- An alternative synthesis of the breast cancer drug fulvestrant (Faslodex): catalyst control over C-C bond formation
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Fulvestrant (Faslodex) was synthesized in four steps (35% overall yield) from 6-dehydronandrolone acetate. Catalyst controlled, room temperature, diastereoselective 1,6-addition of the zirconocene derived from commercially available 9-bromonon-1-ene was used in the key C-C bond forming step.
- Caprioglio, Diego,Fletcher, Stephen P.
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Read Online
- Impurity control method of fulvestrant
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The invention belongs to the field of pharmaceutical chemicals, and relates to a fulvestrant impurity control method, which is characterized in that from the introduction of chiral carbon to the synthesis of a fulvestrant intermediate compound represented by a formula VII-1, multi-step and step-by-step control is performed on 7beta isomer impurities, so that the 7beta isomer content of the VII-1 compound is between 0.1% and 0.3%, and finally the qualified fulvestrant bulk drug with stable quality is prepared. The impurity control method is simple to operate, low in production cost and high intotal yield, and can be applied to large-scale industrial production.
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- Processes and intermediates for preparing fulvestrant
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The present invention provides a method and an intermediate for preparing fulvestrant, and relates to a method for preparing fulvestrant, and an intermediate (5) of fulvestrant, and a synthetic methodthereof. The method provided by the invention can be used for obtaining high-purity fulvestrant, and is suitable for industrial mass production.
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- Method for preparing fulvestrant and intermediates
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The invention relates to a method for preparing fulvestrant and intermediates, particularly to a method for preparing a fulvestrant intermediate. According to the method, estradiol is used as a starting raw material, and is linked to a protecting group to obtain an intermediate 1; the benzyl site of the intermediate 1 is hydroxylated to obtain an intermediate 2; the intermediate 2 is oxidized to obtain an intermediate 3; the intermediate 3 and an intermediate 4 (1,9-dibromo nonane is subjected to iodination to obtain an intermediate 4, ie., 1,9-diiodononane) are subjected to a condensation reaction to obtain an intermediate 5 (a compound represented by a formula I); the intermediate 5 and an intermediate 7 (4,4,5,5,5-pentafluoropentanol and p-toluenesulfonyl chloride are condensed, and thecondensed product reacts with thiourea to obtain p-toluenesulfonic acid pentafluorothiourea salt) are subjected to a reaction to obtain an intermediate 8; the intermediate 8 is subjected to deprotection-reduction to obtain an intermediate 9; and the intermediate 9 is oxidized to obtain a target product. The method has the advantages of simple operation process, high yield of fulvestrant and highpurity of fulvestrant, and is suitable for industrial mass production.
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Paragraph 0055-0058
(2020/04/17)
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- Fulvestrant preparation method
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The invention provides a new fulvestrant synthesis method, which has characteristics of mild reaction condition, simple route and high yield and high purity of each reaction intermediate, can obtain high-purity fulvestrant through re-crystallization without column chromatography, and is suitable for industrial production. The specific technical scheme of the present invention comprises that a compound represented by a formula I and a reagent are subjected to a halogenation reaction in a solvent to generate a compound represented by a formula II; the compound represented by the formula II and thiourea are subjected to a reflux reaction in a solvent to generate a compound represented by a formula III; the compound represented by the formula III and a compound represented by a formula IV aresubjected to a nucleophilic substitution reaction and a hydrolysis reaction in an alkali solution and an organic solvent to generate a compound represented by a formula V; and the compound representedby the formula V is oxidized with an acetic acid hydrogen peroxide oxidation system in a solvent to obtain fulvestrant.
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- Fulvestrant intermediate
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The present invention provides a new fulvestrant intermediate compound represented by a formula III, wherein the mass spectrum of the intermediate III is [M+H]237.2082. According to the present invention, with the application of the intermediate to prepare fulvestrant, the route is simple, the yield and the purity of each reaction intermediate are high, the high-purity fulvestrant can be obtained through re-crystallization without column chromatography, and the method is suitable for industrial production.
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Paragraph 0081-0085; 0112-0123
(2019/10/01)
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- Preparing method of fulvestrant
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The invention relates to a preparing method of a steroid compound, in particular to preparing of fulvestrant. The compound 1 serves as the initial raw material, or the compound 1 is used for synthesizing the fulvestrant. The method is high in selectivity, the selectivity and yield of a 7-site side chain can be improved, the construction of an aromatic ring is avoided, after-reaction treatment is simple, and operation is easy. Conventional reagents are used, reactions except the catalysis reaction where precious metal is used are more environmentally friendly compared with the prior art, and therefore the certain energy consumption reduction potential is realized.
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- Improved method for recovering fulvestrant with unqualified isomer ratio
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The invention relates to an improved method for recovering fulvestrant with an unqualified isomer ratio. A halide is adopted as a reduction catalyst for replacing reductants with potential safety hazard and environmental pollution in the prior art, so that the discharge of three wastes (waste gas, waste water and industrial residue) is reduced, the recovery rate of the fulvestrant is greatly improved, the recovery rate of the unqualified fulvestrant can reach about 70%, and thus the improved method is beneficial for industrial popularization.
