WO2005077882A1 - Oligolactate having substituent in side chain - Google Patents

Oligolactate having substituent in side chain Download PDF

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Publication number
WO2005077882A1
WO2005077882A1 PCT/JP2005/003084 JP2005003084W WO2005077882A1 WO 2005077882 A1 WO2005077882 A1 WO 2005077882A1 JP 2005003084 W JP2005003084 W JP 2005003084W WO 2005077882 A1 WO2005077882 A1 WO 2005077882A1
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Prior art keywords
group
formula
protecting group
hydrogen atom
compound represented
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PCT/JP2005/003084
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French (fr)
Japanese (ja)
Inventor
Mikio Watanabe
Masahiro Murakami
Jiro Takano
Kenta Yagi
Junpei Takahashi
Masahiro Yoshidome
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Tokai Education Instruments Co., Ltd.
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Priority claimed from JP2004041334A external-priority patent/JP4445770B2/en
Priority claimed from JP2004041332A external-priority patent/JP4560304B2/en
Priority claimed from JP2004041333A external-priority patent/JP4445769B2/en
Application filed by Tokai Education Instruments Co., Ltd. filed Critical Tokai Education Instruments Co., Ltd.
Publication of WO2005077882A1 publication Critical patent/WO2005077882A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings

Definitions

  • the present invention relates to an oligolactic acid ester having an aminoethyl group, a hydroxylethyl group or a carboxylmethyl group in a side chain, and a method for producing the same. More specifically, the present invention relates to a linear or cyclic oligoester ester having an aminoethyl group, a hydroxylethyl group or a carboxymethyl group in a side chain, and a method for producing the same.
  • Background art
  • a cyclic and / or linear poly-L-lactic acid mixture having a degree of condensation of 3 to 19 can be used as an antineoplastic agent (Japanese Patent Application Laid-open No. Hei 9-222 7388 and Japanese Patent Laid-open No. Hei 10-13001). It is reported that it is useful as a QOL improving agent for cancer patients (Japanese Patent Application Laid-Open No. 2000-239171).
  • a cyclic and / or chain polylactic acid mixture having a condensation degree of 3 to 19 has a hypoglycemic effect and is useful as a medicament for preventing and / or treating diabetes or diabetic complications. It is known (International Publication iwo 0 1/0 1 0 4 5 1).
  • the above-mentioned polylactic acid mixture is useful for suppressing excessive appetite, promoting basal metabolism, and improving and / or preventing obesity. Further, it has been demonstrated that the above-mentioned polylactic acid mixture exhibits various physiological activities such as immunostimulation, protection against microbial infection, antiallergy, antistress, and reduction of side effects of anticancer drugs.
  • oligolactic acid mixtures having a degree of condensation 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.
  • a derivative having a substituent on the side chain of the lactic acid unit is synthesized, and its biological activity is evaluated to identify an oligolactic acid having higher biological activity. It is desirable to go.
  • aminoethyl groups, hydroxylethyl groups, or amino acids There are no reports on the synthesis of compounds having a ropoxylmethyl group. Disclosure of the invention
  • the present inventors have conducted intensive studies in order to solve the above problems, and as a result, first synthesized a linear oligolactic acid ester having an aminoethyl group, a hydroxylethyl group, or a carboxymethyl group in a side chain, and then synthesized this into a molecule. By subjecting it to a cyclization reaction by internal dehydration condensation, we succeeded in synthesizing a cyclic oligolactic acid ester having an aminoethyl group in the side chain. The present invention has been completed based on this finding.
  • one CH ⁇ CHs- NHR 1 -CH 2 CH 2 -OR ⁇ or one CH 2 - shows a COOR 1, wherein, R 1 is a protecting group of the Amino group, hydroxyl protecting group, or R 2 represents a protecting group for a hydrogen atom or a hydroxyl group; R 3 represents a protecting group for a hydrogen atom or a carboxyl group; wherein R 1 and R 3 are the same as each other; May be different from each other, and preferably different from each other.
  • A represents a methyl group, one C ⁇ CHs—NHR 1 -CH 2 CH 2 —OR or one CH 2 —COOR 1 , and all A are not methyl groups.
  • one all the above or the plurality of a other than a methyl group CH 2 CH 2 - NHR 1 _CH 2 CH 2 - oR 1, or _CH 2 - shows the same type of substituents selected from COOR 1, where R 1 represents an amino group-protecting group, a hydroxyl group-protecting group or a hydroxyl group-protecting group; a plurality of R 1 may be the same or different;
  • R 2 represents a hydrogen atom or a hydroxyl group;
  • R 3 represents a hydrogen atom or a carboxyl-protecting group;
  • m represents an integer of 1 to 5
  • A represents a methyl group, one CHsCHs—NHR 1 -CH 2 CH 2 -OR ⁇ or _CH 2 —COOR 1 , except when all A are methyl groups, and Multiple A's other than the group all represent the same kind of substituents selected from —CH 2 CH 2 —NHR 1 —CH 2 CH 2 —OR 1 , or one CH 2 —CO OR 1 , where R 1 represents an amino-protecting group, a hydroxyl-protecting group or a carboxyl-protecting group; a plurality of R 1 s may be the same or different; n is an integer of 1 to 5)
  • a compound represented by the formula (1) or a salt thereof According to a first aspect of the present invention, there is provided a compound represented by the formula (1) or a salt thereof.
  • R 1 represents a protecting group for an amino group
  • R 2 represents a protecting group for a hydrogen atom or a hydroxyl group
  • R 3 represents a protecting group for a hydrogen atom or a carboxyl group
  • R 11 and R 12 each independently represent a protecting group for an amino group or a hydrogen atom
  • R 2 represents a protecting group for a hydrogen atom or a hydroxyl group
  • R 3 represents a protecting group for a hydrogen atom or a carboxyl group.
  • R 1 represents a protecting group for an amino group or a hydrogen atom
  • R 2 represents a protecting group for a hydrogen atom or a hydroxyl group
  • R 3 represents a protecting group for a hydrogen atom or a carboxyl group.
  • R 1 represents a protecting group for an amino group or a hydrogen atom
  • a method for producing a compound represented by the above formula (4) which comprises subjecting a compound represented by the above formula (3) to a cyclization reaction by intramolecular dehydration condensation. A method is provided.
  • R 1 represents a protecting group for an amino group or a hydrogen atom
  • R 2 represents a hydrogen atom or a protecting group for a hydroxyl group
  • R 3 represents a hydrogen atom or a protecting group for a carboxyl group
  • n represents 1-4. Indicates an integer
  • a compound represented by the above formula (5) is A method for producing a compound represented by the above formula (6) is provided, which includes subjecting the compound to a cyclization reaction by intramolecular dehydration condensation.
  • R 1 represents a protecting group for a hydroxyl group
  • R 2 represents a protecting group for a hydrogen atom or a hydroxyl group
  • R 3 represents a protecting group for a carboxyl group
  • XI and X 2 represent a methyl group or a hydroxyethyl group which may be protected (except when XI and X 2 are simultaneously a methyl group), and R 2 is a hydrogen atom or R 3 represents a protecting group for a hydrogen atom or a carboxyl group.
  • X 1 and X 2 represent a methyl group or an optionally protected hydroxyethyl group, and n Xs each independently represent a methyl group or an optionally protected hydroxyethyl group.
  • R 2 represents a hydrogen atom or a hydroxyl-protecting group, and R 3 represents a hydrogen atom or carboxyl. Represents a protecting group of the group, and n represents an integer of 1 to 4)
  • R 1 represents a hydrogen atom or a protecting group for a hydroxyl group
  • n Xs each independently represent a methyl group or an optionally protected hydroxyethyl group
  • n represents an integer of 1 to 5.
  • the compound represented by the above formula (4) comprises subjecting the compound represented by the formula (2) or the compound represented by the formula (3) to a cyclization reaction by intramolecular dehydration condensation. ) Is provided.
  • a compound represented by the formula (1) or a salt thereof R1 ooc.
  • R 1 represents a protecting group for a carbonyl group
  • R 2 represents a protecting group for a hydrogen atom or a hydroxyl group
  • R 3 represents a protecting group for a carboxyl group.
  • R 1 and R 3 are different from each other. Indicates a group
  • R 1 represents a carboxyl protecting group or a hydrogen atom
  • R 2 represents a hydrogen atom or a hydroxyl protecting group
  • R 3 represents a carboxyl protecting group or a hydrogen atom.
  • R 1 represents a protecting group for a lipoxyl group or a hydrogen atom
  • R 2 represents a hydrogen atom or a protecting group for a hydroxyl group
  • R 3 represents a protecting group for a lipoxyl group or a hydrogen atom.
  • R 1 represents a carboxyl protecting group or a hydrogen atom, and n represents an integer of 1 to 5.
  • n 1 or 2.
  • the compound represented by the above formula (2) or (3) is subjected to a cyclization reaction by intramolecular dehydration condensation. Is provided, wherein the compound is 1 or 2.
  • the present invention relates to a compound represented by the formula (1) from the formula (1) having an aminoethyl group or a salt thereof, and a compound represented by the formula (3) or the formula (5) having an aminoethyl group.
  • the present invention relates to a method for producing a compound represented by the formula (4) or the formula (6) having an aminoethyl group by cyclizing a compound in a molecule.
  • RR 11 ⁇ Pi R 12 represents a protecting group or a hydrogen atom ⁇ amino group
  • R 2 represents a hydrogen atom or a protecting group of a hydroxyl group
  • R 3 is Shows a protecting group for a hydrogen atom or a carboxyl group.
  • Type of the protective group Amino group represented by R ⁇ R 11 and R 12 is not particularly limited and can be appropriately selected by those skilled in the art.
  • Specific examples of a protecting group for an amino group include a substituted or unsubstituted alkyloxyl carbonyl group (for example, an alkylsilyl group, a substituted or unsubstituted aryl group, a halogen atom, a substituted or unsubstituted group).
  • Carbamate-type amino-protecting groups such as substituted or unsubstituted aryloxycarbonyl groups, substituted or unsubstituted heterocyclic oxycarbonyl groups, substituted or unsubstituted alkyldithiocarbonyl groups, and amide-type amino protection And N-alkyl-type amino protecting groups.
  • substituted or unsubstituted alkyloxycarbonyl group include, for example, methyloxycanoleponinole, ethyloxycanoleponinole, isobutyloxycanoleponyl, t-butylo Xycarbonyl group, t-amyloxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group, 2-trimethylsilylethyloxycarbonyl group, phenylethyloxycarbonyl group, 1 _ (1 -adamantyl) — 1-methylethyloxalicarponyl group, 1,1-dimethyl _2 -haloethyloxycanoleponinole group, 1,1 -dimethinole 2,2 -dibromoethynoleoxycanoleponyl group, 1 , 1-Dimethinole _ 2,2,2-Trichloroethynoleoxycanolepodin
  • substituted or unsubstituted alkenyloxycarbonyl group examples include a vinyloxycarbonyl group, an aryloxycarbonyl group, a 1-isopropylaryloxycarbonyl group, a cinnaminoleoxycarbonyl group, —Nitrocinaminoloxycarbonyl group and the like.
  • substituted or unsubstituted heterocyclic oxycarbonyl group examples include an 8-quinolyloxycarbonyl group, an N-piperidinyloxycarbonyl group, and the like.
  • substituted or unsubstituted aryloxycarbonyl group examples include, for example, a phenyl / reoxycanolepodinole group and an m-2-trophenyloxycanolepodinole group.
  • amide-type amino protecting group examples include, for example, a formyl group, an acetyl group, a chloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, a phenyl acetyl group, and a benzoyl group.
  • N-alkyl type amino protecting groups include benzyl group, N-di (4-methoxyphenyl) methyl group, N-5-dibenzosuberyl group, N-triphenylmethyl group, (4-methoxyphenyl) diphenylmethyl Group, N—9_phenylphenyl Examples include a enyl group, an aryl 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.
  • Methyl methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy ) Methyl group, 2- (trimethinolesilyl) ethoxymethyl group, tetrahydroxypyrael group, 3-bromotetrahydroviranyl group, tetrahydrothiopyrael group, 4-methoxytetrahydropyranyl group, 4-methoxytetrahydropyranopyl-, 4-methoxy Tetrahydrothioviranyl S, S-dioxide group, tetrahydrofuranyl group, tetrahydrothiofuranlaninole group;
  • 1-Ethoxyshetyl group 1-Methyl_1-methoxethyl group, 1- (Isopropoxy) ethyl group, 2,2,2-Trichloromethylethyl group, 2- (phenylselenyl) ethynole group, t-Ptinole group, Phenyl group, cinnaminole group, p-chloropheninole group, benzyl, 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, ⁇ _naphthyldiphenylmethyl group, ⁇ -methoxyphenyldiphenylmethyl group, ⁇ — ( ⁇ , Bromophenacyloxy)
  • N-phenylcarbamate, N-imidazolylcarbamate, porate, nitrate, N, N, N ,, N'-tetramethylphosphorodiamidate, 2,4-dinitrophenenoresnorolenate The type 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 carboxyl-protecting group include, for example, CM alkynole groups such as methinole, ethynole, n-propynole, isopropynole, n-, iso-, sec-, tert-butynole, and n-hexynole groups.
  • CM alkynole groups such as methinole, ethynole, n-propynole, isopropynole, n-, iso-, sec-, tert-butynole, and n-hex
  • C-alkyl group substituted with 1 to 3 halogens such as bromo-butynole and trichloromethyl (eg, chlorine, bromine, fluorine, iodine, etc.), benzyl, p-nitrobenzyl, o-nitrobenzyl, p- Nitro, Cw alkoxy group (eg, methoxy, ethoxy, etc.) or Cw alkyl group (eg, methyl, ethynole, n- or iso-propynole, n—, iso— , which may be 1 or 2 substituted by sec- or tert- butyl, etc.), etc.
  • halogens such as bromo-butynole and trichloromethyl (eg, chlorine, bromine, fluorine, iodine, etc.), benzyl, p-nitrobenzyl, o-nitrobenzyl, p- Nitro, Cw alkoxy group (eg
  • C 7 _ 14 Ararukiru group, Asetokishi Mechinore, propylene old Nino les oxymethyl, n —, iso-, butyrinoleoxymethinole, valeryloxymethyl, bivaloyloxymethyl, 1 (or 2—) acetoxyethyl, 1 (or 2— or 3—) acetoxypropyl, 1 _ (Or 2— or 3— or 4—) acetoxyptyl, 1 _ (or 2—) propionyloxyxethyl, 1— (or 2 _ or 3—) propionyloxypropyl, 1 (or 2 _) butyryloxy Shetyl, 1 (or 2—) isobutyryloxyethyl, 1— (or 2—) vivaloyloxityl, 1 (or 2—) hexanoyloxyxetil, isobutylyloxy methyl, 2-E chill Petit Lil O carboxymethyl, 3, 3-d
  • CH Arukiru groups such, for example, CH-alkanesulfonyl-CH alkyl groups such as 2-mesylethyl group, for example, methoxycanoleponinoleoxymethinole, ethoxycarboninoleoxymethinole, propoxycanoleponyloxymethyl, tert-butoxycarponyloxymethyl, 1 _ (Or 2—) methoxycarponyloxyshetyl, 1— (or 2—) ethoxycarponyloxyshetyl, Cw alkoxycarponyloxy, such as 1-1 (or 2—) isopropoxycarbonyloxyshetyl _ d_ 4 alkyl group, t chromatography butyldimethylsilyl, tri C ⁇ 4 alkyl silyl groups such as trimethylsilyl, Ariru, C 2 _ 6 such as meta Ariru CH alkoxy-methyl groups
  • 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 on the side chain of the lactic acid dimer, and the compound represented by the formula (3) is It is a compound having one aminoethyl group which may be protected on the side chain of lactic acid dimer.
  • 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 a 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, -dicyclohexylcarpoimide and 4-dimethylaminopyridine. By subjecting it to
  • the compound represented by the formula (5) of the present invention is a compound having one aminoethyl group which may be protected on the side chain of trimer to hexamer of lactic acid.
  • the compound represented by the formula (6) is a cyclized product of a dimer to a hexamer of diacid, and is a compound having one aminoethyl group which may be protected in a side chain.
  • the compound represented by the formula (6) is prepared by converting the compound represented by the formula (5) in the presence of diisopropylethylamine, 4-dimethylaminoviridine, and 2,4,6-trichloromethylbenzoyl chloride.
  • the compound can be synthesized by subjecting it to a cyclization reaction by dehydration condensation.
  • benzyl ether lactate (3) and ratatoyl lactate bromophenacyl ester (2) are condensed using DCC and DMAP, and the resulting 4 is treated with zinc and acetic acid to remove the hydroxyl group.
  • lactic acid trimer benzyl ether (5) was synthesized. Then, zinc and acetic acid are allowed to act on 6 obtained by condensation with ratatoyl bromophenacyl lactate (2) to deprotect the carboxyl group, and pentamer lactic acid benzyl ether (7) is obtained.
  • di-butyl dicarbonate acts on (s)-(-)-4-amino-2-hydroxybutyric acid (8) to protect the amino group, and 2,4, -dibromoacetophenone is further converted. Getting worked 10 Can do.
  • the obtained (5) and (7) are condensed with the (s)-(-)-4-amino-2-hydroxybutyric acid derivative (10), and the corresponding hydroxyl group is replaced with a benzyl group and the carboxyl group is replaced with a promofunacyl group.
  • a chain oligoester (lla), (lib) having a protected aminoethyl group is obtained.
  • zinc and acetic acid are allowed to act on the resulting product to deprotect the carboxyl group, and chain oligoesters (13a), (13b) having free aminoethyl groups in both the hydroxyl group and the hydroxyl group by catalytic reduction. Is obtained. .
  • esters can be synthesized.
  • (Method B) Enterobactin (1) which is known as an antibiotic, has a cyclic ester structure with three side chains, and is also known as a molecular recognition compound, such as capturing iron ions in the side chains. .
  • the object is to synthesize a compound having a structure as shown in the following 2.
  • bromophenacylester synthesis of 3 was studied using derivative (3), in which the amino group, which is the basic unit for synthesizing 2, was protected with a t-butoxycarbonyl group as a starting material. That is, 3 is reacted with promorphinyl bromide in the presence of triethylamine to obtain 4.
  • This method is a method for synthesizing a cyclic oligoester composed of two types of -hydroxy acids. First, as the unit for synthesizing the ester, the hydroxyl group of lactic acid (1)
  • a condensation reaction of the previously synthesized 3 and 6 can be carried out to obtain a compound (7) in which two kinds of -hydroxy acids are bonded.
  • Cyclic polylactic acid can be synthesized by cyclizing compound 9 by an intramolecular condensation reaction.
  • the present invention provides a compound represented by the formulas (1) to (4) having a hydroxylethyl group or a salt thereof, and a compound represented by the formula (2) or the formula (3) having a hydroxylethyl group.
  • the present invention relates to a method for producing a compound represented by the formula (4) by cyclizing a compound in a molecule.
  • R 1 represents a protecting group for a hydroxyl group
  • R ′ 2 represents a protecting group for a hydrogen atom or a hydroxyl group
  • R 3 represents a protecting group for a carboxyl group.
  • the hydroxyl-protecting group represented by protecting groups and R 2 of the hydroxyl groups represented by R 1 are different groups.
  • XI and X2 represent a methyl group or a hydroxyethyl group which may be protected (however, when XI and X2 are simultaneously a methyl group, R 2 represents a hydrogen atom or a protecting group for a hydroxyl group, and R 3 represents a hydrogen atom or a protecting group for a hydroxyl group.
  • the protecting group for the hydroxyethyl group and the protecting group for the hydroxyl group represented by R 2 are different groups.
  • XI and X2 represent a methyl group or a hydroxyethyl group which may be protected, and n Xs each independently represent a methyl group or a protected ethyl group.
  • R 2 represents a hydrogen atom or a hydroxyl-protecting group, provided that XI, X 2 and ⁇ n X all simultaneously form a methyl group; 3 represents a hydrogen atom or a carboxyl group-protecting group, and n represents an integer of 1 to 4.
  • the protecting group for each hydroxyethyl group and the protecting group for the hydroxyl group represented by R 2 are different groups.
  • R 1 represents a hydrogen atom or a hydroxyl-protecting group
  • n Xs each independently represent a methyl group or an optionally protected hydroxyxethyl group; Represents an integer of 1 to 5.
  • each independently means that n Xs may be the same or different groups, and are mutually independently selected groups.
  • the types of the protecting group for the hydroxyl group and the protecting group for the hydroxyethyl group represented by R 1 or R 2 are not particularly limited, and can be appropriately selected by those skilled in the art. Specific examples of the above protecting group include those described herein above as the protecting group for a hydroxyl group. ⁇ '
  • the type 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 the carbonyl group include those described above in the present specification.
  • 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 on the side chain of the lactic acid dimer, and the compound represented by the formula (3) is It is a compound having at least one hydroxyethyl group which may be protected on the side chain of a monomer to a hexamer.
  • the compound represented by the formula (4) is a cyclized product of dimer to hexamer of lactic acid, and is a compound having at least one hydroxyethyl group which may be protected in a side chain.
  • the conjugate represented by the formula (4) can be synthesized by subjecting the compound represented by the formula (2) or (3) to a cyclization reaction by intramolecular dehydration condensation.
  • a cyclic lactic acid oligoester having a hydroxyxethyl group can be synthesized by condensing 2,4-dihydroxybutanoic acid (3) with a linear lactic acid oligomer (4) and then cyclizing.
  • L-malic acid (1) is reacted with porane tetrahydrofuran to obtain 2, and the resulting 2 is reacted with benzaldehyde to obtain a dioxolane derivative (3) in which the 2- and 4-hydroxyl groups have reacted.
  • benzaldehyde is reacted with benzaldehyde to obtain a dioxolane derivative (3) in which the 2- and 4-hydroxyl groups have reacted.
  • Chromium trioxide, pyridine, acetic anhydride, and ari-butanol are allowed to act on 3 to give 4, and then triethylsilane and trifluoroacetic acid are allowed to act to give 5.
  • L-Lactic acid (6) is reacted with er-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 is reacted with oxalyl chloride to form an acid chloride (8 ), And then a condensation reaction with 5 gives the corresponding 9.
  • TBDMSCl er-butyldimethylsilane chloride
  • the present invention provides a compound represented by the formula (1) to the formula (4) having a carboxylmethyl group or a salt thereof, and a compound represented by the formula (2) or the formula (3) having a propyloxylmethyl group.
  • the present invention relates to a method for producing a compound represented by the formula (4) by cyclizing a compound in a molecule.
  • R 1 represents a carboxyl group-protecting group or a hydrogen atom
  • R 2 represents a hydrogen atom or a hydroxyl-protecting group
  • R 3 represents a carboxyl group. Represents a protecting group or a hydrogen atom.
  • 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 those described herein above.
  • the type of the carboxyl-protecting group represented by R 1 and R 3 is not particularly limited, and can be appropriately selected by those skilled in the art. Specific examples of the carboxyl-protecting group include those described above in this specification.
  • the compound represented by the formula (1) is a compound having a carboxylmethyl group protected on the side chain of lactic acid.
  • the compound represented by the formula (2) is a compound having an olepoxylmethyl group which may be protected in the side chain of the lactic acid dimer, and the compound represented by the formula (3) is It is a compound having an optionally protected lipoxylmethyl group in the side chain of the monomer.
  • the compound represented by the formula (4) is a cyclized product of dimer to hexamer of lactic acid, and is a compound having a carboxylmethyl group which may be protected in a side chain.
  • the compound represented by the formula (4) may be, for example, a linear lactic acid oligomer having a carboxylmethyl group protected on the side chain such as the compound of the formula (2) or the formula (3) is 2, 4, 6
  • the compound can be synthesized by subjecting it to a cyclization reaction by intramolecular dehydration condensation in the presence of -trichlorobenzoyl chloride.
  • the specific synthetic route of the compound of the present invention described above will be described with reference to the examples described in the present specification as examples. First, different protecting groups are introduced into the two carboxyl groups of malic acid.
  • ⁇ -hydroxy acid esters having different chain lengths can be obtained by another synthetic route using 2.
  • a lactic acid oligomer having a lipoxylmethyl group protected in the side chain such as Compound 6
  • a cyclic lactic acid oligomer having a carboxylmethyl group in the side chain can be synthesized.
  • the compound having an aminoethyl group, a hydroxyethyl group or a carboxylmethyl group of the present invention can sometimes exist as a salt.
  • a metal salt include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a magnesium salt and a potassium salt, an aluminum salt, and a zinc salt.
  • alkali metal salt such as a sodium salt and a potassium salt
  • an alkaline earth metal salt such as a magnesium salt and a potassium salt
  • an aluminum salt such as aluminum salt
  • zinc salt such as sodium salt and a magnesium salt
  • various hydrates, solvates and polymorphs of the compound of the present invention are also within the scope of the present invention.
  • the compound having an aminoethyl group, a hydroxyethyl group or a hepoxylmethyl group of the present invention has stereoisomers because of containing an asymmetric carbon, but all possible isomers and two or more kinds of the isomers are present. Mixtures containing the bodies in any proportion are also within the scope of the present invention. That is, the compound of the present invention includes a mixture of various optical isomers such as an optically active substance, a racemate, and a diastereomer, and an isolated form thereof.
  • the configuration of the compound of the present invention having an aminoethyl group, a hydroxylethyl group or a propyloxylmethyl group depends on the configuration of a 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 the L-form, the 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, it is preferable to use the L-form as the configuration of the lactic acid unit.
  • reaction mixture was filtered through a Buchner funnel using a ceramic, concentrated, filtered through silica gel, and concentrated to obtain 1.1577 g of lactic acid tetramer benzyl ether in a yield of 96.3%. .
  • N, N'-dicyclohexylurea was removed by suction filtration using a Buchner funnel, extracted with dichloromethane (20 ml ⁇ 3), washed with saturated saline, 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 pentamer lactic acid benzyl ether bromophenacyl ester in a yield of 74.2%.
  • Example A-9 In a 200-ml three-necked round-bottomed flask cooled in an ice bath under a nitrogen atmosphere, a solution of 2.2422 g (10.2 mol) of l-OlTHF in N-1-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid was added. It was added, dropwise lmlTHF solution Toryechiruamin 1.03 5 lg (10.2mmol).
  • N-1-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid phenic acid was added to a solution of 0.1824 g (l. Olmmol) of benzyl lactate in 1.2 ml of dichloromethane at room temperature.
  • a solution of 1.451 g (2.98 mmol) of noreste in 5.2 ml of dichloromethane was added, and further a solution of 0.0122 g (0.1 mmol) of 4-dimethylaminopyridine in 0.4 ml of methane was added.
  • N-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid was added to a solution of 2.7311 g (15.lmmol) of benzyl ether lactate in 5 ml of dichloromethane.
  • a solution of 19.2312 g (4.2 mol) of fenacinoleestenole in 110 ml of dichloromethane was added, and a solution of 0.0122 g (0.10 marl) of 4-dimethylaminopyridine in 1 ml of dichloromethane was added.
  • N-butoxycarbonyl- (s)-(-)-4-Tamino 2-H was added to a solution of 0.3165 g (0.976 marl ol) of lactic acid trimer benzyl ether in 3.5 ml of dichloromethane.
  • a solution of 1.2404 g (2.98 benzyl) of droxybutanoic acid bromophenacyl ester in 13 ml of dichloromethane was added, and a solution of 0.0137 g (0.112 mmol) of 4-dimethylaminopyridine in 1 ml of dichloromethane was further added.
  • Example A-18 At room temperature under a nitrogen atmosphere, N-1-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid was added to a 1.9288 g (4.12 mmol) of lactic acid pentamer benzyl ether in 14 ml of dichloromethane at room temperature. A solution of 12.4974 g (30.02 marl) of bromophenacyl ester in 80 ml of dichloromethane was added, and further a solution of 0.0164 g (0.13 mmol) of 4-dimethylaminopyridine in 1 ml of dichloromethane was added.
  • the reaction was quenched with 20 ml of a saturated aqueous sodium chloride solution and extracted with hexane (50 ml ⁇ 3). The organic phase was concentrated, and this was used as a 10 mL THF solution. Next, a 10 ml aqueous solution of lithium carbonate (lg) was added at room temperature, stirred for 45 minutes, and washed with hexane. This solution was adjusted to pH 3 with 1N aqueous hydrogen sulfate aqueous solution, extracted with ethyl acetate (50 ml X 3), dried over magnesium sulfate, and filtered.
  • Nt-butoxycarponyl- (S)-(-)-4- 4-amino-2-hydroxybutyric acid-p-bromophenacyl ester in dichloromethane solution 1.2519 g (3 mmol) of 15 ml dichloromethane solution, N-N, -dicyclohexane
  • a solution of 0.2830 g of xylcarposimide in 5 ml of dichloromethane and a solution of 0.0184 g of 4-dimethylaminopyridine in 5 ml of dichloromethane were added, and the mixture was stirred for 15 minutes, returned to room temperature, and further stirred for 5 hours.
  • reaction mixture was concentrated in vacuo, filtered through a silica gel (hexane 1 to developing solvent acetic Echiru: 2) silica gel column chromatography performed isolated and purified have use a cyclic (S) one 2 one ((S) one 2 ((S) - 2 one ((S) one 2 one O carboxymethyl prop Neu Loki Shi) Puropanoirokishi) Puropanoirokishi) - 4 - (eri - butoxide deer Lupo sulfonyl amino) Butanoiru the (35c) 0.1904g, 90.8% of the yield Rate obtained.
  • silica gel column chromatography performed isolated and purified have use a cyclic (S) one 2 one ((S) one 2 ((S) - 2 one ((S) one 2 one O carboxymethyl prop Neu Loki Shi) Puropanoirokishi) Puropanoirokishi) - 4 - (eri - butoxide deer Lupo sulfon
  • reaction mixture was concentrated under reduced pressure, filtered using silica gel, and then isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 2) to obtain cyclic (S) -2-((S )-2- ((S)-2- ((S)-2- ((S)-2-oxypropanoyloxy) propanoyloxy) propanoyloxy) propanoyloxy)-4- (ar 0.2475 g of (Toxicarponylamino) butanol (35e) was obtained in a yield of 87.5%.
  • Example B_ 7 Synthesis of (S) -benzyl-2-((S) -2-((S) -2- (benzyloxy) propanoyloxy) propanoyloxy) -4- (tert-butyldimethylsilyloxy) butanoate
  • Example B_ 9 Synthesis of (S) -4- (tert-butyldimethylsilyloxy) -2-((S) -2-((S) -2-hydroxypropanoyloxy) propanoyloxy) butanoic acid
  • a THF solution of the obtained product was added dropwise to a mixed solution of 0.220 g (3.92 mol) of potassium hydroxide and 4 ml of THF dissolved in 1.3 ml of water, and the mixture was 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 a universal pH test paper.
  • Example B-22 (S) -tert-htyl 4- (benzyloxy) -2-((S) -2- (tert-butyldimethylsilyloxy) propanoyloxy) butanoate
  • the obtained crude product was dissolved in dichloromethane (3 ml), the system was brought to 0 ° C., 0.53 g (4.2 mmol) of oxalyl chloride was added, and then DMF droplets were added dropwise. After stirring at 0 ° C for 1 hour, the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain a crude acid chloride.
  • the obtained crude product was dissolved in 5 ml of getyl ether, and the temperature of the system was adjusted to 0 ° C. Then, 1.7 ml of pyridine and a 3 ml ether solution of 0.976 g (2.9 propyl) of (4) were sequentially added.
  • dichloromethane 3 ml
  • Example C-5 Synthesis of (S) -4- (benzyloxy) -2-((S) -2-hydroxypropanoy 1 oxy) -4-oxobutanoic acid
  • 0.157 g (0.382 mmol) of (7) was dissolved in 8 ml of acetonitrile, 8 drops of hydrofluoric acid was added, and the mixture was stirred for 1 hour.
  • the mixture was filtered with a glass filter, and the residue was sequentially washed with a saturated ammonium chloride solution, a saturated sodium hydrogen carbonate solution, and hexane to obtain a filtrate.
  • an oligolactic acid ester having an aminoethyl group, a hydroxylethyl group or a carboxylmethyl group in a side chain as a single compound.
  • the oligolactic acid ester having an aminoethyl group, a hydroxylethyl group or a propyloxylmethyl group in the side chain provided by the present invention is used as a pharmaceutical, a pharmaceutical raw material, a food additive, a cosmetic raw material, a pharmaceutical raw material, a pharmaceutical additive. It is useful as an object.
  • the oligolactic acid ester having an aminoethyl group in the side chain of the present invention enables the synthesis of a derivative having further enhanced functionality by secondary modification.
  • lipophilicity can be increased by acylation or alkylation, or water-soluble by polyethylene glycolation. Also, by immobilizing it on a carrier surface 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.
  • a carrier surface such as silica or polymer beads

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Abstract

A chain or cyclic oligolactate having an aminoethyl, hydroxyethyl, or carboxymethyl group in a side chain. A chain oligolactate having an aminoethyl, hydroxyethyl, or carboxymethyl group in a side chain is synthesized first. This chain oligolactate is subjected to cyclization by intramolecular dehydrating condensation. Thus, a cyclic oligolactate having the substituent, e.g., aminoethyl, in a side chain can be synthesized.

Description

明細書  Specification
側鎖に置換基を有するオリゴ乳酸エステル 技術分野  Oligolactic acid ester having a substituent on the side chain
本発明は、 側鎖にアミノエチル基、 ヒドロキシルェチル基又はカルボキシルメ チル基を有するオリゴ乳酸エステル並びにその製造方法に関する。 より詳細には、 本発明は、 側鎖にアミノエチル基、 ヒドロキシルェチル基又はカルポキシルメチ ル基を有する鎖状又は環状のオリゴ轧酸エステル、 並びにその製造方法に関する。 背景技術  The present invention relates to an oligolactic acid ester having an aminoethyl group, a hydroxylethyl group or a carboxylmethyl group in a side chain, and a method for producing the same. More specifically, the present invention relates to a linear or cyclic oligoester ester having an aminoethyl group, a hydroxylethyl group or a carboxymethyl group in a side chain, and a method for producing the same. Background art
縮合度 3〜1 9の環状及び 又は鎖状のポリ L一乳酸混合物は、 抗悪性腫瘍剤 として （特開平 9一 2 2 7 3 8 8号公報おょぴ特開平 1 0— 1 3 0 1 5 3号公 報）、 また癌患者の Q O L改善剤として （特開 2 0 0 0 - 2 3 9 1 7 1号公報） 有用であることが報告されている。 また、 縮合度 3〜1 9の環状及び 又は鎖状 のポリ乳酸混合物が、 血糖低下作用を有し、 糖尿病又は糖尿病の合併症の予防及 び/又は治療のための医薬として有用であることも判明している （国際公 iwo 0 1 / 0 1 0 4 5 1号公報）。 また、 上記のポリ乳酸混合物は、 過剰な食欲の抑 制、 基礎代謝増進並びに肥満の改善及び/又は予防、 のために有用であることも 判明している。 さらに、上記のポリ乳酸混合物は、免疫賦活、微生物感染の防御、 抗アレルギー、 抗ストレス、 及ぴ抗癌剤の副作用の軽減など多様な生理活性を示 すことが実証されている。  A cyclic and / or linear poly-L-lactic acid mixture having a degree of condensation of 3 to 19 can be used as an antineoplastic agent (Japanese Patent Application Laid-open No. Hei 9-222 7388 and Japanese Patent Laid-open No. Hei 10-13001). It is reported that it is useful as a QOL improving agent for cancer patients (Japanese Patent Application Laid-Open No. 2000-239171). In addition, a cyclic and / or chain polylactic acid mixture having a condensation degree of 3 to 19 has a hypoglycemic effect and is useful as a medicament for preventing and / or treating diabetes or diabetic complications. It is known (International Publication iwo 0 1/0 1 0 4 5 1). It has also been found that the above-mentioned polylactic acid mixture is useful for suppressing excessive appetite, promoting basal metabolism, and improving and / or preventing obesity. Further, it has been demonstrated that the above-mentioned polylactic acid mixture exhibits various physiological activities such as immunostimulation, protection against microbial infection, antiallergy, antistress, and reduction of side effects of anticancer drugs.
