Method for producing deuterated compound

Abstract

To provide a method for producing a deuterated compound, by which the deuterated compound obtained by deuterating the hydrogen atom at the α - position of an α - amino acid or an α - hydroxy acid in high stereoselectivity can be produced in a high deuteration ratio in spite of a short time at a low cost, and which is also applicable to industrial production.SOLUTION: A method for producing a deuterated compound in which a hydrogen atom at an α - position of an α - amino acid or an α - hydroxy acid is deuterated, the method comprising allowing an α - amino acid or an α - hydroxy acid, heavy water, and hydrogen gas or heavy hydrogen gas to flow through a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst in the absence of a base to react the α - amino acid or the α - hydroxy acid with the heavy water.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a deuterated compound in which the hydrogen atom at the α-position of an α-amino acid or an α-hydroxy acid is deuterated. [Background technology]

[0002] Compounds in which intramolecular CH is deuterated (deuterated or tritiated) to CD (also known as deuterated compounds or deuterium-labeled compounds) have improved chemical stability due to the kinetic isotope effect. This has led to active research into their application in deuterium-labeled drugs (heavy drugs) with improved efficacy and functional organic materials such as optical fibers and organic electroluminescent materials with improved functionality. Peptide drugs, in particular, are linked by repeated peptide bonds, which make them susceptible to degradation and racemization by enzymes in the body. Deuterium-labeled peptides have attracted attention for their potential to solve these problems. Alpha-hydroxy acids, including lactic acid, are also highly useful as pharmaceutical ingredients, and their deuterated forms (deuterated alpha-hydroxy acids) are gaining attention for their metabolic inhibition properties.

[0003] However, there are still few practical reports on the synthesis of deuterium-labeled α-amino acids, which are the raw materials for deuterium-labeled peptides, and deuterated α-hydroxy acids (methods for stereoselectively deuterizing the α-position of α-amino acids or α-hydroxy acids). For example, Professor Sajiki and his colleagues at Gifu Pharmaceutical University and the present applicant have established an HD exchange reaction that proceeds in heavy water (DO) using hydrogen gas (H) as an activator for a carbon-supported platinum group catalyst. Michelotti et al. have reported the introduction of deuterium atoms into the α-position of amino acids in DO under a basic H atmosphere (NaOH) using ruthenium / carbon (Ru / C) as a catalyst (Non-Patent Document 1). However, the reaction described in Non-Patent Document 1 requires the coexistence of at least an equivalent amount of NaOH, typically three equivalents, to suppress racemization. Without the coexistence of a base, the α-position hydrogen atom cannot be stereoselectively deuterized, and even if deuteration is achieved, the deuterium introduction rate is only 40% (see Comparative Example I-1 below). Furthermore, depending on the type of amino acid used as the substrate, a longer reaction time may be required; for example, glycine and leucine require reaction times of up to 72 hours. Furthermore, when aromatic rings coexist in the same molecule, there is a problem that nuclear reduction occurs at the same time. As such, the reaction described in Non-Patent Document 1 has room for improvement in order to make it a practical deuteration method, and it cannot be used as an industrial method for producing deuterated compounds. Furthermore, Non-Patent Document 2 and Patent Document 1 also describe a method for introducing a deuterium atom into the α-position of an amino acid by heating and stirring the amino acid in heavy water under an atmosphere of deuterium gas (D2) or hydrogen gas (H2) and in the presence of a ruthenium catalyst. However, the methods described in Non-Patent Document 2 and Patent Document 1 require a long reaction time, as in Non-Patent Document 1, in order to obtain a deuterium-labeled α-amino acid in good yield. For example, when alanine or the like is applied to the method described in Non-Patent Document 2, it takes 36 hours, and when glycine is applied to the method described in Patent Document 1, it takes 24 hours. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 5454140 [Non-patent literature]

[0005] [Non-Patent Document 1] Org. Process Res. Dev. 2017, Vol.21, Issue 11, p.1741-1744 [Non-patent document 2] Angew. Chem. Int. Ed. 2015, Vol.54, Issue 36, p.10474-10477 Summary of the Invention [Problem to be solved by the invention]

[0006] However, deuterated compounds, particularly highly useful deuterium-labeled α-amino acids and deuterated α-hydroxy acids, are generally expensive, and therefore there is a strong demand for methods that can be industrially produced while reducing production costs. However, the method described in Non-Patent Document 1 requires the disposal of excess base after the reaction, which actually increases costs. Moreover, as mentioned above, each of the methods described in Non-Patent Documents 1 and 2 and Patent Document 1 requires a long-term batchwise heating reaction, which not only increases heating costs but also reduces productivity, making them unusable as methods for industrially producing deuterated compounds.

[0007] An object of the present invention is to provide a method for producing deuterated compounds by deuterating the hydrogen atom at the α-position of an α-amino acid or an α-hydroxy acid with high stereoselectivity, at a high deuteration rate even in a short time, at low cost, and which is also applicable to industrial production. [Means for solving the problem]

[0008] The present inventors have conducted extensive research into the deuteration of α-amino acids or α-hydroxy acids, focusing on a flow-type heating reaction in which the reaction solution is transferred to a catalyst cartridge filled with a heterogeneous catalyst and the target reaction is initiated and progressed within the cartridge, rather than the batch-type heating reaction method previously considered. As a result, they have discovered that the desired deuteration reaction can be initiated and progressed, even in a short time, to produce deuterated compounds with a high deuteration rate, without the need for the coexistence of a base or excessively high temperatures, by simply flowing α-amino acids or α-hydroxy acids, heavy water, and hydrogen gas or deuterium gas through a region filled with a specific catalyst (catalyst-filled region). Furthermore, they have found that the rapid release of the reaction product from the catalyst-filled region (reaction field) can prevent a decrease in stereoselectivity while maintaining a high deuteration rate. Furthermore, this deuteration reaction occurs and is completed in the absence of a base, which allows for easy post-treatment (no base removal work is required), thereby reducing costs. Thus, the deuteration reaction discovered by the present inventors allows for a high deuteration rate, high stereoselectivity, a shorter reaction time, and reduced costs. It can be carried out continuously by simply circulating the above components through a reaction field, making it applicable to industrial production. The present invention was completed through further investigation based on these findings.

[0009] That is, the above-mentioned problems of the present invention have been solved by the following means. <1> A method for producing a deuterated compound by deuterating a hydrogen atom at the α-position of an α-amino acid or an α-hydroxy acid, comprising: A method for producing a deuterated compound, comprising flowing an α-amino acid or an α-hydroxy acid, heavy water, and hydrogen gas or deuterium gas through a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst in the absence of a base, thereby reacting the α-amino acid or the α-hydroxy acid with the heavy water. <2> The α-amino acid or α-hydroxy acid is a compound represented by the following general formula [1]: <1> The manufacturing method described in [ka] In general formula [1], R 1 represents a hydroxy group or an amino group, and R 2 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a carboxyalkyl group, an aminoalkyl group, an amidoalkyl group, an arylalkyl group, or a heteroarylalkyl group; R 1 and R 2 may be bonded to form a 5- or 6-membered heterocyclic group.

[0010] <3> the catalyst comprises a ruthenium catalyst; <1> or <2> The manufacturing method described in <4> The ruthenium catalyst comprises ruthenium carbon. <3> The manufacturing method described in <5> The catalyst comprises rhodium carbon. <1> or <2> The manufacturing method described in <6> The reaction is carried out at a reaction temperature of 60 to 120°C. <1> ~ <5> The manufacturing method according to any one of the above. <7> The reaction is carried out in the absence of a solvent. <1> ~ <6> The manufacturing method according to any one of the above. <8> A method for producing a deuterated compound by deuterating a hydrogen atom at the α-position of an α-amino acid or an α-hydroxy acid, comprising: a step 1 in which an α-amino acid or an α-hydroxy acid, heavy water, and hydrogen gas or deuterium gas are passed through a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst in the absence of a base, thereby reacting the α-amino acid or the α-hydroxy acid with the heavy water; Step 2 of recovering heavy water from the reaction solution obtained in step 1; Step 3: flowing the α-amino acid or α-hydroxy acid, the heavy water recovered in Step 2, and hydrogen gas or deuterium gas through the flow path in the absence of a base to react the α-amino acid or α-hydroxy acid with the recovered heavy water; The method for producing a deuterated compound comprising: <9> After performing the steps 1 and 2 in this order or simultaneously, the steps 3 and 2 are repeatedly performed in this order or simultaneously. <8> The manufacturing method described in [Effects of the Invention]

[0011] The method for producing a deuterated compound of the present invention can produce a deuterated compound by deuterating the hydrogen atom at the α-position of an α-amino acid or an α-hydroxy acid with high stereoselectivity, at a high deuteration rate even in a short time, and at low cost, and can be applied to industrial production. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 is a schematic diagram showing an example of a deuteration apparatus that can be suitably used in the method for producing a deuterated compound of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] In the present invention, unless otherwise specified, the term "deuterium atom" refers to one or both of a deuterium (D) atom and a tritium (T) atom. Heavy water refers to water having a deuterium atom in place of a hydrogen atom, and examples thereof include DO and TO. Note that the oxygen atom in heavy water is usually 16 O atom, 17 O atom, 18 It may be an O atom. In the present invention, deuterium gas refers to a gas having a deuterium atom in place of at least one hydrogen atom in hydrogen gas, and examples thereof include D2, T2, DT, HD, and HT gases.

[0014] In the present invention, the hydrogen atom at the α-position of an α-amino acid or α-hydroxy acid generally refers to a hydrogen atom bonded to the carbon atom (α-position) to which an amino group or a hydroxyl group and an acid group are bonded, and may be simply referred to as an "α hydrogen atom" in the present invention. Furthermore, the carbon atom at the α-position of an α-amino acid or α-hydroxy acid may be simply referred to as an "α carbon atom." In the present invention, deuteration (reaction) refers to the conversion (substitution) of α-hydrogen atoms in a substrate with deuterium atoms, and the converted α-hydrogen atoms may be all or a part of the α-hydrogen atoms in the substrate. Note that in the present invention, it is sufficient that the α-hydrogen atoms are (position-)selectively deuterated, and hydrogen atoms other than the α-hydrogen atoms present in the substrate may also be deuterated. In the present invention, the deuteration rate refers to the ratio (molar ratio: %) of α-hydrogen atoms substituted with deuterium atoms to the α-hydrogen atoms before the deuteration reaction, among deuterized and chemically equivalent α-hydrogen atoms in the substrate. In the production method of the present invention, the achieved deuteration rate is not uniquely determined depending on the type of substrate or catalyst, the type of α-hydrogen atoms, the difference in the step (step 1 or step 3), the number of cycles, etc. In the production method of the present invention, a high deuteration rate can be achieved, for example, 55% or more, and even 75% or more, even if the deuteration reaction is carried out for a short time.

[0015] In the present invention, when reaction conditions, amounts of raw material compounds, etc. are described using numerical ranges, and when the upper and lower limits of the numerical range are described separately, any of the upper and lower limits can be appropriately combined to form a specific numerical range. On the other hand, when multiple numerical ranges expressed using "to" are set and described, the upper and lower limits forming the numerical range are not limited to the specific combinations written before and after "to" as specific numerical ranges, and can be a numerical range obtained by appropriately combining the upper and lower limits of each numerical range. Note that in the present invention, a numerical range expressed using "to" means a range that includes the numerical values ​​written before and after "to" as the upper and lower limits.

[0016] In the present invention, the term "compound" is used to mean not only the compound itself, but also its salts and ions. It also means derivatives obtained by partially modifying the compound by introducing a substituent or the like, as long as the effect of the present invention is not impaired. In the present invention, substituents, linking groups, etc. (hereinafter referred to as substituents, etc.) that are not specified as substituted or unsubstituted mean that the group may have an appropriate substituent. Therefore, even when a YYY group is simply described in the present invention, this YYY group includes not only an embodiment in which it has no substituent, but also an embodiment in which it further has a substituent. This also applies to compounds in which it is not specified as substituted or unsubstituted. Preferred substituents include, for example, the substituent Z described below. In the present invention, when there are a plurality of substituents etc. designated by a specific symbol, or when a plurality of substituents etc. are simultaneously specified, it means that the respective substituents etc. may be the same or different from each other. Furthermore, even if not otherwise specified, when a plurality of substituents etc. are adjacent, they may be linked to each other or condensed to form a ring. In the present invention, when the number of carbon atoms of a certain group is specified, this number of carbon atoms means the number of carbon atoms of the group itself unless otherwise specified in the present invention. In other words, when this group has a further substituent (excluding groups that can be interpreted as one group when further substituted, such as branched alkyl groups), the number of carbon atoms means the number of carbon atoms counted without including the number of carbon atoms of the substituent.

[0017] [[Method of producing the deuterated compound of the present invention]] The method for producing a deuterated compound of the present invention (hereinafter sometimes simply referred to as the "production method of the present invention") involves reacting an α-amino acid or an α-hydroxy acid with deuterium by continuously flowing the α-amino acid (compound) or α-hydroxy acid (compound), heavy water, and hydrogen gas or deuterium gas through a channel filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst in the absence of a base. The production method of the present invention makes it possible to produce deuterated compounds in which the α-hydrogen atom of the α-amino acid or α-hydroxy acid is replaced with a deuterium atom, i.e., an α-amino acid (deuterated α-amino acid) or α-hydroxy acid (deuterated α-hydroxy acid) having at least one deuterium atom at the α-position. In the production method of the present invention, the α-amino acid or α-hydroxy acid, heavy water, and hydrogen gas or deuterium gas are usually passed through the catalyst-filled region continuously (successively), but the passage may be stopped at any time during the passage.

[0018] As described above, the production method of the present invention can produce deuterated compounds in which the α-hydrogen atoms of α-amino acids or α-hydroxy acids are deuterated with high stereoselectivity, at a high deuteration rate even in a short time, and at low cost, and can be applied to industrial production. In the production method of the present invention, the amount of catalyst present in the catalyst-filled region (reaction field) is in relative excess relative to the number of α-amino acid or α-hydroxy acid molecules flowing through that region. This is believed to result in efficient contact of the α-amino acid or α-hydroxy acid with the catalyst, thereby initiating and accelerating the deuteration reaction. As a result, even without the coexistence of a base (even under neutral conditions), the deuteration reaction proceeds rapidly and is completed in a short time, achieving a high deuteration rate and high stereoselectivity. Meanwhile, since there is no opportunity for contact with the catalyst after passing through the catalyst-filled region, side reactions such as racemization (stereoinversion) do not occur or progress even if the α-carbon atom is an asymmetric carbon atom, and high stereoselectivity is believed to be maintained. Furthermore, post-treatment to remove the base from the reaction product is not required. As described above, the production method of the present invention is simple in operation and easy in post-treatment, yet can achieve a high deuteration rate, stereoselectivity, and a short reaction time, and is therefore highly useful as an industrial production method.

[0019] First, the components (raw material compounds) used in the production method of the present invention will be explained. The components used in the production method of the present invention may be one type only or two or more types.

[0020] [Components to be distributed in the flow path] In the production method of the present invention, an α-amino acid or α-hydroxy acid (substrate), heavy water, and hydrogen gas or deuterium gas (hereinafter sometimes referred to as "(deuterium) gas") are circulated through a flow channel described below. In the production method of the present invention, the substrate, heavy water, and (deuterium) gas may coexist (be in a mixed state) when flowing through the catalyst-packed region in the flow channel, and may be introduced into the flow channel separately or as a mixture of two or more. In the production method of the present invention, the substrate and heavy water are preferably introduced into the flow channel as a mixture (substrate solution), and (deuterium) gas is preferably introduced into the flow channel separately from the substrate solution. The substrate solution is preferably a solution in which the substrate is dissolved in heavy water at least in the catalyst-packed region, and more preferably a solution at the time of preparation before flowing through the catalyst-packed region. The concentration of the substrate in the substrate solution will be described below.

[0021] <Substrate> In the production method of the present invention, at least one compound selected from the group consisting of an α-amino acid and an α-hydroxy acid is used as the substrate. The number of α-hydrogen atoms per molecule of the substrate is not particularly limited as long as it is one or more, and can be one to four, with one or two being preferred. The number of amino groups or hydroxy groups contained in the α-amino acid and α-hydroxy acid is not particularly limited and can be, for example, 1 to 4, but is preferably 1. The number of carboxy groups or acid groups contained in the α-amino acid and α-hydroxy acid is also not particularly limited and can be, for example, 1 to 4, but is preferably 1. The acid group contained in the α-hydroxy acid is not particularly limited and can include various acid groups contained in the substituent Z described below, but is preferably a carboxy group.

[0022] The α-carbon atom may be an asymmetric carbon atom. That is, the α-amino acid and α-hydroxy acid may be racemic or chiral (one of a pair of optical isomers with respect to the α-carbon atom). In the production method of the present invention, the deuteration reaction proceeds and is completed while maintaining high stereoselectivity of the substrate, and therefore, the desired chiral deuterated compound can be produced using the corresponding chiral substrate.

[0023] The α-amino acid and α-hydroxy acid are preferably compounds that do not contain atoms that can act as catalyst poisons, such as sulfur atoms, since these can inhibit the deuteration reaction.

[0024] The α-amino acid and α-hydroxy acid are preferably compounds represented by the following general formula [1]: [ka]

[0025] In the general formula [1], R 1 represents a hydroxy group or an amino group. R 1 The amino group that can be taken as -N(R A )2. R A represents a hydrogen atom, an alkyl group, or an aryl group, and preferably a hydrogen atom or an alkyl group. A may be the same or different, and at least one of them is preferably a hydrogen atom, and more preferably both are hydrogen atoms. R A The alkyl group that can be taken as R is not particularly limited, and examples thereof include the alkyl groups of the substituent Z described below. Among these, alkyl groups having 1 to 12 carbon atoms are more preferred, alkyl groups having 1 to 6 carbon atoms are even more preferred, and alkyl groups having 1 to 3 carbon atoms are particularly preferred. A The alkyl group may have a straight chain, branched chain or cyclic chain structure. R AThe aryl group that can be taken as R is not particularly limited, and examples thereof include the aryl groups of the substituent Z described below. Among these, an aryl group having 6 to 18 carbon atoms is more preferred, an aryl group having 6 to 14 carbon atoms is even more preferred, and an aryl group having 6 to 10 carbon atoms is particularly preferred. A The aryl group may be either monocyclic or polycyclic. As will be described later, R 1 The above groups that can be taken as R 2 may form a ring together with the following groups which may be taken as

[0026] In the general formula [1], R 2 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a carboxyalkyl group, an aminoalkyl group, an amidoalkyl group, an arylalkyl group or a heteroarylalkyl group, and is preferably a hydrogen atom, an alkyl group or a carboxyalkyl group.

[0027] R 2 The alkyl group that can be used as R may be any unsubstituted alkyl group, and examples thereof include the alkyl groups of the substituent Z described below. Among these, alkyl groups having 1 to 12 carbon atoms are more preferred, alkyl groups having 1 to 6 carbon atoms are even more preferred, and alkyl groups having 1 to 4 carbon atoms are particularly preferred. 2 The alkyl group may have a straight chain, branched chain or cyclic chain structure.

[0028] R 2 The hydroxyalkyl group that can be used as R is an alkyl group having at least one hydroxy group. 2Examples include groups in which at least one hydroxy group has been introduced into the above alkyl groups which can take the form of: The number of hydroxy groups in the hydroxyalkyl group is not particularly limited and can be, for example, 1 to 4, but is preferably 1. The position at which the hydroxy group is introduced (the position of the carbon atom forming the alkyl group) is not particularly limited, and the hydroxy group can be introduced into a carbon atom from the 1-position (the carbon atom bonded to the α-carbon atom) to the n-position (n indicates the number of carbon atoms in the alkyl group) relative to the α-carbon atom. The hydroxy group is preferably introduced into the terminal of the alkyl group.

