CN102276603B - Clean preparation method of moxifloxacin hydrochloride - Google Patents
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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
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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 FQNS, 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, in lung tissue, also can reach very high density, and result of treatment is good, short treating period.
Bibliographical information Moxifloxacin hydrochloride synthetic mainly contains following several method:
The compound 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 in reaction process, is difficult to avoid producing the competition replacement of C7-F and C6-F, 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 compound 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 compound method is formula as follows:
The compound 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-NSC 57182/I-hydroxybenzotriazole (DCC/HOBT) effect or at SOCl
2Existence condensation down gets the acid amides thing, and the acid amides thing is with (S, S)-2,8-diazabicyclo [4,3,0] nonane behind the generation nucleophilic substitution reaction, gets Moxifloxacin hydrochloride with sodium hydroxide, salt s.t. 1 under 8-diazacyclo [5,4,0] hendecene-7 (DBU) exists again successively.DCC is a strong carcinogen, and DBU costs an arm and a leg, unsuitable suitability for industrialized production.
The compound 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 THF and methyl alcohol, Moxifloxacin and hydrochloric acid effect generate Moxifloxacin hydrochloride.THF belongs to the low-flash inflammable liquid, can generate volatile superoxide, brings great hidden to safety in production, is unfavorable for industry's enlarging production.
The compound method of the disclosed Moxifloxacin hydrochloride of patent CN200910104481 " a kind of compound 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.
It is high to find that first huge legendary turtle is closed the Moxifloxacin hydrochloride yield that condensation method makes again after relatively; And reaction conditions is gentle, starting material are easy to get; Be 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 midbody Moxifloxacin through crystallization or extraction; Moxifloxacin is prone to the outburst 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, filter and filter motionlessly again, be difficult to suitability for industrialized production; To use a large amount of extraction agent methylene dichloride during extraction and produce great amount of wastewater and contaminate environment.
Summary of the invention is in order to overcome the deficiency of above-mentioned prior art, the present invention provide 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 said 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: in reaction flask, drop into boric acid and diacetyl oxide, 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 reacts 2-3h, cooling then, crystallization, filtration, washing, dry inner complex, wherein said boric acid, diacetyl oxide, the 1-cyclopropyl-6 of getting in 120-130 ℃; 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 said step 1), crystallization operation are: reaction finishes; Reaction solution is cooled to 0-10 ℃, stirs then down and drip water, dropwise; Continue to stir 1.5-2h down in 0-10 ℃; Said 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 said step 1) is: filtration finishes, with 2-4 washing leaching cake of moisture.
Drying operation in the said step 1) is: filter, washing finishes, and at 45 ℃-55 ℃ of temperature, vacuum-drying to moisture≤10.0%, obtains inner complex dry powder.
Said 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.
Said 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.
Said step 2) in, filter, being operating as of washing: growing the grain finishes, and filters, with ethanol washing leaching cake at twice.
Said step 2) in, exsiccant is operating as: wet-milling vacuum-drying, 45-55 ℃ of drying temperature of control, vacuum-drying to moisture≤4.5% get Moxifloxacin hydrochloride dry powder.
Its reaction scheme is shown in the following figure:
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 practiced thrift cost; The present invention do not isolate the midbody 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 title product Moxifloxacin hydrochloride through ethanol and salt s.t., 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 does further to set forth through 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, with frozen water 990g washing leaching cake at twice, filtration; Wet-milling vacuum-drying, 45 ℃ of drying temperatures of control, vacuum-drying to moisture≤10.0% get inner complex dry powder 145.0g;
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, temperature control reacts 2h for 70 ℃; 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, with ethanol 840g washing leaching cake at twice, filtration; Wet-milling vacuum-drying, 45 ℃ of drying temperatures of control, vacuum-drying to moisture≤4.5% get Moxifloxacin hydrochloride dry powder 109.5g.
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 to moisture≤10.0% get inner complex dry powder 150.2g;
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, temperature control reacts 3h for 80 ℃; 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, with ethanol 1120g washing leaching cake at twice, filtration; Wet-milling vacuum-drying, 55 ℃ of drying temperatures of control, vacuum-drying to moisture≤4.5% get Moxifloxacin hydrochloride dry powder 110.5g.
