Potassium Phosphate, Tribasic → 2-(10-Fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 592912Notes

Reaction equation

[CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[S:19][C:20]3[CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][C:25]=3[N:26]=2)[C:3]1=[O:28].Cl[C:30]1[C:35]([CH:36]=[O:37])=[C:34]([N:38]2[CH2:51][CH2:50][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[C:48]([F:49])=[C:40]3[C:39]2=[O:52])[N:33]=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[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(#N)C.O>[F:49][C:48]1[C:47]2[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=2[N:41]2[CH2:50][CH2:51][N:38]([C:34]3[N:33]=[CH:32][CH:31]=[C:30]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[S:19][C:20]6[CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][C:25]=6[N:26]=5)[C:3](=[O:28])[N:2]([CH3:1])[CH:7]=4)[C:35]=3[CH:36]=[O:37])[C:39](=[O:52])[C:40]=12

Participants

Conditions

Temperature: 100 °C

Procedure

A 50-mL round-bottomed flush equipped with a reflux condenser was charged with 1-methyl-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylamino)-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 216a (200 mg, 0.50 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (174 mg, 0.50 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (21 mg, 0.025 mmol), and acetonitrile/water (15/1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. for 1 h under N2 protection. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (70/1 to 30/1) to afford 223a (167 mg, 57%) as yellow solid. MS-ESI: [M+H]+ 588.1

Workup

customA 50-mL round-bottomed flush
customequipped with a reflux condenser
customAfter bubbling nitrogen through the mixture for 30 minutes
customAnalysis of reaction mixture by LCMS

Sources & evidence

ORD record: ord-77d6727ad0984fe98e1b8fa5703ca2fa
Source dataset: uspto-grants-2016_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09238655B2

Reaction notes

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