[0029] R 2 The carboxyalkyl group that can be used as R is an alkyl group having at least one carboxy group. 2 Examples include groups in which at least one carboxy group has been introduced into the above alkyl groups which can take the form of: The number of carboxy groups in the carboxyalkyl group is not particularly limited and can be, for example, 1 to 4, but is preferably 1. The position at which the carboxy group is introduced (the position of the carbon atom forming the alkyl group) is not particularly limited, and the carboxy group can be introduced into a carbon atom from the 1st position (the carbon atom bonded to the α carbon atom) to the nth position (n indicates the number of carbon atoms in the alkyl group) relative to the α carbon atom. The carboxy group is preferably introduced into the terminal of the alkyl group.

[0030] R 2 The aminoalkyl group that can be used as R is an alkyl group having at least one amino group. 2 Examples of the amino group include the above alkyl groups having at least one amino group introduced therein. 1The amino group may be the same as the amino group described above, and the preferred ones are also the same. The number of amino groups that the aminoalkyl group has is not particularly limited, and can be, for example, 1 to 4, but is preferably 1. The position at which the amino group is introduced (the position of the carbon atom forming the alkyl group) is not particularly limited, and the amino group can be introduced at the carbon atom from the 1st position (the carbon atom bonded to the α carbon atom) to the nth position (n indicates the number of carbon atoms in the alkyl group) relative to the α carbon atom. The amino group is preferably introduced at the terminal of the alkyl group.

[0031] R 2 The amido alkyl group that can be used as R may be an alkyl group having at least one amido group. 2 The amide group may be any of the above alkyl groups having at least one amide group introduced therein. B )2 and R B As for the above R A The same can be mentioned as above, and preferred examples are also the same. The number of amide groups that the amide alkyl group has is not particularly limited, and can be, for example, 1 to 4, but is preferably 1. The position at which the amide group is introduced (the position of the carbon atom forming the alkyl group) is not particularly limited, and the amide group can be introduced at the carbon atom from the 1st position (the carbon atom bonded to the α carbon atom) to the nth position (n indicates the number of carbon atoms in the alkyl group) relative to the α carbon atom. The amide group is preferably introduced at the terminal of the alkyl group.

[0032] R 2 The arylalkyl group that can be used as R is an alkyl group having at least one aryl group. 2 Examples of the aryl group include the above alkyl groups having at least one aryl group introduced therein. AThe aryl group may be the same as the aryl group described above, and the preferred ones are also the same. The number of aryl groups in the arylalkyl group is not particularly limited, and can be, for example, 1 to 3, but is preferably 1. The position at which the aryl group is introduced (the position of the carbon atom forming the alkyl group) is not particularly limited, and the aryl group can be introduced at the carbon atom from the 1st position (the carbon atom bonded to the α carbon atom) to the nth position (n indicates the number of carbon atoms in the alkyl group) relative to the α carbon atom. The aryl group is preferably introduced at the terminal of the alkyl group.

[0033] R 2 The heteroarylalkyl group that can be used as R is an alkyl group having at least one heteroaryl group. 2 Examples of the heteroaryl group include groups in which at least one heteroaryl group is introduced into the above alkyl group. The heteroaryl group is not particularly limited, and examples include aromatic heterocyclic groups in the heterocyclic group of the substituent Z described below. Of these, heteroaryl groups having 5 to 17 carbon atoms are preferred, and 5- or 6-membered heteroaryl groups having at least one heteroatom (e.g., oxygen atom, nitrogen atom) as a ring-constituting atom are more preferred. The heteroaryl group may be monocyclic or polycyclic. The number of heteroaryl groups in the heteroarylalkyl group is not particularly limited, and can be, for example, 1 to 3, with 1 being preferred. The position at which the heteroaryl group is introduced (the position of the carbon atom forming the alkyl group) is not particularly limited, and can be introduced into a carbon atom from the 1st position (the carbon atom bonded to the α carbon atom) to the nth position (n indicates the number of carbon atoms in the alkyl group) relative to the α carbon atom. The heteroaryl group is preferably introduced at the terminal of the alkyl group.

[0034] In the general formula [1], R 1 and R 2 and may be bonded to form a 5- or 6-membered heterocyclic group. As the 5- or 6-membered heterocyclic group, R 1and examples thereof include a 5- or 6-membered aliphatic heterocyclic group in the heterocyclic group of the substituent Z described below, such as a pyrrolidine ring group, a tetrahydrofuran ring group, a piperidine ring group, and a tetrahydropyran ring group.

[0035] The compound represented by the general formula [1] may have a substituent. The substituent that this compound may have is not particularly limited, and examples thereof include the substituent Z described below.

[0036] (α-amino acid) The α-amino acid used in the production method of the present invention is R 2 CH(N(R A )2) A compound represented by COOH, R 2 is R in the general formula [1] 2 is the same as R A is the R of the amino group A It is the same as R 2 and N may be bonded to form a heterocycle. The α-amino acid may have a carboxy group or a hydroxy group as a substituent, but preferably does not have a sulfur atom. Examples of α-amino acids include various known α-amino acids, and among these, glycine, alanine, valine, leucine, isoleucine, proline, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, phenylalanine, serine, tyrosine, threonine, tryptophan, etc. are preferred. In the present invention, when the α-carbon atom of an α-amino acid or an α-hydroxy acid is an asymmetric carbon atom, unless otherwise specified, the α-amino acid, α-hydroxy acid, and specific compounds thereof all include racemic forms (RS mixtures), R forms, and S forms with respect to the α-carbon atom. The structural formulas of some specific examples of α-amino acids are shown below.

[0037] [ka]

[0038] (α-hydroxy acid) The α-hydroxy acid used in the production method of the present invention is R 2 CH(OH)G A is a compound represented by R 2 is R in the general formula [1] 2 is the same as G A represents the above-mentioned acid group, and a carboxy group is preferred. 2 and O may be bonded to form a heterocycle. The α-hydroxy acid may further have a carboxy group or a hydroxy group as a substituent, but preferably does not have a sulfur atom. Examples of α-hydroxy acids include compounds in which the amino group in various known α-amino acids is replaced with a hydroxy group, such as glycolic acid, lactic acid, 2-hydroxyisovaleric acid (2-hydroxy-3-methylbutyric acid), leucic acid (2-hydroxyisocaproic acid / 2-hydroxy-4-methylvaleric acid), 2-hydroxy-3-methylvaleric acid, 2-tetrahydrofuroic acid (tetrahydrofuran-2-carboxylic acid), 3-methylmalic acid (2-hydroxy-3-methylsuccinic acid / 2-hydroxy-3-methylbutanedioic acid), 2-hydroxyglutaric acid (2-hydroxypentanedioic acid), malic acid, and tartaric acid. The structural formulas of some specific examples of α-hydroxy acids are shown below.

[0039] [ka]

[0040] - Substituent Z - Alkyl groups (preferably alkyl groups having 1 to 20 carbon atoms, for example, methyl, ethyl, isopropyl, t-butyl, pentyl, heptyl, 1-ethylpentyl, benzyl, 2-ethoxyethyl, 1-carboxymethyl, etc.), alkenyl groups (preferably alkenyl groups having 2 to 20 carbon atoms, for example, vinyl, allyl, oleyl, etc.), alkynyl groups (preferably alkynyl groups having 2 to 20 carbon atoms, for example, ethynyl, butadiynyl, phenylethynyl, etc.), cycloalkyl groups (preferably cycloalkyl groups having 3 to 20 carbon atoms, for example, cyclopropyl, cyclopentyl, etc.), In the present specification, alkyl groups generally include cycloalkyl groups, but will be described separately here), aryl groups (preferably aryl groups having 6 to 26 carbon atoms, for example, phenyl, 1-naphthyl, 4-methoxyphenyl, 2-chlorophenyl, 3-methylphenyl, etc.), heterocyclic groups (preferably heterocyclic groups having 2 to 20 carbon atoms, more preferably 5- or 6-membered heterocyclic groups having at least one oxygen atom, sulfur atom or nitrogen atom as a ring-constituting atom. Heterocyclic groups include aromatic heterocyclic groups and aliphatic heterocyclic groups. Aliphatic heterocyclic groups are included, for example, tetrahydropyran ring groups, tetrahydrofuran ring groups, 2-pyridyl, 4-pyridyl, 2-imidazolyl, 2-benzimidazolyl, 2-thiazolyl, 2-oxazolyl, pyrrolidone groups, etc.), alkoxy groups (preferably alkoxy groups having 1 to 20 carbon atoms, for example, methoxy, ethoxy, isopropyloxy, benzyloxy, etc.), aryloxy groups (preferably aryloxy groups having 6 to 26 carbon atoms, for example, phenoxy, 1-naphthyloxy, 3-methylphenoxy, 4-methoxyphenoxy, etc.), heterocyclic oxy groups (the above-mentioned a group in which an -O- group is bonded to a heterocyclic group), an alkoxycarbonyl group (preferably an alkoxycarbonyl group having 2 to 20 carbon atoms, for example, ethoxycarbonyl, 2-ethylhexyloxycarbonyl, dodecyloxycarbonyl, etc.), an aryloxycarbonyl group (preferably an aryloxycarbonyl group having 7 to 26 carbon atoms, for example, phenoxycarbonyl, 1-naphthyloxycarbonyl, 3-methylphenoxycarbonyl, 4-methoxyphenoxycarbonyl, etc.), a heterocyclicoxycarbonyl group (a group in which an -O-CO- group is bonded to the above heterocyclic group), an amino group,Substituted amino groups (preferably alkylamino groups having 1 to 20 carbon atoms, and arylamino groups having 6 to 26 carbon atoms, for example, N,N-dimethylamino, N,N-diethylamino, N-ethylamino, anilino, etc.), sulfamoyl groups (-SO2NH2), substituted sulfamoyl groups (preferably sulfamoyl groups having 1 to 20 carbon atoms, for example, N,N-dimethylsulfamoyl, N-phenylsulfamoyl, etc.), acyl groups (including alkylcarbonyl groups, alkenylcarbonyl groups, alkynylcarbonyl groups, arylcarbonyl groups, and heterocyclic carbonyl groups), and preferably an acyl group having 1 to 20 carbon atoms, such as acetyl, propionyl, butyryl, octanoyl, hexadecanoyl, acryloyl, methacryloyl, crotonoyl, benzoyl, naphthoyl, or nicotinoyl; an acyloxy group (including an alkylcarbonyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, or a heterocyclic carbonyloxy group, preferably an acyloxy group having 1 to 20 carbon atoms, such as acetyloxy, propionyloxy, butyryloxy, octanoyloxy, hexadecanoyloxy, or acryloyloxy); yloxy, methacryloyloxy, crotonoyloxy, nicotinoyloxy, etc.), aryloyloxy groups (preferably aryloyloxy groups having 7 to 23 carbon atoms, for example, benzoyloxy, naphthoyloxy, etc.), carbamoyl groups (preferably carbamoyl groups having 1 to 20 carbon atoms, for example, N,N-dimethylcarbamoyl, N-phenylcarbamoyl, etc.), acylamino groups (preferably acylamino groups having 1 to 20 carbon atoms, for example, acetylamino, benzoylamino, etc.), alkylthio groups (preferably alkylthio groups having 1 to 20 carbon atoms, for example methylthio, ethylthio, isopropylthio, benzylthio, etc.), arylthio groups (preferably arylthio groups having 6 to 26 carbon atoms, for example, phenylthio, 1-naphthylthio, 3-methylphenylthio, 4-methoxyphenylthio, etc.), heterocyclic thio groups (groups in which an -S- group is bonded to the above heterocyclic group), alkylsulfonyl groups (preferably alkylsulfonyl groups having 1 to 20 carbon atoms, for example, methylsulfonyl, ethylsulfonyl, etc.), arylsulfonyl groups (preferably arylsulfonyl groups having 6 to 22 carbon atoms, for example, benzenesulfonyl, etc.),Alkylsilyl groups (preferably alkylsilyl groups having 1 to 20 carbon atoms, for example, monomethylsilyl, dimethylsilyl, trimethylsilyl, triethylsilyl, etc.), arylsilyl groups (preferably arylsilyl groups having 6 to 42 carbon atoms, for example, triphenylsilyl, etc.), alkoxysilyl groups (preferably alkoxysilyl groups having 1 to 20 carbon atoms, for example, monomethoxysilyl, dimethoxysilyl, trimethoxysilyl, triethoxysilyl, etc.), aryloxysilyl groups (preferably aryloxysilyl groups having 6 to 42 carbon atoms, for example, triphenyloxysilyl, etc.), phosphite groups (-OPH(=O)(-OH)), substituted phosphite groups (preferably phosphite groups having 1 to 20 carbon atoms, for example, -OP(=O)(-OH)(R, P )), a phosphoryl group (-OPH2(=O)), a substituted phosphoryl group (preferably a phosphate group having 1 to 20 carbon atoms, for example, -OP(=O)(R P )2), a phosphonyl group (preferably a phosphonyl group having 1 to 20 carbon atoms, for example, —P(═O)(R P )2), a phosphinyl group (-PH2), a substituted phosphinyl group (preferably a phosphinyl group having 1 to 20 carbon atoms, for example, -P(R P )2), a phosphonic acid group (—PO(OH)2), a substituted phosphonic acid group (preferably a phosphonic acid group having 1 to 20 carbon atoms, for example, —PO(OR P ) 2), sulfo group (sulfonic acid group), carboxy group, hydroxy group, sulfanyl group, cyano group, halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom, etc.). P is a substituent (preferably a group selected from the substituent Z). Furthermore, each of the groups listed as the substituent Z may be further substituted with the above-mentioned substituent Z.

