Acetic Acid → Methyl 2-tert-butoxy-2-(6-(4-fluorobenzyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate

HRID 470922Notes

Reaction equation

HRID 470922 reaction equation
[C:1]([O:5][CH:6]([C:11]1[C:12]([CH:30]([CH3:32])[CH3:31])=[N:13][C:14]2[C:15]([CH3:29])([CH3:28])[CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH:30]([CH3:32])[CH3:31])=[N:13][C:14]2[C:15]([CH3:29])([CH3:28])[CH2:16][N:17]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=3)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 176Acetic Acid2×HCID 680234-FluorobenzaldehydeHCID 5049666Sodium triacetoxyborohydride2×HCID 86692192Methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate2×

Product 1

HCID 86692195Methyl 2-tert-butoxy-2-(6-(4-fluorobenzyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetateYield 59.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol) and 4-fluorobenzaldehyde (0.048 mL, 0.452 mmol) was stirred in CH2Cl2 (1 mL) at 0° C. for 45 min. AcOH (2.59 μl, 0.045 mmol) was added followed by NaBH(OAc)3 (9.58 mg, 0.045 mmol). After stirring at 0° C. for an additional 5 min, the reaction mixture was stirred at room temperature for 22 h. Additional NaBH(OAc)3 (9.58 mg, 0.045 mmol) and AcOH (2.59 μl, 0.045 mmol) were added and the mixture was stirred for an additional 1 h. The mixture was quenched with satd NaHCO3 and the product was extracted with CH2Cl2, dried (Na2SO4), filtered and adsorbed onto silica gel. The product was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-tert-butoxy-2-(6-(4-fluorobenzyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (14.7 mg, 47% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.34 (ddd, J=2.14, 5.72, 8.32 Hz, 1H), 7.24-7.28 (m, 2H), 7.14-7.20 (m, 2H), 7.06-7.14 (m, 1H), 6.99 (t, J=8.70 Hz, 2H), 4.83 (s, 1H), 3.71 (s, 3H), 3.45-3.60 (m, 2H), 3.40 (d, J=13.43 Hz, 1H), 3.23 (d, J=15.26 Hz, 1H), 3.06 (d, J=15.26 Hz, 1H), 2.50 (d, J=10.99 Hz, 1H), 2.34 (d, J=11.29 Hz, 1H), 1.33 (d, J=2.44 Hz, 6H), 1.28 (s, 3H), 1.11 (d, J=6.71 Hz, 3H), 0.98 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −114.17, −116.52. LCMS (M+H) calcd for C33H41F2N2O3: 551.30. found: 551.4. By NMR.

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 22 h
  2. stirringthe mixture was stirred for an additional 1 h
  3. customThe mixture was quenched with satd NaHCO3
  4. extractionthe product was extracted with CH2Cl2
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. customThe product was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane)

Sources & evidence

ORD record
ord-4b0f76dbf502481c9b9de935f0878755
Source dataset
uspto-grants-2014_01
Patent number
US08629276B2

Reaction notes

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