WO2005030730A1

WO2005030730A1 - PROCESS FOR PRODUCING OPTICALLY ACTIVE α-AMINO-ϵ-CAPROLACTAM OR SALT THEREOF AND INTERMEDIATE FOR THE PRODUCTION

Info

Publication number: WO2005030730A1
Application number: PCT/JP2004/014186
Authority: WO
Inventors: Kenichi Sakai; Rumiko Sakurai; Atsushi Yuzawa; Kaoru Hatahira
Original assignee: Yamakawa Chemical Industry Co., Ltd.; Ajinomoto Co., Inc.
Priority date: 2003-09-29
Filing date: 2004-09-28
Publication date: 2005-04-07
Also published as: JP2005104874A

Abstract

An industrially advantageous production process which is an improved process for the production of an optically active α-amino-ϵ-caprolactam (ACL). By the process, a desired optically active isomer having a high optical purity can be obtained with the aid of an optical resolver available at low cost in a large amount. An optically active phenylalanine derivative, in particular, N-p-toluenesulfonyl-L-phenylalanine, is used as a resolver to optically resolve DL-ACL by the diastereomeric method. A solvent having a permittivity suitably selected is used as a reaction medium for this optical resolution to precipitate a diastereomeric salt. Thus, a diastereomeric salt containing D-ACL or L-ACL can be selectively obtained.

Description

Specification

Process for producing optically active _α -amino- _ε monoprolatam or a salt thereof and intermediate of production

Technical field

[0001] The present invention relates to a method for producing optically active α-amino-ε-proratam (hereinafter abbreviated as “ACL”). Here, the term "ACL" includes not only the free form but also the salt form. The term "DL-ACL" also encompasses a mixture of D-ACL and L ACL, which contains a large number (not overwhelmingly) of either optically active forms that are unique to racemic ACL only.

[0002] The present invention also relates to novel diastereomeric salts formed as intermediates in the process of producing optically active ACL. The distereomeric salts also include the solvates (eg, hydrates).

Background art

[0003] Optically active ACL is known as an intermediate for producing L or D lysine, and is an optical resolution agent for amino acids (Patent Document 1), and also an antitumor agent (Patent Document 2) It is a compound useful as an intermediate in the manufacture of a drug such as amnesian improving drug (patent document 3) and RU-81843, which is a new drug for osteoporosis. There have been various reports on how to manufacture optically active ACL.

In the stereomer method, for example, as a resolving agent

(I) 2-Aminocyclohexylcarboxylic acid derivative (Patent Document 4)

(Mouth) tartaric acid (patent document 5)

(Iii) N-Benzylglutamic acid (Patent Document 6)

(2) N-power rubamoyl valine (Patent Document 7)

(E) N-Benzoylmethionine (Patent Document 8)

(H) N-Benzoylaranine (Patent Document 9)

(G) N-Acetyl indoline 2-Carboxylic acid (Patent Document 10)

I know how to use it.

[0005] In the preferential crystallization method, (H) Salt and magnesium complex (Patent Document 11)

(I) Nickel complex (Patent Document 12)

Methods are known, and others,

(N) L α amino-ε one strong prolatatum assimilable yeast (Patent Document 13)

There is also a method using

When the above-mentioned known diasteromeric method is used, although a racemic ACL (that is, an isomer ratio is 1: 1) optically active ACL is obtained, when one kind of optically active substance of an optical resolving agent is used In most cases, only optically active ACL of either D-body or L-one can be obtained. As an example, when L-containing ベンゾ -benzoyl daltanic acid is used as the resolving agent, various solvents such as water, acetone, methanol, Ν, ホルムアミド -dimethyl formamide, etc. Crystallized soluble salts only.

[0007] In the preferential crystallization method using an achiral resolving agent, only one type of resolving agent can obtain both optical activity of ACL, but only in a state in which the isomer ratio of ACL is inclined to either direction. Since preferential crystallization is possible, it is not possible to obtain optically active ACL from racemic ACL, and the yield is low, which is disadvantageous for industrial implementation. The method for producing optically active ACL using yeast can only obtain one of the optically active forms, and it is not practical because its production efficiency is low.

[0008] The inventors solved the drawbacks of the prior art as described above in producing optically active ACL, which occupies an important position as an intermediate for synthesizing a pharmacologically active compound. Use compounds which are inexpensive and readily available on an industrial scale as erasers and resolving agents, and, if desired, obtain high optical purity with both D-body and L-body of ACL. We researched intensively for the production method of optically active ACL suitable for industrial implementation.

[0009] As a result, the inventors used an optically active fluoroanine derivative, typically an optically active ρ トルエン -toluene sulfoyl ferralanin, as an optical resolution agent, from racemic ACL to optically active ACL and It has been found that the desired optically active ACL can be obtained by forming a distereomeric salt of the compound and double-decomposing the obtained salt. This optical resolving agent can be industrially obtained in large quantities and inexpensively. [0010] The inventors of the present invention further studied the D ACL salt even if the same optical resolving agent is used depending on the polarity (expressed as dielectric constant) of the solvent used in the above-mentioned distereomer method. And L ACL salt may be precipitated, and it has been found that there is a close relationship between the optical purity of the di-stereomer salt and the polarity of the solvent.

[0011] Among known techniques for optical resolution of ACL, those using the optically active phthalocyanine derivative which the inventors focused on as a resolving agent are none but those using an L-glutamic acid derivative as a resolving agent (patent document) 14, 15) is disclosed.

[0012] These known techniques are also according to the distereomer method, and even when the same optical resolving agent is used, it is reported that a solvent capable of forming the distereomeric salt selectively obtains the D-body or L-monomer of ACL selectively. It is done. However, these only described fragmentary phenomena, and systematic considerations based on the physical properties of the solvent such as the dielectric constant (ε) were not made.

[0013] On the other hand, the inventors obtained the knowledge on the relationship between the solvent and the precipitated diasteromer salt obtained as follows: As an optical resolution agent, the above-mentioned typical example, Ν-Ρ-toluenesulfo-lou L-phenylanine (abbreviated as “Ts-L-Phe”) can be used

(1) When a solvent having a medium dielectric constant, for example, methanol (ε = 33), Ν, Ν-dimethylformamide ( _ε = 37) and dimethylsulfoxide (ε = 49), the salt of L ACL is Obtained with high optical purity.

(2) When using a low dielectric constant solvent, such as 1,2-dichloroethane (ε = 11) or black mouth form (ε = 5), or a high dielectric constant solvent such as water (ε = 78) The salt of D-ACL is obtained with high optical purity.

(3) A solvent is mixed and adjusted to an arbitrary dielectric constant, for example, a combination of water and ethanol, a dielectric constant of methanol or dimethyl sulfoxide, or a value corresponding to a dielectric constant of Ν, Ν-dimethylformamide When the solvent is used, a salt of L ACL is obtained with high optical purity.

(4) an induction having a dielectric constant between black hole form (ε = 5) and dimethyl sulfoxide (ε = 49) When using a solvent with a conductivity of around 28, for example, 85% isopropanol water (ε = 27) or 90% ethanol water (ε = 29), D- ACL salt or L ACL salt is obtained. Force Optical purity is low.

(5) A solvent having a dielectric constant between dimethylsulfoxide (ε = 49) and water (ε = 78) near 60, for example, 45% methanol-containing water (ε = 58) or 30% ethanol-containing water When (ε = 62) is used, the force optical purity for obtaining L ACL salt or D- ACL salt is low.

The above tendency is as follows in general.

[Formula 1] Poorly soluble di-stereomer

Optical resolution agent (L-form) Thus, it was found that there is a close relationship between the dielectric constant of the solvent used and the DZL and optical purity of the resulting diasteromeric salt, so use this relationship Thus, while using one type of optical resolving agent, it becomes possible to efficiently separate both optically active substances simply by exchanging the solvent, and a solvent suitable for the desired optical resolution can be used as in conventional trial and error. It became possible to choose by no means.

