JPH07247286A - Method for optically resolving nitrogen-containing cyclic compound - Google Patents

Abstract

PURPOSE:To optically resolve a nitrogen-containing cyclic compound useful as an intermediate for medicines, etc., by treating the optical isomer mixture of the cyclic compound having an asymmetric carbon atom and a basic nitrogen atom an optically active diacyl tartaric acid, etc., and subsequently optically separating the formed isomer salts from each other by the utilization of the difference between the solubilities of the optical isomers. CONSTITUTION:A method for optically resolving a nitrogen-containing cyclic compound comprises treating the optical isomer mixture of a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring, such as a compound of formula I or II (e.g. 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1, 2-a]azepine) with an optically active diacyl tartaric acid of formula III [R<1> is acry; (S) exhibits the S configuration] (e.g. dibenzoyl-L-tartaric acid.monohydrate) or an optically active diacyl tartaric acid of formula IV [R<2> is acyl; (R) exhibits the R configuration] (e.g. dibenzoyl-D- tartaric acid.monohydrate) for forming the salt comprising the compounds in a molar ratio of 2:1, and subsequently utilizing the difference between the solubilities of the optical isomers, thus optically resolving the recemate mixture in high optical purities.

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

FIELD OF THE INVENTION The present invention relates to an efficient method for optical resolution of "a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring" which is useful as a synthetic intermediate for a compound which can be used as a medicine. And preferably relates to an efficient method for optical resolution of “a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring”, which is useful as a synthetic intermediate for a compound having an antiallergic action and an antiasthmatic action, and further Is 1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] useful as a synthetic intermediate for compounds having antiallergic and antiasthmatic activities.
The present invention relates to an optical resolution method for azepine.

[0003]

2. Description of the Related Art 1 Regarding optical resolution method, for example, as disclosed in Japanese Patent Application Laid-Open No. 3-279383, an optical resolution method of "cyclic compound having asymmetric carbon and basic nitrogen atom in the ring" For this, the following two methods are known.

[Method A]: A compound is subjected to acylation of a nitrogen atom using an optically active acylating agent, and the resulting isomer mixture is separated, deacylated and isolated. how to.

[Method B]: For racemic compounds,
A method in which 0.5 molar equivalent of an optically active diacyl tartaric acid is allowed to act, the resulting salt is separated, and then freed with a base to be isolated.

However, in [A method], an expensive acylating agent is used, and the number of steps becomes long, while [B method]
Method has a problem that the optical yield is low in one division operation and the same operation must be repeated several times.
These methods have not been industrially available.

2 Asymmetric carbon and basic nitrogen atom in the ring
The "cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring" to which the optical resolution method of the present invention can be applied to the cyclic compound having the asymmetric carbon atom and the basic nitrogen atom are present in the ring. There is no particular limitation as long as it is a 5- to 5-cyclic heterocyclic group, and there are many such known compounds. For example, 1, 2, 3, 4, 10,
14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine derivative, 1,2,3,4,1
0,14b-Hexahydropyrazino [1,2-a] pyrrolo [2,1-c] [1,4] benzazepine derivatives and the like are known, and this compound is disclosed in, for example, JP-A-3-27.
Japanese Patent No. 9383 discloses it as a synthetic intermediate of a compound having an extremely excellent antihistamine action, antiallergic action and antiasthma action.

[0008]

DISCLOSURE OF THE INVENTION The present inventors have found that "a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring"
As a result of many years of intensive research on the new optical resolution method of, a salt having a molar ratio of the optically active substance and the resolving agent of 2: 1 was preferentially crystallized unlike the known method. The present inventors have completed the present invention by finding that the dividing method is a simple method that is simple, efficient, and excellent in industrial use.

[0009]

[Constitution of the invention]

[0010]

The present invention provides a mixture of an optically active substance of the general formula (I) with a "cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring".

[0011]

[Chemical 5]

[In the formula, R ¹ represents an acyl group, and (S) represents S coordination. ] An optically active diacyl tartaric acid represented by the following or a general formula (II)

[0013]

[Chemical 6]

