CN1461748A - Synthesis process of jiatisasin - Google Patents
Synthesis process of jiatisasin Download PDFInfo
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- CN1461748A CN1461748A CN 02115900 CN02115900A CN1461748A CN 1461748 A CN1461748 A CN 1461748A CN 02115900 CN02115900 CN 02115900 CN 02115900 A CN02115900 A CN 02115900A CN 1461748 A CN1461748 A CN 1461748A
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Abstract
A process for synthesizing a medicine "Jiatishaxing" from 2,4,5-trifluoro-3-methoxy benzoate includes such steps as acylating by bichlorosulfoxide, substituting with dimethyl melonate, dydrolyzing in p-methyl benzoic acid, ammoniating with cyclopropanamine, thermal cyclizing, refining in ethylacetate-water to obtain its intermediate, complexing and condensating. Its advantages are simple process and high output rate up to 54% and purity up to 98.2%.
Description
The present invention relates to the synthetic field of pharmaceutical chemicals.
Background technology: Gatifloxacin is the antimicrobial drug of the quinolones of U.S.'s exploitation listing, English name: gatifloxaein, trade(brand)name: Teguin.At present domesticly develop, does not still have the producer of formal this medicine of production.The synthesis technique of existing Gatifloxacin is: a, with 2,4,5-three fluoro-3-methoxybenzoic acids are raw material, through the inferior maple acidylate of dichloro, separate 3-methoxyl group-2,4, the 5-trifluorobenzoyl chloride; B and diethyl malonate replace, separate 3-methoxyl group 2,4,5-trifluoro-benzene formyl diethyl malonate; C, hydrolysis under the catalysis of dilute sulphuric acid, extracting and separating make 3-methoxyl group-2,4,5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester; D, with the triethyl orthoformate addition, separate with 2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group)-3-ethoxy ethyl acrylate; E, with the cyclopropylamine ammonification, separate to make 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-3-cyclopropylamino ethyl propenoate; Through cyclization filtration, ethanol refining the intermediate 1-cyclopropyl-6 of synthetic Gatifloxacin, 7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester; Through complexing, condensation, make Gatifloxacin again.The weak point of this technology is with 2,4,5-three fluoro-3-methoxybenzoic acids are produced ring 1-cyclopropyl-6,7-two fluoro-1, the technology of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester all will be separated after per step reaction, operates extremely loaded down with trivial details, the yield of product and purity are not high yet, are respectively 25-48% and 98%.
Technology contents: purpose of the present invention is exactly with 2 at existing, 4,5-three fluoro-3-methoxybenzoic acids are produced ring 1-cyclopropyl-6,7-two fluoro-1, the technology of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester, all to separate after per step reaction, operate extremely loaded down with trivial details, the deficiency that the yield of its cyclized ester and purity are not high yet, and a kind of synthesis technique of Gatifloxacin is provided, its technology is simple, and the yield and the purity of cyclized ester also are improved.Synthesis technique of the present invention is: with 2; 4; the hydrolysis that is raw material in the inferior maple acidylate of dichloro and diethyl malonate replacement, acidity of 5-three fluoro-3-methoxybenzoic acids and with the cyclopropylamine ammonification; the heating cyclization makes the intermediate 1-cyclopropyl-6 of synthetic Gatifloxacin; 7-two fluoro-1; 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester is used 1-cyclopropyl-6 again, 7-two fluoro-1, and 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester synthesizes Gatifloxacin.With 2,4,5-three fluoro-3-methoxybenzoic acids are the synthetic 1-cyclopropyl-6 of raw material, 7-two fluoro-1, and the technology of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester goes on foot to gather and is:
A, acylation reaction: 2,4, add inferior maple of dichloro and dehydrated alcohol in the 5-three fluoro-3-methoxybenzoic acids, carry out acylation reaction, reflux is cooled to 65-75 ℃, makes 3-methoxyl group-2,4, the 5-trifluorobenzoyl chloride;
B, substitution reaction: a, magnesium and ethanol are heated to 35-45 ℃ together, stir and add CCl down
4B, with diethyl malonate with also add wherein after toluene mixes, heat to 50-70 ℃, constant temperature 1-1.5h is cooled to-5--10 ℃; C, with 3-methoxyl group-2,4, the 5-trifluorobenzoyl chloride adds, and stirs; D, stirring add sulfuric acid down, are stirred to the solution clarification in 0-10 ℃; E, tell oil phase, the water methylbenzene extraction merges organic phase, washes with water, and reclaim under reduced pressure toluene, residuum are 3-methoxyl group-2,4,5-trifluoro-benzene formyl diethyl malonate;
C, hydrolysis: a, at 3-methoxyl group-2,4, add p-methylbenzoic acid in the 5-trifluoromethyl benzonitrile acyl group diethyl malonate, reflux is reduced to room temperature; B, reactant CH
2Cl
2Extract, tell organic layer, organic layer is washed then with the washing of yellow soda ash saturated solution, adds Na
2SO
