WO2017122822A1 - Intermédiaire de production de composé depsipeptide, et son procédé de production - Google Patents

Intermédiaire de production de composé depsipeptide, et son procédé de production Download PDF

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WO2017122822A1
WO2017122822A1 PCT/JP2017/001140 JP2017001140W WO2017122822A1 WO 2017122822 A1 WO2017122822 A1 WO 2017122822A1 JP 2017001140 W JP2017001140 W JP 2017001140W WO 2017122822 A1 WO2017122822 A1 WO 2017122822A1
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group
formula
tritylthio
compound
configuration
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千加史 石岡
憲 西條
加藤　正
紘一 成田
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Tohoku University NUC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses

Definitions

  • the present invention relates to a method for producing an optically active amide carboxylic acid derivative useful as an intermediate for producing a depsipeptide compound, which is expected as an excellent novel molecular target anticancer agent, and a novel production intermediate thereof.
  • HDAC histone deacetylase
  • PI3K phosphatidyl inositol 3-kinase
  • R 1 ′ represents an amino acid side chain, a lower alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group
  • R 3 ′ and R 4 ′ are the same or different and represent hydrogen
  • An atom, an amino acid side chain, a lower alkyl group, a lower alkylidene group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group is represented.
  • the broken bond represents a single bond or a double bond.
  • the present invention seeks to solve the problems of such conventional methods, and provides a method for producing a depsipeptide compound intermediate that can be achieved in a shorter reaction step, and a production intermediate and a method for producing the same.
  • the purpose is to provide.
  • the present inventor has established an efficient method for obtaining an important intermediate of a depsipeptide compound, which is expected as an excellent novel molecular target anticancer agent, as a single optical isomer in a short process. Completed the invention.
  • the present invention includes the following aspects.
  • R 1 represents an amino acid side chain other than hydrogen, methyl and n-butyl
  • R 2 represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms
  • * represents an asymmetric carbon.
  • ⁇ represents an asymmetric carbon, D configuration or L configuration
  • TrS represents a tritylthio group.
  • R 1 represents an amino acid side chain other than hydrogen, methyl, and n-butyl. * Represents an asymmetric carbon, and is a configuration of 3′R or 3 ′S. ⁇ indicates an asymmetric carbon. And represents the configuration of D or L. TrS represents a tritylthio group.)
  • R 1 represents an amino acid side chain other than hydrogen and methyl
  • R 2 represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms
  • ⁇ represents an asymmetric carbon, D Body or L configuration.
  • R 1 is hydrogen, amino acid side chain other than methyl and n- butyl, The process according to claim 3.
  • R 1 represents an amino acid side chain other than hydrogen, methyl and n-butyl
  • R 2 represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms
  • * represents an asymmetric carbon.
  • ⁇ represents an asymmetric carbon, D configuration or L configuration
  • TrS represents a tritylthio group.
  • the present invention also includes the following aspects.
  • R 5 represents an alkyl group having 1 to 10 carbon atoms which may have a substituent.
  • R 5 is as described above. * Represents an asymmetric carbon, and the bond indicated by a wavy line is a mixture of 3′R and 3 ′S configurations.
  • R 5 represents an alkyl group having 1 to 10 carbon atoms which may have a substituent. * Represents an asymmetric carbon, and the bond shown by a wavy line is a 3′R isomer or a 3 ′S isomer. A mixture of configurations.)
  • the number of steps is shorter than that of the conventional method, and the formula (1) is an important common intermediate of depsipeptide compounds represented by formulas (1) and (2).
  • An optically active amide carboxylic acid derivative represented by IV) can be obtained.
  • the number of steps from the starting material to the compound represented by the formula (IV) can be reduced from 14 steps of the conventional method to 6 steps, and the total yield of important intermediates and the overall reaction can be reduced. Efficiency can be improved dramatically.
  • production costs can be reduced, production management, etc. can be greatly improved, and depsipeptide compounds expected as excellent novel molecular target anticancer agents can be efficiently produced. It becomes possible.
  • the compounds of formula (1) and (2) can be synthesized by following the schemes A and B below. it can.
  • the hydroxyl group of the compound of the formula (II) is protected with a p-methoxybenzyl (hereinafter referred to as “PMB”) group.
  • PMB p-methoxybenzyl
  • the compound of the formula (II ′) is a known compound described in the literature (see Non-Patent Documents 1 to 3 above), but the compound of the formula (II) in which the hydroxyl group is unprotected is a novel compound not described in the literature. is there.
  • step (i) the compounds of formulas (II ′) and (3) are condensed, and then the PMB group is removed and ester hydrolysis is performed to obtain a tetrapeptide derivative (compound of formula (4)).
  • step (ii) intramolecular esterification and intramolecular disulfide bond formation are performed to achieve synthesis of the depsipeptide compound (1).
  • the synthesis of the depsipeptide compound (2) is carried out in the same manner as in the method of Scheme A as shown in Scheme B. That is, in step (i), the compounds of formulas (II ′) and (5) are condensed to obtain a tetrapeptide derivative (compound of formula (6)).
  • step (ii) intramolecular esterification, intramolecular disulfide bond formation, and tert-butyldimethylsilyl (hereinafter referred to as “TBS”) group deprotection are sequentially performed to synthesize a compound of formula (2) Has been completed.
  • TBS tert-butyldimethylsilyl
  • R 1 represents an amino acid side chain, an alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group, preferably an amino acid side chain.
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, an amino acid side chain, a lower alkyl group, a lower alkylidene group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group.
  • a broken bond represents a single bond or a double bond.
  • Non-patent documents 1 to 3 describe the synthesis route and detailed synthesis method of the compound of formula (II ′).
  • Schemes C, D and E a method for synthesizing the compound of formula (II ′) will be described.
  • commercially available 1,3-propanediol compound of formula (7)
  • an intermediate sulfone formula (12) Compound
  • the other optically active aldehyde compound of formula (16)
  • is the other intermediate is a known compound and is synthesized according to the method described in the literature (Non-patent Document 4).
  • hydrocarbon group means a hydrocarbon group in which the group is linear, branched, cyclic, or a combination thereof.
  • the hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group.
  • hydrocarbon groups having 1 to 10 carbon atoms include alkyl groups, alkenyl groups, alkynyl groups, aryl groups, aralkyl groups, and the like.
  • alkyl group examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, Examples thereof include alkyl groups such as decyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group.
  • alkenyl group examples include alkenyl groups such as vinyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group and decenyl group.
  • alkynyl group examples include alkynyl groups such as ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group, nonynyl group, decynyl group and the like.
  • aryl group examples include aryl groups such as a phenyl group, a tolyl group, and a naphthyl group.
  • Alkyl group represents an arylalkyl group.
  • examples of the “aralkyl group” include benzyl group, 1-phenylethyl group, naphthalen-1-ylmethyl group, naphthalen-2-ylmethyl group and the like.
  • alkylidene group examples include methylene, ethylidene, propylidene, cyclopropylidene, butylidene, pentylidene, hexylidene and the like.
  • hydrocarbon group examples include lower hydrocarbon groups such as those having 1 to 6 carbon atoms, particularly 1 to 3 carbon atoms.
  • substituents that the hydrocarbon group may have include halogen groups such as a fluoro group, a chloro group, a bromo group, and an iodo group, a nitro group, a cyano group, a hydroxyl group, a hydroxyl group protected with a protective group, an amino group, and a protective group. And an amino group protected with a group.
  • the number of substituents is exemplified by about 1 to 3.
  • hydroxyl protecting group examples include a lower alkyl group, a benzyl group, a p-methoxybenzyl group (PMB group), a tert-butyldimethylsilyl group (TBS group), and the like.
  • the “lower alkyl group” means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, isopropyl group, t-butyl group, propyl group.
  • Protecting groups for amino groups include tert-butoxycarbonyl group (Boc group), benzyloxycarbonyl group (Cbz group), 9-fluorenylmethyloxycarbonyl group (Fmoc group), p-toluenesulfonyl group (tosyl group) Etc. are exemplified.
  • amino acid side chain other than hydrogen, methyl and n-butyl refers to any amino acid side chain moiety present in natural or unnatural amino acids (particularly ⁇ -amino acids) other than glycine, alanine and norleucine.
