JP2006137694A - 3-(n-acylamino)- 2-acyloxy-3-(4-tetrahydropyranyl)-2-propenoate and its production method - Google Patents
3-(n-acylamino)- 2-acyloxy-3-(4-tetrahydropyranyl)-2-propenoate and its production method Download PDFInfo
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Abstract
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本発明は、3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステル及びその製法に関する。3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステルは、医薬や農薬等の原料や合成中間体として有用な化合物である。 The present invention relates to 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate and a process for producing the same. 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester is a useful compound as a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals.
本発明の3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステルは、新規な化合物であり、従来までにその存在や製法は全く知られていなかった。 The 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester of the present invention is a novel compound, and its existence and production method are completely known so far. There wasn't.
本発明の課題は、即ち、上記問題点を解決し、簡便な方法によって、3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステルを高収率で製造出来る、工業的に好適な3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステル及びその製法を提供することである。 The object of the present invention is to solve the above-mentioned problems and to obtain a high yield of 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate by a simple method. The present invention provides an industrially suitable 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate and a process for producing the same.
前記課題に鑑み、本発明者らが鋭意検討を行った結果、以下に示す簡便な方法によって3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステルを高収率で製造出来る方法を見出し、本発明を完成させた。 In view of the above problems, as a result of intensive studies by the present inventors, 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid was obtained by a simple method shown below. The present inventors have found a method capable of producing an ester with a high yield and completed the present invention.
即ち、本発明の課題は、一般式（１） That is, the subject of this invention is general formula (1).
（式中、Ｒ、Ｒ１及びＲ２は、それぞれ独立して、炭化水素基を示す。）
で示される3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステル（以下、化合物（１）と称する）によって解決される。
(In the formula, R, R 1 and R 2 each independently represent a hydrocarbon group.)
It is solved by 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester (hereinafter referred to as compound (1)).
本発明の課題は、又、酸の存在下、一般式（２） The subject of the present invention is also a general formula (2) in the presence of an acid.
（式中、Ｒ及びＲ１は、前記と同義である。）
で示される2-アシルオキシ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸エステル（以下、化合物（２）と称する）と、一般式（３）
(In the formula, R and R 1 are as defined above.)
2-acyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoic acid ester (hereinafter referred to as compound (2)) represented by formula (3)
（式中、Ｒ２は、前記と同義である。）
で示されるアミド化合物（以下、化合物（３）と称する）とを反応させることを特徴とする、一般式（１）
(Wherein R 2 has the same meaning as described above.)
And an amide compound (hereinafter referred to as compound (3)) represented by the general formula (1)
（式中、Ｒ、Ｒ１及びＲ２は、前記と同義である。）
で示される化合物（１）の製法によっても解決される。
(In the formula, R, R 1 and R 2 are as defined above.)
It can also be solved by the production method of the compound (1) represented by
本発明により、簡便な方法によって、3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステルを高収率で製造することが可能であり、且つ、工業的に好適な3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステル及びその製法を提供することが出来る。 According to the present invention, 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester can be produced in a high yield by a simple method, and Industrially suitable 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester and process for producing the same can be provided.
本発明の新規な化合物（１）は、前記の一般式（１）で示される（なお、化合物（１）は、Ｅ体及びＺ体のいずれの構造もとり得る。）。その一般式（１）において、Ｒ、Ｒ１及びＲ２は、それぞれ独立して、炭化水素基であり、具体的には、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等のアルキル基；シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基、シクロノニル基、シクロデシル基等のシクロアルキル基；ベンジル基、フェネチル基等のアラルキル基；フェニル基、トリル基、キシリル基、ナフチル基等のアリール基が挙げられるが、好ましくはメチル基、エチル基である。なお、これらの基は、各種異性体を含む。 The novel compound (1) of the present invention is represented by the general formula (1) (note that the compound (1) can take any structure of E-form and Z-form). In the general formula (1), R, R 1 and R 2 are each independently a hydrocarbon group. Specifically, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, Hexyl, heptyl, octyl, nonyl, decyl and other alkyl groups; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and other cycloalkyl groups An aralkyl group such as a benzyl group or a phenethyl group; an aryl group such as a phenyl group, a tolyl group, a xylyl group or a naphthyl group; These groups include various isomers.
