WO2015154637A1 - Procédé de préparation d'un intermédiaire de la silodosine - Google Patents

Procédé de préparation d'un intermédiaire de la silodosine Download PDF

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Publication number
WO2015154637A1
WO2015154637A1 PCT/CN2015/075757 CN2015075757W WO2015154637A1 WO 2015154637 A1 WO2015154637 A1 WO 2015154637A1 CN 2015075757 W CN2015075757 W CN 2015075757W WO 2015154637 A1 WO2015154637 A1 WO 2015154637A1
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Prior art keywords
compound
formula
palladium
group
bis
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PCT/CN2015/075757
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English (en)
Chinese (zh)
Inventor
刘琦
严加浩
徐爽
靳灿辉
谭玉东
孙仲猛
曹林法
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江苏和成新材料有限公司
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Publication of WO2015154637A1 publication Critical patent/WO2015154637A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a method for preparing an intermediate of silodosin and a novel intermediate compound involved in the method.
  • Benign prostatic hyperplasia is a common and frequently-occurring disease in middle-aged and elderly men.
  • drugs used to treat BPH are mainly divided into two categories: ⁇ 1 adrenergic receptor ( ⁇ -AR) antagonist and 5 ⁇ reductase inhibitor.
  • ⁇ -AR antagonists are characterized by fast, safe and efficient.
  • Silodosin is an alpha-AR antagonist of BPH for the treatment of dysuria caused by benign prostatic hyperplasia.
  • Silodosin has a selective inhibitory effect on urethral smooth muscle contraction, and reduces intraurethral pressure, but has no significant effect on blood pressure, and has few side effects, and thus can be used for treating benign prostatic hyperplasia.
  • synthetic methods for silodosin there are many synthetic methods for silodosin, but there is a lack of a simple process, high yield, and suitable for industrial large-scale production.
  • optically active R-compound of formula M below is a key intermediate in the preparation of silodosin.
  • Asymmetric reductive amination with L-phenylglycinol gives the desired product.
  • the method uses L-phenylglycinol, reductive amination to obtain a mixture of diastereomers of the following formula III (diastereomer ratio 3.8:1),
  • sirolimus As a key intermediate for the preparation of silodosin, a compound of the formula M has been used to prepare sirolimus which has been reported in JP2001199956, JP2006188470, WO2011124704.
  • the present invention has been proposed in the synthesis of silodosin based on the prior art, since the preparation of the key intermediate, optically active compound M, generally complicates the synthesis process and is costly.
  • the method can improve the industrial production feasibility of synthesizing the compound, reducing the risk and cost.
  • One aspect of the present invention provides a method for preparing a compound of Formula M, which in turn comprises the following five steps:
  • the method specifically includes the following steps:
  • An organozinc reagent is prepared by reacting with zinc powder, and the organozinc reagent is reacted with a compound of formula 5 under the catalysis of a palladium catalyst and an organic ligand to obtain a compound of formula 7
  • R represents a benzyl group or a benzoyl group.
  • the steps 1) to 5) are each carried out in an organic solvent, and the organic solvents in the steps 1) to 5) are each independently selected from the group consisting of C 1 -C 4 lower alcohols, toluene, and A group consisting of toluene, glacial acetic acid, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, trifluoroacetic acid, ethyl acetate, N,N-dimethylformamide, and combinations thereof.
  • the alkaline agent in step 1) is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium iodide, sodium hydrogencarbonate, diisopropylethylenediamine, pyridine, choline.
  • the palladium catalyst in step 4) is selected from the group consisting of palladium acetate, tetrakis(triphenylphosphine)palladium, palladium chloride, [1,1'-bis(diphenylphosphine) dioxin Iron] palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride Methyl chloride complex, bis(tricyclohexylphosphine)palladium dichloride, bis(triphenylphosphine)palladium(II) dichloride, bis(dibenzylideneacetone)palladium(0), tris(dibenzylidene) Acetone) dipalladium chloroform adduct, di(acetylacetonate)palladium(II), palladium hydroxide carbon, palladium carbon, (1,5-cyclooctadiene) palladium dichloride
  • the organic ligand in step 4) is selected from the group consisting of triphenylphosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9 - dimethylxanthene, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Di-tert-butylcyclohexylphosphine, tri(o-tolyl)phosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 1,2,3,4,5 -pentaphenyl-1'-(di-tert-butylphosphine)ferrocene, 1,1'-bis(diphenyl)
