4-Methylmorpholine → 2-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide

HRID 720188Notes

Reaction equation

HRID 720188 reaction equation
Cl.[NH2:2][CH:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:13]([NH2:15])=[O:14])[CH2:8][CH:7]1[CH2:27][CH3:28])=[O:5].C(OC([CH2:44][C:45]([NH2:50])([CH3:49])[C:46](O)=[O:47])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[NH2:50][C:45]([CH3:49])([CH3:44])[C:46]([NH:2][CH:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:13]([NH2:15])=[O:14])[CH2:8][CH:7]1[CH2:27][CH3:28])=[O:5])=[O:47]

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 19692748Boc-aminoisobutyric acidHCID 695876512-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide HCl

Product 1

HCID 219015352-{4-[2-(2-Amino-2-methyl-propionylamino)-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamideYield 97.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionamide HCl (0.22 g, 0.4 mmol) and t-butyloxycarbonyl-α-aminoisobutyric acid (AIB) (0.09 g, 0.5 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (0.17 g, 0.9 mmol) and 1-hydroxybenzotriazole (0.07 g, 0.5 mmol) are dissolved in anhydrous DMF (2.5 mL). This reaction mixture is cooled to 0° C., then N-methylmorpholine (0.14 mL, 1.3 mmol) is added. This reaction mixture is placed in a refrigerator for overnight. EtOAc (25 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL), the organic layers combined, washed with water (2×50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.22 g (77% yield) of the desired product which is used without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.80–7.64 (m, 4H), 7.45–7.30 (m, 3H), 7.20–7.10 (2H), 6.95–6.85 (m, 2H), 6.95–6.85 (m, 2H), 6.65–632 (m, 1H), 5.50–5.02 (m, 2H), 4.78–4.00 (m, 1H), 3.70–3.10 (m, 3H), 3.02–2.64 (m, 6H), 2.50–2.35 (m, 1H), 2.15–1.76 (m, 1H), 1.55–1.21 (m, 18H), 0.75–0.65 (m, 3H); 13C NMR, (CDCl3, 300 MHz) δ 174.5, 174.4, 174.0, 170.0, 169.8, 163.7, 160.4, 155.0, 137.0, 133.6, 132.3, 131.4, 131.3, 131.2, 131.0, 130.8, 128.1, 127.8, 127.6, 126.6, 126.2, 125.6, 125.3, 118.4, 115.8, 115.7, 115.6, 115.5, 115.2, 110.8, 80.0, 70.2, 69.9, 56.9, 56.7, 55.4, 51.5, 51.2, 51.0, 50.1, 49.9, 41.8, 39.6, 37.8, 32.6, 28.5, 28.3, 26.7, 26.0, 25.6, 23.1, 22.2, 10.7, 10.1.

Workup

  1. customthe organic layer is separated
  2. extractionThe aqueous layer is extracted with EtOAc (3×30 mL)
  3. washwashed with water (2×50 mL)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-f33a9c37fc2f4b4f93aa6530cc16118b
Source dataset
uspto-grants-2006_11
Patent number
US07132539B2

Reaction notes

Loading…