本発明の化合物（１）は、前記の化合物（２）と前記の化合物（３）とを反応させることによって得られる。 The compound (1) of the present invention can be obtained by reacting the compound (2) with the compound (3).
本発明の反応において使用する化合物（２）は、前記の一般式（２）で示される。その一般式（２）において、Ｒ１及びＲは、前記と同義である。なお、化合物（２）は、反応工程式（１） The compound (2) used in the reaction of the present invention is represented by the general formula (2). In the general formula (2), R 1 and R are as defined above. In addition, compound (2) is reaction process formula (1).
（式中、Ｘは、ハロゲン原子を示し、Ｒ及びＲ１は、前記と同義である。）
で示されるように、4-アセチルテトラヒドロピラン（化合物（４））と炭酸ジエステル（化合物（５））とを反応させて3-(4-テトラヒドロピラニル)-3-オキソプロパン酸エステル（化合物（６））とした後、これにハロゲン化剤を反応させて2-ハロゲノ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸エステル（化合物（７））を得、次いで、有機カルボン酸（化合物（８））を反応させることによって得ることが出来る化合物である（後の参考例１〜３に記載）。
(In the formula, X represents a halogen atom, and R and R 1 are as defined above.)
As shown in the above, 4-acetyltetrahydropyran (compound (4)) and a carbonic acid diester (compound (5)) are reacted to give 3- (4-tetrahydropyranyl) -3-oxopropanoic acid ester (compound ( 6)), and then a halogenating agent is reacted with this to obtain 2-halogeno-3- (4-tetrahydropyranyl) -3-oxopropanoic acid ester (compound (7)), and then an organic carboxylic acid It is a compound that can be obtained by reacting (Compound (8)) (described in Reference Examples 1 to 3 below).
本発明の反応において使用する化合物（３）は、前記の一般式（３）で示される。その一般式（３）において、Ｒ、Ｒ１及びＲ２は、前記と同義である。 The compound (3) used in the reaction of the present invention is represented by the general formula (3). In the general formula (3), R, R 1 and R 2 are as defined above.
前記化合物（３）の使用量は、化合物（２）1モルに対して、好ましくは0.5〜10モル、更に好ましくは1〜5モルである。 The amount of compound (3) to be used is preferably 0.5 to 10 mol, more preferably 1 to 5 mol, per 1 mol of compound (2).
本発明の反応において使用する酸は、例えば、メタンスルホン酸、エタンスルホン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、p-メトキシベンゼンスルホン酸、p-ブロモベンゼンスルホン酸等の有機スルホン酸類；硫酸、クロロ硫酸等の無機スルホン酸類；フッ化水素酸、塩酸、臭化水素酸、ヨウ化水素酸等のハロゲン化水素酸類；クロロ酢酸、ジクロロ酢酸等のハロゲン化カルボン酸類；硝酸が挙げられるが、好ましくは有機スルホン酸類、無機スルホン酸類、更に好ましくは有機スルホン酸類が使用される。なお、これらの酸は、単独又は二種以上を混合して使用しても良い。 Examples of the acid used in the reaction of the present invention include methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-methoxybenzenesulfonic acid, and p-bromobenzenesulfonic acid. Organic sulfonic acids; inorganic sulfonic acids such as sulfuric acid and chlorosulfuric acid; hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; halogenated carboxylic acids such as chloroacetic acid and dichloroacetic acid; nitric acid Preferably, organic sulfonic acids, inorganic sulfonic acids, and more preferably organic sulfonic acids are used. In addition, you may use these acids individually or in mixture of 2 or more types.
前記酸の使用量は、化合物（２）1モルに対して、好ましくは0.01〜10モル、更に好ましくは0.1〜3モルである。 The amount of the acid to be used is preferably 0.01 to 10 mol, more preferably 0.1 to 3 mol, per 1 mol of compound (2).
