JPS6115066B2 - - Google Patents

Description

Detailed Description of the Invention The present invention provides optically active 2-(4-hydroxyphenyl) glycine by optical resolution of DL-2-(4-hydroxyphenyl)glycine.
-Hydroxyphenyl)glycine.

Optically active 2-(4-hydroxyphenyl)glycine is a compound useful as a pharmaceutical intermediate.

Conventionally, enzymatic methods, diastereomer methods, selective crystallization methods, and the like have been known as optical resolution methods for DL-2-(4-hydroxyphenyl)glycine.

As an enzymatic method, acylation is performed by a chemical reaction,
There are methods such as asymmetric hydrolysis by enzymatic treatment, optical resolution, and deacylation by hydrolysis, but these methods require deacylation after optical resolution, and when using the enzymatic method, the reaction solution is diluted. Therefore, it is necessary to evaporate a large amount of water. Furthermore, the yield is also low.

In the diastereomer method, expensive optically active substances (for example, in JP-A-51-32541, α-3
-bromocamphor -10-sulfonic acid) must be used.

According to the selective crystallization method, expensive optically active substances and special enzymes are not required, and DL-2-(4-hydroxyphenyl)glycine can be separated more economically than conventional enzyme methods, diastereomer methods, etc. It is expected that it will be possible. As a selective crystallization method, a method using p-toluenesulfonate or m-xylenesulfonate is known (JP-A-50-111033, JP-A-50-111033).
No. 142534). In these methods, DL-2-(4-
Crystallizing only the optically active salt from an aqueous solution by utilizing the fact that the solubility of p-toluenesulfonate or m-xylenesulfonate of hydroxyphenyl)glycine in water is greater than the solubility of the optically active salt. The optically active 2-(4-hydroxyphenyl)glycine is then separated.

However, in the method using m-xylene sulfonate or p-toluene sulfonate, the optical purity of the optically active salt obtained is low, and it is insufficient to be used as a pharmaceutical intermediate as it is, and the optical purity can be improved by recrystallization. need to be raised. Also,
Recovery of sulfonic acids after separation of optically active 2-(4-hydroxyphenyl)glycine is very difficult because sulfonic acids themselves or their salts, such as Na salts, have a high solubility in water.

Due to these drawbacks, DL-2-(4
-Hydroxyphenyl)glycine by selective crystallization is not industrially advantageous.

Conventionally, optical resolution of amino acids by selective crystallization has been studied for various amino acid salts;
It is completely difficult to predict whether selective crystallization will occur depending on the chemical structure and physicochemical properties of the salt formed by an amphoteric amino acid and an acid or base, such as stability, crystal structure, solubility, etc. In addition, it is impossible to use it industrially unless it satisfies factors such as optical purity of optically active amino acids, recovery and regeneration of resolving agents, and racemization of unnecessary optically active amino acids or salts. .

The inventors have discovered that 2-(4-hydroxyphenyl)
By synthesizing various salts of glycine and finally investigating the problems mentioned above, we investigated the feasibility of optical resolution by selective crystallization, and found that we obtained products with high optical purity, and that the resolving agent The present invention has been completed by discovering an industrially advantageous selective crystallization method that facilitates the recovery of .

The present invention combines DL-2-(4-hydroxyphenyl)glycine (hereinafter abbreviated as DL-HPG) with a mineral acid and 2-methyl-7-naphthalenesulfonic acid (hereinafter abbreviated as MNS) or 2-methyl-7-naphthalenesulfonic acid (hereinafter abbreviated as MNS). DL-HPG/MNS salt or DL prepared by mixing with naphthol-6-sulfonic acid (hereinafter abbreviated as NLS)
−Optically active in supersaturated aqueous solutions of HPG/NLS salts
A method for producing optically active HPG, which comprises inoculating HPG/MNS salt or optically active HPG/NLS salt, selectively crystallizing the optically active salt of the same type, and desulfonating the optically active salt by a conventional method. It is. Either one of the optically active salts may be present in excess in the DL salt aqueous solution, but in that case, an optically active salt of the same type as the optically active salt present in excess is inoculated.

