Tetrabutylammonium Fluoride → 3-{4-[2-(4-Chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-fluoro-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester

HRID 2384912Notes

Reaction equation

HRID 2384912 reaction equation
[Al](C)(C)C.CO[C:7]([C:9]1[S:10][C:11]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:12][C:13]=1[C:14]#[C:15][Si](C)(C)C)=[O:8].[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][C:40]=2[F:46])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:15]=[CH:14][C:13]4[CH:12]=[C:11]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)[S:10][C:9]=4[C:7]3=[O:8])=[CH:41][C:40]=2[F:46])[CH2:37]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]

Participants

7

Reactant 4

HCID 2724141Tetrabutylammonium FluorideHCID 16682925TrimethylaluminumHCID 689531643-(4-Amino-2-fluoro-phenoxy)-azetidine-1-carboxylic acid tert-butyl esterHCID 68953726HCID 68953726, compound

Product 1

HCID 689499923-{4-[2-(4-Chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-fluoro-phenoxy}-azetidine-1-carboxylic acid tert-butyl esterYield 80.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Add 2.0 M Al(CH3)3 (1.28 mL, 2.56 mmol) to a suspension of 5-(4-chloro-phenyl)-3-trimethylsilanylethynyl-thiophene-2-carboxylic acid methyl ester (0.851 g, 2.44 mmol) and 3-(4-amino-2-fluoro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.688 g, 2.44 mmol) in toluene (20 mL). Stir the reaction at 60° C. for 4 h. Cool the mixture to 0° C., quench with 2.0 M NaOH (5 mL) and water (20 mL) and then extract with CHCl3 (3×50 mL). Dry with Na2SO4, filter, and concentrate. Dissolve the crude material in THF (50 mL), treat with 1.0 M TBAF (2.93 mL, 2.93 mmol) and stir at RT overnight. Dilute with EtOAc (100 mL), wash with water (3×40 mL), dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 5% CH3OH/CHCl3 to give 1.03 g (80%) of the title compound. LC-MS/ES m/z (35Cl) 526.9 [M+H]+.

Workup

  1. customthe reaction at 60° C. for 4 h
  2. customquench with 2.0 M NaOH (5 mL) and water (20 mL)
  3. extractionextract with CHCl3 (3×50 mL)
  4. dry with materialDry with Na2SO4
  5. filtrationfilter
  6. concentrationconcentrate
  7. dissolutionDissolve the crude material in THF (50 mL)
  8. stirringstir at RT overnight
  9. washwash with water (3×40 mL)
  10. dry with materialdry with Na2SO4
  11. filtrationfilter
  12. concentrationconcentrate
  13. customPurify the crude material by chromatography
  14. washeluting with 5% CH3OH/CHCl3

Sources & evidence

ORD record
ord-c38b57c8986640fab0651cadacb0c944
Source dataset
uspto-grants-2012_09
Patent number
US08263772B2

Reaction notes

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