Diisopropylcarbodiimide → Dasatinib Leu-NH2

HRID 2410245Notes

Reaction equation

HRID 2410245 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:49]([OH:51])=O)[CH2:45][CH:46]([CH3:48])[CH3:47].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:49]([NH2:3])=[O:51])[CH2:45][CH:46]([CH3:48])[CH3:47]

Participants

7

Reactant 4

HCID 12734DiisopropylcarbodiimideHCID 83170L-Leucine, N-((1,1-dimethylethoxy)carbonyl)-HCID 3062316DasatinibHCID 111854944-(Dimethylamino)pyridinium 4-toluenesulfonate

Product 1

HCID 131731795Dasatinib Leu-NH2Yield 61%

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-Leu-OH (111 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 resulting 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%, 25 CV). The obtained solid was dissolved 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 5% NaCl. The desired product was obtained (146 mg, yield: 61%) as a white solid; 1H NMR (500 MHz, CD3OD). δ 0.98 (m, 6H), 1.46 (m, 1H), 1.60 (m, 1H), 1.80 (m, 1H), 2.33 (s, 3H), 2.48 (s, 3H), 2.62 (t, 4H), 2.74 (t, 2H), 3.50 (m, 1H), 3.65 (t, 4H), 4.33 (m, 2H), 6.02 (s, 1H), 7.25 (m, 2H), 7.36 (d, 1H), 8.15 (s, 1H); LC-MS (m/z) calcd., 600.2. Found 601.1 [M+H]+.

Workup

  1. waitAfter this period
  2. stirringto stir for an additional 20 minutes
  3. customThe resulting 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%, 25 CV)
  8. dissolutionThe obtained solid was dissolved 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 and 5% NaCl

Sources & evidence

ORD record
ord-8560f25dc3624c5c82aaee0dd2796073
Source dataset
uspto-grants-2014_08
Patent number
US08816077B2

Reaction notes

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