CN101481381B - Method for preparing ciprofloxacin by piperazine reaction - Google Patents
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 60
- 229960003405 ciprofloxacin Drugs 0.000 title claims abstract description 42
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 21
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052751 metal Inorganic materials 0.000 claims abstract description 12
- 239000002184 metal Substances 0.000 claims abstract description 12
- 239000000706 filtrate Substances 0.000 claims abstract description 10
- 239000000047 product Substances 0.000 claims abstract description 10
- 239000011968 lewis acid catalyst Substances 0.000 claims abstract description 9
- 239000002841 Lewis acid Substances 0.000 claims abstract description 8
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 239000012752 auxiliary agent Substances 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical class [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical class OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- HDYRYUINDGQKMC-UHFFFAOYSA-M acetyloxyaluminum;dihydrate Chemical compound O.O.CC(=O)O[Al] HDYRYUINDGQKMC-UHFFFAOYSA-M 0.000 claims description 2
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 claims description 2
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical group [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940009827 aluminum acetate Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical class OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 229910052742 iron Chemical group 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 239000010452 phosphate Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical class [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 10
- -1 aluminum (III) Lewis acid Chemical class 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000004904 shortening Methods 0.000 abstract description 2
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 238000001953 recrystallisation Methods 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 229960001229 ciprofloxacin hydrochloride Drugs 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000010812 external standard method Methods 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- 238000004042 decolorization Methods 0.000 description 4
- 229960001484 edetic acid Drugs 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 0 *c(cc(c1c2)N(C3CC3)C=C(C(O)=O)C1=O)c2F Chemical compound *c(cc(c1c2)N(C3CC3)C=C(C(O)=O)C1=O)c2F 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012434 nucleophilic reagent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- RSSNICRIXPNUQK-UHFFFAOYSA-N 1-chlorocyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(Cl)CC1 RSSNICRIXPNUQK-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229940058302 antinematodal agent piperazine and derivative Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 238000012658 bimolecular nucleophilic substitution Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000012822 chemical development Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a method for preparing ciprofloxacin by piperazine reaction. The technical problems to be solved are as follows: (1) reducing amount of a solvent or using no solvent, (2) reducing consumption of the piperazine, and (3) shortening the reaction time, simplifying operation, and enhancing overall yield. The method is characterized by (a) mixing the piperazine as shown in formula (iii) with the cyclopropane carboxylic acid as shown formula (ii) at the mol ratio of 1-10:1, adding metal Lewis acid catalyst with the chemical equivalent of 1%-30% for thorough reaction in an aqueous system at the temperature of 80-150 DEG C to obtain reaction solution, wherein, the metal Lewis acid catalyst is selected from one or more of aluminum (III) Lewis acid and iron (III) Lewis acids; (b) adding inorganic base to the reaction solution at the temperature of 20 DEG C-100 DEG C to regulate pH value of the reaction system to 9-12, and filtering while the system is hot; and (c) regulating the pH value of the filtrate to 7-8 with the inorganic base for recrystallization to obtain the product.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing ciprofloxacin through piperazification.
Background
Ciprofloxacin, 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid, is one of the excellent representatives of the third generation of quinolones, successfully synthesized in 1981 by the German Bayer pharmaceutical industry, and has the following structure:
ciprofloxacin is mainly prepared by condensing receptor fluoroquinolone with nucleophilic reagent piperazine and derivatives thereof (hereinafter referred to as piperazification reaction), and the reaction is as follows:
wherein,
x is F, Cl or Ms,
r ═ H or c (o) OEt.
The piperazilation reaction is bimolecular nucleophilic substitution reaction, and the property of a leaving group, the activity of a nucleophilic reagent, solvent conditions, reaction temperature, time, an additive and the like influence the conversion rate and the condensation efficiency of the condensation reaction.
When X is F or Ms, the leaving performance is good, C-6 competitive reaction byproducts can be avoided, but the raw material cost is high;
when R ═ c (o) OEt, the piperazination yield can be improved, but the raw material cost is high;
in the research of preparing ciprofloxacin by the condensation reaction of 7-site chlorocyclopropane carboxylic acid and piperazine, the selection of a reaction medium, namely a solvent system is emphasized.
