Abstract
For a series of active phosphonate esters, the anhydride abbreviated as ANPTA (6a) exhibits the highest reactivity in the preparation of ceftriaxone. The synthesis of ceftriaxone was optimized with the pilot-scale yield reaching 95.7%. The results were explained from the structural viewpoint and supported by analysis of the calculated Mulliken atomic charge distribution.
Introduction
The antibiotics β-lactams [1, 2] are normally acyl derivatives of 7-aminocephalosporanic acid (7-ACA; Figure 1) [3–5]. There are many relevant antibiotics, including cefotaxime, ceftriaxone, and ceftazidime, among others [6]. To increase the yields of the antibiotics synthesis by elevating the activation efficiency of acylation of the amino group in 7-ACA, various types of acylating agents have been developed, of which carboxylic thiol esters, pyridinecarboxylic acid esters, and carboxylic trinitrophenyl esters are the most representative reagents [7]. Currently, third-generation cephalosporins, such as ceftriaxone sodium and cefotaxime sodium, are normally synthesized by using 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic thiobenzothiazole ester (popular name: AE-active ester; Figure 2) derived from 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetic acid (ATMA) and 2,2′-dibenzothiazolyl disulfide (popular name: accelerator DM) [8, 9]. This highly reactive AE-active ester is now accounting for 80% of those commercially available reagents. However, in order to ensure complete reaction, DM, as the starting material, is used in excess to consume the other starting material – ATMA, and remains in the preparation of AE-active ester. Meanwhile, DM can hardly be eliminated once absorbed and toxic amounts accumulate, thus motivating the US Food and Drug Administration and some European countries to regulate the residual amount of DM in cephalosporins such as ceftriaxone. To this end, it is imperative to develop novel active esters without using accelerator DM [10–12].
Core structure of cephalosporin.
Structure of AE-active ester.
According to the synthesis requirements of cephalosporins, the density functional theory (DFT) B3LYP/6-311+G(d,p) method was used to obtain the equilibrium geometries of the active esters and to analyze the charge distribution.
Therefore, we herein designed and prepared a series of active phosphonate esters to replace the original acylating agent, which were successfully applied in the synthesis of ceftriaxone.
Cephalosporins, which contain thiazolidine-β-lactam rings, are isolated from fungi Cephalosporium analogous to Penicillium. Natural cephalosporins comprise cephalosporin C, N, and P [13, 14]. The typical core structure of cephalosporins is shown in Figure 1.
Phosphate, an important metabolic substance in the human body, is involved in amino acid metabolism commonly in the form of phosphopyridoxal coenzyme. Because it does not remain in the human body with low cytotoxicity, developing active phosphonate esters is beneficial to improving the security of administering cephalosporin drugs [15, 16]. Furthermore, being electronegative, sulfur and oxygen in P-S and P-O bonds are prone to enhancing the electron-withdrawing ability and nucleophilicity of phosphorus-containing groups, and the active phosphonate ester has high activity. Therefore, active esters are commonly applied in modifying second-generation and third-generation cephalosporins by augmenting activity and relieving side effects [17]. Appropriate phosphoryl active esters were then screened (Scheme 1) and applied in the preparation of ceftriaxone, verifying that such active esters were superior to AE-active ester (Figure 2).
Synthesis route of active phosphonate esters.
Reagents and conditions: (a) CH2 Cl2, Et3 N, N(C4 H9)3; (b) under nitrogen at 0–5°C.
Results and discussion
Effects of types of active esters
As shown in Table 1, of all ATMA-based active phosphonate esters, 2-(2-aminothiazol-5-yl)-2-(methoxyimino)acetic(O,O-bis(4-nitrophenyl)phosphorothioic)anh-ydride (ANPTA, 6a) is most active in the synthesis of ceftriaxone. Compared with commonly used benzothiazole AE-active esters [8, 9], the use of ANPTA causes increases in the yield of ceftriaxone from 92.5% to 97.8% (HPLC), with the increase in purity from 90.1% to 95.7%.
