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

HRID 718452Notes

Reaction equation

HRID 718452 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].[Cl:35][C:36]1[S:37][C:38]([CH2:41]O)=[CH:39][N:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.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:27]=[CH:28][C:29]([O:32][CH2:41][C:38]3[S:37][C:36]([Cl:35])=[N:40][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]

Participants

8

Reactant 5

HCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 2763180(2-Chloro-1,3-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 118307753(2S)-2-tert-butoxy-2-[5-[4-[(2-chlorothiazol-5-yl)methoxy]phenyl]-4-(4,4-dimethyl-1-piperidyl)-2,6-dimethyl-3-pyridyl]acetic acidYield 3%

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), (2-chlorothiazol-5-yl)methanol (23.94 mg, 0.160 mmol) and Ph3P-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-(5-(4-((2-chlorothiazol-5-yl)methoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (0.9 mg, 1.573 μmol, 2.95% yield). 1H NMR (400 MHz, METHANOL-d4) δ 7.69 (s, 1H), 7.37-7.32 (m, 1H), 7.24-7.17 (m, 2H), 7.16-7.10 (m, 1H), 5.55 (s, 1H), 5.42 (s, 2H), 2.68 (s, 3H), 2.28 (s, 3H), 1.36 (br. s., 3H), 1.31 (br. s., 1H), 1.20 (s, 9H), 0.84 (s, 6H). 4H of piperidine were not resolved. LCMS (M+H)=572.5.

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-747023a4bcb5446c9b40652b1a8df43c
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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