JPH08183779A - Production of optically active piperazine derivative and intermediate for production - Google Patents

Abstract

PURPOSE: To obtain the subject compound useful as a synthetic intermediate for a therapeutic agent for AIDS by using a recoverable and recyclable reagent for optical resolution in high optical resolution efficiency and by decomposing a diastereomer salt prepared by reacting a specific (RS)-piperazine derivative with a prescribed reagent for optical resolution. CONSTITUTION: (A) An (RS)-piperazine-2-carboxylic acid-N-t-butylamide of formula I is reacted with (B) a reagent for optical resolution such as an optical revolving compound of formula II [Ar is phenyl or naphthyl which may be replaced with one to three 1-6C alkyls, halogens, nitros or alkoxyls; n is 0 or 1], e.g. in a molar ratio of the component A:B of 1:0.1 to 2.0, especially 1:0.5 to 1.0 and (C) a solvent such as water, methanol or ethanol to give a diastereomer salt such as a compound of formula III (* is position of asymmetric carbon), which is selectively precipitated and separated from the component C and decomposed to give the objective compound, an optically active piperazine-2-carboxylic acid-N-t-butylamide.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an optically active piperazine derivative, particularly piperazine-2-carboxylic acid-Nt-
It relates to a method for producing butyramide. The invention also relates to the diastereomeric salts of the novel compounds obtained as intermediates in the process of their preparation.

[0002]

2. Description of the Related Art Merck has announced a group of compounds as HIV protease inhibitors which are therapeutic agents for AIDS [JP-A-5-279337], among which L-73.
The compound named 5,524 is considered to be the most effective.
This material has the structure of Formula VI below. [C & EN
May 16, 1994, p6]

[0003]

[Chemical 10]

Regarding the synthesis of L-735 and 524,
J. P. Based on the invention of Vacca et al.
-279337, D.I. There is also a research report by Askin et al. [Tetrahedron Lett. 35
(5) 673-6 (1994)]. In any case, as an intermediate of the synthesis, an optically active form of piperazine-2-carboxylic acid-Nt-butyramide represented by the following formula I, or NH represented by the formula VII is protected with a t-butoxycarbonyl group. However, an optically active substance is required.

[0005]

[Chemical 11]

[0006]

[Chemical 12]

Regarding the optical resolution of Compound I, Askin
Et al. Use (S) -camphorsulfonic acid in the above literature, but the details are not shown. On the other hand, regarding piperazine-2-carboxylic acid, which is a precursor of Compound I, it has been reported that the (2S) form can be obtained by optical resolution using (S) -camphorsulfonic acid at a molar ratio of 2 [Felder et al. Helv. Chim. Acta,
43 888-896 (1960)]. Furthermore, it has been announced that Compound I can be optically resolved using L-pyroglutamic acid as a resolving agent. In this case, L-pyroglutamic acid obtained by ring closure of easily available L-glutamic acid is R of compound I.
Forming a sparingly soluble diastereomeric salt with the body and forming the desired S
-The body is recovered from the mother liquor.

Since all of these known optical resolving agents are extremely soluble in water, it is difficult to recover them for reuse after using them for resolution. In order to inexpensively produce the L-735,524, the compound of the formula I (or VI) which is a constituent component (the part surrounded by a line) of the compound of the formula VI.
It is indispensable to provide the compound (I) at a low cost, and for that purpose, it is desired to efficiently carry out the optical resolution of the compound I and select an optical resolution agent which can be recovered and reused.

[0009]

The object of the present invention is to meet the above-mentioned needs and to improve the optical resolution technique of piperazine derivatives of the formula I, more specifically to optically active piperazine-2-carboxylic acid-N- An object of the present invention is to provide an improved method for producing t-butyramide.

The diastereomeric salts formed in the above-mentioned optical resolution process are novel compounds, and their provision is also included in the object of the present invention.

[0011]

The method for producing an optically active piperazine derivative of the present invention is represented by the formula (RS)-
Piperazine-2-carboxylic acid-Nt-butyramide (hereinafter abbreviated as "2-PBC");

[0012]

[Chemical 13]

An optically active agent which is an optically active N-acylated amino acid represented by the general formula II or III:

[0014]

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[In the formula II, Ar represents a phenyl group or a naphthyl group which may be substituted by _{1 to} 3 C _{1 to} C ₆ alkyl groups, halogen atoms, nitro groups or alkoxy groups, and n = 0. Or 1. ]

[0016]

[Chemical 15]

[In the formula III, Alk represents a C ₁ -C ₆ alkyl group, and n = 0 or 1. ] In a solvent to form a diastereomeric salt of general formula IV or V,

[0018]

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[0019]

[Chemical 17]

One diastereomer salt is selectively precipitated from a solvent and separated, and the separated diastereomer salt is decomposed to give an optically active piperazine-2-carboxylic acid-N-
Obtaining t-butyramide.

Of the optical resolving agents represented by the above general formulas II and III, particularly important ones are the following Np-tosyl-L-phenylalanine (formula IIa, hereinafter referred to as “N -Ts-L-Phe ") and Np-tosyl-D-phenylglycine (formula
IIb, hereinafter abbreviated as "N-Ts-D-PG").

[0022]

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[0023]

[Chemical 19]

The optical resolving agents used in the present invention are mostly novel compounds although some compounds are known. These compounds can be synthesized according to a conventional method by reacting the corresponding amino acid with a halide or an anhydride of sulfonic acid. Particularly, sulfonic acid chloride is easily available and generally gives an amide in a high yield. Amino acid is dissolved as an alkali metal salt in a solvent, and then,
The synthesis by the so-called Schotten-Baumann method, in which the acid chloride is added while neutralizing the hydrochloric acid produced in the reaction, is advantageous.

The compound of the general formula II is generally a solid having good crystallinity and often has relatively low solubility in water. Therefore, by acidifying the alkaline aqueous solution with a mineral acid, the free acid can be easily recovered in high yield.

The optical resolving agent II synthesized by the above method has sufficient chemical purity and optical purity as it is, but if necessary, lower alcohols, hydrous lower alcohols, or aromatic hydrocarbons such as benzene and toluene. , And aromatic hydrocarbons and a mixed solvent of aliphatic hydrocarbons such as hexane can be recrystallized and purified. Further, not only the chemical purity but also the optical purity is improved by an acid precipitation operation in which the carboxylic acid is dissolved in an alkaline aqueous solution and made acidic with a mineral acid such as hydrochloric acid or sulfuric acid.

As the reaction medium, various solvents can be used, such as water, methanol, ethanol, isopropanol,
N-butanol, benzene, toluene, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dioxane, dimethylformamide, dimethyl sulfoxide, diethyl ether, diisopropyl ether, and the like, and mixtures thereof can be used. Particularly, a lower alcohol such as methanol and a mixed solvent of alcohols are preferable.

Further, the solubility of the diastereomeric salt is changed by adding water to the lower alcohol, and the optical purity of the salt produced is improved or the amount of the solvent is increased by using a mixed solvent containing an appropriate amount of water. Can be reduced. In the case of methanol, by adding 10 to 30% of water, the required amount of solvent can be reduced to about 1/2 as compared with the case of using methanol alone, resulting in a significant improvement in productivity.

The optical resolving agent is the 2-PB to be resolved.
It is used in a molar ratio range of 0.1 to 2.0 with respect to C.
The preferred range is 0.5 to 1.0. 2-PB
C is a diacid base and the resolving agent N-acylated amino acid is a monobasic acid, but as a diastereomeric salt it is 1: 1.
It is not worthwhile to use a molar ratio of more than 1.0, since the salt of ## STR1 ## will precipitate out. Although the yield of the diastereomeric salt decreases slightly as the molar ratio falls below 1.0, there is no big difference, and even at a molar ratio of 0.5, precipitation of a sufficient amount of salt is observed.

Optical resolution of piperazine-2-carboxylic acid with camphorsulfonic acid forms a diastereomeric salt in which two molecules of the optical resolving agent are bound to the piperazine compound. In the method of the present invention, 2-P which is a diacid group is used.
One molecule of BC and one molecule of N-acylated amino acid form a diastereomeric salt and optical resolution is achieved. This is an unexpected finding, and the fact that highly efficient optical resolution can be carried out using a relatively small amount of optical resolution agent is industrially very important.

To form a diastereomeric salt IV or V from an amide I and an optical resolving agent II or III, I and II
Alternatively, III is added to the solvent and heated to a temperature not higher than the boiling point of the solvent to dissolve it, and then cooled to crystallize the diastereomeric salt IV or V. At this time, it is preferable to add a seed crystal of a desired salt in order to precipitate a salt having high optical purity. In this system, generally, a salt with high optical purity is easily crystallized, but an appropriate amount of solvent is used, and the temperature is gradually lowered from the dissolved state to avoid rapid crystallization, and a well-grown salt crystal is precipitated. Is desirable. Solid-liquid separation is performed using an ordinary filter or centrifuge. High-purity diastereomeric salt crystals are obtained by washing with a suitable solvent.

The novel compound provided by the present invention is a diastereomeric salt represented by the following general formula IV. The crystals of this salt may incorporate water or solvent molecules to stabilize the crystal structure.

[0033]

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After the selective precipitation of the sparingly soluble diastereomeric salt in the above-mentioned production method, the salt of the enantiomer of 2-PBC (easily soluble) is dissolved in the mother liquor. 2-PB from now on
C can be recovered, racemized by heating with a base, and subjected to optical resolution again. Since racemization proceeds without particular difficulty, this may be performed according to a known method.

