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CAS No. : | 185629-32-7 | MDL No. : | MFCD08689703 |
Formula : | C8H8FNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DOMJYWCXCVFKCA-UHFFFAOYSA-N |
M.W : | 169.15 | Pubchem ID : | 11182865 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 42.08 |
TPSA : | 52.32 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.1 cm/s |
Log Po/w (iLOGP) : | 1.72 |
Log Po/w (XLOGP3) : | 1.74 |
Log Po/w (WLOGP) : | 1.62 |
Log Po/w (MLOGP) : | 1.75 |
Log Po/w (SILICOS-IT) : | 1.4 |
Consensus Log Po/w : | 1.64 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.22 |
Solubility : | 1.01 mg/ml ; 0.00598 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.46 |
Solubility : | 0.593 mg/ml ; 0.0035 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.39 |
Solubility : | 0.692 mg/ml ; 0.00409 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.37 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium on activated charcoal; hydrogen In ethanol; ethyl acetate at 20℃; for 16 h; | A mixture of methyl 3-fluoro-4-nitrobenzoate (2.50 g,12.5 mmol) and Pd/C (300 mg, 10 wtpercent) in 1:1 EtOAc/EtOH (40 mL) was stirred at rt for 16h under 1 atm of H2. The mixture was filtered through Celite and concentrated to give the titlecompound (2.1 g, 99percent) as a beige solid. MS (ES+) C8H8FNO2 requires: 169, found: 170[M+Hj |
98% | With palladium 10% on activated carbon; hydrogen In methanol; ethyl acetate at 20℃; for 6 h; | Methyl 3-fluoro-4-nitrobenzoate (1.0 g, 5.00 mmol) is dissolved in ethyl acetate (5 mL) and methanol (5 mL), followed by adding 10percent Pd/C (150 mg), and the reaction mixture reacts at room temperature for 6 hrs in a hydrogen gas atmosphere, then filtered with siliceousearth, rotated to remove the solvent, so as to obtain a white solid, that is methyl 3-fluoro-4-aminobenzoate, with the yield of 98percent. Spectrum is : 1H NMR (400 MHz, CDCl3) δ: 7.69(m, 1H), 7.66(m, 1H), 6.76(m, 1H), 4.17(s , 2H), 3.88(s , 3H). |
95% | With hydrogen In ethanol; ethyl acetate | 2. Methyl 4-amino-3-fluorobenzoate[00155]; Methyl 3- fluoro-4-nitrobenzoate (5.18 g, 26.0 mmol) in a 1 : 1 mixture (50 mL) of EtOH and AcOEt with 10percent Pd/C (0.52 g) was hydrogenated on a Parr hydrogenation apparatus at 40 psi. Pd/C was removed by filtration through a pad of Celite.(R). 545. The filtrate was concentrated under vacuum. The residue was diluted with AcOEt, washed with brine, and dried over anhydrous MgSO4. Evaporation of solvent under vacuum gave the title compound (4.17 g, 95percent yield) as a pale solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium on activated charcoal; hydrogen; In ethanol; ethyl acetate; at 20℃; under 760.051 Torr; for 16h; | A mixture of methyl 3-fluoro-4-nitrobenzoate (2.50 g,12.5 mmol) and Pd/C (300 mg, 10 wt%) in 1:1 EtOAc/EtOH (40 mL) was stirred at rt for 16h under 1 atm of H2. The mixture was filtered through Celite and concentrated to give the titlecompound (2.1 g, 99%) as a beige solid. MS (ES+) C8H8FNO2 requires: 169, found: 170[M+Hj |
98% | With palladium 10% on activated carbon; hydrogen; In methanol; ethyl acetate; at 20℃; for 6h; | Methyl 3-fluoro-4-nitrobenzoate (1.0 g, 5.00 mmol) is dissolved in ethyl acetate (5 mL) and methanol (5 mL), followed by adding 10% Pd/C (150 mg), and the reaction mixture reacts at room temperature for 6 hrs in a hydrogen gas atmosphere, then filtered with siliceousearth, rotated to remove the solvent, so as to obtain a white solid, that is methyl 3-fluoro-4-aminobenzoate, with the yield of 98%. Spectrum is : 1H NMR (400 MHz, CDCl3) delta: 7.69(m, 1H), 7.66(m, 1H), 6.76(m, 1H), 4.17(s , 2H), 3.88(s , 3H). |
97.2% | With palladium on activated charcoal; hydrogen; In methanol; for 16h; | Methyl 3-fluoro-4-nitrobenzoate (2.00 g, 10.1 mmol),It was added to methanol (40 mL), Pd/C (200 mg) was added and hydrogenated for 16 hr. Filtering,The filtrate is concentrated to give the title compound(1.65 g, yield: 97.2%). |
95% | With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; under 2068.65 Torr; | 2. Methyl 4-amino-3-fluorobenzoate[00155]; Methyl 3- fluoro-4-nitrobenzoate (5.18 g, 26.0 mmol) in a 1 : 1 mixture (50 mL) of EtOH and AcOEt with 10% Pd/C (0.52 g) was hydrogenated on a Parr hydrogenation apparatus at 40 psi. Pd/C was removed by filtration through a pad of Celite 545. The filtrate was concentrated under vacuum. The residue was diluted with AcOEt, washed with brine, and dried over anhydrous MgSO4. Evaporation of solvent under vacuum gave the title compound (4.17 g, 95% yield) as a pale solid. |
5%-palladium/activated carbon; | methyl 4-amino-3-fluorocarboxylate [prepared by hydrogenation in the presence of 5% Pd/C of methyl 2-fluoro-4-nitrobenzoate which in turn was prepared according to literature precedent (J. Org. Chem., 1990; 55: 2034-2044)] | |
With hydrogen;palladium 10% on activated carbon; In methanol; ethyl acetate; at 30℃; for 16h;Inert atmosphere; | Into a 2000-mL round-bottom flask maintained with a nitrogen atmosphere, was placed a solution of methyl 3-fluoro-4- nitrobenzoate (98 g, 492.46 mmol, 1.00 equiv) in ethyl acetate:methanol=l : l (1000 mL). Then Pd/C (10 g, 10 wt%, Degussa type) was added. The flask was fitted with a balloon of hydrogen, and the heterogeneous reaction mixture was stirred for 16 h under a hydrogen atmosphere at 30 C. The catalyst solids were filtered off and the filtrate was concentrated under vacuum to give the deisred product methyl 4-amino-3-fluorobenzoate. | |
With hydrogen;palladium on activated charcoal; In methanol; ethyl acetate; at 30℃; for 16h;Inert atmosphere; | Into a 2000-mL round-bottom flask maintained with a nitrogen atmosphere, was placed a solution of methyl 3-fluoro-4- nitrobenzoate (98 g, 492.46 mmol, 1.00 equiv) in ethyl acetate:methanol=l : l (1000 mL). Then Pd/C (10 g) was added. The resulting solution was stirred for 16 h under a hydrogen atmosphere at 30oC. The solids were filtered out. The filtrate was concentrated under vacuum, and methyl 4-amino-3-fluorobenzoate was obtained as a pale solid. | |
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 4h; | 3-Fluoro-4-nitrobenzoic acid (956 mg, 4.85 mmol) was dissolved in methanol (30 mL) under argon atmosphere, Pd/C (180 mg) was added and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 4 h. The catalyst was filtered off and the solvent removed in vacuo. Yield: 769 mg (94.7%); light grey crystals. (0429) 1H NMR (400 MHz, DMSO-d6) d 3.76 (s, 3H), 6.09 (s, 2H), 6.78 (m, 1H), 7.51 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride;palladium on charcoal; In methanol; ethyl acetate; | A solution of 3-fluoro-4-nitrobenzoic acid (1.6 g, 8.65 mmole) in 35 mL methanol at 0 C. was treated dropwise with 1.27 mL of thionyl chloride, stirred at room temperature overnight and volatile material removed in vacuo. The product was purified by flash chromatography (SiO2, 5% methanol/dichloromethane) to provide 1.7 g of a 3:2 mixture consisting of methyl 3-fluoro-4-nitrobenzoate and 3-methoxy-4-nitrobenzoic acid (65). The mixture was used directly in the next step. 150 mg of 10% palladium on charcoal was added to a solution of the above mixture consisting of methyl 3-fluoro-4-nitrobenzoate and 3-methoxy-4-nitrobenzoic acid (1.7 g) in 50 mL ethyl acetate and maintained under H2 (45 psi) for two hours. The reaction mixture was filtered over Celite and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 10% methanol/dichloromethane), giving 0.7 g of methyl 4-amino-3-fluorobenzoate as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With bromine; acetic acid; at 20 - 150℃; for 50h; | KSCN (4.82 g, 49.7 mmol) wasadded to a solution of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> (2.1 g, 12 mmol) in AcOH (15 mL).The mixture was stirred at rt until it became a clear solution. Then a solution of Br2 (2.19 g, 13.7 mmol) in AcOH (5 mL) was added dropwise and the resulting mixture stirred at rt for 48h. At that time an additional amount of Br2 (600 mg, 3.73 mmol) in AcOH (2 mL) was added dropwise. The mixture was heated at 50 C for 2 h. The reaction mixture was filtered andH20 was added to the filtrate. Aqueous NH4OH was then added to adjust the pH to 8. The resulting mixture was filtered and the solid collected to give the title compound (1.8 g, 64%) as a yellow solid. MS (ES+) C9H7FN2O2S requires: 226, found: 227 [M+Hf?. |
48% | With bromine; In ethyl acetate; at 10 - 30℃; for 48.5h; | Methyl 3-fluoro-4-aminobenzoate (830 mg, 4.9 mmol) and potassium sulfocyanide (1.9 mg,19.6 mmol) are dissolved in ethyl acetate (10 mL), followed by dripping broime (250 muL, 4.9 mmol) dissolved in ethyl acetate (5 mL) at 10 C in 30 min, after that, the temperature is increased to 30 C ,and the reaction mixture continues to react for 48 hrs, then the mixture is diluted with water (30 mL), followed by adjusting pH to 8?9 with ammonium hydroxide, and the resulted mixture is filtered, washed, and vacuumed to dryness, so as to obtain a yellow solid of 530 mg, that is methyl 2-amnio-4-flurobenzo[d]thiazole-6-carboxylate, with a yield of 48%. Spectrum is: 1H NMR (400 MHz, DMSO) delta: 8.16(m, 1H), 8.14(s , 2H), 7.56(m, 1H), 3.83(s , 3H). |
22.6% | With bromine; In acetic acid; at 25℃; for 16h; | The fluorobenzoate 4-amino -3- (1.65g, 9.8mmol), KSCN (3.79g, 39.1mmol)was added to glacial aceticacid (30 mL) in 15 minutes, a solution of bromine (1.57 g of, 9.8 mmol), react at 25 C for 16 hours.After adding water (100 mL), the mixture wasadjusted to pH 8withaqueous ammonia, filtered, and evaporated to give the title compound (500 mg, yield: 22.6%). |
3. Methyl 2-amino-4-fluorobenzo[d]thiazole-6-carboxylate[00156] ; To a solution of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> (2.00 g, 11.8 mmol) in AcOH (25 mL) was added KSCN at rt in one portion, and the resulting mixture was stirred at rt until it became a clear solution. Then, bromine (1.89 g, 11.8 mmol) in AcOH (10 mL) was added at rt over 45 min, and the whole reaction mixture was stirred at rt for 20 hr. The precipitate that formed during the reaction was removed by filtration. The filtrate was poured into water (100 mL) and basified with cons. NH3 H2O to pH 8-9. The resulting precipitate was collected by suction filtration and dried at 6O0C under vacuum to give a crude product (1.17 g). This crude was a mixture of the title product and the starting material (methyl 4-amino-3- fluorobenzoate) in a ratio of 1.3 to 1. However, this crude product was directly used in the next step without further purification. | ||
With bromine; acetic acid; at 10 - 20℃; | To a solution of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> (2.84 g, 16.8 mmol) and KSCN (6.52 g, 67.1 mmol) in acetic acid (40 mL) cooled to 10 C bromine (1.72 mL, 33.5 mmol) in acetic acid (2 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight.The suspension was cooled on ice bath and 25% aqueous NH3 solution (200 mL) was added dropwise. The precipitate was filtered off, suspended in ethyl acetate (180 mL) and water (100 mL), filtered off and dried. The residue was dispersed in methanol (100 mL), sonicated, heated, filtered and successively washed with hot methanol and the mother liquid evaporated under reduced pressure. Yield: 1.02 g (26.9%); yellow solid. (0432) 1H NMR (400 MHz, DMSO-d6) d 3.85 (s, 3H), 7.58 (dd, J = 11.5, 1.6 Hz, 1H), 8.16 (s, 2H), 8.18 (d, J = 1.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Oxone; sodium bromide; In water; acetonitrile; at 25℃; for 2h; | a) 4-Amino-3-bromo-5-fluoro-benzoic acid methyl ester To a solution of <strong>[185629-32-7]4-amino-3-fluoro-benzoic acid methyl ester</strong> (10.0 g, 57.9 mmol) in ACN (280 mL) is added water (60 mL) and NaBr (6.02 g, 57.9 mmol). To this solution is slowly added a solution of oxone (35.9 g, 57.9 mmol) in water (80 mL). After stirring for 2 h at 25 C., the mixture is extracted with EtOAc. Combined extracts are washed with NaS2O3 solution and brine, dried over MgSO4 and evaporated. The title compound is obtained after crystallization from diisopropylether as a beige solid: TLC (toluene-EtOAc 1:1) Rf=0.67; HPLC RtA=1.66 min; ESIMS [M-H]-=246 and 248; 1H-NMR (400 MHz, CDCl3): delta 7.96 (d, 1H), 7.63 (dd, 1H), 3.84 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Iodine monochloride; calcium carbonate; In ethanol; water; at 20 - 25℃; for 48h; | a) 4-Amino-3-fluoro-5-iodo-benzoic acid methyl ester To a suspension of <strong>[185629-32-7]4-amino-3-fluoro-benzoic acid methyl ester</strong> (25.0 g, 140 mmol) in EtOH-water 3:2 (200 mL) and CaCO3 (25.1 g, 246 mmol) is added in portions iodine monochloride (10.8 mL, 210 mmol) at 25 C. The mixture is stirred for 48 h at ambient temperature and then slowly diluted with a large amount of NaHCO3 solution. The organic solvent is removed under reduced pressure and the aqueous phase is extracted with EtOAc. The combined extracts are washed with water and brine, dried over MgSO4 and evaporated. The crude product is triturated with diisopropylether, filtered off and dried to afford the title compound as a brownish solid: TLC (toluene) Rf=0.29; HPLC RtA=1.74 min; ESIMS [M-H]-=294; 1H-NMR (400 MHz, CDCl3): delta 8.13 (d, 1H), 7.62 (dd, 1H), 3.84 (s, 3H). | |
With iodine; silver sulfate; In ethanol; at 20℃; for 1h; | 3.101. Compound 95: 4-[4-(Cyclopropanecarbonyl-amino)-l-methyl-lH-imidazo[4,5- c]pyridin-6-yl]-methyl-amino}-3-difluoromethoxy-5-fluoro-benzamide 3.101.1. Step i): 4-Amino-3-fluoro-5-iodo-benzoic acid methyl ester Iodine (1 eq, 3.76 g) is dissolved in EtOH (80 mL) at room temperature followed by the addition of <strong>[185629-32-7]4-amino-3-fluoro-benzoic acid methyl ester</strong> (1 eq, 2.5 g) and silver sulfate (1 eq, 4.61 g). After lh, the silver salts are filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in DCM and washed with sat. Na2S203, passed through a phase separator and concentrated to afford the desired product that is used as such in the next step. | |
