CN111187284A - Preparation method of cefaclor - Google Patents
Preparation method of cefaclor Download PDFInfo
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- CN111187284A CN111187284A CN202010163311.5A CN202010163311A CN111187284A CN 111187284 A CN111187284 A CN 111187284A CN 202010163311 A CN202010163311 A CN 202010163311A CN 111187284 A CN111187284 A CN 111187284A
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- cefaclor
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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
- C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
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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 cefaclor, which comprises the following steps: salifying 7-amino-3-chloro-cephalosporanic acid and organic base, performing acylation condensation reaction on the salified reaction liquid and activated reaction liquid of D-phenylglycine and trifluoroacetic acid succinimide, performing acidolysis and decoloration, filtering, dripping filtrate into water, adjusting the pH value to the isoelectric point of cefaclor by using alkali, performing crystal growth, filtering, washing and drying to obtain cefaclor. Through the mode, the preparation method of cefaclor provided by the invention is short in process route, can directly obtain cefaclor by adopting a one-step method, saves the process time, greatly saves the cost of production raw materials, improves the quality yield of the product, has high purity and good color grade of the product, and can realize large-scale production.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a preparation method of cefaclor.
Background
Cefaclor is a semisynthetic second-generation oral cephalosporin, has strong killing effect on various gram-positive bacteria and gram-negative bacteria, has high efficiency, broad spectrum and better chemical stability, and is one of important medicaments for clinically treating bacterial infection at present. Since the successful marketing of cefaclor in the seventies of the twentieth century, cefaclor has been widely applied and highly advocated by people because of its broad spectrum, high efficiency and good clinical safety. The chemical formula is as follows:
traditionally, cefaclor is prepared by generally adopting 7-amino-3-chloro-cephalosporanic acid as a raw material to react with nitrogen-containing organic base, carrying out acylation reaction in the presence of a catalyst, adding N, N-dimethylformamide to form a compound, and converting to obtain the cefaclor raw material medicament. The method has the advantages of long process steps, high synthesis difficulty, low product yield and poor color grade, so that the production cost of cefaclor is high, the sale price is very expensive, the wide application of cefaclor products is limited, and the wide-range clinical application cannot be obtained particularly in insuffient developing countries.
The preparation method of cefaclor disclosed in patent CN102796120 is as follows:
salifying 7-amino-3-chloro-cephalosporanic acid and nitrogen-containing organic base, carrying out acylation condensation reaction on a mixed acid anhydride solution obtained by phenylglycine dane salt and pivaloyl chloride under the action of a catalyst, adding acid for hydrolysis and decoloring, filtering, dripping filtrate into water, adjusting the pH value to the isoelectric point of cefaclor by using alkali, growing crystals, filtering, washing and drying to obtain cefaclor.
The preparation method of cefaclor disclosed in patent CN103757085 is as follows:
in the presence of enzyme, 7, A, C, A and D, phenylglycine methyl ester salt derivative form a reaction mixed solution to react to generate cefaclor, wherein cefaclor seed crystals are added into the reaction mixed solution before the generated cefaclor is precipitated.
The cefaclor preparation method has the defects of high production cost, high pollution of used reagents, low product yield and the like.
Disclosure of Invention
The invention mainly solves the technical problem of providing a preparation method of cefaclor, which has simple process route and low raw material cost.
In order to solve the technical problems, the invention adopts a technical scheme that: the preparation method of cefaclor is provided, which comprises the following steps:
salifying 7-amino-3-chloro-cephalosporanic acid and organic base, performing acylation condensation reaction on the salified reaction liquid and activated reaction liquid of D-phenylglycine and trifluoroacetic acid succinimide, performing acidolysis and decoloration, filtering, dripping filtrate into water, adjusting the pH value to the isoelectric point of cefaclor by using alkali, performing crystal growth, filtering, washing and drying to obtain cefaclor.
The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the solvent used for the dissolution and salt formation of 7-amino-3-chlorocephalosporanic acid (7-ACCA) and tetramethylguanidine is dichloromethane.
Preferably, the temperature at which the 7-amino-3-chlorocephalosporanic acid (7-ACCA) and tetramethylguanidine dissolve to form a salt is 0 ℃.
Preferably, the solvent used for activating the D-phenylglycine is dichloromethane.
Preferably, the activation reaction temperature of D-phenylglycine is 25 ℃.
Preferably, in the activation reaction of D-phenylglycine, the ratio of D-phenylglycine: trifluoroacetic acid succinimide: the molar ratio of triethylamine is 1:1.1: 2.
Preferably, the condensation reaction temperature is 10-30 ℃.
Preferably, the base used for adjusting the pH is 10% by mass of aqueous ammonia.
Preferably, the pH is 4 to 6.
Preferably, the temperature for growing the crystals is 0 ℃.
Preferably, the time for growing the crystals is 2 hours.
