JPH1087636A - Production of optically active n-t-butyl-2-piperazinamide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially obtain the subject compound in a high yield by a simple and economically excellent method by using an optical resolving agent capable of being easily recovered. SOLUTION: (RS)-N-t-butyl-2-piperazinamides used as raw materials comprise a racemic mixture containing both the isomeric compounds in equal amounts, respectively. 0.1-2.0 mole of dibenzoyl tartrate as an optical resolving agent is brought into contact with 1 mole of the raw material to obtain the diastereoisomer salts. A liquid containing the diastereoisomer salts is cooled or concentrated, and the crystals are deposited in the temperature range of -20 to 80 deg.C. The diastereoisomer salt crystals are suspended in water, etc., and hydrochloric acid as a decomposing agent is added to remove the optical resolving agent. The filtrate is concentrated to obtain the hydrochloric acid salt of (R)-N-t-butyl-2-piperazinamide, etc. The salt is treated with an ion exchange resin to separate the optical resolving agent, and the filtrate is concentrated to obtain the optically active N-t-butyl-2-piperazinamide of the formula (* is an asymmetric carbon).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an optically active Nt-
The present invention relates to a method for producing butyl-2-piperazinamide.

[0002]

2. Description of the Related Art Optically active Nt-butyl-2-piperazinamide is a compound useful as an intermediate of pharmaceuticals such as anti-HIV drugs. Since piperazine amide is a racemate, it must be optically resolved to be optically active in order to obtain the above synthetic intermediate.

[0003] N-t-butyl-2-amine using an optical resolving agent
As an optical resolution method of piperazine amide, a method using optically active camphorsulfonic acid (Tetrahedr) is used.
onLett. , Vol. 35, No. 5, p673
1994), a method using optically active lactic acid, malic acid or tartaric acid (JP-A-8-3145), an optically active N
A method using -tosyl-L-phenylalanine (Japanese Patent Application Laid-Open No. 8-183779) and the like are known.

[0004]

However, in the method using camphorsulfonic acid as the optical resolving agent, the diastereomeric salt of camphorsulfonic acid / Nt-butyl-2-piperazineamide is regenerated in order to increase the optical purity. The crystallization must be repeated, which results in low yields.
In addition, since the crystal form of the diastereomer salt obtained is flocculent, it takes a long time for filtration and drying of the salt after crystallization, so that complicated operations are required. Is disadvantageous.

Further, in the method using optically active lactic acid, malic acid or tartaric acid, it is extremely difficult to recover by an operation such as extraction since the optical resolving agent is a water-soluble substance which is hardly soluble in an organic solvent. There is a problem that there is.

Further, in the method using optically active N-tosyl-L-phenylalanine, although the recovery of the optical resolving agent is relatively easy, the method itself is expensive and economically difficult for industrial use. Disadvantageous.

From the above, optically active Nt-butyl-2-piperazinamide can be obtained easily and industrially in a high yield, and furthermore, an optically resolving agent to be used can be easily recovered. Development of a division method was desired.

The present invention has been made in view of the above problems, and an object of the present invention is to provide an optically active Nt-butyl-2-piperazinamide with a high yield by using an easily resolving agent. It is to provide an economically superior production method which can be obtained at a high rate.

[0009]

Means for Solving the Problems As a result of intensive studies on the above-mentioned problems, the present inventors have found that (RS) -Nt-butyl-2-piperazinamide can be used as an optical resolving agent by using optically active dibenzoyl-tartaric acid. The inventors have found that the above-mentioned problems can be solved by dividing, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (I) characterized in that (RS) -Nt-butyl-2-piperazinamide is optically resolved using an optically active dibenzoyl-tartaric acid as an optical resolution agent. To produce optically active Nt-butyl-2-piperazinamide.

[0011]

Embedded image

(In the formula, * represents an asymmetric carbon atom.) Hereinafter, the present invention will be described in detail.

The optical resolving agent used in the present invention is optically active dibenzoyl-tartaric acid, and any of its D-form and L-form can be used.

In the present invention, (RS) -Nt-butyl-2-piperazinamide used as a raw material is
For example, a method in which dihalogeno-N-t-butyl-propionamide and N, N'-dibenzylethylenediamine are used as raw materials and then hydrogenation after ring closure, a method in which Nt-butyl-pyrazinecarboxamide is hydrogenated, and the like. A racemic mixture containing equal amounts of chemically synthesized (R) -N-t-butyl-2-piperazinamide and (S) -N-t-butyl-2-piperazinamide, or any one of these It is a mixture containing optical isomers in equal amounts or more.

