JP2971091B2 - 2'-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester New method for producing methyl ester - Google Patents
2'-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester New method for producing methyl esterInfo
- Publication number
- JP2971091B2 JP2971091B2 JP7278490A JP7278490A JP2971091B2 JP 2971091 B2 JP2971091 B2 JP 2971091B2 JP 7278490 A JP7278490 A JP 7278490A JP 7278490 A JP7278490 A JP 7278490A JP 2971091 B2 JP2971091 B2 JP 2971091B2
- Authority
- JP
- Japan
- Prior art keywords
- nitrophenyl
- dihydropyridine
- methylamino
- benzyl
- dimethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は下記の式： で表わされる1,4−ジヒドロピリジン誘導体の製造法に
関する。この化合物（以下、ニカルジピンと略記する）
は降圧剤および血管拡張剤として有用な化合物である。DETAILED DESCRIPTION OF THE INVENTION (Industrial application field) The present invention provides the following formula: And a method for producing a 1,4-dihydropyridine derivative represented by the formula: This compound (hereinafter abbreviated as nicardipine)
Are compounds useful as antihypertensives and vasodilators.
（従来の技術および発明が解決しようとする課題） ニカルジピンは上記式からも分かるように、２つのカ
ルボン酸エステルが異なるアルコキシ基であるために、
その合成法には工夫が必要である。例えば、アセト酢酸
エステルとｍ−ニトロベンズアルデヒドとを反応させ、
得られる２−（ｍ−ニトロベンジリデン）アセト酢酸エ
ステルと３−アミノクロトン酸エステルとを縮合させる
方法（特開昭55−45075号公報、特開昭56−6410号公
報）が知られている。その他の方法は、さらに多工程を
要するなどのため実用上問題があった。(Problems to be Solved by the Prior Art and the Invention) As can be seen from the above formula, nicardipine has two different carboxylate esters having different alkoxy groups.
The synthesis method requires some contrivance. For example, reacting acetoacetic ester with m-nitrobenzaldehyde,
A method of condensing the obtained 2- (m-nitrobenzylidene) acetoacetic acid ester with a 3-aminocrotonic acid ester (JP-A-55-45075, JP-A-56-6410) is known. Other methods have practical problems because they require more steps.
（課題を解決するための手段） 従って、本発明はニカルジピンを簡易に、かつ効率よ
く製造する方法を提供するものである。(Means for Solving the Problems) Accordingly, the present invention provides a method for easily and efficiently producing nicardipine.
本発明の製造方法の一例を以下のスキームに示す。 One example of the production method of the present invention is shown in the following scheme.
上記スキームにおける反応の一般的条件は以下の通り
である。 The general conditions of the reaction in the above scheme are as follows.
工程（ａ）:m−ニトロベンズアルデヒド＋（Ｉ）→（I
I） 温度（時間）:0−100℃，室温（２時間） 溶媒：テトラヒドロフラン，エーテル等 工程（ｂ）：（II）＋（III）→（IV） 温度（時間）:50−120℃，ピリジン還流温度（１時
間） 溶媒：ピリジン，ピコリン等。Step (a): m-nitrobenzaldehyde + (I) → (I
I) Temperature (time): 0-100 ° C, room temperature (2 hours) Solvent: tetrahydrofuran, ether, etc. Step (b): (II) + (III) → (IV) Temperature (time): 50-120 ° C, pyridine Reflux temperature (1 hour) Solvent: pyridine, picoline, etc.
工程（ｃ）：（IV）＋（Ｖ）→ニカルジピン 温度:0−100℃,60℃（５時間） 溶媒：エチルアルコール，メチルアルコール，イソプ
ロピルアルコール等。Step (c): (IV) + (V) → Nicardipine Temperature: 0-100 ° C., 60 ° C. (5 hours) Solvent: ethyl alcohol, methyl alcohol, isopropyl alcohol, etc.
試薬：テトラキストリフェニルホスフィンパラジウム
＋CO （上記条件中、下線は好ましい条件を示す） 以下に本発明を実施例により、さらに具体的に説明す
るが、本発明は本実施例に限定されることはない。Reagent: tetrakistriphenylphosphine palladium + CO (in the above conditions, underlines indicate preferable conditions) The present invention will be described more specifically with reference to examples below, but the present invention is not limited to the examples. .
（実施例） 工程（ａ） ｍ−ニトロベンズアルデヒド（1.51g,10mM）を無水テ
トラヒドロフラン（10ml）に溶解し、ブロモアセトン
（2.06g、15mM、1.5当量）とテトラ−ｔ−ブチルオキシ
ジルコニウム（7.66g、20mM、２モル当量）を室温下加
え、さらに同条件下２時間撹拌した。塩化アンモニウム
水溶液で反応を停止させ、エーテル抽出した。溶媒を留
去後シリカゲルカラムクロマトグラフィーにて精製し、
目的物を1.62g（60％）の収率で得た。(Example) Step (a) m-Nitrobenzaldehyde (1.51 g, 10 mM) was dissolved in anhydrous tetrahydrofuran (10 ml), bromoacetone (2.06 g, 15 mM, 1.5 equivalents) and tetra-t-butyloxyzirconium (7.66 g) , 20 mM, 2 molar equivalents) at room temperature and further stirred for 2 hours under the same conditions. The reaction was quenched with aqueous ammonium chloride and extracted with ether. After evaporating the solvent, the residue was purified by silica gel column chromatography,
The desired product was obtained in a yield of 1.62 g (60%).
