Structure of 568577-88-8
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CAS No. : | 568577-88-8 |
Formula : | C16H24BNO3 |
M.W : | 289.18 |
SMILES Code : | CC1(C)C(C)(C)OB(C2=CC=C(N3CCOCC3)C=C2)O1 |
MDL No. : | MFCD04112544 |
InChI Key : | UCPALIMHMYIZPZ-UHFFFAOYSA-N |
Pubchem ID : | 2795361 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
45.16% | General procedure: To a stirred solution of intermediate 4a (3.0 g, 15.1 mmol) in 1,4 dioxone (30 mL), bis(pinocolate)diboran (4.5 g, 17.7 mmol) and potassium acetate (2.98 g, 30.4 mmol) was added. The resultant was degasified with nitrogen for 20 mm. Then, Pd(dppf)C12 (0.62 g, 0.75 mmol) was added to it. It was heated at 90C over night. The reaction mixture was diluted with water and extracted with ethyl acetate; the organic layer waswashed with water and brine solution and was then concentrated. The product was purified by combiflash to yield the title product (3.4 g, 91 .39%) as a yellow semi solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.94% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; for 4h;Heating / reflux; | To a solution of intermediate 24 [(20G,] 82.64 mmol) in dioxane (200ml) was added 4,4, 5, [5-TETRAMETHYL- [1,] 3, [2]-DIOXABORO) ANE (13. 2 M), 99.] 17 [MMOL),] dichloro bis [(TRIPHENYLPHOSPHINE) PALLADIUM (II)] (3g, 4.13 [MMOL)] and triethylamine (34.5 [ML,] 247.93 mmol) and the mixture was heated under reflux during 4 hours and then poured into water. After extraction with [CH2CI2,] the organic phase was dried over [NA2SO4] and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2) to give the title compound as an orange oil which crystallised (19.98 g, 83.94%) ; [[APCI] MS] m/z 289.07 (MH+). |
83.74% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; for 24h;Heating / reflux; | To a solution of intermediate 12 (15g, [62MMOL)] in dioxane (400ml) were added 4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (9. [9MOI,] [68MOL),] [DICHLOROBIS (TRIPHENYLPHOSPHINE) PALLADIUM (LL)] (2. [17G,] 3. 1mmol) and triethylamine (25. 8ml, 186 [MMOL)] and the mixture was heated under reflux for 24 h and then poured into water. After extraction with [CH2CI2,] the organic phase was dried over [NA2SO4] and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2, and after trituration with pentane, the title compound was obtained as a brown solid [(15G,] 83.74%) ; m. p. [114-116C.] |
83.94% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; for 4h;Heating / reflux; | To a solution of intermediate 8 (20g, 82.64 [MMOL)] in dioxane (200 [ML)] was added 4,4, 5, [5-TETRAMETHYL- [1,] 3, [2]-DIOXABOROLANE] (13.2 ml, 99.17 [MMOL),] dichloro bis [(TRIPHENYLPHOSPHINE) PALLADIUM (11)] (3g, 4.13 [MMOL)] and triethylamine (34. 5 ml, 247.93 [MMOL)] and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled, poured into water and extracted with CH2CI2. The combined organic phases were dried over [NA2SO4] and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with [CH2CI2TO] give the title cornpound was obtained as an orange oil which crystallised (19.98 g, 83.94%) ; [[APCI] MS] m/z 289.07 [(MH+).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; for 18h;Heating / reflux; | To a solution of intermediate 15 (3g, 10.3 [MMOL)] in DME (100 mL) was added tetrakis [(TRIPHENYLPHOSPHINE) PALLADIUM (0)] (1.2g, 10% mol), intermediate 9 (3.86g, 13.4 [MMOL)] and [NA2CO3] [(2M,] 10.3 ml) and the mixture was heated under reflux for 18 hours. The cooled mixture was poured into water and extracted with [CH2CI2.] The organic phase was washed with water, dried over [NA2SO4] and filtered. Evaporation of the solvent in vacuo gave a crude oil which was purified by chromatography on silica gel (CH2CI2/MeOH, 97: 3) to give the title compound (3.77g, 98%); [APCI MS} [M/Z 374.] 13 [(MH+).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
e-Cyclobutyl^-iodo-delta.thetaJ.delta-tetrahydro^H-II ,3]thiazolo[4,5-d]azepine (may be prepared as described in Description 12) (90mg, 0.27mmol), 4-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]morpholine (94mg, 0.324 mmol), EPO <DP n="72"/>bis(triphenylphosphine)palladium (II) chloride (19 mg, 10%mol) and sodium carbonate (106 mg, 1.0 mmol) were added together in dioxan (2 ml) and water (0.5 ml) and the resulting mixture was heated under reflux under argon for 2 hours. After this time the reaction mixture was allowed to cool down, acidified to pH=1 with 2N hydrochloric acid, applied to an ion exchange cartridge (SCX), washed with methanol and then a 2M ammonia in methanol solution. The basic fractions were then evaporated in vacuo and the crude material purified using silica gel chromatography to afford the product (E110); MS (ES+) m/e 370 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 129 4-(3,4-diethoxyphenyl)-N-[4-(4-(morpholin-4-yl)phenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and <strong>[568577-88-8]4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine</strong> (36.1 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(4-(morpholin-4-yl)phenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (12.8 mg) was obtained. HPLC (220 nm) purity 90% (retention time 1.93 min) MS (ESI+, m/e) 580 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 160 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(4-(morpholin-4-yl)phenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and <strong>[568577-88-8]4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine</strong> (36.1 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(4-(morpholin-4-yl)phenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (8.6 mg) was obtained. HPLC (220 nm) purity 89% (retention time 1.86 min) MS (ESI+, m/e) 534 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 0.25h;Microwave irradiation; Inert atmosphere; | To a solution of 5,7-dichloro-3-methylpyrido[4,3- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 90℃; | A mixture of (5)-7-chloro-5-(3-(hydroxymethyl)pyrrolidin-l -yl)-3-methylpyrido [4,3- f]pyrimidin-4(3H)-one (26 mg, 0.088 mmol), 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)morpholine (28 mg, 0.097 mmol), Pd(PPh3)4 (10.2 mg, 0.0088 mmol), K2CO3 (36 mg, 0.26 mmol), 2-propanol (3 mL) and H2O (1 mL) was stirred at 900C overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified on slilica gel flash column chromatography (eluent: 0- 10% methanol in dichloromethane) to afford (5)-5-(3-(hydroxymethyl)pyrrolidin-l-yl)-3-methyl-7-(4- morpholinophenyl)pyrido [4,3- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 0.25h;Microwave irradiation; Inert atmosphere; | 4-morpholinophenylboronic acid pinacol ester (28.8 mg, 0.099 mmol), 2M aqueous Na2CO3 solution (149 muL, 0.298 mmol), and a catalytic amount of Pd(PPh3)4 were added to a solution of 7-chloro-5- (4-(hydroxymethyl)thiazol-2-ylamino)-3-methylpyrido[4,3-(i]pyrimidin-4(3H)-one (32.2 mg, 0.099 mmol) in 1,4-dioxane (1.0 mL). The reaction mixture was purged with N2 and heated at 140 0C by a microwave reactor for 15 minutes. The mixture was then cooled, quenched with H2O (5 mL) and extracted with ethyl acetate (3 x 2.5 mL). The combined organic layers were evaporated under vacuo and the residue was purified by preparatory LC/MS to provide the title compound; 1H NMR (CD3OD, 400 MHz) delta 8.58 (s, IH), 8.27 (d, / = 8.8 Hz, 2H), 7.75 (s, IH), 7.40 (d, / = 8.8 Hz, 2H), 7.26 (s, IH), 4.70 (s, 2H), 3.97 (t, / = 4.8 Hz, 4H), 3.67 (s, 3H), 3.49 (t, / = 4.8 Hz, 4H); HPLC-MS calculated for C22H22N6O3S (M +H+) 451.1, found 451.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 0.25h;Microwave irradiation; Inert atmosphere; | To a solution of 7-chloro-5-(4-methoxybenzyloxy)-3-methylpyrido[4,3- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 140℃; for 0.25h;Microwave irradiation; Inert atmosphere; | To a solution of 5-(2-(lH-pyrazol-4-yl)ethoxy)-7-chloro-3-methylpyrido[4,3- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride; dichlorobis(trimethylphosphine)nickel; In tetrahydrofuran; at 100℃; for 12h;Inert atmosphere; Sealed tube; | Under an argon atmosphere,4.2 mg (0.015 mmol) of dichlorobis (trimethylphosphine) nickel,98.4 mg (0.5 mmol) of 4- (4-chlorophenyl) morpholine,152 mg (1.0 mmol) of cesium fluoride, 4,4,5,5,4 ', 4', 5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolanyl ) 140 mg (0.55 mmol),180 mg (1.05 mmol) of trimethyl (2,2,2-trifluoroethoxy) silane and 0.5 mL of tetrahydrofuran were added and sealed,And the mixture was stirred at 100 C. for 12 hours.After the reaction vessel was cooled to room temperature, 1 mL of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with 8 mL of ethyl acetate, and the obtained organic phases were combined.The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: chloroform: ethyl acetate = 4: 1: 0 to 4: 1: 1)123 mg (white solid, yield 86%) of 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] morpholine was obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tert-Butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (200 mg) was dissolved in DME (10 ml), and water (5 ml), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabolan-2-yl)phenyl]morpholine (219 mg), sodium carbonate (216 mg), and tetrakis(triphenylphosphine)palladium (20 mg) were added thereto, followed by stirring at 80 C. overnight. The reaction mixture was cooled to room temperature, and then water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc=2/1). The obtained solid was dissolved in 4 M hydrogen chloride/EtOAc, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and to the residue was added a 1 M aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl3. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was dissolved in EtOH, and oxalic acid (52 mg) was added thereto. The precipitated solid was collected by filtration to obtain N-[(4'-morpholin-4-ylbiphenyl-3-yl)methyl]glycinamide oxalate (126 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 150℃; for 0.5h;Inert atmosphere; Microwave irradiation; | In a muwave vial, 6-bromopyrazolo[1,5-a]pyrimidine, 9, (0.25 g, 1.26 mmol, 1.0 eq), <strong>[568577-88-8]4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine</strong>, 10, (0.36 g, 1.26 mmol, 1.0 eq), and Pd(dppf)Cl2?DCM (52.0 mg, 0.06 mmol, 0.05 eq) were added. The muwave vial was evacuated under reduced pressure and purged with Argon (3x). To the mixture was added 1,4-dioxane (9 mL), followed by a solution of K3PO4 (0.54 g, 2.52 mmol, 2.0 eq) in H2O (4.0 mL). The reaction was heated to 150 C for 30 min under microwave irradiation. The reaction was added to EtOAc: H2O (1:1, 100 mL). The organic layer was separated, washed with H2O (25 mL), Brine (25 mL), dried (MgSO4), filtered and concentrated. The material was purified by reverse-phase HPLC (5-35% acetonitrile: H2O w/ 0.1% TFA) to afford 4-(4-(pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)morpholine, 11 (0.25 g, 71% yield).LCMS: RT = 0.560 min, >98% (at) 215 and 254 nM, m/z = 281.