A facile total synthesis of imatinib base and its analogues

Article abstract of DOI:10.1021/op700270n

Imatinib and its analogues were successfully synthesized by an improved method in 19.5-46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for the synthesis of imatinib was prepared by coppercatalyzed iV-arylation of heteroarylamme in 82% yield. The copper salts were used instead of the expensive palladium compounds in this C-N bond-forming reaction. The intermediate nitro compound was reduced by a N₂H ₄.H₂O/FeCl₃/C system using water as a solvent in good yield.

Full text of DOI:10.1021/op700270n

Organic Process Research & Development 2008, 12, 490–495
A Facile Total Synthesis of Imatinib Base and Its Analogues
Yi-Feng Liu,† Cui-Ling Wang,*,‡ Ya-Jun Bai,† Ning Han,§ Jun-Ping Jiao,† and Xiao-Li Qi†
Applied Chemical Institute, Northwest UniVersity, Xi’an 710069, P.R. China, School of Life Science, Northwest UniVersity,
Xi’an 710069, P.R. China, and Department of Clinical Laboratory, Mental Health Center of Weinan,
Weinan 714000, P.R. China
Abstract:
Imatinib and its analogues were successfully synthesized by an
improved method in 19.5– 46.2% total yield of six main steps.
Pyrimidinyl amine was prepared by the reaction of enaminone
and guanidine nitrate without the use of a toxic cyanamide. N-(2-
Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key
intermediate for the synthesis of imatinib was prepared by copper-
catalyzed N-arylation of heteroarylamine in 82% yield. The copper
salts were used instead of the expensive palladium compounds in
this C-N bond-forming reaction. The intermediate nitro com-
pound was reduced by a N2H4 ·H2O/FeCl3/C system using water
Figure 1. Chemical structure of imatinib base.
first synthesized by Zimmermann in 1993 (Scheme 1).2 This
method dealt with virulent cyanamide which was used for the
synthesis of phenylguanidine derivatives. In this protocol, the
synthesis of enaminone was complicated by three steps involv-
ing metal sodium and low temperature. The yields of all steps
were not shown in Zimmermann’s paper and patent document.
Loiseleur et al.3 described a process for the preparation of
imatinib base (Scheme 2), in which compound 10 was prepared
by the reductive amination of aldehydes using Pt/C-catalyzed
hydrogenation. This scheme involved Pd2(dba)3CHCl3-catalyzed
C-N coupling reaction with the of use of organophosphorus
reagent rac-BINAP as ligand. Subsequently, Kompella4 and
Szakacs5 also respectively provided an improved process based
on Loiseleur’s method. However, the insufficiencies of these
approaches are (i) the use of a toxic, hazardous reagent cyan-
amide and (ii) using high-cost palladium as catalyst for C-N
coupling reaction. Therefore, these approaches cannot be used
in large-scale industrial applications.
We aimed our research work towards developing an indus-
trially feasible and cost-effective process for the preparation of
imatinib and its analogues. An improved method for the
preparation of imatinib is described in this paper (Scheme 3).
In this protocol, the reaction of enaminone with guanidine nitrate
gave pyrimidinyl amine (compound 13),6 and the coupling
reaction of 2-bromo-1-methyl-4- nitrobenzene with compound
13 was processed in the presence of CuI and N,N′-dimethyl-
ethylene-diamine (DMEDA) ligand to give the key intermediate
as a solvent in good yield.
Introduction
Imatinib mesylate (Gleevec, N-(4-methyl-3-(4-(pyridin-3-yl)-
pyrimidin-2-ylamino)phenyl)-4-((4-methyl piperazin-1-yl)m-
ethyl)benzamide methanesulfonate, STI571, its base such as
Figure 1) is known as an inhibitor of tyrosine kinases and is
indicated for the treatment of chronic myeloid leukemia (CML)
and gastrointestinal stromal tumors (GISTs).1 Imatinib is a
2-phenylamino-pyrimidine derivative. It was developed by
Novartis Pharma AG, Basel, Switzerland, and licensed for
treatment of patients with chronic myeloid leukaemia by the
U.S. Food and Drug Administration (FDA) on 7 November
2001.
In recent years, research concerning imatinib has increased
over the years in particular due to its positive effects on those
patients with chronic myeloid leukemia. But, the method for
synthesis of imatinib has been rarely reported. Imatinib was
* Corresponding author: School of Life Science, TaiBai road No. 229, Xi’an,
710069, P.R. China. Telephone: +86 029 83703107. E-mail: wangcuiling2406@
sina.com.
† Applied Chemical Institute, Northwest University.
‡ School of Life Science, Northwest University.
§ Department of Clinical Laboratory, Mental Health Center of Weinan.
(1) (a) Li, X. Q.; Yang, J.; Chen, X. J.; Liu, J.; Li, H. R.; Zheng, J.; He,
Y.; Chen, Z.; Huang, S. Cancer Genet. Cytogenet. 2007, 176, 166.
(b) El Hajj Dib, I.; Gallet, M.; Mentaverri, R.; Sévenet, N.; Brazier,
M.; Kamel, S. Eur. J. Pharmacol. 2006, 551, 27. (c) Crossman, L. C.;
Brien, S. O. Leuk. Res. 2004, 28S1, S3. (d) Van Oosterom, A. T.;
Judson, J.; Verweij, E.; Stroobants, S.; Donato, D. P. E.; Dimitrijevic,
S.; Martens, M.; Webb, A.; Sciot, R.; Van Glabbeke, M.; Silberman,
S.; Nielsen, O. S. Lancet 2001, 358, 1421. (e) Buchdunger, E.; Cioffi,
C. L.; Law, N.; Stover, D.; Ohno-Jones, S.; Druker, B. J.; Lydon,
N. B. J. Pharmacol. Exp. Ther. 2000, 295, 139. (f) Krystal, G. W.;
Honsawek, S.; Litz, J.; Buchdunger, E. Clin. Cancer Res. 2000, 6,
3319. (g) Weisberg, E.; Griffin, J. D. Blood 2000, 95, 34981. (h)
Druker, B. J.; Lydon, N. B. Clin. InVest 2000, 105, 3.
(2) (a) Zimmermann, J. EP Patent 564,409, 1993. (b) Zimmermann, J.
U.S. Patent 5,521,184, 1996. (c) Zimmermann, J.; Buchdunger, E.;
Mett, H.; Meyer, T.; Lydon, N. B.; Traxler, P. Bioorg. Med. Chem.
Lett. 1996, 11, 1221.
(3) Loiseleur, O.; Kaufmann, D.; Abel, S.; Buerger, H. M.; Meisenbach,
M.; Schmitz, B.; Sedelmeier, G. W.O.Patent 03/066,613, 2003.
(4) Kompella, A.; Bhujanga Rao, A. K. S.; Venkaiah Chowdary, N. W.O.
Patent 2004/108,699, 2004.
(5) Szakacs, Z.; Beni, S.; Varga, Z.; Orfi, L.; Keri, G.; Noszal, B. J. Med.
Chem. 2005, 48, 249.
(6) Huang, W.-S.; Shakespeare, W. C. Synthesis 2007, 2121.
490
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Vol. 12, No. 3, 2008 / Organic Process Research & Development
10.1021/op700270n CCC: $40.75
2008 American Chemical Society
Published on Web 04/15/2008

Scheme 1. Zimmermann’s route for the preparation of imatinib base
Scheme 2. Loiseleur’s route for the preparation of imatinib base
6 in 82% yield. Intermediate 6 was reduced by N2H4 ·H2O/
FeCl3/C system in water solvent. Sequentially, compound 7 was
acylated with the corresponding acid chlorides to give the amide
18. The aminating reaction of benzyl chloride on the amide 18
molecule with 1-methylpiperazine finally yielded imatinib base.
yield. In contrast to Zimmermann’s route, formation of pyri-
midinyl cycle by the reaction of enaminone with guanidine
nitrate (not to use N-arylguanidine prepared by a toxic cyana-
mide) is more valuable. Though the C-N coupling reaction
was not used in Zimmermann’s route, the synthesis of 4-((4-
methylpiperazin-1-yl)methyl)benzoyl chloride (compound 8)
was complicated by expensive Pt/C-catalyzed hydrogenation.
