JP2004161749A - Method for producing optically active, nitrogen-containing compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for recovering an optically active, nitrogen-containing compound from the salt of an optically active nitrogen-containing compound with optically active tartaric acid obtained by an optical resolution by using the optically active tartaric acid as a resolving agent. <P>SOLUTION: This optically active nitrogen-containing compound is produced simply and in a high yield by decomposing the salt of the optically active nitrogen-containing compound with optically active tartaric acid obtained by the optical resolution by using the optically active tartaric acid as a resolving agent by using an alkaline earth metal hydroxide represented by calcium hydroxide, preferably by 1.0-1.5 fold molar amount and removing the optically active tartaric acid as a hardly dissolvable salt. <P>COPYRIGHT: (C)2004,JPO

Description

  The present invention relates to a method for producing an optically active nitrogen-containing compound by desalting a salt of an optically active nitrogen-containing compound and an optically active tartaric acid.

  Optically active nitrogen-containing compounds are useful as various pharmaceutical intermediates, agricultural chemical intermediates, etc., but chemically synthesized nitrogen-containing compounds are racemic, and in order to obtain optically active compounds, optical resolution is required. It is necessary to make full use of the method. One of the useful resolving agents is optically active tartaric acid, and it is known that the optically active nitrogen-containing compound obtained by optical resolution using optically active tartaric acid forms a salt with optically active tartaric acid. ing. As a method of recovering the optically active nitrogen-containing compound from this salt, a method of extracting with an organic solvent in an alkaline aqueous solution is known. Specifically, a method of adding a high-concentration, large excess aqueous sodium hydroxide solution to a diastereomer salt and extracting the mixture with an organic solvent such as diethyl ether or benzene (Non-Patent Document 1), A method has been reported in which a large excess sodium hydroxide aqueous solution is added to separate the separated amine layer, and the operation of removing water from the amine layer with sodium hydroxide or the like is repeated, followed by distillation (Non-Patent Document 2). I have. As described above, any of the bases used in the known technique is a hydroxide of an alkali metal such as sodium hydroxide or potassium hydroxide.

  A method for producing optically active 2-methylpiperazine is known as a method described in a known literature in which an optically active nitrogen-containing compound is recovered after performing optical resolution using optically active tartaric acid. That is, (±) -2-methylpiperazine is reacted with optically active tartaric acid to produce 2-methylpiperazine monotartrate as two diastereomeric salts, and utilizing the difference in solubility in a mixed solvent thereof. This is a method of optical division. As a method for recovering optically active 2-methylpiperazine from the salt with optically active tartaric acid thus obtained, sodium hydroxide or potassium hydroxide is generally used. For example, in Patent Literature 1 and Patent Literature 2, (+)-2-methylpiperazine is recovered using sodium hydroxide, but the total yield from the crystallization step to the salt-removing step is described as 57%. No mention is made of the yield in the desalination step. In some cases, salting with sodium hydroxide was performed, but it was stated that sodium hydroxide and potassium hydroxide should be used in an amount about 4 times the molar amount of the diastereomer salt. There is no description in the examples regarding the yield in the desalination step. Further, in Patent Document 4, salt is decomposed using 2.6 times the molar amount of sodium hydroxide with respect to the diastereomer salt, and distilled under reduced pressure to obtain (R) -2-methylpiperazine. The total yield from the salting step to the distillation step is 71.0%, and even if the distillation yield is assumed to be 90%, the yield in the salting step is not satisfactory at 78.8%. .

  On the other hand, Patent Literature 5 reports an example of performing salt-decomposition using potassium hydroxide. The amount of the salt used is 0.89 to 14.4 times by mole based on the diastereomer salt. However, the yield in the desalting step was as low as 71 to 75%.

