JPS61191679A - Method of optical resolution of cyclic carbonyl compound - Google Patents

Abstract

PURPOSE:To subject an enantiomer mixture of an optically active specific cyclic compound containing a carbonyl group and no aromatic substituted group to optical resolution efficiently, by using a resolving agent comprising a polysaccharide or its derivative as an active ingredient. CONSTITUTION:An enantiomer mixture of an optically active cyclic compound consisting of 4, 5, 6, 7, 10, or 12-membered ring containing a carbonyl group and no aromatic substituted group is effectively subjected to optical resolution by using a resolving agent comprising a polysaccharide, preferably a homoglycan having preferably high regularity and uniform bond style, especially cellulose from which high-purity polysaccharide is easily obtained, or a derivative of the polysaccharide obtained by replacing part or the whole, preferably >=85% H or OH or the polysaccharide with another atom group selected from groups shown by the formula I-III (R is 1-3C aliphatic group, 3-8C alicyclic group, etc.) as an active ingredient. The polysaccharide is suitable especially for industrial chromatography separation since its raw material is easily obtainable and the polysaccharide is stable.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for obtaining each enantiomer of an aliphatic cyclic compound containing a carbonyl group by optical resolution. The optically resolved compound can be used as it is for its physiological activity, but it can also be used as an intermediate in organic synthesis to obtain various optically active compounds. The optically active compounds obtained in this way are used as medicines and agrochemicals, and are in diverse demand as optical materials such as liquid crystals and reagents for research.

For example, pantoyllactone is used as a raw material for the pharmaceutical pantothenic acid, γ-alkylbutyrolactones are used as fragrances, and β-lactams are used as the backbone of penicillins, cephalosporins, and other antibiotics and antitumor substances. It is deeply involved in their physiological activities. As described in the section on prior art, such physiological effects usually differ between optical isomers.

On the other hand, these cyclic compounds also serve as precursors of various acyclic compounds that exist more widely. for example,
Lactones become oxycarboxylic acids when ring-opened, and become 1,3-diol when reduced. Similarly, lactams correspond to aminocarboxylic acids, aminoalcohols, etc., and cyclic ureas, cyclic carbamates, cyclic anhydrides, and cyclic carbonates correspond to diamines, aminoalcohols, dicarboxylic acids, and when reduced, diols and diols, respectively. Examples of the practical use of these possible products are too numerous to list; for example, aminoalcohols are often the basis of various pharmaceuticals, including β-adrenergic blockers.

Appears as a book structure. In addition, diols are, for example, 1.3
The optically active form of -butadiol is thought to be effective against diabetes, and is also used as a raw material for catalysts for asymmetric synthesis. 1,4-bentanediol is used in the asymmetric synthesis of the physiologically active substance prefeldin A.

[Conventional technology]

As mentioned above, each enantiomer of an asymmetric compound often has different effects on living organisms, and for this reason optical resolution and asymmetric synthesis methods are one of the biggest challenges in current organic chemistry. There is.

Conventional methods for obtaining optically active substances include asymmetric synthesis, optical resolution after induction into diastereomers, and biochemical methods using enzymes or microorganisms. Asymmetric synthesis methods have the problem of not being able to obtain the desired compound with high optical purity, and diastereomer derivatization cannot be easily achieved using diastereomer derivatization methods. However, there was a problem in that equimolar amounts of different types of optically active compounds were required. Biochemical methods have the disadvantage that it is difficult to identify appropriate enzymes and microorganisms.

[Problem that the invention seeks to solve]

Aliphatic cyclic compounds containing carbonyl groups, such as lactones and lactams, as mentioned above, are neither acidic nor basic chemically, so they do not form diastereomeric salts, such as in the case of pantoyl lactone. First, it had to be resolved once in the free acid form and then by forming its optically active amine salt. This is not an industrially good method since it increases the number of chemical conversions and also requires recovery of the optically active amine pair.