本発明の反応は、溶媒中にて行われるのが好ましく、使用する溶媒としては、反応を阻害しないものならば特に限定されず、例えば、水；メタノール、エタノール、イソプロピルアルコール、n-プロピルアルコール、イソブチルアルコール、t-ブチルアルコール等のアルコール類；トリエチルアミン、トリブチルアミン等のアミン類；ピリジン、メチルピリジン、ジメチルアミノピリジン等のピリジン類；キノリン、イソキノリン、メチルイソキノリン等のキノリン類；N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン等のアミド類；N,N'-ジメチルイミダゾリジノン等の尿素類；ジメチルスルホキシド、スルホラン等のスルホキシド類；ジオキサン、シクロプロピルメチルエーテル等のエーテル類；トルエン、キシレン等の芳香族炭化水素類；酢酸エチル、酢酸ブチル等のカルボン酸エステル類が挙げられるが、好ましくはアルコール類、更に好ましくはメタノール、エタノールが使用される。なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。 The reaction of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, n-propyl alcohol, Alcohols such as isobutyl alcohol and t-butyl alcohol; amines such as triethylamine and tributylamine; pyridines such as pyridine, methylpyridine and dimethylaminopyridine; quinolines such as quinoline, isoquinoline and methylisoquinoline; N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide and N-methylpyrrolidone; Ureas such as N, N'-dimethylimidazolidinone; Sulfoxides such as dimethyl sulfoxide and sulfolane; Ethers such as dioxane and cyclopropylmethyl ether Class: Toluene, Xylene Aromatic hydrocarbons such as carboxylic acid esters such as ethyl acetate and butyl acetate are preferable, but alcohols are preferable, and methanol and ethanol are more preferable. In addition, you may use these solvents individually or in mixture of 2 or more types.
前記溶媒の使用量は、反応液の均一性や攪拌性により適宜調節するが、化合物（２）1gに対して、好ましくは0.5〜50g、更に好ましくは1〜20gである。 The amount of the solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 0.5 to 50 g, more preferably 1 to 20 g, relative to 1 g of compound (2).
本発明の反応は、例えば、化合物（２）、化合物（３）、酸及び溶媒を混合し、攪拌しながら反応させる等の方法によって行われる。その際の反応温度は、好ましくは-10〜200℃、更に好ましくは20〜180℃、特に好ましくは60〜160℃であり、反応圧力は特に制限されない。 The reaction of the present invention is performed by, for example, a method of mixing the compound (2), the compound (3), an acid and a solvent and reacting them with stirring. The reaction temperature at that time is preferably −10 to 200 ° C., more preferably 20 to 180 ° C., particularly preferably 60 to 160 ° C., and the reaction pressure is not particularly limited.
なお、本発明の反応によって化合物（１）が得られるが、これは、反応終了後、中和、抽出、濾過、濃縮、蒸留、再結晶、晶析、カラムクロマトグラフィー等の一般的な方法によって単離・精製される。又、化合物（１）は、一般式（４） Compound (1) is obtained by the reaction of the present invention, and this is carried out by a general method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after completion of the reaction. Isolated and purified. Further, the compound (1) has the general formula (4)
（式中、Ｒ、Ｒ１及びＲ２は、前記と同義である。）
で示されるイミン体の構造もとり得る。
(In the formula, R, R 1 and R 2 are as defined above.)
The structure of the imine body shown by can be also taken.
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。 Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
参考例１（化合物（６）［Ｒ＝メチル基］；3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチルの合成）
攪拌装置、温度計、滴下漏斗及び蒸留装置を備えた内容積500mlのガラス製フラスコに、4-アセチルテトラヒドロピラン35.0g(273mmol)、炭酸ジメチル280.0g(3.1mol)及びナトリウムメトキシド16.3g(302mmol)を加え、副生するメタノールを留出させながら、80〜85℃で2時間反応させた。反応終了後、反応液を5〜10℃まで冷却した後、反応液にトルエン175ml、6mol/l塩酸55ml(330mmol)、水35mlの順で加えた。有機層を分離した後、水層をトルエン70mlで２回抽出した。有機層を減圧下で濃縮した後、濃縮物をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン/酢酸エチル＝1/1(容量比)）で精製して、無色液体として、純度93.9％（示差屈折率による分析値）の3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチル40.9gを得た(単離収率：76％)。
3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチルの物性値は以下の通りであった。
Reference Example 1 (Compound (6) [R = methyl group]; synthesis of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate)
In a glass flask having an internal volume of 500 ml equipped with a stirrer, thermometer, dropping funnel and distillation device, 35.0 g (273 mmol) of 4-acetyltetrahydropyran, 280.0 g (3.1 mol) of dimethyl carbonate and 16.3 g (302 mmol) of sodium methoxide ) Was added, and the reaction was carried out at 80 to 85 ° C. for 2 hours while distilling out by-product methanol. After completion of the reaction, the reaction solution was cooled to 5 to 10 ° C., and 175 ml of toluene, 55 ml of 6 mol / l hydrochloric acid (330 mmol) and 35 ml of water were added to the reaction solution in this order. After separating the organic layer, the aqueous layer was extracted twice with 70 ml of toluene. After the organic layer was concentrated under reduced pressure, the concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 1/1 (volume ratio)) to obtain a colorless liquid with a purity of 93.9% (differential refractive index) 40.9 g of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate was obtained (isolation yield: 76%).