In the present invention, the optical resolution of (RS) -Nt-butyl-2-piperazinamide is performed according to the following procedure and conditions.

First, 0.1 to 2.0 mol per mol of (RS) -Nt-butyl-2-piperazinamide in a solvent.
Moles, preferably 0.3-1.3 moles of (-)-dibenzoyl-L-tartaric acid or (+)-dibenzoyl-D-
Contact tartaric acid to obtain diastereomeric salts.

The solvent used here is optically active dibenzoyl-tartaric acid or (RS) -Nt-butyl-
It is not particularly limited as long as it dissolves 2-piperazinamide and does not chemically change these compounds in the solution and precipitates diastereomeric salts. For example, water, methanol, ethanol, A polar solvent such as propanol, acetone, acetonitrile, and ethyl acetate, or a mixed solvent thereof can be used. Of these, methanol is particularly preferred for obtaining a high optical resolution yield.

The amount of the solvent used is 1 to 30 times, preferably 2 to 10 times the amount of the diastereomer salt obtained theoretically.

The method of contacting the above-mentioned optical resolving agent with (RS) -Nt-butyl-2-piperazinamide includes:
(RS) -Nt-butyl-2-piperazinamide and the optical resolving agent are separately dissolved in
Examples thereof include a method of mixing under stirring at a temperature of 0 ° C. all at once or dropwise, and a method of dissolving them simultaneously or sequentially in a solvent.

Next, the solution containing the diastereomer salt obtained by the above-mentioned contact is cooled or concentrated. At that time, a seed crystal of the desired diastereomer salt may be added as necessary. As a result, a sparingly soluble diastereomer salt crystallizes.

The temperature at which the sparingly soluble diastereomer salt is precipitated from the solvent may be within the range of the freezing point to the boiling point of the solvent used, and is appropriately determined according to the purpose. Is sufficient.

Crystals of the sparingly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation. Can be purified by recrystallization from the above solvent, preferably methanol.

On the other hand, the remaining mother liquor from which the sparingly soluble diastereomer salt has been separated may be used as it is, or may be concentrated and / or cooled to precipitate a readily soluble diastereomer salt, which can be separated.

Each of the diastereomeric salts thus obtained is decomposed by an appropriate method to obtain an optical resolving agent and (R)
-Nt-butyl-2-piperazinamide, or (S)
-Nt-butyl-2-piperazineamide can be separated and collected.

The method for decomposing the diastereomer salt is arbitrary and not particularly limited. For example, a method of treating the solvent with a decomposing agent such as an acid or an alkali in a solvent can be applied. That is, the diastereomer salt is suspended in water or the like, hydrochloric acid is added as a decomposing agent, the precipitated optical resolving agent is removed, and the filtrate is concentrated to give (R) -N-t-butyl-2-yl. Piperazine amide or the hydrochloride salt of (S) -Nt-butyl-2-piperazinamide is obtained.

Further, diastereomeric salts are successively added to a sulfuric acid or hydrochloric acid aqueous solution, and the insoluble optical resolving agent is filtered off. Then, the filtrate is made alkaline with sodium hydroxide to make it n-butanol or the like. By extracting and concentrating with an organic solvent of (R), (R) -Nt-butyl-2-piperazinamide or (S) -Nt-butyl-2-piperazinamide can be obtained.

After the optical resolving agent is extracted with an organic solvent such as diethyl ether or ethyl acetate, the lower aqueous solution is made alkaline by adding sodium hydroxide, and n-butano-
Extraction and concentration with an organic solvent such as
t-butyl-2-piperazinamide or (S) -Nt
-Butyl-2-piperazinamide can be obtained.
If the lower phase aqueous solution is concentrated and crystallized as it is, (R)
-Nt-butyl-2-piperazinamide or (S)-
The sulfate and hydrochloride of Nt-butyl-2-piperazineamide are obtained.

Further, using a cation exchange resin and an anion exchange resin, an optical resolving agent and (R) -Nt-butyl-2
-Piperazinamide or (S) -Nt-butyl-2-
Optically active Nt-butyl-2-piperazinamide can also be obtained by separating from piperazine amide and then concentrating.