The sparingly soluble diastereomeric salt obtained by selective precipitation can be easily decomposed by the action of acid or alkali to obtain an optically active form of 2-PBC. Usually, an acid is added to the diastereomeric salt to precipitate the N-acylated amino acid, which is then filtered off, or the N-acylated amino acid is extracted with a suitable organic solvent to separate it from the acidic solution of 2-PBC. To do. However, since the desired optically active 2-PBC is often used in a form in which the 4-position imino group is protected with t-butoxycarbonyl group as described above, a diastereomer salt is reacted with a protecting reagent, It is advantageous to separate 2-PBC as a 4-t-butoxycarbonyl derivative from the optical resolving agent.
Specifically, di-t-butyl dicarbonate is allowed to act on the diastereomeric salt in the presence of triethylamine, and the produced 4-t-butoxycarbonylpiperazine-2-carboxylic acid-Nt-butyramide is used as a solvent. Extract and separate from salt of optical resolving agent. When the 4-t-butoxycarbonyl derivative is treated with an acid, the t-butoxycarbonyl group is easily eliminated, and the optically active piperazine-2-carboxylic acid-N-
The t-butylamide regenerates.

The optical resolving agent can be recovered in a high yield by acidifying an aqueous solution of an alkali or amine salt with a strong acid and filtering the precipitated crystals.

When various substituents are introduced into the Ar group of the optical resolving agent II, a result different from that of the unsubstituted phenyl group is obtained. Introducing an alkyl group or a halogen atom at the p- or o-position of the phenyl group improves the yield and optical purity of salt IV, especially o- and p-methyl, p-
II with t-butyl, p-chloro and p-bromo substituted phenyl groups gives a salt with an optical purity of 97% or more in a yield of 95% or more. When the number of methyl substituents is increased, the performance is slightly deteriorated, and particularly in the case of the 2,4,6-tri-substituted product, the precipitation of salt crystals tends to be delayed. In the case of a sterically crowded 2,4,6-triisopropylphenyl group, L
-Despite being a derivative of phenylalanine
(R) -I and a sparingly soluble salt are prepared and crystallized.

Even if a 1- or 2-naphthyl group is used instead of the phenyl group, intermediate resolution results are obtained. A compound substituted with a methoxy group or a nitro group having a strong polarity also optically resolves I, but its performance is slightly inferior to that of an alkyl-substituted compound. The monomethyl-substituted product, particularly the easily available p-methyl-substituted product, gives the best results in terms of yield and optical purity.

The aromatic amino acid used as the raw material of the optical resolving agent II is phenylglycine when n = 0 and phenylalanine when n = 1. Phenylglycine is a D-form (R-form) as an intermediate of the antibiotic ampicillin.
However, phenylalanine is industrially produced in large quantities in the L-form (S-form) as a raw material for the synthetic sweetener aspartame, and both are easily and inexpensively available. Compound II with S configuration synthesized from L-phenylalanine (n = 1)
Forms a sparingly soluble salt with the S form of piperazine derivative I (except for 2,4,6-triisopropyl derivative)
On the other hand, R-configuration II (n = 0), which is a derivative of D-phenylglycine, crystallizes by forming a sparingly soluble salt with the R-form of I. This makes it possible to obtain both the R-form and the S-form of the piperazine derivative I.

[0040]

【Example】

[Resolving Agent Production Example 1] N-p-tosyl-L-phenylalanine (N-pTs-
Preparation of L-Phe) 4.95 g (30 mmol) of L-phenylalanine in water 15
ml and a liquid dispersed in 36 ml of a 2N-sodium hydroxide aqueous solution were cooled in an ice-water bath, and while vigorously stirring, a mixed liquid of 6.86 g (36 mmol) of p-toluenesulfonyl chloride and 12 ml of tetrahydrofuran was added dropwise.

After completion of dropping, the mixture was stirred for 10 minutes under cooling with an ice-water bath, and then for 1 hour at room temperature. Then 2N hydrochloric acid 2
1.5 ml was added, and N-pTs was added with 100 ml chloroform.
-L-Phe was extracted. The chloroform phase was washed with water, dried and the solvent was distilled off to obtain 8.32 g of crude crystals of N-pTs-L-Phe. The yield based on L-phenylalanine as a raw material was 86.9%. This N-pT
N-pTs-L-P was obtained by recrystallizing the s-L-Phe crude crystal once from a mixed solvent of isopropanol-water.
5.78 g of he crystals were obtained. The total yield based on the raw material L-phenylalanine was 60.4%. Melting point 160.0-161.5 [deg.] C.

[Preparation Example 2 of resolving agent] Production of N-p-chlorobenzenesulfonyl-L-phenylalanine (N-pClBs-L-Phe) A mixture of 1.65 g (10 mmol) of L-phenylalanine and 5 ml of 2N sodium hydroxide aqueous solution was prepared. While vigorously stirring while cooling with an ice-water bath, a mixed solution of 2.32 g (11 mmol) of p-chlorobenzenesulfonyl chloride and 3 ml of tetrahydrofuran, and 6 ml of 2N aqueous sodium hydroxide solution were alternately divided into 3 times. Dropped. After completion of dropping, the mixture was stirred for 5 minutes under cooling with an ice-water bath, and subsequently for 1 hour at room temperature. Then, 2 ml of 6N hydrochloric acid was added, and N-pClBs-L-Phe was extracted with 80 ml of methyl isobutyl ketone. The methyl isobutyl ketone phase was dried and the solvent was evaporated to give crude N-pClBs-L-Phe as an oil. This N-pClBs-L-Phe
By adding benzene to the crude product for crystallization, N
2.05 g of -pClBs-L-Phe crystal was obtained.
The total yield based on the raw material L-phenylalanine was 60.
4%. Melting point 132.0-134.0 [deg.] C.

The above operation was carried out by N-Ars-L-Phe
The aryl group Ar forming the compound (wherein the amino acid is L-phenylalanine in compound II) was repeated variously, and all the crystallized oils were recrystallized once. The yields and melting points of those products are shown in Table 1.

Table 1 No. N-Ars-L-Phe Single recrystallization Yield after Ar group in melting point (%) (° C) 1 Phenyl 83.8 121.0 to 123.0 2 2-Methylphenyl 34.8 98.0 to 102.0 3 4-Methylphenyl 60.4 160.0 to 161.5 4 4-ethylphenyl 88.3 130.0 to 132.0 5 4-t-butylphenyl 66.8 111.0 to 113.0 6 2,5-dimethylphenyl 68.5 125.0 to 128.0 7 2,4,6-trimethylphenyl 79.0 71.0 to 81.0 8 2,4, 6-triisopropylphenyl 32.5 86.0-90.0 9 4-chlorophenyl 60.4 132.0-134.0 10 4-bromophenyl 43.8 139.0-141.0 11 4-methoxyphenyl 84.2 141.0-143.0 12 2-nitrophenyl 78.3 136.5-138.5 13 3-nitrophenyl 36.6 160.0 to 161.5 14 4-nitrophenyl 49.1 163.0 to 165.0 15 1-naphthyl 54.6 136.0 to 138.0 16 2-naphthyl 78.6 147.0 to 149.0 In Table 1, no. 9 shows the data of the above example again.

[Resolving Agent Production Example 3] N-p-tosyl-D-phenylglycine (N-Ts-D)
-PG) Preparation of D-phenylglycine 4.53 g (30 mmol), water 15
While vigorously stirring the mixed solution of 2 ml of 2N sodium hydroxide aqueous solution with 36 ml of 2N sodium hydroxide solution, a mixed solution of 6.86 g (36 mmol) of p-tosyl chloride and 7 ml of tetrahydrofuran was added dropwise. After completion of dropping, cool down in an ice water bath for 10
The mixture was stirred for 1 minute and then at room temperature for 1 hour. Then, 21.5 ml of 2N hydrochloric acid was poured, and the precipitated N-Ts-D-PG crude crystal was collected by filtration. When this crude crystal was washed with water and dried,
The yield was 7.10 g, which was 77.6% with respect to the raw material D-phenylglycine. This N-Ts-D
By recrystallizing the -PG crude crystal once with a mixed solvent of isopropanol-water, N-Ts-D-PG crystal was obtained in 5.
85 g were obtained. The total yield based on the raw material D-phenylglycine was 63.9%. Melting point 172.0-1
76.0 ° C.

[Resolving Agent Production Example 4] N-mesityl-L-phenylalanine (N-Ms-L-
Preparation of Phe) L-Phenylalanine (1.65 g, 10 mmol) dissolved in a 2N aqueous sodium hydroxide solution was vigorously stirred under cooling with an ice-water bath, while 1.26 g (11 mmol) of methanesulfonyl chloride. ) And tetrahydrofuran 3 ml and 2N aqueous sodium hydroxide solution 6 ml
Was alternately added in 3 divided portions. After completion of dropping, the mixture was stirred for 5 minutes under cooling with an ice-water bath, and subsequently for 1 hour at room temperature. Then add 2 ml of 6N hydrochloric acid and add 30 ml of chloroform.
N-Ms-L-Phe was extracted with ml. The chloroform phase was washed with water, dried, and the solvent was distilled off to give N-Ms-L-
The crude Phe product was obtained as an oil. This crude product was purified by silica gel column chromatography (eluent: chloroform, ethyl acetate) to give N-
1.00 g of a purified Ms-L-Phe product was obtained as an oil. The total yield based on L-phenylalanine as a raw material was 41.0%.

Example 1 (RS) -2-PBC 1.
85 g (10 mmol) and 3. N-Ts-L-Phe.
19 g (10 mmol) were dissolved in 28 ml of methanol with heating. Crystals of (S) -2-PBC.N-Ts-L-Phe salt prepared in advance in this solution 1
mg was added as a seed crystal and left overnight at room temperature. The precipitated crystals were filtered off to obtain a diastereomeric salt (S)-
2-PBC.N-Ts-L-Phe (crude salt) 2.49
g was obtained.

The crude diastereomer salt was recrystallized from methanol to give (S) -2-PBC.N-Ts-LP
2.39 g of he purified salt was obtained. Melting point: 171.0 to 173.0 ° C. Specific optical rotation: [α] _D ²³ + 10.9 ° (C 0.974
MeOH) yield: (S) -2 in raw material (RS) -2-PBC
Yield to PBC (think half) was 94.8% at this stage.

