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HETEROCYCLES, Vol. 85, No. 7, 2012
phosphoryl chloride in the presence of N,N-diisopropylethylamine at 110 °C for 30 hours. The reaction
mixture was then concentrated under reduced pressure to remove excess phosphoryl chloride. After
aqueous work up, the product was precipitated from isopropyl acetate-heptane, and was isolated as a
brown solid in 86% yield and greater than 99% purity.
In summary, we report an efficient synthesis of 5,7-dichlorothiazolo[5,4-d]pyrimidine under relatively
mild conditions from readily available starting materials. This 4-step synthesis, which has been scaled up
to a 100 gram scale, gave this versatile building block in 57% overall yield.
EXPERIMENTAL
Ethyl 5-(ethoxycarbonylamino)thiazole-4-carboxylate (16) A 500 mL round-bottomed flask equipped
with a magnetic stirrer, thermocouple probe and N2 bubbler was charged with 1 M potassium t-butoxide
in THF (180 mL, 180 mmol). The contents of the flask were cooled with a dry-ice acetone bath to below
-25 °C, then 14 (18.0 g, 159 mmol) was added over 5 min while maintaining the internal temperature
below -25 °C. After stirring at this temperature for 10 min, 15 (21.0 g, 160 mmol) was added dropwise
over 10 min, while maintaining the internal temperature below -20 °C. After the addition was complete,
the mixture was stirred for 10 min, then warmed to 0 °C over 30 min. The reaction was then quenched
with acetic acid (10.5 mL, 183 mmol), diluted with water (90 mL), and concentrated under reduced
pressure to remove THF. The residue was extracted with isopropyl acetate (180 mL). The organic layer
was washed with water (2 × 90 mL), and concentrated under reduced pressure to give 16 (35.9 g, 92%
1
yield) as a brown oil, which solidified upon standing at room temperature. H NMR (300 MHz,
DMSO-d6) δ 10.01 (s, 1H), 8.59 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.31 (t, J =7.1
13
Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, DMSO-d6) δ 163.72, 152.56, 146.49, 145.08,
126.76, 62.71, 60.80, 14.14, 14.10; HRMS m/z calcd. for C9H12N2O4S+H 245.0591, found 245.0591.
(4-Carbamoylthiazol-5-yl)carbamic acid ethyl ester (17)4 A 250 mL round-bottomed flask equipped
with a magnetic stirrer, heating mantle and condenser was charged with 16 (18.0 g, 73.7 mmol) and
ethanol (18 mL). The suspension was stirred at 40 °C until all the solids had dissolved. The resulting
solution was diluted with water (36 mL), then ammonium hydroxide (72 mL, 1.85 mol) was added. The
mixture was stirred at 40 °C overnight, then diluted with water (72 mL) and heated under gentle reflux for
30 min. After cooling to room temperature, the resulting solid was collected by filtration, washed with
water (2 × 72 mL) and dried at 80 °C under vacuum overnight to give 17 (11.7 g, 74% yield) as a white
solid. mp 244.0 °C (decomp);4 1H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.58 (s, 1H), 7.88 (s, 1H),
7.78 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 165.98,
125.50, 144.22, 142.71, 128.87, 62.41, 14.18; HRMS m/z calcd. for C7H9N3O3S+H 216.0440, found
216.0437.