[0041] <Heavy water> In the production method of the present invention, heavy water is used as a deuterium source. As described above, the heavy water is preferably DO. A mixture of heavy water with water (heavy water with a purity of less than 100%) can also be used, and the content of heavy water in the mixture (purity of heavy water) is appropriately determined taking into consideration the amount of heavy water supplied, which will be described later, and can be, for example, 40 mol % or more. In the present invention, deuterium oxide can be used as a mixture with a solvent, but it is preferable that the mixture does not contain a solvent. Specifically, it is preferable to flow the substrate, etc., at least through the catalyst-packed region in the absence of a solvent. In the present invention, "no solvent (in the absence of a solvent)" includes an embodiment in which the content (amount present) of the solvent is 0 parts by mass per 100 parts by mass of deuterium oxide when the substrate, etc., is flowed at least through the catalyst-packed region, as well as an embodiment in which the content (amount present) of the solvent is less than 1 part by mass. When a mixture of deuterium oxide and a solvent is used, the content of deuterium oxide in the mixture (purity of deuterium oxide) is appropriately determined taking into account the amount of deuterium oxide supplied, as described below, and can be, for example, 50% by mass or more. The solvent is not particularly limited as long as it does not inhibit the deuteration reaction, and examples thereof include alcohol solvents, general organic solvents (e.g., hydrocarbon solvents, ester solvents, aromatic solvents), and deuterated solvents thereof. Only one solvent or two or more solvents may be used.

[0042] <Hydrogen gas or deuterium gas> In the production method of the present invention, hydrogen gas or deuterium gas is usually used as the hydrogen source for activating the catalyst described below, but hydrogen gas and deuterium gas can also be used in combination. The hydrogen gas or deuterium gas used in the production method of the present invention is not particularly limited, and ordinary hydrogen gas or deuterium gas can be used. By using hydrogen gas or deuterium gas in combination with the substrate and heavy water, the deuteration reaction can be carried out while suppressing a decrease in catalytic activity. Hydrogen gas or deuterium gas can also be used in combination with an inert gas that does not reduce catalytic activity, such as nitrogen gas or a rare earth gas. When a mixed gas of hydrogen gas or deuterium gas with an inert gas is used, the content of hydrogen gas or deuterium gas in the mixed gas is not particularly limited, and from the viewpoint of sufficiently activating the catalyst, it is preferably 0.1% (volume basis) or more, more preferably 1% (volume basis) or more, and even more preferably 5% (volume basis) or more.

[0043] <Catalyst> The (heterogeneous) catalyst used in the production method of the present invention is a catalyst containing at least one of a ruthenium catalyst and a rhodium catalyst. In terms of the reactivity of the deuteration reaction (e.g., reaction temperature, reaction time, deuteration rate), the catalyst preferably contains a ruthenium catalyst, and is more preferably a ruthenium catalyst. In the present invention, the catalyst containing a ruthenium catalyst includes two embodiments: a mode in which a ruthenium catalyst is used alone, and a mode in which a mixed catalyst containing a ruthenium catalyst and a rhodium catalyst or another catalyst is used. The content of the ruthenium catalyst in the mixed catalyst is not particularly limited and can be appropriately determined taking into consideration the reactivity of the deuteration reaction, etc., and can be, for example, 50 mass% or more of the mixed catalyst.

[0044] (Ruthenium catalyst) The ruthenium catalyst includes those in which the valence of the ruthenium atom is usually 0 to 8, preferably 0, and specific examples include ruthenium metal, ruthenium compounds, and ruthenium complexes. The ruthenium metal may be the metal itself or ruthenium metal immobilized on a support. Any known support used in this field can be used, including, for example, carbon materials (carbon) such as activated carbon, alumina, silica, zeolite, diatomaceous earth, molecular sieves, silk, polymers, and ion exchange resins. Specific examples of the catalyst in which ruthenium metal is immobilized on a support include ruthenium carbon, ruthenium alumina, and ruthenium silica, in which ruthenium is supported on a carbon material (carbon), alumina, or silica, and ruthenium carbon is more preferred. Examples of ruthenium compounds include ruthenium hydroxide, ruthenium dioxide, ruthenium tetroxide, ruthenium chloride, and ruthenium acetate. Examples of ruthenium complexes include RuCl2(PPh3)3, which has triphenylphosphine as a ligand. Ruthenium compounds and ruthenium complexes immobilized on the above supports can also be used. The ruthenium catalyst preferably contains ruthenium metal, more preferably contains ruthenium carbon, and more preferably is ruthenium carbon.

[0045] (Rhodium catalyst) The rhodium catalyst includes those in which the valence of the rhodium atom is usually 0 to 3, preferably 0, and specific examples include rhodium metal, rhodium compounds, and rhodium complexes. The rhodium metal may be the metal itself or rhodium metal immobilized on the above-mentioned carrier. Specific examples of the catalyst in which rhodium metal is immobilized on a carrier include rhodium carbon, rhodium alumina, and rhodium silica, in which rhodium is supported on a carbon material (carbon), alumina, or silica, and rhodium carbon is more preferred. Examples of rhodium compounds include rhodium oxide, rhodium chloride, and rhodium acetate. Examples of rhodium complexes include RhCl(PPh3)3, which has triphenylphosphine as a ligand. Rhodium compounds and rhodium complexes immobilized on the above-mentioned carriers can also be used. The rhodium catalyst preferably contains rhodium metal, more preferably contains rhodium carbon, and more preferably is rhodium carbon.

[0046] In the catalyst fixed on the carrier, the content of ruthenium metal or rhodium metal is not particularly limited, but is preferably 0.5 to 50 mass % and more preferably 1 to 20 mass % relative to the total mass of the catalyst fixed on the carrier.

[0047] (Other catalysts) Examples of the other catalysts include ruthenium catalysts and rhodium catalysts, as well as catalysts described in Patent Document 1 and Non-Patent Documents 1 and 2. For other catalysts, reference can be made to these documents as appropriate, and the contents thereof are incorporated herein in their entirety as part of the present specification.

[0048] In the present invention, the catalyst includes not only an embodiment using at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst (catalyst only), but also an embodiment using at least one catalyst as a mixture with a component that does not have catalytic activity. Examples of the component that does not have catalytic activity include components that do not inhibit the deuteration reaction and do not react with (heavy) hydrogen gas, such as boron nitride, alumina, and diatomaceous earth (including celite). Examples of the mixture of at least one catalyst and a component that does not have catalytic activity include a mixture of a catalyst and a component that does not have catalytic activity in an appropriate combination, such as a mixture of a ruthenium catalyst and / or a rhodium catalyst with boron nitride. The mixing ratio (mass ratio) of the at least one catalyst (including a support) and the component that does not have catalytic activity is not particularly limited and may be set appropriately, but may be, for example, 1:0.1 to 10.