The above (S) -2-PBC.N-Ts-L
-Phe purified salt was further purified by recrystallization from methanol, but neither melting point nor optical rotation was observed. Therefore, it can be seen that the diastereomeric salt precipitated from the reaction solvent is sufficiently high in purity by one recrystallization.

(S) -2-PBC.N-Ts-L-Ph
e The IR spectrum of the purified salt is shown in FIG.

Then, the above (S) -2-PBC.N-
0.50 g of the purified Ts-L-Phe salt was dissolved in 3 ml of methanol together with 0.18 g of triethylamine, and 0.22 g of di-t-butyl dicarbonate 0.20 g of methanol was dissolved therein.
A solution in 5 ml was added and the reaction was allowed to stir at room temperature for 1 hour.

The solvent was distilled off from the reaction solution, 1 ml of water and 0.2 ml of 6N-NaOH aqueous solution were added to the resulting residue, and 6 ml of toluene was used to (S)-(+)-4-t-butoxy. Carbonylpiperazine-2-carboxylic acid-Nt-butyramide (this is abbreviated as (S) -Boc-2-PBC) was extracted. When the toluene phase was dried and the solvent was distilled off, (S) -Boc-2-PBC was obtained as an oily substance, which was crystallized when treated with 1 ml of n-hexane. Yield 0.26g. Specific rotation: [α] _D ²¹ + 26.5 ° (C 1.008)
MeOH) Optical purity: 100% [by HPLC method using "Chiralpak AS" (Daicel). ] Melting point: 97.5 to 100 ° C. ¹ H-NMR (solvent CDCl ₃ , TMS standard) δ 1.35 ppm (s, 9H) 1.46 ppm (s, 9H) 1.84 ppm (br, 1H) 2.7 -3.0 ppm (m, 3H) 3.18-3.21 ppm (q, 2H) 4.06-4.08 ppm (d, 2H) 6.50 ppm (br, 1H) Yield: Yield from purified salt 90%, used (RS)-
The yield based on (S) -2-PBC in 2-PBC is 85.
%.

Incidentally, 0.31 g of N-Ts-L-Phe was recovered by acidifying the aqueous phase after extraction of (S) -Boc-2-PBC by adding 0.3 ml of 6N-HCl. Recovery rate 98%.

[Embodiment 2] 1. of (RS) -2-PBC.
85 g (10 mmol) and 1. N-Ts-L-Phe.
75 g (5.5 mmol) were dissolved in 19 ml of methanol with heating. This solution was prepared in advance
(S) -2-PBC.N-Ts-L-Phe salt crystals 1 mg
Was inoculated and left overnight at room temperature. The precipitated diastereomeric salt was filtered off to obtain (S) -2-PBC.N-Ts-L
-2.18 g of crude Phe salt was obtained.

This diastereomeric salt was diluted with methanol to 1 part.
After purification twice, (S) -2-PBC.N-Ts-L-Ph
e Purified salt 2.06 g was obtained. Raw material (RS) -2-P
The overall yield for (S) -2-PBC in BC was 81.6% at this stage. Melting point: 170.5-172.5 ° C.

The above (S) -2-PBC.N-Ts-L
-(P) -Phe purified salt (0.50 g) was treated in the same manner as in Example 1 to give (S) -Boc-2-PBC.
24 g was obtained. The yield from the purified salt is 86%, and the total yield based on (S) -2-PBC in the (RS) -2-PBC used is 70%. Melting point: 97.5 to 100 ° C. Specific optical rotation: [α] _D ²³ + 26.8 ° (C 1.014
MeOH) Optical purity: 100% (HPLC).

[Embodiment 3] (RS) -2-PBC 0.
37 g (2 mmol) and 0.61 g of N-Ts-D-PG
(2 mmol) was dissolved under heating in 4.4 ml of a mixed solvent of benzene: ethanol = 10: 1. (R) -2-PBC.N-Ts prepared in advance was added to this solution.
1 mg of crystals of -D-PG salt was inoculated and left at room temperature overnight. The precipitated diastereomeric salt was filtered off to obtain (R)
0.53 g of 2-PBC.N-Ts-D-PG crude salt was obtained. (R) -2- in the raw material (RS) -2-PBC
The overall yield based on PBC was 109% at this stage.

(R) -2-PBC.N-Ts-D-PG crude salt (0.53 g) was treated in the same manner as in Example 1 to give (R) -Boc-2-PBC. 28 g was obtained. Yield from crude salt was 92%, used (RS) -2-
Total yield based on (R) -2-PBC in PBC is 100%
Is. Specific rotation: [α] _D ²³ -15.8 ° (C 1.012
MeOH) Optical purity: 67% (HPLC).

[Example 4] 0.7 of (RS) -2-PBC
4 g (4.0 mmol) and 1. N-Ts-L-Phe.
02 g (3.2 mmol) of 5.1 ml of methanol and 0.9 of water
It melt | dissolved in the mixed liquid of ml under heating. 1 mg of (S) -2-PBC.N-Ts-L-Phe salt crystals prepared in advance was added as a seed crystal, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were filtered off to obtain (S) -2-PBC.N-Ts
0.93 g of -L-Phe salt was obtained. Raw material (RS) -2
The yield based on (S) -2-PBC in -PBC is 92.
2%, optical purity of (S) -2-PBC in salt is 98.0
% Ee (HPLC).

The same experiment as above was repeated, changing the amount of the optical resolving agent used and the water / methanol ratio of the solvent.
The results are shown in Table 2.

Table 2 No. N-Ts-L-Phe Total amount of solvent in solvent (ml) Crude Diaz (S) -PBC / (RS) -2-PBC H ₂ O / (RS) -PBC (g) Tereomer Optical purity (molar ratio) (%) Salt yield (%) (% ee) 1 0.6 15 8.1 77.8 98.7 2 0.6 30 8.1 71.6 98.8 3 0.55 50 8.1 76.6 94.2 4 0.7 0 8.1 96.0 98.8 5 0.7 15 8.1 86.2 96.7 6 0.7 30 8.1 82.6 97.3 7 0.7 50 8.1 89.0 97.4 8 0.8 10 8.1 91.0 98.1 9 0.8 15 8.1 92.2 98.0 10 0.8 16.7 8.1 87.0 96.8 11 0.8 30 8.1 86.0 99.0 In Table 2, the optical purity of (S) -PBC is crude salt. It is the value of the inside. No. 9 is a reprint of the data of the above example.

[Example 5] 0.3 of (RS) -2-PBC
7 g (2.0 mmol) and N-Ts-L-Phe of 0.
38 g (1.2 mmol) was dissolved in 4.0 ml of water with heating,
1 mg of (S) -2-PBC.N-Ts-L-Phe salt was inoculated and left at room temperature overnight. The precipitated crystals were separated by filtration to obtain 0.40 g of (S) -2-PBC.N-Ts-L-Phe salt. The yield of (S) -2-PBC in (RS) -2-PBC of the raw material was 80.0%, and the optical purity of (S) -2-PBC in the salt was 93.6% ee (HP
LC).

[Example 6] 0.74 g of (RS) -PBC
(4.0 mmol) and 0.89 g of N-Ts-L-Phe
(2.8 mmol) was added to 6 ml of 1-butanol, heated and dissolved, and then (S) -PBC prepared in advance.
Inoculation of 1 mg of N-Ts-L-Phe crystals and standing overnight at room temperature gave 0.84 g of (S) -PBC.N-Ts-L-Phe crude salt. The yield based on (S) -PBC in (RS) -PBC of the raw material was 83.8%.
The optical purity of (S) -PBC in this crude salt is 97.7%.
ee (HPLC).

The same experiment as above was repeated, except that the amount of the optical resolving agent, the composition of the solvent and the amount of the solvent used in Examples 5 and 6 were changed. Table 3 shows the results.

Table 3 No. N-Ts-L-Phe Solvent Total amount of solvent (ml) Crude Diaz (S) -PBC / (RS) -2-PBC / (RS) -PBC (g) Tereomer Optical purity ( Molar ratio) Salt yield (%) (% ee) 1 0.7 15% H ₂ O / EtOH 8.1 76.6 96.9 2 0.55 5% H ₂ O / n-PrOH 10.8 76.4 99.4 3 0.7 30% H ₂ O / i-PrOH 8.1 69.4 94.7 4 0.7 1-BuOH 8.1 83.8 97.7 5 0.7 5% H ₂ O / 1-BuOH 8.1 63.8 98.6 6 0.7 10% H ₂ O / i-BuOH 8.1 60.4 92.6 7 0.7 15% H ₂ O / 2-BuOH 8.1 39.0 99.2 8 0.7 5% H ₂ O / 1-PenOH 8.1 90.4 95.4 9 0.7 5% H ₂ O / 1-HexOH 8.1 88.2 95.7 4 shows the data of the above example again. EtOH is ethanol, PrOH is propanol, BuOH is butanol, PenOH is pentanol, and HexOH is hexanol.

Example 7 0.56 g of (RS) -PBC
(3.0 mmol) and 1. of N-pClBs-L-Phe.
02 g (3.0 mmol) was added to 6 ml of methanol, heated and dissolved, and then prepared (S) -PB
Inoculated with 1 mg of crystals of C.N-pClBs-L-Phe,
Let stand overnight at room temperature, then (S) -PBC.N-pClBs-
0.75 g of L-Phe crude salt was obtained. Raw material (RS)
-The yield based on (S) -PBC in PBC is 95.0%.
Met. The optical purity of (S) -PBC in this crude salt was 97.0% ee (HPLC).

Example 8 Optical Resolving Agent N-Ars-L-
The same operation as in Example 7 was performed using various Phe Ar groups, using methanol or ethanol as a solvent, and changing the amount used. The results are shown in Table 4.