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 to moisture≤10.0% get inner complex dry powder 145.2g;
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, temperature control reacts 2.5h for 75 ℃; 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, with ethanol 980g washing leaching cake at twice, filtration; Wet-milling vacuum-drying, 50 ℃ of drying temperatures of control, vacuum-drying to moisture≤4.5% get Moxifloxacin hydrochloride dry powder 111.9g.
Claims (6)
1. the clean method for preparing of a Moxifloxacin hydrochloride, it is characterized in that: said 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: in reaction flask, drop into boric acid and diacetyl oxide, 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 reacts 2-3h, cooling then, crystallization, filtration, washing, dry inner complex, wherein said boric acid, diacetyl oxide, the 1-cyclopropyl-6 of getting in 120-130 ℃; 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;
Cooling in the said step 1), crystallization operation are: reaction finishes; Reaction solution is cooled to 0-10 ℃, stirs then down and drip water, dropwise; Continue to stir 1.5-2h down in 0-10 ℃; Said 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;
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;
Said step 2) in, dissolving, hydrolysis, salify, crystalline are operating as: concentrated finishing, in residue, add ethanol, and 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.
2. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: the washing operation in the said step 1) is: filter and finish, with 2-4 washing leaching cake of moisture.
3. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: the drying operation in the said step 1) is: filter, washing finishes, and at 45 ℃-55 ℃ of temperature, vacuum-drying to moisture≤10.0%, obtains inner complex dry powder.
4. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1 is characterized in that: said step 2), spissated being operating as: reaction finishes, and reaction solution is cooled to 40-50 ℃, vacuum decompression concentrates and reclaim acetonitrile.
5. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1 is characterized in that: said step 2), filter, being operating as of washing: growing the grain finishes, and filters, with ethanol washing leaching cake at twice.
6. the clean method for preparing of Moxifloxacin hydrochloride according to claim 1; It is characterized in that: said step 2); Exsiccant is operating as: wet-milling vacuum-drying, 45-55 ℃ of drying temperature of control, vacuum-drying to moisture≤4.5% get Moxifloxacin hydrochloride dry powder.
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| CN104860944A (en) * | 2015-06-09 | 2015-08-26 | 内蒙古东北六药集团有限公司 | Production method of moxifloxacin hydrochloride |
| US9388178B2 (en) | 2012-12-04 | 2016-07-12 | Mankind Research Centre | Process for the preparation of moxifloxacin hydrochloride |
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| CN103183671A (en) * | 2011-12-29 | 2013-07-03 | 天津康鸿医药科技发展有限公司 | Novel moxifloxacin hydrochloride crystal, and preparation method and application thereof |
| CN102603738B (en) * | 2012-02-24 | 2013-12-11 | 天津市汉康医药生物技术有限公司 | Stable moxifloxacin hydrochloride compound |
| CN102924449B (en) * | 2012-10-30 | 2015-08-12 | 重庆福安药业集团庆余堂制药有限公司 | Moxifloxacin hydrochloride H crystal form and preparation method thereof and pharmaceutical composition |
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| CN104817557B (en) * | 2014-04-04 | 2017-05-31 | 江苏天一时制药有限公司 | A kind of stable crystal form of moxifloxacin hydrochloride and preparation method thereof |
| CN104211701B (en) * | 2014-04-17 | 2016-05-04 | 南京优科生物医药研究有限公司 | A kind of method of preparing MOXIFLOXACIN impurity B and impurity D |
| CN104031043B (en) * | 2014-05-28 | 2016-03-16 | 成都克莱蒙医药科技有限公司 | A kind of Moxifloxacin hydrochloride synthetic method |
| CN108570061B (en) * | 2018-08-06 | 2021-03-02 | 沈阳林特制药有限公司 | Preparation method of zabbixing |
| CN114539244B (en) * | 2020-11-18 | 2023-04-14 | 沈阳药科大学 | Preparation method of moxifloxacin hydrochloride |
| CN112759590B (en) * | 2020-11-19 | 2021-12-31 | 内蒙古源宏精细化工有限公司 | Preparation method of moxifloxacin |
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Cited By (2)
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| US9388178B2 (en) | 2012-12-04 | 2016-07-12 | Mankind Research Centre | Process for the preparation of moxifloxacin hydrochloride |
| CN104860944A (en) * | 2015-06-09 | 2015-08-26 | 内蒙古东北六药集团有限公司 | Production method of moxifloxacin hydrochloride |
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