1-Hydroxybenzotriazole → (4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester

HRID 1989066Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1989066
[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:29](=[O:30])[CH2:28][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]

Komponenten

8

Edukt 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2762732(4-Methylpiperazin-1-yl)acetic acidHCID 29948379tert-butyl N-[4-(piperidin-4-yl)phenyl]carbamate

Produkt 1

HCID 68677424(4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl esterAusbeute 83 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

(4-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI (0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL). After 16 h, water (10 mL) and CH2Cl2 (10 mL) were added. The organic layer was washed with water (3×10 mL), dried (MgSO4) and concentrated. Chromatography (0-15% EtOAc/hexanes gradient) provided 0.24 g (83%) of (4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester. (4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.16 g) (72%) of 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone tri-TFA salt (52 mg g, 0.079 mmol) were combined in i-PrOH (1 mL) and TEA (25 mg, 0.25 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 8.6 mg of 8-indan-5-yl-2-(4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 7.40-7.42 (m, 2H), 7.17-7.26 (m, 3H), 7.06-7.09 (m, 2H), 4.30 (q, 2H, J=7.1 Hz), 3.07 (br s, 1H), 2.87-2.93 (m, 6H), 2.48-2.67 (m, 7H), 2.28 (br s, 3H), 2.05-2.12 (m, 2H), 1.72-1.82 (m, 2H), 1.49 (br s, 2H), 1.31 (t, 3H, J=7.1 Hz).

Aufarbeitung

  1. washThe organic layer was washed with water (3×10 mL)
  2. dry with materialdried (MgSO4)
  3. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-3d43b6d541dc4bd39acc0fa25145bd93
Quelldatensatz
uspto-grants-2010_01
Patentnummer
US07642270B2

Notizen zur Reaktion

Wird geladen…