JP3400105B2 - Optically active sulfonic acid derivative and production method thereof - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an optically active sulfonic acid derivative, a salt thereof and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION There are various methods for optical resolution of racemic amino acids. An optically active resolving agent is allowed to act on a racemate to form a pair of diastereomeric salts. The optical resolution method used is one of the industrially advantageous methods. For example, the basic amino acid or acidic amino acid is reacted with an acidic resolving agent or a basic resolving agent to form a diastereomeric salt. However,
For neutral amino acids, a suitable derivative such as an N-acyl derivative is converted into a typical acidic substance and then reacted with a basic resolving agent, or an ester or amide is converted into a typical basic substance. After that, it has a drawback that it requires an acidic resolving agent to act and that after optical resolution these protective groups must be removed without racemization. On the other hand, if a strong acid resolving agent is used, it forms a salt with any amino acid, so there is no need to change the amino acid into a derivative, and after the optical resolution, it can be desalted under mild conditions such as neutralization reaction and ion exchange resin treatment. Amino acids can be optically resolved with industrial advantage. As such a strongly acidic optical resolving agent, camphorsulfonic acid, bromocamphorsulfonic acid, cholestenonesulfonic acid, hydroxymethanesulfonic acid, etc. are known, but they are all derived from natural products and are expensive. There remains a problem that it is chemically unstable and inconvenient when the non-natural type is required.

Further, various optically active sulfonic acids useful as optical resolving agents, especially amino acid optical resolving agents have been reported. For example, in Japanese Examined Patent Publication No. 2-59828, the formula:

[Chemical 4] (In the formula, R ′ represents a lower alkyl group, a lower alkoxy group or a halogen atom) An optically active 1- (monosubstituted phenyl) ethanesulfonic acid derivative is useful as an optical resolving agent for DL-α-amino acids. It is disclosed that there is. Further, JP-B-3-12051 discloses the use of optically active α-phenylpropanesulfonic acid as an optical resolving agent for amino acids. Japanese Patent Publication No. 3-12052
The publication likewise discloses the use of α-phenylethanesulfonic acid. Further, JP-A-5-271169 discloses an optical resolution method of DL-tert-leucine using an optically active 1- (4-substituted phenyl) ethanesulfonic acid.

[0004]

DISCLOSURE OF THE INVENTION As a result of various studies conducted by the present inventors, the optically active sulfonic acid derivative represented by the following formula (I) can be an excellent optical resolving agent, and particularly DL-amino acid It was found that the compound has excellent optical characteristics as an optical resolving agent and completed the present invention.

That is, the present invention provides an optically active sulfonic acid derivative useful as an optical resolving agent, particularly as an optical resolving agent for amino acids, a salt thereof and a method for producing the same.

The present invention has the general formula (I)

[Chemical 5] (In the formula, R is a lower alkyl group, and at least two of R _{1 to} R ₅ are the same or different and each is a group selected from a lower alkyl group, a lower alkoxy group, a trihalogenomethyl group, a nitro group and a halogen atom. , The remaining groups represent hydrogen atoms) optically active sulfonic acid derivative (provided that
1- (2,3,4-trichlorophenyl) ethanesulfonic acid is excluded) or a salt thereof.

As the optically active sulfone derivative (I) of the present invention, in the general formula (I), for example, R is a lower alkyl group having 1 to 4 carbon atoms such as methyl group and ethyl group, and R ₁ to
At least two of R ₅ are the same or different and each is a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group; Methoxy group, ethoxy group, n
-Propoxy group, isopropoxy group, n-butoxy group,
1 to 1 carbon atoms such as isobutoxy and methylenedioxy groups
4 lower alkoxy group; trihalogenomethyl group such as trifluoromethyl group; nitro group; or halogen atom such as fluorine atom, chlorine atom, bromine atom, and the rest of the groups are hydrogen atoms. Among these, preferred compounds include, in the general formula (I), R is a methyl group, and 2 to 3 of R _{1 to} R ₅ are halogen atoms such as chlorine atom and fluorine atom, methoxy group or methyl group. And a compound that is More preferable compounds include compounds in which R is a methyl group and 2 to 3 of R _{1 to} R ₅ are halogen atoms or methyl groups.

