CN101941969A - Preparation method of moxifloxacin hydrochloride - Google Patents
Preparation method of moxifloxacin hydrochloride Download PDFInfo
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- CN101941969A CN101941969A CN 201010298408 CN201010298408A CN101941969A CN 101941969 A CN101941969 A CN 101941969A CN 201010298408 CN201010298408 CN 201010298408 CN 201010298408 A CN201010298408 A CN 201010298408A CN 101941969 A CN101941969 A CN 101941969A
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Abstract
The invention discloses a preparation method of moxifloxacin hydrochloride, comprising the steps of: reacting the 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid and the S,S-2,8-diazabicyclo[4.3.0]nonane to prepare the moxifloxacin in the presence of organic base in organic solvent under the reaction temperature of 60 to 85 DEG C; separating the moxifloxacin, processing the moxifloxacin by concentrated hydrochloric acid in organic solvent under the reaction temperature of 60 to 85 DEG C to obtain the moxifloxacin hydrochloride.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of Moxifloxacin hydrochloride.
Background technology
Moxifloxacin hydrochloride (moxifloxacin hydrochloride, 1-cyclopropyl-7-(S, S-2,8-diazabicyclo [4.3.0] nonane-8-yl)-6-fluoro-8-methoxyl group-4-oxo-1,4-dihydro-3-quinoline carboxylic acid hydrochloride) be the 4th generation the fluoroquinolone antibacterial agent thing.It has broad-spectrum antibacterial action, as human and animal's antibacterials, can treat the infection that various bacteria causes effectively, and structural formula is as follows:
Moxifloxacin is highly effective antiseptic-germicide, and describes first in patent EP0350733.EP0550903 discloses Moxifloxacin, and (S, S) structure demonstrate gram positive organism, comprise streptococcal pneumonia, streptococcus aureus, streptococcus pyogenes, have better anti-microbial activity than Sparfloxacin and Ciprofloxacin.
US5157117 discloses 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1, and 4-dihydro-3-quinoline carboxylic ester prepares the inner complex of corresponding ethyl-borate with boric acid and acetic anhydride in the presence of zinc chloride, it is prepared into GATIFLOXACIN.
CN101514201 discloses 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid ethyl ester prepares the inner complex of corresponding ethyl-borate with boric acid and acetic anhydride in the presence of zinc chloride, with S, S-2,8-diazabicyclo [4.3.0] the nonane 3h that in the presence of alkali and solvent, refluxes, the evaporated under reduced pressure solvent, resistates adds sherwood oil, filters the solid that obtains and is dissolved in 7% NaOH solution, 80 ℃ are stirred 3h down, reduce to the room temperature after-filtration, filtrate transfers to neutrality with 5% acetum, filtration drying, obtain Moxifloxacin, yield is 72.6%.
WO2008059223A2 discloses 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1, the inner complex of 4-dihydro-3-quinoline carboxylic acid ethyl ester and boric acid and the corresponding boric acid propyl ester of propionic anhydride prepared in reaction, in the presence of organic bases with S, S-2,100 ℃ of reactions of 8-diazabicyclo [4.3.0] nonane 3h, regulate PH to 1.0-2.0 with hydrochloric acid after cooling to 25-30 ℃, resistates adds entry behind the evaporate to dryness, regulates PH to 7.5-9.0 with ammoniacal liquor, extraction back solvent evaporated, the resistates dissolve with methanol, hydrochloric acid is regulated PH to 1.0-2.0, filters, drying under reduced pressure obtains Moxifloxacin hydrochloride, and yield is 55.6%.
EP1992626 discloses 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2,8-diazabicyclo [4.3.0] nonane, with DMF or DMSO is solvent, reacts 6-8h down at 65-70 ℃, and reaction system is cooled to 25-30 ℃, add entry and stir 2h, filtering product washes with water, and 75 ℃ of following drying under reduced pressure obtain the crude product Moxifloxacin.With L (+)-tartrate or fumaric acid is solvent with DMF, and Moxifloxacin is carried out chiral separation, removes (R, R) isomer impurities obtains corresponding Moxifloxacin salt, adds concentrated hydrochloric acid under the room temperature, filter, 50-55 ℃ of drying under reduced pressure obtains Moxifloxacin hydrochloride, and yield is 68.8%.
Exist in the aforesaid method yield on the low side, need the chirality folding problem of grading, had a strong impact on the cost of Moxifloxacin hydrochloride, restricted the industrial production of Moxifloxacin hydrochloride.