The DL salts and optically active salts used in or via the method of the present invention are new compounds, but when carrying out the method of the present invention, they are The usual methods can be applied. That is, first, a saturated or nearly saturated mineral acid aqueous solution of the DL salt is prepared. In this case, the DL salt and mineral acid may be dissolved in water, or DL-HPG, MNS or NLS, and the mineral acid may be added to water to prepare a DL salt mineral acid aqueous solution. In this case, one of the optically active salts may be used in excess as described above.

Industrially, it is convenient to prepare an aqueous salt solution by adding 2-(4-hydroxyphenyl)glycine, MNS or NLS, and a mineral acid to water at a warm temperature.

The addition ratio of naphthalene sulfonic acid derivatives (MNS or NLS) and mineral acids to DL-HPG is DL-HPG.
- 0.2 to 3 mol, preferably 0.25 to 1.5 mol, of the naphthalene sulfonic acid derivative and 0 to 3 mol, preferably 0.1 to 1 mol of the mineral acid, per 1 mol of HPG.
In the above, the total amount of the naphthalene sulfonic acid derivative and the mineral acid must be 1 mol or more, and is usually 5 mol or less, preferably 3 mol or less.

As the mineral acid, sulfuric acid, hydrochloric acid, etc. can be used, but sulfuric acid is usually used. In the case of hydrochloric acid, it is preferable to use an amount 1.5 to 2.0 times the amount of mineral acid mentioned above.

To give a specific example of the ratio of each component that allows the optically active salt with the highest optical purity to be obtained in good yield, DL-
The molar ratio of HPG: naphthalene sulfonic acid derivative: mineral acid is 1:1:0.2 or 1:0.4:0.6 or 1:
This is the case of 0.5:0.5.

A supersaturated aqueous solution of the DL salt obtained as above was inoculated with a small amount of crystals of one of the optically active salts,
Optically active salts of the same type as the inoculated optically active salts can be crystallized by cooling while standing still or with gentle stirring.

Next, a pure optically active salt is obtained by separating the liquid and crystal.

DL-2-(4-hydroxyphenyl)glycine and the above naphthalenesulfonic acid derivative, or salts of both, are added to the mother liquor to prepare a saturated or nearly saturated aqueous solution. Through this operation, an aqueous solution of DL salt at or close to saturation is prepared, in which an optically active salt opposite to that crystallized previously is present in excess. The aqueous solution is inoculated with crystals of the optically active salt present in excess, and the other pure optically active salt is obtained in the same manner as the crystallization of the optically active salt described above.

Thereafter, by repeating the same operation, the D-form salt and the L-form salt can be crystallized and separated alternately, and a quantitative split yield can be obtained.

The excess amount of the optically active substance in the aqueous solution of the DL substance salt to be subjected to the optical resolution treatment is 0 to 25% by weight, preferably 5 to 15% by weight of the DL substance. In the operation of selectively crystallizing D-form salt and L-form salt alternately,
The excess amount represents the excess amount of one optically active substance before separation, as well as the excess amount of the other optically active substance when the mother liquor after separation is saturated with DL body salt.

The obtained optically active salt can be neutralized by a conventional method to obtain optically active 2-(4-hydroxyphenyl)glycine. That is, it is neutralized with alkali metals, alkaline earth metals, or their salts, such as caustic soda, sodium chloride, calcium chloride, or slaked lime, or with ammonia, amines, and the like. Alternatively, it may be treated with an ion exchange resin by a conventional method.

The optically active substance obtained in the present invention can be purified by recrystallizing from water if necessary, but it has high optical purity as it is, and does not require purification such as recrystallization.
Can be used as a pharmaceutical intermediate.

When only one optically active substance is used as the target compound, the selectively crystallized salt of the other optically active substance can be racemized by heating in an aqueous solution to about 140 to 180°C according to a conventional method. can be used as a raw material in the method of the present invention.

The present invention will be explained in detail below with reference to Examples.