  • Examples of natural amino acid side chain moieties are —CH (CH 3 ) 2 [valine], —CH 2 CH (CH 3 ) 2 [leucine], —CH ( CH 3 ) CH 2 CH 3 [isoleucine], — (CH 2 ) 4 NH 2 [lysine], — (CH 2 ) 3 NHC ( ⁇ NH) NH 2 [arginine], —CH 2 (5-1H-imidazolyl) [Histidine], —CH 2 CONH 2 [asparagine], —CH 2 CO 2 H [aspartic acid], —CH 2 SH [cysteine], —CH 2 CH 2 CONH 2 [glutamine], —CH 2 CH 2 CO 2 H [glutamate], - CH 2 C 6 H 5 [ phenylalanine], - CH 2 (4- OH-C 6 H 4) [ tyrosine], - CH 2 (3-1H- indolyl) [T
  • Examples of the unnatural amino acid side chain moiety are —CH 2 CH 3 [ ⁇ -aminobutyric acid], —CH 2 CH 2 CH (CH 3 ) 2 [ Homoleucine], —CH 2 C 6 H 11 [cyclohexylalanine], — (CH 2 ) 3 NHCONH 2 [citrulline], —CH 2 CH 2 OH [homoserine], — (CH 2 ) 3 NH 2 [ornithine] and the like can give.
  • amino acid side chains of nonpolar or low polarity amino acids such as valine, leucine, isoleucine, phenylalanine, methionine, homoleucine, cyclohexylalanine and the like are preferable.
  • amino acid side chain other than hydrogen and methyl refers to the amino acid side chain and n-butyl described above as “amino acid side chain other than hydrogen, methyl and n-butyl”.
  • TrS represents the following tritylthio group.
  • * represents an asymmetric carbon and is a configuration of 3'R or 3'S.
  • ⁇ represents an asymmetric carbon, and is a D configuration or an L configuration. That is, the compound of the formula (I) represents any one of the following compounds.
  • the isomer mixture of the present invention contains the compound represented by the formula (IIIa) and the compound represented by the formula (IIIb) constituting the isomer mixture in an arbitrary ratio.
  • a racemate containing an equal amount of each isomer may be used.
  • ⁇ represents an asymmetric carbon and has a configuration of either D-form or L-form.
  • the compound of the formula (IV) refers to a compound represented by the following formula (IVa).
  • the compound of the formula (IV) refers to a compound represented by the following formula (IVb). Note that the configuration of the asymmetric carbon is maintained through the reaction of the present invention.
  • R 3 , R 3 ′, R 4 and R 4 ′ are monovalent groups (for example, hydrogen atom, amino acid side chain, lower alkyl group, lower alkenyl group, substituted or unsubstituted aryl group or substituted Or an unsubstituted aralkyl group), the bond is a single bond.
  • R 3 , R 3 ′, R 4 and R 4 ′ are divalent groups (for example, alkylidene groups), the bond is a double bond.
  • the compound of the formula (IIb) having a 3′R configuration is useful as an intermediate for the production of romidepsin (a cancer molecular target therapeutic agent), which is a kind of depsipeptide compound (see Non-Patent Document 1). .
  • optically active amide carboxylic acid ester derivatives represented by the formulas (Ia) and (Ib), respectively, and the optically active amide carboxylic acid derivatives represented by the formulas (IIa) and (IIb) are novel compounds not described in the literature, It is a compound first discovered by the present inventors.
  • Steps (i) and (ii)] (E) -5-tritylthio-2-pentenal represented by formula (V) in step (ii) is a known compound, and is commercially available according to known methods (Non-Patent Documents 5 and 6) (formula (22) Can be synthesized through two steps (see Reference Examples 1 and 2).
  • Step (iii) In the step (iii), an acetate ester derivative represented by the formula (VI) is added to (E) -5-tritylthio-2-pentenal represented by the formula (V) in the presence of a base to obtain a compound represented by the formula (VII) (RS, E) -3-Hydroxy-7-tritylthio-4-heptenoate derivative, which is a mixture of the isomers shown (see Example 1).
  • Usable bases include, for example, alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium tert-butoxide and sodium tert-butoxide; lithium diisopropylamide (LDA), lithium isopropylcyclohexyl Examples thereof include alkali metal amides such as amide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide. Two or more of these bases may be used in combination. Alkali metal amides are preferable, and LDA is more preferable.
  • the base used is 0.1 to 10 equivalents, preferably 0.8 to 1.2 equivalents, based on the acetate derivative.
  • the reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction in this step.
