Jan-Feb 2003
Preparative Route to 2-Ethoxycarbonylimidazole-4-phosphonat
161
Diethyl Ethynylphosphate (6).
Ethyl 2-Imino-2-isopropyloxy-acetate (12).
To a stirred solution of 5 (9.15 g, 91 mmol) in dry THF (300
ml), kept under nitrogen atmosphere, 3 M EtMgBr (40 mL, 120
mmol) in ether was added dropwise at rt. The reaction mixture
was stirred for 2 h at rt, and then cooled to 0 °C. At this temper-
To a solution of 11 (25 g, 0.25 mol) in 2-propanol (60 mL) and
under a nitrogen atmosphere, HCl was added during 20 min-
(g)
utes at 10 °C. Stirring was continued for 12 h at the same temper-
ature. After cooling (0 °C), the reaction mixture was filtered and
the solid thus obtained washed with 2-propanol (10 mL), and
dried to give 12•HCl (43.4 g, 88%) as a white solid (m.p. 113 °C,
ature, ClP(O)(OEt) (13.7 mL, 91 mmol) was added, the reac-
2
tion mixture stirred for an additional 1 h and allowed to reach rt
(1 h). Then, saturated aq. NH Cl (30 mL) was added and the
not recrystallized). Then, to a stirred solution of K CO (46.6 g,
4
2 3
resulting pale yellow precipitate filtered and washed with ether
(2 x 50 mL). The combined organic phases were dried over
0.33 mol) in water (185 mL) and tert-BuOMe (176 mL) at 5 °C
was added 12•HCl (110g, 0.56 mol). The water phase was
extracted with tert-BuOMe (88 mL), and the resulting organic
layers concentrated under reduced pressure to give 43.4 g of 12
(96.5%) as an colorless oil, b.p. 62 °C (0.2 psi).
MgSO and concentrated in vacuo (35 °C) to a brown oil which
4
was immediately solubilized in CHCl (450 mL). Then, 10% aq.
3
Na CO (300 mL) was added at rt and the reaction mixture
2
3
stirred for 0.5 h. The aq. phase was extracted with CHCl (2x50
3
4-Amino-imidazole-2,5-dicarboxylate (13).
mL) and the combined organic phases dried over MgSO and
4
To a stirred solution of 10•oxalate (2.3 g, 10 mmol) in ethanol
(23 mL), 12 (2 g, 12 mmol) in neat phase was slowly added for
30 minutes at rt. Then the reaction mixture was stirred for 3 h,
and the resulting precipitate was collected by filtration, washed
with ethanol (2 mL) and dried to afford 2.21 g of 13 (82%) as a
concentrated in vacuo to give 12.4 g (84%) of 6 as a yellow oil.
The product was sufficiently pure (TLC R = 0.25, silica gel,
f
cyclohexane-ethyl acetate 1:1) for direct use in the next step
without further purification.
2-Ethoxycarbonylimidazole-4-phosphonate (1a).
1
white solid, m.p. 192-194 °C (not recrystallized). H NMR (300
To a stirred solution of 7 (30.5 g, 231 mmol), TEA (38.6 ml,
MHz, DMSO): δ 1.3 (m, 6H, CH ), 4.25 (m, 4H, CH ), 5.92 (bs,
3
2
277 mmol) in CHCl (500 mL) at 10 °C was added dropwise 6
2H, NH ), 12.42 (bs, NH). MS (EI): m/z 227 (100%). IR (KBr)
3480, 3220, 3055, 1677, 1628, 1273, 1152 cm .
3
2
-1
(57.6 g, 231 mmol) in CHCl (100 mL) during 45 min. The reac-
3
tion mixture was stirred for 21 h at rt. The mixture was washed
Diethyl Imidazole-2,4-dicarboxylate (1b).
successively with sat. NaCl (3x100 mL) and H O (30 mL) and
2
To a solution of 13 (1 g, 4.4 mmol) in a 50% aq. solution of
the organic phase dried over MgSO . Then silica gel (50 g) was
4
H PO (2.5 mL), NaNO (0.46 g, 6.7 mmol) in water (3.4 mL)
added and finally the mixture filtered through a small Celite col-
3
2
2
was added dropwise at rt. The reaction mixture was stirred for 2
h, and 3% NaOH (5 mL) was added until pH = 7-8. Then, the pre-
cipitate was collected by filtration, washed with water (3 x 5 mL)
and dried to give 0.82 g of 1b (92.5%) as a white solid, m.p. 174-
umn. The filtrate was concentrated in vacuo to afford 82 g of
crude 8 as a pale yellow oil (TLC R = 0.8, silica gel, ethyl
f
acetate-methanol 9:1) which was used in the next step without
1
further purification. H NMR (400MHz, DMSO): δ 1.26 (m, 9H,
1
3
176 °C (not recrystallized). H NMR (250 MHz DMSO): δ 1.32
CH ), 3.98 (m, 6H, CH ), 5.16 (dd, 1H,
J
= 12Hz - cis;
3
2
HH
2
3
(m, 6H, CH ), 4.34 (m, 4H, CH ), 8.04 (s, CH), 14 (very bs, NH).
