CN103772412B - A kind of preparation method of Pazufloxacin intermediate - Google Patents
A kind of preparation method of Pazufloxacin intermediate Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of Pazufloxacin intermediate.Described preparation method is: under suitable solvent and suitable temp, Compound II per under mineral alkali and phase-transfer catalyst effect with 1,2-ethylene dichloride carries out cyclopropanization reaction, then be hydrolyzed the backflow of this reaction system direct heating reaction, obtains described Pazufloxacin midbody compound IV through aftertreatment; The weight ratio of described mineral alkali and described Compound II per is 1.5 ~ 2.5:1; The ratio of described solvent and described Compound II per is 14 ~ 16mL:1g.Compared with prior art, in preparation method of the present invention, adopt the alkali of certain concentration and specified quantitative, adopt " one kettle way " to carry out two-step reaction thus, simplify unit operation; And the three wastes produced in preparation process are few, environmental protection pressure is little, and yield is high, is suitable for suitability for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, particularly relate to a kind of preparation method of Pazufloxacin intermediate.
Background technology
Pazufloxacin (Pazufloxacin, I) is that can act on Topoisomerase Ⅳ and DNA gyrase, anti-bacteria DNA copies and plays anti-microbial effect simultaneously by the Comprecin of Japan folic hill chemical company in exploitation listing in 2002.The clinical efficacy of Pazufloxacin is equal or be slightly better than s-generation quinolones as Ofloxacine USP 23, Ciprofloxacin and levofloxacin magnitude, and its curative effect is better than other quinolones kinds.
The major ingredient that Pazufloxacin is applied clinically is the mesylate of Pazufloxacin, i.e. T-3762 (Pazutloxacinmesylate), chemical name: (S)-10-(1-amino-1-cyclopropyl) the fluoro-3-methyl of-9--7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid mesylate, structural formula is as follows:
Document DE3913245, JP084107, JP0226472 etc. all relate to the synthesis route of Pazufloxacin.The synthesis route of Pazufloxacin is mainly following two classpaths:
First kind method: take tetrafluorobenzoic aid as starting raw material, before quinolone female ring is formed, introduce 1-amino-1-cyclopropyl, in this kind of synthetic route, be divided into again two synthetic routes:
(1) take tetrafluorobenzoic aid as raw material, through esterification, the decarboxylation of hydrolysis reaction rear section, with diphenyl diazomethane, formaldehyde addition reaction, or product after decarboxylation directly and N, N, N ', N '-tetramethyl-diamino first [(Me
2n)
2cH
2] reaction, 4-(1-carboxymethyl-cyclopropyl)-2 is hydrolyzed to obtain again after cyclopropylization reaction, 3,5-trifluoromethyl benzonitrile acetoacetic ester, beta-keto acid ester group is generated through Curtius rearrangement, transesterify, hydrolysis reaction, react with Dimethylformamide dimethyl alcohol, (s)-2-amino methanol again, finally by Pazufloxacin obtained after cyclization, hydrolysis, hydrogenolysis.
(2) be raw material with tetrafluorobenzoic aid, after esterification, at 4, nucleophilic substitution reaction occur with the carbanion of the cyanoacetic acid tert-butyl ester; then selective hydrolysis decarboxylation; cyclopropyl is generated, simultaneously Ester hydrolysis with glycol dibromide; reset through cyan-hydrolysis and Hoffmann; obtained 4-(the amino cyclopropyl of 1-)-2,3,5-trifluoro-benzoic acids, protection amino; obtain pyruvate through chloride and ketone acid esterification, then obtain Pazufloxacin after cyclization and hydrolysis reaction.
Equations of The Second Kind method: with Levofloxacin synthetic intermediate (S)-9, the fluoro-3-methyl of 10-bis--7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester is starting raw material, through with ethyl cyanoacetate condensation after, then hydrolysis decarboxylation obtains itrile group compounds II under Catalyzed by p-Toluenesulfonic Acid; With 1 under the effect of highly basic and triethylbenzyl brometo de amonio, 2-ethylene dibromide carry out Cyclopropanated after compound III, then compound III is hydrolyzed to obtain amides IV under concentrated hydrochloric acid or vitriol oil effect, this compound obtains compound V under clorox effect after Hoffmann resets, finally and after methylsulfonic acid salify obtain T-3762 I, its synthetic route is as follows:
At present, the synthesis technique of existing Pazufloxacin adopts above-mentioned Equations of The Second Kind method to carry out mostly.
