Ammonia → HCID 66604465, compound

HRID 2410863Notes

Reaction equation

Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.CC([O-])=O.[K+].Br[C:39]1[CH:40]=[C:41]([C:58]([NH2:60])=[O:59])[C:42]2[NH:43][C:44]3[CH:45]=[C:46]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[CH:47]=[CH:48][C:49]=3[C:50]=2[N:51]=1.CC1(C)C(C)(C)OB(C2C=CC(CN3CCOCC3)=NC=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N>CO.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.O.COCCOC>[O:55]1[CH2:56][CH2:57][N:52]([C:46]2[CH:47]=[CH:48][C:49]3[C:50]4[N:51]=[C:39]([C:2]5[CH:7]=[N:6][C:5]([CH2:8][N:9]6[CH2:14][CH2:13][O:12][CH2:11][CH2:10]6)=[CH:4][CH:3]=5)[CH:40]=[C:41]([C:58]([NH2:60])=[O:59])[C:42]=4[NH:43][C:44]=3[CH:45]=2)[CH2:53][CH2:54]1

Participants

Conditions

Temperature: 100 °C

Procedure

A microwave vial containing a mixture of 4-((5-bromopyridin-2-yl)methyl)morpholine (537 mg, 2.09 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (583 mg, 2.30 mmol), KOAc (410 mg, 4.18 mmol) and PdCl2(dppf)-CH2Cl2 adduct (85 mg, 0.10 mmol) was flushed with nitrogen, dioxane (5 mL) was added. and the vial was sealed and heated at 100° C. for 6 hr. The reaction was filtered and the solid was washed with EtOAc. The filtrate was and washed with water, brine, and dried over MgSO4. Removal of the solvent left 750 mg of crude 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)morpholine (750 mg) as a brown thick oil that was used as such. A microwave vial containing a mixture of 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (60 mg, 0.14 mmol), 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)morpholine (130 mg, 0.171 mmol), PdCl2(dppf)-CH2Cl2 adduct (12 mg, 0.014 mmol) was flushed with nitrogen. DME (2.5 mL) and Na2CO3 (0.36 mL, 0.72 mmol, 2.0 M aq. solution) were added and the vial was sealed and heated at 100° C. for 5 hr. 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; gradient of 0 to 60% B over 10 min at 42 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH gave 7-morpholino-2-(6-(morpholinomethyl)pyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (25 mg, 0.050 mmol, 35% yield) as a solid. MS (ESI) m/z 473.21 (M+H). 1H NMR (500 MHz, Acetone) δ ppm 10.75 (1H, s), 9.36 (1H, d, J=2.14 Hz), 8.58 (1H, dd, J=8.09, 2.29 Hz), 8.35 (1H, s), 8.10-8.22 (2H, m), 7.62 (1H, d, J=7.93 Hz), 7.29 (1H, d, J=2.14 Hz), 7.18 (1H, br. s.), 7.07 (1H, dd, J=8.85, 2.14 Hz), 3.80-3.87 (4H, m), 3.71 (2H, s), 3.64-3.69 (4H, m), 3.28-3.35 (4H, m), 2.47-2.57 (4H, m).

Workup

additionA microwave vial containing
customwas flushed with nitrogen, dioxane (5 mL)
additionwas added
customand the vial was sealed
filtrationThe reaction was filtered
washthe solid was washed with EtOAc
washwashed with water, brine
dry with materialdried over MgSO4
customRemoval of the solvent
waitleft 750 mg of crude 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)morpholine (750 mg) as a brown thick oil that
additionA microwave vial containing
customwas flushed with nitrogen
customthe vial was sealed
temperatureheated at 100° C. for 5 hr

Sources & evidence

ORD record: ord-e26b7a1625024dcd929fb549d604290b
Source dataset: uspto-grants-2014_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08815840B2

Reaction notes

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