JP2008094744A - Process for producing piperidin-4-one derivative using bisaminol ether compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a process for producing a piperidin-4-one derivative useful as an agricultural and pharmaceutical intermediate. <P>SOLUTION: The piperidin-4-one derivative represented by the formula (III-1) or (III-2) is produced by reaction of a bisaminol ether compound represented by the formula (I) and an acetone derivative represented by the formula (II) in the presence of a metal iodide to function as a Lewis acid, or a Lewis acid and an alkali metal iodide or an alkaline earth metal iodide. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel process for producing piperidin-4-one derivatives, which are useful intermediates for agricultural medicine.

  Among the piperidin-4-one derivatives useful as an agricultural and pharmaceutical intermediate, as a method for producing an isotropane derivative having a crosslinked structure, for example, as shown in the following formula, cyclopentanone is used in one step using a Double Mannich reaction. Methods for cyclization are known. (See Non-Patent Document 1)

Synlett, 2004, (13), 2359-2363

However, although the method described in Non-Patent Document 1 is excellent in yield, the substrate of the Mannich reaction is limited to a substrate with relatively high reactivity, and the resulting product is 2- When the ester is hydrolyzed and decarboxylated under normal conditions, the product is decomposed and the yield is low. Thus, there are disadvantages in that it is poor in practical use and is versatile.
An object of the present invention is to provide a method for producing a piperidin-4-one skeleton typified by an isotropane skeleton having a high yield and high versatility, which can be used industrially.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have made a metal iodide acting as a Lewis acid, or reacting a Lewis acid with an alkali metal iodide or an alkaline earth metal iodide, The present inventors have found that versatility can be obtained for the substrate to be reacted, and the present invention has been completed.

（式中、Ｒ_１１は、水素原子または有機基を表し、Ｒ_１２及びＲ_１３は、それぞれ独立に有機基を表し、または一体となって化学的に許容される環構造を構成する官能基を表す。）で表されるビスアミノールエーテル化合物と、式（II）

（式中、Ｒ_１〜Ｒ_４は、それぞれ独立に、水素原子、または有機基を表し、Ｒ_１とＲ_３は、一体となって化学的に許容される環構造を構成する官能基を表す。）で表されるアセトン誘導体を、ルイス酸として作用する金属ヨウ化物、またはルイス酸及びアルカリ金属ヨウ化物もしくはアルカリ土類金属ヨウ化物存在下に反応させることを特徴とする式（III−１）または（III−２）

（式中、Ｒ_１１、Ｒ_１〜Ｒ_４は、前記と同じ意味を表し、Ｒ_１４及びＲ_１５は、それぞれ独立に有機基を表し、または一体となって化学的に許容される環構造を構成する官能基を表す。）で表されるピペリジン−４−オン誘導体の製造方法、
（２）式（I）中、化学的に許容される環構造を構成する官能基が、アルキレン基であることを特徴とする上記（１）に記載のピペリジン−４−オン誘導体の製造方法、
（３）式（II）で表される化合物が、式（IV）

（式中、Ｒ_２１は、有機基を表し、点線は、化学的に許容される環構造を構成する官能基を表し、ｎは、０または化学的に許容される置換基数を表し、ｎが２以上の場合、Ｒ_２１同士は、同一または相異なっており、カルボニル基のα位は、少なくとも１つの水素原子を有するものとする。）で表される環状ケトン体であることを特徴とする上記（１）に記載のピペリジン−４−オン誘導体の製造方法、
（４）ルイス酸が、(Ｒ_１０１)_ｎＳｉ(Ｘ^１)_４−ｎ（式中、Ｒ_１０１は炭化水素基を表し、ｎは１ないし３を表し、ｎが２以上の場合、Ｒ_１０１同士は、同一または相異なっていてもよく、Ｘ^１は、臭素原子、または塩素原子を表す。）であることを特徴とする上記（１）に記載のピペリジン−４−オン誘導体の製造方法、および
（５）ルイス酸として作用する金属ヨウ化物がＭｅ_３ＳｉＩであることを特徴とする上記（１）記載のピペリジン−４−オン誘導体の製造方法に関する。 That is, the present invention
(1) Formula (I)

(In the formula, R ₁₁ represents a hydrogen atom or an organic group, R ₁₂ and R ₁₃ each independently represents an organic group, or a functional group that forms a chemically acceptable ring structure together. A bisaminol ether compound represented by formula (II)

(In the formula, R _{1 to} R ₄ each independently represent a hydrogen atom or an organic group, and R ₁ and R ₃ represent a functional group that forms a chemically acceptable ring structure together. )) Is reacted in the presence of a metal iodide which acts as a Lewis acid, or a Lewis acid and an alkali metal iodide or alkaline earth metal iodide. Or (III-2)

(Wherein R ₁₁ , R _{1 to} R ₄ represent the same meaning as described above, and R ₁₄ and R ₁₅ each independently represent an organic group, or together form a chemically acceptable ring structure. A method for producing a piperidin-4-one derivative represented by:
(2) The method for producing a piperidin-4-one derivative according to the above (1), wherein the functional group constituting the chemically acceptable ring structure in the formula (I) is an alkylene group,
(3) The compound represented by the formula (II) is represented by the formula (IV)

(Wherein R ₂₁ represents an organic group, the dotted line represents a functional group constituting a chemically acceptable ring structure, n represents 0 or the number of chemically acceptable substituents, and n represents In the case of 2 or more, R _21's are the same or different and the α-position of the carbonyl group has at least one hydrogen atom.) A process for producing the piperidin-4-one derivative according to (1) above,
(4) The Lewis acid is (R ₁₀₁ ) _n Si (X ¹ ) _4-n (wherein R ₁₀₁ represents a hydrocarbon group, n represents 1 to 3, and when n is 2 or more, R ₁₀₁ May be the same or different from each other, and X ¹ represents a bromine atom or a chlorine atom.) The method for producing a piperidin-4-one derivative according to the above (1), And (5) the method for producing a piperidin-4-one derivative according to the above (1), wherein the metal iodide acting as a Lewis acid is Me ₃ SiI.

In the present invention, by using a metal iodide acting as a Lewis acid, or a Lewis acid and an alkali metal iodide or an alkaline earth metal iodide, a substrate is reacted for a general purpose when performing a Mannich reaction. I was able to do it.
As a result, it has become possible to provide a method for producing a piperidin-4-one skeleton typified by an isotropane skeleton, which has a high yield, is highly versatile and can be used industrially.

In the present invention, a bisaminol ether compound represented by the formula (I), an acetone derivative represented by the formula (II), a piperidin-4-one represented by the formula (III-1) or the formula (III-2) Derivatives and substituents of the cyclic ketone body represented by the formula (IV) are described below.
The “organic group” in the substituents R _{11 to} R ₁₃ , R _{1 to} R ₄ , R ₁₄ and R ₁₅ is a group that does not inhibit this reaction (for example, a group that is not reactive under the reaction conditions in this method). And a group that does not cause steric hindrance of the reaction), and examples thereof include a hydrocarbon group and a heterocyclic group.

The hydrocarbon group and the heterocyclic group also include a hydrocarbon group and a heterocyclic group having a substituent. The hydrocarbon group includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and a group in which these are bonded.
Examples of the aliphatic hydrocarbon group include 1 to 20 carbon atoms (preferably 1 to 1) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, decyl, and dodecyl groups. 10, more preferably an alkyl group of about 1 to 3); an alkenyl group of about 2 to 20 carbon atoms (preferably 2 to 10, more preferably 2 to 3) such as vinyl, allyl, 1-butenyl group; Examples thereof include alkynyl groups having about 2 to 20 carbon atoms (preferably 2 to 10, more preferably 2 to 3) such as propynyl groups.

As the alicyclic hydrocarbon group, a cycloalkyl group having about 3 to 20 carbon atoms (preferably 3 to 15, more preferably 5 to 8) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl group; cyclopentenyl A cycloalkenyl group having about 3 to 20 carbon atoms (preferably 3 to 15 and more preferably 5 to 8) such as cyclohexenyl group; perhydronaphthalen-1-yl group, norbornyl, adamantyl, tetracyclo [4.4 0.1 ^2,5 . 1 ^7,10 ] bridged cyclic hydrocarbon groups such as dodecan-3-yl groups.
Examples of the aromatic hydrocarbon group include groups having about 6 to 14 (preferably 6 to 10) carbon atoms such as phenyl and naphthyl groups.

