CN109517001B - Preparation method of cefotiam hydrochloride - Google Patents
Preparation method of cefotiam hydrochloride Download PDFInfo
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- CN109517001B CN109517001B CN201811377784.4A CN201811377784A CN109517001B CN 109517001 B CN109517001 B CN 109517001B CN 201811377784 A CN201811377784 A CN 201811377784A CN 109517001 B CN109517001 B CN 109517001B
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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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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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
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of cefotiam hydrochloride, belonging to the technical field of medicine synthesis, and the preparation method comprises the following steps: adding the compound II, a condensing agent, water and an organic solvent into a reaction bottle for dissolving, controlling the temperature at 0-10 ℃, slowly adding aminothiazole acetic acid (III), adding alkali to adjust the pH value, stirring for reacting for 1-2h, controlling the residue of the compound II to be below 3%, adding dichloromethane for extracting, adding concentrated hydrochloric acid, adding activated carbon for decoloring, crystallizing by using acetone, centrifuging and drying to obtain cefotiam hydrochloride (I). The preparation method provided by the invention shortens the reaction route, is easy to operate, has high yield and purity, produces few by-products, has the advantage of environmental friendliness, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of cefotiam hydrochloride.
Background
Cefotiam hydrochloride, the chemical name of which is (6R,7R) -7- [ [ (2-amino-4-thiazolyl) acetyl ] amino ] -3- [ [1- [2- (dimethylamino) ethyl ] -1H-tetrazol-5-yl ] thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid dihydrochloride, is a second-generation cephalosporin antibiotic, and a mixed powder preparation of dihydrochloride (Cefotiam dihydrate) thereof and buffer sodium carbonate (trade name of Pansporin) is clinically used. The product has similar action on gram-positive bacteria as cefazolin, and has strong antibacterial effect on Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Haemophilus. It also has antibacterial effect on Citrobacter, Enterobacter, and indole positive proteobacteria.
In the existing methods for preparing cefotiam hexetil hydrochloride, the following approaches are generally available:
the first process comprises the following steps: the process comprises the steps of reacting aminothiazole acetic acid with a halogenating reagent to prepare an activated acyl chloride intermediate, and carrying out 7-bit acylation reaction with 7-ACA, wherein the 7-bit acylation reaction has strict requirements on low-temperature reaction, the acyl chloride intermediate is easy to hydrolyze, the addition method needs to be strictly controlled, and in addition, the acyl chloride intermediate is in a slightly soluble state and is subjected to solid-liquid two-phase reaction with the 7-ACA, so that the yield of the acylation step is influenced, and the total yield of the final product is influenced. The halogenating agent used can pollute the air, and is not beneficial to industrial production.
And a second process: aminothiazole acetic acid reacts with pivaloyl chloride to prepare an anhydride intermediate, and then the anhydride intermediate and 7-ACA undergo 7-bit acylation reaction, which still has strict requirements on low-temperature reaction.
Disclosure of Invention
The invention aims to provide a novel preparation method of cefotiam hydrochloride aiming at the defects of the prior art, the preparation method shortens the reaction route, is easy to control the reaction process, has higher yield and purity, produces few by-products, has the advantage of environmental friendliness, and is suitable for industrial production.
The synthetic route of the invention is as follows:
a preparation method of cefotiam hydrochloride comprises the following steps:
adding the compound II, a condensing agent, water and an organic solvent into a reaction bottle for dissolving, controlling the temperature at 0-10 ℃, slowly adding aminothiazole acetic acid (III), adding alkali to adjust the pH value, stirring for reacting for 1-2h, controlling the residue of the compound II to be below 3%, adding dichloromethane for extracting, adding concentrated hydrochloric acid, adding activated carbon for decoloring, crystallizing by using acetone, centrifuging and drying to obtain cefotiam hydrochloride (I).
Preferably, the preparation method of the compound II comprises the following steps: adding 1- (2-dimethylaminoethyl) -1,2,3, 4-tetramizole-5-mercaptan (DMMT), boron trifluoride-acetonitrile, acetonitrile and butanol into a reaction tank, controlling the temperature to be 0-5 ℃, slowly dropwise adding 7-ACA, controlling the temperature to be 0-5 ℃, stirring and reacting for 1.5h, adding a proper amount of hydrochloric acid during the reaction process, after the reaction is finished, introducing dry hydrogen chloride gas, crystallizing with acetone, centrifuging and drying to obtain a compound II.
