CN105294648B - A kind of preparation method of sitafloxacin - Google Patents
A kind of preparation method of sitafloxacin Download PDFInfo
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- CN105294648B CN105294648B CN201510862616.4A CN201510862616A CN105294648B CN 105294648 B CN105294648 B CN 105294648B CN 201510862616 A CN201510862616 A CN 201510862616A CN 105294648 B CN105294648 B CN 105294648B
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a kind of preparation method of sitafloxacin; 2 are utilized in the synthetic method of the present invention; the fluobenzoic acid of 3,4 trichlorine 5 is that initiation material generates key intermediate V by coupling, the condensation of two steps, and then intermediate V is condensed again, deprotection reaction prepares sitafloxacin.This method initiation material is easy to get, and post processing is simple, and product yield improves, and is the synthetic route of an economical and convenient, is adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, more particularly to a kind of preparation method of sitafloxacin.
Background technology
Sitafloxacin (Sitafloxacin) be Japanese first pharmacy Sankyo Co., Ltd after lavo-ofloxacin, newly open
A kind of strength broad spectrum quinolone antimicrobial of hair, there is double inhibition effect to pneumococcus DNA gyrase and topological isodynamic enzyme, use
In treatment serious intractable bacterium infection, recurrent infection and some drug-fast bacteria infections.
Sitafloxacin has good pharmacokinetic characteristics due to containing a cis fluorine cyclopropylamine group in structure,
And adverse reaction can be mitigated, the more most of similar drugs of its antibacterial activity in vitro are remarkably reinforced.It is blue to Gram-negative bacteria, leather
Family name's positive cocci and the antibacterial activity of anaerobic bacteria are 4~32 times of lavo-ofloxacin, the resistance to quinolone common to many clinics
Class bacterial strain also possesses good bactericidal action.Sitafloxacin oral absorption is good, and bioavailability is more than 70%, and Tissue distribution is wide,
The drug concentration in many tissues outside central nervous system is above serum-concentration.Therefore, sitafloxacin is expected to turn into treatment
Respiratory tract, urogenital tract, abdominal cavity and skin soft tissue etc. is single or the important drugs of mixed cell infection.
Sitafloxacin chemistry is entitled：7- [(7S) -7- amino -5- azaspiros [2.4] hept- 5- yls] fluoro- 1- of the chloro- 6- of -8-
[(1R, 2S) -2- fluorine cyclopropyl]-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acids.Structural formula is as follows：
The synthesis of its existing process route is as follows：
1) it is to be condensed with 2,4,5- trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl esters for initiation material and triethyl orthoformate, then and (1R,
2S)-(-) after the condensation of-cis-1- amino -2- fluorine cyclopropane tosilate, the cyclization in the presence of sodium hydroxide, then in hydrochloric acid
Under the conditions of hydrolyze takes off ester group, with (s)-(-) -7- t-butoxycarbonyl amino -5- azaspiros [2.4] heptane be condensed, with thionyl chloride
Chlorination, finally Deprotection obtains sitafloxacin in the presence of sodium hydroxide, and specific route is as follows：
2) it is to be condensed with 2,4,5- tri- fluoro- 3- chlorobenzoyls ethyl acetate for initiation material and triethyl orthoformate, then and
After the condensation of (1R, 2S)-(-)-cis-1- amino -2- fluorine cyclopropane tosilate, the cyclization in the presence of sodium hydroxide, then
Takes off ester group is hydrolyzed under the conditions of hydrochloric acid, is condensed with (s)-(-) -7- t-butoxycarbonyl amino -5- azaspiros [2.4] heptane, finally takes off
Protection group obtains sitafloxacin, and specific route is as follows：
The synthetic route of prior art has that step is relatively long, and post processing is cumbersome, and product yield is low, and cost is higher to be lacked
Point, it is significant to find a simple synthetic route of economy.
The content of the invention
Present invention aims at a kind of preparation method of sitafloxacin is provided, the preparation method initiation material is easy to get, technique
Simply, easy post-processing, product yield improve, and are adapted to industrialized production.
