High-purity alasset intermediate compound and preparation method thereof

Abstract

The invention discloses a high-purity alaraniset intermediate compound and a preparation method thereof, and belongs to the technical field of drug synthesis, the structural formula of the intermediate compound is 1, 6-benzyloxy-1-hydroxy-2-bromo-3, 4-dihydronaphthalene, the preparation method comprises the following steps: 1, reacting 6-benzyloxy-1-hydroxy-2-bromo-3, 4-dihydronaphthalene with m-methoxybenzoyl chloride to form ester, and then reacting the ester with m-methoxybenzoyl chloride to form ester; carrying out intramolecular Friedel-Crafts alkylation reaction under the catalysis of Lewis acid to form a ring; step 2, performing alkaline high-temperature hydrolysis on the product in the step 1 to remove hydroxyl into double bonds and carboxylic acid; and step 3, enabling the product obtained in the step 2 to react with DPPA, and carrying out rearrangement reaction to obtain the 7-benzyloxy-3-(4-methoxy-2-Boc aminobenzene)-1. When 1, 6-benzyloxy-1-hydroxy-2-bromine-3, 4-dihydronaphthalene provided by the invention is used as a raw material to synthesize an ilastrant intermediate, expensive noble metal catalysis is avoided, the total yield can reach 35% or above, the purity can reach 99.6%, and the product can be stably prepared through a simple process and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a high-purity intermediate compound of elacestrant and a preparation method thereof. BACKGROUND

[0002] Elacestrant is a new type of oral selective estrogen receptor degrader, which was approved by the European Commission in 2023 for the treatment of breast cancer. Specifically, it is used for the treatment of ER+, HER2- locally advanced or metastatic breast cancer patients with activated ESR1 mutation. Studies have shown that elacestrant can bind to estrogen receptor alpha, induce estrogen receptor alpha protein degradation through the proteasome pathway, and thus inhibit 17beta-estradiol-mediated cell proliferation.

[0003] In the prior art, CN117229156A discloses a preparation method of an intermediate of elacestrant, and the synthetic route is as follows: This strategy has many defects: 1) the synthetic route is long, 2) the starting material compound of formula VIII has few commercial suppliers and is expensive, with high cost, 3) in the Suzuki reaction step of the compound of formula IV and the compound of formula III, alkyl boronic acid generally exists in the form of a monomer and a trimer mixture, and it is difficult to accurately quantify; and in the reaction process, deprotonation and beta-H elimination are easily occurred, resulting in that the actual amount is much larger than the theoretical value, and the transmetalation of alkyl boronic acid ester and Pd catalyst is more difficult, which requires the use of TlOH, Tl2CO3 and other toxic bases for activation, therefore, this strategy is not suitable for industrial production.

[0004] For example, CN116969848 discloses a synthesis method of an intermediate of elacestrant. Compared with the original research process route, the synthesis route has higher yield, good product purity and shorter synthesis steps, and has good application prospect. However, the starting material 6-hydroxy-3,4-dihydro-1H-2-naphthalenone is less available.

[0005] For another example, patent CN119912339 discloses a synthesis method of an intermediate of elacestrant, and patent CN118184524 discloses a synthesis method of an intermediate of elacestrant.

[0006] The above synthesis routes for constructing C-C bonds all need to be catalyzed by noble metals, which has high cost and high requirement for equipment, and cannot meet the demand of large-scale production. Therefore, a new production process is urgently needed. SUMMARY

[0007] The application aims to provide a high-purity intermediate compound of Irasposag and a preparation method thereof, and the intermediate compound of irasposag is synthesized by taking 1, 6-benzyloxy-1-hydroxy-2-bromo-3, 4-dihydronaphthalene as a raw material, the expensive noble metal catalysis is avoided, the total yield can reach more than 35%, the purity can reach 99.6%, the product can be stably prepared through a simple process, and the technical problem is solved.

[0008] The technical scheme for solving the above technical problem is as follows: a high-purity intermediate compound of irasposag, characterized in that the structural formula of the intermediate compound is as follows: 1, 6-benzyloxy-1-hydroxy-2-bromo-3, 4-dihydronaphthalene. In the formula, R1 and R2 are methyl, benzyl, substituted benzyl, methoxy acyl, benzyloxy acyl, substituted silicon group, aryl acyl, alkyl acyl, aryl acyl sulfonic acyl, and alkyl sulfonic acyl.

