JPS6051154A - Phenylalanine o-toluenesulfonic acid salt and production of optically active phenylalanine using the same - Google Patents

Abstract

PURPOSE:To produce the titled compound in high purity, by adding a salt of an optically active compound to a supersaturated solution of a novel DL-phenylalanine o-toluenesulfonic acid salt to effect the preferential crystallization of an optically active compound, and removing the o-toluenesulfonic acid from the product. CONSTITUTION:A supersaturated solution of a novel DL-phenylalanine o-toluenesulfonic acid salt is added with a novel optically active phenylalanine o-toluenesulfonic acid salt to effect the preferential crystallization of the same kind of the optically active salt, or a supersaturated solution of a phenylalanine o-toluenesulfonic acid salt containing either of the optically active salt in excess is added with the optically active salt existing in the above solution in excess to effect the preferential crystallization of the same kind of the optically active compound, and the product is subjected to the removal of the o-toluenesulfonic acid to obtain an optically active phenylalanine. Since the o-toluenesulfonic acid salt has high solubility in water, it has excellent resolution efficiency.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention 1d relates to phenylalanine 〇-toluenesulfonate and a method for producing optically active phenylalanine using the same.

L-phenylalanine is one of the essential amino acids and is an important compound as a component of amino acid infusions. Recently, it has become increasingly important as a raw material for the artificial sweetener aspartame. Furthermore, D-phenylalanine is also a substance that is attracting attention as a raw material for various pharmaceuticals including antibiotic modifiers.

A known method for producing optically active phenylalanine is to convert DL-phenylalanine into p-xylene sulfonate or β-s7talenes sulfonate and then optically resolve it by preferential crystallization (Japanese Patent Publication No. 51-46104). (see official bulletin).

However, this method has the disadvantage that the solubility of p-xylene sulfonate and λ-naphthalene sulfonate of phenylalanine in water is extremely low, and the efficiency of splitting into one stop is extremely low.

The phenylalanine 0-toluenesulfonate of the present invention has about six times the solubility in water as the above-mentioned sulfonate, so by using this salt, optical resolution of phenylalanine can be carried out efficiently. .

Next, Table 1 shows the physicochemical properties of the compounds of the present invention and known sulfonate salts.

Table 1 Phenylalanine/O)luenesulfonate of the present invention is synthesized as follows. KO-) in water or aqueous solvent
Luenesulfonic acid, its alkaline earth salt, or its alkaline earth metal salt is dissolved, and phenylalanine is gradually added thereto. When the above-mentioned salts of 0-toluenesulfonic acid are used, it is necessary to add a mineral acid such as sulfuric acid or hydrochloric acid to convert the O-)toluenesulfonic acid into a free form.

The solution thus obtained was concentrated to an appropriate concentration.

Separate and collect the precipitated crystals. If the above operation is carried out while hot, it is also possible to precipitate crystals of the target product by cooling and separate and collect the crystals.

However, industrially, it is not necessary to isolate it as a salt, and a solution of DL-phenylalanine and 0-toluenesulfonic acid synthesized as described above can be used as a salt. , can be used for optical separation.

In order to carry out the optical resolution of the present invention, first, DL-Z technology; - Prepare a supersaturated solution of 0-toluenesulfonate. Therefore, according to a conventional method, a mixture of DL-phenylalanine/0-toluenesulfonate or a salt containing an excess of optically active salt of either one may be made into a saturated solution at high temperature, and then cooled or concentrated.

However, industrially, it is saturated at high temperature and slowly cools 7V,
The best method is to use a supersaturated solution.

The solvent used can be water or a mixed solvent of water and a water-soluble organic solvent such as alcohols, ketones, lower fatty acids, or aprotic polar solvents.

Specific examples of water-soluble organic solvents include the following.

Methanol, ethanol, probanol, inpropanol, butanols, cyclohexanol, acetone,
Methyl ether ketone, acetic acid, propio7 fst M,
Examples include, but are not limited to, halogenoacetic acids, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N,N'-dimethylimidazolidinone, and N-methylpyrrolidone.