Synthetic route of the present invention is as follows：
A kind of preparation method of sitafloxacin, prepared method comprise the following steps：
A, initiation material 2,3,4- tri- chloro- 5- fluobenzoic acids (II) and (1R, 2S)-(-)-cis-1- amino -2- fluorine ring third
Alkane tosilate reacts in catalyst, part, organic solvent and alkaline environment is made compound III；
B, compound III is reacted with double (trichloromethyl) carbonic esters under the conditions of atent solvent and certain temperature, is prepared
Compounds Ⅳ；
C, compounds Ⅳ reacts prepare compound in organic solvent, N- methylimidazoles with malonic acid ester type compound solution
Ⅴ。
D, compound V and (S)-(-) -7- t-butoxycarbonyl amino -5- azaspiro [2.4] heptane are in organic solvent and alkali
Under the conditions of prepare compound VI；
E, compound VI is deprotected, is refining to obtain chemical compounds I.
Wherein, catalyst described in the step a be cuprous iodide, cuprous bromide, stannous chloride, cupric iodide, cupric oxide or
Acetylacetone copper, preferably cuprous iodide.The part is N, N- dimethyl-ethylenediamines, 1,10- phenanthroline or L-PROLINE, preferably
N, N- dimethyl-ethylenediamine.Copper compound catalyst used, part, 2,3,4- tri- chloro- 5- fluobenzoic acids (II), (1R, 2S)-
(-)-cis-1- amino -2- fluorine cyclopropane tosilate mol ratio is 0.1~0.2:0.1~0.2:1:1.5~2.Ability
Domain inventor is by a large amount of screenings, preferred molar ratio 0.1:0.2:1:1.5, product yield and purity are higher.Described is organic
Solvent is isopropanol, the tert-butyl alcohol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE or 1,4- dioxies
Six rings, preferably DMF.The alkali is selected from anhydrous phosphoric acid potassium, Anhydrous potassium carbonate or Carbon Dioxide caesium, preferably without
Water potassium phosphate.
Described atent solvent described in step b is selected from toluene, dimethylbenzene, dichloromethane, dichloroethanes or n-butyl ether, excellent
Select dichloromethane.Reaction temperature is 40-60 DEG C.
Organic solvent described in step c is selected from DMF.Described malonic acid ester type compound be selected from β-
Hydroxy acrylic acid ester sodium salt, beta-hydroxy acrylate sylvite, beta-hydroxy acrylic acid lithium salts or diethyl malonate.N- methylimidazoles
It is 1~3 with compounds Ⅳ mol ratio:1, preferred molar ratio 1:1.
Organic solvent described in step d is selected from methanol, ethanol, n-butanol, ether or DMF；Described alkali
Selected from Anhydrous potassium carbonate, anhydrous potassium hydroxide or without water sodium hydroxide, alkali used and the mol ratio of compound V are 2~1:1.
Step e concrete operation steps are to add trifluoroacetic acid with dichloromethane mixed solution to have compound VI to react
In bottle, it is stirred at room temperature 1 hour, reaction stops, rotary evaporation.Surplus materials is added into appropriate ethyl acetate to be dissolved,
It is 10~12 to adjust pH using 40% sodium hydroxide solution, then is filtered, washs to obtain sitafloxacin crude product.Described is refined
Process is：Sitafloxacin crude product is added in deionized water and alcohol mixture, adds decolorizing with activated carbon, stirring is warming up to 50~70
DEG C, 1 hour of insulated and stirred is filtered while hot, and filter cake with ethanol, deionized water with being washed respectively.Merge cleaning solution and filtrate, use matter
To measure the sodium hydroxide solution that fraction is 40% and adjust pH to 7, be cooled to 10 DEG C, filtering, filter cake is washed with deionized, is dried under reduced pressure,
Obtain sitafloxacin fine work.
