Potassium Carbonate → 6-(3-(Hydroxyethoxy)thiophen-2-YL)-1-((tetrahydro-2H-pyran-4-YL)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one

HRID 388134Notes

Reaction equation

HRID 388134 reaction equation
OC[C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[N:13]=[C:12]2[N:14]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:15](=[O:17])[NH:16][C:11]2=[N:10][CH:9]=1.[CH:25]([C:27]1C=CSC=1B(O)O)=[O:26].[BH4-].[Na+].BrC1N=C2N(CC3CCOCC3)C(=[O:47])NC2=NC=1.C(=O)([O-])[O-].[K+].[K+]>CO.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].O.O1CCOCC1>[OH:26][CH2:25][CH2:27][O:47][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[N:13]=[C:12]2[N:14]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:15](=[O:17])[NH:16][C:11]2=[N:10][CH:9]=1

Participants

10

Reactant 5

HCID 11430Potassium CarbonateHCID 27734293-Formyl-2-thiopheneboronic Acid (contains varying amounts of Anhydride)HCID 4311764Sodium borohydrideHCID 249860416-(3-(Hydroxymethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-oneHCID 866263956-Bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one

Product 1

HCID 674336796-(3-(Hydroxyethoxy)thiophen-2-YL)-1-((tetrahydro-2H-pyran-4-YL)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-oneYield 40.4%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
25 °C

Procedure

6-(3-(Hydroxymethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. To a solution of 3-formylthiophen-2-ylboronic acid (0.156 g, 1 mmol) in methanol (2 mL) was added sodium tetrahydroborate (0.378 g, 10.00 mmol). The mixture was stirred at 25° C. for 10 min. 6-Bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 101.B) (0.157 g, 0.500 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (0.041 g, 0.050 mmol), potassium carbonate (0.138 g, 1.000 mmol), 1,4-dioxane (2 mL), and water (6.00 ml) were then added. The reaction mixture was heated in a Biotage Emrys Optimizer microwave reactor at 140° C. for 30 min. The reaction mixture was then extracted with ethyl acetate (3×25 mL) and washed with aqueous sodium bicarbonate (3×25 ml). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was subjected to silica gel chromatography (100% ethyl acetate). Concentration of the desired fractions afforded the title compound (0.070 g, 40.4%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.20 (s, 1H), 7.54 (d, J=5.2, 1H), 7.21 (d, J=5.2, 1H), 5.30 (t, J=5.4, 1H), 4.67 (d, J=5.6, 2H), 3.85-3.82 (m, 2H), 3.73 (d, J=7.2, 2H), 3.27-3.22 (m, 2H), 2.15-2.07 (m, 1H), 1.57-1.54 (m, 2H), 1.34-1.23 (m, 2H); MS (ESI) m/z 347.1 [M+1]+.

Workup

  1. temperatureThe reaction mixture was heated in a Biotage Emrys Optimizer microwave reactor at 140° C. for 30 min
  2. extractionThe reaction mixture was then extracted with ethyl acetate (3×25 mL)
  3. washwashed with aqueous sodium bicarbonate (3×25 ml)
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-ebd204e8aae54eb8958e60916feaca08
Source dataset
uspto-grants-2013_02
Patent number
US08372976B2

Reaction notes

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