IR（赤外吸収）1660cm-1 工程（ｂ） メチル−２−ｍ−ニトロフェニル−１−ブロモビニル
ケトン（2.70g,10mM）をピリジン（10ml）に溶解し、３
−アミノクロトン酸メチルエステル（1.15g,10mM）を加
え１時間加熱した。反応終了後ピリジンを減圧下留去
し、残査をシリカゲルカラムクロマトグラフィーで精製
し目的物を（1.82g,50％）得た。IR (infrared absorption) 1660 cm -1 Step (b) Methyl-2-m-nitrophenyl-1-bromovinylketone (2.70 g, 10 mM) was dissolved in pyridine (10 ml), and
-Aminocrotonic acid methyl ester (1.15 g, 10 mM) was added and the mixture was heated for 1 hour. After completion of the reaction, pyridine was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product (1.82 g, 50%).
NMR δ 3.80（3H,s,COOCH3） 工程（ｃ） 出発原料（3.63g,10mM）をDMF（ジメチルホルムアミ
ド,10ml）に溶解し、溶存酸素を除去した。これにテト
ラキストリフェニルホスフィンパラジウム（1.15g,1m
M）及び（Ｎ−メチル−Ｎ−ベンジルアミノ）エチルア
ルコール（1.65g,10mM）を加え、60℃の温度、一酸化炭
素気流下５時間撹拌した。反応終了後、DMFを減圧下留
去し、目的物をシリカゲルカラムクロマトグラフィーに
て精製して（2.40g,50％）得た。本生成物の各種スペク
トルデータは特開昭55−45075号公報に記載されたニカ
ルジピンのスペクトルデータと完全に一致した。NMR δ 3.80 (3H, s, COOCH 3 ) Step (c) The starting material (3.63 g, 10 mM) was dissolved in DMF (dimethylformamide, 10 ml) to remove dissolved oxygen. Add tetrakistriphenylphosphine palladium (1.15g, 1m
M) and (N-methyl-N-benzylamino) ethyl alcohol (1.65 g, 10 mM) were added, and the mixture was stirred at a temperature of 60 ° C. under a stream of carbon monoxide for 5 hours. After completion of the reaction, DMF was distilled off under reduced pressure, and the target product was purified by silica gel column chromatography to obtain (2.40 g, 50%). Various spectrum data of this product completely coincided with the spectrum data of nicardipine described in JP-A-55-45075.
（発明の効果） 本発明の方法により、ニカルジピンを簡易かつ効率よ
く製造することができ、かつ工程数が少ないので大量に
反応を行う場合にも極めて有利である。(Effect of the Invention) According to the method of the present invention, nicardipine can be easily and efficiently produced, and the number of steps is small.
───────────────────────────────────────────────────── フロントページの続き (54)【発明の名称】 ２’６―ジメチル―４―（ｍ―ニトロフェニル）―１，４―ジヒドロピリジン―３，５―ジカル ボン酸 ２―（Ｎ―ベンジル―Ｎ―メチルアミノ）エチルエステル メチルエステルの新規製造 法 ──────────────────────────────────────────────────続 き Continued on the front page (54) [Title of the Invention] 2'6-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 2- (N-benzyl-) N-methylamino) ethyl ester New method for producing methyl ester
Claims (1)
般式（Ｉ）で示されるハロゲン化アセトン XCH2COCH3 ……（Ｉ） （式中、Ｘは臭素若しくはヨウ素を示す）をテトラｔ−
ブチルオキシジルコニウムの存在下で反応させて、一般
式（II）で示される化合物を得る工程 （式中、Ｘは臭素若しくはヨウ素を示す） （ｂ） 上記一般式（II）で示される化合物を下記の式
（III）で示される化合物 と反応させて下記の式（IV）で示される化合物を得る工
程 及び、 （ｃ） 上記式（IV）で示される化合物を下記の式
（Ｖ）で示される化合物 とPd（０）及び一酸化炭素の存在下で反応する工程 を含む2,6−ジメチル−４−（ｍ−ニトロフェニル）−
1,4−ジヒドロピリジン−3,5−ジカルボン酸 ２−（Ｎ
−ベンジル−Ｎ−メチルアミノ）エチルエステル メチ
ルエステルの製造法。(A) m-nitrobenzaldehyde and halogenated acetone XCH 2 COCH 3 (I) (I) wherein X represents bromine or iodine are represented by tetra-t-
Reacting in the presence of butyloxyzirconium to obtain a compound of general formula (II) (Wherein, X represents bromine or iodine) (b) A compound represented by the following formula (III) is replaced with a compound represented by the following formula (III) To obtain a compound represented by the following formula (IV) And (c) converting the compound represented by the above formula (IV) into a compound represented by the following formula (V) Reacting with Pd (0) and carbon monoxide in the presence of 2,6-dimethyl-4- (m-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid 2- (N
-Benzyl-N-methylamino) ethyl ester A method for producing methyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7278490A JP2971091B2 (en) | 1990-03-22 | 1990-03-22 | 2'-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester New method for producing methyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7278490A JP2971091B2 (en) | 1990-03-22 | 1990-03-22 | 2'-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester New method for producing methyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03275670A JPH03275670A (en) | 1991-12-06 |
| JP2971091B2 true JP2971091B2 (en) | 1999-11-02 |
Family
ID=13499363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7278490A Expired - Fee Related JP2971091B2 (en) | 1990-03-22 | 1990-03-22 | 2'-Dimethyl-4- (m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester New method for producing methyl ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2971091B2 (en) |
-
1990
- 1990-03-22 JP JP7278490A patent/JP2971091B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH03275670A (en) | 1991-12-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |