JP3089996B2 - Method for producing optically active piperazine derivative and intermediate for production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Merck has published a group of compounds as HIV protease inhibitors which can be used as a therapeutic agent for AIDS (Japanese Patent Application Laid-Open No. Hei 5-279337).
A compound named 5,524 is considered promising.
This material has the structure of Formula V below. [C & EN
May 16, 1994, p6]

[0003]

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With respect to the synthesis of L-735,524,
J. P. The above-mentioned Japanese Patent Application Laid-open No.
-279337, D.I. A research report by Askin et al. [Tetrahedron Lett. 35
(5) 673-6 (1994)]. In any case, as an intermediate in the synthesis, an optically active form of piperazine-2-carboxylic acid-Nt-butylamide represented by the following formula I, or NH protected by a t-butoxycarbonyl group represented by the formula VI However, an optically active substance is required.

[0005]

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[0006]

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

[0008] All of these known optical resolving agents are extremely soluble in water, so it is difficult to recover and reuse after using for resolving. In order to produce L-735,524 inexpensively, a compound of formula I (or VI), which is a component of the compound represented by formula V (portion surrounded by a line)
It is essential to provide at low cost)
To that end, it is desirable to efficiently perform the optical resolution of Compound I and to select an optical resolution agent that can be recovered and reused.

[0009]

SUMMARY OF THE INVENTION An 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, and more specifically to optically active piperazine-2-carboxylic acid-N-. It is to provide an improved method for producing t-butylamide.

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

[0011]

The process for producing the optically active piperazine derivative of the present invention is represented by the formula (RS)-
Piperazine-2-carboxylic acid-Nt-butylamide (hereinafter abbreviated as “2-PBC”);

[0012]

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

[0014]

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[0015] [In the formula II, R represents a linear or branched alkyl group of C ₁ -C _6, methylthioethyl group or a C _1,
It represents a hydroxyalkyl group -C _2. Ar is 1
Represents a phenyl group or a naphthyl group which may be substituted with up to 3 C ₁ -C ₆ alkyl groups, halogen atoms, nitro groups or alkoxy groups. Reacting in a solvent to form a diastereomeric salt of general formula III,

[0016]

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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-butylamide.

Among the optical resolving agents represented by the above general formula II, particularly important ones are the following N-tosyl-L-alanine (formula IIa, hereinafter abbreviated as "N-Ts-L-Ala"). , N-tosyl-D-alanine and N-tosyl-
L-valine (Formula IIb, hereinafter abbreviated as "N-Ts-L-Val").

[0019]

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[0020]

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The optical resolving agent used in the present invention can be synthesized by reacting the corresponding amino acid with a sulfonic acid halide or anhydride according to a conventional method. In particular, sulfonic chloride is readily available and generally gives the amide in high yield. An amino acid is dissolved in a solvent as an alkali metal salt, and acid chloride is added thereto while neutralizing hydrochloric acid generated by the reaction, so-called Schotten-B
Synthesis by the aumann method 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 making the aqueous alkaline solution acidic with a mineral acid, it can be easily recovered as a free acid in high yield.

The optical resolving agent II synthesized by the above method has sufficient chemical purity and optical purity as it is. However, if necessary, lower alcohols, hydrated lower alcohols, or aromatic hydrocarbons such as benzene and toluene may be used. And a mixed solvent of an aromatic hydrocarbon and an aliphatic hydrocarbon such as hexane for recrystallization. An acid precipitation operation of dissolving in an aqueous alkali solution and precipitating a carboxylic acid by acidifying with a mineral acid such as hydrochloric acid or sulfuric acid also improves not only the chemical purity but also the optical purity.

As the reaction medium, various solvents can be used, such as water, methanol, ethanol, n-propanol,
Isopropanol, n-butanol, isobutanol,
Pentanol, hexanol, 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 mixed solvent of lower alcohols such as methanol and ethanol and alcohols is preferable.

The addition of water to the lower alcohol changes the solubility of the diastereomer salt, and the use of a mixed solvent containing an appropriate amount of water improves the optical purity of the produced salt or reduces the amount of the solvent. Or you can.

Further, as shown in Examples described later, when an alanine derivative is used as an optical resolving agent, the configuration of 2-PBC obtained is reversed depending on the solvent used. That is, an R-form is obtained in the alcohol system, whereas an S-form is obtained in the aqueous system. By utilizing this and appropriately selecting and combining a resolving agent and a solvent, a desired optically active substance can be obtained.

The optical resolving agent is 2-PB to be split.
C is used in a molar ratio of 0.1 to 2.0 with respect to C.
A preferred range is from 0.5 to 1.0. 2-PB
C is a diacid base, and the N-acylated amino acid of the resolving agent is a monobasic acid, but 1: 1 as a diastereomer salt.
It is not worthwhile to use a molar ratio of more than 1.0, since the salt of is precipitated. As the molar ratio falls below 1.0, the yield of diastereomeric salts slightly decreases, but there is no great difference, and even at a molar ratio of 0.5, a sufficient amount of salt precipitates.

