WO2004090013A1

WO2004090013A1 - Process for producing cyclic lactic acid oligomer

Info

Publication number: WO2004090013A1
Application number: PCT/JP2004/004676
Authority: WO
Inventors: Mikio Watanabe; Masashi Takama; Jiro Takano; Masahiro Murakami
Original assignee: Amato Pharmaceutical Products, Ltd.; Tokai Education Instruments Co., Ltd.
Priority date: 2003-04-02
Filing date: 2004-03-31
Publication date: 2004-10-21
Also published as: TW200519136A; JP2004307560A

Abstract

A process for efficiently producing a cyclic lactic acid oligomer having a desired degree of condensation. The process comprises reacting the terminal carboxy group of a chain lactic acid oligomer having a degree of polymerization of m (m is an integer of 3 to 15) as a starting material with the -OR group of a compound represented by O=R (wherein R is a cyclic or chain organic group) preferably in the presence of a base and then cyclizing n molecules of the oligomer preferably in the presence of a catalyst. The degree of condensation of the cyclic lactic acid oligomers yielded depends on the degree of condensation of the chain lactic acid oligomer having a degree of polymerization of m, i.e., n times the number m. Usually, a mixture of cyclic lactic acid oligomers having a degree of polymerization of m·n (i.e., oligomers in each of which the number of lactic acid units is m·n) is obtained.

Description

Description Manufacturing method of cyclic lactic acid oligomer

The present invention relates to a method for producing a cyclic lactic acid oligomer. More specifically, the present invention relates to a method for producing a cyclic lactic acid oligomer having a degree of condensation that is a multiple of the degree of condensation of a cyclized chain lactic acid oligomer. Background art

Various synthetic methods have been proposed to obtain cyclic lactic acid oligomers that are expected to be useful.

In order to synthesize a single cyclic lactic acid oligomer having a desired chain length, for example, an attempt has been made to sequentially synthesize a linear oligolactic acid having a desired chain length on a solid phase and finally cyclize (for example, , Non-Patent Document 1.). In such a synthesis method, there is a problem that the method is extremely complicated including protection of a functional group, and furthermore, the final yield is low and the method is not practical.

By performing a dehydration condensation reaction of lactic acid under reduced pressure, a linear and / or cyclic lactic acid oligomer mixture having a degree of condensation of 3 to L9 has been synthesized (for example, see Patent Document 1). In this production method, it is not easy to control the generated cyclic polylactic acid to have a constant composition. Therefore, the production method provided a mixture of linear and cyclic lactic acid polymers containing a high polymer and having a wide molecular weight distribution.

A method for producing a cyclic lactic acid oligomer containing no chain lactic acid oligomer has been disclosed by the applicant of the present application (for example, see Patent Documents 2 and 3). Lactide (3,6-dimethyl-1,4—) formed by dehydration condensation of two molecules of lactic acid In the case of the production method of dehydration polymerization using dioxane-1,2,5-dione) as a raw material (Patent Document 2), an alkali metal compound is used as a catalyst, and by selecting the type of the catalyst, substantially only cyclic lactic acid oligomer can be obtained. Can also be obtained selectively (Patent Document 3). The reaction product is a mixture of cyclic lactic acid oligomers having different chain lengths in which the number of lactic acid units changes to 2, 3, 4,.... Patent Document 1: JP-A-9-227388

Patent Document 2: WO 01 / 21613A1 Pan fret

Patent Document 3: WO 01 / 21612A1 pamphlet

Non-patent Document 1: Kuisle 0., Quinoa E. (Quinoa) and Riguera R. (Riguera R.)

"Journal of Organic Chemistry (J. Org. Chem.) '\ 1999, 64 volume p8063

If there is a method for producing a cyclic lactic acid polymer that gives a product having a simple polymer composition, a cyclic lactic acid oligomer having a specific chain length can be easily isolated as a single compound using this method. The method is also meaningful for the development of new uses for cyclic lactic acid oligomers. The present inventors have intensively studied a production method capable of directly synthesizing a cyclic lactic acid oligomer having a constant chain length as a single compound. As a result, the method of the present invention for selectively producing a cyclic lactic acid oligomer whose degree of condensation is a multiple of the degree of condensation of the linear lactic acid oligomer as the raw material has been completed.

The present invention provides a method for synthesizing a cyclic lactic acid oligomer having a desired degree of condensation. Further, another object of the present invention is to provide a method for obtaining a product capable of efficiently separating a cyclic lactic acid oligomer having a specific length. Summary of the Invention

The production method of the present invention

(i) Equation (1)

The terminal carboxyl group of the linear lactic acid m-mer oligomer (m is an integer of 3 to 15) represented by

0 = R (2)

(In the formula, R is a cyclic or chain organic group.)

And react with

Form

(ii) Next, cyclize the obtained linear lactic acid m-mer oligomer (3)

A method for producing a cyclic lactic acid oligomer represented by formula (4) and containing mn lactic acid units (n is an integer of 1 or more).

In the production method of the present invention,

In the above formula (2), the compound represented by 0 = R is represented by the following formula

R 2

0: C

1

ヽ…)

(Wherein, R ¹ is a linear or cyclic organic group which may have a substituent, and R ² is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group or an amino group, or R ¹ It is a chain organic group that forms a ring structure by bonding to an atom.)

R ¹ may be an aliphatic group, an aryl group or a heterocyclic group (these groups may have a substituent).

In particular, it is preferable that R ¹ be a halogen-substituted phenyl group and R ² be a halogen atom.

