Ethyl 4,4,4-trifluoroacetoacetate → HCID 9844328, compound

HRID 1350179Notes

Reaction equation

HRID 1350179 reaction equation
[CH2:1]([C@@H:5]1[CH2:23][O:22][C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:7]2[N:6]1[CH2:24][C:25]([F:28])([F:27])[F:26])[NH:13][C:12](=[O:17])[CH:11]=[C:10]3[C:18]([F:21])([F:20])[F:19])[CH:2]([CH3:4])[CH3:3].NC1C=CC2N(CC(F)(F)F)[C@H](CC(C)C)COC=2C=1.C(OC(=O)CC(C(F)(F)F)=O)C>C1(C)C=CC=CC=1>[CH2:1]([C@@H:5]1[CH2:23][O:22][C:16]2[C:7](=[CH:8][C:9]3[C:10]([C:18]([F:20])([F:21])[F:19])=[CH:11][C:12](=[O:17])[NH:13][C:14]=3[CH:15]=2)[N:6]1[CH2:24][C:25]([F:28])([F:26])[F:27])[CH:2]([CH3:3])[CH3:4]

Participants

5

Reactant 3

HCID 67793Ethyl 4,4,4-trifluoroacetoacetateHCID 16658990HCID 16658990, compoundHCID 44442973HCID 44442973, compound2×

Product 1

HCID 9844328HCID 9844328, compoundYield 9%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
95 °C

Procedure

(3R)-2,3,4,7-Tetrahydro-3-isobutyl-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-8H-[1,4]oxazino[2,3-f]quinolin-8-one (Compound 155, Structure 17 of Scheme III, where R1, R3, R4, R5, R7, R8=H, R2=trifluoromethyl, R6=isobutyl, R=CH2CF2), and (2R)-1,2,3,6-tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-f]quinolin-7-one (Structure 18 of Scheme III, where R1, R3, R4, R5, R7=H, R=trifluoromethyl, R6=isobutyl, R13=CH2CF3): This compound was prepared by treatment of (3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine (0.13 g, 0.45 mmol) and ethyl-4,4,4-trifluoroacetoacetate (0.25 g, 1.4 mmol) in 6 mL toluene heated at reflux for 3 h, followed by removal of solvent and treatment with 3 mL concentrated H2SO4 heated to 95° C. for 1 h. The mixture was poured into water (100 mL), neutralized with 6N NaOH, and extracted with chloroform (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The baseline impurities and were removed and partial purification achieved by flash chromatography (95:5 CH2Cl2:MeOH). Further purification by HPLC (Kromasil, 0.5″ semi-prep column, 70% MeOH/water at 3 mL/min) afforded 5.0 mg (3%) of Compound 155, and recrystallization of the other impure fractions (ethyl acetate:hexanes) afforded 17 mg (9%) of (2R)-1,2,3,6-tetrahydro-2-isobutyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-7H-[1,4]oxazino[3,2-g]quinolin-7-one, the regioisomer of Compound 155. Data for Compound 155: 1H NMR (500 MHz, CDCl3) δ 12.0–12.4 (v broad s, 1H), 7.15 (s, 1H), 7.13 (d, J=9.0, 1H), 7.01 (d, J=9.0, 1H), 4.34 (d, J=11, 1H), 3.99 (broad d, J=10, 1H), 3.75–3.85 (m, 1H), 3.65–3.75 (m, 1H), 3.35–3.40 (m, 1H), 1.70–1.80 (m, 1H), 1.40–1.50 (m, 1H), 1.30–1.40 (m, 1H), 0.95 (d, J=6.5, 3H), 0.93 (d, J=7.0, 3H).

Workup

  1. temperatureheated
  2. temperatureat reflux for 3 h
  3. customfollowed by removal of solvent and treatment with 3 mL concentrated H2SO4
  4. additionThe mixture was poured into water (100 mL)
  5. extractionextracted with chloroform (3×50 mL)
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe baseline impurities and were removed
  11. custompartial purification
  12. customFurther purification by HPLC (Kromasil, 0.5″ semi-prep column, 70% MeOH/water at 3 mL/min)
  13. customafforded
  14. custom5.0 mg (3%) of Compound 155, and recrystallization of the other impure fractions (ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-90090f4630fe423da89730f4f817151a
Source dataset
uspto-grants-2007_05
Patent number
US07214690B2

Reaction notes

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