  Known examples of the method for isolating an optically active nitrogen-containing compound from a salt other than an optically active 2-methylpiperazine / optically active tartaric acid include diastereomers comprising an optically active amine and an optically active carboxylic acid or an optically active sulfonic acid. A method is known in which a salt is brought into contact with an alcohol solution containing 6 to 50% by weight of water in the presence of an alkali metal hydroxide to isolate a free amine from the alcohol layer (Patent Document 6). According to the examples of this patent, an alcohol solvent having a water content of 7% by weight was prepared from a salt of optically active 2-methylpiperazine and N-benzenesulfonyl-L-aspartic acid or a salt of 3-hydroxypyrrolidine and p-toluenesulfonyl-L-phenylalanine. The optically active nitrogen-containing compound is recovered at a high recovery rate of 97% or more by adding sodium hydroxide therein. However, in this method, since the resolving agent N-benzenesulfonyl-L-aspartic acid or p-toluenesulfonyl-L-phenylalanine is recovered as a sodium salt, it is essential to carry out the salt dissolution in an alcohol solvent. .

  Further, in Patent Document 7, an inorganic alkali is brought into contact with an optically active amine and an optically active tartrate salt in an alcohol solution in which 5 to 40% by weight of water coexists with the crystal, thereby converting the optically active tartaric acid into an inorganic alkali salt. Methods of recovery have been reported. According to an embodiment of this method, an optically active diaminocyclohexane and an optically active tartaric acid salt, an optically active 1,2-diaminopropane and an optically active tartaric acid salt, and an optically active 1-phenylethylamine and an optically active tartaric acid salt, In an alcohol solvent having a water content of 4 to 14% by weight, salt is decomposed with sodium hydroxide or potassium hydroxide to recover an optically active nitrogen-containing compound at a high recovery of 98% or more. Also in this method, it is indispensable to carry out the salt removal in an alcohol solvent in order to recover the optically active tartaric acid as a sodium salt or a potassium salt.

  However, in the case of using an alcohol solvent, recovery of the solvent is indispensable from an economical and environmental point of view, and there are concerns about problems such as the generation of impurities as a by-product when recycling is repeated.

Therefore, in a known technique, when an optically active nitrogen-containing compound is recovered from a salt with optically active tartaric acid using an alkali metal hydroxide represented by sodium hydroxide or potassium hydroxide, water alone is used. The recovery rate of the optically active nitrogen-containing compound in the desalting step using a solvent is less than 80% in all cases, and it is actually difficult to carry out the method industrially.
JP-A-3-279375 Japanese Patent No. 3032547 JP-A-1-149775 JP 2002-80459 A JP 2001-131157 A Japanese Patent No. 312449 Japanese Patent No. 312454 Journal of American Chemical Society, 81, 290 (1959) Canadian Journal of Chemistry, 54, 2639, (1976)

  Therefore, creation of a method for recovering an optically active nitrogen-containing compound in high yield from a salt of an optically active nitrogen-containing compound and an optically active tartaric acid obtained by optical resolution has been strongly desired.

  The present inventors have conducted intensive studies on a method for producing an optically active nitrogen-containing compound obtained by desolving a salt of an optically active nitrogen-containing compound and an optically active tartaric acid, and completed the present invention. That is, the present invention is characterized in that, when the optically active nitrogen-containing compound and the salt of the optically active tartaric acid are salted to recover the optically active nitrogen-containing compound, a salt of an alkaline earth metal is used in the aqueous solvent. This is a method for producing an optically active nitrogen-containing compound.

  According to the present invention, an optically active nitrogen-containing compound can be recovered in a high yield from a salt of the optically active nitrogen-containing compound and the optically active tartaric acid.

  Hereinafter, the present invention will be described in detail.

  The specific method of this reaction will be exemplified.

  The synthesis of the salt of the optically active nitrogen-containing compound and the optically active tartaric acid used in the present invention is generally carried out by dissolving or mixing the (±) -nitrogen-containing compound and the optically active tartaric acid in a solvent, and forming two types. The compound can be obtained by filtering a poorly soluble salt as a crystal using the difference in solubility between diastereomeric salts. The detailed method is as described in the known literature (JP-A-2002-80459, JP-A-2001-131157, and JP-A-3032547).

