Selective alkylation of a 6,7-dihydroxyquinazoline

Tetrahedron Letters

Volumn 46, Issue 45, 2005, Pages 7715-7719

  Harris, Craig S ^a   Hennequin, Laurent F ^a   Kettle, Jason G ^a   Willerval, Olivier A ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Mitsunobu; Quinazoline; Selective

Indexed keywords

6,7 DIHYDROXYQUINAZOLINE; ERLOTINIB; GEFITINIB; LAPATINIB; QUINAZOLINE DERIVATIVE; UNCLASSIFIED DRUG; VANDETANIB;

ALKYLATION; ARTICLE; DRUG SELECTIVITY; DRUG SYNTHESIS; QUANTITATIVE ANALYSIS;

EID: 26444475360     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2005.09.038     Document Type: Article

References (15)

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8. 4 dissolved in 100 ml of water.
9. O. Mitsunobu Synthesis 1 1981
10. D.Y. Curtin Rec. Chem. Prog. 15 1954 111
11. On average, exposure of 7 to solution-phase Mitsunobu conditions resulted in formation of 15-20% of bis-phenol by LCMS. This figure could not be significantly improved upon by changing the order of addition of Mitsunobu reagents.
12. The regiochemistry of the 6-OPiv-7-OH intermediate 6 was determined by NMR experiments. In comparison, to the parent bis-phenol 4, the proton at C-5 shifted 0.5 ppm downfield (as opposed to C-8 proton which did not move) and a NOE was observed between the C-5 proton and the aniline N-H.
13. Solution-based alkylation of 6 resulted in a 52% overall yield of 6,7-heteroalkylated final compound. The main impurities, as judged by LCMS, were homoalkylated product (5-10%) and N-alkylation of the desired compound (5%). Both impurities are practically eliminated using polymer-supported triphenylphosphine suggesting that access to the reactive sites on the polymer is dictated by steric hindrance.
14. A.B. Charette, M.K. Janes, and A.A. Boezio J. Org. Chem. 66 2001 2178
15. Typically: To a stirred suspension of polymer-supported triphenylphosphine (3 equiv), the first alcohol (3 equiv) in DCM (5 ml/g of resin) at 0°C, was added di-tert-azadicarboxylate (DTAD, 3 equiv) followed by 6. The reaction mixture was slowly agitated for 1 h at room temperature, filtered and the filtrate was concentrated. The residue (containing 7 ) was dissolved in methanolic ammonia (7 N) and stirred for 5 h, concentrated to dryness, re-dissolved in THF and re-concentrated to dryness. Phenol 8 was subsequently added to a stirred suspension of polymer-supported triphenylphosphine (4 equiv), the second alcohol (4 equiv), and DTAD (4 equiv) at 0°C. The reaction mixture was slowly agitated for 1 h at room temperature, concentrated and purified by preparative LCMS to afford the desired 6,7-bis-alkylatedquinazolines 9 in acceptable to excellent overall yields.