4Drying is filtered, and the reclaim under reduced pressure methylene dichloride promptly makes 3-methoxyl group-2,4,5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester;
D, addition reaction: at 3-methoxyl group-2,4, add triethyl orthoformate and acid anhydrides in the 5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester, reflux, the reclaim under reduced pressure acid anhydrides makes 2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group)-3-ethoxy ethyl acrylate;
E, amination reaction: at 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-add dehydrated alcohol in the 3-ethoxy ethyl acrylate, be cooled to-3-0 ℃, add ring third ammonia, 0-10 ℃ of stirring, decompression recycling ethanol is to there not being overhead product, obtain 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-3-cyclopropylamino acrylate acetoacetic ester;
F, ring-closure reaction: in 2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group)-3-cyclopropylamino acrylate acetoacetic ester, add methylformamide and salt of wormwood; be heated to 90-110 ℃, insulation 1-1.5h, filtered while hot; filter cake is washed with hot methylformamide; filtrate is freezing, filters, and filter cake is washed with cold ethanol; refining with ethyl acetate-water as solvent at last; dry 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester.
Advantage of the present invention: 1, saved many numerous and diverse sepn processes; 2, use catalyzer p-methylbenzoic acid and the dimethyl formamide of solely holding, make 1-cyclopropyl-6,7-two fluoro-1, the yield of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester reaches 5 4%; 3, with ethyl acetate-water as solvent is refining can more effective removal organic impurity and inorganic impurity than with ethanol, purity reaches more than 98.2%.
Embodiment:
One, 2,4,5-three fluoro-3-methoxybenzoic acids are produced 1-cyclopropyl-6,7-two fluoro-1, and the technology of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester:
A, acylation reaction: in 250ml single port bottle, add 2,4,5-three fluoro-3-methoxybenzoic acid 50g, dry toluene 100ml, the inferior maple 27ml of dichloro, reflux 4h is cooled to 70 ℃, the inferior maple and 2 of reclaim under reduced pressure dichloro, 4,5-three fluoro-3-methoxybenzoic acid raffinates, the what is said or talked about yellow oil that obtains is 3-methoxyl group-2,4, the 5-trifluorobenzoyl chloride;
B, substitution reaction: a, add magnesium 7.2g in the 1000ml there-necked flask, ethanol 70ml is heated to 40 ℃, stirs to add 3mlCCl down
4To white cigarette is arranged; B, with diethyl malonate 40ml, and slowly be added dropwise in the above-mentioned there-necked flask after toluene 120ml mixes, keep bottle interior temperature to 50-70 ℃, insulation 1h is cooled in the there-necked flask temperature-5--10 ℃ in the ice bath groove; C, with 3-methoxyl group-2,4, the 5-trifluorobenzoyl chloride slowly is added dropwise in the above-mentioned there-necked flask, in the dropping process in the control bottle temperature-5-0 ℃, finishes and stirs 1h; D, stirring add 170ml20% sulfuric acid down again, are stirred to the solution clarification in 0-10 ℃; E, tell oil phase, water merges organic phase with 3 * 80ml methylbenzene extraction, washes with 2 * 100ml, and reclaim under reduced pressure toluene, residuum are 3-methoxyl group-2,4,5-trifluoro-benzene formyl diethyl malonate;
C, hydrolysis: a, at 3-methoxyl group-2,4, add 200ml water and 0.8g p-methylbenzoic acid in the 5-trifluoromethyl benzonitrile acyl group diethyl malonate, reflux 9h, (it is big that quantity of reflux is wanted) reduces to room temperature; B, reactant CH
2Cl
2Extract, tell organic layer, organic layer is used 2 * 50ml washing again with the washing of 1 * 100ml yellow soda ash saturated solution, adds 20gNa
2SO
4Drying is filtered, and the reclaim under reduced pressure methylene dichloride promptly makes 3-methoxyl group-2,4,5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester;
D, addition reaction:, add 200ml acid anhydrides and 36g triethyl orthoformate in the 5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester at 3-methoxyl group-2,4, reflux 8h, the reclaim under reduced pressure acid anhydrides obtains reddish-brown oily matter and is 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-the 3-ethoxy ethyl acrylate;
E, amination reaction: at 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-add the 250ml dehydrated alcohol in the 3-ethoxy ethyl acrylate, be cooled to 0 ℃, drip people 22g (28ml) ring third ammonia, stir 2h at 0-10 ℃, decompression recycling ethanol is to there not being overhead product, obtain 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-3-cyclopropylamino ethyl propenoate;
F, ring-closure reaction: in 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-3-cyclopropylamino ethyl propenoate, add 200ml methylformamide and 60g salt of wormwood, be heated to 100 ℃, insulation 1h, filtered while hot, filter cake is washed with the hot methylformamide of 50ml, filtrate is freezing, filters, and filter cake is washed with cold ethanol 20ml, refining with ethyl acetate-water as solvent at last, dry 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester.