[0049] <base> In the production method of the present invention, when the substrate, etc., is circulated through at least the catalyst-packed region, a base is not present, for example, by actively circulating the base or by mixing the base with the catalyst and packing the base (the substrate, etc., is circulated through at least the catalyst-packed region in the absence of a base). As described above, the production method of the present invention performs the deuteration reaction in a flow system, so that the deuteration reaction occurs and progresses rapidly even without the coexistence of a base, and is completed while maintaining the three-dimensional structure of the substrate. In the present invention, "in the absence of a base" includes an embodiment in which the amount of base present is 0 mol per 1 mol of substrate when the substrate, etc., is circulated through at least the catalyst-packed region, as well as an embodiment in which the amount of base present is 0.1 mol or less. The base that can be present may be one type only, or two or more types. The base may be an inorganic base or an organic base. Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and cesium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal phosphates such as sodium phosphate, disodium hydrogen phosphate, potassium phosphate, and dipotassium hydrogen phosphate. Examples of the organic base include alkali metal organic acid salts such as sodium acetate, potassium acetate, sodium propionate, and potassium propionate; alkali metal alkoxides such as sodium methoxide and potassium methoxide; tertiary amine compounds such as trimethylamine, triethylamine, ethyldiisopropylamine, diethylisopropylamine, triisopropylamine, benzyldimethylamine, and benzyldiethylamine; and pyridine compounds such as pyridine, methylpyridine, and dimethylpyridine.

[0050] <Other ingredients> In the production method of the present invention, components that do not fall under any of the substrate, heavy water, (heavy) hydrogen gas, catalyst, base, and solvent (other components) may be used.

[0051] [Production method of the present invention] As described above, the production method of the present invention is a flow deuteration method in which an α-amino acid or an α-hydroxy acid, heavy water, and hydrogen gas or deuterium gas are flowed in the absence of a base through a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst, thereby carrying out a deuteration reaction of the α-amino acid or the α-hydroxy acid.

[0052] <Manufacturing equipment> In the production method of the present invention, an apparatus equipped with a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst is usually used. The apparatus for carrying out the production method of the present invention is not particularly limited as long as it can carry out a flow reaction, and various flow reactor apparatuses can be used, for example, a deuteration apparatus shown in FIG. The deuteration apparatus 1 shown in FIG. 1 includes a flow path having a catalyst-filled region 2 filled with a catalyst, i.e., a catalyst cartridge 2 in FIG. 1; a substrate solution supply path 3 connected to the catalyst-filled region 2 and transporting and supplying a mixture of a substrate and heavy water (substrate solution); a (heavy) hydrogen gas supply path 4 connected to the catalyst-filled region 2 and transporting and supplying (heavy) hydrogen gas; a pump attached to the substrate solution supply path 3, i.e., a syringe pump 3A in FIG. 1; a reaction solution transfer path 5 connected to the end of the catalyst-filled region 2 opposite to the above-mentioned supply paths 3 and 4 and transporting a reaction solution; and a heater (not shown in FIG. 1) for heating the catalyst-filled region 2.

[0053] In the deuteration apparatus 1, the supply channels 3 and 4 are each independently connected to the catalyst-filled region 2 on the opposite side (upstream side) of the catalyst-filled region 2 with respect to the reaction solution transfer channel 5, and a substrate solution reservoir and a (heavy) hydrogen gas cylinder (neither of which are shown in FIG. 1) are connected and arranged on the upstream side (opposite the catalyst-filled region 2) of each supply channel. In the deuteration apparatus 1, the catalyst filling region 2, the supply channels 3 and 4, the reaction liquid transfer channel 5, the pump 3A, and the like are not particularly limited and may be any commonly used components. The deuteration apparatus 1 may further include a device for realizing the reaction conditions set in the catalyst-filled region 2, such as a pressurizer. An apparatus suitable for use in the production method of the present invention, which will be described later and in which heavy water is recovered and reused, is not particularly limited, and an example thereof is a deuteration apparatus having a configuration in which a heavy water recovery apparatus is provided downstream of the reaction solution transfer path 5 in the deuteration apparatus 1 shown in FIG. 1, and the heavy water separated and recovered by this heavy water recovery apparatus is connected to a substrate solution preparation apparatus (not shown in FIG. 1).

[0054] <Deuteration reaction step> The deuteration reaction step in the production method of the present invention is a step in which an α-amino acid or an α-hydroxy acid, heavy water, and (heavy) hydrogen gas are passed through a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst in the absence of a base, thereby reacting the α-amino acid or the α-hydroxy acid with the heavy water. Specifically, when the deuteration apparatus 1 is used, the substrate solution is supplied from the substrate solution supply channel 3 by the pump 3A, and the (heavy) hydrogen gas is supplied from the (heavy) hydrogen gas supply channel 4 to the catalyst cartridge 2, respectively, and the substrate and heavy water are reacted while they are circulated.

[0055] The amount of the substrate supplied (used) is preferably 1 to 1000 mol, more preferably 1 to 100 mol, per mol of the catalyst (excluding the carrier and converted into metal elements) filled in the catalyst cartridge 2. The amount of heavy water supplied (used) can be 1 mol or more per mol of α-hydrogen atoms contained in the substrate, but from the viewpoint of the deuteration rate, it is preferably 10 mol or more, more preferably 100 mol or more, and even more preferably 1000 mol or more. The upper limit of the amount of heavy water supplied is not particularly limited, and as an example, it can be 10,000 mol or less, preferably 5,000 mol or less, per mol of α-hydrogen atoms. The amount of (heavy) hydrogen gas supplied (used) is not particularly limited as long as it can promote and restore catalytic activity, and is, for example, preferably 1 to 1000 mol, more preferably 1 to 500 mol, per mol of catalyst (calculated as metal element excluding the support). When a substrate solution is used in the deuteration reaction step, the concentration of the substrate in the substrate solution is not particularly limited and can be appropriately set in consideration of the solubility of the substrate, the type or amount of catalyst used, the above-mentioned supply amount of substrate or heavy water, etc., and is preferably set so as to satisfy the above-mentioned supply amount of substrate and / or heavy water. The concentration of the substrate in the substrate solution can be, for example, 1 to 5000 mmol / L (mM), and from the viewpoint of reactivity, it is preferably 5 to 1000 mmol / L, and more preferably 10 to 500 mmol / L.

[0056] The supply rates of the substrate, heavy water, and (heavy) hydrogen gas cannot be uniquely set because they vary depending on the reaction scale, the inner diameter of the flow channel (catalyst-filled region), etc., and can be set appropriately depending on the supply amounts of the substrate, heavy water, or (heavy) hydrogen gas, the reaction time, etc. As an example of each supply rate, the following ranges can be mentioned. The supply rate of heavy water can be, for example, 0.01 to 1000 mL / min, and preferably 0.01 to 100 mL / min. The supply rate of the substrate is not particularly limited, but it is preferable to set the supply rate of the substrate and the supply rate of heavy water in consideration of the supply amount so that the supply times are the same. The supply rate of (heavy) hydrogen gas can be, for example, 1 to 30 mL / min, and preferably 1 to 20 mL / min. When a substrate solution is used in the deuteration reaction step, the supply rate of the substrate solution is not particularly limited and can be appropriately set in consideration of the solubility of the substrate, the type or amount of catalyst used, the above-mentioned supply rate of the substrate or heavy water, etc., and is preferably set so as to satisfy the above-mentioned supply rate of the substrate or heavy water. The supply rate of the substrate solution can be, for example, 0.001 to 100 mL / min, and preferably 0.01 to 10 mL / min.

[0057] The reaction conditions in the catalyst-filled region are not particularly limited as long as the deuteration reaction of the substrate proceeds, and can be set appropriately. For example, the reaction temperature is preferably 50° C. or higher, and more preferably 60° C. or higher, and even more preferably 65° C. or higher, in that the reaction time can be further shortened while realizing high stereoselectivity. The upper limit temperature can be set to, for example, 300° C. or lower, and is preferably 150° C. or lower, more preferably 120° C. or lower, and is more preferably 90° C. or lower, and particularly preferably 85° C. or lower, in that a high deuteration rate can be achieved in a short reaction time. Because the production method of the present invention is a flow method, a high deuteration rate can be achieved, and the reaction time can be set significantly shorter than the reaction time in a batch-type deuteration reaction. The reaction time is appropriately determined depending on the amount and rate of supply of the substrate solution, etc., the flow path length of the catalyst-filled region, etc., and can be, for example, 10 seconds to 3 hours, and preferably 1 minute to 1 hour. In the present invention, the reaction time refers to the time required for the substrate solution (substrate and heavy water) supplied to the catalyst-filled region to pass through the catalyst-filled region, and does not refer to the time from the start to the end of supply of the substrate solution (the implementation time of the deuteration reaction step). The pressure in the catalyst-filled region is not particularly limited and may be open (atmospheric pressure) or pressurized, and can be set appropriately depending on the feed rate of the substrate solution, etc. For example, 1 to 1 × 10 7 It can be Pa.

[0058] In the deuteration reaction step, as described above, when the substrate solution and (heavy) hydrogen gas are supplied to the catalyst-packed region, the deuteration reaction of the substrate is rapidly initiated and promoted by the catalyst while flowing through the catalyst-packed region. The substrate solution flowing through the catalyst-packed region may be in the form of a liquid or gas, as long as it comes into contact with the catalyst and is subjected to catalytic action. In this way, an exchange reaction between the α-hydrogen atom of the substrate and the deuterium atom of the heavy water proceeds, yielding a reaction solution containing a substrate whose α-hydrogen atom has been deuterated (deuterated compound) and hydrogenated heavy water (e.g., HDO). Deuterated compounds will be described later.

[0059] <Other processes> The production method of the present invention may include steps other than the deuteration reaction step (referred to as "other steps"). Examples of the other steps include a separation step or purification step of the deuterated compound obtained by the deuteration reaction, a catalyst activation step or regeneration step, and a cleaning step of the catalyst-packed region (a recovery step of the deuterated compound remaining in the catalyst-packed region).

