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CAS No. : | 1032528-06-5 | MDL No. : | MFCD18762017 |
Formula : | C21H32BNO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AYUCJBOQVMWQJD-UHFFFAOYSA-N |
M.W : | 373.29 | Pubchem ID : | 58326444 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In tetrahydrofuran for 5 h; Reflux | Step 5: tert-Butyl {1 -[4-(4,4,5,5-tetramethy-1 ,3,2-dioxaborolan-2-yl)phenyl]- cyclobutyl}carbamate [lnt-1 B] 27.75 g (55 mmol) [1-(4-Bromophenyl)cyclobutyl]carbamic acid fe/f-butyl ester, 23.76 mmol (93.6 mmol) bis-(pinacolato)diboron, 25 g (255 mmol) potassium acetate and 2.08 g (2.55 mmol) 1 , 1 '-bis(diphenylphosphino)ferrocenedichloro- palladium(ll) in 500 mL degassed THF were heated for three hours at reflux. The colour of the reaction mixture turned from dark red to black. Due to an incomplete reaction heating was continued for another two hours. The reaction mixture was poured on water (400 mL) and diluted with ethyl acetate (700 mL). After stirring for 30' the organic phase was separated and the aqueous phase was reextracted twice with ethyl acetate (400 and 200 mL). The combined organic extracts were washed with brine (200 mL) and dried (sodium sulfate). After evaporation of the solvent the residue was purified by chromatography (Biotage) yielding 28.99 g (91.3percent) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.51 -7.67 (m, 3H), 7.38 (d, 2H), 2.22-2 42 (m, 4H), 1.88-2.02 (m, 1 H), 1.63-1.80 (m, 1 H), 1.00-1.38 (m, 21 H) ppm. |
90.8% | With potassium acetate In tetrahydrofuranReflux | 10 g (30.7 mmol) [1 -(4-Bromophenyl)-cyclobutyl]-carbamic acid tert. -butyl ester, 8.56 g (33.7 mmol) bis-(pinacolato)diboron, 750.9 mg (0.92 mmol) 1 ,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(ll) and 9.03 g (92 mmol) potassium acetate are given in 180 mL THF which has been degassed for 10'. The reaction mixture is heated at reflux until the starting material has disappeared (usually two hours). At 60 °C the reaction mixture turns dark. The reaction mixture is poured on water (200 ml_) and ethyl acetate (500 ml_) is added. The mixture is vigorously stirred for two hours. After separation of the organic phase the aqueous phase is extracted once more with ethyl acetate (300 ml_). The combined organic extracts are washed with brine and dried (sodium sulfate). After evaporation of the solvent the residue, a black oil, is purified by chromatography on silicagel (eluents: hexane/ ethyl acetate). 10.4 g (90.8percent) of the title compound are obtained.MS (ES+, M+1 ): 3741H-NMR (400 MHz, d6-DMSO): δ 7.61 (d, 2H), 7.55-7.65 (br. 1 H), 7.35 (d, 2H), 2.22-2.42 (m, 4H), 1 .88-2.02 (m, 1 H), 1 .65-1 .82 (m, 1 H), 1 .00-1 .38 (m, 21 H). |
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere | Potassium acetate (2.41 g) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.25 g) are sequentially added to a DMF (25 mL) solution of the product (3.21 g) of Reference Example 56(3), and the mixture was placed in a nitrogen atmosphere. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (360 mg) was added thereto, and the mixture was stirred at 80° C. for 10 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (3.20 g, yield: 87percent) as a colorless solid. 1H-NMR (CDCl3) δ: 7.79 (2H, d, J=8.0 Hz), 7.43 (2H, d, J=8.0 Hz), 5.07 (1H, br s), 2.59-2.31 (4H, m), 2.14-2.03 (1H, m), 1.90-1.78 (1H, m), 1.36 (9H, s), 1.34 (12H, s) ESI-MS m/z 374 (MH+) |
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In water; N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere | Reference Example 56(4) tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate Potassium acetate (2.41 g) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.25 g) are sequentially added to a DMF (25 mL) solution of the product (3.21 g) of Reference Example 56(3), and the mixture was placed in a nitrogen atmosphere. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (360 mg) was added thereto, and the mixture was stirred at 80°C for 10 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (3.20 g, yield: 87percent) as a colorless solid. 1H-NMR (CDCl3) δ: 7.79 (2H, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.0 Hz), 5.07 (1H, br s), 2.59 - 2.31 (4H, m), 2.14 - 2.03 (1H, m), 1.90 - 1.78 (1H, m), 1.36 (9H, s), 1.34 (23H, s) ESI-MS m/z374 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;bis(tri-tert-butylphosphine)palladium(0); In 1,4-dioxane; at 80℃; for 46h; | tert-butyl{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate (8-6) A mixture of tert-butyl[1-(4chlorophenyl)cyclobutyl]carbamate (1-1, 2 g, 7 mmol) and Pd(PBu3)2 (0.1 g, 0.2 mmol), KOAc (1 g, 10.6 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2 g, 8.5 mmol) in 1,4-dioxane (5 1 mL) was stirred at 80 C. for 46 hrs. The reaction mixture was cooled and filtered and the filtrate was concentrated in vacuo and partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with water and then with brine, separated and dried over MgSO4. Upon solvent removal, the residue was dissolved in a limited amount of DMSO and purified by flash silica gel chromatography (100% hexane to 90% hexane/10% EtOAc) to 8-6 as a white solid. MS (M+H)+: observed=374.3, calculated=374.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis(tri-tert-butylphosphine)palladium(0); In 1,4-dioxane; 1-methyl-pyrrolidin-2-one; water; at 80℃; for 0.166667h;Microwave irradiation; | tert-Butyl {1-[4-(2-phenyl-9-pyrazin-2-yl[1,2,4]triazolo[4',3':1,6]pyrido[2,3-b]pyrazin-3-yl)phenyl]cyclobutyl}carbamate (8-7) To a microwave vial was added 3-chloro-2-phenyl-9-pyrazin-2-yl[1,2,4]triazolo[4',3':1,6]pyrido[2,3-b]pyrazine (8-5, 0.151 g, 0.421 mmol), tert-butyl{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate (8-6, 0.236 g, 0.631 mmol), potassium carbonate (0.174 g, 1.262 mmol), bis(tri-t-butylphosphine)palladium(0) (21.51 mg, 0.042 mmol), water (0.2 mL), NMP (0.2 mL), and 1.4 Dioxane (0.8 mL). The reaction mixture was then heated to 80 C. under microwave irradiation for 10 minutes. The reaction mixture was then permitted to cool to room temperature, diluted with NMP/MeOH, and filtered through a syringe filter. The resulting residue was then purified by reverse phase column chromatography (Sunfire C18) eluding with 5 to 100% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were then concentrated in vacuo to give 8-7 as a green solid. HRMS (M+H)+: observed=571.2591, calculated=571.2565. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 7-chloro-4- methoxy-3H-benzoimidazole-5-carboxylic acid methyl ester (0.34 g, 1.41 mmol) in DMF (14 mL) at 0C, under an argon atmosphere, was added sodium hydride (68 mg, 1.70 mmol) portionwise. After 10 min, (2-chloromethoxy-ethyl)-trimethylsilane (0.30 mL, 1.70 mmol) was added dropwise. The reaction mixture was stirred at 0C for 2.5 hours before being quenched into ice/water (40 mL). The resultant biphasic mixture was separated and extracted with ethyl acetate (2 x 40 mL). The combined organic phase was washed with brine (40 mL), dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (Si02, gradient 0 to 60% EtOAc in pentane) to give a mixture of the title compounds as a yellow oil (0.46 g, 88%). LCMS (Method A): RT = 4.69 min, [M+H]+ = 371/379 and RT = 4.74 min, [M+H]+ = 371/379.Step 3: 7-Chloro-4-methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimcarboxylic acid and 7-chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H- benzoimidazole-5-carboxylic acid: To a stirred suspension of a mixture of 7-chloro-4- methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5-carboxylic acid and 7- chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazole-5-carboxylic acid (0.46 g, 1.24 mmol) in MeOH (4.0 mL) and water (4.0 mL), was added sodium hydroxide (0.24 g, 6.20 mmol) portionwise. The reaction mixture was stirred at 75C for 1 hour. Upon cooling to RT, water (30 mL) was added and the pH of the resultant mixture was adjusted to ~7 by careful addition of 12 M aqueous HCI solution. The resulting suspension was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (Na2S0 ), filtered and concentrated in vacuo, to yield a mixture of the title compounds as an off-white glass (0.44 g, 100%). LCMS (Method A): RT = 4.44 min, [M+H]+ = 357/359 and RT = 4.51 min, [M+H]+ = 357/359. Step 4: 7-Chloro-4-methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzcarboxylic acid methoxy-methyl-amide and 7-chloro-4-methoxy-1-(2-trimethylsilanyl- ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide: Following the procedure used to prepare /V-dimethoxy-W-methyl-nicotinamide, a mixture of 7- chloro-4-methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5-carboxylic acid and 7-chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazole-5- carboxylic acid (0.44 g, 5.88 mmol) were reacted to give a mixture of the title compounds as an oil (0.40 g, 81 %). LCMS (Method A): RT = 4.27 min, [M+H]+ = 400/402 and RT = 4.40 min, [M+H]+ = 400/402.Step 5: 1-[7-Chloro-4-methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazol-5- yl]-3-phenyl-propynone and 1-[7-chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)- 1H-benzoimidazol-5-yl]-3-phenyl-propynone: To a solution of a mixture of 7-chloro-4- methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide and 7-chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1 H- benzoimidazole-5-carboxylic acid methoxy-methyl-amide (1 10 mg, 0.275 mmol) in anhydrous THF (2.0 mL) at 0C, was added phenylethynyl magnesium bromide solution (1 M in THF, 0.41 mL, 0.41 mmol). The reaction mixture was allowed to warm to RT. After 18 h, the reaction mixture was cooled to 0C and further phenylethynyl magnesium bromide solution (1 M in THF, 0.41 mL, 0.41 mmol) was added and the reaction was allowed to warm to RT. After a further 24 h, the reaction mixture was quenched with saturated aqueous ammonium chloride solution. The resultant biphasic mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 0 to 50% EtOAc in pentane) to afford a mixture of the title compounds (0.11 g, 64%). LCMS (Method A): RT = 4.81 min, [M+H]+ = 441/443 and RT = 5.04 min, [M+H]+ = 441/443. Step 6: 4-Chloro-7-iodo-8-phenyl-1-(2-trimethylsilanyl-ethoxymd]imidazol-6-one and 4-chloro-7-iodo-8-phenyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H- chromeno[7,8-d]imidazol-6-one: Following the procedure used to prepare 6-fluoro-3- iodo-2-phenyl-chromen-4-one, a mixture of 1-[7-chloro-4-methoxy-3-(2-trimethylsilanyl- ethoxymethyl)-3H-benzoimidazol-5-yl]-3-phenyl-propynone and 1-[7-chloro-4-methoxy-1- (2-trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazol-5-yl]-3-phenyl-propynone (64 mg, 0.145 mmol) were reacted to furnish a mixture of the title compounds (54 mg, 80%). LCMS (Method A): RT = 4.75 min, [M+H]+ = 553/555 and RT = 4.96 min, [M+H]+ = 553/555.Step 7: ( 1-{4-[4-Chloro-6-oxo-8-phenyl- 1-(2-trimethylsilanyl-ethoxymethyl)- 1, 6-dihydro- chromeno[7,8-d]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester and (1- {4-[4-chlorc 6-oxc 8-phenyl-3-(4-trimethylsilanyl-butyl)-3^-dihydd]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester: Following the procedure for {1 -[4-(6-fluoro-4-oxo-2-... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 4-chloro-7-iodo-8-phenyl-1 H-chromeno[7,8-d]imidazol-6-one (59 mg, 0.14 mmol) in DMF (1.0 mL) was added potassium carbonate (157 mg, 1.13 mmol) and iodomethane (0.06 mL, 0.95 mmol) at RT. After 2 h, the reaction mixture was poured into water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2S04), filtered and concentrated in vacuo to afford a mixture of the title compounds as an off-white solid (48 mg, 80%). LCMS (Method A): RT = 4.25 min, [M+H]+ = 437/439 and RT = 4.44 min, [M+H]+ = 437/439. Step 3: {1 -[4-(4-Chloro-3-methyl-6-oxo-8-phenyl-3,6-dihydro-chromeno[7,8-d]imidazol-7- yl)-phenyl]-cyclobutyl}-carbamic acid terf-butyl ester and {1-[4-(4-chloro-1-methyl-6-oxo- 8-phenyl-1 ,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester: Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl- 4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid terf-butyl ester, a mixture of 4- chloro-7-iodo-3-methyl-8-phenyl-3H-chromeno[7,8-d]imidazol-6-one and 4-chloro-7-iodo- 1-methyl-8-phenyl-1 H-chromeno[7,8-d]imidazol-6-one were reacted to give a mixture of the title compounds as a glass (43 mg, 69%). LCMS (Method A): RT = 4.76 min, [M+H]+ = 556/558 and RT = 4.85 min, [M+H]+ = 556/558. Step 4: 7-[4-(1 -Amino-cyclobutyl)-phenyl]- -chloro-3-methyl-8-phenyl-3H-chromeno[7,8- d]imidazol-6-one hydrochloride: To a stirred solution of {1-[4-(4-chloro-3-methyl-6-oxo-8- phenyl-3,6-dihydro-chromeno[7,8-d]imida2ol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert- butyl ester and {1-[4-(4-chloro-1-methyl-6-oxo-8-phenyl-1 ,6-dihydro-chromeno[7,8- d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (43 mg, 0.08 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at RT. After 1 h, the reaction mixture was concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 0 to 20% MeOH in DCM) to yield a white solid. This crude residue was dissolved in a mixture of MeOH (0.5 mL), water (1.5 mL) and 1 M HCI (0.1 mL) and chromatographed on a 10 g C18 cartridge {30 to 60% MeOH in water + 1 M HCI (60 μ in each 10 mL of eluent)} to give the title compound as a white solid (4.0 mg). LCMS (Method E): RT = 3.27 min, [M+H]+ = 456/458. nH NMR (300 MHz, CD3OD): δ 8.40 (s, 1 H), 7.99 (s, 1 H), 7.60-7.49 (m, 4H), 7.47 7.30 (m, 5H), 4.29 (s, 3H), 2.86-2.58 (m, 4H), 2.36-2.22 (m, 1 H), 2.06-1.92 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 7-chloro-4- methoxy-3H-benzoimidazole-5-carboxylic acid methyl ester (0.34 g, 1.41 mmol) in DMF (14 mL) at 0C, under an argon atmosphere, was added sodium hydride (68 mg, 1.70 mmol) portionwise. After 10 min, (2-chloromethoxy-ethyl)-trimethylsilane (0.30 mL, 1.70 mmol) was added dropwise. The reaction mixture was stirred at 0C for 2.5 hours before being quenched into ice/water (40 mL). The resultant biphasic mixture was separated and extracted with ethyl acetate (2 x 40 mL). The combined organic phase was washed with brine (40 mL), dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (Si02, gradient 0 to 60% EtOAc in pentane) to give a mixture of the title compounds as a yellow oil (0.46 g, 88%). LCMS (Method A): RT = 4.69 min, [M+H]+ = 371/379 and RT = 4.74 min, [M+H]+ = 371/379.Step 3: 7-Chloro-4-methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimcarboxylic acid and 7-chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H- benzoimidazole-5-carboxylic acid: To a stirred suspension of a mixture of 7-chloro-4- methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5-carboxylic acid and 7- chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazole-5-carboxylic acid (0.46 g, 1.24 mmol) in MeOH (4.0 mL) and water (4.0 mL), was added sodium hydroxide (0.24 g, 6.20 mmol) portionwise. The reaction mixture was stirred at 75C for 1 hour. Upon cooling to RT, water (30 mL) was added and the pH of the resultant mixture was adjusted to ~7 by careful addition of 12 M aqueous HCI solution. The resulting suspension was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (Na2S0 ), filtered and concentrated in vacuo, to yield a mixture of the title compounds as an off-white glass (0.44 g, 100%). LCMS (Method A): RT = 4.44 min, [M+H]+ = 357/359 and RT = 4.51 min, [M+H]+ = 357/359. Step 4: 7-Chloro-4-methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzcarboxylic acid methoxy-methyl-amide and 7-chloro-4-methoxy-1-(2-trimethylsilanyl- ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide: Following the procedure used to prepare /V-dimethoxy-W-methyl-nicotinamide, a mixture of 7- chloro-4-methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5-carboxylic acid and 7-chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazole-5- carboxylic acid (0.44 g, 5.88 mmol) were reacted to give a mixture of the title compounds as an oil (0.40 g, 81 %). LCMS (Method A): RT = 4.27 min, [M+H]+ = 400/402 and RT = 4.40 min, [M+H]+ = 400/402.Step 5: 1-[7-Chloro-4-methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazol-5- yl]-3-phenyl-propynone and 1-[7-chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)- 1H-benzoimidazol-5-yl]-3-phenyl-propynone: To a solution of a mixture of 7-chloro-4- methoxy-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide and 7-chloro-4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1 H- benzoimidazole-5-carboxylic acid methoxy-methyl-amide (1 10 mg, 0.275 mmol) in anhydrous THF (2.0 mL) at 0C, was added phenylethynyl magnesium bromide solution (1 M in THF, 0.41 mL, 0.41 mmol). The reaction mixture was allowed to warm to RT. After 18 h, the reaction mixture was cooled to 0C and further phenylethynyl magnesium bromide solution (1 M in THF, 0.41 mL, 0.41 mmol) was added and the reaction was allowed to warm to RT. After a further 24 h, the reaction mixture was quenched with saturated aqueous ammonium chloride solution. The resultant biphasic mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 0 to 50% EtOAc in pentane) to afford a mixture of the title compounds (0.11 g, 64%). LCMS (Method A): RT = 4.81 min, [M+H]+ = 441/443 and RT = 5.04 min, [M+H]+ = 441/443. Step 6: 4-Chloro-7-iodo-8-phenyl-1-(2-trimethylsilanyl-ethoxymd]imidazol-6-one and 4-chloro-7-iodo-8-phenyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H- chromeno[7,8-d]imidazol-6-one: Following the procedure used to prepare 6-fluoro-3- iodo-2-phenyl-chromen-4-one, a mixture of 1-[7-chloro-4-methoxy-3-(2-trimethylsilanyl- ethoxymethyl)-3H-benzoimidazol-5-yl]-3-phenyl-propynone and 1-[7-chloro-4-methoxy-1- (2-trimethylsilanyl-ethoxymethyl)-1 H-benzoimidazol-5-yl]-3-phenyl-propynone (64 mg, 0.145 mmol) were reacted to furnish a mixture of the title compounds (54 mg, 80%). LCMS (Method A): RT = 4.75 min, [M+H]+ = 553/555 and RT = 4.96 min, [M+H]+ = 553/555.Step 7: ( 1-{4-[4-Chloro-6-oxo-8-phenyl- 1-(2-trimethylsilanyl-ethoxymethyl)- 1, 6-dihydro- chromeno[7,8-d]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester and (1- {4-[4-chlorc 6-oxc 8-phenyl-3-(4-trimethylsilanyl-butyl)-3^-dihydd]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester: Following the procedure for {1 -[4-(6-fluoro-4-oxo-2-... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 21h;Inert atmosphere; | To a round-bottom flask was added 3-bromo-2-phenyl-1-benzopyran-4- one (27.1 mg, 0.09 mmol) and {1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- phenyl]-cyclobutyl}-carbamic acid terf-butyl ester (50.4 mg, 0.135 mmol) intoluene:ethanol (4:1 , 2.5 mL) and 2 M aqueous sodium carbonate (1 mL). The solution was degassed for 20 minutes, after which time, tetrakis(triphenylphosphine) palladium (5.2 mg, 5 mol%) was added. The reaction mixture was heated to 80C using an oil bath with a water cooled reflux condenser, while stirring for 21 hours. The reaction mixture cooled to RT, suspended in ethyl acetate and washed with brine, dried (MgS04), filtered, and concentrated in vacuo. The resulting residue was purified by silica gelchromatography (10:1 to 5:1 hexane:EtOAc gradient) to give a white solid (12.2 mg, 94%). 1H-NMR (400 MHz, CDCI3) δ 8.30 (d, 1 H), 7.66 (dd, 1 H), 7.53 (dd, 1 H), 7.38-7.45 (m, 3H), 7.30-7.36 (m, 3H), 7.27 (d, 2H), 7.19 (d, 2H), 5.1 1 (bs, 1 H), 2.35-2.58 (m, 4H), 1.91-2.09 (m, 1 H), 1.77-1.88 (m, 1 H), 1.38 (bs, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 125℃; for 2h;Inert atmosphere; microwave reactor; | To a microwave vial were added 7- iodo-8-phenyl-1 H-9-oxa-1 ,2-diaza-cyclopenta[a]naphthalen-6-one (100 mg, 0.257 mmol), {1-[4-(4,4,5,5-tetramethy.-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert- butyl ester (115 mg, 0.308 mmol), sodium carbonate solution (2 M in water, 1 ml_), tetrakis(triphenylphosphine)palladium(0) (44.5 mg, 0.039 mmol) and DME (3 ml_). The reaction mixture was purged using nitrogen and heated in a microwave reactor at 125C for 1 hour. Further portions of {1-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg, 0.134 mmol) andtetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) were added and the mixture was heated in a microwave reactor at 125C for a further 1 hour. The reaction mixture was partitioned between EtOAc and water and the resulting biphasic mixture was separated. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with water and brine, dried (Na2S04), filtered, andconcentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 30 to 70% EtOAc in cyclohexane) to afford the title compound (55.1 mg, 42%) as a yellow gum. LC S (Method H): RT = 3.95 min, [M+H]+ = 508. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 125℃; for 0.25h;Inert atmosphere; microwave reactor; | 7-Bromo-3-iodo-2-phenyl-chromen-4-one (320 mg, 0.75 mmol), {1- [4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert- butyl ester (295 mg, 0.8 mmol), tetrakis(triphenyphosphine)palladium (0) (87 mg, 0.075 mmol) and sodium carbonate (159 mg, 1.5 mmol) were suspended in DME (10 mL) and water (5 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The reaction mixture was heated in a microwave at 125C for 15 min. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases separated. The organic layer was washed with brine (20 mL), dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (Si02, 20 % ethyl acetate in cyclohexane) to give the title compound as a pale yellow foam (200 mg, 49%). LCMS (Method A): RT = 5.45 min, [M+H]+ = 546/548. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 125℃; for 0.5h;Inert atmosphere; microwave reactor; | To a microwave vial were added 6-fluoro-3-iodo-2-phenyl-chromen- 4-one (55 mg, 0.15 mmol), {1-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]- cyclobutylj-carbamic acid tert-butyl ester (62 mg, 0.165 mmol, prepared as described in WO2008/070016), sodium carbonate solution (2M in water, 0.26 mL, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) and DME (3 mL). The reaction mixture was purged using argon and heated in a microwave reactor to 125 C for 30 min. The mixture was partitioned between water (2 mL) and EtOAc (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL). The combined organic extracts were washed with brine (5 mL), dried (Na2S04), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 0 to 30 % ethyl acetate in cyclohexane) to afford the title compound (22 mg, 30%). 1H NMR (400 MHz, CDCI3): δ 7.95-7.90 (m, H), 7.57-7.52 (m, 1 H), 7.46-7.30 (m, 6H), 7.28-7.22 (m, 2H), 7.21-7.16 (m, 2H), 5.03 (s, 1 H), 2.64-2.31 (m, 4H), 2.14-2.00 (m, 1 H), 1.89-1.77 (m, 1 H), 1.48-1.18 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 80℃;Inert atmosphere; | Step 1: tert-Butyl (1-(4-(4-oxo-5-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-6- yl)phenyl)cyclobutyl)carbamate: To a solution of 6-iodo-5-phenylfuro[2,3-af]pyrimidin- 4(3H)-one (65 mg, 0.19 mmol, prepared as described in WO2006/004658) in DMF (3 mL) was added ferf-butyl (1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)cyclobutyl)carbamate (72 mg, 0.19 mmol, prepared as described inWO2008/070016), Pd(dppf)CI2 (16 mg, 0.02 mmol), K2C03 (66 mg, 0.48 mmol) and water (1 mL). The reaction was then heated at 80C overnight under a nitrogen atmosphere. After cooling to RT, ethyl acetate and water was added, the layers were separated, and the aqueous extracted once more with ethyl acetate. The combined organic layers were then washed with water/brine 1 : 1 , dried (Na2S04), filtered, and concentrated in vacuo. The residue was triturated with DCM to provide the title compound as a white solid.LRMS (ESI) M+Na+ = 480. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 80℃; for 3h; | Step 3: tert-Butyl (1-(4-(5-phenylfuro[2,3-d]pyrimidin-6-yl)phenyl)cyclobutyl)carbamate: Pd(PPh3)4 (8.5 mg, 7.37 pmol) was added to a pre-degassed stirred solution of 6-iodo-5- phenylfuro[2,3-d]pyrimidine (47.5 mg, 0.148 mmol), K3P0 (93.9 mg, 0.443 mmol) and fe/f-butyl(1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (82.6 mg, 0.221 mmol) in 4:1 , DMF/H20 (2.5 mL). The temperature was increased to 80 C. After 3 hours, the reaction mixture was partitioned between EtOAc (5.0 mL) and H20 (5.0 mL). The resulting biphasic mixture was separated, the aqueous layer extracted using EtOAc (2 * 5.0 mL), the combined organic phase was washed using brine (3 * 5.0 mL), dried (Na2S04) and the solvents were removed in vacuo. The remaining residue was purified by flash chromatography (Si02, 0→20%, EtOAc in n-hexane) to give the title compound (61.0 mg, 94%) as a colourless oil. H NMR (400 MHz, CDCI3): δ 9.01 (s, 1 H), 8.91 (s, 1 H), 7.70 (d, 2H), 7.55-7.38 (m, 7H), 5.19 (s, 1 H), 2.60-2.40 (m, 4H), 2.19-2.06 (m, 1 H), 1.95-1.82 (m, 1 H), 1.49-1.13 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 120℃; for 0.333333h;Microwave irradiation; Sealed tube; | Step 3: tert-Butyl (1-(4-(2-phenylfuro[3,2-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate: Pd(PPh3)4 (18.0 mg, 0.0156 mmol) was added to a stirred solution of 3-iodo-2- phenylfuro[3,2-6]pyridine (100 mg, 0.31 1 mmol), K3P04 (198 mg, 0.934 mmol) and tert- butyl (1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (174 mg, 0.467 mmol, prepared as described in WO2008/070016) in 4: 1 , DMF/H20 (5.0 mL). The reaction vessel was sealed and heated to 120 C for 20 minutes using microwave conditions. The reaction mixture was partitioned between EtOAc (5.0 mL) and brine (5.0 mL), the resulting biphasic mixture separated, the organic phase washed using further brine (2 χ 5.0 mL) to remove residual DMF, filtered/dried using a phase separator (Isolute SPE), and the solvents removed in vacuo. The remaining residue was purified by flash chromatography (Si02, 0→20%, EtOAc in n-hexane) to give the title compound (88.5 mg, 65%) as a white solid. LCMS (Method A): RT = 7.87 min, M+H+ = 441.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 48h;Reflux; Inert atmosphere; | Step 3: tert-Butyl (1-(4-(3-methyl-2-(methylthio)-4-oxo-5-phenyl-3,4-dihydrofuro[2,3- d]pyrimidin-6-yl)phenyl)cyclobutyl)carbamate: To 6-bromo-3-methyl-2-(methylthio)-5- phenylfuro[2,3-d]pyrimidin-4(3H)-one (4.2 g, 1 1.96 mmol) and tert-butyl 1-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (5.36 g, 14.35 mmol, prepared as described in WO2008/070016) in DME (100 ml) was charged a solution of potassium carbonate (16.53 g, 120 mmol) in water (25.00 ml). The reaction was degassed with N2 for 5 min and Pd(PPh3)4 (1.38 g, 1.2 mmol) added. The reaction was then heated at reflux for 48 h. After cooling to RT the reaction mixture was diluted with water and ethyl acetate. An insoluble solid precipitate formed that was collected by filtration through a sintered funnel, washed with ethyl acetate and dried to afford the title compound (6 g, 97%) as a yellow solid. LCMS (Method E) RT = 1 80 min, M+H+ = 518. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water;Reflux; | Step 2: tert-Butyl 1-(4-(3-(2-methoxyethyl)-2-(methylthio)-4-oxo-5-phenyl-3,4- dihydrofuro[2,3-d]pyrimidin-6-yl)phenyl)cyclobutylcarbamate: To a degassed solution of 6-bromo-3-(2-methoxyethyl)-2-(methylthio)-5-phenylfuro[2,3-c]pyrimidin-4(3H)-one (155mg, 0.392 mmol) and tert-butyl 1-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)cyclobutylcarbamate (176 mg, 0.471 mmol, prepared as described inWO2008/070016) in DME (3 ml) was added potassium carbonate (542 mg, 3.92 mmol) in water (0.75 ml). After further degassing, Pd(PPh3)4 (45 mg, 0.039 mmol) was added and the reaction mixture heated to reflux and maintained at this temperature overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and water and extracted. The organic extracts were washed with brine (3x15 ml), dried andconcentrated in vacuo. The resultant residue was purified by silica gel chromatography (gradient elution 0 to 100% EtOAc/hexane) affording terf-butyl 1-(4-(3-(2-methoxyethyl)- 2-(methylthio)-4-oxo-5-phenyl-3,4-dihydrofuro[2,3-af/pyrimidin-6- yl)phenyl)cyclobutylcarbamate (0.177 g, 0.315 mmol, 80%) as an off-white solid. LCMS (Method A) RT = 8.38 min, M+H+ = 562.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 90℃; for 1.5h;Inert atmosphere; | Step 4: tert-Butyl 1-(4-(2-(methylthio)-5-phenyl-4-(trifluoromethyl)furo[2, 3-d]pyrimidin-6- yl)phenyl)cyclobutylcarbamate: feri-Butyl 1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)cyclobutylcarbamate (1.1g, 2.97 mmol, prepared as described inWO2008/070016), 6-bromo-2-(methylthio)-5-phenyl-4-(trifluoromethyl)furo[2,3- d]pyrimidine (770 mg, 1.98 mmol), and potassium phosphate tribasic (1.26 g, 5.94 mmol) in DMF (30 ml) Water (6 ml) was degassed with N2 for 15 min. Pd(PPh3)4 (114 mg, 0.099 mmol) was added and the reaction mixture heated at 90C for 90 min. After cooling to RT the reaction mixture was diluted with water and extracted twice with ethyl acetate. The ethyl acetate layers were combined and washed with 1 : 1 , watenbrine (x 4). The organic layer was dried (MgS04), filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Si02, gradient 0-50% ethyl acetate in cyclohexane) to afford the desired product as a yellow foamy solid. LC S (Method E) RT = 1.96 min, M+H+ = 556. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In ISOPROPYLAMIDE; water; at 80℃; for 17.1667h;Inert atmosphere; | Step 2: tert-Butyl 1-(4-(3-(cyclopropylmethyl)-2-(methylthio)-4-oxo-5-phenyl-3,4- dihydrofuro[2,3-d]pyrimidin-6-yl)phenyl)cyclobutylcarbamate: A stirred suspension of 6- bromo-3-(cyclopropylmethyl)-2-(methylthio)-5-phenylfuro[2,3-d]pyrimidin-4(3H)-one compound with 6-bromo-4-(cyclopropylmethoxy)-2-(methylthio)-5-phenylfuro[2,3- cflpyrimidine (1 :1 ) (694 mg, 0.887 mmol), ferf-butyl 1-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (497 mg, 1.330 mmol, prepared as described in WO2008/070016) and potassium phosphate (565 mg, 2.660 mmol) in dimethylacetamide (13.6 ml) and water (4.1 ml) was degassed with N2 for 30 min.Tetrakis(triphenylphosphine)palladium(0) (51.2 mg, 0.044 mmol) was added and the suspension degassed with N2 for 5 min. The mixture was heated to 80 C for 70 min. Tetrakis(triphenylphosphine)palladium(0) (51.2 mg, 0.044 mmol) was added and the reaction heated for 16 h. The mixture was cooled, quenched by addition of brine/water (1 :1 v/v, 100 ml) and extracted with ethyl acetate (4 x 25 ml). The combined organic phases were washed with brine/water (1 :1 v/v, 4 x 25 ml), dried (Na2S04), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient 0 to 10% EtOAc in cyclohexane) to afford the title compound (344 mg, 35%). LCMS (Method A) RT = 8.97 min, M+H+ = 558.