With calcium carbonate; In water; at 25℃; for 36h; | [1416] To a solution of EW-2 (14.74 g, 86.96 mmol, 1 eq) in EtOH (150 mL) and H2O (100 mL) were added CaCO3 (15.67 g, 156.53 mmol, 1.8 eq) and IC1 (21.18 g, 130.44 mmol, 6.66 mL, 1.5 eq). The mixture was stirred at 25C. for 36 hr to give a brown suspension. TLC showed the desired spot found. The reaction was diluted with saturated NaHCO3 (200 mL) and extracted with EtOAc (150 mL3). The combine organic layers were washed with brine (100 mL) and dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash column (SiO2, EtOAc in PE from 0 to 30%) to give EW-3 . 1H NMR (400 MHz, CDCl3) delta ppm 8.15 (s, 1H), 7.62-7.68 (m, 1H), 4.59 (br s, 2H), 3.88 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 20℃; for 5h; | To a solution of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> (CAS Number: 185629-32-7) (169 mg, 1.00 mmol) in dichloromethane (2 mL) were added pyridine (0.322 mL, 4.00mmol) and methanesulfonyl chloride (85 1iL, 1.1 mmol) at room temperature. This mixture was allowed to stir at room temperature for 5 hours. The reaction mixture was diluted with 1 mol/L HC1 and extracted with dichloromethane twice. The combined organic extracts were concentrated under a stream of air. The residue was triturated with Et20 and the liquid was removed by decantation to afford the title compound (crude 341 mg). LCMS: R1 = 0.72 mm; mlz (M + 1)÷ = 248. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.7% | In a 25 mL round-bottomed flask, (2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(5-chloro-3-fluoropyridin-2-yl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid 2,2,2-trifluoroacetic acid (1:1) salt(150 mg, 258 mumol, Eq: 1.00), was combined with CH2Cl2 (3 ml) to give a suspension. N-ethyl-N-isopropylpropan-2-amine (117 mg, 157 muL, 902 mol, Eq: 3.5) and diphenylphosphinic chloride (Aldrich, 152 mg, 123 muL, 644 mumol, Eq: 2.5) were added and the reaction was stirred at RT for 10 minutes. Methyl 4-amino-3-fluorobenzoate (Aldrich, 43.6 mg, 258 mumol, Eq: 1.00) was added and the reaction mixture was stirred at RT for 4 days and then concentrated on Rotor Vac.The crude material was dissolved in DMSO and was purified by preparative HPLC (65-100% ACN/H2O, 0.1% TFA). The fractions was combined, concentrated and freeze dried to give a yellow solid (7.5 mg, 4.7% yield) as desired product. MS (ES+) m/z Calcd for C30H27Cl2F3N4O3+H[(M+H)+]: 619, found: 619. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Into a 1000-mL round-bottom flask, was placed a solution of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> (45 g, 266.27 mmol, 1.00 equiv) and NaSCN (86 g, 1.06 mol, 3.99 equiv) in AcOH (350 mL). This was followed by the addition of a solution of Br2 (42 g, 262.50 mmol, 0.99 equiv) in AcOH (150 mL) dropwise at 0 C for 1 h. The resulting solution was stirred for 48 h at 30C, after which point the solids were filtered. The resulting solution was diluted with H20 and the pH was adjusted to pH=8-9 with ammonium hydroxide. The resulting precipitate was collected by filtration to give the desired product methyl 2-amino-4-fluorobenzo[d]thiazole-6-carboxylate as a yellow solid. | ||
With bromine; acetic acid; at 0 - 30℃; | To aIL round-bottom flask was added methyl4-amino-3-fluorobenzoate A-la (20 g,118.24 mmol, 1.0 equiv.), AcOH (400 mL), and NaSCN (38.34 g, 473.33 mmol, 4.0 equiv.).The mixture v.·as cooled at 0 C, and bromine (18.7 g, 117.()1 mmoL 1.0 equiv) was addeddropwise ·with stirring The reaction rnixture was stirred at 0 oc for 2 hours, then at 30 oc for3 days. 400 mL of water was added, the pH value of the solution was adjusted to 9 using25 sodium hydroxide. Solids were collected by filtration and dried in an oven 1..mder reducedpressure, to give 28 g (crude) ofmethyl2-amino-4-fluoro-1,3-benzothiazole-6-carhoxylateA-1 b as a yellow solid. The crude product was carried onto the next step without furtherpurification. | |
With bromine; In acetone; at 0 - 30℃; for 72h; | To a 1L round-bottom flask was added <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> 30a (20 g, 118.24 mmol, 1.0 equiv.), AcOH (400 mL), and NaSCN (38.34 g, 473.33 mmol, 4.0 equiv.). The mixture was cooled at 0 C, and bromine (18.7 g, 117.01 mmol, 1.0 equiv) was added dropwise with stirring. The reaction mixture was stirred at 0 C for 2 hours, then at 30C for 3 days. 400 mL of water was added, the pH value of the solution was adjusted to 9 using sodium hydroxide. Solids were collected by filtration and dried in an oven under reduced pressure, to give 28 g (crude) of methyl 2-amino-4-fluoro-l,3-benzothiazole-6-carboxylate 30b as a yellow solid. The crude product was carried onto the next step without further purification. |
With bromine; acetic acid; at 0 - 30℃; for 74h; | To a 1 L round-bottom flask was added <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> A-la (20 g, 1 18.24 mmol, 1.0 equiv.), AcOH (400 mL), and NaSCN (38.34 g, 473.33 mmoi, 4.0 equiv.) followed by the dropwise addition of bromine (18.7 g, 117.01 mmol, 1.0 equiv.) at 0 C. The reaction mixture was stirred at 0 C for 2 hours, then at 30 C for 3 days. The resulting mixture was quenched with water (400 mL) and the pH value of the solution was adjusted to 9 using sodium hydroxide. Solids were collected by filtration and dried in an oven under reduced pressure, to give of methyl 2-amino-4-fluoro-l,3-benzothiazole-6-carboxylate A-lb (28 g) as a yellow solid. The product was carried on to the next step without further purification. | |
65 g | With bromine; acetic acid; at 0 - 20℃; | To <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> (5b-1) (45 g, 266 mmol) and sodium thiocyanate (86 g, 1064 mmol) in acetic acid (350 ml) at 0 C. was added bromine (13.57 ml, 263 mmol) in AcOH (100 ml) via additional funnel over 1 h, and the mixture was warmed up to RT and stirred for 2 days. The mixture was filtered to collect the first crop of solid, washed with water and dried in the open air to give methyl 2-amino-4-fluorobenzo[d]thiazole-6-carboxylate (5b-2) (65 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 8.28-8.02 (m, 1H), 7.58 (dd, J=11.5, 1.6 Hz, 1H), 3.84 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.5 g | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 16h; | To a solution of the product in Step 1 above (1.47 g, 5.91 mmol) in THF (10 mL) was added <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> (1 g, 5.91 mmol) and Hunig'sBase (3.10 mL, 17.74 mmol). The resulting mixture was stirred for 16 h. The precipitate was filtered and washed with THF and water and dried to give 1.5 g of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; HATU; In dichloromethane; at 20℃; | General procedure: To a solution 15 (490 mg, 1.0 eq, 0.92 mmol) in CH2Cl2 (50 mL) was added HATU (525 mg, 1.5 eq, 1.38 mmol), 4-methylmorpholine (0.30 mL, 3.0 eq, 2.8 mmol) and methyl 3-aminobenzoate hydrochloride (208 mg, 1.2 eq, 1.1 mmol). The reaction mixture was stirred at room temperature overnight. After the solvent was concentrated in vacuo, the residue was purified by chromatography (petroleum ether/acetone = 3/1) to afford compound 16 as white solid (360 mg, 59%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 50℃; | General procedure: To a solution of the corresponding methyl 4-aminobenzoate (1, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and benzo[c][l,2,5]thiadiazole-4-sulfonyl chloride (585 mg, 2.5 mmol). The resulting mixture was stirred at 50C overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HC1, water and brine, dried over Na2S04 and concentrated to give crude product 2, which was confirmed by LCMS, and used in the next reaction without further purification | |
With pyridine; In dichloromethane; at 50℃; | General procedure: To a solution of the corresponding methyl 4-aminobenzoate (1, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and benzo[c][1,2,5]thiadiazole-4-sulfonyl chloride (585 mg, 2.5 mmol). The resulting mixture was stirred at 50 C. overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HCl, water and brine, dried over Na2SO4 and concentrated to give crude product 2, which was confirmed by LCMS, and used in the next reaction without further purification. | |