Preferably, the condensing agent is 4, 6-dimethoxy-2-chloro-1, 3, 5-triazine or 2,4, 6-trichloro-triazine
1,3, 5-triazine in a molar ratio of condensing agent to compound II of 1.1: 1; further preferred is 4, 6-dimethoxy-2-chloro-1, 3, 5-triazine.
Preferably, the organic solvent is acetonitrile, acetone, ethyl acetate or N, N-dimethylformamide, and more preferably, acetonitrile or N, N-dimethylformamide.
Preferably, the base is triethylamine, diethylamine, pyridine or sodium hydroxide, and the mole number of the base is 1.5-1 of the compound II; further preferably, triethylamine or sodium hydroxide.
Preferably, the pH value is 4 to 5.5, and more preferably, the pH value is 5.
Compared with the prior art, the invention has the beneficial effects that:
(1) the compound II and the aminothiazole acetic acid (III) directly react under the condition of a cheap condensing agent, so that the reaction steps are shortened, the total yield of the product is improved, and the use of an acylation reagent polluting the environment is avoided.
(2) The method has the advantages of simple process, easy operation of reaction process, high product yield and purity, less by-products and suitability for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
Preparation of Compound II
Adding 51.97g (0.3mol) of 1- (2-dimethylaminoethyl) -1,2,3, 4-tetraaminooxazole-5-thiol (DMMT), 0.6mol of boron trifluoride-acetonitrile (calculated according to the boron trifluoride), 200ml of acetonitrile and 150ml of butanol into a reaction tank, controlling the temperature to be 0-5 ℃, slowly dropwise adding 81.68g (0.3mol) of 7-ACA, controlling the temperature to be 0-5 ℃, stirring and reacting for 1.5h, controlling the temperature to be 0-5 ℃, and reacting with 2M hydrochloric acid (0.6mol) during the reaction, introducing dry hydrogen chloride gas, crystallizing with acetone, centrifuging and drying to obtain 114.72g of a compound II, wherein the yield is 90% and the purity is 99.3%.
Example 1
Preparation of cefotiam hydrochloride
30g (0.07mol) of a compound II, 80ml of 2-methoxy-4, 6-dichloro-1, 3, 5-triazine (0.077mol), 80ml of water and 160ml of acetonitrile are added into a reaction bottle for dissolution, the temperature is controlled at 0-10 ℃, 11.07g (0.07mol) of aminothiazole acetic acid (III) is slowly added, 0.106mol of triethylamine is added to adjust the pH value to 4, stirring reaction is carried out for 1-2h, the residue of the compound II is controlled below 3 percent, 150ml of dichloromethane is added for extraction, concentrated hydrochloric acid is added, activated carbon is added for decolorization, acetone is used for crystallization, centrifugation and drying are carried out, thus 33.86g of cefotiam hydrochloride (I) is prepared, the yield is 80 percent, the purity is 99.0 percent, and the maximum single impurity is 1.81 percent.
Example 2
Preparation of cefotiam hydrochloride
30g (0.07mol) of compound II, 80ml of 4, 6-dimethoxy-2-chloro-1, 3, 5-triazine (0.07mol), 80ml of water and 160ml of acetone are added into a reaction bottle for dissolution, the temperature is controlled at 0-10 ℃, 11.08g (0.07mol) of aminothiazole acetic acid (III) is slowly added, 0.106mol of triethylamine is added to adjust the pH value to 5, stirring reaction is carried out for 1-2h, the residue of the compound II is controlled below 3 percent, 150ml of dichloromethane is added for extraction, concentrated hydrochloric acid is added, activated carbon is added for decolorization, acetone is used for crystallization, centrifugation and drying are carried out, thus 39.96g of cefotiam hydrochloride (I) is prepared, the yield is 95 percent, the purity is 99.6 percent, and the maximum single impurity is 0.05 percent.