[0060] [Deuterated compounds] The deuterated compound (deuterated compound) obtained by the production method of the present invention is a compound in which all or some of the α-hydrogen atoms in the above-mentioned substrate are deuterated. Examples thereof include the compounds described above as α-amino acids or α-hydroxy acids, preferably compounds in which deuterium atoms have been introduced (substituted) into the α-carbon atoms of the compounds represented by the above general formula [1], specifically, compounds represented by the following general formula [1D], and the compounds synthesized in the Examples. [ka]

[0061] In the general formula [1D], R 1 represents a hydroxy group or an amino group, and R in the above general formula [1] 1 In the general formula [1D], R 2 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a carboxyalkyl group, an aminoalkyl group, an amidoalkyl group, an arylalkyl group, or a heteroarylalkyl group, and R in the above general formula [1] 2 is the same as R 2 Depending on the conditions of the deuteration reaction process, R may take on a deuterium atom. 1 and R 2 Similarly, in the general formula [1D], R 1 and R 2 may be bonded to form a 5- or 6-membered heterocyclic group. The structure of the deuterated compound obtained by the production method of the present invention can be identified by known structural analysis methods and analytical methods for organic compounds. Examples of known structural analysis methods and analytical methods include nuclear magnetic resonance spectroscopy (1 H-NMR, 13 Examples of the methods include C-NMR, infrared absorption spectroscopy (IR), mass spectrometry, elemental analysis, high performance liquid chromatography (HPLC), and combinations thereof.

[0062] [The manufacturing method of the present invention that recovers and reuses heavy water] In the production method of the present invention, the heavy water used in the deuteration reaction step can be recovered and reused in another deuteration reaction step. The production method of the present invention in which heavy water is recovered and reused (hereinafter, may be referred to as one embodiment of the production method of the present invention) is a method for producing a deuterated compound in which the α-hydrogen atom of an α-amino acid or an α-hydroxy acid is deuterated while recovering and reusing heavy water, and is a continuous-flow deuteration method in which steps 1 to 3 described below are performed in this order or simultaneously. In the present invention, as described above, the term "continuous flow deuteration method" refers to a method in which the deuteration reactions in steps 1 and 3 are continuously carried out by supplying a substrate, heavy water, and (heavy) hydrogen gas to a flow path in which a catalyst is placed, and does not refer to continuous carrying out of steps 1 to 3. In addition, in the present invention, "performing steps in order" means the temporal order in which an earlier step and a later step are performed, and also includes a case in which another step is performed between an earlier step and a later step.

[0063] One embodiment of the production method of the present invention includes an embodiment in which, as a continuous cycle reaction, steps 1 and 2 are performed in this order or simultaneously, and then steps 3 and 2 are repeated in this order or simultaneously, with steps 3 and 2 constituting one cycle. Another embodiment of the production method of the present invention includes an embodiment in which, as a continuous circulation reaction, heavy water recovered from the reaction solution obtained in step 1 is circulated while a continuous reaction is carried out (an embodiment in which steps 1 to 3 are carried out simultaneously). In the present invention, each step may be performed once or may be repeated multiple times.

[0064] Step 1: A step of reacting an α-amino acid or an α-hydroxy acid with heavy water (unused heavy water), and hydrogen gas or deuterium gas in the absence of a base by flowing the α-amino acid or α-hydroxy acid with heavy water through a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst. Step 2: A step of recovering heavy water from the reaction solution obtained in Step 1 Step 3: A step of flowing an α-amino acid or an α-hydroxy acid, the heavy water recovered in Step 2, and hydrogen gas or deuterium gas through the flow path in the absence of a base to react the α-amino acid or the α-hydroxy acid with the recovered heavy water.

[0065] Unused heavy water refers to heavy water that has not been used in the method for producing a deuterated compound of the present invention. On the other hand, recovered heavy water (recovered heavy water) refers to heavy water recovered in step 2 from the reaction solution of the reaction specified in step 1 or step 3 above, and includes heavy water containing DO and heavy water in which deuterium atoms have been partially hydrogenated (e.g., HDO, HTO). The recovered heavy water can suppress a decrease in the deuteration rate of the substrate in the subsequent deuteration reaction in step 3, and as a result, can be suitably reused in step 3 of the production method of the present invention. The purity of the heavy water in the recovered heavy water and the type or content of impurities are not particularly limited. The recovered heavy water used in step 3 can be appropriately mixed with unused heavy water depending on the content of heavy water, the reaction efficiency of the deuteration rate reaction, and the like.

[0066] In the continuous cycle reaction method, the above steps 1 and 2 can be carried out in this order or simultaneously, and then the following step 3 for the nth time and step 2 for the (n+1)th time can be carried out in this order or simultaneously. Note that the "step 3 for the first time" here means the same step as the above step 3. n-th step 3: A step of flowing an α-amino acid or an α-hydroxy acid, the heavy water recovered in the n-th step 2, and hydrogen gas or deuterium gas through the flow channel in the absence of a base to react the α-amino acid or the α-hydroxy acid with the recovered heavy water. Step 2 of the n+1th time: A step of recovering heavy water from the reaction solution obtained in Step 3 of the nth time Here, n is an integer of 1 or more, and the upper limit is determined appropriately. In the above "nth step 3," it is specified that the heavy water recovered in the nth step 2 is reused. However, in the present invention, heavy water recovered up to that point, for example, heavy water recovered in any one of the 1st to nth steps 2 or in multiple steps 2, can be reused.

[0067] In the present invention, the substrate used in step 1 and the substrate used in step 3 may be the same or different, and the substrate used in step 1 or step 3 may be a substrate that has already been partially deuterated. Furthermore, the channel (catalyst-filled region) used in step 1 and the channel used in step 3 may be the same or different. By repeatedly performing step 3 and step 2 using the reaction solution obtained in step 3 (continuous cycle reaction method), the reusable recovered heavy water can be repeatedly reused, and while suppressing a decrease in the deuteration rate, the method can be applied to industrial production and further reduce production costs.

[0068] <Process 1> Step 1 in one embodiment of the production method of the present invention is the same as the deuteration reaction step in the production method of the present invention described above.

[0069] <Process 2> Step 2 is a step of recovering heavy water from the reaction solution obtained in the deuteration reaction of Step 1, and recovers heavy water that can suppress a decrease in the deuteration rate from the reaction solution obtained in Step 1. The method for recovering heavy water from the reaction solution is not particularly limited, and known separation methods such as distillation, recrystallization, liquid separation, and membrane separation (separation using a microfiltration membrane, an ultrafiltration membrane, a reverse osmosis membrane, or the like) can be applied. The recovered heavy water contains hydrogenated heavy water and unreacted heavy water, etc. Since the recovered heavy water usually contains an excess of unreacted heavy water, even if it is reused in the deuteration reaction in step 3, a decrease in the deuteration rate due to the coexisting hydrogenated heavy water, etc. can be suppressed.

[0070] <Process 3> Step 3 is a step (second cycle deuteration reaction) in which the substrate is subjected to a deuteration reaction using the recovered heavy water recovered in Step 2 and used in the deuteration reaction in Step 1. The substrate, recovered heavy water, and (heavy) hydrogen gas are circulated through a flow path filled with the catalyst, and the substrate reacts with the heavy water in the recovered heavy water. Step 3 is the same as Step 1 except that recovered heavy water is used, and the reaction conditions are the same as those described in the deuteration reaction step in the production method of the present invention. The reaction conditions in Step 3 may be the same as or different from the reaction conditions in Step 1. In this way, by carrying out steps 1 and 2 of the first cycle and step 3 (corresponding to step 1 of the second cycle), a reaction solution containing a deuterated compound and hydrogenated heavy water is obtained. The deuterated compound is as described above.

[0071] The reaction mixture obtained in step 3 is preferably subsequently subjected to step 2 (step 2 of the second cycle) to isolate the deuterated compound and recover heavy water. The recovered heavy water can be used in the second step 3 (the third cycle of the deuteration reaction). By repeating steps 3 and 2 in this manner, multiple cycles of the substrate deuteration reaction can be carried out while recovering and reusing heavy water. In this case, the recovered heavy water contains an excess of unreacted heavy water, so a decrease in the deuteration rate can be suppressed. Steps 3 and 2 from the second cycle onwards can be repeated in this order. Alternatively, steps 3 and 2 can be carried out simultaneously in parallel, with heavy water being recovered in step 2 and supplied to the catalyst-filled region 2 to carry out the deuteration reaction in step 3 (continuous recovery and reaction of heavy water). Furthermore, steps 1 to 3 can be carried out simultaneously. For example, heavy water can be recovered from the reaction solution produced while carrying out step 1 (step 2) and then the recovered heavy water can be used to carry out step 3, or heavy water recovered from the reaction solution produced while carrying out step 1 (step 2) can be reacted again (step 3). If the heavy water content in the heavy water recovered in step 2 of the second cycle or later (the purity of the heavy water in the recovered heavy water) is insufficient, unused heavy water can be added.

[0072] In one embodiment of the manufacturing method of the present invention, the above-mentioned other steps may also be carried out. [Example]

[0073] The present invention will be described in more detail below based on examples, but the present invention should not be construed as being limited thereby. In the following examples, "parts" and "%" representing compositions are based on mass unless otherwise specified. In the present invention, "room temperature" means 25°C. Furthermore, each operation described below was carried out under normal pressure (1 atm) unless otherwise specified.

[0074] Example I Using α-amino acids as substrates, deuteration reactions were carried out by flow reaction. [Example I-1] 22.3 mg (0.25 mmol) of L-alanine and 10 mL of heavy water were placed in a 30 mL recovery flask to prepare a sample solution (molar concentration of L-alanine / heavy water: 25 mM) as a substrate solution. A catalyst cartridge (φ5 mm × 100 mm, stainless steel) filled with a powder of a homogeneously mixed mixture of 130 mg of 10% ruthenium carbon catalyst (Ru / C) [K type (Ru content 10% by mass) (dry) (N.E. Chemcat Corporation)] and 260 mg of boron nitride (Fujifilm Wako Pure Chemical Industries, Ltd.) (Ru content of the total powder mass was 3.3% by mass, Ru metal amount was 0.13 mmol) was placed in a high-temperature bath (Tokyo Rikakikai Co., Ltd., product name: MCR-1000) heated to 70°C. Next, 5 mL of heavy water was delivered to the catalyst cartridge at a flow rate of 0.1 mL / min for 10 minutes using a syringe pump (YMC, product name: YSP-101), and simultaneously hydrogen gas was delivered to the catalyst cartridge at a flow rate of 2 mL / min using a mass flow controller (FCON, product name: MODEL: C1005-4S2-100-H2) to pre-activate the catalyst.

