JP2011507947A - A production method using a synthetic intermediate of a pyrrolylheptanoic acid derivative and a novel synthetic intermediate. - Google Patents
A production method using a synthetic intermediate of a pyrrolylheptanoic acid derivative and a novel synthetic intermediate. Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
Abstract
【課題】
血中コレステロールの抑制効果のある（３Ｒ、５Ｒ）−７−［２−（４−フルオロフェニル）−５−イソプロピル−３−フェニル−４−（フェニルカルバモイル）−１Ｈ−ピロール−１−イル］−３，５−ジヒドロキシヘプタン酸誘導体を製造するのに用いられる中間体、およびそれから製造されるピロリルヘプタン酸誘導体の製造方法を提供する。
【解決手段】
本発明によれば、５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボニル誘導体は１つの（３Ｒ、５Ｒ）−７−［２−（４−フルオロフェニル）−５−イソプロピル−３−フェニル−４−（フェニルカルバモイル）−１Ｈ−ピロール−１−イル］−３，５−ジヒドロキシヘプタン酸誘導体を含むピロリルヘプタン酸誘導体を製造するための新規合成中間体として提供される。したがって、（３Ｒ、５Ｒ）−７−［２−（４−フルオロフェニル）−５−イソプロピル−３−フェニル−４−（フェニルカルバモイル）−１Ｈ−ピロール−１−イル］−３，５−ジヒドロキシヘプタン酸誘導体をカルボニル誘導体から温和な条件で高収率で短時間で製造することができる。
【選択図】なし【Task】
(3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl]-, which has an effect of suppressing blood cholesterol Provided are intermediates used to produce 3,5-dihydroxyheptanoic acid derivatives, and methods for producing pyrrolylheptanoic acid derivatives produced therefrom.
[Solution]
According to the present invention, 5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole-3-carbonyl derivative is converted into one (3R, 5R) -7- [2- (4-fluorophenyl). ) -5-Isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid derivatives and other novel synthetic intermediates for preparing pyrrolylheptanoic acid derivatives Offered as. Thus, (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl] -3,5-dihydroxyheptane An acid derivative can be produced from a carbonyl derivative under mild conditions and in a high yield in a short time.
[Selection figure] None
Description
本発明は、高脂血症への治療効果を表す（３Ｒ、５Ｒ）−７−［２−（４−フルオロフェニル）−５−イソプロピル−３−フェニル−４−（フェニルカルバモイル）−１Ｈ−ピロール−１−イル］−３，５−ジヒドロキシヘプタン酸誘導体を含む、ピロールヘプタン酸誘導体を製造するための新規合成中間体、およびこれを利用したピロールヘプタン酸誘導体の製造方法に関するものである。 The present invention relates to (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrole which exhibits therapeutic effects on hyperlipidemia The present invention relates to a novel synthetic intermediate for producing a pyrrolheptanoic acid derivative, including a -1-yl] -3,5-dihydroxyheptanoic acid derivative, and a method for producing a pyrrolheptanoic acid derivative using the same.
（３Ｒ、５Ｒ）−７−［２−（４−フルオロフェニル）−５−イソプロピル−３−フェニル−４−（フェニルカルバモイル）−１Ｈ−ピロール−１−イル］−３，５−ジヒドロキシヘプタン酸誘導体（以下「化１誘導体」という。）は、米国特許公報第４，６８１，８９３号および米国特許公報第５，２７３，９９５号に記載されており、ＨＭＧ−ＣｏＡ還元酵素抑制作用およびアシルコエンザイムＡ：コレステロールアシルトランスフェラーゼ（Ａｃｙｌ−ｃｏｅｎｚｙｍｅ Ａ：ｃｈｏｌｅｓｔｅｒｏｌ ａｃｙｌｔｒａｎｓｆｅｒａｓｅ，ＡＣＡＴ）抑制効能があるため高脂血症治療に広く使われている。また、下記化１の構造を有するカルシウム塩の形態で市販される薬品である。 (3R, 5R) -7- [2- (4-Fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid derivative (Hereinafter referred to as “Chemical 1 Derivative”) is described in US Pat. No. 4,681,893 and US Pat. No. 5,273,995, and inhibits HMG-CoA reductase and acylcoenzyme A. : Cholesterol acyltransferase (Acyl-coenzyme A) is widely used in the treatment of hyperlipidemia because of its inhibitory effect. Moreover, it is a chemical | medical agent marketed with the form of the calcium salt which has the structure of following Chemical formula 1.
前記化１誘導体の製造方法は、米国特許公報第４，６８１，８９３号、第５，１２４，４８２号、第５，２１６，１７４号および大韓民国特許公開番号第２００６−８０１５号など、数多くの特許と文献に開示されており、一般的には下記の式１に表した通り、４−（４−フルオロフェニル）−２−イソブチリル−３−フェニル−４−オキソ−Ｎ−フェニル−ブチルアミド誘導体と（４Ｒ−シス）−１，１−ジメチルエチル−６−（２−アミノエチル）−２，２−ジメチル−１，３−ジオキサン−４−アセテート誘導体のピロール化反応で中間体の（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−［２−（４−フルオロフェニル）−５−（１−メチルエチル）−３−フェニル−４−［（フェニルアミノ）カルボニル］−１Ｈ−ピロール−１−イル］エチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテートを製造した後、脱エステル保護反応させて、カルシウムアセテート一水和物と反応させる段階を経て式１の化１が製造される。 There are a number of patents such as US Pat. Nos. 4,681,893, 5,124,482, 5,216,174, and Korean Patent Publication No. 2006-8015. Generally, as shown in the following formula 1, 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butyramide derivatives and ( 4R-cis) -1,1-dimethylethyl-6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate derivative is subjected to pyrrolation reaction of the intermediate (4R-cis) -1,1-dimethylethyl-6- [2- [2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole 1-yl] ethyl] -2,2-dimethyl-1,3-dioxane-4-acetate is prepared and then subjected to a deesterification protection reaction and reaction with calcium acetate monohydrate. 1 is manufactured.
