JPH061757A - Production of optically active alpha-methylbenzylamine - Google Patents

Abstract

PURPOSE:To obtain a compound by using optically active mandelic acid as a resolving agent and adding bis(alpha-methylbenzyl)amine and salts to a reactional system and resolving (RS)-alpha-methylbenzylamine. CONSTITUTION:(RS)-alpha-Methylbenzylamine is made to react with optically active mandelic acid in the presence of a bis(alpha-methylbenzyl)amine of formula I (* indicates asymmetric carbon) and a salt of ammonia or a primary amine with an inorganic acid or an organic acid (e.g. ammonium chloride) and/or water-soluble inorganic salts (e.g. potassium nitrate) in an aqueous medium to afford the objective sparingly soluble optically active diastereomer salt of formula II. Since a crystal of the deposited sparingly soluble diastereomer salt is obtained as a thick hexagonal platy crystal or a rhombic crystal good in filtrability, the product of high optical purity can readily be produced.

Description

Detailed Description of the Invention

[0001]

The present invention relates to (R)-by the diastereomer method from (RS) -α-methylbenzylamine.
Alternatively, it relates to an improvement in the method for producing (S) -α-methylbenzylamine. The process according to the invention gives sparingly soluble diastereomeric salts in crystalline form which are easy to filter.

[0002]

2. Description of the Related Art The demand for optically active compounds is increasing year by year,
Its fields of application are not limited to pharmaceuticals and agricultural chemicals, but also to ferroelectric liquid crystal materials. At the same time, the demand for optical purity is becoming stricter, and especially in the fields of medicine and agricultural chemicals, unnecessary enantiomers tend to be regarded as impurities and eliminated as much as possible. Therefore, it is desired to develop a technique for industrially producing a desired enantiomer with high optical purity.

The diastereomer method is one of the optical resolution techniques suitable for industrial implementation. This method
As is well known, an optically active resolving agent is allowed to act on a racemic compound of interest to precipitate a diastereomer of a desired enantiomer and a resolving agent as a sparingly soluble salt, followed by solid-liquid separation and decomposition. And obtaining an optically active substance.

There are various forms of poorly soluble salts obtained in this process. Of course, it is better for the crystals to be large, but if they are apparently large and have a thin scaly shape or a long thin plate shape, the crystals will be aligned in a direction perpendicular to the centrifugal force when applied to a centrifuge. As a result of the overlap, the filterability of the mother liquor is often deteriorated, and the washability is often impaired. As a result, the optical purity of the obtained product becomes low.
Therefore, obtaining crystals of a poorly soluble diastereomeric salt in an easily filterable form is important in the production of optically active compounds.

One of the inventors has established a technique for producing an optically active substance from racemic α-phenylethylamine, that is, α-methylbenzylamine, by a diastereomer method using optically active mandelic acid as a resolving agent. , Already proposed (Japanese Patent Publication No. 2-4581).

Even in the industrial implementation of the technique, there are the above-mentioned problems. The sparingly soluble diastereomeric salt crystals of α-methylbenzylamine mandelate are generally thin and long hexagonal plates and have poor filterability.

[0007]

The object of the present invention is to provide a method for producing an optically active substance from a racemic α-methylbenzylamine by a diastereomeric method using an optically active mandelic acid as a resolving agent. It is an object of the present invention to provide a method for carrying out the method, in which the crystalline form of the poorly soluble diastereomeric salt is easily filtered, which is improved.

[0008]

The method for producing an optically active α-methylbenzylamine of the present invention comprises the above-mentioned (RS)-
In the method for producing (R)-or (S) -α-methylbenzylamine from α-methylbenzylamine by the diastereomer method, (RS) -α-
Bis (α-methylbenzyl) amine represented by the formula (I) with respect to methylbenzylamine

[0009]

[Chemical 3]

In addition, an optically active mandelic acid is allowed to act as a resolving agent in the presence of a salt of an inorganic acid or an organic acid of ammonia or a primary amine and / or a water-soluble inorganic salt, and is hardly soluble as represented by the formula (II). Optically active diastereomeric salts of

[0011]

[Chemical 4]

(In the formula, * represents an asymmetric carbon atom.)
Is precipitated as crystals that can be easily filtered.

In order to obtain (R) -α-methylbenzylamine in the above production method, (R) -mandelic acid is used as an optical resolving agent, and bis (α) represented by the formula (I) is used. -Methylbenzyl) amine,
Those having a configuration of (R, R) or (R, S), preferably in the presence of the former, as a sparingly soluble diastereomeric salt represented by the formula (II), (R) -α-methylbenzylamine. ( R) -mandelate salt is formed.

