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CAS No. : | 1002309-52-5 | MDL No. : | MFCD11044683 |
Formula : | C12H18BNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IJUNZKOKAXJGRQ-UHFFFAOYSA-N |
M.W : | 235.09 | Pubchem ID : | 45480194 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.58 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 68.44 |
TPSA : | 40.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.07 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.93 |
Log Po/w (WLOGP) : | 0.68 |
Log Po/w (MLOGP) : | 0.73 |
Log Po/w (SILICOS-IT) : | 0.88 |
Consensus Log Po/w : | 0.65 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.08 |
Solubility : | 1.96 mg/ml ; 0.00834 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.37 |
Solubility : | 10.1 mg/ml ; 0.0431 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.1 |
Solubility : | 0.187 mg/ml ; 0.000794 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.97 |
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 |
---|---|---|
23.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 2 h; Microwave irradiation | A solution of 5-bromo-1-methylpyridin-2-one (200.0 mg, 1.06 mmol), bis(pinacolato)diboron (410.0 mg, 1.61 mmol), potassium acetate (270 mg, 2.67 mmol), Pd (dppf)Cl2 (80 mg, 0.11 mmol) in dioxane (5 mL) was heated at 100° C. for 2 h under microwave. The mixture was filtered, washed with water and extracted with ethyl acetate (20 mL*3). The combined organics were dried over Na2SO4, filtered and concentrated to give the crude title compound (59.0 mg, 23.6percent). LCMS (M+H)+ 236. |
160 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In ethylene glycol at 80℃; for 3 h; | To a stirred suspension of 5-bromo-l-methylpyridin-2(lH)-one (470 mg, 2.49 mmol), potassium acetate (736 mg, 7.49 mmol) and bis(pinacolato)diboron (952 mg, 3.74 mmol) in degassed polyethylene glycol-400 (15 mL) was added [1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (204 mg, 0.24 mmol) at RT. The resultant suspension was stirred for 3 h at 80 °C. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (100 mL). The organic layer was concentrated and the residue obtained purified by flash column chromatography to afford 160 mg of the titled product; 1H NMR (300 MHz, CDC13) δ 1.30 (s, 12H), 3.54 (s, 3H), 6.53 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H); APCI- MS (m/z) 236 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: With triethylamine In dichloromethane at 20℃; for 1 h; Stage #2: With sodium hydroxide In 1,4-dioxane at 70℃; for 1 h; |
Example 261B (2.86 g, 10.8 mmol) and triethylamine (6.03 mL, 43.3 mmol) were stirred in dichloromethane (48.1 mL) at ambient temperature. Methanesulfonyl chloride (2.53 mL, 32.4 mmol) was added dropwise and the solution stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dioxane (24 mL) and sodium hydroxide (10 percent w/v, 12 mL, 0.427 mmol) were added, and the solution was heated to 70 °C for 1 hour. The solution was neutralized to a pH of 7 with saturated aqueous NH4CI (200 mL). The aqueous phase was extracted with ethyl acetate (3x125 mL). The combined organics were washed with brine, dried (MgSC^), filtered, then concentrated. The residue was purified by flash chromatography (silica gel, 0-25percent ethyl acetate/hexane gradient,) to afford the title compound (2.79 g, 75percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tricyclohexylphosphine In 1,4-dioxane at 80℃; for 5 h; Inert atmosphere | To a mixture of 5-bromo-1-methylpyridin-2(1H)-one (1.0 g, 5.32 mmol), KOH (0.78 g, 7.98 mmol) and bis(pinacolato)diboron (0.162 g, 6.38 mmol) in 1 ,4-dioxane (20 mL), tricyclohexyiphosphine (149 mg, 0.532 mmol), Pd2dba3 (487 mg, 0.532 mmol) were added under N2 atmosphere. The mixture was stirred at about 80 °C for about 5 h. Then water was added, the aqueous layer was extracted with EtOAc (50 mL x 2), and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and the residue was purified by column chromatograph on silica gel to provide ]-methyl-5-(4, 4,5, 5-tetramethyl-], 3, 2-dioxaborolan-2-yl)pyridin-2(]H)-one (0.80 g, 64percent): ‘H NMR (CDC13) 7.70 (s, 1 H), 7.54 (d, J= 8.8 Hz, 1 H), 6.47 (d, J= 8.8 Hz, 1 H), 3.49 (s, 3 H), 1.24(s, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 80℃; for 3h; | X. l-Methyl-5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2(lH)-one; A mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine(235 mg, 1.00 mmol) and CH3I (426 mg, 3.00 mmol) was heated at 800C for 3 hours. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, and evaporated to dryness to afford l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one that was directly used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;microwave irradiation; | AO. l-(2.2-Difluorobenzordipi.31dioxol-5-yl)-N-(5-methyl-6-(l-methyl-6-oxo-L6-dihvdropyridin-3-yl)pyridin-2-yl)cvclopropanecarboxamide; To a mixture of l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one (68 mg, 0.30 mmol), N-(6-chloro-5-methylpyridin-2-yl)-l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) in DME (1.5 mL) and 2 M Na2CO3 (0.24 mL) was added Pd(PPh3)4 (14 mg, 0.0030 mmol). The mixture was heated in microwave oven at 1200C for 30 min. The mixture was partitioned between ethyl acetate and H2O before the aqueous layer was extracted with ethyl acetate (3x). The combined <n="120"/>organic layers were washed with brine and dried over MgSO4. After the removal solvent, the residue was purified by column chromatography (10-20percent EtOAc -Hexane) to afford l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)-N-(5-methyl-6-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)pyridin-2-yl)cyclopropanecarboxamide (67 mg, 72percent). 1H-NMR (400 MHz, CDCl3) delta 8.06 (d, J = 8.4 Hz, IH), 7.63 (s, IH), 7.57 (d, J = 8.4 Hz, IH), 7.53-7.48 (m, 2H), 7.24 (td, J = 10.0, 1.7 Hz, 2H), 7.12 (d, J = 8.2 Hz, IH), 6.61 (d, J = 9.2 Hz, IH), 3.60 (s, 3H), 2.33 (s, 3H), 1.77 (q, J = 3.6 Hz, 2H), 1.19 (q, J = 3.6 Hz, 2H). MS (ESI) m/e (M+H+) 440.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A degassed mixture of 2-bromo-3-(3-pyrrolidin-1-yl-prop-1-ynyl)-imidazo[1,2-a]pyridine-6-carboxylic acid bis-(3-methyl-butyl)amide (200 mg), intermediate 33a) (145 mg), and 2M aqueous sodium carbonate solution (0.8 ml) in DMF (4 ml) was treated with Pd(PPh3)4 (47.3 mg). The reaction mixture was transferred to a pre-heated oil bath (110°C) and stirred in a sealed tube at this temperature overnight. The mixture was diluted with diethyl ether (50 ml) and washed with water (1 x 20 ml). The aqueous layer was extracted with diethyl ether (2 x 20 ml). The combined organic extract was washed with brine (50 ml), dried over sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography followed by preparative LC-MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 110℃; for 2h; | Example 11 : 5-(5-amino-6-(l-methyl-lH-benzo[dlimidazol-2-yl)pyrazin-2-yl)-l-methylpyridin- 2(lHVone (Compound 1-25) SCHEME XIMethod A Steps 1 -3 Compound 1-25Compound 1-25 was prepared using Method A, Steps 1-3 followed by Method K, Step 1.METHOD K: Step 1: 5-(5-amino-6-(6-methyl-lH-benzo[d]imidazol-2-yl)pyrazin-2-yl)-l- methylpyridin-2(lH)-one[00298] A mixture of 5-bromo-3-(6-methyl-lH-benzimidazol-2-yl)pyrazin-2-amine (100 mg, 0.3288 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (154.6 mg, 0.6578 mmol) , potassium carbonate (136.4 mg, 0.9867 mmol) and [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium (26.86 mg, 0.03289 mmol) in DMF (3 mL) were heated to HO0C for 2 hours. The mixture was diluted with EtOAc, washed with water, and the organic layer concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC [Waters Sunfire C 18, lOuM, IOOA column, gradient 10percent - 95percentB (solvent A: 0.05percent TFA in water, solvent B: CH3CN) over 16 minutes at 25mL/min]. The fractions were collected and freeze-dried to give the title compound (47.4mg, 40percent Yield). MS (ES+) 333 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; | General procedure: A solution of Intermediate 2A (12.50 g, 55.10 mmol), bispinacolatodiboron (20.97 g, 83.00 mmol) and potassium acetate (16.21 g, 165.00 mmol) in dioxane (200 mL) was degassed with nitrogen for 20 minutes. PdCl2(dppf)2CH2Cl2 (4.50 g, 5.51 mmol) was added and the resulting mixture was degassed again for 10 minutes then was heated at 100 C for 12 h. The reaction was cooled to ambient temperature, filtered through Celite and the filtrate was concentrated under reduced pressure. The resultant residue was washed with nhexane to obtain Intermediate 2B (8.55 g, 56.70%) as a black solid. The compound was taken directly to the subsequent step without further purification.1H NMR (300 MHz, DMSOd6) G ppm 1.28- 1.43 (m, 12 H), 2.46 (s, 3 H), 5.41 (s, 2 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.72- 7.87 (m, 1 H). LCMS (MethodI): retention time 1.43 min, [M+H] 275.1. |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 3.5h;Inert atmosphere; | General procedure: 1,3-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one J-1 5-Bromo-1,3-dimethyl-1H-pyridin-2-one C-1 (10.0 g; 48.0 mmol), bis(pinacolato)diboron (16.0 g; 63.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlormethane (2.00 g; 2.376 mmol) and potassium acetate (9.423 g; 96.016 mmol) are introduced into a flask. 