上記したように縮合度 3〜 1 9の環状及び/又は鎖状のオリゴ乳酸混合物は、 多種多様な薬効を示すことが実証されつつあり、 今後も医薬品として開発される ことが期待されている。 オリゴ乳酸を医薬品として開発していくためには、 乳酸 単位の側鎖に置換基を有する誘導体を合成し、 その生理活性を評価することによ り、 より高い生理活性を有するオリゴ乳酸を同定していくことが望ましい。 しか しながら、 オリゴ乳酸中の側鎖にアミノエチル基、 ヒドロキシルェチル基又は力 ルポキシルメチル基を有する化合物の合成についての報告はない。 発明の開示 As described above, cyclic and / or chain oligolactic acid mixtures having a degree of condensation 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 drug, a derivative having a substituent on the side chain of the lactic acid unit is synthesized, and its biological activity is evaluated to identify an oligolactic acid having higher biological activity. It is desirable to go. However, aminoethyl groups, hydroxylethyl groups, or amino acids There are no reports on the synthesis of compounds having a ropoxylmethyl group. Disclosure of the invention
本発明は、 側鎖にアミノエチル基、 ヒドロキシルェチル基又はカルボキシルメ チル基を有する鎖状又は環状のオリゴ乳酸エステルを合成することを解決すベ き課題とした。 本発明はまた、 当該化合物の製造方法を提供することを解決すベ き課題とした。  An object of the present invention is to solve the synthesis of a linear or cyclic oligolactic acid ester having an aminoethyl group, a hydroxylethyl group or a carboxylmethyl group in a side chain. Another object of the present invention is to provide a method for producing the compound.
本発明者らは上記課題を解決するために鋭意検討した結果、 側鎖にアミノエチ ル基、 ヒドロキシルェチル基又はカルボキシルメチル基を有する鎖状のオリゴ乳 酸エステルを先ず合成し、 次いでこれを分子内脱水縮合による環化反応に供する ことにより、 側鎖にアミノエチル基を有する環状のオリゴ乳酸エステルを合成す ることに成功した。 本発明はこの知見に基づいて完成したものである。  The present inventors have conducted intensive studies in order to solve the above problems, and as a result, first synthesized a linear oligolactic acid ester having an aminoethyl group, a hydroxylethyl group, or a carboxymethyl group in a side chain, and then synthesized this into a molecule. By subjecting it to a cyclization reaction by internal dehydration condensation, we succeeded in synthesizing a cyclic oligolactic acid ester having an aminoethyl group in the side chain. The present invention has been completed based on this finding.
即ち、本発明によれば、式（11)で表される化合物又はその塩が提供される。  That is, according to the present invention, there is provided a compound represented by the formula (11) or a salt thereof.
Figure imgf000003_0001
Figure imgf000003_0001
(式中、 Aは、 一 CH^CHs— NHR1 -CH2CH2-OR\ 又は一CH2— COOR1を示し、 ここで、 R1は、 ァミノ基の保護基、 水酸基の保護基又はカル ポキシル基の保護基を示し； R 2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） ここで、 R1と R3とは互いに同一で も異なっていてもよく、 好ましくは互いに異なっている方が望ましい。 (In the formula, A, one CH ^ CHs- NHR 1 -CH 2 CH 2 -OR \ or one CH 2 - shows a COOR 1, wherein, R 1 is a protecting group of the Amino group, hydroxyl protecting group, or R 2 represents a protecting group for a hydrogen atom or a hydroxyl group; R 3 represents a protecting group for a hydrogen atom or a carboxyl group; wherein R 1 and R 3 are the same as each other; May be different from each other, and preferably different from each other.
本発明によればさらに、式（12)で表される化合物又はその塩が提供される。 According to the present invention, there is further provided a compound represented by the formula (12) or a salt thereof.
Figure imgf000004_0001
Figure imgf000004_0001
(式中、 Aは、 メチル基、 一 C ^CHs— NHR1 -CH2CH2-OR 又 は一 CH2— COOR1を示し、 伹し、 全ての Aがメチル基となることはなく、 ま たメチル基以外の複数個の Aは全て上記した一 CH2CH2— NHR1 _CH2 CH2— OR1、又は _CH2— COOR1から選択される同一種類の置換基を示し、 ここで、 R1は、 ァミノ基の保護基、 水酸基の保護基又は力ルポキシル基の保護 基を示し、複数個の R1は同一でも異なっていてもよく ； R2は水素原子又は水酸 基の保護基を示し； R 3は水素原子又はカルボキシル基の保護基を示し； mは 1 〜 5の整数を示す） (In the formula, A represents a methyl group, one C ^ CHs—NHR 1 -CH 2 CH 2 —OR or one CH 2 —COOR 1 , and all A are not methyl groups. one all the above or the plurality of a other than a methyl group CH 2 CH 2 - NHR 1 _CH 2 CH 2 - oR 1, or _CH 2 - shows the same type of substituents selected from COOR 1, where R 1 represents an amino group-protecting group, a hydroxyl group-protecting group or a hydroxyl group-protecting group; a plurality of R 1 may be the same or different; R 2 represents a hydrogen atom or a hydroxyl group; R 3 represents a hydrogen atom or a carboxyl-protecting group; m represents an integer of 1 to 5)
本発明によればさらに、式（13)で表される化合物又はその塩が提供される。  According to the present invention, there is further provided a compound represented by the formula (13) or a salt thereof.
Figure imgf000004_0002
Figure imgf000004_0002
(式中、 Aは、 メチル基、 一 CHsCHs— NHR1 -CH2CH2-OR\ 又 は _CH2— COOR1を示し、 但し、 全ての Aがメチル基となる場合は除き、 ま たメチル基以外の複数個の Aは全て上記した— CH2CH2— NHR1 — CH2 CH2— OR1、又は一 CH2— CO OR1から選択される同一種類の置換基を示し、 ここで、 R1は、 ァミノ基の保護基、 水酸基の保護基又はカルボキシル基の保護 基を示し、 複数個の R1は同一でも異なっていてもよく ； nは 1〜5の整数を示 す） 本発明によれば、 さらに上記式 （1 2 ) で表される化合物を分子内脱水縮合に よる環化反応に供することを含む、 上記式 （1 3 ) で表される化合物の製造方法 が提供される。 (In the formula, A represents a methyl group, one CHsCHs—NHR 1 -CH 2 CH 2 -OR \ or _CH 2 —COOR 1 , except when all A are methyl groups, and Multiple A's other than the group all represent the same kind of substituents selected from —CH 2 CH 2 —NHR 1 —CH 2 CH 2 —OR 1 , or one CH 2 —CO OR 1 , where R 1 represents an amino-protecting group, a hydroxyl-protecting group or a carboxyl-protecting group; a plurality of R 1 s may be the same or different; n is an integer of 1 to 5) According to the present invention, there is provided a method for producing a compound represented by the above formula (13), further comprising subjecting the compound represented by the above formula (12) to a cyclization reaction by intramolecular dehydration condensation. Is done.
本努明によれば、 さらに以下の第一〜第三の態様が提供される。  According to this effort, the following first to third aspects are further provided.
本発明の第一の態様によれば、 式 （1 ) で表される化合物又はその塩が提供さ れる。
Figure imgf000005_0001
According to a first aspect of the present invention, there is provided a compound represented by the formula (1) or a salt thereof.
Figure imgf000005_0001
(式中、 R 1はァミノ基の保護基を示し、 R 2は水素原子又は水酸基の保護基を示 し、 R 3は水素原子又はカルボキシル基の保護基を示す） (Wherein, R 1 represents a protecting group for an amino group, R 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a hydrogen atom or a carboxyl group)
本発明の別の側面によれば、 式 （2 ) で表される化合物又はその塩が提供され る。  According to another aspect of the present invention, there is provided a compound represented by the formula (2) or a salt thereof.
Figure imgf000005_0002
Figure imgf000005_0002
(式中、 R 1 1及び R 1 2はそれぞれ独立にァミノ基の保護基又は水素原子を示し、 R 2は水素原子又は水酸基の保護基を示し、 R 3は水素原子又はカルボキシル基の 保護基を示す） (Wherein R 11 and R 12 each independently represent a protecting group for an amino group or a hydrogen atom, R 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a hydrogen atom or a carboxyl group. Indicates)
本発明のさらに別の側面によれば、 式 （3 ) で表される化合物又はその塩が提 供される。
Figure imgf000006_0001
According to still another aspect of the present invention, there is provided a compound represented by the formula (3) or a salt thereof.
Figure imgf000006_0001
(式中、 R1はァミノ基の保護基又は水素原子を示し、 R2は水素原子又は水酸基 の保護基を示し、 R 3は水素原子又はカルボキシル基の保護基を示す） (In the formula, R 1 represents a protecting group for an amino group or a hydrogen atom, R 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a hydrogen atom or a carboxyl group.)
本発明のさらに別の側面によれば、 式 （4) で表される化合物又はその塩が提 供される。
Figure imgf000006_0002
According to still another aspect of the present invention, there is provided a compound represented by the formula (4) or a salt thereof.
Figure imgf000006_0002
(式中、 R1はァミノ基の保護基又は水素原子を示す） (Wherein, R 1 represents a protecting group for an amino group or a hydrogen atom)
本発明のさらに別の側面によれば、 上記式 （3) で表される化合物を分子内脱 水縮合による環化反応に供することを含む、 上記式 （4) で表される化合物の製 造方法が提供される。  According to still another aspect of the present invention, there is provided a method for producing a compound represented by the above formula (4), which comprises subjecting a compound represented by the above formula (3) to a cyclization reaction by intramolecular dehydration condensation. A method is provided.
本発明のさらに別の側面によれば、 式 （5) で表される化合物又はその塩が提 供される。  According to still another aspect of the present invention, there is provided a compound represented by the formula (5) or a salt thereof.
Figure imgf000006_0003
Figure imgf000006_0003
(式中、 R1はァミノ基の保護基又は水素原子を示し、 R2は水素原子又は水酸基 の保護基を示し、 R 3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） 本発明のさらに別の側面によれば、 式.（6) で表される化合物又はその塩.が ¾ 供される。 (Wherein, R 1 represents a protecting group for an amino group or a hydrogen atom, R 2 represents a hydrogen atom or a protecting group for a hydroxyl group, R 3 represents a hydrogen atom or a protecting group for a carboxyl group, and n represents 1-4. Indicates an integer) According to still another aspect of the present invention, there is provided a compound represented by the formula (6) or a salt thereof.
Figure imgf000007_0001
Figure imgf000007_0001
(式中、 R1はァミノ基の保護基又は水素原子を示す。 nは 1〜4の整数を示す） 本発明のさらに別の側面によれば、 上記式 （5) で表される化合物を分子内脱 水縮合による環化反応に供することを含む、 上記式 （6) で表される化合物の製 造方法が提供される。 (Wherein, R 1 represents a protecting group for an amino group or a hydrogen atom. N represents an integer of 1 to 4.) According to still another aspect of the present invention, a compound represented by the above formula (5) is A method for producing a compound represented by the above formula (6) is provided, which includes subjecting the compound to a cyclization reaction by intramolecular dehydration condensation.
本発明の第二の態様によれば、 式 （1) で表される化合物又はその塩が提供さ れる。
Figure imgf000007_0002
According to a second aspect of the present invention, there is provided a compound represented by the formula (1) or a salt thereof.
Figure imgf000007_0002
(式中、 R1は水酸基の保護基を示し、 R 2は水素原子又は水酸基の保護基を示し、 R 3はカルボキシル基の保護基を示す） (Wherein, R 1 represents a protecting group for a hydroxyl group, R 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a carboxyl group)
本発明の別の側面によれば、 式 （2) で表される化合物又はその塩が提供され る。
Figure imgf000007_0003
According to another aspect of the present invention, there is provided a compound represented by the formula (2) or a salt thereof.
Figure imgf000007_0003
(式中、 XI及ぴ X 2はメチル基又は保護されていてもよいヒドロキシェチル基 を示し （伹し、 XI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、 R 3は水素原子又はカルボキシル基の保護基を示 す） (Wherein XI and X 2 represent a methyl group or a hydroxyethyl group which may be protected (except when XI and X 2 are simultaneously a methyl group), and R 2 is a hydrogen atom or R 3 represents a protecting group for a hydrogen atom or a carboxyl group. You)
本発明のさらに別の側面によれば、 式 （3 ) で表される化合物又はその塩が提 供される。  According to still another aspect of the present invention, there is provided a compound represented by the formula (3) or a salt thereof.
Figure imgf000008_0001
Figure imgf000008_0001
(式中、 X 1及び X 2はメチル基又は保護されていてもよいヒドロキシェチル基 を示し、 n個の Xは^ ·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ェ チル基を示し （伹し、 X I、 X 2及ぴ n個の Xの全てが同時にメチル基となる場 合は除く）、 R 2は水素原子又は水酸基の保護基を示し、 R 3は水素原子又はカル ポキシル基の保護基を示し、 nは 1〜4の整数を示す） (Wherein X 1 and X 2 represent a methyl group or an optionally protected hydroxyethyl group, and n Xs each independently represent a methyl group or an optionally protected hydroxyethyl group. R 2 represents a hydrogen atom or a hydroxyl-protecting group, and R 3 represents a hydrogen atom or carboxyl. Represents a protecting group of the group, and n represents an integer of 1 to 4)
本発明の別の側面によれば、 式 （4 ) で表される化合物又はその塩が提供され る。  According to another aspect of the present invention, there is provided a compound represented by the formula (4) or a salt thereof.
Figure imgf000008_0002
Figure imgf000008_0002
(式中、 R 1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ェチル基を示し、 nは 1〜5の整数を 示す） (In the formula, R 1 represents a hydrogen atom or a protecting group for a hydroxyl group, n Xs each independently represent a methyl group or an optionally protected hydroxyethyl group, and n represents an integer of 1 to 5. Show)
本発明の別の側面によれば、 上記式 （2 ) で表される化合物又は上記式 （3 ) で表される化合物を分子内脱水縮合による環化反応に供することを含む、 上記式 ( 4 ) で表される化合物の製造方法が提供される。  According to another aspect of the present invention, the compound represented by the above formula (4) comprises subjecting the compound represented by the formula (2) or the compound represented by the formula (3) to a cyclization reaction by intramolecular dehydration condensation. ) Is provided.
本発明の第三の態様によれば、 式 （1 ) で表される化合物又はその塩が提供さ れる。 R1 ooc. According to a third aspect of the present invention, there is provided a compound represented by the formula (1) or a salt thereof. R1 ooc.
•R3 (1)  • R3 (1)
Q  Q
(式中、 R 1は力ルポキシル基の保護基を示し、 R 2は水素原子又は水酸基の保護 基を示し、 R 3はカルボキシル基の保護基を示す。 但し、 R 1及び R 3はそれぞれ 異なる基を示す） (Wherein, R 1 represents a protecting group for a carbonyl group, R 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a carboxyl group. However, R 1 and R 3 are different from each other. Indicates a group)
本発明の別め側面によれば、 式 （2 ) で表される化合物又はその塩が提供され る。 o^o  According to another aspect of the present invention, there is provided a compound represented by the formula (2) or a salt thereof. o ^ o
0  0
(式中、 R 1はカルボキシル基の保護基又は水素原子を示し、 R 2は水素原子又は 水酸基の保護基を示し、 R 3はカルボキシル基の保護基又は水素原子を示す。） 本発明のさらに別の側面によれば、 式 （3 ) で表される化合物又はその塩が提 供される。 (Wherein, R 1 represents a carboxyl protecting group or a hydrogen atom, R 2 represents a hydrogen atom or a hydroxyl protecting group, and R 3 represents a carboxyl protecting group or a hydrogen atom.) According to another aspect, a compound represented by the formula (3) or a salt thereof is provided.
Figure imgf000009_0001
Figure imgf000009_0001
(式中、 R 1は力ルポキシル基の保護基又は水素原子を示し、 R 2は水素原子又は 水酸基の保護基を示し、 R 3は力ルポキシル基の保護基又は水素原子を示す。） 本発明のさらに別の側面によれば、 式 （4 ) で表される化合物又はその塩が提 供される。
Figure imgf000010_0001
(Wherein, R 1 represents a protecting group for a lipoxyl group or a hydrogen atom, R 2 represents a hydrogen atom or a protecting group for a hydroxyl group, and R 3 represents a protecting group for a lipoxyl group or a hydrogen atom.) According to still another aspect of the present invention, there is provided a compound represented by the formula (4) or a salt thereof.
Figure imgf000010_0001
(式中、 R1はカルボキシル基の保護基又は水素原子を示し、 nは 1から 5の整 数を示す。） (In the formula, R 1 represents a carboxyl protecting group or a hydrogen atom, and n represents an integer of 1 to 5.)
例えば、 nは 1又は 2である。  For example, n is 1 or 2.
本宪明のさらに別の側面によれば、 上記の式 （2) 又は （3) で表される化合 物を分子内脱水縮合による環化反応に供することを含む、 上記式 （4) において nが 1又は 2である化合物の製造方法が提供される。 発明を実施するための最良の形態  According to still another aspect of the present invention, in the above-mentioned formula (4), the compound represented by the above formula (2) or (3) is subjected to a cyclization reaction by intramolecular dehydration condensation. Is provided, wherein the compound is 1 or 2. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 本発明の実施態様及び実施方法について詳細に説明する。  Hereinafter, an embodiment and an implementation method of the present invention will be described in detail.
(A) アミノエチル基を有する化合物  (A) Compound having an aminoethyl group
本発明は、 アミノエチル基を有する式 （1) から式 '（6) で表される化合物又 はその塩、 並 に、 アミノエチル基を有する式 （3) 又は式 （5) で表される化 合物を分子内で環化することによりアミノエチル基を有する式（4)又は式（6) で表される化合物を製造する方法に関する。  The present invention relates to a compound represented by the formula (1) from the formula (1) having an aminoethyl group or a salt thereof, and a compound represented by the formula (3) or the formula (5) having an aminoethyl group. The present invention relates to a method for producing a compound represented by the formula (4) or the formula (6) having an aminoethyl group by cyclizing a compound in a molecule.
アミノエチル基を有する式 （1) 〜 （6) において、 R R 11及ぴ R 12はァ ミノ基の保護基又は水素原子を示し、 R 2は水素原子又は水酸基の保護基を示し、 R 3は水素原子又はカルボキシル基の保護基を示す。 In the formula (1) - having an aminoethyl group (6), RR 11及Pi R 12 represents a protecting group or a hydrogen atom § amino group, R 2 represents a hydrogen atom or a protecting group of a hydroxyl group, R 3 is Shows a protecting group for a hydrogen atom or a carboxyl group.
R\ R11及び R12で表されるァミノ基の保護基の種類は特に限定されず、 当 業者であれば適宜選択することができる。 ァミノ基の保護基の具体例としては、 置換もしくは無置換のアルキルォキシ力ルポニル基 （置換基としては、 例えば、 アルキルシリル基、 置換もしくは無置換のァリール基、 ハロゲン原子、 置換もし くは無置換の複素環基、 架橋環式炭化水素基、 ァシル基、 アルキルチオ基、 ジシ クロへキシルカルポキシアミド基、 置換もしくは無置換のベンゼンスルホニル基 アルキルスルホニル基、 置換もしくは無置換のホスホニォ基、 シァノ基等が挙げ られる）、 置換もしくは無置換のアルケニルォキシ力ルポニル基 （置換基として は、 .例えば、 ァリール基、 ニトロ基等が挙げられる）、 置換もしくは無置換のァ リールォキシカルポニル基、 置換もしぐは無置換の複素環ォキシカルボ二ル基、 置換もしくは無置換のアルキルジチォカルボニル基等のカルバメート型ァミノ 保護基、 アミ ド型ァミノ保護基、 N—アルキル型ァミノ保護基等が挙げられる。 置換もしくは無置換のアルキルォキシカルボニル基の具体例としては、 例えば、 メチルォキシカノレポ二ノレ基、 ェチルォキシカノレポ二ノレ基、 イソプチルォキシカノレ ポニル基、 t—ブチルォキシカルボニル基、 t—ァミルォキシカルポニル基、 2， 2 , 2—トリクロ口ェチルォキシカルポニル基、 2—トリメチルシリルェチルォ キシカルボニル基、 フエニルェチルォキシカルボ二ル基、 1 _ ( 1ーァダマンチ ル）— 1—メチルェチルオギシカルポニル基、 1， 1ージメチル _ 2—ハロェチ ルォキシカノレポ二ノレ基、 1， 1—ジメチノレー 2， 2—ジブロモェチノレオキシカノレ ポニル基、 1， 1—ジメチノレ _ 2， 2， 2—トリクロロェチノレオキシカノレポ二ノレ 基、 1—メチルー 1—( 4—ビフエ二ルイル）ェチルォキシカルポニル基、 1 _ ( 3， 5ージ一 tーブチルフヱニル）一 1一メチルェチルォキシカルボニル基、 2—（ 2 ，一ピリジル）ェチルォキシカルポニル基、 2—（4，一ピリジル）ェチルォキシ力 ルポニル基、 2— (N， N—ジシクロへキシルカルポキシアミ ド）ェチルォキシ力 ルポニル基、 1—ァダマンチルォキシカノレポ二ノレ基、 ベンジノレォキシカノレポ二ノレ 基、 p—メ トキシベンジルォキシカルポ-ル基、 ： —ニトロべンジルォキシカル ボニル基、 p _ブロモベンジルォキシカルポニル基、 p—クロ口べンジルォキシ カルポニル基、 2 , 4ージクロ口べンジルォキシカルポニル基、 4ーメチルスル フィエルベンジルォキシカルポニル基、 9—アントリルメチルォキシカルポニル 基、 ジフ工ニルメチルォキシカルボニル基、 9 _フルォレニルメチルォキシカル ボニル基、 9一（2， 7—ジブロモ）フルォレニルメチルォキシカルポニル基、 2， 7—ジ— tーブチルー [ 9一（1 0， 1 0—ジォキソーチォキサンチル）]メチルォ キシカルボニル基、 4—メ トキシフエナシルォキシカルポニル基、 2—メチルチ ォェチルォキシカルポニル基、 2—メチルスルホニルェチルォキシカルボニル基、 2—（p—トルエンスルホ -ル）ェチルォキシカルポニル基、 [ 2—（1， 3—ジチ ァニル） ]メチルォキシカルポニル基、 4ーメチルチオフェ二ルォキシカノレポ二ノレ 基、 2， 4—ジメチルチオフエニルォキシカルポニル基、 2—ホスホニォェチル ォキシカルボニル基、 2—トリフエニルホスホニオイソプロピルォキシ力ルポ二 ル基、 1， 1一ジメチノレ一 2—シァノエチルォキシカルポニル基、 m—クロロー p—ァシロキシべンジルォキシカルポニル基、 p _ (ジヒ ドロキシポリル）ベンジ ルォキシカルボ二ル基、 5 —べンゾィソォキサゾリルメチルォキシカルポニル基、 2— (トリフルォロメチル） _ 6—クロモニルメチルォキシカルボニル基、 3， 5 —ジメ トキシベンジルォキシカルボニル基、 o—二トロベンジルォキシカルポ二 ル基、 3， 4—ジメ トキシー 6—二トロべンジルォキシカルポニル基、 フエニル ( o—二トロフエニル）メチルォキシカルポニル基が挙げられる。 Type of the protective group Amino group represented by R \ R 11 and R 12 is not particularly limited and can be appropriately selected by those skilled in the art. Specific examples of a protecting group for an amino group include a substituted or unsubstituted alkyloxyl carbonyl group (for example, an alkylsilyl group, a substituted or unsubstituted aryl group, a halogen atom, a substituted or unsubstituted group). Heterocyclic group, bridged cyclic hydrocarbon group, acyl group, alkylthio group, dicyclohexylcarboxyamide group, substituted or unsubstituted benzenesulfonyl group An alkylsulfonyl group, a substituted or unsubstituted phosphonio group, a cyano group, etc.), a substituted or unsubstituted alkenyloxycarbonyl group (as the substituent, for example, an aryl group, a nitro group, etc.) Carbamate-type amino-protecting groups, such as substituted or unsubstituted aryloxycarbonyl groups, substituted or unsubstituted heterocyclic oxycarbonyl groups, substituted or unsubstituted alkyldithiocarbonyl groups, and amide-type amino protection And N-alkyl-type amino protecting groups. Specific examples of the substituted or unsubstituted alkyloxycarbonyl group include, for example, methyloxycanoleponinole, ethyloxycanoleponinole, isobutyloxycanoleponyl, t-butylo Xycarbonyl group, t-amyloxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group, 2-trimethylsilylethyloxycarbonyl group, phenylethyloxycarbonyl group, 1 _ (1 -adamantyl) — 1-methylethyloxalicarponyl group, 1,1-dimethyl _2 -haloethyloxycanoleponinole group, 1,1 -dimethinole 2,2 -dibromoethynoleoxycanoleponyl group, 1 , 1-Dimethinole _ 2,2,2-Trichloroethynoleoxycanolepodinole, 1-methyl-1- (4-biphenylyl) ethyloxycarponyl, 1 _ (3 5-di-tert-butylphenyl) 1-1-methylethyloxycarbonyl group, 2- (2,1-pyridyl) ethyloxycarbonyl group, 2- (4,1-pyridyl) ethyloxy force Ruponyl group, 2- (N , N-dicyclohexylcarpoxyamide) ethyloxy force Luponyl group, 1-adamantyloxycanoleponinole group, benzinoleoxycanoleponinole group, p-methoxybenzyloxycarbonyl group ,: —Nitrobenzyloxycarbonyl group, p_bromobenzyloxycarbonyl group, p-benzobenzyloxycarbonyl group, 2,4-dichlorobenzyloxycarbonyl group, 4-methylsulfenylbenzyloxycarbonyl group, 9— Anthrylmethyloxycarbonyl, diphenyloxymethyloxycarbonyl, 9-fluorenylmethyloxycarbonyl , 9- (2,7-dibromo) fluorenylmethyloxycarbonyl group, 2,7-di-t-butyl- [9-1 (10,10-dioxothioxantyl)] methyloxycarbonyl group , 4-methoxyphenacyloxycarbonyl group, 2-methylthio Oethyloxycarponyl group, 2-methylsulfonylethyloxycarbonyl group, 2- (p-toluenesulfol) ethyloxycarponyl group, [2- (1,3-dithienyl)] methylo Xycarponyl group, 4-methylthiophenyloxycanoleponinole group, 2,4-dimethylthiophenoxycarbonyl group, 2-phosphonoethyloxycarbonyl group, 2-triphenylphosphonioisopropyloxycarbonyl group, 1, 1-Dimethinole 1- 2-cyanoethyloxycarbonyl group, m-chloro-p-acyloxybenzyloxycarbonyl group, p _ (dihydroxyporyl) benzyloxycarbonyl group, 5-benzoisoxazolylmethyl Oxycarbonyl group, 2- (trifluoromethyl) _ 6-chromonylmethyloxycarbonyl group, 3,5-dimethoxy Benzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, 3,4-dimethoxy-6-nitrobenzyloxycarbonyl group, phenyl (o-nitrophenyl) methyloxycarbonyl group .
置換もしくは無置換のアルケニルォキシカルポニル基の具体例としては、 ビニ ルォキシカルボニル基、 ァリルォキシカルボニル基、 1—イソプロピルァリルォ キシカルポ二ノレ基、 シンナミノレォキシカルボ二ノレ基、 4—ニトロシンナミノレォキ シカルポニル基等が例示される。  Specific examples of the substituted or unsubstituted alkenyloxycarbonyl group include a vinyloxycarbonyl group, an aryloxycarbonyl group, a 1-isopropylaryloxycarbonyl group, a cinnaminoleoxycarbonyl group, —Nitrocinaminoloxycarbonyl group and the like.
置換もしくは無置換の複素環ォキシカルボニル基の具体例としては、 8—キノ リルォキシカルボ二ル基、 N—ピペリジニルォキシ力ルポニル基等が挙げられる。 置換もしくは無置換のァリールォキシカルボニル基の具体例としては、 例えば、 フエ二/レオキシカノレポ二ノレ基、 m—二トロフエニルォキシカノレポ二ノレ基などが例 示される。  Specific examples of the substituted or unsubstituted heterocyclic oxycarbonyl group include an 8-quinolyloxycarbonyl group, an N-piperidinyloxycarbonyl group, and the like. Specific examples of the substituted or unsubstituted aryloxycarbonyl group include, for example, a phenyl / reoxycanolepodinole group and an m-2-trophenyloxycanolepodinole group.
アミ ド型ァミノ保護基の具体例としては、 例えば、 ホルミル基、 ァセチル基、 . クロロアセチル基、 トリクロロアセチル基、 トリフルォロアセチル基、 フエニル ァセチル基、 ベンゾィル基などが挙げられる。  Specific examples of the amide-type amino protecting group include, for example, a formyl group, an acetyl group, a chloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, a phenyl acetyl group, and a benzoyl group.
N—アルキル型ァミノ保護基の具体例としては、 ベンジル基、 N—ジ（4ーメ トキシフヱニル）メチル基、 N— 5—ジベンゾスべリル基、 N—トリフヱニルメ チル基、 （4—メ トキシフエニル）ジフエニルメチル基、 N— 9 _フエニルフルォ レニル基、 ァリル基、 N— [ 2—（トリメチルシリル）エトキシ]メチル基、 N— 3 ーァセトキシプロピル基などが挙げられる。 Specific examples of N-alkyl type amino protecting groups include benzyl group, N-di (4-methoxyphenyl) methyl group, N-5-dibenzosuberyl group, N-triphenylmethyl group, (4-methoxyphenyl) diphenylmethyl Group, N—9_phenylphenyl Examples include a enyl group, an aryl group, an N- [2- (trimethylsilyl) ethoxy] methyl group, and an N-3-acetoxypropyl group.
R 2で表される水酸基の保護基の種類は特に限定されず、 当業者であれば適宜 選択することができる。 水酸基の保護基の具体例としては、 以下のものが挙げら れる。 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.
(エーテル型）  (Ether type)
メチル基、メ トキシメチル基、メチルチオメチル基、ベンジルォキシメチル基、 t—ブトキシメチル基、 2—メ トキシエトキシメチル基、 2 , 2， 2—トリクロ 口エトキシメチル基、 ビス （2—クロ口エトキシ） メチル基、 2— (トリメチノレ シリル） エトキシメチル基、 テトラヒ ドロピラエル基、 3—ブロモテトラヒドロ ビラニル基、 テトラヒ ドロチォピラエル基、 4—メ トキシテトラヒドロピラニル 基、 4—メ トキシテトラヒ ドロチォピラニル基-、 4—メ トキシテトラヒドロチォ ビラニル S , S—ジォキシド基、 テトラヒ ドロフラニル基、 テトラヒ ドロチオフ ラニノレ基；  Methyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy ) Methyl group, 2- (trimethinolesilyl) ethoxymethyl group, tetrahydroxypyrael group, 3-bromotetrahydroviranyl group, tetrahydrothiopyrael group, 4-methoxytetrahydropyranyl group, 4-methoxytetrahydropyranopyl-, 4-methoxy Tetrahydrothioviranyl S, S-dioxide group, tetrahydrofuranyl group, tetrahydrothiofuranlaninole group;
1一エトキシェチル基、 1—メチル _ 1ーメ トキシェチル基、 1— (イソプロ ポキシ） ェチル基、 2， 2 , 2—トリクロ口ェチル基、 2 - (フエ二ルセレニル） ェチノレ基、 t一プチノレ基、 ァリル基、 シンナミノレ基、 p—クロ口フエ二ノレ基、 ベ ンジル 、 p—メ トキシベンジル基、 o _ニトロべンジル基、 p—ニトロべンジ ル基、 p—ハロベンジル基、 p _シァノベンジル基、 3—メチルー 2—ピコリル N—ォキシド基、 ジフエニルメチル基、 5—ジベンゾスべリル基、 トリフヱニル メチル基、 α _ナフチルジフエニルメチル基、 ρ—メ トキシフエニルジフエニル メチル基、 Ρ—（Ρ，一ブロモフエナシルォキシ） フエニルジフエニルメチル基、 9 _アントリル基、 9一 （9一フエニル） キサンテニル基、 9一 （9一フエニル - 1 0—ォキソ） アントリル基、 ベンズイソチアゾリル S， S—ジォキシド基、 ； トリメチルシリル基、 トリェチルシリル基、 イソプロピルジメチルシリル基、 t—ブチルジメチルシリル基 （T B DM S基）、 （トリフエニルメチル） ジメチル シリル基、 t―プチルジフヱニルシリル基、 メチルジィソプロビルシリル基、 メ チルジー t 一ブチルシリル基、 トリベンジルシリル基、 トリ—： p—キシリルシリ ル基、 トリイソプロピルシリル基、 トリフヱニルシリル基； 1-Ethoxyshetyl group, 1-Methyl_1-methoxethyl group, 1- (Isopropoxy) ethyl group, 2,2,2-Trichloromethylethyl group, 2- (phenylselenyl) ethynole group, t-Ptinole group, Phenyl group, cinnaminole group, p-chloropheninole group, benzyl, 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, ρ-methoxyphenyldiphenylmethyl group, Ρ— (Ρ, Bromophenacyloxy) phenyldiphenylmethyl group, 9 _ anthryl group, 9-1 (9-phenyl) xanthenyl group, 9-1 (9-phenyl-10-oxo) ant Group, benzisothiazolyl S, S-dioxide group; trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group (TBDMS group), (triphenylmethyl) dimethylsilyl group, t- Butyldiphenylsilyl group, methyldiisopropylylsilyl group, Chilzye t-butylsilyl group, tribenzylsilyl group, tri-: p-xylylsilyl group, triisopropylsilyl group, triphenylsilyl group;
(エステル型）  (Ester type)
ホノレメート、 ベンゾィゾレホノレメート、 アセテート、 クロ口アセテート、 ジクロ 口アセテー ト、 トリクロ口アセテー ト、 トリフルォロアセテー ト、 メ トキシァセ テート、 トリフエニルメ トキシアセテート、 フエノキシアセテート、 p—クロ口 フエノキシアセテート、 2， 6—ジクロロー 4ーメチノレフエノキシアセテート、 2 , 6—ジクロロ _ 4— ( 1， 1， 3， 3—テトラメチノレブチノレ) フエノキシァ セテート、 2， 4一 ス （1， 1ージメチルプロピル） フエノキシアセテート、 クロロジフエ二ノレアセテー ト、 p— P—フエ二ノレアセテー ト、 3—フエ二ノレプロ ピオネート、 3—べンゾィノレプロピオネート、 イソブチレート、 モノスクシノエ ート、 4—ォキソペンタノエート、 ピバロエート、 ァダマントエート、 クロトネ ート、 4ーメ トキシクロ トネート、 （E ) — 2—メチル一 2—ブテノエ一ト、 ベ ンゾエート、 o— （ジブ口モメチノレ） ベンゾエート、 o— （メ トキシカノレポ二ノレ） ベンゾエート、 p—フエ二ノレべンゾエート、 2， 4 , 6—トリメチノレべンゾエー ト、 p— ; P—ベンゾエート、 一ナフトエート ；  Honolemate, Benzozolehonoremate, Acetate, Black Acetate, Dichro Acetate, Triclo Acetate, Trifluoro Acetate, Methoxy Acetate, Triphenyl Acetate Acetate, Phenoxy Acetate, P-Aro Fenoki Shea acetate, 2,6-dichloro-4-methinolephenoxyacetate, 2,6-dichloro_4- (1,1,3,3-tetramethinolevbutinole) phenoxyacetate, 2,41-1 (1 , 1-dimethylpropyl) phenoxy acetate, chlorodiphenoleacetate, p-P-pheninoleate acetate, 3-phenylenopropionate, 3-benzoinolepropionate, isobutyrate, monosuccinoate, 4 —Oxo pentanoate, pivaloate, adamantoate, croto , 4-Methoxycyclotonate, (E) —2-Methyl-2-butenoate, Benzoate, o— (Jib mouth mometinole) Benzoate, o— (Methoxycanoleponinole) Benzoate, p-Feninole Benzoate, 2,4,6-trimethinolebenzoate, p—; P-benzoate, naphthoate;
(カーボネート型）  (Carbonate type)
メチノレカーボネート、 ェチルカーボネート、 2， 2， 2 _トリクロロェチノレ力 ーポネート、 イソブチルカーボネート、 'ビュルカーボネート、 ァリルカーボネー ト、 シンナミノレカーボネー ト、 ： —二 トロフエ二ノレカーボネー ト、 ベンジノレカー ポネート、 p—メ トキシベンジ Λ ^カーボネート、 3， 4—ジメ トキシベンジノレ力 ーポネート、 o—二トロべンジノレカーポネート、 p _ニトロべンジノレカーボネー ト、 S—べンジノレチォカーボネート ；  Methinocarbonate, ethylcarbonate, 2,2,2-trichloroethynolecarbonate, isobutyl carbonate, 'Butylcarbonate, arylcarbonate, cinnaminolecarbonate, Methoxybenzide carbonate, 3,4-dimethoxybenzinole carbonate, o-nitrobenzinolecarbonate, p_nitrobenzinolecarbonate, S-benzinolethiocarbonate;
(その他）  (Other)
N—フエ二ルカルバメート、 N—イミダゾリルカルバメート、 ポレート、 ニト レート、 N， N， N，， N ' —テトラメチルホスホロジアミダート、 2， 4—ジ 二 ト口フエニノレスノレフエネー ト ： R 3で表されるカルボキシル基の保護基の種類は特に限定されず、 当業者であ れば適宜選択することができる。 カルボキシル基の保護基の具体例としては、 例 えば、 メチノレ、 ェチノレ、 n—プロピノレ、 イ ソプロピノレ、 n —， iso- , sec- , tert 一プチノレ、 n —へキシノレ基等の C Mアルキノレ基、'ブロモー tーブチノレ、 トリクロ 口ェチル等のハロゲン （例えば、 塩素、 臭素、 フッ素、 ヨウ素等） で 1ないし 3 置換された C アルキル基、 ベンジル、 p—ニトロベンジル、 o—二トロべンジ ル、 p—メ トキシベンジル基、 p— t—ブチルベンジル等のニトロ、 Cwアルコ キシ基 （例えばメ トキシ、 エトキシ等） または C wアルキル基 （例えばメチル、 ェチノレ、 n—又は i s o一プロピノレ、 n —、 i s o —、 s e c—又は t e r t— ブチル等） 等で 1または 2置換されていてもよい C7_14ァラルキル基、 ァセトキシ メチノレ、 プロピ才ニノレオキシメチル、 n —， iso - , ブチリノレオキシメチノレ、 バ レリルォキシメチル、 ビバロイルォキシメチル、 1一 (または 2—) ァセトキシ ェチル， 1一 （または 2—または 3—) ァセトキシプロピル， 1 _ (または 2— または 3—または 4—) ァセトキシプチル， 1 _ (または 2—） プロピオニルォ キシェチル， 1— (または 2 _または 3—） プロピオニルォキシプロピル， 1一 (または 2 _) ブチリルォキシェチル， 1一 （または 2—） イソブチリルォキシ ェチル， 1— (または 2—) ビバロイルォキシェチル， 1一 （または 2—) へキ サノィルォキシェチル、 イソプチリルォキシメチル、 2—ェチルプチリルォキシ メチル， 3 ， 3—ジメチルブチリルォキシメチル、 1一 （または 2—） ペンタノ ィルォキシェチル等の C !_4アルカノィルォキシ一 C Hァルキル基、 例えば 2—メ シルェチル基等の C Hアルカンスルホ二ルー C Hアルキル基， 例えばメ トキシカ ノレポニノレオキシメチノレ， エ トキシカルボニノレオキシメチノレ， プロポキシカノレポ二 ルォキシメチル， 第三級ブトキシカルポニルォキシメチル， 1 _ (または 2—） メ トキシカルポニルォキシェチル， 1— (または 2—) エトキシカルポ二ルォキ シェチル， 1一 （または 2—) イソプロポキシカルボニルォキシェチル等の C w アルコキシカルポニルォキシ _ d_4アルキル基、 tーブチルジメチルシリル、 ト リメチルシリル等のトリ C ^ 4アルキルシリル基、 ァリル、 メタ ァリル等の C2_6 アルケニル基、 メ トキシメチル、 エトキシメチル、 プロポキシ メチル、 イソプ 口ポキシメチル等の C Hアルコキシ—メチル基、 （2—メチル チォ） 一ェチル等 の アルキルチオ C Hアルキル基、 3—メチル— 2—ブテュル基、 5—インダ ニル基、 3 _フタリジル基等が用いられる。 N-phenylcarbamate, N-imidazolylcarbamate, porate, nitrate, N, N, N ,, N'-tetramethylphosphorodiamidate, 2,4-dinitrophenenoresnorolenate: The type 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 carboxyl-protecting group include, for example, CM alkynole groups such as methinole, ethynole, n-propynole, isopropynole, n-, iso-, sec-, tert-butynole, and n-hexynole groups. C-alkyl group substituted with 1 to 3 halogens such as bromo-butynole and trichloromethyl (eg, chlorine, bromine, fluorine, iodine, etc.), benzyl, p-nitrobenzyl, o-nitrobenzyl, p- Nitro, Cw alkoxy group (eg, methoxy, ethoxy, etc.) or Cw alkyl group (eg, methyl, ethynole, n- or iso-propynole, n—, iso— , which may be 1 or 2 substituted by sec- or tert- butyl, etc.), etc. C 7 _ 14 Ararukiru group, Asetokishi Mechinore, propylene old Nino les oxymethyl, n —, iso-, butyrinoleoxymethinole, valeryloxymethyl, bivaloyloxymethyl, 1 (or 2—) acetoxyethyl, 1 (or 2— or 3—) acetoxypropyl, 1 _ (Or 2— or 3— or 4—) acetoxyptyl, 1 _ (or 2—) propionyloxyxethyl, 1— (or 2 _ or 3—) propionyloxypropyl, 1 (or 2 _) butyryloxy Shetyl, 1 (or 2—) isobutyryloxyethyl, 1— (or 2—) vivaloyloxityl, 1 (or 2—) hexanoyloxyxetil, isobutylyloxy methyl, 2-E chill Petit Lil O carboxymethyl, 3, 3-dimethyl-butyryl O carboxymethyl, 1 i (or 2) pentanol Iruokishechiru C! _ 4 alkanoate Noi Ruo carboxymethyl one CH Arukiru groups such, for example, CH-alkanesulfonyl-CH alkyl groups such as 2-mesylethyl group, for example, methoxycanoleponinoleoxymethinole, ethoxycarboninoleoxymethinole, propoxycanoleponyloxymethyl, tert-butoxycarponyloxymethyl, 1 _ (Or 2—) methoxycarponyloxyshetyl, 1— (or 2—) ethoxycarponyloxyshetyl, Cw alkoxycarponyloxy, such as 1-1 (or 2—) isopropoxycarbonyloxyshetyl _ d_ 4 alkyl group, t chromatography butyldimethylsilyl, tri C ^ 4 alkyl silyl groups such as trimethylsilyl, Ariru, C 2 _ 6 such as meta Ariru CH alkoxy-methyl groups such as alkenyl group, methoxymethyl, ethoxymethyl, propoxymethyl, and isopropoxymethyl; alkylthio CH alkyl groups such as (2-methylthio) ethyl; 3-methyl-2-butyr group; Nyl group, 3_phthalidyl group and the like are used.
なお、 上記したような保護基の導入法及び脱保護法は当業者に公知であり、 例 ば、 Teodora, W. Green, Protective Groups in Organic Synthesis, John & Wiley & Sons Inc. (1981) などに記載されている。  In addition, methods for introducing and deprotecting a protecting group as described above are known to those skilled in the art.For example, see Teodora, W. Green, Protective Groups in Organic Synthesis, John & Wiley & Sons Inc. (1981). Has been described.
次に、 本発明のアミノエチル基を有する化合物の製造方法について説明する。 式 （1 ) で表される化合物は、 乳酸の側鎖に保護されたアミノエチル基を有す る化合物である。 式 （2 ) で表される化合物は、 乳酸 2量体の側鎖に保護されて いてもよい 2個のアミノエチル基を有する化合物であり、 式 （3 ) で表される化 合物は、 乳酸 2量体の側鎖に保護されていてもよい 1個のアミノエチル基を有す る化合物である。 式 （4 ) で表される化合物は、 乳酸 2量体の環化物であり、 側 鎖に保護されていてもよいアミノエチル基を 1個有する化合物である。 式 （4 ) で表される化合物は、 式 （3 ) で表される化合物を N， N， -ジシクロへキシルカ ルポジイミ ドと 4 -ジメチルァミノピリジンの存在下で分子内脱水縮合による環 化反応に供することによって合成することができる。  Next, a method for producing a compound having an aminoethyl group of the present invention will be described. 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 on the side chain of the lactic acid dimer, and the compound represented by the formula (3) is It is a compound having one aminoethyl group which may be protected on the side chain of lactic acid dimer. 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 a 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, -dicyclohexylcarpoimide and 4-dimethylaminopyridine. By subjecting it to
また、 本発明の式 （5 ) で表される化合物は、 乳酸の 3量体から 6量体の側鎖 に保護されていてもよい 1個のアミノエチル基を有する化合物である。 式 （6 ) で表される化合物は、 轧酸の 3量体から 6量体の環化物であり、 側鎖に保護され ていてもよいアミノエチル基を 1個有する化合物である。 式 （6 ) で表される化 合物は、 式 （5 ) で表される化合物をジイソプロピルェチルァミン、 4 -ジメチル アミノビリジン及び 2， 4, 6-トリクロ口べンゾイルク口ライドの存在下で分子内. 脱水縮合による環化反応に供することによつて合成することができる。  In addition, the compound represented by the formula (5) of the present invention is a compound having one aminoethyl group which may be protected on the side chain of trimer to hexamer of lactic acid. The compound represented by the formula (6) is a cyclized product of a dimer to a hexamer of diacid, and is a compound having one aminoethyl group which may be protected in a side chain. The compound represented by the formula (6) is prepared by converting the compound represented by the formula (5) in the presence of diisopropylethylamine, 4-dimethylaminoviridine, and 2,4,6-trichloromethylbenzoyl chloride. The compound can be synthesized by subjecting it to a cyclization reaction by dehydration condensation.
上記した本発明の化合物の具体的な合成ルートについて以下の （方法 A)、 （方 法 B ) 及び （方法 C ) の 3つを例に挙げて説明する。  The specific synthetic route for the compound of the present invention described above will be described with reference to the following three (Method A), (Method B) and (Method C) as examples.
(方法 A) この方法は、 任意の鎖長の乳酸オリゴエステルを合成し， これに (s) - (-) -4 -ァミノ -2 -ヒ ドロキシ酪酸のァミノ基及ぴカルポキシル基を保護した 化合物と縮合した後， 力ルポキシル基及び水酸基を脱保護し環化する方法である。 初めに鎖状オリゴエステルの力ルポキシル基側末端ュニットの合成について 検討した。 すなわちラクチドを加水分解し 2， 4， -ジブ口モアセトフヱノンを作 用させ， 乳酸ラクトイル ^プロモフヱナシルエステル（2)を得た。 (Method A) This method synthesizes lactate oligoesters of any chain length, (s)-(-)-4-Amino-2-hydroxybutyric acid is condensed with a compound in which the amino and carboxyl groups are protected, followed by deprotection and cyclization of the hydroxyl group and hydroxyl group. First, the synthesis of the terminal unit on the side chain of the linear oligoester was examined. In other words, lactide was hydrolyzed to make 2,4, -dibumotoacetophenone act to obtain lactoyl lactate ^ promopanacyl ester (2).
Figure imgf000017_0001
Figure imgf000017_0001
2  2
次に， 乳酸べンジルエーテル（3)及び乳酸ラタ トイル ブロモフヱナシルエス テル (2)を DCC， DMAPを用いて縮合し， 得られた 4に亜鉛， 酢酸を作用させ， 力 ルポキシル基を脱保護し，乳酸 3量体べンジルエーテル (5)を合成した。続いて， 乳酸ラタ トイル ブロモフエナシルエステル（2)と縮合し得られた 6に亜鉛， 酢 酸を作用させ， カルボキシル基を脱保護し， 乳酸 5 量体べンジルエーテル（7)が 得られる。  Next, benzyl ether lactate (3) and ratatoyl lactate bromophenacyl ester (2) are condensed using DCC and DMAP, and the resulting 4 is treated with zinc and acetic acid to remove the hydroxyl group. With protection, lactic acid trimer benzyl ether (5) was synthesized. Then, zinc and acetic acid are allowed to act on 6 obtained by condensation with ratatoyl bromophenacyl lactate (2) to deprotect the carboxyl group, and pentamer lactic acid benzyl ether (7) is obtained.
Figure imgf000017_0002
次に， アミノエチル基を有するユニッ トの合成を検討した。 すなわち， (s) - (-) - 4-ァミノ- 2 -ヒ ドロキシ酪酸（8)に二炭酸ジ ί -ブチルを作用させアミノ 基を保護し， さらに 2， 4， -ジプロモアセトフヱノンを作用させた 10を得ること ができる。
Figure imgf000017_0002
Next, we investigated the synthesis of a unit having an aminoethyl group. That is, di-butyl dicarbonate acts on (s)-(-)-4-amino-2-hydroxybutyric acid (8) to protect the amino group, and 2,4, -dibromoacetophenone is further converted. Getting worked 10 Can do.
Figure imgf000018_0001
Figure imgf000018_0001
得られた（5)および (7)と（s) - (-) - 4-ァミノ- 2-ヒドロキシ酪酸誘導体（10)を縮 合し， 対応する水酸基をべンジル基， カルボキシル基を プロモフヱナシル基で 保護したアミノエチル基を有する鎖状オリゴエステル（lla)， （lib)を得る。 続い て得られた生成物に亜鉛， 酢酸を作用させ， カルボキシル基を脱保護し， 接触還 元により力ルポキシル基， 水酸基ともに遊離のアミノエチル基を有する鎖状オリ ゴエステル（13a)， （13b)が得られる。.  The obtained (5) and (7) are condensed with the (s)-(-)-4-amino-2-hydroxybutyric acid derivative (10), and the corresponding hydroxyl group is replaced with a benzyl group and the carboxyl group is replaced with a promofunacyl group. A chain oligoester (lla), (lib) 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 chain oligoesters (13a), (13b) having free aminoethyl groups in both the hydroxyl group and the hydroxyl group by catalytic reduction. Is obtained. .
Figure imgf000018_0002
Figure imgf000018_0002
最後に、 得られた鎖状オリゴエステル（13a) , (13b)に 2, 4， 6-トリクロ口ベン ゾイルク口ライドを作用させ， 分子内での脱水縮合によりアミノエチル基を有す る環状オリゴエステルを合成することができる。  Finally, 2,4,6-trichlorobenzoyl chloride is reacted with the obtained chain oligoesters (13a) and (13b), and the cyclic oligoester having an aminoethyl group is obtained by intramolecular dehydration condensation. Esters can be synthesized.
(方法 B ) 抗生物質として知られるェンテロバクチン （1 ) は、 3つの側鎖をも つ環状エステル構造を有しており、 その側鎖で鉄イオンを捕捉するなど分子認識 化合物としても知られている。 以下の 2に示すような構造の化合物を合成するこ とを目的とすることができる。
Figure imgf000019_0001
まず、 2を合成するための基本ュニットとなるアミノ基を t -ブトキシカルボ二 ル基で保護した誘導体（3)を出発原料として 3 のブロモフヱナシルェステル合成 について検討した。 すなわち 3にトリエチルァミン存在下、 臭化プロモフヱナシ ルを反応させ、 4を得る。
Figure imgf000019_0002
(Method B) Enterobactin (1), which is known as an antibiotic, has a cyclic ester structure with three side chains, and is also known as a molecular recognition compound, such as capturing iron ions in the side chains. . The object is to synthesize a compound having a structure as shown in the following 2.
Figure imgf000019_0001
First, bromophenacylester synthesis of 3 was studied using derivative (3), in which the amino group, which is the basic unit for synthesizing 2, was protected with a t-butoxycarbonyl group as a starting material. That is, 3 is reacted with promorphinyl bromide in the presence of triethylamine to obtain 4.
Figure imgf000019_0002
次に、 3にィミダゾール存在下、 塩化 t-プチルジメチルシランを反応させ 5とし た後、 炭酸カリウムで加水分解することによって 6 を得ることができる。 次に、 得られた 6と 4との縮合反応を行う。 すなわち、 DMAP触媒下、 DCCを縮合剤とし 6と 4とを反応させることにより目的とする 7を好収率で得ることができる。 Next, 3 is reacted with t-butyldimethylsilane chloride in the presence of imidazole to obtain 5, and then hydrolyzed with potassium carbonate to obtain 6. Next, a condensation reaction of the obtained 6 and 4 is performed. That is, by reacting 6 and 4 with DCC as a condensing agent under a DMAP catalyst, the desired 7 can be obtained in good yield.
Figure imgf000019_0003
Figure imgf000019_0003
( C ) この方法は 2種類の -ヒドロキシ酸から成る環状オリゴエステルの合成 法である。 まず、 エステルを合成するユニットとして、 乳酸（1)の水酸基おょぴ(C) This method is a method for synthesizing a cyclic oligoester composed of two types of -hydroxy acids. First, as the unit for synthesizing the ester, the hydroxyl group of lactic acid (1)
4 -ァミノ- 2 -ヒドロキシ酪酸 (4)のカルボキシル基を保護した 3と 6を合成する。 始めに 1の水酸基とカルボキシル基をべンジル基で保護し、 カルボキシル基のみ 脱保護した 3を 2段階で得ることができる。
Figure imgf000020_0001
4-Amino-2-hydroxybutyric acid Synthesize 3 and 6 with the carboxyl group of (4) protected. First, the hydroxyl group and carboxyl group can be protected with a benzyl group, and the carboxyl group can be deprotected.
Figure imgf000020_0001
次に 4のァミノ基を Boc基、 カルボキシル基をブロモフエナシルで保護した 6 を 2段階で得ることができる。  Next, 6 in which the amino group of 4 is protected with a Boc group and the carboxyl group with bromophenacyl can be obtained in two steps.
H2NH 2 N
Figure imgf000020_0002
Figure imgf000020_0002
95% 95%  95% 95%
鎖長を延長するため先に合成した 3 と 6の縮合反応を行い、 二種類の · -ヒドロ キシ酸が結合した化合物（7)を得うことができる。
Figure imgf000020_0003
In order to extend the chain length, a condensation reaction of the previously synthesized 3 and 6 can be carried out to obtain a compound (7) in which two kinds of -hydroxy acids are bonded.
Figure imgf000020_0003
85%  85%
得られた 7のフエナシルエステルとベンジルエーテルをそれぞれ脱保護し 9を The resulting phenacyl ester of 7 and benzyl ether were deprotected to give 9
2段階で得ることができる。 化合物 9を分子内縮合反応により環化することによ り環状ポリ乳酸を合成することができる。
Figure imgf000020_0004
Can be obtained in two stages. Cyclic polylactic acid can be synthesized by cyclizing compound 9 by an intramolecular condensation reaction.
Figure imgf000020_0004
64% 77%  64% 77%
(B ) ヒドロキシルェチル基を有する化合物 (B) a compound having a hydroxylethyl group
本発明は、 ヒドロキシルェチル基を有する式 （1 ) から式 （4 ) で表される化 合物又はその塩、 並びに、 ヒドロキシルェチル基を有する式 （2 ) 又は式 （3 ) で表される化合物を分子内で環化することにより式 （4 ) で表される化合物を製 造する方法に関する。  The present invention provides a compound represented by the formulas (1) to (4) having a hydroxylethyl group or a salt thereof, and a compound represented by the formula (2) or the formula (3) having a hydroxylethyl group. The present invention relates to a method for producing a compound represented by the formula (4) by cyclizing a compound in a molecule.
ヒドロキシルェチル基を有する式 （1 ) において、 R 1は水酸基の保護基を示 し、 R'2は水素原子又は水酸基の保護基を示し、 R 3はカルボキシル基の保護基を 示す。 好ましくは、 R 1で示される水酸基の保護基と R 2で示される水酸基の保護 基は異なる基である。 In the formula (1) having a hydroxylethyl group, R 1 represents a protecting group for a hydroxyl group, R ′ 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a carboxyl group. Show. Preferably, the hydroxyl-protecting group represented by protecting groups and R 2 of the hydroxyl groups represented by R 1 are different groups.
ヒドロキシルェチル基を有する式 （2 ) において、 X I及び X 2はメチル基又 は保護されていてもよいヒドロキシェチル基を示し （但し、 X I及ぴ X 2が同時 にメチル基となる場合は除く）、 R 2は水素原子又は水酸基の保護基を示し、 R 3 は水素原子又は力ルポキシル基の保護基を示す。 好ましくは、 ヒドロキシェチル 基の保護基と、 R 2で示される水酸基の保護基は異なる基である。 In the formula (2) having a hydroxylethyl group, XI and X2 represent a methyl group or a hydroxyethyl group which may be protected (however, when XI and X2 are simultaneously a methyl group, R 2 represents a hydrogen atom or a protecting group for a hydroxyl group, and R 3 represents a hydrogen atom or a protecting group for a hydroxyl group. Preferably, the protecting group for the hydroxyethyl group and the protecting group for the hydroxyl group represented by R 2 are different groups.
ヒドロキシルェチル基を有する式 （3 ) において、 X I及び X 2はメチル基又 は保護されていてもよいヒドロキシェチル基を示し、 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ェチル基を示し （但し、 X I、 X 2及 ぴ n個の Xの全てが同時にメチル基となる場合は除く）、 R 2は水素原子又は水酸 基の保護基を示し、 R 3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。 好ましくは、 各々のヒドロキシェチル基の保護基と R 2で示 される水酸基の保護基は異なる基である。 In the formula (3) having a hydroxylethyl group, XI and X2 represent a methyl group or a hydroxyethyl group which may be protected, and n Xs each independently represent a methyl group or a protected ethyl group. R 2 represents a hydrogen atom or a hydroxyl-protecting group, provided that XI, X 2 and ぴ n X all simultaneously form a methyl group; 3 represents a hydrogen atom or a carboxyl group-protecting group, and n represents an integer of 1 to 4. Preferably, the protecting group for each hydroxyethyl group and the protecting group for the hydroxyl group represented by R 2 are different groups.
ヒドロキシルェチル基を有する式 （4 ) において、 R 1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 口キシェチル基を示し、 nは 1〜5の整数を示す。 In the formula (4) having a hydroxylethyl group, R 1 represents a hydrogen atom or a hydroxyl-protecting group, and n Xs each independently represent a methyl group or an optionally protected hydroxyxethyl group; Represents an integer of 1 to 5.
本明細書において 「各々独立に」 とは、 n個の Xは互いに同一でも異なる基で もよく、 相互に独立して選択される基であることを示す。  As used herein, “each independently” means that n Xs may be the same or different groups, and are mutually independently selected groups.
R 1又は R 2で表される水酸基の保護基、並びにヒドロキシェチル基の保護基の 種類は特に限定されず、 当業者であれば適宜選択することができる。 上記の保護 基の具体例としては、 水酸基の保護基として本明細書中上記したものが挙げられ る。 ―' The types of the protecting group for the hydroxyl group and the protecting group for the hydroxyethyl group represented by R 1 or R 2 are not particularly limited, and can be appropriately selected by those skilled in the art. Specific examples of the above protecting group include those described herein above as the protecting group for a hydroxyl group. ― '
R 3で表されるカルボキシル基の保護基の種類は特に限定されず、 当業者であ れば適宜選択することができる。 力ルポキシル基の保護基の具体例としては、 本 明細書中上記したものが挙げられる。 The type 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 the carbonyl group include those described above in the present specification.
次に、 本発明のヒドロキシェチル基を有する化合物の製造方法について説明す 式 （1 ) で表される化合物は、 乳酸の側鎖に保護されたヒドロキシェチル基を 有する化合物である。 式 （2 ) で表される化合物は、 乳酸 2量体の側鎖に保護さ れていてもよいヒドロキシェチル基を有する化合物であり、 式 （3 ) で表される 化合物は、 乳酸の 3量体から 6量体の側鎖に保護されていてもよいヒドロキシェ チル基を 1個以上有する化合物である。 式 （4 ) で表される化合物は、 乳酸の 2 量体から 6量体の環化物であり、 側鎖に保護されていてもよいヒドロキシェチル 基を 1個以上有する化合物である。 式 （4 ) で表される 匕合物は、 式 （2 ) 又は 式 （3 ) で表される化合物を分子内脱水縮合による環化反応に供することによつ て合成することができる。 Next, a method for producing a compound having a hydroxyethyl group of the present invention will be described. 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 on the side chain of the lactic acid dimer, and the compound represented by the formula (3) is It is a compound having at least one hydroxyethyl group which may be protected on the side chain of a monomer to a hexamer. The compound represented by the formula (4) is a cyclized product of dimer to hexamer of lactic acid, and is a compound having at least one hydroxyethyl group which may be protected in a side chain. The conjugate represented by the formula (4) can be synthesized by subjecting the compound represented by the formula (2) or (3) to a cyclization reaction by intramolecular dehydration condensation.
上記した本発明の化合物の具体的な合成ルートについて以下に例を挙げて説 明する。  The specific synthetic route of the compound of the present invention will be described below with reference to examples.
ヒ ドロキシェチル基を有する環状乳酸オリゴエステルは下記に示すように、 2， 4-ジヒドロキシブタン酸 （3) と鎖状乳酸オリゴマー （4) を縮合した後、 環化 反応により合成できるも。  As shown below, a cyclic lactic acid oligoester having a hydroxyxethyl group can be synthesized by condensing 2,4-dihydroxybutanoic acid (3) with a linear lactic acid oligomer (4) and then cyclizing.
Figure imgf000022_0001
Figure imgf000022_0001
まず、 3の 4-位の水酸基を TBDMS基で保護した 2 (S)， 4-ジヒドロキシブタン酸 ベンジルエステルを合成する。 L -リンゴ酸 （5) を出発物質として、 α -ヒドロキ シ酸部分をァセトニドとして保護した後、 残りの力ルポキシル基を還元しアルコ ール （7) とし、 TBDMS基で保護し （8) とする。 得られた 8のカルボキシル基を ベンジルエステルとし、 （S) , 4 -ジヒドロキシブタン酸誘導体 （9) が得られる。
Figure imgf000023_0001
First, 2 (S), 4-dihydroxybutanoic acid benzyl ester in which the 4-position hydroxyl group of 3 is protected by TBDMS group is synthesized. Starting with L-malic acid (5) and protecting the α- hydroxy acid moiety as acetonide, the remaining carboxylic group is reduced to alcohol (7), protected with TBDMS group and protected with TBDMS group (8). I do. Using the obtained carboxyl group of 8 as a benzyl ester, (S), 4-dihydroxybutanoic acid derivative (9) is obtained.
Figure imgf000023_0001
—方、 ¾酸に対して過剰の臭化ベンジルを作用させ、 ベンジルォキシ乳酸ベン ジルとした後、 接触還元によるべンジルエステルの選択的脱保護により、 ベンジ ルォキシ乳酸 （10) が得られる。 10と力ルポキシル基が保護された乳酸オリゴマ 一 (11) との縮合反応後、 力ルポキシル基の保護基を選択的に脱保護することに より、 鎖長の異なるベンジルォキシ乳酸オリゴマー （13) が得られる。
Figure imgf000023_0002
Bn, Phenacyl 12On the other hand, excess benzyl bromide is reacted with diacid to form benzyloxylactate, and benzyloxylactic acid (10) is obtained by selective deprotection of benzyl ester by catalytic reduction. After the condensation reaction between 10 and the lactate oligomer having a protected oxyloxyl group (11), the benzyloxylactate oligomer (13) having a different chain length can be obtained by selectively deprotecting the oxyloxyl group-protecting group. Can be
Figure imgf000023_0002
Bn, Phenacyl 12
Figure imgf000023_0003
Figure imgf000023_0003
13 n = 1 , 2  13 n = 1, 2
ベンジルォキシ乳酸オリゴマー 13と先に合成した 9との縮合反応により、対応 する縮合物 （14) が得られ、 14のベンジル基を脱保護したところ tert-プチルジ メチルシロキシェチル基を有する鎖状乳酸オリゴマー （15) が得られる。 15の環 化反応により、 側鎖にヒ ドロキシルェチル基を有する環状のオリゴ乳酸エステル が得られる。
Figure imgf000024_0001
The condensation reaction of the benzyloxy lactic acid oligomer 13 with the previously synthesized 9 yields the corresponding condensate (14), and the benzyl group of 14 is deprotected. As a result, a chain lactic acid oligomer having a tert-butyldimethylsiloxyshetyl group is obtained. (15) is obtained. By the cyclization reaction of 15, a cyclic oligolactic acid ester having a hydroxyethyl group in the side chain is obtained.
Figure imgf000024_0001
あるいはまた、 L -リンゴ酸 （1 ) にポランテトラヒドロフランを作用させ 2 とし、 得られた 2にべンズアルデヒドを反応させ、 2位と 4位のヒドロキシル基 が反応したジォキソラン誘導体 （3 ) を得ることができる。
Figure imgf000024_0002
Alternatively, L-malic acid (1) is reacted with porane tetrahydrofuran to obtain 2, and the resulting 2 is reacted with benzaldehyde to obtain a dioxolane derivative (3) in which the 2- and 4-hydroxyl groups have reacted. Can be.
Figure imgf000024_0002
1 2 3  one two Three
3に三酸化クロム、 ピリジン、 無水酢酸、 および ari-ブタノールを作用させ 4を得た後、 トリェチルシラン、 トリフルォロ酢酸を作用させ 5を得ることがで きる。  Chromium trioxide, pyridine, acetic anhydride, and ari-butanol are allowed to act on 3 to give 4, and then triethylsilane and trifluoroacetic acid are allowed to act to give 5.
Figure imgf000024_0003
Figure imgf000024_0003
L一乳酸 （6 ) にイミダゾール存在下、 塩化 er -プチルジメチルシラン (TBDMSCl)を作用させ、水酸基おょぴカルポキシル基を TBDMS化した化合物（ 7 ) とし、 塩化ォキザリルを反応させ酸塩化物 （8 ) としたのち、 5との縮合反応を 行うことにより、 対応する 9が得られる。 9の環化反応により、 側鎖にヒドロキ シルェチル基を有する環状のオリゴ乳酸エステルが得られる。  L-Lactic acid (6) is reacted with er-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 is reacted with oxalyl chloride to form an acid chloride (8 ), And then a condensation reaction with 5 gives the corresponding 9. By the cyclization reaction of 9, a cyclic oligolactic acid ester having a hydroxyethyl group in the side chain is obtained.
Figure imgf000024_0004
(C) 力ルポキシルメチル基を有する化合物
Figure imgf000024_0004
(C) a compound having a propyloxylmethyl group
本発明は、 カルボキシルメチル基を有する式 （1 ) から式 （4 ) で表される化 合物又はその塩、 並びに、 力ルポキシルメチル基を有する式 （2 ) 又は式 （3 ) で表される化合物を分子内で環化することにより式 （4 ) で表される化合物を製 造する方法に関する。  The present invention provides a compound represented by the formula (1) to the formula (4) having a carboxylmethyl group or a salt thereof, and a compound represented by the formula (2) or the formula (3) having a propyloxylmethyl group. The present invention relates to a method for producing a compound represented by the formula (4) by cyclizing a compound in a molecule.
カルボキシルメチル基を有する式 （1 ) 〜 （4 ) において、 R 1はカルポキシ ル基の保護基又は水素原ギを示し、 R 2は水素原子又は水酸基の保護基を示し、 R 3はカルボキシル基の保護基又は水素原子を示す。 In the formulas (1) to (4) having a carboxylmethyl group, R 1 represents a carboxyl group-protecting group or a hydrogen atom, R 2 represents a hydrogen atom or a hydroxyl-protecting group, and R 3 represents a carboxyl group. Represents a protecting group or a hydrogen atom.
R 2で表される水酸基の保護基の種類は特に限定されず、 当業者であれば適宜 選択することができる。 水酸基の保護基の具体例としては、 本明細書中上記した ものが挙げられる。 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 those described herein above.
R 1及び R 3で表されるカルボキシル基の保護基の種類は特に限定されず、当業 者であれば適宜選択することができる。 カルボキシル基の保護基の具体例として は、 本明細書中上記したものが挙げられる。 The type of the carboxyl-protecting group represented by R 1 and R 3 is not particularly limited, and can be appropriately selected by those skilled in the art. Specific examples of the carboxyl-protecting group include those described above in this specification.
次に、 本発明のカルポキシルメチル基を有する化合物の製造方法について説明 する。  Next, a method for producing the compound having a carboxylmethyl group of the present invention will be described.
式 （1 ) で表される化合物は、 乳酸の側鎖に保護されたカルボキシルメチル基 を有する化合物である。 式 （2 ) で表される化合物は、 乳酸 2量体の側鎖に保護 されていてもよい力ルポキシルメチル基を有する化合物であり、 式 （3 ) で表さ れる化合物は、 乳酸の 3量体の側鎖に保護されていてもよい力ルポキシルメチル 基を有する化合物である。 式 （4 ) で表される化合物は、 乳酸の 2量体から 6量 体の環化物であり、 側鎖に保護されていてもよいカルボキシルメチル基を有する 化合物である。 式 （4 ) で表される化合物は、 例えば、 式 （2 ) 又は式 （3 ) の 化合物のような側鎖に保護されたカルボキシルメチル基を有する直鎖の乳酸ォ リゴマーを 2, 4, 6-トリクロロべンゾイルク口ライドの存在下で分子内脱水縮合 による環化反応に供することによつて合成することができる。 上記した本発明の化合物の具体的な合成ルートについて、 本明細書に記載の実 施例を例として挙げて説明する。 まず、 リンゴ酸の 2つのカルボキシル基にそれ ぞれ異なる保護基を導入する。 すなわち、 力ルポキシル基とヒドロキシル基を保 護した後、 フリーのカルボキシル基をべンジル基で保護、 続いて、 a -ヒドロキ シ酸をフリーとし、 力ルポキシル基をフエナシル基で保護することにより、 2が 得られる。 '
Figure imgf000026_0001
The compound represented by the formula (1) is a compound having a carboxylmethyl group protected on the side chain of lactic acid. The compound represented by the formula (2) is a compound having an olepoxylmethyl group which may be protected in the side chain of the lactic acid dimer, and the compound represented by the formula (3) is It is a compound having an optionally protected lipoxylmethyl group in the side chain of the monomer. The compound represented by the formula (4) is a cyclized product of dimer to hexamer of lactic acid, and is a compound having a carboxylmethyl group which may be protected in a side chain. The compound represented by the formula (4) may be, for example, a linear lactic acid oligomer having a carboxylmethyl group protected on the side chain such as the compound of the formula (2) or the formula (3) is 2, 4, 6 The compound can be synthesized by subjecting it to a cyclization reaction by intramolecular dehydration condensation in the presence of -trichlorobenzoyl chloride. The specific synthetic route of the compound of the present invention described above will be described with reference to the examples described in the present specification as examples. First, different protecting groups are introduced into the two carboxyl groups of malic acid. In other words, after protecting the hydroxyl group and the hydroxyl group, the free carboxyl group is protected with a benzyl group, and then the a-hydroxy acid is free, and the hydroxyl group is protected with a phenacyl group. Is obtained. '
Figure imgf000026_0001
次に L -乳酸のヒドロキシル基と力ルポキシル基を塩化 ατί -ブチルジメチルシ ランによって保護し、 さらに塩化ォキサリルを反応させ酸塩化物とした後、 2と の縮合反応を行い、 4を得ることができる。  Next, the hydroxyl group and the hydroxyl group of L-lactic acid are protected with ατί-butyldimethylsilane chloride, and oxalyl chloride is further reacted to form an acid chloride, which is then subjected to a condensation reaction with 2 to obtain 4. it can.
Figure imgf000026_0002
Figure imgf000026_0002
3 4  3 4
続いて 4のフヱナシル基を還元的に脱保護するために亜鉛および酢酸を用.いる ことにより、 5を得ることができる。 さらに 5の TBDMS基を脱保護するために、 フッ化水素酸を作用させることにより、 6を得ることができる。  Subsequent use of zinc and acetic acid to reductively deprotect the phenacyl group of 4 gives 5; Further, 6 can be obtained by reacting hydrofluoric acid to deprotect the 5 TBDMS group.
