Hydrochloric Acid → 4-(4-Chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylic acid

HRID 2402117Notes

Reaction equation

HRID 2402117 reaction equation
[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[F:25].O1CCCC1.[OH-].[Li+].Cl>O.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[F:25]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 66749173Ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate

Product 1

HCID 568327594-(4-Chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

In a 50 mL round bottom flask were combined ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (0.245 g, 0.000637 mol), tetrahydrofuran (5.49 mL, 0.0677 mol) and a solution of lithium hydroxide (2.0 M in water, 3.18 mL, 0.00637 mol). The mixture was heated at 80° C. with stirring for 2 days, and then cooled to room temperature and diluted with water. Reaction mixture was then carefully adjusted to pH 5 via addition of 1N HCl and transferred to a separatory funnel containing EtOAc (40 mL). Layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford a white solid, which was dissolved in DCM and adsorbed onto silica gel. Column chromatography (4 g column, gradient elution 0-20% MeOH in DCM) then afforded 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylic acid (118) (31 mg, 14%). LC/MS: (FA) ES+ 357, 359; NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 7.48 (t, 0.1=8.1, 1H), 7.24 (dd, J=1.9, 10.5, 1H), 7.08 (dd, J=1.5, 8.3, 1H), 4.24 (s, 2H), 3.71-3.62 (m, 4H), 3.46-3.38 (m, 4H).

Workup

  1. customIn a 50 mL round bottom flask were combined
  2. temperaturecooled to room temperature
  3. customReaction mixture
  4. customtransferred to a separatory funnel
  5. customLayers were separated
  6. extractionthe aqueous layer was extracted 2×30 mL with EtOAc
  7. washThe combined organic layers were washed 1× brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customto afford a white solid, which
  12. washColumn chromatography (4 g column, gradient elution 0-20% MeOH in DCM)

Sources & evidence

ORD record
ord-ae9de1e0cf904f92a352c85e7cbf223b
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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