JP6580976B2 - Process for producing 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester - Google Patents
Process for producing 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester Download PDFInfo
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本発明は、医薬品原薬の構成成分として有用な１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルの製造方法に関するものである。 The present invention relates to a method for producing 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester useful as a component of an active pharmaceutical ingredient. is there.
１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルは、医薬品原薬、例えば、V2受容体作動薬として知られている１−ベンゾイル−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ[ｂ]アゼピン誘導体の構成成分として有用な化合物である。従って、安全且つ簡便な１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルの工業的な製造方法の開発は重要である。
１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルの合成方法は、次の方法が知られている。
1-Benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester is known as an active pharmaceutical ingredient, for example, a V2 receptor agonist 1 -Benzoyl-2,3,4,5-tetrahydro-1H-benzo [b] azepine derivative is a useful compound as a constituent component. Therefore, it is important to develop a safe and simple industrial method for producing 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester.
As a method for synthesizing 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester, the following method is known.
特許文献１、特許文献２、乃至非特許文献１には、置換又は無置換のアントラニル酸エステルのアミノ基をｐ−トルエンスルホニル基で保護、ブロモ酪酸エチルとの付加反応を行った後に、ｔ−ブトキシカリウムの存在下で分子内縮合反応を行うことにより、置換又は無置換の５−オキソ−１−（ｐ−トルエンスルホニル）−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ[ｂ]アゼピン−４−カルボン酸エステルとし、続いて脱炭酸反応、ｐ−トルエンスルホニル基の脱保護、ベンゾイルクロリドとの付加反応を行うことにより、置換又は無置換の１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピンを合成する方法が記載されているが、ｐ−トルエンスルホニル基によるアミノ基の保護、および脱保護の工程を実施する必要があり、全体の工程数は多くなるため工業的合成に不利である。 In Patent Document 1, Patent Document 2, and Non-Patent Document 1, the amino group of a substituted or unsubstituted anthranilic acid ester is protected with a p-toluenesulfonyl group, and after an addition reaction with ethyl bromobutyrate, t- By performing an intramolecular condensation reaction in the presence of potassium butoxy, substituted or unsubstituted 5-oxo-1- (p-toluenesulfonyl) -2,3,4,5-tetrahydro-1H-benzo [b] azepine Substituted or unsubstituted 1-benzoyl-5-oxo-2,3 by decarboxylation, deprotection of p-toluenesulfonyl group, and addition reaction with benzoyl chloride. , 4,5-Tetrahydro-1H-benzo [b] azepine is described, but the amino group is protected and deprotected with a p-toluenesulfonyl group. You must perform the steps, which is disadvantageous for industrial synthesis since the entire number of steps increases.
非特許文献２には、１，２，３，４−テトラヒドロ−５Ｈ−ベンゾ[ｂ]アゼピン−５−オンを、塩基存在下で炭酸ジアルキルと反応し、対応するエステル基を導入した後に、塩素化剤を用いて活性化された安息香酸類の酸クロリド体との反応により、１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルを合成する方法が記載されているが、本合成法も、アントラニル酸エステルから１，２，３，４−テトラヒドロ−５Ｈ−ベンゾ[ｂ]アゼピン−５−オンを合成するには、アントラニル酸エステルのアミノ基をｐ−トルエンスルホニル基で保護、その後に酪酸エステル基の付加反応、分子内縮合反応、エステル基の脱炭酸反応、及びｐ−トルエンスルホニル基の脱保護反応が必要であり、全体の工程数は多くなるため工業的合成に不利である。 Non-Patent Document 2 discloses that 1,2,3,4-tetrahydro-5H-benzo [b] azepin-5-one reacts with dialkyl carbonate in the presence of a base and introduces a corresponding ester group, then chlorine. 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid by reaction with an acid chloride form of benzoic acid activated with an agent Although a method for synthesizing an ester is described, this synthesis method is also used to synthesize 1,2,3,4-tetrahydro-5H-benzo [b] azepin-5-one from an anthranilate ester. Protection of the amino group of the ester with a p-toluenesulfonyl group, followed by addition reaction of butyric ester group, intramolecular condensation reaction, decarboxylation reaction of ester group, and deprotection reaction of p-toluenesulfonyl group are required. This is disadvantageous for industrial synthesis because the total number of steps increases.
従って、医薬品原薬の構成成分として有用な１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルを安全且つ簡便に合成できる製造方法の確立が望まれている。 Accordingly, a production capable of safely and simply synthesizing 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylate useful as a component of an active pharmaceutical ingredient Establishment of a method is desired.
本発明は、安全且つ簡便に合成できる、一般式（V）にて示される新たな１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステル（V）の工業的な製造方法を提供することを課題とする。 The present invention provides a novel 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4- represented by the general formula (V) that can be synthesized safely and simply. It is an object of the present invention to provide an industrial method for producing a carboxylate ester (V).
安息香酸類に塩素化剤を反応させることにより得られる酸クロリドに、アントラニル酸アルキルを反応させ、次いで塩基の存在下、ブロモ酪酸エステルによりアルキル化した後、塩基の存在下、分子内縮合反応を行うことにより、１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステル（V）を製造する方法を見出し、本発明を完成するに至った。即ち、本発明の主な構成は次の通りである。 An acid chloride obtained by reacting a chlorinating agent with a benzoic acid is reacted with an alkyl anthranilate, then alkylated with a bromobutyric acid ester in the presence of a base, and then subjected to an intramolecular condensation reaction in the presence of a base. To find a method for producing 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester (V) and to complete the present invention It came. That is, the main configuration of the present invention is as follows.
［１］ 一般式（I）
［２］ 前記R3が、メチル基又はエチル基である、請求項１に記載の方法。
［３］ 前記R1が、メチル基、クロロ基、又はトリフルオロメチル基である、請求項１又は２のいずれかに記載の方法。
［４］ 前記R2が、メチル基又はエチル基である、請求項１〜３のいずれかに記載の方法。
[1] General formula (I)
[2] The method according to claim 1, wherein R 3 is a methyl group or an ethyl group.