Examples of the hydrocarbon group in which an aliphatic hydrocarbon group and an alicyclic hydrocarbon group are bonded include cycloalkyl-alkyl groups such as cyclopentylmethyl, cyclohexylmethyl, and 2-cyclohexylethyl groups. The hydrocarbon group in which an aliphatic hydrocarbon group and an aromatic hydrocarbon group are bonded to each other includes an aralkyl group (for example, a C _7-18 aralkyl group) and an alkyl-substituted aryl group (for example, about 1 to about 4). And a phenyl group or a naphthyl group substituted with a C _1-4 alkyl group).

  The hydrocarbon group includes various substituents such as halogen atoms, oxo groups, substituted oxy groups (eg, alkoxy groups, aryloxy groups, aralkyloxy groups, acyloxy groups), substituted oxycarbonyl groups (alkoxycarbonyl groups, Aryloxycarbonyl groups, aralkyloxycarbonyl groups, etc.), substituted or unsubstituted carbamoyl groups, cyano groups, nitro groups, acyl groups, sulfo groups, heterocyclic groups, hydroxyl groups and carboxyl groups protected by conventional protecting groups And so on. In addition, an aromatic or non-aromatic heterocycle may be condensed with the ring of the alicyclic hydrocarbon group or aromatic hydrocarbon group.

The heterocyclic group includes an aromatic heterocyclic ring and a non-aromatic heterocyclic ring. Examples of such a heterocyclic ring include a heterocyclic ring containing an oxygen atom as a hetero atom (for example, 5-membered ring such as furan, tetrahydrofuran, oxazole, isoxazole, and γ-butyrolactone ring, 4-oxo-4H-pyran, tetrahydro 6-membered ring such as pyran, morpholine ring, condensed ring such as benzofuran, isobenzofuran, 4-oxo-4H-chromene, chroman, isochroman ring, 3-oxatricyclo [4.3.1.1 ^4,8 ] undecane 2-one ring, a bridged ring such as 3-oxatricyclo [4.2.1.0 ^4,8 ] nonan-2-one ring), a heterocycle containing a sulfur atom as a hetero atom (for example, thiophene, 5-membered ring such as thiazole, isothiazole, thiadiazole ring, 6-membered ring such as 4-oxo-4H-thiopyran ring, benzothiophene ring Any fused ring), heterocycles containing nitrogen atoms as heteroatoms (eg, 5-membered rings such as pyrrole, pyrrolidine, pyrazole, imidazole, triazole rings, 6-membered rings such as pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine rings) Ring, indole, indoline, quinoline, acridine, naphthyridine, quinazoline, a condensed ring such as a purine ring, etc.). In addition to the substituents that the hydrocarbon group may have, the heterocyclic group includes an alkyl group (eg, a C _1-4 alkyl group such as a methyl or ethyl group), a cycloalkyl group, an aryl group It may have a substituent such as (for example, phenyl, naphthyl group).

  In the compounds represented by the formulas (I), (II), (III-1), (III-2) and (IV), “functional group constituting a chemically acceptable ring structure” means carbon. Examples thereof include a divalent hydrocarbon group having 1 to 20 carbon atoms and a divalent hydrocarbon group having 1 to 20 carbon atoms containing one or more hetero atoms such as O and S. Examples of the hydrocarbon group herein include those obtained by replacing the monovalent hydrocarbon group exemplified in the above “organic group” with a divalent one. These may have a substituent, and examples thereof are the same as those exemplified in the above “organic group”. In particular, an alkylene group having 1 to 20 carbon atoms is preferable, and an alkylene group having 2 to 5 carbon atoms is more preferable.

(Manufacturing method)
The reaction between the bisamyl ether compound represented by formula (I) and the acetone derivative represented by formula (II) is a metal iodide acting as a Lewis acid, or a Lewis acid and an alkali metal iodide or an alkaline earth metal. Performed in the presence of iodide.
The ratio between the bisaminol ether compound and the acetone derivative can be appropriately selected in consideration of reactivity, raw material cost, and the like. Usually, the usage-amount of a bisaminol ether compound is 0.1-10 mol with respect to 1 mol of acetone derivatives, Preferably it is 0.5-2 mol.

Examples of the Lewis acid used in the present invention include aluminum bromide (III), aluminum chloride (III), gallium chloride (III), iron chloride (III), antimony chloride (V), tin chloride (IV), and chloride. Titanium (IV), zinc chloride (II), boron fluoride (III), boron chloride (III), copper trifluoromethanesulfonate (II), zinc trifluoromethanesulfonate (II), diphosphorus pentoxide, Mo (CO ) ₆ and other metal carbonyl complexes, trifluoromethanesulfonic acid lanthanoid-based complexes represented by scandium (III) trifluoromethanesulfonic acid, (R ₁₀₁ ) _n Si (X ¹ ) _{4-n, and the} like.
In the formula of (R ₁₀₁ ) _n Si (X ¹ ) _4-n , R ₁₀₁ represents a hydrocarbon group, n represents 1 to 3, and when n is 2 or more, R ₁₀₁ are the same or different. X represents a bromine atom or a chlorine atom.
Here, the “hydrocarbon group” may be any group that does not inhibit the action as a Lewis acid, and includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and a group in which these groups are bonded. And can be exemplified in the same manner as in the case of the “organic group”.
The Lewis acid is preferably (R ₁₀₁ ) _n Si (X ¹ ) _4-n , and examples thereof include MeSiCl ₃ , Me ₂ SiCl ₂ , Me ₃ SiCl, and Me ₃ SiBr. The use amount of the Lewis acid can be appropriately selected. In particular, when (R ₁₀₁ ) _n Si (X ¹ ) _4-n is used as the Lewis acid, it is preferable to use 1 equivalent or more with respect to the acetone derivative. .
In the present invention, an alkali metal iodide or an alkaline earth metal iodide used together with a Lewis acid is used. Examples of the alkali metal iodide or alkaline earth metal iodide include KI, NaI, RbI, CsI, and CaI _2. MgI _{2 and the} like are exemplified, and NaI and KI are preferable. The amount used can be appropriately selected, but when (R ₁₀₁ ) _n Si (X ¹ ) _4-n is used as the Lewis acid, it is preferably used in an amount of 1 equivalent or more with respect to the Lewis acid.
In the present invention, metal iodides that act as Lewis acids can also be used, for example, Me ₃ SiI, MeSiI _3, AlI ₃ , ZnI ₂ , TiI ₃ and the like.

Examples of the solvent used include aliphatic hydrocarbons such as hexane, heptane, and octane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene, and ethylbenzene; chloroform, dichloromethane, 1,2- Halogenated hydrocarbons such as dichloroethane; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; nitriles such as acetonitrile and benzonitrile. These solvents are used alone or in admixture of two or more.
The amount of the solvent used is not particularly limited and can be appropriately selected according to the type of the reaction system, but is usually about 0.5 times or more by mass ratio with respect to the bisaminol ether compound.

  The reaction temperature can be appropriately selected depending on the reaction component, the type of the catalyst and the like, and is not particularly limited, but is usually from −50 ° C. to the boiling point of the reaction component or solvent, preferably from 0 to 50 ° C. The reaction time is not particularly limited, but is usually about 5 minutes to 10 hours, preferably 30 minutes to 3 hours. The reaction may be performed at normal pressure or under pressure. The reaction atmosphere is not particularly limited as long as the reaction is not inhibited, and may be any of an air atmosphere, a nitrogen atmosphere, an argon atmosphere, and the like. Further, the reaction can be carried out by any method such as batch, semi-batch and continuous methods.

  After completion of the reaction, the reaction product can be separated and purified by separation means such as filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, etc., or a separation means combining these.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to an Example.

Synthesis of 3-Benzyl-3-aza-bicyclo [3.2.1] octan-8-one ethylene ketal Compound (1) Under a nitrogen atmosphere, 1.50 g (10 mmol) of sodium iodide was added and dissolved in 5 ml of acetonitrile. 1.09 g (10 mmol) of chlorotrimethylsilane was added dropwise and stirred for 20 minutes, then cooled to 0 ° C., 0.42 g (5 mmol) of cyclopentanone was added, and the mixture was stirred for 20 minutes. A solution of 0.97 g (5 mmol) of 3-Benzyl- [1,5,3] dioxazepane (2) in acetonitrile (3 ml) was added dropwise at the same temperature over 10 minutes, and the mixture was returned to room temperature and stirred for 1 hour. did. The reaction mixture was poured into saturated aqueous sodium bicarbonate, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give compound (1) as a crude product. It was. Furthermore, isolation and purification were performed using silica gel column chromatography (hexane / ethyl acetate) to obtain 1.01 g (yield 78%) of the target compound (1).