On the other hand, when an attempt is made to obtain (S) -α-methylbenzylamine, (S) -as an optical resolving agent.
Using mandelic acid, bis (α) represented by the formula (I)
-Methylbenzyl) amine has the configuration (S,
S) or (R, S), preferably in the presence of the former, as the sparingly soluble diastereomeric salt represented by formula (II), (S) -α-methylbenzylamine. (S)
Form a mandelate salt. In short, bis (α-
As the methylbenzyl) amine, one having at least one of the configurations, preferably two, which is the same as the configuration of α-methylbenzylamine constituting the sparingly soluble diastereomeric salt to be precipitated is used.

A method for synthesizing bis (α-methylbenzyl) amine is described by MB Eleveld et al., J. Org. Chem., 51 (19), 3
635 (1986). However, this report is intended for the (S, S) form.

Also in the recrystallization step of the poorly soluble diasteromeric salt, optical resolution can be achieved by adding bis (α-methylbenzyl) amine as described above and operating under the condition that the above organic salt or inorganic salt is present. Similar to the reaction step, crystals of the diastereomeric salt are obtained as thick hexagonal plate crystals or rhomboid crystals, and the advantage of easy solid-liquid separation can be enjoyed here as well.

[0017]

The fact that the crystal habit of crystals of an optically active substance is changed by a specific additive has been known for certain amino acids [Lahav et al., Nature, 296, p. Two
1 (1982)]. However, regarding the optical resolution of α-methylbenzylamine, it was not considered that the crystal habit of the sparingly soluble diastereomeric salt could be changed by an additive. Therefore, when the diastereomer method is carried out in the presence of the bis (α-methylbenzyl) amine represented by the formula (I) and a specific salt, the crystal form becomes a thick hexagonal crystal or rhombic crystal with good filterability. That is the fact that the present inventors have found for the first time.

As described above, the bis (α-methylbenzyl) amine is advantageous in that the steric configuration is (R, R) or (S, S) depending on the intended product. It is effective if the weight is 0.005% or more based on the stereomeric salt. What is represented by (R, S) or (S, R) can be used regardless of the intended product, but it needs to be present in an amount of about 0.2 mol% based on the sparingly soluble diastereomeric salt. When bis (α-methylbenzyl) amine does not have the same constitutional portion with respect to the target compound in terms of configuration, the expected effect cannot be obtained even if 1% by weight is added.

Even if benzylamine, ethylamine, diethylamine, N-benzyl-α-methylbenzylamine or the like is added instead of bis (α-methylbenzyl) amine, a change in crystal form of the hardly soluble diastereomer salt is recognized. Absent. From this fact and the above fact, it can be seen that bis (α-methylbenzyl) amine acts in a stereoselective manner with respect to the manifestation of the effect of the present invention.

Since the secondary amine bis (α-methylbenzyl) amine has a low solubility in an aqueous medium,
It may be added to the reaction system together with (RS) -α-methylbenzylamine and neutralized with hydrochloric acid, sulfuric acid or acetic acid to increase the solubility, or added in the form of a mineral acid salt from the beginning.

One group of salts present with bis (α-methylbenzyl) amine is, as mentioned above, salts of inorganic or organic acids of ammonia or primary amines such as ammonium chloride, ammonium acetate, ethylamine sulphate, Examples include benzylamine nitrate. Since α-methylbenzylamine hydrochloride is also effective, a part of (RS) -α-methylbenzylamine to be subjected to optical resolution is neutralized with hydrochloric acid to form a reaction system as shown in the example described later. The same effect can be obtained also by allowing the amount of the resolving agent, ie, the optically active mandelic acid, to exist and subtract the amount of the resolving agent.

Another group is salts of strong electrolytes having high solubility in water, such as sodium chloride, potassium nitrate, magnesium chloride and calcium chloride.

Both groups of salt are
Of course, two or more species or two or more species between groups may be used in combination. The addition amount can be selected from a wide range, and it is used in an amount of 1 to 500 mol%, preferably 5 to 300 mol% based on the hardly soluble diastereomer salt to be produced.

The aqueous medium in which the reaction is carried out means water or water as a main component to which a small amount of an organic solvent such as methanol, ethanol or acetone is added. Water is most suitable for the convenience of operation, and the merit of using another solvent is not found.

