CN102276603A - Clean preparation method of moxifloxacin hydrochloride - Google Patents
Clean preparation method of moxifloxacin hydrochloride Download PDFInfo
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- CN102276603A CN102276603A CN 201110196816 CN201110196816A CN102276603A CN 102276603 A CN102276603 A CN 102276603A CN 201110196816 CN201110196816 CN 201110196816 CN 201110196816 A CN201110196816 A CN 201110196816A CN 102276603 A CN102276603 A CN 102276603A
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- FABPRXSRWADJSP-MEDUHNTESA-N COc(c(N(C1CC1)C=C1C(O)=O)c(cc2F)C1=O)c2N1C[C@H]2NCCC[C@H]2C1 Chemical compound COc(c(N(C1CC1)C=C1C(O)=O)c(cc2F)C1=O)c2N1C[C@H]2NCCC[C@H]2C1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 2
- WEXQOLCYKFJAJZ-ZUZCIYMTSA-N OC(C1=CN(C2CC2)c(c(F)c(c(F)c2)N3C[C@H]4NCCC[C@H]4C3)c2C1=O)=O Chemical compound OC(C1=CN(C2CC2)c(c(F)c(c(F)c2)N3C[C@H]4NCCC[C@H]4C3)c2C1=O)=O WEXQOLCYKFJAJZ-ZUZCIYMTSA-N 0.000 description 1
Abstract
The invention discloses a clean preparation method of moxifloxacin hydrochloride. The method comprises the following steps: generating B(OAc)3 through the heating reaction between boric acid and acetic anhydride; obtaining chelate through the heating reaction between B(OAc)3 and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid; performing nucleophilic substitution reaction between the chelate and (S, S)-2,8-diazabicyclo[4,3,0]nonane in the presence of Et3N; and processing with ethanol and hydrochloric acid to obtain moxifloxacin hydrochloride. The 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid adopted by the method is easily available; and the method has the advantages of simple synthesis path, mild reaction conditions, and relatively high yield, and is very suitable for industrial production and is easy to operate and post-process.
Description
Technical field the present invention relates to a kind of clean method for preparing of Moxifloxacin hydrochloride.
Background technology Moxifloxacin hydrochloride (Moxifloxacin Hydrochloride) be Bayer A.G development the 4th generation fluoroquinolones, chemistry 1-cyclopropyl by name-6-fluoro-8-methoxyl group-7-[(4aS, 7aS)-octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid hydrochloride, commodity are by name visit multiple pleasure (Avelox, Avalox), go on the market in Germany in September, 1999, and obtain FDA approval listing in the U.S. December in the same year.Moxifloxacin is mainly used in the acute aggravation patient of chronic bronchitis, chronic obstructive pulmonary disease, CAP, acute bacterial sinusitis etc. at present.This medical instrument has the favorable tissue penetration power, also can reach very high density in lung tissue, and result of treatment is good, short treating period.
Bibliographical information Moxifloxacin hydrochloride synthetic mainly contains following several method:
The synthetic method of the disclosed Moxifloxacin hydrochloride of European patent EP 550903 " Quinolone-and naphthyridone carboxylic acid derivatives asantibacterial agents " is formula as follows:
This method is directly simple, but is difficult to avoid producing the competition replacement of C7-F and C6-F in reaction process, and the substituted by product of some C6-F generates, and is difficult to separate, and has influenced the yield and the purity of Moxifloxacin.
