Acetaldehyde → (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N2-ethyl-2,3-dihydro-1H-indene-1,2-diamine

HRID 1612355

Reaction equation

HRID 1612355 reaction equation
[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH2:31])=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.[CH:32](=O)[CH3:33].[BH3-]C#N.[Na+]>CO.CC(O)=O.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH:31][CH2:32][CH3:33])=[N:6][C:7]([CH:18]3[CH2:19][CH2:20]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:2][CH2:3]1

Participants

7

Reactant 3

HCID 177Acetaldehyde3×HCID 5003444Sodium cyanoborohydride3×HCID 58583281(1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine

Product 1

HCID 58583310(1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N2-ethyl-2,3-dihydro-1H-indene-1,2-diamineYield 101.1%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidCatalyst3×HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine (0.15 g, 0.33 mmol) in MeOH (3.3 mL) was sequentially added acetaldehyde (22 mg, 0.5 mmol) and AcOH (5 drops). This mixture was stirred for 30 min before addition of NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). Stir at rt overnight. Add additional acetic acid (2 drops), acetaldehyde (29 μL, 0.5 mmol) and NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). After 2 hr, add additional acetic acid (2 drops), acetaldehyde (29 μL, 0.5 mmol) and NaBH3CN (1 M solution in THF, 0.6 mL, 0.6 mmol). After 3 hr, dilute mixture with EtOAc and wash with sat. aq. NaHCO3 and extract with EtOAc (3×40 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 100% ethyl acetate) to afford 0.16 g (44%) of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N2-ethyl-2,3-dihydro-1H-indene-1,2-diamine as a solid: 1H NMR (CDCl3) δ 0.84-1.05, 1.62-1.75, 2.78-2.86, 3.31-3.37, 3.52, 5.22, 5.52, 7.28-7.51; MS (ESI+) for C27H28Cl2N4 m/z 479 (M+H)+.

Workup

  1. waitAfter 2 hr
  2. waitAfter 3 hr
  3. washwash with sat. aq. NaHCO3
  4. extractionextract with EtOAc (3×40 mL)
  5. dry with materialThe combined organic extracts were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurify by biotage MPLC (90 g column, 100% ethyl acetate)

Sources & evidence

ORD record
ord-6ce3ab692dab4f9b8a2963e11383b91f
Source dataset
uspto-grants-2006_01
Patent number
US06992087B2

Linked notes

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