JPS61267577A - Novel production of dextrorotary optical isomer of ym-09730 diastereomer a - Google Patents
Novel production of dextrorotary optical isomer of ym-09730 diastereomer aInfo
- Publication number
- JPS61267577A JPS61267577A JP61012358A JP1235886A JPS61267577A JP S61267577 A JPS61267577 A JP S61267577A JP 61012358 A JP61012358 A JP 61012358A JP 1235886 A JP1235886 A JP 1235886A JP S61267577 A JPS61267577 A JP S61267577A
- Authority
- JP
- Japan
- Prior art keywords
- diastereomer
- optical isomer
- acid
- dextrorotary
- compound
- 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.)
- Pending
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明は、血管拡張剤として有用なYM−09730の
ジアステレオマ−Aの右旋性光学異性体及びその薬理学
的に許容される酸付加塩の新規製造法に関する。Detailed Description of the Invention (Industrial Application Field) The present invention provides a dextrorotatory optical isomer of diastereomer A of YM-09730 useful as a vasodilator and a pharmacologically acceptable acid addition salt thereof. Concerning a new manufacturing method.
(発明の背景)
YM−09730は、化学名を2,6−ジメチル−4−
(m−二トロフェニル)−1,4−ジヒドロピリジン−
3,5−ジカルボン酸−3−(1−ベンジルピロリジン
−3−イル)エステル−5−メチルエステルと称せられ
、つぎの化学構造式で示されるジヒドロピリジン−3,
5−ジカルボン酸エステル誘導体である。(Background of the invention) YM-09730 has a chemical name of 2,6-dimethyl-4-
(m-nitrophenyl)-1,4-dihydropyridine-
Dihydropyridine-3, which is called 3,5-dicarboxylic acid-3-(1-benzylpyrrolidin-3-yl) ester-5-methyl ester and is represented by the following chemical structural formula.
It is a 5-dicarboxylic acid ester derivative.
YM−09730は、血管拡張作用および血圧降下作用
を有し、その作用に持続性があることが報告されている
(特許第1137506号、特公昭57−30111号
公報)。It has been reported that YM-09730 has a vasodilatory effect and a blood pressure lowering effect, and that these effects are sustained (Japanese Patent No. 1137506, Japanese Patent Publication No. 57-30111).
YM−09730は、不斉炭素原子を2個有しておシ、
これらの不斉炭素原子にもとづく異性体が存在すること
が、立体化学的見地より推定される。しかしながら、こ
の異性体の存在については、前記特許公報には記載がな
く、未確認である。YM-09730 has two asymmetric carbon atoms,
The existence of isomers based on these asymmetric carbon atoms is presumed from a stereochemical standpoint. However, the existence of this isomer is not described in the above patent publication and is unconfirmed.
本発明者らは、先にYM−09730のジアステレオマ
−Aとジアステレオマ−Bとを初めて分離し、ジアステ
レオマ−Aがジアステレオマ−Bおよび両ジアステレオ
マ−の混合物に比べて格段にすぐれた特有の薬理効果を
有していることをつきとめた(特願昭59−75998
号)。The present inventors previously separated diastereomer A and diastereomer B of YM-09730 for the first time, and found that diastereomer A has a unique pharmacological effect that is significantly superior to diastereomer B and a mixture of both diastereomers. (Patent application 1987-75998)
issue).
本発明者らはさらにm−ニトロペ/ズアルデヒドと1−
ベンジル−3−アセトアセトキシピロリジンと3−アミ
ノクロトン酸メチルエステルとを反応させるなどの方法
により、得られるYM−09730を、シリカゲルを担
体とし、かつ酢酸エチル−酢酸を溶離液とするカラムク
ロマトグラフィーに付し、ジアステレオマ−Aを分離し
2次いでL−(−3−リンゴ酸などを用いて光学分割し
て塩酸塩の融点が223〜230℃であるジアステレオ
マ−Aの右旋性光学異性体を製造しうろこと、及びこの
異性体がその左旋性光学異性体及びその両異性体の混合
物に比べて格段に優れた特有の薬理効果を有することを
見出した(特願昭59−114098号)。The inventors further discovered that m-nitrope/dualdehyde and 1-
YM-09730 obtained by a method such as reacting benzyl-3-acetoacetoxypyrrolidine with 3-aminocrotonic acid methyl ester was subjected to column chromatography using silica gel as a carrier and ethyl acetate-acetic acid as an eluent. diastereomer A is separated and then optically resolved using L-(-3-malic acid or the like) to produce a dextrorotatory optical isomer of diastereomer A whose hydrochloride has a melting point of 223 to 230°C. It has been found that the white scale and its isomer have unique pharmacological effects that are much superior to its levorotatory optical isomer and the mixture of both isomers (Japanese Patent Application No. 114098/1982).
(解決するための手段)
今回、この新規かつ有用なYM−09730のジアステ
レオマ−Aの右旋性光学異性体の製造法について研究し
た結果、目的とする異性体の収率が高まることを見出し
1本発明を完成した。(Means for Solving the Problem) As a result of researching this new and useful method for producing the dextrorotary optical isomer of diastereomer A of YM-09730, we found that the yield of the desired isomer was increased.1 The invention has been completed.
なお、ジアステレオマ−A自体(dt混合物)はその塩
酸塩の融点が200〜206℃を示し、同180〜18
5℃を示すジアステレオマ−Bと区別される。Note that diastereomer A itself (dt mixture) has a hydrochloride melting point of 200 to 206°C, and a melting point of 180 to 18°C.
It is distinguished from diastereomer B, which exhibits a temperature of 5°C.
また、ジアステレオマ−Aの右旋性光学異性体は、前記
の如くその塩酸塩の融点が223〜230℃を示すもの
である。本発明は、該融点で特定されるYM−0973
0のジアステレオマ−Aの右旋性光学異性体又はその薬
理学的に許容される酸付加塩の新規製造法を提供するも
のである。Further, as mentioned above, the dextrorotary optical isomer of diastereomer A has a hydrochloride having a melting point of 223 to 230°C. The present invention provides YM-0973 specified by the melting point.
