JP4780437B2 - Process for producing 2-oxoimidazolidine derivatives - Google Patents
Process for producing 2-oxoimidazolidine derivatives Download PDFInfo
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Description
本発明は、医薬分野で有用な２−オキソイミダゾリジン誘導体の製造方法に関し、さらに詳しくは、(−) （４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル}−２−オキソイミダゾリジン−４−カルボン酸（一般的名称：イミダプリル）及びその合成中間体の製造方法に関する。 The present invention relates to a method for producing a 2-oxoimidazolidine derivative useful in the pharmaceutical field. More specifically, the present invention relates to (-) (4S) -1-methyl-3-{(2S) -2- [N-((1S ) -1-Ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid (generic name: imidazol) and its synthetic intermediates.
イミダプリルの塩酸塩は、アンジオテンシン変換酵素阻害剤として高血圧症等の治療に用いられている。
従来、イミダプリルの製造方法として、例えば下記の方法が知られている。
Conventionally, for example, the following methods are known as methods for producing imidapril.
本発明の課題はアンジオテンシン変換酵素阻害剤として有用なイミダプリル又はその塩の工業的に有利な製造方法を提供することにある。 An object of the present invention is to provide an industrially advantageous method for producing imidapril or a salt thereof useful as an angiotensin converting enzyme inhibitor.
本発明者は、課題解決のため、まず前記従来技術の各工程について追試した。その反応条件の改良を試み、鋭意検討した結果、前記の全工程（３工程）を２工程にできることを見出し、本発明を完成した。 In order to solve the problem, the present inventor first made a trial for each process of the prior art. As a result of trying to improve the reaction conditions and earnestly examining it, it was found that the above-mentioned all steps (three steps) can be made into two steps, and the present invention was completed.
すなわち本発明は、
（１）（４Ｓ）−１−メチル−３−ベンジルオキシカルボニル−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステル［式（Ｉ）］
とを、臭化リチウム又は塩化リチウムの存在下、反応させて（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステル［式（III）］を得、
(1) (4S) -1-Methyl-3-benzyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid benzyl ester [formula (I)]
And (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl] in the presence of lithium bromide or lithium chloride. ) Amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid benzyl ester [formula (III)]
（２）（４Ｓ）−１−メチル−３−ベンジルオキシカルボニル−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステル［式（Ｉ）］
とを、臭化リチウム又は塩化リチウムの存在下、反応させて（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステル[式（III）]を得る方法
And (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl] in the presence of lithium bromide or lithium chloride. ) Amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid benzyl ester [formula (III)]
本発明では、前記従来の方法における化合物（Ｖ）を経由することなく、化合物（Ｉ）に化合物（II）を反応させて化合物（III）とすることができるので、従来の方法より１工程短縮できる。 In the present invention, the compound (II) can be reacted with the compound (I) to obtain the compound (III) without going through the compound (V) in the conventional method. it can.
本発明において、化合物(Ｉ)と化合物（II）との反応は、通常溶媒中で行われる。その溶媒としては、例えばテトラヒドロフラン、ジオキサン等のエーテル類、アセトン、メチルエチルケトン等のケトン類、ベンゼン、トルエン、モノクロロベンゼン等の芳香族炭化水素、酢酸エチル、酢酸ブチル等のエステル類、アセトニトリル、あるいはそれらの混合溶媒が好適に使用できる。化合物（Ｉ）に対する化合物（II）の使用量は、１〜３倍モル使用するが、好ましくは１〜２倍モル程度である。また、この反応で使用する臭化リチウム又は塩化リチウムの使用量は、化合物（Ｉ）に対して１〜５倍モル使用するが、好ましくは１〜２倍モルである。反応温度は選択された有機溶媒の種類に依存し、厳密に限定されない。一般的に、反応温度は３０〜１２０℃の範囲であり、好ましくは４０〜１００℃の範囲で行われる。
イミダプリル［化合物（IV）］の塩としては、化合物（IV）と生理学的に許容される酸、例えば塩酸塩や硫酸等の鉱酸及び酢酸やマレイン酸等の有機酸との塩が好ましく、なかでも塩酸塩が好ましい。
In the present invention, the reaction between compound (I) and compound (II) is usually carried out in a solvent. Examples of the solvent include ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, and monochlorobenzene, esters such as ethyl acetate and butyl acetate, acetonitrile, and the like. A mixed solvent can be suitably used. The amount of compound (II) used relative to compound (I) is 1 to 3 moles, preferably about 1 to 2 moles. Moreover, although the usage-amount of lithium bromide or lithium chloride used by this reaction is 1-5 times mole with respect to compound (I), Preferably it is 1-2 times mole. The reaction temperature depends on the type of organic solvent selected and is not strictly limited. In general, the reaction temperature is in the range of 30 to 120 ° C, preferably in the range of 40 to 100 ° C.
