JPS6261585B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing optically active P-hydroxyphenylglycine salts.

Optically active P-hydroxyphenylglycine is a useful compound, for example, D-P-hydroxyphenylglycine is important as a raw material compound for semi-synthetic penicillin and semi-synthetic cephalosporin.
Furthermore, LP-hydroxyphenylglycine can be used for the treatment of ischemic heart disease, cardiac dysfunction, diabetes, etc. (Japanese Patent Application Laid-open No. 41432/1983).

However, P-hydroxyphenylglycine does not exist in nature and can only be obtained synthetically.
The synthesized P-hydroxyphenylglycine is
Since it is a DL form, further optical resolution is required to obtain its optically active form. Conventionally, as a chemical resolution method for P-hydroxyphenylglycine, for example, DL-P-hydroxyphenylglycine is converted into N-
Converted to benzyloxycarbonyl derivative, N-chloroacetyl derivative, N-benzoyl derivative,
A method of dividing these into quinine, dehydroabiethylamine, optically active α-phenethylamine, etc. (J.Chem.Soc.(c), 1971, 1920-1922,;
No. 49-56946, Japanese Patent Application Laid-open No. 50-69039) are known. However, all of these methods
DL-P-hydroxyphenylglycine must be converted into an acyl derivative once, the resolving agent is expensive, and there is a risk of racemization during deacylation after optical resolution. Also, a method for resolving DL-P-hydroxyphenylglycine as d-3-bromocamphor-10-sulfonate (Japanese Patent Application Laid-open No. 32541/1983), d-3-bromocamphor-10-sulfonate
8-Sulfonate method
-45069) is also known, but since the L-P-hydroxyphenylglycine salt dissolved in these methods cannot be racemized as it is, it is necessary to racemize it for reuse. The problem was that it had to be converted back to free amino acids.

In view of this situation, the present inventors have conducted intensive research and found that two easily soluble diastereomers formed by DL-P-hydroxyphenylglycine and optically active α-phenylethanesulfonic acid have been developed. The fact that the stereomer is readily epimerized as it is in water or fatty acids, and that the poorly soluble diastereomer of the salt resulting from epimerization can be crystallized even under the epimerization conditions of such easily soluble diastereomer; It has been found that the poorly soluble diastereomer crystallized in this manner exists as stable crystals without being epimerized even under the above epimerization conditions.

The present invention has been completed based on these new findings, and is an easily soluble diastereomer of two diastereomers formed by hydroxyphenylglycine and optically active α-phenylethanesulfonic acid. In this method, the two diastereomers are selectively converted into the poorly soluble diastereomer by epimerization of the diastereomer and crystallization of the poorly soluble diastereomer.

That is, according to the present invention, optically active P-hydroxyphenylglycine/optically active α-phenylethanesulfonate is composed of two types: DL-P-hydroxyphenylglycine/optically active α-phenylethanesulfonate. It can be produced by epimerizing easily soluble diastereomers among the diastereomers and collecting the crystallized poorly soluble diastereomers.

DL-P-hydroxyphenylglycine (hereinafter referred to as DL-HPG) used in the present invention may be a mixture of equal amounts of D-form and L-form, or one optically active form may be contained in excess. It can be something. Such DL-HPG may be, for example, DL-HPG obtained by a synthetic method, or L
- or D-P-hydroxyphenylglycine (hereinafter referred to as D-HPG or L-HPG) in excess, for example, from DL-HPG to D- or L-P-
It may be obtained after separating hydroxyphenylglycine by a known method. these
DL-HPG can be used not only in its free form but also in the form of mineral acid salts such as hydrochloride and sulfate, and organic acid salts such as oxalate and sulfonate.

In addition, optically active α-phenylethanesulfonic acid (hereinafter referred to as optically active PES) is (±)-
(+)-α-phenylethanesulfonic acid (hereinafter referred to as (+)-PES) or (-)-α-phenylethanesulfonic acid (hereinafter referred to as (+)-PES) obtained by optical resolution of α-phenylethanesulfonic acid. , (-)-PES) can be used for the purpose of the present invention, and even in free form, alkali metal salts such as potassium salts and sodium salts, calcium salts, and magnesium salts can be used for the purpose of the present invention. Alkaline earth metal salts such as alkaline earth metal salts or ammonium salts can also be used. Suitably, these optically active PESs are used in a molar ratio of about 0.5 or more to DL-HPG, particularly about 0.8 to 1.1 molar ratio.

The salt obtained by reacting the above-mentioned DL-HPG and optically active PES is a mixture of two types of diastereomers. The conditions for crystallizing mer are not particularly limited.
For example, epimerization can be carried out by heating in the presence of water or stirring in a lower fatty acid in the presence of an aliphatic or aromatic aldehyde. Further, crystallization may be performed at room temperature or under heating. The epimerization of the easily soluble diastereomer is preferably carried out under conditions such that the poorly soluble diastereomer produced by the epimerization crystallizes.

