WO2007099843A1 - DÉRIVÉ α,β-INSATURÉ DE CYCLOHEXANONE, PROCÉDÉ DE SYNTHÈSE DUDIT DÉRIVÉ ET PROCÉDÉ DE SYNTHÈSE D'UN INTERMÉDIAIRE DE LADITE SYNTHÈSE - Google Patents

DÉRIVÉ α,β-INSATURÉ DE CYCLOHEXANONE, PROCÉDÉ DE SYNTHÈSE DUDIT DÉRIVÉ ET PROCÉDÉ DE SYNTHÈSE D'UN INTERMÉDIAIRE DE LADITE SYNTHÈSE Download PDF

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WO2007099843A1
WO2007099843A1 PCT/JP2007/053259 JP2007053259W WO2007099843A1 WO 2007099843 A1 WO2007099843 A1 WO 2007099843A1 JP 2007053259 W JP2007053259 W JP 2007053259W WO 2007099843 A1 WO2007099843 A1 WO 2007099843A1
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group
general formula
compound represented
chloride
formula
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PCT/JP2007/053259
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English (en)
Japanese (ja)
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Masakatsu Shibasaki
Motomu Kanai
Tsuyoshi Mita
Nobuhisa Fukuda
Yuhei Fukuta
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The University Of Tokyo
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Publication of WO2007099843A1 publication Critical patent/WO2007099843A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to an a, j8-unsaturated cyclohexanone derivative, a method for producing the same, and a method for producing an intermediate thereof.
  • the present invention relates to an a, j8-unsaturated cyclohexanone derivative useful as a raw material for an antiviral drug (for example, oseltamivir phosphate, trade name: Tamiflu) against new influenza such as H5N1 and the like.
  • the present invention relates to a production method and a method for producing an intermediate of a;
  • oseltamivir phosphate (trade name: Tamiflu) is said to be effective as a specific medicine against new influenza.
  • Shikimic acid is used as a starting material for the synthesis of oseltamivir phosphate (trade name: Tamiflu) (see, for example, Patent Document 1).
  • Patent Literature l Kim, C.U. et al, J. Am. Chem. Soc. 1997, 119, 681-.
  • shikimic acid is also extracted from i) Toshikimi, ie, octagonal force 'purifying power or ii) power prepared through fermentation of D-glucose power by E. coli i) the extraction' Purification or ii) fermentation has the problem of time and cost.
  • an object of the present invention is to solve the above-described problems.
  • An object of the present invention is to provide a novel method for producing an antiviral drug oseltamivir phosphate (trade name: Tamiflu) that does not use shikimic acid as a raw material, and a novel raw material or intermediate used in the production method. .
  • Another object of the present invention is to provide a novel method for producing these raw materials or intermediates.
  • the object of the present invention is not limited to the raw material of the antiviral drug oseltamivir phosphate (trade name: Tamiflu), but also a novel OC, ⁇ -unsaturated cyclohexanone derivative and a method for producing the same, and a, ⁇ -
  • the object is to provide a method for producing an intermediate of an unsaturated cyclohexanone derivative.
  • R 1 is a t-butoxycarbonyl group, a benzyloxycarbonyl group or a methoxycarbol group
  • R 2 carboxycarboxyl group, benzyloxy It may be a xycarbon group or a methoxycarbol group.
  • R 3 is a t-butoxycarbo ol group, a benzyloxy carbo ol group or a methoxy carbo ol group, and an R 4 carboxy carboxy group.
  • R 4 carboxy carboxy group.
  • R 1 and R 2 are each independently a t-butoxycarbol group, a benzyloxycarboro group, a methoxycarboro group, an acetyl group, A benzyl group, a fluoromethoxycarbonyl group, a paramethoxybenzyl group, a 4-trobenzoyl group, a 3,5-dinitrobenzoyl group, or hydrogen).
  • IT is a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a methoxycarbol group, and an R 2 carboxycarboxyl group, It may be a benzyloxycarbonyl group or a methoxycarbol group.
  • R 3 is a t-butoxycarbol group, a benzyloxycarboro group or a methoxycarboro group, and R 4 carboxycarbol. Or a benzyloxycarbonyl group or a methoxycarbon group.
