Synthesis process of estrogen regulating medicine

Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a synthesis process of an estrogen regulating medicine. A is used as a starting point of a reaction route, J is prepared through naphthalenone reduction and enol etherification, electron-rich biaryl construction, nitro reduction and benzyl deprotection, secondary amine construction, chiral resolution, acetylation and LAH strong reduction in sequence, all the reaction raw materials are low in price and easy to obtain, the process is stable and mild, the yield is high, and the method has high value for adjusting rapid and mild synthesis of estrogen drugs.

Description

Technical Field

[0001] This application relates to the field of drug synthesis technology, and more specifically, to a synthetic process for a drug that regulates estrogen. Background Technology

[0002] Estrogen is a type of steroid hormone primarily synthesized by ovarian follicle cells. By binding to estrogen receptors ERα and ERβ in target cells, it regulates gene expression and performs a wide range of physiological functions, including reproductive organ development, secondary sexual characteristics and body shaping, bone and cardiovascular protection, metabolism, skin health, and mood regulation. Insufficient estrogen can lead to delayed puberty, menstrual irregularities, menopausal syndrome, osteoporosis, and an increased risk of cardiovascular disease. Excessive estrogen levels can stimulate excessive proliferation of the breast and endometrium, increasing the risk of breast cancer, endometrial cancer, and uterine fibroids. Therefore, the regulation of estrogen levels plays a crucial role in human health.

[0003] Breast cancer accounts for 23.8% of all new cancer cases in women, ranking first, and is the leading cause of cancer death among women worldwide. Compound J, as a widely demonstrated promising mixed activity as a selective estrogen receptor α (ERα) modulator / degrader (SERM / SERD) targeting ER+ breast cancer, holds significant importance for precision treatment and health management in patients given the continuously rising incidence of breast cancer.

[0004] The first-generation synthetic route for compound J includes US7612114B, and the second-generation synthetic route includes CN113348163A. However, the raw material barriers are high, there are many intermediates in the synthesis process, the yield is low, and the synthesis depends on high pressure and low temperature process control, which requires high equipment. It is difficult to match small and medium-sized pilot production lines, and the operation is difficult and energy consumption is high, which cannot meet the needs of rapid research and development and industrial production. Summary of the Invention

[0005] To address the problem of easily preparing estrogen-regulating drugs with high yields, this application provides a synthetic process for estrogen-regulating drugs.

[0006] The synthesis process for the estrogen-regulating drug provided in this application includes the following steps: S1: Preparation of compound B: Br2·ether, NaBH4, EtOH, PTSA, and toluene were added to A, and the mixture was heated under reflux to obtain B. S2: Preparation of compound D: B, C, and Pd(PPh3)2Cl2 were added to DMSO, and the mixture was heated and stirred to obtain D. S3: Preparation of compound E: D and Pd / C were added to an EtOH-THF mixed solvent, hydrogen gas was introduced, and the mixture was heated and stirred to obtain E. S4: Preparation of compound G: E and F were pre-condensed in a solvent, and then NaBH4 was added and the reaction was stirred to obtain G: S5: Preparation of compound H: G and the chiral resolving agent were added to a solvent, heated to dissolve, cooled, crystallized, filtered, and then Na2CO3 solution was added to adjust the pH. Extraction and concentration were then performed to obtain H. S6: Preparation of compound I: H was added to pyridine, Ac2O was added dropwise, and the reaction was stirred to obtain I: S7: Preparation of compound J: I was added to a solvent, then LAH was added, the mixture was heated under reflux with stirring, and the mixture was filtered and concentrated to obtain J.

