JPH07300453A - Optically active sulfonium compound, therapeutic agent for allergic diseases containing the same, and method for producing the same - Google Patents

Abstract

(57) [Summary] [Objective] To provide an optically active sulfonium compound used for the treatment of allergic diseases. [Structure] General formula [I] (Wherein Y is an inorganic acid residue or an organic acid residue),
An optically active sulfonium compound used for the treatment of allergic diseases.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the following general formula [I]

[Chemical 4] The present invention relates to an optically active sulfonium compound represented by the formula (Y represents an inorganic acid residue or an organic acid residue), a therapeutic agent for allergic diseases containing the same, and a method for producing the same.

[0002]

2. Description of the Related Art Suplatast tosylate [(±)-[2-
{4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium
p-toluenesulfonate] suppresses IgE antibody production and is useful as a therapeutic agent for allergic diseases (see Japanese Patent Publication No. 3-70698). Since suplatast tosylate is a racemate and has one asymmetric carbon atom as is clear from its chemical formula, it was predicted that two optical antipodes would exist. However, the optical antipode is produced by a method of isolating it from a racemate or an asymmetric synthesis,
No studies on the physicochemical and pharmacological properties of the compound have been considered.

The racemic crystals include a racemic compound (racemic crystal) in which the enantiomer is contained in a ratio of 1: 1 in the single crystal, and a + -form single crystal and a −-form single crystal are mixed in a 1: 1 ratio. There are three types of racemic mixtures (asymmetric crystals), and racemic solid solutions in which the enantiomeric ratio of the whole racemic crystal is 1: 1 although the enantiomeric ratio in the single crystal is not constant. It is known that most of the racemic crystals are racemic compounds, and regarding suplatast tosylate, the racemic crystals produced according to Japanese Patent Publication No. 3-70698 are already prepared by the present inventors. Report made (Abstracts of the 8th Annual Meeting of the Pharmaceutical Society of Japan 48 (199
It is known from 2)) that it is mostly a racemic compound.

Regarding the difference in skin permeability between the racemic compound and the optically active substance, L.S. Sch-3 by Wearley and others
The difference in skin transmittance of 9304 has been studied, and it has been reported that the optically active substance permeates 9.1 times (Pharm. Res., Vol 0, 136 (199).
3)) has been done.

As a method for separating an optically active substance from a racemate, a preferential crystallization method (Ena) in which the optically active substance is used as a seed crystal and the same optically active substance is obtained as a crystal by recrystallization
ntiomers, Racemates and Re
solutions, John Wiley & So
ns, New York (1981)), resolution method via diastereomer (Optical Resolutei)
on Procedures for Chemica
l Compounds, Vol 1-3, Optic
al Resolution Information
Center, New York (1978-198)
4)), a method utilizing complex formation with a synthetic optically active host (Top. Curr. Chem., 140, 43 (1)
987)), direct chromatographic resolution (L
iq. Chromatogr. , 2, 1063 (197)
9)), a division method using an enzyme (enzyme function and precision organic synthesis, CMC (1984)) and the like are generally known.

First, the optical resolution of the racemate by the recrystallization method does not require a special apparatus itself, and the work for recrystallization is simple, so that the workability is excellent and the cost is low. Since it can be made cheaply, it can be said that it is superior to the remaining division methods. By the way, when a racemate is recrystallized, a racemic mixture is crystallized by repeating homochiral interaction, a racemic compound is preferentially crystallized by heterochiral interaction, or a racemic solid solution is produced. Therefore, in the case of optical resolution by the recrystallization method, it may be possible to perform the resolution by the recrystallization method (preferential crystallization method) in the case of a racemic mixture. Therefore, Nohira et al. (Chem. Lett.,
1981, 951). However, even if it is a racemic mixture, it is practically impossible to obtain one of the optically active substances by the recrystallization method without inoculating the seed crystal, unless the crystals are large enough to be discerned by a magnifying glass or a microscope. There is a problem.

On the other hand, in the case of a racemic compound, it is impossible to perform optical resolution by the preferential crystallization method,
A report that an optically active sulfide was recovered by enhancing the optical purity by sublimating a non-racemic solution (J. Or.
g. Chem. , 32, 1867 (1966)) and optically active hydrophilic amino acids using a small amount of hydrophobic amino acids (J. Am. Chem. So.
c. , 110, 561 (1988)), and the like, and the racemic compound is generally optically resolved by a resolution method via a diastereomer, and the enantiomer is an optically active substance. It has not yet been known that optical resolution can be achieved only by recrystallization without using.

[0008]

DISCLOSURE OF THE INVENTION The present invention provides the following general formula [I] showing excellent skin permeability.

[Chemical 5] (In the formula, Y represents an inorganic acid residue or an organic acid residue), a novel optically active sulfonium derivative having excellent skin permeability, a therapeutic agent for allergic diseases containing the same, and a method for producing the same To provide.

[0009]

Means for Solving the Problems The present inventor has been earnestly researching the optical resolution of suplatast tosylate, and it has been generally considered that the racemic compound cannot be optically resolved by the recrystallization method. The present invention has been completed by finding that the optically active substance can be resolved in a high yield, and that the optically active substance optically resolved by these methods is superior in skin permeability as compared with the racemate. That is, the present invention has the following general formula [I]

[Chemical 6] (In the formula, Y represents an inorganic acid residue or an organic acid residue), an optically active sulfonium compound, a therapeutic agent for allergic diseases containing the same, and a method for producing the same.

In the formula, the inorganic acid residue represented by Y is
Hydrochloric acid such as hydrogen chloride, hydrogen bromide and hydrogen iodide, nitric acid, sulfuric acid, tetrafluoroboric acid, perchloric acid, phosphoric acid, metaphosphoric acid and other acid residues, and organic acid residues include methane. Sulfonic acid, toluene sulfonic acid, nitrobenzene sulfonic acid, picryl sulfonic acid, camphor sulfonic acid, 1,
Sulfonic acid residues such as 5-naphthalenedisulfonic acid, and acetic acid, propionic acid, isobutyric acid, fumaric acid, tartaric acid, stearic acid, citric acid, lactic acid, maleic acid, oleic acid, malonic acid, benzoic acid, ascorbic acid, glycyrrhizin Examples thereof include acids and nicotinic acid. Among these acid residues, a sulfonic acid residue is particularly preferable, and an optionally substituted aryl sulfone such as benzenesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, and 1,5-naphthalenesulfonic acid. Acids are more preferred.

The compounds included in the compound of the present invention include: R (-)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-toluenesulfonate (Compound 1 ) S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-toluenesulfonate (Compound 2) R (-)-[2- {4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium benzenesulfonate (Compound 3) S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] Dimethylsulfonium benzenesulfonate (Compound 4) R (- -[2- {4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-nitrobenzenesulfonate (Compound 5) S (+)-[2- {4- (3-ethoxy-2) -Hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-nitrobenzenesulfonate (Compound 6) is exemplified, and Compounds 1 and 2 in which Y is a p-toluenesulfonic acid residue are particularly preferable. The optically active compound of the present invention can be produced by asymmetric synthesis according to the following reaction process formula according to the production method described in Japanese Patent Publication No. 3-70698 or by recrystallizing a racemate of the compound of the present invention. .

<Reaction Process Formula>

[Chemical 7] (In the formula, Y represents the same meaning as described above.)

[Step A] 3-represented by the chemical formula [II]
Methylpropionyl chloride and its optically active chemical formula [I
II] represented by the chemical formula [IV] by reacting 4- (3-ethoxy-2-hydroxypropoxy) aniline represented by II] in the presence of triethylamine.
{4- (3-ethoxy-2-hydroxypropoxy)
Phenylcarbamoyl} ethyl methyl sulfide is prepared. [Step B] The compound of the present invention can be produced by reacting the compound represented by the chemical formula [IV] with the compound represented by the general formula [V]. Details of this manufacturing method are described in Japanese Examined Patent Publication No. 3-70698 and Examples below.

The optically active compound represented by the general formula [III] is produced by the following reaction process formula.

[Chemical 8] The optically active glycidyl tosylate represented by the chemical formula [III-1] is reacted with nitrophenol and sodium hydride to give 4- (3-
Ethoxy-2-hydroxypropoxy) nitrobenzene is obtained. Next, this compound can be catalytically reduced using palladium-carbon to obtain an optically active compound represented by the chemical formula [III]. Details of this production are described in Examples below.

The production method by recrystallization is represented by the following general formula [I]

[Chemical 9] (In the formula, Y represents an inorganic acid residue or an organic acid residue.) The racemic and non-racemic sulfonium compounds are recrystallized a plurality of times for resolution.

More specifically, the racemic or non-racemic form is dissolved in a solvent until it becomes supersaturated, and the dissolved form is added or seed crystals are seeded with the racemic form or optically active form to precipitate crystals. After that, the (+) or (−) optically active substance is obtained from the residual liquid after removing the precipitated crystals. The feature of this method is that the optically active substance is not separated in the precipitated crystal, but the (+) or (−) optically active substance is specifically divided in the residual liquid. By recrystallizing again, the optically active substance having an optical rotation opposite to that of the previously resolved optically active substance is separated in the residual liquid, which means that even a racemic substance can be resolved. It is not possible to predict whether the optically active substance that is resolved in the first recrystallization is the R (-) form or the S (+) form, but it is necessary to measure the degree of optical rotation and to show it in Examples described later. Can be determined by calculating the optical purity by the HPLC method. The configuration of the optically active substance in the residual liquid in the subsequent recrystallization is, for example, the S (+) form in the second recrystallization if the first residual liquid has the R (−) form. The opposite compounds are optically resolved alternately.

The racemic compound to be optically resolved according to the present invention does not have to be a 100% racemic compound, and a racemic mixture or a racemic solid solution may be mixed, and further, the optical purity is + or -It may be a non-racemic compound deviated to the excess side.

The recrystallization solvent used in the present invention is
Alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, dimethylethanol and 2-methylpropanol, halogenated hydrocarbons such as dichloromethane and chloroform, acetone, methyl ether ketone, etc. Alkyl ketones, diethyl ether, diisopropyl ether,
Ethers such as tetrahydrofuran and dioxane, acetic acid esters such as methyl acetate and ethyl acetate, aliphatic hydrocarbons such as hexane, heptane and octane, aprotic polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide. Examples thereof include one kind of water, water and the like, or a mixed solvent of the above various organic solvents, and alcohols are particularly preferable.

The concentration of the starting mixture of each optically active substance in the supersaturated solution depends on the kind of the solvent, the environmental temperature and the relative ratio of each optically active substance, but in many cases, it is 2 W / W% or more, preferably. Is 10 to 50 W / W%.

The temperature for precipitating crystals from the supersaturated solution can be appropriately selected depending on the type of solvent used, the optical purity to be obtained, the amount of recovery and the time required for recovery, but practically it is -30 ° C. -40 ° C, preferably-
It is 30 ° C to 25 ° C. Depending on the solvent used, the solution may freeze, but this is not the case.

