Reaction #76136

Reaction equation

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

Yield 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

Yield 26.0%

Solvents

DMF

Conditions

Workup

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

Procedure

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].

Source