[0007] In the above scheme, C=O is reduced to CH-OH sequentially using NaBH4. Under PTSA catalysis, the secondary alcohol reacts with Br2·ether to obtain B. Pd(PPh3)2Cl2 is reduced and oxidatively added to the Br bond of the naphthalene ring to form a Pd-Ar intermediate. The o-nitro-p-methoxybromobenzene, due to the electron donation of the methoxy group and the high electron cloud density of the aromatic ring, undergoes transmetalation-reductive elimination with Pd-Ar to efficiently construct a biaryl C-C bond. Pd / C adsorbs H2, and after activation, the nitro group is first reduced, followed by hydrogenolysis of the benzyl ether, completing the bifunctional group transformation in one step. The primary amine (-NH2) undergoes nucleophilic addition-dehydration with the aldehyde group to form an imine. NaBH4 selectively reduces the imine to obtain G. The R-configuration is enriched by crystallization to obtain product H. Pyridine acts as an acid-binding agent to absorb the byproduct, and Ac2O undergoes electrophilic substitution of the hydroxyl group to obtain I. LAH provides H-, first cleaving the acetoxy group for deprotection, and then reduction to obtain J. Because the naphthalene ring obtained in S1 has abundant electrons, it enhances the coupling reactivity in S2. The introduction of the nitro group in S2 provides "polar orientation" for hydrogenation in S3, preferentially reducing the nitro group and avoiding premature deprotection of the benzyl group, thus greatly reducing byproducts. The acetylation in S6 temporarily protects the hydroxyl group, and the strong LAH reduction in S7 completes the deacetylation and amide reduction in one step, simplifying the process and reducing byproducts. By adopting the above preparation scheme, the raw materials are all common chemical products, resulting in low cost and high yield. At the same time, the steps only require conventional heating and cooling, avoiding the high process requirements such as 100psi H2 pressure and -25℃ low temperature commonly used in existing technologies.

[0008] In one specific implementation, NaBH4 in S1 is added in ≥2 portions at 0-5℃, Br2·ether and PTSA are added at 20-30℃, the heating temperature is 110-112℃, and the reflux time is 4-6 hours.

[0009] By adopting the above scheme, the addition of NaBH4 is exothermic, the temperature is controlled to prevent bumping, the reaction is more stable, and the excessive reduction of NaBH4 is inhibited, ensuring the singleness of the conversion. Heating at 110-112℃ provides an efficient water separation environment and improves the yield of B.

[0010] In one specific implementation, the reaction temperature in S2 is 120-125°C, the reaction time is 8-12 hours, and the process also includes the following steps: cooling and quenching with ice water, and extraction with ethyl acetate.

[0011] By adopting the above scheme, the homogeneity of the system is ensured, the catalyst has a good activation effect, and the reaction proceeds uniformly and stably. By using o-nitro-p-methoxybromobenzene, the methoxy group donates electrons, making bromobenzene more prone to transmetalation, resulting in a higher yield of D.

[0012] In one specific implementation, S3 contains 5% Pd / C, the heating temperature is 50-60℃, and the H2 concentration is 3-5 atm.

[0013] By adopting the above scheme, Pd / C is not prone to agglomeration and deactivation, has good adsorption effect on H2, and has suitable H2 solubility. It will not be over- or under-hydrogenated, and the reduction and activation are uniform and stable. First, the highly polar nitro group is reduced, and then the benzyl ether is hydrogenated to complete the bifunctional group conversion in one step. The reaction steps are simple, the operation process is simple, and high-pressure equipment is not required.

[0014] In one specific implementation, the pre-condensation temperature in S4 is 0-10℃, and NaBH4 is added in ≥2 portions.

[0015] By adopting the above scheme, the process of E and F pre-condensing to generate imine intermediate is relatively stable, preventing aldehyde self-condensation. By limiting the addition rate of NaBH4, excessively high local concentrations are avoided. NaBH4 selectively reduces the highly polar imine, reducing excessive reduction of aldehyde groups and resulting in fewer byproducts.

[0016] In one specific implementation, S4 further includes the following step: adjusting the pH to 1.5-2.5 with hydrochloric acid.

[0017] By adopting the above scheme, excess NaBH4 was quenched, the reduction was complete, and side reactions were reduced.

[0018] In one specific implementation, the chiral resolving agent in S5 is D-camphor sulfonic acid, and the temperature is gradually reduced to 20-30°C at a rate of 3-8°C / hour.

[0019] By adopting the above scheme, D-camphor sulfonic acid has a good chiral resolving effect, while greatly reducing the cost of traditional resolving agents. By precisely controlling the crystal growth rate through gradient cooling, mixed crystals are avoided and the ee value is improved.

