JP5838590B2 - Process for producing optically active 3-aminopiperidine - Google Patents

Description

  The present invention relates to a method for producing optically active 3-aminopiperidine from racemic 3-aminopiperidine.

  Optically active 3-aminopiperidine is a compound useful as a raw material for pharmaceuticals and agricultural chemicals.

  As a method for producing optically active 3-aminopiperidine, for example, a method in which racemic 3-aminopiperidine is optically resolved using an optically active organic acid such as optically active dibenzoyltartaric acid or optically active N-acetylphenylalanine is known. (Patent Document 1). Among the examples described in this document, the optical resolution is best when optically active dibenzoyltartaric acid is used. Even in this case, the yield of the salt obtained by one crystallization is 40 to 44%. The optical purity of the salt is 88 to 91% d. e. It is described that it was. In order to obtain a high optical purity salt, the treatment for increasing the optical purity is repeated several times, and there are problems in terms of yield and quality as an industrial method for producing optically active 3-aminopiperidine.

  As another example, a method using 2-methoxyphenylacetic acid or Np-toluenesulfonylphenylalanine as a resolving agent is also known (Patent Document 2). Among the examples described in this document, Example 8 using optically active α-methoxyphenylacetic acid is most successful, but the salt obtained by one crystallization has an optical purity of 98% d. . e. The yield of the above is as high as 32%, and this method also has a problem in terms of yield and quality as an industrial optically active 3-aminopiperidine production method.

International Patent Application Publication WO2007 / 075630 JP 2011-12032 A

  Thus, in the prior art, the present situation is that optically active 3-aminopiperidine cannot be produced simply and with high yield, and the creation of an efficient industrial production method has been strongly desired.

  An object of the present invention is to provide a method for producing optically active 3-aminopiperidine simply and in high yield from industrially advantageous and inexpensive raw materials.

  As a result of intensive studies on a method for solving the above problems, the present inventors have reacted optically active N-pipeluidine with optically active N-p-tolylglutamic acid by reacting racemic 3-aminopiperidine with optically active Np-toluylglutamic acid. It has been found that optically active 3-aminopiperidine can be efficiently produced by separating p-toluylglutamate, and the present invention has been achieved.

That is, the present invention reacts racemic 3-aminopiperidine with optically active Np-toluylglutamic acid to separate the optically active Np-toluylglutamate of the optically active 3-aminopiperidine to be produced. - a method of manufacturing a aminopiperidine, solvent to be used when separating the optically active N-p-toluyl glutamates optically active 3-aminopiperidine is, optically active 3 is a mixed solvent of water and main Tano Le -A method for producing aminopiperidine.

  According to the present invention, optically active 3-aminopiperidine can be produced simply and in high yield from industrially advantageous and inexpensive raw materials.

FIG. 1 is an infrared absorption spectrum of a 1: 1 salt of (S) -3-aminopiperidine and Np-toluyl-D-glutamic acid. FIG. 2 is a salt infrared absorption spectrum of a 1: 1 salt of Np-toluyl-L-glutamic acid of (R) -3-aminopiperidine.

  The present invention will be specifically described. The raw material 3-aminopiperidine can be produced by any method. For example, racemic 3-aminopiperidine is produced by hydrogenating 3-aminopyridine in the presence of a catalyst. can do.

  The optically active Np-toluylglutamic acid used in the present invention preferably has an optically active substance in which any one of the enantiomers is in excess of 95% or more, that is, the optical purity is 95% ee or more.

  Optically active Np-toluylglutamic acid can be produced, for example, according to the following reaction formula.

  The optically active Np-toluylglutamic acid is reacted, for example, by adding p-toluoyl chloride to an aqueous solution of optically active glutamic acid sodium salt while adjusting the pH to about 10 with an aqueous sodium hydroxide solution. Then, hydrochloric acid is added to the reaction solution, and the precipitated crystals are separated by filtration and dried to produce optically active Np-toluylglutamic acid.