[3] The method according to any one of claims 1 and 2, wherein R 1 is a methyl group, a chloro group, or a trifluoromethyl group.
[4] The method according to any one of claims 1 to 3, wherein R 2 is a methyl group or an ethyl group.
本発明によれば、１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステル（V）を、発火の危険性のある試薬を使用せず、安価で汎用的な原料のみを使用することにより、少ない工程で製造できることから、工業的な製造方法として有用である。 According to the present invention, 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester (V) is converted into a reagent with a risk of ignition. It is useful as an industrial manufacturing method because it can be manufactured with few steps by using only inexpensive and general-purpose raw materials without using them.
以下に、本発明による１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステル（V）の製造方法を説明する。 Below, the manufacturing method of 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester (V) by this invention is demonstrated.
１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステル（V）は、以下の反応工程式Iに示す本発明の方法で製造することができる。
［反応工程式I］
[Reaction process formula I]
尚、置換基等の定義、説明を以下に記載する。
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、又はヨウ素原子を意味する。
「Ｃ１−Ｃ４アルキル基」とは、１〜４個の炭素原子から成る直鎖若しくは分岐状のアルキル基を意味する。例えば、メチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ−ブチル基、及びｔ−ブチル基等が挙げられ、メチル基、エチル基が好ましい。
「カルボキシ基の保護基」とは、通常、有機合成上カルボキシ基の保護基として知られている基を意味し、（１）直鎖状若しくは分岐鎖状の炭素数１〜４の低級アルキル基（例えば、メチル基、エチル基、ｉ−プロピル基、ｔ−ブチル基）、（２）ハロゲノ低級アルキル基（例えば、２−ヨウ化エチル基、２，２，２−トリクロロエチル基）、（３）低級アルコキシメチル基（例えば、メトキシメチル基、エトキシメチル基、ｉ−ブトキシメチル基）、（４）低級脂肪族アシルオキシメチル基（例えば、ブチリルオキシメチル基、ピバロイルオキシメチル基）、（５）１−低級アルコキシカルボニルオキシエチル基（例えば、１−メトキシカルボニルオキシエチル基、１−エトキシカルボニルオキシエチル基）、（６）アラルキル基（例えば、ベンジル、ｐ−メトキシベンジル基、ｏ−ニトロベンジル基、ｐ−ニトロベンジル基）、（７）ベンズヒドリル基、及び（８）フタリジル基等を例示することができる。
In addition, definitions and explanations of substituents and the like are described below.
“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “C 1 -C 4 alkyl group” means a linear or branched alkyl group consisting of 1 to 4 carbon atoms. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, and a t-butyl group, and a methyl group and an ethyl group are preferable.
The “carboxy-protecting group” usually means a group known as a protecting group for a carboxy group in organic synthesis, and (1) a linear or branched lower alkyl group having 1 to 4 carbon atoms. (For example, methyl group, ethyl group, i-propyl group, t-butyl group), (2) halogeno lower alkyl group (for example, 2-iodoiodide group, 2,2,2-trichloroethyl group), (3 ) Lower alkoxymethyl group (for example, methoxymethyl group, ethoxymethyl group, i-butoxymethyl group), (4) lower aliphatic acyloxymethyl group (for example, butyryloxymethyl group, pivaloyloxymethyl group), ( 5) 1-lower alkoxycarbonyloxyethyl group (for example, 1-methoxycarbonyloxyethyl group, 1-ethoxycarbonyloxyethyl group), (6) aralkyl group (for example, Benzyl, p- methoxybenzyl group, o- nitrobenzyl group, p- nitrobenzyl group) can be exemplified (7) benzhydryl group, and (8) phthalidyl group.
一般式（I）にて示される化合物を適当な溶媒中、触媒量のＮ，Ｎ−ジメチルホルムアミド存在下又は非存在下、塩素化剤を用いて酸クロリドとした後、一般式（II）で表される化合物と適当な溶媒中、適当な塩基の存在下で縮合反応させることによって、一般式（III）にて示される化合物を得ることができる。得られた一般式（III）にて示される化合物とブロモ酪酸エステルを、適当な溶媒中、適当な塩基の存在下で反応させることによって、一般式（IV）にて示される化合物を得ることができる。得られた一般式（IV）にて示される化合物を、適当な溶媒中、適当な塩基の存在下で分子内縮合反応を行うことによって、一般式（V）にて示される化合物を得ることができる。 The compound represented by the general formula (I) is converted into an acid chloride using a chlorinating agent in a suitable solvent in the presence or absence of a catalytic amount of N, N-dimethylformamide, and then the general formula (II) A compound represented by the general formula (III) can be obtained by subjecting the compound represented to a condensation reaction in a suitable solvent in the presence of a suitable base. The compound represented by the general formula (IV) can be obtained by reacting the obtained compound represented by the general formula (III) with a bromobutyric acid ester in a suitable solvent in the presence of a suitable base. it can. The compound represented by the general formula (IV) can be obtained by subjecting the compound represented by the general formula (IV) to an intramolecular condensation reaction in a suitable solvent in the presence of a suitable base. it can.
一般式（I）にて示される化合物と塩素化剤との反応は、通常、適当な溶媒中で行われるが、そのような溶媒としては、ベンゼン、トルエン、キシレン、酢酸エチル、塩化メチレン、クロロホルム等が挙げられ、トルエン、塩化メチレンが好ましい。
一般式（I）にて示される化合物と塩素化剤との反応温度は、２０〜１００℃が好ましく、４０〜６０℃がより好ましい。反応時間は、１〜２４時間が好ましく、１〜４時間がより好ましい。
本反応において使用する塩素化剤の量は、二塩化オキサリルの場合、一般式（I）にて示される化合物に対して１〜１０当量用いるのが好ましく、１〜３当量がより好ましい。
反応完結後は、通常、使用溶媒を減圧溜去し、更にベンゼン、あるいはトルエンを用いて残存する二塩化オキサリル、及び水分を共沸除去し、一般式（II）にて示される化合物との反応に使用する。
The reaction between the compound represented by the general formula (I) and the chlorinating agent is usually carried out in a suitable solvent. Examples of such a solvent include benzene, toluene, xylene, ethyl acetate, methylene chloride, chloroform. Etc., and toluene and methylene chloride are preferable.
The reaction temperature between the compound represented by the general formula (I) and the chlorinating agent is preferably 20 to 100 ° C, more preferably 40 to 60 ° C. The reaction time is preferably 1 to 24 hours, more preferably 1 to 4 hours.
In the case of oxalyl dichloride, the amount of the chlorinating agent used in this reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the compound represented by the general formula (I).
After completion of the reaction, the solvent used is usually distilled off under reduced pressure, and the remaining oxalyl dichloride and water are removed azeotropically using benzene or toluene to react with the compound represented by the general formula (II). Used for.
一般式（I）にて示される化合物の酸クロリドと一般式（II）にて示される化合物との反応は、通常、適当な溶媒中、適当な塩基の存在下で行われるが、そのような溶媒としては、ベンゼン、トルエン、アセトニトリル、酢酸エチル、塩化メチレン、クロロホルム、あるいはこれら有機溶媒と水との二層系溶媒が挙げられ、アセトニトリル、塩化メチレン、有機溶媒と水との二層系溶媒が好ましい。またここで使用される塩基としては、ピリジン、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、アニリン、Ｎ，Ｎ−ジエチルアニリン、Ｎ，Ｎ−ジメチル−４−アミノピリジン等が挙げられ、Ｎ，Ｎ−ジイソプロピルエチルアミン、Ｎ，Ｎ−ジエチルアニリンがより好ましい。
一般式（I）にて示される化合物の酸クロリドと一般式（II）にて示される化合物との反応温度は、０〜６０℃が好ましく、１０〜３０℃がより好ましい。反応時間は、１〜４８時間が好ましく、２〜１２時間がより好ましい。
本反応において使用する化合物量は、一般式（II）にて示される化合物は、一般式（I）にて示される化合物の酸クロリドに対して、１〜３当量用いるのが好ましく、１〜１．５当量がより好ましい。塩基は、前記の方法により合成された一般式（I）にて示される化合物の酸クロリドに対して、１〜５当量用いるのが好ましく、１〜２当量がより好ましい。
反応完結後は、通常、希酸を加えて放置し、析出した固体物をろ取し、乾燥することにより、目的とする一般式（III）の化合物を得ることができる。ここで「希酸を加えて放置する」とは、１Ｎ塩酸、１Ｎ硫酸、１Ｎ硝酸、１Ｎ酢酸等の酸を加え、０〜５０℃、好ましくは１０〜３０℃で放置することを意味する。また「乾燥する」とは、送風乾燥でも減圧乾燥でもよく、温度は２０〜１００℃が好ましく、４０〜６０℃がより好ましい。
The reaction of the acid chloride of the compound represented by the general formula (I) and the compound represented by the general formula (II) is usually performed in a suitable solvent in the presence of a suitable base. Examples of the solvent include benzene, toluene, acetonitrile, ethyl acetate, methylene chloride, chloroform, or a two-layer solvent of these organic solvents and water, and a two-layer solvent of acetonitrile, methylene chloride, organic solvent and water. preferable. Examples of the base used here include pyridine, triethylamine, N, N-diisopropylethylamine, aniline, N, N-diethylaniline, N, N-dimethyl-4-aminopyridine and the like, and N, N-diisopropyl. More preferred are ethylamine and N, N-diethylaniline.
The reaction temperature between the acid chloride of the compound represented by the general formula (I) and the compound represented by the general formula (II) is preferably 0 to 60 ° C, more preferably 10 to 30 ° C. The reaction time is preferably 1 to 48 hours, more preferably 2 to 12 hours.
The amount of the compound used in this reaction is preferably 1 to 3 equivalents of the compound represented by the general formula (II) with respect to the acid chloride of the compound represented by the general formula (I). More preferred is 5 equivalents. The base is preferably used in an amount of 1 to 5 equivalents, more preferably 1 to 2 equivalents, based on the acid chloride of the compound represented by the general formula (I) synthesized by the above method.
After completion of the reaction, the target compound of the general formula (III) can be usually obtained by adding a dilute acid and allowing it to stand, and collecting the precipitated solid matter by filtration and drying. Here, “adding a dilute acid and leaving it to stand” means adding an acid such as 1N hydrochloric acid, 1N sulfuric acid, 1N nitric acid, 1N acetic acid and leaving it at 0 to 50 ° C., preferably 10 to 30 ° C. Further, “drying” may be air drying or vacuum drying, and the temperature is preferably 20 to 100 ° C., more preferably 40 to 60 ° C.
