V. V. Sokolov, S. I. Kozhushkov, S. Nikolskaya, V. N. Belov, M. Es-Sayed, A. de Meijere
FULL PAPER
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solid, m. p. 225Ϫ230°C. Ϫ H NMR ([D6]DMSO, ambient temp.): min. An etheral solution of diazomethane (60 ml, prepared from
δ ϭ 2.82 (s, 3 H, CH3N), 3.45Ϫ3.75 (m, 2 H, CH2N), 4.05 and
6.2 g of crude N-methyl-N-nitrosourea) was added to the mixed
4.20 (m, 1 H, CHN), 5.03 and 5.09 (s, 2 H, CH2O), 7.08 (br. s, 1 anhydride thus prepared, and the resulting solution was kept at Ϫ5
H, NH), 7.23Ϫ7.45 (m, 5 H), 8.05 (br. s, 1 H, NH), 8.67 (br. s, 1 to 0°C for 22 h. The mixture was washed with half-saturated
H, NH), 9.08 (br. s, 1 H, NH), 9.32 (br. s, 1 H, NH), 13.25 and NaHCO3 solution, water, and brine. The organic phase was dried
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13.30 (br. s, 1 H, NH). Two amide rotamers (ca. 1:1). Ϫ H NMR
(MgSO4) and evaporated in vacuo to dryness. Crystallization of the
([D6]DMSO, 100°C): δ ϭ 2.85 (s, 3 H, CH3N), 3.59 (d, J ϭ 7 Hz, residue from CH2Cl2Ϫether gave 10.7 g (84%) of 21b as light yellow
2 H, CH2N), 4.13 (t, J ϭ 7 Hz, 1 H, CHN), 5.08 and 5.09 (AB, crystals, m. p. 116Ϫ118°C,[19] [α]D20 Ϫ13.0° (c ϭ 1.2, acetone), but
J ϭ 13 Hz, 2 H, CH2O), 7.23Ϫ7.40 (m, 5 H). Ϫ 13C NMR 0.0° (!) (c ϭ 1.0, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3384 cmϪ1, 3307, 2957,
(D2OϩNaOH, ambient temp.): δ ϭ 31.43 and 31.82 (ϩ, CH3N),
2111 (CN2), 1721, 1688, 1610, 1507, 1382, 1258, 1196, 1101, 1003,
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39.58 (Ϫ, br., CH2N), 60.50 (ϩ, br., CHN), 67.39 and 67.67 (Ϫ, 752, 697. Ϫ H NMR: δ ϭ 1.62Ϫ1.90 (m, 4 H), 3.88Ϫ4.06 (m, 2
CH2O), 127.25 (ϩ), 127.40 (ϩ), 127.56 (ϩ), 128.06 (ϩ), 128.48 (ϩ), H), 4.24Ϫ4.40 (m, 1 H), 4.96Ϫ5.26 (m, 4 H), 5.26 (s, 2 H), 5.46
135.86 and 136.21 (Cquat), 157.56 and 157.82 (Cquat, NHCOO), (br. s, 1 H, CHN2), 6.30 (br. d, 1 H), 7.25Ϫ7.50 (m, 15 H), 9.34
160.33 and 160.46 (Cquat, br.), 167.29 (Cquat, br.), 175.42 (Cquat, br.)
Ϫ C14H19N5O5 (337.34): calcd. C 49.85, H 5.68, N 20.76; found C (Ϫ), 44.16 (Ϫ), 54.04 (ϩ), 57.57 (ϩ, CHN2), 66.74 (Ϫ), 66.92 (Ϫ),
(br. s, 1 H), 9.53 (br. s, 1 H). Ϫ 13C NMR: δ ϭ 24.57 (Ϫ), 28.06
49.80, H 5.32, N 20.30.
68.88 (Ϫ), 127.96 (ϩ), 128.06 (ϩ), 128.20 (ϩ), 128.43 (ϩ), 128.71
(ϩ), 128.78 (ϩ), 134.43 (Cquat), 136.27 (Cquat), 136.37 (Cquat),
155.60 (Cquat), 155.99 (Cquat), 160.60 (Cquat), 163.46 (Cquat), 193.92
(Cquat). Ϫ MS (EI); m/z (%): 572 (1) [M Ϫ N2ϩ], 108 (67), 91 (100)
[C7H7ϩ]. Ϫ MS (CI, NH3); m/z (%): 601 (49) [M ϩ Hϩ], 573 (100)
[M Ϫ N2 ϩ Hϩ]. Ϫ MS (HR-EI): 572.2270 (C31H32N4O7: calcd.