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide; palladium diacetate; potassium carbonate; In tetrahydrofuran; water; at 70℃; for 4h; | Example 4 [0060] [0061] Iodo Compound 3 (0.1 mmol) obtained in Example 1 and 4-morpholinyl phenylboronic acid pinacol ester (CAS: 568577-88-8) (0.5 mmol) were put in a 25 mL round-bottomed flask, followed by addition of Pd(OAc)2 (0.05 mmol), Bu4NBr (0.15 mmol), K2CO3 (0.3 mmol), and 3 mL THF-H2O (VTHF/VH2O=1). The mixture was heated to 70 C. and the reaction was carried out for 4 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by silica gel column to give Compound 7. [0062] The relevant test data were as follows: 1H-NMR (300 MHz, CDCl3): delta=6.92 (s, 1H), 6.03 (s, 2H), 3.85-3.89 (t, 4H), 3.76 (s, 3H), 3.56 (s, 3H), 3.19-3.22 (t, 4H); 13C-NMR (75 MHz, CDCl3): delta=168.39, 150.00, 147.92, 141.67, 140.78, 128.01, 104.52, 101.83, 66.98, 60.05, 51.95, 49.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 13h;Inert atmosphere; | To a solution of (S)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-yloxy)methyl)morpholine-4-carboxylate (571 mg, 1.5 mmol) in dioxane/H20 (5 m L /0.5 mL) was added Cs2CO3 (733 mg, 2.25 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and <strong>[568577-88-8]4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine</strong> (492 mg, 1.65 mmol). The mixture was stirred at 100 C for 13 hours under N2. The reaction solution was added into 100 mL water, extracted with EA. The organic phase waswashed with brine, concentrated to give an crude product, which was purified byprep-TCL (DGM:MeOH= 50:1) to give yellow solid. MS (m /z): 508 (M +H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 110℃; for 24h;Inert atmosphere; | To a solution of 4-(7-chloropyrido[4,3-b]pyrazin-5-yloxy)cyclohexanone (1.0 mmol) in dioxane/H2O (15 mL / 1.5 mL) was added Cs2CO3 (488.7 mg, 1,5 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol) and <strong>[568577-88-8]4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine</strong> (347 mg, 1.2 mmol). The mixture was stirred at 110 C for 24 hours under N2. The reaction mixture was filtered, concentrated and purified by silica gel column chromatography (EA:PE=2:1) to give yellow solid. MS (m/z): 405 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 160℃; for 0.75h;Microwave irradiation; | A mixture of methy 4-(7-choropyrida[4,3-b]pyrazin-5-yoxy)benzoate (340 mg, 1.0 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y)phenyl)morpholine (347 mg,1.2 mmol), Pd(dppf)CI2 (73 mg, 0.1 mmol) and Cs2CO3 (488 mg, 1.5 mmol) in dimethoxyethane/water (5 mL) was heated at 160 C for 45 minutes in a microwave reactor, The mixture was cooled to room temperature, concentrated and purified by column chromatography (ethyl acetate in petro ether from 0% to 100%) then by C18column to afford 96 mg title compound as yellow solid. MS (m/z): 443 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.9% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; | The compound of example 86 (1 .0 g, 3.34 mmol) was treated with 4-(4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl) morpholine (1 .1 60 g, 4.01 mmol) in DMF (25 mL) in presence of [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(l l) complex with dichloromethane (0.082 g, 0.100 mmol) and sodium carbonate (0.709 g, 6.69 mmol) solution in 5 mL of water according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 0.1 82 g (71 .9 %); 1 H NMR (300 MHz, DMSO-d6): delta 3.55 (t, 4H, 2CH2), 3.73 (t, 4H, 2CH2), 7.00 (d, 1 H, J = 8.7 Hz, Ar), 7.73 (d, 1 H, J = 1 .5 Hz, Ar), 7.77 (s, 1 H, Ar), 7.79 (d, 1 H, J = 9.6 Hz, Ar), 7.82 (s, 1 H, Ar) 7.94 (dd, 1 H, J = 8.7 Hz, J = 2.4 Hz, Ar), 8.1 3 (d, 1 H, J = 8.1 Hz, Ar), 8.42 (dd, 1 H, J = 8.4 Hz, J = 2.4 Hz, Ar), 8.48 (d, 1 H, J = 2.1 Hz, Ar), 8.79 (s, 1 H, Ar), 9.1 7 (d, 1 H, J = 1 .8 Hz, Ar); MS (ES+): m/e 383.1 (M+2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.8% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | 13: 3-(l-Isopropyl-lH-[l,2,3]triazol-4-yl)-5-(4-morpholin-4-yl-phenyl)-pyridin-2-ylam To a solution of 5-bromo-3-(l-isopropyl-lH-[l,2,3]triazol-4-yl)-pyridin-2-ylamine (100 mg, 0.35 mmol) and 4-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-morpholine (88 mg, 0.42 mmol) in 1,4-dioxane (7.0 mL)/water (3.0 mL) was added CS2CO3 (227 mg, 0.70 mmol) at room temperature. The reaction mixture was purged with argon for 30 min. Then Pd(PPh3)4 (20.2 mg, 0.017 mmol) was added and allowed to stir at 100 C for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2S04 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 3-97% MeOH in DCM to afford the title compound as a yellow solid. Yield: 45 mg (34.8%) 1H NMR (DMSO-dg, 400 MHz, TMS) delta: 8.92 (1H, s), 8.25 (1H, d), 8.13 (1H, d), 7.57-7.54 (2H, d), 7.02-7.00 (2H, d), 6.97 (2H, br s,), 4.92-4.85 (1H, m), 3.77-3.74 (4H, t), 3.15-3.12 (4H, t), 1.57-1.56 (6H, d). LC-MS: m/z = 365.2 (MH+), tR = 0Alpha, method A. |
General procedure: To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine(500 mg, 1.77 mmol) and4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholine (537 mg,1.77 mmol) in ethylene glycol dimethyl ether (6.0 mL)/water (4.0 mL) was addedCs2CO3 (1.15 g, 3.54 mmol) at room temperature. Thereaction mixture was purged with argon for 30 min. Then Pd(dppf)Cl2.DCM(72.2 mg, 0.08 mmol) was added and allowed to stir at 140 C for 6 h inmicrowave. After 6 h, the reaction mixture was cooled to RT, diluted with EtOAc(50 mL) and washed with water (50 mL). The organic layer was washed with brinesolution (50 mL), dried over anhydrous Na2SO4 and solventwas evaporated under reduced pressure to afford crude product. The crudecompound was purified by column using 100-200 mesh silica gel. The column waseluted with 5-95% MeOH in DCM to afford the title compound as a brown solid.Yield: 72 mg (10.7%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In 1,2-dimethoxyethane; water; at 140℃; for 0.666667h;Microwave irradiation; | General procedure: Scheme 14, step 3 A mixture of 2-(benzo [d] [1,3] dioxol-5-yl)-N-(6-bromopyridin-2- yl)acetamide (47 mg 0.139 mmol), (5 -(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2- yl)indolin- 1 -yl)(o-tolyl)methanone (36 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol), and sodium carbonate(150 tL of a 2M aqueous solution, 0.297 mmol) in DME (1 ml) was heated in a microwave with stirring at 130 C for 1 hr. The reaction mixture was concentrated under a stream of air. The residue was taken up in EtOAc, dried with MgSO4, and filtered through an Agilent PL-Thiol MP SPE cartridge to remove palladium. The organic layer was concentrated under a stream of air. The residue was taken up inDMSO and subsequently purified by reverse phase chromatography to afford Compound 28.COMPOUND 78 was prepared according to the method described in Scheme 14, step 3 substituting 4-(4-(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)phenyl)morpholine for (5-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)indolin- 1- yl)(o-tolyl)methanone, SiliaCat DPP-Pd for tetrakis(triphenylphosphine)palladium(0), and heating in the microwave at 140C 40 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 65℃; for 3h; | Example 47: Methyl 1 -isopropyl-6-(4-morpholinophenyl)-1 H-indole-4-carboxylate To a solution of the compound of example 10 (1 .5 g, 5.06 mmol, 1 .0 equiv) in 1 ,4-dioxane (10 ml_) were added 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)morpholine (1 .61 1 g, 5.57 mmol, 1 .1 equiv), PdCI2(dppf)-CH2Cl2 adduct (0.124 g, 0.152 mmol, 0.030 equiv) and 2 M aqueous