前記式１で化１誘導体を製造するための出発物質で使われる４−（４−フルオロフェニル）−２−イソブチリル−３−フェニル−４−オキソ−Ｎ−フェニル−ブチルアミドは下記式２の方法により合成されることができる。 4- (4-Fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butyramide used as a starting material for preparing the compound of formula 1 is prepared by the method of formula 2 below. Can be synthesized.
ところで、前記製造方法は無水条件が必要で収率が低いだけでなく、副産物が多い工程であり、２４時間またはそれ以上反応させなければならないなど製造工程に長時間が必要で、３−エチル−５−（２−ヒドロキシエチル）−４−メチルジアゾニウムブロミドのような高価の触媒を使わなければならないので、製剤学的製造に難しい短所がある。 By the way, the production method requires not only anhydrous conditions and a low yield, but also a process with many by-products, and requires a long time for the production process such as a reaction time of 24 hours or more. Since expensive catalysts such as 5- (2-hydroxyethyl) -4-methyldiazonium bromide have to be used, there are disadvantages in pharmaceutical manufacturing.
また、式１で化１誘導体を製造するための出発物質で使われる４−（４−フルオロフェニル）−２−イソブチリル−３−フェニル−４−オキソ−Ｎ−フェニル−ブチルアミドは国際公開特許公報第０３／００４４５７号および大韓民国特許公開公報第２００４−１４３５号に他の製造方法が開始されていて、その製造方法は式３に表した通りである。 In addition, 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butyramide used as a starting material for preparing the compound of formula 1 is disclosed in No. 03/004457 and Korean Patent Publication No. 2004-1435 have been started, and the manufacturing method is as shown in Equation 3.
前記式３で２−ブロモ−１−（４−フルオロフェニル）−２−フェニルエタン−１−オン誘導体は式１に記載された化１誘導体を製造するための出発物質の４−（４−フルオロフェニル）−２−イソブチリル−３−フェニル−４−オキソ−Ｎ−フェニル−ブチルアミドを製造するための反応物質として使われる。しかしながら、前記反応物質で使われる２−ブロモ−１−（４−フルオロフェニル）−２−フェニルエタン−１−オン誘導体は、製造する過程が２４時間またはそれ以上という長時間の反応時間が必要で大量生産が難しく、特に有毒な臭素を使うため作業者にだけでなく、環境的にも非常に有害という短所がある。 In the above formula 3, 2-bromo-1- (4-fluorophenyl) -2-phenylethane-1-one derivative is the starting material 4- (4-fluorophenyl) for preparing the compound 1 described in formula 1. Phenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butyramide is used as a reactant. However, the 2-bromo-1- (4-fluorophenyl) -2-phenylethan-1-one derivative used in the reactants requires a long reaction time of 24 hours or more. Mass production is difficult, especially because it uses toxic bromine, it is very harmful not only for workers but also for the environment.
上記のように、従来の化１誘導体を製造するための中間体の４−（４−フルオロフェニル）−２−イソブチリル−３−フェニル−４−オキソ−Ｎ−フェニル−ブチルアミド誘導体を製造する方法は、低い収率と多くの副産物が生成されるという問題点があり、また、長時間の反応が必要で無水条件などの難しい反応工程が要求され、環境的にも有害で工業化に問題がある。 As described above, a method for producing an intermediate 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butyramide derivative for producing a conventional chemical 1 derivative is as follows. However, there is a problem that a low yield and a lot of by-products are generated, and a long reaction time is required and a difficult reaction process such as anhydrous conditions is required.
したがって、公知の化１誘導体を製造するための中間体の４−（４−フルオロフェニル）−２−イソブチリル−３−フェニル−４−オキソ−Ｎ−フェニル−ブチルアミドの問題点を克服してピロリルヘプタン酸誘導体を製造できる、新しい中間体を用いた製造方法が要求されてきた。 Thus, overcoming the problems of the intermediate 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butyramide for preparing the known compound 1 derivatives There has been a demand for a production method using a new intermediate capable of producing a heptanoic acid derivative.
そこで、本発明者らはピロリルヘプタン酸誘導体を製造するための新規合成中間体を開発し、従来の化１誘導体を製造するための中間体の４−（４−フルオロフェニル）−２−イソブチリル−３−フェニル−４−オキソ−Ｎ−フェニル−ブチルアミドの問題点の低い収率と多くの副産物が生成されることと、無水条件などの難しい反応工程が要求される問題点を解決し、中間体からピロリルヘプタン酸誘導体を製造することによって本発明を完成した。 Therefore, the present inventors have developed a novel synthetic intermediate for producing a pyrrolylheptanoic acid derivative, and 4- (4-fluorophenyl) -2-isobutyryl as an intermediate for producing a conventional chemical 1 derivative. Solves the problems of low yield and many by-products of -3-phenyl-4-oxo-N-phenyl-butyramide, and difficult reaction steps such as anhydrous conditions. The present invention was completed by producing a pyrrolylheptanoic acid derivative from the body.
本発明の目的は、以上のような前記従来の問題点に鑑みてなされたものであり、ピロリルヘプタン酸誘導体を製造するための新規合成中間体およびこれを利用したピロリルヘプタン酸誘導体の製造方法を提供することを課題とする。 The object of the present invention has been made in view of the above-mentioned conventional problems, and a novel synthetic intermediate for producing a pyrrolylheptanoic acid derivative and the production of a pyrrolylheptanoic acid derivative using the same. It is an object to provide a method.
本発明の一態様によれば、ピロリルヘプタン酸誘導体を製造するための新規合成中間体として下記化２と表示される誘導体を提供する。 According to one embodiment of the present invention, a derivative represented by the following chemical formula 2 is provided as a novel synthetic intermediate for producing a pyrrolylheptanoic acid derivative.
式中、Ｒはハロゲンに置換されている、また置換されていない炭素数１ないし６のアルキルオキシ、アリールオキシ、アリールアミノからなる群から選択される残基である。 In the formula, R is a residue selected from the group consisting of alkyloxy, aryloxy, arylamino having 1 to 6 carbon atoms which is substituted or unsubstituted by halogen.
以下、本発明についてより詳しく説明する。
本発明は、ピロリルヘプタン酸誘導体製造に有用な新規合成中間体の前記化２で表示される５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボニル誘導体に関するものである。
本発明の実施形態に係る新規合成中間体の化２の誘導体を製造する概略的な製造方法を下記式４に示した。
Hereinafter, the present invention will be described in more detail.
The present invention relates to a 5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole-3-carbonyl derivative represented by the above chemical formula 2, which is a novel synthetic intermediate useful for producing a pyrrolylheptanoic acid derivative. It is about.
A schematic production method for producing a derivative of Chemical Formula 2 of a novel synthetic intermediate according to an embodiment of the present invention is shown in Formula 4 below.
本発明に係る新規合成中間体の前記化２の誘導体は下記化３のジオン誘導体と下記化４の誘導体を酸性条件下で０ないし１３０℃の温度範囲で酢酸アンモニウムまたは、水酸化アンモニウムの中で一つまたは両方を使って製造する。 The derivative of the chemical formula 2 of the novel synthetic intermediate according to the present invention is a dione derivative of the chemical formula 3 and a derivative of the chemical formula 4 shown below in ammonium acetate or ammonium hydroxide at a temperature range of 0 to 130 ° C. under acidic conditions. Manufacture using one or both.
前記化３の誘導体は、アルキルイソブチリルアセテートから製造することができ、特に残基Ｒがフェニルアミノの場合は一般的に使われる公示の方法（米国特許公報第５，１２４，４８２号；Ｊ． Ｏｒｇ． Ｃｈｅｍ，１９７８，４３，２０８７）でアルキルイソブチリルアセテートとアニリンを反応させて製造し、、また５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボン酸からも製造することができる。 The derivative of Chemical Formula 3 can be prepared from alkylisobutyryl acetate, particularly when the residue R is phenylamino, a commonly used published method (US Pat. No. 5,124,482; J Org. Chem, 1978, 43, 2087) by reacting alkyl isobutyryl acetate with aniline, and 5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole-3 -It can also be produced from carboxylic acids.
また、本発明で反応に使われる化４の１−（４−フルオロフェニル）−２−ヒドロキシ−２−フェニルエタノン誘導体は下記化５の１−（４−フルオロフェニル）−２−フェニルエタノン誘導体から製造されるし、化４の誘導体は下記化５の誘導体を零下の温度条件でリチウムジイソプロピルアミド、カンファリルスルホニルオキサジリジンと反応させて得ることができる。下記化５の誘導体は公示の方法（国際公開特許公報第０３／４４５７号）で２−フェニルアセチルクロリドから高い収率で製造することができる。 Further, the 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone derivative of Chemical Formula 4 used in the reaction in the present invention is a 1- (4-fluorophenyl) -2-phenylethanone of Chemical Formula 5 below. The derivative of Chemical formula 4 can be obtained by reacting the following chemical formula 5 with lithium diisopropylamide and camphorylsulfonyloxaziridine under subzero temperature conditions. The derivative of the following chemical formula 5 can be produced in high yield from 2-phenylacetyl chloride by a publicly disclosed method (International Patent Publication No. 03/4457).
また、本発明は化１誘導体を製造するための新規合成中間体の化２と表示される５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボニル誘導体を利用したピロリルヘプタン酸誘導体の製造方法に関するものである。 In addition, the present invention provides a 5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole-3-carbonyl derivative represented by Chemical Formula 2 as a novel synthetic intermediate for producing the Chemical Formula 1 derivative. The present invention relates to a method for producing a pyrrolylheptanoic acid derivative used.
本発明による新規合成中間体の化２誘導体の５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボニル誘導体を利用したピロリルヘプタン酸誘導体の概略的な製造方法を下記式５に示した。 Schematic production of pyrrolylheptanoic acid derivatives using 5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole-3-carbonyl derivatives of the novel synthetic intermediates 2 according to the present invention The method is shown in Equation 5 below.
式中、Ｒはハロゲン置換される、または置換されていない炭素数１ないし６のアルキルオキシ、アリールオキシ、アリールアミノからなる群から選択される残基で、Ｘはハロゲンである。 In the formula, R is a residue selected from the group consisting of halogen-substituted or unsubstituted alkyloxy, aryloxy, arylamino having 1 to 6 carbon atoms, and X is halogen.
前記式５からわかるように、本発明は化２で表示される誘導体と下記化６の（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−ハロエチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテートを反応させた後、化１誘導体の核心中間体である化７の誘導体を脱エステル保護反応させる段階を含んで化１誘導体を製造することができる。 As can be seen from the above formula 5, the present invention relates to a derivative represented by the formula 2 and (4R-cis) -1,1-dimethylethyl-6- [2-haloethyl] -2,2-dimethyl- After reacting 1,3-dioxane-4-acetate, the chemical formula 1 derivative can be produced by including a step of subjecting the chemical formula 7 derivative, which is the core intermediate of the chemical formula 1 derivative, to a deesterification protection reaction.
