An intermediate for the preparation of fulvestrant and a process for its preparation

Abstract

The present application relates to an intermediate of fulvestrant and a preparation method thereof. Specifically, the present application relates to a compound as shown in formula V and a preparation method thereof, wherein R 1 is hydrogen or a hydroxyl protecting group. The present application also relates to a preparation method for synthesizing fulvestrant via the compound as shown in formula V, which has the advantages of short reaction steps, mild and safe reaction conditions, high selectivity, simple operation and purification, high synthesis efficiency, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to an intermediate for the preparation of fulvestrant and a method thereof. Background Technology

[0002] Fulvestrant (as shown in Formula I) is an estrogen receptor antagonist. In April 2002, AstraZeneca's fulvestrant injection was approved by the FDA, and by 2018 its global sales had exceeded $1 billion.

[0003]

[0004] Existing techniques for the synthesis of fulvestrant mainly involve introducing a side chain at the C7 position of the steroid nucleus. The methods for introducing the side chain can be broadly categorized into two strategies: alkylation and Grignard reagent addition.

[0005] As disclosed in patents CN102827048, CN102993257, CN110938107, CN102993259, WO2009013310, WO2009039700, and US9315540, the alkylation route uses estradiol as a raw material. After protection, the C-6 molecule needs to be oxidized to form an alcohol, and then oxidized to form a ketone. After the alkylation reaction, the ketone needs to be reduced to an alkyl group to obtain the fulvestrant parent structure, making the reaction operation quite cumbersome.

[0006]

[0007] The Grignard addition route uses dehydronandrolone acetate as a starting material, and obtains the fulvestrant parent structure through a two-step reaction involving Grignard addition and aromatization. Regarding the structure of the Grignard reagent, patents WO2002032922 and WO2006015081 disclose that when R is... The route involves the addition of Grignard reagents. Although the route is very simple, the corresponding literature Organic Process Research & Development 2010, 14, 544-552 mentions that when the structure contains both sulfur and bromine, the bromine precursor of the Grignard reagent is unstable and easily degraded. Furthermore, the presence of even a small amount of impurities can make the initiation of the Grignard reagent difficult. Therefore, the requirements for the preservation and purity of the materials are very high.

[0008]

[0009] WO2006015081 and CN103965280B also disclose a scheme for the addition of a relatively short-chain Grignard reagent to dehydronandrolone acetate when R is OTBS. However, in this case, the tert-butyldimethylsilane protecting group needs to be hydrolyzed and converted into a leaving group before the pentafluoropentanethiol fragment can be introduced, thus increasing the length of the synthetic route and the difficulty of purification.

[0010]

[0011] In summary, existing methods for preparing fulvestrant require repeated redox reactions on the support skeleton or repeated protection and deprotection reactions on the side chains, resulting in cumbersome reaction routes, difficult purification, and low synthetic efficiency. Therefore, a more efficient synthetic route for the preparation of fulvestrant is needed. Summary of the Invention

[0012] To address the shortcomings of existing methods for preparing fulvestrant, the inventors, through their unremitting efforts, have invented a new intermediate for preparing fulvestrant and a synthetic method, as well as a method for synthesizing fulvestrant via this intermediate. This method features a short synthetic route, mild and safe reaction conditions, simple operation and purification, high reaction selectivity, and high synthetic efficiency, making it suitable for large-scale production of fulvestrant.

[0013] This invention provides a compound as shown in Formula V.

[0014]

[0015] Among them, R 1 It is a hydrogen or hydroxyl protecting group.

[0016] In a preferred embodiment of the present invention, in the compound represented by formula V, R 1 It is hydrogen, C1-C6 alkyl, C1-C 10 alkyl acyl, aryl acyl or (C 1-10 Alkyl or aryl) 3-silyl.

[0017] In a more preferred embodiment of the present invention, in the compound represented by formula V, R 1 For C1-C 10 Alkyl acyl or aryl acyl.

[0018] In a more preferred embodiment of the present invention, in the compound represented by formula V, R 1 It is an acetyl group.

[0019] The present invention also provides a method for preparing a compound as shown in Formula V, comprising the following steps: subjecting a compound as shown in Formula VI and a compound as shown in Formula VII to an addition reaction to obtain a compound as shown in Formula V; wherein the addition reaction is preferably carried out under the catalysis of a copper reagent;

[0020]

[0021] Among them, R 1 The protecting group is hydrogen or hydroxyl; M is MgCl, MgBr, MgI, or Mg 1 / 2 ZnCl, ZnBr, ZnI, Zn 1 / 2 MnCl, Li or Na.

[0022] In a preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula V, R... 1 It can be hydrogen, C1-C6 alkyl, C1-C 10 alkyl acyl, aryl acyl or (C 1-10 alkyl or aryl) 3-silyl; M is MgCl or MgBr.

[0023] In a more preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula V, R... 1 Can be C1-C 10 Alkyl acyl or aryl acyl; M is MgCl or MgBr.

[0024] In a more preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula V, R... 1 It can be an acetyl group; M is MgBr.

[0025] In the method for preparing the compound as shown in Formula V, the addition reaction produces a mixture of diastereomers. As an example, the ratio of the diastereomers V-7α:V-7β can be 100 to 1:1. The mixture of diastereomers can be directly carried out in the next reaction, or it can be purified to obtain a single isomer before carrying out the next reaction.

