Реакция #76145

Уравнение реакции

diisopropylethylamine

tert-butyl 4-[N-[7-chloro-3-methyl-4-oxo-2-(4-phenylpiperazin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate

tert-Butyl 4-[N-[7-Chloro-3-methyl-4-oxo-2-(4-phenylpiperazin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate

3-(aminomethyl)pyridine

PyBOP

→

4-[N-[7-Chloro-3-methyl-4-oxo-2-(4-phenylpiperazin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide

Растворители

dichloromethane

trifluoroacetic acid

DMF

Условия реакции

Обработка

1. 1
   ДругоеThe trifluoroacetic acid was then removed in vacuo
2. 2
   workup.ADDITIONthe residue was treated with dichloromethane/toluene
3. 3
   Концентрированиеconcentrated in vacuo
4. 4
   Сушкаdried in vacuo over P2O5 (0.182 g)
5. 5
   workup.DISSOLUTIONThis was dissolved in anhydrous DMF (2 ml) under argon
6. 6
   ДругоеThe solution was placed in an ice-bath
7. 7
   Другоеthe ice-bath was removed
8. 8
   workup.STIRRINGstirring
9. 9
   workup.WAITwas continued under argon for 3 h
10. 10
    ДругоеThe clear solution was then partitioned between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (100 ml)
11. 11
    ПромывкаThe organic layer was washed with more saturated aqueous sodium bicarbonate (100 ml), brine (100 ml)
12. 12
    Сушкаdried (Na2SO4)
13. 13
    Концентрированиеconcentrated in vacuo
14. 14
    ДругоеPurification by column chromatography
15. 15
    Промывкаon gradient elution with methanol in dichloromethane (2 to 5%)
16. 16
    Другоеafforded a white solid which
17. 17
    Другоеwas reprecipitated from dichloromethane/hexanes (0.104 g, 71%), mp 214-216° C

Методика

A solution of tert-butyl 4-[N-[7-chloro-3-methyl-4-oxo-2-(4-phenylpiperazin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.140 g, 0.23 mmol) (Preparation Example 22) in dichloromethane (1.7 ml) and trifluoroacetic acid (2.3 ml) was stirred at room temperature for 55 min with protection from the light. The trifluoroacetic acid was then removed in vacuo, and the residue was treated with dichloromethane/toluene, concentrated in vacuo, and dried in vacuo over P2O5 (0.182 g). This was dissolved in anhydrous DMF (2 ml) under argon. The solution was placed in an ice-bath and then a solution of 3-(aminomethyl)pyridine (0.037 g, 0.34 mmol) in anhydrous DMF (0.2 ml) was added followed by PyBOP® (0.125 g, 0.24 mmol), and finally diisopropylethylamine (0.178 g, 1.38 mmol). The solution was stirred at 0° C. for 5 min, then the ice-bath was removed and stirring was continued under argon for 3 h. The clear solution was then partitioned between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic layer was washed with more saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography, on gradient elution with methanol in dichloromethane (2 to 5%), afforded a white solid which was reprecipitated from dichloromethane/hexanes (0.104 g, 71%), mp 214-216° C. 1H-NMR (DMSO-d6) 2.76 (br s) and 3.11 (br s) (8H, N(CH2CH2)2), 3.20 (s, 1H, C≡CH), 3.63 (s, 3H, N3-Me), 3.70 (s, 2H, 2-CH2), 4.37 (s, 2H, CH2C≡C), 4.45 (d, J 5.7 Hz, 2H, CONHCH2), 4.78 (s, 2H, 6-CH2), 6.74 (t obscured, 1H), 6.90 (d, J=8.6 Hz, 2H), and 7.20 (t, J=8.20 Hz, 2H) (C6H5—N(CH2CH2)2N—), 6.76 (d, J=8.7 Hz, 2H, 3,5′-ArH), 7.32 (dd, J=4.6, 7.8 Hz, 1H, pyr 5-H), 7.68 (d, J=7.7 Hz, pyr 4-H), 7.75 (d, J=8.6 Hz, 2H, 2′,6′-ArH), 7.83, 7.93 (2×s, 2H, 5-H, 8-H), 8.43 (d, J=4.7 Hz, pyr 6-H), 8.52 (s, 1H, pyr 2-H), 8.76 (t, J=5.8 Hz, 1H, CONH).

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