JP4524365B2 - Method for producing asymmetric aliphatic tertiary amine - Google Patents

Description

The present invention relates to a method for producing an asymmetric aliphatic tertiary amine. By using the present invention, the target asymmetric aliphatic tertiary amine can be selectively synthesized in high yield.

  Aliphatic secondary amines and aliphatic tertiary amines are extremely important chemical substances used in many chemical industrial products such as pharmaceutical synthesis intermediates.

  Conventionally, a method of alkylating a primary amine with an alkyl halide compound is known as a method for synthesizing an aliphatic secondary amine or an aliphatic tertiary amine. However, in this method, not only an aliphatic secondary amine in which the primary amine is monoalkylated, but also a dialkylation reaction or a trialkylation reaction proceeds to produce a tertiary amine or an ammonium salt. For this reason, it is difficult to produce the target aliphatic amine with high selectivity. In addition, as a by-product, inorganic salts are produced in an amount equivalent to the alkyl halide compound, so that there is a problem that the inorganic salts must be separated and disposed of.

  As another method for producing an aliphatic amine, a method for reductively alkylating aldehydes is also known. However, even with this method, the product becomes a mixture of an aliphatic secondary amine and an aliphatic tertiary amine, and it is still difficult to selectively produce the desired aliphatic amine.

  As a method for selectively synthesizing a target aliphatic amine, Emerson et al. Found a method of reacting an aromatic amine and an aliphatic aldehyde in the presence of Raney Ni (see Non-Patent Document 1). According to this method, the secondary amine can be selectively produced by suppressing the by-production of the tertiary amine to 10%.

Emerson, w.s .; Waters, P.M.Journal of American Chemical Society 1939,61,3145

  However, this method has a problem that a large amount of Raney Ni, which is 6 times or more the substrate weight, is required, and unreacted substances remain, resulting in poor yield. In addition, aldehydes are generally highly toxic and have been suggested to cause mutations in living organisms.

  As another method for selectively obtaining the target aliphatic amine, a synthetic method utilizing a protecting group is known. That is, the primary amine is benzoylated, then the benzoylated primary amine is monoalkylated with an alkyl halide, and finally the benzoyl group is eliminated. According to this method, the secondary amine can be selectively synthesized without by-producting the tertiary amine.

  However, in this method, the number of steps is increased due to the introduction of the protecting group and the elimination of the protecting group, the yield is deteriorated, and as a result, the production cost is increased.

The present invention has been made in view of the above-described conventional circumstances, and can selectively produce the target asymmetric aliphatic tertiary amine in a high yield, using harmful aldehydes. It is an object to be solved to provide a method for producing an asymmetric aliphatic tertiary amine that is not present.

  The inventors have already discovered that a nitrile compound acts as an alkylating agent for an aromatic amine in a reducing atmosphere in the presence of a platinum group element (see Non-Patent Document 2).

60th Annual Meeting of the Japan Society for Process Chemistry 2003 Summer Symposium

  Assuming that this method can be applied to aliphatic amines, alkylation of aliphatic amines can be performed, and as a result of intensive studies, the present invention has been completed.

That is, the method for producing an asymmetric aliphatic tertiary amine of the present invention comprises synthesizing an aliphatic secondary amine by reacting an aliphatic primary amine and an aliphatic nitrile in the presence of a metal rhodium catalyst in a hydrogen atmosphere . Reacting an aliphatic secondary amine different from the aliphatic nitrile with an aliphatic nitrile different from the aliphatic nitrile in a hydrogen atmosphere in the presence of a metal palladium catalyst to form an asymmetric aliphatic tertiary group having three different alkyl groups. A second step of synthesizing the amine;
It is characterized by having .

In the method for producing an asymmetric aliphatic tertiary amine according to the present invention, an aliphatic amine and an aliphatic nitrile are reacted in the presence of a catalyst such as metal palladium or metal rhodium under a hydrogen atmosphere to thereby obtain an alkyl group of the aliphatic nitrile. Binds to aliphatic amines and is alkylated in high yield. Furthermore, this alkylation reaction is different from the case of alkylation of an aromatic amine described in Non-Patent Document 2 above, and by selecting a white metal element, the reaction is stopped by monoalkylation, The reaction can proceed to dialkylation. That is, when metal rhodium is used as a catalyst , monoalkylation becomes the main reaction, and when metal palladium is used, dialkylation becomes the main reaction. For this reason, it becomes possible to selectively synthesize an aliphatic secondary amine or an aliphatic tertiary amine by selecting a catalyst . According to the present invention, by conducting a monoalkylation reaction of an aliphatic primary amine to synthesize an aliphatic secondary amine, a further different alkyl group is introduced into the aliphatic secondary amine by another aliphatic nitrile. Asymmetric tertiary amines with three different alkyl groups can be synthesized in just two steps.

