* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: at 80 - 85℃; for 1 h; Stage #2: With acetic acid In water at 20℃; for 1 h;
Ethyl-6-fluoro-1 -methyl-4-oxo-7-(1 -piperazinyl)-4H-(1 ,3)-thiazeto-[3,2-a]-quinoline-3- carboxylate (100 gms, 0.265 moles) was stirred in water (600 ml) at 25-30°C. To this potassium hydroxide solution (50 gms of potassium hydroxide flakes is dissolved in 200 ml of water) was added and the reaction mass was heated to 80-85°C. The contents were stirred for 1 hour and after completion of reaction, the reaction mass was cooled to 25-30°C. The pH of the reaction mass was adjusted to 6.5-7.0 using 1:1 aqueous acetic acid solution. The contents were stirred at room temperature for 1 hour. The precipitated solid was filtered, washed with water (2 x 100 ml). The solid was slurried in methanol (300 ml) for 1 hour at 25-30°C, filtered, washed with methanol (2 x 50 ml) and dried under vacuum at 70-75°C to yield the title compound [90 gms, 97percent yield, 96percent HPLC purity].
97.3%
at 60 - 70℃; Large scale
the reaction vessel 8. 0kg a compound of formula (II), 112kg water, 6. 0kg potassium hydroxide, and heated to 60~ 70 ° C the hydrolysis reaction, 2 to 3 hours. After completion of the reaction, was cooled to room temperature, 30. 4kg washed with ethyl acetate, the aqueous layer was separated, stirred, adjusted with concentrated hydrochloric acid ρΗ 6~7, stirring was continued for 0.5 hours, the filter cake was suction filtration, an appropriate amount of ethyl washing the filter cake drying, cake was collected, 60~70 ° C hot air circulation drying, to obtain a compound of formula (III) finished 7. 36kg, yield (mol) 96.4percent, purity 97.3percent;
90%
at 20℃; for 5 h;
30 g of ethyl 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazepino [3,2-a] 120ml concentration of 1mol / L of potassium hydroxide solution dissolved, And stirred at room temperature for 5 hours. The solution was neutralized with a 20percent (v/v) acetic acid solution and the pH was adjusted to 7-8 and stirred well. The precipitate was collected by filtration, and the precipitate was washed three times with deionized water and acetonitrile, respectively. The precipitate was then dried in vacuo at 60 ° C to give 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] 3-carboxylic acid 29g, 90percent yield. The obtained 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazepino [3,2-a] quinoline-3-carboxylic acid was 99.1percent pure.
Reference：
[1] Patent: WO2012/1357, 2012, A1, . Location in patent: Page/Page column 22
[2] Patent: CN103113392, 2016, B, . Location in patent: Paragraph 0024; 0037; 0038; 0039
[3] Patent: CN107383069, 2017, A, . Location in patent: Paragraph 0063; 0064
[4] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
[5] Patent: WO2009/93268, 2009, A1, . Location in patent: Page/Page column 15
2
[ 110-85-0 ]
[ 113046-72-3 ]
[ 113028-17-4 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 60℃; for 4 h;
50 g of ethyl 6,7-difluoro-1-methyl-4-oxo-4H- [1,3] thiazine [3,2-a] Dissolve in 5 volumes of DMSO at 60°C, add 40 g of piperazine, and stir at 60°C for 4 hours. The mixture was cooled to room temperature, then 5 volumes of acetonitrile were added and stirring was continued for 4 hours at room temperature. The precipitate was collected by filtration and dried to give 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] Ethyl acid 52.8g, yield 87percent. The yield of 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] quinoline-3-carboxylic acid B Ester purity 99percent.
87%
at 60℃; for 4 h;
Take the ethyl 6,7‐difluoro‐1‐methyl‐4‐oxo‐1H,4H‐[1,3]thiazeto[3,2‐a]quinoline‐3‐carboxylate 50g,Dissolve in 5 volumes of DMSO at 60°C.Then add 40 g of piperazine,Stir at 60°C for 4 hours.Cool the mixture to room temperatureThen add 5 volumes of acetonitrile,Stirring was continued for 4 hours at room temperature.Filter, collect the precipitate, dry,This gives 52.8 g of ethyl 6‐fluoro‐1‐methyl‐4‐oxo‐7‐(piperazin‐1‐yl)‐1H,4H‐[1,3]thiazeto[3,2‐a]quinoline‐3‐carboxylate.Yield 87percent.HPLC detection, ethyl 6‐fluoro‐1‐methyl‐4‐oxo‐7‐(piperazin‐1‐yl)‐1H,4H‐[1,3]thiazeto[3,2‐a]quinoline‐3‐carboxylate purity 99percent .