1,4-Dioxane (100.0 mL) is added and the flask is flushed with argon. The reaction is heated to 90 C. for 3 h. A second portion of bis(pinacolato)diboron (1.200 g; 4.726 mmol) is added and the solution is stirred for an additional 30 min. The reaction mixture is then cooled to RT and filtered through a plug of celite, washed with dioxane (2*100.0 mL). The filtrate is concentrated under reduced pressure. The residue is then dissolved in DCM (200.0 mL) and washed with water (1*100.0 mL). The water layer is extracted DCM (1*100.0 mL). The combined organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified by silica gel chromatography Combiflash (Column Redisep Rf, 330 g; gradient: cyclohexane/EtOAc=100%/0% to 0%/100% over 16 column volumes; flow rate=200 mL/min; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduced pressure. The remaining catalyst is filtered off and washed with ethyl acetate. The filtrate is concentrated under reduced pressure to give the desired product as an oil, which crystallizes upon standing. HPLC-MS: (M+H)+=250; tRet=0.96 min; method M1 | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 2h; | General procedure: To a stirred solution of 5-bromo-1-isopropylpyridin-2(1 H)-one (Step A1.1 - method A) (10 g, 46.3 mmol) in Dioxane (150 ml.) were added Bis(pinacolato)diboron (14.1 g, 55.5 mmol), KOAc (6.08 g, 93 mmol) and PdCI2(dppf) (3.39 g, 4.63 mmol). The reaction mixture was heated up and stirred at 90C for 2 hr. Solvent was partially evaporated under reduced pressure, passed through a pad of Celite; the pad was washed with EtOAc and the resulting filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and aqueous NaHC03 solution, both phases separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to afford, without further purification, the title product (20.69 g, 39.3 mmol, 85% yield) as a dark oil. Rt = 0.98 min (UPLC-MS); ESI-MS = 264.2 [M+1]+ (UPLC-MS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; acetonitrile; at 90℃; for 3h;Inert atmosphere; | (ii) (S)-tert-Buty\\ l-(l-amino-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phoxopropan-2-ylcarbamoyl)cycloheptylcarbamate(S)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2- ylcarbamoyl)cycloheptylcarbamate (Example 35, step (i), 400 mg), l-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (213 mg) and potassium acetate (148 mg) in a mixture of acetonitrile (15 mL) and water (10 mL) and under a nitrogen atmosphere was treated with 1,1 3/4z5(di-tert-butylphosphino)ferrocene palladium dichloride (16 mg) and the mixture stirred and heated at 90 °C for 3h. The reaction mixture was cooled and diluted with water (100ml). The products were extracted into ethyl acetate (2x 100ml) and the combined extracts washed with 10percent aq potassium cabonate (50ml) followed by 5percent> aq citric acid (50 mL). The organic phase was dried and concentrated to dryness to afford the sub-titled compound (320 mg). m/e (APCI+) 512 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In water; acetonitrile; at 85℃; for 18h;Inert atmosphere; | (i) (S)-tert- utyl l-(l-amino-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)-l- oxopropan-2-ylcarbamoy])cyclohexylcarbamate (iS)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (1.5 g) and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (684 mg) in acetonitrile (8 mL) and water (lmL) with potassium acetate (571 mg) was bubbled through with nitrogen and then 1 , 1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5mg) was added and the mixture was heated at 85°C for 18 h. The reaction mixture was allowed to cool to room temperature and absorbed onto silica for purification bychromatography on silica eluting with ethyl acetate, then ethyl acetate / methanol (2:98) as eluent to afford the subtitled compound. m/e (APCI+) 497 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 96℃;Inert atmosphere; | [0176] Step 3: A mixture of l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one 21-3 (78 mg, 0.33 mmol), tert-butyl 4-chloro-3-fluorobenzylcarbamate 21-5 (94 mg, 0.36 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol) and K3P04 (140 mg, 0.66 mmol) in dioxane (1.2 mL) and water (0.1 mL) was stirred at 96 °C under argon overnight. After cooling to room temperature, the mixture was filtered through celite and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography to give crude tert-butyl 3-fluoro-4-(l-methyl-6-oxo- l,6-dihydropyridin-3-yl)benzylcarbamate 21-6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; | Example 43a5-(6-Amino-2-methoxypyridin-3-yl)-1-methylpyridin-2(1H)-one1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (CAS 1002309-52-5, 1.088 g, 4.63 mmol), <strong>[1211533-83-3]5-bromo-6-methoxypyridin-2-amine</strong> (CAS 1211533-83-30, 94 g, 4.63 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)chloride dichloromethane complex (0.113 g, 0.14 mmol) and potassium carbonate (aqueous 2M) (6 mL, 12.00 mmol) in dioxane (10 mL) were heated under argon to 80° C. for 1 h.The mixture was allowed to cool and was filtered through a short pad of Celite.The pad was washed with EtOAc (100 mL).The filtrate was collected and the solvent was removed by rotary evaporation.The crude product was added to a silica gel column and was eluted with 0-3percent MeOH in DCM.The collected fractions were combined and the solvent was removed by rotary evaporation.The residue was redissolved in DCM and the mixture was washed with saturated aqueous Na2CO3, dried over K2CO3, filtered and the solvent was removed by rotary evaporation to yield the title compound (0.402 g, 37percent).1H NMR (500 MHz, DMSO-d6) delta ppm 3.44 (s, 3H) 3.78 (s, 3H) 5.98 (s, 2H) 6.07 (d, 1H) 6.37 (d, 1H) 7.33 (d, 1H) 7.56 (dd, 1H) 7.72 (d, 1H). MS (ES+) m/z 232.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | Step B: Preparation of N-(3 -methyl- 1 -((6-methylpyridin-2-yl methvQ- 1 H- indazol-4-yl)-7-(l-methyl-6-oxo-l,6-dihvdropyridin-3-yl)imidazori,2-a1pyridine-3- carboxamide: 7-Bromo-N-(3 -methyl- 1 -((6-methylpyridin-2-yl)methyl)- 1 H-indazol-4- yl)imidazo[l,2-a]pyridine-3-carboxamide (0.05 g, 0.12 mmol) was dissolved in dimethoxyethane:dimethylformamide (1 : 1, 0.8 mL) in a 2 dram vial, and l-Methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (0.04 g, 0.17 mmol), PdCl2(dppf)*dcm (0.005 g, 0.006 mmol), and 2 M sodium carbonate (0.17 mL, 0.34 mmol) were added. Nitrogen was bubbled through the reaction mixture for 5 minutes before capping the vial and heating in a sand bath at 90 °C overnight. The reaction mixture was diluted with ethyl acetate and water. A greenish precipitate formed and was collected. The crude material was purified by preparatory thin layer chromatography (silica, 20 x 20 cm, 0.5 mm) developed in a chamber with 10percent MeOH/DCM. The UV active band with Rf = 0.1 was isolated and the silica washed with 10percent MeOH/DCM. The filtrate was concentrated to give N-(3 -methyl- l-((6-methylpyridin-2-yl)methyl)-lH-indazol-4-yl)-7-(l-methyl-6-oxo-l, 6- dihydropyridin-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as a beige solid (31 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 3h;Inert atmosphere; Sealed tube; | Step 3: 4-(((3S,4S)-l-(5-cyanopyrimidin-2-yl)-4-ethylpyrrolidin-3-yl)amino)-6-(l- methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)pyrrolo[l ,2-b]pyridazine-3-carboxamide (Example159) [00347] A mixture of 6-bromo-4-(((3S,4S)-l-(5-cyanopyrimidin-2-yl)-4- ethylpyrrolidin-3-yl)amino)pyrrolo[l,2-b]pyridazine-3-carboxamide (20 mg, 0.044 mmol, from Step 1), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (31.0 mg, 0.132 mmol, from Step 2), and PdCl2(dppf)-CH2Ci2 adduct (7.17 mg, 8.79 muiotaetaomicron) was pumped under vacuum and backfilled with nitrogen three times. A 2 M aqueous solution of potassium phosphate tribasic (0.066 mL, 0.132 mmol) and N,N- dimethylformamide (0.5 mL) were added. The mixture was immediately pumped under vacuum and backfilled with nitrogen three times, sealed and placed in a 90 °C heating block for 3 h, then cooled to room temperature. The mixture was filtered to remove the insoluble material. The filtrate was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100percent B over 25 minutes, then a 5-minute hold at 100percent B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (9.4 mg, 44percent yield). 1H NMR (500 MHz, DMSO-i/6) delta ppm 1 1.16 (d, J=7.4 Hz, 1H), 8.77 (d, J=3.0 Hz, 1H), 8.67 (d, J=3.0 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.00 - 7.90 (m, 1H), 7.25 (d, J=1.5 Hz, 1H), 6.48 (d, J=9.4 Hz, 1H), 5.09 - 4.91 (m, 1H), 4.09 - 3.94 (m, 2H), 3.85 (d, J=12.4 Hz, 1H), 3.51 (s, 3H), 2.66 - 2.55 (m, 1H), 1.64 (quin, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); MS (ES+) m/z: 484.2 (M+H); LC retention time: 1.19 min (analytical LCMS Method I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.9% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 16h; | Example 52. Synthesis of (R)-5-(6-(4-chlorophenyl)-l,4-dimethyl-5,6-dihydro- 4H-benzo[b][l,2,4]triazolo[4,3-d][l,4]diazepin-8-yl)-l-methylpyridin-2(lH)-one (Compound 62). To a mixture of (R)-8-bromo-6-(4-chlorophenyl)-l,4-dimethyl-5,6-dihydro- 4H-benzo[b][l,2,4]triazolo[4,3-d][l,4]diazepine (40.2 mg, 0.1 mmol), l-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin-2(lH)-one (44.2 mg, 0.2 mmol),tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), cesium carbonate (98 mg, 0.3 mmol), toluene (2 mL), ethanol (1 mL) and water (3 drops) was stirred at 100°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 * 20 mL). The combined organic layers were washed with water (3 * 20 mL), brine (3 * 20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuum, and then the residue was purified by column chromatography (silica gel, dichloromethane/methanol= 15:1) to give (R)-5-(6-(4-chlorophenyl)-l,4-dimethyl-5,6-dihydro- 4H-benzo[b][l,2,4]triazolo[4,3- d][l,4]diazepin-8-yl)-l-methylpyridin-2(lH)-one as a white solid (15 mg, 34.9percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,4-dioxane; water; at 90℃; under 760.051 Torr; for 2h;Inert atmosphere; | General procedure: Compound 102 (0.45 mmol, 1.0 equiv), 1-methyl-6-oxo-1,6-dihydropyridin-3-ylboronic acid, pinacol ester (0.9 mmol, 2.0 equiv), and Na2C03 (0.9 mmol, 2.0 equiv) were dissolved in dioxane/water (4: 1 v/v, 4 mL). The mixture was bubbled with Ar for 5 min, then charged with PdCl2(amphos)2 (10 molpercent), further purged with Ar, and then heated to 90 °C for 2h. The reaction was then cooled and partitioned in ethyl acetate and saturated sodium bicarbonate. The layers were separated and the water layer was extracted with ethyl acetate (lx). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to provide the product which was purified using flash silica gel chromatography (gradient of 0-50percent ethyl acetate/hexanes followed by 0-7percent methanol/methylene chloride) to provide compound 103. ESI-MS m/z: 473.