Figure imgf000026_0003
Figure imgf000026_0003
4 5 6 また 2 を用いた別の合成経路により、 鎖長の異なる α -ヒドロキシ酸エステル を得ることができる。 化合物 6などの側鎖に保護された力ルポキシルメチル基を 有する乳酸オリゴマーを環化することによって、 側鎖にカルボキシルメチル基を 有する環状の乳酸オリゴマーを合成することができる。 (D) 本発明の化合物全般についての説明 456 In addition, α-hydroxy acid esters having different chain lengths can be obtained by another synthetic route using 2. By cyclizing a lactic acid oligomer having a lipoxylmethyl group protected in the side chain such as Compound 6, a cyclic lactic acid oligomer having a carboxylmethyl group in the side chain can be synthesized. (D) General description of the compound of the present invention
本発明のアミノエチル基、 ヒ ドロキシルェチル基又はカルポキシルメチル基を 有する化合物は塩としても存在することができる場合もある。 このような金属塩 としては、 ナトリウム塩、 カリウム塩等のアルカリ金属塩、 マグネシウム塩、 力 ルシゥム塩等のアルカリ土類金属塩、 アルミニウム塩、 又は亜鉛塩等が挙げられ る。 さらに、 本発明の化合物の各種の水和物、 溶媒和物や結晶多形の物質も本発 明の範囲内のものである。  The compound having an aminoethyl group, a hydroxyethyl group or a carboxylmethyl group of the present invention can sometimes exist as a salt. Examples of such a metal salt include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a magnesium salt and a potassium salt, an aluminum salt, and a zinc salt. Furthermore, various hydrates, solvates and polymorphs of the compound of the present invention are also within the scope of the present invention.
本発明のアミノエチル基、 ヒ ドロキシルェチル基又は力ルポキシルメチル基を 有する化合物には不斉炭素が含まれるため立体異性体が存在するが、 全ての可能 な異性体、 並びに 2種類以上の該異性体を任意の比率で含む混合物も本発明の範 囲内のものである。 即ち、 本発明の化合物は、 光学活性体、 ラセミ体、 ジァステ レオマー等の各種光学異性体の混合物及びそれらの単離されたものを含む。  The compound having an aminoethyl group, a hydroxyethyl group or a hepoxylmethyl group of the present invention has stereoisomers because of containing an asymmetric carbon, but all possible isomers and two or more kinds of the isomers are present. Mixtures containing the bodies in any proportion are also within the scope of the present invention. That is, the compound of the present invention includes a mixture of various optical isomers such as an optically active substance, a racemate, and a diastereomer, and an isolated form thereof.
本発明のアミノエチル基、 ヒドロキシルェチル基又は力ルポキシルメチル基を 有する化合物の立体配置は、 原料として使用する化合物における乳酸単位の立体 配置に依存する。即ち、原料として使用する化合物における乳酸単位として L体、 D体またはその混合物を使用するかにより、 本発明の化合物の立体配置も多様な ものとなる。 本発明においては、 乳酸単位の立体配置としては L体を使用するこ とが好ましい。  The configuration of the compound of the present invention having an aminoethyl group, a hydroxylethyl group or a propyloxylmethyl group depends on the configuration of a 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 the L-form, the 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, it is preferable to use the L-form as the configuration of the lactic acid unit.
以下の実施例により本発明をより具体的に説明するが、 本発明は実施例によつ て限定されることはない。  The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the examples.
実施例 Example
実施例 A— 1 ：
Figure imgf000027_0001
Example A-1:
Figure imgf000027_0001
窒素雰囲気下、 室温にて 100mlナス型フラスコに 40mlのジクロロメタンを入 れ、 酸化銀（I) 10. 0317g (43. 2mmol) を加えた。 さ らに乳酸ラ タ トイル 2.266g(14. Ommol)の 20mlジクロロメタン溶液を加えた後、 臭化べンジル .15ml (34.9imnol) を加えた。 これを 15.5 時間撹拌し、 セライトを用いてブフナー漏 斗でろ過し、 これを濃縮した。 この反応混合物をシリカゲルカラムクロマトグラ フィー（展開溶媒 エーテル一へキサン 1:8)を用いて単離精製を行い生成物を 2.3077g, 48.1%の収率で得た。 Under a nitrogen atmosphere, 40 ml of dichloromethane was put into a 100 ml eggplant-shaped flask at room temperature, and 10.0317 g (43.2 mmol) of silver oxide (I) was added. Lactate ratatoyl After adding 2.266 g (14. Ommol) of a 20 ml dichloromethane solution, .15 ml (34.9 imnol) of benzylbenzene bromide was added. This was stirred for 15.5 hours, filtered through a Buchner funnel using 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 a product in a yield of 48.1%.
[ひ]。18·3=— 84.8° (c=5.1, CHC13) [H]. 18 · 3 = - 84.8 ° ( c = 5.1, CHC1 3)
IR(cm— ： 2989 (Ph)， 1751(00) (NaCl)  IR (cm—: 2989 (Ph), 1751 (00) (NaCl)
¾ - NMR(500MHz， CDC13) ¾ - NMR (500MHz, CDC1 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=ll.5Hz) and 4.75 (2H， d, J=ll.5Hz). 5.16-5.26 (3H, m), 7.30—7.40 (10H, m)  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 = ll.5Hz) and 4.75 (2H, d, J = ll.5Hz). 5.16-5.26 (3H, m), 7.30-7.40 (10H, m)
13C-NMR (125MHz, CDC13) 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 実施例 A— 2
Figure imgf000028_0001
 13 C-NMR (125MHz, CDC1 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 A- 2
Figure imgf000028_0001
窒素雰囲気下、室温にて乳酸べンジルエーテル 3.6252g(20. lmmol)の 10mlジク ロロメタン溶液に，乳酸 2量体 プロモフエナシルエステル 22.1202g(61.6mmol) の 90ml ジクロロメタン溶液を加え、 さらに 4 -ジメチルァミノピリジン 0.1531g(1.25mmol)の 3ml ジクロロメタン溶液を加えた。 これを氷浴にて十分冷 却した後 N， N' -ジシク口へキシルカルポジィミド 5.2033g(25.2腿 ol)の 10mlジ クロロメタン溶液をゆつくり滴下し、 氷浴を取り除いた。 反応混合物を 30分間 撹拌した後、 1 規定の硫酸水素カリウム水溶液で反応を停止した。 副生した N, N' -ジシクロへキシル尿素をブフナー漏斗により吸引濾過を行い取り除き、 ジク ロロメタンで抽出（30ml X 3)したものを飽和食塩水で洗い硫酸マグネシゥムで乾 燥し減圧濃縮した。 これをシリカゲルカラムクロマトグラフィー (展開溶媒酢酸 ェチルーへキサン 1:1)'を用いて単離精製を行い乳酸 3量体べンジルエーテル p~ ブロモフエナシルエステルを 9.0194g， 86.3%の収率で得た。 Under a nitrogen atmosphere, at room temperature, to a solution of benzyl ether lactate (3.6252 g, 20.lmmol) in 10 ml of dichloromethane, add a solution of 22.1202 g (61.6 mmol) of lactic acid dimer promophenacyl ester in 90 ml of dichloromethane, and further add 4-dimethyl. A solution of 0.1531 g (1.25 mmol) of the aminopyridine in 3 ml of dichloromethane was added. This was cooled sufficiently in an ice bath, and a solution of 5.2033 g (25.2 tmol) of N, N'-dicylhexylcarboximide in 10 ml of dichloromethane was slowly added dropwise, and the ice bath was removed. After stirring the reaction mixture for 30 minutes, the reaction was stopped with a 1 N aqueous solution of potassium hydrogen sulfate. The by-produced N, N'-dicyclohexylurea was removed by suction filtration with a Buchner funnel, extracted with dichloromethane (30 ml x 3), washed with saturated saline and dried over magnesium sulfate. It was dried 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, 86.3% yield of lactic acid trimer benzyl ether p ~ bromophenacyl ester. Was.
[o!]D 24.5=— 85.1° (c=0.47, CHC13) [o!] D 24 5 = -. 85.1 ° (c = 0.47, CHC1 3)
IR(cm—り ： 2935 (Ph) , 1761 (C=0) ， 1747 (C=0) ， 1705 (C=0) (NaCl)  IR (cm-RI: 2935 (Ph), 1761 (C = 0), 1747 (C = 0), 1705 (C = 0) (NaCl)
¾-NMR (500MHz, CDC13) ¾-NMR (500MHz, CDC1 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=ll.5Hz) and 4.77 (2H, d, J=ll.5Hz), 5.21-5.26 (2H， m)， 5.32 (IH, 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) 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 = ll.5Hz) and 4.77 (2H, d, J = ll.5Hz), 5.21-5.26 (2H, m), 5.32 (IH, 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)
13C- MR (125MHz, CDC13)， 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 実施例 A— 3 ：
Figure imgf000029_0001
 13 C- MR (125MHz, CDC1 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 carried Example A—3:
Figure imgf000029_0001
窒素雰囲気下、 室温にて 500ml 三口丸底フ ラ ス コ に亜鉛粉末 9.8685g(151. Olmmol)をカロえ、 130ml のエーテルをカロえた.' これに酢酸 9.2994g(154.86mmol)と乳酸 3量体べンジルエーテル ブロモフエナシルエステ ル 5.2332g(10.04腿 ol)の 50mlエーテル溶液を加え 6時間撹拌した。 これを濾過 し減圧下濃縮した。 これをシリカゲルカラムクロマトグラフィー（展開溶媒酢酸 ェチルーへキサン 1:4)を用いて単離精製し乳酸 3 量体べンジルエーテルを 3.0352g, 93.2%の収率で得た。  Under a nitrogen atmosphere, at room temperature, 500 ml three-necked round bottom flask was charged with 9.8685 g (151 Olmol) of zinc powder and 130 ml of ether. '9.2994 g (154.86 mmol) of acetic acid and 3 parts of lactic acid A 50 ml ether solution of 5.2332 g (10.04 tmol) of benzyl ether bromophenacyl ester 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: 4) to obtain 3.0352 g of lactic acid trimer benzyl ether in a yield of 93.2%.
[a]D 23.9 =— 90.6° (c=0.95， CHC13) [a] D 23 9 = - . 90.6 ° (c = 0.95, CHC1 3)
IR(cm— ： 2993 (Ph) , 1755 (C=0) (NaCl)IR (cm—: 2993 (Ph), 1755 (C = 0) (NaCl)
— NMR(500匪 z, CDCI3) δ (ppm)= 1.50 (3H， d， J=7Hz) , 1.57 (3H, d， J=7Hz), 1.60 (3H, d, J=7.5Hz) , 4.14 (1H， q, J=7Hz) , 4.48 (d, J=11.5Hz) and 4.76 (2H, d, J=ll.5Hz), 5.18-5.23 (2H， m)， 7.28—7.38 (5H, m) — NMR (500 band z, CDCI3) δ (ppm) = 1.50 (3H, d, J = 7Hz), 1.57 (3H, d, J = 7Hz), 1.60 (3H, d, J = 7.5Hz), 4.14 ( 1H, q, J = 7Hz), 4.48 (d, J = 11.5Hz) and 4.76 (2H, d, J = ll.5Hz), 5.18-5.23 (2H, m), 7.28-7.38 (5H, m)
13C-NMR (125MHz, CDC13) 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 実施例 A— 4
Figure imgf000030_0001
 13 C-NMR (125MHz, CDC1 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 A- 4
Figure imgf000030_0001
窒素雰囲気下、 室温にて乳酸二量体べンジルエーテル 1.0111g(4.01mmol)の 2.5ml ジクロロメタン溶液に、 乳酸二量体べンジルエステル 2.9622g(11.7膽 ol) の 3.5ml ジクロロメタン溶液を加え、 さらに 4-ジメチルァミノピリジン 0.0209g(0.17讓 ol)の 0.5ml ジクロロメタン溶液を加えた。 これを氷浴にて十分 冷却した後 N， N' -ジシクロへキシルカルポジイミ ド 1.0376g(6.34腿 ol)の 2.5ml ジクロロメタン溶液をゆつく り滴下し、 氷浴を取り除いた。 反応混合物を 30 分 間撹拌した後， 1規定の硫酸水素カリウム水溶液で反応を停止した。 副生した N, N' -ジシクロへキシル尿素をブフナー漏斗により吸引濾過を行い取り除き、 ジク ロロメタンで抽出（30ml X 3)したものを飽和食塩水で洗レ、硫酸マグネシゥムで乾 燥し減圧濃縮した。 これをシリカゲルカラムクロマトグラフィー（展開溶媒 酢酸 ェチルーへキサン 1:1)を用いて単離精製を行い乳酸 4 量体べンジルエーテルべ ンジルエステルを 1.5982g, 82.1%の収率で得た。  At room temperature under a nitrogen atmosphere, at room temperature, to a solution of 1.0111 g (4.01 mmol) of lactic acid dimer benzyl ether in 2.5 ml of dichloromethane, add a solution of 2.9622 g (11.7 glutol) of lactic acid dimer benzyl ester in 3.5 ml of dichloromethane, and further added 4 A solution of 0.0209 g (0.17 benzyl) of -dimethylaminopyridine in 0.5 ml of dichloromethane was added. After sufficiently cooling this in an ice bath, a solution of 1.0376 g (6.34 tmol) of N, N'-dicyclohexylcarpoimide in 2.5 ml of dichloromethane was slowly added dropwise, and the ice bath was removed. After stirring the reaction mixture for 30 minutes, the reaction was stopped with 1 N aqueous potassium hydrogen sulfate solution. The by-produced N, N'-dicyclohexylurea was removed by suction filtration using a Buchner funnel, extracted with dichloromethane (30 ml x 3), washed with saturated saline, 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 1.5982 g of lactic acid tetramer benzyl ether benzyl ester in a yield of 82.1%.
[a]D 15.5=-111.2° (c=0.54, CHC13) [a] D 15. 5 = -111.2 ° (c = 0.54, CHC1 3)
IR(cm— ： 2991 (Ph), 1755 (C=0) (NaCl) IR (cm—: 2991 (Ph), 1755 (C = 0) (NaCl)
¾-NMR (500MHz, CDC13) 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=ll.0Hz) and 4.77 (2H, d, J=ll.5Hz), 5.13 (d, J=12.0Hz) and 5.20 (2H， d， J=12.0Hz), 5.18-5.23 (3H， m), 7.28-7.39 (10H, m) ¾-NMR (500MHz, CDC1 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 = ll.0Hz) and 4.77 (2H, d, J = ll.5Hz), 5.13 (d, J = 12.0Hz) and 5.20 (2H, d, J = 12.0Hz), 5.18-5.23 (3H, m), 7.28-7.39 (10H, m)
13C-NMR (125MHz, CDC13) 5 (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 実施例 A— 5 ：
Figure imgf000031_0001
 13 C-NMR (125MHz, CDC1 3) 5 (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 A-5:
Figure imgf000031_0001
室温にて 50ml二口ナスフラスコに乳酸 4量体べンジルエーテルベンジルエス テル 1.4760g(3.03匪 ol)の 4ml酢酸ェチル溶液を加え、 さらにトリェチルァミン 0.0367g(0.362讓 ol)の 1.5ml酢酸ェチル溶液を加え、パラジウムチヤコール（10%) を 0.1973g加えた。 これを水素置換し 5時間撹拌した。 その後反応混合物をセラ ィ トを用いてブフナー漏斗でろ過しこれを濃縮し、 さらにシリカゲルを用いてろ 過しこれを濃縮し乳酸 4量体べンジルエーテルを 1.1577g、 96.3%の収率で得た。  At room temperature, in a 50 ml two-necked eggplant flask was added a solution of lactic acid tetramer benzyl ether benzyl ester 1.4760 g (3.03 marl ol) in 4 ml ethyl acetate, and further added triethylamine 0.0367 g (0.362 ml ol) in 1.5 ml ethyl acetate. In addition, 0.1973 g of palladium charcoal (10%) was added. This was replaced with hydrogen and stirred for 5 hours. Thereafter, the reaction mixture was filtered through a Buchner funnel using a ceramic, concentrated, filtered through silica gel, and concentrated to obtain 1.1577 g of lactic acid tetramer benzyl ether in a yield of 96.3%. .
[ひ ]。14.6= - 101.2° (c=l.1， CHC13) [H]. . 14 6 = - 101.2 ° ( c = l.1, CHC1 3)
IR(cm_1) ： 2993 (Ph) , 1755 (C=0) (NaCl) IR (cm _1 ): 2993 (Ph), 1755 (C = 0) (NaCl)
NMR(500匪 z， CDCI3) 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 (IH, q， J=7Hz) , 4. 7 (d, J=ll.5Hz) and 4.76 (2H， d, J=11.5Hz)， 5.15 (IH, q, J=7Hz), 5.20 (2H, q, J=7Hz)， 7.27-7.37 (5H, m)  NMR (500 band z, CDCI3) δ (ppm) = 1.49 (3H, d, J = 7 Hz), 1.54 (3H, d, J = 7 Hz), 1.58 (3H, d, J = 7 Hz), 1.60 (3H, d, J = 7Hz), 4.14 (IH, q, J = 7Hz), 4.7 (d, J = ll.5Hz) and 4.76 (2H, d, J = 11.5Hz), 5.15 (IH, q, J = 7Hz), 5.20 (2H, q, J = 7Hz), 7.27-7.37 (5H, m)
13C- MR (125MHz, CDC13) 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 実施例 A— 6
Figure imgf000031_0002
窒素雰囲気下、室温にて乳酸 3量体べンジルエーテル 0.6643g(2.05mmol)の 3ml ジク ロ ロメ タン溶液に、 乳酸 2 量体 プロモフエナシルエステル 2.1595g(6. Olmmol)の 5mlジクロロメタン溶液を加え、 さらに 4 -ジメチルァミノ ピリジン 0.0131g(0.107mmol)の 3mlジクロロメタン溶液を加えた。 これを氷浴に て十分冷却した後 N, N' -ジシクロへキシルカルポジイミ ド 0.5408g(2.62mmol) の 3mlジクロロメタン溶液をゆつくり滴下し、 氷浴を取り除いた。 反応混合物を 30分間撹拌した後、 1規定の硫酸水素カリウム水溶液で反応を停止した。 副生し た N, N' -ジシクロへキシル尿素をブフナー漏斗により吸引濾過を行い取り除き、 ジクロロメタンで抽出（20ml X 3)したものを飽和食塩水で洗い硫酸マグネシゥム で乾燥し減圧濃縮した。 これをシリカゲルカラムクロマトグラフィー（展開溶媒 酢酸ェチルーへキサン 1:4)を用いて単離精製を行い乳酸 5 量体べンジルエーテ ル ブロモフエナシルエステルを 1.0802g, 74.2%の収率で得た。 13 C- MR (125MHz, CDC1 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 A— 6
Figure imgf000031_0002
To a solution of 0.6643 g (2.05 mmol) of lactic acid trimer benzyl ether in 3 ml of dichloromethane at room temperature under a nitrogen atmosphere was added a solution of 2.1595 g (6. Olmmol) of lactic acid dimer promophenacyl ester in 5 ml of dichloromethane. Further, a solution of 0.0131 g (0.107 mmol) of 4-dimethylaminopyridine in 3 ml of dichloromethane was added. Put this in an ice bath After cooling sufficiently, a solution of 0.5408 g (2.62 mmol) of N, N'-dicyclohexylcarpoimide in 3 ml of dichloromethane was slowly added dropwise, and the ice bath was removed. After stirring the reaction mixture for 30 minutes, the reaction was stopped with a 1 N aqueous solution of potassium hydrogen sulfate. The by-produced N, N'-dicyclohexylurea was removed by suction filtration using a Buchner funnel, extracted with dichloromethane (20 ml × 3), washed with saturated saline, 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 pentamer lactic acid benzyl ether bromophenacyl ester in a yield of 74.2%.
[α]。22.9=- 110· 3° (c=0.27， CHC13) [α]. 22. 9 =-110 · 3 ° (c = 0.27, CHC1 3 )
IR(cm— ： 2993 (Ph) , 1770 (C=0), 1705 (C=0) (NaCl) IR (cm—: 2993 (Ph), 1770 (C = 0), 1705 (C = 0) (NaCl)
¾-NMR (500MHz, CDC13) δ (ppm)- 1.48 (3H， d， J=7Hz) ¾-NMR (500MHz, CDC1 3 ) δ (ppm) - 1.48 (3H, d, J = 7Hz)
13C- MR (125MHz, CDC13) 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 実施例 A— 7 ：
Figure imgf000032_0001
 13 C- MR (125MHz, CDC1 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 A-7:
Figure imgf000032_0001
窒素雰囲気下、 室温にて 500ml 三口丸底フラス コに亜鉛粉末 7.8765g(120.5膽 ol)を加え、これに酢酸 7.7331g(128.8励 1)と乳酸 5量体べンジ ルエーテノレ プロモフエナシノレエステノレ 7.5189g(ll.3mmol)の 50mlエーテノレ溶 液を加え 6時間撹拌した。 これを濾過し減圧下濃縮した。 これをシリカゲルカラ ムクロマトグラフィー（展開溶媒酢酸ェチルーへキサン 1:2)を用いて単離精製 し乳酸 5量体べンジルエーテルを 4.8593g, 91.8%の収率で得た。  In a nitrogen atmosphere, at room temperature, add 7.8765 g (120.5 bunol) of zinc powder to a 500 ml three-necked round bottom flask at room temperature, add 7.7331 g (128.8 in 1) of acetic acid and pentamer of lactic acid pentamer. 7.5189 g (ll. 3 mmol) of 50 ml of ethanol solution was added, 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: 2) to obtain 4.8593 g of pentamer of lactic acid at a yield of 91.8%.
[a]D 22.7=—119.3° (c=1.9， CHC13) [a] D 22. 7 = -119.3 ° (c = 1.9, CHC1 3)
IRCcm-1) ： 3518 (COO- H)， 2993 (Ph) , 1755 (C=0) (NaCl) IRCcm -1 ): 3518 (COO-H), 2993 (Ph), 1755 (C = 0) (NaCl)
¾-NMR (500MHz, CDC13) δ (ppm)= 1.49 (3H, d， J=7.0Hz) , 1.56 (3H， d, J=7.5Hz) , 1.58-1.61 (9H， m)， 4.14 (1H, q, J=7.0Hz) , 4.47 (d, J=ll.5Hz) and 4.76 (2H: d, J=11.5Hz), 5.16-5.23 (4H, m), 7.29-7.38 (5H, m) ¾-NMR (500MHz, CDC1 3 ) δ (ppm) = 1.49 (3H, d, J = 7.0Hz), 1.56 (3H, d, J = 7.5Hz), 1.58-1.61 (9H, m), 4.14 (1H, q, J = 7.0Hz), 4.47 (d, J = ll.5Hz) and 4.76 (2H: d, J = 11.5Hz), 5.16-5.23 (4H, m), 7.29-7.38 (5H, m)
13C-NMR (125MHz, CDC13) S (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 実施例 A— 8
Figure imgf000033_0001
 13 C-NMR (125MHz, CDC1 3) S (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 A-8
Figure imgf000033_0001
窒素雰囲気下、氷浴で冷やした 300ml三口丸底フラスコに N- -プトキシカルボ 二ル-（s)- (_)- 4 -ァミノ 2-ヒ ドロキシブタン酸 10.4297g(47.6mmol)の 17mlTHF溶 液を加え、 トリェチルァミン 5.0595g(50.0讓 ol)の 4mlTHF溶液を滴下した。 これ に 2， 4， -ジプロモアセトフェノン 13.9058g(50.0mmol)の 25mlTHF溶液を加え氷 浴をはずした後 1時間撹拌した。 10mlの 1規定硫酸水素力リゥム水溶液で反応を 停止し、 ジクロロメタンで抽出（20ml X 3)したものを飽和食塩水で洗い硫酸マグ ネシゥムで乾燥し減圧濃縮した。これをエーテルから再結晶し N-t-プトキシカル ポニル -（s) -（-）- 4-ァミノ 2-ヒ ドロキシブタン酸 ブロモフエナシルエステルを 19.4687g、 98.3%の収率で得た。  Under a nitrogen atmosphere, add a solution of 10.4297 g (47.6 mmol) of N-butoxycarbonyl- (s)-(_)-4-amino-2-hydroxybutanoic acid in 17 ml of THF to a 300 ml three-necked round bottom flask cooled in an ice bath. A solution of 5.0595 g (50.0 benzyl) of triethylamine in 4 ml of THF was added dropwise. To this was added a solution of 13.9058 g (50.0 mmol) of 2,4, -dibromoacetophenone in 25 ml of THF, and after removing the ice bath, the mixture was stirred for 1 hour. The reaction was quenched with 10 ml of 1N aqueous hydrogen sulfate solution, extracted with dichloromethane (20 ml × 3), washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. This was recrystallized from ether to obtain 19.4687 g of N-t-butoxycarponyl- (s)-(-)-4-amino-2-hydroxybutanoic acid bromophenacyl ester in a yield of 98.3%.
mp=95.1-96.0°C mp = 95.1-96.0 ° C
[α]。17·6=—4.3° (c=5.0, CHC13) [α]. 17 6 =-4.3 ° (c = 5.0, CHC1 3 )
IR(cm_1) ： 3523 (NH) , 3357 (OH) , 2935 (Ph) , 1735 (C=0), 1697(00) (KBr) ¾— NMR(300丽 z， CDCI3) 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) IR (cm _1 ): 3523 (NH), 3357 (OH), 2935 (Ph), 1735 (C = 0), 1697 (00) (KBr) ¾— NMR (300 丽 z, CDCI3) 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)
13C-NMR (125MHz, CDC13) 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 実施例 A— 9 ：
Figure imgf000034_0001
窒素雰囲気下，氷浴で冷やした 200ml三口丸底フラスコに N- 1-ブトキシカルポ 二ル-（s)- (-） - 4-ァミノ 2-ヒ ドロキシブタン酸 2.2422g(10.2贿 ol)の lOmlTHF溶 液を加え、 トリェチルァミン 1.035lg(10.2mmol)の lmlTHF溶液を滴下した。 これ に 2，-ブロモアセトフエノン 2.4211g(12.2mmol)の lOmlTHF溶液を加え水浴をは ずした後 2時間撹拌した。 10mlの 1規定硫酸水素力リゥム水溶液で反応を停止し、 クロロホルムで抽出（30ml X3)したものを飽和食塩水で洗い硫酸マグネシウムで 乾燥し減圧濃縮した. この反応混合物をシリカゲルカラムクロマトグラフィー (展開溶媒 エーテル）を用いて単離精製を行い N-t-ブトキシカルポニル -（s)- (- )-4 -ァミノ 2-ヒ ドロキシブタン酸フエナシルエステルを 3.4019g、 98.9% の収率で得た。 13 C-NMR (125MHz, CDC1 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 A-9:
Figure imgf000034_0001
In a 200-ml three-necked round-bottomed flask cooled in an ice bath under a nitrogen atmosphere, a solution of 2.2422 g (10.2 mol) of l-OlTHF in N-1-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid was added. It was added, dropwise lmlTHF solution Toryechiruamin 1.03 5 lg (10.2mmol). A solution of 2.4211 g (12.2 mmol) of 2, -bromoacetophenone in lOml THF was added thereto, the water bath was removed, and the mixture was stirred for 2 hours. The reaction was quenched with 10 ml of 1N aqueous hydrogen sulfate solution, extracted with chloroform (30 ml X3), washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The reaction mixture was subjected to silica gel column chromatography (developing solvent). Then, Nt-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid phenacyl ester was obtained in a yield of 3.4019 g and 98.9%.
mp=86.6-88.2°Cmp = 86.6-88.2 ° C
Figure imgf000034_0002
Figure imgf000034_0002
IR(cm—り ： 3444 (NH), 3367 (OH), 2983 (Ph)， 1749 (C=0), 1712 (C=0), 1685 (C=0) (KBr)  IR (cm-RI: 3444 (NH), 3367 (OH), 2983 (Ph), 1749 (C = 0), 1712 (C = 0), 1685 (C = 0) (KBr)
¾ー丽 R(300匪 z， CDCI3) 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, ]=7.5Hz) , 7.62 (1H， t, J=7.5Hz) , 7.90 (2H, d, J=7.5Hz)  丽 丽 R (300 bandz, CDCI3) 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,] = 7.5Hz), 7.62 ( 1H, t, J = 7.5Hz), 7.90 (2H, d, J = 7.5Hz)
13C-NMR (125MHz, CDC13) 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 実施例 A— 10 ：
Figure imgf000035_0001
 13 C-NMR (125MHz, CDC1 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 A-10:
Figure imgf000035_0001
アルゴン雰囲気下、室温にて乳酸べンジルエーテル 0.1824g(l. Olmmol)の 1.2ml ジクロロメタン溶液に、 N- 1-ブトキシカルポニル-（s)- (- )-4 -ァミノ 2-ヒドロキ シブタン酸フエナシノレエステ 1.0041g(2.98mmol)の 5.2mlジクロロメタン溶液 を加え、 さらに 4 -ジメチルァミノピリジン 0.0122g(0. lOmmol)の 0.4mlジク口口 メタン溶液を加えた。 これを氷浴にて十分冷却した後 N， N' -ジシクロへキシル カルポジイミ ド 0.2476g(1.20腿 ol)の 10.4mlジクロロメタン溶液をゆつく り滴下 し、 氷浴を取り除いた。 反応混合物を 3.5時間撹拌した後、 1規定の硫酸水素力 リウム水溶液で反応を停止した。 副生した N， N' -ジシクロへキシル尿素をブフ ナー漏斗により吸引濾過を行い取り除き、 クロ口ホルムで抽出（30mlX3)したも のを飽和食塩水で洗い硫酸マグネシウムで乾燥し減圧濃縮した。 これをシリカゲ ルカラムクロマトグラフィー（展開溶媒 エーテル一へキサン 2: 1)を用いて単 離精製を行い生成物を 0.4179g， 82.8%の収率で得た。 Under an argon atmosphere, at room temperature, N-1-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid phenic acid was added to a solution of 0.1824 g (l. Olmmol) of benzyl lactate in 1.2 ml of dichloromethane at room temperature. A solution of 1.451 g (2.98 mmol) of noreste in 5.2 ml of dichloromethane was added, and further a solution of 0.0122 g (0.1 mmol) of 4-dimethylaminopyridine in 0.4 ml of methane was added. This was cooled sufficiently in an ice bath, and a solution of N, N'-dicyclohexylcarpoimide 0.2476 g (1.20 tmol) in 10.4 ml of dichloromethane was slowly added dropwise, and the ice bath was removed. After stirring the reaction mixture for 3.5 hours, the reaction was stopped with a 1N aqueous solution of sodium hydrogen sulfate. The by-produced N, N'-dicyclohexylurea was removed by suction filtration using a Buchner funnel, and the product extracted with chloroform (30 ml × 3) was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. This was subjected to isolation purification using silica gel column chromatography (developing solvent, ether / hexane 2: 1, 1) to obtain 0.4179 g of the product in a yield of 82.8%.
[a]D 15.9= - 28.9° (c=1.0， CHC13) [a] D 15 9 = - . 28.9 ° (c = 1.0, CHC1 3)
IR(cm_1) ： 3384 (NH), 1755(00), 1705(00) (NaCl) IR (cm _1 ): 3384 (NH), 1755 (00), 1705 (00) (NaCl)
^-NMR (300MHz, CDC13) 5 (ppm)= 1.42 (9H， s), 1.50 (3H, dd， J=4.8, 7.2Hz) , 2.18-2.36 (2H, m)， 3.33-3.43 (2H, m), 4.19 (1H， dq, J=l.7, 6.9Hz)， 4. 7 (d, J=ll.7Hz) and 4.49 (d， J=ll.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， ra), 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) 実施例 A— 1 1
Figure imgf000036_0001
 ^ -NMR (300MHz, CDC1 3) 5 (ppm) = 1.42 (9H, s), 1.50 (3H, dd, J = 4.8, 7.2Hz), 2.18-2.36 (2H, m), 3.33-3.43 (2H, m), 4.19 (1H, dq, J = l.7, 6.9Hz), 4.7 (d, J = ll.7Hz) and 4.49 (d, J = ll.7Hz) and 4.74 (d, J = 11.7 Hz), and 4.77 (2H, d, J = 11.7Hz), 4.94 (1H, bs), 5.26—5.33 (1H, ra), 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) A— 1 1
Figure imgf000036_0001
窒素雰囲気下、 室温にて乳酸べンジルエーテル 2. 7311g (15. lmmol)の 5mlジク ロロメタン溶液に、 N- -ブトキシカルポニル-（s) - (-） - 4-ァミノ 2-ヒ ドロキシプ タン酸 プロモフエナシノレエステノレ 19. 2312g (4 . 2譲 ol)の 110ml ジクロロメタ ン溶液を加え、 さらに 4-ジメチルァミノピリジン 0. 0122g (0. 10匪 ol)の 1mlジク ロロメタン溶液を加えた。 これを氷浴にて十分冷却した後 N， N' -ジシクロへキ シルカルポジィミ ド 3. 5558g (17. 2讓 ol)の 20mlジクロロメタン溶液をゆつく り滴 下し、 氷浴を取り除いた。 反応混合物を 30分撹拌した後、 1規定の硫酸水素カリ ゥム水溶液で反応を停止した。 副生した N， N' -ジシクロへキシル尿素をブフナ 一漏斗により吸引濾過を行い取り除き、 クロ口ホルムで抽出（30ml X 3)したもの を飽和食塩水で洗い硫酸マグネシウムで乾燥し減圧濃縮した。 これをシリカゲル カラムクロマトグラフィー（展開溶媒 エーテル ^キサン 1 : 1 )を用いて単離 精製を行い生成物を 6. 8067g， 77. 9%の収率で得た。 実施例 A— 1 2 ： At room temperature under a nitrogen atmosphere, N-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid was added to a solution of 2.7311 g (15.lmmol) of benzyl ether lactate in 5 ml of dichloromethane. A solution of 19.2312 g (4.2 mol) of fenacinoleestenole in 110 ml of dichloromethane was added, and a solution of 0.0122 g (0.10 marl) of 4-dimethylaminopyridine in 1 ml of dichloromethane was added. After sufficiently cooling this in an ice bath, 3.5 ml of N, N'-dicyclohexylcarboamide (20 ml) in 20 ml of dichloromethane was slowly dropped, and the ice bath was removed. After stirring the reaction mixture for 30 minutes, the reaction was stopped with a 1 N aqueous solution of potassium hydrogen sulfate. The by-produced N, N'-dicyclohexylurea was removed by suction filtration using a Buchna funnel, and 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 ^ xan 1: 1) to obtain 6.8067 g of the product in a yield of 77.9%. Example A—12:
Figure imgf000036_0002
Figure imgf000036_0002
窒素雰囲気下、 室温にて 500ml三口丸底フラスコに 2 (s) -ベンジルォキシプロ パノィル- N - 1-ブトキシカルポ二ル-（s) - (-） - 4 -ァミノ 2-ヒ ドロキシブタン酸フ ェナシルエステル 6. 8067g (ll. 8mmol)の 300mlエーテル溶液を加え、 そこに酢酸 20ml (24. 9画 1)を加えた。さらに亜鉛粉末 23. 7420g (36. 3励 1)を加え 1. 5時間撹 拌した。 これを濾過し減圧下濃縮した。 これをシリカゲルカラムクロマトグラフ ィー（展開溶媒 エーテル一^ ^キサン 1 : 1)を用いて単離精製し 2 (s) -ベンジルォ キシプロパノィル- N-t -プトキシカルポ二ル-（s)一 (-） -4 -ァミノ 2-ヒ ドロキシブ タン酸を 2. 6543g， 59. 0%の収率で得た。 実施例 A— 1 3 ：
Figure imgf000037_0001
2 (s) -benzyloxypropanoyl-N-1-butoxycarpanol- (s)-(-)-4- (amino) -2-hydroxybutanoic acid phenic acid in a 500 ml three-necked round bottom flask at room temperature under nitrogen atmosphere To this was added a solution of 6.8067 g (ll. 8 mmol) of ether in 300 ml of ether, and 20 ml of acetic acid (24.9, 1) was added thereto. Further, 23.7420 g (36.3 excitation 1) of zinc powder was added, and the mixture was 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-^-xane 1: 1) and purified by 2 (s) -benzyloxypropanoyl-Nt-butoxycarpanol- (s) -1 (-)-4 -Amino 2-hydroxy Thanic acid was obtained in a yield of 2.6543 g, 59.0%. Example A—13:
Figure imgf000037_0001
室温にて 50ml二口ナスフラスコに 2 (s) -ベンジルォキシプロパノィル- N-t-ブ トキシカルポニル-（s) - (-） - 4-ァミノ 2-ヒ ドロキシブタン酸 1. 7364g (4. 55腿 ol) の 0. 8ml メタノール溶液を加え、 パラジウムチヤコール（5%)を 0. 3572g加えた。 これを水素置換し 2日間撹拌した。 その後反応混合物をセライトを用いてブフナ 一漏斗でろ過しこれを濃縮し、 さらにシリカゲルを用いてろ過しこれを濃縮し生 成物を 1. 2555g、 94. 8%の収率で得た。 実施例 A— 1 4
Figure imgf000037_0002
At room temperature, 2 (s) -benzyloxypropanoyl-Nt-butoxycarponyl- (s)-(-)-4-amino-2-hydroxybutanoic acid 1.7364 g (4.55) 0.8 ml of a methanol solution of thighol) 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 Buchna funnel using celite, concentrated, and further filtered through silica gel. The filtrate was concentrated to obtain 1.2555 g of a product in a yield of 94.8%. Example A—1 4
Figure imgf000037_0002
窒素雰囲気下、 永浴にて十分冷却し N- 1-ブトキシカルボニル -（s) - (-) - 4-アミ ノ 2-ヒドロキシブタン酸ラクトイル 0. 5969g (2. 05mmol)の 190mlジクロロメタン 溶液に、 N， N' -ジシク口へキシルカルポジィミ ド 0. 6551g (3. 18mmol)の 5mlジク ロ ロ メ タ ン溶液をゆつ く り 滴下 し、 4-ジメ チルァ ミ ノ ピ リ ジン 0. 0019g (0. 0016mmol)の 5mlジクロロメタン溶液を加えたのち氷浴を取り除いた。 反応混合物を 30分間撹拌した後、 1規定の硫酸水素力リゥム水溶液で反応を停止 した。 副生した N， N， -ジシクロへキシル尿素をブフナー漏斗により吸引濾過を 行い取り除き、 酢酸ェチルで抽出（20ml X 3)したものを飽和食塩水で洗い硫酸マ グネシゥムで乾燥し減圧濃縮した。 これをシリカゲルカラムクロマトグラフィー (展開溶媒 酢酸ェチルーへキサン 1 : 1)を用いて単離精製を行い生成物を 0. 2273g得た。 実施例 A— 15 ： In a nitrogen atmosphere, cool well in a permanent bath, and add N- 1-butoxycarbonyl- (s)-(-)-amino-4-lactoyl 2-hydroxybutanoate 0.5969 g (2.05 mmol) in 190 ml dichloromethane solution. A solution of 0.6551 g (3.18 mmol) of N, N'-dicyl hexyl carboximide in 5 ml of dichloromethane was slowly added dropwise, and 4-dimethylaminopyridine was 0.0019 g. After adding a solution of (0.006 mmol) in 5 ml dichloromethane, the ice bath was removed. After the reaction mixture was stirred for 30 minutes, the reaction was stopped with a 1N aqueous solution of hydrogen sulfate. The by-produced N, N, -dicyclohexylurea was removed by suction filtration using a Buchner funnel, extracted with ethyl acetate (20 ml × 3), washed with saturated saline, 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 a product. Example A-15:
Figure imgf000038_0001
窒素雰囲気下、 室温にて乳酸 3 量体べンジルエーテル 0.3165g(0.976匪 ol)の 3.5ml ジクロ口メタン溶液に、 N十ブトキシカルボニル-（s) - (-) -4-Tミノ 2-ヒ ドロキシブタン酸 ブロモフエナシルエステル 1.2404g(2.98讓 ol)の 13ml ジク ロロメタン溶液を加え、 さらに 4 -ジメチルァミノピリジン 0.0137g(0.112mmol) の 1ml ジクロロメタン溶液を加えた。 これを氷浴にて十分冷却した後、 N, N' - ジシク口へキシルカルポジィミ ド 0.3148g(l.53醒 ol)の 3.5mlジクロロメタン溶 液をゆつく り滴下し、 氷浴を取り除いた。 反応混合物を 30分間撹拌した後、 1規 定の硫酸水素カリウム水溶液で反応を停止した。 副生した N， N' -ジシクロへキ シル尿素をブフナー漏斗により吸引濾過を行い取り除き、 クロ口ホルムで抽出 (30ml X 3)したものを飽和食塩水で洗い硫酸マグネシゥムで乾燥し減圧濃縮した。 これをシリ力ゲルカラムクロマトグラフィー（展開溶媒 エーテル一へキサン 1:1)を用いて単離精製を行い生成物を 0.4762g, 67.5%の収率で得た。
Figure imgf000038_0001
At room temperature under a nitrogen atmosphere, N-butoxycarbonyl- (s)-(-)-4-Tamino 2-H was added to a solution of 0.3165 g (0.976 marl ol) of lactic acid trimer benzyl ether in 3.5 ml of dichloromethane. A solution of 1.2404 g (2.98 benzyl) of droxybutanoic acid bromophenacyl ester in 13 ml of dichloromethane was added, and a solution of 0.0137 g (0.112 mmol) of 4-dimethylaminopyridine in 1 ml of dichloromethane was further added. After sufficiently cooling this in an ice bath, slowly add 0.3148 g (l.53 ol) of 3.5 ml of a dichloromethane solution of N, N'-disc hexyl carpoimide, and remove the ice bath. Was. After stirring the reaction mixture for 30 minutes, the reaction was stopped with 1N aqueous potassium hydrogen sulfate solution. The by-produced N, N'-dicyclohexylurea was removed by suction filtration using 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 of the product in a yield of 67.5%.
[a]D 18.3=— 2.0° (c=l.0， CHC13) [a] D 18 3 = - . 2.0 ° (c = l.0, CHC1 3)
IR(cm—り ： 3444 (腿）， 3367 (0H), 2983 (Ph) , 1749(00)， 1712(00)， 1685 (C=0) (NaCl)  IR (cm-RI: 3444 (thigh), 3367 (0H), 2983 (Ph), 1749 (00), 1712 (00), 1685 (C = 0) (NaCl)
¾- MR (500MHz, CDC13) δ (ppm)= 1.40 (9H， s), 1.47 (3H， d， J=6.5Hz)， 1.58 (3H， d， J=7.0Hz) , 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) 13C-丽 R(125丽 z, CDClg) 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 実施例 A— 16 ：
Figure imgf000039_0001
 ¾- MR (500MHz, CDC1 3) δ (ppm) = 1.40 (9H, s), 1.47 (3H, d, J = 6.5Hz), 1.58 (3H, d, J = 7.0Hz), 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- 丽 R (125 丽 z, CDClg) 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 A-16:
Figure imgf000039_0001
窒素雰囲気下，室温にて 100ml二口ナスフラスコに亜鉛粉末 2.9603g (45.3腿 ol) を加え、 これに酢酸 2.7100g(45. lmmol)とァミノェチル基を有する乳酸 4量体誘 導体べンジルエーテル ブロモフエナシルエステル 2.1675g(3. OOmmol)の 20ml エーテル溶液を加え 5時間撹拌した。 これを濾過し減圧下濃縮した. これをシリ 力ゲルカラムクロマトグラフィー（展開溶媒酢酸ェチルーへキサン 1:1)を用い て単離精製し生成物を 1.0500g, 66.7%の収率で得た。 実施例 A— 17 ：
Figure imgf000039_0002
Under a nitrogen atmosphere at room temperature, 2.9603 g (45.3 tmol) of zinc powder was added to a 100 ml two-necked eggplant flask, and 2.7100 g (45.1 mmol) of acetic acid and a lactic acid tetramer derivative benzyl ether bromide having an aminoethyl group were added. A solution of 2.1675 g (3.0 mmol) of phenacyl ester in 20 ml of ether 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 a product in a yield of 66.7%. Example A-17:
Figure imgf000039_0002
室温にて 50ml二口ナスフラスコにアミノエチル基を有する乳酸 4量体誘導体 ベンジルエーテル 1.0450g(1.99mmol)のエタノール溶液を加え、 パラジウムチヤ コール（10%)を 0.1992g加えた。 これを水素置換し 13時間撹拌した。 その後反応 混合物をセライトを用いてブフナー漏斗でろ過しこれを濃縮し、 さらにシリカゲ ルを用いてろ過しこれを濃縮し生成物を 0.8089g、 93.3%の収率で得た。 実施例 A— 18
Figure imgf000040_0001
窒素雰囲気下、 室温にて乳酸 5 量体べンジルエーテル 1.9288g(4.12mmol)の 14mlジクロロメタン溶液に、 N- 1 -ブトキシカルポニル-（s) - (- )-4 -ァミノ 2-ヒ ド ロキシブタン酸 ブロモフエナシルエステル 12.4974g(30.02匪 ol)の 80ml ジク ロロメタン溶液を加え、 さらに 4 -ジメチルァミノピリジン 0.0164g(0.13mmol)の lml ジクロロメタン溶液を加えた。 これを氷浴にて十分冷却した後 N， N' -ジシ ク口へキシルカルポジィミ ド 12.4894g(12. lmmol)の 5mlジクロロメタン溶液をゆ つくり滴下し、 氷浴を取り除いた。 反応混合物を 1時間撹拌した後、 1規定の硫 酸水素カリウム水溶液で反応を停止した。 副生した N， N' -ジシクロへキシル尿 素をブフナー漏斗により吸引濾過を行い取り除き、 ジクロロメタンで抽出（30ml X3)したものを飽和食塩水で洗い硫酸マグネシウムで乾燥し減圧濃縮した。 これ をシリカゲルカラムクロマトグラフィー（展開溶媒 酢酸ェチル一へキサン 1:2) を用いて単離精製を行い生成物を 2.9356g, 82.2%の収率で得た。， At room temperature, 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, and 0.1992 g of palladium charcoal (10%) was added. This was replaced with hydrogen and stirred for 13 hours. Thereafter, the reaction mixture was filtered through a Buchner funnel using celite, concentrated, and further filtered using silica gel, and concentrated to obtain 0.8089 g of a product in a yield of 93.3%. Example A-18
Figure imgf000040_0001
At room temperature under a nitrogen atmosphere, N-1-butoxycarbonyl- (s)-(-)-4-amino-2-hydroxybutanoic acid was added to a 1.9288 g (4.12 mmol) of lactic acid pentamer benzyl ether in 14 ml of dichloromethane at room temperature. A solution of 12.4974 g (30.02 marl) of bromophenacyl ester in 80 ml of dichloromethane was added, and further a solution of 0.0164 g (0.13 mmol) of 4-dimethylaminopyridine in 1 ml of dichloromethane was added. After sufficiently cooling this in an ice bath, a solution of 12.4894 g (12.lmmol) of N, N'-dicylhexyl carboxamide in 5 ml of dichloromethane was slowly added dropwise, and the ice bath was removed. After stirring the reaction mixture for 1 hour, the reaction was stopped with a 1 N aqueous solution of potassium hydrogen sulfate. The by-produced N, N'-dicyclohexylurea was removed by suction filtration using a Buchner funnel, extracted with dichloromethane (30 ml X3), washed with saturated saline, 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%. ,
[ひ] D 17.2=— 134.3° (c=0.11, CHC13) [Shed] D 17 2 = -. 134.3 ° (c = 0.11, CHC1 3)
IR(cm— ： 3419 (NH), 2985 (Ph) , 1778 (C=0), 1695 (C=0) (NaCl)  IR (cm—: 3419 (NH), 2985 (Ph), 1778 (C = 0), 1695 (C = 0) (NaCl)
^-NMR (500MHz, CDC13) δ (ppm) = 1.42 (9H, s), 1.48 (3H， d， J=6.5Hz)， 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=ll.5Hz) and 4.75 (2H, d， J=ll.5Hz), 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) ^ -NMR (500MHz, CDC1 3) δ (ppm) = 1.42 (9H, s), 1.48 (3H, d, J = 6.5Hz), 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 = ll.5Hz) and 4.75 (2H, d, J = ll .5Hz), 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)
13C-NMR (125MHz, CDC13) 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 Of 1 3 C-NMR (125MHz, CDC1 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 Of
、 騵鷇 ^ セ響一 ^ ェ、 ^^ ^^ ^m, 騵 鷇 ^ Sekyoichi ^ e, ^^ ^^ ^ m
^ 。 つ Φίΐί阖翻 τつ稱喜挲氺 ¾^ 。 ^^ ！： ；！： / /— ふ マ ¾ 缀 /— ェ 0画 9ΐ · §06^Ί / 一エ / ベ M ^ 9 c 厶 ti二 Twos ユ ^萆 ^. Ίΐί 阖 ίΐί 阖 ίΐί 阖 τ τ 挲 氺 挲 氺 ¾ ¾ ¾. ^^! :;! : / / - Fu Ma ¾缀/ - E 0 stroke 9ΐ · §06 ^ Ί / Ichie / Baie M ^ 9 c厶ti two Twos Yu ^萆
Figure imgf000041_0001
Figure imgf000041_0001
0 z -v m  0 z -v m
(ω ¾2) 88 Ί-8Ζ Ί '(ω 'Η2) ΖΖ '9-0ΐ S £(sq ¾Τ) 16 ·
Figure imgf000041_0002
'Ρ) Lf "t '(ΖΗ8·9=Γ 'b 'ΗΤ) S '(ω ¾S) 0 ·ε— 0Ι ·ε '0 ¾S) IS ー WS-OO'S '06Ί-Ζ8·Χ '(M T9 Ί-69 Ί(ω ¾2) 88 Ί-8Ζ Ί '(ω' Η2) ΖΖ '9-0ΐ S £ ( s q ¾Τ) 16
Figure imgf000041_0002
'Ρ) Lf "t' ( Ζ Η8 · 9 = Γ ' b ' ΗΤ) S '(ω ¾S) 0 · ε— 0ΙΙ''0 ¾S) IS ー WS-OO'S '06 Ί-Ζ8 T9 Ί-69 Ί
' (ZHO ' =Γ 'Ρ ¾S) 6f T '(s ¾6) ·Ι g (εΤθαθ 'ZHTO09) Ηί¾Ν-Ητ '(ZHO' = Γ 'Ρ ¾S) 6f T' (s ¾6) Ιg ( ε Τθαθ 'ZHTO09) Ηί¾Ν-Η τ
(10¾) (0=3) 8 ΐ '(0=0)Ζ9ΖΤ ' (Hd) '(HN)SI S ： (t m )HI (10¾) (0 = 3) 8 ΐ '(0 = 0) Ζ9ΖΤ' (Hd) '(HN) SI S: ( t m) HI
(εΤ0Η3 ' 1'0=3)
Figure imgf000041_0003
( ε Τ0Η3 '1'0 = 3)
Figure imgf000041_0003
。 、 ま^ 0)¾Τ -99 '§099 'Τ 呦 ^^ 濂 H鑭南ェ、 ^¾(T:T ベ 4 ^ 一 ^エ邈¾ — ^ ^ Λ ^ ^^Γζ, ί^Λί^ f Ci  . , ^^ 0) ¾Τ -99 '§099' Τ 呦 ^^ Ci
' 騵镤丄 ϊΠΠΐίΐ^δ :: 。 翻 s' ^a¥ ¾¾4/ 一ェ '騵 镤 丄 ϊΠΠΐίΐ ^ δ ::. S '^ a ¥ ¾¾4 /
O9(lounnig-g)§xg ,8'2 4 ェ 、 ェ a ·^ / 一 r ^べ : 象 鎮: #薔 9邈¾§ ^ ¾ ^ェ/ ？ ( «rai0 -g )S290 'Ζ ϋ^^ ^fl^ (Τ。画 ·9 ） SS9S0 ^^^亜：^ ^^ ^ニ!：1^。^ ^ ¾ 、丄^困 峯暴 O9 (lounnig-g) §xg, 8'2 4 、 ェ · 一 · · · · · · · · · · · · · · · · · · · · · ·: Elephant Township: #Rose 9 邈 ¾§ ^ ¾ ^ ェ /? («Rai0 -g) S290 'Ζ ϋ ^^ ^ fl ^ (Τ. Drawing · 9 ) S S9S0 ^^^ Sub: ^ ^^ ^ d !: 1 ^. ^ ^ 丄, 丄 ^
Figure imgf000041_0004
Figure imgf000041_0004
6 1 -v m^  6 1 -v m ^
l780C00/S00Zdf/X3d Z88..0/S00Z OAV ルを用いてろ過しこれを濃縮し生成物を 1. 0486g、 84. 2%の収率で得た l780C00 / S00Zdf / X3d Z88..0 / S00Z OAV The product was obtained at 1.0486 g in a yield of 84.2%.
実施例 A— 2 1 Example A—2 1
窒素雰囲気下、 0°Cにてィミダゾール 0. 4834 g (8. Ommol)の 12mlジクロロメタ ン溶液に t-ブチルジメチルクロロシラン 0· 6923 g (4. Ommol)の 5ml.ジクロロメタ ン溶液を加え 10分間攪拌し、 N- Boc_ (S) - (-）- 4-ァミノ- 2-ヒ ドロキシ酪酸 0. 2193 g (l. Ommol)の 10mlジクロロメタン溶液をゆつく り滴下し、 1時間攪拌した後室 温に戻し、 さらに 13時間攪拌した。 20mlの飽和塩化ナトリゥム水溶液で反応を 停止しへキサンで抽出（50ml X 3)した。 有機相を濃縮し、 これを lOmlTHF溶液と した。 次に室温にて炭酸力リウム lgの 10ml水溶液を加え 45分間攪拌し、 へキ サンで洗浄した。 この溶液を 1規定硫酸水素力リゥム水溶液により pH3に調整し た後酢酸ェチルで抽出（50ml X 3)したものを硫酸マグネシゥムで乾燥しろ過した, 次に窒素雰囲気下、 0°Cにてこの 20mlジクロロメタン溶液に N-t-ブトキシカル ポニル-（S)- (-）- 4-ァミノ- 2-ヒ ドロキシ酪酸- p-ブロモフエナシルエステル 1. 2519g (3mmol)の 15ml ジクロロメタン溶液、 N- N， -ジシクロへキシルカルポジ イミ ド 0. 2830gの 5mlジクロロメタン溶液、 4 -ジメチルァミノピリジン 0. 0184g の 5mlジクロロメタン溶液を加え 15分攪拌した後室温に戻し、 さらに 5時間攪 拌した。 反応溶液を飽和食塩水 20ml で処理し、 減圧濾過したこの溶液から酢酸 ェチルで抽出（60ml X 3)したものを硫酸マグネシウムで乾燥した。 これを減圧濃 縮 し シ リ カ ゲ ル カ ラ ム ク ロ マ ト グ ラ フ ィ ー （ 展 開 溶 媒 hexane : etylace"fcate=10 : 3)を用いて単離精製し、 生成物を 0. 3735g、 54. 4%の収 率で得た。  Under a nitrogen atmosphere, at 0 ° C, a solution of 0.483 g (8.Ommol) of imidazole in 12 ml of dichloromethane and a solution of 0.623 g (4.Ommol) of t-butyldimethylchlorosilane in 5 ml of dichloromethane were added and stirred for 10 minutes. Then, a solution of 0.2193 g (l. Ommol) of N-Boc_ (S)-(-)-4-amino-2-hydroxybutyric acid in 10 ml of dichloromethane was slowly added dropwise, stirred for 1 hour, and then cooled to room temperature. It was returned and stirred for further 13 hours. The reaction was quenched with 20 ml of a saturated aqueous sodium chloride solution and extracted with hexane (50 ml × 3). The organic phase was concentrated, and this was used as a 10 mL THF solution. Next, a 10 ml aqueous solution of lithium carbonate (lg) was added at room temperature, stirred for 45 minutes, and washed with hexane. This solution was adjusted to pH 3 with 1N aqueous hydrogen sulfate aqueous solution, extracted with ethyl acetate (50 ml X 3), dried over magnesium sulfate, and filtered. Nt-butoxycarponyl- (S)-(-)-4- 4-amino-2-hydroxybutyric acid-p-bromophenacyl ester in dichloromethane solution 1.2519 g (3 mmol) of 15 ml dichloromethane solution, N-N, -dicyclohexane A solution of 0.2830 g of xylcarposimide in 5 ml of dichloromethane and a solution of 0.0184 g of 4-dimethylaminopyridine in 5 ml of dichloromethane were added, and the mixture was stirred for 15 minutes, returned to room temperature, and further stirred for 5 hours. The reaction solution was treated with 20 ml of saturated saline, and the solution was filtered under reduced pressure, extracted with ethyl acetate (60 ml × 3), and dried over magnesium sulfate. This was concentrated under reduced pressure and isolated and purified using silica gel chromatograph (hexane: etylace "fcate = 10: 3) to elute the product. 3735 g, 54.4% yield.
0 0 0 0
II imidazole II  II imidazole II
BocHN、 . TBDMS-CI BocHN へ l  BocHN,. To TBDMS-CI BocHN l
、OH ^ ^ " 丫 、OTBDMS , OH ^ ^ "丫, OTBDMS
OH CH2CI2, 0¾→rt, 13.5h OTBDMS
Figure imgf000043_0001
実施例 A_ 22 ： OH CH 2 CI 2 , 0¾ → rt, 13.5h OTBDMS
Figure imgf000043_0001
Example A_22:
窒素雰囲気下、 0°Cにてィミ.ダゾール 1.3651 g (mmol)の 16mlジクロロメタン溶 液に 1: -プチルジメチルクロロシラン 1.8514 g (mmol)の 2ml ジクロロメタン溶液 を加え 10 分間攪拌し、 N - -ブトキシカルボ二ル-（S)-(-)- 4 -ァミノ- 2-ヒ ドロキ シ酪酸- p-ブロモフエナシルエステル 1.0976g(2.64讀 ol)の 18mlジクロ ロメタン 溶液をゆつく り滴下し 1時間攪拌し、 室温に戻しさらに 12時間攪拌した。 この 反応溶液を減圧濃縮しシリ力ゲルカラムクロマ トグラフィー（展開溶媒 hexane:etylace1:ate=4:l)を用いて単離精製し、 生成物を 1.2599g、 90%の収率で 得た。
Figure imgf000043_0002
Under nitrogen atmosphere, at 0 ° C. To a solution of 1.3651 g (mmol) of imidazole in 16 ml of dichloromethane, add a solution of 1.8514 g (mmol) of 1: -butyldimethylchlorosilane in 2 ml of dichloromethane, stir for 10 minutes, and add N-butoxy. Carbonyl- (S)-(-)-4- 4-amino-2-hydroxybutyric acid-p-bromophenacyl ester 1.0976 g (2.64 readol) of 18 ml of dichloromethane solution was slowly added dropwise and stirred for 1 hour. Then, the mixture was returned to room temperature and stirred for further 12 hours. The reaction solution was concentrated under reduced pressure and isolated and purified using silica gel column chromatography (developing solvent: hexane: etylace1: ate = 4: l) to obtain 1.2599 g of the product in a 90% yield.
Figure imgf000043_0002
実施例 A_ 23 ： Example A_23:
窒素雰囲気下、 室温にて N - Boc-(S)- (- )- 4-ァミ ノ - 2-ヒ ドロキシ酪酸 0.0548g (0.25mmol) の 2ml ジ ク ロ ロ メ タ ン溶液にベ ンジルブ ロ ミ ド 0.07ml (0.6讓 ol)の 2ml ジクロロメタン溶液を加え、 0.1217g(0.525mmol)の酸化 銀 (Π)を加え 16 時間攪拌した後、 酸化銀粉末をろ過した。 これをシリカゲル力 ラムクロマトグラフィー（展開溶媒 hexane:ether=l:2)を用いて単離精製し、 生 成物を 0.0164g、 16%の収率で得た。 At room temperature under a nitrogen atmosphere, benzyl bromide was added to a solution of 0.0548 g (0.25 mmol) of N-Boc- (S)-(-)-4-amino-2-hydroxybutyric acid in 2 ml of dichloromethane. A solution of 0.07 ml (0.6 mL) of the medium in 2 ml of dichloromethane was added, and 0.1217 g (0.525 mmol) of silver oxide (Π) was added. After stirring for 16 hours, the silver oxide powder was filtered. This silica gel force column chromatography (developing solvent h e x a n e: e ther = l: 2) was isolated and purified, to yield the raw Narubutsu 0.0164 g, in 16% yield.
o A n o o A n o
II BnBr, A 20 ιι II BnBr, A 2 0 ιι
BOCHN、 ^\人〜 BOCHN、^^人  BOCHN, ^ \ people ~ BOCHN, ^^ people
OH ^ OBn  OH ^ OBn
OH CH2CI2 OBn 実施例 A— 24 ： OH CH 2 CI 2 OBn Example A—24:
窒素雰囲気下、 0Cにて 0.1096g(0.5藝1)の N-Boc- (S) -（-）-4-ァミノ- 2-ヒド 口キシ酪酸 3mlTHF溶液に、 トリェチルァミン 0.1518g(l.5mmol)を加え 15分攪拌 した後、室温に戻しさらにベンジルブ口ミ ド 0.7ml(0.8mmol)を加え 8時間攪拌し た後、 反応溶液に飽和塩化ァンモニゥム水溶液 3mlで処理し、 ジクロロメタンで 抽出（10mlX3)し、 有機相を硫酸マグネシウムで乾燥し、 減圧下濃縮した。 これ をシリカゲルカラムクロマトグラフィー（展開溶媒 ether)を用いて単離精製し 生成物を 0.057g37%の収率で得た。
Figure imgf000044_0001
実施例 A— 25 ： Under nitrogen atmosphere, at 0C, 0.1518 g (0.5 mmol) of triethylamine was added to 0.1 ml of N-Boc- (S)-(-)-4-amino-2-hydroxybutyric acid in 3 ml of THF at 0C. After stirring for 15 minutes, the temperature was returned to room temperature, and 0.7 ml (0.8 mmol) of benzylbutamide was further added. After stirring for 8 hours, the reaction solution was treated with 3 ml of a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane (10 ml × 3). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. This was isolated and purified using silica gel column chromatography (developing solvent ether) to obtain 0.057 g of a product in a yield of 37%.
Figure imgf000044_0001
Example A-25:
窒素雰囲気下、 室温にて 0.0698g(0.226mmol)のべンジルエステルの 3mlDMF溶 液に 0.1285g(2.8mmol)の水素化ナトリゥムを加え 45分間攪拌し、 これにべンジ ルプロミド 0.06ml(0.5mmol)を加え 3時間攪拌したものに、 飽和塩化アンモニゥ ム 10ml で反応を停止した。 この溶液をジクロロメタンにより抽出（25ml X 3)し、 有機相を硫酸マグネシウムで乾燥した。 これをシリカゲルカラムクロマトグラフ ィー（展開溶媒 hexane:ether=l:2)により単離精製し、 0.0091g得られた。
Figure imgf000044_0002
実施例 A— 26 ： Under nitrogen atmosphere, at room temperature, 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, and the mixture was stirred for 45 minutes, and benzylpromide 0.06 ml (0.5 mmol) was added thereto. The mixture was stirred for 3 hours, and the reaction was stopped with 10 ml of saturated ammonium chloride. 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 .
Figure imgf000044_0002
Example A-26:
室温にて 0.1595g(0.4731舰 ol)のァミノヒドロキシ酪酸べンジルエステルベン ジルエーテルに 0.04g (0.04mmol)のトリェチルァミンの 1ml酢酸ェチル溶液を加 え、 0.0160gの 10%-パラジウムカーボンを加えた後、 水素雰囲気として 1時間 20分の反応を行った後、 パラジウム -カーボンをブフナー漏斗により吸引ろ過に より取り除き、 IN-硫酸水素力リゥム 50mlにより トリェチルァミン塩をフリ一の カルボン酸とした。 この溶液を酢酸ェチルで抽出（50ml X 3)した後、 シリカゲル を用いてろ過し、 0.0334g、 28%の収率で得られた。
Figure imgf000045_0001
実施例 A— 27 ：環状（S)- 2-((S)- 2- ((S)- 2- ((S)- 2-ォキシプロパノイロキシ） プロパノイロキシ) プロパノイロキシ） - 4_( eri-ブトキシカルポニルアミノ）ブ タノィルの合成 At room temperature, 0.04 g (0.04 mmol) of triethylamine in 1 ml of ethyl acetate was added to 0.1595 g (0.4731 mol) of benzyl hydroxyaminobutyrate benzyl ether, and 0.0160 g of 10% palladium carbon was added. After a 1-hour reaction under a hydrogen atmosphere for 1 hour and 20 minutes, palladium-carbon was filtered by suction using a Buchner funnel. The triethylamine salt was converted to a free carboxylic acid with 50 ml of IN-hydrogen sulfate rim. This solution was extracted with ethyl acetate (50 ml × 3), and then filtered through silica gel to obtain 0.0334 g, 28% yield.
Figure imgf000045_0001
Example A-27: Cyclic (S) -2-((S) -2-((S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) -4_ (eri-butoxy Synthesis of (carbonylamino) butanoyl
Figure imgf000045_0002
Figure imgf000045_0002
窒素雰囲気下、室温にて 32c0.2187g(0.5022g)の 450mlジクロロメタン溶液に、 ジイソプロピルェチルァミン 0.1595g(l.234mmol)の 2.5mlジクロロメタン溶液を 加え、 さらに 4-ジメチルァミノピリジン 0.0147g(0.120讓 ol)の 2.5ml ジクロロ メタン溶液を加えた。 この溶液に 2， 4, 6-トリクロ口べンゾイルク口ライ ド 0.1970g(0.8077腕 ol)の 45ml ジクロロメタン溶液を 15時間かけて滴下しさらに 16 時間撹拌した。反応混合物を減圧濃縮し、 シリカゲルを用いてろ過した後、 シ リカゲルカラムクロマトグラフィー（展開溶媒 酢酸ェチルーへキサン 1:2)を用 いて単離精製を行い環状（S)一 2一（(S)一 2 ((S)— 2一（(S)一 2一ォキシプロパノイロキ シ） プロパノイロキシ） プロパノイロキシ） - 4 -（ eri -ブトキシカルポニルアミ ノ）ブタノィル（35c)を 0.1904g、 90.8%の収率で得た。 Under nitrogen atmosphere, at room temperature, to a solution of 0.2187 g (0.5022 g) of 32c in 450 ml of dichloromethane, add a solution of 0.1595 g (l.234 mmol) of diisopropylethylamine in 2.5 ml of dichloromethane, and further add 0.0147 g of 4-dimethylaminopyridine (0.0147 g). 0.120 mL) of 2.5 ml of dichloromethane solution was added. To this solution, a solution of 0.1970 g (0.8077 armol) of 2,4,6-trichlorobenzene was added dropwise in 45 ml of dichloromethane over 15 hours, and the mixture was further stirred for 16 hours. The reaction mixture was concentrated in vacuo, filtered through a silica gel (hexane 1 to developing solvent acetic Echiru: 2) silica gel column chromatography performed isolated and purified have use a cyclic (S) one 2 one ((S) one 2 ((S) - 2 one ((S) one 2 one O carboxymethyl prop Neu Loki Shi) Puropanoirokishi) Puropanoirokishi) - 4 - (eri - butoxide deer Lupo sulfonyl amino) Butanoiru the (35c) 0.1904g, 90.8% of the yield Rate obtained.
環状（S) - 2- ((S) - 2 -（(S) - 2 -（(S) - 2 -ォキシプロパノイロキシ） プロパノイロキ シ） プロパノイロキシ） - 4 -（ er ブトキシカルポニルァミノ）： タノィル（35c) [α]16·7。=-84·3° (c=l.l， CHC13) Cyclic (S) -2-((S) -2-((S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) -4- (erbutoxycarponylamino): Tanoil (35c) [α] 16 · 7 . = -84 · 3 ° (c = ll, CHC1 3)
IR(cm_1) ： 3423 (NH), 1755 (C=0), 1705 (C=0) (NaCl) ¾-NMR (500MHz, CDC13) δ (ppm) =l. 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) IR (cm _1 ): 3423 (NH), 1755 (C = 0), 1705 (C = 0) (NaCl) ¾-NMR (500MHz, CDC1 3 ) δ (ppm) = l. 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)
13C- MR (125MHz, CDC13) S (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 実施例 A— 2 8 ：環状（S) -2- ( (S) - 2 - ( (S) - 2- ( (S) -2- ( (S) -2_ォキシプロパノイロ キシ）プロパノイロキシ）プロパノイロキシ）プロパノイロキシ） - 4 -（iar -ブトキ シカルボニルァミノ）ブタノィルの合成 1 3 C- MR (125MHz, CDC1 3) S (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 A—28: Cyclic (S) -2-((S) -2-((S) -2-((S) -2-((S) -2_oxypropanoyloxy) propanoyloxy)) Synthesis of propanoyloxy) propanoyloxy) -4- (iar-butoxycarbonylamino) butanol
Figure imgf000046_0001
Figure imgf000046_0001
窒素雰囲気下、室温にて 32e0. 2920g (0. 5040g)の 450mlジクロロメタン溶液に、 ジィソプロピルェチルァミン 0. 1557g (l. 205mmol)の 2. 5mlジクロロメタン溶液を 加え、 さらに 4-ジメチルァミノピリジン 0. 0128g (0. 105mmol)の 2. 5ml ジクロロ メタン溶液を加えた。 この溶液に 2， 4, 6-トリクロ口べンゾイルク口ライ ド 0. 1887g (0. 7737腿 ol)の 45ml ジクロロメタン溶液を 15時間かけて滴下しさらに 15 時間撹拌した。反応混合物を減圧濃縮し、 シリカゲルを用いてろ過した後、 シ リカゲルカラムクロマトグラフィー（展開溶媒 酢酸ェチルーへキサン. 1 : 2)を用 いて単離精製を行い環状（S) -2- ( (S) - 2- ( (S) - 2- ( (S) - 2- ( (S) - 2-ォキシプロパノ イロキシ）プロパノイロキシ）プロパノイロキシ）プロパノイロキシ) - 4- ( ar ブ トキシカルポニルァミノ）ブタノィル（35e)を 0.2475g、 87.5%の収率で得た。 環状 (S) -2- ( (S) -2- ( (S) -2 - ( (S) - 2- ( (S) -2-ォキシプロパノイロキシ）プロパノ イロキシ）プロパノィ口キシ）プロパノイロキシ）-4 -（ er-ブトキシカルボニル ァミノ）ブタノィル（35e) Under a nitrogen atmosphere at room temperature, to a solution of 32e0.2920 g (0.5050 g) in 450 ml dichloromethane, add 0.1557 g (l.205 mmol) of diisopropylethylamine in 2.5 ml of dichloromethane and further add 4-dimethyla A solution of 0.0128 g (0.105 mmol) of minopyridine in 2.5 ml of dichloromethane was added. To this solution, 0.187 g (0.7737 tmol) of 45 ml dichloromethane solution of 2,4,6-trichlorobenzene was added dropwise over 15 hours, and the mixture was further stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, filtered using silica gel, and then isolated and purified using silica gel column chromatography (developing solvent: ethyl acetate-hexane 1: 2) to obtain cyclic (S) -2-((S )-2- ((S)-2- ((S)-2- ((S)-2-oxypropanoyloxy) propanoyloxy) propanoyloxy) propanoyloxy)-4- (ar 0.2475 g of (Toxicarponylamino) butanol (35e) was obtained in a yield of 87.5%. Cyclic (S) -2-((S) -2-((S) -2-(-S) -2-((S) -2-oxypropanoyloxy) propanoyloxy) propanoyloxy) propanoyloxy) -4-(Er-butoxycarbonylamino) butanol (35e)
[a]16'8 D=— 115.0。 (c=l.0, CHC13) [a] 16 '8 D = - 115.0. (c = l.0, CHC1 3 )
IR(cm_1) ： 3423 (NH) , 1761(C=0)， 1716 (C-0) (KBr) IR (cm _1 ): 3423 (NH), 1761 (C = 0), 1716 (C-0) (KBr)
¾- MR (500MHz, CDC13) 6 (ppm)=l.34 (9H， s), 1. 5-1.53 (9H, m), 1.94-2.20 (2H， m)， 3.10-3.30 (2H， m), 4.89 (1H, bs)， 5.05-5.17 (6H， m) ¾- MR (500MHz, CDC1 3) 6 (ppm) = l.34 (9H, s), 1. 5-1.53 (9H, m), 1.94-2.20 (2H, m), 3.10-3.30 (2H, m ), 4.89 (1H, bs), 5.05-5.17 (6H, m)
13C-NMR (125MHz, CDC13) 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 実施例 B— 1 ： (S) -benzyl 4- ( ieri- butyl dimethyls ilyloxy) 1 3 C-NMR (125MHz, CDC1 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 Example B-1: (S) -benzyl 4- (ieri-butyl dimethyls ylyloxy)
-2-hydroxybutanoat eの合成
Figure imgf000047_0001
Synthesis of 2-hydroxybutanoate
Figure imgf000047_0001
窒素雰囲気下、 0°Cで、 ベンジルアルコール （2.70g， 25. Ommol) の 50mLの THF 溶液に 1.6M-n-ブチルリチウム （15.0mL, 24. Ommol) をゆっく り滴下し、 10分間 撹拌した。 その後、 （S)- (2,2)- (ジメチル- 1， 3 -ジォキソラン- 4-オン）- 5- eri-ブ チルジメチルシ πキシェチル （5.48g， 19.99mmol) の THF 20mL溶液を滴下し、 1時間間撹拌した後、 30mLの飽和塩化アンモニゥム水溶液で反応停止させ、 20mL の水を加え、 50mLのエーテルで 4回抽出した。 抽出したエーテル層を無水硫酸ナ トリウムで乾燥し、 濾過して濃縮した後、 シリカゲルカラムクロマトグラフィー (Hexane ： Ether = 3 : 1) により単離精製すると、 無色透明の液体 5.816g (17.94ramol) が得られた （ .7°/0)。 Under a nitrogen atmosphere, at 0 ° C, 1.6M n-butyllithium (15.0 mL, 24. Ommol) was slowly added dropwise to a 50 mL THF solution of benzyl alcohol (2.70 g, 25. Ommol), and the mixture was stirred for 10 minutes. Thereafter, a 20 mL solution of (S)-(2,2)-(dimethyl-1,3-dioxolan-4-one) -5-eri-butyldimethylcy-pi-xitytyl (5.48 g, 19.99 mmol) in THF was added dropwise. After stirring for an hour, the reaction was quenched with 30 mL of a saturated aqueous solution of ammonium chloride, added with 20 mL of water, and extracted four times with 50 mL of ether. The extracted ether layer was dried over anhydrous sodium sulfate, filtered and concentrated. After isolation and purification by silica gel column chromatography (Hexane: Ether = 3: 1), 5.816 g (17.94 ramol) of a colorless transparent liquid was obtained. Obtained (.7 ° / 0 ).
