Patent Application
20240209020
The present invention relates to a reaction agent for amide reaction and a method of producing an amide compound using the same.
Conventionally, amide compounds represented by peptides have been used in a wide variety of fields, including pharmaceuticals, cosmetics, and functional foods. Development of synthetic methods thereof has been diligently pursued as an important research goal in synthetic chemistry (NPL 1 to 6). However, there are few truly effective catalysts or reactants other than carboxylic acid activators for the amidation reaction, which is the most important reaction in peptide synthesis. Therefore, it is unavoidable to use a reaction mode that forms by-products, and thus, peptide synthesis, which involves repeating multi-stage reactions, is extremely inefficient from the viewpoint of atom economy (atomic yield). The amount of by-products is large, and there are few effective purification means. As a result, the cost of disposal of by-products and purification constitutes most of the necessary costs for peptide synthesis, and is the largest obstacle to development in this field.
In peptide synthesis, which uses amino acids or derivatives thereof as starting materials, it is desirable for the amidation reaction to proceed with high stereoselectivity. Enzyme reactions in the body are examples of highly stereoselective amidation reactions. For example, in the body, peptides are synthesized with extremely high stereoselectivity through sophisticated use of enzymes and hydrogen bonds. However, enzyme reactions are not suitable for mass production, requiring enormous financial and time costs when applied to synthetic chemistry.
In synthetic chemistry, amidation reactions using catalysts have been examined, but in conventional means, the amide bond is formed primarily through the method of activating carboxylic acid, such that racemization occurs quickly, whereby synthesizing a peptide with high stereoselectivity and efficiency is difficult.
According to conventional methods, it is very difficult to link an additional amino acid or derivative to a peptide comprising a plurality of amino acids or derivatives thereof (chemical ligation) or link two or more peptides via amide bonds. As an amidation method for ligation to such peptides, there are known a method for ligation by using an amino acid having a sulfur atom to utilize the high reactivity of the sulfur atom (NPL 7) and a method for ligation by synthesizing an amino acid hydroxyamine to utilize the high reactivity of the hydroxyamine (NPL 8). However, in the former method, it is difficult to synthesize amino acids having a sulfur atom, and in the latter method, hydroxyamine synthesis involving several steps is necessary. Both methods are time-consuming and costly and have a disadvantage in efficiency.
The present inventors have developed, as techniques for synthesizing an amide compound in a highly chemoselective manner: a method of amidating a carboxylic acid/ester compound having a hydroxy group at the β-position in the presence of a specific metal catalyst (PTL 1); a method of using a hydroxyamino/imino compound as an amino acid precursor and amidating it in the presence of a specific metal catalyst, and then reducing them in the presence of a specific metal catalyst (PTL 2); and a method of amidating a carboxylic acid/ester compound in the presence of specific metal catalyst (PTL 3).
However, there is still a demand to develop a new method that can produce amide compounds by generating amidation reaction in a highly stereoselective manner and/or efficiently for various reactants having carboxyl and amino groups.
Accordingly, an objective of the present invention is to provide a new method of producing amide compounds via amidation reaction in a highly stereoselective manner and/or efficiently using various reactants having carboxyl and amino groups.
As a result of intensive investigations, the present inventors have found that a silane compound having a specific structure has the effect of causing an amidation reaction between a carboxyl group and an amino group, and that such a silane compound can be used as a reaction agent alone or optionally in combination with another secondary silane compound, a Lewis acid catalysts, and/or a phosphorus compound. The present inventors have also found that with the use of such a silane compound, it becomes possible to produce an amide compound via an amidation reactions in a highly stereoselective manner and/or efficiently using various reactants having carboxyl and amino groups, thereby arriving at the present invention.
Thus, the present invention provides the following aspects.
A reaction agent for amide reaction between a carboxyl group and an amino group, comprising at least one compound selected from compounds represented by general formulae (C1) to (C4).
In general formulae (C1) to (C4),
A method of producing, from a compound represented by general formula (1-1) and a compound represented by general formula (1-2), an amide compound represented by general formula (1-3), comprising:
In general formula (1-1),
In general formula (1-2),
In general formula (1-3), each symbol represents the same definition as that of the same symbol in general formulae (1-1) and (1-2) above.
A method of producing, from a compound represented by general formula (2-1), an amide compound represented by general formula (2-2), comprising:
In general formula (2-1),
In general formula (2-2), each symbol represents the same definition as that of the same symbol in general formula (2-1) above.
A method of producing, from a compound represented by general formula (3-1) and a compound represented by general formula (3-2), an amide compound represented by general formula (3-3), comprising:
In general formula (3-1),
In general formula (3-2),
In general formula (3-3), each symbol represents the same definition as that of the same symbol in general formulae (3-1) and (3-2) above.
The method according to any one of Aspects 2 to 4, wherein the reaction is carried out in the presence of a Lewis acid catalyst.
The method according to Aspect 5, wherein the Lewis acid catalyst is a metal compound containing at least one metal selected from the group consisting of titanium, zirconium, hafnium, tantalum, and niobium.
The method according to any one of Aspects 2 to 6, wherein the reaction is carried out in the presence of a phosphorus compound.
The method according to Aspect 7, wherein the phosphorus compound is either a phosphine compound or phosphate compound.
The method according to any one of Aspects 2 to 8, wherein the reaction is carried out as a batch reaction or a flow reaction.
The method according to the present invention allows for the production of an amide compound by causing an amidation reaction in the presence of a silane compound having a specific structure as a reaction agent, in a highly stereoselective manner and/or efficiently and using various reactants having carboxyl and amino groups
The present invention is described hereinafter in detail with reference to specific embodiments thereof. However, the present invention is not limited to the following embodiments and can be carried out in any embodiment that does not deviate from the gist of the present invention.
All the patent publication, unexamined patent publications, and non-patent literature cited in the present disclosure are incorporated herein by reference in their entireties for any purpose.
The term “amino acid” herein refers to a compound having a carboxyl group and an amino group. Unless otherwise specified, the type of an amino acid is not particularly limited. For example, from the viewpoint of optical isomerism, an amino acid may be a D-amino acid or an L-amino acid. From the viewpoint of the relative positions of the carboxyl group and the amino group, an amino acid may be any of an α-amino acid, β-amino acid, γ-amino acid, δ-amino acid, or ε-amino acid. Examples of amino acids include, but are not limited to, natural amino acids that make up proteins. Examples include valine, leucine, isoleucine, alanine, arginine, glutamine, lysine, aspartic acid, glutamic acid, proline, cysteine, threonine, methionine, histidine, phenylalanine, tyrosine, tryptophan, asparagine, glycine, and serine.
The term “peptide” herein refers to a compound comprising a plurality of amino acids linked together via peptide bonds. Unless otherwise specified, the plurality of amino acid units constituting a peptide may be the same type of amino acid unit or may consist of two or more types of amino acid units. The number of amino acids constituting a peptide is not restricted as long as it is two or more. Examples include 2 (also called “dipeptide”), 3 (also called “tripeptide”), 4 (also called “tetrapeptide”), 5 (also called “pentapeptide”), 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100, or more.
The term “lactam” herein refers to a compound comprising a ring formed by an intramolecular amidation bond between a carboxyl group and an amino group in a single molecule, and the term “cyclic peptide” herein refers to a peptide comprising a ring formed by an intramolecular amidation bond between a carboxyl group and an amino group (for example, but not limited to, between a terminal carboxyl group and a terminal amino group) in a single peptide molecule.
The term “amino group” herein refers to a functional group represented by any formula of —NH2, —NRH, and —NRR′ (where R and R′ each represent a substituent) obtained by removing hydrogen from ammonia, a primary amine, and a secondary amine, respectively.
Unless otherwise specified, a hydrocarbon group herein may be either aliphatic or aromatic. An aliphatic hydrocarbon group may be in the form of either a chain or a ring. A chain hydrocarbon group may be linear or branched. A cyclic hydrocarbon group may be monocyclic, bridged cyclic, or spirocyclic. The hydrocarbon group may be saturated or unsaturated. In other words, one, two, or more carbon-carbon double and/or triple bonds may be included. Specifically, “hydrocarbon group” represents a concept including an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, aryl group, etc. Unless otherwise specified, one, two, or more hydrogen atoms of the hydrocarbon group may be replaced with any substituents and one, two, or more carbon atoms of the hydrocarbon group may be replaced with any heteroatoms corresponding to the valence thereof.
The term “hydrocarbon oxy group” herein refers to a group comprising an oxy group (—O—) linked via one bond thereof to the hydrocarbon group as defined above.
The term “hydrocarbon carbonyl group” herein refers to a group comprising a carbonyl group (—C(═O)—) linked via one bond thereof to the hydrocarbon group as defined above.
The term “hydrocarbon sulfonyl group” herein refers to a group comprising a sulfonyl group (—S(═O)2—) linked via one bond thereof to the hydrocarbon group as defined above.
A heterocyclic group may be saturated or unsaturated. In other words, it may contain one, two, or more carbon-carbon double and/or triple bonds. A heterocyclic group may be monocyclic, bridged cyclic, or spirocyclic. The heteroatom included in the constituent atoms of the heterocyclic group is not particularly limited, examples thereof including nitrogen, oxygen, sulfur, phosphorus, and silicon.
The term “heterocyclic oxy group” herein refers to a group comprising an oxy group (—O—) linked via one bond thereof to the heterocyclic group as defined above.
The term “heterocyclic carbonyl group” herein refers to a group comprising a carbonyl group (—C(═O)—) linked via one bond thereof to the heterocyclic group as defined above.
The term “heterocyclic sulfonyl group” herein refers to a group comprising a sulfonyl group (—S(═O)2—) linked via one bond thereof to the heterocyclic group as defined above.
Unless otherwise specified, the term “substituent” herein refers, independently of each other, to any substituent which is not particularly limited so long as the amidation step of the production method according to the present invention proceeds.
Examples include, but are not limited to, a halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, thiol group, sulfonic acid group, amino group, amide group, imino group, imide group, hydrocarbon group, heterocyclic group, hydrocarbon oxy group, hydrocarbon carbonyl group (acyl group), hydrocarbon oxycarbonyl group, hydrocarbon carbonyl oxy group, hydrocarbon substitution amino group, hydrocarbon substitution amino carbonyl group, hydrocarbon carbonyl substitution amino group, hydrocarbon substitution thiol group, hydrocarbon sulfonyl group, hydrocarbon oxysulfonyl group, hydrocarbon sulfonyl oxy group, heterocyclic oxy group, heterocyclic carbonyl group, heterocyclic oxycarbonyl group, heterocyclic carbonyl oxy group, heterocyclic amino group, heterocyclic amino carbonyl group, heterocyclic carbonyl substitution amino group, heterocyclic substitution thiol group, heterocyclic sulfonyl group, heterocyclic oxysulfonyl group, and heterocyclic sulfonyl oxy group. The term “substituents” also may include functional groups obtained by substituting any of the aforementioned functional groups with any of the aforementioned functional groups as long as the valence and physical properties thereof permit. When a functional group has one or more substituents, the number of the substituents is not particularly limited as long as the valence and physical properties thereof permit. When the functional group has two or more substituents, they may be identical to each other or different from each other.
The term Me herein refers to a methyl group, the term Et herein refers to a ethyl group, the term Pr herein refers to a propyl group, the term i-Pr herein refers to an isopropyl group, the term Bu herein refers to a butyl group, and the term t-Bu herein refers to a tert-butyl group.
The term Ac herein refers to a acetyl group, the term acac herein refers to an acetylacetonate, the term Cp herein refers to a cyclopentadienyl, the term Tf herein refers to a trifluoromethane sulfonyl, the term Trt herein refers to a trityl group, the term THF herein refers to a tetrahydrofuran, the term DCM herein refers to a dichloromethane, and the term DMSO herein refers to a dimethyl sulfoxide.
Amino acids and residues thereof may herein be represented by three-letter abbreviations well known to a person skilled in the art. The three-letter abbreviations of major amino acids are shown in the following table.
β-homoamino acids and residues thereof may herein be represented by “Ho” followed by three-letter abbreviations of corresponding β-amino acids.
The term “reaction agent” for an amide reaction between a carboxyl group and an amino group herein refers to an agent capable of causing or promoting an amide reaction between a carboxyl group and an amino group.
A statement including two or more words linked with a slash (“/”) in the listing of the names of compounds or substituents encompass all compound or substituent names obtained by choosing one of the listed words alone, unless otherwise specified or unless the context clearly indicates otherwise. For example, the statement “(2-/3-/4-)methyl imidazole group” refers to a “2-methyl imidazole group, 3-methyl imidazole group, and 4-methyl imidazole group,” and the statement “(mono/di/tri/tetra/penta/hexa/hepta/octa/nona)fluoro(butyl/butoxy) group” refers to a “monofluorobutyl group, difluorobutyl group, trifluorobutyl group, tetrafluorobutyl group, pentafluorobutyl group, hexafluorobutyl group, heptafluorobutyl group, octafluorobutyl group, nonafluorobutyl group, monofluorobutoxy group, difluorobutoxy group, trifluorobutoxy group, tetrafluorobutoxy group, pentafluorobutoxy group, hexafluorobutoxy group, heptafluorobutoxy group, octafluorobutoxy group, and nonafluorobutoxy group.”
An aspect of the present invention relates to reaction agent for an amide reaction between a carboxyl group and an amino group (hereinafter also referred to as “reaction agent according to the present invention”), comprising at least one silane compound selected from the compounds represented by general formulae (C1) to (C4) (hereinafter also referred to as a “silane compound (C)”).
The definition of each symbol in general formulae (C1) to (C4) is as follows.
Rc1 to Rc3, independently of each other, represent a hydrogen atom or a linear or branched chain alkyl or alkoxy group having one to ten (preferably 1 to 5, or 1 to 3) carbon atoms which may have one or more substituents. However, at least two of Rc1 to Rc3 represent an unsubstituted or substituted alkyl or alkoxy group. In other words, Rc1 to Rc3 includes zero or one hydrogen atom.
Rc4 and Rc5, independently of each other, represent a linear or branched chain alkyl or alkoxy group having one to ten (preferably 1 to 5, or 1 to 3) carbon atoms which may have one or more substituents.