Table 4 No. N-Ars-L-Phe solvent Total amount of solvent Ar group in crude dias (RS) -PBC (ml) / tereomer Optical purity (RS) -PBC (g) Salt yield (%) (% ee) 1 Phenyl MeOH 9.0 91.8 78.2 (S-form) 2 2-methylphenyl MeOH 18.0 99.8 97.3 (S-form) 3 4-ethylphenyl MeOH 10.8 97.0 93.2 (S-form) 4 4-t-butylphenyl MeOH 10.8 84.4 98.4 (S-form) 52 5-Dimethylphenyl MeOH 9.0 101.8 84.2 (S isomer) 6 2,4,6-Trimethylphenyl MeOH 10.8 39.0 94.0 (S isomer) 7 2,4,6-Tri-i-EtOH 13.0 67.4 90.4 (R isomer) Propylphenyl 8 4-chlorophenyl MeOH 10.8 95.0 97.0 (S isomer) 9 4-bromophenyl MeOH 21.6 95.8 97.2 (S isomer) 10 4-methoxyphenyl MeOH 19.8 80.4 89.8 (S isomer) 11 2-nitrophenyl MeOH 10.8 69.6 94.6 (S isomer) ) 12 3-Nitrophenyl EtOH 10.8 106.1 46.1 (S-form) 13 4-Nitrophenyl EtOH 10.8 19.8 93.2 (S-form) 14 1-Naphthyl EtOH 10.8 74.0 94.6 (S-form) 15 2- (R, S) -PBC optical purity of at Fuchiru EtOH 16.2 117.0 67.9 (S form) Table 4 is a value in the crude salt production.

[Embodiment 9] 0.56 of (RS) -PBC
g (3.0 mmol) and 0.92 g of N-Ts-D-PG
(3.0 mmol) was added to a mixed solvent of 6 ml of benzene and 0.6 ml of ethanol, heated and dissolved, and then (R) -PBC.N-Ts-D-PG crystal 1 was prepared in advance.
Inoculate mg, leave overnight, (R) -PBC.N-Ts
1.11 g of crude salt of -D-PG was obtained. Raw material (R
The yield based on R-PBC in S) -PBC is 150.8.
%Met. This (R) -PBC ・ N-Ts-DP
By recrystallizing the G crude salt twice with a benzene-ethanol mixed solvent, (R) -PBC.N-Ts-D-PG was obtained.
0.60 g of purified salt was obtained. The yield based on (R) -PBC in (RS) -PBC of the raw material was 82.0%.
The optical purity of (R) -PBC in the purified salt of (R) -PBC.N-Ts-D-PG is 97.7% ee (HPL
C).

[Example 10] 0.7 of (RS) -PBC
4 g (4.0 mmol) and 0.97 of N-Ms-L-Phe
g (4.0 mmol) was added to 7 ml of ethanol, heated and dissolved, and then prepared (S) -PBC.
1 mg of N-Ms-L-Phe crystal was inoculated and left overnight at room temperature to obtain 0.40 g of (S) -PBC.N-Ms-L-Phe crude salt. The yield based on (S) -PBC in (RS) -PBC as a raw material was 46.6%.
The optical purity of (S) -PBC in this crude salt is 98.5%.
ee (HPLC).

[Embodiment 11] (RS) -2-PBC-1
5.0 kg (81.0 gmol) and N-Ts-L-Phe
20.7 kg (64.8 gmol) of 85 wt% methanol 1
It melt | dissolved by heating at 05 liters. While gradually cooling with stirring, when reaching 62 ° C., the seed crystal (S) -2-PBC.N-Ts-L-Phe salt 5 prepared in advance was used.
0 g was added and it took about 5 hours to cool to 20 ° C.
The precipitated crystals were separated by filtration and washed with a small amount of methanol. Obtained (S) -2-PBC.N-Ts-LP
The he salt was dried at 60 ° C. overnight. Yield 18.8kg (3
7.2 gmol). The yield based on the half amount of (RS) -2-PBC used was 92%, and the optical purity of (S) -2-PBC in the salt was 100% ee (HPLC).

The above salt was added to 140 liters of methanol, and 7.7 kg (76.1 gmol) of triethylamine was added. To this, 8.1 kg of di-t-butyl dioxide (3 kg
A solution of 7.2 gmol) dissolved in 15 kg of methanol was added and reacted. After distilling off about 100 liters of methanol, 125 liters of water and 60 kg of toluene were added. The toluene layer was separated, and the remaining aqueous layer was further extracted twice with 60 kg of toluene each. About 18 kg of toluene layer
The mixture was concentrated to 40 ° C., 40 kg of methylcyclohexane was added thereto, and the mixture was heated and dissolved at 50 ° C. and then cooled, and the precipitated crystals were separated by filtration. This was washed with 10 kg of methylcyclohexane, then heated at 60 ° C. under reduced pressure and dried.
The yield of (S) -Boc-2-PBC is 8.5 kg (29.
8 gmol) and the optical purity was 100% ee (HPLC method).

As the solvent used for the extraction of Boc-2-PBC, xylenes, chlorobenzenes, ethyl acetate, n-butanol, isobutanol or the like can be used instead of toluene. In addition to methylcyclohexane, aliphatic and alicyclic hydrocarbons such as hexane and cyclohexane can be used as the solvent added for crystallization.

Introduction (S) -2-PBC ・ N-Ts-L
About 120 liters of mother liquor after filtering off Phe was distilled to remove methanol and concentrated to about 30 liters. To this, 100 liters of water was added, and 11.5 kg of concentrated hydrochloric acid was added to make it strongly acidic. After the precipitated N-Ts-L-Phe was filtered off, the mother liquor was neutralized with caustic soda until it became neutral, and the total liquid volume was concentrated to 35 liters. 8.7 kg of 30% caustic soda was added to make it alkaline, and 60 kg of n-propanol was added to extract 2-PBC. The n-propanol layer was concentrated to 28 liters, 180 g of flake caustic soda was added, and the mixture was heated under reflux for 1 hour. Propanol was distilled off and 8 kg of crude 2-PB
C was recovered. The optical purity measured by HPLC is 2
It was confirmed that the racemization was completed at% ee or less.

Instead of the above n-propanol, n-butanol, isobutanol, etc. can be used as an extraction solvent.

After the salt of (S) -2-PBC was converted to Boc, the aqueous layer after separating from the toluene layer was acidified with hydrochloric acid to recover N-Ts-L-Phe. The total amount of N-Ts-L-Phe recovered from salt and mother liquor was 1
With a weight of 9.2 kg, the recovery rate was 93%. The dry product has a melting point of 160 to 161 ° C. and an optical purity of 100% ee and can be reused as it is.

[0077]

INDUSTRIAL APPLICABILITY According to the present invention, an optically active piperazine derivative, particularly piperazine-2-carboxylic acid-Nt-butyramide, can be produced with high yield and high optical purity. Upon formation of the diastereomeric salt,
The optically active N-acylated amino acid, which is an optical resolving agent, can be used in an equimolar amount or less relative to the piperazine derivative and can be recovered and reused. The remaining optically active substance obtained by separating the desired optically active substance can be racemized and used again as a raw material. Combined with the fact that the purification of diastereomeric salts by recrystallization is extremely simple and that a cheap and easy-to-use solvent such as methanol can be used as a solvent, the production cost of the optically active substance is When compared with the optical resolution of, it will be significantly lower. Thereby, the HIV protease inhibitor L-735,524
Low-cost manufacturing of.

[Brief description of drawings]

FIG. 1 is an IR absorption spectrum of a purified salt of (S) -2-piperazine-2-carboxylic acid-Nt-butylamide.Np-tosyl-L-phenylalanine, which is a diastereomeric salt obtained in Examples. .

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[Procedure amendment]

[Submission date] September 11, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0046

[Correction method] Change

[Correction content]

[Resolving Agent Production Example 4] N-methanesulfonyl-L-phenylalanine (NM
Preparation of s-L-Phe) L-phenylalanine (1.65 g, 10 mmol) dissolved in a 2N aqueous sodium hydroxide solution was stirred vigorously while cooling with an ice-water bath, and methanesulfonyl chloride 1 was added. A mixture of 0.26 g (11 mmol) and 3 ml of tetrahydrofuran and 6 ml of 2N aqueous sodium hydroxide solution.
Was alternately added in 3 divided portions. After completion of dropping, the mixture was stirred for 5 minutes under cooling with an ice-water bath, and subsequently for 1 hour at room temperature. Then add 2 ml of 6N hydrochloric acid and add 30 ml of chloroform.
N-Ms-L-Phe was extracted with ml. The chloroform phase was washed with water, dried, and the solvent was distilled off to give N-Ms-L-
The crude Phe product was obtained as an oil. This crude product was purified by silica gel column chromatography (eluent: chloroform, ethyl acetate) to give N-
1.00 g of a purified Ms-L-Phe product was obtained as an oil. The total yield based on L-phenylalanine as a raw material was 41.0%.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0072

[Correction method] Change

[Correction content]

The above salt was added to 140 liters of methanol, and 7.7 kg (76.1 gmol) of triethylamine was added. To this, 8.1 kg of di-t-butyl dicarbonate (3
A solution of 7.2 gmol) dissolved in 15 kg of methanol was added and reacted. After distilling off about 100 liters of methanol, 125 liters of water and 60 kg of toluene were added. The toluene layer was separated, and the remaining aqueous layer was further extracted twice with 60 kg of toluene each. About 18 kg of toluene layer
The mixture was concentrated to 40 ° C., 40 kg of methylcyclohexane was added thereto, and the mixture was heated and dissolved at 50 ° C. and then cooled, and the precipitated crystals were separated by filtration. This was washed with 10 kg of methylcyclohexane, then heated at 60 ° C. under reduced pressure and dried.
The yield of (S) -Boc-2-PBC is 8.5 kg (29.
8 gmol) and the optical purity was 100% ee (HPLC method).

[Procedure amendment]

[Submission date] January 23, 1996

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction content]

[Document name] Statement

Title: Method for producing optically active piperazine derivative and intermediate for production

[Claims]

Embedded image An optical resolving agent which is an optically active N-acylated amino acid represented by the general formula II or III.

