CN104860944A - Production method of moxifloxacin hydrochloride - Google Patents
Production method of moxifloxacin hydrochloride Download PDFInfo
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- CN104860944A CN104860944A CN201510312292.7A CN201510312292A CN104860944A CN 104860944 A CN104860944 A CN 104860944A CN 201510312292 A CN201510312292 A CN 201510312292A CN 104860944 A CN104860944 A CN 104860944A
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- 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 discloses a production method of moxifloxacin hydrochloride. The method comprises the following steps: with an intermediate 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ethyl ester of gatifloxacin and (S,S)-2,8-diazacyclo bicycle[4,3,0] nonane as initial materials, chelating, condensing, and salifying to prepare the moxifloxacin hydrochloride. The production method has the beneficial effects that the production technology is relatively mild, easy to operate, free of a special requirement on equipment, relatively high in yield, and suitable for industrialized mass production.
Description
Technical field
The present invention relates to a kind of pharmaceutical methods, i.e. the production method of Moxifloxacin hydrochloride.
Background technology
Moxifloxacin hydrochloride chemical name: the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6--dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro-6H-pyrrolo-[3,4-b] pyridine-6-base]-4-oxo-3-quinoline carboxylic acid hydrochloride
Structural formula:
Molecular formula: C
21h
24fN
3o
4hCl
Molecular weight: 437.89
Moxifloxacin hydrochloride (Moxinoxacin) is a new 8-methoxy fluoroquinolone class broad spectrum antibiotic, and its chemical structure has significantly different from other fluoroquinolone veriety, and 8 carbon atoms of its molecular structure introduce methoxy group.This medicine is the kind new medicine developed by German Bayer company, and within 1999, first in Germany's listing, successively in country's listing and application such as Britain, the U.S., Mexico, 2002 in Discussion on Chinese Listed.This product had both maintained the anti-microbial activity of early stage fluoroquinolones to gram-negative bacteria, enhance gram positive coccus simultaneously, atypical pathogens is as mycoplasma, chlamydozoan, and the anti-microbial activity of legionella and anerobe, there is wide spectrum, efficient, low toxicity, in low-level resistance, without advantages such as obvious phototoxicities, can be used for treating respiratory tract infection.This product oral absorption is quick and complete, and the concentration in respiratory tract is significantly higher than Main Pathogenic Bacteria---streptococcus pneumoniae, the minimal inhibitory concentration (MIC of hemophilus influenzae and moraxelle catarrhalis
90), also have bacterial strain this product of penicillin and Macrolide resistance and act on well.Moxifloxacin hydrochloride untoward reaction is slight, the impact that unable to take food thing is taken in, and drug drug interaction is few, is specially adapted to the outpatient service treatment of respiratory tract infection.The mechanism of action of Moxifloxacin hydrochloride is interference II, IV topoisomerase, topoisomerase is DNA replication dna, repair and transcribe in key enzyme.From molecular composition, Moxifloxacin hydrochloride is by 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxo-1,4-dihydro-3-quinolinic acid and (S, S)-octahydro-6H-pyrrolo-[3,4, b] pyridine two portions composition, with Moxifloxacin hydrochloride obtained after hydrochloric acid salify.
Moxifloxacin hydrochloride synthesis document is more, enumerates following several according to the type of production method:
Synthetic method disclosed in patent 93100215.X " quinolonecarboxylic acid and naphthalene piperidine ketone acid derivant ":
The method be the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid with (S, S)-2,8-diazacyclo dicyclo [4,3,0] nonane directly carry out condensation reaction, then with hydrochloric acid salify.The method is directly simple, but in reaction process, be difficult to the competitive substitution avoiding producing C6-F and C7-F, and form by product, more difficult separation, affects the quality of product.
Synthetic method disclosed in patent CN1279683A " preparation method of 8-methoxy-quinolone ":
The method with the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7,8-tri--dihydro-4-oxo-3-quinoline carboxylic acid first with (S, S)-2,8-diazacyclo dicyclo [4,3,0] nonane carry out condensation reaction, then carry out the methoxyl group of in condensation 8 with sodium methylate.But (S, S)-2,8-diazacyclo dicyclo [4 in the market, 3,0] price of nonane is more expensive, and at (S, S)-2,8-diazacyclo dicyclos [4,3,0] also have single step reaction after nonane condensation, final finished is for (S, S)-2, the turnover ratio of 8-diazacyclo dicyclo [4,3,0] nonane is not high, product cost is high, does not have economic worth.
