CN102295652A - Improvement method for pazufloxacin mesylate synthesis process - Google Patents
Improvement method for pazufloxacin mesylate synthesis process Download PDFInfo
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Abstract
The invention relates to an improved synthesis method for pazufloxacin mesylate. According to the present invention, S-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,-de]benzoxazine-6-carboxylic acid is adopted as a raw material, the raw material is subjected to nucleophilic substitution, cyclization, hydrolysis, Hofmann degradation and salification to obtain the pazufloxacin mesylate. In addition, with the present invention, the reaction is improved, and the following technologcial conditions factors influencing on the yield and the quality are evaluated: reaction time, reaction temperature and the like; the finally-determined optimized process has advantages of simple operation steps, short production period, less pollution and the like; the total yield is substantially increased, and the method is applicable for the industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of improved T-3762, belong to pharmaceutical chemistry technical field.
Background technology
T-3762 [Pazufloxacin mesylate, chemical name: (S)-10-(the amino cyclopropyl of 1-)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid], be antibiotic by development of Japan folic hill KCC and exploitation, its patent No. is: DE3913245, went on the market in Japan first in March, 2002.Many clinical study results show, its has a broad antifungal spectrum, the Plasma Concentration height of intravenously administrable, rapid-action, little to central nervous system toxicity, activity in vivo to golden Portugal bacterium all is better than levofloxacin, the husky star of promise oxygen, Ciprofloxacin, Ofloxacine USP 23 etc., particularly various resistance Staphylococcus also there is activity preferably, has good application prospects.
At present, the production of China's fluoroquinolones bulk drug outlet is existing necessarily scale, has occupied 30% the market share in the world, has been one of main base of fluoroquinolones bulk drug supply.Because of T-3762 all is better than or is equivalent to several mouthfuls of kinds of application at present in curative effect, resistance, toxic side effect, and has certain price advantage, might become and be connected and the transition third generation and the 4th generation, substitute the tool of levofloxacin magnitude and finish the advantage kind of power, therefore, being subjected to vast manufacturer and distributors especially payes attention to.
According to bibliographical information, the synthetic route of T-3762 mainly contains two classes at present, and first kind synthetic route is to introduce the amino cyclopropyl of 1-before the female ring of quinolone forms; The second class synthetic route is to introduce the amino cyclopropyl of 1-after the female ring of quinolone forms.
First kind synthetic route is starting raw material with the tetrafluorobenzoic aid through condensation, hydrolysis, cyclization, cyan-hydrolysis, degraded, amido protecting, condensation again, ammonification, cyclization, goes protection and salify to get T-3762.Synthetic route is as follows:
First kind synthetic route, because route is longer, reaction is complicated, and used industrial chemicals kind is many and toxicity is big, and operation is loaded down with trivial details, and the document yield is lower, and producer does not adopt this type of technology basically at present.
The second class synthetic route, with the tetrafluorobenzoic aid be starting raw material through acidylate, condensation, hydrolysis, condensation, ammonification, cyclization, condensation again, hydrolysis, cyclization, cyan-hydrolysis, degraded, salify gets T-3762.As follows:
The second class synthetic route, with respect to first kind synthetic route, route is short, reaction is simple, and used industrial chemicals kind is less, technical maturity, producer adopts this type of technology basically at present.
Though it is a lot of that the second class synthetic route is improved than first kind synthetic route, the intermediate synthesis step is relative complex still, uses raw material type, catalyst type, end product yield all to await improving, and reduces cost, and increases the production operability.In addition, though at present domestic have research to T-3762 synthetic, major part still is in laboratory stage, still has gap with suitability for industrialized production.Therefore a kind of suitability for industrialized of necessary design is produced, and has the synthesis technique of high yield, with short production cycle, cost is low, environmental pollution is little T-3762.
Summary of the invention
The objective of the invention is to: the improvement synthetic method of the T-3762 that a kind of suitability for industrialized produces is provided, byproduct of reaction is less, yield obviously improves, with short production cycle, cost is low, environmental pollution is little, and is beneficial to industrial applications.