Summary of the invention
The objective of the invention is on the basis of existing technology, provide that a kind of technology is simple, cost is low, yield is high, be fit to the preparation method of industrial Moxifloxacin hydrochloride.
Purpose of the present invention can reach by following measure:
A kind of preparation method of Moxifloxacin hydrochloride may further comprise the steps:
(a) in organic solvent, temperature of reaction is 60-85 ℃, and organic bases exists down, with 1-cyclopropyl-6, and 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2,8-diazabicyclo [4.3.0] nonane prepared in reaction Moxifloxacin;
(b) Moxifloxacin is separated, in organic solvent, temperature of reaction is 60-85 ℃, handles Moxifloxacin with concentrated hydrochloric acid, is converted into Moxifloxacin hydrochloride.
The reaction scheme of present method is as follows:
Be selected from acetonitrile, tetrahydrofuran (THF), methyl alcohol, dehydrated alcohol or the Virahol one or more at the organic solvent described in the step (a); Be preferably selected from acetonitrile or the tetrahydrofuran (THF) one or more, more preferably acetonitrile.
1-cyclopropyl-6 in the step (a), 7-two fluoro-8-methoxyl group-4-oxos-1, the mass volume ratio of 4-dihydro-3-quinoline carboxylic acid and organic solvent is 1:3～1:20(g/ml), is preferably 1:4～1:10(g/ml), more preferably 1:5.Organic bases described in the step (a) is selected from triethylamine, 1,8-diazacyclo [5,4,0]-7-hendecene, N, in the N-diisopropylethylamine one or more are preferably selected from triethylamine, 1,8-diazacyclo [5,4,0]-in the 7-hendecene one or more, more preferably triethylamine.1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1, the mol ratio of 4-dihydro-3-quinoline carboxylic acid and organic bases is 1:0.1～1:2, is preferably 1:0.1～1:1, more preferably 1:0.2.
1-cyclopropyl-6 in the step (a), 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2, the mol ratio of 8-diazabicyclo [4.3.0] nonane is 1:1～1:1.2, is preferably 1:1～1:1.1, more preferably 1:1.1.
In one embodiment, step (a) adopts following steps: earlier with 1-cyclopropyl-6, and 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid is dissolved in the acetonitrile, stirs under the room temperature to add S, S-2 down, 8-diazabicyclo [4.3.0] nonane, triethylamine is warming up to backflow, reaction 5h, after being cooled to room temperature, 0 ℃ of crystallization 12h filters, the minor amounts of acetonitrile washing leaching cake obtains the crude product Moxifloxacin.
Organic solvent described in the step (b) is selected from one or more in anhydrous methanol, dehydrated alcohol, Virahol or the tetrahydrofuran (THF), is preferably selected from anhydrous methanol, dehydrated alcohol, the Virahol one or more, more preferably dehydrated alcohol.The mass volume ratio of Moxifloxacin and organic solvent is 1:10～1:30(g/ml) in the step (b), is preferably 1:15～1:25(g/ml), more preferably 1:20.
The mol ratio of Moxifloxacin and concentrated hydrochloric acid is 1:1～1:4 in the step (b), preferred 1:1～1:1.2, more preferably 1:1.Wherein concentrated hydrochloric acid can be selected the concentration of 31%-37% for use, preferably adopts the concentration of 35%-37%.
Before Moxifloxacin separates back and hydrochloric acid reaction in the step (b), be that 1.33～3.33kpa, temperature are dry under 30-50 ℃ the condition to Moxifloxacin at pressure earlier; Moxifloxacin hydrochloride preparation and separate after, be that 1.33～3.33kpa, temperature are drying treatment under 40-50 ℃ the condition at pressure.
The separation of indication can be various separation means commonly used such as crystallization, filtration in present method.
The Moxifloxacin hydrochloride that step (b) obtains can further carry out refinement treatment, with the higher product of preparation purity.
In one embodiment, step (b) adopts following steps: be dissolved in the dehydrated alcohol after will Moxifloxacin separating, reflux state adds concentrated hydrochloric acid down, be cooled to room temperature after, 0 ℃ of crystallization 12h filters, a small amount of absolute ethanol washing filter cake obtains Moxifloxacin hydrochloride.
According to a preferred embodiment of the invention, the method for preparing Moxifloxacin hydrochloride comprises the following steps:
(a) with the acetonitrile be solvent, temperature of reaction is 60-85 ℃, and triethylamine exists down, with 1-cyclopropyl-6, and 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2, the reaction of 8-diazabicyclo [4.3.0] nonane is converted into Moxifloxacin;
(b) with after the separation of the Moxifloxacin in the step (a), be 1.33～3.33kpa at pressure, temperature is a 30-50 ℃ of drying down;
(c) with ethanol be solvent, temperature of reaction is 60-85 ℃, and the Moxifloxacin with concentrated hydrochloric acid treatment step (b) obtains is converted into Moxifloxacin hydrochloride;
(d) with after the separation of the Moxifloxacin hydrochloride in the step (c), be 1.33～3.33kpa at pressure, temperature is a 40-50 ℃ of drying down.
The present invention is with 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid is a raw material, by with S, S-2,8-diazabicyclo [4.3.0] nonane replaces, be converted into the Moxifloxacin hydrochloride that hydrochloride, recrystallizing and refining have obtained high yield and purity with the concentrated hydrochloric acid reaction, its quality product height, and technology is simple, the reaction conditions gentleness is easy to control, reaction solvent easily reclaims and recycling, and the aftertreatment energy consumption is low, and reaction process is difficult for taking place racemization, need not to split, be difficult for producing dissolvent residual, cost is low, is fit to suitability for industrialized production.
Embodiment
Should be appreciated that those skilled in the art can carry out various various modifications and the improvement that do not depart from the spirit and scope of the invention to the present invention based on content disclosed herein.They should all drop in the application's the scope of patent protection of claim definition.In addition, should be appreciated that embodiment provided herein only is used to purpose of the present invention is described, and should not be construed as restriction of the present invention.
Embodiment 1: the preparation of Moxifloxacin
In three mouthfuls of round-bottomed flasks of 500 mL, add acetonitrile 300 mL, add 1-cyclopropyl-6 under the stirring at room successively, 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid 59.0 g(0.2 mol), S, S-2,8-diazabicyclo [4.3.0] nonane 27.8 g(0.22 mol), triethylamine 4.0 g(0.04 mol), be warming up to 80 ℃ gradually, stop heating behind the back flow reaction 5h, after continuation is stirred and is cooled to room temperature, 0 ℃ of following stirring and crystallizing 12h, filter, 10 mL * 3 acetonitrile washing leaching cakes are 1.33～3.33 kpa at pressure, temperature is under 50 ℃, drying obtains crude product Moxifloxacin 73.2 g, and yield is 91.2%, and it is 98.46% that HPLC detects purity.
Embodiment 2: the preparation of Moxifloxacin
In three mouthfuls of round-bottomed flasks of 2000 mL, add tetrahydrofuran (THF) 1180 mL, add 1-cyclopropyl-6 under the stirring at room successively, 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid 118.1 g(0.4mol), S, S-2,8-diazabicyclo [4.3.0] nonane 55.5 g(0.44 mol), N, N-diisopropylethylamine 25.8 g(0.2 mol), be warming up to 80 ℃ gradually, stop heating behind the back flow reaction 7h, after continuation was stirred and is cooled to room temperature, 0 ℃ of following stirring and crystallizing 12h filtered, 20 mL * 3 acetonitrile washing leaching cakes, at pressure is 1.33～3.33 KPa, and temperature is under 50 ℃, and drying obtains crude product Moxifloxacin 144.2 g, yield is 89.8%, and it is 98.79% that HPLC detects purity.
Embodiment 3: the preparation of Moxifloxacin hydrochloride
In three mouthfuls of round-bottomed flasks of 3 L, add dehydrated alcohol 1.46 L, add crude product Moxifloxacin 73.2 g(0.182 mol under the stirring at room), be warming up to backflow gradually, add concentrated hydrochloric acid 18.5 g(0.182 mol), stop heating, after continuation was stirred and is cooled to room temperature, 0 ℃ of following stirring and crystallizing 12h filtered, 50 mL * 3 absolute ethanol washing filter cakes, at pressure is 1.33～3.33 kpa, and temperature is under 50 ℃, and drying obtains crude product Moxifloxacin hydrochloride 72.4 g, yield is 90.8%, and it is 99.87% that HPLC detects purity.
