JP3178086B2 - Method for producing optically active α-methylbenzylamine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for preparing (R) -α-methylbenzylamine from (RS) -α-methylbenzylamine by a diastereomer method.
Alternatively, the present invention relates to an improvement in a method for producing (S) -α-methylbenzylamine. By the process of the present invention, poorly soluble diastereomeric salts are obtained in crystalline form that is easy to filter.

[0002]

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

One of the optical resolution techniques suitable for industrial implementation is the diastereomer method. This method
As is well known, a diastereomer of a desired enantiomer and a resolving agent is precipitated as a sparingly soluble salt by allowing an optically active resolving agent to act on a racemic form of a target substance, and the solid is separated and then decomposed. And obtaining an optically active substance.

[0004] The form of the hardly soluble salt obtained in this process is various. Of course, it is better for the crystal to be large, but if it is apparently large, it is thin scale-like or long and thin plate-like, and when it is applied to a centrifuge, the crystals are arranged in a direction perpendicular to the centrifugal force. As a result, the filterability of the mother liquor is deteriorated, and the washability is often impaired. As a result, the optical purity of the resulting product is reduced.
Therefore, obtaining crystals of a sparingly soluble diastereomer salt in an easily filterable form is important in producing an optically active compound.

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

[0006] Even in the industrial implementation of the technology, there are the problems described above. The sparingly soluble diastereomer salt crystals of α-methylbenzylamine mandelate are generally thin and long hexagonal plates, and have poor filterability.

[0007]

An object of the present invention is to provide a process for producing an optically active substance from racemic α-methylbenzylamine by a diastereomer method using optically active mandelic acid as a resolving agent. Another object of the present invention is to provide a method for improving the crystal form of a sparingly soluble diastereomer salt by making it easy to filter.

[0008]

The process for producing optically active α-methylbenzylamine according to the present invention is described above by using (RS)-
In the method for producing (R)-or (S) -α-methylbenzylamine from α-methylbenzylamine by a diastereomer method, (RS) -α-
Bis (α-methylbenzyl) amine represented by formula (I) with respect to methylbenzylamine

[0009]

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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 to form a poorly soluble compound represented by the formula (II) Active diastereomeric salts of

[0011]

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(In the formula, * represents an asymmetric carbon atom.)
Wherein at least one of the two configurations of bis (α-methylbenzyl) amine is the same as that of α-methylbenzylamine constituting the sparingly soluble diastereomer salt to be precipitated. By using the same one, a sparingly soluble diastereomer salt is precipitated as crystals that can be easily filtered.

In order to obtain (R) -α-methylbenzylamine in the above-mentioned production method, bis (α) represented by the formula (I) is used by using (R) -mandelic acid as an optical resolving agent. -Methylbenzyl) amine,
Those having a configuration of (R, R) or (R, S), preferably the former, are present as (R) -α-methylbenzylamine. (R) as a poorly soluble diastereomer salt represented by the formula (II). R) -Mandelate is formed.

On the other hand, when trying to obtain (S) -α-methylbenzylamine, (S) -α-methylbenzylamine is used as an optical resolving agent.
A bis (α-methylbenzyl) amine represented by the formula (I) having the configuration (S, S) or (R, S), preferably the former, using mandelic acid; (S) -α-methylbenzylamine as a poorly soluble diastereomer salt represented by (II)
(S) -Mandelate is formed. In short, as bis (α-methylbenzyl) amine, at least one, and preferably two, of the configurations of its two asymmetric centers are:
The same configuration as that of α-methylbenzylamine constituting the poorly soluble diastereomer salt to be precipitated is used.

The synthesis of bis (α-methylbenzyl) amine is described in MB Eleveld et al., J. Org. Chem., 51 (19), 3
635 (1986). However, this report is intended for the (S, S) form.

In the step of recrystallization of a sparingly soluble diasteromer salt, the above-mentioned bis (α-methylbenzyl) amine is added, and the operation is carried out under the condition that the above-mentioned organic salt or inorganic salt is present. As in the reaction step, the diastereomeric salt crystals are obtained as thick hexagonal plate crystals or rhombic crystals, and the advantage that solid-liquid separation is easy can be enjoyed here as well.

[0017]

It has been known for certain amino acids that the crystal habit of the crystal of the optically active substance is changed by a specific additive [Lahav et al., Nature, vol. 296, p. 2
1 (1982)]. However, regarding the optical resolution of α-methylbenzylamine, it was not even considered that the crystal habit of the sparingly soluble diastereomer 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 is changed to a thick hexagonal crystal or rhombic crystal with good filterability. This is the fact that the present inventors have found for the first time.

As described above, bis (α-methylbenzyl) amine is advantageously used in a configuration of (R, R) or (S, S) depending on the intended product, and is preferably a poorly soluble diamine. 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 irrespective of the target substance, but requires the presence of about 0.2% by weight based on the sparingly soluble diastereomer salt. In the case where bis (α-methylbenzyl) amine does not have the same constituent portion as the target product in steric configuration, the expected effect cannot be obtained even if 1% by weight is added.

Even when benzylamine, ethylamine, diethylamine, N-benzyl-α-methylbenzylamine or the like is added in place of bis (α-methylbenzyl) amine, a change in the crystal form of the sparingly soluble diastereomer salt is observed. Absent. From this fact and the above fact, it is suggested that bis (α-methylbenzyl) amine acts stereoselectively with respect to the manifestation of the effect of the present invention.

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 salt from the beginning.

One group of salts which may be present with bis (α-methylbenzyl) amine is, as noted above, salts of inorganic or organic acids of ammonia or primary amines, such as ammonium chloride, ammonium acetate, ethylamine sulfate, And 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 examples described later. The same effect can also be obtained by allowing a resolving agent, ie, an optically active mandelic acid, to act in the presence thereof and subtracting the amount thereof.

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

The salts of both groups have two
It goes without saying that more than one kind or two or more kinds between groups may be used in combination. The addition amount can be selected from a wide range, and is used in an amount of 1 to 500 mol%, preferably 5 to 300 mol%, based on the poorly soluble diastereomer salt to be formed.

The aqueous medium in which the reaction is carried out means water or a mixture of water and a small amount of an organic solvent such as methanol, ethanol or acetone. Water is optimal for the convenience of operation, and there is no particular advantage in using other solvents.

[0025]

[Example 1] (RS) -α-methylbenzylamine 10 in 21.8 g of water
g (82.5 mmol) was dissolved, and 6.91 g (45.4 mmol) of (R) -mandelic acid and 3.87 of 35% hydrochloric acid were added to the solution.
g (37.1 mmol). Further, (R, R)-
6.5 mg of bis (α-methylbenzyl) amine hydrochloride was added, and the mixture was dissolved by heating with stirring and cooled slowly to 5 ° C. after cooling. 7.65 g of diastereomer salt (R) -α-methylbenzyl. (R) -mandelic acid salt (28.0 mm
ol) precipitated. These crystals were thick hexagons and had good filterability.

The sparingly soluble diastereomer salt formed in the reaction solution should be 11.27 g (41.3 mmol) including the (R) -isomer corresponding to half the (RS) -isomer and the resolving agent. That is, 0.05% by weight of (R, R) -bis (α-methylbenzyl) amine was added to this salt. The coexisting salt is a hydrochloride (37.1 mmol) formed from the rest of the (RS) form and the added hydrochloric acid, and its amount is about 90 mol% with respect to the poorly soluble salt. It will be.

The yield of the sparingly soluble salt described above was used (R
It was 68% with respect to the (R) form in the S) form, and the optical purity was 98.6% ee. (Specific rotation +40.7 ゜ / 2
Example 2 Example 1 was repeated, except that the amount of (R, R) -bis (α-methylbenzyl) amine hydrochloride added was changed. Crystals of the same poorly soluble diastereomer salt were obtained.

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

Example 4 Bis (α-methylbenzyl)
A mixture of the same amount of the (R, R) form and the (S, S) form was used as the amine, and the other conditions were the same as in Example 1.
The obtained sparingly soluble diasteremer salt (R) -α-methylbenzylamine. (R) -mandelic acid salt was a crystal that was easily filtered.

Example 5 The amine to be added was (R, S)
Example 1 was changed to -bis (α-methylbenzyl) amine.
Was repeated. The result was not much different.

[Example 6] In Example 1, sodium chloride was further added as a coexisting salt in an amount of 120 mol% to the sparingly soluble diasteremer salt to be precipitated. Crystals with diamond shape and very good filterability were obtained.

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

The obtained crystals were thick hexagons and had good filterability. The recrystallized purified product has a yield of 76% and an optical purity of 1.
It was 00% 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 examples are summarized in a table.