  • the acidic condition in step 5) is obtained by adding an acid or a hydrogen chloride gas, wherein the acid is selected from the group consisting of concentrated hydrochloric acid, trifluoroacetic acid, acetic acid or formic acid, wherein the concentrated hydrochloric acid is a volume concentration. It is 37% hydrochloric acid.
  • the palladium catalyst in the step 4) is selected from the group consisting of palladium acetate, bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium chloroform adduct or di(acetyl). Acetone) Palladium (II).
  • the palladium catalyst in the step 4) is bis(acetylacetonate)palladium(II).
  • the organic ligand in the step 4) is selected from the group consisting of tri-tert-butylphosphine, 2-dicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl, 2-bicyclic ring Hexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphine)ferrocene Or 4,5-bisdiphenylphosphino-9,9-dimethyloxazepine.
  • the organic ligand in the step 4) is 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphine)ferrocene.
  • the reaction temperature of the step 1), the step 2) and the step 3) is 50 to 200 ° C
  • the reaction time is 1 to 10 h
  • the reaction temperature is 60 to 150 ° C
  • the reaction time is It is 3 to 8 hours.
  • the reaction temperature of the step 4) and the step 5) is -20 to 50 ° C
  • the reaction time is 1 to 10 h, preferably the reaction temperature is -10 to 30 ° C, and the reaction time is 1 to 5 h. .
  • One aspect of the present invention provides novel intermediate compounds involved in the above preparation methods:
  • One aspect of the present invention provides a method of preparing a compound of Formula 6, comprising the steps of:
  • the method specifically includes the following steps:
  • a compound represented by the formula SLD-9C is reacted with thionyl chloride for 3 to 10 hours under an organic solvent-containing reflux condition to obtain a compound represented by the formula SLD-8C.
  • reaction conditions include the aforementioned reaction of the compound of the formula M. Conditions are not the only way to implement the technical solution of the present invention. Those skilled in the art can implement the technical solution of the present invention by modifying the reaction conditions according to actual needs without departing from the gist of the present invention.
  • An advantage of the present invention is that the compound of formula M synthesized by the process of the invention can be used as an intermediate compound for the synthesis of sirolimus. This method has the following advantages:
  • reaction conditions are mild, and the operation is simple and suitable for industrial production.
  • Figure 1 is a 1 H NMR chart of the compound SLD-8C
  • Figure 2 is a 1 H NMR chart of the compound SLD-7C
  • Figure 3 is a 1 H NMR chart of the compound SLD-6C
  • Figure 4 is a 1 H NMR chart of Compound 6
  • FIG. 5 is a MS diagram of Compound 3-1
  • Figure 6 is a MS diagram of Compound 3-2.
  • FIG. 7 is a MS diagram of Compound 4-1
  • FIG. 8 is a MS diagram of Compound 4-2.
  • FIG. 9 is a MS diagram of Compound 5-1.
  • FIG. 10 is a MS diagram of Compound 5-2;
  • Figure 11 is a 1 H NMR chart of Compound 7-1;
  • Figure 12 is a 1 H NMR chart of Compound 7-2;
  • Figure 13 is a 1 H NMR chart of Compound M-1;
  • Figure 14 is a 1 H NMR chart of Compound M-2.
  • the compound of the formula 2-1 is replaced with the compound of the formula 2-2, and the compound of the formula 3-2 is obtained by the same method.
  • the compound of the formula 3-1 is replaced with the compound of the formula 3-2, and the compound of the formula 4-2 is obtained by the same method.
  • the compound of the formula 4-1 is replaced with the compound of the formula 4-2, and the compound of the formula 5-2 is obtained by the same method.
  • the compound of the formula 5-1 is replaced with the compound of the formula 5-2, and the compound of the formula 7-2 is obtained by the same method.
  • a compound of the formula 7-1 is replaced with a compound of the formula 7-2, and a compound of the formula M-2 is obtained by the same method.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation d'un intermédiaire de la silodosine. Ledit intermédiaire a la structure de (M), où R est un benzyle ou un benzoyle. Ledit procédé de préparation est caractérisé par une voie de réaction courte, un fonctionnement simple, un faible coût, un rendement élevé, un processus stable, etc. Le procédé est approprié pour une production industrielle, et a valeur d'application industrielle très élevée. L'invention concerne également des composés intermédiaires pour la préparation de l'intermédiaire représenté par M.
PCT/CN2015/075757 2014-04-10 2015-04-02 Procédé de préparation d'un intermédiaire de la silodosine WO2015154637A1 (fr)