The physical properties of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate were as follows.
1H-NMR(CDCl3,δ(ppm))；1.68〜1.82(4H,m)、2.66〜2.72(1H,m)、3.38〜3.47(2H,m)、3.51(2H,s)、3.75(3H,s)、3.97〜4.04(2H,m)
CI-MS(m/e)；187(M+1)
1 H-NMR (CDCl 3 , δ (ppm)); 1.68 to 1.82 (4H, m), 2.66 to 2.72 (1H, m), 3.38 to 3.47 (2H, m), 3.51 (2H, s), 3.75 ( 3H, s), 3.97 to 4.04 (2H, m)
CI-MS (m / e); 187 (M + 1)
参考例２（化合物（７）［Ｘ＝塩素原子、Ｒ＝メチル基］；2-クロロ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチルの合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積25mlのガラス製フラスコに、参考例１で合成した3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチル16g(85.9mmol)を加え、氷水浴下で0℃まで冷却した。次いで、塩化スルフリル11.6g(85.9mmol)をゆるやかに滴下した後、室温で15時間反応させた。反応終了後、反応液を再び0℃まで冷却し、水32ml及びトルエン48mlをゆるやかに滴下し、10分間攪拌した後に、有機層を分液した。水層をトルエン16mlで抽出し、該有機層と抽出液を合わせて、無水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃縮し、薄茶色油状液体として、純度94.6％（ガスクロマトグラフィーによる面積百分率）の2-クロロ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチル18.5gを得た(単離収率：92％)。
2-クロロ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチルの物性値は以下の通りであった。
Reference Example 2 (Compound (7) [X = chlorine atom, R = methyl group]; synthesis of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate)
16 g (85.9 mmol) of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in Reference Example 1 was added to a glass flask having an internal volume of 25 ml equipped with a stirrer, a thermometer and a dropping funnel. Cool to 0 ° C. in an ice-water bath. Next, 11.6 g (85.9 mmol) of sulfuryl chloride was gently added dropwise, followed by reaction at room temperature for 15 hours. After completion of the reaction, the reaction solution was cooled again to 0 ° C., 32 ml of water and 48 ml of toluene were gently added dropwise and stirred for 10 minutes, and then the organic layer was separated. The aqueous layer was extracted with 16 ml of toluene, and the organic layer and the extract were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a pale brown oily liquid, methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate with a purity of 94.6% (area percentage by gas chromatography) 18.5 g was obtained (isolation yield: 92%).
The physical properties of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate were as follows.
