Hydrochloric Acid → ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate

HRID 561194Notes

Reaction equation

HRID 561194 reaction equation
[N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[N:8][N:7]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>CN(C=O)C>[F:25][C:24]([F:27])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:14]1[CH2:13][CH2:12][N:11]([C:9]2[S:10][C:6]([C:5]3[N:1]=[N:2][N:3]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:4]=3)=[N:7][N:8]=2)[CH2:16][CH2:15]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 7748Ethyl bromoacetateHCID 24758Sodium hydrideHCID 159806391-[5-(2H-Tetrazol-5-yl)-1,3,4-thiadiazol-2-yl}-4-[2-(trifluoromethyl)phenoxy]piperidine

Product 1

HCID 86620455ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 1-[5-(2H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]-4-[2-(trifluoromethyl)phenoxy]piperidine (262 mg, 0.66 mmol) in DMF (5 mL) was treated with NaH (60% in oil) (42 mg, 1.05 mmol) at −78° C. The mixture was warmed to 0° C. and, after 10 min, ethyl bromoacetate (150 μL, 1.35 mmol) was added dropwise. The final reaction mixture was warmed and stirred at room temperature until TLC indicated disappearance of the starting material. The reaction mixture was poured into aqueous 1 N HCl, extracted with EtOAc and washed with brine. The organic layer was dried (Na2SO4) and filtered. Solvents were removed in vacuo to afford the crude product, which was purified by column chromatography on silica gel (eluting with 10-50% EtOAc/hexanes) to afford ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate as the more polar regioisomer, Rf=0.2 (50% EtOAc/hexanes). 1H NMR (400 MHz, acetone-d6): δ7.70-7.61 (m, 2H), 7.40 (d, 1H), 7.14 (t, 1H), 5.81 (s, 2H), 5.10-5.04 (m, 1H), 4.31 (q, 2H), 3.94-3.85 (m, 2H), 3.86-3.77 (m, 2H), 2.29-2.20 (m, 2H), 2.11-2.03 (dd, 2H), 1.31 (t, 3H).

Workup

  1. customThe final reaction mixture
  2. temperaturewas warmed
  3. extractionextracted with EtOAc
  4. washwashed with brine
  5. dry with materialThe organic layer was dried (Na2SO4)
  6. filtrationfiltered
  7. customSolvents were removed in vacuo
  8. customto afford the crude product, which
  9. customwas purified by column chromatography on silica gel (eluting with 10-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-1a94afc4679d47968befad5db89bef54
Source dataset
uspto-grants-2011_11
Patent number
US08063224B2

Reaction notes

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