WO2004087724A1 - Procede pour la production de derive de cyclopentanone $g(a),$g(b),$g(g)-substitue - Google Patents

Procede pour la production de derive de cyclopentanone $g(a),$g(b),$g(g)-substitue Download PDF

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Publication number
WO2004087724A1
WO2004087724A1 PCT/JP2004/004484 JP2004004484W WO2004087724A1 WO 2004087724 A1 WO2004087724 A1 WO 2004087724A1 JP 2004004484 W JP2004004484 W JP 2004004484W WO 2004087724 A1 WO2004087724 A1 WO 2004087724A1
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group
substituted
formula
unsubstituted
carbon atoms
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PCT/JP2004/004484
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English (en)
Japanese (ja)
Inventor
Akira Onodera
Yohei Kobashi
Yoshihiro Kimura
Koumei Ohta
Chihiro Yokoo
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Taisho Pharmaceutical Co., Ltd.
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Priority to JP2005504234A priority Critical patent/JP4591778B2/ja
Publication of WO2004087724A1 publication Critical patent/WO2004087724A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • 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
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

Definitions

  • the present invention relates to a, ⁇ , ⁇ -substitution useful as a pharmaceutical or a synthetic intermediate thereof.
  • ⁇ , ⁇ -Substituted cyclopentenonone derivatives are useful as pharmaceuticals or their intermediates.
  • 13,14-didehydroprostaglandin derivatives (compounds represented by the following formula), which are ⁇ ,, ⁇ -substituted cyclopentenonone derivatives having a triple bond at the 13-position, have recently attracted attention as compounds having a strong platelet aggregation inhibitory action (Japanese Patent Application Laid-Open No. Hei 6-192922).
  • the first example is a method for producing a 13,14-didehydroprostaglandin E derivative using the key reaction of ring opening of an epoxide with an organoaluminum acetylide reagent as shown in Reaction Formula 1 below (J. Fr. i ed et al., Te trahedron Letters, 1973, 14, 3899-3902.).
  • the second example is a production example using Corey lactone as a starting material, as shown in the following reaction formula 2.
  • the dehydrohalogenation reaction is allowed to proceed during the Wittig reaction to form a triple bond at the 13-position, resulting in 13,14-didehydroprostaglandin E.
  • This is a method for producing derivatives ( Gandolfi et al., ⁇ Farmaco Edition Sciences, 27, 1255 (1972).)
  • a third example is a method for producing a 13,14-didehydroprostaglandin ⁇ derivative by reacting an ⁇ , ⁇ -substituted cyclopentenone derivative with an organometallic reagent represented by the following formula [ ⁇ ] (Patent No. 2) No. 5,366,226), and the claims contain an organometallic reagent containing a triple bond [ ⁇ ], but there is no description of the examples.
  • an organoaluminum acetylide reagent is allowed to act on a cyclopentenone derivative having a getylaminomethyl group at the ⁇ -position to form an exomethylene compound, and then the ⁇ side chain is formed.
  • This is a method for producing a 13,14-didehydroprostaglandin derivative by adding Michael (F. Sato et al., J. Org. Chem., 1991, 56, 3205-3207.).
  • OTBS (T S) R1 alkyl group, cyclohexyl group
  • the a side chain is introduced stepwise, which is advantageous for producing a wide variety of derivatives.
  • it can be obtained by the introduction reaction of i3 side chain.
  • the ratio of the trans-form to the cis-form of the exo-methylene form fluctuates greatly, from 1.5 to 23: 1, making it difficult to obtain the desired trans-form stably (see Table 1).
  • the present inventors have made intensive studies to achieve the above object, and as a result, in the presence of a trialkylsilyl triflate, an a, r-substituted cyclopentenone derivative represented by the formula [I] was converted to a compound represented by the formula [III].
  • a substituted ethynyl organometallic reagent shown By reacting the substituted ethynyl organometallic reagent shown, a substituted ethynyl group can be introduced at the / 3 position in a highly stereoselective manner.
  • the present inventors have found a process for obtaining a 1,3-i-substituted cyclopentene nonone derivative with higher yield and higher stereoselectivity than ever before, and completed the present invention.
