* 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.
With potassium hydroxide In water at 60℃; for 6 h;
3 g of starting material 9, 10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyridine[1,2,3,8] - [1,4] -benzoxazine-6-carboxylate, 4.58 water, 4.5 8 ^ methylpiperazine and 0.22 8 (81percent)Potassium hydroxide, incubated at 60 ° C, and the reaction produced alcohol was removed during the reaction and the reaction was carried out for about 6 hours. The temperature is raised to the reflux reaction until the raw material disappears. N-methylpiperazine was completely substituted and N-methylpiperazine was recovered under reduced pressure. After acid, alkali pH adjustment, by extraction, washing, concentration and other steps. Finally, the concentrated solid was recrystallized from methanol, filtered and the mother liquor was concentrated and separated on a silica gel column (mobile phase methanol: dichloromethane = 1: 8). The solid was combined to give the ofloxacin product 3.44 g yeleld 95.8percent. Compounds were determined by melting point, high molecular mass spectrometry, molecular weight, and nuclear magnetic resonance spectroscopy. The product was the same product as the product obtained in Example 7 and was anloxacin product.
89%
With nano iron oxide on ZrO2 coated sulfonic acid In water for 0.416667 h; Reflux
General procedure: A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1a (1 mmol) and Nethylpiperazine2y (1.5 mmol) and n-FZSA (0.06 g) as catalystin H2O (5 ml) were heated under reflux for the appropriatetime. The reaction was monitored by TLC. After appropriatetime, the catalyst was separated using an externalmagnet and washed with hot ethanol (5 mL). The reactionmixture was then cooled to room temperature. The precipitatedsolid was collected by filtration, and recrystallized fromethanol 96percent to give desired compound in high yields.
83%
at 150℃; Microwave irradiation
General procedure: A mixture of 6-chloro-4-cyclopropyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid 1a (1 g, 3.5 mmol) with N-ethylpiperazine 2c (0.6 g, 5.25mmol) was loaded in a small flask fitted with a micro condenser, placed in the microwave reactor and irradiated for 25 min at 150°C under solvent free conditions. The reaction progress was monitored by TLC. Upon completion of the process, addition of hot absolute ethanol (10 mL) to the reaction mixture was followed by filtration. The filtrate was concentrated and stored at room temperature for precipitation. The solid was filtered off and recrystallized from absolute ethanol to give compound 3c.
Reference：
[1] Patent: CN103755722, 2016, B, . Location in patent: Paragraph 0062-0063
[2] Letters in Organic Chemistry, 2018, vol. 15, # 9, p. 739 - 746
[3] Russian Journal of General Chemistry, 2016, vol. 86, # 12, p. 2865 - 2869[4] Zh. Obshch. Khim., 2016, vol. 86, # 12, p. 2865 - 2869,5
[5] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 12, p. 4907 - 4913
[6] Heterocycles, 1998, vol. 48, # 6, p. 1111 - 1116
[7] Heterocycles, 1999, vol. 51, # 7, p. 1563 - 1572
[8] Patent: US4382892, 1983, A,
[9] Patent: CN103360410, 2016, B, . Location in patent: Paragraph 0014; 0045; 0046
2
[ 109-01-3 ]
[ 82419-35-0 ]
[ 82419-36-1 ]
Reference：
[1] Patent: US5521310, 1996, A,
3
[ 109-01-3 ]
[ 82419-35-0 ]
[ 82419-36-1 ]
Reference：
[1] Patent: US5521310, 1996, A,
4
[ 82419-35-0 ]
[ 82419-36-1 ]
Reference：
[1] Patent: US5051505, 1991, A,
5
[ 178233-30-2 ]
[ 429-41-4 ]
[ 82419-35-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With hydrogenchloride; potassium hydroxide In tetrahydrofuran; ethanol; chloroform; water
EXAMPLE 1 Preparation of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid (I: X=fluoro, R=methyl) 220 mg (0.447 mmol) of ethyl 2-(2-nitro-3,4,5-trifluoro) benzoyl-3-(1-t-butyldimethylsilyloxyprop-2-ylamino) acrylate (II: X, X1 =fluoro, X2 =nitro, R=methyl, R1 =ethyl, R2,R3 =methyl, R4 =t-butyl) was added to 10 ml of tetrahydrofuran and cooled to 0° C. To this solution, 0.41 g (1.56 mmol) of tetrabutyl ammonium fluoride dissolved in tetrahydrofuran was added dropwise, and stirred for 30 min. and refluxed under heat for another 30 min. Thereafter, 2 ml of 10percent potassium hydroxide aqueous solution was added and refluxed under heat for 30 min. After being cooled to room temperature, the reaction mixture was filtered to remove unsolved substance. The filtered liquid was removed under reduced pressure (25° C./10 mmHg) and 20 ml of water was added to the residue left. The resulting aqueous solution was washed with 5 ml of chloroform once and then, 1 N hydrochloric acid solution was slowly added, to adjust pH of the aqueous solution into 3. Filtration was carried out to obtain a solid which was, in turn, washed with 5 ml of water and 5 ml of a mixture solution of ethanol and ethyl other (volume ratio 1:4), respectively and then, dried, to give 108 mg of the object solid product (yield 86percent). m.p.: 308° C. (dec.); NMR(TFA-d1) ppm: 9.39(1H, s), 8.10(1H, dd, J=10.8H), 5.11-5.26(1H, m), 4.79(1H, dd, J=2.12H), 4.65(1H, dd, J=2.12H), 1.82(3H, d, J=6.7H).