When each of Rc1 to Rc5 represents an alkyl or alkoxy group having one or more substituents, examples of the substituents are as explained above, among which halogen atoms are preferred. Examples of the number of substituents include 5, 4, 3, 2, 1, or 0.
Zc represents a 5- to 10-membered (preferably 5-, 6-, or 10-membered) heterocyclic group that contains one or more (preferably 2 to 4, more preferably 2 or 3) nitrogen atoms as ring-constituting atoms and may have one or more substituents. When the heterocyclic group has one or more substituents, examples of the substituents are as explained above. Preferred among these include alkyl groups (e.g., linear or branched chain alkyl groups having one to ten carbon atoms; hereinafter also referred to as —R), alkoxy groups (—O—R), amino group (—NH2), alkyl amino groups (—NHR), dialkyl amino groups (—NR2; where the two alkyl groups R's may be either identical to each other or different from each other), and thioalkyl groups (—SR), as well as groups derived from these groups via substitutions with one or more halogen atoms (e.g., bromine or chlorine atom). Examples of the number of substituents include 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0. When it has two or more substituents, may be either identical to each other or different from each other.
Examples of nitrogen-containing heterocyclic groups of Zc, although are not limited to: pyrrol group, imidazole group, pyrazole group, triazole group (1,2,3-triazole group, 1,2,4-triazole group), piperidyl group, pyridinyl group, piperazinyl group, tetrazol group, indol group, and benzimidazole group, as well as groups derived from these groups via substitutions with various substituents mentioned above, such as (2-/3-/4-/5-)methyl imidazole groups and (2,3-/2,4-/2,5-)dimethyl imidazole groups. Preferred among these include imidazole group, pyrazole group, triazole group, and 2-methyl imidazole group.
Yc represents a hydrogen atom or a halogen atom such as chlorine atom or bromine atom.
Rc6 represents a linear or branched chain alkyl, alkoxy, or alkylcarbonyl group having one to ten (preferably 1 to 5, or 1 to 3) carbon atoms which may have one or more substituents. When this group has one or more substituents, examples of the substituents are as explained above, among which halogen atoms are preferred. Examples of the number of substituents include 5, 4, 3, 2, 1, or 0.
s represents an integer of 1 or 2, provided that when s is 2, then Rc6 is absent.
Examples of the compounds represented by general formula (C1) include: 1-(trimethylsilyl)imidazole (TMSIM), dimethylethylsilylimidazole (DMESI), dimethyl isopropylsilylimidazole (DMIPSI), 1-(tert-butyldimethylsilyl)imidazole (TBSIM), 1-(trimethylsilyl)triazole, 1-(tert-butyldimethylsilyl)triazole, dimethylsilylimidazole, dimethylsilyl(2-methyl)imidazole. Preferred among these include 1-(trimethylsilyl)imidazole (TMSIM) and 1-(tert-butyldimethylsilyl)imidazole (TBSIM).
Examples of the compounds represented by general formula (C2) include: trimethylbromosilane (TMBS) and trimethylchlorosilane (TMCS). Preferred among these include trimethylbromosilane (TMBS).
Examples of the compounds represented by general formula (C3) include: N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA), N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), and N,O-bis(trimethylsilyl)acetamide (BSA). Preferred among these include N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA).
Examples of the compounds represented by general formula (C4) include: N-(trimethylsilyl)dimethylamine (TMSDMA), N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA), and hexamethyldisilazane (HMDS). Preferred among these include N-(trimethylsilyl)dimethyl amine (TMSDMA) and N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA).
Any one silane compound (C) may be used alone, or any two or more silane compounds (C) may be used in any combination.
It is a novel finding previously unknown to the art that the silane compound (C) can function as a reaction agent causing an amidation reaction in one or more reactant compounds having a carboxyl group and/or an amino group, between the carboxyl group and the amino group thereof.
According to an aspect of the present invention, the compound represented by general formula (C1) where Rc1 to Rc3 each represent methyl and Zc represents imidazole, i.e., 1-(trimethylsilyl)imidazole (TMSIM), may be excluded from the scope of the silane compound (C).
Another aspect of the present invention relates to a method of producing an amide compound method (hereinafter also referred to as “the production method according to the present invention”) using the silane compound (C) as reaction agents. The method includes using one or more compounds having a carboxyl group and/or an amino group as reactants, and causing an amidation reaction between the carboxyl group and the amino group. The production method of the present invention can be broadly classified into the following modes, depending on the types of the reactants used and the target compound produced by the amidation reaction.
In addition, among specific embodiments included in Embodiment (1) above, the following specific embodiment is especially interesting.
Likewise, Embodiment (2) includes a specific embodiment in which the first compound is a peptide and the second compound (lactam compound) is a cyclic peptide.
The combinations of the reactants and the target compounds in Embodiments (1) to (3) are described below.
Embodiment (1) relates to a method for using a compound having a carboxyl group represented by formula (1-1) (hereinafter also referred to as “compound (1-1)”) and a compound having an amino group represented by formula (1-2) (hereinafter also referred to as “compound (1-2)”) as reactants, and producing an amide compound represented by formula (1-3) by causing an intermolecular amidation reaction between the carboxyl group of compound (1-1) and the amino group of compound (1-2) in the presence of a silane compound (C) mentioned above.
In other words, in this embodiment, the carboxyl and amino groups possessed by the different compounds (1-1) and (1-2) are linked via an amidation reaction to produce a novel amide compound (1-3).
The definition of each symbol in general formulae (1-1), (1-2), and (1-3) are as follows.
R11 and R12, independently of each other, represent (i) a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents or (ii) a monovalent group formed by linking, optionally via a linking group, two or more multivalent hydrocarbon and/or heterocyclic groups that each may have one or more substituents. Roughly speaking, when each of R11 and/or R12 is (i), then the compound (1-1) and/or (1-2) may be a monomer or a low molecular compound, while when each of R11 and/or R12 is (ii), then the compound (1-1) and/or (1-2) may be a polymer or a macromolecular compound.
When each of R11 and R12 is, independently of each other, (i) a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents, the details thereof are as follows.
When each of R11 and/or R12 is a monovalent hydrocarbon group that may have one or more substituents, the number of carbon atoms of the hydrocarbon group (including its substituents, if any) is not particularly limited, but the upper limit thereof may be, for example, 40 or less, 30 or less, 20 or less, 16 or less, or 12 or less. The lower limit thereof depends on the type of the hydrocarbon group, but may be 1 or more for alkyl groups, 2 or more for alkenyl and alkynyl groups, and 3 or more, such as 4 or more, or 5 or more, for cycloalkyl groups. Examples of the number of atoms include, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40.
When each of R11 and/or R12 is a monovalent heterocyclic group that may have one or more substituents, the total number of carbon atoms and hetero atoms of the heterocyclic group (including its substituents, if any) is not particularly limited, but the upper limit thereof may be, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the heterocyclic structure, but may typically be 3 or more, for example 4 or more, or 5 or more. Examples of the number of atoms include, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40.
Among them, each of R11 and R12 may preferably be, independently of each other, an amino group, alkyl group, alkenyl group, cycloalkyl group, alkoxy group, aryl group, aryloxy group, acyl group, heterocyclic group, or heterocyclic oxy group that may have one or more substituents.
Examples of R11 and R12 include, but are not limited to, the following.
*Alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, decyl group, and nonyl group;
*Cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, bicyclooctyl group, and spirooctyl group;
*Aryl groups such as phenyl group, benzyl group, tolyl group, naphthyl group, and anthracenyl group;
*Heterocyclic groups such as furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydro pyridyl group, hexahydro pyrimidyl group, hexahydro pyridazyl group, 1,2,4,6-tetrahydro pyridyl group, 1,2,4,6-tetrahydro pyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, 2,3-dihydro-1H-imidazolyl group, pyrazolyl group, 4,5-dihydro-1H-pyrazolyl group, 2,3-dihydro-1H-pyrazolyl group, oxazolyl group, 4,5-dihydro-1,3-oxazolyl group, 2,3-dihydro-1,3-oxazolyl group, 2,5-dihydro-1,3-oxazolyl group, thiazolyl group, 4,5-dihydro-1,3-thiazolyl group, 2,3-dihydro-1,3-thiazolyl group, 2,5-dihydro-1,3-thiazolyl group, and carbazolyl group; and
*Heterocyclic oxy groups such as furanyl oxy group, pyrrolyl oxy group, indolyl oxy group, and quinolyl oxy group.
Of the groups mentioned above, those having a carboxyl group may or may not have a protective group. When such a group with a carboxyl group has a protective group, the reaction selectivity with the carboxyl group on the right side of formula (1-1) is usually superior to that with the carboxyl groups present on the other substituents, although it may also depend on the reactivity of the compound (1-1) and the compound (1-2) used in the reaction.
When each of R11 and R12 is, independently of each other, (ii) a monovalent group formed by linking, optionally via a linking group, two or more multivalent hydrocarbon and/or heterocyclic groups that each may have one or more substituents, the details thereof are as follows.
Such multivalent hydrocarbon groups or heterocyclic groups include multivalent (e.g., di-, tri-, tetra-, or penta-valent, or even higher) hydrocarbon groups or heterocyclic groups obtained by removing one or more hydrogen atoms from the monovalent hydrocarbon or heterocyclic groups mentioned above. When two or more (e.g., two, three, four, five, or more) of these multivalent hydrocarbon or heterocyclic groups are linked together, they may be linked by direct bonds or with intervening linking groups. Such linking groups are not particularly limited, but may be selected, independently of each other, from the structures listed below (where, in the chemical formulae below, A represents a monovalent hydrocarbon group or a heterocyclic group, each of which may independently have one or more substituents. When two A's are present in the same group, they may be identical to each other or different from each other).
As mentioned above, when each of R11 and/or R12 is (ii) a monovalent group formed by linking, optionally via a linking group, two or more multivalent hydrocarbon and/or heterocyclic groups that each may have one or more substituents, then the compound (1-1) and/or (1-2) typically is a polymer or a macromolecular compound. Examples of such polymers and macromolecular compounds include, but are not limited to, the following.
*Peptides/proteins (which will be explained in Embodiment (3) below in details);
*Nucleic acids (e.g., DNA (deoxyribonucleic acid) and RNA (ribonucleic acid));
*Polysaccharides (e.g., cellulose, amylose, starch, chitin, and chitosan);
*Complex polysaccharides (e.g., lipopolysaccharides and glycoproteins);
*Lipids (e.g., simple lipids, phospholipids, and glycolipids);
*Natural and synthetic resins (e.g., phenol resins, silicone resins, epoxy resins, melamine resins, urea resins, unsaturated polyester resins, alkyd resins, polyvinyl chloride, polyethylene, polyethylene glycol, polypropylene, polystyrene, polyvinyl acetate, polylactate, polyester, polyurethane, polyamide (e.g., nylon), (meth)acrylic resin, polyvinyl chloride, polyvinylidene chloride, and natural and synthetic rubbers).
R13 represents a hydrogen atom, carboxyl group, or hydroxyl group, or a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents. The details of the substituents, if any, are described above. Examples of the number of the substituents include 5, 4, 3, 2, 1, or 0.
When R13 is a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents, there may be an intervening linking group between the hydrocarbon group or heterocyclic group and the nitrogen atom to which the hydrocarbon group or heterocyclic group binds. Such linking groups are not particularly limited, but may be selected, independently of each other, from the structures shown below (where, in the chemical formulae below, A represents a monovalent hydrocarbon group or a heterocyclic group, each of which may independently have one or more substituents. When two A's are present in the same group, they may be identical to each other or different from each other).
The upper limit of the number of the carbon atoms contained in each hydrocarbon group (including its substituents, if any) may be, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the hydrocarbon group, but may be 1 or more for alkyl groups, 2 or more for alkenyl and alkynyl groups, and 3 or more, such as 4 or more, or 5 or more, for cycloalkyl groups. Examples of the number of atoms include, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The upper limit of the number of the carbon atoms and hetero atoms included in each heterocyclic group (including its substituents, if any) may be, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the heterocyclic structure, but may be typically 3 or more, for example 4 or more, or 5 or more. Examples of the number of atoms include, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
R12 and R13 may be bound to each other to form, together with the nitrogen atom to which R12 and R13 bind, a hetero ring that may have one or more substituents. The details of the substituents, if any, are described above. Examples of the number of such substituents include, for example, 5, 4, 3, 2, 1, or 0.
The upper limit of the total number of carbon atoms and hetero atoms included in each heterocyclic group (including its substituents, if any) may be, for example 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the heterocyclic structure, but may be typically 3 or more, for example 4 or more, or 5 or more. Examples of the number of atoms include, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
Examples of such hetero rings include, but are not limited to, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydro pyridyl group, hexahydro pyrimidyl group, hexahydro pyridazyl group, 1,2,4,6-tetrahydro pyridyl group, 1,2,4,6-tetrahydro pyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, 2,3-dihydro-1H-imidazolyl group, pyrazolyl group, 4,5-dihydro-TH-pyrazolyl group, 2,3-dihydro-TH-pyrazolyl group, oxazolyl group, 4,5-dihydro-1,3-oxazolyl group, 2,3-dihydro-1,3-oxazolyl group, 2,5-dihydro-1,3-oxazolyl group, thiazolyl group, 4,5-dihydro-1,3-thiazolyl group, 2,3-dihydro-1,3-thiazolyl group, and 2,5-dihydro-1,3-thiazolyl group.
Embodiment (1) relates to a method for using a compound having a carboxyl group and an amino group represented by formula (2-1) (hereinafter also referred to as “compound (2-1)”) as a reactant, and producing a lactam compound represented by formula (2-2) by causing an intramolecular amidation reaction between the carboxyl group and the amino group of compound (2-1) in the presence of a silane compound (C) mentioned above.
In other words, in this embodiment, the carboxyl and amino groups possessed by the same compound (2-1) are linked via an intramolecular amidation reaction to cause cyclization and produce a novel lactam compound (2-2).
The definition of each symbol in general formulae (2-1) and (2-2) are as follows.