  • R 1 and R 2 are each independently a t-butoxycarbol group, a benzyloxycarboro group, a methoxycarboro group, an acetyl group, A benzyl group, a fluoromethoxycarbonyl group, a paramethoxybenzyl group, a 4-trobenzoyl group, a 3,5-dinitrobenzoyl group, or hydrogen).
  • R 1 is t- butoxycarbonyl - group, benzylidene A carboxyl group or a methoxycarboxyl group, wherein in (a) di-butyl dicarbonate, benzyloxycarboxyl chloride or methoxycarbochloride is used, and R 2 is a t-butoxycarbol group, benzyloxyl. It may be a carbo group or a methoxy group.
  • R 1 and R 2 are each independently a t-butoxycarbol group, a benzyloxycarboro group, a methoxycarboro group, an acetyl group, a benzyl group, Which represents a fluoromethoxycarbonyl group, a paramethoxybenzyl group, a 4_-trobenzoyl group, a 3,5-dinitrobenzoyl group, or hydrogen).
  • the compound represented by ⁇ a is reduced with triphenylphosphine, tributylphosphine, triethylphosphine, trimethylphosphine or a solid support thereof, and then hydrolyzed, and the resulting amine compound is present in the presence of pyridine.
  • R 1 is a t-butoxycarbol group, a benzoxycarbon group or a methoxycarbol group, and a) in ditbutyldicarbonate, benzylo It is preferable to use xycarbon chloride or methoxy carbochloride, and R 2 is a t-butoxy carbyl group, a benzyloxy carbo yl group or a methoxy carbo yl group.
  • R 3 is a t-butoxycarbol group, a benzoxycarbon group or a methoxycarbole group, and in c) triphenylphosphine or It is preferable to use tributylphosphine and have an R 4 force-butoxycarbo ol group, a benzyloxy carbo ol group or a methoxy carbo ol group.
  • R 3 and R 4 are each independently t-butoxycarbol group, benzyloxycarboro group, methoxycarboro group, acetyl group, benzyl group , A fluoromethoxycarbonyl group, a paramethoxybenzyl group, a 4_-trobenzoyl group, a 3,5-dinitrobenzoyl group, or hydrogen).
  • a compound represented by the general formula VI is generally reacted with i) diazabicycloundecene, ii) benzyloxycarbonyl chloride, iii) sodium methoxide, and iv) Dess-Martin periodinane. Obtaining the compound represented by the formula ⁇ ′.
  • trimethylsilyl azide triethylsilyl azide, t-butyldimethylsilyl azide, azide in the presence of a catalyst containing a ligand and a metal species M
  • M is also selected from the group forces consisting of titanium, zirconium, aluminum, gallium and rare earth elements
  • the compound represented by the formula IX is converted into i) di-t-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbon chloride, acid anhydride (eg, acetic anhydride, propionic acid anhydride, etc.), benzyl chloride, Sequential reaction with fluorenylmethyl carboyl chloride, paramethybenzyl chloride, 4-trobenzoyl chloride or 3,5-di-trobenzoyl chloride and 4-dimethylaminopyridine, and ii) NaOH And obtaining a compound represented by the general formula ⁇ ⁇ a or ⁇ ′ b.
  • ytterbium, yttrium, lanthanum, cerium, brazeodymium, samarium, europium, gadolinium, dysprosium, holmium, and erbium group power should be selected! / ,.
  • step represented by the formula IV ′ obtained in step f) is reacted with N-odosuccinimide or iodine; and e ′ ) d ')
  • the compound obtained in the step is reacted sequentially with i) diazabicycloundecene, ii) benzyloxychloride, iii) sodium methoxide, and iv) Dess-Martin periodinane.
  • X is ⁇
  • ⁇ is ⁇ -2 or ⁇ -3
  • R 1 is t-butoxycarbol group, benzyloxycarbo ol group or methoxycarboxyl. It is a bonyl group
  • R 2 may be a t-butoxycarbonyl group, a benzyloxycarbonyl group or a methoxycarboxyl group! /.
  • the metal species M contained in the catalyst is M (ZR 7 ) (Z represents N or O, and R 7 has 2 to 6 carbon atoms. , Substituted or unsubstituted straight mn
  • m and n are metal alkoxides or metal amides represented by the metal M stoichiometrically determined).
  • the metal species M contained in the catalyst may be yttrium.
