Cyanamide → 5-(6,7-dimethoxyquinazolin-4-yl)-N2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine

HRID 2063294Notes

Reaction equation

HRID 2063294 reaction equation
Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[N:17]([C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)=[C:18]=[S:19].[N:34]#[C:35][NH2:36]>C(O)(C)(C)C.C(#N)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][N:4]=[C:3]2[C:2]1[S:19][C:18]([NH:17][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:32][CH:33]=2)=[N:34][C:35]=1[NH2:36]

Participants

5

Reactant 3

HCID 9864CyanamideHCID 118461221-(2-(4-Isothiocyanatophenoxy)ethyl)pyrrolidineHCID 598058494-(Bromomethyl)-6,7-dimethoxyquinazoline

Product 1

HCID 249871705-(6,7-dimethoxyquinazolin-4-yl)-N2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine

Reagents, catalysts & solvents 1

HCID 22050040Acetonitrile tert-butanolSolvent

Procedure

4-(Bromomethyl)-6,7-dimethoxyquinazoline (E-1) (291 mg), 1-(2-(4-isothiocyanatophenoxy)ethyl)pyrrolidine (C-1) (330 mg, 1 eq) and cyanamide (100 mg, 2 eq) were dissolved in 1/1 anhydrous t-butanol/acetonitrile (8 mL). The reaction was stirred for 3 h at room temperature, then quenched with brine. The reaction was extracted with a mixture of ethyl acetate and methanol. The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum and dried overnight under vacuum. The residue was taken up in anhydrous tetrahydrofuran (10 mL) and cooled to −70° C. under nitrogen. Then 2.5 mL of a 1.6 M solution of n-butyllithium in hexanes was added. After 0.5 h at −70° C. the cooling bath was removed. After a total of 4 h the reaction was quenched with water, extracted with a mixture of ethyl acetate and methanol, dried over anhydrous sodium sulfate and concentrated under vacuum. The highly polar product was purified by radial chromatography (chromatotron) eluting with 95% dichloromethane and 5% 2M ammonia in methanol to yield 5-(6,7-dimethoxyquinazolin-4-yl)-N2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine, compound #1, as a bright orange solid (39 mg); 1H NMR (DMSO-d6, 300 MHz) 8.60 (s, 1H), 8.46 (br s, 2H), 7.58 (m, 3H), 7.15 (s, 1H), 6.93 (d, 2H), 4.05 (t, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.83 (t, 2H), 2.50 (m, 4H), 1.70 (m, 4H) ppm; MS (ES) 493.17 (M+H).

Workup

  1. customquenched with brine
  2. extractionThe reaction was extracted with a mixture of ethyl acetate and methanol
  3. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  4. concentrationconcentrated under vacuum
  5. customdried overnight under vacuum
  6. temperaturecooled to −70° C. under nitrogen
  7. additionThen 2.5 mL of a 1.6 M solution of n-butyllithium in hexanes was added
  8. customAfter 0.5 h at −70° C. the cooling bath was removed
  9. customAfter a total of 4 h the reaction was quenched with water
  10. extractionextracted with a mixture of ethyl acetate and methanol
  11. dry with materialdried over anhydrous sodium sulfate
  12. concentrationconcentrated under vacuum
  13. customThe highly polar product was purified by radial chromatography (chromatotron)
  14. washeluting with 95% dichloromethane and 5% 2M ammonia in methanol

Sources & evidence

ORD record
ord-28070109048d47589dc7793ba9095970
Source dataset
uspto-grants-2012_10
Patent number
US08288382B2

Reaction notes

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