The synthetic method of the disclosed Moxifloxacin hydrochloride of patent WO2005012285 " AN IMPROVED PROCESS FOR THE PREPARATION OFMOXIFLOXACIN HYDROCHLORIDE " is formula as follows:
Boric acid and diacetyl oxide reacting by heating generate B (OAc)
3, B (OAc)
3With 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester reacting by heating gets inner complex, and inner complex is with (S, S)-2,8-diazabicyclo [4,3,0] nonane is at Et
3After under N exists nucleophilic substitution reaction taking place, get Moxifloxacin with sodium hydroxide and acetic acid treatment successively again, Moxifloxacin and hydrochloric acid effect generate Moxifloxacin hydrochloride.Patent WO2008059223 " PROCESS FOR THE SYNTHESIS OF MOXIFLOXACINHYDROCHLORIDE " report does not use diacetyl oxide and uses propionic anhydride instead, and synthetic method is formula as follows:
The synthetic method of the disclosed Moxifloxacin hydrochloride of patent WO2008059521 " NOVEL PROCESS FOR THE PREPARATION OF MOXIFLOXACINHYDROCHLORIDE AND ANOVEL POLYMORPH OF MOXIFLOXACIN " is formula as follows:
1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid and diethylamine are at N, under N-dicyclohexylcarbodiimide/I-hydroxybenzotriazole (DCC/HOBT) effect or at SOCl
2Have down that condensation gets the acid amides thing, the acid amides thing with (S, S)-2,8-diazabicyclo [4,3,0] nonane is 1,8-diazacyclo [5,4,0] after under hendecene-7 (DBU) exists nucleophilic substitution reaction taking place, get Moxifloxacin hydrochloride with sodium hydroxide, salt acid treatment successively again.DCC is a strong carcinogen, and DBU costs an arm and a leg, and is not suitable for suitability for industrialized production.
The synthetic method of the disclosed Moxifloxacin hydrochloride of patent CN02131962 " preparation method of 8-methoxy-quinolone " is formula as follows:
1-cyclopropyl-6,8-two fluoro-7-[(4aS, 7aS)-octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid is that mixed solvent C8-F generation methoxylation under the effect of sodium tert-butoxide (or potassium) or sodium tert-amyl alcohol (or potassium) gets Moxifloxacin with tetrahydrofuran (THF) and methyl alcohol, and Moxifloxacin and hydrochloric acid effect generate Moxifloxacin hydrochloride.Tetrahydrofuran (THF) belongs to the low-flash inflammable liquid, can generate volatile superoxide, brings huge hidden danger to safety in production, is unfavorable for industry's enlarging production.
The synthetic method of the disclosed Moxifloxacin hydrochloride of patent CN200910104481 " a kind of synthetic method of Moxifloxacin hydrochloride " is formula as follows:
Raw material quinolone carboxylic acid fluoro complex be difficult for to obtain, and the step that has increased last protection deprotection causes operation steps elongated, and the production cycle prolongs, from the angle of economy and be not suitable for suitability for industrialized production.
Find that first huge legendary turtle closes the Moxifloxacin hydrochloride yield height that condensation method makes again after relatively, and reaction conditions gentleness, starting material are easy to get, it is a synthetic route preferably, but the raw material that this method adopts is a 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester, price is more expensive; And to obtain the operation steps of intermediate Moxifloxacin through crystallization or extraction, Moxifloxacin easily breaks out nucleation at crystallisation process and causes just separating out a lot, the bad control of pH value, to pass through crystallization filtration, the filtering process of mother liquor recrystallize repeatedly otherwise yield is very low, filtration is filtered motionless again, is difficult to suitability for industrialized production; To and produce a large amount of waste water and contaminate environment with a large amount of extraction agent methylene dichloride during extraction.
Summary of the invention is in order to overcome above-mentioned the deficiencies in the prior art, the invention provides a kind of simple and direct, reaction conditions is gentle, operation and aftertreatment is simple, yield is higher, cost is low, be suitable for the clean method for preparing of the Moxifloxacin hydrochloride of suitability for industrialized production.
