JP2005075754A - Method for optical resolution of trans-1,2-bis(3,5-dimethylphenyl)-1,2-ethanediamine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide optically active 1,2-bis(3,5-dimethylphenyl)-1,2-ethanediamine useful as an optical resolution agent or as the ligand of an asymmetric catalyst in an asymmetric synthesis reaction. <P>SOLUTION: This method for the optical resolution of trans-1,2-bis(3,5-dimethylphenyl)-1,2-ethanediamine comprises dissolving the racemate of the trans-1,2-bis(3,5-dimethylphenyl)-1,2-ethanediamine in at least one solvent selected from water and methanol in the presence of an optically active tartaric acid and then crystallizing the compound. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for purifying optically active trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine useful as a ligand and an optical resolution agent for an asymmetric catalyst in an asymmetric synthesis reaction. About.

  Optically active trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine is a compound useful as a ligand for an asymmetric catalyst, an optical resolving agent, etc. Asymmetric reduction reaction (Patent Document 1), asymmetric reduction reaction of imines (Patent Document 2), asymmetric 1,4-reduction reaction of α, β-unsaturated carboxylic acid amides (Patent Document 3) Used as a raw material.

  As a method for producing trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine, a method through imine coupling and debenzylation is disclosed (Patent Document 4). As an optical resolution method, as shown by the route of the following formula (A), a method of using various trans-1,2-diaryl-1,2-ethanediamine racemates in an ethanol solvent using optically active tartaric acid is proposed. (Non-Patent Document 1).

JP-A-9-151143 WO-98 / 39276 Japanese Patent Laid-Open No. 11-246501 Japanese Patent Laid-Open No. 2002-338531 Tetrahedron Asymmetry, 6, 3 (1995)

  An object of the present invention is to provide an optically active trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine, which is useful as a raw material for asymmetric synthesis reaction, with high recovery and high optical yield. It is an object of the present invention to provide an optical resolution method that can be obtained by:

Therefore, as a result of intensive studies to solve the above problems, the present inventor has optically converted a racemic body of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine in a specific solvent. It has been found that the object can be achieved by acting an active tartaric acid derivative,
The present invention has been reached.

  That is, the present invention provides a racemate of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine, at least one selected from water and methanol in the presence of optically active tartaric acid. This is an optical resolution method of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine which is crystallized after being dissolved in a solvent comprising:

  According to the method of the present invention, a racemate of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine is optically resolved using optically active tartaric acid in a specific solvent. Thus, optically active trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine can be obtained with high recovery and high optical yield. This optically active diamine is useful as a ligand for an asymmetric catalyst and an optical resolution agent in an asymmetric synthesis reaction.

  Hereinafter, the optical resolution method of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine of the present invention (hereinafter referred to as “method of the present invention”) will be described in detail.

  In the method of the present invention, among optically active tartaric acids used as an optical resolving agent, dextrorotatory tartaric acid (L-(+)-tartaric acid) and levorotatory tartaric acid (D-(-)-tartaric acid) are selectively used. (−)-Trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine and (+)-trans-1,2-bis (3,5-dimethylphenyl) -1,2 -Ethanediamine can be resolved. That is, when L-(+)-tartaric acid is used as a resolving agent, (−)-trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine is When (-)-tartaric acid is used, (+)-trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine is obtained.

  In addition, the amount of optically active tartaric acid used in the salt formation reaction between trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine and optically active tartaric acid is trans-1,2-bis (3 , 5-dimethylphenyl) -1,2-ethanediamine is 0.7 molar equivalent or more. 0.9 to 1.1 molar equivalents are preferable in terms of high recovery rate and optical purity of optically active trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine.

As a solvent, the solvent which consists of at least 1 sort (s) chosen from methanol and water is mentioned, Preferably, the mixed solvent of water and methanol is mentioned.
When the amount of methanol used is too small, oily impurities present in the crude trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine precipitate. In some cases, if the amount of water used is too small, the amount of solvent required increases. For these reasons, the volume ratio of water and methanol is preferably 1/9 to 9/1.