[In the formula, R ² represents an acyl group, and (R) represents R coordination. ] The optically active diacyl tartaric acid represented by the above formula is allowed to act, and the moles of the optically active compound of "a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring" and the compound (I) or the compound (II). A novel industrial optical resolution method of "a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring", which is characterized by forming a salt having a ratio of 2: 1 and utilizing a difference in solubility. In particular, “a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring” is 1, 2,
3,4,10,14b-hexahydrodibenzo [c,
f] pyrazino [1,2-a] azepine, which is an optical resolution method, and further includes 1,2,3,4,10,14.
b-hexahydrodibenzo [c, f] pyrazino [1,2
-A] The optically active diacyltartaric acid represented by the above general formula (I) is allowed to act on the optically active mixture of azepine, and the molar ratio of the optically active substance and the compound (I) is 2:
(R) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a, characterized in that it forms a salt of 1 and utilizes the difference in solubility. ] A new industrial optical resolution method for azepine, and
To an optically active mixture of 2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine, an optically active diacyltartaric acid represented by the above general formula (II) is added. (S) -1,2,3, which is characterized in that a salt having a molar ratio of the optically active substance and the compound (II) of 2: 1 is formed by utilizing the difference in solubility.
It is a novel industrial optical resolution method of 4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine.

The "cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring" is a 2 to 5 ring compound having at least one asymmetric carbon atom and at least one basic nitrogen atom in the ring. And a large number of such groups, for example, morphine derivatives such as morphine and codeine; tropine derivatives such as atropine; 1, 2, 3, 4, 1
0,14b-Hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine, 1,2,3,4,10,14
b-hexahydropyrazino [1,2-a] pyrrolo [2,2
There may be mentioned azepine derivatives such as 1-c] [1,4] benzazepine, preferably 1 asymmetric carbon and 1
The above-mentioned basic nitrogen atom is a 2- to 5-cyclic heterocyclic group present in the ring, and more preferably 1 asymmetric carbon and 1 "basic nitrogen atom capable of forming a salt". Is a 2- to 5-cyclic heterocyclic group present in the ring, more preferably an azepine derivative, and most preferably 1, 2, 3, 4,
10,14b-Hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine and 1,2,3,4,10,
14b-hexahydropyrazino [1,2-a] pyrrolo [2,1-c] [1,4] benzazepine.

"Acyl group" in the definition of R ¹ and R ^2.
And, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl,
8-methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl,
Alkylcarbonyl groups such as 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylheptadecylcarbonyl, nonadecylcarbonyl, aicosylcarbonyl, heniicosylcarbonyl, chloro Halogenated alkylcarbonyl groups such as acetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl "Aliphatic acyl group" such as; benzylyl group such as benzoyl, α-naphthoyl, β-naphthoyl,
2,4,6-trimethylbenzoyl, 2-toluoyl,
Lower alkylated arylcarbonyl groups such as 4-toluoyl, 4-anisoyl, 2-methoxybenzoyl,
Lower alkoxylated arylcarbonyl groups such as 2,4-dimethoxybenzoyl, 4-nitrobenzoyl, 2-
Nitrobenzoyl, nitrated arylcarbonyl groups such as 2,4-dinitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, aryl such as 4-phenylbenzoyl Arylcarbonyl group such as arylcarbonyl group, 4-bromobenzoyl, 2-bromobenzoyl, 2,4-dibromobenzoyl, 4-chlorobenzoyl, 2-chlorobenzoyl, 2,4-dichlorobenzoyl “Aromatic acyl group” such as; lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, halogen such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl. Or bird "Alkoxycarbonyl groups" such as grade alkylsilyl group lower alkoxycarbonyl group substituted with; vinyl carbonyl, "alkenylcarbonyl group" such as arylcarbonyl; benzylcarbonyl, 4
-Methoxybenzylcarbonyl, 3,4-dimethoxybenzylcarbonyl, 2-nitrobenzylcarbonyl, 4
Examples thereof include an “aralkylcarbonyl group” in which the aryl ring may be substituted with 1 to 2 lower alkoxy or nitro groups such as —nitrobenzylcarbonyl, and preferably an “aliphatic acyl group”. And “aromatic acyl group”, more preferably “aromatic acyl group”, and most preferably arylcarbonyl group, lower alkylated arylcarbonyl group, lower alkoxylated aryl group. And a lower arylalkylcarbonyl group, more preferably an arylcarbonyl group and a lower alkylated arylcarbonyl group, and most preferably a benzoyl group and a 4-toluoyl group.

The "optical resolution method" comprises a salt forming step and a freeing step of separating an optically active substance from the salt. In the salt forming step, the amount of the optical resolving agent used is such that the ratio of the optically active substance and the compound (I) or the compound (II) must be 2: 1. ) Or the type of acyl group of compound (II) (in the case of the actual weight used), the amount used can be easily calculated, and a certain range before and after the calculated amount can be calculated. Can be used. For example, when two kinds of optically active substances are present, the suitable amount of the optical resolving agent is as follows. That is, the abundance ratio of the (R) body and the (S) body is
When m: n (however, m + n = 1, 1> m, n> 0), the optimum use amount is 0.5 × mole equivalent and (0.5 × m)
m + n) molar equivalent, and a range including about 10% before and after each can be mentioned as a suitable amount to be used. Therefore,
The amount used in the case of a racemate is 0.25 molar equivalent and 0.
It becomes 75 molar equivalents.