  As the optically active Np-toluylglutamic acid, either Np-toluyl-L-glutamic acid or Np-toluyl-D-glutamic acid can be used. When Np-toluyl-L-glutamic acid is used for separation, the general formula

A salt of (R) -3-aminopiperidine and Np-toluyl-L-glutamic acid represented by the formula is obtained as crystals. When Np-toluyl-D-glutamic acid is used, the general formula

The salt of (S) -3-aminopiperidine and Np-toluyl-D-glutamic acid represented by the formula is obtained as crystals.

  The amount of the optically active Np-toluylglutamic acid used for separating the optically active Np-toluylglutamate of the optically active 3-aminopiperidine is 0.5 to 1. A 2-fold mole is preferred. At that time, mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and propionic acid which are optically inactive substances can be allowed to coexist. In that case, the amount of optically active Np-toluylglutamic acid used can be reduced.

The solvent to be used for separation, it is necessary not to react with the substrate is a mixture of water and main Tano Le.

  The amount of the solvent used for the separation is preferably 3 to 30 times the weight of the racemic 3-aminopiperidine.

  The method for separating the optically active Np-toluylglutamate of the optically active 3-aminopiperidine includes a raw racemic 3-aminopepyridine, an optically active Np-toluylglutamic acid, a solvent, and optionally mineral acids. Or a method of mixing and dissolving organic acids and filtering the precipitated salt. In this case, after adding the racemic 3-aminopiperidine as a raw material and a solvent, a method of adding optically active Np-toluylglutamic acid, and in some cases mineral acids or organic acids with stirring, conversely, solvent and optical For example, a method of adding raw material racemic 3-aminopiperidine with stirring after charging active Np-toluylglutamic acid, and optionally mineral acids or organic acids, is preferred. The temperature at which these raw materials are charged can be arbitrarily selected within the range of −10 ° C. to the boiling point of the solvent. The temperature at which the deposited salt is filtered is preferably 0 ° C to 30 ° C. When the influence of the mother liquor adhesion is large, or when producing a product with a particularly high optical purity, the optically active 3-aminopiperidine optically deposited after the solvent is added and dissolved again or washed with a slurry and cooled. By filtering the crystals of active N-toluyl glutamate, the optical purity can be easily increased. In this case, water, methanol, ethanol, propanol, or a mixture thereof can be used as the solvent.

  The method of desolvating the optically active N-toluylglutamate of the optically active 3-aminopiperidine thus obtained and isolating the optically active 3-aminopiperidine can be carried out by the following method. For example, optically active 3-aminopiperidine and an optically active Np-toluylglutamic acid salt dissolved in water are added with hydrochloric acid at least twice the molar amount of the salt, and the precipitated crystals are filtered to obtain optical activity. Np-toluylglutamic acid is removed. A sodium hydroxide aqueous solution was added to this filtrate to adjust the pH to about 12, and then concentrated. Ethanol was added to the concentrated residue, the precipitated sodium chloride was filtered, and the filtrate was concentrated and distilled. Optically active 3-aminopiperidine can be obtained as a fraction. Further, optical activity is obtained by adding at least twice mol of hydrochloric acid to a salt solution of optically active 3-aminopiperidine and optically active Np-toluylglutamic acid in water, and filtering the precipitated crystals. Np-toluylglutamic acid is removed, and the filtrate is concentrated, and then an organic solvent such as ethanol is added and crystallized to isolate dihydrochloric acid of optically active 3-aminopiperidine. Here, instead of hydrochloric acid, mineral acids such as sulfuric acid and phosphoric acid, carboxylic acids such as formic acid, acetic acid, propionic acid and citric acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid are also used. be able to.

  By using the racemic 3-aminopiperidine that can be produced at low cost as a raw material, the optically active Np-toluylglutamic acid that can be used industrially can be used to achieve high yield and high purity. The following optically active 3-aminopiperidine can be produced.