The present invention is improved on the basis of the second class building-up reactions of prior art, use the synthesis step of levofloxacin, technical maturity, our several steps reactions after to nucleophilic substitution and cyclization are simultaneously improved: select for use DMSO to accelerate speed of response as solvent in the nucleophilic substitution reaction, the optimization experiment condition significantly improves the productive rate of intermediate yield IX, and prepare in the last handling process of IX at ethyl cyanoacetate, need not to obtain solid, directly drop into next step reaction, solved this step and be difficult for the solidified shortcoming with oily matter; In addition, in the X process of hydrolysis reaction preparation, increase the consumption of alkali and significantly reduce the reaction times, effectively reduce byproduct of reaction, improve the efficient of hydrolysis reaction and the yield of product.
The present invention is as follows with the initial complete synthetic route of tetrafluorobenzoic aid (II):
The yield of the synthetic route route synthesizing methanesulfonic acid Pazufloxacin of the present invention after optimizing obviously is better than the document yield, reaches 67% in the VIII total recovery, even if reach 59% through amplifying the production total recovery.
Because ring-closure reaction product compound VIII [(S)-9,10-two fluoro-3-methyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,-de] benzoxazine-6-carboxylic acid] belong to commercially available and buy, so in amplifying reaction, be that raw material amplifies preparation, obtain T-3762 I through nucleophilic substitution, cyclization, hydrolysis, Hofmann degradation, salify and make this reaction scheme shorten with VIII.May further comprise the steps:
(1) nucleophilic substitution reaction, (S)-10-(cyano group ethoxycarbonyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [preparation of 1,4] benzoxazine-6-carboxylic acid, ethyl ester (IX), chemical equation:
(2) (S)-and 10-cyano methyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2, the 3-de] [preparation of 1,4] benzoxazine-6-carboxylic acid (X)
(2) (S)-10-(1-cyano group cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [preparation of 1,4] benzoxazine-6-carboxylic acid (XI), chemical equation:
(3) (S)-10-(1-carbamyl cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [preparation of 1,4] benzoxazine-6-carboxylic acid (XII), chemical equation:
(4) (S)-10-(the amino cyclopropyl of 1-)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid is the preparation of Pazufloxacin (XIII), chemical equation:
(5) preparation of T-3762 (I), chemical equation:
Wherein step (1) is a nucleophilic substitution reaction, adopt DMF as reaction solvent in the prior art mostly, but DMF easily decomposes generation formate and dimethylamine under alkaline condition, the specific inductivity 45 of DMSO, belong to non-protonic solvent, also be polar solvent, find that by test DMSO can accelerate nucleophilic substitution reaction as reaction solvent, effectively shorten the time of nucleophilic substitution reaction.In addition, in the X process of the hydrolysis reaction of step (2) preparation, increase the consumption of alkali and significantly reduce the reaction times, reaction times of 72 hours in the bibliographical information is shortened to 24 hours, effectively reduce byproduct of reaction, improve the efficient of hydrolysis reaction and the yield of product.
In addition, also choose the nucleophilic substitution reaction influence factor: reaction times, temperature of reaction.Experiment parameter is optimized design, finds out top condition with the yield and the quality situation of the finished product.
Adopting step (1) and (2) is the concrete experimental technique of the X of starting raw material preparation with VIII: DMSO is cooled to 0 ℃, drips ethyl cyanoacetate, stirred 1 hour under 0 ℃ of left and right sides condition, add VIII, slowly be warming up to (50,60,70 ℃), reaction (6,8,10 hours), be cooled to room temperature, regulate pH value to 4, ethyl acetate extraction merges organic layer, the saturated common salt water washing, anhydrous sodium sulfate drying, be evaporated to dried, red-brown oily matter IX, mechanical stirring is being housed, in the three-necked bottle of reflux condensing tube, add IX and 1, the 4-dioxane, water, the tosic acid monohydrate stirs, reflux 24 hours, add water cooling, place refrigerator cold-storage and spend the night, make and separate out solid fully, suction filtration, washing, ether washing, the dry intermediate X that gets.
The yield of product is to obtain the VIII of intermediate X to drop into, and the quality of product is by thin-layer chromatography method checked for impurities spot number.
