Method for producing heterocycle-containing amino acid compound

Abstract

To provide a method for manufacturing a heterocycle-containing amino acid compound that is blended in a fertilizer to allow for crop farming even in alkaline poor soil, and is useful as a chelator component having an iron uptake ability.SOLUTION: The present invention discloses a method for manufacturing a heterocycle-containing amino acid compound represented by the formula (1), including the step of reacting a 3-5-membered nitrogen-containing saturated heterocyclic compound, such as tert-butylproline, with the position 2 substituted with a carboxyl group or its protective group, an aminobutyrate derivative, such as tert-butyl ester of 3-amino-1-tert-butoxybutyric acid, and an acrolein and a cyanation agent. [R1a is H or CO2R1b; R1b is H or a protective group of a carboxyl group; R2a is H or OR2b; R2b is H or a protective group of a hydroxyl group; R3 is H or a protective group of an amino group; R4 is H or a protective group of a carboxyl group; n is an integer of 1-3].SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a heterocycle-containing amino acid compound. [Background technology]

[0002] Various trace metal elements are involved in plant growth and function maintenance, and if there is a deficiency in these trace metal elements, the plant cannot grow normally. For example, iron is an element necessary for respiration, photosynthesis, DNA synthesis, etc., and is in particular the active central metal of the enzyme essential for the biosynthesis of chlorophyll. Therefore, iron deficiency causes chlorosis (iron deficiency yellowing), in which the leaves turn yellow.

[0003] On the other hand, poor soil that is not suitable for agriculture accounts for approximately 67% of the world's total land area, and half of this is alkaline soil. In such alkaline soil, iron exists in the form of water-insoluble trivalent ferric hydroxide (Fe(OH)3), so plants cannot absorb enough iron through their roots, resulting in iron deficiency, which is a problem.

[0004] It is known that grasses, such as barley, rice, wheat, and corn, secrete mugineic acids (chelating agents) from their roots, such as mugineic acid represented by the following formula (A) and 2'-deoxymugineic acid (DMA) represented by the following formula (B). The chelating agents dissolve iron by forming a complex with iron, and the complex is then taken up into the plant body via a specific transporter. [ka]

[0005] This allows them to absorb iron ions from alkaline soil, but generally they have a low ability to secrete mugineic acids, and there are many Gramineae plants, such as rice and corn, that cannot grow in alkaline soil.

[0006] Therefore, the present inventors have proposed a heterocycle-containing amino acid compound that is useful as a chelating agent having iron uptake ability and can be supplied as a fertilizer, in order to enable agriculture even in poor alkaline soil (Patent Documents 1 and 2). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 6347396 [Patent Document 2] Patent No. 6744530 Summary of the Invention [Problem to be solved by the invention]

[0008] The heterocycle-containing amino acid compounds described in Patent Documents 1 and 2 are synthesized by a method including the following steps 1 to 4: (Step 1) a step of oxidatively cleaving the vinyl group of a compound having a vinyl group at one end and an amino group protected by a protecting group at the other end to form an aldehyde, and reacting the aldehyde with a heterocycle-containing amino acid (reductive amination reaction); (Step 2) protecting the carboxyl group of the reaction product of Step 1 and deprotecting the protecting group of the amino group; (Step 3) reacting the reaction product of Step 2 with a compound having a formyl group at one end and a hydroxyl group protected by a protecting group at the other end; and (Step 4) A step of deprotecting the hydroxyl-protecting group of the reaction product of Step 3.

[0009] The above method requires four steps, but if it can be synthesized with fewer steps and from easily available raw materials, it will be of great industrial value. Therefore, the main object of the present invention is to provide a simple method for producing a heterocycle-containing amino acid compound. [Means for solving the problem]

[0010] As a result of intensive research to solve the above problems, the present inventors have discovered the following steps A and B: (A) Formula (2): [ka] [In the formula, R 4 is a hydrogen atom or a protecting group for a carboxyl group, n is an integer from 1 to 3. or a salt thereof, acrolein, a cyanating agent, and a compound represented by the following formula (3): [ka] [In the formula, R 1a is a hydrogen atom or COR 1b and R 1b is a hydrogen atom or a protecting group for a carboxyl group, R 2a is a hydrogen atom or OR 2b and R 2b is a protecting group for a hydrogen atom or a hydroxyl group, R 3 is a protecting group for a hydrogen atom or an amino group. or a salt thereof; and (B) The compound obtained in step A, represented by the following formula (1): [ka] [In the formula, R 1a is a hydrogen atom or COR 1b and R 1b is a hydrogen atom or a protecting group for a carboxyl group, R 2a is a hydrogen atom or OR 2b and R 2b is a protecting group for a hydrogen atom or a hydroxyl group, R 3 is a protecting group for a hydrogen atom or an amino group, R4 is a hydrogen atom or a protecting group for a carboxyl group, n is the same as above. or a salt thereof, by hydrolysis to convert the cyano group of the compound represented by the formula: The present inventors have found that a heterocycle-containing amino acid compound can be easily produced by a method comprising the steps of: Based on this finding, the present inventors have further investigated and completed the present invention.

