PROCESS FOR THE PREPARATION OF 5-AMINO-QUINOLIN-2(1H)-ONES AND THEIR TAUTOMER FORMS 5-AMINO-QUINOLIN-2-OLS

Abstract

The present invention relates to a novel process for the preparation of 5-Amino-quinolin-2(1H)-ones and its tautomer's 5-amino-quinolin-2-ols. The present invention further comprises various novel compounds which are obtained during the preparation of 5-Amino-quinolin-2(1H)-ones and its tautomer's 5-amino-quinolin-2-ols.

Claims

1. Process for preparation of a 5-amino-quinolin-2H(1H)-one compound of formula (I) ##STR00034## wherein X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and C1; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms; wherein said compound is either produced by route (A), reduction of the nitro-group of a compound of formula (II) ##STR00035## wherein X.sup.1, X.sup.2, X.sup.3, R.sup.1 and R.sup.2 are as defined in formula (I) or by route (B), Heck reaction and in-situ cyclisation of a compound of formula (III), ##STR00036## wherein X.sup.1, X.sup.2 and X.sup.3 are as defined in formula (I), and Y is selected from Cl or Br, with the proviso that YCl or Br when X.sup.1, X.sup.2 and X.sup.3F, H or YBr when one of X.sup.1, X.sup.2 or X.sup.3Cl with an acrylate compound of formula (IV) ##STR00037## wherein R.sup.1 and R.sup.2 are as defined in formula (I), and R.sup.3 is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-C.sub.12-alkyl, substituted or unsubstituted C.sub.2-C.sub.12-alkenyl, substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.12-alkoxy, C.sub.1-C.sub.12-alkylaryl and aryl, or any salt thereof or by route (C), cyclisation of a compound of formula (V) ##STR00038## wherein X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and Cl; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms and R.sup.3 is as defined in formula (IV) in presence of an activation agent.

2. The process according to claim 1, wherein in route (A) a compound of formula (II) is produced by cyclisation of a compound of formula (VI) ##STR00039## wherein X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and Cl; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms; and R.sup.3 is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-C.sub.12-alkyl, substituted or unsubstituted C.sub.2-C.sub.12-alkenyl, substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.12-alkoxy, C.sub.1-C.sub.12-alkylaryl and aryl in the presence of an activation agent.

3. The process according to claim 2, wherein in route (A), the compound of formula (VI) is produced by a Heck reaction of a compound of formula (VII) ##STR00040## wherein X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and Cl; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms and Y is as defined in formula (III) with an acrylate compound of formula (IV) ##STR00041## wherein R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms; and R.sup.3 is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-C.sub.12-alkyl, substituted or unsubstituted C.sub.2-C.sub.12-alkenyl, substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.12-alkoxy, C.sub.1-C.sub.12-alkylaryl and aryl, or any salt thereof or by reduction of one of the nitro-groups of a compound of formula (IX) ##STR00042## wherein X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and C1; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms and R.sup.3 is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-C.sub.12-alkyl, substituted or unsubstituted C.sub.2-C.sub.12-alkenyl, substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.12-alkoxy, C.sub.1-C.sub.12-alkylaryl and aryl,

4. The process according to claim 3, wherein in route (A), the compound of formula (VII) is produced by a reduction of a compound of formula (VIII) ##STR00043## wherein X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and Cl; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms and X and Y are identical or different and are selected from the group of halogen atoms, with the proviso that YCl, Br when X.sup.1, X.sup.2 and X.sup.3F, H or YBr when one of X.sup.1, X.sup.2 or X.sup.3Cl.

5. The process according to claim 1, wherein in route (B), a compound of formula (III) is produced by a reduction of both nitro groups of a compound of formula (VIII) ##STR00044## wherein X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and Cl; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms and X and Y are identical or different and are selected from the group of halogen atoms, with the proviso that YCl, Br when X.sup.1, X.sup.2 and X.sup.3F, H or YBr when one of X.sup.1, X.sup.2 or X.sup.3Cl.