[0009] A preparation method of the high-purity intermediate compound of irasposag comprises the following steps. Step 1: when R1 = benzyl and R2 = methyl; At normal temperature, 1.79 kg of formula I is added into 18 L of tetrahydrofuran, stirring is started, 2.7 kg of triethylamine is added, the temperature is lowered to 0-5 degrees, m-methoxybenzoyl chloride is added dropwise, the temperature is raised to 20-25 degrees after the addition is completed, stirring is continued until the raw material is completely converted, 17 L of water is added, the product is extracted by ethyl acetate, and the product is obtained by drying and evaporating to dryness, with a molar yield of 2.5 kg, 95%, and GC of 98.2%; Step 2: when R1 = benzyl and R2 = methyl; At normal temperature, 2.5 kg of formula II is added into 25 L of dichloromethane, stirring is started, 1.36 kg of aluminum chloride is added, the temperature is raised to reflux until the raw material is completely converted, the temperature is lowered to 10-15 degrees, the mixture is poured into ice water, and the product is obtained by evaporating to dryness from the separated organic phase, with a molar yield of 1.88 kg, 95%, and HPLC of 99.3%; Step 3: when R1 = benzyl and R2 = methyl, formula IV compound is synthesized; Formula III 1.86 kg is added into 18 L of water, 386 g of sodium hydroxide is added, the temperature is raised to 80-90 degrees, stirring is continued until the reaction is completed, hydrochloric acid is added to adjust the pH to 1-2, filtration is performed, and white solid 1.77 kg is obtained by air drying at 60 degrees, with a molar yield of 95% and HPLC of 99.6%; Step 4: when R1 = benzyl and R2 = methyl, formula VI compound is synthesized when R is a tert-butyl group; 1.65 kg of Formula IV was added to 16.5 L of tert-butanol, 695 g of triethylamine, and 1.51 kg of DPPA. The mixture was heated to 80-90 °C and stirred until the reaction was complete. The mixture was then hot-filtered, the mother liquor was evaporated to dryness, and the product was obtained by slurrying with alkaline water. After air drying, 1.93 kg of an off-white solid was obtained. The molar yield was 92%, and the HPLC yield was 99.6%. Steps 5 to 6: Synthesis of compounds with R1 = benzyl and R2 = methyl (form VIII); 1.51 kg of Formula III was added to 15 L of methanol, purged with nitrogen, palladium on carbon was added, purged with hydrogen, and hydrogenated at 30°C under normal pressure until the raw material was completely converted. The palladium on carbon was removed by filtration, and hydrochloric acid was introduced until deprotection was complete. The mixture was cooled to 0-5°C and filtered to obtain the product hydrochloride. After free separation, 1.44 kg of the target product was obtained. The molar yield was 95%, and the HPLC yield was 99.6%. In step 1, 6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene reacts with m-methoxybenzoyl chloride to form an ester, which then undergoes an intramolecular Friedel-Crafts alkylation reaction to form a cyclization under Lewis acid catalysis. Step 2: The product from Step 1 is subjected to alkaline high-temperature hydrolysis to dehydroxylate the hydroxyl groups into double bonds and carboxylic acids; Step 3, the product of step 2 and DPPA reacted and rearranged to give 7-benzyloxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene; Step 4 and the product of step 3 are then reduced with hydrogen to obtain 7-hydroxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene. Step 5 and Step 4 products are acid-protected to obtain the target product, the ellaxis group intermediate (Formula VIII), wherein the compound of Formula VIII can be resolved in one step to obtain the key intermediate of the target ellaxis group.

[0010] Preferably, the compound of formula I reacts with m-methoxybenzoyl chloride under tertiary amine conditions in an organic solvent, wherein the tertiary amine is an organic base, or triethylamine, and the molar ratio of the base to the compound of formula I is 1-1.5:1, or 1.2:1.

[0011] Preferably, the alcohol is a C1-C6 alkyl alcohol, or ethylene glycol, and the molar ratio of the alcohol to the compound of formula I is 1-1.5:1, or 1.2:1. The organic solvent is an aprotic solvent, or tetrahydrofuran, and the volume ratio of the organic solvent to the compound of formula I is 2-5:1, or 3:1.

[0012] Preferably, the compound of formula II is cyclized in an inert solvent by Lewis acid catalysis to obtain the target product of formula III. The Lewis acid includes aluminum salts and iron salts such as aluminum trichloride, boron salts such as aluminum tribromide, boron trifluoride, and ferric tribromide, and may also be aluminum trichloride. The molar ratio of the organolithium to the compound of formula II is 1 to 3:1, and may also be 1.05:1.

[0013] Preferably, the inert solvent is a chlorinated hydrocarbon solvent, or it can be dichloromethane, and the volume ratio of the organic solvent to the compound of formula II is 3~8:1, or it can be 5:1.

