CN102060860A - Preparation method of Marbofloxacin - Google Patents
Preparation method of Marbofloxacin Download PDFInfo
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Abstract
The invention discloses a preparation method of Marbofloxacin, which comprises the following steps: (1) mixing a compound disclosed as Formula (V) with phenylmethane, triethylamine and N-methylpiperazine, heating to react for 8-12 hours, cooling to room temperature, adding purified water and potassium hydroxide, reacting at 60-90 DEG C for 3-5 hours, cooling to 20-25 DEG C, separating out a water phase, regulating the pH value of the water phase to 6.8-7.2 with hydrochloric acid, extracting with dichloromethane, and concentrating while depressurizing to obtain a compound disclosed as Formula (IV); and (2) reacting the compound disclosed as Formula (IV) with potassium hydroxide in medium water at 125-160 DEG C under the pressure of 0.1-0.4 MPa for 5-12 hours to obtain a compound disclosed as Formula (II), dropwisely adding a formic acid water solution and a formaldehyde water solution when the temperature drops to 40-50 DEG C, carrying out cyclization reaction at 70-75 DEG C for 6-10 hours, and carrying out after-treatment on the reaction product to obtain the Marbofloxacin. The invention utilizes a new intermediate to prepare Marbofloxacin, has the advantages of short reaction time, low cost and high product purity, and is suitable for commercial production.
Description
(1) technical field
The present invention relates to a kind of preparation method of animal specific antimicrobial drug, particularly a kind of novel method for preparing Marbofloxacin.
(2) background technology
Marbofloxacin (marbofloxacin) is the novel fluoroquinolone antibacterial agent of animal specific, chemistry is by name: 9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyridine [3,2,1-i, j] [4,1,2] Ben Bing oxadiazine-6-carboxylic acids are developed by Roche Holding Ag, and structural formula is as follows:
The Marbofloxacin intermediate: 6-fluoro-1,4-dihydro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid an alkali metal salt, its structural formula is suc as formula shown in (II):
M is an alkali metal cation.
Compound shown in the formula (II): 6-fluoro-1,4-dihydro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid an alkali metal salt is the important intermediate of synthetic Marbofloxacin, it is open already in Chinese patent CN1053907C, and this patent system is equipped with the method for Marbofloxacin shown in Scheme1:
This method is that the compound shown in the through type (III) reacted about 20～100 hours with the normal alkali metal hydroxide of 10mol at least in 80～120 ℃ in water medium, generation is suc as formula the Marbofloxacin intermediate shown in (II), wherein can produce ethanol in the hydrolytic process, ethanol can generate the impurity E that European Pharmacopoeia 6.1 is put down in writing with the hydroxyl reaction in the formula (II).Use formic acid formaldehyde that formula (II) is carried out ring-closure reaction then, obtain the Marbofloxacin shown in the formula (I) with the alkali neutralization at last.
Aforesaid method long reaction time, and the impurity shown in the meeting formula of generation (E) in the reaction process obviously needs repeatedly refining could the removal, and the production cost height is unfavorable for commercially producing.
(3) summary of the invention
The purpose of this invention is to provide a kind of novel method for preparing the high purity Marbofloxacin, this method reaction times is short, and the purity height has reduced production cost, suitable commercially producing.
The technical solution used in the present invention is as follows:
A kind of preparation method suc as formula the Marbofloxacin shown in (I), described method is carried out according to following steps: (1) is with 6 shown in the formula V, 7,8-three fluoro-1,4-dihydro-1-(N-methyl formamido group)-4-oxo-3-quinoline carboxylic acid ethyl ester and toluene, triethylamine and N methyl piperazine mix, be heated to backflow, reaction 8～12h, be cooled to room temperature, add entry and potassium hydroxide, be warming up to 60～90 ℃ of reactions 3～5 hours again, be cooled to 20～25 ℃, tell water, water is transferred pH to 6.8～7.2 with hydrochloric acid, uses dichloromethane extraction then, gets the dichloromethane layer concentrating under reduced pressure and gets compound shown in the formula (IV): 6,8-two fluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid; Compound shown in the described formula V is 1: 4～7: 0.2～0.6: 0.4～0.6: 4～7: 0.3～0.8 with the ratio of the quality that feeds intake of toluene, triethylamine, N methyl piperazine, water and potassium hydroxide; (2) with compound shown in the formula (IV) in water medium, 125～160 ℃ in 0.1～0.4Mpa time and potassium hydroxide reaction 5～12h, obtain compound shown in the formula (II): 6-fluoro-1,4-dihydro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid or its sylvite, reaction solution is cooled to 40～50 ℃, drip aqueous formic acid, formalin, be warming up to 70～75 ℃ of cyclization 6～10h, reactant obtains Marbofloxacin shown in the formula (I) through aftertreatment; The mass ratio of compound and water, potassium hydroxide is 1: 1.67～3.34: 0.79～1.59 shown in the formula (IV) described in the step (2); The volumetric usage that the volumetric usage of described aqueous formic acid folding hundred back formic acid is counted 1.33～2.66mL/g, formalin folding hundred back formaldehyde with the quality of compound shown in the formula (IV) is counted 0.81～1.62mL/g with the quality of compound shown in the formula (IV);
M is H or alkali metal cation in the formula (II), and described alkali metal cation is K
+
The volume of the said aqueous formic acid of the present invention, formalin folding hundred back formic acid, formaldehyde is meant the volume that is converted to pure formic acid, formaldehyde, and formic acid, formaldehyde can add with the form of its aqueous solution usually, and water of the present invention recommends to use purified water usually.
In the described step (1) compound shown in the formula V be preferably 1: 4 with the ratio of the quality of toluene, triethylamine, N methyl piperazine, water and potassium hydroxide～5: 0.3～0.4: 0.4～0.46: 5.6～6.8: 0.43～0.75.
Hydrochloric acid equivalent concentration is 6～12mol in the described step (1).
The temperature of reaction of reaction solution and potassium hydroxide is 125 ℃ in the described step (2), and the reaction times is 12h.
The mass ratio of compound and water, potassium hydroxide is 1: 2.4～3: 1.1～1.2 shown in the formula (IV) described in the described step (2), more preferably 1: 1.8～3: 1.0～1.5; The volumetric usage of described aqueous formic acid folding hundred back formic acid is preferably 1.60～2.13mL/g, formalin folding hundred back formaldehyde in the quality of compound shown in the formula (IV) volumetric usage is preferably 1.08～1.35mL/g in the quality of compound shown in the formula (IV).
Formic acid described in the described step (2) adds with the form of aqueous formic acid, and the mass concentration of described aqueous formic acid is 94%, and the mass concentration of described formalin is 37%.
Aftertreatment described in the described step (2) is: reaction solution is cooled to 0～5 ℃, filter, filter cake washs with purified water, filters, filter cake is dissolved with purified water, transfer pH to 8.5 with ammoniacal liquor, use dichloromethane extraction, organic addition anhydrous sodium sulfate drying, filter, the filtrate decompression distillation obtains the Marbofloxacin crude product, with 50% ethanolic soln crystallization, makes Marbofloxacin; The volumetric usage of described ethanolic soln is counted 40～50mL/g with the quality of Marbofloxacin crude product; The volumetric usage of common described methylene dichloride is preferably counted 40mL/g with Marbofloxacin crude product quality.
The mass concentration of described ammoniacal liquor is 24～28%.
Pressure in the described step (2) is the pressure that reaction system produces under temperature of reaction, does not apply any extraneous pressure.
Room temperature of the present invention typically refers to 20～25 ℃.
Compared with prior art, beneficial effect of the present invention is mainly reflected in:
The present invention utilizes new intermediate and method to prepare Marbofloxacin, shortens the reaction times, reduces production costs; Compared with prior art, products obtained therefrom purity and yield all are improved, and the impurity E generation that does not have European Pharmacopoeia 6.1 to be put down in writing, and meet the European Pharmacopoeia regulation, and suitable commercially producing has the good social economic benefit.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Purified water density is 1g/mL.
Embodiment 1: the preparation of compound shown in the intermediate formula (IV) of Marbofloxacin
Add toluene 200g successively to flask, N methyl piperazine 21.5g, triethylamine 17g, stir then and drop into 6 of 50g down, 7,8-three fluoro-1,4-dihydro-1-(N-methyl formamido group)-4-oxo-3-quinoline carboxylic acid ethyl ester is warming up to backflow, reacts 12 hours, be cooled to room temperature (25 ℃) then, add purified water 250g and potassium hydroxide 23.5g, be warming up to 90 ℃ of reactions 3 hours again, be cooled to 25 ℃, tell water, with the normal hydrochloric acid of 6mol adjust pH to 7.0, use the 250mL dichloromethane extraction then, the organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure gets 6,8-two fluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid 32.1g.