1H-NMR(CDCl3,δ(ppm))；1.74〜1.83(4H,m)、3.06〜3.16(1H,m)、3.41〜3.50(2H,m)、3.85(3H,s)、3.99〜4.05(2H,m)、4.93(1H,s)、3.86(0.50H,s)、12.48(0.17H,d,J=1.46Hz)
CI-MS(m/e)；221(M+1)、223(M+3)
1 H-NMR (CDCl 3 , δ (ppm)); 1.74 to 1.83 (4H, m), 3.06 to 3.16 (1H, m), 3.41 to 3.50 (2H, m), 3.85 (3H, s), 3.99 to 4.05 (2H, m), 4.93 (1H, s), 3.86 (0.50H, s), 12.48 (0.17H, d, J = 1.46Hz)
CI-MS (m / e); 221 (M + 1), 223 (M + 3)
参考例３（化合物（２）［Ｒ、Ｒ１＝メチル基］；2-アセチルオキシ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチルの合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積100mlのガラス製フラスコに、参考例２で合成した2-クロロ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチル10.0g(42.9mmol)、酢酸3.0g(49.8mmol)及びN,N-ジメチルホルムアミド30mlを加えた。次いで、攪拌しながらトリエチルアミン5.0g(49.8mmol)をゆるやかに滴下し、室温で14時間反応させた。反応終了後、反応液にトルエン100mlを加えた後、濾過した。濾物をトルエン50mlで洗浄し、濾液と洗浄液を合わせて減圧下で濃縮した。濃縮物をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン/酢酸エチル＝2/1（容量比））で精製し、無色液体として、純度99.9％以上（ガスクロマトグラフィーによる面積百分率）の2-アセチルオキシ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチル9.2gを得た(単離収率：88％)。
2-アセチルオキシ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチルの物性値は以下の通りであった。
Reference Example 3 (Compound (2) [R, R 1 = methyl group]; Synthesis of methyl 2-acetyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate)
10.0 g (42.9) of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in Reference Example 2 was placed in a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer and a dropping funnel. mmol), 3.0 g (49.8 mmol) of acetic acid and 30 ml of N, N-dimethylformamide were added. Next, 5.0 g (49.8 mmol) of triethylamine was slowly added dropwise with stirring, and the mixture was reacted at room temperature for 14 hours. After completion of the reaction, 100 ml of toluene was added to the reaction solution and then filtered. The residue was washed with 50 ml of toluene, and the filtrate and the washing solution were combined and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 2/1 (volume ratio)) and, as a colorless liquid, 2-acetyloxy- with a purity of 99.9% or more (area percentage by gas chromatography) 9.2 g of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate was obtained (isolation yield: 88%).
The physical properties of methyl 2-acetyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate were as follows.
1H-NMR(CDCl3,δ(ppm))；1.68〜1.87(4H,m)、2.24(3H,s)、2.99〜3.06(1H,m)、3.40〜3.51(2H,m)、3.83(3H,s)、3.98〜4.03(2H,m)、5.66(1H,s)
CI-MS(m/e)；245(M+1)
1 H-NMR (CDCl 3 , δ (ppm)); 1.68 to 1.87 (4H, m), 2.24 (3H, s), 2.99 to 3.06 (1H, m), 3.40 to 3.51 (2H, m), 3.83 ( 3H, s), 3.98 to 4.03 (2H, m), 5.66 (1H, s)
CI-MS (m / e); 245 (M + 1)
実施例１（化合物（１）［Ｒ、Ｒ１＝メチル基、Ｒ２＝イソプロピル基］3-(N-イソブチリルアミノ)-2-アセチルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸メチルの合成）
攪拌装置を備えた内容積100mlのガラス製フラスコに、参考例３と同様な方法で合成した2-アセチルオキシ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸メチル300mg(1.23mmol)、イソ酪酸アミド214mg(2.46mmol)、p-トルエンスルホン酸一水和物70mg(0.37mmol)及びキシレン3mlを加え、攪拌しながら140〜150℃で7時間反応させた。反応終了後、反応液を減圧下で濃縮した後、濃縮物をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン/酢酸エチル＝1/1（容量比））で精製し、白色固体として、純度99％以上（ガスクロマトグラフィーによる面積百分率）の3-(N-イソブチリルアミノ)-2-アセチルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸メチル40mgを得た(単離収率：10％)。
3-(N-イソブチリルアミノ)-2-ピバロイルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸メチルは、以下の物性値で示される新規な化合物である。
Example 1 (compound (1) [R, R 1 = methyl group, R 2 = isopropyl group] 3- (N-isobutyrylamino) -2-acetyloxy-3- (4-tetrahydropyranyl) -2 -Synthesis of methyl propenoate)
300 mg (1.23 mmol) of methyl 2-acetyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 3 in a glass flask equipped with a stirrer and having an internal volume of 100 ml Then, 214 mg (2.46 mmol) of isobutyric acid amide, 70 mg (0.37 mmol) of p-toluenesulfonic acid monohydrate and 3 ml of xylene were added, and the mixture was reacted at 140 to 150 ° C. for 7 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 1/1 (volume ratio)) to give a white solid having a purity of 99% or more 40 mg of methyl 3- (N-isobutyrylamino) -2-acetyloxy-3- (4-tetrahydropyranyl) -2-propenoate (area percentage by gas chromatography) was obtained (isolation yield: Ten%).
Methyl 3- (N-isobutyrylamino) -2-pivaloyloxy-3- (4-tetrahydropyranyl) -2-propenoate is a novel compound represented by the following physical property values.
