JP2002128745A - Method for producing optically active 1,2-bis(2,4,6- trimethylphenyl)-1,2-ethanediamine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optically active 1,2-bis(2,4,6-trimethylphenyl)-1,2- ethanediamine useful as a ligand of an asymmetric catalyst and a reagent for an optical resolution in an asymmetric synthetic reaction. SOLUTION: This method for producing the optically active 1,2-bis(2,4,6- trimethylphenyl)-1,2-ethanediamine comprises a step of adding optically active hydroxycarboxylic acids to (±)-1,2-bis(2,4,6-trimethylphenyl)-1,2-ethanediamine and crystallizing to carry out the optical resolution after heating and dissolving in a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an optically active 1,2-bis (2,4,6-trimethylphenyl) -1,1 which is useful as an asymmetric catalyst ligand and an optical resolution agent in an asymmetric synthesis reaction. The present invention relates to a method for producing 2-ethanediamine.

[0002]

BACKGROUND OF THE INVENTION Generally, optically active trans-1,2-diphenylethanediamine can be obtained by optical resolution of the corresponding racemate. For example, Japanese Unexamined Patent Publication No.
No. 1 discloses a method for isolating an optically active substance by optical resolution of (±) -1,2-diphenylethanediamine. That is, it has been clarified that diastereomeric salts formed by reacting (±) -1,2-diphenylethanediamine with optically active mandelic acid can be separated using the difference in solubility. The obtained hardly soluble diastereomer salt is released as a diamine by treating with a base, and can be purified by a recrystallization operation.

[0003] Several methods are known for producing racemic trans-1,2-diphenylethanediamine. For example, Journal of the American Chem
icalSociety, 81 , 4464 (1959) discloses a production method using a process represented by the following formula (A) [formula 1] using benzaldehyde and ammonia as starting materials. That is, benzaldehyde (a) is reacted with ammonia to form hydrobenzamide (b), cyclized by heating to amarin (c), and then reacted under basic conditions to obtain isoamarin (d). Further, after reacting with acetic anhydride, the ring is opened with hydrochloric acid to form a diamide compound (e) and hydrolyzed with hydrobromic acid, whereby trans-1,2-diphenylethanediamine (f) can be produced.

[0004]

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[0005] Various improvements have been made to this route, for example, see Tetrahedron Letters, 38 , 8631 (199).
In 7), trans-amalin (d) is reduced with aluminum amalgam and then hydrolyzed to give trans-
A method for synthesizing 1,2-diphenylethanediamine has been reported. Japanese Patent Application Laid-Open No. 11-12232 discloses that a non-protonic polar solvent such as 1,3-dimethylimidazolidinone can be used to convert trans-1,2-diphenylethane from hydrobenzamide (b) in one pot. A method for producing a diamine is disclosed. Also, Japanese Patent Application Laid-Open No. 2000-86593 discloses that the iso-amarin (d) can be transformed into trans-1,2 in one pot by the same route.
-A process for producing diphenylethanediamine is disclosed.

As another method for producing racemic trans-1,2-diphenylethanediamine, there is known a method in which benzaldehyde is used as a raw material and Pedee is passed through silylimine (g).
The method of rsen et al. (Formula (B) [Formula 2], Journal of the
American Chemical Society, 109 , 3152 (1987)) and the method of Corey et al. Using benzyl (h) as a raw material (the following formula (C)
[Formula 3], Journal of the American Chemical Societ
y, 111 , 5493 (1989)).

[0007]

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[0008]

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On the other hand, optically active 1,2-bis (2,4,6
-Trimethylphenyl) -1,2-ethanediamine is
Since it is sterically bulkier than 1,2-diphenyl-1,2-ethanediamine, it is expected to be more effective as a ligand of an asymmetric catalyst or as an optical resolving agent. actually,
JP-A-9-151143 discloses WO 98/39276 as a raw material for a catalyst in an asymmetric reduction reaction of ketones.
JP-A-11-246501 discloses a catalyst for the asymmetric reduction reaction of imines, and α,
It is used as a raw material for a catalyst in the asymmetric 1,4-reduction reaction of β-unsaturated carboxylic acid amides. But,
1,2-bis (2,4,6-trimethylphenyl)-
Regarding the method for producing 1,2-ethanediamine, there have been no specific reports on the trans-isomer production method and the optical resolution method.