  In the method of the present invention, the salt formation reaction between diamine and tartaric acid is performed, for example, by the following method. Trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine and 1.0 molar equivalent of optically active tartaric acid are added to the solvent consisting of at least one selected from water and methanol. And dissolve by heating. If the solvent does not dissolve even after sufficient time, the solvent is added and completely dissolved. After dissolution, a hardly soluble diastereomeric salt precipitates upon cooling. By separating the precipitated crystals by filtration, when L-(+)-tartaric acid is used as a resolving agent, (−)-trans-1,2-bis (3,5-dimethylphenyl) -1,2- Ethanediamine / L-(+)-tartrate, on the other hand, when D-(-)-tartaric acid is used, (+)-trans-1,2-bis (3,5-dimethylphenyl) -1, 2-Ethanediamine / D-(-)-tartrate is obtained. The obtained salt can be purified by recrystallization as necessary.

  The tartaric acid salt thus obtained was treated with a base such as sodium hydroxide, and the released optically active trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine was mixed with dichloromethane, ethyl acetate. (-)-Or (+)-trans-1,2-bis (3,5-dimethylphenyl) having high optical purity by extraction with an organic solvent such as ether or toluene and then distilling off the solvent -1,2-ethanediamine can be quantitatively recovered from the tartrate salt. At this time, the optically active tartaric acid present in the basic aqueous solution can be quantitatively recovered and reused without being accompanied by a decrease in optical purity by acid treatment.

  Next, a method for producing racemic trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine used as a raw material in the method of the present invention will be described. Racemic trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine is prepared according to the process shown in the following formula (B) (Patent Document 4).

  That is, in the presence of magnesium sulfate, benzylamine (f) was added to 3,5-dimethylbenzaldehyde (e) in a tetrahydrofuran solvent and stirring was continued at room temperature. Then, magnesium sulfate was filtered off and removed, and the filtrate was concentrated under reduced pressure. Then, imine (g) is obtained with a good yield. Next, 0.83 molar equivalent of titanium tetraisopropoxide and then 2.1 molar equivalent of isopropylmagnesium chloride are added to imine (g) at 0 ° C. in a tetrahydrofuran solvent, followed by reaction at room temperature. Thereafter, a large excess of 50% by mass aqueous potassium hydroxide solution, then a large excess of sodium fluoride and celite were added, the solid was filtered off, and the filtrate was concentrated under reduced pressure to give 1,2-bis (3,5-dimethyl). Phenyl) -1,2-ethanediamine-N, N′-dibenzyl can be obtained in good yield. This crude product includes cis-1 in addition to the desired product trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl (h). , 2-bis (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl (i) is included, but this cis-1,2-bis (3,5- Since dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl (i) is hardly soluble in an alcohol solvent, an alcohol solvent is added to the obtained crude product, and the precipitated solid is separated. Can be removed.

  Examples of the alcohol solvent used in the step of removing cis-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl (i) include methanol, ethanol, Examples include n-propanol, i-propanol, and n-butanol. Of these, ethanol is preferred.

  The amount of the alcohol solvent to be used is not particularly limited, but is preferably in the range of 0.5 to 10 by mass ratio with respect to the crude product obtained by the above method. If the amount is less than this, the recovery rate of the desired product, trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl may be lowered, and more Using this amount is ineffective and uneconomical. The precipitated cis-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl can be removed by ordinary operations such as filtration and centrifugation.

  Next, in a hydrogen atmosphere, trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′- in ethanol at 60 ° C. using 10 mass% Pd / C as a catalyst. After reacting the dibenzyl compound (h), the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give racemic trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine. (J) is obtained with good yield. The obtained racemic crude diamine can be used in the next optical resolution step as it is.

EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.
(Production Example 1)
Preparation of N-benzyl-3,5-dimethylbenzaldimine (g) Under a nitrogen atmosphere, 5.39 g (40.2 mmol) of 3,5-dimethylbenzaldehyde (e) and 4.27 g (39. 9 mmol), 4.0 g of magnesium sulfate and 40 mL of tetrahydrofuran were added, and the mixture was stirred at room temperature for 5 hours. Thereafter, the reaction mixture was filtered through Celite, and the residue was further washed twice with 20 mL of tetrahydrofuran. Thereafter, the filtrate was concentrated under reduced pressure to obtain 8.69 g (crude yield: 98%) of a crude product of N-benzyl-3,5-dimethylbenzaldimine (g).

