Preparation method of raloxifene EP impurity B

Abstract

The invention discloses a preparation method of a raloxifene EP impurity B. The preparation method comprises the following steps: taking 6-methoxy-2-(4-methoxyphenyl) benzothiophene (I) as a raw material, dissolving the 6-methoxy-2-(4-methoxyphenyl) benzothiophene (I) in a solvent I, adding NIS, then adding a free radical initiator, and reacting to obtain an intermediate III; dissolving 4-[2-(1-pyrrolidinyl) ethyoxyl] benzoic acid hydrochloride (II) in a solvent II, adding the solvent II or not, then adding a chlorinating agent, and reacting to generate an intermediate IV; dissolving the intermediate III in a solvent III, adding Lewis acid, then adding the intermediate IV, and carrying out Friedel-Crafts acylation reaction to generate an intermediate V; dissolving the intermediate V in a solvent IV, adding a demethylation reagent, and generating a bisphenol hydroxyl intermediate VI under a demethylation condition; dissolving the intermediate VI in a solvent V, adding a reducing agent, and performing reduction reaction to generate an intermediate VII; and dissolving the intermediate VII in formic acid, stirring, spin-drying, and finally freeze-drying to generate a formate target product VIII.

Description

Technical Field

[0001] The present invention relates to the technical field of compound synthesis, and particularly relates to a preparation method of raloxifene EP impurity B. Background Art

[0002] Raloxifene is a selective estrogen receptor modulator (SERM), mainly used for the prevention and treatment of osteoporosis in postmenopausal women. It mimics the action of estrogen, increases bone density, reduces the risk of fractures, and has an antagonistic effect on the breast and uterus, avoiding some side effects of traditional estrogen therapy. The mechanism of action of raloxifene is based on its selective regulation of estrogen receptors: for the bone and cardiovascular systems, raloxifene exhibits estrogenic agonist effects, which can increase bone density, reduce total cholesterol and low-density lipoprotein (LDL) levels, thereby reducing the risk of fractures and improving cardiovascular health; for the breast and uterus: raloxifene exhibits estrogenic antagonist effects and does not stimulate breast and endometrial hyperplasia, so it does not increase the risk of breast cancer and endometrial cancer; in addition, raloxifene can also reduce the stroke risk in postmenopausal women, which may be related to its regulatory effects on cholesterol and inflammation.

[0003] Compared with traditional estrogen replacement therapy (HRT) and other selective estrogen receptor modulators (such as tamoxifen), raloxifene has the following advantages: higher safety, raloxifene does not stimulate the breast and endometrium, avoiding the risk of breast cancer and endometrial cancer, while traditional estrogen therapy may increase these risks; has cardiovascular protection. Raloxifene can reduce total cholesterol and LDL levels and has a protective effect on 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 significantly 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 profile is milder than that of traditional estrogen therapy.

[0004] Raloxifene, as a selective estrogen receptor modulator (SERM), the study of its drug impurities is an important part of drug quality control. The impurities of raloxifene mainly include by-products, degradation products or isomers generated during the synthesis process. According to the literature and test reports, the main impurities that have been identified include: Raloxifene Impurity 1, which is the 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 are mostly involved in changes such as hydroxyl group substitution, sulfonation or isomerization, which may affect the safety and effectiveness of the drug. The limit control of raloxifene impurities is the core requirement of drug review. For example: impurity profile study. By systematically analyzing the sources of impurities (such as synthetic intermediates, degradation products), reasonable impurity limit standards are formulated. The Chinese Pharmaceutical Journal and other literature have reported the impurity profile study methods of raloxifene hydrochloride; safety assessment. Some impurities may have potential toxicity, such as the toxicological data of Raloxifene Impurity 1 need to be verified through in vitro and in vivo tests; stability study. Accelerated test and long-term stability test can evaluate the generation trend of impurities during storage and provide a basis for the drug's shelf life.