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Paragraph 0012; 0014
(2018/04/02)
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- Fulvestrant and preparation method of intermediate thereof
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The invention relates to fulvestrant and preparation of an intermediate and comprises a method for preparing fulvestrant from new isothiourea sulfonate. The route is short, the operation is simple, raw materials are easy to obtain, the condition is mild, the overall reaction time is greatly shortened, the production cost is reduced, the total yield is high, no protective group is introduced into hydroxyl in 3 and 17 positions, and the method is suitable for large-scale industrial production.
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Paragraph 0050; 0051; 0052
(2017/09/05)
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- Preparation of fulvestrant
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The invention relates to a preparation method of fulvestrant, in particular to preparation of the fulvestrant realized under the condition of beta-cyclodextrin/NBS through oxidizing a compound shown as a formula I. By using the method, the generation of fulvestrant peroxidating impurities can be completely avoided.
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Paragraph 0017
(2017/02/09)
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- A new compound and its preparation method and elimination method (by machine translation)
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The invention relates to medical and chemical field, provides a new compound, the compounds have the formula I structure, is preparing novel anti-breast cancer drug of fulvestrant in the process more difficult to avoid one of the impurity. The present invention provides a compound of formula I of the synthetic route, and to reduce or avoid the preparation of fluorine Uygursi Qun produced in the process of method, and in its generated after the method of removing it, not only reduces the growing into this impurity the waste of raw materials, also there to have ruled out the impurities to the rear edge of fulvestrant to purification of the product and the impact of the yield. (by machine translation)
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Paragraph 0067; 0068
(2018/01/06)
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- A new method for the synthesis of fulvestrant (by machine translation)
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The invention discloses a new method for the synthesis of fulvestrant, it is in order to intermediate X and five fluorine amyl alcohols as the starting material as the starting material, obtained through the four-step reaction of fulvestrant, this line does not need to column chromatography purification, the crude final product only needs to re-crystallization can be obtained the fulvestrant accord with Pharmacopoeia standards, overall yield is 50 the [...] 60%, and the raw material are industrial product, is easy to obtain, the quality is easy to control. (by machine translation)
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Paragraph 0065-0070
(2018/02/04)
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- PROCESS FOR THE PREPARATION OF FULVESTRANT
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The present invention relates to an improved process for the preparation of Fulvestrant (I). Also, provided is novel intermediate of Fulvestrant and a process for the preparation of the same.
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- PROCESS AND INTERMEDIADES FOR THE PREPARATION OF 7-ALKYLATED STEROIDS
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A process for preparing compounds of formula (I), or a salt, solvate or stereoisomer thereof, including Fulvestrant, which process comprises free radical to a compound of formula (III), or a salt, solvate or stereoisomer thereof. The invention also refers to intermediates of said process.
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- PROCESS FOR PREPARING 7-ALPHA-[9-(4,4,5,5,5-PENTAFLUOROTHIOPENTYL) NONYL]ESTRA-1,3,5(10)-TRIENE-3,17-BETA-DIOL
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A process is described for the industrial scale preparation of 7a-[9-(4,4,5,5,5- 5 pentafluorothiopentyI)nonyl]estra-1,3,5(10)-triene-3,17?-diol, a precursor of steroids with hormonal activity which include Fulvestrant.
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Paragraph 0075; 0076; 0077; 0078; 0079
(2014/09/02)
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- PROCESSES AND INTERMEDIATES FOR THE PRODUCTION OF FULVESTRANT
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The invention relates to a compound of formula (1) wherein R1 represents hydrogen or an acetyl group and R2 represents a methyl, acetyl, or benzyl group, to its preparation, and to its use in the preparation of fulvestrant.
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Page/Page column 32
(2010/04/30)
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- Fulvestrant: From the laboratory to commercial-scale manufacture
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The development of a commercial manufacturing process for fulvestrant (the active ingredient in 'Faslodex') is described. Key steps in the synthesis are stereoselective 1,6-addition of an organocuprate to a steroidal dienone followed by copper-mediated aromatisation of the A-ring. The strategy for dealing with noncrystalline intermediates is outlined. The production of drug substance of acceptable quality is critically dependent on limiting the formation of key impurities. The origin of these impurities is discussed, and measures to prevent or control their formation are described.
- Brazier, Eve J.,Hogan, Philip J.,Leung, Chiu W.,O'Kearney-McMullan, Anne,Norton, Alison K.,Powell, Lyn,Robinson, Graham E.,Williams, Emyr G.
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experimental part
p. 544 - 552
(2011/07/30)
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- Process for the manufacture of 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)- triene-3,17-beta-diol
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The present invention provides a novel multi-step process for the manufacturing Fulvestrant, which is economical and convenient to operate at commercial scale, and requires only simple chromatographic separations after the coupling step of adding the side chain to the 7 position of the steroid.
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Page/Page column 4
(2010/07/10)
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- PROCESS FOR THE MANUFACTURE OF 7-ALPHA-[9-(4,4,5,5,5-PENTA FLUOROPENTVLSULPHINVL) NONVLLESTRA-L,3,5-(10)- TRIENE-3,17-BETA-DIOL
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The present invention provides a novel multi-step process for the manufacturing Fulvestrant, which is economical and convenient to operate at commercial scale, and requires only simple chromatographic separations after the coupling step of adding the side chain to the 7 position of the steroid.
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Page/Page column 7
(2009/05/29)
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- Process for the preparation of 7alpha-alkylated 19-norsteroids
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Processes useful in the preparation of pharmaceutical compounds such as fulvestrant and processes for the preparation of fulvestrant.
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Page/Page column 26
(2008/06/13)
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