JP3053861B2 - 1,4-dihydropyridine derivative - Google Patents
1,4-dihydropyridine derivativeInfo
- Publication number
- JP3053861B2 JP3053861B2 JP2334655A JP33465590A JP3053861B2 JP 3053861 B2 JP3053861 B2 JP 3053861B2 JP 2334655 A JP2334655 A JP 2334655A JP 33465590 A JP33465590 A JP 33465590A JP 3053861 B2 JP3053861 B2 JP 3053861B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- suspension
- solution
- crystallized
- seed crystal
- 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 - Lifetime
Links
Description
【発明の詳細な説明】 産業上の利用分野 本発明は融点が170〜171℃である2,6−ジメチル−４
−（３−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−３−（１−ベンジル−３−ピペリ
ジル）エステル−５−メチルエステルの塩酸塩（以下、
化合物Ａと称す）及びその製法並びに化合物Ａから融点
が198〜199℃である2,6−ジメチル−４−（３−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−３−（１−ベンジル−３−ピペリジル）エステル−
５−メチルエステルの塩酸塩（以下、化合物Ｂと称す）
の製造法に関する。化合物Ａ及びＢは血圧降下剤、血管
拡張剤等の循環器官用薬として有用な化合物である。The present invention relates to 2,6-dimethyl-4 having a melting point of 170-171 ° C.
-(3-nitrophenyl) -1,4-dihydropyridine-
Hydrochloride of 3,5-dicarboxylic acid-3- (1-benzyl-3-piperidyl) ester-5-methyl ester (hereinafter, referred to as “hydrochloride”)
Compound A), its production method and 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- having a melting point of 198 to 199 ° C. (1-benzyl-3-piperidyl) ester-
5-methyl ester hydrochloride (hereinafter, referred to as compound B)
A method for producing the same. Compounds A and B are compounds useful as drugs for circulatory organs such as antihypertensives and vasodilators.
従来の技術 化合物Ｂ及びその製法、例えば2,6−ジメチル−４−
（３−ニトロフェニル）−1,4−ジヒドロピリジン−3,5
−ジカルボン酸モノメチルエステルと１−ベンジル−３
−ヒドロキシピペリジンとの反応による方法、３−ニト
ロベンジリデンアセト酢酸メチルと３−アミノクロトン
酸−１−ベンジル−３−ピペリジルエステルとの反応に
よる方法等が知られている（特開昭59−70667号公報、
同59−137461号公報）。PRIOR ART Compound B and its preparation method, for example, 2,6-dimethyl-4-
(3-nitrophenyl) -1,4-dihydropyridine-3,5
Dicarboxylic acid monomethyl ester and 1-benzyl-3
And a method by reaction between methyl 3-nitrobenzylideneacetoacetate and 3-aminocrotonic acid-1-benzyl-3-piperidyl ester, and the like (see JP-A-59-70667). Gazette,
No. 59-137461).
発明が解決しようとする課題 従来の方法では高純度の化合物Ｂを得るには繰返し再
結晶操作が必要である。Problems to be Solved by the Invention According to the conventional method, repeated recrystallization operations are required to obtain high-purity Compound B.
化合物Ｂを簡単に収率よく高純度で製造する方法が求
められている。There is a need for a method for easily producing compound B with high yield and high purity.
課題を解決するための手段 本発明は化合物Ａ及びその製法並びに化合物Ａの溶液
又は懸濁液に種晶として化合物Ｂの結晶を添加して化合
物Ｂを晶出させることを特徴とする高純度の化合物Ｂの
製造法に関する。Means for Solving the Problems The present invention provides a compound A and a process for producing the same, and a compound B having a high purity characterized by adding a compound B crystal as a seed crystal to a solution or suspension of the compound A to crystallize the compound B. The present invention relates to a method for producing compound B.
化合物Ａの理化学的性質は以下の通りである。 The physicochemical properties of Compound A are as follows.
融点:170〜171℃ IR（KBr,cm-1）:1695,1520,1345 反応によって得られる化合物Ｂの粗精製物から高純度
（99.6％以上）の化合物Ｂを得るには化合物Ｂをまず化
合物Ａに変換し、次いで本発明方法を適用することによ
って高純度の化合物Ｂを得ることができる。Melting point: 170-171 ° C IR (KBr, cm -1 ): 1695, 1520, 1345 To obtain a highly purified (more than 99.6%) compound B from a crude product of compound B obtained by the reaction, compound B must first be compounded. By converting into A and then applying the method of the present invention, highly pure compound B can be obtained.