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,4-dioxane; water; for 4h;Reflux; | [1118] A mixture of compound 329 (10.40 g, 27.2 mmol), <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (9.58 g, 40.7 mmol), sodium carbonate (5.76 g, 54.3 mmol) and PdCl2(Amphos)2 (0.962 g, 1.358 mmol)) in dioxane/water (4:1, 208 mL)) was heated to reflux for 4 h. The mixture was cooled to room temperature and water (200 mL) was added. The solid was filtered, washed with water, and dried overnight. The solid was purified by column chromatography eluting with 0-10percent MeOH/dichloromethane to give compound 359. ESI-MS m/z: 456.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 110℃; for 0.5h;Microwave irradiation; | A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-lH-pyridine-2-one (Synchem Inc. 0.056 g, 0.24 mmol), the product from Example 261C (0.068 g, 0.2 mmol), tetrakis(tiriphenylphosphine) palladium(O) (0.012 g, 0.01 mmol) and sodium carbonate 2M (0.2 mL, 0.40 mmol) in toluene (1 mL), ethanol (0.25 mL) and water (0.5 mL) was heated by microwave at 110 °C for 30 minutes. The reaction mixture was filtered through a 0.45muiotaeta Nylon filter disk to remove solids and the filtrate was partitioned between ethyl acetate and brine. The organic layer was separated and concentrated. Purification by reverse phase HPLC (C 18, 0- 100 percent CH3CN/water (0.1 percent TFA)) afforded the title compound (0.028 g, 37percent). 1H NMR (300 MHz, DMSO-d6) delta 9.73 (s, 1 H) 7.88 (d, J=2.38 Hz, 1 H) 7.56 (dd, J=9.52, 2.78 Hz, 1 H) 7.28 - 7.36 (m, 2 H) 7.26 (d, J=2.78 Hz, 1 H) 7.16 - 7.22 (m, 1 H) 7.05 (t, J=7.34 Hz, 1 H) 7.00 (d, J=8.73 Hz, 1 H) 6.90 (d, J=7.93 Hz, 2 H) 6.35 - 6.40 (m, 1 H) 3.44 (s, 3 H) 3.03 (s, 3 H). MS (ESI+) m z 371 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Example 261B (2.86 g, 10.8 mmol) and triethylamine (6.03 mL, 43.3 mmol) were stirred in dichloromethane (48.1 mL) at ambient temperature. Methanesulfonyl chloride (2.53 mL, 32.4 mmol) was added dropwise and the solution stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dioxane (24 mL) and sodium hydroxide (10 percent w/v, 12 mL, 0.427 mmol) were added, and the solution was heated to 70 °C for 1 hour. The solution was neutralized to a pH of 7 with saturated aqueous NH4CI (200 mL). The aqueous phase was extracted with ethyl acetate (3x125 mL). The combined organics were washed with brine, dried (MgSC^), filtered, then concentrated. The residue was purified by flash chromatography (silica gel, 0-25percent ethyl acetate/hexane gradient,) to afford the title compound (2.79 g, 75percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; | 4-bromo-5- fluoro-2-nitrotoluene (Aldrich, 0.234 g, 1.0 mmol), l-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)-1H-pyridin-2-one (Synchem, Inc.0.235 g, 1.0 mmol), bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol) and sodium carbonate 2M (1.5 mL, 3.0 mmol) were combined in DME (4 mL) and water (4.0 mL), sparged with nitrogen and heated by microwave at 120 °C for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (Na2SO4), treated with mercaptopropyl silica gel for 30 minutes, filtered and concentrated to afford the title compound (0.262 g, 99percent). |
99% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Example 257A 5-(2-fluoro-4-methyl-5-nitrophenyl)-1-methylpyridin-2(1H)-one [1076] 4-bromo-5-fluoro-2-nitrotoluene (Aldrich, 0.234 g, 1.0 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)-1H-pyridin-2-one (Synchem, Inc. 0.235 g, 1.0 mmol), bis(triphenylphosphine)palladium(II)chloride (0.035 g, 0.05 mmol) and sodium carbonate 2M (1.5 mL, 3.0 mmol) were combined in DME (4 mL) and water (4.0 mL), sparged with nitrogen and heated by microwave at 120° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (Na2SO4), treated with mercaptopropyl silica gel for 30 minutes, filtered and concentrated to afford the title compound (0.262 g, 99percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 110℃; for 0.5h;Microwave irradiation; | Example 224 N-[3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenoxyphenyl]methanesulfonamide [1000] A mixture of <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-one</strong> (Synchem Inc. 0.056 g, 0.24 mmol), the product from Example 261C (0.068 g, 0.2 mmol), tetrakis(tiriphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) and sodium carbonate 2M (0.2 mL, 0.40 mmol) in toluene (1 mL), ethanol (0.25 mL) and water (0.5 mL) was heated by microwave at 110° C. for 30 minutes. The reaction mixture was filtered through a 0.45 mum Nylon filter disk to remove solids and the filtrate was partitioned between ethyl acetate and brine. The organic layer was separated and concentrated. Purification by reverse phase HPLC (C18, 0-100percent CH3CN/water (0.1percent TFA)) afforded the title compound (0.028 g, 37percent). 1H NMR (300 MHz, DMSO-d6) delta 9.73 (s, 1H) 7.88 (d, J=2.38 Hz, 1H) 7.56 (dd, J=9.52, 2.78 Hz, 1H) 7.28-7.36 (m, 2H) 7.26 (d, J=2.78 Hz, 1H) 7.16-7.22 (m, 1H) 7.05 (t, J=7.34 Hz, 1H) 7.00 (d, J=8.73 Hz, 1H) 6.90 (d, J=7.93 Hz, 2H) 6.35-6.40 (m, 1H) 3.44 (s, 3H) 3.03 (s, 3H). MS (ESI+) m/z 371 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; | Preparation G 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)- 1 -methylpyridin-2( 1 H)-one1005491 3 -bromo-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine [Preparation F] (763 mg,3.03 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2( 1 H)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 nimol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mE) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOHJDCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H). |
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; | Intermediate 5 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)- 1 -methylpyridin-2( 1 H)-one1003011 3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine [Intermediate 4] (763 mg,3.03 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2( 1 H)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mE) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mE) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOH/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) mz = 281.2 (M+I{). |
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; | Intermediate 5 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -vD- 1 -methylpyridin-2( 1 HVone [00359] 3-Bromo-4-methyl-l -phenyl- lH-pyrazol-5-amine [Intermediate 4] (763 mg, 3.03 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOH/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H). |
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; | 1004931 Step C: Preparation of 5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1- methylpyridin-2( 111)-one: 3-bromo-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine (763 mg, 3.03 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2( 1 H)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mE), water (5 mL) and EtOH (2.5 mL). The reaction mixture was heated to 95°C in a sealed tube for 16 hours. The mixture was cooled, filtered and the filtrate was concentrated. The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with saturated NaC1 (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica column chromatography eluting with 2percent MeOHJDCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) mlz = 281.2 (M+H). |
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; | 3-Bromo-4-methyl-l -phenyl- lH-pyrazol-5 -amine (763 mg, 3.03 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOH/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H). |
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; | Intermediate 8 5-(5-amino-4-methyl- 1 -phenyl- 1 FI-pyrazol-3-yl)- 1 -methylpyridin-2(1 H)-one (006691 3-Bromo-4-methyl-l-phenyl-1H-pyrazol-5-amine [Intermediate 7] (763 mg, 3.03 mmol), 1 -methyl-5-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2( 1 H)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOFI/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) mz = 281.2 (M+H). |
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; | 3-bromo-4-methyl-l-phenyl-lH-pyrazol-5-amine (763 mg, 3.03 mmol), l-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine (20 mL), dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2percent MeOH/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00211] To a solution of 89 (60 mg, 0.11 mmol) in dioxane (2 mL) was added 1-methyl- 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2( 1H)-one (50 mg, 0.21 mmol), Pd(dppf)C12 (15 mg, 0.02 mmol), Cs2CO3 (98 mg, 0.33 mmol) and H20 (0.2 mL) under N2.The mixture was stirred at 100 °C for 8 h. The mixture was added with water (10 mL) andextracted with EtOAc (5 mL x 3). The combined organic layers were dried over sodiumsulfate, filtered, concentrated, purified by preparative TLC (petroleum ether: ethyl acetate= 1:8) and separated by HC1 preparative HPLC to afford the compound I-A19 (HC1 salt, 10.4 mg,15percent) as a white solid. LCMS: tR = 0.727 mm in 5-95AB_1.5min chromatography (MKRP18e 25-2mm), MS (ESI) m/z 591.1 [M+H]. ?H NMR (CD3OD): oe 8.12 (d, J= 2.0 Hz,1H), 7.95 (dd, J= 2.4, 9.2 Hz, 1H), 7.91 (d, J= 8.4 Hz, 2H), 7.73 (s, 4H), 7.65 (d, J= 8.4 Hz,2H), 6.68 (d, J= 9.6 Hz, 1H), 4.80-4.60 (m, 5H) , 3.97 (s, 2H), 3.69 (s, 3H), 3.23 (q, J= 7.2Hz, 2H), 2.13-2.00 (m, 1H), 1.24 (t, J= 7.2 Hz, 3H), 1.12 (d, J= 6.8 Hz, 3H), 0.89 (d, J= 6.8Hz, 3H). Isomer SFC tR = 3.807 mm in 8 mm chromatography (Column: AS-H; MethodName: AS-H_S_5_40_3 mL_8 mm_iS cm, ee = 96.10percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 12h; | 5.1.51 Methyl 1-methyl-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazole-3-carboxylate (36) To a mixture of <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (34, 2.3 g, 9.78 mmol) and methyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (35, 1.25 g, 4.70 mmol) in DMF (40 mL) and water (10 mL) were added Pd(PPh3)4 (814 mg, 0.71 mmol) and Cs2CO3 (3.06 g, 9.40 mmol), and the mixture was stirred at 80 °C for 12 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0-5percent MeOH in CHCl3) to give 36 (812 mg, 70percent) as colorless solid. 