Table 1-1, the nucleophilic substitution reaction experiment condition is investigated
| Sequence number | Reaction times/h | Temperature of reaction ℃ | Impurity spot number | Yield % |
| 1 | 8 | 50 | 4 | 89.1 |
| 2 | 10 | 50 | 3 | 88.4 |
| 3 | 16 | 50 | 5 | 84.3 |
| 4 | 8 | 60 | 2 | 94.1 |
| 5 | 10 | 60 | 1 | 95.5 |
| 6 | 16 | 60 | 1 | 91.6 |
| 7 | 8 | 70 | 1 | 97.1 |
| 8 | 10 | 70 | 2 | 96.8 |
| 9 | 16 | 70 | 1 | 91.3 |
[0037] By the interpretation of table 1-1, can find that when temperature was selected 60,70 ℃, the reaction times was selected 8 or 10 hours, the yield of intermediate X is apparently higher than the yield in 50 ℃ of temperature selections and 6 hours reaction times, and the by product of reaction is also minimum.Determine that further optimum reaction conditions is 70 ℃ of temperature and 8 hours reaction times.
50 ℃ the temperature of reaction of as seen instructing in the document of prior art and 16 hours or longer reaction times, not only yield is low, the by product showed increased.Therefore, 60,70 ℃ temperature of reaction that the present invention chooses and 8 or 10 hours reaction times not only shorten the reaction times, obviously improve yield, also better controlled the amount of by product.
In addition, this preparation technology also has the little advantage of pollution.The general treatment process of the three wastes in preparation technology (waste gas, waste liquid, waste residue):
Waste gas absorbs with alkali (acid) liquid to be handled; Waste liquid reclaims and uses, and that should not recycle neutralizes through acid or alkali, enters biological degradation processing such as biological degradation Chi Yong again, and processing back liquid enters sewage works and handles; The waste residue burning disposal.Because this technology has been bought VIII in amplifying preparation process, thus after be starting raw material in the production process with VIII, three wastes processing also begins with this product, its specific operation process is as follows:
The invention embodiment
Further specify the present invention below in conjunction with specific embodiment, but do not limit the present invention.
Embodiment 1 is the preparation of the starting raw material chamber of experimentizing with VIII
(S)-10-(cyano group ethoxycarbonyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [the preparation of 1,4] benzoxazine-6-carboxylic acid (X): stirring is being housed, in the three-necked bottle of dropping funnel and drying installation, add DMSO (6), sodium hydride (3.69g), frozen water is cooled to 0 ℃, drips ethyl cyanoacetate (17ml), stirs 1 hour under 0 ℃ of left and right sides condition, obtain clarifying reaction liquid, add VIII (7.14g), slowly be warming up to 70 ℃ of reactions 8 hours, be cooled to room temperature, pour frozen water (290ml) into, regulate pH value to 4 with Glacial acetic acid, ethyl acetate extraction three times merges organic layer in batches, the saturated aqueous common salt washed twice, anhydrous sodium sulfate drying, be evaporated to dried, red-brown oily matter IX, this product need not solidify, and is directly used in next step reaction.In the three-necked bottle that mechanical stirring, reflux condensing tube are housed, add previous step amount IX, 1,4-dioxane (60ml), water (10ml), tosic acid monohydrate (4.65g), stir, reflux 24 hours, cold slightly, add water (15ml) cooling, place to refrigerate in the refrigerator and spend the night, make and separate out solid fully, suction filtration, wash three times, ether washs once, and drying got product X 6.64g, yield 95% (in VIII) in 5 hours under 105 ℃ of conditions.
(S)-10-(1-cyano group cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1, the preparation of 4] benzoxazine-6-carboxylic acid (XI): stirring is being housed, in the three-necked bottle of dropping funnel and prolong, add NaOH (14.5g), water (30ml), frozen water are cooled to 0 ℃, add benzyl triethyl ammonium bromide (6.84g), stirring at room half an hour, gradation adds X (6.64g), stirs half an hour, splash into 1,2-ethylene dibromide (9.74g) needs dropwise half an hour approximately, slowly is warming up to 45 ℃ of stirring reactions 3 hours, be cooled to room temperature, stirring is spent the night.Water (100ml) dilution is regulated pH value to 5 with Glacial acetic acid under the frozen water cooling conditions, separates out solid, suction filtration, and the chloroform washed twice is washed three times, and ether washs once, and constant pressure and dry is 6 hours under 105 ℃ of conditions, gets product XI6.7g, yield 93%.
(S)-10-(1-carbamyl cyclopropyl)-9-fluoro-3-methyl-7-oxo-2; 3-dihydro-7H-pyridine [1; 2,3-de] [the preparation of 1,4] benzoxazine-6-carboxylic acid (XII): in the three-necked bottle of stirring is housed; add the vitriol oil (20ml); frozen water is cooled to 0 ℃, adds XI (6.7g), stirs; slowly be warming up to room temperature, stirring reaction spends the night.Reaction solution is poured in the mixture of ice and water, made crystallization, suction filtration, washing makes it neutral, and the ether washing is drained, and drying is 6 hours under 105 ℃ of conditions, gets product XII6.65g, yield 94%.