(molar yield: 74.41%, HPLC:99.79%)
Embodiment 2: the preparation of compound shown in the intermediate formula (IV) of Marbofloxacin
Add toluene 350g, N methyl piperazine 30g in flask successively, triethylamine 30g stirs then and drops into 6 of 50g down, 7,8-three fluoro-1,4-dihydro-1-(N-methyl formamido group)-4-oxo-3-quinoline carboxylic acid ethyl ester, be warming up to backflow, reacted 8 hours, and be cooled to room temperature (25 ℃) then, add the potassium hydroxide of purified water 350g and 40g, be warming up to 60 ℃ of reactions 5 hours again, be cooled to 25 ℃, tell water, with the normal hydrochloric acid of 6mol adjust pH to 7.0.Use dichloromethane extraction then, the organic phase anhydrous sodium sulfate drying filters, and concentrating under reduced pressure gets 6,8-two fluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid 32.1g.
(molar yield: 77.65%, HPLC:99.85%)
Embodiment 3: the preparation of Marbofloxacin
With embodiment 1 method make 6,8-two fluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid 25g drops into 500mL stainless steel still, add 60mL purified water and 28.6g potassium hydroxide, 125 ℃ of temperature of reaction, the interior pressure is 0.1Mpa, reacts 12 hours; Be cooled to 50 ℃, drip the formic acid of 45mL94% and the formaldehyde of 10.8mL 37%, drip to finish and be warming up to 75 ℃ of reactions 6 hours, be cooled to 0 ℃ then, filter, wash with purified water, drop into filter cake in the 500mL flask and add the 150mL purified water, dissolving with the ammoniacal liquor adjust pH to 8.5 of mass concentration 24%, is used dichloromethane extraction, organic addition anhydrous sodium sulfate drying, filter, the filtrate decompression distillation obtains 17.97g Marbofloxacin crude product, obtains the 16.75g Marbofloxacin after 50% the ethanolic soln crystallization with 720mL.(molar yield: 65.15%, HPLC:99.92%, the method according to European Pharmacopoeia 6.1 does not detect impurity E)
Embodiment 4: the preparation of Marbofloxacin
The 25g 6 that embodiment 2 methods are made, 8-two fluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid puts into 500mL stainless steel still, add 80mL purified water and 38g potassium hydroxide, 140 ℃ of temperature of reaction, the interior pressure is 0.2Mpa, reacts 8 hours; Be cooled to 40 ℃, drip the formic acid of 62mL94% and the formaldehyde of 15mL 37%, drip to finish and be warming up to 70 ℃ of reactions 6 hours, be cooled to 5 ℃ then, filter, wash with purified water, drop into filter cake in the 500mL flask and add the 150mL purified water, dissolving with the ammoniacal liquor adjust pH to 8.5 of mass concentration 28%, is used dichloromethane extraction, organic addition anhydrous sodium sulfate drying, filter, the filtrate decompression distillation obtains 18.75g Marbofloxacin crude product, obtains the 18.0g Marbofloxacin after the 50% ethanolic soln crystallization with 764mL.(molar yield: 70.0%, HPLC:99.98%, the method according to European Pharmacopoeia 6.1 does not detect impurity E)
Embodiment 5: the preparation of Marbofloxacin
The 25g 6 that embodiment 1 method is made, 8-two fluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid puts into 500mL stainless steel still, add 45mL purified water and 22g potassium hydroxide, 160 ℃ of temperature of reaction, the interior pressure is 0.4Mpa, reacts 5 hours; Be cooled to 50 ℃, drip the formic acid of 31.25mL 94% and the formaldehyde of 7.5mL 37%, drip to finish and be warming up to 75 ℃ of reactions 10 hours, be cooled to 5 ℃ then, filter, wash with purified water, drop into filter cake in the 500mL flask and add the 150mL purified water, dissolving with the ammoniacal liquor adjust pH to 8.5 of mass concentration 28%, is used dichloromethane extraction, organic addition anhydrous sodium sulfate drying, filter, the filtrate decompression distillation obtains 19.35g Marbofloxacin crude product, obtains the 18.65g Marbofloxacin after 50% the ethanolic soln crystallization with 900mL.