The concentration of phenylalanine O-)luenesulfonate in a supersaturated solution varies depending on the temperature at the time of separation, but it is about 8 to 15 W//v% when the solvent is water, and 15 to 15 W//v% when a mixed solvent is used. Approximately 35 W/V% is preferable.

Optically active nophenylalanine + O) luenesulfonate is usually obtained from K by inoculating seed crystals into a supersaturated solution of the DL monolithic salt produced as described above.

It is naturally preferable that the seed crystals used for inoculation be of high purity. The larger the amount of inoculation, the better, but a solute amount of about 105 cm is sufficient.

The crystallization temperature can be 0 to 50°C, but it is convenient to set it around room temperature.

When an optically active salt existing in excess is inoculated into a supersaturated solution containing an excess of one optically active salt to preferentially crystallize the optically active salt of the same type, the optical rotation of the solution is As the preferential crystallization progresses, it gradually decreases and finally its direction is reversed, but it can continue as it is. The amount of crystallization is 2 to 2 times the amount of dissolved optically active salt.
It is preferable to cut off at 5 times.

Add the racemate to the mother liquor excluding the crystallized crystals to make a supersaturated solution, inoculate the same optically active salt as the optically active salt dissolved in excess in the mother liquor, and perform preferential crystallization in the same manner as above. By doing so, the other optically active salt can be obtained.

In addition, as is generally known, in order to stabilize the supersaturated state, appropriate coexisting salts such as phenylalanine sulfate,
Addition of phenylalanine hydrochloride, phenylalanine benzenesulfonate, phenylalanine alkylbenzenesulfone H salts, phenylalanine-substituted benzenesulfonate salts, etc. may facilitate the optical resolution operation.

The method described above can be carried out either batchwise or continuously.

Optically active phenylalanine 0-
Although toluene sulfonate is not necessarily optically pure, it can be made into a highly pure optically active salt by recrystallizing from water or a mixture of water and the water-soluble organic solvent described above.

Optically active phenylalanine 0-
Optically active phenylalanine can be obtained by dissolving or dispersing toluene sulfonate in water or a mixture of water and a water-soluble organic solvent, and decomposing the salt by neutralization or passing through an ion exchange resin.

The present invention will be explained in detail by way of examples below.

Example 1 0-1-luenesulfonic acid 2 water fO 45.5 y
v, (mixed with 220 ml of water and dissolved at 70°C, then gradually added 30.0f of DL-:phenylalanine, and finally raised the temperature to 90°C to make a homogeneous solution.7'c0 This solution was dissolved at 70°C.
After cooling to 0°C, the precipitated crystals were collected, washed with a small amount of water, and dried. I got it.

Yield 82.7%.

NMR spectrum of DL-phenylalanine 0-toluenesulfonate.

Attribution -CH3-CH2--(:H< aromatic ring ppm
2.55 3.1-5.34. i~4.5 7.3~7
．． 9 Number of protons: 3 2 = 1 9 Infrared absorption spectrum of DL-phenylalanine/0-toluenesulfonate.

Absorption position ((m-1) 1753 1695 1600
1218 1190 1174 114m Intensity Medium Medium Medium Strong Weak Weak Weak Absorption position 1020 750 614 Intensity Medium Medium Medium Melting point of DL-phenylalanine 〇-toluenesulfonate 201-202.5 °C Example 2 0-Toluenesulfonic acid 2 water fO 45.5 F @
After mixing 220aJK of water and dissolving at 70°C, gradually add 30% of D-phenylalanine. Of was added. Thereafter, in the same manner as in Example 1, 52.2 F of D-phenylalanine/0-toluenesulfone salt was obtained.

Yield: 85.4% N of D-phenylalanine 0-toluene nulphonate
MR spectrum.・ Attribution -CHs -CH2-CH〈 Aromatic ring ppm 2
．． 55 3. +~3.3 4. j~4.3 7.3~7
．． 9 Number of protons: 3-219 Infrared absorption spectrum of D-phenylalanine/0-toluenesulfonate.