Synthetic route disclosed in patent WO2005012285 " AN IMPROVED PROCESS FOR THEPREPARATION OF MOXIFLOXACIN HYDROCHLORIDE ":
The method is with boric acid and diacetyl oxide and 1-cyclopropyl-6,7-bis-fluoro-1,4-dihydro-8-methoxyl group-4-oxo--3-quinoline carboxylic acid ethyl ester reacting by heating generates inner complex, again with (S, S)-2,8-diazacyclo dicyclos [4,3,0] nonane generation condensation reaction, generates Moxifloxacin hydrochloride with hydrochloric acid reaction.This patent setting-up point is higher, and the color of products obtained therefrom is comparatively dark, and the impurity N-methyl Moxifloxacin content of generation is higher, and not easily removes, and aftertreatment is comparatively loaded down with trivial details, is unfavorable for industrialized production.
The disclosed synthetic method of patent CN102675306A " preparation method of a kind of Moxifloxacin or its salt ":
The method is 1-cyclopropyl-6,7-bis-fluoro-1,4-dihydro-8-methoxyl group-4-oxo--3-quinoline carboxylic acid ethyl ester and (S, S)-2,8-diazacyclo dicyclo [4,3,0] nonane take ethanol as solvent, Lewis acid is catalyzer direct reaction, add water after reaction and hydrochloric acid be hydrolyzed and obtain.This route can produce a large amount of hydrofluoric acid, not only poisonous, and corrodibility is strong, and the metal catalyst added is easy and carboxylic acid forms complex compound, not easily removes, and the little ring consumption of Moxifloxacin is also comparatively large, is unfavorable for industrialized production.
The synthetic method of the disclosed Moxifloxacin hydrochloride of patent CN200910104481 " a kind of synthetic method of Moxifloxacin hydrochloride ":
The method Raw quinoline promise carboxylic acid fluoro complex not easily obtains, and adds the step of protection deprotection, operation steps is extended, is not suitable for industrialized production.
The synthetic method of the disclosed Moxifloxacin hydrochloride of patent WO2008059521 " NOVEL PROCESS FOR THE PREPARATION OFMOXIFLOXACIN HYDROCHLORIDE AND A NOVEL POLYMORPH OFMOXIFLOXACIN ":
The method is that the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo--3-quinoline carboxylic acid and diethylamine are at N, the lower condensation of N-dicyclohexylcarbodiimide/I-hydroxybenzotriazole (DCC/HOBT) effect obtains acid amides thing, acid amides thing and (S, S)-2,8-diazacyclo dicyclo [4,3,0] nonane is 1, and 8, diazacyclo [5,4,0 [there is nucleophilic substitution reaction under hendecene-7 (DBU) existence, then obtains Moxifloxacin hydrochloride with HCl treatment.But DCC is strong carcinogen, and DBU is expensive, is not suitable for industrialized production.
The synthesis of Moxifloxacin hydrochloride is in fact parent nucleus C
7position and side chain (S, S)-2,8-diazacyclo dicyclo [4,3,0] nonane generation nucleophilic substitution reaction, although C
7position is in the contraposition of 4 carbonyls, and cloud density is relatively low, nucleophilic substitution reaction occurs, but C
8the electronic effect that pushes away by force of position methoxyl group reduces C
7the activity of leaving away of-F, not easily reacts nucleophilic substitution reaction; In addition, C
7-F and C
6also there is competitive substitution between-F, therefore reduce C further
7the effect that position cloud density reacts in this step is most important.According to the method for synthesis Gatifloxacin, if by parent nucleus and side chain direct polycondensation, yield is very low; Adopt chelating method that yield can be made greatly to improve.
Summary of the invention
The present invention seeks to overcome the deficiencies in the prior art and technological difficulties, provide a kind of technics comparing gentle, easy handling, do not have special requirement to equipment, yield is higher, and cost is low, little to environmental influence, be applicable to the Moxifloxacin hydrochloride production method of industrialized mass.
Above-mentioned purpose is realized by following technical scheme: the production method providing a kind of Moxifloxacin hydrochloride, is characterized in: described production method comprises following steps:
1) in reaction flask, diacetyl oxide, boric acid, zinc chloride is added, in 90 ~ 110 DEG C of reactions 1 ~ 3 hour, add the fluoro-Isosorbide-5-Nitrae of intermediate 1-cyclopropyl-6, the 7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester of Gatifloxacin, in 80 ~ 120 DEG C of reactions 1 ~ 5 hour, reaction Bi Jiangwen, crystallization, filters, drying, obtains inner complex.The mol ratio of the wherein fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester and diacetyl oxide, boric acid, zinc chloride is 1: 2 ~ 10: 0.5 ~ 3: 0.1 ~ 1.
2) in reaction flask, add acetonitrile, inner complex, triethylamine, in the acetonitrile solution of 10 ~ 70 DEG C of dropping (S, S)-2,8-diazacyclo dicyclo [4,3,0] nonanes, after dropwising, in 10 ~ 70 DEG C of reactions 1 ~ 5 hour, react complete.Concentrating under reduced pressure, adds dissolve with ethanol, and temperature control 0 ~ 30 DEG C drips concentrated hydrochloric acid salify, crystallization, filters, dry, obtains Moxifloxacin hydrochloride.Wherein inner complex and triethylamine, (S, S)-2,8-the mol ratio of diazacyclo dicyclo [4,3,0] nonane be 1: 0.5 ~ 3: 0.5 ~ 3; Wherein the weight ratio of inner complex and acetonitrile is 1: 1 ~ 10.
Above-mentioned steps 1) in aftertreatment, reaction Bi Jiangwen, crystallisation step: reaction is finished to cool to 10 ~ 40 DEG C and added water, stir 1 ~ 5 hour in 10 ~ 40 DEG C, wherein 1-cyclopropyl-6, the weight ratio of the fluoro-Isosorbide-5-Nitrae of 7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester and water is 1: 10 ~ 30.
Above-mentioned steps 1) in aftertreatment, filtration step: filter, be washed to mother liquor near-neutral pH to 5 ~ 7.
Above-mentioned steps 2) in, (S, S)-2,8-diazacyclo dicyclo [4,3,0] nonane acetonitrile solution in: (S, S)-2,8-the weight ratio of diazacyclo dicyclo [4,3,0] nonane and acetonitrile be 1: 1 ~ 10.
Above-mentioned steps 2) in aftertreatment, concentrating under reduced pressure step: be cooled to 10 ~ 45 DEG C, opens vacuum pump pressure and concentrates, vacuum tightness-0.04 ~-0.09MPa.
Above-mentioned steps 2) in aftertreatment, dissolving step: add ethanol stirring and dissolving, wherein the weight ratio of inner complex and ethanol is 1:1 ~ 5.
Above-mentioned steps 2) in aftertreatment, salify, crystallisation step: drip concentrated hydrochloric acid and regulate pH to 1 ~ 2, in 0 ~ 30 DEG C of crystallization 1 ~ 5 hour.
The route of the above-mentioned synthetic method of the present invention is summarized as follows:
Beneficial effect of the present invention:
1. the raw material 1-cyclopropyl-6 that the present invention is used, 7-bis-fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester is the intermediate of Gatifloxacin, with (S, S)-2,8-diazacyclo dicyclo [4,3,0] there is sale in nonane market, and price is lower, steady quality, reduces production cost.
2. the present invention significantly improves quality and the yield of product by the acetonitrile solution of control temperature dropping (S, S)-2,8-diazacyclo dicyclo [4,3,0] nonane.
3. the present invention is easy to suitability for industrialized production, relative to the technique of other documents or patent report, technique of the present invention be easier to operation, reaction conditions gentle, special requirement is not had to equipment, be applicable to industrialized mass.
4. the solvent recuperation used in the present invention is easy to use, and in present method, acetonitrile is reclaimed by concentrating under reduced pressure, and ethanol is by mother liquor Distillation recovery, and the acetonitrile of recovery and ethanol can reuse, and reduce manufacturing cost, decrease the impact on environment.
Accompanying drawing explanation
Fig. 1 is the schema of this synthetic method;
Fig. 2 is the HPLC spectrogram of Moxifloxacin hydrochloride product of the present invention;
Fig. 3 is the HPLC spectrogram of reference product Moxifloxacin hydrochloride.
Embodiment
Make explanation specifically below by way of specific embodiment to content of the present invention, but protection scope of the present invention is not limited to following examples, every technology, technique realized based on technical scheme of the present invention all belongs to equivalency range of the present invention.
The first embodiment:
1) 1-cyclopropyl-6, 7-bis-fluoro-1, the preparation of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester inner complex: in reaction flask, add diacetyl oxide 300g, zinc chloride 20, boric acid 50g, be heated to 100 DEG C of reactions 2 hours, be cooled to 50 DEG C, add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 150g, be warming up to 110 DEG C of reactions 3 hours, reaction Bi Jiangzhi 30 DEG C, add water 3000ml, stir 3 hours in 25 DEG C, filter, be washed to mother liquor near-neutral pH to 6, 60 DEG C of dryings, obtain off-white color solid 182g yield 92.7%, mp:114.5 DEG C (standard is 113 ~ 117 DEG C).
2) preparation of Moxifloxacin hydrochloride: add acetonitrile 800g, inner complex 160g in reaction flask, triethylamine 50g, drips (S in 25 DEG C, S)-2,8-diazacyclo dicyclos [4,3,0] acetonitrile solution ((S, S)-2,8-diazacyclo dicyclo [4 of nonane, 3,0] nonane 47g, acetonitrile 100g), after dropwising, in 25 DEG C of reactions 3 hours, react complete.Open vacuum pump pressure concentrated (vacuum tightness-0.04 ~-0.09MPa), concentrated completely add ethanol 800g, stirring and dissolving, temperature control 25 DEG C drips concentrated hydrochloric acid, is adjusted to pH=2, in 25 DEG C of crystallizations 3 hours.Filter, wash with ethanol, 60 DEG C of constant pressure and dries, obtain yellow crystalline solid 125g yield 75.5%, specific optical rotation [a]
d 20for-126 ° (standard is-125 ° to-138 °).
The second embodiment:
1) 1-cyclopropyl-6, 7-bis-fluoro-1, the preparation of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester inner complex: in reaction flask, add diacetyl oxide 100g, zinc chloride 6, boric acid 15g, be heated to 100 DEG C of reactions 2 hours, be cooled to 50 DEG C, add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 150g, be warming up to 110 DEG C of reactions 3 hours, reaction Bi Jiangzhi 30 DEG C, add water 1500ml, stir 3 hours in 25 DEG C, filter, be washed to mother liquor near-neutral pH to 6, 60 DEG C of dryings, obtain off-white color solid 175g yield 89.1%, mp:116.2 DEG C (standard is 113 ~ 117 DEG C).
2) preparation of Moxifloxacin hydrochloride: add acetonitrile 200g, inner complex 160g in reaction flask, triethylamine 20g, drips (S in 25 DEG C, S)-2,8-diazacyclo dicyclos [4,3,0] acetonitrile solution ((S, S)-2,8-diazacyclo dicyclo [4 of nonane, 3,0] nonane 30g, acetonitrile 50g), after dropwising, in 25 DEG C of reactions 3 hours, react complete.Open vacuum pump pressure concentrated (vacuum tightness-0.04 ~-0.09MPa), concentrated completely add ethanol 200g, stirring and dissolving, temperature control 25 DEG C drips concentrated hydrochloric acid, is adjusted to pH=2, in 25 DEG C of crystallizations 3 hours.Filter, wash with ethanol, 60 DEG C of constant pressure and dries, obtain yellow crystalline solid 121g yield 73.1%, specific optical rotation [a]
d 20for-128 ° (standard is-125 ° to-138 °).
The third embodiment:
1) 1-cyclopropyl-6, 7-bis-fluoro-1, the preparation of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester inner complex: in reaction flask, add diacetyl oxide 500g, zinc chloride 60, boric acid 85g, be heated to 100 DEG C of reactions 2 hours, be cooled to 50 DEG C, add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 150g, be warming up to 110 DEG C of reactions 3 hours, reaction Bi Jiangzhi 30 DEG C, add water 4500ml, stir 3 hours in 25 DEG C, filter, be washed to mother liquor near-neutral pH to 7, 60 DEG C of dryings, obtain off-white color solid 186g yield 94.7%, mp:114.8 DEG C (standard is 113 ~ 117 DEG C).
