JP2004244392A - New carbonic acid ester and amidation reaction using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a dehydrative condensation agent demanded in the fields of organic synthesis, pharmaceuticals, agrochemicals, or the like, and other fields, and to provide a method for the synthesis of a carbonamide, especially a dehydrative condensation agent effective for completely suppressing the racemization of a peptide in a peptide synthesis and easily usable under mild conditions. <P>SOLUTION: The problems are solved by newly synthesizing 1,1'-(carbonyldioxy)di[2(1H)-pyridone] compounds and using the compound as the dehydrative condensation agents. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

【０００８】
（式中Ｒ^１，Ｒ^２はそれぞれ水素，アルキル基，アルケニル基，アルキニル基，アルコキシ基，脂環，芳香環，ヘテロ環，ハロゲン，ニトロ基，シアノ基，トリフルオロメチル基のいずれかで，同一であっても異なっていても良い）で示される新規炭酸エステルである。本発明に係る化合物は文献未載の新規化合物であり，その製造法としては下記反応式に従って合成することができる。
【０００９】
【化６】

【００１０】
式中Ｒ^１，Ｒ^２はそれぞれ水素，アルキル基，アルケニル基，アルキニル基，アルコキシ基，脂環，芳香環，ヘテロ環，ハロゲン，ニトロ基，シアノ基，トリフルオロメチル基のいずれかで，同一であっても異なっていても良い。使用するオキソピリジノールＡ，Ｂの比率は特に定めないがトリホスゲンＣに対し，合計６当量使用することが望ましい。なお，トリホスゲンＣに代えてホスゲン，ジホスゲン，Ｎ，Ｎ’−カルボニルジイミダゾールなどを使用することもできる。ここで使用し得る溶媒はベンゼン，トルエン，ＴＨＦ，ＤＭＦ，ジエチルエーテル，アセトニトリル，ジクロロエタン，ジクロロメタン，クロロホルム，及びその他の有機溶媒から適宜選択される。使用し得る塩基はピリジン，トリエチルアミン，水酸化カリウム，水酸化ナトリウム，炭酸水素ナトリウムなどから適宜選択される。反応温度は通常−１０℃から溶媒の還流温度，好ましくは０℃から３０℃の範囲内で適宜選択される。反応に要する時間は反応温度，濃度により異なるが，通常は１時間から４８時間，好ましくは１２時間から２４時間の範囲内で適宜選択される。
【００１１】
以下に下記一般式（ＩＩ）
【化７】

【００１２】
で示される新規炭酸エステル，１，１’−（カルボニルジオキシ）ジ［２（１Ｈ）−ピリドン］を本発明の代表的な例として取り上げ，本発明の有用性を明らかにする。
【００１３】
【化８】

【００１４】
上記の反応ではカルボン酸に対し，アミンおよびビス（２−オキシ−１−ピリジル）カルボネートをそれぞれ１〜２当量用いることが望ましいが，それぞれ１．８当量用いることがさらに望ましい。以下に種々のカルボン酸とアミンを脱水縮合した結果を示す。
【００１５】
【表１】

【００１６】
表１に示すように脱水縮合剤として１，１’−（カルボニルジオキシ）ジ［２（１Ｈ）−ピリドン］を用いることにより，高い収率で対応するカルボン酸アミドを得ることができた。エントリー２に示すように求核性の弱いアニリンのごときアミンでもほぼ定量的に反応が進行した。エントリー３に示すように環状アミンにも適用可能であった。また，エントリー４，５のごとき不飽和カルボン酸とアミンの反応においては，ＥＤＣやＤＰＣなどを脱水縮合剤として用いた場合は，塩基触媒の影響により目的物の幾何異性化を伴う場合が多い。例えば，ＥＤＣ／ＤＭＡＰを用いた（Ｅ）−クロトン酸と３−フェニルプロピルアミンの脱水縮合反応では４％の（Ｚ）−異性体が，（Ｚ）−アンゲリカ酸と３−フェニルプロピルアミンでは１６％の（Ｅ）−異性体が副生する。これに対し，１，１’−（カルボニルジオキシ）ジ［２（１Ｈ）−ピリドン］を用いた場合は幾何異性体の副生をまったく伴わず目的物のみを高収率で得ることができた。
【００１７】
次に脱水縮合剤として１，１’−（カルボニルジオキシ）ジ［２（１Ｈ）−ピリドン］を用いたジペプチド，トリペプチドの反応例を示す。
【００１８】
【表２】