Reference：
[1] Patent: CN107383069, 2017, A, . Location in patent: Paragraph 0061; 0062
[2] Patent: CN107501298, 2017, A, . Location in patent: Paragraph 0055; 0056
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
[4] Patent: US4843070, 1989, A,
[5] Patent: WO2009/93268, 2009, A1, . Location in patent: Page/Page column 15
3
[ 110-85-0 ]
[ 113028-17-4 ]
Yield
Reaction Conditions
Operation in experiment
74%
at 10 - 55℃; for 9.16667 h;
5,6-difluoro-1-methyl-4-oxo-4H-[1 ,3]-thiazeto-[3,2-a]-quinoline-3-carboxylic acid ethyl ester of formula (II) (100 gms, 0.321 moles) was stirred in 500 ml of DMF at room temperature. Piperazine (76 gms, 0.882 moles) was added at room temperature and stirred for 10 minutes. The temperature was slowly raised to 50-55°C and the reaction mass was stirred at 50-55°C for 5 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C and stirred for 2 hours. The reaction mass was further chilled to 10-15°C and stirred for 2 hours. The precipitated solid was filtered, washed of chilled DMF (2 x 50 ml). The solid was slurry washed with water (300 ml), filtered, washed with water ( 2 x 100 ml) and dried under vacuum at 70-75°C to yield the title compound [90 gms, 74 percent yield, 95percent HPLC purity].
50 g of ethyl 6,7-difluoro-1-methyl-4-oxo-4H- [1,3] thiazine [3,2-a] Dissolve in 5 volumes of DMSO at 60C, add 40 g of piperazine, and stir at 60C for 4 hours. The mixture was cooled to room temperature, then 5 volumes of acetonitrile were added and stirring was continued for 4 hours at room temperature. The precipitate was collected by filtration and dried to give 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] Ethyl acid 52.8g, yield 87%. The yield of 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] quinoline-3-carboxylic acid B Ester purity 99%.
87%
In dimethyl sulfoxide; at 60℃; for 4h;
Take the ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate 50g,Dissolve in 5 volumes of DMSO at 60C.Then add 40 g of piperazine,Stir at 60C for 4 hours.Cool the mixture to room temperatureThen add 5 volumes of acetonitrile,Stirring was continued for 4 hours at room temperature.Filter, collect the precipitate, dry,This gives 52.8 g of ethyl 6-fluoro-1-methyl-4-oxo-7-(piperazin-1-yl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate.Yield 87%.HPLC detection, ethyl 6-fluoro-1-methyl-4-oxo-7-(piperazin-1-yl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate purity 99% .
In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
EXAMPLE 4 Ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate Ethyl 6,7-difluoro-1-methyl-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate (5.0 g) was suspended in 150 ml of N,N-dimethylformamide and the suspension was stirred with 4.6 g of piperazine at room temperature for 48 hours. N,N-Dimethylformamide was evaporated in vacuo and to the residue was added ice water to collect the crystals by filtration. Purification by a column chromatography (silica gel/chloroform-methanol (1:1)) gave 3.0 g of desired compound, m.p. 224 C. (decompn.). Elementary analysis calculated for C18 H20 FN3 O3 S.3/4H2 O. Calcd (%): C 55.30, H 5.54, N 10.74. Found (%): C 55.29, H 5.52, N 10.37.