The invention has the beneficial effects that: according to the invention, trifluoroacetic acid succinimide is adopted to activate the carboxyl of D-phenylglycine, so that the yield of the condensation reaction is improved, and acyl chloride or acid anhydride and other reagents with high toxicity and large pollution are avoided, and the preparation method is green and environment-friendly. The adopted organic solvent is single and recyclable, the solubility of the 7-ACCA and the nitrogenous organic base after salification is increased, the reaction activity is greatly improved, the reaction yield is indirectly improved, the reaction is mild, the treatment is simple, and the method is suitable for industrial production.
Detailed Description
Example 1
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 20 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, filtering after decoloring aqueous phase activated carbon, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 5, growing crystals at 0 ℃ for 2h, filtering, and drying a filter cake to obtain 75g of cefaclor with the yield of 95.8%.
Example 2
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 10 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, filtering after decoloring aqueous phase activated carbon, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 5, growing crystals at 0 ℃ for 2h, filtering, and drying a filter cake to obtain 73g of cefaclor, wherein the yield is 93.2%.
Example 3
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 30 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, filtering after decoloring aqueous phase activated carbon, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 5, growing crystals at 0 ℃ for 2h, filtering, and drying a filter cake to obtain 70g of cefaclor with the yield of 89.4%.
Example 4
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 20 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, filtering after decoloring aqueous phase activated carbon, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 4, growing crystals at 0 ℃ for 2h, filtering, and drying a filter cake to obtain 69g of cefaclor, wherein the yield is 88.1%.
Example 5
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 20 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, filtering after decoloring aqueous phase activated carbon, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 6, growing crystals at 0 ℃ for 2h, filtering, and drying a filter cake to obtain 71g of cefaclor with the yield of 90.7%.
Comparative example 1
According to patent CN102796120, prepared as follows:
weighing 7-amino-3-chloro cephalosporanic acid 50g, dissolving in dichloromethane 250ml, adding into a 500ml four-mouth reaction bottle, cooling the reaction system to-10 ℃ -5 ℃, adding tetramethylguanidine 36g, and stirring for 30 minutes to obtain 7-amino-3-chloro cephalosporanic acid solution; adding 200ml of dichloromethane and 100ml of N, N-dimethylacetamide into a 1000ml four-mouth reaction flask, weighing 78g of phenylglycine dane salt and 0.05g of 4-dimethylaminopyridine, adding the weighed materials into the mixed solution, stirring for 10 minutes, putting the four-mouth reaction flask into liquid nitrogen to reduce the temperature of a reaction system to-35 ℃ -30 ℃, dropwise adding 31.8g of pivaloyl chloride into the reaction flask, and stirring and reacting for 1 hour at the temperature of-75 ℃ -65 ℃ to obtain a mixed anhydride solution; dropwise adding the 7-amino-3-chloro cephalosporanic acid solution prepared in the step (1) into the mixed anhydride solution prepared in the step (2), reacting for 4 hours at the temperature of-50 ℃ -40 ℃, tracking and detecting the reaction end point through high performance liquid chromatography, adding 350g of deionized water and 55g of concentrated hydrochloric acid into the system when the content of the 7-amino-3-chloro cephalosporanic acid in the system is less than 2mg/ml after the reaction is finished, stirring for 30 minutes, and standing for layering to obtain an upper layer which is a water solution formed by cefaclor and acid; adding activated carbon into a water solution of cefaclor and acid salt for decoloring, filtering to obtain a filtrate, adding 75g of purified water into a reaction bottle, dropwise adding the filtrate into the water while dropwise adding ammonia water with the mass percent of 10%, adjusting the pH value of the solution in the reaction bottle to the isoelectric point of cefaclor until the filtrate is completely crystallized, growing the crystals for 2 hours, filtering, washing with purified water, and drying to obtain 72.5g of cefaclor with the yield of 92.6%.
Comparative example 2
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 0 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, filtering after decoloring aqueous phase activated carbon, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 5, growing crystals at 0 ℃ for 2h, filtering, and drying a filter cake to obtain 65g of cefaclor with the yield of 83%.
Comparative example 3
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 40 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, decoloring the water phase with activated carbon, filtering, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 5, growing the crystals at 0 ℃ for 2h, filtering, and drying the filter cake to obtain 63g of cefaclor, wherein the yield is 80.46%.
Comparative example 4
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 20 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, decoloring the water phase with active carbon, filtering, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 3, growing the crystals at 0 ℃ for 2h, filtering, and drying the filter cake to obtain 50g of cefaclor with the yield of 63.8%.
Comparative example 5
Weighing 50g of 7-amino-3-chloro cephalosporanic acid and 250ml of dichloromethane in 500ml of sikou ping, cooling to-10 ℃, adding 36g of tetramethyl guanidine, stirring for 30min at 0 ℃ to obtain a 7-amino-3-chloro cephalosporanic acid solution, and protecting with nitrogen at 0 ℃ for later use.