【００１９】
表２において，ＬＯＣは酸成分の光学純度−ペプチド成分の光学純度であり，ラセミ化した割合を表している。エントリー１，２はペプチド成分の旋光度よりＬＯＣを決定した。エントリー３〜６は酸成分およびペプチド成分のＨＰＬＣ分析によりＬＯＣを決定した。エントリー１，２のように，アミノ基をＺ−基で保護したアミノ酸とグリシンエステルからのジペプチド合成では，ラセミ化はまったく観測されなかった。さらにエントリー３，４に示すように，ジペプチドとアミノ酸エステルのカップリング反応によるトリペプチド合成においてもカルボン酸残基のラセミ化は進行しなかった。対象例としてエントリー５，６にＴＢＴＵおよびＤＣＣを脱水縮合剤として用いた場合の結果を示した。いずれもラセミ化を完全に抑制することはできなかった。
【００２０】
【実施例】
以下，本発明を実施例により更に詳細に説明する。なお，本発明の範囲は，かかる実施例に限定されないことは言うまでもない。本発明の範囲内では変形が可能なことは当業者には明らかであろう。
【００２１】
実施例１
１，１’−（カルボニルジオキシ）ジ［２（１Ｈ）−ピリドン］の合成
２−ヒドロキシピリジンＮ−オキシド１．０ｇ（９．００ｍｍｏｌ）およびトリホスゲン０．４５ｇ（１．５１ｍｍｏｌ）をジクロロメタン３０ｍｌに溶解し，０℃で攪拌しながらピリジン１．５ｍｌを加えた。室温で２４時間攪拌した後，エバポレーターで溶媒を除去した。アルゴン雰囲気下，エーテル３０ｍｌで３回洗浄した後，ＴＨＦ ５０ｍｌを加え室温で２時間攪拌した。３０分静置した後アルゴン雰囲気下，ろ過した。ろ液をエバポレーターで濃縮し，得られた黄色い残留物にＴＨＦ ５０ｍｌを加え，上記の操作を３回繰り返した。ジクロロメタン３ｍｌとエーテル６ｍｌを加え静置した後，アルゴン雰囲気下，薄い黄色の上澄みを除去した。この操作を２度繰り返した。４５℃で溶媒を減圧留去することにより，１，１’−（カルボニルジオキシ）ジ［２（１Ｈ）−ピリドン］の白色結晶１．０２ｇを得た（収率９０．５％）。
以下に主な物性を示す。
融点：１４２〜１４４℃
^１Ｈ ＮＭＲ （ＣＤＣｌ_３） ^ＴＭ： ７．６４ （２Ｈ， ｄｄ， Ｊ＝７．２，２．２Ｈｚ， Ｈ−６）， ７．４０ （２Ｈ， ｄｄｄ， Ｊ＝９．３，６．９，２．２Ｈｚ， Ｈ−４）， ６．７３ （２Ｈ， ｄｄ， Ｊ＝９．３，１．８Ｈｚ， Ｈ−３）， ６．２３ （２Ｈ， ｄｄｄ， Ｊ＝７．２，６．９，１．８Ｈｚ， Ｈ−５），^１３Ｃ ＮＭＲ （ＣＤＣｌ_３） ^ＴＭ： １５６．３（２）， １５０．２（Ｃ−Ｏ）， １４０．０（４）， １３４．５（６）， １２２．９（３）， １０５．５（５）
【００２２】
実施例２
３−フェニル−Ｎ−ベンジルプロパンアミドの合成
１，１’−（カルボニルジオキシ）ジ［２（１Ｈ）−ピリドン］ ５４．８ｍｇ（０．２２１ｍｍｏｌ）をジクロロメタン０．８ｍｌに溶かし，室温で３−フェニルプロピオン酸１８．４ｍｇ（０．１２３ｍｍｏｌ）を加え，そのまま１時間攪拌した。３−フェニルプロピオン酸が完全に消費されたことをＴＬＣで確認した後，室温でベンジルアミン２３．６ｍｇ（０．２２１ｍｍｏｌ）をジクロロメタン１．０ｍｌに溶かした溶液を加えた。３０分間攪拌した後，エバポレーターで溶媒を除去した。分取ＴＬＣ（ヘキサン／エチルアセテート＝１／１）で精製し，３−フェニル−Ｎ−ベンジルプロパンアミドの白色固体２８．４ｍｇを得た（収率９７％）。
以下に主な物性を示す。
融点：８０℃
ＩＲ （ＫＢｒ） ３２９０， １６５０， １５４０ ｃｍ^−１，^１Ｈ ＮＭＲ （ＣＤＣｌ_３） ^ＴＭ： ７．３０−７．０９ （１０Ｈ， ｍ， Ｐｈ）， ５．６８ （１Ｈ， ｂｒ ｓ， ＮＨ）， ４．３６ （２Ｈ， ｄ， Ｊ＝５．６Ｈｚ， Ｂｎ）， ２．９６ （２Ｈ， ｔ， Ｊ＝７．６Ｈｚ， Ｈ−３） ， ２．４８ （２Ｈ， ｔ， Ｊ＝７．６Ｈｚ， Ｈ−２），^１３Ｃ ＮＭＲ （ＣＤＣｌ_３） ^ＴＭ： １７１．８（１）， １４０．７（Ｐｈ）， １３８．１（Ｐｈ）， １２８．６（Ｐｈ）， １２８．５（Ｐｈ）， １２８．４（Ｐｈ）， １２７．７（Ｐｈ）， １２７．４（Ｐｈ）， １２６．２（Ｐｈ）， ４３．５（Ｂｎ）， ３８．４（２）， ３１．７（３）
【００２３】
実施例３
Ｎ−［Ｎ−（Ｎ−カルボベンゾキシグリシル）−Ｌ−フェニルアラニル］−Ｌ−バリンメチルエステルの合成
１，１’−（カルボニルジオキシ）ジ［２（１Ｈ）−ピリドン］ ７７．０ｍｇ（０．３１０ｍｍｏｌ）をジクロロメタン１．３ｍｌに溶かし，０℃でＮ−（Ｎ−カルボベンゾキシグリシル）−Ｌ−フェニルアラニン６１．４ｍｇ（０．１７２ｍｍｏｌ）をジクロロメタン０．８ｍｌに溶かした溶液を加え，室温下でそのまま１時間攪拌した。Ｎ−（Ｎ−カルボベンゾキシグリシル）−Ｌ−フェニルアラニンが完全に消費されたことをＴＬＣで確認した後，Ｌ−バリンメチルエステル塩酸塩５２．０ｍｇ（０．３１０ｍｍｏｌ）とトリエチルアミン３１．４ｍｇ（０．３１０ｍｍｏｌ）をジクロロメタン１．２ｍｌに溶かした溶液を−１８℃で加えた。５分間攪拌した後，氷冷した食塩水１０ｍｌを加えた。有機層を抽出し，１Ｍ塩酸，水，食塩水で洗浄した後，硫酸ナトリウムで乾燥した。ろ過した後，エバポレーターで溶媒を除去し，分取ＴＬＣ（ヘキサン／エチルアセテート＝１／３）で精製し，Ｎ−［Ｎ−（Ｎ−カルボベンゾキシグリシル）−Ｌ−フェニルアラニル］−Ｌ−バリンメチルエステルの白色固体６３．２ｍｇを得た（収率７８％）。
以下にＨＰＬＣの条件を示す。
カラム：Ｋｒｏｍａｓｉｌ ＫＲ１００−１０ Ｃ１８ （４．６×２５ ｃｍ）
移動相：アセトニトリル／水（０．１％トリフルオロ酢酸）＝４８／５２
流速：１．５ｍＬ／ｍｉｎ
検出波長：２２０ｎｍ
ｔ_Ｒ＝９．５ｍｉｎ （ＬＬ−体），ｔ_Ｒ＝１０．６ｍｉｎ （ＤＬ−体）
【００２４】
【発明の効果】
上記のごとく，本発明は新規炭酸エステルおよびそれを用いたアミド化反応に関するものである。本発明は，有機合成や医薬，農薬等の属する分野およびその他の分野で要求されている脱水縮合剤およびカルボン酸アミドの合成法を提供するものである。特にペプチドの合成においては目的物のラセミ化を完全に抑制することができ，簡便かつ温和な条件下，反応を進行させることができた。ペプチド鎖の逐次延長法，セグメントカップリング双方において非常に有効な脱水縮合剤ということができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel carbonic acid ester and an amidation reaction using the same, and provides a method for synthesizing a dehydrating condensing agent and a carboxylic acid amide required in the fields of organic synthesis, pharmaceuticals, pesticides, and the like and other fields. To do. In particular, in peptide synthesis, it is intended to completely suppress racemization of the target substance and to provide a simple and mild peptide bond formation reaction under mild conditions.
