The synthesis of the anti-cancer compound 2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}-E-allyl)acetamide (CP-724,714) (1) on multikilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthesis was investigated to identify a safe, environmentally friendly, and robust process for the production of this drug candidate. A convergent and selective synthesis of the candidate was identified which utilizes a Heck coupling of a protected allylamine to install the critical olefin.

Derivatives of 2H-1-benzopyran (1), also known as chromenes, are prominent natural products of many genera of the Asteraceae possessing a wide range of valuable physiological activities. 1 They are also useful intermediates in the synthesis of complex natural products, such as pterocarpans. 2The synthesis of 2H-1-benzopyrans is of considerable current interest. 3 Most pertinent to the present research are synthetic methods involving (1) the palladium-catalyzed coupling of o-iodophenols and tertiary allylic alcohols, 4 (2) the iodoetherification 5 or selenoetherification 6 of o-allylic phenols and subsequent elimination, and (3) the direct oxidation of o-allylic phenols by DDQ 7 or potassium dichromateAdogen 464. 7u While all of these methods afford good yields of 2,2-disubstituted 2H-1-benzopyrans and iodoetherification or direct oxidation afford 2-aryl-2H-1-benzopyrans as well, none of these methods has been reported to work on phenols possessing a wide variety of substitution patterns in the allylic side chain.The cyclization of o-allylic phenols by palladium(II) salts has been reported to produce a variety of cyclic ethers. Phenols bearing a simple allyl, 2-butenyl or cinnamyl group react with NaOMe and stoichiometric amounts of PdCl 2 (PhCN) 2 , stoichiometric Pd(OAc) 2 , or catalytic Pd(OAc) 2 plus Cu(OAc) 2 •H 2 O to afford exclusively 5-membered ring products. 8 However, 2-(2-butenyl)phenol has been reported to react directly with PdCl 2 in methanol to produce a mixture of 5-and 6-membered ring ethers in low yield. While the yields are improved using Pd(OAc) 2 , only 5-membered ring products are obtained. 8 Analogous reactions on 2-(3-methyl-2-butenyl)phenol afford predominantly 6-membered ring ethers using PdCl 2 and a mixture of 5-and 6-membered ring ethers when PdCl 2 plus NaOAc or Pd(OAc) 2 alone are employed. 9 A mixture of 5-membered ring double bond isomers has been observed in the reaction of 2-(2-cycloalkenyl)phenols and Pd(OAc) 2 . 10 The latter process could be made catalytic if run under 1 atm of O 2 . Finally, early attempts to effect the enantioselective cyclization of 2-(2-butenyl)phenol using chiral π-allylpalladium catalysts in the presence of O 2 and Cu(OAc) 2 afforded mixtures of 5-membered ring ethers with low enantioselectivities, 11 but recently 2-(2,3-dimethyl-2-butenyl)phenol and 2-(3,4-dimethyl-3-pentenyl)phenol have been cyclized to the corresponding 5-and 6-membered ring ethers respectively with high enantioselectivities using 10 mol % Pd(O 2 CCF 3 ) 2 , a chiral ligand and benzoquinone. 12 We have observed that the use of an appropriate Pd catalyst under the right reaction conditions will very cleanly produce high yields of 2H-1-benzopyrans from a wide variety of o-allylic phenols and that air can be employed as the sole reoxidant for palladium (eq 1).We 13 and others 14 have previously shown that catalytic amounts of palladium acetate in the presence of oxygen and DMSO provides an excellent Pd(II) catalyst for the cyclization of functionalized alkenes and the conversion of enol...

2,2,2-Trifluoro- and trichloroethyl imidates, which are easily prepared by reaction of a nitrile and a trihaloethanol in the presence of HCl, have proven to be excellent reagents for the preparation of amidines under mild reaction conditions. Depending on the nature of the amine nucleophile, the imidates can react either as the free-base or the hydrochloride salt in a telescoped process. In several cases, the p-bromobenzoate salt of the desired product was directly isolated from the reaction mixture.

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