  • hydrocarbon solvents such as pentane, hexane, benzene, toluene and xylene; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform, 1,1,1-trichloroethane and monochlorobenzene; diethyl ether, Ether solvents such as tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane and cyclopentylmethyl ether; acetonitrile, propionitrile, nitromethane, nitroethane, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, etc.
  • polar aprotic solvents such as benzane, hexane, benzene, tol
  • reaction temperature can vary depending on the solvent used, it can usually be carried out from ⁇ 100 ° C. to the reflux temperature of the reaction solvent.
  • LDA low density polyethylene glycol
  • it is preferably carried out at ⁇ 80 to ⁇ 20 ° C.
  • the reaction time may vary depending on the solvent used and the reaction temperature, but is usually 10 minutes to 24 hours. Preferably, it is 30 minutes to 3 hours.
  • the acetic acid ester derivative used is used in an amount of 1.0 to 10.0 equivalents relative to (E) -5-tritylthio-2-pentenal (compound represented by the formula (V)). 0-4.0 equivalents are used.
  • the obtained product (compound of formula (VII)) can be subjected to usual post-treatment.
  • the normal post-treatment includes, for example, quench (reaction stop) and extraction.
  • it can refine
  • the product (compound represented by the formula (VII)) is an isomer mixture in which the configuration of hydroxyl groups is mixed (in some embodiments, a racemate (an equivalent mixture of R and S forms)). As obtained.
  • step (iv) the (RS, E) -3-hydroxy-7-tritylthio-4-heptenoate derivative, which is a mixture of isomers represented by formula (VII), is hydrolyzed in the presence of a base or an acid.
  • Examples of the base used in this step include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate.
  • Examples of the acid include sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid. Preferred is a base, and more preferred is sodium hydroxide.
  • the reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction in this step.
  • solvents such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol
  • ether solvents such as THF and 1,4-dioxane
  • polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide Sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and water.
  • Preferred are methanol, ethanol, THF, acetonitrile, and water, and more preferred are methanol, ethanol, and water.
  • reaction temperature can vary depending on the solvent used, it can usually be carried out from ⁇ 100 ° C. to the reflux temperature of the reaction solvent. Preferably, it is 0 to 80 ° C.
  • the reaction time may vary depending on the solvent used and the reaction temperature, but is usually 10 minutes to 24 hours. Preferably, it is 30 minutes to 3 hours.
  • the obtained product (compound of formula (III)) can be subjected to usual post-treatment. Furthermore, it can refine
  • Step (v) is represented by formula (IV) in the presence of a condensing agent to (RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid, which is a racemate represented by formula (III).
  • the optically active amide carboxylic acid ester derivatives represented by the formulas (Ia) and (Ib) are each converted into a single optical compound by reacting the optically active amino acid derivative, and separating and purifying the resulting two diastereomeric mixtures. It is produced as an isomer (see Examples 3 to 5).
  • Examples of the condensing agent used in this step include 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexa Phosphonium condensing agents such as fluorophosphate (PyBOP) and chlorotripyrrolidinophosphonium hexafluorophosphate (PyCrop); N, N′-diisopropylcarbodiimide (DIC) and 1-ethyl-3- (3-dimethylamino) Carbodiimide condensing agents such as propyl) carbodiimide (EDC); triazine condensates such as (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholium chloride n-hydrate Agent; N, N′-carbonylimidazole (CDI ) I
  • additives can be added to make the reaction proceed more efficiently.
  • Usable additives include triazole compounds such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxyazabenzotriazole (HOAt); triatylamine, pyridine, 4-dimethylaminopyridine, diethylamine and N, N- Examples thereof include amine compounds such as diisopropylethylamine. An amine compound is preferred, and N, N-diisopropylethylamine is therefore preferred.
  • the reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction in this step.
  • solvents such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol
  • hydrocarbon solvents such as pentane, hexane, benzene, toluene and xylene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane and cyclopentylmethyl ether
  • acetonitrile, propionitrile, nitromethane, nitroethane examples thereof include polar aprotic solvents such as N, N-dimethylformamide, N, N-di
  • reaction temperature can vary depending on the solvent used, it can usually be carried out from ⁇ 100 ° C. to the reflux temperature of the reaction solvent. Preferably, it is 0 to 50 ° C.
  • the reaction time may vary depending on the solvent used and the reaction temperature, but is usually 10 minutes to 24 hours. Preferably, it is 30 minutes to 3 hours.
  • Separation and purification of the two diastereomeric mixtures produced should be carried out by applying conventional techniques such as precipitation, crystallization, gel filtration and silica gel column chromatography. Each compound can be obtained as a single optical isomer.
  • a preferred separation / purification method is silica gel column chromatography.
  • a method using an optical resolving agent is known as a method for preparing an optically active compound.
  • an optical resolution agent it is necessary to operate the optical resolution agent before performing optical resolution and to remove the optical resolution agent after performing optical resolution.
  • there is no need to perform such an operation in this step and there is a feature in that optical resolution of a compound used in the next step is performed as it is.
  • the optically active amide carboxylic acid ester derivatives represented by the formulas (Ia) and (Ib) are hydrolyzed in the presence of a base or an acid to give the corresponding formulas (IIa) and (IIb), respectively.
  • a base or an acid which is an optically active amide carboxylic acid derivative.
  • the base used in this step include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate.
  • the acid include sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid. Preferred is a base, and more preferred is lithium hydroxide.
  • the reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction in this step.
  • solvents such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol
  • ether solvents such as THF and 1,4-dioxane
  • polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide Sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and water.
  • you may mix and use 2 or more types among the said solvent.
  • Preferred are methanol, ethanol, THF, acetonitrile, and water, and more preferred are methanol, ethanol, and water.
  • reaction temperature can vary depending on the solvent used, it can usually be carried out from ⁇ 100 ° C. to the reflux temperature of the reaction solvent. Preferably, it is 0 to 80 ° C.
  • the reaction time may vary depending on the solvent used and the reaction temperature, but is usually 10 minutes to 24 hours. Preferably, it is 30 minutes to 5 hours.
  • the obtained product (compounds of the formulas (IIa) and (IIb)) can be subjected to usual post-treatment. Furthermore, it can refine
  • the transformation shown in the following scheme G is carried out according to the methods described in Patent Document 1 and Non-Patent Documents 1 and 2, and depsipeptide It was confirmed that a similar compound (compound of formula (1′a)) can be synthesized (see Reference Examples 4 to 7).
  • the optically active tripeptide derivative represented by the formula (3a) was prepared according to the method described in Non-Patent Documents 1 and 2 (see Reference Example 3). Note that the production intermediate represented by the formula (IIa-1) does not require a step of deprotecting the protecting group because the hydroxyl group is unprotected. Therefore, by using the production intermediate of the present invention, the desired depsipeptide compound can be produced with a smaller number of steps than in the conventional method (see Scheme A).
  • n-butyllithium 1.6 M hexane solution, 27.9 ml, 45 mmol
  • diisopropylamine 6.0 ml, 42 mmol
  • tetrahydrofuran 28 ml
  • ethyl acetate VI-1 (4.0 ml, 42 mmol) was slowly added dropwise to the reaction solution at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 30 minutes.
  • the diastereomeric mixture was further separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1) to give (S, E) -isomer (Ia-1) (1.30 g, 23%) and ( R, E) -isomer (Ib-1) (1.30 g, 23%) was obtained.
  • the total yield (total yield) of the (S, E) -isomer (Ia-1) and (R, E) -isomer (Ib-1) was 2.83 g (50%) and 2.78 g (49%), respectively. )Met.
  • Acrolein (22) (1.3 ml, 20 mmol) and triethylamine (2.8 ml, 20 mmol) were added to a solution of triphenylmethanethiol (5.00 g, 18 mmol) in dichloromethane (36 ml) at room temperature, and the same temperature was maintained for 1 hour. Stir. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 3- (tritylthio) propanal (23) (6.45 g, 100%) as a white solid. This compound was used in the next reaction without purification (see Reference Example 2). .
  • the reaction mixture was diluted with ethyl acetate (200 ml) and washed with 3M aqueous hydrochloric acid (50 ml ⁇ 2), saturated aqueous sodium hydrogen carbonate (50 ml ⁇ 2) and saturated brine (80 ml). After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off, and 2- ⁇ (R) -2-[(S) -2- (tert-butoxycarbonylamino) -3- (tritylthio) propanamide] -3- (Naphthalen-1-yl) propanamide ⁇ acetic acid methyl ester (28) was obtained. This compound was used in the next reaction without purification.
