CN103664940A - Preparation method of moxifloxacin impurity - Google Patents
Preparation method of moxifloxacin impurity Download PDFInfo
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- CN103664940A CN103664940A CN201410009419.3A CN201410009419A CN103664940A CN 103664940 A CN103664940 A CN 103664940A CN 201410009419 A CN201410009419 A CN 201410009419A CN 103664940 A CN103664940 A CN 103664940A
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- HBTYEEPIXANDDV-DCMVPRFGSA-N CN1[C@H](CN(C2)c(c(F)cc3c4N(C(CC5)C5C5)C=C(C(O)=O)C3=O)c4C5=O)[C@H]2CCC1 Chemical compound CN1[C@H](CN(C2)c(c(F)cc3c4N(C(CC5)C5C5)C=C(C(O)=O)C3=O)c4C5=O)[C@H]2CCC1 HBTYEEPIXANDDV-DCMVPRFGSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to a preparation method of a moxifloxacin impurity. The preparation method comprises the following step: performing esterification, substitution and hydrolysis reactions on moxifloxacin serving as a raw material to prepare 1-cyclopropyl-6-fluo-8-methoxy-7-((4aS,7aS)-1-methyl-octahydropyrrolo[3,4-b]-6-yl)-4-ox-1,4-dihydro-3-quinoline carboxylic acid, namely, an impurity M of the moxifloxacin. The preparation method has the characteristics of short synthesizing process route, easiness in process operation, high product purity and the like. The obtained substance can be applied to research of moxifloxacin hydrochloride-related substances.
Description
Technical field
The preparation method who the present invention relates to prepare a kind of Moxifloxacin impurity M, belongs to pharmaceutical chemistry field.
Background technology
Moxifloxacin hydrochloride (moxifloxacin hydrochloride, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro pyrrolo-[3,4-b] pyridine-6-yl]-4-oxygen-3-quinoline carboxylic acid hydrochloride) be that Bayer A.G researches and develops a kind of third generation Comprecin, 1999 first in Germany and U.S.'s listing.Moxifloxacin hydrochloride had both kept the anti-microbial activity of early stage quinolones to Gram-negative bacteria, have simultaneously and strengthened gram-positive microorganism, atypical pathogenic agent is as mycoplasma, chlamydozoan, and the anti-microbial activity of legionella and anerobe, there is spectrum, efficient, low toxicity, low-level resistance, without advantages such as obvious phototoxicities, can be used for treating the upper respiratory tract and lower respiratory infection.
By to Moxifloxacin hydrochloride impurity analysis, in can producing Moxifloxacin hydrochloride, impurity carry out quantitatively and qualitative, thereby improves Moxifloxacin hydrochloride quality product, for broad masses' safe medication provides safeguard.
According to the Moxifloxacin hydrochloride high performance liquid phase detection method providing in EP7.0, to find to exist one and be different from the Moxifloxacin unknown impuritie that pharmacopeia is reported about 12 minutes, research confirms that this impurity M structure is as follows:
Summary of the invention
The preparation method who the object of this invention is to provide a kind of above-mentioned Moxifloxacin impurity M.
Object of the present invention can be achieved through the following technical solutions:
A preparation method of Moxifloxacin impurity M, comprises following steps:
1) formula (I) compound 1-cyclopropyl base-6-fluoro-1,4-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro pyrrolo-[3,4-b] pyridine-6-yl]-4-oxygen-3-quinoline carboxylic acid under the effect of acid or acylating reagent with alcohol action-reaction preparation formula (II) 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro pyrrolo-[3,4-b] pyridine-6-yl]-4-oxygen-3-quinoline carboxylic ester;
2) formula (II) and the fluoro-8-methoxyl group-7-of iodomethane reaction production (III) compound 1-cyclopropyl base-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b]-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic ester;
3) formula (III) hydrolysis obtains the fluoro-8-methoxyl group-7-of formula (M) compound 1-cyclopropyl base-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b]-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid.
Step 1) in, described acid is the vitriol oil, and described acylating reagent is selected from one or more in thionyl chloride, oxalyl chloride, phosphorus oxychloride, preferably oxalyl chloride.The reaction solvent that adopts is a kind of in methyl alcohol, ethanol, propyl alcohol or Virahol; the volume ratio of acid or acylating reagent and solvent is 1:1～1: 50; preferably 1: 1～1: 5; more preferably 1: 5; temperature of reaction is 0-85 ℃; preferably 50 ℃, reaction can obtain the formula (II) of purity 95%, and product is colourless viscous liquid.
