JP7596113B2 - Method for producing 2-acetyl-1-pyrroline - Google Patents

Description

The present invention relates to a method for producing 2-acetyl-1-pyrroline.

2-acetyl-1-pyrroline, represented by the following formula (1), is known to be an aroma component of various natural plant essential oils, as well as an aroma component contained in grains such as rice or dishes made with grains. 2-acetyl-1-pyrroline has a highly distinctive odor and a very low threshold, and is therefore attracting attention as a flavoring material for foods, etc.

On the other hand, 2-acetyl-1-pyrroline is an unstable compound that is easily decomposed by heat, oxygen, etc. For this reason, research has been conducted on methods for producing 2-acetyl-1-pyrroline. For example, Patent Document 1 describes a method in which 2-acetylpyrrole represented by the following formula (2) is hydrogenated to obtain 2-(1-hydroxyethyl)pyrrolidine [also known as 1-(pyrrolidin-2-yl)ethanol] represented by the following formula (3), which is then oxidized with silver carbonate to obtain 2-acetyl-1-pyrroline.

Patent Document 2 describes a method for obtaining 2-acetyl-1-pyrroline using proline as a starting material through an esterification reaction, a halogenation reaction, a dehydrohalogenation reaction, and a Grignard reaction.

U.S. Pat. No. 4,522,838 JP 2007-153785 A

However, the inventors' investigations have revealed that the production method described in Patent Document 1 has a low yield, uses silver carbonate containing a precious metal as an oxidizing agent, and uses special reagents in the reaction, making the operation complicated and therefore economically unuseful. In addition, the production method described in Patent Document 2 uses proline as a starting material and can selectively produce only 2-acetyl-1-pyrroline through the steps of (1) esterification reaction, (2) halogenation reaction and dehydrohalogenation reaction, and (3) Grignard reaction, but the production involves three steps, making it economically unuseful due to the large number of steps.

Based on the above, the object of the present invention is to provide a method for producing 2-acetyl-1-pyrroline that can produce 2-acetyl-1-pyrroline economically and in high yield.

As a result of intensive research, the inventors have discovered that 2-acetyl-1-pyrroline can be produced economically and in high yields by oxidizing 2-(1-hydroxyethyl)pyrrolidine with manganese dioxide.

Thus, the following is a brief overview of the representative inventions disclosed in this application.

[1] A method for producing 2-acetyl-1-pyrroline, comprising: (a) a step of oxidizing 2-(1-hydroxyethyl)pyrrolidine with an oxidizing agent, wherein the oxidizing agent is manganese dioxide.
[2] The method for producing 2-acetyl-1-pyrroline according to [1], wherein the step (a) is carried out at a temperature of 20° C. or higher and lower than 60° C.
[3] The method for producing 2-acetyl-1-pyrroline according to [1] or [2], wherein in the step (a), anhydrous magnesium sulfate or anhydrous sodium sulfate is used in combination with the oxidizing agent.
[4] The method for producing 2-acetyl-1-pyrroline according to any one of [1] to [3], wherein in the step (a), diatomaceous earth is used in combination with the oxidizing agent.
[5] The method for producing 2-acetyl-1-pyrroline according to any one of [1] to [4], wherein in the step (a), an ether solvent is used as a reaction solvent.

According to the present invention, 2-acetyl-1-pyrroline can be produced economically and in high yield.

One embodiment of the present invention will be described in detail below. In this specification, "~" means a range including a lower limit and an upper limit.

(Method for producing 2-acetyl-1-pyrroline)
Hereinafter, a method for producing 2-acetyl-1-pyrroline according to one embodiment of the present invention (hereinafter, sometimes referred to as the present production method) will be described in detail.

This production method includes (a) a step of oxidizing 2-(1-hydroxyethyl)pyrrolidine with an oxidizing agent (hereinafter referred to as (a) oxidation step), where the oxidizing agent is manganese dioxide. According to this production method, 2-acetyl-1-pyrroline can be produced economically and in high yield.