Patent Document 1: Japanese Patent Application Laid-Open No. 59-67721

Patent Document 2: US Pat. No. 6,239,127

Patent Document 3: U.S. Pat. No. 5,166,150 Patent Document 4: Japanese Patent Application Laid-Open No. 9-241227

Patent Document 5: JP-A-59-44358

Patent Document 6: Japanese Patent Publication No. 48-3634

Patent Document 7: Japanese Examined Patent Publication No. 46-12130

Patent Document 8: Japanese Patent Application Laid-Open No. 62-114969

Patent Document 9: Japanese Patent Application Laid-Open No. 62-114968

Patent Document 10: Japanese Patent Application Laid-Open No. 61-24573

Patent Document 11: U.S. Patent No. 4062839

Patent Document 12: Japanese Examined Patent Publication No. 60-15622

Patent Document 13: JP-A-58-155096

Patent Document 14: Japanese Examined Patent Publication No. 48-15954

Patent Document 15: Japanese Examined Patent Publication No. 48-6475

Disclosure of the invention

Problem that invention tries to solve

[0015] The first object of the present invention is to provide optically active AC based on the new findings of the inventors as described above.

It is an industrially advantageous method for producing L, which is an inexpensive and can be obtained in large quantities using an optical resolving agent, and can obtain a desired optically active substance with high optical purity. It is to do.

[0016] A second object of the present invention is that, in the production of an optically active ACL for achieving the first object, either D-body or L-integral of ACL can be easily obtained, as desired. It is about providing a manufacturing method.

Means to solve the problem

[0017] The method for producing the ACL of the present invention for achieving the first object is the following formula (1)

[Formula 2]

(1)

It is characterized in that the DL-ACL represented by is optically resolved by the di-stereomer method, using an optically active phenylanine derivative as a resolving agent.

[0018] The method for producing the ACL of the present invention for achieving the second object is characterized in that, in carrying out the above-mentioned diastereomer method, a diastereomeric monosalt using a solvent selected based on the value of the dielectric constant. To selectively obtain a diastereomer salt containing D- ACL or L ACL. For example, when using Ts—L Phe as an optical resolving agent, by using a solvent or a mixed solvent having an appropriate dielectric constant, D—ACL 'Ts—L—Phe salt or L ACL' Ts—L— Phe You can take away the salt.

Effect of the invention

[0019] If the method for producing the ACL of the present invention to achieve the first object is carried out, a large amount of optically active phthalocyanine compound used as an optical resolution agent can be obtained inexpensively. Suitable for the Geostereomer process, as can be seen in the examples below, this process can be carried out industrially advantageously.

[0020] If the method for producing the ACL of the present invention to achieve the second object is carried out, the desired D-ACL can be obtained by selecting the type of solvent based on the dielectric constant while using the same optical resolving agent. Or L You can get an ACL.

BEST MODE FOR CARRYING OUT THE INVENTION

[0021] The production method of the present invention is a geostereomer method. That is, an optical resolving agent is caused to act on a DL- ACL (as described above, or a mixture of a racemate or D- ACL and L ACL) in a solvent to form a di-stereomeric salt and separate one of the di-stereomeric salts. And their salts are decomposed to obtain the desired optically active substance.

An optically active fluorolanin derivative used as an optical resolution agent is represented by the following formula (2)

[Chemical 3]

(2)

(Wherein, R represents an asyl group or a sulfo group, and * represents the position of an asymmetric carbon atom). The compounds represented by are preferred. Examples of the acyl group represented by R include a formyl group, an acetyl group, an oxalyl group, a benzyl group, a toluoyl group and the like, and a sulfonyl group includes a methanesulfonyl group, a benzenesulfonyl group, a toluenesulfonyl group and the like. It is raised.

[0023] Examples of the optically active N-asylphenyl-ruranin derivatives include N-formylphenylan, N-acetylferranin, N-benzoyl-leuranin, N0-toluoyl-leuranin, N-p-toluoylpharanine. And N methanesulfonyl phenyla luranin, N benzene sulfo yulfaran, N-o toluene sulfo y lu aranin, N p -toluene sulfo y gel feranin and the like.