(S)-10-(the amino cyclopropyl of 1-)-9-fluoro-3-methyl-7-oxo-2,3 dihydros-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid is the preparation of Pazufloxacin (XIII): in the three-necked bottle that stirring, prolong are housed, add NaOH (7.65g), water (40ml), frozen water are cooled to about 0 ℃, the NaClO solution (40ml) of adding 9%, add XII (6.65g) again, slowly be warming up to room temperature, stirring reaction spends the night.Reheat to 70 ℃ reaction 1 hour is cooled to room temperature, adds water (30ml), regulates pH value to 6 with concentrated hydrochloric acid, separates out solid, suction filtration, and washing is drained, and drying is used the DMF recrystallization, and drying got product XIII5.09g, yield 83% in 3 hours under 80 ℃ of conditions.
The preparation of T-3762 (I): in the three-necked bottle that stirring, dropping funnel are housed, add XIII (5.09g), water (15ml), stir, the frozen water cooling drips methylsulfonic acid (1.28g), slowly is warming up to room temperature, stirring reaction 1 hour adds gac 2g, restir half an hour, suction filtration, filtrate is concentrated into dried, adds alcohol dilution, suction filtration, washing with alcohol is drained, drying is 4 hours under 80 ℃ of conditions, gets the little yellow crystals 6.64g of T-3762 I, yield 97%.
In VIII, total recovery is 67%.
Embodiment 2 is that starting raw material amplifies preparation with VIII
1, (S)-10-(cyano group ethoxycarbonyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2, the 3-de] [preparation of 1,4] benzoxazine-6-carboxylic acid, ethyl ester (IX).
(1) chemical equation:
(2) feed ratio
(3) step
Stirring is being housed, in the three-necked bottle of dropping funnel and drying installation, add DMSO (13L), sodium hydride (840g), frozen water is cooled to 0 ℃, drips ethyl cyanoacetate (3.9L), stirs half an hour under 0 ℃ of condition, obtain clarifying reaction liquid, add VIII (1630g), slowly be warming up to 70 ℃ of reactions 8 hours, be cooled to room temperature, pour in the frozen water (66L), regulate pH value to 4, ethyl acetate extraction three times, saturated aqueous common salt washed twice with Glacial acetic acid in batches, merge organic layer, anhydrous sodium sulfate drying, be evaporated to dried, red-brown oily matter IX, this product need not solidify, and is directly used in next step reaction.
Quality control:
Proterties: red-brown oily matter (solidifying the back is the off-white color solid, fusing point: 119～121 ℃)
TLC detects: gel GF 254 plate
Developping agent: ethyl acetate-sherwood oil-methyl alcohol-Glacial acetic acid=5: 5: 2: 0.2
Colour developing: fluorescence
Result: be single spot, Rf:0.40～0.50
2, (S)-10-cyano methyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2, the 3-de] [preparation of 1,4] benzoxazine-6-carboxylic acid (X)
(1) chemical equation:
(2) feed ratio
(3) step
In the three-necked bottle that mechanical stirring, reflux condensing tube are housed, add previous step amount IX, 1,4-dioxane (13L), water (2.36L), tosic acid monohydrate (1062g), stir, reflux 24 hours, cold slightly, add water (3.5L) cooling, place to refrigerate in the refrigerator and spend the night, make and separate out solid fully, suction filtration, wash three times, ether washing once, dry product X 1495g, average yield 94% (in VIII).
