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CAS No. : | 59025-55-7 | MDL No. : | MFCD00001997 |
Formula : | C7H3F2NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HNENEALJPWJWJY-UHFFFAOYSA-N |
M.W : | 155.10 | Pubchem ID : | 593258 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 34.14 |
TPSA : | 29.43 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) : | -5.17 cm/s |
Log Po/w (iLOGP) : | 1.96 |
Log Po/w (XLOGP3) : | 2.92 |
Log Po/w (WLOGP) : | 2.77 |
Log Po/w (MLOGP) : | 2.38 |
Log Po/w (SILICOS-IT) : | 2.85 |
Consensus Log Po/w : | 2.58 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.98 |
Solubility : | 0.163 mg/ml ; 0.00105 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.2 |
Solubility : | 0.098 mg/ml ; 0.000632 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.93 |
Solubility : | 0.181 mg/ml ; 0.00116 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.69 |
Signal Word: | Danger | Class: | 3,6.1 |
Precautionary Statements: | P261-P270-P240-P210-P233-P243-P241-P242-P271-P264-P280-P284-P370+P378-P342+P311-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P301+P310+P330-P304+P340+P311-P403+P233-P403+P235-P405-P501 | UN#: | 2478 |
Hazard Statements: | H226-H301+H331-H315-H319-H334-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
96.9% | at 12.9 - 19℃; for 4.91667 h; | Example 5; N-(2,4-Difluorophenyl)-N'-(4-methoxy-3-(4'-bromo-I '-methyl-lH-pyrazol-5'- yl) phenyl)urea (8); Both portions of 5-(2' -methoxy-5' -aminophenyl)-4-bromo-l-methyl-IH-pyrazole (2) from the previous example were combined by dissolution in toluene (15 L) at 27.6° C, suction filtration of the resulting solution, and rotary evaporation of the filtrate at <50° C and 10 mm HgA to a constant weight of 1127.0 g. A solution of 7 (1102.0 g of the 1127.0 g evaporation residue) in toluene (11.02 L) was stirred and refluxed at atmospheric pressure through a Dean-Stark trap under nitrogen. to remove 0.8 mL of water. After the condensate had become completely clear with no further accumulation of water in the Dean-Stark trap, the toluene solution was cooled under nitrogen to 12.9° C. To the resulting solution stirred under nitrogen was added 2,4- difluorophenyl isocyanate (617.9 g) by addition funnel over 40 minutes at a rate sufficiently slow to enable the reaction mixture to be maintained at 12.9-19° C with reactor jacket cooling. Solid started to precipitate in the reaction mixture about half way through the addition. After the addition had been completed, the reaction slurry continued to be stirred at 16° C under nitrogen. Conversion of 7 to 8 was 90percent, 91.2percent, and 92.6percent five, 60, and. 120 minutes, respectively, after the addition had been completed. Three hours after the addition had been completed, a second portion of 2,4-difluorophenyl isocyanate (24.4 g) was added, and, after continued stirring of the reaction mixture at 16° C under nitrogen for an additional 30 minutes, conversion of 7 to 8 was 94percent. One hour after the second addition, a third portion of 2,4-difluorophenyl isocyanate (9.7 g) was added, and, after continued stirring of the reaction mixture at 16° C under nitrogen for an additional 15 minutes, conversion of 7 to 8 was 95percent. The reaction mixture was then stirred at 20° C under nitrogen for an'additional 14.75 hours, after which conversion of 7 to 8 was 100percent. The reaction mixture was suction filtered, and the filtered solid was washed with 2.6° C toluene (2 x 1100 mL) and dried at 100° C and pressures falling to 1 mm HgA to provide 8 (1654.9 g, 96.9 percent yield) of 98.2 percent purity by HPLC with ca. 0.9 mole percent desbromo 8 as the largest impurity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.94% | at -5 - 70℃; for 11 h; Large scale | To a solution of 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine (16.7 kg) in acetonitrile (78.6 kg) in a 200 L-glass jacketed reactor with overhead stirring and nitrogen blanket at an internal temperature of <−10° C. 2,4-difluorophenyl-isocyanate (9.68 kg) was controlled charged through a 1 micron line filter at a rate substantially slow enough to prevent co-precipitation of the starting material in the product. After continued stirring at <−10° C. for approximately 1 hour post completion of the 2,4-difluorophenyl-isocyanate addition, the conversion of starting material to product was substantially complete. The product slurry was filtered and washed with cold acetonitrlie (26.3 kg) at <−5° C. producing the acetonitrile solvate of the product. Full house vacuum (30 in Hg ) was applied to the bottom outlet filter/dryer while nitrogen flowed through from the top enhancing the removal of volatile solvents without application of heat. Samples were removed from the bulk material and LOD was determined using an IR-200 Moisture Analyzer Instrument (Denver Instrument Company). The time course is shown below: |
92.9% | at -10℃; for 1 h; Inert atmosphere | To a solution of 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamme (16.7 kg) in acetonitπle (78.6 kg) m a 200 L glass jacketed reactor with overhead stirring and nitrogen blanket at an internal temperature of < -10 0C 2,4-difluorophenyl-isocyanate (9.68 kg) was controlled charged through a 1 micron line filter at a rate substantially slow enough to prevent co-precipitation of the starting material in the product. After continued stirring at < -10 0C for approximately 1 hour post completion of the 2,4-difluorophenyl-isocyanate addition, the conversion of starting material to product was substantially complete. The product slurry was filtered and washed with cold acetonitπle (26.3 kg) at < -5 0C producing the acetomtπle solvate of the product. Full house vacuum (~30 in Hg ) was applied to the bottom outlet filter/dryer while nitrogen flowed through from the top enhancing the removal of volatile solvents without application of heat. Samples were removed from the bulk material and LOD was determined using an IR-200 Moisture Analyzer Instrument (Denver Instrument Company). The time course is shown below:Drying of the "wetcake" was maintained at ambient temperature under full house vacuum (-30 in Hg ) for about 19.5 h at which time the LOD was 7.28percent. At this point, the temperature was raised to 70 °C under full house vacuum (-30 in Hg ) for 11 hrs to afford l-[3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (24.2 kg, 99.94percent ΗPLC purity, form I determined by PXRD, and 92.9percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | In tetrahydrofuran Ambient temperature; | |
77.8% | In tetrahydrofuran | 1 EXAMPLE 1 EXAMPLE 1 2,4-Difluorophenyl isocyanate (0.24 ml) was added to a solution of 3-amino-6-chloro-4-phenylquinoline (509 mg) in anhydrous tetrahydrofuran (8 ml), and the mixture was allowed to stand at room temperature for 20 hrs. The precipitated crystals were collected by filtration. The filtrate was concentrated and the precipitated crystals were collected by filtration. Thus obtained crystals were combined and recrystallized from ethanol to give 6-chloro-3-[3-(2,4-difluorophenyl)ureido]-4-phenylquinoline as colorless crystals (638 mg, 77.8 %). m.p. 206°14 207° C. Elemental analysis for C22 H14 ClF2 N3 O: Calculated: C, 64.48; H, 3.44; N, 10.25. Found C, 64.23; H, 3.55; N, 10.04. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In dichloromethane for 1h; | |
97% | In dichloromethane at 0℃; for 1h; | |
50% | In dichloromethane at 0℃; for 1h; |
With potassium carbonate Heating; | ||
In dichloromethane | 1.C Preparation of N'-(2,4-difluorophenyl)-N-heptyl-N-[5-(6-nitro-1H-benzimidazol-2-ylthio)pentyl]urea Part C. To a solution of N-(5-hydroxypentyl)-N-heptylamine (11.65 g, 0.0578 mol) in methylene chloride (75 mL) under a nitrogen atmosphere cooled to 0°, 2,4-difluorophenylisocyanate (8.97 g, 0.0578 mol) was added slowly. The reaction mixture was stirred for 1 hour, poured into 1 N aqueous HCl (200 mL) and was extracted with ethyl acetate (300 mL). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated to give N'-(2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea as a pale yellow oil (20.0 g, 0.056 mol). 1 H NMR (CDCl3) δ8.03 (m,1H), 6.88-6.59 (m,2H), 6.45 (bs,1H), 3.68 (t,2H,J=6.7 Hz). | |
In dichloromethane | 1.C Preparation of N'-(2,4-difluorophenyl)-N-heptyl)-N-[5-(9H-purin-6-ylthio)pentyl]urea Part C. To a solution of N-(5-hydroxypentyl)-N-heptylamine (11.65 g, 0.0578 mol) in methylene chloride (75 mL) under a nitrogen atmosphere cooled to 0°, 2,4-difluorophenylisocyanate (8.97 g, 0. 0578 mol) was added slowly. The reaction mixture was stirred for 1 hour, poured into 1 N aqueous HCl (200 mL) and extracted with ethyl acetate (300 mL). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and was concentrated to give N'-{2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea as a pale yellow oil (20.0 g, 0.056 mol). 1 H NMR (CDCl3) δ8.03 (m, 1H), 6.88-6.59 (m, 2H), 6.45 (bs, 1H), 3.68 (t, 2H, J=8.4 Hz), 3.33 (m, 4H), 1.81-1.22 (m, 16H), 0.91 (t,3H, J=6.7 Hz). | |
In dichloromethane | 118.C Preparation of N-[5-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]-pentyl]-N'-(2,4-difluorophenyl)-N-heptylurea Part C. To a solution of N-(5-hydroxypentyl)-N-heptylamine (11.65 g, 0.0578 mol) in methylene chloride (75 mL) under a nitrogen atmosphere cooled to 0°, 2,4-difluorophenylisocyanate (8.97 g, 0.0578 mol) was added slowly. The reaction mixture was stirred for 1 hour, poured into 1N aqueous HCl (200 mL) and was extracted with ethyl acetate (300 mL). The combined organic layer was washed with water, brine, dried over magnesium sulfate and was concentrated to give N'-(2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea as a pale yellow oil (20.0 g, 0.056 mol). 1 H NMR (CDCl3) δ8.03(m,1H), 6.88-6.59(m,2H), 6.45(bs,1H), 3.68(t,2H), 3.33(m,4H), 1.81-1.22(m,16H), 0.907(t,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | In toluene;Inert atmosphere; | General procedure: To a solution of compounds (4a-4h) (0.82 mM, 1 eq) in drytoluene (10 ml), the required isocyanates (1.60 mM, 2.0 eq) wereadded under nitrogen. The reaction mixture was stirred at roomtemperature for 4-5 h and monitored by TLC. The solid precipitateso obtained was filtered and washed with toluene to remove theexcess isocyanate, dried and collected the products (5a-5z?) as such. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In toluene for 0.5h; Heating; | |
84% | In toluene | 236 N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [272] Example 236 N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea [272] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) was dissolved in toluene (10 ml) with heat, 2,4-difluorophenyl isocyanate (120 μl) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 128 mg of the title compound (yield: 84%). 1 H-NMR (DMSO-d6, 500 MHz): δ 3.94 (s, 3H), 3.95 (s, 3H), 6.46 (d, J=4.9Hz, 1H), 7.03~7.10 (m, 1H), 7.22 (d, J=9.2Hz, 2H), 7.28~7.35 (m, 1H), 7.39 (s, 1H), 7.52 (s, 1H), 7.59 (d, J=9.2Hz, 2H) 8.05~8.12 (m, 1H) 8.47 (d, J=5.5Hz, 1H), 8.52 (s, 1H), 9.15 (s, 1H) Mass spectrometry data (FD-MS, m/z) 451 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine; 2,4-diflurophenylisocyanate In N,N-dimethyl acetamide at 20℃; Stage #2: With sodium hydroxide In water | 1.78 To a solution of 3-(4-Bromo-2-methyl-2H-pyrazol-3-y])-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.96 g, 2.47 mmol) in 10 mL of DMA was added 2,4-difluoro phenyl isocyanate (0.42 g, 2.71 mmol), and the mixture was stirred at ambient temperature overnight The reaction mixture was diluted with DMSO and was purified by RP-HPLC. The fractions containing the product were pooled and evaporated to a small volume. The aqueous solution was neutralized with 1N NaOH to a pH of 9.0 and the product was extracted with ethyl acetate (2×, 50 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to produce 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-3-(2,4-difluoro-phenyl)-urea as a colorless solid in 59% yield. LCMS m/z (%)=520 (M+H 79Br, 100), 522 (M+H 81Br, 98). 1H NMR (400Mz DMSO-d6) δ: 9.03 (bs, 1H), 8.49 (bs, 1H), 8.01-8.1 (m, 1H), 7.61 (s, 1H), 7.51 (dd, J=8.96 and 2.73 Hz, 1H), 7.35 (d, J=2.72 Hz, 1H), 7.27-7.33 (m, 1H), 7.15 (d, J=9.04 Hz, 1H), 7.04-7.09 (m, 1H), 4.01-4.11 (m, 2H), 3.67 (s, 3H), 2.51-2.73 (m, 2H), 2.34-2.38 (bs, 4H), 1.59-1.63 (bs, 4H). |