The salt of imidapril [compound (IV)] is preferably a salt of compound (IV) with a physiologically acceptable acid, for example, a mineral acid such as hydrochloride or sulfuric acid, and an organic acid such as acetic acid or maleic acid. But the hydrochloride is preferred.
本発明で使用する化合物（Ｉ）は、前記の特許文献１に記載の方法により、また化合物（II）は、特開昭６２−４８６９６号公報に記載の方法により製造した。
［実施例１］（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステル
Ｎ−［（１Ｓ）−１−（エトキシカルボニル）−３−フェニルプロピル］−Ｌ−アラニンのＮ−カルボキシ無水物１．１４ｇ（３．７３ミリモル）のトルエン１０ ｍｌの溶液に、（４Ｓ）−１−メチル−３−ベンジルオキシカルボニル−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステル０．９２ｇ（２．５０ミリモル）及び臭化リチウム０．２６ｇ（３．００ミリモル）を加え、８０℃で４時間撹拌した。室温まで冷却した後、水９ ｍｌを加え０．５時間撹拌した。有機層を水５ ｍｌで洗浄し、硫酸マグネシウムで乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン−酢酸エチル＝１：１）で精製することにより、油状の（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステルを１．０５ｇ（収率：８４．７％）得た。
比旋光度［α］２０ Ｄ：−５９.０°（Ｃ＝１.０、ＥｔＯＨ）
ＮＭＲ(ＣＤＣｌ３)δ（ppm）：１.２６(３Ｈ、ｔ)、１.２８(３Ｈ、ｄ)、１.８４−２.０４(２Ｈ、ｍ)、２.６０−２.７６(２Ｈ、ｍ)、２.８５(３Ｈ、ｓ)、３.２６(１Ｈ、ｔ)、３.３３(１Ｈ、ｄｄ)、３.６９(１Ｈ、ｔ)、４.０８−４.２１(２Ｈ、ｍ)、４.７１(１Ｈ、ｑ)、４.８０(１Ｈ、ｄｄ)、５.１４(１Ｈ、ｄ)、５.２４(１Ｈ、ｄ)、７.１１−７.４０(１０Ｈ、ｍ)
Compound (I) used in the present invention was produced by the method described in Patent Document 1 and Compound (II) was produced by the method described in JP-A-62-48696.
Example 1 (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine -4-carboxylic acid benzyl ester N-[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanine N-carboxyanhydride 1.14 g (3.73 mmol) in 10 ml toluene To the solution was added 0.92 g (2.50 mmol) of (4S) -1-methyl-3-benzyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid benzyl ester and 0.26 g (3.00 mmol) of lithium bromide. ) And stirred at 80 ° C. for 4 hours. After cooling to room temperature, 9 ml of water was added and stirred for 0.5 hour. The organic layer was washed with 5 ml of water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate = 1: 1) to give (4S) -1-methyl-3-{(2S) -2- [N-((1S)) -1-Ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid benzyl ester was obtained in an amount of 1.05 g (yield: 84.7%).