Quality control:
Proterties: white crystal
Fusing point: 232～236 ℃
TLC detects: gel GF 254 plate
Developping agent: ethyl acetate-sherwood oil-chloroform-methanol-Glacial acetic acid=2: 2: 1: 1: 0.5
Colour developing: fluorescence
Result: be single spot, Rf:0.35～0.45
HPLC detects: detect wavelength: 238nm; Concentration: 300 μ g/ml; Solvent: methyl alcohol;
Moving phase: acetonitrile-10% methylsulfonic acid triethylamine solution-1.0mol/L dipotassium hydrogen phosphate-water (70: 10: 7: 113), 3, (S)-10-(1-cyano group cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [the preparation of 1,4] benzoxazine-6-carboxylic acid (XI)
(1) chemical equation:
(2) feed ratio
(3) step
In the three-necked bottle that stirring, dropping funnel and prolong are housed, add NaOH (3580g), water (7.5L), frozen water is cooled to about 0 ℃, add benzyl triethyl ammonium bromide (1346g), stirring at room 1 hour, gradation adds X (X 1495g), stirred 1 hour, splash into glycol dibromide (2114g), needed dropwise in 2 hours approximately, slowly be warming up to 45 ℃, stirring reaction 3 hours is cooled to room temperature, and stirring is spent the night.Water (22L) dilution is regulated pH value to 5 with Glacial acetic acid under the frozen water cooling conditions, separates out solid, suction filtration, and the chloroform washed twice is washed three times, and ether washs once, and drying is 6 hours under 105 ℃ of conditions, gets product XI1486g, yield 91%.
Quality control:
Proterties: off-white color solid
Fusing point: 277～282 ℃
TLC detects: gel GF 254 plate
Developping agent: ethyl acetate-sherwood oil-chloroform-methanol-Glacial acetic acid=2: 2: 1: 1: 0.5
Colour developing: fluorescence
Rf：0.45～0.55
4, (S)-10-(1-carbamyl cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2, the 3-de] [preparation of 1,4] benzoxazine-6-carboxylic acid (XII)
(1) chemical equation:
(2) feed ratio
(3) step
In the three-necked bottle of stirring is housed, add the vitriol oil (5200ml), frozen water is cooled to 0 ℃, adds XI (1486g), stirs, and slowly is warming up to room temperature, and stirring reaction spends the night.Reaction solution is poured in the mixture of ice and water, made crystallization, suction filtration, washing makes it neutral, and the ether washing is drained, and drying is 6 hours under 105 ℃ of conditions, gets product XII1461g, yield 93%.
Quality control:
Proterties: off-white color solid
Fusing point: 276～280 ℃ (Dec)
TLC detects: gel GF 254 plate
Developping agent: chloroform-methanol-Glacial acetic acid=2: 2: 1
Colour developing: fluorescence
Rf：0.75～0.85
5, (S)-10-(the amino cyclopropyl of 1-)-9-fluoro-3-methyl-7-oxo-2, [1,4] benzoxazine-6-carboxylic acid is the preparation of Pazufloxacin (XIII) to 3-dihydro-7H-pyridine [1,2,3-de]
(1) chemical equation:
(2) feed ratio
(3) step
In the three-necked bottle that stirring, prolong are housed, add NaOH (900g), water (4.7L), frozen water is cooled to about 0 ℃, adds 9% NaClO solution (4.37L), adds XII (564g) again, slowly is warming up to room temperature, and stirring reaction spends the night.Reheat to 70 ℃ reaction 1 hour is cooled to room temperature, adds water (3.52L), regulates pH value to 6 with concentrated hydrochloric acid, separates out solid, suction filtration, and washing is drained, and drying is used the DMF recrystallization, gets product XIII 1043g, yield 78%.
Quality control:
Proterties: faint yellow needle-like crystal
Fusing point: 263～265 ℃
TLC detects: gel GF 254 plate
Developping agent: chloroform-methanol-water-triethylamine=1: 5: 2: 0.2
Colour developing: fluorescence
Result: be single spot, Rf:0.42～0.52
HPLC detects: detect wavelength: 254nm; Concentration: 200 μ g/ml; Solvent: moving phase;
Moving phase 1: acetonitrile-10% methylsulfonic acid triethylamine solution-1.0mol/L dipotassium hydrogen phosphate-water (30: 10: 7: 170); Moving phase 2:
Acetonitrile-10% methylsulfonic acid triethylamine solution-1.0mol/L dipotassium hydrogen phosphate-water (45: 10: 7: 138);
Annotate: the preparation of 10% methylsulfonic acid triethylamine solution: under the condition of ice bath, slowly add methylsulfonic acid 30ml in 200ml water, triethylamine 30ml after the dissolving fully, adds water to 300ml.
6, the preparation of T-3762 (I)
(1) chemical equation:
(2) feed ratio
(3) step
In the three-necked bottle that stirring, dropping funnel are housed, add XIII (1043g), water (5000ml) stirs, the frozen water cooling drips methylsulfonic acid (416g), slowly is warming up to room temperature, stirring reaction 1 hour adds gac 25g, restir half an hour, suction filtration, filtrate is concentrated into dried, adds alcohol dilution, suction filtration, washing with alcohol is drained, drying is 4 hours under 80 ℃ of conditions, gets the little yellow crystals 1236g of T-3762 I, yield 95%.