  • HATU '-Tetramethyluronium hexafluorophosphate
  • the obtained residue was purified by silica gel column chromatography (chloroform / methanol 40: 1) to obtain (7S, 11R, 14S, 17R, E) -7-hydroxy-11-isopropyl-17- (naphthalen-1-ylmethyl). ) -9,12,15,18-tetraoxo-1,1,1-triphenyl-14-tritylthiomethyl-2-thia-10,13,16,19-tetraaza-5-henecocene-21-acid methyl ester (24) (242 mg, 92%) was obtained as a white amorphous.
  • the compound of the formula (II) according to the present invention is useful as an intermediate for producing a depsipeptide compound which is expected as an excellent novel molecular target anticancer agent.
  • the depsipeptide compounds of the formulas (1) and (2) obtained using the compound of the formula (II) according to the present invention have a completely new mechanism of action of HDAC / PI3K double inhibition. As disclosed in International Publication (Patent Document 1), it is also effective against intractable cancers that are ineffective against cancer drugs. In addition, since the depsipeptide compound is a molecular target drug that acts specifically on cancer, it has little effect on cells and tissues other than cancer cells, and it is heavy even when used at high doses for living organisms. It is also disclosed in the above publication that the possibility of serious side effects is low.

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Abstract

La présente invention vise à fournir un procédé industriellement avantageux pour produire un dérivé d'acide amidocarboxylique optiquement actif, qui est un intermédiaire important d'un composé depsipeptide attendu comme un excellent nouvel agent anticancéreux à cible moléculaire, un intermédiaire de production du composé depsipeptide, ainsi qu'un procédé de production de l'intermédiaire de production. La présente invention décrit un dérivé ester d'acide amidocarboxylique optiquement actif représenté par la formule (I) ci-dessous (dans la formule, R1, R2, *, † et TrS sont tels que définis dans la description).
PCT/JP2017/001140 2016-01-13 2017-01-13 Intermédiaire de production de composé depsipeptide, et son procédé de production Ceased WO2017122822A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113861267A (zh) * 2021-10-25 2021-12-31 深圳湾实验室坪山生物医药研发转化中心 一种缩酯环肽类化合物lzg-pku-h及其合成方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009141657A1 (fr) * 2008-05-22 2009-11-26 Karus Therapeutics Limited Depsipeptides et leur utilisation thérapeutique
JP2010510302A (ja) * 2006-11-23 2010-04-02 ユニバーシティ、オブ、サウサンプトン デプシペプチドおよびその治療的使用
WO2013047509A1 (fr) * 2011-09-30 2013-04-04 国立大学法人東北大学 Nouvel inhibiteur de phosphatidylinositol-3-kinase et composition pharmaceutique
WO2015131355A1 (fr) * 2014-03-05 2015-09-11 清安医药科技武汉有限公司 Préparation du produit naturel thaïlandepsine b inhibiteur de l'histone désacétylase

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010510302A (ja) * 2006-11-23 2010-04-02 ユニバーシティ、オブ、サウサンプトン デプシペプチドおよびその治療的使用
WO2009141657A1 (fr) * 2008-05-22 2009-11-26 Karus Therapeutics Limited Depsipeptides et leur utilisation thérapeutique
WO2013047509A1 (fr) * 2011-09-30 2013-04-04 国立大学法人東北大学 Nouvel inhibiteur de phosphatidylinositol-3-kinase et composition pharmaceutique
WO2015131355A1 (fr) * 2014-03-05 2015-09-11 清安医药科技武汉有限公司 Préparation du produit naturel thaïlandepsine b inhibiteur de l'histone désacétylase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TOSHIYA TAKIZAWA ET AL.: "Synthetic Studies on Spiruchostatin A, a Potent Histone Deacetylase Inhibitor", JOURNAL OF TOHOKU PHARMACEUTICAL UNIVERSITY, vol. 54, 2007, pages 33 - 47 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113861267A (zh) * 2021-10-25 2021-12-31 深圳湾实验室坪山生物医药研发转化中心 一种缩酯环肽类化合物lzg-pku-h及其合成方法和应用
CN113861267B (zh) * 2021-10-25 2023-06-27 深圳湾实验室坪山生物医药研发转化中心 一种缩酯环肽类化合物lzg-pku-h及其合成方法和应用

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