JP2005232047A - Oligolactic acid ester containing hydroxyethyl group on side chain - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To synthesize a chain or cyclic oligolactic acid ester containing a hydroxyethyl group on the side chain. <P>SOLUTION: A chain oligolactic acid ester containing a hydroxyethyl group on the side chain is firstly synthesized and then subjected to cyclization reaction by intramolecular dehydration condensation to synthesize a cyclic oligolactic acid ester containing a hydroxyethyl group on the side chain. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an oligolactic acid ester having a hydroxylethyl group in the side chain and a method for producing the same. More specifically, the present invention relates to a linear or cyclic oligolactic acid ester having a hydroxylethyl group in the side chain, and a method for producing the same.

  A cyclic and / or chain poly L-lactic acid mixture having a condensation degree of 3 to 19 is used as an antineoplastic agent (Japanese Patent Laid-Open Nos. 9-227388 and 10-130153), and a QOL improving agent for cancer patients. (JP 2000-239171 A) are reported to be useful. It was also found that cyclic and / or chain polylactic acid mixtures having a condensation degree of 3 to 19 have a hypoglycemic effect and are useful as a medicament for the prevention and / or treatment of diabetes or diabetic complications. (International Publication WO01 / 010451). It has also been found that the polylactic acid mixture described above is useful for suppressing excessive appetite, promoting basal metabolism and improving and / or preventing obesity. Furthermore, the polylactic acid mixture described above has been demonstrated to exhibit various physiological activities such as immunostimulation, protection against microbial infection, antiallergy, antistress, and reduction of side effects of anticancer agents.

  As described above, cyclic and / or chain oligolactic acid mixtures having a condensation degree of 3 to 19 are being demonstrated to exhibit a wide variety of medicinal effects, and are expected to be developed as pharmaceuticals in the future. In order to develop oligolactic acid as a pharmaceutical product, we will synthesize derivatives with substituents on the side chain of the lactic acid unit and evaluate the bioactivity to identify oligolactic acid with higher bioactivity. It is desirable. However, there is no report about the synthesis | combination of the compound which has a hydroxylethyl group in the side chain in oligo lactic acid.

JP-A-9-227388 JP-A-10-130153 JP 2000-239171 A International Publication WO01 / 010451

  An object of the present invention is to synthesize a linear or cyclic oligolactic acid ester having a hydroxylethyl group in the side chain. Another object of the present invention is to provide a method for producing the compound.

  As a result of intensive studies to solve the above problems, the present inventors first synthesized a chain-like oligolactic acid ester having a hydroxylethyl group in the side chain, and then subjected this to a cyclization reaction by intramolecular dehydration condensation. As a result, a cyclic oligolactic acid ester having a hydroxylethyl group in the side chain was successfully synthesized. The present invention has been completed based on this finding.

（式中、Ｒ¹は水酸基の保護基を示し、Ｒ²は水素原子又は水酸基の保護基を示し、Ｒ³はカルボキシル基の保護基を示す） That is, according to the present invention, a compound represented by the formula (1) or a salt thereof is provided.

(Wherein R ¹ represents a hydroxyl protecting group, R ² represents a hydrogen atom or a hydroxyl protecting group, and R ³ represents a carboxyl protecting group)

（式中、Ｘ１及びＸ２はメチル基又は保護されていてもよいヒドロキシエチル基を示し（但し、Ｘ１及びＸ２が同時にメチル基となる場合は除く）、Ｒ²は水素原子又は水酸基の保護基を示し、Ｒ³は水素原子又はカルボキシル基の保護基を示す） According to another aspect of the present invention, a compound represented by the formula (2) or a salt thereof is provided.

(Wherein X1 and X2 represent a methyl group or an optionally protected hydroxyethyl group (except when X1 and X2 simultaneously become a methyl group), and R ² represents a hydrogen atom or a hydroxyl protecting group. R ³ represents a hydrogen atom or a protecting group for a carboxyl group)

（式中、Ｘ１及びＸ２はメチル基又は保護されていてもよいヒドロキシエチル基を示し、ｎ個のＸは各々独立にメチル基又は保護されていてもよいヒドロキシエチル基を示し（但し、Ｘ１、Ｘ２及びｎ個のＸの全てが同時にメチル基となる場合は除く）、Ｒ²は水素原子又は水酸基の保護基を示し、Ｒ³は水素原子又はカルボキシル基の保護基を示し、ｎは１〜４の整数を示す） According to still another aspect of the present invention, a compound represented by the formula (3) or a salt thereof is provided.

(In the formula, X1 and X2 each represent a methyl group or an optionally protected hydroxyethyl group, and n X's each independently represent a methyl group or an optionally protected hydroxyethyl group (provided that X1, If all of X2 and the n X is a methyl group at the same time excluding), R ² represents a hydrogen atom or a protecting group of a hydroxyl group, R ³ represents a hydrogen atom or a protecting group of a carboxyl group, n represents 1 Indicates an integer of 4)

（式中、Ｒ¹は水素原子又は水酸基の保護基を示し、ｎ個のＸは各々独立にメチル基又は保護されていてもよいヒドロキシエチル基を示し、ｎは１〜５の整数を示す） According to another aspect of the present invention, a compound represented by the formula (4) or a salt thereof is provided.

(In the formula, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, n X's each independently represents a methyl group or an optionally protected hydroxyethyl group, and n represents an integer of 1 to 5)

  According to another aspect of the present invention, the compound represented by the above formula (4) comprising subjecting the compound represented by the above formula (2) or the compound represented by the above formula (3) to a cyclization reaction by intramolecular dehydration condensation. The method of manufacturing the compound represented by this is provided.

  According to the present invention, it is possible to provide an oligolactic acid ester having a hydroxylethyl group in the side chain as a single compound. The oligolactic acid ester having a hydroxylethyl group in the side chain provided by the present invention is useful as a pharmaceutical, a pharmaceutical raw material, a food additive, a cosmetic raw material, a pharmaceutical raw material, a pharmaceutical additive, and the like. In addition, the oligolactic acid ester having an aminoethyl group in the side chain of the present invention can synthesize a derivative further enhanced in functionality by secondary modification. For example, it is possible to increase fat solubility by acylation or alkylation, or to make it water-soluble by polyethylene glycolation. In addition, by immobilizing on the surface of a carrier such as silica or polymer beads, it can be applied to search for ligands, application to special separation columns, and development of sensors with selectivity for special metals. it can.

Hereinafter, embodiments and methods of the present invention will be described in detail.
In the present invention, the compound represented by formula (1) to formula (4) or a salt thereof, and the compound represented by formula (2) or formula (3) are cyclized in the molecule to formula (4). It is related with the method of manufacturing the compound represented by this.

In Formula (1), R ¹ represents a hydroxyl protecting group, R ² represents a hydrogen atom or a hydroxyl protecting group, and R ³ represents a carboxyl protecting group. Preferably, the hydroxyl protecting group represented by R ¹ and the hydroxyl protecting group represented by R ² are different groups.

In the formula (2), X1 and X2 represents a methyl group or a protected or unprotected hydroxyethyl group (except if X1 and X2 is a methyl group at the same time), R ² is a protective hydrogen atom or a hydroxyl group R ³ represents a hydrogen atom or a protecting group for a carboxyl group. Preferably, the hydroxyethyl group protecting group and the hydroxyl protecting group represented by R ² are different groups.

In the formula (3), X1 and X2 each represent a methyl group or an optionally protected hydroxyethyl group, and each of the n Xs independently represents a methyl group or an optionally protected hydroxyethyl group (provided that X1, X2 and n X are all methyl groups at the same time), R ² represents a hydrogen atom or hydroxyl protecting group, R ³ represents a hydrogen atom or carboxyl protecting group, and n represents An integer of 1 to 4 is shown. Preferably, the protecting group for each hydroxyethyl group and the protecting group for the hydroxyl group represented by R ² are different groups.

In Formula (4), R ¹ represents a hydrogen atom or a hydroxyl-protecting group, n X's each independently represent a methyl group or an optionally protected hydroxyethyl group, and n represents an integer of 1 to 5. Show.
In the present specification, “each independently” means that n Xs may be the same or different from each other, and are groups independently selected from each other.

The type of the hydroxyl protecting group represented by R ¹ or R ² and the hydroxyethyl protecting group are not particularly limited and can be appropriately selected by those skilled in the art. Specific examples of the protecting group include the following.
(Ether type)
Methyl group, methoxymethyl group, methylthiomethyl group, benzyloxymethyl group, t-butoxymethyl group, 2-methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, bis (2-chloroethoxy) methyl group, 2- (trimethylsilyl) ethoxymethyl group, tetrahydropyranyl group, 3-bromotetrahydropyranyl group, tetrahydrothiopyranyl group, 4-methoxytetrahydropyranyl group, 4-methoxytetrahydrothiopyranyl group, 4-methoxytetrahydrothio Pyranyl S, S-dioxide group, tetrahydrofuranyl group, tetrahydrofuranyl group;

  1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, 1- (isopropoxy) ethyl group, 2,2,2-trichloroethyl group, 2- (phenylselenyl) ethyl group, t-butyl group, Allyl group, cinnamyl group, p-chlorophenyl group, benzyl group, p-methoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, p-halobenzyl group, p-cyanobenzyl group, 3-methyl-2-picolyl N-oxide group, diphenylmethyl group, 5-dibenzosuberyl group, triphenylmethyl group, α-naphthyldiphenylmethyl group, p-methoxyphenyldiphenylmethyl group, p- (p′-bromophenacyloxy) phenyldiphenylmethyl Group, 9-anthryl group, 9- (9-phenyl) xanthenyl group, 9- (9-phenyl-10-oxo) Ntoriru group, benzisothiazolyl S, S- dioxide group;

  Trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group (TBDMS group), (triphenylmethyl) dimethylsilyl group, t-butyldiphenylsilyl group, methyldiisopropylsilyl group, methyldi-t-butylsilyl group , Tribenzylsilyl group, tri-p-xylylsilyl group, triisopropylsilyl group, triphenylsilyl group;

(Ester type)
Formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, p-P-phenylacetate 3-phenylpropionate, 3-benzoylpropionate, isobutyrate, monosuccinoate, 4-oxopentanoate, pivaloate, adamantate, crotonate, 4-methoxy Tonate, (E) -2-methyl-2-butenoate, benzoate, o- (dibromomethyl) benzoate, o- (methoxycarbonyl) benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate, p-P- Benzoate, α-naphthoate;

(Carbonate type)
Methyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate, isobutyl carbonate, vinyl carbonate, allyl carbonate, cinnamyl carbonate, p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl Carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate;

(Other)
N-phenyl carbamate, N-imidazolyl carbamate, borate, nitrate, N, N, N ′, N′-tetramethyl phosphorodiamidate, 2,4-dinitrophenyl sulfenate:

The kind of the protecting group for the carboxyl group represented by R ³ is not particularly limited and can be appropriately selected by those skilled in the art. Specific examples of the protecting group for carboxyl group include, for example, C _1-8 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-, iso-, sec-, tert-butyl, n-hexyl group, bromo A C _1-6 alkyl group substituted 1 to 3 with a halogen such as t-butyl or trichloroethyl (eg, chlorine, bromine, fluorine, iodine, etc.), benzyl, p-nitrobenzyl, o-nitrobenzyl, p- Methoxybenzyl group, nitro such as pt-butylbenzyl, C _1-4 alkoxy group (eg methoxy, ethoxy etc.) or C _1-4 alkyl group (eg methyl, ethyl, n- or iso-propyl, n-, iso-, sec-, tert-butyl, etc.) and the like, which may be mono- or disubstituted by C _7-14 aralkyl group, acetoxymethyl, propionyloxymethyl, n-, iso-, Butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, 1- (or 2-) acetoxyethyl, 1- (or 2- or 3-) acetoxypropyl, 1- (or 2- or 3- or 4 -) Acetoxybutyl, 1- (or 2-) propionyloxyethyl, 1- (or 2- or 3-) propionyloxypropyl, 1- (or 2-) butyryloxyethyl, 1- (or 2-) iso Butyryloxyethyl, 1- (or 2-) pivaloyloxyethyl, 1- (or 2-) hexanoyloxyethyl, isobutyryloxymethyl, 2-ethylbutyryloxymethyl, 3,3-dimethylbuty Lil oxymethyl, 1- (or 2-) C _1-4 alkanoyloxy -C _1-4 alkyl group such as pentanoyloxy ethyl, e.g. - Meshiruechiru C _1-4 alkanesulfonyl -C _1-4 alkyl group such as, for example, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyl-oxymethyl, tert-butoxycarbonyl oxymethyl, 1- (or 2-) C _1-4 alkoxycarbonyloxy-C _1-4 alkyl group such as methoxycarbonyloxyethyl, 1- (or 2-) ethoxycarbonyloxyethyl, 1- (or 2-) isopropoxycarbonyloxyethyl, t-butyldimethyl Tri C _1-4 alkylsilyl groups such as silyl and trimethylsilyl, C _2-6 alkenyl groups such as allyl and methallyl, C _1-4 alkoxy-methyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl and isopropoxymethyl, C _1-4 alkyl such as (2-methylthio) -ethyl Kirthio C _1-4 alkyl group, 3-methyl-2-butenyl group, 5-indanyl group, 3-phthalidyl group and the like are used.

  The above-described methods for introducing and deprotecting protecting groups are known to those skilled in the art, and are described, for example, in Teodora, W. Green, Protective Groups in Organic Synthesis, John & Wiley & Sons Inc. (1981). Has been.

  In some cases, the compounds of the present invention may also exist as salts. Examples of such metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, and zinc salts. Furthermore, various hydrates, solvates and polymorphic substances of the compounds of the present invention are also within the scope of the present invention.

  Since the compounds of the present invention contain asymmetric carbons, stereoisomers exist, but all possible isomers and mixtures containing two or more of these isomers in any ratio are also within the scope of the present invention. Is. That is, the compound of the present invention includes a mixture of various optical isomers such as an optically active substance, a racemate, a diastereomer and the like and an isolated product thereof.

  The configuration of the compound of the present invention depends on the configuration of the lactic acid unit in the compound used as a raw material. That is, the configuration of the compound of the present invention varies depending on whether L-form, D-form or a mixture thereof is used as the lactic acid unit in the compound used as a raw material. In the present invention, the L-form is preferably used as the steric configuration of the lactic acid unit.

Next, the manufacturing method of the compound of this invention is demonstrated.
The compound represented by the formula (1) is a compound having a hydroxyethyl group protected on the side chain of lactic acid. The compound represented by the formula (2) is a compound having a hydroxyethyl group which may be protected by the side chain of the lactic acid dimer, and the compound represented by the formula (3) is a trimer of lactic acid. To a hexamer in the side chain, which is a compound having one or more hydroxyethyl groups which may be protected. The compound represented by the formula (4) is a cyclized product of dimer to hexamer of lactic acid, and is a compound having one or more hydroxyethyl groups which may be protected in the side chain. The compound represented by formula (4) can be synthesized by subjecting the compound represented by formula (2) or formula (3) to a cyclization reaction by intramolecular dehydration condensation.

The specific synthesis route of the above-described compound of the present invention will be described below with examples.
As shown below, the cyclic lactic acid oligoester having a hydroxyethyl group can be synthesized by condensing 2,4-dihydroxybutanoic acid (3) with a chain lactic acid oligomer (4) and then cyclizing reaction.

  First, 2 (S), 4-dihydroxybutanoic acid benzyl ester in which the 4-position hydroxyl group of 3 is protected with a TBDMS group is synthesized. After protecting L-malic acid (5) as a starting material and the α-hydroxy acid moiety as acetonide, the remaining carboxyl group is reduced to alcohol (7) and protected with TBDMS group (8). The resulting 8 carboxyl groups are converted to benzyl esters to obtain (S), 4-dihydroxybutanoic acid derivative (9).

  On the other hand, excess benzyl bromide is allowed to act on lactic acid to form benzyloxylactic acid benzyl, and then benzyloxylactic acid (10) is obtained by selective deprotection of the benzyl ester by catalytic reduction. After the condensation reaction of 10 with the lactic acid oligomer (11) with the carboxyl group protected, the benzyloxylactic acid oligomer (13) with a different chain length is obtained by selectively deprotecting the protective group of the carboxyl group.

  The corresponding condensate (14) is obtained by the condensation reaction of benzyloxylactic acid oligomer 13 and 9 synthesized previously, and the benzyl group of 14 is deprotected to form a chain lactic acid oligomer having a tert-butyldimethylsiloxyethyl group (15) is obtained. By the cyclization reaction of 15, a cyclic oligolactic acid ester having a hydroxylethyl group in the side chain is obtained.

  Alternatively, borane tetrahydrofuran is allowed to act on L-malic acid (1) to give 2, and benzaldehyde is reacted with the resulting 2 to obtain a dioxolane derivative (3) in which the hydroxyl groups at the 2-position and 4-position are reacted. .

  Chromium trioxide, pyridine, acetic anhydride, and tert-butanol are allowed to act on 3 to obtain 4, and then 5 can be obtained by reacting triethylsilane and trifluoroacetic acid.

  L-lactic acid (6) is reacted with tert-butyldimethylsilane chloride (TBDMSCl) in the presence of imidazole to form a compound (7) having a hydroxyl group and a carboxyl group converted to TBDMS, and oxalyl chloride is reacted to form an acid chloride (8) Then, the corresponding 9 is obtained by performing a condensation reaction with 5. By the cyclization reaction of 9, a cyclic oligolactic acid ester having a hydroxylethyl group in the side chain is obtained.

  The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the examples.

Example 1: Synthesis of (S) -benzyl 4- (tert-butyldimethylsilyloxy) -2-hydroxybutanoate

  1.6 M-n-butyllithium (15.0 mL, 24.0 mmol) was slowly added dropwise to a 50 mL THF solution of benzyl alcohol (2.70 g, 25.0 mmol) at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. Thereafter, a 20 mL THF solution of (S)-(2,2)-(dimethyl-1,3-dioxolan-4-one) -5-tert-butyldimethylsiloxyethyl (5.48 g, 19.99 mmol) was added dropwise. After stirring for hours, the reaction was quenched with 30 mL of saturated aqueous ammonium chloride, 20 mL of water was added and extracted four times with 50 mL of ether. The extracted ether layer was dried over anhydrous sodium sulfate, filtered and concentrated, and then isolated and purified by silica gel column chromatography (Hexane: Ether = 3: 1) to obtain 5.816 g (17.94 mmol) of a colorless transparent liquid. (89.7%).

¹ H-NMR (500MHz, CDCl ₃ )
δ (ppm) = 0.070 (s, 6H), 0.887 (s, 9H), 1.87-1.93 (m, 1H), 2.04-2.10 (m, 1H), 3.78-3.83 (m, 2H), 4.40 (q, J = 4.0, 1H), 5.21 (dd, J = 12.5, 15.5Hz, 2H), 7.32-7.40 (m, 5H)

Example 2: (S) -benzyl-2-((S) -2- (benzyloxy) propanoyloxy) -4-
(tert-butyldimethylsilyloxy) butanoate (TBDMSOMe-Bn2LaBn)

  In a nitrogen-substituted two-necked eggplant flask, 0.539 g (2.99 mmol) benzyl ether lactate and 0.956 g (2.95 mmol) 2-hydroxy-4- (tert-butyldimethylsiloxybutane) in 20 mL dichloromethane solvent at 0 ° C. Acid benzyl ester was added, and DMAP 0.430 g (3.52 mmol) in 10 mL of dichloromethane was added and stirred.After 10 minutes, DCC 0.820 g (3.97 mmol) in 10 mL dichloromethane was added and stirred for 3 hours. Saturated aqueous ammonium chloride solution was added, suction filtered, 20 mL saturated aqueous sodium hydrogen carbonate solution was further added, and liquid separation was performed with ether (40 mL × 4) The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Subsequently, isolation and purification by silica gel column chromatography (Hexane: ether = 3: 1) gave 1.36 g (2.79 mmol) of a chain lactic acid dimer derivative having a tert-butyldimethylsiloxyethyl group. It was (94.7%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.061 (s, 6H), 0.875 (s, 9H), 1.45 (d, J = 7.0Hz, 3H), 2.01-2.19 (m, 2H), 3.68-3.76 (m, 2H), 4,12 (q, J = 7.0Hz, 1H), 4.58 (dd, J = 6.5, 164.0Hz, 2H), 5.18 (dd, J = 12.0, 25.5Hz, 2H) , 5.32 (dd, J = 3.5, 9.0Hz, 1H), 7.28-7.37 (m, 10H)

