JP2011162494A - Method for producing 4-formylpiperidine acetal derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrial production method obtainable of a 4-formylpiperidine acetal derivative in a high yield and in a short step. <P>SOLUTION: The method comprises catalytically hydrogenating a 4-formylpyridine acetal derivative represented by formula (1) (wherein R<SP>1</SP>and R<SP>2</SP>are alkyl groups which may be the same or different and may be linked with each other to form a ring) in the presence of a catalyst containing rhodium or ruthenium to produce the corresponding 4-formylpiperidine acetal. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing a 4-formylpiperidine acetal derivative useful as a raw material for pharmaceuticals, agricultural chemicals and the like.

The following methods are known as methods for producing 4-formylpiperidine acetal derivatives.
(1) 4-hydroxymethylpiperidine is reacted with benzyl chloroformate in the presence of potassium carbonate, and the resulting N-benzyloxycarbonyl-4-hydroxymethylpiperidine is treated with pyridinium chlorochromate to oxidize, Oxycarbonyl-4-formylpiperidine is obtained. This is treated with methanol and trimethyl orthoformate in the presence of a catalytic amount of p-toluenesulfonic acid to acetalize to give N-benzyloxycarbonyl-4-formylpiperidine dimethyl acetal. Further, a method for obtaining 4-formylpiperidine dimethyl acetal by removing the benzyloxycarbonyl group by heating in ethanol-cyclohexene in the presence of 10% palladium carbon (Patent Document 1).
(2) N-benzyloxycarbonyl-4-formylpiperidine is treated with trimethylorthoformate in the presence of a catalytic amount of p-toluenesulfonic acid to acetalize to obtain N-benzyloxycarbonyl-4-formylpiperidinedimethylacetal. . A method of obtaining 4-formylpiperidine dimethyl acetal by treating this with 10% palladium carbon and ammonium formate to remove the benzyloxycarbonyl group (Patent Document 2).
(3) 4-hydroxymethylpiperidine is reacted with benzyl chloroformate in the presence of triethylamine, and the resulting N-benzyloxycarbonyl-4-hydroxymethylpiperidine is treated with Dess-Martin reagent to oxidize and N-benzyloxy Carbonyl-4-formylpiperidine is obtained. This is reacted with ethylene glycol in the presence of a catalytic amount of p-toluenesulfonic acid to acetalize to obtain N-benzyloxycarbonyl-4- (1,3-dioxolan-2-yl) piperidine. Further, after that, the benzyloxycarbonyl group is removed by catalytic hydrogenation reaction using 10% palladium carbon to obtain 4- (1,3-dioxolan-2-yl) piperidine (Patent Document 3).

  However, in the method (1), pyridinium chlorochromate used as an oxidizing agent is highly toxic and requires a stoichiometric amount or more, so that it is used in a large amount, and this produces harmful waste. Since the process is multistage, the total yield is as low as 10% (vs. 4-hydroxymethylpiperidine), which is not satisfactory as an industrial method. The method (2) uses the intermediate N-benzyloxycarbonyl-4-formylpiperidine obtained by the method (1) as a raw material. The industrial production method of this compound is not known, and it is difficult to obtain raw materials, such as using a highly toxic oxidizing agent as in the method (1). In addition, considering the production of this raw material, the entire process is multistage and is not an industrial method. In the method (3), the Dess-Martin reagent used as an oxidizing agent is expensive and requires more than the stoichiometric amount, and the reagent is a high-valence compound of iodine. Due to the potential danger and the multi-step process, the overall yield is as low as 40% (vs. 4-hydroxymethylpiperidine), which is not satisfactory as an industrial method.

WO02 / 06255 JP 2002-348287 A Special table 2008-510684 gazette

  The objective of this invention is providing the industrial manufacturing method which can obtain a 4-formyl piperidine acetal derivative with a sufficient yield and a short process.

  In order to solve the above-mentioned problems, the present inventors have conducted extensive studies on a method for producing a 4-formylpiperidine acetal derivative in an industrially high yield and in a short process, and as a result, a 4-formylpyridine acetal derivative was obtained. The present inventors have found a method for catalytic hydrogenation in the presence of a catalyst containing rhodium or ruthenium, and completed the present invention.

（式中、Ｒ^１とＲ^２は、同一又は異なっても良いアルキル基を示し、また、相互に結合して環を形成しても良い。）
で表される４−ホルミルピリジンアセタール誘導体を、ロジウム又はルテニウムを含有する触媒の存在下に接触水素化することによる、下記一般式（２）

（式中、Ｒ^１とＲ^２は、前記と同じ。）
で表される４−ホルミルピペリジンアセタール誘導体の製造方法である。 That is, the present invention provides the following general formula (1)

(In the formula, R ¹ and R ² represent the same or different alkyl groups, and may be bonded to each other to form a ring.)
The following general formula (2) is obtained by catalytically hydrogenating a 4-formylpyridine acetal derivative represented by the following formula in the presence of a catalyst containing rhodium or ruthenium.

(In the formula, R ¹ and R ² are the same as described above.)
It is a manufacturing method of 4-formyl piperidine acetal derivative represented by these.

  According to the present invention, a 4-formylpiperidine acetal derivative can be easily produced industrially in high yield and in a short process. The 4-formylpiperidine acetal derivative can be easily converted into N-substituted-4-formylpiperidine useful as a raw material for pharmaceuticals, agricultural chemicals and the like.

Hereinafter, the present invention will be described in detail.
In the 4-formylpyridine acetal derivative represented by the general formula (1), R ¹ and R ² may be the same or different and may be bonded to each other to form a ring. The alkyl group is a linear or branched hydrocarbon group having 1 to 10 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl. Group and the like. Examples of the case where an alkyl group is bonded to each other to form a ring include a 1,3-dioxolanyl group, a 4-methyl-1,3-dioxolanyl group, and a 1,3-dioxanyl group.

Specific examples of the 4-formylpyridine acetal derivative include 4-formylpyridine dimethyl acetal, 4-formylpyridine diethyl acetal, 4-formylpyridine dipropyl acetal, 4-formylpyridine diisopropyl acetal, 4-formylpyridine dibutyl acetal, 4 -(1,3-dioxolan-2-yl) pyridine, 4- (4-methyl-1,3-dioxolan-2-yl) pyridine, 4- (1,3-dioxan-2-yl) pyridine and the like It is done.
The 4-formylpyridine acetal derivative is obtained from a readily available 4-formylpyridine by a method described in the literature (for example, Example 1 of Japanese Patent Publication No. 2005-504004 or Greene's Protective Groups in organic synthesis edition, 2007). Year, John Wiley & Sons, Inc.). Specifically, there is a method of synthesizing 4-formylpyridine acetal derivative by reacting 4-formylpiperidine with alcohol or trialkyl orthoformate in the presence of an acid catalyst. Or it can also synthesize | combine using the method (for example, patent 3098099) of literature literature from 4-cyano pyridine which can be obtained easily. Specifically, the 4-formylpyridine acetal derivative is synthesized by catalytic hydrogenation of 4-cyanopyridine in the presence of an acid and an alcohol. The obtained 4-formylpyridine acetal derivative can be isolated and purified and used in the subsequent step, or can be used in an unisolated state as long as the subsequent step is not affected.

The rhodium or ruthenium-containing catalyst used in the present invention is not particularly limited as long as it is a rhodium or ruthenium-containing catalyst. For example, a catalyst supported on a carrier can be used. Examples of the carrier include diatomaceous earth, pumice, activated carbon, graphite, silica gel, alumina, magnesium oxide, zirconium oxide, titanium oxide, zeolite, calcium carbonate, and barium sulfate, and rhodium carbon or ruthenium carbon is preferable. More preferred is rhodium carbon.
For platinum group metals other than rhodium and ruthenium, for example, the platinum catalyst does not allow the desired reaction to proceed, and the palladium catalyst does not proceed with the nuclear hydrogenation of the pyridine ring, and the acetal dealkoxylation side reaction takes precedence. (For example, a 4-monoalkoxy compound is by-produced), which is not preferable.
On the other hand, when the catalyst containing rhodium or ruthenium according to the present invention is used, the nuclear hydrogenation of the pyridine ring proceeds with priority over dealkoxylation. In particular, in a catalyst containing rhodium, dealkoxylation which is a side reaction is suppressed, and the desired 4-formylpiperidine acetal derivative can be obtained with high selectivity. The amount of the catalyst used (in metal) is 0.005 to 2% by weight, preferably 0.01 to 1% by weight, based on the 4-formylpyridine acetal derivative, from the viewpoint of reaction rate and economy.

  The reaction can be carried out either without a solvent or in a solvent. When the solvent is used, it is not particularly limited as long as it does not adversely affect the reaction. For example, water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, 2-butanol, tert- Alcohols such as butanol, diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, ethers such as tetrahydrofuran, dioxolane, dioxane, pentane, cyclopentane, hexane, cyclohexane, heptane, methyl Aliphatic hydrocarbons such as cyclohexane, esters such as ethyl acetate and ethyl propionate, amides such as N, N-dimethylformamide and 2-pyrrolidone, and halogenated hydrocarbons such as chloroform. And the like. These may be used singly or in combination, and are preferably alcohols alone or a mixed solvent of alcohols and water.

  The reaction pressure is 0.1 to 30 MPa, preferably 0.1 to 5 MPa. The reaction temperature is usually 20 to 300 ° C, preferably 40 to 150 ° C, more preferably 70 to 120 ° C. When the temperature is lower than this temperature range, a sufficient reaction rate cannot be obtained, and when the temperature is high, side reactions and decomposition reactions are involved, so the yield is lowered.

  Specific compounds of the 4-formylpiperidine acetal derivative represented by the general formula (2) include 4-formylpiperidinedimethylacetal, 4-formylpiperidinediethylacetal, 4-formylpiperidinedipropylacetal, 4-formylpiperidinediisopropylacetal 4-formylpiperidine dibutyl acetal, 4- (1,3-dioxolan-2-yl) piperidine, 4- (4-methyl-1,3-dioxolan-2-yl) piperidine, 4- (1,3-dioxane -2-yl) piperidine and the like.

  EXAMPLES Hereinafter, although this invention is further demonstrated by a preparation example, an Example, and a comparative example, this invention is not limited to these. In addition, the GC area percentage in the following preparation examples and examples represents the area percentage of the compound by gas chromatography analysis.

[Preparation Example 1] Synthesis of 4-formylpyridine dimethyl acetal While stirring in a 3 L reaction flask, 160.7 g (1.5 mol) of 4-formylpyridine, 480.6 g (15 mol) of methanol, 220.7 g of concentrated sulfuric acid (2 .3 moles) and the reaction was carried out at 50 ° C. for 3 hours. After concentrating the reaction mixture, neutralization extraction and liquid separation were performed using 600 g of 30% aqueous sodium hydroxide and 8000 g of toluene. The obtained organic layer was concentrated and distilled to obtain 140.2 g (0.92 mol, GC area percentage 99%, yield 61%) of colorless liquid 4-formylpyridine dimethyl acetal.

[Example 1] Synthesis of 4-formylpiperidine dimethyl acetal In a 200 mL autoclave, 1.5 g (9.8 mmol) of 4-formylpyridine dimethyl acetal obtained in Preparation Example 1, 4.5 g of methanol, 5% rhodium carbon 75 mg of a catalyst (water content: 50% by mass) (0.13% by mass with respect to the raw material in terms of metal rhodium) was charged, and the mixture was reacted with stirring at a hydrogen pressure of 0.8 MPa and a reaction temperature of 80 ° C. for 6 hours. The catalyst was filtered off from the reaction mixture and concentrated to obtain 1.6 g (9.8 mmol, crude yield 100%) of crude 4-formylpiperidinedimethylacetal as a colorless liquid. As a result of analysis by gas chromatography (GC), the face percentage of the target 4-formylpiperidine dimethyl acetal was 95%, and the face percentage of the by-product 4-methoxymethylpiperidine was 3%.

[Preparation Example 2] Synthesis of 4-formylpyridine diethyl acetal A 30-liter reactor was charged with 30 kg (280 mol) of 4-formylpyridine, 129 kg (280 mol) of ethanol, and 27.5 kg (280 mol) of concentrated sulfuric acid. The reaction was carried out at 2 ° C. for 2 hours. The reaction mixture was concentrated, triethyl orthoformate was added, and the reaction was carried out at 70 ° C. for 1 hour. Neutralization extraction and liquid separation were performed using 112 kg of 20% sodium hydroxide aqueous solution and 75 kg of toluene. By concentrating the obtained organic layer, a solution (255 mol, yield 91%) containing 46.2 kg of 4-formylpyridine diethyl acetal as an orange liquid was obtained.

[Example 2] Synthesis of 4-formylpiperidine diethyl acetal 19 kg of a solution containing 4-formylpyridine diethyl acetal obtained in Preparation Example 2 in a 200 L reactor (112 mol of 4-formylpyridine charged), ethanol 51 0.0 kg, water 30.6 kg, 5% rhodium carbon catalyst (moisture content 50 mass%) 2.0 kg (0.25 mass% relative to the raw material in terms of metal rhodium) was charged, with stirring, hydrogen pressure 0.8 MPa, The reaction was carried out at a reaction temperature of 80 ° C. for 8 hours. The catalyst was filtered off from the reaction mixture and concentrated to obtain 17.8 kg (94.8 mol, 85% yield) of 4-formylpiperidine diethyl acetal as a brown liquid. As a result of GC analysis, the surface percentage of the target 4-formylpiperidine diethyl acetal was 95%, and the surface percentage of the byproduct 4-ethoxymethylpiperidine was 4%. The crude product was distilled to obtain 4-formylpiperidine diethyl acetal having a surface percentage of 98%.

[Preparation Example 3] Synthesis of 4-formylpyridine dibutyl acetal In a 3 L autoclave, 104.1 g (1.0 mol) of 4-cyanopyridine, 460 g of water, 232.3 g (2.3 mol) of concentrated sulfuric acid, 5% palladium -1% copper / carbon catalyst (moisture content 50% by mass) 3g (0.07% by mass with respect to the raw material in terms of metallic palladium) and 300 mg of copper sulfate pentahydrate were charged, and hydrogen pressure 0.8 MPa with stirring The reaction was performed at a reaction temperature of 60 ° C. for 8 hours. The catalyst was filtered off from the reaction mixture and concentrated. To this, 593.0 g (8.0 mol) of butanol was added, and the reaction was carried out for 4 hours while stirring and distilling off the azeotropic component of water and butanol at the reflux temperature. After cooling the reaction solution, neutralization extraction and liquid separation were performed using 500 g of methylcyclohexane and 500 g of a 30% aqueous sodium hydroxide solution. The obtained organic layer was concentrated and distilled to obtain 154.3 g (0.65 mol, GC area percentage 97%, yield 65%) of 4-formylpyridinedibutylacetal as a colorless liquid.

[Example 3] Synthesis of 4-formylpiperidine dibutyl acetal In a 1 L autoclave, 65.0 g (0.27 mol) of 4-formylpyridine dibutyl acetal obtained in Preparation Example 3, 260 g of isopropyl alcohol, 5% rhodium carbon catalyst (Moisture content: 50% by mass) 6.5 g (0.25% by mass in terms of metal rhodium based on the raw material) was charged, and the mixture was reacted with stirring at a hydrogen pressure of 0.8 MPa and a reaction temperature of 80 ° C. for 8 hours. The catalyst was filtered off from the reaction mixture, concentrated and distilled to obtain 53.3 g (0.22 mol, yield 81%) of 4-formylpiperidinedibutylacetal as a colorless liquid. As a result of GC analysis, the surface percentage of the target 4-formylpiperidine dibutyl acetal was 98%, and the surface percentage of the by-product 4-butoxymethylpiperidine was 1%.

[Preparation Example 4] Synthesis of 4- (1,3-dioxolan-2-yl) pyridine With stirring in a 500 mL reaction flask, 32.1 g (0.30 mol) of 4-formylpyridine and 20.5 g of ethylene glycol (0. 33 mol) and 39.2 g (0.4 mol) of concentrated sulfuric acid were charged, and the reaction was carried out at 100 ° C. for 3 hours. After cooling the reaction mixture, neutralization extraction and liquid separation were performed using 150 g of toluene and 110 g of a 30% aqueous sodium hydroxide solution. The obtained organic layer was concentrated and distilled to give 27.2 g (0.18 mol, GC area percentage 99%, yield 60%) of colorless liquid 4- (1,3-dioxolan-2-yl) pyridine. )

[Example 4] Synthesis of 4- (1,3-dioxolan-2-yl) piperidine In a 200 mL autoclave, 1.0 g of 4- (1,3-dioxolan-2-yl) pyridine obtained in Preparation Example 4 was added. (6.6 mmol), 9.0 g of isopropyl alcohol, 50 mg of 5% rhodium carbon catalyst (water content: 50% by mass) (0.13% by mass with respect to the raw material in terms of metal rhodium) are charged, and the hydrogen pressure is 1 MPa under stirring. The reaction was conducted at a reaction temperature of 100 ° C. for 5 hours. The catalyst was filtered off from the reaction mixture and concentrated to obtain 1.0 g (6.6 mmol, crude yield 100%) of crude 4- (1,3-dioxolan-2-yl) piperidine as a colorless liquid. It was. As a result of GC analysis, the surface percentage of the desired 4- (1,3-dioxolan-2-yl) piperidine was 98%, and no by-product 4-monoalkoxy compound was detected.

[Preparation Example 5] Synthesis of 4- (1,3-dioxane-2-yl) pyridine To a 3 L autoclave, 208.2 g (2.0 mol) of 4-cyanopyridine and 304.4 g of 1,3-propanediol ( 4.0 mol), water 360 g (10.0 mol), concentrated sulfuric acid 464.6 g (4.5 mol), 5% palladium-1% copper / carbon catalyst (water content 50 mass%) 6 g (in terms of metallic palladium) 0.07 mass% with respect to the raw material) and 700 mg of copper sulfate pentahydrate were charged, and the mixture was reacted for 36 hours under stirring at a hydrogen pressure of 0.8 MPa and a reaction temperature of 60 ° C. After the catalyst was filtered off from the reaction mixture, neutralization extraction and liquid separation were performed using 900 g of toluene and 870 g of a 30% aqueous sodium hydroxide solution. The obtained organic layer was concentrated and distilled to give 214.7 g (1.3 mol, GC area percentage 99%, yield 65%) of colorless liquid 4- (1,3-dioxan-2-yl) pyridine. )

[Example 5] Synthesis of 4- (1,3-dioxan-2-yl) piperidine In a 1 L autoclave, 100.0 g of 4- (1,3-dioxan-2-yl) pyridine obtained in Preparation Example 5 was prepared. (0.61 mol), isopropyl alcohol 300 g, 5% rhodium carbon catalyst (moisture content 50 mass%) 5 g (0.13 mass% relative to the raw material in terms of metal rhodium) were charged, and hydrogen pressure 0.8 MPa with stirring. The reaction was conducted at a reaction temperature of 100 ° C. for 6 hours. The catalyst was filtered off from the reaction mixture, concentrated and distilled to obtain 90.1 g (0.53 mol, yield 87%) of colorless liquid 4- (1,3-dioxan-2-yl) piperidine. . As a result of GC analysis, the surface percentage of the desired 4- (1,3-dioxan-2-yl) piperidine was 97%, and no by-product 4-monoalkoxy compound was detected.

[Preparation Example 6] Synthesis of 4- (4-methyl-1,3-dioxolan-2-yl) pyridine While stirring in a 200 mL reaction flask, 10.7 g (100 mmol) of 4-formylpyridine, 1,2-propanediol 15.2 g (0.20 mol) and concentrated sulfuric acid 19.6 g (0.20 mol) were charged and reacted at 100 ° C. for 3 hours. After cooling the reaction solution, neutralization extraction / separation was performed using 100 g of toluene and 50 g of a 30% aqueous sodium hydroxide solution. The obtained organic layer was concentrated and distilled to obtain 12.1 g (73 mmol, GC area percentage 99%, yield) of colorless liquid 4- (4-methyl-1,3-dioxolan-2-yl) pyridine. 73%).

[Example 6] Synthesis of 4- (4-methyl-1,3-dioxolan-2-yl) piperidine In a 200 mL autoclave, 4- (4-methyl-1,3-dioxolane- obtained in Preparation Example 6 was added. 2-yl) pyridine 1.7 g (10.3 mmol), isopropyl alcohol 15 g, 5% rhodium carbon catalyst (moisture content 50 mass%) 85 mg (0.13 mass% relative to the raw material in terms of metal rhodium) While stirring, the reaction was carried out at a hydrogen pressure of 0.8 MPa and a reaction temperature of 100 ° C. for 5 hours. The catalyst was filtered off from the reaction mixture, concentrated and distilled to give 1.6 g (9.2 mmol, yield 89%) of colorless liquid 4- (4-methyl-1,3-dioxolan-2-yl) piperidine. ) As a result of GC analysis, no by-product 4-monoalkoxy compound was detected.

[Example 7] Synthesis of 4-formylpiperidine diethyl acetal In a 200 mL autoclave, 5.0 g (27.6 mmol) of 4-formylpyridine diethyl acetal obtained in the same manner as in Preparation Example 2, 15 g of methylcyclohexane, 5% A ruthenium carbon catalyst (moisture content 50 mass%) 1.0 g (0.5 mass% with respect to the raw material in terms of metal ruthenium) was charged and reacted at a hydrogen pressure of 3.0 MPa and a reaction temperature of 140 ° C. for 4 hours. The catalyst was filtered off from the reaction mixture. As a result of GC analysis, the surface percentage of the target 4-formylpiperidine diethyl acetal was 87%, and the surface percentage of the by-product 4-ethoxymethylpiperidine was 11%.

[Comparative Example 1] Synthesis of 4-formylpiperidine diethyl acetal using platinum carbon In a 200 mL autoclave, 5.0 g (27.6 mmol) of 4-formylpyridine diethyl acetal obtained in the same manner as in Preparation Example 2, ethanol 15 g, 5% platinum carbon catalyst (moisture content 50% by mass) 1.0 g (0.5% by mass with respect to the raw material in terms of metal platinum) was charged, and under stirring, the hydrogen pressure was 3.0 MPa and the reaction temperature was 140 ° C. Reacted for hours. The catalyst was filtered off from the reaction mixture. As a result of GC analysis, the surface percentage of the target 4-formylpiperidine diethyl acetal was 1%, and the surface percentage of 4-formylpyridine diethyl acetal as a raw material was 97%.

Comparative Example 2 Synthesis of 4-formylpiperidine diethyl acetal using palladium carbon In a 200 mL autoclave, 5.0 g (27.6 mmol) of 4-formylpyridine diethyl acetal obtained in the same manner as in Preparation Example 2, ethanol 15 g, 5% palladium carbon catalyst (moisture content 50 mass%) 1.0 g (0.5 mass% in terms of metal palladium with respect to the raw material) was charged, and under stirring, hydrogen pressure 3.0 MPa, reaction temperature 140 ° C. Reacted for hours. The catalyst was filtered off from the reaction mixture. As a result of GC analysis, the surface percentage of the target 4-formylpiperidine diethyl acetal was 0%. The main product was 4-ethoxymethylpyridine and the area percentage was 15%. Further, the surface percentage of 4-formylpyridine diethyl acetal as a raw material was 85%.

Claims (3)

The following general formula (1)

(In the formula, R ¹ and R ² represent the same or different alkyl groups, and may be bonded to each other to form a ring.)
The following general formula (2) is obtained by catalytically hydrogenating a 4-formylpyridine acetal derivative represented by the following formula in the presence of a catalyst containing rhodium or ruthenium.

(In the formula, R ¹ and R ² are the same as described above.)
The manufacturing method of 4-formyl piperidine acetal derivative represented by these.   The method for producing a 4-formylpiperidine acetal derivative according to claim 1, wherein the catalyst is rhodium carbon.   The method for producing a 4-formylpiperidine acetal derivative according to claim 1, wherein the catalyst is ruthenium carbon.