R21 represents (i) a divalent hydrocarbon group or heterocyclic group that may have one or more substituents or (ii) a divalent group formed by linking, optionally via a linking group, two or more multivalent hydrocarbon and/or heterocyclic groups that each may have one or more substituents. Roughly speaking, when R21 is (i), then the compound (2-1) may be a monomer or a low molecular compound, while when R21 is (ii), then the compound (2-1) may be a polymer or a macromolecular compound.
When R21 is (i) a divalent hydrocarbon group or heterocyclic group that may have one or more substituents, examples thereof include divalent hydrocarbon or heterocyclic groups obtained by removing any hydrogen atom from the monovalent hydrocarbon or heterocyclic groups described for R11 in formula (1-1) and R12 in formula (1-2) above. Other details are the same as those described for R11 in formula (1-1) and R12 in formula (1-2) above.
On the other hand, when R21 is (ii) a divalent group formed by linking, optionally via a linking group, two or more multivalent hydrocarbon and/or heterocyclic groups that each may have one or more substituents, examples thereof include divalent groups obtained by removing any hydrogen atom from the monovalent groups including two or more multivalent hydrocarbon groups or heterocyclic groups linked together described for R11 in formula (1-1) and R12 in formula (1-2) above. Other details are the same as those described for R11 in formula (1-1) and R12 in formula (1-2) above.
R22 represents a hydrogen atom, carboxyl group, hydroxyl group, or a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents. Details of R22 are the same as those described for R13 in formula (1-2) above.
R21 and R22 may be bound to each other to form, together with the nitrogen atom to which R21 and R22 bind, a hetero ring that may have one or more substituents. The details of such a hetero ring are the same as those described for the hetero ring formed by the bonding of R12 and R13 in formula (1-2) above.
Embodiment (3) relates to a method for using an amino acid or peptide represented by formula (3-1) (hereinafter also referred to as “compound (3-1)”) and an amino acid or peptide represented by formula (3-2) (hereinafter also referred to as “compound (3-2)”) as reactants, and producing a peptide represented by formula (3-3) by causing an intermolecular amidation reaction between the terminal carboxyl group of compound (3-1) and the terminal amino group of compound (3-2) in the presence of a silane compound (C) mentioned above.
In other words, in this embodiment, the carboxyl and amino groups possessed by the different peptides (3-1) and (3-2) are linked via an amidation reaction to produce a novel peptide (3-3).
The definition of each symbol in general formulae (3-1), (3-2), and (3-3) are as follows.
R31, R32, R34, and R36, independently of each other, represent a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, or thiol group, or a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents. The details of the substituents, if any, are described above. Examples of the number of such substituents include, for example, 5, 4, 3, 2, 1, or 0.
When each of R31, R32, R34, and/or R36 is a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents, then there may be an intervening linking group between the hydrocarbon group or heterocyclic group and the carbon atom to which the hydrocarbon group or heterocyclic group binds. Such linking groups are not limited, but may be selected, independently of each other, from the structures indicated below (where, in the chemical formulae below, A represents a monovalent hydrocarbon group or a heterocyclic group, each of which may independently have one or more substituents. When two A's are present in the same group, they may be identical to each other or different from each other).
The number of carbon atoms contained in each hydrocarbon group (including its substituents, if any) is not particularly limited, but the upper limit thereof may be, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the hydrocarbon group, but may be 1 or more for alkyl groups, 2 or more for alkenyl and alkynyl groups, and 3 or more, such as 4 or more, or 5 or more, for cycloalkyl groups. Examples of the number of atoms include, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The upper limit of the total number of carbon atoms and hetero atoms included in each heterocyclic group (including its substituents, if any) may be, for example 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the heterocyclic structure, but may be typically 3 or more, for example 4 or more, or 5 or more. Examples of the number of atoms include, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
Among them, each of R31, R32, R34, and R36 may preferably be selected, independently of each other, from hydrogen atom, hydroxyl group, thiol group, carboxyl group, nitro group, cyano group, or halogen atom, or, that may have one or more substituents, amino group, alkyl group, alkenyl group, cycloalkyl group, alkoxy group, aryl group, aryloxy group, acyl group, heterocyclic group, and heterocyclic oxy group.
Examples of R31, R32, R34, and R36 include, but are not limited to, the following.
*Hydrogen atom, hydroxyl group, thiol group, carboxyl group, nitro group, and cyano group;
*Halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom;
*Alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, decyl group, and nonyl group;
*Alkenyl groups such as ethenyl group, propenyl group, allyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, and octenyl group;
*Alkylyl groups such as propargyl group;
*Cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, bicyclooctyl group, and spirooctyl group;
*Alkoxy groups such as methoxy group, ethoxy group, propoxy group, butoxy group, sec-butoxy group, and tert-butoxy group;
*Aryl groups such as phenyl group, benzyl group, tolyl group, naphthyl group, and anthracenyl group;
*Aryloxy groups such as phenyloxy group, benzyloxy group, and naphthyloxy group;
*Acyl groups such as acetyl group, propionyl group, benzoyl group, p-methoxybenzoyl group, and cinnamoyl group;
*Unsubstituted amino group and substitution amino groups such as dimethyl amino group, benzyl amino group, and triphenylmethyl amino group;
*Heterocyclic groups such as furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-TH-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydro pyridyl group, hexahydro pyrimidyl group, hexahydro pyridazyl group, 1,2,4,6-tetrahydro pyridyl group, 1,2,4,6-tetrahydro pyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, 2,3-dihydro-1H-imidazolyl group, pyrazolyl group, 4,5-dihydro-1H-pyrazolyl group, 2,3-dihydro-1H-pyrazolyl group, oxazolyl group, 4,5-dihydro-1,3-oxazolyl group, 2,3-dihydro-1,3-oxazolyl group, 2,5-dihydro-1,3-oxazolyl group, thiazolyl group, 4,5-dihydro-1,3-thiazolyl group, 2,3-dihydro-1,3-thiazolyl group, 2,5-dihydro-1,3-thiazolyl group, carbazolyl group; and
*Heterocyclic oxy groups such as furanyl oxy group, pyrrolyl oxy group, indolyl oxy group, and quinolyl oxy group.
Of the groups mentioned above, those having a carboxyl group may or may not have a protective group. When such a group with a carboxyl group has a protective group, the reaction selectivity with the carboxyl group on the right side of formula (3-1) is usually superior to that with the carboxyl groups present on the other substituents, although it may also depend on the reactivity of the compound (3-1) and the compound (3-2) used in the reaction.
R33 and R36, independently of each other, represent a hydrogen atom, carboxyl group, or hydroxyl group, or, a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents. The details of the substituents, if any, are described above. Examples of the number of such substituents include, for example, 5, 4, 3, 2, 1, or 0.
When each of R33 and/or R36 is a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents, then there may be an intervening linking group between the hydrocarbon group or heterocyclic group and the carbon atom to which the hydrocarbon group or heterocyclic group binds. Such linking group are not limited, but may be selected, independently of each other, from the structures indicated below (where, in the chemical formulae below, A represents a monovalent hydrocarbon group or a heterocyclic group, each of which may independently have one or more substituents. When two A's are present in the same group, they may be identical to each other or different from each other).
The upper limit of the number of carbon atoms hydrocarbon group (including its substituents, if any) may be, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the hydrocarbon group, but may be 1 or more for alkyl groups, 2 or more for alkenyl and alkynyl groups, and 3 or more, such as 4 or more, or 5 or more, for cycloalkyl groups. Examples of the number of atoms include, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The upper limit of the total number of carbon atoms and hetero atoms of each heterocyclic group (including its substituents, if any) may be, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the heterocyclic structure, but may typically be 3 or more, for example 4 or more, or 5 or more. Examples of the number of atoms include, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
Among them, each of R33 and R36 may preferably be selected, independently of each other, from hydrogen atom, hydroxyl group, or carboxyl group, or, that may have one or more substituents, alkyl group, alkenyl group, cycloalkyl group, alkoxy group, aryl group, aryloxy group, acyl group, heterocyclic group, and heterocyclic oxy group.
Examples of R33 and R36 include, but are not limited to, the following.
*Hydrogen atom, hydroxyl group, and carboxyl group;
*Alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, decyl group, and nonyl group;
*Alkenyl groups such as ethenyl group, propenyl group, allyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, and octenyl group;
*Alkylyl groups such as propargyl group;
*Cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, bicyclooctyl group, and spirooctyl group;
*Aryl groups such as phenyl group, benzyl group, tolyl group, naphthyl group, anthracenyl group; and
*Heterocyclic groups such as furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydro pyridyl group, hexahydro pyrimidyl group, hexahydro pyridazyl group, 1,2,4,6-tetrahydro pyridyl group, 1,2,4,6-tetrahydro pyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, 2,3-dihydro-1H-imidazolyl group, pyrazolyl group, 4,5-dihydro-1H-pyrazolyl group, 2,3-dihydro-1H-pyrazolyl group, oxazolyl group, 4,5-dihydro-1,3-oxazolyl group, 2,3-dihydro-1,3-oxazolyl group, 2,5-dihydro-1,3-oxazolyl group, thiazolyl group, 4,5-dihydro-1,3-thiazolyl group, 2,3-dihydro-1,3-thiazolyl group, 2,5-dihydro-1,3-thiazolyl group, and carbazolyl group.
R31 and R33 may be bound to each other to form, together with the carbon atom to which R31 binds and the nitrogen atom to which R33 binds, a hetero ring that may have one or more substituents. Likewise, R34 and R36 may be bound to each other to form, together with the carbon atom to which R34 binds and the nitrogen atom to which R36 binds, a hetero ring that may have one or more substituents. The details of the substituents, if any, are described above. Examples of the number of such substituents include, for example, 5, 4, 3, 2, 1, or 0.
The upper limit of the total number of carbon atoms and hetero atoms of each heterocyclic group (including its substituents, if any) may be, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the heterocyclic structure, but may typically be 3 or more, for example 4 or more, or 5 or more. Examples of the number of atoms include, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
Examples of such hetero rings include, but are not limited to, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydro pyridyl group, hexahydro pyrimidyl group, hexahydro pyridazyl group, 1,2,4,6-tetrahydro pyridyl group, 1,2,4,6-tetrahydro pyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-TH-imidazolyl group, 2,3-dihydro-1H-imidazolyl group, pyrazolyl group, 4,5-dihydro-TH-pyrazolyl group, 2,3-dihydro-TH-pyrazolyl group, oxazolyl group, 4,5-dihydro-1,3-oxazolyl group, 2,3-dihydro-1,3-oxazolyl group, 2,5-dihydro-1,3-oxazolyl group, thiazolyl group, 4,5-dihydro-1,3-thiazolyl group, 2,3-dihydro-1,3-thiazolyl group, and 2,5-dihydro-1,3-thiazolyl group.
A1 to A4, independently of each other, represent a divalent aliphatic hydrocarbon group that may have one or more substituents having 1 to 3 carbon atoms. Examples include, but are not limited to, methylene group, ethylene group, propylene group, and isopropylene group, as well as any groups derived from these groups via substituition with one or more substituents. Examples of the number of such substituents include, for example, 3, 2, 1, or 0.
p1 to p4, independently of each other, represent an integer of 0 or 1.
m and n, independently of each other, represent an integer of equal to or greater than 1 corresponding to the number of the structure units parenthesized with [ ]. In other words, m represents the number of the amino acid residues parenthesized with [ ] in general formula (3-1). When m is 1, then the compound (3-1) is an amino acid, while when m is equal to or greater than 2, then the compound (3-1) is a peptide. Likewise, n represents the number of the amino acid residues parenthesized with [ ] in general formula (3-2). When n is 1, then the compound (3-2) is an amino acid, while n is equal to or greater than 2, then the compound (3-2) is a peptide. The upper limit of each of m and n is not particularly limited so long as the amidation step proceeds, but may preferably be, for example, 100 or less, 80 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, 15 or less, 12 or less, or 10 or less. Examples of each of m and n, independently of each other, include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, and 100.
Needless to say, when m is equal to or greater than 2, then each of R1, R2, R3, A1, A2, p1, and p2 in the structure parenthesized with [ ] may be either identical to each other or different from each other among the two or more amino acid residues. Likewise, when n is equal to or greater than 2, then each of R4, R5, R5, A3, A4, p3, and p4 in the structure parenthesized with [ ] may be either identical to each other or different from each other among the two or more amino acid residues. In other words, when each of the compound (3-1) and/or the compound (3-2) is a peptide, the two or more amino acid units constituting the peptide may be identical to each other or different from each other.
T1 represents a hydrogen atom or a monovalent substituent. The type of the monovalent substituent is not particularly restricted, but may be selected from the examples of R33 and R36 mentioned above, as well as any protective groups for amino groups (hereinafter also referred to as PG1). The protective group PG1 for amino groups is not restricted as long as the amino group can be protected so that it does not react in the amidation process and can be deprotected and converted to an amino group after the reaction.
There are a wide variety of protective groups for amino groups, PG1, known to the art. Examples thereof include monovalent hydrocarbon groups that may have one or more substituents and monovalent heterocyclic groups that may have one or more substituents. Preferred among these are monovalent hydrocarbon groups that may have one or more substituents. There may be any intervening linking group between the hydrocarbon group or heterocyclic group and the nitrogen atom of the amino group to be protected (the nitrogen atom in formula (3-1) to which PG1 binds). Such a linking group is not particularly limited, but may be selected, independently of each other, from the linking groups listed below (where, in the chemical formulae below, A represents a monovalent hydrocarbon group or a heterocyclic group, each of which may independently have one or more substituents. When two A's are present in the same group, they may be identical to each other or different from each other).
The number of carbon atoms in the protective group PG1 may typically be 1 or more, or 3 or more, and typically 20 or less, or 15 or less.
Among them, the amino-protective group PG1 may preferably be one or more selected from the group consisting of a monovalent hydrocarbon group, acyl group, hydrocarbon oxycarbonyl group, hydrocarbon sulfonyl group, and amide group that may have one or more substituents.
Specific examples of the amino-protective group PG1 are listed below. Incidentally, an amino-protective group may be referred to either by the name of the functional group excluding the nitrogen atom of the amino group to which it binds or by the name of the group including the nitrogen atom to which it binds. The following list includes either or both of these names for each protective group.
