JP2001002677A - Production of purified 1,4-dihydropyridine - Google Patents
Production of purified 1,4-dihydropyridineInfo
- Publication number
- JP2001002677A JP2001002677A JP11178267A JP17826799A JP2001002677A JP 2001002677 A JP2001002677 A JP 2001002677A JP 11178267 A JP11178267 A JP 11178267A JP 17826799 A JP17826799 A JP 17826799A JP 2001002677 A JP2001002677 A JP 2001002677A
- Authority
- JP
- Japan
- Prior art keywords
- dihydropyridines
- dihydropyridine
- methyl
- crude
- phthalimidoethoxy
- 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.)
- Granted
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、精1,4−ジヒド
ロピリジン類の製造方法に関する。TECHNICAL FIELD The present invention relates to a method for producing purified 1,4-dihydropyridines.
【0002】[0002]
【従来の技術】下記式(5) 2. Description of the Related Art The following equation (5)
【0003】で示される4−(2−クロロフェニル)−
3−エトキシカルボニル−5−メトキシカルボニル−6
−メチル−2−(2−フタルイミドエトキシ)メチル−
1,4−ジヒドロピリジンに代表される一般式(1) (式中、R1およびR2はそれぞれ同一または相異なっ
て、低級アルキル基を表わし、R3およびR4はそれぞれ
同一または相異なって、水素原子、ハロゲン原子もしく
はトリフルオロメチル基を表わす。)で示される1,4
−ジヒドロピリジン類は、高血圧、狭心症に有効な医薬
品の重要な中間体として知られている。[0003] 4- (2-chlorophenyl)-
3-ethoxycarbonyl-5-methoxycarbonyl-6
-Methyl-2- (2-phthalimidoethoxy) methyl-
General formula (1) represented by 1,4-dihydropyridine (In the formula, R 1 and R 2 are the same or different and represent a lower alkyl group, and R 3 and R 4 are the same or different and represent a hydrogen atom, a halogen atom or a trifluoromethyl group.) 1, 4 indicated by
-Dihydropyridines are known as important intermediates of drugs effective for hypertension and angina.
【0004】かかる1,4−ジヒドロピリジン類の製造
方法としては、例えば4−(2−フタルイミドエトキ
シ)アセト酢酸エステル類とベンズアルデヒド類を反応
させ、次いで3−アミノクロトン酸エステル類を酢酸の
存在下に反応させる方法、4−(2−フタルイミドエト
キシ)アセト酢酸エステル類、ベンズアルデヒド類およ
び3−アミノクロトン酸エステル類を酢酸の存在下に反
応させる方法等が知られている(例えばJournal
of Medicinal Chemistry,2
9,1696(1986)等)。As a method for producing such 1,4-dihydropyridines, for example, 4- (2-phthalimidoethoxy) acetoacetate is reacted with benzaldehyde, and then 3-aminocrotonate is reacted in the presence of acetic acid. A reaction method, a method of reacting 4- (2-phthalimidoethoxy) acetoacetic acid esters, benzaldehydes and 3-aminocrotonic acid esters in the presence of acetic acid, and the like are known (for example, Journal).
of Medicinal Chemistry, 2
9 , 1696 (1986)).
【0005】かかる公知の方法で得られる1,4−ジヒ
ドロピリジン類は、種々の不純物を含んでいるため、通
常メタノール、酢酸エチル等の溶媒中で再結晶され、精
製されている。しかしながら、不純物のなかでも、例え
ば3,5−ジ(アルコキシカルボニル)−2,6−ジメ
チル−1,4−ジヒドロピリジン類、3,5−ジ(アル
コキシカルボニル)−2,6−ビス(2−フタルイミド
エトキシメチル)−1,4−ジヒドロピリジン類等の目
的物以外の1,4−ジヒドロピリジン骨格を有する不純
物は、目的物と構造が類似しているため、かかる再結晶
処理を行なっても除去されにくく、該不純物の含量をさ
らに低下させるためには、再結晶処理を繰り返す必要が
あった。[0005] The 1,4-dihydropyridines obtained by such a known method contain various impurities, and are usually recrystallized and purified in a solvent such as methanol or ethyl acetate. However, among the impurities, for example, 3,5-di (alkoxycarbonyl) -2,6-dimethyl-1,4-dihydropyridines, 3,5-di (alkoxycarbonyl) -2,6-bis (2-phthalimide Impurities having a 1,4-dihydropyridine skeleton other than the target substance, such as ethoxymethyl) -1,4-dihydropyridines, are similar in structure to the target substance, and therefore are not easily removed even by such recrystallization treatment. In order to further reduce the content of the impurities, it was necessary to repeat the recrystallization treatment.
【0006】[0006]
【発明が解決しようとする課題】このような状況のも
と、本発明者らは、不純物、特に目的物以外の1,4−
ジヒドロピリジン骨格を有する不純物がさらに少ない精
1,4−ジヒドロピリジン類の製造方法について、鋭意
検討したところ、1,4−ジヒドロピリジン類を主成分
とする粗1,4−ジヒドロピリジン類を、酢酸の存在
下、芳香族炭化水素系溶媒等の特定の溶媒中で晶析処理
して、該1,4−ジヒドロピリジン類の酢酸塩の結晶を
得、該酢酸塩の結晶をアルコール系溶媒等の特定の溶媒
と接触させて、精1,4−ジヒドロピリジン類の結晶を
分離することにより、不純物、特に目的物以外の1,4
−ジヒドロピリジン骨格を有する不純物の少ない精1,
4−ジヒドロピリジン類が得られることを見出し、本発
明に至った。Under these circumstances, the present inventors have developed impurities, especially 1,4-butane other than the target substance.
After diligent studies on a method for producing purified 1,4-dihydropyridines having even less impurities having a dihydropyridine skeleton, crude 1,4-dihydropyridines containing 1,4-dihydropyridines as a main component were prepared in the presence of acetic acid. Crystallize in a specific solvent such as an aromatic hydrocarbon solvent to obtain crystals of the acetate of the 1,4-dihydropyridines, and contact the crystals of the acetate with a specific solvent such as an alcohol solvent. Then, by separating the crystals of the purified 1,4-dihydropyridines, impurities, particularly 1,4
-An impurity with a small amount of impurities having a dihydropyridine skeleton 1,
The present inventors have found that 4-dihydropyridines can be obtained, and have reached the present invention.
【0007】[0007]
【課題を解決するための手段】すなわち、本発明は、一
般式(1) (式中、R1およびR2はそれぞれ同一または相異なっ
て、低級アルキル基を表わし、R3およびR4はそれぞれ
同一または相異なって、水素原子、ハロゲン原子もしく
はトリフルオロメチル基を表わす。)で示される1,4
−ジヒドロピリジン類を主成分とする粗1,4−ジヒド
ロピリジン類を、酢酸の存在下、脂肪族炭化水素系溶
媒、芳香族炭化水素系溶媒およびハロゲン化炭化水素系
溶媒からなる群から選ばれる少なくとも一種の溶媒中で
晶析処理して、該1,4−ジヒドロピリジン類の酢酸塩
の結晶を得、該酢酸塩の結晶をアルコール系溶媒、ケト
ン系溶媒、エステル系溶媒およびエーテル系溶媒からな
る群から選ばれる少なくとも一種の溶媒と接触させて、
精1,4−ジヒドロピリジン類の結晶を分離することを
特徴とする精1,4−ジヒドロピリジン類の製造方法を
提供するものである。That is, the present invention provides a compound represented by the following general formula (1): (In the formula, R 1 and R 2 are the same or different and represent a lower alkyl group, and R 3 and R 4 are the same or different and represent a hydrogen atom, a halogen atom or a trifluoromethyl group.) 1, 4 indicated by
At least one selected from the group consisting of aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents and halogenated hydrocarbon solvents in the presence of acetic acid, To obtain crystals of the acetate of the 1,4-dihydropyridines, and the crystals of the acetate are formed from the group consisting of alcohol solvents, ketone solvents, ester solvents and ether solvents. Contacting with at least one solvent selected,
It is intended to provide a method for producing pure 1,4-dihydropyridines, which comprises separating crystals of pure 1,4-dihydropyridines.