In N,N-dimethyl-formamide; at 20 - 25℃;Product distribution / selectivity;
Example 7: Preparation of Ulifloxacin ethyl ester; Method A: Dimethylformamide (13.94 It), ethyl 6,7-difluoro-l-methyl-4-oxo-4H- (l,3)thiazeto(3,2-a)quinoline-3-carboxylate (1.39kg) and piperazine (1.39kg) were stirred at 20- 25C for 20-22 hours. Reaction completion was checked by TLC. Water (69.5 It) was added and the reaction mixture was filtered, washed with water and dried to obtain 1.11kg of ulifloxacin ethyl ester having purity 97.47 % by HPLC.
ethyl 6-fluoro-1-methyl-7-<4-<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-1-piperazyl>-4-oxo-4H-<1,3>thiazeto<3,2-a>-quinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydrogencarbonate; In N,N-dimethyl-formamide;
EXAMPLE 1 Ethyl 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4yl)methyl-1-piperazinyl]-4oxo-4H-[1,3-]thiazeto[3,2-a]quinoline-3-carboxylate. Ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate (3.88 g) and 1.23 g of potassium bicarbonate were suspended in 20 ml of N,N-dimethylformamide, 2.38 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one was dropped thereinto with ice cooling, and the mixture was stirred for 3 hours. After the reaction, the solvent was evaporated in vacuo therefrom at 50 C. and the residue was extracted with chloroform containing a few amount of methanol. The extract was washed with water, dried, the solvent was evaporated therefrom and the residue was purified by a column chromatography (chloroform-methanol/silica gel) to give 3.32 g of desired product. M.p. 241-243 C. (decompn.) Elem. Anal. for C23 H24 FN3 O6 S; Calcd. (%) C: 56.43 H: 4.94 N: 8.58; Found (%) C: 56.13 H: 4.99 N: 8.26. IR (KBr) nu (cm-1): 1820, 1720 (carbon-yl). NMR (CF3 CO2 D)(ppm) 1.51(3H, COOCH2 CH3, t), 2.31(3H, STR10 s), 2.35(3H, STR11 d), 3.40~4.30(8H, proton in piperazine ring, m), 4.55(2H, STR12 s), 4.65(2H, COOCH2 CH3, q), 6.51(1H, STR13 q), 7.05(1H, 8-proton, d), 8.11(1H, 5-proton, d).
Ethyl-6-fluoro-1 -methyl-4-oxo-7-(1 -piperazinyl)-4H-(1 ,3)-thiazeto-[3,2-a]-quinoline-3- carboxylate (100 gms, 0.265 moles) was stirred in water (600 ml) at 25-30C. To this potassium hydroxide solution (50 gms of potassium hydroxide flakes is dissolved in 200 ml of water) was added and the reaction mass was heated to 80-85C. The contents were stirred for 1 hour and after completion of reaction, the reaction mass was cooled to 25-30C. The pH of the reaction mass was adjusted to 6.5-7.0 using 1:1 aqueous acetic acid solution. The contents were stirred at room temperature for 1 hour. The precipitated solid was filtered, washed with water (2 x 100 ml). The solid was slurried in methanol (300 ml) for 1 hour at 25-30C, filtered, washed with methanol (2 x 50 ml) and dried under vacuum at 70-75C to yield the title compound [90 gms, 97% yield, 96% HPLC purity].
97.3%
With water; potassium hydroxide; at 60 - 70℃;Large scale;
the reaction vessel 8. 0kg a compound of formula (II), 112kg water, 6. 0kg potassium hydroxide, and heated to 60~ 70 C the hydrolysis reaction, 2 to 3 hours. After completion of the reaction, was cooled to room temperature, 30. 4kg washed with ethyl acetate, the aqueous layer was separated, stirred, adjusted with concentrated hydrochloric acid rhoEta 6~7, stirring was continued for 0.5 hours, the filter cake was suction filtration, an appropriate amount of ethyl washing the filter cake drying, cake was collected, 60~70 C hot air circulation drying, to obtain a compound of formula (III) finished 7. 36kg, yield (mol) 96.4%, purity 97.3%;
90%
With potassium hydroxide; at 20℃; for 5h;
30 g of ethyl 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazepino [3,2-a] 120ml concentration of 1mol / L of potassium hydroxide solution dissolved, And stirred at room temperature for 5 hours. The solution was neutralized with a 20% (v/v) acetic acid solution and the pH was adjusted to 7-8 and stirred well. The precipitate was collected by filtration, and the precipitate was washed three times with deionized water and acetonitrile, respectively. The precipitate was then dried in vacuo at 60 C to give 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] 3-carboxylic acid 29g, 90% yield. The obtained 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazepino [3,2-a] quinoline-3-carboxylic acid was 99.1% pure.