1H-NMR?(500MHz,?DMSO-d6)?δ(ppm):?0.88～0.90?(m,1H),?1.00～1.06?(m,1H),?1.08～1.13?(m,1H),?1.16～1.22?(m,1H),?1.69～1.84?(m,4H),?2.64～2.66?(m,1H),?2.90～2.94?(m,1H),?3.17-3.19?(m,1H),?3.59?(s,3H),?3.62?(s,1H),?3.73～3.77?(m,1H),?3.85～3.90?(m,2H),?4.05～4.09?(m,1H),?4.12～4.17?(m,1H),?7.68?(d,1H),?8.66?(s,1H),?8.87?(s,1H),?10.12?(s,1H),?15.12?(s,1H)。
13C-NMR?(125MHz,?DMSO-d6)?δ(ppm):?8.30,?9.48,?17.47,?20.46,?34.05,?40.52,?41.39,?51.78,?54.00,?54.37,?61.80,?106.38,?117.24,?134.44,?136.61,?140.38,?150.26,?151.44,?153.43,?165.73,?175.91。
MS?(ESI):?402?[M-HCl+H]
?+?。
Embodiment 4: the preparation of Moxifloxacin hydrochloride
In three mouthfuls of round-bottomed flasks of 5 L, add dehydrated alcohol 2.88L, add crude product Moxifloxacin 144.2 g(0.359 mol under the stirring at room), be warming up to backflow gradually, add concentrated hydrochloric acid 36.4 g(0.359 mol), stop heating, after continuation was stirred and is cooled to room temperature, 0 ℃ of following stirring and crystallizing 12h filtered, 100 mL * 3 absolute ethanol washing filter cakes, at pressure is 1.33～3.33 kpa, and temperature is under 50 ℃, and drying obtains crude product Moxifloxacin hydrochloride 143.8 g, yield is 91.5%, and it is 99.80% that HPLC detects purity.
Claims (10)
1. the preparation method of a Moxifloxacin hydrochloride may further comprise the steps:
(a) in organic solvent, temperature of reaction is 60-85 ℃, and organic bases exists down, with 1-cyclopropyl-6, and 7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2,8-diazabicyclo [4.3.0] nonane prepared in reaction Moxifloxacin;
(b) Moxifloxacin is separated, in organic solvent, temperature of reaction is 60-85 ℃, handles Moxifloxacin with concentrated hydrochloric acid, is converted into Moxifloxacin hydrochloride.
2. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that the organic solvent described in the step (a) is selected from one or more in acetonitrile, tetrahydrofuran (THF), methyl alcohol, dehydrated alcohol or the Virahol; Be preferably selected from acetonitrile or the tetrahydrofuran (THF) one or more.
3. the preparation method of Moxifloxacin hydrochloride according to claim 1, it is characterized in that 1-cyclopropyl-6 in the step (a), 7-two fluoro-8-methoxyl group-4-oxos-1, the mass volume ratio of 4-dihydro-3-quinoline carboxylic acid and organic solvent is 1:3～1:20(g/ml), is preferably 1:4～1:10(g/ml).
4. the preparation method of Moxifloxacin hydrochloride according to claim 1, it is characterized in that the organic bases described in the step (a) is selected from triethylamine, 1,8-diazacyclo [5,4,0]-and 7-hendecene, N, one or more in the N-diisopropylethylamine, be preferably selected from triethylamine, 1, in 8-diazacyclo [5,4,0]-7-hendecene one or more.
5. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1, and the mol ratio of 4-dihydro-3-quinoline carboxylic acid and organic bases is 1:0.1～1:2, is preferably 1:0.1～1:1.
6. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid and S, S-2, the mol ratio of 8-diazabicyclo [4.3.0] nonane is 1:1～1:1.2, is preferably 1:1～1:1.1.
7. the preparation method of Moxifloxacin hydrochloride according to claim 1, it is characterized in that the organic solvent described in the step (b) is selected from one or more in anhydrous methanol, dehydrated alcohol, Virahol or the tetrahydrofuran (THF), be preferably selected from anhydrous methanol, dehydrated alcohol, the Virahol one or more.
8. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that in the step (b) that the mass volume ratio of Moxifloxacin and organic solvent is 1:10～1:30(g/ml), is preferably 1:15～1:25(g/ml).
9. the preparation method of Moxifloxacin hydrochloride according to claim 1 is characterized in that the mol ratio of middle Moxifloxacin of step (b) and concentrated hydrochloric acid is 1:1～1:4, preferred 1:1～1:1.2.
