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CN-122010758-A - Method for preparing key intermediate of ilalastine

CN122010758ACN 122010758 ACN122010758 ACN 122010758ACN-122010758-A

Abstract

The invention discloses a method for preparing a key intermediate of a medicine ilalastine. The method takes 6-bromo-7, 8-dihydronaphthalene-2-ol as a raw material, and prepares the N- (2- (6-hydroxy-1, 2,3, 4-tetrahydronaphthalene-2-yl) -5-methoxyphenyl) acetamide serving as an intermediate of the ilast through four-step reactions of etherification, coupling, nickel catalytic hydrogenation and ether bond cleavage. The method avoids using expensive palladium metal catalyst, reduces the hydrogenation cost and has the characteristics of high yield and convenient post-treatment by adopting the trityl etherification of 2-alcohol and Raney nickel catalytic hydrogenation. The invention has large-scale application prospect.

Inventors

  • TANG JIE
  • SHAN YIFAN
  • ZOU GANG

Assignees

  • 上海格苓凯生物科技有限公司

Dates

Publication Date
20260512
Application Date
20251231

Claims (10)

  1. 1. A method for preparing a key intermediate N- (2- (6-hydroxy-1, 2,3, 4-tetrahydronaphthalene-2-yl) -5-methoxyphenyl) acetamide of ilalastine is characterized in that 6-bromo-7, 8-dihydronaphthalene-2-ol is used as a raw material, and the key intermediate N- (2- (6-hydroxy-1, 2,3, 4-tetrahydronaphthalene-2-yl) -5-methoxyphenyl) acetamide of ilalastine is prepared through the steps of trityl etherification, coupling, nickel catalytic hydrogenation and ether bond cleavage reaction of 2-hydroxy, and the synthetic route of the method is as follows: ; wherein Tr is trityl.
  2. 2. The method according to claim 1, characterized in that it comprises the steps of: (1) Etherification, namely dissolving a compound (6-bromo-7, 8-dihydronaphthalene-2-ol) in a first solvent, adding trityl chloride and organic base, and carrying out etherification reaction to obtain a compound (2), wherein the reaction process is shown as a reaction formula (A): ; Reactive (A) (2) The coupling reaction is carried out by dissolving compound in formula (2) in second solvent, adding potassium carbonate, 2-acetamido-5-methoxy phenylboronic acid pinacol ester and catalyst, coupling reacting to obtain compound in formula (3), and reacting with formula (B): ; Reactive (B) (3) The hydrogenation reaction is carried out by dissolving the compound of formula (3) in a third solvent, adding into catalyst, and hydrogenation reacting to obtain the compound of formula (4), wherein the reaction process is shown as reaction formula (C): ; Reactive (C) (4) Ether bond cleavage, namely dissolving the compound shown in the formula (4) in a fourth solvent, adding lithium chloride, and performing ether bond cleavage reaction to obtain the compound shown in the formula (5), wherein the reaction process is shown in the reaction formula (D): ; Formula (D).
  3. 3. The method according to claim 2, wherein in the step (1), the weight ratio of the compound of formula (1), trityl chloride and organic base is 1:0.5-2:0.5-2, and or the organic base comprises any one or more of triethylamine, pyridine and trimethylpyridine, and or the first solvent comprises any one or two of dichloromethane and acetonitrile.
  4. 4. The method according to claim 2, wherein in the step (1), the etherification reaction is carried out at a temperature of 10 to 100 ℃ and/or the etherification reaction is carried out for a time of 1 to 12 hours.
  5. 5. The method according to claim 2, wherein in the step (2), the weight ratio of the compound of formula (2), potassium carbonate, 2-acetamido-5-methoxyphenylboronic acid pinacol ester and the catalyst is 1:0.3-2:0.3-2:0.01-0.05, and/or the catalyst comprises any one or two of PdCl 2 (PPh 3 ) 2 ,Pd(PPh 3 ) 4 , and/or the second solvent comprises one or two of dioxane and tetrahydrofuran.
  6. 6. The method according to claim 2, wherein in the step (2), the coupling reaction is performed at a temperature of 50 to 100 ℃ and/or the coupling reaction is performed for a time of 2 to 12 hours.
  7. 7. The method according to claim 2, wherein in the step (3), the weight ratio of the compound of formula (3) to the catalyst is 1:0.05-0.10, and/or the catalyst comprises any one or more of Raney nickel, palladium on carbon and palladium hydroxide, and/or the third solvent comprises any one or more of methanol, ethanol and isopropanol.
  8. 8. The method according to claim 2, wherein in the step (3), the temperature of the hydrogenation reaction is 25-100 ℃, and/or the time of the hydrogenation reaction is 12-48 hours.
  9. 9. The method according to claim 2, wherein in the step (4), the weight ratio of the compound of formula (4) to lithium chloride is 1:0.1-5, and/or the fourth solvent comprises one or two of methanol, ethanol and isopropanol.
  10. 10. The method according to claim 2, wherein in the step (4), the temperature of the ether bond cleavage reaction is 25 to 100 ℃, and/or the time of the ether bond cleavage reaction is 12 to 48 hours.

