Potassium Carbonate → 6-Methoxy-1-methyl-7-{[1-((2S)-5-oxo-pyrrolidin-2-ylmethyl)-(2S,3S)-2-phenyl-piperidin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one

HRID 1244008Notes

Reaction equation

HRID 1244008 reaction equation
C(OCC)(=O)C.CO.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[CH2:21][NH:22][C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][C@H:24]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:17]([CH3:35])[C:16](=[O:36])[CH2:15][CH2:14]2.C(=O)([O-])[O-].[K+].[K+].[O:43]=[C:44]1[NH:48][CH:47]([CH2:49]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:46][CH2:45]1>CN(C=O)C.C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[CH2:21][NH:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:49][C@@H:47]3[CH2:46][CH2:45][C:44](=[O:43])[NH:48]3)[C@H:24]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:17]([CH3:35])[C:16](=[O:36])[CH2:15][CH2:14]2

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 28146098243-59-5HCID 103093706-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-oneHCID 21584119Ethylacetate methanol

Product 1

HCID 696545316-Methoxy-1-methyl-7-{[1-((2S)-5-oxo-pyrrolidin-2-ylmethyl)-(2S,3S)-2-phenyl-piperidin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-oneYield 10%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

To of (S)-(+)-5-(Hydroxymethyl)-2-pyrrolidinone (1.0 g 8.69 mmol) and triethylamine (1.21 ml, 8.69 mmol) in 50 mL of methylene chloride was added 1.66 g (8.69 mmol) of p-toluenesulfonyl chloride. The resultant solution was stirred at room temperature for 3 days. The organic solution was washed 1× with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (95:5 ethyl acetate/methanol) gave 1.65 g (71%) of toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as a white powder that was used in the next step. Rf=0.29 (95:5 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 1.65–1.80 (m, 1H), 2.15–2.35 (m, 3H), 2.42 (s, 3H), 3.80–3.90 (m, 2H), 3.95–4.05 (m, 1H), 6.53 (bs, 1H), 7.30–7.35 (d, J=8.4 Hz, 2H), 7.74–7.76 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 21.7, 22.8, 29.3, 52.6, 72.0, 127.9, 130.1, 132.4, 145.4, 178.0. To 150 mg (0.40 mmol) of 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one, potassium carbonate (55 mg, 0.40 mmol), and catalytic KI in 4 mL of DMF was added toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester (107 mg, 0.40 mmol) The suspension was heated to 60° C. for 16 hours. The reaction was diluted with methylene chloride and washed 3× with water, 2× with brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (85:15 ethyl acetate/methanol) gave 19 mg (10%) of the title compound, a white foam. Rf=0.10 (85:15 ethyl acetate/methanol). MS (M+H)+=477.2; 1H NMR (400 MHz, CDCl3): δ 1.30–1.60 (m, 3H), 1.78–1.82 (dd, J=12.6, 3.0 Hz, 1H), 1.98–2.16 (m, 6H), 2.20–2.30 (m, 1H), 2.50–2.52 (dd, J=12.6, 11.0 Hz, 1H), 2.54–2.58 (t, J=7.4 Hz, 2H), 2.68 (bs, 1H), 2.76–2.80 (t, J=7.4 Hz, 2H), 3.14 (s, 3H), 3.25–3.29 (m, 1H), 3.30 (bs, 1H), 3.37–3.40 (d, J=13.9 Hz, 1H), 3.49 (s, 3H), 3.62–3.66 (d, J=13.9 Hz, 1H), 3.86–3.91 (m, 1H), 6.49 (s, 1H), 6.50–6.55 (bs, 1H), 6.60 (s, 1H), 7.20–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 20.1, 25.0, 25.5, 27.3, 29.6, 29.9, 31.8, 45.6, 50.8, 53.7, 55.5, 56.3, 61.1, 72.4, 109.9, 116.28, 127.1, 128.3, 128.9, 133.6, 140.6, 152.9, 170.0, 177.5. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid (Mp=203–207° C.).

Workup

  1. washwashed 3× with water, 2× with brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-64e053dca0654f908331a7506d191b79
Source dataset
uspto-grants-2006_10
Patent number
US07119207B2

Reaction notes

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