The present invention provides a novel method for producing a dextrorotary optical isomer of diastereomer-A or a pharmacologically acceptable acid addition salt thereof.
ここに薬理学的に許容される酸付加塩としてはL−(→
−リンゴ酸塩などの有機酸塩や塩酸塩などの鉱酸塩であ
る。Here, the pharmacologically acceptable acid addition salt is L-(→
-Organic acid salts such as malate and mineral acid salts such as hydrochloride.
本発明の化合物(I)は9式(n)
で示される 5−メトキシカルボニル−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−カルボン酸の左旋性光学異性体またはラセ
ミ体またはそれらの反応性誘導体と9式(III)
で示される 1−ベンジル−3−ヒドロキシピロリジン
の左旋性光学異性体またはラセミ体とを反応させること
により製造することができる。Compound (I) of the present invention is a levorotatory optical compound of 5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid represented by formula (n) It can be produced by reacting an isomer or racemate or a reactive derivative thereof with a levorotatory optical isomer or racemate of 1-benzyl-3-hydroxypyrrolidine represented by formula (III).
この反応はカルボン酸エステル形成反応であシ、一般的
に用いられる手法が適宜使用できる。This reaction is a carboxylic acid ester forming reaction, and commonly used techniques can be used as appropriate.
この反応による立体化学上の反転はない。化合物(n)
の反応性誘導体としては酸クロリド、酸プロミド等の酸
ハライド、酸無水物、混合酸無水物及び活性エステル等
が挙げられる。化合物([1)を遊離のカルボン酸のま
ま使用する場合はジシクロへキシルカルボジイミド等の
縮合剤の存在下に行われる。There is no stereochemical inversion due to this reaction. Compound (n)
Examples of reactive derivatives include acid halides such as acid chlorides and acid bromides, acid anhydrides, mixed acid anhydrides, and active esters. When compound ([1) is used as a free carboxylic acid, the reaction is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide.
反応は、メチレンクロリド、ジメチルホルムアミド等の
有機溶媒中、冷却下乃至室温下で行うのが有利である。The reaction is advantageously carried out in an organic solvent such as methylene chloride or dimethylformamide under cooling or at room temperature.
出発原料である化合物(■)、化合物([1)のいずれ
もが左旋性光学異性体である場合、生成物は本質的にジ
アステレオマ−Aの右旋性光学異性体だけであるから、
抽出、濃縮などの慣用操作により目的物を単離できるが
、必要に応じてカラムクロマトグラフィーを行ってもよ
い。また、化合物(■)、化合分冊)の少なくとも一方
がラセミ体である場合は1反応液中には目的のジアステ
レオマ−Aの右旋性光学異性体の他にジアステレオマ−
Aの左旋性光学異性体、ジアステレオマ−Bの右、左旋
性光学異性体等が含まれるので、抽出、濃縮などの他に
カラムクロマトグラフィー、分別再結晶を行えば目的物
を単離することができる。When both the starting materials, compound (■) and compound ([1), are levorotatory optical isomers, the product is essentially only the dextrorotatory optical isomer of diastereomer-A.
The target product can be isolated by conventional operations such as extraction and concentration, but column chromatography may also be performed if necessary. In addition, if at least one of the compounds (■) and compound booklet) is a racemate, one reaction solution contains diastereomers in addition to the dextrorotatory optical isomer of diastereomer A of interest.
Since the levorotatory optical isomer of A and the right and levorotatory optical isomers of diastereomer B are included, the target product can be isolated by performing column chromatography and fractional recrystallization in addition to extraction and concentration. can.
例えば、ジアステレオマ−Aの右旋性光学異性体とジア
ステレオマ−Bの左旋性光学異性体の混合物はシリカゲ
ルを担体とし、酢酸エチル−酢酸を容離液とするカラム
クロマトグラフィーに付し、 YM −09730の
ジアステレオマ−Aの右旋性光学異性体を分離するか、
またはL−(→−リンゴ酸と反応させてジアステレオマ
−Aの右旋性光学異性体及びジアステレオマ−Bの左旋
性光学異性体のL −(→−リンゴ酸塩とし、これを分
別再結晶することによシジアステレオマ−Aの右旋性光
学異性体の1.−(→−リンゴ酸塩を得る。For example, a mixture of the dextrorotatory optical isomer of diastereomer A and the levorotatory optical isomer of diastereomer B is subjected to column chromatography using silica gel as a carrier and ethyl acetate-acetic acid as the eluent, and yields YM-09730. to separate the dextrorotary optical isomers of diastereomer-A,
Alternatively, reacting with L-(→-malic acid to obtain L-(→-malate) of the dextrorotary optical isomer of diastereomer A and the levorotatory optical isomer of diastereomer B, and fractionally recrystallizing these. The dextrorotary enantiomer 1.-(→-malate of Yoshidiastereomer-A is obtained.
カラムクロマトグラフィーによる分離では。In separation by column chromatography.
最初の溶出液よりジアステレオマ−Aの右旋性光学異性
体、後の溶出液よりジアステレオマ−Bの左旋性光学異
性体を取得することができる。The dextrorotatory optical isomer of diastereomer A can be obtained from the first eluate, and the levorotatory optical isomer of diastereomer B can be obtained from the later eluate.
担体として使用されるシリカゲルとしてはカラムクロマ
トグラフィーに一般に使用されるものであれば特に制限
はない。溶離液である酢酸エチルと酢酸との混合比につ
いては特に制限はないが2通常酢酸エチルを主体とし、
これに歩容量の酢酸を混合したものが好ましい、混合比
は概ね酢酸エチル30〜50v/vに対し、酢酸1〜1
0v/v程度が便利であり、酢酸の配合量が低下すると
目的化合物の溶出時間が長くなる。The silica gel used as a carrier is not particularly limited as long as it is commonly used in column chromatography. There are no particular restrictions on the mixing ratio of the eluent ethyl acetate and acetic acid, but 2 usually ethyl acetate is used as the main component,
It is preferable to mix this with a walking amount of acetic acid.The mixing ratio is approximately 30-50v/v of ethyl acetate to 1-1% of acetic acid.
