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

HRID 1923138Notes

Reaction equation

HRID 1923138 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][S:19](=[O:23])(=[O:22])[CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].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]>[CH2:30]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH:14]([N:16]5[CH2:17][CH2:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21]5)[CH2:15]4)[S:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596058185-Chloro-2-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine

Product 1

HCID 596058284-(5-(2-ethyl-1H-benzo[d]imidazol-1-yl)-2-((3-(1,1-dioxo-thiomorpholino)azetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholineYield 60.2%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
145 °C

Procedure

A mixture of 5-chloro-2-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (150 mg, 0.33 mmol), 2-ethylbenzimidazole (58 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium (15 mg, 0.02 mmol), Xphos (31 mg, 0.07 mmol) and Cs2CO3 (213 mg, 0.65 mmol) in dioxane (3 mL) was purged with argon then heated at 145° C. for 45 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording 436 as a foam (113 mg, 60%). LCMS (Method I): RT 2.59 min, [M+H]+ 569.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.79-7.75 (m, 1 H); 7.33-7.27 (m, 2 H); 4.41 (m, 4 H); 4.02 (s, 2 H); 3.91-3.81 (m, 4 H); 3.72 (m, 2 H); 3.39-3.30 (m, 3 H); 3.16 (m, 2 H); 3.08 (m, 4 H); 2.90-2.85 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)

Workup

  1. customwas purged with argon
  2. filtrationThe reaction mixture was filtered through a pad of celite
  3. washwashing with EtOAc
  4. concentrationThe filtrate was concentrated in vacuo
  5. custompurified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%)

Sources & evidence

ORD record
ord-8a822e7dd38e4a088c654fb975c79548
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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