6. The process according to claim 1, wherein in route (C), a compound of formula (V) is produced by a reduction of both nitro groups of a compound of formula (IX) ##STR00045## in which X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and Cl; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms and R.sup.3 is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-C.sub.12-alkyl, substituted or unsubstituted C.sub.2-C.sub.12-alkenyl, substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.12-alkoxy, C.sub.1-C.sub.12-alkylaryl and aryl.

7. The process according to claim 6, wherein in route (C), the compound of formula (IX) is produced by a Heck reaction of a compound of formula (VIII) ##STR00046## wherein X.sup.1, X.sup.2 and X.sup.3 are identical or different and independently selected from the group consisting of H, F and Cl; and R.sup.1 and R.sup.2 may be same or different and are independently selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-haloalkyl or halogen atoms and X and Y are identical or different and are selected from the group of halogen atoms, with the proviso that YCl, Br when X.sup.1, X.sup.2 and X.sup.3F, H or YBr when one of X.sup.1, X.sup.2 or X.sup.3Cl. with an acrylate compound of the general formula (IV) ##STR00047## wherein R.sup.1 and R.sup.2 are as above, and R.sup.3 is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-C.sub.12-alkyl, substituted or unsubstituted C.sub.2-C.sub.12-alkenyl, substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl, substituted or unsubstituted C.sub.1-C.sub.12-alkoxy, C.sub.1-C.sub.12-alkylaryl and aryl, or any salt thereof.

8. The process according to claim 1, wherein in route (B), a compound of formula (I) is produced by a Heck reaction and in-situ cyclisation of a compound of formula (III) with an acrylate compound of formula (IV), wherein an intermediate compound of formula (V) is obtained between the Heck reaction and the cyclisation reaction.

9. A compound of the following formula (X) ##STR00048##

10. A compound of the following formula (XI) ##STR00049##

11. A compound of the following formulae (XIIa) and (XIIb) ##STR00050## ##STR00051##

12. A compound of the following formula (XIII) ##STR00052##

13. A compound of the following formula (XIV) ##STR00053##

Description

EXAMPLES

[0235] The invention is illustrated by the following examples without limiting the invention to the same.

[0236] The following reactions for the subsequent preparation of a compound according to formula (I) via different steps and different intermediate product compounds also include the preparation of every tautomer of the compounds (e.g. lactam-lactim-tautomerism).

[0237] The following abbreviations are used:

[0238] MW=molecular weight, MS=mass spectrometry, GC=gas chromatography, NMR=nuclear magnetic resonance.

[0239] The analytical data given below have been collected using the following instruments:

[0240] NMR: Bruker Avance III (400 MHz) or BRUKER Avance III (600 MHz), measured at 300K;

[0241] LC-MS: Waters Acquity UPLC with 3100 Mass Detector.

[0242] GC: Perkin Elmer Autosystem XL, column: HP5, carrier gas: helium

[0243] GC-MS: Agilent 6890 GC, column: DB-1, 10 m, iD 0.18 mm, film 0.4 m, injector: 250 C., flow: 1.6 mm/min He, oven: 0 min 50 C., 1 min 50 C., 7.75 min 320 C., 11 min 320 C., Hewlett-Packard 5973 MSD, MSD: 280 C., EI

Preparation of Starting Material

Preparation of 2-bromo-5-fluoro-1,3-dinitrobenzene

[0244] ##STR00027##

[0245] 4-Fluoro-2,6-dinitrophenol (CAS 364-32-9, 16.1 g, 79.4 mmol as a 32 weight % solution in toluene) was placed in a reaction vessel and DMF (24.4 mL, 317 mmol) was added. The reaction mixture was heated to 80 C. and then phosphorus tribromide (11.7 mL, 119 mmol) was added over 20 minutes. The reaction was stirred for another four hours at 77 C. and after cooling was left standing over night. The reaction was again heated to 85 C. for three hours and at that point all starting material had reacted. After cooling to 60 C. water (100 mL) was added to the reaction mixture (exotherm to 80 C.). The phases were separated and the aqueous phase was extracted with toluene (50 mL). The combined organic phases were successively washed with water (220 mL), saturated sodium chloride solution (10 mL) and dried over magnesium sulfate. After filtration the filtrate was concentrated under vacuum. n-Heptane was added and the resulting suspension was concentrated even further. 2-Bromo-5-fluoro-1,3-dinitrobenzene (17.1 g, purity 99 area % HPLC, yield 80%) was isolated through filtration.