[0002]
[Prior art]
The dehydration-condensation reaction to give a carboxylic acid amide from a carboxylic acid and an amine is one of the fundamental and important organic synthesis reactions. Various dehydration condensing agents have been developed and their usefulness has been reported. For example, 1,3-dicyclohexylcarbodiimide (DCC) (for example, see Non-Patent Document 1) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (for example, see Non-Patent Document 2) Has long been used as a dehydrating condensing agent. In addition, the inventors have previously reported that carbonate-based compounds such as di (2-pyridyl) carbonate (DPC) and O, O'-di (2-pyridyl) thiocarbonate (DPTC) have been used in the presence of a basic catalyst. Reported that it is an excellent dehydrating condensing agent that gives carboxylic acid amide (for example, see Non-Patent Document 3).
[0003]
On the other hand, peptides that are physiologically active substances have an amide bond in the structure. Peptide synthesis methods include a sequential extension method in which amino acids are condensed one by one and a segment coupling method in which two peptides are condensed to obtain a longer peptide. In the former sequential extension method, when the peptide is extended, the product becomes gradually insoluble and purification becomes difficult. Therefore, in the sequential extension method, the purity decreases as the peptide chain is extended, so that the synthesis is limited to the synthesis of a peptide chain having 10 to 15 constituent amino acids. To solve the purification problem, a solid-phase synthesis method in which amino acids are supported on a resin has been developed. However, problems such as low reproducibility of the reaction and the necessity of washing with a large amount of solvent after the reaction are pointed out. Have been. In addition, there is a risk that the amino acid at the C-terminal may racemize during condensation in both the sequential extension method and the segment coupling method. For example, when an attempt is made to extend the peptide chain by activating the carboxyl group of a peptide whose N-terminus is protected with an acyl group, the activated amino acid residue may be racemized. This is thought to be due to the formation of an oxazolone ring during the reaction. On the other hand, when a tert-butoxycarbonyl group (Boc group) or a benzyloxycarbonyl group (Z group) having a urethane-type structure is used as an N-terminal protecting group, racemization can be suppressed. In the segment coupling method, it is only necessary to bring Gly having no asymmetric center to the amino acid at the C-terminal or to bring an amino acid which is hard to racemize. Amino acids to be avoided include Cys, His, Phe, Lys, Thr, Ile, Val and the like. It is said that it is better to avoid poorly reactive amino acids such as Val, Ile and Thr at the N-terminal of the segment. Therefore, the amino acids that can be used without any problems are limited, and studies to overcome these limitations