Also, trans-1,2-diphenyl-
It was unclear whether the method for producing 1,2-ethanediamine and the optical resolution method can be directly applied. The only report on the preparation of the diamine is Zh, University of Illinois, USA.
ang, Wei (Ph.D. thesis, University o
f Illinois, 1991). In this paper, it is mentioned in the text that the intended trans-isomer can be obtained by applying the coupling reaction of silylimine by Pedersen et al. Represented by the above formula (B).

However, a detailed description of the method for producing trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine and its optical resolution method by chemical formulas, experimental items, and the like is omitted. Until now, the physical properties of the compound, the optical resolution method, and the relation between these compounds and the absolute configuration have not been clarified.

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to provide an optically active 1,2-bis (2,4,6-trimethylphenyl)-having excellent stereoselectivity as a raw material of a catalyst for an asymmetric synthesis reaction. An object of the present invention is to provide a practical method capable of producing 1,2-ethanediamine. In particular, to provide a practical optical resolution method for trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine, whose effective optical resolution method has not been clarified. It is in.

[0013]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventor has proposed using trans-1,2-bis (2,4,6 -Trimethylphenyl) -1,2-ethanediamine has been studied intensively for a method capable of optical resolution. As a result, trans-1,2-bis (2,4,
The present inventors have found that the above object can be achieved by allowing optically active mandelic acid to act on (6-trimethylphenyl) -1,2-ethanediamine, and have reached the present invention.

That is, in order to solve the above-mentioned problems, the present invention provides (±) -1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine with an optically active hydroxycarboxylic acid. Adding a compound, heating and dissolving in a solvent, crystallization and optical resolution, including a step of optically active 1,2-bis (2,4,6-trimethylphenyl)-
It is intended to provide a method for producing 1,2-ethanediamine.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the optically active 1,2- of the present invention
The method for producing bis (2,4,6-trimethylphenyl) -1,2-ethanediamine (hereinafter, referred to as “method of the present invention”) will be described in detail. In the method of the present invention, examples of the optically active hydroxycarboxylic acid compound used as the optical resolving agent include optically active tartaric acid, optically active malic acid, optically active mandelic acid, and preferably optically active mandelic acid. Among optically active mandelic acids, dextrorotatory mandelic acid ((S)-(+)-
Mandelic acid) and levorotatory mandelic acid ((R)-(-)-
By using (mandelic acid) properly, (−)-1, 2
-Bis (2,4,6-trimethylphenyl) -1,2-
Ethanediamine and (+)-1,2-bis (2,4,6-
(Trimethylphenyl) -1,2-ethanediamine can be efficiently separated with high optical purity. That is,
When (S)-(+)-mandelic acid is used as a resolving agent, (-)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine, on the other hand, ( R)
When (-)-mandelic acid is used, (+)-1,
2-bis (2,4,6-trimethylphenyl) -1,2
-Ethanediamine is obtained with good yield and high optical purity.

Further, (±) -1,2-bis (2,4,6
-Trimethylphenyl) -1,2-ethanediamine and the optically active mandelic acid in the salt formation reaction with the optically active mandelic acid were (±) -1,2-bis (2,4,6).
-Trimethylphenyl) -1,2-ethanediamine is at least 1.5 molar equivalents, preferably from 1.8 to
When 2.1 molar equivalents of optically active mandelic acid are used, the optically active diamine, ie, (-)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine, or (+ ) -1,2-bis (2,4,6-
(Trimethylphenyl) -1,2-ethanediamine is obtained with high yield and high optical purity.