Example 8: Preparation of Ulifloxacin;Tertiary butanol (5.55It), 6-fluoro-l-methyl-4-oxo-7-(l-piperazinyl)-4H-[l,3]thiazeto [3,2- a]quinoline-3-carboxylic acid ethyl ester (1.1 lkg), potassium hydroxide (0.37kg) and water (2.75 It) were added at room temperature. The reaction mixture was heated to 600C and maintained for 1.5 hours. Reaction completion was checked by TLC. This was followed by the addition of water (22.2 It) and acetic acid (0.39 It). The reaction mixture was filtered, washed with water followed by slurry wash with acetone (2.22 It) twice and dried to obtain 0.95 kg of ulifloxacin having purity 97.56% by HPLC.
ethyl 7-(4-acetonyl-1-piperazinyl)-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 5 Ethyl 7-(4-acetonyl-1-piperazinyl)-6-fluoro-1-methyl-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate Ethyl 6-fluoro-1-methyl-7-(1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate (3.8 g) was suspended in 50 ml of N,N-dimethylformamide, 1.66 g of potassium carbonate was added thereto, 1.65 g of bromoacetone was dropped in with ice cooling and stirring, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured over into ice water and the crystals separated out were collected by filtration, washed with water, dried and recrystallized from ethanol to give 3.7 g of desired compound in colorless powdery crystals, m.p. 196-200 C. (decompn.). Elementary analysis calculated for C21 H24 FN3 O4 S: Calcd (%): C 58.18, H 5.58, N 9.69. Found (%): C 57.93, H 5.39, N 9.46.
6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 10: Preparation of prulifloxacin hydrochloride; Method A: To the mixture of dimethylformamide (1.5 It) and 6-fluoro-l-methyl-4-oxo-7-(l- piperazinyl)-lH,4H-[l,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (0.3kg), 4-bromomethyl-5- methyl- 1, 3 -dioxolen-2-one, obtained above was added and cooled to 0-50C. Triethylamine (0.87kg) in dimethylformamide (0.3 It) was added slowly in 1-2 hours. After completion of the reaction (monitored by TLC), dichloromethane (3.0 It) and water (1.5 It) were added to the reaction mixture. The layers were separated and aqueous layer was extracted twice with dichloromethane (1.5 It). All organic layers were combined, dried over sodium sulfate followed by distillation. Methanolic hydrochloride (20-25 % w/w, 0.24 It) was added to organic layer at 0- 5C and stirred. The solid, thus precipitated out was filtered, washed with dichloromethane and dried to obtain 0.36kg of the title compound having purity 92.73 % by HPLC. Example 11: Purification of prulifloxacin hydrochlorideDimethylformamide (1.34 It) was added to prulifloxacin hydrochloride (67g) and reaction mass was heated to 110-112C for 1 hour. The reaction mixture was cooled to 25-300C and stirred for 2 hours, filtered, washed with N,iV-dimethylforamide. The product was slurry washed with isopropanol (0.670 It) and dried to obtain 48.8g of title compound having purity 99.30 % by HPLC.
ethyl 5,6-difluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline carboxylate[ No CAS ]
[ 113028-17-4 ]
Yield
Reaction Conditions
Operation in experiment
74%
In N,N-dimethyl-formamide; at 10 - 55℃; for 9.16667h;
5,6-difluoro-1-methyl-4-oxo-4H-[1 ,3]-thiazeto-[3,2-a]-quinoline-3-carboxylic acid ethyl ester of formula (II) (100 gms, 0.321 moles) was stirred in 500 ml of DMF at room temperature. Piperazine (76 gms, 0.882 moles) was added at room temperature and stirred for 10 minutes. The temperature was slowly raised to 50-55C and the reaction mass was stirred at 50-55C for 5 hours. After completion of the reaction, the reaction mass was cooled to 25-30C and stirred for 2 hours. The reaction mass was further chilled to 10-15C and stirred for 2 hours. The precipitated solid was filtered, washed of chilled DMF (2 x 50 ml). The solid was slurry washed with water (300 ml), filtered, washed with water ( 2 x 100 ml) and dried under vacuum at 70-75C to yield the title compound [90 gms, 74 % yield, 95% HPLC purity].
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