1H NMR (DMSO-d6) delta 3.44 (s, 3H), 3.74 (s, 3H), 3.91 (s, 3H), 6.39 (d, 1H, J = 9.3 Hz), 7.51 (dd, 1H, J = 9.4, 2.6 Hz), 7.86 (d, 1H, J = 2.6 Hz), 7.94 (s, 1H); MS (ESI) m/z 248 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tricyclohexylphosphine; In 1,4-dioxane; at 80℃; for 5h;Inert atmosphere; | To a mixture of 5-bromo-1-methylpyridin-2(1H)-one (1.0 g, 5.32 mmol), KOH (0.78 g, 7.98 mmol) and bis(pinacolato)diboron (0.162 g, 6.38 mmol) in 1 ,4-dioxane (20 mL), tricyclohexyiphosphine (149 mg, 0.532 mmol), Pd2dba3 (487 mg, 0.532 mmol) were added under N2 atmosphere. The mixture was stirred at about 80 °C for about 5 h. Then water was added, the aqueous layer was extracted with EtOAc (50 mL x 2), and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and the residue was purified by column chromatograph on silica gel to provide ]-methyl-5-(4, 4,5, 5-tetramethyl-], 3, 2-dioxaborolan-2-yl)pyridin-2(]H)-one (0.80 g, 64percent): ?H NMR (CDC13) 7.70 (s, 1 H), 7.54 (d, J= 8.8 Hz, 1 H), 6.47 (d, J= 8.8 Hz, 1 H), 3.49 (s, 3 H), 1.24(s, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; water; at 90℃; for 0.333333h; | General procedure: N-[3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide A mixture of 5-bromo-1-methylpyridin-2-one (100 mg, 0.532 mmol), [3-(methanesulfonamido)phenyl]boronic acid (171.1 mg, 0.798 mmol), KOAc (130.0 mg, 1.326 mmol) and Pd(dppf)Cl2 (38.9 mg, 0.05 mmol) in dioxane/H2O (2 mL/0.5 mL) was stirred at 90° C. for 20 min. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA=1:1) to give the title compound (30.0 mg, 20percent) as a brown solid. 1H NMR (CDCl3, 400 MHz) delta 7.65-7.60 (dd, J1=7.6 Hz, J2=2.4 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 6.86 (brs, 1H), 6.67 (d, J=9.2 Hz, 1H), 3.65 (s, 3H), 3.05 (s, 3H). LCMS (M+H)+ 279.5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one was treated with 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene in a manner similar to Example 94 to give the title compound. 1H NMR (CDCl3, 400 MHz): delta 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.68-765 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.64 (s, 3H), 3.07 (s, 3H), 1.28-1.25 (m, 1H), 0.69-0.65 (m, 2H), 0.34-0.38 (m, 2H). LCMS (M+H)+ 334. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃;Inert atmosphere; | The title compound of step 3 (62 mg, 0.2 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (57 mg, 0.24 mmol), K2CO3 (82 mg, 0.6 mmol), Pd(dppf)Cl2 (6.2 mg) in 1,4-dioxane/water (4:1) (5 mL) were heated at 85° C. under N2 overnight. Silica gel chromatography (PE:EA=1:1) gave the title compound (56.6 mg, 97percent) as a brown oil. 1H NMR (300 MHz, CDCl3): delta 1.66 (3H, t, J=6.0 Hz), 2.63-2.71 (2H, m), 3.05 (3H, s), 3.60 (3H, s), 6.64 (1H, d, J=9.0 Hz), 7.28-7.33 (2H, m), 7.48 (1H, d, J=9.0 Hz), 7.70 (1H, s), 7.82-7.85 (1H, m). LCMS: 292 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; | The title compound of step 3 (120 mg, 0.34 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (89 mg, 0.37 mmol), Na2CO3 (72 mg, 0.68 mmol) and Pd(dppf)Cl2 (15 mg) in DMF/H2O (6 ml/1.5 ml) under N2 were heated at 100° C. for 1 h. EA extractive work up and preparative TLC (PE:EtOAc=0:1) gave the title compound (62 mg, 55percent). 1H NMR (CD3OD, 400 MHz): delta 7.92 (dd, J1=2.4 Hz, J2=5.6 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.65-7.61 (m, 2H), 6.69 (m, J=9.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.89-2.86 (m, 2H), 1.51-1.45 (m, 2H), 0.68-0.65 (m, 1H), 0.45-0.40 (m, 2H), 0.04-0.00 (m, 2H). LCMS: 332 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.5% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 70℃;Inert atmosphere; | The title compound from step 4 (50 mg, 0.15 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (42 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg, 14.9 umol) and K3PO4 (63 mg, 0.3 mmol) in dioxane (5 mL) and water (5 drops) were degassed and then heated to 70° C. under N2 overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by column chromatography (PE:DCM:EA=3:0:1 to 0:1:4) followed by preparative HPLC to afford the title compound (17.09 mg, 31.5percent) as an off-white solid. 1H NMR (CDCl3, 400 MHz) delta 7.50 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H), 5.96 (s, 1H), 5.16 (s, 2H), 3.86 (d, J=6.8 Hz, 1H), 3.63 (s, 3H), 2.99 (s, 3H), 1.26-1.21 (m, 1H), 0.70-0.66 (m, 2H), 0.36-0.32 (m, 2H). LCMS: 365.0 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 90℃; for 1h;Microwave irradiation; | A mixture of the title compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd(dppf)Cl2 (10 mg, 8percent) and 3-bromo-4-ethoxybenzene-1-sulfonamide (48 mg, 0.17 mmol) was suspended in 1,4-dioxane (880 muL) and saturated bicarbonate solution (aq) (220 muL). The mixture was heated to 95° C. using microwave irradiation (normal) for 60 min. The crude reaction mixture was filtered through a short plug of celite, the plug was washed with additional 1,4-dioxane (1 ml), and the combined filtrate was purified by prep-HPLC. The fractions were combined and lyophilized to give the title compound (14 mg, 27percent) as a white solid. 1HNMR (DMSO, 400 MHz): delta 1.33 (t, J=6.9, 3H), 3.49 (s, 3H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz, 1H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1H), 7.72-7.74 (m, 2H), 7.89 (d, J=2.6 Hz, 1H). LCMS (M+H)+=309. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 105℃; for 0.5h;Microwave irradiation; | 3-Bromo-4-(2,4-difluorophenoxy)benzenesulfonamide (1 eq., 62 mg), the title compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd(dppf)Cl2 (10 mg, 8percent) in 1,4-dioxane (880 muL) and saturated bicarbonate solution (aq) (220 muL) were reacted at 105° C. for 30 min in a manner similar to Example 117. Work up and preparative HPLC, also in a similar manner, gave the title compound (12 mg, 18percent) as a white solid. 1H NMR (DMSO, 400 MHz): delta 3.51 (s, 3H), 6.49 (d, J=9.4, 1H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz, 1H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1H), 7.72-7.74 (m, 2H), 7.89 (d, J=2.6 Hz, 1H). LCMS (M+H)+=393. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14 mg | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 0.0833333h; | General procedure: PdCl2(dppf)CH2CI2 complex (30.1 mg, 0.037 mmol) was added to a stirred mixture of 2-bromo-6-(4-chlorophenyl)-5-(3,8-di methyl-[1 ,2,4]triazolo[4, 3-a]pyridin-6-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)-5,6-di hydropyrrolo[3,4-b]pyrrol-4( 1 H)-one (Step 3 of Example 25,240 mg, 0.368 mmol) and K3P04 (312 mg, 1.472 mmol) in dioxane (3 mL) and water (1 mL) at80°C and then heated up to 110°C. 1-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (Step 2 of Example 25, 541 mg, 0.920 mmol) was added. The reactionmixture was stirred at 110 °Cfor 10 mm, diluted in EtOAc/water, and extracted twice withEtOAc. The combined organic extracts were washed with brine, dried (Na2504), filtered and the filtrate was concentrated. The residue was loaded onto a Varian PL-Thiol MP SPE cartridge (to remove metals traces) and eluted with MeOH. The resulting filtrate was concentrated. The residue was purified by silica gel chromatography on Combiflash Isco (eluent: MeOH/DCM;gradient: 1.6 mm 0percent MeOH, 0percent to 7.6percent MeOH in 17.7 mm, 7.6percent to 9.4percent MeOH in 8.2 mm; flow: 40 mL/min) to afford the title compound (187 mg) as a beige solid. The title compound was prepared using an analogous procedure to that described in Step 4 ofExample 25 using 2-bromo-5-(5-chloro- 1 -methyl-6-oxo- 1 ,6-dihydropyridi n-3-yl)-6-(4-chlorophenyl)- 1 -methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1 H)-one (Step 5 of Example 38, 150 mg, 0.321 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (Step 1 of Example 42, 377 mg, 0.642 mmol). The reaction mixture was stirred for 5 mm at 110CC. DCM was used instead of EtOAc in the workup. The crude was loaded onto a VarianPL-Thiol MP SPE cartridge (to remove metals traces) and eluted with MeOH. After concentration, the residue was purified by chromatography (1percent ammonia/5percent MeOH/DCM) to afford a beige foam. This foam was purified by by preparative achiral SF0 (column: 4-EP, 250 x 30mm, 5pm, 60A, Princeton; eluent: MeOH/scCO2 gradient: 1 mm 20percent MeOH, 20percent to 25percent MeOH in 6 mm, 25percent to 50percent MeOH in 1 mm, i.s mm 50percent MeOH; flow: 100 mL/min). Triturationof the resulting material in Et20 afforded the title compound (14 mg) as a colorless solid. Rf=0.24(1percent ammonia/5percent MeOH/DCM); Rt: 0.79 mm (LC-MS 1); MS mlz: 495.1 [M+H](LC-MS 1);1H NMR (400 MHz, DMSO-d6) O 3.25 (5, 3 H) 3.42 (5, 6 H) 6.23 (5, 1 H) 6.30 - 6.45 (m, 2 H)7.30 (m, J=8.60 Hz, 2 H) 7.41 (m, J=8.60 Hz, 2 H) 7.52 (dd, J=9.38, 2.74 Hz, 1 H) 7.78 - 7.91(m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 mg | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 0.25h; | General procedure: PdCl2(dppf)CH2CI2 complex (30.1 mg, 0.037 mmol) was added to a stirred mixture of 2-bromo-6-(4-chlorophenyl)-5-(3,8-di methyl-[1 ,2,4]triazolo[4, 3-a]pyridin-6-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)-5,6-di hydropyrrolo[3,4-b]pyrrol-4( 1 H)-one (Step 3 of Example 25,240 mg, 0.368 mmol) and K3P04 (312 mg, 1.472 mmol) in dioxane (3 mL) and water (1 mL) at80°C and then heated up to 110°C. 1-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (Step 2 of Example 25, 541 mg, 0.920 mmol) was added. The reactionmixture was stirred at 110 °Cfor 10 mm, diluted in EtOAc/water, and extracted twice withEtOAc. The combined organic extracts were washed with brine, dried (Na2504), filtered and the filtrate was concentrated. The residue was loaded onto a Varian PL-Thiol MP SPE cartridge (to remove metals traces) and eluted with MeOH. The resulting filtrate was concentrated. The residue was purified by silica gel chromatography on Combiflash Isco (eluent: MeOH/DCM;gradient: 1.6 mm 0percent MeOH, 0percent to 7.6percent MeOH in 17.7 mm, 7.6percent to 9.4percent MeOH in 8.2 mm; flow: 40 mL/min) to afford the title compound (187 mg) as a beige solid. The title compound was prepared using an analogous procedure to that described