Therefore, according to the method for producing an asymmetric aliphatic tertiary amine of the present invention, the target asymmetric aliphatic tertiary amine can be selectively produced with good yield, and harmful aldehydes can be used. Absent.

The catalyst can be used as it is, such as palladium black or platinum black, but is preferably supported on a carrier such as carbon, silica or alumina. By carrying it on the carrier, the catalyst is finely dispersed and the function as a catalyst is enhanced. In addition, recovery of the catalyst after the reaction is facilitated. The inventors have confirmed that if carbon is used as a carrier, the target aliphatic amine can be synthesized with extremely high yield and high selectivity.

The catalyst is rhodium metal in the first step. If metal rhodium is used as a catalyst, monoalkylation of an aliphatic amine becomes the main reaction, and therefore an aliphatic secondary amine can be selectively synthesized.

In the second step, the catalyst is metallic palladium. When metal palladium is used as the catalyst, the dialkylation of the aliphatic amine is the main reaction, so that an asymmetric aliphatic tertiary amine can be selectively synthesized.

When the catalyst is palladium metal, it is preferable to add an acid. According to the test results of the inventors, when dialkylation of an aliphatic amine using metal palladium as a catalyst, if an acid is added, an aliphatic tertiary amine can be synthesized even more selectively. The reaction is promoted, and the residual ratio of unreacted raw materials can be reduced. In this case, if an organic acid and / or organic acid salt is used as the acid, an aliphatic tertiary amine can be obtained in a high yield.

In the method for producing an asymmetric aliphatic tertiary amine of the present invention, a protic solvent or an aprotic solvent can be used as a reaction solvent, and a mixed solvent can also be used. According to the test results of the inventors, if the reaction solvent is methanol, the aliphatic nitrile acts as an alkylating agent almost quantitatively, which is preferable.

  Examples 1 to 35 embodying the present invention will be described below.

(Examples 1-18)
In Examples 1 to 18, as shown in the following formula, the aliphatic amine (1) was reacted in the presence of a Pd / C catalyst and a nitrile compound in a hydrogen atmosphere to perform alkylation.

  That is, first, 1 mmol of an aliphatic amine and 5 mmol of a nitrile compound shown in Table 1 (3 mmol in Example 1) are dissolved in 1 ml of methanol (Examples 3, 5, 7, 9 to 13, 15, and 16 are further acidified). As well as 1 mmol of ammonium acetate). Further, 10% by mass of Pd / C on which 10% by mass of Pd is supported with respect to the carbon carrier (however, in Examples 10 and 18, 20% by mass and in Example 11 was set to 30% by mass), Stir for a predetermined time in a hydrogen atmosphere. Thereafter, the reaction solution is filtered through a 0.45 μm membrane filter to remove Pd / C. Further, Pd / C is washed with ethyl acetate, and the washing solution is combined with the filtrate. To the filtrate thus obtained, 10 ml of ethyl acetate and 10 ml of water were added, and the ethyl acetate layer was washed with a saturated sodium chloride solution, separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give Table 1. The alkylated aliphatic amine was obtained in the ratio shown in the following. In addition, the aliphatic amine and the nitrile compound were used as they were without purifying commercially available products unless otherwise specified in Table 1. When the nitrile compound was distilled and used, it was distilled in the presence of calcium hydride. Moreover, Aldrich (20,569-9) was used for Pd / C carrying 10% by mass of Pd.

From Table 1, it can be seen that all of the starting aliphatic amines are alkylated with aliphatic nitriles, and the products tend to be dialkylated as the main component rather than monoalkylated. That is, when palladium is used as a catalyst, dialkylation of an aliphatic amine can be selectively performed. In addition, the comparison between Example 2 and Example 3 shows that when ammonium acetate is added as the acid substance, the proportion of dialkylation increases compared to the case where ammonium acetate is not added (similar tendency is It was also observed in the comparison between Example 4 and Example 5 and in the comparison between Example 6 and Example 7). This shows that it is more selectively dialkylated by the addition of acid.