[0014] Preferably, the compound of formula III undergoes ring-opening dehydration under alkaline conditions to obtain the target product of formula IV. The alkaline is an inorganic alkaline, and may also be sodium hydroxide. The molar ratio of the alkaline to the compound of formula I is 1-1.5:1, and may also be 1.2:1.

[0015] Preferably, the compound of formula IV reacts with DPPA in an organic alcohol under alkaline conditions to obtain the target product of formula V. The base is an organic base, which can also be triethylamine. The molar ratio of the base to the compound of formula IV is 1-3:1, which can also be 1.5:1. The organic alcohol is an organic alcohol, which can also be tert-butanol. The volume ratio of the alcohol to the compound of formula I is 2-10:1, which can also be 5:1.

[0016] Preferably, the target compound of formula VI is obtained by hydrogenation reduction of compound V in an organic solvent. The organic solvent includes a protic solvent, and may also be methanol. The volume ratio of the protic solvent to compound V is 2 to 10:1, and may also be 5:1.

[0017] Preferably, compound VI is deacidified in an organic solvent to obtain the target compound XII, wherein compound XII can be resolved in one step to obtain the alasin group intermediate XII.

[0018] The beneficial effects of this invention are: using 1,6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene as a raw material to synthesize the intermediate of alastraline avoids expensive noble metal catalysis, the total yield can reach more than 35%, the purity can reach 99.6%, and the product can be stably prepared by a simple process, which is suitable for industrial production. Attached Figure Description

[0019] The advantages of the present invention, both above and / or other aspects, will become clearer and more readily understood through the following detailed description taken in conjunction with the accompanying drawings, which are merely illustrative and do not limit the invention, wherein: Figure 1 This is the NMR spectrum of a compound of formula II in this invention; Figure 2 This is a liquid phase spectrum of a compound of formula II in this invention; Figure 3 This is the NMR spectrum of a compound of Formula I in one embodiment of the present invention; Figure 4 This is a liquid phase spectrum of a compound of formula I in an embodiment of the present invention; Figure 5 The NMR spectrum of a compound of Formula II in this invention. Figure 6 This is a liquid phase spectrum of a compound of formula II in this invention; Figure 7 This is the NMR spectrum of a compound of Formula I in one embodiment of the present invention; Figure 8 This is the NMR spectrum of a compound of Formula I in an embodiment of the present invention. Detailed Implementation

[0020] In the following description, an embodiment of a high-purity alasin intermediate compound and its preparation method according to the present invention will be described with reference to the accompanying drawings.

[0021] The embodiments described herein are specific implementations of the present invention, used to illustrate the concept of the invention, and are illustrative and exemplary, and should not be construed as limiting the implementation or scope of the invention. In addition to the embodiments described herein, those skilled in the art can employ other obvious technical solutions based on the content disclosed in the claims and specification of this application. These technical solutions include those that make any obvious substitutions and modifications to the embodiments described herein.

[0022] Appendix to this instruction manual Figures 1-8 The figures are schematic diagrams to illustrate the concept of the invention, showing the shapes of the various parts and their interrelationships. Please note that, to clearly demonstrate the structure of the components in the embodiments of the invention, the figures are not drawn to the same scale. The same reference numerals are used to denote the same parts.

[0023] Example 1: A high-purity alasin intermediate compound comprising: 1, 6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene, the structural formula of which is: Wherein, R1 and R2 are methyl, benzyl, substituted benzyl, methoxyyl, benzyloxyyl, substituted silyl, aromatic acyl, alkyl acyl, aromatic sulfonyl, and alkyl sulfonyl.