Step 2), in, selected alcohol is methyl alcohol, ethanol, propyl alcohol, Virahol, particular methanol, Virahol, more preferably Virahol.
Step 3) in, methylating reagent used is methyl iodide, solvent for use is a kind of in N'N dimethyl formamide, dioxane, tetrahydrofuran (THF), preferred N'N dimethyl formamide, temperature of reaction is 0-80 ℃, preferably 50-60 ℃, with preferably 60 ℃, obtains product and can obtain the formula (III) of 95% left and right through column chromatography (ethyl acetate: sherwood oil: methyl alcohol=10: 100: 5).
Step 3) in, while carrying out methylation reaction, alkali used is a kind of in salt of wormwood, sodium carbonate, triethylamine, preferably salt of wormwood.Methyl iodide and formula 2) molar ratio ratio be 1: 1～1: 5, preferably 1: 3-1: 5, more preferably 1: 5, alkali and formula 2) molar ratio be 1: 1～1: 3, preferably 1: 2.
Step 4) in, the sodium hydroxide solution that the reaction alkali lye used that is hydrolyzed is 10-30%, preferably 20%, solvent for use is methylene dichloride, after reaction finishes, with pH to the 6-8 left and right of hydrochloric acid soln regulation system, retain methylene dichloride phase, after dry, decompression and solvent recovery, can obtain the colourless mucus of formula (M).
Step 4) in, formula (M) prepares hydrochloride with hydrogen chloride gas, and formula (M) is dissolved in to methyl alcohol, passes into hydrogen chloride gas, can obtain the white solid of formula (M).
Step 4) in, formula (M) can be used the mixing solutions recrystallization of methyl alcohol, water (1: 1), obtains the white crystal of formula (M), and purity can reach more than 98%.
In one embodiment, the preparation method of formula (M) compound can be prepared by following route:
The present invention is with 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro pyrrolo-[3,4-b] pyridine-6-yl]-4-oxygen-3-quinoline carboxylic acid is starting raw material, through reactions such as over-churning, replacement, hydrolysis, the fluoro-8-methoxyl group-7-of preparation 1-cyclopropyl-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b]-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid, i.e. a kind of impurity M of Moxifloxacin.It is short that the present invention has synthesis route, and technological operation is simple, and product purity is compared with high.Gained material can be used for the research of Moxifloxacin hydrochloride related substances.
Embodiment
By specific embodiment, the present invention is further elaborated, but right of the present invention is not limited to embodiment content.For the those of ordinary skill of technical field of the present invention, without departing from the inventive concept of the premise, can also make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment mono-
Step 1: 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro pyrrolo-[3,4-b] pyridine-6-yl] preparation of-4-oxygen-3-quinoline carboxylic isopropyl ester
In the there-necked flask of 250mL, add Virahol 100mL, under stirring, add 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro pyrrolo-[3,4-b] pyridine-6-yl]-4-oxygen-3-quinoline carboxylic acid (10g, 0.025mol), add again DMF3-5 to drip, be cooled to 0 ℃, slowly drip oxalyl chloride (16.0g, 0.125mol), dropwise insulated and stirred 30min, then be warming up to 50 ℃ of stirring reaction 8h, stopped reaction, 50 ℃ of decompression and solvent recoveries, obtain colourless mucus 9.7g.
1HNMR(DMSO-d
6，400MHz)δppm：9.68(s，1H，ArH)，8.67(s，1H，NH)，7.70(d，1H，ArH)，4.16(m，1H，CH
2)，4.07(m，1H，CH
2)，3.87(m，2H，CH
2)，3.75(m，1H，CH
2)，3.56(m，4H，CH
2)，3.20(d，1H，CH)，2.94(d，1H，CH)，2.66(m，1H，CH)，2.50(s，3H，CH
3)，2.46(s，3H，CH
3)，1.79(m，4H，CH
2)，1.81(m，1H，CH
2)，1.77(m，1H，CH
2)，1.74(m，1H，CH
2)，1.69(m，1H，CH
2)；MS(FAB)：416(M+1)
The preparation of the fluoro-8-methoxyl group-7-of step 2 1-cyclopropyl-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b]-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid isopropyl ester
Above-mentioned mucus is put in N'N-dimethyl formamide (50mL), stirred lower dissolving, under room temperature, add salt of wormwood (6.9g, 0.05mol), then by methyl iodide (15.4g, 0.125mol) add, stirring at room 1h, is warming up to 60 ℃ of stirring reaction 4h.Stopped reaction, puts into reaction solution in water (500mL), and with methylene dichloride (100mL * 3) extraction, combined dichloromethane solution, anhydrous sodium sulfate drying spends the night.Decompression and solvent recovery, obtains water white transparency mucus.Products therefrom column chromatography (ethyl acetate: sherwood oil: methyl alcohol=10: 100: 5) obtains light yellow mucus 5.3g.