(molar yield: 72.54%, HPLC:99.95%, the method according to European Pharmacopoeia 6.1 does not detect impurity E)
Comparative Examples 1: the preparation of Marbofloxacin
According to disclosed among the Chinese patent CN1053907C with formula (II) 6-fluoro-1,4-dihydro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid an alkali metal salt is the method for feedstock production Marbofloxacin, referring to 19-21 page or leaf in the Chinese patent CN1053907C specification sheets.(HPLC:97.15%, according to the method for European Pharmacopoeia 6.1, detecting impurity E content is 0.8%, need make with extra care the requirement that just can meet European Pharmacopoeia 6.1 for 3 times with 50% ethanolic soln.)
By Comparative Examples as can be known, traditional method is compared with the inventive method, and yield is low relatively, and impurity is many.
Claims (9)
1. preparation method suc as formula the Marbofloxacin shown in (I), it is characterized in that described method carries out according to following steps: (1) is with 6 shown in the formula V, 7,8-three fluoro-1,4-dihydro-1-(N-methyl formamido group)-4-oxo-3-quinoline carboxylic acid ethyl ester and toluene, triethylamine and N methyl piperazine mix, be heated to backflow, reaction 8～12h, be cooled to room temperature, add entry and potassium hydroxide, be warming up to 60～90 ℃ of reactions 3～5 hours again, be cooled to 20～25 ℃, tell water, water is transferred pH to 6.8～7.2 with hydrochloric acid, uses dichloromethane extraction then, gets the dichloromethane layer concentrating under reduced pressure and gets compound shown in the formula (IV): 6,8-two fluoro-1,4-dihydro-1-(N-methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid; Compound shown in the described formula V is 1: 4～7: 0.2～0.6: 0.4～0.6: 4～7: 0.3～0.8 with the ratio of the quality that feeds intake of toluene, triethylamine, N methyl piperazine, water and potassium hydroxide; (2) with compound shown in the formula (IV) in water medium, 125～160 ℃ in 0.1～0.4Mpa time and potassium hydroxide reaction 5～12h, obtain compound shown in the formula (II): 6-fluoro-1,4-dihydro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid or its sylvite, reaction solution is cooled to 40～50 ℃, drip aqueous formic acid, formalin, be warming up to 70～75 ℃ of cyclization 6～10h again, reactant obtains Marbofloxacin shown in the formula (I) through aftertreatment; The mass ratio of compound and water, potassium hydroxide is 1: 1.67～3.34: 0.79～1.59 shown in the formula (IV) described in the step (2); The volumetric usage that the volumetric usage of described aqueous formic acid folding hundred back formic acid is counted 1.33～2.66mL/g, formalin folding hundred back formaldehyde with the quality of compound shown in the formula (IV) is counted 0.81～1.62mL/g with the quality of compound shown in the formula (IV);
M is H or alkali metal cation in the formula (II), and described alkali metal cation is K
+
2. preparation method as claimed in claim 1 is characterized in that the compound shown in the middle formula V of described step (1) and the ratio of the quality of toluene, triethylamine, N methyl piperazine, water and potassium hydroxide are 1: 4～5: 0.3～0.4: 0.4～0.46: 5.6～6.8: 0.43～0.75.
3. preparation method as claimed in claim 1, its this be characterised in that hydrochloric acid equivalent concentration is 6～12mol in the described step (1).
4. preparation method as claimed in claim 1 is characterized in that the temperature of reaction of middle reaction solution of described step (2) and potassium hydroxide is 125 ℃, and the reaction times is 12h.
5. preparation method as claimed in claim 1 is characterized in that the mass ratio of compound shown in the formula (IV) described in the described step (2) and water, potassium hydroxide is 1: 2.4～3: 1.1～1.2; The volumetric usage of described aqueous formic acid folding hundred back formic acid is counted 1.60～2.13mL/g with the quality of compound shown in the formula (IV), and the volumetric usage of formalin folding hundred back formaldehyde is counted 1.08～1.35mL/g with the quality of compound shown in the formula (IV).