2) preparation of Moxifloxacin hydrochloride: add acetonitrile 1500g, inner complex 160g in reaction flask, triethylamine 110g, drips (S in 25 DEG C, S)-2,8-diazacyclo dicyclos [4,3,0] acetonitrile solution ((S, S)-2,8-diazacyclo dicyclo [4 of nonane, 3,0] nonane 130g, acetonitrile 250g), after dropwising, in 25 DEG C of reactions 3 hours, react complete.Open vacuum pump pressure concentrated (vacuum tightness-0.04 ~-0.09MPa), concentrated completely add ethanol 800g, stirring and dissolving, temperature control 25 DEG C drips concentrated hydrochloric acid, is adjusted to pH=2, in 25 DEG C of crystallizations 3 hours.Filter, wash with ethanol, 60 DEG C of constant pressure and dries, obtain yellow crystalline solid 128g yield 77.3%, specific optical rotation [a]
d 20for-129 ° (standard is-125 ° to-138 °).
4th kind of embodiment:
1) 1-cyclopropyl-6, 7-bis-fluoro-1, the preparation of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester inner complex: in reaction flask, add diacetyl oxide 300g, zinc chloride 10, boric acid 50g, be heated to 110 DEG C of reactions 1 hour, be cooled to 50 DEG C, add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 150g, be warming up to 120 DEG C of reactions 1 hour, reaction Bi Jiangzhi 40 DEG C, add water 3000ml, stir 5 hours in 35 DEG C, filter, be washed to mother liquor near-neutral pH to 6, 60 DEG C of dryings, obtain off-white color solid 181g yield 92.2%, mp:116.5 DEG C (113 ~ 117 DEG C, document).
2) preparation of Moxifloxacin hydrochloride: add acetonitrile 800g, inner complex 160g in reaction flask, triethylamine 40g, drips (S in 65 DEG C, S)-2,8-diazacyclo dicyclos [4,3,0] acetonitrile solution ((S, S)-2,8-diazacyclo dicyclo [4 of nonane, 3,0] nonane 50g, acetonitrile 150g), after dropwising, in 65 DEG C of reactions 1 hour, react complete.Open vacuum pump pressure concentrated (vacuum tightness-0.04 ~-0.09MPa), concentrated completely add ethanol 800g, stirring and dissolving, temperature control 30 DEG C drips concentrated hydrochloric acid, is adjusted to pH=1, in 30 DEG C of crystallizations 5 hours.Filter, wash with ethanol, 60 DEG C of constant pressure and dries, obtain yellow crystalline solid 129g yield 77.9%, specific optical rotation [a]
d 20for-130 ° (standard is-125 ° to-138 °).
5th kind of embodiment:
1) 1-cyclopropyl-6, 7-bis-fluoro-1, the preparation of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester inner complex: in reaction flask, add diacetyl oxide 300g, zinc chloride 10, boric acid 50g, be heated to 90 DEG C of reactions 3 hours, be cooled to 40 DEG C, add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 150g, be warming up to 80 DEG C of reactions 5 hours, reaction Bi Jiangzhi 35 DEG C, add water 3000ml, stir 1 hour in 10 DEG C, filter, be washed to mother liquor near-neutral pH to 7, 60 DEG C of dryings, obtain off-white color solid 188g yield 95.8%, mp:115.8 DEG C (113 ~ 117 DEG C, document).
2) preparation of Moxifloxacin hydrochloride: add acetonitrile 800g, inner complex 160g in reaction flask, triethylamine 40g, drips (S in 10 DEG C, S)-2,8-diazacyclo dicyclos [4,3,0] acetonitrile solution ((S, S)-2,8-diazacyclo dicyclo [4 of nonane, 3,0] nonane 50g, acetonitrile 150g), after dropwising, in 10 DEG C of reactions 5 hours, react complete.Open vacuum pump pressure concentrated (vacuum tightness-0.04 ~-0.09MPa), concentrated completely add ethanol 800g, stirring and dissolving, temperature control 0 DEG C drips concentrated hydrochloric acid, is adjusted to pH=2, in 0 DEG C of crystallization 1 hour.Filter, wash with ethanol, 60 DEG C of constant pressure and dries, obtain yellow crystalline solid 131g yield 79.1%, specific optical rotation [a]
d 20for-126 ° (standard is-125 ° to-138 °).