Compounds 15 and 17 were easily synthesized by conventional
method, or purchased from a chemical company.
For the coupling reaction of compounds 13 and 15, we
incipiently adopted the conventional Ullmann reaction.8 Using
copper powder as a catalyst, the reaction of 2-iodo-1-methyl-
4-nitrobenzene with pyrimidinyl amine 13 at elevated temper-
atures (200 °C) yielded only 5% of the aimed for compound,
and the main products were biaryl compound. In recent years,
the “classic” Ullmann reaction has been transformed into
“Ullmann-type” reactions including copper-catalyzed nucleo-
philic aromatic substitution between various nucleophiles with
aryl halides. In “Ullmann-type” reactions, the use of copper
salts of catalyst, base, and ligand allowed the coupling reaction
Results and Discussion
N,N-Dimethylformamide dimethyl acetal (DMF-DMA), as
well as other N,N-dimethylformamide dialkyl acetals are very
useful reagents in organic synthesis. As a formylating reagent,
DMF-DMA is used in the synthesis of enaminones from active
methylene compounds. Enaminones are found to be useful
intermediates in the formation and modification of many
heterocyclic compounds. In general, enaminone formation has
been conducted in refluxing aromatic hydrocarbons. In this
paper, The enamination of acetylpyridine with DMF-DMA in
xylene provided enaminone 5 in 92.6% yield.7 The refluxing
reaction of enaminone 5 with guanidine nitrate was processed
in n-butanol for 10 h, to give pyrimidinyl amine 13 in 85.5%
(7) (a) Schuda, P. F.; Ebner, C. B.; Morgan, T. M. Tetrahedron Lett. 1986,
27, 2567. (b) Lowe, W.; Braun, B.; Muller, B. J. Heterocycl. Chem.
1994, 31, 1577. (c) Selic, L.; Gradadolnik, S. G.; Stanovnik, B. HelV.
Chim. Acta 1997, 80, 2418.
(8) (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Hartwig, J. F. Pure
Appl. Chem. 1999, 71, 1417. (c) Driver, M. S.; Hartwig, J. F. J. Am.
Chem. Soc. 1997, 119, 8232.
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491

Scheme 3. Schematic synthetic procedure of imatinib and its analogues
to go smoothly in mild conditions.9 However, copper-mediated
N-arylation of heteroarylamines based on the “Ullmann-type”
reaction was rarely reported, although there were a few
examples of Pd-catalyzed N-arylation of heteroarylamines by
the Buchwald-Hartwig cross-coupling reaction in the past
literature.3,10 However, the high cost of palladium and the use
of toxic organophosphous reagents still remained for this
method. We used copper salts instead of expensive palladium
compounds in the coupling reaction of heteroarylamine and
employed various copper sources, ligands, bases, and solvents
to evaluate and set up the most effective conditions. The detailed
contents about optimization of the reaction conditions for
copper-mediated N-arylation of the heteroarylamines has been
published.11 The optimal reaction conditions were the use of
CuI as catalyst, N,N′-dimethylethylenediamine as ligand, KI as
accelerant, and K2CO3 as base, and the reaction was processed
in dioxane at 100 °C for 20 h. A key intermediate 6 was first
prepared by this copper-catalyzed C-N bond-forming reaction
on the optimized condition in 82% yield.
respectively Fe/HCl, SnCl2/HCl, hydrazine hydrate/Raney Ni,
hydrazine hydrate/FeCl3/C system as reducing agents. The
observed results show that Fe/HCl and SnCl2/HCl were incon-
venient for the isolation of the product due to production of
the emulsions of metallic hydroxides. SnCl2 also was more
expensive and toxic. In comparison to other reduction process,
the reduction with hydrazine hydrate produces harmless byprod-
ucts such as nitrogen gas and water.12 Nitro compound 6 was
reduced efficiently by hydrazine hydrate in the presence of a
catalytic amount of FeCl3/C in 83.8% yield.
