A method for preparing raloxifene EP impurity B

Abstract

This invention discloses a method for preparing raloxifene EP impurity B, comprising the following steps: dissolving 6-methoxy-2-(4-methoxyphenyl)benzothiophene (Ⅰ) as a raw material in solvent one, adding NIS, and then adding a free radical initiator to react and obtain intermediate III; dissolving 4-[2-(1-pyrrolidinyl)ethoxy]benzoate salt (II) in solvent two, adding solvent two or not, and then adding a chlorinating agent to react and generate intermediate IV; dissolving intermediate III in solvent three, adding a Lewis acid, and then adding intermediate IV, and performing a Friedel-Crafts acylation reaction to generate intermediate V; dissolving intermediate V in solvent four, adding a demethylating agent, and generating bisphenol hydroxyl intermediate VI under demethylation conditions; dissolving intermediate VI in solvent five, adding a reducing agent, and generating intermediate VII through a reduction reaction; dissolving intermediate VII in formic acid, stirring, evaporating, and finally lyophilizing to generate the formate target product VIII.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and in particular to a method for preparing raloxifene EP impurity B. Background Technology

[0002] Raloxifene is a selective estrogen receptor modulator (SERM) primarily used to prevent and treat osteoporosis in postmenopausal women. It increases bone density and reduces fracture risk by mimicking the effects of estrogen, while also having antagonistic effects on the breast and uterus, avoiding some of the side effects of traditional estrogen therapy. Raloxifene's mechanism of action is based on its selective regulation of estrogen receptors: for the skeletal and cardiovascular systems, raloxifene exhibits estrogen agonist effects, increasing bone density and lowering total cholesterol and low-density lipoprotein (LDL) levels, thereby reducing fracture risk and improving cardiovascular health; for the breast and uterus, raloxifene exhibits estrogen antagonist effects, not stimulating breast and endometrial hyperplasia, and therefore does not increase the risk of breast and endometrial cancer; furthermore, raloxifene can reduce the risk of stroke in postmenopausal women, possibly related to its regulatory effects on cholesterol and inflammation.

[0003] Compared to traditional estrogen replacement therapy (HRT) and other selective estrogen receptor modulators (such as tamoxifen), raloxifene offers the following advantages: Greater safety; raloxifene does not stimulate the breast and endometrium, avoiding the risk of breast and endometrial cancer, which traditional estrogen therapy may increase; Cardiovascular protection; raloxifene can lower total cholesterol and LDL levels, protecting the cardiovascular system, while some estrogen replacement therapies may increase the risk of cardiovascular events; Clear indications; raloxifene is specifically used for osteoporosis in postmenopausal women and is effective in reducing the incidence of vertebral fractures; Fewer side effects; Although raloxifene may cause side effects such as venous thromboembolism, the overall side effect spectrum is milder than that of traditional estrogen therapy.

[0004] Raloxifene, as a selective estrogen receptor modulator (SERM), requires impurity studies as a crucial aspect of drug quality control. Impurities in raloxifene primarily include byproducts, degradation products, or isomers generated during synthesis. Based on literature and test reports, the main identified impurities include: raloxifene impurity 1, a mesylate derivative of raloxifene hydrochloride; raloxifene EP impurity B and other impurities (A, C, D, E, etc.) and other unnamed impurities. The chemical structures of these impurities often involve changes such as hydroxyl substituents, sulfonation, or isomerization, which may affect the safety and efficacy of the drug. Limiting raloxifene impurities is a core requirement of drug review. This includes: impurity profiling studies, which involve systematically analyzing the sources of impurities (such as synthetic intermediates and degradation products) to establish reasonable impurity limit standards. Literature such as the *Chinese Pharmaceutical Journal* reports on methods for impurity profiling studies of raloxifene hydrochloride; safety assessment, as some impurities may have potential toxicity, such as the toxicological data for raloxifene impurity 1, which requires verification through in vitro and in vivo experiments; and stability studies. Accelerated testing and long-term stability testing can assess the formation trend of impurities during storage, providing a basis for the shelf life of drugs.