J
=12Hz, CH=), 7.02 (bs, 2H, NH ), 7.32 (dd, 1H,
J
=
3
2
PH
2
HH
3
MS (EI): m/z 212 (16%), 140 (100%). IR (KBr) 3125, 1730,
12Hz – cis;
J
= 11Hz, CH=). MS(FAB,Gly-SGly): m/z 295
(MH ). Determination of the syn-anti stereochemistry was out of
the scope of this study.
PH
-1
+
1700, 1282, 1177, 1030 cm .
Anal. Calcd. for C H N O : C, 50.95; H, 5.70; N, 13.20 %.
9
12 2 4
Found: C, 50.70; H, 5.53; N, 13.24 %.
Compound 8 was dissolved in xylene (400 ml) and the solution
was heated at reflux for 24 h and cooled to rt and the solid was
Acknowledgements.
filtered, washed with CH Cl (3x50 mL) and the combined
2
2
organic phases concentrated in vacuo to give a red oil which was
purified by silica gel chromatography using a ethyl acetate-
methanol mixture (9-1) as eluent to give 1a (21 g, 27%) as a pale
We thank Y. Amboise and P. Ganil for their technical assis-
tance.
yellow oil (TLC R = 0.53, silica gel, ethyl acetate-methanol 9:1).
f
REFERENCES AND NOTES
1
H NMR (500 MHz, DMSO): δ 1.24 (t, 6H, J= 7Hz, 2x CH ),
3
1.34 (t, 3H, J= 7Hz, CH ), 4.02 (q, 4H, J=7Hz, CH O), 4.45 (q,
3
2
*
E-mail: serge.mignani@aventis.com ; Fax : 33 1 55 71 80 14 .
2H, J= 7Hz, CH O), 7.82 (bs, 1H, CH=), 13.85 (bs, 1H, NH). MS
2
[1] For a review, see: A. Doble, Pharmacol. Ther., 81, 163 (1999)
and references cited therein.
[2] S. Nakanishi, Science, 258, 597 (1992) and references cited
therein.
+.
(EI): m/z 276 (M ). IR (CCl ) 2984, 1723, 1482, 1382, 1248,
4
-1
1031 cm .
Anal. Calcd for C
H N O P: C, 43.48; H, 6.20; N, 10.14 %.
10 17 2 5
[3] For recent publication in this field, see: S. Mignani, J-M.
Stutzmann, and M. Vuilhorgne, Trends in Heterocyclic Chemistry, 8, 49
(2002).
Found: C, 43.72; H, 6.34; N, 10.18 %.
2-Amino-2-cyano-acetate (10•oxalate).
[4] J-C. Aloup, F. Audiau, M. Barreau, D. Damour, A. Genevois-
Borella, J-C. Hardy, P. Jimonet, F. Manfré, S. Mignani, and Y. Ribeill,
Patent applications, WO 9631511 (1996); Chem. Abstr. 126, 8136
(1997).
[5a] [a] I. V. Komarov, M. Y. Kornilov, A. V. Turov, M. V.
Gorichko, V. O. Popov, A. A. Tolmachev, and A. J. Kirby, Tetrahedron,
51, 12417 (1995); I. V. Komarov, A. V. Strizhak, and M. Y. Kornilov,
Synthetic Commun. 28, 2355 (1998); Q. Dang, M. D. Erion, M. R. Reddy,
E. D. Robinsion, S. R. Kasibhatla, and K. R. Reddy, Patent applications,
To a stirred solution of 9 (120 g, 0.85 mol) in ethanol (1.1 L),
50% Pt/C (30g) in water (30 mL) were added at rt. The reaction
mixture was hydrogenated under a pressure of 59 psi during 72 h.
The resulting solid was filtered off, washed with ethanol (2 x 100
mL), and finally the filtrate treated with oxalic acid (73.7 g) in
ethanol (440 mL) at 5 °C to give a white solid which was washed
with ethanol (4 x 100 mL) and dried to afford 92.2 g of
10•oxalate (53.5%), m.p. 106-108 °C (not recrystallized).