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 90℃; for 1.5h;Inert atmosphere; | Step 5: tert-Butyl (1-(4-(4-methoxy-2-(methylthio)-5-phenylfuro[2,3-d]pyrimidin-6- yl)phenyl)cyclobutyl)carbamate: A solution of 6-bromo-4-methoxy-2-(methylthio)-5- phenylfuro[2,3-c/]pyrimidine (0.8 g, 2.3 mmol), tert-butyl (1 -(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (1.27 g, 3.4 mmol, prepared as described in WO2008/070016), and potassium phosphate tribasic (1.45 g, 6.8 mmol) in DMF:H20 3:1 (20 mL) was degassed by bubbling N2 through the reaction mixture for 10 min.Tetrakis(triphenylphosphine)palladium(0) (131 mg, 0.1 mmol) was then charged to the reaction and heated at 90C under a nitrogen atmosphere until complete by LCMS (1.5 h). The mixture was partitioned between water (40 mL) and EtOAc (30 mL). The aqueous phase was extracted once more with ethyl acetate (30 mL). The combined organic phases were washed with water: brine 1 :1 (5x20 mL), dried (MgS04), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 0 to 20 % ethyl acetate in hexane) to afford the title compound as a white solid (710 mg, 60%). LCMS RT = 8.88 min, M+H+ = 518. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 80℃; for 0.333333h;Inert atmosphere; Microwave irradiation; | Step 2: tert-Butyl (1-(4-(4-oxo-5-phenyl-4,4a-dihydrofuro[2,3-d]pyrimidin-6- yl)phenyl)cyclobutyl)carbamate: To a microwave vial were charged 6-bromo-2- (methylthio)-5-phenylfuro[2,3-c/]pyrimidin-4(3H)-one (30 mg, 0.09 mmol), tert-butyl (1-(4- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.13 mmol, prepared as described in WO2008/070016), and potassium phosphate tribasic (57 mg, 0.27 mmol) in DMF:H20 5:1 (2.5mL). The reaction mixture was degassed by bubbling N2 through the reaction mixture for 10 min.Tetrakis(triphenylphosphine)palladium(0) (5 mg, 4 pmol) was charged and the vial was heated in a microwave reactor at 80 C for 20 min. The mixture was partitioned between water (2 mL) and ethyl acetate (3 mL). The layers separated and the aqueous phase was extracted once more with ethyl acetate (3 mL). Combined organic phases were washed with H20: brine 1 :1 (4x 3 mL), dried (MgS04), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 0 to 40 % ethyl acetate in hexane) to afford the title compound (8 mg, 18%). LCMS RT = 7.26 min, M+H+ = 504. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; for 5.0h;Reflux; | Step 5: tert-Butyl {1 -[4-(4,4,5,5-tetramethy-1 ,3,2-dioxaborolan-2-yl)phenyl]- cyclobutyl}carbamate [lnt-1 B] 27.75 g (55 mmol) [1-(4-Bromophenyl)cyclobutyl]carbamic acid fe/f-butyl ester, 23.76 mmol (93.6 mmol) bis-(pinacolato)diboron, 25 g (255 mmol) potassium acetate and 2.08 g (2.55 mmol) 1 , 1 '-bis(diphenylphosphino)ferrocenedichloro- palladium(ll) in 500 mL degassed THF were heated for three hours at reflux. The colour of the reaction mixture turned from dark red to black. Due to an incomplete reaction heating was continued for another two hours. The reaction mixture was poured on water (400 mL) and diluted with ethyl acetate (700 mL). After stirring for 30' the organic phase was separated and the aqueous phase was reextracted twice with ethyl acetate (400 and 200 mL). The combined organic extracts were washed with brine (200 mL) and dried (sodium sulfate). After evaporation of the solvent the residue was purified by chromatography (Biotage) yielding 28.99 g (91.3%) of the title compound. 1H NMR (400 MHz, DMSO-d6): delta 7.51 -7.67 (m, 3H), 7.38 (d, 2H), 2.22-2 42 (m, 4H), 1.88-2.02 (m, 1 H), 1.63-1.80 (m, 1 H), 1.00-1.38 (m, 21 H) ppm. |
90.8% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran;Reflux; | 10 g (30.7 mmol) [1 -(4-Bromophenyl)-cyclobutyl]-carbamic acid tert. -butyl ester, 8.56 g (33.7 mmol) bis-(pinacolato)diboron, 750.9 mg (0.92 mmol) 1 ,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(ll) and 9.03 g (92 mmol) potassium acetate are given in 180 mL THF which has been degassed for 10'. The reaction mixture is heated at reflux until the starting material has disappeared (usually two hours). At 60 C the reaction mixture turns dark. The reaction mixture is poured on water (200 ml_) and ethyl acetate (500 ml_) is added. The mixture is vigorously stirred for two hours. After separation of the organic phase the aqueous phase is extracted once more with ethyl acetate (300 ml_). The combined organic extracts are washed with brine and dried (sodium sulfate). After evaporation of the solvent the residue, a black oil, is purified by chromatography on silicagel (eluents: hexane/ ethyl acetate). 10.4 g (90.8%) of the title compound are obtained.MS (ES+, M+1 ): 3741H-NMR (400 MHz, d6-DMSO): delta 7.61 (d, 2H), 7.55-7.65 (br. 1 H), 7.35 (d, 2H), 2.22-2.42 (m, 4H), 1 .88-2.02 (m, 1 H), 1 .65-1 .82 (m, 1 H), 1 .00-1 .38 (m, 21 H). |
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10.0h;Inert atmosphere; | Potassium acetate (2.41 g) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.25 g) are sequentially added to a DMF (25 mL) solution of the product (3.21 g) of Reference Example 56(3), and the mixture was placed in a nitrogen atmosphere. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (360 mg) was added thereto, and the mixture was stirred at 80 C. for 10 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (3.20 g, yield: 87%) as a colorless solid. 1H-NMR (CDCl3) delta: 7.79 (2H, d, J=8.0 Hz), 7.43 (2H, d, J=8.0 Hz), 5.07 (1H, br s), 2.59-2.31 (4H, m), 2.14-2.03 (1H, m), 1.90-1.78 (1H, m), 1.36 (9H, s), 1.34 (12H, s) ESI-MS m/z 374 (MH+) |
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In water; N,N-dimethyl-formamide; at 80℃; for 10.0h;Inert atmosphere; | Reference Example 56(4) tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate Potassium acetate (2.41 g) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.25 g) are sequentially added to a DMF (25 mL) solution of the product (3.21 g) of Reference Example 56(3), and the mixture was placed in a nitrogen atmosphere. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (360 mg) was added thereto, and the mixture was stirred at 80C for 10 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (3.20 g, yield: 87%) as a colorless solid. 1H-NMR (CDCl3) delta: 7.79 (2H, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.0 Hz), 5.07 (1H, br s), 2.59 - 2.31 (4H, m), 2.14 - 2.03 (1H, m), 1.90 - 1.78 (1H, m), 1.36 (9H, s), 1.34 (23H, s) ESI-MS m/z374 (MH+) |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; for 3.0h;Reflux; | 27.75 g (55 mmol) [1 -(4-Bromo-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester,23.76 mmol (93.6 mmol) bis-(pinacolato)diboron, 25 g (255 mmol) potassium acetate and 2.08 g (2.55 mmol) 1 ,1 '-bis(diphenylphosphino)ferrocenedichloro- palladium(ll) in 500 mL degassed THF were heated for three hours at reflux. The colour of the reaction mixture turned from dark red to black. Due to an incomplete reaction heating was continued for another two hours. The reaction mixture was poured on water (400 mL) and diluted with ethyl acetate (700mL). After stirring for 30' the organic phase was separated and the aqueous phase was reextracted twice with ethyl acetate (400 and 200 mL). The combined organic extracts were washed with brine (200 mL) and dried (sodium sulfate). After evaporation of the solvent the residue was purified by chromatography (Biotage) yielding 28.99 g (91 .3%) of the title compound.1 H NMR (400 MHz, d6-DMSO): delta 7.51 -7.67 (m, 3H), 7.38 (d, 2H), 2.22-2.42 (m, 4H), 1 .88-2.02 (m, 1 H), 1 .63-1 .80 (m, 1 H), 1 .00-1 .38 (m, 21 H) ppm. | |