本発明で化２の誘導体と化６の誘導体は、アセトニトリル、トルエン、ヘプタン、 ジメチルホルムアミドの中で選択された一種以上の溶媒下で、５０ないし１２０℃の温度範囲で触媒として１８−クラウン−６またはヨウ化カリウムを一つまたは両方選択して反応を進行する。 In the present invention, the derivatives of Chemical Formula 2 and Chemical Formula 6 are 18-crown-6 as a catalyst in a temperature range of 50 to 120 ° C. in one or more solvents selected from acetonitrile, toluene, heptane and dimethylformamide. Alternatively, one or both of potassium iodide is selected to proceed with the reaction.
本発明の一実施態様に係るピロリルヘプタン酸誘導体製造に必要な前記化６の（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−ハロエチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテートは、よく研究され商業的に供給されている中間体を利用して製造することができる。 (4R-cis) -1,1-dimethylethyl-6- [2-haloethyl] -2,2-dimethyl-1, which is necessary for the production of a pyrrolylheptanoic acid derivative according to an embodiment of the present invention, 3-Dioxane-4-acetate can be prepared utilizing well-studied and commercially supplied intermediates.
本発明では、化６誘導体は公知の方法を応用し下記式６の方法で、中間体（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−ヒドロキシエチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテートから製造した（Ｔｅｔｒａｈｅｄｒｏｎ Ａｓｙｍｍｅｔｒｙ，１９９３，４（５），７９３〜８０５）。 In the present invention, the chemical formula 6 derivative is obtained by applying a known method to the intermediate (4R-cis) -1,1-dimethylethyl-6- [2-hydroxyethyl] -2,2-dimethyl by the method of the following formula 6. Prepared from -1,3-dioxane-4-acetate (Tetrahedron Asymmetry, 1993, 4 (5), 793-805).
本発明の一実施態様によるピロリルヘプタン酸誘導体中間体および上記の段階を含む中間体の製造方法は、反応が簡単かつ反応収率が優秀で、高脂血症治療薬製造に有用に使われることができる。 The method for producing a pyrrolylheptanoic acid derivative intermediate according to an embodiment of the present invention and the intermediate comprising the above steps is useful for producing a therapeutic drug for hyperlipidemia because the reaction is simple and the reaction yield is excellent. be able to.
前記の説明のごとく、本発明の一態様は新規合成中間体の化２の５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボニル誘導体を提供することによって、これを利用する段階を含む化１誘導体の核心中間体の（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−［２−（４−フルオロフェニル）−５−（１−メチルエチル）−３−フェニル−４−［（フェニルアミノ）カルボニル］−１Ｈ−ピロール−１−イル］エチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテートの製造方法は簡単で温和な反応条件で、短時間で製造することができ、ピロリルヘプタン酸誘導体製造に有用に使われることができる。 As described above, one aspect of the present invention is to provide a novel synthetic intermediate of the 2- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole-3-carbonyl derivative of formula 2. The core intermediate of (4R-cis) -1,1-dimethylethyl-6- [2- [2- (4-fluorophenyl) -5- (1-methyl) Ethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrol-1-yl] ethyl] -2,2-dimethyl-1,3-dioxane-4-acetate is simple and mild It can be produced in a short time under various reaction conditions, and can be usefully used for producing a pyrrolylheptanoic acid derivative.
以下、本発明の実施例を通して発明の内容を詳しく説明する。下記実施例は本発明の例示のために記述されており、本発明の範囲を逸脱することなしに多様な変形、追加および代替がなされることを理解されたい。 Hereinafter, the content of the invention will be described in detail through examples of the present invention. It will be understood that the following examples are given by way of illustration of the invention and that various modifications, additions and substitutions may be made without departing from the scope of the invention.
１−（４−フルオロフェニル）−２−ヒドロキシ−２−フェニルエタノンの製造
１−（４−フルオロフェニル）−２−フェニルエタノン０．５ｇ（２．３ｍｍｏｌ）をテトラヒドロフラン５０ｍｌに溶かした後、０℃ 以下まで冷却した。リチウムジイソプロピルアミド１．８ｍｌ（３．５ｍｍｏｌ）を５ｍｌのテトラヒドロフランに溶かした後、０℃ 以下で冷却させた１−（４−フルオロフェニル）−２−フェニルエタノン溶液に滴加した。適加３０分後カンファリルスルホニルオキサジリジン１ｇ（４．７ｍｍｏｌ）を５ｍｌのテトラヒドロフランに溶かした後、０℃ 以下で冷却させた１−（４−フルオロフェニル）−２−フェニルエタノン溶液に加えた後０℃に常温で保った。３０分後飽和アンモニウムクロリド溶液で反応を終結させた後、エチルアセテートを加えて抽出した。抽出したエチルアセテートを水と飽和食塩水で洗浄した後、減圧濃縮しカラムクロマトグラフィーで精製した後白色結晶０．３８ｇ（収率７１％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ： ５．９（ｄ，１Ｈ），７．０５（ｍ，２Ｈ），７．２８〜７．４０（ｍ，５Ｈ），７．９２〜８．２０（ｍ，２Ｈ）
Ｍａｓｓ（Ｍ＋１）： ２３１
Preparation of 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone After dissolving 0.5 g (2.3 mmol) of 1- (4-fluorophenyl) -2-phenylethanone in 50 ml of tetrahydrofuran, Cooled to below 0 ° C. Lithium diisopropylamide (1.8 ml, 3.5 mmol) was dissolved in 5 ml of tetrahydrofuran and then added dropwise to a 1- (4-fluorophenyl) -2-phenylethanone solution cooled at 0 ° C. or lower. 30 minutes later, 1 g (4.7 mmol) of camphorylsulfonyloxaziridine was dissolved in 5 ml of tetrahydrofuran and added to 1- (4-fluorophenyl) -2-phenylethanone solution cooled at 0 ° C. or lower. And then kept at 0 ° C. at room temperature. After 30 minutes, the reaction was terminated with a saturated ammonium chloride solution, followed by extraction with ethyl acetate. The extracted ethyl acetate was washed with water and saturated brine, concentrated under reduced pressure and purified by column chromatography to obtain 0.38 g of white crystals (yield 71%).