572.2271 for M ϪN2ϩ).
Reaction of 2-(N-Benzyloxycarbonyl-N-methylamino)-3-(3-car-
bamoylguanidino)propionic Acid (19) with 1-(3-dimethyl-
animopropyl)-3-ethylcarbodiimide Hydrochloride: A suspension of
the acid 19 (169 mg, 0.50 mmol), the carbodiimide (100 mg, 0.52
mmol) and 4-pyrrolidinopyridine (5 mg, 0.03 mmol) in DMF (20
ml) was stirred at room temp. for 3 d. The solvent was evaporated
at 30Ϫ50°C under reduced pressure (1 Torr), and the residue was
treated with diluted NaHCO3 solution (5 ml), the solids were fil-
tered off, washed with water (5 ml), ethanol (5 ml) and ether, and
dried in the air. According to the NMR spectra, the solid residue
(50 mg) consisted of the acid 19 and the cyclization product 3-Z
(ca. 1:1).
5-{N-Methyl-N-[Nβ,Nε,Nω-tri(benzyloxycarbonyl)-(S)-β-homo-
arginyl]amino}-3,4,5,6-tetrahydro-2-ureidopyrimidin-4-one (23): A
solution of 21b (4.41 g, 7.34 mmol) and 3 (1.47 g, 7.94 mmol) in
DMA (250 ml, HPLC grade, Aldrich) was irradiated in a pyrex
reactor with a medium pressure mercury lamp (150 W) under nitro-
gen at room temp. for 3 h. The solvent was evaporated at 30Ϫ50°C
under reduced pressure (1 Torr), the residue was dissolved in warm
CH2Cl2 (150 ml), the solution washed quickly with water (2ϫ50
ml), brine (50 ml), dried over a small portion of MgSO4, the solvent
evaporated, and the residue crystallized from etherϪCH2Cl2 to give
2.07 g of crude 23, m. p. 110Ϫ117°C. Further recrystallization from
CH2Cl2 gave 1.67 g (30%) of pure 23, m. p. 126Ϫ131°C. Ϫ 1H
NMR: δ ϭ 1.50Ϫ1.80 (m, 4 H, γϩδ-H), 2.43Ϫ2.60 (m, 2 H, α-H),
2.83 and 2.88 (s, 3 H, CH3N), 3.30Ϫ3.62 (m, 2 H, 6-H), 3.87Ϫ4.10
(m, 3 H, βϩε-H), 4.85 and 5.0 (m, 1 H, 5-H), 5.07 (m, 2 H, β-
PhCH2), 5.12 (s, 2 H, PhCH2), 5.24 (s, 2 H, PhCH2), 5.77 and 5.93
(d, 1 H, β-NH), 7.23Ϫ7.45 (m, 15 H, Ph), 9.28 (br. s, 2 H), 9.45
(br. s, 1 H), 10.25 (br. s, 1 H), 11.6 (br, 1 H). Ϫ The product was
a mixture of diastereomers in a ratio of ca. 1:1. A sample with
diastereomeric ratio 3:1 was obtained after another recrystalliza-
tion from CHCl3 accompanied with a great loss of the substance.
3,4,5,6-Tetrahydro-5-methylamino-2-ureidopyrimidin-4-one (3): To
a
solution of 5-(N-benzyloxycarbonyl-N-methylamino)-3,4,5,6-
tetrahydro-2-ureidopyrimidin-4-one (3-Z) (4.00 g, 12.5 mmol) in
dimethylacetamide (100 ml) kept under N2 was added with stirring
at room temp. 10% Pd/C (500 mg). The reaction mixture was
purged with H2 for 15 min, and stirring was continued overnight in
a slow flow of hydrogen. The mixture was purged with N2, filtered
through a 1 cm layer of Celite , the solvent evaporated at 30Ϫ50°C
under reduced pressure (1 Torr), and the residue was stirred with
ether (100 ml). The solid was filtered off with suction, washed with
ether, and dried in the air to give 2.31 g (100%) of 3 as a colorless
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solid, m. p. 186Ϫ188°C. Ϫ H NMR ([D6]DMSO): δ ϭ 2.30 (s, 3
H, CH3N), 3.08Ϫ3.20 (m, 2 H, CH2N), 3.66 (mc, 1 H, CHN), 7.00
(br. s, 1 H, NH), 8.02 (br. s, 1 H, NH), 9.8 (br. s, 2 H, NH). Ϫ 13C
NMR ([D6]DMSO): δ ϭ 34.33 (ϩ, CH3N), 41.82 (Ϫ, CH2N), 56.02
(ϩ, CHN), 157.85 (Cquat, br.), 158.11 (Cquat), 178.10 (Cquat, br.). Ϫ
MS (EI); m/z (%): 185 (63) [Mϩ], 168 (52) [M Ϫ NH3ϩ], 156 (29),
[M Ϫ CH2NHϩ], 142 (9) [M Ϫ HNCOϩ], 129 (28), 115 (42), 86
(30), 72 (25), 71 (28), 57 (100), 43 (48). Ϫ MS (HR-EI): 185.0912
(C6H11N5O2: calcd. 185.0913).