[0020] In one specific implementation, the temperature at which Ac2O is added dropwise in S6 is 0-10°C, the temperature at which the reaction is stirred is 20-30°C, and the process also includes the following steps: quenching with ice water and extraction with ethyl acetate.

[0021] By adopting the above scheme and limiting the Ac2O dropping temperature, the hydrolysis of Ac2O was suppressed, the reaction yield was improved, and fewer byproducts were produced after quenching with ice water.

[0022] In one specific implementation scheme, LAH in S7 is added in ≥2 portions at 0-5℃, and the heating, reflux and stirring reaction process is carried out at a temperature of 64-68℃ for 6-8 hours. It also includes the following steps: quenching with ice water, and simultaneously conducting an ice bath during the quenching process.

[0023] By adopting the above scheme, low-temperature feeding avoids excessively high local concentrations of LAH, prevents exothermic temperature rise and boiling, reduces excessive reduction, stabilizes H- activity, and ensures sufficient and stable reduction.

[0024] In one specific implementation, the mass ratio of B, C and Pd(PPh3)2Cl2 in S2 is (120-130):(115-120):(16-17).

[0025] By adopting the above scheme, the nitro group introduction effect may be better at this mass ratio, so that the hydrogenation in S3 provides a better "polarity guidance" and the purity is greatly improved.

[0026] In one specific implementation, the mass ratio of I to LAH in S7 is (35-40):(5-7).

[0027] By adopting the above scheme, the LAH concentration is appropriate, the one-step deacetylation and amide reduction effect is good, the reducing power is not too strong and a lot of by-products are not generated, and the number of steps is reduced.

[0028] In summary, this application has the following beneficial effects: This application presents a mild and easy-to-operate reaction with high safety. The raw materials are inexpensive and readily available, the reaction process exhibits excellent stability, few side reactions, and high yield. It simplifies the process, improves economic efficiency, and reduces production difficulty, making it highly valuable for rapid laboratory iteration, mechanistic exploration, and emergency production of estrogen-regulating drugs. Detailed Implementation

[0029] To further aid in understanding the technical solution of the present invention, several specific implementation examples are provided below to describe the technical solution of the present invention in more detail. All of these described embodiments are only some embodiments of the present invention, and not all of them. The following specific embodiments can be combined with each other. The same or similar concepts or processes may not be described again in some embodiments. Unless otherwise specified, the reaction devices, monomer compounds and other materials involved in the following embodiments are commercially available.

[0030] The following examples are further illustrations of the present invention, but the present invention is not limited thereto. Example

[0031] Example 1 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0032] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0033] Yield: 87%; Purity: ≥94%.

[0034] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl2: 16.2g; Dimethyl sulfoxide (DMSO): 800 mL (solvent).

[0035] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0036] Yield: 78%; Purity: ≥92%.

[0037] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0038] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0039] Yield: 88%; Purity: ≥95%.

[0040] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0041] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0042] Yield: 88%; Purity: ≥96%.

[0043] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0044] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0045] Yield: 75%; Purity: ≥94%.

[0046] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0047] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0048] Yield: 90%; Purity: ≥97%.

[0049] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0050] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0051] Yield: 83%; Purity: ≥93%.

[0052] Example 2 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0053] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, add NaBH4 in 1 batch, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0054] Yield: 83%; Purity: ≥90%.

[0055] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl 2： 16.2g; Dimethyl sulfoxide (DMSO): 800 mL.

[0056] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0057] Yield: 77%; Purity: ≥91%.

[0058] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0059] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0060] Yield: 88%; Purity: ≥94%.

[0061] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0062] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0063] Yield: 88%; Purity: ≥95%.

[0064] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0065] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0066] Yield: 75%; Purity: ≥93%.

[0067] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0068] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0069] Yield: 90%; Purity: ≥96%.

[0070] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0071] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0072] Yield: 83%; Purity: ≥92%.

[0073] Example 3 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0074] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0075] Yield: 87%; Purity: ≥94%.

[0076] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl2: 16.2g; Dimethyl sulfoxide (DMSO): 800 mL.

