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

반응식

HRID 2428179 반응식
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]

참가 물질

8

반응물 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

생성물 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 Ester수율 52.3%

시약·촉매·용매 3

HCID 3007855Zincchloride촉매HCID 178418397HCID 178418397, 화합물촉매HCID 8028Tetrahydrofuran용매2회

반응 조건

온도
-78 °C

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-4940696d440c44059a3070c35355dbda
출처 데이터셋
uspto-grants-2011_06
특허 번호
US07968720B2

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