In the compound represented by the above formula (5), R ² is preferably a nitrogen atom-containing group, and the nitrogen atom is preferably bonded to a carbon atom of R ¹ to form a heteroaromatic ring. In this case, particularly as the compound represented by the formula (5), 21 pyridone is preferably used. The method for producing a cyclic lactic acid oligomer of the present invention is characterized in that the above (i) is carried out in the presence of a base. As the base, amines or pyridine derivatives are particularly preferred.

The above (ii) is preferably carried out in the presence of aminoviridines. Alternatively, the above (ii) is preferably performed in the presence of aromatic sulfonic acids.

In the method for producing a cyclic lactic acid oligomer of the present invention, it is preferable that the above (i) and (ii) are performed in an atmosphere of argon and / or nitrogen. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the synthesis of a cyclic lactic acid oligomer from a linear lactic acid trimer.

TEA is triethylamine, DMAP is 4-N, N-dimethylaminoviridine, and toluene is toluene. refl means reflux.

FIG. 2 shows the synthesis of a cyclic lactic acid oligomer from a linear lactic acid tetramer.

TEA is triethylamine, DMAP is 4-N, N-dimethylaminoviridine, and toluene is toluene. refl means reflux. BEST MODE FOR CARRYING OUT THE INVENTION

The method for producing a cyclic lactic acid oligomer according to the present invention includes the following steps (i) and (ii).

ω formula (1)

The terminal carboxyl group of the linear lactic acid m-mer oligomer represented by the formula (m is an integer of 2 or more), preferably in the presence of a base,

0 = R (2)

(Wherein R is a cyclic or chain organic group).

Form

(ii) Next, the obtained chain lactic acid m-mer oligomer (3) is cyclized.

The product of the above (ii) has mn lactic acid units (n is an integer of 1 or more.

) Containing cyclic lactic acid oligomer,

(4). In order to obtain a cyclic lactic acid oligomer having a desired chain length, it is necessary to appropriately select the chain length of a single linear lactic acid oligomer as a starting material, as described later. The above-mentioned production method according to the present invention includes at least an ester formation step (i) and a cyclization step (ii). The details of each reaction are shown below.

In the step (i), the terminal carboxyl group of the linear lactic acid m-mer oligomer represented by the formula (1) (m is an integer of 2 or more) is replaced with a compound represented by 0 == R With one OR group. This reaction is preferably performed in the presence of a base. The active group OR is bonded to the terminal carboxyl group of the linear lactic acid oligomer to form a linear lactic acid m-mer oligomer ester represented by the formula (3). In the next step (ii), the above-mentioned linear lactic acid m The oligomeric ester is cyclized, preferably in the presence of a catalyst. For example, under the condition that the solvent is refluxed, the n chain lactic acid m-mer oligomer esters are polymerized to become one molecule when one OR group is eliminated from the ester of the terminal carboxyl group, one COOR, and Cyclize. As a result, a mixture of the cyclic lactic acid mil-mer oligomer (expressed by the formula (4), where n is a multiple of the m-mer and is an integer of 1 or more), which is the product, is produced. According to the production method of the present invention, a cyclic lactic acid oligomer is produced as a product by performing the above steps (i) and (ii) using a linear lactic acid m-mer oligomer which is a single compound as a raw material. It is possible to selectively obtain a mixture of mn-mers (this is n-fold of m-mers, where n is an integer of 1 or more). The degree of condensation of the resulting cyclic lactic acid oligomer mn-mer is 3 to 60 on average, and preferably 3 to 24.

As used herein, the term "degree of condensation" refers to the number of lactic acid units that are repeating units in the lactic acid polymer. The term “n-fold” refers to a lactic acid oligomer containing n lactic acid m-mer oligomer skeletons as a starting material. Specifically, if the compound is synthesized according to the method of the present invention using a single compound of a linear lactic acid trimer oligomer as a starting material, a trimer (n = l), a hexamer (n = 2), A mixture containing 9-mer (n = 3), 12-mer (n = 4), 3n-mer cyclic lactate oligomers is produced (Fig. 1). However, the proportion of each monomer contained therein is not the same. Similarly, when starting from a linear lactic acid tetramer, a mixture mainly containing a cyclic milk chain oligomer as shown in FIG. 2 is usually obtained.

The cyclic oligomer thus formed, which can have a degree of condensation m and a multiple n, is generally expressed as follows. If a single linear lactic acid m-mer is used as a starting material, the cyclic lactic acid oligomer product represented by the above formula (4) will be an oligomer which is n-fold with respect to the m-mer, that is, the mn content It is a mixture of body oligomers (oligomers with mn lactic acid units). Therefore, the degree of condensation of the cyclic lactic acid oligomer contained in the resulting mixture does not take a continuous number such as m, m + 1, m + 2, m + 3 It is specified by the degree of condensation of the linear lactic acid m-mer oligomer as a substance. Furthermore, n is an integer greater than or equal to one, and of these integers, n generally takes two or more values.

As described above, the cyclic lactic acid oligomer produced by the method of the present invention is a mixture having a specific composition in which the cyclic lactic acid oligomer (mnmer) having a specific chain length is mainly contained. Recovering a single cyclic lactic acid oligomer having a desired degree of condensation from such a mixture of relatively simple compositions is much more than recovering from a mixture of cyclic lactic acid oligomers having a continuous chain length distribution. It is considered easy. Therefore, a single cyclic lactic acid oligomer can be efficiently isolated. Further, by selecting the type of the starting m-lactic acid oligomer and the type of the reactant represented by the formula (2), the composition of the mixture can be adjusted as desired. one of.