Technical scheme of the present invention is: a kind of preparation method of Moxifloxacin hydrochloride, and described preparation method may further comprise the steps:
1) inner complex (1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid-O
3, O
4-two acetic acid close the boron ester) preparation: drop into boric acid and diacetyl oxide in reaction flask, temperature control 110-120 ℃ of reaction 1.5-2h reaction generates B (OAc)
3, gained B (OAc)
3Again with 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid is in 120-130 ℃ of reaction 2-3h, cooling then, crystallization, filtration, washing, the dry inner complex that gets, wherein said boric acid, diacetyl oxide, 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid's weight ratio is 0.3-0.4: 2.0-3.0: 1;
2) preparation of Moxifloxacin hydrochloride: in reaction flask, add step 1 gained inner complex, acetonitrile, (S, S)-2,8-diazabicyclo [4,3,0] nonane, triethylamine are behind the temperature control 70-80 ℃ of reaction 2-3h, through concentrating, dissolving, hydrolysis, salify, crystallization, filtration, washing, drying obtain Moxifloxacin hydrochloride, wherein said inner complex, acetonitrile, (S, S)-2, the weight ratio of 8-diazabicyclo [4,3,0] nonane, triethylamine is 1: 2.5-5.0: 0.28-0.38: 0.35-0.5.
Cooling in the described step 1), crystallization operation are: reaction finishes, reaction solution is cooled to 0-10 ℃, stir then and drip water down, dropwise, continue to stir 1.5-2h down in 0-10 ℃, described 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid is 1 with the weight ratio that drips water: 6-9.
Washing operation in the described step 1) is: filtration finishes, with 2-4 washing leaching cake of moisture.
Drying operation in the described step 1) is: filter, washing finishes, and to moisture≤10.0%, obtains inner complex dry powder in 45 ℃-55 ℃ of temperature, vacuum-drying.
Described step 2) in, spissated being operating as: reaction finishes, and reaction solution is cooled to 40-50 ℃, the concentrated acetonitrile that reclaims of vacuum decompression.
Described step 2) in, dissolving, hydrolysis, salify, crystalline are operating as: concentrated finishing, in residue, add ethanol, and after the stirring and dissolving, transfer pH1-2 in 20-30 ℃ of Dropwise 5-10mol/L hydrochloric acid, drip and finish insulated and stirred 1-1.5h; Be cooled to 0-10 ℃, stir growing the grain 2-3h, wherein said inner complex and alcoholic acid weight ratio are 1: 6-8.
Described step 2) in, filter, being operating as of washing: growing the grain finishes, and filters, with ethanol washing leaching cake at twice.
Described step 2) in, exsiccant is operating as: wet-milling vacuum-drying, 45-55 ℃ of drying temperature of control, vacuum-drying get Moxifloxacin hydrochloride dry powder to moisture≤4.5%.
Its reaction scheme is shown in the below:
The invention has the beneficial effects as follows: adopt aforesaid method, the present invention adopts 1-cyclopropyl-6 more cheap and easy to get, 7-two fluoro-1, and 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid is a raw material, has saved cost; The present invention do not isolate the intermediate Moxifloxacin in process of production and inner complex with (S, S)-2,8-diazabicyclo [4,3,0] nonane is at Et
3After under N exists nucleophilic substitution reaction taking place, directly obtain the target product Moxifloxacin hydrochloride through ethanol and salt acid treatment, simplified operation steps, solved filtration problem, replaced the environmentally friendly and three wastes of methyl alcohol to be easy to handle with ethanol: the water-containing acetic acid waste liquid through fractionation reclaim stay use it for anything else, acetonitrile can recycled after reclaiming, ethanol can recycled after reclaiming.
