Methanol → 2-tert-butoxy-2-[4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-[(1R,2R)-2-phenylcyclopropanecarbonyl]-5,7-dihydro-1,6-naphthyridin-3-yl]acetic acid

HRID 470936Notes

Reaction equation

HRID 470936 reaction equation
[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([C@@H:45]2[CH2:47][C@H:46]2[C:48](Cl)=[O:49])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CO>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:48]([C@@H:46]3[CH2:47][C@H:45]3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:49])[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 887MethanolHCID 8471TriethylamineHCID 13656trans-2-Phenyl-1-cyclopropanecarbonyl chlorideHCID 717115302-Tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid

Product 1

HCID 717116042-tert-butoxy-2-[4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-[(1R,2R)-2-phenylcyclopropanecarbonyl]-5,7-dihydro-1,6-naphthyridin-3-yl]acetic acidYield 41.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the mixture cooled to 0° C. Added to this was (1R,2R)-2-phenylcyclopropanecarbonyl chloride (10 μl, 0.07 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air, taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% CF3CO2H, Sunfire 19×100 mm, C18, 5 μm). The product-containing fractions were combined, concentrated to remove the organic solvent and the resulting precipitate isolated by filtration to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-((1R,2R)-2-phenylcyclopropanecarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (5.5 mg, 39% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 6.61-7.66 (9H, m), 4.70-4.87 (1H, m), 4.09-4.63 (2H, m), 3.40-4.02 (3H, m), 2.24-2.49 (1H, m), 2.06-2.23 (1H, m), 1.80-1.96 (1H, m), 1.45-1.76 (1H, m), 1.20-1.45 (10H, m), 1.11-1.19 (3H, m), 0.86-1.03 (8H, m). 19F NMR (500 MHz, CD3OD) δ ppm −115.29, −115.86. LCMS (M+H) calcd for C12H42FN2O4: 573.31. found: 573.08.

Workup

  1. concentrationthe mixture was concentrated under a stream of air
  2. custompurified by preparative HPLC (10% AcCN/90% H2O/0.1% CF3CO2H, Sunfire 19×100 mm, C18, 5 μm)
  3. concentrationconcentrated
  4. customto remove the organic solvent
  5. customthe resulting precipitate isolated by filtration

Sources & evidence

ORD record
ord-1a30772b5710426083c8b07ba270beb3
Source dataset
uspto-grants-2014_01
Patent number
US08629276B2

Reaction notes

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