Tributylphosphine → tert-butyl (3R,4S)-3-({cyclopropyl[3-{[(1R,2R)-2-(ethoxy-carbonyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

HRID 658265

Reaktionsgleichung

Reaktionsgleichung von HRID 658265
[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.O[CH2:71][C@@H:72]1[CH2:74][C@H:73]1[C:75]([O:77][CH2:78][CH3:79])=[O:76].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:71][C@@H:72]3[CH2:74][C@H:73]3[C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1

Komponenten

7

Edukt 4

HCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 29920784Ethyl (1R,2R)-2-(hydroxymethyl)cyclopropanecarboxylateHCID 68492454tert-Butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl]-amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

Produkt 1

HCID 86639858tert-butyl (3R,4S)-3-({cyclopropyl[3-{[(1R,2R)-2-(ethoxy-carbonyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 1140TolueneLösungsmittelHCID 22728543Water ethylacetateLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

To a solution of tert-butyl(3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in toluene (0.1 M) was added 1,1′-(azodicarbonyl)dipiperidine (1.2 eq.), ethyl (1R,2R)-2-(hydroxyl-methyl)cyclopropanecarboxylate (2 eq.) from the previous step, and tri-n-butylphosphine (1.2 eq.). The reaction was heated to 80° C. and stirred for 18 h. While hot, the reaction was diluted with EtOAc/water. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 40% EtOAc in Hex) to afford the title compound as an oil.

Aufarbeitung

  1. extractionThe aqueous layer was extracted with EtOAc
  2. washThe combined organic extracts were washed with brine
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by flash column chromatography (SiO2, 40% EtOAc in Hex)

Quellen und Nachweise

ORD-Eintrag
ord-b713bfe33d4947b7845fa1d1652a0f71
Quelldatensatz
uspto-grants-2011_12
Patentnummer
US08076359B2

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