Cephalosporins, which contain thiazolidine-β-lactam rings, are isolated from fungi Cephalosporium analogous to Penicillium. Natural cephalosporins comprise cephalosporin C, N, and P [1] - [4] . There are many relevant antibiotics, including cefotaxime, ceftriaxone, and ceftazidime, among others [5] [6] . The typical core structure of cephalosporins is shown in Figure 1. The routine synthetic procedure was first with 7-

aminocephalosporanic acid (7-ACA) as raw material. 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 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-aminothia- zole-4-yl)-2-methoxyiminoacetic acid (ATMA) and 2,2’-dibenzothiazolyl disulfide (popular name: accelerator DM) (Figure 2) [8] [9] . In this reaction route, the raw material DM is often excessive and remains in the preparation of AE-active ester and is toxic for animals, which is stipulated the residual amount in US Food and Drug Administration and some European countries in cephalosporins. Hence, developing novel active esters without using accelerator DM is imperative [10] - [12] . Phosphphate is found to synthesis active phosphonate esters that are beneficial to improving the security of administering cephalosporin drugs [13] [14] . Our research group has reported the detail synthetic route in the previous articles [15] [16] . It is shown that the novel phosphonate esters (Figure 3) have high activity and are superior to AE-active ester, which are commonly applied in modifying second-generation and third-generation cephalosorins [17] .

According to a series of experimental synthesized active phosphonate esters, the yield of ceftriaxone with different active ester increases compared with commonly used benzothiazole AE-active ester [15] . Among these esters, 2-(2-aminothiazol-5-yl)-2-(me- thoxyimino)acetic(O,O-bis(4-nitrophenyl)phosphorothioic)anh-ydride (6a) is most active in the synthesis of ceftriaxone. In order to elucidate novel active phosphonate esters, a quantum chemistry calculation study was used. This paper is focused on the theoretical elucidation active phosphonate esters of Cephalosporin antibiotics’ intermediate. We mainly study the properties of the compounds 6a, 6b, 1a and 1b comparing to the AE-active ester that is now accounting for 80% of these commercially available reagents.

The calculation procedures are as follows. The computational accuracy, feasibility and economical computational time are considered when choosing the computational levels and basis sets. The geometrical parameters are optimized at the B3LYP level with a standard 6-311+G(d, p) [18] [19] basis set. The B3LYP/6-311+G(d,p) is proved to be an outstanding method for prediction of thermochemical kinetics and vibrational frequencies

of Organic Compounds. All structures of active phosphonate esters have been located on the potential energy surface (PES) by performing full geometry optimization without any symmetry restriction, and their natures including local minima have been identified by performing frequency calculations at the same level, from which the zero point energies (ZPEs) have also been derived. All of the quantum chemical calculations were performed in the framework of DFT using Gaussian by the Gaussian 03 program [20] .

Density functional theory B3LYP/6-311+G(d,p) method was employed to theoretically elucidate a series of active phosphonate esters application in preparation of Cephalosporin antibiotic’s intermediate. First, the stable equilibrium geometries including comparing to the AE-active ester were obtained. It was found that the Ethyl-aminothiazoly Loximate (AT) molecule fragment is almost planar sheet, but it is almost perpendicular to the plane of phosphoryl ester. Moreover, the calculated Mulliken atomic charge distribution and frontier molecular orbital analysis of these esters showed that the amino N atom connected to the Thiazole ring of the AT had the maximum negative charge, which suggested that this area had high molecular activity. The high activity of 6a active ester can be attributed to the two aspects including large negative charge and steric space. Energy gap between E_HOMO and E_LUMO, ΔE_L-H, indicated also that compound 6a has high reaction activity. The theory calculation results can explain the experimental phenomenon and predict that the novel active phosphonate ester has a hopeful application prospect in preparation of Cephalosporin antibiotics’ intermediate.

This work was financially supported by Research Project of Shandong Province Science and Technology Development (No. 2014GSF117002). We also thank International Cooperation Training Project for Outstanding Young Teachers in the Colleges and Universities of Shandong Province.

Sun, Y.M., Ren, H.X., Wei, X.F. and Zhang, G.Q. (2016) Theoretical Insights Elucidate Novel Active Phosphonate Esters―Cephalosporin Antibiotics’ Intermediate. Open Journal of Inorganic Chemistry, 6, 219-228. http://dx.doi.org/10.4236/ojic.2016.64017