in Step 4 of Example 25 using 2-bromo-6-(4-chlorophenyl)- 1 -cyclopropyl-5-(1 ,5-di methyl-6-oxo- 1,6-dihydropyridin-3-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Step 1 of Example 63, 150 mg,0.317 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one(Step 1 of Example 42, 497 mg, 0.635 mmol). The reaction mixture was stirred for 15 mm at110CC. DCM was used instead of EtOAc in the workup. The crude was loaded onto a VarianPL-Thiol MP SPE cartridge (to remove metals traces) and eluted with MeOH. Afterconcentration, the residue was purified by silica gel column chromatography (1percent ammonia/5percent MeOH/DCM). The resulting material was purified by preparative achiral SF0 (column: 4-Ethyl pyridine, 250 x 30mm, 5pm, 60A, Princeton; eluent: MeOH/scCO2 gradient: 1 mm 17percent MeOH, 17percent to 22percent MeOH in 6 mm, 22percent to 50percent MeOH in 1 mm, i.s mm 50percent MeOH; flow: 100 mLlmin). Trituration of the resulting material in Et20 afforded the title compound (70 mg) as acolorless solid. Rf= 0.20(1percent ammonia/5percent MeOH/DCM); Rt: 0.81 mm (LC-MS 1); MS mlz:501.2 [M+H] (LC-MS 1); 1H NMR (400 MHz, DMSO-d6) O 0.25 - 0.44 (m, 1 H) 0.67 - 0.85 (m, 2H) 1.11 - 1.21 (m, 1 H) 1.92 (5, 3 H) 2.96-3.06 (m, 1 H) 3.35 (5, 3 H) 3.44 (5, 3 H) 6.24 (5, 1 H)6.30 - 6.44 (m, 2 H) 7.23 - 7.34 (m, 2 H) 7.34 - 7.47 (m, 3 H) 7.60 - 7.73 (m, 2 H) 7.91 (d, J=2.73Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.9% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 28 - 100℃; for 1h;Inert atmosphere; Microwave irradiation; | Tripotassium phosphate (672 mg, 3.17 mmol) was added to a stirred solution of (4S)-7-chloro-N-(pyridin-3-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxa-mide (500 mg, 1.583 mmol), and <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (447 mg, 1.900 mmol) in 1,4-dioxane (10 mL), and water (2.000 mL) at 28 C. The reaction mixture was degassed for 10 min then was added Pd2(dba)3 (72.5 mg, 0.079 mmol), and X-phos (75 mg, 0.158 mmol). The reaction mixture was further degassed for 15 min. The reaction mixture was stirred for 1 hr in Microwave at 100 C. The reaction mixture was cooled to 28 C. and was partitioned between water (10 mL) and EtOAc (25 mL). EtOAc layer was separated and was dried over anhydrous Na2SO4, filtered and filtrate was evaporated to afford crude as brown solid (TLC eluent: 10% MeOH in EtOAc: Rf-0.2; UV active). The crude was purified by column chromatography using silica gel (100-200 mesh), and the product was eluting with 2% MeOH in Ethyl acetate to afford (4S)-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(pyridin-3-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide (272 mg, 0.679 mmol, 42.9% yield) as off white solid, LCMS (m/z): 389.27 [M+H]+. 1H NMR (400 MHz, CDCl3): delta ppm 12.93 (s, 1H), 8.61 (d, J=2.41 Hz, 1H), 8.33 (dd, J=4.71, 1.43 Hz, 1H), 8.05-8.20 (m, 1H), 7.74-7.87 (m, 2H), 7.57 (d, J=7.89 Hz, 1H), 7.22-7.33 (m, 1H), 7.09 (d, J=7.89 Hz, 1H), 6.65-6.82 (m, 1H), 5.67 (dd, J=5.81, 3.18 Hz, 1H), 3.64 (s, 3H), 3.08-3.28 (m, 3H), 3.00 (dd, J=12.06, 3.29 Hz, 1H), 2.33 (qd, J=9.98, 4.49 Hz, 1H), 2.00-2.12 (m, 1H). |
42.9% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 28 - 100℃; for 1h;Microwave irradiation; | Tripotassium phosphate (672 mg, 3.17 mmol) was added to a stirred solution of (4S)-7- chloro-N-(pyridin-3-yl)-3,4-dihydro-l,4-methanopyrido[2,3-^][l,4]diazepine-5(2H)- carboxa-mide (500 mg, 1.583 mmol), and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2(lH)-one (447 mg, 1.900 mmol) in 1,4-dioxane (10 mL), and water (2.000 mL) at 28 C. The reaction mixture was degassed for 10 min then was added Pd2(dba)3 (72.5 mg, 0.079 mmol), and X-phos (75 mg, 0.158 mmol). The reaction mixture was further degassed for 15 min. The reaction mixture was stirred for 1 hr in Microwave at 100 C. The reaction mixture was cooled to 28 C and was partitioned between water (10 mL) and EtOAc (25 mL). EtOAc layer was separated and was dried over anhydrous Na2S04, filtered and filtrate was evaporated to afford crude as brown solid (TLC eluent: 10% MeOH in EtOAc: R/-0.2; UV active). The crude was purified by column chromatography using silica gel (100-200 mesh), and the product was eluting with 2% MeOH in Ethyl acetate to afford (4,S)-7-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-N- (pyridin-3 -yl)-3 ,4-dihydro- 1 ,4-methanopyrido[2,3 -b] [ 1 ,4]diazepine-5(2H)-carboxamide (272 mg, 0.679 mmol, 42.9 % yield) as off white solid, LCMS (m/z): 389.27 [M+H]+. 1H NMR (400 MHz, CDC13): delta ppm 12.93 (s, 1 H), 8.61 (d, J=2.41 Hz, 1 H), 8.33 (dd, J = 4.71, 1.43 Hz, 1 H), 8.05 - 8.20 (m, 1 H), 7.74 - 7.87 (m, 2 H), 7.57 (d, J = 7.89 Hz, 1 H), 7.22 - 7.33 (m, 1 H), 7.09 (d, J = 7.89 Hz, 1 H), 6.65 - 6.82 (m, 1 H), 5.67 (dd, J = 5.81, 3.18 Hz, 1H), 3.64 (s, 3 H), 3.08 - 3.28 (m, 3 H), 3.00 (dd, J = 12.06, 3.29 Hz, 1 H), 2.33 (qd, J= 9.98, 4.49 Hz, 1 H), 2.00 - 2.12 (m, 1 H). Example 245 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.2% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 28 - 100℃; for 1h;Inert atmosphere; Microwave irradiation; | Tripotassium phosphate (804 mg, 3.79 mmol) was added to a stirred solution of (4S)-7-chloro-N-(pyrazin-2-yl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carboxa-mide (500 mg, 1.579 mmol), and <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (445 mg, 1.894 mmol) in 1,4-dioxane (10 mL), and water (2.000 mL) at 28 C. The reaction mixture was degassed for 10 min then was added Pd2(dba)3 (72.3 mg, 0.079 mmol), and X-phos (75 mg, 0.158 mmol). The reaction mixture was further degassed for 15 min. The reaction mixture was stirred for 1 hour in microwave at 100 C. The reaction mixture was cooled to 28 C. and was partitioned between water (10 mL) and ethyl acetate (2×15 mL). Ethyl acetate layer was separated and was dried over anhydrous Na2SO4, filtered and filtrate was evaporated to afford crude brown solid (TLC eluent: 10% MeOH in EtOAc: Rf-0.2; UV active). The crude was purified by column chromatography using (100-200 mesh) silica gel and was eluted with 2% MeOH in EtOAc to afford (4S)-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-(pyrazin-2-yl)-3,4-dihydro-1,4-methanopy-rido[2,3-b][1,4]diazepine-5(2H)-carboxamide (330 mg, 0.840 mmol, 53.2% yield) as off-white solid, LCMS (m/z): 390.26 [M+H]+. 1H NMR (400 MHz, CDCl3): delta ppm 13.78 (s, 1H), 9.61 (d, J=1.53 Hz, 1H), 8.57 (d, J=2.63 Hz, 1H), 8.33 (d, J=2.63 Hz, 1H), 8.22 (dd, J=2.52, 1.64 Hz, 1H), 7.88 (dd, J=9.54, 2.74 Hz, 1H), 7.57 (d, J=7.89 Hz, 1H), 7.18 (d, J=8.11 Hz, 1H), 6.69 (d, J=9.43 Hz, 1H), 5.69 (dd, J=5.92, 3.07 Hz, 1H), 3.78 (s, 3H), 3.12-3.30 (m, 3H), 3.01 (dd, J=12.06, 3.29 Hz, 1H), 2.28-2.41 (m, 1H), 2.00-2.13 (m, 1H) |
53.2% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 28 - 100℃; for 1h;Microwave irradiation; | Tripotassium phosphate (804 mg, 3.79 mmol) was added to a stirred solution of (4S)-7- chloro-N-(pyrazin-2-yl)-3,4-dihydro-l,4-methanopyrido[2,3-^][l,4]diazepine-5(2H)- carboxa -mide (500mg, 1.579 mmol), and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2(lH)-one (445 mg, 1.894 mmol) in 1,4-dioxane (10 mL), and water (2.000 mL) at 28 C. The reaction mixture was degassed for 10 min then was added Pd2(dba)3 (72.3 mg, 0.079 mmol), and X-phos (75 mg, 0.158 mmol). The reaction mixture was further degassed for 15 min. The reaction mixture was stirred for 1 hour in microwave at 100 C. The reaction mixture was cooled to 28 C and was partitioned between water (10 mL) and ethyl acetate (2 x 15 mL). Ethyl acetate layer was separated and was dried over anhydrous Na2S04, filtered and filtrate was evaporated to afford crude brown solid (TLC eluent: 10% MeOH in EtOAc: R/-0.2; UV active). The crude was purified by column chromatography using (100-200 mesh) silica gel and was eluted with 2% MeOH in EtOAc to afford (45)-7-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-N- (pyrazin-2-yl)-3,4-dihydro-l,4-methanopy-rido[2,3-^][l,4]diazepine-5(2H)-carboxamide (330 mg, 0.840 mmol, 53.2 % yield) as off-white solid, LCMS (m/z): 390.26 [M+H]+. 1H NMR (400 MHz, CDC13): delta ppm 13.78 (s, 1 H), 9.61 (d, J=1.53 Hz, 1 H), 8.57 (d, J=2.63 Hz, 1 H), 8.33 (d, J=2.63 Hz, 1 H), 8.22 (dd, J=2.52, 1.64 Hz, 1 H), 7.88 (dd, J=9.54, 2.74 Hz, 1 H), 7.57 (d, J=7.89 Hz, 1 H), 7.18 (d, J=8.11 Hz, 1 H), 6.69 (d, J=9.43 Hz, 1 H), 5.69 (dd, J=5.92, 3.07 Hz, 1 H), 3.78 (s, 3 H), 3.12 - 3.30 (m, 3 H), 3.01 (dd, J=12.06, 3.29 Hz, 1 H), 2.28 - 2.41 (m, 1 H), 2.00 - 2.13 (m, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 1h;Inert atmosphere; Sealed tube; | To a solution of l-(4-(4-iodooxazol-2-yl)-2-(4-(5-isopropyl-l,3,4-thiadiazol-2- yl)phenoxy)benzyl)pyrrolidin-2-one (30 mg, 0.051 mmol) in 1.2 mL of degassed 5: 1 dioxane/water was added l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2(lH)-one (18 mg, 0.077 mmol), [l,l '-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (3.33 mg, 0.512 umol), and sodium carbonate (10.8 mg, 0.102 mmol). The reaction mixture was heated at 120 °C for 1 h in a sealed tube. The reaction mixture was then cooled to ambient temperature, diluted with ethyl acetate, and washed with water and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via reverse-phase HPLC, eluting with 5percent acetonitrile in water (0.05percent NH4OH used as a modifier) initially, grading to 95percent acetonitrile in water. The desired fractions were concentrated to give the title compound. HRMS: mlz = 568.1996 [M+l]+. 1H NMR (500 MHz, CDC13): delta 7.94 (d, J= 8.5 Hz, 3 H); 7.88 (d, J= 8.0 Hz, 1 H); 7.76 (s, 1 H); 7.69 (s, 1 H); 7.55-7.57 (m, 1 H); 7.49 (d, J = 8.0 Hz, 1 H); 7.06 (d, J= 8.4 Hz, 2 H); 6.63 (d, J= 9.4 Hz, 1 H); 4.57 (s, 2 H); 3.61 (s, 3 H); 3.49-3.51 (m, 1 H); 3.34 (t, J= 7.0 Hz, 2 H); 2.38 (t, J= 8.1 Hz, 2 H); 1.98-2.00 (m, 2 H); 1.49 (d, J= 6.9 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In acetonitrile; at 120℃; for 0.75h;Inert atmosphere; Microwave irradiation; Sealed tube; | 3-Bromo-4-[(S)-3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopentapyrimidin-4-yl]-benzonitrile (intermediate 35) (100 mg, 0.20 mmol) and 1-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (62.3 mg, 0.27 mmol) are suspended in acetonitrile (4 mL) and are degassed with a stream of argon gas. 1,1?-Bis(di-tert-butylphosphino)ferrocene-palladium dichloride, complex with dichloromethane 1:1 (2.0 mg, 0.002 mmol) and potassium carbonate solution (2 mol/L, 306 muL, 0.61 mmol) are added and the mixture reacted unter microeave irradiation in a sealed vial at 120° C. for 45 min. The reaction mixture is filtrated over a layer of silica gel and basic aluminum oxide 1:1 and purified by reversed phase HPLC. Yield: 57 mg; ESI mass spectrum [M+H]+=519; retention time HPLC: 0.98 min (method Z018_S04) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
