JP6164610B2 - Antifouling agent for underwater organisms with amino acid isonitrile skeleton - Google Patents

Description

  The present invention relates to an antifouling agent for aquatic organisms containing a compound having an amino acid isonitrile skeleton as an active ingredient. The present invention also relates to a novel compound having an antifouling activity for underwater organisms, a method for producing the compound, and a method for using the antifouling agent for the underwater organisms.

  Among marine organisms, barnacles, mussels and bryozoans are known as underwater organisms. Underwater organisms adhere to the surface and / or the interior of fishing facilities or materials such as ships, fishing nets or buoys, cooling water intake facilities such as thermal power plants or nuclear power plants, and seawater intake facilities such as aquariums. If the underwater organisms adhere to these facilities or materials, for example, there may be an influence such as a decrease in power generation capacity due to a decrease in the navigation performance of the ship or a decrease in the amount of cooling water intake.

  In order to control underwater organisms, antifouling agents have been used that substantially suppress the adhesion of underwater organisms by applying them to an adhesion target such as a ship. Conventionally, an antifouling agent for aquatic organisms containing an organic tin compound such as tributyltin oxide (TBTO) or a heavy metal compound such as cuprous oxide as an active ingredient has been used. In particular, an antifouling agent containing an organotin compound as an active ingredient has been widely used in the form of a paint for painting the bottom of a ship because it has an excellent antifouling effect. However, it has become clear that organotin compounds have an effect on other marine organisms, such as the sterilization of snails. For this reason, in Japan, the manufacture and use of antifouling agents containing organotin compounds as active ingredients are currently prohibited.

  At present, an antifouling agent for aquatic organisms containing cuprous oxide or a specific agricultural chemical as an active ingredient is used. However, these compounds are thought to exhibit their antifouling activity by biocidal activity against underwater organisms. For this reason, there is a concern that these compounds also cause marine environmental pollution by diffusion into the ocean.

  Therefore, in recent years, attempts have been made to develop a novel antifouling agent for aquatic organisms using a natural physiologically active substance having repellent activity against aquatic organisms as a lead compound.

  For example, Patent Document 1 describes a compound represented by the formula (I), which is a sesquiterpene having an isocyano group, and an antifouling agent containing the compound as an active ingredient. The compound represented by the formula (I) described in this document is a compound developed using a novel sesquiterpene having an isonitrile group isolated and determined from a sea slug as a lead compound.

  Patent Document 2 describes an antifouling agent against harmful adhering organisms in water comprising a compound represented by Chemical Formula I having an isocyano group, an amide group or an amino group.

  Patent Document 3 discloses a compound represented by chemical formula I having a cyclohexane skeleton having an isocyano group or formamide group, and a compound represented by chemical formula I having a benzene skeleton having an isocyano group, formamide group or N-methylformamide group. An antifouling agent against aquatic harmful organisms consisting of selected compounds is described.

  Patent Document 4 describes an isonitrile compound represented by the general formula (I) having an alkyl skeleton having an isocyano group, and an underwater harmful biofouling agent containing the isonitrile compound.

  Patent Document 5 describes an antifouling agent against harmful organisms in water containing a secondary isonitrile compound represented by the general formula (I) having a cyclohexane skeleton having an isocyano group and an acyl group.

JP-A-10-95754 Japanese Patent No. 4152092 Japanese Patent No.4920002 Japanese Patent No.4933261 International Publication No. 2010/109855 Pamphlet

  As described above, antifouling agents for organisms attached to water that contain compounds having various structures as active ingredients are known. However, these antifouling agents have room for further improvement from the viewpoint of the level of antifouling activity, production costs and / or safety.

  Therefore, an object of the present invention is to provide a novel antifouling agent for aquatic organisms having superior characteristics as compared with known antifouling agents.

  As a result of various studies on means for solving the above problems, the present inventors have found that an amino acid isonitrile derivative obtained by converting an amino group of an amino acid into an isocyano group has only a high adhesion inhibitory activity against barnacle cypris larvae. And found low toxicity. The present inventors have also found that the amino acid isonitrile derivative can be efficiently produced in several steps using an amino acid as a starting material. Based on the above findings, the present inventors have completed the present invention.

  That is, the gist of the present invention is as follows.

［式中、
R¹及びR²は、それぞれ独立して、水素、又は置換若しくは非置換のアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアリール、ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、アリール縮合シクロアルキル若しくはアリール縮合ヘテロシクロアルキルであるか、或いは
R¹及びR²は、それらが結合する炭素原子と一緒になって置換若しくは非置換のシクロアルキル、シクロアルケニル、シクロアルキニル又はヘテロシクロアルキルを形成し、或いは
R¹及びR²は、一緒になって置換若しくは非置換のアルキリデンを形成し、
R³は、水素、ハロゲン、ヒドロキシル、置換若しくは非置換のアミノ、又は置換若しくは非置換のアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、ヘテロシクロアルキル、アルコキシ、シクロアルコキシ、ヘテロシクロアルコキシ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、アリールオキシ、アリールアルキルオキシ、アリールアルケニルオキシ、ヘテロアリールオキシ、ヘテロアリールアルキルオキシ、アリール縮合シクロアルキル、アリール縮合ヘテロシクロアルキル若しくはアシルオキシであり、
Lは、単結合、又は置換若しくは非置換のアルキレン、アルケニレン若しくはアルキニレン（前記2価基は、=N-、-O-及び-S-から選択される1個以上のヘテロ原子、又はエポキシ、-N(R^N1)-、-CO-、-COO-、-SO-及び-SO₂-から選択される1個以上のヘテロ原子基、或いはシクロアルキレン、シクロアルケニレン、シクロアルキニレン、アリーレン及びヘテロアリーレンから選択される1個以上の置換若しくは非置換の基をその鎖中に含んでいてもよい）であり、
R^N1は、水素、ヒドロキシル、又は置換若しくは非置換のアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、ヘテロシクロアルキル、アルコキシ、シクロアルコキシ、ヘテロシクロアルコキシ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、アリールオキシ、アリールアルキルオキシ、アリールアルケニルオキシ、ヘテロアリールオキシ、ヘテロアリールアルキルオキシ、アリール縮合シクロアルキル若しくはアリール縮合ヘテロシクロアルキルである。］
で表される化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含有する水中付着生物の防汚剤。 (1) Formula (I):

[Where:
R ¹ and R ² are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Aryl-fused cycloalkyl or aryl-fused heterocycloalkyl, or
R ¹ and R ² together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycloalkyl, or
R ¹ and R ² together form a substituted or unsubstituted alkylidene;
R ³ is hydrogen, halogen, hydroxyl, substituted or unsubstituted amino, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy , Aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, arylalkyloxy, arylalkenyloxy, heteroaryloxy, heteroarylalkyloxy, aryl-fused cycloalkyl, aryl-fused heterocycloalkyl or acyloxy,
L is a single bond, or substituted or unsubstituted alkylene, alkenylene or alkynylene (wherein the divalent group is one or more heteroatoms selected from = N-, -O- and -S-, or epoxy,- One or more heteroatom groups selected from N (R ^N1 )-, -CO-, -COO-, -SO- and -SO _2- , or cycloalkylene, cycloalkenylene, cycloalkynylene, arylene and heteroarylene The chain may contain one or more substituted or unsubstituted groups selected from
R ^N1 is hydrogen, hydroxyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryl, heteroaryl, arylalkyl, Heteroarylalkyl, aryloxy, arylalkyloxy, arylalkenyloxy, heteroaryloxy, heteroarylalkyloxy, aryl-fused cycloalkyl or aryl-fused heterocycloalkyl. ]
An antifouling agent for aquatic organisms that contains a compound represented by the formula:

［式中、L^a、R^1a、R^2a、R^3a、R^4a及びR^5aは、以下の［i］〜［iii］のいずれかを満たす：
[i]
L^aは、単結合であり、
R^1aは、水素であり、
R^2aは、-CH₂CH₂-S-CH₃、-CH₂CH₂-CN、-CH₂CH₂CH₂CH₂-NHR^5a、-CH₂CH₃、-CH₂-OR^4a、又は

（式中、*は、炭素原子との結合点を示す）であるか、或いは
R^1a及びR^2aは、一緒になってエチリデンを形成し、
R^3aは、ヒドロキシル又は非置換のアリールアルキルオキシであり、
R^4aは、水素又は非置換のアリールアルキルであり、
R^5aは、水素又は非置換のアシルである。
[ii]
L^aは、エタン-1,1-ジイルであり、
R^1a及びR^2aは、水素であり、
R^3aは、ヒドロキシル又は非置換のアリールアルキルオキシである。
[iii]
L^aは、単結合であり、
R^1a及びR^2aは、ベンジル、又は

（式中、*は、炭素原子との結合点を示す）であり、
R^3aは、ヒドロキシル又は非置換のアリールアルキルオキシであり、
R^5aは、水素又は非置換のアシルである。］
で表される化合物若しくはその塩、又はそれらの溶媒和物。 (2) Formula (Ia):

^{Wherein, L a, R 1a, R} 2a, R 3a, R 4a and R ^5a are the following satisfy any of [i] ~ [iii]:
[i]
L ^a is a single bond,
R ^1a is hydrogen;
R ^2a is —CH ₂ CH ₂ —S—CH ₃ , —CH ₂ CH ₂ —CN, —CH ₂ CH ₂ CH ₂ CH ₂ —NHR ^5a , —CH ₂ CH ₃ , —CH ₂ —OR ^4a , or

(Wherein * represents the point of attachment to the carbon atom) or
R ^1a and R ^2a together form an ethylidene;
R ^3a is hydroxyl or unsubstituted arylalkyloxy;
R ^4a is hydrogen or unsubstituted arylalkyl;
R ^5a is hydrogen or unsubstituted acyl.
[ii]
L ^a is ethane-1,1-diyl,
R ^1a and R ^2a are hydrogen,
R ^3a is hydroxyl or unsubstituted arylalkyloxy.
[iii]
L ^a is a single bond,
R ^1a and R ^2a are benzyl, or

(Wherein * represents the point of attachment to the carbon atom),
R ^3a is hydroxyl or unsubstituted arylalkyloxy;
R ^5a is hydrogen or unsubstituted acyl. ]
Or a salt thereof, or a solvate thereof.

［式中、L^a、R^1a、R^2a、R^3a、R^4a及びR^5aは、前記（2）と同義である。］
で表される化合物とギ酸又はそのアルキルエステルとを反応させて、式（IIIa）：

［式中、L^a、R^1a、R^2a、R^3a、R^4a及びR^5aは、前記（2）と同義である。］
で表されるホルムアミド化合物を得る、ホルムアミド形成工程；
ホルムアミド形成工程で得られる式（IIIa）で表されるホルムアミド化合物と酸ハロゲン化物とを塩基存在下で反応させて、式（Ia）で表される化合物を得る、イソシアノ基形成工程；
を含む、前記方法。 (3) A method for producing a compound represented by formula Ia according to (2) above, comprising the following steps:
Formula (IIa):

[Wherein, L ^a , R ^1a , R ^2a , R ^3a , R ^4a and R ^5a have the same meanings as in (2) above. ]
A compound represented by formula (IIIa):

[Wherein, L ^a , R ^1a , R ^2a , R ^3a , R ^4a and R ^5a have the same meanings as in (2) above. ]
A formamide formation step of obtaining a formamide compound represented by:
An isocyano group forming step of obtaining a compound represented by the formula (Ia) by reacting the formamide compound represented by the formula (IIIa) obtained in the formamide forming step with an acid halide in the presence of a base;
Said method.

  (4) A method for controlling aquatic organisms, comprising treating at least one of the aquatic organisms and adhesion objects with the antifouling agent for aquatic organisms according to (1).

  (5) A paint containing the antifouling agent for aquatic organisms described in (1) above and a coating film forming component.

  (6) The antifouling agent for aquatic organisms according to (1) above, comprising the compound represented by formula I in the form of a conjugate of the compound and an amino acid, peptide or solid phase carrier.

  (7) A conjugate of the compound represented by formula Ia according to (2) above and an amino acid, peptide or solid phase carrier.

  According to the present invention, it is possible to provide a novel antifouling agent for aquatic organisms having superior characteristics as compared with known antifouling agents.

<1. Antifouling agent for underwater organisms>
The present invention is directed to formula (I):

で表される化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含有する水中付着生物の防汚剤に関する。

Or a salt thereof, or a solvate thereof as an active ingredient.

As used herein, “alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing the specified number of carbon atoms. For example, “C ₁ -C ₅ alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing at least 1 and at most 5 carbon atoms. Suitable alkyls include, but are not limited to, linear or branched C, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl. it can be mentioned ₁ -C ₅ alkyl. In the present specification, “alkylene” means a divalent group in which one hydrogen atom of the alkyl is removed. Suitable alkylenes include, for example, linear or branched C ₁ -C ₅ alkylenes such as methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene and pentylene.

In the present specification, “alkenyl” means a group in which one or more CC single bonds of the alkyl are substituted with double bonds. Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 Mention may be made of straight-chain or branched C ₂ -C ₅ alkenyl such as -methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl and 1-pentenyl. In the present specification, “alkenylene” means a divalent group in which one hydrogen atom of the alkenyl is removed. Suitable alkenylene includes, for example, linear or branched C ₂ -C ₅ alkenylene such as vinylene, propenylene, isopropenylene, 2-methyl-1-propenylene, 3-butenylene and 4-pentenylene. it can.

In the present specification, “alkynyl” means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds. Suitable alkynyls include, but are not limited to, straight chain such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and 1-pentynyl. Alternatively, branched C ₂ -C ₅ alkynyl may be mentioned. Further, in the present specification, “alkynylene” means a divalent group in which one hydrogen atom of the alkynyl is removed.

In the present specification, “alkylidene” means a divalent group in which a CC single bond located at the bond terminal of the alkyl is substituted with a double bond. Suitable alkylidene include, without limitation, may include, for example, ethylidene, a C ₂ -C ₅ alkylidene, straight chain or branched chain, such as vinylidene and propane-2-ylidene.

As used herein, “cycloalkyl” means an alicyclic alkyl containing the specified number of carbon atoms. For example, “C ₃ -C ₆ cycloalkyl” means a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms. Suitable cycloalkyls include, but are not limited to, C ₃ -C ₆ cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present specification, “cycloalkenyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with double bonds. Suitable cycloalkenyl include, without limitation, may include, for example cyclobutenyl, cyclopentenyl and C ₃ -C ₆ cycloalkenyl cyclohexenyl.

In the present specification, “cycloalkynyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with triple bonds. Suitable cycloalkynyl, but are not limited to, for example cyclobutynyl, mention may be made of C ₃ -C ₆ cycloalkynyl such cyclopentynyl and cyclohexenyl.

  In the present specification, “heterocycloalkyl” means that one or more carbon atoms of the cycloalkyl, cycloalkenyl or cycloalkynyl are each independently selected from nitrogen (N), sulfur (S) and oxygen (O). Means a group substituted by a hetero atom. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heterocycloalkyl include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. be able to.

In the present specification, “alkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the alkyl, alkenyl or alkynyl. Suitable alkoxy includes, but is not limited to, C ₁ -C ₅ alkoxy such as methoxy, ethoxy, propoxy, butoxy and pentoxy.

In the present specification, “cycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the above cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable alkoxy include, but are not limited to, may be, for example, cyclopropoxy, a C ₃ -C ₆ cycloalkoxy, such as cyclobutoxy and cyclopentoxy.

  In the present specification, “heterocycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heterocycloalkyl.

In the present specification, “aryl” means an aromatic ring group having 6 to 15 carbon atoms. Suitable aryls include, but are not limited to, C ₆ -C ₁₅ aryls such as phenyl, biphenyl, naphthyl and anthracenyl.

In the present specification, “arylalkyl” means a group in which one of hydrogen atoms of the alkyl is substituted with the aryl. Preferred arylalkyl include, but are not limited to, for example benzyl, can be mentioned C ₇ -C ₁₆ arylalkyl, such as 1-phenethyl and 2-phenethyl.

In the present specification, “arylalkenyl” means a group in which one of the hydrogen atoms of the alkenyl is substituted with the aryl. Suitable arylalkenyls include, but are not limited to, C ₈ -C ₁₇ arylalkenyls such as styryl.

  In the present specification, “heteroaryl” means that one or more carbon atoms of the aryl are each independently substituted with a heteroatom selected from nitrogen (N), sulfur (S) and oxygen (O). Means group. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heteroaryl include, but are not limited to, for example, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, Examples include pyrimidinyl, quinolinyl, isoquinolinyl and indolyl.

  In the present specification, “heteroarylalkyl” means a group in which one of the hydrogen atoms of the alkyl is substituted with the heteroaryl. Suitable heteroarylalkyl includes, but is not limited to, indol-3-ylmethyl.

In the present specification, “aryloxy” means a group in which a hydroxyl hydrogen atom is substituted with the aryl. Suitable aryloxy includes, but is not limited to, C ₆ -C ₁₅ aryloxy such as phenoxy, biphenyloxy, naphthyloxy and anthryloxy (anthracenyloxy).

In the present specification, “arylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the arylalkyl. Suitable arylalkyloxy includes, but is not limited to, C ₇ -C ₁₆ arylalkyloxy such as benzyloxy, 1-phenethyloxy and 2-phenethyloxy.

In the present specification, “arylalkenyloxy” means a group in which a hydroxyl hydrogen atom is substituted with the arylalkenyl. Suitable aryl alkenyloxy include, but are not limited to, can be exemplified C ₈ -C ₁₇ arylalkenyl oxy example styryloxy like.

  In the present specification, “heteroaryloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroaryl. Suitable heteroaryloxy include, but are not limited to, furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, iso Oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy and indolyloxy it can.

  In the present specification, “heteroarylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroarylalkyl.

  In the present specification, the “aryl fused cycloalkyl” means a fused ring group formed by the condensation of the aryl and cycloalkyl. Suitable aryl-fused cycloalkyls include, but are not limited to, benzocyclobutenyl, indanyl, tetrahydronaphthyl, and the like.

  In the present specification, the “aryl fused heterocycloalkyl” means a fused ring group formed by condensing the aryl and the heterocycloalkyl. Suitable aryl fused cycloalkyls include, but are not limited to, 2,3-dihydroindolyl and 1,2,3,4-tetrahydroquinolinyl.