Synthesis of 3-Benzyl-3-aza-bicyclo [3.2.1] octan-8-one ethylene ketal Compound (1) Under a nitrogen atmosphere, 0.83 g (5.5 mmol) of sodium iodide was added to 5 ml of acetonitrile and dissolved. Dichlorodimethylsilane 0.71 g (5.5 mmol) was added dropwise and stirred for 20 minutes, then cooled to 0 ° C., added with cyclopentanone 0.42 g (5 mmol), and stirred for 20 minutes. A solution of 0.97 g (5 mmol) of 3-Benzyl- [1,5,3] dioxazepane (2) in acetonitrile (3 ml) was added dropwise at the same temperature over 10 minutes, and the mixture was returned to room temperature and stirred for 1 hour. did. The reaction mixture was poured into saturated aqueous sodium bicarbonate, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give compound (1) as a crude product. It was. When analyzed by HPLC, the yield was 83.4%.

Reference example 1
3-Benzyl-3-aza-bicyclo [3.2.1] octan-8-one ethylene ketal Acid hydrolysis of compound (1) 3-Benzyl-3-aza-bicyclo [3.2.1] octan- purified by silica gel column 0.26 g (1 mmol) of 8-one ethylene ketal compound (1) was dissolved in 1,4-dioxane (1 ml), 0.3 ml of 30% fuming sulfuric acid was added dropwise, and the mixture was stirred for 30 minutes. The reaction solution was poured into ice water, neutralized with 1M aqueous sodium hydroxide solution, extracted with hexane / ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. As a crude product, 3-Benzyl-3-aza-bicyclo [3.2.1] octan-8-one compound (3) was obtained. When analyzed by HPLC, the yield was 96.0%.

Reference example 2
Synthesis of 3-Benzyl- [1,5,3] dioxazepane (2) 30.0 g (1 mol) of paraformaldehyde was added to a solution of toluene (200 ml) in 31.0 g (1 mol) of ethylene glycol and 53.6 g (0.5 mol) of benzylamine. ) And azeotropic dehydration by heating. The reaction was stopped when approximately 18 g (1 mol) of water was distilled off, and the solvent was distilled off to obtain 89.2 g (˜92% in pure content) of Compound (2) as a crude product.

Claims (5)

Formula (I)

(In the formula, R ₁₁ represents a hydrogen atom or an organic group, R ₁₂ and R ₁₃ each independently represents an organic group, or a functional group that forms a chemically acceptable ring structure together. A bisaminol ether compound represented by formula (II)

(In the formula, R _{1 to} R ₄ each independently represent a hydrogen atom or an organic group, and R ₁ and R ₃ represent a functional group that forms a chemically acceptable ring structure together. )) Is reacted in the presence of a metal iodide which acts as a Lewis acid, or a Lewis acid and an alkali metal iodide or alkaline earth metal iodide. Or (III-2)

(Wherein R ₁₁ , R _{1 to} R ₄ represent the same meaning as described above, and R ₁₄ and R ₁₅ each independently represent an organic group, or together form a chemically acceptable ring structure. Represents a functional group to constitute.) A method for producing a piperidin-4-one derivative represented by: The method for producing a piperidin-4-one derivative according to claim 1, wherein the functional group constituting the chemically acceptable ring structure in formula (I) is an alkylene group. The compound represented by formula (II) is represented by formula (IV)

(Wherein R ₂₁ represents an organic group, the dotted line represents a functional group constituting a chemically acceptable ring structure, n represents 0 or the number of chemically acceptable substituents, and n represents In the case of 2 or more, R _21's are the same or different and the α-position of the carbonyl group has at least one hydrogen atom.) The manufacturing method of the piperidin-4-one derivative of Claim 1. When the Lewis acid is (R ₁₀₁ ) _n Si (X ¹ ) _4-n (wherein R ₁₀₁ represents a hydrocarbon group, n represents 1 to 3, and n is 2 or more, R ₁₀₁ 2. The method for producing a piperidin-4-one derivative according to claim 1, which may be the same or different, and X represents a bromine atom or a chlorine atom. The method for producing a piperidin-4-one derivative according to claim 1, wherein the metal iodide acting as a Lewis acid is Me ₃ SiI.