CN102718781B - Preparation method of prulifloxacin - Google Patents
Preparation method of prulifloxacin Download PDFInfo
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- CN102718781B CN102718781B CN201210139610.0A CN201210139610A CN102718781B CN 102718781 B CN102718781 B CN 102718781B CN 201210139610 A CN201210139610 A CN 201210139610A CN 102718781 B CN102718781 B CN 102718781B
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Abstract
The invention relates to a synthetic method of prulifloxacin, comprising the steps of: stirring DMDO-Cl and sodium iodide in an organic solvent, carrying out a one-pot reaction of the unseparated reaction liquid, a compound 2 and alkali substances to obtain the prulifloxacin. The synthetic method of the invention is advantaged in that the raw material DMDO-Cl used in the invention is cheap, easily available, and easily stored and transported, the prulifloxacin synthesized by the method has high yield, increased purity, and the operation is convenient.
Description
Technical field
The present invention relates to the preparation method that a kind of carbostyril family antibacterial drugs is new, be specifically related to a kind of preparation method of prulifloxacin.
Background technology
Prulifloxacin (prulifloxacin) is the fluoroquinolone antibacterial agent jointly researched and developed by Nippon Shinyaku Co., Ltd. (JP) Tokyo To, Japan and Ming Yezhiguo company, in 2002 in Japanese Initial Public Offering.This product has broad spectrum antibiotic activity, similar to Ofloxacin (ofloxacin) to the antibacterial activity of S. aureus L-forms, be greater than Ciprofloxacin (ciprofloxacin), to streptococcic specific activity Ofloxacin large 5 times, suitable with Ciprofloxacin to colibacillary activity, to the antibacterial activity of Klebsiella Pneumoniae, serratia marcesens, Pseudomonas aeruginosa than Ciprofloxacin and large 2 ~ 3 times of Ofloxacin, clinically can be used for treatment pneumonia, acute/chronic bronchitis, sphagitis and the chronic secondary infection of respiratory tract etc.
Following chemical formula, patent CN1024194C report uses 4-chloromethyl-5-methyl isophthalic acid, 3-dioxa cyclenes pentanedione-X((DMDO-X, X is halogen) and the fluoro-7-piperazine of 6--1-methyl-4-oxo-4H-[1,3] sulfur nitrogen heterocycle butane also [3,2-a] quinoline-3-carboxylic acid (compound ii) be obtained by reacting prulifloxacin.Compound ii research report extensively, and has commercially available, and the method becomes prulifloxacin present stage topmost synthetic route.
4-chloromethyl-5-methyl isophthalic acid, 3-dioxa cyclenes pentanedione-X can be lower chemical formula 4-chloromethyl-5-methyl isophthalic acid, 3-dioxa cyclenes pentanedione-Cl(DMDO-Cl), 4-chloromethyl-5-methyl isophthalic acid, 3-dioxa cyclenes pentanedione-Br(DMDO-Br), 4-chloromethyl-5-methyl isophthalic acid, 3-dioxa cyclenes pentanedione-I(DMDO-I) in three materials any one, wherein DMDO-Cl source is easy to get, but reactivity and weak effect.DMDO-Br not easily obtains, so Tatsuya Fuii etc. [Chem.Pharm.Bull.43 (11), 1872-1877 (1995)] report, DMDO-Cl and sodium bromide are reacted in organic solvent, filter, obtained DMDO-Br filtrate is used for reaction.But the activity that responds equally not high.DMDO-I reactivity is best, but has source and store the shortcomings such as difficulty.Occupy the reason that DMDO-I reactivity is best, be necessary to work out a kind of DMDO-Cl raw material adopting source to be easy to get, be converted into DMDO-I dereaction, utilize the condition that reactivity is best, for the synthesis of prulifloxacin.
Summary of the invention
The object of the invention is to the preparation method that openly a kind of prulifloxacin is new.
The present invention seeks to be achieved through the following technical solutions:
The invention provides the method for a kind of synthesizing prulifloxacin (prulifloxacin, 1), it is characterized in that the method comprises the steps:
Step 1, with 4-chloromethyl-5-methyl isophthalic acid, 3-dioxa cyclenes pentanedione (DMDO-Cl) is initiation material, adds iodide, stirs to obtain reactant liquor A in organic solvent I;
Step 2, reactant liquor A is without separation, directly and following formula II compound (the fluoro-7-piperazine of 6--1-methyl-4-oxo-4H-[1, 3] sulfur nitrogen heterocycle butane also [3, 2-a] quinoline-3-carboxylic acid), alkaloids, dimethyl formamide mixes, one pot reaction obtains prulifloxacin, raw material rate of charge is with molar basis, DMDO-Cl: iodide: organic solvent I: compound ii: alkaloids: dimethyl formamide=1 ~ 2:1 ~ 3:5 ~ 1000:1:1 ~ 3:10 ~ 2000, molar ratio is preferably 1.1 ~ 1.5:1.4 ~ 2.5:10 ~ 40:1:1.3 ~ 2.5:30 ~ 200.
