WO1995014032A1 - Procede pour produire du cholesterol hydroxyle en position 25 - Google Patents

Procede pour produire du cholesterol hydroxyle en position 25 Download PDF

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Publication number
WO1995014032A1
WO1995014032A1 PCT/JP1994/001937 JP9401937W WO9514032A1 WO 1995014032 A1 WO1995014032 A1 WO 1995014032A1 JP 9401937 W JP9401937 W JP 9401937W WO 9514032 A1 WO9514032 A1 WO 9514032A1
Authority
WO
WIPO (PCT)
Prior art keywords
cholesterol
ruthenium
producing
reaction
production method
Prior art date
Application number
PCT/JP1994/001937
Other languages
English (en)
Japanese (ja)
Inventor
Teizo Shinozaki
Tomoyasu Iwaoka
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU10340/95A priority Critical patent/AU1034095A/en
Publication of WO1995014032A1 publication Critical patent/WO1995014032A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present invention relates to a method for hydroxylating cholesterols at the 25-position. More specifically, the present invention relates to a reaction using a ruthenium compound as a catalyst in an oxidation reaction for introducing a hydroxyl group into the 25-position of cholesterol.
  • vitamin D 3 such as osteoporosis therapeutic agents are synthesized from cholesterol, and the like. Active form of vitamin D 3 compounds have a hydroxyl group at the 2 position 5, but in order to introduce hydroxyl groups into two 5-position, the reaction many problems as described above is that not remain There is a need to do.
  • the present invention solves these industrial problems by (1) ensuring cheap and large amounts of starting materials, (2) significantly shortening the manufacturing process, (3) avoiding the use of highly toxic and dangerous chemicals, and (4) anhydrous conditions. improvement of avoiding such operability, 5 a significant reduction in manufacturing equipment by shortening the process, it is intended to cane attainable and 6 inevitable manufacturing costs Bok reduction of P
  • the present inventors have introduced inexpensive and large quantities.
  • Various methods for the production of 25-hydroxylated product using cholesterol as a starting material were studied.
  • the cholestanol derivative saturated with the double bond of cholesterol is hydroxylated by an oxidation system using a co-oxidant using a ruthenium compound as a catalyst, so that the 25-position hydroxylated product can be directly and highly selectively formed.
  • Starting materials such as cholesterols having a hydrogen atom at the 25-position include cholesterol double bond-saturated compounds (for example, cholestanol ⁇ coprostanol) and cholesterol double bonds that are oxidatively stable protecting groups.
  • a bromine adduct of cholesterol a compound in which the hydroxyl group at position 3 of these compounds is protected with a protecting group such as an acetyl group (eg, acetyl cholesterol, acetyl propyl prostanol), (Eg, cholestanone, coprostanone).
  • these compounds may have a substituent or a functional group (for example, an acetyl group or a halogen atom) which is stable to oxidation.
  • Preferable examples of cholesterol include cholesterol, coprostanol, acetylcholethanol, acetylcoprostanol, cholestanone, coprosylnon, and the like. can give.
  • An example of a preferred embodiment of the present invention is to convert a cholesterol to a cholestanol derivative by saturating the double bond at the 5-position by a conventional method, and then protecting or oxidizing a hydroxyl group as necessary.
  • a ruthenium compound is used as a catalyst to perform oxidation using an oxidation system using a co-oxidant such as periodic acid. This is shown in the equation.
  • the product obtained here is optional.
  • the ruthenium compound means a ruthenium salt or ruthenium oxide, preferably a compound such as ruthenium trichloride, ruthenium dioxide or ruthenium tetroxide.
  • the amount of the catalyst used in the reaction varies depending on the starting compounds, reaction conditions, and the like, but is preferably 1 mol% to 50 mol%, more preferably 1 mol% to 10 mol%.
