Hydrochloric Acid → benzyl N-(1-methyl-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl)carbamate

HRID 2068543Notes

Reaction equation

HRID 2068543 reaction equation
CS[C:3]1[C@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[N:4]=1.[CH2:25]([NH2:28])[C:26]#[CH:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.Cl>CCOCC>[CH3:27][C:26]1[N:4]2[C:5]3[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=3[CH2:7][CH2:8][CH:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]2=[N:28][CH:25]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 246701,1'-Biphenyl, mixt. with 1,1'-oxybis(benzene)HCID 239041PropargylamineHCID 521998p-Toluenesulfonic acid monohydrateHCID 58304100benzyl N-[(3R)-2-methylsulfanyl-4,5-dihydro-3H-1-benzazepin-3-yl]carbamate

Product 1

HCID 58304076benzyl N-(1-methyl-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl)carbamateYield 70.1%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

Combine benzyl N-[(3R)-2-methylsulfanyl-4,5-dihydro-3H-1-benzazepin-3-yl]carbamate (500 mg, 1.47 mmol), propargylamine (197.28 μL, 2.94 mmol), and p-toluenesulfonic acid monohydrate (30 mg, 157.71 μmoles) in phenyl ether-biphenyl mixture (2 mL, 6.53 mmol) (Dowtherm A) and stir the mixture for approximately 45 minutes at 180° C. Cool the reaction, and add ether (20 mL), then 2M HCl (20 mL). Stir for a few minutes, remove the aqueous layer, and extract the organic layer with 2N HCl (2×). Combine the aqueous layers and basify with ammonium hydroxide (28%) until alkaline. Collect the precipitate by filtration, wash it with water, and dry it in a vacuum oven. Purify the precipitate by flash chromatography (50% of a 5% solution of ammonia/methanol (2M) in dichloromethane to 90% of the 5% solution) to give the title compound (358 mg, 70%) as an off white solid: MS (m/z): 348 (M+1). Retention time for Isomer 1 (S Isomer)=3.3 min; Isomer 2 (R Isomer)=3.7 min. (Chiralpak AD-H column; 100% EtOH with 0.2% dimethylethylamine; flow rate 1.0 mL/min; 225 nM). Chiral analysis indicates about 20% racemization.

Workup

  1. temperatureCool
  2. customthe reaction
  3. customremove the aqueous layer
  4. extractionextract the organic layer with 2N HCl (2×)
  5. customCollect the precipitate
  6. filtrationby filtration
  7. washwash it with water
  8. customdry it in a vacuum oven
  9. customPurify the precipitate by flash chromatography (50% of a 5% solution of ammonia/methanol (2M) in dichloromethane to 90% of the 5% solution)

Sources & evidence

ORD record
ord-b0fcb68d5a8645ff97b4a8bbccfc3eef
Source dataset
uspto-grants-2012_10
Patent number
US08299061B2

Reaction notes

Loading…