In the optical resolution of piperazine-2-carboxylic acid with camphorsulfonic acid, a diastereomeric salt is formed in which two molecules of an optical resolution agent are bonded to a piperazine compound. In the method of the present invention, the diacid base 2-P
One molecule of BC and one molecule of N-acylated amino acid form a diastereomeric salt to achieve optical resolution. This is an unexpected finding, and the fact that efficient optical resolution can be achieved using relatively small amounts of optical resolving agent is of great industrial importance.

In order to form diastereomer salt III from amide I and optical resolving agent II, I and II are added to a solvent, dissolved by heating to a temperature lower than the boiling point of the solvent, and then cooled to obtain a diastereomer salt. The salt III crystallizes out. 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, a salt having a high optical purity is generally easily crystallized.However, by using an appropriate amount of a solvent and gradually lowering the temperature from the dissolved state to avoid rapid crystallization, a sufficiently grown salt crystal can be obtained. It is desirable to precipitate. The solid-liquid separation is performed using a usual filter or centrifuge. By washing with an appropriate solvent, high purity diastereomeric salt crystals can be obtained. The resulting diastereomer salt can be purified to an optically pure salt by recrystallization from a suitable solvent. Generally, practically sufficient optical purity can be obtained by one recrystallization.

The novel compound provided by the present invention is a diastereomeric salt represented by the following general formula III.
Water or solvent molecules may be incorporated into the salt crystals to stabilize the crystal structure.

[0031]

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

The poorly soluble diastereomer salt obtained by selective precipitation can be easily decomposed by the action of an acid or alkali to obtain an optically active 2-PBC. Usually, an acid is added to the diastereomer salt to precipitate the N-acylated amino acid and separated by filtration, or the N-acylated amino acid is extracted with an appropriate organic solvent and separated from the acidic solution of 2-PBC. I do. However, the desired optically active 2-PBC is often used in a form in which the 4-position imino group is protected with a t-butoxycarbonyl group as described above, and thus 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 diastereomer salt in the presence of triethylamine, and the resulting 4-t-butoxycarbonylpiperazine-2-carboxylic acid-Nt-butylamide is dissolved in a solvent. Extract and separate from the salt of the 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-
t-Butylamide regenerates.

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

The substituent on the Ar group of the optical resolving agent II has a great influence on the performance of optical resolution. Compounds having an alkyl group or a halogen atom at the p- or o-position of the phenyl group, especially o- and p-methyl, pt-butyl, p-
II with -chloro and p-bromo substituted phenyl groups,
Give good results. In general, monomethyl-substituted compounds, particularly readily available p-methyl-substituted products, give excellent results in both yield and optical purity.

The amino acid used as a raw material of the optical resolving agent II includes amino acids having a linear or branched alkyl group such as alanine, α-aminobutyric acid, valine, leucine and isoleucine, and substitution with methionine, serine or threonine. L-form or D-form of amino acids having an alkyl group
The body is used. In particular, easily available D- and L
-Alanine, valine, L-leucine, L-isoleucine and the like are suitable. L- such as L-valine and L-leucine
P-Toluenesulfonamide II derived from amino acids
Forms a poorly soluble salt with (S) -I, whereas IIa, a derivative of L-alanine, forms a poorly soluble salt with (R) -I. This makes it possible to separate the R-form and the S-form of I using relatively easily available L-amino acids. Of course, p-derived from D-alanine
-When toluenesulfonamide II is used, a sparingly soluble salt with (S) -I is precipitated, and the derivative II of D-valine is (R)-
Forms a sparingly soluble salt with I.

[0037]

【Example】

[Preparation example 1 of resolving agent] Production of N-tosyl-L-alanine (N-Ts-L-Ala) 17.82 g (0.20 mol) of L-alanine was dissolved in 100 ml of 2N-sodium hydroxide aqueous solution, and p -Add 41.90 g (0.22 mol) of toluenesulfonyl chloride,
A 2N aqueous solution of sodium hydroxide was added dropwise with vigorous stirring to carry out the reaction while keeping the pH of the reaction solution around 9. Since the pH became constant within 2 to 3 hours, the mixture was filtered to remove unreacted acid chloride, and concentrated hydrochloric acid was added to make the pH 0.5 or less. As a result, the separated oil was allowed to cool and crystallized. After filtration and washing with water, drying was performed to obtain 40.0 g of white crystals. 82.3% yield. m
p133.5-134.5 ° C (literature value * 135-6
° C). 99.9% purity by neutralization titration. * Sakota et al., "The Chemical Society of Japan", 90 (1), 77 (1969).

