Triphenylphosphine → (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate

HRID 718348Notes

Reaction equation

HRID 718348 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][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[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][CH2:44][CH2:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 11776Triphenylphosphine2×HCID 5462977Diethyl azodicarboxylate2×HCID 137472413-(4-Fluorophenyl)propan-1-ol2×HCID 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 118314213(S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetateYield 68.2%

Reagents, catalysts & solvents 1

HCID 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 (0.04 g, 0.085 mmol), 3-(4-fluorophenyl)propan-1-ol (0.066 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, cold bath was removed and stirred overnight (13 h) at rt. LCMS at this point showed presence of about 50% unreacted phenol. So, added additional 3-(4-fluorophenyl)propan-1-ol (0.066 g, 0.427 mmol), Ph3P (0.067 g, 0.256 mmol) and DEAD (0.041 ml, 0.256 mmol) at r. After stirring for 5 h, reaction mixture was concentrated and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(3-(4-fluorophenyl)propoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0351 g, 0.058 mmol, 68.0% yield) as glassy solid. 1H NMR (500 MHz, CDCl3) δ 7.14-7.23 (m, 3H), 7.06-7.09 (m, 1H), 6.95-7.03 (m, 4H), 6.09 (s, 1H), 4.27 (qd, J=7.1, 10.8 Hz, 1H), 4.18 (qd, J=7.1, 10.7 Hz, 1H), 3.99-4.07 (m, 2H), 3.19 (d, J=12.0 Hz, 1H), 2.88 (t, J=12.3 Hz, 1H), 2.82-2.91 (t, J=7.6 Hz, 2H), 2.61 (s, 3H), 2.28 (d, J=12.0 Hz, 1H), 2.21 (s, 3H), 2.11-2.18 (m, 2H), 2.06 (t, J=11.5 Hz, 1H), 1.56 (dt, J=3.9, 12.6 Hz, 1H), 1.38 (dt, J=3.6, 12.7 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.18-1.21 (m, 1H), 1.08 (d, J=12.1 Hz, 1H), 0.91 (s, 3H), 0.66 (s, 3H). LCMS (M+H)=605.3.

Workup

  1. customcold bath was removed
  2. stirringAfter stirring for 5 h
  3. customreaction mixture
  4. concentrationwas concentrated
  5. custompurified by prep-HPLC

Sources & evidence

ORD record
ord-b867c0dd1bbb482ea8f3a5bb6e269ce9
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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