Methylamine → [2-[2-Ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester

HRID 720181Notes

Reaction equation

HRID 720181 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:19](O)=[O:20])[CH2:14][CH:13]1[CH2:33][CH3:34])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[N:46]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:45]C1.F[P-](F)(F)(F)(F)F.CN.C1COCC1.C(N(CC)CC)C>ClCCl.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:19](=[O:20])[NH:46][CH3:45])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:14][CH:13]1[CH2:33][CH3:34])=[O:11])([CH3:4])([CH3:2])[CH3:3]

Participants

9

Reactant 5

HCID 6329MethylamineHCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 2724699PyBOPHCID 219015692-{4-[2-Tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid

Product 1

HCID 69587828[2-[2-Ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl esterYield 73%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 36, (1.7 g, 3.0 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (PyBOP) (2.0 g, 3.8 mmol) in anhydrous dichloromethane (10 mL) are added 2 M methyl amine solution in THF (1.5 mL, 3.0 mmol) and triethyl amine (1.0 mL, 7.4 mmol). The reaction mixture is placed in a refrigerator overnight. EtOAc (50 mL) and water (200 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product is purified over silica (EtOAc/hexane, 1:1) to afford 1.3 g (73% yield) of the desired product. 1H NMR (CDCl3, 300 MHz, δ): 7.75–7.65 (m, 3H), 7.55 (s, 1H), 7.39–7.29 (m, 2H), 7.29–7.2 (m, 1H), 7.10–7.02 (m, 2H), 6.90–6.82 (m, 2H), 6.51–6.30 (m, 1H), 5.31 (d, J=10.4 Hz, 1H), 4.85–4.15 (m, 2.5H), 3.55–3.12 (m, 3H), 3.00–2.05 (m, 10H), 1.85–1.45 (m, 10H), 0.7 (m, 3H); 13C NMR, (CDCl3, 300 MHz) δ 174.0, 172.0, 171.0, 170.0, 163.9, 160.6, 155.2, 137.4, 133.8, 132.4, 131.5, 131.4, 131.3, 131.2, 128.4, 128.0, 127.8, 126.4, 125.8, 116.0, 115.7, 115.4, 80.0, 70.9, 70.7, 60.7, 55.4, 52.1, 51.2, 51.0, 50.5, 49.8, 41.9, 40.2, 39.4, 38.0, 32.4, 28.6, 26.3, 23.3, 22.3, 21.4, 14.5, 10.8, 10.3.

Workup

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

Sources & evidence

ORD record
ord-3eaf4f21e2644ab68daccc74816608a9
Source dataset
uspto-grants-2006_11
Patent number
US07132539B2

Reaction notes

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