WO2023071328A1 - Procédé de synthèse de 8-amino-1-octane-1-{[2-(triméthylsilyl)éthoxy]méthoxy}octane-3-one - Google Patents

Procédé de synthèse de 8-amino-1-octane-1-{[2-(triméthylsilyl)éthoxy]méthoxy}octane-3-one Download PDF

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Publication number
WO2023071328A1
WO2023071328A1 PCT/CN2022/107743 CN2022107743W WO2023071328A1 WO 2023071328 A1 WO2023071328 A1 WO 2023071328A1 CN 2022107743 W CN2022107743 W CN 2022107743W WO 2023071328 A1 WO2023071328 A1 WO 2023071328A1
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WO
WIPO (PCT)
Prior art keywords
trimethylsilyl
ethoxy
methoxy
amino
octane
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PCT/CN2022/107743
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English (en)
Chinese (zh)
Inventor
吴磊
钱祥云
张晓红
曾陵
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苏州富士莱医药股份有限公司
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Publication of WO2023071328A1 publication Critical patent/WO2023071328A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/06—Zinc compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of 8-amino-1- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ octane-3-one.
  • ⁇ -lipoic acid is a vitamin-like compound that can eliminate free radicals that accelerate aging and cause disease. It is both water-soluble and fat-soluble. Universal antioxidant drug. ⁇ -lipoic acid has a certain effect on the treatment of many diseases such as liver disease, diabetes, HIV virus, tumor, nervous system degeneration, radiation injury, arsenic, mercury, cadmium and other heavy metal poisoning, for example, it can assist in the treatment of type II diabetes and improve Pancreatic islets function in glucose metabolism, protect nerve cells, prevent cataracts, prevent muscle damage and so on.
  • diseases such as liver disease, diabetes, HIV virus, tumor, nervous system degeneration, radiation injury, arsenic, mercury, cadmium and other heavy metal poisoning, for example, it can assist in the treatment of type II diabetes and improve Pancreatic islets function in glucose metabolism, protect nerve cells, prevent cataracts, prevent muscle damage and so on.
  • Dihydrolipoic acid has a stronger antioxidant capacity than lipoic acid, and the regeneration of endogenous antioxidants and the repair of oxidative damage must be achieved in the form of dihydrolipoic acid.
  • R-lipoic acid is the natural form of lipoic acid in the human body. As a vitamin drug, its curative effect is better than that of racemic ⁇ -lipoic acid. It can promote skeletal muscle glucose uptake, reduce plasma insulin and free fatty acid levels, and improve blood sugar levels in the treatment of type II diabetes.
  • R-lipoic acid is more active than racemic ⁇ -lipoic acid in the synthesis of glycogen under the action of insulin, the oxidation of glucose, and the increase of oxygen content in animal blood.
  • R-lipoic acid has more and more replaced, and will eventually replace racemic ⁇ -lipoic acid, and has become a commonly used drug and nutritional supplement.
  • R-lipoic acid there are many methods for preparing R-lipoic acid in the world, but there are three main types: one is the current industrialized method for preparing R-lipoic acid, which uses 6,8-dichlorooctanoic acid ethyl ester as the starting material, and undergoes thioxocyclization and cyclization. , hydrolysis to obtain racemic ⁇ -lipoic acid, and then use a resolving agent for multiple resolutions to obtain R-lipoic acid after refining. The yield of this step is not more than 50%.
  • the process of this method is relatively complicated , especially not easy to obtain pure product; the third is to hydrolyze racemic 6,8-dichlorooctanoic acid ethyl ester into ( ⁇ ) dichlorooctanoic acid, and then use a resolving agent to split, rethio and cyclization, the method is basically The cost can be saved, but because about 50% of S-(-)-6,8-dichlorooctanoic acid is still unused, the cost is high.
  • the task of the present invention is to provide a kind of synthetic method of 8-amino-1- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ octane-3-one.
  • the chemical name of the lipoic acid intermediate is 8-amino-1- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ octane-3-one, and the chemical structural formula is as shown in formula 1:
  • step A) Synthesis of intermediate-2, the intermediate-1 obtained in step A) is mixed with zinc powder, lithium chloride, trimethylchlorosilane, 1,2-dibromoethane and tetrahydrofuran, and reacted to form a zinc bromide intermediate body, and control the reaction temperature and reaction time to generate the zinc bromide intermediate, then 3- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ propionic acid methyl ester and the zinc
  • the bromide intermediate is subjected to a substitution reaction in a tetrakis(triphenylphosphine) palladium and tetrahydrofuran system, and after acid deprotection, water washing, post-treatment and purification, intermediate-2 (formula INT-2) is obtained, and the reaction formula is:
  • step B) the intermediate-2 obtained in step B) is subjected to a catalytic hydrogenation deprotection reaction to obtain the lipoic acid intermediate 8-amino-1- ⁇ [2-(trimethylsilyl)ethoxy]methoxy Base ⁇ octane-3-one (formula 1), the reaction formula is:
  • the method and conditions for the N-Boc protection of the reaction between benzhydrylamine and di-tert-butyl dicarbonate described in step A) are conventional methods and conditions for this type of reaction in the art.
  • the solvent described in step A) is N,N-dimethylformamide or N,N-dimethylacetamide; the diphenylmethylamine, sodium hydride, 1,5-di
  • the molar ratio of bromopentane is 1.0:(1.5-2.0):(1.3-1.5).
  • reaction temperature and reaction time of controlling the N-H hydrogen extraction reaction to form the sodium salt intermediate of the amino group in step A) are to control the reaction temperature and time to 0-25°C and 30min-1h, respectively.
  • the temperature of the substitution reaction in step A) is 20-35°C, and the reaction time is 6-12h.
  • the intermediate-1 methyl 3- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ propionate, zinc powder, lithium chloride
  • the molar ratio of trimethylchlorosilane and tetrakis(triphenylphosphine)palladium is 1.0:1.0:(3.0-6.0):(1.5-2.5):(0.05-0.1):(0.05-0.1).
  • reaction temperature and reaction time for controlling the reaction to form the zinc bromide intermediate in step B) are to control the reaction temperature and time to 40-60° C. and 1-3 h, respectively.
  • the temperature of the substitution reaction in step B) is 20-35°C, and the reaction time is 2-6h.
  • the acid deprotection in step B) uses trifluoroacetic acid.
  • the method and conditions for the catalytic hydrogenation deprotection reaction in step C) are conventional methods and conditions for this type of reaction in the art.
  • the technical solution provided by the invention has the following technical effects: first, the process conditions are mild, and the purity of each intermediate is high, which is beneficial to the quality control and improvement of the raw material drug; Reasonable and environmentally friendly, it can be produced in large quantities to meet the needs of use, and is suitable for industrial production.
  • the starting material 3- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ propionate methyl ester can be obtained by Oxymethyl chloride can be obtained by ether synthesis.
  • the synthetic product is the lipoic acid intermediate 8-amino-1- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ octane-3-one:
  • the synthetic product is the lipoic acid intermediate 8-amino-1- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ octane-3-one:
  • the synthetic product is the lipoic acid intermediate 8-amino-1- ⁇ [2-(trimethylsilyl)ethoxy]methoxy ⁇ octane-3-one:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Est divulgué un procédé de synthèse de 8-amino-1-{[2-(triméthylsilyl)éthoxy]méthoxy}octane-3-one, qui appartient au domaine technique de la synthèse chimique pharmaceutique. Le procédé comprend les étapes consistant à : tout d'abord, protéger la diphénylméthylamine avec N-Boc, puis faire réagir la diphénylméthylamine protégée avec de l'hydrure de sodium pour préparer un intermédiaire de sel de sodium correspondant, et soumettre l'intermédiaire de sel de sodium et le 1,5-dibromopentane à une réaction de substitution pour obtenir un intermédiaire-1 ; préparer l'intermédiaire-1 en un intermédiaire de bromure de zinc, puis faire réagir l'intermédiaire de bromure de zinc avec le méthyle 3-{[2-(triméthylsilyl)éthoxy]méthoxy}propionate pour produire un intermédiaire-2, et soumettre l'intermédiaire-2 à une réaction de déprotection par hydrogénation catalytique pour obtenir le 8-amino-1-{[2-(triméthylsilyl)éthoxy]méthoxy}octane-3-one intermédiaire d'acide lipoïque. La présente technique présente des conditions de traitement modérées, les matières premières sont facilement disponibles, la pureté de chaque intermédiaire est élevée, le contrôle qualité et l'amélioration de la production de médicament en vrac sont facilités et le procédé est approprié pour une production industrielle.
PCT/CN2022/107743 2021-10-28 2022-07-26 Procédé de synthèse de 8-amino-1-octane-1-{[2-(triméthylsilyl)éthoxy]méthoxy}octane-3-one WO2023071328A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111262548.X 2021-10-28
CN202111262548.XA CN113717210B (zh) 2021-10-28 2021-10-28 一种8-氨基-1-{[2-(三甲基硅基)乙氧基]甲氧基}辛烷-3-酮的合成方法