【0008】[0008]
【発明の実施の形態】下記一般式(1) で示される1,4−ジヒドロキシピリジン類の式中、R
1およびR2はそれぞれ同一または相異なって、低級アル
キル基を表わし、R3およびR4はそれぞれ同一または相
異なって、水素原子、ハロゲン原子もしくはトリフルオ
ロメチル基を表わす。DESCRIPTION OF THE PREFERRED EMBODIMENTS The following general formula (1) In the formula of the 1,4-dihydroxypyridines represented by
1 and R 2 are the same or different and represent a lower alkyl group, and R 3 and R 4 are the same or different and represent a hydrogen atom, a halogen atom or a trifluoromethyl group.
【0009】低級アルキル基としては、例えばメチル
基、エチル基、n−プロピル基、イソプロピル基、n−
ブチル基、イソブチル基、sec−ブチル基、t−ブチ
ル基、n−ヘキシル基等の炭素数1〜6の直鎖もしくは
分枝鎖状の低級アルキル基が挙げられ、なかでも炭素数
1〜4の低級アルキル基が好ましい。ハロゲン原子とし
ては、例えばフッ素原子、塩素原子、臭素原子、ヨウ素
原子等が挙げられ、フッ素原子、塩素原子が好ましく、
塩素原子が特に好ましい。The lower alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-
Examples thereof include a linear or branched lower alkyl group having 1 to 6 carbon atoms such as a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, and an n-hexyl group. Are preferred. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and a fluorine atom and a chlorine atom are preferable,
A chlorine atom is particularly preferred.
【0010】かかる1,4−ジヒドロピリジン類として
は、例えば4−フェニル−3,5−ジ(メトキシカルボ
ニル)−6−メチル−2−(2−フタルイミドエトキ
シ)メチル−1,4−ジヒドロピリジン、4−フェニル
−3−エトキシカルボニル−5−メトキシカルボニル−
6−メチル−2−(2−フタルイミドエトキシ)メチル
−1,4−ジヒドロピリジン、4−(2−クロロフェニ
ル)−3,5−ジ(メトキシカルボニル)−6−メチル
−2−(2−フタルイミドエトキシ)メチル−1,4−
ジヒドロピリジン、4−(2−クロロフェニル)−3−
エトキシカルボニル−5−メトキシカルボニル−6−メ
チル−2−(2−フタルイミドエトキシ)メチル−1,
4−ジヒドロピリジン、Examples of such 1,4-dihydropyridines include 4-phenyl-3,5-di (methoxycarbonyl) -6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine, Phenyl-3-ethoxycarbonyl-5-methoxycarbonyl-
6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine, 4- (2-chlorophenyl) -3,5-di (methoxycarbonyl) -6-methyl-2- (2-phthalimidoethoxy) Methyl-1,4-
Dihydropyridine, 4- (2-chlorophenyl) -3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,
4-dihydropyridine,
【0011】4−(2,3−ジクロロフェニル)−3,
5−ジ(メトキシカルボニル)−6−メチル−2−(2
−フタルイミドエトキシ)メチル−1,4−ジヒドロピ
リジン、4−(2,3−ジクロロフェニル)−3−エト
キシカルボニル−5−メトキシカルボニル−6−メチル
−2−(2−フタルイミドエトキシ)メチル−1,4−
ジヒドロピリジン、4−(2,3−ジクロロフェニル)
−3−メトキシカルボニル−5−エトキシカルボニル−
6−メチル−2−(2−フタルイミドエトキシ)メチル
−1,4−ジヒドロピリジン、4- (2,3-dichlorophenyl) -3,
5-di (methoxycarbonyl) -6-methyl-2- (2
-Phthalimidoethoxy) methyl-1,4-dihydropyridine, 4- (2,3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-
Dihydropyridine, 4- (2,3-dichlorophenyl)
-3-methoxycarbonyl-5-ethoxycarbonyl-
6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine,
【0012】4−(2−クロロ−3−トリフルオロメチ
ルフェニル)−3,5−ジ(メトキシカルボニル)−6
−メチル−2−(2−フタルイミドエトキシ)メチル−
1,4−ジヒドロピリジン、4−(2−クロロ−3−ト
リフルオロメチルフェニル)−3−メトキシカルボニル
−5−エトキシカルボニル−6−メチル−2−(2−フ
タルイミドエトキシ)メチル−1,4−ジヒドロピリジ
ン、4−(2−クロロ−3−トリフルオロメチルフェニ
ル)−3−エトキシカルボニル−5−メトキシカルボニ
ル−6−メチル−2−(2−フタルイミドエトキシ)メ
チル−1,4−ジヒドロピリジン等が挙げられる。4- (2-chloro-3-trifluoromethylphenyl) -3,5-di (methoxycarbonyl) -6
-Methyl-2- (2-phthalimidoethoxy) methyl-
1,4-dihydropyridine, 4- (2-chloro-3-trifluoromethylphenyl) -3-methoxycarbonyl-5-ethoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine And 4- (2-chloro-3-trifluoromethylphenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine.
【0013】本発明において用いられる粗1,4−ジヒ
ドロピリジン類は、1,4−ジヒドロピリジン類を主成
分とするものであり、粗1,4−ジヒドロピリジン類中
の1,4−ジヒドロピリジン類の含量は、通常70重量
%以上、好ましくは75重量%以上であり、不純物とし
て、例えば3,5−ジ(アルコキシカルボニル)−2,
6−ジメチル−1,4−ジヒドロピリジン類、3,5−
ジ(アルコキシカルボニル)−2,6−ビス(2−フタ
ルイミドエトキシメチル)−1,4−ジヒドロピリジン
類等の目的物以外の1,4−ジヒドロピリジン骨格を有
する不純物等を含んでいる。また、該粗1,4−ジヒド
ロピリジン類中には、例えばメタノール、イソプロパノ
ール、トルエン、クロロホルム、酢酸等の溶媒等が含ま
れていてもよい。The crude 1,4-dihydropyridines used in the present invention are mainly composed of 1,4-dihydropyridines, and the content of the 1,4-dihydropyridines in the crude 1,4-dihydropyridines is as follows. , Usually 70% by weight or more, preferably 75% by weight or more. As impurities, for example, 3,5-di (alkoxycarbonyl) -2,2
6-dimethyl-1,4-dihydropyridines, 3,5-
It contains impurities having a 1,4-dihydropyridine skeleton other than the target substance such as di (alkoxycarbonyl) -2,6-bis (2-phthalimidoethoxymethyl) -1,4-dihydropyridine. The crude 1,4-dihydropyridines may contain a solvent such as methanol, isopropanol, toluene, chloroform, acetic acid and the like.
【0014】かかる粗1,4−ジヒドロピリジン類は、
1,4−ジヒドロピリジン類を主成分とするものであれ
ば特に限定されず、例えば下記一般式(2) (式中、R1は上記と同一の意味を表わす。)で示され
る4−(2−フタルイミドエトキシ)アセト酢酸エステ
ル類、一般式(3) (式中、R2は上記と同一の意味を表わす。)で示され
る3−アミノクロトン酸エステル類および一般式(4) (式中、R3およびR4はそれぞれ上記と同一の意味を表
わす。)で示されるベンズアルデヒド類を、酢酸の存在
下に反応させ、濃縮あるいは冷却する方法、あるいは一
般式(2)で示される4−(2−フタルイミドエトキ
シ)アセト酢酸エステル類と一般式(4)で示されるベ
ンズアルデヒド類を反応させ、次いで一般式(3)で示
される3−アミノクロトン酸エステル類を、酢酸の存在
下に反応させ、濃縮あるいは冷却する方法等により得ら
れる。Such crude 1,4-dihydropyridines include:
It is not particularly limited as long as it has 1,4-dihydropyridines as a main component. For example, the following general formula (2) (Wherein, R 1 has the same meaning as described above), represented by the formula (3): (Wherein R 2 has the same meaning as described above), and a 3-aminocrotonate represented by the general formula (4): (Wherein, R 3 and R 4 have the same meanings as described above), and are reacted in the presence of acetic acid and concentrated or cooled, or represented by the general formula (2). 4- (2-phthalimidoethoxy) acetoacetic ester is reacted with a benzaldehyde represented by the general formula (4), and then a 3-aminocrotonate represented by the general formula (3) is reacted in the presence of acetic acid. It is obtained by a method of reacting and concentrating or cooling.