The acylating reaction of compound 7 was more easily
processed in very good yield due to high activity of 4-(chlo-
romethyl)benzoyl chloride. Finally, the mixture of intermediate
18 and 1-methylpiperazine was heated to reflux temperature
and maintained for 2 h, and imatinib base was obtained in 91.4%
yield (HPLC purity of 99.5%). Nine analogues of imatinib were
also synthesized (Table 1).
According to our scheme for the preparation of imatinib,
six main steps (a, b, d, e, g, h in Scheme 3) in the reaction may
produce some byproducts such as in step a: methanol; step b:
sodium nitrate, dimethylamine; step d: potassium bromide, a
small amount of catalyst and ligand; step e: nitrogen gas, a small
amount of catalyst; steps g, h: hydrogen chloride gas. Proper
post treatment of these byproducts is harmless to the environ-
ment. Dimethylamine and hydrogen chloride gas can be
absorbed by respectively the diluent solution of HCl and NaOH.
Toxic cyanamide and organophosphorus reagent were not used
for consideration of the safety of operator and environment.
Reduction of nitro compounds can be achieved by several
reagents in solution-phase reactions. Reactions with metals
(usually Fe, Sn, Zn, or Al) in the presence of small amounts of
acids are the most vigorous reduction methods. We used
(9) (a) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609. (b) Ma, D.;
Cai, Q. Org. Lett. 2003, 5, 3799. (c) Wolf, C.; Liu, S.; Mei, X.; August,
A. T.; Casimir, M. D. J. Org. Chem. 2006, 71, 3270. (d) Pan, Y.; Lu,
H.; Fang, Y.; Fang, X.; Chen, L.; Qian, J.; Wang, J.; Li, C. Synthesis
2007, 1242.
(10) (a) Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org.
Lett. 2002, 4, 3481. (b) Anderson, K. W.; Tundel, R. E.; Ikawa, T.;
Altman, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
6523.
(11) Liu, Y. F.; Bai, Y. J.; Zhang, J.; Li, Y. Y.; Jiao, J. P.; Qi, X. L. Eur.
J. Org. Chem. 2007, 36, 6084.
(12) Larsen, J. W.; Freund, M.; Kim, K. Y.; Sidovar, M.; Stuart, J. Carbon
2000, 38, 655.
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Table 1. Results of synthesis of imatinib and its analoguesa
a Experiments were performed on a 0.1 mol scale for steps a, b, c, f; 1 mmol scale for steps d, e, g, h. b Isolated yield. c The total is the total yields of six main steps (a, b,
d, e, g, h) in Scheme 3.
Conclusions
In conclusion, we have developed a mild, convenient, and
Experimental Section
General. All reactions were processed under a nitrogen
atmosphere in oven-dried Schlenk-type glassware. Elemental
analyses were performed by Elementar Vario EL III. IR spectra
inexpensive approach for the preparation of imatinib and its
analogues. Imatinib and nine analogues were obtained in good
yield. In this protocol, the reaction of enaminone with guanidine
was processed to give pyrimidinyl amine without the use of a
toxic cyanamide. It is exciting that N-(2-methyl-5-nitrophenyl)-
4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for
the synthesis of imatinib was prepared by a copper-catalyzed
C-N bond-forming reaction of heteroarylamine. We also used
the N2H4 ·H2O/FeCl3/C system to reduce the intermediate nitro
compound. As a result this improved method for the preparation
of imatinib is less hazardous and more environmentally friendly,
and has potential for industrial application.