On the other hand, compounds containing aromatic rings are often relatively easy to optically resolve due to the size of the aromatic ring and lack of conformational freedom, and in this sense, γ-phenyl-γ
- It is no wonder that there are examples of butyrolactone being optically resolved by chromatographic methods. However, direct optical resolution has been difficult for aliphatic cyclic compounds that do not contain many aromatic substituents that are useful synthetically or physiologically, and that contain carbonyl groups.

[Means for solving problems]

As a result of extensive studies, the present inventors have discovered that these cyclic compounds can be efficiently optically resolved using a separation agent containing a polysaccharide derivative as an active ingredient. The polysaccharide-based separating agent used here has an abundance of raw materials, and is relatively easily prepared from them. It also has excellent chemical stability and has the conditions to enable industrial chromatographic separation.

That is, the present invention provides a wide range of asymmetric cyclic compounds that do not contain aromatic substituents and contain a carbonyl group as shown below. The present invention relates to a method for optically resolving organic compounds, which is characterized by optically resolving an organic compound using a separating agent containing a derivative as an active ingredient.

The cyclic compound containing a carbonyl group and not containing an aromatic substituent that is optically resolved by the method of the present invention is one having a carbon number of 15 or less and having a skeleton included in any one of the following general formulas.

By substituting the hydrogen bonded to the carbon of this skeleton with another atomic group, a compound having asymmetry becomes a target of optical resolution. The substituents mentioned here include CI, Br, 1.
F, R, 0R (R=H, Cl31 CJs+CH*
OH,CHtCQCH3,C0C)Is, Co□CH
! , CO□CtHs.

CH=CH, CB-CHCHs, CH(C)Is
)z, CN, CHtCH).

SH, SR, SO□R (R=CHs, CJs), N
Examples include O□+N3. A specific example would be: In general, the smaller the number of ring members, the easier it is to divide.

The separating agent used in the present invention contains polysaccharides and derivatives thereof as active ingredients. The polysaccharide referred to here may be any optically active polysaccharide, including synthetic polysaccharides, natural polysaccharides, and modified natural polysaccharides, but it is preferably a highly regular homoglycan with a constant bonding pattern. It is something. More preferred are cellulose, amylose, β-1,4-chitosan, chitin, β-1,4-mannan, β-1,4-xylan, inulin, and α-1°, from which highly pure polysaccharides can be easily obtained. 3-glucan, β-1,3
-Glucan etc.

A polysaccharide derivative is one in which some or all, preferably 85% or more, of the hydrogen atoms on the hydroxyl groups of the polysaccharide are replaced with other atomic groups. The atomic group here is , and R is an aliphatic group having 1 to 3 carbon atoms, a cycloaliphatic group having 3 to 8 carbon atoms, an aromatic group or a heteroaromatic group having 4 to 20 carbon atoms. , all may have a substituent. These derivatives can be easily obtained using various known chemical reactions. These polysaccharides and their derivatives are particularly suitable for industrial chromatographic separation because of their ease of raw material availability and stability.

In the optical resolution method of the present invention, by selecting an appropriate polysaccharide or its derivative from among these polysaccharides or derivatives thereof, it is possible to perform optical resolution of the desired derivative.

Methods of using the separating agent in the present invention include the following.

In order to use it as a liquid chromatography method or a gas chromatography method, the polysaccharide or its derivative can be used by filling a column as it is, by holding it on a carrier and packing it, or by coating it on a capillary column.

Since the separation agent for chromatography is preferably in the form of particles, in order to use the polysaccharide or its derivative as a separation agent for compounds, it is preferable to crush the polysaccharide or its derivative or form it into beads.

The size of the particles varies depending on the size of the column or plate used, but is 1 μI11 to 10 m+a, preferably 1 μm to 300 μm, and the particles are preferably porous.