[Resolving Agent Production Example 2] In the same manner as described above, p-toluenesulfonamide was synthesized from various L-amino acids. Table 1 shows the yield and melting point.

Table 1 Resolving agent No. L-amino acid Yield (%) Melting point (° C.) Reference value (° C.) 2 Valine 92.6 149.5-150.5 148-93 Leucine 95.2 123.5-125 123-44 Isoleucine 89.7 134 −136.5 130− 25 Methionine 96.7> 120 179−80 * Sakota et al., “Journal of the Chemical Society of Japan” 90 (1), 77 (1969); McChesney et al. Am. Chem. Soc., 59 , 1116-8 (1937).

[Example 1] (RS) -2-PBC
85 g (10 mmol) and N-Ts-L-Ala 2.4
3 g (10 mmol) was dissolved by heating in 6 g of ethanol.
(R) -2-prepared beforehand was added to this solution.
1 mg of PBC.N-Ts-L-Ala salt crystals were added as seed crystals, and left at room temperature overnight. The precipitated crystals are separated by filtration and the diastereomer salt (R) -2-PBC.N-Ts
1.88 g of -L-Ala (crude salt) was obtained. (RS)
The yield based on -2-PBC was 43.9%, and the optical purity of (R) -2-PBC in the salt was 90.4 by HPLC analysis.
% Ee.

1.0 g of this salt was dissolved in 4 g of ethanol heated to 60 to 65 ° C., cooled, and the precipitated crystals were filtered to obtain 0.7 g of a purified salt. Melting point 17
1.0-172.0 ° C, the optical purity of (R) -2-PBC in the salt was 99.97% (HPLC method). Optical rotation [α] _D ²⁵ + 4.83 ° of purified salt (C = 2.0, MeO
H) The IR spectrum is shown in FIG.

[Embodiment 2] (RS) -2-PBC
85 g and 2.71 g of N-Ts-L-Val (10
mmol) was dissolved by heating in 7 g of ethanol. The seed crystal ((S) -2-PB) prepared in advance was added to this solution.
C.N-Ts-L-Val) (1 mg) was added and left overnight. The precipitated crystals were filtered, and 1.70 of diastereomer salt (S) -2-PBC.N-Ts-L-Val was obtained.
g was obtained. 37. Yield based on (RS) -2-PBC
The optical purity of (S) -2-PBC in the salt by HPLC analysis was 34.3% and 84.3%.

1.0 g of this salt was dissolved in 2 g of ethanol at 60 to 65 ° C., cooled, and the precipitated crystals were filtered to obtain 0.71 g of a purified salt. Melting point 180.0
At −182.0 ° C., the optical purity of (S) -2-PBC in the salt was 99.2%. Optical rotation of purified salt [α] _D ²⁵ +
21.6 ° (C = 2.0, MeOH) IR spectrum is shown in FIG.

Examples 3 to 5 Each of 1.85 g of (RS) -2-PBC was subjected to optical resolution using three types of resolving agents in the same manner as in Example 2. Table 2 shows the results.

Table 2 Example 3 4 5 Optical resolution agent N-Ts-L-Leu N-Ts-L-Ile N-Ts-L-Met Same amount (g) 2.85 2.85 3.03 Diastereomer salt yield ( g) 1.75 1.75 1.53 Yield (%) 37.2 37.2 31.3 Optical purity (% ee) 60.6 79.5 96.3 Same as above Purified optical purity (% ee) 95.9 96.8 100.0 Melting point (° C) 179.5-181.5 177-180.5 154.5-156.

Examples 6 to 8 1.85 g (10 mmol) of (RS) -2-PBC and 2.71 g of N-Ts-L-Val were dissolved in a solvent shown in Table 3 by heating. Optical division was performed according to the method of the second embodiment. The results are shown in Table 3.

Table 3 Example 6 7 8 Solvent Methanol n-Butanol Amount used (g) 5.3 161 6.8 Diastereomer salt Yield (%) 8.8 24.4 18.0 Optical purity (% ee) 60.3 95.8 40.8

Examples 9 to 11 The amounts of (RS) -2-PBC and N-Ts-L-Ala shown in Table 4 were dissolved in a solvent shown in Table 4 by heating. Optical division was performed according to The results are shown in Table 4.

Table 4 Example 9 10 11 Solvent Water Methanol 90% Isopropanol * Usage (g) 15.0 5.3 19.0 (RS) -2-PBC (g) 3.70 1.85 3.70 N-Ts-L-Ala (g) 4.86 2.43 3.89 Molar ratio 1.0 1.0 0.8 2-PBC salt Yield (%) 29.8 26.8 28.0 Optical purity (% ee) 90.4 (S) 89.1 (R) 97.7 (R) * Contains 10% water.

