Cesium carbonate → 1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidine-4-carboxylic Acid

HRID 1807460Notes

Reaction equation

HRID 1807460 reaction equation
[OH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:23]1[S:24][C:25]2[C:30]([N:31]=1)=[CH:29][CH:28]=[CH:27][N:26]=2.C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[K+]>CN(C=O)C.C(O)(C)C.O>[N:31]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[S:24][C:23]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[CH:20][CH:21]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 14797Potassium HydroxideHCID 133428032-Chloro-[1,3]thiazolo[5,4-b]pyridineHCID 57448391Ethyl 1-[2-(4-hydroxyphenoxy)ethyl]piperidine-4-carboxylate

Product 1

HCID 574483201-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidine-4-carboxylic AcidYield 39%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3776IsopropanolSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of ethyl 1-[2-(4-hydroxyphenoxy)ethyl]piperidine-4-carboxylate (400 mg, 1.37 mmol) and 2-chloro[1,3]thiazolo[5,4-b]pyridine (231 mg, 1.37 mmol) in DMF (6 mL) was added Cs2CO3 (887 mg, 2.73 mmol). The resultant dark red-orange suspension was stirred at rt for 1 h. The reaction mixture was concentrated, and the residue re-dissolved in CH2Cl2 (10 mL) and filtered. To a solution of this crude material in isopropyl alcohol was added 1 N KOH (1 equiv.). The mixture was allowed to stir at rt for 2 h and then poured into water and basified to pH 9. The resultant solution was extracted with a 1:1 solution of CHCl3/isopropyl alcohol. The combined organic extracts were dried, filtered, and concentrated to afford the title compound (39% over two steps). 1H NMR (400 MHz, DMSO-d6): 8.43 (dd, J=4.8, 1.5, 1H), 8.07 (dd, J=8.2, 1.5, 1H), 7.50 (dd, J=8.2, 4.8, 1H), 7.44-7.34 (m, 2H), 7.10-7.04 (m, 2H), 4.11 (t, J=5.8, 2H), 2.94-2.82 (m, 2H), 2.70 (t, J=5.8, 2H), 2.27-2.15 (m, 1H), 2.15-2.04 (m, 2H), 1.85-1.71 (m, 2H), 1.64-1.47 (m, 2H). MS (ESI): mass calcd. for C20H21N3O4S, 399.13; m/z found, 400.1 [M+H]+.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionthe residue re-dissolved in CH2Cl2 (10 mL)
  3. filtrationfiltered
  4. stirringto stir at rt for 2 h
  5. extractionThe resultant solution was extracted with a 1:1 solution of CHCl3/isopropyl alcohol
  6. customThe combined organic extracts were dried
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-c1b76a46b58e42a894d5fdba6e2e6daa
Source dataset
uspto-grants-2013_01
Patent number
US08357684B2

Reaction notes

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