反应 #76136

反应方程式

sodium hydride

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

lithium chloride

sodium hydride

2-dimethylaminoethyl chloride

2-dimethylaminoethyl chloride

chloride

→

solid

收率 26.0%

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

收率 26.0%

溶剂

DMF

反应条件

后处理

1. 1
   workup.WAITfor an additional 16 h at room temperature
2. 2
   温度The reaction mixture was then heated to 70° C.
3. 3
   workup.STIRRINGStirring
4. 4
   workup.WAITwas continued at this temperature for 2 hours under argon
5. 5
   其他the the solvent was removed in vacuo
6. 6
   其他the residue was partitioned between ethyl acetate (150 ml) and water (200 ml)
7. 7
   洗涤The organic layer was washed with more water (150 ml)
8. 8
   萃取The aqueous washings were extracted with more ethyl acetate (2×50 ml)
9. 9
   洗涤The combined ethyl acetate extracts were washed with brine ((50 ml)
10. 10
    干燥dried (Na2SO4)
11. 11
    浓缩concentrated in vacuo
12. 12
    其他Purification by column chromatography
13. 13
    洗涤on elution with ether/hexanes/MeOH (v/v/v: 5:4: 1)

实验过程

To a solution of of tert-butyl 4-[N-[7-chloro-4-oxo-2-piperidin-1-ylmethyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.250 g, 1.69 mmol) in anhydrous DMF (10 ml) under argon was added lithium chloride (0.071 g, 6.24 mmol). When the lithiumn chloride had dissolved the reaction mixture was cooled to 4° C. in an ice-bath and then sodium hydride (60% dispersion in mineral oil, 21 mg, 0.52 mmol) in one portion followed by 2-dimethylaminoethyl chloride (free base, 0.690 g, 6.40 mmol). Stirring was continued at 4° C. for 15 min and then for an additional 16 h at room temperature. The reaction mixture was then heated to 70° C. and then more sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added followed by 2-dimethylaminoethyl chloride (free base, 0.690 g, 6.40 mmol). Stirring was continued at this temperature for 2 hours under argon; the the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (150 ml) and water (200 ml). The organic layer was washed with more water (150 ml). The aqueous washings were extracted with more ethyl acetate (2×50 ml). The combined ethyl acetate extracts were washed with brine ((50 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography on elution with ether/hexanes/MeOH (v/v/v: 5:4: 1) afforded a white solid (0.074 g, 26%), mp 75-77° C.; 1H-NMR (DMSO-d6) 1.35-1.49 (m, 15H, tBu, piperidine CH2CH2CH2), 2.19 (s, 6H, NMe2), 2.40 (m, 4H, piperidine CH2NCH2), 2.53 (t (obscured), 2H, Me2NCH2), 3.27 (s, 1H, C≡CH), 3.61 (s, 2H, 2-CH2), 4.23 (t, J=7.0 Hz, 2H, N3—CH2), 4.40 (s, 2H, CH2C≡C), 4.79 (s, 2H, 6-CH2), 6.77 (d, J=9.0 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.9 Hz, 2′,6′-ArH), 7.82, 7.87 (2×s, 2H, 5-H, 8-H); MS (ESI, m/z) 592, 594 [(M+H)+, 100%, 38% respectively; Cl isotopic pattern].

来源