1H-NMR (CDCl3) δ: 5.9 (d, 1H), 7.05 (m, 2H), 7.28-7.40 (m, 5H), 7.92-8.20 (m, 2H) )
Mass (M + 1): 231
４−メチル−３−オキソ−Ｎ−アミルベンゼンアミドの製造
エチルイソブチリルアセテート１０ｇ（６３．２ｍｍｏｌ）をトルエン３０ｍｌに溶かした後、アニリン６．５ｇ（７０ｍｍｏｌ）を加え３時間還流させた。反応終結後１Ｎ ＨＣｌ ５０ｍｌを、得られた反応香合仏に加え、撹拌して有機層を分離した。有機層を５０ｍｌエチルアセテートで薄めて蒸留水と飽和食塩水で洗浄した後、減圧濃縮して得た茶色オイルを核酸で洗浄して１０．５ｇ（収率８１％）の茶色オイルを得た。
＊１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．１４（ｄ、６Ｈ），２．７１（ｍ、１Ｈ），３．５８（ｓ、２Ｈ），７．０９（ｍ、１Ｈ），７．２４〜７．３１（ｍ、２Ｈ），７．５３（ｄ、２Ｈ），９．２０（ｂ、１Ｈ）
Ｍａｓｓ（Ｍ＋１）：２０６
Production of 4-methyl-3-oxo-N- amylbenzeneamide 10 g (63.2 mmol) of ethylisobutyryl acetate was dissolved in 30 ml of toluene, and then 6.5 g (70 mmol) of aniline was added and refluxed for 3 hours. I let you. After completion of the reaction, 50 ml of 1N HCl was added to the obtained reaction fragrant Buddha and stirred to separate the organic layer. The organic layer was diluted with 50 ml ethyl acetate and washed with distilled water and saturated brine, and then the brown oil obtained by concentration under reduced pressure was washed with nucleic acid to obtain 10.5 g (yield 81%) of brown oil.
* 1H-NMR (CDCl3) δ: 1.14 (d, 6H), 2.71 (m, 1H), 3.58 (s, 2H), 7.09 (m, 1H), 7.24-7 .31 (m, 2H), 7.53 (d, 2H), 9.20 (b, 1H)
Mass (M + 1): 206
５−（４−フルオロフェニル）−２−イソプロピル−Ｎ、４−ジフェニル−１Ｈ−ピロール−３−カルボキサミドの製造
実施例２で製造された４−メチル−３−オキソ−Ｎ−アミルベンゼンアミド誘導体３ｇ（１４．６ｍｍｏｌ）を酢酸５０ｍｌに溶かした後、実施例１で製造された１−（４−フルオロフェニル）−２−ヒドロキシ−２−フェニルエタノン誘導体３．３ｇ（１４．６ｍｍｏｌ）を得られた反応混合液に加えた。反応混合液に酢酸アンモニウム１２ｇ（１４６ｍｍｏｌ）を加え１１０〜１２０℃ 温度で２時間還流させた。反応終了後反応液を冷却し蒸留水で薄めた後エチルアセテートで３回抽出した。抽出した溶液を蒸留水と飽和食塩水で洗浄して減圧濃縮した。得られた誘導体をカラムクロマトグラフィーで精製し白色の固体表題誘導体４．７ｇ（収率８１％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．４０（ｄ、６Ｈ），４．０８（ｍ、１Ｈ），６．９０〜７．２３（ｍ、１０Ｈ），７．３８〜７．５１（ｍ、５Ｈ），８．３８（ｂ、１Ｈ），
Ｍａｓｓ（Ｍ＋１）：３９９
Preparation of 5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrole-3-carboxamide 4-Methyl-3-oxo-N-amyl prepared in Example 2 After dissolving 3 g (14.6 mmol) of the benzeneamide derivative in 50 ml of acetic acid, 3.3 g (14.6 mmol) of the 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone derivative prepared in Example 1 was used. ) Was added to the resulting reaction mixture. To the reaction mixture, 12 g (146 mmol) of ammonium acetate was added and refluxed at a temperature of 110 to 120 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled, diluted with distilled water, and extracted three times with ethyl acetate. The extracted solution was washed with distilled water and saturated brine, and concentrated under reduced pressure. The obtained derivative was purified by column chromatography to obtain 4.7 g (yield 81%) of a white solid title derivative.