The review of this condensation process by liu yong et al (vol. 7 of 2002. 21. of chemical development) at the university of tianjin indicated that the aprotic solvent did not solvate with the nucleophile and facilitated the condensation reaction, and the solvents studied earlier were usually aprotic solvents DMSO, DMF, acetonitrile, pyridine, etc., but such reaction media are very harmful to the environment during production.
Piperazine reaction yield after 7 hours in isoamyl alcohol solvent was 73.7%.
In order to overcome the harm of reaction medium to environment in production, a mild aqueous solution system with strong polarity and protonicity can be used for substitution, the condensation yield of 7-position chlorine substituent is 65%, and the yield of 6-position fluorine substituent impurity is 8% -10% (U.R. Kalkote, Tetrahedron Letter1996, 37, 6785).
The research on the feasibility of ciprofloxacin hydrochloride crystallization is carried out by national industrial crystallization technology research and popularization center entrusted to Tianjin university at a certain pharmaceutical factory in China, and an undisclosed solvent system B, an optimal material ratio and ciprofloxacin (g) are determined: anhydrous piperazine (g): the feeding amount ratio of the solvent B (ml) is 1: 2: 5, reacting for 6-7 hours at the proper temperature of 128-131 ℃, decompressing and recovering the solvent and part of piperazine from the mixture obtained by condensation, adding water and acid for dissolving, decoloring and filtering, and adjusting the pH value to be neutral to obtain a mixture of ciprofloxacin and a 6-position competition reaction byproduct, wherein the condensation yield is 93%; and crystallizing to obtain ciprofloxacin hydrochloride, wherein the yield of ciprofloxacin hydrochloride is 76-77% in terms of ciprofloxacin, and the HPLC purity is 93%. The technology is still an organic solvent system, the reaction time is long, and the yield is required to be improved.
Disclosure of Invention
The technical problems to be solved by the invention are 1) reducing or not using solvent, 2) reducing the using amount of piperazine, and 3) shortening reaction time, simplifying operation and improving overall yield.
The method for preparing ciprofloxacin by piperazification reaction is characterized in that,
a) and (b) mixing piperazine shown in formula (iii) and cyclopropane carboxylic acid shown in formula (ii) in a molar ratio of 1-10: 1, (preferably 3-6: 1, more preferably 3-4: 1) adding a metal Lewis acid catalyst with a chemical equivalent of 1% -30%, and fully reacting in an aqueous system at 80 ℃ -150 ℃ (preferably 80 ℃ -114 ℃, or 115 ℃ -130 ℃) to obtain a reaction solution containing a formula (i), wherein the reaction formula is as follows:
the metal Lewis acid catalyst is one or more of aluminum (III) Lewis acid and iron (III) Lewis acid;
b) adding inorganic base (or aqueous solution thereof) into the reaction solution at the temperature of 20-100 ℃ to adjust the pH value of the reaction system to 9-12, and filtering while the reaction solution is hot;
c) and adding inorganic acid into the filtrate to adjust the pH value to 7-8, and crystallizing to obtain a product (ciprofloxacin crude product).
The water contained in the reaction system may be water in the reactant solution, or may be water added to the reaction system (or a combination thereof), and the total weight of water in the reaction system is within 8 times of the weight of the cyclopropanecarboxylic acid. The reaction can be smoothly carried out in the presence of water in the system without using an organic solvent.
Adding an auxiliary agent after the step a) is finished, wherein the molar amount of the auxiliary agent is 1-5 times that of the metal Lewis acid; the auxiliary agent is selected from one or more of benzoic acid, tartaric acid, citric acid, oxalic acid, EDTA, commercially available soluble salts of EDTA, phosphate, hydrogen phosphate, dihydrogen phosphate, halide, fluoride, and hydrates of the above salts. The auxiliary agent can form a water-soluble complex with metal in Lewis acid in water or can precipitate the metal out of the water, thereby effectively controlling the content of metal ions in the ciprofloxacin.