[0005] In recent years, impurity research on raloxifene has involved multiple stages, including structural identification, analytical method development, safety assessment, and quality control. Advanced analytical techniques and standardized management effectively ensure the safety and efficacy of the drug. In the future, with advancements in detection technology and more detailed regulatory requirements, impurity research will further optimize the clinical application of raloxifene. In drug development and manufacturing, impurity control and analysis are core requirements for drug review. Impurity profiling studies systematically analyze impurity sources (such as synthetic intermediates and degradation products) to establish reasonable impurity limit standards. In recent years, research on raloxifene impurities has gradually gained attention, and related literature and patents have emerged continuously. However, the synthetic method for raloxifene EP impurity B has not yet been reported in detail, which limits in-depth research and quality control of this impurity.

[0006] Therefore, developing an efficient and reliable method for preparing raloxifene EP impurity B is of great significance for improving the impurity profile of raloxifene, ensuring drug quality, and promoting the optimization of raloxifene's clinical application. This invention aims to provide a method for preparing raloxifene EP impurity B with a rationally designed process and simple post-processing, providing a qualified impurity standard for raloxifene impurity research. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a method for preparing raloxifene EP impurity B.

[0008] To achieve the above objectives, the present invention provides a method for preparing raloxifene EP impurity B, comprising the following steps:

[0009] Step S1: Dissolve 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I) as a raw material in solvent one, add NIS, and then add a free radical initiator to react and obtain intermediate III. The reaction equation is as follows:

[0010]

[0011] Step S2: Dissolve 4-[2-(1-pyrrolidinyl)ethoxy]benzoate salt (II) in solvent II, with or without solvent II, then add a chlorinating agent. The reaction produces intermediate IV, and the reaction equation is as follows:

[0012]

[0013] Step S3: Dissolve intermediate III in solvent III, add Lewis acid, then add intermediate IV, and perform Friedel-Crafts acylation to generate intermediate V. The reaction equation is as follows:

[0014]

[0015] Step S4: Dissolve intermediate V in solvent four, add a demethylating agent, and generate bisphenol hydroxyl intermediate VI under demethylation conditions. The reaction equation is as follows:

[0016]

[0017] Step S5: Dissolve intermediate VI in solvent 5, add a reducing agent, and generate intermediate VII through a reduction reaction. The reaction equation is as follows:

[0018]

[0019] Step S6: Dissolve intermediate VII in formic acid, stir, evaporate to dryness, and finally freeze-dry to obtain the formate target product VIII. The reaction equation is as follows:

[0020]

[0021] Preferably, in step S1, the molar ratio of 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I) to NIS and the free radical initiator is 1:(1.2-2.0):(0.05-0.1); the free radical initiator is selected from AIBN or BPO; the solvent is selected from one or more of THF, MeCN, DCM, and DMF; and the reaction temperature in step S1 is room temperature to 120°C, and the reaction time is 6-24 h.

[0022] More preferably, in step S1, the molar ratio of 6-methoxy-2-(4-methoxyphenyl)benzothiophene (Ⅰ) to NIS and the free radical initiator is 1:2:0.1; the free radical initiator is preferably AIBN; the solvent is DCM; the reaction temperature of step S1 is 25°C, and the reaction time is 12-18h.

[0023] Preferably, in step S2, 4-[2-(1-pyrrolidinyl)ethoxy]benzoate (II) is dissolved in thionyl chloride, or other chlorinating agents are added, which are selected from oxaloyl chloride, PCl3, PCl5 or triphosgene. When other chlorinating agents are added, solvent II is selected from one or more of THF, DCM, and MeCN. The reaction temperature of step S2 is room temperature to 110°C, and the reaction time is 1-4 hours.

[0024] More preferably, in step S2, the 4-[2-(1-pyrrolidinyl)ethoxy]benzoate (II) is dissolved in thionyl chloride without the need for solvent addition, and the reaction temperature is 90°C and the reaction time is 1 h.

[0025] Preferably, the molar ratio of intermediate III to Lewis acid and intermediate IV in step S3 is 1:(1-2):(1-3); the Lewis acid is selected from one or more of AlCl3, FeCl3, BF3, and TiCl4; the solvent is selected from one or more of DCM, THF, MeOH, MeCN, and DMF; the reaction temperature in step S3 is -30℃ to 80℃, and the reaction time is 8-16h.

[0026] More preferably, the molar ratio of intermediate III to Lewis acid and intermediate IV in step S3 is 1:1.5:3; the Lewis acid is selected as AlCl3; the solvent is DCM; the reaction temperature of step S3 is -30℃, and the reaction time is 16h.