As the solvent, methanol, ethanol,
Examples thereof include alcohol solvents such as 1-propanol, 2-propanol, 1-butanol, 1-propanol, and 1-hexanol, and mixtures thereof, and preferably, methanol, ethanol, and 2-propanol.

In the method of the present invention, the salt formation reaction between a diamine and mandelic acid is carried out, for example, by the following method. (±) -1,2-Bis (2,4,6-trimethylphenyl) -1,2-ethanediamine and 2.0 molar equivalents of optically active mandelic acid are added to the alcohol solvent and dissolved by heating. If it does not dissolve even after a sufficient time, the alcohol compound is added and completely dissolved. After dissolution, a sparingly soluble diastereomer salt precipitates upon cooling. By filtering out the precipitated crystals,
When (+)-mandelic acid is used as a resolving agent, (-)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine / (+)-mandelic acid salt is used. On the other hand, when (−)-mandelic acid is used, (+)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine / (−)-mandelic acid salt is used. can get. The obtained salt can be purified by recrystallization if necessary.

The thus obtained mandelic acid salt is treated with a base such as sodium hydroxide to release the optically active 1,2.
-Bis (2,4,6-trimethylphenyl) -1,2-
After ethanediamine is extracted with an organic solvent such as dichloromethane, ethyl acetate, ether, and toluene, the solvent is distilled off to obtain (−)-or (+)-1,2-bis (2) having high optical purity. , 4,6-Trimethylphenyl) -1,2-ethanediamine can be recovered quantitatively from the mandelic acid salt. At this time, the optically active mandelic acid present in the basic aqueous solution can be quantitatively recovered and reused by acid treatment without lowering the optical purity.

Next, in the method of the present invention, the racemic trans-1,2-bis (2,2
A method for producing 4,6-trimethylphenyl) -1,2-ethanediamine will be described for reference. The racemic trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine can be obtained by a process shown in the following formula (D) (Chem. A method utilizing a ring reaction).

[0021]

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That is, 2,4,6-trimethylbenzaldehyde (k) is converted to lithium bis (trimethylsilyl)
After reacting with the amide, trimethylsilane chloride was added and stirring was continued.
Filtration of the filtrate under reduced pressure gives silylimin (l).
Next, in the presence of an equimolar amount of niobium tetrachloride-tetrahydrofuran complex, the above-obtained silylimine (l) is reacted at room temperature in 1,2-dimethoxyethane solvent and treated with a base to obtain the desired compound. Racemic trans-1,
2-bis (2,4,6-trimethylphenyl) -1,2
-Ethanediamine (m) is obtained in good yield. The obtained racemic crude diamine is subjected to an acid treatment and a base treatment, and can be used as it is in the next optical resolution step.

[0023]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 187 g (0.63 mol) of a racemic trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine and (R)-
192 g (1.26 mol) of (-)-mandelic acid was placed in a flask, 7 L of 2-propanol was added thereto, and the mixture was dissolved by heating. Drying gave 121 g of the mandelic acid salt of the diamine. [α] _D ²⁸ + 37.5 ゜ (c 1.38,
(MeOH) The obtained salt was dissolved in dichloromethane, extracted with a sodium hydroxide aqueous solution (3 equivalents or more), and dried over sodium sulfate.The dichloromethane was distilled off under reduced pressure to obtain 59 g of the objective optically active diamine. Was collected. The yield based on (+)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine in the racemic diamine was 64%. [α] _D ²⁶ +
196.8 ゜ (c 0.83, CH ₂ Cl ₂ ), optical purity> 98% ee.