  • X 1 and X 2 are the same or different and represent an oxygen atom, a sulfur atom, a methylene group, a vinylene group, an ethynylene group or an arelenylene group, and n and q are the same or different and represent an integer of 0 to 6, ni and p are the same or different and each represent an integer of 0 to 2, r represents an integer of 0 to 3.
  • R 1 represents a hydrogen atom, a nitrile group
  • -OR 6 (formula Wherein R 6 represents a hydroxyl-protecting group.)
  • -C00R 7 wherein, R 7 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted carbon atom number) 2 to 10 alkenyl groups, substituted or unsubstituted alkynyl groups, 2 to 10 alkynyl groups, substituted or unsubstituted cycl
  • R 8 is. Represents an alkyl group of one to six carbon atoms
  • BrZn or LiR 8 3 Al indicates, R 3 is a substituted or unsubstituted carbon atoms 1 to 1 0 alkyl groups, substituted or unsubstituted alkenyl groups having 2 to 10 carbon atoms, substituted or unsubstituted alkynyl groups having 2 to 10 carbon atoms, substituted or unsubstituted carbon atoms
  • Z represents a hydrogen atom or Z′R 4 (wherein Z ′ represents an oxygen atom or a sulfur atom, and R 4 represents a hydroxyl-protecting group
  • R5 represents a trialkylsilyl group
  • A, RR 2, R 3 and Z are Ru as defined der above.
  • the method for producing an ⁇ , ⁇ , ⁇ -substituted cyclopentene non-trialkylsilyl enol ester represented by the formula:
  • a non-aqueous condition of an ⁇ , ⁇ , ⁇ -substituted cyclopentene non-trialkylsilyl enol ether represented by the formula [V]
  • the substituted or unsubstituted alkyl group having 1 to 10 carbon atoms means a linear or branched alkyl group, such as a methyl group, an ethyl group, an ⁇ -propyl group, and an isopropyl group.
  • ⁇ -butyl group isobutyl group, t_butyl group, n-pentyl group, n-hexyl group, 2-methylpentyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycle Hexoxyloxymethyl, benzyl, phenoxymethyl, 2-methoxyethyl, 2-chloroisopropyl, 2-methylhexyl, 2,5-dimethylhexyl, 2,6-dimethylheptyl Group, 2- (2, -methylcyclohexyl) pentyl group, n-octyl group, 3- (3'-methoxyphenyl) octyl group, 5-chloromethoxyheptyl group, n-decanyl group .
  • the substituent in the alkyl group is not particularly limited as long as it does not participate in the reaction.
  • examples include a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyloxy group having 3 to 10 carbon atoms, and phenyl.
  • Alkyl, cycloalkyloxy, phenyl and phenoxy groups are unsubstituted, one or more halogen atoms, linear or branched alkyl groups having 1 to 4 carbon atoms or carbon atoms It may have several to four substituents such as a linear or branched alkoxy group.
  • halogen atom examples include fluorine, chlorine, bromine, and iodine.
  • linear or branched alkyl group having 1 to 4 carbon atoms examples include a methyl group, an ethyl group, an isopropyl group and a t-butyl group.
  • Examples of the linear or branched alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an isopropyloxy group, an 11-butoxy group and a t-butoxy group.
  • the substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms means a linear or branched alkenyl group, such as a bier group, an aryl group, a 2,6-dimethyl-5-heptenyl group, 1,3-butadienyl group, ⁇ -propenyl-butenyl group, 4-pentenyl group, 3-chloro-1,5-hexagenenyl group, 2-methyl-4-pentenyl group,-(1'-ethoxyl) 2-methyl-4-pentenyl group, 3-ethyl-4- (4'-methoxycyclohexyl) -1,5-hexenyl group and 3-isopropyl-4-pentenyl group.
  • a bier group such as a bier group, an aryl group, a 2,6-dimethyl-5-heptenyl group, 1,3-butadienyl group, ⁇ -propenyl-butenyl
  • the substituent in the alkenyl group is not particularly limited as long as it does not participate in the reaction.
  • examples include a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyloxy group having 3 to 10 carbon atoms, and phenyl.
