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Ethyl 4-piperidinecarboxylate → HCID 86648396, Verbindung

HRID 409457
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 409457
[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[N:22]([C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=2)[CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.[NH:44]1[CH2:54][CH2:53][CH:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:45]1.C(N(C(C)C)CC)(C)C>C(O)(CC)C.ClCCl>[CH2:51]([O:50][C:48]([CH:47]1[CH2:53][CH2:54][N:44]([C:29]2[N:28]=[C:27]([N:22]3[CH2:21][C@@H:20]([N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:42])([F:43])[F:1])[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=4)[C:8]4[N:9]=[CH:10][C:11]([C:14]5[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=5)=[CH:12][N:13]=4)[CH2:24][C@H:23]3[CH2:25][CH3:26])[C:32]([Cl:33])=[CH:31][N:30]=2)[CH2:45][CH2:46]1)=[O:49])[CH3:52]
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

6

Edukt 3

HCID 70770Ethyl 4-piperidinecarboxylate2×HCID 81531Diisopropylethylamine2×HCID 59614356HCID 59614356, Verbindung

Produkt 1

HCID 86648396HCID 86648396, Verbindung

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittel
HCID 6568
(+-)-2-Butanol
Lösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

A mixture of 3,5-bis(trifluoromethyl)benzyl-[(3S,5R)-1-(2,5-dichloro-pyrimidin-4-yl)-5-ethyl-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (50.6 mg, 0.0784 mmol), ethyl isonipecotate (31 μL, 0.196 mmol) and diisopropyl-ethylamine (21 μL, 0.118 mmol) in sec-butanol (2 mL) is stirred at 120° C. for 10 hour. After addition of ethyl isonipecotate (12 μL, 0.0784 mmol) and diisopropyl-ethylamine (27 μL, 0.157 mmol), the mixture is stirred for additional 8 hours. The mixture is diluted with dichloromethane and washed with waterm 1N HCl aq, and the brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:2 to 5% MeOH in AcOEt) to give (1-[5-chloro-4-((2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-pyrimidin-2-yl]-piperidine-4-carboxylic acid ethyl ester, 34.7 mg). The obtained solid is dissolved in MeOH (2.5 mL), 1N NaOH aq (225 μL, 0.225 mmol) and water (0.3 mL), and the resulting mixture was stirred at room temperature for 18 hour. 1N HCl (225 μL, 0.225 mmol) and then MeOH were added to the mixture and the solvent was removed by evaporation. The residue was dissolved in dichloromethane and then filtered. The filtrate was evaporated to give 1-[5-chloro-4-((2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-pyrimidin-2-yl]-piperidine-4-carboxylic acid (29.2 mg, 51%).

Aufarbeitung

  1. stirringthe mixture is stirred for additional 8 hours
  2. washwashed with waterm 1N HCl aq
  3. dry with materialthe brine, dried over sodium sulfate
  4. concentrationconcentrated in vacuo
  5. customThe obtained residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:2 to 5% MeOH in AcOEt)

Quellen und Nachweise

ORD-Eintrag
ord-fe05f23a566e4a9ab2130a8f45dca088
Quelldatensatz
uspto-grants-2014_06
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08759365B2

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