A typical racemic compound of the sulfonium compound represented by the general chemical formula [I] which can be used in the present invention is represented by the chemical formula [VI] in which Y is a sulfonic acid residue (±). -[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-toluenesulfonate (common name: suplatast tosylate), chemical formula [V
II] represented by (±)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl}
Ethyl] dimethyl sulfonium benzene sulfonate (common name: suplatast benzene sulfonate), (±)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethyl sulfonium p represented by the chemical formula [VIII] -Nitrobenzene sulfonate (common name: p-nitrobenzene sulfonic acid suplatast) etc. can be illustrated.

[Chemical 10]

The reason why the sulfonium compound represented by the general formula [I] can be optically resolved by the recrystallization method is that the melting enthalpy of the racemate is substantially the same as the melting enthalpy of the optically active substance. It can be inferred that it is due to that. In other words, the racemic compound has a racemic compound (R
S-type) and two kinds of optically active substances (RR-type and SS-type) exist, but when recrystallizing them, if the solute concentration is high in a supersaturated state, in the solution,

[Chemical 11] Reversible solute reaction occurs. Of these, the reaction,
When the equilibrium of 1 proceeds to the right, the resulting crystals become a racemic mixture, and when the equilibrium of the reaction proceeds to the right, the resulting crystals become a racemic compound. Here, if the solubility of the racemic compound is lower than that of the optically active substance, the racemic compound is preferentially crystallized as it is. On the other hand, if the enthalpies of fusion of the racemic compound and each of the optically active substances are substantially the same, the enthalpies of crystallization are considered to be close, and therefore, a racemic solid solution is produced or is induced by crystallization of the racemic compound. Part or part of the reaction proceeds to the right to generate a crystal of an optically active substance, which serves as a nucleus to precipitate a crystal of the optically active substance on the side together with a racemic compound, and as a result, in the recrystallized mother liquor, It is inferred that the ratio of the opposite optically active substance is increased and the compound is optically resolved.

Therefore, in the present method, the higher the stability of the racemic supersaturated solution and the more difficult it is to crystallize, the longer the equilibrium between solutes exists, and the more the above phenomenon occurs.

It can be said that a compound which can be optically resolved by this method is a compound having the following conditions. That is, in the compound, the enthalpies of crystallization between the racemate and each optically active substance are similar, the stability of the supersaturated solution is high, and the compound does not crystallize easily. Further, as a typical method of the recrystallization method, there is a method according to the following (I) to (VII). (I) A racemic mixture of optically active substances is dissolved in a soluble solvent under heating to bring it into a supersaturated state, and crystals are precipitated by leaving it at a constant temperature. The optical purity of the recrystallized mother liquor left to stand is examined, and when the target optical purity is reached, the recrystallized mother liquor is separated, and the solvent is distilled off or concentrated to bring it to a supersaturated state, whereby the optically active substance or One of the crystals, which is rich in optical activity, can be obtained. (II) If a soluble solvent is added again to the crystals generated in the operation of (I), and the mixture is heated to dissolve to a supersaturated state and left at a constant temperature, the optically active substance opposite to (I) is enriched. The recrystallized mother liquor can be obtained. By carrying out the same operation as in (I), an optically active substance opposite to (I) or a crystal rich in optical activity opposite to (I) can be obtained from this recrystallization mother liquor. (III) In carrying out (I) and (II),
The raw material racemate may be inoculated as a seed crystal in order to promote crystal growth, or it may be left undissolved when the supersaturated solution is not completely dissolved, and further stirred It is efficient. (IV) Instead of preparing a supersaturated solution, a racemic or optically active mixture is heated to a temperature equal to or higher than the melting point to melt, or a soluble solvent is added as it is to obtain a saturated solution, which is then cooled. To make it supersaturated,
It is also possible to operate in the same manner as (I). (V) In carrying out (I), (II) and (IV), it is possible to achieve a supersaturated state by adding an insoluble solvent instead of leaving or cooling. (VI) The recrystallized mother liquor of high optical purity obtained by optical resolution is distilled off under reduced pressure, and the residue is heated and dissolved in a solvent having low solubility so that almost all the crystals can be recovered quickly. By leaving it under various conditions, an optically active substance with high optical purity can be obtained. In carrying out (VII) and (VI), it is desirable to inoculate the optically active substance to be obtained.

When the compound of the present invention thus obtained is used as a therapeutic agent for allergic diseases, it is usually formulated by incorporating a pharmacologically acceptable pharmaceutical carrier. As the carrier, those usually used in the art can be used, and examples thereof include an excipient, a binder, a lubricant and a disintegrant.

The dosage unit form of the preparation of the present invention may be either oral or parenteral, and examples of the oral dosage form include tablets, pills, powders, solutions, suspensions, emulsions, granules, Examples of the parenteral preparation form include capsules and the like, and injections, suppositories, ointments, creams, gel ointments, patches, tapes, nasal drops, eye drops and the like can be illustrated. Particularly preferred are suppositories, ointments, creams, gel ointments,
It is a dosage form in which a drug can be administered by transdermal absorption of a patch, tape, eye drop, nasal drop, and the like.

In the case of molding into tablets, as a carrier, for example, lactose, sucrose, sodium chloride, glucose,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, simple syrup, glucose solution,
Starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters , Sodium lauryl sulphate, monoglyceride stearate, starch, disintegrants such as lactose, sucrose, stearic acid, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulphate, glycerin A moisturizing agent such as starch, an adsorbent such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and a lubricant such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Further, the tablets may be tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets and multilayer tablets.

In the case of molding in the form of pills, as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc., binders such as gum arabic powder, tragacanth powder, gelatin etc. , Laminaran,
A disintegrant such as agar can be used. In the case of molding into a suppository, a carrier such as polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semisynthetic glyceride or the like can be used. Capsules are prepared by mixing the compound of the present invention with the various carriers exemplified above and filling hard gelatin capsules, ointment capsules and the like. When prepared in the form of paste, cream and gel, for example, white petrolatum, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicone, bentonite and the like can be used as a diluent.

The amount of the compound of the present invention contained in the preparation is not particularly limited and may be appropriately selected, but it is usually about 1 to 70% by weight in the preparation. In addition to the above components, the formulation may contain a colorant, a flavoring agent, a preservative, an antioxidant and the like, if necessary. Examples of the preservative include methylparaben, propylparaben, thymol and the like. Examples of the antioxidant include dibutylhydroxytoluene and propyl gallate. Examples of the ultraviolet absorber include oxybenzone and ethyl paraaminobenzoate.

Formulation examples will be specifically described below. Formulation Example 1 (1) Compound 1 5.0 parts (2) 1,3-butylene glycol 5.0 parts (3) Stearic acid 3.0 parts (4) Stearyl alcohol 0.5 parts (5) Beeswax 0 0.5 parts (6) glyceryl monostearate 3.0 parts (7) polyoxyethylene (5 mol) hydrogenated castor oil 0.5 parts (8) diethyl sebacate 0.25 parts (9) white petrolatum 82.25 parts The components (1) and (2) were dissolved under heating at 50 ° C. to prepare a mixture I. On the other hand, the components (3) to (9) were uniformly mixed under heating at 75 ° C to prepare a mixture II. Next,
Mixture II is added with stirring under heating at 60 ° C., and the whole is allowed to cool to obtain an external preparation.

[Formulation Example 2] (1) Compound 2 5.0 parts (2) Polyethylene glycol 400 12.5 parts (3) Methylparaben 0.1 part (4) Stearic acid 3.0 parts (5) Stearyl alcohol 0.5 parts (6) Beeswax 0.5 parts (7) Glyceryl monostearate 3.0 parts (8) Polyoxyethylene (5 mol) hydrogenated castor oil 0.5 parts (9) Diethyl sebacate 1.0 parts (10) White petrolatum 73.8 parts (11) Propylparaben 0.1 part Components (1) to (3) were dissolved under heating at 50 ° C to prepare a mixture I. On the other hand, the components (4) to (11) were uniformly mixed under heating at 75 ° C to prepare a mixture II. Next, the mixture II is added with stirring at a temperature of 60 ° C. while stirring, and the whole is allowed to cool to obtain an external preparation.

[0032]

[Effects] The present invention is capable of optically separating an optically active substance having a high bioavailability from a racemic body of the sulfonium compound by this constitution, which is a recrystallization method which is simple in equipment and does not require a special device. It can be manufactured with high purity.

[0033]

EXAMPLES The contents of the present invention will be described in more detail with reference to some experimental examples for carrying out the present invention together with comparative examples, but the present invention is not limited thereto.