have been actively conducted. For example, the above-mentioned dehydrating condensing agents DCC, EDC, etc., and 1-hydroxybenzotriazole (HOBt) (for example, see Non-Patent Document 4) or 1-hydroxy-7-azabenzotriazole (HOAt) (for example, see Non-Patent Document 5) It has been studied to suppress racemization by using a combination of coupling additives such as). In the coupling reaction between Bz-Val-OH and Val-OMe using DCC as a dehydrating condensing agent, when HOBt was not added, 61.5% of the DL-isomer was produced, whereas the equivalent amount of HOBt was equivalent to DCC. When using HOAt, it is suppressed to 41.9%, and when using HOAt, it is suppressed to 14.4%. Further, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphonium hexafluorophosphate (BOP) having a HOBt unit (for example, see Non-Patent Document 6) and O- (benzotriazol-1-yl) -N , N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), O- (benzotriazol-1-yl) -N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU) (For example, see Non-Patent Document 7), phosphonium-type and uronium-type dehydration-condensation agents have been developed and used as dehydration-condensation agents without racemization. For example, in the reaction of Z-Gly-Phe-OH and Val-OMe, the ratio of the DL-isomer when BOP is used is 4.8%, and when TBTU is used, racemization is suppressed to 1.4%. ing. Furthermore, it is known that the rate of racemization suppression is improved by adding a coupling additive such as HOBt. In the reaction of Z-Gly-Phe-OH and Val-OMe, when BOP is combined with HOBt, the ratio of DL-isomer is 1.2%, and when HOBt is combined with TBTU, racemization is 0.2%. It is suppressed.
[0004]
[Non-Patent Document 1] J. C. Sheehan, 1 other, "Journal of American Chemical Society", 1955, Vol. 77, p. 1067
[Non-Patent Document 2] J. C. Sheehan, et al., "Journal of Organic Chemistry", 1961, Vol. 26, p. 2525
[Non-Patent Document 3] Isa Shiina and three others, "Bulltin of the Chemical Society of Japan", 2000, Vol. 73, p. 2811
[Non-Patent Document 4] W. Konig, et al., Chemische Berichte, 1970, Vol. 103, p. 788
[Non-Patent Document 5] LA Carpino, "Journal of American Chemical Society", 1993, Vol. 115, p. 4397
[Non-Patent Document 6] B. Castro, et al., "Tetrahedron Letters", 1975, p. 1219
[Non-Patent Document 7] R. Knorr, et al., "Tetrahedron Letters", 1989, Vol. 30, p. 1927
[0005]
[Problems to be solved by the invention]
However, the above-mentioned reaction using BOP or TBTU and HOBt generally requires a low temperature and a long time. Further, since HOBt needs to be added, it cannot be said to be an optimal method from the viewpoint of atomic efficiency. Therefore, strict suppression of racemization in peptide synthesis remains a difficult task even today. There is a strong demand for a dehydrating condensing agent that can completely suppress racemization of peptides and can be used more easily and under mild conditions.
[0006]
[Means for Solving the Problems]
The inventors have conducted intensive studies and as a result have completed the present invention.
[0007]
The present invention relates to the following general formula (I)
Embedded image