125 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In acetonitrile; at 100 - 120℃;Inert atmosphere; Microwave irradiation; | 4-[5-Acetyl-3,6-dimethyl-2-oxo-l-(3-trifluoromethyl-phenyl)-l,2,3,4-tetrahydro-pyrimidin- 4-yl]-3-bromo-benzonitrile (intermediate 4)(400 mg, 0.81 mmol) and N-methyl-lH- pyridin-2-one-5-boronic acid pinacol ester (248 mg, 1.06 mmol) are suspended in acetonitrile (15 mL) and are degassed with a stream of argon. Potassium carbonate solution (2 mol/L, 1.22 mL, 2.44 mmol) and l . l-bis(diphenylphosphino)-ferrocendichloro- palladium(II), complex with dichloromethane (1 : 1) (6.34 mg, 0.008 mmol) are added and the reaction is stirred at 100 °C overnight. Additional N-methyl-lH-pyridin-2-one-5- boronic acid pinacol ester (100 mg, 0.4 mmol) and l . l-bis(diphenylphosphino)- ferrocendichloropalladium(II), complex with dichloromethane (1 : 1) (2 mg, 0.002 mmol) are added and the reaction is continued at 120 °C for 60 min under microwave irradiation. The reaction mixture is filtrated over a layer of silica gel and basic aluminum oxide 1 : land purified by reversed phase HPLC. Yield: 125 mg; ESI mass spectrum [M+H]+ = 521;Retention time HPLC: 1.01 min (HPLC method Z018 S04). The enantiomer separation is performed by preparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IA, 10 x 250 mm, 5 muiotaeta, 20percent methanol and 20 mM NH3 in supercritical C02, 40 °C, flow 10 ml/min, 120 bar back pressure) .Yield 55 mg;retention time: 1.6 min (early eluting enantiomer) (method: I_IA_20_MEOH_NH3). The configuration of example 16 is assigned based on the X-Ray structure of example 16 in complex with neutrophil elastase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 0.5h;Inert atmosphere; Sealed tube; | Step A: 2'-Chloro-l-methvl-5'-nitro-3,4'-bipyridin-6(lH)-one To a stirred mixture of 4-bromo-2-chloro-5-nitropyridine (200 mg, 0.842 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (218 mg, 0.927 mmol), and dichloro l,l'-bis(diphenylphosphino)ferrocene palladium(ll) dichloromethane adduct (68.8 mg, 0.084 mmol) in deoxygenated l,4-dioxane:water - 5:l (6 mL) was added Na2C03 (179 mg, 1.69 mmol) and the resultant mixture was heated at 80 °C for 30 min in a sealed tube. The reaction mixture was then diluted with EtOAc and washed with water and brine. The organic layer was dried over a2S04, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 5:95, to give the title compound. MS: m/z = 266.0 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.6% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; Sonication; | Example 207:7-(3 -Bromophenyl)-5-( 1 -(tetrahydro-2H-pyran-4-yl)- 1 H-pyrazol-5 -yl)pyrrolo [2, i-f] [1 ,2,4]triazin-4-amine (20 mg, 0.046 mmol), i-methyl-S -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (16.05 mg, 0.068 mmol), and Na2CO3 (0.068 mL, 0.068 mmol) were combined in a vial fitted with a septum. The mixture was dissolved in a mixture of dioxane (1.5 mL) and water (0.5 mL). The vessel was degassed with N2 as described previously. PdCl2(dppf)-CH2C12 adduct (5.58 mg, 6.83 .imol) wasadded and the degassing process was repeated. The reaction mixture was heated at 120°C in a microwave for 30 mm. The reaction complex was filtered, washed with water, and extracted with ethyl acetate (20 mL x 3). The organic layers were mixed, dried, concentrated and purified by preparative LC method C to provide 5-(3-(4-amino-5-(1- (tetrahydro-2H-pyran-4-yl)- 1 H-pyrazol-5-yl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-7-yl)phenyl)- 1-methylpyridin-2(1H)-one (6.5 mg, 29.6percent yield). LCMS (M+H) = 468.15. ?H NMR(500 MHz, DMSO-d6) oe 1.81 (m, 2H), 2.10 (m, 2H), 3.32 (t, 2H), 3.49 (s, 3H), 3.88 (m,2H), 4.36 (m, 1H), 6.47(s, 1H), 6.53 (d, 1H), 7.35 (s, 1H), 7.57 (m, 2H), 7.69 (s, 1H),7.92 (dd, 1H), 7.95 (s, 1H), 8.07 (s, 1H), 8.11 (d, 1H), 8.19 (s, 1H), 8.20 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.72% | With pyridine; copper diacetate; In dichloromethane; for 168h;Molecular sieve; | Example 18: 7-(lH-Indazol-6-yl)-5-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5- yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine (15 mg, 0.037 mmol), l-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (17.61 mg, 0.075 mmol), copper (II) acetate (10.21 mg, 0.056 mmol), pyridine (6.06 mu, 0.075 mmol), 400 mg of 3 angstrom sieves (4A) and DCM (5 mL) were combined and stirred lightly for one week. The reaction complex was filtered with CELITE®, washed with water and the filtrate was extracted with ethyl acetate (5 mL x 3). The organic layers were combined, dried, and concentrated. The crude residue was purified by preparative LC/MS Method B to obtain 5 -(6-(4-amino-5 -( 1 -(tetrahydro-2H-pyran-4-yl)- 1 H-pyrazol-5-yl)pyrrolo [2,1- fJ[l,2,4]triazin-7-yl)-lH-indazol-l-yl)-l-methylpyridin-2(lH)-one (4.7 mg, 9.26 muiotaetaomicron, 24.72percent yield). LC/MS (M+H)+ = 508.30. XH NMR (500 MHz, DMSO-de) delta 1.82 (bs, 2H), 2.10 (m, 2H), 3.32 (t, 2H), 3.46 (m, 2H), 3.91 (s, 3H), 4.39 (m, 1H), 6.47 (s, 1H), 6.62 (d, 1H), 7.40 (s, 1H), 7.69 (s, 1H), 7.83 (d, 1H), 7.96 (m, 3H), 8.11 (s, 1H), 8.31 (s, 1H). 8.38 (s, 1H), 8.43 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; dimethyl sulfoxide; at 20℃; | The titled compound was prepared by the reaction of 2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (90 mg, 0.38 mmol) with Step 1 intermediate (100 mg, 0.42 mmol) using potassium carbonate (176 mg, 1.27 mmol) and [1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (35 mg, 0.04 mmol) in a mixture of DMSO and water (12 mL, 3: 1) at RT as per the procedure described in Step 1 of Intermediate 1 to yield 63 mg of the product. 1H NMR (300 MHz, CDC13) delta 3.59 (s, 3H), 6.40 (d, = 9.3 Hz, 1H), 7.08 (d, = 9.6 Hz, 1H), 7.78 (d, = 8.7 Hz, 2H), 7.86 (s, 1H), 8.28 (d, = 8.7 Hz, 2H), 8.61 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 95℃; for 1.5h;Inert atmosphere; | In a 2-neck flask was placed 6-bromo-2-chloro-N-((5-chloropyridin-3- yl)methyl)quinazolin-4-amine (1.152 g, 3 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl-1 3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.776 g, 3.30 mmol), PdCI2(dppf)-CH2CI2 adduct (0.245 g,0.300 mmol), and K2003 (1.368 g, 9.90 mmol). The air was removed and re-filled with N2 (2-3 times). Then added a mixture of 1,4-dioxane (10 ml) and water (5 ml) was added and stirred at 95 00 (pre-heated) for 1.5 h. After cooling to rt, H20 (20 mL) was added and the solid wasfiltered, washed with H20 (5 mL x 2), and then dried. Then, the product was triturated with 10percentEtOAc/hexane and dried to give crude 5-(2-chloro-4-(((5-chloropyridin-3-yl)methyl)amino)quinazolin-6-yl)-1 -methylpyridin-2(1 H)-one (1.52 g, 2.77 mmol, 92 percent yield). The crude material contained some impurity was used without further purification. 40 mg of material was submitted for purification for screening. MS (M+H)=412. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 95℃; for 2h;Inert atmosphere; | In a 2-neck flask was placed 6-bromo-2-chloro-N-(3-chlorobenzyl)quinazolin-4-amine(766 mg, 2 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one(517 mg, 2.200 mmol), PdCI2(dppf)-CH2CI2 adduct (163 mg, 0.20 mmol), and K2003 (912 mg,6.6 mmol). The air was removed and re-filled with N2 (2-3 times). Then added a mixture of 1,4-dioxane (6 ml) and water (3 ml) was added and stirred at 95 00 (pre-heated) for 2 h. After cooling to rt, H20 (20 mL) was added and the solid was filtered, washed with H20 (3 mL x 2), and then dried. The dried solid was put into 5percent EtOAc hexane (30 mL), vigorously stirred for 30 m in, and then filtered to give 5-(2-chloro-4-((3-chlorobenzyl)amino)quinazolin-6-yl)- 1- methylpyridin-2(1H)-one (741 mg, 1.441 mmol, 72.1 percent crude yield) as yellow solid. The materialca. 80percent purity was used without further purification. 20 mg of crude material was submitted for purification for screening. MS (M+H)= 411. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.7 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 85℃; for 1.5h;Inert atmosphere; | In a 2-neck flask was placed 6-bromo-4-((3-chlorobenzyl)amino)-N-(1-methylpiperidin-4- yl)quinoline-2-carboxamide (146 mg, 0.15 mmol?50percent purity), 1 -methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (70.5 mg, 0.30 mmol), PdCI2(dppf)-CH2CI2 adduct (12.25 mg, 0.015 mmol), and K2003 (124 mg, 0.90 mmol). The air was removed and re-filledwith N2 (2-3 times). Then a mixture of 1,4-dioxane (1.5 mL) and water (0.5 mL) was added and stirred at 85 00 (pre-heated) for 1.5 h. After cooling to rt, the organic layer was separated and extracted with EtOAc (2 x 2 mL). The combined organic layer was dried over Na2504 and filtered. After removal of the solvent, the product was filtered through a PL-Thiol MP resin and eluted with MeOH. The filtrate was concentrated, re-dissolved in DMF, filtered, and then purifiedto give 4-((3-chlorobenzyl)ami no)-6-( 1 -methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)-N-(1 - methylpiperidin-4-yl)quinoline-2-carboxamide, 2TFA (26.7 mg, 0.036 mmol, 23.92 percent yield). 1H NMR (400 MHz, DMSO-d6) O 9.41 (5, 1H), 9.00 (5, 1H), 8.58 (5, 1H), 8.34 (d, J= 2.7 Hz, 1H), 8.19?8.00(m, 3H), 7.50(s, 1H), 7.40?7.31 (m, 3H), 7.20(s, 1H), 6.59(d, J= 9.5 Hz, 1H),4.79 (5, 2H), 4.08?3.94 (m, 1 H), 3.54 (5, 3H), 3.47 (d, J = 12.2 Hz, 2H), 3.10 (q, J = 11.2 Hz,2H), 2.76 (d, J = 4.6 Hz, 3H), 2.08 ? 1.75 (m, 4H); MS (M+H)= 516. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.5% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 75 - 80℃; for 1.5h;Inert atmosphere; | In a microwave tube was placed (S)-4-(6-bromo-2-chloroquinazolin-4-yl)-3- phenylmorpholine (809 mg, 2 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2(1H)-one (517 mg, 2.20 mmol), PdCI2(dppf)-CH2CI2 adduct (163 mg, 0.20 mmol), and potassium carbonate (912 mg, 6.60 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (6 mL)/water (3 mL) was added and heated at 75-80 00 for 1.5 h. Aftercooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (5 mL x2). The combined organic layer was dried over Na2504 and filtered. After removal of solvent, the product was purified by silica gel chromatography using 0-10% MeOH/EtOAc as the eluent to give (S)-5-(2-chloro-4-(3-phenylmorpholino)quinazolin-6-yl)-1-methylpyridin-2(1 H)-one (636 mg, 1.469 mmol, 73.5% yield). MS (M+H)= 433. |