According to the present invention, the optically active sulfone derivative (I) has the general formula (I)

[Chemical 6] (Wherein R and R _{1 to} R ₅ have the same meanings as described above), the racemic sulfonic acid derivative is reacted with an optically active amino acid, and the difference in solubility between the two diastereomeric salts produced is used. Then, a salt of the optically active amino acid of the sulfonic acid derivative (I), which is one of the sparingly soluble diastereomeric salts, and an optically active amino acid can be separated and collected, and if desired, can be produced by decomposing the salt. .

The reaction of the racemic sulfonic acid derivative (I) with the optically active amino acid can be carried out by mixing and dissolving both compounds in a suitable solvent.

Racemic sulfonic acid derivative used in the present invention
(I) may be in the free form, in addition to alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts and other amine salts. It can be used in the invention. Further, the reaction solution used when the racemic sulfonic acid derivative (I) is synthesized may be used. Further, in addition to an equivalent mixture of the d-form and the l-form obtained by chemical synthesis, a so-called low-purity optically active substance containing one optically active substance in excess can be used. Further, as the optically active amino acid as a resolving agent, for example, alanine, valine, leucine,
Isoleucine, phenylalanine, phenylglycine,
Hydroxyphenylglycine, tyrosine, tryptophan, serine, threonine, proline, cysteine, glutamic acid, aspartic acid, histidine, ornithine,
Optically active substances such as lysine, citrulline and aminobutyric acid can be used. These optically active amino acids are not limited to the free form, but also include inorganic acid salts such as hydrochlorides and sulfates, oxalates, benzenesulfonates, toluenesulfonates, xylenesulfonates, chlorobenzenesulfonates, nitrobenzenesulfonates. Also, organic acid salts such as naphthalene sulfonate and methane sulfonate can be used.
The amount of the optically active amino acid or salt thereof used as the resolving agent is 0.3 to 1.5 mol, preferably 0.5 to 1.0 mol, per 1 mol of the racemic sulfonic acid derivative (I). is there. As the solvent used in this reaction, any solvent can be used as long as it has an appropriate solubility without hindering the formation of a salt, but an aqueous solvent is particularly preferable. Such aqueous solvents include water; lower alkanols such as methanol and ethanol; acetone; dioxane; tetrahydrofuran; dimethylformamide; dimethylsulfoxide;
A fatty acid such as acetic acid or propionic acid; or a mixed solvent thereof can be preferably used, but water is particularly preferable. This reaction can be carried out in the temperature range from the boiling point of the reaction solution to the freezing point, but preferably 5 to 80 ° C.

Of the diastereomeric salts thus produced, the crystallization operation of the sparingly soluble diastereomeric salt can be easily carried out by cooling the reaction solution, concentrating it, or adding an organic solvent. The salt can be obtained as highly pure crystals. The sparingly soluble diastereomeric salt that has precipitated can be separated and obtained by an ordinary solid-liquid separation method, for example, a method such as filtration or centrifugation.

The sparingly soluble diastereomeric salt obtained above can be further subjected to treatments such as washing and recrystallization, if necessary.

The sparingly soluble diastereomeric salt thus obtained can be easily converted into the optically active sulfonic acid derivative (I) by a conventional method such as ion exchange resin treatment or alkali treatment.

The optically active sulfonic acid derivative (I) obtained as described above is useful as an optical resolving agent for racemic basic compounds, and particularly has various properties as an optical resolving agent for DL-amino acids. Therefore, the compound (I) is preferably used to optically resolve the DL-α-amino acid to optically active α-amino acid.
Can lead to amino acids.