  • the metal species M contained in the catalyst is yttrium triisopropoxide or yttrium tris [ ⁇ , ⁇ -bis (trimethylsilyl) amide]. Should be included.
  • trimethylsilyl azide triethylsilyl azide, t-butyldimethylsilyl azide, azide in the presence of a catalyst containing a ligand and a metal species M
  • M is also selected from the group forces consisting of titanium, zirconium, aluminum, gallium and rare earth elements
  • the compound represented by the formula IX is converted into i) di-t-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbon chloride, acid anhydride (eg, acetic anhydride, propionic acid anhydride, etc.), benzyl chloride, Fluorenylmethylcarbol chloride, paramethoxybenzyl chloride, 4-trobenzoyl chloride or 3,5-di-trobenzoyl mouthlid and And ii) sequentially obtaining a compound represented by the general formula ⁇ by reacting with 4-dimethylaminopyridine and ii) NaOH.
  • ytterbium, yttrium, lanthanum, cerium, brazeodymium, samarium, europium, gadolinium, dysprosium, holmium, and erbium group power should be selected! / ,.
  • X is ⁇
  • ⁇ is ⁇ -2 or ⁇ -3
  • R is t-butoxycarbol group, benzyloxycarbo ol group or methoxycarbol group.
  • R 2 is preferably a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a methoxycarbon group.
  • R 7 is a substituted or unsubstituted linear or branched or cyclic alkyl group having 2 to 6 carbon atoms, substituted or unsubstituted linear or A branched or cyclic alkenyl group, a substituted or unsubstituted aromatic group or a trialkylsilyl group, and m and n are integers determined stoichiometrically by the metal M). Or it may be included as a metal amide! /.
  • the metal species M contained in the catalyst may be yttrium.
  • the metal species M contained in the catalyst is yttrium triisopropoxide or yttrium tris [ ⁇ , ⁇ -bis (trimethylsilyl) amide]. Good.
  • R 1 may be a t-butoxycarbo group
  • R 2 may be a t-butoxycarbo group
  • R 1 is a acetyl group and R 2 is a t-butoxycarbonyl group! /.
  • R 1 may be a t-butoxycarbonyl group and R 2 may be a t-butoxycarbo group.
  • R 1 is a acetyl group and R 2 is a t-butoxycarbonyl group! /,
  • R 3 is a acetyl group and R 4 force ⁇ -butoxycarbol group, benzyloxycarbo ol group, 9-fluorenylmethoxy It is preferably a carbo group, a trichloro ethoxy carbo yl group, or an aryloxy carbo ol group, and preferably an R 4 strength-butoxy carbonyl group.
  • R 3 is a acetyl group and R 4 force ⁇ -butoxycarbol group, benzyloxycarboro group, 9-fluore-methoxyl-carbo- R 4 group, trioxy ethoxy carbo yl group, or aryloxy carbo ol group, and preferably R 4 strength -butoxy carbonyl group.
  • the present invention it is possible to provide a method for producing a novel antiviral drug oseltamivir phosphate (trade name: Tamiflu) that does not use shikimic acid as a raw material, and a raw material or an intermediate used in the production method. .
  • the present invention also provides a method for producing these raw materials or intermediates. Togashi.
  • the present invention provides a j8-unsaturated cyclohexanone derivative represented by the general formula I or ⁇ .
  • the general formula I or II includes all stereoisomers.
  • R 1 ! ⁇ 4 each independently represents t-butoxycarbol group, benzyloxycarboro group, methoxycarboro group, acetyl group, benzyl group, or fluoromethoxycarbole.
  • R 1 is a t-butoxycarbo ol group, a benzyloxy carbo ol group or a methoxy carbo ol group and R 2 is a t butoxy carbo ol group, a benzyloxy carbo ol group or It is preferably a methoxycarbol group.
  • R 3 is a t-butoxycarbol group, a benzyloxycarboxyl- And a R 4 carboxycarbonyl group, a benzyloxycarbonyl group, or a methoxycarbol group.
  • R 3 is a acetyl group and R 4 force ⁇ -butoxycarbol group, benzyloxycarbol group, 9-fluoromethoxymethoxy group, trichloro ethoxy group
  • a carbo group or a carboxy group is preferred, and an R 4 carboxy group is preferred.