1
were recorded on a Bruker Equinox-55. H NMR(400 MHz)
and 13C NMR (100 MHz) spectra were recorded on a Varian
Inova 400 MHz instrument using DMSO-d6 and CDCl3 as the
solvent with chemical shifts reported relative to tetramethylsilane
(TMS). The purity of products was analyzed by Shimadzu LC-
10AT high performance liquid chromatograph with a DAD
detector and a Shim-pack VP-ODS C18 column (150 mm ×
4.6 mm). All materials were weighed in the air. Flash column
chromatography was performed with silica gel (100–200 mesh).
All reagents were used as purchased from commercial suppliers
without further purification.
Vol. 12, No. 3, 2008 / Organic Process Research & Development
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493

Synthetic Procedure for Imatinib and Its Analogues. Here
is detailed approach for the preparation of imatinib base. The
same synthetic procedure used to make imatinib was used for
all the imatinib analogues.
4-(pyridin-3-yl) pyrimidin-2-amine (0.307 g, 1 mmol), hydrazine
monohydrate (0.154 g of 65% solution in water, 2 mmol), FeCl3
(2.1 mg, 0.013 mmol), active carbon (0.02 g), and water (40
mL). The reaction mass was heated to 80 °C and maintained
for 6–8 h. TLC of reaction mass indicated the absence of starting
compound. The reaction mixture was cooled down to room
temperature. Insoluble materials were filtered off, and the filtrate
was extracted with ethyl acetate (10 mL × 5). The organic
layers were then washed with brine and dried over anhydrous
MgSO4. The solvent was removed in vacuo, and the resultant
precipitate was purified by Kugelrohr distillation to give 0.232
g (83.8%) of the product as yellow crystals. Mp 140–141 °C
(lit.:4 140–143 °C).
4-(Chloromethyl)benzoyl Chloride (17). Into a 250 mL,
one neck, round-bottomed, flask equipped with a mechanical
stirrer and reflux condenser were charged 4-(hydroxymethyl)-
benzoic acid (15.2 g, 0.1 mol), dichloromethane (50 mL), and
thionyl chloride (50 mL). The reaction mass was heated to re-
flux temperature and maintained for 5 h. The excess thionyl
chloride and dichloromethane were removed off in vacuo. The
residue was cooled to 0–5 °C, and maintained for 12 h to give
16.5 g (87.2%) of the title compound as white crystals. mp
30–32 °C.
4-(Chloromethyl)-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimi-
din-2-ylamino)phenyl)benzamide (18). Into a 25 mL, one
neck, round-bottomed, flask equipped with a mechanical stirrer
and reflux condenser were charged 6-methyl-N-(4-(pyridin-3-
yl)pyrimidin-2-yl)benzene-1,3-diamine (0.277 g, 1 mmol),
THF (5 mL), and TEA (0.29 mL, 2 mmol). The reaction
mass was cooled down to 0 °C and maintained for 10 min. A
solution of 4-(chloromethyl)benzoyl chloride (0.217 g, 1.15
mmol) in THF (2 mL) was added dropwise within 10 min. TLC
of reaction mass indicated the absence of starting compound.
After stirring at 0 °C for 3 h, to the reaction mass was added
water (15 mL) dropwise, and a light-yellow precipitate appeared.
Then, the resultant precipitate was collected by filtration, washe
with 100 mL of water, and dried at 75–80 °C to yield 0.399 g
(93.0%) of the desired product as light-yellow crystals. Mp
266–268 °C.