[0077] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0078] Yield: 78%; Purity: ≥92%.

[0079] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0080] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0081] Yield: 88%; Purity: ≥95%.

[0082] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0083] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0084] Yield: 88%; Purity: ≥96%.

[0085] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0086] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0087] Yield: 75%; Purity: ≥94%.

[0088] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0089] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0090] Yield: 90%; Purity: ≥97%.

[0091] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0092] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0093] Yield: 83%; Purity: ≥93%.

[0094] Example 4 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0095] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0096] Yield: 87%; Purity: ≥94%.

[0097] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl2: 16.2g; Dimethyl sulfoxide (DMSO): 800 mL.

[0098] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0099] Yield: 78%; Purity: ≥92%.

[0100] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 10% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0101] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0102] Yield: 89%; Purity: ≥91%.

[0103] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0104] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0105] Yield: 88%; Purity: ≥94%.

[0106] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0107] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0108] Yield: 74%; Purity: ≥92%.

[0109] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0110] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0111] Yield: 89%; Purity: ≥95%.

[0112] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0113] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0114] Yield: 82%; Purity: ≥92%.

[0115] Example 5 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0116] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0117] Yield: 87%; Purity: ≥94%.

[0118] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl2: 16.2g; Dimethyl sulfoxide (DMSO): 800 mL.

[0119] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0120] Yield: 78%; Purity: ≥92%.

[0121] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0122] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 2 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0123] Yield: 86%; Purity: ≥93%.

[0124] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0125] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0126] Yield: 85%; Purity: ≥95%.

[0127] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0128] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0129] Yield: 73%; Purity: ≥94%.

[0130] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0131] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0132] Yield: 88%; Purity: ≥97%.

[0133] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0134] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0135] Yield: 81%; Purity: ≥92%.

[0136] Example 6 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0137] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0138] Yield: 87%; Purity: ≥94%.

[0139] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl2: 16.2g; Dimethyl sulfoxide (DMSO): 800 mL.

[0140] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0141] Yield: 78%; Purity: ≥92%.

[0142] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0143] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0144] Yield: 88%; Purity: ≥95%.

[0145] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0146] Preparation steps: Add E and F to the solvent and mix. Stir in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 4 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0147] Yield: 89%; Purity: ≥93%.

[0148] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0149] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0150] Yield: 74%; Purity: ≥93%.

[0151] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0152] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0153] Yield: 89%; Purity: ≥96%.

[0154] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0155] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0156] Yield: 82%; Purity: ≥92%.

[0157] Example 7 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0158] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0159] Yield: 87%; Purity: ≥94%.

[0160] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl2: 16.2g; Dimethyl sulfoxide (DMSO): 800 mL.

[0161] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0162] Yield: 78%; Purity: ≥92%.

[0163] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0164] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0165] Yield: 88%; Purity: ≥95%.

[0166] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0167] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0168] Yield: 88%; Purity: ≥96%.

[0169] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0170] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 10°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0171] Yield: 75%; Purity: ≥91%.

[0172] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0173] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0174] Yield: 90%; Purity: ≥95%.

[0175] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0176] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0177] Yield: 83%; Purity: ≥93%.

[0178] Example 8 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0179] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0180] Yield: 87%; Purity: ≥94%.

[0181] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 139.0g; Pd(PPh3)2Cl2: 16.2g; Dimethyl sulfoxide (DMSO): 800 mL.

[0182] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0183] Yield: 74%; Purity: ≥91%.

[0184] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0185] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0186] Yield: 88%; Purity: ≥95%.

[0187] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0188] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0189] Yield: 88%; Purity: ≥96%.

[0190] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0191] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0192] Yield: 75%; Purity: ≥94%.

[0193] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0194] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0195] Yield: 90%; Purity: ≥97%.

[0196] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0197] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0198] Yield: 83%; Purity: ≥93%.

[0199] Example 9 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0200] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0201] Yield: 87%; Purity: ≥94%.

[0202] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl2: 13.8g; Dimethyl sulfoxide (DMSO): 800 mL.

[0203] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0204] Yield: 65.1%; Purity: ≥90%.

