JPS5830301B2 - N-benzoyl-tracis-2-aminocyclohexanecarboxylic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the optical resolution of racemates, and more specifically, the present invention relates to optical resolution of racemates, and more specifically, optically inactive dA-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid is resolved to obtain optical resolution. dl-
The object of the present invention is to easily and completely optically resolve the 4-isomer and 1-isomer from N-benzoyl-trans-2-aminocyclohexanecarboxylic acid in a high yield.

dl-N-benzoyl-trans-2- according to the invention
dll-, a raw material for aminocyclohexanecarboxylic acid
) Lance-2-aminocyclohexanecarboxylic acid is β
- It is an amino acid and the amino group and carboxyl group bond to the cyclohexane ring in the equatorial plane (equa-tori
al ), so once optically resolved, this substance is extremely stable and difficult to racemize by acid, alkali, or heating.

Therefore, if this compound can be easily and inexpensively optically resolved, it can be used as an optically stable bifunctional monomer.
It is also a useful compound that can be used as a new synthetic optical resolving agent to replace so-called natural optical resolving agents such as quinine, purusin, or tartaric acid.
To obtain this compound, dl-trans-2-aminocyclohexanecarboxylic acid was converted into N-benzoyl form, and dl
A method for optically resolving -N-benzoyl-2-aminocyclohexanecarboxylic acid using quinine or l-ephedrine (Bull.

Chem, Soc, Japan, 43.2230 (19
70), a method of selectively crystallizing 1 or dl-N-benzoyl-2-aminocyclohexanecarboxylic acid from a 70% methanol aqueous solution by a seeding method and performing optical resolution [Journal of the Society of Organic Synthetic Chemistry, 28, 866 (1970)] and so on.

However, these methods have disadvantages in that they have poor dividing efficiency and are not economically advantageous, require complicated operations, and are difficult to obtain pure 4- and 1-body.

In view of the usefulness of dl-h lance-2-aminocyclohexanecarboxylic acid, the present inventors discovered the benzoyl form of dA! -N-benzoyl-trans-2-aminocyclohexanecarboxylic acid As a result of various studies on optical resolution methods, in selective crystallization, the amine acid of N-benzoyl-trans-2-aminocyclohexanecarboxylic acid,
By using ammonium salts or alkali metal salts, a high-yield and stable optical resolution method was discovered and the present invention was completed.

In carrying out the method of the present invention, the amine salt, ammonium salt or alkali metal salt of dl-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid is
Optically inactive N-benzoyl-
A racemic form of trans-2-aminocyclohexanecarboxylic acid is heated and dissolved to make it supersaturated, and optically active N
A small amount of crystals of -benzoyl-trans-2-aminocyclohexanecarboxylic acid is inoculated and then cooled, crystals of the same type of active substance are crystallized not as its salt but as the carboxylic acid and separated from the mother liquor.

Next, the mother liquor was supplemented with the racemic form, and crystals of N-benzoyl-trans-2-aminocyclohexanecarboxylic acid, which has an optical rotation opposite to that of the previously inoculated active form, were inoculated to crystallize crystals of the same type of active form. Let it come out.

By repeating such operations, optically inactive N-benzoyl-trans-2-aminocyclohexanecarboxylic acid can be easily and completely optically resolved.

According to this method, N has sufficient solubility even when cold.
-benzoyl-trans-2-aminocyclohexanecarboxylic acid salts are free N-benzoyl-trans-2-
It is in equilibrium with aminocyclohexanecarboxylic acid and acts as a buffer against the crystallization pressure of the enantiomer, so the crystallized liquid phase and the crystalline phase of the inoculated active substance maintain a stable phase equilibrium relationship from beginning to end. .

Therefore, according to this method, it is possible to crystallize the same amount of the active substance as the dissolved racemate.

dJ! used in this method! Salts of '-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid have a high solubility in the crystallization solution, and therefore have a greater stabilizing effect on the crystallization solution, such as ethanolamine, 1-amino-2 - Salts with amino alcohols such as propatool and 2-amino-1-butanol are preferred, but salts with various other organic amine salts, alkali metal salts such as sodium and potassium salts, and inorganic bases such as ammonium salts are preferred. Salts are also effective.

Examples of the solvent used in the present invention include water, methanol, ethanol, aqueous methanol solution, and aqueous ethanol solution.

After the first crystallization of an optically active compound, the number of optically active compounds with opposite optical rotation to that of the crystallized compound increases in the solution. It is also possible to naturally raise the active form to a super high level without inoculating seeds.

The actual practice of the invention involves dissolving dl-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid and its pre-prepared salt in a solvent and then inoculating the optically active species; In a solution in which dl-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid is dissolved, an equimolar amount or less of di-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid to form a salt is added. An organic amine, an alkali metal, or an ammonium compound may be added and dissolved to form a salt, and the dl-compound that did not form a salt may be optically resolved.

The method of the present invention is characterized in that optically active N-benzoyl-trans-2-aminocyclohexanecarboxylic acid is crystallized in a higher yield and purity than in the conventional method, and the crystals that are crystallized are free of the salt thereof. -2-Aminocyclohexanecarboxylic acid itself.

Next, the method of the present invention will be explained with reference to Examples.