[0008]
(Wherein R ¹ and R ² are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alicyclic, aromatic, heterocyclic, halogen, nitro, cyano, trifluoromethyl, (Which may be the same or different). The compound according to the present invention is a novel compound which has not been described in any literature, and can be synthesized according to the following reaction formula as a production method.
[0009]
Embedded image

[0010]
In the formula, each of R ¹ and R ² is the same as any of hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alicyclic ring, an aromatic ring, a heterocyclic ring, a halogen, a nitro group, a cyano group, and a trifluoromethyl group. Or different. Although the ratio of oxopyridinol A and B to be used is not particularly limited, it is preferable to use a total of 6 equivalents to triphosgene C. In addition, phosgene, diphosgene, N, N'-carbonyldiimidazole, etc. can be used in place of triphosgene C. The solvent that can be used here is appropriately selected from benzene, toluene, THF, DMF, diethyl ether, acetonitrile, dichloroethane, dichloromethane, chloroform, and other organic solvents. The base that can be used is appropriately selected from pyridine, triethylamine, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and the like. The reaction temperature is appropriately selected usually from -10 ° C to the reflux temperature of the solvent, preferably from 0 ° C to 30 ° C. The time required for the reaction varies depending on the reaction temperature and concentration, but is usually appropriately selected within the range of 1 hour to 48 hours, preferably 12 hours to 24 hours.
[0011]
The following general formula (II)
Embedded image

