815A (en) * | 2020-09-18 | 2020-12-01 | 河北凯力昂生物科技有限公司 | Synthesis method of 1- (2-dimethylaminoethyl) -1H-5-mercapto-tetrazole |
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Application publication date: 20100901 |