Formaldehyde → (S)-N-((methylthio)methyl)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine

HRID 1054481Notes

Reaction equation

HRID 1054481 reaction equation
[F:1][C:2]([F:22])([F:21])[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)=[CH:10][N:9]=1.[CH3:23][S-:24].[Na+].[CH2:26]=O>C1COCC1.O>[CH3:23][S:24][CH2:26][NH:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:11]2[CH:10]=[N:9][C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[C:2]([F:1])([F:21])[F:22])=[N:13][CH:12]=2)[N:19]=1

Participants

6

Reactant 3

HCID 712Formaldehyde2×HCID 4378561Sodium methanethiolateHCID 86727117(S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine2×

Product 1

HCID 86727119(S)-N-((methylthio)methyl)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amineYield 75.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

A 350 mL pressure vessel was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 3, 10 g, 32.3 mmol) and sodium methanethiolate (4.53 g, 64.7 mmol), which were dissolved in a mixture of THF (64.7 mL) and water (43.1 mL). Aqueous 37% formaldehyde (5.25 mL, 64.7 mmol) was added and the reaction mixture was heated to 90° C. for 2 hours. Another 2 eq. of aqueous 37% formaldehyde were added and the reaction mixture was heated for an additional 2 hours. The reaction mixture was then cooled to 25° C. The layers were separated in the separatory funnel and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified using silica gel chromatography, eluting with EtOAc:Hex (30:70) to yield 9 g (24.36 mmol, 75%) of the title product as an oil; 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 2H), 7.56-7.43 (m, 1H), 7.41 (t, J=6.6 Hz, 1H), 7.13 (d, J=7.3 Hz, 1H), 6.51 (d, J=8.2 Hz, 1H), 5.18-4.98 (m, 1H), 4.59 (d, J=6.7 Hz, 2H), 3.69 (dd, J=10.3, 4.9 Hz, 2H), 2.21-2.0 (m, 4H), 2.12 (s, 3H); m/z found [M+H]+=370.35.

Workup

  1. temperaturethe reaction mixture was heated for an additional 2 hours
  2. temperatureThe reaction mixture was then cooled to 25° C
  3. customThe layers were separated in the separatory funnel
  4. extractionthe aqueous layer was extracted with EtOAc (3×)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified
  10. washeluting with EtOAc

Sources & evidence

ORD record
ord-d2056bcfe0cc4796b0a9d95fa0c7ee46
Source dataset
uspto-grants-2016_07
Patent number
US09394308B2

Reaction notes

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