Can find out, about the synthesis of compound IV in above-mentioned document, usually adopt Compound II per under the effect of alkali and phase-transfer catalyst, in organic solvent, normally ketones solvent, such as, with 1 in acetone, 2-ethylene dibromide carries out cyclopropanization reaction, then obtains compound III through aftertreatment;
To the hydrolysis reaction of nitrile compounds III, usually there are acid hydrolysis and basic hydrolysis two kinds of modes.
Acid hydrolysis utilizes hydrochloric acid or sulfuric acid to carry out as reagent usually.But when adopting acid hydrolysis, the acidity of reaction system is stronger, the side reactions such as the open loop of easy initial ring propane or carboxyl decarboxylation, cause the yield that reacts not high, the product purification shortcoming such as not easily; And when adopting acid hydrolysis mode, the necessary advanced row relax of alkaline ring-closure reaction system of back, after obtaining Compound II per, just can carry out acid hydrolysis mode, " one kettle way " therefore cannot be used to carry out.
Basic hydrolysis utilizes NaOH water solution system usually, but if the out of true of the condition control of reaction under this system, the easy direct hydrolysis of itrile group is carboxylic acid; In order to overcome above-mentioned deficiency, people adopt H
2o
2/ NaOH system is hydrolyzed, and usually carries out in the organic solvent of ketone.This step working method reported in above-mentioned document is, after ring-closure reaction completes, stratification, obtain the ketone organic layer solution (acetone soln normally containing compound III) containing compound III, in this acetone soln, add certain density hydrogen peroxide solution again, and utilize sodium hydroxide solution to keep the alkalescence of reaction system, finally obtain compound IV, advantage is that the selectivity of reaction is better, and the product purity obtained is higher.But, also there is very large shortcoming in this synthesis technique, main manifestations is, hydrogen peroxide and organic solvent of ketone is related in reaction process, especially the contact of acetone, and with the heating of reaction system, therefore need accurately to control reaction conditions (rate of addition of such as hydrogen peroxide and concentration etc.) in the process of producing, and there is larger potential safety hazard.
Because the synthetic route of current Pazufloxacin intermediate exists the defects such as yield is low, potential safety hazard is high, environmental protection pressure is large, therefore people are high for security, simple to operate, cost is low, the Pazufloxacin preparation method of environmental protection still exists demand, this just needs the synthesis technique researching and developing new Pazufloxacin and intermediate thereof, for the preparation method improving Pazufloxacin gives security.
Summary of the invention
For the deficiencies in the prior art, the present inventor, in the favorite outer discovery of the building-up process of Pazufloxacin intermediate, only uses the alkali of certain concentration and specified quantitative just can obtain Pazufloxacin intermediate with high yield; it is high that the method has yield; cost is low, easy and simple to handle, is suitable for the features such as large-scale production
The invention provides a kind of preparation method of Pazufloxacin intermediate, said method comprising the steps of:
Under suitable solvent and suitable temp, Compound II per (the fluoro-3-methyl of (s)-10-second cyano group-9--7-oxo-2, 3-dihydro-7H-pyridine [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid, ethyl esters) under mineral alkali and phase-transfer catalyst effect with 1, 2-ethylene dichloride carries out cyclopropanization reaction, then be hydrolyzed the backflow of this reaction system direct heating reaction, described Pazufloxacin midbody compound IV((s is obtained through aftertreatment)-10-(1-carbamyl cyclopropyl) the fluoro-3-methyl of-9--7-oxo-2, 3-dihydro-7H-pyridine [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acids), the weight ratio of described mineral alkali and described Compound II per is 1.5 ~ 2.5:1, the ratio of described solvent and described Compound II per is 14 ~ 16mL:1g.
Preferably, described mineral alkali is sodium hydroxide and/or potassium hydroxide; Described solvent is in the mixture of water or water and acetone, butanone, 4-methyl two pentanone or pentanone, and in mixture, the volume of water accounts for more than 2/3rds of all solvents.