(Examples 19 to 34)
In Examples 19 to 34, as shown in the following formula, an aliphatic amine was reacted in the presence of an Rh / C catalyst and a nitrile compound in a hydrogen atmosphere to perform alkylation.

That is, first, 1 mmol of an aliphatic amine and 2 mmol of a nitrile compound shown in Table 2 (however, 5 mmol in Example 32) are dissolved in 1 ml of methanol. Further, 10% by mass of Rh / C in which 5% by mass of Rh is supported with respect to the carbon support is added, and the mixture is stirred for a predetermined time in a hydrogen atmosphere. Thereafter, the reaction solution is filtered through a 0.45 μm membrane filter to remove Rh / C. Further, Rh / C is washed with ethyl acetate, and the washing solution is combined with the filtrate. The filtrate thus obtained was subjected to the same extraction and distillation under reduced pressure as in Examples 1 to 18 to obtain aliphatic amines at the ratios shown in Table 2. The aliphatic amine and the aliphatic nitrile were used as they were without purifying commercially available products unless otherwise specified in Table 2. When aliphatic nitrile was used after distillation, it was distilled in the presence of calcium hydride. Moreover, WAKO (186-01011) of Wako Pure Chemical Industries Ltd. was used for Rh / C carrying 5 mass% Rh.

From Table 2, it can be seen that the starting aliphatic amines are all alkylated with aliphatic nitriles, and that the product has been terminated in the monoalkylation stage. That is, if rhodium is used as a catalyst, monoalkylation of an aliphatic amine can be selectively performed.

(Example 35)
In Example 35, as shown in the following formula, first, decylamine, which is an aliphatic primary amine, is reacted in the presence of a Rh / C catalyst and butyronitrile in a hydrogen atmosphere to convert a butylated aliphatic secondary amine to obtain. Further, the aliphatic secondary amine thus synthesized was reacted in the presence of a Pd / C catalyst and acetonitrile in a hydrogen atmosphere to obtain an ethylated asymmetric aliphatic tertiary amine.

  In other words, decylamine (78.7 mg, 0.5 mmol), butyronitrile (69.1 mg, 1 mmol) and 5% Rh / C (7.9 mg, 10 wt% of the substrate) were suspended in methanol (1 mL) under a hydrogen atmosphere. Stir with. After 34 hours, Rh / C was removed with a 0.45 μm membrane filter, washed with methanol, and the residue concentrated under reduced pressure was purified by column chromatography to obtain N-butyldecylamine (87.3 mg, 82%).

  Subsequently, N-butyldecylamine (53.4 mg, 0.25 mmol), acetonitrile (51.3 mg, 5 mmol) and 10% Pd / C (10.7 mg, 20 wt% of the substrate) were suspended in methanol (0.5 mL). Stir in a hydrogen atmosphere. After 28 hours, Pd / C was removed with a 0.45 μm membrane filter, washed with methanol, and concentrated under reduced pressure to obtain N-butyl-N-ethyldecylamine (55.5 mg, 92%).

In this way, by using the Rh / C catalyst and the Pd / C catalyst properly and performing alkylation twice with different aliphatic nitriles, an asymmetric aliphatic tertiary amine can be obtained with high selectivity and high yield. did it.

The present invention can be used for selectively synthesizing a target asymmetric aliphatic tertiary amine in a high yield.

Claims (4)

A first step in which an aliphatic primary amine and an aliphatic nitrile are reacted in the presence of a metal rhodium catalyst in a hydrogen atmosphere to synthesize an aliphatic secondary amine;
The aliphatic secondary amine and an aliphatic nitrile different from the aliphatic nitrile are reacted in the presence of a metal palladium catalyst in a hydrogen atmosphere to synthesize an asymmetric aliphatic tertiary amine having three different alkyl groups. The second step,
A process for producing an asymmetric aliphatic tertiary amine, comprising : Wherein in the second step, the manufacturing method according to claim 1 asymmetric aliphatic tertiary amine, wherein the addition of an organic acid and / or organic acid salts. The method for producing an asymmetric aliphatic tertiary amine according to claim 2, wherein the organic acid salt is ammonium acetate . The method for producing an asymmetric aliphatic tertiary amine according to any one of claims 1 to 3 , wherein methanol is used as a reaction solvent in the first step and the second step .