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WO2023071328A1 true WO2023071328A1 (fr) 2023-05-04

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Publication number Priority date Publication date Assignee Title
CN113717210B (zh) * 2021-10-28 2022-02-18 苏州富士莱医药股份有限公司 一种8-氨基-1-{[2-(三甲基硅基)乙氧基]甲氧基}辛烷-3-酮的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112469279A (zh) * 2018-07-09 2021-03-09 洛桑大学 预防和控制真菌病原体的杀真菌剂
CN113185494A (zh) * 2021-05-17 2021-07-30 苏州富士莱医药股份有限公司 一种r-硫辛酸的制备方法
CN113429386A (zh) * 2021-07-09 2021-09-24 苏州富士莱医药股份有限公司 一种r-硫辛酸的合成方法
CN113717210A (zh) * 2021-10-28 2021-11-30 苏州富士莱医药股份有限公司 一种8-氨基-1-{[2-(三甲基硅基)乙氧基]甲氧基}辛烷-3-酮的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112469279A (zh) * 2018-07-09 2021-03-09 洛桑大学 预防和控制真菌病原体的杀真菌剂
CN113185494A (zh) * 2021-05-17 2021-07-30 苏州富士莱医药股份有限公司 一种r-硫辛酸的制备方法
CN113429386A (zh) * 2021-07-09 2021-09-24 苏州富士莱医药股份有限公司 一种r-硫辛酸的合成方法
CN113717210A (zh) * 2021-10-28 2021-11-30 苏州富士莱医药股份有限公司 一种8-氨基-1-{[2-(三甲基硅基)乙氧基]甲氧基}辛烷-3-酮的合成方法

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