Cesium carbonate → 4-(5-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-2-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine

HRID 1923171Notes

Reaction equation

HRID 1923171 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:28]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1)([CH3:30])[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH:28]([C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH:14]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:15]4)[S:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)([CH3:30])[CH3:29]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 221212-(propan-2-yl)-1H-1,3-benzodiazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596060255-Chloro-7-morpholin-4-yl-2-[3-(tetrahydro-pyran-4-yl)azetidin-1-ylmethyl]thiazolo[5,4-d]pyrimidine

Product 1

HCID 596052184-(5-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-2-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholineYield 34%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 5-chloro-7-morpholin-4-yl-2-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]thiazolo[5,4-d]pyrimidine (0.1 g, 0.25 mmol), 2-isopropyl-1H-benzoimidazole 0.078 g, 0.49 mmol), Xphos (0.024g, 0.049 mmol), Pd2(dba)3 (0.012 g, 0.012 mmol) and Cs2CO3 (0.159 g, 0.49 mmol) in dioxane (1.5 mL) was subjected to microwave irradiation at 145° C. for 45 min. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 5:95) to give 470 as a yellow solid (0.044 g, 34%). LCMS (Method I): RT=2.88 min, [M+H]+ 534.2. 1H NMR (400 MHz, DMSO-d): δ 7.89-7.85 (m, 1 H); 7.66-7.61 (m, 1 H); 7.28-7.22 (m, 2 H); 4.36-4.30 (m, 4 H); 4.00 (s, 2 H); 3.97-3.89 (m, 1 H); 3.85 (dd, J=11.2, 4.0 Hz, 2 H); 3.79 (t, J=4.6 Hz, 4 H); 3.49 (t, J=7.3 Hz, 2 H); 3.39-3.35 (m, 2 H); 3.07 (t, J=6.8 Hz, 2 H); 2.27-2.21 (m, 1 H); 1.73-1.64 (m, 1 H); 1.52 (d, J=13.1 Hz, 2 H); 1.33 (dd, J=6.8, 4.0 Hz, 6 H); 1.10 (td, J=12.2, 4.6 Hz, 2 H)

Workup

  1. customirradiation at 145° C. for 45 min
  2. filtrationThe reaction mixture was filtered through Celite
  3. concentrationthe filtrate was concentrated in vacuo
  4. customThe residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 5:95)

Sources & evidence

ORD record
ord-f1142773658e487094c9656fe7737fc6
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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