32.2g of D-phenylglycine, 43g of triethylamine and 45.7g of trifluoroacetic acid succinimide are put in 200ml of dichloromethane to react for 2 hours at 25 ℃, then the temperature is reduced to 0 ℃, 7-amino-3-chloro cephalosporanic acid solution is slowly dropped into the dichloromethane to react for 2 hours at 20 ℃. And (3) dripping 4M HCl into the reaction solution to adjust the PH value to 2, stirring for 2h at room temperature, standing for layering, decoloring the water phase with activated carbon, filtering, dripping 10 wt% ammonia water into the filtrate, adjusting the PH value to 7, growing the crystals at 0 ℃ for 2h, filtering, and drying the filter cake to obtain 62g of cefaclor with the yield of 79.2%.
| Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | |
| Condensation temperature C | 20 | 10 | 30 | 20 | 20 | -50~-40 | 0 | 40 | 20 | 20 |
| pH of crystallization | 5 | 5 | 5 | 4 | 6 | 4-5 | 5 | 5 | 3 | 7 |
| Yield% | 95.8 | 93.2 | 89.4 | 88.1 | 90.7 | 92.6 | 83 | 80.46 | 63.8 | 79.2 |
By integrating the embodiments and the comparative examples, under the preferable conditions, the yield of the method is high, the carboxyl of the D-phenylglycine is activated by adopting the trifluoroacetic acid succinimide, the condensation reaction yield is improved, the use of reagents with large toxicity, such as acyl chloride or acid anhydride, and the like is avoided, and the method is green and environment-friendly. The adopted organic solvent is single and recyclable, the solubility of the 7-ACCA and the nitrogenous organic base after salification is increased, the reaction activity is greatly improved, the reaction yield is indirectly improved, the reaction is mild, the treatment is simple, and the method is suitable for industrial production.
Claims (10)
1. A preparation method of cefaclor is characterized by comprising the following steps:
dissolving 7-amino-3-chloro cephalosporanic acid (7-ACCA) and tetramethylguanidine in dichloromethane at 0 ℃ to form salt, and obtaining a solution for later use; activating D-phenylglycine and trifluoroacetic acid succinimide in a dichloromethane solution of triethylamine, then dripping into a 7-ACCA solution at 0 ℃, preserving heat at 20 ℃, reacting for 3 hours, adding acid for hydrolysis, separating liquid to obtain a cefaclor salt aqueous solution, decoloring with activated carbon, adjusting pH with ammonia water until solid is separated out, growing crystals at 0 ℃ for 2 hours, filtering, and drying to obtain cefaclor.
2. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the solvent used for the dissolution and salt formation of 7-amino-3-chlorocephalosporanic acid (7-ACCA) and tetramethylguanidine is dichloromethane.
3. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the temperature at which 7-amino-3-chlorocephalosporanic acid (7-ACCA) and tetramethylguanidine dissolve to form salt is 0 ℃.
4. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the solvent used for activating D-phenylglycine is dichloromethane.
5. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the activation reaction temperature of D-phenylglycine is 25 ℃.
6. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the ratio of D-phenylglycine: trifluoroacetic acid succinimide: the molar ratio of triethylamine is 1:1.1: 2.
7. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the condensation reaction temperature is 10-30 ℃.
8. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the base used for adjusting the pH is 10% by mass of aqueous ammonia.
9. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the PH is 4-6.
10. The improved process for the synthesis of cefaclor as claimed in claim 1, wherein the crystallization temperature is 0 ℃ and the crystallization time is 2 h.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1328340A (en) * | 1970-12-17 | 1973-08-30 | Smith Kline French Lab | 3-heterocyclic thiomethylcephalosporins |
| US20020198375A1 (en) * | 2000-12-04 | 2002-12-26 | Pfizer Inc. | Coupling process and intermediates useful for preparing cephalosporins |
| WO2011055247A1 (en) * | 2009-11-09 | 2011-05-12 | Jawaharlal Nehru Centre For Advanced Scientific Research | A synthetic cyclic dipeptide and a process thereof |
| CN102796120A (en) * | 2012-08-24 | 2012-11-28 | 苏州中联化学制药有限公司 | Method for preparing cefaclor |
| CN104610280A (en) * | 2015-02-12 | 2015-05-13 | 浙江东邦药业有限公司 | Preparation method of cephalotin acid |
-
2020
- 2020-03-10 CN CN202010163311.5A patent/CN111187284A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1328340A (en) * | 1970-12-17 | 1973-08-30 | Smith Kline French Lab | 3-heterocyclic thiomethylcephalosporins |
| US20020198375A1 (en) * | 2000-12-04 | 2002-12-26 | Pfizer Inc. | Coupling process and intermediates useful for preparing cephalosporins |
| WO2011055247A1 (en) * | 2009-11-09 | 2011-05-12 | Jawaharlal Nehru Centre For Advanced Scientific Research | A synthetic cyclic dipeptide and a process thereof |
| CN102796120A (en) * | 2012-08-24 | 2012-11-28 | 苏州中联化学制药有限公司 | Method for preparing cefaclor |
| CN104610280A (en) * | 2015-02-12 | 2015-05-13 | 浙江东邦药业有限公司 | Preparation method of cephalotin acid |
Non-Patent Citations (1)
| Title |
|---|
| 虞正烨 等: "一种绿色安全的头孢噻吩酸合成工艺", 《浙江化工》 * |
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