一般式（III）にて示される化合物と「ブロモ酪酸エステル」との反応は、通常、適当な溶媒中、適当な塩基の存在下で行われるが、「ブロモ酪酸エステル」としては、通常、ブロモ酪酸メチル、ブロモ酪酸エチルが好ましい。ここで使用される溶媒としては、アセトン、アセトニトリル、１，４−ジオキサン、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド、テトラヒドロフラン等が挙げられ、Ｎ，Ｎ−ジメチルホルムアミド、アセトンが好ましい。またここで使用される塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、ｔ−ブトキシカリウム、水酸化ナトリウム、水素化ナトリウム、ｎ−ブチルリチウム等が挙げられ、炭酸カリウム、炭酸セシウムが好ましい。
本工程の反応温度は、２０〜１５０℃が好ましく、５０〜１００℃がより好ましい。反応時間は、１〜７２時間が好ましく、６〜４８時間がより好ましい。
本反応において使用する化合物量は、「ブロモ酪酸エステル」は、一般式（III）にて示される化合物に対して１〜１０当量用いるのが好ましく、１〜３当量がより好ましい。塩基は、一般式（III）にて示される化合物に対して１〜２０当量用いるのが好ましく、１〜５当量がより好ましい。
反応終了後は、通常、希酸を加えた後、適当な溶媒で抽出後にカラムクロマトグラフィー精製をすることにより、目的とする一般式（IV）にて示される化合物を得ることができる。ここで、「希酸を加えて」とは、１Ｎ塩酸、１Ｎ硫酸、１Ｎ硝酸、１Ｎ酢酸、１Ｎトリフルオロ酢酸等の酸を加えることを意味する。また、抽出溶媒としては、トルエン、キシレン、酢酸エチル、ジエチルエーテル、クロロホルム、ジクロロメタン等が挙げられ、好ましくはトルエン、酢酸エチルが挙げられる。
The reaction of the compound represented by the general formula (III) with “bromobutyric acid ester” is usually carried out in an appropriate solvent in the presence of an appropriate base. Methyl butyrate and ethyl bromobutyrate are preferred. Examples of the solvent used here include acetone, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, N, N-dimethylformamide, tetrahydrofuran and the like, and N, N-dimethylformamide and acetone are preferable. Examples of the base used here include sodium carbonate, potassium carbonate, cesium carbonate, t-butoxypotassium, sodium hydroxide, sodium hydride, n-butyllithium and the like, and potassium carbonate and cesium carbonate are preferred.
20-150 degreeC is preferable and, as for the reaction temperature of this process, 50-100 degreeC is more preferable. The reaction time is preferably 1 to 72 hours, more preferably 6 to 48 hours.
The amount of the compound used in this reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, based on the compound represented by the general formula (III). The base is preferably used in an amount of 1 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the compound represented by the general formula (III).
After completion of the reaction, usually the target compound represented by the general formula (IV) can be obtained by adding dilute acid, followed by extraction with an appropriate solvent and column chromatography purification. Here, “adding dilute acid” means adding an acid such as 1N hydrochloric acid, 1N sulfuric acid, 1N nitric acid, 1N acetic acid, and 1N trifluoroacetic acid. Examples of the extraction solvent include toluene, xylene, ethyl acetate, diethyl ether, chloroform, dichloromethane and the like, preferably toluene and ethyl acetate.
一般式（IV）にて示される化合物の縮合反応は、通常、適当な溶媒中、適当な塩基を用いて行われるが、ここで使用される溶媒としては、酢酸エチル、テトラヒドロフラン、１，４−ジオキサン、アセトン、アセトニトリル等が挙げられ、テトラヒドロフラン、１，４−ジオキサンが好ましい。またここで使用される塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、ｔ−ブトキシカリウム、ナトリウムメトキシド、水酸化ナトリウム等が挙げられ、ｔ−ブトキシカリウムが好ましい。
本工程の反応温度は、−２０〜４０℃が好ましく、０〜１０℃がより好ましい。反応時間は、１〜２４時間が好ましく、１〜４時間がより好ましい。
本反応において使用する化合物量は、塩基は、一般式（IV）にて示される化合物に対して１〜２０当量用いるのが好ましく、１〜５当量がより好ましい。
反応終了後は、通常、酸を加えて放置し、析出した固体物をろ取し、乾燥することにより、目的とする一般式（V）にて示される化合物を得ることができる。ここで「酸を加えて放置する」とは、塩酸、硫酸、硝酸、酢酸、トリフルオロ酢酸、又はｐ−トルエンスルホン酸等の酸を加え、０〜５０℃、好ましくは１０〜３０℃で放置することを意味する。また「乾燥する」とは、送風乾燥でも減圧乾燥でもよく、温度は２０〜１００℃が好ましく、４０〜６０℃がより好ましい。
The condensation reaction of the compound represented by the general formula (IV) is usually carried out in a suitable solvent using a suitable base. Examples of the solvent used here include ethyl acetate, tetrahydrofuran, 1,4- Dioxane, acetone, acetonitrile and the like can be mentioned, and tetrahydrofuran and 1,4-dioxane are preferable. Examples of the base used here include sodium carbonate, potassium carbonate, cesium carbonate, t-butoxy potassium, sodium methoxide, sodium hydroxide and the like, and t-butoxy potassium is preferable.
The reaction temperature in this step is preferably -20 to 40 ° C, more preferably 0 to 10 ° C. The reaction time is preferably 1 to 24 hours, more preferably 1 to 4 hours.
The amount of the compound used in this reaction is preferably 1 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the compound represented by the general formula (IV).
After completion of the reaction, usually, an acid is added and the mixture is allowed to stand. The precipitated solid is collected by filtration and dried to obtain the target compound represented by the general formula (V). Here, “add acid and leave” means adding acid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid, and leaving at 0 to 50 ° C., preferably 10 to 30 ° C. It means to do. Further, “drying” may be air drying or vacuum drying, and the temperature is preferably 20 to 100 ° C., more preferably 40 to 60 ° C.
以下に、実施例を挙げて本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。
実施例における核磁気共鳴（1H-NMR）スペクトルは、テトラメチルシランを標準物質としてケミカルシフト値をδ値（ppm）で記載した。分裂パターンは、一重線を「s」、二重線を「d」、三重線を「t」、四重線を「q」、二重線−二重線を「dd」、三重線−二重線を「td」、多重線を「m」、幅広い線を「br」で示した。質量分析は、エレクトロスプレーイオン化法（ESI）で行った。
Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
The nuclear magnetic resonance ( 1 H-NMR) spectra in the examples are described with chemical shift values as δ values (ppm) using tetramethylsilane as a standard substance. The split pattern is: single line “s”, double line “d”, triple line “t”, quadruple line “q”, double line-double line “dd”, triple line—two The double line is shown as “td”, the multiple line as “m”, and the wide line as “br”. Mass spectrometry was performed by electrospray ionization (ESI).