[0024] A method for preparing a high-purity alasin intermediate compound includes the following steps, and its structural formula is as follows: Step 1: When R1 = benzyl, R2 = methyl At room temperature, 1.79 kg of Formula I was added to 18 L of tetrahydrofuran, and stirring was started. 2.7 kg of triethylamine was added, the temperature was lowered to 1 degree, and m-methoxybenzoyl chloride was added dropwise. After completion, the temperature was raised to 20 degrees and stirred until the raw material was completely converted. 17 L of water was added, and the product was extracted with ethyl acetate. The product was dried and evaporated to dryness to obtain 2.5 kg of product. Molar yield: 95%, GC: 98.2%. Step 2: When R1 = benzyl and R2 = methyl; At room temperature, 2.5 kg of Formula II was added to 25 L of dichloromethane, and stirring was started. 1.36 kg of aluminum trichloride was added, and the mixture was heated to reflux until the starting material was completely converted. The mixture was then cooled to 10 degrees Celsius, rinsed with ice water, and the organic phases were evaporated to dryness to obtain 1.88 kg of the product. Molar yield: 95%, HPLC: 99.3%. Step 3: Synthesis of compound IV when R1 = benzyl and R2 = methyl; 1.86 kg of Formula III was added to 18 L of water, along with 386 g of sodium hydroxide. The mixture was heated to 80 °C and stirred until complete. Hydrochloric acid was added to adjust the pH to 1. The mixture was filtered and dried under blast air at 60 °C to obtain 1.77 kg of an off-white solid. Molar yield: 95%, HPLC: 99.6%. Step 4: When R1 = benzyl and R2 = methyl, and R is tert-butyl, compound VI is synthesized; 1.65 kg of Formula IV was added to 16.5 L of tert-butanol, 695 g of triethylamine, and 1.51 kg of DPPA. The mixture was heated to 80 °C and stirred until the reaction was complete. The mixture was then hot-filtered, the mother liquor was evaporated to dryness, and the product was obtained by slurrying with alkaline water. The product was then air-dried to obtain 1.93 kg of an off-white solid. The molar yield was 92%, and the HPLC yield was 99.6%. Steps 5 to 6: Synthesis of compounds with R1 = benzyl and R2 = methyl (form VIII); 1.51 kg of Formula III was added to 15 L of methanol, purged with nitrogen, and then palladium on carbon was added and purged with hydrogen. The mixture was hydrogenated at 30°C under normal pressure until the raw material was completely converted. The palladium on carbon was removed by filtration, and hydrochloric acid was introduced until deprotection was complete. The mixture was cooled to 1°C and filtered to obtain the product hydrochloride. After free separation, 1.44 kg of the target product was obtained. The molar yield was 95%, and the HPLC yield was 99.6%. The structure is as follows: In step 1, 6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene reacts with m-methoxybenzoyl chloride to form an ester, which then undergoes an intramolecular Friedel-Crafts alkylation reaction to form a cyclization under Lewis acid catalysis. Step 2: The product from Step 1 is subjected to alkaline high-temperature hydrolysis to dehydroxylate the hydroxyl groups into double bonds and carboxylic acids; Step 3, the product of step 2 and DPPA reacted and rearranged to give 7-benzyloxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene; Step 4 and the product of step 3 are then reduced with hydrogen to obtain 7-hydroxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene. Step 5 and Step 4 products are acid-protected to obtain the target product, the ellaxis group intermediate (Formula VIII), wherein the compound of Formula VIII can be resolved in one step to obtain the key intermediate of the target ellaxis group.

[0025] The compound of Formula I reacts with m-methoxybenzoyl chloride under tertiary amine conditions in an organic solvent, wherein the tertiary amine is an organic base, and may also be triethylamine, and the molar ratio of the base to the compound of Formula I is 1:1, or may be 1.2:1.

[0026] The alcohol is a C1-C6 alkyl alcohol, and may also be ethylene glycol. The molar ratio of the alcohol to the compound of formula I is 1:1, or may be 1.2:1. The organic solvent is an aprotic solvent, or may be tetrahydrofuran. The volume ratio of the organic solvent to the compound of formula I is 2:1, or may be 3:1.

[0027] Compound II is cyclized in an inert solvent via Lewis acid catalysis to obtain the target product, Formula III. The Lewis acid includes aluminum and iron salts such as aluminum trichloride, boron salts such as aluminum tribromide, boron trifluoride, and ferric tribromide, and may also be aluminum trichloride. The molar ratio of the organolithium to compound II is 1:1, or may be 1.05:1.

[0028] The inert solvent is a chlorinated hydrocarbon solvent, or it can be dichloromethane. The volume ratio of the organic solvent to the compound of formula II is 3:1, or it can be 5:1.

[0029] Compound III is subjected to ring-opening dehydration under alkaline conditions to obtain the target product, Formula IV. The alkaline is an inorganic base, or sodium hydroxide. The molar ratio of the base to compound I is 1:1, or 1.2:1.

[0030] Compound IV reacts with DPPA in an organic alcohol under alkaline conditions to give the target product, Formula V. The base is an organic base, which can also be triethylamine. The molar ratio of the base to compound IV is 1:1, which can also be 1.5:1. The alcohol is an organic alcohol, which can also be tert-butanol. The volume ratio of the alcohol to compound I is 2:1, which can also be 5:1.

[0031] Compound V is hydrogenated and reduced in an organic solvent to obtain the target compound VI. The organic solvent includes a protic solvent, and may also be methanol. The volume ratio of the protic solvent to compound V is 2:1, or may be 5:1.

[0032] Compound VI was deacidified in an organic solvent to obtain the target compound XII, wherein compound XII can be resolved in one step to obtain the intermediate XII of the alas group.

