Triethylamine → Methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoate

HRID 1930191Notes

Reaction equation

HRID 1930191 reaction equation
CS(Cl)(=O)=O.[C:6]([C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH2:32]O)[C:28]([O:30][CH3:31])=[O:29])=[CH:23][C:22]=3[Cl:34])=[C:17]([F:35])[CH:16]=2)[C:12]([CH3:36])=[N:11][C:10]=1[CH3:37])(=[O:8])[NH2:7].C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[C:6]([C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[CH2:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:23][C:22]=3[Cl:34])=[C:17]([F:35])[CH:16]=2)[C:12]([CH3:36])=[N:11][C:10]=1[CH3:37])(=[O:8])[NH2:7]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 25517Ammonium ChlorideHCID 31297Methanesulfonyl chlorideHCID 59627634Methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]-3-hydroxypropanoate2×

Product 1

HCID 59627693Methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoateYield 40.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

Methanesulfonyl chloride (0.145 L, 1865 mmol) was added over 5 minutes to a stirred solution of methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′-fluorobiphenyl-4-yl)-3-hydroxypropanoate (Intermediate 31-8; 488 g, 1065 mmol) and triethylamine (0.520 L, 3730 mmol) in tetrahydrofuran (5.0 L) at 10° C. The reaction was heated to 50° C. and left stirring for 2 hours. The reaction was then cooled to 20° C. The mixture was diluted with ethyl acetate (10.0 L), then water (3.0 L) was added. Saturated aqueous ammonium chloride solution (4.1 L) was added. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2.5 L). The organics were combined, washed with 50% brine/water (5.0 L), dried (magnesium sulphate), filtered and the solvent removed in vacuo. The crude product was dissolved in dichloromethane and then chromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column), eluting with a solvent gradient of 0-70% ethylacetate/isohexane. Pure fractions were evaporated to dryness to afford methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoate (188 g, 40%) as a white solid.

Workup

  1. waitleft
  2. temperatureThe reaction was then cooled to 20° C
  3. customThe organic layer was separated
  4. extractionthe aqueous layer extracted with ethyl acetate (2.5 L)
  5. washwashed with 50% brine/water (5.0 L)
  6. dry with materialdried (magnesium sulphate)
  7. filtrationfiltered
  8. customthe solvent removed in vacuo
  9. dissolutionThe crude product was dissolved in dichloromethane
  10. customchromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column)
  11. washeluting with a solvent gradient of 0-70% ethylacetate/isohexane
  12. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-d38a6c64d34b46f98cfa18857d0a5f4b
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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