［実施例１］
１−［２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンゾイル］−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エチル
２−［２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル
アルゴン雰囲気下、２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）安息香酸（1.08 g）、Ｎ，Ｎ−ジメチルホルムアミド（0.1 mL）のトルエン（10 mL）溶液に、二塩化オキサリル（0.86 mL）を氷浴下で加えた。反応液を６０℃で２時間撹拌した後、反応溶媒を減圧溜去し、トルエンを用いて減圧下で共沸した。得られた酸クロリド体のアセトニトリル（3 mL）溶液を、アントラニル酸エチル（0.99 g）、Ｎ，Ｎ−ジエチルアニリン（2.1 mL）のアセトニトリル（7 mL）溶液に、氷浴下で加えた。反応液を室温で一晩撹拌後、1N塩酸（10 mL）、水（20 mL）を加えて、室温で１時間撹拌した。析出した固形物をろ過し、水（5 mL）で洗浄し、一晩減圧乾燥することにより２−［２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル（1.66 g）の粉末を得た。
1H-NMR (400MHz, CDCl3) δppm: 11.55 (s 1H), 8.87 (dd, J = 2.0, 8.0 Hz, 1H), 8.08 (dd, J = 2.0, 8.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62-7.54 (m, 3H), 7.12 (t, J = 8.0 Hz, 1H), 6.26 (d, J = 2.0 Hz, 1H), 4.35 (q, J = 8.0 Hz, 2H), 2.61 (s, 3H), 2.37 (s, 3H), 1.38 (t, J = 8.0 Hz, 3H).
ESI/MS(m/z): 384 (M+H)+.
［実施例１−（ｂ）］
２−［Ｎ−（４−エトキシ−４−オキソブチル）−２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル
２−［２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル（実施例１−（ａ）で製造，0.36 g）、ブロモ酪酸エチル（0.23 g）及び炭酸カリウム（0.42 g）をＮ，Ｎ−ジメチルホルムアミド（3.6 mL）中、１００℃で一晩撹拌した。反応液を室温まで放冷し、酢酸エチル（10 mL）、水（10 mL）を加えて、室温で１時間撹拌した。有機層を分離し、水層を酢酸エチル（10 mL）で抽出した。併せた有機層を水（10 mL）で３回洗浄し、飽和食塩水（10 mL）で洗浄し、無水硫酸ナトリウムを加えた。抽出した粗生成物をろ過、減圧濃縮し、カラムクロマトグラフィーで精製することにより、２−［Ｎ−（４−エトキシ−４−オキソブチル）−２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル（0.31 g）の粉末を得た。
1H-NMR (400MHz, CDCl3) δppm: 8.03-7.79 (m, 1H), 7.66-7.56 (m, 1H), 7.37-7.17 (m, 4H), 7.10-7.01 (m, 2H), 6.25-6.15 (m, 1H), 4.51-4.33 (m, 3H), 4.12-3.91 (m, 2H), 3.27-3.21 (m, 1H), 2.47-2.30 (m, 8H), 2.10-1.84 (m, 2H), 1.42-1.36 (m, 3H), 1.26-1.19 (m, 3H).
ESI/MS(m/z): 479 (M+H)+.
［実施例１−（ｃ）］
１−［２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンゾイル］−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エチル
２−［Ｎ−（４−エトキシ−４−オキソブチル）−２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル（実施例１−（ｂ）で製造，0.36 g）のテトラヒドロフラン（1.8 mL）溶液に、ｔ−ブトキシカリウムの1N テトラヒドロフラン溶液（1.51 mL）を氷浴中で加えた。反応液を氷浴中で１時間撹拌後、6N 塩酸溶液（0.27 mL）を加えた。反応液を減圧濃縮した後、イソプロピルアルコール（2 mL）を加えて、室温で１時間撹拌した。析出した固形物をろ過し、水（10 mL）で洗浄し、一晩減圧乾燥することにより、１−［２−メチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エチル（0.19 g）の粉末を得た。
1H-NMR (400MHz, CDCl3) δppm: 12.71 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.11-7.03 (m, 2H), 6.84 (brd, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 4.75 (td, J = 4.0, 12.0 Hz, 1H), 4.35-4.23 (m, 2H), 3.74-3.68 (m, 1H), 2.94-2.91 (m, 1H), 2.37-2.31 (m, 6H), 2.15 (td, J = 4.0, 12.0 Hz, 1H), 1.37 (t, J = 8.0 Hz, 3H).
ESI/MS(m/z): 432 (M+H)+, 430 (M-H)-.
[Example 1]
1- [2-Methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carbon Ethyl acid
2- [2-Methyl-4- (3-methyl-1H-pyrazol-1-yl) benzamide] ethyl benzoate under argon atmosphere, 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) Oxalyl dichloride (0.86 mL) was added to a toluene (10 mL) solution of benzoic acid (1.08 g) and N, N-dimethylformamide (0.1 mL) in an ice bath. After the reaction solution was stirred at 60 ° C. for 2 hours, the reaction solvent was distilled off under reduced pressure and azeotroped under reduced pressure using toluene. A solution of the obtained acid chloride in acetonitrile (3 mL) was added to a solution of ethyl anthranilate (0.99 g) and N, N-diethylaniline (2.1 mL) in acetonitrile (7 mL) in an ice bath. The reaction mixture was stirred at room temperature overnight, 1N hydrochloric acid (10 mL) and water (20 mL) were added, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was filtered, washed with water (5 mL), and dried under reduced pressure overnight to give 2- [2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzamide] benzoic acid. Ethyl (1.66 g) powder was obtained.