Beneficial effects of the present invention are as follows：
1. initiation material 2,3, the chloro- 5- fluobenzoic acids of 4- tri- and (1R, 2S)-(-)-cis-1- amino -2- fluorine cyclopropane pair
Toluene fulfonate carries out coupling reaction under copper compound catalytic condition, and product yield more than 90%, purity is high, impurity content
It is low.Known by Ullmann coupling reaction mechanism, when halogen ortho position has electron-withdrawing group (- COOH), be advantageous to 2 chlorine atoms and occur
React (detailed in Example 1), through validation trial, reaction product is mainly based on the compound III of 2, while optimize technique
The selectivity of state modulator product, make compound III product yield and purity be higher and impurity is less, not under the influence of step experiment
Carry out.
2. two (trichloromethyl) carbonic esters are solid matter, can be reacted in organic solvent medium with compound III
Compounds Ⅳ is generated, the reaction is homogeneous reaction, and yield is higher；And two (trichloromethyl) carbonate reaction amount it is relatively controllable, nothing
Excess compounds III need to be added, therefore it is higher to obtain compounds Ⅳ purity.
3. adding N- methylimidazoles in step c reactions, improve product yield.
4. the synthetic route initiation material is easy to get, processing step shortens, and operation process is easy, and overall product yield carries
Height, it is a simple and economic synthetic method.
Embodiment
The content of the invention of the present invention is described in further detail below by specific embodiment, but therefore not limited
Determine present disclosure.
Embodiment 1
The preparation of compound III
Under nitrogen protection, sequentially added in reaction bulb 2,3,4- tri- chloro- 5- fluobenzoic acids (II) (20.9g,
80mmol), (1.5g, 8mmol) cuprous iodide, (2.9g, 16mmol) 1,10- phenanthroline, 100ml DMFs,
(21.2g, 100mmol) anhydrous phosphoric acid potassium, (39.6g, 160mmol) (1R, 2S)-(-)-cis-1- amino -2- fluorine ring third is added dropwise
Alkane tosilate DMF solution, 20~25 DEG C of reaction temperature, stirring reaction, maintenance reaction 10 hours,
After reaction terminates, PH=4.5 is adjusted, is cooled to 0 DEG C, is filtrated to get solid 21.0g, yield 93%, although from theory analysis 3
Chlorine atom may participate in 2 coupling competitive reactions with 4 chlorine atoms, be tested and analyzed through instrument, compound III content 99.1%,
Impurity A content 0.5%, impurity B does not detect.
Embodiment 2
The preparation of compound III
Under nitrogen protection, sequentially added in reaction bulb 2,3,4- tri- chloro- 5- fluobenzoic acids (II) (20.9g,
80mmol), (0.8g, 8mmol) stannous chloride, (2.9g, 16mmol) 1,10- phenanthroline, 100ml DMFs,
(32.6g, 100mmol) Carbon Dioxide caesium, (29.7g, 120mmol) (1R, 2S)-(-)-cis-1- amino -2- fluorine ring third is added dropwise
Alkane tosilate DMF solution, 20~25 DEG C of reaction temperature, stirring reaction, maintenance reaction 10 hours,
After reaction terminates, PH=4.5 is adjusted, 0 DEG C is cooled to, is filtrated to get the 20.5g of solid chemical compound III, yield 91%, is examined through instrument
Analysis is surveyed, compound III content 99.2%, Impurity A content 0.3%, impurity B does not detect.
Embodiment 3
The preparation of compounds Ⅳ
(17.4g, 60mmol) is added into the 250mL four-hole bottles equipped with agitator, thermometer and circulation condensation device to change
Compound III and 150mL dichloromethane, turn on agitator and circulation condensation device, are warming up to 50 DEG C, stir complete to compound III
Dissolving, obtains compound III solution；Two commercially available (trichloromethyl) carbonic esters of 20g are dissolved in 40mL dichloromethane, obtained
Two (trichloromethyl) carbonate solutions；Described two (trichloromethyl) carbonate solutions are slowly added dropwise into compound III solution,
Drip off within 1.5 hours, then heat to 60 DEG C and react 2 hours, obtain compounds Ⅳ solution.After being down to room temperature, by the compound
IV solution is filtered, and 18.0g, yield 98%, HPLC purity 99.9% are weighed as after drying.