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CN201410144175.X 2014-04-10
CN201410144175.XA CN104974073B (zh) 2014-04-10 2014-04-10 一种制备西洛多辛中间体的方法

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10421719B2 (en) 2015-09-30 2019-09-24 Urquima S.A. Maleic acid salt of a silodosin intermediate
CN113461910A (zh) * 2021-07-02 2021-10-01 江苏大学 一种聚乙叉降冰片烯二乙烯基联苯类共聚物及其制备方法
CN115197043A (zh) * 2022-07-05 2022-10-18 中国石油大学(华东) 一种共价键连接的苝二聚体及其制备方法

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CN109574902B (zh) * 2017-09-28 2022-07-01 安徽省庆云医药股份有限公司 一种西洛多辛中间体的制备方法
CN109574903A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种制备西洛多辛中间体的方法
CN111471003B (zh) * 2019-01-24 2022-09-23 上海皓元医药股份有限公司 一种立他司特中间体的制备方法
CN114805170B (zh) * 2021-01-29 2024-03-29 四川青木制药有限公司 一种新型赛洛多辛手性中间体的制备方法
CN114751852B (zh) * 2022-05-23 2023-09-15 山西库邦生物医药科技有限公司 一种西咯多辛关键中间体的制备方法
CN115838349B (zh) * 2023-02-20 2023-07-14 南京桦冠生物技术有限公司 一种3-(7-氰基-5-(2-氧代丙基)吲哚啉-1-基)苯甲酸丙酯的制备方法

Citations (3)

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JP2001199956A (ja) * 2000-01-14 2001-07-24 Kissei Pharmaceut Co Ltd 光学活性なインドリン誘導体の製造方法およびその製造中間体
CN101993407A (zh) * 2009-08-27 2011-03-30 浙江华海药业股份有限公司 用于制备西洛多辛的吲哚啉化合物及其制备方法
CN103420893A (zh) * 2013-08-02 2013-12-04 江苏和成新材料有限公司 制备西洛多辛中间体的方法

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JP5208934B2 (ja) * 2007-07-03 2013-06-12 浜理薬品工業株式会社 光学活性アミンの製造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001199956A (ja) * 2000-01-14 2001-07-24 Kissei Pharmaceut Co Ltd 光学活性なインドリン誘導体の製造方法およびその製造中間体
CN101993407A (zh) * 2009-08-27 2011-03-30 浙江华海药业股份有限公司 用于制备西洛多辛的吲哚啉化合物及其制备方法
CN103420893A (zh) * 2013-08-02 2013-12-04 江苏和成新材料有限公司 制备西洛多辛中间体的方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10421719B2 (en) 2015-09-30 2019-09-24 Urquima S.A. Maleic acid salt of a silodosin intermediate
CN113461910A (zh) * 2021-07-02 2021-10-01 江苏大学 一种聚乙叉降冰片烯二乙烯基联苯类共聚物及其制备方法
CN115197043A (zh) * 2022-07-05 2022-10-18 中国石油大学(华东) 一种共价键连接的苝二聚体及其制备方法

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