[0026]

[0027] In the method for preparing the compound as shown in Formula V, the addition reaction can be carried out in an organic solvent. The organic solvent can be a conventional solvent for this type of reaction in the art, or it can be a C6-C solvent. 10 One or more of the following: alkane solvents (such as n-hexane, n-heptane), aromatic solvents (such as toluene), and ether solvents (such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane). The amount of the organic solvent used can be the conventional amount used in this type of reaction in the art; for example, the molar concentration of the compound represented by formula VI in the organic solvent can be 0.001 to 5 mol / L.

[0028] In the preparation method of the compound shown in Formula V, the molar concentration of the compound shown in Formula VI in the organic solvent is preferably 0.005, 0.01, 0.05, 0.1, 0.5, 1.0 or 5.0 mol / L.

[0029] In the method for preparing the compound shown in Formula V, the copper reagent may be one or more of cuprous chloride, cuprous bromide, cuprous iodide, and cuprous trifluoromethanesulfonate. The amount of copper reagent used may be the conventional amount used in this type of reaction in the art; for example, the molar ratio of the copper reagent to the compound shown in Formula VI may be 0.001 to 1:1.

[0030] In the preparation method of the compound shown in Formula V, the molar ratio of the copper reagent to the compound shown in Formula VI is preferably 0.01:1, 0.05:1, 0.1:1, 0.3:1, 0.5:1 or 1:1.

[0031] In the method for preparing the compound as shown in Formula V, the molar ratio of the compound shown in Formula VII to the compound shown in Formula VI can be 1 to 10:1.

[0032] In the method for preparing the compound as shown in Formula V, the molar ratio of the compound shown in Formula VII to the compound shown in Formula VI is further preferably 5:1, 4:1, 3:1, 2:1 or 1:1.

[0033] In the preparation method of the compound shown in Formula V, the progress of the addition reaction can be monitored using conventional testing methods in the art (such as TLC, HPLC, GC or NMR, preferably HPLC), and the reaction endpoint is generally taken as when the compound shown in Formula VI no longer reacts.

[0034] In the method for preparing the compound as shown in Formula V, the reaction temperature of the addition reaction can be a conventional temperature for this type of reaction in the art, for example, -50 to 50°C.

[0035] In the method for preparing the compound as shown in Formula V, the reaction temperature of the addition reaction is further preferably -30°C, -20°C, -10°C, 0°C, 10°C, or 20°C.

[0036] The present invention also provides a compound as shown in Formula VII.

[0037]

[0038] Where M is MgCl, MgBr, MgI, or Mg 1 / 2 ZnCl, ZnBr, ZnI, Zn1 / 2 MnCl, Li or Na.

[0039] In a preferred embodiment of the present invention, M is MgCl or MgBr.

[0040] In a more preferred embodiment of the present invention, M is MgBr.

[0041] The present invention also provides a method for preparing a compound as shown in Formula VII, comprising the following steps: reacting the compound as shown in Formula VIII with a metal, or subjecting it to an exchange reaction with an organometallic compound to obtain the compound as shown in Formula VII.

[0042]

[0043] Where X is chlorine, bromine, or iodine; M is MgCl, MgBr, MgI, or Mg 1 / 2 ZnCl, ZnBr, ZnI, Zn 1 / 2 MnCl, Li or Na.

[0044] In a preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula VII, X is chlorine or bromine, and M is MgCl or MgBr.

[0045] In a more preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula VII, X is bromine and M is MgBr.

[0046] In a preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula VII, the compound as shown in Formula VIII undergoes a Grignard reaction with metallic magnesium to obtain the compound as shown in Formula VII, wherein the metallic magnesium may be one or more of magnesium powder and magnesium shavings.

[0047] In the method for preparing the compound as shown in Formula VII, the Grignard reaction can be carried out in an organic solvent. The organic solvent can be a conventional solvent for this type of reaction in the art, for example, one or more ether solvents (such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, dioxane). The amount of organic solvent used can be a conventional amount for this type of reaction in the art; for example, the molar concentration of the compound shown in Formula VIII in the organic solvent can be 0.001–5 mol / L.

[0048] In the method for preparing the compound as shown in Formula VII, the molar concentration of the compound shown in Formula VIII in the organic solvent is preferably 0.005, 0.01, 0.05, 0.1, 0.5, 1.0 or 5.0 mol / L.

[0049] In the method for preparing the compound as shown in Formula VII, the molar ratio of the metallic magnesium to the compound as shown in Formula VIII can be 0.5 to 10:1.

[0050] In the method for preparing the compound as shown in Formula VII, the molar ratio of the metallic magnesium to the compound as shown in Formula VIII is further preferably 0.5:1, 0.8:1, 0.9:1, 0.95:1, 1:1, 1.5:1, 2:1, 3:1 or 5:1.

[0051] In the method for preparing the compound as shown in Formula VII, the reaction temperature of the Grignard reaction can be a conventional temperature for this type of reaction in the art, for example, -20 to 80°C.

[0052] In the method for preparing the compound as shown in Formula VII, the reaction temperature of the Grignard reaction is further preferably -10℃, 0℃, 10℃, 20℃, 30℃, 40℃, 50℃ or 80℃.

[0053] The present invention also provides a compound as shown in Formula III,

[0054]

[0055] Among them, R 1 It is a hydrogen or hydroxyl protecting group; R 2 It is a hydroxyl protecting group.

[0056] In a preferred embodiment of the present invention, in the compound represented by Formula III, R 1 It is hydrogen, C1-C6 alkyl, C1-C 10 alkyl acyl, aryl acyl or (C 1-10 alkyl or aryl) 3-silyl; R 2 For C1-C 10 Alkyl acyl or aryl acyl.