Reference：
[1] Patent: US5952494, 1999, A,
6
[ 82419-34-9 ]
[ 82419-35-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 12, p. 4907 - 4913
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 23, p. 4213 - 4216
[3] Patent: CN103360410, 2016, B, . Location in patent: Paragraph 0014; 0043; 0044
7
[ 86760-99-8 ]
[ 82419-35-0 ]
Reference：
[1] Heterocycles, 1999, vol. 51, # 7, p. 1563 - 1572
[2] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 12, p. 4907 - 4913
8
[ 113933-52-1 ]
[ 82419-35-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 10, p. 4098 - 4102
[2] Patent: CN103360410, 2016, B,
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 12, p. 4907 - 4913
14
[ 82419-32-7 ]
[ 82419-35-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 12, p. 4907 - 4913
15
[ 82419-26-9 ]
[ 82419-35-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 12, p. 4907 - 4913
16
[ 82419-33-8 ]
[ 82419-35-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 12, p. 4907 - 4913
17
[ 94695-50-8 ]
[ 82419-35-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 10, p. 4098 - 4102
18
[ 107359-16-0 ]
[ 82419-35-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 10, p. 4098 - 4102
19
[ 74-96-4 ]
[ 82419-35-0 ]
[ 82419-34-9 ]
Yield
Reaction Conditions
Operation in experiment
88.6%
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 5 h;
40 g of fluorfluoric acid was suspended in 200 mL of N,N-dimethylformamide, and bromoethane and 21.6 g of potassium carbonate were added to obtain a white suspension, which was reacted at 50 °C. for 5 hours, and the reaction was completed. The mixture was returned to room temperature and filtered to give a white solid 60 g. The solid was added to 200 mL of dichloromethane and 200 mL of methanol, stirred at 40 °C, filtered, and the undissolved solid was continuously added to 200 mL of dichloromethane and 200 mL of methanol. , Stir at 40 °C, filter, and combine the filtrates with spin-dry, add 300 mL of diethyl ether, stir at room temperature, and filter to obtain a white solid compound II
Reference：
[1] Patent: CN107586302, 2018, A, . Location in patent: Paragraph 0022; 0023; 0024
With nano iron oxide on ZrO2 coated sulfonic acid; In water; for 0.45h;Reflux;
General procedure: A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1a (1 mmol) and Nethylpiperazine2y (1.5 mmol) and n-FZSA (0.06 g) as catalystin H2O (5 ml) were heated under reflux for the appropriatetime. The reaction was monitored by TLC. After appropriatetime, the catalyst was separated using an externalmagnet and washed with hot ethanol (5 mL). The reactionmixture was then cooled to room temperature. The precipitatedsolid was collected by filtration, and recrystallized fromethanol 96% to give desired compound in high yields.
91%
at 150℃;Microwave irradiation;
General procedure: A mixture of 6-chloro-4-cyclopropyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid 1a (1 g, 3.5 mmol) with N-ethylpiperazine 2c (0.6 g, 5.25mmol) was loaded in a small flask fitted with a micro condenser, placed in the microwave reactor and irradiated for 25 min at 150C under solvent free conditions. The reaction progress was monitored by TLC. Upon completion of the process, addition of hot absolute ethanol (10 mL) to the reaction mixture was followed by filtration. The filtrate was concentrated and stored at room temperature for precipitation. The solid was filtered off and recrystallized from absolute ethanol to give compound 3c.
With potassium hydroxide; In water; at 60℃; for 6h;
3 g of starting material 9, 10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyridine[1,2,3,8] - [1,4] -benzoxazine-6-carboxylate, 4.58 water, 4.5 8 ^ methylpiperazine and 0.22 8 (81%)Potassium hydroxide, incubated at 60 C, and the reaction produced alcohol was removed during the reaction and the reaction was carried out for about 6 hours. The temperature is raised to the reflux reaction until the raw material disappears. N-methylpiperazine was completely substituted and N-methylpiperazine was recovered under reduced pressure. After acid, alkali pH adjustment, by extraction, washing, concentration and other steps. Finally, the concentrated solid was recrystallized from methanol, filtered and the mother liquor was concentrated and separated on a silica gel column (mobile phase methanol: dichloromethane = 1: 8). The solid was combined to give the ofloxacin product 3.44 g yeleld 95.8%. Compounds were determined by melting point, high molecular mass spectrometry, molecular weight, and nuclear magnetic resonance spectroscopy. The product was the same product as the product obtained in Example 7 and was anloxacin product.
