CN112279869A - Novel production process of ceftiofur - Google Patents
Novel production process of ceftiofur Download PDFInfo
- Publication number
- CN112279869A CN112279869A CN202011316836.4A CN202011316836A CN112279869A CN 112279869 A CN112279869 A CN 112279869A CN 202011316836 A CN202011316836 A CN 202011316836A CN 112279869 A CN112279869 A CN 112279869A
- Authority
- CN
- China
- Prior art keywords
- water
- stirring
- ceftiofur
- filtering
- activated carbon
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J29/00—Catalysts comprising molecular sieves
-
- 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
-
- 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
-
- 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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of a novel production process of ceftiofur, wherein the production method comprises the following steps: synthesizing 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid; adding 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid to dichloromethane, and stirring; slowly dripping triethylamine, and stirring; slowly adding AE-active ester, then adding water, and stirring; standing for layering, and separating out a water phase; adding purified water into the organic phase, stirring, separating out the water phase, combining the water phases, washing with dichloromethane, adding activated carbon into the water phase for decoloring, and performing suction filtration; adjusting the pH value of the filtrate to 2.5, and performing suction filtration; dissolving the filter cake with acetone, adding activated carbon for decolorization, and filtering the activated carbon; slowly dripping water into the acetone solution, crystallizing, filtering, washing and drying to obtain ceftiofur; the purification method is simple, the production period is short, the cost is low, and the method is beneficial to industrial mass production; the method does not use gases with high difficulty and toxicity, and has low production difficulty and low cost.
Description
Technical Field
The invention relates to the field of medical science, in particular to a novel production process of ceftiofur.
Background
Ceftiofur hydrochloride, (6R, 7R) -7- [2- (2-aminothiazole-4-yl) (methoxyimino) acetamido ] -3- [ (2-furylcarbonyl) thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. English name: ceftiifur CAS NO: 103980-44-5, formula: c19h17n5o7s3. hcl. Molecular weight: 560.03. the appearance was off-white to pale yellow powder. Insoluble in water, practically insoluble in ethanol, slightly soluble in acetone and tetrahydrofuran, and readily soluble in dimethyl sulfoxide and N, N-dimethylformamide.
Ceftiofur is a semi-synthetic cephalosporin special for the third generation of animals. Sodium salts and hydrochloride salts are typically prepared for injection. The antibacterial agent has wide antibacterial spectrum and strong antibacterial activity, and has strong antibacterial activity on gram-positive bacteria, gram-negative bacteria and anaerobic bacteria, wherein the gram-positive bacteria and the first generation cephalosporin are similar or weaker, and the antibacterial agent has strong antibacterial activity on gram-negative bacteria such as escherichia coli, salmonella typhi, multi-bactericidal and hemolytic pasteurella, streptococcus and the like. It was successfully developed in the 80's of the 20 th century. The drug is first marketed in the united states in 1988, and is officially approved by several countries in the united states, canada, japan and europe for the treatment of respiratory diseases in beef cattle, dairy cows, horses, pigs and sheep, due to its excellent antibacterial activity and pharmacokinetic characteristics.
The traditional method for preparing ceftiofur sodium uses organic amine with high difficulty and toxicity as a catalyst, so that the cost is high, the environmental pollution is serious, and the health of production operators is greatly influenced.