(+)-PES as optically active PES in the above
When using DL-HPG/optically active PES salt, D
-HPG・(+)-PES and L-HPG・(+)-PES are obtained as a mixture of two diastereomers, but under the above epimerization conditions, D-HPG・(+)-PES becomes a poorly soluble diastereomer, L-HPG・(+)-
PES becomes a readily soluble diastereomer.

On the other hand, when (-)-PES is used as the optically active PES, L-HPG/(-)-PES becomes a poorly soluble diastereomer, and D-HPG/(-)-PES becomes a readily soluble diastereomer. Become.

Therefore, when crystallizing DL-HPG/optically active PES under the above epimerization conditions, D-HPG/(+)-PES or L-HPG/ (−)−
PES first crystallizes out, and the easily soluble diastereomer D-HPG・(−)-PES or L-HPG・
Epimerization of (+)-PES progresses, and the resulting poorly soluble diastereomer further crystallizes. Moreover, once crystallized poorly soluble diastereomers do not undergo epimerization, if epimerization and fractional crystallization are performed, DL-HPG and optically active PES in the reaction system
are substantially all poorly soluble diastereomers D
−HPG・(+)−PES or L−HPG・(−)−PES
can be obtained as When the above epimerization reaction is carried out by heating in the presence of water, DL-HPG
All you have to do is add a small amount of water to optically active PES and heat it, and the reaction will occur at about 80-160℃, especially about 100-150℃.
The process progresses smoothly.

Furthermore, when the epimerization reaction is carried out in the coexistence of a lower fatty acid and an aliphatic or aromatic aldehyde, it can be carried out in a solvent or without a solvent. In this case, the raw material DL-HPG, optically active
Epimerization easily proceeds by mixing and stirring PES, lower fatty acids, aldehydes, and, if necessary, a solvent in any order. This operation can be carried out at room temperature or the reflux temperature of the solvent or lower fatty acid, but is preferably carried out at about 50-110°C. When using any of these methods, DL−
The poorly soluble diastereomers that originally exist among HPG and optically active PES are fractionally crystallized from water or lower fatty acids. Epimerization may be carried out, or the reaction may be carried out in a heterogeneous system while the poorly soluble diastereomer is crystallized. Furthermore, the reaction temperature may be lowered as appropriate during the epimerization reaction to collect poorly soluble diastereomers; in either case, the reaction proceeds easily. Furthermore, if desired, epimerization of easily soluble diastereomers may be carried out at a low concentration, followed by appropriate cooling to crystallize poorly soluble salts.

Examples of lower fatty acids that can be used for the above purpose include fatty acids having 1 to 5 carbon atoms such as formic acid, acetic acid, propionic acid, butyric acid, and valeric acid, and glacial acetic acid is particularly preferred because it is easily available. The concentration of lower fatty acids is not particularly limited, but is usually about
It is preferable to use it at a concentration of 50 W/V% or more, especially about 80 W/V% or more, and the above-mentioned DL-HPG
It is appropriate to use about 2 to 50 times the amount of the optically active PES salt. On the other hand, examples of aldehydes include formaldehyde, acetaldehyde, propionaldehyde, n-butyraldehyde, i-butyraldehyde, saturated or unsaturated aliphatic aldehydes such as acrolein, or benzaldehyde, salicylaldehyde, hydroxybenzaldehyde, nitrobenzaldehyde, anisaldehyde. , aromatic aldehydes such as furfural can be used, especially salicylaldehyde,
It is preferable to use n-butyraldehyde or the like.
These aldehydes are DL-HPG and optically active PES.
It is appropriate to use a molar ratio of 0.01 to 0.2 to the salt. When carrying out using a solvent, the solvent is inert to the above-mentioned raw material DL-HPG, lower fatty acids and aldehydes, and is difficult to use for D-HPG・(+)-PES or L-HPG・(−)-PES. Any solvent can be used as long as it can be precipitated as a soluble salt, and examples of such solvents include water, benzene, and toluene.

Furthermore, in the present invention, whether the epimerization reaction is carried out in the presence of water or in the presence of fatty acids or aldehydes, if free amino acids are allowed to coexist with the raw material DL-HPG, epimerization can be achieved. oxidation reaction can be promoted.
Any amino acid can be used, and it may be an optically active form, a racemate, or even a mixture of amino acids. However, it is generally preferable to use HPG because it prevents foreign amino acids from being mixed into the hardly soluble salt that is precipitated. Free amino acids are approximately 0.01 to PES
It is appropriate to use it in a molar ratio of ~0.2.