In VIII, total recovery reaches 59% to this preparation technology after industry is amplified.
As seen the total recovery after industry is amplified of the synthesis technique after the present invention improves still reaches 59%, and is considerable, suitability for industrialized production.
Claims (3)
1. the synthetic method of an improved T-3762 may further comprise the steps:
(1) nucleophilic substitution reaction, (S)-10-cyano methyl-9-fluoro-3-methyl-7-oxo-2, [preparation of 1,4] benzoxazine-6-carboxylic acid (X), chemical equation is 3-dihydro-7H-pyridine [1,2,3-de]
(2) (S)-and 10-(1-cyano group cyclopropyl)-9-fluoro-3-methyl-7-oxo-2, [preparation of 1,4] benzoxazine-6-carboxylic acid (XI), chemical equation is 3-dihydro-7H-pyridine [1,2,3-de]
(3) (S)-and 10-(1-carbamyl cyclopropyl)-9-fluoro-3-methyl-7-oxo-2, [preparation of 1,4] benzoxazine-6-carboxylic acid (XII), chemical equation is 3-dihydro-7H-pyridine [1,2,3-de]
(4) (S)-and 10-(the amino cyclopropyl of 1-)-9-fluoro-3-methyl-7-oxo-2, [1,4] benzoxazine-6-carboxylic acid is the preparation of Pazufloxacin (XIII) to 3-dihydro-7H-pyridine [1,2,3-de], and chemical equation is
(5) preparation of T-3762 (I), chemical equation is
It is characterized in that with the VIII being feedstock production (S)-10-(cyano group ethoxycarbonyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1, the concrete steps of 4] benzoxazine-6-carboxylic acid (X) are: DMSO is cooled to 0 ℃, drips ethyl cyanoacetate, stirred 1 hour under 0 ℃ of left and right sides condition, add VIII, slowly be warming up to 60-70 ℃ of reaction 8-10 hour, be cooled to room temperature, regulate pH value to 4, ethyl acetate extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, be evaporated to dried, get red-brown oily matter IX, mechanical stirring is being housed, in the three-necked bottle of reflux condensing tube, add IX and 1, the 4-dioxane, water, tosic acid-hydrate, stir, reflux 24 hours adds water cooling, the placement refrigerator cold-storage spends the night, make and separate out solid fully, suction filtration, washing, the ether washing, the dry product X that gets.
2. the synthetic method of the described improved T-3762 of claim 1 is characterized in that with the VIII being feedstock production (S)-10-(cyano group ethoxycarbonyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [concrete steps of 1,4] benzoxazine-6-carboxylic acid (X) are: DMSO is cooled to 0 ℃, drip ethyl cyanoacetate, under 0 ℃ of left and right sides condition, stirred 1 hour, add VIII, slowly be warming up to 70 ℃ of reactions 8 hours, be cooled to room temperature, regulate pH value to 4, ethyl acetate extraction merges organic layer, the saturated common salt water washing, anhydrous sodium sulfate drying, be evaporated to dried, red-brown oily matter IX, mechanical stirring is being housed, in the three-necked bottle of reflux condensing tube, add IX and 1, the 4-dioxane, water, the tosic acid monohydrate stirs, reflux 24 hours, add water cooling, place refrigerator cold-storage and spend the night, make and separate out solid fully, suction filtration, washing, ether washing, the dry product X that gets.
