PAPER
Pyrrolino[2,3-d]pyrimidin-6-one Derivatives
2399
IR (KBr): 1709 cm–1 (C=O).
(80:20). Compound 20 was isolated using preparative HPLC. Com-
pounds 18 and 20 were not isolated.12
1H NMR (DMSO-d6): δ = 3.41 (s, 2 H), 3.69 (s, 3 H), 7.90 (s, 1 H).
13C NMR (DMSO-d6): δ = 178.3, 172.0, 150.2, 98.7, 54.9, 31.3.
HRMS: m/z calcd for C7H6N2Na2O4: 228.0123; found: 228.0146.
17a
White solid; mp 129–131 °C.
IR (KBr): 3302, 3223 (NH2), 1724 cm–1 (C=O).
1H NMR (CDCl3): δ = 3.69 (s, 2 H), 3.73 (s, 3 H), 5.74 (br s, 2 H),
Methyl 2-(4,6-Dichloropyrimidin-5-yl)acetate (16)
A suspension of the disodium salt 15 (502 g, 1.80 mol) was added
to POCl3 (2.5 L, 10.00 equiv, 2.53 mol) over 1 h with stirring by
keeping the temperature below 50 °C. The resulting mixture was
stirred at 50 °C for 0.5 h, and then the suspension was heated to
80 °C slowly over 1 h. The homogenous solution obtained was
stirred at 80 °C for 1 h. The temperature of the reaction was then
raised to 100 °C and maintained for 2 h. HPLC analysis indicated
consumption of starting material. The reaction mixture was cooled
to 60 °C and POCl3 was removed under vacuum. The concentrated
reaction mixture was added dropwise to ice water (12 L). The pH
was adjusted to 7–8 with aq 10 M NaOH. The slurry was stirred for
20 min at 20 °C and filtered. The wet cake was dissolved in MTBE
(2 L), filtered, and the MTBE layer was washed with H2O (500 mL).
The MTBE layer was separated and refluxed with activated char-
coal (20 g) for 1 h. The mixture was cooled to r.t. and filtered. The
filtrate was concentrated to 200 mL under vacuum and heptane (200
mL) was added to the residue. The slurry obtained was stirred for 30
min and filtered. The product obtained was washed with n-heptane
(100 mL) and dried under vacuum; yield: 373 g (77%); off-white
solid; HPLC purity: 97.7%; mp 65–67 °C.
8.26 (s, 1 H).
13C NMR (CDCl3): δ = 170.2, 163.4, 159.7, 156.6, 108.1, 52.7, 33.7.
HRMS: m/z calcd for C7H8ClN3O2: 201.0305; found: 201.0303.
19
White solid; mp 131–134 °C.
IR (KBr): 3319, 3202 (NH2), 1728 cm–1 (C=O).
1H NMR (CDCl3): δ = 1.24 (d, J = 6.2 Hz, 6 H), 3.66 (s, 2 H), 5.03
(m, 1 H), 5.60 (br s, 2 H), 8.3 (s, 1 H).
13C NMR (CDCl3): δ = 169.3, 163.5, 159.7, 156.5, 108.5, 69.7, 34.3,
21.6.
HRMS: m/z calcd for C9H12ClN3O2: 229.0618; found: 229.0626.
7-[(2,4-Dimethoxyphenyl)methyl]-4-chloro[2,3-d]pyrimidin-6-
one (12b)
To a 3-necked flask equipped with a mechanical stirrer, thermocou-
ple, and N2 inlet was added 16 (56 g, 253.4 mmol) and DMF (392
mL, 7 vol). The reaction mixture was degassed by purging with N2.
DIPEA (40.9 g, 316.7 mmol) was added to the reaction mixture un-
der N2. 2,4-Dimethoxybenzylamine (48.7 g, 291.3 mmol) was
charged into the flask at 20–35 °C. The reaction contents were
warmed to 50–60 °C and stirred at this temperature for 4 h. The re-
action completion was checked by HPLC analysis. The reaction
contents were cooled to 40–45 °C. H2O (360 mL) was added drop-
wise into the flask by maintaining a temperature of 40–45 °C. The
reaction mixture was stirred at 40–45 °C for 6 h and analyzed by
HPLC. The reaction pH was adjusted to 6.5–7.5 with aq 0.3 M HCl
(123.2 g). H2O (364 mL) was charged dropwise to the flask by
maintaining a temperature of 35–45 °C. The contents were stirred at
35–45 °C for 2 h. The reaction slurry was cooled to 5–10 °C and
stirred for 2 h. The slurry was filtered and the cake was washed with
DMF–H2O (28 mL:84 mL, 1:3). The wet cake was transferred to a
3 neck flask equipped with a mechanical stirrer, thermocouple, and
reflux condenser. Toluene (190 mL) was added and the contents
were heated to 75–85 °C. The contents were stirred at 75–85 °C for
75 min. The contents were cooled to 2–7 °C and stirred for 2 h. The
slurry was filtered and the cake was washed with cold toluene (48
mL). The product was dried under vacuum at 50–60 °C for 10–12
h; yield: 81 g (88%); yellow solid; HPLC purity: 99.9%, mp 170–
173 °C.