The optically active dibenzoyl-tartaric acid recovered by the decomposition of the diastereomer salt can be reused.

The isolated (R) -Nt-butyl-2-piperazinamide or (S) -Nt-butyl-2-piperazinamide can be purified by recrystallization or the like, if necessary.

[0031]

According to the present invention, (RS) -Nt-butyl-2-piperazinamide can be optically resolved with a very simple method in a good yield and with high optical purity.

Further, the optically active dibenzoyl-tartaric acid which is an optical resolving agent can be easily recovered from the diastereomer salt by treating with an acid or an alkali, and the recovered optical resolving agent can be used repeatedly.

[0033]

The present invention will be described below in detail with reference to examples. In the examples, the optical purity is measured as follows.

Optical purity; diastereomer salt 5 mg, N
After suspending t-butyl-2-piperazinamide in 0.5 cc of acetonitrile and adding 1 drop of triethylamine to make a homogeneous solution, or dissolving the diastereomeric salt, isolated Nt-butyl-2-isolate A solution prepared by dissolving piperazine amide in 0.5 cc of acetonitrile is prepared. There, 2,3,4,6-tetraacetyl-β-D-glucopyranosyl isothiocyanate (hereinafter abbreviated as GITC)
0.5cc of acetonitrile solution (concentration = 8mg / cc)
And left to stand at room temperature for 20 minutes.

Thereafter, 2 cc of acetonitrile was added and diluted, and analyzed under the following HPLC conditions.

HPLC conditions; column; ODS-80TM 4.6 mm * 15 cm mobile phase; CH ₃ CN / ｛(50 mM KH ₂ PO ₄ /
10% H ₃ PO ₄ ) = pH 3.0｝ = 38: 62 Flow rate; 1 cc / min Column temperature; 40 ° C. UV; 254 nm retention time; GI of (R) -Nt-butyl-2-piperazinamide
TC derivative 39.5min GI of (S) -Nt-butyl-2-piperazinamide
TC derivative 42.8 min The optical purity of the recovered optically active dibenzoyl-tartaric acid was determined by comparing the optical purity with that before forming a diastereomer salt by specific rotation.

Example 1 (RS) -Nt-butyl-2-piperazinamide 40
g in 176 cc of MeOH, and (-)-
A solution prepared by dissolving 81.36 g of dibenzoyl-L-tartaric acid / H ₂ O in 176 cc of methanol was charged into a 1-L jacket-type reaction vessel equipped with a programmed constant-temperature circulating device, a stirrer, and a condenser, and heated to 60 ° C. After maintaining at the same temperature for 1 hour, the mixture was cooled to 20 ° C. in 2 hours with stirring, and maintained for 17 hours.

The precipitated salt was filtered and dried, and 44.5 g of (S) -Nt-butyl-2-piperazinamide.
(-)-Dibenzoyl-L-tartrate was obtained as a white powder. The yield was 38% based on (RS) -Nt-butyl-2-piperazinamide, and the optical purity was 83%.
ee.

Further, by recrystallization once with 222 cc of methanol, 28.7 g of (S) -Nt-butyl-2-piperazinamide. (-)-Dibenzoyl-L was obtained.
-Tartrate with an optical purity of 99% ee, (RS) -Nt-
Obtained in a yield of 24% based on butyl-2-piperazinamide.

10 g of the obtained diastereomer salt was added to water 4
The suspension was suspended in 0 cc, and the pH was adjusted to 1.0 by adding 12N hydrochloric acid under stirring so that the temperature did not exceed 30 ° C. afterwards,
After extracting twice with 40 cc of ethyl acetate, the organic phase containing the resolving agent was separated, and (-)-dibenzoyl-L-tartaric acid was recovered at a yield of 99% without a decrease in optical purity. On the other hand, the aqueous phase
After adding a 40 wt% aqueous sodium hydroxide solution at room temperature to adjust the pH to 13.0, the mixture was extracted twice with 40 cc of n-BuOH. After concentration and drying, (S) -Nt-butyl-2-
Piperazine amide was obtained as colorless crystals with a recovery of 90% and an optical purity of 99% ee.