Furthermore, the pressure resistance of the separation agent is improved, swelling due to solvent replacement,
In order to prevent shrinkage and improve the number of theoretical plates, the polysaccharide or its derivative is preferably retained on a carrier. The appropriate size of the carrier varies depending on the size of the column or plate used, but is generally 1 μm to 100111 μm, preferably 1 μm to 300 μm. The carrier is preferably porous, with an average pore diameter of 10 to 100 μm, preferably 50 to 10,000 μm. The amount of polysaccharide or its derivative retained is 1 to 100% by weight based on the carrier.
, preferably 5 to 50% by weight.

The method for retaining the polysaccharide or its derivative on the carrier may be either a chemical method or a physical method. Physical methods include dissolving the polysaccharide or its derivative in a soluble solvent, mixing well with the carrier, and distilling off the solvent with air flow under reduced pressure or heating, or dissolving the polysaccharide or its derivative in a soluble solvent. There is also a method of dispersing the solvent by stirring and dispersing it in a liquid that is incompatible with the solvent after thoroughly mixing it with a carrier.

When crystallizing the polysaccharide or its derivative held on the carrier in this way, a treatment such as heat treatment can be performed. Furthermore, by adding a small amount of solvent to once swell or dissolve the polysaccharide or its derivative, and then distilling off the solvent again, it is possible to change the retention state and, ultimately, the separation ability.

The carrier may be a porous organic carrier or a porous inorganic carrier, preferably a porous inorganic carrier. Suitable porous organic carriers include polymeric substances such as polystyrene, polyacrylamide, and polyacrylate. Suitable porous inorganic carriers include synthetic or natural substances such as silica, alumina, magnesia, titanium oxide, glass, silicates, and kaolin, which may be surface-treated to improve their affinity with the polysaccharide or its derivatives. You may do so. Examples of surface treatment methods include silanization using an organic silane compound and surface treatment using plasma polymerization.

When using polysaccharides or their derivatives for optical resolution, the separation characteristics may change depending on their physical states such as molecular weight, crystallinity, and orientation, even if the derivatives are chemically the same. Heat treatment, etching, and other physical or chemical treatments can be applied after or during the process of imparting a shape suitable for use. or,
Poly-11M derivatives synthesized by heterogeneous reactions often retain the higher-order structure of the starting polysaccharide, and even if they are chemically identical to those synthesized by homogeneous reactions, they have a different higher-order structure, and this makes them different. May result in separation properties.

Solvents that dissolve polysaccharides or their derivatives cannot be used as developing solvents when used in liquid chromatography, but when polysaccharides or their derivatives are bonded to a carrier by a chemical method,
There are no particular restrictions when the polysaccharide or its derivative is crosslinked.

In addition, when performing thin layer chromatography, 0.1 μn
A separation agent of the present invention consisting of particles of about 1 to 0.1 mm and, if necessary, a small amount of a binder, of 0.1 mm to 1001 mm.
It is sufficient to form a layer having a thickness of .

[Optical separation method]

Examples of means for obtaining the optically active substance of the present invention using the above separation agent include chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography.

The developing solvent used in liquid chromatography or thin layer chromatography is not particularly limited, except for a liquid that dissolves or reacts with the separating agent. When the separation agent is bonded to a carrier by a chemical method or made insolubilized by crosslinking, there are no restrictions except for the reactive liquid. Needless to say, the separation characteristics of compounds or optical isomers change depending on the developing solvent, so it is desirable to consider various developing solvents.

[Effect]

It is not clear why a cyclic compound containing a carbonyl group is effectively optically resolved by the method of the present invention. However, in order to achieve optical resolution, it is necessary at least to be well adsorbed to the separating agent. In this respect, for example, even when comparing aliphatic compounds having the same ester bond, cyclic compounds such as γ-butyrolactone show stronger adsorption to the separation agent than acyclic compounds such as methyl acetate. . This is probably because the decrease in entropy of bond rotation due to adsorption is small in cyclic compounds, but by forming a ring in this way, it is possible to have a strong interaction with the polysaccharide derivative, and it also increases the molecular stability. It is thought that the conformation is extremely restricted, making it easier to identify the asymmetric structure of the molecule. Furthermore, substituents on the ring may also be involved in adsorption.