73.5% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 1.5h;Inert atmosphere; | In a microwave tube was placed (S)-4-(6-bromo-2-chloroquinazolin-4-yl)-3-phenylmorpholine (809 mg, 2 mmol), <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (517 mg, 2.20 mmol), PdCl2(dppf)-CH2Cl2 adduct (163 mg, 0.20 mmol), and potassium carbonate (912 mg, 6.60 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (6 ml)/water (3 ml) was added and heated at 70 C for 1.5 hr. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic layer was dried (Na2SO4) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 0-10% MeOH/EtOAc as the eluent to give (S)-5-(2-chloro-4-(3-phenylmorpholino)quinazolin-6-yl)-1-methylpyridin-2(1H)-one (636 mg, 1.469 mmol, 73.5 % yield). 1H NMR (400 MHz, DMSO-d6) delta 8.02 (dd, J = 8.8, 1.9 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 7.7 Hz, 2H), 7.42 (t, J = 7.6 Hz, 3H), 7.32 (t, J = 7.3 Hz, 1H), 6.33 (d, J = 9.5 Hz, 1H), 5.66 (d, J = 3.4 Hz, 1H), 4.41 - 4.28 (m, 2H), 3.98 - 3.89 (m, 2H), 3.71 (t, J = 7.6 Hz, 2H), 3.41 (s, 3H). LC-MS (Method 1): tR = 3.29 min, m/z (M+H)+ = 433. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 75℃; for 1h;Inert atmosphere; | In a microwave tube was placed tert-butyl (S)-4-(6-bromo-2-chloroquinazolin-4-yl)-3- phenylpiperazine-1-carboxylate (Example 291, STEP 1, 756 mg, 1.5 mmol), 1-methyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2(1 H)-one (388 mg, 1.65 mmol), PdCI2(dppf)-CH2CI2 adduct (122 mg, 0.15 mmol), and potassium carbonate (684 mg, 4.95 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (6 mL)/water (3mL) was added and heated at 75 00 for 1 hr. After cooling to room temperature, H20 (6 mL) and hexane (6 mL) were added. The solid was filtered, washed with H20 (3 mL x 3) and hexane (5 mL x 3), and then dried to give tert-butyl (S)-4-(2-chloro-6-(1-methyl-6-oxo-1 ,6-dihydropyridin-3- yl)quinazolin-4-yl)-3-phenylpiperazine-1-carboxylate (768 mg, 1.443 mmol, 96percent yield). The material contained some impurity and was used for next step without further purification. MS(M+H)= 532. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.07 g | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 2h;Microwave irradiation; | Step a. To a stirred solution of tert-butyl 6-bromo-4-phenylisoindoline-2-carboxylate (prepared as in step a of Example 5, 0.200 g, 0.536 mmol) in 1,4-dioxane: water (9: 1, 5 ml) were added Na2C03 (0.113 g, 1.072 mmol) and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)- one (CAS Number 1002309-52-5; 0.189 g) at rt in a microwave tube. The reaction mixture was degassed for 30 min before addition of PdCl2(dppf) (0.039 g, 0.053 mmol). The resulting reaction mixture was heated at 120°C for 2 h in Microwave. The reaction mixture was cooled to rt and poured into water (30 ml). The resulting mixture was extracted with EtOAc (3 x 10 ml). The combined organic phase dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was purified by flash-column chromatography (3.1 percent MeOH in DCM) yielding tert-butyl 6- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenylisoindoline-2-carboxylate (0.070 g, 0.173 mmol). LCMS: Method A, 2.505 min, MS: ES+ 403.4 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃; for 4h;Inert atmosphere; | A mixture of <strong>[6693-08-9]2,4,6-trichloro-5-fluoropyrimidine</strong> (736 mg, 3.7 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (860 mg, 3.7 mmol), Pd(PPh3)4 (295 mg, 0.26 mmol), K3PO4 (0.92 mL, 2 mol/L, aq) in dioxane (24 mL) was bubbled with N2 for 5 min. The mixture was stirred at 80° C. for 4 h. After the mixture was diluted with water, it was extracted with EtOAc; the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with a gradient of EtOAc [0 to 80percent] in DCM. The fractions were collected and concentrated under reduced pressure to afford the title compound (190 mg, 19percent) as a white solid. LCMS (M+H)+275. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
590 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; at 75℃; for 3h;Inert atmosphere; | To a solution of 4,6-dichloro-2-methoxypyrimidine (986 mg, 5.5 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl41,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (1.0 g, 4.3 mmol) in 1,4-dioxane (15 mL) was added Pd(dppf)2Cl2 (312 mg, 0.43 mmol) and K3PO4 (2.7 mL, 11 mmol, 4.0 mol/L). The mixture was stirred at 75° C. under N2 for 3 h. The mixture was cooled to room temp, diluted with saturated NH4Cl solution (50 mL) and extracted with DCM (50 mL*2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc, 1:1) to afford the title compound (590 mg, 2.4 mmol) as a white solid. 1H NMR (400 MHz, CDCl3): delta 8.41 (d, J=2.4 Hz, 1H), 7.88 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.13 (s, 1H), 6.65 (d, J=10 Hz, 1H), 4.07 (s, 3H), 3.66 (s, 1H). LCMS (M+H)+252 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; at 75℃; for 4h;Inert atmosphere; | A mixture of the title compound of Step 1 (3.0 g, 10 mmol), 1-methyl-5-(4,4,5,5-tetra-methyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (2.3 g, 10 mmol), Pd(dppf)Cl2 (732 mg, 1.0 mmol) and 3.75 M K3PO4 (6.6 mL, 25 mmol) in 1,4-dioxane (40 mL) was heated to 75° C. for 4 hr under N2. After the mixture was cooled to room temp, it was poured into H2O and was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:3) to give the title compound (1.8 g, 49percent) as a yellow solid. 1H NMR (300 MHz, CDCl3) delta ppm 8.33 (s, 1H), 7.85 (m, 1H), 7.34 (m, 1H), 7.22 (s, 1H), 6.98-6.96 (m, 2H), 6.88 (m, 1H), 6.67 (m, 1H), 5.20 (s, 2H), 3.63 (s, 3H), 3.50 (s, 3H). LCMS (M+H)+374. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; Sealed tube; | 4-[2-Methoxy-4-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (I-164') In a vial 4-(4-iodo-2-methoxy-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester L-59 (189.7 mg; 0.425 mmol), <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one</strong> J-4 (100.0 mg; 0.425 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane (34.7 mg; 0.043 mmol) are introduced. N,N-dimethylformamide (800 muL) and an aqueous solution of sodium carbonate solution (2N, 0.530 mL) are added. The vial is flushed with argon and sealed. The reaction mixture is heated at 100° C. for 1 h. To the reaction mixture one drop of water is added and the mixture is filtered and purified with the basic (ammonia buffer) RP HPLC system (column: X-Bridge C-18 30*50 mm). The product containing fractions are concentrated under reduced pressure. HPLC-MS: (M+H)+=428; tRet=1.03 min; method M1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | The 4 - bromo - N - (phenyl (tetrahydro - 2H - pyran -4 - yl) methyl) pyridine -2 - amine (70 mg, 0.2 mmol), 1 - methyl -5 - (4, 4, 5, 5 - tetramethyl - 1, 3, 2 - two oxygen boron fifth heavenly stem link -2 - yl) pyridine -2 (1 H) - one (57 mg, 0 . 24 mmol), potassium carbonate (55 mg, 0.4 mmol) and [1, 1' - double-(diphenyl phosphino) ferrocene] [...] (II) (29 mg, 0 . 04 mmol) dissolved in 1, 4 - dioxane/water (2 ml, v/v=5/1) in, and in the 100 °C and under the protection of nitrogen stirring overnight. Adding water to the reaction solution and the extraction of ethyl acetate, ethyl acetate layer water and saturated salt water washing, drying (water-free sodium sulphate), filtering and concentrating, the residue for preparation - HPLC separation and purification, the title compound obtained (35 mg, 47percent), as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | The 4 - bromo - N - methyl - N - (phenyl (tetrahydro - 2H - pyran -4 - yl) methyl) pyridine -2 - amine (70 mg, 0 . 194 mmol), 1 - methyl -5 - (4, 4, 5, 5 - tetramethyl - 1, 3, 2 - two oxygen boron fifth heavenly stem link -2 - yl) pyridine -2 (1 H) - one (54 mg, 0 . 23 mmol), potassium carbonate (53 mg, 0 . 39 mmol) and [1, 1' - double-(diphenyl phosphino) ferrocene] [...] (II) (28 mg, 0 . 038 mmol) dissolved in 1, 4 - dioxane/water (2 ml, v/v=5/1) in, and in the 100 °C and under the protection of nitrogen stirring overnight. Adding water to the reaction solution and the extraction of ethyl acetate, ethyl acetate layer water and saturated salt water washing, drying (water-free sodium sulphate), filtering and concentrating, the residue for preparation - HPLC separation and purification, the title compound obtained (16 mg, 21percent), as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium carbonate; potassium carbonate; In 1,4-dioxane; water; at 100℃; | The 4 - bromo -6 - (2, 5 - dimethyl - 1H - pyrrole -1 - yl) - N - methyl - N - (phenyl (tetrahydro - 2H - pyran -4 - yl) methyl) pyridine -2 - amine (89 mg, 0 . 19 mmol), 1 - methyl -5 - (4, 4, 5, 5 - tetramethyl - 1, 3, 2 - two oxygen boron fifth heavenly stem link -2 - yl) pyridine -2 (1 H) - one (54 mg, 0 . 23 mmol), potassium carbonate (52 mg, 0 . 38 mmol) and [1, 1' - double-(diphenyl phosphino) ferrocene] [...] (II) (28 mg, 0 . 