Synthesis of ceftriaxone with different active esters.
| Code of active ester | Yield of ceftriaxone % | Purity of ceftriaxone % (HPLC) | Color of ceftriaxone |
|---|---|---|---|
| AE-active ester | 90.1 | 92.5 | Pale yellow |
| 1a | 91.2 | 95.8 | Pale yellow |
| 2a | 92.8 | 95.8 | White |
| 3a | 93.4 | 95.3 | Yellow |
| 4a | 91.0 | 94.7 | Pale yellow |
| 5a | 91.6 | 96.2 | Pale yellow |
| 6a (ANPTA) | 95.7 | 97.8 | White |
| 1b | 91.7 | 96.2 | Pale yellow |
| 2b | 93.3 | 96.7 | White |
The Mulliken atomic charge distribution can well explain the higher activity of ANPTA. Tables 2 and 3 give the calculated part Mulliken atomic charge distribution of the active esters. All N and O atoms have negative charges concentrated at AT molecular fragments. Moreover, the amino N (8) atom connected to the thiazole ring of AT has maximum negative charge. These findings suggest that this area has high molecular activity and easily coordinates biological macromolecules. When 7-ACA undergoes a reaction with the phosphonate active esters, the C16-O21 bond is broken. Then, the synthesis of ceftriaxone is completed (Scheme 2). As listed in Tables 2 and 3, the charge on C16 atom is negative. When the R substituent, that is, the ethyl group, is changed to the p-nitrophenyl group, the negative charge on the C16 atom increases. The results can be attributed to the electron-withdrawing effect of the nitro group, which is consistent with the experimental observation that the nitrophenyl derivative ANPTA is highly active. In addition, the optimized structures of active phosphonate ester can be shown at the B3LYP/6-311+G(d,p) level. The ethyl-aminothiazoly loximate (AT) molecular fragment is almost a planar sheet, being almost perpendicular to the plane of phosphoryl ester. However, the steric structures of phosphoryl ester with sulfur and oxygen in P-S and P-O bonds are similar. When R is a p-nitrophenyl substituent, two benzene rings are almost vertical to each other due to the steric effect. (For the relevant structure, see supplementary material: S5.) In conclusion, the high activity of the active ester ANPTA (6a) can be attributed to the electronic features in the molecule.
Calculated Mulliken atomic charges of AE-active esters for X = O(S), R = Et (compounds 2a and 1b).
| Atom | Charge (X = O) | Charge (X = S) | Atom | Charge (X = O) | Charge (X = S) |
|---|---|---|---|---|---|
| S1 | -0.088404 | -0.046261 | C16 | -0.512285 | -0.375505 |
| C2 | -0.128987 | -0.182908 | O17 | 0.048156 | 0.117513 |
| O3 | -0.163310 | -0.040990 | C18 | -0.231232 | -0.244536 |
| C4 | 0.711214 | 0.918978 | O20 | -0.139254 | -0.140705 |
| C5 | -0.297619 | -0.339169 | O21 | -0.173887 | -0.140772 |
| N6 | -0.090859 | -0.080687 | P24 | 0.166952 | -0.310921 |
| N8 | -0.303431 | -0.300217 | O25 | -0.250323 | -0.169908 |
| C10 | -0.058120 | 0.108411 | O(S)26 | 0.031299 | 0.042225 |
| C11 | -0.130257 | -0.422135 | C27 | -0.294822 | -0.212809 |
| N15 | -0.259018 | -0.345016 |
Calculated Mulliken atomic charges of AE-active esters for X = O(S), R = p-nitrophenyl (compounds 6a and 2b).
| Atom | Charge (X = O) | Charge (X = S) | Atom | Charge (X = O) | Charge (X = S) |
|---|---|---|---|---|---|
| S1 | -0.089855 | -0.098049 | O21 | 0.218750 | 0.266653 |
| C2 | -0.280297 | -0.276021 | P24 | -0.045287 | -0.117455 |
| O3 | -0.066869 | 0.074834 | O25 | -0.046130 | -0.000435 |
| C4 | 0.931253 | 1.007407 | O26 (S49) | 0.032494 | 0.130594 |
| C5 | -0.239864 | 0.177783 | C27 (26) | -0.405757 | 0.074142 |
| N6 | -0.083803 | -0.088637 | C29 (28) | 0.356254 | 0.186055 |
| N8 | -0.288201 | -0.289096 | C33 (32) | -0.420840 | -0.362453 |
| C10 | 0.299641 | 0.222995 | C41 (40) | 0.193885 | 0.153668 |
| C11 | -0.353063 | -0.271779 | C44 (43) | 0.004787 | -0.161934 |
| N15 | -0.283129 | -0.245743 | C46 (45) | -0.187235 | -0.348535 |
| C16 | -1.127062 | -1.461412 | N43 (42) | -0.242968 | -0.244139 |
| O17 | 0.106771 | 0.115018 | O49 (48) | 0.001866 | 0.002158 |
| C18 | -0.229614 | -0.229991 | O13 | -0.001296 | -0.000716 |
| O20 | 0.024536 | 0.054591 |
Synthesis of ceftriaxone with active phosphonate ester.
