HOAt → HCID 25206784, compound

HRID 387684Notes

Reaction equation

HRID 387684 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:20](O)=[O:21])[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:51][C:46]1[CH:45]=[C:44]([CH:49]=[C:48]([F:50])[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]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=[C:2]([Cl:1])[CH:3]=1)=[O:21])[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:39])([F:40])[F:41])[CH:33]=2)[CH2:31][CH2:30]1

Participants

9

Reactant 4

HCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68474958HCID 68474958, compoundHCID 86643873HCID 86643873, compound

Product 1

HCID 25206784HCID 25206784, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

Added, under an argon atmosphere and at a temperature close to 20° C., to a solution of 180 mg of 7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid in 2.2 cm3 of anhydrous dimethylformamide are 0.25 cm3 of triethylamine and 263 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), then 90 mg of 1-hydroxy-7-azabenzotriazole and 127 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring, under argon, for 15 h at a temperature close to 20° C. The reaction medium is then added to 10 cm3 of water and 20 cm3 of ethyl acetate. After decanting, the organic phase is washed with 10 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 10 cm3 of water, then 10 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa). The residual solution (around 2 cm3) is purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 50% heptane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 274 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a beige foam.

Workup

  1. additionAdded, under an argon atmosphere and at a temperature
  2. customclose to 20° C
  3. customAfter decanting
  4. washthe organic phase is washed with 10 cm3 of a saturated aqueous solution of ammonium chloride, five lots of 10 cm3 of water
  5. dry with material10 cm3 of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure (5 kPa)
  8. customThe residual solution (around 2 cm3) is purified by flash chromatography over silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm; eluent: 50% heptane/50% ethyl acetate)
  9. concentrationAfter concentrating the fractions under reduced pressure, 274 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide
  10. customare obtained in the form of a beige foam

Sources & evidence

ORD record
ord-47dda1667370494e94bbe687236d14c9
Source dataset
uspto-grants-2013_02
Patent number
US08372864B2

Reaction notes

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