Embodiment 4
The preparation of compounds Ⅳ
(17.4g, 60mmol) is added into the 250mL four-hole bottles equipped with agitator, thermometer and circulation condensation device to change
Compound III and 150mL dimethylbenzene, turn on agitator and circulation condensation device, are warming up to 50 DEG C, stir completely molten to compound III
Solution, obtains compound III solution；Two commercially available (trichloromethyl) carbonic esters of 20g are dissolved in 40mL dimethylbenzene, obtain two (three
Chloromethyl) carbonate solution；Described two (trichloromethyl) carbonate solutions are slowly added dropwise into compound III solution, 1.5 is small
When drip off, then heat to 40 DEG C react 2 hours, obtain compounds Ⅳ solution.After being down to room temperature, by the compounds Ⅳ solution
Filter, 17.6g, yield 96%, HPLC purity 99.7% are weighed as after drying.
Embodiment 5
The preparation of compound V
Under nitrogen protection, (16.2g, 52mmol) compounds Ⅳ dissolving DMF 150ml and (4ml,
1.030g/ml) in N- methylimidazoles mixed solution, mixture is heated 60 DEG C, stirring adds beta-hydroxy propylene after 30 minutes
Sodium salt (7.4g, 60mmol).Temperature is maintained 60 DEG C and kept for 2 hours at this temperature, mixture is cooled to 20
~25 DEG C and it is stirred for 2 hours.Then, product filtered and washed on the filter using 80mL methanol, dried, obtain chemical combination
The 14.2g of thing V, yield 82%, HPLC purity 99.7%.
Not plus N- methylimidazoles carry out the comparative example of the preparation of compound V
Under nitrogen protection, in (16.2g, 52mmol) compounds Ⅳ dissolving 150ml DMF solution,
60 DEG C are heated to, stirring adds beta-hydroxy acrylate sodium salt (7.4g, 60mmol) after 30 minutes.Temperature is maintained 60 DEG C
And kept for 2 hours at this temperature, mixture is cooled to 20~25 DEG C and is stirred for 2 hours.Then, by product filter and
Washed, dried using 80mL methanol on filter, obtain the 8.7g of compound V, yield 50.1%, HPLC purity 99.7%.
Embodiment 6
The preparation of compound V
Under nitrogen protection, (16.2g, 52mmol) compounds Ⅳ dissolving DMF 150ml and (12ml,
1.030g/ml) in N- methylimidazoles mixed solution, mixture is heated 60 DEG C, stirring adds malonic acid diethyl after 30 minutes
Ester (9.6g, 60mmol).Temperature is maintained 60 DEG C and kept for 2 hours at this temperature, mixture is cooled to 20~25 DEG C
And it is stirred for 2 hours.Then, product filtered and washed on the filter using 80mL methanol, dried, obtain compound V
13.7g, yield 79%, HPLC purity 99.5%.
Embodiment 7
The preparation of compound VI
Compound V (13.0g, 32mmol), (S)-(-) -7- t-butoxycarbonyl amino -5- azepines are added in reaction bulb
Spiral shell [2.4] heptane (13.6g, 64mmol), DMF (150ml) and Anhydrous potassium carbonate (8.8g, 64mmol), are stirred
Mix down and be warming up to 50-60 DEG C and react 3 hours, be concentrated under reduced pressure after reaction solution is slightly cold, water 100ml and dichloromethane are added in residue
150ml, stirring, pH value is adjusted to 4 with glacial acetic acid, liquid separation, water layer is extracted three times with dichloromethane, is merged organic layer, is used saturation
Sodium chloride solution washs, and is filtered after anhydrous magnesium sulfate is dried, filtrate decompression concentration, adds ethanol 100ml in residue, keeps
Temperature 50 C stirs 20 minutes, is cooled to room temperature, adds ethyl acetate 100ml, 10 DEG C are stirred 1 hour, are filtered, filter cake oil
Ether washs, and drains, 30 DEG C are dried under reduced pressure 8 hours, obtain the 17.4g of compound solid VI, yield 97%, HPLC purity 99.8%.