  • the present invention provides an a, ⁇ -unsaturated cyclohexanone derivative represented by the general formula I or II ′.
  • I ⁇ to R 4 have the same definition as above.
  • R 1 is a t-butoxycarbonyl group, a benzyloxycarbon group, or a methoxycarbon group
  • R 2 is a t-butoxycarbonyl group, a benzyloxycarbo ol group, or It is preferably a methoxycarbol group.
  • R 3 is a t-butoxycarbol group, a benzyloxycarboro group or a methoxycarboro group, and an R 4 force butoxycarboxyl group, a benzyloxycarboro group or It is preferably a methoxycarbol group.
  • R 3 is a acetyl group and R 4 force-butoxycarbol group, benzyloxypolyol group, 9-fluorenylmethoxycarbol group, trichlorodiethyl ethoxy.
  • a carbo group or a carboxy group is more preferable, and an R 4 carboxy group is preferable.
  • the a, ⁇ -unsaturated cyclohexanone derivative represented by the general formula I or II, particularly ⁇ or ⁇ ', can be used as a starting material for oseltamivir phosphate (trade name: Tamiflu) as described later. You can.
  • a -unsaturated cyclohexanone derivative represented by the general formula I or II, particularly ⁇ or ⁇ ' can be prepared as described below.
  • a represented by the general formula I or II, particularly ⁇ or ⁇ '; j8 -unsaturated cyclohexanone derivatives are converted to oseltamivir phosphate via a, j8 -unsaturated cyclohexanone derivatives ( Trade name: Tamiflu) is also recognized as an intermediate in the process.
  • the a, ⁇ -unsaturated cyclohexanone derivative represented by the general formula I or II of the present application, particularly ⁇ or ⁇ ′, is used as a starting material or an intermediate of the above-mentioned oseltamivir phosphate (trade name: Tamiflu). It can be used as various raw materials.
  • the a, ⁇ -unsaturated cyclohexanone derivative described above can be produced as follows. That is, the compound represented by the above general formula I or ⁇ can be prepared as follows: a) —The compound represented by the general formula Ilia or ⁇ a is converted into triphenylphosphine, tributylphosphine, After reduction with triethylphosphine or trimethylphosphine or a solid support thereof, hydrolysis is carried out, and the resulting amine compound is dissolved in the presence of pyridine in the presence of di-t-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarboxychloride, Acid anhydrides (eg acetic anhydride, propionic anhydride, etc.), benzyl chloride, fluorenylmethyl carbo yl chloride, paramethoxy benzyl chloride, 4-trobenzoyl chloride or 3, 5-di- A compound represented by the general formula IV is
  • R 1 is a t-butoxycarbonyl group, a benzyloxycarbonyl group or a methoxycarbonyl group, particularly a t-butoxycarbon group, and a) in di-butyl dicarbonate, benzyloxy Use carbochloride or methoxycarbochloride
  • R 2 is a t-butoxycarbol, benzyloxycarboro or methoxycarboro group, in particular a t-butoxycarboro group! /.
  • step a) includes a force dependent on the compound including the compound represented by the general formula Ilia or ⁇ a to be used, a forceful solvent using triphenylphosphine or tributylphosphine, etc.
  • the temperature is preferably carried out under conditions such as the temperature of a solvent widely used in organic synthesis.
  • step b) depends on the compound including the compound represented by the general formula IV or IV ′ to be used, but is preferably performed under conditions such as a solvent * temperature widely used in organic synthesis. .
  • a compound represented by general formula VI is reacted sequentially with i) diazabicycloundecene, ii) benzyloxycarbol chloride, iii) sodium methoxide, and iv) Dess-Martin periodinane.
  • a compound represented by ⁇ or ⁇ ′ can be obtained.
  • R 3 is a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a methoxycarbon group, particularly a t-butoxycarbol group, and in c) triphenylphosphine or tributyl It is preferable to use phosphine and have an R 4 strength, butoxycarbox group, benzyloxycarboxyl group, or methoxycarboxyl group, particularly a benzyloxycarboro group.
  • step c) is a force that depends on the compound including the compound represented by the general formula nib or Ill'b used tetrahydrofuran (hereinafter sometimes abbreviated as "THF"), di- It is preferable to use a solvent such as oxane, ether, toluene, methylene chloride, water, etc. under a temperature condition of 0 to 80 ° C.