89%
With nano iron oxide on ZrO2 coated sulfonic acid; In water; for 0.416667h;Reflux;
General procedure: A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1a (1 mmol) and Nethylpiperazine2y (1.5 mmol) and n-FZSA (0.06 g) as catalystin H2O (5 ml) were heated under reflux for the appropriatetime. The reaction was monitored by TLC. After appropriatetime, the catalyst was separated using an externalmagnet and washed with hot ethanol (5 mL). The reactionmixture was then cooled to room temperature. The precipitatedsolid was collected by filtration, and recrystallized fromethanol 96% to give desired compound in high yields.
83%
at 150℃;Microwave irradiation;
General procedure: A mixture of 6-chloro-4-cyclopropyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid 1a (1 g, 3.5 mmol) with N-ethylpiperazine 2c (0.6 g, 5.25mmol) was loaded in a small flask fitted with a micro condenser, placed in the microwave reactor and irradiated for 25 min at 150C under solvent free conditions. The reaction progress was monitored by TLC. Upon completion of the process, addition of hot absolute ethanol (10 mL) to the reaction mixture was followed by filtration. The filtrate was concentrated and stored at room temperature for precipitation. The solid was filtered off and recrystallized from absolute ethanol to give compound 3c.
In water; dimethyl sulfoxide;
EXAMPLE 3 1.0 g of <strong>[82419-35-0]9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid</strong> and 2.85 g of N-methylpiperazine were added to 15 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100 to 110 C. (bath temperature) for 12 hours and the reaction mixture was concentrated to dryness in vacuo and 40 ml of water was added to the residue. Then the product was extracted with chloroform. The extract was dried and concentrated to dryness in vacuo. The residue was recrystallized from ethanol to provide 550 mg of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid as colorless needles with m.p. 250-257 C. (with decomposition). Analysis for C18 H20 FN3 O4; Calculated: C 59.82, H 5.58, N 11.63; Found: C 59.62, H 5.59, N 11.65.
With triethylamine; In dimethyl sulfoxide; at 90℃;
500ml three-necked flask was added 58.5g (), 58.5gDMSO, 117gN- methylpiperazine, triethylamine 29g,Stirring heated to 90 , the reaction was kept 8-10h.Bi insulation, vacuum recovery DMSO, keeping the temperature <90 , vacuum <-. 098MPa, no liquid to flow out, addInto 150ml water, stirring warming up to an appropriate amount of hydrochloric acid was dropped to adjust the pH = 3.0 at 60 , the material dissolved, 1g of activated carbon removalAfter color filtered and the filtrate was adjusted to pH = 7.0 with lye, white solid precipitation, cooling to 20 was filtered ofloxacin. DriedOfloxacin was 64.4g (). The yield was 128.8% by weight.
EXAMPLE 4 140 mg of <strong>[82419-35-0]9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid</strong> and 404 mg of 4-hydroxypiperidine were added to 2 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100 to 110 C. (bath temperature) for 5.5 hours and the reaction mixture was concentrated to dryness in vacuo. Water was added to the residue and the mixture was neutralized with diluted hydrochloric acid to yield precipitate. The precipitate was collected by filtration, washed with water, and then recrystallized from ethanol to provide 66 mg of 9-fluoro-10-(4-hydroxy-1-piperidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with m.p. 220-240 C. (with decomposition). Analysis for C18 H19 FN2 O5; Calculated: C 59.66, H 5.29, N 7.73; Found: C 59.24, H 5.26, N 7.65.
With sulfuric acid; acetic acid; In water; for 4h;Reflux;
500ml three-neck flask was added 65g of formula (), 240ml glacial acetic acid, 65ml water, 12ml of concentrated sulfuric acid. StirWarmed to reflux. Pending formula () dissolved reflux insulation 3-5h. Bi insulation, vacuum recovery of glacial acetic acid, maintaining the temperature<80 , vacuum <-. 09MPa. To stop when no liquid outflow, the residue was added 300ml of water, cooled with stirring to 30 When filtered, the filter cake was washed well with water until the filtrate was neutral, and dried to give the cake of formula (XVI). Dry goods weight 58.5g, heavyThe amount of 117% yield.