Embodiment the present invention is further elaborated by following examples:
Embodiment 1:
1) inner complex (1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid-O
3, O
4-two acetic acid close the boron ester) preparation: drop into diacetyl oxide 220g, boric acid 33g in the reaction flask, 110 ℃ of reactions of temperature control 1.5h.Reaction finishes, and is cooled to 50 ℃; With 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid 110g joins in the above-mentioned reaction solution, finishes 120 ℃ of reaction 2h; Reaction finishes, and temperature of charge is reduced to 0 ℃, splashes into water 660g then, drips to finish, and 0 ℃ is stirred 1.5h; Filter, use frozen water 990g washing leaching cake at twice, filter; Wet-milling vacuum-drying, 45 ℃ of drying temperatures of control, vacuum-drying get inner complex dry powder 145.0g to moisture≤10.0%;
2) preparation of Moxifloxacin hydrochloride: in reaction flask, add inner complex 140.0g, acetonitrile 350g, (S, S)-2,8-diazabicyclo [4,3,0] nonane 39.2g and triethylamine 49g, 70 ℃ of reactions of temperature control 2h; Reaction finishes, and is cooled to 40 ℃, vacuum decompression and concentrates, and reclaims acetonitrile; Concentrated finishing adds ethanol 840g in residue, after the stirring and dissolving, transfer pH to 1 in 20 ℃ of Dropwise 5 mol/L hydrochloric acid, stirs 1h in 20 ℃ then; Be cooled to 0 ℃, stir growing the grain 2h; Growing the grain finishes, and filters, and uses ethanol 840g washing leaching cake at twice, filters; Wet-milling vacuum-drying, 45 ℃ of drying temperatures of control, vacuum-drying get Moxifloxacin hydrochloride dry powder 109.5g to moisture≤4.5%.
Embodiment 2:
1) inner complex (1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid-O
3, O
4-two acetic acid close the boron ester) preparation: drop into diacetyl oxide 330g, boric acid 44g in the reaction flask, 120 ℃ of reactions of temperature control 2h.Reaction finishes, and is cooled to 60 ℃; With 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid 110g joins in the above-mentioned reaction solution, finishes 130 ℃ of reaction 3h; Reaction finishes, and temperature of charge is reduced to 10 ℃, splashes into water 990g then, drips to finish, and 10 ℃ are stirred 2h; Filter, water 1200g divides washing leaching cake four times, filters; Wet-milling vacuum-drying, 55 ℃ of drying temperatures of control, vacuum-drying get inner complex dry powder 150.2g to moisture≤10.0%;
2) preparation of Moxifloxacin hydrochloride: in reaction flask, add inner complex 140.0g, acetonitrile 700g, (S, S)-2,8-diazabicyclo [4,3,0] nonane 53.2g and triethylamine 70g, 80 ℃ of reactions of temperature control 3h; Reaction finishes, and is cooled to 50 ℃, vacuum decompression and concentrates, and reclaims acetonitrile; Concentrated finishing adds ethanol 1120g in residue, after the stirring and dissolving, drip the 10mol/L hydrochloric acid in 30 ℃ and transfer pH to 2, stirs 1.5h in 30 ℃ then; Be cooled to 10 ℃, stir growing the grain 3h; Growing the grain finishes, and filters, and uses ethanol 1120g washing leaching cake at twice, filters; Wet-milling vacuum-drying, 55 ℃ of drying temperatures of control, vacuum-drying get Moxifloxacin hydrochloride dry powder 110.5g to moisture≤4.5%.
Embodiment 3:
1) inner complex (1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid-O
3, O
4-two acetic acid close the boron ester) preparation: drop into diacetyl oxide 280g, boric acid 40g in the reaction flask, 115 ℃ of reactions of temperature control 2h.Reaction finishes, and is cooled to 55 ℃; With 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid 110g joins in the above-mentioned reaction solution, finishes 125 ℃ of reaction 2.5h; Reaction finishes, and temperature of charge is reduced to 5 ℃, splashes into water 820g then, drips to finish, and 5 ℃ are stirred 2h; Filter, water 1100g divides washing leaching cake three times, filters; Wet-milling vacuum-drying, 50 ℃ of drying temperatures of control, vacuum-drying get inner complex dry powder 145.2g to moisture≤10.0%;
2) preparation of Moxifloxacin hydrochloride: in reaction flask, add inner complex 140.0g, acetonitrile 520g, (S, S)-2,8-diazabicyclo [4,3,0] nonane 46.2g and triethylamine 60g, 75 ℃ of reactions of temperature control 2.5h; Reaction finishes, and is cooled to 45 ℃, vacuum decompression and concentrates, and reclaims acetonitrile; Concentrated finishing adds ethanol 980g in residue, after the stirring and dissolving, drip the 7.5mol/L hydrochloric acid in 25 ℃ and transfer pH to 1.5, stirs 1h in 25 ℃ then; Be cooled to 5 ℃, stir growing the grain 2.5h; Growing the grain finishes, and filters, and uses ethanol 980g washing leaching cake at twice, filters; Wet-milling vacuum-drying, 50 ℃ of drying temperatures of control, vacuum-drying get Moxifloxacin hydrochloride dry powder 111.9g to moisture≤4.5%.