  • THF tetrahydrofuran
  • a solvent such as force form, methylene chloride, toluene, ether, etc., which depends on the compound including the compound represented by the general formula V or V ′ used, is used. It is preferable to carry out under a temperature condition of 0 to 80 ° C.
  • a solvent such as chloroform, methylene chloride, toluene, ether, THF, or water depending on the compound including the compound represented by the general formula VI or VI ′ to be used is used. It is preferable to use it at a temperature of 0 to 80 ° C!
  • R 3 is a acetyl group and R 4 force ⁇ -butoxycarbol group, benzyloxycarbonyl group, 9-fluoromethoxycarbol
  • a compound represented by the following formula lie or ⁇ ′ c is preferably an R 4 force 3 ⁇ 4-butoxycarbonyl group, which is preferably a group, a chloroethoxycarbol group, or an aryloxycarboro group.
  • Compound (wherein R 4a is a t-butoxycarbol group, a benzyloxycarboro group, a 9-fluoromethoxycarboro group, a triclonal ethoxycarboro group, or an aryloxycarboro group.
  • R 4 group 3 ⁇ 4—butoxycarbonyl group is preferably a group of formula Ilia or ⁇ ′ a, in particular R 3 of the formula Ilia or ⁇ ′ a is a t-butoxycarbonyl. It can be obtained from the compound as a group (the following formula IIIc or ⁇ c) by the following method
  • the above step is preferably performed using a solvent such as chloroform, methylene chloride, dichloroethane, toluene, methanol, ether, and the like at a temperature of 10 to 80 ° C.
  • a solvent such as chloroform, methylene chloride, dichloroethane, toluene, methanol, ether, and the like at a temperature of 10 to 80 ° C.
  • step k) is preferably carried out using a solvent such as black mouth form, methylene chloride, dichloroethane, toluene and ether under a temperature condition of 10 to 80 ° C! /.
  • a solvent such as black mouth form, methylene chloride, dichloroethane, toluene and ether under a temperature condition of 10 to 80 ° C! /.
  • a solvent such as butanol, propanol or ethanol is used for the reaction with cesium carbonate, and a solvent such as methylene chloride, chloroform or dichloroethane is used for the reaction with Dess-Martin pyridine. It is preferable to carry out under a temperature condition of ⁇ 80 ° C.
  • the present invention also provides a method for producing an intermediate of an a, ⁇ -unsaturated cyclohexanone derivative represented by the general formula I or ⁇ or II or II ′.
  • -unsaturated cyclohex Sanone derivatives are prepared by the general formula Ilia or ⁇ ⁇ a or m′b or mb (which can be abbreviated as general formula ⁇ ). These compounds can be prepared by the following method. Therefore, the present invention provides an intermediate in the process for producing the above-mentioned (X, ⁇ -unsaturated cyclohexanone derivative, that is, a process for producing a compound represented by the general formula ⁇ .
  • a compound represented by the formula VII (wherein Y represents one of the groups represented by Y-1 to Y-6) is represented by the general formula VIII (in the formula VIII, R 5 Is 0 to 5 substituents, X is P, As, N or S, especially P, q is an integer of 1 or 2 (when X is P, As or N, q is 2 And when X is S, q is 1), n is an integer from 0 to 3, and A to A are each independently hydrogen,
  • trimethylsilyl azide triethylsilyl azide, t-butyldimethylsilyl azide, azide under a catalyst containing a ligand and a metal species M
  • M is also selected from the group forces consisting of titanium, zirconium, aluminum, gallium and rare earth elements
  • the compound represented by the formula IX is converted into i) di-t-butyl dicarbonate, benzyloxycarbonyl chloride, methoxycarbon chloride, acid anhydride (eg, acetic anhydride, propionic acid anhydride, etc.), benzyl chloride, Sequential reaction with fluorenylmethyl carboyl chloride, paramethybenzyl chloride, 4-trobenzoyl chloride or 3,5-di-trobenzoyl chloride and 4-dimethylaminopyridine, and ii) NaOH
  • the compound represented by general formula ⁇ can be obtained.
  • Y is preferably Y-2 or Y-3.
  • the catalyst used is composed of the ligand and the metal species M as described above.