9-(4-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6<i>H</i>-1-oxa-3a-aza-phenalene-5-carboxylic acid methyl ester[ No CAS ]
Trans-4-(2-fluoro-ethyl)-3-tertbutoxycarbonylamino-piperidine[ No CAS ]
[ 82419-35-0 ]
(3S) 7-[Trans-3-amino-4-(2-fluoroethyl)-piperidine-1-yl]-9-fluoro-2,3-dihydro-3-methyl-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 9 (3S) 7-[Trans-3-amino-4-(2-fluoroethyl)-piperidine-1-yl]-9-fluoro-2,3-dihydro-3-methyl-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hydrochloride. A procedure similar to Examples 8 and 9 above is used using <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong> (Precursor C) and Trans 4-(2-fluoro-ethyl)-3-tertbutoxycarbonylamino-piperidine (Precursor H) as the starting materials. The procedure utilizes the same reaction conditions and molar ratio of reactants as Examples 7 and 8.
10-[4-[(5-(S)-Acetamidomethyloxazolidine-2-one-3-yl)-2-fluorophenyl]piperazine-1-yl]-6-carboxy-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 2 Preparation of 10-[4-[(5-(S)-Acetamidomethyloxazolidine-2-one-3-yl)-2-fluorophenyl]piperazine-1-yl]-6-carboxy-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine (Compound 6) Compound 6 was prepared from 5-(S)-aminomethyl-3-(3-fluoro-4-piperazinophenyl)oxazolidine-2-one (0.372 g, 1.1 mmol) and 9.10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (0.281 g, 1 mmol) according to the General Procedure for the Synthesis of Quinolone-7-yl Linked Oxazolidinones. The reaction was performed at 110 C. for 24 h. Yield 0.444 g (74%). MS (m/z): 598 [M+H]+. Rt 4.5 min. The separation of enantiomers by chiral HPLC provides the preferred (S)-configuration isomer.
EXAMPLE 4 Preparation of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [,1,2,3-de][1,4]-benzoxazine-6-carboxylic acid (I: X=fluoro, R=methyl) Ethyl 2-(2,3,4,5-tetrafluoro) benzoyl-3-?1-t-butyldimethylsilyloxyprop-2-ylamino)acrylate (II. X, X1, X2 =fluoro, R=methyl, R1 =ethyl, R2, R3 =-ethyl, R4 =t-butyl) was treated in the same manner as that of Example 3, to give the object solid product (yield 88%). m.p.: >300 C.
(An alternative synthesis is to react 4-amino-1-hydroxy-1,1-butanediphosphonic acid tetramethyl ester with bis-(2-chloroethyl)amine.) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid is prepared following the procedure of example 2 of U.S. Pat. No. 4,382,892. The 6-carboxylic acid is then subjected to the procedure of example 3 of U.S. Pat. No. 4,382,892 except substituting for N-methylpiperazine an equivalent amount of 4-(1-piperazyl)-1-hydroxy-4,4-butanediphosphonic acid tetramethyl ester.
4.0 g of this product was dissolved in 50 ml of a mixture of concentrated hydrochloric acid and acetic acid (1:4 by volume) and this mixture was refluxed for 3 hours on an oil bath. After cooling the precipitated crystal was collected by filtration, washed thoroughly with water. The crystal was washed with a mixture of ethanol and ether (1/4 volume ratio) and was dried in vacuo to provide 3.7 g of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid as transparent plates with m.p. above 300 C.
60
[ 178233-30-2 ]
[ 429-41-4 ]
[ 82419-35-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With hydrogenchloride; potassium hydroxide; In tetrahydrofuran; ethanol; chloroform; water;
EXAMPLE 1 Preparation of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid (I: X=fluoro, R=methyl) 220 mg (0.447 mmol) of ethyl 2-(2-nitro-3,4,5-trifluoro) benzoyl-3-(1-t-butyldimethylsilyloxyprop-2-ylamino) acrylate (II: X, X1 =fluoro, X2 =nitro, R=methyl, R1 =ethyl, R2,R3 =methyl, R4 =t-butyl) was added to 10 ml of tetrahydrofuran and cooled to 0 C. To this solution, 0.41 g (1.56 mmol) of tetrabutyl ammonium fluoride dissolved in tetrahydrofuran was added dropwise, and stirred for 30 min. and refluxed under heat for another 30 min. Thereafter, 2 ml of 10% potassium hydroxide aqueous solution was added and refluxed under heat for 30 min. After being cooled to room temperature, the reaction mixture was filtered to remove unsolved substance. The filtered liquid was removed under reduced pressure (25 C./10 mmHg) and 20 ml of water was added to the residue left. The resulting aqueous solution was washed with 5 ml of chloroform once and then, 1 N hydrochloric acid solution was slowly added, to adjust pH of the aqueous solution into 3. Filtration was carried out to obtain a solid which was, in turn, washed with 5 ml of water and 5 ml of a mixture solution of ethanol and ethyl other (volume ratio 1:4), respectively and then, dried, to give 108 mg of the object solid product (yield 86%). m.p.: 308 C. (dec.); NMR(TFA-d1) ppm: 9.39(1H, s), 8.10(1H, dd, J=10.8H), 5.11-5.26(1H, m), 4.79(1H, dd, J=2.12H), 4.65(1H, dd, J=2.12H), 1.82(3H, d, J=6.7H).
