Ammonium Chloride → (rac.)-(1R*,5S*)-7-{6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-pyridin-3-yl}-9-methyl-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic Acid 3-tert-butyl Ester 6-ethyl Ester

HRID 2428179

Reaktionsgleichung

Reaktionsgleichung von HRID 2428179
Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[Cl:20])=[N:6][CH:7]=1.[Li]CCCC.[CH2:26]([O:28][C:29]([C:31]1[C@@H:32]2[N:47]([CH3:48])[C@H:36]([CH2:37][C:38]=1OS(C(F)(F)F)(=O)=O)[CH2:35][N:34]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:33]2)=[O:30])[CH3:27].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([O:28][C:29]([C:31]1[C@@H:32]2[N:47]([CH3:48])[C@H:36]([CH2:37][C:38]=1[C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]3[C:17]([Cl:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[Cl:20])=[CH:4][CH:3]=1)[CH2:35][N:34]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:33]2)=[O:30])[CH3:27]

Komponenten

8

Edukt 4

HCID 25517Ammonium ChlorideHCID 44158352(rac.)-(1R*,5S*)-9-Methyl-7-trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl esterHCID 448166685-Bromo-2-(2-(2,6-dichloro-4-methylphenoxy)ethoxy)pyridineHCID 178418339Butyllithium

Produkt 1

HCID 131728972(rac.)-(1R*,5S*)-7-{6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-pyridin-3-yl}-9-methyl-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic Acid 3-tert-butyl Ester 6-ethyl EsterAusbeute 52,3 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 3007855ZincchlorideKatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
-78 °C

Versuchsvorschrift

A sol. of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridine (790 mg, 2.10 mmol) in THF (18 mL) was cooled to −78° C. BuLi (1.6M in hexane, 2.65 mL, 4.20 mmol) was added. The mixture was stirred at −78° C. for 1 h, and ZnCl2 (1M in THF, 6.30 mL, 6.30 mmol) was added. The mixture was allowed to warm to rt. A sol. of (rac.)-(1R*,5S*)-9-methyl-7-trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (WO 2003/093267; 641 mg, 1.40 mmol) in THF (3.00 mL), and then Pd(PPh3)4 (40 mg, 0.035 mmol) were added. The mixture was rapidly heated to 55° C., and was stirred at this temperature for 20 min. The mixture was allowed to cool to rt, and aq. sat. NH4Cl was added. The solvents were partially removed under reduced pressure, and the rest was diluted with EtOAc. This mixture was washed with water. The aq. layer was extracted back with EtOAc (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:3→EtOAc) yielded the title compound (444 mg, 52%). LC-MS: tR=0.94 min; ES+: 606.28.

Aufarbeitung

  1. temperatureto warm to rt
  2. temperatureThe mixture was rapidly heated to 55° C.
  3. stirringwas stirred at this temperature for 20 min
  4. temperatureto cool to rt
  5. customThe solvents were partially removed under reduced pressure
  6. additionthe rest was diluted with EtOAc
  7. washThis mixture was washed with water
  8. extractionThe aq. layer was extracted back with EtOAc (3×)
  9. dry with materialextracts were dried over MgSO4
  10. filtrationfiltered
  11. customthe solvents were removed under reduced pressure
  12. customPurification of the crude by FC (EtOAc/heptane 1:3→EtOAc)

Quellen und Nachweise

ORD-Eintrag
ord-4940696d440c44059a3070c35355dbda
Quelldatensatz
uspto-grants-2011_06
Patentnummer
US07968720B2

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