  • cycloalkyl group, cycloalkyloxy group, phenyl group and phenoxy group are unsubstituted, one or more halogen atoms, linear or branched having 1 to 4 carbon atoms. It may have a substituent such as a chain alkyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • the substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms means a linear or branched alkynyl group, for example, 2-propynyl group, n-butynyl group, n-decynyl group, 2- Bromo-3-pentynyl, 2-methyl-5-heptynyl, 2-methoxy-6-methyl-7-en-3-octynyl, 3-cyclohexyloxy-1-en-4- A xynyl group.
  • the substituent in the alkynyl group is not particularly limited as long as it does not participate in the reaction, for example, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyloxy group having 3 to 10 carbon atoms, phenyl Group, phenoxy group, linear or branched alkoxy group having 1 to 4 carbon atoms, halogen atom and linear or branched alkenyl group having 2 to 6 carbon atoms.
  • One or more selected groups may be mentioned. Among them, a cycloalkyl group, a cycloalkyloxy group, a phenyl group and a phenoxy group are unsubstituted.
  • One or more halogen atoms, 1 carbon atom It may have a substituent such as a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • a linear or branched alkenyl group having 2 to 6 carbon atoms is, for example, a vinyl group, a propenyl group, a 2-methyl-2-butenyl group, a 1,3-butadienyl group, a 2,4- Dimethyl-1,4-pentenyl phenyl group.
  • a linear or branched alkyl group having 1 to 6 carbon atoms is, for example, a methyl group, an ethyl group, an isopropyl group, an n-propyl group, an n-butyl group, a t-butyl group, a hexyl group Are listed.
  • a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms is, for example, a cycl group, a cyclobutyl group, a cyclopentyl group, a 2,4-dimethylcyclopentyl group, a cyclohexyl group, a 2-methylcyclo group.
  • the substituent in the cycloalkyl group is not particularly limited as long as it does not participate in the reaction.
  • Examples of the substituted or unsubstituted phenyl group include a phenyl group, a 4-bromophenyl group, and a 2-methyl-4-methoxyphenyl group.
  • the substituent in the phenyl group is not particularly limited as long as it does not participate in the reaction.
  • examples include a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a carbon atom having 1 to 4 carbon atoms.
  • Examples of the substituted or unsubstituted phenoxy group include a phenoxy group, a 2-methylphenoxy group, a 2-chlorophenoxy group, and a 4-isopropoxyphenoxy group.
  • the substituent in the phenoxy group is not particularly limited as long as it does not participate in the reaction.
  • examples include a halogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a carbon atom having 1 to 4 carbon atoms.
  • Examples of the substituted or unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms include a 2-methylcyclohexyloxy group and a 3-bromooxyheptyloxy group.
  • the substituent in the cycloalkyloxy group is not particularly limited as long as it does not take part in the reaction.
  • examples thereof include an octogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a carbon atom.
  • One or a plurality of groups selected from the group of linear or branched alkoxy groups having a number of 1 to 4 are exemplified.
  • the protecting group for the lipoxyl group may be any group that functions as a protecting group in each reaction, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, a benzyl group, a substituted benzyl group. And diphenylmethyl group, methoxymethyl group, trichloroethyl group, triethylsilyl group, t-butyldimethylsilyl group, 2- (trimethylylsilyl) ethyl group, and aryl group.
  • the substituted benzyl group is not particularly limited as long as it does not participate in the reaction.
  • the hydroxyl-protecting group may be any group that functions as a protecting group in each reaction, and includes a trialkylsilyl group, an alkoxyalkyl group, an aralkyloxyalkyl group, a trityl group or a tetrahydropyranyl (THP) group.
  • THP tetrahydropyranyl
  • trimethylsilyl group triethylsilyl group, t-butyldimethylsilyl group, methoxymethyl group, benzyloxymethyl group, acetyl group, benzoyl group, benzyl group, P-methoxybenzyl group, p-methoxybenzyl group, And a tri (P-methoxyphenyl) methyl group and a benzyloxycarbonyl group.
  • the protecting group for the thiol group may be any group that functions as a protecting group in each reaction, and examples thereof include a benzyl group, a 4-methoxybenzyl group, a diphenylmethyl group, a trityl group, a methoxymethyl group, and a benzyloxycarbonyl group. .