ethyl 2-(2,3,4,5-tetrafluoro) benzoyl-3-(1-t-butyldimethylsilyloxy-prop-2-ylamino)acrylate[ No CAS ]
[ 82419-35-0 ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 2 Preparation of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid (I: X=fluoro, R=methyl) 202 mg (0.436 mmol) of ethyl 2-(2,3,4,5-tetrafluoro) benzoyl-3-(1-t-butyldimethylsilyloxy-prop-2-ylamino)acrylate (II: X, X1, X2 =fluoro, R=methyl, R1 -ethyl, R2, R3 m=ethyl, R4 =t-butyl) was added to 10 ml of tetrahydrofuran and cooled to 0 C.
With sodium hydroxide; triethylamine; In hydrogenchloride; methanol; diethyl ether; chloroform; dimethyl sulfoxide;
Method 1 14.3 g of the compound [8] are suspended in 600 ml of ethyl ether and 70 ml of trifluoride of etherate diethyl boron, and kept agitating at room temperature for 5 hours. The floating liquid is eliminated by decantation and added to the ethylic ether residue and filtered. The solid is washed with ethyl ether and dried. The product obtained is solved in 100 ml of DMSO, and 14.2 ml of triethylamine and 7.3 ml of 4-methyl-piperazine are added to the solution. The mixture is agitated for 18 hours at room temperature and the solvent is eliminated by distillation. Ethyl ether is added to the residue and filtered. The yellow powder obtained is suspended in 400 ml of methanol at 95%, and then 25 ml of triethylamine are added. The mixture is reflux heated for 25 hours and the solvent is eliminated by distillation at reduced pressure. The residue is solved in 500 ml of chlorhydric acid at 10% and washed three times with chloroform. The pH of the washed solution is adjusted at 11 with an aqueous solution of 4N sodium hydroxide and then it is taken to pH 7.3 with 1N HCL. The solution is extracted three times with portions of 2 liters of chloroform and the combined extract is dried on sodium sulphate. The chloroform is eliminated by distillation and the resulting crystals will be recrystallized from ethanol/ethylic ether to obtain 12 g of the product [9] (m.p. 226-230 C. with decomposition).
9-fluoro-2,3dihydro-3-methyl-10-(4-methyl-1-piperazynil)-7-oxo-7H-pyrid(1,2,3-de) (1,4)-benzoxazine-6-carboxylic acid[ No CAS ]
[ 82419-36-1 ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; dimethyl sulfoxide;
Method 2 46 ml (0.42 mmol) of N-methylpiperazine are added, at room temperature, to a solution of 70 mg (0.21 mmol) of 9,10-difluoro-2,3dihydro-3-methyl-7-oxo-7H-pyrid(1,2,3-de) (1,4)-benzoxazine-6-carboxylic acid [8] in 1.5 ml of DMSO. The solution is heated at 100 C. for 2 hours. Then the solvent is eliminated at reduced pressure and 2 ml of ethanol are added to the bulk of the reaction thus obtaining a precipitate that, after filtering, provides 75 mg (79%) of the desired product, Ofloxacina or 9-fluoro-2,3dihydro-3-methyl-10-(4-methyl-1-piperazynil)-7-oxo-7H-pyrid(1,2,3-de) (1,4)-benzoxazine-6-carboxylic acid [9] (m.p. 226-230 C. with decomposition).
10-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid[ No CAS ]
UIKRM-1-033[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide; acetonitrile;
EXAMPLE Z18 STR106 1.4 g (5 mmol) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong> are reacted in 15 ml of acetonitrile/7.5 ml of dimethylformamide with 0.85 g (7.7 mmol) of 1,4-diazabicyclo[2.2.2]octane and 0.7 g (5.6 mmol) of (+)-[S,S]-2,8-diazabicyclo[4.3.0]nonane in an analogous manner to EXAMPLE Z1A. Yield: 1.24 g (64% of theory) of 10-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, Melting point: 265-268 C. (with decomposition), [alpha]D: -232.2 (c=0.58, CHCl3). 3S-10-([S,S]-2,8-Diazabicyclo[4.3.0]non-8-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid is also obtained in an analogous manner.