In the present specification, “acyl” means a group in which a monovalent group selected from the groups described above and carbonyl are linked. Suitable acyls include, but are not limited to, C ₁ -C ₅ aliphatic acyls such as formyl, acetyl and propionyl, and C ₇ -C ₁₆ aromatic acyls such as benzoyl.

  The groups described above are each independently unsubstituted or can be further substituted with one or more monovalent or divalent groups.

  In the present specification, “halogen” or “halo” means fluorine, chlorine, bromine or iodine.

  The present inventors have found a compound represented by the formula (I) as a compound having a high antifouling activity for organisms attached to water.

In the compound represented by the formula (I), R ¹ , R ² , R ³ , L, R ^N1 , Z ¹ and Z ² need to satisfy the following definitions.

R ¹ and R ² are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Aryl-fused cycloalkyl or aryl-fused heterocycloalkyl, or
R ¹ and R ² together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycloalkyl, or
R ¹ and R ² together form a substituted or unsubstituted alkylidene;
R ³ is hydrogen, halogen, hydroxyl, substituted or unsubstituted amino, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy , Aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, arylalkyloxy, arylalkenyloxy, heteroaryloxy, heteroarylalkyloxy, aryl-fused cycloalkyl, aryl-fused heterocycloalkyl or acyloxy,
L is a single bond, or substituted or unsubstituted alkylene, alkenylene or alkynylene (wherein the divalent group is one or more heteroatoms selected from = N-, -O- and -S-, or epoxy,- One or more heteroatom groups selected from N (R ^N1 )-, -CO-, -COO-, -SO- and -SO _2- , or cycloalkylene, cycloalkenylene, cycloalkynylene, arylene and heteroarylene The chain may contain one or more substituted or unsubstituted groups selected from
R ^N1 is hydrogen, hydroxyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryl, heteroaryl, arylalkyl, Heteroarylalkyl, aryloxy, arylalkyloxy, arylalkenyloxy, heteroaryloxy, heteroarylalkyloxy, aryl-fused cycloalkyl or aryl-fused heterocycloalkyl.

R ¹ and R ² are each independently hydrogen, or substituted or unsubstituted C _{1 to} C ₅ alkyl, C _{2 to} C ₅ alkenyl, C _{2 to} C ₅ alkynyl, C _{3 to} C ₁₅ cycloalkyl, C ₄ -C ₁₅ cycloalkenyl, C ₄ -C ₁₅ cycloalkynyl, C ₆ -C ₁₅ aryl, C ₆ -C ₁₅ heteroaryl, C ₅ -C ₁₅ heterocycloalkyl, C ₇ -C ₁₆ arylalkyl, C ₇ ~ C ₁₆ heteroarylalkyl, C ₈ -C ₁₈ aryl fused cycloalkyl or aryl fused C ₈ -C ₁₈ heterocycloalkyl, or R ¹ and R ^{2 taken} together are substituted or unsubstituted C ₁ it is preferable to form a -C ₅ alkylidene, hydrogen, or a substituted or unsubstituted C ₁ -C ₅ alkyl, C ₇ -C ₁₆ arylalkyl or C ₇ -C ₁₆ or heteroarylalkyl, or, R ¹ and R ² is a substituted or unsubstituted together It is more preferable to form a C ₁ -C ₅ alkylidene of conversion, hydrogen, or a substituted or unsubstituted methyl, ethyl, propyl (e.g. isopropyl), butyl (e.g., n- butyl or sec- butyl), benzyl or indole - It is particularly preferred that it is 3-ylmethyl or that R ¹ and R ² together form a substituted or unsubstituted ethylidene.

R ³ is hydrogen, halogen, hydroxyl, substituted or unsubstituted amino, or substituted or unsubstituted C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C ₃ -C ₁₅ cyclo alkyl, C ₄ -C ₁₅ cycloalkenyl, C ₄ -C ₁₅ cycloalkynyl, C ₅ -C ₁₅ heterocycloalkyl, C ₁ -C ₅ alkoxy, C ₃ -C ₁₅ cycloalkoxy, C ₅ -C ₁₅ heterocycloalkoxy , C ₆ -C ₁₅ aryl, C ₆ -C ₁₅ heteroaryl, C ₇ -C ₁₆ arylalkyl, C ₇ -C ₁₆ heteroarylalkyl, C ₆ -C ₁₅ aryloxy, C ₇ -C ₁₆ arylalkyloxy, C ₇ -C ₁₆ arylalkenyl aryloxy, C ₆ -C ₁₅ heteroaryloxy, C ₇ -C ₁₆ heteroarylalkyl alkyloxy, C ₈ -C ₁₈ aryl-fused-cycloalkyl, C ₈ -C ₁₈ aryl-fused-heterocycloalkyl or C _{1 ~C 5} reeds Is preferably oxy, hydrogen, halogen, hydroxyl, substituted or unsubstituted amino, or substituted or unsubstituted C ₁ -C ₅ alkoxy, C ₃ -C ₁₅ cycloalkoxy, C ₅ -C ₁₅ heterocycloalkoxy, C ₆ -C ₁₅ aryloxy, C ₇ -C ₁₆ arylalkyloxy, C ₇ -C ₁₆ arylalkenyl aryloxy, C ₆ -C ₁₅ heteroaryloxy, C ₇ -C ₁₆ heteroarylalkyl alkyloxy or C ₁ -C ₅ more more preferably acyloxy, hydrogen, halogen, hydroxyl, or substituted or unsubstituted C ₁ -C ₅ alkoxy, be a C ₇ -C ₁₆ arylalkyloxy or C ₇ -C ₁₆ heteroarylalkyloxy Preferably, it is hydrogen, hydroxyl, or substituted or unsubstituted methoxy, isopropyloxy or benzyloxy. It is particularly preferred.

L represents a single bond, or a substituted or unsubstituted C ₁ -C ₅ alkylene, preferably a C ₂ -C ₅ alkenylene, or C ₂ -C ₅ alkynylene, a single bond, or a substituted or unsubstituted C ₁ ~ C ₅ alkylene is more preferable, and single bond or substituted or unsubstituted methylene or ethylene (for example, ethane-1,2-diyl or ethane-1,1-diyl) is particularly preferable.

The divalent group L is one or more heteroatoms selected from = N-, -O- and -S-, or epoxy, -N (R ^N1 )-, -CO-, -COO-, -SO - and -SO ₂ - 1 or more heteroatoms groups selected from, or C ₃ -C ₁₅ cycloalkylene, C ₄ -C ₁₅ cycloalkenylene, C ₄ -C ₁₅ cycloalkynylene, C ₆ -C ₁₅ arylene And one or more substituted or unsubstituted groups selected from C ₆ -C ₁₅ heteroarylene may be included in the chain.

R ^N1 is hydrogen, hydroxyl, or substituted or unsubstituted C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C ₃ -C ₁₅ cycloalkyl, C ₄ -C ₁₅ cycloalkenyl , C ₄ -C ₁₅ cycloalkynyl, C ₅ -C ₁₅ heterocycloalkyl, C ₁ -C ₅ alkoxy, C ₃ -C ₁₅ cycloalkoxy, C ₅ -C ₁₅ heterocycloalkoxy, C ₆ -C ₁₅ aryl, C ₆ -C ₁₅ heteroaryl, C ₇ -C ₁₆ arylalkyl, C ₇ -C ₁₆ heteroarylalkyl, C ₆ -C ₁₅ aryloxy, C ₇ -C ₁₆ arylalkyloxy, C ₇ -C ₁₆ aryl alkenyloxy, preferably C ₆ -C ₁₅ heteroaryl aryloxy, C ₇ -C ₁₆ heteroarylalkyl alkyloxy, C ₈ -C ₁₈ aryl-fused cycloalkyl or C ₈ -C ₁₈ aryl-fused-heterocycloalkyl, hydrogen, or substituted or Non-replacement More preferably C ₁ is -C ₅ alkyl, particularly preferably hydrogen.

When R ¹ , R ² , R ³ , L and R ^N1 have a substituent, the substituent is halogen, cyano, isocyano, -NZ ¹ Z ² , -OZ ¹ , -SZ ¹ , -C (= O ) -Z ¹ , -C (= NH) -Z ¹ (Z ¹ and Z ² are each independently hydrogen, hydroxyl, or substituted or unsubstituted amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , Cycloalkynyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy, arylalkyloxy, arylalkenyloxy, heteroaryloxy, heteroarylalkyloxy, aryl Fused cycloalkyl, aryl fused heterocycloalkyl or acyl), alkyl, alkenyl, al One or more 1 selected from the group consisting of nyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl-fused cycloalkyl and aryl-fused heterocycloalkyl A valent group (the substituent may be further substituted with a monovalent group selected from the substituents).

The substituent is halogen, cyano, isocyano, -NZ ¹ Z ² , -OZ ¹ , -SZ ¹ , -C (= O) -Z ¹ , -C (= NH) -Z ¹ , or substituted or unsubstituted C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, C ₃ -C ₁₅ cycloalkyl, C ₄ -C ₁₅ cycloalkenyl, C ₄ -C ₁₅ cycloalkynyl of, C ₆ -C ₁₅ aryl, C ₆ -C ₁₅ heteroaryl, C ₅ -C ₁₅ heterocycloalkyl, C ₇ -C ₁₆ arylalkyl, C ₇ -C ₁₆ heteroarylalkyl, C ₈ -C ₁₈ aryl-fused cycloalkyl or C ₈ ~ Preferably it is C ₁₈ aryl fused heterocycloalkyl, more preferably cyano, isocyano, —NZ ¹ Z ² , —OZ ¹ , —SZ ¹ , or —C (═O) —Z ¹ , Isocyano, -NH-C (= O) CH ₃ , -OC (= O) CH ₃ , -SCH ₃ , -OH (hydroxyl), -O-benzyl, or -C (= O) -O-benzyl. It is particularly preferred.

Z ¹ and Z ² are each independently hydrogen, hydroxyl, substituted or unsubstituted amino, or substituted or unsubstituted C _{1 to} C ₅ alkyl, C _{2 to} C ₅ alkenyl, C _{2 to} C ₅ alkynyl, C ₃ -C ₁₅ cycloalkyl, C ₄ -C ₁₅ cycloalkenyl, C ₄ -C ₁₅ cycloalkynyl, C ₅ -C ₁₅ heterocycloalkyl, C ₁ -C ₅ alkoxy, C ₃ -C ₁₅ cycloalkoxy, C ₅ -C ₁₅ heterocycloalkoxy, C ₆ -C ₁₅ aryl, C ₆ -C ₁₅ heteroaryl, C ₇ -C ₁₆ arylalkyl, C ₇ -C ₁₆ heteroarylalkyl, C ₆ -C ₁₅ aryloxy, C ₇ ~ C ₁₆ arylalkyloxy, C ₇ -C ₁₆ arylalkenyl aryloxy, C ₆ -C ₁₅ heteroaryloxy, C ₇ -C ₁₆ heteroarylalkyl alkyloxy, C ₈ -C ₁₈ aryl-fused-cycloalkyl, C ₈ -C ₁₈ aryl Condensed heterocycloalkyl More it is to be C ₁ -C ₅ acyl is preferably, hydrogen, hydroxyl, or substituted or unsubstituted C ₁ -C ₅ alkyl, C ₇ -C ₁₆ arylalkyloxy or C ₁ -C ₅ acyl Particular preference is given to hydrogen or substituted or unsubstituted methyl, ethyl, propyl (eg isopropyl) or butyl (eg n-butyl or sec-butyl), benzyl, benzyloxy or acetyl.

Preferred compounds represented by formula (I) include the definitions described above for R ¹ , R ² , R ³ , L, R ^N1 , Z ¹ and Z ² in any combination.

からなる群より選択される。 Particularly preferred compounds of the formula (I) are:

Selected from the group consisting of

  In the present invention, the compound represented by the formula (I) and the compounds represented by the formulas (Ia), (IIa) and (IIIa) described below include not only the compound itself but also a salt thereof. . The counter ion of the salt of the compound of the present invention is not limited, but includes, for example, a cation such as sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion, or chloride ion. , Bromide ion, formate ion, acetate ion, maleate ion, fumarate ion, benzoate ion, ascorbate ion, pamoate ion, succinate ion, bismethylenesalicylate ion, methanesulfonate ion, ethanedisulfonate ion, propion Acid ion, tartrate ion, salicylate ion, citrate ion, gluconate ion, aspartate ion, stearate ion, palmitate ion, itaconic acid ion, glycolate ion, p-aminobenzoate ion, glutamic acid ON, benzene sulfonate ion, cyclohexyl sulfamate ion, methane sulfonate ion, ethane sulfonate ion, isethionate ion, benzene sulfonate ion, p-toluene sulfonate ion, naphthalene sulfonate ion, phosphate ion, nitrate ion, Anions such as sulfate ions, carbonate ions, bicarbonate ions or perchlorate ions are preferred. When the compound represented by the formula (I) or the formula (Ia) is in the form of a salt with the counter ion, the compound is used without substantially reducing the antifouling activity of the aquatic organisms. Can do.

  The compound represented by the formula (I) and the compounds represented by the formulas (Ia), (IIa) and (IIIa) described below are not limited to the above-mentioned or the following compounds themselves, but the compounds or their salts. Also included are solvates. Solvents that can form solvates with the compounds or salts thereof include, but are not limited to, for example, methanol, ethanol, 2-propanol (isopropyl alcohol), dimethyl sulfoxide (DMSO), acetic acid, ethanolamine or acetic acid. An organic solvent such as ethyl or water is preferred. When the compound represented by the formula (I) or the formula (Ia) or a salt thereof is in the form of a solvate with the above-mentioned solvent, the compound without substantially reducing the antifouling activity of the aquatic organisms. Can be used.

  The compound represented by the formula (I) and the compounds represented by the formulas (Ia), (IIa) and (IIIa) described below include not only the above or the following compounds themselves but also their protected forms. . In the present invention, the “protected form” means a form in which a protecting group is introduced into one or a plurality of functional groups (for example, a carboxylic acid group). In the present invention, a “protecting group” is a group that is introduced into a specific functional group in order to prevent undesired progress of the reaction, and is quantitatively removed under specific reaction conditions. Means a group that is substantially stable under the above reaction conditions. The protecting group that can form a protected form of the compound is not limited, but, for example, in the case of a protecting group for a carboxylic acid group, an arylalkyl ester (for example, benzyl ester), or an alkyl ester (for example, methyl, ethyl, or Isopropyl ester) is preferred. When the compound represented by the formula (I) or the formula (Ia) is a protected form by the protecting group, the compound can be used without substantially reducing the antifouling activity of the organism attached to water. .

  When the compound represented by the formula (I) and the compounds represented by the formulas (Ia), (IIa) and (IIIa) described below have one or more stereocenters (chiral centers), The compound also includes the individual enantiomers and diastereomers of the compound, and mixtures thereof such as racemates.

  The compound represented by the formula (I) and the compounds represented by the formulas (Ia), (IIa) and (IIIa) described below are not only the above or the following compounds themselves, but also the compounds, amino acids, The form of the connection body with a peptide or a solid-phase carrier is also included. In the case of a conjugate, one or a plurality of amino acids, peptides, or solid phase carriers formed through a reactive group (for example, an amino group, a carboxyl group, or a hydroxyl group) included in the compound. It may have a bond (for example, an amide bond, an ester bond, or an ether). Examples of the amino acid include various natural and non-natural amino acids. Examples of the peptide include various functional peptides and physiologically active peptides known in the art. Examples of the solid phase carrier include organic or inorganic carriers such as hydrogel and silicon. When the compound represented by the formula (I) or the formula (Ia) or a salt thereof is in the form of a conjugate, an additional characteristic or function is added to the compound without substantially reducing the antifouling activity of the aquatic organisms. (Eg, additional physiological activity, solubility, dispersibility and / or stability) can be imparted.

  The compound represented by the formula (I) of the present invention can exhibit high antifouling activity (for example, adhesion inhibition activity) and / or can exhibit high safety. In the present invention, the “antifouling activity” means an adhesion inhibitory activity that inhibits or suppresses the adhesion of aquatic organisms to an adhesion target. In the present invention, “high safety” means, but is not limited to, for example, low toxicity and / or high biodegradability. The reason why the antifouling agent for aquatic organisms of the present invention has the above-described characteristics can be explained as follows. Note that the present invention is not limited to the following actions and principles.

  The adhesion-inhibiting activity of the compound represented by the formula (I) of the present invention can be usually expressed in at least one mode of repelling and growth inhibition, typically in a repelling mode. By expressing the adhesion-inhibiting activity of aquatic organisms in the above-described manner, the compound represented by the formula (I) of the present invention has a low toxicity and a high antibacterial property as compared with an antifouling agent based on a biocidal activity. The soiling activity can be expressed.

  The compound represented by the formula (I) of the present invention has a skeleton in which an amino group of an amino acid is converted to an isocyano group. Therefore, when the antifouling agent for underwater organisms according to the present invention is applied to an adhesion target such as a ship, for example, in the form of a paint, the compound represented by the formula (I) contained in the antifouling agent is The isocyano group is rapidly hydrolyzed to form a formamide group, which is then converted back to a compound having an amino acid skeleton. A compound having an amino acid skeleton can be metabolized and biodegraded by an organism (for example, fish and shellfish) inhabiting the surrounding environment where the attached object exists. Therefore, the compound represented by the formula (I) of the present invention has high biodegradability. In addition, the compound represented by the formula (I) of the present invention has low toxicity to living organisms inhabiting the surrounding environment where the attached object exists.

  By having the above characteristics, the compound represented by the formula (I) can exhibit high antifouling activity and / or high safety.

で表される化合物若しくはその塩、又はそれらの溶媒和物に関する。 <2. New compounds>
The present invention also provides a compound of formula (Ia):

Or a salt thereof, or a solvate thereof.

  The compound represented by the formula (Ia) is a novel compound found by the present inventors.

In the compound represented by the formula (Ia), L ^a , R ^1a , R ^2a , R ^3a , R ^4a and R ^5a must satisfy any of the following [i] to [iii].