[0075] After preactivation, the sample solution was pumped through the catalyst cartridge at a flow rate of 0.05 mL / min for 200 minutes while continuing to pump hydrogen gas. The deuteration reaction was carried out. The time required for the deuteration reaction to pass through the area filled with Ru / C powder was 40 minutes. The L-alanine supply rate was 2 mol per mol of Ru metal, the deuterium supply rate was 2200 mol per mol of L-alanine α-hydrogen atoms, and the hydrogen gas supply rate was 140 mol per mol of Ru metal. After the reaction, 5 mL of deuterium oxide was pumped through the catalyst cartridge at a flow rate of 0.05 mL / min, and hydrogen gas was simultaneously pumped through the catalyst cartridge at a flow rate of 2 mL / min to ensure that no reaction solution remained in the catalyst cartridge. Then, 10 mL of water was pumped through the catalyst cartridge at a flow rate of 0.2 mL / min to clean the interior of the catalyst cartridge. The recovered solution (the reaction solution, the deuterium oxide, and the water used for cleaning) was concentrated under reduced pressure and then vacuum-dried for 24 hours. When the mass was measured and (heavy) water was found to remain, 10 mL of ethanol, an azeotropic solvent for water, was added, and the mixture was further concentrated under reduced pressure and vacuum dried again for 24 hours. In this way, L-deuterated alanine having a deuterium atom as the α-hydrogen atom was synthesized. The recovery rate (mass basis) of the obtained product (the total mass of L-deuterated alanine, unreacted L-alanine, and impurities) relative to the mass of L-alanine used in the deuteration reaction was calculated, and the recovery rate was found to be 98%.

[0076] The dried product was dissolved in 1 mL of heavy water, and 0.25 mmol of pyridine-d5 was added as an internal standard. 1 H-NMR was measured and the deuteration ratio was calculated. 1 After H-NMR measurement, the product was concentrated under reduced pressure again, then dissolved in 1 mL of water, and heavy water (approximately 1 mmol) was added. 2 H-NMR was measured to confirm the deuterated peaks. Also, 2The product after H-NMR measurement was concentrated under reduced pressure and labeled using a DL-amino acid labeling kit (Nacalai Tesque), and then the optical purity was calculated by HPLC analysis. Specifically, a reverse-phase column (GL Sciences, product name: InertSustain C18) was used in an HPLC (Shimadzu, product name: SHIMADZU LC-20AD) with a mobile phase of 20% acetonitrile in 0.1% formic acid aqueous solution / 50% acetonitrile in 0.1% formic acid aqueous solution. The mobile phase was a 100:0 to 0:100 gradient of solution A:B, and 1 μL of the resulting reaction solution was injected at a flow rate of 1 mL / min. The optical purity was calculated from the area value detected at 340 nm. The results are shown in Table 1 below. The synthesized L-deuterated alanine was identified as follows. Unlabeled L-alanine and DL-alanine and synthetic L-deuterated alanine 1 H-NMR and 2 H-NMR was measured, and the chemical shifts and HPLC retention times in each chart were compared to confirm their agreement.

[0077] [Example I-2] The deuteration reaction of Example I-2 was carried out in the same manner as in Example I-1, except that the flow rate of the sample solution was changed from 0.05 mL / min to 0.1 mL / min (0.5 times the flow time). The resulting product was identified, and the recovery rate, deuteration rate, and optical purity of the resulting product were calculated in the same manner as in Example I-1. The results are shown in Table 1.

[0078] [Example I-3] The deuteration reaction of Example I-3 was carried out in the same manner as in Example I-1, except that the amount of L-alanine used was changed from 22.3 mg (0.25 mmol) to 11.1 mg (0.125 mmol). The resulting product was identified, and the recovery rate, deuteration rate, and optical purity of the resulting product were calculated in the same manner as in Example 1. The results are shown in Table 1.

[0079] [Example I-4] The deuteration reaction of Example I-4 was carried out in the same manner as in Example I-1, except that the amount of L-alanine used was changed from 22.3 mg (0.25 mmol) to 11.1 mg (0.125 mmol) and the temperature of the high-temperature bath was changed from 70°C to 90°C. The resulting product was identified, and the recovery rate, deuteration rate, and optical purity of the resulting product were calculated in the same manner as in Example I-1. The results are shown in Table 1.

[0080] [Example I-5] The deuteration reaction of Example I-5 was carried out in the same manner as in Example I-1, except that the amount of L-alanine used was changed from 22.3 mg (0.25 mmol) to 11.1 mg (0.125 mmol) and the temperature of the high-temperature bath was changed from 70°C to 100°C. The obtained product was identified in the same manner as in Example I-1, and the recovery rate and deuteration rate of the obtained product were calculated. The results are shown in Table 1. The optical purity of the product obtained in Example I-1 was measured and found to be >99% ee.

[0081] In Table 1 below, "substrate concentration" refers to the substrate concentration of the sample solution, "flow rate" refers to the flow rate of the sample solution, and "Quant." in the recovery rate column indicates that the product was quantitatively recovered after the deuteration reaction. The same applies to Tables 2 to 4 described below.

[0082] [Table 1]

[0083] [Comparative example I-1] A recovery flask was charged with 2 mL of heavy water, 89 mg (1 mmol) of L-alanine, and 36 mg of 5% ruthenium carbon catalyst (Ru / C), and the flask was sealed. The flask was then purged with N2 and H2, and filled with H2 until the pressure reached 1 atmosphere. The flask was then heated to 90°C, and the deuteration reaction was carried out for 12 hours. After the reaction, the flask was returned to room temperature, purged with N2, and the flask was opened to obtain the reaction solution. The reaction mixture was concentrated to give the product. 1 H-NMR was measured to calculate the deuteration rate, which was found to be 40%.

[0084] [Example I-6 and Comparative Examples I-2 to I-4] The deuteration reactions of Example I-6 and Comparative Examples I-2 to I-4 were carried out in the same manner as in Example I-1, except that the 10% ruthenium carbon catalyst (Ru / C) in Example I-1 was changed to a 10% palladium carbon catalyst (Pd / C) [K type (Pd content 10% by mass) (dry) (manufactured by N.E. Chemcat Corporation)] (Comparative Example I-2), a 10% platinum carbon catalyst (Pt / C) [K type (Pt content 10% by mass) (dry) (manufactured by N.E. Chemcat Corporation)] (Comparative Example I-3), a 10% iridium carbon catalyst (Ir / C) [K type (Ir content 10% by mass) (dry) (manufactured by N.E. Chemcat Corporation)] (Comparative Example I-4), or a 10% rhodium carbon catalyst (Rh / C) [K type (Rh content 10% by mass) (dry) (manufactured by N.E. Chemcat Corporation)] (Example I-6). The resulting product was identified, and the recovery rate and deuteration rate were calculated in the same manner as in Example I-1. The results are shown in Table 2 together with the results of Example I-1.

[0085] [Table 2]

[0086] [Examples I-7 to I-11] The deuteration reactions of Examples I-7 to I-11 were carried out in the same manner as in Example 1, except that in Example I-1, 22.3 mg (0.25 mmol) of L-alanine was replaced with 18.8 mg (0.25 mmol) of glycine (Example I-7), 29.3 mg (0.25 mmol) of L-valine (Example I-8), 32.8 mg (0.25 mmol) of L-leucine (Example I-9), 32.8 mg (0.25 mmol) of L-isoleucine (Example I-10), or 28.8 mg (0.25 mmol) of L-proline (Example I-11). The obtained products were identified in the same manner as in Example I-1, and the recovery rate, deuteration rate, and optical purity of the obtained products were calculated. The results are shown in Table 3.

[0087] [Examples I-12 and I-13] The deuteration reactions of Examples I-12 and I-13 were carried out in the same manner as in Example I-1, except that 33.3 mg (0.25 mmol) of L-aspartic acid (Example I-12) or 36.8 mg (0.25 mmol) of L-glutamic acid (Example I-13) was used instead of 22.3 mg (0.25 mmol) of L-alanine in Example I-1, the amount of boron nitride used was changed from 260 mg to 1040 mg, and the size of the catalyst cartridge was changed from φ5 mm × 100 mm to φ10 mm × 100 mm. The obtained products were identified in the same manner as in Example I-1, and the recovery rate, deuteration rate, and optical purity of the obtained products were calculated. The results are shown in Table 3.

[0088] Although not shown in Table 3, the deuterated peaks of L-deuterated valine, L-deuterated leucine, and L-deuterated isoleucine were identified and quantified in the same manner as in Example I-1. As a result, it was found that the peaks derived from deuterium atoms that had substituted hydrogen atoms other than the α-hydrogen atom were in trace amounts, and that hydrogen atoms other than the α-hydrogen atom were almost not deuterated. This confirms that the deuteration reaction according to the production method of the present invention exhibits high regioselectivity.

[0089] [Table 3]

[0090] [Comparative example I-5] The deuteration reaction of Comparative Example I-5 was carried out in the same manner as in Example I-1, except that 32.8 mg (0.25 mmol) of L-leucine and 30 mg (0.75 mmol) of sodium hydroxide were used instead of 22.3 mg (0.25 mmol) of L-alanine. The resulting reaction solution was neutralized with 5M hydrochloric acid, extracted with ethyl acetate, and concentrated to isolate the product. The resulting product was identified in the same manner as in Example I-1, and the recovery rate, deuteration rate, and optical purity of the resulting product were calculated. The total mass of the sodium salt of L-leucine (0.25 mmol) and NaOH (0.5 mmol) was taken as 100% theoretical yield, and the recovery rate was calculated from the difference between this and the actual yield. The resulting yield was 49.2 mg (84% recovery), the deuteration rate of α-hydrogen atoms was 96%, and the optical purity was >99% ee.

