DOI 10.

1007/s10593-014-1599-8
Chemistry of Heterocyclic Compounds, Vol. 50, No. 9, December, 2014 (Russian Original Vol. 50, No. 9, September, 2014)

LETTERS TO THE EDITOR

EMPLOYMENT OF THE TiCl4–ANISOLE–PYRIDINE

SYSTEM IN THE CONDENSATION OF AMIDES WITH
AROMATIC AMINES

D. Chernyak1, Yu. Ponomaryov1, L. L. Varacheva1, А. Lebedev1*, and А. Chernobroviy1

Keywords: amidines, erlotinib, pyridine, titanium(IV) chloride.

Amidine fragment (–N–C=N–) is frequently present in the structures of biologically active compounds
and active pharmaceutical ingridients [1-4], 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., POCl3, SOCl2). 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 TiCl4 in reactions of amides with aromatic amines is limited to few cases [7, 8].
Recently [9] we were able to employ the TiCl4–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-meth-
oxyethoxy)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 TiCl4–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 TiCl4–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.

______
*To whom correspondence should be addressed, e-mail: antons.lebedevs@gmail.com.
1
Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga, LV-1006, Latvia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1469-1472, September, 2014.
Original article submitted September 5, 2014.

1354 0009-3122/14/5009-1354©2014 Springer Science+Business Media New York

 Ar
O HN
1) TiCl4, PhOMe, Py
O O
MeO NH 90°C, 30 min MeO N
MeO 2) ArNH2, 110°C, 5 h MeO
O N O N
1 2a-d
2 a Ar = 3-ethynylphenyl, b Ar = 2-ClC6H4, c Ar = 4-MeOC6H4, d Ar = 3-Py

In order to increase the consumption of the starting amide 1 and yield of the product 2a, while
simultaneously preventing decomposition of the product in an acidic medium, we decided to use an additional
base which would bind hydrogen chloride evolved in the reaction. In the search for the optimal conditions of
this transformation, we have surprisingly found that the use of pyridine as the base allows to bring the
conversion of the starting amide 1 to one end, respectively increasing the yield of the desired product 2a, and
the rate of reaction also increases. Given the fact that the pyridine was used in more than fourfold excess
relative to TiCl4, its volume was sufficient to use it as a solvent. Being more polar than previously used ethers,
pyridine better dissolves the starting amide 1, which in part is also one of the favorable factors for the increased
reaction rate.
During the optimization, the best results were obtained with a brief treatment of the amide 1 suspension
in pyridine with the TiCl4–PhOMe pyridine complex at 90°C and subsequently heating the resulting solution
with 3-ethynylaniline at 110°C. The reaction is complete on average in 5 h. In a series of several dozen
experiments to obtain consistant yields of compound 2a around 70-75%, the optimization of the isolation
protocol allowed to receive technical erlotinib (2a) with a purity of 97-98%.
We tested the efficiency of the developed method in the reaction of amide 1 with other aromatic amines.
As expected, p-methoxyaniline was more reactive due to the presence of electron-donating methoxy group
(yield of compound 2c 83%), although less reactive o-chloroaniline also gave quite satisfactory yield of
compound 2b (67%). For unclear reasons, the reaction with 3-aminopyridine was the slowest under standard
conditions (110°C, 5 h), complete conversion of the amide 1 was never achieved, hence the yield of compound
2d was only 56%.
Quinazoline aromatic system formed in the reaction of the amide 1 with aromatic amines probably
contributes to the reaction rate. To ascertain the applicability of this method to amides with isolated amide group
not forming aromatic or conjugated systems in reactions of this type, we performed the condensation of
4-phenylpyrrolidin-2-one (3) with p-toluidine under conditions designed for the synthesis of erlotinib (2a). It was
found that the lactam 3 also reacts with the aromatic amine upon the action of TiCl4–PhOMe in pyridine, although
in this case the conversion was incomplete providing the amidine 4 in 62% yield.

Ph Ph
1) TiCl4, PhOMe, Py
90°C, 30 min Me
2) 4-MeC6H4NH2
N O N N
H 110°C, 5 h H
3 4

The structure of compound 4 was confirmed by X-ray structural analysis (Fig. 1).
Thus, we have developed a method for the synthesis of amidines by reaction of amides with aromatic
amines in the presence of titanium(IV) chloride and anisole. The novelty of the present method consists in the
use of pyridine both as a base and solvent, that have not previously been described for this type of reactions
involving titanium(IV) chloride. Employment of pyridine allowed to carry out this reaction with aromatic
amines possessing a low reactivity, reaching the complete conversion of the parent amide utilizing only a slight
excess of the amine. The weakly basic medium supported by an excess of pyridine upon the reaction allows to
use the reaction with compounds containing the acid-labile groups.

