2-Chloroethyl isocyanate → {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} (2-chloroethyl)carbamate

HRID 1184654Notes

Reaction equation

HRID 1184654 reaction equation
[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].[Cl:33][CH2:34][CH2:35][N:36]=[C:37]=[O:38]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]2[N:20]([C:18](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[CH3:1])=[CH:16][C:15]=3[CH3:17])[CH2:21][CH2:22][CH2:23][CH:24]([O:32][C:37](=[O:38])[NH:36][CH2:35][CH2:34][Cl:33])[C:25]=2[CH:30]=1

Participants

5

Reactant 2

HCID 160352-Chloroethyl isocyanateHCID 216237Tolvaptan

Product 1

HCID 86708937{7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} (2-chloroethyl)carbamateYield 82%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

Tolvaptan (1.0 g, 2.2 mmol) was suspended in toluene (7 ml). 2-Chloroethyl isocyanate (0.28 ml, 3.3 mmol) and 4-dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) were added thereto, and the mixture was stirred at 80° C. for 24 hours. After cooling to room temperature, the insoluble materials were filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=54:46→33:67). The purified product was concentrated under reduced pressure to obtain 1.0 g of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethyl)carbamate as white amorphous solid.

Workup

  1. temperatureAfter cooling to room temperature
  2. filtrationthe insoluble materials were filtered off
  3. washwashed with ethyl acetate
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. customThe residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=54:46→33:67)
  6. concentrationThe purified product was concentrated under reduced pressure

Sources & evidence

ORD record
ord-9557162d57b747b49db1b568ee972bde
Source dataset
uspto-grants-2014_03
Patent number
US08669229B2

Reaction notes

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