More preferably, described mineral alkali is sodium hydroxide, and the weight ratio of described mineral alkali and described Compound II per is 1.8 ~ 2.2:1, is more preferably 2:1; Described solvent is in the mixture of water or water and 4-methyl two pentanone, and the ratio of described solvent and described Compound II per is 15mL:1g.Use water as reaction solvent, not only can reduce costs, and can the with an organic solvent environmental pollution caused be avoided, reduce the pressure of environmental protection.
Preferably, described phase-transfer catalyst is selected from quaternary ammonium salt.
More preferably, described phase-transfer catalyst is selected from benzyltriethylammoinium chloride, and the weight ratio of described phase-transfer catalyst and described Compound II per is 0.2 ~ 0.4:1, is preferably 0.3:1.
Preferably, described suitable temp is 0 ~ 5 DEG C; The time of described cyclopropanization reaction is 2 ~ 6 hours; The time of described hydrolysis reaction is 2 ~ 6 hours.
The temperature of described hydrolysis reaction is 60 ~ 110 DEG C, is preferably 100 ~ 110 DEG C.
Preferably, described aftertreatment is: be 6 with acid for adjusting pH after reaction system being down to 20 ~ 30 DEG C, stirs and keeps pH to stablize, continuing to stir, then filter and obtain compound IV after then system temperature being down to 10 ~ 20 DEG C.
More preferably, described preparation method is specially: in reaction vessel, add by the sodium hydroxide of 20 weight parts and be the alkali lye that the water of 100mL is made in its amount of the weight 10g of described Compound II per, under stirring, the temperature of reaction system is down to 0 ~ 5 DEG C, add benzyltriethylammoinium chloride 3 weight part, stir 1 hour, the Compound II per of 10 weight parts is added at 0 ~ 5 DEG C, 5 DEG C are stirred 1 hour, add in its amount of the weight 10g of described Compound II per for the 4-methyl-2 pentanone of 50mL and 1 of 4.5 weight parts, the mixing solutions of 2-ethylene dichloride composition, finish, after reaction system stirring at room temperature reacts 5 hours, reheat to back flow reaction 2 ~ 3 hours, cooling, treat that the temperature of system is between 20 ~ 30 DEG C, dropping hydrochloric acid neutralizes, to pH=6, reaction system becomes muddy, a large amount of solid is had to separate out, stir repetition measurement pH value after 10 minutes to stablize, stirring is continued 1 hour after cooling to 10 ~ 20 DEG C, filtration obtains compound IV.
Compared with prior art, in preparation method of the present invention, adopt the alkali of certain concentration and specified quantitative, adopt " one kettle way " to carry out two-step reaction thus, simplify unit operation; Complete after cyclopropane reacts completely, reaction system need not process, and also need not add other material, only need raise the temperature of reaction system, hydrolysis reaction can occur, obtained Pazufloxacin midbody compound IV.The two-step reaction process in above-mentioned document that changes uses different reaction conditionss, without the need to isolation andpurification compound III, thus realizes the simplification of unit operation, effectively enhances productivity, and reduces production cost; And the three wastes produced in preparation process are few, environmental protection pressure is little, and yield is high, is suitable for the features such as suitability for industrialized production.
Embodiment
Below by embodiment, the present invention is described further.Should be understood that these embodiments only for the object of illustration, do not limit the scope of the invention.Meanwhile, the apparent change made the present invention of those skilled in the art and modification are also contained within the scope of the invention.
Various raw material used in embodiment and reagent are commercially available purchase if no special instructions.
Nucleus magnetic resonance by Bruker-AMX300 type nmr determination, German Bruker company; Mass spectrum is measured by HP-5989A type mass spectrograph, Agilent company of the U.S..