(Production Example 2)
Preparation of trans-1,2-bis- (3,5-dimethylphenyl) ethanediamine-N, N′-dibenzyl (h) N-benzyl-3,5-obtained in Production Example 1 under a nitrogen atmosphere To a tetrahydrofuran solution (50 mL) of 1.00 g (4.48 mmol) of a crude product of dimethylbenzaldimine (g) was added 1.05 g (3.69 mmol) of titanium tetraisopropoxide and cooled to 0 ° C. To this, 4.6 mL (9.2 mmol) of a 2 mol / L tetrahydrofuran solution of isopropylmagnesium chloride was slowly added dropwise over 10 minutes. The reaction mixture was stirred at 0 ° C. for 30 minutes and then warmed to room temperature over 30 minutes. Furthermore, after stirring at room temperature for 3 hours, 3 mL of 50 mass% potassium hydroxide aqueous solution was added slowly, and it stirred at room temperature for 30 minutes. Thereafter, 1 g of sodium fluoride and 1 g of celite were added, and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the residue was washed twice with 20 mL of tetrahydrofuran. The obtained filtrate was concentrated under reduced pressure to obtain 0.997 g of a yellow oily substance. When 1 g of ethanol was added to 0.931 g of this oily substance and stirred at room temperature for about 15 minutes, a white solid was precipitated. The solid was filtered off, washed twice with 1 g of ethanol, and the resulting filtrate was concentrated under reduced pressure to obtain trans-1,2-bis- (3,5-dimethylphenyl) -1,2- 0.85 g of a crude product of ethanediamine-N, N′-dibenzyl (h) was obtained (crude yield 90%). From the NMR analysis, this trans-1,2-bis- (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl (h) crude product contained cis-1,2 -Bis- (3,5-dimethylphenyl) -1,2-ethanediamine-N, N'-dibenzyl (i) was not detected. Further, the filtered white solid was dried under reduced pressure to obtain cis-1,2-bis- (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl (i) 0. .05 g was obtained (yield 5%).

(Production Example 3)
Preparation of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine (j) Under hydrogen atmosphere, 0.1 g of 10% by mass Pd / C (50% by mass water-containing product) and 2 mL of ethanol And vigorously stirred at normal pressure and 60 ° C. for 1 hour. Thereafter, 0.495 g of a crude product of trans-1,2-bis- (3,5-dimethylphenyl) -1,2-ethanediamine-N, N′-dibenzyl (h) obtained in Production Example 2 ( 1.10 mmol) ethanol solution (3 mL) was added and stirred vigorously at 60 ° C. for a further 7.5 hours. The reaction mixture was cooled to room temperature and then filtered, and the residue was washed twice with 2 mL of ethanol. The obtained filtrate was concentrated under reduced pressure to obtain 0.276 g of a crude product of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine (j) ( (Rough yield 93%).

  A racemic form of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine (1.33 g, 4.97 mmol) and L-(+)-tartaric acid (745 mg, 4.96 mmol) were placed in a flask. Then, 340 mL of a methanol / water mixture solution having a volume ratio of 1/1 was added (tartrate concentration 14.6 mmol / L), heated and dissolved at 70 ° C., and then cooled to room temperature. After standing overnight, the precipitated crystals were separated by filtration, washed once with 30 mL of a methanol / water mixture with a volume ratio of 1/1, twice with 20 mL of methanol, and then vacuum dried to obtain 538 mg of diamine tartrate. .