Particularly, "a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring" is 1, 2, 3, 4, 10,
In the case of 14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine, when compound (I) is reacted to form a 2: 1 salt, (S) -1,2,
3,4,10,14b-hexahydrodibenzo [c,
Since the salt of f] pyrazino [1,2-a] azepine and compound (I) has a higher solubility, (R) -1,2,3,3
4,10,14b-Hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine can be selectively optically resolved and compound (II) is allowed to act to form a 2: 1 salt. And (R) -1,2,3,4,10,14b
-Hexahydrodibenzo [c, f] pyrazino [1,2-
a) The salt of azepine and compound (II) has a higher solubility, so (S) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] ]
Azepine can be selectively optically resolved. In this case, a compound in which the acyl group of compound (I) or compound (II) is a benzoyl group is particularly preferable as a resolving agent, and when the optically active substance is a racemate, it is usually used for a mixture of optically active substances. , 0.2-0.3 molar equivalent or 0.7
This is done by using ~ 0.8 molar equivalents.

The salt formation step is usually carried out by dropping a solution of compound (I) or compound (II) previously dissolved in a small amount of a solvent into a mixture of a mixture of an optically active substance and a solvent. The solvent used in the salt forming reaction is not particularly limited as long as it is usually used as a solvent, but preferably water, a water-soluble organic solvent, or a mixed solvent of water and a water-soluble organic solvent is used. As such a water-soluble organic solvent,
There is no particular limitation as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably ethers such as tetrahydrofuran and dioxane; methanol, ethanol and n-propanol. , Alcohols such as isopropanol; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexa Examples thereof include amides such as methylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane, and alcohols are more preferable. The solvent is preferably alcohols and hydrous alcohols, most preferably methanol and hydrous methanol containing 20% or less by volume of water.

The reaction temperature is usually 0 ° C. to reflux temperature, but preferably, the reaction temperature is maintained at about 60 ° C. to 80 ° C. during and about 30 minutes after the dropping, and then gradually cooled,
Finally, the salt is filtered at a temperature around 10 to 30 ° C.

If necessary, the desired compound thus obtained is subjected to a conventional method,
For example, it can be separated and purified by recrystallization or reprecipitation.

The free process is carried out by adding a salt and an equivalent amount or a small excess of a base to the salt to a two-phase solvent consisting of a water-insoluble organic solvent and water, and stirring the mixture. The non-water-soluble organic solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably hexane, heptane, ligroin, an aliphatic hydrocarbon such as petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; sulfoxides such as dimethyl sulfoxide and sulfolane. Can be mentioned. The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate. Alkali metal hydrogen carbonates such as potassium hydrogen carbonate and lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Sodium hydroxide, potassium hydroxide, barium hydroxide, water Alkali metal hydroxides such as lithium oxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium Alkali metal alkoxides such as t-butoxide and lithium methoxide Examples thereof include mercaptan alkali metal compounds such as methyl mercaptan sodium and ethyl mercaptan sodium, more preferably alkali metal hydrogen carbonate, alkali metal carbonate and alkali metal hydroxide, and most preferable. Is an alkali metal hydrogen carbonate.

This step is carried out in the temperature range of 0 ° C. to the reflux temperature. When an alkali metal hydroxide is used as the base, it is preferably 0 to 20 ° C., and the alkali metal hydrogen carbonate or the alkali metal carbonate is used as the base. When a salt is used, the temperature is preferably 60 ° C to 80 ° C.

After completion of the reaction, the target compound is prepared according to a conventional method.
Taken from the reaction mixture. For example, it can be obtained by separating the water-insoluble organic layer containing the target compound, washing with water or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method such as recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, such as silica gel, alumina, or magnesium-silica gel florisil. Column chromatography using various carriers; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and
Haas Co., Ltd.), a method using a synthetic adsorbent such as partition column chromatography using a carrier such as Diaion HP-20 (manufactured by Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be carried out by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

[0025]

Industrial Applicability The novel optical resolution method of the present invention is different from the known methods in that a salt having a molar ratio of the optically active substance and the resolving agent of 2: 1 is preferentially crystallized. It is an optical resolution method, which is an excellent method that can be industrially used because it is simple and efficient to obtain an optically active substance having an extremely high optical purity, and a commercially available resolving agent is used.

Hereinafter, the present invention will be described more specifically with reference to examples.