Example 3: (S) -2-((S) -2- (benzyloxy) propanoyloxy) -4-
(tert-butyldimethylsilyloxy) butanoic acid (TBDMSOMe-Bn2La)

  Add 0.937 g (2.00 mmol) of chain benzyloxylactic acid dimer benzyl ester having tert-butyldimethylsiloxyethyl group, 10 mL of ethanol, and 0.1 g of 10% -palladium carbon to an Erlenmeyer flask. The mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, and the reaction flask was washed with ether and then concentrated on a rotary evaporator. Further, the mixture was placed under reduced pressure for 12 hours or more with a vacuum pump to completely remove the solvent, and 0.743 g (1.87 mmol) of the desired product was obtained (93.7%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.0445 (s, 6H), 0.882 (s, 9H), 1.49 (d, J = 6.5Hz, 3H), 2.06-2.12 (m, 2H), 3.70-3.81 (m, 2H), 4,15 (q, J = 6.5Hz, 1H), 4.61 (dd, J = 11.5, 153.0Hz, 2H), 5.31 (q, J = 4.5Hz, 1H), 7.28 -7.38 (m, 5H)

Example 4: (S) -4- (tert-butyldimethylsilyloxy) -2-((S) -2-hydroxypropanoyloxy)
Synthesis of butanoic acid (TBDMSOMe-2La)

  Add 0.500 g (1.03 mmol) of chain benzyloxylactic acid dimer benzyl ester having tert-butyldimethylsiloxyethyl group, 10 mL of ethanol, and 0.1 g of 10% -palladium carbon to an Erlenmeyer flask, and hydrogen in a catalytic reduction apparatus. The mixture was stirred at room temperature for 10 hours. The reaction solution was filtered, and the reaction flask was washed with ether and then concentrated on a rotary evaporator. Furthermore, when the solvent was completely removed under reduced pressure with a vacuum pump for 12 hours or more, 0.294 g (0.960 mmol) of the desired product was obtained (93.2%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.096 (s, 6H), 0.880 (s, 9H), 1.49 (d, J = 5.5Hz, 3H), 2.04-2.16 (m, 2H), 3.67-3.81 (m, 2H), 4,37 (q, J = 7.0Hz, 1H), 4.62 (dd, J = 11.5, 148.5Hz, 2H), 5.28-5.31 (m, 1H)

Example 5: (2S) -benzyl4- (tert-butyldimethylsilyloxy) -2- (2-((2-methoxyethoxy)
Synthesis of (methoxy) propanoyloxy) butanoate (TBDMSOMe-MEM2LaBn)

  In a nitrogen-substituted two-necked eggplant-shaped flask, 0.53 g (2.97 mmol) lactic acid benzyl ether and 0.95 g (2.93 mmol) 2-hydroxy-4- (tert-butyldimethylsiloxybutane) in 20 mL dichloromethane solvent at 0 ° C. Acid benzyl ester was added, and DMAP 0.430 g (3.52 mmol) in 10 mL of dichloromethane was added and stirred.After 10 minutes, DCC 0.820 g (3.97 mmol) in 10 mL dichloromethane was added and stirred for 3 hours. Saturated aqueous ammonium chloride solution was added, suction filtered, 20 mL saturated aqueous sodium hydrogen carbonate solution was further added, and liquid separation was performed with ether (40 mL × 4) The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Thereafter, isolation and purification by silica gel column chromatography (Hexane: ether = 3: 1) gave 1.21 g (2.50 mmol) of a chain lactic acid dimer derivative having a tert-butyldimethylsiloxyethyl group. Was (85.2%)

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.020 (s, 6H), 0.869 (s, 9H), 1.44 (d, J = 7.0Hz, 3H), 2.00-2.15 (m, 2H), 3.38 (s, 3H), 3.61-3.76 (m, 4H), 4,36 (q, J = 6.5Hz, 1H), 4.77 (q, J = 7.5Hz, 2H), 5.16 (dd, J = 12.5, 21.0Hz, 2H), 5.26 (q, J = 4.0Hz, 1H), 7.31-7.35 (m, 5H)

Example 6: (2S) -4- (tert-butyldimethylsilyloxy) -2- (2-((2-methoxyethoxy))
Synthesis of (methoxy) propanoyloxy) butanoic acid (TBDMSOMe-MEM2La)

  Add 0.30 g (0.64 mmol) of chain benzyloxylactic acid dimer benzyl ester having tert-butyldimethylsiloxyethyl group, 10 mL of ethanol, and 0.1 g of 10% -palladium carbon to an Erlenmeyer flask, and hydrogen in a catalytic reduction apparatus. The mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, and the reaction flask was washed with ether and then concentrated on a rotary evaporator. Further, the mixture was placed under reduced pressure for 12 hours or more with a vacuum pump to completely remove the solvent, and 0.23 g (0.59 mmol) of the desired product was obtained (92.2%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.083 (s, 6H), 0.876 (s, 9H), 1.48 (d, J = 7.0Hz, 3H), 2.04-2.14 (m, 2H), 3.38 (s, 3H), 3.54 (t, J = 4.5Hz, 2H), 3.68-3.80 (m, 4H), 4.37 (q, J = 7.0Hz, 1H), 4.56 (br s, 1H), 4.79 ( dd, J = 7.0, 19.0Hz, 2H), 5.24 (dd, J = 4.5, 7.5Hz, 1H)

Example 7: (S) -benzyl-2-((S) -2-((S) -2- (benzyloxy) propanoyloxy) propanoyloxy)
-4- (tert-butyldimethylsilyloxy) butanoate synthesis (TBDMSOMe-Bn3LaBn)

  In a nitrogen-substituted two-necked eggplant flask, 1.77 g (7.01 mmol) lactic acid dimer benzyl ether and 2.10 g (6.47 mmol) 2-hydroxy-4-tert-butyldimethyl in 20 mL dichloromethane solvent at 0 ° C. A 10 mL solution of siloxybutanoic acid benzyl ester and DMAP 1.71 g (14.02 mmol) in dichloromethane was added and stirred for 10 minutes. Further, 2.90 g (14.06 mmol) of DCC in 10 mL dichloromethane was added and stirred for 3 hours. Thereafter, 30 mL of a saturated aqueous ammonium chloride solution was added, suction filtered, and 30 mL of a saturated aqueous sodium bicarbonate solution was further added, followed by liquid separation with ether (50 mL × 4). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and then isolated and purified by silica gel column chromatography (Hexane: ether = 3: 1) to obtain 2.59 g (4.64 mmol) of tert-butyldimethylsiloxyethyl group. A chain lactic acid trimer derivative having a thiophene was obtained (71.8%)