[0057] In a more preferred embodiment of the present invention, in the compound represented by Formula III, R 1 For C1-C 10 Alkyl acyl or aryl acyl; R 2 For C1-C 10 Alkyl acyl or aryl acyl.

[0058] In a more preferred embodiment of the present invention, in the compound represented by Formula III, R 1 It is an acetyl group; R 2 It is either acetyl or propionyl.

[0059] The present invention also provides a method for preparing a compound as shown in Formula III, comprising the following steps: preparing a compound as shown in Formula V by an aromatization reaction and a phenolic hydroxyl protection reaction; wherein the aromatization reaction is preferably carried out in the presence of a copper salt;

[0060] in,

[0061] R 1 It is a hydrogen or hydroxyl protecting group; R 2 It is a hydroxyl protecting group.

[0062] In a preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula III, R... 1 It can be hydrogen, C1-C6 alkyl, C1-C 10 alkyl acyl, aryl acyl or (C 1-10 alkyl or aryl) 3-silyl; R 2 For C1-C 10 Alkyl acyl or aryl acyl.

[0063] In a more preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula III, R... 1 C1-C can be selected. 10 Alkyl acyl or aryl acyl; R 2 For C1-C 10 Alkyl acyl or aryl acyl.

[0064] In a more preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula III, R... 1 It can be an acetyl group; R 2 It is either acetyl or propionyl.

[0065] In a more preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula III, R... 1 It can be an acetyl group; R 2 It is an acetyl group.

[0066] In the preparation method of the compound shown in Formula III, the aromatization reaction can be carried out in an organic solvent. The organic solvent can be a conventional solvent for this type of reaction in the art, and can also be one or more of the following: nitrile solvents (such as n-acetonitrile, propionitrile, butyronitrile, benzonitrile), amide solvents (such as N,N-dimethylformamide, N,N-dimethylacetamide), sulfone solvents (such as dimethyl sulfoxide, sulfolane), aromatic solvents (such as toluene), and ether solvents (such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane). The amount of organic solvent used can be the conventional amount used for this type of reaction in the art; for example, the molar concentration of the compound shown in Formula V in the organic solvent can be 0.001–5 mol / L.

[0067] In the preparation method of the compound shown in Formula III, the molar concentration of the compound shown in Formula V in the organic solvent may be further preferably 0.005, 0.01, 0.05, 0.1, 0.5, 1.0 or 5.0 mol / L.

[0068] In the method for preparing the compound shown in Formula III, the copper salt may be one or more of copper chloride, copper bromide, copper iodide, copper sulfate, copper acetate, copper nitrate, and copper trifluoromethanesulfonate. The amount of copper salt used may be the conventional amount used in this type of reaction in the art; for example, the molar ratio of the copper salt to the compound shown in Formula V may be 0.5 to 10:1.

[0069] In the preparation method of the compound shown in Formula III, the molar ratio of the copper salt to the compound shown in Formula V is preferably 0.5:1, 0.8:1, 0.9:1, 1:1, 2:1, 3:1 or 5:1.

[0070] In the preparation method of the compound shown in Formula III, the phenolic hydroxyl protection reaction is carried out under the action of an acylation reagent. The acylation reagent can be one or more of alkyl acylation reagents (such as acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride) or aryl acylation reagents (such as benzoyl chloride, benzoic anhydride, p-methylbenzoyl chloride, p-methylbenzoic anhydride). The amount of the acylation reagent used can be the conventional amount used in this type of reaction in the art; for example, the molar ratio of the acylation reagent to the compound shown in Formula V can be 1 to 10:1.

[0071] In the preparation method of the compound shown in Formula III, the amount of the acylation reagent can be the conventional amount used in this type of reaction in the art. For example, the molar ratio of the acylation reagent to the compound shown in Formula V can be further preferably 1:1, 2:1, 3:1, 5:1 or 8:1.

[0072] In the preparation method of the compound shown in Formula III, the process of the aromatization reaction can be monitored using conventional testing methods in the art (such as TLC, HPLC, GC or NMR, preferably HPLC), and the reaction endpoint is generally taken as when the compound shown in Formula V no longer reacts.

[0073] In the method for preparing the compound as shown in Formula III, the reaction temperature of the aromatization reaction can be a conventional temperature for this type of reaction in the art, for example, -20 to 60°C.

[0074] In the method for preparing the compound as shown in Formula III, the reaction temperature of the aromatization reaction can be further preferably -10℃, 0℃, 10℃, 20℃, 30℃, 40℃, 50℃ or 60℃.

[0075] The present invention also provides a method for preparing fulvestrant as shown in Formula I, specifically comprising the following steps:

[0076]

[0077] Among them, R 1 It is a hydrogen or hydroxyl protecting group; R 2 The protecting group is a hydroxyl group; M is MgCl, MgBr, MgI, or Mg 1 / 2 ZnCl, ZnBr, ZnI, Zn 1 / 2 MnCl, Li or Na.

[0078] 1) The compounds shown in Formula VI and Formula VII undergo an addition reaction to yield the compound shown in Formula V; the addition reaction is preferably carried out in the presence of a copper reagent; the copper reagent is preferably one or more of cuprous chloride, cuprous bromide, cuprous iodide, and cuprous trifluoromethanesulfonate.