As described above, the optically active sulfone derivative (I) of the present invention is useful as an optical resolving agent for DL-α-amino acids, and α-amino acids are optically resolved by using the optically active sulfonic acid derivative (I). If it does, it has the following advantages. (1) Since the optically active sulfonic acid derivative (I) used in the present invention is a strongly acidic resolving agent, the racemic amino acid to be resolved is a basic amino acid or a neutral or acidic amino acid, and these amino acids are esterified. Alternatively, it can be applied to resolution of a wide range of amino acids without having to lead to derivatives such as amides. (2) Optically active sulfonic acid derivative (I) is a synthetic resolving agent, which is different from the conventional optically active sulfonic acid derived from natural products.
(+) Body and (-) body can be freely obtained, so (+)
The body and the (-) body can be used properly. (3) Since the optically active sulfonic acid derivative (I) as a resolving agent is very stable both chemically and optically, recovery of the resolving agent,
Easy to reuse. (4) The salt formation reaction and crystallization operation can be carried out in an aqueous solvent, and the operation is extremely simple.

The racemic sulfonic acid derivative (I) which is the starting material compound of the present invention is, for example, J. Chem. Soc., 115.
9 (1927), the corresponding racemic alcohol can be halogenated and the resulting racemic halide type can be sulfonated.

[0016]

【Example】

[Production Method of Optically Active Sulfonic Acid Derivative] Example 1 (1) 135 g of 2 ′, 4′-dichloroacetophenone was suspended in 540 ml of methanol, and 13.5 g of sodium borohydride was added to the suspension at 15 to 25 ° C. 2 at 25 ° C
Stir for hours. After the reaction, methanol is distilled off, 2N hydrochloric acid is added to the obtained residue, and the mixture is extracted with ethyl acetate. The obtained organic layer was washed with water and dried, and then the solvent was distilled off to give a crude (±) -1-
135 g of (2,4-dichlorophenyl) ethyl alcohol
To get

(2) 130 g of (±) -1- (2,4-dichlorophenyl) ethyl alcohol was dissolved in 250 ml of toluene, and a solution of 92 g of phosphorus tribromide in toluene was added to the solution.
After dropping at -10 ° C, the mixture is stirred at room temperature for 2 hours. After the reaction, water is added to the solution under cooling, and the aqueous layer is extracted with toluene. The toluene layers were collected, washed with water, dried and the solvent was distilled off to obtain 176 g of oily (±) -1- (2,4-dichlorophenyl) bromoethane.

(3) To 162 g of (±) -1- (2,4-dichlorophenyl) bromoethane, 362 ml of water and 121 g of sodium sulfite are added, and the mixture is stirred at 95 to 100 ° C. for 20 hours. After adding 300 ml of water to the reaction solution and washing with ethyl acetate, 137 ml of concentrated hydrochloric acid is added to the aqueous layer. The water layer is 7
The mixture is heated to 0 to 80 ° C., 67 g of L-leucine is added and dissolved, and the mixture is gradually cooled. The precipitated crystals are collected by filtration, washed with cold water, and dried to obtain crude (-)-1- (2,4-dichlorophenyl) ethanesulfonic acid.L-leucine salt 98.6 g. [α] ²⁵ _D : -17.3 ° (c = 1, H ₂ O) The crude salt was recrystallized from water three times to obtain (-)-1- (2,4-dichlorophenyl) ethanesulfonic acid.L. -Leucine salt 5
1 g is obtained. [α] ²⁵ _D : −34.0 ° (c = 1, H ₂ O), [α] ²⁵ _D : −11.0 ° (c = 1, methanol) Mp .: 175 to 176 ° C. IR ( KBr) cm ⁻¹ : 3500, 2995, 1730,
_{1590,1475 NMR (DMSO-d 6)} δ: 0.92 (d, 6H, J = 7.
0 Hz), 1.43 (d, 3H, J = 7.0 Hz), 1.65 (m,
4H), 3.85 (m, 1H), 4.23 (q, 1H, J = 7.0H
z), 7.30 to 7.80 (m, 3H)