N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phe-
nyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (1). Into
a 25 mL, one neck, round-bottomed, flask equipped with a
mechanical stirrer and reflux condenser were charged 4-(chlo-
romethyl)-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylami-
no) phenyl)benzamide (0.429 g, 1 mmol), and 1-methylpiper-
azine (11.1 mL, 0.1 mol). The reaction mass was heated to
reflux temperature and maintained for 3 h. TLC of reaction mass
indicated the absence of compound (18). The reaction mixture
was cooled down to room temperature, and water (10 mL) was
added. At the same time, a white precipitate appeared. Then,
the resultant precipitate was collected by filtration. Washing with
100 mL of water and drying at 75–80 °C yielded 0.45 g (91.4%,
HPLC purity of 99.5%) of the desired product as white crystals.
Mp 207–210 °C (lit.:5 206–209 °C); IR (KBr) 3412, 3291, 2969,
2966, 2935, 2804, 2720, 1630, 1590, 1534, 1509, 1480, 1452,
1418, 1384, 1350, 1009, 831, 763, 703, 669; 1H NMR(DMSO-
d6) δ 10.19(s, 1H), 9.28(s, 1H), 9.02(s, 1H), 8.69(d, J ) 4.0
Hz, 1H),8.52(d, J ) 5.2 Hz, 1H), 8.48(d, J ) 8.0 Hz, 1H),
3-(Dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (5).
Into a 250 mL, one neck, round-bottomed flask equipped with
a mechanical stirrer and reflux condenser were charged acetylpy-
ridine (11 mL, 0.1 mol), N,N-dimethylformamide dimethylacetal
(27 mL, 0.2 mol), and xylene (35 mL). The reaction mass was
heated to 140 °C and maintained for 20 h, and the methanol
formed in the reaction was removed every 4 h by distillation.
When TLC of reaction mass indicated the absence of starting
compound, the reaction mixture was cooled down to room
temperature. Hexane (20 mL) was added to the reaction mass
and kept under stirring for 20 min without allowing the mass
temperature to change more than 5 °C. The resultant reaction
mass was collected by filtration and washed with hexane, and
the crude product was recrystallized from xylene to give 16.3 g
(92.6%) of the desired product as yellow crystals. Mp 81–82
°C (lit.:13 82–84 °C).
4-(Pyridin-3-yl)pyrimidin-2-amine (13). Into a 250 mL,
one neck, round-bottomed flask equipped with a mechanical
stirrer and reflux condenser were charged 3-(dimethylamino)-
1-(pyridin-3-yl) prop-2-en-1-one (17.6 g, 0.1 mol), guanidine
nitrate (12.2 g, 0.1 mol), sodium hydroxide (4 g, 0.1 mol), and
n-butanol (125 mL). The reaction mass was heated to reflux
temperature and maintained for 12 h. TLC of reaction mass
indicated the absence of starting compound. The reaction
mixture was cooled down to room temperature. The precipitate
was collected by filtration and was washed with 500 mL of
water. The wet cake was dried in the oven at 75–80 °C, and
14.7 g (85.5%) of the desired product was obtained as white
crystals. Mp 189–191 °C (lit.:14 186–188 °C).
2-Bromo-1-methyl-4-nitrobenzene (15). See: Organic Syn-
theses; Wiley and Sons: New York, 1963; Collect. Vol. 4, p
114 and 1958; Vol. 38, p 11.
N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-
amine (6). 4-(Pyridin-3-yl)pyrimidin-2- amine (0.189 g, 1.1
mmol), CuI (47.6 mg, 0.25 mmol), and anhydrous K2CO3
(0.276 g, 2 mmol) were added to a Schlenk-type three-neck
flask fitted with thermometer, magnetic stirbar, and septum. The
flask was evacuated and back filled with N2 three times. Dioxane
(5 mL), 2-bromo-1-methyl-4- nitrobenzene (0.216 g, 1 mmol),
and DMEDA (22.0 mg, 0.25 mmol) were added by syringe at
room temperature. The reaction mixture was stirred at 100 °C
for 20 h and cooled to room temperature. Concentrated
ammonia (4 mL) and a saturated solution of NaCl (20 mL)
were added, and the mixture was extracted with ethyl acetate
(3 × 15 mL). The organic layers were concentrated in vacuo,
and the residue was purified by column chromatography on
silica gel to give 0.252 g (82.0%) of the title compound as
yellowish powder. Mp 194–195 °C (lit.:4 194–199 °C).
