Cesium carbonate → HCID 178476868, compound

HRID 1948122Notes

Reaction equation

HRID 1948122 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:20]3[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]3)=[C:13]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[CH2:14]3)[C:5]([C:27]([F:30])([F:29])[F:28])=[CH:4][N:3]=1.[CH2:31]([O:33][P:34]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([NH2:46])=[CH:44][CH:45]=1)(=[O:38])[O:35][CH2:36][CH3:37])[CH3:32].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:31]([O:33][P:34]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([NH:46][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([C@H:20]4[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]4)=[C:13]4[C:17]=3[C:16](=[O:18])[N:15]([CH3:19])[CH2:14]4)[C:5]([C:27]([F:28])([F:30])[F:29])=[CH:4][N:3]=2)=[CH:44][CH:45]=1)(=[O:38])[O:35][CH2:36][CH3:37])[CH3:32]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59649360Diethyl[(6-aminopyridin-3-yl)methyl]phosphonate2×HCID 178479962HCID 178479962, compound2×

Product 1

HCID 178476868HCID 178476868, compoundYield 11%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a suspension of 7-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 308C, 200 mg, 0.45 mmol. 36:64 mixture of regioisomers with the minor as the desired one), diethyl[(6-aminopyridin-3-yl)methyl]phosphonate (Compound 309A, 111 mg, 0.45 mmol), Pd(OAc)2 (5.09 mg, 0.023 mmol), Xantphos (26.2 mg, 0.045 mmol), and Cs2CO3 (296 mg, 0.91 mmol) in dry dioxane (2.8 mL) was bubbled nitrogen for 2 min. This mixture was then irradiated at 160° C. for 40 min in a CEM microwave reactor. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated and purified by silica gel chromatography (1-5% MeOH in DCM) to give 32.6 mg of the title compound (yield: 11%), the more polar of the two regioisomers on the TLC. 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=7.2 Hz, 6H), 1.44 (m, 2H), 1.63 (m, 2H), 1.91 (m, 2H), 2.16 (m, 2H), 2.50 (m, 1H), 3.12 (d, J=21.2 Hz, 2H), 3.22 (s, 3H), 3.77 (m, 1H), 4.02-4.10 (m, 4H), 4.39 (s, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 8.22 (s, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.45 (s, 1H), 8.62 (d, J=8.4 Hz, 1H), 10.59 (s, 1H). MS (ES+): m/z 649.18 [MH+]. HPLC: tR=3.38 min (ZQ3, polar—5 min).

Workup

  1. customwas bubbled nitrogen for 2 min
  2. customThis mixture was then irradiated at 160° C. for 40 min in a CEM microwave reactor
  3. filtrationthe reaction mixture was filtered
  4. concentrationthe filtrate was concentrated
  5. custompurified by silica gel chromatography (1-5% MeOH in DCM)

Sources & evidence

ORD record
ord-0c68b5bdf33345ddbe9e6630488bbb0a
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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