(4) 51 g of (-)-1- (2,4-dichlorophenyl) ethanesulfonic acid.L-leucine salt is dissolved in methanol and neutralized with 25% aqueous ammonia. After stirring for 1 hour at the same temperature, the precipitated L-leucine is filtered off. The filtrate was concentrated, the residue was dissolved in pure water, and IR-120
It is passed through a (H ⁺ ) strongly acidic cation exchange resin (manufactured by Organo Corporation) and then washed with pure water. The passing solution and the washing solution are combined and concentrated to obtain 33.4 g of (-)-1- (2,4-dichlorophenyl) ethanesulfonic acid. Sodium salt : [α] ²⁵ _D : −52.2 ° (c = 1, H ₂ O) Mp: 260 to 261 ° C. IR (KBr) cm ⁻¹ : 3460, 1655, 1590,
1475 NMR (DMSO-d ₆ ) δ: 1.48 (d, 3H, J = 7.0)
Hz), 4.30 (q, 1H, J = 7.0 Hz), 7.30 to 7.
90 (m, 3H)

Examples 2 to 6 The corresponding starting material compounds were treated in the same manner as in Examples 1- (1) to 1- (3) to obtain the compounds shown in Tables 1 and 2 below, and then the obtained Tables 1 and 2 The compound of Example 1- (4) was treated in the same manner as in Example 1- (4) to give the compounds of Table 3 below.

[0021]

[Table 1]

[0022]

[Table 2]

[0023]

[Table 3]

Example 7 (±) -1- (3,4-) obtained by treating in the same manner as in Example 8 described later.
Various optically active α-amino acids shown in Table 4 below were added to 10 g of an aqueous solution containing 8 g of dimethylphenyl) ethanesulfonic acid.
Add 0 mol ratio and solvent and dissolve by heating. After cooling, the precipitated sparingly soluble diastereomeric salt is collected by filtration and dried. The salt was made into a 10% aqueous solution, passed through a column packed with IR-120 (H ⁺ ) strongly acidic ion exchange resin, and the effluent was concentrated to give an optically active 1- (3,4-dimethylphenyl) ethanesulfonic acid. An aqueous solution is obtained. The results are shown in Table 4 below.

[0025]

[Table 4]

Example 8 [Raw compound: (±) -1- (2,4-dichlorophenyl) ethanesulfonic acid production method] (1) (±) -1- (2,4-dichlorophenyl) bromoethane (162 g) and water (362 ml) And sodium sulfite 12
Add 1 g and stir at 95-100 ° C. for 20 hours. After adding 300 ml of water to the reaction solution and washing with ethyl acetate, 137 ml of concentrated hydrochloric acid is added to the aqueous layer. The aqueous layer is heated to 70 to 80 ° C., 67 g of DL-leucine is added and dissolved, and the mixture is cooled. The precipitated crystals are collected by filtration, washed with cold water and dried.
190 g of (±) -1- (2,4-dichlorophenyl) ethanesulfonic acid / DL-leucine salt is obtained. NMR (DMSO-d ₆ ) δ: 0.92 (d, 6H, J = 7.0
Hz), 1.43 (d, 3H, J = 7.0 Hz), 1.65 (m, 4
H), 3.85 (m, 1H), 4.23 (q, 1H, J = 7.0H
z), 7.3 to 7.8 (m, 3H) (2) (±) -1- (2,4-dichlorophenyl) ethanesulfonic acid / DL-leucine salt (190 g) was dissolved in methanol to prepare 25% aqueous ammonia. Neutralize with. After stirring for 1 hour at the same temperature, the precipitated DL-leucine is filtered off. The filtrate is concentrated, the residue is dissolved in pure water, passed through an IR-120 (H ⁺ ) strongly acidic cation exchange resin (manufactured by Organo Co.), and then washed with pure water. Concentrate the passing liquid and washing liquid together,
150 g of an aqueous solution containing 120 g of (±) -1- (2,4-dichlorophenyl) ethanesulfonic acid is obtained. (3) Using 10 g of an aqueous solution containing 3.7 g of (±) -1- (2,4-dichlorophenyl) ethanesulfonic acid, the same treatment as in Example 7 was performed with various optically active amino acids shown in Table 5 below. The results are shown in Table 5.