[0027] Preferably, the molar ratio of intermediate V to demethylating agent in step S4 is 1:(3-7); the solvent is selected from one or more of DCM, THF, MeOH, MeCN, and acetic acid; the reaction temperature in step S4 is room temperature to 150°C, and the reaction time is 12-24 h.

[0028] More preferably, the molar ratio of intermediate V to demethylating agent in step S4 is 1:3; the solvent is acetic acid; the reaction temperature in step S4 is 118°C and the reaction time is 12 hours.

[0029] Preferably, the molar ratio of intermediate VI to reducing agent in step S5 is 1:(1-3); the reducing agent is selected from iron powder and zinc powder; the solvent is selected from one or more of water, THF, MeOH, MeCN, and acetic acid; the reaction temperature in step S5 is room temperature to 100°C, and the reaction time is 8-24 hours.

[0030] More preferably, the molar ratio of intermediate VI to reducing agent in step S5 is 1:3; the reducing agent is selected as iron powder; the solvent is selected as acetic acid; and the reaction temperature in step S5 is 50°C. ， The reaction time is 8 hours.

[0031] Preferably, intermediate VII in step S6 is dissolved in formic acid; the mass-to-volume ratio of intermediate VII to formic acid is 1:(2-10); the stirring reaction temperature in step S6 is room temperature to 50°C, and the reaction time is 0.5-1h.

[0032] More preferably, the mass-to-volume ratio of intermediate VII to formic acid in step S6 is 1:8; the stirring reaction temperature in step S6 is 50°C, and the stirring time is 0.5 h.

[0033] The technical solution of this invention has the following beneficial effects:

[0034] This invention uses 6-methoxy-2-(4-methoxyphenyl)benzothiophene I and 4-[2-(1-pyrrolyl)ethoxy]benzoate II as raw materials. First, I is iodinated to obtain intermediate III. Then, II is reacted with a chlorinating agent to obtain acyl chloride intermediate IV. Next, III and IV undergo a Friedel-Crafts acylation reaction to obtain intermediate V. Then, under demethylation conditions, V loses the methyl groups of the two methoxy groups to obtain intermediate VI. Under reducing conditions, iodine is reduced to obtain intermediate VII. Intermediate VII forms a salt with formic acid to obtain the target impurity molecule VIII. The purity of the target product TM obtained by this preparation method can reach over 95%.

[0035] Step S1: Iodination reaction

[0036] Efficient iodination conversion: By selecting appropriate solvents (such as dichloromethane, tetrahydrofuran, etc.) and free radical initiators (such as AIBN or BPO), this step achieves efficient iodination of 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I). Optimized molar ratios (1:1.2-2.0:0.05-0.1) and reaction conditions (room temperature to solvent reflux temperature) ensure high selectivity and rapid conversion, significantly improving the yield of intermediate III.

[0037] Mild reaction conditions: The reaction is carried out at room temperature or solvent reflux temperature, which avoids side reactions and equipment requirements caused by high temperature, reduces the danger and difficulty of the reaction, and shortens the reaction time (6-24h), thus improving production efficiency.

[0038] Step S2: Acyl chloride reaction:

[0039] Diverse selection of chlorination reagents: This step offers a variety of chlorination reagents to choose from (such as thionyl chloride, oxalyl chloride, PCl3, PCl5, etc.), allowing the reaction to be flexibly adjusted according to actual needs and safety requirements. For example, the use of oxalyl chloride can avoid the high toxicity issues associated with thionyl chloride while maintaining efficient acyl chlorination conversion.

[0040] Rapid reaction and high yield: Optimized reaction temperature (room temperature or solvent reflux temperature) and time (1-4 h) ensured the rapid conversion of 4-[2-(1-pyrrolidinyl)ethoxy]benzoate salt (II) to acyl chloride intermediate IV, while reducing the formation of byproducts and improving the purity and yield of the target product.

[0041] Step S3: Friedel-Crafts acylation reaction

[0042] Efficient acylation conversion: By rationally selecting Lewis acids (such as AlCl3, FeCl3, BF3, TiCl4) and optimizing the reaction molar ratio (1:1-2:1-3), this step achieves efficient Friedel-Crafts acylation reaction of intermediate III and acyl chloride IV to generate intermediate V. Optimized reaction conditions (room temperature or solvent reflux temperature, 8-16 h) ensure high selectivity and high yield of the reaction.

