Hydrochloric Acid → (S)-2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid

HRID 718470Notes

Reaction equation

HRID 718470 reaction equation
[OH-].[K+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][C:24]([C:28]#[N:29])([CH3:27])[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:34][CH:35]=2)[C:20]=1[N:21]1[CH2:22][CH2:23][C:24]([C:28]#[N:29])([CH3:27])[CH2:25][CH2:26]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 118307880(S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate

Product 1

HCID 118307816(S)-2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acidYield 19.2%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
90 °C

Procedure

The potassium hydroxide (213 mg, 3.8 mmol) was added to a (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (233 mg, 0.38 mmol) in ethanol (4 mL) and stirred for 6 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid 41.8 mg (19%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.35 (m, 2H), 7.19 (d, J=7.3 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 7.07-7.05 (m, 1H), 7.01-6.99 (m, 2H), 5.61 (s, 1H), 4.27-4.23 (m, 1H), 4.19-4.15 (m, 1H), 3.51 (br. s, 4H), 3.04 (t, J=6.6 Hz, 2H), 2.48 (s, 3H), 2.05 (s, 3H), 1.73-1.59 (m, 3H), 1.39-1.35 (m, 1H), 1.26 (s, 3H), 1.12 (s, 9H). UPLC (M+H)=574.5.

Workup

  1. extractionextracted with EtOAc
  2. washthe organic layer was washed with brine
  3. dry with materialdried (MgSO4)
  4. customThe crude material was purified by prep HPLC

Sources & evidence

ORD record
ord-5bb5a876cac64062971af4562f92b87e
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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