With pyridine; at 50℃; | General procedure: To a solution of the corresponding methyl 4-aminobenzoate (1, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and benzo[c][l,2,5]thiadiazole-4-sulfonyl chloride (585 mg, 2.5 mmol). The resulting mixture was stirred at 50C overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HC1, water and brine, dried over Na2S04 and concentrated to give crude product 2, which was confirmed by LCMS, and used in the next reaction without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 70℃; | (0191) To a stirred solution of glycine tert-butylester (Aldrich, 26.1 g, 0.15 mol) in DMF (400 mL) was added HATU (Aldrich, 85 g, 0.22 mol), DIPEA (Aldrich, 96.3 g, 0.74 mol) and <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> (Combi-blocks, 22 g, 01.13 mol). The mixture was stirred at 70 C. overnight and then cooled to rt and partioned between EtOAc (2×500 mL) and water. The organic layer was washed with brine and dried over sodium sulfate and concentrated. The residue was chromatographed (EtOAc/Hexane, 5:1) to give a white solid. 18.7 g, 43%. 1H NMR (CDCl3, 400 MHz): delta 8.63 (s, 1H), 8.40-8.44 (t, 1H, J=8.4 Hz), 7.79-7.81 (t, 1H, J=8.8 Hz), 7.71-7.74 (dd, 1H, J1=11.6 Hz, J2=1.6 Hz), 5.33 (s, 1H), 3.95-3.97 (d, 2H, J=6.4 Hz), 3.88 (s, 3H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In acetone; at 0 - 5℃;Inert atmosphere; | In an inert (N2) 20 I reactor vessel, <strong>[185629-32-7]methyl 4-amino-3-fluoro-benzoate</strong> (SM-3-l) (500 g, 296 mol) was dissolved in acetone (2,00 I) and pyridine (721 ml, 8,87 mol) was added. The reaction mixture was cooled to 0C. A solution of phenyl chloroformate (465 ml, 3,70 mol) in acetone (3,00 I) was added at 0-5C during 45-60 mm. The reaction mixture was stirred for 1 h at 0-5C, upon a white suspension has formed.After warming up to 20-25 C, water (7,65 I) was added and the reaction mixture was stirred for 60 mm. The suspension was filtered and the filter cake was washed well with water (27,8 I). The wet product was dried under vacuum for 16-40 h at 50C to give O-phenyl-N-3-fluoro-4- methoxycarbonylphenyl] carbamate (SM-2-I) (861 g, 2,98 mol, 101%) as a light beige solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.7% | In ethanol;Reflux; | 4-chloro-3-nitropyridine (5.2g, 1.0eq, 32.9mmol) and <strong>[185629-32-7]4-amino-3-fluorophenyl acetate</strong> (5.6g,1.1 eq, 32.9mmol) dissolved in 30mLEtOH, the resulting reaction solution Refluxed overnight.After completion of the reaction was monitored by TLC,concentrated under reduced pressure after EtOAc (10mL) to give a yellow solid was recrystallized (6.1g, Y = 63.7%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 1h; | j00495J To a solution of methyl 4.-ainino-3-fluorohenzoate (500 mg, 3 mrnol) and DIPEA (1.65 mL, 9 mmol) in MeCN (5 mL) was added acryloyl chloride (320 mg, 16 mmoi) dropwise at 0 C. The reaction was stirred at ii for I h, then Na2CO3 aq.(sat,) was added, the resulting mixture was extracted with DCM (20 rnL x 2). The combined organic layer was concentrated and recrvstalized from EA to give YLIUi)1 164 (190 mg, 28 %) as white solid, LCMS (mz): 224 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With hydrazine; at 70℃; for 15h;Inert atmosphere; | 4-Amino-3-fluorophenylhydrazide. Methyl 4-amino-3 -fluorob enzoate (250 mg, 1.48 mmols) was added to a 10 mL round bottom flask with stir bar, followed by addition of anhydrous hydrazine (500 1iL, 15.9 mmols). The reaction was then heated to 70C under N2 for 15 hours. After cooling, the mixture was poured into deionized water (40 mL), and the resulting precipitate was filtered and rinsed with additional water (50 mL) to give the product as a tan solid (130 mg, 52%). ?HNIVIR (400 MHz; DMSO-d6) = 9.41 (s, 1H), 7.48 (dd, J=12.8 Hz, 1.7 Hz, 1H), 7.43 (dd, J= 8.6, 1.7 Hz, 1H), 6.74 (t, J= 8.6 Hz, 1H), 5.66 (br, 2H),4.36 (br s, 2H). ?3C NIVIR (100 MFIz; DMSO-d6) 5= 165.4, 149.5 (d, J= 236.8 Hz), 139.5 (d,J 12.9 Hz), 124.0, 120.3 (d, J 4.8 Hz), 114.8 (d, J 3.9 Hz), 113.7 (d, J 19.6 Hz). ?9FNMR (376 IVIHz; DMSO-d6) = -136.96 (dd, J= 12.0, 9.2 Hz). Referenced againstCF3COOHat -76.55 ppm. (ESI) m/z calcd for C7H8FN3O (M) 169.0645, found 169.1001. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | General procedure: Standard Procedure a for the Preparation of Thazolidinone Derivatives (0051) To a solution of aniline in toluene was added benzaldehyde and Na2SO4 anhydrous at room temperature, and it was stirred at room temperature or reflux for 5-20 h to obtain the imine intermediate. Then 2-mercaptoacetic acid was added to the reaction mixture, and it was reflux for 8-22 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10-20% NaOH(aq), HCl(aq) or brine. The organic layer was dried over MgSO4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified to give the desired product. Example 38 Methyl 3-fluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate Following standard procedure A, <strong>[185629-32-7]methyl 4-amino-3-fluorobenzene carboxylate</strong> (0.680 g, 4.02 mmol), 4-fluorobenzaldehyde (1.00 g, 8.04 mmol), Na2SO4 (1.14 g, 8.04 mmol), 2-mercaptoacetic acid (0.500 mL, 7.20 mmol), and toluene (10 mL) were used to carry out the reaction. It was reflux 5 h for the first step and 20 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 3-fluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (0.340 g, 24%) as a yellow gum. 1H NMR (CDCl3, 400 MHz) delta 7.74-7.69 (m, 2H), 7.33 (dd, 2H), 7.16 (dd, 1H), 6.95 (t, 2H), 6.17 (s, 1H), 3.94 (s, 2H), 3.88 (s, 3H); LC-MS (ESI) m/z 350.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74 mg | With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | Example 67A Methyl 4-[(6-bromo-7-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0608) (0609) To a solution of 200 mg (0.47 mmol) of the compound from example 20A and 87 mg (0.52 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 1 ml of 49 DMF under argon were added, in small portions at RT, 53 mg (0.47 mmol) of 153 potassium tert-butoxide, and the mixture was stirred at RT for 15 min. Subsequently, a further 26 mg (0.24 mmol) of potassium tert-butoxide were added in small portions, and the mixture was stirred at RT for another 15 min. Thereafter, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution and diluted with 6 ml of 43 water. The solids formed were filtered off, washed twice with water and dried under reduced pressure. The solids were then taken up in dichloromethane and purified by means of column chromatography (50 g of silica gel, eluent: cyclohexane/ethyl acetate 9:1, Biotage). 