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.071 (s, 6H), 0.881 (s, 9H), 1.49 (d, J = 7.0Hz, 3H), 1.56 (d, J = 7.0Hz, 3H), 2.03-2.16 (m, 2H), 3.69-3.74 (m, 2H), 4,14 (q, J = 7.0Hz, 1H), 4.62 (dd, J = 11.5, 148.5Hz, 2H), 5.12 -5.25 (m, 3H), 5.32 (q, J = 4.5Hz, 1H), 7.28-7.47 (m, 10H)

Example 8: (S) -2-((S) -2-((S) -2- (benzyloxy) propanoyloxy) propanoyloxy) -4-
Synthesis of (tert-butyldimethylsilyloxy) butanoic acid (TBDMSOMe-Bn3La)

  Add 0.670 g (1.20 mmol) of chain benzyloxylactic acid trimer benzyl ester having tert-butyldimethylsiloxyethyl group, 10 mL of ethanol, and 0.1 g of 10% -palladium carbon to an Erlenmeyer flask, and hydrogen in a catalytic reduction apparatus. The mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, and the reaction flask was washed with ether and then concentrated on a rotary evaporator. Further, the mixture was placed under reduced pressure for 12 hours or more with a vacuum pump to completely remove the solvent, and 0.550 g (1.17 mmol) of the desired product was obtained (97.5%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.088 (s, 6H), 0.876 (s, 9H), 1.49 (d, J = 7.0Hz, 3H), 1.60 (d, J = 7.0Hz, 3H), 2.05-2.16 (m, 2H), 3.71-3.80 (m, 2H), 4,13 (q, J = 7.0Hz, 1H), 4.62 (dd, J = 11.5, 142.5Hz, 2H), 5.22 (q, J = 7.5Hz, 1H), 5.29 (dd, J = 4.5, 7.5Hz, 1H), 7.27-7.38 (m, 5H)

Example 9: (S) -4- (tert-butyldimethylsilyloxy) -2-((S) -2-((S) -2-hydroxypropanoyloxy)
propanoyloxy) butanoic acid synthesis
(TBDMSOMe-3La)

  Add 0.937 g (1.00 mmol) of chain benzyloxylactic acid trimer benzyl ester having tert-butyldimethylsiloxyethyl group, 10 mL of ethanol and 0.1 g of 10% -palladium carbon to an Erlenmeyer flask. The mixture was stirred at room temperature for 6 hours. The reaction solution was filtered, and the reaction flask was washed with ether and then concentrated on a rotary evaporator. Further, the mixture was placed under reduced pressure with a vacuum pump for 12 hours or more to completely remove the solvent, and 0.367 g (9.70 mmol) of the desired product was obtained (97.0%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.048 (s, 6H), 0.877 (s, 9H), 1.48 (d, J = 7.0Hz, 3H), 1.59 (d, J = 7.0Hz, 3H), 2.02-2.20 (m, 2H), 3.69-3.80 (m, 2H), 4,36 (q, J = 7.0Hz, 1H), 5.14-5.28 (m, 4H)

Example 10: (S)-((S) -1- (benzyloxy) -1-oxopropan-2-yl) -2-((S) -2- (benzyloxy)
synthesis of propanoyloxy) -4- (tert-butyldimethylsilyloxy) butanoate
BnLa- (TBDMSOMe) -2LaBn

  In a nitrogen-substituted two-necked eggplant flask, 0.36 g (2.00 mmol) benzyl ether lactate and 0.750 g (1.89 mmol) 2-hydroxy-4- (tert-butyldimethylsiloxybutane) in 20 mL dichloromethane solvent at 0 ° C. Acid benzyl ester was added, and a solution of DMAP 0.31 g (2.50 mmol) in 10 mL of dichloromethane was added and stirred.After 10 minutes, DCC 0.820 g (3.97 mmol) of 10 mL in dichloromethane was added and stirred for 3 hours. Saturated aqueous ammonium chloride solution was added, suction filtered, 20 mL saturated aqueous sodium hydrogen carbonate solution was further added, and liquid separation was performed with ether (40 mL × 4) The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Thereafter, the product was isolated and purified by silica gel column chromatography (Hexane: ether = 1: 1) to obtain 0.926 g (1.65 mmol) of the desired product (87.7%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.0465 (s, 6H), 0.892 (s, 9H), 1.50 (d, J = 6.5Hz, 3H), 1.54 (d, J = 7.0Hz, 3H), 1.95-2.00 (m, 1H), 2.18-2.25 (m, 1H), 3.67-3.77 (m, 2H), 4,14 (q, J = 7.0Hz, 1H), 4.61 (dd, J = 11.5, 164.0Hz, 2H), 5.12-5.24 (m, 3H), 5.30 (dd, J = 3.5, 10.0Hz, 1H), 7.28-7.38 (m, 10H)

Example 11: (S) -2-((S) -2-((S) -2- (benzyloxy) propanoyloxy) -4-
Synthesis of (tert-butyldimethylsilyloxy) butanoyloxy) propanoic acid
BnLa- (TBDMSOMe) -2La

  Add 0.60 g (1.07 mmol) of benzyloxylactic acid dimer benzyl ester having tert-butyldimethylsiloxyethyl group, 10 mL of ethanol, and 0.1 g of 10% -palladium carbon to an Erlenmeyer flask, and hydrogen in a catalytic reduction apparatus. The mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, and the reaction flask was washed with ether and then concentrated on a rotary evaporator. After the raw material contained in a trace amount was filtered and separated by a silica gel column (ether), the solvent was completely removed to obtain 0.395 g (0.843 mmol) of the desired product (78.7%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.0515 (d, J = 3.5Hz, 6H), 0.884 (s, 9H), 1.48 (d, J = 7.0Hz, 3H), 1.53 (d, J = 7.0Hz, 3H), 1.99-2.07 (m, 1H), 2.21-2.28 (m, 1H), 3.70-3.81 (m, 2H), 4,11-4.23 (m, 2H), 4.61 (dd, J = 11.5, 145.5Hz, 2H), 5.12-5.25 (m, 3H), 5.30 (dd, J = 3.5, 4.5Hz, 1H), 7.27-7.38 (m, 5H)

Example 12: (S) -benzyl 2-((S) -2-((S) -2-((S) -2- (benzyloxy) propanoyloxy)
propanoyloxy) propanoyloxy) -4- (tert-butyldimethylsilyloxy) butanoate synthesis (TBDMSOMe-Bn4LaBn)

  In a nitrogen-substituted two-necked eggplant-shaped flask, 0.226 g (0.697 mmol) lactic acid trimer benzyl ether and 0.35 g (1.08 mmol) 2-hydroxy-4- (tert-butyl) in 10 mL dichloromethane solvent at 0 ° C. Dimethylsiloxybutanoic acid benzyl ester, 0.33 g (2.7 mmol) of DMAP was added and stirred for 10 minutes, and then DCC 0.60 g (2.91 mmol) of 10 mL dichloromethane solution was added and stirred for 2 hours, and then 10 mL of saturated ammonium chloride aqueous solution. Then, 10 mL of saturated aqueous sodium hydrogen carbonate solution was added, and liquid separation was performed with ether (25 mL × 4) The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and then a silica gel column. When isolated and purified by chromatography (Hexane: Ether = 1: 1), 0.35 g (0.555 mmol) of benzyloxylactic acid tetramer benzyl ester having tert-butyldimethylsiloxyethyl group was obtained (79.3%). .

