Cesium carbonate → 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 1476649Notes

Reaction equation

HRID 1476649 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+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.COCCOC>[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

6

Reactant 3

HCID 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 2

HCID 11050900Dichlorobis(tricyclohexylphosphine)pallium (II)CatalystHCID 80711,2-DimethoxyethaneSolvent

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 (1.00 g, B99), (2-fluorophenyl)boronic acid (337 mg), dichlorobis(tricyclohexylphosphine)palladium (137 mg) and aqueous cesium carbonate solution (1.4 ml, 2.0 M) are placed in a microwave tube and DME (15 ml) is added. The reaction vessel is sealed and the mixture is subjected to microwave irradiation at 150° C. with stirring for 40 min. The mixture is allowed to cool to RT, additional (2-fluorophenyl)boronic acid (52 mg) is added and the vessel is subjected to microwave irradiation at 150° C. for additional 40 min. The mixture is allowed to cool to RT and then filtered over a plug of silica (eluent: DCM). After removal of all volatile materials the residue is purified by flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 1/0 to 2/3 (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 which is crystallized from toluene and directly used for step 2.

Workup

  1. customThe reaction vessel is sealed
  2. customirradiation at 150° C.
  3. customirradiation at 150° C. for additional 40 min
  4. temperatureto cool to RT
  5. filtrationfiltered over a plug of silica (eluent: DCM)
  6. customAfter removal of all volatile materials the residue
  7. customis purified by flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 1/0 to 2/3 (v/v)]

Sources & evidence

ORD record
ord-468de167bd0d41a983c736053c0fc6be
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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