  • the metal species M is M (ZR 7 ) (Z represents N or O, R 7 has 2 to 6 carbon atoms,
  • the rare earth element is preferably selected from ytterbium, yttrium, lanthanum, cerium, praseodymium, samarium, europium, gadolinium, dysprosium, holmium, and erbium.
  • M is particularly preferably yttrium, and it is particularly preferred that the metal species M is comprised of yttrium triisopropoxide or yttrium tris [ ⁇ ⁇ , ⁇ ⁇ -bis (trimethylsilyl) amide].
  • X is preferably P.
  • a and A are preferably hydrogen and A and A are preferably fluorine.
  • the substituents R 5 may be the same or different.
  • the f) step depends on the compound used. Propion-tolyl, acetonitryl, buthiguchi-tolyl, THF, dioxane, methylene chloride, toluene, ether, etc. It is preferable to carry out under such conditions.
  • a compound represented by the general formula IV or IV ' (hereinafter simply abbreviated as "IV” in this description) can be obtained by the step f).
  • this is a raw material or an intermediate of a compound (enone form) represented by the general formula II or ⁇ ′ (hereinafter, simply referred to as “/” in this description! /).
  • It is a raw material or an intermediate of a compound (enone form) represented by force or general formula I or ⁇ (hereinafter simply abbreviated as “I” in this description). Therefore, the compound represented by the general formula I or II can be obtained using the compound represented by the general formula IV.
  • b ′) a compound represented by general formula IV by reacting a compound represented by general formula IV with diacid selenium, benzene selenate or cobalt naphthalenate-oxygen and Dess-Martin periodinane. Can be obtained.
  • D ′) a step of reacting a compound represented by the general formula IV ′ with N-dosuccinimide or iodine; and e ′) a compound obtained in step d ′), i) diaza And a step of sequentially reacting with bicycloundecene, ii) benzyloxycarbonyl chloride, iii) sodium methoxide, and iv) Dess-Martin periodinane, thereby obtaining a compound represented by the general formula ⁇ I can.
  • the solvents described above in the steps b), d) and e) various conditions, and the like can be used.
  • step g) depends on the compound used, etc. It is preferable to use a solvent such as water, methylene chloride, chloroform, toluene, THF, ether, water and the like under a temperature condition of 0 to 100 ° C.
  • a solvent such as water, methylene chloride, chloroform, toluene, THF, ether, water and the like under a temperature condition of 0 to 100 ° C.
  • Fig. 1 is a scheme that gives an overview of the following examples.
  • Example 1 Instead of yttrium (Y (0 to Pr)) used in Example 1, the metals shown in Table 1 below were used.
  • Dess-Martin periodinane (941 mg, 2.22 mmol) was added at room temperature, heated to 80 ° C. and stirred for 12 hours. After confirming the disappearance of the raw materials by TLC, saturated sodium bicarbonate water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over bow glass, filtered, and concentrated to obtain a crude product. This was dissolved in 15 mL of methylene chloride, and Dess-Martin periodinane (941 mg, 2.22 mmol) was added under ice cooling, followed by stirring for 40 minutes. Saturated aqueous sodium sulfite solution was added, and the product was extracted with ethyl acetate.
  • reaction was performed at 50 ° C for 4 hours.
  • Trifluoroacetic acid 24 mL, 0.316 mmol
  • a methylene chloride solution 0.3 mL
  • 3-pentyl ether 6. mg, 0.158 mmol
  • the reaction solution was concentrated, and the residue was dissolved in methylene chloride (0.2 mL).
  • a methylene chloride solution of triethylamine 11 mL, 0.079 mmol
  • Boc 2 O 0.0158 mmol
  • N-odosuccinimide (NIS: 1.08 g, 4.72 mmol) was added to a black mouth form solution (50 mL) of Boc, Ac form V (804 mg, 3.16 mmol), and the mixture was stirred at room temperature for 23 hours. NIS 500 mg was added and stirring was continued at 60 ° C for 10 hours. DBU (1.5 mL, 6.32 mmol) was reacted here for 12 hours, and then the reaction solution was concentrated.