Embodiment 8
The preparation of compound VI
Compound V (13.0g, 32mmol), (S)-(-) -7- t-butoxycarbonyl amino -5- azepines are added in reaction bulb
Spiral shell [2.4] heptane 13.6g (64mmol), DMF (150ml) and Anhydrous potassium carbonate (4.4g, 32mmol), are stirred
Mix down and be warming up to 50-60 DEG C and react 3 hours, be concentrated under reduced pressure after reaction solution is slightly cold, water 100ml and dichloromethane are added in residue
150ml, stirring, 10% glacial acetic acid is added to be adjusted to pH=4, liquid separation, water layer is extracted three times with dichloromethane, merges organic layer, with full
Wash with sodium chloride solution, filtered after anhydrous magnesium sulfate is dried, filtrate decompression is concentrated, and ethanol 100ml is added in residue, is protected
Hold temperature 50 C to stir 20 minutes, be cooled to room temperature, add petroleum ether 100ml, 10 DEG C are stirred 1 hour, are filtered, filter cake oil
Ether washs, and drains, 30 DEG C are dried under reduced pressure 8 hours, obtain the 16.5g of compound solid VI, yield 92%, HPLC purity 99.6%.
Embodiment 9
The preparation of sitafloxacin (I)
Trifluoroacetic acid 150ml and dichloromethane 100ml mixed solutions are added to fill compound VI (15.5g,
27.6mmol) in reaction bulb, it is stirred at room temperature 1 hour.Reaction stops, rotary evaporation.Surplus materials is added into appropriate acetic acid
Ethyl ester is dissolved, and it is 10~12 to adjust pH using 40% sodium hydroxide solution, separates water layer, water layer dichloromethane 100ml
Washing, then is filtered, and filter cake wash three times with ethanol, then is washed with deionized three times, dry faint yellow solid it is western he
Husky star crude product 10.4g, yield 92%, HPLC purity 99.5%.
Sitafloxacin crude product 9.8g is added in deionized water 100ml and ethanol 200ml mixtures, adds decolorizing with activated carbon,
Stirring is warming up to 50~55 DEG C, and 1 hour of insulated and stirred is filtered while hot, and filter cake with ethanol, deionized water with being washed respectively.Merge
Cleaning solution and filtrate, pH to 7 is adjusted with the sodium hydroxide solution that mass fraction is 40%, is cooled to 10 DEG C, filters, filter cake deionization
Water washing, 30 DEG C are dried under reduced pressure 10 hours, obtain off-white powder 8.9g, yield 91%, HPLC purity 99.9%.
Embodiment 10
The preparation of sitafloxacin (I)
Trifluoroacetic acid 150ml and dichloromethane 100ml mixed solutions are added to fill compound VI (19.1g,
33mmol) in reaction bulb, it is stirred at room temperature 1 hour.Reaction stops, rotary evaporation.Surplus materials is added into appropriate acetic acid second
Ester is dissolved, and it is 10~12 to adjust pH using 40% sodium hydroxide solution, separates water layer, water layer is washed with 100ml dichloromethane
Wash, then filtered, filter cake is washed three times with ethanol, then is washed with deionized three times, dry faint yellow solid Xi Tasha
Star crude product 17.4g, yield 94%, HPLC purity 99.6%.
Sitafloxacin crude product 16.6g is added in deionized water 100ml and ethanol 200ml mixtures, adds decolorizing with activated carbon,
Stirring is warming up to 65~70 DEG C, and 1 hour of insulated and stirred is filtered while hot, and filter cake with ethanol, deionized water with being washed respectively.Merge
Cleaning solution and filtrate, pH to 7 is adjusted with the sodium hydroxide solution that mass fraction is 40%, is cooled to 10 DEG C, filters, filter cake deionization
Water washing, 30 DEG C are dried under reduced pressure 10 hours, obtain off-white powder 15.4g, yield 93%, HPLC purity 99.9%.