74 mg (30% of theory, 100% purity) of the 251 title compound were obtained. (0610) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.11 (s, 1H), 8.39 (s, 1H), 8.28 (t, 1H), 8.20 (s, 1H), 7.92 (dd, 1H), 7.85 (dd, 1H), 7.66-7.61 (m, 2H), 7.60-7.49 (m, 3H), 3.89 (s, 3H), 2.43 (s, 3H). (0611) LC/MS (Method 1, ESIpos): Rt=1.32 min, m/z=527/529 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 42 4-[(6,7-Dichloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid (0929) (0930) 100 mg (0.26 mmol) of the compound from example 22A and 44.4 mg (0.26 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> were dissolved in 2 ml of 49 DMF. 73 mg (0.65 mmol) of 153 potassium tert-butoxide were added in portions to the solution. The reaction mixture was stirred at RT for 1 h, and then 1.3 ml (1.3 mmol) of 1 M 196 sodium hydroxide solution were added. The mixture was then stirred at 80 C. for 1 h. After cooling to RT, the mixture, without further workup, was purified by means of preparative HPLC (method 6). After the solvent-water mixture had been removed and the residue had been dried under reduced pressure, 78 mg (59% of theory, 93% purity) of the 468 title compound were obtained. (0931) 1H-NMR (400 MHz, DMSO-d6): [ppm]=13.25 (br. s, 1H), 11.07 (s, 1H), 8.41 (s, 1H), 8.24 (t, 1H), 8.06 (s, 1H), 7.89 (dd, 1H), 7.81 (dd, 1H), 7.69-7.60 (m, 2H), 7.60-7.48 (m, 3H), 2.43 (s, 3H). (0932) LC/MS (Method 1, ESIpos): Rt=1.15 min, m/z=469/471 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Example 68A Methyl 4-([6-bromo-2-(4-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate (0612) (0613) To a solution of 200 mg (0.49 mmol) of the compound from example 26A and 82 mg (0.49 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2 ml of 49 DMF under argon was added 0.73 ml (0.73 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF, and the mixture was stirred at RT for 1 h. Subsequently, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with 20 ml each time of ethyl acetate. The combined organic phases were washed once with 40 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by means of column chromatography (50 g of silica gel, eluent: cyclohexane/ethyl acetate 4:1, Biotage). 193 mg (77% of theory, 100% purity) of the 253 title compound were obtained. (0614) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.08 (s, 1H), 8.27 (t, 1H), 8.05 (d, 1H), 8.00-7.97 (m, 1H), 7.96-7.88 (m, 2H), 7.85 (dd, 1H), 7.73-7.65 (m, 2H), 7.38 (t, 2H), 3.89 (s, 3H), 2.43 (s, 3H). (0615) LC/MS (Method 1, ESIpos): Rt=1.25 min, m/z=511/513 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Example 69A Methyl 4-([6-bromo-2-(3-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate (0616) (0617) To a solution of 170 mg (0.41 mmol) of the compound from example 28A and 70 mg (0.41 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2 ml of 49 DMF under argon was added 0.62 ml (0.62 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF, and the mixture was stirred at RT for 1 h. Subsequently, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with 20 ml each time of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by means of column chromatography (25 g of silica gel, eluent: cyclohexane/ethyl acetate 9:1, Biotage). 108 mg (51% of theory, 100% purity) of the 255 title compound were obtained. (0618) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.09 (s, 1H), 8.27 (t, 1H), 8.06 (d, 1H), 8.01-7.90 (m, 3H), 7.85 (dd, 1H), 7.66-7.55 (m, 1H), 7.51-7.44 (m, 2H), 7.41-7.33 (m, 1H), 3.89 (s, 3H), 2.44 (s, 3H). (0619) LC/MS (Method 1, ESIpos): Rt=1.25 min, m/z=511/513 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Example 70A Methyl 4-([6-bromo-2-(2-fluorophenyl)-3-methylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoate (0620) (0621) To a solution of 200 mg (0.49 mmol) of the compound from example 30A and 82 mg (0.49 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2.4 ml of 49 DMF under argon was added 0.73 ml (0.73 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF, and the mixture was stirred at RT for 1 h. Subsequently, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with 20 ml each time of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was admixed with 4 ml of 204 acetonitrile and the mixture was treated in an ultrasound bath, whereupon there was precipitation of solids. The solids were filtered off, washed with 4 ml of acetonitrile and dried under reduced pressure. 164 mg (63% of theory, 96% purity) of the 257 title compound were obtained. (0622) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.18 (s, 1H), 8.25 (t, 1H), 8.09-8.04 (m, 1H), 8.02 (d, 1H), 7.99-7.94 (m, 1H), 7.91 (dd, 1H), 7.85 (dd, 1H), 7.66-7.57 (m, 1H), 7.57-7.50 (m, 1H), 7.45-7.37 (m, 2H), 3.89 (s, 3H), 2.32 (s, 3H). (0623) LC/MS (Method 3, ESIpos): Rt=1.54 min, m/z=511/513 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Example 79A Methyl 4-[(6-bromo-5-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0654) (0655) To a solution of 357 mg (0.84 mmol) of the compound from example 78A and 156 mg (0.92 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 1.0 ml of 49 DMF under argon was added 0.84 ml (0.84 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF. The mixture was stirred at RT for 2.5 h. Subsequently, another 0.84 ml (0.84 mmol) of a 1 M solution of potassium tert-butoxide in THF was added, and stirring of the mixture was continued at RT overnight. Thereafter, the mixture was admixed with 30 ml of 10% 83 aqueous citric acid solution and 30 ml of 43 water. The precipitate formed was filtered off, washed twice with 10 ml of water and dried under reduced pressure. 289 mg of a 283 product batch were obtained, in which the title compound, by LC/MS analysis, was present in 4% purity (3% of theory). This material was used in subsequent reactions without further purification. (0656) LC/MS (Method 23, ESIpos): Rt=4.16 min, m/z=527/529 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Example 82A Methyl 4-[(6-chloro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0663) (0664) To a solution of 210 mg (0.71 mmol) of 291 6-chloro-3-methyl-2-phenylquinoline-4-carboxylic acid in 5 ml of 49 DMF were added, at RT, 239 mg (1.41 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong>, 402 mg (1.06 mmol) of 292 HATU and 182 mg (1.41 mmol) of 293 N,N-diisopropylethylamine. The mixture was stirred at 60 C. for 1 h. After cooling to RT, the mixture was introduced into 10% 83 aqueous citric acid solution, and the precipitate formed was filtered off, washed three times with water and dried under reduced pressure. The material thus obtained was suspended in 4.5 ml of DMF, 117 mg (0.69 mmol) of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> and 0.94 ml (0.94 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF were added to the suspension at RT, and the mixture was stirred at RT for 30 min. Thereafter, the mixture was introduced into 30 ml of 10% aqueous citric acid solution, and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in a mixture of 294 DMSO, 43 water and 204 acetonitrile and, after some suspended material had been filtered off, purified by means of preparative HPLC (method 19). The combined product-containing fractions were concentrated down to a residual volume of aqueous phase, and the aqueous residue was extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate, filtered and concentrated. The residue was dried under reduced pressure. 