Here, the details of the inventors' investigations will be described. Patent Document 1 describes a method for producing 2-acetyl-1-pyrroline using silver carbonate as an oxidizing agent, but the production method described in Patent Document 1 has a problem that the yield is low and silver carbonate containing a precious metal is used as the oxidizing agent, making it economically unusable. Therefore, the inventors have investigated inexpensive oxidizing agents to replace silver carbonate. Conventionally, when oxidizing 2-acetyl-1-pyrroline, only the method using silver carbonate described in Patent Document 1 and J. Argic. Food Chem (1983) pp823-826, the method using a carbonyl compound in the presence of an aluminum catalyst described in JP-A-2014-073999, and the method using Dess-Martin periodinane described in WO2010/149744 were known. Therefore, the inventors investigated (1) potassium permanganate as an oxidizing agent to replace silver carbonate, but found that only a small amount of 2-acetyl-1-pyrroline was obtained, and a large amount of by-products was obtained.

The inventors therefore screened for oxidizing agents that are milder than potassium permanganate as an alternative to silver carbonate. More specifically, they investigated (2) iron(III) chloride, (3) copper(II) bromide and potassium tert-butoxide, and (4) manganese dioxide (manganese(IV) oxide) (see the Examples below for details). As a result, it was found that 2-acetyl-1-pyrroline was not obtained when (2) and (3) were used. On the other hand, it was found that 2-acetyl-1-pyrroline was obtained in high yield when (4) manganese dioxide was used, as shown in the Examples below.

Traditionally, manganese dioxide has been known in the field of organic synthetic chemistry as a relatively mild oxidizing agent, selectively oxidizing only allyl alcohol, benzyl alcohol, and propargyl alcohol, while the oxidation reaction of other alcohols is very slow. In particular, the substrates for oxidizing secondary alcohols are limited, and it takes a long time to use a large excess of oxidizing agent, so it has been considered uneconomical. In addition, in the oxidation of nitrogen-containing cyclic compounds, manganese dioxide is known to oxidize heteroalicyclic compounds to heteroaromatic compounds, but its application to the oxidation of pyrrolidine to 1-pyrroline is not known.

Therefore, it was truly surprising that the inventors discovered that manganese dioxide can be used as an oxidizing agent to efficiently obtain 2-acetyl-1-pyrroline by oxidizing 2-(1-hydroxyethyl)pyrrolidine. As a result of the above, the inventors came up with the present manufacturing method.

In the oxidation step (a) of the present production method, the amount of manganese dioxide used is not particularly limited, but is preferably in the range of 5 to 40 equivalents, and more preferably in the range of 10 to 20 equivalents. By specifying the amount of manganese dioxide used in this way, the yield of 2-acetyl-1-pyrroline can be improved.

In the present production method, the temperature during the oxidation step (a) is not limited, but it is preferable to carry out the oxidation step (a) at 20°C or higher and lower than 60°C. As shown in the examples described later, if the oxidation step (a) is carried out at a temperature lower than room temperature (20 to 30°C; the same applies below) (for example, 0°C), the oxidation reaction slows down and the reaction time becomes long, making it unsuitable for industrial production, and if the oxidation step (a) is carried out at 60°C or higher, the target product 2-acetyl-1-pyrroline may be decomposed by heating, resulting in a decrease in yield. As described later, if the boiling point of the solvent used is within this temperature range, the oxidation step (a) may be carried out under heating reflux conditions.

The inventors have confirmed that when silver carbonate is used as an oxidizing agent, as in the method for producing 2-acetyl-1-pyrroline described in Patent Document 1, the reaction is very slow at 20 to 60°C, as in the present production method, and that it is appropriate to heat and reflux at, for example, 80°C. In other words, the present production method is capable of proceeding with the oxidation reaction at a lower temperature than conventional methods, which is believed to have led to the production of 2-acetyl-1-pyrroline in a higher yield than conventional methods without decomposing it.

In addition, in the oxidation step (a) of the present production method, the reaction time is not particularly limited and can be adjusted appropriately depending on the reaction temperature, but in the case of industrial (large-scale) use, a range of 1 to 40 hours is preferable. In order to obtain 2-acetyl-1-pyrroline in high yield, it is preferable to carry out the reaction in the oxidation step (a) at room temperature (20 to 30°C) for 4 to 16 hours.