The compound (such as a chain lactic acid oligomer) used in the production method of the present invention or the generated cyclic lactic acid oligomer may be a mixture of isomers without particular distinction between stereoisomers. Similarly, these compounds may be in various forms such as salts (sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt, zinc salt, etc.), hydrates, solvates, and polymorphs. Hereinafter, as a compound used in the production method of the present invention, a chain lactate oligomer as a raw material, a compound represented by the formula (2) 0 = R, a reaction auxiliary such as a base, and a solvent will be described in detail. It will be explained, and the process will be explained in detail. Linear lactic acid oligomer

In the production method of the present invention, a single chain lactic acid oligomer represented by the formula (1) is used as a starting material for synthesizing the cyclic lactic acid oligomer (4). The linear lactic acid oligomer can start from any linear m-mer condensate of lactic acid, where m is an integer of 2 or greater. m is an integer from 2 to 30 And is usually an integer of 3 to 15, preferably 3 to 10, and more preferably 3 to 6. When m is 1, it is a monomer of lactic acid, and when m is 2, it is ratatoyl lactate.

Actually, in order to obtain a cyclic lactic acid oligomer having a desired chain length, the chain length of the linear lactic acid oligomer of a single compound as a raw material is appropriately set. As described above, the selection may be made in consideration of the degree of condensation m of the starting material and the relationship between the product and its n-fold.

A method for producing a linear oligolactic acid having such a specific chain length has already been proposed by the same applicant as the present application (Japanese Patent Application No. 2002-042009). According to this method, a linear lactic acid oligomer having a constant chain length between a dimer and a 20-mer can be directly synthesized as a single compound. Thus, in the present invention, a chain lactic acid oligomer desired as a starting material can be directly prepared using this method. Compound Q = R

Before cyclizing the linear lactic acid oligomer, a specific protecting group is bound to the terminal lipoxyl group to activate the terminal. A compound capable of donating one OR group as a functional group therefor, that is, a compound represented by the above general formula (2), 0 = R (R is a cyclic or chain organic group.) 1S Chain Used for reaction with lactic acid oligomers. Note that an “organic group” is an atomic group contained in an organic compound and refers to a substance that acts as a group. Specifically, it is a chain or cyclic group having carbon or hydrogen (all of which may be substituted), and is an aliphatic group, aryl group, heterocyclic group or a combination thereof ( May have a substituent.). For example, it may be an alkyl group, a phenyl group, or a nitrogen-containing aromatic heterocyclic group (these groups may have a substituent). The compound capable of donating an active group represented by one OR, 0 = R (the compound represented by the above formula (2)) is preferably a compound represented by the following formula (5) and containing a carboxyl group . The R portion corresponds to == C (R ¹ ) R ² in the equation (5).

R ²

0 = C

-..(Five

)

(In the formula, R ¹ is a linear or cyclic organic group which may have a substituent, and R ² is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, an amino group, or other than these groups. Or a chain-like organic group that forms a ring structure by bonding to the atom of R ^1. )

In the method of the present invention, as the compound represented by the formula (5), two particularly preferable compound groups as described later, and a system of a preferred embodiment using them are established. In the above formula (5), R ¹ is a linear or cyclic organic group which may be substituted. As the chain or cyclic organic group, preferably a group having carbon and hydrogen, specifically, an aliphatic group, an aryl group or a heterocyclic group, and even if these groups have a substituent, Good.

Examples of the aliphatic group which may have a substituent include a lower alkyl group, a lower alkenyl group or a lower alkynyl group, a lower haloalkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a lower alkylthio group, Examples thereof include a lower alkylsulfinyl group and a lower alkylsulfonyl group. The number of carbon atoms in the aliphatic group is not particularly limited. Generally, it is 1 to 10, preferably 1 to 6, and particularly preferably 1 to 4. Also, the chain type is not particularly limited, but may be any of a linear chain, a branched chain, a cyclic chain or a combination thereof.

The above groups will be specifically described below, but the present invention is not limited to only these examples. Examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, and a group that is an isomer of these groups. Examples of the lower alkenyl group include vinyl, propenyl, butenyl, and the latter two groups. A lower alkynyl group such as an ethyl group, a provinyl group, a butenyl group, or a group that is an isomer thereof; a lower cycloalkyl group such as a cyclopropyl group or a cyclobutyl group; Group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctanyl group, etc .; lower alkyl groups include fluoromethyl group, difluoromethyl group, dichloroethyl group, bromopropyl group, etc .; Toxyl, ethoxy, propoxy, butoxy, isomers of these, etc .; Examples of the haloalkoxy group include monofluoromethoxy, chloro-propoxy group, and isomers thereof. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, ethoxycarbonyl group, and propoxycarbonyl group. Examples of the alkylthio group include a methylthio group and an ethylthio group. Groups, propylthio groups, butylthio groups, and isomers thereof; alkylsulfinyl groups such as methylsulfinyl, ethylsulfiel, propylsulfinyl, butylsulfiel, and isomers thereof And the like. Examples of the alkyls-le-honinole group include a methinoles-no-le-honinole group, an ethyls-no-le-honinole group, a propinole-sno-lephonyl group, a butylsulfonyl group, and isomers thereof.

The aryl group which may have a substituent is an aryl group having 6 to 24 carbon atoms, preferably 6 to 12 carbon atoms, and the aryl group has one or more substituents. You may. Specific examples of the aryl group include a phenyl group, a treyl group, a naphthyl group, a benzyl group, a phenethyl group, a phenoxy group, a mesityl group, and a p-methoxyphenyl group.

An optionally substituted heterocyclic group refers to a 5- or 10-membered saturated or unsaturated monocyclic or condensed 5- or 10-membered ring containing at least one oxygen atom, nitrogen atom, sulfur atom or phosphorus atom. It is a ring. Specific examples of the heterocyclic group include, for example, pyridyl, imidazolyl, quinolyl,, isoquinolyl, pyrimidinyl, pyrazine \ phthalazine ^, triadinole, frinole, chedi-, pyrrolinole, oxazolyl, isoxazolyl, thiazolyl , Thiadiazolyl, triazolyl, benzimidazolyl, pyrrolidino, morpholino, pyrazoporyl and the like. These heterocycles may have one or more substituents.