Example 2 The procedure of Example 1 was repeated, except that (+)-dibenzoyl-D-tartaric acid was used as the resolving agent, to give (R) -Nt-butyl-2-piperazinamide. ) -Dibenzoyl-
40 g of D-tartrate were obtained as a white powder. (RS)-
The yield was 34% based on Nt-butyl-2-piperazineamide, and the optical purity was 80% ee.

Further, 23.6 g of (R) -Nt-butyl-2-piperazinamide. (+)-Dibenzoyl-D was recrystallized once with 200 cc of methanol.
-Tartrate was obtained in a yield of 20.2% (based on (RS) -Nt-butyl-2-piperazinamide). As a result of the analysis, the optical purity of (R) -Nt-butyl-2-piperazinamide was 98.5% ee.

Example 3 A 300 cc Erlenmeyer flask was charged with 3.57 g of (RS) -Nt-butyl-2-piperazinamide in 50 c of methanol.
solution in c, (-) - dibenzoyl -L- tartaric acid · H ₂ O7.25g successively added a solution of ethyl acetate 50 cc, was stirred on heating for 1 hour at 60 ° C.. afterwards,
The mixture was stirred at room temperature for 15 hours, and the precipitated salt was filtered and dried.
61 g of (S) -Nt-butyl-2-piperazinamide. (-)-Dibenzoyl-L-tartrate as a white powder, 25% yield ((RS) -Nt-butyl-2-piperazine) (Amide standard). As a result of the analysis, the optical purity was 95% ee.

After adding 20 cc of a mixed solvent of H ₂ O and ethyl acetate at a volume ratio of 1: 1 to the precipitated salt, 12N hydrochloric acid was added to adjust the pH to 1.0. After stirring at room temperature for 30 minutes, the organic phase was separated after standing, and (-)-dibenzoyl-L-tartaric acid was recovered at 98%. The aqueous layer was made alkaline in the same manner as in Example 1, then extracted and concentrated twice with 20 cc of n-butanol, further recrystallized with isopropyl alcohol, and then (S) -N-t with an optical purity of 98% ee. 0.62 g of -butyl-2-piperazinamide (yield 70
%, (S) -Nt-butyl-2-piperazinamide.
(Based on (-)-dibenzoyl-L-tartrate) Obtained as colorless crystals.

Example 4 A 300 cc Erlenmeyer flask was charged with 3.57 g of (RS) -Nt-butyl-2-piperazinamide in methanol 25c.
A solution of 7.25 g of (−)-dibenzoyl-L-tartaric acid / H ₂ O dissolved in 25 cc of methanol was sequentially added to the solution, and the mixture was heated and stirred at 60 ° C. for 1 hour. afterwards,
(S) -Nt-butyl-2-piperazinamide.
10 mg of (-)-dibenzoyl-L-tartrate was added as seed crystals, and the mixture was stirred at room temperature for 15 hours. The precipitated salt was filtered and dried, and 2.3 g of (S) -Nt-butyl-2-piperazinamide was obtained. -(-)-Dibenzoyl-L-tartrate was obtained as a white powder (yield 23%, based on (RS) -Nt-butyl-2-piperazinamide). Diastereomeric salts were decomposed in the same manner as in Example 3, extracted with n-butanol and concentrated to obtain (S) -Nt-butyl-2-piperazinamide with an optical purity of 97% ee.

Comparative Example In a 300 cc Erlenmeyer flask, 3.57 g of (RS) -Nt-butyl-2-piperazinamide was added with 40 c of ethanol.
c) and a solution obtained by dissolving 8.95 g of (+)-10-camphorsulfonic acid in 40 cc of ethanol were sequentially added, and the same operation as in Example 3 was carried out to obtain (S) -Nt-butyl-2-. 2.5 g of piperazine amide / (+)-10-camphasulfonate as flocculent 20% yield
(Based on (RS) -Nt-butyl-2-piperazinamide). The optical purity of the obtained salt was 60% ee. Further, recrystallization from ethanol gave 1.8 g of a diastereomer salt (18% yield, (RS) -N-t).
-Butyl-2-piperazinamide standard). However, its optical purity was 83% ee.

Claims (1)

[Claims] 1. An optical system represented by the general formula (I), wherein (RS) -Nt-butyl-2-piperazinamide is optically resolved using an optically active dibenzoyl-tartaric acid as an optical resolving agent. Process for producing active Nt-butyl-2-piperazinamide. Embedded image (In the formula, * represents an asymmetric carbon atom.)