[0246] .sup.1H-NMR (CDCl.sub.3, 400 MHz): =7.72 ppm (d, .sup.3J=8.0 Hz, 2H); .sup.13C-NMR (CDCl.sub.3, 150.9 MHz): =160.6 (.sup.1J.sub.C-F=259 Hz), 152.2 (br.), 116.0 (.sup.2J.sub.C-F=26.6 Hz), 102.8 ppm (.sup.4J.sub.C-F=5.2 Hz); LC-MS (ESI): m/z=201.0 [(M1).sup.].

Preparation Example 1

Preparation of 2-bromo-5-fluorobenzene-1,3-diamine (step (B2))

[0247] ##STR00028##

[0248] 2-Bromo-5-fluoro-1,3-dinitrobenzene (41.0 g, 153 mmol) and zinc (66.4 g, 995 mmol) were put in a reaction vessel and suspended in acetonitrile (267 mL). Hydrochloric acid (176 mL, 35% in water, 1.99 mol) was slowly added at 20-30 C. (exotherm! Temperature held with ice water cooling) over one hour. After one hour more zinc (1.3 g, 19.9 mmol) was added and after an additional hour the starting material and the reaction intermediates were converted to the product. The acidic reaction mixture was treated with saturated sodium bicarbonate solution (95.0 g, 8.6% in water, 97.3 mmol). Acetonitrile was removed under vacuum at 40 C. yielding a darkened suspension of the product. The product was extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and the drying agent was filtered off. After standing overnight a dark solid appeared which was dissolved in ethyl acetate. Activated charcoal was added and after stirring for a while filtered off. To the filtrate n-heptane was added and the mixture was concentrated on the rotatory evaporator to a thick suspension. The solid was filtered off and washed with n-heptane to give 2-bromo-5-fluorobenzene-1,3-diamine (27.4 g, purity 99 area % HPLC, yield 86%) as off white solid.

[0249] .sup.1H-NMR (CDCl.sub.3, 400 MHz): =5.94 (d, .sup.3J=8.0 Hz, 2H), 4.13 ppm (br. S, 4H); .sup.13C-NMR (CDCl.sub.3, 150.9 MHz): =163.3 (.sup.1J.sub.C-F=240 Hz), 145.7 (.sup.3J.sub.C-F=13.5 Hz), 92.4 (.sup.2J.sub.C-F=26.6 Hz), 91.5 ppm (.sup.4J.sub.C-F=2.5 Hz); LC-MS (ESI+): m/z=205.0; 207.0 [(M+1).sup.+].

Alternative Preparation of 2-bromo-5-fluorobenzene-1,3-diamine (step (B2))

[0250] A mixture of 2-Bromo-5-fluoro-1,3-dinitrobenzene (5.0 g, 18.87 mmol), ethyl acetate (25 g, 27.8 ml) and sponge cobalt catalyst (1.15 g, Raney-type cobalt, BASF: Actimet Co, previously washed with ethanol (2 times) and ethyl acetate (2 times)) was stirred in a Parr autoclave at 60 C. under 20 bar hydrogen pressure for 3 hours. Then the autoclave was cooled to 20 C. and the pressure was released to atmospheric pressure. The suspension was filtered into a flask containing 100 ml heptane and the filter was washed with 5 ml ethyl acetate. The filtrate was concentrated on a rotatory evaporator to obtain 2-bromo-5-fluorobenzene-1,3-diamine as a beige shiny solid (3.7 g, 96% purity by .sup.1H-NMR, yield 92%).

[0251] GC-MS (EI.sup.+): R.sub.t=4.445 min (index 1488, 100 area %), m/z=204/206 [M.sup.+].

[0252] .sup.1H-NMR (CDCl.sub.3, 400 MHz): =4.14 (br, 4H), 5.94 (d, .sup.3J=10.4 Hz, 2H) ppm.

Preparation of 5-amino-7-fluoroquinolin-2(1H)-one (or its tautomer 5-amino-7-fluoroquinolin-2-ol) (step (B1))

[0253] ##STR00029##

[0254] 2-Bromo-5-fluorobenzene-1,3-diamine (10.0 g, 48.3 mmol) was dissolved in 1,4-dioxane (65.0 mL) and nitrogen was bubbled through the solution for 15 minutes to degas the solution. Palladium (II) acetate (152 mg, 676 mol), 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (365 mg, 744 mol) and potassium carbonate (8.01 g, 57.9 mmol) were added. After the addition of butyl acrylate (7.56 mL, 53.1 mmol) the reaction mixture was heated to reflux for 5 hours and 50 minutes. After standing over night at room temperature the reaction was heated to reflux for another four hours and 30 minutes. The formed solid was isolated by filtration; the filter cake was washed with ethyl acetate, then suspended in water (60 mL) and filtration yielded 5-amino-7-fluoroquinolin-2(1H)-one (7.15 g, purity >98 area % HPLC, yield 81%) as a beige solid.

[0255] .sup.1H-NMR (DMSO-D.sup.6, 400 MHz): =11.48 (br. s, 1H), 8.05 (d, .sup.3J=9.8 Hz, 1H), 6.24 (s, 2H), 6.22 (d, .sup.3J=9.9 Hz, 1H), 6.19 (dd, .sup.3J.sub.H-F=10.6 Hz, .sup.4J=2.6 Hz, 1H), 6.13 ppm (dd, .sup.3J.sub.H-F=11.9 Hz, 4J=2.5 Hz, 1H); .sup.13C-NMR (DMSO-D.sup.6, 150.9 MHz): =164.3 (.sup.1J.sub.C-F=241 Hz), 162.2, 148.3 (.sup.3J.sub.C-F=15.0 Hz), 141.7 (.sup.3J.sub.C-F=15.0 Hz), 135.2, 116.6, 103.1, 92.9 (.sup.2J.sub.C-F=25.7 Hz), 88.2 ppm (d, .sup.2J.sub.C-F=34.7 Hz); LC-MS (ESI+): m/z=179.0 [(M.sup.+1).sup.+].

Preparation Example 2

Preparation of 2-bromo-5-fluoro-3-nitroaniline (step (A4))

[0256] ##STR00030##

[0257] 2-Bromo-5-fluoro-1,3-dinitrobenzene (11.6 g, 43.8 mmol) was dissolved in ethanol (50.0 mL) and iron powder (7.33 g, 131 mmol) were added. The mixture was heated to 60 C. and hydrochloric acid (35 w % aqueous solution, 23.2 mL, 263 mmol) were added over 45 minutes. The reaction was stirred at 80 C. for additional 75 minutes and then cooled to room temperature. Toluene (50 mL) and water were added and the mixture was filtered over a paper filter. The phases were separated and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were washed with hydrochloric acid (5 w %, 50 mL) and then filtered over a plug of silica (eluent n-heptane/ethyl acetate 7/3). The solvents were evaporated and the product was obtained as a bright yellow solid (7.30 g, purity 88.9 area % HPLC, yield 72%).

[0258] .sup.1H-NMR (DMSO-D.sup.6, 600 MHz): =7.07 (dd, .sup.3J.sub.H-F=8.2 Hz, .sup.4J=2.9 Hz, 1H), 6.80 (dd, .sup.3J.sub.H-F=11.0 Hz, .sup.4J=2.9 Hz, 1H), 6.33 ppm (br. s, 2H); .sup.13C-NMR (DMSO-D.sup.6, 150.9 MHz): =161.1 (.sup.1J.sub.C-F=244.5 Hz), 151.7 (.sup.3J.sub.C-F=12.1 Hz), 149.2 (.sup.3J.sub.C-F=13.6 Hz), 103.0 (.sup.2J.sub.C-F=25.7 Hz), 98.9 (.sup.2J.sub.C-F=28.7 Hz), 92.3 ppm (.sup.4J.sub.C-F=3.0 Hz); LC-MS (ESI+): m/z=235.0/237.0 [(M.sup.+1).sup.+].

[0259] A use test in the following Heck reaction revealed that the iron content was too high for the reaction to work. Therefore the material was further purified by column chromatography (n-heptane/ethyl acetate on silica).

Preparation of butyl (2E)-3-(2-amino-4-fluoro-6-nitrophenyl)acrylate (step A3 a)

[0260] ##STR00031##

[0261] 2-Bromo-5-fluoro-3-nitroaniline (2.00 g, purity 92 area % HPLC, 7.83 mmol) was dissolved in N,N-dimethyl formamide (15 mL) and the mixture was degassed by bubbling argon through the stirred reaction mixture for 45 minutes. Thereafter the following compounds were added in the following order: potassium acetate (1.92 g, 19.6 mmol), tetra-n-buthyl ammonium bromide (505 mg, 1.57 mmol), tris-ortho-tolyl phosphine (119 mg, 391 mol) and buthyl acylate (2.00 g, 15.6 mmol). Then the reaction mixture was heated to 100 C. and one third of the palladium (II) acetate (in total 43.9 mg, 196 mol) was added. After 15 minutes at 100 C. 4 area % HPLC of the starting material were left and another third of the palladium (II) acetate was added. Fifteen minutes later the last third of palladium (II) acetate was added and the reaction mixture was left cooling to 45 C. after another 15 minutes at 100 C. The warm reaction mixture was poured onto cold water (250 mL). After five minutes of stirring the mixture was extracted with ethyl acetate (50 mL) and the aqueous phase again was extracted with ethyl acetate (225 mL). The combined organic phases were dried over sodium sulfate and after evaporation of the solvents the product was obtained as a brown waxy solid (2.50 g, purity 73 area % HPLC, yield 83%).

[0262] .sup.1H-NMR (DMSO-D.sup.6, 400 MHz): =7.49 (d, .sup.3J=16.3 Hz, 1H), 7.02 (dd, .sup.3J.sub.H-f=8.4 Hz, .sup.4J=2.6 Hz, 1H), 6.78 (dd, .sup.3J.sub.H-f=11.1 Hz, .sup.4J=2.6 Hz, 1H), 6.23 (br. s, 2H), 6.13 (d, .sup.3J=16.3 Hz, 1H), 4.14 (t, .sup.3J=6.6 Hz, 2H), 1.66-1.57 (m, 2H), 1.42-1.32 (m, 2H), 0.91 ppm (t, .sup.3J=7.4 Hz, 3H); .sup.13C-NMR (DMSO-D.sup.6, 150.9 MHz): =165.5, 161.8 (.sup.1J.sub.C-F=245.8 Hz), 150.8 (.sup.3J.sub.C-F=12.3 Hz), 150.1 (.sup.3J.sub.C-F=12.6 Hz), 136.2, 123.1, 108.2 ppm (.sup.4J.sub.C-F=2.5 Hz), 104.5 (.sup.2J.sub.C-F=24.2 Hz), 98.9 (.sup.2J.sub.C-F=28.5 Hz), 64.0, 30.2, 18.6, 13.6 ppm; LC-MS (ESI): m/z=281.1 [(M1).sup.]. The Z-Isomer was only obtained in minor amounts (less then 5%).