（式中、*は、炭素原子との結合点を示す）であるか、或いは
R^1a及びR^2aは、一緒になってエチリデンを形成し、
R^3aは、ヒドロキシル又は非置換のアリールアルキルオキシであり、
R^4aは、水素又は非置換のアリールアルキルであり、
R^5aは、水素又は非置換のアシルである。 [i]
L ^a is a single bond,
R ^1a is hydrogen;
R ^2a is —CH ₂ CH ₂ —S—CH ₃ , —CH ₂ CH ₂ —CN, —CH ₂ CH ₂ CH ₂ CH ₂ —NHR ^5a , —CH ₂ CH ₃ , —CH ₂ —OR ^4a , or

(Wherein * represents the point of attachment to the carbon atom) or
R ^1a and R ^2a together form an ethylidene;
R ^3a is hydroxyl or unsubstituted arylalkyloxy;
R ^4a is hydrogen or unsubstituted arylalkyl;
R ^5a is hydrogen or unsubstituted acyl.

[ii]
L ^a is ethane-1,1-diyl,
R ^1a and R ^2a are hydrogen,
R ^3a is hydroxyl or unsubstituted arylalkyloxy.

（式中、*は、炭素原子との結合点を示す）であり、
R^3aは、ヒドロキシル又は非置換のアリールアルキルオキシであり、
R^5aは、水素又は非置換のアシルである。 [iii]
L ^a is a single bond,
R ^1a and R ^2a are benzyl, or

(Wherein * represents the point of attachment to the carbon atom),
R ^3a is hydroxyl or unsubstituted arylalkyloxy;
R ^5a is hydrogen or unsubstituted acyl.

In the case of [i], R ^3a is preferably hydroxyl or benzyloxy, and more preferably benzyloxy. R ^4a is preferably hydrogen or benzyl, more preferably benzyl. R ^5a is preferably hydrogen or acetyl.

In the case of [ii], R ^3a is preferably hydroxyl or benzyloxy, and more preferably benzyloxy.

In the case of [iii], R ^1a and R ^2a are preferably the same group. R ^3a is preferably hydroxyl or benzyloxy, and more preferably benzyloxy. R ^5a is preferably hydrogen or acetyl, more preferably acetyl.

Preferred compounds represented by formula (Ia) are any combination of the definitions described above for L ^a , R ^1a , R ^2a , R ^3a , R ^4a and R ^5a in each of [i] to [iii]. Is included.

からなる群より選択される。 Particularly preferred compounds of the formula (Ia) are:

Selected from the group consisting of

<3. Manufacturing method>
The present invention also relates to a method for producing a compound represented by formula (I) or formula (Ia).

で表される化合物とギ酸又はそのアルキルエステルとを反応させて、式（IIIa）：

で表されるホルムアミド化合物を得る、ホルムアミド形成工程を含むことが必要である。 [3-1. Formamide formation process]
The method for producing the compound represented by the formula (I) or the formula (Ia) of the present invention is represented by the formula (IIa):

A compound represented by formula (IIIa):

It is necessary to include a formamide forming step for obtaining a formamide compound represented by the formula:

In the formulas (IIa) and (IIIa), L ^a , R ^1a , R ^2a , R ^3a , R ^4a and R ^5a have the same ^meanings as described above.

  The formic acid or its alkyl ester used in this step is preferably formic acid or ethyl formate or a combination thereof. The formic acid or its alkyl ester is preferably used in the range of 5 to 200 equivalents, more preferably in the range of 10 to 30 equivalents, relative to the compound represented by the formula (IIa). By using the above-mentioned reactant, the amino group of the compound represented by the formula (IIa) can be formylated to form a compound represented by the formula (IIIa) having a formamide group.

  In this step, it is preferable to react the compound represented by the formula (IIa) with formic acid or an alkyl ester thereof in the presence of acetic anhydride, p-toluenesulfonic acid (p-TsOH), or a combination thereof. The reactant is preferably used in the range of 5 to 200 equivalents, more preferably in the range of 10 to 30 equivalents, relative to the compound represented by the formula (IIa). Formation of the formamide group can be promoted by reacting in the presence of the above-mentioned reactant.

  This step may be performed in the absence of a solvent or may be performed in the presence of a solvent. When carried out in the presence of a solvent, the solvent is preferably carbon tetrachloride or acetonitrile or a combination thereof. By using the solvent, the yield of the formamide compound represented by the formula (IIIa) obtained as a result can be improved. However, if any of the reactants described above are liquid under the reaction conditions, this step is preferably performed in the absence of a solvent. By carrying out this step in the absence of a solvent, the production cost can be reduced.

  In this step, the temperature at which the compound represented by formula (IIa) is reacted with formic acid or an alkyl ester thereof is preferably in the range of 0 to 80 ° C, more preferably in the range of 20 to 60 ° C. . The reaction time is preferably 10 minutes or more (for example, in the range of 10 minutes to 48 hours), more preferably in the range of 30 minutes to 24 hours, and in the range of 30 minutes to 6 hours. Particularly preferred. By carrying out this step under the above conditions, the yield of the formamide compound represented by the formula (IIIa) obtained as a result can be improved.

  In addition, the compound represented by the formula (IIa) used in this step may be prepared by self-preparation, purchasing a corresponding amino acid or a derivative thereof, and further introducing a protective group as necessary. Etc. may be prepared by carrying out the above. Either case is included in the embodiment of this step.

[3-2. Isocyano group formation process]
The method for producing a compound represented by formula (I) or formula (Ia) of the present invention comprises reacting a formamide compound represented by formula (IIIa) obtained in the formamide formation step with an acid halide in the presence of a base. It is necessary to include the step of forming an isocyano group to obtain a compound represented by the formula (Ia).

  This step can be carried out, for example, by referring to the method described in Japanese Patent No. 5212945.

  The acid halide used in this step is preferably a phosphoric acid halide or a sulfonic acid halide, and more preferably a phosphoric acid halide.

The phosphoric acid halide is more preferably a compound having a structure in which 1 to 3 of 3 hydroxyl groups bonded to a phosphorus atom of orthophosphoric acid (H ₃ PO ₄ ) are substituted with halogen, A compound having a structure in which two or three hydroxyl groups are substituted by halogen is more preferable. When hydroxyl groups are present, it is preferred that one or two of the hydroxyl groups are substituted with further groups. Said further group, a substituted or unsubstituted C ₆ -C ₁₅ aryloxy is preferably a substituted or unsubstituted C ₁ -C ₂₀ alkoxy, or substituted or unsubstituted C ₁ -C ₂₀ dialkylamino, substituted or more preferably non-substituted of C ₆ -C ₁₅ aryloxy, and particularly preferably an unsubstituted C ₆ -C ₁₅ aryloxy (e.g., phenoxy). The halogen is preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine. Particularly preferred phosphoric acid halides are diphenyl chlorophosphate ((PhO) ₂ POCl), phenyl dichlorophosphate (PhOPOCl ₂ ), diethyl chlorophosphate, ethyl dichlorophosphate (EtOPOCl ₂ ), dimethylaminophosphoryl dichloride (Me ₂ NPOCl _2). ), Bis (dimethylamino) chlorophosphine oxide ((Me ₂ N) ₂ POCl), or phosphoryl chloride (POCl ₃ ).

  The sulfonic acid halide used in this step is preferably a halide of tosylic acid (p-toluenesulfonic acid). The halogen is preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine. A particularly preferred sulfonic acid halide is tosylic acid chloride (p-TsCl).

  In this step, the acid halide is preferably used in the range of 1.0 to 5.0 equivalents, more preferably in the range of 1.2 to 1.8 equivalents, relative to the formamide compound represented by the formula (IIIa).

  By carrying out this step using the above acid halide, the yield of the compound represented by the formula (Ia) obtained as a result can be improved.

  Although the base used in this process is not limited, For example, an aliphatic and aromatic amine, a heterocyclic compound, etc. can be mentioned. The base is preferably triethylamine, N, N-diisopropylethylamine or pyridine, and more preferably pyridine.

  In this step, the base is preferably used in the range of 1.0 to 10.0 equivalents, more preferably in the range of 2.0 to 5.0 equivalents, relative to the formamide compound represented by the formula (IIIa).

  By carrying out this step using the above acid halide, the yield of the compound represented by the formula (Ia) obtained as a result can be improved.

  In this step, the temperature at which the formamide compound represented by formula (IIIa) is reacted with the acid halide in the presence of a base is preferably in the range of 0 to 80 ° C, and preferably in the range of 20 to 30 ° C. Is more preferable. The reaction time is preferably 10 minutes or more (for example, in the range of 10 minutes to 48 hours), more preferably in the range of 30 minutes to 24 hours, and in the range of 30 minutes to 6 hours. Particularly preferred. By carrying out this step under the above conditions, the yield of the compound represented by the formula (Ia) obtained as a result can be improved.

[3-3. Protecting group introduction step and deprotection step]
The method for producing the compound represented by the formula (I) or the formula (Ia) of the present invention can be applied to the compound represented by the formula (I), (Ia), (IIa) and / or (IIIa), if desired. A protecting group introducing step for introducing a protecting group and / or a deprotecting step for removing the protecting group may be included. By carrying out the protecting group introduction step, a protected form of the compound represented by the formula (I), (Ia), (IIa) and / or (IIIa) can be formed. Further, by carrying out the deprotection step, from the protected form of the compound represented by formula (I), (Ia), (IIa) and / or (IIIa), formula (I), (Ia), (IIa ) And / or (IIIa) can be formed again.

  The protected form of the compound represented by the formula (I), (Ia), (IIa) and / or (IIIa) formed in the protecting group introduction step is the protected form of the compound described above (for example, a carboxylic acid group). It is preferable that it is a protection form.

  In the method of the present invention, the protecting group introduction step and the deprotection step can be carried out by applying a protecting group introduction reaction and a deprotection reaction known in the art.

  In the method of the present invention, the protecting group introduction step and the deprotection step can be appropriately performed at a desired stage. For example, a protective group introduction step may be performed after the formamide formation step to form a protected form of the compound represented by the formula (IIIa) in which the carboxylic acid group is protected, and the protective group may be formed before the formamide formation step. An introduction step may be performed to form a protected form of the compound represented by formula (IIa) in which the carboxylic acid group is protected. Similarly, a deprotection step may be performed after the isocyano group formation step to form a compound represented by the formula (Ia) from which the protection group has been removed, and the deprotection step may be performed before the isocyano group formation step. It may be carried out to form a compound represented by the formula (IIIa) from which the protecting group has been removed. Alternatively, the compound represented by the formula (Ia) may be obtained as the protected form without carrying out the deprotection step but carrying out the protecting group introduction step. Either case is encompassed by the method embodiments of the present invention.

<4. How to use>
The antifouling agent for aquatic organisms of the present invention may optionally contain one or more additional components in addition to the compound represented by formula (I) or formula (Ia), which is an active ingredient. In this case, the antifouling agent for aquatic organisms of the present invention is a composition comprising an active ingredient compound represented by formula (I) or formula (Ia) and optionally one or more additional components. Provided.

  In the composition containing the antifouling agent for aquatic organisms of the present invention, the compound represented by the formula (I) or the formula (Ia) as an active ingredient is 0.1 to 50 mass with respect to the total mass of the composition. % Is preferably contained, and more preferably in the range of 0.1 to 30% by mass. By containing the compound represented by the formula (I) or the formula (Ia) within the above range, the antifouling effect of organisms attached to water can be expressed.

  Examples of the one or more additional components include, but are not limited to, a film-forming component, a solvent, and a surfactant. Therefore, the antifouling agent for aquatic organisms of the present invention contains the following form: a compound represented by formula (I) or formula (Ia) which is an active ingredient, and one or more coating film forming components A form of a solution containing a compound represented by formula (I) or formula (Ia) which is an active ingredient and one or more solvents; or a formula (I) or formula which is an active ingredient In the form of an emulsion containing the compound represented by (Ia) and one or more surfactants.

  As the coating film forming component, various components such as a base resin and a curing agent that are usually used in the paint field can be used. Examples of the base resin include, but are not limited to, acrylic resin, polyester resin, polyether resin, polycarbonate resin, phthalic acid resin, vinyl resin, epoxy resin, and urethane resin. Although the said hardening | curing agent is not limited, For example, a polyisocyanate resin etc. can be mentioned.

  As the solvent, various components such as water or an organic solvent usually used in the paint field can be used. Examples of the organic solvent include aromatic hydrocarbons such as xylene and toluene, alicyclic hydrocarbons such as cyclohexane and ethylcyclohexane, and saturated aliphatic hydrocarbons such as n-hexane.

  Examples of the surfactant include an anionic surfactant (eg, alkylbenzene sulfonate or fatty acid salt), a cationic surfactant (organic ammonium salt), or a nonionic surfactant (eg, polyoxyethylene) that is commonly used in the paint field. Alkyl ethers) can be used.

  The composition containing the antifouling agent for aquatic organisms of the present invention may optionally contain additional additives commonly used in the paint field such as plasticizers, solvents, desiccants, reaction accelerators and reaction retarders, or color pigments. You may further contain a component. What is necessary is just to set the compounding quantity of these additional components suitably according to the desired objective in the range which does not inhibit the effect of the antifouling agent of the underwater adhesion organism of this invention demonstrated above.

  The composition (for example, paint, solution or emulsion) containing the antifouling agent for aquatic organisms of the present invention may optionally contain 1 in addition to the compound represented by formula (I) or formula (Ia) as an active ingredient. One or more additional active ingredients may be included. Further active ingredients include, for example, copper sulfate, cuprous oxide, bis-2-pyridinedithiol copper salt, pyridine triphenylboron, triphenyl (octadecylboron), bisdimethyldithiocarbamoyl zinc ethylenebisdithiocarbamate or tetraethylthiuram disulfide. In addition to known antifouling agents for underwater organisms, mention may be made of known antifouling agents for underwater organisms, as described in Japanese Patent No. 4933261, Japanese Patent No. 4152092 or Japanese Patent No. 492002 be able to. By containing the further active ingredient as described above, the antifouling effect by the composition of the present invention can be further improved.

  The antifouling agent for underwater organisms of the present invention can be applied to various underwater organisms. Examples of underwater organisms to which the antifouling agent of the present invention can be applied include, but are not limited to, barnacles (for example, cypris larvae), mussels, bryozoans, and hydroworms. By applying the antifouling agent for underwater organisms of the present invention to the underwater organisms as described above, the attachment of the underwater organisms to the attachment object can be effectively inhibited.

  The antifouling agent for underwater organisms of the present invention can effectively exhibit antifouling activity when applied to various adherends to which the underwater organisms can adhere. Examples of attachment objects to which the antifouling agent of the present invention can be applied include, but are not limited to, fishery facilities and materials such as ships, fishing nets or buoys, and fishery and fishery culture facilities such as oysters or scallops. Materials, surfaces and / or interiors of cooling water intake facilities such as thermal power plants or nuclear power plants, seawater intake facilities such as aquariums, nets and struts used for aquaculture, and seawater salt concentration sensors. . As described above, the antifouling agent for aquatic organisms of the present invention is highly safe because it has low toxicity and / or high biodegradability. For this reason, the antifouling agent for aquatic organisms of the present invention can also be applied to adherents such as aquaculture facilities and materials where the persistence of the drug is a major problem. By applying the antifouling agent for aquatic organisms of the present invention to the adherent as described above, the adhesion of the aquatic organisms can be effectively inhibited.

  The compound represented by the formula (I) or the formula (Ia) has a high adhesion inhibitory activity against various aquatic organisms. Therefore, the present invention also relates to a method for controlling aquatic organisms, comprising treating at least one of the aquatic organisms and adhesion objects with the antifouling agent for aquatic organisms of the present invention. In the method of the present invention, it is preferable that the underwater attached organism and the attached object to be treated with the antifouling agent are the above-mentioned attached organism and attached object.

  The method of the present invention may optionally further comprise treating the aquatic organism with an additional agent in addition to the antifouling agent of the aquatic organism of the present invention. The further agent is preferably the further active ingredient described above. In this case, the order in which at least one of the aquatic organisms and the adhesion target is treated with the antifouling agent for aquatic organisms and the further agent of the present invention is not particularly limited. For example, the antifouling agent of the aquatic organisms of the present invention and the additional agent may be treated simultaneously (in a single or separate formulation) or may be treated sequentially. In addition to the antifouling agent for aquatic organisms of the present invention, by treating the aquatic organisms with a further agent, the adhesion of the aquatic organisms to the adherent can be more significantly inhibited.

  In addition, the antifouling effect of the compound represented by the formula (I) or the formula (Ia) of the present invention and / or a further drug is disclosed in Japanese Patent No. 4933261 or Nogata et al. (Nogata et al., Biofouling, 2004, It can be evaluated by measuring the adhesion inhibitory activity of the compound with reference to Vol. 20, p87-91).

  When at least one of the underwater organisms and the adhesion target is treated with the antifouling agent for underwater organisms of the present invention, it is preferably used in the form of the composition described above (for example, paint, solution or emulsion). In this case, an application method (for example, a coating method) such as a paint that is usually used in the paint field can be used.