10-[(1α,5α,6α)-6-tert Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dimethyl sulfoxide;
A. 10-[(1alpha,5alpha,6alpha)-6-tert Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid A solution of [1alpha,5alpha,6alpha]-6-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hexane (75 mg, 0.38 mmol) and 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid (100 mg, 0.36 mmol) in dimethylsulfoxide (6 ml) and triethylamine (1 ml) was heated at 80 C. for 72 hours. Solvent was removed in vacuo, and the residue was partitioned between chloroform and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo, to give a yellow powder. This was further purified by column chromatography (eluant: 50:50:1 chloroform:methanol:concentrated ammonium hydroxide), supplying the title product as a yellow solid, mp 170-173 C. (decomp.) (98 mg, 0.21 mmol, 59% yield).
With triethylamine; In dimethyl sulfoxide;
A. 10-[(1alpha,5alpha,6alpha)-6-tert Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid A solution of [1alpha,5alpha,6alpha]-6-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hexane (75 mg, 0.38 mmol) and <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong> (100 mg, 0.36 mmol) in dimethylsulfoxide (6 ml) and triethylamine (1 ml) was heated at 80C for 72 hours. Solvent was removed in vacuo , and the residue was partitioned between chloroform and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow powder. This was further purified by column chromatography (eluant: 50:50:1 chloroform: methanol: concentrated ammonium hydroxide), supplying the title product as a yellow solid, mp 170-173C (decomp.) (98 mg, 0.21 mmol, 59% yield).
EXAMPLE 8 10-(1-Methyl-4-piperidyloxy)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid (Compound No. 12) 9,10-Difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid (280 mg) was reacted and treated in a similar manner to Example 7, whereby 38 mg of the title compound was obtained. Melting point: 234-238 C. 1 H-NMR (DMSO-d6) delta: 1.45(d,3H,J=7Hz), 1.67-1.98(m,4H), 2.21(s,3H), 2.60-2.71(m.2H). 4.35-4.50(m,2H), 4.60-4.70(m,1H), 4.91-5.04(m,1H), 7.70(d,1H,J=11Hz), 9.03(s,1H).
EXAMPLE 23 STR349 The reaction is carried out analogously to Example 22 with 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and the reaction product obtained is purified by chromatography on silica gel using methylene chloride/methanol/17% strength aqueous ammonia solution (30:8:1) as the mobile phase. 10-(2,8-Diazabicyclo[4.3.0]non-8-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid of melting point 291-292 C. (with decomposition) is obtained.
68
[ 123594-04-7 ]
[ 82419-35-0 ]
(4-chloro-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 27 10 -(4-chloro-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl- 7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR171 141 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 115 mg of 4-chloroisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 70 mg of the target compound. Melting Point: 281-285 C. (decomposed) 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.63 (1H, d, J=14HZ, C8 --H), 7.35 (3H, brs, ARM-H), 4.95-5.30 (4H, m, 2 x --CH2 N--), 4.30-4.95 (3H, m, C2 --H, C3 --H), 1.45 (3H, d, J=7HZ; CH3)
Example 22 10-(4-fluoro-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl- 7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR160 141 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 206 mg of 4-fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 71 mg of the target compound. Melting Point: above 300 C. 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.65 (1H, d, J=14HZ, C8 --H), 7.10-7.50 (3H, m, ARM-H), 5.00-5.30 (4H, m, 2 x --CH2 N--), 4.30-5.00 (3H, m, C2--H, C3--H), 1.50 (3H, d, J=7HZ, CH3)
Example 10 10-(4-methoxy-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR137 131 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 224 mg of 4-methoxyisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 99 mg of the target compound. Melting Point: 262-264 C. 1H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.64 (1H, d, J=13HZ, C8 --H), 6.90-7.36 (3H, m, ARM-H), 4.95-5.20 (4H, m, 2 x --CH2 N--), 4.30-4.95 (3H, m, C2 --H, C3 --H), 3.82 (3H, s, OCH3), 1.50 (3H, d, J=7HZ, CH3)
Example 8 10-(4-amino-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR135 157 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 242 mg of 4-aminoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 119 mg of the target compound. Melting Point: above 244247 C. (decomposed) 1 H-NMR (DMSO-d6) delta:8.98 (1H, s, C5 --H), 7.65 (1H, d, J=13HZ, C8 --H), 6.45-7.10 (3H, m, ARM-H), 4.99-5.20 (4H, m, 2 x --NCH2 --), 4.30-4.95 (3H, m, C2 --H, C3 --H), 1.50 (3H, d, J=7H, CH3)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 11 10-(5-ethylamino-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR138 141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 97 mg of 5-ethylaminoisoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 109 mg of the target compound. Melting Point: above 300 C. 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.62 (1H, d, J=13HZ, C8 --H), 6.50-7.10 (3H, m, ARM-H), 4.80-5.10 (4H, m, 2 x --CH2 N--), 4.35 and 4.60 (each 1H, ABq, C2 --H), 3.05 (2H, q, J=7HZ, --CH2 CH3), 1.50 (3H, d, J=7HZ, C2 -CH3), 1.17 (3H, t, J=7HZ, --CH2 CH3)