Examples of unsubstituted or substituted hydrocarbon groups includes: alkyl groups such as methyl group, ethyl group, and propyl group; alkenyl groups such as ethenyl group, propenyl group, and allyl group; alkylyl groups such as propargyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group; aryl groups such as phenyl group, benzyl group, p-methoxybenzyl group, tolyl group, and triphenylmethyl group (Troc group); and substituted hydrocarbon groups such as cyanomethyl group. The number of carbon atoms may typically be 1 or more, or 3 or more, and typically 20 or less, or 15 or less.
Examples of unsubstituted or substituted acyl groups includes: benzoyl group (Bz), o-methoxybenzoyl group, 2,6-dimethoxy benzoyl group, p-methoxybenzoyl group (PMPCO), cinnamoyl group, and phthaloyl group (Phth).
Examples of unsubstituted or substituted hydrocarbon oxycarbonyl groups includes: tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz or Z), methoxycarbonyl group, ethoxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, 2-phenyl ethoxycarbonyl group, 1-(1-adamanthyl)-1-methylethoxycarbonyl group, 1-(3,5-di-t-butylphenyl)-1-methylethoxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group (Alloc), N-hydroxypiperidinyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, 2-(1,3-dithianyl)methoxycarbonyl, m-nitrophenoxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group (Troc), and 9-fluorenylmethyloxycarbonyl group (Fmoc).
Examples of unsubstituted or substituted hydrocarbon sulfonyl groups includes: methane sulfonyl group (Ms), toluenesulfonyl group (Ts), and 2- or 4-nitro benzene sulfonyl (Ns) group.
Examples of unsubstituted or substituted amide groups includes: acetamide, o-(benzoyloxymethyl)benzamide, 2-[(t-butyl-diphenyl-siloxy)methyl]benzamide, 2-toluenesulfonamide, 4-toluenesulfonamide, 2-nitro benzene sulfonamide, 4-nitro benzene sulfonamide, tert-butylsulfinyl amide, 4-toluenesulfonamide, 2-(trimethylsilyl)ethane sulfonamide, and benzyl sulfonamide.
In terms of deprotection methods, the protective group PG1 may be deprotected by, e.g., at least one of the following methods: deprotection by hydrogenation, deprotection by weak acid, deprotection by fluorine ion, deprotection by one-electron oxidizing agent, deprotection by hydrazine, and deprotection by oxygen.
Preferred examples of the amino protective group PG1 include mesyl group (Ms), tert-butoxycarbonyl group (Boc), benzyl group (Bn or Bzl), benzyloxycarbonyl group (Cbz), benzoyl group (Bz), p-methoxybenzyl group (PMB), 2,2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), 2,4-dinitrophenyl group (2,4-DNP), phthaloyl group (Phth), p-methoxybenzoyl group (PMPCO), cinnamoyl group, toluenesulfonyl group (Ts), 2- or 4-nitrobenzenesulfonyl group (Ns), cyanomethyl group, and 9-fluorenylmethyloxycarbonyl group (Fmoc). These protective groups are preferred because, as mentioned above, they can easily protect the amino group and can be removed under relatively mild conditions.
More preferable examples of the amino protective group PG1 include mesyl group (Ms), tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), benzyl group (Bn), p-methoxybenzyl group (PMB), 2,2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), p-methoxybenzoyl group (PMPCO), benzoyl group (Bz), cyanomethyl group, cinnamoyl group, 2- or 4-nitrobenzenesulfonyl group (Ns), toluenesulfonyl group (Ts), phthaloyl group (Phth), 2,4-dinitrophenyl group (2,4-DNP), and 9-fluorenylmethyloxycarbonyl group (Fmoc).
Even more preferable examples of the amino protective group PG1 include mesyl group (Ms), tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), benzyl group (Bn), p-methoxybenzyl group (PMB), 2,2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), p-methoxybenzoyl group (PMPCO), benzoyl group (Bz), cyanomethyl group, and cinnamoyl group.
T2 represents a hydrogen atom or a monovalent substituent. The type of the monovalent substituent is not particularly limited, but may be selected from the examples of R31, R32, R34, and R36 mentioned above, as well as protective groups for carboxyl group (hereinafter also referred to as PG2). The carboxyl protective group PG2 is not limited as long as the carboxyl group can be protected so that it does not react in the amidation process, and then can be deprotected and converted to a carboxyl group after the reaction.
Examples of the carboxyl protective group PG2 include monovalent hydrocarbon groups or heterocyclic groups that may have one or more substituents. The details of the substituents, if any, are described above. Examples of the number of such substituents include, for example, 5, 4, 3, 2, 1, or 0.
The upper limit of the number of carbon atoms of each hydrocarbon group (including its substituents, if any) may be for example 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the hydrocarbon group, but may be 1 or more for alkyl groups, 2 or more for alkenyl and alkynyl groups, and 3 or more, such as 4 or more, or 5 or more, for cycloalkyl groups. Examples of the number of atoms include, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
The upper limit of the total number of carbon atoms and hetero atoms of each heterocyclic group (including its substituents, if any) may be, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit thereof depends on the type of the heterocyclic structure, but may typically be 3 or more, for example 4 or more, or 5 or more. Examples of the number of atoms include, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
Examples of the carboxyl protective group PG2 include, but are not limited to, the following.
*Alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, decyl group, and nonyl group;
*Alkenyl groups such as ethenyl group, propenyl group, allyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, and octenyl group;
*Alkylyl groups such as propargyl group;
*Cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, bicyclooctyl group, and spirooctyl group;
*Aryl groups such as phenyl group, benzyl group, tolyl group, naphthyl group, anthracenyl group;
*Heterocyclic groups such as furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-TH-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydro pyridyl group, hexahydro pyrimidyl group, hexahydro pyridazyl group, 1,2,4,6-tetrahydro pyridyl group, 1,2,4,6-tetrahydro pyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, 2,3-dihydro-1H-imidazolyl group, pyrazolyl group, 4,5-dihydro-1H-pyrazolyl group, 2,3-dihydro-1H-pyrazolyl group, oxazolyl group, 4,5-dihydro-1,3-oxazolyl group, 2,3-dihydro-1,3-oxazolyl group, 2,5-dihydro-1,3-oxazolyl group, thiazolyl group, 4,5-dihydro-1,3-thiazolyl group, 2,3-dihydro-1,3-thiazolyl group, 2,5-dihydro-1,3-thiazolyl group, and carbazolyl group; and
*Silicon-based protective groups such as trimethylsilyl (TMS) group, triethylsilyl (TES) group, triisopropylsilyl (TIPS) group, tri(tert-butyl)silyl (TBS) group, and tert-butyldiphenylsilyl (TBDPS) group.
In Embodiment (3), it is preferable to adjust the reaction procedure as described below in such a manner that (a) the first amino acid or peptide (3-1) is first contacted with the silane compound (C), and (b) finally with the second amino acid or peptide (3-2). This makes it possible to selectively form an amide bond between the terminal carboxyl group of the compound (3-1) on the right side of the formula and the terminal amino group of the compound (3-2) on the left side of the formula and link them together, even when any amino groups or any carboxyl groups present in the reactant compounds (3-1) and (3-2) that should not be subject to amidation reaction (e.g., the amino group of the compound (3-1) on the left side of the formula, or the carboxyl group on the right in the compound (3-2) on the right side of the formula) are not protected with protective groups PG1 or PG2. Therefore, when this reaction procedure is employed, it is preferred that at least either of T1 and T2 is a hydrogen atom, and it is more preferred that both of T1 and T2 are hydrogen atoms.
With regard to the compound (3-2), the amino group on the left side of general formula (3-2) may form a salt with an acid. In this case, examples of the acid include, but are not limited to’ aliphatic carboxylic acids with 1 to 5 carbon atoms, such as acetic acid and propionic acid; and trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and sulfonic acid.
Embodiment (3) is deemed a specific embodiment of Embodiment (1) in which the compound (1-1) and the compound (1-2) are both amino acids or peptides and the compound (1-3) is a peptide. Likewise, Embodiment (2) has a specific embodiment in which the compound (2-1) is an amino acid or peptide and the compound (2-3) is a cyclic peptide. The details of such a specific embodiment are clear to those skilled in the art, taking into account the details of Embodiments (2) and (3) explained above.
In all of these embodiments, some or all of the reactant compounds may be linked or immobilized to a substrate, resin, or other carrier at any of their substituents. In this case, the type of the substrate, resin, or other carrier is not limited. Any known substrate, resin, or other carrier can be used as long as it does not substantially interfere with the amide reaction in the production method according to the present invention and does not depart from the purpose of the present invention. There are no restrictions the manner of linking and immobilizing the reactant compound to the substrate, resin, or other carrier, although it is preferable to form a covalent bond between any substituent of the reactant compound and any substituent present on the substrate, resin, or other carrier. There are also no restrictions on the type of each substituent and the method of forming a covalent bond. Any known substituent and covalent bond formation method can be used as long as it does not substantially interfere with the amide bond reaction in the production method according to the present invention and does not depart from the purpose of the present invention. When the reactant compounds are amino acids or peptides, such as in the case of Embodiment (3), the reactant compound may be linked and immobilized to a substrate, resin, or other carrier by covalent bonding using a carboxyl or amino group of the reactant compound (other than the carboxyl or amino group being the target of the amide reaction). Such a mode can be regarded as a variation of the embodiment in which the carboxyl or amino group of the reactant compound (other than the carboxyl or amino group being the target of the amide reaction) is protected by introducing a protective group.
The amounts of the reactant compounds used in the production method according to the present invention depend on the embodiment of the production method according to the present invention, but are generally as follows.
In the case of Embodiment (1), the amount ratio between the compound (1-1) and the compound (1-2) is not particularly limited, but may be determined as follows. The molar ratio of the compound (1-2) to 1 mol of the compound (1-1) may be typically 0.1 mol or more, for example 0.2 mol or more, 0.3 mol or more, or 0.5 mol or more, and may be typically 20 mol or less, for example 10 mol or less, 8 mol or less, 6 mol or less, 5 mol or less, or 2 mol or less. It is preferable to use the compound (1-1) in a higher amount than that of the compound (1-2) in order to increase the efficiency of the reaction. Specifically, the molar ratio of the compound (1-2) to 1 mol of the compound (1-1) may be 0.5 or less. Needless to say, it is necessary to use at least 1 mol of each of the reactant compounds (1-1) and (1-2) for 1 mol of the target compound (1-3) to be produced.
In the case of Embodiment (3), the amount ratio between the compound (3-1) and the compound (3-2) is the same as in Embodiment (1). Specifically, although the ratio in Embodiment (3) is not particularly limited to, the molar ratio of the compound (3-2) to 1 mol of the compound (3-1) may typically be 0.1 mol or more, for example 0.2 mol or more, 0.3 mol or more, or 0.5 mol or more, and also may be typically 20 mol or less, for example 10 mol or less, 8 mol or less, 6 mol or less, 5 mol or less, or 2 mol or less. It is preferable to use the compound (3-1) in a higher amount than that of the compound (3-2) in order to increase the efficiency of the reaction. Specifically, the molar ratio of the compound (3-2) to 1 mol of the compound (3-1) may be 0.5 or less. Needless to say, it is necessary to use at least 1 mol of each of the reactant compounds (3-1) and (3-2) for 1 mol of the target compound (3-3) to be produced.
On the other hand, in the case of Embodiment (2), such an adjustment of the amount ratio is unnecessary since only one reactant is used, i.e., the compound (2-1). Needless to say, it is necessary to use at least 1 mol of the reactant compound (2-1) for 1 mol of the target compound (2-2) to be produced.
The amount(s) of the silane compound (C) (the reaction agent according to the present invention) is not particularly limited, so long as the desired amidation reaction between a carboxyl group and an amino group can be induced through the implementation of the production method according to the present invention. For example, for 1 mol of each reactant compound, each of the silane compound (C) may be used in an amount of typically 0.1 mol or more, for example 0.2 mol or more, 0.3 mol or more, 0.5 mol or more, or 1 mol or more. On the other hand, there is no restriction on the upper limit of the amount of silane compound (C) used. For example, for 1 mol of each reactant compound, each of the silane compound (C) may be used in an amount of typically 20 mol or less, for example, 10 mol or less, 8 mol or less, 6 mol or less, or 5 mol or less, or 2 mol or less for reaction efficiency. When two or more silane compound (C) are used, the total amount of the two or more silane compound (C) may preferably satisfy the range mentioned above.
In the production method according to the present invention, the reaction system may contain a Lewis acid catalyst, in addition to the reactant compound(s) and the silane compound (C) (the reaction agent(s) according to the present invention). Various advantages may be obtained by carrying out a reaction in the presence of a Lewis acid catalyst in the reaction system, such as improved reaction yield and stereoselectivity. On the other hand, however, if a Lewis acid catalyst is used, it may be necessary to separate and remove the Lewis acid catalyst from the reaction product. Therefore, it is preferable to determine whether or not to use a Lewis acid catalyst in consideration of the purpose of using the production method according to the present invention.
When a Lewis acid catalyst is used in the production method according to the present invention, the type of catalyst is not limited, but it may preferably be a metal compound that functions as a Lewis acid.
Examples of metal elements constituting the metal compound include various metals belonging to groups 2 through 15 of the periodic table. Examples of such metal elements include boron, magnesium, aluminum, gallium, indium, silicon, calcium, lead, bismuth, mercury, transition metals, and lanthanoid elements. Examples of transition metals include scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, tin, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, and thallium. Examples of lanthanoid elements include lanthanum, cerium, neodymium, samarium, europium, gadolinium, holmium, erbium, thulium, ytterbium. From the viewpoint of excellent reaction acceleration and highly stereoselective production of amide compounds, the metal element may preferably be one or more selected from titanium, zirconium, hafnium, tantalum, niobium, boron, vanadium, tungsten, neodymium, iron, lead, cobalt, copper, silver, palladium, tin, and thallium, more preferably one or more selected from titanium, zirconium, hafnium, tantalum, and niobium. The metal compound may contain one, two or more metal atoms. If the metal compound contains two or more metal atoms, the two or more metal atoms may be either of the same metal element or of different metal elements.
