Diisopropylethylamine → (S)-5-chloro-2-(1-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

HRID 2379002Notes

Reaction equation

HRID 2379002 reaction equation
[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)=[C:31]([CH:34]=1)[C:32]#[N:33].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]2[CH2:40][CH2:39][N:38]([C:17](=[O:18])[CH2:16][C@H:14]3[C:13](=[O:20])[N:12]([CH2:21][C:22]([F:23])([F:25])[F:24])[CH2:11][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[C:2]([Cl:1])=[CH:3][C:4]=4[CH2:15]3)[CH2:37][CH:36]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 59732027(S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acidHCID 688927975-Chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

Product 1

HCID 23658012(S)-5-chloro-2-(1-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrileYield 52.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

In an oven-dried round bottom flask, (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (44.1 mg, 0.173 mmol) were dissolved in DMF (2 ml). To this solution was added DIEA (0.093 ml, 0.532 mmol) followed by PyBOP (69.3 mg, 0.133 mmol). The reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere for 3 hours during which time it became dark red in color. The DMF was evaporated under high vacuum. The residue was subjected to column chromatography (silica, 20:1 CH2Cl2/2M NH3 in MeOH). The most pure fractions were collected, evaporated and again subjected to column chromatography (silica, 40:1 CH2Cl2/2M NH3 in MeOH). The fractions were collected, evaporated and dried overnight under vacuum to give (S)-5-chloro-2-(1-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (40 mg, 0.069 mmol, 52.1% yield) as a light tan solid. 1H NMR (500 MHz, MeOD) δ ppm 1.24-1.34 (m, 1H) 2.50-2.60 (m, 3H) 2.60-2.76 (m, 2H) 2.95-3.05 (m, 1H) 3.14-3.23 (m, 2H) 3.82-3.91 (m, 1H) 3.90-4.02 (m, 1H) 4.05-4.14 (m, 1H) 4.53-4.62 (m, 2H) 5.54 (d, J=17.4 Hz, 1H) 6.07 (d, J=13.7 Hz, 1H) 7.21 (s, 1H) 7.46 (d, J=8.3 Hz, 1H) 7.64 (d, J =8.5 Hz, 1H) 7.78 (s, 1H) 8.24 (s, 1H); MS (ESI): 575 (M-1H); Rf=1.90 (4 min run).

Workup

  1. customThe DMF was evaporated under high vacuum
  2. customThe most pure fractions were collected
  3. customevaporated
  4. customThe fractions were collected
  5. customevaporated
  6. customdried overnight under vacuum

Sources & evidence

ORD record
ord-cd17d9ae53ee4ea2b2861a59203ff8de
Source dataset
uspto-grants-2008_12
Patent number
US07470680B2

Reaction notes

Loading…