[0043] Mild reaction conditions and high selectivity: Mild reaction conditions are adopted to avoid side reactions and equipment requirements caused by high temperature and high pressure. At the same time, by precisely controlling the reaction time, the high selectivity of the target product is ensured and the generation of impurities is reduced.

[0044] Step S4: Demethylation reaction

[0045] Efficient demethylation conversion: By optimizing the amount of demethylating reagent (1:3-7) and reaction conditions (room temperature or solvent reflux temperature, 12-24 h), this step achieved efficient demethylation of intermediate V to generate bisphenol hydroxyl intermediate VI. Optimized reaction conditions ensured high selectivity and rapid conversion, improving the yield of the target product. Mild reaction conditions avoided side reactions and equipment requirements caused by high temperature and pressure. Simultaneously, precise control of the reaction time ensured the high purity of the target product and reduced impurity generation.

[0046] Step S5: Reduction reaction

[0047] Efficient reduction and conversion: By optimizing the selection of reducing agents (such as iron powder or zinc powder) and reaction conditions (room temperature or solvent reflux temperature, 8-24 h), this step achieved an efficient reduction reaction of intermediate VI to generate intermediate VII. The optimized reaction conditions ensured high selectivity and rapid conversion, improving the yield of the target product.

[0048] Mild reaction conditions and high safety: Mild reaction conditions are adopted to avoid side reactions and equipment requirements caused by high temperature and high pressure. At the same time, by selecting low-toxicity reducing agents (such as iron powder), the danger of the reaction and the difficulty of operation are reduced, and the safety of the process is improved.

[0049] Step S6: Salt formation reaction

[0050] Simplified salt formation process: This step achieves rapid formation of the target product VIII by dissolving intermediate VII in formic acid and stirring the reaction. Optimized reaction conditions (room temperature or 50°C, 0.5-1 h) ensure high selectivity and rapid conversion of the reaction, simplifying the operation process.

[0051] High-purity target product: By precisely controlling the mass-to-volume ratio of intermediate VII to formic acid (1:2-10), the high purity of the target product was ensured, and the generation of impurities was reduced. Simultaneously, high-purity raloxifene EP impurity B could be obtained through simple rotary evaporation and lyophilization.

[0052] Mild reaction conditions and high safety: This invention employs mild reaction conditions in each step of the reaction, avoiding the use of high temperature, high pressure, or highly toxic reagents. For example, in the acyl chloride reaction (step S2), various chlorinating reagents (such as thionyl chloride, oxalyl chloride, etc.) can be selected, and the reaction conditions can be flexibly adjusted according to specific needs, reducing operational risks. Furthermore, this invention uses iron powder or zinc powder as a reducing agent in the reduction reaction (step S5), avoiding the use of highly toxic or highly reactive chemical reagents, further improving process safety.

[0053] This invention employs simple and efficient post-processing methods, such as extraction, rotary evaporation, and column chromatography, after each reaction step, eliminating the need for complex separation and purification steps. For example, in the final salt formation reaction (step S6), the target product can be obtained simply by stirring, rotary evaporation, and freeze-drying, greatly simplifying the operation process, reducing production costs, and improving the reproducibility and scalability of the experiment.

[0054] Providing support for drug quality control: The preparation method of raloxifene EP impurity B fills a gap in the field of impurity synthesis. The method provided by this invention enables the stable preparation of high-purity impurity standards, providing strong support for impurity profile studies, limit control, and safety assessment of raloxifene. This is of great significance for improving the quality standard system of raloxifene and ensuring the safety and efficacy of the drug.

[0055] Promoting the research and clinical application of raloxifene: This invention not only provides key technical support for the study of impurities in raloxifene, but also provides a reference for optimizing the production process and quality control standards of raloxifene. Through in-depth research on the properties and effects of impurities, the clinical application of raloxifene can be further optimized, improving the safety and efficacy of the drug, and promoting its widespread application in the prevention and treatment of osteoporosis. Attached Figure Description

[0056] Figure 1 A process flow diagram for the preparation of raloxifene EP impurity B provided by the present invention;

[0057] Figure 2 The NMR spectrum of intermediate III provided by this invention;

[0058] Figure 3 The mass spectrum of intermediate IV provided by this invention;

[0059] Figure 4 The mass spectrum of intermediate V provided by the present invention;

[0060] Figure 5 The HPLC chromatogram of raloxifene EP impurity B provided by this invention;

[0061] Figure 6 The mass spectrum of raloxifene EP impurity B provided by this invention;