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Ϫ H NMR ([D6]DMSO, 50°C): δ ϭ 1.30Ϫ1.82 (m, 4 H, γϩδ-H),
2.30Ϫ2.60 (m, 2 H, α-H), 2.63 and 2.86 (major) (s, 3 H, CH3N),
3.20Ϫ3.60 (m, 2 H, 6-H), 3.80Ϫ3.90 (m, 3 H, βϩε-H), 4.93 (m, 1
H, 5-H), 4.98 (m, 2 H, β-PhCH2), 5.06 (s, 2 H, PhCH2), 5.12 (s, 2
H, PhCH2), 6.60 (br., 2 H), 7.00 (br. s, 1 H), 7.22Ϫ7.42 (m, 15 H,
Ph), 9.09 (br. s, 2 H), 9.3 (br, 1 H). Ϫ 13C NMR ([D6]DMSO,
50°C): δ ϭ 25.00, 31.11 (br), 32.82, 38.10 (br), 44.47, 47.75 (br),
47.96 (br), 52.16, 64.94, 65.98, 67.96, 127.32, 127.40, 127.51,
127.64, 128.00, 128.04, 128.27, 135.10, 136.96 (2 C), 154.76, 155.26
(br), 159.0 (br), 159.44, 162.66, 170.62 (br), 170.72 (br). Ϫ MS
(FAB); m/z (%): 758 (100) [M ϩ Hϩ], 759 (35) [M ϩ 2 Hϩ], 780
(45) [M ϩ Naϩ].
NͰ,Nδ,Nω-Tri(benzyloxycarbonyl)--arginine (20b) was prepared
according to the reported procedure[18] in 71% yield and recrys-
tallized from hexane/CH2Cl2 (1:1, v/v). Its melting point, optical
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rotation, and H-NMR spectrum were identical with the reported
data. Ϫ 13C NMR ([D6]DMSO): δ ϭ 25.37 (Ϫ), 28.11 (Ϫ), 44.20
(Ϫ), 53.80 (ϩ), 65.45 (Ϫ), 66.15 (Ϫ), 68.25 (Ϫ), 127.78 (ϩ), 127.87
(ϩ), 128.00 (ϩ), 128.39 (ϩ), 128.57 (ϩ), 135.32 (Cquat), 137.00
(Cquat), 137.14 (Cquat), 154.99 (Cquat), 156.21 (Cquat), 159.75 (Cquat),
162.94 (Cquat), 173.84 (Cquat).
3,4,5,6-Tetrahydro-5-{N-methyl-N-[(S)-β-homoarginyl]amino}-
2-ureidopyrimidin-4-one Dihydrochloride, TAN-1057 A/B (1a/b). To
a suspension of the tris-Z-derivative 23 (1.16 g, 15.3 mmol of the
(S)-1,3-Di(benzyloxycarbonyl)-1-(4-benzyloxycarbonyamino-6- 1:1 epimeric mixture) in anhydrous MeOH (100 ml) was added
diazo-5-oxohexyl)guanidine (21b): Triethylamine (3.0 ml, 22 mmol) PdCl2 (28.7 mmol). The reaction vessel was degassed, charged in
and isobutyl chloroformate (2.8 ml, 22 mmol) were added with
stirring to a cooled (Ϫ20°C) solution of 20b (12.2 g, 21.0 mmol) in
three cycles with H2 and stirred for 2 h under a slow flow of H2.
The suspension was purged with N2, the catalyst filtered off, and
CH2Cl2 (240 ml), and the mixture was stirred for an additional 15 the filtrate evaporated in vacuo to dryness. The solid residue was
782 Eur. J. Org. Chem. 1998, 777Ϫ783