30 mL of dichloromethane was added to 456 mg of the obtained salt, and after separation and extraction twice with 20 mL of a 1 mol / L aqueous sodium hydroxide solution and once with 10 mL of water, the obtained dichloromethane phase was dried over sodium sulfate. Sodium sulfate was filtered off, washed with 30 mL of dichloromethane, and the dichloromethane phase was concentrated under reduced pressure to obtain 242 mg of the target optically active diamine. The recovery rate of the charged racemic trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine was 21%. [α] _D ³¹ = −44.2 ° (c 0.968, CHCl ₃ ). Optical purity calculated based on literature values of specific rotation> 99% ee [literature values: [α] _D ²³ = −43, 4 ° (c 0.82, CHCl ₃ ), non-patent document 1].

  Dichloromethane (50 mL) was added to 1.54 g of the salt recovered by concentrating the mother liquor obtained in Example 1 under reduced pressure, and the resulting dichloromethane was separated and extracted twice with 40 mL of 1 mol / L sodium hydroxide aqueous solution and once with 20 mL of water. The phase was dried with sodium sulfate. Sodium sulfate was filtered off, washed with 30 mL of dichloromethane, and the dichloromethane phase was concentrated under reduced pressure to obtain 939 mg of diamine. To this diamine, 240 mL of a methanol / water mixture with a volume ratio of 1/1 and 525 mg of D-(-)-tartaric acid were added (tartaric acid salt concentration: 14.6 mmol / L), and the mixture was heated and dissolved at 70 ° C. . After standing overnight, the precipitated crystals were separated by filtration, washed once with 30 mL of a methanol / water mixture at a volume ratio of 1/1, twice with 20 mL of methanol, and then vacuum dried to obtain 526 mg of diamine tartrate. .

30 mL of dichloromethane was added to 475 mg of the obtained salt, and after separation and extraction twice with 20 mL of 1 mol / L aqueous sodium hydroxide solution and once with 10 mL of water, the obtained dichloromethane phase was dried over sodium sulfate. Sodium sulfate was filtered off, washed with 30 mL of dichloromethane, and the dichloromethane phase was concentrated under reduced pressure to obtain 228 mg of the objective optically active diamine. The recovery rate of the racemic mixture charged at the beginning of Example 1 with respect to the total amount of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine was 19%. [α] _D ³¹ = 40.0 ° (c 0.912, CHCl ₃ ). Optical purity calculated based on literature values of specific rotation = 92% ee.

(Comparative Example 1)
Racemic 427 mg (1.59 mmol) of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine and 239 mg (1.59 mmol) of L-(+)-tartaric acid were placed in a flask. A volume ratio of 1/1 ethanol / water mixture (110 mL) was added (tartrate concentration: 14.5 mmol / L) and heated to 70 ° C., but it was not completely dissolved. Furthermore, when ethanol was gradually added at 70 ° C., it was dissolved when 55 mL was added. Thereafter, it was cooled to room temperature and allowed to stand overnight, but almost no crystals were precipitated. Therefore, when the solution was cooled to 0 ° C., a white powdery solid was precipitated. The precipitated solid was separated by filtration, washed twice with 10 mL of ethanol, and then vacuum-dried to obtain 247 mg of diamine tartrate.
30 mL of dichloromethane was added to 247 mg of the obtained salt, and after separation and extraction twice with 15 mL of 1 mol / L aqueous sodium hydroxide solution and once with 15 mL of water, the obtained dichloromethane phase was dried over sodium sulfate. Sodium sulfate was filtered off, washed with 30 mL of dichloromethane, and then the dichloromethane phase was concentrated under reduced pressure to obtain 136 mg of diamine. The specific rotation of this diamine was [α] _D ³² = −5.3 ° (c 1.360, CHCl ₃ ). The recovery rate of the charged racemic body with respect to the total amount of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine was 32%. Optical purity calculated based on literature values of specific rotation = 12% ee.

  The optically active 1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine obtained by the method of the present invention is useful as an asymmetric catalyst ligand and an optical resolution agent in an asymmetric synthesis reaction. .

Claims (2)

  A racemate of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine is dissolved in a solvent consisting of at least one selected from water and methanol in the presence of optically active tartaric acid. And then optical resolution of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine which crystallizes. The method for optical resolution of trans-1,2-bis (3,5-dimethylphenyl) -1,2-ethanediamine according to claim 1, wherein the solvent is a mixed solvent of water and methanol.