  • the co-oxidizing agent means an inorganic oxidizing agent such as periodates and hypochlorites, and an organic oxidizing agent such as morpholinoxide. These oxidizing agents are inexpensive and stable. It forms an oxidation reaction system with the catalyst.
  • Solvents used in this reaction include water and saturated hydrocarbons, ketones, esters, halogenated hydrocarbons that are stable under oxidizing conditions such as hexane, butanone, ethyl acetate, carbon tetrachloride or dichloromethane.
  • the mixture is desirably carried out in a two-phase solvent system in the presence or absence of a solvent such as acetonitrile.
  • This reaction is carried out at 10 ° C to 80 ° C, preferably at 20 ° C to 50 ° C.
  • the reaction time of this reaction can be selected according to the progress of the reaction by tracking the reaction with thin layer chromatography, high performance liquid chromatography, or the like.
  • the 25-hydroxylated product of the target compound can be isolated and purified by ordinary means after collecting the target product in the organic layer by solvent extraction from the reaction solution itself or by adding a new appropriate solvent. S o.
  • Example 2 The same reaction and operation as in Example 1 were performed using 3.87 g of 5 ⁇ -cholestan-3-one in place of cholestanol in Example 1. Yield 1.05 g, 26% yield.
  • the present invention relates to the industrial production of the 25-hydroxylated cholesterol, which is useful as an intermediate for the production of pharmaceuticals, by (1) securing inexpensive and large quantities of starting materials, (2) significantly reducing the production process, and (3) toxicity and danger. It is possible to avoid the use of highly expensive chemicals, ⁇ improve operability such as avoiding anhydrous conditions, 5 drastically reduce manufacturing equipment by shortening the process, 6 reduce inevitable manufacturing costs.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Cette invention se rapporte à un procédé pour produire un 25-hydroxycholestérol en hydroxylant un cholestérol à la position 25 à l'aide d'un composé de ruthénium utilisé comme catalyseur. Ce procédé peut servir à l'échelle industrielle pour produire un cholestérol hydroxylé en position 25 utile comme intermédiaire pour la fabrication de médicaments et il permet: 1) de fournir la substance de départ en grande quantité à faible coût, 2) de raccourcir considérablement les étapes de production, 3) d'éviter l'utilisation de produits chimiques hautement toxiques ou dangereux, 4) d'améliorer l'aptitude du composé intermédiaire à être transformé, par exemple en évitant d'utiliser un état anhydre, 5) de restreindre considérablement les installations de production en raccourcissant les étapes de production, et 6) de réduire les coûts de production nécessaires.
PCT/JP1994/001937 1993-11-19 1994-11-17 Procede pour produire du cholesterol hydroxyle en position 25 WO1995014032A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU10340/95A AU1034095A (en) 1993-11-19 1994-11-17 Process for producing 25-hydroxylated cholesterol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/338727 1993-11-19
JP33872793 1993-11-19

Publications (1)

Publication Number Publication Date
WO1995014032A1 true WO1995014032A1 (fr) 1995-05-26

Family

ID=18320901

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/001937 WO1995014032A1 (fr) 1993-11-19 1994-11-17 Procede pour produire du cholesterol hydroxyle en position 25

Country Status (2)

Country Link
AU (1) AU1034095A (fr)
WO (1) WO1995014032A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920531A (en) * 1973-04-01 1975-11-18 Yehuda Mazur Preparation of derivatives of cholesterol
JPS55108898A (en) * 1979-02-15 1980-08-21 Teijin Ltd 25-hydroxy-24-oxocholesterol derivative and its preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920531A (en) * 1973-04-01 1975-11-18 Yehuda Mazur Preparation of derivatives of cholesterol
JPS55108898A (en) * 1979-02-15 1980-08-21 Teijin Ltd 25-hydroxy-24-oxocholesterol derivative and its preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. CHEM. SOC., PERKIN TRANS. 1, No. 23 (1977), pages 2565-2571. *

Also Published As

Publication number Publication date
AU1034095A (en) 1995-06-06

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