[0025]

【Example】

[Example 1] 10 g (82.5 mmol) of (RS) -α-methylbenzylamine was dissolved in 21.8 g of water, and 6.91 g (45.4 mmol) of (R) -mandelic acid and 35
% Hydrochloric acid 3.87 g (37.1 mmol) was added. Further, (R, R) -bis (α-methylbenzyl) amine hydrochloride (5.6 mg) was added, and the mixture was heated with stirring to dissolve it, followed by gradual cooling and then cooling to 5 ° C. Diastereomeric salt (R)
-Α-Methylbenzyl. (R) -mandelate 7.65
g (28.0 mmol) was deposited. The crystals were thick hexagons and had good filterability.

Since the sparingly soluble diastereomeric salt formed in the reaction solution should be 11.27 g (41.3 mmol) including the (R) component corresponding to half of the (RS) component and the resolving agent. , (R, R) -bis (α-methylbenzyl) amine was added in an amount of 0.05% by weight based on this salt. Also, the coexisting salt was the hydrochloride salt (37.1 mmol) formed by the rest of the (RS) form and the added hydrochloric acid, so the amount was about 90 mol% relative to the sparingly soluble salt. It will be.

The yields of the above-mentioned sparingly soluble salts were used (R
It was 68% based on the (R) form in the (S) form, and the optical purity was 98.6% ee. (Specific rotation + 40.7 ° / 2
0 ° C.) Example 2 Example 1 was repeated, varying the amount of (R, R) -bis (α-methylbenzyl) amine hydrochloride added. Crystals of a similar sparingly soluble diastereomeric salt were obtained.

Example 3 As the amine to be added (S,
The same procedure as in Example 1 was carried out using (S) -bis (α-methylbenzyl) amine (hydrochloride) as an optical resolving agent and (S) -mandelic acid. The sparingly soluble diastereomer salt (S) -α-methylbenzylamine. (S) -mandelate salt was precipitated. As with Example 1, thick hexagonal crystals that were easy to filter were obtained.

Example 4 Bis (α-methylbenzyl)
As the amine, an equal mixture of (R, R) and (S, S) isomers was used, and other conditions were the same as in Example 1.
The hardly soluble diasteremer salt (R) -α-methylbenzylamine. (R) -mandelate obtained was a crystal that was easily filtered.

[Example 5] The added amine was (R, S).
-Bis (α-methylbenzyl) amine, Example 1
Was repeated. The result was not so different.

[Example 6] In Example 1, a form was carried out in which sodium chloride was further added as a coexisting salt in an amount of 120 mol% to the sparingly soluble diastereomer salt to be precipitated. Rhombic crystals with very good filterability were obtained.

Example 7 The sparingly soluble diastereomeric salt (R) -α-methylbenzylamine obtained in Example 1
10.4 g (38.5 mmol) of (R) -mandelate salt,
It was dissolved in 89.4 g of water with heating together with 0.23 g (3.9 mmol) of sodium chloride. In addition, (R,
R) -bis (α-methylbenzyl) amine hydrochloride was added to 5.
2 mg (0.02 mmol) was added. The liquid was heated with stirring, and once dissolved, it was cooled to precipitate a sparingly soluble diastereomeric salt.

The obtained crystals were thick hexagons and had good filterability. The recrystallized product has a yield of 76% and an optical purity of 9
It was 8.6% ee.

[Examples 8 to 12] Example 7 was repeated in the same manner except that the coexisting salt was changed to various salts other than α-methylbenzylamine hydrochloride. The operating conditions and the morphology of the crystals obtained in each of the above-mentioned examples are summarized in the table.

[Comparative Examples 1 to 5] (RS)
Optical resolution of -α-methylbenzylamine with (R) -mandelic acid was carried out: 1) no bis (α-methylbenzyl) amine was added. 2) No coexisting salt. 3) Use (S, S) -bis (α-methylbenzyl) amine hydrochloride as an additive. 4) Similarly, (R) -N-benzyl-α-methylbenzylamine hydrochloride is used as an additive. And 5) also using diethylamine hydrochloride.

In all cases, it was not possible to obtain crystals of a sparingly soluble salt having good filterability. The conditions are shown in the table.