solution of Na2C03 (7.60 ml_, 15.19 mmol, 3.0 equiv) and stirred reaction mass at 65 SC for 3 h. After the reaction is complete, the reaction mass is cooled to room temperature and passed through celite. The filtrate was washed with water, brine and concentrated. The residue obtained was further purified by column (silica gel, (2.5:7.5) ethyl acetate: petroleum ether) to obtain the title compound. Yield: 1 .2 g (63 %); 1 H NMR (CDCI3, 500 MHz): delta 8.16 (s, 1 H), 7.74 (s, 1 H), 7.65 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 2.5 Hz, 1 H), 7.14 (d, J = 2.5 Hz, 1 H), 7.04 (d, J = 8 Hz, 2H), 4.76 (m, 1 H), 4.02 (s, 3H), 3.92 (d, J = 4 Hz, 4H), 3.24 (d, J = 4.5 Hz, 4H), 1 .58 (d, J = 5.5 Hz, 6H); MS (ESI+): m/z 379.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.3% | A 100 mL sealed tube was charged with intermediate 43 (0.1 g, 0.345 mmol), intermediate 3 (0.071 g, 0.288 mmol) 1,4-dioxane (10.0 mL) and water (4.0 mL). Tothe above solution potassium phosphate tribasic (0.18 g, 0.864 mmol) was added and degasified with argon for 15 mm. Then, Pd(PPh3)4 (0.017 g, 0.014 mmol) was added and the resulting mixture was subjected to microwave irradiation at 120 00 for 60 mm. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate, the organic layer was washed with water, brine solution, dried and concentrated. The crude product was purified by the column chromatography to yield the desired product (0.04 g, 33.3%). LCMS: (M+H) =329.0Similarly following intermediates have been synthesized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 10h;Reflux; Inert atmosphere; | General procedure: To a mixture of 1,2,4-oxadiazole 7(45mg, 0.13 mmol), tetrakis(triphenylphosphine)palladium(0) (7.6mg, 6.5×10-3mmol), and boronic acid or boronic acid pinacol esters (0.20mmol) in a mixed solvent of dioxane (3 mL) and H2O (0.5 mL) was added potassium carbonate (45 mg, 0.32 mmol),and the mixture was refluxed for 10 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether/acetone (2:1) to afford the desired products2a-2v, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.72 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 85℃;Inert atmosphere; | F) 1-benzyl-4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine [1036] To a mixture of 1-benzyl-3-iodo-4-methoxy-1H-pyrazolo[4,3-c]pyridine (0.75 g), <strong>[568577-88-8]4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine</strong> (0.60 g) and sodium carbonate (0.44 g) in DME/ water (6 mL/3 mL) was added dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) (73 mg) under nitrogen atmosphere. The reaction mixture was stirred overnight at 85C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (0.72 g). MS(ESI+): [M+H]+ 401.2. MS(ESI+), found: 401.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 130℃; for 1.5h;Microwave irradiation; | A) 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine [0831] A mixture of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (250 mg) obtained in Step C of Example 35, <strong>[568577-88-8]4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine</strong> (265 mg), tetrakis(triphenylphosphine)palladium(0) (35.3 mg) and 2M aqueous potassium carbonate solution (169 mg) in DMF (2 mL) was stirred under microwave irradiation at 130C for 1.5 hr. The reaction mixture was added to water, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (240 mg). 1H NMR (300 MHz, CDCl3) delta 3.23-3.30 (4H, m), 3.84-3.93 (4H, m), 4.11 (3H, s), 6.75 (1H, dt, J = 6.0, 1.3 Hz), 7.01 (2H, d, J = 8.7 Hz), 7.09-7.18 (2H, m), 7.48 (1H, tt, J = 8.5, 6.0 Hz), 7.94-8.03 (3H, m). MS (ESI+): [M+H]+ 423.2. MS (ESI+), found: 423.3 |
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