Sodium Carbonate → HCID 66604856, compound

HRID 2410843Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:6]=[CH:5]2.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:43]1[CH:44]=[C:45]([C:62]([NH2:64])=[O:63])[C:46]2[NH:47][C:48]3[CH:49]=[C:50]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:51]=[CH:52][C:53]=3[C:54]=2[N:55]=1.CC1(C)C(C)(C)OB(C2C=C3C(=CC=2)N(CCN2CCOCC2)N=C3)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[O:59]1[CH2:60][CH2:61][N:56]([C:50]2[CH:51]=[CH:52][C:53]3[C:54]4[N:55]=[C:43]([C:2]5[CH:3]=[C:4]6[C:8](=[CH:9][CH:10]=5)[N:7]([CH2:11][CH2:12][N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[N:6]=[CH:5]6)[CH:44]=[C:45]([C:62]([NH2:64])=[O:63])[C:46]=4[NH:47][C:48]=3[CH:49]=2)[CH2:57][CH2:58]1

Participants

Conditions

Temperature: 100 °C

Procedure

A microwave vial containing a mixture of 4-(2-(5-bromo-1H-indazol-1-yl)ethyl)morpholine (549 mg, 1.77 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (494 mg, 1.95 mmol), potassium acetate (347 mg, 3.54 mmol) and PdCl2(dppf)-CH2Cl2 adduct (72 mg, 0.088 mmol) was flushed with nitrogen. Dioxane (4.5 mL) was added, the vial was sealed and heated at 100° C. for 5 hrs. This was diluted with EtOAc, washed with water and brine, and dried over MgSO4. Removal of the solvent left crude 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethyl)morpholine (1 gm) as a oil which was used as such. A microwave vial containing a mixture of 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (50 mg, 0.120 mmol), crude 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethyl)morpholine (83 mg, 0.17 mmol), and PdCl2(dppf)-CH2Cl2 adduct (9.8 mg, 0.012 mmol), was flushed with nitrogen. DME (2 mL) and aq. Na2CO3 (0.30 mL, 0.60 mmol, 2.0 M) were added and the vial was sealed and heated at 100° for 6 hrs. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, elution gradient of 0 to 60% B over 20 min at 42 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-morpholino-2-(1-(2-morpholinoethyl)-1H-indazol-5-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (35 mg, 0.067 mmol, 56% yield) as a solid. MS (ESI) m/z 526.24 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.21 (1H, s), 8.61 (1H, s), 8.55 (1H, br. s.), 8.37 (1H, dd, J=9.16, 1.53 Hz), 8.35 (1H, s), 8.19 (1H, s), 8.10 (1H, d J=8.85 Hz), 7.79-7.86 (2H, m), 7.23 (1H, d, J=1.83 Hz), 7.02 (1H, dd, J=8.70, 1.98 Hz), 4.58 (2H, t, J=6.56 Hz), 3.77-3.87 (4H, m), 3.49-3.56 (4H, m), 3.21-3.27 (4H, m), 2.82 (2H, t, J=6.56 Hz), 2.41-2.49 (4H, m).

Workup

additionA microwave vial containing
customwas flushed with nitrogen
additionDioxane (4.5 mL) was added
customthe vial was sealed
additionThis was diluted with EtOAc
washwashed with water and brine
dry with materialdried over MgSO4
customRemoval of the solvent
waitleft crude 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethyl)morpholine (1 gm) as a oil which
additionA microwave vial containing
customwas flushed with nitrogen
customthe vial was sealed
temperatureheated at 100° for 6 hrs
washPreparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, elution gradient of 0 to 60% B over 20 min at 42 mL/min)

Sources & evidence

ORD record: ord-63e7e26de4dd4cebb362c54f9bdedbe1
Source dataset: uspto-grants-2014_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08815840B2

Reaction notes

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