  The (±) -nitrogen-containing compound used in the synthesis of the salt of the optically active nitrogen-containing compound and the optically active tartaric acid is preferably a cyclic compound in which one or two of the atoms constituting the ring are nitrogen atoms, more preferably The number of ring members of the nitrogen compound is 4 to 7, and more preferably, the general formula (1)

（式中、Ｒは、ｉ）炭素数１〜４のアルキル基、ｉｉ）炭素数１〜４のアルコキシ基、ｉｉｉ）フェニル基、ｉｖ）アラルキル基、ｖ）ハロゲン基、ｉｖ）カルボキシル基、ｖ）カルバモイル基、ｖｉ）アルキル基の炭素数が１〜４のＮ−アルキルカルバモイル基、ｖｉｉ）水酸基、ｖｉｉｉ）アミノ基、メチルアミノ基、ジメチルアミノ基などのＮ−アルキルアミノ基を示し、式中、Ｘは、ｉ）水素原子、ｉｉ）炭素数１〜４のアルキル基、ｉｉｉ）フェニル基、ｉｖ）アラルキル基、ｖ）アシル基、ｖｉ）アルキルオキシカルボニル基、ｖｉｉ）アリールオキシカルボニル基を示す。さらに、ｎは３〜６の整数であり、且つ、ｍは１≦ｍ≦ｎを満たす整数を示す。ただし、ｍが２以上の場合、複数存在するＲが同一であっても、また異なっていてもよい。）で表される含窒素環状化合物、または一般式（２）

Wherein R is i) an alkyl group having 1 to 4 carbon atoms, ii) an alkoxy group having 1 to 4 carbon atoms, iii) a phenyl group, iv) an aralkyl group, v) a halogen group, iv) a carboxyl group, v A) a carbamoyl group, vi) an N-alkylcarbamoyl group having 1 to 4 carbon atoms in the alkyl group, vii) a hydroxyl group, viii) an N-alkylamino group such as an amino group, a methylamino group or a dimethylamino group. And X represent i) a hydrogen atom, ii) an alkyl group having 1 to 4 carbon atoms, iii) a phenyl group, iv) an aralkyl group, v) an acyl group, vi) an alkyloxycarbonyl group, and vii) an aryloxycarbonyl group. . Further, n is an integer of 3 to 6, and m is an integer satisfying 1 ≦ m ≦ n. However, when m is 2 or more, a plurality of Rs may be the same or different. Or a nitrogen-containing cyclic compound represented by the general formula (2)

（式中、Ｒは、ｉ）炭素数１〜４のアルキル基、ｉｉ）炭素数１〜４のアルコキシ基、ｉｉｉ）フェニル基、ｉｖ）アラルキル基、ｖ）ハロゲン基、ｉｖ）カルボキシル基、ｖ）カルバモイル基、ｖｉ）アルキル基の炭素数が１〜４のＮ−アルキルカルバモイル基、ｖｉｉ）水酸基、ｖｉｉｉ）アミノ基を示し、式中、ＸおよびＹは、ｉ）水素原子、ｉｉ）炭素数１〜４のアルキル基、ｉｉｉ）フェニル基、ｉｖ）アラルキル基、ｖ）アシル基、ｖｉ）アルキルオキシカルボニル基、ｖｉｉ）アリールオキシカルボニル基を示す。さらに、ｐ、ｑは０≦ｐ，ｑ≦５および３≦ｐ＋ｑ≦５を同時に満たす整数であり、式中、ｒは１≦ｒ≦ｐ＋ｑを満たす整数である。ただし、ｒが２以上の場合、複数存在するＲが同一であっても、また異なっていてもよい。）で表される含窒素環状化合物である。

Wherein R is i) an alkyl group having 1 to 4 carbon atoms, ii) an alkoxy group having 1 to 4 carbon atoms, iii) a phenyl group, iv) an aralkyl group, v) a halogen group, iv) a carboxyl group, v A) a carbamoyl group, vi) an N-alkylcarbamoyl group having 1 to 4 carbon atoms in an alkyl group, vii) a hydroxyl group, viii) an amino group, wherein X and Y are i) a hydrogen atom, ii) carbon number 1 to 4, an alkyl group, iii) a phenyl group, iv) an aralkyl group, v) an acyl group, vi) an alkyloxycarbonyl group, and vii) an aryloxycarbonyl group. Further, p and q are integers satisfying simultaneously 0 ≦ p, q ≦ 5 and 3 ≦ p + q ≦ 5, and in the formula, r is an integer satisfying 1 ≦ r ≦ p + q. However, when r is 2 or more, a plurality of Rs may be the same or different. )).

