ꢀꢀꢀꢁ
158ꢀ ꢀH.-x. Ren et al.: Functions of novel active phosphonate esters
phosphorus oxychloride, dimethyl phosphate, and diethyl phos- 2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(O,O-di-p-tol-
phate were obtained from Shanghai Chemical Co., Ltd. 7-ACA was ylphosphorothioic) anhydride (ATPTA, 5a) A pale yellow solid;
purchased from Huabei Zhongrun Pharmaceutical Co., Ltd. Tetrahy- yield 89%; mp 103–107°C; 1H NMR: δ 7.22 (s, 2H), 7.45 (s, 1H), 3.93 (s,
dro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione (TTA) was obtained 3H), 7.02 (m, 4H), 7.16 (m, 4H) 2.34 (s, 3H); 13C NMR: δ 172.4, 168.9,
from Shandong Jincheng Pharmaceutical Co., Ltd. Other analytically 166.0, 164.0, 150.2, 130.1, 121.3, 120.3, 108.0, 64.3, 21.3; IR: 3450, 3240,
pure reagents were bought from Shanghai Xinran Chemical Co., Ltd.
3100, 1695, 1670, 740, 730 cm-1. Anal. Calcd for C20H20O5N3S2P: C, 50.31;
H, 4.19; N, 8.80. Found: C, 49.98; H, 4.85; N, 8.67.
2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(O,O-bis(4-
nitrophenyl)phosphorothioic)anhydride (ANPTA, 6a) A pale yel-
low solid; yield 95%; mp 118–122°C; 1H NMR: δ 7.22 (s, 2H), 7.45 (s, 1H),
3.93 (s, 3H), 7.34 (m, 4H), 7.79 (m, 4H); 13C NMR: 172.4, 168.9, 166.0,
164.0, 156.3, 140.5, 126.3, 121.9, 108.0, 64.3; IR: 3450, 3250, 3130, 1695,
1665, 740, 710 cm-1. Anal. Calcd for C18H14O9N5S2P: C, 40.07; H, 2.59; N,
12.98. Found: C, 39.94; H, 3.81; N, 15.38.
Synthesis of 2-(2-aminothiazol-4-yl)-
2-(methoxyimino)acetic(O,O-dimethylphos-
phoro-thioic) anhydride (AMPTA, 1a)
Dimethyl dithiophosphate (28.40 g, 0.20 mol) was placed in a three-
neck flask and treated dropwise with phosphorus oxychloride
(31.20 g, 0.10 mol). The mixture was allowed to react at 0–5°C for
1 h and then distilled under reduced pressure, yielding a light yel-
low liquid of chlorinated dimethyl phosphorothioate ester (30.10 g,
93%).
Dichloromethane (200 mL) under a nitrogen atmosphere was
treated dropwise with ATMA (20.10 g, 0.10 mol), triethylenediamine
(0.13 g, 0.11 mol), tri-n-butylamine (20.1 g, 0.11 mol), and finally with
chlorinated dimethyl phosphorothioate ester (26.46 g, 0.09 mol). The
mixture was stirred until a solution was formed. The solution was
allowed to react under nitrogen at 0–5°C for 3 h and then washed
with distilled water (250 mL), 5% saturated NaHCO3 (2ꢀ× ꢀ150 mL) and
saturated NaCl (3ꢀ× ꢀ150 mL), dried over MgSO4, and filtered. Afer dilu-
tion with n-hexane (300 mL), the resultant precipitate of 1a was fil-
tered and washed with n-hexane (2ꢀ× ꢀ25 mL): a pale yellow solid; yield
30.87 g (95%); mp 78–81°C; 1H NMR: δ 7.25 (s, 2H), 7.52 (s, 1H), 3.91(s,
3H), 3.78 (m, 3H), 3.78 (m, 3H); 13C NMR: δ 168.9, 166.0, 164.0, 121.2,
108.0, 64.3, 54.8 (2C); IR: 3450, 3240, 3100, 1690, 1675, 750 cm-1. Anal.
Calcd for C8H12O5N3S2P: C, 29.54; H, 3.69; N, 14.77. Found: C, 29.39; H,
3.74; N, 14.81. Compounds 2a–6a, 1b, and 2b were prepared in a simi-
lar way.
2 - ( 2 - A m i n o t h i a z o l - 4 - y l ) - 2 - ( m e t h o x y i m i n o )
acetic(diethylphosphoric) anhydride (AEPPA, 1b) A yellow solid;
1
yield 88%; mp 87–91°C; H NMR: δ 7.23 (s, 2H), 7.48 (s, 1H), 3.79 (m,
4H), 3.92 (m, 3H), 1.29 (m, 6H), 13C NMR: δ 168.5, 167.0, 122.3, 108.0,
64.3, 63.1, 63.1, 17.3, 17.1; IR: 3450, 3240, 3100, 1690, 1675, 1220, 730
cm-1. Anal. Calcd for C10H16O6N3SP: C, 35.52; H, 4.74; N, 12.43. Found: C,
35.61; H, 4.82; N, 12.35.