¾— NMR (500MHz, CDC13) S (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. 0 (q， J=4.0, 1H), 5.21 (dd， J=12.5, 15.5Hz, 2H), 7.32-7.40 (m, 5H) 実施例 B— 2 ： (S) -benzyl-2- ( (S) -2- (benzyloxy) propanoyloxy) -4- ( ieri-butyldimethylsilyloxy)butanoate (TBDMS0Me~Bn2LaBn) ¾- NMR (500MHz, CDC1 3) S (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), 4.0 ( q, J = 4.0, 1H), 5.21 (dd, J = 12.5, 15.5Hz, 2H), 7.32-7.40 (m, 5H) Example B—2: (S) -benzyl-2- ((S)- 2- (benzyloxy) propanoyloxy) -4- (ieri-butyldimethylsilyloxy) butanoate (TBDMS0Me ~ Bn2LaBn)
Figure imgf000048_0001
窒素置換した二口ナス型フラスコで、 0°Cで 20mL のジクロロメタン溶媒中 0.539g (2.99mmol) の乳酸べンジルエーテノレ、 および 0.956g (2.95讓 ol) の 2- ヒ ドロキシ- 4- ( e i" "ブチルジメチルシロキシブタン酸ベンジルエステルを加え さらに DMAP 0.430g (3.52mmol) のジクロロメタン 10mL溶液を加え撹拌した。 10 分後、 DCC 0.820g (3.97mmol) の lOmLジクロロメタン溶液を加え、 3時間撹拌し た。 その後、 20mL の飽和塩化アンモニゥム水溶液を加え、 吸引濾過し、 さらに 20mLの飽和炭酸水素ナトリゥム水溶液を加え、エーテル（40mLX4) で分液操作を 行った。 有機層を無水硫酸マグネシウムで乾燥し、 濾過、 濃縮した後、 シリカゲ ルカラムクロマトグラフィー（Hexane ： ether = 3 ： 1) で単離精製したところ、 1.36g (2.79醒 ol) の -プチルジメチルシ口キシェチル基を有する鎖状乳酸 2 量体誘導体が得られた （94.7%)。
Figure imgf000048_0001
In a two-necked eggplant-shaped flask purged with nitrogen, 0.539 g (2.99 mmol) of benzyl ether acetate and 0.956 g (2.95 acetyl) of 2-hydroxy-4- (ei "" in 20 mL of dichloromethane solvent at 0 ° C. Butyldimethylsiloxybutanoic acid benzyl ester was added, and a solution of 0.430 g (3.52 mmol) of DMAP in 10 mL of dichloromethane was further stirred, and after 10 minutes, a solution of 0.820 g (3.97 mmol) of DCC in 10 mL of dichloromethane was added, followed by stirring for 3 hours. Thereafter, 20 mL of a saturated aqueous solution of ammonium chloride was added thereto, followed by suction filtration, followed by addition of 20 mL of a saturated aqueous solution of sodium hydrogen carbonate, and liquid separation with ether (40 mL × 4) .The organic layer was dried over anhydrous magnesium sulfate, filtered and dried. After concentration, the residue was isolated and purified by silica gel column chromatography (Hexane: ether = 3: 1), and it had 1.36 g (2.79 ol) of -butyldimethyldimethyl oxethyl group. Chain acid dimer derivative that was obtained (94.7%).
— NMR (500MHz, CDC13) δ (ppm) =0.061 (s, 6H)， 0.875 (s, 9H)， 1.45 (d， J-7. OHz 3H)， 2.01-2.19 (m, 2H)， 3.68-3.76 (m, 2H)， 4,12 (q, J=7. OHz, 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. OHz, 1H), 7.28-7.37 (m， 10H) 実施例 B— 3 ： (S)一 2 - ( (S)—2 - (benzyloxy) propanoyloxy) - 4一 ( ierz^-butyldimethylsilyloxy) butanoic acid (TBDMS0Me-Bn2La) - NMR (500MHz, CDC1 3) δ (ppm) = 0.061 (s, 6H), 0.875 (s, 9H), 1.45 (. D, J-7 OHz 3H), 2.01-2.19 (m, 2H), 3.68- 3.76 (m, 2H), 4,12 (q, J = 7. OHz, 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. OHz, 1H), 7.28-7.37 (m, 10H) Example B—3: (S) -1 2-((S) —2-(benzyloxy) propanoyloxy)-4 (ierz ^ -butyldimethylsilyloxy) butanoic acid (TBDMS0Me-Bn2La)
OBn ,,,.,OBn OBn ,,,., OBn
- o丄。 , 1賴 -c, o丄。 -o 丄. , 1賴 -c, o 丄.
TBDM.SOへ、、、" 0 Bn rt， 20min. TBDMSOへ、、、'.1 ^γ01"1 To TBDM.SO, " 0 Bn rt , 20 min. To TBDMSO, '. 1 ^ γ 01 " 1
O O 三角フラスコに 0. 937g (2. OOmmol) の ar -プチルジメチルシ口キシェチル基 を有する鎖状べンジロキシ乳酸二量体べンジルエステルと 10mL のエタノール、 さらに 10%-パラジウムカーボンを 0. lg加え、 接触還元装置で水素雰囲気下、 室 温で 30分撹拌した。反応溶液を濾過し、反応フラスコをエーテルで洗浄した後、 ロータリーエバポレーターで濃縮した。 さらに真空ポンプで 12 時間以上減圧下 に置き、 溶媒を完全に除去したところ、 0. 743g (1. 87mmol)の目的物が 得られた (93. 7%) 0 In an OO Erlenmeyer flask, 0.937 g (2.OO mmol) of benzyl dibenzyloxylactate dimer with ar-butyldimethylcyclohexyl, 10 mL of ethanol, and 0.1 lg of 10% palladium carbon were added. The mixture was stirred at room temperature for 30 minutes in a hydrogen atmosphere with a catalytic reduction device. The reaction solution was filtered, the reaction flask was washed with ether, and then concentrated on a rotary evaporator. Further placed under vacuum over 12 hours at a vacuum pump, The solvent was completely removed, the desired product of 0. 743 g (1. 87 mmol) was obtained (93.7%) 0
— NMR (500MHz, CDC13) 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=ll. 5, 153. 0Hz, 2H)， 5. 31 (q, J=4. 5Hz, 1H) , 7. 28-7. 38 (m, 5H) 実施例 B— 4 ： (S) -4- (tert-butyldimethylsilyloxy) -2- ( (S) - 2- hydroxypropanoyloxy) butanoic acidの合成 (TBDMS0Me~2La) - NMR (500MHz, CDC1 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 = 6.5 Hz, 1H), 4.61 (dd, J = ll. 5, 153 0Hz, 2H), 5.31 (q, J = 4.5Hz, 1H), 7.28-7.38 (m, 5H) Example B-4: (S) -4- (tert-butyldimethylsilyloxy) Synthesis of -2- ((S)-2-hydroxypropanoyloxy) butanoic acid (TBDMS0Me ~ 2La)
Figure imgf000049_0001
Figure imgf000049_0001
三角フラスコに 0. 500g (1. 03mmol) の ieri-プチルジメチルシ口キシェチル基 を有する鎖状べンジロキシ乳酸二量体べンジルエステルと lOmL のエタノール、 さらに 10%-パラジウムカーボンを 0. lg加え、 接触還元装置で水素雰囲気下、 室 温で 10 時間撹拌した。 反応溶液を濾過し、 反応フラスコをエーテルで洗浄した 後、 ロータリーエバポレーターで濃縮した。 さらに真空ポンプで 12 時間以上減 圧下に置き、 溶媒を完全に除去したところ、 0.294g (0.960mmol) の目的物が得 られた （93.2%)。 In a Erlenmeyer flask, add 0.50 g (1.03 mmol) of a linear benzyloxylactate dimer benzyl ester having ieri-butyldimethylcyclohexyl group, lOmL of ethanol, and 0.1 lg of 10% palladium carbon, and then contact The mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere in a reducing apparatus. The reaction solution was filtered, the reaction flask was washed with ether, and then concentrated on a rotary evaporator. Further reduced by more than 12 hours with vacuum pump The solvent was completely removed under pressure, and 0.294 g (0.960 mmol) of the desired product was obtained (93.2%).
¾— NMR (500MHz, CDC13) 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) 実施例 B— 5 : (2S) -benzyU- ( tert-butyldime thylsilyloxy) - 2 - (2- ( (2 - me thoxye thoxy)me thoxy) propanoyloxy) bu tanoa teの合成 (TBDMSOMe— MEM2LaBn) ¾- NMR (500MHz, CDC1 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 B— 5: ( 2S) -benzyU- (tert-butyldime thylsilyloxy)-2-(2- ((2-me thoxye thoxy) me thoxy) propanoyloxy) Synthesis of bu tanoa te (TBDMSOMe— MEM2LaBn)
Figure imgf000050_0001
窒素置換した二口ナス型フラスコで、 0°Cで 20mLのジクロロメタン溶媒中 0.53g (2.97腿 ol) の乳酸べンジノレエーテノレ、 および 0.95g (2.93mmol) の 2-ヒ ドロキ シ- 4- (z¾r-ブチルジメチルシロキシブタン酸べンジルエステルを加え、 さらに DMAP 0.430g (3.52mmol) のジクロロメタン 10mL溶液を加え撹拌した。 10分後、 DCC 0.820g (3.97mmol) の 10mLジクロロメタン溶液を加え、 3時間撹拌した。 そ の後、 20mLの飽和塩化アンモニゥム水溶液を加え、 吸引濾過し、 さらに 20mLの 飽和炭酸水素ナトリウム水溶液を加え、 エーテル (40mLX4) で分液操作を行った。 有機層を無水硫酸マグネシウムで乾燥し、 濾過、 濃縮した後、 シリカゲルカラム クロマトグラフィー（Hexane ： ether = 3 ： 1) で単離精製したところ、 1.21g (2.50mmol) の ieri-プチルジメチルシ口キシェチル基を有する鎖状乳酸 2量体 誘導体が得られた （85.2%)
Figure imgf000050_0001
In a nitrogen-substituted two-necked eggplant-shaped flask, 0.53 g (2.97 tmol) of benzoinoleate acetic acid and 0.95 g (2.93 mmol) of 2-hydroxy-4- in 20 mL of dichloromethane solvent at 0 ° C (z¾r-Butyldimethylsiloxybutanoic acid benzyl ester was added, and a solution of 0.430 g (3.52 mmol) of DMAP in 10 mL of dichloromethane was further stirred.After 10 minutes, a solution of 0.820 g (3.97 mmol) of DCC in 10 mL of dichloromethane was added, and the mixture was added for 3 hours. After that, 20 mL of a saturated aqueous solution of ammonium chloride was added thereto, followed by suction filtration, followed by addition of 20 mL of a saturated aqueous solution of sodium hydrogen carbonate, and liquid separation with ether (40 mL × 4). After drying, filtration and concentration, the product was isolated and purified by silica gel column chromatography (Hexane: ether = 3: 1), and it had 1.21 g (2.50 mmol) of ieri-butyl dimethylcyxethyl group. Linear lactic acid dimer derivative was obtained (85.2%)
—雇 R (500MHz, CDC13) S (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) 実施例 B— 6 ： (2S) -4- (tert-butyl dimethyl silyloxy) -2- (2- ( (2- methoxyethoxy methoxy prooanoy 1 oxy) butano ι c acidの^ ·β¾ (TBDMS0Me-MEM2La) - employment R (500MHz, CDC1 3) S (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, 21.0 Hz, 2H), 5.26 (q, J = 4.0Hz, 1H), 7.31-7.35 (m, 5H) Example B—6: (2S) -4- (tert-butyl dimethyl silyloxy) -2- (2-((2-methoxyethoxy methoxy prooanoy 1 oxy) butano ι c acid ^ · β¾ (TBDMS0Me-MEM2La)
Figure imgf000051_0001
三角フラスコに 0.30g (0.64mmol) の ar -ブチノレジメチノレシロキシェチノレ基 を有する鎖状べンジロキシ乳酸二量体べンジルエステルと 10mL のエタノール、 さらに 10%-パラジウムカーボンを O.lg加え、 接触還元装置で水素雰囲気下、 室 温で 30分撹拌した。反応溶液を濾過し、反応フラスコをエーテルで洗浄した後、 ロータリーェパポレーターで濃縮した。 さらに真空ポンプで 12 時間以上減圧下 に置き、 溶媒を完全に除去したところ、 0.23g (0.59mmol)の目的物が 得られた (92.2%)。
Figure imgf000051_0001
In an Erlenmeyer flask, 0.30 g (0.64 mmol) of a linear benzyloxylactate dimer benzyl ester having an ar-butinoresinethylensiloxyxetinole group, 10 mL of ethanol, and 10% -palladium carbon were added to O.lg. The mixture was stirred at room temperature for 30 minutes in a hydrogen atmosphere with a catalytic reduction device. The reaction solution was filtered, the reaction flask was washed with ether, and then concentrated on a rotary evaporator. Furthermore, the solvent was completely removed by placing the mixture under reduced pressure for 12 hours or more using a vacuum pump. As a result, 0.23 g (0.59 mmol) of the target compound was obtained (92.2%).
¾- NMR (500MHz, CDC13) 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. OHz, 2H), 5.24 (dd, J=4.5, 7.5Hz, 1H) , ¾- NMR (500MHz, CDC1 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.OHz, 2H), 5.24 (dd, J = 4.5, 7.5Hz, 1H),
実施例 B_ 7 ： (S) -benzyl-2- ( (S) -2- ( (S) -2- (benzyloxy) propanoyloxy) propanoyloxy) - 4 - (tert-butyldimethylsilyloxy) butanoateの合成 Example B_ 7: Synthesis of (S) -benzyl-2-((S) -2-((S) -2- (benzyloxy) propanoyloxy) propanoyloxy) -4- (tert-butyldimethylsilyloxy) butanoate
(TBDMSOMe- Bn3LaBn)  (TBDMSOMe-Bn3LaBn)
Figure imgf000051_0002
窒素置換した二口ナス型フラスコで、 0°Cで 20mLのジクロロメタン溶媒中 1.77g (7. Olmmol) の乳酸二量体べンジルエーテル、 および 2.10g (6.47mmol) の 2 -ヒ ドロキシ -4- tert-プチ) ジメチルシロキシブタン酸べンジルェステル、 DMAP 1..71g (14.02mmol) のジクロロメタン 10mL溶液を加え 10分撹拌し、 さらに DCC 2.90g (14.06mmol) の 10mLジクロロメタン溶液を加え、 3時間撹拌した。その後、 30mLの飽和塩化アンモニゥム水溶液を加え、 吸引濾過し、 さらに 30mLの飽和炭 酸水素ナトリウム水溶液を加え、 エーテル (50mLX4) で分液操作を行った。 有機 層を無水硫酸マグネシウムで乾燥し、 濾過、 濃縮した後、 シリカゲルカラムクロ マトグラフィー（Hexane ： ether = 3 : 1) で単離精製したところ、 2.59g (4.64mmol) の er -プチルジメチルシ口キシェチル基を有する鎖状乳酸三量体 誘導体が得られた （71.8%)
Figure imgf000051_0002
In a nitrogen-purged two-necked eggplant-shaped flask, 1.77 g (7.Olmmol) of benzyl dimer of lactic acid and 2.10 g (6.47 mmol) of 2-hydroxy-4- in 20 mL of dichloromethane solvent at 0 ° C. (tert-petit) Benzylester dimethylsiloxybutanoate, a solution of 1.1.7 g (14.02 mmol) of DMAP in 10 mL of dichloromethane and stirring for 10 minutes, further added a solution of 2.90 g (14.06 mmol) of DCC in 10 mL of dichloromethane and stirred for 3 hours . Thereafter, 30 mL of a saturated aqueous solution of ammonium chloride was added thereto, followed by suction filtration. Further, 30 mL of a saturated aqueous solution of sodium hydrogencarbonate 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 = 3: 1) to obtain 2.59 g (4.64 mmol) of er-butyldimethylsilicone. A linear lactic acid trimer derivative having a xicetyl group was obtained (71.8%)
- NMR (500MHz, CDC13) 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=ll.5, 148.5Hz, 2H), 5.12-5.25 (m, 3H)， 5.32 (q， J=4.5Hz, 1H)， 7.28-7.47 (m， 10H) 実施例 B— 8 : (S) -2- ( (S) -2- ( (S) -2— (benzyloxy) propanoyloxy) - NMR (500MHz, CDC1 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 = ll.5, 148.5Hz, 2H), 5.12 -5.25 (m, 3H), 5.32 (q, J = 4.5Hz, 1H), 7.28-7.47 (m, 10H) Example B-8: (S) -2- ((S) -2- ((S ) -2— (benzyloxy) propanoyloxy)
propanoyloxy) -4- (tert-butyldimethylsilyloxy) butanoic acidの合成 Synthesis of propanoyloxy) -4- (tert-butyldimethylsilyloxy) butanoic acid
(TBDMS0Me-Bn3La) (TBDMS0Me-Bn3La)
Figure imgf000052_0001
Figure imgf000052_0001
三角フラスコに 0.670g (1.20mmol) の arz チルジメチルシロキシェチル基 を有する鎖状べンジロキシ乳酸三量体べンジルエステルと 10mL のエタノール、 さらに 10°/。-パラジウムカーボンを 0. lg加え、 接触還元装置で水素雰囲気下、 室 温で 30分撹拌した。反応溶液を濾過し、反応フラスコをエーテルで洗浄した後、 ロータリーエバポレーターで濃縮した。 さらに真空ポンプで 12 時間以上減圧下 に置き、 溶媒を完全に除去したところ、 0.550g (1.17趣 ol) の目的物が得られた — NMR (500MHz, CDC13) 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=ll.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) In an Erlenmeyer flask, 0.670 g (1.20 mmol) of benzyl dibenzyloxylactate trimer having arz dimethyldimethylsiloxetyl group and 10 mL of ethanol, and then 10 ° /. -Add 0.1 lg of palladium carbon, and use a catalytic reduction unit under a hydrogen atmosphere The mixture was stirred at warm for 30 minutes. The reaction solution was filtered, the reaction flask was washed with ether, and then concentrated on a rotary evaporator. Further placed under vacuum over 12 hours at a vacuum pump, The solvent was completely removed, the desired product of 0.550 g (1.17 flavor ol) was obtained - NMR (500MHz, CDC1 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 = ll.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)
実施例 B_ 9 ： (S) - 4- (tert- butyldimethylsilyloxy)- 2- ((S)- 2- ((S) - 2 - hydroxypropanoyloxy) propanoyloxy) butanoic acidの合成 Example B_ 9: Synthesis of (S) -4- (tert-butyldimethylsilyloxy) -2-((S) -2-((S) -2-hydroxypropanoyloxy) propanoyloxy) butanoic acid
(TBDMSOMe- 3La)  (TBDMSOMe-3La)
Figure imgf000053_0001
Figure imgf000053_0001
三角フラスコに 0.937g (LOO讓 ol) の iar -ブチノレジメチルシ口キシェチル基 を有する鎖状べンジロキシ乳酸三量体べンジルエステルと 10mL のエタノール、 さらに 10% -パラジウムカーボンを O.lg加え、 接触還元装置で水素雰囲気下、 室 温で 6時間撹拌した。反応溶液を濾過し、反応フラスコをエーテルで洗浄した後、 ロータリーエバポレーターで濃縮した。 さらに真空ポンプで 12 時間以上減圧下 に置き、 溶媒を完全に除去したところ、 0.367g (9.70mmol) の目的物が得られた  In an Erlenmeyer flask, add 0.937 g (LOO alcohol) of a linear benzyloxylactic acid trimer benzyl ester having iar-butynoledimethylsixyl group and 10 mL of ethanol, and 10% of palladium carbon to O.lg, and then contact The mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere with a reducing device. The reaction solution was filtered, the reaction flask was washed with ether, and then concentrated on a rotary evaporator. Further, the solvent was completely removed by putting the vacuum pump under reduced pressure for 12 hours or more, and 0.367 g (9.70 mmol) of the target product was obtained.
一 NMR (500MHz, CDC13) 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) 実施例 B— 1 0 ： (S)- ((S)- 1- (benzyloxy)- 1 - oxopropan- 2- yl)-2- ((S)- 2 - (benzyloxy) propanoyloxy)一 4一 (tert一 butyldimethy丄 si丄 yloxy) butanoate の合成 BnLa- (TBDMSOMe) - 2LaBn One NMR (500MHz, CDC1 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 B—10: (S)-((S) -1- (benzyloxy) -1-oxopropan-2-yl) -2-((S) -2- (benzyloxy) propanoyloxy) 1-14-1 (tert Synthesis of one butyldimethy 丄 si 丄 yloxy) butanoate BnLa- (TBDMSOMe)-2LaBn
Figure imgf000054_0001
Figure imgf000054_0001
窒素置換した二口ナス型フラスコで、 0°Cで 20mLのジクロロメタン溶媒中 0.36g (2. OOmmol) の乳酸べンジノレエーテル、 および 0.750g (1.89mmol) の 2-ヒ ドロキ シ- 4- ( tert-ブチルジメチルシロキシプタン酸べンジルェステルを加え、 さらに DMAP 0.31g (2.50mmol) のジクロロメタン 10mL溶液を加え撹拌した。 10分後、 DCC 0.820g (3.97mmol) の 10mLジクロロメタン溶液を加え、 3時間撹拌した。 そ の後、 20mLの飽和塩化アンモニゥム水溶液を加え、 吸引濾過し、 さらに 20mLの 飽和炭酸水素ナトリウム水溶液を加え、 エーテル (40mLX4) で'分液操作を行った。 有機層を無水硫酸マグネシウムで乾燥し、 濾過、 濃縮した後、 シリカゲルカラム クロマトグラフィー（Hexane ： ether = 1 ： 1) で単離精製したところ、 0· 926g (1.65画 1) の目的物が得られた （87.7%)。  In a nitrogen-substituted two-necked eggplant-shaped flask, 0.36 g (2.OO mmol) of benzylinoleate lactate and 0.750 g (1.89 mmol) of 2-hydroxy-4- (0 Benzylester tert-butyldimethylsiloxybutanoate was added, and a solution of 0.31 g (2.50 mmol) of DMAP in 10 mL of dichloromethane was further stirred, and after 10 minutes, a solution of 0.820 g (3.97 mmol) of DCC in 10 mL of dichloromethane was added, followed by stirring for 3 hours. Thereafter, 20 mL of a saturated aqueous solution of ammonium chloride was added thereto, followed by suction filtration, further addition of 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, and separation of the organic layer with ether (40 mL × 4). After drying, filtration and concentration, the residue was isolated and purified by silica gel column chromatography (Hexane: ether = 1: 1) to give 0.926 g (1.65 fraction 1) of the desired product (87.7%).
一 NMR (500MHz, CDC13) 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=ll.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) 実施例 B_ l 1 ： (S) -2- ( (S) -2- ( (S) -2- (benzyloxy) propanoyloxy) -4- (tert-butyldimethylsilyloxy) butanoyloxy) ropanoic acidの合成 BnLa-(TBDMS0Me)-2La One NMR (500MHz, CDC1 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 = ll. 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 B_ l 1: (S) -2 -Synthesis of ((S) -2- ((S) -2- (benzyloxy) propanoyloxy) -4- (tert-butyldimethylsilyloxy) butanoyloxy) ropanoic acid BnLa- (TBDMS0Me) -2La
Figure imgf000055_0001
三角フラスコに 0.60g (1.07匪 ol) の ar-ブチルジメチルシロキシェチル基 を有する鎖状べンジロキシ乳酸二量体べンジルエステルと 10mL のエタノール、 さらに 10%-パラジウムカーボンを 0. lg加え、 接触還元装置で水素雰囲気下、 室 温で 30分撹拌した。反応溶液を濾過し、反応フラスコをエーテルで洗浄した後、 ロータリーエバポレーターで濃縮した。 微量に含まれていた原料をシリカゲル力 ラム（エーテル） により濾過、分離した後、溶媒を完全に除去したところ、 0.395g (0.843匪 ol)の目的物が 得られた （78.7%)。
Figure imgf000055_0001
To a conical flask, add 0.60 g (1.07 marl ol) of a linear benzyloxy lactic acid dimer benzyl ester having an ar-butyldimethylsiloxetyl group, 10 mL of ethanol, and 0.1 lg of 10% palladium carbon, and perform catalytic reduction. The mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere in the apparatus. The reaction solution was filtered, the reaction flask was washed with ether, and then concentrated on a rotary evaporator. The material contained in a trace amount was filtered and separated by silica gel column (ether), and the solvent was completely removed. As a result, 0.395 g (0.843 bandol) of the desired product was obtained (78.7%).
- NMR (500MHz, CDC13) δ ( pm) =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=ll.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) 実施例 B_ l 2 ： (S) -benzyl 2- ( (S) -2- ( (S) -2- ( (S) -2- (benzyloxy) - NMR (500MHz, CDC1 3) δ (pm) = 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 = ll.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 B_l2: (S) -benzyl 2- ((S) -2- ((S) -2- ((S) -2- (benzyloxy)
propanoyloxy) propanoyloxy) propanoyloxy) - 4- (tert-butyldimethylsilyloxy) butanoateの合成 （TBDMSOMe- Bn4LaBn) propanoyloxy) propanoyloxy) propanoyloxy)-Synthesis of 4- (tert-butyldimethylsilyloxy) butanoate (TBDMSOMe-Bn4LaBn)
Figure imgf000055_0002
Figure imgf000055_0002
窒素置換した二口ナス型フラスコで、 0°Cで lOraL のジクロロメタン溶媒中 0.226g (0.697mmol) の轧酸三量体べンジノレエーテル、 および 0.35g (1.08讓 ol) の 2-ヒ ドロキシ- 4- ( eri -ブチルジメチノレシロキシブタン酸べンジノレエステノレ、 0.33g (2.7讓 ol) の DMAPを加え 10分撹拌し、 さらに DCC O.60g (2.91讓 ol) の 10mLジクロロメタン溶液を加え、 2時間撹拌した。 その後、 10mLの飽和塩化アン モニゥム水溶液を加え、 吸引濾過し、 さらに 10mL の飽和炭酸水素ナトリウム水 溶液を加え、 エーテル（25mLX4) で分液操作を行った。 有機層を無水硫酸マグネ シゥムで乾燥し、 濾過、 濃縮した後、 シリカゲルカラムクロマトグラフィー (Hexane ： Ether = 1 : 1) で単離精製したところ、 0.35g (0.555mmol) の tert— ブチルジメチルシ口キシェチル基を有するベンジロキシ乳酸四量体べンジルェ ステルが得られた (79.3%)。 In a two-necked eggplant-shaped flask purged with nitrogen, at 0 ° C in lOraL dichloromethane solvent 0.226 g (0.697 mmol) of benzoic acid trimer benzolenoether, and 0.35 g (1.08 benzyl) of 2-hydroxy-4- (eri-butyl dimethylenosiloxybutanoate benzoinolenate, 0.33 g (2.7 parts ol) of DMAP was added and stirred for 10 minutes, and then DCC O.60 g (2.91 parts ol) of 10 ml of dichloromethane solution was added, and the mixture was stirred for 2 hours, and then 10 ml of a saturated aqueous solution of ammonium chloride was added, followed by suction filtration. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and then subjected to silica gel column chromatography (Hexane: Isolation and purification with Ether = 1: 1) yielded 0.35 g (0.555 mmol) of a benzyloxylactic acid tetramer benzyl ester having a tert-butyldimethylcyxethyl group (79.3%).
^-NMR (500MHz, CDC13) 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=1L5, 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) 実施例 B_ 1 3 ： (S) - benzyl- 2_ ( (S) _2_ ( (S) - 2_ ( (S) _2- (benzyloxy) ^ -NMR (500MHz, CDC1 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 = 1L5, 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 B_13: (S) -benzyl- 2_ ((S) _2_ ((S)-2_ ((S) _2- (benzyloxy)
propanoyloxy) - 4 - (tert- butyldimethylsilyloxy)bu"anoyloxy)propanoi丄 oxy )· butanoateの合成 BnLa- (TBDMSOMe) _2La- (TBDMSOMe) -LaBn propanoyloxy)-4-(tert-butyldimethylsilyloxy) bu "anoyloxy) propanoi 丄 oxy) butanoate Synthesis BnLa- (TBDMSOMe) _2La- (TBDMSOMe) -LaBn
Figure imgf000056_0001
Figure imgf000056_0001
窒素置換した二口ナス型フラスコで、 0°Cで 5mLのジクロロメタン溶媒中 0.33g (0.84ramol) の BnLa- (TBDMSOMe) - 2La、 および 0.32g (0.99mmol) の 2-ヒドロキシ -4-(ier -ブチルジメチルシロキシブタン酸べンジルエステルを加え、 さらに DMAP 0.18g (1.50mmol) のジクロロメタン 5mL溶液を加え撹拌した。 10分後、 DCC 0.30g (1.45mmol) の 5mLジクロロメタン溶液を加え、 3時間撹拌した。 その後、 10mLの飽和塩化アンモニゥム水溶液を加え、 吸引濾過し、 さらに 10mLの飽和炭 酸水素ナトリウム水溶液を加え、 エーテル (20mLX4) で分液操作を行った。 有機 層を無水硫酸マグネシウムで乾燥し、 濾過、 濃縮した後、 シリカゲルカラムクロ マトグラフィー（Hexane ： ether = 3 : 1) で単離精製したところ、 0.394g (0.51 1) の目的物が得られた （60.7 In a two-necked eggplant-shaped flask purged with nitrogen, 0.33 g in 5 mL of dichloromethane solvent at 0 ° C (0.84 ramol) of BnLa- (TBDMSOMe) -2La, and 0.32 g (0.99 mmol) of benzyl 2-hydroxy-4- (ier-butyldimethylsiloxybutanoate), and 0.18 g (1.50 mmol) of DMAP in dichloromethane After 10 minutes, a solution of 0.30 g (1.45 mmol) of DCC in 5 mL of dichloromethane was added, and the mixture was stirred for 3 hours.After that, 10 mL of a saturated aqueous solution of ammonium chloride was added, followed by suction filtration, and further 10 mL of saturated carbon An aqueous solution of sodium hydrogen oxychloride was added, and the mixture was separated with ether (20 mL × 4) The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and then subjected to silica gel column chromatography (Hexane: ether = 3: 1). After isolation and purification, 0.394 g (0.511) of the desired product was obtained (60.7 g).
¾- NMR (500MHz, CDC13) 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=ll.5, 160.5Hz, 2H 5.11-5.32 (m, 5H), 7.28-7.37 (m, 10H) 実施例 B_ 14 ：ベンジルォキシラクトイル乳酸フエナシルエステルの合成
Figure imgf000057_0001
 ¾- NMR (500MHz, CDC1 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 = ll.5, 160.5Hz, 2H 5.11-5.32 (m, 5H), 7.28-7.37 (m, 10H) Example B_14: Benzoxylactoyl lactate phenacyl ester Synthesis
Figure imgf000057_0001
窒素置換した二口ナス型フラスコで、 0°Cで 50mL のジクロロメタン溶媒中 1. 2g (7.88mmol) の乳酸べンジルエーテル、 および 1.65g (7.92mmol) の乳酸フ ェナシルエステル、 1.22g (9.99mmol) の DMAPを加え 10分撹拌し、 さらに DCC 2.06g (9.98mmol) の 20mLジクロロメタン溶液を加え、 3時間撹拌した。その後、 30mLの飽和塩ィヒアンモニゥム水溶液を加え、 吸引濾過し、 さらに 30mLの飽和炭 酸水素ナトリウム水溶液を加え、 エーテル (50mLX4) で分液操作を行った。 有機 層を無水硫酸マグネシウムで乾燥し、 濾過、 濃縮した後、 シリカゲルカラムクロ マトグラフィー（Hexane ： ether = 1 : 1) で単離精製したところ、 1.50g (4.05mmol) の乳酸 2量体誘導体 （ベンジルエーテル、 ベンジルエステル） が得 られた （51.4%)。 1.2 g (7.88 mmol) benzyl ether lactate and 1.65 g (7.92 mmol) phenacyl lactate, 1.22 g (9.99 mmol ) Was added and 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 an aqueous saturated sodium chloride solution was added thereto, followed by suction filtration. Further, 30 mL of an aqueous saturated sodium hydrogencarbonate solution 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 1.50 g (4.05 mmol) of a lactic acid dimer derivative ( Benzyl ether, benzyl ester) (51.4%).
