Sodium Hydroxide → (2S)-2-tert-butoxy-2-[4-(4,4-dimethyl-1-piperidyl)-2,6-dimethyl-5-[4-[(4-methyl-2-phenyl-thiazol-5-yl)methoxy]phenyl]-3-pyridyl]acetic acid

HRID 718451

Reaction equation

HRID 718451 reaction equation
[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[N:37]=[C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][C:40]=1[CH2:41]O.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:41][C:40]3[S:39][C:38]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[N:37][C:36]=3[CH3:35])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]

Participants

7

Reactant 4

HCID 14798Sodium HydroxideHCID 736541(4-Methyl-2-phenyl-thiazol-5-yl)-methanolHCID 5462977Diethyl azodicarboxylateHCID 118314205(S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate

Product 1

HCID 118307815(2S)-2-tert-butoxy-2-[4-(4,4-dimethyl-1-piperidyl)-2,6-dimethyl-5-[4-[(4-methyl-2-phenyl-thiazol-5-yl)methoxy]phenyl]-3-pyridyl]acetic acidYield 34.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), (4-methyl-2-phenylthiazol-5-yl)methanol (32.9 mg, 0.160 mmol) and Ph3-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DEAD (0.025 mL, 0.160 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-((4-methyl-2-phenylthiazol-5-yl)methoxy)phenyl)pyridin-3-yl)acetic acid (11.6 mg, 0.018 mmol, 34.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.89 (d, J=7.3 Hz, 2H), 7.52-7.41 (m, 4H), 7.25 (d, J=8.1 Hz, 1H), 7.14 (t, J=7.9 Hz, 2H), 7.10-7.04 (m, 1H), 5.82 (br. s., 1H), 5.41 (q, J=12.8 Hz, 2H), 3.26 (d, J=11.7 Hz, 1H), 2.77 (br. s., 1H), 2.47 (s, 3H), 2.43 (s, 3H), 2.15 (d, J=10.3 Hz, 1H), 2.07 (s, 3H), 1.88 (br. s., 1H), 1.46 (br. s., 1H), 1.24 (br. s., 1H), 1.15 (br. s., 1H), 1.12 (s, 9H), 0.92 (d, J=10.3 Hz, 1H), 0.77 (br. s., 3H), 0.51 (br. s., 3H). LCMS (M+H)=628.6.

Workup

  1. filtrationmixture was filtered
  2. customto remove polymer
  3. concentrationconcentrated
  4. temperatureMixture was then cooled
  5. custompurified by prep-HPLC

Sources & evidence

ORD record
ord-2245934141eb47fe8e24213d3e3d7674
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Linked notes

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