[0012]
The usefulness of the present invention will be clarified by taking 1,1 ′-(carbonyldioxy) di [2 (1H) -pyridone] as a typical example of the present invention.
[0013]
Embedded image

[0014]
In the above reaction, it is preferable to use 1 to 2 equivalents of amine and bis (2-oxy-1-pyridyl) carbonate with respect to the carboxylic acid, respectively, and it is more preferable to use 1.8 equivalents of each. The results of dehydration condensation of various carboxylic acids and amines are shown below.
[0015]
[Table 1]

[0016]
As shown in Table 1, by using 1,1 ′-(carbonyldioxy) di [2 (1H) -pyridone] as a dehydrating condensing agent, a corresponding carboxylic acid amide could be obtained in a high yield. As shown in entry 2, the reaction proceeded almost quantitatively even with amines such as aniline having low nucleophilicity. As shown in entry 3, it was also applicable to cyclic amines. In addition, in the reaction of an unsaturated carboxylic acid with an amine such as entries 4 and 5, when EDC or DPC is used as a dehydrating condensing agent, geometric isomerization of the target product is often accompanied by the influence of a base catalyst. For example, in the dehydration condensation reaction of (E) -crotonic acid and 3-phenylpropylamine using EDC / DMAP, 4% of the (Z) -isomer is obtained, and in (Z) -angelic acid and 3-phenylpropylamine, 16% of the (Z) -isomer is used. (E) -Isomer is by-produced. On the other hand, when 1,1 ′-(carbonyldioxy) di [2 (1H) -pyridone] is used, only the desired product can be obtained in high yield without any by-product of geometric isomer. Was.
[0017]
Next, a reaction example of dipeptide and tripeptide using 1,1 ′-(carbonyldioxy) di [2 (1H) -pyridone] as a dehydration condensing agent will be described.
[0018]
[Table 2]

[0019]
In Table 2, LOC is the optical purity of the acid component minus the optical purity of the peptide component, and represents the ratio of racemization. In entries 1 and 2, the LOC was determined from the optical rotation of the peptide component. Entry 3-6 determined LOC by HPLC analysis of acid and peptide components. As in entries 1 and 2, racemization was not observed at all in the synthesis of dipeptides from glycine esters and amino acids in which the amino group was protected with a Z-group. Further, as shown in entries 3 and 4, racemization of carboxylic acid residues did not progress in the synthesis of tripeptides by the coupling reaction between dipeptides and amino acid esters. As a target example, entries 5 and 6 show the results when TBTU and DCC were used as dehydrating condensing agents. None of them could completely suppress racemization.
[0020]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples. It goes without saying that the scope of the present invention is not limited to the embodiment. It will be apparent to those skilled in the art that variations are possible within the scope of the invention.
[0021]
Example 1
Synthesis of 1,1 ′-(carbonyldioxy) di [2 (1H) -pyridone] 1.0 g (9.00 mmol) of 2-hydroxypyridine N-oxide and 0.45 g (1.51 mmol) of triphosgene were added to 30 ml of dichloromethane. The mixture was dissolved and 1.5 ml of pyridine was added with stirring at 0 ° C. After stirring at room temperature for 24 hours, the solvent was removed with an evaporator. After washing three times with 30 ml of ether under an argon atmosphere, 50 ml of THF was added, and the mixture was stirred at room temperature for 2 hours. After allowing to stand for 30 minutes, the mixture was filtered under an argon atmosphere. The filtrate was concentrated with an evaporator, 50 ml of THF was added to the obtained yellow residue, and the above operation was repeated three times. After 3 ml of dichloromethane and 6 ml of ether were added and allowed to stand, a pale yellow supernatant was removed under an argon atmosphere. This operation was repeated twice. The solvent was distilled off under reduced pressure at 45 ° C. to obtain 1.02 g of white crystals of 1,1 ′-(carbonyldioxy) di [2 (1H) -pyridone] (yield 90.5%).
The main physical properties are shown below.
Melting point: 142-144 ° C
¹ H NMR (CDCl ₃ ) ^TM : 7.64 (2H, dd, J = 7.2, 2.2 Hz, H-6), 7.40 (2H, ddd, J = 9.3, 6.9, 2.2 Hz, H-4), 6.73 (2H, dd, J = 9.3, 1.8 Hz, H-3), 6.23 (2H, ddd, J = 7.2, 6.9, 1.8 Hz, H-5), ¹³ C NMR (CDCl ₃ ) ^™ : 156.3 (2), 150.2 (CO), 140.0 (4), 134.5 (6), 122. 9 (3), 105.5 (5)
[0022]
Example 2