Example 1 dl-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid CI') 5.00ji (0,02
2 mol) and 2-amino-1-butanol 1.80
g (0,022 mol) at 40vol1% of 50TLl
Dissolve in methanol aqueous solution.

Add 1.00% of the racemic form of [1] to this solution. ! Immediately after heating and dissolving li', 0.0:l of the 4 forms of [D] was uniformly dispersed as seeds, and when left for 1 hour, crystals of the active form of 0.61 (first crystallization yield 67%) were precipitated. do.

This is filtered, washed with a small amount of 70vol 1% methanol aqueous solution, and dried.

The optical rotation of this product is (aD=+45°) and is completely optically resolved.

Furthermore, 1.01 of the racemic form of [D] is dissolved by heating, 0.03 g of the racemic form [D] is dispersed in the mother liquor, and the same procedure is performed to obtain 1.05 g of the racemic form of D.

The optical rotation of this product is @D-45°, and the optical resolution is completely optically resolved.

Note that the optical rotation of the active form of pure CI) is −±45°.

(C=0.5, ethanol) Example 2 dl-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid CI) 4.00 g (0,016 m
o l ) and 1-amino-2-propatool 1.21
g (0,016 mol) is dissolved in 40 ml of 40 vol 1% methanol aqueous solution.

After heating and dissolving 1.00 g of the racemic form of D, immediately disperse 0.0:l of the 4 forms of CI as seeds into this solution and leave it for 1 hour to obtain 0.66 g (1st crystallization yield 66%) of active substance crystals are precipitated.

The optical rotation of this material is completely optically resolved at 1101D - 145°.

Next, racemic forms i and oog of [D] are heated and dissolved in the mother liquor, one form of [D] is uniformly dispersed in a 0.0:l ratio as a seed, and the same procedure is performed to obtain 1.01 g of crystals of the active form.

The optical rotation of this material is (2)1)=-45°, and the optical rotation is completely optically resolved.

Furthermore, the racemic forms o and sog of
．． 77 g of crystals precipitate.

The optical rotation of this substance is +43°, making it an almost pure [D4 body].

Example 3 Ammonium salt of dl-N-benzoyl-2-aminocyclohexanecarboxylic acid (,r)1o, iog and ■22
．． 10 g was dissolved by heating in 600 TILl of 70 vol 1% methanol aqueous solution.

After cooling this to about 60℃ [4 pieces of I 0.03g
Distribute it evenly and leave it alone.

After 6 hours, 3.5 g of active substance (1st crystallization yield: 34
%) is precipitated.

This is separated by decanting and washed with a small amount of methanol.

The optical rotation of this material is (b) D=+45°, and the optical rotation is completely optically divided.

Furthermore, racemic form 5 of CI) and OOg were dissolved in the mother liquor by heating and inoculated with 1 form of CI), and after 8 hours, 5.
One crystal of 629 is obtained.

The optical rotation of this material is 1=-40', which means that the optical rotation is almost completely optically resolved.

Example 4 50.0 g (0.22 mol) of dl-N-benzoyl-trans-2-aminocyclohexanecarboxylic acid was added to a 500 rrLl aqueous solution containing an equivalent amount of NaOH and dissolved by stirring.

After heating and dissolving the racemic form 1.309 marked in this solution, immediately disperse 0.0:l of the four forms of [I] as seeds and leave it for 5 hours to precipitate 0.93 g of crystals of the active form ( The first crystallization yield was 71.5%).

The optical rotation of this product is 1) = +45°, and the optical rotation is completely optically resolved.

Next, heat and dissolve racemic forms i, oo& of [D] in the mother liquor, disperse one form of (I) as a seed in a 0.0:1 ratio, and perform the same procedure to obtain 1.02 g of crystals of the active form. .

The optical rotation of this product is (cx% = -45°) and is completely optically resolved.

Control Example: dl-N-benzoyl trans-
2-aminocyclohexanecarboxylic acid (1:I) 10
．． 9, add 800 parts of 70% methanol to it, and heat on a water bath to completely dissolve the racemate.

This is allowed to cool at room temperature, and when the liquid temperature reaches 50 to 60°C, the four crystals 0.1.9 of (2) are inoculated and left for 10 hours to grow crystals.

The solvent is decanted into another flask and the crystals are washed with a small amount of methanol and dried.

The amount of crystallization in the first round was 0.8 g (8%).

As a result, four compounds with an optical purity of 90% or more are obtained.

Next, add a mark corresponding to the amount of crystallization to the solution part, heat and dissolve again, and this time inoculate one crystal o, ig of [D] and leave it.

Separate the precipitated crystals in the same manner as before. The amount of crystallization after the second time was 1.1 to 1.6 g.

Thereafter, crystals of the enantiomers are alternately inoculated in the same manner to obtain the active form.

Finally, it is recrystallized using 95% ethanol for purification.

Table 1 shows the yields of the first batch of Examples of the present invention and Control Examples.

Claims (1)

[Claims] In a solution containing Idl-N-benzoyl-trans-2-ami
-dl-N- characterized in that it is inoculated with crystals of benzoyl-trans-2-aminocyclohexanecarboxylic acid
Optical resolution method of benzoyltrans-2-aminocyclohexanecarboxylic acid.