  Specifically, R is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an alkyl group such as a tert-butyl group, a methoxy group, an ethoxy group, an n-propoxy group, Alkoxy groups such as isopropoxy group, n-butoxy group and tert-butoxy group, phenyl groups such as phenyl group, o-toluyl group, m-toluyl group, p-toluyl group, p-chlorophenyl group and p-methoxyphenyl group Aralkyl groups such as benzyl group, p-chlorophenylmethyl group, halogen groups such as fluoro group, chloro group, bromo group, iodo group, carboxyl group, carbamoyl group, N-methylcarbamoyl group, N-tert-butoxycarbamoyl group, etc. N-alkylcarbamoyl group, hydroxyl group, amino group, methylamino group, dimethylamino group, etc. An N- alkyl-substituted amino group, particularly preferably a hydrogen atom, an alkyl group, an aralkyl group, a hydroxyl group, an amino group. On the other hand, X and Y represent a hydrogen atom, an alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a phenyl group, an o-toluyl group, and an m-toluyl group. Phenyl group such as p-toluyl group, p-chlorophenyl group, p-methoxyphenyl group, benzyl group, aralkyl group such as p-chlorophenylmethyl group, acetyl group, propionyl group, butanoyl group, acyl group such as benzoyl group, Alkyloxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, tert-butoxycarbonyl, vinyloxycarbonyl group and allyloxycarbonyl group, and aryloxycarbonyl groups such as phenoxycarbonyl group and benzyloxycarbonyl group Is particularly preferred A hydrogen atom, a methyl group, a benzyl group, an acetyl group, tert- butoxycarbonyl group, and the like benzyloxycarbonyl group.

  The optically active nitrogen-containing compound may be either a liquid or a solid, and the solid may be of various shapes, from a lump to a pellet that has been scraped. Various optically active tartaric acids, from natural products to synthetic products, can be used, and either D-tartaric acid or L-tartaric acid may be used. When 2-methylpiperazine is used as the nitrogen-containing compound, when D-tartaric acid is used to form a salt of (±) -2-methylpiperazine and an optically active monotartaric acid, (−)-2- Methyl piperazine, that is, a salt of (S) -2-methyl piperazine and D-tartaric acid can be obtained. On the other hand, when L-tartaric acid is used, (+)-2-methylpiperazine, that is, a salt of (R) -2-methylpiperazine and D-tartaric acid can be obtained in the same manner.

  The precipitated diastereomer salt can be easily separated from the diastereomer salt in the mother liquor by a filtration operation.

  In a conventionally known method, a diastereomer salt isolated as a crystal is salted with a water-soluble base, and then optically active by extracting optically active 2-methylpiperazine released with an organic solvent such as toluene and benzene. It can be separated and recovered from tartaric acid. However, at this time, since the optically active 2-methylpiperazine is easily soluble in water, when it is recovered by extraction, the recovery rate is less than 80%.

  The salt of the alkaline earth metal used in the present invention is not particularly limited, but is typified by hydroxide, halide, sulfate and the like of the alkaline earth metal. Specifically, hydroxides such as magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, magnesium chloride, calcium chloride, strontium chloride, chlorides such as barium chloride, magnesium bromide, calcium bromide, Strontium bromide, bromides such as barium bromide, magnesium sulfate, calcium sulfate, strontium sulfate, sulfates such as barium sulfate, magnesium carbonate, calcium carbonate, strontium carbonate, carbonates such as barium carbonate can be mentioned, preferably. Are hydroxides, chlorides and sulfates, particularly preferably hydroxides and sulfates, more preferably hydroxides, and particularly preferably calcium hydroxide. The shape of the calcium hydroxide is not particularly limited, and may be in the form of powder or granules, or may be a slurry such as water.