[0011] The present invention includes the following aspects. [Section 1] The following formula (1): [ka] [In the formula, R 1a is a hydrogen atom or COR 1b and R 1b is a hydrogen atom or a protecting group for a carboxyl group, R 2a is a hydrogen atom or OR 2b and R 2b is a protecting group for a hydrogen atom or a hydroxyl group, R 3 is a protecting group for a hydrogen atom or an amino group, R 4 is a hydrogen atom or a protecting group for a carboxyl group, n is an integer from 1 to 3. A method for producing a compound represented by the formula: The following formula (2): [ka] [In the formula, R 4 and n is the same as above. or a salt thereof, acrolein, a cyanating agent, and a compound represented by the following formula (3): [ka] [In the formula, R 1a , R 2a, and R 3 is the same as above] or a salt thereof. [Section 2] The following formula (4): [ka] [In the formula, R 1c is a hydrogen atom or a carboxyl group, R 2c is a hydrogen atom or a hydroxyl group, n is an integer from 1 to 3. A method for producing a compound represented by the formula: The following formula (1): [ka] [In the formula, R 1a is a hydrogen atom or COR 1b and R 1b is a hydrogen atom or a protecting group for a carboxyl group, R 2a is a hydrogen atom or OR 2b and R 2b is a protecting group for a hydrogen atom or a hydroxyl group, R 3 is a protecting group for a hydrogen atom or an amino group, R 4 is a hydrogen atom or a protecting group for a carboxyl group, n is the same as above. or a salt thereof, by hydrolysis, converting a cyano group of the compound represented by the formula: [Section 3] Item 3. The method according to Item 2, wherein step B is carried out in the presence of an acid. [Section 4] Item 4. The method of item 3, wherein the acid is an inorganic acid. [Section 5] Item 5. The method according to item 3 or 4, wherein the acid is at least one selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, and nitric acid. [Section 6] the carboxyl-protecting group is an alkyl group, an alkenyl group, or an aralkyl group, the hydroxyl-protecting group is an alkyl group, an aralkyl group, a silyl group, or a trialkylsilyl group; Item 6. The method according to any one of Items 2 to 5, wherein the amino-protecting group is an alkoxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group. [Section 7] Furthermore, the following formula (2): [ka] [In the formula, R 4 and n is the same as above. or a salt thereof, acrolein, a cyanating agent, and a compound represented by the following formula (3): [ka] [In the formula, R 1a , R 2a , and R 3 is the same as above] or a salt thereof to obtain a compound represented by formula (1). [Section 8] The following formula (1): [ka] [In the formula, R 1a is a hydrogen atom or COR 1b and R 1b is a hydrogen atom or a protecting group for a carboxyl group, R 2a is a hydrogen atom or OR 2b and R 2b is a protecting group for a hydrogen atom or a hydroxyl group, R3 is a protecting group for a hydrogen atom or an amino group, R 4 is a hydrogen atom or a protecting group for a carboxyl group, n is an integer from 1 to 3. A compound represented by the formula: [Section 9] the carboxyl-protecting group is an alkyl group, an alkenyl group, or an aralkyl group, the hydroxyl-protecting group is an alkyl group, an aralkyl group, a silyl group, or a trialkylsilyl group; Item 9. The compound or salt thereof according to item 8, wherein the amino-protecting group is an alkoxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group. Effect of the Invention

[0012] The present invention provides a simple method for producing a heterocycle-containing amino acid compound. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] 1.Definition In this specification, "C a-b " means that the number of carbon atoms in question is an integer between a and b.

[0014] As used herein, the term "protecting group" refers to a group used to protect a functional group from certain chemical reactions.

[0015] In the present specification, the term "protective group for a carboxyl group" refers to a concept that encompasses all of the protective groups commonly used in the art for protecting a carboxyl group, such as the protective groups described in PROTECTIVE GROUPS in ORGANIC SYNTHESIS (TW Green; PGM Wuts). Examples of the protective group for a carboxyl group include an alkyl group which may have one or more substituents, an alkenyl group which may have one or more substituents, a cycloalkyl group which may have one or more substituents, an aryl group which may have one or more substituents, and an aralkyl group which may have one or more substituents.

[0016] In this specification, the term "protective group for hydroxyl group" refers to a concept that includes all protective groups that are commonly used in the art to protect hydroxyl group, such as protective groups described in PROTECTIVE GROUPS in ORGANIC SYNTHESIS (TW Green; PGM Wuts). Examples of the protective group for hydroxyl group include an alkyl group that may have one or more substituents, a cycloalkyl group that may have one or more substituents, an aryl group that may have one or more substituents, an aralkyl group that may have one or more substituents, a 2-tetrahydropyranyl group that may have one or more substituents, an alkylcarbonyl group that may have one or more substituents, an arylcarbonyl group that may have one or more substituents, an aralkylcarbonyl group that may have one or more substituents, and a silyl group (-SiH3) that may have one or more substituents.

[0017] In the present specification, the term "protecting group for amino group" refers to a concept that includes all protecting groups that are commonly used in the art to protect amino groups, such as the protecting groups described in PROTECTIVE GROUPS in ORGANIC SYNTHESIS (TW Green; PGM Wuts). Examples of the protecting group for amino group include an alkylcarbonyl group that may have one or more substituents, an arylcarbonyl group that may have one or more substituents, an aralkylcarbonyl group that may have one or more substituents, an alkoxycarbonyl group that may have one or more substituents, an alkenyloxycarbonyl group that may have one or more substituents, an aryloxycarbonyl group that may have one or more substituents, an aralkyloxycarbonyl group that may have one or more substituents, an alkylsulfonyl group that may have one or more substituents, and an arylsulfonyl group that may have one or more substituents.

[0018] In this specification, the term "alkyl group" refers to a concept that includes linear alkyl groups and branched alkyl groups. Examples of the alkyl group include linear C alkyl groups such as methyl groups, ethyl groups, n-propyl groups, n-butyl groups, n-pentyl groups, and n-hexyl groups. 1-10 Alkyl groups: branched chain C such as isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, and 2-ethylhexyl groups. 3-10 Examples of such groups include alkyl groups.

[0019] In the present specification, the term "alkenyl group" refers to a concept that includes linear alkenyl groups and branched alkenyl groups. Examples of the alkenyl group include linear C alkenyl groups such as vinyl groups, 1-propenyl groups, and allyl groups. 1-10 Alkenyl groups; branched chain C such as 1-methylethenyl group, 2-methyl-2-propenyl group, etc. 3-10 Alkenyl groups and the like.

[0020] In the present specification, the term "cycloalkyl group" refers to a cyclic alkyl group. Examples of the cycloalkyl group include C cyclopentyl group, cyclohexyl group, etc. 5-20 Examples of such groups include cycloalkyl groups.

[0021] In the present specification, the term "aryl group" refers to a monovalent aromatic hydrocarbon group. Examples of the aryl group include C aryl groups such as phenyl and naphthyl groups. 6-20 Examples of the alkyl group include an aryl group.

[0022] In the present specification, the term "aralkyl group" refers to an arylalkyl group. Examples of the aralkyl group include C arylalkyl groups such as benzyl, trityl, and phenethyl groups. 7-20 Examples of the alkyl group include an aryl group.

[0023] As used herein, an “alkylcarbonyl group” refers to a group represented by the formula: R A -CO-(wherein, R A is an alkyl group). Examples of the alkylcarbonyl group include C groups such as methylcarbonyl group (acetyl group), ethylcarbonyl group, propylcarbonyl group (n-propylcarbonyl group, isopropylcarbonyl group), and butylcarbonyl group (n-butylcarbonyl group, isobutylcarbonyl group, s-butylcarbonyl group, and t-butylcarbonyl group). 1-10 Examples thereof include an alkylcarbonyl group.

[0024] As used herein, an “arylcarbonyl group” refers to a group represented by the formula: R B -CO-(wherein, R B The arylcarbonyl group is, for example, a C benzoyl group, a naphthoyl group, etc. 6-20 Examples thereof include an arylcarbonyl group.

[0025] As used herein, an “aralkylcarbonyl group” refers to a group represented by the formula: R C -CO-(wherein, R Cis an aralkyl group). Examples of the aralkylcarbonyl group include C 7-20 Examples thereof include an aralkylcarbonyl group.

[0026] As used herein, an "alkoxycarbonyl group" refers to a group represented by the formula: R D -O-CO-(wherein, R D The alkoxycarbonyl group refers to a group represented by the formula (I is an alkyl group). Examples of the alkoxycarbonyl group include C groups such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group (n-propoxycarbonyl group, isopropoxycarbonyl group), and a butoxycarbonyl group (n-butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, and t-butoxycarbonyl group). 1-10 Examples thereof include an alkoxycarbonyl group.

[0027] As used herein, an “alkenyloxycarbonyl group” refers to a group represented by the formula: R E -O-CO-(wherein, R E is an alkenyl group). Examples of the alkenyloxycarbonyl group include a vinyloxycarbonyl group, an allyloxycarbonyl group, a propenyloxycarbonyl group, and the like. 1-10 Examples thereof include an alkenyloxycarbonyl group.

[0028] As used herein, an “aryloxycarbonyl group” refers to a group represented by the formula: R F -O-CO-(wherein, R F The aryloxycarbonyl group is, for example, a C aryloxycarbonyl group such as a phenyloxycarbonyl group or a naphthyloxycarbonyl group. 6-20 Examples thereof include an aryloxycarbonyl group.

[0029] As used herein, an “aralkyloxycarbonyl group” refers to a group represented by the formula: R G -O-CO-(wherein, R GThe aralkyloxycarbonyl group is, for example, a C aryloxycarbonyl group such as a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, or a phenethyloxycarbonyl group. 7-20 Examples thereof include an aralkyloxycarbonyl group.

[0030] As used herein, an “alkylcarbonyloxy group” refers to a group represented by the formula: R H -CO-O-(wherein, R H is an alkyl group). Examples of the alkylcarbonyloxy group include C groups such as acetyloxy, propionyloxy (n-propionyloxy, isopropionyloxy), butyryloxy (n-butyryloxy, isobutyryloxy, s-butyryloxy, and t-butyryloxy). 1-10 Examples thereof include an alkylcarbonyloxy group.

