Hydrochloric Acid → HCID 68866575, compound

HRID 1983855Notes

Reaction equation

HRID 1983855 reaction equation
[CH:1]12BC(CCC1)CCC2.[C:10]([O:15][CH3:16])(=[O:14])[CH2:11][CH:12]=[CH2:13].Br[C:18]1[CH:19]=[C:20]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([Cl:35])=[C:31](C)[CH:32]=3)[O:27][C:26](=[O:36])[C:25]=2[CH2:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=2[C:48]([F:51])([F:50])[F:49])=[O:39])[CH:21]=[CH:22][CH:23]=1.CC[C@@H]([C@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)CC(O)=O)=O)CCCNC(N)=N)=O)C(C)C)=O)CC1C=CC(O)=CC=1)=O)C(N[C@H](C(N1[C@H](C(N[C@H](C(O)=O)CC2C=CC=CC=2)=O)CCC1)=O)CC1NC=NC=1)=O)C.C[O-].[Na+].Cl>O1CCCC1>[Cl:35][C:30]1([CH3:1])[CH:29]=[C:28]2[C:33](=[C:24]([C:20]3[CH:19]=[C:18]([CH2:13][CH2:12][CH2:11][C:10]([O:15][CH3:16])=[O:14])[CH:23]=[CH:22][CH:21]=3)[CH:25]([CH2:37][C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=3[C:48]([F:49])([F:50])[F:51])=[O:39])[C:26](=[O:36])[O:27]2)[CH:32]=[CH:31]1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 77314Methyl 3-butenoateHCID 789669-Borabicyclo(3.3.1)nonaneHCID 10942334Sodium MethoxideHCID 54753138HCID 54753138, compoundHCID 178455907HCID 178455907, compound

Product 1

HCID 68866575HCID 68866575, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

A solution of 0.4N 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (300 ml, 0.12 mol) was added dropwise to a solution of methyl 3-butenoate (12.01 g, 0.12 mol) in tetrahydrofuran (5 ml) at room temperature under nitrogen atmosphere, and the mixture was stirred for 3 hours. This reaction mixture was added dropwise to a solution of 2-[4-(3-bromophenyl)-7-chloro-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide obtained in Reference Example 4 (34.12 g, 0.06 mol), sodium methoxide (9.72 g, 0.18 mol) and (1,1′-bis-(diphenylphosphino)ferrocene)palladium dichloride (9.8 g, 0.012 mol) in tetrahydrofuran (150 ml) at room temperature under nitrogen atmosphere, and the mixture was refluxed for 17 hours. To the reaction mixture was added an aqueous solution of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over magnesium sulfate. The extract was concentrated, and roughly purified by silica gel column chromatography to obtain a crude product of methyl 4-{3-[7-chloro-3-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-7-methyl-2-oxo-2H-chromen-4-yl]phenyl}butanoate (34.96 g). This was dissolved in a mixed solvent of ethanol (300 ml) and tetrahydrofuran (300 ml), an 2N aqueous solution of sodium hydroxide (118.5 ml, 0.237 mol) was added thereto, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with water. The extract was washed with diethyl ether, neutralized with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography and then re-crystallized from acetonitrile to obtain the title compound (12.04 g): mp 196° C.

Workup

  1. temperaturethe mixture was refluxed for 17 hours
  2. extractionthe mixture was extracted with ethyl acetate
  3. washThe extract was washed with water and saturated saline
  4. dry with materialdried over magnesium sulfate
  5. concentrationThe extract was concentrated
  6. customroughly purified by silica gel column chromatography

Sources & evidence

ORD record
ord-7c1c94cfef404a3dbe008ba4a87ae2e3
Source dataset
uspto-grants-2009_06
Patent number
US07541478B2

Reaction notes

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