[0033] Example 2 A method for preparing a high-purity alasin intermediate compound includes the following steps, and its structural formula is as follows: Step 1: When R1 = benzyl, R2 = methyl At room temperature, 1.79 kg of Formula I was added to 18 L of tetrahydrofuran, and stirring was started. 2.7 kg of triethylamine was added, the temperature was lowered to 2 degrees Celsius, and m-methoxybenzoyl chloride was added dropwise. After completion, the temperature was raised to 30 degrees Celsius and stirred until the raw material was completely converted. 17 L of water was added, and the product was extracted with ethyl acetate. The product was dried and evaporated to dryness to obtain 2.5 kg of product. Molar yield: 95%, GC: 98.2%. Step 2: When R1 = benzyl and R2 = methyl; At room temperature, 2.5 kg of Formula II was added to 25 L of dichloromethane, and stirring was started. 1.36 kg of aluminum trichloride was added, and the mixture was heated to reflux until the starting material was completely converted. The mixture was then cooled to 20 degrees Celsius, rinsed with ice water, and the organic phases were evaporated to dryness to obtain 1.88 kg of the product. Molar yield: 95%, HPLC: 99.3%. Step 3: Synthesis of compound IV when R1 = benzyl and R2 = methyl; 1.86 kg of Formula III was added to 18 L of water, along with 386 g of sodium hydroxide. The mixture was heated to 80 °C and stirred until complete. Hydrochloric acid was added to adjust the pH to 1. The mixture was filtered and dried under blast air at 60 °C to obtain 1.77 kg of an off-white solid. Molar yield: 95%, HPLC: 99.6%. Step 4: When R1 = benzyl and R2 = methyl, and R is tert-butyl, compound VI is synthesized; 1.65 kg of Formula IV was added to 16.5 L of tert-butanol, 695 g of triethylamine, and 1.51 kg of DPPA. The mixture was heated to 90 °C and stirred until the reaction was complete. The mixture was then hot-filtered, the mother liquor was evaporated to dryness, and the product was obtained by slurrying with alkaline water. The product was then air-dried to obtain 1.93 kg of an off-white solid. The molar yield was 92%, and the HPLC yield was 99.6%. Steps 5 to 6: Synthesis of compounds with R1 = benzyl and R2 = methyl (form VIII); 1.51 kg of Formula III was added to 15 L of methanol, purged with nitrogen, palladium on carbon was added, purged with hydrogen, and hydrogenated at 30°C under normal pressure until the raw material was completely converted. The palladium on carbon was removed by filtration, and hydrochloric acid was introduced until deprotection was complete. The mixture was cooled to 2°C and filtered to obtain the product hydrochloride. After free separation, 1.44 kg of the target product was obtained. The molar yield was 95%, and the HPLC yield was 99.6%. The structure is as follows: In step 1, 6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene reacts with m-methoxybenzoyl chloride to form an ester, which then undergoes an intramolecular Friedel-Crafts alkylation reaction to form a cyclization under Lewis acid catalysis. Step 2: The product from Step 1 is subjected to alkaline high-temperature hydrolysis to dehydroxylate the hydroxyl groups into double bonds and carboxylic acids; Step 3, the product of step 2 and DPPA reacted and rearranged to give 7-benzyloxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene; Step 4 and the product of step 3 are then reduced with hydrogen to obtain 7-hydroxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene. Step 5 and Step 4 products are acid-protected to obtain the target product, the ellaxis group intermediate (Formula VIII), wherein the compound of Formula VIII can be resolved in one step to obtain the key intermediate of the target ellaxis group.

[0034] The compound of Formula I reacts with m-methoxybenzoyl chloride under tertiary amine conditions in an organic solvent, wherein the tertiary amine is an organic base, and may also be triethylamine, and the molar ratio of the base to the compound of Formula I is 1.1:1, or may also be 1.2:1.

[0035] The alcohol is a C1-C6 alkyl alcohol, and may also be ethylene glycol. The molar ratio of the alcohol to the compound of formula I is 1.1:1, and may also be 1.2:1. The organic solvent is an aprotic solvent, and may also be tetrahydrofuran. The volume ratio of the organic solvent to the compound of formula I is 3:1, and may also be 3:1.

[0036] Compound II is cyclized in an inert solvent via Lewis acid catalysis to obtain the target product, Formula III. The Lewis acid includes aluminum and iron salts such as aluminum trichloride, boron salts such as aluminum tribromide, boron trifluoride, and ferric tribromide, and may also be aluminum trichloride. The molar ratio of the organolithium to compound II is 1.1:1, and may also be 1.05:1.

[0037] The inert solvent is a chlorinated hydrocarbon solvent, or it can be dichloromethane. The volume ratio of the organic solvent to the compound of formula II is 4:1, or it can be 5:1.