〔Effect of the invention〕

As described above, the present invention has established a method for obtaining an optically active substance useful as a pharmaceutical or a synthetic intermediate from a racemic raw material by a simple chromatography technique.

〔Example〕

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but it goes without saying that the present invention is not limited thereto.

As a column for liquid chromatography, a stainless steel column having a length of 25 am and an inner diameter of 0.46 cee was used, which was filled with a packing material in which about 2% by weight of a cellulose derivative was supported on diphenylsilane.

In addition, the detection of the eluting optical isomer was carried out using an ultraviolet detector (Shimabara 5
PD-n), differential refractometer (Showa Denko 5hodex RI
SE 31) and a polarimeter equipped with a flow cell (JASCO Corporation DIP 181).

The parameter α used in the examples is defined as follows.

Example 1 0L-pantoyllactone (manufactured by Tokyo Kasei Co., Ltd.) was prepared by treating cellulose triacetate with diphenylsilane.
Ichrosper St 1000 with a diameter of 4.611Il filled with a separating agent supported at about 22% by weight
FIG. 1 shows a chromatogram obtained by optical resolution using a column with a diameter of φ and a length of 25 cll. kl 1-4.18
, kl8·5.10, α=1.22. The eluent was a 9:1 mixture of hexane-2-propertool, and the flow rate was 0.
5ml/wins Analysis temperature is 20℃, detection wavelength 2
Ultraviolet absorption at 30 nm was used. In addition, the D-C-) form and L-(+) form were determined by adding D-(-)-pantoyllactone (manufactured by Tokyo Kasei Co., Ltd.) to the above racemic form and performing chromatography. This was done because the intensity of the later eluting peaks was high.

Example 2 FIG. 2 shows a chromatogram of β-butyrolactone separated under the same conditions as in Example 1. kll・7.20, g1
It was 2.9.44, α snow 1.31.

[Brief explanation of the drawing]

FIGS. 1 and 2 are diagrams showing split chromatograms obtained by the method of the present invention. Applicant's agent: Kaoru Furuya, proceduralist, Fu Seishobai) March 19, 1985 1, Indication of the case, Patent Application No. 60-32437 2, Name of the invention: Optical resolution method for cyclic carbonyl compounds 3, Amendment Patent applicant (290) Daicel Chemical Industries, Ltd. 4, agent Nakai Building 1-3 Nihonbashi Yokoyama-cho, Chuo-ku, Tokyo ) line 6-7 from the bottom of specification 2 rl, 3-diol”
was corrected as “diol”.
, 3-butanediol" and corrected fil, same page 4, line 1 "compound" was corrected as "substance"
1, page 5, line 6, “many” is corrected to “is,” +11 page 5, line 7, “include”, “many” is added after “include” (1) page 5, line 4, “is” Add “wo” after “carbonyl group” (1) 2 lines on the right side of the first general formula on page 6, rx=o,
s+NRJ with rX=0. S, NR, C1+□”
Correction (1) Delete ORJ, page 7 line 4 r, fil Same page 7 true line 4 rCJs, r after J (, +I
It, C4119゜Cs1l++l added +11 After "N3" on page 7, line 7, FOR'(R''
= H, CI + 3゜ C o Hs, Czllt) Add J (11, page 7, add the following chemical formula after the unwritten chemical formula (11, page 7, true 1 line, "and so on," is replaced with "and so on."
(11, p. 8, lines 1-2, "Generally, it is easy to divide." Lichrospher 5
i1000) J was added (11, page 17, line 4, after "α=1°31.", the line was changed and the following Example 3 was added. The following compounds were separated using what was supported on the top.Chemical formula % formula % of each compound

Claims (1)

[Claims] 4,5,6 containing no aromatic substituents and containing a carbonyl group
, 7-, 10-, and 12-membered rings.