Embedded image [In the formula II, Ar represents a phenyl group or a naphthyl group which may be substituted with ₁ to 3 C _{1 to} C ₆ alkyl groups, halogen atoms, nitro groups or alkoxy groups, and n = 0 or 1 . ]

Embedded image [In the formula III, Alk represents a C _{1 to} C ₆ alkyl group, and n = 0 or 1. ] By reacting in a solvent, the general formula IV
Or forming a diastereomeric salt of V,

[Chemical 4] [In the formula, Ar has the above-mentioned meaning and n is the above-mentioned value. * Represents the position of the asymmetric carbon atom. ]

Embedded image [In the formula, Alk has the above-mentioned meaning, and n is the above-mentioned value. * Represents the position of the asymmetric carbon atom. An optical method comprising selectively precipitating one diastereomeric salt from a solvent to separate the diastereomeric salt, and decomposing the separated diastereomeric salt to obtain optically active piperazine-2-carboxylic acid-Nt-butyramide. A method for producing an active piperazine derivative.

[Chemical 6] [In the formula, Ar has the above-mentioned meaning and n is the above-mentioned value. * Represents the position of the asymmetric carbon atom. ]

[Chemical 7] [In the formula, Alk has the above-mentioned meaning, and n is the above-mentioned value. * Represents the position of the asymmetric carbon atom. ]

Embedded image [In the formula, * represents the position of the asymmetric carbon atom. ]

[Chemical 9] [In the formula, * represents the position of the asymmetric carbon atom. ]

Detailed Description of the Invention

[0001]

The present invention relates to an optically active piperazine derivative, particularly piperazine-2-carboxylic acid-Nt-
It relates to a method for producing butyramide. The invention also relates to the diastereomeric salts of the novel compounds obtained as intermediates in the process of their preparation.

[0002]

2. Description of the Related Art Merck has announced a group of compounds as HIV protease inhibitors which are therapeutic agents for AIDS [JP-A-5-279337], among which L-73.
The compound named 5,524 is considered to be the most effective.
This material has the structure of Formula VI below. [C & EN
May 16, 1994, p6]

[0003]

[Chemical 10]

Regarding the synthesis of L-735 and 524,
J. P. Based on the invention of Vacca et al.
-279337, D.I. There is also a research report by Askin et al. [Tetrahedron Lett. 35
(5) 673-6 (1994)]. In any case, as an intermediate of the synthesis, an optically active form of piperazine-2-carboxylic acid-Nt-butyramide represented by the following formula I, or NH represented by the formula VII is protected with a t-butoxycarbonyl group. However, an optically active substance is required.

[0005]

[Chemical 11]

[0006]

[Chemical 12]

Regarding the optical resolution of Compound I, Askin
Et al. Use (S) -camphorsulfonic acid in the above literature, but the details are not shown. On the other hand, regarding piperazine-2-carboxylic acid, which is a precursor of Compound I, it is reported that the (2S) form can be obtained by optical resolution using (S) -camphorsulfonic acid at a molar ratio of 2 [Felder et al. Helv. Chim. Acta,
43 888-896 (1960)]. Furthermore, it has been announced that Compound I can be optically resolved using L-pyroglutamic acid as a resolving agent. In this case, L-pyroglutamic acid obtained by ring closure of easily available L-glutamic acid is R of compound I.
Forming a sparingly soluble diastereomeric salt with the body and forming the desired S
-The body is recovered from the mother liquor.

Since all of these known optical resolving agents are extremely soluble in water, it is difficult to recover them for reuse after using them for resolution. In order to inexpensively produce the L-735,524, the compound of the formula I (or VI) which is a constituent component (the part surrounded by a line) of the compound of the formula VI.
It is indispensable to provide the compound (I) at a low cost, and for that purpose, it is desired to efficiently carry out the optical resolution of the compound I and select an optical resolution agent which can be recovered and reused.

[0009]

The object of the present invention is to meet the above-mentioned needs and to improve the optical resolution technique of piperazine derivatives of the formula I, more specifically to optically active piperazine-2-carboxylic acid-N- An object of the present invention is to provide an improved method for producing t-butyramide.

The diastereomeric salts formed in the above-mentioned optical resolution process are novel compounds, and their provision is also included in the object of the present invention.

[0011]

The method for producing an optically active piperazine derivative of the present invention is represented by the formula (RS)-
Piperazine-2-carboxylic acid-Nt-butyramide (hereinafter abbreviated as "PBC");

[0012]

[Chemical 13]

An optically active agent which is an optically active N-acylated amino acid represented by the general formula II or III:

[0014]

Embedded image

[In the formula II, Ar represents a phenyl group or a naphthyl group which may be substituted by _{1 to} 3 C _{1 to} C ₆ alkyl groups, halogen atoms, nitro groups or alkoxy groups, and n = 0. Or 1. ]

[0016]

[Chemical 15]

[In the formula III, Alk represents a C ₁ -C ₆ alkyl group, and n = 0 or 1. ] In a solvent to form a diastereomeric salt of general formula IV or V,

[0018]

Embedded image

[0019]

[Chemical 17]

One diastereomer salt is selectively precipitated from a solvent and separated, and the separated diastereomer salt is decomposed to give an optically active piperazine-2-carboxylic acid-N-
Obtaining t-butyramide.

Of the optical resolving agents represented by the above general formulas II and III, particularly important ones are the following N-tosyl-L-phenylalanine (formula IIa, hereinafter referred to as “N-Ts”, which belongs to the group of the general formula II. -L-Phe ")
And N-tosyl-D-phenylglycine (formula IIb, hereinafter abbreviated as "N-Ts-D-PG").

[0022]

Embedded image

[0023]

[Chemical 19]

The optical resolving agents used in the present invention are mostly novel compounds although some compounds are known. These compounds can be synthesized according to a conventional method by reacting the corresponding amino acid with a halide or an anhydride of sulfonic acid. Particularly, sulfonic acid chloride is easily available and generally gives an amide in a high yield. Amino acid is dissolved as an alkali metal salt in a solvent, and then,
The synthesis by the so-called Schotten-Baumann method, in which the acid chloride is added while neutralizing the hydrochloric acid produced in the reaction, is advantageous.

The compound of the general formula II is generally a solid having good crystallinity and often has relatively low solubility in water. Therefore, by acidifying the alkaline aqueous solution with a mineral acid, the free acid can be easily recovered in high yield.

The optical resolving agent II synthesized by the above method has sufficient chemical purity and optical purity as it is, but if necessary, lower alcohols, hydrous lower alcohols, or aromatic hydrocarbons such as benzene and toluene. , And aromatic hydrocarbons and a mixed solvent of aliphatic hydrocarbons such as hexane can be recrystallized and purified. Further, not only the chemical purity but also the optical purity is improved by an acid precipitation operation in which the carboxylic acid is dissolved in an alkaline aqueous solution and made acidic with a mineral acid such as hydrochloric acid or sulfuric acid.

Various solvents can be used as the reaction medium, and water, methanol, ethanol, n-propanol,
Isopropanol, n-butanol, isobutanol,
Benzene, toluene, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dioxane, dimethylformamide, dimethyl sulfoxide, diethyl ether, diisopropyl ether, and the like, and mixtures thereof can be used. Particularly, a lower alcohol such as methanol and a mixed solvent of alcohols are preferable.

Further, the solubility of the diastereomeric salt is changed by adding water to the lower alcohol, and the optical purity of the salt produced is improved or the amount of the solvent is increased by using a mixed solvent containing an appropriate amount of water. Can be reduced. In the case of methanol, by adding 10 to 30% of water, the required amount of solvent can be reduced to about 1/2 as compared with the case of using methanol alone, resulting in a significant improvement in productivity.

The optical resolving agent is used in a molar ratio of 0.1 to 2.0 with respect to the PBC to be resolved.
The preferred range is 0.5 to 1.0. Although PBC is a diacid base and the N-acylated amino acid of the resolving agent is a monobasic acid, a 1: 1 salt is precipitated as a diastereomeric salt, so a molar ratio of more than 1.0 should be used. Is
Well worthless. Although the yield of the diastereomeric salt decreases slightly as the molar ratio falls below 1.0, there is no big difference, and even at a molar ratio of 0.5, precipitation of a sufficient amount of salt is observed.

Optical resolution of piperazine-2-carboxylic acid with camphorsulfonic acid forms a diastereomeric salt in which two molecules of the optical resolving agent are bound to the piperazine compound. In the method of the present invention, PBC which is a diacid group
And one molecule of the N-acylated amino acid form a diastereomeric salt to achieve optical resolution. This is an unexpected finding, and the fact that highly efficient optical resolution can be carried out using a relatively small amount of optical resolution agent is industrially very important.

To form a diastereomeric salt IV or V from an amide I and an optical resolving agent II or III, I and II
Alternatively, III is added to the solvent and heated to a temperature not higher than the boiling point of the solvent to dissolve it, and then cooled to crystallize the diastereomeric salt IV or V. At this time, it is preferable to add a seed crystal of a desired salt in order to precipitate a salt having high optical purity. In this system, generally, a salt with high optical purity is easily crystallized, but an appropriate amount of solvent is used, and the temperature is gradually lowered from the dissolved state to avoid rapid crystallization, and a well-grown salt crystal is precipitated. Is desirable. Solid-liquid separation is performed using an ordinary filter or centrifuge. High-purity diastereomeric salt crystals are obtained by washing with a suitable solvent.

The novel compound provided by the present invention is a diastereomeric salt represented by the following general formula IV. The crystals of this salt may incorporate water or solvent molecules to stabilize the crystal structure.

[0033]

Embedded image

After the selective precipitation of the sparingly soluble diastereomeric salt in the above-mentioned production method, the enantiomer salt of PBC (easily soluble) is dissolved in the mother liquor. From this, PBC can be recovered, heated and racemized with a base, and again subjected to optical resolution. Since racemization proceeds without particular difficulty, this may be performed according to a known method.

The sparingly soluble diastereomeric salt obtained by selective precipitation can be easily decomposed by the action of acid or alkali to obtain an optically active form of PBC. Usually, an acid is added to the diastereomeric salt to precipitate the N-acylated amino acid, which is filtered off, or
Alternatively, the N-acylated amino acid is extracted with a suitable organic solvent to separate it from the acidic solution of PBC. However, the desired optically active PBC has the t-imino group at t-position as described above.
Since it is often used in a form protected with a butoxycarbonyl group, a diastereomer salt is reacted with a protecting reagent,
It is advantageous to separate PBC as a 4-t-butoxycarbonyl derivative from the optical resolving agent. Specifically, di-t-butyl dicarbonate is allowed to act on the diastereomeric salt in the presence of triethylamine, and the produced 4-t-butoxycarbonylpiperazine-2-carboxylic acid-Nt-butyramide is used as a solvent. Extract and separate from salt of optical resolving agent.
When the 4-t-butoxycarbonyl derivative is treated with an acid,
The t-butoxycarbonyl group is easily eliminated, and the optically active piperazine-2-carboxylic acid-Nt-butyramide is regenerated.

The optical resolving agent can be recovered in a high yield by acidifying an aqueous solution of an alkali or amine salt with a strong acid and filtering the precipitated crystals.

When various substituents are introduced into the Ar group of the optical resolving agent II, a result different from that of the unsubstituted phenyl group is obtained. Introducing an alkyl group or a halogen atom at the p- or o-position of the phenyl group improves the yield and optical purity of salt IV, especially o- and p-methyl, p-
II with t-butyl, p-chloro and p-bromo substituted phenyl groups gives a salt with an optical purity of 97% or more in a yield of 95% or more. When the number of methyl substituents is increased, the performance is slightly deteriorated, and particularly in the case of the 2,4,6-tri-substituted product, the precipitation of salt crystals tends to be delayed. In the case of a sterically crowded 2,4,6-triisopropylphenyl group, L
-Despite being a derivative of phenylalanine
(R) -I and a sparingly soluble salt are prepared and crystallized.

Even if a 1- or 2-naphthyl group is used instead of the phenyl group, intermediate resolution results are obtained. A compound substituted with a methoxy group or a nitro group having a strong polarity also optically resolves I, but its performance is slightly inferior to that of an alkyl-substituted compound. The monomethyl-substituted product, particularly the easily available p-methyl-substituted product, gives the best results in terms of yield and optical purity.

The aromatic amino acid used as the raw material of the optical resolving agent II is phenylglycine when n = 0 and phenylalanine when n = 1. Phenylglycine is a D-form (R-form) as an intermediate of the antibiotic ampicillin.
However, phenylalanine is industrially produced in large quantities in the L-form (S-form) as a raw material for the synthetic sweetener aspartame, and both are easily and inexpensively available. Compound II with S configuration synthesized from L-phenylalanine (n = 1)
Forms a sparingly soluble salt with the S form of piperazine derivative I (except for 2,4,6-triisopropyl derivative)
On the other hand, R-configuration II (n = 0), which is a derivative of D-phenylglycine, crystallizes by forming a sparingly soluble salt with the R-form of I. This makes it possible to obtain both the R-form and the S-form of the piperazine derivative I.

[0040]

EXAMPLES [Resolution Agent Production Example 1] N-tosyl-L-phenylalanine (N-Ts-LP)
Preparation of he) 4.95 g (30 mmol) of L-phenylalanine in water 15
ml and a liquid dispersed in 36 ml of a 2N-sodium hydroxide aqueous solution were cooled in an ice-water bath, and while vigorously stirring, a mixed liquid of 6.86 g (36 mmol) of p-toluenesulfonyl chloride and 12 ml of tetrahydrofuran was added dropwise.

After completion of dropping, the mixture was stirred for 10 minutes under cooling with an ice-water bath, and then for 1 hour at room temperature. Then 2N hydrochloric acid 2
1.5 ml was added, and N-Ts- was added with 100 ml of chloroform.
L-Phe was extracted. The chloroform phase was washed with water, dried and the solvent was distilled off to obtain 8.32 g of crude crystals of N-Ts-L-Phe. The yield based on L-phenylalanine as a raw material was 86.9%. This N-Ts-L
By recrystallizing the crude crystal of -Phe from the mixed solvent of isopropanol-water once, 5.78 g of N-Ts-L-Phe crystal was obtained. The total yield based on the raw material L-phenylalanine was 60.4%. Melting point 160.
0 to 161.5 ° C.

[Preparation Example 2 of resolving agent] Production of N-p-chlorobenzenesulfonyl-L-phenylalanine (N-pClBs-L-Phe) A mixture of 1.65 g (10 mmol) of L-phenylalanine and 5 ml of 2N sodium hydroxide aqueous solution was prepared. While vigorously stirring while cooling with an ice-water bath, a mixed solution of 2.32 g (11 mmol) of p-chlorobenzenesulfonyl chloride and 3 ml of tetrahydrofuran, and 6 ml of 2N aqueous sodium hydroxide solution were alternately divided into 3 times. Dropped. After completion of dropping, the mixture was stirred for 5 minutes under cooling with an ice-water bath, and subsequently for 1 hour at room temperature. Then, 2 ml of 6N hydrochloric acid was added, and N-pClBs-L-Phe was extracted with 80 ml of methyl isobutyl ketone. The methyl isobutyl ketone phase was dried and the solvent was evaporated to give crude N-pClBs-L-Phe as an oil. This N-pClBs-L-Phe
By adding benzene to the crude product for crystallization, N
2.05 g of -pClBs-L-Phe crystal was obtained.
The total yield based on the raw material L-phenylalanine was 60.
4%. Melting point 132.0-134.0 [deg.] C.

The above operation was carried out by N-Ars-L-Phe
The aryl group Ar forming the compound (wherein the amino acid is L-phenylalanine in compound II) was repeated variously, and all the crystallized oils were recrystallized once. The yields and melting points of those products are shown in Table 1.

Table 1 No. N-Ars-L-Phe Single recrystallization Yield after Ar group in melting point (%) (° C) 1 Phenyl 83.8 121.0 to 123.0 2 2-Methylphenyl 34.8 98.0 to 102.0 3 4-Methylphenyl 60.4 160.0 to 161.5 4 4-ethylphenyl 88.3 130.0 to 132.0 5 4-t-butylphenyl 66.8 111.0 to 113.0 6 2,5-dimethylphenyl 68.5 125.0 to 128.0 7 2,4,6-trimethylphenyl 79.0 71.0 to 81.0 8 2,4, 6-triisopropylphenyl 32.5 86.0-90.0 9 4-chlorophenyl 60.4 132.0-134.0 10 4-bromophenyl 43.8 139.0-141.0 11 4-methoxyphenyl 84.2 141.0-143.0 12 2-nitrophenyl 78.3 136.5-138.5 13 3-nitrophenyl 36.6 160.0 to 161.5 14 4-nitrophenyl 49.1 163.0 to 165.0 15 1-naphthyl 54.6 136.0 to 138.0 16 2-naphthyl 78.6 147.0 to 149.0 In Table 1, no. 9 shows the data of the above example again.

[Resolving Agent Production Example 3] N-tosyl-D-phenylglycine (N-Ts-DP)
Preparation of G) D-Phenylglycine 4.53 g (30 mmol), water 15
ml and a mixed solution of 36 ml of 2N sodium hydroxide aqueous solution were vigorously stirred under cooling with an ice water bath, a mixed solution of 6.86 g (36 mmol) of p-toluenesulfonyl chloride and 7 ml of tetrahydrofuran was added dropwise. After the completion of dropping, the mixture was stirred for 10 minutes under cooling with an ice-water bath, and then for 1 hour at room temperature.
Then, 21.5 ml of 2N hydrochloric acid was poured in to precipitate N-Ts.
The crude crystal of -D-PG was collected by filtration. When the crude crystals were washed with water and dried, the yield was 7.10 g, which was 77.6% based on the raw material D-phenylglycine. The N-Ts-D-PG crude crystals were recrystallized once with a mixed solvent of isopropanol-water to give N-Ts-D-PG.
5.85 g of PG crystals were obtained. The total yield based on the raw material D-phenylglycine was 63.9%. Melting point 172.0-176.0 ° C.

[Resolving Agent Production Example 4] N-methanesulfonyl-L-phenylalanine (NM
Preparation of s-L-Phe) L-phenylalanine (1.65 g, 10 mmol) dissolved in a 2N aqueous sodium hydroxide solution was stirred vigorously while cooling with an ice-water bath, and methanesulfonyl chloride 1 was added. A mixture of 0.26 g (11 mmol) and 3 ml of tetrahydrofuran and 6 ml of 2N aqueous sodium hydroxide solution.
Was alternately added in 3 divided portions. After completion of dropping, the mixture was stirred for 5 minutes under cooling with an ice-water bath, and subsequently for 1 hour at room temperature. Then add 2 ml of 6N hydrochloric acid and add 30 ml of chloroform.
N-Ms-L-Phe was extracted with ml. The chloroform phase was washed with water, dried, and the solvent was distilled off to give N-Ms-L-
The crude Phe product was obtained as an oil. This crude product was purified by silica gel column chromatography (eluent: chloroform, ethyl acetate) to give N-
1.00 g of a purified Ms-L-Phe product was obtained as an oil. The total yield based on L-phenylalanine as a raw material was 41.0%.

Example 1 (RS) -PBC 1.85
g (10 mmol) and 3.19 of N-Ts-L-Phe
g (10 mmol) was dissolved in 28 ml of methanol with heating. This solution was prepared in advance (S)
1 mg of crystals of -PBC.N-Ts-L-Phe salt was added as a seed crystal, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were filtered off to obtain a diastereomeric salt, (S) -PBC.N.
2.49 g of -Ts-L-Phe (crude salt) was obtained.

The crude diastereomer salt was recrystallized from methanol to give (S) -PBC.N-Ts-L-Ph.
e 2.39 g of purified salt was obtained. Melting point: 171.0 to 173.0 ° C. Specific optical rotation: [α] _D ²³ + 10.9 ° (C 0.974
MeOH) yield: (S) -PBC in (RS) -PBC as a raw material
Yield (assumed to be half) is 94.8 at this stage.
%Met.

