Dichloromethane → Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-6-methoxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate

HRID 712343Notes

Reaction equation

HRID 712343 reaction equation
Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]([Br:17])[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[CH3:20][C:21]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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]>[Br:17][C:4]1[C:5]2[S:9][C:8]([NH:10][C:11](=[O:12])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:16]=[C:2]([C:30]2[CH:29]=[N:28][C:27]([N:24]3[CH2:25][CH2:26][C:21]([CH3:20])([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23]3)=[N:32][CH:31]=2)[C:3]=1[O:18][CH3:19]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 66976878Ethyl 4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylateHCID 866639681-(5,7-Dibromo-6-methoxy-1,3-benzothiazol-2-yl)-3-ethyl-urea2×

Product 1

HCID 86664051Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-6-methoxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate

Reagents, catalysts & solvents 3

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

Conditions

Temperature
110 °C

Procedure

1-(5,7-Dibromo-6-methoxy-1,3-benzothiazol-2-yl)-3-ethyl-urea (Intermediate 14) (234 mg, 0.57 mmol), ethyl 4-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperidine-4-carboxylate (716 mg, 1.14 mmol, 60 mass %) and PdCl2(dppf).DCM (23 mg, 0.03 mmol) were dissolved in dioxane (7.5 mL) in a 10-20 mL microwave vial and a solution of cesium carbonate (559 mg, 1.72 mmol) in water (2.5 mL) was added. The vial was capped, the mixture degassed and heated in the microwave at 110° C. for 30 minutes. The mixture was poured into water and extracted into EtOAc (4×40 mL). The organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness in vacuo. The mixture was purified by chromatography, Biotage SP4, 40 g Si cartridge, 10-100% EtOAc in heptane. Two compounds were detected with the same mass ion (m/z) and retention time by LCMS but were distinct by TLC (60% EtOAc in heptane) so were assumed to be two regioisomers. The relevant fractions were combined to give the desired compound as a pale yellow oil, 47 mg (14%). MS: 577.04/579.07 [M+H]+.

Workup

  1. customThe vial was capped
  2. customthe mixture degassed
  3. additionThe mixture was poured into water
  4. extractionextracted into EtOAc (4×40 mL)
  5. washThe organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated to dryness in vacuo
  8. customThe mixture was purified by chromatography, Biotage SP4, 40 g Si cartridge, 10-100% EtOAc in heptane

Sources & evidence

ORD record
ord-cb3c4eb4b2b646b0ad2e4a4142cbc531
Source dataset
uspto-grants-2015_11
Patent number
US09181234B2

Reaction notes

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