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

HRID 718343Notes

Reaction equation

HRID 718343 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].[F:29][C:30]1[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=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]=[C:30]([F:29])[CH:31]=3)=[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 16218125(4-((3-Fluorobenzyl)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 118314209(S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((3-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetateYield 64.9%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0443 g, 0.097 mmol), (4-((3-fluorobenzyl)oxy)phenyl)boronic acid (0.036 g, 0.146 mmol) and 2M Na2CO3 (0.122 ml, 0.243 mmol) in DMF 92 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.011 g, 9.73 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-((3-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0361 g, 0.063 mmol, 64.3% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.39 (dt, J=5.8, 7.9 Hz, 1H), 7.24-7.27 (m, 1H), 7.22 (dd, J=2.1, 9.5 Hz, 1H), 7.17-7.20 (m, 1H), 7.02-7.10 (m, 4H), 6.03 (br. s., 1H), 5.12-5.20 (m, 2H), 4.23-4.31 (m, 1H), 4.19 (qd, J=7.1, 10.7 Hz, 1H), 3.06-3.28 (m, 1H), 2.85 (br. s., 1H), 2.65 (br. s., 3H), 2.26 (br. s., 3H), 1.96-2.11 (m, 1H), 1.27 (t, J=7.1 Hz, 4H), 1.20 (s, 9H), 0.90 (br.s., 3H), 0.66 (br. s., 3H). 5H of piperidine were not resolved. LCMS (M+H)=577.4.

Workup

  1. customwas degassed for 10 min
  2. customdegassed for 5 min
  3. customplaced in a oil bath
  4. temperaturepre-heated to 110 C
  5. temperaturecooled
  6. custompurified by pre-HPLC

Sources & evidence

ORD record
ord-09eac1b239904d5ab0983b845a69d181
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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