In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In dichloromethane at 20℃; | 1.80 To a solution of 4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.08 g, 0.256 mmol) in 2.0 mL of dichloromethane was addded 2,4-difluoro phenyl isocyanate (0.042 g, 0.280 mmol), and the mixture was stirred at ambient temperature overnight. The DCM was evaporated from the reaction mixture, the crude residue was dissolved in 5.0 mL of DMSO and purified by RP-HPLC. The proper fractions were collected and lyophilized to afford the 1-(2,4fluoro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea as an off-white solid in 75% yield. LCMS m/z (%)=439 (M+H). 1H NMR (400 MHz, Acetone-d6) δ: 8.46 (bs, 1H), 7.96-8.02 (m, 1H), 7.48 (dd, J=8.9 and 2.72 Hz, 1H), 7.39-7.41 (m, 2H), 7.31 (d, J=1.81 Hz, 1H), 7.17 (t, J=1.42 Hz, 1H), 6.94 (d, J=8.94 Hz, 1H), 6.7-6.8 (m, 2H), 6.01 (d, J=1.78 Hz, 1H), 4.62 (t, J=4.74 Hz, 2H), 4.33 (t, J=5.07 Hz, 2H), 3.48 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With PS-DIEA In dichloromethane at 20℃; | 7.a Example 7; a) Methyl 2-({4-[2-([(2,4-difluorophenyl)amino]carbonyl}amino)ethyl]phenoxy}methyl)benzoate 2, 4-Difluorophenyl isocyanate (26.5 mg, 0.171 mmol) and methyl [2-{ [4-(2-] aminoethyl) phenoxy] methyl} benzoate hydrochloride (55 mg, 0.171 mmol) were mixed in DCM (4 ml). [PS-DEA] (3. 66mmol/g, 140 mg, 0.512 mmol) was added. The mixture was shaken at room temperature overnight. White precipitates were falling out. The mixture was evaporated to dry. The residue (with addition of DCM, a suspension) was loaded on a column [(ISOLUTE (E)] SI, [2G/6ML)] and eluted with DCM and then MeOH/DCM (1: 99). White solid product 51 mg was obtained, yield 68%. 1H NMR (400 MHz, DMSO-d6): 8 2.65 (t, 2H), 3.26-3. 31 [(M,] 2H), 3.79 (s, 3H), 5.36 (s, 2H), 6.49 (t, 1H), 6.88-6. 97 [(M,] 3H, 7.12-7. 22 [(M,] 3H), 7.44 (t, 1H), 7. [58-7. 65 (M,] 2H), 7.88 (d, [1H),] 8.01-8. 07 [(M,] 1H) and 8.23 (s, br, [1H).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In dichloromethane at 20℃; for 18.1667h; | 1.164.4 To a solution of 1-(5-amino-2-methoxy-phenyl)-3-diethylamino-propenone (1.78g, 7.18 mmole) in methylene chloride (60 ml) was added a solution of 2, 4-difluorophenyl isocyanate (1.34g, 8.62 mmole) in methylene chloride (10 ml) over a period of 10 minutes. The reaction mixture was stirred at ambient temperature for 18 hrs. The solvent was evaporated and the resulting solid was purified on silica (Biotage) using DCM to 30% ethyl acetate in DCM as eluant. The fractions containing the product were evaporated in vacuo to furnish a yellow solid (2.7g, 96%). LCMS m/z (%) = 404 (M+H, 100),1H NMR (Bruker, 400 MHz, DMSO-d,sub>6) δ: 8.91 (bs, 1H), 8.41 (bs, 1H), 8.06-8.12 (m, 1H), 7.46-7.48 (d, J= 8.68 Hz 1H), 7.42 (bs, 1H), 7.29-7.35 (m, 1H), 7.01-7.08 (m, 2H), 5.5 (bs, 1H), 3.78 (s, 3H), 3.27 (bs, 4H), 1.13-1.2 (t, J= 7. 01 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | In toluene; at 12.9 - 19℃; for 4.91667h; | Example 5; N-(2,4-Difluorophenyl)-N'-(4-methoxy-3-(4'-bromo-I '-methyl-lH-pyrazol-5'- yl) phenyl)urea (8); Both portions of 5-(2' -methoxy-5' -aminophenyl)-4-bromo-l-methyl-IH-pyrazole (2) from the previous example were combined by dissolution in toluene (15 L) at 27.6 C, suction filtration of the resulting solution, and rotary evaporation of the filtrate at <50 C and 10 mm HgA to a constant weight of 1127.0 g. A solution of 7 (1102.0 g of the 1127.0 g evaporation residue) in toluene (11.02 L) was stirred and refluxed at atmospheric pressure through a Dean-Stark trap under nitrogen. to remove 0.8 mL of water. After the condensate had become completely clear with no further accumulation of water in the Dean-Stark trap, the toluene solution was cooled under nitrogen to 12.9 C. To the resulting solution stirred under nitrogen was added 2,4- difluorophenyl isocyanate (617.9 g) by addition funnel over 40 minutes at a rate sufficiently slow to enable the reaction mixture to be maintained at 12.9-19 C with reactor jacket cooling. Solid started to precipitate in the reaction mixture about half way through the addition. After the addition had been completed, the reaction slurry continued to be stirred at 16 C under nitrogen. Conversion of 7 to 8 was 90%, 91.2%, and 92.6% five, 60, and. 120 minutes, respectively, after the addition had been completed. Three hours after the addition had been completed, a second portion of 2,4-difluorophenyl isocyanate (24.4 g) was added, and, after continued stirring of the reaction mixture at 16 C under nitrogen for an additional 30 minutes, conversion of 7 to 8 was 94%. One hour after the second addition, a third portion of 2,4-difluorophenyl isocyanate (9.7 g) was added, and, after continued stirring of the reaction mixture at 16 C under nitrogen for an additional 15 minutes, conversion of 7 to 8 was 95%. The reaction mixture was then stirred at 20 C under nitrogen for an'additional 14.75 hours, after which conversion of 7 to 8 was 100%. The reaction mixture was suction filtered, and the filtered solid was washed with 2.6 C toluene (2 x 1100 mL) and dried at 100 C and pressures falling to 1 mm HgA to provide 8 (1654.9 g, 96.9 % yield) of 98.2 % purity by HPLC with ca. 0.9 mole % desbromo 8 as the largest impurity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 8h; | 24.C Step C: tert-Butyl ((1S, 2S)-2-[4-([(2,4- difluorophenyl)amino lcarbonyl1amino )cyclohexyll-1-f f(3S)-3-fluoropyrrolidin- 1-yl] carbonyl}propyl)carbamate; To a solution of the material prepared in Step B (0.020 g, 0.054 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.019 mL, 0.11 mmol) and 2,6- difluorophenylisocyanate (0.010 mL, 0.081 mmol). After 8 h at ambient temperature the reaction was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by reverse phase HPLC (32% - 70% acetonitrile in water) afforded the title compound as a while solid. LC/MS 427.2 (M+1-Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In toluene at 60℃; for 14h; | 55 1,1-Dicyclohexyl-N-(2,4-difluorophenyl)-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide 1,1-Dicyclohexyl-N-(2,4-difluorophenyl)-tetrahydro-3-oxo-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide 1,1-Dicyclohexyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.13 g, 0.42 mmol) was dissolved in toluene (1.5 mL). 2,4-Difluorophenyl isocyanate (0.10 g, 0.64 mmol) was added thereto, and the mixture was stirred at 60°C for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane: ethyl acetate = 3: 2) and crystallized from hexane to obtain the title compound (0.12 g, yield 59%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In tetrahydrofuran at 0℃; for 1h; | 168 To a solution of 1,1-bis(4-methylphenyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.62 mmol) in tetrahydrofuran (6 mL) was added 2,4-difluorophenyl isocyanate (0.090 mL, 0.76 mmol) at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane : ethyl acetate = 98 : 2 to hexane : ethyl acetate = 1 : 1), and then recrystallized from diisopropyl ether to obtain the title compound (0.20 g, yield 68%). Melting point 120-122°C. 1H NMR (CDCl3) δ 2.28 (1H, dd, J=11.4 Hz, 13.4 Hz), 2.32 (3H, s), 2.34 (3H, s), 2.98-3.21 (2H, m), 3.81-3.85 (1H, m), 3.90-4.01 (2H, m), 4.44 (1H, dd, J=3.6 Hz, 11.3 Hz), 6.38-6.39 (1H, m), 6.82-6.89 (2H, m), 7.13-7.21 (6H, m), 7.38 (2H, d, J=8.3 Hz), 7.84-7.92 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide (34.7 g, 0.1 mol) in methanol (347 mL) was added acetyl chloride (3 molar equivalents, 23 mL, 0.32 mol) at O0C and the solution was stirred at 450C for 24h. Formation of 3-(4-bromo-2-methyl- 2H-pyrazol-3-yl)-4-methoxy-phenylamine and consumption of N-[3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenyl]-acetamide were monitored by LCMS. The volatiles were removed, and the resulting residue was dissolved back in methanol (350 mL). Diisopropylethylamine (DIEA) (3 molar equivalents, 56.1 mL, 0.32 mol) was added at room temperature, and, after 0.5h isocyanate (1.1 molar equivalents, 12.73 mL, 0.101 mol) was then introduced at room temperature. Formation of l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and consumption of 3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenylamine were monitored by LCMS, and, after 3 hr, the mixture was heated to 8O0C and diluted using water (70 mL). The white solid product was filtered, washed using water (70 mL), and dried to provide l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-3-(2,4-difluoro-phenyl)-urea (32.46 g, 74.28 mmol, 69% yield). Example 5: Preparation of l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (2,4-difluoro-phenyl)-urea from N- [4-methoxy-3-(2-methyl-2H-pyrazoI-3-yl)-phenyl] - acetaniide:To a mixture of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (1 g, 4.08 mmol) in methanol (5 mL) was added NuBS (1.2 molar equivalent, 871 mg, 4.9 mmol) and the resulting mixture was stirred at room temperature for 2h. Formation of N-[3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxy-rhohenyl]-acetamide and consumption of N-[4-methoxy-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-acetamide were monitored by LCMS. The crude mixture was cooled to O0C, and acetyl chloride (6 molar equivalents, 1.32 mL, 24.28 mmol) was added. The resulting mixture was stirred at 450C for 24h while formation of 3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenylamine and consumption of N-[3-(4-bromo-2-methyl-2H-pyrazol- EPO <DP n="40"/>3-yl)-4-methoxy-phenyl]-acetamide were monitored by LCMS. The volatiles were removed, and the resulting residue was dissolved back in methanol (5mL). DIEA (3 molar equivalents, 2.13 mL, 12.24 mmol) was added at room temperature and after 0.5h, isocyanate (1.1 molar equivalents, 0.53 mL, 4.49 mmol) was then introduced at room temperature. Formation of l-[3- (4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and consumption of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine were monitored by LCMS, and, after 3 hr, the mixture was diluted using water (2mL). The white solid product was filtered, washed using water (10 mL), and dried to provide l-[3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (1.55 g, 3.43 mmol, 84% yield). |
Yield | Reaction Conditions | Operation in experiment |
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52% | Stage #1: 6-bromo-3-isopropyl[1,2,4]triazolo[4,3-a]pyridine hydrochloride With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at 0℃; for 1h; Stage #2: 2,4-diflurophenylisocyanate In tetrahydrofuran; diethyl ether at 0 - 20℃; for 2.33333h; | 11 A suspension of 6-bromo-3-isopropyl[1 ,2,4]triazolo[4,3-a]pyridine hydrochloride (2.00 g, 7.23 mmol) in THF (18 ml_) was cooled to 0 0C and treated with isopropylmagnesium chloride in diethyl ether (2.0 M THF solution, 7.5 mL, 15.0 mmol). The internal temperature of the reaction was not allowed to exceed 0 0C. The resulting dark solution was allowed to stir for 1 hour and then the reaction was treated with 2,4-difluorophenyl isocyanate (neat oil 1.00 g, 10.3 mmol). The cooling bath was removed and the reaction was allowed to warm to room temperature (approximately 20 minutes) on its own accord and was stirred for an additional 2 hours. At this time, the reaction was quenched with saturated ammonium chloride solution and brine (100 and 300 mL, respectively), and was extracted with ethyl acetate (3 X 250 mL). The resulting organic extracts were Na2SO4 dried, filtered, and concentrated in vacuo to a residue that was recrystalized from boiling ethyl acetate (3 to 5 mL volume). The resulting solid was collected and in vacuo dried to provide a solid (1.20 g, 52 %). 1H NMR (400 MHz, O4-MeOH) δ 9.00 (s, 1H), 7.88 (app dd, J = 9.2, 1.0 Hz, 1 H), 7.85 (app , J= 9.2 Hz, 1 H), 7.71 (app q, J = 6.2 Hz, 1 H)1 7.08 (dt, J = 9.0, 2.5 Hz, 1 H), 7.01 (app t, J = 6.5, 1 H), 3.61 (septet, J = 6.5 Hz, 1 H), 1.50 (d, J = 6.8 Hz1 6H); LC/MS C-18 column, tr = 1.82 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50 0C). ES-MS m/z317 (M+H). ES-HRMS m/z 317.1224 (M+H calcd for Ci6H15F2N4O requires 317.1208). |
