4-Methylmorpholine → (R)-N-ethyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

HRID 716293Notes

Reaction equation

HRID 716293 reaction equation
[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)[CH3:34].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N)C.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][S:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1)[CH3:34]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 11198Ethylamine hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 58324505(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid

Product 1

HCID 58324369(R)-N-ethyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamideYield 22.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (32.7 mg, 0.171 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (26.1 mg, 0.171 mmol), and DMF (Volume: 0.5 mL) were stirred together to give a yellow solution. Ethanamine hydrochloride (9.28 mg, 0.114 mmol) and 4-methylmorpholine (0.065 mL, 0.593 mmol) were added. The reaction was stirred at room temperature for 4 hours. The crude reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (12.0 mg, 22.6%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 7.79 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.53 (s, 1H), 6.85-7.00 (m, 3H), 5.96 (br. s., 1H), 5.06 (d, J=13.4 Hz, 1H), 4.43 (dd, J=10.5, 3.4 Hz, 1H), 3.39-3.54 (m, 4H), 3.30 (br. s., 4H), 3.15 (td, J=12.9, 2.3 Hz, 1H), 3.00 (br. s., 1H), 2.87 (d, J=10.4 Hz, 2H), 2.60 (br. s., 4H), 2.42 (d, J=1.5 Hz, 1H), 1.25 (t, J=7.2 Hz, 3H). [M+H] calc'd for C24H30N6O2S, 467. found, 467. MP: 288.9° C.

Workup

  1. customto give a yellow solution
  2. customThe crude reaction
  3. customwas purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer)
  4. concentrationconcentrated until a white solid
  5. customprecipitated
  6. filtrationThe precipitate was filtered off
  7. customdried in vacuum

Sources & evidence

ORD record
ord-6966a275543448b38968ecc9dbbeb28b
Source dataset
uspto-grants-2015_11
Patent number
US09187497B2

Reaction notes

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