【0015】一般式(2)で示される4−(フタルイミ
ドエトキシ)アセト酢酸エステル類としては、例えば4
−(フタルイミドエトキシ)アセト酢酸メチル、4−
(フタルイミドエトキシ)アセト酢酸エチル、4−(フ
タルイミドエトキシ)アセト酢酸n−プロピル、4−
(フタルイミドエトキシ)アセト酢酸イソプロピル、4
−(フタルイミドエトキシ)アセト酢酸t−ブチル等が
挙げられる。The 4- (phthalimidoethoxy) acetoacetic esters represented by the general formula (2) include, for example, 4
-Methyl (phthalimidoethoxy) acetoacetate, 4-
Ethyl (phthalimidoethoxy) acetoacetate, n-propyl 4- (phthalimidoethoxy) acetoacetate, 4-
(Phthalimidoethoxy) isopropyl acetoacetate, 4
-(Phthalimidoethoxy) t-butyl acetoacetate and the like.
【0016】一般式(3)で示される3−アミノクロト
ン酸エステル類としては、例えば3−アミノクロトン酸
メチル、3−アミノクロトン酸エチル、3−アミノクロ
トン酸n−プロピル、3−アミノクロトン酸イソプロピ
ル、3−アミノクロトン酸t−ブチル等が挙げられる。Examples of the 3-aminocrotonates represented by the general formula (3) include methyl 3-aminocrotonate, ethyl 3-aminocrotonate, n-propyl 3-aminocrotonate, and 3-aminocrotonic acid. Isopropyl, t-butyl 3-aminocrotonate and the like.
【0017】一般式(4)で示されるベンズアルデヒド
類としては、例えばベンズアルデヒド、2−クロロベン
ズアルデヒド、3−クロロベンズアルデヒド、4−クロ
ロベンズアルデヒド、2−トリフルオロメチルベンズア
ルデヒド、3−トリフルオロメチルベンズアルデヒド、
2,3−ジクロロベンズアルデヒド、2−クロロ−3−
トリフルオロメチルベンズアルデヒド、2−トリフルオ
ロメチル−3−クロロベンズアルデヒド等が挙げられ
る。Examples of the benzaldehyde represented by the general formula (4) include benzaldehyde, 2-chlorobenzaldehyde, 3-chlorobenzaldehyde, 4-chlorobenzaldehyde, 2-trifluoromethylbenzaldehyde, 3-trifluoromethylbenzaldehyde,
2,3-dichlorobenzaldehyde, 2-chloro-3-
Trifluoromethylbenzaldehyde, 2-trifluoromethyl-3-chlorobenzaldehyde and the like.
【0018】本発明は、一般式(1)で示される1,4
−ジヒドロピリジン類を主成分とする粗1,4−ジヒド
ロピリジン類を、酢酸の存在下、脂肪族炭化水素系溶
媒、芳香族炭化水素系溶媒およびハロゲン化炭化水素系
溶媒からなる群から選ばれる少なくとも一種の溶媒中で
晶析処理して、該1,4−ジヒドロピリジン類の酢酸塩
の結晶を得、該酢酸塩の結晶をアルコール系溶媒、ケト
ン系溶媒、エステル系溶媒およびエーテル系溶媒からな
る群から選ばれる少なくとも一種の溶媒と接触させて、
精1,4−ジヒドロピリジン類の結晶を分離するもので
ある。According to the present invention, 1,4 represented by the general formula (1)
At least one selected from the group consisting of aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents and halogenated hydrocarbon solvents in the presence of acetic acid, To obtain crystals of the acetate of the 1,4-dihydropyridines, and the crystals of the acetate are formed from the group consisting of alcohol solvents, ketone solvents, ester solvents and ether solvents. Contacting with at least one solvent selected,
It separates crystals of pure 1,4-dihydropyridines.
【0019】まず、粗1,4−ジヒドロピリジン類を、
酢酸の存在下、脂肪族炭化水素系溶媒、芳香族炭化水素
系溶媒およびハロゲン化炭化水素系溶媒からなる群から
選ばれる少なくとも一種の溶媒中で晶析処理し、該1,
4−ジヒドロピリジン類の酢酸塩の結晶を得る工程につ
いて説明する。First, crude 1,4-dihydropyridines are
In the presence of acetic acid, crystallization treatment in at least one solvent selected from the group consisting of aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents and halogenated hydrocarbon solvents,
The step of obtaining crystals of an acetate salt of 4-dihydropyridines will be described.
【0020】脂肪族炭化水素系溶媒としては、例えばペ
ンタン、ヘキサン、ヘプタン、オクタン、デカン、シク
ロヘキサン等の炭素数5〜10の直鎖状、分枝状もしく
は環状の脂肪族炭化水素類が挙げられ、実用的にはヘキ
サン、ヘプタン、シクロヘキサンが好ましい。芳香族炭
化水素系溶媒としては、例えばトルエン、キシレン、メ
シチレン、ベンゼン、エチルベンゼン等の炭素数6〜1
0の芳香族炭化水素系溶媒が挙げられ、実用的には、ト
ルエン、キシレン、メシチレンが好ましい。ハロゲン化
炭化水素としては、例えばジクロロメタン、ジクロロエ
タン、クロロホルム、四塩化炭素、クロロベンゼン、ジ
クロロベンゼン、ブロモベンゼン、ジブロモベンゼン等
が挙げられ、実用的にはジクロロエタン、クロロホル
ム、クロロベンゼン、ジクロロベンゼンが好ましい。Examples of the aliphatic hydrocarbon-based solvent include linear, branched or cyclic aliphatic hydrocarbons having 5 to 10 carbon atoms, such as pentane, hexane, heptane, octane, decane and cyclohexane. Practically, hexane, heptane and cyclohexane are preferred. Examples of the aromatic hydrocarbon-based solvent include 6-1 carbon atoms such as toluene, xylene, mesitylene, benzene, and ethylbenzene.
An aromatic hydrocarbon solvent of 0 is mentioned, and toluene, xylene and mesitylene are practically preferable. Examples of the halogenated hydrocarbon include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, bromobenzene, dibromobenzene, and the like. Practically, dichloroethane, chloroform, chlorobenzene, and dichlorobenzene are preferable.
【0021】かかる溶媒のなかでも、1,4−ジヒドロ
ピリジン類およびその酢酸塩の溶解度等の点で、芳香族
炭化水素系溶媒が好ましく、トルエン、クロロベンゼン
が特に好ましい。なお、溶媒は、それぞれ単独で用いて
もよいし、混合して用いてもよい。Among these solvents, aromatic hydrocarbon solvents are preferred in view of the solubility of 1,4-dihydropyridines and their acetates, and toluene and chlorobenzene are particularly preferred. The solvents may be used alone or as a mixture.
【0022】溶媒の使用量は、その種類にもよるが、あ
まり多すぎると、1,4−ジヒドロピリジン類の取得率
が悪くなるため、粗1,4−ジヒドロピリジン類に対し
て、通常0.5〜10重量倍、好ましくは1〜3重量倍
である。The amount of the solvent used depends on the type of the solvent. However, if the amount is too large, the yield of 1,4-dihydropyridines becomes poor. It is 10 to 10 times by weight, preferably 1 to 3 times by weight.
