Amidine fragment (-N-C=N-) is frequently present in the structures of biologically active compounds and active pharmaceutical ingridients [1][2][3][4], since exhibits the properties of pharmacophoric group. Possessing four bonds, which might be linked with the diverse substituents, amidine fragment can be a part of linear structures or nitrogen-containing heterocycles. Additionally, the fragment may serve as a bridgehead in bicyclic molecules, for example, in 1, 8-diazobycyclo[5.4.0]undec-7-ene, employed in the organic synthesis [5], and also in the antipsychotic drug, risperidone [3].One of the most common methods for the synthesis of amidines is the reaction of amides with amines in the presence of condensing agents (e.g., POCl 3 , SOCl 2 ). Titanium(IV) chloride is also used as the condensation agent for the preparation of amidines [6], usually in the form of complexes with the aromatic ethers, such as anisole (PhOMe) [1], that makes the reagent much easier to handle. However, our literature search uncovered that titanium(IV) chloride is primarily being used in the reactions of amides with aliphatic amines, moreover the amine utilized in large excess. Employment of TiCl 4 in reactions of amides with aromatic amines is limited to few cases [7,8].Recently [9] we were able to employ the TiCl 4 -PhOMe complex as a condensation agent in the synthesis of anticancer drug (for non-small cell lung cancer), erlotinib (2а), starting from 6,7-bis(2-methoxyethoxy)quinazolin-4(3Н)-оne (1). The majority of the patented methods for the synthesis of erlotinib involves the preparation of the activated intermediate (e.g., 4-chloroquinazoline derivative [10]) from amide 1, the reaction of which with 3-ethynylaniline yields the target compound 2a. In contrast, using the TiCl 4 -PhOMe complex in polar aprotic solvents (dioxane and diglyme) allowed us to obtain erlotinib (2a) with satisfactory yields in one-pot condensation of amide 1 with 3-ethynylaniline. However, in the course of further development of this method we revealed several drawbacks: poor reproducibility of results (conversion of the starting amide 1 and the yield of product), presumably due to the high sensitivity of a condensing agent to presence of moisture. Adding further amounts of the TiCl 4 -PhOMe complex to the reaction mixture in order to increase the conversion of amide 1 lead to resinification of the reaction mixture, which was presumably due to the instability of triple bond of 3-ethynylaniline and the product 2a in acidic medium.