Examples of the substituent which the aliphatic group, aryl group or heterocyclic group may have include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom and an iodine atom), a cyano group and a nitro group. , Amino group, alkyl group, haloalkyl group, thioalkylthio group, alkylsulfiel group, alkylsulfonyl group, acyl group, alkoxy group, alkoxyalkyl group, alkoxycarbonyl group, carbamoyl group, aryl group, aryloxy group, aryloxy Examples thereof include a xycarbonyl group, an arylthio group, an arylsulfonyl group, a carboxamide group, an alkylsulfonamide group, an arylsulfonamide group, and a sulfamoyl group. Although R ^{1 serving} as a protecting group for the terminal carboxyl group of the linear lactic acid oligomer has been specifically described above, they are merely examples, and the present invention is not limited thereto. On the other hand, in the above formula (5), as the atom or group that R ² can take, specifically, a halogen atom, a hydroxyl group, a carboxyl group, an acyl group, a nitro group, A mino group, a linear or branched, linear or cyclic alkyl group, a linear or branched, linear or cyclic alkenyl group, a linear or branched, linear or cyclic alkynyl group, an acyloxy group, Anolexoxy group, anolexoxy carboxy group, alkoxycarbonyloxy group, carboxamide group, sulfonamide group, carbamoyl group, levamoyloxy group, sulfamoinole group, aryl group, aryloxy group, aryloxy group Carbonyl group, aryloxycarbonyloxy group, N-acylsulfamoyl group, N-sulfamoylcarbamoyl group, alkylsulfonyl group, arylsulfonyl group, anoreoxycarbonylamino group, aryloxycarbonylamino group , Sulfo group, mercapto group, thiocyanato group, isothiosi Nato group, alkylsulfinyl group, arylsulfinyl group, alkylthio group, sulfamoylamino group, arylthio group, heterocyclic group (for example, containing at least one or more of nitrogen, oxygen and iodide, and having 3 to 12 members Monocyclic ring, condensed ring), heterocyclic oxy group or heterocyclic thio group. As the compound represented by the above formula (5), it is preferable that the compound is bonded to the terminal carboxyl group of the linear lactic acid oligomer as an active group to activate the terminal of the oligomer and to be a group that is conveniently eliminated upon subsequent cyclization. Preferably contains a substituent having an electron-withdrawing property. From this viewpoint, as the R ² in the formula (5), a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group or an amino group is desirable among the above groups. Particularly, an acid halide or a compound similar thereto is preferable.

Specifically, an acid halide or a compound similar thereto is preferable. Particularly suitable compound groups include acyl halides in which is a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom). Particularly, a phenyl group in which R ¹ may be substituted is preferable, and particularly, halogen, nitrite A phenyl group substituted by one or more with a mouth group, a cyano group, or the like is desirable.

Specifically, a compound which is a halogen-substituted phenyl group is preferable. This includes, for example, 2,6-dichlorobenzene, 2,4,6—trichlorobenzoyl, 41-benzobenolenochloride, 2,4,6— Examples thereof include halogenated acyls such as tribromobenzoyl bromide, and particularly preferably used are 2,6-dicyclopentyl benzoyloxylide and 2,4,6-trichlorobenzoylbenzoylide. These are used alone or in combination of two or more. Such compounds constitute one of the two particularly preferred groups of compounds described above. In the above formula (5), the compound may form a ring structure by bonding the atom of R ^{1 and} the atom of R ² . In this case, R ² is a chain organic group that forms a ring structure by bonding to the atom of R ¹ . These include, for example, aliphatic groups that may be substituted, chain groups containing heteroatoms (nitrogen, oxygen, and io atoms).

Specifically, a compound in which R ² is a nitrogen atom-containing group and the nitrogen atom is bonded to a carbon atom of R ¹ to form a hetero ring, particularly a heteroaromatic ring, is preferably used. Of such heteroaromatic ring compounds, those in which the nitrogen is bonded to a hydrogen atom and a carbonyl group is present adjacent to the nitrogen are particularly desirable. These include 2-pyridones, 2 (3/1) -virazinones, oxazolones, 2_quinolones, isoquinolones, pyrimidines 1,2 UH, 3 diones, 1,4-dihidrone ^ indole Specific examples thereof include 2-ones, 1,7 dihydro-6H-purine 6-ones, and 3H-1,2,4-triazolu-3,5 (4H) monodione.

Among these compounds, 2-pyridones are particularly preferably used. This 2-pyridone is similar to the above-mentioned halogenated acyls. It provides a convenient group for the selective cyclization of the linear lactic acid oligomer and is positioned as another suitable group of compounds. The 2-pyridones provide a pyridyloxy group (a more preferred active group is a 2-phenylpyridyloxy group) as a functional group for activating the carboxyl terminal of the linear lactic acid oligomer. Specific examples include 6-phenyl-2-pyridone, 4-methyl-6-phenyl-12-pyridone, 6-benzyl-2-pyridone, 6-tolyl-2-pyridone, and the like. These may be used alone or in combinations of two or more. The molar ratio of the amounts of the linear lactic acid oligomer represented by the formula (1) and the compound represented by the formula (2) is not particularly limited, and can be set in consideration of an equilibrium point, cost, and the like. The ratio is preferably from 1: 0.7 to 1:20, more preferably from 1: 1 to 1:10. When halogenated acyls are used as the compound represented by the formula (2), the amount used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents to the starting material. 5 equivalents. When a pyridone is used as the compound represented by the formula (2), the amount of the pyridone is usually 1 to 20 equivalents, preferably 5 to 12 equivalents, more preferably 6 to 10 equivalents to the starting material. Quantity.