IR (KBr): 1734 cm–1 (C=O).
1H NMR (DMSO-d6): δ = 3.75 (s, 3 H), 3.98 (s, 2 H), 8.70 (s, 1 H).
13C NMR (DMSO-d6): δ = 168.1, 162.4, 156.6, 126.7, 52.7, 35.6.
HRMS: m/z calcd for C7H6Cl2N2O2: 219.9806; found: 219.9890.
4-Chloro-2-pyrrolino[2,3-d]pyrimidin-6-one (12a)
To a 5 L autoclave was added 16 (100 g, 452.45 mmol, 1.00 equiv)
and ammonia/i-PrOH (2.6 M, 600 mL, 1.56 mol, 3.5 equiv). The
mixture was further diluted with i-PrOH (960 mL, final ammonia
strength was 1 M) at 20 °C and the flask was filled with N2. The
contents were heated to 90–93 °C and stirred for 16 h. The reaction
was sampled after 16 h and analyzed by HPLC. The data indicated
that the starting material was consumed and the product area was
about 70%. The autoclave was cooled to r.t. and the reaction mix-
ture was concentrated to obtain a brown solid (103.5 g). The solid
was dissolved in EtOAc (1.4 L). Activated charcoal (10 g; 0.1 wt)
was added, and the mixture was refluxed for 1 h. After filtration, the
charcoal was discarded and the organic layer was washed with brine
(3 × 140 mL). The organic layer was dried (MgSO4) and concentrat-
ed to afford 70.6 g of a yellow solid. Four batches were prepared on
a 100 g scale in an autoclave and combined to obtain 284 g of crude
12a. This crude product (284 g) was refluxed in CH2Cl2 (1.4 L) for
5 h and then n-heptane (280 mL) was added dropwise. The mixture
was stirred for 1 h and cooled to r.t. slowly. The slurry obtained was
filtered and washed with n-heptane (50 mL). The product obtained
was dried under vacuum; yield: 183 g (60%); pale yellow solid;
HPLC purity: 98.5%; mp 188–190 °C.
IR (KB): 1680 cm–1 (C=O).
1HNMR (DMSO-d6): δ = 3.71 (s, 3 H), 3.78 (s, 3 H), 3.81 (s, 2 H),
4.73 (s, 2 H), 6.37 (dd, J = 2.6, 8.3 Hz, 1 H), 6.55 (d, J = 2.2 Hz, 1
H), 6.92 (d, J = 8.3 Hz, 1 H), 8.58 (s, 1 H).
13C NMR (DMSO-d6): δ = 173.5, 166.1, 160.4, 58.0, 157.9, 151.5,
128.3, 116.8, 115.6, 104.9, 98.8, 56.0, 55.7, 38.2, 33.5.
IR (KBr): 1680 cm–1 (C=O).
1H NMR (DMSO-d6): δ = 3.62 (s, 2 H), 8.51 (s, 1 H), 11.68 (s, 1 H).
13C NMR (DMSO-d6): δ = 174.9, 166.8, 157.8, 151.6, 117.3, 34.1.
HRMS: m/z calcd for C6H4ClN3O: 169.0043; found: 169.0034.
HRMS: m/z calcd for C15H14ClN3O3: 319.0724; found: 319.0738.
7-(α-Methylbenzyl)-4-chloro[2,3-d]pyrimidin-6-one (12c)
Synthesis of 12c on a 10 g scale was accomplished in a similar man-
ner following the procedure described for 12b from 16 and α-meth-
ylbenzylamine; yield: 9.67 g (78%); brown solid; HPLC purity:
99.9%; mp 82–85 °C.
IR (KBr): 1680 cm–1 (C=O).
1H NMR (DMSO-d6): δ = 1.84 (d, J = 7.0 Hz, 3 H), 3.78 (d, J = 4.8
Isolation of Methyl 2-(4-Amino-6-chloropyrimidin-5-yl)acetate
(17a)andIsopropyl2-(4-Amino-6-chloropyrimidin-5-yl)acetate
(19)
The mother liquor from the above reaction was concentrated to af-
ford about 90 g of a yellow solid. This sample was enriched with
17a, 18, 19, and 20. Compound 17a was isolated by column chro-
matography using EtOAc and petroleum ether (bp 60–80 °C)
Hz, 2 H), 5.60 (m, 1 H), 7.30 (m, 5 H), 8.58 (s, 1 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2396–2400