Acetone Cyanohydrin → US11401286, Example 138

HRID 1508806Notes

Reaction equation

HRID 1508806 reaction equation
O[CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)[C:48]#[N:49].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:48]([CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3]1)#[N:49]

Participants

6

Reactant 4

HCID 6406Acetone CyanohydrinHCID 11776TriphenylphosphineHCID 97268Di-tert-butyl azodicarboxylateHCID 90110206US11401286, Example 135

Product 1

HCID 90338531US11401286, Example 138

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 25-mL round bottom flask was charged with 2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (Diastereomer B, 0.030 g, 0.085 mmol) and triphenylphosphine (0.112 g, 0.43 mmol) and acetone cyanohydrin (0.039 mL, 0.43 mmol) in THF. To this stirred solution at 0° C. was added di-tert-butyl azodicarboxylate (0.098 g, 0.43 mmol). After stirring for 24 h, the reaction mixture was absorbed onto silica (2 g) and was purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as the eluent to afford 2-(4-((2-(3-cyanocyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (Diastereomer A: 0.021 g, 68%) as a colorless oil. MW=360.45. 1H NMR (CD3OD, 300 MHz) δ 7.34-7.28 (m, 2H), 7.20-7.14 (m, 2H), 6.69 (s, 1H), 3.50 (s, 2H), 3.28-3.10 (m, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.23-2.08 (m, 6H), 2.00-1.86 (m, 1H), 1.83-1.67 (m, 1H); ESI MS m/z 361 [M+H]+. Treatment with 1.25M HCl in methanol (0.093 mL, 0.115 mmol) afforded the title compound (Diastereomer A: 0.020 g, 89%) as a white solid. MW=396.91. M.p. 215-217° C. decomp. 1H NMR (DMSO-d6, 500 MHz) δ 13.74 (br s, 1H), 9.47 (br s, 1H), 7.50 (s, 1H), 7.37-7.31 (m, 2H), 7.27-7.20 (m, 2H), 6.90 (s, 1H), 6.72 (s, 1H), 3.40 (s, 2H), 3.03 (br s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.32-2.05 (m, 7H), 1.89-1.80 (m, 1H), 1.77-1.65 (m, 1H); APCI MS m/z 361 [M+H]+.

Workup

  1. customthe reaction mixture was absorbed onto silica (2 g)
  2. customwas purified by chromatography on silica

Sources & evidence

ORD record
ord-d5386db4b8b340bba0dd80fece7e73dd
Source dataset
uspto-grants-2015_12
Patent number
US09221843B2

Reaction notes

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