[0079] 2) The compound shown in Formula V undergoes an aromatization reaction and a phenolic hydroxyl protection reaction to obtain the compound shown in Formula III; the aromatization reaction is preferably carried out in the presence of a copper salt; the copper salt is preferably one or more of copper chloride, copper bromide, copper iodide, copper sulfate, copper acetate, copper nitrate, and copper trifluoromethanesulfonate; the phenolic hydroxyl protection reaction is carried out in the presence of an acylation reagent, the acylation reagent being acetic anhydride or propionic anhydride;

[0080] 3) The compounds shown in Formula III and Formula IV undergo a substitution reaction to obtain the compound shown in Formula II; the substitution reaction is preferably carried out in the presence of a base; the base is preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate;

[0081] 4) The compound shown in Formula II is oxidized to obtain the compound shown in Formula I; the oxidation reaction is preferably carried out under the action of an oxidizing agent; the oxidizing agent is preferably one or more of hydrogen peroxide, m-chloroperoxybenzoic acid, peroxytert-butanol, and peracetic acid;

[0082] In a preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula I, R... 1 It can be hydrogen, C1-C6 alkyl, C1-C 10 alkyl acyl, aryl acyl or (C 1-10 alkyl or aryl) 3-silyl; R 2 For C1-C 10 Alkyl acyl or aryl acyl; M is MgCl or MgBr.

[0083] In a more preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula I, R... 1 Can be C1-C 10 Alkyl acyl or aryl acyl; R 2 For C1-C 10 Alkyl acyl or aryl acyl; M is MgCl or MgBr.

[0084] In a more preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula I, R... 1 It can be an acetyl group; R 2 It is acetyl or propionyl; M is MgBr.

[0085] In a more preferred embodiment of the present invention, the method for preparing fulvestrant as shown in Formula I includes the following steps:

[0086] 1) The compounds shown in formula VIa and VIIa undergo Grignard addition reactions to give the compound shown in formula Va;

[0087] 2) The compound shown in formula Va was subjected to aromatization and protection of the phenolic hydroxyl group by acetic anhydride to obtain the compound shown in formula IIIa;

[0088] 3) The compounds shown in Formula IIIa and Formula IV undergo substitution reactions to give the compound shown in Formula II;

[0089] 4) The compound shown in Formula II undergoes an oxidation reaction to obtain the compound shown in Formula I.

[0090] A further preferred embodiment includes the following steps:

[0091] 1) The compounds shown in formula VIa and VIIa undergo Grignard addition reaction in the presence of cuprous chloride to give the compound shown in formula Va;

[0092] 2) The compound shown in formula Va undergoes aromatization and protection of the phenolic hydroxyl group by acetic anhydride in the presence of copper bromide and lithium bromide to yield the compound shown in formula IIIa.

[0093] 3) Compounds shown in Formula IIIa and Formula IV undergo a substitution reaction in the presence of sodium hydroxide to obtain compounds shown in Formula II;

[0094] 4) The compound shown in Formula II undergoes an oxidation reaction in the presence of hydrogen peroxide and peracetic acid to yield the compound shown in Formula I;

[0095]

[0096] On the other hand, the present invention also provides a method for preparing fulvestrant according to one of the formulas, comprising the step of preparing fulvestrant from 1,9-dichlorononane, 1-chloro-9-bromononane or 1-chloro-9-iodononane.

[0097]

[0098] 1,9-Dichlorononane or 1-chloro-9-bromononane are commercially available.

[0099] 1-Chloro-9-bromononane can also be prepared by chlorination of 9-bromo-1-nonanol.

[0100] For the preparation of 1-chloro-9-iodononane, please refer to: J.Org.Chem.1963,28,1254-1259.

[0101] Alternatively, compound IV is commercially available or prepared according to literature WO2008044033.

[0102] The synthesis of compound VI can be found in the Canadian Journal of Chemistry 1984, 62, 2740–2747. Specifically, it involves oxidizing nandrolone with tetrachlorobenzoquinone to obtain dehydronandrolone, followed by protection of the hydroxyl groups.

[0103]

[0104] Alternatively, it can be prepared by deprotecting dehydronandrolone acetate and then replacing it with other protecting groups;

[0105]

[0106] If available, the compound of formula V can also be prepared by using a portion of the product from the above reaction steps via a shorter route; for example, the compound of formula V can be prepared by purchasing the aforementioned formula VI and then following the steps provided in the above method.

[0107] On the other hand, the present invention also provides a method for preparing fulvestrant, wherein the method first prepares the compound represented by formula V or formula III according to the method provided above, and then prepares fulvestrant from the compound represented by formula V or formula III according to a known method. The method can be found in the following references: WO2002032922; WO2006015081; Organic Process Research & Development 2010, 14, 544-552.

[0108] The beneficial effects of this invention are:

[0109] 1) This invention uses a terminal chlorine-containing metal reagent VII (especially a terminal chlorine-containing Grignard reagent VIIA) for addition reaction. The resulting product V can be aromatized and directly introduce a pentafluoropentanethiol fragment with chlorine as the leaving group, thereby avoiding the use of protecting groups and the transformation of functional groups in the prior art and shortening the steps of the fulvestrant synthesis route.

[0110] 2) When the Grignard reagent VIIA with chlorine at the end is used in the addition reaction, the reaction selectivity is high and the ratio of diastereomers produced can reach 9:1.

[0111] 3) The conditions of this invention are mild, and there are no reaction conditions of ultra-low temperature (e.g., less than -40°C) or ultra-high temperature (e.g., greater than 80°C).

[0112] 4) The synthesis process of the present invention is simple, and qualified products can be obtained without column chromatography, making it easy to achieve industrial-scale production.

