Dichloromethane → tert-Butyl 3(R)-[(1S,2S)-2-(Acetylamino)-3-(3,5-difluorophenyl)-1-hydroxypropyl]-5-(2,2-dimethylpropyl)-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

HRID 1436738Notes

Reaction equation

HRID 1436738 reaction equation
[C:1]([NH:4][C@@H:5]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[C@@H:6]([C@H:8]1[CH2:17][C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2Br)[CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[OH:7])(=[O:3])[CH3:2].ClCCl.[I-].[CH2:41]([Zn+])[C:42]([CH3:45])([CH3:44])[CH3:43].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:4][C@@H:5]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[C@@H:6]([C@H:8]1[CH2:17][C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:10][N:9]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[OH:7])(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 25517Ammonium ChlorideHCID 69014743tert-Butyl 3(R)-[(1S,2S)-2-(Acetylamino)-3-(3,5-difluorophenyl)-1-hydroxypropyl]-5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylateHCID 178445888HCID 178445888, compound

Product 1

HCID 86615384tert-Butyl 3(R)-[(1S,2S)-2-(Acetylamino)-3-(3,5-difluorophenyl)-1-hydroxypropyl]-5-(2,2-dimethylpropyl)-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylateYield 46%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Dissolve tert-butyl 3(R)-[(1S,2S)-2-(acetylamino)-3-(3,5-difluorophenyl)-1-hydroxypropyl]-5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (46.0 mg, 0.0808 mmol) in tetrahydrofuran (1.00 mL) in a sealed tube flushed with nitrogen. Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.3 mg, 0.0040 mmol) and 0.500 M of neopentyl zinc iodide in tetrahydrofuran (0.808 mL) dropwise at room temperature. Stir the resulting green solution at room temperature for six hours. Heat to 50° C. for three days. Add saturated ammonium chloride solution (2 mL) and dilute with ethyl acetate (30 mL). Add water (10 mL) and separate the layers. Extract the aqueous layer (1×30 mL) with ethyl acetate. Combine the organic layers and dry over magnesium sulfate. Purify (Biotage medium pressure chormatography eluting with 1.5% methanol:dichloromethane) to give desired product (21.8 mg, 46%) as an off-white foam.

Workup

  1. customflushed with nitrogen
  2. customdropwise at room temperature
  3. temperatureHeat to 50° C. for three days
  4. customAdd water (10 mL) and separate the layers
  5. extractionExtract the aqueous layer (1×30 mL) with ethyl acetate
  6. dry with materialdry over magnesium sulfate
  7. customPurify
  8. wash(Biotage medium pressure chormatography eluting with 1.5% methanol:dichloromethane)

Sources & evidence

ORD record
ord-cb114758f084483fb3cfb17df9cb8967
Source dataset
uspto-grants-2009_11
Patent number
US07618978B2

Reaction notes

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