6-Methyl-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-
diamine (7). Into a 100 mL, one neck, round-bottomed flask
equipped with a mechanical stirrer, reflux condenser, and
thermometer socket were charged N-(2-methyl-5-nitrophenyl)-
(13) Tseng, S. S.; Dusza, J. P.; Epstein, J. W. U.S. Patent 4,888,345, 1989.
(14) Bennett, G. B.; Mason, R. B.; Alden, L. J. J. Med. Chem. 1978, 21,
623.
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8.08(s, 1H), 7.90(d, J ) 8.0 Hz, 2H), 7.55–7.43(m, 5H), 7.20(d,
J ) 8.8 Hz, 1H), 3.52(s, 2H), 2.34(bs, 8H), 2.22(s, 3H), 2.15(s,
3H); 13C NMR (CDCl3) δ 173.8, 165.4, 162.7, 159.0, 151.5,
148.5, 142.5, 137.8, 136.5, 134.9, 133.8, 132.7, 130.8, 129.3,
126.9, 124.1, 123.8, 124.0, 115.2, 112.9, 108.4, 62.5, 55.1, 53.1,
46.0, 17.7; Anal. Calcd for C29H31N7O: C, 70.55; H, 6.33; N,
19.87. Found: C, 70.13; H, 6.20; N, 19.32.
N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phe-
nyl)-4-(piperidin-1-ylmethyl)benzamide (1a): mp 197–200
°C; 13C NMR (CDCl3) δ 173.8, 165.5, 160.5, 159.0, 148.5,
147.4, 142.6, 137.8, 136.6, 135.0, 133.8, 132.6, 130.8, 129.5,
127.0, 124.1, 123.8, 115.3, 112.9, 108.4, 63.2, 54.5, 25.8, 17.7;
Anal. Calcd for C29H30N6O: C, 72.77; H, 6.32; N, 17.57. Found:
C, 72.46; H, 6.10; N, 17.35.
N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phe-
nyl)-4-(morpholinomethyl)benzamide (1b): mp 210–212 °C;
13C NMR (CDCl3) δ 173.8, 165.4, 162.7, 160.5, 159.0, 151.5,
148.5, 137.7, 136.6, 134.9, 134.0, 132.6, 130.8, 129.3, 127.1,
124.2, 123.7, 115.3, 113.0, 108.3,66.9, 62.9, 53.6, 17.7; Anal.
Calcd for C28H28N6O2: C, 69.97; H, 5.88; N, 17.50. Found: C,
69.71; H, 5.65; N, 17.25.
4-((1H-Imidazol-1-yl)methyl)-N-(4-methyl-3-(4-(pyridin-
3-yl)pyrimidin-2-ylamino)phenyl)benzamide (1c): mp 200–203
°C; 13C NMR (CDCl3) δ 172.8, 163.1, 160.9, 155.7, 150.2,
148.6, 142.1, 138.9, 136.0, 134.7, 133.7, 133.1, 131.0, 130.5,
129.0, 128.4, 127.6, 125.3, 124.5, 120.5, 110.9, 102.8, 54.1,
17.2; Anal. Calcd for C27H23N7O: C, 70.25; H, 5.03; N, 21.25.
Found: C, 69.99; H, 5.15; N, 21.01.
C29H29N5O2: C, 72.62; H, 6.09; N, 14.61. Found: C, 72.46; H,
5.89; N, 14.29.