  The amount of the alkaline earth metal salt to be used is generally 0.5 to 3.0 mole times, preferably 0.1 mol, based on the optically active tartaric acid in the salt of the optically active nitrogen-containing compound and the optically active tartaric acid to be decomposed. The molar ratio is 8 to 2.0 times, more preferably 1.0 to 1.5 times.

  Next, there is no particular limitation on when to add the alkaline earth metal salt. The salt of the optically active nitrogen-containing compound and the salt of the optically active tartaric acid may be added to the aqueous solution, or the salt of the optically active nitrogen-containing compound and the optically active tartaric acid may be added to an aqueous slurry of calcium hydroxide. The addition of the salt of an alkaline earth metal is usually carried out at a temperature in the range of 0 to 90 ° C., but is preferably carried out at around room temperature in terms of operability and safety.

  When the nitrogen-containing compound is easily soluble in water, it is usually essential to carry out the desalting in a solvent containing 50% by weight or more of water. It is 1 to 10 times by weight, preferably 1 to 7 times by weight, and more preferably 2 to 5 times by weight of tartaric acid salt. If the amount of the solvent is too small, the slurry concentration of the alkaline earth metal salt of the optically active tartaric acid generated by the salt removal becomes too high, resulting in poor stirring, and there is a danger that the salt removal becomes insufficient. If it is too much, the amount of the salt of the optically active nitrogen-containing compound and the optically active tartaric acid is reduced, which is economically disadvantageous in terms of production efficiency.

  On the other hand, when the nitrogen-containing compound is hardly soluble in water, the optically active nitrogen-containing compound released by the salt removal can be extracted to the organic solvent layer side using an organic solvent. Specific examples of the organic solvent include benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, n-propylbenzene, isopropylbenzene, aromatic hydrocarbons such as mesitylene, n-pentane, n-hexane, aliphatic hydrocarbons such as n-heptane, n-octane, n-nonane, n-decane, 1-butanol, 2-butanol, isobutanol, 1-pentanol, 2-pentanol, 3-pentanol, Examples include alcohols such as pentanol, ethers such as diethyl ether, di-n-propyl ether, diisopropyl ether, methyl-tert-butyl ether, and tetrahydrofuran, and ketones such as methyl ethyl ketone, 2-pentanone, 3-pentanone, and methyl isobutyl ketone. Can and good Details, aromatic hydrocarbons and alcohols. In this case, the recovery of the nitrogen-containing compound can be increased by repeating the extraction operation.

  Desalting is usually performed in the range of around room temperature to 100 ° C, preferably in the range of 30 to 100 ° C, more preferably in the range of 50 to 100 ° C. If the temperature is too low, there is a risk that the salt solution will be insufficient. Usually, the time required for demineralization is from 1 to 24 hours, and the salting yield increases as the time increases, but it is disadvantageous in terms of productivity. .

  The difference between the present invention and the prior art will be clarified below by taking as an example a case where salt is dissolved using calcium hydroxide in an aqueous solvent.

In the present invention, at the end of the desalting step, optically active tartaric acid is precipitated as sparingly soluble calcium tartrate according to the following formula, and the optically active nitrogen-containing compound is present in the mother liquor.
<The present invention>
Solid (optically active nitrogen-containing compound and salt of optically active tartaric acid) + solid (calcium hydroxide)
→ Mother liquor (optically active nitrogen-containing compound) + solid (optically active calcium tartrate)
On the other hand, when salting is carried out with sodium hydroxide or potassium hydroxide as in the prior art, optically active tartaric acid is greatly different from the present invention in that it exists in a solution as a sodium salt or a potassium salt.
<Conventional technology>
Solid (salt of optically active nitrogen-containing compound and optically active tartaric acid) + (aqueous sodium hydroxide solution)
→ Solution (optically active nitrogen-containing compound) + solution (optically active sodium tartrate)
As described above, according to the present invention, optically active tartaric acid can be removed out of the system as a hardly soluble salt, so that the optically active nitrogen-containing compound and the optically active tartaric acid can be easily recovered, which is industrially very significant.