Preparation embodiment 1
In 250mL there-necked flask, add the alkali lye be made into by the water of 20g sodium hydroxide and 100mL, by the greenhouse cooling to 0 of reaction system ~ 5 DEG C under stirring, add benzyltriethylammoinium chloride 3g, stir 1 hour, the starting compound II((s of 10g is added at 0 ~ 5 DEG C) the fluoro-3-methyl of-10-second cyano group-9--7-oxo-2, 3-dihydro-7H-pyridine [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid, ethyl esters, by commercially available), about 5 DEG C are stirred 1 hour, add the acetone of 50mL and 1 of 4.5g, the mixing solutions of 2-ethylene dichloride composition, finish, after reaction system stirring at room temperature reacts 5 hours, reheat to back flow reaction 6 hours, cooling, treat that the temperature of system is between 20 ~ 30 DEG C, drip the neutralization of half strength hydrochloric acid, to about pH=6, reaction system becomes muddy, a large amount of solid is had to separate out, stir repetition measurement pH value after 10 minutes to stablize, stirring is continued 1 hour after cooling to 10 ~ 20 DEG C, it is compound IV ((s)-10-(1-carbamyl cyclopropyl) the fluoro-3-methyl of-9--7-oxo-2 that filtration obtains white solid, 3-dihydro-7H-pyridine [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acids), about 8.2g, yield 79%, mp277.0 ~ 279.0.
1HNMR(300MHz,DMSO-d
6)δ15.04(s,1H),9.04(s,1H),7.60(d,J=6Hz,1H),6.98(s,1H),6.76(s,1H),4.99(s,1H),4.64(s,1H),4.45(s,1H),1.52~1.46(m,2H),1.47(s,3H),1.06(s,2H);Ms-ESI:347[M
++1]。
Preparation embodiment 2
In 250mL there-necked flask, add the alkali lye be made into by the water of 20g sodium hydroxide and 100mL, by the greenhouse cooling to 0 of reaction system ~ 5 DEG C under stirring, add benzyltriethylammoinium chloride 3g, stir 1 hour, the starting compound II of 10g is added at 0 ~ 5 DEG C, about 5 DEG C are stirred 1 hour, add the 4-methyl-2 pentanone of 50mL and 1 of 4.5g, the mixing solutions of 2-ethylene dichloride composition, finish, after reaction system stirring at room temperature reacts 5 hours, reheat to back flow reaction 3 hours, cooling, treat that the temperature of system is between 20 ~ 30 DEG C, drip the neutralization of half strength hydrochloric acid, to about pH=6, reaction system becomes muddy, a large amount of solid is had to separate out, stir repetition measurement pH value after 10 minutes to stablize, stirring is continued 1 hour after cooling to 10 ~ 20 DEG C, it is compound IV that filtration obtains white solid, about 8.8g, yield 85%.Through confirming, the structure of this target compound is identical with the structure of preparation embodiment 1 target compound.
Preparation embodiment 3
In 250mL there-necked flask, add the alkali lye be made into by the water of 15g sodium hydroxide and 150mL, by the greenhouse cooling to 0 of reaction system ~ 5 DEG C under stirring, add benzyltriethylammoinium chloride 3g, stir 1 hour; The starting compound II of 10g is added at 0 ~ 5 DEG C, about 5 DEG C are stirred 1 hour, add 1 of 4.5g, the mixing solutions of 2-ethylene dichloride composition, finishes, after reaction system stirring at room temperature reacts 5 hours, reheat to back flow reaction 2 hours, cooling, treats that the temperature of system is between 20 ~ 30 DEG C, drips the neutralization of half strength hydrochloric acid, to about pH=6, reaction system becomes muddy, has a large amount of solid to separate out, and stirs repetition measurement pH value after 10 minutes and stablizes, stirring is continued 1 hour after cooling to 10 ~ 20 DEG C, it is compound IV, about 8.5g that filtration obtains white solid, yield 82%.Through confirming, the structure of this target compound is identical with the structure of preparation embodiment 1 target compound.
