Sodium Carbonate → (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate

HRID 718342Notes

Reaction equation

HRID 718342 reaction equation
Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:29][O:30][C:31]1[CH:47]=[CH:46][CH:45]=[CH:44][C:32]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:32]3[CH:44]=[CH:45][CH:46]=[CH:47][C:31]=3[O:30][CH3:29])=[CH:40][CH:39]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 16218049(4-((2-Methoxybenzyl)oxy)phenyl)boronic acidHCID 118314215Ethyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate

Product 1

HCID 118314208(S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetateYield 68.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0433 g, 0.095 mmol), (4-((2-methoxybenzyl)oxy)phenyl)boronic acid (0.037 g, 0.143 mmol) and 2M Na2CO3 (0.119 ml, 0.238 mmol) in DMF (2 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (10.99 mg, 9.51 μmol) was added, degassed for 5 min and placed in a oil bath pre-heated to 110° C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.038 g, 0.065 mmol, 67.9% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.51 (dd, J=1.6, 7.4 Hz, 1H), 7.34 (dt, J=1.7, 7.8 Hz, 1H), 7.15-7.18 (m, 1H), 7.04-7.10 (m, 3H), 7.01 (dt, J=0.9, 7.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.03 (br. s., 1H), 5.17-5.25 (m, 2H), 4.23-4.31 (m, 1H), 4.19 (qd, J=7.1, 10.7 Hz, 1H), 3.91 (s, 3H), 3.05-3.28 (m, 1H), 2.87 (br. s., 1H), 2.66 (br. s., 3H), 2.28 (br. s., 3H), 1.95-2.15 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.20 (s, 9H), 0.9 (br.s., 3H), 0.68 (br. s., 3H). 5H of piperidine were not resolved. LCMS (M+H)=589.4.

Workup

  1. customwas degassed for 10 min
  2. customdegassed for 5 min
  3. customplaced in a oil bath
  4. temperaturecooled
  5. custompurified by pre-HPLC

Sources & evidence

ORD record
ord-515ac8aaf5da40e58de821dab631a621
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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