  • the trialkylsilyl triflate includes, for example, t-butyldimethylsilyl triflate.
  • the trialkylsilyl group includes, for example, a trimethylsilyl group, a t-butyldimethylsilyl group, and a triethylsilyl group.
  • the acid includes a mineral acid, an organic acid, a Lewis acid, and the like. More specifically, the mineral acid includes, for example, an organic solvent solution of hydrogen chloride, concentrated sulfuric acid, and phosphoric acid.
  • organic acid examples include trifluoroacetic acid, benzenesulfonic acid, P-toluenesulfonic acid, methanesulfonic acid, and dodecylbenzene sulfonic acid.
  • Lewis acids include, for example, titanium (IV) chloride, zinc chloride, zinc bromide, zinc trifluoromethanesulfonate, magnesium perchlorate, magnesium trifluoromethanesulfonate, boron trifluoride-ethyl chloride complex, aluminum chloride ( 111) and getyl aluminum chloride.
  • the compound of the formula [I] can be produced, for example, according to the method described in Patent No. 2570796, Eur. J. Org. Chem. 1999, 265-2662, and the like.
  • the compound of the formula [III] can be prepared according to a usual method for preparing an organometallic reagent.
  • organozinc reagent of the formula [III] M is BrZn
  • first heat active zinc and 1,2-dibromoethane in tetrahydrofuran to prepare a tetrahydrofuran solution of zinc bromide (ZnBr 2 ).
  • ZnBr 2 zinc bromide
  • it can be prepared by adding it to a separately prepared lithium salt represented by the formula [III] '»ii (CHI).
  • the amount of zinc bromide used is 0.5 to 2 equivalents, preferably 0.8 to 1.2 equivalents are good.
  • Organoaluminum ate complex can be prepared by adding trialkylaluminum (A1R 8 3) the lithium salt of the formula was prepared in the same manner as described above [III] '.
  • the amount of the trialkylaluminum used is 0.5 to 2 equivalents, preferably 0.8 to 1.2 equivalents, relative to the lithium salt.
  • the solvent used for the preparation of the compound of the formula [II] is not particularly limited and may be any solvent which does not inhibit the reaction, and examples thereof include tetrahydrofuran, geethylether, cyclopentyl methyl ether, toluene and hexane.
  • the compound of the formula [IV] can be produced, for example, by the following method.
  • the trialkylsilyl triflate is added to the compound of the formula [I] in an amount of 0.5 to 5 equivalents, preferably 0.8 to 5 equivalents.
  • the organic zinc reagent of the formula [III] is used in an amount of 0.5 to 5 equivalents, preferably 0.8 to 3 equivalents to the compound of the formula [I].
  • the reaction temperature is -100 to 50 ° C, preferably -80 to 30 ° C, and the reaction time is usually 5 minutes to 50 hours.
  • the formula [I] 0.5 to the Toriarukirushi Lil triflate 3 equivalents, preferably 0.8 to 2 equivalents, when the organoaluminate complex of the formula [III] is used in an amount of 0.5 to 4 equivalents, preferably 0.8 to 2 equivalents to the compound of the formula [I] Is good.
  • the reaction temperature is -100 to 20 ° C, preferably _80 to 0 ° C, and the reaction time is usually 5 minutes to 5 hours.
  • the solvent used in these reactions is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, getyl ether, cyclopentylmethyl ether, hexane, and toluene.
  • the compound of the formula [V] can be produced, for example, by the following method, that is, a method of reacting a compound of the formula [IV] with an acid under non-aqueous conditions.
  • the acid include a mineral acid, an organic acid, and a Lewis acid, and preferably include benzenesulfonic acid, P-toluenesulfonic acid, methanesulfonic acid, and magnesium perchlorate.
  • the acid is used in an amount of 0.5 to 3 equivalents, preferably 1 to 2 equivalents, to the compound of the formula [IV].
  • the reaction temperature is ⁇ 100 to 50 ° C., preferably ⁇ 80 to 30 ° C., and the reaction time is usually 0.5 to 20 hours.
  • the solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction, and examples include tetrahydrofuran, getyl ether, dichloromethane, chloroform, toluene, and acetonitrile.