[0205] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0206] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0207] Yield: 88%; Purity: ≥94%.

[0208] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0209] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0210] Yield: 88%; Purity: ≥96%.

[0211] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0212] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0213] Yield: 75%; Purity: ≥94%.

[0214] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0215] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0216] Yield: 90%; Purity: ≥97%.

[0217] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 12.1g; Tetrahydrofuran (THF): 800 mL.

[0218] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0219] Yield: 83%; Purity: ≥93%.

[0220] Example 10 S1: Preparation of compound B: raw material: A: 2-Naphthol: 100.0g; Bromoethyl ether (Br2·ether): 78.0 g; Sodium borohydride (NaBH4): 25.5g; p-Toluenesulfonic acid (PTSA): 1.3g; Ethanol (EtOH): 500 mL; Toluene: 500 mL.

[0221] Preparation steps: Add A to ethanol, maintain the temperature at 0°C in an ice bath, divide NaBH4 into 3 portions, add them one at a time at 10-minute intervals, react for 1.5 hours, and monitor with TLC; then raise the temperature to 25°C, add Toluene, then add EtOH and PTSA, reflux in an oil bath at 110°C to remove water for 5 hours, cool, wash the organic phase with water, dry with anhydrous Na2SO4, and distill under reduced pressure to obtain B.

[0222] Yield: 87%; Purity: ≥94%.

[0223] S2: Preparation of compound D: raw material: Product B of S1: 125.0g; o-Nitro-4-methoxybromobenzene (CAS: 99-09-2): 118.0g; Pd(PPh3)2Cl2: 16.2g; Dimethyl sulfoxide (DMSO): 800 mL.

[0224] Preparation steps: B, C, and Pd(PPh3)2Cl2 were added to DMSO and stirred at 120°C for 10 hours (the starting material disappeared as monitored by TLC). After cooling, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined and subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 8:1) to obtain D.

[0225] Yield: 78%; Purity: ≥92%.

[0226] S3: Preparation of compound E: raw material: S2 product D (biarylnitro compound): 145.0g; 5% Palladium on Carbon (Pd / C): 14.5g; Ethanol / tetrahydrofuran (EtOH / THF = 1:1): 1500 mL.

[0227] Preparation steps: Add D and 5% Pd / C to EtOH-THF mixed solvent, place in a hydrogenation reactor, stir for 14 hours at 55°C and 4 atm H2 atmosphere, filter to remove Pd / C, concentrate the filtrate under reduced pressure, and recrystallize from methanol to obtain product E.

[0228] Yield: 88%; Purity: ≥95%.

[0229] S4: Preparation of compound G: raw material: Product E (aminobiaryl compound) of S3: 116.0 g; 4-Formylbenzamide (aldehyde amide): 46.7g; Sodium borohydride (NaBH4): 12.1g; Methanol (MeOH): 1000mL.

[0230] Preparation steps: Add E and F to the solvent and mix. Stir the mixture in an ice bath at 5°C for 1 hour until the reaction solution becomes clear. Then add NaBH4 in 3 portions, 10 minutes apart each time. After reacting for 5 hours, adjust the pH to 2 with hydrochloric acid to quench the reaction. Extract with ethyl acetate and wash with saturated NaHCO3 solution until neutral to obtain G.

[0231] Yield: 88%; Purity: ≥96%.

[0232] S5: Preparation of compound H: raw material: S4 product G (racemic mixture): 112.0 g; D-Camphorsulfonic acid (D-CSA, CAS: 35839-71-5): 61.6g; Ethanol / water (EtOH / H2O = 4:1): 1200mL.

[0233] Preparation steps: G and D-camphorsulfonic acid were added to a mixed solvent and heated under reflux at 75°C for 30 minutes until completely dissolved. After complete dissolution, the mixture was kept at this temperature for 10 minutes and then cooled to 25°C in a gradient of 5°C / hour. Crystals were grown for 12 hours and then filtered to obtain a chiral salt. The chiral salt was then added to a 10wt% Na2CO3 solution to adjust the pH to 9, extracted with dichloromethane, and concentrated to obtain a chiral amine.