3. the synthetic method of the described improved T-3762 of claim 1, concrete steps are:
(S)-and 10-(cyano group ethoxycarbonyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [the preparation of 1,4] benzoxazine-6-carboxylic acid (X): DMSO is cooled to 0 ℃, drips ethyl cyanoacetate, under 0 ℃ of left and right sides condition, stirred 1 hour, add VIII, slowly be warming up to 70 ℃ of reactions 8 hours, be cooled to room temperature, regulate pH value to 4, ethyl acetate extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, be evaporated to dried, get red-brown oily matter IX, mechanical stirring is being housed, in the three-necked bottle of reflux condensing tube, add IX and 1, the 4-dioxane, water, the tosic acid monohydrate, stir, reflux 24 hours adds water cooling, the placement refrigerator cold-storage spends the night, make and separate out solid fully, suction filtration, washing, the ether washing, the dry product X that gets;
(S)-and 10-(1-cyano group cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1, the preparation of 4] benzoxazine-6-carboxylic acid (XI): stirring is being housed, in the three-necked bottle of dropping funnel and prolong, add NaOH, water, frozen water are cooled to 0 ℃, add benzyl triethyl ammonium bromide, stirring at room half an hour, gradation adds X, stirs 0.5 hour, splash into 1, the 2-ethylene dibromide slowly was warming up to 45 ℃ of stirring reactions 3 hours, was cooled to room temperature, stirring is spent the night, dilute with water is regulated pH value to 5 with Glacial acetic acid under the frozen water cooling conditions, separates out solid, suction filtration, the chloroform washing, washing, ether washing, constant pressure and dry is 6 hours under 105 ℃ of conditions, gets the product XI;
(S)-and 10-(1-carbamyl cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1, the preparation of 4] benzoxazine-6-carboxylic acid (XII): in the three-necked bottle of stirring is housed, add the vitriol oil, frozen water is cooled to 0 ℃, add XI, stir, slowly be warming up to room temperature, stirring reaction spends the night, and reaction solution is poured in the mixture of ice and water, makes crystallization, suction filtration, washing makes it neutral, the ether washing, drain, drying is 6 hours under 105 ℃ of conditions, gets the product XII;
(S)-and 10-(the amino cyclopropyl of 1-)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid is the preparation of Pazufloxacin: stirring is being housed, in the three-necked bottle of prolong, add NaOH, water, frozen water are cooled to about 0 ℃, add 9% NaClO solution, add XII again, slowly be warming up to room temperature, stirring reaction spends the night, reheat to 70 ℃ reaction 1 hour, be cooled to room temperature, add water, regulate pH value to 6, separate out solid with concentrated hydrochloric acid, suction filtration, drying is drained in washing, use the DMF recrystallization, drying got product XIII in 3 hours under 80 ℃ of conditions;
The preparation of T-3762 (I): in the three-necked bottle that stirring, dropping funnel are housed, add XIII, water, stir, the frozen water cooling drips methylsulfonic acid, slowly is warming up to room temperature, stirring reaction 1 hour adds gac 11g, restir half an hour, suction filtration, filtrate is concentrated into dried, adds alcohol dilution, suction filtration, washing with alcohol is drained, drying is 4 hours under 80 ℃ of conditions, gets the T-3762 I.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772412A (en) * | 2012-10-23 | 2014-05-07 | 浙江海森药业有限公司 | Preparation method of pazufloxacin intermediate |
| 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 |
| CN104031064A (en) * | 2014-05-29 | 2014-09-10 | 上海应用技术学院 | Pazufloxacin impurity and preparation method thereof |
| CN110041329A (en) * | 2019-05-27 | 2019-07-23 | 天地恒一制药股份有限公司 | A kind of preparation method of tosufloxacin tosilate monohydrate |
| WO2023272962A1 (en) * | 2021-06-30 | 2023-01-05 | 海南海神同洲制药有限公司 | Method for detecting small polar impurities in pazufloxacin mesylate bulk drug |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772412A (en) * | 2012-10-23 | 2014-05-07 | 浙江海森药业有限公司 | Preparation method of pazufloxacin intermediate |
| CN103772412B (en) * | 2012-10-23 | 2016-03-16 | 浙江海森药业有限公司 | A kind of preparation method of Pazufloxacin intermediate |
| 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 |
| CN104031064A (en) * | 2014-05-29 | 2014-09-10 | 上海应用技术学院 | Pazufloxacin impurity and preparation method thereof |
| CN104031064B (en) * | 2014-05-29 | 2016-04-27 | 上海应用技术学院 | A kind of Pazufloxacin impurity and preparation method thereof |
| CN110041329A (en) * | 2019-05-27 | 2019-07-23 | 天地恒一制药股份有限公司 | A kind of preparation method of tosufloxacin tosilate monohydrate |
| CN110041329B (en) * | 2019-05-27 | 2021-08-10 | 天地恒一制药股份有限公司 | Preparation method of tosufloxacin tosylate monohydrate |
| WO2023272962A1 (en) * | 2021-06-30 | 2023-01-05 | 海南海神同洲制药有限公司 | Method for detecting small polar impurities in pazufloxacin mesylate bulk drug |
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