【0023】粗1,4−ジヒドロピリジン類は、酢酸の
存在下に晶析処理することが重要であり、酢酸の使用量
は、粗1,4−ジヒドロピリジン類中に含まれる1,4
−ジヒドロピリジン類に対して、通常1モル倍以上、該
1,4−ジヒドロピリジン類の酢酸塩の取得率を上げる
観点から、好ましくは1.5モル倍以上、より好ましく
は2モル倍以上である。酢酸の使用量の上限は特にない
が、経済的な観点から、通常5モル倍以下である。な
お、用いた粗1,4−ジヒドロピリジン類中に酢酸が含
まれている場合には、粗1,4−ジヒドロピリジン類中
に含まれる酢酸を含めて、酢酸の使用量を決めてもよ
い。It is important that the crude 1,4-dihydropyridines are crystallized in the presence of acetic acid, and the amount of acetic acid used depends on the amount of 1,4 contained in the crude 1,4-dihydropyridines.
It is usually at least 1 mol times, more preferably at least 1.5 mol times, more preferably at least 2 mol times, the molar ratio of the 1,4-dihydropyridines to the dihydropyridines. There is no particular upper limit on the amount of acetic acid, but it is usually 5 mol times or less from an economical viewpoint. In addition, when acetic acid is contained in the used crude 1,4-dihydropyridines, the amount of acetic acid used may be determined, including acetic acid contained in the crude 1,4-dihydropyridines.
【0024】晶析処理は、通常の晶析処理でよく、例え
ば粗1,4−ジヒドロピリジン類を、酢酸の存在下、溶
媒に溶解させ、次いで冷却する方法等が挙げられ、得ら
れた1,4−ジヒドロピリジン類の酢酸塩の結晶は、通
常の濾過操作により容易に取り出すことができる。取り
出した該酢酸塩の結晶は、必要に応じて、上記した溶媒
で洗浄処理したり、乾燥処理してもよい。The crystallization treatment may be a usual crystallization treatment, for example, a method in which crude 1,4-dihydropyridines are dissolved in a solvent in the presence of acetic acid, and then cooled. Crystals of the acetate salt of 4-dihydropyridines can be easily removed by a usual filtration operation. The taken out crystals of the acetate may be subjected to a washing treatment or a drying treatment with the above-mentioned solvent, if necessary.
【0025】かくして得られた1,4−ジヒドロピリジ
ン類の酢酸塩の結晶を、アルコール系溶媒、ケトン系溶
媒、エステル系溶媒およびエーテル系溶媒からなる群か
ら選ばれる少なくとも一種の溶媒と接触させることによ
り、精1,4−ジヒドロピリジン類の結晶が得られる。The thus obtained crystals of the acetate salt of 1,4-dihydropyridines are brought into contact with at least one solvent selected from the group consisting of alcohol solvents, ketone solvents, ester solvents and ether solvents. And crystals of pure 1,4-dihydropyridines are obtained.
【0026】1,4−ジヒドロピリジン類の酢酸塩の結
晶を前記溶媒と接触させる操作は、特に限定されず、通
常該酢酸塩と前記溶媒を混合することにより行われる。
かかる操作においては、例えば攪拌等により該酢酸塩の
結晶と前記溶媒との接触をよくすることが好ましい。The operation of bringing the crystals of the acetate of 1,4-dihydropyridines into contact with the solvent is not particularly limited, and is usually performed by mixing the acetate with the solvent.
In such an operation, it is preferable to improve the contact between the crystals of the acetate and the solvent by stirring or the like.
【0027】アルコール系溶媒としては、例えばメタノ
ール、エタノール、n−プロパノール、イソプロパノー
ル、n−ブタノール、イソブタノール、sec−ブタノ
ール、t−ブタノール、ヘキサノール等の炭素数1〜6
の低級アルコール系溶媒が挙げられ、実用的な面で、メ
タノール、エタノール、イソプロパノールが好ましく、
なかでもメタノールが特に好ましい。ケトン系溶媒とし
ては、例えばアセトン、メチルエチルケトン、ジエチル
ケトン、メチルプロピルケトン、メチルイソブチルケト
ン等の炭素数3〜8の脂肪族ケトン系溶媒が挙げられ、
実用的には、アセトン、メチルエチルケトン、メチルイ
ソブチルケトンが好ましい。Examples of the alcohol-based solvent include those having 1 to 6 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, t-butanol and hexanol.
Lower alcohol solvents, methanol, ethanol, and isopropanol are preferable in practical terms,
Of these, methanol is particularly preferred. Examples of the ketone solvent include aliphatic ketone solvents having 3 to 8 carbon atoms such as acetone, methyl ethyl ketone, diethyl ketone, methyl propyl ketone, and methyl isobutyl ketone.
Practically, acetone, methyl ethyl ketone and methyl isobutyl ketone are preferred.
【0028】エステル系溶媒としては、例えば酢酸メチ
ル、酢酸エチル、酢酸n−プロピル、プロピオン酸メチ
ル等の脂肪族カルボン酸低級アルキルエステルが挙げら
れ、実用的には酢酸エチルが好ましい。エーテル系溶媒
としては、ジエチルエーテル、ジイソプロピルエーテ
ル、メチルt−ブチルエーテル、ジメトキシエタン、ジ
エトキシメタン、テトラヒドロフラン等の炭素数4〜8
のエーテル系溶媒が挙げられ、実用的には、ジエチルエ
ーテル、テトラヒドロフランが好ましい。Examples of the ester solvent include lower alkyl esters of aliphatic carboxylic acids such as methyl acetate, ethyl acetate, n-propyl acetate, and methyl propionate. Practically, ethyl acetate is preferred. Examples of the ether solvent include C4 to C8 such as diethyl ether, diisopropyl ether, methyl t-butyl ether, dimethoxyethane, diethoxymethane, and tetrahydrofuran.
And ether-based solvents are preferred, and practically, diethyl ether and tetrahydrofuran are preferred.
【0029】上記した溶媒は、単独で用いてもよいし、
混合して用いてもよい。かかる溶媒の使用量は、1,4
−ジヒドロピリジン類の酢酸塩と用いた溶媒が十分に接
触するに足る量であればよく、1,4−ジヒドロピリジ
ン類の酢酸塩に対して、通常0.5重量倍以上、好まし
くは1重量倍以上である。使用量の上限は、特に制限さ
れないが、容積効率を考慮すると、実用的には10重量
倍以下、好ましくは5重量倍以下である。The above-mentioned solvents may be used alone,
You may mix and use. The amount of such solvent used is 1,4
Any amount may be used as long as the acetate of dihydropyridines and the solvent used are in sufficient contact with each other, and usually at least 0.5 times by weight, preferably at least 1 times by weight, relative to the acetate of 1,4-dihydropyridines. It is. Although the upper limit of the amount used is not particularly limited, it is practically 10 times by weight or less, preferably 5 times by weight or less in consideration of volumetric efficiency.
【0030】1,4−ジヒドロピリジン類の酢酸塩の結
晶を上記した溶媒と接触させる温度は、通常0〜100
℃、好ましくは0〜50℃である。The temperature at which the crystals of the acetate of 1,4-dihydropyridines are brought into contact with the above-mentioned solvent is usually from 0 to 100.
° C, preferably from 0 to 50 ° C.
【0031】かくして、1,4−ジヒドロピリジン類の
酢酸塩の結晶を上記した溶媒と接触させることにより、
精1,4−ジヒドロピリジン類の結晶が得られる。精
1,4−ジヒドロピリジン類の結晶は、通常の濾過等に
より容易に分離でき、分離した精1,4−ジヒドロピリ
ジン類の結晶は、必要に応じて洗浄処理、乾燥処理等行
なってもよい。By bringing the crystals of the acetate of 1,4-dihydropyridines into contact with the above-mentioned solvent,
Crystals of purified 1,4-dihydropyridines are obtained. Crystals of the purified 1,4-dihydropyridines can be easily separated by ordinary filtration or the like, and the separated crystals of the purified 1,4-dihydropyridines may be subjected to washing treatment, drying treatment, etc., if necessary.
