Methylamine → [2-[2-Cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester

HRID 720170Notes

Reaction equation

HRID 720170 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH2:22]C2C=CC3C(=CC=CC=3)C=2)[C:19]([OH:21])=O)[C:14](=[O:33])[CH:13]1[CH2:34][CH:35]1[CH2:37][CH2:36]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:46]N.ON1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2N=N1.C[N:59]1[CH2:64]COCC1.CN(C)[CH2:67][CH2:68][CH2:69]N=C=NCC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:19](=[O:21])[NH:59][CH3:64])[CH2:22][C:56]2[CH:55]=[CH:54][C:53]3[C:52](=[CH:46][CH:69]=[CH:68][CH:67]=3)[CH:57]=2)[C:14](=[O:33])[CH:13]1[CH2:34][CH:35]1[CH2:37][CH2:36]1)=[O:11])([CH3:3])([CH3:2])[CH3:4]

Participants

7

Reactant 5

HCID 6329MethylamineHCID 79724-MethylmorpholineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 219015722-{4-[2-tert-Butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid

Product 1

HCID 72406548[2-[2-Cyclopropylmethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl esterYield 93%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid, 16, (114 mg, 0.18 mmol)) in DMF (2 mL) are added methylamine (2M, 0.11 mL, 0.22 mmol), 1-hydroxybenzotriazole (53 mg, 0.39 mmol), N-methylmorpholine (63 mg, 0.62 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (41 mg, 0.21 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue, which is purified over silica gel (hexanes/ethyl acetate, 1:4) to afford 108 mg (93% yield) of the desired product. 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.73–7.86 (m, 3H), 7.70 (s, 1H), 7.38–7.52 (m, 3H), 7.14–7.30 (m, 2H), 6.91–7.04 (m, 2H), 5.54–5.72 (m, 1H), 4.50–4.78 (m, 2H), 4.28–4.40 (m, 0.3H), 4.03–4.15 (m, 0.7H), 3.72–3.81 (m, 0.3H), 3.58–3.68 (m, 0.3H), 3.42–3.53 (m, 2H), 3.12–3.32 (m, 2H), 2.70–3.00 (m, 6H), 1.41 (s, 5H), 1.34 (s, 4H), 0.66–1.30 (m, 2H), −0.60–−0.12 (m, 4.3H), −0.80–−0.68 (m, 0.7H); MS (ESMS) m/z 631.3 (M+H)+.

Workup

  1. customquenched with aqueous NH4Cl
  2. extractionextracted several times with ethyl acetate
  3. dry with materialThe combined extracts are dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo to a residue, which
  6. customis purified over silica gel (hexanes/ethyl acetate, 1:4)

Sources & evidence

ORD record
ord-ef642003980849bb9ad1a0b057e2b098
Source dataset
uspto-grants-2006_11
Patent number
US07132539B2

Reaction notes

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