The most preferable optically active phagelanin derivative is the optically active N p -toluenesulfonyl sulfonylanine of the following formula (3).

[Formula 4]

(Wherein * represents the position of the asymmetric carbon atom)

[0025] The solvent used to carry out the diasteromeric method is, in principle, water such as water, methanol, alcohols such as ethanol, n-propanol and isopropanol, acetyl ethers such as ethanol, n-propanol and isopropanol, and ethers such as methyl-tert-butyl ether and tetrahydrofuran. , Methyl acetate, ethyl acetate, isopropyl acetate, acetates such as butyl acetate, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetates such as dimethylyl-tolyls, methylene chloride, Halogenated hydrocarbons such as chloroform, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, amides such as formaldehyde, N, N-dimethylformamide, amides such as acetoamide, and dimethyl sulfate Luhoxyd-like inclusions Like compounds such is not limited to forces which may be mentioned by way of example. One type may be used alone, or two or more types may be mixed and used.

As described above, the polarity of the solvent, that is, the dielectric constant largely influences the optical orientation and the optical purity of the resulting distereomeric salt. For example, Ts-L Phe as an optical resolving agent If used, a solvent with a medium dielectric constant, specifically greater than 28 and less than 60 is suitable if the target ACL is L-integral, for example, methanol (ε = 33), Ν, It is preferable to use a mixed solvent adjusted to have a dielectric constant such as di-dimethylformamide (ε = 37) or dimethylsulfoxide (ε = 49) or equivalent. On the other hand, when the purpose is D-ACL, the dielectric constant is lower than the above range, ie, 28 or less, for example, black hole form (ε = 5) or 1, 2-dichloroethane. When using a mixed solvent adjusted to have a dielectric constant such as (ε = 11) or equivalent, or using a solvent whose dielectric constant is higher than the above range, that is, more than 60. Good.

The amount of solvent used affects the performance such as yield and optical purity. The appropriate amount used depends on the type of solvent.

[0028] The amount of the optically active optically active ferrianin derivative which is an optical resolution agent is selected from the range of 0.5-2 mol with respect to 1 mol of DL- ACL. In order to efficiently separate D- ACL and L ACL, a preferable range is 0.4 to 1.5 moles, and a more preferable range is 0.9 to 1.1 moles. The optimal molar ratio will vary somewhat depending on the type of optical resolving agent and solvent chosen.

[0029] The reaction for forming the distereomeric salt may be carried out according to known techniques without particular limitation. As a specific example, the raw material DL-ACL is added to the solvent, and dissolved by heating to a temperature below the boiling point of the solvent under normal pressure, and an optical resolving agent is added thereto. The addition may be performed at one time or may be performed gradually. The optical resolution agent may remain in the form of a solution dissolved in a solvent, which is convenient for addition.

The optical resolution of the present invention has suitable ranges and combinations with respect to the degree of polarity of the solvent and the amount used, and the type and dosage of the optical resolving agent. Those skilled in the art will be able to find optimal conditions by referring to the practical data described later and adding some experiments if necessary.

[0031] The reaction mixture in which the diasteromeric salt is formed precipitates the sparingly soluble diasteromeric salt by cooling or by concentrating the solvent, and is obtained as a solid by filtration or centrifugation. The obtained diasteromeric salt, in particular, L AC L 'Ts-L Phe salt represented by the following formula (4) and a hydrate thereof

[Chem. 5]

Or represented by the following equation (5): D— ACL 'Ts— L Phe salt

[Chemical 6]

Are all novel compounds and form part of the present invention.

[0032] The double decomposition of the obtained diasteromeric salt to obtain D or L ACL may be carried out according to a method known to those skilled in the art. For example, since this diasteromeric salt is a salt of an organic amine and a carboxylic acid, it can be subjected to salt formation by the action of a strong base or a strong acid, and crystallization can further separate the target optically active ACL. According to this method, optically active ACLs are usually separated as salts of strong acids or salts of strong bases used for salt formation. If necessary, the target optically active ACL can be recovered by neutralization and further crystallization.

[0033] When the target optically active ACL is only one isomer, unwanted isomers remaining in the mother liquor that has been optically resolved by the diasteromer method are racemized by a known method, and then subjected to optical resolution again. If you use it, the thing is, of course.

In general, in the diasteromeric method, when either one of the optical isomers is in excess, it is experienced that a salt containing it can be precipitated and recovered with a higher yield and optical purity than expected. Are known. This phenomenon is also used in the practice of the present invention. It can be used. For example, in order to obtain more D— ACL, L ACL′Ts— LP He salt is first precipitated, the solvent is distilled off from the split mother liquor formed by solid-liquid separation, and the residue is D— ACL 'Ts. L-A solvent can be deposited preferentially by precipitation of Phe salt, for example, a low dielectric constant solvent such as isopropanol or its water-containing solvent, or a high dielectric constant solvent such as water to carry out dissolution and precipitation. ACL'Ts-L Phe salt can be obtained in high yield and high purity.

Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to this. The raw materials DL— ACL used in the examples are all racemic ACL. The measurement of the optical purity of ACL was performed by HPLC under the following conditions.

Column: OA — 5000 (Sumi 化 Analysis Center)

Mobile phase: ImM copper sulfate solution

Flow rate: 0.5 mL / mm

Column temperature: 20 ° C

Detector: JASCO “UV-970” wavelength 254 nm retention time is

D-ACL: 12. lmin ゝ L— ACL: 9. 8 min

Example 1

[0036] L ACL'Ts-Production of L Phe salt monohydrate

(Optically active Ts—L-Phe's DL—optical division of ACL)

To 50 g (390 mmol) of DL-ACL (moisture: 3.7%), 500 g of methanol and 24.6 g (390 mmol) of Ts-L-Phel were added (molar ratio 1: 1) and dissolved by heating. The solution was gradually cooled to 48 ° C., and a small amount of L ACL′Ts-L Phe salt monohydrate prepared separately was used as a seed crystal and cooled to 20 ° C. The precipitated crystals were separated by filtration and dried to obtain 52.6 g of L ACL'Ts-L-Phe salt monohydrate. The yield was 29%, and the optical purity of ACL of this salt was 93% de.

Example 2

[0037] D — ACL'Ts — L — Production of Phe Salt

(Optically active Ts—L-Phe's DL—optical division of ACL)

10 g (78 mmol) of DL— ACL (containing 3. 7% water), 74 g of black foam and Ts— L Phe 25 g (78 mmol) was added (molar ratio 1: 1) and dissolved by heating. The solution was gradually cooled to room temperature, and the precipitated crystals were separated by filtration and then dried to obtain 8.4 g of D-ACL'Ts-L-Phe salt. The yield was 24. 1%, and the optical purity of ACL of this salt was 68.5% de. Example 3

[0038] D-ACL · Ts-production of L-Phe salt

The diasteromeric salt was separated by the optical resolution in Example 1, and the remaining mother liquor solvent was distilled off, and 41 g of water and 333 g of isopropanol were added and dissolved by heating. The solution was cooled to 66 ° C., a small amount of seed was prepared as seed crystals of D-ACL'Ts-L Phe salt prepared separately, and the solution was cooled to 20 ° C. The precipitated crystals were separated by filtration and dried to obtain 71.4 g of D-ACL'Ts-L-Phe salt. The yield is 41% (DL-ACL standard), and the optical purity of ACL of this salt is 92% ae7.

Example 4

[0039] Optical resolution agent recovery and D — manufacture of ACL · hydrochloride

10 g (22 mmol) of D-ACL'Ts-L Phe salt prepared in Example 3 was separated, 100 g of water was added and dissolved by heating to 60 ° C. To this solution was added dropwise 5. 4 g (52 mmol) of 35% aqueous hydrochloric acid, and the solution was further heated to 80 ° C. and maintained at that temperature for 1 hour. The solution was gradually cooled to 80 ° C., and the precipitated crystals were separated by filtration to recover 7. Og of Ts-L Phe used as a resolving agent (a recovery rate of 98%).