[0234] Yield: 75%; Purity: ≥94%.

[0235] S6: Preparation of Compound I: raw material: S5 product H (chiral amine): 72.8g; Acetic anhydride (Ac2O): 27.5g; Pyridine: 500 mL.

[0236] Preparation steps: Add H to pyridine, add Ac2O dropwise to the pyridine solution at 0°C over 30 minutes, stir at 25°C for 4 hours, quench with ice water, extract with ether, and wash away pyridine with dilute hydrochloric acid to obtain I.

[0237] Yield: 90%; Purity: ≥97%.

[0238] S7: Preparation of compound J: Raw material: S6 product I (acetylated intermediate): 76.5g; Lithium aluminum hydride (LAH): 15.0g; Tetrahydrofuran (THF): 800 mL.

[0239] Preparation steps: Add I to THF solution, then add LAH in 3 batches at 0°C under nitrogen protection, with each batch 10 minutes apart. Heat to reflux at 66°C and stir for 7 hours. Control the temperature in an ice bath, slowly add 100 mL of water under ice bath, stir for 30 minutes until no bubbles are present, filter, and concentrate to obtain product J.

[0240] Yield: 79%; Purity: ≥85%.

[0241] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A synthetic process for a drug that regulates estrogen, characterized in that: The synthesis process includes the following steps: S1: Preparation of compound B: Br2·ether, NaBH4, EtOH, PTSA, and toluene were added to A, and the mixture was heated under reflux to obtain B. S2: Preparation of compound D: B, C, and Pd(PPh3)2Cl2 were added to DMSO, and the mixture was heated and stirred to obtain D. S3: Preparation of compound E: D and Pd / C were added to an EtOH-THF mixed solvent, hydrogen gas was introduced, and the mixture was heated and stirred to obtain E. S4: Preparation of compound G: E and F were pre-condensed in a solvent, and then NaBH4 was added and the reaction was stirred to obtain G: S5: Preparation of compound H: G and the chiral resolving agent were added to a solvent, heated to dissolve, cooled, crystallized, filtered, and then Na2CO3 solution was added to adjust the pH. Extraction and concentration were then performed to obtain H. S6: Preparation of compound I: H was added to pyridine, Ac2O was added dropwise, and the reaction was stirred to obtain I: S7: Preparation of compound J: I was added to a solvent, then LAH was added, the mixture was heated under reflux with stirring, and the mixture was filtered and concentrated to obtain J.

2. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... In S1, NaBH4 is added in ≥2 portions at 0-5℃, Br2·ether and PTSA are added at 20-30℃, the heating temperature is 110-112℃, and the reflux time is 4-6 hours.

3. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... The reaction temperature in S2 is 120-125℃, the reaction time is 8-12 hours, and it also includes the following steps: cooling and quenching with ice water, and extraction with ethyl acetate.

4. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... The S3 has a Pd / C ratio of 5%, a heating temperature of 50-60℃, and an H2 pressure of 3-5 atm.

5. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... The pre-condensation temperature in S4 is 0-10℃, and NaBH4 is added in ≥2 portions; S4 also includes the following steps: hydrochloric acid is adjusted to pH 1.5-2.5 for quenching.

6. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... The chiral resolving agent in S5 is D-camphor sulfonic acid, and the temperature is gradually reduced to 20-30℃ at a rate of 3-8℃ / hour.

7. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... The S6 step involves adding Ac2O at a temperature of 0-10℃ and stirring at a temperature of 20-30℃, and also includes the following steps: quenching with ice water and extraction with ethyl acetate.

8. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... The LAH in S7 is added in ≥2 portions at 0-5℃. The heating, reflux, and stirring reaction process is carried out at a temperature of 64-68℃ for 6-8 hours. The process also includes the following steps: quenching with ice water, and simultaneously conducting an ice bath during the quenching process.

9. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... The mass ratio of B, C, and Pd(PPh3)2Cl2 in S2 is (120-130):(115-120):(16-17).

10. The synthesis process of the estrogen-regulating drug according to claim 1, characterized in that... The mass ratio of I to LAH in S7 is (35-40):(5-7).

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