HOAt → HCID 25206782, compound

HRID 387681Notes

Reaction equation

HRID 387681 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([C:20]([OH:22])=O)[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.Cl.[NH2:24][C@@H:25]([CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([F:51])[CH:45]=1)[C@H:26]([OH:42])[CH2:27][NH:28][C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[CH2:31][CH2:30]1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C>[F:50][C:48]1[CH:49]=[C:44]([CH:45]=[C:46]([F:51])[CH:47]=1)[CH2:43][C@H:25]([NH:24][C:20]([C:4]1[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH3:19])[C:9](=[O:12])[C:10]=2[CH:11]=[C:2]([CH3:1])[CH:3]=1)=[O:22])[C@H:26]([OH:42])[CH2:27][NH:28][C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:31][CH2:30]1

Participants

9

Reactant 4

HCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68473089HCID 68473089, compoundHCID 86643873HCID 86643873, compound

Product 1

HCID 25206782HCID 25206782, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

Added to a solution of 33 mg of 7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid in 0.5 cm3 of anhydrous dimethylformamide are 0.05 cm3 of triethylamine and 51 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), then 17 mg of 1-hydroxy-7-azabenzotriazole and 24 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring for 15 h at a temperature close to 20° C. 20 cm3 of water and 30 cm3 of ethyl acetate are added to the reaction medium. After decanting, the organic phase is washed with 20 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 20 cm3 of water, then 20 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). The residue is dissolved in 2 cm3 of dichloromethane then purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 60% heptane/40% ethyl acetate). After concentrating the fractions under reduced pressure, 68 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a colorless oil.

Workup

  1. customclose to 20° C
  2. customAfter decanting
  3. washthe organic phase is washed with 20 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 20 cm3 of water
  4. dry with material20 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated to dryness under reduced pressure (5 kPa)
  7. dissolutionThe residue is dissolved in 2 cm3 of dichloromethane
  8. customthen purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 60% heptane/40% ethyl acetate)
  9. concentrationAfter concentrating the fractions under reduced pressure, 68 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide
  10. customare obtained in the form of a colorless oil

Sources & evidence

ORD record
ord-44fb6be209e14fe693d581eee48fd74d
Source dataset
uspto-grants-2013_02
Patent number
US08372864B2

Reaction notes

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