[0113] 5) The synthesis efficiency of fulvestrant in this invention has significant advantages.

[0114] Unless otherwise stated, the terminology used in this invention has the following meanings:

[0115] The hydroxyl protecting group of this invention is a suitable group for hydroxyl protection known in the art, see reference (“Protective Groups in Organic Synthesis”, 5). Th The hydroxyl protecting group in Ed.TWGreene & P.GMWuts. As an example, the hydroxyl protecting group may be (C 1-10Alkyl or aryl) 3-silyl, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 Alkyl or substituted alkyl groups, such as methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, p-methylbenzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C 6-10 Aryloxy)carbonyl.

[0116] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 10 carbon atoms, preferably including 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point, preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, or oxo; non-limiting examples include, but are not limited to, methyloxymethyl, ethyloxymethyl, benzyl, p-methoxybenzyl, p-methylbenzyl, 2-tetrahydropyranyl, etc.

[0117] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, more preferably phenyl and naphthyl, and most preferably phenyl. The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0118] Abbreviation list:

[0119] abbreviation Full name MTBE Methyl tert-butyl ether Ac Acetyl TBS tert-butyldimethylsilyl Bz benzoyl Bn benzyl MOM methyloxymethyl THP 2-Tetrahydropyranyl TsO- p-Toluenesulfonate HPLC Liquid chromatography

[0120] The table below shows the structural formulas of the compounds involved in the examples.

[0121]

[0122]

[0123] Detailed Implementation

[0124] The present invention will be explained in detail below with specific examples to enable those skilled in the art to have a more comprehensive understanding of the present invention. The specific examples are only used to illustrate the technical solutions of the present invention and do not limit the present invention in any way.

[0125] Example 1: Preparation of compound VIIIa

[0126] Compound IXa (50 g) and thionyl chloride (50 mL) were added to a 500 mL three-necked flask. The internal temperature was maintained below 20 °C, and pyridine (10 mL) was added dropwise. The reaction was continued at 20 °C for 48 h. TLC showed that the starting material reacted completely. The reaction solution was quenched in ice water, extracted with MTBE, and the organic phase was washed with saturated sodium bicarbonate. After drying and concentration, 52.6 g of compound VIIIa was obtained, with a yield of 97%.

[0127] 1 H NMR(400MHz,Chloroform-d)δ3.53(td,J=6.7,0.9Hz,2H),3.41(td,J=6.9,0.8Hz,2H),1.8 5(p,J=7.0Hz,2H),1.81–1.72(m,2H),1.43(dq,J=12.9,6.8Hz,4H),1.32(d,J=4.5Hz,6H).

[0128] Example 2: Preparation of compound VIIa

[0129] Magnesium shavings (6.42 g) were added to a reaction flask, followed by anhydrous tetrahydrofuran (380 mL). Compound VIIIa (46.1 g) was added at 20 °C. After the addition was complete, the reaction was stirred at room temperature for 2 h to obtain compound VIIa, which was then set aside.

[0130] Example 3: Preparation of compound VIIa

[0131] Compound VIIIa (46.1 g) was added to a reaction flask, followed by anhydrous tetrahydrofuran (380 mL). The mixture was cooled to 0 °C, and isopropyl magnesium bromide tetrahydrofuran solution (1.0 eq) was added dropwise. After the addition was complete, the reaction was stirred for another 2 h to obtain compound VIIa, which was then set aside.

[0132] Example 4: Preparation of compound VIIb

[0133] Magnesium shavings (6g) were added to a reaction flask, followed by anhydrous tetrahydrofuran (380mL). Compound VIIIb (48g) was added at 20°C. After the addition was complete, the reaction was stirred at room temperature for 2 hours to obtain compound VIIb, which was then set aside.

[0134] Example 5: Preparation of compound VIIc

[0135] Magnesium shavings (6 g) were added to a reaction flask, followed by anhydrous tetrahydrofuran (380 mL). Compound VIIIc (32.7 g) was added at 20 °C. After the addition was complete, the reaction was stirred at room temperature for 2 h to obtain compound VIIb, which was then set aside.

[0136] Example 6: Preparation of compound VIId

[0137] Magnesium filings (6.42 g) were added to a reaction flask, followed by anhydrous tetrahydrofuran (380 mL). Compound VIIIa (46.1 g) was added at 20 °C. After the addition was complete, the reaction was stirred at room temperature for 2 h to obtain compound VIIa. The VIIa solution was cooled to 0 °C, and anhydrous ZnCl2 tetrahydrofuran solution (1.0 eq) was added. The mixture was stirred for another 2 h to obtain compound VIId, which was then set aside.

[0138] Example 7: Preparation of compound VIIe

[0139] Compound VIIIa (46.1 g) was added to a reaction flask, followed by anhydrous tetrahydrofuran (380 mL). The mixture was cooled to -30 °C, and diethylzinc tetrahydrofuran solution (0.5 eq) was added dropwise. After the addition was complete, the reaction was stirred for another 2 h to obtain compound VIIe, which was then set aside for later use.

[0140] Example 8: Preparation of compound VIIf

[0141] Compound VIIIa (46.1 g) was added to a reaction flask, followed by anhydrous tetrahydrofuran (380 mL). The mixture was cooled to -30 °C, and 2.5 eq of tert-butyllithium tetrahydrofuran solution was added dropwise. After the addition was complete, the reaction was stirred for 2 h to obtain compound VIIf. It was stored at -30 °C for later use.