Ligands constituting the metal compound may be selected according to the type of the metal element. Examples of ligands include: substituted or unsubstituted linear- or branched-chain alkoxy groups containing 1 to 10 carbon atoms, such as methoxy group, ethoxy group, propoxy group, butoxy group, trifluoroethoxy group, and trichloroethoxy group; halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom; aryloxy groups having 1 to 10 carbon atoms; acetylacetonate group (acac), acetoxy group (AcO), trifluoromethane sullfonate group (TfO); substituted or unsubstituted linear- or branched-chain alkyl groups having 1 to 10 carbon atoms; phenyl group, oxygen atom, sulfur atom, group —SR (where R represents a substituent exemplified by substituted or unsubstituted hydrocarbon groups containing 1 to 20 carbon atoms), group —NRR′ (where R and R′, independently of each other, represent a hydrogen atom or a substituent exemplified by substituted or unsubstituted hydrocarbon groups containing 1 to 20 carbon atoms), and cyclopentadienyl (Cp) group.
Preferred metal compounds among these are titanium compounds, zirconium compounds, hafnium compounds, tantalum compounds, or niobium compounds. Examples of these metal compounds are indicated below.
Examples of titanium compounds include those represented by TiX14 (where 4 X1's, independently of each other, represent any of the ligands exemplified above, provided that 4 X1's may be the same type of ligand or different from each other). When X1 is an alkoxy group, it may preferably be a linear- or branched-chain alkoxy group having 1 to 10 carbon atoms, more preferably a linear- or branched-chain alkoxy group having 1 to 5 carbon atoms, still more preferably a linear- or branched-chain alkoxy group having 1 to 4 carbon atoms. When X1 is an aryloxy group, it may preferably be an aryloxy group having 1 to 20 carbon atoms, more preferably an aryloxy group having 1 to 15 carbon atoms, still more preferably an aryloxy group having 1 to 10 carbon atoms. These ligands may have one or more substituents. When X1 is a halogen atom, it may preferably be a chlorine atom or a bromine atom. Preferred examples of titanium compounds include Ti(OMe)4, Ti(OEt)4, Ti(OPr)4, Ti(Oi-Pr)4, Ti(OBu)4, Ti(Ot-Bu)4, Ti(OCH2CH(Et)Bu)4, CpTiCl3, Cp2TiCl2, Cp2Ti(OTf)2, (i-PrO)2TiCl2, and (i-PrO)3TiCl.
Examples of zirconium compounds include those represented by ZrX24 (where 4 X2's, independently of each other, represent any of the ligands exemplified above, provided that 4 X2's may be the same type of ligand or different from each other). When X2 is an alkoxy group, it may preferably be a linear- or branched-chain alkoxy group having 1 to 10 carbon atoms, more preferably a linear- or branched-chain alkoxy group having 1 to 5 carbon atoms, still more preferably a linear- or branched-chain alkoxy group having 1 to 4 carbon atoms. When X2 is an aryloxy group, it may preferably be an aryloxy group having 1 to 20 carbon atoms, more preferably an aryloxy group having 1 to 15 carbon atoms, still more preferably an aryloxy group having 1 to 10 carbon atoms. These ligands may have one or more substituents. When X2 is a halogen atom, it may preferably be a chlorine atom or a bromine atom. Preferred examples of zirconium compounds include Zr(OMe)4, Zr(OEt)4, Zr(OPr)4, Zr(Oi-Pr)4, Zr(OBu)4, Zr(Ot-Bu)4, Zr(OCH2CH(Et)Bu)4, CpZrCl3, Cp2ZrCl2, Cp2Zr(OTf)2, (i-PrO)2ZrCl2, and (i-PrO)3ZrCl.
Examples of hafnium compounds include those represented by HfX34 (where 4 X3's, independently of each other, represent any of the ligands exemplified above, provided that 4 X3's may be the same type of ligand or different from each other). When X3 is an alkoxy group, it may preferably be a linear- or branched-chain alkoxy group having 1 to 10 carbon atoms, more preferably a linear- or branched-chain alkoxy group having 1 to 5 carbon atoms, still more preferably a linear- or branched-chain alkoxy group having 1 to 4 carbon atoms. When X3 is an aryloxy group, it may preferably be an aryloxy group having 1 to 20 carbon atoms, more preferably an aryloxy group having 1 to 15 carbon atoms, still more preferably an aryloxy group having 1 to 10 carbon atoms. These ligands may have one or more substituents. When X3 is a halogen atom, it may preferably be a chlorine atom or a bromine atom. Preferred examples of hafnium compounds include HfCp2Cl2, HfCpCl3, and HfCl4.
Examples of tantalum compounds include those represented by TaX45 (where 5 X4's, independently of each other, represent any of the ligands exemplified above, provided that 5 X4's may be the same type of ligand or different from each other). When X4 is an alkoxy group, it may preferably be a linear- or branched-chain alkoxy group having 1 to 10 carbon atoms, more preferably a linear- or branched-chain alkoxy group having 1 to 5 carbon atoms, still more preferably a linear- or branched-chain alkoxy group having 1 to 4 carbon atoms. When X4 is an aryloxy group, it may preferably be an aryloxy group having 1 to 20 carbon atoms, more preferably an aryloxy group having 1 to 15 carbon atoms, still more preferably an aryloxy group having 1 to 10 carbon atoms. These ligands may have one or more substituents. When X4 is a halogen atom, it may preferably be a chlorine atom or a bromine atom. Preferred examples of tantalum compounds include tantalum alkoxide compounds (e.g., compounds in which X4 is an alkoxy group) such as Ta(OMe)5, Ta(OEt)5, Ta(OBu)5, Ta(NMe2)5, Ta(acac)(OEt)4, TaCl5, TaCl4(THF), and TaBr5. Other examples are those in which X4 is an oxygen, such as Ta2O5.
Examples of niobium compounds include those represented by NbX55 (where 5 X5's, independently of each other, represent any of the ligands exemplified above, provided that 5 X5's may be the same type of ligand or different from each other). When X5 is an alkoxy group, it may preferably be a linear- or branched-chain alkoxy group having 1 to 10 carbon atoms, more preferably a linear- or branched-chain alkoxy group having 1 to 5 carbon atoms, still more preferably a linear- or branched-chain alkoxy group having 1 to 4 carbon atoms. When X5 is an aryloxy group, it may preferably be an aryloxy group having 1 to 20 carbon atoms, more preferably an aryloxy group having 1 to 15 carbon atoms, still more preferably an aryloxy group having 1 to 10 carbon atoms. These ligands may have one or more substituents. When X5 is a halogen atom, it may preferably be a chlorine atom or a bromine atom. Preferred examples of niobium compounds include niobium alkoxide compounds (e.g., compounds in which X5 is an alkoxy group) such as NbCl4(THF), NbCl5, Nb(OMe)5, and Nb(OEt)5. Other examples are those in which X5 is an oxygen, such as Nb2O5.
Preferred metal compounds as Lewis acid catalysts in the production method according to the present invention also depend on the type of the reactant compound(s).
For example, in the case of Embodiment (3) where the compound (3-1) and the compound (3-2) are both amino acids (i.e., m and n are both 1), then a tantalum or niobium compound is preferred as a Lewis acid catalyst.
On the other hand, in the case of Embodiment (3) where at least either the compound (3-1) and the compound (3-2) is a peptide (i.e., at least either m and n is equal to or greater than 2), then the Lewis acid catalyst may preferably be a titanium compound, zirconium compound, or hafnium compound, more preferably a titanium compound. The reason for this is not clear, but presumably because titanium catalysts are suitable for activation in a 7-membered ring including the peptide bond as the starting functional group, due to the small atomic radius of the titanium metal, which has little effect on the steric hindrance of the peptide chain.
These Lewis acid catalysts may be used either singly or in combination of any two or more.
The amount of the Lewis acid catalyst used is not limited so long as the desired amidation reaction between carboxyl and amino groups can be induced through the implementation of the production method according to the present invention. For example, when the amount of each reactant compound used is considered 100 mol %, the amount of the Lewis acid catalyst may preferably be 0.1 mol % or more, for example 0.2 mol % or more, or 0.3 mol % or more, and may preferably be 30 mol % or less, for example 20 mol % or less, or 15 mol % or less.
The Lewis acid catalyst may be loaded on a carrier. There are no particular restrictions on the carrier on which the Lewis acid catalyst is to be loaded, and any known carrier can be used. Also, any known method can be used to load the Lewis acid catalyst on the carrier.
In the production method according to the present invention, the reaction system may contain a phosphorus compound, in addition to the reactant compound(s) and the silane compound (C) (the reaction agent(s) according to the present invention), as well as and/or the Lewis acid catalyst optionally used. Various advantages may be obtained by conducting the reaction with a phosphorus compound in the reaction system, such as improved reaction yield and stereoselectivity.
When a phosphorus compound is used in the production method according to the present invention, the type of the phosphorus compound used is not particularly limited, but it may preferably be a trivalent phosphorus compound such as a phosphine compound or a phosphate compound.
Preferred phosphine compounds include those represented by general formula R3P or (RO)3P (where R, independently of each other, represents an aliphatic or aromatic hydrocarbon group or heterocyclic group that may have one or more substituents. preferably an alkyl group having 1 to 10 carbon atoms or an aryl group having 6 to 12 carbon atoms, the substituents (if any) being preferably, independently of each other, selected form alkyl groups or alkoxy groups having 1 to 5 carbon atoms and halogen atoms). Examples of such phosphine compounds include trimethyl phosphine, triethyl phosphine, tripropyl phosphine, trimethyloxy phosphine, triethyloxy phosphine, tripropyloxy and phosphine, triphenyl phosphine, trinaphthyl phosphine, and triphenyloxy phosphine, as well as compounds derived from these compounds via substitution with one or more substituents such as methyl group, methoxy group, and fluoro group, including tris(4-methylphenyl)phosphine, tris(4-methoxyphenyl)phosphine, tris(4-fluorophenyl)phosphine, tris(4-methylphenyloxy)phosphine, tris(4-methoxyphenyloxy)phosphine, and tris(4-fluorophenyloxy)phosphine.
Preferred phosphate compounds include those represented by general formula (RO)3PO (where R, independently of each other, represents an aliphatic or aromatic hydrocarbon group or heterocyclic group that may have one or more substituents. preferably an alkyl group having 1 to 10 carbon atoms or an aryl group having 6 to 12 carbon atoms, the substituents (if any) being preferably, independently of each other, selected form alkyl groups or alkoxy groups having 1 to 5 carbon atoms and halogen atoms). Examples of such phosphine compounds include trimethyl phosphate, triethyl phosphate, tripropyl phosphate, trimethyloxy phosphate, triethyloxy phosphate, tripropyloxy phosphate, triphenyl phosphate, trinaphthyl phosphate, and triphenyloxy phosphate, as well as compounds derived from these compounds via substitution with one or more substituents such as methyl group, methoxy group, and fluoro group, including tris(4-methylphenyl)phosphate, tris(4-methoxyphenyl)phosphate, tris(4-fluorophenyl)phosphate, tris(4-methylphenyloxy)phosphate, tris(4-methoxyphenyloxy)phosphate, and tris(4-fluorophenyloxy)phosphate.
It is also possible to use multivalent phosphine compounds or multivalent phosphate compounds, which can be obtained by linking two or more molecules of any of the phosphine compounds or phosphate compounds mentioned above. Examples of such multivalent phosphine compounds or multivalent phosphate compounds include 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) and 5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole (SEGPHOS).
When a phosphorus compound is used in the production method according to the present invention, the among of the phosphorus compound used is not particularly limited, although when the amount of the reactant compound is considered to be 100 mol %, the amount of the phosphorus compound may be 0.1 mol % or more, and 20 mol % or less, or 10 mol % or less.
In the production method according to the present invention, the reaction system may contain one or more other ingredients, in addition to the reactant compound(s) and the silane compound (C) (the reaction agent(s) according to the present invention), as well as the Lewis acid catalyst and/or the phosphorus compound optionally used. Various advantages may be obtained by conducting the reaction with a phosphorus compound in the reaction system, such as improved reaction yield and stereoselectivity.
For example, from the viewpoint of increasing reaction efficiency, a base may be coexisted during the amidation reaction. The type of the base is not particularly limited, but examples thereof include amines having 1 to 3 linear- or branched-chain alkyl groups having 1 to 10 carbon atoms, such as triethylamine (Et3N), diisopropylamine (i-Pr2NH), and diisopropylethylamine (i-Pr2EtN). There are no restrictions as to the amount of the base used is not particularly limited, but when the amount of each reactant compound is considered to be 100 mol %, the amount of the base used may be 0.1 mol % or more, or 5 mol % or more, and may be 120 mol % or less, or 100 mol % or less.
Amidation by the production method according to the present invention can be carried out by contacting the reactant compound(s) with the silane compound (C), and optionally with the Lewis acid catalyst, the phosphorus compound, and/or the other ingredients if used. The order of contacting these components is not limited, and all may be mixed simultaneously or sequentially in any order. Specific examples include, but are not limited to, the following procedures.
For example, if there are no other carboxyl groups, amino groups, and/or other reactive groups than the carboxyl and amino groups being the target of the desired amidation reaction, or if such other carboxyl groups, amino groups, or other reactive groups are protected with protective groups, the order of contact is not particularly limited. However, from the standpoint of reaction efficiency, it is preferred to mix the reactant compounds and the silane compound (C) simultaneously, optionally with the Lewis acid catalyst, the phosphorus compound, and/or the other components. When each of other carboxyl groups and/or amino groups than the target carboxyl and amino groups is protected with a protective group, it would be necessary to carry out a protection step to introduce the protective group before the amidation reaction, and also a deprotection step to remove the protective group after the amidation reaction.
On the other hand, when, as in the case of Embodiment (3), the terminal carboxyl group of the first amino acid or peptide (3-1) is reacted with the terminal carboxyl group of the second amino acid or peptide (3-2), the reaction may preferably be carried out in the following order: (a) the first amino acid or peptide (3-1) is contacted with the silane compound (C); and (b) the second amino acid or peptide (3-2) is then brought into contact. This procedure allows selective amidation reaction to occur between the terminal carboxyl group of the first amino acid or peptide (3-1) and the terminal amino group of the second amino acid or peptide (3-2) without protecting other carboxyl and/or amino groups of each reactant compound that are not subject to the amidation reaction. This reaction procedure is highly desirable from the standpoint of efficiency since it eliminates the need for a protection step to introduce a protecting group before the amidation reaction and a deprotection step to remove the protecting group after the amidation reaction. In this reaction procedure, the timing of addition of optionally used components (such as the Lewis acid catalyst, the phosphorus compound, and/or the other ingredients) is not restricted and can be added at any stage.
