4-Methylmorpholine → 2-{4-[2-Tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester

HRID 720178Notes

Reaction equation

HRID 720178 reaction equation
[CH3:1][O:2][C:3](=[O:24])[CH:4]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:22][CH3:23])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[CH3:25][C:26]([O:29][C:30]([NH:32][C@@H:33]([C:42](O)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:31])([CH3:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:42](=[O:43])[CH:33]([NH:32][C:30]([O:29][C:26]([CH3:27])([CH3:25])[CH3:28])=[O:31])[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[CH:18]([CH2:22][CH3:23])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 2734493(2R)-2-(((tert-butoxy)carbonyl)amino)-3-(4-fluorophenyl)propanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 695875432-(3-Ethyl-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester

Product 1

HCID 695875682-{4-[2-Tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl esterYield 91%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

2-(3-Ethyl-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 34, (2.1 g, 6.4 mmol) and N-Boc-D-4-fluorophenylalanine (1.9 g, 6.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (4.9 g, 12.9 mmol) are dissolved in anhydrous DMF (20 mL). This reaction mixture is cooled to 0° C., then N-methylmorpholine (0.75 mL, 6.8 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (75 mL) and water (300 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×150 mL). The combined organic layers are washed with water (100 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue is purified over silica (EtOAc/Hexane, 1:2) to afford 3.5 g (91% yield) of the desired product. 1H NMR (CDCl3, δ): 7.82–7.75 (m, 3H), 7.62 (s, 1H), 7.52–7.40 (M, 2H), 7.34 (m, 1H), 7.22–7.25 (m, 2H), 7.02–6.92 (m2H), 5.75–5.62 (M, 1H), 5.18 (d, J=7.7 Hz, 0.5H), 4.90 (quartet, J=7.7 Hz, 1H), 4750–4.62 (m, 0.5H), 4.50–4.25 (m, 1H), 3.64 (d, J=9.7 Hz, 3H), 3.58–3.38 (m, 1.5H), 3.30–2.90 (m, 6H), 2.90–2.70 (m, 1H), 2.62–2.25 (d, J=11.6 Hz, 1H), 2.15–2.00 (m, 1H), 1.78–1.50 (m, 1.5H), 1.42 (s, 9H), 1.35–1.20 (m, 1H), 0.6 (t, J=9.7 Hz, 2H); 13C NMR, δ 174.2, 171.6, 171.0, 170.2, 164.0, 160.2, 156, 135.7, 133.7, 132.4, 131.4, 131.3, 128.1, 127.8, 127.6, 127.5, 126.2, 125.7, 115.7, 115.5, 115.4, 115.3, 79.9, 68.9, 68.7, 55.9, 54.1, 53.7, 51.4, 51.2, 51.0, 47.5, 46.6, 40.1, 39.1, 38.1, 35.4, 28.5, 22.9, 21.9, 10.6, 10.0

Workup

  1. customis placed in a refrigerator overnight
  2. customthe organic layer is separated
  3. extractionThe aqueous layer is extracted with EtOAc (3×150 mL)
  4. washThe combined organic layers are washed with water (100 mL)
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe resulting residue is purified over silica (EtOAc/Hexane, 1:2)

Sources & evidence

ORD record
ord-9c4a08dcf33247379ad2c5ac4efe8320
Source dataset
uspto-grants-2006_11
Patent number
US07132539B2

Reaction notes

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