【0032】[0032]
【発明の効果】本発明の方法によれば、1,4−ジヒド
ロピリジン類を主成分とする粗1,4−ジヒドロピリジ
ン類から、不純物、特に目的物以外の1,4−ジヒドロ
ピリジン骨格を有する不純物が少ない精1,4−ジヒド
ロピリジン類を得ることができる。According to the method of the present invention, impurities, especially impurities having a 1,4-dihydropyridine skeleton other than the target substance, are removed from the crude 1,4-dihydropyridines mainly composed of 1,4-dihydropyridines. A small amount of purified 1,4-dihydropyridines can be obtained.
【0033】[0033]
【実施例】以下、実施例により、本発明をさらに詳細に
説明するが、本発明はこれら実施例により何ら限定され
るものではない。EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.
【0034】1,4−ジヒドロピリジン類および不純物
の含量は、高速液体クロマトグラフィ(LC)分析法に
より、酢酸の含量はガスクロマトグラフィ分析法により
求めた。なお、不純物の含量は、LC面積百分率値で表
わした。結晶の融点は、全自動融点測定装置(METT
LER社製 FP62)を用いて測定した。The contents of 1,4-dihydropyridines and impurities were determined by high performance liquid chromatography (LC), and the content of acetic acid was determined by gas chromatography. In addition, the content of the impurity was represented by LC area percentage value. The melting point of the crystal can be measured using a fully automatic melting point analyzer (METT
The measurement was performed using FP62 manufactured by LER.
【0035】また、実施例において、目的物以外の1,
4−ジヒドロピリジン骨格を有する不純物をA成分、B
成分と略記した。A成分は、4−(2−クロロフェニ
ル)−3,5−ジ(メトキシカルボニル)−2,6−ジ
メチル−1,4−ジヒドロピリジンを表わし、B成分
は、4−(2−クロロフェニル)−3,5−ジ(エトキ
シカルボニル)−2,6−ビス(2−フタルイミドエト
キシメチル)−1,4−ジヒドロピリジンを表わす。Further, in the examples, 1
An impurity having a 4-dihydropyridine skeleton is represented by component A, B
Abbreviated as component. The component A represents 4- (2-chlorophenyl) -3,5-di (methoxycarbonyl) -2,6-dimethyl-1,4-dihydropyridine, and the component B represents 4- (2-chlorophenyl) -3, Represents 5-di (ethoxycarbonyl) -2,6-bis (2-phthalimidoethoxymethyl) -1,4-dihydropyridine.
【0036】参考例1 攪拌装置、冷却管を付した反応容器に、(2−フタルイ
ミドエトキシ)アセト酢酸エチル141.7g(純度:
70.7重量%)および2−プロパノール564.7g
を加え、内温25℃でo−クロロベンズアルデヒド6
1.7gを滴下した。さらにピペリジン3.75gを加
えた後、同温度で6時間攪拌、保持した。その後、酢酸
35.1gを加え、減圧下、内温50℃で濃縮し、濃縮
残渣に酢酸602.4gおよび3−アミノクロトン酸メ
チル151.6gを加え、内温45℃に昇温した。同温
度で9時間攪拌、保持した後、5時間かけて内温20℃
に冷却し、同温度で2時間攪拌、保持した。析出結晶を
濾別し、結晶を、酢酸/水、次いで水で洗浄した後、減
圧条件下、55℃で乾燥し、粗4−(2−クロロフェニ
ル)−3−エトキシカルボニル−5−メトキシカルボニ
ル−6−メチル−2−(2−フタルイミドエトキシ)メ
チル−1,4−ジヒドロピリジン160.4gを得た
(含量:79.9重量%、A成分:0.60%、B成
分:0.75%、酢酸:9.0重量%)。Reference Example 1 In a reaction vessel equipped with a stirrer and a condenser, 141.7 g of ethyl (2-phthalimidoethoxy) acetoacetate (purity:
70.7% by weight) and 564.7 g of 2-propanol
And o-chlorobenzaldehyde 6 at an internal temperature of 25 ° C.
1.7 g was added dropwise. After addition of 3.75 g of piperidine, the mixture was stirred and maintained at the same temperature for 6 hours. Thereafter, 35.1 g of acetic acid was added, and the mixture was concentrated under reduced pressure at an internal temperature of 50 ° C. To the concentrated residue were added 602.4 g of acetic acid and 151.6 g of methyl 3-aminocrotonate, and the temperature was raised to an internal temperature of 45 ° C. After stirring and holding at the same temperature for 9 hours, the internal temperature is 20 ° C. over 5 hours.
And stirred and maintained at the same temperature for 2 hours. The precipitated crystals are separated by filtration, washed with acetic acid / water and then with water, dried at 55 ° C. under reduced pressure, and crude 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl- 160.4 g of 6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine was obtained (content: 79.9% by weight, A component: 0.60%, B component: 0.75%, Acetic acid: 9.0% by weight).
【0037】実施例1 攪拌装置、冷却管を付した反応容器に、粗4−(2−ク
ロロフェニル)−3−エトキシカルボニル−5−メトキ
シカルボニル−6−メチル−2−(2−フタルイミドエ
トキシ)メチル−1,4−ジヒドロピリジン120.0
g(含量:79.9重量%、A成分:0.60%、B成
分:0.75%、酢酸:9.0重量%)およびトルエン
156gを加え、内温75℃まで昇温し、完溶させた。
内温70℃で酢酸12.0gを加え、内温65℃で30
分保温した後、6時間かけて内温5℃まで冷却した。内
温5℃で一晩保冷熟成した後、析出した4−(2−クロ
ロフェニル)−3−エトキシカルボニル−5−メトキシ
カルボニル−6−メチル−2−(2−フタルイミドエト
キシ)メチル−1,4−ジヒドロピリジンの酢酸塩を濾
別した。該酢酸塩を容器にとり、メタノール120gと
混合し、30分間室温で攪拌した。結晶を濾別後、もう
一度同じ操作を繰り返した。再度結晶を濾別し、減圧
下、55℃で5時間乾燥し、精4−(2−クロロフェニ
ル)−3−エトキシカルボニル−5−メトキシカルボニ
ル−6−メチル−2−(2−フタルイミドエトキシ)メ
チル−1,4−ジヒドロピリジン92.9g(含量:9
7.4重量%、A成分:0.02%、B成分:0.12
%、酢酸:検出限界以下)を得た。精製収率:94.4
%。Example 1 A reaction vessel equipped with a stirrer and a condenser was charged with crude 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl. -1,4-dihydropyridine 120.0
g (content: 79.9% by weight, A component: 0.60%, B component: 0.75%, acetic acid: 9.0% by weight) and 156 g of toluene. Was dissolved.
At an internal temperature of 70 ° C., 12.0 g of acetic acid was added.
After keeping the temperature for 5 minutes, it was cooled to an internal temperature of 5 ° C. over 6 hours. After ripening at an internal temperature of 5 ° C. overnight, the precipitated 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4- The acetate salt of dihydropyridine was filtered off. The acetate was placed in a container, mixed with 120 g of methanol, and stirred at room temperature for 30 minutes. After filtering off the crystals, the same operation was repeated once. The crystals were filtered off again, dried under reduced pressure at 55 ° C. for 5 hours, and purified with 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl. 92.9 g of -1,4-dihydropyridine (content: 9
7.4% by weight, A component: 0.02%, B component: 0.12
%, Acetic acid: below the detection limit). Purification yield: 94.4
%.
【0038】実施例2 攪拌装置、冷却管を付した反応容器に、粗4−(2−ク
ロロフェニル)−3−エトキシカルボニル−5−メトキ
シカルボニル−6−メチル−2−(2−フタルイミドエ
トキシ)メチル−1,4−ジヒドロピリジン150.0
g(含量:85.4重量%、A成分:0.57%、B成
分:0.47%、酢酸:10.0重量%)およびトルエ
ン195gを加え、内温75℃まで昇温し、完溶させ
た。内温70℃で酢酸15.0gを加え、同温度で30
分保温した後、6時間かけて内温5℃まで冷却した。内
温5℃で2時間保冷熟成した後、析出した4−(2−ク
ロロフェニル)−3−エトキシカルボニル−5−メトキ
シカルボニル−6−メチル−2−(2−フタルイミドエ
トキシ)メチル−1,4−ジヒドロピリジンの酢酸塩を
濾別した。該酢酸塩を容器にとり、メタノール150g
と混合し、30分間室温で攪拌した。結晶を濾別後、も
う一度同じ操作を繰り返した。再度結晶を濾別し、減圧
下、55℃で5時間乾燥し、精4−(2−クロロフェニ
ル)−3−エトキシカルボニル−5−メトキシカルボニ
ル−6−メチル−2−(2−フタルイミドエトキシ)メ
チル−1,4−ジヒドロピリジン124.8g(含量:
97.7重量%、A成分:0.03%、B成分:0.0
7%、酢酸:検出限界以下)を得た。精製収率:95.