[0038] Compound III is subjected to ring-opening dehydration under alkaline conditions to obtain the target product, Formula IV. The alkaline is an inorganic base, or sodium hydroxide. The molar ratio of the base to compound I is 1.1:1, or 1.2:1.

[0039] Compound IV reacts with DPPA in an organic alcohol under alkaline conditions to give the target product, Formula V. The base is an organic base, which may also be triethylamine. The molar ratio of the base to compound IV is 1.1:1, which may also be 1.5:1. The alcohol is an organic alcohol, which may also be tert-butanol. The volume ratio of the alcohol to compound I is 3:1, which may also be 5:1.

[0040] Compound V is hydrogenated and reduced in an organic solvent to obtain the target compound VI. The organic solvent includes a protic solvent, and may also be methanol. The volume ratio of the protic solvent to compound V is 3:1, or may be 5:1.

[0041] Compound VI was deacidified in an organic solvent to obtain the target compound XII, wherein compound XII can be resolved in one step to obtain the intermediate XII of the alas group.

[0042] Example 3 A method for preparing a high-purity alasin intermediate compound includes the following steps, and its structural formula is as follows: Step 1: When R1 = benzyl, R2 = methyl At room temperature, 1.79 kg of Formula I was added to 18 L of tetrahydrofuran, and stirring was started. 2.7 kg of triethylamine was added, the temperature was lowered to 3 degrees Celsius, and m-methoxybenzoyl chloride was added dropwise. After completion, the temperature was raised to 30 degrees Celsius and stirred until the raw material was completely converted. 17 L of water was added, and the product was extracted with ethyl acetate. The product was dried and evaporated to dryness to obtain 2.5 kg of product. Molar yield: 95%, GC: 98.2%. Step 2: When R1 = benzyl and R2 = methyl; At room temperature, 2.5 kg of Formula II was added to 25 L of dichloromethane, and stirring was started. 1.36 kg of aluminum trichloride was added, and the mixture was heated to reflux until the starting material was completely converted. The mixture was then cooled to 10 degrees Celsius, rinsed with ice water, and the organic phases were evaporated to dryness to obtain 1.88 kg of the product. Molar yield: 95%, HPLC: 99.3%. Step 3: Synthesis of compound IV when R1 = benzyl and R2 = methyl; 1.86 kg of Formula III was added to 18 L of water, along with 386 g of sodium hydroxide. The mixture was heated to 80 °C and stirred until complete. Hydrochloric acid was added to adjust the pH to 1. The mixture was filtered and dried under blast air at 60 °C to obtain 1.77 kg of an off-white solid. Molar yield: 95%, HPLC: 99.6%. Step 4: When R1 = benzyl and R2 = methyl, and R is tert-butyl, compound VI is synthesized; 1.65 kg of Formula IV was added to 16.5 L of tert-butanol, 695 g of triethylamine, and 1.51 kg of DPPA. The mixture was heated to 85 °C and stirred until the reaction was complete. The mixture was then hot-filtered, the mother liquor was evaporated to dryness, and the product was obtained by slurrying with alkaline water. The product was then air-dried to obtain 1.93 kg of an off-white solid. The molar yield was 92%, and the HPLC yield was 99.6%. Steps 5 to 6: Synthesis of compounds with R1 = benzyl and R2 = methyl (form VIII); 1.51 kg of Formula III was added to 15 L of methanol, purged with nitrogen, palladium on carbon was added, purged with hydrogen, and hydrogenated at 25°C under normal pressure until the raw material was completely converted. The palladium on carbon was removed by filtration, and hydrochloric acid was introduced until deprotection was complete. The mixture was cooled to 3°C and filtered to obtain the product hydrochloride. After free separation, 1.44 kg of the target product was obtained. The molar yield was 95%, and the HPLC yield was 99.6%. The structure is as follows: In step 1, 6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene reacts with m-methoxybenzoyl chloride to form an ester, which then undergoes an intramolecular Friedel-Crafts alkylation reaction to form a cyclization under Lewis acid catalysis. Step 2: The product from Step 1 is subjected to alkaline high-temperature hydrolysis to dehydroxylate the hydroxyl groups into double bonds and carboxylic acids; Step 3, the product of step 2 and DPPA reacted and rearranged to give 7-benzyloxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene; Step 4 and the product of step 3 are then reduced with hydrogen to obtain 7-hydroxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene. Step 5 and Step 4 products are acid-protected to obtain the target product, the ellaxis group intermediate (Formula VIII), wherein the compound of Formula VIII can be resolved in one step to obtain the key intermediate of the target ellaxis group.

[0043] The compound of Formula I reacts with m-methoxybenzoyl chloride under tertiary amine conditions in an organic solvent, wherein the tertiary amine is an organic base, and may also be triethylamine, and the molar ratio of the base to the compound of Formula I is 1.4:1, or may also be 1.2:1.

