Acetic Acid → HCID 59253041, compound

HRID 884757Notes

Reaction equation

HRID 884757 reaction equation
[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([NH2:24])[C:14]=2[CH3:25])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].[CH:30](=O)[CH3:31].C(O)(=O)C>CO>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([NH:24][CH2:30][CH3:31])[C:14]=2[CH3:25])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1

Participants

6

Reactant 4

HCID 176Acetic Acid2×HCID 177Acetaldehyde2×HCID 5003444Sodium cyanoborohydride2×HCID 59252976HCID 59252976, compound

Product 1

HCID 59253041HCID 59253041, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a mixture of 2-amino-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (3.04 g, 9.06 mmol) and sodium cyanoborohydride (1.00 g, 15.9 mmol) in methanol (25 mL), acetaldehyde (2.00 mL, 35.6 mmol) was added followed by dropwise addition of acetic acid (2.5 mL, 44 mmol) (caution: exothermic reaction with gas evolution). The obtained clear colorless solution was stirred at r.t. for 30 min. More sodium cyanoborohydride (1 g), acetaldehyde (1 ml), and acetic acid (2 ml) were added and stirring continued for 2 hour. LC-MS indicated a full conversion to the title product with formation of traces of the double alkylation product (UV 1.3%, tR=1.5, m/z (MH+) 392.4). The reaction mixture was partitioned between 5% aq. NaHCO3 (100 ml, pH=7) and ethyl acetate (3×50 mL), the combined organic solutions were washed with water 3 times, and evaporated to give 3.2 g of colorless solid residue. The crude product was transferred into 100 g prepacked SiO2 column with 1,2-dichloroethane and flash chromatographed with gradient 20% to 50% ethyl acetate in heptane. The title product came out with 40-50% ethyl acetate to give 2.73 g of colorless foam after evaporation and drying in high vacuo at 60° C. for 2 hours. LC-MS (m/z) 364.6 (MH+); tR=1.33. LC— high res. MS: calculated for C22H26N3O2 (MH+) 364.2020. found 364.2006. 1H NMR (250 MHz, 70° C., DMSO-d6, DMSO-d5=2.5 ppm): 0.96 (t, J=7.3 Hz, 3H, Me of Et), 1.13 (t, J=7.3 Hz, 3H, Me of EtNH), 1.72-1.94 (m, 2H, CH2 of Et), 2.38 (s, 3H, Me), 2.97 (quintet, J=7.1 Hz, 2H, CH2 of EtNH), 5.0 (q (unres. dt), J=6.8 Hz, J=8.2 Hz, 1H, CHNHCO), 6.05 (t, J=6.6 Hz, 1H, NHEt), 7.27 (m, 1H), 7.31-7.5 (m, 5H), 7.62 (m, 1H), 8.26 (d, J=8 Hz, 1H, C8-H), 8.68 (br. d, J=8.1 Hz, 1H). 13C APT (125 MHz, 25° C., DMSO-d6=39.88 ppm): 11.65 (CH3 of Et), 12.99 (CH3 of NHEt), 16.55 (br, CH3), 29.58 (CH2 of Et), 44.99 (CH2 of NHEt), 55.29 (CHNHCO), 114.3 (C), 123.73 (br, CH), 123.82 (C), 126.4 (CH), 126.93 (CH of Ph), 127.21 (CH), 127.47 (C8-H), 128.64 (CH of Ph), 132.89 (br, CH), 134.3 (C), 139.21 (C3), 143.92 (C1 of Ph), 160.82 (CON), 166.12 (CONH).

Workup

  1. additionwas added
  2. stirringstirring
  3. waitcontinued for 2 hour

Sources & evidence

ORD record
ord-e930afe8ea6643448a42c8638ee0b95f
Source dataset
uspto-grants-2012_08
Patent number
US08242134B2

Reaction notes

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