1HNMR(DMSO-d
6，400MHz)δppm：9.69(s，1H，ArH)，7.73(d，1H，ArH)，4.61(m，1H，CH
2)3.83(m，2H，CH
2)，3.72(m，1H，CH
2)，3.55(m，4H，CH
2)，3.20(d，1H，CH)，2.94(d，1H，CH)，2.69(m，1H，CH)，2.52(s，3H，CH
3)，2.49(m，3H，CH
3)，2.41(s，3H，CH
3)，1.79(m，4H，CH
2)，1.81(m，1H，CH
2)，1.75(m，1H，CH
2)，1.72(m，1H，CH
2)，1.69(m，1H，CH
2)；MS(FAB)：430(M+1)
The fluoro-8-methoxyl group-7-of step 3 1-cyclopropyl-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b]-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid preparation
Above-mentioned mucus is put in methylene dichloride (50mL), slowly add 20% sodium hydroxide solution (30mL), stirring reaction 8h under room temperature, is cooled to 0 ℃, slowly in system, drips 10% hydrochloric acid soln, the pH to 6-8 of regulation system, insulated and stirred 30min, separatory, retains dichloromethane layer, methylene dichloride phase saturated brine (30mL) washing, anhydrous sodium sulfate drying spends the night.Decompression and solvent recovery, obtains colourless viscous liquid 3.5g, is directly used in the next step.
The preparation of the fluoro-8-methoxyl group-7-of step 4 1-cyclopropyl-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b]-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid hydrochloride
Above-mentioned mucus is dissolved in methyl alcohol (20mL), under stirring under room temperature, slowly in solution, passes into hydrogen chloride gas, along with the adularescent solid that passes into of hydrochloric acid produces, ventilation 10min left and right, stops ventilation, stirring reaction 4h under room temperature, filter methyl alcohol for filter cake (5mL) washing.50 ℃ of vacuum-dryings, obtain white solid 2.7g.
1HNMR(DMSO-d
6，400MHz)δppm：15.12(s，1H，COOH)，9.69(s，1H，ArH)，7.73(d，1H，ArH)，4.61(m，1H，CH
2)3.83(m，2H，CH
2)，3.72(m，1H，CH
2)，3.55(m，4H，CH
2)，3.20(d，1H，CH)，2.94(d，1H，CH)，2.69(m，1H，CH)，2.52(s，3H，CH
3)，2.49(m，3H，CH
3)，2.41(s，3H，CH
3)，1.79(m，4H，CH
2)，1.81(m，1H，CH
2)，1.75(m，1H，CH
2)，1.72(m，1H，CH
2)，1.69(m，1H，CH
2)；MS(FAB)：416(M+1)
The fluoro-8-methoxyl group-7-of step 5 1-cyclopropyl-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b]-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid hydrochloride is refining
Above-mentioned white solid is put in the mixing solutions (15mL) of methyl alcohol, water (1: 1), be warming up to 60 ℃, stir 30min, be naturally cooled to room temperature, stir 2h, filter, dry, obtain the fluoro-8-methoxyl group-7-of 1-cyclopropyl-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b]-6-yl) the white crystal 1.4g of-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid hydrochloride (M).
It is 99% left and right that HPLC detects chemical purity.
Claims (8)
1. a preparation method for Moxifloxacin hydrochloride impurity formula (M) compound, its feature comprises following steps:
1) formula (I) compound 1-cyclopropyl base-6-fluoro-1,4-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro pyrrolo-[3,4-b] pyridine-6-yl]-4-oxygen-3-quinoline carboxylic acid under the effect of acid or acylating reagent with alcohol action-reaction preparation formula (II) 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro pyrrolo-[3,4-b] pyridine-6-yl]-4-oxygen-3-quinoline carboxylic ester;
2) formula (II) and iodomethane reaction production (III) compound 1-cyclopropyl base-6-fluoro-8-methoxyl group-74 (4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b] pyridine-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic ester;
3) formula (III) hydrolysis obtains the fluoro-8-methoxyl group-7-of formula (M) compound 1-cyclopropyl base-6-((4aS, 7aS)-1-methyl-octahydro pyrrolo-[3,4-b] pyridine-6-yl)-4-oxygen-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid.