  The optically active 3-aminopiperidine thus obtained is a useful compound as a raw material for pharmaceuticals and agricultural chemicals.

  Hereinafter, the present invention will be described in more detail with reference to examples.

<3-aminopiperidine quantitative analysis (GC)>
In Examples, 3-aminopiperidine contained in a salt was quantified by adding an internal standard substance to a solution obtained by dissolving a salt in an aqueous sodium hydroxide solution to obtain a salt-dissolved solution, and then injecting the solution into GC (gas chromatography).
Column: Inert Cap 1 (GL Science)
60m-0.25mm I.D. D. 0.4μm
Temperature: 100 ° C (5 minutes) → 7 ° C / min → 170 ° C
Inlet: 270 ° C
Detector: 270 ° C
Carrier gas: Helium (total flow rate 52ml / min)
Split ratio: 19.

<Optical purity analysis (HPLC) of 3-aminopiperidine>
The optical purity of 3-aminopiperidine was analyzed by HPLC (high performance liquid chromatography) after labeling with di-p-toluoyl-D-tartaric anhydride (manufactured by Toray Fine Chemical Co., Ltd.).
Column: CAPCELL PAK C18 TYPE SG-120 (Shiseido)
5μm, 150mm-4.6mmφ
Mobile phase: Liquid A; 0.03% NH3 aqueous solution (pH 4.7, using acetic acid)
Liquid B; acetonitrile A / B = 65/35
Flow rate: 0.5 ml / min
Detector: UV 243nm
Temperature: 40 ° C.

Example 1
Production of N-p-toluyl-L-glutamate of (R) -3-aminopiperidine 0.50 g (5.0 mmol) of racemic 3-aminopiperidine, Np-toluyl in a stoppered sample bottle with a capacity of 10 ml -1.33 g (5.0 mmol) of L-glutamic acid, 2.78 g of methanol, and 0.48 g of water were added, and the mixture was dissolved by heating to 60 ° C, and N-p of (R) -3-aminopiperidine -10 mg of toluyl-L-glutamate was added. After cooling to 10 ° C., the precipitated crystals were filtered and dried to obtain 0.84 g of salt. The optical purity of 3-aminopiperidine contained in the salt was 94.0% e.e. e. (R-form).

  A part of this salt was collected to quantitatively determine 3-aminopiperidine. The content was 27.3%, and this salt was 1: 1 of 3-aminopiperidine and Np-toluyl-L-glutamic acid. To be confirmed. Yield 46%.

Example 2
Production of N-p-toluyl-L-glutamate of (R) -3-aminopiperidine 0.50 g (5.0 mmol) of racemic 3-aminopiperidine, Np-toluyl in a stoppered sample bottle with a capacity of 10 ml -0.93 g (3.5 mmol) of L-glutamic acid, 0.16 g (1.5 mmol) of 35% hydrochloric acid, 2.78 g of methanol, and 0.30 g of water were added and dissolved by heating to 60 ° C. , (R) -3-aminopiperidine Np-toluyl-L-glutamate 10 mg was added. After cooling to 10 ° C., the precipitated crystals were filtered and dried to obtain 0.76 g of salt. The optical purity of 3-aminopiperidine contained in the salt was 96.3% e.e. e. (R-form).

  A part of this salt was collected to quantify 3-aminopiperidine. The content was 27.4%, and this salt was 1: 1 of 3-aminopiperidine and Np-toluyl-L-glutamic acid. To be confirmed. Yield 42%.

Example 3
Preparation of (S) -3-aminopiperidine Np-toluyl-D-glutamate 1.00 g (10.0 mmol) racemic 3-aminopiperidine, Np-toluyl in a 20 ml stoppered sample bottle -2.65 g (10.0 mmol) of D-glutamic acid, 5.55 g of methanol, and 0.97 g of water were added, and the mixture was dissolved by heating to 60 ° C, and N-p of (S) -3-aminopiperidine -10 mg of toluyl-D-glutamate was added. After cooling to 10 ° C., the precipitated crystals were filtered and dried to obtain 1.57 g of salt. The optical purity of 3-aminopiperidine contained in the salt is 95.5% e.e. e. (S body).