The reaction of the above step (i) is desirably performed in the presence of a base. Possibly, the base acts as a catalyst when the terminal carboxyl group of the linear lactic acid oligomer is esterified. As such a base, either an inorganic base or an organic base can be used.

Inorganic bases include hydroxides, hydrides, carbonates, and hydrogen carbonates of alkali metals such as lithium, sodium, and potassium; hydroxides, hydrides, carbonates, and hydrogen carbonates of alkaline earth metals such as magnesium and calcium Salt; Metal alkoxides such as sodium methylate and sodium ethylate; metal weak acid salts such as sodium acetate, sodium monohydrogen phosphate and hydrogen phosphate monophosphate.

Examples of the organic base include ammonia; pyridine derivatives such as pyridine, 2-chloro-1-methylpyridinium iodide and 4-dimethylaminopyridine; quaternary ammonium salts; trimethylamine, triethylamine, and dimethylethyl. Amines such as amine, diisopropylethylamine, aniline, naphthylamine or a substituted product thereof; toluidines, xylidines, aminophenols, anilidines, phenetidines, aminobenzaldehydes, aminobenzonitrile , Aminobenzophenones, aminobiphenyls and the like. Among these, particularly preferred bases include triethylamine, diisopropylethylamine, 2-chloro-111-methylpyridinium iodide and the like. These are used alone or in combination of two or more.

-When using acyl halides such as 2,4,6-trichlorobenzoic acid as the compound represented by the general formula (2), the base used is triethylamine, disopropylethylamine, etc. Are preferred. The amount of the amines to be used is generally 1 to 30 equivalents, preferably 1 to: L0 equivalent, more preferably 1 to 3 equivalents to the starting material.

On the other hand, when a pyridone such as 6-phenyl-2-pyridone is used as the compound represented by the general formula (2), the base used is an amine such as triethylamine and a pyridine derivative such as a pyridinium salt. (Including pyridine). The amount of the amines and pyridinium salt to be used is generally 1 to 30 equivalents, preferably 10 to 20 equivalents, more preferably 15 to 18 equivalents, based on the starting material. Other reaction aids

In the cyclization reaction of step (ii), the following reaction auxiliaries are also used. When using a halogenated acyl such as 2,4,6-trichlorobenzoic anhydride as the compound represented by the general formula (2), aminoviridines, especially 41N, N-dimethyla Minopyridine (DMAP) is used as a cord. The amount of DMAP used is 0.01 to 10 equivalents, preferably 1 to 5 equivalents. When using 6-phenyl-2-pyridones as the compound represented by the general formula (2), aromatic sulfonic acids may be used as a catalyst. Examples of aromatic sulfonic acids include benzenesulfonic acid, p-toluenesulfonic acid, 0-toluenesulfonic acid, m-toluenesulfonic acid, and naphthalene-α-sulfonic acid. Among them, a particularly preferred catalyst is ρ-toluenesulfonic acid and the like, and its use amount is from 0.01 equivalent to 1 equivalent. Organic solvent

The reaction according to the production method of the present invention is preferably carried out in the presence of a reaction solvent, and any solvent may be used as long as it dissolves the raw materials and the reaction aid and does not react with these substances or products. There are no particular restrictions. Ketone solvents such as acetone, methyl ethyl ketone, cyclopentanone and cyclohexanone; nitrile solvents such as acetonitrile; hydrocarbon solvents such as hexane, benzene, alkyl benzene, toluene or xylene; Ν, Ν_dimethylformamide Amide solvents such as amide, Ν, Ν-dimethylacetamide, Ν-methyl-2-pyrrolidone; getyl ether, dimethoxetane, methoxetinole ether, tetrahydrofuran, 1,4-dioxane, 1, Ether solvents such as 3-dioxan, bis (2- (methoxetyl) ether, bis (2- [methoxetoxy] ethyl) ether; etyl acetate, petit acetate Ester solvents such as dimethylsulfoxide, dimethylsulfone, sulfolane, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, tetramethylurea, phenol, chlorophenol, cresol, anisolinole, Examples thereof include chlorohonolem, dichloromethane, dichloroethylene, and trichloroethylene. In particular, a solvent having excellent solubility of the reactants and having a relatively low boiling point is preferably used. Specifically, toluene (boiling point 110 ° C), tetrahydrofuran (boiling point 66 ° C), dichloromethane (boiling point 40.2)

Preferred are 1,2-dichloroethane (boiling point 83.7 ° C), trichloroethylene (boiling point 86.4 ° C), and acetonitrile (boiling point 81.6 ° C). In particular, benzene, toluene, or xylene is desirable in view of cost. These solvents are used alone or in combination of two or more. Reaction conditions

The step (i) of ester formation is usually performed at 4 to 40 ° C, preferably at room temperature. Next, the cyclization step (ii) is performed at 50 to 130 ° C, preferably 70 to 110 ° C. The temperature at that time is also related to the selectivity of the generated cyclic oligomer. The reaction pressure is not particularly limited, and may be normal pressure. As the reaction atmosphere, an inert gas atmosphere such as a nitrogen gas or an argon gas can be used in each step. The reaction time cannot be determined unequivocally, but usually, the step (i) is efficient for 2 to 20 hours, preferably 2 to 12 hours, and the step (ii) is; ~ 24 hours, preferably 5 ~: 12 hours are efficient.