[0142] Example 9: Preparation of compound VIIg

[0143] Magnesium filings (6.42 g) were added to a reaction flask, followed by anhydrous tetrahydrofuran (380 mL). Compound VIIIa (46.1 g) was added at 20 °C. After the addition was complete, the reaction was stirred at room temperature for 2 h to obtain compound VIIa. The VIIa solution was cooled to 0 °C, and anhydrous manganese dichloride tetrahydrofuran solution (1.0 eq) was added. The mixture was stirred for another 2 h to obtain compound VIIg, which was then set aside.

[0144] Example 10: Preparation of compound Va

[0145] Compound VIa (20 g) and cuprous chloride (1.42 g) were added to a reaction flask, followed by tetrahydrofuran (120 mL). At -20 °C, a tetrahydrofuran solution of compound VIIa (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -20 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 28.0 g of compound Va, with a yield of 92%. The diastereomer ratio was 7α:7β = 9:1.

[0146] MS(ESI)m / z:477(M+H + ).

[0147] 1 H NMR (400MHz, Chloroform-d) δ5.82(s,1H),4.61(t,1H),3.52(t,2H),2.52(dd,J=14Hz,J=2Hz,1H),2.38~2.42(m,1H),2.21~2.29(m, 3H),2.15~2.21(m,1H),2.03(s,3H),1.96~2.02(m,1H),1.85~1.88(m,1H),1.68~1.79(m,5H),1.46~1.60(m,4H),0.95~1.42(m,18H).

[0148] Example 11: Preparation of compound Va

[0149] Compound VIa (20 g) and cuprous chloride (1.42 g) were added to a reaction flask, followed by tetrahydrofuran (120 mL). At -20 °C, a tetrahydrofuran solution of compound VIIb (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -20 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate. After drying, the phase was concentrated to give 25.2 g of compound Va, with a yield of 83%. The diastereomer ratio was 7α:7β = 8:1.

[0150] MS(ESI)m / z:477(M+H + ).

[0151] 1 H NMR (400MHz, Chloroform-d) δ5.82(s,1H),4.61(t,1H),3.52(t,2H),2.52(dd,J=14Hz,J=2Hz,1H),2.38~2.42(m,1H),2.21~2.29(m, 3H),2.15~2.21(m,1H),2.03(s,3H),1.96~2.02(m,1H),1.85~1.88(m,1H),1.68~1.79(m,5H),1.46~1.60(m,4H),0.95~1.42(m,18H).

[0152] Example 12: Preparation of compound Va

[0153] Compound VIa (20 g) and cuprous chloride (1.42 g) were added to a reaction flask, followed by tetrahydrofuran (120 mL). At -10 °C, a tetrahydrofuran solution of compound VIIc (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -10 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 22.7 g of compound Va, with a yield of 75%. The diastereomer ratio was 7α:7β = 7:1.

[0154] MS(ESI)m / z:477(M+H + ).

[0155] 1 H NMR (400MHz, Chloroform-d) δ5.82(s,1H),4.61(t,1H),3.52(t,2H),2.52(dd,J=14Hz,J=2Hz,1H),2.38~2.42(m,1H),2.21~2.29(m, 3H),2.15~2.21(m,1H),2.03(s,3H),1.96~2.02(m,1H),1.85~1.88(m,1H),1.68~1.79(m,5H),1.46~1.60(m,4H),0.95~1.42(m,18H).

[0156] Example 13: Preparation of compound Va

[0157] Compound VIa (20 g) and cuprous chloride (1.42 g) were added to a reaction flask, followed by tetrahydrofuran (120 mL). At -10 °C, a tetrahydrofuran solution of compound VIId (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -10 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate. After drying, the phase was concentrated to give 11.0 g of compound Va, with a yield of 38%.

[0158] Example 14: Preparation of compound Va

[0159] Compound VIa (20 g) and cuprous chloride (1.42 g) were added to a reaction flask, followed by tetrahydrofuran (120 mL). At -10 °C, a tetrahydrofuran solution of compound VIIe (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -10 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 10.0 g of compound Va, with a yield of 33%.

[0160] Example 15: Preparation of compound Va

[0161] Compound VIa (20 g) and cuprous chloride (1.42 g) were added to a reaction flask, followed by tetrahydrofuran (120 mL). At -10 °C, a tetrahydrofuran solution of compound VIIf (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -10 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate. After drying, the phase was concentrated to give 8.0 g of compound Va, with a yield of 26%.

[0162] Example 16: Preparation of compound Va

[0163] Compound VIa (20 g) and cuprous chloride (1.42 g) were added to a reaction flask, followed by tetrahydrofuran (120 mL). At -10 °C, a tetrahydrofuran solution of compound VII (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -10 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 18.0 g of compound Va, with a yield of 60%.

[0164] Example 17: Preparation of compound Vb

[0165] Compound VIb (2 g) and cuprous chloride (263 mg) were added to a reaction flask, followed by tetrahydrofuran (15 mL). At -30 °C, a tetrahydrofuran solution of compound VIIa (1.5 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -30 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 2.24 g of compound Vb, with a yield of 78%. The diastereomer ratio was 7α:7β = 9:1.

[0166] MS(ESI)m / z:539(M+H + ).

[0167] Example 18: Preparation of compound Vc

[0168] Compound VIc (2 g) and cuprous bromide (280 mg) were added to a reaction flask, followed by 15 mL of tetrahydrofuran. At 0 °C, a tetrahydrofuran solution of compound VIIa (1.5 eq.) was added dropwise. After the addition was complete, the reaction was stirred at 0 °C for 1 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 2.13 g of compound Vc, with a yield of 70%. The diastereomer ratio was 7α:7β = 5:1.

