Oxalyl chloride → Methyl 3-(4-(N-butyl-4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)phenyl)propanoate

HRID 528885Notes

Reaction equation

HRID 528885 reaction equation
[Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].C(Cl)(=O)C(Cl)=O.[CH2:51]([NH:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])=[CH:58][CH:57]=1)[CH2:52][CH2:53][CH3:54].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[CH2:51]([N:55]([C:56]1[CH:57]=[CH:58][C:59]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])=[CH:60][CH:61]=1)[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:17])=[O:18])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:4]=1)=[O:44])[CH2:52][CH2:53][CH3:54]

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 71061016Methyl 3-(4-(butylamino)phenyl)propanoate2×HCID 71062224HCID 71062224, compound

Product 1

HCID 71063126Methyl 3-(4-(N-butyl-4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)phenyl)propanoateYield 57%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent

Procedure

To a solution of 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (116 mg, 0.18 mmol) in CH2Cl2 (1.0 mL) was added oxalyl chloride (48 μL, 0.55 mmol) followed by 1 drop of DMF. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (1.0 mL), and methyl 3-(4-(butylamino)phenyl)propanoate (Intermediate 122A, 17 mg, 0.074 mmol) and i-Pr2EtN (32 μL, 0.18 mmol) were added. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The crude oil was purified by preparative HPLC to give the title compound (30 mg, 57%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.73 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 8.07-8.06 (m, 1H), 8.04-8.00 (m, 2H), 7.94-7.91 (m, 1H), 7.74-7.66 (m, 2H), 7.48 (br s, 1H), 7.39 (br s, 1H), 7.21-7.19 (m, 3.5H), 7.03 (br s, 1H), 6.98-6.96 (m, 0.5H), 6.90 (br s, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.43 (br s, 1H), 4.73 (br s, 1H), 4.44 (br s, 1H), 4.26 (br s, 1H), 4.10 (br s, 1H), 3.90 (br s, 1H), 3.60-3.56 (m, 3H), 3.48 (br s, 2H), 2.94 (br s, 1H), 2.79-2.71 (m, 2H), 2.54-2.46 (m, 2H), 2.12 (s, 3H), 1.43-1.24 (m, 4H), 0.89-0.83 (m, 3H); MS (ESI+) m/z 847.0 (M+H)+.

Workup

  1. customThe resulting reaction mixture
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in CH2Cl2 (1.0 mL)
  4. stirringThe reaction mixture was stirred at room temperature for 2 h
  5. concentrationconcentrated in vacuo
  6. customThe crude oil was purified by preparative HPLC

Sources & evidence

ORD record
ord-8a34bb94cc9a45bfafd5c67831deb244
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Reaction notes

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