تفاعل #76136

معادلة التفاعل

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

المردود 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

المردود 26.0%

المذيبات

DMF

ظروف التفاعل

المعالجة

1. 1
   workup.WAITfor an additional 16 h at room temperature
2. 2
   درجة الحرارةThe 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
   أخرىthe the solvent was removed in vacuo
6. 6
   أخرىthe residue was partitioned between ethyl acetate (150 ml) and water (200 ml)
7. 7
   غسيلThe organic layer was washed with more water (150 ml)
8. 8
   استخلاصThe aqueous washings were extracted with more ethyl acetate (2×50 ml)
9. 9
   غسيلThe combined ethyl acetate extracts were washed with brine ((50 ml)
10. 10
    تجفيفdried (Na2SO4)
11. 11
    تركيزconcentrated in vacuo
12. 12
    أخرىPurification by column chromatography
13. 13
    غسيلon elution with ether/hexanes/MeOH (v/v/v: 5:4: 1)

الإجراء التجريبي

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].

المصدر