Rational design and synthesis of novel Syk-kinase inhibitors

Article abstract of DOI:10.1016/j.mencom.2012.03.006

Molecular modeling and subsequent synthesis of novel Syk-kinase inhibitors, 7H-pyrrolo[2,3-d]pyrimidine and 1,3,5-triazine derivatives, have been carried out. The best of the obtained compounds demonstrated to inhibit Syk-kinase activity at IC₅₀

Full text of DOI:10.1016/j.mencom.2012.03.006

Electronic supplementary materials Mendeleev Commun., 2012, 22, 73−74
Rational design and synthesis of novel Syk-kinase inhibitors
Alexey A. Zeifman, Ilya Yu. Titov, Igor V. Svitanko, Tatiana V. Rakitina, Aleksey V.
Lipkin, Viktor S. Stroylov, Oleg V. Stroganov, Fedor N. Novikov* and Ghermes G. Chilov
6-[(6-Chloropyrimidin-4-yl)amino]-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-one.
2,4-Dichloro-1,3,5-triazine (0.17 g, 1.15 mmol, prepared according to ref. 1 was dissolved in
5 ml of dry degassed DMF. 6-Amino-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3-(4H)-one
(0.22 g, 1.15 mmol, prepared according to ref. 2 was added and the reaction mixture was stirred
at 60 °C for 8 h under inert atmosphere. Solvent was evaporated at 5 Torr. The residue was
washed with water (2x5 ml) and separated chromatographically eluting with
chloroform: methanol mixture of increasing polarity. The standard workup procedure afforded
the title product (0.28 g, 0.92 mmol, 80%). 1H NMR (500 MHz, DMSO-d6) 1.12 (s, 3Н), 1.13 (s,
3Н), 7.43 (d, 1Н), 7.85 (d, 1Н), 7.88 (s, 1Н), 7.65 (bs, 1H), 10.84 (s ,1H).
2,2-Dimethyl-6-((4-[(3,4,5-trimetoxyphenyl)amino]-pyrimidin-4-yl)amino)-2H-pyrid[3,2-
b][1,4]oxazin-3(4H)-one 1.
The above compound (0.28 g, 0.95 mmol) was dissolved in dry degassed DMF.
Trimetoxyaniline (0.17 g, 0.92 mmol) was added and the reaction mixture is stirred at 110 °C for
6 h under inert atmosphere. Solvent was evaporated at 5 Torr. The residue was washed with
water (2x5 ml) and separated chromatographically eluting with chloroform−methanol mixture of
increasing polarity. The standard workup procedure afforded compound 1 (0.62 g, 65%). 1H
NMR (500 MHz, DMSO-d6) 1.11 (s, 3Н), 1.12 (s, 3Н), 3.82 (s, 3Н), 3.84 (s, 6Н), 6.79 (s, 2Н),
7.42 (d, 1Н), 7.61 (s, 1Н), 7.81 (d, 1H), 7.93 (bs., 1Н), 7.96 (bs., 1Н), 10.39 (s, 1H).
Synthesis of compound 2
Methyl 2-methyl-2-[(2-nitropyridin-3-yl)oxy]propanoate.
To a solution of 2-nitro-3-hydroxypyridine (0.35 g, 2.5 mmol) in dry DMF (5 ml) cooled to 0 °C
sodium hydride (0.12 g, 3.0 mmol, 60% suspension in mineral oil) was added and the mixture
was stirred at the same temperature for 2 h. Methyl dibromoacetate (0.52 g, 3.0 mmol) was