[0031] As used herein, an “alkylsulfonyl group” refers to a group represented by the formula: R I -SO2-(wherein, R I The alkylsulfonyl group is a group represented by the formula (C) such as methylsulfonyl group and ethylsulfonyl group. 1-10 Examples thereof include an alkylsulfonyl group.

[0032] As used herein, an “arylsulfonyl group” refers to a group represented by the formula: R J -SO2-(wherein, R J is an aryl group). The arylsulfonyl group is a group represented by the formula (C), such as a phenylsulfonyl group or a naphthylsulfonyl group. 6-20 Examples thereof include an arylsulfonyl group.

[0033] In the present specification, the term "substituent" refers to another atom or atomic group that replaces the hydrogen atom to be substituted. Examples of the substituent include, but are not limited to, a halogen atom, a nitro group, an alkoxy group, an alkylcarbonyloxy group, and the like.

[0034] In this specification, the term "halogen atom" is a concept that includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0035] As used herein, an "alkoxy group" refers to a group represented by the formula: R K O-(wherein, R K The alkoxy group refers to a group represented by the formula (I is an alkyl group). Examples of the alkoxy group include a C group such as a methoxy group, an ethoxy group, a propoxy group (n-propoxy group, isopropoxy group), and a butoxy group (n-butoxy group, isobutoxy group, s-butoxy group, and t-butoxy group). 1-10 Examples thereof include an alkoxy group.

[0036] For example, specific examples of the alkyl group having one or more substituents include C alkyl groups such as a methoxymethyl group and an ethoxyethyl group. 1-6 Alkoxy C 1-6 Alkyl group; C such as methoxyethoxymethyl group 1-6 Alkoxy C 1-6 Alkoxy C 1-6 Alkyl groups: acetoxymethyl, acetoxyethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, and other C 1-6 Alkylcarbonyloxy C 1-6 Examples of such groups include alkyl groups.

[0037] Specific examples of the aralkyl group having one or more substituents include nitroaralkyl groups such as o-, m-, or p-nitrobenzyl group and 2,4-dinitrobenzyl group; haloaralkyl groups such as p-chlorobenzyl group and p-bromobenzyl group; and C aralkyl groups such as p-methoxybenzyl group. 1-6 Examples thereof include an alkoxyaralkyl group.

[0038] Specific examples of the silyl group having one or more substituents include a trialkylsilyl group, an alkyldiarylsilyl group, etc. Examples of the trialkylsilyl group include tri-C groups such as a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a triisopropylsilyl (TIPS) group, and a t-butyldimethylsilyl (TBS) group.1-6 Examples of the alkyldiarylsilyl group include C silyl groups such as t-butyldiphenylsilyl (TBDPS) group. 1-6 AlkyldiC 6-12 Examples thereof include an arylsilyl group.

[0039] 2. A compound represented by formula (1) or a salt thereof The compound represented by formula (1) or a salt thereof is a useful intermediate for producing a compound represented by formula (4) or a salt thereof.

[0040] R 1a is a hydrogen atom or COR 1b and R 1b R is a hydrogen atom or a protecting group for a carboxyl group. 1b is preferably a protecting group for a carboxyl group, more preferably an alkyl group, an alkenyl group, or an aralkyl group, and further preferably a C protecting group such as a methyl group, an ethyl group, or a t-butyl group. 1-6 Alkyl group; C such as allyl group 2-6 Alkenyl group; or C such as benzyl group, trityl group, etc. 7-20 It is an aralkyl group.

[0041] R 2a is a hydrogen atom or OR 2b and R 2b R is a hydrogen atom or a protecting group for a hydroxyl group. 2b is preferably a protecting group for a hydroxyl group, more preferably an alkyl group, an aralkyl group, a silyl group, or a trialkylsilyl group, and further preferably a C group such as a methyl group, an ethyl group, or a t-butyl group. 1-6 Alkyl group; C such as benzyl group 7-20 Aralkyl groups; silyl groups; or tri-C groups such as TMS, TIPS, and TBS groups. 1-6 It is an alkylsilyl group.

[0042] R 3 R is a hydrogen atom or a protecting group for an amino group. 3is preferably a protecting group for an amino group, more preferably an alkoxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group, and further preferably a C 1-6 Alkoxycarbonyl group; allyloxycarbonyl group, etc. 2-6 Alkenyloxycarbonyl group; or benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc. 7-20 It is an aralkyloxycarbonyl group.

[0043] R 4 R is a hydrogen atom or a protecting group for a carboxyl group. 4 is preferably a protecting group for a carboxyl group, more preferably an alkyl group, an alkenyl group, or an aralkyl group, and further preferably a C protecting group such as a methyl group, an ethyl group, or a t-butyl group. 1-6 Alkyl group; C such as allyl group 2-6 Alkenyl group; or C such as benzyl group, trityl group, etc. 7-20 It is an aralkyl group.

