4-Methylmorpholine → (1-(4-Hydroxy-benzyl)-2-{2-[2-(3-hydroxy-propyl)-benzofuran-3-ylmethyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester

HRID 1054015Notes

Reaction equation

HRID 1054015 reaction equation
[C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:52]1[CH2:56][CH2:55][CH2:54][CH:53]1[CH2:57][C:58]1[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[O:60][C:59]=1[CH2:67][CH2:68][CH2:69][OH:70]>CN1C(=O)CCC1.O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:18]([N:52]1[CH2:56][CH2:55][CH2:54][CH:53]1[CH2:57][C:58]1[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[O:60][C:59]=1[CH2:67][CH2:68][CH2:69][OH:70])=[O:20])([CH3:5])([CH3:6])[CH3:7]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 117439L-Tyrosine, N-(1,1-dimethylethoxy)carbonyl-HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 671485293-(3-Pyrrolidin-2-ylmethyl-benzofuran-2-yl)-propan-1-ol

Product 1

HCID 67147965(1-(4-Hydroxy-benzyl)-2-{2-[2-(3-hydroxy-propyl)-benzofuran-3-ylmethyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl esterYield 92.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent2×

Procedure

A solution containing Boc-L-tyrosine (577 mg, 2.1 mmol) and HATU (716 mg, 1.8 mmol) in anhydrous NMP (6 mL) was treated with NMM (0.3 mL, 2.7 mmol) at ambient temperature. After 10 min, a solution containing 61 (429 mg, 1.7 mmol) in NMP (5 mL) was added. After 2 d, the reaction mixture was diluted with water and the product was extracted with diethyl ether. The combined ether extracts were washed with water and dilute aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (10% MeOH/DCM) to afford 821 mg (92%) of 62 as a pale yellow foam. 1H NMR (CDCl3, 300 MHz) δ8.54 (br 2, 1H), 7.66-7.63 (m, 1H), 7.36-7.32 (m, 1H), 7.21-7.06 (m, 5H), 6.83 (d, J=8.4 Hz, 2H), 5.58 (d, J=9.0 Hz, 1H), 4.64-4.56 (m, 1H), 4.34-4.31 (m, 1H), 3.92-3.88 (m, 1H), 3.70 (app t, J=5.7 Hz, 2H), 3.51-3.26 (m, 1H), 3.18-2.79 (m, 4H), 2.01-1.97 (m, 2H), 1.69-1.47 (m, 1H), 1.42 (s, 9H) ppm.

Workup

  1. additionwas added
  2. waitAfter 2 d
  3. extractionthe product was extracted with diethyl ether
  4. washThe combined ether extracts were washed with water and dilute aqueous NaHCO3, brine
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by flash silica gel chromatography (10% MeOH/DCM)

Sources & evidence

ORD record
ord-e2df9b63ad344efbb89c525bdbdcefe7
Source dataset
uspto-grants-2016_07
Patent number
US09394249B2

Reaction notes

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