added dropwise keeping the temperature below 5 °C. The reaction mixture was stirred for 4 h at
ambient temperature, and then at 60°C for 4 h. Solvent was evaporated, the residue was washed
with water (3x10 ml), dried and recrystallized from toluene, giving the title compound (0.53 g,
2.2 mmol, 87%). 1H NMR (500 MHz, DMSO-d6) 1.13 (s, 6H), 3.29 (s, 3H), 7.83 (d, 1Н), 7.91 (t,
1Н), 8.32 (d, 1Н).
Methyl 2-methyl-2-[(6-bromo-2-nitropyridin-3-yl)oxy]propanoate.
To a solution of the above product (0.53 g, 2.2 mmol) in glacial acetic acid (5 ml) dry bromine
(0.42 g, 2.6 mmol) was added dropwise. The reaction mixture was stirred for 2 h. Anhydrous
sodium acetate (0.25 g, 3.0 mmol) was added and the reaction mixture was stirred at 40°C for 8 h
and then poured into water. The formed precipitate was filtered out, washed with water to neutral
pH and dried to give the title compound (0.82 g, 1.6 mmol, 73%). 1H NMR (500 MHz, DMSO-
d6) 1.13 (s, 6Н), 3.25 (s, 3Н), 7.76 (d, 1Н), 8.18 (d, 1Н).
6-Bromo-2,2-dimethyl-2H-pyrid[3,2-b][1,4]oxazin-3(4H)-one 3.
To a suspension of the above product (0.82 g, 1.6 mmol) in concentrated hydrochloric acid
(40 ml) cooled to -5°C tin(II) chloride (1.0 g) dissolved in methanol (10 ml) was added
maintaining the given temperature. The reaction mixture is stirred at 0°C for 12 h, quenched with
sodium carbonate and filtered. The supernatant was evaporated and subjected to extraction with
anhydrous ethanol using Soxhlet-type extractor, giving compound 3 (0.26 g, 1.0 mmol, 62%). 1H
NMR (500 MHz, DMSO-d6) 1.12 (s, 3Н), 1.13 (s, 3Н), 7.56 (d, 1Н), 8.13 (d, 1Н), 10.43 (s, 1Н).
2-Chloro-7Н-pyrrolo[2,3-d]pyrimidine .
To a suspension of 2-hydroxy-7H-pyrrolo[2,3-d]pyrimidine (0.2 g, 4.2 mmol, prepared
according to ref. 3 in phosphorus oxychloride (0.4 ml, 4.2 mmol) N,N-dimethylaniline (0.4 ml,
3.0 mmol) was added. The reaction mixture was stirred at 60°C for 6 h, cooled to room
temperature and poured into a mixture of ice (100 g) and ether (50 ml). The organic layer was
separated, and the aqueous layer was twice extracted with water. The combined organic extract
was washed with saturated aqueous sodium bicarbonate solution (3x50 ml) and dried. The
solvent was evaporated and the residue was distilled to give the title compound (0.19 g,
1.25 mmol, 83%). 1H NMR (500 MHz, DMSO-d6) 6.71 (d, 1Н), 6.92 (d, 1Н), 7.82 (s, 1Н), 10.03
(bs., 1Н).
N-(3,4,5-Trimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine.
3,4,5-Trimethoxyaniline (0.23 g, 1.25 mmol) was added to a solution of the above compound
(0.19 g, 1.25 mmol) in dry degassed DMF (5 ml) and the reaction mixture was stirred at 110°C
for 6 h under inert atmosphere. Solvent was evaporated at 5 Torr. The residue was washed with

water (2x5 ml) and separated chromatographically eluting with chloroform−methanol mixture of
increasing polarity. The standard workup procedure afforded the title product (0.3 g, 1.0 mmol,
80%). 1H NMR (500 MHz, DMSO-d6) 3,74 (s, 3H), 3,81 (s, 6H), 6.72 (s, 2H), 6.79 (d, 1Н), 6.82
(d, 1Н), 7.32 (s, 1Н), 7.42 (bs., 1Н), 10.03 (s, 1H).
2,2-Dimethyl-6-(2-[(3,4,5-trimethoxyphenyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2H-
pyrid[3,2-b][1,4]oxazin-3(4H)-one 2.
The above compound (0.3 g, 1.0 mmol) was added to a solution of compound 3 (0.26 g,
1.0 mmol) in dry degassed DMF (5 ml) and the mixture was stirred at 60°C for 8 h under inert
atmosphere. The solvent was evaporated at 5 Torr. The residue was washed with water (2x5 ml)
and separated chromatographically eluting with chloroform−methanol mixture of increasing
polarity. The standard workup procedure afforded target compound 2 (0.28 g, 0.6 mmol, 60%).
1H NMR (500 MHz, DMSO-d6) 1.12 (s, 3H), 1.13 (s, 3H), 3.78 (s, 3H), 3.81 (s, 6H), 6.68-6.73
(m, 3Н), 6.75 (d, 1H), 7.28 (s, 1H), 7.78 (d, 1Н), 8.03 (d, 1H), 7.23 (bs., 1Н).
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