Hydrochloric Acid → Methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]-3-hydroxypropanoate

HRID 1930190Notes

Reaction equation

HRID 1930190 reaction equation
[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:12]([F:28])[CH:11]=2)[C:7]([CH3:29])=[N:6][C:5]=1[CH3:30])(=[O:3])[NH2:2].[C:31](=O)([O-])[O-:32].[K+].[K+].C=O.Cl>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH2:31][OH:32])[C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:12]([F:28])[CH:11]=2)[C:7]([CH3:29])=[N:6][C:5]=1[CH3:30])(=[O:3])[NH2:2]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 11430Potassium CarbonateHCID 59627722Methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]acetate2×

Product 1

HCID 59627634Methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]-3-hydroxypropanoateYield 74%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
30 °C

Procedure

A stirred solution of methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′-fluorobiphenyl-4-yl)acetate (Intermediate 31-7; 615 g, 1437 mmol) in DMF (2.5 L) was cooled to 15° C., under a nitrogen atmosphere. Potassium carbonate (214 g, 1545 mmol) was then added followed by paraformaldehyde (47.5 g, 1581 mmol). The reaction was stirred for 5 hours at 30° C. The reaction was then added to stirred water (25.0 L) and ethyl acetate (10.0 L). Concentrated hydrochloric acid (430 ml) was then added slowly with stirring. The aqueous layer was separated and extracted with ethyl acetate (7.5 L). The organics were combined and washed with, 50% brine/water (10.0 L), dried (magnesium sulphate), filtered and the solvent was removed in vacuo. Gave methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]-3-hydroxypropanoate (762 g) as a yellow gum, 64% by LCMS (therefore 488 g, 74% yield). The material was used crude in the next stage.

Workup

  1. additionThe reaction was then added
  2. stirringwith stirring
  3. customThe aqueous layer was separated
  4. extractionextracted with ethyl acetate (7.5 L)
  5. washwashed with, 50% brine/water (10.0 L)
  6. dry with materialdried (magnesium sulphate)
  7. filtrationfiltered
  8. customthe solvent was removed in vacuo

Sources & evidence

ORD record
ord-14b0f2d32d354d9dbd33af922163aaec
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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