Preparation embodiment 4
In 250mL there-necked flask, add the alkali lye be made into by the water of 22g sodium hydroxide and 100mL, by the greenhouse cooling to 0 of reaction system ~ 5 DEG C under stirring, add benzyltriethylammoinium chloride 3g, stir 1 hour, the starting compound II of 10g is added at 0 ~ 5 DEG C, about 5 DEG C are stirred 1 hour, add the 4-methyl-2 pentanone of 50mL and 1 of 4.5g, the mixing solutions of 2-ethylene dichloride composition, finish, after reaction system stirring at room temperature reacts 5 hours, reheat to back flow reaction 3 hours, cooling, treat that the temperature of system is between 20 ~ 30 DEG C, drip the neutralization of half strength hydrochloric acid, to about pH=6, reaction system becomes muddy, a large amount of solid is had to separate out, stir repetition measurement pH value after 10 minutes to stablize, stirring is continued 1 hour after cooling to 10 ~ 20 DEG C, it is compound IV that filtration obtains white solid, about 8.7g, yield 84%.Through confirming, the structure of this target compound is identical with the structure of preparation embodiment 1 target compound.
Preparation embodiment 5
In 250mL there-necked flask, add the alkali lye be made into by the water of 18g sodium hydroxide and 100mL, by the greenhouse cooling to 0 of reaction system ~ 5 DEG C under stirring, add benzyltriethylammoinium chloride 3g, stir 1 hour, the starting compound II of 10g is added at 0 ~ 5 DEG C, about 5 DEG C are stirred 1 hour, add the 4-methyl-2 pentanone of 50mL and 1 of 4.5g, the mixing solutions of 2-ethylene dichloride composition, finish, after reaction system stirring at room temperature reacts 5 hours, reheat to back flow reaction 3 hours, cooling, treat that the temperature of system is between 20 ~ 30 DEG C, drip the neutralization of half strength hydrochloric acid, to about pH=6, reaction system becomes muddy, a large amount of solid is had to separate out, stir repetition measurement pH value after 10 minutes to stablize, stirring is continued 1 hour after cooling to 10 ~ 20 DEG C, it is compound IV that filtration obtains white solid, about 8.6g, yield 83%.Through confirming, the structure of this target compound is identical with the structure of preparation embodiment 1 target compound.
Preparation embodiment 6
In 250mL there-necked flask, add the alkali lye be made into by the water of 20g potassium hydroxide and 150mL, by the greenhouse cooling to 0 of reaction system ~ 5 DEG C under stirring, add benzyltriethylammoinium chloride 3g, stir 1 hour; The starting compound II of 10g is added at 0 ~ 5 DEG C, about 5 DEG C are stirred 1 hour, add 1 of 4.5g, the mixing solutions of 2-ethylene dichloride composition, finishes, after reaction system stirring at room temperature reacts 5 hours, reheat to back flow reaction 2 hours, cooling, treats that the temperature of system is between 20 ~ 30 DEG C, drips the neutralization of half strength hydrochloric acid, to about pH=6, reaction system becomes muddy, has a large amount of solid to separate out, and stirs repetition measurement pH value after 10 minutes and stablizes, stirring is continued 1 hour after cooling to 10 ~ 20 DEG C, it is compound IV, about 7.9g that filtration obtains white solid, yield 76%.Through confirming, the structure of this target compound is identical with the structure of preparation embodiment 1 target compound.
It will be understood by those skilled in the art that under the instruction of this specification sheets, some amendments or change can be made to the present invention.These modifications and variations also should within the scope of the claims in the present invention.
Claims (10)
1. a preparation method for Pazufloxacin intermediate, described preparation method is:
Under suitable solvent and suitable temp, Compound II per under mineral alkali and phase-transfer catalyst effect with 1,2-ethylene dichloride carries out cyclopropanization reaction, and be then hydrolyzed the backflow of this reaction system direct heating reaction, obtains described Pazufloxacin midbody compound IV through aftertreatment; The weight ratio of described mineral alkali and described Compound II per is 1.5 ~ 2.5:1; The ratio of described solvent and described Compound II per is 14 ~ 16mL:1g.
2. the preparation method of Pazufloxacin intermediate according to claim 1, is characterized in that, described mineral alkali is sodium hydroxide and/or potassium hydroxide; Described solvent is in the mixture of water or water and acetone, butanone, 4-methyl two pentanone or pentanone, and in mixture, the volume of water accounts for more than 2/3rds of all solvents.
3. the preparation method of Pazufloxacin intermediate according to claim 2, is characterized in that, described mineral alkali is sodium hydroxide, and the weight ratio of described mineral alkali and described Compound II per is 1.8 ~ 2.2:1; Described solvent is in the mixture of water or water and 4-methyl two pentanone, and the ratio of described solvent and described Compound II per is 15mL:1g.
