1,2-Dichloroethane → (S)-2-{[(3S,8S)-3-[4-(3,4-Dimethyl-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid

HRID 708729Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 708729
C(O[C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38]C)=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.[CH3:52][C:53]1[CH:54]=[C:55]([CH:58]=[CH:59][C:60]=1[CH3:61])[CH2:56]Br.C(=O)([O-])[O-].[K+].[K+].C(Cl)CCl.[CH3:72][C:73]1[O:74][C:75]([CH3:81])=[C:76](C(O)=O)[N:77]=1>CN(C=O)C.C(Cl)Cl.O>[CH3:52][C:53]1[CH:54]=[C:55]([CH:58]=[CH:59][C:60]=1[CH3:61])[CH2:56][O:51][C:48]1[CH:47]=[CH:46][C:45]([C@H:43]2[CH2:42][O:41][C:13]3=[CH:14][C:15]4[CH2:16][C@@H:17]([C:18]([NH:19][C@@H:20]([CH2:21][C:22]5[CH:23]=[CH:24][C:25]([C:28]6[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=6[CH3:35])=[CH:26][CH:27]=5)[C:36]([OH:38])=[O:37])=[O:40])[N:8]([C:6]([C:76]5[N:77]=[C:73]([CH3:72])[O:74][C:75]=5[CH3:81])=[O:7])[CH2:9][C:10]=4[CH:11]=[C:12]3[O:44]2)=[CH:50][CH:49]=1

Komponenten

9

Edukt 5

HCID 111,2-DichloroethaneHCID 11430Potassium CarbonateHCID 27954652,5-Dimethyl-1,3-oxazole-4-carboxylic acidHCID 131991903,4-Dimethylbenzyl bromideHCID 58327310(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester

Produkt 1

HCID 58327384(S)-2-{[(3S,8S)-3-[4-(3,4-Dimethyl-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (30 mg) was dissolved in DMF and 3,4-dimethylbenzyl bromide (2 equiv) and potassium carbonate (3 eq.) added. The reaction mixture was stirred at room temperature and was poured onto EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The mixture was purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes/EtOAc+1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) was added. The mixture was stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM. TEA (3 eq.) was added and the mixture used in the following reaction sequence. In a separate vial, EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. This solution was added to the above mixture and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes/EtOAc+1% MeOH; 1:1 hexanes/EtOAc+2% MeOH; 1:1 hexanes/EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 822.

Aufarbeitung

  1. dry with materialThe organic layer was dried over sodium sulfate
  2. concentrationconcentrated
  3. customThe mixture was purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes/EtOAc+1% MeOH)
  4. dissolutionThe resulting compound was dissolved in 2 mL DCM
  5. addition1 mL 4N HCl (dioxane) was added
  6. stirringThe mixture was stirred at room temperature for 1.5 hours
  7. concentrationwas concentrated
  8. customthe mixture used in the following reaction sequence
  9. stirringstirred for 40 minutes
  10. additionThis solution was added to the above mixture
  11. stirringstirred for 12 hours
  12. customThe reaction mixture was directly purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes/EtOAc+1% MeOH; 1:1 hexanes/EtOAc+2% MeOH; 1:1 hexanes/EtOAc+3% MeOH)

Quellen und Nachweise

ORD-Eintrag
ord-9f188573dd40470c98eee78297066fc9
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09175003B2

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