  • Aziridine (11.7 mg, 0.032 mmol) was dissolved in 3-pentanol (0.1 mL), and a solution of boron trifluoride ether complex in 3-pentanol (0.1 M, 0.63 mL, 0.063 mmol) was cooled with ice. It was dripped at. After 1 hour, water, saturated aqueous sodium hydrogen carbonate, and ethyl acetate were added, and the product was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium nitrate, filtered, and concentrated to obtain a crude product of 3-pentyl ether.
  • Trifluoroacetic acid (TFA, 30 mL) was added to a methylene chloride solution of 0.5-pentyl ether (0.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and pyridine (1 mL), 4-dimethylaminopyridine and acetic anhydride were added to the residue and reacted at room temperature for 1 hour. The reaction solution was concentrated and subjected to silica gel column chromatography purification to obtain Z and Ac isomers (3 process yield 42%).
  • FIG. 1 is a scheme for bird's-eye view of Examples 1 to 25.
  • FIG. 2 This is a scheme overlooking Examples 26 to 35.

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Abstract

La présente invention concerne un nouveau procédé de synthèse du médicament antiviral oseltamivir phosphate (nom commercial : Tamiflu) sans utiliser d'acide shikimique au titre de produit de départ ; la présente invention concerne également un nouveau produit de départ ou intermédiaire pouvant être employé dans le procédé de synthèse. Il s'agit d'un composé de formule générale (I) ou (II) suivante (où R1 et R4 représentent chacun indépendamment un groupement t-butoxycarbonyle, benzyloxycarbonyle, acétyle, benzyle, fluorénylméthoxycarbonyle, p-méthoxybenzyle, 4-nitrobenzoyle, 3,5-dinitrobenzoyle ou un atome d'hydrogène).
PCT/JP2007/053259 2006-02-23 2007-02-22 DÉRIVÉ α,β-INSATURÉ DE CYCLOHEXANONE, PROCÉDÉ DE SYNTHÈSE DUDIT DÉRIVÉ ET PROCÉDÉ DE SYNTHÈSE D'UN INTERMÉDIAIRE DE LADITE SYNTHÈSE WO2007099843A1 (fr)

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JP2008502731A JPWO2007099843A1 (ja) 2006-02-23 2007-02-22 α，β−不飽和シクロヘキサノン誘導体及びその製造方法、並びにその中間体の製造方法

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JP2009215266A (ja) * 2008-03-12 2009-09-24 Kose Corp シキミ酸を有効成分とする美白剤
JP2011016784A (ja) * 2009-09-01 2011-01-27 Okayama Univ １，３−ジオキソラン化合物及びその製造方法
CN102459147A (zh) * 2009-06-09 2012-05-16 国立大学法人冈山大学 含有硝基的醚化合物及其制备方法
CN102659615A (zh) * 2012-05-09 2012-09-12 中国药科大学 奥司他韦衍生物、其制备方法及其医药用途
WO2015049700A1 (fr) * 2013-10-04 2015-04-09 Council Of Scientific And Industrial Research Procédé pour la préparation d'intermédiaire pour la préparation de phosphate d'oseltamivir

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FUKUTA Y. ET AL.: "De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3", J. AM. CHEM. SOC., vol. 128, no. 19, 17 May 2006 (2006-05-17), pages 6312 - 6313 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009215266A (ja) * 2008-03-12 2009-09-24 Kose Corp シキミ酸を有効成分とする美白剤
CN102459147A (zh) * 2009-06-09 2012-05-16 国立大学法人冈山大学 含有硝基的醚化合物及其制备方法
JP2011016784A (ja) * 2009-09-01 2011-01-27 Okayama Univ １，３−ジオキソラン化合物及びその製造方法
CN102659615A (zh) * 2012-05-09 2012-09-12 中国药科大学 奥司他韦衍生物、其制备方法及其医药用途
WO2015049700A1 (fr) * 2013-10-04 2015-04-09 Council Of Scientific And Industrial Research Procédé pour la préparation d'intermédiaire pour la préparation de phosphate d'oseltamivir
JP2016537315A (ja) * 2013-10-04 2016-12-01 カウンシル オブ サイエンティフィック アンド インダストリアル リサーチ リン酸オセルタミビル調製用中間体の調製方法
US9522922B2 (en) 2013-10-04 2016-12-20 Council Of Scientific And Industrial Research Process for the preparation of intermediate for the preparation of oseltamivir phosphate

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