6th kind of embodiment:
1) 1-cyclopropyl-6, 7-bis-fluoro-1, the preparation of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester inner complex: in reaction flask, add diacetyl oxide 300g, zinc chloride 10, boric acid 50g, be heated to 100 DEG C of reactions 2 hours, be cooled to 40 DEG C, add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 150g, be warming up to 100 DEG C of reactions 2 hours, reaction Bi Jiangzhi 25 DEG C, add water 3000ml, stir 3 hours in 25 DEG C, filter, be washed to mother liquor near-neutral pH to 7, 60 DEG C of dryings, obtain off-white color solid 180g yield 91.7%, mp:116.6 DEG C (standard is 113 ~ 117 DEG C).
2) preparation of Moxifloxacin hydrochloride: add acetonitrile 800g, inner complex 160g in reaction flask, triethylamine 40g, drips (S in 40 DEG C, S)-2,8-diazacyclo dicyclos [4,3,0] acetonitrile solution ((S, S)-2,8-diazacyclo dicyclo [4 of nonane, 3,0] nonane 50g, acetonitrile 150g), after dropwising, in 40 DEG C of reactions 2 hours, react complete.Open vacuum pump pressure concentrated (vacuum tightness-0.04 ~-0.09MPa), concentrated completely add ethanol 800g, stirring and dissolving, temperature control 20 DEG C drips concentrated hydrochloric acid, is adjusted to pH=2, in 20 DEG C of crystallizations 2 hours.Filter, wash, 60 DEG C of constant pressure and dries, obtain yellow crystalline solid 135g yield 81.5% with ethanol, specific optical rotation [a] D20 is-127 ° (standard is for-125 ° to-138 °).
Experimental example:
In order to investigate the quality of the Moxifloxacin hydrochloride that the present invention produces, we and kinds of processes have carried out a large amount of contrast experiments, all prove that the present invention has advantage in quality or production cost.Particularly contrast with chelating technique relatively, obtain the result of affirmative.Only exemplify an example below:
The Moxifloxacin hydrochloride product of Moxifloxacin hydrochloride product of the present invention and patent WO2005012285 is contrasted.Analyzed by high performance liquid chromatography (HPLC), obtain Fig. 2 and Fig. 3 of Figure of description.Wherein, Fig. 2 is the Moxifloxacin hydrochloride HPLC spectrogram that the present invention produces; Its experimental data is as table 1:
Table 1
Peak table
Detector A Ch1 293nm
| Peak # | Title | Retention time | Highly | Area | Area % | Theoretical tray # | Resolution | Tailing factor |
| 1 | 20.559 | 317 | 11069 | 0.027 | 9037 | 0.00 | 0.90 | |
| 2 | Moxifloxacin hydrochloride | 23.017 | 869687 | 40988503 | 99.973 | 5449 | 2.33 | 0.91 |
| Amount to | 870004 | 40999571 | 100.000 |
Fig. 3 is the Moxifloxacin hydrochloride HPLC spectrogram produced by patent WO2005012285.Its experimental data is in table 2:
Table 2
Peak table
Survey device A Ch1 293nm
| Peak # | Title | Retention time | Highly | Area | Area % | Theoretical tray # | Resolution | Tailing factor |
| 1 | 12.013 | 123 | 3351 | 0.008 | 4272 | 0.00 | 1.07 | |
| 2 | N-methyl Moxifloxacin | 16.863 | 2200 | 87255 | 0.198 | 4156 | 5.44 | 0.89 |
| 3 | 19.288 | 676 | 22802 | 0.052 | 7459 | 2.50 | 0.80 | |
| 4 | Moxifloxacin hydrochloride | 21.620 | 886352 | 43998040 | 99.706 | 4480 | 2.13 | 0.84 |
| 5 | 34.039 | 228 | 16115 | 0.037 | 6288 | 8.25 | 1.10 | |
| Amount to | 889579 | 44127563 | 100.000 |
Experiment prove: N-methyl Moxifloxacin do not detected in the product that the present invention produces, its single impurity much smaller than 0.1%, namely lower than the requirement of CFDA.And N-methyl Moxifloxacin content occupies high detected by the product contrasting technique, visible quality product of the present invention is obviously better than the quality product of prior art.