これを具体的に実施するには化合物Ｂの粗精製物を適
当な溶媒、例えば炭素数１〜４のアルコール、好ましく
はエタノールに−30〜150℃で溶解又は懸濁させて50％
（W/W）以下、好ましくは10〜40％（W/W）の濃度の溶液
又は懸濁液を得る。In order to specifically carry out this process, the crude product of Compound B is dissolved or suspended in a suitable solvent, for example, an alcohol having 1 to 4 carbon atoms, preferably ethanol at -30 to 150 ° C to obtain 50%
A solution or suspension having a concentration of (W / W) or less, preferably 10 to 40% (W / W) is obtained.
次いで、これに化合物Ａの種晶を化合物Ｂに対して0.
01〜１％（W/W）加えて化合物Ａを晶出させ分離する。Next, the compound A was seeded with the seed crystal at a concentration of 0.
Compound A is crystallized by adding 01-1% (W / W) and separated.
化合物Ｂを製造するには先ず、化合物Ａを溶媒に−30
〜100℃で、50％（W/W）以下、好ましくは10〜30％（W/
W）の濃度に溶解又は懸濁させる。溶媒としてはクロロ
ホルム、アセトン、エタノール、メタノール、エーテル
等が単独又は組み合わせて用いられ、好ましくはエタノ
ールとアセトンの混合液が用いられる。To produce compound B, first, compound A is added to a solvent of -30.
At ~ 100 ° C, 50% (W / W) or less, preferably 10-30% (W / W)
Dissolve or suspend to a concentration of W). As the solvent, chloroform, acetone, ethanol, methanol, ether or the like is used alone or in combination, and a mixed solution of ethanol and acetone is preferably used.
前記で得られた化合物Ａの溶液又は懸濁液に化合物Ｂ
の種晶を化合物Ａに対して0.01〜１％（W/W）加えて化
合物Ｂを晶出させ分離する。Compound B is added to the solution or suspension of Compound A obtained above.
The compound B is crystallized by adding a seed crystal of 0.01 to 1% (W / W) with respect to the compound A, and separated.
以下に実施例及び参考例を示す。 Examples and reference examples are shown below.
実施例１ 参考例で得られた化合物Ｂの粗結晶20.0gをエタノー
ル60mlで加熱還流下溶解後、60℃まで冷却した。同温度
で化合物Ａの結晶0.05gを接種し、徐冷後、45℃で１時
間攪拌した。ついで、氷冷下に冷却し、析出する結晶を
取することにより、化合物Ａの針状結晶19.2g（収率9
6.0％）を得た。該結晶の液体クロマトグラフィー分析
による純度は99.8％であった。Example 1 20.0 g of the crude crystals of the compound B obtained in the reference example were dissolved in 60 ml of ethanol while heating under reflux, and then cooled to 60 ° C. At the same temperature, 0.05 g of Compound A crystals were inoculated, cooled slowly, and stirred at 45 ° C. for 1 hour. Then, the mixture was cooled under ice-cooling, and the precipitated crystals were collected to obtain 19.2 g of compound A needle-like crystals (yield 9%).
6.0%). The purity of the crystals by liquid chromatography was 99.8%.
融点:170〜171℃ IR（KBr,cm-1）:1695,1520,1345 実施例２ 参考例で得られた化合物Ｂの粗結晶20.0gをエタノー
ル80mlに懸濁した後、該懸濁液に室温下、化合物Ａの結
晶0.05gを添加した。ついで、室温下で３時間激しく攪
拌後、取することにより化合物Ａの針状結晶18.5g
（収率92.5％）を得た。該結晶の液体クロマトグラフィ
ー分析による純度は99.5％であった。Melting point: 170-171 ° C. IR (KBr, cm −1 ): 1695, 1520, 1345 Example 2 20.0 g of the crude crystals of the compound B obtained in the reference example were suspended in 80 ml of ethanol and then added to the suspension. At room temperature, 0.05 g of Compound A crystals was added. Then, after vigorously stirring at room temperature for 3 hours, the mixture was collected to obtain 18.5 g of compound A needle crystals.