[0169] MS(ESI)m / z:479(M+H + ).

[0170] Example 19: Preparation of compound Vd

[0171] Compound VId (2 g) and cuprous iodide (306 mg) were added to a reaction flask, followed by tetrahydrofuran (15 mL). At -10 °C, a tetrahydrofuran solution of compound VIIa (1.2 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -10 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 2.35 g of compound Vd, with a yield of 81%. The diastereomer ratio was 7α:7β = 8:1.

[0172] MS(ESI)m / z:525(M+H + ).

[0173] Example 20: Preparation of compound Ve

[0174] Compound VIe (2 g) and cuprous trifluoromethanesulfonate (244 mg) were added to a reaction flask, followed by 15 mL of 2-methyltetrahydrofuran. At -30 °C, a tetrahydrofuran solution of compound VIIb (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -30 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 2.28 g of compound Ve, with a yield of 80%. The diastereomer ratio was 7α:7β = 9:1.

[0175] MS(ESI)m / z:549(M+H + ).

[0176] Example 21: Preparation of compound Vf

[0177] Compound VIf (2 g) and cuprous chloride (122 mg) were added to a reaction flask, followed by tetrahydrofuran (15 mL). At -20 °C, a tetrahydrofuran solution of compound VIIa (1.3 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -20 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 2.25 g of compound Vf, with a yield of 77%. The diastereomer ratio was 7α:7β = 9:1.

[0178] MS(ESI)m / z:519(M+H + ).

[0179] Example 22: Preparation of compound Vg

[0180] Compound VIg (20 g) and cuprous chloride (1.42 g) were added to a reaction flask, followed by tetrahydrofuran (120 mL). At -10 °C, a tetrahydrofuran solution of compound VIIa (2.5 eq.) was added dropwise. After the addition was complete, the reaction was stirred at -10 °C for 2 h. HPLC showed complete conversion of the starting material. The reaction was quenched with acetic acid, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to give 18.6 g of compound Vg, a yield of 58%. The diastereomer ratio was 7α:7β = 8:1.

[0181] Example 23: Preparation of compound IIIa

[0182] Copper bromide (5.62 g) and lithium bromide (1.55 g) were added to a reaction flask, followed by acetonitrile (15 mL) and acetic anhydride (1.23 g). The reaction was stirred at 20 °C for 30 min, and then a solution of compound Va (5 g) in acetonitrile (15 mL) was added dropwise. The reaction was continued at 20 °C with stirring for 3 h. HPLC monitoring showed complete conversion of the starting material. The reaction solution was added dropwise to a mixture of thiourea, toluene, and water, and stirred for 30 min. Sodium bicarbonate was added, and the mixture was stirred for 10 min. The mixture was filtered through a diatomaceous earth filter, washed with toluene, and the filtrate was separated into layers. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to give 4.87 g of compound IIIa, yield: 90%.

[0183] MS(ESI)m / z:517(M+H + ).

[0184] 1 H NMR(400MHz,Chloroform-d)δ7.27(d,J=9.6Hz,1H),6.87(dd,J=8.4Hz,J=2.4Hz,1H),6.78(d,J =2.4Hz,1H),4.70(t,J=8.4Hz,1H),3.53(t,J=6.8Hz,2H),2.90(t,J=16.8Hz,J=5.2Hz,1H),2.75 (d,J=16.8Hz,1H),2.29~2.37(m,1H),2.28(s,3H),2.20~2.26(m,1H),2.06(s,3H),1.84~1.87( m,1H),1.72~1.79(m,3H),1.59~1.68(m,3H),1.37~1.55(m,8H),1.18~1.48(m,18H),0.82(s,1H)

[0185] Example 24: Preparation of compound IIIb

[0186] Copper bromide (3.71 g) and lithium bromide (1.02 g) were added to a reaction flask, followed by acetonitrile (10 mL) and propionic anhydride (0.77 g). The reaction was stirred at 20 °C for 30 min, and then a solution of compound Va (3.3 g) in acetonitrile (10 mL) was added dropwise. The reaction was continued at 20 °C with stirring for 3 h. HPLC monitoring showed complete conversion of the starting material. The reaction solution was added dropwise to a mixture of thiourea, toluene, and water, and stirred for 30 min. Sodium bicarbonate was added, and the mixture was stirred for 10 min. The mixture was filtered through a diatomaceous earth filter, washed with toluene, and the filtrate was separated into layers. The organic phase was washed with saturated sodium chloride solution, dried, and concentrated to give 3.24 g of compound IIIb, yield: 88%.

[0187] MS(ESI)m / z:531(M+H + ).

[0188] 1 H NMR(400MHz,Chloroform-d)δ7.28(d,J=8.8Hz,1H),6.84(dd,J=8.4Hz,J=2.4Hz,1H),6.78(d, J=2.4Hz,1H),4.67(t,J=8.4Hz,1H),3.52(t,J=6.8Hz,2H),2.90(dd,J=16.8Hz,J=5.2Hz,1H), 2.75(d,J=16.8Hz,1H),2.56(q,J=15.2Hz,2H),2.19~2.39(m,3H),2.06(s,3H),1.83~1.87(m, 1H),1.72~1.79(m,3H),1.62~1.67(m,1H),1.39~1.58(m,8H),1.17~1.27(m,14H),0.82(s,3H)

[0189] Example 25: Preparation of Compound II

[0190] Compound IIIa (4.38 g) and compound IV (4.5 g) were added to a reaction flask, followed by 25 mL of DMF. 40% sodium hydroxide (8.4 g) was added at 20 °C. The reaction was continued with stirring at 20 °C for 2 h, and HPLC showed complete conversion of the starting material. Acetic acid was added to quench the reaction, followed by dilution with water, extraction with MTBE, and washing of the organic phase successively with saturated sodium bicarbonate and sodium chloride solutions. After drying, the phase was concentrated to give 4.51 g of compound II (yield: 90%).