Disclosure of Invention
The invention aims to provide a novel production process of ceftiofur, which aims to solve the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of a novel production process of ceftiofur, wherein the production method comprises the following steps:
s1: sequentially adding 7-aminocephalosporanic acid, thiofuran formic acid, a solid base catalyst, zeolite and water into a reaction kettle, stirring and reacting for 1.5-2.5h at room temperature, filtering, adjusting the pH of filtrate to 5.5-6.5 by using a proper amount of hydrochloric acid, filtering, washing filter cakes with water to obtain white solid, and performing vacuum drying to obtain 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid;
s2: adding the 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid obtained in the step S1 into dichloromethane, stirring and cooling to-5 ℃, and keeping the temperature constant;
s3: slowly dropwise adding triethylamine, and stirring uniformly after the triethylamine is added for 0.5-1.5 h;
s4: slowly adding AE-active ester, then adding water, and uniformly stirring;
s5: keeping the temperature, standing for 4h, layering into an organic phase and a water phase, and separating out the water phase;
s6: adding purified water into the organic phase obtained in the step S5, stirring for 15min, and separating out a water phase;
s7: combining the water phases obtained in the step S5 and the step S6, washing with dichloromethane, adding activated carbon into the water phase for decoloring for 30min, and performing suction filtration to obtain a filtrate;
s8: adjusting the pH value of the filtrate obtained in the step S7 to 2.5 by using a 4N hydrochloric acid solution at the temperature of 5 ℃, and performing suction filtration to obtain a filter cake;
s9: dissolving the filter cake obtained in the step S8 with acetone, adding activated carbon for decoloring, and filtering the activated carbon to obtain an acetone solution;
s10: and (4) slowly dropwise adding water into the acetone solution obtained in the step S9, crystallizing, filtering, washing, and drying in an oven at 35 ℃ to obtain ceftiofur.
Preferably, the acetone temperature in step S8 is 0-7 ℃.
Preferably, the water temperature in step S10 is 0-7 ℃.
Preferably, the stirring speed in step S3 and step S4 is 150-400r/min, and the stirring time is 1-2 h.
Has the advantages that:
the invention has the beneficial effects that: according to the novel production process of ceftiofur, provided by the invention, the solid base catalyst and zeolite are adopted to catalyze the condensation of 7-aminocephalosporanic acid and thiofuran formic acid, the method is simple to produce and high in safety, the purity of the obtained product can reach 99.2%, the yield can reach 99.0%, the purification method is simple, the production period is short, the cost is low, and the industrial mass production is facilitated; the method does not use gases with high difficulty and toxicity, and has low production difficulty and low cost.
Detailed Description
The technical solution of the present patent will be described in further detail with reference to the following embodiments.
A preparation method of a novel production process of ceftiofur, wherein the production method comprises the following steps: s1: sequentially adding 7-aminocephalosporanic acid, thiofuran formic acid, a solid base catalyst, zeolite and water into a reaction kettle, stirring and reacting for 1.5-2.5h at room temperature, filtering, adjusting the pH of filtrate to 5.5-6.5 by using a proper amount of hydrochloric acid, filtering, washing filter cakes with water to obtain white solid, and performing vacuum drying to obtain 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid; s2: adding the 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid obtained in the step S1 into dichloromethane, stirring and cooling to-5 ℃, and keeping the temperature constant; s3: slowly dropwise adding triethylamine, and stirring uniformly after the triethylamine is added for 0.5-1.5 h; s4: slowly adding AE-active ester, then adding water, and uniformly stirring; s5: keeping the temperature, standing for 4h, layering into an organic phase and a water phase, and separating out the water phase; s6: adding purified water into the organic phase obtained in the step S5, stirring for 15min, and separating out a water phase; s7: combining the water phases obtained in the step S5 and the step S6, washing with dichloromethane, adding activated carbon into the water phase for decoloring for 30min, and performing suction filtration to obtain a filtrate; s8: adjusting the pH value of the filtrate obtained in the step S7 to 2.5 by using a 4N hydrochloric acid solution at the temperature of 5 ℃, and performing suction filtration to obtain a filter cake; s9: dissolving the filter cake obtained in the step S8 with acetone, adding activated carbon for decoloring, and filtering the activated carbon to obtain an acetone solution; s10: and (4) slowly dropwise adding water into the acetone solution obtained in the step S9, crystallizing, filtering, washing, and drying in an oven at 35 ℃ to obtain ceftiofur.
Further, the acetone temperature in step S8 is 0 to 7 ℃.
Further, the water temperature in step S10 is 0-7 ℃.
Further, the stirring speed in step S3 and step S4 is 150-400r/min, and the stirring time is 1-2 h.