  • the side chain is highly stereoselectively induced in the trans configuration with respect to the ⁇ side chain.
  • a compound of the formula [IV] is reacted with a compound of the formula [I] and an organometallic reagent of the formula [111] in the presence of one or more equivalents of a trialkylsilyl triflate. This is a process for obtaining a compound of the formula [V] at a stroke without isolating the compound of formula (I).
  • the amount of the organozinc reagent of the formula [III] (M is BrZn) to the compound of the formula [I] is 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, and the amount of topyldimethylsilyl triflate used is 1 to 3 equivalents, preferably 1., based on the organozinc reagent of the formula [III] (M is BrZn). 5-2.5 It is better to use the equivalent.
  • the reaction temperature is ⁇ 100 to 50 ° C., preferably ⁇ 80 to 30 ° C., and the reaction time is usually 150 hours.
  • the solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, getyl ether, cyclopentyl methyl ether, hexane, and toluene.
  • THF represents tetrahydrofuran
  • Me represents a methyl group
  • TBS represents a t-butyldimethylsilyl group
  • TES represents a triethylsilyl group
  • HPLC high-performance liquid chromatography
  • Dissolve compound 9 (0.20 g, 0.34 tmol) showing relative configuration in dichloromethane (4. OiiiL), add benzenesulfonic acid (0.06 g, 0.38 mmol) at -78 ° C, and at the same temperature for 3 hours Stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the substituted echel side chain at the i3 position is introduced into the trans configuration in a highly stereoselective manner with respect to the protected hydroxyl group at the a position to efficiently obtain a trans form having a desired high physiological activity.
  • Table 3 The right column of Table 3 shows the results of the present invention, and the left column shows the results of the conventional method (Table 1).
  • the detrialkylsilylation reaction with an acid under non-aqueous conditions of the present invention can control the ⁇ side chain to the trans configuration in a highly stereoselective manner with respect to the 3 side chains.
  • Table 4 shows the results of the detrialkylsilyl cosmic reaction of the t-butyldimethylsilyl enol ether.
  • the results for the hydrous system are shown in Reaction Formula 4.
  • the ratio of the trans-form to the cis-form in the detrialkylsilylation reaction by an acid under non-aqueous conditions of the present invention is from 24 to 220: 1, and the desired trans-form is higher than that in a water-containing system. Highly stereoselective. Table 4
  • Compound 1 and compound 8 used in the present invention can be obtained by the following methods (Reference Examples 1 to 13), but are not limited to these Reference Examples.
  • the production method of the present invention provides a safer and more stereoselective method for various substituted ethyl groups at the ⁇ -position of an ⁇ , ⁇ -substituted cyclobennone derivative having a desired side chain than the conventional method. It is possible to provide a synthesis of Q !, a 3, ⁇ -substituted cyclopentenonone derivative, which is very useful as an industrially suitable drug or an intermediate thereof.

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Abstract

La présente invention a trait à un procédé par lequel un dérivé de cyclopentanone α,β,η-substitué utile en tant que médicament ou intermédiaire de production de médicament est produit de manière plus efficace et plus fiable que par les techniques connues. Le composé présentant une stéréostructure souhaitée peut être produit de manière stéréosélective en un rendement satisfaisant.
PCT/JP2004/004484 2003-03-31 2004-03-30 Procede pour la production de derive de cyclopentanone $g(a),$g(b),$g(g)-substitue WO2004087724A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04270294A (ja) * 1991-02-26 1992-09-25 Fumie Satou α−メチレンシクロペンタノン誘導体の製造法
JPH05294924A (ja) * 1992-04-21 1993-11-09 Taisho Pharmaceut Co Ltd プロスタグランジンｅ１類縁体

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4029251B2 (ja) * 1997-02-04 2008-01-09 小野薬品工業株式会社 ω−シクロアルキル−プロスタグランジンＥ２誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04270294A (ja) * 1991-02-26 1992-09-25 Fumie Satou α−メチレンシクロペンタノン誘導体の製造法
JPH05294924A (ja) * 1992-04-21 1993-11-09 Taisho Pharmaceut Co Ltd プロスタグランジンｅ１類縁体

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