- Preparation method of tibolone
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The invention discloses a preparation method of tibolone, and belongs to the technical field of preparation and processing of steroid hormone drugs. According to the method, 6,7-didehydronorethindroneis used as an initial raw material, and tibolone is prepared through Grignard reaction, dietherification reaction and hydrolysis reaction. The 7-methyl introduction step is included in the Grignard reaction step in the synthesis route, so that special protection on 17-site hydroxyl is avoided, and the ratio of the 7-alpha methyl intermediate to the 7-beta methyl isomer obtained through the reaction is larger than 20:1; therefore, the single 7-alpha methyl intermediate can be obtained through simple treatment without chromatographic separation, the purification process is simple, and the purity of the final product reaches 99.0% or above, and the yield is higher than 60%; the raw materials are cheap and easily available, the reaction steps are few, the reaction conditions are mild and safe, and the control operation is easy; in addition, reagents used in the reaction are low in environmental pollution, and good economic and social benefits are achieved.
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Paragraph 0034; 0037-0038; 0041-0042; 0045-0046; 0049
(2020/11/25)
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- Synthetic method of tibolone
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The intention relates to a synthesis method of tibolone, which specifically comprises the following steps: 1) ethynylation reaction: introducing acetylene gas into an acidic decarboxylate (I) toluenesolution as a raw material, and reacting to obtain norethindrone (II); 2) acylation reaction: adding acetic anhydride and an acid-binding agent into the norethindrone (II) obtained in the step 1), controlling the room temperature, dropwise adding acetyl chloride, and stirring to react for 6 hours until the raw material is completely reacted to obtain an acylate (III); 3) carrying out debrominationreaction on the acylate to obtain 4, 6-diene norethindrone acetate (V); 4) methylation reaction: adding an ether solvent into the 4, 6-diene norethindrone acetate (V), cooling to -10 to 30 DEG C, dropwisely adding a methylation reagent, controlling the temperature at 0-5 DEG C, and stirring to react until the raw material reaction is complete, thereby obtaining 7alpha-methyl norethindrone acetate(VI); 5) transposition reaction: reacting the 7 alpha- methyl norethindrone acetate (VI) to obtain a transposition substance (VII) wet product, and 6) hydrolysis reaction: reacting the transpositionsubstance (VII) to obtain the tibolone.
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Paragraph 0028-0029; 0040-0043
(2020/05/01)
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- FLUORESCENCE BASED DETECTION OF SUBSTANCES
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A method for the fluorescent detection of a substance, the method comprising providing particles comprising a metal or a metal oxide core, wherein one or more optionally fluorescently tagged antibodies or human specific peptide nucleic acid (PNA) oligomers for binding to a substance is/are bound, directly or indirectly, to the surface of the metal or metal oxide; contacting a substrate, which may or may not have the substance on its surface, with the particles for a time sufficient to allow the antibody/PNA oligomer to bind with the substance; removing those particles which have not bound to the substrate; if the antibodies or PNA oligomers are not fluorescently tagged, contacting the substrate with one or more fluorophores that selectively bind with the antibody and/or substance, then optionally washing the substrate to remove unbound fluorophores; and illuminating the substrate with appropriate radiation to show the fluorophores on the substrate.
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- PROCESS FOR THE PREPARATION OF PURE CRYSTALLINE TIBOLONE
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There is disclosed a process for the preparation of Tibolone crystalline forms I and II characterized by high purity and low particle size.
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Page/Page column 4-9
(2008/06/13)
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- PROCESS AND INTERMEDIATES TO PREPARE l7?-hydroxy-7alpha-methyl-19-nor-17alpha-pregn-5(10)-en-20-yn-3-one
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The present invention is a process for the preparation of l7?-hydroxy-7alpha-methyl-19-nor-17alpha-pregn-5(10)-en-20-yn-3-one (17alpha-ethynyl-l7?-hydroxy-7alpha-methyl-5(10)-estren-3-one, tibolone) of formula 1, which comprises hydrolysis of 17alpha-ethynyl-l7?-hydroxy-7alpha-methyl-5(10)-estrene 3,3-cyclic ketals of formula 2, where groups R1, R2, R3 and R4 are hydrogen atoms or alkyl groups, or R1 and R3, taken together with the carbon atoms within the dioxolane ring to which they are attached, form an alicyclic ring fused to the dioxolane ring, with R2 and R4 being hydrogen atoms, or R1 and R3 together with the carbon atoms to which they are attached form an aromatic ring fused to the dioxolane ring, where R2 and R4, taken together, form a chemical bond within said aromatic ring. In addition, the present invention includes an intermediate, compound of formula 2 and two processes to prepare 17alpha-ethynyl-17(3-hydroxy-7alpha-methyl-5(10)-estrene 3,3-cyclic ketals of formula 2: (a) by contacting 17alpha-ethynyl-l7?hydroxy-7alpha-methyl-4-estren-3-one with vicinal diols in the presence of a protic acid, and (b) by contacting 7alpha-methyl-5(10)-estrene-17-one 3,3-cyclic ketals of formula 4, where R1-R4 are defined as above, with metal acetylides, in inert solvents.
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- PROCESS FOR THE PRODUCTION OF TIBOLONE
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Disclosed is a process for the synthesis of 17β-hydroxy-7α-methyl- 19-nor-17α-pregn-5(10)-ene-20-yne-3-one (tibolone, 11) and intermediates useful for the synthesis thereof: (11).
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