2. preparation method according to claim 1; it is characterized in that step 1) in; described acid is the vitriol oil; described acylating reagent is selected from one or more in thionyl chloride, oxalyl chloride, phosphorus oxychloride; the reaction solvent that adopts is a kind of in methyl alcohol, ethanol, propyl alcohol or Virahol; the volume ratio of acid or acylating reagent and solvent is 1: 1～1: 50, and temperature of reaction is 0-85 ℃.
3. preparation method according to claim 1, is characterized in that step 2) in, selected alcohol is methyl alcohol, ethanol, propyl alcohol, Virahol.
4. preparation method according to claim 1, is characterized in that step 3) in, methylating reagent used is methyl iodide, and solvent for use is a kind of in N'N dimethyl formamide, dioxane, tetrahydrofuran (THF), and temperature of reaction is 0-80 ℃.
5. preparation method according to claim 1, is characterized in that step 3) in, while carrying out methylation reaction, alkali used is a kind of in salt of wormwood, sodium carbonate, triethylamine.Methyl iodide and formula 2) molar ratio ratio be 1: 1～1: 5, alkali and formula 2) molar ratio be 1: 1～1: 3.
6. preparation method according to claim 1, is characterized in that step 4) in, the sodium hydroxide solution that the reaction alkali lye used that is hydrolyzed is 10-30%, solvent for use is methylene dichloride.
7. preparation method according to claim 1, is characterized in that step 4) in, formula (M) prepares hydrochloride with hydrogen chloride gas, and solvent for use is methyl alcohol.
8. preparation method according to claim 1, is characterized in that step 4) in, the mixing solutions recrystallization of the available methanol-water of formula (M), the ratio of methanol-water is 1: 1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928217A (en) * | 2015-12-31 | 2017-07-07 | 江苏天时制药有限公司 | A kind of Analogue of moxifloxacin and preparation method thereof, purposes |
| CN107880036A (en) * | 2017-09-27 | 2018-04-06 | 浙江海洋大学 | A kind of 2 oxo 2 (aryl aniline) ethyls substitution MOXIFLOXACIN series compound with anti-prostate cancer activity |
| CN107880037A (en) * | 2017-09-27 | 2018-04-06 | 浙江海洋大学 | A kind of 2 oxos 2（Aryl aniline）The synthetic method of ethyl substitution MOXIFLOXACIN series compound and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130059880A1 (en) * | 2011-07-29 | 2013-03-07 | F.I.S. - Fabbrica Italiana Sintetici S.P.A. | Moxifloxacin hydrochloride compounds and intermediates and methods for making same |
| CN103396416A (en) * | 2013-07-17 | 2013-11-20 | 南京优科生物医药研究有限公司 | Preparation method of moxifloxacin impurity F |
| CN103467466A (en) * | 2013-09-04 | 2013-12-25 | 桂林南药股份有限公司 | Synthesis method of moxifloxacin hydrochloride impurity |
-
2014
- 2014-01-09 CN CN201410009419.3A patent/CN103664940A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130059880A1 (en) * | 2011-07-29 | 2013-03-07 | F.I.S. - Fabbrica Italiana Sintetici S.P.A. | Moxifloxacin hydrochloride compounds and intermediates and methods for making same |
| CN103396416A (en) * | 2013-07-17 | 2013-11-20 | 南京优科生物医药研究有限公司 | Preparation method of moxifloxacin impurity F |
| CN103467466A (en) * | 2013-09-04 | 2013-12-25 | 桂林南药股份有限公司 | Synthesis method of moxifloxacin hydrochloride impurity |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928217A (en) * | 2015-12-31 | 2017-07-07 | 江苏天时制药有限公司 | A kind of Analogue of moxifloxacin and preparation method thereof, purposes |
| CN107880036A (en) * | 2017-09-27 | 2018-04-06 | 浙江海洋大学 | A kind of 2 oxo 2 (aryl aniline) ethyls substitution MOXIFLOXACIN series compound with anti-prostate cancer activity |
| CN107880037A (en) * | 2017-09-27 | 2018-04-06 | 浙江海洋大学 | A kind of 2 oxos 2（Aryl aniline）The synthetic method of ethyl substitution MOXIFLOXACIN series compound and application |
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Application publication date: 20140326 |