Table No. Additive Concentration Coexisting salt Concentration Crystal * 1 wt% * 2 mol% Embodiment Example 1 (R, R) -BαMBA 0.05 αMBA 90 B 2 (R, R) -BαMBA 0.007 αMBA 90 B 3 (S, S) -BαMBA 0.05 αMBA 90 B 4 (R, R) + (S, S) 0.05 αMBA 90 B -BαMBA 5 (R, S) -BαMBA 0.29 αMBA 90 B 6 (R, R) -BαMBA 0.05 Sodium chloride 120 C + αMBA 90 7 (R, R) -BαMBA 0.05 αMBA 10 B 8 (R, R) -BαMBA 0.05 Sodium chloride 10 B 9 (R, R) -BαMBA 0.05 Benzylamine 10 B 10 (R, R) -BαMBA 0.05 Ethylamine 10 B 11 (R, S) -BαMBA 0.05 Ammonium chloride 10 B 12 (R, R) -BαMBA 0.05 Ammonium acetate 10 B Comparative Example 1-αMBA 90 A 2 (R, R)- αMBA 0.05 - - A 3 (S, S) -BαMBA 1.00 αMBA 90 A 4 (R) -N- benzyl - 2.18 αMBA 90
A α-methylbenzylamine 5 diethylamine 0.20 αMBA 90 A * 1 Added as the hydrochloride salt. * 2 The amine was present as the hydrochloride salt. BαMBA: Bis (α-methylbenzyl) amine Crystal form A: Long and thin hexagonal plate crystal B: Hexagonal crystal C:
Rhombus

[0038]

INDUSTRIAL APPLICABILITY When the optically active α-methylbenzylamine is produced by the method of the present invention, a sparingly soluble diastereomeric salt formed in the process, that is, (R) -α-methylbenzylamine. (R) -mandel Acid salt and (S) -α
The -methylbenzyl. (S) -mandelate salt is obtained as a hexagonal crystal and, depending on the reaction conditions, a rhomboidal crystal, instead of the usual long and thin hexagonal plate crystal. These crystals have good filterability, the mother liquor “breaks” well during solid-liquid separation using a centrifuge, and the cake can be effectively washed. It is possible to obtain a diastereomeric salt that is almost free. This benefit is also obtained in recrystallisation purification of sparingly soluble diastereomeric salts from aqueous media.

Therefore, according to the present invention, in response to the demand for optically active α-methylbenzylamine having high optical purity,
It is possible to respond without increasing the cost.

[Procedure amendment]

[Submission date] September 4, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction content]

As described above, the bis (α-methylbenzyl) amine is advantageous in that the steric configuration is (R, R) or (S, S) depending on the intended product. It is effective if the weight is 0.005% or more based on the stereomeric salt. The compound represented by (R, S) or (S, R) can be used regardless of the intended product, but it needs to be present in an amount of about 0.2% by weight based on the sparingly soluble diastereomeric salt. When bis (α-methylbenzyl) amine does not have the same constitutional portion with respect to the target compound in terms of configuration, the expected effect cannot be obtained even if 1% by weight is added.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0033

[Correction method] Change

[Correction content]

The obtained crystals were thick hexagons and had good filterability. The recrystallized product has a yield of 76% and an optical purity of 1.
It was 00% ee.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroyuki Nohira 51-5 Ryoke Okubo, Urawa City, Saitama Prefecture

Claims (4)

[Claims] 1. An (R)-or (S) -α from (RS) -α-methylbenzylamine by a diastereomeric method.
In the method for producing methylbenzylamine, bis (α-methylbenzyl) amine represented by the formula (I) is used for (RS) -α-methylbenzylamine in an aqueous medium. In addition, an optically active mandelic acid is allowed to act as a resolving agent in the presence of a salt of an inorganic acid or an organic acid of ammonia or a primary amine and / or a water-soluble inorganic salt, and the sparingly soluble optical activity represented by the formula (II) is obtained. Diastereomeric salt (In the formula, * represents an asymmetric carbon atom.) The method for producing an optically active α-methylbenzylamine, which comprises depositing crystals as crystals that are easy to filter. 2. An (R) -mandelic acid is used as an optical resolving agent, and a bis (α-methylbenzyl) amine represented by the formula (I) has a configuration of (R, R) or (R, R).
S) is present to form (R) -α-methylbenzylamine. (R) -mandelate as the sparingly soluble diastereomeric salt of formula (II). 3. A (S) -mandelic acid is used as an optical resolving agent, and a bis (α-methylbenzyl) amine represented by the formula (I) has a configuration of (S, S) or (R,
S) is present to form (S) -α-methylbenzylamine. (S) -mandelate as the sparingly soluble diastereomeric salt of formula (II). 4. A sparingly soluble optically active diastereomer salt represented by the above formula (II) is converted into a bis (α-methylbenzyl) amine represented by the above formula (I) and an inorganic substance of ammonia or a primary amine. An optically active α-methylbenzylamine characterized by being recrystallized from an aqueous medium in which a salt of an acid or an organic acid and / or a water-soluble inorganic salt is present to precipitate an optically active diastereomer salt as a crystal which is easily filtered. Manufacturing method.