1H-NMR (CDCl3) δ: 1.40 (d, 6H), 4.08 (m, 1H), 6.90 to 7.23 (m, 10H), 7.38 to 7.51 (m, 5H) ), 8.38 (b, 1H),
Mass (M + 1): 399
エチル−５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−３−カルボキシラートの製造
エチルイソブチリルアセテート１ｇ（６．３ｍｍｏｌ）を酢酸５０ｍｌに溶かした後実施例１で得た１−（４−フルオロフェニル）−２−ヒドロキシ−２−フェニルエタノン１．６ｇ（７ｍｍｏｌ）を加えた。酢酸アンモニウム４．８ｇ（６３ｍｍｏｌ）を加えて２時間還流させた。反応終了後反応液を冷却し蒸留水で薄めた後エチルアセテートで３回抽出した。抽出した溶液を蒸留水と飽和食塩水で洗浄して減圧濃縮した。得られた誘導体をカラムクロマトグラフィーで精製して白色の固体表題誘導体１．６ｇ（収率７１％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．０１（ｔ、３Ｈ），１．３８（ｄ、６Ｈ），３．８５（ｍ、１Ｈ），４．０８（ｑ、２Ｈ），６．９０〜６．９８（ｍ、２Ｈ），７．０３〜７．１２（ｍ、２Ｈ），７．２１〜７．３５（ｍ、５Ｈ）
Ｍａｓｓ（Ｍ＋１）：３５２
Preparation of ethyl-5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-3-carboxylate 1 g (6.3 mmol) of ethylisobutyrylacetate was dissolved in 50 ml of acetic acid. 1.6 g (7 mmol) of 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone obtained in Example 1 was added. 4.8 g (63 mmol) of ammonium acetate was added and refluxed for 2 hours. After completion of the reaction, the reaction solution was cooled, diluted with distilled water, and extracted three times with ethyl acetate. The extracted solution was washed with distilled water and saturated brine, and concentrated under reduced pressure. The obtained derivative was purified by column chromatography to obtain 1.6 g (yield 71%) of a white solid title derivative.
1H-NMR (CDCl3) δ: 1.01 (t, 3H), 1.38 (d, 6H), 3.85 (m, 1H), 4.08 (q, 2H), 6.90-6. 98 (m, 2H), 7.03 to 7.12 (m, 2H), 7.21 to 7.35 (m, 5H)
Mass (M + 1): 352
５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボン酸の製造
実施例４で得たエチル５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボキシラート１ｇ（２．８ｍｍｏｌ）をメタノール２０ｍｌに溶かした後、水酸化ナトリウム１．２ｇ（２８ｍｍｏｌ）水溶液を加え２４時間還流させた。反応終了後反応液を冷却し１Ｎ ＨＣｌで中和させた後エチルアセテートで３回抽出した。抽出した溶液を蒸留水と飽和食塩水で洗浄して減圧濃縮した。得られた誘導体をカラムクロマトグラフィーで精製して白色の固体表題誘導体０．５ｇ（収率５５％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．４１（ｄ、６Ｈ），３．９０（ｍ、１Ｈ），６．９１〜７．１２（ｍ、４Ｈ），７．２０〜７．３５（ｍ、５Ｈ）
Ｍａｓｓ（Ｍ＋１）：３２４
Preparation of 5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid Ethyl 5- (4-fluorophenyl) -2-isopropyl obtained in Example 4 After dissolving 1 g (2.8 mmol) of -4-phenyl-1H-pyrrole-3-carboxylate in 20 ml of methanol, an aqueous solution of 1.2 g (28 mmol) of sodium hydroxide was added and refluxed for 24 hours. After completion of the reaction, the reaction solution was cooled, neutralized with 1N HCl, and extracted three times with ethyl acetate. The extracted solution was washed with distilled water and saturated brine, and concentrated under reduced pressure. The obtained derivative was purified by column chromatography to obtain 0.5 g (yield 55%) of a white solid title derivative.
1H-NMR (CDCl3) δ: 1.41 (d, 6H), 3.90 (m, 1H), 6.91 to 7.12 (m, 4H), 7.20 to 7.35 (m, 5H) )
Mass (M + 1): 324
５−（４−フルオロフェニル）−２−イソプロピル−Ｎ、４−ジフェニル−１Ｈ−ピロール−３−カルボキサミドの製造
実施例５で得た５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボン酸０．５ｇ（１．５ｍｍｏｌ）をテトラヒドロフラン１０ｍｌに溶かした後０℃で冷却した。トリエチルアミン０．６５ｍｌ（４．６ｍｍｏｌ）を加えた後クロロリン酸ジエチル０．２７４ｍｌ（３ｍｍｏｌ）を徐々に滴加した。３０分後アニリン０．２２ｇ（２．３ｍｍｏｌ）を加えて常温で４時間撹拌した。反応終了後有機層を５０ｍｌエチルアセテートで薄めて蒸留水と飽和食塩水で洗浄した後、減圧濃縮して誘導体を得た。得られた誘導体をカラムクロマトグラフィーで精製して白色の固体表題誘導体０．５２ｇ（収率８５％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．４０（ｄ、６Ｈ），４．０８（ｍ、１Ｈ），６．９０〜７．２３（ｍ、１０Ｈ），７．３８〜７．５１（ｍ、５Ｈ），８．３８（ｂ、１Ｈ）
Ｍａｓｓ（Ｍ＋１）：３９９
Preparation of 5- (4-fluorophenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrole-3-carboxamide 5- (4-Fluorophenyl) -2-isopropyl obtained in Example 5 -4-Phenyl-1H-pyrrole-3-carboxylic acid 0.5 g (1.5 mmol) was dissolved in 10 ml of tetrahydrofuran and then cooled at 0 ° C. After adding 0.65 ml (4.6 mmol) of triethylamine, 0.274 ml (3 mmol) of diethyl chlorophosphate was gradually added dropwise. After 30 minutes, 0.22 g (2.3 mmol) of aniline was added and stirred at room temperature for 4 hours. After completion of the reaction, the organic layer was diluted with 50 ml ethyl acetate, washed with distilled water and saturated brine, and then concentrated under reduced pressure to obtain a derivative. The obtained derivative was purified by column chromatography to obtain 0.52 g (yield 85%) of a white solid title derivative.