78 mg (25% of theory, 100% purity) of the 295 title compound were obtained. (0665) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=11.10 (s, 1H), 8.28 (t, 1H), 8.15-8.07 (m, 1H), 7.91 (d, 1H), 7.88-7.79 (m, 3H), 7.66-7.60 (m, 2H), 7.60-7.49 (m, 3H), 3.89 (s, 3H), 2.43 (s, 3H). (0666) LC/MS (Method 1, ESIpos): Rt=1.19 min, m/z=449 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Example 85A Methyl 4-[(6-tert-butyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0675) (0676) To a solution of 200 mg (0.63 mmol) of the compound from example 84A and 127 mg (0.75 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 5.0 ml of 49 DMF under argon were added 357 mg (0.94 mmol) of 292 HATU and 162 mg (1.25 mmol) of 293 N,N-diisopropylethylamine. The mixture was stirred at 60 C. overnight. Subsequently, another 127 mg (0.51 mmol) of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> were added, and the mixture was stirred at 60 C. for a further 7.5 h and then left to stand at RT for about 80 h. Thereafter, 0.94 ml (0.94 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF was added, and the mixture was stirred for a while and then left to stand at RT for a further night. Another 0.94 ml (0.94 mmol) of a 1 M solution of potassium tert-butoxide in THF was added, and the mixture was first stirred at RT for 8 h and then left to stand at RT for a further night. Thereafter, the mixture was introduced into about 40 ml of 5% 83 aqueous citric acid solution, and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (method 18). The combined product-containing fractions were concentrated, and the residue was taken up in dichloromethane, concentrated again and then dried under reduced pressure. 86 mg (28% of theory, 98% purity) of the 302 title compound were obtained. (0677) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=11.07 (s, 1H), 8.10 (t, 1H), 8.05 (d, 1H), 7.96 (dd, 1H), 7.92 (dd, 1H), 7.87 (dd, 1H), 7.77 (d, 1H), 7.65-7.60 (m, 2H), 7.59-7.49 (m, 3H), 3.89 (s, 3H), 2.42 (s, 3H), 1.38 (s, 9H). (0678) LC/MS (Method 1, ESIpos): Rt=1.28 min, m/z=471 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h; | Example 90A Methyl 3-fluoro-4-([3-methyl-6-(pentafluoro-lambda6-sulfanyl)-2-phenylquinolin-4-yl]carbonyl}amino)benzoate (0695) (0696) 100 mg (0.23 mmol) of the compound from example 89A and 39 mg (0.23 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> were dissolved in 2 ml of 49 DMF. 0.57 ml (0.57 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF was added, and stirring of the mixture was continued at RT for 1 h. This was followed by addition of 61 ethyl acetate and 43 water. The phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated. The residue was stirred in a 84 pentane/45 tert-butyl methyl ether mixture. The solids were filtered off and dried under reduced pressure. 117 mg (87% of theory, 91% purity) of the 315 title compound were obtained. (0697) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=11.17 (s, 1H), 8.35-8.22 (m, 3H), 8.15 (t, 1H), 7.96-7.84 (m, 2H), 7.71-7.63 (m, 2H), 7.63-7.44 (m, 3H), 3.89 (s, 3H), 2.48 (s, 3H). (0698) LC/MS (Method 1, ESIpos): Rt=1.33 min, m/z=541 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 60℃; for 4.5h; | Example 98A Methyl 4-[(6-bromo-3-fluoro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0727) (0728) To a solution of 200 mg (0.58 mmol) of the compound from example 97A in 4.1 ml of 49 DMF were added, at RT, 195 mg (1.16 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong>, 330 mg (0.87 mmol) of 292 HATU and 149 mg (1.16 mmol) of 293 N,N-diisopropylethylamine. The mixture was first stirred at 60 C. for 4.5 h and then left to stand at RT for two days. Thereafter, the mixture was introduced into aqueous 10% 83 aqueous citric acid solution, and extracted twice with 30 ml of ethyl acetate. The combined organic phases were washed once with 60 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was taken up in 3 ml of 294 DMSO and 3 ml of 204 acetonitrile, and purified by means of preparative HPLC (Method 18). 51 mg (16% of theory, 91% purity) of the 341 title compound were obtained. (0729) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.25 (s, 1H), 8.39 (t, 1H), 8.17-8.12 (m, 2H), 8.09-8.03 (m, 2H), 8.00 (dd, 1H), 7.92 (dd, 1H), 7.85 (dd, 1H), 7.65-7.57 (m, 3H), 3.89 (s, 3H). (0730) LC/MS (Method 23, ESIpos): Rt=4.30 min, m/z=497/499 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h; | Example 101A Methyl 4-[(3-chloro-6-iodo-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0737) (0738) To a solution of 110 mg (0.23 mmol) of the compound from example 100A and 61 mg (0.36 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2 ml of 49 DMF was added 0.36 ml (0.36 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF, and the mixture was stirred at RT for 1 h. Subsequently, the mixture was purified directly by means of preparative HPLC (method 24). 46 mg (31% of theory, 90% purity) of the 348 title compound were obtained. (0739) LC/MS (Method 23, ESIpos): Rt=4.26 min, m/z=561 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h; | Example 104A Methyl 4-[(6-bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0746) (0747) To a mixture of 80 mg (0.19 mmol) of the compound from example 103A and 49 mg (0.29 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2 ml of 49 DMF was added 0.29 ml (0.29 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF, and the mixture was stirred at RT for 1 h. Subsequently, the mixture was purified directly by means of preparative HPLC (method 24). 45 mg (38% of theory, 85% purity) of the 354 title compound were obtained. (0748) LC/MS (Method 23, ESIpos): Rt=4.19 min, m/z=513/515 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 106A Methyl 4-[(6-bromo-3-cyclopropyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0754) (0755) To a solution of 400 mg (1.09 mmol) of the compound from example 105A in 6 ml of 49 DMF were added, at RT, 367 mg (2.17 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong>, 620 mg (1.63 mmol) of 292 HATU and 281 mg (2.17 mmol) of 293 N,N-diisopropylethylamine. The mixture was stirred at 60 C. for 5 h. Thereafter, a further 140 mg (1.09 mmol) of N,N-diisopropylethylamine were added, and the mixture was stirred at 60 C. for another 2 h. After cooling to RT, 2.17 ml (2.17 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF were added, and stirring of the mixture was continued at RT for 18 h. Subsequently, another 2.17 ml (2.17 mmol) of a 1 M solution of potassium tert-butoxide in THF were added, and stirring of the mixture was continued at RT for another 2 h. Thereafter, the mixture was introduced into 80 ml of a 10% 83 aqueous citric acid solution, and extracted twice with 50 ml each time of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was taken up in a mixture of 294 DMSO and 43 water, and purified by means of preparative HPLC (method 18). 3.4 mg (0.6% of theory, 100% purity) of a first batch of the title compound and 33 mg (5% of theory, 77% purity) of a second batch of the 362 title compound were obtained. (0756) 1H-NMR (500 MHz, DMSO-d6): [ppm]=11.04 (s, 1H), 8.31 (t, 1H), 8.07-8.03 (m, 2H), 7.96-7.91 (m, 2H), 7.86 (dd, 1H), 7.76 (dd, 2H), 7.56-7.48 (m, 3H), 3.90 (s, 3H), 2.43-2.32 (m, 1H), 0.68 (d, 2H), 0.32 (d, 2H). (0757) LC/MS (Method 1, ESIpos): Rt=1.31 min, m/z=519/521 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 108A Methyl 4-[(6-bromo-3,8-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0762) (0763) To a solution of 500 mg (1.32 mmol, 94% purity) of the compound from example 107A in 9 ml of 49 DMF were added, at RT, 448 mg (2.65 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong>, 755 mg (1.98 mmol) of 292 HATU and 342 mg (2.65 mmol) of 293 N,N-diisopropylethylamine. The mixture was stirred at 60 C. for 2 h. Thereafter, a further 171 mg (1.32 mmol) of N,N-diisopropylethylamine were added, and the mixture was stirred at 60 C. for another 7 h. After cooling to RT, 2.65 ml (2.65 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF were added, and stirring of the mixture was continued at RT for 2 h. Subsequently, another 2.65 ml (2.65 mmol) of a 1 M solution of potassium tert-butoxide in THF were added, and stirring of the mixture was continued at RT for two days. Thereafter, the mixture was introduced into 200 ml of a 10% 83 aqueous citric acid solution. The precipitate formed was filtered off and dried under reduced pressure. 651 mg (78% of theory, 80% purity) of the 367 title compound were obtained. (0764) LC/MS (Method 1, ESIpos): Rt=1.35 min, m/z=507/509 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