2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(bis(4-nitro-
phenyl)phosphoric) anhydride (ANPPA, 2b) A yellow solid; yield
1
87%; mp 109–113°C; H NMR: δ 7.22 (s, 2H), 7.45 (s, 1H), 3.93 (s, 3H),
7.24 (d, 4H, J ꢀ= ꢀ 8.0 Hz), 7.81(d, 4H, J ꢀ= ꢀ 8.0 Hz); 13C NMR: 171.7, 167.8,
165.0, 163.0, 154.3, 142.5, 125.3, 120.9, 106, 62.3; IR: 3450, 3240, 3100,
1690, 1675, 1230, 740 cm-1. Anal. Calcd for C18H14O10N5SP: C, 41.31; H,
2.68; N, 13.38. Found: C, 40.98; H, 3.23; N, 13.48.
Synthesis of 7-amino-3-[(2,5-dihydro-6-
hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)-
2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(O,O-diethyl- thiomethyl]cephalosporanic acid (7-ACT)
phosphorothioic) anhydride (AEPTA, 2a) A pale yellow solid; yield
1
Acetonitrile (150 mL) was stirred and treated with 7-ACA (20.41 g,
0.075 mol), TTA (11.92 g, 0.075 mol), and a small quantity of EDTA.
The temperature was increased to 30°C, and the mixture was treated
with boron trifluoride-acetonitrile complex (86 g, 0.077 mol). Stirring
was continued for an additional 20 min, afer which time the mixture
became a solution. Afer another 10 min the solution was cooled below
5°C, treated with water (20 mL) and aqueous ammonium hydroxide to
pH 3.0. The precipitated crystals of 7-ACT were collected afer 20 min
and washed with cold ethanol (3ꢀ× ꢀ50 mL); yield 24.59 g (88)%; mp 193–
196°C; 1H NMR: δ 3.92 (s, 3H), 3.59 (br, 2H), 4.20 (d, J ꢀ= ꢀ 13 Hz), 4.31(d,
2H, J ꢀ= ꢀ 13 Hz), 4.98 (d, 1H, J ꢀ= ꢀ 5 Hz), 5.60–5.75 (m, 1H), 9.27 (d, 2H, J ꢀ= ꢀ
8 Hz); 13C NMR: δ 193.0, 164.1, 163.0, 161.9, 154.0, 130.7, 120.9, 59.9, 58.7,
35.4, 27.3, 19.4; IR: 3480, 3400, 1755, 1730, 1710, 710 cm-1. Anal. Calcd for
C12H13N5O5S2: C, 38.78; H, 3.50; N, 18.84. Found: C, 37.91; H, 3.67; N, 18.97.
94%; mp 84–86°C; H NMR: δ 7.23 (s, 2H), 7.48 (s, 1H), 3.79 (m, 6H),
3.92 (m, 3H), 4.01 (m, 2H), 1.29 (m, 3H); 13C NMR: δ 168.5, 167.0, 122.3,
108.0, 64.3, 63.1, 17.3, 17.1; IR: 3450, 3250, 3100, 1690, 1675, 740 cm-1.
Anal. Calcd for C10H16O5N3S2P: C, 33.99; H, 4.69; N, 11.89. Found: C,
34.14; H, 4.64; N, 11.91.
2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(O,O-di-tert-
butyl-phosphorothioic) anhydride (ABPTA, 3a) A pale yellow
solid: yield 90%; mp 91–93°C; 1H NMR: δ 7.22 (s, 2H), 7.45 (s, 1H), 3.93
(s, 3H), 1.19 (m, 18H); 13C NMR: δ 172.4, 168.9, 166.0, 164.0, 108.0, 69.3,
64.8, 30.9, 30.8; IR: 3450, 3260, 3100, 1690, 1670, 740 cm-1. Anal. Calcd
for C12H24O5N3S2P: C, 37.41; H, 6.23; N, 10.91. Found: C, 37.82; H, 6.31;
N, 10.86.
2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(O,O-diphe-
nylphosphorothioic) anhydride (APPTA, 4a) A pale yellow solid;
1
yield 87%; mp 98–102°C; H NMR: δ 7.22 (s, 2H), 7.45 (s, 1H), 3.93 (s,
Synthesis of ceftriaxone in the presence of
phosphonate active esters
3H), 7.08 (d, 4H, J ꢀ= ꢀ 7.2 Hz), 7.21 (d, 4H, J ꢀ= ꢀ 1.8 Hz), 7.28 (dd, 2H, J ꢀ= ꢀ
1.8 and 1.6 Hz); 13C NMR: 172.4,168.9, 166.0, 164.0, 150.2, 130.1, 121.3,
120.3, 108.0, 64.3; IR: 3450, 3240, 3150, 1690, 1675, 750, 730 cm-1. Anal.
Calcd for C18H16O5N3S2P: C, 48.11; H, 3.56; N, 9.35. Found: C, 47.92; H, Dichloromethane (240 mL) was cooled to 0–5°C and treated with
4.11; N, 9.16. ethanol (7.5 mL), EDTA, and sodium bisulfite (small quantities). Afer
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