  A part of this salt was collected to quantify 3-aminopiperidine. The content was 27.5%, and this salt was 1: 1 of 3-aminopiperidine and Np-toluyl-D-glutamic acid. To be confirmed. Yield 43%.

  A salt bottle with a capacity of 10 ml was charged with 1.00 g of this salt and 0.97 g of water, heated to 60 ° C. to dissolve, and 5.55 g of methanol was added when heated. After cooling to 10 ° C., the precipitated crystals were filtered and dried to obtain 0.91 g of salt. The optical purity of 3-aminopiperidine contained in the salt is 99.8% e.e. e. (S body). Yield 91%. The infrared absorption spectrum is shown in FIG.

Reference example 1
Preparation of (R) -3-aminopiperidine Np-toluyl-L-glutamate 0.50 g (5.0 mmol) of racemic 3-aminopiperidine, Np-toluyl in a 50 ml stoppered sample bottle After charging 1.33 g (5.0 mmol) of L-glutamic acid and 17.5 g of methanol, the mixture was heated to 60 ° C. and dissolved to give N-p-toluyl-L-glutamic acid of (R) -3-aminopiperidine. 10 mg of salt was added. After cooling to 27 ° C., the precipitated crystals were filtered and dried to obtain 0.94 g of salt. The optical purity of 3-aminopiperidine contained in the salt is 76.8% e.e. e. (R-form). Yield 51%.

Example 4
Production of (R) -3-aminopiperidine Np-toluyl-L-glutamate In a 500 ml four-necked flask equipped with a stirrer, thermometer and condenser, 22.0 g of racemic 3-aminopiperidine (0. 220 mol), 40.9 g (0.154 mol) of Np-toluyl-L-glutamic acid, 122.1 g of methanol, 13.2 g of water, 6.9 g of 35% hydrochloric acid (0.066 mol) And dissolved by stirring. (R) -3-Aminopiperidine Np-toluyl-L-glutamate 50 mg was added. After cooling to 3 ° C., the precipitated crystals were filtered and dried to obtain 36.8 g of salt. The optical purity of 3-aminopiperidine contained in the salt is 96.9% e.e. e. (R-form).

  A part of this salt was collected to quantify 3-aminopiperidine. The content was 27.5%, and this salt was 1: 1 of 3-aminopiperidine and Np-toluyl-L-glutamic acid. To be confirmed. Yield 46%.

  Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 36.2 g of the above salt and 52.4 g of water were charged, dissolved by heating, and then 159.7 g of methanol was further added. After cooling to 3 ° C., the precipitated crystals were filtered and dried to obtain 32.5 g of salt. The optical purity of 3-aminopiperidine contained in the salt is 99.8% e.e. e. (R-form). Yield 90%. The infrared absorption spectrum is shown in FIG.

Comparative Examples 1-15
Table 1 shows the results of optical resolution with various optical resolution agents using 5.0 mmol of racemic 3-aminopiperidine. In Comparative Examples 2 to 5, 7, 8, 12, and 14, optical resolution was not possible, and a racemate was obtained. In Comparative Examples 1, 6, 9, 10, and 15, optical resolution was possible, but the optical purity of 3-aminopiperidine was 84% e.e. e. The optical purity was low. In Comparative Examples 11 and 13, a salt of 3-aminopiperidine could not be obtained.

Claims (1)

Process for producing optically active 3-aminopiperidine by reacting racemic 3-aminopiperidine with optically active Np-toluylglutamic acid and separating optically active Np-toluylglutamate of the optically active 3-aminopiperidine to be produced a is, solvent to be used when separating the optically active N-p-toluyl glutamates optically active 3-aminopiperidine is process for producing an optically active 3-aminopiperidine is a mixed solvent of water and main Tano Le .

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