D-HPG・(+)-PES or L-HPG・(-)- which is a poorly soluble diastereomer that crystallizes after the completion of the reaction
PES can be collected as highly pure crystals by conventional methods such as filtration and centrifugation. Further, if necessary, the obtained crystals can be subjected to treatments such as washing and recrystallization. The poorly soluble diastereomer thus obtained, namely D-HPG.(+)-PES or L-HPG.(-)-PES, is further subjected to a conventional deacidification treatment such as alkali treatment or ion exchange resin treatment. Free D-HPG or L-HPG can thereby be obtained. For example, when an aqueous solution of the above salt is adjusted to the isoelectric point of HPG with an alkali, it will separate into D-HPG and (+)-PES or L-HPG and (-)-PES, and only D- or L-HPG will form crystals. Precipitate. Moreover, the (+)- or (-)-PES recovered by deacidification treatment can be used repeatedly for the purpose of the present invention.

As mentioned above, in the conventional chemical separation, DL−HPG100
However, according to the present invention, DL-HPG can be obtained from (-)-PES.
Alternatively, DL-HPG can be obtained by a simple procedure of reacting with (+)-PES and crystallizing the poorly soluble diastereomer salt under epimerization conditions of the easily soluble diastereomer of the formed salt. Substantially all of the desired optically active HPG can be converted. Therefore, the present invention is similar to the conventional
This method is advantageous as an industrial production method for optically active PHG, as there is no need to introduce DL-HPG into other derivatives, and there is no need to racemize unnecessary optically active substances after the optical resolution step as in conventional methods. It is a method.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 (1) DL-HPG hydrochloride 10.0g was reacted with (+)-PES ammonium salt 9.98g in 10ml water.
Two diastereomers of -HPG/(+)-PES were formed, and 0.82 g of DL-HPG was added thereto and heated in an autoclave at 140°C for 12 hours. After the reaction was completed, 1.82 g of a 50% aqueous solution of (+)-PES and 10 ml of water were added and stirred at room temperature for 1 hour.

By filtering and drying the precipitated crystals, D-
17.73 g of HPG.(+)-PES was obtained.

[α] ²⁵ _D -76.5° (C=1, methanol) Optical purity 97.3% (2) Add 44 ml of methanol to 14.5 g of D-HPG・(+)-PES obtained in (1) and add water while stirring. Add sodium oxide aqueous solution to adjust the pH to 6. D- by stirring at room temperature for 2 hours and filtering.
Obtained 6.5 g of HPG.

[α] ²⁵ _D -158.0゜(C=1,N-HCl) Optical purity 99.8% Example 2 11.0 g of DL-HPG, 12.2 g of (-)-PES ammonium salt, 5.1 ml of concentrated hydrochloric acid and 10 ml of water were added in an auto Heated in a crepe at 120°C for 23 hours. Then, 2.2 g of a 50% aqueous solution of (-)-PES and water were added to the reaction mixture.
10 ml was added and stirred at room temperature for 1 hour. By filtering and drying the precipitated crystals, L-HPG・(-)-PES20.0
I got g.

[α] ²⁵ _D +74.9° (C=1, methanol) Optical purity 95.6% Example 3 Add 30 ml of methanol to 10 g of D-HPG・(+)-PES obtained in Example 1 and suspend at about 50°C. The pH was adjusted to 6 with aqueous ammonia, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration and 4.51 g of D-HPG [[α]] ²⁵ _D −
157.9° (C=1, N-HCl)], the mother liquor was concentrated to dryness and dried to obtain 5.97 g of (+)-PES ammonium salt. Add 0.8 ml of concentrated sulfuric acid, 0.3 ml of salicylaldehyde and 70 ml of glacial acetic acid to 5.97 g of this (+)-PES ammonium salt, and add DL-
4.74 g of HPG was gradually added, stirred at the same temperature for 3.5 hours, and 0.3 ml of salicylaldehyde was added. After further stirring at the same temperature for 3.5 hours, the mixture was concentrated under reduced pressure to remove acetic acid. Add 10 ml of water to the residue, stir at room temperature for 1 hour, filter the precipitated crystals, wash and dry to obtain 7.62 g of D-HPG.(+)-PES.

[α] ²⁵ _D -75.1° (C=1, methanol) Optical purity 95.7% Example 4 50% aqueous solution of DL-HPG16.72g and (+)-PES
Add 300 ml of water to 37.24 g of the mixture, stir at 40-50°C for 3 hours, and further stir at room temperature for 2 hours. Precipitated D-HPG・(+)-PES 16.74 g [[α] ²⁵ _D −74.
Five
゜(C=1, methanol) optical purity 95.0%] was collected by filtration.