Experimental Example 1 Preparation of R (-)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-toluenesulfonate (Compound 1) (R)- Synthesis of 4- (3-ethoxy-2-hydroxypropoxy) nitrobenzene To a mixed solution of 0.189 g of sodium hydride (washed with hexane) and 6 ml of anhydrous dimethylformamide, 0.962 g of p-nitrophenol and 3 ml of anhydrous dimethylformamide under ice cooling. After dropwise adding the mixed solution of, the mixture is stirred at the same temperature for 15 minutes.
(2R)-(-) glycidyl tosylate 1.5 at the same temperature
A mixture of g and 3 ml of anhydrous dimethylformamide is added dropwise. Stir for 15 minutes at the same temperature and for 3 days at room temperature.
The reaction solution is dried under reduced pressure at room temperature, 40 ml of ether is added to the residue, and impurities are removed by filtration. The filtrate is concentrated under reduced pressure at room temperature, 30 ml of absolute ethanol and 9 drops of concentrated sulfuric acid are added to the residue, and the mixture is refluxed for 1 hour. After release, 120 ml of chloroform
Add, and wash and concentrate. The residue was subjected to silica gel column chromatography (silica gel 150 ml) and eluted with ethanol / chloroform (1: 1) to obtain 0.69 g (yield 43.7%) of the title compound as a pale yellow oil. H ¹ -NMR (100 MHz DMSO-d6) δ:
1.11 (3H, t, J = 7Hz), 3.3-3.6
(2H, m), 3.47 (2H, q, J = 7Hz),
3.8-4.3 (3H, m), 5.20 (1H, d, J
= 5 Hz), 7.16 (2H, d, J = 9 Hz), 8.
20 (2H, d, J = 9 Hz) Synthesis of (R) -4- (3-ethoxy-2-hydroxypropoxy) aniline (R) -4- (3-ethoxy-2-hydroxypropoxy) nitrobenzene 0.575 g, 20 ml of ethanol
And a mixed solution of 60% of 5% Pd-C are catalytically reduced at room temperature and 2 atm (reaction time 3 hours). The reaction solution was filtered, and the filtrate was concentrated to obtain 0.238 g (yield 47.3%) of the title compound as a light brown oily substance. H ¹ -NMR (100 MHz DMSO-d6) δ:
1.10 (3H, t, J = 7Hz), 3.2-3.6
(2H, m), 3.44 (2H, q, J = 7Hz),
3.65-4.0 (3H, m), 4.61 (2H, b
s), 4.97 (1H, d, J = 5Hz), 6.4
6.8 (4H, m) (R) -2- {4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl methyl sulfide synthesis (R) -4- (3-Ethoxy-2-hydroxypropoxy) ) In a mixed solution of 2.11 g of aniline, 20 ml of dichloromethane and 1.12 g of triethylamine, at 20 ° C or lower, 3-
1.38 g of methyl mercaptopropionyl chloride are added dropwise. After stirring at the same temperature for 30 minutes, the mixture is further stirred at room temperature for 3 hours. The reaction solution was twice with 10 ml of 2N hydrochloric acid and 10 m of water.
Wash twice with 1 and dehydrate dry over magnesium sulfate. 20 ml of ether is added to the residue, suspended and then filtered.
The crystals collected by filtration were recrystallized from benzene to give the title compound 1.
69 g (yield 54.2%) was obtained. Melting point 101-102
° C. Elemental analysis Calculated value as C ₁₅ H ₂₃ NO ₄ S C: 57.49 H: 7.40 N: 4.47 Measured value C: 57.32 H: 7.07 N: 4.41 H ¹ -NMR (100 MHz DMSO-d6) δ:
1.11 (3H, t, J = 7Hz), 2.08 (3H,
S), 2.4-2.9 (4H, m), 3.2-3.6.
(2H, m), 3.45 (2H, q, J = 7Hz),
3.7-4.0 (3H, m), 5.06 (1H, d, J
= 5 Hz), 6.87 (2H, d, J = 9 Hz), 7.
49 (2H, d, J = 9Hz), 9.81 (1H, b
s) Synthesis of R (-)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-toluenesulfonate (Compound 1) (R) -2- {4- ( A mixture of 30 g of 3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl methyl sulfide, 100 ml of dichloromethane and 72 g of methyl p-toluenesulfonate is stirred at room temperature for 12 days. 300 ml of methyl ethyl ketone is added to the reaction solution, and the mixture is stirred at room temperature for 30 minutes and then left standing. After removing the supernatant by decantation, 100 ml of acetone is added, and the mixture is stirred at room temperature for 30 minutes. After standing (2 days) until crystallization,
Filter. The crystals collected by filtration were purified with ethanol / ether to give the title compound (24.9 g) as white crystals (yield 52.1).
%) Was obtained. Mp 83-85 Calculated ℃ Elemental analysis _{C 23 H 33 NO 7 S 2} C: 55.29 H: 6.66 N: 2.80 Found C: 55.03 H: 6.56 N: 2.87 FAB-MS m / z = 328 (M-tosylic acid +)

[Outer 1] H ¹ -NMR (100 MHz DMSO-d6) δ:
1.10 (3H, t, J = 7Hz), 2.28 (3H,
S), 2.93 (6H, S), 2.93 (2H, t, J
= 6 Hz), 3.2-3.6 (4H, m), 3.45
(2H, q, J = 7Hz), 3.7-4.0 (3H,
m), 5.07 (1H, d, J = 5Hz), 6.89
(2H, d, J = 9 Hz), 7.11 (2H, d, J =
8 Hz), 7.50 (2H, d, J = 8 Hz), 7.5
0 (2H, d, J = 9Hz), 10.14 (1H, b
s)

[Experimental Example 2] Production of S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-toluenesulfonate (Compound 2) The following compounds were synthesized by the same method as in 1. (R) -4- (3-Ethoxy-2-hydroxypropoxy) nitrobenzene pale yellow oil H ¹ -NMR (100 MHz DMSO-d6) δ:
1.11 (3H, t, J = 7Hz), 3.3-3.6
(2H, m), 3.47 (2H, q, J = 7Hz),
3.8-4.3 (3H, m), 5.20 (1H, d, J
= 5 Hz), 7.16 (2H, d, J = 9 Hz), 8.
20 (2H, d, J = 9 Hz) (S) -4- (3-ethoxy-2-hydroxypropoxy) aniline Light brown oil H ¹ -NMR (100 MHz DMSO-d6) δ:
1.10 (3H, t, J = 7Hz), 3.2-3.6
(2H, m), 3.45 (2H, q, J = 7Hz),
3.65-4.0 (3H, m), 5.0 (3H, b
s), 6.4-6.8 (4H, m) (S) -2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethylmethyl sulfide Melting point 101 to 102.5 ° C Elemental analysis C Calculated value for ₁₅ H ₂₃ NO ₄ S C: 57.49 H: 7.40 N: 4.47 Measured value C: 56.95 H: 6.98 N: 4.38 H ¹ -NMR (100 MHz DMSO-d6 ) Δ:
1.11 (3H, t, J = 7Hz), 2.08 (3H,
S), 2.4-2.9 (4H, m), 3.2-3.6.
(2H, m), 3.45 (2H, q, J = 7Hz),
3.7-4.0 (3H, m), 5.06 (1H, d, J
= 5 Hz), 6.87 (2H, d, J = 9 Hz), 7.
49 (2H, d, J = 9Hz), 9.82 (1H, b
s) S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-toluenesulfonate (Compound 2) white crystals, melting point 82-84 ° C elemental analysis C ₂₃ Calculated value for H ₃₃ NO ₇ S ₂ C: 55.29 H: 6.66 N: 2.80 Actual value C: 54.91 H: 6.36 N: 2.81 FAB-MS m / z = 328 ( M-tosylic acid +)