¾-NMR (500MHz, CDC13) δ (ppm) =1.49 (dd, J=7.0, 11.5Hz， 3H), 1.70 (dd, J=5.0 ¾-NMR (500MHz, CDC1 3 ) δ (ppm) = 1.49 (dd, J = 7.0, 11.5Hz, 3H), 1.70 (dd, J = 5.0
7. OHz, 3H), 4.17 (quinted, J=2. OHz, 1H)， 4.47 (dd, J=9.5， 11.5Hz, 1H)， 4.757. OHz, 3H), 4.17 (quinted, J = 2. OHz, 1H), 4.47 (dd, J = 9.5, 11.5Hz, 1H), 4.75
(dd, J=ll.5, 24.5Hz, 1H), 4.75 (dd, J=11.5， 24.5Hz, 1H), 5.27-5.35 (m, 2H),(dd, J = ll.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. OHz, 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) 実施例 B— 1 5 ：ベンジルォキシ乳酸 3量体フエナシルエステルの合成 5.55 (dd, J = 14.5, 21.OHz, 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 B—15: Synthesis of benzyloxylactic acid trimer phenacyl ester
Figure imgf000058_0001
Figure imgf000058_0001
窒素置換した二口ナス型フラスコで、 0°Cで 20mL のジクロロメタン溶媒中 0.72g (4. OOmmol) の乳酸べンジルエーテル、 および 1.34g (4.80腿 ol) の乳酸二 量体フエナシルエステル、 0.49g (4mmol) の DMAPを加え 10分撹拌し、 さらに DCC 1.00g (4.85mmol) の 10mLジクロロメタン溶液を加え、 1時間撹拌した。その後、 15mLの飽和塩化アンモニゥム水溶液を加え、 吸引濾過し、 さらに 15mLの飽和炭 酸水素ナトリウム水溶液を加え、 エーテル（50mLX4) で分液操作を行った。 有機 層を無水硫酸マグネシウムで乾燥し、 濾過、 濃縮した後、 シリカゲルカラムクロ マトグラフィー（Hexane ： ether = 1 : 1) で単離精製したところ、 1.49g (3.36nmol) のべンジロキシ乳酸三量体フエナシルエステルが得られた （84.0%)。 ¾ - MR (500MHz, CDC13) δ (ppm) = 1.50 (d， J=6.5Hz, 3H)， 1.61 (d, J-7. OHz, 3H), 1.71 (d， J=4.5Hz, 3H)， 3.47 (q, J=7. OHz, 1H)， 4.14 (q, J=7. OHz, 1H), 4.48 (d, J=ll.5Hz, 1H), 4.77 (d, J=11.5Hz, 1H), 5.22 (q, J=7. OHz, 1H), 5.27 (dd, J=2.0, 16.5Hz, 1H)， 5.33 (q, J=7. OHz, 1H)， 7.27-7.43 (m， 5H)， 7.47-7.50 (m, 2H)， 7.59-7.62 (m, 1H), 7.88 (d， ]=7.5Hz, 2H) 実施例 B— 1 6 ：ベンジロキシ乳酸四量体フエナシルエステルの合成 In a nitrogen-substituted two-necked eggplant-shaped flask, 0.72 g (4.0 OO mmol) of benzyl ether lactate and 1.34 g (4.80 tmol) of dimeric lactic acid phenacyl ester in 20 mL of dichloromethane solvent at 0 ° C were prepared. g (4 mmol) of DMAP was added, and the mixture was stirred for 10 minutes. Further, a solution of 1.00 g (4.85 mmol) of DCC in 10 mL of dichloromethane was added, and the mixture was stirred for 1 hour. Thereafter, 15 mL of a saturated aqueous solution of ammonium chloride was added thereto, followed by suction filtration. Further, 15 mL of a saturated aqueous solution of sodium hydrogencarbonate 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 nmol) of benzyloxylactic acid trimer The phenacyl ester was obtained (84.0%). ¾ - MR (500MHz, CDC1 3 ) δ (ppm) = 1.50 (d, J = 6.5Hz, 3H), 1.61 (. D, J-7 OHz, 3H), 1.71 (d, J = 4.5Hz, 3H) , 3.47 (q, J = 7. OHz, 1H), 4.14 (q, J = 7. OHz, 1H), 4.48 (d, J = ll.5Hz, 1H), 4.77 (d, J = 11.5Hz, 1H ), 5.22 (q, J = 7. OHz, 1H), 5.27 (dd, J = 2.0, 16.5Hz, 1H), 5.33 (q, J = 7. OHz, 1H), 7.27-7.43 (m, 5H) , 7.47-7.50 (m, 2H), 7.59-7.62 (m, 1H), 7.88 (d,] = 7.5Hz, 2H) Example B-16: Synthesis of benzyloxylactic acid tetramer phenacyl ester
Figure imgf000059_0001
Figure imgf000059_0001
窒素置換した二口ナス型フラスコで、 0°C、20mLのジクロロメタン溶媒中 0.757g (3. Ommol) の乳酸二量体べンジルエーテルと、 0.840 (3.0麵 ol) の乳酸二量体フ ェナシルエステル、 およぴ 0.550g (4.5mmol) の DMAPを加え 10分撹拌した後、 DCC 0.928g (4.5mmol) の 10mLジクロロメタン溶液を加え 2時間撹拌した。 その 後、 15mLの飽和塩化アンモニゥム水溶液を加え、 吸引濾過し、 さらに 15mLの飽 和炭酸水素ナトリウム水溶液を加え、 エーテル（50mLX4) で分液操作を行った。 有機層を無水硫酸マグネシウムで乾燥し、 濾過、 濃縮した後、 シリカゲルカラム クロマトグラフィー（Hexane ： ether = 1 : 2) で単離精製したところ、 1.24g (2.40mmol) のべンジロキシ乳酸四量体フエナシルエステルが得られた （80.0%)。 ー丽 R (500MHz, CDC13) 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=ll.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) 実施例 B— 1 7 ： (3S, 6S) -3- (2- (tert-butyldimethylsilyloxy) ethyl) In a two-necked eggplant-shaped flask purged with nitrogen, 0.757 g (3.0 mmol) of benzyl dimer of lactic acid and phenacyl ester of 0.840 (3.0 mol) of lactic acid dimer in 20 mL of dichloromethane solvent at 0 ° C. After adding 0.550 g (4.5 mmol) of DMAP and stirring for 10 minutes, a solution of 0.928 g (4.5 mmol) of DCC in 10 mL of dichloromethane was added, followed by stirring for 2 hours. Thereafter, 15 mL of a saturated aqueous solution of ammonium chloride was added thereto, followed by suction filtration. Further, 15 mL of a saturated aqueous solution of sodium hydrogencarbonate 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) of benzyloxylactic acid tetramer Nasyl ester was obtained (80.0%). Over丽R (500MHz, CDC1 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 = ll.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 m, 3H) Example B—17: (3S, 6S) -3- (2- (tert-butyldimethylsilyloxy) ethyl)
-6-methyl-l, 4—diox騰- 2， 5-dione TBDMSOMe - cyclic 2Laの合成
Figure imgf000060_0001
-6-methyl-l, 4-diox-Temperature 2, 5-dione TBDMSOMe-Synthesis of cyclic 2La
Figure imgf000060_0001
アルゴン置換した二口ナス型フラスコに 0. 41g (2. Ommol) の DCC、 0. 37g (3. 0mmol)の DMAP、 および 0. 32g (2. Ommol)の DMAP ' HClをそれぞれ lOmL (全量 30mL) のジクロロメタンに溶かして加え、 0. 294g (0. 96ramol)の TBDMSOMe- 2Laを 10mLの THF、 20mLのジクロロメタンの混合溶媒に溶かし、 16時間かけて反応容 器に加えた。 加える際は容器の壁を伝わるようにし、 常に均一の量が流れ込むよ うにした。 さらに 1時間撹拌した後、 全量が 20mL程度になるまでエバポレータ 一で濃縮し、濾過して固体を取り除き、再び濃縮した（固体はエーテルで洗つた）。 シリカゲルカラムクロマトグラフィー （Hexane ： EtOAc = 3 : 1) で単離精製し たところ 0. 086g (0. 30mmol)の環状物を得た （31. 6%)。 0.41 g (2.0 mmol) of DCC, 0.37 g (3.0 mmol) of DMAP, and 0.32 g (2. ) Was dissolved in dichloromethane, and 0.294 g (0.96 ramol) 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. The addition was made to travel down the wall of the container so that an even volume always flowed. After stirring for an additional hour, the mixture was concentrated with an evaporator until the total volume was about 20 mL, filtered to remove solids, and concentrated again (the solids were washed with ether). Silica gel column chromatography (Hexane: EtOAc = 3: 1 ) in to give the cyclic product isolated purified at 0. 086g (0. 30mmol) (3 1. 6%).
一 NMR (500MHz, CDC13) 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. OHz, 1H) 実施例 B— 1 8 ： (3S， 6S) -3- (2-ヒドロキシェチル） -6-メチル- 1， 4-ジォキサン -2， 5-ジオン（64)の合成 （ヒドロキシェチル基を有する環状乳酸二量体の合成） HOMe— cyclic 2La One NMR (500MHz, CDC1 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. OHz, 1H) Example B—18: (3S, 6S) -3- (2-hydroxyethyl) -6-methyl-1,4-dioxane Synthesis of -2,5-dione (64) (Synthesis of cyclic lactic acid dimer having hydroxyethyl group) HOMe—cyclic 2La
Figure imgf000060_0002
Figure imgf000060_0002
88.6% 反応容器で 0. 081g (0. 284腿 ol) の（62)を 2. 8mLのァセトニトリルに溶かし、 2 滴のフッ化水素酸を滴下し、 20分撹拌した。 TLCにより反応終了を確認後、 飽和 炭酸水素ナトリウムを 10mL加え、 クロ口ホルム （10mL X 5) で抽出した。 クロ口 ホルム層を無水硫酸マグネシウムで乾燥した後、 濾過し、 濃縮した。 生成物に微 量の不純物が含まれていたため、 シリカゲルカラムクロマトグラフィー （クロ口 ホルム ： エタノール = 10 : 1) により単離精製したところ、 0. 438g (0. 252mmol) の（64)が得られた。 目的物はエーテル、 へキサンなどに不溶、 酢酸ェチル、 クロ ロホノレム、 エタノーノレに可溶である。 In an 88.6% reaction vessel, 0.081 g (0.284 tmol) of (62) was dissolved in 2.8 mL of acetonitrile, 2 drops of hydrofluoric acid was added dropwise, and the mixture was stirred for 20 minutes. After confirming the completion of the reaction by TLC, saturate 10 mL of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform (10 mL × 5). The mouth layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Since the product contained a small amount of impurities, it was isolated and purified by silica gel column chromatography (form: ethanol = 10: 1) to obtain 0.438 g (0.252 mmol) of (64). Was. The target product is insoluble in ether, hexane, etc., and soluble in ethyl acetate, chlorophonolem, and ethanol.
(3S, 6S) - 3- (2-ヒドロキシェチル） - 6 -メチル- 1, 4-ジォキサン - 2， 5 -ジオン（64) Rf=0. 19 (CHC13 ： Ethanol = 10 ： 1)(3S, 6S) - 3- ( 2- hydroxy-E Chill) - 6 - methyl - 1, 4-Jiokisan - 2, 5 - dione (64) R f = 0 19 . (CHC1 3: Ethanol = 10: 1)
- NMR (500MHz, CDC13) 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) -NMR (500 MHz, CDC1 3 ) δ (ppm) = 1.46 (d, J = 7.0 Hz, 2H), 2.29—2.38, 2.68-2.74 (m, 2H), 3 20 (br s, 1H), 4.30 (dt, J = 6.5, 9.5 Hz, 1H), 4.37 (q, J = 7.0 Hz, 1H), 4.47 (dt, J = 7.0, 9.0Hz, 1H), 5.50 (t, J = 9.0Hz, 1H)
13C-NMR (125MHz, CDC13) δ (ppm) = 20. 09， 20. 28， 28. 63, 28. 74, 65. 16， 66. 76， 66. 87, 68. 30， 68. 44, 172. 50, 174. 50 実施例 B— 1 9 ： (S) - tert-butyl 4- (benzyloxy) -2- ( tert- butyldimethylsilyloxy) butanoate
Figure imgf000061_0001
窒素雰囲気下、 0°Cにおいてイミダゾール 0. 246 g (3. 61mmol) のジクロ口メタ ン溶液に t-ブチルジメチルシリルク口ライ ド 0. 261 g (1. 73mmol) のジクロロメ タ ン 溶 液 を 加 え 15 分 攪 拌 後 、 （S) - teri - butyl 4- (benzyloxy) -2-hydroxybutanoate 0. 436 g (1. 64mmol)を加え 4時間攪拌した。 水で処理し、 ジクロロメタンで抽出した。 硫酸マグネシウムで乾燥後、 濃縮し、 シリカゲルカラムクロマトグラフィー （展開溶媒 Hexane： Ether= 4 ： 1 ) を用 い て 単 離 精 製 を 行 っ た と こ ろ 、 （S) - - butyl 4- (benzyloxy) -2- ( ieri-butyldimethylsilyloxy) butanoate を 0. 399 g (75. 1%) の収率で得た。 1 3 C-NMR (125MHz, CDC1 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 B—19: (S) -tert-butyl 4- (benzyloxy) -2- (tert-butyldimethylsilyloxy) butanoate
Figure imgf000061_0001
Under nitrogen atmosphere, at 0 ° C, 0.261 g (1.73 mmol) of dichloromethane solution was added to 0.246 g (3.61 mmol) of imidazole in methane solution of dichloromethane at 0 ° C. After stirring for an additional 15 minutes, 0.436 g (1.64 mmol) of (S) -teri-butyl 4- (benzyloxy) -2-hydroxybutanoate was added, and the mixture was stirred for 4 hours. Treated with water and extracted with dichloromethane. After drying over magnesium sulfate, the mixture was concentrated, and subjected to isolation and purification using silica gel column chromatography (developing solvent Hexane: Ether = 4: 1). (S)--butyl 4- (benzyloxy) ) -2- (ieri-butyldimethylsilyloxy) butanoate 0.39 g (75.1%) In a yield of
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) 実施例 B— 20 ： (S) -4- (benzyloxy) -2- ( ieri-butyldimet ylsilyloxy) butanoic acid 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 B-20: (S) -4- (benzyloxy) -2- (ieri-butyldimet ylsilyloxy) butanoic acid
TBDMS-CI
Figure imgf000062_0001
TBDMS-CI
Figure imgf000062_0001
窒素雰囲気下、 0°Cにおいてイミダゾール 0.271 g (3.98mmol) のジクロ口メタ ン溶液 に ジ メ チ ル ァ ミ ノ ピ リ ジ ン 0.0480 g ( 0.39mmol ) と (S) -4- (benzyloxy; -2-hydroxvbutanoic acid 0.250 g (1.19讓 ol) のシク口ロメ タン溶液を加え 15分攪拌した。その後、 t' 口ライド 0.625 g (4.15墮 ol)のジクロロメタン溶液を加え 21時間攪拌した。 20ml塩化水素（0.1N) を滴下し、エーテルで抽出した。有機相を飽和炭酸水素ナトリゥム溶液で洗浄し、 続けて飽和塩化ナトリゥム溶液で洗浄した。 硫酸ナトリゥムで乾燥後、 濃縮する ことにより生成物を得た。 得られた生成物はそのまま次の反応に用いた。  In a nitrogen atmosphere, at 0 ° C, 0.0480 g (0.39 mmol) of dimethylaminopyridine was added to a solution of 0.271 g (3.98 mmol) of imidazole in dichloromethane at 0 ° C and (S) -4- (benzyloxy;- A solution of 0.250 g (1.19 benzyl) of 2-hydroxvbutanoic acid in cyclomethan methane was added and stirred for 15 minutes, followed by a solution of 0.625 g (4.15 malt ol) of t'-mouth in dichloromethane and stirred for 21 hours. (0.1N) was added dropwise, and the mixture was extracted with ether.The organic phase was washed with a saturated sodium hydrogen carbonate solution, followed by a saturated sodium chloride solution, dried over sodium sulfate, and concentrated to obtain a product. The obtained product was directly used for the next reaction.
0°Cにおいて 1.3ml の水に溶かした水酸化カリウム 0.220 g (3.92脑 ol) と 4mlTHFの混合溶液に、 得られた生成物の THF溶液を滴下し 30分攪拌した。 10ml の水を加えエーテルで抽出した。 水相に冷却した塩化水素 （3N) を滴下し、 万能 pH試験紙を用いて pHを 3にした。 酢酸ェチルで抽出し、 硫酸ナトリゥムで乾燥 後 、 濃 縮 す る こ と に よ り (S) -4- (benzyloxy; -2- ( ierz butyldimethylsilyloxy) butanoic acid を 0.306 g (79.2%) の収率で得た。  At 0 ° C., a THF solution of the obtained product was added dropwise to a mixed solution of 0.220 g (3.92 mol) of potassium hydroxide and 4 ml of THF dissolved in 1.3 ml of water, and the mixture was 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 a universal pH test paper. It was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give (S) -4- (benzyloxy; -2- (ierzbutyldimethylsilyloxy) butanoic acid in a yield of 0.306 g (79.2%). Obtained.
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. 9 (q, J=11.5Hz, 2H)， 7. 28-7. 38 (m, 5H) 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), 4.9 (q, J = 11.5Hz, 2H), 7. 28-7. 38 (m, 5H)
実施例 B— 2 1 ： (S) -4- (benzyloxy) -2-hydroxybutanoic acid OHExample B—21: (S) -4- (benzyloxy) -2-hydroxybutanoic acid OH
Figure imgf000063_0001
Figure imgf000063_0001
窒 素 雰 囲 気 下 、 室 温 に お い て （S) - eri- butyl (S) -eri-butyl at room temperature in a nitrogen atmosphere
4- (benzyloxy) -2-hydroxybutanoate 0. 263 g (0. 987 ol) の 1ml ジクロロメタ ン溶液に 1mlのトリフルォロ酢酸を滴下し、 1時間攪拌した。酢酸ェチルを加え、 濃縮し、再び酢酸ェチルを加え濃縮の操作を 3回繰り返した後、真空ポンプで 24 時間以上減圧下に置き、 ト リ フルォロ酢酸を完全に除去したところTo a solution of 0.23 g (0.987 ol) of 4- (benzyloxy) -2-hydroxybutanoate in 1 ml of dichloromethane, 1 ml of trifluoroacetic acid was added dropwise and stirred for 1 hour. The procedure of adding ethyl acetate, concentrating, adding ethyl acetate again and concentrating was repeated three times, and then the vacuum pump was placed under reduced pressure for at least 24 hours to completely remove trifluoroacetic acid.
(S) -4- (benzyloxy) -2-hydroxybutanoic acid を 0. 203 g (97. 6%)の収率で得た。 δ (ppm) = 2. 06-2. 28 (m, 2H) , 3. 71—3. 78 (m, 2H 4. 40 (s, 1H) , 4. 55 (s， 2H) ,(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) 7. 28-7. 38 (m, 5H)
実施例 B - 2 2 ： (S) - tert-h tyl 4- (benzyloxy) - 2- ( (S) - 2- ( tert- butyldimethylsilyloxy) propanoyloxy) butanoate Example B-22: (S) -tert-htyl 4- (benzyloxy) -2-((S) -2- (tert-butyldimethylsilyloxy) propanoyloxy) butanoate
Figure imgf000063_0002
Figure imgf000063_0002
アルゴン雰囲気下、 室温においてィミダゾール 1. 70 g (25. Ommol) の DMF溶液 に t-プチルジメチルシリルク口ライド 1. 88 g (12. 5mmol) の DMF溶液と L-乳酸 0. 450 g (5. OOmmol) の DMF溶液を加え 16時間攪拌した。 飽和炭酸水素ナトリウ ム水溶液で処理し、 へキサンで抽出した。 有機相を飽和塩化ナトリゥム水溶液で 洗浄し、 硫酸ナトリウムで乾燥後、 濃縮することにより生成物を得た。 得られた 生成物はそのまま次の反応に用いた。  At room temperature under an argon atmosphere, 1.70 g (25.Ommol) of imidazole was added to a DMF solution of 1.88 g (12.5 mmol) of t-butyldimethylsilyl chloride and 0.450 g of L-lactic acid (5. OOmmol) in DMF was added and stirred for 16 hours. The mixture was treated with a saturated aqueous solution of sodium hydrogen carbonate 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 for the next reaction.
窒素雰囲気下、 0°Cにおいて得られた生成物のジクロロメタン溶液に 0. 87ml (10. Ommol) の塩化ォキサリルを滴下し、 次いで DMF溶液を 1滴加え、 0°Cで 2 時間、 室温で 3時間攪拌した。 減圧濃縮することにより粗生成物を得た。 得られ た粗生成物をドライエーテルに溶解し、 一 20°Cにおいてピリジン 0.316 g ( 3.99mmol ) (S) - ieri-butyl - (benzyloxy) -2~hydroxybutanoate 0.257 g (0.965mmol) のエーテル溶液を滴下し、 1.5時間攪拌した。 飽和炭酸水素ナトリ ゥム水溶液で処理し、 酢酸ェチルで抽出した。 飽和塩化ナトリウム水溶液で洗浄 し、 硫酸マグネシウムで乾燥後、 濃縮してシリカゲルカラムクロマトグラフィー (展開溶媒 Hexane ： Ether = 4 ： 1) を用いて単離精製を行ったところ、 (S) - ieri-butyl Under a nitrogen atmosphere, at 0 ° C, 0.87 ml (10.O mmol) of oxalyl chloride was added dropwise to a dichloromethane solution of the obtained product, and then a drop of DMF solution was added. The mixture was stirred at room temperature for 3 hours. The crude product was obtained by concentrating under reduced pressure. The obtained crude product was dissolved in dry ether, and at 20 ° C, an ether solution of 0.316 g (3.99 mmol) of pyridine (S) -ieri-butyl- (benzyloxy) -2-hydroxybutanoate 0.257 g (0.965 mmol) was added. The mixture was added dropwise and stirred for 1.5 hours. The mixture was treated with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After washing with a saturated aqueous sodium chloride solution, drying over magnesium sulfate, concentrating and isolating and purifying using silica gel column chromatography (developing solvent Hexane: Ether = 4: 1), (S) -ieri-butyl
4一 (benzyloxy)—2— { {S)一 2— ( ar— buty丄 dimethylsily丄 oxyノ propanoyloxy butanoate を 0.236 g (54.1%) の収率で得た。  4- (benzyloxy) -2-({(S) -1-2- (ar-butysidimethylsily ノ oxy) propanoyloxy butanoate was obtained in a yield of 0.236 g (54.1%).
δ (ppm) = 0.089 (d, J=13. OHz, 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. OHz, 1H)， 4.49 (s, 2H)， 5.08 (dd, J=4.5, 4. OHz, 1H), 7.36—7.27 (m， 5H) 実施例 B— 2 3 ： (S) - ieri-butyl-4- (benzyloxy) -2- ( (S) -4- (benzyloxy) -2- ( ieri-butyldimethylsilyloxy) butanoyloxy) butyrate  δ (ppm) = 0.089 (d, J = 13. OHz, 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.OHz, 1H), 4.49 (s, 2H), 5.08 (dd, J = 4.5, 4.OHz, 1H), 7.36 —7.27 (m, 5H) Example B—23: (S) -ieri-butyl-4- (benzyloxy) -2-((S) -4- (benzyloxy) -2- (ieri-butyldimethylsilyloxy) butanoyloxy) butyrate
OTBDMSOTBDMS
B V Y0H +
Figure imgf000064_0001
BVY 0H +
Figure imgf000064_0001
窒 素 雰 囲 気 下 、 0 °c に お い て (S) -4- (benzyloxy; -2- ( ieri-butyldimethylsilyloxy) butanoic acid 0.306 g ( 0.944讓 ol ) の ジ ク 口 口 メ タ ン 液 に （S)- artbutyl -4- (benzyloxy) -2-hydroxybutanoate 0.266 g (1.00腿 ol) とジメチルァミノピ リジン 0.248 g (2.03mmol) の各々のジクロロメタン溶液を加え 15分攪拌後、 ジ シクロへキシルカルポジイミ ド 0.411 g (2. OOmmol) のジクロロメタン溶液を滴 下し 6時間攪拌した。 吸引ろ過後、 飽和塩化アンモニア水溶液と飽和炭酸水素ナ トリウム水溶液で処理し、 へキサンで抽出した。 硫酸マグネシウムで乾燥後、 濃 縮してシリカゲルカラムクロマトグラフィー （展開溶媒 Hexane： Ether =2： 1) で単離精製を行ったところ、 （S)-
Figure imgf000065_0001
- 2 - ( (S) -4 - (benzyloxy; - 2 - ( ieri-butyldimethylsilyloxy) butanoyloxy butyrate を 0.0506 g (9.37%) の収率で得た。 In a nitrogen atmosphere, at 0 ° C, a solution of 0.306 g (0.944 alcohol) of (S) -4- (benzyloxy; -2- (ieri-butyldimethylsilyloxy) butanoic acid was added. (S) -artbutyl-4- (benzyloxy) -2-hydroxybutanoate 0.266 g (1.00 t ol) and dimethylaminopyridine 0.248 g (2.03 mmol) in dichloromethane solution were added. After stirring for 15 minutes, dicyclohexylcarpoimimid was added. 0.411 g (2.0 mmol) of dichloromethane was added dropwise, and the mixture was stirred for 6 hours. The mixture was treated with an aqueous thorium solution and extracted with hexane. After drying over magnesium sulfate, the solution was concentrated and purified by silica gel column chromatography (developing solvent Hexane: Ether = 2: 1).
Figure imgf000065_0001
-2-((S) -4-(benzyloxy;-2-(ieri-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) 実施例 C一 1 ： (S) - 4 - benzyl 1-phenacyl 2 - hydroxysuccinateの合成 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) Example C-1: Synthesis of (S) -4-benzyl 1-phenacyl 2-hydroxysuccinate
Figure imgf000065_0002
Figure imgf000065_0002
窒素雰囲気下、室温において水素化ナトリゥム 0.816g(17mmol)に乾燥した Ν,Ν - ジメチルホルムアミ ド（DMF)7ml を加え、 この混合物に（1)2.93g(16.8mmol)の 15mlDMF溶液をゆっくり加え、 系を 0°Cにして 15分間攪拌した。 この後、 ベンジ ルブロミド 3.16g(18.5mmol)の 6mlDMF瑢液を加え、 2時間攪拌した。 飽和塩化ァ ンモニゥム溶液で処理し、 飽和食塩水を加え、 ジクロロメタンで抽出を行った。 続いて硫酸マグネシウムで乾燥したのち、 減圧濃縮し、 シリカゲルカラムクロマ トグラフィー（展開溶媒 Ac0EVHexane=l:3)を用いて単離精製を行ったところ (2)が 3.59g (79%)の収率で得られた。 室温において（2)2.64g(10匪 ol)の 100mlァセトニトリル溶液にフッ化水素酸 75 滴を加え、 2.5 時間攪拌した。 飽和炭酸水素ナトリウム溶液で処理し、 飽和塩化 アンモ-ゥム溶液を加え、 エーテルで抽出した。 続いて硫酸マグネシウムで乾燥 したのち、 減圧濃縮し、 シリカゲルカラムクロマトグラフィー（展開溶媒 Ei er/Hexane=2:l)を用いて単離精製を行ったところ、 （3)がほぼ当量的に得られ た。 Under nitrogen atmosphere, at room temperature, 0.816 g (17 mmol) of sodium hydride was added with 7 ml of dried Ν, Ν-dimethylformamide (DMF). To this mixture was slowly added a solution of 2.93 g (16.8 mmol) of (1) in 15 ml of DMF. The system was brought to 0 ° C and stirred for 15 minutes. Thereafter, 3.16 g (18.5 mmol) of benzyl bromide in 6 ml of DMF was added, and the mixture was stirred for 2 hours. The mixture was treated with a saturated ammonium chloride solution, saturated saline was added, and the mixture was extracted with dichloromethane. Then After drying over magnesium sulfate and concentrated under reduced pressure, silica gel column chromatography (developing solvent Ac0EVHexan e = l: 3) yield of was then isolated and purified by using (2) 3.59 g (79%) Rate obtained. At room temperature, 75 drops of hydrofluoric acid was added to a solution of 2.64 g (10 marl) in 100 ml of acetonitrile, and the mixture was stirred for 2.5 hours. The mixture was treated with a saturated sodium bicarbonate solution, a saturated ammonium chloride solution was added, and the mixture was extracted with ether. Subsequently, the extract was dried over magnesium sulfate, concentrated under reduced pressure, and then isolated and purified using silica gel column chromatography (developing solvent: Ether / Hexane = 2: l). Was.
窒素雰囲気下、室温において（3)10mlTHF溶液にトリェチルァミン 1. lg(llmmol) の lOmlTHF 溶 液 を カ卩 え 、 5 分 間 攪 拌 し た 。 こ の 後 、 2 - Bromoacetphenone2.20g(llmmol)の lOmlTHF溶液を加え、 3時間攪拌した。 飽 和塩化アンモ-ゥム溶液で処理し、 飽和食塩水を加え、 エーテルで抽出した。 続 いて硫酸マグネシウムで乾燥したのち、減圧濃縮を行った。 Hexaneで洗浄して単 離精製を行つたところ（4)が 3.21g (94%)の収率で得られた。  At room temperature under a nitrogen atmosphere, (3) lOml THF solution of 1.lg (llmmol) of triethylamine was added to 10ml THF solution and stirred for 5 minutes. Thereafter, a solution of 2.20 g (ll mmol) of 2-bromoacetphenone in 10 ml THF was added, and the mixture was stirred for 3 hours. The mixture was treated with a saturated ammonium chloride solution, saturated saline was added, and the mixture was extracted with ether. Subsequently, after drying over magnesium sulfate, concentration under reduced pressure was performed. After washing with Hexane and performing isolation purification, (4) was obtained in a yield of 3.21 g (94%).
H1 -雨 R (500MHz, CDC13) δ (ppm)=2.993 (1H, dd, J=6.5Hz, 17. OHz),H 1 - Rain R (500MHz, CDC1 3) δ (ppm) = 2.993 (1H, dd, J = 6.5Hz, 17. OHz),
3.068 (1H, dd, J=9.0Hz, 17. OHz)， 4.760 (1H, q, J=5. OHz) ,3.068 (1H, dd, J = 9.0Hz, 17.OHz), 4.760 (1H, q, J = 5.OHz),
5.192 (2H, dd, J=12.5Hz, 19. OHz), 5.400(2H, dd, J=16.5Hz, 23. OHz) , 7.359(6H，m), 7.501 (2H, t, J=7.5Hz), 7.626 (1H, t, J=7.5Hz), 7.876 (2H, d, J=7.5Hz) 実施例 C一 2 ： (S)-4-benzyl 1-phenacyl 2- ((S)- 2- (tert- butyldimethylsilyloxy) ropanoyloxy) succinate Bn - Ma - 1 - TBDMS- Phenaの合成 5.192 (2H, dd, J = 12.5Hz, 19.OHz), 5.400 (2H, dd, J = 16.5Hz, 23.OHz), 7.359 (6H, m), 7.501 (2H, t, J = 7.5Hz) , 7.626 (1H, t, J = 7.5Hz), 7.876 (2H, d, J = 7.5Hz) Example C-1: (S) -4-benzyl 1-phenacyl 2- ((S)-2- ( tert-butyldimethylsilyloxy) ropanoyloxy) succinate Bn-Ma-1-Synthesis of TBDMS- Phena
?H ? H
入 ノ OH Input OH
X l X l
Figure imgf000066_0001
Figure imgf000066_0001
5 6  5 6
窒素雰囲気下、 室温において L-乳酸 0.270g(3.0mmol)、 tert -プチルジメチル シリルクロ リ ド 1· 09g(7.2腿 ol)、 ィ ミダゾール 0.901g(13.2纖 ol)を乾燥した DMF に溶解し、 18 時間攪拌した。 この混合物に飽和炭酸水素ナトリウム溶液を加え、 へキサンで抽出した。 有機層を飽和食塩水で洗浄し、 無水硫酸マ： 燥し、 減圧濃縮してジシリル化した粗製生物を得た。 得られた粗製物をジクロ口 メタン 3mlに溶解し、 系を 0 °Cとした後、 塩化ォキサリル 0. 533g (4. 2mmol)を加 え、 ついで DMF滴を滴下した。 0 °Cで一時間攪拌した後、 室温で 2時間攪拌し、 減圧濃縮して、 酸クロリ ドの粗生成物を得た。 得られた粗生成物をジェチルエー テル 5mlに溶解し、 系を 0 °Cとした後、 ピリジン 1. 7mlと、 （4) 0. 976g (2. 9讓 ol) の 3mlエーテル溶液を順次加えた。 0でで 1時間攪拌した後、 飽和炭酸水素ナト リゥム水溶液を加え、 酢酸ェチルで抽出した。 有機層を飽和塩化アンモニゥム溶 液で洗浄し、 次に飽和食塩水で洗浄した。 有機層を無水硫酸マグネシウムで乾燥 し、 減圧濃縮し、 シリ カゲルカラムクロマ トグラフィー（展開溶媒 Ether/Hexane=l： 1)を用いて単離精製を行ったところ（6)が 0. 890g (52%)の収率 で得られた。 Under nitrogen atmosphere, at room temperature, 0.270 g (3.0 mmol) of L-lactic acid, 1.0 g (7.2 t) of tert-butyldimethylsilyl chloride and 0.901 g (13.2 fiber) of imidazole were dissolved in dry DMF, and Stirred for hours. To this mixture was added a saturated sodium hydrogen carbonate solution, and the mixture was extracted with hexane. The organic layer was washed with a saturated saline solution, and anhydrous sulfuric acid: It was dried and concentrated under reduced pressure to obtain a disilylated crude product. The obtained crude product was dissolved in dichloromethane (3 ml), the system was brought to 0 ° C., 0.53 g (4.2 mmol) of oxalyl chloride was added, and then DMF droplets were added dropwise. After stirring at 0 ° C for 1 hour, the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain a crude acid chloride. The obtained crude product was dissolved in 5 ml of getyl ether, and the temperature of the system was adjusted to 0 ° C. Then, 1.7 ml of pyridine and a 3 ml ether solution of 0.976 g (2.9 propyl) of (4) were sequentially added. Was. After stirring at 0 for 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and isolated and purified using silica gel column chromatography (developing solvent Ether / Hexane = 1: 1). %).
tf-NMR (500MHz, CDC13) δ (ppm) =0. 077 (6Η, d, J=8. OHz) , 0. 893 (9H, s) , 1. 451 (3H， d, J=5. 0Hz)， 3. 095 (1H, dd, J=8. 5Hz， 10. 5Hz) , 3. 208 (1H， dd, J=3. 5Hz, 8. 5Hz)， 4. 380 (1H, q, J=7. OHz) , 5. 181 (2H, s) , 5. 362 (2H, dd, J=16. 5Hz, 12. OHz) , 5. 685 (1H, dd, J=3. 5Hz, 8. 5Hz) , 7. 356 (6H， m)， 7. 523 (2H, t, ]=7. 5Hz) , 7. 610 (1H， t, J=7. 5Hz)， 7. 861 (2H， d, J=7. 5Hz) 実施例 C一 3 ： (S) -4- (benzyloxy) -2- ( (S) -2- (tert-butyldimethylsilyloxy) propanoyloxy) -4-oxobutanoic acidの合成 tf-NMR (500MHz, CDC1 3 ) δ (ppm) = 0. 077 (6Η, d, J = 8. OHz), 0. 893 (9H, s), 1. 451 (3H, d, J = 5. 0Hz), 3.095 (1H, dd, J = 8.5Hz, 10.5Hz), 3.208 (1H, dd, J = 3.5Hz, 8.5Hz), 4.380 (1H, q, J = 7.OHz), 5.181 (2H, s), 5.362 (2H, dd, J = 16.5Hz, 12.OHz), 5.685 (1H, dd, J = 3.5Hz, 8. 5 Hz), 7.356 (6H, m), 7.523 (2H, t,] = 7.5Hz), 7.610 (1H, t, J = 7.5Hz), 7.861 (2H, d, (J = 7.5 Hz) Example C-13: Synthesis of (S) -4- (benzyloxy) -2-((S) -2- (tert-butyldimethylsilyloxy) propanoyloxy) -4-oxobutanoic acid
Figure imgf000067_0001
窒素雰囲気下、 室温において（6) 2. 00g (3. 51mmol)を 70ml エーテルに溶解し、 酢酸 6 ml (10. 48mmol)、 亜鉛 2. 29g (35. 02讓 ol)を順次加え、 2 0時間攪拌した。 この混合物をグラスフィルターでろ過し、 残查を酢酸ェチルで洗浄し、 ろ液を得 た。 ろ液を飽和炭酸水素ナトリウム溶液で抽出し、 有機層を硫酸マグネシウムで 乾燥したのち、 減圧濃縮し、 シリカゲルカラムクロマトグラフィー（展開溶媒
Figure imgf000067_0001
Under a nitrogen atmosphere, at room temperature, 2.00 g (3.51 mmol) of (6) was dissolved in 70 ml of ether, and 6 ml (10.48 mmol) of acetic acid and 2.29 g of zinc (35.02 benzyl) were added in that order. Stirred for hours. This mixture was filtered with a glass filter, and the residue was washed with ethyl acetate to obtain a filtrate. The filtrate was extracted with saturated sodium hydrogen carbonate solution, and the organic layer was extracted with magnesium sulfate. After drying, it is concentrated under reduced pressure and silica gel column chromatography (developing solvent).