Examples
S1: 20kg of 7-aminocephalosporanic acid, 30kg of thiofuran formic acid, 2kg of solid base catalyst, 1kg of zeolite and 250kg of water are sequentially added into a 500L reaction kettle, the mixture is stirred and reacted for 2 hours at room temperature, the filtrate is filtered, the pH of the filtrate is adjusted to 5.5 by using a proper amount of 6N hydrochloric acid, the filtrate is filtered, a filter cake is washed by water to obtain a white solid, and the white solid is dried in vacuum to obtain 37.1kg of 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid with the yield of 99.1 percent and the purity of 99.2 percent (;
s2: adding 20kg of 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid obtained in step S1 to 300kg of dichloromethane, stirring and cooling to-5 ℃, and keeping the temperature constant at-5-0 ℃;
s3: slowly adding 11.9 kg of triethylamine dropwise after about 1 hour, stirring at the stirring speed of 150-400r/min for 1-2 hours,
s4: slowly adding 24.7kg of AE-active ester, then adding 10kg of water, and stirring at the stirring speed of 150-;
s5: keeping the temperature at 5-7 deg.C, standing for 4 hr, separating into organic phase and water phase, separating water phase,
s6: adding 20kg of purified water to the organic phase obtained in step S5, stirring for 15min, and separating out the water phase;
s7: mixing the water phases obtained in the steps S5 and S6, washing with 15L dichloromethane, decolorizing the water phase with 2.5kg activated carbon for 30min, and vacuum filtering to obtain filtrate;
s8: adjusting the pH value of the filtrate obtained in the step S7 to 2.5 by using a 4N hydrochloric acid solution at the temperature of 5 ℃, and performing suction filtration to obtain a filter cake;
s9: dissolving the filter cake obtained in the step S8 with 25kg of acetone at 0-7 ℃, adding 1kg of activated carbon for decolorization, and filtering the activated carbon to obtain an acetone solution;
s10: 100kg of water with the temperature of 0-7 ℃ is slowly dripped into the acetone solution obtained in the step S9, and the ceftiofur 26.3k g is obtained after crystallization, filtration, rinsing by purified water and drying in a 35 ℃ oven, wherein the yield is 85.7 percent and the purity is 98.1 percent (HPLC).
According to the novel production process of ceftiofur, provided by the invention, the solid base catalyst and zeolite are adopted to catalyze the condensation of 7-aminocephalosporanic acid and thiofuran formic acid, the method is simple to produce and high in safety, the purity of the obtained product can reach 99.2%, the yield can reach 99.0%, the purification method is simple, the production period is short, the cost is low, and the industrial mass production is facilitated; the method does not use gases with high difficulty and toxicity, and has low production difficulty and low cost.
The embodiments described above are preferred embodiments of the present invention, and not all embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (4)
1. The preparation method of the novel production process of ceftiofur is characterized by comprising the following steps:
s1: sequentially adding 7-aminocephalosporanic acid, thiofuran formic acid, a solid base catalyst, zeolite and water into a reaction kettle, stirring and reacting for 1.5-2.5h at room temperature, filtering, adjusting the pH of filtrate to 5.5-6.5 by using a proper amount of hydrochloric acid, filtering, washing filter cakes with water to obtain white solid, and performing vacuum drying to obtain 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid;
s2: adding the 7-amino-3- [ (2-furyl-carbonyl) -thiomethyl ] -3-cephem-4-carboxylic acid obtained in the step S1 into dichloromethane, stirring and cooling to-5 ℃, and keeping the temperature constant;
s3: slowly dropwise adding triethylamine, and stirring uniformly after the triethylamine is added for 0.5-1.5 h;
s4: slowly adding AE-active ester, then adding water, and uniformly stirring;
s5: keeping the temperature, standing for 4h, layering into an organic phase and a water phase, and separating out the water phase;
s6: adding purified water into the organic phase obtained in the step S5, stirring for 15min, and separating out a water phase;
s7: combining the water phases obtained in the step S5 and the step S6, washing with dichloromethane, adding activated carbon into the water phase for decoloring for 30min, and performing suction filtration to obtain a filtrate;
s8: adjusting the pH value of the filtrate obtained in the step S7 to 2.5 by using a 4N hydrochloric acid solution at the temperature of 5 ℃, and performing suction filtration to obtain a filter cake;
s9: dissolving the filter cake obtained in the step S8 with acetone, adding activated carbon for decoloring, and filtering the activated carbon to obtain an acetone solution;
s10: and (4) slowly dropwise adding water into the acetone solution obtained in the step S9, crystallizing, filtering, washing, and drying in an oven at 35 ℃ to obtain ceftiofur.