[0062] Figure 7 The NMR spectrum of raloxifene EP impurity B provided by this invention. Detailed Implementation

[0063] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0064] Example 1

[0065] Reference Figures 1 to 7 This invention provides a method for preparing raloxifene EP impurity B, comprising the following steps:

[0066]

[0067] Step S1: Intermediate I (10 g, 36.99 mmol, 1 eq) was added to DMF (50 ml), followed by DMSO (2 ml), then NIS (12.48 g, 55.48 mmol, 2 eq) and AIBN (607 mg, 3.69 mmol, 0.1 eq). The mixture was stirred overnight at room temperature. The next day, LC-MS analysis confirmed the presence of product. The reaction mixture was poured into an ice-water bath and extracted with EA. Column chromatography yielded 13.68 g of intermediate III; yield 93.3%. MS: (ESI) m / z [M+1] + 395.99, 397.08. 1 ¹H NMR (400MHz, CDCl₃) δ 7.60 (d, J = 8.9 Hz, 1H), 7.55–7.51 (m, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.9, 2.4 Hz, 1H), 6.94–6.89 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H). (See reference.) Figure 2 ;

[0068]

[0069] Step S2: Intermediate II (6.0 g, 24.06 mmol, 1 eq) was added to SOCl2 (50 ml) and a catalytic amount of DMF (0.5 ml), and the mixture was heated to 90 °C for 1 h. The SOCl2 in the reaction solution was then removed by distillation to obtain a yellow solid (Intermediate IV), MS: (ESI) m / z [M+1] + The signal peak of methyl ester is 264.23, which can be referenced. Figure 3 .

[0070]

[0071] Step S3: Anhydrous aluminum chloride (1.01 g, 75.71 mmol, 5 eq) was added to DCM (40 ml). A mixed DCM solution of intermediate III (6 g, 15.15 mmol, 1 eq) and intermediate IV (6.08 g, 22.71 mmol, 1.5 eq) was then added at -30 °C and stirred. TLC showed the reaction was complete after 12 h. The reaction solution was then slowly poured into ice water, extracted with DCM, and the organic phase was evaporated to dryness. Column chromatography (DCM:MeOH = 50:1) yielded intermediate V 7.26 g, 76.3% yield. MS: (ESI) m / z [M+1] + 628.16, for reference Figure 4 ;

[0072]

[0073] Step S4: Add intermediate V (1.6 g, 2.55 mmol, 1 eq) to HBr-CH3COOH (18 ml), heat to 118 °C and stir for 12 h. Then pour the reaction solution into water, adjust the pH to about 8 with sodium carbonate solid, extract with EA, evaporate the EA phase to dryness, and purify the crude product by column chromatography to obtain 1.10 g of intermediate VI, yield 71.9%, which is directly used in the next step.

[0074]

[0075] Step S5: Add intermediate VI (0.8 g, 1.33 mmol, 1 eq) to CH3COOH (18 ml), add iron powder (2 g), heat to 50 °C and stir to react for 8 h; filter, remove acetic acid to obtain 0.56 g intermediate VII, yield 88.9%, MS: (ESI) m / z [M+1]+: 474.19, which can be referenced. Figure 6 ;

[0076]

[0077] Step S6: Intermediate VII (0.5 g, 1.06 mmol, 1 eq) was added to formic acid (4 ml), heated to 50 °C and stirred for 0.5 h. After reaction, the formic acid was removed by rotary evaporation and the product was lyophilized to obtain target product VIII 0.55 g, with a yield of 99%. The spectral data of raloxifene EP impurity B in target product VIII are as follows: ESI-LCMS (m / z): 555.04 (M+H)+, 1H NMR(400MHz,DMSO)δ5.80(d,J=8.2Hz,1H),4.66(s,1H),4.16(s,1H),4.04(dd,J=16.3,3 .6Hz,2H),3.78(d,J=11.2Hz,1H),3.51(s,1H),3.02(d,J=12.2Hz,1H),2.90-2.79(m,1H) ,2.43(d,J=7.2Hz,1H),2.33-1.95(m,6H),1.86(s,3H),1.77(t,J=12.2Hz,1H),1.37(s,9 H), 1.28 (s, 3H), 1.13 (s, 3H), 1.09 (s, 3H), 0.87 (d, J = 11.9Hz, 6H), 0.79 (d, J = 6.6Hz, 3H).