With potassium acetate; palladium diacetate; XPhos; In acetonitrile; at 75℃;Inert atmosphere; | Step 1: tert-butyl (l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclobutyl)carbamate: tert-butyl (l-(4-bromophenyl)cyclobutyl)carbamate (10.0 g, 30.7 mmol), b 5,-(pinacolato)diboron (9.34 g, 36.8 mmol), palladium(II) acetate (0.344 g, 1.53 mmol), X-Phos (1.47 g, 3.07 mmol) and potassium acetate (9.03 g, 92 mmol) were combined in MeCN (120 ml). The vessel was purged with N2 for 10 mins and then heated at 75 C overnight. The mixture was allowed to cool to RT and was filtered through Celite, washing with MeCN. The filtrate was concentrated in vacuo to afford a pale yellow solid. Purification by column chromatography (220 g cartridge, 0-20%EtOAc/isohexane) afforded the title compound (8.91 g, 23.9 mmol) as a white solid, which was used directly in the next step without analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; In ethanol; water; toluene; at 120℃;microwave irradiation; | A mixture of 2-bromo-5-methyl-3-phenylimidazo[1 ,2-a]pyridine (38 mg, 0.13 mmol), tert-butyl {1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]cyclobutyl}carbamate (see step 4, 64 mg, 0.17 mmol) and potassium phosphate (84.3 mg, 0.40 mmol) in 1 .2 ml toluene/ ethanol/ water (1/2/1 ) was heated to 120C in a single mode microwave reactor (Biotage). This experiment was repeated employing the same protocol. Both reaction mixtures were combined and partitioned between dichloromethane and water. The mixture was filtered through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography (Snap cartridge, hexane/ethyl acetate 95/5 -> hexane/ ethyl acetate 1/1 ) to give 49 mg of the title compound (34 % overall yield).UPLC-MS: RT = 1 .12 min; m/z [ES+]= 454 (M+1 )+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 105℃; for 18h;Inert atmosphere; | 500 mg (2 mmol) 7-Chloro-6-phenyl-imidazo[1 ,2-b]pyrinnicline (intermediate example lnt-1 -0) which contains 8% of 6-phenyl-imidazo[1 ,2-b]pyrimidine, 1 .1 g (3 mmol) {1 -[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}- carbamic acid tert. -butyl ester, 73.6 mg (0.9 mmol) 1 ,1bis(diphenylphosphino)ferrocenedichloropalladium(ll) and 636.8 mg (6 mmol) sodium carbonate (10%) are given in a microwave vial. 14 mL dioxane and 3.9 mL water which have been degassed are added. The reaction mixture is purged with nitrogen and stirred for 18 h at 105 C. The reaction has been carried out trice under the same conditions. The four reaction mixtures have been jointly worked up. They are poured on 150 mL water and 500 mL EtOAc and vigorously stirred for two hours. After separation of the organic phase the aqueous phase is extracted with ethyl acetate. The combined organic extracts are washed with water and dried over sodium sulfate. After removal of the drying agent the solvent is evaporated. However, in this residue only traces of the title compound have been found. Therefore, the aqueous phase has been diluted with 600 mLdichloromethane and extracted (no separation of the phases). After the weekend a solid has precipitated in the organic phase. The organic phase with the solid has been separated frome the aqueous phase and the solvent is removed without drying the phase before. The residue is suspended in a small amount ofdichloromethane, sucked off via a paper filter and washed with dichloromethane yielding 700 mg of the desired compound.1H-NMR (300 MHz, d6-DMSO): δ 9.01 (s, 1 H), 7.92 (d, 1 H), 7.78 (d, 1 H), 7.50-7.62 (m, 1 H),7.20-7.40 (m, 8H), 2.25-2.42 (m, 4H), 1 .88-2.05 (m, 1 H), 1 .65-1 .82 (m, 1 H), 0.98-1 .42 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; 1-methyl-pyrrolidin-2-one; water; at 80℃; for 0.166667h;microwave irradiation; | A mixture of 5-chloro-2-methyl-6-phenyl[1 ,2,4]triazolo[1 ,5-a]pyrimidine (59 mg, 0.24 mmol), {1 -[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]- cyclobutylj-carbamic acid tert-butyl ester (134 mg), potassium carbonate (100 mg), Pd(PfBu3)2 (CAS No. 53199-31 -8, 12.3 mg), NMP (0.1 1 mL), dioxane (0.46 mL) and water (0.2 mL) was heated under microwave irradiation (Biotage Initiator 60) at 80 C for 10 min. The reaction was diluted with water, extracted with EtOAc and the organic layer dried and concentrated. Purification was achieved withchromatography on solica gel (Eluant: gradient elution DCM to 95% DCM / ethanol), followed by trituration with DIP / EtOAc to give the title compound (76 mg) which was used in the next step without further purification.UPLC-MS: RT = 1 .33 min; m/z = 456.28 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 100℃; for 0.833333h;microwave irradiation; | To a mixture of 2-bromo-5-chloro-6-phenyl[1 ,2,4]triazolo[1 ,5-a]pyrimidine (870 mg) and {1 -[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}- carbamic acid tert-butyl ester (1 .15 g) in DME (9.5 mL), was added 10% aqueous sodium carbonate (6.2 mL) and Pd(dppf)Cl2 (1 14 mg). The resulting orange red suspension was heated under microwave irradiation at 100 C for 50 minutes. On cooling the mixture was partitioned between DCM and water, the aqueous phase extracted with DCM and the combined organic phases washed with brine, dried and concentrated. Purification was achieved by chromatography on silica gel to give slightly impure title compound (360 mg) as a white foam.UPLC-MS: RT = 1 .46 min; m/z = 471 .28 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; 1-methyl-pyrrolidin-2-one; water; for 0.5h;microwave irradiation; | 150 mg (0.62 mmol) 7-Chloro-2-methyl-6-phenyl-imidazo[1 ,2-a]pyrimidine(intermediate example lnt-1 -1 ), 299 mg (0.8 mmol) {1 -[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 255 mg (1 .85 mmol) potassium carbonate, 31 .5 mg (0.06 mmol) bis (tri-tert.- butylphosphin)palladium(O) are given in 1 .2 mL dioxane, 1 .1 mL water and 0.3 mL NMP (no complete dissolution). The reaction mixture is stirred for 30' in the microwave. The reaction mixture is poured on water and extracted twice with EtOAc. The combined organic extracts are washed with water and dried over sodium sulfate. After removal of the drying agent the solvent is evaporated and the residue is purified by chromatography on silicagel (eluents: dichloromethane/ methanol) yielding 191 .5 mg of the title compound which is contaminated.MS (CI+, M+1 ): 4951H-NMR (300 MHz, d6-DMSO): δ 8.90 (s, 1 H), 7.63 (s, 1 H), 7.10-7.36 (m, 9H), 2.19-2.42 (m, with a singulet within, 7H), 1 .80-2.01 (m, 1 H), 1 .62-1 .80 (m, 1 H), 0.93-1 .39 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 90℃; for 0.833333h;microwave irradiation; Inert atmosphere; | To 690 mg (2.4 mmol) (7-Chloro-6-phenyl-imidazo[1 ,2-a]pyrimidin-5-yl)- cyclopropylamine in 8.3 mL DME (no complete dissolution) are added 1 .18 g (3.15 mmol) {1 -[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}- carbamic acid tert. -butyl ester, 5 mL aqueous sodium carbonate solution (10%) and 98.9 mg (0.121 mmol) 1 ,1bis(diphenylphosphino)ferrocenedichloropalladium(ll). The reaction mixture is purged with argon and heated for 50' at 90 C in the microwave (no complete dissolution). After addition of 50 mL water and 150 mL dichloromethane the reaction mixture is vigorously stirred for one hour. The organic phase is separated and the aqueous phase is extracted twice with dichloromethane (150 mL each). The combined organic extracts are washed with water, dried, filtrated and the solvent is removed. The residue is purified by chromatography on silicagel (eluents: dichloromethane/ methanol) yielding 407.6 mg of a product which contains the desired title compound only in minor amounts and additional fractions 242.6 mg which contains the desired compound strongly contaminated.MS (ES+, M+1 ): 496 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 90℃; for 18h;Inert atmosphere; | 200 mg (0.53 mmol) tert.