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 11.55 (s 1H), 8.87 (dd, J = 2.0, 8.0 Hz, 1H), 8.08 (dd, J = 2.0, 8.0 Hz, 1H), 7.84 (d , J = 2.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62-7.54 (m, 3H), 7.12 (t, J = 8.0 Hz, 1H), 6.26 (d, J = 2.0 Hz , 1H), 4.35 (q, J = 8.0 Hz, 2H), 2.61 (s, 3H), 2.37 (s, 3H), 1.38 (t, J = 8.0 Hz, 3H).
ESI / MS (m / z): 384 (M + H) + .
[Example 1- (b)]
2- [N- (4-Ethoxy-4-oxobutyl) -2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzamide] ethyl benzoate 2- [2-methyl-4- (3 -Methyl-1H-pyrazol-1-yl) benzamide] ethyl benzoate (prepared in Example 1- (a), 0.36 g), ethyl bromobutyrate (0.23 g) and potassium carbonate (0.42 g) were added N, N- Stir in dimethylformamide (3.6 mL) at 100 ° C. overnight. The reaction mixture was allowed to cool to room temperature, ethyl acetate (10 mL) and water (10 mL) were added, and the mixture was stirred at room temperature for 1 hr. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed 3 times with water (10 mL), washed with saturated brine (10 mL), and anhydrous sodium sulfate was added. The extracted crude product was filtered, concentrated under reduced pressure, and purified by column chromatography to give 2- [N- (4-ethoxy-4-oxobutyl) -2-methyl-4- (3-methyl-1H-pyrazole -1-yl) benzamide] ethyl benzoate (0.31 g) powder was obtained.
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 8.03-7.79 (m, 1H), 7.66-7.56 (m, 1H), 7.37-7.17 (m, 4H), 7.10-7.01 (m, 2H), 6.25 -6.15 (m, 1H), 4.51-4.33 (m, 3H), 4.12-3.91 (m, 2H), 3.27-3.21 (m, 1H), 2.47-2.30 (m, 8H), 2.10-1.84 (m, 2H), 1.42-1.36 (m, 3H), 1.26-1.19 (m, 3H).
ESI / MS (m / z): 479 (M + H) + .
[Example 1- (c)]
1- [2-Methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carbon Ethyl 2- [N- (4-ethoxy-4-oxobutyl) -2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzamide] ethyl benzoate (Example 1- (b)) To a solution of preparation, 0.36 g) in tetrahydrofuran (1.8 mL), 1N tetrahydrofuran solution (1.51 mL) of potassium t-butoxy was added in an ice bath. The reaction mixture was stirred in an ice bath for 1 hour, and 6N hydrochloric acid solution (0.27 mL) was added. The reaction mixture was concentrated under reduced pressure, isopropyl alcohol (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was filtered, washed with water (10 mL), and dried under reduced pressure overnight to give 1- [2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzamide]- A powder of ethyl 5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylate (0.19 g) was obtained.
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 12.71 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H) , 7.18 (t, J = 8.0 Hz, 1H), 7.11-7.03 (m, 2H), 6.84 (brd, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 4.75 (td, J = 4.0, 12.0 Hz, 1H), 4.35-4.23 (m, 2H), 3.74-3.68 (m, 1H), 2.94-2.91 (m, 1H), 2.37 -2.31 (m, 6H), 2.15 (td, J = 4.0, 12.0 Hz, 1H), 1.37 (t, J = 8.0 Hz, 3H).
ESI / MS (m / z): 432 (M + H) + , 430 (MH) - .
［実施例２］
１−［２−クロロ−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンゾイル］−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エチル
２−［２−クロロ−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル
２−クロロ−４−（３−メチル−１Ｈ−ピラゾール−１−イル）安息香酸を用いて、実施例１−（ａ）と同様の方法で反応を行うことにより、表記化合物を得た。
1H-NMR (400MHz, CDCl3) δppm: 11.60 (brs 1H), 8.86 (d, J = 8.0 Hz, 1H), 8.08 (dd, J = 4.0, 8.0 Hz, 1H), 7.83-7.82 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.64-7.62 (m, 2H), 7.14 (td, J = 2.0, 8.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 4.35 (q, J = 8.0 Hz, 2H), 2.37 (s, 3H), 1.38 (t, J = 8.0 Hz, 3H).
ESI/MS(m/z): 384 (M+H)+.
［実施例２−（ｂ）］
２−［２−クロロ−Ｎ−（４−エトキシ−４−オキソブチル）−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル
２−［２−クロロ−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド］安息香酸エチル（実施例２−（ａ）で製造）を用いて、実施例１−（ｂ）と同様の方法で反応を行うことにより、表記化合物を得た。
1H-NMR (400MHz, CDCl3) δppm: 7.82 (td, J = 2.0, 8.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.33-7.31 (m, 2H), 7.23-7.17 (m, 3H), 6.18 (d, J = 2.0 Hz, 1H), 4.53-4.46 (m, 1H), 4.42(q, J = 8.0 Hz, 2H), 4.13-4.07 (m, 3H), 3.21-3.16 (m, 1H), 2.52-2.35 (m, 3H), 2.29 (s, 3H), 1.42 (t, J = 8.0 Hz, 3H), 1.22 (t, J = 8.0 Hz, 3H).
ESI/MS(m/z): 498 (M+H)+.
［実施例２−（ｃ）］
１−［２−クロロ−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンゾイル］−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エチル
２−（２−クロロ−Ｎ−（４−エトキシ−４−オキソブチル）−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンズアミド）安息香酸エチル（実施例２−（ｂ）で製造）を用いて、実施例１−（ｃ）と同様の方法で反応を行うことにより、表記化合物を得た。
1H-NMR (400MHz, CDCl3) δppm: 12.71 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.59-7.57 (m, 1H), 7.23-7.19 (m, 3H), 7.11 (td, J = 2.0, 8.0 Hz, 1H), 7.03-7.00 (m, 1H), 6.90 (brs, 1H), 6.19 (d, J = 2.0 Hz, 1H), 4.78 (td, J = 2.0, 12.0 Hz, 1H), 4.36-4.29 (m, 2H), 3.71 (dd, J = 4.0, 12.0 Hz, 1H), 2.93 (dd, J = 4.0, 16.0 Hz, 1H), 2.19 (s, 3H), 2.14 (td, J = 4.0, 16.0 Hz, 1H), 1.38 (t, J = 6.0 Hz, 3H).
