Proton sponge → HCID 49806735, compound

HRID 576097Notes

Reaction equation

HRID 576097 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[CH2:11][N:10](C)[CH2:9]2)=[CH:4][CH:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.ClC(OC(Cl)C)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]4[N:19]=[N:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 88675Proton spongeHCID 5213051-Chloroethyl chloroformateHCID 68660965HCID 68660965, compound

Product 1

HCID 49806735HCID 49806735, compoundYield 33.2%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of 4-(4-chlorophenyl)-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (69 mg, 0.17 mmol) in 1,2-dichloroethane (5 mL) at 0° C. was added proton sponge (37 mg, 0.17 mmol) and 1-chloroethyl chloroformate (56 μL, 0.51 mmol) dropwise. The resultant mixture was stirred at 0° C. for one hour and then heated at reflux for 1.5 hours. After concentrating the mixture in vacuo, the crude intermediate was taken up in methanol (5.0 mL) and heated at reflux for 1 hour. After concentrating in vacuo, the crude product obtained was purified by preparative thin layer chromatography using 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide as eluent to give 4-(4-chlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (22 mg, 33%) as a light yellow oil: [α]23D +7.5° (c 0.08, methanol). To a solution of the newly obtained tetrahydroisoquinoline (20 mg, 0.051 mmol) in acetonitrile (1 mL) was added L-tartaric acid (8 mg, 0.051 mmol) followed by slow addition of water (4 mL). The resultant solution was lyophilized for two days to give the correspondent L-tartrate salt (>99% AUC HPLC) as an off-white solid: 1H NMR (CD3OD, 500 MHz) δ 8.39 (d, J=9.0 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.17 (s, 1H), 8.03 (dd, J=8.0, 2.0 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 1H), 4.65-4.53 (m, 3H), 4.42 (s, 2H), 3.80-3.76 (m, 1H), 3.47-3.43 (m, 1H); ESI MS m/z 390 [M+H]+.

Workup

  1. temperatureheated
  2. temperatureat reflux for 1.5 hours
  3. concentrationAfter concentrating the mixture in vacuo
  4. temperatureheated
  5. temperatureat reflux for 1 hour
  6. concentrationAfter concentrating in vacuo
  7. customthe crude product obtained
  8. customwas purified by preparative thin layer chromatography

Sources & evidence

ORD record
ord-42e441f5af19478fa48cd962d97fb292
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

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