By concentrating the mother liquor to dryness and drying the residue, L
Obtain -HPG・(+)-PES. Next, add 60ml of glacial acetic acid and 0.55ml of salicylaldehyde.
The mixture was stirred at 100°C for 6 hours. After cooling to room temperature, the precipitated crystals are collected by filtration and dried to obtain D-HPG.
15.9 g of (+)-PES was obtained.

[α] ²⁵ _D -74.2° (C = 1, methanol) Optical purity 94.7% Example 5 (1) D-HPG obtained in the same manner as Example 1 (1)
Add 15 ml of water to 15 g of (+)-PES and adjust the pH to 6 with aqueous ammonia while suspending at approximately 60°C. After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration and dried to obtain 6.46 g of D-HPG.

[α] ²⁵ _D -158.2° (C=1, N-HCl) (2) The mother liquor was concentrated to dryness and the residue was dried to obtain 9 g of (+)-PES ammonium salt.
Next, 4 ml of concentrated hydrochloric acid, 0.6 g of n-butyraldehyde and 100 ml of propionic acid were added to this, and while heating, 7 g of DL-HPG was gradually added and the mixture was heated at 100°C for 5 minutes.
Stir for an hour and add 0.6 g of n-butyraldehyde.
and stirred at the same temperature for 5 hours. The reaction solution was concentrated under reduced pressure to remove propionic acid, and the residue was dissolved in water.
After adding 15 ml of D-
Obtain 11.5 g of HPG.(+)-PES.

[α] ²⁵ _D -74.8° (C=1, methanol) Optical purity 95.4% Reference example (1) According to the method described in the literature [J.Chem.Soc., 1159 (1927)], (±)-α- phenethyl alcohol
500 g was brominated by a conventional method, and the obtained (±)-α-phenethyl bromide was sulfonated. Add 376 g of D-HPG, 620 ml of concentrated hydrochloric acid, and 4 ml of water to the resulting reaction mixture, dissolve by heating, and then heat to 20°C.
Stir for 2 hours. Pure D- is obtained by filtering the precipitated crystals, washing with water, drying and recrystallizing.
Obtain 290 g of HPG.(+)-PES.

[α] ²⁵ _D -78.9° (C = 1, methanol) (2) Suspend the D-HPG・(+)-PES obtained in (1) in methanol, and adjust the pH to 6 by adding an aqueous sodium hydroxide solution. Stir accordingly. D- to precipitate
HPG is filtered off, and the mother liquor is concentrated to remove methanol. Then, by adding water, treating with IR-120 (H ⁺ ) ion exchange resin, and concentrating the effluent, 10% of (+)-α-phenylethanesulfonic acid was obtained.
Obtain a % solution.

[α] ²⁵ _D +6.2° (C = 1, water) (3) In (1), the same amount of L-HPG is used instead of D-HPG, but pure L-HPG·(-)-PES is obtained.

[α] ²⁵ _D +78.9° (C=1, methanol) (4) By treating L-HPG・(-)-PES obtained in (3) in the same manner as in (2), (-)- Obtain a 10% aqueous solution of α-phenylethanesulfonic acid [α] ²⁵ _D -6.2° (C=1, water)

Claims (1)

[Scope of Claims] 1. A poorly soluble diastereomer of two diastereomers of DL-P-hydroxyphenylglycine/optically active α-phenylethanesulfonate which is epimerized and crystallized. Optically active P- characterized by collecting diastereomers
Method for producing hydroxyphenylglycine/optically active α-phenylethanesulfonate. 2. Perform fractional crystallization of two diastereomers of DL-P-hydroxyphenylglycine optically active α-phenylethanesulfonate under epimerization conditions of the easily soluble diastereomer of the salt, and crystallize. 2. The method according to claim 1, wherein a poorly soluble diastereomer of the salt is collected. 3 After separately crystallizing the poorly soluble diastereomer of the two diastereomers of DL-P-hydroxyphenylglycine/optically active α-phenylethanesulfonate, the dissolved easily soluble diastereomer was epimerized. 2. The method according to claim 1, wherein the poorly soluble diastereomer is collected. 4 Claim 1 in which the epimerization reaction is carried out by heating in the presence of water or in the coexistence of a lower fatty acid and an aliphatic or aromatic aldehyde.
2. The method described in Section 2, Section 2, or Section 3. 5. Claims 1, 2, 3, or 4 in which free amino acids coexist during epimerization.
The method described in section. 6 Perform fractional crystallization and epimerization of two diastereomers of DL-P-hydroxyphenylglycine/(+)-α-phenylethanesulfonate in the presence of water and under heating conditions to crystallize. A method according to claim 1, 2, 3, 4, or 5 for collecting DP-hydroxyphenylglycine (+)-α-phenylethanesulfonate. .