From the resulting cyclic lactic acid oligomer mixture, a cyclic lactic acid oligomer single compound having a desired chain length can be separated from unreacted starting materials, by-products, and the like by using ordinary separation methods, for example, high performance liquid chromatography. It can be obtained in a pure state from a cyclic lactic acid oligomer having another chain length. The mechanism by which the cyclic lactic acid oligomer mixture having a specific chain length is produced based on the production method of the present invention is considered as follows. However, the present invention is not bound in any sense by any theory explaining the reaction mechanism.

In the above step (i), an ester represented by the formula (3) is formed, and this intermediate is usually separable.

(3) In the subsequent step (ii), the n chain lactic acid m-mer oligomers are polymerized to form one molecule, and are likely to undergo “head-to-tail condensation” (head Cyclization in the form of-to- tayl condensation) also occurs. Depending on the number of m-mer molecules added at that time (ie, n), it is considered that an n-fold cyclic oligomer is formed. Such selective cyclization results in a cyclic lactic acid oligomer product with a unique composition. Preferred embodiments according to the method of the present invention are shown below. In this case, among the compounds represented by the above formula (2), particularly preferred compounds are acyl halides or 2-pyridones.

When a 2,4,6-trichlorobenzoyl group is used as the active group, the linear lactic acid trimer is reacted with 2,4,6-tric-open-benzoyl-c-ride in the presence of triethylamine to react. After the mixed anhydride, without isolation, 4 N, N— When the reaction is carried out under reflux in the presence of dimethylaminopyridine (DMAP) in a solvent such as toluene, a mixture containing three types of cyclic compound trimer, hexamer and 9-mer is obtained ( Figure 1 ). When the NMR spectra of the trimer, hexamer, and 9mer are measured, the chemical shifts of methylproton and methineproton are different from each other, and can be discriminated. If the mass spectrum is further measured, each can be confirmed by the CI method (isobutane).

Similarly, starting from a linear lactic acid tetramer, tetramers, octamers, dimers, and the like are produced in the same manner as described above (FIG. 2), and their presence can be confirmed.

—- Next, when a 2-phenylpyridyloxy group is used as the active group, the linear lactic acid tetramer and 2-phenylene are added in the presence of 2-chloro-1-N-methylpyridinium iodide and triethylamine. By reacting with -lupyridone, the corresponding 2-phenylpyridyl ester is obtained in good yield as shown in the following formula. Although this ester can be isolated, it is cyclized by refluxing in a solvent such as pyridine in the presence of toluenesulfonic acids without isolation, and contains cyclic lactic acid tetramer as the main component. A mixture forms.

In any case, those skilled in the art can appropriately set or change the used substance, the used amount, the ratio, the treatment content and the procedure, the reaction condition, and the like. Example

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples. Unless otherwise specified,% means% by weight.

Example 1

Under an argon atmosphere, at room temperature, to a 5 ml solution of 0.1170 g (0.4996 mmol) of the linear lactic acid trimer in THF (tetrahydrofuran) was added 0.1535 ml (2 equivalents) of triethylamine, followed by 2,4,6-trichlorobenzene. 5 ml of a THF solution containing 0.261 g (2 equivalents) of Nzoyluk mouth light was added, and the mixture was stirred for 2 hours. The resulting mixture was filtered under an argon atmosphere, and then diluted with 250 ml of toluene. 0.3667 g (6 equivalents) of DMAP was dissolved in 50 ml of toluene and refluxed. When a high reflux state was reached, 250 ml of a dilute toluene solution of the above mixture was dropped over 5 hours using an automatic dropping device. Reflux was continued for 30 minutes after the completion of the dropwise addition, and after the completion of the reflux, the mixture was cooled to room temperature. This was concentrated and separated by column chromatography (eluent: benzene: ethyl acetate = 15: 4). A mixture of cyclic lactic acid hexamer and cyclic lactic acid 9-mer was 0.0231 g, and cyclic lactic acid 12 amounts 0.0066 _{g of a} body fraction and 0.0255 _{g of a} mixture containing these oligomers were obtained. Cyclic lactic acid dodecamer was analyzed by column chromatography (eluent: benzene: ethyl acetate = 15: Example 2 which could be easily isolated by 4)

Under an argon atmosphere, 0.218 g (1.6285 mmol) of 6-phenyl-2-pyridone, 0.4078 g (l. 5962 mmol) of triethylaniline 2-chloro-1-methylpyridinium and triethylamine 0.132 g (l. 6128 mmol) was dissolved in dry toluene, and a 30 ml toluene solution was stirred at room temperature for 1 hour. While keeping this solution at 60 ° C, 0.0519 g (0.2216 ramol) of linear lactic acid trimer and 0.0240 g (0.2372 ramol) of triethylamine were dissolved in dry toluene to obtain a solution of 18 ml. Was dropped over 9 hours using an automatic dropping device. Thereafter, the temperature was maintained for 30 minutes and then cooled to room temperature. This was concentrated and isolated by column chromatography (eluate: dichloromethane: methanol = 100: 3) to obtain 0.0733 g (86%) of a linear lactate trimer pyridyl ester.