[0044] R 1a , R 2a , R 3 , and R 4 The combination of R 1a is a hydrogen atom or COR 1b and R 1b is a protecting group for the carboxyl group, and R 2a is a hydrogen atom or OR 2b and R 2b is a protecting group for a hydroxyl group, and R 3 is a hydrogen atom, and R 4 is a protecting group for a carboxyl group. 1a CO2R 1b and R 1b is a protecting group for the carboxyl group, and R 2a OR 2b and R 2b is a protecting group for the hydroxyl group, and R 3 is a hydrogen atom, and R 4is preferably a protecting group for a carboxyl group. 1a CO2R 1b and R 1b is a protecting group for the carboxyl group, and R 2a is a hydrogen atom, and R 3 is a hydrogen atom, and R 4 is preferably a protecting group for a carboxyl group. 1a is a hydrogen atom, and R 2a OR 2b and R 2b is a protecting group for the hydroxyl group, and R 3 is a hydrogen atom, and R 4 is preferably a protecting group for a carboxyl group.

[0045] n is an integer from 1 to 3.

[0046] The salt of the compound represented by formula (1) is not particularly limited. Examples of such salts include inorganic acid salts such as hydrochloride, sulfate, and nitrate; carboxylates such as acetate, trifluoroacetate, oxalate, and benzoate; organic acid salts such as sulfonate, such as methanesulfonate, and p-toluenesulfonate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as dimethylammonium and triethylammonium. The salt is preferably an inorganic acid salt, and more preferably a hydrochloride.

[0047] The compound represented by formula (1) or a salt thereof includes optical isomers such as enantiomers and diastereomers, and racemates.

[0048] 3. Method for producing the compound represented by formula (1) or a salt thereof In one embodiment, the method for producing a compound represented by formula (1) or a salt thereof includes a step A of reacting a compound represented by formula (2) or a salt thereof, acrolein, a cyanating agent, and a compound represented by formula (3) or a salt thereof.

[0049] R in Equation (2) 4and n are as explained in formula (1). Either the compound represented by formula (2) or a salt thereof may be used. In the case of a salt of a compound, the salt of the compound represented by formula (2) is not particularly limited, but may be the same as the salts exemplified for the salt of the compound represented by formula (1). In the case where the salt affects the reaction, it is preferable to use the compound after desalting.

[0050] The amount of acrolein used is, for example, 0.1 mol or more, preferably 0.5 mol or more, and more preferably 1 mol or more, relative to 1 mol of the compound represented by formula (2) or a salt thereof. The amount of acrolein used is, for example, 5 mol or less, preferably 4 mol or less, more preferably 3 mol or less, and more preferably 2 mol or less, relative to 1 mol of the compound represented by formula (2) or a salt thereof.

[0051] Examples of the cyanating agent include hydrogen cyanide; alkali metal cyanides such as sodium cyanide and potassium cyanide; and organic cyanating reagents such as trimethylsilyl cyanide and acetone cyanohydrin. The amount of the cyanating agent used is, for example, 0.1 mol or more, preferably 0.5 mol or more, and more preferably 1 mol or more, relative to 1 mol of the compound represented by formula (2) or a salt thereof. The amount of the cyanating agent used is, for example, 5 mol or less, preferably 4 mol or less, more preferably 3 mol or less, and more preferably 2 mol or less, relative to 1 mol of the compound represented by formula (2) or a salt thereof.

[0052] R in Equation (3) 1a , R 2a , and R 3is as explained in formula (1). It may be either a compound represented by formula (3) or a salt thereof. In the case of a salt of a compound, the salt of the compound represented by formula (3) is not particularly limited, but may be the same as the salt exemplified in the salt of the compound represented by formula (1). In addition, when the salt affects the reaction, it is preferable to use it after desalting. The amount of the compound represented by formula (3) or its salt to be used is, for example, 0.1 mol or more, preferably 0.5 mol or more, and more preferably 1 mol or more, relative to 1 mol of the compound represented by formula (2) or its salt. In addition, the amount of the compound represented by formula (3) or its salt to be used is, for example, 5 mol or less, preferably 4 mol or less, more preferably 3 mol or less, and more preferably 2 mol or less, relative to 1 mol of the compound represented by formula (2) or its salt.

[0053] The reaction of the compound represented by formula (2) or its salt, acrolein, a cyanating agent, and the compound represented by formula (3) or its salt usually proceeds by mixing these components. The mixing order is not particularly limited, and the reaction proceeds regardless of the order of mixing. One example of the mixing method is a method in which the compound represented by formula (2) or its salt is mixed with acrolein, then mixed with the compound represented by formula (3) or its salt, and finally mixed with the cyanating agent (hereinafter referred to as "mixing method 1"). Another example is a method in which a mixture of the compound represented by formula (2) or its salt and acrolein is mixed with a mixture of the compound represented by formula (3) and the cyanating agent (hereinafter referred to as "mixing method 2"). Another example is a method in which the compound represented by formula (2) or its salt, acrolein, a cyanating agent, and the compound represented by formula (3) or its salt are mixed together (hereinafter referred to as "mixing method 3").