Absorption position (Cm=) 1755 1695 1600
+248 4190 1174 1140 Strength Medium
Medium Medium Strong Weak Weak Weak Absorption position 1020750 614 Intensity Medium Medium Medium Melting point of D-phenylalanine 0-toluenesulfonate 220-221°C Example 3 0-) Luenesulfonic acid dihydrate 20. Bf to water 10
After mixing at 0mlV and dissolving at 70°C, ICL-phenylalanine 13.7F was gradually added. Hereinafter, in the same manner as in Example 1, L-phenylalanine o-t and luenesulfonate 24. ” ')?Tb.

Yield 86.2% L-phenylalanine-0-1 luenesulfonate N
MR spectrum.

Attribution -CH3-CH2--CH〈 Aromatic ring ppm 2.
55 3. j~3.3 4.1~4.5 7.5~7.
9 Number of protons: 3 2 1 9 Infrared absorption spectrum of L-phenylalanine o-toluenesulfonate.

Absorption position (c+rr-') 1755 1695 16
o0 1218 1190 1174 H4 [1 Intensity Medium Medium Strong - Weak Weak Weak Absorption position 1020 750 6+4 Intensity Medium Medium Medium Melting point of L-phenylalanine 〇-toluenesulfonate 220-221 °C Example 4 DL-phenylalanine O-) Luensulfone fi&
1i5r, L-phenylalanine/O) luenesulfonate α16f1 water 55g was charged into a 10Qd beaker and heated. Since it was dissolved at 48°C, it was cooled while stirring slowly. At 30°C, 1 oz of L-phenylalanine-0-toluene was added. The mixture was gradually cooled, and since a considerable amount of crystals precipitated at 27°C, it was filtered through a filtration filter.

The crystals were slightly washed with water and dried. ayr8y L-phenylalanine 0-toluenesulfonate fr” (41'
), and the specific rotation is [0g1%5-7.86° (C""
+ + water) and has an optical purity of 86.5%.

DL-Phenylalanine・0 in PM after crystals are sent from house to house
- Toluenesulfonate was added a5y and dissolved by heating. After cooling in a 25°C trench, D-phenylalanine 0-
Volatile crystals of toluenesulfonate were inoculated with n003. When I slowly turned off the stopper, crystals were observed to precipitate, and after 10 minutes I separated the crystals from the furnace and washed them with water. After drying, 0502 D-phenylalanine 0-)luenesulfonate was obtained. The specific optical rotation of this substance is (α']2o5−1−6.95°(C”
1+water), and the optical purity was 76.7%.

Example 5 Optical separation was performed using exactly the same preparation as in Example 4.

However, the active salt added to 7 was D-integrated instead of L-integrated, and the inoculated seed crystal was also D-integrated.

Crystals were crystallized in the same manner as in Example 4.

n362 D-phenylalanine 0-toluenesulfonate was obtained, and the specific rotation was (α”V−+9.1°(C
==1. water), and the optical purity was 99.7%.

Similarly to Example 2, DL-phenylalanine 0-
Toluene sulfonate 11 was added, dissolved by heating, and then cooled with slow stirring.

Seed crystals of phenylalanine 0-toluenesulfonate were inoculated at 30°C. The mixture was gradually cooled, and the precipitated crystals were separated in a furnace at 27°C, washed with water, and dried. L-phenylalanine 0-toluenesulfonate of n492 was obtained, and the specific rotation U (α:I 'D''-7
-(13°(c=1+water)te;hb, optical purity is 77.
It was 2%.

Example 6 500 m (! 5 in glass flask) A urea aqueous solution filtration 9
12, ○-Toluenesulfonic acid 2H2076, sulfuric acid 1.9? Add it and heat it up. To this solution, 53 DL-phenylalanine and 22 L-phenylalanine were gradually added and dissolved.

The mixture was gradually cooled from 60°C to 25°C in about 2 hours.

Here, L-phenylalanine/0-toluenesulfonate n j5 F was added, and crystals were precipitated while slowly shaking. After about 7 days, the crystals were collected using a centrifuge, washed with about 50 ml of water, and dried under vacuum.
0.5f of phenylalanine-0-toluenesulfonate was obtained, and the optical purity of this product was 88.9% and 7'C.

Example 7 A 50 (1aJ glass flask was charged with 252 ml of a 50.6 v/V% dimethylacetamide aqueous solution, and heated at 60'C.
O-) luenesulfonic acid dihydrate 5 while stirring with IC.
+, 3f, 11)) Luenesulfonic acid monohydrate 4. Dissolve By and add DL-phenylalanine 40
．． 259, L-phenylalanine 1.75F was gradually added and dissolved.