The silane compound (C) may be either added to the reaction system directly as the final compound or may be generated in the reaction system by reacting raw material compounds for the desired compound in the system. For example, when a silyl imidazole compound (e.g., dimethylsilyl(2-methyl)imidazole) is used as the silane compound (C), the desired silylimidazole compound can be synthesized by adding a corresponding silyl halide (e.g., silyl chloride) and a corresponding imidazole compound (e.g., 2-methylimidazole) in the system and causing them to react each other. In this case, since the amount of hydrogen halide (e.g., hydrochloric acid) generated is equivalent to the amount of the silyl imidazole compound, it is necessary to use two or more equivalents of the imidazole compound to the silyl halide. A person skilled in the art can select and implement various methods for the in-system synthesis of such silane compounds based on technical common knowledge.
From the viewpoint of increasing reaction efficiency, amidation may be carried out in an organic solvent. The type of the organic solvent is not particularly limited, examples thereof including: aromatic hydrocarbons such as toluene and xylene; pentane; ethers such as petroleum ether, 1-methyltetrahydrofuran (1-MeTHF), diisopropylether (i-Pr2O), diethylether (Et2O), cyclopentylmethylether (CPME): esters such as ethyl acetate (AcOEt); and organic acids such as acetic acid. These organic solvents may be used either singly or in combination of any two or more.
The concentration of each reactant compound in the reaction system is not restricted, but from the viewpoint of increasing reaction efficiency, it may be between 2 volume % and 70 volume %.
The conditions for the amidation reaction in the production method according to the present invention are not limited as long as the reaction proceeds, although examples of the conditions for each reaction step are described below.
When the reactant compound(s) is mixed with the silane compound (C) simultaneously, along with optionally-used components such as the Lewis acid catalyst, the phosphorus compound, and/or the other ingredients, the reaction condition are not limited as long as the reaction proceeds, examples thereof being as follows.
The reaction temperature is not limited as long as the reaction proceeds, although it may typically be 0° C. or more, particularly 10° C. or more, especially 20° C. or more, and also may typically be 100° C. or less, particularly 80° C. or less, especially 60° C. or less. In this regard, the production method according to the present invention is advantageous because the amidation reaction sufficiently proceeds even under a mild condition, e.g., at a temperature of 60° C. or less.
The reaction pressure is not limited as long as the reaction proceeds, and the reaction may be carried out under reduced, normal, or pressurized pressure, but may typically be carried out under normal pressure.
The reaction atmosphere is also not limited as long as the reaction proceeds, but the reaction may be carried out under an atmosphere of inert gas such as argon or nitrogen.
The reaction time is also not limited as long as the reaction proceeds. However, in order for the reaction to proceed sufficiently and efficiently, the reaction time may be 10 minutes or more, particularly 20 minutes or more, or 30 minutes or more, and may be 80 hours or less, particularly 60 hours or less, or 50 hours or less.
On the other hand, in the case of Embodiment (3) in which the reaction is carried out in such an order as to omit the protection step and the deprotection step, i.e., in such a manner that (a) the first amino acid or peptide (3-1) is contacted with the silane compound (C); and (b) the second amino acid or peptide (3-2) is then brought into contact, the reaction conditions for each of steps (a) and (b) are not limited as long as the reaction proceeds, examples thereof being as follows.
The reaction temperature at step (a) is not limited as long as the reaction proceeds, although it may typically be 0° C. or more, particularly 10° C. or more, especially 20° C. or more, and also may typically be 100° C. or less, particularly 80° C. or less, especially 60° C. or less.
The reaction time at step (a) is not limited as long as the reaction proceeds. However, in order for the reaction to proceed sufficiently and efficiently, the reaction time may be 10 minutes or more, particularly 20 minutes or more, or 30 minutes or more, and also may be 10 hours or less, particularly 5 hours or less, or 3 hours or less.
The reaction temperature at step (b) is not limited as long as the reaction proceeds, although it may typically be 0° C. or more, particularly 10° C. or more, especially 20° C. or more, and also may typically be 100° C. or less, particularly 80° C. or less, especially 60° C. or less.
The reaction time at step (b) is not limited as long as the reaction proceeds. However, in order for the reaction to proceed sufficiently and efficiently, the reaction time may be 10 minutes or more, particularly 20 minutes or more, or 30 minutes or more, and also may be 10 hours or less, particularly 5 hours or less, or 3 hours or less.
The reaction pressure and atmosphere at steps (a) and (b) are not limited as long as the reaction proceeds, although the reaction may typically be carried out under normal pressure and under an atmosphere of inert gas such as argon or nitrogen.
In all of these embodiments, the production method according to the present invention (or, if the method includes two or more steps, each of the steps) may be carried out in a sequential manner (batch) or in a continuous manner (flow). Details of specific procedures for implementing a sequential method (batch method) and a continuous method (flow method) are well known in the art.
The production method according to the present invention may include the step of carrying out various post-processing onto the amido compound produced via the amidation reaction.
For example, the amide compound formed may be isolated and purified according to conventional methods such as column chromatography, recrystallization, etc.
When T1 is the protective group PG1 and/or T2 is the protective group PG2, the amino group protected by PG1 and/or the carboxyl group protected by PG2 of the amide compound produced may be deprotected, optionally after post-processing steps such as isolation and purification.
The method of deprotecting the amino group protected by PG1 is not particularly restricted, and various methods can be used depending on the type of protecting group PG1. Examples include deprotection by hydrogenation, deprotection by weak acids, deprotection by fluorine ions, deprotection by one-electron oxidants, deprotection by hydrazine, and deprotection by oxygen. The deprotection by hydrogenation may be carried out by, e.g.; (a) a method of causing deprotection in the presence of hydrogen gas using a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium-carbon hydroxide, etc., as a reduction catalyst; and (b) a method of causing deprotection in the presence of a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium-carbon hydroxide, etc., using a hydrotreating reductant such as sodium borohydride, lithium aluminum hydride, lithium borohydride, diborane, etc.
The method of deprotecting the carboxyl group protected by PG2 is not particularly restricted, and various methods can be used depending on the type of protecting group PG2. Examples include deprotection by hydrogenation, deprotection by bases, and deprotection by weak acids. In the case of deprotection with a base, a strong base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. can be used.
After conducting the amidation reaction by the production method according to the present invention, the resulting amide compound (if necessary, after deprotection) can be subjected to the production method according to the present invention again as a new reactant compound and linked to another reactant compound by an amide bond.
For example, in the case of Embodiment (3), a peptide obtained via an amidation reaction through the production method according to the present invention can be subjected to the production method according to the present invention to thereby cause an amidation reaction between the terminal amino or carboxyl group of the peptide and the terminal carboxyl or amino group of another amino acid or peptide to produce a novel peptide. Thus, the production method according to the present invention can be repeated in sequence, whereby a peptide having any amino acid sequence can be synthesized in principle.
Alternatively, after an amidation reaction is carried out via the production method according to the present invention, the resulting peptide may be bound to another amino acid using any other amidation methods. An example of such other amidation methods is the method described in WO 2018/199147 A (PTL 3), which was also developed by the present inventors. The method described in WO 2018/199147 A is a method for forming an amide bond between the carboxyl group of a first amino acid or peptide and the amino group of a second amino acid in the presence of a metal catalyst such as a specific tantalum or niobium compound. Specifically, in the case of Embodiment (3), the carboxyl protective group PG2 of the compound (3-2) may be selected from the protective groups that can react in the presence of a metal catalyst such as a certain tantalum or niobium compound used in the method described in WO 2018/199147 A. This compound (3-2) may be used in the production method according to the present invention to thereby produce the compound (3-3), which may be subjected to the method described in WO 2018/199147 A, thereby linking the compound (3-3) with another amino acid via amidation reaction.
The present invention will be described in more detail below with reference to examples. However, the present invention should in no way be bound by the following examples, and can be implemented in any form within the scope that does not depart from the purpose of the invention.
Production of amide compounds using the production method according to the present invention was carried out in accordance with the methods described in the example sections below.
In the following examples, diastereomeric or enantiomeric ratios were determined by 1H-NMR analysis (measuring instrument: JEOL 400SS (JEOL Ltd.); measurement conditions: 400 MHz; solvent: CDCl3), unless otherwise stated.
L-Ala-Ot-Bu·HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine (Aldrich Co. LLC) to produce L-Ala-Ot-Bu.
A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer, Boc-L-Asp(OH)-Ot-Bu (Watanabe Chemical Industries, Ltd., 578.6 mg, 2.0 mmol), the L-Ala-Ot-Bu (145.2 mg, 1.0 mmol), 1-(trimethylsilyl)imidazole (Tokyo Chemical Industry Co., Ltd., 308.6 mg, 2.2 mmol), and Ta(OMe)5 (Aldrich Co. LLC, 33.6 mg, 0.10 mmol), and the vial was closed with a screw cap and sealed under an argon atmosphere. This screw-cap vial was then taken out of the glove box and placed in an oil bath, stirred at a reaction temperature of 50° C. for 72 hours, and then removed from the oil bath and allowed to cool to room temperature. The resulting reaction product in the screw-cap vial was diluted with chloroform (Waco Chemical Industries, Ltd., 15 mL) and purified with flash silica gel column chromatography (ethyl acetate/n-hexane), subjected to removal of the solvent using an evaporator, whereby Boc-L-Asp(L-Ala-Ot-Bu)-Ot-Bu(393.0 mg) was obtained as a white solid. The yield was 94%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 1-1 except that Boc-L-Asp(OH)-Ot-Bu was changed to Boc-L-Lys(Boc)-OH (Watanabe Chemical Industries, Ltd., 692.8 mg, 2.0 mmol), whereby Boc-L-Lys(Boc)-L-Ala-Ot-Bu(424.8 mg) was obtained. The yield was 90%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 1-1 except that Boc-L-Asp(OH)-Ot-Bu was changed to Boc-L-Pro-OH (Watanabe Chemical Industries, Ltd., 430.5 mg, 2.0 mmol), whereby Boc-L-Pro-L-Ala-Ot-Bu(341.4 mg) was obtained. The yield was 99%, and the diastereomeric ratio was >99:1.
In a similar manner to that in Example 1-1, a vial was charged with Boc-L-Ala-OH (Watanabe Chemical Industries, Ltd., 378.4 mg, 2.0 mmol), Gly-Ot-Bu (Combi-Blocks Inc., 131.2 mg, 1.0 mmol), 1-(trimethylsilyl)imidazole (308.6 mg, 2.2 mmol), and Ta(OMe)5 (33.6 mg, 0.10 mmol), and then closed with a screw cap and sealed under an argon atmosphere, and allowed to cause reaction in a similar manner to that in Example 1-1, whereby Boc-L-Ala-Gly-Ot-Bu (290.5 mg) was obtained as a white solid. The yield was 96%, and the enantiomer ratio was >99:1.
L-Trp(Boc)-Ot-Bu·HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Trp(Boc)-Ot-Bu.
The reaction was carried out in the same manner as in Example 1-4 except that Gly-Ot-Bu was changed to the thus-produced L-Trp(Boc)-Ot-Bu (360.5 mg, 1.0 mmol), whereby Boc-L-Ala-L-Trp(Boc)-Ot-Bu (486.1 mg) was obtained as a white solid. The yield was 91%, and the diastereomeric ratio was >99:1.
L-Asp(t-Bu)-Ot-Bu-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Asp(t-Bu)-Ot-Bu.
The reaction was carried out in the same manner as in Example 1-4 except that Gly-Ot-Bu was changed to the thus-produced L-Asp(t-Bu)-Ot-Bu (245.3 mg, 1.0 mmol), whereby Boc-L-Ala-L-Asp(t-Bu)-Ot-Bu (415.9 mg) was obtained as a white solid. The yield was 99%, and the diastereomeric ratio was >99:1.
L-Cys(Trt)-Ot-Bu-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Cys(Trt)-Ot-Bu.
The reaction was carried out in the same manner as in Example 1-4 except that Gly-Ot-Bu was changed to the thus-produced L-Cys(Trt)-Ot-Bu (419.5 mg, 1.0 mmol), whereby Boc-L-Ala-L-Cys(Trt)-Ot-Bu (585.0 mg) was obtained as a white solid. The yield was 99%, and the diastereomeric ratio was >99:1.
L-Lys(Boc)-Ot-Bu-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Lys(Boc)-Ot-Bu.
The reaction was carried out in the same manner as in Example 1-4 except that Gly-Ot-Bu was changed to the thus-produced L-Lys(Boc)-Ot-Bu (302.4 mg, 1.0 mmol), whereby Boc-L-Ala-L-Lys(Boc)-Ot-Bu (462.1 mg) was obtained as a white solid. The yield was 98%, and the diastereomeric ratio was >99:1.
L-Arg(Mtr)-Ot-Bu-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Arg(Mtr)-Ot-Bu.
The reaction was carried out in the same manner as in Example 1-4 except that Gly-Ot-Bu was changed to the thus-produced L-Arg(Mtr)-Ot-Bu (442.6 mg, 1.0 mmol), whereby Boc-L-Ala-L-Arg(Mtr)-Ot-Bu (530.6 mg) was obtained as a white solid. The yield was 86%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 1-4 except that Gly-Ot-Bu was changed to L-Asn-Ot-Bu (Watanabe Chemical Industries, Ltd., 188.2 mg, 1.0 mmol) and chloroform (0.5 mL) was added, whereby Boc-L-Ala-L-Asn-Ot-Bu (345.4 mg) was obtained as a white solid. The yield was 96%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 1-4 except that Gly-Ot-Bu was changed to L-His(Trt)-Ot-Bu (Watanabe Chemical Industries, Ltd., 453.6 mg, 1.0 mmol), whereby Boc-L-Ala-L-His(Trt)-Ot-Bu (611.6 mg) was obtained as a white solid. The yield was 98%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 1-4 except that Boc-L-Ala-OH was changed to Bz-L-Ala-OH (Watanabe Chemical Industries, Ltd., 386.4 mg, 2.0 mmol) and Gly-Ot-Bu was changed to L-Pro-Ot-Bu (Watanabe Chemical Industries, Ltd., 145.2 mg, 1.0 mmol), whereby Bz-L-Ala-L-Pro-Ot-Bu (314.9 mg) was obtained as a white solid. The yield was 91%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 1-1 except that Boc-L-Ala-OH was changed to Boc-L-Asn(Trt)-OH (Watanabe Chemical Industries, Ltd., 949.2 mg, 2.0 mmol), L-Ala-Ot-Bu was changed to L-Ala-Ot-Bu·HCl (181.7 mg, 1.0 mmol), which was used without neutralization, DMSO (0.5 mL) was added, and the reaction temperature was changed to 40° C., whereby Boc-L-Asn(Trt)-L-Ala-Ot-Bu (214.2 mg) was obtained. The yield was 71%, and the diastereomeric ratio was >99:1.