2. The preparation method of the novel production process of ceftiofur according to claim 1, which is characterized in that: the acetone temperature in step S8 is 0-7 ℃.
3. The preparation method of the novel production process of ceftiofur according to claim 1, which is characterized in that: the water temperature in step S10 is 0-7 ℃.
4. The preparation method of the novel production process of ceftiofur according to claim 1, which is characterized in that: the stirring speed in the step S3 and the step S4 is 150-.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011316836.4A CN112279869A (en) | 2020-11-20 | 2020-11-20 | Novel production process of ceftiofur |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011316836.4A CN112279869A (en) | 2020-11-20 | 2020-11-20 | Novel production process of ceftiofur |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112279869A true CN112279869A (en) | 2021-01-29 |
Family
ID=74398456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011316836.4A Withdrawn CN112279869A (en) | 2020-11-20 | 2020-11-20 | Novel production process of ceftiofur |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112279869A (en) |
-
2020
- 2020-11-20 CN CN202011316836.4A patent/CN112279869A/en not_active Withdrawn
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2004108953A (en) | POLYMORPHIC FORMS OF RIFAXIMINE, METHODS FOR THEIR PRODUCTION AND THEIR APPLICATION IN MEDICAL DRUGS | |
| SU753361A3 (en) | Method of preparing 7-acylamino-3-cephem-4-carboxylic acid unsaturated derivatives or their salts | |
| JP2006511561A (en) | Crystalline cefdinir salt | |
| WO2013189117A1 (en) | One-step synthesizing method of levofloxacin and ofloxacin | |
| CA1274821A (en) | .beta.-LACTAM ANTIBIOTICS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS OR GROWTH-PROMOTERS IN LIVESTOCK REARING OR AS ANTIOXIDANTS | |
| CN101220040A (en) | Preparation of cefixime cephalosporin and fine purification method | |
| EP2385054B1 (en) | Cefdinir acid double salt and its preparation | |
| CN101735250B (en) | Synthesis method of ceftezole sodium compound | |
| DK174331B1 (en) | Crystallized cephemic acid addition salts, its preparation and use in the manufacture of a medicament, and medicament containing the salt | |
| CN103319503A (en) | Preparation method of cefdinir | |
| CN112279869A (en) | Novel production process of ceftiofur | |
| CN101654458A (en) | Preparation method of hydrochloric acid ceftiofur | |
| CN105859747B (en) | A kind of preparation method of cefepime Hydrochloride suitable for industrialized production | |
| AU2006300882B2 (en) | Crystalline sodium salt of cephalosporin antibiotic | |
| CN102559829A (en) | Synthetic method of ceftriaxone sodium crude salt | |
| CN106046024B (en) | A kind of preparation method of Cefpodoxime Proxetil | |
| CN115093432A (en) | Preparation process of ceftiofur sodium | |
| CN108299469B (en) | Preparation method of cefotiam hydrochloride | |
| GB2043070A (en) | Preparation of sodium cefuroxime | |
| WO2013010297A1 (en) | Method for purifying ceftizoxime sodium | |
| CN109232609B (en) | Method for preparing high-purity cefpodoxime proxetil | |
| CN113185538B (en) | Preparation method of cefpodoxime acid | |
| CN111233894B (en) | Cefditoren pivoxil delta3Process for the preparation of isomers | |
| US6555679B2 (en) | Method for preparation of ceftiofur sodium from its hydrohalide salts | |
| CN110563750B (en) | Synthesis method of cefazedone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20210129 |