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Cesium carbonate → {3,5-Dichloro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-phenyl}-methanol

HRID 2366224
Notes
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Reaction equation

HRID 2366224 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([Cl:18])[C:7]=1[C:8]1[S:9][C:10]2[C:11](Cl)=[N:12][CH:13]=[CH:14][C:15]=2[N:16]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([Cl:18])[C:7]=1[C:8]1[S:9][C:10]2[C:11]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)=[N:12][CH:13]=[CH:14][C:15]=2[N:16]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 5728526-Methylpyrimidin-4-amine2×HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86668999[3,5-Dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-phenyl]-methanol

Product 1

HCID 56953205{3,5-Dichloro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-phenyl}-methanol
Yield 40%

Reagents, catalysts & solvents 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of [3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-phenyl]-methanol (0.063 g, 0.18 mmol), 4-amino-6-methylpyrimidine (0.022 g, 0.20 mmol), Pd2(dba)3 (0.003 g, 3.6 mmol), XantPhos (0.003 g, 5.0 pmol) and cesium carbonate (0.117 g, 0.36 mmol) in dioxane (1.1 mL) was degassed with nitrogen and subjected to microwave irradiation at 150° C. for 30 minutes. Further 4-amino-6-methylpyrimidine (0.011 g, 0.10 mmol), Pd2(dba)3 (0.006 g, 7.2 pmol), and XantPhos (0.006 g, 10.0 pmol) were added and the mixture subjected to further microwave irradiation at 150° C. for 60 minutes. The reaction mixture was diluted with MeOH and passed through a nylon filter. The filtrate was concentrated under reduced pressure then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M ammonia in MeOH. The eluent was concentrated under reduced pressure and the resultant residue was purified by silica gel flash chromatography eluting with 0-100% EtOAc in DCM to give the desired compound as a yellow solid (0.030 g, 40% yield). 1H NMR (300 MHz, CDCl3): δ 8.68 (s, 1H), 8.42 (br s, 1H), 8.18-8.04 (m, 1H), 7.77 (d, J=5.7 Hz, 1H), 7.50 (s, 2H), 4.72 (s, 2H), 2.55 (s, 3H). LCMS (Method C): RT=2.90 min, m/z: 418 [M+H+].

Workup

  1. customwas degassed with nitrogen
  2. customirradiation at 150° C. for 30 minutes
  3. customthe mixture subjected to further microwave irradiation at 150° C. for 60 minutes
  4. filtrationfilter
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. washwas washed with MeOH
  7. washthe product eluted with 2M ammonia in MeOH
  8. concentrationThe eluent was concentrated under reduced pressure
  9. customthe resultant residue was purified by silica gel flash chromatography
  10. washeluting with 0-100% EtOAc in DCM

Sources & evidence

ORD record
ord-bb7826d9f4264efb90ed6fa3dfe43b8d
Source dataset
uspto-grants-2014_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08697708B2

Reaction notes

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