Month 2014
An Efficient Synthesis of Pemetrexed Disodium
completed, to the reaction mixture was added dichloromethane
(80 mL) and deionized water (80 mL), stirred for 15 min, and then,
the resulting mixture was allowed to separate, the aqueous layer
was extracted with dichloromethane (50 mL), the combined organic
layers were evaporated to give a yellow viscous oil, which was
added with petroleum ether (90 mL) and ethyl acetate (30 mL),
stirred for 30 min at 40°C, and a large amount of light yellow solid
appeared; the solid was filtered at 40°C and dried to give 7
(11.92 g, 85.5% yield). mp: 168–170°C (lit.[7] mp: 169–171°C). 1H
NMR (400 MHz, DMSOÀd6) δ: 1.15 ~ 1.20 (m, 6H),1.97 ~ 2.13
(m, 4H), 2.46 (t, J=7.6Hz, 2H), 2.68~2.78 (m, 2H), 4.00~4.13
(m, 4H), 4.40~4.45 (m, 1H), 6.73 (br, 1H), 7.29 (d, J=8.0Hz,
2H), 7.79 (d, J= 8.0 Hz, 2H), 8.66 (d, J= 8.0 Hz, 1H),10.42 (s, 1H),
10.61 (s, 1H). 13C NMR (100 MHz, DMSOÀd6) δ: 14.03, 25.69,
27.97, 30.15, 36.11, 51.94, 54.87, 59.89, 60.50, 98.70, 113.40,
117.60, 127.37, 128.16, 131.07, 146.28, 151.31, 152.18, 159.28,
166.63, 171.82, 172.19. IR (KBr. cmÀ1) 3337 (m), 3209 (m), 2981
(w), 1736 (s), 1664 (s), 1522 (m), 1432 (m), 1374 (m), 1259 (w),
1019 (w), 854 (w), 774 (m).
4-(4-(Methoxycarbonyl)phenyl)butanoicacid (10).
Melting
point: 76–78°C (lit.[13] mp: 76.5–78°C). 1H NMR (400 MHz,
CDCl3) δ: 1.96~ 2.00 (m, 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.73
(t, J = 7.8 Hz, 2H), 3.90 (s, 3H), 7.25 (d, J = 7.8 Hz, 2H), 7.96
(d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 25.83, 33.23,
34.98, 52.04, 128.1, 128.5, 129.8, 146.7, 167.1, 179.5. IR (KBr.
cmÀ1) 3428 (m), 2919 (m), 2850 (w), 1721 (s), 1607 (m), 1559
(m), 1436 (m), 1282 (s), 1110 (s), 797 (w), 699 (w). HRMS
(ESI), calcd: C12H14O4, [MÀ H]+ m/z: 221.0892, found:221.0824.
2,4-Dimethoxy-6-morpholino-1,3,5-triazine (11). Melting
point: 128–130°C (lit.[14] mp: 129–130°C). 1H NMR (400 MHz,
CDCl3) δ: 3.73 (t, J = 4.8 Hz, 4H), 3.85 (t, J = 4.2 Hz, 4H), 3.96 (s,
6H). 13C NMR (100 MHz, CDCl3) δ: 43.96, 54.52, 66.60, 166.8,
172.3. IR (KBr. cmÀ1) 1580 (s), 1541 (s), 1468 (s), 1365 (m),
1306 (w), 1252 (m), 1208 (m), 1128 (m), 1071 (w), 1006 (m),
875 (m), 810 (m). HRMS (ESI), calcd: C9H14N4O3 [M+ H]+ m/z:
227.1066, found: 227.1136.
N-[4-[2-(2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]
pyrimidin-5-yl)ethyl]-benzoyl]-L-glutamic acid disodium
REFERENCES AND NOTES
salt( pemetrexed disodium, 1).
Intermediate 7 (10.00 g,
[1] Ochi, N.; Yamane, H.; Yamagishi, T.; Takigawa, N. Lung
Cancer 2013, 80, 111.
20mmol) was added to a 2 N aqueous sodium hydroxide
solution (100 mL). The mixture was stirred for 2 h at room
temperature, and then, the pH of the solution was adjusted to
7.5 ~ 8.5 using 1 N hydrochloric acid, the solution was stirred
for 30 min at room temperature, ethanol (100 mL) was added
and further stirred for 10 min, then the solution was kept in
refrigerator over night, and a large amount of off-white solid
appeared. After filtration, the solid was added ethanol (120 mL)
and deionized water (40 mL), stirred for 30min at room
temperature, then the solution was kept in refrigerator over
night again, and white crystal appeared, the crystal was filtered
and dried to give 1 (6.10 g, 65.1% yield) with a purity of
99.9%. mp > 260°C (lit.[7] mp> 250°C). 1H NMR (400 MHz,
D2O) δ: 1.90~ 1.96 (m, 1H), 2.04~ 2.10 (m, 1H), 2.20 ~ 2.22
(m, 2H), 2.81 (m, 4H), 4.21~ 4.23 (m, 1H), 6.28 (s, 1H), 7.12
(d, J = 7.8 Hz, 2H), 7.57 (d, J = 7.8Hz, 2H). 13C NMR
(100MHz, D2O) δ: 26.78, 28.45, 34.34, 35.48, 56.0, 98.81,
115.44, 118.09, 127.0, 128.49, 130.68, 146.7, 150.8, 152.25,
161.42, 170.03, 179.04, 182.34. IR (KBr. cmÀ1) 3017 (w),
2954 (m), 2870 (w), 1733 (s), 1619 (s), 1609 (m), 1429 (m),
1274 (s), 1202 (m), 1111 (m), 1017 (w), 936 (w), 767 (m),
705 (m). HRMS (ESI), calcd: C20H19N5Na2O6 [M + H]+ m/z:
472.1131, found:472.1206.
[2] Tiseo, M.; Gelsomino, F.; Bartolotti, M.; Brili, M. P.;
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[5] Pippen, J.; Elias, A. D.; Neubauer, M.; Stokoe, C.; Vaughn,
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[8] Kjell, D. P.; Slattery, B. J.; Barnett, C. J. U.S. Patent
6,013,828, 2000; Chem Abstr 2000, 132, 64061x.
[9] Taylor, E. C.; Liu, B. J Org Chem 2001, 66, 3726.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet