JP2005232046A - Oligolactic acid ester containing aminoethyl group on side chain - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To synthesize a chain or cyclic oligolactic acid ester containing an aminoethyl group on the side chain. <P>SOLUTION: A chain oligolactic acid ester containing an aminoethyl 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 an aminoethyl group on the side chain. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an oligolactic acid ester having an aminoethyl 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 an aminoethyl 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 an aminoethyl 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 an aminoethyl 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 an aminoethyl group in the side chain, and then subjected this to a cyclization reaction by intramolecular dehydration condensation. Thus, a cyclic oligolactic acid ester having an aminoethyl group in the side chain was successfully synthesized. The present invention has been completed based on this finding.

  That is, according to the present invention, a compound represented by the formula (1) or a salt thereof is provided.

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

  According to another aspect of the present invention, a compound represented by the formula (2) or a salt thereof is provided.

(In the formula, R ¹¹ and R ¹² each independently represent an amino protecting group or a hydrogen atom, R ² represents a hydrogen atom or a hydroxyl protecting group, and R ³ represents a hydrogen atom or a carboxyl protecting group. )

  According to still another aspect of the present invention, a compound represented by the formula (3) or a salt thereof is provided.

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

  According to still another aspect of the present invention, a compound represented by the formula (4) or a salt thereof is provided.

(Wherein R ¹ represents an amino-protecting group or a hydrogen atom)

  According to still another aspect of the present invention, there is provided a process for producing a compound represented by the above formula (4), which comprises subjecting the compound represented by the above formula (3) to a cyclization reaction by intramolecular dehydration condensation. Provided.

  According to still another aspect of the present invention, a compound represented by the formula (5) or a salt thereof is provided.

(In the formula, R ¹ represents an amino protecting group or a hydrogen atom, R ² represents a hydrogen atom or a hydroxyl protecting group, R ³ represents a hydrogen atom or a carboxyl protecting group, and n represents 1 to 4) Indicates an integer)

According to still another aspect of the present invention, a compound represented by the formula (6) or a salt thereof is provided.

(Wherein R ¹ represents an amino-protecting group or a hydrogen atom. N represents an integer of 1 to 4)

  According to still another aspect of the present invention, there is provided a process for producing a compound represented by the above formula (6), which comprises subjecting the compound represented by the above formula (5) to a cyclization reaction by intramolecular dehydration condensation. Provided.

  According to the present invention, an oligolactic acid ester having an aminoethyl group in the side chain can be provided as a single compound. The oligolactic acid ester having an aminoethyl 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 the formula (1) to the formula (6) or a salt thereof, and the compound represented by the formula (3) or the formula (5) are cyclized in the molecule to formula (4). ) Or a method for producing a compound represented by formula (6).
In the formulas (1) to (6), R ¹ , R ¹¹ and R ¹² represent an amino group protecting group or a hydrogen atom, R ² represents a hydrogen atom or a hydroxyl protecting group, and R ³ represents a hydrogen atom or a carboxyl group. A protecting group for the group is shown.

The kind of the protecting group for the amino group represented by R ¹ , R ¹¹ and R ¹² is not particularly limited, and can be appropriately selected by those skilled in the art. Specific examples of the amino-protecting group include a substituted or unsubstituted alkyloxycarbonyl group (for example, an alkylsilyl group, a substituted or unsubstituted aryl group, a halogen atom, a substituted or unsubstituted heterocyclic ring). Groups, bridged cyclic hydrocarbon groups, acyl groups, alkylthio groups, dicyclohexylcarboxamide groups, substituted or unsubstituted benzenesulfonyl groups, alkylsulfonyl groups, substituted or unsubstituted phosphonio groups, cyano groups, etc.), substituted Or an unsubstituted alkenyloxycarbonyl group (for example, an aryl group, a nitro group, etc.), a substituted or unsubstituted aryloxycarbonyl group, a substituted or unsubstituted heterocyclic oxycarbonyl group, a substituted or An alkyl such as an unsubstituted alkyldithiocarbonyl group Formate type amino protecting group, amide type amino protecting group, such as N- alkyl type amino protective group.

  Specific examples of the substituted or unsubstituted alkyloxycarbonyl group include, for example, methyloxycarbonyl group, ethyloxycarbonyl group, isobutyloxycarbonyl group, t-butyloxycarbonyl group, t-amyloxycarbonyl group, 2,2, 2-trichloroethyloxycarbonyl group, 2-trimethylsilylethyloxycarbonyl group, phenylethyloxycarbonyl group, 1- (1-adamantyl) -1-methylethyloxycarbonyl group, 1,1-dimethyl-2-haloethyloxycarbonyl Group, 1,1-dimethyl-2,2-dibromoethyloxycarbonyl group, 1,1-dimethyl-2,2,2-trichloroethyloxycarbonyl group, 1-methyl-1- (4-biphenylyl) ethyloxy Carbonyl group, 1- (3,5-di-t-butyl Phenyl) -1-methylethyloxycarbonyl group, 2- (2′-pyridyl) ethyloxycarbonyl group, 2- (4′-pyridyl) ethyloxycarbonyl group, 2- (N, N-dicyclohexylcarboxamido) ethyloxy Carbonyl group, 1-adamantyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-bromobenzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, 2,4 -Dichlorobenzyloxycarbonyl group, 4-methylsulfinylbenzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, diphenylmethyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, 9- (2,7-dibromo) Fluoresce Rumethyloxycarbonyl group, 2,7-di-t-butyl- [9- (10,10-dioxo-thioxanthyl)] methyloxycarbonyl group, 4-methoxyphenacyloxycarbonyl group, 2-methylthioethyloxycarbonyl group 2-methylsulfonylethyloxycarbonyl group, 2- (p-toluenesulfonyl) ethyloxycarbonyl group, [2- (1,3-dithianyl)] methyloxycarbonyl group, 4-methylthiophenyloxycarbonyl group, 2,4 -Dimethylthiophenyloxycarbonyl group, 2-phosphonioethyloxycarbonyl group, 2-triphenylphosphonioisopropyloxycarbonyl group, 1,1-dimethyl-2-cyanoethyloxycarbonyl group, m-chloro-p-acyloxybenzyl Oxycarbonyl group, p- (dihydroxy Boryl) benzyloxycarbonyl group, 5-benzoisoxazolylmethyloxycarbonyl group, 2- (trifluoromethyl) -6-chromonylmethyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, o-nitrobenzyl Examples thereof include an oxycarbonyl group, a 3,4-dimethoxy-6-nitrobenzyloxycarbonyl group, and a phenyl (o-nitrophenyl) methyloxycarbonyl group.

