Triethylamine → HCID 86695245, compound

HRID 1504080Notes

Reaction equation

HRID 1504080 reaction equation
FC(F)(F)[C:3]([OH:5])=O.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:18]3[C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[S:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:12][CH2:11]1.[CH2:31]([N:33](CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.C1COCC1>C1COCC1.C(Cl)Cl>[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[C:18]3[C:19]4[CH2:20][N:21]([C:3]([NH:33][CH3:31])=[O:5])[CH2:22][CH2:23][C:24]=4[S:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:14][CH2:15]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 66615946Methylamine tetrahydrofuranHCID 86695243HCID 86695243, compound

Product 1

HCID 86695245HCID 86695245, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a 3-necked round-bottom flask containing a solution of N,N-dimethyl-4-[8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yloxy]cyclohexan-1-amine trifluoroacetate (300 mg, 1.00 equiv, 30% purity) in THF (50 mL) was added triethylamine (0.4 mL). The solution was stirred at 0° C. for 10 min under nitrogen. Then triphosgene (300 mg, 1.0 mmol) in 10 mL of DCM was added via syringe at 0° C. and stirred for 2 h at room temperature. Then methanamine-THF (2 M, 1.8 mL) was added at 0° C. and the resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of methanol and concentrated under vacuum. The residue was pre-purified by a silica gel column with DCM/MeOH (30:1-10:1) to give the crude product, which was purified by preparative HPLC under the following conditions (Waters): Column: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; mobile phase, water with 0.05% NH4HCO3 and CH3CN (9% CH3CN up to 21% in 12 min, up to 95% in 2 min, down to 9% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. After concentration in vacuo and lyophilization overnight, the corresponding 3-[[4-(dimethylamino)cyclohexyl]oxy]-N-methyl-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene-12-carboxamide (30 mg) was obtained as a white solid. MS (ES): m/z 390 (M+H)+ and 412 (M+Na)+. 1H NMR (300 MHz, CD3OD): δ 8.50 (1H, s), 5.30-5.21 (1H, m), 4.78 (2H, s), 3.75 (2H, t), 2.95 (2H, t), 2.78 (3H, s), 2.50-2.30 (9H, m), 2.07 (2H, d), 1.8-1.62 (2H, m), 1.60-1.50 (2H, m).

Workup

  1. stirringstirred for 2 h at room temperature
  2. stirringthe resulting solution was stirred overnight at room temperature
  3. customThe reaction was quenched by the addition of methanol
  4. concentrationconcentrated under vacuum
  5. customThe residue was pre-purified by a silica gel column with DCM/MeOH (30:1-10:1)
  6. customto give the crude product, which
  7. customwas purified by preparative HPLC under the following conditions (Waters)
  8. waitmobile phase, water with 0.05% NH4HCO3 and CH3CN (9% CH3CN up to 21% in 12 min
  9. waitup to 95% in 2 min
  10. waitdown to 9% in 2 min)
  11. concentrationAfter concentration in vacuo and lyophilization overnight

Sources & evidence

ORD record
ord-f893168e011546e58ad18edbd824a136
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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