Example 1 100 g (0.70 mol) of 2-methylnaphthalene was heated and melted, and 84.5 g (0.84 mol) of 98% sulfuric acid was added thereto while stirring, and the mixture was kept at 160°C for 4 hours. During this time, the water produced was distilled off. After cooling, it was recrystallized with hydrochloric acid to remove unreacted sulfuric acid and the like, and was further washed with benzene to remove unreacted 2-methylnaphthalene and other by-products. The yield of the product was 119.7, and the main component was MNS.

DL-HPG15.9g (0.095mol), D-HPG0.83
g (0.005 mol), obtained as above
A mixture of 11.1 g (0.05 mol) of MNS, 5.2 g (0.05 mol) of 95% sulfuric acid, and 120 g of water was stirred and heated to 70°C to dissolve. Cool the transparent liquid to 50℃ and
20 mg of HPG/MNS crystals were added and allowed to stand for 1 hour. Needle-shaped crystals were precipitated, so they were separated by shaking in a centrifuge.
It was added in batches and washed, and then dried at 70°C until it reached a constant weight. Obtained D-HPG・MNS salt 3.8
g, specific optical rotation [α] ²² _D -56.4° (C=1, water).

D synthesized separately from pure D-HPG and MNS
-[α] of HPG/MNS salt ²² _D -57.0° (C=1,
water), so the D− obtained by splitting
The optical purity of the HPG/NMS salt was 98.9%.

The obtained D-HPG·MNS salt was recrystallized from hot water.

[α] ²² _D -57.0° (C=1, water), optical purity 100
It was %.

The washing solution of the crystals was collected by drying under reduced pressure and was reused in Example 3.

Example 2 DL-HPG2.0 was added to the mother liquor from which the crystals were separated in Example 1.
g and 2.7 g of MNS were added and heated to 70°C to dissolve. The transparent liquid was cooled to 50° C., 20 mg of L-HPG·MNS crystals were added thereto, and the mixture was allowed to stand still for 1 hour.

Needle-shaped crystals were precipitated and separated by shaking with a centrifuge, and the obtained crystals were washed by adding 10 ml of water at 5°C in three portions, and then dried at 70°C until a constant weight was reached. Obtained L-HPG・MNS salt 3.9 g [α] ²² _D +
It was 55.8° (C=1, water).

L separately synthesized from pure L-HPG and MNS
-[α] of HPG/MNS salt ²² _D +56.3° (C=1,
water), so the L-
The optical purity of the HPG/MNS salt was 99%.

The washing solution of the crystals was collected by drying under reduced pressure and was reused in Example 4.

Example 3 To the mother liquor from which the crystals were separated in Example 2, the recovered HPG/MNS, 1.8 g of DL-HPG, and 2.5 g of MNS from Example 1 were added and dissolved by heating to 70°C. The transparent liquid was cooled to 50°C, 20 mg of D-HPG/MNS crystals were added thereto, and the mixture was allowed to stand still for 1 hour. Needle-shaped crystals were precipitated, so they were separated by shaking with a centrifuge, and the obtained crystals were washed by adding 10 ml of water at 5°C in three portions, and then heated at 70°C.
It was dried until it reached a constant weight. The obtained D-HPG・
4.5 g of MNS salt, [α] ²² _D -57.0° (C=1, water), with an optical purity of 100%.

The washing solution of the crystals was collected by drying under reduced pressure and reused.

Example 4 The recovered HPG/MNS, DL-HPG 1.8 g and NMS 2.5 g of Example 2 were added to the mother liquor from which the crystals were separated in Example 3, and the operations of Example 2 and Example 3 were repeated to obtain L. -HPG/MNS and D-HPG/MNS could be obtained alternately. The split yield was quantitative.

Example 5 11.7 g (0.03 mol) of D-HPG/MNS salt was added to 20 ml of water at 50°C, and 6.8 g (0.068 mol) of a 40% caustic soda aqueous solution was added thereto with stirring, followed by cooling on ice. Suction filter the crystals with 30ml of 1% caustic soda aqueous solution.
Washed with. This crystal is the sodium salt of MNS, and MNS can be quantitatively determined by treatment with an ion exchange resin.
I was able to play it. The filtrate and washing solution were combined and concentrated under reduced pressure until the volume was reduced to about half, then heated to 50°C, adjusted the pH of the liquid to 6.0 with hydrochloric acid under stirring, cooled on ice for 1 hour, filtered,
After washing with water and drying, 4.6 g of D-HPG crystals were obtained.
Yield 92%, [α] ²² _D −160° (C=1, N-HCl),
The optical purity was 100%.