Specific rotation [α] 20 D : −59.0 ° (C = 1.0, EtOH)
NMR (CDCl 3 ) δ (ppm): 1.26 (3H, t), 1.28 (3H, d), 1.84-2.04 (2H, m), 2.60-2.76 (2H M), 2.85 (3H, s), 3.26 (1H, t), 3.33 (1H, dd), 3.69 (1H, t), 4.08-4.21 (2H, m), 4.71 (1H, q), 4.80 (1H, dd), 5.14 (1H, d), 5.24 (1H, d), 7.11-7.40 (10H, m )
［実施例２］（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル}−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステルのマレイン酸塩
Ｎ−［（１Ｓ）−１−（エトキシカルボニル）−３−フェニルプロピル］−Ｌ−アラニンのＮ−カルボキシ無水物１０．７６ｇ（３５．２ミリモル）のトルエン１００ ｍｌの溶液に、（４Ｓ）−１−メチル−３−ベンジルオキシカルボニル−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステル１０ｇ（２７．１ミリモル）及び臭化リチウム３．０６ｇ（３５．２ミリモル）を加え、８０℃で６時間撹拌した後、トリエチルアミン２．７４ｇ（２７．１ミリモル）を加え、さらに３時間８０℃で攪拌した。室温まで冷却した後、水１００ｍｌを加え０.５時間撹拌した。有機層を水５０ｍｌで洗浄し、硫酸マグネシウムで乾燥した。硫酸マグネシウムを除去した後、ジイソプロピルエーテル２００ｍｌを加えた。この溶液に、マレイン酸２.８３ｇ（２４．４ミリモル）のエタノール１２ｍｌの溶液を室温で滴下した後、終夜攪拌した。析出した結晶をろ取し、少量のジイソプロピルエーテル−エタノール(２５：１)で洗浄することにより（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステルのマレイン酸塩を１０．１０ｇ（収率：６０．９％）得た。
ｍｐ． ９５−９６℃
比旋光度［α］２５ Ｄ： −５０.３°（Ｃ＝１.０、ＥｔＯＨ）
ＮＭＲ（ＣＤＣｌ３）δ（ppm）：１.３３（３Ｈ、ｔ）、１.４１（３Ｈ、ｄ）、２.２８（２Ｈ、ｄｄ）、２.７０−２.８６（２Ｈ、ｍ）、２.８８（３Ｈ、ｓ）、３.３８（１Ｈ、ｄｄ）、３.６６（１Ｈ、ｔ）、３.８４（１Ｈ、ｔ）、４.２２−４.３４（２Ｈ、ｍ）、４.８３（１Ｈ、ｄｄ）、５.１１−５.２７（３Ｈ、ｍ）、６.３０(２Ｈ、ｓ)、７.１６−７.４０(１０Ｈ、ｍ)
[Example 2] (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine -4-carboxylic acid benzyl ester maleate N-[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanine N-carboxyanhydride 10.76 g (35.2 mmol) In a solution of 100 ml of toluene, 10 g (27.1 mmol) of (4S) -1-methyl-3-benzyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid benzyl ester and 3.06 g (35. 2 mmol) and stirred at 80 ° C. for 6 hours. Then, 2.74 g (27.1 mmol) of triethylamine was added, and the mixture was stirred at 80 ° C. for 3 hours. It was. After cooling to room temperature, 100 ml of water was added and stirred for 0.5 hour. The organic layer was washed with 50 ml of water and dried over magnesium sulfate. After removing the magnesium sulfate, 200 ml of diisopropyl ether was added. To this solution, a solution of 2.83 g (24.4 mmol) of maleic acid in 12 ml of ethanol was added dropwise at room temperature and stirred overnight. The precipitated crystals were collected by filtration and washed with a small amount of diisopropyl ether-ethanol (25: 1) to give (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1 10.10 g (yield: 60.9%) of maleate of -ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid benzyl ester.