  Here, the solubility of metal tartaric acid salt in water, which is the scientific basis of the present invention, is shown.

  The solubility of the alkaline earth metal salt of tartaric acid obtained when salting is performed using a hydroxide of an alkaline earth metal is 1.22% of magnesium tartrate (26 ° C.) and 0.029% of calcium tartrate (25 ° C.) , Strontium tartrate 0.18% (25 ° C) and barium tartrate 0.028% (21 ° C), both of which are hardly soluble salts.

  On the other hand, the solubility of the alkali metal salt of tartaric acid obtained when salting is performed using an alkali metal hydroxide has a solubility of 30% for sodium tartrate (24 ° C.) and 40% for potassium tartrate (15.6 ° C.). Salt.

  Therefore, the alkali metal salt of tartaric acid, which is generated when an alkali metal hydroxide is used, is dissolved in water. Therefore, separation from the optically active nitrogen-containing compound is substantially impossible in a solvent containing 50% by weight or more of water. Impossible.

  On the other hand, when the alkaline earth metal salt of the present invention is used, it can be seen that separation from the optically active nitrogen-containing compound is easy.

  ADVANTAGE OF THE INVENTION According to this invention, the optically active nitrogen-containing compound and the salt of optically active tartaric acid are salt-decomposed using the alkali metal salt in the solvent containing 50 weight% or more of water, and an optically active nitrogen-containing compound is easily obtained. And can be recovered in high yield.

  Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

  The optically active 2-methylpiperazine is described below as an example.

  The quantitative determination of the optically active 2-methylpiperazine in the mother liquor obtained at the time of the salt dissolution was carried out by an internal standard method using gas chromatography (GC). The analysis conditions are as follows.

Model Shimadzu GC-14B
Column NEUTRABOND-1 0.25mmφ × 60m
He flow rate 50ml / min
COL temperature 70 ℃ (10min.) → (+ 20 ℃ / min) → 270 ℃ (10min.)
INJ temperature 230 ℃
DET temperature 230 ° C
DET FID
Injection volume 0.1 μl
Inner target triglyme
Retention time 2-Methylpiperazine 10.2min.
Triglyme 17.3 min.
The optical purity of the optically active 2-methylpiperazine was measured by liquid chromatography (HPLC), and was calculated from the area ratio between the R-form peak and the S-form peak. When the S body is selectively generated, it is calculated according to the following equation.

Optical purity (% ee.) = (S-form peak area-R-form peak area)
/ (Area value of S-form peak + area value of R-form peak) x 100
The analysis conditions are as follows.

Model Shimadzu LC-10Vp
Column Mightysil RP18GP, 4.6 mm x 15 cm (Kanto Chemical)
Mobile phase 0.03% aqueous ammonia (adjusted to pH 4.7 with acetic acid) / acetonitrile
= 467/33 (v / v)
Flow rate 1.0ml / min
Temperature 40 ℃
Detector UV (243nm)
A method for preparing a sample for analysis will be described. In the case of a salt of optically active 2-methylpiperazine and optically active tartaric acid, 0.3 g of the crystal of optically active 2-methylpiperazine / optically active tartaric acid is taken in a 10-ml sample bottle, and dissolved by adding 3 ml of 1N sodium hydroxide solution. 3 ml of chloroform is added thereto, and after stirring, the lower layer is collected in a 50 ml volumetric flask, and diluted to the marked line with acetonitrile. 0.3 ml of the solution is collected in a 5 ml sample bottle, 0.8% O, 0'-p-ditoluoyl-L-tartaric anhydride solution is added, and the mixture is allowed to stand in a 50 ° C warm bath for 1 hour. Finally, 1 ml of 2% phosphoric acid aqueous solution is added, and the mixture is allowed to stand for 10 minutes. After desalting, in the case of the optical purity of optically active 2-piperazine in the mother liquor, the mother liquor is first concentrated, and when it becomes cloudy, extracted twice with chloroform. Thereafter, the treatment is carried out in the same manner as in the case of the salt of optically active 2-methylpiperazine and optically active tartaric acid.