Example 6 DL-HPG7.93g (0.0475mol), L-HPG0.42
g (0.0025 mol), NLS6.2 g (0.025 mol), 95%
Mix 2.58g of sulfuric acid (0.025mol) and 25g of water,
It was heated to 70°C and dissolved. This aqueous solution was cooled to 60° C., left to stand, and 10 mg of L-HPG/NLS salt was added thereto and allowed to cool for 20 minutes. During this time, the liquid temperature dropped to 20°C. Powdery crystals were precipitated and filtered with suction, and the crystals were washed with a small amount of cold water and dried at 70°C until they reached a constant weight. 2.5 g of the obtained L-HPG/NLS salt had a specific optical rotation [α] ²² _D +43.9° (C=1, water).

separately synthesized from pure L-HPG and NLS,
[α] of the recrystallized L-HPG・NLS salt was ²² _D +57.1° (C=1, water), so the optical purity of this product was
It was 76.9%.

Example 7 DL- was added to the mother liquor from which the crystals were separated in Example 6.
1.19 g (0.0071 mol) of HPG, 1.77 g (0.0071 mol) of NLS, and 4 g of water were added and dissolved by heating to 70°C. This aqueous solution was cooled to 60° C., allowed to stand, and 10 mg of D-HPG/NLS salt was added thereto and allowed to cool for 20 minutes.
During this time, the liquid temperature dropped to 20°C. Powdery crystals were precipitated, so they were filtered with suction, washed with a small amount of cold water, and dried at 70°C until they reached a constant weight. The obtained D-
The HPG/NLS salt was 2.65 g, and the specific optical rotation [α] ²² _D -46.1° (C=1, water).

separately synthesized from pure D-HPG and NLS,
[α] of the recrystallized D-HPG・NLS salt was ²² _D −57.6° (C=1, water), so the optical purity of this product was
It was 80.0%. The obtained crude D-HPG/NLS salt crystals were dissolved in 10 g of boiling water, slowly cooled, and purified D-HPG/NLS salt crystals were dissolved in 10 g of boiling water.
Add 5 mg of HPG/NLS crystals, let it stand until it reaches room temperature, then filter out the precipitated crystals, wash with water, and refine D-HPG/NLS.
1.5 g of crystal was obtained. [α] ²² _D -57.1 (C=1, water) Optical purity was 99.1%.

Example 8 DL- was added to the mother liquor from which the crystals were separated in Example 7.
1.19 g (0.0071 mol) of HPG, 1.77 g (0.0071 mol) of NLS, and 4 g of water were added and dissolved by heating to 70°C. The following operation was performed according to Example 6, and L-HPG・
2.6 g of NLS salt, [α] ²² _D +49.7° (C=1, water), optical purity 87.0% was obtained.

Example 9 The purified D-HPG/2-NLS salt crystals obtained in Example 7 were dissolved in 15 g of water, and a column of strong acid type ion exchange resin Amberlite IR-120B (resin amount 14 ml, diameter
After washing with water, the adsorbed D-HPG was eluted with aqueous ammonia and concentrated to dryness under reduced pressure to obtain 0.60 g of D-HPG. Yield 95%,
[α] ²² _D −157.8° (C=1, 1N-hydrochloric acid).

Claims (1)

[Claims] 1 DL-2-(4-hydroxyphenyl)glycine prepared by mixing mineral acid and 2-methyl-7-naphthalenesulfonic acid or 2-naphthol-6-sulfonic acid The optically active 2-(4-hydroxy Optically active 2-(phenyl)glycine characterized by inoculating 2-methyl-7-naphthalenesulfonate or 2-naphthol-6-sulfonate to selectively crystallize the same optically active salt. A method for producing 4-hydroxyphenyl)glycine.