1,2-Dimethoxyethane → tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(2-fluorophenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate

HRID 1476630Notes

Reaction equation

HRID 1476630 reaction equation
Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[O:31][N:30]=[C:29]([CH2:32][CH3:33])[N:28]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.CCOC(C)=O.O>[CH2:32]([C:29]1[N:28]=[C:27]([CH2:26][N:5]2[C:4]3[CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[F:34])[S:10][C:9]=3[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:6]2=[O:25])[O:31][N:30]=1)[CH3:33]

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10796Cesium carbonateHCID 27343542-Fluorophenylboronic acid2×HCID 67258967Tert-butyl 4-{6-bromo-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate

Product 1

HCID 67257510tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(2-fluorophenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 11050900Dichlorobis(tricyclohexylphosphine)pallium (II)Catalyst2×HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Tert-butyl 4-{6-bromo-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (250 mg, compound B99), (2-fluorophenyl)boronic acid (65 mg), dichlorobis(tricyclohexylphosphine)palladium (17 mg) and aqueous cesium carbonate solution (0.35 ml, 2.0 M) are placed in a microwave tube and DME (8 ml) is added. The reaction vessel is sealed and the mixture is subjected to microwave irradiation at 150° C. with stirring for 20 min. The mixture is allowed to cool to RT and additional (2-fluorophenyl)boronic acid (19 mg) and dichlorobis(tricyclohexylphosphine)palladium (9 mg) are added. The mixture is again subjected to microwave irradiation at 150° C. with stirring for 20 min and then allowed to cool to RT. After addition of water and extraction with EtOAc the combined organic layers are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. All volatile materials are removed in vacuo and the residue is purified by flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/1 (v/v)] to afford tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(2-fluorophenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate as a solid.

Workup

  1. customThe reaction vessel is sealed
  2. customirradiation at 150° C.
  3. customirradiation at 150° C.
  4. stirringwith stirring for 20 min
  5. temperatureto cool to RT
  6. washare washed with saturated aqueous sodium chloride solution
  7. dry with materialdried over sodium sulfate
  8. customAll volatile materials are removed in vacuo
  9. customthe residue is purified by flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/1 (v/v)]

Sources & evidence

ORD record
ord-86ccbe96fbdc4fe9b6109f316c86b3d0
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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