Sodium t-butoxide → 1'-(2-(3,5-Difluorophenyl)-3-methyl-1,7-naphthyridin-4-yl)-6'-(4-morpholinyl)-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]-pyridine]

HRID 1618742Notes

Reaction equation

HRID 1618742 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]3[NH:35][CH2:34][C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:30]3=[N:31][CH:32]=2)[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:19][C:14]1[CH:13]=[C:12]([C:4]2[C:3]([CH3:20])=[C:2]([N:35]3[C:29]4[C:30](=[N:31][CH:32]=[C:27]([N:24]5[CH2:25][CH2:26][O:21][CH2:22][CH2:23]5)[CH:28]=4)[C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:34]3)[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[C:16]([F:18])[CH:15]=1

Participants

6

Reactant 3

HCID 23676156Sodium t-butoxideHCID 672847056'-Morpholino-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]HCID 672860074-Chloro-2-(3,5-difluorophenyl)-3-methyl-1,7-naphthyridine

Product 1

HCID 672853711'-(2-(3,5-Difluorophenyl)-3-methyl-1,7-naphthyridin-4-yl)-6'-(4-morpholinyl)-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]-pyridine]

Reagents, catalysts & solvents 2

HCID 54751079XPhos PalladacycleCatalystHCID 1140TolueneSolvent

Procedure

Prepared according to procedure Y using 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,7-naphthyridine (40 mg, 0.138 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (37.9 mg, 0.138 mmol), sodium tert-butoxide (26.4 mg, 0.275 mmol) and XPhos precatalyst (10.4 mg, 0.014 mmol) in toluene (4 mL) at 110° C. for 2 h. Purification by reverse phase HPLC (10 to 50% acetonitrile in water) gave 1′-(2-(3,5-difluorophenyl)-3-methyl-1,7-naphthyridin-4-yl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]-pyridine]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.59 (1H, d, J=1.0 Hz), 8.57 (1H, d, J=5.9 Hz), 7.69 (1H, d, J=2.3 Hz), 7.51 (1H, dd, J=5.9, 1.0 Hz), 7.15-7.22 (2H, m), 6.94-7.01 (1H, m), 5.82 (1H, d, J=2.3 Hz), 4.12-4.21 (2H, m), 3.94-4.05 (2H, m), 3.71-3.81 (4H, m), 3.59 (2H, tt, J=11.4, 2.8 Hz), 2.93-3.07 (4H, m), 2.28-2.45 (5H, m), 1.72-1.88 (2H, m). Mass Spectrum (ESI) m/e=530.2 (M+1).

Workup

  1. customPrepared
  2. customat 110° C.
  3. customfor 2 h
  4. customPurification by reverse phase HPLC (10 to 50% acetonitrile in water)

Sources & evidence

ORD record
ord-c9b352cf7ba9442eb026f428318e2e86
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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