Sodium hydride → 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyloxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-one

HRID 1191601Notes

Reaction equation

HRID 1191601 reaction equation
[H-].[Na+].[Cl:3][C:4]1[C:9]([F:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[CH:13]=[N:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:26])[NH:20]2.[Si](Cl)(C(C)(C)C)(C)C.[F:35][C:36]([F:41])([F:40])[CH:37]1[O:39][CH2:38]1.C([Li])CCC.[Si](N1C2C(=C(N=CC3C=CC(OC)=C(F)C=3Cl)C=C(F)C=2)C=CC1=O)(C(C)(C)C)(C)C>C1COCC1.CCCCCC.C(OCC)C>[Cl:3][C:4]1[C:9]([F:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[CH:13]([NH:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:26])[NH:20]2)[C:37]1([C:36]([F:41])([F:40])[F:35])[CH2:38][O:39]1

Participants

10

Reactant 6

HCID 24758Sodium hydrideHCID 28928tert-Butyldimethylsilyl chlorideHCID 5207692-(Trifluoromethyl)oxiraneHCID 685370925-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]amino}-7-fluoro-1H-quinolin-2-oneHCID 685410251-{t-Butyldimethylsilyl}-5-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]amino}-7-fluoroquinolin-2-oneHCID 178418339Butyllithium

Product 1

HCID 462221905-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyloxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-one

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent4×HCID 8058HexaneSolvent2×

Procedure

To 1.6 g (9 mmol) 5-amino-7-fluoro-1H-quinolin-2-one and 1.69 g (9 mmol) 2-chloro-3-fluoro-4-methoxybenzaldehyde in 27 ml toluene and 8 ml 1,4-dioxane are added 1.96 ml acetic acid and 7 ml tetrabutyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 1 hour. Phases are separated and addition of ethylacetate is repeated two times while stirring is done under reflux and phases are separated while they are still hot. The combined organic phases are concentrated and the residue is purified by flash chromatography on silica gel (ethyl acetate, then methanol in dichloromethane 15% to 20%) to yield 2.17 g of 5-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]-amino}-7-fluoro-1H-quinolin-2-one. 465 mg NaH (55% in mineraloil, 9.7 mmol) were washed with dry THF and suspended together with 2.6 g (7.5 mmol) of 5-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]amino}-7-fluoro-1H-quinolin-2-one in 90 ml THF. t-Butyldimethylsilyl chloride is added as solid and the mixture is stirred for 3.5 hours while it becomes a clear solution. In parallel 0.96 ml 1,1,1-trifluoro-2,3-epoxypropane in 24 ml THF and 7 ml hexane are cooled to −100° C. and 4.5 ml of a 2.5 M n-butyl lithium solution in hexane are added over 10 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition the previously prepared 1-{t-butyldimethylsilyl}-5-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]amino}-7-fluoroquinolin-2-one solution in THF is added over 30 minutes while the temperature does not exceed −95° C. After 3 hours at −100° C. 7.5 ml diethyl ether are added and the reaction mixture is warmed to room temperature over one hour. The reaction is quenched by addition of saturated ammonium chloride solution. After stirring for 30 minutes the phases are separated and the aqueous layer is extracted with dichloromethan, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (ethyl acetate in hexane 50 to 100%) yields 2.14 g of 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyloxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-one which is used for some of the following examples for opening of the oxirane ring with different nucleophiles.

Workup

  1. customdoes not exceed −95° C
  2. additionis added over 30 minutes while the temperature
  3. customdoes not exceed −95° C
  4. waitAfter 3 hours at −100° C
  5. customThe reaction is quenched by addition of saturated ammonium chloride solution
  6. stirringAfter stirring for 30 minutes the phases
  7. customare separated
  8. extractionthe aqueous layer is extracted with dichloromethan
  9. washthe combined organic phases are washed with brine
  10. dry with materialdried over sodium sulphate
  11. customevaporated

Sources & evidence

ORD record
ord-c9b8009edc9f40189b110bbe307fdf97
Source dataset
uspto-grants-2014_03
Patent number
US08680117B2

Reaction notes

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