Preparation of 7-fluoro-5-nitroquinolin-2(1H)-one (and its tautomer 7-fluoro-5-nitroquinolin-2-ol) (step (A2))

[0263] ##STR00032##

[0264] (2E)-3-(2-Amino-4-fluoro-6-nitrophenyl)acrylate (2.00 g, purity 80%, 5.67 mmol) was dissolved in methanol (40 mL) and sodium methylate (1.02 g, 30% solution in methanol) was added. The reaction was heated to 60 C., kept at that temperature for five hours minutes, then left standing over night at room temperature and then again heated to 60 C. for eight hours. The methanol was partially removed by distillation and ethyl acetate was added. The formed solid was filtered off and washed with more ethyl acetate. The thereby obtained sodium salt of the product was dissolved in water and the pH was adjusted to 2 with hydrochloric acid. The product was obtained by filtration as a brownish solid (730 mg, purity 97 area % HPLC, yield 60%). Additional product was found in the mother liquor of the first filtration. It was isolated after evaporation of the solvents through the procedure described above (210 mg, purity 68 area % HPLC, yield 12%).

[0265] .sup.1H-NMR (DMSO-D.sup.6, 600 MHz): =12.30 (s, 1H), 8.18 (d, .sup.3J=10.1 Hz, 1H), 7.87 (dd, .sup.3J.sub.H-F=8.7 Hz, .sup.4J=2.5 Hz, 1H), 7.40 (dd, .sup.3J.sub.H-F=9.3 Hz, .sup.4J=2.4 Hz, 1H), 6.72 ppm (d, .sup.3J=10.1 Hz, 1H); .sup.13C-NMR (DMSO-D.sup.6, 151 MHz): =160.8 (.sup.1J.sub.C-F=249.6 Hz), 160.8, 147.2 (.sup.3J.sub.C-F=11.1 Hz), 141.5 (.sup.3J.sub.C-F=12.3 Hz), 133.8, 124.3, 108.8 (.sup.4J.sub.C-F=1.9 Hz), 107.3 (.sup.2J.sub.C-F=28.8 Hz), 106.4 ppm (.sup.2J.sub.C-F=25.0 Hz); LC-MS (ESI): m/z=209.0 [(M1)].

Preparation of 5-amino-7-fluoroquinolin-2(1H)-one (step (A1))

[0266] ##STR00033##

[0267] 7-fluoro-5-nitroquinolin-2(1H)-one (650 mg, purity 97 area %, 3.02 mmol) was dissolved in methanol (50.0 mL) and ammonium formate (1.52 g, 24.2 mmol) and palladium on charcoal (10% Pd, 50 mg, 47.0 mol) were added. The reaction mixture was heated to 50 C. for 105 minutes, and then the catalyst was filtered off and washed with methanol. To the mother liquor water (20 mL) was added and the pH was adjusted to 5 with aqueous hydrochloric acid. A precipitate formed and after evaporation of some of the methanol even more precipitate formed. The solid was filtered off and washed with water. After drying the product was obtained as a light brown crystalline solid (504 mg, purity 98 area % HPLC, yield 91%).

[0268] .sup.1H-NMR (DMSO-D.sup.6, 400 MHz): =11.48 (br. s, 1H), 8.05 (d, .sup.3J=9.8 Hz, 1H), 6.24 (s, 2H), 6.22 (d, .sup.3J=9.9 Hz, 1H), 6.19 (dd, .sup.3J.sub.H-F=10.6 Hz, .sup.4J=2.6 Hz, 1H), 6.13 ppm (dd, .sup.3J.sub.H-F=11.9 Hz, 4J=2.5 Hz, 1H); .sup.13C-NMR (DMSO-D.sup.6, 150.9 MHz): =164.3 (.sup.1J.sub.C-F=241 Hz), 162.2, 148.3 (.sup.3J.sub.C-F=15.0 Hz), 141.7 (.sup.3J.sub.C-F=15.0 Hz), 135.2, 116.6, 103.1, 92.9 (.sup.2J.sub.C-F=25.7 Hz), 88.2 ppm (d, .sup.2J.sub.C-F=34.7 Hz); LC-MS (ESI+): m/z=179.0 [(M.sup.+1).sup.+].