In addition, in the present production method, it is preferable to use anhydrous magnesium sulfate or anhydrous sodium sulfate (hereinafter referred to as anhydrous magnesium sulfate, etc.) in combination with the oxidizing agent in the oxidation step (a). In this way, the anhydrous magnesium sulfate, etc. traps water that is generated as a by-product when 2-(1-hydroxyethyl)pyrrolidine is oxidized to obtain 2-acetyl-1-pyrroline, and the oxidation reaction can be promoted. Furthermore, although the oxidation step (a) is a solid-liquid reaction, by using anhydrous magnesium sulfate, etc. in combination with manganese dioxide, manganese dioxide is supported on the anhydrous magnesium sulfate, etc., and the dispersibility of manganese dioxide can be ensured. As a result, when the present production method is scaled up, the scale dependency of the oxidation step (a) can be reduced.

In the oxidation step (a) of the present production method, the amount of anhydrous magnesium sulfate, etc. used is not particularly limited, but is usually selected appropriately from the range of 0.2 to 5 times, preferably 0.5 to 2 times, the mass of the reaction substrate.

In addition, in the present manufacturing method, it is preferable to use diatomaceous earth in combination with the oxidizing agent in the oxidation step (a). As described above, the oxidation step (a) is a solid-liquid reaction, but by using diatomaceous earth in combination with manganese dioxide, the manganese dioxide is supported on the diatomaceous earth, and the dispersibility of the manganese dioxide can be ensured. As a result, when the present manufacturing method is scaled up, the scale dependency of the oxidation step (a) can be reduced.

In the oxidation step (a) of the present manufacturing method, the amount of diatomaceous earth used is not particularly limited, but is usually selected appropriately from the range of 0.2 to 5 times, and preferably 0.5 to 2 times, the mass of the reaction substrate. An example of diatomaceous earth is Celite (registered trademark).

In the present production method, the solvent in the oxidation step (a) is not particularly limited, but it is preferable to use an aprotic solvent as the solvent. Examples of aprotic solvents include pentane, hexane, cyclohexane, diethyl ether, cyclopentyl methyl ether (hereinafter referred to as CPME), and methyl tert-butyl ether (hereinafter referred to as MTBE). Among them, ether-based solvents such as diethyl ether, CPME, and MTBE are more preferable, and MTBE is the most preferable. The suitability of the solvent for the oxidation step (a) was examined mainly from three viewpoints: (i) the boiling point is within or higher than the range of the preferable reaction temperature of the oxidation step (a) described above, and the reaction can proceed sufficiently; (ii) the boiling point is low, and the distillation of the target product can be prevented during solvent recovery after the reaction; and (iii) it is not affected by the reaction (specifically, it is not oxidized). In this regard, diethyl ether is preferred because its boiling point (34.6°C) is within the range of the preferred reaction temperature for the (a) oxidation step, and its boiling point is relatively low, resulting in little loss of the target product during solvent recovery. CPME is preferred because its boiling point (106°C) is above the preferred reaction temperature for the (a) oxidation step, and is unlikely to produce peroxides and is highly stable. MTBE is even more preferred because its boiling point (55.2°C) is above the preferred reaction temperature for the (a) oxidation step, and its boiling point is relatively low, resulting in little loss of the target product during solvent recovery, and is also unlikely to produce peroxides and is highly stable.

In the oxidation step (a) of the present production method, the amount of the solvent used is not particularly limited, but is usually selected appropriately from the range of 0.5 to 100 times the volume (volume = solvent [mL]/reactant [g], the same applies below), preferably 3 to 20 times the volume.

In this manufacturing method, the raw material 2-(1-hydroxyethyl)pyrrolidine can be obtained by any method, but as one example, 2-acetylpyrrole can be hydrogenated (reduced) to obtain 2-(1-hydroxyethyl)pyrrolidine (hereinafter referred to as (b) hydrogenation step). In this manufacturing method, the (b) hydrogenation step may be included before the (a) oxidation step, if necessary.