[0005] In recent years, the impurity study of raloxifene has involved multiple aspects such as structure identification, analytical method development, safety assessment and quality control. Through advanced analytical techniques and standardized management, the safety and efficacy of drugs can be effectively guaranteed. In the future, with the progress of detection technology and the refinement of regulatory requirements, impurity research will further promote the optimization of raloxifene's clinical application. During the drug R & D and production process, the control and analysis of impurities are the core requirements of drug review. Impurity profile study formulates reasonable impurity limit standards by systematically analyzing the sources of impurities (such as synthetic intermediates, degradation products). In recent years, the research on raloxifene impurities has gradually received attention, and relevant literature and patents have emerged continuously. However, the synthesis method of Raloxifene EP Impurity B has not been reported in detail, which limits the in-depth study and quality control of this impurity.

[0006] Therefore, developing an efficient and reliable preparation method for Raloxifene EP Impurity B is of great significance for improving the impurity profile study of raloxifene, ensuring drug quality and promoting the optimization of raloxifene's clinical application. The purpose of the present invention is to provide a preparation method for Raloxifene EP Impurity B with reasonable process design and simple post-treatment, so as to provide qualified impurity reference standards for the impurity study of raloxifene. Summary of the Invention

[0007] Aiming at the problems existing in the prior art, the present invention provides a preparation method for Raloxifene EP Impurity B

[0008] In order to achieve the above object, the present invention provides a preparation method for Raloxifene EP Impurity B, comprising the following steps:

[0009] Step S1: Take 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I) as a raw material, dissolve it in Solvent 1, add NIS, and then add a radical initiator. React to obtain Intermediate III. The reaction equation is as follows:

[0010]

[0011] Step S2: Take 4-[2-(1-pyrrolidino)ethoxy]benzoic acid hydrochloride (II), dissolve it in Solvent 2, add Solvent 2 or not, and then add a chlorinating agent. React to generate Intermediate IV. The reaction equation is as follows:

[0012]

[0013] Step S3: Take Intermediate III, dissolve it in Solvent 3, add a Lewis acid, and then add Intermediate IV. Perform a Friedel-Crafts acylation reaction to generate Intermediate V. The reaction equation is as follows:

[0014]

[0015] Step S4: Take Intermediate V, dissolve it in Solvent 4, add a demethylating reagent, and generate a bisphenol hydroxyl intermediate VI under demethylation conditions. The reaction equation is as follows:

[0016]

[0017] Step S5: Take Intermediate VI, dissolve it 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: Take Intermediate VII, dissolve it in formic acid, stir, spin-dry, and finally lyophilize to generate the formate target product VIII. The reaction equation is as follows:

[0020]

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

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

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

[0024] More preferably, 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride (II) in step S2 is dissolved in thionyl chloride, no solvent is added, the reaction temperature is 90 °C, and the reaction time is 1 h.

[0025] Preferably, the molar dosage ratio of intermediate III to the 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 third solvent is selected from one or more of DCM, THF, MeOH, MeCN, and DMF; the reaction temperature in step S3 is -30 °C to 80 °C, and the reaction time is 8 - 16 h.

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

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

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

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

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

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

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

[0033] Adopting the technical solution of the present invention has the following beneficial effects:

[0034] The present invention uses 6 - methoxy - 2-(4 - methoxyphenyl)benzothiophene I and 4 - [2-(1 - pyrrolidinyl)ethoxy]benzoic acid hydrochloride II as raw materials. First, I is iodinated to obtain intermediate III. Then II reacts 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 removes the methyl groups of two methoxy groups to obtain intermediate VI. Under reduction 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 more than 95%.

[0035] Step S1: Iodination reaction

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

[0037] Mild reaction conditions: The reaction is carried out at room temperature or the reflux temperature of the solvent, avoiding side reactions and equipment requirements caused by high temperature, reducing the risk and operation difficulty of the reaction, shortening the reaction time (6 - 24h) at the same time, and improving production efficiency.

[0038] Step S2: Acyl chlorination reaction:

[0039] Diverse choices of chlorinating reagents: This step provides a variety of chlorinating reagents (such as thionyl chloride, oxalyl chloride, PCl3, PCl5, etc.), enabling 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 problem brought by thionyl chloride while maintaining efficient acyl chlorination conversion.

[0040] Fast reaction and high yield: The optimized reaction temperature (room temperature or the reflux temperature of the solvent) and time (1 - 4h) ensure the rapid conversion of 4 - [2 - (1 - pyrrolidinyl)ethoxy]benzoic acid hydrochloride (II) into the acyl chloride intermediate IV, reducing the generation of by - products at the same time, and improving the purity and yield of the target product.