  As described above, the antifouling agent for aquatic organisms of the present invention can exhibit an antifouling effect by specifically inhibiting the adhesion of aquatic organisms. Further, the antifouling agent for aquatic organisms of the present invention can be rapidly biodegraded in the ecosystem of the surrounding environment where the adherent is present. In addition, the antifouling agent for aquatic organisms of the present invention can be produced by a small number of steps using an inexpensive compound such as an amino acid as a starting material. Therefore, according to the present invention, it is possible to provide an antifouling agent for aquatic organisms having high antifouling effects, high safety, and / or low production costs.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

グリシン（5.20 g, 69.23 mmol）を、ギ酸（25 mL）中に溶解し、無水酢酸（3.0 eq, 21.3 mL）を加えて、室温にて24時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノール及び酢酸エチルを加えて再結晶化し、対応するホルムアミド（1a）（4.81 g, 46.66 mmol, 67%）を得た。化合物1a（0.95 g, 9.18 mmol）を、DMF（20 mL）中にて、臭化ベンジル（1.5 eq, 1.64 mL）及び炭酸カリウム（3.2 eq, 3.99 g)と、室温で48時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1→1：9）により精製し、対応するベンジルエステル（1b）（400 mg, 2.02 mmol, 22%）を得た。化合物1b（514.8 mg, 2.66 mmol）をDCM（10 mL）中に加え、得られた混合物に(PhO)₂POCl（1.5 eq, 582 μL）及びピリジン（5.0 eq, 1.88 mL）を加え、2.5時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）により精製し、イソニトリル（1）（59.1 mg, 0.31 mmol, 12 %）を得た。黄色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.44-7.31 (5H, m), 5.24 (2H, s), 4.25 (2H, s).
¹³C NMR (150 MHz, CDCl₃) δ163.9, 161.5, 134.5, 129.0, 128.9, 128.7, 68.4, 43.7.
IR (neat) 3091, 3066, 3035, 2973, 2942, 2163, 1758, 1456, 1195, 752, 698 cm^-1.
MS (ESI) 計算値：193.0977（C₁₀H₁₃N₂O₂ ⁺ [M+NH₃]⁺）；測定値：193.0979. <I: Preparation of compound>
[I-1: Glycine derivative]

Glycine (5.20 g, 69.23 mmol) was dissolved in formic acid (25 mL), acetic anhydride (3.0 eq, 21.3 mL) was added, and the mixture was stirred at room temperature for 24 hours to be reacted. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol and ethyl acetate to obtain the corresponding formamide (1a) (4.81 g, 46.66 mmol, 67%). Compound 1a (0.95 g, 9.18 mmol) was reacted with benzyl bromide (1.5 eq, 1.64 mL) and potassium carbonate (3.2 eq, 3.99 g) in DMF (20 mL) at room temperature for 48 hours. It was. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 1: 9) to obtain the corresponding benzyl ester (1b) (400 mg, 2.02 mmol, 22%). Compound 1b (514.8 mg, 2.66 mmol) was added in DCM (10 mL), and (PhO) ₂ POCl (1.5 eq, 582 μL) and pyridine (5.0 eq, 1.88 mL) were added to the resulting mixture for 2.5 hours. The reaction was carried out with stirring. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain isonitrile (1) (59.1 mg, 0.31 mmol, 12%). Yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.44-7.31 (5H, m), 5.24 (2H, s), 4.25 (2H, s).
¹³ C NMR (150 MHz, CDCl ₃ ) δ163.9, 161.5, 134.5, 129.0, 128.9, 128.7, 68.4, 43.7.
IR (neat) 3091, 3066, 3035, 2973, 2942, 2163, 1758, 1456, 1195, 752, 698 cm ^-1 .
MS (ESI) _{calcd: 193.0977 (C 10 H 13 N} 2 O 2 + [M + NH 3] +); found: 193.0979.

アラニン（5.11 g, 57.36 mmol）を、ギ酸（25 mL）中に溶解し、無水酢酸（3.0 eq, 17.6 mL）を加えて、室温にて91時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノール及び酢酸エチルを加えて再結晶化し、対応するホルムアミド（2a）（2.26 g, 19.31 mmol, 34%）を得た。化合物2a（1.31 g, 11.17 mmol）を、DMF（20 mL）中にて、臭化ベンジル（1.5 eq, 2.0 mL）及び炭酸カリウム（3.5 eq, 5.41 g）と、室温で72時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）により精製し、対応するベンジルエステル（2b）（1.81 g, 8.76 mmol, 78%）を得た。化合物2b（236.8 mg, 1.14 mmol）をDCM（2 mL）中に加え、得られた混合物にPhOPOCl₂（1.8 eq, 310 μL）及びピリジン（5.0 eq, 0.46 mL）を加え、2.5時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）により精製し、イソニトリル（2）（95.6 mg, 0.55 mmol, 48%）を得た。黄色油状物。
¹H NMR (400 MHz, CDCl₃) δ7.43-7.31 (5H, m), 5.23 (2H, s), 4.42-4.29 (1H, m), 1.64 (3H, d, J = 7.6 Hz).
13C NMR (100 MHz, CDCl3) δ167.1, 159.8, 134.7, 128.9, 128.8, 128.4, 68.3, 51.9, 19.5.
IR (neat) 3066, 3035, 2989, 2946, 2144, 1753, 1456, 1197, 752, 698 cm^-1.
MS (ESI) 計算値：207.1134（C₁₁H₁₅N₂O₂ ⁺ [M+NH₃]⁺）；測定値：207.1135. [I-2: Alanine derivative]

Alanine (5.11 g, 57.36 mmol) was dissolved in formic acid (25 mL), acetic anhydride (3.0 eq, 17.6 mL) was added, and the mixture was reacted at room temperature for 91 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol and ethyl acetate to obtain the corresponding formamide (2a) (2.26 g, 19.31 mmol, 34%). Compound 2a (1.31 g, 11.17 mmol) was reacted with benzyl bromide (1.5 eq, 2.0 mL) and potassium carbonate (3.5 eq, 5.41 g) in DMF (20 mL) by stirring at room temperature for 72 hours. It was. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding benzyl ester (2b) (1.81 g, 8.76 mmol, 78%). Compound 2b (236.8 mg, 1.14 mmol) was added to DCM (2 mL), and PhOPOCl ₂ (1.8 eq, 310 μL) and pyridine (5.0 eq, 0.46 mL) were added to the resulting mixture, followed by stirring for 2.5 hours. Went. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain isonitrile (2) (95.6 mg, 0.55 mmol, 48%). Yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.43-7.31 (5H, m), 5.23 (2H, s), 4.42-4.29 (1H, m), 1.64 (3H, d, J = 7.6 Hz).
13C NMR (100 MHz, CDCl3) δ 167.1, 159.8, 134.7, 128.9, 128.8, 128.4, 68.3, 51.9, 19.5.
IR (neat) 3066, 3035, 2989, 2946, 2144, 1753, 1456, 1197, 752, 698 cm ^-1 .
MS (ESI) _{calcd: 207.1134 (C 11 H 15 N} 2 O 2 + [M + NH 3] +); found: 207.1135.

バリン（5.11 g, 43.60 mmol）を、ギ酸（25 mL）中に溶解し、無水酢酸（2.9 eq, 13 mL）を加えて、室温にて24時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノールを加えて再結晶化し、対応するホルムアミド（3a）（4.27 g, 29.21 mmoL, 67%）を得た。化合物3a（1.02 g, 7.03 mmol）を、DMF（20 mL）中にて、臭化ベンジル（1.5 eq, 1.25 mL）及び炭酸カリウム（3.0 eq, 2.92 g）と、室温で20時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）により精製し、対応するベンジルエステル（3b）（1.54 g, 6.56 mmol, 93%）を得た。化合物3b（228.4 mg, 0.97 mmol）をDCM（1 mL）中に加え、得られた混合物にPhOPOCl₂（1.2 eq, 175 μL）及びピリジン（5.0 eq, 0.39 mL）を加え、2時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝9：1）により精製し、イソニトリル（3）（104.4 mg, 0.48 mmol, 50%）を得た。黄色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.40-7.33 (5H, m), 5.24-5.23 (2H, m), 4.20-4.19 (1H, m), 2.37-2.30 (1H, m), 1.08 (3H, d, J = 7.2 Hz), 0.96 (3H, d, J = 7.2 Hz).
¹³C NMR (150 MHz, CDCl₃) δ166.2, 160.5, 134.6, 128.7, 128.6, 128.4, 67.9, 62.9, 31.2, 19.2, 16.5.
IR (neat) 3091, 3066, 3033, 2969, 2935, 2148, 1753, 1456, 1261, 752, 698 cm^-1.
MS (ESI) 計算値：240.1000（C₁₃H₁₅NNaO₂ ⁺ [M+Na]⁺）；測定値：240.0997. [I-3: Valine derivative]

Valine (5.11 g, 43.60 mmol) was dissolved in formic acid (25 mL), acetic anhydride (2.9 eq, 13 mL) was added, and the mixture was reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol to obtain the corresponding formamide (3a) (4.27 g, 29.21 mmoL, 67%). Compound 3a (1.02 g, 7.03 mmol) was reacted with benzyl bromide (1.5 eq, 1.25 mL) and potassium carbonate (3.0 eq, 2.92 g) in DMF (20 mL) at room temperature for 20 hours. It was. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding benzyl ester (3b) (1.54 g, 6.56 mmol, 93%). Compound 3b (228.4 mg, 0.97 mmol) was added to DCM (1 mL), and PhOPOCl ₂ (1.2 eq, 175 μL) and pyridine (5.0 eq, 0.39 mL) were added to the resulting mixture, and the reaction was stirred for 2 hours. Went. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1) to obtain isonitrile (3) (104.4 mg, 0.48 mmol, 50%). Yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.40-7.33 (5H, m), 5.24-5.23 (2H, m), 4.20-4.19 (1H, m), 2.37-2.30 (1H, m), 1.08 ( 3H, d, J = 7.2 Hz), 0.96 (3H, d, J = 7.2 Hz).
¹³ C NMR (150 MHz, CDCl ₃ ) δ166.2, 160.5, 134.6, 128.7, 128.6, 128.4, 67.9, 62.9, 31.2, 19.2, 16.5.
IR (neat) 3091, 3066, 3033, 2969, 2935, 2148, 1753, 1456, 1261, 752, 698 cm ^-1 .
MS (ESI) _{calcd: 240.1000 (C 13 H 15 NNaO} 2 + [M + Na] +); found: 240.0997.

ロイシン（2.18 g, 16.63 mmol）を、ギ酸（10 mL）中に溶解し、無水酢酸（3.0 eq, 5.11 mL）を加えて、室温にて91時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノール及び酢酸エチルを加えて再結晶化し、対応するホルムアミド（4a）（1.43 g, 8.96 mmol, 54%）を得た。化合物4a（1.43 g, 8.99 mmol）を、DMF（20 mL）中にて、臭化ベンジル（1.5 eq, 1.70 mL）及び炭酸カリウム（3.2 eq, 3.96 g）と、室温で22時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：2）により精製し、対応するベンジルエステル（4b）（1.40 g, 5.62 mmol, 63%）を得た。化合物4b（825.3 mg, 3.31 mmol）をDCM（4 mL）中に加え、得られた混合物にPhOPOCl₂（1.8 eq, 890 μL）及びピリジン（5.0 eq, 1.34 mL）を加え、2時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）により精製し、イソニトリル（4）（426.0 mg, 1.84 mmol, 56%）を得た。黄色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.41-7.33 (5H, m), 5.26-5.19 (2H, m), 4.32-4.28 (1H, m), 1.93-1.82 (2H, m), 1.73-1.66 (1H, m), 0.97 (3H, d, J = 7.2 Hz), 0.95 (3H, d, J = 7.2 Hz).
¹³C NMR (150 MHz, CDCl₃) δ166.9, 160.2, 134.6, 128.7, 128.6, 128.3, 68.0, 55.2, 41.6, 24.7, 22.5, 20.8.
IR (neat) 3091, 3066, 3035, 2960, 2873, 2146, 1754, 1454, 1270, 750, 698 cm^-1.
MS (ESI) 計算値：254.1157（C₁₄H₁₇NNaO₂ ⁺ [M+Na]⁺）；測定値： 254.1156. [I-4: Leucine derivative]

Leucine (2.18 g, 16.63 mmol) was dissolved in formic acid (10 mL), acetic anhydride (3.0 eq, 5.11 mL) was added, and the mixture was reacted at room temperature for 91 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol and ethyl acetate to obtain the corresponding formamide (4a) (1.43 g, 8.96 mmol, 54%). Compound 4a (1.43 g, 8.99 mmol) was reacted with benzyl bromide (1.5 eq, 1.70 mL) and potassium carbonate (3.2 eq, 3.96 g) in DMF (20 mL) at room temperature for 22 hours. It was. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 2) to obtain the corresponding benzyl ester (4b) (1.40 g, 5.62 mmol, 63%). Compound 4b (825.3 mg, 3.31 mmol) was added to DCM (4 mL), and PhOPOCl ₂ (1.8 eq, 890 μL) and pyridine (5.0 eq, 1.34 mL) were added to the resulting mixture, followed by stirring for 2 hours. Went. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain isonitrile (4) (426.0 mg, 1.84 mmol, 56%). Yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.41-7.33 (5H, m), 5.26-5.19 (2H, m), 4.32-4.28 (1H, m), 1.93-1.82 (2H, m), 1.73- 1.66 (1H, m), 0.97 (3H, d, J = 7.2 Hz), 0.95 (3H, d, J = 7.2 Hz).
¹³ C NMR (150 MHz, CDCl ₃ ) δ166.9, 160.2, 134.6, 128.7, 128.6, 128.3, 68.0, 55.2, 41.6, 24.7, 22.5, 20.8.
IR (neat) 3091, 3066, 3035, 2960, 2873, 2146, 1754, 1454, 1270, 750, 698 cm ^-1 .
MS (ESI) _{calcd: 254.1157 (C 14 H 17 NNaO} 2 + [M + Na] +); found: 254.1156.

イソロイシン（4.99 g, 38.06 mmol）を、ギ酸（25 mL）中に溶解し、無水酢酸（3.0 eq, 10.8 mL）を加えて、室温にて20時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノールを加えて再結晶化し、対応するホルムアミド（5a）（4.67 g, 29.26 mmol, 77%）を得た。化合物5a（1.81 g, 11.40 mmol）を、DMF（25 mL）中にて、臭化ベンジル（1.5 eq, 2.03 mL）及び炭酸カリウム（3.1 eq, 4.85 g）と、室温で24時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）により精製し、対応するベンジルエステル（4b）（3.10 g, quant）を得た。化合物5b（520.1 mg, 2.09 mmol）をDCM（2 mL）中に加え、得られた混合物にPhOPOCl₂（1.5 eq, 470 μL）及びピリジン（5.0 eq, 0.84 mL）を加え、1.5時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝5：1）により精製し、イソニトリル（5）（230.0 mg, 0.99 mmol, 48%）を得た。黄色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.41-7.33 (5H, m), 5.26-5.19 (2H, m), 4.36-4.19 (1H, m), 2.12-2.02 (1H, m), 1.53-1.26 (2H, m), 1.07-0.84 (6H, m).
¹³C NMR (150 MHz, CDCl₃) δ166.4, 166.0, 160.5, 160.4, 134.5, 134.5, 128.5, 128.5, 128.2, 67.7, 67.7, 62.0, 60.7, 37.5, 37.2, 26.2, 23.9, 05.7, 13.8, 11.2, 10.9.
IR (neat) 3091, 3066, 3035, 2967, 2935, 2148, 1754, 1384, 1255, 1193, 752, 698 cm^-1.
MS (ESI) 計算値：254.1157（C₁₄H₁₇NNaO₂ ⁺ [M+Na]⁺）；測定値： 254.1158. [I-5: Isoleucine derivative]

Isoleucine (4.99 g, 38.06 mmol) was dissolved in formic acid (25 mL), acetic anhydride (3.0 eq, 10.8 mL) was added, and the mixture was reacted at room temperature for 20 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol to obtain the corresponding formamide (5a) (4.67 g, 29.26 mmol, 77%). Compound 5a (1.81 g, 11.40 mmol) was reacted with benzyl bromide (1.5 eq, 2.03 mL) and potassium carbonate (3.1 eq, 4.85 g) in DMF (25 mL) at room temperature for 24 hours. It was. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding benzyl ester (4b) (3.10 g, quant). Compound 5b (520.1 mg, 2.09 mmol) was added to DCM (2 mL), and PhOPOCl ₂ (1.5 eq, 470 μL) and pyridine (5.0 eq, 0.84 mL) were added to the resulting mixture, followed by stirring for 1.5 hours. Went. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to obtain isonitrile (5) (230.0 mg, 0.99 mmol, 48%). Yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.41-7.33 (5H, m), 5.26-5.19 (2H, m), 4.36-4.19 (1H, m), 2.12-2.02 (1H, m), 1.53- 1.26 (2H, m), 1.07-0.84 (6H, m).
¹³ C NMR (150 MHz, CDCl ₃ ) δ166.4, 166.0, 160.5, 160.4, 134.5, 134.5, 128.5, 128.5, 128.2, 67.7, 67.7, 62.0, 60.7, 37.5, 37.2, 26.2, 23.9, 05.7, 13.8, 11.2, 10.9.
IR (neat) 3091, 3066, 3035, 2967, 2935, 2148, 1754, 1384, 1255, 1193, 752, 698 cm ^-1 .
MS (ESI) _{calcd: 254.1157 (C 14 H 17 NNaO} 2 + [M + Na] +); found: 254.1158.

フェニルアラニン（3.45 g, 20.89 mmol）を、ギ酸（25 mL）中に溶解し、無水酢酸（3.0 eq, 6.0 mL）を加えて、室温にて19時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノールを加えて再結晶化し、対応するホルムアミド（6a）（3.50 g, 18.13 mmol, 87%）を得た。化合物6a（1.12 g, 5.81 mmol）を、DMF（20 mL）中にて、臭化ベンジル（1.4 eq, 1.04 mL）及び炭酸カリウム（3.1 eq, 2.52 g）と、室温で21時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）により精製し、対応するベンジルエステル（6b）（1.36 g, 4.81 mmol, 83%）を得た。化合物6b（700.1 mg, 2.47 mmol）をDCM（2 mL）中に加え、得られた混合物にPhOPOCl₂（1.8 eq, 665 μL）及びピリジン（5.0 eq, 1.00 mL）を加え、1.5時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：2）により精製し、イソニトリル（6）（370.8 mg, 1.40 mmol, 57%）を得た。黄色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.40-7.14 (10H, m), 5.20 (2H, s), 4.50-4.46 (1H, m), 3.29-3.10 (2H, m).
¹³C NMR (150 MHz, CDCl₃) δ165.9, 161.1, 134.4, 134.2, 129.3, 128.8, 128.7, 128.7, 128.5, 127.8, 68.2, 58.1, 38.9.
IR (neat) 3098, 3064, 3035, 2958, 2937, 2150, 1754, 1498, 1456, 1270, 750, 700 cm^-1.
MS (ESI) 計算値：288.1000（C₁₇H₁₅NNaO₂ ⁺ [M+Na]⁺）；測定値：288.0999. [I-6: Phenylalanine derivative]

Phenylalanine (3.45 g, 20.89 mmol) was dissolved in formic acid (25 mL), acetic anhydride (3.0 eq, 6.0 mL) was added, and the mixture was reacted at room temperature for 19 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol to obtain the corresponding formamide (6a) (3.50 g, 18.13 mmol, 87%). Compound 6a (1.12 g, 5.81 mmol) was reacted with benzyl bromide (1.4 eq, 1.04 mL) and potassium carbonate (3.1 eq, 2.52 g) in DMF (20 mL) at room temperature for 21 hours. It was. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding benzyl ester (6b) (1.36 g, 4.81 mmol, 83%). Compound 6b (700.1 mg, 2.47 mmol) was added to DCM (2 mL), and PhOPOCl ₂ (1.8 eq, 665 μL) and pyridine (5.0 eq, 1.00 mL) were added to the resulting mixture, followed by stirring for 1.5 hours. Went. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 2) to obtain isonitrile (6) (370.8 mg, 1.40 mmol, 57%). Yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ 7.40-7.14 (10H, m), 5.20 (2H, s), 4.50-4.46 (1H, m), 3.29-3.10 (2H, m).
¹³ C NMR (150 MHz, CDCl ₃ ) δ165.9, 161.1, 134.4, 134.2, 129.3, 128.8, 128.7, 128.7, 128.5, 127.8, 68.2, 58.1, 38.9.
IR (neat) 3098, 3064, 3035, 2958, 2937, 2150, 1754, 1498, 1456, 1270, 750, 700 cm ^-1 .
MS (ESI) _{calcd: 288.1000 (C 17 H 15 NNaO} 2 + [M + Na] +); found: 288.0999.