[0054] Step A is usually carried out in the presence of a solvent. The solvent may be a polar solvent or a non-polar solvent. Examples of polar solvents include water; halogenated hydrocarbons such as methylene chloride; alcohols such as isopropanol; ethers such as tetrahydrofuran and dioxane; and nitriles such as acetonitrile. Examples of non-polar solvents include aromatic hydrocarbons such as toluene. The solvent may be used alone or in combination of two or more. The solvent is preferably a polar solvent, more preferably an ether such as tetrahydrofuran.

[0055] Step A can be carried out in the absence or presence of a base. For example, when step A is carried out at a low temperature of -15°C or lower, or when the compound represented by formula (2) or a salt thereof is mixed with acrolein, it is preferable to carry out the step in the presence of a base. Examples of the base include triethylamine (TEA), diisopropylethylamine (DIPEA), tetramethylguanidine (TMG), diazabicyclooctane (DABCO), diazabicyclononene (DBN), diazabicycloundecene (DBU), triazabicyclodecene (TBD), N-methyl-triazabicyclodecene (MTBD), pyridine, 4-dimethylaminopyridine (DMAP), and the like. The base can be used alone or in combination of two or more types.

[0056] The amount of the base used is, for example, 0.005 mol or more, preferably 0.01 mol or more, relative to 1 mol of the compound represented by formula (2) or a salt thereof. The amount of the base used is, for example, 0.1 mol or less, preferably 0.05 mol or less, relative to 1 mol of the compound represented by formula (2) or a salt thereof.

[0057] Step A can be carried out in the absence or presence of an acid. Examples of acids include, but are not limited to, aliphatic carboxylic acids such as acetic acid, trifluoroacetic acid, and pivalic acid; aromatic carboxylic acids such as benzoic acid; and sulfonic acids such as tosylic acid. The acid can be used alone or in combination of two or more. The acid is preferably an aliphatic carboxylic acid such as acetic acid or trifluoroacetic acid.

[0058] The amount of the acid used is, for example, 0.005 mol or more, preferably 0.01 mol or more, more preferably 0.02 mol or more, relative to 1 mol of the compound represented by formula (2) or a salt thereof. The amount of the acid used is, for example, 5 mol or less, preferably 3 mol or less, more preferably 1 mol or less, relative to 1 mol of the compound represented by formula (2) or a salt thereof.

[0059] The reaction temperature is not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, -100°C or higher, preferably -90°C or higher, and more preferably -80°C or higher. When the four components are mixed at once as in the mixing method 3, the reaction temperature can be room temperature, for example, within the range of 5 to 35°C. On the other hand, when the four components are mixed in a predetermined order as in the mixing methods 1 and 2, the compound represented by formula (2) or a salt thereof and acrolein are mixed at, for example, -15°C or lower, preferably -30°C or lower, more preferably -40°C or lower, and more preferably -50°C or lower, and other mixing may be performed at room temperature, for example, within the range of 5 to 35°C.

[0060] The method for producing a compound represented by formula (1) or a salt thereof may further include a purification step in addition to step A. Examples of the purification method include filtration, extraction, concentration, chromatography, or a combination thereof. Furthermore, the method for producing a compound represented by formula (1) or a salt thereof may further include an optical resolution step in addition to step A.

[0061] 4. A compound represented by formula (4) or a salt thereof R 1c is a hydrogen atom or a carboxyl group, and R 2cR is a hydrogen atom or a hydroxyl group. 1c and R 2c The combination of R 1c is a carboxyl group, and R 2c is a hydroxyl group, R 1c is a carboxyl group, and R 2c is a hydrogen atom, or R 1c is a hydrogen atom, and R 2c is a hydroxyl group.

[0062] n is an integer from 1 to 3.

[0063] The salt of the compound represented by formula (4) is not particularly limited, but may be the same as the salts exemplified for the compound represented by formula (1).

[0064] 5. Method for producing a compound represented by formula (4) or a salt thereof In one embodiment, the method for producing a compound represented by formula (4) or a salt thereof includes a step B of converting a cyano group of a compound represented by formula (1) or a salt thereof into a carboxyl group by hydrolysis.

[0065] The method for hydrolyzing the cyano group is not particularly limited, but is usually hydrolyzed with an acid. Examples of the acid include inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, and nitric acid. The acid may be used alone or in combination of two or more. The amount of the acid used is, for example, 1 mole or more, preferably 2 moles or more, and more preferably 3 moles or more, relative to 1 mole of the compound represented by formula (4) or a salt thereof. The amount of the acid used is, for example, 100 moles or less, preferably 50 moles or less, and more preferably 30 moles or less, relative to 1 mole of the compound represented by formula (4) or a salt thereof.

[0066] The reaction temperature of the hydrolysis is not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, 80° C. or higher, preferably 90° C. or higher, and more preferably 100° C. or higher. The reaction temperature is, for example, 150° C. or lower, preferably 140° C. or lower, and more preferably 130° C. or lower.

[0067] Depending on the type of protecting group, it may be simultaneously removed in the hydrolysis reaction in step B, but a step of removing (deprotecting) the protecting group may be further included for the protecting group that is not removed in the hydrolysis reaction in step B. The deprotection method may be appropriately selected depending on the type of protecting group, and for example, PROTECTIVE GROUPS in ORGANIC SYNTHESIS (written by TW Green and PGM Wuts) may be referred to.