Described iodide are at least one in sodium iodide, KI, are preferably sodium iodide; Described organic solvent I is any one or a few the mixed solvent in acetone, dimethyl formamide (DMF), acetonitrile, is preferably acetone;
Described alkaloids is sodium acid carbonate, sodium carbonate, saleratus, potash, Cs
2cO
3, at least one in DIPEA (DIPEA), be preferably saleratus or DIPEA.
The DMDO-Cl raw material that the inventive method uses cheaply is easy to get, easily stores transport, and preparation process activity is high, the method synthesizing prulifloxacin yield is high, purity improve, easy and simple to handle, solve the problem that prior art exists the low or storage difficulties of DMDO-X reactivity, be beneficial to suitability for industrialized production.
Experimental example and embodiment are used for further illustrating but are not limited to the present invention below.
Experimental example 1: comparative experiments
1, reference literature Chem.Pharm.Bull.43 (11) 1872-1877,1995 report methods prepare prulifloxacin
DMDO-Cl (2.26g, 15.2mmol) be dissolved in 5.5ml DMF, add sodium bromide (3.08g, 30.3mmol), 303K stirs 1 hour, adds 11ml acetone, continue reaction 1 hour, reacting liquid filtering, filtrate decompression removing acetone, this solution contains DMDO-Br 14.1mmol.Compound ii (5.00g, 11.6mmol) drop in 32ml DMF, add above-mentioned DMDO-Br solution, in 10 minutes, add saleratus (2.69g, 26.9mmol), 304K stirs 3 hours, and reactant liquor is poured in 120ml frozen water afterwards, separates out precipitation, filter, vacuum drying obtains 4.80g prulifloxacin crude product, and yield is 89.7%, and purity is 89.9%.
2, bibliography Chem.Pharm.Bull.43 (11) 1872-1877,1995 report methods prepare prulifloxacin
DMDO-Cl (6.45g, 43.5mmol) be dissolved in 16ml DMF, add sodium bromide (8.73g, 84.9mmol), 303K stirs 1 hour, adds 30ml acetone, continue reaction 1 hour, reacting liquid filtering, filtrate decompression removing acetone, this solution contains DMDO-Br 40.2mmol.Compound ii (15.00g, 34.8mmol) drop in 90ml DMF, add above-mentioned DMDO-Br solution, in 10 minutes, drip DIPEA (5.28g, 39.6mmol), 304K stirs 1 hour, and reactant liquor is poured in 360ml frozen water afterwards, separates out precipitation, filter, vacuum drying obtains 14.28g prulifloxacin crude product, and yield is 88.9%, and purity is 93.7%.
3, prepare according to embodiment 1 method
DMDO-Cl (2.24g, 15.1mmol) be dissolved in 5.5ml DMF, add sodium iodide (3.28g, 22.0mmol), 303K stirs 1 hour, adds 11ml acetone, continue stirring 1 hour, reactant liquor, without separation, adds 32ml DMF, compound ii (5.00g, 11.6mmol), saleratus (2.69g in reactant liquor, 26.9mmol), 293K stirs 3 hours, and reactant liquor is poured in 120ml frozen water afterwards, separates out precipitation, filter, vacuum drying obtains 4.93g prulifloxacin crude product, and yield is 92.1%, and purity is 94.2%.
4, prepare according to embodiment 2 method
DMDO-Cl (6.44g, 43.4mmol) be dissolved in 16ml DMF, add sodium iodide (8.87g, 59.2mmol), 303K stirs 1 hour, add 30ml acetone, continue stirring 1 hour, reactant liquor is without separation, 90ml DMF is added in reactant liquor, compound ii (15.00g, 34.8mmol), DIPEA (5.28g is dripped in 10 minutes, 39.6mmol), 304K stirs 1 hour, reactant liquor is poured in 120ml frozen water afterwards, separate out precipitation, filter, vacuum drying obtains 14.83g prulifloxacin crude product, yield is 92.3%, purity is 94.3%.
5, to wet crude product according to preparing prulifloxacin in embodiment 8, wet crude product is dry
Acetone 40Kg is dropped in reactor, open and stir, add anhydrous sodium iodide 7.8Kg, logical cooling water, add DMDO-Cl 7.0Kg, 20-30 DEG C of stirring reaction, again by DMF 234Kg suction reactor, add compound ii 13.0Kg, saleratus 6.9Kg, stirring reaction, reactant liquor is proceeded to (less than 5 DEG C) in the water of 4 times amount of precooling, stir and separate out solid, survey pH value, be 6-7 with hydrochloric acid adjust pH, centrifugal filtration after stirring and crystallizing, obtain solid, for prulifloxacin wets crude product, prulifloxacin crude product vacuum drying of wetting obtains 15.98Kg prulifloxacin crude product, yield is 92.3%, purity is 94.3%.
