5-Methoxy[1,3]thiazolo[5,4-b]pyridin-2-amine → (R)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-phenyl-propionamide

HRID 889595Notes

Reaction equation

HRID 889595 reaction equation
[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[N:24]=[C:23]2[S:25][C:26]([NH2:28])=[N:27][C:22]2=[CH:21][CH:20]=1>S(Cl)(Cl)=O.C1COCC1.N1C=CC=CC=1>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:28][C:26]2[S:25][C:23]3[C:22]([N:27]=2)=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[N:24]=3)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

6

Reactant 2

HCID 28015575-Methoxy[1,3]thiazolo[5,4-b]pyridin-2-amineHCID 44248629(R)-3-cyclopentyl-2-phenyl-propionic acid

Product 1

HCID 86625463(R)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-phenyl-propionamide

Reagents, catalysts & solvents 3

HCID 1049PyridineSolventHCID 8028TetrahydrofuranSolventHCID 24386Thionyl ChlorideSolvent

Conditions

Temperature
50 °C

Procedure

The title D compound, (R)-3-cyclopentyl-2-phenyl-propionic acid (1.66 g, 7.605 mmol) is dissolved in thionyl chloride (15 mL) and heated at 50° C. for 1.5 h. The reaction is then cooled to RT and concentrated to afford a yellow oil. This is dissolved in anhydrous THF (10 mL) and added dropwise to a solution of the title E compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (1.38 g, 7.605 mmol) in anhydrous pyridine (10 mL) at 0° C. The reaction is allowed to stir and warm to RT. After 2 h, the reaction is concentrated to remove the THF and most of the pyridine. The resulting brown oil is dissolved in ethyl acetate (250 mL)/1 N HCl (250 mL) and extracted further with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a brown oil. This is chromatographed over silica eluting with 5→60% ethyl acetate in hexanes to afford (R)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-phenyl-propionamide as a yellow foam: 1H NMR (400 MHz, DMSO-D6) 1.1 (m, 2 H) 1.4 (dd, J=7.2, 4.7 Hz, 2 H) 1.6 (m, 3 H) 1.7 (m, 3 H) 2.1 (m, 1 H) 3.9 (m, 4 H) 6.9 (d, J=8.8 Hz, 1 H) 7.3 (m, 1 H) 7.4 (m, 4 H) 8.0 (d, J=8.6 Hz, 1 H) 12.5 (s, 1 H); LC/MS 382.1 (M+1), 380.2 (M−1).

Workup

  1. temperatureThe reaction is then cooled to RT
  2. concentrationconcentrated
  3. customto afford a yellow oil
  4. temperaturewarm to RT
  5. concentrationthe reaction is concentrated
  6. customto remove the THF
  7. dissolutionThe resulting brown oil is dissolved in ethyl acetate (250 mL)/1 N HCl (250 mL)
  8. extractionextracted further with ethyl acetate
  9. dry with materialThe combined organic layer is dried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto afford the crude product as a brown oil
  13. customThis is chromatographed over silica eluting with 5→60% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-088c29ef6c4043d8b34b677715d11f49
Source dataset
uspto-grants-2012_08
Patent number
US08252931B2

Reaction notes

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