After that, cool it to 27℃ and 7℃. :o Now add 108 ml of L-phenylalanine 0-toluenesulfonate,
The mixture was gradually cooled to 21° C. over 1 hour.

The precipitated crystals were separated using a centrifuge and washed with 25 ml of water.

The obtained crystals were dried under vacuum to obtain 8.849 L-phenylalanine/0-toluenesulfone salt. 8k.

Optical purity was 89.6%. 1 of this crystal 81 with water
The crystals obtained by recrystallization were dispersed in water and neutralized with an aqueous ammonia solution. Thereafter, a small amount of water was distilled off from the slurry, and precipitated crystals tf were separated. After vacuum drying 2.1
3f L-phenylalanine was obtained. The specific optical rotation of this substance is [α) 290-66,8° (C-1
, water), and the optical purity was 98.3%.

Example 8 50m1 Erlenmeyer flask KDL-Phenylalanine O-
) Luenesulfonic acid 1i5f, L-phenylalanine.
O-1-luenesulfonate n+s! P.

Prepare 6 ml of methanol and 16.1 ml of water and heat to dissolve σ
Let's not. Cool from 58°C with slow stirring to 20°C.
When the temperature reached I2℃, L-phenylalanine
Inoculated with O-1-luenesulfonate noosr. 1
When the temperature reached 31°C after 5 minutes, the precipitated crystals were filtered, washed with water, and dried under vacuum to obtain a282 L-phenylalanine o-toluenesulfonate, whose specific optical rotation was [α) 2 ．． ．． 5 = -8,69° (C =
'lr water), which had an optical purity of 95.4%.

Example 9 50 m1 Erlenmeyer flask 1 CDL-phenylalanine
Prepare O-toluenesulfone e salt 6-5y, L-phenylalanine 0-toluenesulfonate 0182, inpropanol 10g, water, 10m, and heat at 50°C.
It was dissolved by raising the temperature to . Cool while stirring slowly, 2
When the temperature reached 5°C, seed crystals of L-phenylalanine-0-toluenesulfonate [1005F] were inoculated.

After about 1 hour, the mixture was cooled at 23° C., and the precipitated crystals were separated and washed with water. After vacuum drying, α422 L-phenylalanine 〇-toluenesulfonate salt was obtained, and the specific optical rotation of this product was [α)′D −, 8-6s.

(C==j, water), and the optical purity was 94.9%.

Example 10 An optical resolution experiment was carried out in exactly the same manner as in Example 9.

However, 26 ml of 50% acetic acid water was used as the solvent.

The crystals precipitated in a sautee were filtered, washed with water, and dried under vacuum to obtain L-phenylalanine/0-toluenesulfonate of [1289], with a specific optical rotation of [α] of 211. ”
--8.08° (c, = 1.water), and the optical purity was 88.7°.

Example 11 Optical resolution was performed using Example 70 liquid, and the obtained i&D-
Phenylalanine 0-toluenesulfonate is recrystallized from 4 times the amount of water to produce a purified product with an optical purity of 99.4 5
．． I got 72. Of this, 5.52 is methanol 30ml
50% sodium hydroxide water bath solution 37 was added while stirring.

After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes and filtered. The crystals were washed with methanol and -A was completely dried to obtain 2.32 D~phenylalanine. The specific optical rotation of this substance is [α]
'2D. =+ss, q° (C: i, water), and the optical purity was 98.6.

Patent applicant: Nippon Kayaku Co., Ltd.

Claims (2)

[Claims] (1) Phenylalanine O-)luenesulfonate (2) Optically active phenylalanine 0-
Either all toluenesulfonate is inoculated to preferentially crystallize the optically active salt of the same type, or one of the optically active salts is added to a supersaturated solution of phenylalanine/0-toluenesulfonate in excess. An optically active compound, which is characterized in that it is inoculated with a salt of the existing optically active substance, preferentially crystallizes the optically active substance of the same type, and is collected and treated with 0-toluenesulfonic acid after 7 days. Manufacturing method for Reala 5.