Diisopropylethylamine → (3R)-Methyl 2-(2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

HRID 528859Notes

Reaction equation

HRID 528859 reaction equation
[Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].Cl.[CH2:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][C@H:47]([C:55]([O:57][CH3:58])=[O:56])[NH:46]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:46]2[C@@H:47]([C:55]([O:57][CH3:58])=[O:56])[CH2:48][C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:45]2)=[O:11])[C:6]=1[CH3:7]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 71060992(R)-methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochlorideHCID 710621452-(4-Chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid2×

Product 1

HCID 71086288(3R)-Methyl 2-(2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylateYield 37.6%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 50 mg, 0.080 mmol) in CH2Cl2 (890 μL) was added 1-chloro-N,N-2-trimethylprop-1-en-1-amine (21 μL, 0.16 mmol). After stirring for 30 min at room temperature, (R)-methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (20 mg, 0.088 mmol) in THF (900 μL) was added followed by i-Pr2EtN (42 μL, 0.24 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then quenched with sat. aq. NH4Cl solution and extracted with EtOAc (1×). The organic layer was washed with 1N aq. HCl solution, and the combined aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (24 mg, 37%). 1H NMR (1:1 CD3OD:CDCl3, 1:1 mixture of amide rotamers) δ 8.62 (d, J=15.9 Hz, 1H), 8.20 (dd, J=13.9, 9.0 Hz, 1.5H), 8.13-7.85 (m, 5H), 7.63-7.52 (m, 1.5H), 7.47 (d, J=8.4 Hz, 1H), 7.24-7.06 (m, 3.5H), 6.93 (d, J=6.8 Hz, 0.5H), 5.17 (t, J=5.4 Hz, 0.5H), 5.02 (d, J=17.6 Hz, 0.5H), 4.75 (d, J=5.9 Hz, 1H), 4.49 (d, J=18.0 Hz, 1.5H), 3.64 (br s, 1.5H), 3.55-3.41 (m, 2.5H), 3.27-3.09 (m, 4H), 3.05-2.99 (m, 0.5H), 2.31 (s, 1.5H), 2.24 (s, 1.5H), 1.50-0.95 (m, 8H), 0.95-0.82 (m, 3H), 0.74 (t, J=7.5 Hz, 1.5H), 0.71-0.63 (m, 1.5H); MS(ESI+) m/z 798.3 (M+H)+.

Workup

  1. customThe resulting reaction mixture
  2. stirringwas stirred at room temperature for 1 h
  3. customquenched with sat. aq. NH4Cl solution
  4. extractionextracted with EtOAc (1×)
  5. washThe organic layer was washed with 1N aq. HCl solution
  6. extractionthe combined aqueous layer was extracted with EtOAc (2×)
  7. dry with materialThe combined organic extracts were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-678bf1e819e047ba987466de4b002ebe
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Reaction notes

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