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.005 (s, 6H), 0.871 (s, 9H), 1.49 (d, J = 7.0Hz, 3H), 1.59-1.61 (m, 6H), 2.01-2.19 (m, 2H), 3.16-3.22 (m, 2H), 3.68-3.76 (m, 2H), 4.12 (q, J = 6.5Hz, 2H), 4.58 (dd, J = 11.5, 163.5Hz, 2H), 5.18 (dd, J = 12.5, 25.5Hz, 2H), 5.32 (dd, J = 4.0, 9.0Hz, 1H), 7.28-7.34 (m, 10H)

Example 13: (S) -benzyl-2-((S) -2-((S) -2-((S) -2- (benzyloxy) propanoyloxy) -4-
Synthesis of (tert-butyldimethylsilyloxy) butanoyloxy) propanoiloxy) -butanoate
BnLa- (TBDMSOMe) -2La- (TBDMSOMe) -LaBn

  In a nitrogen-substituted two-necked eggplant flask, 0.33 g (0.84 mmol) BnLa- (TBDMSOMe) -2La and 0.32 g (0.99 mmol) 2-hydroxy-4- (tert- Butyldimethylsiloxybutanoic acid benzyl ester was added, and DMAP 0.18 g (1.50 mmol) in 5 mL of dichloromethane was stirred, and after 10 minutes, DCC 0.30 g (1.45 mmol) in 5 mL of dichloromethane was added and stirred for 3 hours. Thereafter, 10 mL of saturated aqueous ammonium chloride solution was added, suction filtered, 10 mL of saturated aqueous sodium bicarbonate solution was further added, and liquid separation was performed with ether (20 mL × 4), and the organic layer was dried over anhydrous magnesium sulfate, After filtration and concentration, the product was isolated and purified by silica gel column chromatography (Hexane: ether = 3: 1) to obtain 0.394 g (0.51 mmol) of the desired product (60.7%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.035 (d, J = 3.5Hz, 6H), 0.045 (d, J = 4.5Hz, 6H), 0.857 (s, 9H), 0.898 (s, 9H), 1.49 (d, J = 7.0Hz, 3H), 1.54 (d, J = 7.0Hz, 3H), 2.00-2.31 (m, 4H), 3.65-3.82 (m, 4H), 4,14 (q , J = 7.0Hz, 1H), 4.61 (dd, J = 11.5, 160.5Hz, 2H), 5.11-5.32 (m, 5H), 7.28-7.37 (m, 10H)

Example 14: Synthesis of benzyloxylactoyl lactate phenacyl ester

  In a nitrogen-substituted two-necked eggplant flask, 1.42 g (7.88 mmol) benzyl lactate ether and 1.65 g (7.92 mmol) lactate phenacyl ester, 1.22 g (9.99 mmol) DMAP in 50 mL dichloromethane solvent at 0 ° C. Was added, and the mixture was stirred for 10 minutes. Further, a solution of DCC 2.06 g (9.98 mmol) in 20 mL of dichloromethane was added, and the mixture was stirred for 3 hours. Thereafter, 30 mL of a saturated aqueous ammonium chloride solution was added, suction filtered, and 30 mL of a saturated aqueous sodium hydrogen carbonate solution was further added, followed by liquid separation with ether (50 mL × 4). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and isolated and purified by silica gel column chromatography (Hexane: ether = 1: 1). As a result, 1.50 g (4.05 mmol) of lactic acid dimer derivative (benzyl) Ether, benzyl ester) was obtained (51.4%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 1.49 (dd, J = 7.0, 11.5Hz, 3H), 1.70 (dd, J = 5.0, 7.0Hz, 3H), 4.17 (quinted, J = 2.0 Hz, 1H), 4.47 (dd, J = 9.5, 11.5Hz, 1H), 4.75 (dd, J = 11.5, 24.5Hz, 1H), 4.75 (dd, J = 11.5, 24.5Hz, 1H), 5.27-5.35 (m, 2H), 5.55 (dd, J = 14.5, 21.0Hz, 1H), 7.26-7.39 (m, 5H), 7.49 (t, J = 7.5, 2H), 7.62 (t, J = 7.5, 1H) , 7.89-7.91 (m, 1H)

Example 15: Synthesis of benzyloxylactic acid trimer phenacyl ester

  In a nitrogen-substituted two-necked eggplant flask, 0.72 g (4.00 mmol) lactate benzyl ether and 1.34 g (4.80 mmol) lactate dimer phenacyl ester, 0.49 g (4 mmol) in 20 mL dichloromethane solvent at 0 ° C. Of DMAP was added and stirred for 10 minutes, and further DCC 1.00 g (4.85 mmol) in 10 mL dichloromethane was added and stirred for 1 hour. Thereafter, 15 mL of a saturated aqueous solution of ammonium chloride was added, suction filtered, 15 mL of a saturated aqueous solution of sodium bicarbonate was added, and liquid separation was performed with ether (50 mL × 4). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and then isolated and purified by silica gel column chromatography (Hexane: ether = 1: 1) to obtain 1.49 g (3.36 mmol) benzyloxylactic acid trimer phenacyl. The ester was obtained (84.0%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 1.50 (d, J = 6.5Hz, 3H), 1.61 (d, J = 7.0Hz, 3H), 1.71 (d, J = 4.5Hz, 3H) , 3.47 (q, J = 7.0Hz, 1H), 4.14 (q, J = 7.0Hz, 1H), 4.48 (d, J = 11.5Hz, 1H), 4.77 (d, J = 11.5Hz, 1H), 5.22 (q, J = 7.0Hz, 1H), 5.27 (dd, J = 2.0, 16.5Hz, 1H), 5.33 (q, J = 7.0Hz, 1H), 7.27-7.43 (m, 5H), 7.47-7.50 ( m, 2H), 7.59-7.62 (m, 1H), 7.88 (d, J = 7.5Hz, 2H)