Example 9 10-(5-amino-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR136 157 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 242 mg of 5-aminoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 124 mg of the target compound. Melting Point: 272-276 C. 1 H-NMR (DMSO-d6) delta:8.90 (1H, s, C5 --H), 7.58 (1H, d, J=14HZ, C8 --H), 6.45-7.02 (3H, m, ARM-H), 4.80-5.20 (4H, m, 2 x --NCH2 --,C3 --H), 4.25-4.65 (2H, m, C2 --H), 1.46 (3H, d, J=7HZ, CH3)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 31 10-(4-bromo-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR179 142 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7--oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 149 mg of 4-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 103 mg of the target compound. Melting Point: 291-295 C. (decomposed) 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.20-7.70 (4H, m, C8 --H, ARM-H), 4.96-5.30 (4H, m, 2 x --CH2 N--), 4.30-4.96 (C2 --H, C3 --H), 1.45 (3H, brs, CH3)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 33 10-(5-bromo-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR183 142 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 150 mg of 5-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 63 mg of the target compound. Melting Point: 290-294 C. (decomposed) 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.30-7.70 (4H, 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.30-7.70 (4H, m, C8 --H, ARM-H), 4.96-5.23 (4H, m, 2 x --CH2 N--), 4.30-4.96 (3H, m, C2 --H, C3 --H), 1.48 (3H, d, J=7HZ)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 37 10-(5-methoxy-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl- 7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR189 141 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 104 mg of 5-methoxyisoindoline, 121 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 105 mg of the target compound. Melting Point: 251-256 C. (decomposed) 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.62 (1H, d, J=14HZ, C8 --H), 6.83-7.30 (3H, m, ARM-H), 4.97-5.15 (4H, m, 2 x --CH2 N--), 4.30-4.96 (3H, m, C2 --H, C3 --H), 3.78 (3H, s, OCH3), 1.48 (3H, d, J=7HZ, --CH3)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 62 10-(4-nitro-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl- 7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR254 185 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 131 mg of the target compound.
methyl 2,3-dihydro-1H-isoindole-5-carboxylate hydrochloride[ No CAS ]
[ 127168-49-4 ]
Yield
Reaction Conditions
Operation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 94 10(5-methoxycarbonyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR288 142 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 45 mg of the target compound. Melting Point: 257-262 C.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 101 10-(4-hydroxymethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR305 281 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 120 mg of the target compound. Melting Point: 205-209 C. (decomposed) 1 H-NMR (DMSO-d6) delta: 8.95 (1H, s, C5 --H), 7.62 (1H, d, J=14Hz, C8 --H), 7.27 (3H, brs, ARM-H), 4.91-5.21 (6H, m, 2 x --CH2 N--, C3 --H, OH), 4.34-4.64 (4H, m, --CH2 OH, C2 --H), 1.49 (3H, J=7Hz, CH3)
5-acetamidomethylisoindoline hydrobromide[ No CAS ]
[ 82419-35-0 ]
10-(5-acetamidomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
(1) 422 mg of 9,10-difluoro-2,3-dihydro-3methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 382 mg of 10-(5-acetamidomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid.
(5-chloro-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example 23 -(5-chloro-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl- 7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR161 136 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 101 mg of 5-chloroisoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 63 mg of the target compound. Melting Point: 294-300 C. (decomposed) 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.60 (1H, d, J=15HZ, C8 --H), 7.30-7.50 (3H, m, ARM-H), 4.95-5.20 (4H, m, 2 x --CH2 N--), 4.30-4.95 (3H, m, C2 --H, C3 --H) 1.48 (3H, d, J=7HZ, CH3)
4-(t-butyldimethylsilyl)-1-methyl piperazine[ No CAS ]
[ 82419-35-0 ]
[ 82419-36-1 ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 5 9-Fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-Benzoxazin-6-carboxylic Acid (R2: Methyl) In a manner similar to that of Example 4, 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazin- 6-carboxylic acid (II, X: fluoro) is reacted with 4-(t-butyldimethylsilyl)-1-methylpiperazine (III, R2, R3 and R4: methyl; R5: t-butyl) to obtain a solid compound. Yield. 94%. Melting point: 249 to 250 C.
10-(2,5-diazabicyclo[2.2.2]oct-2-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
EXAMPLE 5 10-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid A solution of 0.56 g (2.0 mmol) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong>, 0.41 g (2.2 mmol) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 25 ml of acetonitrile was heated under reflux for 18 hours. The solution was evaporated to dryness and the residue was triturated with methanol and filtered to give 0.20 g of the title compound, 260-265 C.