52% | Stage #1: 6-bromo-3-isopropyl[1,2,4]triazolo[4,3-a]pyridine hydrochloride With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at 0℃; for 1h; Stage #2: 2,4-diflurophenylisocyanate In tetrahydrofuran; diethyl ether at 20℃; for 2.33333h; Neat (no solvent); Stage #3: With ammonium chloride In tetrahydrofuran; diethyl ether; water | 11 A suspension of 6-bromo-3-isopropyl[1,2,4]triazolo[4,3-a]pyridine hydrochloride(2.00 g, 7.23 mmol) in THF (18 ml) was cooled to 0 °C and treated with isopropylmagnesiumchloride in diethyl ether (2.0 M THF solution, 7.5 mL, 15.0 mmol). The internal temperature of thereaction was not allowed to exceed 0 °C. The resulting dark solution was allowed to stir for 1hour and then the reaction was treated with 2,4-difluorophenyl isocyanate (neat oil 1.00 g, 10.3mmol). The cooling bath was removed and the reaction was allowed to warm to roomtemperature (approximately 20 minutes) on its own accord and was stirred for an additional 2hours. At this time, the reaction was quenched with saturated ammonium chloride solution andbrine (100 and 300 mL, respectively), and was extracted with ethyl acetate (3 X 250 mL). Theresulting organic extracts were Na2SO4 dried, filtered, and concentrated in vacuoto a residue thatwas recrystalized from boiling ethyl acetate (3 to 5 mL volume). The resulting solid was collectedand in vacua dried to provide a solid (1.20 g, 52 %). 1H NMR (400 MHz, d4-MeOH) 5 9.00 (s, 1H),7.88 (appdd, J= 9.2,1.0 Hz, 1H), 7.85 (appd, J= 9.2 Hz, 1H), 7.71 (appq, J= 6.2 Hz, 1H),7.08 (dt, J= 9.0, 2.5 Hz, 1H), 7.01 (appt, J= 6.5, 1H), 3.61 (septet, J= 6.5 Hz, 1H), 1.50 (d, J =6.8 Hz, 6H); LC/MS C-18 column, tr = 1.82 minutes (5 to 95% acetonitrile/water over 5 minutes at1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z317 (M+H). ES-HRMS m/z317.1224(M+H caicd for C-ieH^Fa^O requires 317.1208). |
Yield | Reaction Conditions | Operation in experiment |
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99.94% | In acetonitrile; at -5 - 70℃; for 11h;Large scale; | To a solution of 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine (16.7 kg) in acetonitrile (78.6 kg) in a 200 L-glass jacketed reactor with overhead stirring and nitrogen blanket at an internal temperature of <-10 C. 2,4-difluorophenyl-isocyanate (9.68 kg) was controlled charged through a 1 micron line filter at a rate substantially slow enough to prevent co-precipitation of the starting material in the product. After continued stirring at <-10 C. for approximately 1 hour post completion of the 2,4-difluorophenyl-isocyanate addition, the conversion of starting material to product was substantially complete. The product slurry was filtered and washed with cold acetonitrlie (26.3 kg) at <-5 C. producing the acetonitrile solvate of the product. Full house vacuum (30 in Hg ) was applied to the bottom outlet filter/dryer while nitrogen flowed through from the top enhancing the removal of volatile solvents without application of heat. Samples were removed from the bulk material and LOD was determined using an IR-200 Moisture Analyzer Instrument (Denver Instrument Company). The time course is shown below: |
92.9% | In acetonitrile; at -10℃; for 1h;Inert atmosphere; | To a solution of 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamme (16.7 kg) in acetonit?le (78.6 kg) m a 200 L glass jacketed reactor with overhead stirring and nitrogen blanket at an internal temperature of < -10 0C 2,4-difluorophenyl-isocyanate (9.68 kg) was controlled charged through a 1 micron line filter at a rate substantially slow enough to prevent co-precipitation of the starting material in the product. After continued stirring at < -10 0C for approximately 1 hour post completion of the 2,4-difluorophenyl-isocyanate addition, the conversion of starting material to product was substantially complete. The product slurry was filtered and washed with cold acetonit?le (26.3 kg) at < -5 0C producing the acetomt?le solvate of the product. Full house vacuum (~30 in Hg ) was applied to the bottom outlet filter/dryer while nitrogen flowed through from the top enhancing the removal of volatile solvents without application of heat. Samples were removed from the bulk material and LOD was determined using an IR-200 Moisture Analyzer Instrument (Denver Instrument Company). The time course is shown below:Drying of the "wetcake" was maintained at ambient temperature under full house vacuum (-30 in Hg ) for about 19.5 h at which time the LOD was 7.28%. At this point, the temperature was raised to 70 C under full house vacuum (-30 in Hg ) for 11 hrs to afford l-[3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (24.2 kg, 99.94% EtaPLC purity, form I determined by PXRD, and 92.9% yield). |
In propan-1-ol; at 0 - 80℃; for 0.25 - 3h;Product distribution / selectivity; | After a stirred mixture of methanol (90 mL), 50 wt % aqueous NaOH (61.60 g, ca. 40.4 mL, 0.7705 mole, 4.993 equivalents), andN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-acetamide (50.0 g, 0.1542 moles, 1.000 equivalent) had been heated under nitrogen with a 9O0C oil bath for 8.5 hr, the conversion of N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl] -acetamide to 3 -(4-bromo-2-methyl-2H-pyrazol-3 -yl)-4-methoxy-phenylamine EPO <DP n="37"/>was found by HPLC to be 99.6%. Substantially all the methanol was then removed by distillation at reduced pressure. While maintaining the stirred residue at less than 5O0C, water (150 mL) and then cone, aqueous HCl (64 mL) were added to achieve a neutral pH of 7. Upon stirring at room temperature for 2 h, product 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine precipitated as a light tan solid, which was collected by suction filtration, washed with water (2 x 75 mL), air dried for two hours, and then dissolved in n-propanol (240 mL). 2,4- Difluorophenylisocyanate (19.5 g, 0.12572 mole, 0.815 equivalents) was added to the solution of crude 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine at a rate sufficiently slow to maintain the stirred reaction mixture at 40-500C with cooling. After the addition had been completed, stirring at that temperature was continued for 30 minutes, at which time conversion of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine to l-[3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea was found by HPLC to be 98%. To improve stirrability, acetone (70 mL) and water (300 mL) were added. The resulting mixture was heated to 750C and then filtered. The filtered solid is washed with water and dried to provide l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.Example 2: Preparation of l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (2,4-difluoro-phenyl)-urea fromiV-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-acetamide (Telescoping by Extraction).A mixture of methanol (9 mL), 50 wt % aqueous NaOH (6.16g, 4.04 mL (at) d=1.525 g/mL, 77mmol, 5 equiv.) andN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]- acetamide (5g, 15.4 mmol, 1 equiv.) was stirred under nitrogen and heated with a 9O0C oil-bath. LC/MS analysis revealed conversions of N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-acetamide to 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine of 86.4% after 3.5 h and 99.5% after an additional hour. After a total heating period of 5.5 h at 9O0C, methanol was distilled off the reaction mixture under reduced pressure, and the residue was diluted with water (20 mL). The aqueous mixture was then extracted with toluene three times (30 mL, 20 mL, and 15 mL). The toluene layers were combined and washed with water (4 X 15 mL) until the aqueous wash was neutral (pH 7). The toluene solution was filtered and concentrated under reduced pressure until about 12-15 mL toluene remained with the product [3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine, theoretical yield of 4.35 g, 15.4 mmol]. After n-propanol (35 mL) was added to the crude 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- EPO <DP n="38"/>phenylamine, 2,4-difluorophenyl isocyanate (2.62g, 2.00 mL, 16.9 mmol, 1.1 equiv.) was added dropwise while the stirred reaction mixture was maintained at 0-5C with cooling. The mixture was then allowed to warm to room temperature. After approximately 15 min., a solid started to precipitate. n-Propanol (10 mL) added to facilitate stirring, and the resulting mixture was filtered. The filtered white solid was washed with n-propanol (10 mL) and dried overnight at 6O0C at about 20 torr to provide l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro- phenyl)-urea 4.25g (63%). HPLC purity, 99.05 (by peak area). IH NMR (Bruker 400 MHz, DMSO-^6) delta 9.01 (s, IH, NH), 8.45 (IH, NH), 8.05 (m, IH, ArH), 7.61 (s, IH, ArH), 7.53 (dd, IH, J = 3 Hz, 9 Hz, ArH), 7.36 (d, IH, J = 3 Hz, ArH), 7.30 (m, IH, ArH), 7.16 (d, IH, J=9 Hz), 7.08 (m, IH, ArH), 3.77 (s, 3 H), 3.63 (s, 3 H).Example 4: Preparation of l-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (2,4-difluoro-phenyl)-urea fromiV-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-acetamide: EPO <DP n="39"/>To a mixture of N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide (3 g, 9.25 mmol) in 1-propanol (3 mL)and water (6 mL) was added sulfuric acid (2 molar equivalents, 1.81 g, 18.51 mmol) at room temperature and the solution was stirred at 1020C for 5h. Formation of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine and consumption of N-[3-(4-bromo-2-metriyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide were monitored by LCMS. Potassium carbonate (2.2 molar equivalents, 2.81 g, 20.36 mmol) was added, the resulting mixture was stirred for 0.5h, and the solid salts were removed by filtrati... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In tetrahydrofuran | 249 N-[4-[4-[(2,4-Difluorophenyl)aminocarbonylamino]phenyl]phenyl]-(2-chloro-5-nitrophenyl)carboxamide Example 249 N-[4-[4-[(2,4-Difluorophenyl)aminocarbonylamino]phenyl]phenyl]-(2-chloro-5-nitrophenyl)carboxamide The title compound (0.50 g, yield 96%) was obtained according to the procedure described in Example 236 using N-[4-(4-aminophenyl)phenyl]-(2-chloro-5-nitrophenyl)carboxamide (0.37 g, 1.0 mmol) prepared in Example 192, THF (5 ml) and 2,4-difluorophenyl isocyanate (0.19 g, 1.2 mmol). 1H-NMR (DMSO-d6, 400 MHz): δ(ppm) 7.00-7.06 (1H, m), 7.29 (1H, ddd, J=11.4, 8.9, 2.7 Hz), 7.51 (2H, d, J=8.7 Hz), 7.60 (2H, d, J=8.7 Hz), 7.65 (2H, d, J=8.7 Hz), 7.75 (2H, d, J=8.7 Hz), 8.04-8.12 (1H, m), 8.32 (1H, dd, J=8.8, 2.7 Hz), 8.46 (1H, d, J=2.7 Hz), 8.51 (1H, s), 9.10 (1H, bs), 10.75 (1H, s); MS(FAB) m/z: 523 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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73% | With hydrogenchloride; N-ethyl-N,N-diisopropylamine In toluene | 35 3-(4-{1-[3-(2,4-Difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic Acid Methyl Ester: EXAMPLE 35 3-(4-{1-[3-(2,4-Difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic Acid Methyl Ester: To a solution of 2-ethoxy-3-[4-(1-heptylaminomethyl-cyclopropyl)-phenyl]-propionic acid methyl ester (54 mg, 0.13 mmol), and 2,4-difluorophenylisocyanate (0.156 mmol, 0.01 85 mL) in toluene (2.5 mL) was added N,N-diisopropylethylamine (0.29 mmol, 0.050 mL). The mixture was allowed to stir at room temperature for 18 hours, then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2*). The organic layers were combined, washed with 2 M HCl (1*), brine (1*), dried over anhydrous sodium sulfate, and concentrated to give a clear film. The crude product was chromatographed on silica (Merck silica gel 60, art#9385-3) eluding with 20% ethyl acetate/hexanes to give 3-(4-{1-[3-(2,4-difluoro-phenyl)-1-heptyl-ureidomethyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester as a clear film (50 mg, 73%). 1H NMR δ (CDCl3): 7.90-7.80 (m, 1H); 7.27 (d, J=7.89 Hz, 2H); 7.15 (d, J=7.88 Hz, 2H); 6.81-6.70 (m, 2H); 6.19 (d, J=2.49 Hz, 2H); 3.94 (dd, J=7.47, 5.81 Hz, 1H); 3.67 (s, 3H); 3.63 (dq, J=9.13, 7.05, 1H); 3.48 (br.s, 2H); 3.25 (dq, J=9.13, 7.05 Hz, 1H); 3.09 (t, J=7.68 Hz, 2H); 2.95-2.87 (m, 2H); 1.49 (quint, J=7.06 Hz, 2H); 1.32-1.13 (m, 8H); 1.10 (t, J=7.06 Hz, 3H); 0.95-0.80 (m, 6H) MS: m/z531.1 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
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54% | With hydrogenchloride; N-ethyl-N,N-diisopropylamine In toluene | 41 3-(4-{2-[3-(2,4-Difluoro-phenyl)-1-hentyl-ureido]-ethyl}-phenyl)-2,2-dimethyl-propionic Acid: EXAMPLE 41 3-(4-{2-[3-(2,4-Difluoro-phenyl)-1-hentyl-ureido]-ethyl}-phenyl)-2,2-dimethyl-propionic Acid: To a solution of 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid (23 mg, 0.072 mmol), and N,N-diisopropylethylamine (0.152 mmol, 0.0264 mL) dissolved in toluene (2 mL) was added 2,4-difluorophenylisocyanate (0.0796 mmol, 0.0094 mL). The mixture was allowed to stir at room temperature for 72 hours, then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2*). The organic layers were combined, washed with 2 M HCl (2*), brine (2*), dried over anhydrous sodium sulfate, and concentrated to give a clear film. The crude product was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluding with 5% methanol/methylene chloride to give 3-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2,2-dimethyl-propionic acid as a clear film (18.5 mg, 54%). 1H NMR δ (CDCl3): 8.05-7.94 (m, 1H); 7.12 (d, J=8.31 Hz, 2H); 7.09 (d, 2H, J=7.89 Hz); 6.87-6.75 (m, 2H); 6.28 (d, J=3.32 Hz, 1H); 3.50 (t, J=7.48 Hz, 2H); 3.18 (t, J=7.69 Hz, 2H); 2.87 (t, J=7.48 Hz, 2H); 2.84 (s, 2H); 1.57 (quint, J=6.86 Hz, 3H); 1.35-1.20 (m, 8H); 1.15 (s, 6H); 0.86 (t, J=6.86 Hz, 3H) MS: m/z475.3 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
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In N-methyl-acetamide; | PREPARATION 24 Ethyl 2-[3-(2,4-difluorophenyl)ureido]thiazol-4-ylglyoxylate Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5.8 g of 2,4-difluorophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a white powder having the following physical properties. Melting Point: 245 to 263 C. (with decomposition). Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide) delta ppm: 1.33 (3H, triplet, J=7 Hz), 4.38 (2H, quartet. J=7 Hz), 7.05-7.15 (1H, multiplet), 7.35 (1H, doublet of doublets of doublets, J=11, 9 and 3 Hz), 8.00 (1H, doublet of triplets, J=6 and 9 Hz), 8.42 (1H, singlet), 8.79 (1H, broad singlet), 11.22 (1H, broad singlet). |
Yield | Reaction Conditions | Operation in experiment |
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68.9% | With triethylamine In tetrahydrofuran; water | 11 EXAMPLE 11 EXAMPLE 11 To a mixture of 5-amino-2-chloro-4-(2-methylphenyl)thieno[2,3-b]pyridine hydrochloride ethanol solvate (160 mg) and tetrahydrofuran (3 ml) were added dropwise triethylamine (0.07 ml) and 2,4-difluorophenyl isocyanate (0.12 ml). The mixture was stirred at room temperature for 5 hours and the solvent was distilled off. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over MgSO4 and the solvent was distilled off. To the residue was added isopropyl ether to obtain N-[2-chloro-4-(2-methylphenyl)thieno[2,3-b]pyridin-5-yl]-N'-[2,4-difluorophenyl)urea (133 mg, 68.9%) as crystals. crystals were recrystallized from ethanol to obtain colorless prisms, mp; 225°-226° C. Elemental analysis for C21 H14 ClF2 N3 OS, Calcd.: C, 58.68; H, 3.28; N, 9.77; Found: C, 58.78; H, 3.41; N, 9.59 |
Yield | Reaction Conditions | Operation in experiment |
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78% | With hydrogenchloride In <i>N</i>-methyl-acetamide; dichloromethane | 9 N-(2,4-Difluorophenyl)-1-ethyl-6-benzoyloxindole-3-carboxamide (3, R3 =2,4-difluorophenyl, R4 =6-benzoyl, R5 =C2 H5) EXAMPLE 9 N-(2,4-Difluorophenyl)-1-ethyl-6-benzoyloxindole-3-carboxamide (3, R3 =2,4-difluorophenyl, R4 =6-benzoyl, R5 =C2 H5) To a slurry of 48 mg. (2 mmoles) of sodium hydride in 2 ml. of dimethylformamide was added 300 mg. (1.13 mmoles) of 1-ethyl-6-benzoyloxindole followed after 20 minutes by the addition of 310 mg. (2 mmoles) of 2,4-difluorophenylisocyanate. After stirring for 30 minutes the reaction was added to a mixture of 2N hydrochloric acid and methylene chloride. The organic phase was separated, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from diisopropyl ether--methylene chloride to give 371 mg. (78% yield) of the desired product, m.p. 149°-151° C. The NMR (CDCl3) spectrum showed absorption at 1.31 (t, J=7 Hz, CH3), 3.92 (q, J=7 Hz, CH2), 4.45 (s, CH), 6.6-8.4 (m, ArH) and 9.85 (bs, NH) ppm. |
78% | With hydrogenchloride In <i>N</i>-methyl-acetamide; dichloromethane | 9 N-(2,4-Difluorophenyl)-1-ethyl-6-benzoyloxindole-3-carboxamide (3, R3 =2,4-difluorophenyl, R4 =6-benzoyl, R5 =C2 H5) EXAMPLE 9 N-(2,4-Difluorophenyl)-1-ethyl-6-benzoyloxindole-3-carboxamide (3, R3 =2,4-difluorophenyl, R4 =6-benzoyl, R5 =C2 H5) To a slurry of 48 mg. (2 mmoles) of sodium hydride in 2 ml. of dimethylformamide was added 300 mg. (1.13 mmoles) of 1-ethyl-6-benzoyloxindole followed after 20 minutes by the addition of 310 mg. (2 mmoles) of 2,4-difluorophenylisocyanate. After stirring for 30 minutes the reaction was added to a mixture of 2N hydrochloric acid and methylene chloride. The organic phase was separated, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from diisopropyl ether - methylene chloride to give 371 mg. (78% yield) of the desired product, m.p. 149°-151° C. The NMR (CDCl3) spectrum showed absorption at 1.31 (t, J=7 Hz, CH3), 3.92 (q, J=7 Hz, CH2), 4.45 (s, CH), 6.6-8.4 (m, ArH) and 9.85 (bs, NH) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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In triethylamine | 3 EXAMPLE 3 EXAMPLE 3 Reaction of 2.4 g of 2-pyrroloylacetonitrile with 3.1 g of 2,4-difluorophenyl isocyanate in the presence of 2.0 g Et3 N in 25 ml of glyme and isolation similarly to the preceding examples, followed by trituration with and recrystallization from ethanol gives β-oxo-α-(2,4-difluorophenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 169°-171°. |
Yield | Reaction Conditions | Operation in experiment |
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97% | In chloroform | 37 Example 37 Example 37 N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (200 mg) was dissolved in chloroform (15 ml), and 2,4-difluorophenyl isocyanate (88 μl) was then added to the solution. The mixture was heated under reflux for one hr. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (4/1) to give 287 mg (yield 97%) of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 2.17 (s, 3H), 2.26 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H), 6.31 (d, J = 5.4 Hz, 1H), 6.57 (s, 1H), 6.81 - 6.95 (m, 3H), 7.00 (s, 1H), 7.43 (s, 1H), 7.55 (s, 1H), 7.59 (s, 1H), 8.05 - 8.13 (m, 1H), 8.47 (d, J = 5.4 Hz, 1H) Mass analysis, found (FD-MS, m/z): 479 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In chloroform | 72 Example 72 Example 72 N-(2,4-Difluorophenyl)-N'-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}urea 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (24 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration andwas washed to give 55 mg (yield 72%) of the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ 3.98 (s, 3H), 3.99 (s, 3H), 7.04 - 7.08 (m, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.29 - 7.35 (m, 1H), 7.38 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.56 (s, 1H), 8.06 - 8.14 (m, 1H), 8.51 - 8.54 (m, 1H), 8.54 (s, 1H), 9.11 - 9.12 (m, 1H) Mass analysis, found (ESI-MS, m/z): 453 (M++1) |
With triethylamine In chloroform at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In chloroform | P.10 Production Example 10: Production Example 10: N-(4-[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N'-(2,4-difluorophenyl)urea 4-[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylaniline (300 mg) was dissolved in chloroform (5 ml). 2,4-Difluorophenyl isocyanate (200 μl) was then added to the solution, and the mixture was stirred at 70°C overnight. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (75/25) to give 368 mg (yield 88%) of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 2.17 (s, 3H), 2.26 (s, 3H), 4.06 (s, 3H), 5.33 (s, 2H), 6.29 (d, J = 5.1 Hz, 1H), 6.42 (s, 1H), 6.76 - 6.93 (m, 3H), 6.70 (s, 3H), 7.30 - 7.54 (m, 7H), 7.60 (s, 1H), 8.04 - 8.12 (m, 1H), 8.44 (d, J = 5.4 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In chloroform | P.13 Production Example 13: Production Example 13: N-(4-[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N'-(2,4-difluorophenyl)-urea 4-[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chloroaniline(260 mg) was dissolved in chloroform (10 ml). 2,4-Difluorophenyl isocyanate (198 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (10/1) to give 337 mg (yield 94%) of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 4.04 (s, 3H), 5.32 (s, 2H), 6.49 (d, J = 5.1 Hz, 1H), 6.86 - 6.96 (m, 3H), 7.10 - 7.17 (m, 2H), 7.22 - 7.28 (m, 1H), 7.28 - 7.41 (m, 3H), 7.45 - 7.53 (m, 4H), 7.96 - 8.04 (m, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.49 (d, J = 5.4 Hz, 1H) Mass analysis, found (ESI-MS, m/z): 562, 564 (M++1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-butylamino-piperidine-1-carboxylic acid tert-butyl ester; 2,4-diflurophenylisocyanate With triethylamine In ISOPROPYLAMIDE at 20℃; for 0.0833333h; Stage #2: With hydrogenchloride In ethyl acetate at 20℃; for 0.333333h; | 2 N-butyl-N'-(2,4-difluorophenyl)-N-piperidin-4-ylurea hydrochloride Example 2 N-butyl-N'-(2,4-difluorophenyl)-N-piperidin-4-ylurea hydrochloride To a solution of tert-butyl 4-(butylamino)piperidin-1-carboxylate (1 g) in dimethylacetamide (13 ml) was added triethylamine (1.6 ml) and 2,4-difluorophenyl isocyanate (907 mg). The reaction mixture was stirred for 5 minutes at room temperature. To reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. To the solution of the obtained compound (1.28 g) in ethyl acetate (2 ml) was added 4N hydrogen chloride in ethyl acetate solution (10 ml). The reaction mixture was stirred for 20 minutes at room temperature, and concentrated. The obtained residue was washed with tert-butyl methyl ether, dried to give the title compound having the following physical data. TLC: Rf0.52 (dichloromethane: methanol: acetic acid = 5: 1: 0.1); NMR (CD3OD): δ 0.99, 1.34-1.47, 1.60-1.71, 1.95-2.01, 2.08-2.22, 3.03-3.13, 3.27-3.34, 3.44-3.50, 4.13, 7.00, 7.37, 8.01. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In dichloromethane at 20℃; for 24h; | 216.1 To a solution of aniline 46 (500 mg, 0.948 mmol) in DCM (10 ml) was added 2,4- difluoro-1-isocyanatobenzene (441 mg, 3 eq, 2.84 mmol) and the reaction mixture was stirred at RT for 24 hours. The mixture was concentrated and purified via column chromatography (eluent 10% MeOH in EtOAc) to afford 350 (600 mg, 93%) as a white solid. MS (m/z) = 683.7 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenylamine trifluoroacetate With N-ethyl-N,N-diisopropylamine In dichloromethane Stage #2: 2,4-diflurophenylisocyanate at 20℃; | 1.142 To a solution of [3-(2-METHYL-2H-PYRAZOL-3-YL)-4-TRIFLUOROMETHOXY-PHENYL]-CARBAMIC acid TERT- butyl ester (21.8 mg, 0.05 mmol) in methylene chloride (0.5 mL), trifluroacetic acid (0.5 mL) was added and reaction mixture stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure to afford 3- (4-BROMO-2-METHYL-2H-PYRAZOL-3-YL)-4-TRIFLUOROMETHOXY-PHENYLAMINE trifluoroacetate as a colorless oil in quantitative yield. LCMS m/z (%) = 336 (M+H 79BR, 100), 338 (M+H 8 BR, 95). This compound was dissolved in methylene chloride (0.8 mL) then treated with N, N- DIISOPROPYLETHYLAMINE until pH = 7-8.2, 4-DIFLUOROPHENYL isocyanate (8.5 mg, 0.055 mmol) was added and reaction mixture stirred at room temperature overnight and concentrated to give a residue that was subjected to a purification by flash chromatography (SIO2, Hexanes/EtOAc gradient elution) to afford Compound 113 as a white solid in 46.3% yield. LCMS m/z (%) = 491 (M+H 79BR, 100), 493 (M+H 81Br, 98). H NMR (400 MHz, CD30D) 8 : 8.06-8. 