L-Ile-Ot-Bu-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Ile-Ot-Bu.
In a similar manner to that in Example 1-1, a vial was charged with Boc-β-HoGly-OH (Watanabe Chemical Industries, Ltd., 182.9 mg, 1.0 mmol), the L-Ile-Ot-Bu (Watanabe Chemical Industries, Ltd., 93.6 mg, 0.5 mmol), 1-(trimethylsilyl)imidazole (154.3 mg, 1.1 mmol), and Ta(OMe)5 (16.8 mg, 0.05 mmol), and was closed with a screw cap and sealed under an argon atmosphere. The mixture was then allowed to cause reaction in the same manner as in Example 1-1 except that the stirring was made at a reaction temperature of 40° C. for 48 hours, whereby Boc-β-HoGly-L-Ile-Ot-Bu (179.0 mg) was obtained as a white solid. The yield was 99%, and the diastereomeric ratio was >99:1.
In addition, the reaction was carried out in the same manner except that instead of L-Ala-Ot-Bu, L-Ile-Ot-Bu, L-Ile-Ot-Bu-HCl (111.9 mg, 0.5 mmol) was used as such without neutralization, whereby Boc-β-HoGly-L-Ile-Ot-Bu (178.9 mg) was obtained. The yield was >99%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 2-1 except that Boc-β-HoGly-OH was changed to Bz-Q-HoGly-OH(Tokyo Chemical Industry Co., Ltd., 193.2 mg, 1.0 mmol), whereby Bz-β-HoGly-L-Ile-Ot-Bu (175.5 mg) was obtained as a white solid. The yield was 97%, and the diastereomeric ratio was >99:1.
In addition, the reaction was carried out in the same manner except that instead of L-Ala-Ot-Bu, L-Ile-Ot-Bu, L-Ile-Ot-Bu-HCl described in Example 2-1 (111.9 mg, 0.5 mmol) was used as such without neutralization, whereby Bz-β-HoGly-L-Ile-Ot-Bu (175.5 mg) was obtained. The yield was 97%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 2-1 except that Boc-β-HoGly-OH was changed to Boc-L-β-HoAla-OH (Combi-Blocks Inc., 203.2 mg, 1.0 mmol), and L-Ile-Ot-Bu was changed to L-Ala-Ot-Bu described in Example 1-1 (72.6 mg, 0.5 mmol), whereby Boc-L-β-HoAla-L-Ala-Ot-Bu (160.1 mg) was obtained as a white solid. The yield was 97%, and the diastereomeric ratio was >99:1.
In addition, the reaction was carried out in the same manner except that instead of L-Ala-Ot-Bu, L-Ala-Ot-Bu, L-Ala-Ot-Bu-HCl described in Example 1-1 (90.8 mg, 0.5 mmol) was used as such without neutralization, whereby Boc-L-Q-HoAla-L-Ala-Ot-Bu (160.0 mg) was obtained. The yield was 97%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 2-1 except that Boc-β-HoGly-OH was changed to Boc-L-β-HoAla-OH (Combi-Blocks Inc., 203.2 mg, 1.0 mmol), and L-Ile-Ot-Bu was changed to L-Val-Ot-Bu (Combi-Blocks Inc., 86.7 mg, 0.5 mmol), whereby Boc-L-β-HoAla-L-Val-Ot-Bu (174.7 mg) was obtained as a white solid. The yield was 97%, and the diastereomeric ratio was >99:1.
In addition, the reaction was carried out in the same manner except that instead of L-Val-Ot-Bu, L-Val-Ot-Bu·HCl (Watanabe Chemical Industries, Ltd., 104.9 mg, 0.5 mmol) was used as such without neutralization, whereby Boc-L-β-HoAla-L-Val-Ot-Bu (174.8 mg) was obtained. The yield was 97%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 2-1 except that Boc-β-HoGly-OH was changed to Boc-L-β-HoPhe-OH (Watanabe Chemical Industries, Ltd., 279.3 mg, 1.0 mmol), L-Ile-Ot-Bu was changed to L-Ser(t-Bu)-Ot-Bu (Watanabe Chemical Industries, Ltd., 108.7 mg, 0.5 mmol), and the reaction temperature was set at 50° C., whereby Boc-L-β-HoPhe-L-Ser(t-Bu)-Ot-Bu (238.1 mg) was obtained as a white solid. The yield was 99% or more, and the diastereomeric ratio was >99:1.
In addition, the reaction was carried out in the same manner except that instead of L-Ser(t-Bu)-Ot-Bu, L-Ser(t-Bu)-Ot-Bu·HCl (Watanabe Chemical Industries, Ltd., 126.9 mg, 0.5 mmol) was used as such without neutralization, whereby Boc-L-β-HoPhe-L-Ser(t-Bu)-Ot-Bu (239.0 mg) was obtained. The yield was >99%, and the diastereomeric ratio was >99:1.
L-Lys(Boc)-Ot-Bu·HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Lys(Boc)-Ot-Bu.
The reaction was carried out in the same manner as in Example 2-1 except that Boc-β-HoGly-OH was changed to Boc-L-β-HoPhg-OH (Watanabe Chemical Industries, Ltd., 265.3 mg, 1.0 mmol), L-Ile-Ot-Bu was changed to the thus-produced L-Lys(Boc)-Ot-Bu (151.1 mg, 0.5 mmol), and the reaction temperature was set at 50° C., whereby Boc-L-β-HoPhg-L-Lys(Boc)-Ot-Bu (266.5 mg) was obtained as a white solid. The yield was 97% or more, and the diastereomeric ratio was >99:1.
In addition, the reaction was carried out in the same manner except that instead of L-Lys(Boc)-Ot-Bu, L-Lys(Boc)-Ot-Bu·HCl (Watanabe Chemical Industries, Ltd., 169.4 mg, 0.5 mmol) was used as such without neutralization, whereby Boc-L-β-HoPhg-L-Lys(Boc)-Ot-Bu (265.2 mg) was obtained. The yield was 96%, and the diastereomeric ratio was >99:1.
L-Leu-Ot-Bu-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Leu-Ot-Bu.
The reaction was carried out in the same manner as in Example 2-1 except that Boc-β-HoGly-OH was changed to Boc-L-β-HoMet-OH (Combi-Blocks Inc., 263.4 mg, 1.0 mmol), and L-Ile-Ot-Bu was changed to the thus-produced L-Leu-Ot-Bu (93.6 mg, 0.5 mmol), whereby Boc-L-β-HoMet-L-Leu-Ot-Bu (203.3 mg) was obtained as a white solid. The yield was 94%, and the diastereomeric ratio was >99:1.
In addition, the reaction was carried out in the same manner except that instead of L-Leu-Ot-Bu, L-Leu-Ot-Bu·HCl (Watanabe Chemical Industries, Ltd., 111.9 mg, 0.5 mmol) was used as such without neutralization, whereby Boc-L-β-HoMet-L-Leu-Ot-Bu (210.8 mg) was obtained. The yield was 97%, and the diastereomeric ratio was >99:1.
L-Ala-OMe·HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Ala-OMe.
A 5.0-mL screw-cap vial dried in a glove box was charged, under an argon atmosphere, with a stirrer, Boc-L-Ala-OH (Watanabe Chemical Industries, Ltd., 94.6 mg, 0.50 mmol), the L-Ala-OMe(26.8 mg, 0.25 mmol), 1-(trimethylsilyl)imidazole (70.1 mg, 0.50 mmol), and Ta(OMe)5(8.40 mg, 0.025 mmol), and was closed with a screw cap and sealed. This screw-cap vial was then taken out of the glove box and placed in an oil bath, stirred at a reaction temperature of 60° C. for 24 hours, removed from the oil bath and allowed to cool to room temperature. The resulting reaction product in the screw-cap vial was diluted with chloroform and transferred to a separatory funnel with distilled water (20 mL), and extracted twice with chloroform (20 mL). The extract solution was dried with anhydrous magnesium sulfate, and then filtered to obtain a filtrate. The filtrate was then transferred to a 5 mL screw-cap vial, and the solvent was removed from the filtrate with a rotary evaporator, whereby Boc-L-Ala-L-Ala-OMe was obtained.
The thus-obtained Boc-L-Ala-L-Ala-OMe contained in a vessel was mixed, in a glove box under an argon atmosphere, L-Ala-Ot-Bu obtained in accordance with the method described in Example 1-1 (72.5 mg, 0.50 mmol), 2,2′:6′,2″:6″,2′″-quarter-pyridine (synthesized in accordance with the method described in Wachter et al., Chem. Commun. 2016, 52[66]:10121-10124, 7.8 mg, 0.025 mmol), and Ta(OMe)5 (8.40 mg, 0.025 mmol), and was closed with a screw cap and sealed. This screw-cap vial was then taken out of the glove box and placed in an oil bath, and stirred at a reaction temperature of 70° C. for 48 hours, removed from the oil bath and allowed to cool to room temperature. The resulting reaction product in the screw-cap vial was diluted with chloroform (13 mL), purified with flash column chromatography (ethyl acetate/n-hexane), and subjected to removal of the solvent using an evaporator, whereby Boc-L-Ala-L-Ala-L-Ala-Ot-Bu (80.4 mg) was obtained as a white solid. The yield was 83%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 3-1 except that Boc-L-Ala-OH was changed to Boc-Leu-OH (Watanabe Chemical Industries, Ltd., 115.5 mg, 0.5 mmol), whereby Boc-L-Leu-L-Ala-L-Ala-Ot-Bu (97.5 mg) was obtained as a white solid. The yield was 91%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 3-1 except that Boc-L-Ala-OH was changed to Boc-Phe-OH (Watanabe Chemical Industries, Ltd., 140.1 mg, 0.5 mmol), whereby was obtained as a white solid Boc-L-Phe-L-Ala-L-Ala-Ot-Bu (96.1 mg) was obtained as a white solid. The yield was 83%, and the diastereomeric ratio was >99:1.
The reaction was carried out in the same manner as in Example 3-1 except that Boc-L-Ala-OH was changed to Cbz-Gly-OH (Watanabe Chemical Industries, Ltd., 104.5 mg, 0.5 mmol), whereby Cbz-Gly-L-Ala-L-Ala-Ot-Bu (92.6 mg) was obtained as a white solid. The yield was 91%, and the diastereomeric ratio was >99:1.
L-Leu-OMe·HCl (Watanabe Chemical Industries, Ltd.) and Gly-Ot-Bu HCl (Watanabe Chemical Industries, Ltd.) were neutralized with Amberlyst® A21 free amine to produce L-Leu-OMe and Gly-Ot-Bu, respectively.
The reaction was carried out in the same manner as in Example 3-1 except that L-Ala-OMe was changed to L-Leu-OMe (36.3 mg, 0.25 mmol), whereby Boc-L-Ala-L-Leu-OMe was synthesized. This product was then subjected to the same reaction as in Example 3-1 except that L-Ala-Ot-Bu was changed to Gly-Ot-Bu (65.5 mg, 0.50 mmol), whereby Boc-L-Ala-L-Leu-Gly-Ot-Bu (91.3 mg) was obtained as a white solid. The yield was 88%, and the diastereomeric ratio was >99:1.
L-Met-OMe-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Met-OMe.
The reaction was carried out in the same manner as in Example 3-1 except that L-Ala-OMe was changed to L-Met-OMe (40.8 mg, 0.25 mmol), whereby Boc-L-Ala-L-Met-Ala-Ot-Bu (101.0 mg) was obtained as a white solid. The yield was 91%, and the diastereomeric ratio was >99:1.
L-Val-Ot-Bu-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Val-Ot-Bu.
The reaction was carried out in the same manner as in Example 3-1 except that L-Ala-Ot-Bu was changed to the thus-produced L-Val-Ot-Bu (Watanabe Chemical Industries, Ltd., 130.1 mg, 0.75 mmol), whereby Boc-L-Ala-L-Ala-L-Val-Ot-Bu (84.1 mg) was obtained as a white solid. The yield was 81%, and the diastereomeric ratio was >99:1.
L-Met-Ot-Bu-HCl (Watanabe Chemical Industries, Ltd.) was neutralized with Amberlyst® A21 free amine to produce L-Met-Ot-Bu.
The reaction was carried out in the same manner as in Example 3-1 except that L-Ala-Ot-Bu was changed to the thus-produced L-Leu-Ot-Bu (Watanabe Chemical Industries, Ltd., 103.1 mg, 0.50 mmol), whereby Boc-L-Ala-L-Ala-L-Met-Ot-Bu (106.1 mg) was obtained as a white solid. The yield was 95%, and the diastereomeric ratio was >99:1.
A 5.0-mL screw-cap vial dried in a glove box was charged, under an argon atmosphere, with a stirrer, Boc-Gly-Gly-Gly-OH (Watanabe Chemical Industries, Ltd., 144.6 mg, 0.50 mmol), Ala-L-Ala-Ot-Bu (54.1 mg, 0.25 mmol), 1-(trimethylsilyl)imidazole (77.1 mg, 0.55 mmol), Ti(Oi-Pr)4 (Aldrich Co. LLC, 3.6 mg, 0.0125 mmol), and CHCl3 (0.25 mL), and was closed with a screw cap and sealed. This screw-cap vial was then taken out of the glove box and placed in an oil bath, stirred at a reaction temperature of 50° C. for 72 hours, and then removed from the oil bath and allowed to cool to room temperature.
