Tributylphosphine → (rac.)-(1R*,5S*)-3-{4-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-phenyl}-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl Ester

HRID 2428185Notes

Reaction equation

HRID 2428185 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:9]([CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:8][CH2:7]2)=[O:4].[Cl:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=1[C:36]1[CH:40]=[C:39]([CH2:41]O)[O:38][N:37]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:9]([CH2:10][C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:41][C:39]3[O:38][N:37]=[C:36]([C:29]4[C:30]([F:35])=[CH:31][CH:32]=[C:33]([F:34])[C:28]=4[Cl:27])[CH:40]=3)=[CH:16][CH:17]=1)[CH2:8][CH2:7]2)=[O:4]

Participants

6

Reactant 4

HCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 67148834HCID 67148834, compoundHCID 131728967(rac.)-(1R*,5S*)-3-(4-Hydroxy-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl Ester

Product 1

HCID 131728975(rac.)-(1R*,5S*)-3-{4-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-phenyl}-8-aza-bicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic Acid 8-tert-butyl Ester 2-methyl EsterYield 99.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A mixture of compound B4 (6.80 g, 18.9 mmol), [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-yl]-methanol (6.97 g, 28.3 mmol), ADDP (9.55 g, 37.8 mmol) and PBu3 (85%, 13.8 mL, 56.6 mmol) in toluene (280 mL) was heated to reflux for 1 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:1) yielded the title compound (11.0 g, 99%). LC-MS: tR=1.14 min; ES+: 587.30.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 1 h
  3. customthe solvents were removed under reduced pressure
  4. customPurification of the residue by FC (EtOAc/heptane 1:1)

Sources & evidence

ORD record
ord-ca56c8ed7e654a4888eff9e891bd0f5e
Source dataset
uspto-grants-2011_06
Patent number
US07968720B2

Reaction notes

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