[0027]

[Table 5]

Example 9 A mixture of 30 g of various (±) -sulfonic acid derivatives shown in Table 6 below and D-p-hydroxyphenylglycine or L-leucine in a 1.0 molar ratio was dissolved by heating in water and cooled with ice. Two
Stir for hours. The precipitated crystals are collected by filtration, dried and recrystallized in the same solvent. The resulting diastereomeric salt is dissolved in water,
Pass the solution through a column packed with a strongly acidic ion exchange resin and wash with water. By combining and concentrating the effluent and wash,
A candy-like optically active sulfonic acid derivative is obtained. This product is a chemically and optically pure optically active sulfonic acid. The results are shown in Table 6 below.

[0029]

[Table 6]

[Optical Resolution of DL-Amino Acid] Reference Example 1 A mixture of 10 g of DL-amino acid and an optically active sulfonic acid (1.0 mol ratio) shown in Table 7 below was dissolved in a solvent by heating, and the mixture was allowed to stand at room temperature for one day. . The precipitated crystals are collected by filtration, washed and dried to obtain a diastereomeric salt. The salt is dissolved in water to make an aqueous solution of about 5%, and the solution is passed through a column filled with a strongly acidic ion exchange resin and washed with water. The amino acid adsorbed on the resin is eluted with 2N aqueous ammonia. The eluate is concentrated to dryness, then a small amount of cold water or methanol is added to cool and the precipitated crystals are collected by filtration to obtain the optically active amino acid (salt decomposition yield: 8
5-95%). The results are shown in Table 7 below.

[0031]

[Table 7]

[0032]

The optically active sulfonic acid derivative (I) of the present invention
Is useful as an optical resolving agent, particularly as an optical resolving agent for free amino acids, and can be used for optical resolution of a variety of racemates as compared with conventional optical resolving agents, and has high optical resolution efficiency. Further, the optically active sulfonic acid derivative (I) of the present invention is chemically stable and is easy to chemically synthesize, and thus is an industrially excellent optical resolving agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-5-271169 (JP, A) JP-A 1-29345 (JP, A) JP-A 59-170057 (JP, A) JP-A 6- 199781 (JP, A) JP-A-7-133248 (JP, A) JP-A-8-503930 (JP, A) International Publication 94/006760 (WO, A1) (58) Fields investigated (Int.Cl. ⁷⁾ , DB name) C07C 309/00 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. General formula (I): (In the formula, 2 to 3 of R _{1 to} R ₅ are the same or different and represent a halogen atom, methoxy or methyl, and the remaining groups represent a hydrogen atom). 1- (2,3,4-trichlorophenyl) ethanesulfonic acid is excluded) or a salt thereof. 2. The optically active sulfonic acid derivative or a salt thereof according to claim 1, wherein 2 to 3 of R _{1 to} R ₅ are the same or different and are halogen atoms or methyl, and the remaining groups are hydrogen atoms. . 3. Either R ₁ or R ₂ , and R
The optically active sulfonic acid derivative or a salt thereof according to claim 2, wherein ₃ is a halogen atom or methyl, and the remaining groups are hydrogen atoms. 4. An optically active sulfonic acid derivative of any of the following three compounds or a salt thereof.・ 1- (3,4-Dimethylphenyl) ethanesulfonic acid ・ 1- (2,4-dichlorophenyl) ethanesulfonic acid ・ 1- (3,4-dichlorophenyl) ethanesulfonic acid 5. A method for producing an optically active amino acid by optically resolving a DL-amino acid using the optically active sulfonic acid derivative according to any one of claims 1 to 4.