N-(4-Methyl-3-(4-(pyridin-2-yl)pyrimidin-2-ylamino)phe-
nyl)-4-((4-methylpiperazin-1-yl)methyl) benzamide (1f): mp
159–161 °C; 13C NMR (CDCl3) δ 173.5, 163.4, 162.9, 161.0,
155.1, 149.3, 142.5, 138.7, 137.0, 134.2, 132.6, 130.5, 129.3,
126.8, 124.7, 124.1, 120.4, 110.8, 107.4, 61.5, 55.6, 53.1, 44.5,
17.7; Anal. Calcd for C29H31N7O: C, 70.55; H, 6.33; N, 19.87.
Found: C, 70.23; H, 6.42; N, 19.08.
N-(4-Methyl-3-(4-(pyrazin-2-yl)pyrimidin-2-ylamino)phe-
nyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide(1g). mp
195–197 °C; 13C NMR (CDCl3) δ 172.7, 164.2, 163.4, 159.1,
145.9, 144.2, 143.8, 142.0, 141.5, 138.7, 133.6, 132.3, 130.0,
128.7, 126.9, 124.3, 112.1, 61.8, 55.0, 52.9, 45.7, 17.8; Anal.
Calcd for C28H30N8O: C, 67.98; H, 6.12; N, 22.66. Found: C,
67.57; H, 6.19; N, 22.13.
N-(3-(4-(Furan-2-yl)pyrimidin-2-ylamino)-4-methylphe-
nyl)-4-((4-methylpiperazin-1-yl)methyl) benzamide (1h): mp
170–172 °C; 13C NMR (CDCl3) δ 168.1, 158.4, 156.3, 151.8,
144.8, 142.3, 137.9, 136.5, 133.9, 130.7, 129.2, 127.0, 123.9,
112.8, 112.5, 106.6, 54.9, 52.9, 45.9, 17.7; Anal. Calcd for
C28H30N6O2: C, 69.67; H, 6.27; N, 17.42. Found: C, 69.85; H,
6.04; N, 17.11.
N-(4-Methyl-3-(4-(thiophen-2-yl)pyrimidin-2-ylamino)phe-
nyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (1i): mp
186–188 °C; 13C NMR (CDCl3) δ 172.3, 163.6, 159.9, 157.0,
141.8, 140.0, 138.7, 133.2, 132.0, 130.1, 129.3, 127.5, 127.3,
127.0, 124.9, 123.8, 111.5, 108.2, 104.7, 62.3, 54.4, 52.7, 42.9,
17.6; Anal. Calcd for C28H30N6OS: C, 52.32; H, 4.71; N, 13.08.
Found: C, 52.48; H, 4.51; N, 13.16.
N-(4-Methyl-3-(4-phenylpyrimidin-2-ylamino)phenyl)-4-
(piperidin-1-ylmethyl)benzamide (1d): mp 202–207 °C; 13
C
NMR (CDCl3) δ 173.7, 165.4, 160.4, 158.5, 138.0, 137.0, 136.5,
133.7, 130.8, 129.4, 129.0, 128.8, 127.2, 126.9, 123.8, 116.9,
115.0, 112.6, 108.6., 63.3, 54.5, 25.9, 17.7; Anal. Calcd for
C30H31N5O: C, 75.43; H, 6.55; N, 14.67. Found: C, 75.20; H,
6.38; N, 14.49.
N-(4-Methyl-3-(4-phenylpyrimidin-2-ylamino)phenyl)-4-
(morpholinomethyl)benzamide (1e): mp 200–206 °C; 13C
NMR (CDCl3) δ 174.1, 163.7, 161.0, 158.9, 142.1, 139.0, 133.5,
133.0, 132.4, 130.2, 129.7, 129.1, 127.9, 127.6, 127.1, 124.3,
111.8, 107.4, 104.8, 67.2, 59.9, 54.4, 17.6; Anal. Calcd for
Acknowledgment
Financial support was provided by the Nature Science
Foundation of ShaanXi Province, China (03JC01), and Scientific
Technology Foundation of Educational Committee of ShaanXi
Province, China (2003k08-G5).
Received for review November 23, 2007.
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