In the filtrate obtained by the above filtration separation, 6.5 g (49 mmol) of a 30% aqueous solution of sodium hydroxide was added, and the pH was adjusted to 10.5. After adding 0.1 g of activated carbon and stirring for 1 hour, the activated carbon was removed by filtration. After distilling off the solvent of the filtrate, ethanol was added to precipitate sodium chloride, and stirring was carried out at 50 ° C. for 1 hour to separate force crystals by filtration to remove sodium chloride. The filtrate was added with 3.5 g (34 mmol) of 35% hydrochloric acid aqueous solution and 41.5 g of ethanol, heated to 50 ° C., and then gradually cooled to 25 ° C. The precipitated crystals were separated by filtration and dried to obtain 3.2 g of D-ACL 'hydrochloride. The yield based on DL-ACL used as the raw material was 36%, and the optical purity was 99.9% ee or more.

Example 5

[0041] L ACL'Ts-Purification of L Phe salt monohydrate 1 g of L ACL'Ts-L Phe salt monohydrate prepared in Example 1 was separated, and 6.4 g of methanol was dissolved, and then recrystallized. Optical purity: 99. 9% de or more L ACL'Ts-L-Phe salt 1 hydrate was obtained. The salt was hygroscopic and stabilized when it contained 0.5 equivalents of water.

Melting point: 101. 5-107. 5 ° C., 160. 5-162. 0 ° C.

Optical rotation: [α] 22 + 20.7 ° (cO. 1, EtOH)

D

Water content: 5. 80% (Karl Fischer titration)

IR (KBr) cm ^_1 : 3598, 3424, 3312, 3194, 3024, 2924, 2858, 1665, 1596,

1472, 1385, 1303, 1157, 1097, 555

JH NMR (DMSO-d, 400%) δ: 8.11-8.01 (m, 1H), 7.57 (d, J = 8.4 Hz, 2%),

6

7.30 (d, J = 8.4 Hz, 2H), 7.17-7.12 (m, 5H), 3.92 (d, J = 11.2 Hz, IH), 3.40 (t, J = 5.2 Hz, IH), 3.15— 3.09 (m, 2H), 2.95 (dd, J = 5.2 Hz, 13.2 Hz, IH), 2.88 (dd, J = 5.2 Hz, 13.2 Hz, IH), 2.36 (s, 3H), 1.89-1.81 (m, 2H ), 1.75-1.72 (m, IH), 1.62-1.40 (m, 2H), 1.25-1. 19 (m, IH)

Example 6

[0043] D-ACL · Ts-L-Purification of Phe salt

One gram of the D-ACL'Ts-L-Phe salt prepared in Example 3 was separated, dissolved in 1.lg of water and 9. 9 g of isopropanol and dissolved and recrystallized. Optical purity 98. 8% de D-ACL'Ts-L Phe salt was obtained.

[0044] Melting point: 180. 5—183. C

Optical rotation: [α] 22 + 30.5 ° (cO. 1, EtOH)

D

Water content: 0.12% (Karl-Fisher titration)

IR (KBr) cm ^_1 : 3338, 3264, 2930, 2856, 1692, 1613, 1562, 1381, 1315,

1152, 661

^J H NMR (DMSO-d, 400%) δ: 8.11-8.01 (m, 1H), 7.57 (d, J = 8.4 Hz, 2%),

6

7.30 (d, J = 8.4 Hz, 2H), 7.19-7.10 (m, 5H), 3.92 (d, J = 11.2 Hz, IH), 3.40 (t, J = 5.2 Hz, IH), 3.16— 3.02 (m , 2H), 2.95 (dd, J = 5.2 Hz, 13.2 Hz, IH), 2.88 (dd, J = 5.2 Hz, 13.6 Hz, IH), 2.36 (s, 3H), 1.88-1.81 (m, 2H), 1.75-1.71 (m, IH), 1.58-1.43 (m, 2H), 1.25-1.18 (m, IH) Example 7

[0045] The procedure of Example 1 was repeated using various solvents instead of methanol. The conditions and results are summarized in Table 1 below.