1H-NMR(CDCl3,δ(ppm))；1.19(4H,d,J=6.8Hz)、1.24(2H,d,J=6.8Hz)、1.45〜1.59(2H,m)、1.79〜1.83(2H,m)、2.13〜2.78(2H,m)、2.16(3H,s)、3.69〜4.05(4H,m)、3.73(3H,s)、6.45(0.67H,brs)、8.57(0.33H,brs)
CI-MS(m/e)；314(M+1)
1 H-NMR (CDCl 3 , δ (ppm)); 1.19 (4H, d, J = 6.8 Hz), 1.24 (2H, d, J = 6.8 Hz), 1.45 to 1.59 (2H, m), 1.79 to 1.83 (2H, m), 2.13 to 2.78 (2H, m), 2.16 (3H, s), 3.69 to 4.05 (4H, m), 3.73 (3H, s), 6.45 (0.67H, brs), 8.57 (0.33H) , brs)
CI-MS (m / e); 314 (M + 1)
本発明は、3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステル及びその製法に関する。3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステルは、医薬や農薬等の原料や合成中間体として有用な化合物である。 The present invention relates to 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate and a process for producing the same. 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester is a useful compound as a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals.
Claims (3)
で示される3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステル。 General formula (1)
3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester represented by
で示される2-アシルオキシ-3-(4-テトラヒドロピラニル)-3-オキソプロパン酸エステルに、一般式（３）
で示されるアミド化合物を反応させることを特徴とする、一般式（１）
で示される3-(N-アシルアミノ)-2-アシルオキシ-3-(4-テトラヒドロピラニル)-2-プロペン酸エステルの製法。 In the presence of an acid, general formula (2)
2-acyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate represented by the general formula (3)
Wherein the amide compound represented by the general formula (1) is reacted.
A method for producing 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate represented by the formula:
The process for producing 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate according to claim 2, wherein the reaction is carried out in a solvent.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60500446A (en) * | 1982-12-27 | 1985-04-04 | バイオテツク ソシエテ アノニム | Acylated enamide compounds, pharmaceutical compositions containing them, and methods for producing the compounds |
| JPS632964A (en) * | 1986-05-30 | 1988-01-07 | メルク エンド カムパニ− インコ−ポレ−テツド | Bis(cyclopropanecarboxamide)alkadienedionic acid as renal dipeptidase inhibitor |
| WO2003091202A1 (en) * | 2002-04-25 | 2003-11-06 | Ono Pharmaceutical Co., Ltd. | Diketohydrazine derivative compounds and drugs contaiing the compounds as the active ingredient |
| JP2005314231A (en) * | 2004-04-27 | 2005-11-10 | Ono Pharmaceut Co Ltd | Method for producing 3-[(cycloheptylcarbonyl)amino]-2-oxo-3-(tetrahydro-2h-pyran-4-yl)propanoic acid ester |
| JP2006137693A (en) * | 2004-11-12 | 2006-06-01 | Ube Ind Ltd | Carboxylate of 2-acyloxy-3-(4-tetrahydropyranyl)-3-amino-2-propenoate and its production method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60500446A (en) * | 1982-12-27 | 1985-04-04 | バイオテツク ソシエテ アノニム | Acylated enamide compounds, pharmaceutical compositions containing them, and methods for producing the compounds |
| JPS632964A (en) * | 1986-05-30 | 1988-01-07 | メルク エンド カムパニ− インコ−ポレ−テツド | Bis(cyclopropanecarboxamide)alkadienedionic acid as renal dipeptidase inhibitor |
| WO2003091202A1 (en) * | 2002-04-25 | 2003-11-06 | Ono Pharmaceutical Co., Ltd. | Diketohydrazine derivative compounds and drugs contaiing the compounds as the active ingredient |
| JP2005314231A (en) * | 2004-04-27 | 2005-11-10 | Ono Pharmaceut Co Ltd | Method for producing 3-[(cycloheptylcarbonyl)amino]-2-oxo-3-(tetrahydro-2h-pyran-4-yl)propanoic acid ester |
| JP2006137693A (en) * | 2004-11-12 | 2006-06-01 | Ube Ind Ltd | Carboxylate of 2-acyloxy-3-(4-tetrahydropyranyl)-3-amino-2-propenoate and its production method |
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