The Lewis acid catalyst has a general formula of MXYZ, wherein M is aluminum (III) or iron (III), and X, Y and Z are respectively and independently selected from halogen, nitrogen, phosphorus, oxygen, hydroxyl, alkoxy and alkyl acetoxyl; alternatively, the lewis acid catalyst is a hydrate thereof.
The invention adds metal Lewis acid catalyst in piperazine reaction, adopts water phase reaction, and controls the water quantity of the reaction system, thereby greatly improving the reaction efficiency.
The invention has the advantages that:
1) and the solvent-free aqueous phase reaction is adopted, so that the environmental pollution is greatly reduced.
2) The usage amount and consumption of piperazine are reduced, and the production cost is reduced.
3) The reaction speed is accelerated, the production period is shortened, and the energy consumption is reduced; the total yield is improved by about 5 percent compared with the prior traditional process.
Detailed Description
The invention is further described below by way of examples, which are provided for illustrative purposes only and are not intended to limit the scope of the invention.
Example 1:
a) 100.0g of cyclopropanecarboxylic acid and six-membered carboxylic acid were put into a 1L four-necked flask141.2g of pentapiperazine, slowly heating to 70-80 ℃, adding 3g of catalyst anhydrous aluminum trichloride, heating to about 120 ℃, carrying out reflux reaction for 1-3 h, and monitoring by TLC to complete the reaction. b) Adding an auxiliary agent Na2HPO415g, dropwise adding 18.5g/50ml of NaOH/water solution, and adjusting the pH value of the reaction system to 9-12; after the dropwise addition, stirring is continued for 20min, 3g of activated carbon is added, reflux decolorization is carried out for 0.5h, and the mixture is filtered while the mixture is hot (the filtering temperature is kept above 80 ℃). c) Adjusting the pH value of the filtrate to 7-8 by using hydrochloric acid, stirring at room temperature for crystallization, heating to 70-80 ℃, stirring for 0.5h, filtering while hot, and washing a filter cake for 3 times by using 150ml of hot purified water at about 50 ℃; and drying the filter cake to obtain a crude ciprofloxacin product which is a light yellow solid and about 116 g. The crude yield was 99%.
And (3) HPLC analysis and detection: purity: 94.8%, 6-position fluorine substituted impurity (Rf ═ 1.2): 4.1%, decarboxylates: 0.02%, ethylenediamine analog: 0.09%, unknown impurity a (Rf ═ 0.15): 0.14%, unknown impurity B (Rf ═ 1.8): 0.8 percent. Measuring the chromatographic content by an external standard method: 85.0 percent. The actual conversion yield was 85.0% × 99% ═ 84.1%.
The ciprofloxacin hydrochloride is prepared by salifying and refining according to a literature method, the total yield is 78 percent based on the ciprofloxacin, and the quality of the ciprofloxacin accords with the standard of European pharmacopoeia.
Example 2:
a) 100.0g of cyclopropanecarboxylic acid and 61.2g of anhydrous piperazine are put into a 1L four-mouth bottle, slowly heated to 70-80 ℃, added with 5g of catalyst crystalline aluminum trichloride and 100g of purified water, heated to about 115 ℃, refluxed for 3-4 h, and monitored by TLC to be completely reacted. b) Adding 6g of auxiliary agent potassium benzoate, dropwise adding 18.5g/50ml of NaOH/water solution, and adjusting the pH value of the reaction system to 9-12; after the dropwise addition, stirring is continued for 20min, 3g of activated carbon is added, reflux decolorization is carried out for 0.5h, and the mixture is filtered while the mixture is hot (the filtering temperature is kept above 80 ℃). c) Adjusting the pH value of the filtrate to 7-8 with hydrochloric acid, stirring at room temperature for crystallization, heating to 70-80 ℃, stirring for 0.5h, filtering while hot, and washing a filter cake with 150ml of hot purified water at about 50 ℃ for 3 times; and drying the filter cake to obtain a crude ciprofloxacin product which is a light yellow solid and is about 112.5 g. The crude yield was 96%.
