Dichloromethane → (5'-Chloro-2'-fluoro-[2,4']bipyridinyl-6-yl)-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester

HRID 1623236Notes

Reaction equation

HRID 1623236 reaction equation
Br[C:2]1[N:7]=[C:6]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C([O-])(O)=O.[Na+].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]>[Cl:25][C:26]1[C:27]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][C:19]([CH3:23])([CH3:24])[CH2:18]3)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[N:7]=2)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1

Participants

9

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 44754822(5-Chloro-2-fluoropyridin-4-yl)boronic acidHCID 58284736tert-butyl 6-bromopyridin-2-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate

Product 1

HCID 66937149(5'-Chloro-2'-fluoro-[2,4']bipyridinyl-6-yl)-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of tert-butyl 6-bromopyridin-2-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (710 mg, 1.778 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid, PdCl2(dppf).CH2Cl2 adduct (145 mg, 0.178 mmol) in DME (7 mL) and 2M aqueous Na2CO3 solution (2.3 mL, 1.778 mmol) was heated in a sealed tube at about 98° C. for 2 hr. The mixture was cooled to ambient temperature and diluted with EtOAc (˜100 mL) and saturated aqueous NaHCO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 (2×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, 25 min, EtOAc/heptane=0/100 to 25/75 over 25 min] providing (R/S)-tert-butyl 5′-chloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate as a highly viscous, colorless oil. Yield: 605 mg. LCMS (m/z): 394.1 {loss of tert Bu-group}/450.2 [M+H]+; Retention time=1.24 min.

Workup

  1. washThe separated organic layer was washed with saturated aqueous NaHCO3 (2×)
  2. dry with materialdried over Na2SO4
  3. filtrationfiltered off
  4. concentrationconcentrated in vacuo
  5. customThe resulting residue was purified by column chromatography [SiO2, 40 g, 25 min, EtOAc/heptane=0/100 to 25/75 over 25 min]

Sources & evidence

ORD record
ord-954ab4609cdb458ab11af85efc15c28f
Source dataset
uspto-grants-2014_07
Patent number
US08778951B2

Reaction notes

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