In acetonitrile;
REFERENCE EXAMPLE 5 10-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid A solution of 0.56 g (2.0 mmol) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong>, 0.41 g (2.2 mmol) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 25 ml of acetonitrile was heated under reflux for 18 hours. The solution was evaporated to dryness and the residue was triturated with methanol and filtered to give 0.20 g of the title compound, 260-265C.
10-(cis-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dimethyl sulfoxide; In methanol;
EXAMPLE 28 10-(cis-3-t-Butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid A mixture of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (0.5 g), anhydrous dimethyl sulfoxide (10 ml) and cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.54 g) was stirred for 2 hours at 90-100 C. and then concentrated. To the residue was added methanol and the resulting precipitate was collected by filtration and then washed with cold methanol to give the title compound (0.58 g) as yellowish powder, mp 219-220 C. Analysis (%) for C23 H28 FN3 O6.H2 O, Calcd. (Found): C, 57.61 (57.79); H, 6.31 (6.11); N, 8.76 (8.68).
EXAMPLE 27 9-Fluoro-2,3-dihydro-3-methyl-10-(7-methyl-2,7-diazaspiro[4.4]non-2-yl)-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid A suspension of 0.42 g (1.97 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 25 ml acetonitrile was treated with 0.85 g (5.80 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.52 g (1.85 mmol) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid was added. The mixture was stirred two hours at room temperature and then refluxed overnight. The product which crystallized on cooling was filtered, washed with acetonitrile and recrystallized from acetonitrile to afford 0.45 g of the title compound, mp 227-230 C. (dec). Analysis calculated for C21 H22 N3 FO4: C, 63.15; H, 5.55; N, 10.52; Found: C, 63.13; H, 5.73; N, 10.51.
In acetonitrile;
EXAMPLE 27 9-Fluoro-2,3-dihydro-3-methyl-10-(7-methyl-2,7-diazaspiro[4.4]non-2-yl)-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid A suspension of 0.42 g (1.97 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 25 ml acetonitrile was treated with 0.85 g (5.80 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.52 g (1.85 mmol) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid was added. The mixture was stirred carboxylic acid was added. The mixture was stirred two hours at room temperature and then refluxed overnight. The product which crystallized on cooling was filtered, washed with acetonitrile and recrystallized from acetonitrile to afford 0.45 g of the title compound, mp 227-230 C. (dec). Analysis calculated for C21 H22 N3 FO4: C, 63.15; H, 5.55; N, 10.52; Found: C, 63.13; H, 5.73; N, 10.51.
10-[2-[(Ethylamino)methyl]-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3,-de]-1,4-benzoxazine-6-carboxylic acid[ No CAS ]
10-[3-[(ethylamino)-methyl]-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-ethyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
EXAMPLE 20 10-[2-[(Ethylamino)methyl]-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid 0.75 g (2.7 mmole) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong>, 40 ml acetonitrile and 1.03 g (8.00 mmole) of N-ethyl-3-pyrrolidinemethanamine were refluxed overnight. The reaction mixture was cooled in an ice bath and then filtered. The precipitate was washed with ethanol/ether (4:1), and then with ether until dry to give 0.86 g of 10-[3-[(ethylamino)-methyl]-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-ethyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 221-224 C. Analysis for C20 H21 FN3 O4.1/2H2 O: C, 60.29; H, 6.33, N, 10.55. Found: C, 60.45, H, 6.21, N, 10.80.
In acetonitrile;
EXAMPLE 20 10-[2-[(Ethylamino)methyl]-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3,-de]-1,4-benzoxazine-6-carboxylic acid 0.75 g (2.7 mmole) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong>, 40 ml acetonitrile and 1.03 g (8.00 mmole) of N-ethyl-3-pyrrolidinemethanamine were refluxed overnight. The reaction mixture was cooled in an ice bath and then filtered. The precipitate was washed with ethanol/ether (4:1), and then with ether until dry to give 0.86 g of 10-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-ethyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 221-224 C. Analysis for C20 H21 FN3 O4.1/2H2 O C, 60.29; H, 6.33, N, 10.55 Found C, 60.45, H, 6.21, N, 10.80
9-Fluoro-2,3-dihydro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine;
EXAMPLE 6 9-Fluoro-2,3-dihydro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid A mixture of 0.18 g (0.6 mmol) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong>, 0.3 ml (3.0 mmol) of thiomorpholine and 20 ml of pyridine was heated under reflux for 21 hours. The solution was evaporated to dryness, the residue was triturated with hot methanol, and filtered to give 0.05 g of the title compound, mp>300.
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