  Specific examples of the substituted or unsubstituted alkenyloxycarbonyl group include vinyloxycarbonyl group, allyloxycarbonyl group, 1-isopropylallyloxycarbonyl group, cinnamyloxycarbonyl group, 4-nitrocinnamyloxycarbonyl group and the like. Is done.

  Specific examples of the substituted or unsubstituted heterocyclic oxycarbonyl group include an 8-quinolyloxycarbonyl group and an N-piperidinyloxycarbonyl group.

  Specific examples of the substituted or unsubstituted aryloxycarbonyl group include a phenyloxycarbonyl group and an m-nitrophenyloxycarbonyl group.

  Specific examples of the amide type amino protecting group include formyl group, acetyl group, chloroacetyl group, trichloroacetyl group, trifluoroacetyl group, phenylacetyl group, benzoyl group and the like.

  Specific examples of the N-alkyl type amino protecting group include benzyl group, N-di (4-methoxyphenyl) methyl group, N-5-dibenzosuberyl group, N-triphenylmethyl group, (4-methoxyphenyl) Examples thereof include a diphenylmethyl group, an N-9-phenylfluorenyl group, an allyl group, an N- [2- (trimethylsilyl) ethoxy] methyl group, and an N-3-acetoxypropyl group.

The type of the hydroxyl-protecting group represented by R ² is not particularly limited and can be appropriately selected by those skilled in the art. Specific examples of the hydroxyl-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 an aminoethyl group protected on the side chain of lactic acid. The compound represented by the formula (2) is a compound having two aminoethyl groups which may be protected by the side chain of the lactic acid dimer, and the compound represented by the formula (3) is a lactic acid 2 It is a compound having one aminoethyl group which may be protected on the side chain of the monomer. The compound represented by the formula (4) is a cyclized product of lactic acid dimer, and is a compound having one aminoethyl group which may be protected in the side chain. The compound represented by the formula (4) is obtained by subjecting the compound represented by the formula (3) to a cyclization reaction by intramolecular dehydration condensation in the presence of N, N′-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. Can be synthesized.

  Moreover, the compound represented by Formula (5) of this invention is a compound which has one aminoethyl group which may be protected by the side chain of the trimer of lactic acid to the hexamer. The compound represented by the formula (6) is a cyclized product of a lactic acid trimer to a hexamer, and is a compound having one aminoethyl group which may be protected in the side chain. The compound represented by formula (6) is obtained by cyclization of the compound represented by formula (5) by intramolecular dehydration condensation in the presence of diisopropylethylamine, 4-dimethylaminopyridine and 2,4,6-trichlorobenzoyl chloride. It can synthesize | combine by using for reaction.

  The specific synthesis route of the above-described compound of the present invention will be described by taking the following three methods (Method A), (Method B) and (Method C) as examples.

(Method A) In this method, a lactic acid oligoester having an arbitrary chain length is synthesized and condensed with a compound in which the amino group and carboxyl group of (s)-(−)-4-amino-2-hydroxybutyric acid are protected. Then, the carboxyl group and the hydroxyl group are deprotected and cyclized.

  First, the synthesis of the carboxyl side terminal unit of the chain oligoester was studied. That is, lactide was hydrolyzed and reacted with 2, 4'-dibromoacetophenone to obtain lactoyl lactyl p-bromophenacyl ester (2).

  Next, lactate benzyl ether (3) and lactate lactoyl p-bromophenacyl ester (2) are condensed using DCC and DMAP, and the resulting 4 is reacted with zinc and acetic acid to deprotect the carboxyl group, Lactic acid trimer benzyl ether (5) was synthesized. Subsequently, 6 obtained by condensation with lactoyl lactoyl p-bromophenacyl ester (2) is reacted with zinc and acetic acid to deprotect the carboxyl group, and lactic acid pentamer benzyl ether (7) is obtained.

  Next, the synthesis of a unit having an aminoethyl group was studied. That is, (s)-(-)-4-amino-2-hydroxybutyric acid (8) was reacted with di-t-butyl dicarbonate to protect the amino group and further reacted with 2,4'-dibromoacetophenone. Can be obtained.

  The obtained (5) and (7) were condensed with the (s)-(-)-4-amino-2-hydroxybutyric acid derivative (10), and the corresponding hydroxyl group was replaced with a benzyl group and the carboxyl group with a p-bromophenacyl group. A chain oligoester (11a) or (11b) having a protected aminoethyl group is obtained. Subsequently, zinc and acetic acid are allowed to act on the resulting product to deprotect the carboxyl group, and catalytic reduction yields chain oligoesters (13a) and (13b) having both a carboxyl group and a hydroxyl group free aminoethyl groups. It is done.

  Finally, 2, 4, 6-trichlorobenzoyl chloride is allowed to act on the obtained chain oligoesters (13a) and (13b) to synthesize cyclic oligoesters having aminoethyl groups by dehydration condensation within the molecule. Can do.

(Method B) Enterobactin (1), which is known as an antibiotic, has a cyclic ester structure having three side chains, and is also known as a molecular recognition compound, such as capturing iron ions at the side chains. Yes. The object can be to synthesize a compound having a structure as shown in the following 2.

  First, synthesis of bromophenacyl ester 3 was studied using a derivative (3) in which the amino group serving as a basic unit for synthesizing 2 was protected with a t-butoxycarbonyl group. That is, bromophenacyl bromide is reacted with 3 in the presence of triethylamine to obtain 4.

  Next, 6 is obtained by reacting 3 with t-butyldimethylsilane chloride in the presence of imidazole to make 5 and then hydrolyzing with potassium carbonate. Next, the obtained 6 and 4 are subjected to a condensation reaction. That is, the desired 7 can be obtained in a good yield by reacting 6 and 4 with DCC as a condensing agent under a DMAP catalyst.

(C) This method is a method for synthesizing a cyclic oligoester composed of two kinds of α-hydroxy acids. First, as a unit for synthesizing an ester, 3 and 6 in which the hydroxyl group of lactic acid (1) and the carboxyl group of 4-amino-2-hydroxybutyric acid (4) are protected are synthesized. First, the hydroxyl group and carboxyl group of 1 can be protected with a benzyl group, and 3 in which only the carboxyl group is deprotected can be obtained in two steps.

  Next, 6 in which the amino group of 4 is protected with a Boc group and the carboxyl group is protected with bromophenacyl can be obtained in two steps.

In order to extend the chain length, the previously synthesized 3 and 6 condensation reactions are performed to obtain a compound (7) in which two types of .-hydroxy acids are bonded.

  The resulting 7 phenacyl ester and benzyl ether can be deprotected to obtain 9 in two steps. Cyclic polylactic acid can be synthesized by cyclizing compound 9 by intramolecular condensation reaction.

  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:

  Under a nitrogen atmosphere, 40 ml of dichloromethane was placed in a 100 ml eggplant-shaped flask at room temperature, and 10.0317 g (43.2 mmol) of silver (I) oxide was added. Further, 2.266 g (14.0 mmol) of lactoyl lactate in 20 ml of dichloromethane was added, followed by 4.15 ml (34.9 mmol) of benzyl bromide. This was stirred for 15.5 hours, filtered through a Buchner funnel with celite, and concentrated. The reaction mixture was isolated and purified using silica gel column chromatography (developing solvent ether-hexane 1: 8) to obtain 2.3077 g of the product in a yield of 48.1%.

[α] ^D _18.3 = -84.8 ° (c = 5.1, CHCl ₃ )
IR (cm ^-1 ): 2989 (Ph), 1751 (C = O) (NaCl)
¹ H-NMR (500 MHz, CDCl ₃ )
δ (ppm) = 1.47 (3H, d, J = 6.5Hz), 1.56 (3H, d, J = 7Hz), 4.13 (1H, q, J = 7Hz), 4.45 (d, J = 11.5Hz) and 4.75 (2H, d, J = 11.5Hz). 5.16-5.26 (3H, m), 7.30-7.40 (10H, m)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 67.2, 68.9, 72.0, 73.8, 127.9, 128.1, 128.3, 128.5, 128.6, 128.7, 135.2, 137.5, 170.3, 172.9

Example 2:

  To a 10 ml dichloromethane solution of 3.6252 g (20.1 mmol) benzyl ether lactate at room temperature under a nitrogen atmosphere, add a 90 ml dichloromethane solution of 22.1202 g (61.6 mmol) lactic acid dimer p-bromophenacyl ester, and then add 4-dimethylamino A solution of 0.1531 g (1.25 mmol) of pyridine in 3 ml of dichloromethane was added. After sufficiently cooling this in an ice bath, a 10 ml dichloromethane solution of 5.2033 g (25.2 mmol) of N, N′-dicyclohexylcarbodiimide was slowly added dropwise to remove the ice bath. The reaction mixture was stirred for 30 minutes and then quenched with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N′-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with dichloromethane (30 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 1) to obtain 9.0194 g of lactic acid trimer benzyl ether p-bromophenacyl ester in a yield of 86.3%.

[α] ^D _24.5 = -85.1 ° (c = 0.47, CHCl ₃ )
IR (cm ^-1 ): 2935 (Ph), 1761 (C = O), 1747 (C = O), 1705 (C = O) (NaCl)
¹ H-NMR (500 MHz, CDCl ₃ )
δ (ppm) = 1.50 (3H, d, J = 6.5Hz), 1.60 (3H, d, J = 7Hz), 1.68 (3H, d, J = 7Hz), 4.14 (1H, q, J = 7Hz), 4.47 (d, J = 11.5Hz) and 4.77 (2H, d, J = 11.5Hz), 5.21-5.26 (2H, m), 5.32 (1H, q, J = 7Hz), 5.47 (1H, d, J = 16Hz), 7.30-7.47 (5H, m), 7.64 (2H, d, J = 75Hz), 7.75 (2H, d, J = 7.5Hz)
¹³ C-NMR (125 MHz, CDCl ₃ ), δ (ppm) = 16.8, 17.0, 18.8, 66.3, 68.6, 69.1, 72.0, 73.7, 127.9, 128.1, 128.5, 129.3, 132.3, 132.5, 137.6, 169.8, 170.0

Example 3:

  Under a nitrogen atmosphere, 9.8685 g (151.01 mmol) of zinc powder was added to a 500 ml three-necked round bottom flask at room temperature, and 130 ml of ether was added. To this was added a 50 ml ether solution of 9.2994 g (154.86 mmol) of acetic acid and 5.2332 g (10.04 mmol) of lactic acid trimer benzyl ether p-bromophenacyl ester, and the mixture was stirred for 6 hours. This was filtered and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 4) to obtain 3.0352 g of lactic acid trimer benzyl ether in a yield of 93.2%.

[α] ^D _23.9 = -90.6 ° (c = 0.95, CHCl ₃ )
IR (cm ^-1 ): 2993 (Ph), 1755 (C = O) (NaCl)
¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm) = 1.50 (3H, d, J = 7 Hz), 1.57 (3H, d, J = 7 Hz), 1.60 (3H, d, J = 7.5 Hz), 4.14 (1H, q, J = 7Hz), 4.48 (d, J = 11.5Hz) and 4.76 (2H, d, J = 11.5Hz), 5.18-5.23 (2H, m), 7.28-7.38 (5H, m)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 16.7, 16.8, 18.7, 68.7, 70.0, 72.0, 73.7, 128.0, 128.2, 128.5, 137.4, 170.0, 137.0, 175.3

Example 4:

  To a 2.5 ml dichloromethane solution of 1.0111 g (4.01 mmol) of lactic acid dimer benzyl ether at room temperature under a nitrogen atmosphere, add a 3.5 ml dichloromethane solution of 2.9622 g (11.7 mmol) of lactic acid dimer benzyl ester, and further add 4-dimethyl A solution of 0.0209 g (0.17 mmol) of aminopyridine in 0.5 ml dichloromethane was added. After sufficiently cooling this in an ice bath, a 2.5 ml dichloromethane solution of 1.0376 g (6.34 mmol) of N, N′-dicyclohexylcarbodiimide was slowly added dropwise to remove the ice bath. The reaction mixture was stirred for 30 minutes and then quenched with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N′-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with dichloromethane (30 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 1) to obtain lactic acid tetramer benzyl ether benzyl ester in a yield of 1.5982 g, 82.1%.

[α] ^D _15.5 = -111.2 ° (c = 0.54, CHCl ₃ )
IR (cm ^-1 ): 2991 (Ph), 1755 (C = O) (NaCl)
¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 1.50 (3H, d, J = 7Hz), 1.53 (3H, d, J = 7Hz), 1.55 (3H, d, J = 7Hz), 1.63 ( 3H, d, J = 7Hz), 4.15 (1H, q, J = 6.8Hz), 4.48 (d, J = 11.0Hz) and 4.77 (2H, d, J = 11.5Hz), 5.13 (d, J = 12.0 Hz) and 5.20 (2H, d, J = 12.0Hz), 5.18-5.23 (3H, m), 7.28-7.39 (10H, m)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 16.7, 16.8, 18.8, 67.2, 68.6, 69.0, 69.3, 72.1, 73.7, 127.9, 128.1, 128.3, 128.5, 128.6, 128.7, 169.7, 170.0, 172.9

Example 5:

  At room temperature, add 4760 ml (3.03 mmol) of lactic acid tetramer benzyl ether benzyl ester to a 50 ml two-necked eggplant flask, then add 0.0367 g (0.362 mmol) of triethylamine in 1.5 ml ethyl acetate, and add palladium charcoal. (10%) was added in 0.173 g. This was replaced with hydrogen and stirred for 5 hours. Thereafter, the reaction mixture was filtered through a Buchner funnel using Celite and concentrated, and further filtered using silica gel, and this was concentrated to obtain 1.1577 g of lactic acid tetramer benzyl ether in a yield of 96.3%.

[α] ^D _14.6 = -101.2 ° (c = 1.1, CHCl ₃ )
IR (cm ^-1 ): 2993 (Ph), 1755 (C = O) (NaCl)
¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 1.49 (3H, d, J = 7Hz), 1.54 (3H, d, J = 7Hz), 1.58 (3H, d, J = 7Hz), 1.60 ( 3H, d, J = 7Hz), 4.14 (1H, q, J = 7Hz), 4.47 (d, J = 11.5Hz) and 4.76 (2H, d, J = 11.5Hz), 5.15 (1H, q, J = 7Hz), 5.20 (2H, q, J = 7Hz), 7.27-7.37 (5H, m)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 16.6, 16.7, 16.8, 18.7, 68.6, 68.9, 69.0, 72.0, 73.7, 127.9, 128.1, 128.5, 137.4, 169.7, 170.0, 173.0, 175.5

Example 6

  To a 3 ml dichloromethane solution of lactic acid trimer benzyl ether 0.6643 g (2.05 mmol) at room temperature under a nitrogen atmosphere, a 5 ml dichloromethane solution of lactic acid dimer p-bromophenacyl ester 2.1595 g (6.01 mmol) was added. -A solution of 0.0131 g (0.107 mmol) of dimethylaminopyridine in 3 ml of dichloromethane was added. After sufficiently cooling this in an ice bath, a solution of 0.5408 g (2.62 mmol) of N, N′-dicyclohexylcarbodiimide in 3 ml of dichloromethane was slowly added dropwise to remove the ice bath. The reaction mixture was stirred for 30 minutes and then quenched with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N′-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with dichloromethane (20 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent ethyl acetate-hexane 1: 4) to obtain 1.0802 g of lactic acid pentamer benzyl ether p-bromophenacyl ester in a yield of 74.2%.

[α] ^D _22.9 = -110.3 ° (c = 0.27, CHCl ₃ )
IR (cm ^-1 ): 2993 (Ph), 1770 (C = O), 1705 (C = O) (NaCl)
¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 1.48 (3H, d, J = 7Hz)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 16.7, 16.7, 16.8, 17.0, 18.8, 66.3, 68.6, 69.0, 69.1, 69.2, 72.0, 73.7, 127.9, 128.1, 128.5, 129.2, 129.4, 132.3 , 132.6, 137.5, 169.7, 169.7, 170.0, 172.9, 190.3

Example 7:

  In a 500 ml three-necked round bottom flask at room temperature under a nitrogen atmosphere, 7.8765 g (120.5 mmol) of zinc powder was added, and to this, 7.7331 g (128.8 mmol) of acetic acid and 7.5189 g (11.3 of lactic acid pentamer benzyl ether p-bromophenacyl ester). mmol) in 50 ml ether was added and stirred for 6 hours. This was filtered and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 2) to obtain lactic acid pentamer benzyl ether in a yield of 91.8%, 4.8593 g.

[α] ^D _22.7 = -119.3 ° (c = 1.9, CHCl ₃ )
IR (cm ^-1 ): 3518 (COO-H), 2993 (Ph), 1755 (C = O) (NaCl)
¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm) = 1.49 (3H, d, J = 7.0 Hz), 1.56 (3H, d, J = 7.5 Hz), 1.58-1.61 (9H, m), 4.14 ( 1H, q, J = 7.0Hz), 4.47 (d, J = 11.5Hz) and 4.76 (2H, d, J = 11.5Hz), 5.16-5.23 (4H, m), 7.29-7.38 (5H, m)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 16.6, 16.6, 16.7, 16.8, 18.7, 68.6, 68.9, 69.0, 69.0, 72.0, 73.7, 127.9, 128.1, 128.4, 137.4, 169.6, 169.8, 170.0 , 173.0, 175.1

Example 8

  Under a nitrogen atmosphere, a 17 ml THF solution of 10.4297 g (47.6 mmol) of Nt-butoxycarbonyl- (s)-(−)-4-amino-2-hydroxybutanoic acid was added to a 300 ml three-necked round-bottomed flask cooled in an ice bath. A 4 ml THF solution of g (50.0 mmol) was added dropwise. To this was added a 25 ml THF solution of 13.9058 g (50.0 mmol) of 2,4′-dibromoacetophenone and the ice bath was removed, followed by stirring for 1 hour. The reaction was quenched with 10 ml of 1N aqueous potassium hydrogen sulfate solution, extracted with dichloromethane (20 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was recrystallized from ether to obtain 19.4687 g of N-t-butoxycarbonyl- (s)-(−)-4-amino-2-hydroxybutanoic acid p-bromophenacyl ester in a yield of 98.3%.