Reagents and conditions: (a) CH3 CN, BF3-CH3 CN, 5–30°C; (b) CH2 Cl2, Et3 N, CH3 CN, 0–5°C.
Process optimization
Based on the orthogonal design method [18, 19], the reaction yield is affected by main factors of the ratio of isopropanol/water/ethyl acetate, the molar ratio of active phosphonate ester/7-ACT, and the reaction time. We obtained the following optimum preparation conditions for ceftriaxone: molar ratio of active phosphonate ester/7-ACT of 1:1.5, ratio of isopropanol/water/ethyl acetate of 2:4:1, and reaction time of 6 h. Notably, prolonging the reaction time increases the yield but also decreases the product purity (For the relevant data, see supplementary material: S1, S2, S3, and S4). Under the optimized conditions, the yield of ceftriaxone reached 95.7%, being 5% higher than that using AE-active ester.
Conclusions
According to the preparation requirements of cephalosporins, we herein designed and synthesized a series of active phosphonate esters. ANPTA (6a) is most reactive in the preparation of ceftriaxone, which is supported by the stereoelectronic features of the reagent. The reaction conditions were optimized by orthogonal experiments: molar ratio of active phosphonate ester/7-ACT = 1:1.5, ratio of isopropanol/water/ethyl acetate 2:4:1, and the reaction time = 6 h. The pilot-scale yield of ceftriaxone was increased by 5% to 95.7% from that of using AE-active ester.
Experimental
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded in DMSO-d6 using a Bruker ARX-300 spectrometer. Contents and purities were analyzed by a Waters 515 HPLC instrument. Elemental analyses were determined by using a CARLO-ERBA 1106 elemental analyzer. Melting points were measured using a WRS-2A melting point analyzer (Shanghai Jingke Scientific Instruments Co., Ltd.). IR spectra were recorded by Bruker TENSOR 27. ATMA was purchased from Shandong Jincheng Pharmaceutical Co., Ltd. Triethylenediamine, phosphorus oxychloride, dimethyl phosphate, and diethyl phosphate were obtained from Shanghai Chemical Co., Ltd. 7-ACA was purchased from Huabei Zhongrun Pharmaceutical Co., Ltd. Tetrahydro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione (TTA) was obtained from Shandong Jincheng Pharmaceutical Co., Ltd. Other analytically pure reagents were bought from Shanghai Xinran Chemical Co., Ltd.
Synthesis of 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic(O,O-dimethylphosphoro-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 yellow 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 (2×150 mL) and saturated NaCl (3×150 mL), dried over MgSO4, and filtered. After dilution with n-hexane (300 mL), the resultant precipitate of 1a was filtered and washed with n-hexane (2×25 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 C8 H12 O5 N3 S2 P: 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 similar way.
2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(O,O-diethylphosphorothioic) anhydride (AEPTA, 2a) A pale yellow solid; yield 94%; mp 84–86°C; 1H 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 C10 H16 O5 N3 S2 P: 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 C12 H24 O5 N3 S2 P: 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-diphenylphosphorothioic) anhydride (APPTA, 4a) A pale yellow solid; yield 87%; mp 98–102°C; 1H NMR: δ 7.22 (s, 2H), 7.45 (s, 1H), 3.93 (s, 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 C18 H16 O5 N3 S2 P: C, 48.11; H, 3.56; N, 9.35. Found: C, 47.92; H, 4.11; N, 9.16.