(1) A solution of toluene sulfonic acid in a catalytic amount of 30 ml was maintained at 60 ° C. as a solution of toluene, and 25 ml of a toluene solution of the above product was added dropwise thereto over 9 hours using an automatic dropping device. After dropping, keep the temperature for 30 minutes, It was then cooled to room temperature. This was concentrated and separated by column chromatography (eluent: dichloromethane: methanol = 100: 2) to obtain 0.0015 g of a plurality of cyclic lactic acids (cyclization yield: 4%). Example 3

To a 5 ml solution of 0.1633 g (0.4320ramol) of linear lactic acid tetramer in THF at room temperature and a 2.5 ml THF solution of triethylamine (1.1 equivalents) was added, followed by 2,4,6-trick. 2.5 ml of a THF solution of a mouth benzoyl quenche (1 equivalent) was added and stirred for 2 hours. The obtained mixture was filtered under an argon atmosphere, concentrated, dissolved in 350 ml of toluene, and refluxed. When the temperature became high, 0.3677 g (6 equivalents) of DMAP was dissolved in 150 ml of toluene, and then refluxed for 5 hours. After the completion of the reflux, the mixture was cooled to room temperature. This was concentrated and separated by column chromatography (eluent: benzene: ethyl acetate = 15: 4) to obtain an 81.5% cyclic lactate oligomer mixture. This oligomer could be isolated from the fraction containing the cyclic lactic acid 16-mer by column chromatography (eluent: benzene: ethyl acetate = 15: 4). Example 4

Triethylamine and 0.1535 ml (2 equivalents) were added to 5 ml of a THF solution of 0.1170 g (0.4996 mmol) of linear lactic acid tetramer at room temperature under an argon atmosphere, followed by addition of 2,4,6-trichlorobenzene. A mouth solution (0.251 g) in THF (5 ml) was added, and the mixture was stirred for 2 hours. The resulting mixture was filtered under an argon atmosphere and diluted with 250 ml of toluene. 0.3667 g (6 equivalents) of DMAP was dissolved in 50 ml of toluene and refluxed. When the state became a high reflux state, 250 ml of a diluted toluene solution of the above product was dropped over 5 hours by using an automatic dropping device. After the completion of the dropwise addition, reflux was further continued for 30 minutes. After the completion of the reflux, the mixture was cooled to room temperature. This was concentrated and separated by column chromatography (eluent: benzene: ethyl acetate = 15: 4). A mixture of cyclic lactic acid 8-mer and cyclic lactic acid 12-mer was 0.0231 g, and cyclic lactic acid 16-mer was obtained. 0.0066 g was obtained. The synthesis ratio of cyclic oligomer in both mixtures determined by NMR was 55:45. Cyclic lactic acid 16-mer could be isolated by column chromatography (eluent: benzene: ethyl acetate = 15: 4). Example 5

2.5 ml of a solution of triethylamine (2.3 equivalents) in THF was added to 10 ml of a 0.11 g (0.3595 mmol) solution of the linear lactic acid tetramer at room temperature in an atmosphere of 2,4,6-trichloromethane. Lipstick (2.2 equivalents)]: 1 ^ solution 2. 51111 was added, and further 15 ml of a DMAP (2.2 equivalents) THF solution was added and stirred for 2 hours. The resulting mixture was filtered in a nitrogen stream, diluted with 250 ml of dry toluene and refluxed. The mixture was refluxed for 5 hours and cooled to room temperature after the completion of the reflux. This was concentrated and separated by column chromatography (eluent: benzene: ethyl acetate = 15: 4) to obtain a cyclic lactic acid mixture containing cyclic lactic acid octamer. Example 6

To a 4.5 ml THF solution of 0.036 g (0.2730 mmol) of linear lactic acid tetramer at room temperature under an argon atmosphere was added 1.4 ml of a solution of triethylamine (2.3 equivalents) in THF. 6-Triclo-benzoyl chloride (2.2 equivalents) THF solution (1.2 ml) was added and stirred for 2 hours. The resulting mixture was filtered in a nitrogen stream, diluted with 250 ml of dry toluene, and refluxed. 0.3677g (6 (Equivalent) was dissolved in 50 ml of toluene, and then refluxed for 5.5 hours. After the completion of the reflux, the mixture was cooled to room temperature. This was concentrated and separated by column chromatography (eluent: benzene: ethyl acetate = 15: 4) to obtain a mixture of cyclic lactic acid tetramer and cyclic lactic acid octamer (28%). Example 7

Under an argon atmosphere, at room temperature, 6_phenyl-2-pyridone 0.61515 g (3.981 mmol), iodide 2 —chloro-one-methylpyridinium 1.0086 g (3. 948 mmol) and 0.479 g (4.031 mmol) of triethylamine were dissolved in dichloromethane to make a 75 ml dichloromethane solution, and the mixture was stirred for 1 hour. This solution was refluxed, and when it became highly refluxed, 0.1435 g (0.4685 mmol) of linear lactic acid tetramer and 40 mL of 0.5543 g (0.5366 mmol) of triethylamine were automatically added dropwise to a 40 mL dichloromethane solution. It was dropped over 9 hours using an apparatus. Thereafter, reflux was continued for 30 minutes, and after completion of the reflux, the mixture was cooled to room temperature and concentrated.

A solution of p-toluenesulfonic acid in a catalytic amount of 30 ml of dichloromethane was refluxed. When a high reflux state was reached, 20 ml of a concentrated dichloromethane solution of the above compound was dropped over 9 hours using an automatic dropping apparatus, and then reflux was continued for 30 minutes. After the completion of the reflux, the mixture was cooled to room temperature and concentrated. Column chromatography Separation by luffy (eluent: benzene: ethyl acetate = 15: 4) gave crude lactic acid (0.0037 g, cyclization yield 2.6%). Example 8

0.3361 g (2.121 mmol) of 6-phenyl-2-pyridone at room temperature under an argon atmosphere were added. 0.5452 g (2.134 mmol) of dimethyl and 0.2206 g (2.180 mmol) of triethylamine were dissolved in 35 ml of dichloromethane and stirred for 1 hour. When the solution was refluxed to a high reflux state, 0.072 g (0.2847 mmol) of the linear lactic acid tetramer and 0.0283 g (0.3419 mmol) of triethylamine in 20 ml of a dichloromethane-containing methane solution were added thereto. The solution was added dropwise over 9 hours using an automatic dropper, and then reflux was continued for 30 minutes. After the completion of the reflux, the mixture was cooled to room temperature and concentrated. Isolation by column chromatography (eluent: benzene: ethyl acetate = 15: 4) gave 0.0713 g (54%) of a tetrameric lactic acid pyridone ester.