[0191] MS(ESI)m / z:591(M+H + ).

[0192] 1 H NMR(400MHz,Chloroform-d)δ7.15(d,J=8.4Hz,1H),6.63(dd,J=8.8Hz,J=2.4Hz,1H),6.5 5(d,J=2.4Hz,1H),4.67(s,1H),3.75(t,J=7.6Hz,1H),2.86(dd,J=16.8Hz,J=5.2Hz,1H),2 .71(d,J=16.8Hz,1H),2.59(t,J=6Hz,2H),2.50(t,J=7.2Hz,2H),2.28~2.34(m,2H),2.11 ~2.23(m,3H),1.84~1.92(m,3H),1.72~1.75(m,1H),1.53~1.65(m,4H),1.17~1.50(m,24H)

[0193] Example 26: Preparation of Compound II

[0194] Compound IIIb (3 g) and compound IV (3.08 g) were added to a reaction flask, followed by 20 mL of DMF. 5.25 g of 40% sodium hydroxide was added at 20 °C. The reaction was continued with stirring at 20 °C for 2 h, and HPLC showed complete conversion of the starting material. Acetic acid was added to quench the reaction, followed by dilution with water, extraction with MTBE, and washing of the organic phase successively with saturated sodium bicarbonate and sodium chloride solutions. After drying, the solution was concentrated to give 2.77 g of compound II, yield: 83%.

[0195] MS(ESI)m / z:591(M+H + ).

[0196] 1 H NMR(400MHz,Chloroform-d)δ7.15(d,J=8.4Hz,1H),6.63(dd,J=8.8Hz,J=2.4Hz,1H),6.5 5(d,J=2.4Hz,1H),4.67(s,1H),3.75(t,J=7.6Hz,1H),2.86(dd,J=16.8Hz,J=5.2Hz,1H),2 .71(d,J=16.8Hz,1H),2.59(t,J=6Hz,2H),2.50(t,J=7.2Hz,2H),2.28~2.34(m,2H),2.11 ~2.23(m,3H),1.84~1.92(m,3H),1.72~1.75(m,1H),1.53~1.65(m,4H),1.17~1.50(m,24H)

[0197] Example 27: Preparation of Compound I

[0198] Compound II (4.31 g) was dissolved in ethyl acetate (15 mL), followed by the addition of acetic acid (2.63 g) and 17.5% hydrogen peroxide (3.12 g). The reaction was stirred at 20 °C for 10 h, and HPLC showed complete conversion of the starting material. The reaction was quenched by the addition of sodium sulfite solution. Extraction was performed with ethyl acetate. The organic phase was washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried, concentrated, and recrystallized from ethyl acetate to give 3.52 g of compound I (yield: 80%). Purity: 99.7%.

[0199] MS(ESI)m / z:607(M+H + ).

[0200] 1H NMR(400MHz,Chloroform-d)δ7.11(d,J=8.4Hz,1H),6.63(d,J=8.4Hz,1H),6.55(s,1H),3.74(t,J=8.5Hz,1H),2.90-2.53(m,6H),2.3 5-2.03(m,7H),1.99-1.83(m,1H),1.80-1.67(m,3H),1.60(qt,J=8.5,3.3Hz,2H),1.53-1.11(m,19H),1.08-0.95(m,1H),0.77(s,3H).

[0201] Since the invention has been described according to its specific embodiments, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of the invention.

Claims

1. A process for the preparation of fulvestrant, characterized in that, comprising the steps of 1) adding a compound of formula VI and a compound of formula VII to obtain a compound of formula V; 2) subjecting the compound of formula V to an aromatization reaction and a phenolic hydroxyl protection reaction to obtain a compound of formula III; 3) subjecting the compound of formula III and a compound of formula IV to a substitution reaction to obtain a compound of formula II; 4) subjecting the compound of formula II to an oxidation reaction to obtain a compound of formula I; Among them, R 1 H, C1-C6 alkyl acyl, Bn, Bz, THP, or TBS; R 2 It is a C1-C6 alkyl acyl group; M is MgCl, MgBr, MgI, ZnCl, ZnBr, ZnI, Zn 1 / 2 MnCl or Li.

2. The process for the preparation of fulvestrant according to claim 1, characterized in that, R 1 is acetyl, Bn, Bz, THP or TBS; R 2 is acetyl or propionyl; M is MgBr or MgCl.

3. The process for the preparation of fulvestrant according to claim 2, characterized in that, R 1 is acetyl; R 2 is acetyl; M is MgBr.

4. The method of preparing fulvestrant according to claim 1, characterized by, comprising the steps of 1) subjecting a compound of formula Via and a compound of formula VIIa to a Grignard addition reaction to obtain a compound of formula Va; 2) subjecting the compound of formula Va to an aromatization reaction and a phenolic hydroxyl protection reaction to obtain a compound of formula Ilia; 3) subjecting the compound of formula Ilia and a compound of formula IV to a substitution reaction to obtain a compound of formula II; 4) subjecting the compound of formula II to an oxidation reaction to obtain a compound of formula I;

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