Nitrogen → (rac.)-(1R*,5S*)-7-{6-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-pyridin-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic Acid 3,9-di-tert-butyl Ester 6-methyl Ester

HRID 2428188Notes

Reaction equation

HRID 2428188 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:10]([CH2:11][C:12]=1OS(C(F)(F)F)(=O)=O)[CH2:9][N:8]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:7]2)=[O:4].[Cl:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=1[C:45]1[CH:49]=[C:48]([CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55](B3OC(C)(C)C(C)(C)O3)=[CH:54][N:53]=2)[O:47][N:46]=1.N#N>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.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>[CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C@H:10]([CH2:11][C:12]=1[C:55]1[CH:54]=[N:53][C:52]([O:51][CH2:50][C:48]3[O:47][N:46]=[C:45]([C:38]4[C:39]([F:44])=[CH:40][CH:41]=[C:42]([F:43])[C:37]=4[Cl:36])[CH:49]=3)=[CH:57][CH:56]=1)[CH2:9][N:8]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:7]2)=[O:4]

Participants

8

Reactant 3

HCID 947NitrogenHCID 671487962-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridineHCID 131728979(rac.)-(1R*,5S*)-7-Trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl ester

Product 1

HCID 131728978(rac.)-(1R*,5S*)-7-{6-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-pyridin-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic Acid 3,9-di-tert-butyl Ester 6-methyl EsterYield 73%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
80 °C

Procedure

(rac.)-(1R*,5S*)-7-Trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl ester (WO 2006/021402, 4.72 g, 8.90 mmol) and 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (5.77 g crude, about 13.4 mmol) were dissolved in a mixture of DME (59.3 mL) and aq. 2M Na2CO3 (44.5 mL). The mixture was degassed with N2, and Pd(PPh3)4 (514 mg, 0.445 mmol) was added. The mixture was heated rapidly to 80° C., and was stirred at this temperature for 1 h. The mixture was diluted with EtOAc (100 mL), and washed with water (100 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc 100%→EtOAc/MeOH 95:5) yielded the title compound (4.56 g, 73%). LC-MS: tR=1.15 min, ES+: 703.25.

Workup

  1. additionwas added
  2. washwashed with water (100 mL)
  3. dry with materiallayer was dried over MgSO4
  4. filtrationfiltered
  5. customthe solvents were removed under reduced pressure
  6. customPurification of the crude by FC (EtOAc 100%→EtOAc/MeOH 95:5)

Sources & evidence

ORD record
ord-424d602ee6b34dcab5e37c9aa19aab48
Source dataset
uspto-grants-2011_06
Patent number
US07968720B2

Reaction notes

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