チロシン（3.56 g, 19.63 mmol）を、ギ酸（20 mL）中に溶解し、無水酢酸（3.0 eq, 5.6 mL）を加えて、室温にて24時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノール及び酢酸エチルを加えて再結晶化し、対応するホルムアミド（7a）（985.3 mg, 4.71 mmol, 24 %）を得た。化合物7a（968.1 mg, 4.62 mmol）を、DMF（20 mL）中にて、臭化ベンジル（1.5 eq, 0.82 mL）及び炭酸カリウム（3.0 eq, 1.91 g）と、70℃で47時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1→2：3）により精製し、対応するベンジルエステル（7b）（290.2 mg, 0.97 mmol, 21%）を得た。化合物7b（287.9 mg, 0.96 mmol）を、無水酢酸（2 mL）中に溶解し、ピリジン（1.5 eq, 116.2 μL）を加えて、室温にて18時間撹拌し反応させた。反応終了後、反応混合物を飽和食塩水及び酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）により精製し、対応するアセチル化物（7c）（321.1 mg, 0.94 mmol, quant）を得た。化合物7c（138.4 mg, 0.41 mmol）を、DCM（5 mL）中に加え、得られた混合物にPhOPOCl₂（1.2 eq, 73 μL）及びピリジン（5.0 eq, 0.16 mL）を加え、4時間撹拌し反応を行った。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）により精製し、イソニトリル（7）（16.2 mg, 0.05 mmol, 12 %）を得た。黄色油状物。
1H NMR (400 MHz, CDCl3) δ7.44-7.28 (5H, m), 7.22-6.98 (4H, m), 5.20 (2H, s), 4.50-4.43 (1H, m), 3.27-3.09 (2H, m), 2.29 (3H, s).
13C NMR (100 MHz, CDCl3) δ169.4, 165.9, 1661.3, 150.4, 134.4, 131.8, 130.5, 128.9, 128.8, 128.7, 122.1, 68.5, 58.0, 38.3, 21.3.
IR (neat) 3091, 3066, 3035, 2939, 2148, 1756, 1454, 1220, 752, 700 cm^-1
MS (ESI) 計算値：346.1055（C₁₉H₁₇NNaO₄ ⁺ [M+Na]⁺）；測定値：346.1055. [I-7: Tyrosine derivative]

Tyrosine (3.56 g, 19.63 mmol) was dissolved in formic acid (20 mL), acetic anhydride (3.0 eq, 5.6 mL) was added, and the mixture was reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol and ethyl acetate to obtain the corresponding formamide (7a) (985.3 mg, 4.71 mmol, 24%). Compound 7a (968.1 mg, 4.62 mmol) was stirred in DMF (20 mL) with benzyl bromide (1.5 eq, 0.82 mL) and potassium carbonate (3.0 eq, 1.91 g) at 70 ° C for 47 hours. I let you. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 2: 3) to obtain the corresponding benzyl ester (7b) (290.2 mg, 0.97 mmol, 21%). Compound 7b (287.9 mg, 0.96 mmol) was dissolved in acetic anhydride (2 mL), pyridine (1.5 eq, 116.2 μL) was added, and the mixture was stirred at room temperature for 18 hours to be reacted. After completion of the reaction, the reaction mixture was extracted with saturated brine and ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain the corresponding acetylated product (7c) (321.1 mg, 0.94 mmol, quant). Compound 7c (138.4 mg, 0.41 mmol) was added in DCM (5 mL), and PhOPOCl ₂ (1.2 eq, 73 μL) and pyridine (5.0 eq, 0.16 mL) were added to the resulting mixture and stirred for 4 hours. Reaction was performed. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to obtain isonitrile (7) (16.2 mg, 0.05 mmol, 12%). Yellow oil.
1H NMR (400 MHz, CDCl3) δ7.44-7.28 (5H, m), 7.22-6.98 (4H, m), 5.20 (2H, s), 4.50-4.43 (1H, m), 3.27-3.09 (2H, m), 2.29 (3H, s).
13C NMR (100 MHz, CDCl3) δ169.4, 165.9, 1661.3, 150.4, 134.4, 131.8, 130.5, 128.9, 128.8, 128.7, 122.1, 68.5, 58.0, 38.3, 21.3.
IR (neat) 3091, 3066, 3035, 2939, 2148, 1756, 1454, 1220, 752, 700 cm ^-1
MS (ESI) _{calcd: 346.1055 (C 19 H 17 NNaO} 4 + [M + Na] +); found: 346.1055.

トリプトファン（4.01 g, 19.6 mmol）を、ベンジルアルコール（4 mL）中に溶解し、CSA（1.1 eq, 5.00 g）を加えて、60℃にて3日間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝5：1→3：1→1：1→1：2→1：4）により精製し、対応するベンジルエステル（8a）（600.2 mg, 2.04 mmol, 10 %）を得た。化合物8a（546.5 mg, 1.86 mmol）を、ギ酸エチル（30 mL）中に溶解し、p-TsOH（0.1 eq, 35.3 mg）を加えて、60℃にて2日間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1→1：2）により精製し、対応するホルムアミド（8b）（491.7 mg, 1.53 mmol, 82 %）を得た。化合物8b（462.9 mg, 1.43 mmol）をDCM (5 mL）中に加え、得られた混合物にPhOPOCl₂（1.5 eq, 322 μL）及びピリジン（5.0 eq, 0.10 mL）を加え、室温にて2時間撹拌し反応を行った。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝4：1→3：1）により精製し、イソニトリル（8）（113.2 mg, 0.37 mmol, 26 %）を得た。赤色油状物。
¹H NMR (400 MHz, CDCl₃) δ8.07 (1H, s), 7.58-7.53 (1H, m), 7.46-7.30 (5H, m), 7.24-7.10 (4H, m), 5.18-5.10 (2H, m), 4.60-4.54 (1H, m), 3.51-3.32 (2H, m).
¹³C NMR (100 MHz, CDCl₃) δ166.5, 160.4, 136.2, 134.7, 128.8, 128.8, 128.5, 126.9, 123.8, 122.6, 120.0, 118.3, 111.6, 108.6, 68.3, 57.6, 29.7.
IR (neat) 3417, 3062, 3035, 2954, 2929, 2150, 1749, 1457, 1213, 744, 698 cm^-1.
MS (ESI) 計算値： 327.1110（C₁₉H₁₆N₂NaO₂ ⁺ [M+Na]⁺）；測定値：327.1107. [I-8: Tryptophan derivative]

Tryptophan (4.01 g, 19.6 mmol) was dissolved in benzyl alcohol (4 mL), CSA (1.1 eq, 5.00 g) was added, and the mixture was stirred at 60 ° C. for 3 days for reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 4) to give the corresponding benzyl ester (8a) (600.2 mg, 2.04 mmol, 10%). Compound 8a (546.5 mg, 1.86 mmol) was dissolved in ethyl formate (30 mL), p-TsOH (0.1 eq, 35.3 mg) was added, and the mixture was stirred at 60 ° C. for 2 days for reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 1: 2) to obtain the corresponding formamide (8b) (491.7 mg, 1.53 mmol, 82%). Compound 8b (462.9 mg, 1.43 mmol) was added to DCM (5 mL), and PhOPOCl ₂ (1.5 eq, 322 μL) and pyridine (5.0 eq, 0.10 mL) were added to the resulting mixture, followed by 2 hours at room temperature. The reaction was carried out with stirring. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1 → 3: 1) to obtain isonitrile (8) (113.2 mg, 0.37 mmol, 26%). Red oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ8.07 (1H, s), 7.58-7.53 (1H, m), 7.46-7.30 (5H, m), 7.24-7.10 (4H, m), 5.18-5.10 ( 2H, m), 4.60-4.54 (1H, m), 3.51-3.32 (2H, m).
¹³ C NMR (100 MHz, CDCl ₃ ) δ166.5, 160.4, 136.2, 134.7, 128.8, 128.8, 128.5, 126.9, 123.8, 122.6, 120.0, 118.3, 111.6, 108.6, 68.3, 57.6, 29.7.
IR (neat) 3417, 3062, 3035, 2954, 2929, 2150, 1749, 1457, 1213, 744, 698 cm ^-1 .
MS (ESI) _{calcd: 327.1110 (C 19 H 16 N} 2 NaO 2 + [M + Na] +); found: 327.1107.

グルタミン酸（376.5 mg, 2.56 mmol）を、ベンジルアルコール（2 mL）中に溶解し、CSA（2.0 eq, 1.18 g）を加えて、60℃にて4日間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝5：1→3：1→1：1→1：2→1：4）により精製し、対応するベンジルエステル（9a）（286.1 mg, 0.87 mmol, 33 %）を得た。化合物9a（713.3 mg, 2.18 mmol）を、ギ酸エチル（30 mL）中に溶解し、p-TsOH（0.1 eq, 41.4 mg）を加えて、60℃にて2日間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）により精製し、対応するホルムアミド（9b）（557.4 mg, 1.56 mmol, 72 %）を得た。化合物9b（259.1 mg, 0.79 mmol）をDCM（5 mL）中に加え、得られた混合物にPhOPOCl₂（1.5 eq, 178 μL）及びピリジン（5.0 eq, 0.55 mL）を加え、室温にて2.5時間撹拌し反応を行った。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）により精製し、イソニトリル（9）（91 mg, 0.28 mmol, 35%）を得た。黄色油状物。
¹H NMR (400 MHz, CDCl₃) δ7.42-7.29 (10H, m), 5.22 (2H, s) 5.12 (2H, s), 4.50-4.44 (1H, m), 2.66-2.49 (2H, m), 2.37-2.26 (1H, m), 2.24-2.13 (1H, m).
¹³C NMR (100 MHz, CDCl₃) δ171.5, 166.0, 135.5, 134.5, 128.9, 128.8, 128.7, 128.7, 128.5, 128.4, 68.5, 66.9, 55.6, 29.5, 27.8.
IR (neat) 3091, 3068, 3033, 2952, 2927, 2148, 1737, 1454, 1184, 1166, 750, 698 cm^-1.
MS (ESI) 計算値： 360.1212（C₂₀H₁₉NNaO₄ ⁺ [M+Na]⁺）；測定値：360.1211. [I-9: Glutamic acid derivative]

Glutamic acid (376.5 mg, 2.56 mmol) was dissolved in benzyl alcohol (2 mL), CSA (2.0 eq, 1.18 g) was added, and the mixture was stirred at 60 ° C. for 4 days for reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 4) to give the corresponding benzyl ester (9a) (286.1 mg, 0.87 mmol, 33%). Compound 9a (713.3 mg, 2.18 mmol) was dissolved in ethyl formate (30 mL), p-TsOH (0.1 eq, 41.4 mg) was added, and the mixture was stirred at 60 ° C. for 2 days for reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding formamide (9b) (557.4 mg, 1.56 mmol, 72%). Compound 9b (259.1 mg, 0.79 mmol) was added to DCM (5 mL), and PhOPOCl ₂ (1.5 eq, 178 μL) and pyridine (5.0 eq, 0.55 mL) were added to the resulting mixture, followed by 2.5 hours at room temperature. The reaction was carried out with stirring. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain isonitrile (9) (91 mg, 0.28 mmol, 35%). Yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.42-7.29 (10H, m), 5.22 (2H, s) 5.12 (2H, s), 4.50-4.44 (1H, m), 2.66-2.49 (2H, m ), 2.37-2.26 (1H, m), 2.24-2.13 (1H, m).
¹³ C NMR (100 MHz, CDCl ₃ ) δ171.5, 166.0, 135.5, 134.5, 128.9, 128.8, 128.7, 128.7, 128.5, 128.4, 68.5, 66.9, 55.6, 29.5, 27.8.
IR (neat) 3091, 3068, 3033, 2952, 2927, 2148, 1737, 1454, 1184, 1166, 750, 698 cm ^-1 .
MS (ESI) _{calcd: 360.1212 (C 20 H 19 NNaO} 4 + [M + Na] +); found: 360.1211.

アスパラギン酸（303.1 mg, 2.28 mmol）を、ベンジルアルコール（1 mL）中に溶解し、CSA（2.0 eq, 1.05 g）を加えて、60℃にて24時間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝2：1→1：1→1：2→1：4）により精製し、対応するベンジルエステル（10a）（391.0 mg, 1.25 mmol, 55 %）を得た。化合物10a（391.0 mg, 1.25 mmol）を、ギ酸エチル（20 mL）中に溶解し、p-TsOH（0.1 eq, 23.7 mg）を加えて、60℃にて41時間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）により精製し、対応するホルムアミド（10b）（277.4 mg, 0.71 mmol, 57 %）を得た。化合物10b（277.4 mg, 0.81 mmol）をDCM（5 mL）中に加え、得られた混合物にPhOPOCl₂ （1.5 eq, 182 μL）及びピリジン（5.0 eq, 0.56 mL）を加え、室温にて2時間撹拌し反応を行った。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝5：1→4：1）により精製し、イソニトリル（10）（11.8 mg, 0.036 mmol, 5 %）を得た。黄色油状物。
¹H NMR (400 MHz, CDCl₃) δ7.43-7.31 (10H, m), 5.22 (2H, s), 5.16 (2H, s), 4.75-4.67 (1H, m), 3.14-2.95 (2H, m).
¹³C NMR (100 MHz, CDCl₃) δ168.1, 165.3, 161.7, 135.0, 134.4, 128.9, 128.8, 128.8, 128.7, 128.6, 128.5, 68.8, 67.6, 52.4, 37.5.
IR (neat) 3114, 3091, 3066, 2952, 2896, 2150, 1739, 1456, 1270, 1168, 748, 698 cm^-1.
MS (ESI) 計算値： 346.1055（C₁₉H₁₇NNaO₄ ⁺ [M+Na]⁺）；測定値：346.1056. [I-10: Aspartic acid derivative]

Aspartic acid (303.1 mg, 2.28 mmol) was dissolved in benzyl alcohol (1 mL), CSA (2.0 eq, 1.05 g) was added, and the mixture was reacted at 60 ° C. for 24 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 → 1: 1 → 1: 2 → 1: 4) to give the corresponding benzyl ester (10a) (391.0 mg, 1.25 mmol, 55%) Obtained. Compound 10a (391.0 mg, 1.25 mmol) was dissolved in ethyl formate (20 mL), p-TsOH (0.1 eq, 23.7 mg) was added, and the mixture was stirred at 60 ° C. for 41 hours for reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding formamide (10b) (277.4 mg, 0.71 mmol, 57%). Compound 10b (277.4 mg, 0.81 mmol) was added to DCM (5 mL), and PhOPOCl ₂ (1.5 eq, 182 μL) and pyridine (5.0 eq, 0.56 mL) were added to the resulting mixture, and the mixture was stirred at room temperature for 2 hours. The reaction was carried out with stirring. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1 → 4: 1) to obtain isonitrile (10) (11.8 mg, 0.036 mmol, 5%). Yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.43-7.31 (10H, m), 5.22 (2H, s), 5.16 (2H, s), 4.75-4.67 (1H, m), 3.14-2.95 (2H, m).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.1, 165.3, 161.7, 135.0, 134.4, 128.9, 128.8, 128.8, 128.7, 128.6, 128.5, 68.8, 67.6, 52.4, 37.5.
IR (neat) 3114, 3091, 3066, 2952, 2896, 2150, 1739, 1456, 1270, 1168, 748, 698 cm ^-1 .
MS (ESI) _{calcd: 346.1055 (C 19 H 17 NNaO} 4 + [M + Na] +); found: 346.1056.