4. the preparation method of the Pazufloxacin intermediate according to any one of claims 1 to 3, is characterized in that, described phase-transfer catalyst is selected from quaternary ammonium salt.
5. the preparation method of the Pazufloxacin intermediate according to any one of claims 1 to 3, is characterized in that, described phase-transfer catalyst is selected from benzyltriethylammoinium chloride, and the weight ratio of described phase-transfer catalyst and described Compound II per is 0.2 ~ 0.4:1.
6. the preparation method of the Pazufloxacin intermediate according to any one of claims 1 to 3, is characterized in that, described suitable temp is 0 ~ 5 DEG C; The time of described cyclopropanization reaction is 2 ~ 6 hours; The time of described hydrolysis reaction is 2 ~ 6 hours.
7. the preparation method of the Pazufloxacin intermediate according to any one of claims 1 to 3, it is characterized in that, described aftertreatment is: be 6 with acid for adjusting pH after reaction system being down to 20 ~ 30 DEG C, stir and keep pH to stablize, then continue after system temperature being down to 10 ~ 20 DEG C to stir, then filter and obtain compound IV.
8. the preparation method of the Pazufloxacin intermediate according to any one of claims 1 to 3, it is characterized in that, described method is specially: in reaction vessel, add by the sodium hydroxide of 20 weight parts and be the alkali lye that the water of 100mL is made in its amount of the weight 10g of described Compound II per, under stirring, the temperature of reaction system is down to 0 ~ 5 DEG C, add benzyltriethylammoinium chloride 3 weight part, stir 1 hour, the Compound II per of 10 weight parts is added at 0 ~ 5 DEG C, 5 DEG C are stirred 1 hour, add in its amount of the weight 10g of described Compound II per for the 4-methyl-2 pentanone of 50mL and 1 of 4.5 weight parts, the mixing solutions of 2-ethylene dichloride composition, finish, after reaction system stirring at room temperature reacts 5 hours, reheat to back flow reaction 2 ~ 3 hours, cooling, treat that the temperature of system is between 20 ~ 30 DEG C, dropping hydrochloric acid neutralizes, to pH=6, reaction system becomes muddy, a large amount of solid is had to separate out, stir repetition measurement pH value after 10 minutes to stablize, stirring is continued 1 hour after cooling to 10 ~ 20 DEG C, filtration obtains compound IV.
9. the preparation method of Pazufloxacin intermediate according to claim 3, is characterized in that, the weight ratio of described mineral alkali and described Compound II per is 2:1.
10. the preparation method of Pazufloxacin intermediate according to claim 5, is characterized in that, the weight ratio of described phase-transfer catalyst and described Compound II per is 0.3:1.
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| CN104031063A (en) * | 2014-05-29 | 2014-09-10 | 上海应用技术学院 | Quinolone compound as well as preparation method and application thereof |
| CN105622632B (en) * | 2014-10-29 | 2018-06-29 | 浙江海森药业股份有限公司 | A kind of carbostyril compound and preparation method thereof |
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| CN102295652A (en) * | 2011-06-27 | 2011-12-28 | 辽宁海神联盛制药有限公司 | Improvement method for pazufloxacin mesylate synthesis process |
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| JP2832535B2 (en) * | 1989-04-04 | 1998-12-09 | 富山化学工業株式会社 | Method for solubilizing quinolone carboxylic acid or its salt |
| KR0132192B1 (en) * | 1994-04-27 | 1998-04-17 | 이종호 | Process for the preparation of pyridone carboxylic acid derivatives |
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| US4990508A (en) * | 1988-04-23 | 1991-02-05 | Toyama Chemical Co., Ltd. | Pyridone carboxylic acid derivatives and salts thereof, process for producing the same and antibacterial agents comprising the same |
| CN102295652A (en) * | 2011-06-27 | 2011-12-28 | 辽宁海神联盛制药有限公司 | Improvement method for pazufloxacin mesylate synthesis process |
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| 帕珠沙星的合成;张文治，等，;《武汉大学学报（理学版）》;20030430;第49卷(第2期);第227-230页 * |
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