2%。融点:148℃。Example 2 A reaction vessel equipped with a stirrer and a condenser was charged with crude 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl. -1,4-dihydropyridine 150.0
g (content: 85.4% by weight, A component: 0.57%, B component: 0.47%, acetic acid: 10.0% by weight) and 195 g of toluene. Was dissolved. At an internal temperature of 70 ° C., 15.0 g of acetic acid was added.
After keeping the temperature for 5 minutes, it was cooled to an internal temperature of 5 ° C. over 6 hours. After aging for 2 hours at an internal temperature of 5 ° C, the precipitated 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4- The acetate salt of dihydropyridine was filtered off. Take the acetate in a container and add 150 g of methanol.
And stirred at room temperature for 30 minutes. After filtering off the crystals, the same operation was repeated once. The crystals were filtered off again, dried under reduced pressure at 55 ° C. for 5 hours, and purified with 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl. 124.8 g of -1,4-dihydropyridine (content:
97.7% by weight, A component: 0.03%, B component: 0.0
7%, acetic acid: below the detection limit). Purification yield: 95.
2%. Melting point: 148 [deg.] C.
【0039】実施例3 攪拌装置、冷却管を付した反応容器に、粗4−(2−ク
ロロフェニル)−3−エトキシカルボニル−5−メトキ
シカルボニル−6−メチル−2−(2−フタルイミドエ
トキシ)メチル−1,4−ジヒドロピリジン20.0g
(含量:87.5重量%、A成分:0.49%、B成
分:0.45%、酢酸:10.3重量%)およびトルエ
ン36gを加え、内温70℃まで昇温し、完溶させた。
酢酸2.0gを添加した後、内温65℃で1時間保温し
た後、8時間かけて内温20℃まで冷却した。内温20
℃で2時間保温熟成した後、結晶を濾過した。得られた
結晶を10gのトルエンで洗浄した後、減圧下、55℃
で5時間乾燥し、4−(2−クロロフェニル)−3−エ
トキシカルボニル−5−メトキシカルボニル−6−メチ
ル−2−(2−フタルイミドエトキシ)メチル−1,4
−ジヒドロピリジン酢酸塩17.9g(含量:89.2
重量%、A成分:0.03%、B成分:0.01%、酢
酸:9.7重量%)を得た。酢酸塩の取得率:90.9
%、酢酸塩の融点:118℃。得られた酢酸塩は、実施
例1と同様にメタノールで処理することにより、精4−
(2−クロロフェニル)−3−エトキシカルボニル−5
−メトキシカルボニル−6−メチル−2−(2−フタル
イミドエトキシ)メチル−1,4−ジヒドロピリジンを
得ることができる。Example 3 Crude 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl was placed in a reaction vessel equipped with a stirrer and a condenser. -1,4-dihydropyridine 20.0 g
(Content: 87.5% by weight, A component: 0.49%, B component: 0.45%, acetic acid: 10.3% by weight) and 36 g of toluene were added, and the internal temperature was raised to 70 ° C to complete dissolution. I let it.
After adding 2.0 g of acetic acid, the mixture was kept at an internal temperature of 65 ° C. for 1 hour, and then cooled to an internal temperature of 20 ° C. over 8 hours. Inner temperature 20
After aging for 2 hours at ℃, the crystals were filtered. The obtained crystals were washed with 10 g of toluene, and then, under reduced pressure, at 55 ° C.
For 5 hours, and 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4
17.9 g of dihydropyridine acetate (content: 89.2)
Wt%, A component: 0.03%, B component: 0.01%, acetic acid: 9.7% by weight). Acetic acid acquisition rate: 90.9
%, Melting point of acetate: 118 ° C. The resulting acetate was treated with methanol in the same manner as in Example 1 to give 4-
(2-chlorophenyl) -3-ethoxycarbonyl-5
-Methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine can be obtained.
【0040】実施例4 実施例3において、粗4−(2−クロロフェニル)−3
−エトキシカルボニル−5−メトキシカルボニル−6−
メチル−2−(2−フタルイミドエトキシ)メチル−
1,4−ジヒドロピリジン20.0g(含量:84.6
重量%、A成分:0.44%、B成分:0.26%、酢
酸:7.7重量%)を用い、酢酸2.0gを添加しない
以外は実施例3と同様に実施し、4−(2−クロロフェ
ニル)−3−エトキシカルボニル−5−メトキシカルボ
ニル−6−メチル−2−(2−フタルイミドエトキシ)
メチル−1,4−ジヒドロピリジンの酢酸塩14.4g
(含量:89.2重量%、A成分:0.03%、B成
分:0.003%、酢酸:9.1重量%)を得た。酢酸
塩の取得率:76.0%。得られた酢酸塩は、実施例1
と同様にメタノールで処理することにより、精4−(2
−クロロフェニル)−3−エトキシカルボニル−5−メ
トキシカルボニル−6−メチル−2−(2−フタルイミ
ドエトキシ)メチル−1,4−ジヒドロピリジンを得る
ことができる。Example 4 In Example 3, crude 4- (2-chlorophenyl) -3 was used.
-Ethoxycarbonyl-5-methoxycarbonyl-6
Methyl-2- (2-phthalimidoethoxy) methyl-
20.0 g of 1,4-dihydropyridine (content: 84.6)
%, A component: 0.44%, B component: 0.26%, acetic acid: 7.7% by weight), and the same procedure as in Example 3 was carried out except that 2.0 g of acetic acid was not added. (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy)
14.4 g of methyl-1,4-dihydropyridine acetate
(Content: 89.2% by weight, A component: 0.03%, B component: 0.003%, acetic acid: 9.1% by weight). Acquisition rate of acetate: 76.0%. The obtained acetate was prepared in Example 1
By treating with methanol in the same manner as described above, purified 4- (2
-Chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine can be obtained.
【0041】実施例5 実施例3において、実施例4で用いたと同じ粗4−(2
−クロロフェニル)−3−エトキシカルボニル−5−メ
トキシカルボニル−6−メチル−2−(2−フタルイミ
ドエトキシ)メチル−1,4−ジヒドロピリジン20.
0gを用い、トルエン36gに代えてクロロベンゼン3
6gを用い、酢酸2.0gを添加しない以外は実施例3
と同様に実施して、4−(2−クロロフェニル)−3−
エトキシカルボニル−5−メトキシカルボニル−6−メ
チル−2−(2−フタルイミドエトキシ)メチル−1,
4−ジヒドロピリジンの酢酸塩13.2g(含量:8
9.1重量%、A成分:0.05%、B成分:0.00
3%、酢酸:9.1重量%)を得た。酢酸塩の取得率:
69.5%。得られた酢酸塩は、実施例1と同様にメタ
ノールで処理することにより、精4−(2−クロロフェ
ニル)−3−エトキシカルボニル−5−メトキシカルボ
ニル−6−メチル−2−(2−フタルイミドエトキシ)
メチル−1,4−ジヒドロピリジンを得ることができ
る。Example 5 In Example 3, the same crude 4- (2) as used in Example 4 was used.
-Chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine 20.
Chlorobenzene 3 instead of 36 g of toluene.
Example 3 except that 6 g was used and 2.0 g of acetic acid was not added.