グルタミン（2.08 g, 4.21 mmol）を、ギ酸（20 mL）中に溶解し、無水酢酸（3.0 eq, 4.06 mL）を加えて、室温にて23時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノール及び酢酸エチルを加えて再結晶化し、対応するホルムアミド（11a）（1.61 g, 9.26 mmol, 65 %）を得た。化合物11a（1.60 g, 9.17 mmol）を、DMF（20 mL）中にて、臭化ベンジル（1.5 eq, 1.63 mL）及び炭酸カリウム（3.0 eq, 3.79 g）と、60℃で3時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮し、酢酸エチルを加えて再結晶化し、対応するベンジルエステル（11b）（453.3 mg, 1.71 mmol, 19 %）を得た。化合物11b（232.2 mg, 0.89 mmol）を、DCM（10 mL）中に加え、PhOPOCl₂（1.5 eq, 197 μL）及びピリジン（5.0 eq, 609 μL）を加え、室温にて2.5時間撹拌し反応を行った。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）により精製し、イソニトリル（11）（53.8 mg, 0.22 mmol, 25 %）を得た。黄色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.43-7.32 (5H, m), 5.25 (2H, s), 4.49-4.42 (1H, m), 2.65-2.74 (2H, m), 2.38-2.17 (2H, m).
¹³C NMR (150 MHz, CDCl₃) δ165.0, 162.9, 134.2, 129.2, 128.9, 128.7, 69.0, 55.0, 28.5, 13.7.
IR (neat) 3089, 3064, 3035, 2956, 2250, 2152, 1754, 1456, 1214, 750, 698 cm^-1.
MS (ESI) 計算値： 251.0797（C₁₃H₁₂N₂NaO₂ ⁺ [M+Na]⁺）；測定値：251.0797. [I-11: Glutamine derivative]

Glutamine (2.08 g, 4.21 mmol) was dissolved in formic acid (20 mL), acetic anhydride (3.0 eq, 4.06 mL) was added, and the mixture was reacted at room temperature for 23 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol and ethyl acetate to obtain the corresponding formamide (11a) (1.61 g, 9.26 mmol, 65%). Compound 11a (1.60 g, 9.17 mmol) was stirred in DMF (20 mL) with benzyl bromide (1.5 eq, 1.63 mL) and potassium carbonate (3.0 eq, 3.79 g) at 60 ° C for 3 hours. I let you. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure, recrystallized from ethyl acetate, and the corresponding benzyl ester (11b) (453.3 mg, 1.71 mmol, 19%) was obtained. Obtained. Compound 11b (232.2 mg, 0.89 mmol) was added to DCM (10 mL), PhOPOCl ₂ (1.5 eq, 197 μL) and pyridine (5.0 eq, 609 μL) were added, and the reaction was stirred at room temperature for 2.5 hours. went. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to obtain isonitrile (11) (53.8 mg, 0.22 mmol, 25%). Yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.43-7.32 (5H, m), 5.25 (2H, s), 4.49-4.42 (1H, m), 2.65-2.74 (2H, m), 2.38-2.17 ( 2H, m).
¹³ C NMR (150 MHz, CDCl ₃ ) δ165.0, 162.9, 134.2, 129.2, 128.9, 128.7, 69.0, 55.0, 28.5, 13.7.
IR (neat) 3089, 3064, 3035, 2956, 2250, 2152, 1754, 1456, 1214, 750, 698 cm ^-1 .
MS (ESI) _{calcd: 251.0797 (C 13 H 12 N} 2 NaO 2 + [M + Na] +); found: 251.0797.

メチオニン（5.23 g, 35.06 mmol）を、ギ酸（25 mL）中に溶解し、無水酢酸（3.0 eq, 10.8 mL）を加えて、室温にて48時間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノール及び酢酸エチルを加えて再結晶化し、対応するホルムアミド（12a）（4.39 g, 24.76 mmol, 71%）を得た。化合物12a（2.34 g, 13.20 mmol）を、DMF（20 mL）中にて、臭化ベンジル（1.5 eq, 2.35 mL）及び炭酸カリウム（3.0 eq, 5.49 g）と、室温で24時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1→2：1）により精製し、対応するベンジルエステル（12b）（1.48 g, 5.54 mmol, 42%）を得た。化合物12b（735.3 mg, 2.75 mmol）をDCM（2 mL）中に加え、得られた混合物にPhOPOCl₂（1.8 eq, 740 μL）及びピリジン（5.0 eq, 1.11 mL）を加え、2.5時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）により精製し、イソニトリル12（173.7 mg, 0.6973 mmol, 25%）を得た。黄緑色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.37-7.30 (5H, m), 5.23-5.17 (2H, m), 4.54-4.50 (1H, m), 2.65-2.57 (2H, m), 2.19-2.10 (2H, m), 2.03 (3H, s).
¹³C NMR (150 MHz, CDCl₃) δ166.1, 160.8, 134.4, 128.6, 1283.5, 128.3, 68.1, 55.0, 31.7, 29.4, 15.2.
IR (neat) 3089, 3066, 3033, 2969, 2917, 2148, 1756, 1456, 1440, 1272, 1211, 752, 698 cm^-1.
MS (ESI) 計算値：272.0712（C₁₃H₁₅NNaO₂S⁺ [M+Na]⁺）；測定値： 272.0721. [I-12: Methionine derivative]

Methionine (5.23 g, 35.06 mmol) was dissolved in formic acid (25 mL), acetic anhydride (3.0 eq, 10.8 mL) was added, and the mixture was allowed to react at room temperature for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol and ethyl acetate to obtain the corresponding formamide (12a) (4.39 g, 24.76 mmol, 71%). Compound 12a (2.34 g, 13.20 mmol) was reacted with benzyl bromide (1.5 eq, 2.35 mL) and potassium carbonate (3.0 eq, 5.49 g) in DMF (20 mL) at room temperature for 24 hours. It was. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 2: 1) to obtain the corresponding benzyl ester (12b) (1.48 g, 5.54 mmol, 42%). Compound 12b (735.3 mg, 2.75 mmol) was added to DCM (2 mL), and PhOPOCl ₂ (1.8 eq, 740 μL) and pyridine (5.0 eq, 1.11 mL) were added to the resulting mixture, followed by stirring for 2.5 hours. Went. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain isonitrile 12 (173.7 mg, 0.6973 mmol, 25%). Yellowish green oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.37-7.30 (5H, m), 5.23-5.17 (2H, m), 4.54-4.50 (1H, m), 2.65-2.57 (2H, m), 2.19- 2.10 (2H, m), 2.03 (3H, s).
¹³ C NMR (150 MHz, CDCl ₃ ) δ166.1, 160.8, 134.4, 128.6, 1283.5, 128.3, 68.1, 55.0, 31.7, 29.4, 15.2.
IR (neat) 3089, 3066, 3033, 2969, 2917, 2148, 1756, 1456, 1440, 1272, 1211, 752, 698 cm ^-1 .
MS (ESI) _{calcd: 272.0712 (C 13 H 15 NNaO} 2 S + [M + Na] +); found: 272.0721.

Nε-アセチル-リジン（703.4 mg, 3.74 mmol）を、ベンジルアルコール（2 mL）中に溶解し、CSA（3.0 eq, 2.59 g）を加えて、60℃にて4日間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝5：1→3：1→1：1→1：2→1：4）により精製し、対応するベンジルエステル（13a）（249.7 mg, 0.90 mmol, 24 %）を得た。化合物13a（250.3 mg, 0.90 mmol）を、ギ酸エチル（5 mL）中に溶解し、無水酢酸（6.0 eq, 0.51 mL）を加えて、室温にて７日間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1→1：4）により精製し、対応するホルムアミド（13b）（160.8 mg, 0.53 mmol, 58 %）を得た。化合物13b（84.3 mg, 0.28 mmol）をDCM（5 mL）中に加え、得られた混合物にPhOPOCl₂（1.5 eq, 62 μL）及びピリジン（5.0 eq, 108 μL）を加え、室温にて3時間撹拌し反応を行った。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝2：7→1：8）により精製し、イソニトリル13（23.5 mg, 0.082 mmol, 30 %）を得た。無色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.41-7.31 (5H, m), 5.22 (2H, s), 4.32-4.28 (1H, m), 3.26-3.15 (2H, m), 2.01-1.87 (5H, m), 1.57-1.41 (4H, m).
¹³C NMR (100 MHz, CDCl₃) δ170.2, 166.5, 160.5, 134.7, 128.9, 128.8, 128.5, 68.3, 56.6, 39.2, 32.3, 28.7, 23.4, 22.6.
IR (neat) 3303, 3087, 3068, 3035, 2937, 2865, 2148, 1753, 1654, 1456, 1197, 750, 698 cm^-1.
MS (ESI) 計算値：311.1372（C₁₆H₂₀N₂NaO₃ ⁺ [M+Na]⁺）；測定値：311.1372. [I-13: Nε-acetyl-lysine derivative]

Nε-acetyl-lysine (703.4 mg, 3.74 mmol) was dissolved in benzyl alcohol (2 mL), CSA (3.0 eq, 2.59 g) was added, and the mixture was stirred at 60 ° C. for 4 days for reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 4) to give the corresponding benzyl ester (13a) (249.7 mg, 0.90 mmol, 24%). Compound 13a (250.3 mg, 0.90 mmol) was dissolved in ethyl formate (5 mL), acetic anhydride (6.0 eq, 0.51 mL) was added, and the mixture was reacted at room temperature for 7 days. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 1: 4) to obtain the corresponding formamide (13b) (160.8 mg, 0.53 mmol, 58%). Compound 13b (84.3 mg, 0.28 mmol) was added to DCM (5 mL), and PhOPOCl ₂ (1.5 eq, 62 μL) and pyridine (5.0 eq, 108 μL) were added to the resulting mixture. The reaction was carried out with stirring. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 7 → 1: 8) to obtain isonitrile 13 (23.5 mg, 0.082 mmol, 30%). Colorless oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.41-7.31 (5H, m), 5.22 (2H, s), 4.32-4.28 (1H, m), 3.26-3.15 (2H, m), 2.01-1.87 ( 5H, m), 1.57-1.41 (4H, m).
¹³ C NMR (100 MHz, CDCl ₃ ) δ170.2, 166.5, 160.5, 134.7, 128.9, 128.8, 128.5, 68.3, 56.6, 39.2, 32.3, 28.7, 23.4, 22.6.
IR (neat) 3303, 3087, 3068, 3035, 2937, 2865, 2148, 1753, 1654, 1456, 1197, 750, 698 cm ^-1 .
MS (ESI) _{calcd: 311.1372 (C 16 H 20 N} 2 NaO 3 + [M + Na] +); found: 311.1372.

フェニルアラニンメチルエステル塩酸塩（3.03 g, 14.07 mmol）を、ギ酸エチル（10 mL）中に溶解し、p-トルエンスルホン酸（269.1 mg, 1.41 mmol, 0.1 eq）及びトリエチルアミン（1.96 mL, 14.07 mmol, 1.0 eq）を加え、65℃、46 時間加熱還流した。反応終了後、反応混合物に酢酸エチル（50 mL）を加え、1 M塩酸、飽和炭酸水素ナトリウム水溶液、及び飽和食塩水で順次洗浄し、さらに無水硫酸マグネシウムで乾燥、濾過した後、濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン : 酢酸エチル = 1 : 1）により精製し、対応するホルムアミド（14a）（2.42 mg, 11.67 mmol, 83%）を得た。化合物14a（599.4 mg, 2.89 mmol）に、ピリジン（1.16 mL, 14.45 mmol, 5.0 eq）及びジクロロリン酸フェニル（651 μL, 4.34 mmol, 1.5 eq）を加え、室温、1 時間撹拌した。反応終了後、反応混合物に飽和食塩水（50 mL）を加え、酢酸エチル（150 mL）で抽出した。有機層を、1 M塩酸、飽和炭酸水素ナトリウム水溶液、及び飽和食塩水で順次洗浄し、さらに無水硫酸マグネシウムで乾燥、濾過した後、濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル=6：1）により精製し、イソニトリル14（154.6 mg, 0.82 mmol, 28%）を得た。黄色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.35-7.24 (5H, m), 4.46 (1H, dd, J = 8.3 Hz,4.8 Hz), 3.77 (3H, d, J = 2.1 Hz), 3.24 (1H, dd, J = 13.8 Hz, 4.8 Hz), 3.12 (1H, dd, J = 13.8 Hz, 8.3 Hz).
¹³C NMR (600 MHz, CDCl₃) δ166.4, 160.8, 134.3, 129.1, 128.7, 127.7, 57.9, 53.3, 38.7.
IR (neat) 3032, 2148, 1755, 1603, 1497, 1456, 1439, 1273, 1217, 1178, 748, 702 cm^-1.
MS (ESI) 計算値：212.0688 （C₁₁H₁₁NNaO₂, [M+Na]⁺）；測定値： 212.0681. [I-14: Phenylalanine methyl ester derivative]

Phenylalanine methyl ester hydrochloride (3.03 g, 14.07 mmol) was dissolved in ethyl formate (10 mL), p-toluenesulfonic acid (269.1 mg, 1.41 mmol, 0.1 eq) and triethylamine (1.96 mL, 14.07 mmol, 1.0 eq) was added, and the mixture was heated to reflux at 65 ° C. for 46 hours. After completion of the reaction, ethyl acetate (50 mL) was added to the reaction mixture, washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, further dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding formamide (14a) (2.42 mg, 11.67 mmol, 83%). Pyridine (1.16 mL, 14.45 mmol, 5.0 eq) and phenyl dichlorophosphate (651 μL, 4.34 mmol, 1.5 eq) were added to compound 14a (599.4 mg, 2.89 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated brine (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, further dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 6: 1) to give isonitrile 14 (154.6 mg, 0.82 mmol, 28%). Yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.35-7.24 (5H, m), 4.46 (1H, dd, J = 8.3 Hz, 4.8 Hz), 3.77 (3H, d, J = 2.1 Hz), 3.24 ( 1H, dd, J = 13.8 Hz, 4.8 Hz), 3.12 (1H, dd, J = 13.8 Hz, 8.3 Hz).
¹³ C NMR (600 MHz, CDCl ₃ ) δ166.4, 160.8, 134.3, 129.1, 128.7, 127.7, 57.9, 53.3, 38.7.
IR (neat) 3032, 2148, 1755, 1603, 1497, 1456, 1439, 1273, 1217, 1178, 748, 702 cm ^-1 .
MS (ESI) _{calcd: 212.0688 (C 11 H 11 NNaO} 2, [M + Na] +); found: 212.0681.

フェニルアラニン（880.0 mg, 5.33 mmol）に、CSA（2.51 g, 10.66 mmol, 2.0 eq）及びイソプロパノール（2.05 mL, 26.65 mmol, 5.0 eq）を加え、60℃、47時間撹拌した。反応終了後、反応混合物に飽和食塩水（50 mL）を加え、酢酸エチル（150 mL）で抽出した。有機層を、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに無水硫酸マグネシウムで乾燥、濾過した後、濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル=1：1）により精製し、対応するイソプロピルエステル（15a）（517.6 mg, 2.50 mmol, 47%）を得た。化合物15a（645.5 mg, 3.11 mmol）をギ酸エチル（10 mL）中に溶解し、p-トルエンスルホン酸（61.7 mg, 0.32 mmol, 0.1 eq）を加え、65℃、62 時間加熱還流した。反応終了後、反応混合物に酢酸エチル（50 mL）を加え、1 M塩酸、飽和炭酸水素ナトリウム水溶液、及び飽和食塩水で順次洗浄し、さらに無水硫酸マグネシウムで乾燥、濾過した後、濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル=1：1）により精製し、対応するホルムアミド15b（619.9 mg, 2.63 mmol, 85%）を得た。化合物15b（209.5 mg, 0.89 mmol）に、ピリジン（358 μL, 4.45 mmol, 5.0 eq）及びジクロロリン酸フェニル（200 μL, 1.34 mmol, 1.5 eq）を加え、室温、50分間撹拌した。反応終了後、反応混合物に飽和食塩水（50 mL）を加え、酢酸エチル（150 mL）で抽出した。有機層を、1 M塩酸、飽和炭酸水素ナトリウム水溶液、及び飽和食塩水で順次洗浄し、さらに無水硫酸マグネシウムで乾燥、濾過した後、濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル=8：1）により精製し、イソニトリル15（73.7 mg, 0.34 mmol, 38%）を得た。黄色油状物。
¹H NMR (400 MHz, CDCl₃) δ7.36-7.27 (5H, m), 5.11-5.02 (1H, m), 4.40 (1H, dd, J = 8.7 Hz, 5.5 Hz), 3.25 (1H, dd, J = 13.7 Hz, 5.5 Hz), 3.14 (1H, dd, J = 13.7 Hz, 8.7 Hz), 1.25 (6H, dd, J = 5.5 Hz, 2.7 Hz).
¹³C NMR (400 MHz, CDCl₃) δ165.6, 160.6, 134.4, 129.3, 128.7, 127.8, 70.9, 58.2, 38.9, 21.5.
IR (neat) 3034, 2148, 1749, 1604, 1495, 1468, 1456, 1389, 1377, 1279, 1217, 1182, 918, 906, 748, 700 cm^-1.
MS (ESI) 計算値：204.1001（C₁₃H₁₅NNaO₂, [M+Na]⁺）；測定値：240.1004. [I-15: Phenylalanine isopropyl ester derivative]

CSA (2.51 g, 10.66 mmol, 2.0 eq) and isopropanol (2.05 mL, 26.65 mmol, 5.0 eq) were added to phenylalanine (880.0 mg, 5.33 mmol), and the mixture was stirred at 60 ° C. for 47 hours. After completion of the reaction, saturated brine (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed successively with sodium hydrogen carbonate and saturated brine, further dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding isopropyl ester (15a) (517.6 mg, 2.50 mmol, 47%). Compound 15a (645.5 mg, 3.11 mmol) was dissolved in ethyl formate (10 mL), p-toluenesulfonic acid (61.7 mg, 0.32 mmol, 0.1 eq) was added, and the mixture was heated to reflux at 65 ° C. for 62 hours. After completion of the reaction, ethyl acetate (50 mL) was added to the reaction mixture, washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, further dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give the corresponding formamide 15b (619.9 mg, 2.63 mmol, 85%). Pyridine (358 μL, 4.45 mmol, 5.0 eq) and phenyl dichlorophosphate (200 μL, 1.34 mmol, 1.5 eq) were added to compound 15b (209.5 mg, 0.89 mmol), and the mixture was stirred at room temperature for 50 minutes. After completion of the reaction, saturated brine (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, further dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 8: 1) to give isonitrile 15 (73.7 mg, 0.34 mmol, 38%). Yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.36-7.27 (5H, m), 5.11-5.02 (1H, m), 4.40 (1H, dd, J = 8.7 Hz, 5.5 Hz), 3.25 (1H, dd , J = 13.7 Hz, 5.5 Hz), 3.14 (1H, dd, J = 13.7 Hz, 8.7 Hz), 1.25 (6H, dd, J = 5.5 Hz, 2.7 Hz).
¹³ C NMR (400 MHz, CDCl ₃ ) δ165.6, 160.6, 134.4, 129.3, 128.7, 127.8, 70.9, 58.2, 38.9, 21.5.
IR (neat) 3034, 2148, 1749, 1604, 1495, 1468, 1456, 1389, 1377, 1279, 1217, 1182, 918, 906, 748, 700 cm ^-1 .
MS (ESI) _{calcd: 204.1001 (C 13 H 15 NNaO} 2, [M + Na] +); found: 240.1004.