6. preparation method as claimed in claim 1 is characterized in that the aqueous formic acid mass concentration described in the described step (2) is 94%, and the formalin mass concentration is 37%.
7. preparation method as claimed in claim 1 is characterized in that the aftertreatment described in the described step (2) is: reaction solution is cooled to 0～5 ℃, filters, filter cake washs with purified water, filter, filter cake is dissolved with purified water, transfer pH to 8.5 with ammoniacal liquor, use dichloromethane extraction, organic addition anhydrous sodium sulfate drying filters, and the filtrate decompression distillation obtains the Marbofloxacin crude product, with 50% ethanolic soln crystallization, make Marbofloxacin.
8. preparation method as claimed in claim 7 is characterized in that the volumetric usage of ethanolic soln in described step (2) aftertreatment is counted 40～50mL/g with Marbofloxacin crude product quality.
9. preparation method as claimed in claim 7 is characterized in that the mass concentration of ammoniacal liquor in the described step (2) is 24%～28%.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198905A (en) * | 2015-10-14 | 2015-12-30 | 海门慧聚药业有限公司 | Method for preparing ultrapure marbofloxacin through purification |
| CN105968025A (en) * | 2016-05-13 | 2016-09-28 | 河北科技大学 | Preparation method for 3-(methylbenzylamino)-2-(2,3,4,5-tetrafluorobenzoyl)ethyl acrylate |
| CN107056811A (en) * | 2017-04-20 | 2017-08-18 | 山东方明邦嘉制药有限公司 | A kind of process for purification of Marbofloxacin |
| CN107383058A (en) * | 2017-08-28 | 2017-11-24 | 海门慧聚药业有限公司 | Preparation of marbofloxacin |
| CN107445977A (en) * | 2017-07-13 | 2017-12-08 | 江西傲新生物科技有限公司 | A kind of water-soluble Marbofloxacin and preparation method and application |
| CN110283186A (en) * | 2019-07-19 | 2019-09-27 | 海门慧聚药业有限公司 | A kind of crystal form of Marbofloxacin and preparation method thereof |
| CN115557966A (en) * | 2022-10-19 | 2023-01-03 | 浙江国邦药业有限公司 | Preparation method of marbofloxacin |
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| EP0259804A2 (en) * | 1986-09-12 | 1988-03-16 | F. Hoffmann-La Roche Ag | Pyrido[3,2,1-ij]-1,3,4-benzoxadiazine derivatives, process for their preparation, resulting pharmaceutical preparations and intermediates for use in the process |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198905A (en) * | 2015-10-14 | 2015-12-30 | 海门慧聚药业有限公司 | Method for preparing ultrapure marbofloxacin through purification |
| CN105968025A (en) * | 2016-05-13 | 2016-09-28 | 河北科技大学 | Preparation method for 3-(methylbenzylamino)-2-(2,3,4,5-tetrafluorobenzoyl)ethyl acrylate |
| CN105968025B (en) * | 2016-05-13 | 2018-04-27 | 河北科技大学 | The preparation method of 3- (methylbenzylamide) -2- (2,3,4,5- tetrafluoros benzoyl) ethyl acrylate |
| CN107056811A (en) * | 2017-04-20 | 2017-08-18 | 山东方明邦嘉制药有限公司 | A kind of process for purification of Marbofloxacin |
| CN107445977A (en) * | 2017-07-13 | 2017-12-08 | 江西傲新生物科技有限公司 | A kind of water-soluble Marbofloxacin and preparation method and application |
| CN107445977B (en) * | 2017-07-13 | 2019-08-09 | 江西傲新生物科技有限公司 | A kind of water solubility Marbofloxacin and the preparation method and application thereof |
| CN107383058A (en) * | 2017-08-28 | 2017-11-24 | 海门慧聚药业有限公司 | Preparation of marbofloxacin |
| CN107383058B (en) * | 2017-08-28 | 2019-07-26 | 海门慧聚药业有限公司 | Preparation of marbofloxacin |
| CN110283186A (en) * | 2019-07-19 | 2019-09-27 | 海门慧聚药业有限公司 | A kind of crystal form of Marbofloxacin and preparation method thereof |
| CN115557966A (en) * | 2022-10-19 | 2023-01-03 | 浙江国邦药业有限公司 | Preparation method of marbofloxacin |
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| CN102060860B (en) | 2013-04-10 |
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