Example 3
Preparation of cefotiam hydrochloride
30g (0.07mol) of compound II, 80ml of 2,4, 6-trichloro-1, 3, 5-triazine (0.077mol), 80ml of water and 160ml of N, N-dimethylformamide are added into a reaction bottle for dissolving, 11.07g (0.07mol, molecular weight: 158.18) of aminothiazole acetic acid (III) is slowly added into the reaction bottle at the temperature of 0-10 ℃, 0.07mol of sodium hydroxide is added for adjusting the pH to 5.5, stirring reaction is carried out for 1-2h, the residue of the compound II is controlled below 3 percent, 150ml of dichloromethane is added for extraction, concentrated hydrochloric acid is added, activated carbon is added for decoloration, acetone is used for crystallization, centrifugation and drying, 39.24g of cefotiam hydrochloride (I) is prepared, the yield is 93 percent, the purity is 99.3 percent, and the maximum single impurity content is 0.07 percent.
Claims (4)
1. The preparation method of cefotiam hydrochloride is characterized by comprising the following steps: adding a compound II, a condensing agent, water and an organic solvent into a reaction bottle for dissolving, controlling the temperature at 0-10 ℃, slowly adding aminothiazole acetic acid (III), adding alkali to adjust the pH value, stirring for reacting for 1-2h, controlling the residue of the compound II to be below 3%, adding dichloromethane for extracting, adding concentrated hydrochloric acid, adding activated carbon for decoloring, crystallizing by using acetone, centrifuging and drying to obtain cefotiam hydrochloride (I); the preparation method of the compound II comprises the following steps: adding 1- (2-dimethylaminoethyl) -1,2,3, 4-tetramizole-5-mercaptan (DMMT), boron trifluoride-acetonitrile, acetonitrile and butanol into a reaction tank, controlling the temperature to be 0-5 ℃, slowly dropwise adding 7-ACA, controlling the temperature to be 0-5 ℃, stirring and reacting for 1.5h, adding a proper amount of hydrochloric acid during the reaction process, after the reaction is finished, introducing dry hydrogen chloride gas, crystallizing with acetone, centrifuging and drying to obtain a compound II; the condensing agent is 4, 6-dimethoxy-2-chloro-1, 3, 5-triazine or 2,4, 6-trichloro-1, 3, 5-triazine, and the molar ratio of the condensing agent to the compound II is 1.1: 1; the organic solvent is acetonitrile, acetone, ethyl acetate or N, N-dimethylformamide; the alkali is triethylamine, diethylamine, pyridine or sodium hydroxide, and the mole number of the alkali is 1.5-1 times of that of the compound II; the pH value is 5;
the synthetic route is as follows:
2. the method of claim 1, wherein the condensing agent is 4, 6-dimethoxy-2-chloro-1, 3, 5-triazine.
3. The method of claim 1, wherein the organic solvent is acetonitrile or N, N-dimethylformamide.
4. The method of claim 1, wherein the base is triethylamine or sodium hydroxide.
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| CN110563749A (en) * | 2019-09-11 | 2019-12-13 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of cefotiam hydrochloride compound |
| CN111440197A (en) * | 2020-04-09 | 2020-07-24 | 辽宁美亚制药有限公司 | Preparation method of ceftriaxone sodium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101648961A (en) * | 2009-08-25 | 2010-02-17 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
| CN106967092A (en) * | 2017-04-12 | 2017-07-21 | 山东裕欣药业有限公司 | A kind of preparation method of Cefazedone |
| CN108299469A (en) * | 2017-01-12 | 2018-07-20 | 重庆常捷医药有限公司 | A kind of preparation method of cefotiam chloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101648961A (en) * | 2009-08-25 | 2010-02-17 | 哈药集团制药总厂 | Method and equipment for preparing cefotiam hydrochloride |
| CN108299469A (en) * | 2017-01-12 | 2018-07-20 | 重庆常捷医药有限公司 | A kind of preparation method of cefotiam chloride |
| CN106967092A (en) * | 2017-04-12 | 2017-07-21 | 山东裕欣药业有限公司 | A kind of preparation method of Cefazedone |
Non-Patent Citations (1)
| Title |
|---|
| 头孢替安盐酸盐合成方法研究;王彪;《黑龙江科技信息》;20120405;第4页 * |
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