[0078] Example 2

[0079] This invention provides a method for preparing raloxifene EP impurity B, comprising the following steps:

[0080]

[0081] Step S1: Intermediate 1 (10 g, 36.99 mmol, 1 eq) was added to DMF (50 ml), followed by NIS (12.48 g, 55.48 mmol, 2 eq) and BPO (890 mg, 3.69 mmol, 0.1 eq). The mixture was stirred overnight at room temperature, and the presence of product was detected by LC-MS the next day. The reaction solution was poured into an ice-water bath and extracted with EA. Column chromatography yielded 13.08 g of product III, with a yield of 89.2%. The detection data were the same as in Example 1.

[0082]

[0083] Step S2: Add intermediate II (6.0 g, 24.06 mmol, 1 eq) to COCl2 (50 ml) and catalytic amount DMF (0.5 ml), and react at 90 °C for 1 h. Then remove the COCl2 from the reaction solution by distillation to obtain a yellow solid (IV), which is directly added to the next step.

[0084]

[0085] Step S3: TiCl4 (5.74 g, 30.28 mmol, 2 eq) was added to DCM (40 ml), and a mixed DCM solution of III (6.1 g, 15.4 mmol, 1 eq) and IV (6.1 g, 22.78 mmol, 1.48 eq) was added at -30 °C. After reacting for 10 h, TLC showed that the reaction was complete. The reaction solution was slowly poured into ice water, and then extracted with DCM. The organic phase was evaporated to dryness, and column chromatography was performed: DCM:MeOH = 50:1 to give product V 7.1 g, yield 73.4%. The detection data were the same as in Example 1.

[0086]

[0087] Step S4: Dissolve V (1.6 g, 2.55 mmol, 1 eq) in DCM (20 ml), add TMSI (1.53 g, 7.65 mmol, 3 eq), heat to 40 °C and stir for 12 h. TLC showed that the reaction was complete. Pour the reaction solution into water, extract with DCM, evaporate the DCM phase to dryness, and purify the crude product by column chromatography to obtain 1.21 g of product VI, yield 79.1%.

[0088]

[0089] Step S5: Add VI (0.8 g, 1.33 mmol, 1 eq) to CH3COOH (18 ml), add zinc powder (2 g), and heat to 50 °C with stirring. The reaction proceeded for 6 h, and TLC showed complete reaction. Filter and remove acetic acid to obtain 0.50 g of product VII, yield 79.4%. Detection data were the same as in Example 1.

[0090]

[0091] Step S6 is the same as in Example 1, and the spectral data of raloxifene EP impurity B is the same as in Example 1.

[0092] As shown in the above examples, this invention uses 6-methoxy-2-(4-methoxyphenyl)benzothiophene I and 4-[2-(1-pyrrolyl)ethoxy]benzoate II as raw materials. I is first iodinated to obtain intermediate III. II is then reacted with a chlorinating agent to obtain acyl chloride intermediate IV. Next, III and IV undergo a Friedel-Crafts acylation reaction to obtain intermediate V. Then, under demethylation conditions, V loses the methyl groups of the two methoxy groups to obtain intermediate VI. Under reducing conditions, iodine is reduced to obtain intermediate VII. Intermediate VII forms a salt with formic acid to obtain the target impurity molecule VIII. The purity of the target product TM obtained by this preparation method can reach over 95%.

[0093] Step S1: Iodination reaction

[0094] Efficient iodination conversion: By selecting appropriate solvents (such as dichloromethane, tetrahydrofuran, etc.) and free radical initiators (such as AIBN or BPO), this step achieves efficient iodination of 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I). Optimized molar ratios (1:1.2-2.0:0.05-0.1) and reaction conditions (room temperature to solvent reflux temperature) ensure high selectivity and rapid conversion, significantly improving the yield of intermediate III.

[0095] Mild reaction conditions: The reaction is carried out at room temperature or solvent reflux temperature, which avoids side reactions and equipment requirements caused by high temperature, reduces the danger and difficulty of the reaction, and shortens the reaction time (6-24h), thus improving production efficiency.

[0096] Step S2: Acyl chloride reaction:

[0097] Diverse selection of chlorination reagents: This step offers a variety of chlorination reagents to choose from (such as thionyl chloride, oxalyl chloride, PCl3, PCl5, etc.), allowing the reaction to be flexibly adjusted according to actual needs and safety requirements. For example, the use of oxalyl chloride can avoid the high toxicity issues associated with thionyl chloride while maintaining efficient acyl chlorination conversion.

[0098] Rapid reaction and high yield: Optimized reaction temperature (room temperature or solvent reflux temperature) and time (1-4 h) ensured the rapid conversion of 4-[2-(1-pyrrolidinyl)ethoxy]benzoate salt (II) to acyl chloride intermediate IV, while reducing the formation of byproducts and improving the purity and yield of the target product.

[0099] Step S3: Friedel-Crafts acylation reaction

[0100] Efficient acylation conversion: By rationally selecting Lewis acids (such as AlCl3, FeCl3, BF3, TiCl4) and optimizing the reaction molar ratio (1:1-2:1-3), this step achieves efficient Friedel-Crafts acylation reaction of intermediate III and acyl chloride IV to generate intermediate V. Optimized reaction conditions (room temperature or solvent reflux temperature, 8-16 h) ensure high selectivity and high yield of the reaction.

[0101] Mild reaction conditions and high selectivity: Mild reaction conditions are adopted to avoid side reactions and equipment requirements caused by high temperature and high pressure. At the same time, by precisely controlling the reaction time, the high selectivity of the target product is ensured and the generation of impurities is reduced.

[0102] Step S4: Demethylation reaction

[0103] Efficient demethylation conversion: By optimizing the amount of demethylating reagent (1:3-7) and reaction conditions (room temperature or solvent reflux temperature, 12-24 h), this step achieved efficient demethylation of intermediate V to generate bisphenol hydroxyl intermediate VI. Optimized reaction conditions ensured high selectivity and rapid conversion, improving the yield of the target product. Mild reaction conditions avoided side reactions and equipment requirements caused by high temperature and pressure. Simultaneously, precise control of the reaction time ensured the high purity of the target product and reduced impurity generation.

[0104] Step S5: Reduction reaction

[0105] Efficient reduction and conversion: By optimizing the selection of reducing agents (such as iron powder or zinc powder) and reaction conditions (room temperature or solvent reflux temperature, 8-24 h), this step achieved an efficient reduction reaction of intermediate VI to generate intermediate VII. The optimized reaction conditions ensured high selectivity and rapid conversion, improving the yield of the target product.

[0106] Mild reaction conditions and high safety: Mild reaction conditions are adopted to avoid side reactions and equipment requirements caused by high temperature and high pressure. At the same time, by selecting low-toxicity reducing agents (such as iron powder), the danger of the reaction and the difficulty of operation are reduced, and the safety of the process is improved.

[0107] Step S6: Salt formation reaction

[0108] Simplified salt formation process: This step achieves rapid formation of the target product VIII by dissolving intermediate VII in formic acid and stirring the reaction. Optimized reaction conditions (room temperature or 50°C, 0.5-1 h) ensure high selectivity and rapid conversion of the reaction, simplifying the operation process.

[0109] High-purity target product: By precisely controlling the mass-to-volume ratio of intermediate VII to formic acid (1:2-10), the high purity of the target product was ensured, and the generation of impurities was reduced. Simultaneously, high-purity raloxifene EP impurity B could be obtained through simple rotary evaporation and lyophilization.

[0110] Mild reaction conditions and high safety: This invention employs mild reaction conditions in each step of the reaction, avoiding the use of high temperature, high pressure, or highly toxic reagents. For example, in the acyl chloride reaction (step S2), various chlorinating reagents (such as thionyl chloride, oxalyl chloride, etc.) can be selected, and the reaction conditions can be flexibly adjusted according to specific needs, reducing operational risks. Furthermore, this invention uses iron powder or zinc powder as a reducing agent in the reduction reaction (step S5), avoiding the use of highly toxic or highly reactive chemical reagents, further improving process safety.

[0111] This invention employs simple and efficient post-processing methods, such as extraction, rotary evaporation, and column chromatography, after each reaction step, eliminating the need for complex separation and purification steps. For example, in the final salt formation reaction (step S6), the target product can be obtained simply by stirring, rotary evaporation, and freeze-drying, greatly simplifying the operation process, reducing production costs, and improving the reproducibility and scalability of the experiment.

[0112] Providing support for drug quality control: The preparation method of raloxifene EP impurity B fills a gap in the field of impurity synthesis. The method provided by this invention enables the stable preparation of high-purity impurity standards, providing strong support for impurity profile studies, limit control, and safety assessment of raloxifene. This is of great significance for improving the quality standard system of raloxifene and ensuring the safety and efficacy of the drug.

