Diisopropylcarbodiimide → Dasatinib Val-NH2

HRID 2410246Notes

Reaction equation

HRID 2410246 reaction equation
CC(C)[N:3]=C=NC(C)C.[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH:43](C(OC(C)(C)C)=O)[C@H:44]([C:48]([OH:50])=O)[CH:45]([CH3:47])[CH3:46].C1(C)C=CC(S([O-])(=O)=O)=CC=1.CN(C)C1C=C[NH+]=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH2:43][C@H:44]([C:48]([NH2:3])=[O:50])[CH:45]([CH3:47])[CH3:46]

Participants

7

Reactant 4

HCID 12734DiisopropylcarbodiimideHCID 83693Boc-L-ValineHCID 3062316DasatinibHCID 111854944-(Dimethylamino)pyridinium 4-toluenesulfonate

Product 1

HCID 131731796Dasatinib Val-NH2Yield 68%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

DIC (302 mg, 2.4 mmol) was added with stirring to a DMF (4 mL) solution of dasatinib (196 mg, 0.4 mmol), Boc-Val-OH (104 mg, 0.48 mmol), and DPTS (124 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for five hours. After this period, DCM (100 mL) was added to the reaction mixture which was allowed to stir for an additional 20 minutes. The mixture was transferred into a separatory funnel and washed with 5% NaCl (100 mL×3). The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography (biotage: DCM/CH3OH, CH3OH, 5-10%, 20 CV). The obtained solid was redissolved in 5.0 mL of TFA/DCM (2:3) and the solution was stirred at room temperature for one hour. TFA and DCM were removed under reduced pressure. The residue was dissolved in 150 mL of DCM and the resulting solution was washed with 5% Na2CO3 and then 5% NaCl. The desired product was obtained (160 mg, yield: 68%) as a white solid; 1H NMR (500 MHz, CD3OD). δ 0.96 (d, 3H), 0.99 (d, 3H), 2.03 (m, 1H), 2.32 (s, 3H), 2.47 (s, 3H), 2.59 (t, 4H), 2.71 (t, 2H), 3.64 (t, 4H), 4.32 (m, 2H), 6.00 (s, 1H), 7.22 (m, 2H), 7.34 (d, 1H), 8.14 (s, 1H); LC-MS (m/z) calcd., 586.2. Found 587.2 [M+H]+.

Workup

  1. waitAfter this period
  2. stirringto stir for an additional 20 minutes
  3. customThe mixture was transferred into a separatory funnel
  4. washwashed with 5% NaCl (100 mL×3)
  5. dry with materialThe organic phase was dried over Na2SO4
  6. customthe solvent removed under reduced pressure
  7. customThe resulting residue was purified by column chromatography (biotage: DCM/CH3OH, CH3OH, 5-10%, 20 CV)
  8. dissolutionThe obtained solid was redissolved in 5.0 mL of TFA/DCM (2:3)
  9. stirringthe solution was stirred at room temperature for one hour
  10. customTFA and DCM were removed under reduced pressure
  11. dissolutionThe residue was dissolved in 150 mL of DCM
  12. washthe resulting solution was washed with 5% Na2CO3

Sources & evidence

ORD record
ord-ad272eb70319438aa9c5b0776fa04804
Source dataset
uspto-grants-2014_08
Patent number
US08816077B2

Reaction notes

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