A solution of p-toluenesulfonic acid in a catalytic amount of 30 ml of dichloromethane was refluxed, and when a high reflux state was reached, 20 ml of a dichloromethane solution of the above compound, which was concentrated using an automatic dropping device, was added dropwise over 9 hours. And then 30 minutes Reflux was continued for a while. After the completion of the reflux, the mixture was cooled to room temperature and concentrated. When this was separated by column chromatography (eluent: benzene: ethyl acetate = 15: 4), the crude yield of multiple cyclic lactic acids was 0. 0049 g (cyclization yield 6%) were obtained. Comparative Example 1

• Synthesis of cyclic lactic acid trimer

At room temperature under an argon atmosphere, 6-phenyl-2-pyridone 0.3811 g (2.2261 mmol), iodide 2-chloro-1-methylpyridinium 0.5775 g (2.2604) Orchid ol) and 0.2286 g (2.2591 mmol) of triethylamine were dissolved in 5 ml of dichloromethane, further diluted with 50 ral of dry toluene and stirred for 1 hour, and the solution was kept at 75 ° C. Then, 0.0883 g (0.38831 tmol) of chain lactic acid trimer and 0.0370 g (0.3656 mmol) of triethylamine were dissolved in ⁵ ml of dichloromethane to prepare a 30 ml toluene solution. And dropped over 9 hours. Thereafter, the temperature was maintained for 30 minutes, and then cooled to room temperature. This was concentrated and isolated by column chromatography (eluent: dichloromethane: methanol = 100: 3) to obtain 0.146 g (86%) of lactic acid trimer pyridyl ester. A catalytic amount of p-toluenesulfonic acid was dissolved in 5 ml of dichloromethane to make a 30 ml toluene solution. This was kept at 75 ° C., and 30 ml of a toluene solution of the above-mentioned compound, which was concentrated using an automatic dropping device, was added dropwise over 10 hours, and then reflux was continued for 30 minutes. After the completion of the reflux, the mixture was cooled to room temperature and concentrated. Separation by column chromatography (eluent: dichloromethane: methanol = 100: 3) showed that almost no cyclic lactic acid derivative was obtained, and crude lactic acid trimer pyridyl ester was 0.0475 g (70% yield). Collected at Industrial potential

According to the production method of the present invention, the cyclic lactic acid oligomer produced is an n-fold of a linear lactic acid m-mer oligomer as a starting material, and has a lactic acid mn-mer oligomer having mn lactic acid units. Is obtained.

According to the production method of the present invention, a mixture having a composition capable of efficiently separating a cyclic lactic acid oligomer having a desired degree of condensation can be obtained, and the degree of condensation of the linear lactic acid m-mer oligomer as a starting material and the reaction material The composition of the resulting mixture can be adjusted by selecting the type.

The cyclic lactic acid oligomer having a specific chain length can be easily isolated as a single compound using the method for producing a cyclic lactic acid polymer that gives a product having a simple polymer composition of the present invention. Therefore, the method is also meaningful for the development of new uses of cyclic lactic acid oligomers in the pharmaceutical field and the like.

Claims

The scope of the claims

1. (i) Equation (1)

The terminal cal of the linear lactic acid m-mer oligomer represented by the formula ( _m is an integer of 3 to 15)

A boxyl group to a compound

0 = R (2)

(In the formula, R is a chain or cyclic organic group.)

And react with

Form

(ii) Next, cyclize the obtained linear lactic acid m-mer oligomer (3) A method for producing a cyclic lactic acid oligomer represented by the formula (4) and comprising mn lactic acid units (n is an integer of 1 or more).

2. The compound represented by the above formula (2), where 0 = R, is represented by the following formula

R 2

o: C

1

·'·(Five)

(Wherein, R ¹ is a linear or cyclic organic group which may have a substituent, R ² is a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group or an amino group, or R ¹ 2. The method for producing a cyclic lactic acid oligomer according to claim 1, wherein the cyclic lactic acid oligomer is a chain organic group which forms a ring structure by bonding to an atom.

3. The ring according to claim 2, wherein R ¹ is an aliphatic group, an aryl group, or a heterocyclic group (these groups may have a substituent). A method for producing a lactic acid oligomer.

4. The process for producing a cyclic lactic acid oligomer according to claim 2, wherein R ¹ is a halogen-substituted phenyl group, and R ² is a halogen atom. Construction method.

5. In the compound represented by the above formula (5), is a nitrogen atom-containing group, and the nitrogen atom is bonded to a carbon atom of R ¹ to form a heteroaromatic ring. A method for producing the cyclic lactic acid oligomer according to claim 2.

6-The method for producing a cyclic lactic acid oligomer according to claim 5, wherein the compound represented by the formula (5) is a 2-pyridone.

7. The method for producing a cyclic lactic acid oligomer according to any one of claims 1 to 6, wherein (i) is performed in the presence of a base.

8. The method for producing a cyclic lactic acid oligomer according to claim 7, wherein the base is an amine or a pyridine derivative.

9. The method for producing a cyclic lactic acid oligomer according to claim 1, wherein (i i) is performed in the presence of aminoviridines.

10. The method for producing a cyclic lactic acid oligomer according to claim 1 or 2, wherein the method is carried out in the presence of an aromatic sulfonic acid (ii).