Ammonium Chloride → (S)-1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-pyrrolidine-2-carboxylic acid amide

HRID 708300Notes

Reaction equation

HRID 708300 reaction equation
[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](C=O)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1C(O)=O.C(O[BH-](O[C:43](=[O:45])[CH3:44])OC(=O)C)(=O)C.[Na+].C([N:50](CC)C(C)C)(C)C.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>ClCCCl.ClCCl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:26][N:25]5[CH2:32][CH2:31][CH2:30][C@H:44]5[C:43]([NH2:50])=[O:45])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]

Participants

10

Reactant 7

HCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 145742L-ProlineHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 582036922-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde

Product 1

HCID 58204061(S)-1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-ylmethyl]-pyrrolidine-2-carboxylic acid amideYield 11.8%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde (0.100 g, 0.294 mmol) in 1,2-dichloroethane (3.0 mL) was added L-proline (0.0372 g, 0.323 mmol) and 4 Å molecular sieves. After 2 hours, Sodium triacetoxyborohydride (0.124 g, 0.588 mmol) was added. The reaction was stirred at room temperature overnight, diluted with dichloromethane, filtered and concentrated. The crude was redissolved in tetrahydrofuran (1.5 mL). N,N-diisopropylethylamine (0.409 mL, 0.00235 mol), ammonium chloride (0.0628 g, 0.00118 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.128 g, 0.000338 mol) were added and the reaction was stirred at room temperature for 5 hours. Saturated NaHCO3 was added and the mixture was extracted with 3 times with ethyl acetate. The organic phases were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to give 546 as a white solid (15.2 mg). MS(ESI+) 439.2. 1H NMR (400 MHz, DMSO) δ 8.30 (d, J=8.1 Hz, 1H), 8.10 (s, 1H), 7.24 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.2, 1.5 Hz, 1H), 7.07 (d, J=1.3 Hz, 1H), 7.04 (d, J=1.7 Hz, 1H), 5.88-5.77 (m, 1H), 4.36 (t, J=5.0 Hz, 2H), 3.85 (d, J=13.4 Hz, 1H), 3.43 (t, J=5.1 Hz, 2H), 3.40 (d, J=13.5 Hz, 1H), 3.01-2.87 (m, 2H), 2.24 (dd, J=16.3, 8.1 Hz, 1H), 2.13-1.99 (m, 1H), 1.77-1.65 (m, 3H), 1.55 (d, J=6.6 Hz, 6H)

Workup

  1. filtrationfiltered
  2. concentrationconcentrated
  3. dissolutionThe crude was redissolved in tetrahydrofuran (1.5 mL)
  4. stirringthe reaction was stirred at room temperature for 5 hours
  5. extractionthe mixture was extracted with 3 times with ethyl acetate
  6. dry with materialdried with MgSO4
  7. concentrationconcentrated
  8. customThe crude was purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-8a65e52291154f33a85c5a1bfeab937b
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

Loading…