Claims (4)
1. a kind of preparation method of sitafloxacin, it is characterised in that the preparation method comprises the following steps：
A, initiation material 2,3,4- tri- chloro- 5- fluobenzoic acids (II) and (1R, 2S)-(-)-cis-1- amino -2- fluorine cyclopropane pair
Toluene fulfonate reacts in catalyst, part, organic solvent and alkaline environment, and compound III is made；The catalyst is iodine
Change cuprous, cuprous bromide, stannous chloride, cupric iodide, cupric oxide or acetylacetone copper；The part is selected from N, N- dimethyl second two
Amine, 1,10- phenanthroline or L-PROLINE；Copper compound catalyst used, part, the chloro- 5- fluobenzoic acids (II) of 2,3,4- tri-,
(1R, 2S)-(-)-cis-1- amino -2- fluorine cyclopropane tosilate mol ratio is 0.1~0.2:0.1~0.2:1:1.5
~2；The organic solvent is selected from isopropanol, the tert-butyl alcohol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), N- methylpyrroles
Alkanone or 1,4- dioxane；The alkali is selected from anhydrous phosphoric acid potassium, Anhydrous potassium carbonate or Carbon Dioxide caesium；
B, compound III is reacted with double (trichloromethyl) carbonic esters under the conditions of atent solvent and certain temperature, prepares chemical combination
Thing IV；Described atent solvent is selected from toluene, dimethylbenzene, dichloromethane, dichloroethanes or n-butyl ether；The reaction temperature is
40-60℃；Described organic solvent is pyridine, toluene, DMF or dichloroethanes；
C, compounds Ⅳ reacts prepare compound V in organic solvent, N- methylimidazoles with malonic acid ester type compound solution；
Described organic solvent is selected from DMF；Described malonic acid ester type compound is selected from beta-hydroxy acrylate sodium
Salt or diethyl malonate；N- methylimidazoles are 1~3 with compounds Ⅳ mol ratio:1；
D, compound V and (S)-(-) -7- t-butoxycarbonyl amino -5- azaspiros [2.4] heptane are in organic solvent and alkali condition
Lower prepare compound VI；
E, compound VI is deprotected, is refining to obtain chemical compounds I；
Compound III：Compounds Ⅳ：Compound V：Compound VI：
2. according to the method described in claim 1, it is characterised in that organic solvent described in step d is selected from methanol, ethanol, just
Butanol, ether or DMF；Described alkali is selected from Anhydrous potassium carbonate, anhydrous potassium hydroxide or anhydrous hydroxide
Sodium, alkali used and the mol ratio of compound V are 2~1:1.
3. according to the method described in claim 1, it is characterised in that the deprotection concrete operations described in step e are by trifluoro
Acetic acid adds with dichloromethane mixed solution to be had in the reaction bulb of compound VI, is stirred at room temperature 1 hour, and reaction stops,
Rotary evaporation, surplus materials is added into appropriate ethyl acetate and dissolved, using 40% sodium hydroxide solution adjust pH be 10~
12, then filtered, wash to obtain sitafloxacin crude product.
4. according to the method described in claim 1, it is characterised in that the subtractive process described in step e is：Sitafloxacin is thick
Product are added in deionized water and alcohol mixture, add decolorizing with activated carbon, and stirring is warming up to 50~70 DEG C, insulated and stirred 1 hour, taken advantage of
Heat filtering, filter cake merge cleaning solution and filtrate with being washed respectively with ethanol, deionized water, with the hydrogen-oxygen that mass fraction is 40%
Change sodium solution and adjust pH to 7, be cooled to 10 DEG C, filtering, filter cake is washed with deionized, is dried under reduced pressure, and obtains sitafloxacin fine work.
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