[Example 1]
75 g of water was charged into a 200 ml four-necked flask equipped with a thermometer, a condenser and a stirrer, and 25.1 g of (S) -2-methylpiperazine.D-tartrate was dried in advance (= 0.100 mol, 2-0.1 g). The optical purity of methylpiperazine = 99.5% ee.) And 7.8 g (= 0.100 mol) of 95% pure calcium hydroxide were added. The slurry was heated to 70 to 80 ° C., stirred for 3 hours, and then cooled to room temperature. Next, undissolved salts were filtered off to obtain a mother liquor.

  From the result of GC analysis in the mother liquor, it was found that 9.2 g (= 0.0918 mol) of optically active 2-methylpiperazine was present in the mother liquor (yield 91.8%). From the result of HPLC analysis, the optical purity of (S) -2-methylpiperazine was 99.5% ee. Met.

[Example 2]
75 g of water was charged into a 200 ml four-necked flask equipped with a thermometer, a condenser and a stirrer, and 25.1 g of (S) -2-methylpiperazine.D-tartrate was dried in advance (= 0.100 mol, 2-0.1 g). The optical purity of methyl piperazine = 99.3% ee.) And 9.4 g (= 0.121 mol) of 95% pure calcium hydroxide were added. The slurry was heated to 70 to 80 ° C., stirred for 3 hours, and then cooled to room temperature. Next, undissolved salts were filtered off to obtain a mother liquor.

  From the result of the GC analysis in the mother liquor, it was found that 9.3 g (= 0.0928 mol) of optically active 2-methylpiperazine was present in the mother liquor (yield 92.8%). From the results of HPLC analysis, the optical purity of (S) -2-methylpiperazine was 99.3% ee. Met.

[Example 3]
300 g of water was charged into a 1 L four-necked flask equipped with a thermometer, a condenser, and a stirrer, and 98.3 g (= 0.391 mol, 2-91 mol) of (S) -2-methylpiperazine.D-tartrate previously dried. The optical purity of methyl piperazine = 99.4% ee.) And 39.6 g (= 0.508 mol) of 95% pure calcium hydroxide were added. The slurry was heated to 80 to 82 ° C., stirred for 3 hours, and then cooled to room temperature. Next, undissolved salts were filtered off to obtain a mother liquor.

  From the result of GC analysis in the mother liquor, it was found that 39.1 g (= 0.390 mol) of optically active 2-methylpiperazine was present in the mother liquor (yield 99.8%). From the results of HPLC analysis, the optical purity of (S) -2-methylpiperazine was 99.4% ee. Met.

[Comparative example]
In a 100 ml four-necked flask equipped with a thermometer, a condenser and a stirrer, 50 g of water was charged, and 25.1 g of (S) -2-methylpiperazine.D-tartrate salt dried in advance (= 0.100 mol, 2-0.1 g) (The optical purity of methylpiperazine = 99.4% ee.) Was added and dissolved. To this, 10.8 g (= 0.130 mol) of a 48% by weight aqueous sodium hydroxide solution was added at 30 to 40 ° C., followed by stirring for 1 hour. Thereto, 50 ml of toluene was added, and the released (S) -2-methylpiperazine was extracted.

  From the result of GC analysis of the extract, it was found that 7.8 g (= 0.0779 mol) of optically active 2-methylpiperazine was present in the extract (yield: 77.9%). From the results of HPLC analysis, the optical purity of (S) -2-methylpiperazine was 99.4% ee. Met.

  INDUSTRIAL APPLICABILITY The present invention is applied to recover an optically active nitrogen-containing compound from a salt of an optically active nitrogen-containing compound and an optically active tartaric acid, but the application range is not limited thereto.