Example 16: Synthesis of benzyloxylactic acid tetramer phenacyl ester

  In a nitrogen-substituted two-necked eggplant-shaped flask, 0.757 g (3.0 mmol) of lactic acid dimer benzyl ether, 0.840 (3.0 mmol) of lactic acid dimer phenacyl ester, and 0.550 g in 0 mL of 20 mL of dichloromethane solvent After adding (4.5 mmol) of DMAP and stirring for 10 minutes, DCC 0.928 g (4.5 mmol) in 10 mL of dichloromethane was added and stirred for 2 hours. Thereafter, 15 mL of a saturated aqueous solution of ammonium chloride was added, suction filtered, 15 mL of a saturated aqueous solution of sodium bicarbonate was added, and liquid separation was performed with ether (50 mL × 4). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and then isolated and purified by silica gel column chromatography (Hexane: ether = 1: 2) to obtain 1.24 g (2.40 mmol) benzyloxylactic acid tetramer phenacyl. The ester was obtained (80.0%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 1.49 (d, J = 7.0Hz, 3H), 1.60 (d, J = 7.0Hz, 3H), 1.61 (d, J = 7.5Hz, 3H) , 1.69 (d, J = 7.0Hz, 3H), 3.42-3.50 (m, 1H), 4.07-4.16 (m, 1H), 4.62 (dd, J = 11.5, 146.5Hz, 2H), 5.14-5.32 (m , 4H), 5.50 (dd, J = 16.0, 23.0Hz, 1H), 7.27-7.38 (m, 5H), 7.43-7.51 (m, 2H), 7.56-7.63 (m, 1H), 7.83-7.89 (m , 3H)

Example 17: (3S, 6S) -3- (2- (tert-butyldimethylsilyloxy) ethyl) -6-methyl-1,4-
Synthesis of dioxane-2,5-dione TBDMSOMe-cyclic 2La

  Dissolve 0.41 g (2.0 mmol) of DCC, 0.37 g (3.0 mmol) of DMAP, and 0.32 g (2.0 mmol) of DMAP · HCl in 10 mL (total volume 30 mL) of dichloromethane in an argon-substituted two-necked eggplant type flask. In addition, 0.294 g (0.96 mmol) of TBDMSOMe-2La was dissolved in a mixed solvent of 10 mL of THF and 20 mL of dichloromethane, and added to the reaction vessel over 16 hours. When adding, it was made to travel along the wall of the container so that a uniform amount would always flow. After further stirring for 1 hour, the mixture was concentrated with an evaporator until the total amount reached about 20 mL, filtered to remove the solid, and concentrated again (the solid was washed with ether). Isolation and purification by silica gel column chromatography (Hexane: EtOAc = 3: 1) gave 0.086 g (0.30 mmol) of a cyclic product (31.6%).

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 0.037 (s, 6H), 0.858 (s, 9H), 1.65 (d, J = 7.0Hz, 3H), 2.02-2.08 (m, 1H), 2.31-2.37 (m, 1H), 3.80-3.82 (m, 2H), 5.03 (q, J = 6.5Hz, 1H), 5.16 (dd, J = 4.0, 9.0Hz, 1H)

Example 18: Synthesis of (3S, 6S) -3- (2-hydroxyethyl) -6-methyl-1,4-dioxane-2,5-dione (64) (cyclic lactic acid dimer having a hydroxyethyl group) Synthesis)
HOMe-cyclic 2La

  In a reaction vessel, 0.081 g (0.284 mmol) of (62) was dissolved in 2.8 mL of acetonitrile, and 2 drops of hydrofluoric acid was added dropwise and stirred for 20 minutes. After confirming the completion of the reaction by TLC, 10 mL of saturated sodium bicarbonate was added, and the mixture was extracted with chloroform (10 mL × 5). The chloroform layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Since a trace amount of impurities was contained in the product, it was isolated and purified by silica gel column chromatography (chloroform: ethanol = 10: 1) to obtain 0.438 g (0.252 mmol) of (64). The target product is insoluble in ether, hexane, etc., and soluble in ethyl acetate, chloroform, and ethanol.

(3S, 6S) -3- (2-Hydroxyethyl) -6-methyl-1,4-dioxane-2,5-dione (64)
R _f = 0.419 (CHCl ₃ : Ethanol = 10: 1)
¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 1.46 (d, J = 7.0Hz, 2H), 2.29-2.38, 2.68-2.74 (m, 2H), 3.20 (br s, 1H), 4.30 ( dt, J = 6.5, 9.5Hz, 1H), 4.37 (q, J = 7.0Hz, 1H), 4.47 (dt, J = 7.0, 9.0Hz, 1H), 5.50 (t, J = 9.0Hz, 1H)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 20.09, 20.28, 28.63, 28.74, 65.16, 66.76, 66.87, 68.30, 68.44, 172.50, 174.50

Example 19: (S) -tert-butyl 4- (benzyloxy) -2- (tert-butyldimethylsilyloxy) butanoate

  Under a nitrogen atmosphere, at 0 ° C., 0.261 g (3.61 mmol) of imidazole was added to a dichloromethane solution of 0.261 g (1.73 mmol) of t-butyldimethylsilyl chloride and stirred for 15 minutes, and then (S) -tert-butyl 4- ( 0.436 g (1.64 mmol) of benzyloxy) -2-hydroxybutanoate was added and stirred for 4 hours. Treated with water and extracted with dichloromethane. After drying over magnesium sulfate, concentration and isolation and purification using silica gel column chromatography (developing solvent Hexane: Ether = 4: 1), (S) -tert-butyl 4- (benzyloxy) -2- (tert-butyldimethylsilyloxy) butanoate was obtained in a yield of 0.399 g (75.1%).

δ (ppm) = 0.072 (d, J = 25.0Hz, 6H), 0.908 (s, 9H), 1.45 (s, 9H), 1.86-2.09 (m, 2H), 3.54-3.64 (m, 2H), 4.25 (dd, J = 4.0, 4.5Hz, 1H), 4.49 (dd, J = 12.0, 16.5Hz, 2H), 7.27-7.38 (m, 5H)

Example 20: (S) -4- (benzyloxy) -2- (tert-butyldimethylsilyloxy) butanoic acid

  In a nitrogen atmosphere at 0 ° C, 0.271 g (3.98 mmol) of imidazole was added to 0.0480 g (0.39 mmol) of dimethylaminopyridine and 0.250 g (1.19 mmol) of dichloromethane (S) -4- (benzyloxy) -2-hydroxybutanoic acid. The solution was added and stirred for 15 minutes. Thereafter, 0.625 g (4.15 mmol) of dichloromethane solution of t-butyldimethylsilyl chloride was added and stirred for 21 hours. 20 ml of hydrogen chloride (0.1N) was added dropwise and extracted with ether. The organic phase was washed with saturated sodium bicarbonate solution followed by saturated sodium chloride solution. After drying with sodium sulfate, the product was obtained by concentration. The obtained product was directly used in the next reaction.

  A THF solution of the obtained product was added dropwise to a mixed solution of 0.220 g (3.92 mmol) of potassium hydroxide dissolved in 1.3 ml of water and 4 ml of THF at 0 ° C. and stirred for 30 minutes. 10 ml of water was added and extracted with ether. Cooled hydrogen chloride (3N) was added dropwise to the aqueous phase, and the pH was adjusted to 3 using universal pH test paper. Extraction with ethyl acetate, drying over sodium sulfate, and concentration gave (S) -4- (benzyloxy) -2- (tert-butyldimethylsilyloxy) butanoic acid in a yield of 0.306 g (79.2%).