[Outside 2] H ¹ -NMR (100 MHz DMSO-d6) δ:
1.10 (3H, t, J = 7Hz), 2.28 (3H,
S), 2.93 (6H, S), 2.93 (2H, t, J
= 6 Hz), 3.2-3.6 (4H, m), 3.45
(2H, q, J = 7Hz), 3.7-4.0 (3H,
m), 5.07 (1H, d, J = 5Hz), 6.89
(2H, d, J = 9 Hz), 7.11 (2H, d, J =
8 Hz), 7.49 (2H, d, J = 9 Hz), 7.5
0 (2H, d, J = 8Hz), 10.14 (1H, b
s)

The melting point, the enthalpy of fusion, and the solubility in isopropanol of each optically active substance of the racemate and the minus form (compound 1) and the plus form (compound 2) obtained by the methods of Experimental Examples 1 and 2 above were measured. Is shown in Table 1. The melting point was measured by using differential thermal analysis.

[Table 1]

[Experimental Example 3] Production of R (-)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium benzenesulfonate (Compound 3) Methyl p-toluenesulfonate The title compound was synthesized by the same method as in Experimental Example 1 except that methyl benzenesulfonate was used instead of. Melting point 110.1 ° C. H ¹ -NMR (270 MHz DMSO-d6) δ:
1.11 (3H, t, J = 7Hz), 2.93 (6H,
S), 2.93 (2H, t, J = 6Hz), 3.4-
3.6 (4H, m), 3.45 (2H, q, J = 7H
z), 3.8-4.0 (3H, m), 5.07 (1H,
d, J = 4 Hz), 6.89 (2H, d, J = 9H)
z), 7.31 (3H, m), 7.48 (2H, d, J
= 9 Hz), 7.61 (2H, m), 10.11 (1
H, S)

Experimental Example 4 Preparation of S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium benzenesulfonate (Compound 4) Methyl p-toluenesulfonate The title compound was synthesized by the same method as in Experimental Example 2 except that methyl benzenesulfonate was used instead of. Melting point 108.7 ° C. H ¹ -NMR (270 MHz DMSO-d6) δ:
1.10 (3H, t, J = 7Hz), 2.93 (6H,
S), 2.93 (2H, t, J = 6Hz), 3.4-
3.6 (4H, m), 3.45 (2H, q, J = 7H
z), 3.8-4.0 (3H, m), 5.06 (1H,
d, J = 4 Hz), 6.89 (2H, d, J = 9H)
z), 7.31 (3H, m), 7.48 (2H, d, J
= 9 Hz), 7.61 (2H, m), 10.11 (1
H, S)

Experimental Example 5 Preparation of R (-)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-nitrobenzenesulfonate (Compound 5) p-Toluenesulfone The title compound was synthesized by the same method as in Experimental Example 2 except that methyl p-nitrobenzenesulfonate was used instead of methyl acidate. Oily H ¹ -NMR (270 MHz DMSO-d6) δ:
1.11 (3H, t, J = 7Hz), 2.93 (6H,
S), 2.93 (2H, t, J = 5Hz), 3.4-
3.5 (4H, m), 3.48 (2H, q, J = 7H
z), 3.8-4.0 (3H, m), 5.07 (1H,
d, J = 3 Hz), 6.90 (2H, d, J = 9H)
z), 7.47 (2H, d, J = 9 Hz), 7.84
(2H, d, J = 9 Hz), 8.20 (2H, d, J =
9Hz), 10.08 (1H, S)

Experimental Example 6 Preparation of S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium p-nitrobenzenesulfonate (Compound 6) p-Toluenesulfone The title compound was synthesized by the same method as in Experimental Example 2 except that methyl p-nitrobenzenesulfonate was used instead of methyl acidate. Oily H ¹ -NMR (270 MHz DMSO-d6) δ:
1.11 (3H, t, J = 7Hz), 2.93 (6H,
S), 2.93 (2H, t, J = 5Hz), 3.4-
3.5 (4H, m), 3.48 (2H, q, J = 7H
z), 3.8-4.0 (3H, m), 5.06 (1H,
d, J = 4 Hz), 6.90 (2H, d, J = 9H
z), 7.47 (2H, d, J = 9 Hz), 7.84
(2H, d, J = 9 Hz), 8.20 (2H, d, J =
9Hz), 10.08 (1H, S)

[Experimental Example 7] 10 ml of methanol was added to 9.2 g of racemic suplatast tosylate produced according to the method described in Japanese Examined Patent Publication No. 3-70698, and 4
After heating to 0 ° C and dissolving, diisopropyl ether 2
0 ml was added and the mixture was left at -30 ° C for 3 days. The precipitated crystals were filtered off, and the obtained recrystallized mother liquor was distilled under reduced pressure to remove the solvent to obtain 0.2535 g of an oily substance (recovery rate 5.5%, optical purity 97.5% ee (+ excess)). Obtained. After adding 10 ml of methanol to the precipitated crystals and heating to 40 ° C. to dissolve the crystals, 20 ml of diisopropyl ether was added, and −30 ° C.
Left for 47 days. The precipitated crystals were separated by filtration, and the obtained recrystallized mother liquor was distilled under reduced pressure to remove the solvent to obtain R (-)-[2-
{4- (3-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl} ethyl] dimethylsulfonium
p-toluenesulfonate (Compound 1) oily substance 0.17
70 g (recovery rate 3.8%, optical purity 98.2% ee (-
Excess)) was obtained. As a reference, the first time of Experimental Example 3,
Liquid chromatograms of the oily substance obtained in the second time are shown in FIGS. 1 and 2. FIG. 1 is a liquid chromatogram of the oily substance obtained from the first recrystallization mother liquor, and it was also observed from this that the + form of suplatast tosylate was optically resolved with high optical purity. On the other hand, FIG. 2 is a liquid chromatogram of an oily substance obtained from the second recrystallization mother liquor,
It was also observed from this that the negative form of suplatast tosylate was optically resolved with high optical purity.