[0113] Promoting the research and clinical application of raloxifene: This invention not only provides key technical support for the study of impurities in raloxifene, but also provides a reference for optimizing the production process and quality control standards of raloxifene. Through in-depth research on the properties and effects of impurities, the clinical application of raloxifene can be further optimized, improving the safety and efficacy of the drug, and promoting its widespread application in the prevention and treatment of osteoporosis.

[0114] The above description is merely a preferred embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural transformations made using the contents of the present invention's specification and drawings under the inventive concept of the present invention, or direct / indirect applications in other related technical fields, are included within the patent protection scope of the present invention.

Claims

1. A method for preparing raloxifene EP impurity B, characterized in that, Includes the following steps: Step S1: Dissolve 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I) as a raw material in solvent one, add NIS, and then add a free radical initiator to react and obtain intermediate III. The reaction equation is as follows: Step S2: Take 4-[2-(1-piperidinyl)ethoxy]benzoate salt (II), dissolve it in solvent II or without solvent II, then add a chlorinating agent to react and generate intermediate IV. The reaction equation is as follows: Step S3: Dissolve intermediate III in solvent III, add Lewis acid, then add intermediate IV, and perform Friedel-Crafts acylation to generate intermediate V. The reaction equation is as follows: The Lewis acid is selected from one or more of AlCl3, FeCl3, and TiCl4; Step S4: Dissolve intermediate V in solvent four, add a demethylating agent, and generate bisphenol hydroxyl intermediate VI under demethylation conditions. The demethylating agent is HBr-CH3COOH or TMSI. The reaction equation is as follows: Step S5: Dissolve intermediate VI in solvent 5, add a reducing agent, and generate intermediate VII through a reduction reaction. The reaction equation is as follows: Step S6: Dissolve intermediate VII in formic acid, stir, evaporate to dryness, and finally freeze-dry to obtain the formate target product VIII. The reaction equation is as follows: 。 2. The method for preparing raloxifene EP impurity B according to claim 1, characterized in that, In step S1, the molar ratio of 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I) to NIS and the free radical initiator is 1:(1.2-2.0):(0.05-0.1); the free radical initiator is selected from AIBN or BPO; the solvent is selected from one or more of THF, MeCN, DCM, and DMF; and the reaction temperature in step S1 is room temperature to 120°C. o C, the reaction time is 6-24h.

3. The method for preparing raloxifene EP impurity B according to claim 1, characterized in that, In step S2, 4-[2-(1-piperidinyl)ethoxy]benzoate (II) is dissolved in thionyl chloride, or other chlorinating agents are added, selected from oxaloyl chloride, PCl3, PCl5, or triphosgene. When other chlorinating agents are added, solvent II is selected from one or more of THF, DCM, and MeCN. The reaction temperature in step S2 is room temperature to 110°C. o C, the reaction time is 1-4 hours.

4. The method for preparing raloxifene EP impurity B according to claim 1, characterized in that, In step S3, the molar ratio of intermediate III to Lewis acid and intermediate IV is 1:(1-2):(1-3); the solvent is selected from one or more of DCM, THF, MeOH, MeCN, and DMF; the reaction temperature in step S3 is -30°C. o C to 80 o C, the reaction time is 8-16 hours.

5. The method for preparing raloxifene EP impurity B according to claim 1, characterized in that, In step S4, the molar ratio of intermediate V to the demethylating agent is 1:(3-7); the solvent is selected from one or more of DCM, THF, MeOH, MeCN, and acetic acid; the reaction temperature in step S4 is room temperature to 150°C. o C, the reaction time is 12-24 hours.

6. The method for preparing raloxifene EP impurity B according to claim 1, characterized in that, The molar ratio of intermediate VI to reducing agent in step S5 is 1:(1-3); the reducing agent is selected from iron powder and zinc powder; the solvent is selected from one or more of water, THF, MeOH, MeCN, and acetic acid; the reaction temperature in step S4 is room temperature to 100°C. o C, the reaction time is 8-24 hours.

7. The method for preparing raloxifene EP impurity B according to claim 1, characterized in that, In step S6, intermediate VII is dissolved in formic acid; the mass-to-volume ratio of intermediate VII to formic acid is 1:(2~10); the stirring reaction temperature in step S6 is room temperature to 50°C. o C, the reaction time is 0.5~1h.

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