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

HRID 720168Notes

Reaction equation

HRID 720168 reaction equation
[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:17]1=[O:26])[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.[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:37](=[O:38])[CH:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:40][C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[CH:18]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:17]1=[O:26])[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

6

Reactant 4

HCID 8471TriethylamineHCID 2724699PyBOPHCID 2734493(2R)-2-(((tert-butoxy)carbonyl)amino)-3-(4-fluorophenyl)propanoic acidHCID 695878362-(3-Cyclopropylmethyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester

Product 1

HCID 695873442-{4-[2-Tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl esterYield 71%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-(3-cyclopropylmethyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 14, (528 mg, 1.44 mmol) in CH2Cl2 (5.0 mL) are added 2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (489 mg, 1.67 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (951 mg, 1.83 mmol) and triethyl amine (174 mg, 1.72 mmol). The reaction mixture is stirred for 10 hours, quenched with 10% NaHCO3 aqueous solution and extracted several times with EtOAc. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a crude residue which is purified over silica gel (silica gel, hexanes/ethyl acetate, 1:1) to afford 651 mg (71% yield) of the desired product. 1H NMR (300 MHz, CDCl3, Rotamers) δ 7.66–7.85 (m, 3H), 7.55 (s, 1H), 7.39–7.53 (m, 2H), 7.28–7.38 (m, 1H), 7.04–7.18 (m, 2H), 6.86–7.01 (m, 2H), 5.63 (dd, J=11.4, 5.4 Hz, 0.5H), 5.47 (dd, J=11.4, 5.4 Hz, 0.5H), 5.28–5.38 (m, 0.5H), 4.82–4.98 (m, 1H), 4.56–4.80 (m, 1H), 4.30–4.43 (m, 0.5H), 3.75–3.91 (m, 4H), 3.50–3.62 (m, 1H), 2.92–3.36 (m, 4H), 2.64–2.88 (m, 2H), 1.38 (s, 5H), 1.35 (s, 4H), 0.91–1.18 (m, 2H), −0.64–0.17 (m, 5H); 13C NMR (75 MHz, CDCl3, Rotamers) δ 170.69, 170.54, 169.37, 168.55, 167.10, 155.09, 154.84, 134.05, 133.71, 133.53, 133.49, 132.60, 132.41, 131.79, 131.28, 131.17, 130.89, 130.79, 128.74, 128.66, 127.94, 127.86, 127.73, 127.63, 127.50, 127.03, 126.63, 126.57, 126.14, 115.94, 115.66, 115.56, 115.28, 80.34, 79.87, 58.82, 57.26, 56.42, 52.76, 51.66, 51.32, 44.08, 42.79, 41.36, 39.92, 38.75, 37.43, 36.72, 36.58, 34.92, 34.54, 28.44, 7.12, 4.74, 4.69, 4.34, 4.31; MS (ESMS) m/z 632.2 (M+H)+.

Workup

  1. customquenched with 10% NaHCO3 aqueous solution
  2. extractionextracted several times with EtOAc
  3. dry with materialThe combined extracts are dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo to a crude residue which
  6. customis purified over silica gel (silica gel, hexanes/ethyl acetate, 1:1)

Sources & evidence

ORD record
ord-ccea8d0049234bb4a630e89096b3ba2b
Source dataset
uspto-grants-2006_11
Patent number
US07132539B2

Reaction notes

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