Potassium Carbonate → 1,1-dimethylethyl (2S)-4-{[5'-(aminomethyl)-2'-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate

HRID 2080330Notes

Reaction equation

HRID 2080330 reaction equation
Cl.Br[C:3]1[CH:4]=[C:5]([CH2:10][NH2:11])[CH:6]=[CH:7][C:8]=1[F:9].[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH2:21][C@@H:20]1[CH3:35])=[O:18])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:22]3[CH2:23][CH2:24][N:19]([C:17]([O:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:18])[C@@H:20]([CH3:35])[CH2:21]3)[CH:27]=2)[CH:4]=1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 27249011-(3-Bromo-4-fluorophenyl)methanamine hydrochlorideHCID 25132855{3-[((3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid

Product 1

HCID 251325161,1-dimethylethyl (2S)-4-{[5'-(aminomethyl)-2'-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylateYield 37.3%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
150 °C

Procedure

To a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (1.68 g, 7 mmol) in dioxane/H2O (10 mL/3.3 mL) was added {3-[((3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid (2.33 g, 7 mmol), K2CO3 (4.83, 35 mmol) and Pd(PPh3)4 (405 mg, 0.35 mmol). The resulting mixture was heated at 150° C. in a pressure vessel for 2 hours, then cooled to rt and diluted with EtOAc (50 mL). The organic layer was collected and the aqueous layer was extracted by EtOAc (30 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by Gilson preparatory HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 90/10, v/v, over 12 min), to give the title compound (1.08 g, 37%). LC/MS: m/z, 414 (M+H), 1.83 min.

Workup

  1. temperaturecooled to rt
  2. customThe organic layer was collected
  3. extractionthe aqueous layer was extracted by EtOAc (30 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by Gilson preparatory HPLC
  8. washeluting with acetonitrile/water/0.1% TFA (10/90 to 90/10

Sources & evidence

ORD record
ord-0ca4abd654c54d1ab340093a7dd43ca1
Source dataset
uspto-grants-2011_04
Patent number
US07932247B2

Reaction notes

Loading…