Sodium Hydroxide → 2-Tert-butoxy-2-[4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(3-phenylphenyl)-5,7-dihydro-1,6-naphthyridin-3-yl]acetic acid

HRID 470940Notes

Reaction equation

HRID 470940 reaction equation
[C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:16][C:15]([CH3:18])([CH3:17])[C:14]3[N:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]([CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24])=[C:10]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:9]=3[CH2:8]2)[CH:2]=1.O.[OH-].[Li+].[OH-].[Na+]>>[C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:16][C:15]([CH3:18])([CH3:17])[C:14]3[N:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]([CH:22]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])[C:23]([OH:25])=[O:24])=[C:10]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:9]=3[CH2:8]2)[CH:2]=1

Participants

4

Reactant 3

HCID 14798Sodium HydroxideHCID 168937Lithium hydroxide, monohydrateHCID 86692196Methyl 2-(6-([1,1'-biphenyl]-3-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate2×

Product 1

HCID 717117452-Tert-butoxy-2-[4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(3-phenylphenyl)-5,7-dihydro-1,6-naphthyridin-3-yl]acetic acidYield 42.5%

Conditions

Temperature
70 °C

Procedure

A mixture of methyl 2-(6-([1,1′-biphenyl]-3-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (intermediate 8) (10 mg, 0.017 mmol), lithium hydroxide monohydrate (2.12 mg, 0.05 mmol) and 1N NaOH (0.17 mL) were stirred at 70° C. for 16 h. The mixture was then filtered and purified by preparative HPLC (10% CH3CN/90% H2O/0.1% CF3CO2H, Xterra 19×100 mm, C18, 5 μm column) to give 2-(6-([1,1′-biphenyl]-3-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetic acid (4.2 mg, 41% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 7.62-7.47 (m, 3H), 7.46-7.38 (m, 3H), 7.38-7.29 (m, 3H), 7.26 (t, J=7.9 Hz, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.96 (s, 1H), 6.77 (dd, J=8.2, 1.5Hz, 1H), 4.92 (d, br. s., 1H), 4.07 (d, J=15.6 Hz, 1H), 3.71 (d, J=15.6 Hz, 1H), 3.63 (dt, J=12.8, 6.4 Hz, 1H), 3.49 (d, J=12.5Hz, 1H), 3.37 (br. s., 1H), 1.48 (d, J=3.7 Hz, 6H), 1.32 (d, J=6.4 Hz, 3H), 1.20 (d, J=6.7 Hz, 3H), 1.01 (s, 9H). 19F NMR (500 MHz, CD3OD) δ ppm −115.74. LCMS (M+H) calcd for C37H42FN2O3: 581.3. found: 581.5.

Workup

  1. filtrationThe mixture was then filtered
  2. custompurified by preparative HPLC (10% CH3CN/90% H2O/0.1% CF3CO2H, Xterra 19×100 mm, C18, 5 μm column)

Sources & evidence

ORD record
ord-37cd7cbff4b449e9a70db2b2f5347e9d
Source dataset
uspto-grants-2014_01
Patent number
US08629276B2

Reaction notes

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