Synthesis of 3-phenyl-N-benzylpropanamide 54.8 mg (0.221 mmol) of 1,1 '-(carbonyldioxy) di [2 (1H) -pyridone] was dissolved in 0.8 ml of dichloromethane, and the solution was dissolved at room temperature in 3-ml. 18.4 mg (0.123 mmol) of phenylpropionic acid was added and stirred for 1 hour. After confirming by TLC that 3-phenylpropionic acid was completely consumed, a solution of 23.6 mg (0.221 mmol) of benzylamine in 1.0 ml of dichloromethane was added at room temperature. After stirring for 30 minutes, the solvent was removed with an evaporator. Purification by preparative TLC (hexane / ethyl acetate = 1/1) gave 28.4 mg of 3-phenyl-N-benzylpropanamide as a white solid (yield 97%).
The main physical properties are shown below.
Melting point: 80 ° C
^{IR (KBr) 3290, 1650,} 1540 cm -1, 1 H NMR (CDCl 3) TM: 7.30-7.09 (10H, m, Ph), 5.68 (1H, br s, NH), 4 .36 (2H, d, J = 5.6 Hz, Bn), 2.96 (2H, t, J = 7.6 Hz, H-3), 2.48 (2H, t, J = 7.6 Hz, H -2), ¹³ C NMR (CDCl ₃ ) ^TM : 171.8 (1), 140.7 (Ph), 138.1 (Ph), 128.6 (Ph), 128.5 (Ph), 128. 4 (Ph), 127.7 (Ph), 127.4 (Ph), 126.2 (Ph), 43.5 (Bn), 38.4 (2), 31.7 (3)
[0023]
Example 3
Synthesis of N- [N- (N-carbobenzoxyglycyl) -L-phenylalanyl] -L-valine methyl ester 1,1 ′-(carbonyldioxy) di [2 (1H) -pyridone] 77. 0 mg (0.310 mmol) was dissolved in 1.3 ml of dichloromethane, and a solution of 61.4 mg (0.172 mmol) of N- (N-carbobenzoxyglycyl) -L-phenylalanine in 0.8 ml of dichloromethane was dissolved at 0 ° C. The mixture was stirred at room temperature for 1 hour. After confirming by TLC that N- (N-carbobenzoxyglycyl) -L-phenylalanine was completely consumed, 52.0 mg (0.310 mmol) of L-valine methyl ester hydrochloride and 31.4 mg of triethylamine ( 0.310 mmol) in 1.2 ml of dichloromethane was added at -18 ° C. After stirring for 5 minutes, 10 ml of ice-cooled saline was added. The organic layer was extracted, washed with 1M hydrochloric acid, water and brine, and dried over sodium sulfate. After filtration, the solvent was removed with an evaporator, and the residue was purified by preparative TLC (hexane / ethyl acetate = 1/3) to give N- [N- (N-carbobenzoxyglycyl) -L-phenylalanyl]-. 63.2 mg of a white solid of L-valine methyl ester was obtained (78% yield).
The HPLC conditions are shown below.
Column: Kromasil KR100-10 C18 (4.6 × 25 cm)
Mobile phase: acetonitrile / water (0.1% trifluoroacetic acid) = 48/52
Flow rate: 1.5 mL / min
Detection wavelength: 220 nm
t _R = 9.5min (LL- _body), t R = _10.6min (DL- body)
[0024]
【The invention's effect】
As described above, the present invention relates to a novel carbonate and an amidation reaction using the same. The present invention provides a method for synthesizing a dehydrating condensing agent and a carboxylic acid amide required in the fields to which organic synthesis, pharmaceuticals, agricultural chemicals, and the like belong and in other fields. In particular, in the synthesis of peptides, racemization of the target product could be completely suppressed, and the reaction could proceed under simple and mild conditions. It can be said to be a very effective dehydration condensing agent in both the sequential extension method of peptide chains and segment coupling.

Claims (4)

The following general formula (I)

(Wherein R ¹ and R ² are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alicyclic, aromatic, heterocyclic, halogen, nitro, cyano, trifluoromethyl, Which may be the same or different). The novel carbonate according to claim 1, represented by the following general formula (II), wherein R ¹ and R ^{2 in} the general formula (I) are hydrogen.

The novel carbonate according to claim 1 and the following general formula (III)

Wherein R ³ is an alkyl group, an alkenyl group, an alkynyl group, an alicyclic ring, an aromatic ring, or a heterocyclic ring, which may be substituted; and then reacting with the following general formula (IV) )

(Wherein R ⁴ is hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alicyclic ring, an aromatic ring, or a heterocyclic ring, and may be substituted; and R ⁵ is a hydrogen, an alkyl group, an alkenyl group, an alkynyl group. , A carboxyl group, an alicyclic ring, an aromatic ring, or a heterocyclic ring, R ⁴ and R ⁵ may be the same or different, and R ⁴ and R ⁵ are a methylene chain. Characterized by the reaction of an amine represented by the formula: The method for synthesizing a carboxylic acid amide according to claim 3, wherein the novel carbonate represented by the general formula II is used.