スレオニン（6.24 g, 52.34 mmol）を、ギ酸（25 mL）中に溶解し、無水酢酸（3.0 eq, 14.8 mL）を加えて、室温にて2日間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、メタノール及び酢酸エチルを加えて再結晶化し、対応するホルムアミド（16a）（2.62 mg, 17.80 mmol, 34 %）を得た。化合物16a（2.63 g, 17.85 mmol）を、DMF（25 mL）中にて、臭化ベンジル（1.5 eq, 3.18 mL）及び炭酸カリウム（3.0 eq, 7.37 g）と、70℃で5日間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：4）により精製し、対応するベンジルエステル（16b）（761.8 mg, 3.21 mmol, 18%）を得た。化合物16b（749.1 mg, 3.16 mmol）を無水酢酸（6 mL）中に溶解し、ピリジン（1.5 eq, 0.38 mL）を加えて、室温にて6時間撹拌し反応させた。反応終了後、反応混合物を飽和食塩水及び酢酸エチルで抽出した。有機層を塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1）により精製し、対応するアセチル化物（16c）（785.0 mg, 2.81 mmol, 89%）を得た。化合物16c（131.8 mg, 0.47 mmol）をDCM（6 mL）中に加え、得られた混合物にPhOPOCl₂（1.2 eq, 85 μL）及びピリジン（5.0 eq, 0.33 mL）を加え、6時間撹拌し反応を行った。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を塩酸、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝9：1）により精製し、イソニトリル16（56.3 mg, 0.28 mmol, 59 %）を得た。黄色油状物。
¹H NMR (400 MHz, CDCl₃) δ7.62-7.31 (5H, m), 7.16-7.07 (1H, m), 5.27 (2H, s), 2.05 (3H, d, J = 7.2 Hz)
¹³C NMR (100 MHz, CDCl₃) δ170.3, 160.1, 141.9, 135.0, 128.8, 128.7, 128.4, 120.7, 67.9, 15.1.
IR (neat) 3324, 2068, 2027, 2981, 2966, 2940, 2123, 1724, 1452, 1270, 1211, 754, 703 cm^-1.
MS (ESI) 計算値：219.1134（C₁₂H₁₅N₂O₂ ⁺ [M+NH₃]⁺ ）；測定値：219.1106. [I-16: Threonine derivative]

Threonine (6.24 g, 52.34 mmol) was dissolved in formic acid (25 mL), acetic anhydride (3.0 eq, 14.8 mL) was added, and the mixture was reacted at room temperature for 2 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and recrystallized by adding methanol and ethyl acetate to obtain the corresponding formamide (16a) (2.62 mg, 17.80 mmol, 34%). Compound 16a (2.63 g, 17.85 mmol) was stirred in DMF (25 mL) with benzyl bromide (1.5 eq, 3.18 mL) and potassium carbonate (3.0 eq, 7.37 g) at 70 ° C for 5 days. I let you. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 4) to obtain the corresponding benzyl ester (16b) (761.8 mg, 3.21 mmol, 18%). Compound 16b (749.1 mg, 3.16 mmol) was dissolved in acetic anhydride (6 mL), pyridine (1.5 eq, 0.38 mL) was added, and the mixture was reacted at room temperature for 6 hours. After completion of the reaction, the reaction mixture was extracted with saturated brine and ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding acetylated product (16c) (785.0 mg, 2.81 mmol, 89%). Compound 16c (131.8 mg, 0.47 mmol) was added to DCM (6 mL), and PhOPOCl ₂ (1.2 eq, 85 μL) and pyridine (5.0 eq, 0.33 mL) were added to the resulting mixture, and the reaction was stirred for 6 hours. Went. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium hydrogen carbonate, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1) to obtain isonitrile 16 (56.3 mg, 0.28 mmol, 59%). Yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.62-7.31 (5H, m), 7.16-7.07 (1H, m), 5.27 (2H, s), 2.05 (3H, d, J = 7.2 Hz)
¹³ C NMR (100 MHz, CDCl ₃ ) δ170.3, 160.1, 141.9, 135.0, 128.8, 128.7, 128.4, 120.7, 67.9, 15.1.
IR (neat) 3324, 2068, 2027, 2981, 2966, 2940, 2123, 1724, 1452, 1270, 1211, 754, 703 cm ^-1 .
MS (ESI) _{calcd: 219.1134 (C 12 H 15 N} 2 O 2 + [M + NH 3] +); found: 219.1106.

β-アラニン（2.94 g, 33.05 mmol）を、ギ酸（25 mL）中に溶解し、無水酢酸（3.0 eq, 9.3 mL）を加えて、室温にて3日間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、対応するホルムアミド（17a）を得た。化合物17aを、DMF（20 mL）中にて、臭化ベンジル（1.5 eq, 5.88 mL）及び炭酸カリウム（3.0 eq, 27.3 g）と、60℃にて6時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝2：1→1：1→1：2→1：4）により精製し、対応するベンジルエステル（17b）（673.3 mg, 3.25 mmol, 10%）を得た。化合物17b（672.7 mg, 3.25 mmol）をDCM（10 mL）中に加え、得られた混合物にp-TsCl（1.5 eq, 817.4 mg）及びピリジン（2.0 eq, 523 μL）を加え、4.5時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝8：1）により精製し、イソニトリル17（300.6 mg, 1.59 mmol, 49%）を得た。無色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.44-7.30 (5H, m), 5.17 (2H, s), 3.70 (2H, t, J = 6.0 Hz), 2.78 (2H, t, J = 6.0 Hz).
¹³C NMR (150 MHz, CDCl₃) δ169.3, 157.7, 135.3, 128.8, 128.7, 128.5, 67.2, 37.3 (t), 37.2 (t), 37.2 (t), 34.3.
IR (neat) 3089, 3066, 3035, 2956, 2892, 2154, 1741, 1390, 1216, 752, 698 cm^-1.
MS (ESI) 計算値：207.1134（C₁₁H₁₅N₂O₂ ⁺ [M+NH₃]⁺）；測定値：207.1136. [I-17: β-alanine derivative]

β-alanine (2.94 g, 33.05 mmol) was dissolved in formic acid (25 mL), acetic anhydride (3.0 eq, 9.3 mL) was added, and the mixture was allowed to react at room temperature for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the corresponding formamide (17a). Compound 17a was reacted with benzyl bromide (1.5 eq, 5.88 mL) and potassium carbonate (3.0 eq, 27.3 g) in DMF (20 mL) by stirring at 60 ° C. for 6 hours. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 → 1: 1 → 1: 2 → 1: 4) to give the corresponding benzyl ester (17b) (673.3 mg, 3.25 mmol, 10%) Obtained. Compound 17b (672.7 mg, 3.25 mmol) was added to DCM (10 mL), p-TsCl (1.5 eq, 817.4 mg) and pyridine (2.0 eq, 523 μL) were added to the resulting mixture, and the mixture was stirred for 4.5 hours. Reaction was performed. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 8: 1) to obtain isonitrile 17 (300.6 mg, 1.59 mmol, 49%). Colorless oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.44-7.30 (5H, m), 5.17 (2H, s), 3.70 (2H, t, J = 6.0 Hz), 2.78 (2H, t, J = 6.0 Hz ).
¹³ C NMR (150 MHz, CDCl ₃ ) δ169.3, 157.7, 135.3, 128.8, 128.7, 128.5, 67.2, 37.3 (t), 37.2 (t), 37.2 (t), 34.3.
IR (neat) 3089, 3066, 3035, 2956, 2892, 2154, 1741, 1390, 1216, 752, 698 cm ^-1 .
MS (ESI) _{calcd: 207.1134 (C 11 H 15 N} 2 O 2 + [M + NH 3] +); found: 207.1136.

2-アミノ酪酸（3.06 g, 29.68 mmol）を、ギ酸（30 mL）中に溶解し、無水酢酸（3.0 eq, 8.4 mL）を加えて、室温にて7日間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、対応するホルムアミド（18a）を得た。残留物を、DMF（30 mL）中にて、臭化ベンジル（1.5 eq, 5.28 mL）及び炭酸カリウム（4.0 eq, 16.3 g）を加え、60℃にて5時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝2：1→1：1→1：2）により精製し、対応するベンジルエステル（18b）（4.656 g, 21.01 mmol, 81%）を得た。化合物18b（527.8 mg, 2.39 mmol）を、DCM（5 mL）中に加え、得られた混合物にPhOPOCl₂（1.5 eq, 554 μL）及びピリジン（5.0 eq, 961 μL）を加え、30分間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝10：1）により精製し、イソニトリル18（322.0 mg, 1.59 mmol, 66%）を得た。無色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.41-7.32 (5H, m), 5.25-5.20 (2H, m), 4.28-4.24 (1H, m), 2.04-1.90 (2H, m), 1.06 (3H, t, J = 7.8 Hz).
¹³C NMR (150 MHz, CDCl₃) δ166.6, 160.2, 134.8, 128.9, 128.8, 128.5, 68.2, 58.2, 26.5, 9.7.
IR (neat) 3091, 3066, 3035, 2977, 2940, 2150, 1756, 1456, 1384, 1191, 752, 698 cm^-1.
MS (ESI) 計算値：226.0844（C₁₂H₁₃NNaO₂ ⁺ [M+Na]⁺）；測定値：226.0847. [I-18: 2-aminobutyric acid derivative]

2-Aminobutyric acid (3.06 g, 29.68 mmol) was dissolved in formic acid (30 mL), acetic anhydride (3.0 eq, 8.4 mL) was added, and the mixture was stirred at room temperature for 7 days to be reacted. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the corresponding formamide (18a). To the residue, benzyl bromide (1.5 eq, 5.28 mL) and potassium carbonate (4.0 eq, 16.3 g) were added in DMF (30 mL), and the mixture was reacted at 60 ° C. for 5 hours. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 → 1: 1 → 1: 2) to obtain the corresponding benzyl ester (18b) (4.656 g, 21.01 mmol, 81%). Compound 18b (527.8 mg, 2.39 mmol) was added in DCM (5 mL), and PhOPOCl ₂ (1.5 eq, 554 μL) and pyridine (5.0 eq, 961 μL) were added to the resulting mixture and stirred for 30 minutes. Reaction was performed. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to obtain isonitrile 18 (322.0 mg, 1.59 mmol, 66%). Colorless oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.41-7.32 (5H, m), 5.25-5.20 (2H, m), 4.28-4.24 (1H, m), 2.04-1.90 (2H, m), 1.06 ( (3H, t, J = 7.8 Hz).
¹³ C NMR (150 MHz, CDCl ₃ ) δ166.6, 160.2, 134.8, 128.9, 128.8, 128.5, 68.2, 58.2, 26.5, 9.7.
IR (neat) 3091, 3066, 3035, 2977, 2940, 2150, 1756, 1456, 1384, 1191, 752, 698 cm ^-1 .
MS (ESI) _{calcd: 226.0844 (C 12 H 13 NNaO} 2 + [M + Na] +); found: 226.0847.

2-アミノイソ酪酸（3.48 g, 33.75 mmol）を、ギ酸（30 mL）中に溶解し、無水酢酸（3.0 eq, 9.6 mL）を加えて、室温にて4日間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、対応するホルムアミド（19a）を得た。化合物19aを、アセトニトリル（60 mL）中にて、臭化ベンジル（1.5 eq, 6.0 mL）及び炭酸カリウム（4.0 eq, 18.6 g）と、60℃にて7時間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物を、ヘキサン及び酢酸エチルを加えて再結晶化し、対応するベンジルエステル（19b）（5.51 g, 24.93 mmol, 74%）を得た。化合物19b（637.5 mg, 2.83 mmol）を、DCM（5 mL）中に加え、得られた混合物にPhOPOCl₂（1.5 eq, 669 μL）及びピリジン（5.0 eq, 1.16 mL）を加え、1時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝10：1）により精製し、イソニトリル19（273.5 mg, 1.35 mmol, 48%）を得た。無色油状物。
¹H NMR (400 MHz, CDCl₃) δ7.41-7.30 (5H, m), 5.23 (2H, s), 1.67 (6H, s).
¹³C NMR (100 MHz, CDCl₃) δ169.4, 158.1, 135.0, 128.8, 128.7, 128.2, 68.3, 59.8, 27.6.
IR (neat) 3091, 3066, 3035, 2944, 2140, 1751, 1459, 1392, 1274, 1153, 750, 698 cm^-1.
MS (ESI) 計算値：226.0844（C₁₂H₁₃NNaO₂ ⁺ [M+Na]⁺）；測定値：226.0841. [I-19: 2-aminoisobutyric acid derivative]

2-Aminoisobutyric acid (3.48 g, 33.75 mmol) was dissolved in formic acid (30 mL), acetic anhydride (3.0 eq, 9.6 mL) was added, and the mixture was allowed to react at room temperature for 4 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the corresponding formamide (19a). Compound 19a was reacted with benzyl bromide (1.5 eq, 6.0 mL) and potassium carbonate (4.0 eq, 18.6 g) in acetonitrile (60 mL) by stirring at 60 ° C. for 7 hours. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized by adding hexane and ethyl acetate to obtain the corresponding benzyl ester (19b) (5.51 g, 24.93 mmol, 74%). Compound 19b (637.5 mg, 2.83 mmol) was added to DCM (5 mL), and PhOPOCl ₂ (1.5 eq, 669 μL) and pyridine (5.0 eq, 1.16 mL) were added to the resulting mixture and stirred for 1 hour. Reaction was performed. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give isonitrile 19 (273.5 mg, 1.35 mmol, 48%). Colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.41-7.30 (5H, m), 5.23 (2H, s), 1.67 (6H, s).
¹³ C NMR (100 MHz, CDCl ₃ ) δ169.4, 158.1, 135.0, 128.8, 128.7, 128.2, 68.3, 59.8, 27.6.
IR (neat) 3091, 3066, 3035, 2944, 2140, 1751, 1459, 1392, 1274, 1153, 750, 698 cm ^-1 .
MS (ESI) _{calcd: 226.0844 (C 12 H 13 NNaO} 2 + [M + Na] +); found: 226.0841.

3-アミノ酪酸（1.15 g, 11.20 mmol）を、ギ酸（10 mL）中に溶解し、無水酢酸（3.0 eq, 3.2 mL）を加えて、室温にて7日間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、対応するホルムアミド（20a）を得た。化合物20aをアセトニトリル（20 mL）中にて、臭化ベンジル（1.5 eq, 1.99 mL）及び炭酸カリウム（4.0 eq, 6.17 g）と、60℃にて2日間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1→1：2）により精製し、対応するベンジルエステル（20b）（1.10 g, 4.97 mmol, 44%）を得た。化合物20b（547.7 mg, 2.48 mmol）をDCM（5 mL）中に加え、得られた混合物にPhOPOCl₂（1.5 eq, 575 μL）及びピリジン（5.0 eq, 997 μL）を加え、1時間半撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝10：1）により精製し、イソニトリル20（218.5 mg, 1.08 mmol, 43%）を得た。無色油状物。
¹H NMR (600 MHz, CDCl₃) δ7.40-7.32 (5H, m), 5.17 (2H, s), 4.16-4.08 (1H, m), 2.84-2.76 (1H, m), 2.63-2.56 (1H, m), 1.46-1.42 (3H, m).
¹³C NMR (150 MHz, CDCl₃) δ169.1, 156.2, 135.2, 128.7, 128.5, 128.4, 67.1, 46.5 (t), 46.5 (t), 46.4 (t), 41.6, 21.5.
IR (neat) 3091, 3066, 3035, 2942, 2886, 2142, 1737, 1456, 1388, 1184, 750, 700 cm^-1.
MS (ESI) 計算値：226.0844（C₁₂H₁₃NNaO₂ ⁺ [M+Na]⁺）；測定値：226.0845. [I-20: 3-aminobutyric acid derivative]

3-aminobutyric acid (1.15 g, 11.20 mmol) was dissolved in formic acid (10 mL), acetic anhydride (3.0 eq, 3.2 mL) was added, and the mixture was stirred at room temperature for 7 days to be reacted. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the corresponding formamide (20a). Compound 20a was reacted with benzyl bromide (1.5 eq, 1.99 mL) and potassium carbonate (4.0 eq, 6.17 g) in acetonitrile (20 mL) by stirring at 60 ° C. for 2 days. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 1: 2) to obtain the corresponding benzyl ester (20b) (1.10 g, 4.97 mmol, 44%). Compound 20b (547.7 mg, 2.48 mmol) was added to DCM (5 mL), and PhOPOCl ₂ (1.5 eq, 575 μL) and pyridine (5.0 eq, 997 μL) were added to the resulting mixture, and the mixture was stirred for 1.5 hours. Reaction was performed. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to obtain isonitrile 20 (218.5 mg, 1.08 mmol, 43%). Colorless oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ7.40-7.32 (5H, m), 5.17 (2H, s), 4.16-4.08 (1H, m), 2.84-2.76 (1H, m), 2.63-2.56 ( 1H, m), 1.46-1.42 (3H, m).
¹³ C NMR (150 MHz, CDCl ₃ ) δ169.1, 156.2, 135.2, 128.7, 128.5, 128.4, 67.1, 46.5 (t), 46.5 (t), 46.4 (t), 41.6, 21.5.
IR (neat) 3091, 3066, 3035, 2942, 2886, 2142, 1737, 1456, 1388, 1184, 750, 700 cm ^-1 .
MS (ESI) _{calcd: 226.0844 (C 12 H 13 NNaO} 2 + [M + Na] +); found: 226.0845.

4-アミノ酪酸（3.22 g, 31.23 mmol）を、ギ酸（30 mL）中に溶解し、無水酢酸（3.0 eq, 8.9 mL）を加えて、室温にて7日間撹拌し反応させた。反応終了後、反応混合物を減圧下濃縮し、対応するホルムアミド（21a）を得た。化合物21aを、DMF（30 mL）中にて、臭化ベンジル（1.5 eq, 5.55 mL）及び炭酸カリウム（4.0 eq, 17.2 g）と、60℃にて4日間撹拌し反応させた。反応終了後、反応混合物に水を加え失活させて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝1：1→1：2→1：4）により精製し、対応するベンジルエステル（21b）（363.2 mg, 1.64 mmol, 5%）を得た。化合物21b（363.2 mg, 1.64 mmol）をDCM（5 mL）中に加え、得られた混合物にp-TsCl（1.5 eq, 413.3 mg）及びピリジン（2.0 eq, 265 μL）を加え、1.5時間撹拌し反応を行った。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、水、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝9：1）により精製し、イソニトリル21（160.8 mg, 0.79 mmol, 48%）を得た。無色油状物。
¹H NMR (400 MHz, CDCl₃) δ7.45-7.30 (5H, m), 5.13 (2H, s), 3.56-3.42 (2H, m), 2.56 (2H, t, J = 7.2 Hz), 2.08-1.95 (2H, m).
¹³C NMR (100 MHz, CDCl₃) δ172.1, 157.0 (t), 156.9 (t), 156.9 (t), 135.7, 128.7, 128.5, 128.4, 66.7, 41.0 (t), 40.9 (t), 40.8 (t), 30.6, 24.4.
IR (neat) 3091, 3064, 3033, 2948, 2888, 2150, 1733, 1456, 1231, 1166, 750, 698 cm^-1.
MS (ESI) 計算値：226.0844（C₁₂H₁₃NNaO₂ ⁺ [M+Na]⁺）；測定値：226.0847. [I-21: 4-aminobutyric acid derivative]

4-Aminobutyric acid (3.22 g, 31.23 mmol) was dissolved in formic acid (30 mL), acetic anhydride (3.0 eq, 8.9 mL) was added, and the mixture was stirred at room temperature for 7 days to be reacted. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the corresponding formamide (21a). Compound 21a was reacted with benzyl bromide (1.5 eq, 5.55 mL) and potassium carbonate (4.0 eq, 17.2 g) in DMF (30 mL) by stirring at 60 ° C. for 4 days. After completion of the reaction, the reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 1: 2 → 1: 4) to obtain the corresponding benzyl ester (21b) (363.2 mg, 1.64 mmol, 5%). Compound 21b (363.2 mg, 1.64 mmol) was added to DCM (5 mL), and p-TsCl (1.5 eq, 413.3 mg) and pyridine (2.0 eq, 265 μL) were added to the resulting mixture, followed by stirring for 1.5 hours. Reaction was performed. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, water, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1) to give isonitrile 21 (160.8 mg, 0.79 mmol, 48%). Colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.45-7.30 (5H, m), 5.13 (2H, s), 3.56-3.42 (2H, m), 2.56 (2H, t, J = 7.2 Hz), 2.08 -1.95 (2H, m).
¹³ C NMR (100 MHz, CDCl ₃ ) δ172.1, 157.0 (t), 156.9 (t), 156.9 (t), 135.7, 128.7, 128.5, 128.4, 66.7, 41.0 (t), 40.9 (t), 40.8 (t), 30.6, 24.4.
IR (neat) 3091, 3064, 3033, 2948, 2888, 2150, 1733, 1456, 1231, 1166, 750, 698 cm ^-1 .
MS (ESI) _{calcd: 226.0844 (C 12 H 13 NNaO} 2 + [M + Na] +); found: 226.0847.

O-ベンジルセリン（350.8 mg, 1.80 mmol）を、ベンジルアルコール（2 mL）中に溶解し、CSA（1.2 eq, 498.8 mg）を加えて、60℃にて2日間撹拌し反応させた。反応終了後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝4：1→2：1→1：1→1：4）により精製し、対応するベンジルエステル（22a）（383.0 mg, 1.34 mmol, 75 %）を得た。化合物22a（979.4 mg, 3.43 mmol）をギ酸（5 mL）中に溶解し、無水酢酸（3.0 eq, 0.97 mL）を加えて室温にて25時間撹拌し反応させた。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）により精製し、対応するホルムアミド（22b）（1.05 g, 3.35 mmol, 97 %）を得た。化合物22b（524.3 mg, 1.67 mmol）をDCM (5 mL）中に加え、得られた混合物にPhOPOCl₂ (1.5 eq, 388 μL)及びピリジン（5.0 eq, 674 μL）を加え、室温にて2時間撹拌し反応を行った。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を、塩酸、炭酸水素ナトリウム、及び飽和食塩水で順次洗浄し、さらに硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）により精製し、イソニトリル22（18.3 mg, 0.062 mmol, 4 %）を得た。赤色油状物。
¹H NMR (400 MHz, CDCl₃) δ 7.42-7.21 (10H, m), 5.29-5.20 (2H, m), 4.63-4.54 (2H, m), 4.51-4.40 (1H, m), 3.91-3.81 (2H, m).
¹³C NMR (100 MHz, CDCl₃) δ 164.7, 161.5, 136.9, 134.6, 128.9, 128.8, 128.5, 128.2, 127.8, 73.7, 69.5, 68.5, 56.9.
IR (neat) 3087, 3064, 3033, 2952, 2871, 2152, 1756, 1456, 1280, 1195, 1112, 738, 698 cm^-1.
MS (ESI) 計算値：318.1106（C₁₈H₁₇NNaO₃ ⁺ [M+Na]⁺）; 測定値：318.1104. [I-22: Serine derivative]

O-benzylserine (350.8 mg, 1.80 mmol) was dissolved in benzyl alcohol (2 mL), CSA (1.2 eq, 498.8 mg) was added, and the mixture was stirred at 60 ° C. for 2 days for reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1 → 2: 1 → 1: 1 → 1: 4) to give the corresponding benzyl ester (22a) (383.0 mg, 1.34 mmol, 75%) Obtained. Compound 22a (979.4 mg, 3.43 mmol) was dissolved in formic acid (5 mL), acetic anhydride (3.0 eq, 0.97 mL) was added, and the mixture was reacted at room temperature for 25 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the corresponding formamide (22b) (1.05 g, 3.35 mmol, 97%). Compound 22b (524.3 mg, 1.67 mmol) was added to DCM (5 mL), and PhOPOCl ₂ (1.5 eq, 388 μL) and pyridine (5.0 eq, 674 μL) were added to the resulting mixture. The reaction was carried out with stirring. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, and saturated brine, further dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain isonitrile 22 (18.3 mg, 0.062 mmol, 4%). Red oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.21 (10H, m), 5.29-5.20 (2H, m), 4.63-4.54 (2H, m), 4.51-4.40 (1H, m), 3.91-3.81 (2H, m).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.7, 161.5, 136.9, 134.6, 128.9, 128.8, 128.5, 128.2, 127.8, 73.7, 69.5, 68.5, 56.9.
IR (neat) 3087, 3064, 3033, 2952, 2871, 2152, 1756, 1456, 1280, 1195, 1112, 738, 698 cm ^-1 .
MS (ESI) _{calcd: 318.1106 (C 18 H 17 NNaO} 3 + [M + Na] +); found: 318.1104.

化合物1（112.1 mg, 0.64 mmol）を、アセトニトリル（10 mL）に溶解し、水酸化カリウム（90.7 mg, 1.62 mmol, 2.5 eq）、及びベンジルブロミド（169 μL, 0.64 mmol, 2.2 eq）を加え、室温で72時間反応させた。反応終了後、反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を、水、及び飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝10：1）により精製し、イソニトリル23（138.9 mg, 0.39 mmol, 61%）を得た。無色油状物。
¹H-NMR (600 MHz, CDCl₃) δ7.33-7.17 (13H, m), 7.07 (2H, dd, J = 7.6, 1.4 Hz), 3.37 (2H, d, J = 13.7 Hz), 3.07 (2H, d, J = 13.7 Hz).
¹³C-NMR (150 MHz, CDCl₃) δ167.8, 161.4, 134.4, 133.4, 130.3, 128.6, 128.5, 128.4, 128.3, 127.9, 70.4, 68.1, 45.0.
IR (neat) 3109, 3088, 3064, 3032, 3008, 2964, 2933, 2141, 1755, 1738, 1497, 1443, 1277, 1271, 1088, 1030, 746, 700 cm^-1.
MS (ESI) 計算値：378.1470 C₂₄H₂₁NNaO₂ ⁺ [M+Na]⁺; 実測値：378.1474. [I-23: Phenylalanine analog]

Compound 1 (112.1 mg, 0.64 mmol) is dissolved in acetonitrile (10 mL), potassium hydroxide (90.7 mg, 1.62 mmol, 2.5 eq) and benzyl bromide (169 μL, 0.64 mmol, 2.2 eq) are added, The reaction was allowed to proceed for 72 hours at room temperature. After completion of the reaction, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to obtain isonitrile 23 (138.9 mg, 0.39 mmol, 61%). Colorless oil.
¹ H-NMR (600 MHz, CDCl ₃ ) δ7.33-7.17 (13H, m), 7.07 (2H, dd, J = 7.6, 1.4 Hz), 3.37 (2H, d, J = 13.7 Hz), 3.07 ( (2H, d, J = 13.7 Hz).
¹³ C-NMR (150 MHz, CDCl ₃ ) δ167.8, 161.4, 134.4, 133.4, 130.3, 128.6, 128.5, 128.4, 128.3, 127.9, 70.4, 68.1, 45.0.
IR (neat) 3109, 3088, 3064, 3032, 3008, 2964, 2933, 2141, 1755, 1738, 1497, 1443, 1277, 1271, 1088, 1030, 746, 700 cm ^-1 .
MS (ESI) calc .: 378.1470 C ₂₄ H ₂₁ NNaO ₂ ⁺ [M + Na] ⁺ ; found: 378.1474.

化合物1（125.7 mg, 0.72 mmol）を、トルエン／クロロホルム（7 mL／3 mL）に溶解し、炭酸セシウム（513.5 mg, 1.58 mmol, 2.2 eq）、及び4-アセトキシベンジルブロミド（362.7 mg, 1.58 mmol, 2.2 eq）を加え、室温で48時間反応させた。反応終了後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、水、及び飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮を行った。残留物をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）により精製し、イソニトリル24（85.7 mg, 0.18 mmol, 25%）を得た。無色油状物。
¹H-NMR (600 MHz, CDCl₃) δ7.35-7.28 (3H, m), 7.25-7.19 (4H, m), 7.15-7.09 (2H, m), 7.02-6.97 (4H, m), 5.03 (2H, s), 3.35 (2H, d, J = 13.7 Hz), 3.07 (2H, d, J = 13.7 Hz), 2.30 (6H, s).
¹³C-NMR (150 MHz, CDCl₃) δ169.3, 167.6, 161.8, 150.4, 134.3, 131.3, 130.8, 128.7, 128.6, 128.5, 121.7, 70.2, 68.3, 44.2, 21.2.
IR (neat) 3651, 3494, 3064, 3037, 3010, 2964, 2935, 2139, 1749, 1606, 1456, 1443, 1421, 1369, 1272, 1192, 1167, 1109, 912, 850, 754, 698 cm^-1.
MS (ESI) 計算値：494.1580 C₂₈H₂₅NNaO₆ ⁺ [M+Na]⁺;実測値：494.1584. [I-24: Tyrosine analog]

Compound 1 (125.7 mg, 0.72 mmol) was dissolved in toluene / chloroform (7 mL / 3 mL), cesium carbonate (513.5 mg, 1.58 mmol, 2.2 eq), and 4-acetoxybenzyl bromide (362.7 mg, 1.58 mmol). , 2.2 eq) and allowed to react for 48 hours at room temperature. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain isonitrile 24 (85.7 mg, 0.18 mmol, 25%). Colorless oil.
¹ H-NMR (600 MHz, CDCl ₃ ) δ7.35-7.28 (3H, m), 7.25-7.19 (4H, m), 7.15-7.09 (2H, m), 7.02-6.97 (4H, m), 5.03 (2H, s), 3.35 (2H, d, J = 13.7 Hz), 3.07 (2H, d, J = 13.7 Hz), 2.30 (6H, s).
¹³ C-NMR (150 MHz, CDCl ₃ ) δ169.3, 167.6, 161.8, 150.4, 134.3, 131.3, 130.8, 128.7, 128.6, 128.5, 121.7, 70.2, 68.3, 44.2, 21.2.
IR (neat) 3651, 3494, 3064, 3037, 3010, 2964, 2935, 2139, 1749, 1606, 1456, 1443, 1421, 1369, 1272, 1192, 1167, 1109, 912, 850, 754, 698 cm ^-1 .
MS (ESI) calc: 494.1580 C ₂₈ H ₂₅ NNaO ₆ ⁺ [M + Na] ⁺ ; found: 494.11584.

<II: Usage example>
[II-1: Activity measurement test for cypris larvae of vertical barnacles]
According to the method described in Japanese Patent No. 4933261 or the method described in the literature of Nogata et al.

  As the example compounds, the example compounds 1 to 21 prepared above were used.

  As Comparative Example Compound 1, copper sulfate was used.

  Cypris larvae of the vertical barnacles were grown in natural seawater at 25 ° C placed in an incubator at 25 ° C. In the following test, barnacle larvae obtained on day 5 after hatching were stored at 4 ° C. for 2 days.

  About 2 ml of a test compound in methanol was dispensed into each well of a 24-well polystyrene multi-well plate (3.2 ml / well, well diameter 15.5 mm, well height 17.6 mm, Corning). The multiwell plate was air dried to evaporate the methanol. Test compounds were dispensed at final concentrations of 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 μg / ml. Depending on the adherence rate and / or mortality of the test compound, the test compound was additionally dispensed to a final concentration of 0.001, 0.003, 30 and 100 μg / ml. Thereafter, 6 individual barnacle Cyprus larvae were transplanted into each well together with 2 ml of natural seawater filtered in advance. The multiwell plate was left in an incubator at 25 ° C., and barnacle larvae were grown at 25 ° C. for 5 days. In the above procedure, a control test was performed by dispensing a methanol solution containing no test compound. Four tests (4 wells) were carried out for each test compound concentration group and control group. The natural seawater used in the above test was prepared by diluting natural seawater (salt concentration 36 g / kg) collected in the coastal area near Onjuku, Chiba Prefecture with distilled water to a salt concentration of 32 g / kg. .

  Five days after the start of the test, the number of attached and dead barnacle larvae in each well was counted under a stereomicroscope. For each test group and control group, the barnacle larvae adherence rate (%) and mortality rate (%) in each well were calculated from the total of the above counts for the total number of barnacle larvae in quadruplicate (4 wells) did.

The test was repeated three times, and the adhesion rate (%) and mortality rate (%) of barnacle larvae in each test group and control group were calculated from the average values. Moreover, for each test compound, the dose - Create a deposition rate response curve, the concentration which inhibits the attachment of barnacles larvae 50% (hereinafter referred to as EC ₅₀₎ was determined. Similarly, for each test compound, the dose - Create mortality response curve, the concentration causing the death of the barnacle larvae 50% was determined (hereinafter referred to as LC _50). The results are shown in Tables 1 and 2.

Claims (10)

Formula (I):

[Where:
R ¹ and R ² are each independently hydrogen, substitution or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted butyl, substituted benzyl, or unsubstituted indol-3-ylmethyl Or
R ¹ and R ² are both substituted or unsubstituted benzyl,
R ¹ and R ² together form an unsubstituted ethylidene ;
R ³ is hydrogen, arsenate Dorokishiru or unsubstituted methoxy, isopropyloxy or benzyloxy,
L is a single bond or methylene, ethane-1,2-diyl or ethane-1,1-diyl ;
When R ¹ and R ² have a substituent, the substituent is cyano, isocyano, —NH—C (═O) CH ₃ , —OC (═O) CH ₃ , —SCH ₃ , —OH, —O -Benzyl or -C (= O) -O-benzyl. ]
An antifouling agent for aquatic organisms that contains a compound represented by the formula: The compound represented by formula (I) is:

2. The antifouling agent for aquatic organisms according to claim 1, selected from the group consisting of: The compound represented by formula (I) is:

3. The antifouling agent for aquatic organisms according to claim 2, wherein the antifouling agent is selected from the group consisting of: Formula (Ia):

^{Wherein, L a, R 1a, R} 2a, R 3a, R 4a and R ^5a are the following satisfy any of [i] ~ [iii]:
[i]
L ^a is a single bond,
R ^1a is hydrogen;
R ^2a is - either a CH ₂ CH ₂ -C N, or
R ^1a and R ^2a together form an ethylidene;
R ^3a is hydroxyl or unsubstituted arylalkyl Oki sheet.
[ii]
L ^a is ethane-1,1-diyl,
R ^1a and R ^2a are hydrogen,
R ^3a is hydroxyl or unsubstituted arylalkyloxy.
[iii]
L ^a is a single bond,
R ^1a and R ^2a are benzyl, or

(Wherein * represents the point of attachment to the carbon atom),
R ^3a is hydroxyl or unsubstituted arylalkyloxy;
R ^5a is hydrogen or unsubstituted acyl. ]
Or a salt thereof, or a solvate thereof. The compound represented by formula (Ia) is:

5. The compound of claim 4, wherein the compound is selected from the group consisting of: A method for producing a compound of formula Ia according to claim 4 or 5 , comprising the following steps:
Formula (IIa):

^{Wherein, L a, R 1a, R} 2a, R 3a, 及 Beauty R ^5a are as defined in claim 4. ]
A compound represented by formula (IIIa):

^{Wherein, L a, R 1a, R} 2a, R 3a, 及 Beauty R ^5a are as defined in claim 4. ]
A formamide formation step of obtaining a formamide compound represented by:
An isocyano group forming step of obtaining a compound represented by the formula (Ia) by reacting the formamide compound represented by the formula (IIIa) obtained in the formamide forming step with an acid halide in the presence of a base;
Said method. A method for controlling aquatic organisms, comprising treating at least one of the aquatic organisms and adhesion objects with the antifouling agent for aquatic organisms according to any one of claims 1 to 3 . 4. A paint containing the antifouling agent for organisms attached to water according to any one of claims 1 to 3, and a film-forming component. The compound represented by Formula I is in the form of a conjugate having a structure in which the compound and an amino acid, peptide or solid phase carrier are linked by one or more bonds selected from the group consisting of an amide bond and an ester bond. The antifouling agent for aquatic organisms according to any one of claims 1 to 3, which is contained. A structure in which the compound represented by the formula Ia according to claim 4 or 5 and an amino acid, a peptide or a solid phase carrier are linked by one or more bonds selected from the group consisting of an amide bond and an ester bond. A connected body.