δ (ppm) = 0.114 (d, J = 8.0Hz, 6H), 0.917 (s, 9H), 2.04-2.12 (m, 2H), 3.61 (dd, J = 6.0, 15.0Hz, 2H), 4.43 (t , J = 5.5Hz, 1H), 4.49 (q, J = 11.5Hz, 2H), 7.28-7.38 (m, 5H)

Example 21: (S) -4- (benzyloxy) -2-hydroxybutanoic acid

  Under a nitrogen atmosphere, 1 ml of trifluoroacetic acid was added dropwise to 1 ml of a dichloromethane solution of 0.263 g (0.987 mmol) of (S) -tert-butyl 4- (benzyloxy) -2-hydroxybutanoate at room temperature and stirred for 1 hour. After adding ethyl acetate and concentrating, adding ethyl acetate again and repeating the concentration operation three times, the mixture was placed under reduced pressure for 24 hours or more with a vacuum pump to completely remove trifluoroacetic acid (S) -4- ( Benzyloxy) -2-hydroxybutanoic acid was obtained in a yield of 0.203 g (97.6%).

δ (ppm) = 2.06-2.28 (m, 2H), 3.71-3.78 (m, 2H), 4.40 (s, 1H), 4.55 (s, 2H), 7.28-7.38 (m, 5H)

Example 22: (S) -tert-butyl 4- (benzyloxy) -2-((S) -2- (tert-butyldimethylsilyloxy)
propanoyloxy) butanoate

  To a DMF solution of 1.70 g (25.0 mmol) of imidazole at room temperature under an argon atmosphere, add a DMF solution of 1.88 g (12.5 mmol) of t-butyldimethylsilyl chloride and a DMF solution of 0.450 g (5.00 mmol) of L-lactic acid and stir for 16 hours. did. Treated with saturated aqueous sodium bicarbonate and extracted with hexane. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated to obtain a product. The obtained product was directly used in the next reaction.

Under a nitrogen atmosphere, 0.87 ml (10.0 mmol) of oxalyl chloride was added dropwise to a dichloromethane solution of the obtained product at 0 ° C., and then 1 drop of DMF solution was added, followed by stirring at 0 ° C. for 2 hours and at room temperature for 3 hours. The crude product was obtained by concentration under reduced pressure. The obtained crude product was dissolved in dry ether, and an ether solution containing 0.316 g (3.99 mmol) of pyridine and 0.257 g (0.965 mmol) of (S) -tert-butyl 4- (benzyloxy) -2-hydroxybutanoate at −20 ° C. Was added dropwise and stirred for 1.5 hours. Treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. After washing with saturated aqueous sodium chloride solution, drying over magnesium sulfate, concentration and isolation and purification using silica gel column chromatography (developing solvent Hexane: Ether = 4: 1), (S) -tert-butyl 4- (benzyloxy) -2-((S) -2- (tert-butyldimethylsilyloxy) propanoyloxy)
Butanoate was obtained in a yield of 0.236 g (54.1%).

δ (ppm) = 0.089 (d, J = 13.0Hz, 6H), 0.901 (s, 9H), 1.44 (s, 9H), 1.45 (d, J = 7.0Hz, 3H), 2.04-2.22 (m, 2H ), 3.54-3.60 (m, 2H), 4.38 (dd, J = 6.5, 7.0Hz, 1H), 4.49 (s, 2H), 5.08 (dd, J = 4.5, 4.0Hz, 1H), 7.36-7.27 ( m, 5H)

Example 23: (S) -tert-butyl-4- (benzyloxy) -2-((S) -4- (benzyloxy) -2-
(tert-butyldimethylsilyloxy) butanoyloxy) butyrate

(S) -4- (benzyloxy) -2- (tert-butyldimethylsilyloxy) at 0 ° C under nitrogen atmosphere
(S) -tert-butyl-4- (benzyloxy) -2-hydroxybutanoate 0.266g (1.00mmol) and dimethylaminopyridine 0.248g (2.03mmol) in dichloromethane solution of butanoic acid 0.306g (0.944mmol) After stirring for 15 minutes, a dichloromethane solution of 0.411 g (2.00 mmol) of dicyclohexylcarbodiimide was added dropwise and stirred for 6 hours. After suction filtration, the mixture was treated with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium bicarbonate, and extracted with hexane. After drying with magnesium sulfate, concentration and isolation and purification by silica gel column chromatography (developing solvent Hexane: Ether = 2: 1), (S) -tert-butyl-4- (benzyloxy) -2-
((S) -4- (benzyloxy) -2- (tert-butyldimethylsilyloxy) butanoyloxy) butyrate was obtained in a yield of 0.0506 g (9.37%).

δ (ppm) = 0.0805 (d, J = 20.5Hz, 6H), 0.910 (s, 9H), 1.43 (s, 9H), 1.92-1.98, 2.04-2.11, 2.15-2.26 (m, 4H), 3.52- 3.58 (m, 2H), 3.59-3.69 (m, 2H), 4.46-4.49 (m, 3H), 4.50 (dd, J = 12.0, 15.5Hz, 2H), 5.08 (dd, J = 4.5, 4.0Hz, 1H), 7.27-7.35 (m, 10H)

Claims (5)

A compound represented by the formula (1) or a salt thereof.

(Wherein R ¹ represents a hydroxyl protecting group, R ² represents a hydrogen atom or a hydroxyl protecting group, and R ³ represents a carboxyl protecting group) A compound represented by formula (2) or a salt thereof.

(Wherein X1 and X2 represent a methyl group or an optionally protected hydroxyethyl group (except when X1 and X2 simultaneously become a methyl group), and R ² represents a hydrogen atom or a hydroxyl protecting group. R ³ represents a hydrogen atom or a protecting group for a carboxyl group) A compound represented by formula (3) or a salt thereof.

(In the formula, X1 and X2 each represent a methyl group or an optionally protected hydroxyethyl group, and n X's each independently represent a methyl group or an optionally protected hydroxyethyl group (provided that X1, If all of X2 and the n X is a methyl group at the same time excluding), R ² represents a hydrogen atom or a protecting group of a hydroxyl group, R ³ represents a hydrogen atom or a protecting group of a carboxyl group, n represents 1 Indicates an integer of 4) A compound represented by formula (4) or a salt thereof.

(In the formula, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, n X's each independently represents a methyl group or an optionally protected hydroxyethyl group, and n represents an integer of 1 to 5) Comprising subjecting the compound represented by the formula (2) according to claim 2 or the compound represented by the formula (3) according to claim 3 to a cyclization reaction by intramolecular dehydration condensation. The manufacturing method of the compound represented by the formula (4) of description.