mp. 95-96 ° C
Specific rotation [α] 25 D : −50.3 ° (C = 1.0, EtOH)
NMR (CDCl 3 ) δ (ppm): 1.33 (3H, t), 1.41 (3H, d), 2.28 (2H, dd), 2.70-2.86 (2H, m), 2.88 (3H, s), 3.38 (1H, dd), 3.66 (1H, t), 3.84 (1H, t), 4.22-4.34 (2H, m), 4 .83 (1H, dd), 5.11-5.27 (3H, m), 6.30 (2H, s), 7.16-7.40 (10H, m)
［実施例３］（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸
（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステルのマレイン酸塩９．３０g（１５．２ミリモル）、酢酸エチル４７ｍｌ及び水９３ｍｌの混合溶液に、炭酸カリウム２.１ｇ（１５．２ミリモル）を徐々に加える。０．５時間攪拌した後、有機層を水４７ｍｌで洗浄した。硫酸マグネシウムで乾燥した後、減圧濃縮した。残渣をテトラヒドロフラン１８６ｍｌに溶解し、５％Ｐｄ−Ｃ７４４ｍｇ存在下で接触還元を行った。反応終了後、Ｐｄ−Ｃを除去し、スラリー状になるまで減圧濃縮した。ジイソプロピルエーテル９３ｍｌを加えて、室温で終夜攪拌した。結晶をろ取し、ジイソプロピルエーテルで洗浄することにより、（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸を５．８２ｇ（収率：９４．５％）得た。
ｍｐ． １４４−１４５℃
比旋光度［α］２０ Ｄ： −７１.４°（Ｃ＝０.５、ＥｔＯＨ）
ＮＭＲ（ＤＭＳＯ−ｄ６）δ（ppm）：１.０８−１.１８（６Ｈ、ｍ）、１.６８−１.８５（２Ｈ、ｍ）、２.５０−２.６３（２Ｈ、ｍ）、２.７４（３Ｈ、ｓ）、３.０８−３.１５（１Ｈ、ｂｒ）、３.３５（１Ｈ、ｄｄ）、３.７０（１Ｈ、ｔ）、４.０２（２Ｈ、ｑ）、４.５４−４.６３（２Ｈ、ｍ）、７.１１−７.２８（５Ｈ、ｍ）
Example 3 (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine -4-carboxylic acid (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine To a mixed solution of 9.30 g (15.2 mmol) of maleic acid salt of -4-carboxylic acid benzyl ester, 47 ml of ethyl acetate and 93 ml of water, 2.1 g (15.2 mmol) of potassium carbonate is gradually added. After stirring for 0.5 hour, the organic layer was washed with 47 ml of water. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in 186 ml of tetrahydrofuran and subjected to catalytic reduction in the presence of 744 mg of 5% Pd-C. After completion of the reaction, Pd—C was removed and concentrated under reduced pressure until a slurry was obtained. 93 ml of diisopropyl ether was added and stirred at room temperature overnight. The crystals are collected by filtration and washed with diisopropyl ether to give (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino. ] 5.82 g (yield: 94.5%) of propionyl} -2-oxoimidazolidine-4-carboxylic acid was obtained.
mp. 144-145 ° C
Specific rotation [α] 20 D : −71.4 ° (C = 0.5, EtOH)
NMR (DMSO-d 6 ) δ (ppm): 1.08-1.18 (6H, m), 1.68-1.85 (2H, m), 2.50-2.63 (2H, m) 2.74 (3H, s), 3.08-3.15 (1H, br), 3.35 (1H, dd), 3.70 (1H, t), 4.02 (2H, q), 4.54-4.63 (2H, m), 7.11-7.28 (5H, m)
本発明によれば、イミダプリル又はその塩を製造するに際し、従来の方法より１工程短縮できるので、工業的に有利である。 According to the present invention, when imidapril or a salt thereof is produced, one step can be shortened compared to the conventional method, which is industrially advantageous.
Claims (2)
ついで接触還元することを特徴とする（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸［式（IV）］またはその塩の製造方法。
(4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2, which is characterized by catalytic reduction -Process for producing oxoimidazolidine-4-carboxylic acid [formula (IV)] or a salt thereof.
とＮ−［（１Ｓ）−１−（エトキシカルボニル）−３−フェニルプロピル］−Ｌ−アラニンのＮ−カルボキシ無水物［式（II）］
とを、臭化リチウム又は塩化リチウムの存在下、反応させて（４Ｓ）−１−メチル−３−｛（２Ｓ）−２−［Ｎ−（（１Ｓ）−１−エトキシカルボニル−３−フェニルプロピル）アミノ］プロピオニル｝−２−オキソイミダゾリジン−４−カルボン酸ベンジルエステル[式（III）]を得る方法。
And N-[(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanine N-carboxy anhydride [formula (II)]
And (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl] in the presence of lithium bromide or lithium chloride. ) Amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid benzyl ester [Formula (III)]
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| KR100915175B1 (en) * | 2007-09-12 | 2009-09-03 | 네오코리아(주) | Process for preparing imidapril |
| JP7533824B2 (en) * | 2020-12-10 | 2024-08-14 | 学校法人東邦大学 | Compounds, derivatization reagents, analytical methods, and methods for separation and/or quantification |
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