Example 2 4.7 g of the salt recovered and concentrated from the mother liquor of Example 1 was taken, and dichloromethane / NaOH (4 equivalents,
1.25 g), and the organic layer was separated, dried and concentrated to obtain 2.6 g of diamine as crystals. 2.58 g of this diamine and 2.64 of (S)-(+)-mandelic acid
g (2.0 equivalents) and a mixture of 100 ml of 2-propanol were dissolved while heating, and allowed to stand at room temperature overnight. The precipitated crystals were separated by filtration, washed (IPA 30 ml), and dried in vacuo to give purified salt 1.
25 g were obtained as white crystals. [α] _D ²⁷ − 38.9
゜ (c1.02, MeOH) Treated with sodium hydroxide as in Example 1, extracted and concentrated to give (-)-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethane The diamine was obtained as white crystals. (0.62 g, quantitative from mandelate)
[α] _D ²⁶ −196.0 ゜ (c 1.06, CH ₂ Cl ₂ ), optical purity>
98% ee.

Reference Example 1 N-trimethylsilyl-
Preparation of 2,4,6-trimethylbenzylideneimine Hexamethyldisilazane 43 was placed in a flask equipped with a Dim funnel, a dropping funnel, a stirrer, and a septa rubber.
ml (0.202 mol) under a nitrogen stream, THF 250m
Add l. Next, a solution of n-butyllithium in 126 ml (0.202 mol) of 1.6 M hexane was added under ice-cooling, and the mixture was stirred for a while. Then, 2,4,6-trimethylbenzaldehyde 2
A solution of 9 g (0.196 mol) in THF (100 ml) was added from a dropping funnel. After stirring for 30 minutes under ice cooling, 26 ml (0.202 mol) of trimethylsilane chloride was added, and stirring was continued for another 30 minutes. Next, salt is precipitated when the reaction solution is concentrated under reduced pressure, so that the salt is removed by filtration with a glass filter,
The salt was washed with dichloromethane, the filtrate was recovered, concentrated again, and distilled under reduced pressure to obtain N-trimethylsilyl-
2,4,6-trimethylbenzylideneimine 36.4
g was obtained (85% yield). Boiling point 126-129 ℃ / 10m
mHg.

Reference Example 2 Preparation of trans-1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine 50 g (0.132 mol) of a niobium tetrachloride THF complex was placed in a reaction vessel.
l) was taken and 600 ml of 1,2-dimethoxyethane was added at room temperature under a nitrogen stream. Next, 20.0 g (0.091 mol) of silylimine prepared in Reference Example 1 was added to dimethoxyethane (20%).
0 ml) solution was added and stirring continued for 8 hours. After being left overnight at room temperature, the solvent was distilled off with an evaporator to obtain a black oil. An aqueous sodium hydroxide solution (10% w / v, 600 ml) was added to the mixture under ice-cooling, and the mixture was stirred for 1 hour. A white solid was deposited. The filtrate was extracted with dichloromethane (3 × 500 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off using an evaporator to obtain 14 g of a concentrate. The concentrate is diluted with toluene, treated with 1N hydrochloric acid (pH １1), the aqueous phase is separated, the diamine liberated after being made basic with sodium hydroxide is extracted with toluene, and concentrated to give a crude product. 9.6 g of the product were obtained (crude yield 71%).

[0028]

According to the method of the present invention, (±) -1,2
-Bis (2,4,6-trimethylphenyl) -1,2-
By optically resolving ethanediamine using optically active mandelic acid, optically active 1,2-bis (2,4,6
-Trimethylphenyl) -1,2-ethanediamine can be produced. This optically active diamine is useful as a ligand of an asymmetric catalyst in an asymmetric synthesis reaction and as an optical resolution reagent.

Claims (3)

[Claims] 1. An optically active hydroxycarboxylic acid compound is added to (±) -1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine, and the mixture is heated and dissolved in a solvent. After, including the step of crystallization and optical resolution,
A method for producing optically active 1,2-bis (2,4,6-trimethylphenyl) -1,2-ethanediamine. 2. The optically active 1,2-bis (2,4,6-trimethylphenyl) according to claim 1, wherein the optically active hydroxycarboxylic acid compound is an optically active mandelic acid.
A method for producing 1,2-ethanediamine. 3. The optically active 1,2-bis (2,4,6) according to claim 1 or 2, wherein the solvent is an alcohol compound.
-Trimethylphenyl) -1,2-ethanediamine.