mp = 95.1-96.0 ℃
[α] ^D _17.6 = -4.3 ° (c = 5.0, CHCl ₃ )
IR (cm ^-1 ): 3523 (NH), 3357 (OH), 2935 (Ph), 1735 (C = O), 1697 (C = O) (KBr)
¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) = 1.43 (9H, s), 1.96-2.07 (1H, m), 2.11-2.22 (1H, m), 3.34-3.47 (2H, m), 3.55 (1H, d, J = 5.4Hz), 4.44-4.50 (1H, m), 5.00 (1H, bs), 5.32 (d, J = 16Hz) and 5.50 (2H, d, J = 16Hz), 7.76 (2H , d, J = 8.7Hz), 7.78 (2H, d, J = 8.7Hz)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 28.4, 34.4, 36.6, 66.3, 68.6, 79.5, 129.2, 129.4, 132.3, 132.5, 156.6, 174.0, 190.8

Example 9:

  Under a nitrogen atmosphere, add a 10 ml THF solution of 2.2422 g (10.2 mmol) of Nt-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid to a 200 ml three-necked round-bottomed flask cooled in an ice bath. A 1 ml THF solution of g (10.2 mmol) was added dropwise. To this was added a 10 ml THF solution of 2.4211 g (12.2 mmol) of 2, -bromoacetophenone, and the ice bath was removed, followed by stirring for 2 hours. The reaction was quenched with 10 ml of 1N aqueous potassium hydrogen sulfate solution, extracted with chloroform (30 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This reaction mixture was isolated and purified using silica gel column chromatography (developing solvent ether) to obtain 3.4019 g, 98.9 of Nt-butoxycarbonyl- (s)-(−)-4-amino-2-hydroxybutanoic acid phenacyl ester. % Yield.

mp = 86.6-88.2 ℃
[α] ^D _18.3 = -2.0 ° (c = 1.0, CHCl ₃ )
IR (cm ^-1 ): 3444 (NH), 3367 (OH), 2983 (Ph), 1749 (C = O), 1712 (C = O), 1685 (C = O) (KBr)
¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) = 1.40 (9H, s), 1.96-2.07 (1H, m), 2.11-2.22 (1H, m), 3.33-3.49 (2H, m), 4.44 -4.50 (1H, m), 5.04 (1H, bs), 5.36 (d, J = 16Hz) and 5.55 (2H, d, J = 16Hz), 7.50 (2H, t, J = 7.5Hz), 7.62 (1H , t, J = 7.5Hz), 7.90 (2H, d, J = 7.5Hz)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 28.4, 34.3, 36.7, 66.5, 68.7, 79.3, 127.8, 128.9, 133.8, 134.1, 156.6, 174.0, 191.7

Example 10:

  Under an argon atmosphere, at room temperature, 0.1824 g (1.01 mmol) of lactate benzyl ether in a 1.2 ml dichloromethane solution was added 1.0041 g of phenacyl ester of Nt-butoxycarbonyl- (s)-(−)-4-amino-2-hydroxybutanoic acid ( 2.98 mmol) in 5.2 ml dichloromethane was added, followed by addition of 0.0122 g (0.10 mmol) of 4-dimethylaminopyridine in 0.4 ml dichloromethane. After sufficiently cooling this in an ice bath, a solution of N, N′-dicyclohexylcarbodiimide (0.2476 g, 1.20 mmol) in 10.4 ml dichloromethane was slowly added dropwise, and the ice bath was removed. The reaction mixture was stirred for 3.5 hours and then quenched with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N′-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with chloroform (30 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent ether-hexane 2: 1) to obtain 0.4179 g of the product in a yield of 82.8%.

[α] ^D _15.9 = -28.9 ° (c = 1.0, CHCl ₃ )
IR (cm ^-1 ): 3384 (NH), 1755 (C = O), 1705 (C = O) (NaCl)
¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) = 1.42 (9H, s), 1.50 (3H, dd, J = 4.8, 7.2 Hz), 2.18-2.36 (2H, m), 3.33-3.43 (2H , m), 4.19 (1H, dq, J = 1.7, 6.9Hz), 4.47 (d, J = 11.7Hz) and 4.49 (d, J = 11.7Hz) and 4.74 (d, J = 11.7Hz), and 4.77 (2H, d, J = 11.7Hz), 4.94 (1H, bs), 5.26-5.33 (1H, m), 5.56 (d, J = 16.5Hz) and 5.59 (2H, d, J = 16.5Hz), 7.28 -7.39 (5H, m), 7.50 (2H, t, J = 7.5Hz), 7.62 (1H, t, J = 7.5Hz), 7.90 (2H, d, J = 7.5Hz)

Example 11

  Nt-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid p-bromophenacyl ester 19.2312 in a 5 ml dichloromethane solution of 2.7311 g (15.1 mmol) benzyl lactate at room temperature under nitrogen atmosphere A 110 ml dichloromethane solution of g (46.2 mmol) was added, and further a 1 ml dichloromethane solution of 0.0122 g (0.10 mmol) of 4-dimethylaminopyridine was added. After sufficiently cooling this in an ice bath, a solution of N, N′-dicyclohexylcarbodiimide (3.5558 g, 17.2 mmol) in 20 ml dichloromethane was slowly added dropwise, and the ice bath was removed. The reaction mixture was stirred for 30 minutes and then quenched with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N′-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with chloroform (30 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent ether-hexane 1: 1) to obtain 6.8067 g of the product in a yield of 77.9%.

Example 12:

  In a 500 ml three-neck round bottom flask at room temperature under a nitrogen atmosphere, 2 (s) -benzyloxypropanoyl-Nt-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid phenacyl ester 6.8067 g ( 11.8 mmol) in 300 ml ether was added and acetic acid 20 ml (24.9 mmol) was added. Further, 23.7420 g (36.3 mmol) of zinc powder was added and stirred for 1.5 hours. This was filtered and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent ether-hexane 1: 1), and 2 (s) -benzyloxypropanoyl-Nt-butoxycarbonyl- (s)-(-)-4-amino-2 -Hydroxybutanoic acid was obtained in a yield of 2.6543 g, 59.0%.