10. the preparation method of Moxifloxacin hydrochloride according to claim 1, it is characterized in that Moxifloxacin separates in the step (b) after, be that 1.33～3.33kpa, temperature are dry under 30-50 ℃ the condition to Moxifloxacin at pressure earlier; Moxifloxacin hydrochloride preparation and separate after, be that 1.33～3.33kpa, temperature are drying treatment under 40-50 ℃ the condition at pressure.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321083A (en) * | 2011-07-14 | 2012-01-18 | 福建省福抗药业股份有限公司 | A kind of anhydrous hydrochloric acid Moxifloxacin new crystal F and preparation method thereof |
| CN102675306A (en) * | 2011-03-17 | 2012-09-19 | 苏州中科天马肽工程中心有限公司 | Preparing method of moxifloxacin or slat thereof |
| CN102675313A (en) * | 2011-10-12 | 2012-09-19 | 郭峰 | Preparation method of moxifloxacin hydrochloride |
| CN103543230A (en) * | 2012-07-09 | 2014-01-29 | 北大方正集团有限公司 | Method for separating and measuring moxifloxacin hydrochloride and enantiomer thereof |
| CN104725377A (en) * | 2014-04-04 | 2015-06-24 | 江苏天一时制药有限公司 | New crystal form of moxifloxacin hydrochloride and preparation method thereof |
| CN104817557A (en) * | 2014-04-04 | 2015-08-05 | 江苏天一时制药有限公司 | Moxifloxacin hydrochloride stable crystal form and preparation method thereof |
| CN111024831A (en) * | 2018-10-09 | 2020-04-17 | 江苏正大丰海制药有限公司 | Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography |
| CN111320622A (en) * | 2018-12-15 | 2020-06-23 | 上虞京新药业有限公司 | Method for synthesizing moxifloxacin hydrochloride |
| CN115322191A (en) * | 2022-07-25 | 2022-11-11 | 苏州汉德创宏生化科技有限公司 | Method for synthesizing moxifloxacin hydrochloride |
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| CN1074218A (en) * | 1992-01-10 | 1993-07-14 | 拜尔公司 | Quinolone-and naphthyridonecarboxylic acid derivatives |
| EP1992626A1 (en) * | 2007-05-10 | 2008-11-19 | Sandoz AG | Process for the preparation of moxifloxacin hydrochloride |
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Patent Citations (2)
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| CN1074218A (en) * | 1992-01-10 | 1993-07-14 | 拜尔公司 | Quinolone-and naphthyridonecarboxylic acid derivatives |
| EP1992626A1 (en) * | 2007-05-10 | 2008-11-19 | Sandoz AG | Process for the preparation of moxifloxacin hydrochloride |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675306A (en) * | 2011-03-17 | 2012-09-19 | 苏州中科天马肽工程中心有限公司 | Preparing method of moxifloxacin or slat thereof |
| CN102321083A (en) * | 2011-07-14 | 2012-01-18 | 福建省福抗药业股份有限公司 | A kind of anhydrous hydrochloric acid Moxifloxacin new crystal F and preparation method thereof |
| CN102321083B (en) * | 2011-07-14 | 2013-05-15 | 福建省福抗药业股份有限公司 | Preparation method of new anhydrous moxifloxacin hydrochloride crystal F |
| CN102675313A (en) * | 2011-10-12 | 2012-09-19 | 郭峰 | Preparation method of moxifloxacin hydrochloride |
| CN103543230A (en) * | 2012-07-09 | 2014-01-29 | 北大方正集团有限公司 | Method for separating and measuring moxifloxacin hydrochloride and enantiomer thereof |
| CN104725377A (en) * | 2014-04-04 | 2015-06-24 | 江苏天一时制药有限公司 | New crystal form of moxifloxacin hydrochloride and preparation method thereof |
| CN104817557A (en) * | 2014-04-04 | 2015-08-05 | 江苏天一时制药有限公司 | Moxifloxacin hydrochloride stable crystal form and preparation method thereof |
| CN104725377B (en) * | 2014-04-04 | 2017-06-06 | 江苏天一时制药有限公司 | Crystal form of moxifloxacin hydrochloride and preparation method thereof |
| CN111024831A (en) * | 2018-10-09 | 2020-04-17 | 江苏正大丰海制药有限公司 | Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography |
| CN111320622A (en) * | 2018-12-15 | 2020-06-23 | 上虞京新药业有限公司 | Method for synthesizing moxifloxacin hydrochloride |
| CN115322191A (en) * | 2022-07-25 | 2022-11-11 | 苏州汉德创宏生化科技有限公司 | Method for synthesizing moxifloxacin hydrochloride |
| CN115322191B (en) * | 2022-07-25 | 2023-12-26 | 苏州汉德创宏生化科技有限公司 | Synthetic method of moxifloxacin hydrochloride |
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| CN101941969B (en) | 2012-05-23 |
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