JPH0827073A - Racemization of optically active alpha-aryl alkylamine - Google Patents

Abstract

PURPOSE:To easily carry out with a safe and inexpensive reagent a racemization of the subject compound useful as an optical resolution agent, by bringing a specific Schiff base into contact with a base followed by hydrolyzing the Schiff base. CONSTITUTION:(A) An optically active Schiff base formed from (1) an optically active alpha-aryl alkylamine of the formula (Ar is an aryl; R is an alkyl; the carbon atom on * site is an asymmetric carbon atom) and (2) an arylaldehyde is brought into contact with (B) a base (pref. a metal alkoxide, metal hydroxide or organic amine) to effect racemization followed by hydrolyzing the component (A) to effect racemization, thus obtaining the objective compound.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION Optically active α-arylalkylamines are important substances as optical resolving agents for obtaining optically active compounds from racemic carboxylic acids. In particular, among α-arylalkylamines represented by the following chemical formula 2, amines in which the aryl group is a phenyl group and the alkyl group is a methyl or ethyl group are often used as optical resolving agents. Furthermore,
The S-form amine in which the aryl group is a phenyl group or a methyl-substituted phenyl group is an important substance as a raw material for the strong sweetening substance disclosed in US Pat. No. 5,286,509.

[0002]

Embedded image (In the formula, Ar represents an aryl group, R represents an alkyl group, and the carbon at the * position represents an asymmetric carbon.)

In order to obtain an optically active substance synthetically, a method of synthesizing a racemate to be asymmetrically synthesized and optically resolving it is used.
There are two ways. When an optically active substance required by optical resolution is obtained from the racemate of, it is generally industrially adopted because it is economical to racemate the unnecessary optical isomer and use it again as a raw material. Often. Also, in the case of asymmetric synthesis, the asymmetric yield is infinite.
In order to obtain an optically active substance at a lower cost except for the case where it is close to 0% ee, a method of separating an unnecessary optical active substance and then racemizing an unnecessary optical isomer to perform optical resolution. Will also be needed.

[0004]

2. Description of the Related Art A racemization method for optically active α-arylalkylamines is already known. JP-A-4-2
According to the method described in 75258 and the method of the reference, they use materials having extremely high reactivity, such as metal alkoxides, alkali metal amides and alkali metal hydrides. However, even if we take up only the fact that they are water-prohibited substances as a property common to these substances, it is never an industrial one if we take thorough measures to prevent water from entering the system and the dangers when water is mixed. I can't say that.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to find an industrial method which can racemate an optically active α-arylalkylamine easily and safely and operably without the above-mentioned drawbacks of known racemization methods. is there.

[0006]

As a result of earnest studies for solving such problems, surprisingly, a Schiff derived from an optically active α-arylalkylamine and an arylaldehyde represented by the following Chemical formula 3 Base with potassium te
Not only metal alkoxides such as rt butoxide,
The present invention has been completed by finding that it can be easily racemized by mixing with a base having a milder property such as potassium hydroxide and organic amine.

[0007]

Embedded image (In the formula, Ar represents an aryl group, R represents an alkyl group, and the carbon at the * position represents an asymmetric carbon.)

That is, according to the method of the present invention, α of the optically active substance is
Mixing an optically active Schiff base produced by contacting an arylalkylamine with an aryl aldehyde with an inexpensive and easy to handle base such as potassium hydroxide will racemize the amine in the form of the Schiff base.
By hydrolyzing this racemized Schiff base, the raw material arylaldehyde and the target substance, racemized α
-It can be decomposed into an arylalkylamine.
Since the produced aryl aldehyde can be used again for the production of the Schiff base, it can be said that it is an industrially extremely advantageous method for racemizing an optically active α-arylalkylamine.

As the optically active α-arylalkylamine applicable to the present invention, it is essential that the α-carbon of the amino group has hydrogen as shown in the following chemical formula 4. On the other hand, although the types of the aryl group and the alkyl group are not limited, in general, in consideration of the use of the optically active amine, that is, it is often used as an optical resolving agent, the aryl group includes a phenyl group and a substituent It can be applied to a phenyl group, a naphthyl group, or a naphthyl group having a substituent. Examples of the alkyl group include methyl group, ethyl group, n-propyl group, i-propyl group and the like.

[0010]

[Chemical 4] (In the formula, Ar represents an aryl group, R represents an alkyl group, and the carbon at the * position represents an asymmetric carbon.)

The aryl group of the aryl aldehyde used is an unsubstituted phenyl group or a phenyl group having 1 to 5 substituents selected from halogen, alkyl groups, alkoxy groups, nitro groups, hydroxyl groups or ester groups. And can be widely used, such as naphthyl group,
Industrially, it is recommended to use an aldehyde having a chloro group, a methyl group, a methoxy group, a nitro group, or a phenyl group having one hydroxyl group, or an unsubstituted phenyl group aldehyde, because it is economical.

In order to produce a Schiff base, these aryl aldehydes are used in an amount of 0.2 to 10 times mol, preferably 0.8 to 1. mol, based on the optically active α-arylalkylamine.
Use 2 times mole. In some cases, the reaction proceeds only by mixing the two, but by removing the water generated by the progress of the reaction by an appropriate method, the reaction becomes easier to complete.

As the base used for racemizing the obtained Schiff base, hydroxides such as sodium hydroxide and potassium hydroxide, alkoxides such as sodium methoxide and potassium tert-butoxide, 1,
An organic amine such as 8-diazabicyclo [5.4.0] -7-undecene (commonly called DBU) is used.
When the solubility of the base used is extremely low in the reaction solution, it is also effective to increase the solubility by adding a phase transfer catalyst such as a quaternary ammonium salt.

The amount of these bases used is effective for racemization even with a very small amount of the catalyst with respect to the Schiff base, but in order to accelerate the racemization reaction rate, it is 0.01 times mol or more, preferably 0. It is necessary to use 1 times or more moles. Of course, even if it is used more than the Schiff base, there is no problem with racemization.

In the racemization, these Schiff bases and a base which is a racemizing agent are carried out in a suitable solvent. Examples of such a solvent include alcohols such as methanol, ethanol and butanol, aromatics such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, halogens such as dichloromethane and 1,2-dichloroethane. Alkyl halides, dimethylformamide, dimethyl sulfoxide, trialkyl phosphate and the like are used. Also,
It is possible to proceed with racemization even in a state where substantially no solvent is used.

The racemization reaction proceeds even at room temperature, but in order to shorten the reaction time, it is better to heat it to 50 ° C. or higher.

After the Schiff base is racemized, water can be added to the reaction solution to easily decompose the starting aryl aldehyde and racemic amine. At this time, an organic solvent immiscible with water is used as a solvent for the racemization reaction,
When hydrochloric acid is used as the water that decomposes the Schiff base, the amine is extracted as the hydrochloride in the aqueous layer, and the hydrophobic aryl aldehyde remains in the organic layer, so that both can be easily separated. The aryl aldehyde thus obtained is again mixed with an optically active amine to form a Schiff base, which can be used for racemization.

[0018]

The present invention will be described in more detail with reference to the following examples. The analysis for obtaining the racemization rate of α-arylalkylamine was carried out using an optically active HPLC column (Crown Pack CR (+)). Further, the racemization rate is ((R × 2) when the S-form amine is used as a raw material.
/ (S + R)) × 100%.

[0019]

Example 1 (S) -α-phenylpropylamine 1.
35 g (10 mmol) and 1.26 g (9 mmol) of p-chlorobenzaldehyde were dissolved in 25 ml of methylene chloride, 3 g of anhydrous magnesium sulfate was added, and the mixture was stirred overnight at room temperature, and magnesium sulfate was removed by suction filtration. The filtrate was concentrated under reduced pressure, and hexane was added for crystallization. Crystals of (S) -N- (p-chlorobenzylidene) -α-phenylpropylamine by suction filtration 2.28
g (8.85 mmol) was obtained. This crystal 0.242
g (0.939 mmol) of tert-butanol 15
0.24 g of potassium tert-butoxide dissolved in ml
(2.14 mmol) was added and the mixture was heated under reflux for 5 hours.
2 ml of this reaction solution was collected, 20 ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes to decompose the Schiff base into an aldehyde and an amine. The produced p-chlorobenzaldehyde was extracted and removed with methylene chloride, and then the aqueous layer was subjected to HPLC.
Was analyzed. Racemization rate 90.5%.

[0020]

Comparative Example 1 (S) -α-phenylpropylamine 0.
085 g (0.63 mmol) was dissolved in 10 ml of tert-butanol and potassium tert-butoxide 0.1 was added.
6 g (1.43 mmol) was added and the mixture was refluxed for 5 hours.
The subsequent treatment was the same as in Example 1. As a result of the analysis,
Only a trace amount of R form was detected.