1H-NMR (CDCl3) δ: 1.40 (d, 6H), 4.08 (m, 1H), 6.90 to 7.23 (m, 10H), 7.38 to 7.51 (m, 5H) ), 8.38 (b, 1H)
Mass (M + 1): 399
（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−ヨードエチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテートの製造
（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−ヒドロキシエチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテート誘導体５ｇ（１８ｍｍｏｌ）をジメチルホルムアミド１００ｍｌに溶かした後トリフェニルホスフィン５．３ｇ（２０ｍｍｏｌ）を加えて撹拌した。ジメチルホルムアミドに溶かしたヨウ素５．２ｇ （２０ｍｍｏｌ）を加えた後常温で６時間撹拌した。反応終了後、炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。減圧濃縮してカラムクロマトグラフィーで精製して無色のオイル誘導体０．９８ｇ（収率７０％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．３７（ｓ、３Ｈ），１．４２（ｓ、９Ｈ），１．４９（ｓ、３Ｈ），１．０５〜１．５８（ｍ、２Ｈ），１．８５（ｍ、２Ｈ），２．２３〜２．４８（ｍ、２Ｈ），３．２６（ｍ、２Ｈ），３．９７（ｍ、１Ｈ），４．２５（ｍ、１Ｈ）
Ｍａｓｓ（Ｍ＋Ｎａ）：４０７
Preparation of (4R-cis) -1,1-dimethylethyl-6- [2-iodoethyl] -2,2-dimethyl-1,3-dioxane-4-acetate (4R-cis) -1,1-dimethylethyl After dissolving 5 g (18 mmol) of -6- [2-hydroxyethyl] -2,2-dimethyl-1,3-dioxane-4-acetate derivative in 100 ml of dimethylformamide, 5.3 g (20 mmol) of triphenylphosphine was added. Stir. After adding 5.2 g (20 mmol) of iodine dissolved in dimethylformamide, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and saturated brine. Concentration under reduced pressure and purification by column chromatography gave 0.98 g of colorless oil derivative (yield 70%).
1H-NMR (CDCl3) δ: 1.37 (s, 3H), 1.42 (s, 9H), 1.49 (s, 3H), 1.05-1.58 (m, 2H), 1. 85 (m, 2H), 2.23 to 2.48 (m, 2H), 3.26 (m, 2H), 3.97 (m, 1H), 4.25 (m, 1H)
Mass (M + Na): 407
（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−［２−（４−フルオロフェニル）−５−（１−メチルエチル）−３−フェニル−４−［（フェニルアミノ）カルボニル］−１Ｈ−ピロール−１−イル］エチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテートの製造
実施例３または、実施例６で製造した５−（４−フルオロフェニル）−２−イソプロピル−Ｎ、４−ジフェニル−１Ｈ−ピロール−３−カルボキサミド１ｇ（２．５ｍｍｏｌ）をアセトニトリル１０ｍｌに溶かした後炭酸カリウム（Ｋ２ＣＯ３） ０．６９ｇ（５ｍｍｏｌ），１８−クラウン−６（１８−ｃｒｏｗｎ−６） ０．３３ｇ（０．１２ｍｍｏｌ）を加えて撹拌した。実施例７で製造した（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−ヨードエチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテート１．２ｇ（３ｍｍｏｌ）を加えた後、還流させて一晩撹拌した。反応終結後、室温まで冷却した後、飽和クエン酸水溶液、炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。減圧濃縮して得た茶色オイルをカラムクロマトグラフィーで精製し、白色固体の表題誘導体１．１ｇ（収率６５％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．３０（ｓ、３Ｈ），１．３５（ｓ、３Ｈ），１．４３（ｓ、９Ｈ），１．５３（ｄ、６Ｈ），１．０５〜１．７０（ｍ、４Ｈ），２．２０〜２．４４（ｍ、２Ｈ），３．５７（ｍ、１Ｈ），３．６８（ｍ、１Ｈ），３．８５（ｍ、１Ｈ），４．０７（ｍ、１Ｈ），４．１５（ｍ、１Ｈ），６．８０〜７．３０（ｍ、１４Ｈ）
Ｍａｓｓ（Ｍ＋Ｎａ）：６７７
(4R-cis) -1,1-dimethylethyl-6- [2- [2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrol-1-yl] ethyl] -2,2-dimethyl-1,3-dioxane-4-acetate 5- (4-fluoro) prepared in Example 3 or Example 6 Phenyl) -2-isopropyl-N, 4-diphenyl-1H-pyrrole-3-carboxamide 1 g (2.5 mmol) was dissolved in 10 ml of acetonitrile, and then potassium carbonate (K 2 CO 3) 0.69 g (5 mmol), 18-crown-6 (18-crown-6) 0.33 g (0.12 mmol) was added and stirred. 1.2 g (3 mmol) of (4R-cis) -1,1-dimethylethyl-6- [2-iodoethyl] -2,2-dimethyl-1,3-dioxane-4-acetate prepared in Example 7 was added. Then, the mixture was refluxed and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and then washed with a saturated aqueous citric acid solution, an aqueous sodium bicarbonate solution, and a saturated saline solution. The brown oil obtained by concentration under reduced pressure was purified by column chromatography to obtain 1.1 g (yield 65%) of the title derivative as a white solid.