-Butyl-(5-chloro-6-phenyl-2-pyridine-2-yl- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)-amine are given in 1 .8 ml_ DME (no complete dissolution). After addition of 394 mg (1 .05 mmol) {1 -[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 0.97 ml aqueous sodium carbonate (10%), and 19.3 mg (23.8 mmol) 1 ,1bis(diphenylphosphino)ferrocenedichloropalladium(ll) the reaction mixture is evaporated three times and purged with argon and heated for 18 hours at 90 C. The reaction mixture is diluted with water (15 ml_) and dichloromethane (30 ml_) and stirred for one hour at room temperature. The organic phase is separated and the aqueous phase is extracted twice with dichloromethane (30 ml each). The combined organic extracts are washed with water and brine, dried and filtrated. After removal of the solvent the residue is purified by chromatography on silicagel (eluents: dichloromethane/ methanol) yielding 310 mg of the title compound which is however contaminated.MS (ES+, M+1 ): 5901H-NMR (400 MHz, d6-DMSO): δ 8.79 (d, 1 H), 8.29 (d, 1 H), 8.01 (dd, 1 H), 7.12- 7.64 (m, 10H), 2.19-2.42 (m, 4H), 1 .82-2.02 (m, 1 H), 1 .60-1 .82 (m, 1 H), 1 .18-1 .49 (m, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 100℃; for 0.75h;microwave irradiation; Inert atmosphere; | A mixture of (5-chloro-2-methyl-6-phenyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)- isopropyl-amine (374 mg) and {1 -[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (926 mg) in DME (6 mL) was treated with 10% aqueous sodium carbonate (2.49 mL) and placed under nitrogen. Pd(dppf)Cl2 (45.6 mg) was added and the mixture heated under microwave irradiation at 100 C for 45 minutes. On cooling the reaction was partitioned between water and EtOAc, the aqueous phase extracted with EtOAc and the combined organic phases dried and concentrated. Purification was achieved by chromatography on silica gel (eluent: gradient elution 100% hexane to 100% EtOAc) to afford the title compound, slightly contaminated with (5-chloro-2-methyl- 6-phenyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-7-yl)-isopropyl-amine.UPLC-MS: RT = 1 .47 min; m/z = 513.32 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; at 90℃; for 24h;Microwave irradiation; Inert atmosphere; | {1-[4-(7-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester 100 mg (0.44 mmol) 6-Chloro-7-phenyl-imidazo[1,2-b]pyridazine (intermediate example Int-1-0) in 1.5 mL DME, 178.8 mg (0.48 mmol) <strong>[1032528-06-5]{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester</strong>, 0.85 mL aqueous sodium carbonate (10%) and 16 mg (0.02 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(II) were put in a microwave vial (no complete dissolution). The reaction mixture was degassed with argon, the vial closed with a cap and put in a heating block. The reaction mixture was stirred for 18 h at 90 C. (complete dissolution). Due to the still presence of starting material additional 86 mg boronic ester, 0.42 mL aqueous base and 8 mg palladium catalyst were added and stirring was continued for 6 hours at 90 C. 20 mL water and 100 mL dichloromethane were added and the reaction mixture was vigorously stirred for one hour. After separation of the organic phase the aqueous phase was extracted once more with dichloromethane. The combined organic extracts were washed with water and dried over sodium sulfate. After removal of the drying agent the solvent was evaporated and the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 109 mg (56.8%) of the desired compound which was yet slightly contaminated. MS (ES+, M+1): 441 1H-NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.22-7.41 (m, 7H), 7.12-7.22 (m, 2H), 2.40-2.65 (m, 4H), 1.95-2.18 (m, 1H), 1.72-1.93 (m, 1H), 1.12-1.53 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; water; toluene; at 100℃;Inert atmosphere; | Step 1: Preparation of tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.800 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (2 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (1.15 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis (triphenylphosphine) palladium (0) added (0.08 g). The reaction was again degassed for 5 minutes and stirred at 100 C. overnight. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The aqueous phase was extracted with dichloromethane (2*75 mL) and the organic extracts were combined and washed with water (1*50 mL), brine (1*50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.6 g, 52%). 1H NMR (DMSO-d6) 400 MHz δ 8.41 (s, 1H), 8.04 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.96 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.53-7.48 (m, 2H), 7.45-7.08 (m, 11H), 6.91-6.86 (m, 1H), 6.67-6.62 (m, 1H), 2.45-2.32 (m, 4H), 2.07-1.94 (m, 1H), 1.85-1.73 (m, 1H), 1.28 (bs, 9H); LCMS: 556 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; water; toluene; at 100℃;Inert atmosphere; | Step 4: Preparation of tert-butyl (1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate To a suspension of 3-bromo-2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.197 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (4 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.353 g, 2 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis (triphenylphosphine) palladium (0) added (0.054 g). The reaction was again degassed for 5 minutes and stirred at 100 C. overnight. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The aqueous phase was extracted with dichloromethane (2*100 mL) and the organic extracts were combined and washed with brine (1*100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10-60% ethyl acetate in hexanes) gave tert-butyl (1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.042 g, 15%) as a yellow solid. LCMS: 584 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; water; toluene; at 100℃;Inert atmosphere; | Step 4: Preparation of 2-(3-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetic acid To a suspension of methyl 2-(3-bromo-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.15 g, 1 eq.) in a mixture of toluene (8 mL), ethanol (8 mL), and saturated sodium bicarbonate (2 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.219 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis (triphenylphosphine) palladium (0) added (0.045 g). The reaction was again degassed for 5 minutes and stirred at 100 C. overnight. The reaction mixture was cooled to room temperature and poured onto water (30 mL). The aqueous phase was extracted with dichloromethane (2*30 mL) and the organic extracts were combined and washed with water (1*50 mL), brine (1*50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (0-100% ethyl acetate in hexanes) gave 2-(3-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetic acid (0.04 g, 19%). LCMS: 538 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; water; toluene; for 15h;Reflux; | Example 12 Preparation of tert-butyl {1-[4-(9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate A mixture of 3-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (1.48 g, 4.7 mmol), tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate (2.12 g, 5.7 mmol), sat.NaHCO3 (4 mL), and tetrakis (triphenylphosphine) palladium (0) (0.55 g, 0.47 mmol) in toluene-ethanol (1/1, 40 mL) was heated to refluxed temperature for 15 hours. After cooling to room temperature the reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography (hexane/ethyl acetate) to give a yellow solid (quant.). 1HNMR (CDCl3) 400 MHz δ: 8.09-8.06 (m, 2H), 7.39 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.30 (td, J=7.6, 1.5 Hz, 1H), 7.15 (d, J=8.0 Hz, 2H), 7.16-7.10 (m, 1H), 6.98 (dd, J=8.0, 1.2 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.70 (dd, J=7.7, 4.9 Hz, 1H), 6.27 (s, 1H), 5.08 (s, 1H), 2.57-2.39 (m, 4H), 2.18-2.07 (m, 1H), 1.93-1.84 (m, 1H), 1.48-1.19 (brs, 9H); LC/MS [M+H]: 480. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere; | Step 1: tert-butyl 1-(4-(6-(5,5^^-tetramethyl-5^J^-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)cyclobutylcarbamate:To a solution of tert-butyl 1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate (178.9 mg, 0.479 mmol) and 2-bromo-6-(5, 5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine (150 mg, 0.436 mmol) in DMF (2 ml) was added 2M Na2C03 (aq) (0.44 ml, 1 .743 mmol). Nitrogen was bubbled through the mixture for 5 min. PdCI2(dppf)CH2CI2 (17.8 mg, 0.022 mmol) was added, and the reaction mixture was heated at 80 C for 18 h under nitrogen. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, dried (MgS04) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound as a white solid (107 mg, 48 %).LCMS (Method F): RT = 2.13 min, M+H+ = 51 1 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3: 1 -{4-[9-(4-Fluorophenyl)-3-phenylpyrimido[1 ,2-£>]indazol-2-yl}phenyl}- cyclobutylamine260 mg of the mixture described in step 2 in 15 mL 4M hydrogen chloride in dioxane were stirred over night at room temperature. After evaporation of the solvent the residue was treated with saturated sodium bicarbonate solution. This aqueous solution was extracted three times with dichloromethane. The combined organic extracts were worked up as already described. The residue was purified by column chromatography on silicagel (eluents: dichloromethane/ methanol) and additional HPLC yielding 24.1 mg of the title compound 1 -{4-[9-(4-fluorophenyl)-3- phenylpyrimido[1 ,2-Jb]indazol-2-yl}phenyl}cyclobutylamine and 12.1 mg of the regioisomer 1 -{4-[2-(4-fluorophenyl)-3-phenylpyrimido[1 ,2-£>]indazol-9-yl}phenyl}- cyclobutylamine.UPLC-MS: RT = 1 .09 min; m/z = 468 (ES+, M-NH2); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2: (1 -{4-[9-Fluorophenyl)-3-phenylpyrimido[1 ,2-£>]indazol-2-yl]phenyl}- cyclobutyl)carbamic acid fe/f-butyl ester194 mg of the mixture described in step 1 , 2-chloro-9-(4-fluorophenyl)-3-phenyl- pyrimido[1 ,2-£>]indazole, the regioisomer 9-bromo-2-(4-fluorophenyl)-3-phenyl- pyrimido[1 ,2-£>]indazole and the bisproduct 2,9-bis-(4-fluorophenyl)-3-phenyl- pynmido[1 ,2-Jb]indazole, 213.2 mg (0.57 mmol) {1 -[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid fe/f-butyl ester, 42 mg (0.052 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(ll) and 0.96 mL aqueous sodium carbonate solution (10%) in 1 .8 mL dimethoxyethane were heated in the microwave oven for 60' at 120 C. After the usual work up as described in step 1 , the mixture (260.3 mg) was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.6% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 105℃; | Example lnt-2-0{1 -[4-(9-Bromo-3-phenylpyrimido[1,2-/)]indazol-2-yl)phenyl]cyclobutyl}- carbamic acid ferf-butyl ester1 g (2.9 mmol) 9-Bromo-2-chloro-3-phenylpyrimido[1 ,2-b]indazole (intermediate example lnt-1 -2), 1 .09 g (2.9 mmol) {1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl]cyclobutyl}carbamic acid fe/f-butyl ester, 322 mg (0.28 mmol) tetrakis(triphenylphosphine)palladium and 886 mg (8.4 mmol) sodium carbonate in 30 ml_ dioxane and 4.2 ml_ water were heated over night at 105 C. The reaction mixture was poured on water/ dichloromethane and vigorously stirred for 30'. The organic phase was separated, washed with brine, dried, filtered, and the solvent was evaporated. The residue was purified by HPLC yielding 346.4 mg (20.6%) of the title compound.MS (ES+, M+1 ): 569/ 571 (Br isotopes)(400 MHz, dDMSO): δ 9.43 (s, 1 H), 8.42 (s, 1 H), 7.80 (d, 1 H), 7.72 (d, 1 H), 7.59 (br., 1 H), 7.22-7.48 (m, 9H), 2.19-2.43 (m, 4H), 1 .84-2.05 (m, 1 H), 1 .63-1 .84 (m, 1 H), 0.95-1 .48 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In 1,2-dimethoxyethane; water; at 120℃; for 0.666667h;Microwave irradiation; | Step 2: (1 -{4-[4-(Cyclopropylamino)-9-fluoro-3-phenylpyrimido[1 ,2-£>]indazol-2- yl]phenyl}cyclobutyl)carbamic acid fe/f-butyl ester300 mg (0.9 mmol) (2-Chloro-9-fluoro-3-phenylpyrimido[1 ,2- 3]indazol-4-yl)- cyclopropylamine, 444.4 mg (1 .2 mmol) {1 -[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid fe/f-butyl ester, 1 .6 mL aqueous sodium carbonate (10%) and 31 .2 mg (0.04 mmol) 1 , 1bis(diphenylphosphino)ferrocenedichloropalladium(ll) were given in 2.9 mL dimethoxyethane and heated for 40' in the microwave at 120 C. The reaction mixture was poured on water and ethyl acetate and stirred vigorously for 30 minutes. The organic phase was separated and washed twice with brine. After drying with sodium sulfate the solvent was removed and the crude residue (720 mg) was used in the next step without further purification.UPLC-MS: RT = 1 .73 min; m/z = 564 (ES+, M+1 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In 1,2-dimethoxyethane; water; at 120℃; for 1h;Microwave irradiation; | Step 2: (1 -{4-[8-(3-Cyanophenyl)-3-phenylpyrimido[1 ,2-£>]indazol-2-yl]phenyl}- cyclobutyl)carbamic acid fe/f-butyl ester179 mg of the mixture described in step 1 , 3-(2-chloro-3-phenylpyrimido[1 ,2- jb]indazol-8-yl)benzonitrile and the byproduct 3-[2-(3-cyanophenyl)-3-phenyl- pyrimido[1 ,2-Jb]indazol-8-yl]benzonitrile, 210.5 mg (0.56 mmol) {1 -[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid fe/f-butyl ester, 38.4 mg (0.047 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(ll) and 0.87 ml_ aqueous sodium carbonate solution (10%) in 1.6 ml_dimethoxyethane were heated in the microwave oven for 60' at 120 C. After the usual work up described in step 1 , the mixture (239.4 mg) was used in the next step without further purification.UPLC-MS: RT = 1 .67 min; m/z = 592 (ES+, M+1 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.7% | With sodium carbonate;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In 1,2-dimethoxyethane; at 100℃; for 0.5h;Microwave irradiation; | Example 1 :1 -[4-(9-Fluoro-3^henylpyrimido[1,2-/)]indazol-2-yl)phenyl]cyclobutylamine Step 1 : {1 -[4-(9-Fluoro-3-phenylpyrimido[1 ,2-£>]indazol-2-yl)phenyl]cyclobutyl}- carbamic acid fe/f-butyl esterTo 620 mg (2.1 mmol) 2-Chloro-9-fluoro-3-phenylpyrimido[1 ,2-Jb]indazole(intermediate example lnt-1 -0) and 1 .1 g (2.9 mmol) {1 -[4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid ie f-butyl ester in 7.2 mL 1 ,2 dimethoxyethane were added 3.8 mL aqueous sodium carbonate (10%) and 170 mg (0.2 mmol) 1 , 1 bis(diphenylphosphino)ferrocenedichloropalladium(ll). The reaction mixture was stirred for 30' in the microwave at 100 C and subsequently evaporated to dryness. The residue (770 mg = 72.7%) was used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 105℃;Microwave irradiation; | Step 2: (1 -{4-[10-(4-Cyanophenyl)-3-phenylpyrimido[1 ,2-£>]indazol-2-yl]phenyl}- cyclobutyl)carbamic acid fe/f-butyl ester1 14 mg (0.3 mmol) 4-(2-Chloro-3-phenylpyrimido[1 ,2-Jb]indazol-10-yl)benzonitrile, 122.9 g (0.3 mmol) {1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]- cyclobutyl}carbamic acid fe/f-butyl ester , 34.6 mg (0.03 mmol)tetrakistriphenylphosphinepalladium(O) and 95 mg (0.90 mmol) sodium carbonate in 3.2 mL dioxane and 0.45 mL water were heated in a microwave vial which had been sealed with a microwave cap over night at 105 C (heating block). After the usual work up, the crude mixture (235 mg) was used in the next step without further purification |
Tags: 1032528-06-5 synthesis path| 1032528-06-5 SDS| 1032528-06-5 COA| 1032528-06-5 purity| 1032528-06-5 application| 1032528-06-5 NMR| 1032528-06-5 COA| 1032528-06-5 structure
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