The resulting reaction product in the screw-cap vial was diluted with chloroform (15 mL), purified with flash column chromatography (methanol/chloroform), and then subjected to removal of the solvent using an evaporator, whereby Boc-Gly-Gly-Gly-L-Ala-L-Ala-Ot-Bu (121.4 mg) was obtained. The yield was 99%, and the diastereomeric ratio was >99:1.
A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), N-α,N-β-di-tert-butyl-L-α,β-diaminopropanic acid dicyclohexyl ammonium salt (Boc-L-Dap(Boc)-OH·DCHA, 485.7 mg, 1.0 mmol), imidazole (149.8 mg, 2.2 mmol), chloroform (0.25 mL), chlorodimethylsilane (Me2HSiCl, 104.1 mg, 1.1 mmol), L-valine-tert-butyl ester (H-L-Val-Ot-Bu, 86.7 mg, 0.5 mmol), tantalum methoxide (Ta(OMe)5, 16.8 mg, 0.05 mmol) in this order, and was sealed with a septum and a screw cap. This reaction vessel was removed from the glove box and placed in an oil bath heated at 50° C., and stirred vigorously for 48 hours. The reaction vessel was then removed from the oil bath and allowed to cool to room temperature, and the reaction product was diluted with chloroform (3.0 mL), and then transferred to a prepared silica gel column (10% ethyl acetate/hexane mixture) using a Pasteur pipette. This procedure was repeated three times more, and the screw cap, septum, and Pasteur pipette used were washed with the same solution. silica gel column chromatography (10 to 80% ethyl acetate/hexane mixture) The reaction product was purified with, whereby a desired dipeptide (Boc-L-Dap(Boc)-L-Val-Ot-Bu) was obtained as a white solid. The production amount was 222.9 mg, the yield 97%, and the diastereomeric ratio was dr>99:1. In this reaction system, imidazole reacts with chlorodimethylsilane to produce dimethylsilylimidazole (Me2HSiIm).
The reaction was carried out in the same manner as in Example 4-1 except that L-valine-tert-butyl ester was changed to L-valine-tert-butyl ester hydrochloride (H-L-Val-Ot-Bu-HCl, 104.9 mg, 0.5 mmol), whereby a desired dipeptide (Boc-L-Dap(Boc)-L-Val-Ot-Bu) was obtained as a white solid. The production amount was 223.0 mg, the yield 97%, and the diastereomeric ratio was dr>99:1.
The reaction was carried out in the same manner as in Example 4-1 except that L-valine-tert-butyl ester was changed to N-methyl-L-alanine-tert-butyl ester (Me-L-Ala-Ot-Bu, 72.6 mg, 0.5 mmol), and N-α,N-β-di-tert-butyl-L-α,β-diaminopropanic acid dicyclohexyl ammonium salt was changed to N-tert-butyl-L-β-homoalanine (Boc-L-β-HoAla-OH, 203.2 mg, 1.0 mmol), whereby a desired dipeptide (Boc-L-HoAla-(N-Me)L-Ala-Ot-Bu) was obtained as a white solid. The production amount was 133.1 mg, the yield 77%, and the diastereomeric ratio was dr>99:1.
The reaction was carried out in the same manner as in Example 4-3 except that N-methyl-L-alanine-tert-butyl ester was changed to N-methyl-L-alanine-tert-butyl ester hydrochloride (Me-L-Ala-Ot-Bu·HCl, 97.8 mg, 0.5 mmol), whereby a desired dipeptide (Boc-L-HoAla-(N-Me)L-Ala-Ot-Bu) was obtained as a white solid. The production amount was 129.2 mg, the yield 75%, and the diastereomeric ratio was dr>99:1.
The reaction was carried out in the same manner as in Example 4-1 except that L-valine-tert-butyl ester was changed to 1-amino cyclopropane carbonic acid ethyl ester (cPropn-O-Et, 64.6 mg, 0.5 mmol), and N-α,N-β-di-tert-butyl-L-α,β-diaminopropanic acid dicyclohexyl ammonium salt was changed to 2-(N-tert-butyl-amino)isobutyric acid (Boc-β-HoAib-OH, 217.3 mg, 1.0 mmol), whereby a desired dipeptide (Boc-β-Aib-cPropn-O-Et) was obtained as a white solid. The production amount was 156.0 mg, the yield 95%.
The reaction was carried out in the same manner as in Example 4-5 except that 1-amino cyclopropane carbonic acid ethyl ester was changed to 1-amino cyclopropane carbonic acid ethyl ester hydrochloride (cPropn-O-Et·HCl, 83.8 mg, 0.5 mmol), whereby a desired dipeptide (Boc-β-Aib-cPropn-O-Et) was obtained as a white solid. The production amount was 155.9 mg, the yield 95%.
The reaction was carried out in the same manner as in Example 4-1 except that L-valine-tert-butyl ester was changed to 2-amino isobutyric acid —N-tert-butyl ester (Aib-Ot-Bu, 79.6 mg, 0.5 mmol), and N-α,N-β-di-tert-butyl-L-α,β-diaminopropanic acid dicyclohexyl ammonium salt was changed to N-tert-butyl-β-homoglycine (Boc-β-HoGly-OH, 189.2 mg, 1.0 mmol), whereby a desired dipeptide (Boc-β-HoGly-Aib-Ot-Bu) was obtained as a white solid. The production amount was 145.0 mg, the yield 88%.
The reaction was carried out in the same manner as in Example 4-7 except that 2-amino isobutyric acid —N-tert-butyl ester was changed to 2-amino isobutyric acid —N-tert-butyl ester hydrochloride (Aib-Ot-Bu·HCl, 97.8 mg, 0.5 mmol), whereby a desired dipeptide (Boc-β-HoGly-Aib-Ot-Bu) was obtained as a white solid. The production amount was 142.6 mg, the yield 86%.
A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-alanine-tert-butyl ester (L-Ala-Ot-Bu, 145.2 mg, 1.0 mmol), N-tert-butyl-L-alanine (Boc-L-Ala-OH, 378.4 mg, 2.0 mmol), imidazole (299.6 mg, 4.4 mmol), chloroform (0.5 mL), and chlorodimethylsilane (Me2HSiCl, 208.2 mg, 2.2 mmol) in this order, and was sealed with a septum and a screw cap. This reaction vessel was removed from the glove box, and stirred vigorously at room temperature for 22 hours. The reaction product was then diluted with chloroform (3.0 mL), and then transferred to a prepared silica gel column (10% ethyl acetate/hexane mixture) using a Pasteur pipette. This procedure was repeated three times more, and the screw cap, septum, and Pasteur pipette used were washed with the same solution. The reaction product was purified with silica gel column chromatography (10 to 100% ethyl acetate/hexane mixture), whereby a desired dipeptide (Boc-L-Ala-L-Ala-Ot-Bu) was obtained as a white solid. The production amount was 306.9 mg, the yield was 97%, and the diastereomeric ratio was dr>99:1. In this reaction system, imidazole reacts with chlorodimethylsilane to produce dimethylsilylimidazole (Me2HSiIm).
The reaction was carried out in the same manner as in Example 4-9 except that L-alanine-tert-butyl ester was changed to L-alanine-tert-butyl ester hydrochloride (L-Ala-Ot-Bu·HCl, 181.7 mg, 1.0 mmol), whereby a desired dipeptide (Boc-L-Ala-L-Ala-Ot-Bu) was obtained as a white solid. The production amount was 217.2 mg, the yield 69%, and the diastereomeric ratio was dr>99:1.
The reaction was carried out in the same manner as in Example 4-9 except that imidazole was changed to 2-methylimidazole (361.2 mg, 4.4 mmol), whereby a desired dipeptide (Boc-L-Ala-L-Ala-Ot-Bu) was obtained as a white solid. The production amount was 314.7 mg, the yield >99%, and the diastereomeric ratio was dr=99:1. In this reaction system, 2-methylimidazole reacts with chlorodimethylsilane to produce dimethylsilyl(2-methylimidazole) (Me2HSi(2-Me-Im)).
The reaction was carried out in the same manner as in Example 4-11 except that L-alanine-tert-butyl ester was changed to L-alanine-tert-butyl ester hydrochloride (L-Ala-Ot-Bu·HCl, 181.7 mg, 1.0 mmol), whereby a desired dipeptide (Boc-L-Ala-L-Ala-Ot-Bu) was obtained as a white solid. The production amount was 217.2 mg, the yield 69%, and the diastereomeric ratio was dr>99:1.
A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer, benzoic acid (Waco Chemical Industries, Ltd., 244.2 mg, 2.0 mmol), isobutyl amine (Waco Chemical Industries, Ltd., 73.1 mg, 1.0 mmol), 1-(trimethylsilyl)imidazole (Tokyo Chemical Industry Co., Ltd., 308.6 mg, 2.2 mmol), Ta(OMe)5 (Aldrich Co. LLC, 33.6 mg, 0.10 mmol), and the vial was closed with a screw cap and sealed under an argon atmosphere. This screw-cap vial was then taken out of the glove box and placed in an oil bath, stirred at a reaction temperature of 50° C. for 48 hours, removed from the oil bath and allowed to cool to room temperature. The resulting reaction product in the screw-cap vial was diluted with chloroform (Waco Chemical Industries, Ltd., 15 mL) and purified with flash silica gel column chromatography (ethyl acetate/n-hexane), subjected to removal of the solvent using an evaporator, whereby N-isobutyl benzamide was obtained as a white solid. The production amount was 177.1 mg, and the yield was >99%.
*Example 5-2: Synthesis of N-benzylcyclohexa-3-ene carboxamide
A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer, 3-cyclohexene-1-carbonic acid (Tokyo Chemical Industry Co., Ltd., 252.3 mg, 2.0 mmol), benzylamine (Waco Chemical Industries, Ltd., 107.2 mg, 1.0 mmol), 1-(trimethylsilyl)imidazole (Tokyo Chemical Industry Co., Ltd., 308.6 mg, 2.2 mmol), Ta(OMe)5 (Aldrich Co. LLC, 33.6 mg, 0.10 mmol), and the vial was closed with a screw cap and sealed under an argon atmosphere. This screw-cap vial was then taken out of the glove box and placed in an oil bath, stirred at a reaction temperature of 50° C. for 48 hours, removed from the oil bath and allowed to cool to room temperature. The resulting reaction product in the screw-cap vial was diluted with chloroform (Waco Chemical Industries, Ltd., 15 mL) and purified with flash silica gel column chromatography (ethyl acetate/n-hexane), subjected to removal of the solvent using an evaporator, whereby N-benzylcyclohexa-3-ene carboxamide was obtained as a white solid. The production amount was 204.5 mg, and the yield was 95%.
A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer, 2-cyclopentene-1-acetic acid (Aldrich Co. LLC, 252.3 mg, 2.0 mmol), benzylamine (Waco Chemical Industries, Ltd., 107.2 mg, 1.0 mmol), 1-(trimethylsilyl)imidazole (Tokyo Chemical Industry Co., Ltd., 308.6 mg, 2.2 mmol), Ta(OMe)5 (Aldrich Co. LLC, 33.6 mg, 0.10 mmol), and the vial was closed with a screw cap and sealed under an argon atmosphere. This screw-cap vial was then taken out of the glove box and placed in an oil bath, stirred at a reaction temperature of 50° C. for 48 hours, removed from the oil bath and allowed to cool to room temperature. The resulting reaction product in the screw-cap vial was diluted with chloroform (Waco Chemical Industries, Ltd., 15 mL) and purified with flash silica gel column chromatography (ethyl acetate/n-hexane), subjected to removal of the solvent using an evaporator, whereby N-benzyl-2-(cyclopent-2-en-1-yl)acetamide was obtained as a white solid. The production amount was 198.0 mg, and the yield was 92%.
A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer, acetic acid (Aldrich Co. LLC, 252.2 mg, 2.0 mmol), amino methyl cyclohexane (Tokyo Chemical Industry Co., Ltd., 113.2 mg, 1.0 mmol), 1-(trimethylsilyl)imidazole (Tokyo Chemical Industry Co., Ltd., 308.6 mg, 2.2 mmol), Ta(OMe)5 (Aldrich Co. LLC, 33.6 mg, 0.10 mmol), and the vial was closed with a screw cap and sealed under an argon atmosphere. This screw-cap vial was then taken out of the glove box and placed in an oil bath, stirred at a reaction temperature of 50° C. for 48 hours, removed from the oil bath and allowed to cool to room temperature. The resulting reaction product in the screw-cap vial was diluted with chloroform (Waco Chemical Industries, Ltd., 15 mL) and purified with flash silica gel column chromatography (ethyl acetate/n-hexane), subjected to removal of the solvent using an evaporator, whereby N-(cyclohexylmethyl)-2-(furan-2-yl)acetamide was obtained as a white solid. The production amount was 214.7 mg, and the yield was 97%.
A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer, 2-naphthalene acetic acid (Tokyo Chemical Industry Co., Ltd., 372.4 mg, 2.0 mmol), amino methyl cyclohexane (Tokyo Chemical Industry Co., Ltd., 113.2 mg, 1.0 mmol), 1-(trimethylsilyl)imidazole (Tokyo Chemical Industry Co., Ltd., 308.6 mg, 2.2 mmol), Ta(OMe)5 (Aldrich Co. LLC, 33.6 mg, 0.10 mmol), and the vial was closed with a screw cap and sealed under an argon atmosphere. This screw-cap vial was then taken out of the glove box and placed in an oil bath, stirred at a reaction temperature of 50° C. for 48 hours, removed from the oil bath and allowed to cool to room temperature. The resulting reaction product in the screw-cap vial was diluted with chloroform (Waco Chemical Industries, Ltd., 15 mL) and purified with flash silica gel column chromatography (ethyl acetate/n-hexane), subjected to removal of the solvent using an evaporator, whereby N-(cyclohexylmethyl)-2-(naphthalen-2-yl)acetamide was obtained as a white solid. The production amount was 278.8 mg, and the yield was 99%.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2019-197845 | Oct 2019 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2020/040951 | 10/30/2020 | WO |