[0041] Step S3: Friedel - Crafts acylation reaction

[0042] Efficient acylation conversion: By reasonably selecting Lewis acids (such as AlCl3, FeCl3, BF3, TiCl4) and optimizing the reaction molar ratio (1:1 - 2:1 - 3), this step realizes the efficient Friedel - Crafts acylation reaction of intermediate III and acyl chloride IV to generate intermediate V. The optimized reaction conditions (room temperature or the reflux temperature of the solvent, 8 - 16h) ensure the 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 generation 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 dosage of the demethylating reagent (1:3 - 7) and reaction conditions (room temperature or the reflux temperature of the solvent, 12 - 24h), this step realizes the efficient demethylation reaction of intermediate V to generate the bis - phenol hydroxyl intermediate VI. The optimized reaction conditions ensure the high selectivity and rapid conversion of the reaction, improving the yield of the target product; 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 - purity generation of the target product is ensured, and the generation of impurities is reduced.

[0046] Step S5: Reduction reaction

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

[0048] Mild reaction conditions and high safety: By adopting mild reaction conditions, side reactions and equipment requirements caused by high temperature and high pressure are avoided. At the same time, by selecting a reducing agent with low toxicity (such as iron powder), the risk and operation difficulty of the reaction are reduced, improving the safety of the process.

[0049] Step S6: Salt formation reaction

[0050] Simple salt formation operation: By dissolving intermediate VII in formic acid and stirring for reaction, this step achieves the rapid generation of the target product VIII. The 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 - volume ratio of intermediate VII to formic acid (1:2 - 10), the high - purity generation of the target product is ensured, reducing the generation of impurities. At the same time, through simple operations such as rotary evaporation and freeze - drying, high - purity raloxifene EP impurity B can be obtained.

[0052] Mild reaction conditions and high safety: The present invention adopts 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 acylation reaction (step S2), a variety of chlorinating reagents (such as thionyl chloride, oxalyl chloride, etc.) can be selected, and the reaction conditions can be flexibly adjusted according to specific requirements, reducing the operation risk. In addition, the present invention uses iron powder or zinc powder as the reducing agent in the reduction reaction (step S5), avoiding the use of highly toxic or highly reactive chemical reagents, further improving the safety of the process.

[0053] The present invention adopts simple and efficient post - treatment methods after each step of the reaction, such as extraction, rotary evaporation and column chromatography, etc., without complex separation and purification steps. For example, in the final salt formation reaction (step S6), the target product can be obtained through simple stirring, rotary evaporation and freeze - drying, greatly simplifying the operation process, reducing the production cost, and at the same time improving the repeatability and scalability of the experiment.

[0054] Provide support for drug quality control: The preparation method of raloxifene EP impurity B fills the gap in the synthesis field of this impurity. Through the method provided by the present invention, high-purity impurity reference standards can be stably prepared, providing strong support for the impurity profile research, limit control, and safety evaluation of raloxifene. This is of great significance for improving the quality standard system of raloxifene and ensuring the safety and effectiveness of drugs.

[0055] Promote the research and clinical application of raloxifene: The present invention not only provides key technical support for the impurity research of raloxifene, but also provides a reference for optimizing the production process and quality control standards of raloxifene. By deeply studying the properties and effects of impurities, the clinical application plan of raloxifene can be further optimized, improving the safety and efficacy of the drug, and promoting its wide application in the prevention and treatment of osteoporosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 Process preparation flow chart of raloxifene EP impurity B provided by the present invention;

[0057] Figure 2 1H-NMR spectrum of Intermediate III provided by the present invention;

[0058] Figure 3 Mass spectrum of Intermediate IV provided by the present invention;

[0059] Figure 4 Mass spectrum of Intermediate V provided by the present invention;

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

[0061] Figure 6 Mass spectrum of raloxifene EP impurity B provided by the present invention;

[0062] Figure 7 1H-NMR spectrum of raloxifene EP impurity B provided by the present invention. DETAILED DESCRIPTION OF THE INVENTION