[0068] The method for producing a compound represented by formula (4) or a salt thereof preferably further includes step A in addition to step B. The method for producing a compound represented by formula (4) or a salt thereof may further include a purification step. Examples of the purification method include filtration, extraction, concentration, chromatography, recrystallization, or a combination thereof. The method for producing a compound represented by formula (4) or a salt thereof may further include an optical resolution step. EXAMPLES

[0069] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these. The abbreviations in the examples have the following meanings. tBu: tertiary butyl THF: tetrahydrofuran Et2O: Diethyl ether DBU: Diazabicycloundecene TFA: Trifluoroacetic acid TMSCN: Trimethylsilylcyanide iPrOH: Isopropanol

[0070] Example 1. Synthesis of t-butyl (3-cyano-3-(((S)-3,4-di-t-butoxy-4-oxobutyl)amino)propyl)-L-prolinate (4) (Method 1) [ka]

[0071] tBu-proline (1) (59 mg, 0.34 mmol) was dissolved in THF (1.2 mL). DBU (0.1 M THF solution) (0.17 mL, 0.017 mmol) was added and cooled to -78 ° C. Acrolein (2) (25 μL, 0.34 mmol) was added to the reaction solution and stirred at -78 ° C for 2 hours. tBu-aminobutyric acid solution (tBu-aminobutyric acid (3) (79 mg, 0.34 mmol) dissolved in THF (0.5 mL)) and 0.1 M THF solution of TFA (34 μL, 0.0034 mmol) were added to the reaction solution and stirred at -78 ° C for 2 hours. Then, TMSCN (51 μL, 0.41 mmol) and iPrOH (31 μL, 0.41 mmol) were added and stirred for 2 hours. After the reaction was completed, the mixture was diluted with Et2O and then saturated aqueous NaHCO3 solution was added. The mixture was extracted with Et2O, and the organic phase was dried over MgSO4, filtered, and concentrated (NMR yield 80%). The concentrated residue was purified by column chromatography (n-hexane / ethyl acetate (4:1) to obtain the title compound (4) (108 mg, 68%) as a yellow liquid.

[0072] Example 2. Synthesis of t-butyl (3-cyano-3-(((S)-3,4-di-t-butoxy-4-oxobutyl)amino)propyl)-L-prolinate (4) (Method 2) [ka]

[0073] tBu-proline (1) (123 mg, 0.71 mmol) was dissolved in THF (3.6 mL). DBU (5 μL, 0.035 mmol) was added and cooled to -78 °C. Acrolein (2) (53 μL, 0.71 mmol) was added to the reaction solution and stirred at -78 °C for 2 hours. A previously prepared tBu-aminobutyric acid solution (a solution of tBu-aminobutyric acid (3) (167 mg, 0.72 mmol) in iPrOH (3 mL) was added with NaCN (42 mg, 0.85 mmol) and TFA (66 μL, 0.85 mmol) and stirred at room temperature for 15 hours) was added to the reaction solution and stirred at -78 °C for 2 hours. After the reaction was completed, the solution was diluted with Et2O and then saturated NaHCO3 aqueous solution was added. Extraction with Et2O, drying of the organic phase over MgSO4, filtering and concentration afforded the title compound (4) (NMR yield 55%). 1H NMR(400 MHz, CD3OD): 4.10 (dd, J = 4.4, 8.4Hz, 1H), 4.06 (dd, J = 5.3, 7.2Hz, 1H), 3.85 (t, J = 6.5Hz, 1H), 3.80 (dd, J = 6.4, 7.3Hz, 1H), 3.19-3.14 (m, 1H), 3.09-3.04 (m, 1H), 2.96-2.85 (m, 2H), 2.07-2.54 (m, 2H), 2.34 (ddd, J = 8.0, 12.4, 16Hz, 1H), 2.15-2.06 (m, 1H), 2.01-1.74 (m, 7H), 1.48 (s, 18H), 1.99 (s, 9H)

[0074] Example 3. Synthesis of (3-carboxy-3-(((S)-3-carboxy-3-hydroxypropyl)amino)propyl)-L-proline (5) [ka]

[0075] Compound (4) (474 ​​mg, 1.01 mmol) was added with 12 M aqueous hydrochloric acid (5 mL) and stirred at 0°C for 30 minutes, and then the reaction solution was warmed to room temperature and stirred for another hour. The reaction solution was then warmed to 100°C and stirred for 19 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The concentrated residue was dissolved in H2O (1.5 mL), and activated carbon (100 mg) was added and stirred at room temperature for 5 minutes. The solution was filtered, and the filtrate was concentrated. The resulting residue was purified with ion exchange resin (H2O → 5% NH3) to obtain the title compound (5) (214.6 mg, 70%) as a brown solid. 1H NMR(500 MHz, D2O): 4.43 (dd, J = 4.3, 8.1Hz, 1H), 4.20 (td, J = 5.5, 9.6Hz, 1H), 3.96 (dd, J = 4.4, 8.6Hz, 1H), 3.91 (t, J = 6.7Hz, 1H), 3.82 (ddd, J = 3.7, 7.2, 11Hz, 1H), 3.60-3.37 (m, 2H), 3.34-3.18 (m, 3H), 2.56-2.50 (m, 1H), 2.37-2.26 (m, 3H), 2.23-1.95 (m, 4H)