Claims (8)
1. a production method for Moxifloxacin hydrochloride, is characterized in that: described production method comprises following steps:
Step 1: add diacetyl oxide, boric acid, zinc chloride in reaction flask, in 90 ~ 110 DEG C of reactions 1 ~ 3 hour, add 1-cyclopropyl-6,7-bis-fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester, in 80 ~ 120 DEG C of reactions 1 ~ 5 hour, reaction Bi Jiangwen, crystallization, filters, dry, obtain inner complex, wherein, 1-cyclopropyl-6, the mol ratio of the fluoro-Isosorbide-5-Nitrae of 7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester and diacetyl oxide, boric acid, zinc chloride is 1: 2 ~ 10: 0.5 ~ 3: 0.1 ~ 1;
Step 2: add acetonitrile, inner complex, triethylamine in reaction flask, drips (S, S)-2 in 10 ~ 70 DEG C, the acetonitrile solution of 8-diazacyclo dicyclo [4,3,0] nonane, after dropwising, in 10 ~ 70 DEG C of reactions 1 ~ 5 hour, react complete, concentrating under reduced pressure, add dissolve with ethanol, temperature control 0 ~ 30 DEG C drips concentrated hydrochloric acid salify, crystallization, filters, dry, obtain Moxifloxacin hydrochloride, wherein, inner complex and triethylamine, (S, S)-2, the mol ratio of 8-diazacyclo dicyclo [4,3,0] nonane is 1: 0.5 ~ 3: 0.5 ~ 3; Wherein the weight ratio of inner complex and acetonitrile is 1: 1 ~ 10.
2. the production method of a kind of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: in step 1, described reaction Bi Jiangwen, crystallisation step: reaction is finished to cool to 10 ~ 40 DEG C and added water, stir 1 ~ 5 hour in 10 ~ 40 DEG C, the weight ratio of the wherein fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester and water is 1: 10 ~ 30.
3. the production method of a kind of Moxifloxacin hydrochloride according to claim 1, is characterized in that: in step 1, described filtration step: filter, be washed to mother liquor near-neutral pH to 5 ~ 7.
4. the production method of a kind of Moxifloxacin hydrochloride according to claim 1, it is characterized in that: in step 2, described (S, S)-2,8-diazacyclo dicyclo [4,3,0] acetonitrile solution of nonane, (S, S)-2, the weight ratio of 8-diazacyclo dicyclo [4,3,0] nonane and acetonitrile is 1: 1 ~ 10.
5. the production method of a kind of Moxifloxacin hydrochloride according to claim 1, is characterized in that: in step 2, described concentrating under reduced pressure step: be cooled to 10 ~ 45 DEG C, opens vacuum pump pressure and concentrates, vacuum tightness-0.04 ~-0.09MPa.
6. the production method of a kind of Moxifloxacin hydrochloride according to claim 1, is characterized in that: in step 2, described dissolving step: add ethanol stirring and dissolving, and wherein the weight ratio of inner complex and ethanol is 1:1 ~ 5.
7. the production method of a kind of Moxifloxacin hydrochloride according to claim 1, is characterized in that: in step 2, described salify, crystallisation step: drip concentrated hydrochloric acid and regulate pH to 1 ~ 2, in 0 ~ 30 DEG C of crystallization 1 ~ 5 hour.
8. the production method of a kind of Moxifloxacin hydrochloride according to claim 1, is characterized in that: described production method is summarized by following structural formula:
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| CN108409735A (en) * | 2018-05-23 | 2018-08-17 | 武汉武药科技有限公司 | A kind of purification process of moxifloxacin hydrochloride and the preparation method of moxifloxacin hydrochloride |
| CN111777632A (en) * | 2020-07-20 | 2020-10-16 | 浙江国邦药业有限公司 | Preparation method of moxifloxacin hydrochloride chelate |
| CN115819402A (en) * | 2022-12-13 | 2023-03-21 | 无锡福祈制药有限公司 | Preparation method of balofloxacin |
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