AcOEt/Hexane=l:2)を用いて単離精製を行つたところ（7)が 0.591g(41%)の収率で 得られた。 When isolation and purification were performed using AcOEt / Hexane = 1: 2), (7) was obtained in a yield of 0.591 g (41%).
H'-NMR (500MHz, CDC13) δ (ppm) =0.064 (6Η, d, J=10.5Hz) , 0.886(9H, s), 1.41K3H, d, J=7. OHz), 2.990 (2H, d, J=6.5Hz) , 4.361 (1H, q, J=7.0Hz), H'-NMR (500MHz, CDC1 3 ) δ (ppm) = 0.064 (6Η, d, J = 10.5Hz), 0.886 (9H, s), 1.41K3H, d, J = 7. OHz), 2.990 (2H, d, J = 6.5Hz), 4.361 (1H, q, J = 7.0Hz),
5.156 (2H， s), 5.560 (1H, t, J=6. OHz) , 7.352 (6H， m) 5.156 (2H, s), 5.560 (1H, t, J = 6. OHz), 7.352 (6H, m)
実施例 C一 4 ： (S) -4-benzyl 1 - tert- butyl 2- ( (S) -2-hydroxypropanoyloxy) succinateの合成Example C-1-4: Synthesis of (S) -4-benzyl 1-tert-butyl 2-((S) -2-hydroxypropanoyloxy) succinate
TBDMS , H  TBDMS, H
HF  HF
o'z、o O ^ U 0" 、 u0 O  o'z, o O ^ U 0 ", u0 O
BnOOCヽ.、、上ノ 0、 ' 、  BnOOC ヽ. ,, top 0, ',
、Ph MeCN BnOOC\.,、  , Ph MeCN BnOOC \. ,,
、Ph O O  , Ph O O
6 8  6 8
室温において（6)0.093g(0.163ramol)をァセトニトリル 6mlに溶解し、 フッ化水 素酸 6滴を加え、 1時間攪拌した。 これを飽和炭酸水素ナトリウムで処理し、 ェ 一テルで抽出した後、 飽和食塩水で洗浄した。 続いて硫酸マグネシウムで乾燥し たのち、 減圧濃縮したところ（8)が 0.054g(75%)の収率で得られた。  At room temperature, 0.093 g (0.163 ramol) of (6) was dissolved in 6 ml of acetonitrile, 6 drops of hydrofluoric acid was added, and the mixture was stirred for 1 hour. This was treated with saturated sodium bicarbonate, extracted with ether, and washed with saturated saline. Subsequently, after drying over magnesium sulfate and concentrating under reduced pressure, (8) was obtained in a yield of 0.054 g (75%).
H1- MR(500丽 z，CDCl3) δ (ppm)=l. 58 (3Η, d, 7. OHz), 3.113 (1H, dd, 8.5Hz, 16.5Hz), 3.247 (1H, dd, 8.5Hz, 16.5Hz), 4.29 (1H, m), 5.203 (1H, q, J=12. OHz), 5.382 (2H, dd, J=16. OHz, 109.0Hz), 5.759 (1H, dd, J=4. OHz, 9. OHz) , 7.360 (6H, m) , 7.495 (2H, t， J=7. OHz)， 7.624 (1H， t, J=7. OHz) , 7.871 (2H, d， J=7. OHz) H 1 -MR (500 丽 z, CDCl 3 ) δ (ppm) = l.58 (3Η, d, 7.OHz), 3.113 (1H, dd, 8.5Hz, 16.5Hz), 3.247 (1H, dd, 8.5 Hz, 16.5Hz), 4.29 (1H, m), 5.203 (1H, q, J = 12.OHz), 5.382 (2H, dd, J = 16.OHz, 109.0Hz), 5.759 (1H, dd, J = 4. OHz, 9. OHz), 7.360 (6H, m), 7.495 (2H, t, J = 7. OHz), 7.624 (1H, t, J = 7. OHz), 7.871 (2H, d, J = 7. OHz)
実施例 C— 5 ： (S) - 4 - (benzyloxy) - 2- ( (S) -2-hydroxypropanoy 1 oxy) - 4 - oxobutanoic acidの合成
Figure imgf000069_0001
室温において（7) 0. 157g (0. 382mmol)をァセトニトリル 8mlに溶解し、 フッ化水 素酸 8滴を加え、 1時間攪拌した。 これを飽和炭酸水素ナトリウムで処理し、 飽 和塩化アンモニゥム水溶液を加え、 エーテルで抽出した。 続いて硫酸マグネシゥ ムで乾燥したのち、 減圧濃縮し、 シリカゲルカラムクロマトグラフィー（展開溶 媒 Ether/Hexane=2 : l)を用いて単離精製を行ったところ（9)が 0. 0"g (87%)の収 率で得られた。 Example C-5: Synthesis of (S) -4- (benzyloxy) -2-((S) -2-hydroxypropanoy 1 oxy) -4-oxobutanoic acid
Figure imgf000069_0001
At room temperature, 0.157 g (0.382 mmol) of (7) was dissolved in 8 ml of acetonitrile, 8 drops of hydrofluoric acid was added, and the mixture was stirred for 1 hour. This was treated with saturated sodium bicarbonate, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ether. Subsequently, the extract was dried over magnesium sulfate, concentrated under reduced pressure, and isolated and purified using silica gel column chromatography (developing solvent Ether / Hexane = 2: l). 87%).
H1-腿 R (500MHz, CDC13) 6 (ppm) =1. 454 (3H， d， J=6. 5Hz)， 3. 021 (2H, d， J=6. 5Hz)， 4. 281 (1H, q, J=7. 0Hz) , 5. 175 (2H, dd, J=8. 0Hz, 20. 0Hz) , 5. 630 (1H, dd, J-5. 5Hz, 6. 5Hz) , 7. 365 (6H, m) 実施例 C一 6 ： (S) - 4- benzyl 1-phenacyl 2- ( (S) - 2- ( (S) - 2- (tert- butyldimethylsilyloxy) propanoyloxy) propanoyloxy) succinateの合成 H 1 -. Thigh R (500MHz, CDC1 3) 6 (ppm) = 1 454 (. 3H, d, J = 6 5Hz), 3. 021 (. 2H, d, J = 6 5Hz), 4. 281 ( 1H, q, J = 7.0 Hz), 5.175 (2H, dd, J = 8.0 Hz, 20.0 Hz), 5.630 (1H, dd, J-5.5 Hz, 6.5 Hz), 7 365 (6H, m) Example C-16: (S) -4-benzyl 1-phenacyl 2-((S) -2-((S) -2- (tert-butyldimethylsilyloxy) propanoyloxy) propanoyloxy) succinate Synthesis
Figure imgf000069_0002
Figure imgf000069_0002
12 13  12 13
4 0 °Cにおいてラクチド 5. 26g (30mmol)を 60ml の蒸留水に加え、 4. 75時間攪 拌し、 減圧濃縮して、 ラクトイル乳酸がほぼ当量得られた。 At 40 ° C., 5.26 g (30 mmol) of lactide was added to 60 ml of distilled water, stirred for 4.75 hours, and concentrated under reduced pressure to obtain almost equivalent amount of lactoyl lactic acid.
次に窒素雰囲気下、 0 °Cにおいてラタトイル乳酸に 4 (N，N -ジメチルァミノ）ピ リジン（DMAP) 1. lOg Ommol)の 6mlDMF溶液、ィミダゾール 2. 45g (36mmol)の 4mlDMF 溶液を順次加え、 5分間攪拌した。 この混合物に tert -ブチルジメチルシリルク ロリ ド 4 98g (33mmol)の lOmlDMF溶液を加え、 6時間攪拌した。 飽和塩化アンモ ニゥム溶液で処理し、エーテルで抽出し、飽和炭酸水素ナトリゥム溶液で洗浄し、 有機層を飽和食塩水で洗浄した。 続いて硫酸マグネシウムで享乞燥したのち、 減圧 濃縮し、 シリカゲル力ラムクロマトグラフィー（展開溶媒 Ether/Hexane=l： 1)を 用いて精製を行った。 Next, 4 (N, N-dimethylamino) pi to ratatoyl lactic acid at 0 ° C under nitrogen atmosphere. A solution of lysine (DMAP) (1 lOg Ommol) in 6 ml DMF and a solution of 2.45 g (36 mmol) of imidazole in 4 ml DMF were sequentially added and stirred for 5 minutes. To this mixture was added a solution of 98 g (33 mmol) of tert-butyldimethylsilyl chloride in lOmlDMF, and the mixture was stirred for 6 hours. The mixture was treated with a saturated ammonium chloride solution, extracted with ether, washed with a saturated sodium hydrogen carbonate solution, and the organic layer was washed with a saturated saline solution. Subsequently, the mixture was washed with magnesium sulfate, concentrated under reduced pressure, and purified using silica gel column chromatography (developing solvent Ether / Hexane = 1: 1).
窒素雰囲気下、 室温において（6) 5. 07g (14. 8mmol)の 10mlジクロロメタン溶液 に（12) 4. 96g (17. 9mmol)の 10mlジクロロメタン溶液、 DMAP2. 44g (20mmol)の 20ml ジクロロメタン溶液を順次に加え、 系を .0 °Cに冷却した。 この後、 Ν, Ν' -ジシク 口へキシルカルポジィミ ド（DCC) 4. 13g (20mmol)の 20ml 'ジクロロメタン溶液を加 え、 3時間攪拌した。 混合物をグラスフィルターでろ過し、 残查を飽和塩化アン モ -ゥム溶液、 飽和炭酸水素ナトリウム溶液、 へキサンで順次洗浄し、 ろ液を得 た。 ろ液をへキサンで抽出し、 硫酸マグネシウムで乾燥したのち、 減圧濃縮し、 シリカゲルカラムクロマトグラフィー（展開溶媒 Ether/Hexane=l : l)を用いて単 離精製を行つたところ（13)が 7. 50g (84%)の収率で得られた。  At room temperature under a nitrogen atmosphere, (12) 4.96 g (17.9 mmol) of 10 ml dichloromethane solution and DMAP2.44 g (20 mmol) of 20 ml dichloromethane solution were sequentially added to 5.07 g (14.8 mmol) of 10 ml dichloromethane solution at room temperature. And the system was cooled to 0.0 ° C. Thereafter, a solution of 4.13 g (20 mmol) of Ν, Ν'-disuccinic hexyl carboximide (DCC) in 20 ml of dichloromethane was added, and the mixture was stirred for 3 hours. The mixture was filtered with a glass filter, and the residue was sequentially washed with a saturated ammonium chloride solution, a saturated sodium hydrogen carbonate solution, and hexane to obtain a filtrate. The filtrate was extracted with hexane, dried over magnesium sulfate, concentrated under reduced pressure, and subjected to isolation and purification using silica gel column chromatography (developing solvent Ether / Hexane = 1: l). Obtained in a yield of 50 g (84%).
H1 - NMR (500匪 z，CDCl3) 8 (ppm) =0. 076 (6H, d, J=12. 5Hz) , 0. 893 (9H, s) , 1. 427 (3H, d, J=6. 5Hz)， 1. 439 (3H, d, J=7. 0Hz)， 1. 544 (3H， d, J=7. 0Hz)，H 1 -NMR (500 band z, CDCl 3 ) 8 (ppm) = 0.076 (6H, d, J = 12.5 Hz), 0.893 (9H, s), 1.427 (3H, d, J = 6.5 Hz), 1.439 (3H, d, J = 7.0 Hz), 1.544 (3H, d, J = 7.0 Hz),
3. 093 (1H, dd, J=8. 5Hz, 17. 0Hz) , 3. 206 (1H, dd， J=3. 5Hz, 17. 0Hz)，3.093 (1H, dd, J = 8.5 Hz, 17.0 Hz), 3.206 (1H, dd, J = 3.5 Hz, 17.0 Hz),
4. 379 (1H, q, J=6. 5Hz) , 5. 179 (2H， s) , 5. 360 (2H, dd, J=16. 5Hz, 118. 0Hz) , 5. 685 (1H, dd, J=4. 0Hz, 8. 5Hz) , 7. 345 (6H, m) , 7. 487 (2H, t, J=7. 5Hz) , 7. 614 (1H， t， J=7. 5Hz)， 7. 865 (2H， d， J=7. 5Hz) 実施例 C— 7 ： (S) _4- (benzyloxy) - 2- ( (S) - 2- ( (S)_2- (tert - buty丄 dimethylsilyloxy) propanoyloxy) propanoyloxy) -4-oxobutanoic acid の合 成 BnO4.379 (1H, q, J = 6.5 Hz), 5.179 (2H, s), 5.360 (2H, dd, J = 16.5 Hz, 118.0 Hz), 5.685 (1H, dd) , J = 4.0 Hz, 8.5 Hz), 7.345 (6H, m), 7.487 (2H, t, J = 7.5 Hz), 7.614 (1H, t, J = 7.5 Hz) , 7.865 (2H, d, J = 7.5 Hz) Example C-7: (S) _4- (benzyloxy)-2- ((S)-2- ((S) _2- (tert-buty 丄Synthesis of dimethylsilyloxy) propanoyloxy) propanoyloxy) -4-oxobutanoic acid BnO
Figure imgf000071_0001
Figure imgf000071_0001
14  14
窒素雰囲気下、 室温において（13)3.60g(6mmol)を 35ml エーテルに溶解し、 酢 酸 10.81111(18811111101)、 亜鉛11.8§(18011111101)を順次加ぇ、 20時間攪拌した。 この 混合物をグラスフィルターでろ過し、 残查を酢酸ェチルで洗浄し、 ろ液を得た。 ろ液を飽和炭酸水素ナトリゥム溶液で抽出し、 有機層を硫酸マグネシウムで乾燥 したのち、 減圧濃縮し、 シリカゲルカラムクロマトグラフィー（展開溶媒 AcOEt/Hexane=l:2)を用いて単離精製を行つたところ（14)が 2.80g(96%)の収率で 得られた。 Under a nitrogen atmosphere, and dissolved at room temperature (13) 3.60 g (6 mmol) in 35ml ether, acetic acid 10.81111 (18,811,111,101), sequentially pressurizing tut zinc 11.8 § (18011111101), and stirred for 20 hours. This mixture was filtered with a glass filter, and the residue was washed with ethyl acetate to obtain a filtrate. The filtrate was extracted with a saturated sodium hydrogen carbonate solution, the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and isolated and purified using silica gel column chromatography (developing solvent: AcOEt / Hexane = 1: 2). However, (14) was obtained in a yield of 2.80 g (96%).
tf-NMR (500MHz, CDC13) δ (ppm) =0.104 (6Η, d, J=3. OHz) , 0.903 (9H, s) , 1. 37 (3H d, J-7.0Hz) 1.535 (3H, d, J=7. OHz) 3.005 (2H dd, J=2. OHz, 6.5Hz) , 4.391 (IH, q, J=6.5Hz), 5.113(1H, q, J=7.0Hz), 5.175 (2H, s) , 5.586 (IH, t, J=5.0Hz: 6.5Hz), 7.346 (6H, m) 実施例 C _ 8 ： (S) -4- (benzyloxy) -2- ( (S) -2- ( (S) -2-hydroxypropanoyloxy) propanoyloxy) -4-oxobutanoic acidの合成 tf-NMR (500MHz, CDC1 3 ) δ (ppm) = 0.104 (6Η, d, J = 3. OHz), 0.903 (9H, s), 1. 37 (3H d, J-7.0Hz) 1.535 (3H, d, J = 7.OHz) 3.005 (2H dd, J = 2.OHz, 6.5Hz), 4.391 (IH, q, J = 6.5Hz), 5.113 (1H, q, J = 7.0Hz), 5.175 (2H , s), 5.586 (IH, t, J = 5.0Hz : 6.5Hz), 7.346 (6H, m) Example C _ 8: (S) -4- (benzyloxy) -2-((S) -2- Synthesis of ((S) -2-hydroxypropanoyloxy) propanoyloxy) -4-oxobutanoic acid
Figure imgf000071_0002
Figure imgf000071_0002
14 15  14 15
室温において（14)1.45g(3mmol)をァセトニトリル 60ml に溶解し、 フッ化水素 酸 60滴を加え、 1時間攪拌した。 これを飽和炭酸水素ナトリウムで処理し、 飽 和塩化アンモニゥム溶液を加え、 エーテルで抽出した。 続いて硫酸マグネシウム で乾燥したのち、 減圧濃縮し、 シリカゲルカラムクロマトグラフィー（展開溶媒 Ether)を用いて単離精製を行ったところ（15)が 0· 884g(80%)の収率で得られた。 tf-NMR (500MHz, CDC13) δ (ppm) =1. 73 (3Η, d, J=7.0Hz) , 1.548 (3H d, J=7.0Hz) , 3.013(2H, d, J-6.0Hz), 4.359 (1H, q, J=7.0Hz), 5.176 (3H m)At room temperature, 1.45 g (3 mmol) of (14) was dissolved in 60 ml of acetonitrile, and hydrogen fluoride was added. 60 drops of acid were added and stirred for 1 hour. This was treated with saturated sodium hydrogen carbonate, a saturated ammonium chloride solution was added, and the mixture was extracted with ether. Subsequently, the extract was dried over magnesium sulfate, concentrated under reduced pressure, and isolated and purified using silica gel column chromatography (developing solvent Ether) to obtain 0.884 g (80%) of (15) in a yield of 0.884 g. . tf-NMR (500MHz, CDC1 3 ) δ (ppm) = 1. 73 (3Η, d, J = 7.0Hz), 1.548 (3H d, J = 7.0Hz), 3.013 (2H, d, J-6.0Hz) , 4.359 (1H, q, J = 7.0Hz), 5.176 (3H m)
5.585 (1H, t, J=6.0Hz), 7.369 (6H, m) 実施例 C一 9 ： (benzyl 2- ((2S 5S) - 5 - methyl- 3 6- dioxo- 1 4— dioxan - 2-yl) acetateの合成 5.585 (1H, t, J = 6.0Hz), 7.369 (6H, m) Example C-1 9: (benzyl 2- ((2S 5S) -5-methyl-36-dioxo- 14-dioxan-2- yl) Synthesis of acetate
Figure imgf000072_0001
Figure imgf000072_0001
9 16 窒素雰囲気下、 室温において（9)0.149g(0.504讓 ol) の 4ml ジクロロメタン溶 液に Diisopropyl ehtyl amine 0.195g(l.512腿 ol)の 3mlジクロ ロメタン溶液、 2, 4, 6, -Trichlrobenzoyl chloride 0.246g(l.008mmol) CD 3ml ジクロロメタン溶 液を順次加え、 続いてジクロロメタン溶液を 230ml加えて 3時間攪拌した。  9 16 At room temperature under nitrogen atmosphere, (9) 0.149 g (0.504 benzyl) of 4 ml of dichloromethane solution in 0.1 ml of diisopropyl ehtyl amine 0.15 g (l.512 liter) of dichloromethane solution, 2, 4, 6,- Chloride 0.246 g (l.008 mmol) CD 3 ml dichloromethane solution was added sequentially, followed by 230 ml dichloromethane solution and stirred for 3 hours.
また、 窒素雰囲気下 DMAP0.246 g (2.016mmol) を 75mlのジクロロメタン溶液 に溶かし込み、 これに攪拌し終えた混合物を 16 時間かけて滴下した。 一時間攪 拌したのち、 ろ過し、 減圧濃縮した。 シリカゲルカラムクロマトグラフィー（展 開溶媒 Benzen/Ac0Et=5: 1)を用いて単離精製を行ったところ (16)が 0.010g(7%)の 収率で得られた。  In a nitrogen atmosphere, 0.246 g (2.016 mmol) of DMAP was dissolved in 75 ml of a dichloromethane solution, and the stirred mixture was added dropwise over 16 hours. After stirring for one hour, the mixture was filtered and concentrated under reduced pressure. Isolation and purification were performed using silica gel column chromatography (developing solvent: Benzen / Ac0Et = 5: 1) to obtain (16) in a yield of 0.010 g (7%).
H1- MR (500MHz, CDC13) δ (ppm) =1.691 (3H, d， J=7.0Hz)， 3.057 (1H, dd, J=6.5, 17.5Hz), 3.222 (1H, dd, J=5.0, 17.5Hz), 5.087(1H, q, J=7.0Hz), 5.187 (2H, s), 5.410(lH，dd, J=5.0, 6.5Hz), 7.361 (6H, m) 産業上の利用可能性 H 1 - MR (500MHz, CDC1 3) δ (ppm) = 1.691 (3H, d, J = 7.0Hz), 3.057 (1H, dd, J = 6.5, 17.5Hz), 3.222 (1H, dd, J = 5.0 , 17.5Hz), 5.087 (1H, q, J = 7.0Hz), 5.187 (2H, s), 5.410 (lH, dd, J = 5.0, 6.5Hz), 7.361 (6H, m) Industrial applicability
本発明により、 側鎖にアミノエチル基、 ヒドロキシルェチル基又はカルポキシ ルメチル基を有するオリゴ乳酸エステルを単一の化合物として提供することが 可能になった。 本発明により提供される側鎖にアミノエチル基、 ヒドロキシルェ チル基又は力ルポキシルメチル基を有するオリゴ乳酸エステルは、 医薬品、 医薬 品原料、 食品添加物、 香粧料原料、 製剤原料、 製剤添加物等として有用である。 また、 本発明の側鎖にアミノエチル基を有するオリゴ乳酸エステルは、 二次修飾 によってさらに機能性を高めた誘導体の合成が可能となる。 例えば、 ァシル化や アルキル化によって脂溶性を高めたり、 ポリエチレングリコール化によって水溶 性にすることが可能である。 また、 シリカや高分子ビーズなどの担体表面に固定 化することによって、 リガンドの探索や、 特殊な分離カラムへの応用や、 特殊な 金属との選択性を有するセンサーなどの開発に応用することもできる。  According to the present invention, it has become possible to provide an oligolactic acid ester having an aminoethyl group, a hydroxylethyl group or a carboxylmethyl group in a side chain as a single compound. The oligolactic acid ester having an aminoethyl group, a hydroxylethyl group or a propyloxylmethyl group in the side chain provided by the present invention is used as a pharmaceutical, a pharmaceutical raw material, a food additive, a cosmetic raw material, a pharmaceutical raw material, a pharmaceutical additive. It is useful as an object. Further, the oligolactic acid ester having an aminoethyl group in the side chain of the present invention enables the synthesis of a derivative having further enhanced functionality by secondary modification. For example, lipophilicity can be increased by acylation or alkylation, or water-soluble by polyethylene glycolation. Also, by immobilizing it on a carrier surface 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.

Claims

求の範囲 Scope
1. 式 （1 1) で表される化合物又はその塩。 1. A compound represented by the formula (11) or a salt thereof.
〇
Figure imgf000074_0001
Yes
Figure imgf000074_0001
(式中、 Aは、 一 CH2CH2— NHR^ -CH2CH2-OR\ 又は— CH2— COOR1を示し、 ここで、 R1は、 ァミノ基の保護基、 水酸基の保護基又はカル ポキシル基の保護基を示し； R 2は水素原子又は水酸基の保護基を示し； R3は水 素原子又は力ルポキシル基の保護基を示す） (In the formula, A, one CH 2 CH 2 - NHR ^ -CH 2 CH 2 -OR \ or - CH 2 - shows a COOR 1, wherein, R 1 is a protective group, a hydroxyl protecting group of the Amino group Or a protecting group for a carboxyl group; R 2 represents a protecting group for a hydrogen atom or a hydroxyl group; R 3 represents a protecting group for a hydrogen atom or a hydroxyl group.
2. 式 （12) で表される化合物又はその塩。  2. A compound represented by the formula (12) or a salt thereof.
Figure imgf000074_0002
Figure imgf000074_0002
(式中、 Aは、 メチル基、 一CH^CHs— NHR1 -CH2CH2-OR\ 又 は一CHs— COOR1を示し、 但し、 全ての Aがメチル基となることはなく、 ま たメチル基以外の複数個の Aは全て上記した— CH2CH2— NHR1 _CH2 CH2— OR1、又は一CHs— COOR1から選択される同一種類の置換基を示し、 ここで、 R1は、 ァミノ基の保護基、 水酸基の保護基又はカルボキシル基の保護 基を示し、複数個の R1は同一でも異なっていてもよく ； R2は水素原子又は水酸 基の保護基を示し； R 3は水素原子又は力ルポキシル基の保護基を示し； mは 1 〜 5の整数を示す） (In the formula, A represents a methyl group, one CH ^ CHs—NHR 1 -CH 2 CH 2 -OR \ or one CHs—COOR 1 , but not all A are methyl groups. all of the plurality of a other than a methyl group and the - CH 2 CH 2 - NHR 1 _CH 2 CH 2 - oR 1, or shows the same type of substituents selected from a CHS-COOR 1, wherein R 1 represents an amino group-protecting group, a hydroxyl group-protecting group or a carboxyl group-protecting group; a plurality of R 1 may be the same or different; R 2 represents a hydrogen atom or a hydroxyl group-protecting group; R 3 represents a hydrogen atom or a protecting group for a propyloxyl group; m represents an integer of 1 to 5)
3. . 式 （13) で表される化合物又はその塩。
Figure imgf000075_0001
3. A compound represented by the formula (13) or a salt thereof.
Figure imgf000075_0001
(式中、 Aは、 メチル基、 一 CH2CH2— NHR — C H 2 C H 2— O R 1、 又 は— CH2— COOR1を示し、 伹し、 全ての Aがメチル基となる場合は除き、 ま たメチル基以外の複数個の Aは全て上記した一 CH2CH2— NHR1 — CH2 CHg— OR1、又は一 CHs— COOR1から選択される同一種類の置換基を示し、 ここで、 R1は、 ァミノ基の保護基、 水酸基の保護基又は力ルポキシル基の保護 基を示し、 複数個の R1は同一でも異なっていてもよく ； nは 1〜5の整数を示 す） (In the formula, A represents a methyl group, one CH 2 CH 2 — NHR — CH 2 CH 2 —OR 1 , or — CH 2 — COOR 1 , and if all A are methyl groups, And a plurality of A's other than a methyl group all represent the same kind of substituent selected from the above-mentioned one CH 2 CH 2 — NHR 1 — CH 2 CHg—OR 1 or one CHs—COOR 1 ; wherein, R 1 is a protecting group of the Amino group, a protecting group of the protected group or force Rupokishiru group for a hydroxyl group, a plurality of R 1 may be the same or different; indicates n is an integer of 1 to 5 You)
4. 請求項 2に記載の式 （12) で表される化合物を分子内脱水縮合による 環化反応に供することを含む、 請求項 3に記載の式 （13) で表される化合物の 製造方法。  4. The method for producing a compound represented by the formula (13) according to claim 3, comprising subjecting the compound represented by the formula (12) according to claim 2 to a cyclization reaction by intramolecular dehydration condensation. .
5. 式 （1) で表される化合物又はその塩。  5. A compound represented by the formula (1) or a salt thereof.
Figure imgf000075_0002
Figure imgf000075_0002
. (式中、 R1はァミノ基の保護基を示し、 R 2は水素原子又は水酸基の保護基を示 し、 R 3は水素原子又は力ルポキシル基の保護基を示す） (In the formula, R 1 represents a protecting group for an amino group, R 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a hydrogen atom or a propyloxyl group.)
6. 式 （2) で表される化合物又はその塩。 (2)6. A compound represented by the formula (2) or a salt thereof. (2)
Figure imgf000076_0001
Figure imgf000076_0001
(式中、 R 11及ぴ R 12はそれぞれ独立にァミノ基の保護基又は水素原子を示し、 R 2は水素原子又は水酸基の保護基を示し、 R 3は水素原子又はカルボキシル基の 保護基を示す） (Wherein, R 11 and R 12 each independently represent a protecting group for an amino group or a hydrogen atom, R 2 represents a hydrogen atom or a protecting group for a hydroxyl group, and R 3 represents a protecting group for a hydrogen atom or a carboxyl group. Show)
7. 式 （3) で表される化合物又はその塩。  7. A compound represented by the formula (3) or a salt thereof.
Figure imgf000076_0002
Figure imgf000076_0002
(式中、 R1はァミノ基の保護基又は水素原子を示し、 R 2は水素原子又は水酸基 の保護基を示し、 R 3は水素原子又はカルボキシル基の保護基を示す） (In the formula, R 1 represents a protecting group for an amino group or a hydrogen atom, R 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a hydrogen atom or a carboxyl group.)
8. 式 （4) で表される化合物又はその塩。
Figure imgf000076_0003
8. A compound represented by the formula (4) or a salt thereof.
Figure imgf000076_0003
(式中、 R1はァミノ基の保護基又は水素原子を示す） (Wherein, R 1 represents a protecting group for an amino group or a hydrogen atom)
9. 請求項 7に記載の式 （3) で表される化合物を分子内脱水縮合による環 化反応に供することを含む、 請求項 8に記載の式 （4) で表される化合物の製造 方法。  9. A process for producing a compound represented by the formula (4) according to claim 8, comprising subjecting the compound represented by the formula (3) according to claim 7 to a cyclization reaction by intramolecular dehydration condensation. .
10. 式 （5) で表される化合物又はその塩。
Figure imgf000077_0001
10. A compound represented by the formula (5) or a salt thereof.
Figure imgf000077_0001
(式中、 R1はァミノ基の保護基又は水素原子を示し、 R2は水素原子又は水酸基 の保護基を示し、 R 3は水素原子又は力ルポキシル基の保護基を示し、 nは 1〜 4の整数を示す） (Wherein, R 1 represents a protecting group for an amino group or a hydrogen atom, R 2 represents a hydrogen atom or a protecting group for a hydroxyl group, R 3 represents a hydrogen atom or a protecting group for a hydroxyl group, and n represents 1 to Indicates an integer of 4)
11. 式 （6) で表される化合物又はその塩。  11. A compound represented by the formula (6) or a salt thereof.
Figure imgf000077_0002
Figure imgf000077_0002
(式中、 R1はァミノ基の保護基又は水素原子を示す。 nは 1〜4の整数を示す）(Wherein, R 1 represents a protecting group for an amino group or a hydrogen atom. N represents an integer of 1 to 4)
12. 請求項 10に記載の式 （5) で表される化合物を分子内脱水縮合によ る環化反応に供することを含む、 請求項 1 1に記載の式 （6) で表される化合物 の製造方法。 12. The compound represented by the formula (6) according to claim 11, which comprises subjecting the compound represented by the formula (5) according to claim 10 to a cyclization reaction by intramolecular dehydration condensation. Manufacturing method.
13. 式 （1) で表される化合物又はその塩。
Figure imgf000077_0003
13. A compound represented by the formula (1) or a salt thereof.
Figure imgf000077_0003
(式中、 R1は水酸基の保護基を示し、 R 2は水素原子又は水酸基の保護基を示し、 R 3はカルボキシル基の保護基を示す） (Wherein, R 1 represents a protecting group for a hydroxyl group, R 2 represents a protecting group for a hydrogen atom or a hydroxyl group, and R 3 represents a protecting group for a carboxyl group)
14. 式 （2) で表される化合物又はその塩。 (2)14. A compound represented by the formula (2) or a salt thereof. (2)
Figure imgf000078_0001
Figure imgf000078_0001
(式中、 X 1及び X 2はメチル基又は保護されていてもよいヒドロキシェチル基 を示し （但し、 XI及び X 2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、 R 3は水素原子又はカルボキシル基の保護基を示 す） (Wherein, X 1 and X 2 represent a methyl group or a hydroxyethyl group which may be protected (except when XI and X 2 are simultaneously a methyl group), and R 2 is a hydrogen atom or R 3 represents a protecting group for a hydrogen atom or a carboxyl group.
15. 式 （3) で表される化合物又はその塩。  15. A compound represented by the formula (3) or a salt thereof.
Figure imgf000078_0002
Figure imgf000078_0002
(式中、 X 1及ぴ X 2はメチル基又は保護されていてもよいヒドロキシェチル基 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ェ チル基を示し （但し、 ΧΓ、 X 2及ぴ η個の Xの全てが同時にメチル基となる場 合は除く）、 R 2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 ポキシル基の保護基を示し、 ηは 1〜4の整数を示す） (Wherein X 1 and X 2 represent a methyl group or an optionally protected hydroxyethyl group, and n Xs each independently represent a methyl group or an optionally protected hydroxyethyl group. (However, except when all of ΧΓ, X 2 and η X are simultaneously a methyl group), R 2 represents a hydrogen atom or a hydroxyl-protecting group, and R 3 represents a hydrogen atom or a carboxyl group. Represents a protecting group, and η represents an integer of 1 to 4.)
16. 式 （4) で表される化合物又はその塩。  16. A compound represented by the formula (4) or a salt thereof.
1One
Figure imgf000078_0003
Figure imgf000078_0003
(式中、 R1は水素原子又は水酸基の保護基を示し、 η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ェチル基を示し、 ηは 1〜5の整数を 示す） (Wherein, R 1 represents a hydrogen atom or a protecting group for a hydroxyl group, η Xs each independently represent a methyl group or an optionally protected hydroxyethyl group, and η represents an integer of 1 to 5. Show)
17. 請求項 14に記載の式 （2) で表される化合物又は請求項 15に記載 の式 （3) で表される化合物を分子内脱水縮合による環化反応に供することを含 む、 請求項 16に記載の式 （4') で表される化合物の製造方法, 17. Including subjecting the compound represented by the formula (2) according to claim 14 or the compound represented by the formula (3) according to claim 15 to a cyclization reaction by intramolecular dehydration condensation. A method for producing a compound represented by the formula (4 ′) according to claim 16,
18. 式 （1) で表される化合物又はその塩。 18. A compound represented by the formula (1) or a salt thereof.
)R2 ) R2
R100  R100
-R3 (1)  -R3 (1)
(式中、 R1はカルボキシル基の保護基を示し、 R 2は水素原子又は水酸基の保護 基を示し、 R 3はカルボキシル基の保護基を示す。 但し、 R1及ぴ R 3はそれぞれ 異なる基を示す） (Wherein, R 1 represents a carboxyl protecting group, R 2 represents a hydrogen atom or a hydroxyl protecting group, and R 3 represents a carboxyl protecting group. However, R 1 and R 3 are different from each other. Indicates a group)
19. 式 （2) で表される化合物又はその塩。  19. A compound represented by the formula (2) or a salt thereof.
。 。 （2) . . (2)
0 0
(式中、 R1は力ルポキシル基の保護基又は水素原子を示し、 R 2は水素原子又は 水酸基の保護基を示し、 R 3はカルボキシル基の保護基又は水素原子を示す。）(In the formula, R 1 represents a protecting group for a hydroxyl group or a hydrogen atom, R 2 represents a hydrogen atom or a protecting group for a hydroxyl group, and R 3 represents a protecting group for a carboxyl group or a hydrogen atom.)
20. 式 （3) で表される化合物又はその塩。 20. A compound represented by the formula (3) or a salt thereof.
Figure imgf000079_0001
Figure imgf000079_0001
(式中、 R1はカルボキシル基の保護基又は水素原子を示し、 R 2は水素原子又は 水酸基の保護基を示し、 R 3は力ルポキシル基の保護基又は水素原子を示す。）(In the formula, R 1 represents a carboxyl-protecting group or a hydrogen atom, R 2 represents a hydrogen atom or a hydroxyl-protecting group, and R 3 represents a protecting group for a hydroxyl group or a hydrogen atom.)
21. 式 （4) で表される化合物又はその塩。 21. A compound represented by the formula (4) or a salt thereof.
Figure imgf000079_0002
(式中、 R1はカルボキシル基の保護基又は水素原子を示し、 nは 1から 5の整 数を示す。）
Figure imgf000079_0002
(In the formula, R 1 represents a carboxyl protecting group or a hydrogen atom, and n represents an integer of 1 to 5.)
22. nが 1又は 2である、 請求項 21に記載の化合物又はその塩。  22. The compound or a salt thereof according to claim 21, wherein n is 1 or 2.
23. 請求項 1 9又は 20に記載の式 （2) 又は （3) で表される化合物を 分子内脱水縮合による環化反応に供することを含む、 請求項 22に記載の化合物 の製造方法。  23. The method for producing a compound according to claim 22, comprising subjecting the compound represented by the formula (2) or (3) according to claim 19 or 20 to a cyclization reaction by intramolecular dehydration condensation.
PCT/JP2005/003084 2004-02-18 2005-02-18 Oligolactate having substituent in side chain WO2005077882A1 (en)

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