The above (S) -PBC.N-Ts-LP
The purified salt of he was further recrystallized from methanol, but neither melting point nor optical rotation was observed.
Therefore, the diastereomeric salt precipitated from the reaction solvent is
It can be seen that the purity is sufficiently high after one recrystallization.

The IR spectrum of the (S) -PBC.N-Ts-L-Phe purified salt is shown in FIG.

Then, the above (S) -PBC.N-Ts
0.50 g of -L-Phe purified salt was dissolved in 3 ml of methanol together with 0.18 g of triethylamine, and then,
Di-t-butyl dicarbonate 0.22 g methanol 0.5 ml
The solution in was added and the reaction was allowed to stir at room temperature for 1 hour.

The solvent was distilled off from the reaction solution, 1 ml of water and 0.2 ml of 6N-NaOH aqueous solution were added to the resulting residue, and 6 ml of toluene was used to (S)-(+)-4-t-butoxy. Carbonylpiperazine-2-carboxylic acid-Nt-butyramide (this is abbreviated as (S) -Boc-PBC) was extracted. The toluene phase was dried and the solvent was distilled off to obtain (S) -Boc-PBC as an oil,
This was crystallized when treated with 1 ml of n-hexane.
Yield 0.26g. Specific rotation: [α] _D ²¹ + 26.5 ° (C 1.008)
MeOH) Optical purity: 100% [by HPLC method using "Chiralpak AS" (Daicel). ] Melting point: 97.5 to 100 ° C. ¹ H-NMR (solvent CDCl ₃ , TMS standard) δ 1.35 ppm (s, 9H) 1.46 ppm (s, 9H) 1.84 ppm (br, 1H) 2.7 -3.0ppm (m, 3H) 3.18-3.21ppm (q, 2H) 4.06-4.08ppm (d, 2H) 6.50ppm (br, 1H) REC: Yield from purified salt 90% used (R
The yield based on (S) -PBC in (S) -PBC is 85%.
Is.

Incidentally, 0.31 g of N-Ts-L-Phe was recovered by adding 0.3 ml of 6N-HCl to make the aqueous phase after extraction of (S) -Boc-PBC acidic. Recovery rate 98%.

Example 2 (RS) -PBC 1.85
g (10 mmol) and 1.75 of N-Ts-L-Phe
g (5.5 mmol) was dissolved in 19 ml of methanol with heating. This solution was inoculated with 1 mg of (S) -PBC.N-Ts-L-Phe salt crystals prepared in advance, and the mixture was allowed to stand at room temperature overnight. The precipitated diastereomeric salt was filtered off to obtain (S) -PBC.N-Ts-LP
2.18 g of crude salt of he were obtained.

This diastereomeric salt was diluted with methanol to 1 part.
After purification twice, 2.06 g of (S) -PBC.N-Ts-L-Phe purified salt was obtained. The total yield of (S) -PBC in the starting material (RS) -PBC was 81.6 at this stage.
%Met. Melting point: 170.5-172.5 ° C.

The above (S) -PBC.N-Ts-LP
By treating 0.50 g of he purified salt in the same manner as in Example 1, 0.24 g of (S) -Boc-PBC was obtained. The yield from the purified salt was 86%, which was used (R
The total yield based on (S) -PBC in (S) -PBC is 70.
%. Melting point: 97.5 to 100 ° C. Specific optical rotation: [α] _D ²³ + 26.8 ° (C 1.014
MeOH) Optical purity: 100% (HPLC).

Example 3 (RS) -PBC 0.37
g (2 mmol) and 0.61 g (2 mm of N-Ts-D-PG)
ol) was dissolved under heating in 4.4 ml of a mixed solvent of benzene: ethanol = 10: 1. (R) -PBC.N-Ts-DP was prepared in advance in this solution.
1 mg of G salt crystals was inoculated and left overnight at room temperature. The precipitated diastereomeric salt was filtered off to obtain (R) -PBC.
0.53 g of N-Ts-D-PG crude salt was obtained. The total yield based on (R) -PBC in (RS) -PBC of the raw material was 109% at this stage.

By treating 0.53 g of (R) -PBC.N-Ts-D-PG crude salt in the same manner as in Example 1, 0.28 g of (R) -Boc-PBC was obtained. The yield from the crude salt is 92% and the total yield based on (R) -PBC in the (RS) -PBC used is 100%. Specific rotation: [α] _D ²³ -15.8 ° (C 1.012
MeOH) Optical purity: 67% (HPLC).

[Example 4] 0.74 of (RS) -PBC
g (4.0 mmol) and 1.0 of N-Ts-L-Phe
2 g (3.2 mmol) of methanol 5.1 ml and water 0.9 ml
It melt | dissolved in the mixed liquid of under heating. Crystals of (S) -PBC.N-Ts-L-Phe salt prepared in advance 1 mg
Was added as a seed crystal, and the mixture was allowed to stand at room temperature overnight. The precipitated crystals were filtered off to obtain (S) -PBC.N-Ts-L-Phe
0.93 g of salt was obtained. The yield of (S) -PBC in (RS) -PBC of the raw material was 92.2%, and the optical purity of (S) -PBC in the salt was 98.0% ee (HPL
C).

The same experiment as above was repeated, changing the amount of the optical resolving agent used and the water / methanol ratio of the solvent.
The results are shown in Table 2.

Table 2 No. N-Ts-L-Phe Total amount of solvent in solvent (ml) Crude Diaz (S) -PBC / (RS) -PBC H ₂ O / (RS) -PBC (g) Tereomer Optical purity (Molar ratio) (%) Salt yield (%) (% ee) 1 0.6 15 8.1 77.8 98.7 2 0.6 30 8.1 71.6 98.8 3 0.55 50 8.1 76.6 94.2 4 0.7 0 8.1 96.0 98.8 5 0.7 15 8.1 86.2 96.7 6 0.7 30 8.1 82.6 97.3 7 0.7 50 8.1 89.0 97.4 8 0.8 10 8.1 91.0 98.1 9 0.8 15 8.1 92.2 98.0 10 0.8 16.7 8.1 87.0 96.8 11 0.8 30 8.1 86.0 99.0 In Table 2, the optical purity of (S) -PBC is The value of things. No. 9 is a reprint of the data of the above example.

Example 5 (RS) -PBC 0.37
g (2.0 mmol) and 0.3 of N-Ts-L-Phe
8 g (1.2 mmol) was dissolved in 4.0 ml of water under heating,
1 mg of (S) -PBC.N-Ts-L-Phe salt was inoculated and left at room temperature overnight. The precipitated crystals were filtered off and the (S) -PBC.N-Ts-L-Phe salt was added to 0.4
0 g was obtained. (S) -PB in (RS) -PBC of the raw material
The yield based on C was 80.0%, and the optical purity of (S) -PBC in the salt was 93.6% ee (HPLC).

[Example 6] 0.74 g of (RS) -PBC
(4.0 mmol) and 0.89 g of N-Ts-L-Phe
(2.8 mmol) was added to 6 ml of 1-butanol, heated and dissolved, and then (S) -PBC prepared in advance.
Inoculation of 1 mg of N-Ts-L-Phe crystals and standing overnight at room temperature gave 0.84 g of (S) -PBC.N-Ts-L-Phe crude salt. The yield based on (S) -PBC in (RS) -PBC of the raw material was 83.8%.
The optical purity of (S) -PBC in this crude salt is 97.7%.
ee (HPLC).

The same experiment as above was repeated, except that the amount of the optical resolving agent, the composition of the solvent and the amount of the solvent used in Examples 5 and 6 were changed. Table 3 shows the results.

Table 3 No. N-Ts-L-Phe Solvent Solvent Total amount (ml) Crude Diaz (S) -PBC / (RS) -PBC / (RS) -PBC (g) Tereomer Optical purity (molar ratio) ) Salt yield (%) (% ee) 1 0.7 15% H ₂ O / EtOH 8.1 76.6 96.9 2 0.55 5% H ₂ O / n-PrOH 10.8 76.4 99.4 3 0.7 30% H ₂ O / i-PrOH 8.1 69.4 94.7 4 0.7 1-BuOH 8.1 83.8 97.7 5 0.7 5% H ₂ O / 1-BuOH 8.1 63.8 98.6 6 0.7 10% H ₂ O / i-BuOH 8.1 60.4 92.6 7 0.7 15% H ₂ O / 2-BuOH 8.1 39.0 99.2 8 0.7 5% H ₂ O / 1-PenOH 8.1 90.4 95.4 9 0.7 5% H ₂ O / 1-HexOH 8.1 88.2 95.7 In Table 3, No. 4 shows the data of the above example again. EtOH is ethanol, PrOH is propanol, BuOH is butanol, PenOH is pentanol, and HexOH is hexanol.

Example 7 0.56 g of (RS) -PBC
(3.0 mmol) and 1. of N-pClBs-L-Phe.
02 g (3.0 mmol) was added to 6 ml of methanol, heated and dissolved, and then prepared (S) -PB
Inoculated with 1 mg of crystals of C.N-pClBs-L-Phe,
Let stand overnight at room temperature, then (S) -PBC.N-pClBs-
0.75 g of L-Phe crude salt was obtained. Raw material (RS)
-The yield based on (S) -PBC in PBC is 95.0%.
Met. The optical purity of (S) -PBC in this crude salt was 97.0% ee (HPLC).

Example 8 Optical Resolving Agent N-Ars-L-
The same operation as in Example 7 was performed using various Phe Ar groups, using methanol or ethanol as a solvent, and changing the amount used. The results are shown in Table 4.