2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(O,O-di-p-tolylphosphorothioic) anhydride (ATPTA, 5a) A pale yellow solid; yield 89%; mp 103–107°C; 1H NMR: δ 7.22 (s, 2H), 7.45 (s, 1H), 3.93 (s, 3H), 7.02 (m, 4H), 7.16 (m, 4H) 2.34 (s, 3H); 13C NMR: δ 172.4, 168.9, 166.0, 164.0, 150.2, 130.1, 121.3, 120.3, 108.0, 64.3, 21.3; IR: 3450, 3240, 3100, 1695, 1670, 740, 730 cm-1. Anal. Calcd for C20 H20 O5 N3 S2 P: 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 yellow 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 C18 H14 O9 N5 S2 P: C, 40.07; H, 2.59; N, 12.98. Found: C, 39.94; H, 3.81; N, 15.38.
2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetic(diethylphosphoric) anhydride (AEPPA, 1b) A yellow solid; yield 88%; mp 87–91°C; 1H 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 C10 H16 O6 N3 SP: 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-nitrophenyl)phosphoric) anhydride (ANPPA, 2b) A yellow solid; yield 87%; mp 109–113°C; 1H 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 C18 H14 O10 N5 SP: 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)-thiomethyl]cephalosporanic acid (7-ACT)
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, after which time the mixture became a solution. After 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 after 20 min and washed with cold ethanol (3×50 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 C12 H13 N5 O5 S2: C, 38.78; H, 3.50; N, 18.84. Found: C, 37.91; H, 3.67; N, 18.97.
Synthesis of ceftriaxone in the presence of phosphonate active esters
Dichloromethane (240 mL) was cooled to 0–5°C and treated with ethanol (7.5 mL), EDTA, and sodium bisulfite (small quantities). After addition of 7-ACT (24 g, 0.065 mol), the mixture was treated successfully with triethylamine (10 mL), a phosphonate active ester (AMPTA: 26.4 g, 0.08 mol) and sulfurous acid (1 mL). The mixture was stirred at 0–5°C for 1 h, treated with ethanol (7.5 mL), and stirred for another 3 h. The mixture was thereafter extracted with sodium acetate solution (18%, 2×40 mL), and the upper layers were combined in a 1000 mL three-neck bottle, heated to 18–20°C, and dropwise added to 500 mL of acetone (from slow to fast). The resultant precipitate was vacuum-filtered and crystallized from ethyl acetate to give a white product (ceftriaxone) in the yield of 32.7 g (91%); purity 95.8% by HPLC; mp 154–158°C; 1H NMR: δ 6.78 (s, 1H), 5.61(dd, 1H, J = 7.9 and 4.8 Hz), 5.03 (1H, d, J = 4.8 Hz), 3.54 (1H, d, J = 17.2 Hz), 3.29 (1H, d, J = 17.2 Hz), 4.67 (1H, d, J = 12.1 Hz), 4.02 (1H, d, J = 12.1 Hz), 3.79 (s, 3H), 3.41 (s, 3H); 13C NMR: δ 193.0, 176.0, 164.1, 163.0, 160.6, 154.0, 130.7, 120.9, 61.2, 59.2, 58.5, 57.5, 35.4, 29.3, 27.8, 19.7; IR: 3480, 3450, 3360, 1765, 1740, 1710, 730. Anal. Calcd for C18 H18 N8 O7 S3: C, 38.94; H, 3.25; N, 20.19. Found: C, 38.71; H, 3.49; N, 19.89.
The results of synthesis of ceftriaxone with other phosphonate active esters are summarized in Table 1.
Calculation details
The DFT method B3LYP with the 6-311+G(d,p) basis set [20] was used to optimize the molecular geometries and to determine the vibrational frequencies for all molecules in vacuum. All quantum chemical calculations were accomplished by using the Gaussian 03 program [21].
Acknowledgments
This study was financially supported by Natural Science Funds of Shandong Province of China (Y2007B42), the University Institutes Innovation Program of Jinan Science and Technology Bureau (201102046), Research Funds of Shandong Jianzhu University (XN110110) and Research Funds for the Doctoral Program of Shandong Jianzhu University (XNBS1309), Program for Changjiang Scholars and Innovative Research Team in University (Grant no. IRT1066).
References
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