Ethylamine hydrochloride → (1S,2R)-4'-(4-Chlorophenyl)-N-ethyl-2',3',9'-trimethylspiro[cyclopropane-1,6'-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-carboxamide

HRID 1772338Notes

Reaction equation

HRID 1772338 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26](O)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[CH:29]([N:32](CC)C(C)C)(C)[CH3:30].Cl.C(N)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26]([NH:32][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 5

HCID 11198Ethylamine hydrochlorideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57404934(1S,2R)-4'-(4-Chlorophenyl)-2',3',9'-trimethylspiro[cyclopropane-1,6'-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-carboxylic acid2×

Product 1

HCID 67951116(1S,2R)-4'-(4-Chlorophenyl)-N-ethyl-2',3',9'-trimethylspiro[cyclopropane-1,6'-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-carboxamideYield 35.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of crude (1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-carboxylic acid (Compound 228; 0.09 g, 0.218 mmol) in DCM (2.4 mL) was added N,N-diisopropylethylamine (0.190 ml, 1.090 mmol), ethylamine hydrochloride (0.071 g, 0.872 mmol) and HOBt (0.017 g, 0.109 mmol). The mixture was stirred for 10 min at rt (still heterogeneous) before HATU (0.166 g, 0.436 mmol) was added, still at rt. After 20 min, the reaction was filtered on a pad of silica gel. The silica gel was successively rinsed with EtOAc/hexane (5:5) to (10:0) and DCM/MeOH (9:1). The filtrate was concentrated to dryness, and the residue was purified by reverse phase chromatography to give the desired product as an off-white solid (34 mg). LRMS (M+H)+: 440 m/z. 1H NMR (major conformer reported only) (400 MHz, DMSO-d6) δ 8.36 (br. s., 1H), 7.37-7.54 (m, 4H), 2.89-3.01 (m, 1H), 2.69-2.82 (m, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 2.07 (dd, J=5.15, 8.81 Hz, 1H), 1.92 (t, J=6.40 Hz, 1H), 1.78 (t, J=8.00 Hz, 1H), 1.43 (s, 3H), 0.84 (t, J=7.10 Hz, 3H).

Workup

  1. additionwas added, still at rt
  2. filtrationthe reaction was filtered on a pad of silica gel
  3. washThe silica gel was successively rinsed with EtOAc/hexane (5:5) to (10:0) and DCM/MeOH (9:1)
  4. concentrationThe filtrate was concentrated to dryness
  5. customthe residue was purified by reverse phase chromatography

Sources & evidence

ORD record
ord-041e7e17c41b4cdc9adeaebab3fb00c0
Source dataset
uspto-grants-2016_02
Patent number
US09249161B2

Reaction notes

Loading…