Acetic Acid → HCID 178477632, compound

HRID 1777825Notes

Reaction equation

HRID 1777825 reaction equation
[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]3[CH2:24][NH:23][C@@H:22]([CH:25]([CH3:27])[CH3:26])[C:19]3=[N:20][CH:21]=2)=[O:15])=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[F:28][C:29]([F:39])([F:38])[C@H:30]1[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32][CH2:31]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]3[CH2:24][N:23]([CH2:36][C@H:33]4[CH2:32][CH2:31][C@H:30]([C:29]([F:28])([F:38])[F:39])[CH2:35][CH2:34]4)[C@@H:22]([CH:25]([CH3:26])[CH3:27])[C:19]3=[N:20][CH:21]=2)=[O:15])=[N:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 118274975(S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamideHCID 178520943HCID 178520943, compound

Product 1

HCID 178477632HCID 178477632, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (3.6 g, 9.25 mmol), trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (3.3 g, 18.5 mmol) in anhydrous MeOH (100 mL) was added acetic acid dropwise until the pH was between 6 and 7. Sodium cyanoborohydride (1.7 g, 27.75 mmol) was added portionwise at rt. The mixture was heated to 70° C. for 1 h. Upon completion, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), then the organic phase was washed with water (3×100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%), then further purified by a chiral column using the following conditions: instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; column: AD 300 mm×50 mm, 10 μm; mobile phase: A: supercritical CO2, B: iPrOH (0.05% diethylamine), A:B=60:40 at 200 mL/min; column temp: 38° C.; nozzle pressure: 100 bar; nozzle temp: 60° C.; evaporator temp: 20° C.; trimmer temp: 25° C.; wavelength: 220 nm. Isomer SFC tR=2.28 min in 12 min chromatography was isolated as the major isomer, which was then further purified by reverse-phase HPLC to give (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (2, HCl salt) as a light yellow solid. LC-MS tR=0.69 min in 1 min chromatography, MS (ESI) m/z 553.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 9.12 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.36-8.32 (m, 2H), 7.75 (d, J=8.0 Hz, 1H), 5.16 (d, J=15.6 Hz, 1H), 4.89-4.87 (m, 2H), 4.73 (d, J=15.2 Hz, 1H), 3.42-3.34 (m, 3H), 3.31-3.28 (m, 2H), 2.58-2.51 (m, 1H), 2.20-1.90 (m, 6H), 1.50-1.39 (m, 2H), 1.33 (d, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 1.24-1.20 (m, 2H), 1.10 (d, J=6.8 Hz, 3H). HCl preparative HPLC method mobile phase A: water with 0.05% HCl; mobile phase B: CH3CN; flow rate: 80 mL/min; detection: UV 220 nm/254 nm; column: Phenomenex Gemini C18 (250 mm×50 mm×5 μm); column temperature: 30° C.

Workup

  1. temperatureUpon completion, the reaction mixture was cooled to rt
  2. concentrationconcentrated under reduced pressure
  3. dissolutionThe residue was dissolved in ethyl acetate (100 mL)
  4. washthe organic phase was washed with water (3×100 mL) and brine (100 mL)
  5. dry with materialThe organic layer was dried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%)
  9. customfurther purified by a chiral column
  10. custom38° C.
  11. custom60° C.
  12. customevaporator temp
  13. custom20° C.
  14. custom25° C.
  15. customIsomer SFC tR=2.28 min in 12 min chromatography was isolated as the major isomer, which
  16. customwas then further purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-cda555b381994d2e9845d58ebb881954
Source dataset
uspto-grants-2016_02
Patent number
US09266886B2

Reaction notes

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