[Experimental Example 8] Ethanol was added to 20.00 g of (-)-Suplatast tosylate having an optical purity of 8.2% ee.
40 ml of the solution was added and heated to 70 ° C to dissolve,
It was left at -30 ° C for 7 days. The precipitated crystals were separated by filtration, and the obtained recrystallized mother liquor was distilled under reduced pressure to remove the solvent to obtain 3.27 g of an oily substance (recovery rate 30.3%, optical purity 98.6%).
ee (-excess) was obtained. After mixing 10 ml of acetone with the obtained oily substance, 5 ml of diisopropyl ether was added, 1 to 2 mg of (−)-suplatast tosilate was inoculated, and the mixture was allowed to stand at −30 ° C. for 3 days, and the precipitated crystals were filtered. It was taken and dried at room temperature under reduced pressure for 2 days to give 2.81 g of (−)-supratast tosilate (recovery rate from oily product: 86.
0%, optical purity 98.4% ee) was obtained. Crystals obtained by the first recrystallization ((+) with an optical purity of 6.0% ee
-Suplatast tosylate) was added with 40 ml of ethanol, heated to 70 ° C to dissolve, and allowed to stand at 5 ° C for 4 days and at -30 ° C for 2 days. The precipitated crystals were separated by filtration, and the obtained recrystallized mother liquor was evaporated under reduced pressure to remove the solvent to obtain 2.02 g of an oily substance (recovery rate 22.0%, optical purity 97.3% ee (+ excess)).
Got After mixing 10 ml of acetone with the obtained oily substance, 5 ml of diisopropyl ether was added, and (+)
-Inoculate 1-2 mg of suplatast tosylate at -30 ° C
After standing for 5 days, the precipitated crystals were collected by filtration and dried at room temperature under reduced pressure for 2 days to give 1.77 g of (+)-suplatast tosylate (recovery rate from oily matter: 87.6%, optical purity: 95%). 0.7% ee (+ excess) was obtained. To the crystals obtained by the second recrystallization ((−)-Suplatast tosylate with an optical purity of 6.0% ee), 40 ml of ethanol was added to give 7
Dissolve by warming to 0 ° C, 5 ° C for 10 days, and -30 ° C for 6 days.
Left for days. The precipitated crystals were filtered off, and the recrystallized mother liquor obtained was subjected to solvent removal under reduced pressure. 10 ml of acetone was added to the oily product, and then 5 ml of diisopropyl ether was added, (−)- After inoculating 1-2 mg of suplatast tosylate and leaving at -30 ° C for 3 days,
The precipitated crystals were collected by filtration, dried under reduced pressure at room temperature for 2 days, and 1.64 g of (-)-suplatast tosylate (recovery ratio 1
5.0% and optical purity 97.5% ee) were obtained. 40 ml of ethanol was added to the crystal obtained by the third recrystallization ((+)-Suplatast tosilate having an optical purity of 5.7% ee).
Was added and the mixture was heated to 70 ° C. to dissolve it, and left at −15 ° C. for 19 days and −30 ° C. for 2 days. The precipitated crystals were separated by filtration, and the obtained recrystallized mother liquor was evaporated under reduced pressure to remove the solvent, and 10 ml of acetone was mixed with the oily substance. After that, 5 ml of diisopropyl ether was added, and (+)-
Inoculated with 1 to 2 mg of suplatast tosylate and allowed to stand at -30 ° C for 5 days, the precipitated crystals were collected by filtration and dried at room temperature under reduced pressure for 2 days (+)-suplatast tosylate 1.
19 g (recovery rate 12.8%, optical purity 97.2% ee)
Got

[Experimental Example 9] 10 ml of acetone was added to 10.00 g of (+)-supratast tosylate having an optical purity of 61.7% ee and dissolved by heating, and 10 to 20 mg of (±) -supratast tosylate was added. At room temperature after inoculation
After being left for 10 days at 5 ° C. for 10 days and at −15 ° C. for 10 days, the precipitated crystals were filtered off, and the obtained recrystallized mother liquor was evaporated under reduced pressure to remove the solvent by 5.89 g (recovery rate). 72.8
%, Optical purity 98.2% ee (+ excess) was obtained.

[Experimental Example 10] A solution prepared by adding 4 ml of isopropanol to 1.0 g of racemate of suplatast tosylate produced according to the method described in Japanese Examined Patent Publication No. 3-70698 and heating at 70 ° C. to dissolve the solution. Sample No. 1 at 25 ° C for 7 days, 15 ° C for 7 days, 5 ° C
For 7 days and at −5 ° C. for 7 days, and the optical purity of each solution was determined by HPLC (CHIRALCEL OD [4.
8 x 250 mm Daicel chemistry] Elution solution n-hexane / ethanol / dichloromethane / trifluoroacetic acid /
Diethylamine = 800: 200: 100: 5: 1) was -1.22, -55.9, respectively.
It was -88.5 and -94.3% ee. Next, the precipitated crystals were filtered off, and further 4 ml of isopropanol was added to this.
Is added and heated to 70 ° C to prepare a dissolved solution,
When the optical purity of each solution was measured in the same manner as the previous time by leaving it at 7 ° C. for 7 days, 15 ° C. for 7 days, 5 ° C. for 7 days, and −5 ° C. for 7 days, respectively, +65.5, +89.1,
It was +99.3 and + 100.0% ee. Further, the same operation was repeated once more and the optical purity was measured. The results were -70.4, -90.7, -97.9,-, respectively.
It was 98.0% ee. Thereafter, the same method as N
o. 2, No. 3 was prepared and the optical purity was measured. The results are shown in Table 2.

