Sodium Carbonate → (rac.)-(1R*,5S*)-7-{6-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-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 2428186Notes

Reaction equation

HRID 2428186 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C@@H:7]2[N:22]([CH3:23])[C@H:11]([CH2:12][C:13]=1OS(C(F)(F)F)(=O)=O)[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8]2)=[O:5])[CH3:2].[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1[C:40]1[CH:44]=[C:43]([CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][N:48]=2)[O:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([O:3][C:4]([C:6]1[C@@H:7]2[N:22]([CH3:23])[C@H:11]([CH2:12][C:13]=1[C:50]1[CH:49]=[N:48][C:47]([O:46][CH2:45][C:43]3[O:42][N:41]=[C:40]([C:33]4[C:34]([F:39])=[CH:35][CH:36]=[C:37]([F:38])[C:32]=4[Cl:31])[CH:44]=3)=[CH:52][CH:51]=1)[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8]2)=[O:5])[CH3:2]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 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 671487962-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

Product 1

HCID 131728976(rac.)-(1R*,5S*)-7-{6-[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-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 EsterYield 81.4%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

(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; 1.00 g, 2.18 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 (1.41 g, 3.27 mmol) were dissolved in DME (14.5 mL), and aq. 2M Na2CO3 (11.0 mL) was added. The mixture was degassed with N2 (5 min). Pd(PPh3)4 (126 mg, 0.109 mmol) was added, and the mixture was rapidly heated to 80° C. The mixture was stirred at this temperature for 1 h, and was allowed to cool to rt. The mixture was diluted with EtOAc (100 mL), and was 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(CH2Cl2/MeOH 95:5) yielded the title compound (1.12 g, 81%). LC-MS: tR=0.91 min; ES+: 631.34.

Workup

  1. customThe mixture was degassed with N2 (5 min)
  2. temperatureto cool to rt
  3. washwas washed with water (100 mL)
  4. dry with materiallayer was dried over MgSO4
  5. filtrationfiltered
  6. customthe solvents were removed under reduced pressure
  7. customPurification of the crude by FC(CH2Cl2/MeOH 95:5)

Sources & evidence

ORD record
ord-8fcea0fde9c547858f3300d88722485c
Source dataset
uspto-grants-2011_06
Patent number
US07968720B2

Reaction notes

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