Formaldehyde → Acetoacetic Acid

HRID 1640171Notes

Reaction equation

HRID 1640171 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]5[NH:29][CH2:30][CH2:31][N:32]=5)[CH:23]=4)[CH:18]=3)[CH2:13][NH:12]2)=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].C=O.[C:39]([BH3-])#N.[Na+].[C:43]([O-:46])(O)=[O:44].[Na+]>C(#N)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]5[NH:29][CH2:30][CH2:31][N:32]=5)[CH:23]=4)[CH:18]=3)[CH2:13][N:12]2[CH3:39])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35].[CH3:16][C:17]([CH2:18][C:43]([OH:46])=[O:44])=[O:21]

Participants

8

Reactant 4

HCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 23585480HCID 23585480, compound

Product 2

HCID 96Acetoacetic AcidYield 17%HCID 23585167HCID 23585167, compound

Reagents, catalysts & solvents 2

HCID 887MethanolCatalystHCID 6342AcetonitrileSolvent

Procedure

To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-6-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-54) (70.0 mg, 0.11 mmol), in acetonitrile (1.0 mL), was added formaldehyde (37% solution in water, 42 μL, 0.56 mmol) and sodium cyanoborohydride (28.8 mg, 0.46 mmol). A few drops of MeOH were added and the reaction was allowed to stir for 1 h. Saturated NaHCO3 solution was added and the mixture was extracted with EtOAc (2×). The combined organic solutions were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography and then further purified by HPLC (250 mm C18 column) eluting with acetonitrile containing 30% to 100% 10 mM ammonium acetate in water (20 min gradient), to give N-[4-chloro-3-(trifluoromethyl)phenyl]-6-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]-oxy}-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-11) as the diacetate salt (12 mg, 17%). 1H NMR (300 MHz, CD3OD): δ 8.58 (d, 1H), 8.17 (d, 1H), 7.85-7.81 (m, 1H), 7.62 (d, 1H), 7.55 (d, 1H), 7.26 (d, 1H), 7.16-7.13 (m, 1H), 6.99-6.97 (m, 2H), 4.07 (d, 1H), 4.04 (s, 4H), 3.71 (d, 1H), 3.46-3.41 (m, 1H), 3.24-3.06 (m, 2H), 2.53 (s, 3H), and 1.91 (s, 6H). LCMS: (FA) ES+ 530.3, ES− 528.2.

Workup

  1. extractionthe mixture was extracted with EtOAc (2×)
  2. washThe combined organic solutions were washed with brine
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. customevaporated
  6. customThe residue was purified by column chromatography
  7. customfurther purified by HPLC (250 mm C18 column)
  8. washeluting with acetonitrile containing 30% to 100% 10 mM ammonium acetate in water (20 min gradient)

Sources & evidence

ORD record
ord-95fbd59c8d2243ebb04fe0e8cd2944f7
Source dataset
uspto-grants-2012_02
Patent number
US08110687B2

Reaction notes

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