Table 4 No. N-Ars-L-Phe solvent Total amount of solvent Ar group (ml) in crude dias (R or S) / tereomer-PBC Optically pure (RS) -PBC (g) Salt yield (%) Degree (% ee) 1 Phenyl MeOH 9.0 91.8 78.2 (S isomer) 22 2-Methylphenyl MeOH 18.0 99.8 97.3 (S isomer) 34-Ethylphenyl MeOH 10.8 97.0 93.2 (S isomer) 4 4-t-butylphenyl MeOH 10.8 84.4 98.4 (S isomer) 5 2,5-Dimethylphenyl MeOH 9.0 101.8 84.2 (S body) 6 2,4,6-Trimethylphenyl MeOH 10.8 39.0 94.0 (S body) 7 2,4,6-Tri-i-EtOH 13.0 67.4 90.4 (R body) ) Propylphenyl 8 4-chlorophenyl MeOH 10.8 95.0 97.0 (S form) 9 4-bromophenyl MeOH 21.6 95.8 97.2 (S form) 10 4-methoxyphenyl MeOH 19.8 80.4 89.8 (S form) 11 2-nitrophenyl MeOH 10.8 69.6 94.6 (S-form) 12 3-nitrophenyl EtOH 10.8 106.1 46.1 (S-form) 13 4-nitrophenyl EtOH 10.8 19.8 93.2 (S-form) 14 1-naphthyl EtOH 10.8 74.0 94.6 (S-form) 1 5 2-Naphthyl EtOH 16.2 117.0 67.9 (S-form) In Table 4, the optical purity of (R, S) -PBC is the value in crude salt.

[Embodiment 9] 0.56 of (RS) -PBC
g (3.0 mmol) and 0.92 g of N-Ts-D-PG
(3.0 mmol) was added to a mixed solvent of 6 ml of benzene and 0.6 ml of ethanol, heated and dissolved, and then (R) -PBC.N-Ts-D-PG crystal 1 was prepared in advance.
Inoculate mg, leave overnight, (R) -PBC.N-Ts
1.11 g of crude salt of -D-PG was obtained. Raw material (R
The yield based on R-PBC in S) -PBC is 150.8.
%Met. This (R) -PBC ・ N-Ts-DP
By recrystallizing the G crude salt twice with a benzene-ethanol mixed solvent, (R) -PBC.N-Ts-D-PG was obtained.
0.60 g of purified salt was obtained. The yield based on (R) -PBC in (RS) -PBC of the raw material was 82.0%.
The optical purity of (R) -PBC in the purified salt of (R) -PBC.N-Ts-D-PG is 97.7% ee (HPL
C).

[Example 10] 0.7 of (RS) -PBC
4 g (4.0 mmol) and 0.97 of N-Ms-L-Phe
g (4.0 mmol) was added to 7 ml of ethanol, heated and dissolved, and then prepared (S) -PBC.
1 mg of N-Ms-L-Phe crystal was inoculated and left overnight at room temperature to obtain 0.40 g of (S) -PBC.N-Ms-L-Phe crude salt. The yield based on (S) -PBC in (RS) -PBC as a raw material was 46.6%.
The optical purity of (S) -PBC in this crude salt is 98.5%.
ee (HPLC).

[Embodiment 11] (RS) -PBC 15.
0 kg (81.0 gmol) and 2 of N-Ts-L-Phe
0.7 kg (64.8 gmol) of 85 wt% methanol 105
It melt | dissolved in 1 liter by heating. While gradually cooling with stirring, 6
When the temperature reached 2 ° C, 50 g of seed crystal (S) -PBC · N-Ts-L-Phe salt prepared in advance was added, and the mixture was cooled to 20 ° C in about 5 hours. The precipitated crystals were separated by filtration and washed with a small amount of methanol. The obtained (S) -PBC.N-Ts-L-Phe salt was dried overnight at 60 ° C. Yield 18.8 kg (37.2 gmol).
The yield based on the half amount of (RS) -PBC used was 92%,
The optical purity of (S) -PBC in salt is 100% ee (HP
LC).

The above salt was added to 140 liters of methanol, and 7.7 kg (76.1 gmol) of triethylamine was added. To this, 8.1 kg of di-t-butyl dicarbonate (3
A solution of 7.2 gmol) dissolved in 15 kg of methanol was added and reacted. After distilling off about 100 liters of methanol, 125 liters of water and 60 kg of toluene were added. The toluene layer was separated, and the remaining aqueous layer was further extracted twice with 60 kg of toluene each. About 18 kg of toluene layer
The mixture was concentrated to 40 ° C., 40 kg of methylcyclohexane was added thereto, and the mixture was heated and dissolved at 50 ° C. and then cooled, and the precipitated crystals were separated by filtration. This was washed with 10 kg of methylcyclohexane, then heated at 60 ° C. under reduced pressure and dried.
The yield of (S) -Boc-PBC is 8.5 kg (29.8 gm).
ol) and optical purity was 100% ee (HPLC method).

As the solvent used for the extraction of Boc-PBC, xylenes, chlorobenzenes, ethyl acetate, n-butanol, isobutanol or the like can be used instead of toluene. In addition to methylcyclohexane, aliphatic and alicyclic hydrocarbons such as hexane and cyclohexane can be used as the solvent added for crystallization.

Introduction (S) -PBC.N-Ts-L-
About 120 liters of the mother liquor after Phe was filtered off was distilled to remove methanol and concentrated to about 30 liters. To this, 100 liters of water was added, and 11.5 kg of concentrated hydrochloric acid was added to make it strongly acidic. After the precipitated N-Ts-L-Phe was filtered off, the mother liquor was neutralized with caustic soda until it became neutral, and the total liquid volume was concentrated to 35 liters. 8.7 kg of 30% caustic soda was added to make it alkaline, and 60 kg of n-propanol was added to extract PBC. The n-propanol layer was concentrated to 28 liters, 180 g of flake caustic soda was added, and the mixture was heated under reflux for 1 hour. The propanol was distilled off and 8 kg of crude PBC was recovered. Optical purity measured by HPLC is 2% ee
It was confirmed below that the racemization was completed.

Instead of the above n-propanol, n-butanol, isobutanol, etc. can be used as an extraction solvent.

After the salt of (S) -PBC is Boc-ized,
Acidify the aqueous layer after separating it from the toluene layer with hydrochloric acid,
N-Ts-L-Phe was recovered. The total amount of N-Ts-L-Phe recovered from the salt and mother liquor was 19.
At 2 kg, the recovery rate was 93%. The melting point of the dried product is 16
It has 0 to 161 ° C and an optical purity of 100% ee, and can be reused as it is.

[0077]

INDUSTRIAL APPLICABILITY According to the present invention, an optically active piperazine derivative, particularly piperazine-2-carboxylic acid-Nt-butyramide, can be produced with high yield and high optical purity. Upon formation of the diastereomeric salt,
The optically active N-acylated amino acid, which is an optical resolving agent, can be used in an equimolar amount or less relative to the piperazine derivative and can be recovered and reused. The remaining optically active substance obtained by separating the desired optically active substance can be racemized and used again as a raw material. Combined with the fact that the purification of diastereomeric salts by recrystallization is extremely simple and that a cheap and easy-to-use solvent such as methanol can be used as a solvent, the production cost of the optically active substance is When compared with the optical resolution of, it will be significantly lower. Thereby, the HIV protease inhibitor L-735,524
Low-cost manufacturing of.

[Brief description of drawings]

FIG. 1 is an IR absorption spectrum of a purified salt of (S) -2-piperazine-2-carboxylic acid-Nt-butylamide.Np-tosyl-L-phenylalanine, which is a diastereomeric salt obtained in Examples. .

Claims (7)

[Claims] 1. An (RS) -piperazine-2-carboxylic acid-Nt-butyramide represented by the formula I: embedded image And an optical resolving agent which is an optically active N-acylated amino acid represented by the general formula II or III: [In the formula II, Ar represents a phenyl group or a naphthyl group which may be substituted with ₁ to 3 C _{1 to} C ₆ alkyl groups, halogen atoms, nitro groups or alkoxy groups, and n = 0 or 1 . ] [Chemical 3] [In the formula III, Alk represents a C _{1 to} C ₆ alkyl group, and n = 0 or 1. ] By reacting in a solvent, the general formula IV
Or forming a diastereomeric salt of V, [In the formula, Ar has the above-mentioned meaning and n is the above-mentioned value. * Represents the position of the asymmetric carbon atom. ] [Chemical 5] [In the formula, Alk has the above-mentioned meaning, and n is the above-mentioned value. * Represents the position of the asymmetric carbon atom. An optical method comprising selectively precipitating one diastereomeric salt from a solvent to separate the diastereomeric salt, and decomposing the separated diastereomeric salt to obtain optically active piperazine-2-carboxylic acid-Nt-butyramide. A method for producing an active piperazine derivative. 2. A compound of formula II or III relative to a compound of formula I in a molar ratio I: II (or III) = 1: 0.1-2.
The method according to claim 1, wherein the reaction is carried out at a ratio of 0, preferably 0.5 to 1.0. 3. The solvent is water, or a lower alcohol, in particular methanol, ethanol, i-propanol, n-butanol or hexanol, or a mixture of one of these and water. 1
Manufacturing method. 4. When decomposing the diastereomeric salt separated from the solvent, the NH group at the 4-position of the piperazine ring is converted to t-.
The method according to claim 1, further comprising the step of protecting with a butoxycarbonyl group.
The method for producing an optically active piperazine derivative, which comprises isolating a target compound as a 4-t-butoxycarbonyl derivative. 5. A diastereomeric salt of an optically active piperazine derivative represented by the general formula IV or V and an optically active N-acylated amino acid. [Chemical 6] [In the formula, Ar has the above-mentioned meaning and n is the above-mentioned value. * Represents the position of the asymmetric carbon atom. ] [Chemical 7] [In the formula, Alk has the above-mentioned meaning, and n is the above-mentioned value. * Represents the position of the asymmetric carbon atom. ] 6. The salt of claim 5 of formula IVa, especially the (S, S) form. Embedded image [In the formula, * represents the position of the asymmetric carbon atom. ] 7. The salt of claim 5 represented by formula IVb, especially the (R, R) form. [Chemical 9] [In the formula, * represents the position of the asymmetric carbon atom. ]