| Nature has abundant sterols resources. Androstendione(AD), the product of sterols restrictive degraded by microorganism at C17 side-chain, possessing common steroid nucleus skeleton and easy modification of 17-keto-group, becomes an ideal raw material for steroid hormone drugs after diosgenin. In view of the steroid drugs mostly contain hydroxyacetone or dihydroxyacetone side-chain such as in 17α-hydropreganance and Cortisone Acetate, the introduction of the specific side-chain at C17 site is crucial for synthesis of steroid drugs starting from sterols. To focus on the introduction of the specific side-chain at C17 and the chemical transformation related, this paper carried out the synthetic study for cortisone acetate starting from AD. Main contents include the following five parts:(1) Selective protection of steroid C3-keto carbonyl researched. To prevent the effects on C3-keto group during the course of C17 side-chain introduction, the selective protection study by the enol ether method for androstene(AD), and the enamine method for a key intermediate: 21-deoxcortisone carried out respectively. Results demonstrate that: AD enol ether method and 21-deoxycortisone enamine protection method all meets the subsequent alkaline or acidic reaction requirements, with the merits of high chemo-selectivity, mild reaction condition, and simple operation.(2) Routes for the synthesis of Cortisone Acetate via 17α-hydropreganance researched. In order to introduce Cortisone Acetate C17 dihydroxyacetone side-chain to AD, an ethylene two-carbon unit was firstly introduced by Wittig reaction,then through selective oxidation Ketohydroxylation, this ?17(20) steroidal alkene converted to 17α-hydropreganance, which is a synthetic precursor of some contraceptive drugs and a key intermediate in the synthesis of some important corticosteroids, Cortisone acetate. In the course of Cortisone Acetate preparation, both A and B paths unity in one route were designed and constructed according to the different “time” for the C11-OH introduction. In path A, The step of microbial fermentation was put behind 17α-hydropreganance, which realized the “joint” with the existing process through 21-deoxycortisone, and solved the problem of the unification of the process from the new starting material(AD) and the old(diosgenin). In path B, the microbial fermentation put in the final step, thus the transformation of substance S is more efficient, and modularized intensive superiority(chemistry synthesis module or biological fermentation module) highlighted especially in scale production.(3) Routes for the synthesis of Cortisone Acetate by HWE reaction studied. In order to introduce the structural characteristics of cortisone acetate C17 side-chain more efficiently and straightforward, the organic phosphine reagents corresponding to different side-chain features designed and synthesized respectively for the Wittig and HWE reaction. Results showed that: one-step directly introducing cortisone acetate C17 side-chain by Wittig or HWE reaction is not feasible. The reason attributed to the instability of the ylide reagents, lacking stability group in phosphonate reagents and steric hindrance of steroid C17-keto. While the indirect method for synthesis of cortisone acetate by HWE reaction was successful, it followed by reduction, esterification, de-protection, Ketohydroxylation with seven steps. The process has the merits of simple treatment, high yield, is a more practical route for the synthesis of cortisone acetate from AD.(4) The selective oxidation ?17(20) steroid alkene to prepare α-hydroxy ketones in single-step investigated. After AD introduction of C17 unsaturated side-chain, the oxidation ?17(20) steroidal olefin to 17α-hydroxy-20-one is the fundamental step for synthesis of Cortisone Acetate. This part selects Pregna-4, 17(20)-dien-3-one as the research object, experiments of the selective oxidation of Ketohydroxylation in different oxidation system, and single factor experiment optimization Plietker’s Oxone/Ru Cl3/Na HCO3 oxidation system were investigated. Finally, based on above results, we proposed and built a new Oxone/Ru Cl3/n-Bu4 NBr bi-phase transfer catalytic oxidation system, and after optimized by orthogonal experiment design, the yield rose from 40% to 60%(n=3). The oxidation system has the advantage of green, straightforward, high efficiency, high chemo-selectivity and less by-product species.(5) The oxidation of Pregna-4, 17(20)-dien-3-one by Peroxyacetic acid studied. In the process of the selective oxidation ?17(20) steroid alkene to prepare α-hydroxy ketones in one-step, when using peracetic acid/acetic acid solution as oxidant, α-hydroxy ketone product was not gained except two 18-nor steroidal compounds, including a novel pentacyclic steroid. The structure of both products was confirmed by infrared spectroscopy(IR), nuclear magnetic resonance spectroscopy(1D 2D NMR), single crystal X ray diffraction(XRD), and high-resolution mass spectrometry(HR-MS) technique, respectively. Proposed mechanism of the tandem EpoxidationRearrangement-Epoxidation reaction was verified by control tests, and results show that the method of preparing 18-nor steroids in one-pot, is suitable for substrates such as ?17(20), ?13(14) and 17ζ, 20ζ-epoxy steroids, and tolerant to the 4-en-3-one structure because of the chemo-selectivity. The structure of the novel pentacyclic steroid contains a 2-oxadicyclo [2.2.1] heptane subunit, which constructs a new ring E bridging with ring D, and the mechanism of its formation can be understood the epoxy bond further opening in acid and spontaneous intramolecular cyclization. |
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