5-Bromo-2-(2-(2,6-dichloro-4-methylphenoxy)ethoxy)pyridine → (rac.)-(1R*,5S*)-3-{6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-pyridin-3-yl}-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl Ester

HRID 2428187

反応式

HRID 2428187 の反応式
[Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[Cl:25])=[N:11][CH:12]=1.[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:34]([CH2:35][C:36]=1OS(C(F)(F)F)(=O)=O)[CH2:33][CH2:32]2)=[O:29]>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>[CH3:26][O:27][C:28]([C:30]1[C@@H:31]2[N:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:34]([CH2:35][C:36]=1[C:7]1[CH:12]=[N:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[Cl:25])=[CH:9][CH:8]=1)[CH2:33][CH2:32]2)=[O:29]

参加物

7

反応物 3

HCID 448166685-Bromo-2-(2-(2,6-dichloro-4-methylphenoxy)ethoxy)pyridineHCID 131728966(rac.)-(1R*,5S*)-3-Trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl EsterHCID 178418339Butyllithium

生成物 1

HCID 131728977(rac.)-(1R*,5S*)-3-{6-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-pyridin-3-yl}-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl Ester収率 78.3%

試薬・触媒・溶媒 3

HCID 3007855Zincchloride触媒HCID 178418397HCID 178418397、化合物触媒HCID 8028Tetrahydrofuran溶媒3 回

反応条件

温度
-78 °C

実験手順

BuLi (1.6 M in hexane, 12.0 mL, 19.2 mmol) was added to the sol. of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridine (5.45 g, 14.4 mmol) in THF (120 mL) at −78° C. The mixture was stirred at −78° C. for 60 min, and ZnCl2 (1M in THF, 28.9 mL, 28.9 mmol) was added. The mixture was allowed to warm up to rt, and compound A1 (4.00 g, 9.63 mmol) in dry THF (50 mL) and Pd(PPh3)4 (277 mg, 0.240 mmol) in THF (2 mL) were added. The mixture was heated to 70° C. for 1 h, and was quenched with aq. sat. NH4Cl (70 mL). The mixture was extracted with EtOAc (3×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of crude by FC(CH2Cl2/MeOH 99:1→98:2→97:3→96:4→95:5) yielded the title compound (4.25 g, 78%). LC-MS: tR=1.16 min; ES+: 563.11.

後処理

  1. temperatureto warm up to rt
  2. temperatureThe mixture was heated to 70° C. for 1 h
  3. customwas quenched with aq. sat. NH4Cl (70 mL)
  4. extractionThe mixture was extracted with EtOAc (3×)
  5. dry with materiallayers were dried over MgSO4
  6. filtrationfiltered
  7. customthe solvents were removed under reduced pressure
  8. customPurification of crude by FC(CH2Cl2/MeOH 99:1→98:2→97:3→96:4→95:5)

出典と根拠

ORDレコード
ord-50de53571be8418896785652447dc2da
出典データセット
uspto-grants-2011_06
特許番号
US07968720B2

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