Two, with 1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester is through complexing, condensation, the technology step of synthetic Gatifloxacin poly-with prior art with, can be referring to the exploration of " middle traditional Chinese medical science is economized pharmaceutical worker's industry magazine " 2001,10 (05)-Gatifloxacin synthesis methods.
Claims (1)
1, a kind of synthesis technique of Gatifloxacin, with 2,4,5-three fluoro-3-methoxybenzoic acids are raw material through the inferior maple acidylate of dichloro, replace with diethyl malonate, in the acidity hydrolysis and with the cyclopropylamine ammonification, the heating cyclization makes the intermediate 1-cyclopropyl-6 of synthetic Gatifloxacin, 7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester; Use 1-cyclopropyl-6 again, 7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester synthesizes Gatifloxacin; It is characterized in that with 2,4 5-three fluoro-3-methoxybenzoic acids are the synthetic 1-cyclopropyl-6 of raw material, 7-two fluoro-1, the technology of 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester goes on foot to gather and is:
A, acylation reaction: 2,4, add inferior maple of dichloro and dehydrated alcohol in the 5-three fluoro-3-methoxybenzoic acids, carry out acylation reaction, reflux is cooled to 65-75 ℃, makes 3-methoxyl group-2,4, the 5-trifluorobenzoyl chloride;
B, substitution reaction: a, magnesium and ethanol are heated to 35-45 ℃ together, stir and add CCl down
4B, with diethyl malonate with also add wherein after toluene mixes, heat to 50-70 ℃, constant temperature 1-1.5h is cooled to-5--10 ℃; C, with 3-methoxyl group-2,4, the 5-trifluorobenzoyl chloride adds, and stirs; D, stirring add sulfuric acid down, are stirred to the solution clarification in 0-10 ℃; E, tell oil phase, the water methylbenzene extraction merges organic phase, washes with water, and reclaim under reduced pressure toluene, residuum are 3-methoxyl group-2,4,5-trifluoro-benzene formyl diethyl malonate;
C, hydrolysis: a, at 3-methoxyl group-2,4, add p-methylbenzoic acid in the 5-trifluoromethyl benzonitrile acyl group diethyl malonate, reflux is reduced to room temperature; B, reactant CH
2Cl
2Extract, tell organic layer, organic layer is washed then with the washing of yellow soda ash saturated solution, adds Na
2SO
4Drying is filtered, and the reclaim under reduced pressure methylene dichloride promptly makes 3-methoxyl group-2,4,5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester;
D, addition reaction: at 3-methoxyl group-2,4, add triethyl orthoformate and acid anhydrides in the 5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester, reflux, the reclaim under reduced pressure acid anhydrides makes 2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group)-3-ethoxy ethyl acrylate;
E, amination reaction: at 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-add dehydrated alcohol in the 3-ethoxy ethyl acrylate, be cooled to-3-0 ℃, add cyclopropylamine, 0-10 ℃ of stirring, decompression recycling ethanol is to there not being overhead product, obtain 2-(3-methoxyl group-2,4,5-trifluoro-benzene formyl)-3-cyclopropylamino acrylate acetoacetic ester;
F, ring-closure reaction: in 2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group)-3-cyclopropylamino acrylate acetoacetic ester, add dimethyl formamide and salt of wormwood; be heated to 90-110 ℃; insulation 1-1.5h, filtered while hot, filter cake is washed with hot dimethyl formamide; the filtrate freezing and filtering; filter cake is washed with cold ethanol, and is refining with ethyl acetate-water as solvent at last, dry 1-cyclopropyl-6; 7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716373A (en) * | 2022-04-14 | 2022-07-08 | 内蒙古源宏精细化工有限公司 | Preparation method of gatifloxacin cyclized ester |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716373A (en) * | 2022-04-14 | 2022-07-08 | 内蒙古源宏精细化工有限公司 | Preparation method of gatifloxacin cyclized ester |
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