810 mg | With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 38A Methyl 4-[(6-bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0496) (0497) 1.00 g (2.55 mmol) of the compound from example 2A were dissolved in 10 ml of 49 DMF. To the solution were added 474 mg (2.80 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> and 429 mg (3.82 mmol) of 153 potassium tert-butoxide. The reaction mixture was stirred at RT for 1 h and then stirred into a mixture of 50 ml of 44 ice-water, 50 ml of 159 ammonium chloride solution and 100 ml of 61 ethyl acetate. The organic phase was removed, washed twice with water and once with saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by means of column chromatography (silica gel, eluent: 5% ethyl acetate/95% cyclohexane?15% ethyl acetate/85% cyclohexane?45% ethyl acetate/55% 160 cyclohexane, Biotage). The product-containing fractions were concentrated and the residue was stirred in 10 ml of 45 tert-butyl methyl ether. The solids were filtered off, washed twice with 5 ml of tert-butyl methyl ether and then stirred in 4 ml of ethyl acetate for three days. The solids were then filtered off again and dried under reduced pressure. 810 mg (64% of theory, 99% purity) of the 161 title compound were obtained. (0498) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=11.10 (s, 1H), 8.27 (t, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.95-7.90 (m, 2H), 7.85 (dd, 1H), 7.64-7.62 (m, 2H), 7.58-7.51 (m, 3H), 3.89 (s, 3H), 2.43 (s, 3H). (0499) LC/MS (Method 1, ESIpos): Rt=1.27 min, m/z=493/495 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Example 54A Methyl 3-fluoro-4-[(6-fluoro-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate (0558) (0559) To a solution of 200 mg (0.60 mmol) of the compound from example 4A and 102 mg (0.60 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2.5 ml of 49 DMF were added, in small portions at RT, 68 mg (0.60 mmol) of 153 potassium tert-butoxide, and the mixture was stirred at RT for 15 min. Subsequently, a further 34 mg (0.31 mmol) of potassium tert-butoxide were added in small portions, and the mixture was stirred at RT for a further 15 min. Thereafter, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of column chromatography (25 g of silica gel, eluent: cyclohexane/ethyl acetate 85:15, Biotage). 198 mg (76% of theory, 100% purity) of the 215 title compound were obtained. (0560) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.07 (s, 1H), 8.28 (t, 1H), 8.17 (dd, 1H), 7.91 (d, 1H), 7.84 (dd, 1H), 7.73 (td, 1H), 7.65-7.59 (m, 2H), 7.59-7.47 (m, 4H), 3.89 (s, 3H), 2.43 (s, 3H). (0561) LC/MS (Method 1, ESIpos): Rt=1.16 min, m/z=433 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 64 4-([6-(Difluoromethyl)-3-methyl-2-phenylquinolin-4-yl]carbonyl}amino)-3-fluorobenzoic acid (1018) (1019) 55 mg (0.18 mmol) of the compound from example 94A were dissolved in 2 ml of 49 DMF under argon, and 57 mg (0.35 mmol) of N,N?-carbonyldiimidazole were added at RT. The reaction mixture was stirred at 60 C. overnight, and then 43 water and 61 ethyl acetate added. The phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was dissolved in 1.55 ml of 124 dichloromethane, and 29.8 mg (0.26 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> were added. Subsequently, 0.44 ml (0.44 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF was added. The reaction mixture was stirred at RT overnight, and then 0.88 ml (0.88 mmol) of a 1 M solution of 329 lithium hydroxide in water was added. The reaction mixture was then stirred at 50 C. for 3 h. The mixture was then cooled to RT, adjusted to pH 1-2 with 4 M hydrochloric acid and, without further workup, purified by means of preparative HPLC (method 6). The product fractions were concentrated and the residue was dried under reduced pressure. In this way, 20 mg (23% of theory, 90% purity) of the 517 title compound were obtained. (1020) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=13.24 (br. s, 1H), 11.08 (s, 1H), 8.35-8.17 (m, 2H), 8.09 (s, 1H), 7.98-7.87 (m, 2H), 7.82 (dd, 1H), 7.67-7.62 (m, 2H), 7.60-7.51 (m, 3H), 7.31 (t, 1H), 2.45 (s, 3H). (1021) LC/MS (Method 1, ESIpos): Rt=1.03 min, m/z=451 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76 mg | Example 30 3-Fluoro-4-[(6-iodo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoic acid (0881) (0882) 100 mg (0.23 mmol) of the compound from example 6A and 39 mg (0.23 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> were dissolved in 1.7 ml of 49 DMF. 64 mg (0.57 mmol) of 153 potassium tert-butoxide were added in portions to the solution. The reaction mixture was stirred at RT for 1 h, and then 1.3 ml (1.3 mmol) of 1 M 196 sodium hydroxide solution were added. The mixture was then stirred at 80 C. for 1 h. After cooling to RT, the mixture, without further workup, was purified by means of preparative HPLC (method 6). After the solvent-water mixture had been removed and the residue had been dried under reduced pressure, 76 mg (62% of theory, 98% purity) of the 444 title compound were obtained. (0883) 1H-NMR (400 MHz, DMSO-d6): [ppm]=13.25 (br. s, 1H), 11.04 (s, 1H), 8.19 (t, 1H), 8.18 (d, 1H), 8.06 (dd, 1H), 7.93-7.84 (m, 2H), 7.82 (dd, 1H), 7.66-7.59 (m, 2H), 7.59-7.47 (m, 3H), 2.42 (s, 3H). (0884) LC/MS (Method 1, ESIpos): Rt=1.07 min, m/z=527 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 55A Methyl 4-[(3,6-dimethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0562) (0563) To a solution of 200 mg (0.61 mmol) of the compound from example 8A and 103 mg (0.61 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2.4 ml of 49 DMF were added, in small portions at RT, 69 mg (0.61 mmol) of 153 potassium tert-butoxide, and the mixture was stirred at RT for 15 min. Subsequently, a further 34 mg (0.30 mmol) of potassium tert-butoxide were added in small portions, and the mixture was stirred at RT for a further 15 min. Thereafter, 21 mg (0.12 mmol) of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> and 14 mg (0.12 mmol) of potassium tert-butoxide were added, and the mixture was stirred at RT for another 30 min. Subsequently, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (Method 5). The combined product-containing fractions were concentrated, and the residue was taken up in dichloromethane, concentrated again and then dried under reduced pressure. 