Claims

1. The following formula (1): 【Chemistry 1】 [In the formula, R １ａ is a hydrogen atom or CO ２ R １ｂ and R １ｂ is a hydrogen atom or a protecting group for a carboxyl group, and the protecting group for a carboxyl group is an alkyl group, an alkenyl group, or an aralkyl group, R ２ａ is a hydrogen atom or OR ２ｂ and R ２ｂ is a protecting group for a hydrogen atom or a hydroxyl group, and the protecting group for a hydroxyl group is an alkyl group, an aralkyl group, a silyl group, or a trialkylsilyl group; R ３ is a hydrogen atom or an amino-protecting group, and the amino-protecting group is an alkoxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group, R ４ is a hydrogen atom or a protecting group for a carboxyl group, and the protecting group for a carboxyl group is an alkyl group, an alkenyl group, or an aralkyl group, n is an integer from 1 to 3. A method for producing a compound represented by the formula: The following formula (2): 【Chemistry 2】 [In the formula, R ４ and n is the same as above. or a salt thereof, acrolein, a cyanating agent, and a compound represented by the following formula (3): 【Chemistry 3】 [In the formula, R １ａ , R ２ａ , and R ３ is the same as above. or a salt thereof, A method in which, in the step A, a compound represented by formula (2) or a salt thereof is mixed with acrolein, then mixed with a compound represented by formula (3) or a salt thereof, and finally mixed with a cyanating agent, or a mixture of a compound represented by formula (2) or a salt thereof and acrolein is mixed with a mixture of a compound represented by formula (3) or a salt thereof and a cyanating agent.

2. The following formula (4): 【Chemistry 4】 [In the formula, R １ｃ is a hydrogen atom or a carboxyl group, R ２ｃ is a hydrogen atom or a hydroxyl group, n is an integer from 1 to 3. A method for producing a compound represented by the formula: The following formula (1): 【Chemistry 5】 [In the formula, R １ａ is a hydrogen atom or CO ２ R １ｂ and R １ｂ is a hydrogen atom or a protecting group for a carboxyl group, and the protecting group for a carboxyl group is an alkyl group, an alkenyl group, or an aralkyl group, R ２ａ is a hydrogen atom or OR ２ｂ and R ２ｂ is a protecting group for a hydrogen atom or a hydroxyl group, and the protecting group for a hydroxyl group is an alkyl group, an aralkyl group, a silyl group, or a trialkylsilyl group; R ３ is a hydrogen atom or an amino-protecting group, and the amino-protecting group is an alkoxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group, R ４ is a hydrogen atom or a protecting group for a carboxyl group, and the protecting group for a carboxyl group is an alkyl group, an alkenyl group, or an aralkyl group, n is the same as above. or a salt thereof, by hydrolysis to convert a cyano group of the compound represented by the formula:

3. The method of claim 2 , wherein step B is carried out in the presence of an acid.

4. The method of claim 3 , wherein the acid is an inorganic acid.

5. The method according to claim 3 or 4, wherein the acid is at least one selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, and nitric acid.

6. Furthermore, the following formula (2): 【Chemistry 6】 [In the formula, R ４ and n is the same as above. or a salt thereof, acrolein, a cyanating agent, and a compound represented by the following formula (3): 【Chemistry 7】 [In the formula, R １ａ , R ２ａ , and R ３ is the same as above. or a salt thereof to obtain a compound represented by formula (1), The method according to any one of claims 2 to 5, wherein in the step A, the compound represented by formula (2) or a salt thereof is mixed with acrolein, then mixed with the compound represented by formula (3) or a salt thereof, and finally mixed with the cyanating agent, or the mixture of the compound represented by formula (2) or a salt thereof and acrolein is mixed with a mixture of the compound represented by formula (3) or a salt thereof and the cyanating agent.

7. The following formula (1): 【Chemistry 8】 [In the formula, R １ａ is a hydrogen atom or CO ２ R １ｂ and R １ｂ is a hydrogen atom or a protecting group for a carboxyl group, and the protecting group for a carboxyl group is an alkyl group, an alkenyl group, or an aralkyl group, R ２ａ is a hydrogen atom or OR ２ｂ and R ２ｂ is a protecting group for a hydrogen atom or a hydroxyl group, and the protecting group for a hydroxyl group is an alkyl group, an aralkyl group, a silyl group, or a trialkylsilyl group; R ３ is a hydrogen atom or an amino-protecting group, and the amino-protecting group is an alkoxycarbonyl group, an alkenyloxycarbonyl group, or an aralkyloxycarbonyl group, R ４ is a hydrogen atom or a protecting group for a carboxyl group, and the protecting group for a carboxyl group is an alkyl group, an alkenyl group, or an aralkyl group, n is an integer from 1 to 3. A compound represented by the formula:

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