1]

No solvent solvent amount dielectric constant optical purity D / L yield

(Note 1) (ε) degree (% de) (%)

1 Chlorohore 7 7 5 6 9 D 2 4

2 1, 2 ジエタン 6 1 1 6 1 D 4 3

3 Methyl isopyl ketone 4 5 1 3 4 1 D 6 2

4 Isopropanol 5 0 1 8 3 2 D 6 4

5 ethanol 3 2 2 4 7 D 6 8

6 8 9% Isopropanol water 1 1 2 5 2 9 D 5 9

7 8 5% isopropanol water 1 0 2 7 2 2 D 5 5

8 90% ethanol-containing water 1 5 2 9 1 0 L 6 0

9 8 1% ethanol water containing 1 2 3 4 9 9 L 2 4

1 0 9 5% Methanol-containing water 1 6 3 5 9 2 1 5

1 1 N, N—Dimethylformamide 2 7 3 7 9 0 2 7

1 2 7 4% ethanol containing water 1 4 3 8 1 0 0 1 3

1 3 Ethylene glycol 4 3 3 9 9 9 L 3 8

1 4 dimethyl sulfoxide 3 2 4 9 9 6 1 19

1 5 6 0% methanol containing water 1 1 5 1 9 5 L 9

1 6 5 5% methanol water 5 5 3 2 5 L 4 0

1 7 4 5? Methanol-containing methanol water 8 5 8 3 L 4 8

1 8 3 0% ethanol water containing water 1 0 6 2 6 D 4 3

1 9 3 5 3⁄45 Methanol-containing water 6 6 3 1 3 D 1 6

2 0 1 0% Methanol-containing water 1 9 7 4 3 5 D 3 7

2 1 Water 1 8 7 8 2 8 D 3 0 Note 1 D L—weight ratio of solvent to A C L

Industrial applicability

[0046] The present invention is directed to a method for producing optically active ACL, which can be obtained arbitrarily, regardless of whether the target optically active substance is a D-body or an L unit. It can respond to flexibility.

Claims

The scope of the claims

[1] It is a method to produce one strength proratatam (hereinafter abbreviated as "ACL")

A production method characterized by optically resolving the DL-ACL represented by and using a optically active phenylanin derivative as a resolving agent by the diastereomer method.

[2] As a resolving agent, the following formula (2)

[Formula 2]

(Wherein, R represents an asyl group or a sulfo group, and * represents the position of an asymmetric carbon atom).

2. The process according to claim 1, wherein the optically active phenalanin derivative represented by is used. As a resolving agent, the following formula (3)

[Chemical 3]

(Wherein * represents the position of the asymmetric carbon atom)

The process according to claim 1, wherein the optically active N-p-toluenesulfonyl group represented by is used.

By depositing the diastereomeric salt using a solvent selected based on the value of the dielectric constant, it selectively removes the diastereomeric salt containing D— ACL or L ACL. A method for producing any one of claims 1 and 3, which is to be carried out.

[5] The method according to claim 4, wherein the diastereomeric salt containing L ACL is selectively obtained by performing precipitation of the diastereomeric salt using a solvent having a dielectric constant of more than 28 and 60 or less.

[6] The method according to claim 4, wherein the diastereomer salt containing D-ACL is selectively obtained by performing precipitation of the diastereomer salt using a solvent having a dielectric constant value of 28 or less, or more than 60. Production method.

[7] lower equation (4)

[Formula 4]

L ACL · N-p-Toluenesulfo-rou L-Ferranin salt and its hydrate.

[8] lower equation (5)

[Chem. 5]

D— ACL · N — p — Toluenesulfo-Lo L — Fuerranin salt,