Example 13:

  In a 50 ml two-necked eggplant flask at room temperature, 1.7364 g (4.55 mmol) of 2 (s) -benzyloxypropanoyl-Nt-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid 0.8 ml methanol The solution was added and 0.3572 g of palladium charcoal (5%) was added. This was replaced with hydrogen and stirred for 2 days. Thereafter, the reaction mixture was filtered through a Buchner funnel with celite and concentrated, and further filtered through silica gel to concentrate it to obtain the product (1.2555 g, 94.8% yield).

Example 14:

  In a nitrogen atmosphere, the sample was sufficiently cooled in an ice bath, and N, N′- was added to a solution of 0.5969 g (2.05 mmol) lactoyl Nt-butoxycarbonyl- (s)-(−)-4-amino-2-hydroxybutanoate in 190 ml dichloromethane. A 5 ml dichloromethane solution of 0.6551 g (3.18 mmol) of dicyclohexylcarbodiimide was slowly added dropwise, and after adding a 5 ml dichloromethane solution of 0.0019 g (0.0016 mmol) of 4-dimethylaminopyridine, the ice bath was removed. The reaction mixture was stirred for 30 minutes and then quenched with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N′-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with ethyl acetate (20 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 1) to obtain 0.2273 g of the product.

Example 15:

  To a 3.5 ml dichloromethane solution of 0.3165 g (0.976 mmol) of lactic acid trimer benzyl ether at room temperature under a nitrogen atmosphere, p-bromo Nt-butoxycarbonyl- (s)-(−)-4-amino-2-hydroxybutanoate A 13 ml dichloromethane solution of 1.2404 g (2.98 mmol) of phenacyl ester was added, and further a 1 ml dichloromethane solution of 0.0137 g (0.112 mmol) of 4-dimethylaminopyridine was added. This was sufficiently cooled in an ice bath, and then a 3.5 ml dichloromethane solution of 0.3148 g (1.53 mmol) of N, N′-dicyclohexylcarbodiimide was slowly added dropwise to remove the ice bath. The reaction mixture was stirred for 30 minutes and then quenched with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N′-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with chloroform (30 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent ether-hexane 1: 1) to obtain 0.4762 g, 67.5% yield of the product.

[α] ^D _18.3 = -2.0 ° (c = 1.0, CHCl ₃ )
IR (cm ^-1 ): 3444 (NH), 3367 (OH), 2983 (Ph), 1749 (C = O), 1712 (C = O), 1685 (C = O) (NaCl)
¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm) = 1.40 (9H, s), 1.47 (3H, d, J = 6.5 Hz), 1.58 (3H, d, J = 7.0 Hz), 1.59 (3H, d, J = 7.0Hz), 2.14-2.22, 2.26-2.33 (2H, m), 3.25-3.43 (2H, m), 4.12 (1H, q, J = 7.0Hz), 4.46 (d, J = 11.5Hz ) and 4.74 (2H, d, J = 11.5Hz), 4.97 (1H, bs), 5.22 (d, J = 16.5Hz) and 5.44 (2H, d, J = 16.5Hz), 5.12-5.19 (3H, m ), 7.26-7.36 (5H, m), 7.61 (2H, d, J = 9.0Hz), 7.72 (2H, d, J = 8.5Hz)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 16.7, 16.8, 18.8, 28.4, 31.2, 36.3, 66.4, 68.5, 69.1, 70.6, 72.0, 73.7, 76.9, 127.9, 128.1, 128.5, 129.2, 129.5 , 132.4, 132.5, 137.5, 155.9, 168.9, 169.8, 170.0, 172.9, 190.3

Example 16:

  Under a nitrogen atmosphere, 2.9603 g (45.3 mmol) of zinc powder was added to a 100 ml two-necked eggplant flask at room temperature, and 2.7100 g (45.1 mmol) of acetic acid and lactic acid tetramer derivative benzyl ether p-bromophenate having an aminoethyl group were added thereto. A 20 ml ether solution of 2.1675 g (3.00 mmol) of silester was added and stirred for 5 hours. This was filtered and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 1) to obtain 1.0500 g of the product in a yield of 66.7%.

Example 17:

  An ethanol solution of 1.0450 g (1.99 mmol) of lactic acid tetramer derivative benzyl ether having an aminoethyl group was added to a 50 ml two-necked eggplant flask at room temperature, and 0.992 g of palladium charcoal (10%) was added. This was purged with hydrogen and stirred for 13 hours. Thereafter, the reaction mixture was filtered through a Buchner funnel with celite and concentrated, and further filtered through silica gel to concentrate it to obtain 0.8089 g of a product with a yield of 93.3%.

Example 18:

  In a nitrogen atmosphere, lactic acid pentamer benzyl ether 1.9288 g (4.12 mmol) in 14 ml dichloromethane solution was added Nt-butoxycarbonyl- (s)-(−)-4-amino-2-hydroxybutanoic acid p-bromophenate. An 80 ml dichloromethane solution of 12.4974 g (30.02 mmol) of the silester was added, and further a 1 ml dichloromethane solution of 0.0164 g (0.13 mmol) of 4-dimethylaminopyridine was added. After sufficiently cooling this in an ice bath, a 5 ml dichloromethane solution of 12.4894 g (12.1 mmol) of N, N′-dicyclohexylcarbodiimide was slowly added dropwise to remove the ice bath. The reaction mixture was stirred for 1 hour and then quenched with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N′-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with dichloromethane (30 ml × 3), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 2) to obtain 2.9356 g of the product in a yield of 82.2%.

[α] ^D _17.2 = -134.3 ° (c = 0.11, CHCl ₃ )
IR (cm ^-1 ): 3419 (NH), 2985 (Ph), 1778 (C = O), 1695 (C = O) (NaCl)
¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm) = 1.42 (9H, s), 1.48 (3H, d, J = 6.5 Hz), 1.57-1.60 (12H, m), 2.16-2.22, 2.26-2.32 (2H, m), 3.28-3.32, 3.38-3.42 (2H, m), 4.13 (1H, q, J = 6.8Hz), 4.46 (d, J = 11.5Hz) and 4.75 (2H, d, J = 11.5 Hz), 4.93 (1H, m), 5.15-5.29 (5H, m), 5.23 (d, J = 16.5Hz) and 5.47 (2H, d, J = 16.5Hz), 7.27-7.37 (5H, m), 7.63 (2H, d, J = 8.5Hz), 7.73 (2H, d, J = 8.5Hz)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 16.6, 16.7, 16.7, 16.8, 18.8, 28.4, 31.2, 36.3, 66.3, 68.6, 68.9, 69.0, 69.2, 70.6, 72.0, 73.7, 79.3, 127.9 , 128.1, 128.4, 129.2, 129.5, 132.4, 132.5, 137.5, 155.8, 168.9, 169.7, 169.7, 170.0, 172.9, 190.3

Example 19

  Under nitrogen atmosphere, 3.0563 g (46.7 mmol) of zinc powder was added to a 100 ml two-necked eggplant flask at room temperature, and 2.7052 g (45.0 mmol) of acetic acid and lactic acid hexamer derivative benzyl ether p-bromophene having an aminoethyl group were added thereto. A 20 ml ether solution of 2.8731 g (3.31 mmol) of silester was added and stirred for 4.5 hours. This was filtered and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent, ethyl acetate-hexane 1: 1) to obtain 1.4660 g, 66.1% yield.

[α] ^D _19.4 = -81.9 ° (c = 0.17, CHCl ₃ )
IR (cm ^-1 ): 3415 (NH), 2987 (Ph), 1757 (C = O), 1718 (C = O) (NaCl)
¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm) = 1.44 (9H, s), 1.49 (3H, d, J = 7.0 Hz), 1.59-1.61 (12H, m), 1.87-1.90, 2.00-2.20 , 2.46-2.51 (2H, m), 3.10-3.40 (2H, m), 4.13 (1H, q, J = 6.8Hz), 4.47 (d, J = 11.5Hz) and 4.76 (2H, d, J = 11.5 Hz), 4.91 (1H, bs), 5.10-5.22 (5H, m), 7.28-7.38 (5H, m)

Example 20

  An ethanol solution of 1.4490 g (2.16 mmol) of lactic acid hexamer derivative benzyl ether having an aminoethyl group was added to a 50 ml two-necked eggplant flask at room temperature, and 0.1758 g of palladium charcoal (10%) was added. This was purged with hydrogen and stirred for 14 hours. Thereafter, the reaction mixture was filtered through a Buchner funnel with celite and concentrated, and further filtered through silica gel to concentrate the product to obtain 1.0486 g in a yield of 84.2%.

Example 21
Under a nitrogen atmosphere, at 0 ° C, 0.49234 g (8.0 mmol) of imidazole in 12 ml dichloromethane solution was added 0.6923 g (4.0 mmol) of 5 ml dichloromethane solution in t-butyldimethylchlorosilane, stirred for 10 minutes, and N-Boc- (S)- A solution of 0.2-193 g (1.0 mmol) of (-)-4-amino-2-hydroxybutyric acid in 10 ml dichloromethane was slowly added dropwise, stirred for 1 hour, returned to room temperature, and further stirred for 13 hours. The reaction was quenched with 20 ml of saturated aqueous sodium chloride solution and extracted with hexane (50 ml × 3). The organic phase was concentrated and made into a 10 ml THF solution. Next, a 10 ml aqueous solution of 1 g of potassium carbonate was added at room temperature, stirred for 45 minutes, and washed with hexane. The solution was adjusted to pH 3 with 1N aqueous potassium hydrogen sulfate solution, extracted with ethyl acetate (50 ml × 3), dried over magnesium sulfate and filtered.

  Next, 15 ml of 1.2519 g (3 mmol) of Nt-butoxycarbonyl- (S)-(−)-4-amino-2-hydroxybutyric acid-p-bromophenacyl ester was added to this 20 ml dichloromethane solution at 0 ° C. under a nitrogen atmosphere. Dichloromethane solution, N-N′-dicyclohexylcarbodiimide 0.2830 g in 5 ml dichloromethane solution and 4-dimethylaminopyridine 0.0184 g in 5 ml dichloromethane solution were added and stirred for 15 minutes, then returned to room temperature and further stirred for 5 hours. The reaction solution was treated with saturated brine (20 ml) and filtered under reduced pressure. The solution extracted with ethyl acetate (60 ml × 3) was dried over magnesium sulfate. This was concentrated under reduced pressure and isolated and purified using silica gel column chromatography (developing solvent hexane: etylacetate = 10: 3) to obtain 0.3735 g of the product in a yield of 54.4%.

Example 22:
Under a nitrogen atmosphere, at 0 ° C., to a solution of 1.3651 g (mmol) of imidazole in 16 ml of dichloromethane was added 1.8514 g (mmol) of t-butyldimethylchlorosilane in 2 ml of dichloromethane and stirred for 10 minutes. Nt-butoxycarbonyl- (S)-( -)-4-Amino-2-hydroxybutyric acid-p-bromophenacyl ester 1.0976 g (2.64 mmol) in 18 ml dichloromethane was slowly added dropwise and stirred for 1 hour, then returned to room temperature and further stirred for 12 hours. The reaction solution was concentrated under reduced pressure and isolated and purified using silica gel column chromatography (developing solvent hexane: etylacetate = 4: 1) to obtain the product in 1.599 g at a yield of 90%.

Example 23:
N-Boc- (S)-(-)-4-amino-2-hydroxybutyric acid 0.0548 g (0.25 mmol) in 2 ml dichloromethane solution at room temperature under nitrogen atmosphere 0.07 ml (0.6 mmol) in 2 ml dichloromethane solution After adding 0.1217 g (0.525 mmol) of silver (II) oxide and stirring for 16 hours, the silver oxide powder was filtered. This was isolated and purified using silica gel column chromatography (developing solvent hexane: ether = 1: 2) to obtain 0.0164 g of the product in a yield of 16%.

Example 24:
Under a nitrogen atmosphere, 0.1518 g (1.5 mmol) of triethylamine was added to 0.1096 g (0.5 mmol) of N-Boc- (S)-(−)-4-amino-2-hydroxybutyric acid 3 ml THF solution at 0 ° C. for 15 minutes. After stirring, the temperature was returned to room temperature, 0.7 ml (0.8 mmol) of benzyl bromide was further added and stirred for 8 hours, and then the reaction solution was treated with 3 ml of saturated aqueous ammonium chloride solution and extracted with dichloromethane (10 ml × 3). It was dried over magnesium and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent ether) to obtain the product in a yield of 0.057 g at 37%.