00 (M, 1H), 7.71 (dd, J= 9.00 Hz, 2.74 Hz, 1H), 7.65- 7.62 (M, 2H), 7.48 (d, J= 9.00 Hz, 1H), 7.09-7. 00 (M, 1H), 6.99-6. 94 (M, 1H), 3.76 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | 10.D To a solution of iV-(3-(aminomethyl)benzyl)-3,5-dichloro-2-hydroxy-N-(4- (trifluoromethyl)benzyl)benzenesulfonamide (40 mg, 0.08mmol) in DMF (2 mL) was added 2,4-difluorophenyl isocyanate (10.0 μL, 0.09 mmol). The resulting mixture was stirred at rt for 3 h under nitrogen. The mixture was concentrated and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated and lyophilized to give a white solid (30 mg, 57%). 1H NMR (CD3OD): δ 7.59 (d, J= 2.8 Hz, 1H), 7.52 (d, J= 2.2 Hz, 1H), 7.48 (d, J= 7.7 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.39-7.37 (m, 4H), 7.31 (t, J = 7.7 Hz, 2H), 7.24 (d, J= 7.7 Hz, 2H), 7.19 (t, J = 7.1 Hz, 2H), 7.09 (m, 2H), 7.02 (s, 1H), 6.89 (d, J = 6.6 Hz, 1H), 4.48 (s, 2H), 4.40 (s, 2H), 4.23 (s, 2H); MS (ESI): (M+H)+ = 714.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In tetrahydrofuran at 20℃; for 48h; | 103.1 Step 1: Ethyl 3-(4-(3-(2,4-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5- carboxylate; Ethyl 3-(4-amino-3-methylphenyl)isoxazole-5-carboxylate (1.0 equiv.), 2,4-difluoro phenyl isocyanate (1.2 equiv.) and tetrahydrofuran in a round-bottom flask was stirred at room temperature for 48 hours. The solid precipitate was filtered and washed with a minimum quantity of THF and dried in vacuo to afford the title compound as a white solid (75%); 1H NMR (300 MHz, DMSO-d6) δ: 1.29-1.34 (t, J = 7.0 Hz, 3H), 2.29 (s, 3H), 4.32- 4.39 (q, 2H), 7.00-7.05 (m, IH), 7.26-7.33 (m, IH), 7.72-7.75 (d, J = 8.4 Hz, IH), 7.80 (s, 2H), 8.09-8.16 (m, 2H), 8.45 (s, IH), 9.09 (s, IH); IR (KBr) 3297, 3134, 2991, 1727, 1654, 1590, 1558, 1500, 1460, 1424, 1287, 1250, 1139, 1029, 841 cm1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.65% | In tetrahydrofuran at 20℃; | 104.5 Step 5: Methyl 2-(3-(4-(3-(2,4-difluorophenyl) ureido) phenyl)- l,2,4-oxadiazole-5- carboxamido)-3-methylbutanoate; Methyl 2-(3-(4-aminophenyl)-l,2,4-oxadiazole-5-carboxamido)-3 methylbutanoate and 2,4- difluoro-1-isocyanatobenzene was added to THF and stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated and the crude product so obtained was dissolved in ethyl acetate and washed with water, brine, dried by sodium sulfate and concentrated to give a solid. The solid was re-crystallized from Ethyl acetate: Pet ether and was obtained in a yield of 98.65%; 1H NMR (DMSOd6) δ: 0.970 (t, 6H C(CH3)2), 2.488 (m, IH, CHMe2), 3.68 (s, 3H, OCH3), 4.35 (m, IH, NHCH), 7.082 (m, 1Η CH), 7.35 (m, 1H,CH),7.67 (d, 2H, CH) 8.01 l(d, 2H CH), 8.099(m, IH, CH), 8.96 (s, IH, NH), 9.384 (s,lH,NH), 9.677 (d, IH, NH ); ms (m/z) 474 (M++H). |
In tetrahydrofuran at 20℃; for 16h; | 6.1.14. General procedure for the synthesis of oxadiazole analogs possessing a urea linker To a solution of compound 29 (0.5 mmol, 1.0 equiv) in THF (3 ml) was added the appropriately substituted phenyl isocyanate (1.1 equiv) and the mixture was stirred for 16 h at rt. The reaction mixture was then concentrated and purified using flash column chromatography (2:8 EtOAc/petroleum ether) to yield the desired methyl ester. To a solution of the methyl ester (1 equiv) in THF was added 1.0 M solution of LiOH in water (5 equiv) and stirred for 16 h at rt. The solvent was removed and the obtained residue was diluted with water and acidified to pH 2 using 2.0 M HCl. The material thus obtained was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a solid that was crystallized in ethyl acetate to yield the desired acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In tetrahydrofuran at 20℃; | 358.5 Step 5: (S)-methyl 2-(2-(4-(3-(2,4-difluorophenyl)ureido)phenyl)thiazole-4- carboxamido)-3-methylbutanoate; (S)-methyl 2-(2-(4-aminophenyl)thiazole-4-carboxamido)-3-methylbutanoate (150 mg, 0.450 mmol) was taken in 3 mL THF, to this 2,4-difluoro-l-isocyanatobenzene (76.8 mg, 0.495 mol) was added and stirred at RT for 3-4 hr. After completion of reaction solvent was removed under reduced pressure and the residue purified by column chromatography. Yield: 200mg (91%). MS (ESI) m/z: 487(M-H) "; 1HNMR (DMSO-d6, 300MHz): δ 9.369 (s, IH), 8.594 (d, IH), 8.316 (s, IH), 8.291 (s, IH), 8.126 (m, IH), 8.023 (d, 2H), 7.640 (d, 2H), 7.372 (m, IH), 7.106 (m, IH), 4.431 (dd, IH), 3.696 (s, 3H), 2.300 (m, IH), 0.981 (dd, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 20℃; for 16h; | 25 1-(2,4-Difluorophenyl)-3-[2-(5-oxo-4-pyridin-3-yl-2,5-dihydro-1H-pyrazol-1-yl)pyridin-4-yl]-methyl}urea 2.7 g (10 mmol) of the compound from Example 4A are dissolved in 60 ml of 1,2-dichloroethane and provided as a stock solution. 16 mg (0.1 mmol) of 2,4-difluoro-1-isocyanatobenzene are initially charged, and 600 μl (0.1 mmol) of the above stock solution and 26 mg (0.2 mmol) of N,N-diisopropylethylamine (Hünig base) are added. The reaction mixture is stirred at RT for 16 h. For work-up, the solvent is removed under reduced pressure, the residue is taken up in DMSO and filtered and the filtrate is purified directly by preparative LC-MS (Method 8). The product fractions are concentrated under reduced pressure and the residue is dried. Yield: 3 mg (10% of theory) LC-MS (Method 8): Rt=1.33 min; MS (ESIpos): m/z=423 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 2,4-diflurophenylisocyanate; (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: With hydrogenchloride In dichloromethane; water | Intermediate 10 To a solution of 1 ,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1.5g, 7.5 mmol) in anhydrous DCM (3OmL) was added triethylamine (2.59ml_, 19 mmol) and 2,4-difluoro-1-isocyanatobenzene (0.88ml_, 7.5 mmol) the sample was stirred under an argon atmosphere at room temperature for 2hours. The reaction was evaporated and the residue was suspended DCM (3OmL) which was washed with 0.5M aqueous HCI (10OmL), and then water (10OmL). The collected organic layer was dried (MgSO4), filtered and evaporated, the residue was dried in a vac-oven at 400C overnight (approx 18hours) to yield the title compound as a white solid (2.41 g, 91%).1H NMR (CDCI3) 51.22 (3H, d, J=6.58Hz), 1.48 (9H, s), 3.11 (1 H, m), 3.22 (1 H, m), 3.34 (1 H, dd, J=13.37, 3.95Hz), 3.71 (1 H, m), 3.92 (1 H, m), 4.31 (1 H, br m), 6.39 (1 H, NH, br m), 6.85 (2H, m), 7.99 (1 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-methyl-2-oxo-2H-chromene-7-carbonitrile With lithium hexamethyldisilazane In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 2,4-diflurophenylisocyanate In tetrahydrofuran for 1h; Stage #3: With water; ammonium chloride In tetrahydrofuran | 9 EXAMPLE 9 2-(7-Cyano-2-oxo-2H-chromen-4-yl)-N-(2,4-difluoro-phenyl)-acetamide (Compound #15) To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (671 mg, 3.62 mmol) in dry THF (30 mL) at -20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 2,4-difluoro-1-isocyanato-benzene (224 mg) was added into the reaction mixture and the reaction mixture was then stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2,4-difluoro-phenyl)-acetamide as a yellow solid. M/z=341 (M+H+) 363(M+Na+) 1H-NMR (DMSO, 400 MHz) δ (ppm) 10.6(bs, 1H), 7.65(s, 1H), 7.52(d, J=8.1 Hz, 1H), 7.45(m, 1H), 6.8-7.25(m, 3H), 6.45(s, 1H), 3.72(bs2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In tetrahydrofuran at 20℃; for 0.666667h; | 1.1g (1g) trans-6-[3-(2,4-difluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester A tetrahydrofuran (4 mL) solution of the compound (253 mg) obtained in Example (1f) and 2,4-difluoro-phenyl isocyanate (0.10 mL) was stirred at room temperature for 40 minutes and then concentrated. The residue was purified by chromatography (dichloromethane:ethyl acetate=1:0→4:1) to obtain methyl ester (302 mg, 83%). To a tetrahydrofuran (2 mL)/methanol (2 mL) mixed solution of this methyl ester (302 mg), an aqueous sodium hydroxide solution (1.0 mol/L aqueous solution, 1.2 mL) was added at room temperature. The reaction mixture was stirred for 18 hours and concentrated. The residue was diluted with water, then neutralized with a 1 N aqueous hydrochloric acid solution (1.5 mL), and collected by filtration to obtain the title compound (271 mg, 93%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm)=12.0 (1H, s), 8.95 (1H, s), 8.48 (1H, d, J=2.3 Hz), 8.12-8.06 (1H, m), 7.34-7.28 (2H, m), 7.22 (1H, d, J=9.4 Hz), 7.10 (1H, d, J=8.2 Hz), 7.07-7.02 (1H, m), 4.51-4.46 (3H, m), 3.57 (2H, t, J=5.9 Hz), 2.76 (2H, t, J=6.1 Hz), 2.12 (2H, d, J=7.1 Hz), 1.95-1.91 (2H, m), 1.77-1.73 (2H, m), 1.68-1.62 (1H, m), 1.39-1.29 (2H, m), 1.12-1.02 (2H, m) MS (ESI) m/z: 488 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With caesium carbonate In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; | General Method for Synthesis of the Target Urea Derivatives 2a-g General procedure: To a mixture of compound 9 (34 mg, 0.1 mmol) and cesium carbonate (33 mg, 0.1 mmol) in anhydrous THF (3 mL), a solution of the appropriate aryl isocyanate (0.1 mmol) in anhydrous THF (3 mL) was added dropwise at room temperature under N2 atmosphere. The reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, and purification was carried out by flash column chromatography using the appropriate proportion of ethyl acetate and hexane as mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine In toluene at 0 - 80℃; for 3h; | 2.1.1 General procedure for the synthesis of target compounds 3-47 General procedure: The synthetic route for N-fluorinated phenyl-N′-pyrimidyl urea derivatives is depicted in Scheme 1. At first, 40 mL toluene solution which contained 5 mmol fluorine-containing aniline was slowly dropped into another toluene solution which contained 2 mmol BTC (triphosgene) and a few drops Et3N while mixing at 0°C for about 1h. The mixture was stirred at room temperature for 1h and then heated to 80°C until the white solid completely dissolved. The intermediate 1 was isolated and obtained by concentration under reduced pressure and flushing by nitrogen [16,17]. | |
In ethyl acetate at 0℃; Reflux; | General synthetic procedure for substituted phenylurea (2) General procedure: Substituted aniline (54 mmol) wasadded dropwise to a solution of bis(trichloromethyl) carbonate (8.0 g, 27 mmol) in dry ethylacetate (30 mL) at 0-5 oC, the mixture was stirred for 1 h at room temperature and heated underreflux for 5 h, cooled on standing, then solvent was evaporated under reduced pressure to getsubstituted isocyanate. A solution of substituted isocyanate and acetone (20 mL) was addeddropwise to a mixture of ammonia (11 mL, 163 mmol) and acetone (10 mL) at 0-5 oC, themixture was stirred for 10 h at room temperature and evaporated under reduced pressure. Theresidue was washed with water and recrystallized from ethanol. | |
In dichloromethane for 0.25h; | 4.1.2.1 4.1.2.1 1-(4-(tert-butyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (8) Triphosgene (1.77g, 6.03mmol) was dissolved in anhydrous CH2Cl2 (30mL) and the mixture was stirred on the ice-bath for 5min. Tert-butyl-aniline (2.0g, 13.4mmol) in anhydrous CH2Cl2 was added dropwise to the mixture and stirring was continued for 15min. Then triethanolamine (2.2mL, 16.1mmol) diluted with CH2Cl2 (20mL) was added onto the mixture. Stirring was continued for 15min, a solution of triethanolamine (2.2mL, 16.1mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 7 (2.35g, 10.72mmol) in anhydrous CH2Cl2 (30mL) was added and continued stirring for 20min. Subsequently, the ice bath was removed, and the mixture was reacted at room temperature overnight. After completion of the action, the reaction was quenched with dilute NaHCO3.The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by silica gel flash chromatography (PE/AcOEt=3:1) yielding 8 as white solid (3.4g, 64.4%). |
