Triethylamine → 4-Cyano-2,3-dihydro-indole-1-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide

HRID 2367743Notes

Reaction equation

HRID 2367743 reaction equation
[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH2:3][CH2:2]1.C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.Cl.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:45]=[CH:46][CH:47]=1)[C:31]([NH:33][C:34]1[CH:43]=[C:42]2[C:37]([CH2:38][CH2:39][N:40]([CH3:44])[CH2:41]2)=[CH:36][CH:35]=1)=[O:32].CCN(CC)CC>C(#N)C.CN(C)C1C=CN=CC=1.CN(C=O)C.O>[CH3:44][N:40]1[CH2:39][CH2:38][C:37]2[C:42](=[CH:43][C:34]([NH:33][C:31]([C:30]3[CH:29]=[C:28]([CH:47]=[CH:46][CH:45]=3)[CH2:27][NH:26][C:17]([N:1]3[C:9]4[C:4](=[C:5]([C:10]#[N:11])[CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)=[O:18])=[O:32])=[CH:35][CH:36]=2)[CH2:41]1

Participants

9

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 162444432,3-dihydro-1H-indole-4-carbonitrileHCID 666490723-(2-Methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)benzylamine dihydrochloride

Product 1

HCID 679807514-Cyano-2,3-dihydro-indole-1-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamideYield 11.9%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 2,3-dihydro-1H-indole-4-carbonitrile (25 mg, 0.168 mmol) in acetonitrile (3 ml) add CDI (28 mg, 0.168 mmol) followed by 4-dimethylaminopyridine (DMAP) (42 mg, 0.340 mmol) and stir the sealed vial at 90° C. for 4 h. Concentrate the reaction to dryness and add a solution of 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide dihydrochloride (62 mg, 0.17 mmol) and Et3N (0.081 mL, 0.588 mmol) in DMF (3 mL). Stir the sealed vial at 90° C. for 4 h. Dilute the reaction with water (1 mL) and quench with TFA (0.3 mL). Purify this by prep HPLC (10% to 90% CH3CN/water. Pool and concentrate fractions containing product. Suspend the residue in EtOAc (3 mL) and precipitate with hexane (100 mL). Filter washing with hexane to afford the desired product 4-cyano-2,3-dihydro-indole-1-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide as a solid (12 mg, 0.02 mmol). MS, electrospray 467.1 (M+H), rt 1.22 min.

Workup

  1. concentrationConcentrate
  2. customthe reaction to dryness
  3. stirringStir the sealed vial at 90° C. for 4 h
  4. additionDilute
  5. customquench with TFA (0.3 mL)
  6. customPurify this by prep HPLC (10% to 90% CH3CN/water
  7. concentrationPool and concentrate fractions
  8. additioncontaining product
  9. customprecipitate with hexane (100 mL)
  10. filtrationFilter
  11. washwashing with hexane

Sources & evidence

ORD record
ord-41a730c973d24fabba714ef07165a297
Source dataset
uspto-grants-2014_04
Patent number
US08697911B2

Reaction notes

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