And (3) HPLC analysis and detection: purity: 94.3%, 6-position fluorine substituted impurity (Rf ═ 1.2): 4.45%, decarboxylate: 0.04%, ethylenediamine analog: 0.1%, unknown impurity a (Rf ═ 0.15): 0.16%, unknown impurity B (Rf ═ 1.8): 0.9 percent. Measuring the chromatographic content by an external standard method: 82.0 percent. The actual conversion yield was 82.0% × 96% ═ 78.7%.
The ciprofloxacin hydrochloride is prepared by salifying and refining according to a literature method, the total yield is 74.4 percent based on the ciprofloxacin, and the quality of the ciprofloxacin accords with the standard of European pharmacopoeia.
Example 3:
a) 100.0g of cyclopropanecarboxylic acid and 188.3g of hexapentapiperazine are put into a 1L four-mouth bottle, slowly heated to 70-80 ℃, added with 6g of catalyst aluminum sulfate, heated to about 120 ℃, refluxed for 1-3 h, and monitored by TLC to complete the reaction. b) Dropwise adding 18.5g/50ml of NaOH/water solution, and adjusting the pH value of the reaction system to 9-12; after the dropwise addition, stirring is continued for 20min, 3g of activated carbon is added, reflux decolorization is carried out for 0.5h, and the mixture is filtered while the mixture is hot (the filtering temperature is kept above 80 ℃). c) Adjusting the pH value of the filtrate to 7-8 by using hydrochloric acid, stirring at room temperature for crystallization, heating to 70-80 ℃, stirring for 0.5h, filtering while hot, and washing a filter cake for 3 times by using 150ml of hot purified water at about 50 ℃; and drying the filter cake to obtain a crude ciprofloxacin product which is a light yellow solid and about 116 g. The crude yield was 99%.
And (3) HPLC analysis and detection: purity: 95.2%, substitution of the 6-position fluorine for the impurity (Rf ═ 1.2): 3.8%, decarboxylates: 0.02%, ethylenediamine analog: 0.08%, unknown impurity a (Rf ═ 0.15): 0.1%, unknown impurity B (Rf ═ 1.8): 0.75 percent. Measuring the chromatographic content by an external standard method: 86.7 percent. The actual conversion yield was 86.7% × 99% ═ 85.8%.
The ciprofloxacin hydrochloride is prepared by salifying and refining according to a literature method, the total yield is 78 percent based on the ciprofloxacin, and the quality of the ciprofloxacin accords with the standard of European pharmacopoeia.
Example 4:
a) 50.0g of cyclopropanecarboxylic acid and 150g of anhydrous piperazine are put into a 1L four-mouth bottle, slowly heated to 70-80 ℃, added with 5g of catalyst aluminum acetate and 300g of purified water, heated to about 110 ℃, refluxed for 6-8 h, and monitored by TLC to be completely reacted. b) Dropwise adding 9g/30ml of NaOH/water solution, and adjusting the pH value of the reaction system to 9-12; after the dropwise addition, stirring is continued for 20min, 1.5g of activated carbon is added, reflux decolorization is carried out for 0.5h, and the mixture is filtered while the mixture is hot (the filtering temperature is kept above 80 ℃). c) Adjusting the pH value of the filtrate to 7-8 by using hydrochloric acid, stirring at room temperature for crystallization, heating to 70-80 ℃, stirring for 0.5h, filtering while hot, and washing a filter cake for 3 times by using 100ml of hot purified water at about 50 ℃; and drying a filter cake to obtain a crude ciprofloxacin product which is a light yellow solid and about 54.5 g. The crude yield was 93%.
And (3) HPLC analysis and detection: purity: 93.7%, substitution of the 6-position fluorine for the impurity (Rf ═ 1.2): 4.9%, decarboxylates: 0.05%, ethylenediamine analog: 0.12%, unknown impurity a (Rf ═ 0.15): 0.18%, unknown impurity B (Rf ═ 1.8): 1.0 percent. Measuring the chromatographic content by an external standard method: 80.0 percent. The actual conversion yield was 80.0% × 93% ═ 74.4%.