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Fig. 1. Molecular structure of compound 4 with representation of the atoms by thermal vibration ellipsoids of
50% probability.
1
H NMR spectra were recorded on a Bruker Fourier 300 spectrometer (300 MHz) in CDCl3, internal
standard was the residual signal of the protons of the solvent (7.26 ppm). Elemental analysis was conducted on
the analyzer Carlo Erba EA 1106. Melting points were determined on the instrument SRS OptiMelt. The
reaction was monitored by TLC plates Merck TLC Silica gel 60 F254, eluting with EtOAc–Me2CO, 1:1
(compound 2d) and CH2Cl2–MeOH, 10:1 (the other compounds), visualization was with UV light and treatment
with ninhydrin. We used commercial reagents purchased from Acros and AlfaAesar. Quinazolinone 1 was
obtained as described in [10]. Lactam 3 was obtained by the procedure [11].
Reaction of Quinazolinone 1 with Aromatic Amines. A freshly prepared mixture of TiCl4 (1.7 ml,
15 mmol) and anisole (8.2 ml, 75 mmol) was added dropwise with vigorous stirring to a suspension of
quinazolinone 1 (2.94 g, 10 mmol) in absolute pyridine (6.0 ml). During the addition of TiCl4 and anisole, the
reaction mixture was self-heated up to 40-50°C. After the addition of the reagents, the resulting red-brown
solution was heated to 90°C and stirred for 30 min. Then at the same temperature and with vigorous stirring a
solution of the aromatic amine (15 mmol) in abs. pyridine (3.7 ml) was added dropwise. The reaction mixture
was then stirred at 110°C for 5 h, cooled to room temperature, and poured into a vigorously stirred mixture of
saturated NaHCO3 (200 ml) and EtOAc (100 ml). After 30 min of stirring, the mixture was filtered to remove
the precipitated TiO2, the upper layer was separated, washed with H2O (3×100 ml), saturated NaCl (100 ml),
dried over Na2SO4, and evaporated to dryness. The residue was dried in vacuo and recrystallized.
N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (Erlotinib) (2a). Yield 2.99 g
(76%), beige crystals, mp 158-160°С (MeCN) (mp 159-160°С [10]). 1H NMR spectra of the obained compound
2a corresponds to the literature data [10].
N-(2-Chlorophenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (2b). Yield 2.71 g (67%),
colorless crystals, mp 143-145°С (2-PrOH). 1H NMR, δ, ppm (J, Hz): 3.48 (3Н, s, ОСН3); 3.49 (3Н, s, ОСН3);
3.83-3.89 (4Н, m, 2ОСН2СН2ОМе); 4.28-4.34 (4Н, m, 2ОСН2СН2ОМе); 7.05 (1Н, ddd, J = 1.5, J = 7.4,
J = 8.0, H-5 Ar); 7.25 (1Н, s) and 7.26 (1Н, s, H-5,8); 7.35 (1Н, ddd, J = 1.5, J = 7.4, J = 8.4, H-4 Ar); 7.44
(1Н, dd, J = 1.5, J = 8.0, H-6 Ar); 7.77 (1H, br. s, NH); 8.70 (1Н, s, Н-2); 8.71 (1Н, dd, J = 1.5, J = 8.4, H-3
Ar). Found, %: C 59.47; H 5.50; N 10.36. C20H22ClN3O4. Calculated, %: C 59.48; H 5.49; N 10.40.
6,7-Bis(2-methoxyethoxy)-N-(4-methoxyphenyl)quinazolin-4-amine (2c). Yield 3.32 g (83%), pink
crystals, mp 184-186°С (EtOAc) (mp 186-187°С [12]). 1H NMR spectra of the obained compound 2c
corresponds to the literature data [12].
6,7-Bis(2-methoxyethoxy)-N-(3-pyridyl)quinazolin-4-amine (2d). Yield 2.07 g (56%), colorless
crystals, mp 165-167°С (PhMe). 1H NMR, δ, ppm (J, Hz): 3.43 (3Н, s, ОСН3); 3.44 (3Н, s, ОСН3); 3.75-3.86
(4Н, m, 2ОСН2СН2ОМе); 4.18-4.27 (4Н, m, 2ОСН2СН2ОМе); 7.22 (1Н, s, H-5); 7.34 (1Н, dd, J = 4.6, J = 7.3,
H-5 Py); 7.35 (1H, s, H-8); 7.87 (1H, s, NH); 8.36 (1Н, dd, J = 1.2, J = 4.0, H-6 Py); 8.42 (1Н, ddd, J = 1.2,
J = 1.5, J = 7.5, H-4 Py); 8.64 (1Н, s, Н-2); 8.82 (1Н, d, J = 1.5, H-2 Py). Found, %: C 61.52; H 6.03; N 14.98.
C19H22N4O4. Calculated, %: C 61.61; H 5.99; N 15.13.
N-(4-Methylphenyl)-3-phenyl-3,4-dihydro-2H-pyrrol-5-amine (4) was prepared analogously to the
compounds 2a-d from 4-phenylpyrrolidin-2-one (3) (1.61 g, 10 mmol) and p-toluidine (1.61 g, 15 mmol). The
product was purified by column chromatography on silica gel eluting with CH2Cl2–MeOH, 10:1. Yield 1.55 g
1356
(62%), light-pink crystals, mp 124-127°С (EtOAc). 1H NMR, δ, ppm (J, Hz): 2.32 (3Н, s, СН3); 2.75 (1H, dd,
J = 8.0, J = 15.3) and 3.00 (1H, dd, J = 8.0, J = 15.3, 4-СН2); 3.55 (1H, dd, J = 7.0, J = 9.0) and 3.92 (1H, dd,
J = 7.0, J = 9.0, 2-СН2); 3.64 (1Н, q, J = 7.4, 3-CH); 4.76 (1Н, br. s, NH); 7.02 (2H, d, J = 6.8, H Ar); 7.12 (2H,
d, J = 6.8, H Ar); 7.24-7.38 (5H, m, H Ph). Found, %: C 81.29; H 7.22; N 11.06. C17H18N2. Calculated, %:
C 81.56; H 7.25; N 11.19.

Supporting information, containing crystallographic parameters of compound 4, is available to

authorized users.

Work performed as part of a market-oriented research "Development of technologies for the production
of cytostatic and immunomodulatory drugs" funded by the Ministry of Education and Science of the Republic of
Latvia and the JSC "Grindeks".

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