And 4- (2-chlorophenyl) -3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,
13.2 g of acetate of 4-dihydropyridine (content: 8)
9.1% by weight, A component: 0.05%, B component: 0.00
3%, acetic acid: 9.1% by weight). Acetic acid acquisition rate:
69.5%. The resulting acetate was treated with methanol in the same manner as in Example 1 to give pure 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy). )
Methyl-1,4-dihydropyridine can be obtained.
【0042】比較例1 攪拌装置、冷却管を付した反応容器に、実施例1で用い
たと同じ粗4−(2−クロロフェニル)−3−エトキシ
カルボニル−5−メトキシカルボニル−6−メチル−2
−(2−フタルイミドエトキシ)メチル−1,4−ジヒ
ドロピリジン35.1gおよび酢酸エチル63gを加
え、内温80℃まで昇温し、完溶させた。内温77℃で
1時間、攪拌保持した後、3時間かけて内温65℃まで
冷却し、同温度で2時間攪拌保持した。その後、さらに
6時間かけて内温5℃まで冷却し、内温5℃で、一晩保
冷熟成した後、析出結晶を濾取した。結晶を冷酢酸エチ
ル17.6gで洗浄し、減圧下、55℃で乾燥し、4−
(2−クロロフェニル)−3−エトキシカルボニル−5
−メトキシカルボニル−6−メチル−2−(2−フタル
イミドエトキシ)メチル−1,4−ジヒドロピリジン2
6.4g(含量:97.8重量%、A成分:0.07
%、B成分:0.31%、酢酸:検出限界以下)を得
た。精製収率92.0%。Comparative Example 1 The same crude 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2 used in Example 1 was placed in a reaction vessel equipped with a stirrer and a condenser.
35.1 g of-(2-phthalimidoethoxy) methyl-1,4-dihydropyridine and 63 g of ethyl acetate were added, and the mixture was heated to an internal temperature of 80 ° C. and completely dissolved. After stirring and holding at an internal temperature of 77 ° C. for 1 hour, the mixture was cooled to an internal temperature of 65 ° C. over 3 hours and stirred and held at the same temperature for 2 hours. Thereafter, the mixture was further cooled to an internal temperature of 5 ° C. over a further 6 hours, and was cooled and aged at an internal temperature of 5 ° C. overnight, and then the precipitated crystals were collected by filtration. The crystals were washed with 17.6 g of cold ethyl acetate, dried at 55 ° C. under reduced pressure,
(2-chlorophenyl) -3-ethoxycarbonyl-5
-Methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine 2
6.4 g (content: 97.8% by weight, component A: 0.07)
%, B component: 0.31%, acetic acid: below the detection limit). Purification yield 92.0%.
【0043】実施例6 粗4−(2−クロロフェニル)−3−エトキシカルボニ
ル−5−メトキシカルボニル−6−メチル−2−(2−
フタルイミドエトキシ)メチル−1,4−ジヒドロピリ
ジンを、実施例3と同様に、酢酸の存在下、トルエン中
で晶析処理して、4−(2−クロロフェニル)−3−エ
トキシカルボニル−5−メトキシカルボニル−6−メチ
ル−2−(2−フタルイミドエトキシ)メチル−1,4
−ジヒドロピリジンの酢酸塩を得た。該酢酸塩を、4重
量倍のエタノール、イソプロパノール、酢酸エチルおよ
びアセトンとそれぞれ混合し、室温で2時間攪拌した
後、濾過処理し、得られた結晶が、それぞれ4−(2−
クロロフェニル)−3−エトキシカルボニル−5−メト
キシカルボニル−6−メチル−2−(2−フタルイミド
エトキシ)メチル−1,4−ジヒドロピリジンであるこ
とを確認した。Example 6 Crude 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-
(Phthalimidoethoxy) methyl-1,4-dihydropyridine was crystallized in toluene in the presence of acetic acid in the same manner as in Example 3 to give 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl -6-methyl-2- (2-phthalimidoethoxy) methyl-1,4
-The acetate salt of dihydropyridine was obtained. The acetate was mixed with 4 parts by weight of ethanol, isopropanol, ethyl acetate and acetone, stirred at room temperature for 2 hours, filtered, and the obtained crystals were 4- (2-
It was confirmed to be chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine.
【0044】比較例2 実施例6で用いたと同じ4−(2−クロロフェニル)−
3−エトキシカルボニル−5−メトキシカルボニル−6
−メチル−2−(2−フタルイミドエトキシ)メチル−
1,4−ジヒドロピリジンの酢酸塩を、4重量倍のヘキ
サンおよび2重量倍のジクロロエタンと混合し、室温で
2時間攪拌した後、濾過処理したが、得られた結晶は、
それぞれ4−(2−クロロフェニル)−3−エトキシカ
ルボニル−5−メトキシカルボニル−6−メチル−2−
(2−フタルイミドエトキシ)メチル−1,4−ジヒド
ロピリジンの酢酸塩であった。Comparative Example 2 The same 4- (2-chlorophenyl)-as used in Example 6
3-ethoxycarbonyl-5-methoxycarbonyl-6
-Methyl-2- (2-phthalimidoethoxy) methyl-
The acetate of 1,4-dihydropyridine was mixed with 4 times by weight of hexane and 2 times by weight of dichloroethane, stirred at room temperature for 2 hours, and then filtered.
4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-
(2-phthalimidoethoxy) methyl-1,4-dihydropyridine acetate.
Claims (8)
て、低級アルキル基を表わし、R3およびR4はそれぞれ
同一または相異なって、水素原子、ハロゲン原子もしく
はトリフルオロメチル基を表わす。)で示される1,4
−ジヒドロピリジン類を主成分とする粗1,4−ジヒド
ロピリジン類を、酢酸の存在下、脂肪族炭化水素系溶
媒、芳香族炭化水素系溶媒およびハロゲン化炭化水素系
溶媒からなる群から選ばれる少なくとも一種の溶媒中で
晶析処理して、該1,4−ジヒドロピリジン類の酢酸塩
の結晶を得、該酢酸塩の結晶をアルコール系溶媒、ケト
ン系溶媒、エステル系溶媒およびエーテル系溶媒からな
る群から選ばれる少なくとも一種の溶媒と接触させて、
精1,4−ジヒドロピリジン類の結晶を分離することを
特徴とする精1,4−ジヒドロピリジン類の製造方法。1. The general formula (1) (In the formula, R 1 and R 2 are the same or different and represent a lower alkyl group, and R 3 and R 4 are the same or different and represent a hydrogen atom, a halogen atom or a trifluoromethyl group.) 1, 4 indicated by
At least one selected from the group consisting of aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents and halogenated hydrocarbon solvents in the presence of acetic acid, To obtain crystals of the acetate of the 1,4-dihydropyridines, and the crystals of the acetate are formed from the group consisting of alcohol solvents, ketone solvents, ester solvents and ether solvents. Contacting with at least one solvent selected,
A method for producing pure 1,4-dihydropyridines, comprising separating crystals of pure 1,4-dihydropyridines.
の芳香族炭化水素系溶媒である請求項1に記載の精1,
4−ジヒドロピリジン類の製造方法。2. An aromatic hydrocarbon solvent having 6 to 10 carbon atoms.
The aromatic hydrocarbon solvent according to claim 1, which is an aromatic hydrocarbon solvent.
A method for producing 4-dihydropyridines.
が、トルエン、キシレンまたはメシチレンである請求項
2に記載の精1,4−ジヒドロピリジン類の製造方法。3. The method for producing 1,4-dihydropyridines according to claim 2, wherein the aromatic hydrocarbon solvent having 6 to 10 carbon atoms is toluene, xylene or mesitylene.
アルコール系溶媒である請求項1に記載の精1,4−ジ
ヒドロピリジン類の製造方法。4. The process for producing purified 1,4-dihydropyridines according to claim 1, wherein the alcohol solvent is a lower alcohol solvent having 1 to 6 carbon atoms.
メタノール、エタノールまたはイソプロパノールである
請求項4に記載の精1,4−ジヒドロピリジン類の製造
方法。5. A lower alcohol solvent having 1 to 6 carbon atoms,
The method for producing purified 1,4-dihydropyridines according to claim 4, which is methanol, ethanol or isopropanol.