[0044] The alcohol is a C1-C6 alkyl alcohol, and may also be ethylene glycol. The molar ratio of the alcohol to the compound of formula I is 1.4:1, and may also be 1.2:1. The organic solvent is an aprotic solvent, and may also be tetrahydrofuran. The volume ratio of the organic solvent to the compound of formula I is 2.5:1, and may also be 3:1.

[0045] Compound II is cyclized in an inert solvent via Lewis acid catalysis to obtain the target product, Formula III. The Lewis acid includes aluminum and iron salts such as aluminum trichloride, boron salts such as aluminum tribromide, boron trifluoride, and ferric tribromide, and may also be aluminum trichloride. The molar ratio of the organolithium to compound II is 1.04:1, and may also be 1.05:1.

[0046] The inert solvent is a chlorinated hydrocarbon solvent, or it can be dichloromethane. The volume ratio of the organic solvent to the compound of formula II is 4:1, or it can be 5:1.

[0047] Compound III is subjected to ring-opening dehydration under alkaline conditions to obtain the target product, Formula IV. The alkaline is an inorganic base, or sodium hydroxide. The molar ratio of the base to compound I is 1.14:1, or 1.2:1.

[0048] Compound IV reacts with DPPA in an organic alcohol under alkaline conditions to give the target product, Formula V. The base is an organic base, which may also be triethylamine. The molar ratio of the base to compound IV is 1:1, which may also be 1.5:1. The alcohol is an organic alcohol, which may also be tert-butanol. The volume ratio of the alcohol to compound I is 1.6:1, which may also be 5:1.

[0049] Compound V is hydrogenated and reduced in an organic solvent to obtain the target compound VI. The organic solvent includes a protic solvent, and may also be methanol. The volume ratio of the protic solvent to compound V is 4:1, or may be 5:1.

[0050] Compound VI was deacidified in an organic solvent to obtain the target compound XII, wherein compound XII can be resolved in one step to obtain the intermediate XII of the alas group.

[0051] In summary, this high-purity alasin intermediate compound and its preparation method, using 1,6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene as the raw material, synthesizes the alasin intermediate, avoiding expensive noble metal catalysis. The total yield can reach over 35%, and the purity can reach 99.6%. The product can be stably prepared through a simple process, making it suitable for industrial production.

[0052] The technical features disclosed above are not limited to the combinations of the disclosed features with other features. Those skilled in the art can also make other combinations of the technical features according to the purpose of the invention to achieve the purpose of the invention.

Claims

1. A high-purity alasin intermediate compound, characterized in that, Including 1,6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene.

2. A method for preparing a high-purity alasin intermediate compound, characterized in that, The preparation steps are as follows: Step 1: When R1 = benzyl and R2 = methyl; At room temperature, 1.79 kg of Formula I was added to 18 L of tetrahydrofuran, and stirring was started. 2.7 kg of triethylamine was added, the temperature was lowered to 0-5 degrees Celsius, and m-methoxybenzoyl chloride was added dropwise. After completion, the temperature was raised to 20-25 degrees Celsius and stirred until the raw material was completely converted. 17 L of water was added, and the product was extracted with ethyl acetate. The product was dried and evaporated to dryness to obtain 2.5 kg of product. Molar yield: 95%, GC: 98.2%. Step 2: When R1 = benzyl and R2 = methyl; At room temperature, 2.5 kg of Formula II was added to 25 L of dichloromethane, and stirring was started. 1.36 kg of aluminum trichloride was added, and the mixture was heated to reflux until the starting material was completely converted. The mixture was then cooled to 10-15 degrees Celsius, rinsed with ice water, and the organic phases were evaporated to dryness to obtain 1.88 kg of the product. Molar yield: 95%, HPLC: 99.3%. Step 3: Synthesis of compound IV when R1 = benzyl and R2 = methyl; 1.86 kg of Formula III was added to 18 L of water, along with 386 g of sodium hydroxide. The mixture was heated to 80-90 °C and stirred until complete. Hydrochloric acid was added to adjust the pH to 1-2. The mixture was filtered and dried under blast air at 60 °C to obtain 1.77 kg of an off-white solid. The molar yield was 95%, and the HPLC yield was 99.6%. Step 4: When R1 = benzyl and R2 = methyl, and R is tert-butyl, compound VI is synthesized; 1.65 kg of Formula IV was added to 16.5 L of tert-butanol, 695 g of triethylamine, and 1.51 kg of DPPA. The mixture was heated to 80-90 °C and stirred until the reaction was complete. The mixture was then hot-filtered, the mother liquor was evaporated to dryness, and the product was obtained by slurrying with alkaline water. After air drying, 1.93 kg of an off-white solid was obtained. The molar yield was 92%, and the HPLC yield was 99.6%. Steps 5 to 6: Synthesis of compounds with R1 = benzyl and R2 = methyl (form VIII); 1.51 kg of Formula III was added to 15 L of methanol, purged with nitrogen, palladium on carbon was added, purged with hydrogen, and hydrogenated at 30°C under normal pressure until the raw material was completely converted. The palladium on carbon was removed by filtration, and hydrochloric acid was introduced until deprotection was complete. The mixture was cooled to 0-5°C and filtered to obtain the product hydrochloride. After free separation, 1.44 kg of the target product was obtained. The molar yield was 95%, and the HPLC yield was 99.6%. In step 1, 6-benzyloxy-1-hydroxy-2-bromo-3,4-dihydronaphthalene reacts with m-methoxybenzoyl chloride to form an ester, which then undergoes an intramolecular Friedel-Crafts alkylation reaction to form a cyclization under Lewis acid catalysis. Step 2: The product from Step 1 is subjected to alkaline high-temperature hydrolysis to dehydroxylate the hydroxyl groups into double bonds and carboxylic acids; Step 3, the product of step 2 and DPPA reacted and rearranged to give 7-benzyloxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene; Step 4 and the product of step 3 are then reduced with hydrogen to obtain 7-hydroxy-3-(4-methoxy-2-Bocaminobenzene)-1,2-dihydronaphthalene. Step 5 and Step 4 products are acid-protected to obtain the target product, the ellaxis group intermediate (Formula VIII), wherein the compound of Formula VIII can be resolved in one step to obtain the key intermediate of the target ellaxis group.