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

[0064] Example 1

[0065] Refer to Figures 1 to 7 , the present invention provides a preparation method of raloxifene EP impurity B, which includes the following steps:

[0066]

[0067] Step S1: Add intermediate I (10 g, 36.99 mmol, 1 eq) to DMF (50 ml). After adding DMSO (2 ml), add NIS (12.48 g, 55.48 mmol, 2 eq) and AIBN (607 mg, 3.69 mmol, 0.1 eq), and stir at room temperature overnight. The next day, LC-MS detection shows the presence of the product. Pour the reaction solution into an ice-water bath, extract with EA, and perform column chromatography to obtain 13.68 g of intermediate III; the yield is 93.3%. MS: (ESI) m / z [M+1] + 395.99, 397.08. 1 H NMR (400 MHz, 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). For reference, Figure 2 ;

[0068]

[0069] Step S2: Add intermediate II (6.0 g, 24.06 mmol, 1 eq) to SOCl2 (50 ml) and a catalytic amount of DMF (0.5 ml), then heat to 90 °C and react for 1 h. Then distill off the SOCl2 in the reaction solution to obtain a yellow solid (intermediate IV), MS: (ESI) m / z [M+1] + Signal peak of methyl ester: 264.23, for reference Figure 3 .

[0070]

[0071] Step S3: Add anhydrous aluminum chloride (1.01 g, 75.71 mmol, 5 eq) to DCM (40 ml), and at -30 °C, add a mixed DCM (40 ml) solution of intermediate III (6 g, 15.15 mmol, 1 eq) and intermediate IV (6.08 g, 22.71 mmol, 1.5 eq), and stir. After 12 h, TLC shows that the reaction is complete. Then slowly pour the reaction solution into ice water, extract with DCM, rotary evaporate the organic phase, and perform column chromatography: DCM:MeOH = 50:1 to obtain 7.26 g of intermediate V, with a yield of 76.3%. 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 up to 118 °C and stir for reaction for 12 h. Then pour the reaction solution into water, adjust the pH to about 8 with solid sodium carbonate, extract with EA, spin-dry the EA phase, and purify the crude product by column chromatography to obtain 1.10 g of intermediate VI with a yield of 71.9%, which is directly put into 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 up to 50 °C and stir for reaction for 8 h; filter, remove acetic acid by rotary evaporation to obtain 0.56 g of intermediate VII with a yield of 88.9%, MS: (ESI) m / z [M+1]+: 474.19, which can be referred to Figure 6 ;

[0076]

[0077] Step S6: Add intermediate VII (0.5 g, 1.06 mmol, 1 eq) to formic acid (4 ml), heat up to 50 °C and stir for reaction for 0.5 h, then remove formic acid by rotary evaporation and freeze-dry to obtain 0.55 g of the target product VIII with a yield of 99%. The spectral data of the target product VIII, raloxifene EP impurity B, are as follows: ESI-LCMS (m / z): 555.04 (M+H)+, 1H NMR (400 MHz, DMSO) δ 5.80 (d, J = 8.2 Hz, 1H), 4.66 (s, 1H), 4.16 (s, 1H), 4.04 (dd, J = 16.3, 3.6 Hz, 2H), 3.78 (d, J = 11.2 Hz, 1H), 3.51 (s, 1H), 3.02 (d, J = 12.2 Hz, 1H), 2.90 - 2.79 (m, 1H), 2.43 (d, J = 7.2 Hz, 1H), 2.33 - 1.95 (m, 6H), 1.86 (s, 3H), 1.77 (t, J = 12.2 Hz, 1H), 1.37 (s, 9H), 1.28 (s, 3H), 1.13 (s, 3H), 1.09 (s, 3H), 0.87 (d, J = 11.9 Hz, 6H), 0.79 (d, J = 6.6 Hz, 3H).

[0078] Example 2

[0079] The present invention provides a preparation method of raloxifene EP impurity B, which comprises the following steps:

[0080]

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

[0082]

[0083] Step S2: Intermediate II (6.0 g, 24.06 mmol, 1 eq) was added to COCl2 (50 ml) and a catalytic amount of DMF (0.5 ml), and the temperature was raised to 90 °C and reacted for 1 h. Then, COCl2 in the reaction solution was distilled off to obtain a yellow solid (IV) which was directly used in the next step.

[0084]

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

[0086]

[0087] Step S4: V (1.6 g, 2.55 mmol, 1 eq) was dissolved in DCM (20 ml), and TMSI (1.53 g, 7.65 mmol, 3 eq) was added. The temperature was raised to 40 °C and stirred for 12 h. TLC showed that the reaction was complete. The reaction solution was poured into water and extracted with DCM. The DCM phase was dried by rotary evaporation. Column chromatography was used to purify the crude product to obtain 1.21 g of product VI with a yield of 79.1%.

[0088]

[0089] Step S5: Add VI (0.8 g, 1.33 mmol, 1 eq) into CH3COOH (18 ml), add zinc powder (2 g), and raise the temperature to 50 °C for stirring reaction. React for 6 h, and TLC shows that the reaction is complete. Filter, and remove acetic acid by rotary evaporation to obtain 0.50 g of product VII, with a yield of 79.4%. The detection data is the same as that in Example 1.

[0090]

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

[0092] As can be seen from the above examples, the present invention uses 6-methoxy-2-(4-methoxyphenyl)benzothiophene I and 4-[2-(1-pyrrolidino)ethoxy]benzoic acid hydrochloride II as raw materials. First, I is iodinated to obtain intermediate III. Then, II reacts with a chlorinating agent to obtain an acyl chloride intermediate IV. Next, III and IV undergo a Friedel-Crafts acylation reaction to obtain intermediate V. Then, under demethylation conditions, V removes the methyl groups of two methoxy groups to obtain intermediate VI. Under reduction 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] High-efficiency iodination conversion: By selecting suitable solvents (such as dichloromethane, tetrahydrofuran, etc.) and free radical initiators (such as AIBN or BPO), the high-efficiency iodination reaction of 6-methoxy-2-(4-methoxyphenyl)benzothiophene (Ⅰ) is achieved in this step. The optimized molar ratio (1:1.2 - 2.0:0.05 - 0.1) and reaction conditions (from room temperature to the reflux temperature of the solvent) ensure the high selectivity and rapid conversion of the reaction, significantly improving the yield of intermediate III.

[0095] Mild reaction conditions: React at room temperature or the reflux temperature of the solvent, avoiding side reactions and equipment requirements caused by high temperature, reducing the danger and operation difficulty of the reaction, shortening the reaction time (6 - 24 h) at the same time, and improving production efficiency.

[0096] Step S2: Acyl chlorination reaction:

[0097] Diverse selection of chlorinating reagents: This step provides a variety of chlorinating reagents for selection (such as thionyl chloride, oxalyl chloride, PCl3, PCl5, etc.), enabling 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 problem brought by thionyl chloride while maintaining high-efficiency acyl chlorination conversion.

[0098] Fast reaction and high yield: The optimized reaction temperature (room temperature or solvent reflux temperature) and time (1 - 4 h) ensure the rapid conversion of 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride (II) into the acyl chloride intermediate IV, while reducing the formation of by-products and increasing the purity and yield of the target product.

[0099] Step S3: Friedel-Crafts acylation reaction

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

[0101] Mild reaction conditions and high selectivity: The use of mild reaction conditions avoids 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 dosage of the demethylating reagent (1:3 - 7) and the reaction conditions (room temperature or solvent reflux temperature, 12 - 24 h), this step achieves the efficient demethylation reaction of intermediate V to produce the bisphenol hydroxyl intermediate VI. The optimized reaction conditions ensure the high selectivity and rapid conversion of the reaction, increasing the yield of the target product; the use of mild reaction conditions avoids side reactions and equipment requirements caused by high temperature and high pressure. At the same time, by precisely controlling the reaction time, the high purity of the target product is ensured, and the generation of impurities is reduced.

[0104] Step S5: Reduction reaction

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

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

[0107] Step S6: Salt formation reaction

[0108] Simple salt formation operation: By dissolving Intermediate VII in formic acid and stirring for reaction, this step realizes the rapid generation of the target product VIII. The 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-volume ratio of Intermediate VII to formic acid (1:2 - 10), the high-purity generation of the target product is ensured, reducing the generation of impurities. At the same time, through simple rotary evaporation and freeze-drying operations, high-purity Raloxifene EP Impurity B can be obtained.

[0110] Mild reaction conditions and high safety: This invention adopts 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 chlorination 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 requirements, reducing the operation risk. In addition, 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 the safety of the process.

[0111] This invention adopts simple and efficient post-treatment methods after each step of the reaction, such as extraction, rotary evaporation and column chromatography, etc., without complex separation and purification steps. For example, in the final salt formation reaction (Step S6), the target product can be obtained through simple stirring, rotary evaporation and freeze-drying, greatly simplifying the operation process, reducing the production cost, and at the same time improving the repeatability and scalability of the experiment.

[0112] Provide support for drug quality control: The preparation method of Raloxifene EP Impurity B fills the blank in the synthesis field of this impurity. Through the method provided by this invention, high-purity impurity reference standards can be stably prepared, providing strong support for the impurity profile research, limit control and safety evaluation of Raloxifene. This is of great significance for improving the quality standard system of Raloxifene and ensuring the safety and effectiveness of drugs.

[0113] Promote the research and clinical application of Raloxifene: This invention not only provides key technical support for the impurity research of Raloxifene, but also provides a reference for optimizing the production process and quality control standards of Raloxifene. By deeply studying the properties and effects of impurities, the clinical application plan of Raloxifene can be further optimized, improving the safety and efficacy of the drug, and promoting its wide application in the prevention and treatment of osteoporosis.

[0114] The above are only the preferred embodiments of the present invention, and do not limit the patent scope of the present invention accordingly. Any equivalent structural transformation made by using the content of the specification and drawings of the present invention under the inventive concept of the present invention, or any direct / indirect application in other related technical fields shall be included within the patent protection scope of the present invention.

Claims

1. A method for preparing raloxifene EP impurity B, characterized in that: The steps include: Step S1: 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I) is taken as a raw material and dissolved in solvent 1, NIS is added, and then a free radical initiator is added to react to obtain intermediate III. The reaction equation is as follows: Step S2: Take 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride (II), dissolve it in solvent 2 or without solvent 2, then add a chlorinating agent to react to generate intermediate IV. The reaction equation is as follows: Step S3: Dissolve the intermediate III in solvent three, add Lewis acid, and then add intermediate IV, and perform Friedel-Crafts acylation to generate intermediate V. The reaction equation is as follows: Step S4: Dissolve the intermediate V in solvent 4, add a demethylation agent, and generate a bisphenol hydroxy intermediate VI under demethylation conditions. The reaction equation is as follows: Step S5: Dissolve the intermediate VI in solvent 5, add a reducing agent, and generate the intermediate VII through a reduction reaction. The reaction equation is as follows: Step S6: Dissolve the intermediate VII in formic acid, stir, spin dry, and finally freeze-dry to generate the formate target product VIII. The reaction equation is as follows:

2. The method for preparing raloxifene EP impurity B according to claim 1, wherein The molar ratio of 6-methoxy-2-(4-methoxyphenyl)benzothiophene (I) to NIS and free radical initiator in step S1 is 1:(1.2-2.0):(0.05-0.1); the free radical initiator is selected from one of AIBN and BPO; the solvent 1 is selected from one or more of THF, MeCN, DCM, and DMF; the reaction temperature of step S1 is room temperature to 120°C, and the reaction time is 6-24h.

3. The preparation method of raloxifene EP impurity B according to claim 1, characterized in that, The 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride (II) in step S2 is dissolved in thionyl chloride, or other chlorinating agents are added, and the other chlorinating agents are selected from one of oxalyl chloride, PCl3, PCl5 or triphosgene. When other chlorinating agents are added, the second solvent 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.

4. The preparation method of raloxifene EP impurity B according to claim 1, characterized in that, The molar ratio of the intermediate III to the Lewis acid and the intermediate IV in the 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 three is selected from one or more of DCM, THF, MeOH, MeCN, and DMF; the reaction temperature of the step S3 is -30°C to 80°C, and the reaction time is 8-16h.

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

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

7. The method for preparing raloxifene EP impurity B according to claim 1, wherein The intermediate VII in step S6 is dissolved in formic acid; the mass volume ratio of the 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 0.5-1 h.

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