1,2-Dichloroethane → 1-(3-Fluoro-4-(5-(1-phenylcyclobutyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid

HRID 1177501Notes

Reaction equation

HRID 1177501 reaction equation
FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:4].C(C1C=CC=[C:22]([C:26]([CH3:29])([CH3:28])C)[N:21]=1)(C)(C)C.[F:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[C:38]1[S:39][C:40]2[C:45]([N:46]=1)=[CH:44][CH:43]=[C:42]([C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[CH2:48])[N:41]=2.[OH2:55].Cl[CH2:57][CH2:58]Cl>>[F:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][C:32]=1[C:38]1[S:39][C:40]2[C:45]([N:46]=1)=[CH:44][CH:43]=[C:42]([C:47]1([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:58][CH2:57][CH2:48]1)[N:41]=2)[CH2:37][N:21]1[CH2:22][CH:26]([C:28]([OH:4])=[O:55])[CH2:29]1

Participants

6

Reactant 5

HCID 111,2-Dichloroethane2×HCID 962Water2×HCID 67749Trifluoromethanesulfonic anhydrideHCID 685102,6-Di-tert-butylpyridineHCID 591748892-(2-Fluoro-4-methylphenyl)-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine

Product 1

HCID 445990241-(3-Fluoro-4-(5-(1-phenylcyclobutyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid

Conditions

Temperature
-17 °C

Procedure

A solution of N,Ndimethylacetamide (0.320 mL, 3.46 mmol) in 30 mL anhyd. 1,2-DCE in a 3-neck flask under argon fitted with addition funnel was cooled to −17° C. with ice/salt. Trifluoromethanesulfonic anhydride (0.679 mL, 4.04 mmol) was added over 2 min by syringe, and the reaction mixture became yellow and the temperature rose to −13° C. After 5 min, a solution of 2,6-di-tert-butylpyridine (0.893 mL, 4.04 mmol) and 2-(2-fluoro-4-methylphenyl)-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine (1.00 g, 2.89 mmol) in 15 mL DCE was added slowly dropwise via addition funnel over 10 min. The reaction was fitted with a water-cooled reflux condenser and placed in a 110° C. oil bath. After 1 h, the reaction mixture was allowed to cool to ambient temperature overnight. 45 mL water was added and the reaction mixture reheated to 110° C. After 7 h, the reaction mixture was cooled, layers separated, and the aqueous layer was extracted with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated. The crude material was adsorbed onto 5 g silica gel and purify by silica gel chromatography, 0-100% EA/hexanes to give a yellow solid containing the desired product. This was further purified by trituration with diethyl ether to give 3-(2-(2-fluoro-4-methylphenyl)-thiazolo[5,4-b]pyridine-5-yl)-3-phenylcyclobutanone as a light yellow solid. MS (ESI) m/z: calculated: 388.1; Observed: 389.1 (M++1).

Workup

  1. customrose to −13° C
  2. temperaturecooled
  3. temperaturereflux condenser
  4. customplaced in a 110° C.
  5. waitAfter 1 h
  6. temperatureto cool to ambient temperature overnight
  7. customreheated to 110° C
  8. waitAfter 7 h
  9. temperaturethe reaction mixture was cooled
  10. customlayers separated
  11. extractionthe aqueous layer was extracted with DCM
  12. dry with materialThe combined organics were dried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated
  15. custompurify by silica gel chromatography, 0-100% EA/hexanes
  16. customto give a yellow solid

Sources & evidence

ORD record
ord-9946dd17fd534219a748d5dbc568f014
Source dataset
uspto-grants-2010_11
Patent number
US07842685B2

Reaction notes

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