[0027]

Example 1 (R) -1,2,3,4,10,14b-hexahydro
Of dibenzo [c, f] pyrazino [1,2-a] azepine
Production (1) Salt forming step: 1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a]
Azepine racemate (100.2g, 0.40mol)
To a 10% (v / v) hydrous methanol (1200 ml) solution of dibenzoyl-L-tartaric acid monohydrate (37.6).
g, 0.1 mol) of a 10% (v / v) water-containing methanol (300 ml) solution was added dropwise at 70 to 72 ° C., and stirring was continued at the same temperature for 30 minutes. The reaction mixture was slowly cooled to 20 ° C over about 1 hour, and the precipitated crystals were collected by filtration and washed with a small amount of 10% (v / v) hydrous methanol.
Dried, (S) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine: dibenzoyl-L-tartaric acid = 2: 1 salt 1 59.2 g (yield: 67.5%) of a hydrate was obtained. Melting point: 185.5 to 186.5 ° C. (decomposition) [α] _D ²³ : + 288 ° (c = 0.20, N, N-dimethylformamide) Subsequently, the filter wash solution was concentrated to give toluene to the residue. (150
0 ml) and an aqueous sodium hydrogen carbonate solution (sodium hydrogen carbonate 5.88 g) were added, and the mixture was stirred at 70 ° C. After partitioning both layers, the organic layer was concentrated and the optical isomer ratio was (R)
Body: (S) body = 68: 32, and a mixture of 66.4
g (0.265 mol) was recovered. To this, 10% (v
/ V) Hydrous methanol (400 ml) was added and dissolved, followed by dibenzoyl-D-tartaric acid monohydrate (37.6).
g, 0.1 mol) of a 10% (v / v) aqueous methanol (200 ml) solution was added dropwise at 70 to 72 ° C., and stirring was continued at the same temperature for 30 minutes. The reaction mixture was slowly cooled to 20 ° C. over about 1 hour, and the precipitated crystals were collected by filtration and washed with a small amount of 10% (v / v) hydrous methanol.
Dried and dried with (R) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine: dibenzoyl-D-tartaric acid = 2: 1 salt 1 75.2 g (yield 85.7%) of a hydrate was obtained.

Melting point: 186.0-186.5 ° C. (decomposition) [α] _D ²³ : -278 ° (c = 0.20, N, N-dimethylformamide) Elemental analysis value (C ₅₂ H ₅₀ N ₄ O ₈ · H ₂ as O) calculated: C, 71.21; H, 5.98 ; N, 6.39 Found: C, 70.83; H, 5.98 ; N, 6.31 (2) Free process: (R) -1,2,3,4,1 obtained by (1)
0,14b-Hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine: dibenzoyl-D-tartaric acid =
2: 1 salt monohydrate (219.3 g, 0.25 mo)
l), toluene (2000 ml), water (1000 m
1) and sodium hydrogen carbonate (44.2 g, 0.525)
mol) was added and the mixture was stirred at 70 ° C. for 30 minutes. Then both layers were partitioned and the aqueous layer was re-extracted with toluene (500 ml). Match the toluene layers and add water (2 at 500 ml).
And the solvent is distilled off to obtain (R) -1, 2, 3,
Crude crystals of 4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine were quantitatively obtained. The crude crystals were recrystallized from 500 ml of toluene-isopropyl ether [1: 3 (v / v)] to obtain 100.7 g of the title compound. Also, the filtrate was concentrated and then recrystallized in the same manner to obtain 16.8 g of the title compound.

Total yield: 117.5 g (yield 93.8%) Melting point: 130.0-130.5 ° C. [α] _D ²³ : -497 ° (c = 1.00, methanol) Optical purity> 99% ee (3) Optical purity measurement conditions: Column: Chiralcel OJ (manufactured by Daicel Chemical Industries, 4.
6φ × 250 mm) Eluent: 2-propanol / hexane = 2/1; Flow rate:
0.7 ml / min; Retention time: (R) body = about 6.7 minutes (S) body = about 7.8 minutes

[0030]

EXAMPLE 2 1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine 10 (100.3 g) in racemic form (200.3 g, 0.80 mol)
% (V / v) hydrous methanol (3500 ml) solution,
Dibenzoyl-D-tartaric acid monohydrate (75.3 g,
0.2 mol) of 10% (v / v) hydrous methanol (5
(00 ml) solution was added dropwise at 70 to 72 ° C., and stirring was continued at the same temperature for 30 minutes. Then, the reaction mixture was slowly cooled to 20 ° C. over about 1 hour, and the precipitated crystals were collected by filtration, washed with a small amount of 10% (v / v) water-containing methanol and dried to obtain (R) -1, 2,3,4,10,14b
-Hexahydrodibenzo [c, f] pyrazino [1,2-
a] Azepine: Dibenzoyl-D-tartaric acid = 2: 1: 113.7 g of a salt monohydrate was obtained. In addition, about 100
After concentrating to 0 ml, the precipitated crystals were collected by filtration, washed and dried in the same manner, and then (R) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2- a]
Azepine: 1 of the salt of dibenzoyl-D-tartaric acid = 2: 1
17.6 g of hydrate was obtained. Total yield: 131.3 g (yield 74.8%) A part of the obtained salt was freed in the same manner as in Example 1, and the optical purity of the (R) form was measured. 99
% Ee.

[0031]

Example 3 1,2,3,4,10,14b-Hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine racemate (2.50 g, 10 mmol) in methanol (43.7 ml) ) A solution of dibenzoyl-D-tartaric acid monohydrate (940.9 mg, 2.5 mmol) in methanol (6.3 ml) was added dropwise to the solution under reflux, and further 30
Reflux was continued for minutes. Then, the reaction mixture was slowly cooled to 20 ° C. over about 1 hour, the precipitated crystals were collected by filtration, washed with a small amount of methanol, and dried (R) -1,
1.15 g of the salt monohydrate of 2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine: dibenzoyl-D-tartaric acid = 2: 1
(Yield 52.5%) was obtained. A part of the obtained salt was freed in the same manner as in Example 1 and the optical purity of the (R) form was measured. As a result, it was> 99% ee.

[0032]

Example 4 1,2,3,4,10,14b-Hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine racemate (2.50 g, 10 mmol) in methanol (43.7 ml) A solution of dibenzoyl-D-tartaric acid monohydrate (2.82 g, 7.5 mmol) in methanol (6.3 ml) was added dropwise to the solution under reflux, and the reflux was continued for another 30 minutes. Thereafter, the same operation as in Example 3 is performed,
(R) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine:
1.33 g (yield: 60.7%) of a monohydrate of a salt of dibenzoyl-D-tartaric acid = 2: 1 was obtained. A part of the obtained salt was freed in the same manner as in Example 1 and the optical purity of the (R) form was measured. As a result, it was> 99% ee.

[0033]

Example 5 1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine racemate (2.50 g, 10 mmol) in methanol (43.7 ml) ) To the solution, di-p-toluoyl-D-
A solution of tartaric acid monohydrate (1.01 g, 2.5 mmol) in methanol (6.3 ml) was added dropwise under reflux, and further 3
Reflux was continued for 0 minutes. Thereafter, the same operation as in Example 3 is performed,
(R) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a] azepine:
1.22 g (yield 54.1%) of a monohydrate of a salt of di-p-toluoyl-D-tartaric acid = 2: 1 was obtained. Melting point: 182 to 183 ° C. (decomposition) [α] _D ²³ : −270 ° (c = 0.20, N, N-dimethylformamide) Elemental analysis value (as C ₅₂ H ₅₀ N ₄ O ₈ .H ₂ O) Calculated: C, 71.66; H, 6.24; N, 6.12 Found: C, 71.22; H, 6.21; N, 6.19 Part of the salt obtained was carried out. The optical purity of the (R) form was measured by performing free conversion in the same manner as in Example 1 and found to be 99% e.
It was e.

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Claims (4)

[Claims] 1. A mixture of an optically active substance of "a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring" represented by the general formula (I): [In formula, R < ¹ > shows an acyl group and (S) shows S coordination. ] An optically active diacyl tartaric acid represented by the following formula or a compound represented by the general formula (II): [In the formula, R ² represents an acyl group, and (R) represents R coordination. ] The optically active diacyl tartaric acid represented by the above formula is allowed to act, and the moles of the optically active compound of "a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring" and the compound (I) or the compound (II). A method for optical resolution of "a cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring", which comprises forming a salt having a ratio of 2: 1 and utilizing the difference in solubility. 2. A "cyclic compound having an asymmetric carbon atom and a basic nitrogen atom in the ring" is 1,2,3,4,10,14b.
-Hexahydrodibenzo [c, f] pyrazino [1,2-
The optical resolution method according to claim 1, wherein a] is azepine. 3. The compound according to claim 2, wherein the compound (I) is allowed to act to form a salt. Having (R) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a]
Azepine optical resolution method. 4. The compound of formula 2, wherein compound (II) is allowed to act to form a salt. Having (S) -1,2,3,4,10,14b-hexahydrodibenzo [c, f] pyrazino [1,2-a]
Azepine optical resolution method.