038 mmol) is dissolved in 1, 4 - dioxane (6 ml) and water (1 ml) in, and heated to 100 °C stirring overnight. Adding water to the reaction solution and the extraction of ethyl acetate, separating the organic layer, salt water for washing, drying with anhydrous sodium sulfate, filtered and concentrated. The residue fast chromatography for separation and purification (methanol/ethyl acetate=3/97), the title compound as a brown solid from (104 mg, 100percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.3% | In a 2-neck flask was placed 6-bromo-N-(3-chlorobenzyl)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-4-amine (25.2 mg, 0.05 mmol), <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (23.51 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2 adduct (4.08 mg, 5.0 mumol) , and K2CO3 (41.5 mg, 0.30 mmol). The air was removed and re-filled with N2 (2-3 times). Then added a mixture of 1,4-dioxane (1 mL) and water (0.5 ml) was added and stirred at 95 °C (pre-heated) for 1 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL x 3). The compined organic was dried (Na2SO4) and filtered. After removal of solvent, the product was filtered through a PL-Thio-resin, eluted with MeOH. The filtrate was concentrated, dissolved in DMF, filtered, and submitted for purification by semi-preparative HPLC to give 5-(4-((3-chlorobenzyl)amino)-2-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinazolin-6-yl)-1-methylpyridin-2(1H)-one, 2TFA (11.5 mg, 0.015 mmol, 30.3 percent yield) . 1H NMR (400 MHz, DMSO-d6) delta 11.88 (s, 1H), 10.08 (s, 1H), 8.44 (s, 1H), 8.21 (d, J = 2.7 Hz, 1H), 8.05 (s, 1H), 7.90 (dd, J = 9.5, 2.7 Hz, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.40 ? 7.28 (m, 3H), 6.56 (d, J = 9.5 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 3.81 (s, 4H), 3.51 (s, 3H), 3.22 ( br s, 2H), 2.79 (s, 6H), 2.64 (br s, 2H), 2.55 (s, 4H). (including one salt NH.) LC-MS (Method 2): tR = 3.51 min, m/z (M+H)+ = 532. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 0.333333h;Microwave irradiation; | The title compound from Step 1 (60 mg, 0.22 mmol) and <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one</strong> (61 mg, 0.26 mmol) were dissolved in dioxane (0.5 mL). To this solution was added Pd(PPh3)4(12.5 mg, 0.011 mmol) and Na2CO3 (2 M in water, 0.22 mL). The reaction was heated at 120 C. in a microwave for 20 min. The solvent was removed under reduced pressure. The residue was dissolved in MeOH (2 mL), filtered through Celite and purified by preparative-HPLC (10% to 100% MeCN/water, 0.1% FA) to afford the title compound (11 mg, 17% yield). 1H NMR (CD3OD, 400 MHz) delta 8.15 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.32-7.26 (m, 5H), 6.55 (d, J=9.3 Hz, 1H), 4.66 (d, J=9.8 Hz, 1H), 3.60 (s, 3H), 1.76-1.70 (m, 1H), 0.83-0.73 (m, 2H), 0.58-0.45 (m, 2H). LCMS (M+H)+ 306. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.27% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere; | General procedure: A solution of 2chloropyrazine (7.94 g, 69.30 mmol), Intermediate 2B (19.00 g, 69.30 mmol), and potassium phosphate tribasic (36.80 g, 173.00 mmol) in a mixture of 1,4dioxane (100 mL) and H2O (20 mL) was degassed with nitrogen for 10 minutes. PdCl2(dppf)2CH2Cl2 (2.83 g, 3.47 mmol) was added and the resulting mixture was degassed again for 10 minutes then was heated at 100 °C for 12 h. The reaction mixture was cooled to ambient temperature, filtered through the Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep330 g, 40percent EtOAc/nhexane) to obtain Intermediate 2C (13.00 g, 83.00percent) as an offwhite solid.1H NMR (400MHz, DMSOd6) G ppm 2.32 (s, 3 H) , 5.50 (s, 2 H), 7.72 (d, J = 7.5 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 8.73 (d, J = 2.5 Hz, 1 H), 8.77? 8.87 (m, 1 H), 8.91 (d, J = 2.0 Hz, 1 H). LCMS (MethodH): retention time 1.06 min, [M+H] 227.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 1.5h;Inert atmosphere; | General procedure: In a microwave tube was placed (S)-4-(2-chloro-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine (43a, 31.6 mg, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (35.7 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (6.12 mg, 7.50 mumol), and potassium carbonate (62.2 mg, 0.45 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (1.5 ml)/water (0.5 ml) was added and heated at 90 C for 1.5 hr. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was filtered through PL-Thiol MP resin and then eluted with MeOH. After removal of solvent, the crude product was dissolved in DMF, filtered, and submitted for purification by semi-preparative HPLC to give (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, TFA (7.4 mg, 0.012 mmol, 16.16 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 1.5h;Inert atmosphere; | General procedure: In a microwave tube was placed (S)-4-(2-chloro-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine (43a, 31.6 mg, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (35.7 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (6.12 mg, 7.50 mumol), and potassium carbonate (62.2 mg, 0.45 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (1.5 ml)/water (0.5 ml) was added and heated at 90 C for 1.5 hr. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was filtered through PL-Thiol MP resin and then eluted with MeOH. After removal of solvent, the crude product was dissolved in DMF, filtered, and submitted for purification by semi-preparative HPLC to give (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, TFA (7.4 mg, 0.012 mmol, 16.16 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 1.5h;Inert atmosphere; | General procedure: In a microwave tube was placed (S)-4-(2-chloro-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine (43a, 31.6 mg, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (35.7 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (6.12 mg, 7.50 mumol), and potassium carbonate (62.2 mg, 0.45 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (1.5 ml)/water (0.5 ml) was added and heated at 90 C for 1.5 hr. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was filtered through PL-Thiol MP resin and then eluted with MeOH. After removal of solvent, the crude product was dissolved in DMF, filtered, and submitted for purification by semi-preparative HPLC to give (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, TFA (7.4 mg, 0.012 mmol, 16.16 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 1.5h;Inert atmosphere; | General procedure: In a microwave tube was placed (S)-4-(2-chloro-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine (43a, 31.6 mg, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (35.7 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (6.12 mg, 7.50 mumol), and potassium carbonate (62.2 mg, 0.45 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (1.5 ml)/water (0.5 ml) was added and heated at 90 C for 1.5 hr. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was filtered through PL-Thiol MP resin and then eluted with MeOH. After removal of solvent, the crude product was dissolved in DMF, filtered, and submitted for purification by semi-preparative HPLC to give (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, TFA (7.4 mg, 0.012 mmol, 16.16 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 1.5h;Inert atmosphere; | General procedure: In a microwave tube was placed (S)-4-(2-chloro-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl)-3-phenylmorpholine (43a, 31.6 mg, 0.075 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (35.7 mg, 0.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (6.12 mg, 7.50 mumol), and potassium carbonate (62.2 mg, 0.45 mmol). The air was removed and re-filled with N2 (3 times). Then, 1,4-dioxane (1.5 ml)/water (0.5 ml) was added and heated at 90 C for 1.5 hr. After cooling to rt, the layer was separated and the aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was filtered through PL-Thiol MP resin and then eluted with MeOH. After removal of solvent, the crude product was dissolved in DMF, filtered, and submitted for purification by semi-preparative HPLC to give (S)-2-(4-(6-(3,5-dimethylisoxazol-4-yl)-4-(3-phenylmorpholino)quinazolin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol, TFA (7.4 mg, 0.012 mmol, 16.16 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; for 2.5h; | To a stirred solution of Ex-12 prepared in Example 1 (2-benzyl-10-bromo-7- fluoroimidazo[1,2-c]quinazolin-5-amine, 30 mg, 0.081 mmol) in Dioxane (1616 mul) was added boronic acid (38.0 mg, 0.162 mmol), K2CO3 (242 mul, 0.242 mmol), and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride/dichloromethane complex (herein, alternatively Pd(Cl)2(dppf) complex, 16.50 mg, 0.020 mmol). The reaction mixture was heated to 88 C for 2.5 hrs, then the solvent was evaporated and the crude was diluted with DCM. The organic layer was washed with NaHCO3, dried over MgSO4, filtered and concentrated. The crude product was purified by prep-TLC to yield 5-(5-amino-2-benzyl-7-fluoroimidazo[1,2- c]quinazolin-10-yl)-1-methylpyridin-2(1H)-one (Ex-61). LC/MS = 400 [M+1]. |
Tags: 1002309-52-5 synthesis path| 1002309-52-5 SDS| 1002309-52-5 COA| 1002309-52-5 purity| 1002309-52-5 application| 1002309-52-5 NMR| 1002309-52-5 COA| 1002309-52-5 structure
[ 1160790-84-0 ]
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one
Similarity: 0.91
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[ 1256358-90-3 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one
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[ 214360-60-8 ]
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[ 1160790-84-0 ]
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one
Similarity: 0.91
[ 1425045-01-7 ]
1,3-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one
Similarity: 0.90
[ 1256358-90-3 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one
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[ 214360-60-8 ]
N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide
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N-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide
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[ 1160790-84-0 ]
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[ 1256358-90-3 ]
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[ 1201645-46-6 ]
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[ 1227068-67-8 ]
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H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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