Claims (8)
1. the clean method for preparing of a Moxifloxacin hydrochloride, it is characterized in that: described preparation method may further comprise the steps:
1) inner complex 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid-O
3, O
4-two acetic acid close the preparation of boron ester: drop into boric acid and diacetyl oxide in reaction flask, temperature control 110-120 ℃ of reaction 1.5-2h reaction generates B (OAc)
3, gained B (OAc)
3Again with 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid is in 120-130 ℃ of reaction 2-3h, cooling then, crystallization, filtration, washing, the dry inner complex that gets, wherein said boric acid, diacetyl oxide, 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid's weight ratio is 0.3-0.4: 2.0-3.0: 1;
2) preparation of Moxifloxacin hydrochloride: in reaction flask, add step 1 gained inner complex, acetonitrile, (S, S)-2,8-diazabicyclo [4,3,0] nonane, triethylamine are behind the temperature control 70-80 ℃ of reaction 2-3h, through concentrating, dissolving, hydrolysis, salify, crystallization, filtration, washing, drying obtain Moxifloxacin hydrochloride, wherein said inner complex, acetonitrile, (S, S)-2, the weight ratio of 8-diazabicyclo [4,3,0] nonane, triethylamine is 1: 2.5-5.0: 0.28-0.38: 0.35-0.5.
2. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: the cooling in the described step 1), crystallization operation are: reaction finishes, reaction solution is cooled to 0-10 ℃, stir then and drip water down, dropwise, continue to stir 1.5-2h, described 1-cyclopropyl-6 down in 0-10 ℃, 7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid is 1 with the weight ratio that drips water: 6-9.
3. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: the washing operation in the described step 1) is: filter and finish, with 2-4 washing leaching cake of moisture.
4. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: the drying operation in the described step 1) is: filter, washing finishes, and to moisture≤10.0%, obtains described inner complex dry powder in 45 ℃-55 ℃ of temperature, vacuum-drying.
5. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1 is characterized in that: described step 2), spissated being operating as: reaction finishes, and reaction solution is cooled to 40-50 ℃, vacuum decompression concentrates and reclaim acetonitrile.
6. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: described step 2), dissolving, hydrolysis, salify, crystalline are operating as: concentrated finishing, in residue, add ethanol, after the stirring and dissolving, transfer pH to 1-2 in 20-30 ℃ of Dropwise 5-10mol/L hydrochloric acid, drip and finish insulated and stirred 1-1.5h; Be cooled to 0-10 ℃, stir growing the grain 2-3h, wherein said inner complex and alcoholic acid weight ratio are 1: 6-8.
7. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1 is characterized in that: described step 2), filter, being operating as of washing: growing the grain finishes, and filters, with ethanol washing leaching cake at twice.
8. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: described step 2), exsiccant is operating as: wet-milling vacuum-drying, 45-55 ℃ of drying temperature of control, vacuum-drying get Moxifloxacin hydrochloride dry powder to moisture≤4.5%.
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| CN102603738A (en) * | 2012-02-24 | 2012-07-25 | 天津市汉康医药生物技术有限公司 | Stable moxifloxacin hydrochloride compound |
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