When the same optical resolving agent is used, the resulting 2
It was found that the steric configuration of the -PBC salt differs depending on the solvent, and when water was used, it was in contrast to the S-form and in the alcohol the R-form was used.

Example 12 4.56 g of the purified salt of (S) -2-PBC.N-Ts-L-Val produced by the method of Example 2 was dissolved in 30 ml of methanol together with 2.03 g of triethylamine. To this solution was added a solution of 2.18 g of di-tert-butyl dicarbonate in 5 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution, 10 ml of water and 2 ml of 6N-NaOH aqueous solution were added to the obtained residue, and (S)-(+)-4-t was added using 60 ml of toluene.
-Butoxycarbonylpiperazine-2-carboxylic acid-N
-T-butyramide [this is (S) -Boc-2-PB
C). After the toluene phase is dried over magnesium sulfate, the solvent is distilled off to obtain (S)
-Boc-2-PBC is obtained as an oil,
Crystallization upon treatment with 10 ml of hexane. Yield 2.42 g. 97.5-100 ° C, Chiralpak A
It was 100% ee when the optical purity was measured by HPLC method using S (Daicel Chemical). The melting point of the purified product obtained by recrystallization from hexane is 107.5 to 1
08.5 ° C.

[0052]

According to the present invention, optically active piperazine derivatives, particularly piperazine-2-carboxylic acid-Nt-butylamide, can be produced with high yield and high optical purity. In forming the diastereomeric salt,
The optically active N-acylated amino acid, which is an optical resolving agent, can be recovered and reused by using an equimolar amount or less with respect to the piperazine derivative. The remaining optically active substance obtained by separating the desired optically active substance can be racemized and used again as a raw material. These factors, combined with the fact that diastereomeric salts are extremely easy to purify by recrystallization, and the use of inexpensive and easy-to-use solvents such as methanol and ethanol as solvents, make the production cost of optically active substances other. When compared with the general optical division of the above, it is remarkably low. Thereby, the HIV protease inhibitor L-7
35,524 low-cost manufacturing is realized.

[Brief description of the drawings]

FIG. 1 is an IR spectrum of a purified salt of the diastereomer salt (R) -piperazine-2-carboxylic acid-Nt-butylamide.N-tosyl-L-alanine obtained in Example 1.

FIG. 2 is an IR spectrum of a purified salt of the diastereomer salt (S) -piperazine-2-carboxylic acid-Nt-butylamide.N-tosyl-L-valine obtained in Example 2.

────────────────────────────────────────────────── ─── Continuation of front page (56) References JP-A-9-71571 (JP, A) JP-A-4-128270 (JP, A) JP-A-4-18084 (JP, A) JP-A-5-71584 279337 (JP, A) International publication 95/2584 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 241/04 C07B 57/00 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A (RS) -piperazine-2-carboxylic acid-Nt-butylamide of the formula I, [Wherein * represents the position of an asymmetric carbon atom. same as below. And an optically resolving agent which is an optically active N-acylated amino acid represented by the general formula II: In [II formulas, R represents a linear or branched alkyl group, methylthioethyl group or a hydroxyalkyl group of C ₁ -C ₂ of C ₁ -C _6. Ar is one to three C
Represents a phenyl group or a naphthyl group which may be substituted with a ₁ to ₆ alkyl group, a halogen atom, a nitro group or an alkoxy group. Reaction in a solvent to give a compound of the general formula II
Forming a diastereomeric salt of I, [Wherein, R and Ar have the above-mentioned meanings. One diastereomer salt is selectively precipitated from a solvent and separated, and the separated diastereomer salt is decomposed to obtain an optically active piperazine-2-carboxylic acid-Nt-butylamide. A method for producing an active piperazine derivative. 2. The compound of the formula II with respect to the compound of the formula I in a molar ratio I: II = 1: 0.1 to 2.0, preferably 0.5 to 2.0.
The method according to claim 1, wherein the reaction is performed at a ratio of 1.0. 3. The method is carried out using water as a solvent,
2. The process according to claim 1, wherein the process is carried out using a lower alcohol, in particular methanol, ethanol, isopropanol, n-butanol or isobutanol, or a mixture of one of these and water. 4. In decomposing a diastereomer salt separated from a solvent, an NH group at the 4-position of a piperazine ring is replaced with t-
Claim 1 further comprising a step of protecting with a butoxycarbonyl group.
A process for producing an optically active piperazine derivative, comprising isolating the target compound as a 4-t-butoxycarbonyl derivative. 5. A diastereomer salt of an optically active piperazine derivative represented by the general formula III and an optically active N-acylated amino acid. Embedded image [Wherein, R and Ar have the above-mentioned meanings. ] 6. The salt according to claim 5, which is represented by the formula IIIa, which is an (S, R) form and an (R, S) form. Embedded image 7. The salt according to claim 5, which is represented by the formula IIIb, which is in the (S, S) form. Embedded image