[0021]

Example 2 The same as Example 1 except that 0.21 g (0.94 mmol) of (S) -N-benzylidene-α-phenylpropylamine was used. Racemization rate 7
6.6%.

[0022]

Example 3 The same process as in Example 1 was carried out except that 0.12 g (2.13 mmol) of potassium hydroxide was used instead of potassium tert-butoxide. As a result of analysis, the racemization rate was 89.3%.

[0023]

Example 4 The same procedure as in Example 1 was carried out except that 0.12 g of potassium hydroxide was used instead of potassium tert-butoxide, and 1-butanol was used instead of tert-butanol. As a result of analysis, racemization rate is 74.4%
Met.

[0024]

Example 5 Example 1 was repeated except that 0.38 g of 1,8-diazabicyclo [5,4,0] -7-undecene (common name: DBU) was used instead of potassium tert-butoxide, and toluene was used instead of tert-butanol. The same process was carried out. As a result of analysis, the racemization rate was 7.4%.

[0025]

Example 6 0.24 g (0.9) of (S) -N- (p-methoxybenzylidene) -α-phenylpropylamine
The same procedure as in Example 1 was performed except that 4 mmol) was used. As a result of analysis, the racemization rate was 73.8%.

[0026]

Example 7 (S) -N- (p-chlorobenzylidene)
-Α-Phenylethylamine 0.23g (0.94m
(mol) was used, and the same procedure as in Example 1 was performed. As a result of analysis, the racemization rate was 90.1%.

[0027]

Example 8 (S) -N- (p-nitrobenzylidene)
-Α-phenylpropylamine 0.25g (0.94
Example 1 was repeated except that (mmol) was used. As a result of analysis, the racemization rate was 21.4%.

[0028]

Example 9 Potassium tert-butoxide 0.09
The same procedure as in Example 1 was performed except that 7 g (0.37 mmol) was used. As a result of analysis, the racemization rate was 72.9%.

[0029]

Example 10 2.44 g (1) of crystals of (S) -N- (p-chlorobenzylidene) -α-phenylethylamine
0 mmol) with potassium tert-butoxide 0.2
2 g (2 mmol) was added and it heated at 85 degreeC for 1 hour. The crystals were dissolved by heating. After that, the same treatment as in Example 1 was performed. As a result of analysis, the racemization rate was 93.2%.

[0030]

Example 11 (R) -α-phenylpropylamine
67.6 g (0.5 mol, optical purity as R form 3
5% ee) and p-chlorobenzaldehyde 70.3 g
(0.5 mol) was dissolved in 200 ml of 1-butanol and heated for 4 hours while removing water generated by the reaction using a Dean-Stark apparatus. After adding 5.6 g (0.1 mol) of potassium hydroxide to the obtained reaction solution and heating and refluxing for 5 hours, the solvent was distilled off under reduced pressure, and 4N-HC was added to the residue.
l 200 ml was added to decompose the Schiff base. When 200 ml of toluene was added and p-chlorobenzaldehyde was extracted and removed, the aqueous layer was analyzed by HPLC. As a result, 67.4 g (0.50 mo) of α-phenylpropylamine was detected.
1, optical purity of R-form: 1.5% ee). The aqueous layer was adjusted to pH 11 with 48% NaOH and extracted twice with 200 ml of toluene. The toluene layers were collected and concentrated under reduced pressure to obtain 66.9 g of racemic oily α-phenylpropylamine. Recovery rate 99.0
%.

[0031]

According to the method of the present invention, the optically active α-arylalkylamine can be easily racemized using a safe and inexpensive reagent.

Claims (3)

[Claims] 1. An optically active Schiff base formed from an optically active α-arylalkylamine represented by Chemical formula 1 and an aryl aldehyde is brought into contact with a base for racemization, and then the Schiff base is hydrolyzed. A method for racemizing an optically active α-arylalkylamine characterized by obtaining a racemized α-arylalkylamine (In the formula, Ar represents an aryl group, R represents an alkyl group, and the carbon at the * position represents an asymmetric carbon.) 2. The method according to claim 1, wherein the base to be contacted with the Schiff base is a metal alkoxide, a metal hydroxide or an organic amine. 3. The aryl group of the arylaldehyde is an unsubstituted phenyl group or a phenyl group having 1 to 5 substituents selected from halogen, an alkyl group, an alkoxy group, a nitro group, a hydroxyl group or an ester group. The method according to claim 1.