In dichloromethane at 0℃; for 1h; | General procedure: Aniline (140mg, 1.5mmol) and Et3N (202mg, 2mmol) were dissolved in 5mL of dichloromethane and slowly added dropwise to a solution of triphosgene (BTC) (223mg, 0.75mmol) in 10mL of dichloromethane at 0°C. The mixture was then stirred at 0°C for 1h. Then, 5a (300mg, 1mmol) in 1mL of DMF was added at 0°C, and the mixture was then stirred at room temperature for 30min, and the solvent was distilled with a rotary evaporator. The residue was washed with water (10mL×3) and purified via silica gel flash column chromatography to afford 1-(3-((2S,5S)-5-((1H-indol-3-yl)methyl)-3,6-dioxopiperazin-2-yl)propyl)-3-phenylurea (6a) as a pale powder in 74% yield. Compounds 6b-v, 7a-k and 8a-k were prepared similar to 6a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide; at 80 - 100℃; | General procedure: The synthetic route for N-fluorinated phenyl-N?-pyrimidyl urea derivatives is depicted in Scheme 1. At first, 40 mL toluene solution which contained 5 mmol fluorine-containing aniline was slowly dropped into another toluene solution which contained 2 mmol BTC (triphosgene) and a few drops Et3N while mixing at 0C for about 1h. The mixture was stirred at room temperature for 1 h and then heated to 80C until the white solid completely dissolved. The intermediate 1 was isolated and obtained by concentration under reduced pressure and flushing by nitrogen [16,17]. To obtain the final target compounds, the unpurified intermediate 1 was added into a series of substituted pyrimidinamine (5 mmol, as shown in Table 1) solutions which contained a little tetrabutylammonium bromide that was used as phase transfer catalyst. Then, the mixture was agitated at 80-100C for 6-9h. The reaction was detected according to TLC. When the reaction was complete, the product was cooled to room temperature, filtered, and washed with 10% Na2CO3, water, and acetone. The final target compounds were purified by recrystallization (DMF/acetone). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide; at 80 - 100℃; | General procedure: The synthetic route for N-fluorinated phenyl-N?-pyrimidyl urea derivatives is depicted in Scheme 1. At first, 40 mL toluene solution which contained 5 mmol fluorine-containing aniline was slowly dropped into another toluene solution which contained 2 mmol BTC (triphosgene) and a few drops Et3N while mixing at 0°C for about 1h. The mixture was stirred at room temperature for 1 h and then heated to 80°C until the white solid completely dissolved. The intermediate 1 was isolated and obtained by concentration under reduced pressure and flushing by nitrogen [16,17]. To obtain the final target compounds, the unpurified intermediate 1 was added into a series of substituted pyrimidinamine (5 mmol, as shown in Table 1) solutions which contained a little tetrabutylammonium bromide that was used as phase transfer catalyst. Then, the mixture was agitated at 80?100°C for 6?9h. The reaction was detected according to TLC. When the reaction was complete, the product was cooled to room temperature, filtered, and washed with 10percent Na2CO3, water, and acetone. The final target compounds were purified by recrystallization (DMF/acetone). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In acetonitrile at 100℃; for 0.833333h; Microwave irradiation; | |
81% | With triethylamine In acetonitrile | 1 Embodiment (I): Preparation Method (I) of Pyridine Urea Compounds is Applied to Compound 1 to Compound 17 General procedure: At room temperature, add compound a (10 mmol) and compound b (12 mmol) to anhydrous acetonitrile (40 mL), and triethylamine (about 1 ml) was added dropwise with heating, and heated to reflux for 6 hours, then cooled and filter. After washing with water, the residue was dried, and used hot water to wash die residue three times with, then recrystallized in ethanol to obtain a white solid I. EXAMPLE 1 (0070) Compound 1 shown below was prepared according to the method of Embodiment (I) which is substituted compound b by using The product represented as Compound 1 of Example 1 is white solid, and yield is 81%. mp: 191.5° C.-193.8° C. 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=2.5 Hz, 1H, Ar-H), 8.20 (dd, J=4.7, 1.4 Hz, 1H, Ar-H), 8.04 (td, J=9.2, 6.2 Hz, 1H, Ar-H), 7.95 (ddd, J=8.3, 2.6. 1.5 Hz, 1H, Ar-H), 7.34-7.29 (m, 2H, Ar-H), 7.08-7.03 (m, 1H, Ar-H). HRMS-ESI m/z [M+H]+calcd for C12H9F2N3O: 250.0714, found: 250.0776. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; water In acetone at 0 - 20℃; | General synthetic procedure for substituted phenylurea (2) General procedure: Substituted aniline (54 mmol) wasadded dropwise to a solution of bis(trichloromethyl) carbonate (8.0 g, 27 mmol) in dry ethylacetate (30 mL) at 0-5 oC, the mixture was stirred for 1 h at room temperature and heated underreflux for 5 h, cooled on standing, then solvent was evaporated under reduced pressure to getsubstituted isocyanate. A solution of substituted isocyanate and acetone (20 mL) was addeddropwise to a mixture of ammonia (11 mL, 163 mmol) and acetone (10 mL) at 0-5 oC, themixture was stirred for 10 h at room temperature and evaporated under reduced pressure. Theresidue was washed with water and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In dichloromethane at 0 - 20℃; | General procedure for the preparation of compounds 11a-h General procedure: To a suspension of 10 (1.0 equiv) in DCM, a DCM solution of corresponding phenyl isocyanate (1.05 equiv) was added dropwise at 0 °C. The mixture was stirred at room temperature overnight. The resulting solid was removed by filtration, then washed with small amounts of DCM and dried under infrared lamp to afford compound 11a-h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With silica supported cerium chloride In neat (no solvent) at 20℃; for 0.666667h; Sonication; Irradiation; Green chemistry; | Synthetic Procedure for the Synthesis of Compound 6b General procedure: Ultrasonication Method: 4-Nitrophenyl isocyanate (3b) (164 mg, 1 mmol), diethylphosphite (5) (0.16 mL, 1.2 mmol) and the catalyst, SiO2-CeCl3.7H2O (200 mg)were taken into a long necked 50 mL round-bottomed flask. The reaction mixture was irradiated with ultrasounds using BANDELIN SONOREX sonicator at RT for 40 min.After completion of the reaction as checked by TLC, the reaction mixture was soluble in EtOAc and filtered off to remove the catalyst, SiO2-CeCl3.7H2O as a residue again which was washed with EtOAc (3 mL × 2). The combined organic layer was concentrated under reduced pressure and the obtained crude product was subjected to column chromatography using 15%-20% EtOAc: n-hexane as an eluent to afford pure compound, diethyl4-nitrophenylcarbamoylphosphonate (6b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.1% | With triethylamine In dichloromethane at 20℃; for 1h; | 1 Compound 4s - 2: yellow solid; compound at room temperature 3s (35.5 mg, 0 . 25mmol) with 2, 4 - difluoro phenyl isocyanate (1.2eq) is dissolved in methylene chloride, dropping triethylamine (1.2eq), reaction time is one hour, the reaction solution washing, dichloromethane extraction, the combined organic phase, drying and condensing column to obtain the product 56.5 mg, yield 76.1%. |
With triethylamine In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; | 2 4.10. General procedure for synthesis of compounds 9a-k General procedure: A solution of the suitable aryl isocyanate (0.187 mmol) in anhydrous DCM (2 mL) was added drop wise to a stirred solution ofcompound 7 (0.05 g, 0.170 mmol) in DCM (4 mL) under argon atmosphereat 0 °C. The reaction mixture was stirred at rt for 24 h, then the resulting solid was collected by filtration, washed with DCM and dried to yield the target compounds 9a-k in pure form. 4.10.2 4-((2-(3-(2,4-Difluorophenyl)ureido)quinolin-5-yl)oxy)-N-methylpicolin-amide (9b) White solid; yield 96%; mp 253-255 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (br. s, 1H), 10.46 (s, 1H), 8.79 (q, J = 4.8 Hz, 1H), 8.56 (d, J = 5.6 Hz, 1H) 8.37-8.30 (m, 1H), 8.26 (d, J = 9.2 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.44 (td, J = 8.6, 2.8 Hz, 2H), 7.34 (t, J = 8.4 Hz, 2H), 7.23 (dd, J = 5.6, 2.4 Hz, 1H), 7.12 (t, J = 8.8 Hz, 1H), 2.80 (d, J = 4.8 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 166.14, 164.15, 153.33, 153.13, 152.54, 151.16, 149.49, 146.56, 133.23, 131.39, 124.36, 124.16, 122.10, 118.28, 116.30, 114.79, 111.93, 111.63, 109.66, 104.72, 104.31, 104.11, 26.49; HRMS (ESI-TOF) m/z calcd for C23H17F2N5O3Na [M+Na]+: 472.1197, found: 472.1200. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0℃; for 0.5h; | 42 3-(Cyanomethyl)-N-(2,4-difluorophenyl)-3-(4-[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine-1-carboxamide General procedure: Example 41 Methyl 3-(cyanomethyl)-3-(4-[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-1-yl)azetidine-1-carboxylate Methyl chloroformate (7.6 μL, 0.098 mmol) was added to a solution of allyl({1-[3-(cyanomethyl)azetidin-3-yl]piperidin-4-yl}methyl)(trans-2-phenylcyclopropyl)carbamate (20.0 mg, 0.0490 mmol, prepared as described in Example 33, Step 5) and triethylamine (27 μL, 0.20 mmol) in DCM (0.5 mL) at 0° C. The resulting mixture was stirred for 30 min at 0° C. then diluted with DCM, and washed with saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in THF (0.5 mL) and then diethylamine (60 μL) was added, followed by Pd(PPh3)4 (10 mg). A container with the resulting mixture was evacuated then filled with nitrogen and the mixture was stirred at 80° C. for 2 h. The mixture was cooled to room temperature, filtered then purified by prep. HPLC (pH=2, acetonitrile/water+TFA) to afford the desired product as a TFA salt |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine; triethylamine; In tetrahydrofuran; at 10 - 50℃; for 4h; | General procedure: The thiourea and urea derivatives of 6-fluoro-3-(pipe-ridin-4-yl)benzo[d ] isoxazole (8a-g/9a-d) were synthesized using 6-fluoro-3-(piperidin-4-yl)benzo[d ]isoxazole hydrochloride as starting material. The starting material (255 mg, 1 mmol) was dissolved in dry THF (15 mL) in a 50 mL round bottomed flask, to this solution triethylamine (0.14 mL, 1 mmol) and pyridine (2 mL) was added and then stirred the reaction mixture for 3 h at refluxing temperature. The reaction mixture was filtered through Buchner funnel to remove Et3 N.HCl. The filtrate containing (6- fluoro-3-(piperidin-4-yl)benzo[d] isoxazole) (5) was used for the reaction with various isothiocyanates and isocyanates. The filtrate 6-fluoro-3-(piperidin-4-yl)benzo[d ] isox-azole (1 mmol) (5) was allowed to cool to 10 C and 4-nitrophenyl isothiocyanate (180 mg, 1 mmol)(6a) was added, stirred for 3 h at 40 C. The progress of the reaction was monitored by TLC (n-hexane: ethyl acetate 3:1). After completion of reaction, the reaction mixture was diluted with ethyl acetate and washed twice with water. The organic layer was dried over anhydrous sodium sulphate(Na2 SO4 ) and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography using increasing amounts of ethyl acetate in hexane(EtOAc/n-hexane) as eluent to obtain the final product (8a). Same procedure was adopted for the synthesis of remaining compounds (8b-g) and urea derivatives (9a-d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With pyridine at 20℃; for 2h; | 1-[3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)phenyl]-3-(2,4-difluorophenyl)urea (16b) General procedure: A mixture of compound 12 (100 mg, 0.44 mmol), anhydrouspyridine (2 ml) and the aryl isocyanate (0.44 mmol) was stirred atroom temperature for 2 h. The solvent was evaporated. The residuewas triturated with ethanol, filtered and washed with acetonitrileand diisopropyl ether to give the desired products |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N,N'-dimethylpiperazine In tetrahydrofuran at 0 - 40℃; for 4h; | General procedure for the synthesis of urea and thiourea derivatives of lopinavir 7(a-k) General procedure: Lopinavir intermediate (5) (0.75 mmol, 260 mg) and 0.2 mL of dimethylpiperazinein 10 mL of THF were put into a 50-mL round bottom flask. Later, 4-fluorophenylthioisocyanate (1 mmol, 0.13 mL) (6a) was added dropwise to 5 mL of THF, then stirred at 0 °C, and the temperature was slowly raised and maintained at 40 °C and stirred for 2 h. The progress of the reaction was monitored by TLC in ethyl acetate and n-hexane (3:7). After complete consumption of the lopinavir, the solvent from reaction mixture was removed in a rota-evaporator. The crude reaction mixture was washed with cold water followed by hexane to obtain the crude product, N-(5-(3-(4-fluorophenyl)thioureido)-4-hydroxy-1,6-diphenylhexan-2-yl)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanamide (7a). It was recrystallized from ethanol to get pure compound. The same procedure was adopted for the synthesis of remaining title compounds 7(b-k). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In ethyl acetate; Petroleum ether at 20℃; for 1h; Cooling with ice; | Ethyl 2-[(2-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate. General procedure: To a mixed solution of ethyl 4-chloroacetoacetate(3.93 mL, 28.9 mmol) and 2-chlorophenyl isocyanate (3.83 g,31.8 mmol) in petroleum ether/ethyl acetate (40 mL/4.0 mL) cooledwith an ice bath, triethylamine (4.8 g, 34.4 mmol) was addeddropwise. The reaction mixturewas stirred at ambient temperaturefor 1 h. The reaction suspension was diluted with water, 2 N hydrochloricacid solution and ether, and the solid was collected byfiltration and washed successively with water and diethyl ether,and then dried to afford the titled compound (4.35 g, 53%) as acolorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In tetrahydrofuran at 20℃; | General Procedure for the Preparation of Title Compounds 5a-5x General procedure: A 100 mL round bottom was charged with 1-(2,6- dichloro-4-(trifluoromethyl)phenyl) -N-(1-hydroxypropan-2- yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (1 mmol) with various substituted isocyanatobenzenes (1 mmol) in THF (10 mL). The mixture was stirred at room temperature for overnight. The target compounds were filtered and crude solids were recrystallized from ethanol to give the title compounds 5a-5x. All the compounds were synthesized according to this procedure (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In toluene at 20℃; Inert atmosphere; | 4.2. General procedure for the synthesis of 2-thiazolylureaderivatives (5a-5z’) General procedure: To a solution of compounds (4a-4h) (0.82 mM, 1 eq) in drytoluene (10 ml), the required isocyanates (1.60 mM, 2.0 eq) wereadded under nitrogen. The reaction mixture was stirred at roomtemperature for 4-5 h and monitored by TLC. The solid precipitateso obtained was filtered and washed with toluene to remove theexcess isocyanate, dried and collected the products (5a-5z’) as such. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine at 20℃; for 0.5h; | 13.7 Step 7. Synthesis of 13 To a solution of 2,4-difluoro-1-isocyanatobenzene (38 mg, 0.25 mmol) in tetrahydrofuran (3 mL), was added l-[3-amino-4-([[4-(trifluoromethoxy)phenyl]methyl](3,3,3-trifluoropropyl)amino)phenyl]cyclopentane-1-carboxylic acid (80 mg, 0.16 mmol) and triethylamine (48 mg). The mixture was stirred at room temperature for 0.5 h, followed by addition of ethyl acetate (20 mL). The resulting mixture wa washed with of water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: [Column: X Bridge Prep C18 OBD Column, 30*50mm, 5um, 13nm; mobile phase, Waters (0.1% FA) and ACN (60.0% ACN up to 90.0% in 8 min, hold 90.0% in 2 min); Detector, UV 254 nm] to afford the desired product (47.4 mg, 45% yield) as an off- white solid. LCMS C30H27F8N3O4 (ES, m/z): 646.4 [M+H]+; 1HNMR (300 MHz, DMSO-d6): δ 12.23 (brs, 1 H), 9.34 (s, 1 H), 8.55 (s, 1 H), 8.11-8.01 (m, 2 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.37-7.27 (m, 3 H), 7.24-7.15 (m, 1 H), 7.08-7.02 (m, 1 H), 6.92-6.88 (m, 1 H), 4.18 (s, 2 H), 3.21-3.09 (m, 2 H), 2.73-2.50 (m, 4 H), 1.74-1.61 (m, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine In tetrahydrofuran at 20℃; for 2h; | 19.1 Step 1. Synthesis of 19-1 To a solution of 1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclobutane-1-carbonitrile (270 mg, 0.90 mmol) in tetrahydrofuran (5 mL), was added 2,4-difluoro-1-isocyanatobenzene (210 mg, 1.35 mmol) and triethylamine (182 mg, 1.80 mmol). The mixture was then stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate (20 mL), and washed with water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was by silica gel column with ethyl acetate/petroleum ether (1/1) as the eluent to afford the desired product (230 mg, 56% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine In tetrahydrofuran at 20℃; for 1h; | 16.4 Step 4. Synthesis of 16 To a solution of 1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclobutane-1-carboxylic acid (82 mg, 0.26 mmol) in tetrahydrofuran (3 mL), was added triethylamine (53 mg, 0.52 mmol) and 2,4-difluoro-l-isocyanatobenzene (60 mg, 0.39 mmol). The reaction was then stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (20 mL), and washed with water (10 mL x 2). The organic phase was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: [Column, X Bridge Shield RP18 OBD Column, 5um,19* 150mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (15.0% ACN up to 65.0% in 8 min); Detector, UV 254; 220 nm] to afford the desired product (44.7 mg, 37% yield). LCMS (ES, m z): 474.50 [M+H]+; 1H NMR: (300 MHz, DMSO-D6, ppm):5 9.23 (s, 1 H), 8.01-7.88 (m, 2 H), 7.77 (s, 1 H), 7.31-7.25 (m, 1 H), 7.08-7.00 (m, 2 H), 6.86 (d, J = 6.9 Hz, 1 H), 2.90-2.61 (m, 6 H), 2.30-2.20 (m, 2 H), 1.82-1.62 (m, 4 H), 0.83 (d, J = 6.6 Hz, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With triethylamine In tetrahydrofuran at 20℃; for 2.5h; | 20.7 Step 7. Synthesis of 20 To a solution of 1-[3-amino-4-[cyclohexyl(ethyl)amino]phenyl]cyclobutane-1-carboxylic acid (210 mg, 0.66 mmol) and 2,4-difluoro-1-isocyanatobenzene (154.7 mg, 1.00 mmol) in tetrahydrofuran (5 niL), was added triethylamine (200.9 mg, 1.99 mmol). The reaction was stirred at room temperature for 2.5 h before ethyl acetate (50 mL) was added. The mixture was washed with water (50 mL x 2) and brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: [Column, X Bridge Prep C18 OBD Column, 19*150 mm 5 urn; mobile phase, water (10 mmol/L NH4HC03)/ CH3CN ; MeCN from 25.0% to 55.0% in 8 min; Detector, UV 245 nm] to afford the desired product (80.4 mg, 26% yield) as a white solid. LCMS (ES, m/z): 472.5 [M+H ]+; 1H NMR: (300 MHz, DMSO-d6, ppm) : δ9.39 (s, 1 H), 8.74 (s, 1 H), 8.19-7.94 (m, 2 H), 7.33-7.26 (m, 1 H), 7.22-6.97 (m, 2 H), 6.91-6.81 (m, 1 H), 3.00 (q, J = 7.0 Hz, 2 H), 2.75-2.60 (m, 3 H), 2.42-2.25 (m, 2 H), 1.97- 1.53 (m, 7 H), 1.20- 1.00 (m, 5 H), 0.82 (t, J = 7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With triethylamine In tetrahydrofuran at 20℃; for 1.5h; | 21.4 Step 4. Synthesis of 21 To a solution of 1-[3-amino-4-[cyclohexyl(2-methylpropyl)amino]phenyl]cyclobutane-1-carboxylic acid (300 mg, 0.87 mmol) in tetrahydrofuran (6 mL) were added triethylamine (264 mg, 2.61 mmol) and 2,4-difluoro-1-isocyanatobenzene (149 mg, 0.96 mmol). The reaction was then stirred at room temperature for 1.5 h. The mixture was concentrated under vacuum and the residue was purified by Prep-HPLC with the following conditions: [Column: Waters X-bridge C18, 5 um, 19 x 150 mm; Mobile phase A: water (0.05% NH4HCO3), Mobile phase B: CAN; Gradient: 25% CAN to 50% ACN in 8 min; Detector: UV 254 nm] to afford the desired product (62.5 mg, 14% yield) as a white solid. LCMS: (ES, m/z): 500.30 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm): δ 9.31 (s, 1 H), 8.09 (s, 1 H), 7.87-7.79 (m, 2 H), 7.27-7.21 (m, 1 H), 7.05-6.95 (m, 2 H), 6.81-6.78 (m, 1 H), 2.83-2.52 (m, 4 H), 2.28-2.12 (m, 2 H), 1.93-1.53 (m, 6 H), 1.52-1.38 (m, 1 H), 1.37-0.86 (m, 6 H), 0.75 (d, J = 6.5 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine In tetrahydrofuran at 20℃; for 3h; | 1.5 Step 5. Synthesis of 1-5 Into a 100-mL 3-necked round-bottom flask, was placed a solution of 2-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]acetonitrile (1.1 g, 4.24 mmol) in tetrahydrofuran (50 mL), 2,4-difluoro-1-isocyanatobenzene (790 mg, 5.09 mmol), and triethylamine (860 mg, 8.50 mmol). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10-1 :3) to afford 3-[2-[bis(2-methylpropyl)amino]-5-(cyanomethyl)phenyl]-1-(2,4-difluorophenyl)urea (700 mg, 40% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine In tetrahydrofuran at 20℃; for 2h; | 26.6 Step 6. Synthesis of 26 To a solution of 26-4 (180 mg, 0.46 mmol) in tetrahydrofuran (5 mL), were added 2,4-difluoro-1-isocyanatobenzene (78 mg, 0.50 mmol) and triethylamine (69 mg, 0.68 mmol) sequentially. The mixture was then stirred at room temperature for 2 h. The mixture was concentrated under vacuum and the residue was purified by Prep-HPLC with the following conditions: [Column: X bridge, C18, 5 um, 19 x 150 mm; Mobile phase A: water (0.05% NH4HCO3), Mobile phase B: ACN; Gradient: 35% ACN to 60% ACN in 8 min; Detector: UV 254 nm] to afford the desired product (92.2 mg, 37% yield) as a white solid. LCMS: (ES, m z): 550.1 [M+H]+. 1H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.44 (s, 1 H), 8.21 (s, 1 H), 8.05 (s, 1 H), 7.99-7.91 (m, 1 H), 7.35-7.27 (m, 1 H), 7.16 (d, J= 8.1 Hz, 1 H), 7.11-6.98 (m, 1 H), 6.89-6.85 (m, 1 H), 3.25-3.10 (m, 2 H), 3.09-2.92 (m, 4 H), 2.84-2.60 (m, 4 H), 2.39-2.19 (m, 4 H), 2.02-1.82 (m, 2 H), 1.81-1.68 (m, 1 H), 1.41-1.21 (m, 1 H), 0.83 (d, J= 6.6 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In dichloromethane at 20℃; for 12h; | 30.1 Step 1. Synthesis of 30-1 To a solution of 1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]-3,3-difluorocyclobutane-1-carbonitrile (500 mg, 1.49 mmol) and triethylamine (196 mg, 1.94 mmol) in dichloromethane (5 mL), was added 2,4-difluoro-1-isocyanatobenzene (254 mg, 1.64 mmol). The resulting mixture was then stirred at room temperature for 12 h. The reaction was quenched by addition of water/ice (50 mL), extracted with ethyl acetate (30 mL x 3), and washed with brine (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1/20) as the eluent to afford the desired product (700 mg, 96% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With triethylamine In tetrahydrofuran at 20℃; for 12h; | 29.9 Step 9. Synthesis of 29 To a solution of 1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]-3,3-difluorocyclobutane-1-carboxylic acid (40 mg, 0.11 mmol) and triethylamine (17 mg, 0.17 mmol) in tetrahydrofuran (4 mL), was added 2,4-difluoro-1-isocyanatobenzene (21 mg, 0.14 mmol). The resulting mixture was then stirred at room temperature for 12 h. The reaction was quenched byaddition of water/ice (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Pre-TLC to afford the desired product (15.7 mg, 27% yield). LCMS (ES, m z): 510.5 [M+H]+; 1H NMR: (300 MHz, DMSO-d6, ppm): δ 13.01 (brs, 1 H), 9.31 (s, 1 H), 8.1 (s, 1 H), 7.97-7.85 (m, 2 H), 7.31 (t, J = 6 Hz, 1 H), 7.17 (d, J = 6 Hz , 1 H), 7.06 (t, J = 6 Hz, 1 H), 6.93 (t, J = 6 Hz, 1 H), 3.25 (s, 1 H), 3.00-2.86 (m, 3 H), 2.67 (d, J = 6 Hz, 4 H), 1.70-1.61 (m, 2 H) , 0.91 (s, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine In tetrahydrofuran at 20℃; for 2h; | 31.4 Step 4. Synthesis of 31-5 To a solution of methyl 2-[3-amino-4-[bis(2-methylpropyl)amino]phenoxy]acetate (300 mg, 0.97 mmol) in tetrahydrofuran (5 mL), was added triethylamine (147 mg, 1.45 mmol) and then 2,4-difluoro-1-isocyanatobenzene (181 mg, 1.17 mmol). The mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1: 10-1:3) as the eluent to afford the desired product (180 mg, 40% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In tetrahydrofuran at 20℃; for 3h; | 32.4 Step 4. Synthesis of 32-4 To a solution of methyl 2-[3-amino-4-[bis(2-methylpropyl)amino]phenoxy]-2- methylpropanoate (500 mg, 1.49 mmol) in tetrahydrofuran (10 mL), were added triethylamine (451 mg, 4.46 mmol) and then 2,4-difluoro-l-isocyanatobenzene (346 mg, 2.23 mmol). The resulting mixture was then stirred at room temperature for 3 h. The reaction was quenched by addition of water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1/25) as eluent to afford the desired product (570 mg, 78% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine In tetrahydrofuran at 20℃; | 36.6 Step 6. Synthesis of 36-6 Into a 100-mL 3-necked round-bottom flask, was placed a solution of methyl 2-([3-amino-4-[bis(2-methylpropyl)amino]phenyl]sulfanyl)acetate (2 g, 6.16 mmol), 2,4-difluoro-1-isocyanatobenzene (1.15 g, 7.41 mmol), and triethylamine (1.25 g, 12.35 mmol) in tetrahydrofuran (50 mL). The reaction was stirred at room temperature for overnight. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1: 10-1 : 1) to afford the desired product (1.5 g, 51% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine In tetrahydrofuran at 20℃; for 0.5h; | 37.4 Step 4. Synthesis of 37-4 To a solution of 4-(benzylsulfanyl)-1-N,1-N-bis(2-methylpropyl)benzene-l,2- diamine (200 mg, 0.58 mmol) and triethylamine (71 mg, 0.70 mmol) in tetrahydrofuran (10 mL) was added 2,4-difluoro-l-isocyanatobenzene (109 mg, 0.70 mmol). The reaction was then stirred at room temperature for 30 min. The reaction was quenched by addition of water (10 mL), and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with 3 x 50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford the desired product (150 mg, 52% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine In tetrahydrofuran at 20℃; for 0.5h; | 46.5 Step 5. Synthesis of 46-5 A solution of 46-4 (130 mg, 0.31 mmol), 2,4-difluoro-1-isocyanatobenzene (73 mg, 0.47 mmol) and triethylamine (95 mg, 0.94 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 30 min. The mixture was diluted with ethyl acetate (30 mL), and washed with water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1/2) as the eluent to afford the desired product (120 mg, 67% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine In tetrahydrofuran at 20℃; for 3h; | 2.3 Step 3. Synthesis of 2-3 To a solution of 2-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]propanenitrile (546 mg, 2.00 mmol) in tetrahydrofuran (20 mL), were added triethylamine (610 mg, 6.03 mmol) and 2,4-difluoro-1-isocyanatobenzene (456 mg, 2.94 mmol). After stirring at room temperature for 3 h, the reaction was concentrated under vacuum and the residue was purified by Flash-Prep-HPLC [Column: C18; Mobile phase A: Water (0.05% ammonium hydrogen carbonate), mobile phase B: acetonitrile; Gradient: 45% acetonitrile to 85% acetonitrile in 30 min] to afford the desired product (450 mg, 40% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine In tetrahydrofuran at 20℃; for 2h; | 52.7 Step 7. Synthesis of 83-7 To a solution of 83-6 (80 mg, 0.24 mmol) in tetrahydrofuran (10 mL) at 0 °C, were added triethylamine (50 mg, 0.48 mmol) and 2,4-difluoro-1-isocyanatobenzene (75 mg, 0.48 mmol). The reaction was stirred at room temperature for 2 h. The mixture was extracted with ethyl acetate (50 mL) and washed with water (50 mL). The organic phase was concentrated and purified by pre-TLC (petroleum ether/ ethyl acetate = 6/1) to afford the desired product (80 mg, 68% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With triethylamine In tetrahydrofuran at 20℃; for 3h; | 6.3 Step 3. Synthesis of 6-3 To a solution of 2-[3-amino-4-[bis(2-methylpropyl)amino]-5-fluorophenyl]acetonitrile (190 mg, 0.68 mmol) in tetrahydrofuran (3 mL) was added 2,4-difluoro-1-isocyanatobenzene (160 mg, 1.03 mmol) and triethylamine (0.21 g, 2.04 mmol). The mixture was then stirred at room temperature for 3 h. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10 mL x 2). The organic phase was concentrated under vacuum. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1/2) as eluent to afford the desired product (0.14 g, 47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With triethylamine In tetrahydrofuran at 25℃; for 3h; | 7.6 Step 6. Synthesis of 7 To a solution of 1-[3-amino-4-[bis(2-methylpropyl) amino]phenyl]cyclopropane-1- carboxylic acid (530 mg, 1.74 mmol) and 2,4-difluoro-1-isocyanatobenzene (324 mg, 2.09 mmol) in tetrahydrofuran (353 mg, 4.89 mmol), was added triethylamine (5 mL). The reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was concentrated under vacuum and then purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5um, 19 x 150mm; Mobile Phase A: Water with 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 85% B in 8 min; detector: UV 254 nm) to afford 1-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]cyclopropane-l-carboxylic acid (146.8 mg, 18% yield). LRMS: (ES, m/z): [M+H]+= 460.3. 1H NMR (300 MHz, DMSO-d6): δ 12.25 (s, br, 1H), 9.29 (s, 1H), 8.04 (s, 1H), 7.96 - 7.85 (m, 1H), 7.84 (s, 1H), 7.34 - 7.26 (m, 1H), 7.10 (d, J= 8.1 Hz, 1H), 7.09 - 6.93 (m, 1H), 6.91 (d, J= 2.1 Hz, 1H), 2.65 (d, J= 6.9 Hz, 4H), 1.70 - 1.59 (m, 2H), 1.42 - 1.39 (m, 2H), 1.09 - 1.05 (m, 2H), 0.86 (d, J= 6.6 Hz, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With triethylamine In tetrahydrofuran at 25℃; for 3h; | 8.6 Step 6. Synthesis of 8 A mixture of 4-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]oxane-4-carboxylic acid (520 mg, 1.49 mmol), 2,4-difluoro-1-isocyanatobenzene (279 mg, 1.80 mmol) and triethylamine (303 mg, 2.99 mmol) in tetrahydrofuran (5 mL) was stirred at 25 °C for 3 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was concentrated and the residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5um, 19 x 150mm; Mobile Phase A: Water with 0.05% NH4HC03, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 85% B in 8 min; detector: UV 254 nm) to afford 4-[4-[bis(2-methylpropyl)amino]-3-[[(2,4- difluorophenyl)carbamoyl]amino]phenyl]oxane-4-carboxylic acid (88.56 mg, 12%) as a white solid. LRMS (ES, m/z): [M+H]+= 504.5. 1HNMR (300MHz, DMSO-d6) δ 9.30 (s, 1H), 8.04 (s, 1H), 7.97-7.89 (m, 2H), 7.34-7.26 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.07-6.98 (m, 2H), 3.80 (d, J= 11.7, 2H), 3.54-3.41 (m, 2H), 2.66 (d, J = 6.9 Hz, 4H), 2.34 (d, J= 13.2 Hz, 2H), 1.75-1.60, (m, 4H), 0.84 (d, J = 6.6 Hz, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With triethylamine In tetrahydrofuran at 20℃; for 4h; | 9.4 Step 4. Synthesis of 9-4 Into a 25-mL round-bottom flask, was placed tetrahydrofuran (5 mL), methyl l-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopentane-1-carboxylate (350 mg, 1.01 mmol), triethylamine (202 mg, 2.00 mmol), and 2,4-difluoro-1-isocyanatobenzene (188 mg, 1.21 mmol). The resulting solution was stirred at room temperature for 4 h. The reaction was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10-1 :3) to afford methyl 1-[4-[bis(2-methylpropyl)amino]-3-[[(2,4-difluorophenyl)carbamoyl]amino]phenyl]cyclopentane-1-carboxylate (250 mg, 49% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 3h; | 10.2 Step 2. Synthesis of 10-2 Into a 50-mL 3-necked round-bottom flask, was placed tetrahydrofuran (10 mL), triethylamine (387 mg, 3.82 mmol), and 1-[3-amino-4-[bis(2-methylpropyl)amino]phenyl]cyclopentane-1-carbonitrile (600 mg, 1.91 mmol). This was followed by addition of 2,4-difluoro-1-isocyanatobenzene (356 mg, 2.30 mmol) dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 3 h. The reaction was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-1:3) to afford 3-[2-[bis(2-methylpropyl)amino]-5-(1-cyanocyclopentyl)phenyl]-1-(2,4-difluorophenyl)urea (500 mg, 56% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With triethylamine In tetrahydrofuran at 20℃; for 2h; | 11.8 Step 8. Synthesis of 11 To a solution of 1-[3-amino-4-[cyclohexyl(2-methylpropyl)amino]phenyl]cyclopentane-1-carboxylic acid (85 mg, 0.24 mmol) in tetrahydrofuran (50 mL), was added 2,4-difluoro-1-isocyanatobenzene (51 mg, 0.33 mmol) and triethylamine (111 mg, 1.10 mmol) sequentially. The reaction was then stirred at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was re-dissolved in water (50 mL), and the pH value was adjusted to 6 with HC1 (1 N). The mixture was extracted with dichloromethane (50 mL x 2), and washed with brine (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: [Column, C18 silica gel; mobile phase (A: MeCN, B: H2O), MeCN = 96%; Detector, UV 254 nm] to afford the desired product (26.6 mg, 22% yield) as a white solid. LCMS (ES, m z): 514.50 [M+l]+; 1HNMR (300 MHz, DMSO-D6, ppm): δ 12.23 (s, 1 H), 9.37 (t, J = 4.6 Hz, 1 H), 8.14 (s, 1 H), 7.99 (d, J= 2.2 Hz, 1 H), 7.90 (td, J= 9.2, 6.2 Hz, 1 H), 7.32 (td, J= 8.8, 4.5 Hz, 1 H), 7.22 - 6.99 (m, 2 H), 6.99 - 6.85 (m, 1 H), 2.76 (d, J = 7.3 Hz, 2 H), 1.90-1.80 (m, 2 H), 1.77 - 1.47 (m, 9 H), 1.40 - 1.00 (m, 9 H), 0.82 (d, J = 6.5 Hz,6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With triethylamine In tetrahydrofuran at 20℃; for 0.5h; | 12.6 Step 6. Synthesis of 12 A solution of 1-[3-amino-4-[(4,4-difluorocyclohexyl)(2-methylpropyl)amino]phenyl]cyclopentane-1-carboxylic acid (90 mg, 0.23 mmol), 2,4- difluoro-1-isocyanatobenzene (53 mg, 0.34 mmol) and triethylamine (69 mg, 0.69 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 0.5 h. Ethyl acetate (20 mL) was then added and the organic phase was washed with water (10 mL) and brine(10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: [Column: X Bridge Shield RP18 OBD Column, 5um,19* 150mm; mobile phase, Waters(10MMOL/L NH4HCO3) and ACN (35.0% ACN up to 70.0% in 8 min); Detector, 254 nm] to afford the desired product (52.1 mg, 42% yield) as an off-white solid. LCMS (ES, m z): 550.50 [M+H]+; 1HNMR (300 MHz, DMSO-d6, ppm): δ 9.40 (s, 1 H), 8.24 (s, 1 H), 8.09 (d, J = 2.1 Hz, 1 H), 7.96-7.88 (m, 1 H), 7.35-7.27 (m, 1 H), 7.15-6.94 (m, 3 H), 2.89-2.76 (m, 3 H), 2.08-1.24 (m, 17 H), 0.82 (d, J = 6.6 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With pyridine at 20℃; for 18h; Inert atmosphere; | 5 Synthesis of carboxamide-substituted 1-(4-fluorobenzyl)-N-(piperidin-4-yl)-1H-benzo[d]imidazol-2-amine analogues General procedure: General procedure: To a solution of 4 (243mg, 0.5mmol) in dry pyridine (2mL) was added an appropriate isocyanate (0.5mmol). The reaction mixture was stirred under a nitrogen atmosphere overnight. Pyridine was removed under reduced pressure. Toluene (2-3mL) was added and removed in vacuo. This was repeated three times. Finally, the crude residue was purified by silica gel flash chromatography yielding the title compounds. The following compounds were made according to this procedure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: 2,4-diflurophenylisocyanate; tert-butyl 5-(aminomethyl)indoline-1-carboxylate In dichloromethane for 1h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 2h; | 1 Reference Preparation 1 Synthesis of 1-(2,4-difluorophenyl)-3-(2,3-dihydro-1H-indol-5-ylmethyl)urea Stir a mixture of tert-butyl 5-(aminomethyl)indoline-1-carboxylate (4.1 g, 17 mmol) and 2,4-difluoro-1-isocyanatobenzene (3 mL, 24 mmol) in DCM (100 mL) for one hour. Quench the reaction with MeOH and water and concentrate. Dissolve the residue in DCM (30 mL) and add TFA (15 mL) and allow to stand at room temperature for two hours. Concentrate and add saturated aqueous sodium bicarbonate. Extract the mixture with MeOH/DCM (1/5, v/v). Dry the organic layer over anhydrous magnesium sulfate, filter and concentrate the filtrate. Recrystallize from EtOH to give two crops. Combine the crops to give the title compound (3.5 g, 68%). ES/MS (m/z): 304.0 (M+H). |
Tags: 59025-55-7 synthesis path| 59025-55-7 SDS| 59025-55-7 COA| 59025-55-7 purity| 59025-55-7 application| 59025-55-7 NMR| 59025-55-7 COA| 59025-55-7 structure
[ 50528-80-8 ]
1,3,5-Trifluoro-2-isocyanatobenzene
Similarity: 1.00
[ 39718-32-6 ]
1,4-Difluoro-2-isocyanatobenzene
Similarity: 0.94
[ 83594-83-6 ]
1,3-Difluoro-5-isocyanatobenzene
Similarity: 0.85
[ 190774-50-6 ]
2-Fluoro-5-methylphenylisocyanate
Similarity: 0.84
[ 50528-80-8 ]
1,3,5-Trifluoro-2-isocyanatobenzene
Similarity: 1.00
[ 39718-32-6 ]
1,4-Difluoro-2-isocyanatobenzene
Similarity: 0.94
[ 83594-83-6 ]
1,3-Difluoro-5-isocyanatobenzene
Similarity: 0.85
[ 190774-50-6 ]
2-Fluoro-5-methylphenylisocyanate
Similarity: 0.84
[ 50528-80-8 ]
1,3,5-Trifluoro-2-isocyanatobenzene
Similarity: 1.00
[ 39718-32-6 ]
1,4-Difluoro-2-isocyanatobenzene
Similarity: 0.94
[ 83594-83-6 ]
1,3-Difluoro-5-isocyanatobenzene
Similarity: 0.85
[ 190774-50-6 ]
2-Fluoro-5-methylphenylisocyanate
Similarity: 0.84
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