Claims (11)

When desolvating a water-soluble salt comprising an optically active nitrogen-containing compound and an optically active tartaric acid, a salt of an alkaline earth metal is used in a solvent containing 50% by weight or more of water. A method for producing a nitrogen compound. 2. The method for producing an optically active nitrogen-containing compound according to claim 1, wherein the optically active nitrogen-containing compound is a cyclic compound, and one or two of the atoms constituting the ring are nitrogen atoms. 3. The method for producing an optically active nitrogen-containing compound according to claim 2, wherein the number of ring members of the optically active nitrogen-containing compound is 4 to 7. The optically active nitrogen-containing compound has the general formula (1)

Wherein R is i) an alkyl group having 1 to 4 carbon atoms, ii) an alkoxy group having 1 to 4 carbon atoms, iii) a phenyl group, iv) an aralkyl group, v) a halogen group, iv) a carboxyl group, v A) a carbamoyl group, vi) an N-alkylcarbamoyl group having 1 to 4 carbon atoms in an alkyl group, vii) a hydroxyl group, viii) an amino group, and ix) an N-alkylamino group having 1 to 4 carbon atoms in the alkyl group. Wherein X is i) a hydrogen atom, ii) an alkyl group having 1 to 4 carbon atoms, iii) a phenyl group, iv) an aralkyl group, v) an acyl group, vi) an alkyloxycarbonyl group, vii) an aryloxycarbonyl. Represents a group. Further, n is an integer of 3 to 6, and m is an integer satisfying 1 ≦ m ≦ n. However, when m is 2 or more, a plurality of Rs may be the same or different. The method for producing an optically active nitrogen-containing compound according to any one of claims 1 to 3, characterized in that: The optically active nitrogen-containing compound has the general formula (2)

Wherein R is i) an alkyl group having 1 to 4 carbon atoms, ii) an alkoxy group having 1 to 4 carbon atoms, iii) a phenyl group, iv) an aralkyl group, v) a halogen group, iv) a carboxyl group, v A) a carbamoyl group, vi) an N-alkylcarbamoyl group having 1 to 4 carbon atoms in an alkyl group, vii) a hydroxyl group, viii) an amino group, and ix) an N-alkylamino group having 1 to 4 carbon atoms in the alkyl group. Wherein X and Y are i) hydrogen atom, ii) alkyl group having 1 to 4 carbon atoms, iii) phenyl group, iv) aralkyl group, v) acyl group, vi) alkyloxycarbonyl group, vii) aryl Indicates an oxycarbonyl group. Further, p and q are integers satisfying simultaneously 0 ≦ p, q ≦ 5 and 3 ≦ p + q ≦ 5, and in the formula, r is an integer satisfying 1 ≦ r ≦ p + q. However, when r is 2 or more, a plurality of Rs may be the same or different. The method for producing an optically active nitrogen-containing compound according to any one of claims 1 to 3, characterized in that: The method for producing an optically active nitrogen-containing compound according to claim 5, wherein X and Y in the general formula (2) are both hydrogen atoms, and p = q = 2 and r = 1. 7. The method for producing an optically active nitrogen-containing compound according to claim 5, wherein R in the general formula (2) is a methyl group. The method for producing an optically active nitrogen-containing compound according to any one of claims 1 to 7, wherein the solvent contains 80% by weight or more of water. The optically active compound according to any one of claims 1 to 8, wherein the alkaline earth metal salt is any one of a hydroxide, a halide, a sulfate, and a carbonate of the alkaline earth metal. A method for producing a nitrogen compound. The optically active compound according to any one of claims 1 to 9, wherein the alkaline earth metal hydroxide is any one of magnesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide. A method for producing a nitrogen compound. The optically active substance according to any one of claims 1 to 10, wherein the amount of the alkaline earth metal hydroxide used is 1.0 to 1.5 times the molar amount of the optically active tartaric acid. A method for producing a nitrogen compound.