The ciprofloxacin hydrochloride is prepared by salifying and refining according to a literature method, the total yield is 72 percent based on the cyclopropanecarboxylic acid, and the quality meets the standard of European pharmacopoeia.
Example 5:
100.0g of cyclopropanecarboxylic acid and 141.2g of hexapentapiperazine are put into a 1L four-mouth bottle, slowly heated to 70-80 ℃, added with 7g of catalyst ferric trichloride hydrate, heated to about 120 ℃, refluxed for 3-5 h, and monitored by TLC to complete the reaction. Adding an auxiliary agent Ethylene Diamine Tetraacetic Acid (EDTA), dropwise adding 18.5g/50ml of NaOH/water solution, adjusting the pH value of the reaction system to 9-12, continuously stirring for 20min after dropwise adding, adding 3g of activated carbon, refluxing and decoloring for 0.5h, and filtering while hot (keeping the filtering temperature above 80 ℃); adjusting the pH value of the filtrate to be neutral (7-8) by hydrochloric acid, stirring at room temperature for crystallization, heating to 70-80 ℃, stirring for 0.5h, filtering, and washing a filter cake for 3 times by using 150ml of hot purified water with the temperature of about 50 ℃; and drying the filter cake to obtain a crude ciprofloxacin product which is about 116g of a light yellow solid. The crude yield was 99%.
And (3) HPLC analysis and detection: purity: 94.2%, 6-position fluorine substituted impurity (Rf ═ 1.2): 4.6%, decarboxylates: 0.03%, ethylenediamine analog: 0.08%, unknown impurity a (Rf ═ 0.15): 0.15%, unknown impurity B (Rf ═ 1.8): 0.9 percent. Measuring the chromatographic content by an external standard method: 83.0 percent. The actual conversion yield was 83.0% × 99% ═ 82.2%.
The ciprofloxacin hydrochloride is prepared by salifying and refining according to a literature method, the total yield is 73 percent based on the ciprofloxacin, and the quality of the ciprofloxacin accords with the standard of European pharmacopoeia.
Although the present invention has been described in terms of the above specific embodiments, it should be recognized that numerous modifications and variations may be made to the invention by those skilled in the art which fall within the scope of the invention as defined by the appended claims.
Claims (11)
1. A method for preparing ciprofloxacin by piperazification reaction is characterized in that,
a) mixing piperazine shown in a formula (iii) and cyclopropane carboxylic acid shown in a formula (ii) according to a molar ratio of 1-10: 1, adding a metal Lewis acid catalyst with a chemical equivalent of 1-30%, and fully reacting in a water-containing system at 80-150 ℃ to obtain a reaction liquid containing the formula (i), wherein the reaction formula is as follows:
the metal Lewis acid catalyst is metal Lewis acid with a general formula of MXYZ and hydrate thereof, wherein M is aluminum (III) or iron (III), and X, Y, Z is halogen;
b) adding inorganic base into the reaction solution at the temperature of 20-100 ℃ to adjust the pH value of the reaction system to 9-12, and filtering while the reaction solution is hot;
c) and adding inorganic acid into the filtrate to adjust the pH value to 7-8, and crystallizing to obtain the product.
2. A method of making ciprofloxacin according to claim 1, wherein the total weight of water in the system is within 8 times the weight of the ciprofloxacin.
3. The method for preparing ciprofloxacin according to claim 1 or 2, wherein an auxiliary agent is added after step a) is finished, and the molar amount of the auxiliary agent is 1-5 times that of the metal Lewis acid; the auxiliary agent is selected from one or more of benzoic acid, tartaric acid, citric acid, oxalic acid, EDTA, commercially available soluble salts of EDTA, phosphate, hydrogen phosphate, dihydrogen phosphate, halide, fluoride, and hydrates of the above salts.
4. A method of making ciprofloxacin as in claim 1 or 2, wherein the molar ratio of piperazine to ciprofloxacin is from 3 to 6: 1.