Example 25:
Under a nitrogen atmosphere, 0.1285 g (2.8 mmol) of sodium hydride was added to 0.0698 g (0.226 mmol) of benzyl ester in 3 ml of DMF at room temperature and stirred for 45 minutes. The reaction was stopped with 10 ml of saturated ammonium chloride after stirring for a period of time. This solution was extracted with dichloromethane (25 ml × 3), and the organic phase was dried over magnesium sulfate. This was isolated and purified by silica gel column chromatography (developing solvent hexane: ether = 1: 2) to obtain 0.0091 g.

Example 26:
Add 0.04 g (0.04 mmol) of triethylamine in 1 ml of ethyl acetate to 0.1595 g (0.4731 mmol) of aminohydroxybutyric acid benzyl ester benzyl ether at room temperature, add 0.0160 g of 10% -palladium carbon, After reaction for 1 hour and 20 minutes, palladium-carbon was removed by suction filtration with a Buchner funnel, and triethylamine salt was converted to free carboxylic acid with 50 ml of 1N potassium hydrogen sulfate. This solution was extracted with ethyl acetate (50 ml × 3) and then filtered through silica gel to obtain 0.0334 g in a yield of 28%.

Example 27: Cyclic (S) -2-((S) -2-((S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) -4- (tert-butoxycarbonylamino Synthesis of butanoyl

  To a 450 ml dichloromethane solution of 32c0.2187 g (0.5022 g) at room temperature under a nitrogen atmosphere, a 2.5 ml dichloromethane solution of 0.1595 g (1.234 mmol) of diisopropylethylamine was added, and another 0.0147 g (0.120 mmol) of 4-dimethylaminopyridine was added. ml dichloromethane solution was added. To this solution, a 45 ml dichloromethane solution of 0.1970 g (0.8077 mmol) of 2,4,6-trichlorobenzoyl chloride was added dropwise over 15 hours, and the mixture was further stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, filtered through silica gel, isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 2), and cyclic (S) -2-((S)- 2-((S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) -4- (tert-butoxycarbonylamino) butanoyl (35c) was obtained in 0.1904 g, 90.8% yield. It was.

Cyclic (S) -2-((S) -2-((S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) -4- (tert-butoxycarbonylamino) butanoyl (35c) )
[α] ^16.7 _D = -84.3 ° (c = 1.1, CHCl ₃ )
IR (cm ^-1 ): 3423 (NH), 1755 (C = O), 1705 (C = O) (NaCl)
¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm) = 1.39 (9H, s), 1.47-1.58 (9H, m), 1.97-2.24 (2H, m), 3.10-3.35 (2H, m), 4.91 (1H, bs), 5.08-5.26 (4H, m)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 14.1, 16.6, 16.7, 16.8, 20.5, 24.5, 27.9, 28.4, 31.0, 31.2, 36.3, 42.0, 66.7, 69.0, 69.1, 69.2, 69.3, 69.4 , 70.5, 70.7, 71.5, 76.9, 77.1, 77.4, 79.4, 83.8, 155.8, 168.4, 168.5, 168.7, 168.9, 169.2, 169.3, 169.7

Example 28: Cyclic (S) -2-((S) -2-((S) -2-((S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) propanoyloxy) Synthesis of 4- (tert-butoxycarbonylamino) butanoyl

  To a 450 ml dichloromethane solution of 32e0.2920 g (0.5040 g) at room temperature under a nitrogen atmosphere, add a 2.5 ml dichloromethane solution of 0.1557 g (1.205 mmol) of diisopropylethylamine, and further add 0.0128 g (0.105 mmol) of 4-dimethylaminopyridine to 2.5 ml. ml dichloromethane solution was added. To this solution was added dropwise a solution of 0.1887 g (0.7737 mmol) of 2,4,6-trichlorobenzoyl chloride in 45 ml of dichloromethane over 15 hours, and the mixture was further stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, filtered through silica gel, isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 2), and cyclic (S) -2-((S)- 2-((S) -2-((S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) propanoyloxy) -4- (tert-butoxycarbonylamino) butanoyl (35e) 0.2475 g, 87.5% yield.

  Cyclic (S) -2-((S) -2-((S) -2-((S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) propanoyloxy) -4- ( tert-Butoxycarbonylamino) butanoyl (35e)

[α] ^16.8 _D = -115.0 ° (c = 1.0, CHCl ₃ )
IR (cm ^-1 ): 3423 (NH), 1761 (C = O), 1716 (C = O) (KBr)
¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm) = 1.34 (9H, s), 1.45-1.53 (9H, m), 1.94-2.20 (2H, m), 3.10-3.30 (2H, m), 4.89 (1H, bs), 5.05-5.17 (6H, m)
¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm) = 12.2, 14.7, 19.1, 22.5, 26.4, 28.9, 29.0, 34.3, 58.4, 67.1, 67.1, 67.2, 67.3, 68.5, 77.2, 153.8, 166.4, 166.6 , 166.7, 167.2, 167.2, 167.3, 167.3, 167.4, 167.5, 167.6, 167.7, 169.1, 173.0

Claims (8)

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

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

(In the formula, R ¹¹ and R ¹² each independently represent an amino protecting group or a hydrogen atom, R ² represents a hydrogen atom or a hydroxyl protecting group, and R ³ represents a hydrogen atom or a carboxyl protecting group. ) A compound represented by formula (3) or a salt thereof.

(Wherein R ¹ represents an amino-protecting group or a hydrogen atom, R ² represents a hydrogen atom or a hydroxyl-protecting group, and R ³ represents a hydrogen atom or a carboxyl-protecting group) A compound represented by formula (4) or a salt thereof.

(Wherein R ¹ represents an amino-protecting group or a hydrogen atom) The manufacturing method of the compound represented by Formula (4) of Claim 4 including using for the cyclization reaction by intramolecular dehydration condensation the compound represented by Formula (3) of Claim 3. A compound represented by formula (5) or a salt thereof.

(In the formula, R ¹ represents an amino protecting group or a hydrogen atom, R ² represents a hydrogen atom or a hydroxyl protecting group, R ³ represents a hydrogen atom or a carboxyl protecting group, and n represents 1 to 4) Indicates an integer) A compound represented by formula (6) or a salt thereof.

(Wherein R ¹ represents an amino-protecting group or a hydrogen atom. N represents an integer of 1 to 4) The manufacturing method of the compound represented by Formula (6) of Claim 7 including using for the cyclization reaction by intramolecular dehydration condensation the compound represented by Formula (5) of Claim 6.