134 mg (47% of theory, 92% purity) of the 217 title compound were obtained. (0564) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.06 (s, 1H), 8.31 (t, 1H), 8.00 (d, 1H), 7.91 (dd, 1H), 7.84 (dd, 1H), 7.67 (dd, 1H), 7.65-7.60 (m, 3H), 7.59-7.48 (m, 3H), 3.89 (s, 3H), 2.41 (s, 3H). (0565) LC/MS (Method 1, ESIpos): Rt=1.16 min, m/z=429 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 56A Methyl 4-[(6-ethyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0566) (0567) To a solution of 200 mg (0.59 mmol) of the compound from example 10A and 99 mg (0.59 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2 ml of 49 DMF were added, in small portions at RT, 66 mg (0.59 mmol) of 153 potassium tert-butoxide, and the mixture was stirred at RT for 15 min. Subsequently, a further 29 mg (0.26 mmol) of potassium tert-butoxide were added in small portions, and the mixture was stirred at RT for a further 15 min. Thereafter, 40 mg (0.12 mmol) of the compound from example 72 10A and 20 mg (0.12 mmol) of <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> were added, and the mixture was stirred at RT for another 30 min. Subsequently, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (Method 5). The combined product-containing fractions were concentrated, and the residue was taken up in dichloromethane, concentrated again and then dried under reduced pressure. 195 mg (69% of theory, 91% purity) of the 219 title compound were obtained. (0568) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.06 (s, 1H), 8.26 (t, 1H), 8.03 (d, 1H), 7.92 (dd, 1H), 7.85 (dd, 1H), 7.72 (dd, 1H), 7.66-7.60 (m, 3H), 7.59-7.48 (m, 3H), 3.92-3.87 (m, 3H), 2.84 (q, 2H), 2.41 (s, 3H), 1.26 (t, 3H). (0569) LC/MS (Method 1, ESIpos): Rt=1.25 min, m/z=443 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
108 mg | Example 57A Methyl 3-fluoro-4-[(6-isopropyl-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}benzoate (0570) (0571) To 670 mg (2.19 mmol) of the compound from example 75 11A were added 3 ml of 124 dichloromethane and then 0.46 ml (3.51 mmol) of 144 1-chloro-N,N,2-trimethylprop-1-en-1-amine. The mixture was stirred at RT for 30 min, and then 0.53 ml (6.55 mmol) of 145 pyridine and 371 mg (2.19 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> were added. The reaction mixture was stirred at 60 C. for 10 h. After cooling down to RT, the solvent was removed under reduced pressure, and the residue was purified by means of preparative HPLC (method 8) without further workup. 108 mg (10% of theory, 96% purity) of the 221 title compound were obtained. (0572) LC/MS (Method 1, ESIpos): Rt=1.32 min, m/z=457 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 58A Methyl 3-fluoro-4-([3-methyl-2-phenyl-6-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)benzoate (0573) (0574) To 300 mg (0.91 mmol) of the compound from example 78 12A were added 2 ml of 124 dichloromethane and then 0.19 ml (1.45 mmol) of 144 1-chloro-N,N,2-trimethylprop-1-en-1-amine. The mixture was stirred at RT for 30 min, and then 0.22 ml (2.72 mmol) of 145 pyridine and 153 mg (0.91 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> were added. The reaction mixture was stirred at 60 C. for 4 h. After cooling down to RT, the solvent was removed under reduced pressure, and the residue was purified by means of preparative HPLC (method 7) without further workup. 105 mg (20% of theory, 83% purity) of the 223 title compound were obtained. (0575) LC/MS (Method 1, ESIpos): Rt=0.91 min, m/z=483 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Example 59A Methyl 3-fluoro-4-([3-methyl-2-phenyl-6-(trifluoromethoxy)quinolin-4-yl]carbonyl}amino)benzoate (0576) (0577) To a solution of 200 mg (0.50 mmol) of the compound from example 14A and 85 mg (0.50 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2 ml of 49 DMF were added, in small portions at RT, 56 mg (0.50 mmol) of 153 potassium tert-butoxide, and the mixture was stirred at RT for 15 min. Subsequently, a further 28 mg (0.26 mmol) of potassium tert-butoxide were added in small portions, and the mixture was stirred at RT for a further 15 min. Thereafter, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of column chromatography (25 g of silica gel, eluent: cyclohexane/ethyl acetate 85:15, Biotage). The combined product-containing fractions were concentrated, and the residue was taken up in dichloromethane, concentrated again and then dried under reduced pressure. 166 mg (60% of theory, 91% purity) of the 225 title compound were obtained. (0578) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.11 (s, 1H), 8.27-8.17 (m, 2H), 7.92 (dd, 1H), 7.86 (dd, 1H), 7.82 (dd, 1H), 7.75-7.73 (m, 1H), 7.66-7.61 (m, 2H), 7.60-7.44 (m, 4H), 6.77 (t, 1H), 3.89 (s, 3H), 2.45 (s, 3H). (0579) LC/MS (Method 1, ESIpos): Rt=1.26 min, m/z=499 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Example 65A Methyl 4-[(6-bromo-3-ethyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0600) (0601) To a solution of 238 mg (0.59 mmol) of the compound from example 16A and 99 mg (0.59 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2.3 ml of 49 DMF under argon was added 0.88 ml (0.88 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF, and the mixture was stirred at RT for 1 h. Subsequently, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with 20 ml each time of ethyl acetate. The combined organic phases were washed once with 40 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by means of column chromatography (50 g of silica gel, eluent: cyclohexane/ethyl acetate 4:1, Biotage). 206 mg (69% of theory, 100% purity) of the 247 title compound were obtained. (0602) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.13 (s, 1H), 8.22 (t, 1H), 8.06-7.89 (m, 4H), 7.85 (dd, 1H), 7.60-7.49 (m, 5H), 3.89 (s, 3H), 2.91-2.76 (m, 2H), 0.98 (t, 3H). (0603) LC/MS (Method 1, ESIpos): Rt=1.27 min, m/z=507/509 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Example 66A Methyl 4-[(6-bromo-2-phenyl-3-propylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoate (0604) (0605) To a solution of 170 mg (0.40 mmol) of the compound from example 18A and 68 mg (0.40 mmol) of 158 <strong>[185629-32-7]methyl 4-amino-3-fluorobenzoate</strong> in 2 ml of 49 DMF under argon was added 0.61 ml (0.61 mmol) of a 1 M solution of 153 potassium tert-butoxide in 163 THF, and the mixture was stirred at RT for 1 h. Subsequently, the mixture was admixed with 4 ml of a 10% 83 aqueous citric acid solution, diluted with water and extracted twice with 20 ml each time of ethyl acetate. The combined organic phases were washed once with 40 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by means of column chromatography (25 g of silica gel, eluent: cyclohexane/ethyl acetate 9:1, Biotage). 151 mg (72% of theory, 100% purity) of the 249 title compound were obtained. (0606) 1H-NMR (400 MHz, DMSO-d6): [ppm]=11.11 (s, 1H), 8.18 (t, 1H), 8.03 (d, 1H), 7.99 (d, 1H), 7.97-7.90 (m, 2H), 7.86 (dd, 1H), 7.59-7.50 (m, 5H), 3.89 (s, 3H), 2.79 (t, 2H), 1.47-1.30 (m, 2H), 0.67 (t, 3H). (0607) LC/MS (Method 1, ESIpos): Rt=1.31 min, m/z=521/523 [M+H]+. |
Tags: 185629-32-7 synthesis path| 185629-32-7 SDS| 185629-32-7 COA| 185629-32-7 purity| 185629-32-7 application| 185629-32-7 NMR| 185629-32-7 COA| 185629-32-7 structure
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P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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