HOAt → HCID 25206778, compound

HRID 387677Notes

Reaction equation

HRID 387677 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([C:27](O)=[O:28])[C:12]2[CH2:13][CH2:14][N:15]([CH:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[C:16](=[O:19])[C:17]=2[CH:18]=1)#[N:2].Cl.[NH2:31][C@@H:32]([CH2:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[C:53]([F:58])[CH:52]=1)[C@H:33]([OH:49])[CH2:34][NH:35][C:36]1([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=2)[CH2:38][CH2:37]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:58][C:53]1[CH:52]=[C:51]([CH:56]=[C:55]([F:57])[CH:54]=1)[CH2:50][C@H:32]([NH:31][C:27]([C:11]1[C:12]2[CH2:13][CH2:14][N:15]([CH:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[C:16](=[O:19])[C:17]=2[CH:18]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:10]=1)=[O:28])[C@H:33]([OH:49])[CH2:34][NH:35][C:36]1([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:46])([F:47])[F:48])[CH:40]=2)[CH2:38][CH2:37]1

Participants

9

Reactant 4

HCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68471625HCID 68471625, compoundHCID 86643873HCID 86643873, compound

Product 1

HCID 25206778HCID 25206778, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

Added to a solution of 171 mg of 7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid in 2 cm3 of anhydrous dimethylformamide and under an argon atmosphere are 0.198 cm3 of triethylamine and 207 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride, then 71 mg of 1-hydroxy-7-azabenzotriazole and 100.5 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is kept stirring for 15 h at a temperature close to 20° C. 50 cm3 of water and 50 cm3 of ethyl acetate are added to the reaction medium. After decanting, the organic phase is washed with 50 cm3 of a saturated aqueous solution of ammonium chloride, two 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 residual solution (around 3 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, 268 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.

Workup

  1. customclose to 20° C
  2. customAfter decanting
  3. washthe organic phase is washed with 50 cm3 of a saturated aqueous solution of ammonium chloride, two 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. customThe residual solution (around 3 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)
  8. concentrationAfter concentrating the fractions under reduced pressure, 268 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide
  9. customare obtained in the form of a white powder

Sources & evidence

ORD record
ord-077a794030ca417d8ecc61b4609baef0
Source dataset
uspto-grants-2013_02
Patent number
US08372864B2

Reaction notes

Loading…