- A Chemoenzymatic Strategy for the Synthesis of Steroid Drugs Enabled by P450 Monooxygenase-Mediated Steroidal Core Modification
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The synthesis of steroid drugs by multistage modifications of the steroidal core is challenging since site-specific and selective modification is essentially required, which is often difficult or complicated for chemocatalysis. For example, the synthesis of Trenbolone (3), a versatile anabolic-androgenic steroid, relies on a four-step chemical procedure on its core modifications of estra-4,9-diene-3,17-dione (1). Here, we have designed a two-step chemoenzymatic strategy that includes a biocatalytic one-pot C11-hydroxylation/17β-ketoreduction of 1 with a computationally designed P450 monooxygenase and an appropriate 17-ketosteroid reductase to generate 11α-OH-9(10)-dehydronandrolone (2a) as an intermediate followed by chemical dehydration to introduce the double bond at carbons 11 and 12 with the formation of Trenbolone (3). To obtain a highly active and C11-selective enzyme, molecular dynamics simulations were performed, uncovering a crucial role of water molecules for substrate recognition and targeted hydroxylation of steroids. Moreover, Trenbolone is further subjected to esterification to produce Trenbolone acetate (9) that has been widely used in veterinary medicine. Finally, our approach enables the regio- and stereoselective synthesis of both steroid drugs 3 and 9 on a (nearly) gram scale with 83-91% isolated yields, showing great potential for industrial applications.
- Peng, Yaqin,Gao, Chenghua,Zhang, Zili,Wu, Shijie,Zhao, Jing,Li, Aitao
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p. 2907 - 2914
(2022/03/03)
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- Method for preparing pufferone acetate (by machine translation)
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The invention discloses a method for preparing pufferone acetate, and belongs to the technical field of preparation and processing of hormone drugs. The process is carried out 3 - with ethylenedioxy estra-Δ. 5,10 , Δ9,11 -17-ketone is a starting raw material, and the preparation of the 3 botanerone acetate is carried out by 17 reducing the position of the ketone as an alcohol, hydrolyzing the position of the furanone, the 17 oxidative dehydrogenation, and the alcohol acetylation. The method has the advantages of cheap and easily available raw materials, simple reaction control, few byproducts, easy purification and high total yield, has extremely high competitiveness in production cost and operability, is suitable for industrial large-scale production and has good economic benefits. (by machine translation)
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- Synthesis method of trenbolone acetate
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The invention provides a synthesis method of trenbolone acetate. The synthesis method comprises the following steps: step 1), dissolving a 4,9 ring-opening object (I) into methanol; adding potassium borohydride fractionally at 20 to 25 DEG C; after adding the potassium borohydride, carrying out heat preservation and reacting until a TLC (Thin-Layer Chromatography) analysis raw material is completely reacted, so as to obtain a compound (II); step 2), adding diluted acid into a reaction system for finishing reaction of step 1) and regulating the pH (Potential of Hydrogen) value to be neutral; dropwise adding dilute sulfuric acid and carrying out water separation to obtain 17beta-hydroxy-estra-5(10),9(11)-diene-3-one (III); step 3) dissolving the compound (III) into dichloromethane and addingDDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and completely reacting; filtering; washing filtrate and combining a water layer; extracting the water layer by the dichloromethane; combining all dichloromethane layers; dehydrating, vacuum concentrating and drying to obtain trenbolone (IV); step 4) dissolving the trenbolone (IV) into the dichloromethane; adding DMAP (4-dimethylamiopryidine) and acetic anhydride and completely reacting to obtain the trenbolone acetate.
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Paragraph 0008; 0025; 0032; 0033
(2018/05/30)
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