[0045]

[Table 2] From the results in Table 2, it is clear that optically active (+) or (−) suplatast tosylate could be optically resolved from the racemate of suplatast tosylate by the recrystallization method. It is recognized that the lower the value is, the higher the number of times of recrystallization is.

[Experimental Example 11] The melting point, enthalpy of fusion and solubility in isopropanol of each optically active substance and racemate of benzene sulfonic acid suplatast represented by the chemical formula [VII] were measured, and the results are shown in Table 3. .

[0047]

[Table 3] 0.50 g of (±) -Suplatast benzene sulfonate
2 ml of isopropanol was added to and heated to 70 ° C to suspend, and the mixture was suspended at 25 ° C for 10 days, 15 ° C for 10 days, and 5 ° C for 7 days.
After standing for 22 days at −5 ° C. for 22 days, the precipitated crystals were filtered off to obtain a recrystallized mother liquor having an optical purity of 66.7% ee (+ excess).

Next, it was examined that the separation of the compound of the present invention by the recrystallization method is applied only to the sulfonium compound of the present invention, using the compound represented by the general formula [III] as a synthetic raw material of the compound of the present invention. did.

Comparative Example 1 As a comparative example, 4- (3-ethoxy-2-hydroxypropoxy) aniline represented by the chemical formula [III], which is a synthetic raw material for suplatast tosylate, is used.

[Chemical 12] Table 4 shows the results of measurement of the melting point, enthalpy of fusion, and solubility in isopropanol of the racemic compound (1) and each optically active substance (those optically resolved by liquid chromatography in advance).

[0050]

[Table 4] Then, 2 ml of ethanol was added to 0.5 g of (±) -4- (3-ethoxy-2-hydroxypropoxy) aniline, which is a racemic compound, and the mixture was heated to 50 ° C. to be dissolved, and then stored at 5 ° C. Then, when the optical purity was measured over time, 0.5% (-excess) after 1 day and 0.6% after 2 days
(+ Excess) It was 0.0% after 3 days, and the phenomenon that the solution exhibited optical activity was not observed at all.

[Pharmacological Test] Skin Permeability Test 100 mg of each of the optically active forms of suplatast tosylate (Compounds 1 and 2) obtained in Experimental Example 8 was ground in a mortar and 1.9 g of vaseline was added. Mix well to make each ointment, and apply 400 mg of this ointment to the abdominal skin of hairless rats (application area: 5.31 cm ² ) and fix to a vertical cell, and conduct a permeation experiment using 13 ml of water as a permeate. The time-dependent permeation amount was measured by liquid chromatography. The result is shown in FIG. Compounds 1 and 2
Showed superior skin permeability compared to the racemate.

[Pharmacological test] Effect on allogeneic passive anaphylaxis (PCA) Immunology 106, 1002 (197)
According to the method described in 1), the effect of the compound of the present invention on homologous anaphylaxis (PCA) was examined. The PCA inhibition rates of Compound 1 and Compound 2 were 60% and 58.5%, respectively.

[Acute toxicity] Male ddY mice (body weight 2
LD _{50 of} compound 1 and compound 2 calculated by the up-down method using 0 g) was 280 and 267 mg, respectively.
It was / kg.

[Brief description of drawings]

FIG. 1 is a liquid chromatogram of essential parts of an oily substance obtained from a first recrystallization mother liquor in Experimental Example 7.

FIG. 2 is a liquid chromatogram of essential parts of an oily substance obtained from a second recrystallization mother liquor in Experimental Example 7.

FIG. 3 is a graph showing the results of a skin permeability pharmacological test.

Claims (12)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, Y represents an inorganic acid residue or an organic acid residue), which is an optically active sulfonium compound. 2. The optically active sulfonium compound according to claim 1, wherein Y is an organic acid residue. 3. The optically active sulfonium compound according to claim 1, wherein Y is an optionally substituted arylsulfonic acid residue. 4. R (−)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl}
Ethyl] dimethyl sulfonium p-toluene sulfonate. 5. S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl}
Ethyl] dimethyl sulfonium p-toluene sulfonate. 6. R (−)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl}
Ethyl] dimethyl sulfonium benzene sulfonate. 7. S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl}
Ethyl] dimethyl sulfonium benzene sulfonate. 8. R (−)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl}
Ethyl] dimethyl sulfonium p-nitrobenzene sulfonate. 9. S (+)-[2- {4- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl}
Ethyl] dimethyl sulfonium p-nitrobenzene sulfonate. 10. A compound represented by the general formula [I]: A therapeutic agent for an allergic disease comprising an optically active sulfonium compound represented by the formula (wherein Y represents an inorganic acid residue or an organic acid residue). 11. A compound represented by the general formula [I]: (In the formula, Y represents an inorganic acid residue or an organic acid residue), and recrystallizes a racemic or non-racemic compound,
A method for producing an optically active sulfonium compound, characterized in that (+) and (−) optically active substances are alternately obtained. 12. The method for producing an optically active substance according to claim 11, wherein Y is an arylsulfonic acid residue which may be substituted.