Sodium borohydride → N,N-Dibutyl-4-chloro-1-(2-((R)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-5-methyl-1H-pyrazole-3-carboxamide

HRID 528860Notes

Reaction equation

HRID 528860 reaction equation
[Cl:1][C:2]1[C:3]([C:46](=[O:56])[N:47]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:48][CH2:49][CH2:50][CH3:51])=[N:4][N:5]([C:8]2[CH:29]=[CH:28][C:27]([C:30](=[O:45])[NH:31][S:32]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)(=[O:34])=[O:33])=[CH:26][C:9]=2[C:10]([N:12]2[C@@H:21]([C:22](OC)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[C:6]=1[CH3:7].[BH4-].[Na+]>C1COCC1.CO>[CH2:52]([N:47]([CH2:48][CH2:49][CH2:50][CH3:51])[C:46]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:29]=[CH:28][C:27]([C:30](=[O:45])[NH:31][S:32]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)(=[O:34])=[O:33])=[CH:26][C:9]=2[C:10]([N:12]2[C@@H:21]([CH2:22][OH:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[N:4]=1)=[O:56])[CH2:53][CH2:54][CH3:55]

Participants

5

Reactant 2

HCID 4311764Sodium borohydride2×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-carboxylate2×

Product 1

HCID 71062620N,N-Dibutyl-4-chloro-1-(2-((R)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-5-methyl-1H-pyrazole-3-carboxamideYield 34%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (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 (Intermediate 85, 40 mg, 0.050 mmol) in THF (835 μL) and MeOH (170 μL) was added NaBH4 (4 mg, 0.10 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. Additional NaBH4 (20 mg, 0.50 mmol) was added and stirring was continued at room temperature for 30 min. The reaction mixture was then quenched with water, poured into sat. aq. NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo and purified by preparative HPLC to give the title compound (13 mg, 34%). 1H NMR (1:1 CD3OD:CDCl3, mixture of amide rotamers) δ 8.68-8.77 (m, 1H), 8.23 (s, 0.5H), 8.13-7.99 (m, 4.5H), 7.95 (d, J=7.0 Hz, 1.5H), 7.72-7.61 (m, 1H), 7.58-7.45 (m, 1H), 7.23-7.03 (m, 4H), 6.87 (br s, 0.5H), 5.24 (d, J=18.0 Hz, 0.5H), 4.87 (br s, 0.5H), 4.49 (br s, 0.5H), 4.28 (d, J=17.4 Hz, 1H), 4.12 (br s, 1H), 3.63-3.52 (m, 1H), 3.51-3.34 (m, 1.5H), 3.27-2.92 (m, 4H), 2.83-2.53 (m, 1H), 2.28-2.25 (m, 3H), 1.62-0.83 (m, 11H), 0.77-0.69 (m, 2H), 0.64 (br s, 1H); MS(ESI+) m/z 770.3 (M+H)+.

Workup

  1. customThe resulting reaction mixture
  2. stirringstirring
  3. waitwas continued at room temperature for 30 min
  4. customThe reaction mixture was then quenched with water
  5. additionpoured into sat. aq. NH4Cl solution
  6. extractionextracted with EtOAc (3×)
  7. dry with materialThe combined organic extracts were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-2f256132d50548619578c2e551ae9ae3
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Reaction notes

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