Comparative Examples 1 to 5 In the following manner, optical resolution of (RS) -α-methylbenzylamine with (R) -mandelic acid was performed. The poorly soluble diastereomer salt to be precipitated is (R) -α-methylbenzylamine. (R) -mandelic acid salt: 1) Bis (α-methylbenzyl) amine was not added. 2) No coexisting salt was present. 3) (S, S) -Bis (α-methylbenzyl) amine hydrochloride was used as an additive. 4) (R) -N-benzyl-α-methylbenzylamine hydrochloride was used as an additive. 5) Diethylamine hydrochloride was used as an additive.

In each case, crystals of the hardly soluble salt having good filterability could not be obtained. 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 B6 (R, R) -BαMBA 0.05 Sodium chloride 120 C + αMBA 907 (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 B10 (R, R) -BαMBA 0.05 Ethylamine 10 B 11 (R, R) -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 - - was added as 2.18 αMBA 90 A α- methylbenzylamine 5 diethylamine 0.20 αMBA 90 A * 1 hydrochloride - A 3 (S, S) -BαMBA 1.00 αMBA 90 A 4 (R) -N- benzyl. * 2 The amine was present as the hydrochloride. BαMBA: Bis (α-methylbenzyl) amine Crystal Form A: Long and Thin Hexagonal Plate B: Hexagonal C: Rhombic

[0038]

When the optically active α-methylbenzylamine is produced by the method of the present invention, the sparingly soluble diastereomer salt formed in the process, ie, (R) -α-methylbenzylamine. (R) -mandel Acid salt and (S) -α
-Methylbenzyl. (S) -mandelic acid salt is obtained not as a long and thin hexagonal platelet usually seen but as a hexagonal crystal and, depending on reaction conditions, as a rhomboid. Since these crystals have good filterability, the mother liquor is "clear" in solid-liquid separation using a centrifugal separator, and the cake can be effectively washed, so that unnecessary enantiomers are eliminated. It is possible to obtain a diastereomer salt containing almost no diastereomer. This benefit is also obtained in the recrystallization purification of poorly soluble diastereomeric salts from aqueous media.

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

──────────────────────────────────────────────────続 き Continuation of front page (72) Inventor Hiroyuki Nohira 51-5, Ryoke Okubo, Urawa-shi, Saitama (56) References JP-A-5-320102 (JP, A) JP 2-4581 (JP, B2) JP-B-47-18737 (JP, B1) "Bull. Chem. Soc. Jpn.", Vol. 65, no. 7, pages 1747-1750 (1992) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 211/27 C07C 59/50 C07C 209/88 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A method for preparing (R)-or (S) -α from (RS) -α-methylbenzylamine by a diastereomer method.
In the method for producing -methylbenzylamine, bis (α-methylbenzyl) amine represented by the formula (I) is used in an aqueous medium with respect to (RS) -α-methylbenzylamine. And the action of an optically active mandelic acid 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 to give a poorly soluble optical activity represented by the formula (II) Diastereomer salt Wherein * represents an asymmetric carbon atom. At least one of the two steric configurations of bis (α-methylbenzyl) amine is a poorly soluble diamine to be precipitated. Α that constitutes a stereomeric salt
-A method for producing optically active α-methylbenzylamine, comprising using a compound having the same configuration as methylbenzylamine to precipitate a sparingly soluble diastereomer salt as a crystal which can be easily filtered. 2. The method according to claim 1, wherein (R) -mandelic acid is used as an optical resolving agent, and the bis (α-methylbenzyl) amine represented by the formula (I) has a configuration of (R, R) or (R, R).
The method according to claim 1, wherein (R) -α-methylbenzylamine. (R) -mandelic acid salt is formed as a poorly soluble diastereomer salt represented by the formula (II) in the presence of S). 3. A method using (S) -mandelic acid as an optical resolving agent and a bis (α-methylbenzyl) amine represented by the formula (I) having a configuration of (S, S) or (R,
The method according to claim 1, wherein (S) is present to form (S) -α-methylbenzylamine. (S) -mandelic acid salt as a poorly soluble diastereomer salt represented by the formula (II). 4. The poorly soluble optically active diastereomer salt represented by the formula (II) according to claim 1 is replaced by a bis (α-methylbenzyl) amine represented by the formula (I) according to claim 1. And recrystallization from an aqueous medium containing a salt of an inorganic acid or an organic acid of ammonia or a primary amine and / or a water-soluble inorganic salt, thereby precipitating an optically active diastereomer salt as a crystal which can be easily filtered. Production method of optically active α-methylbenzylamine.