5. A method of making ciprofloxacin as claimed in claim 3, wherein the molar ratio of piperazine to ciprofloxacin is from 3 to 6: 1.
6. A method of making ciprofloxacin as in claim 1 or 2, wherein the reaction temperature is from 80 ℃ to 114 ℃, or from 115 ℃ to 130 ℃.
7. A method of making ciprofloxacin as in claim 3, wherein the reaction temperature is from 80 ℃ to 114 ℃, or from 115 ℃ to 130 ℃.
8. A method of making ciprofloxacin as in claim 4, wherein the reaction temperature is from 80 ℃ to 114 ℃, or from 115 ℃ to 130 ℃.
9. A method of making ciprofloxacin as in claim 5, wherein the reaction temperature is from 80 ℃ to 114 ℃, or from 115 ℃ to 130 ℃.
10. A method for preparing ciprofloxacin by piperazification reaction is characterized in that,
a) 100.0g of cyclopropanecarboxylic acid and 188.3g of hexapentapiperazine are put into a 1L four-mouth bottle, slowly heated to 70-80 ℃, added with 6g of catalyst aluminum sulfate, heated to about 120 ℃, refluxed for 1-3 h, and monitored by TLC to be completely reacted; b) dropwise adding 18.5g/50ml of NaOH/water solution, and adjusting the pH value of the reaction system to 9-12; continuously stirring for 20min after dripping, adding 3g of active carbon, refluxing and decolorizing for 0.5h, filtering while hot, and keeping the filtering temperature above 80 ℃; c) adjusting the pH value of the filtrate to 7-8 by using hydrochloric acid, stirring at room temperature for crystallization, heating to 70-80 ℃, stirring for 0.5h, filtering while hot, and washing a filter cake for 3 times by using 150ml of hot purified water at about 50 ℃; and drying the filter cake to obtain a crude ciprofloxacin product which is a light yellow solid and about 116 g.
11. A method for preparing ciprofloxacin by piperazification reaction is characterized in that,
a) adding 50.0g of cyclopropanecarboxylic acid and 150g of anhydrous piperazine into a 1L four-mouth bottle, slowly heating to 70-80 ℃, adding 5g of catalyst aluminum acetate and 300g of purified water, heating to about 110 ℃, carrying out reflux reaction for 6-8 h, and monitoring by TLC to complete the reaction; b) dropwise adding 9g/30ml of NaOH/water solution, and adjusting the pH value of the reaction system to 9-12; continuously stirring for 20min after dripping, adding 1.5g of active carbon, refluxing and decolorizing for 0.5h, filtering while hot, and keeping the filtering temperature above 80 ℃; c) adjusting the pH value of the filtrate to 7-8 by using hydrochloric acid, stirring at room temperature for crystallization, heating to 70-80 ℃, stirring for 0.5h, filtering while hot, and washing a filter cake for 3 times by using 100ml of hot purified water at about 50 ℃; and drying a filter cake to obtain a crude ciprofloxacin product which is a light yellow solid and about 54.5 g.
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| CN102241629B (en) * | 2011-05-12 | 2014-08-20 | 浙江国邦药业有限公司 | Chemical preparation method of norfloxacin |
| CN102643250B (en) * | 2012-04-11 | 2014-04-30 | 浙江新华制药有限公司 | Recovery method of piperazine in condensation mother liquor for preparing ciprofloxacin |
| CN104292159B (en) * | 2014-10-10 | 2016-12-07 | 浙江同丰医药化工有限公司 | A kind of preparation method of norfloxacin, ciprofloxacin and enrofloxacin |
| CN109134403B (en) * | 2018-09-27 | 2022-08-16 | 湖南恒泰化工有限公司 | Preparation method of 2-morpholine ethanesulfonic acid |
| CN109942489A (en) * | 2019-04-25 | 2019-06-28 | 江西大地制药有限责任公司 | A kind of synthetic method of Norfloxacin, Ciprofloxacin and Enrofloxacin |
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