(2) (式中、R1は上記と同一の意味を表わす。)で示され
る4−(2−フタルイミドエトキシ)アセト酢酸エステ
ル類と一般式(4) (式中、R3およびR4はそれぞれ上記と同一の意味を表
わす。)で示されるベンズアルデヒド類を反応させ、次
いで酢酸の存在下、一般式(3) (式中、R2は上記と同一の意味を表わす。)で示され
る3−アミノクロトン酸エステル類を反応させて得られ
る粗1,4−ジヒドロピリジン類である請求項1に記載
の精1,4−ジヒドロピリジン類の製造方法。6. The crude 1,4-dihydropyridines represented by the general formula (2) (Wherein R 1 has the same meaning as described above) and a 4- (2-phthalimidoethoxy) acetoacetic ester represented by the general formula (4): (Wherein R 3 and R 4 have the same meanings as described above), and then reacted with a compound of the general formula (3) in the presence of acetic acid. (Wherein, R 2 has the same meaning as described above), and is a crude 1,4-dihydropyridine obtained by reacting a 3-aminocrotonate ester represented by the formula (1). A method for producing 4-dihydropyridines.
(2)で示される4−(2−フタルイミドエトキシ)ア
セト酢酸エステル類、一般式(3)で示される3−アミ
ノクロトン酸エステル類および一般式(4)で示される
ベンズアルデヒド類を、酢酸の存在下に反応させて得ら
れる粗1,4−ジヒドロピリジン類である請求項1に記
載の精1,4−ジヒドロピリジン類の製造方法。7. A crude 1,4-dihydropyridine is a 4- (2-phthalimidoethoxy) acetoacetic acid ester represented by the general formula (2) or a 3-aminocrotonic acid ester represented by the general formula (3). The method for producing purified 1,4-dihydropyridines according to claim 1, which is a crude 1,4-dihydropyridine obtained by reacting a benzaldehyde represented by the general formula (4) in the presence of acetic acid.
(2−クロロフェニル)−3−エトキシカルボニル−5
−メトキシカルボニル−6−メチル−2−(2−フタル
イミドエトキシ)メチル−1,4−ジヒドロピリジンで
ある請求項1に記載の精1,4−ジヒドロピリジン類の
製造方法。8. The crude 1,4-dihydropyridines are converted to crude 4-
(2-chlorophenyl) -3-ethoxycarbonyl-5
The method for producing purified 1,4-dihydropyridines according to claim 1, which is -methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP17826799A JP4320849B2 (en) | 1999-06-24 | 1999-06-24 | Method for producing purified 1,4-dihydropyridines |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP17826799A JP4320849B2 (en) | 1999-06-24 | 1999-06-24 | Method for producing purified 1,4-dihydropyridines |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2001002677A true JP2001002677A (en) | 2001-01-09 |
JP4320849B2 JP4320849B2 (en) | 2009-08-26 |
Family
ID=16045506
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP17826799A Expired - Fee Related JP4320849B2 (en) | 1999-06-24 | 1999-06-24 | Method for producing purified 1,4-dihydropyridines |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP4320849B2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6653481B2 (en) * | 2000-12-29 | 2003-11-25 | Synthon Bv | Process for making amlodipine |
EP1975167A1 (en) * | 2007-03-30 | 2008-10-01 | Esteve Quimica, S.A. | Acetone solvate of phthaloyl amlodipine |
JP2010100562A (en) * | 2008-10-23 | 2010-05-06 | Daito Kk | Method for purifying intermediate for producing amlodipine |
WO2011055649A1 (en) * | 2009-11-04 | 2011-05-12 | 日産化学工業株式会社 | Crystal forms of sulfonylurea compound and method for producing the same |
-
1999
- 1999-06-24 JP JP17826799A patent/JP4320849B2/en not_active Expired - Fee Related
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6653481B2 (en) * | 2000-12-29 | 2003-11-25 | Synthon Bv | Process for making amlodipine |
EP1975167A1 (en) * | 2007-03-30 | 2008-10-01 | Esteve Quimica, S.A. | Acetone solvate of phthaloyl amlodipine |
WO2008119759A1 (en) * | 2007-03-30 | 2008-10-09 | Esteve Química, S.A. | Acetone solvate of phthaloyl amlodipine |
JP2010523521A (en) * | 2007-03-30 | 2010-07-15 | エステベ キミカ,ソシエダ アノニマ | Acetone solvate of phthaloyl amlodipine |
JP2010100562A (en) * | 2008-10-23 | 2010-05-06 | Daito Kk | Method for purifying intermediate for producing amlodipine |
WO2011055649A1 (en) * | 2009-11-04 | 2011-05-12 | 日産化学工業株式会社 | Crystal forms of sulfonylurea compound and method for producing the same |
US8765640B2 (en) | 2009-11-04 | 2014-07-01 | Nissan Chemical Industries, Ltd. | Crystal forms of sulfonylurea compound and method for producing the same |
Also Published As
Publication number | Publication date |
---|---|
JP4320849B2 (en) | 2009-08-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH0751562B2 (en) | New method for producing 4-substituted 1,4-dihydropyridines | |
SK104598A3 (en) | Process for the manufacture of dihydropyridine derivatives | |
BR112014014604B1 (en) | process for the preparation of a compound, and, isolated and purified compound | |
WO2015124764A1 (en) | Synthesis process of dabigatran etexilate mesylate, intermediates of the process and novel polymorph of dabigatran etexilate | |
JP3491506B2 (en) | Method for producing dihydropyridine derivative | |
JP4320849B2 (en) | Method for producing purified 1,4-dihydropyridines | |
JP4587497B2 (en) | New manufacturing method | |
EP1789412B1 (en) | Crystalline alfuzosin base | |
JP2011006379A (en) | Method for recrystallizing {2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid-3-[1-(diphenylmethyl)azetidin-3-yl]ester-5-isopropyl ester}(azelnidipine), isopropyl alcohol adduct of azelnidipine, and method for producing azelnidipine | |
EP1858851B1 (en) | Preparing method for amorphous lercanidipine | |
US6987185B2 (en) | Method for separating methyl 4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrimidine-carboxylate-recemate | |
JP5463051B2 (en) | Method for producing 1,4-dihydropyridine derivative | |
JP5637710B2 (en) | {2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester } Manufacturing method | |
JP2000198779A (en) | Purification of 3-alkylflavanol derivative | |
JPH07116222B2 (en) | Process for producing 21-desoxyprednisolone-17-ester | |
KR100538475B1 (en) | Improved method for the preparation of intermediate of amlodipine | |
US20230033450A1 (en) | Method for preparing diazoxide | |
JP2007015978A (en) | Production method for amlodipine benzenesulfonate | |
US6355836B1 (en) | Process for the preparation of cis 5-fluoro-2-methyl-1[p-(methylthio)benzyliden]-inden-3-acetic acid | |
JP6433809B2 (en) | Process for producing 1- (3-hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine | |
EP2174940A1 (en) | Process for production of optically active mirtazapine | |
EP0441760A1 (en) | Purification process for N,N-diethylmandelamide | |
RU2146672C1 (en) | Method of synthesis of 3-ethyl-5-methyl(±)2-[(2-aminoethoxy)- -methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine- -dicarboxylate monobenzenesulfonate | |
JP4325023B2 (en) | Method for producing phthalimidoalkoxyacetoacetate esters | |
JP2531660B2 (en) | Method for purifying bis (2,2,6,6-tetramethyl-4-piperidyl) sebacate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD05 | Notification of revocation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7425 Effective date: 20021025 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050927 |
|
RD05 | Notification of revocation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7425 Effective date: 20080125 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20090204 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090210 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090401 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090401 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20090512 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20090525 |
|
R151 | Written notification of patent or utility model registration |
Ref document number: 4320849 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R151 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120612 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120612 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130612 Year of fee payment: 4 |
|
LAPS | Cancellation because of no payment of annual fees |