Acetonitrile → 4'-[(1R)-1-(methylamino)-2-(1-pyrrolidinyl)ethyl]-3-biphenylcarboxamide

HRID 2114452Notes

Reaction equation

HRID 2114452 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:17][C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].CC#N>O1CCOCC1.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].C(Cl)Cl.O>[CH3:16][NH:15][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:18]([NH2:17])=[O:19])[CH:25]=2)=[CH:3][CH:4]=1)[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1

Participants

8

Reactant 4

HCID 6342AcetonitrileHCID 10340Sodium CarbonateHCID 2737814(3-Carbamoylphenyl)boronic acidHCID 57501277[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]methylamine

Product 1

HCID 574890604'-[(1R)-1-(methylamino)-2-(1-pyrrolidinyl)ethyl]-3-biphenylcarboxamideYield 65.8%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalyst2×HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

(1R)-1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (2.65 g, 9.4 mmol) was dissolved in dioxane (100 mL) under argon at room temperature. The resulting solution was magnetically stirred and treated with [3-(aminocarbonyl)phenyl]boronic acid (1.7 g, 10.3 mmol) followed by 15 mL of a 1.88M solution of Na2CO3 (28.2 mmol) and PdCl2(dppf)2·CH2Cl2 (408 mg, 0.5 mmol) all at room temperature. The flask was placed in a preheated 100° C. oil bath and maintained at 100° C. for approximately 18 h after which time it was determined by LCMS to be 60% complete. Additional PdCl2(dppf)2·CH2Cl2, (408 mg, 0.5 mmol) was added and the reaction was allowed to continue at 105° C. for approximately another 6 h. The reaction was determined to be complete by LCMS (Eclipse XDB C18, 4.6×250 mm column, 1.5 mL/min, 10 minutes, gradient from 1-99% CH3CN (0.1% trifluoroacetic acid)/H2O (0.1% trifluoroacetic acid), ES, Rt=4.46 min and m/e 324 [M+1]+). The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under vacuum by rotary evaporation and purified by silica gel chromatography (120 g Redisep silica gel column, 40 um, 60 Å, 50 mL/min, A: (CH2Cl2) B: (Methanol with 1% NH4OH) gradient of 0% -20% B in A, 60 min run; detection at 254 nm) to give 4′-[(1R)-1-(methylamino)-2-(1-pyrrolidinyl)ethyl]-3-biphenylcarboxamide (2.0 g) as a brown oil:

Workup

  1. customwas placed in a preheated 100° C.
  2. customto continue at 105° C.
  3. customapproximately another 6 h
  4. temperatureThe reaction mixture was cooled to room temperature
  5. filtrationfiltered through Celite
  6. concentrationThe filtrate was concentrated under vacuum by rotary evaporation
  7. custompurified by silica gel chromatography (120 g Redisep silica gel column, 40 um, 60 Å, 50 mL/min
  8. custom60 min

Sources & evidence

ORD record
ord-65d2e3426ace4f4cb45b0c8513259856
Source dataset
uspto-grants-2008_10
Patent number
US07432258B2

Reaction notes

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