Description

Method for preparing key intermediate of ilalastine Technical Field The invention belongs to the technical field of organic synthetic chemistry. In particular to a method for preparing a key intermediate of ilalastine. Background Ilast (ELACESTRANT) is a novel oral selective estrogen receptor degrading agent which can be combined with estrogen receptor alpha, induces the degradation of estrogen receptor alpha protein through a proteasome pathway and inhibits 17 beta-estradiol mediated cell proliferation. The European Union committee of 2023 approved (ilalastst ELACESTRANT) for the treatment of ER+, HER 2-locally advanced or metastatic breast cancer patients with an activating ESR1 mutation. The structural formula of the ilast is shown as a formula I. I is a kind of The invention relates to an intermediate N- (2- (6-hydroxy-1, 2,3, 4-tetrahydronaphthalene-2-yl) -5-methoxyphenyl) acetamide of ilast, which is a key intermediate for synthesizing ilast, and has the structure shown in the following formula II: II (II) The original research process of ilalastine is reported by patent document CN113348163a, wherein the synthetic route of the compound of formula (5) is shown in formula III below: Formula III The patent document uses benzyl protected alkenyl bromine to carry out boronization and coupling, and then adopts palladium hydroxide to carry out catalytic hydrogenation to obtain an intermediate compound of the formula (5). The presence of benzyl groups increases the amount of palladium hydroxide used as a metal catalyst, thereby increasing the safety risk and the cost of use of the reaction. Patent document WO2004058682A1 discloses a method for synthesis of ilalastine, wherein the synthesis of the compound of formula (5) is shown in formula IV below: IV (IV) This patent document provides a compound of formula (5) by introducing a nitro group, simultaneously removing a benzyl group by hydrogenation, reducing a double bond, and reducing the nitro group. This route also presents a significant palladium on carbon and safety risk problem. How to avoid or reduce the dosage of the palladium catalyst is of great significance to the mass production. The modification of the phenolic hydroxyl group on the naphthalene ring plays a significant role in the reaction. If acyl and phenolic hydroxyl are utilized to form an ester compound, the ester is easy to hydrolyze in alkaline condition, if alkane silyl ether is formed, the ester compound has instability, if benzyl ether compound is formed, finally, ether bond breakage is needed to be carried out through a palladium catalyst, the safety risk is necessarily caused, the palladium catalyst is expensive, so that the method for searching a proper phenolic hydroxyl modification group and avoiding using an expensive palladium catalyst has important significance for the efficient and simple preparation of the medicine ilabezoar. Disclosure of Invention The invention discloses a method for preparing a key intermediate of ilalastine. The preparation method of the invention takes 6-bromo-7, 8-dihydronaphthalene-2-ol as a raw material, and prepares the N- (2- (6-hydroxy-1, 2,3, 4-tetrahydronaphthalene-2-yl) -5-methoxyphenyl) acetamide serving as an intermediate of the ilast through four-step reactions of etherification, coupling, nickel catalytic hydrogenation and ether bond cleavage. The method avoids using expensive palladium metal catalyst by trityl etherification of 2-alcohol and catalytic hydrogenation of Raney nickel, reduces hydrogenation cost, and has the characteristics of high yield and convenient post-treatment. Benzyl is used as a group for protecting a phenolic hydroxyl group in most patent documents for preparing an intermediate of ilalastol, but in the coupling process, the reaction yield is low due to instability of benzyl, and impurities are many. Therefore, the invention provides that the trityl is used as the protective group of the phenolic hydroxyl for the first time, so that the coupling product can be stably prepared, the yield is improved, and the purification is convenient. No report of nickel catalytic hydrogenation appears in the preparation process of the ilast intermediate, and the reason is that the existence of benzyl is unavoidable that only palladium catalyst can be used for debenzylation, benzyl protecting group is removed under acidic condition, and side reaction with more impurities can appear in the coupling structure, which is unfavorable for reaction. Therefore, the introduction of the trityl protecting group greatly reduces the reduction cost, is convenient and clean to remove, improves the quality standard of products, and is an innovative technical point of the invention. The invention provides a method for preparing a key intermediate of ilast, which takes 6-bromo-7, 8-dihydronaphthalene-2-ol as a raw material and prepares the intermediate N- (2- (6-hydroxy-1, 2,3, 4-tetrahydronaphthalene-2-yl) -5-methoxyphenyl) acetamide of ilast through the