Studies On New Synthetic Methods And Mechanism Of Drospiroenone Intermediates

Steroid drugs have strong pharmacology function. They are mainly used for treatment of various diseases such as rheumatic diseases, cardiovascular, tumors, bacillary encephalitis, skin diseases, endocrine imbalance, the old aged diseases. Drospirenone (DRSP) is an agent that binds to the androgen receptor and blocks its action. It is available in combination with ethinyl estradiol as a new oral contraceptive Yasmin.The key intermediate of DRSP 3β-acetoxy-7α-chloride-5β 6β-epoxy-17,17-ethylendioxy-15β,16β-methylene-5-androstane was stereo-selectively synthesized from 3β-acetoxyandrost-5-en-17-one (dehydro-epiandrosterone acetate) by new route and technological process includ -ing ketal formation at C₁7, bromination at C₁6, dehydrobromination be -tween C₁5 and C₁6, deprotection at C₁7, cyclopropantion between C₁5 and C₁6, the second protection at C₁7, oxidation at C₇, reduction at C₇, epoxidation between C₅ and C₆, chlorination at C₇ total 10 steps with overall yield of 21.2%.Dehydrogenation of dehydroepiandrosterone acetate between C₁5 and C₁6 gives 3β-acetoxyandrosta-5,15-dien-17-one by 4 steps instead of 6 steps in literature. The advantage of new method lies in raising the yield and shortening the synthetic steps. The normal factors in susceptibility to the brominating reaction govern reactivity, with C₅H₅N·HBr·Br₂ >Br₂ being the order in terms of brominating agents and NaI≈KI>Zn dust in terms of debrominating agents. Good yield (76.5%) was obtained, using C5H5N HBr Br₂ as a brominating agent and employing KI as a debrominating agent with lower costs in the bromination. The mecha -nism of dehydrobromination is inferred to be S_N2 by the rate of dehydro bromination direct ratio to the content of t-BuOK and to the concentration of steroid.Molecule energy of the products and by-products in cyclopropantion between C₁5 and C₁6, reduction at C₇, epoxidation between C₅ and C₆, chlorination at C₇ were firstly calculated by quantum chemistry semi-empirical method to expound these reactions's stereoselectivity, and mechanisms and influence factors of the above reactions were studied. It was given that the product 5 is the rate-controlling productand that 14a-H and lower reaction temperature are favor to the formation of the 15p\6p-methylene 5 and not favor to the by-product 15a, 16a-methylene 20 in the cyclopropanation. It was also given that the product 8, 9 and 10 separately in the reduction, in the epoxidation and in the chlorination all are thermodynamics-controlling products. The study showed that increasing the volume of hydrogen transfer reagent and raising the reaction temperature and the existing 19-methyl are favoured to the formation of "⁷fi alcohol" 8 in the reduction.Rate constants " K " at selected temperature and the corresponding activation energy "Ea "were separately calculated in the cyclopropana -tion and in the reduction. The results showed that they all are second order reactions.The synthetic route was shortened in the cyclopropanation by using dimethyloxosulfonium methylide(22). The optimum condition is as follows, ?((CH3)3S+Or ):?(NaH):n(15)=1.10:1.05: 1.00, the temperature is 12°C, the volume fraction of DMSO:THF is 4:1, and the addition way is from 15 to 22 High yields (e.g.80.5%) was obtained. Ordinary oxidants such as CrO3 C5H5N complexes and (C5H5NH)2Cr2O7 were used for the first time in oxidation at C7 and the purifying method was improved. The rate study showed that the oxidation rate order is CrO3C5H5N(l:l)> CrO3 C5H5N (1:2) >(C5H5NH)2Cr207 at earlier stage of oxidation, and CrO3C5H5N(l:2) > CrO3C5H5N(l:l) >(C5H5NH)2Cr2O7 at later stage in terms of the oxidant, and that the yield of the oxidation becomes higher with increasing the oxidant stoichimetry and raising the reaction temperature (e.g. 30°C and ?(6) / n (1:2 complex) =1:20, 71.2%). It also showed that the yield of the " -7/? alcohol" order is Li[Al(OC(CH3)3)3H] (e.g.82.4%)?NaBH4(e.g.l4.5%) in terms of the reductive agent, and that the reduction rate decreases in the course of reduction.The "-7/? alcohol" is stereoselectively epoxidated by f-BuOOH-V2O5 and KMnO4-CuSO4 to give 5p,6(3-epoxy. The former oxidant is cheaper than the latter one in terms of epoxidating agent. Good yield (e.g. 92.1%) is obtained when n(-7j3 alcohol):n(KMnO4)=l:12 and n(8) : ?(CuSO4-5H2O) =1:4. The "two-cyclo" epoxidation mechanism was put forward.