In the (b) hydrogenation step, it is preferable to use a hydrogenation catalyst. The hydrogenation catalyst is not particularly limited, but heterogeneous catalysts such as rhodium alumina and rhodium carbon are preferable, and 5% rhodium carbon is more preferable. In addition, it is preferable to carry out the (b) hydrogenation step in the presence of a solvent. The solvent is not particularly limited, but protic solvents are preferable. Specific examples include formic acid, n-butanol, 2-propanol, nitromethane, ethanol, methanol, acetic acid, and water. Among these, alcohols are preferable, and ethanol is more preferable. The amount of the solvent used is usually selected appropriately from the range of 0.5 to 100 times the volume, preferably 1 to 10 times the volume.

(b) The reaction temperature in the hydrogenation step is, for example, 25 to 100°C, and preferably 50 to 60°C. (b) The reaction time in the hydrogenation step is, for example, 8 to 77 hours, and preferably 8 to 16 hours. (b) The hydrogen pressure in the hydrogenation step is, for example, 0.1 to 10 MPa, and preferably 2 to 4 MPa.

The present invention will be described in more detail below with reference to examples. Note that the present invention is not limited to the following examples.

Example 1 Synthesis of 2-(1-hydroxyethyl)pyrrolidine 50 g of 2-acetylpyrrole and 5 g of 5% Rh carbon powder (hydrated product) were placed in an autoclave, and after replacing with nitrogen, 200 mL of ethanol was added. Thereafter, the atmosphere inside the autoclave was replaced with hydrogen, and the mixture was stirred for 8 hours under conditions of a hydrogen pressure of 3 MPa and 50°C. Solids were removed by filtration, and the reaction solution was recovered using 100 mL of ethanol and concentrated under reduced pressure to obtain 2-(1-hydroxyethyl)pyrrolidine (yield 78%).

[Example 2] Synthesis of 2-acetyl-1-pyrroline (lab scale)
In a 50 mL two-neck flask, 0.57 g of 2-(1-hydroxyethyl)pyrrolidine and 20 mL of methyl tert-butyl ether were added and placed under a nitrogen atmosphere. 4.35 g of manganese dioxide was added and stirred at room temperature (20 to 30° C.) for 4 hours, after which the reaction solution was filtered and analyzed by GC (gas chromatography). Thereafter, the solvent was removed from the reaction solution and distilled under reduced pressure to obtain 2-acetyl-1-pyrroline (0.064 g, isolated yield 12%). It was confirmed that the obtained 2-acetyl-1-pyrroline remained stable as a 1% triacetin solution for 60 days or more.

[Example 3] Synthesis of 2-acetyl-1-pyrroline (large scale)
Manganese dioxide (434.7 g), anhydrous magnesium sulfate (120.4 g), Celite (registered trademark) (115.2 g), and MTBE (2.5 L) were placed in a 5 L four-neck flask and placed under a nitrogen atmosphere. A solution of 2-(1-hydroxyethyl)pyrrolidine (57.6 g) in MTBE (100 mL) was added dropwise to the stirred slurry in the flask and stirred at room temperature for 10 hours. The reaction solution was filtered and analyzed by GC (apparatus: Shimadzu GC-2014, column: GL Sciences TC-1), and 36% of the raw materials were found to remain. Manganese dioxide (434.7 g), anhydrous magnesium sulfate (120.4 g), and Celite (registered trademark, 115.2 g) were added again to the 5 L four-neck flask and stirred under a nitrogen atmosphere for 6 hours. The reaction solution was filtered and analyzed by GC, and the disappearance of the raw materials was confirmed. The solvent was removed from the reaction mixture, and the mixture was then distilled under reduced pressure to give 2-acetyl-1-pyrroline (6.44 g, isolated yield 12%). It was confirmed that the obtained 2-acetyl-1-pyrroline remained stable as a 1% triacetin solution for 60 days or more.

Example 4: Study on the type of oxidizing agent The type of oxidizing agent used in the oxidation of 2-(1-hydroxyethyl)pyrrolidine to obtain 2-acetyl-1-pyrroline was studied.

<Sample 4-1>
2-(1-hydroxyethyl)pyrrolidine (0.57 g) and MTBE (20 mL) were added to a 50 mL two-neck flask and placed under a nitrogen atmosphere. Manganese dioxide (4.35 g) was added thereto, and the mixture was stirred under heating and reflux for 4 hours. The reaction solution was then filtered to obtain 2-acetyl-1-pyrroline.

<Sample 4-2>
An attempt was made to synthesize 2-acetyl-1-pyrroline in the same manner as in Sample 4-1, except that the reaction conditions were room temperature rather than under reflux.

<Sample 4-3>
The synthesis of 2-acetyl-1-pyrroline was attempted in the same manner as in Sample 4-1, except that silver carbonate was used instead of manganese dioxide as the oxidizing agent and cyclohexane was used instead of MTBE as the solvent. Note that 3.4 g of silver carbonate supported on Celite (registered trademark) was used.

<Sample 4-4>
An attempt was made to synthesize 2-acetyl-1-pyrroline in the same manner as in Sample 4-3, except that the reaction conditions were room temperature instead of under reflux.

<Sample 4-5>
The synthesis of 2-acetyl-1-pyrroline was attempted in the same manner as in Sample 4-2, except that potassium permanganate was used instead of manganese dioxide as the oxidizing agent, and acetone was used instead of MTBE as the solvent. Note that 1.8 g of potassium permanganate was used.

<Sample 4-6>
The synthesis of 2-acetyl-1-pyrroline was attempted in the same manner as in Sample 4-2, except that iron chloride (III) was used instead of manganese dioxide as the oxidizing agent, and cyclohexane was used instead of MTBE as the solvent. Note that 4.1 g of iron chloride (III) was used.

<Sample 4-7>
The synthesis of 2-acetyl-1-pyrroline was attempted in the same manner as in Sample 4-2, except that copper(II) bromide was used instead of manganese dioxide as an oxidant, potassium tert-butoxide was used as an additive, and tetrahydrofuran was used instead of MTBE as a solvent. Note that 6.6 g of copper(II) bromide and 2.8 g of potassium tert-butoxide were used.

The oxidizers, solvents, temperatures and results for samples 4-1 to 4-7 are summarized in Table 1.

As shown in Table 1, it was confirmed that Samples 4-1 and 4-2 had improved yields compared to Sample 4-3 (corresponding to the method described in Patent Document 1). Sample 4-2 was found to have a higher yield than Sample 4-1, and to have high purity with no impurities generated by heating.

As shown in Table 1, sample 4-4 was produced by treating sample 4-3 at room temperature rather than under reflux, but the reaction was slow and almost no desired product was obtained. From this, it can be seen that the advantage of using manganese dioxide as the oxidizing agent rather than silver carbonate is that the reaction can be carried out at room temperature, so no impurities are produced by heating and the purity can be increased.

As shown in Table 1, sample 4-5 used potassium permanganate as the oxidizing agent, but only a small amount of 2-acetyl-1-pyrroline was obtained, resulting in a large amount of by-products.

As shown in Table 1, sample 4-6 uses iron chloride (III) as the oxidizing agent, and sample 4-7 uses copper bromide (II) as the oxidizing agent, but in neither case was 2-acetyl-1-pyrroline obtained.

From the above, it was found that 2-acetyl-1-pyrroline can be obtained in high yield by oxidizing 2-(1-hydroxyethyl)pyrrolidine with manganese dioxide.

Example 5 Investigation of Solvent, Reaction Temperature, and Reaction Time The solvent, reaction temperature, and reaction time were investigated in the case of oxidizing 2-(1-hydroxyethyl)pyrrolidine with manganese dioxide to obtain 2-acetyl-1-pyrroline.

<Sample 5-1>
2-(1-hydroxyethyl)pyrrolidine (0.57 g) and cyclohexane (20 mL) were added to a 50 mL two-neck flask and placed under a nitrogen atmosphere. Manganese dioxide (4.35 g) was added thereto and stirred at 0° C. for 3 hours to attempt the synthesis of 2-acetyl-1-pyrroline.

<Sample 5-2>
An attempt was made to synthesize 2-acetyl-1-pyrroline in the same manner as in Sample 5-1, except that the reaction conditions were room temperature instead of 0° C. and the reaction time was 4 hours.

<Sample 5-3>
An attempt was made to synthesize 2-acetyl-1-pyrroline in the same manner as in Sample 5-1, except that the solvent was hexane instead of cyclohexane, the reaction temperature was heating under reflux, and the reaction time was 4 hours.

<Sample 5-4>
An attempt was made to synthesize 2-acetyl-1-pyrroline in the same manner as in Sample 5-1, except that the solvent was MTBE instead of cyclohexane, the reaction temperature was room temperature, and the reaction time was 10 hours.

<Sample 5-5>
An attempt was made to synthesize 2-acetyl-1-pyrroline in the same manner as in Sample 5-4, except that the reaction temperature was heated under reflux and the reaction time was 4 hours.

<Sample 5-6>
An attempt was made to synthesize 2-acetyl-1-pyrroline in the same manner as in Sample 5-4, except that the solvent was changed from MTBE to CPME.

<Sample 5-7>
An attempt was made to synthesize 2-acetyl-1-pyrroline in the same manner as in Sample 5-6, except that the reaction temperature was heated under reflux and the reaction time was 4 hours.

<Sample 5-8>
The synthesis of 2-acetyl-1-pyrroline was attempted in the same manner as in Sample 5-4, except that the solvent was diethyl ether instead of MTBE.

The solvents, boiling points, reaction temperatures, reaction times, and yields for the above samples 5-1 to 5-8 are summarized in Table 2.

As shown in Table 2, samples 5-1 to 5-8 had improved yields compared to sample 4-3 in Table 1 (corresponding to the method described in Patent Document 1), and no particular problems due to the type of solvent were found when manganese dioxide was used as the oxidizing agent.

The fact that samples 5-2, 5-4, 5-5, 5-6, and 5-8 had higher yields than samples 5-1, 5-3, and 5-7 indicates that the appropriate range of reaction temperature is 20°C (room temperature) or higher and lower than 60°C (heating reflux temperature of MTBE). That is, from these results, it is understood that the reaction slows down when the reaction temperature is 0°C as in sample 5-1, and that heating and refluxing at 68°C as in sample 5-3 leads to decomposition and a decrease in yield. Note that if the boiling point of the solvent is high, it may be distilled off together with the solvent during solvent removal, resulting in a decrease in yield, even if the GC yield is high. From this, it was found that MTBE is a suitable solvent for oxidizing 2-(1-hydroxyethyl)pyrrolidine with manganese dioxide.

Claims (5)

(a) oxidizing 2-(1-hydroxyethyl)pyrrolidine with an oxidizing agent;
Including,
In the method for producing 2-acetyl-1-pyrroline, the oxidizing agent is manganese dioxide,
A method for producing 2-acetyl-1-pyrroline, wherein in the step (a), anhydrous magnesium sulfate or anhydrous sodium sulfate is used in combination with the oxidizing agent. (a) oxidizing 2-(1-hydroxyethyl)pyrrolidine with an oxidizing agent;
Including,
In the method for producing 2-acetyl-1-pyrroline, the oxidizing agent is manganese dioxide,
The method for producing 2-acetyl-1-pyrroline, wherein in the step (a), diatomaceous earth is used in combination with the oxidizing agent. (a) oxidizing 2-(1-hydroxyethyl)pyrrolidine with an oxidizing agent;
Including,
In the method for producing 2-acetyl-1-pyrroline, the oxidizing agent is manganese dioxide,
A method for producing 2-acetyl-1-pyrroline, wherein cyclopentyl methyl ether or methyl tert-butyl ether is used as a reaction solvent in the step (a). The process for producing 2-acetyl-1-pyrroline according to any one of claims 1 to 3 ,
The method for producing 2-acetyl-1-pyrroline, wherein the step (a) is carried out at a temperature of 20° C. or higher and lower than 60° C. The method for producing 2-acetyl-1-pyrroline according to claim 1 or 2 ,
In the step (a), diethyl ether is used as a reaction solvent;
The method for producing 2-acetyl-1-pyrroline, wherein the step (a) is carried out at a temperature of 20° C. or higher and not higher than the boiling point of diethyl ether.