(92.5% yield). The purity of the crystals by liquid chromatography was 99.5%.
融点:170〜171℃ IR（KBr,cm-1）:1695,1520,1345 実施例３ 実施例１で得られた化合物Ａ 15.0gをアセトンとエ
タノールの混合液（3:1v/v）90mlで加熱還流下溶解し
た。ついで、50℃に冷却した後、化合物Ｂの結晶0.03g
を接種し、50℃で１時間攪拌した。氷冷下に冷却し析出
する結晶を取することにより化合物Ｂの結晶13.7g
（収率91.3％）を得た。該結晶の液体クロマトグラフィ
ー分析による純度は99.9％であった。Melting point: 170-171 ° C. IR (KBr, cm −1 ): 1695, 1520, 1345 Example 3 15.0 g of the compound A obtained in Example 1 was mixed with 90 ml of a mixture of acetone and ethanol (3: 1 v / v). It melt | dissolved under heating reflux. Then, after cooling to 50 ° C., 0.03 g of compound B crystals
And stirred at 50 ° C. for 1 hour. By cooling under ice-cooling and collecting the precipitated crystals, 13.7 g of Compound B crystals were obtained.
(91.3% yield). The purity of the crystals by liquid chromatography was 99.9%.
融点:198〜199℃ 参考例 ３−ニトロベンジリデンアセト酢酸メチル61.5gと３
−アミノクロトン酸−１−ベンジル−３−ピペリジルエ
ステル塩酸塩88.2gとを600mlのメタノール中で10時間還
流攪拌した後、反応液を減圧濃縮した。該濃縮物をクロ
ロホルム600mlに溶解した後、１規定塩酸600mlを加え激
しく攪拌した。クロロホルム層を採取し、15％食塩水60
0mlで洗浄後、クロロホルム層を濃縮した。この濃縮物
にエタノールとアセトンの混合液（14:86v/v）900mlを
加え攪拌すると黄色の化合物Ｂの粗結晶43.2g（収率32.
0％）が得られた。Melting point: 198-199 ° C. Reference Example 61.5 g of methyl 3-nitrobenzylideneacetoacetate and 3
After 88.2 g of -aminocrotonic acid-1-benzyl-3-piperidyl ester hydrochloride was stirred under reflux in 600 ml of methanol for 10 hours, the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in chloroform (600 ml), and 1N hydrochloric acid (600 ml) was added, followed by vigorous stirring. Collect the chloroform layer and add 15% saline 60
After washing with 0 ml, the chloroform layer was concentrated. To this concentrate was added 900 ml of a mixture of ethanol and acetone (14:86 v / v), and the mixture was stirred.
0%) was obtained.
該結晶の液体クロマトグラフィー分析による純度は98
％であった。The purity of the crystals by liquid chromatography analysis is 98.
%Met.
融点:196〜197℃ IR（KBr,cm-1）:1690,1665,1525,1345 発明の効果 本発明の方法により化合物Ａから簡単に収率よく高純
度で化合物Ｂを得ることができる。Melting point: 196 ° -197 ° C. IR (KBr, cm −1 ): 1690, 1665, 1525, 1345 Effect of the Invention According to the method of the present invention, compound B can be obtained easily from compound A with high yield and high purity.
───────────────────────────────────────────────────── フロントページの続き 審査官 冨永 保 (56)参考文献 特開 昭59−70667（ＪＰ，Ａ) 特開 昭59−225162（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C07D 401/12 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)────────────────────────────────────────────────── ─── continued examiner Tamotsu Tominaga of the front page (56) reference Patent Sho 59-70667 (JP, a) JP Akira 59-225162 (JP, a) (58 ) investigated the field (Int.Cl. 7 , DB name) C07D 401/12 CA (STN) REGISTRY (STN)
Claims (6)
４−（３−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−３−（１−ベンジル−３−ピペ
リジル）エステル−５−メチルエステルの塩酸塩の結
晶。(1) 2,6-dimethyl- having a melting point of 170 to 171 ° C.
Crystals of hydrochloride of 4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- (1-benzyl-3-piperidyl) ester-5-methyl ester.
