Triphenylphosphine → (S)-2-(tert-butoxy)-2-(5-(4-(2,4-difluorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid

HRID 718437Notes

Reaction equation

HRID 718437 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](O)=[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].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][OH:45].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:45][CH2:44][CH2:43][C:37]3[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=3[F:35])=[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])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 5

HCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 5462977Diethyl azodicarboxylateHCID 534034612-(2,4-Difluorophenyl)ethanolHCID 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 118307768(S)-2-(tert-butoxy)-2-(5-(4-(2,4-difluorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acidYield 34.9%

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 (20 mg, 0.043 mmol), 2-(2,4-difluorophenyl)ethanol (33.7 mg, 0.213 mmol) and Ph3P-resin (33.6 mg, 0.128 mmol) in THF (2 mL) was added DEAD (0.020 mL, 0.128 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 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-(2,4-difluorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (8.6 mg, 0.015 mmol, 34.7% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.53-7.45 (m, 1H), 7.28-7.15 (m, 2H), 7.11-6.90 (m, 4H), 5.82 (s, 1H), 4.31-4.18 (m, 2H), 3.08 (t, J=6.6 Hz, 2H), 2.84-2.76 (m, 1H), 2.43 (s, 3H), 2.17 (d, J=10.6 Hz, 1H), 2.05 (s, 3H), 1.49 (br. s., 1H), 1.34-1.27 (m, 1H), 1.17 (d, J=12.5 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=12.8 Hz, 1H), 0.85 (s, 3H), 0.60 (s, 3H). LCMS (M+H)=581.5.

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-bc26d04351454879b7ca36b4d98811c2
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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