Table one reference example and embodiment prepare yield and the comparison or purity table of prulifloxacin
Conclusion: by above reference example with prepare Comparative result by preparation method of the present invention, wherein prepare the yield of synthesizing prulifloxacin by the inventive method and purity (HPLC) is all better than reference example method, operate easier.
Following embodiment all can realize the effect of above-mentioned experimental example.
Embodiment 1:
DMDO-Cl (2.24g, 15.1mmol) be dissolved in 5.5ml DMF, add sodium iodide (3.28g, 22.0mmol), 303K stirs 1 hour, adds 11ml acetone, continue stirring 1 hour, reactant liquor, without separation, adds 32ml DMF, compound ii (5.00g, 11.6mmol), saleratus (2.69g in reactant liquor, 26.9mmol), 293K stirs 3 hours, and reactant liquor is poured in 120ml frozen water afterwards, separates out precipitation, filter, vacuum drying obtains 4.93g prulifloxacin crude product, and yield is 92.1%, and purity is 94.2%.
Embodiment 2:
DMDO-Cl (6.44g, 43.4mmol) be dissolved in 16ml DMF, add sodium iodide (8.87g, 59.2mmol), 303K stirs 1 hour, add 30ml acetone, continue stirring 1 hour, reactant liquor is without separation, 90ml DMF is added in reactant liquor, compound ii (15.00g, 34.8mmol), DIPEA (5.28g is dripped in 10 minutes, 39.6mmol), 304K stirs 1 hour, reactant liquor is poured in 120ml frozen water afterwards, separate out precipitation, filter, vacuum drying obtains 14.83g prulifloxacin crude product, yield is 92.3%, purity is 94.3%.
Embodiment 3
DMDO-Cl (17.4mmol) is dissolved in 6mlDMF, and add sodium iodide (29mmol), 303K stirs 1 hour, add 15ml acetone, continue stirring 1 hour, reactant liquor, without separation, adds 32ml DMF, compound ii (11.6mmol), saleratus (34.8mmol) in reactant liquor, 293K stirs 3 hours, filter, filtrate is poured in 144ml frozen water, separates out precipitation, filter, vacuum drying obtains prulifloxacin crude product.
Embodiment 4
DMDO-Cl (12.8mmol) is dissolved in 6mlDMF, and add KI (15.1mmol), 303K stirs 1 hour, add 10ml acetone, continue stirring 1 hour, reactant liquor, without separation, adds 32ml DMF, compound ii (11.6mmol), potash (11.6mmol) in reactant liquor, 298K stirs 3 hours, filter, filtrate is poured in 144ml frozen water, separates out precipitation, filter, vacuum drying obtains prulifloxacin crude product.
Embodiment 5
DMDO-Cl (15.5mmol), sodium iodide (17.4mmol) add in 10ml acetone, stirring at room temperature 1 hour, reactant liquor is without separation, 32ml DMF, compound ii (11.6mmol), saleratus (20mmol) is added in reactant liquor, stirring at room temperature 3 hours, reactant liquor is poured in 128ml frozen water, separates out precipitation, filter, vacuum drying obtains prulifloxacin crude product.
Embodiment 6
DMDO-Cl (15.5mmol), sodium iodide (17.4mmol) add in 10ml acetonitrile, stirring at room temperature 1 hour, reactant liquor is without separation, 32ml DMF, compound ii (11.6mmol), sodium carbonate (20mmol) is added in reactant liquor, stirring at room temperature 3 hours, reactant liquor is poured in 128ml frozen water, separates out precipitation, filter, vacuum drying obtains prulifloxacin crude product.
Embodiment 7
DMDO-Cl (12.8mmol) is dissolved in 6ml DMF, add KI (15.1mmol), 303K stirs 1 hour, add 10ml dimethyl formamide (DMF), continue stirring 1 hour, reactant liquor is without separation, 32ml DMF, compound ii (11.6mmol), DIPEA (N is added in reactant liquor, N-diisopropylethylamine) (11.6mmol), 298K stirs 3 hours, filters, filtrate is poured in 144ml frozen water, separate out precipitation, filter, vacuum drying obtains prulifloxacin crude product.
Embodiment 8
Acetone 40Kg is dropped in reactor, open and stir, add anhydrous sodium iodide 7.8Kg, logical cooling water, add DMDO-Cl 7.0Kg, 20-30 DEG C of stirring reaction, then by DMF 234Kg suction reactor, add compound ii 13.0Kg, saleratus 6.9Kg, stirring reaction, reactant liquor is proceeded to (less than 5 DEG C) in the water of 4 times amount of precooling, stir and separate out solid, surveying pH value, is 6-7 with hydrochloric acid adjust pH, centrifugal filtration after stirring and crystallizing, obtain solid, for prulifloxacin wets crude product, wet crude product directly carries out subsequent purification operation.