４−（３−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−３−（１−ベンジル−３−ピペ
リジル）エステル−５−メチルエステルの塩酸塩の結晶
（以下、化合物Ａと称す）の溶液又は懸濁液に種晶とし
て融点が198〜199℃である2,6−ジメチル−４−（３−
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−３−（１−ベンジル−３−ピペリジル）エス
テル−５−メチルエステルの塩酸塩の結晶（以下、化合
物Ｂと称す）を添加して化合物Ｂを晶出させることを特
徴とする化合物Ｂの製造法。(2) 2,6-dimethyl- having a melting point of 170 to 171 ° C.
Crystals of hydrochloride of 4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- (1-benzyl-3-piperidyl) ester-5-methyl ester (hereinafter referred to as compound A) 2,6-Dimethyl-4- (3-) having a melting point of 198 to 199 ° C as a seed crystal in a solution or suspension of
Crystals of hydrochloride of (nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- (1-benzyl-3-piperidyl) ester-5-methyl ester (hereinafter referred to as compound B) were added. A method for producing a compound B, wherein the compound B is crystallized by heating.
又は懸濁液に種晶として化合物Ａを添加して化合物Ａを
晶出させ、これを分離した後、さらに該化合物Ａのアセ
トンを含む溶媒の溶液又は懸濁液に種晶として化合物Ｂ
を添加して化合物Ｂを晶出させることを特徴とする化合
物Ｂの製造法。3. A compound A is added as a seed crystal to an alcohol solution or suspension having 1 to 4 carbon atoms of the compound B to crystallize the compound A. After separating this, acetone of the compound A is further added. Compound B as a seed crystal in a solution or suspension of a solvent containing
A compound B is crystallized by adding a compound (A).
晶として化合物Ａを添加して化合物Ａを晶出させ、これ
を分離した後、さらに該化合物Ａのアセトンとエタノー
ルの混合溶媒の溶液又は懸濁液に種晶として化合物Ｂを
添加して化合物Ｂを晶出させることを特徴とする化合物
Ｂの製造法。4. A compound A is added as a seed crystal to an ethanol solution or suspension of the compound B to crystallize the compound A. After separating the compound A, a solution of the compound A in a mixed solvent of acetone and ethanol is further added. Alternatively, a method for producing compound B, wherein compound B is crystallized by adding compound B as a seed crystal to the suspension.
又は懸濁液から化合物Ａを晶出させ、これを分離した
後、さらに該化合物Ａのアセトンを含む溶媒の溶液又は
懸濁液に種晶として化合物Ｂを添加して化合物Ｂを晶出
させることを特徴とする化合物Ｂの製造法。5. A compound A is crystallized from an alcohol solution or suspension of the compound B having 1 to 4 carbon atoms, separated, and further separated into a solution or suspension of a solvent containing acetone of the compound A. A method for producing compound B, wherein compound B is crystallized by adding compound B as a seed crystal.
化合物Ａを晶出させ、これを分離した後、さらに該化合
物Ａのアセトンとエタノールの混合溶媒の溶液又は懸濁
液に種晶として化合物Ｂを添加して化合物Ｂを晶出させ
ることを特徴とする化合物Ｂの製造法。6. A compound A is crystallized from an ethanol solution or suspension of the compound B, separated and separated, and further compounded as a seed crystal in a solution or suspension of a mixed solvent of acetone and ethanol of the compound A. A method for producing a compound B, wherein the compound B is crystallized by adding B.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2334655A JP3053861B2 (en) | 1990-11-30 | 1990-11-30 | 1,4-dihydropyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2334655A JP3053861B2 (en) | 1990-11-30 | 1990-11-30 | 1,4-dihydropyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04208281A JPH04208281A (en) | 1992-07-29 |
| JP3053861B2 true JP3053861B2 (en) | 2000-06-19 |
Family
ID=18279787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2334655A Expired - Lifetime JP3053861B2 (en) | 1990-11-30 | 1990-11-30 | 1,4-dihydropyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3053861B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4544895B2 (en) * | 2004-03-31 | 2010-09-15 | 大日本印刷株式会社 | Method for producing dihydropyridine derivatives |
| CN102746215A (en) * | 2011-04-18 | 2012-10-24 | 张兆勇 | Method for preparing high-purity benidipine hydrochloride |
-
1990
- 1990-11-30 JP JP2334655A patent/JP3053861B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04208281A (en) | 1992-07-29 |
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