Thiazole → (R)-8-cyclopentyl-7-ethyl-5-methyl-2-(thiazol-2-yl)-7,8-dihydropteridin-6(5H)-one

HRID 44892Notes

Reaction equation

[S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.Cl[C:12]1[N:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17](=[O:23])[C@@H:16]([CH2:24][CH3:25])[N:15]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:14]=2[N:13]=1>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:26]1([N:15]2[C:14]3[N:13]=[C:12]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[N:21]=[CH:20][C:19]=3[N:18]([CH3:22])[C:17](=[O:23])[C@H:16]2[CH2:24][CH3:25])[CH2:27][CH2:28][CH2:29][CH2:30]1

Participants

Conditions

Temperature: -78 °C

Procedure

To a solution of thiazole (5 eq) in dry THF, BuLi (5 eq) was added dropwise at −78° C. and this was stirred at −78° C. for 30 min. ZnCl2 (1M in ether, 5 eq) was added and stirred at 0° C. for 30 min, then Intermediate B (1 eq) and Pd(dppf)Cl2 (0.1 eq) were added. The reaction was heated to 70° C. for 16 h; then the mixture was diluted with EtOAc, washed with brine and concentrated. The residue was purified by silica gel flash chromatography to give the title compound. LCMS (0.05% TFA): 344.1 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.04 (bs, 1H), 7.99 (bs, 1H), 7.76 (bs, 1H), 4.41 (m, 2H), 3.42 (s, 3H), 2.16 (m, 2H), 2.09˜1.72 (m, 8H), 0.88 (t, 3H, J=7.5 Hz).

Workup

stirringstirred at 0° C. for 30 min
temperatureThe reaction was heated to 70° C. for 16 h
washwashed with brine
concentrationconcentrated
customThe residue was purified by silica gel flash chromatography

Sources & evidence

ORD record: ord-d3cea99faf724492bd6cb6e3a501f84e
Source dataset: uspto-grants-2013_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08541418B2

Reaction notes

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