1H-NMR (CDCl3) δ: 1.30 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.53 (d, 6H), 1.05-1. 70 (m, 4H), 2.20 to 2.44 (m, 2H), 3.57 (m, 1H), 3.68 (m, 1H), 3.85 (m, 1H), 4.07 (M, 1H), 4.15 (m, 1H), 6.80-7.30 (m, 14H)
Mass (M + Na): 677
エチル１−（２−（（４Ｒ、６Ｒ）−６−（２−ｔ−ブトキシ−２−オキソ−エチル）−２，２−ジメチル−１，３−ジオキサン−４−イル）エチル）−５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボキシラートの製造
エチル５−（４−フルオロフェニル）−２−イソプロピル−４−フェニル−１Ｈ−ピロール−３−カルボキシラート誘導体０．１ｇ（０．２８ｍｍｏｌ）をアセトニトリル５ｍｌに溶かした後、炭酸カリウム（Ｋ２ＣＯ３） ０．０７９ｇ（０．５７ｍｍｏｌ）および１８−クラウン−６（１８−ｃｒｏｗｎ−６） ０．０３７ｇ（０．１４ｍｍｏｌ）を加えて撹拌した。実施例７で製造した（４Ｒ−シス）−１，１−ジメチルエチル−６−［２−ヨードエチル］−２，２−ジメチル−１，３−ジオキサン−４−アセテート０．１３ｇ（０．３ｍｍｏｌ）を加えた後、還流させて徹夜で撹拌した。反応終結後、室温で冷却させた後、飽和クエン酸水溶液、炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。減圧濃縮して得たオイルをカラムクロマトグラフィーで精製し、白色固体の表題誘導体０．１１ｇ（収率６２％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：０．９８（ｔ、３Ｈ），１．３０（ｓ、３Ｈ），１．３５（ｓ、３Ｈ），１．４３（ｓ、９Ｈ），１．５３（ｄ、６Ｈ），１．０〜１．７０（ｍ、４Ｈ），２．２０〜２．４４（ｍ、２Ｈ），３．５７（ｍ、１Ｈ），３．６８（ｍ、１Ｈ），３．８５（ｍ、１Ｈ），４．０５（ｍ、３Ｈ），４．１５（ｍ、１Ｈ），６．９１〜７．１５（ｍ、９Ｈ）
Ｍａｓｓ（Ｍ＋Ｎａ）：６３０
Ethyl 1- (2-((4R, 6R) -6- (2-tert-butoxy-2-oxo-ethyl) -2,2-dimethyl-1,3-dioxan-4-yl) ethyl) -5 Preparation of (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylate Ethyl 5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrole After dissolving 0.1 g (0.28 mmol) of the 3-carboxylate derivative in 5 ml of acetonitrile, 0.079 g (0.57 mmol) of potassium carbonate (K2CO3) and 18-crown-6 (18-crown-6) 0. 037 g (0.14 mmol) was added and stirred. 0.13 g (0.3 mmol) of (4R-cis) -1,1-dimethylethyl-6- [2-iodoethyl] -2,2-dimethyl-1,3-dioxane-4-acetate prepared in Example 7 The mixture was then refluxed and stirred overnight. After completion of the reaction, the reaction solution was cooled at room temperature, and then washed with a saturated citric acid aqueous solution, a sodium hydrogen carbonate aqueous solution, and a saturated saline solution. The oil obtained by concentration under reduced pressure was purified by column chromatography to obtain 0.11 g (yield 62%) of the title derivative as a white solid.
1H-NMR (CDCl3) δ: 0.98 (t, 3H), 1.30 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.53 (d, 6H), 1.0 to 1.70 (m, 4H), 2.20 to 2.44 (m, 2H), 3.57 (m, 1H), 3.68 (m, 1H), 3.85 (M, 1H), 4.05 (m, 3H), 4.15 (m, 1H), 6.91 to 7.15 (m, 9H)
Mass (M + Na): 630
Claims (10)
（式中、Ｒはハロゲン置換される、または置換されていない炭素数１ないし６のアルキルオキシ、アリールオキシ、アリールアミノからなる群から選択される残基である。） A carbonyl derivative represented by the following chemical formula 2.
(In the formula, R is a residue selected from the group consisting of alkyloxy, aryloxy and arylamino having 1 to 6 carbon atoms which are substituted or unsubstituted by halogen.)
（式中、Ｒはハロゲン置換される、または置換されていない炭素数１ないし６のアルキルオキシ、アリールオキシ、アリールアミノからなる群から選択される残基である。） A method for producing a carbonyl derivative comprising reacting a derivative represented by the following chemical formula 3 and a derivative represented by the following chemical formula 4,
(In the formula, R is a residue selected from the group consisting of alkyloxy, aryloxy and arylamino having 1 to 6 carbon atoms which are substituted or unsubstituted by halogen.)
（式中、Ｒはハロゲン置換される、または置換されていない炭素数１ないし６のアルキルオキシ、アリールオキシ、アリールアミノからなる群から選択される残基であり、Ｘはハロゲンである。） A method for producing a derivative of the following chemical formula 7, wherein a derivative of the chemical formula 2 below is reacted with a derivative of the chemical formula 6 below.
(In the formula, R is a residue selected from the group consisting of alkyloxy, aryloxy, arylamino having 1 to 6 carbon atoms which are substituted or unsubstituted by halogen, and X is halogen.)
（式中、Ｒはハロゲン置換される、または置換されていない炭素数１ないし６のアルキルオキシ、アリールオキシ、アリールアミノからなる群から選択される残基である。） 7. The method for producing a chemical formula 7 derivative according to claim 6, wherein a chemical formula 2 derivative is reacted with a chemical formula 2 derivative to produce a chemical formula 2 derivative.
(In the formula, R is a residue selected from the group consisting of alkyloxy, aryloxy and arylamino having 1 to 6 carbon atoms which are substituted or unsubstituted by halogen.)
（式中、残基Ｘはハロゲンである。） A derivative represented by the following chemical formula 6.
(In the formula, residue X is halogen.)
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