[0091] Example II The deuteration reaction was carried out using α-hydroxy acid as a substrate in a flow reaction. [Example II-1] A sample solution (molar concentration of D-lactic acid / heavy water: 25 mM) was prepared by placing 112.6 mg (1.25 mmol) of D-lactic acid (D-LA, optical purity 99% ee) and 50 mL of heavy water in a 100 mL recovery flask. A catalyst cartridge (φ5 mm × 100 mm, stainless steel) filled with a powder (Ru content of the total powder mass was 2.0 mass%, Ru metal amount was 0.13 mmol) made by uniformly mixing 260 mg of 5% ruthenium carbon catalyst (Ru / C) [a dried catalyst of type A (Ru content 5 mass%) (water-containing) (manufactured by N.E. Chemcat Corporation)] and 390 mg of boron nitride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was placed in a high-temperature bath (manufactured by Tokyo Rikakikai Co., Ltd., product name: MCR-1000) heated to 70°C. Next, heavy water was delivered to the catalyst cartridge at a flow rate of 0.1 mL / min for 30 minutes using a Smoothflow pump (manufactured by TACMINA Corporation, product name: Q-5-KR-UP-S), and simultaneously hydrogen gas was delivered to the catalyst cartridge at a flow rate of 2 mL / min using a mass flow controller (manufactured by FCON Corporation, product name: MODEL: C1005-4S2-100-H2) to pre-activate the catalyst. After preactivation, the sample solution was pumped through the catalyst cartridge at a flow rate of 0.1 mL / min for 60 minutes using a Smoothflow pump while continuing to pump hydrogen gas. This deuteration reaction took 20 minutes to pass through the area filled with the Ru / C powder. The amount of D-lactic acid supplied was 1.2 mol per mol of Ru metal, 2200 mol of heavy water per mol of D-lactic acid α-hydrogen atoms, and 41 mol of hydrogen gas per mol of Ru metal. After the reaction, the reaction solution was thoroughly replaced with heavy water (or water) at a flow rate of 0.2 mL / min to ensure no residual reaction solution remained in the catalyst cartridge, and the reaction solution was then collected. In this way, deuterated D-lactic acid having a deuterium atom as the α-hydrogen atom was synthesized.

[0092] To 1 mL of the resulting reaction solution, 22.7 mmol of 1,4-dioxane was added as an internal standard. 1 H-NMR was measured and the deuteration ratio was calculated. The optical purity was calculated by high-performance liquid chromatography (HPLC) analysis. Specifically, a chiral column (SCAS, product name: SUMICHIRAL OA-5000) was used in an HPLC (Shimadzu, product name: SHIMADZU LC-2030C Plus) with a 1 mM copper sulfate aqueous solution as the mobile phase, and 5 μL of the resulting reaction solution was injected while flowing at a flow rate of 1 mL / min. The optical purity was calculated from the area value detected at 254 nm. The results are shown in Table 4 below. The synthesized D-deuterated lactic acid was identified as follows. Unlabeled D-lactate and synthetic D-deuterated lactic acid 1 H-NMR and 2 H-NMR was measured, and the chemical shifts and HPLC retention times in each chart were compared to confirm their agreement.

[0093] [Example II-2] The deuteration reaction of Example II-2 was carried out in the same manner as in Example II-1, except that the flow rate of the sample solution was changed from 0.1 mL / min to 0.03 mL / min (approximately 3.3 times longer than that of Example II-1). The obtained product was identified, and the deuteration rate and optical purity of the obtained product were calculated in the same manner as in Example II-1. The results are shown in Table 4.

[0094] [Example II-3] The deuteration reaction of Example II-3 was carried out in the same manner as in Example II-1, except that the amount of D-lactic acid used was changed from 112.6 mg (1.25 mmol) to 56.3 mg (0.625 mmol) (the molar concentration of D-lactic acid / heavy water in the sample solution was changed from 25 mM to 12.5 mM). The obtained product was identified, and the deuteration rate and optical purity of the obtained product were calculated in the same manner as in Example II-1. The results are shown in Table 4.

[0095] [Example II-4] The deuteration reaction of Example II-4 was carried out in the same manner as in Example II-1, except that the flow rate of the sample solution was changed from 0.1 mL / min to 0.05 mL / min (double the flow time), and the amount of D-lactic acid used was changed from 112.6 mg (1.25 mmol) to 56.3 mg (0.625 mmol) (the molar concentration of D-lactic acid / heavy water in the sample solution was changed from 25 mM to 12.5 mM). The obtained product was identified, and the deuteration rate and optical purity of the obtained product were calculated in the same manner as in Example II-1. The results are shown in Table 4.

[0096] [Table 4]

[0097] [Comparative Example II-1] A 100 mL autoclave was charged with 5 g of D-lactic acid, 50 mL of heavy water, and 1 g of 5% ruthenium carbon catalyst (Ru / C), and then sealed. The autoclave was then purged with N2 and H2, and filled with H2 until the pressure reached 1 atmosphere. The autoclave was then heated to an internal temperature of 80°C, and the deuteration reaction was carried out for 24 hours. After the reaction, the autoclave was returned to room temperature, purged with N2, and then opened to obtain a reaction solution. The resulting reaction mixture 1 The deuteration rate was calculated by H-NMR measurement, and was found to be 0%.

[0098] [Comparative Examples II-2 and II-3] The deuteration reactions of Comparative Examples II-2 and II-3 were carried out in the same manner as in Comparative Example II-1, except that the internal temperature was changed from 80°C to 50°C (Comparative Example II-2) or 120°C (Comparative Example II-3). The resulting reaction mixture 1 The deuteration ratio was calculated by measuring 1 H-NMR, and the deuteration ratio was found to be 0% in Comparative Example II-2 and 8% in Comparative Example II-3.

[0099] The results shown in Examples I and II (Tables 1 to 4) reveal the following. That is, in Comparative Example I-1, in which L-alanine was deuterated in a batchwise reaction system, the deuteration rate was at most 40% even after the reaction was continued for a long period of 12 hours at 90°C. Such a deuteration rate is not suitable for deuteration reactions, not only for industrial production but even for laboratory-scale production. Furthermore, even when a flow-type reaction system was employed, Comparative Examples I-2 to I-4, which used a palladium catalyst, platinum catalyst, or iridium catalyst, had a deuteration rate of 0%, meaning that the α-hydrogen atom of L-alanine could not be deuterated. Furthermore, Comparative Example I-5, in which L-leucine was deuterated in the presence of a base in a flow-type reaction system, achieved a sufficient deuteration rate and optical purity, but required the step of removing the base, making it impossible to achieve cost reduction and simplicity. In Comparative Examples II-1 and II-2, in which D-lactic acid was deuterized in a batchwise reaction, the deuteration rate was 0%, even after the reaction was continued for a long period of 24 hours at 80°C or 50°C, and the α-hydrogen atoms of D-lactic acid could not be deuterized. Even in Comparative Example II-3, in which the reaction temperature was raised to 120°C, the deuteration rate was only 8%.

[0100] In contrast, Examples I-1 to I-13 and II-1 to II-4, in which a flow reaction system was employed to deuterate an α-amino acid or α-hydroxy acid in a channel filled with a ruthenium catalyst or a rhodium catalyst in the absence of a base, enabled the synthesis of deuterated α-amino acids and deuterated α-hydroxy acids with high stereoselectivity (optical purity) through simple procedures and at a high deuteration rate in a short period of time. These results demonstrate that the method for producing deuterated compounds of the present invention, which can achieve a high deuteration rate and a short reaction time despite the simple procedures, is highly useful as an industrial production method. [Explanation of symbols]

[0101] 1 Deuteration device 2 Catalyst filling area (catalyst cartridge) 3 Substrate solution supply path 3A pump (syringe pump) 4 Hydrogen gas (deuterium gas) supply line 5. Reaction liquid transfer path

Claims

1. A method for producing a deuterated compound by deuterating a hydrogen atom at the α-position of an α-amino acid or an α-hydroxy acid, comprising: A method for producing a deuterated compound, comprising flowing an α-amino acid or an α-hydroxy acid, heavy water, and hydrogen gas or deuterium gas through a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst in the absence of a base, thereby reacting the α-amino acid or the α-hydroxy acid with the heavy water.

2. The method according to claim 1, wherein the α-amino acid or α-hydroxy acid is a compound represented by the following general formula [1]: 【Chemistry 1】 In general formula [1], R １ represents a hydroxy group or an amino group, and R ２ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a carboxyalkyl group, an aminoalkyl group, an amidoalkyl group, an arylalkyl group, or a heteroarylalkyl group; R １ and R ２ may be bonded to form a 5- or 6-membered heterocyclic group.

3. The process of claim 1 , wherein the catalyst comprises a ruthenium catalyst.

4. The method of claim 3 , wherein the ruthenium catalyst comprises ruthenium carbon.

5. The process of claim 1 , wherein the catalyst comprises rhodium on carbon.

6. The method according to claim 1, wherein the reaction is carried out at a reaction temperature of 60 to 120°C.

7. The process according to claim 1, wherein the reaction is carried out in the absence of a solvent.

8. A method for producing a deuterated compound by deuterating a hydrogen atom at the α-position of an α-amino acid or an α-hydroxy acid, comprising: Step 1: flowing an α-amino acid or an α-hydroxy acid, heavy water, and hydrogen gas or deuterium gas through a flow path filled with at least one catalyst selected from a ruthenium catalyst and a rhodium catalyst in the absence of a base, thereby reacting the α-amino acid or the α-hydroxy acid with heavy water; Step 2 of recovering heavy water from the reaction solution obtained in step 1; Step 3: flowing the α-amino acid or α-hydroxy acid, the heavy water recovered in Step 2, and hydrogen gas or deuterium gas through the flow path in the absence of a base to react the α-amino acid or α-hydroxy acid with the recovered heavy water; The method for producing a deuterated compound comprising:

9. The manufacturing method according to claim 8 , wherein the steps 1 and 2 are carried out in this order or simultaneously, and then the steps 3 and 2 are repeatedly carried out in this order or simultaneously.

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