ESI/MS(m/z): 452 (M+H)+, 450 (M-H)-.
[Example 2]
1- [2-Chloro-4- (3-methyl-1H-pyrazol-1-yl) benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carbon Ethyl acid
2- [2-Chloro-4- (3-methyl-1H-pyrazol-1-yl) benzamide] ethyl 2-chloro-4- (3-methyl-1H-pyrazol-1-yl) benzoate is used. Then, the title compound was obtained by carrying out the reaction in the same manner as in Example 1- (a).
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 11.60 (brs 1H), 8.86 (d, J = 8.0 Hz, 1H), 8.08 (dd, J = 4.0, 8.0 Hz, 1H), 7.83-7.82 (m , 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.64-7.62 (m, 2H), 7.14 (td, J = 2.0, 8.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H) , 4.35 (q, J = 8.0 Hz, 2H), 2.37 (s, 3H), 1.38 (t, J = 8.0 Hz, 3H).
ESI / MS (m / z): 384 (M + H) + .
[Example 2- (b)]
2- [2-Chloro-N- (4-ethoxy-4-oxobutyl) -4- (3-methyl-1H-pyrazol-1-yl) benzamide] ethyl benzoate 2- [2-chloro-4- (3 -Methyl-1H-pyrazol-1-yl) benzamide] Using ethyl benzoate (produced in Example 2- (a)), the reaction is carried out in the same manner as in Example 1- (b). A compound was obtained.
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 7.82 (td, J = 2.0, 8.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H) , 7.33-7.31 (m, 2H), 7.23-7.17 (m, 3H), 6.18 (d, J = 2.0 Hz, 1H), 4.53-4.46 (m, 1H), 4.42 (q, J = 8.0 Hz, 2H ), 4.13-4.07 (m, 3H), 3.21-3.16 (m, 1H), 2.52-2.35 (m, 3H), 2.29 (s, 3H), 1.42 (t, J = 8.0 Hz, 3H), 1.22 ( t, J = 8.0 Hz, 3H).
ESI / MS (m / z): 498 (M + H) + .
[Example 2- (c)]
1- [2-Chloro-4- (3-methyl-1H-pyrazol-1-yl) benzoyl] -5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carbon Ethyl 2- (2-chloro-N- (4-ethoxy-4-oxobutyl) -4- (3-methyl-1H-pyrazol-1-yl) benzamide) benzoate (in Example 2- (b) The title compound was obtained by carrying out the reaction in the same manner as in Example 1- (c).
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 12.71 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.59-7.57 (m, 1H), 7.23-7.19 (m, 3H), 7.11 (td, J = 2.0, 8.0 Hz, 1H), 7.03-7.00 (m, 1H), 6.90 (brs, 1H), 6.19 (d, J = 2.0 Hz, 1H), 4.78 (td, J = 2.0, 12.0 Hz, 1H), 4.36-4.29 (m, 2H), 3.71 (dd, J = 4.0, 12.0 Hz, 1H), 2.93 (dd, J = 4.0, 16.0 Hz, 1H), 2.19 (s, 3H), 2.14 (td, J = 4.0, 16.0 Hz, 1H), 1.38 (t, J = 6.0 Hz, 3H).
ESI / MS (m / z): 452 (M + H) + , 450 (MH) - .
［実施例３］
１−（２−トリフルオロメチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンゾイル）−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エチル
２−［４−（３−メチル−１Ｈ−ピラゾール−１−イル）−２−トリフルオロメチルベンズアミド］安息香酸エチル
２−トリフルオロメチル−４−（３−メチル−１Ｈ−ピラゾール−１−イル）安息香酸を用いて、実施例１−（ａ）と同様の方法で反応を行うことにより、表記化合物を得た。
1H-NMR (400MHz, CDCl3) δppm: 11.52 (brs, 1H), 8.82 (d, J = 8.0 Hz, 1H), 8.40 (s, 1H), 8.26 (dd, J = 2.0, 8.0 Hz, 1H), 8.08 (dd, J = 2.0, 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.61 (td, J = 4.0, 8.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.16 (td, J = 2.0, 8.0 Hz, 1H), 4.33 (q, J = 8.0 Hz, 2H), 2.27 (s, 3H), 1.36 (t, J = 8.0 Hz, 3H).
ESI/MS(m/z): 419 (M+H)+.
［実施例３−（ｂ）］
２−［Ｎ−（４−エトキシ−４−オキソブチル）−４−（３−メチル−１Ｈ−ピラゾール−１−イル）−２−トリフルオロメチルベンズアミド］安息香酸エチル
２−［４−（３−メチル−１Ｈ−ピラゾール−１−イル）−２−トリフルオロメチルベンズアミド］安息香酸エチル（実施例３−（ａ）で製造）を用いて、実施例１−（ｂ）と同様の方法で反応を行うことにより、表記化合物を得た。
1H-NMR (400MHz, CDCl3) δppm: 8.39-8.26 (m, 1H), 8.18 (s, 1H), 8.06-7.87 (m, 1H), 7.83 (dd, J = 2.0, 8.0 Hz, 1H), 7.81 (dd, J = 2.0, 8.0 Hz, 1H), 7.64-7.20 (m, 3H), 7.04 (dd, J = 2.0, 8.0 Hz, 1H), 4.54 (ddd, J = 2.0, 4.0, 16.0 Hz, 1H), 4.45 (q, J = 8.0 Hz, 2H), 4.40-4.34 (m, 1H), 4.11-3.90 (m, 2H), 3.64-3.42 (m, 1H), 3.14-3.04 (m, 1H), 2.50-2.20 (m, 2H), 2.19 (s, 3H), 1.46-1.36 (m, 3H), 1.26-1.18 (m, 3H).
