반응 #76136

반응 방정식

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

수율 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

수율 26.0%

용매

DMF

반응 조건

후처리

1. 1
   workup.WAITfor an additional 16 h at room temperature
2. 2
   온도The 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
   기타the the solvent was removed in vacuo
6. 6
   기타the residue was partitioned between ethyl acetate (150 ml) and water (200 ml)
7. 7
   세척The organic layer was washed with more water (150 ml)
8. 8
   추출The aqueous washings were extracted with more ethyl acetate (2×50 ml)
9. 9
   세척The combined ethyl acetate extracts were washed with brine ((50 ml)
10. 10
    건조dried (Na2SO4)
11. 11
    농축concentrated in vacuo
12. 12
    기타Purification by column chromatography
13. 13
    세척on elution with ether/hexanes/MeOH (v/v/v: 5:4: 1)

실험 절차

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].

출처