By in chloroform 580Kg suction reactor, open and stir, add the obtained prulifloxacin of step and to wet crude product, warming-in-water is extracted to stirring at 20-30 DEG C, and stratification, collects lower floor's organic phase.The solid matter on upper strata adds 200Kg chloroform again, stirs and extracts, stratification, and collect lower floor's organic phase, solid residue discards.Merge organic phase, add anhydrous magnesium sulfate 6.5Kg, stir dry, filter, removing drier.Proceeded to by solution in concentration tank, when being evaporated to a large amount of solid of precipitation, stop concentrated, raffinate proceeds in crystallizing tank, and less than 5 DEG C cool more than 4 hours, separate out solid.Filter, collect filter cake, 60 DEG C of vacuum drying, obtain prulifloxacin purification product 1.
By in acetonitrile 310Kg suction reactor, add 13Kg prulifloxacin purification product 1,13Kg column chromatography silica gel and 9.0Kg active carbon, add hot reflux 30 minutes, filter while hot, solution is transferred in crystallizing tank, be cooled to less than 5 DEG C cooling crystallizations, filter, collect filter cake, in vacuum drying chamber, less than 65 ± 5 DEG C vacuum drying, obtain prulifloxacin highly finished product.
Claims (1)
1. a method for synthesizing prulifloxacin, is characterized in that the method comprises the steps:
Acetone 40Kg is dropped in reactor, open and stir, add anhydrous sodium iodide 7.8Kg, logical cooling water, add 4-chloromethyl-5-methyl isophthalic acid, 3-dioxa cyclenes pentanedione 7.0Kg, 20-30 DEG C of stirring reaction, again by DMF 234Kg suction reactor, add the fluoro-7-piperazine of 6--1-methyl-4-oxo-4H-[1, 3] sulfur nitrogen heterocycle butane also [3, 2-a] quinoline-3-carboxylic acid 13.0Kg, saleratus 6.9Kg, stirring reaction, reactant liquor is proceeded in the water of 4 times amount being chilled to less than 5 DEG C in advance, stir and separate out solid, survey pH value, be 6-7 with hydrochloric acid adjust pH, centrifugal filtration after stirring and crystallizing, obtain solid, for prulifloxacin wets crude product, wet crude product directly carries out subsequent purification operation,
By in chloroform 580Kg suction reactor, open and stir, add the obtained prulifloxacin of step and to wet crude product, warming-in-water is extracted to stirring at 20-30 DEG C, and stratification, collects lower floor's organic phase; The solid matter on upper strata adds 200Kg chloroform again, stirs and extracts, stratification, and collect lower floor's organic phase, solid residue discards; Merge organic phase, add anhydrous magnesium sulfate 6.5Kg, stir dry, filter, removing drier; Proceeded to by solution in concentration tank, when being evaporated to a large amount of solid of precipitation, stop concentrated, raffinate proceeds in crystallizing tank, and less than 5 DEG C cool more than 4 hours, separate out solid; Filter, collect filter cake, 60 DEG C of vacuum drying, obtain prulifloxacin purification product 1;
By in acetonitrile 310Kg suction reactor, add 13Kg prulifloxacin purification product 1,13Kg column chromatography silica gel and 9.0Kg active carbon, add hot reflux 30 minutes, filter while hot, solution is transferred in crystallizing tank, be cooled to less than 5 DEG C cooling crystallizations, filter, collect filter cake, in vacuum drying chamber, 65 ± 5 DEG C of vacuum drying, obtain prulifloxacin highly finished product.
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Non-Patent Citations (3)
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| "普卢利沙星合成路线图解";刘明亮 等;《中国医药工业杂志》;20001231;第31卷(第11期);第527-528页 * |
| "普卢利沙星的合成";程春生 等;《中国医药工业杂志》;20051231;第36卷(第2期);第67-69页 * |
| "普卢利沙星的合成";马淑涛 等;《中国药物化学杂志》;20051231;第15卷(第6期);第347-350页 * |
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Address after: Cross strait science and Technology Industrial Development Park in Wenjiang District of Chengdu City, Sichuan province 611138 Xinhua Road two No. 666 Sichuan Kelun Pharmaceutical Research Institute Co. Ltd. Patentee after: SICHUAN KELUN DRUG RESEARCH INSTITUTE CO., LTD. Address before: 610500, No. two, No. 520, South Road, Xindu satellite Industrial Development Zone, Sichuan, Chengdu Patentee before: Kelun Pharmaceutical Research Co., Ltd. |