ESI/MS(m/z): 533 (M+H)+.
［実施例３−（ｃ）］
１−［４−（３−メチル−１Ｈ−ピラゾール−１−イル）ベンゾイル］−２−トリフルオロメチル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エチル
２−［Ｎ−（４−エトキシ−４−オキソブチル）−４−（３−メチル−１Ｈ−ピラゾール−１−イル）−２−トリフルオロメチルベンズアミド］安息香酸エチル（実施例３−（ｂ）で製造）を用いて、実施例１−（ｃ）と同様の方法で反応を行うことにより、表記化合物を得た。
1H-NMR (400MHz, CDCl3) δppm: 12.74 (s, 1H), 8.19 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 2.0, 8.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.21 (td, J = 2.0, 8.0 Hz, 1H), 7.09 (td, J = 2.0, 8.0 Hz, 1H), 6.95(dd, J = 2.0, 8.0 Hz, 1H), 6.86 (brs, 1H), 4.81 (td, J = 4.0, 8.0 Hz, 1H), 4.35-4.32 (m, 2H), 3.69 (ddd, J = 2.0, 4.0, 16.0 Hz, 1H), 2.94 (ddd, J = 2.0, 4.0, 16.0 Hz, 1H), 2.19 (s, 3H), 2.14 (dd, J = 4.0, 16.0 Hz, 1H), 1.38 (t, J = 6.0 Hz, 3H).
ESI/MS(m/z): 487 (M+H)+, 485 (M-H)-.
[Example 3]
1- (2-trifluoromethyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl) -5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4 -Ethyl carboxylate
2- [4- (3-Methyl-1H-pyrazol-1-yl) -2-trifluoromethylbenzamide] ethyl benzoate 2-trifluoromethyl-4- (3-methyl-1H-pyrazol-1-yl) The title compound was obtained by carrying out the reaction in the same manner as in Example 1- (a) using benzoic acid.
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 11.52 (brs, 1H), 8.82 (d, J = 8.0 Hz, 1H), 8.40 (s, 1H), 8.26 (dd, J = 2.0, 8.0 Hz, 1H), 8.08 (dd, J = 2.0, 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.61 (td, J = 4.0, 8.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.16 (td, J = 2.0, 8.0 Hz, 1H), 4.33 (q, J = 8.0 Hz, 2H), 2.27 (s, 3H), 1.36 (t, J = 8.0 Hz, 3H).
ESI / MS (m / z): 419 (M + H) + .
[Example 3- (b)]
2- [N- (4-Ethoxy-4-oxobutyl) -4- (3-methyl-1H-pyrazol-1-yl) -2-trifluoromethylbenzamide] ethyl benzoate 2- [4- (3-methyl -1H-pyrazol-1-yl) -2-trifluoromethylbenzamide] ethyl benzoate (prepared in Example 3- (a)) and the reaction is carried out in the same manner as Example 1- (b). This gave the title compound.
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 8.39-8.26 (m, 1H), 8.18 (s, 1H), 8.06-7.87 (m, 1H), 7.83 (dd, J = 2.0, 8.0 Hz, 1H ), 7.81 (dd, J = 2.0, 8.0 Hz, 1H), 7.64-7.20 (m, 3H), 7.04 (dd, J = 2.0, 8.0 Hz, 1H), 4.54 (ddd, J = 2.0, 4.0, 16.0 Hz, 1H), 4.45 (q, J = 8.0 Hz, 2H), 4.40-4.34 (m, 1H), 4.11-3.90 (m, 2H), 3.64-3.42 (m, 1H), 3.14-3.04 (m, 1H), 2.50-2.20 (m, 2H), 2.19 (s, 3H), 1.46-1.36 (m, 3H), 1.26-1.18 (m, 3H).
ESI / MS (m / z): 533 (M + H) + .
[Example 3- (c)]
1- [4- (3-Methyl-1H-pyrazol-1-yl) benzoyl] -2-trifluoromethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4 Ethyl carboxylate 2- [N- (4-Ethoxy-4-oxobutyl) -4- (3-methyl-1H-pyrazol-1-yl) -2-trifluoromethylbenzamide] ethyl benzoate (Example 3- Using (produced in (b)), the title compound was obtained by carrying out the reaction in the same manner as in Example 1- (c).
1 H-NMR (400MHz, CDCl 3 ) δ ppm : 12.74 (s, 1H), 8.19 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 2.0, 8.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.21 (td, J = 2.0, 8.0 Hz, 1H), 7.09 (td, J = 2.0, 8.0 Hz, 1H), 6.95 (dd, J = 2.0 , 8.0 Hz, 1H), 6.86 (brs, 1H), 4.81 (td, J = 4.0, 8.0 Hz, 1H), 4.35-4.32 (m, 2H), 3.69 (ddd, J = 2.0, 4.0, 16.0 Hz, 1H), 2.94 (ddd, J = 2.0, 4.0, 16.0 Hz, 1H), 2.19 (s, 3H), 2.14 (dd, J = 4.0, 16.0 Hz, 1H), 1.38 (t, J = 6.0 Hz, 3H ).
ESI / MS (m / z): 487 (M + H) + , 485 (MH) - .
本発明方法は、医薬品合成中間体として有用な１−ベンゾイル−５−オキソ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾ［ｂ］アゼピン−４−カルボン酸エステルを安全且つ安価に工業的に製造する方法として有用である。 The method of the present invention is a safe and inexpensive industrial production of 1-benzoyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-4-carboxylic acid ester useful as a pharmaceutical synthesis intermediate. It is useful as a manufacturing method.
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