3. The method for preparing a high-purity alasin intermediate compound according to claim 2, characterized in that, The compound of Formula I reacts with m-methoxybenzoyl chloride under tertiary amine conditions in an organic solvent, wherein the tertiary amine is an organic base, and may also be triethylamine, and the molar ratio of the base to the compound of Formula I is 1-1.5:1, and may also be 1.2:

1.

4. The method for preparing a high-purity alasin intermediate compound according to claim 3, characterized in that, The alcohol is a C1-C6 alkyl alcohol, and may also be ethylene glycol. The molar ratio of the alcohol to the compound of formula I is 1-1.5:1, and may also be 1.2:

1. The organic solvent is an aprotic solvent, and may also be tetrahydrofuran. The volume ratio of the organic solvent to the compound of formula I is 2-5:1, and may also be 3:

1.

5. The method for preparing a high-purity alasin intermediate compound according to claim 4, characterized in that, Compound II is cyclized in an inert solvent via Lewis acid catalysis to obtain the target product, Formula III. The Lewis acid includes aluminum and iron salts such as aluminum trichloride, boron salts such as aluminum tribromide, boron trifluoride, and ferric tribromide, and may also be aluminum trichloride. The molar ratio of the organolithium to compound II is 1 to 3:1, and may also be 1.05:

1.

6. The method for preparing a high-purity alasin intermediate compound according to claim 5, characterized in that, The inert solvent is a chlorinated hydrocarbon solvent, or it can be dichloromethane. The volume ratio of the organic solvent to the compound of formula II is 3~8:1, or it can be 5:

1.

7. The method for preparing a high-purity alasin intermediate compound according to claim 6, characterized in that, Compound III is subjected to ring-opening dehydration under alkaline conditions to obtain the target product, Formula IV. The alkaline is an inorganic base, or sodium hydroxide. The molar ratio of the base to compound I is 1-1.5:1, or 1.2:

1.

8. The method for preparing a high-purity alasin intermediate compound according to claim 7, characterized in that, Compound IV reacts with DPPA in an organic alcohol under alkaline conditions to yield the target product, Formula V. The base is an organic base, and may also be triethylamine. The molar ratio of the base to compound IV is 1-3:1, and may also be 1.5:

1. The alcohol is an organic alcohol, and may also be tert-butanol. The volume ratio of the alcohol to compound I is 2-10:1, and may also be 5:

1.

9. The method for preparing a high-purity alasin intermediate compound according to claim 8, characterized in that, Compound V is hydrogenated and reduced in an organic solvent to obtain the target compound VI. The organic solvent includes a protic solvent, and may also be methanol. The volume ratio of the protic solvent to compound V is 2 to 10:1, and may also be 5:

1.

10. The method for preparing a high-purity alasin intermediate compound according to claim 9, characterized in that, Compound VI was deacidified in an organic solvent to obtain the target compound XII, wherein compound XII can be resolved in one step to obtain the intermediate XII of the alas group.

Images