A value of about 0 v/v is convenient, and as the amount of acetic acid decreases, the elution time of the target compound becomes longer.
溶出速度、処理温度は適宜の条件を採用しうる。Appropriate conditions can be adopted for the elution rate and treatment temperature.
一方、L−(→−リンゴ酸を用いる方法は。On the other hand, the method using L-(→-malic acid).
YM−09730のジアステレオマ−Aの右旋性光学異
性体のr、−(→−リンゴ酸塩が結晶性であり。The r,-(→-malate salt of the dextrorotary optical isomer of diastereomer-A of YM-09730 is crystalline.
分別再結晶によりその光学異性体の分離にも利用できる
。この分別再結晶に使用できる溶媒としてはメタノール
、エタノール、アセトン、アセトニトリルなどを挙げる
ことができる。It can also be used to separate its optical isomers by fractional recrystallization. Examples of solvents that can be used in this fractional recrystallization include methanol, ethanol, acetone, and acetonitrile.
このようにして得られたジアステレオマ−Aの右旋性光
学異性体のL−(→−リンゴ酸塩はそのままでも医薬と
して供しうるが、ジアステレオマ−Aの右旋性光学異性
体の酢酸塩などはさらに必要により、塩基で処理して遊
離形とじた後、適当な酸で処理して、好適な他の塩に導
くことができる。The thus obtained L-(→-malate salt of the dextrorotatory optical isomer of diastereomer A) can be used as a medicine as it is, but the acetate salt of the dextrorotary optical isomer of diastereomer A can be used as a medicine. Further, if necessary, the free form can be treated with a base and then treated with a suitable acid to lead to other suitable salts.
(発明の効果)
本発明目的化合物のYM−09730のジアステレオマ
−Aの右旋性光学異性体及びその薬理学的に許容される
酸付加塩は文献未記載の新規化合物であり、冠動脈内直
接投与による冠面流量増加率において、左旋性光学異性
体(を体)の約40倍、各異性体の等景況合物(64体
)の2.5倍の面積比を示し、tた冠動脈への高い親和
性を有する。(Effects of the Invention) The dextrorotatory optical isomer of diastereomer A of YM-09730 and its pharmacologically acceptable acid addition salts, which are the object compounds of the present invention, are new compounds that have not been described in any literature, and are administered directly into the coronary artery. In terms of the rate of increase in coronary flow rate, the area ratio was approximately 40 times that of the levorotatory optical isomer (body) and 2.5 times that of the isomer combination (64 bodies), and Has high affinity.
本発明の製造法によれば、この新規かつ有用なYM−0
9730のジアステレオマ−Aの右旋性光学異性体を1
選択的高収率に製造することができ、産業上の利用価値
が極めて大である。According to the production method of the present invention, this new and useful YM-0
The dextrorotary optical isomer of diastereomer-A of 9730 is 1
It can be selectively produced in high yield and has extremely high industrial utility value.
(実施例)
以下に実施例を掲記し2本発明をさらに詳細に説明する
。なお9本発明の原料化合物である化合物(n)および
(III)は公知の物質であると認められるが1本発明
に適用するに際し、新規。(Example) The present invention will be described in further detail by referring to Examples below. It is recognized that compounds (n) and (III), which are the raw material compounds of the present invention, are known substances, but they are new when applied to the present invention.
有用な方法により製造できたので、参考例に示す。Since it could be produced by a useful method, it is shown as a reference example.
参考例1゜
(1) m−二トロベンズアルデヒド6.04g、ア
セト酢酸tert−ブチルエステル6.32g、ピペリ
ジン0.17gおよび酢酸0.6 mlのベンゼン靜液
20□tを共沸脱水装置を用いて6時間加熱還流に付す
。Reference Example 1゜(1) 20□t of benzene solution containing 6.04 g of m-nitrobenzaldehyde, 6.32 g of tert-butyl acetoacetate, 0.17 g of piperidine, and 0.6 ml of acetic acid was prepared using an azeotropic dehydrator. Heat under reflux for 6 hours.
冷接、水10m1を加え、ベンゼン層を分取する。Add cold water, add 10 ml of water, and separate the benzene layer.
ベンゼン層を飽和炭酸水素ナトリウム水溶液。The benzene layer is saturated with aqueous sodium bicarbonate solution.
飽和食塩水で順次洗浄した後、無水硫酸マグネシウムで
乾燥する。溶媒を減圧下留去した後。After sequentially washing with saturated saline, drying with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure.
得られる残渣をシリカゲルカラムクロマトグラフィーに
付す。n−へキサン:酢酸エチル(5:1容量比)溶出
部より得られる結晶をn−ヘキサンで洗浄し、無色結晶
として2− (m −ニトロベンジリデン)アセト酢酸
tartブチルエステルの幾何異性体の混合物5.82
gを得る。The resulting residue is subjected to silica gel column chromatography. The crystals obtained from the n-hexane:ethyl acetate (5:1 volume ratio) elution were washed with n-hexane, and a mixture of geometric isomers of 2-(m-nitrobenzylidene)acetoacetic acid tart butyl ester was obtained as colorless crystals. 5.82
get g.
融点 33〜36℃。Melting point: 33-36°C.
(2) (1)で得た2−(m−ニトロベンジリデン
)アセト酢酸tert−ブチルエステル3.56gおよ
び3−アミノクロトン酸メチルエステル1.41gとを
tert−ブタノール7ml中20時間加熱還流に付す
。(2) 3.56 g of 2-(m-nitrobenzylidene)acetoacetic acid tert-butyl ester obtained in (1) and 1.41 g of 3-aminocrotonic acid methyl ester were heated under reflux for 20 hours in 7 ml of tert-butanol. .
溶媒を減圧下留去し得られる油状物をn−ヘキサンで処
理し、目的とする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−3−tert−ブチルエステル−5−メチル
エステルヲ黄色結晶トして4.6gを得る。The solvent was distilled off under reduced pressure, and the resulting oil was treated with n-hexane to obtain the desired 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid. Yellow crystals of 3-tert-butyl ester-5-methyl ester were obtained to obtain 4.6 g.
融点 120〜122℃
(3) 25%臭化水素酢酸溶液5 tnlに氷水冷
却下(2)で得た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−3−tert −7”チルエステル−5−メ
チルエステル2.5gのトルエン溶液5mlを滴下する
。氷水冷却下で5分間攪拌した後、氷水50m1に注ぐ
。10%水酸化ナトリウムを用いて塩基性とした後、ト
ルエンで抽出する。水層を濃塩酸で酸性とし、析出する
結晶を沢取する。結晶をエーテルで洗浄して目的とする
5−メトキシカルボニル−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−
カルボン酸(ラセミ体)1.24gを得る。Melting point: 120-122°C (3) 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, obtained in (2) under ice water cooling in 5 tnl of 25% hydrogen bromide acetic acid solution. Add dropwise 5 ml of a toluene solution containing 2.5 g of 5-dicarboxylic acid-3-tert-7" methyl ester. Stir for 5 minutes under cooling with ice water, then pour into 50 ml of ice water. Using 10% sodium hydroxide. The aqueous layer is acidified with concentrated hydrochloric acid and the precipitated crystals are collected. The crystals are washed with ether to obtain the desired 5-methoxycarbonyl-2,6-dimethyl- 4-(m
-nitrophenyl)-1,4-dihydropyridine-3-
1.24 g of carboxylic acid (racemate) is obtained.
融点 203〜204℃(分解)
参考例2゜
m−二トロベンズアルデヒド7.55g、 3−アミノ
クロトン酸メチルエステル5.75gおよびアセト酢酸
tert−ブチルエステル7.90gのtert−ブタ
ノール溶液25 mlを22時間加熱還流する。溶媒を
減圧下留去し、得られる残漬をトルエン150m1に溶
解し、10%塩酸、飽和炭酸水素ナトリウム溶液および
飽和食塩水で順次洗浄した後、無水硫酸マグネシウムで
乾燥する。溶媒を減圧下留去し油状物19.62 gを
得る。これをトルエン20m7に溶解し、氷水冷却下2
5%臭化水素酢酸溶液20m1に滴下する。同温度で5
分間攪拌した後、氷水200 mlに注ぐ。10%水酸
化ナトリウム250mtを加え、塩基性とした後トルエ
ン100 mlで洗浄する。水層を濃塩酸にて酸性とし
、析出する結晶をP取して目的とする 5−メトキシカ
ルボニル−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−カルボン酸(ラ
セミ体)4.51gを得る。なお、光学活性体は、ケミ
カル アンド ファーマシェチカル ブレチ、7 (C
hem。Melting point: 203-204°C (decomposition) Reference example 2: 25 ml of a solution of 7.55 g of m-nitrobenzaldehyde, 5.75 g of 3-aminocrotonic acid methyl ester, and 7.90 g of tert-butyl acetoacetate in tert-butanol was added to 22 Heat to reflux for an hour. The solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 150 ml of toluene, washed successively with 10% hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 19.62 g of an oily substance. Dissolve this in 20 m7 of toluene and cool with ice water for 2
Add dropwise to 20 ml of 5% hydrogen bromide and acetic acid solution. 5 at the same temperature
After stirring for a minute, pour into 200 ml of ice water. Add 250 mt of 10% sodium hydroxide to make it basic, and then wash with 100 ml of toluene. The aqueous layer is made acidic with concentrated hydrochloric acid, and the precipitated crystals are collected to obtain the desired 5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carbonyl. 4.51 g of acid (racemate) is obtained. The optically active substance is Chemical and Pharmaceutical Brech, 7 (C
hem.
Pharm、 Bull、 )、 38 、2809
(1980)に記載の方法により得られる。Pharm, Bull, ), 38, 2809
(1980).
参考例3゜
(1) dt −1−ベンジル−3−ヒドロキシピロ
リジン17.7g、!:D−(→−マンデル酸15.2
gをアセトン66m7に加熱溶解し4°Cに一夜静置し
析出する結晶8.5gを26mtのアセトンから再結晶
して、(S)−(→−1−ベンジルー3−ヒドロキシピ
ロリジンのD−(→マンデル酸塩5.1gを得る。Reference Example 3゜(1) dt -1-benzyl-3-hydroxypyrrolidine 17.7 g,! :D-(→-mandelic acid 15.2
g was heated and dissolved in 66 m7 of acetone, left to stand overnight at 4°C, and 8.5 g of precipitated crystals were recrystallized from 26 mt of acetone to obtain (S)-(→D-( of -1-benzyl-3-hydroxypyrrolidine). → Obtain 5.1 g of mandelate.
比旋光度[α1g −45,5°(C=1.メタノール
)。Specific optical rotation [α1g −45,5° (C=1.methanol).
更に再結晶をくり返しても比旋光度に変化は無かった。Even after repeated recrystallization, there was no change in the specific rotation.
融点101〜102℃。ここに得た(S)一体の塩のN
−CH2−Phの核磁気共鳴スペク)/しは4.03
ppm (1重線、2H)K観測さ、れ、(R)一体の
4.01 ppmにおけるAB型の4重線(J = 1
2.5 Hz)は観測されなかった。Melting point: 101-102°C. The (S) unitary salt N obtained here
-CH2-Ph nuclear magnetic resonance spectrum) / shi is 4.03
ppm (Singlet, 2H) K observed, (R) quartet of type AB at 4.01 ppm (J = 1
2.5 Hz) was not observed.
(2) (S)−(→−1−ベンジルー3−ヒドロキ
シピロリジンのD−(→−マンデル酸塩22gをクロロ
ホルム50+nlに溶解し、クロロホルム層を無水炭酸
ナトリウム14.4gの水90mtの溶液で洗浄し、無
水硫酸マグネシウムで乾燥し、クロロホルムを留去した
後減圧蒸留して(S) −(→−1−ベンジルー3−ヒ
ドロキシピロリジンx1.sgを得る。沸点109℃/
0.65 mmHg 、 [α]賃−3.77°(c
=5、メタノール)。(2) Dissolve 22 g of (S)-(→-1-benzyl-3-hydroxypyrrolidine D-(→-mandelate) in 50+nl of chloroform, and wash the chloroform layer with a solution of 14.4 g of anhydrous sodium carbonate in 90 ml of water. The mixture was dried over anhydrous magnesium sulfate, chloroform was distilled off, and then distilled under reduced pressure to obtain (S) -(→-1-benzyl-3-hydroxypyrrolidine x 1.sg. Boiling point 109°C/
0.65 mmHg, [α] -3.77° (c
= 5, methanol).
参考例4゜
(S) −(→−リンゴ酸75gをベンジルアミン75
m1と170°Cで3時間反応させ(S)−(−)−1
−ベンジル−3−ヒドロキシコバ、り酸イミド5.27
gを得た。Reference example 4゜(S) -(→-75g of malic acid was mixed with 75g of benzylamine
React with m1 at 170 °C for 3 hours (S)-(-)-1
-benzyl-3-hydroxycoba, phosphoric acid imide 5.27
I got g.
融点 99〜101℃;[αコB−s1.1°(C=1
゜メタノール)。Melting point 99-101°C; [α B-s1.1° (C=1
゜methanol).
無水テトラヒドロフラン340 rnlに9.73gの
水素化アルミニウムリチウムを懸濁させ、水冷下無水テ
トラヒドロフラン200 mlに懸濁した前記イミド2
0.5gを滴下した。3時間加熱還流したのち。9.73 g of lithium aluminum hydride was suspended in 340 rnl of anhydrous tetrahydrofuran, and the imide 2 was suspended in 200 ml of anhydrous tetrahydrofuran under water cooling.
0.5 g was added dropwise. After heating under reflux for 3 hours.
冷却し、これに100gの硫酸ナトリウム・10水塩を
加えた。水冷下、−夜攪拌し、不溶物をf去し、F液を
減圧下濃縮して、残渣を減圧蒸留すると、沸点109〜
115°C/ 08 mmHg= [α]B 3.0
0をもツ(S)−(→−1−ベンジルー3−ヒドロキシ
ピロリジン13.8 gが得られた。After cooling, 100 g of sodium sulfate decahydrate was added thereto. Stir overnight under water cooling, remove insoluble materials, concentrate solution F under reduced pressure, and distill the residue under reduced pressure.
115°C/08 mmHg=[α]B 3.0
13.8 g of (S)-(→-1-benzyl-3-hydroxypyrrolidine) was obtained.
このようにして得られた(S) −(→体は、シフト試
薬[Eu −TFMC(III) ]を加えた3位の水
素の核磁気共鳴スペクトルから10%のR−((1)体
を含んでいた。この(S) −8体を参考例3の如くに
D−(→マンデル酸塩とし、3倍容のエタノール次いで
6倍容のエタノール−トルエン(1:5)から再結晶し
て得たマンデル酸塩[[α]; −45,2°コを処理
して。The (S)-(→ body obtained in this way was determined from the nuclear magnetic resonance spectrum of the hydrogen at the 3-position with the addition of a shift reagent [Eu-TFMC(III)], indicating that 10% of the R-((1) body) was This (S) -8 isomer was converted to D-(→ mandelate salt as in Reference Example 3) and recrystallized from 3 volumes of ethanol and then 6 volumes of ethanol-toluene (1:5). The obtained mandelate [[α]; −45,2° was treated.
(S)−H−1−ベンジル−3−ヒドロキシピロリジン
[沸点115〜120℃/ 1.2〜1.5 mmHg
、 [αコB −3,77゜(C=S、 メタノール
)コ8,6gを得る。(S)-H-1-benzyl-3-hydroxypyrrolidine [boiling point 115-120°C/1.2-1.5 mmHg
, 8.6 g of [αcoB -3,77° (C=S, methanol) is obtained.
参考例5゜
9−ボラビシクロ[3,3,1]ノナン(0,5Mテト
ラヒドロフラン溶液)50mtに2−(−))−ピネン
3.4gを加え、60℃で5時間攪拌する。室温に冷却
し、■−ベンジルー3−ピロ!J シ/ y 1.75
gを加える。室温で4日間攪拌した後、0℃でアセトア
ルデヒド1.3 mlを加える。溶媒を減圧留去し。Reference Example 5 3.4 g of 2-(-)-pinene was added to 50 mt of 9-borabicyclo[3,3,1]nonane (0.5M solution in tetrahydrofuran) and stirred at 60°C for 5 hours. Cool to room temperature, ■-benzyru-3-pyro! J shi/y 1.75
Add g. After stirring for 4 days at room temperature, 1.3 ml of acetaldehyde is added at 0°C. The solvent was removed under reduced pressure.
残渣にエーテル20m1を加える。0℃に冷却し。Add 20 ml of ether to the residue. Cool to 0°C.
2−アミンエタノール1.5 mlを加え攪拌する。生
じた沈殿を沢去する。エーテル溶液をIN−塩酸で抽出
し、塩酸層を炭酸ナトリウムでアルカリ性°としジクロ
ロメタンで抽出する。抽出液を無水硫酸マグネシウムで
乾燥、濃縮し、粗生成物1.1gを得る。粗生成−を減
圧蒸留し精製物0.6gを得た。沸点106℃/ 0.
9 mmHg0ここに得た(S)−H−1−ベンジル−
3−ヒドロキシピロリジンはシフト試薬[Eu −TF
MC(ill) ]を加えた3位の水素の核磁気共鳴ス
ペクトルから30%0%エナンチオエフセス、e、)で
あった。Add 1.5 ml of 2-amine ethanol and stir. Sweep away the formed precipitate. The ether solution is extracted with IN-hydrochloric acid, the hydrochloric acid layer is made alkaline with sodium carbonate and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain 1.1 g of a crude product. The crude product was distilled under reduced pressure to obtain 0.6 g of purified product. Boiling point 106℃/0.
9 mmHg0 (S)-H-1-benzyl- obtained here
3-Hydroxypyrrolidine is a shift reagent [Eu-TF
From the nuclear magnetic resonance spectrum of hydrogen at the 3-position with addition of MC(ill)], it was found to be 30% 0% enantioeffes, e,).
実施例1゜
5−メトキシカルボニル−26−ジメチル−4−(m−
ニトロフェニル) −1,4−シヒドロヒリジンー3−
カルボン酸33211!gをジクロロメタン3mlに溶
解し、氷水冷却下かきまぜながら五塩化リン250ff
1gを加え、さらに同温度で1時間攪拌する。Example 1 5-methoxycarbonyl-26-dimethyl-4-(m-
(nitrophenyl) -1,4-cyhydrohyridine-3-
Carboxylic acid 33211! Dissolve g in 3 ml of dichloromethane and add 250 ff of phosphorus pentachloride while stirring while cooling with ice water.
1 g of the mixture was added, and the mixture was further stirred at the same temperature for 1 hour.
反応液を一30℃に冷却し、(s)−1−ベンジル−3
−ヒドロキシピロリジン177fftgを加え、−30
℃で2時間反応させた後、水洗し、飽和炭酸水素ナトリ
ウム水溶液で洗浄後溶媒を留去して油状物を得る。油状
物をシリカゲルカラムクロマトクラフィーに付し、酢酸
エチル−酢酸(5:1v/v )溶出して、高速液体ク
ロマトグラフィー[カラム:ヌクレオシル■5 C+s
4.6mmダX 300mm。The reaction solution was cooled to -30°C, and (s)-1-benzyl-3
- Add 177 fftg of hydroxypyrrolidine, -30
After reacting at ℃ for 2 hours, the mixture is washed with water and saturated aqueous sodium bicarbonate solution, and the solvent is distilled off to obtain an oily substance. The oil was subjected to silica gel column chromatography, eluted with ethyl acetate-acetic acid (5:1 v/v), and then subjected to high performance liquid chromatography [Column: Nucleosil 5 C+s
4.6mm x 300mm.
カラム温度=30℃、移動相:テトラーn−ペンチルア
ンモニウムブロマイド(3mM) 含有0.05 モル
+Jy酸2水素カリウム(pH3)−アセトニトリル(
80:20v/v)、流速:毎分0.9ml、紫外線検
出(λ254nm)コで保持時間28分を示すYM−0
9730のジアステレオマ−Aの右旋性光学異性体を得
た。これをクロロホルム中飽和炭酸水素ナトリウム次い
で希塩酸で処理してYM−09730のジアステレオマ
−への右旋性光学異性体の塩酸塩1611TIgを得る
。Column temperature = 30°C, mobile phase: 0.05 mol of tetra n-pentylammonium bromide (3 mM) + potassium dihydrogen Jy acid (pH 3) - acetonitrile (
80:20v/v), flow rate: 0.9ml per minute, YM-0 showing a retention time of 28 minutes with ultraviolet detection (λ254nm).
The dextrorotary optical isomer of diastereomer-A of 9730 was obtained. This is treated with saturated sodium bicarbonate in chloroform and then dilute hydrochloric acid to yield the hydrochloride salt of the dextrorotary enantiomer of YM-09730 to the diastereomer, 1611TIg.
融点 228〜230°C(分解)
比旋光度[α] +116.3 (C=0.5.メタ
ノール)。Melting point 228-230°C (decomposed) Specific rotation [α] +116.3 (C=0.5.methanol).
実施例 2゜
(−)−5−メトキシカルボニル−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−カルボン酸332 mgをジクロロメタン3
mlに溶解し、水冷下かきまぜながら五塩化リン250
n1gを加え、さらに同温度で1時間攪拌する。反応
液を一30℃に冷却し、(S)−1−ベンジル−3−ヒ
ドロキシピロリジン177 ff1gを加え。Example 2゜(-)-5-methoxycarbonyl-2,6-dimethyl-
332 mg of 4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was dissolved in dichloromethane 3
ml of phosphorus pentachloride while stirring under water cooling.
1 g of the mixture was added, and the mixture was further stirred at the same temperature for 1 hour. The reaction solution was cooled to -30°C, and 177 ff1g of (S)-1-benzyl-3-hydroxypyrrolidine was added.
=30℃で2時間反応させた後9反応液をジクロロメタ
ン5 mlで希釈し、水5ml、次いで飽和炭酸水素ナ
トリウム溶液5 mlで2回洗浄する。溶媒を減圧濃縮
して得られる油状物をシリカゲル(15g使用)カラム
クロマトグラフィーに付し、トルエン−酢酸エチル(4
:1v/v)で溶出して得られる目的物を含む分画を濃
縮する。残留物を5 mlのクロロホルムに溶解し、0
.8規定塩酸−エタノール溶液1 mlを加えて得られ
る溶液を再び減圧濃縮する。After reacting for 2 hours at =30°C, the reaction mixture is diluted with 5 ml of dichloromethane and washed twice with 5 ml of water and then twice with 5 ml of saturated sodium bicarbonate solution. The oil obtained by concentrating the solvent under reduced pressure was subjected to column chromatography using silica gel (15 g), and toluene-ethyl acetate (4
:1v/v) and concentrate the fraction containing the target product. Dissolve the residue in 5 ml of chloroform and
.. Add 1 ml of 8N hydrochloric acid-ethanol solution and concentrate the resulting solution again under reduced pressure.
残留物を2m4のメタノールに溶解し、−夜水冷下に静
置して析出する結晶を濾過、乾燥してYM−09730
のジアステレオマ−Aの右旋性光学異性体の塩酸塩35
0mgを得る。The residue was dissolved in 2 m4 of methanol, left to stand overnight under water cooling, and the precipitated crystals were filtered and dried to yield YM-09730.
Hydrochloride salt of the dextrorotary optical isomer of diastereomer-A 35
Obtain 0 mg.
融点 226−228°C(分解)
比旋光度 [α]。+116.4°(c=1.メタノー
ル)核磁気共鳴スペクトル(CD30D、 TMS内部
標準、δppm)1.80〜2.70 (2H,br
oad m、 C4’−H2)2.32.2.34
(6H,s、 C2、a−CHl)3.0〜4.0
(4H,m、 C2’、!’−H2)3.64
(3H,s、 −COOCH3)4.42
(2H,s、−CHz l )5.08
(LH,s、 C4−H)5.30 (I H
,m、 C3’ −H)7.30〜8.20 (9H
,m、ベンゼン環のH)実施例 3゜
(−)−5−メトキシカルボニル−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−カルボン酸8401r1gをジクロロメタント
N、、N−ジメチルホルムアミドの混合溶媒(4:1
y/v ) 6 mlに懸濁し、水冷下に塩化チオニル
0.2mlを加え、1時間水冷攪拌する。得られた反応
液ニ(S)−1−ヘンシル−3・−ヒドロキシピロリジ
ン450 mgとジクロロメタン3 rntの溶液を水
冷下に滴下し、更に15時間水冷攪拌する。反応液をジ
クロロメタン10m1で希釈し、水10mt、飽和炭酸
水素すl−IJウム水溶液10m1(2回)、飽和食塩
水10m1で順次洗浄する。ジクロロメタン層を無水硫
酸マグネシウムで乾燥後、減圧濃縮して得られる油状物
をシリカゲル(40g使用)カラムクロマトグラフィー
に付し、トルエン−酢酸エチル(初め4 : 1 v/
v、次いで1 : l v/v)で溶出し。Melting point 226-228°C (decomposed) Specific rotation [α]. +116.4° (c=1.methanol) nuclear magnetic resonance spectrum (CD30D, TMS internal standard, δppm) 1.80-2.70 (2H, br
oad m, C4'-H2)2.32.2.34
(6H, s, C2, a-CHl) 3.0-4.0
(4H, m, C2',!'-H2) 3.64
(3H,s, -COOCH3)4.42
(2H,s,-CHzl)5.08
(LH,s, C4-H)5.30 (I H
, m, C3'-H) 7.30-8.20 (9H
, m, H of benzene ring) Example 3゜(-)-5-methoxycarbonyl-2,6-dimethyl-
8401r1g of 4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was dissolved in a mixed solvent of dichloromethane, N,,N-dimethylformamide (4:1
y/v) to 6 ml, add 0.2 ml of thionyl chloride under water cooling, and stir under water cooling for 1 hour. A solution of 450 mg of di(S)-1-hensyl-3·-hydroxypyrrolidine and 3 rnt of dichloromethane in the resulting reaction solution was added dropwise under water cooling, and the mixture was further stirred under water cooling for 15 hours. The reaction solution was diluted with 10 ml of dichloromethane, and washed sequentially with 10 ml of water, 10 ml of a saturated aqueous solution of sodium bicarbonate (twice), and 10 ml of saturated brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting oil was subjected to column chromatography on silica gel (40 g), toluene-ethyl acetate (initially 4:1 v/
v, then eluted with 1:l v/v).
目的物を含む分画を濃縮する。濃縮油状物(990mg
)を10m1のクロロホルムに溶解し、0.8規定塩酸
−エタノール溶液2.6 mlを加えて得られる溶液を
再び減圧濃縮する。残留物を5 mlのメタノールに溶
解し、−夜水冷下に静置して析出する結晶な濾過、乾燥
してYM−09730のジアステレオマ−Aの右旋性光
学異性体の塩酸塩850mgを得る。Concentrate the fraction containing the target product. Concentrated oil (990mg
) in 10 ml of chloroform, add 2.6 ml of 0.8N hydrochloric acid-ethanol solution, and concentrate the resulting solution again under reduced pressure. The residue was dissolved in 5 ml of methanol, left to stand overnight under water cooling, and crystals precipitated by filtration and drying to obtain 850 mg of hydrochloride of the dextrorotatory optical isomer of diastereomer-A of YM-09730.
融点 226−228℃(分解)
比旋光度 [α]D+116.4°(c = 1 、メ
タノール)核磁気共鳴スペクトル
(実施例2で得られる化合物と一致した。)実施例 4
゜
1)実施例3と同様にして得られる濃縮油状物(990
ml )をエタノール10m1に溶解し、再び減圧濃縮
した残留物にエタノール5 mlを加えて溶解する。溶
液を一夜水冷下に静置して析出する結晶を濾過、乾燥し
YM−09730のジアステレオマ−Aの右旋性光学異
性体の遊離塩基730 mgを得る。Melting point: 226-228°C (decomposed) Specific rotation: [α]D+116.4° (c = 1, methanol) Nuclear magnetic resonance spectrum (consistent with the compound obtained in Example 2) Example 4
゜1) Concentrated oil obtained in the same manner as in Example 3 (990
ml) in 10 ml of ethanol, and concentrated again under reduced pressure. To the residue, add 5 ml of ethanol and dissolve. The solution was allowed to stand overnight under water cooling, and the precipitated crystals were filtered and dried to obtain 730 mg of the free base of the dextrorotatory optical isomer of diastereomer A of YM-09730.
融点 137〜139°C
比旋光度 [αコ。+64.8°(e=1.メタノール
)核磁気共鳴スペクトル(CDCl3. TMS内部標
準、δppm)1.40−3.0 (6H,m、 C2
’、4’、、’ −H2)2.34.2.36 (6
H,s、 C2,6−CH3)3.65 (5H,s
、−COOCHl及び−c■2o)5.10 (I H
,s、 C4−H)5.12 (I H,m、 C8
’ −H)5.78 (I H,broad a、
NH)7.1−6〜8.24 (9H,m、ベンゼン環
のH)2) YM〜09730のジアステレオマ−A
の右旋性光学異性体の遊離塩基700 mgをクロロホ
ルム10m1及び0.8N塩酸−エタノール溶液1.8
mlに溶解し、減圧濃縮する。得られた油状物をメタ
ノール3.5 mlに溶解し、−夜氷冷下罠静置して得
られる結晶な濾過、乾燥してYM−09730のジアス
テレオマ−Aの右旋性光学異性体の塩酸塩630■を得
る。Melting point 137-139°C Specific rotation [α] +64.8° (e=1.methanol) nuclear magnetic resonance spectrum (CDCl3. TMS internal standard, δppm) 1.40-3.0 (6H, m, C2
',4',,'-H2)2.34.2.36 (6
H,s, C2,6-CH3)3.65 (5H,s
, -COOCHL and -c■2o)5.10 (I H
,s, C4-H)5.12 (I H,m, C8
'-H) 5.78 (I H, broad a,
NH)7.1-6~8.24 (9H,m, H of benzene ring)2) Diastereomer-A of YM~09730
700 mg of the free base of the dextrorotatory enantiomer of was added to 10 ml of chloroform and 1.8 mL of 0.8N hydrochloric acid-ethanol solution.
ml and concentrate under reduced pressure. The obtained oil was dissolved in 3.5 ml of methanol and left to stand overnight in a trap under ice cooling to obtain a crystalline filtration. After drying, the dextrorotary optical isomer of diastereomer A of YM-09730 was dissolved in hydrochloric acid. Obtain 630 μ of salt.
融点 228〜230℃(分解)
比旋光度 [α] +116.7°(c=1.メタノ
ール)核磁気共鳴スペクトル
(実施例2で得られる化合物と一致した。)長井省三
1、事件の表示
昭和61年特許願第12358号
2 発明の名称
YM −09730のジアステレオマ−Aの右旋性光学
異性体の新規製造法
3 補正をする者
事件との関係 特許出願人
住所 東京都中央区日本橋本町2丁目5番地1名称
(667) 山之内#薬株式会社代表者 森 岡
茂 夫
4、代理人
住所 東京都板橋区小豆沢1丁目1番8号5、補正命令
の日付 −二
昭和61年3月19日(発送日 s、61.3.25)
6、補正の対象
代理権を証明する書面及び明細書
7、補正の内容
(11別紙の通り委任状及び委任状訳文を提出する。Melting point 228-230°C (decomposed) Specific rotation [α] +116.7° (c=1.methanol) Nuclear magnetic resonance spectrum (consistent with the compound obtained in Example 2) Shozo Nagai 1, Incident display Patent Application No. 12358 of 1985 2 New method for producing the dextrorotary optical isomer of diastereomer-A of YM-09730 Title 3 Relationship to the case of the person making the amendment Patent applicant address 2 Nihonbashi Honmachi, Chuo-ku, Tokyo Chome 5-1 name
(667) Yamanouchi Yakuhin Co., Ltd. Representative: Shigeru Morioka 4, Agent address: 1-8-5, Azuzawa 1-chome, Itabashi-ku, Tokyo, Date of amendment order - March 19, 1985 (shipment date: s, 61.3.25)
6. Documents and specifications certifying the power of attorney subject to amendment 7. Contents of amendment (11) Submit a power of attorney and a translation of the power of attorney as shown in Attachment 11.
(2)別紙の通り、明細書の浄書(内容に変更なし)を
提出する。(2) Submit an engraving of the specification (with no changes to the contents) as shown in the attached sheet.
Claims (1)
−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 3−
(1−ベンジルピロリジン−3−イル)エステル 5−
メチルエステルのジアステレオマ−Aの右旋性光学異性
体( I )またはその薬学的に利用できる酸付加塩を製
造するに際し、 (イ)式 ▲数式、化学式、表等があります▼(II) で示される化合物の右旋性光学異性体と式 ▲数式、化学式、表等があります▼(III) で示される化合物の左旋性光学異性体とを反応させ、反
応生成物から上記右旋性光学異性体( I )を得るか、
または(ロ)すくなくとも一方がラセミ体である化合物
(II)と化合物(III)とを反応させ、反応生成物から
カラムクロマトグラフィーまたは分別結晶により上記右
旋性光学異性体( I )を得ることを特徴とする方法。[Claims] The hydrochloride has a melting point of 223 to 230°C (decomposition) (±)
-2,6-dimethyl-4-(m-nitrophenyl)-1
,4-dihydropyridine-3,5-dicarboxylic acid 3-
(1-benzylpyrrolidin-3-yl)ester 5-
When producing the dextrorotary optical isomer (I) of diastereomer A of methyl ester or its pharmaceutically usable acid addition salt, the formula (A) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) The dextrorotatory optical isomer of the compound represented by the formula ▲Mathematical formula, chemical formula, table, etc.▼(III) is reacted with the dextrorotatory optical isomer of the compound shown in (I) or
or (b) reacting compound (II), at least one of which is racemic, with compound (III), and obtaining the above-mentioned dextrorotatory optical isomer (I) from the reaction product by column chromatography or fractional crystallization. How to characterize it.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP60-12051 | 1985-01-24 | ||
JP1205185 | 1985-01-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS61267577A true JPS61267577A (en) | 1986-11-27 |
Family
ID=11794796
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP61012358A Pending JPS61267577A (en) | 1985-01-24 | 1986-01-22 | Novel production of dextrorotary optical isomer of ym-09730 diastereomer a |
Country Status (12)
Country | Link |
---|---|
JP (1) | JPS61267577A (en) |
KR (1) | KR900002342B1 (en) |
CN (1) | CN1023483C (en) |
AT (1) | AT390613B (en) |
CA (1) | CA1273931A (en) |
DK (1) | DK468385A (en) |
ES (1) | ES8607284A1 (en) |
FI (1) | FI83517C (en) |
GR (1) | GR852497B (en) |
IT (1) | IT1221762B (en) |
MX (1) | MX260A (en) |
NO (1) | NO166643C (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002010399A1 (en) * | 2000-08-01 | 2002-02-07 | Kaneka Corporation | Novel carbonyl reductase, gene thereof and method of using the same |
US7652152B2 (en) | 2005-07-20 | 2010-01-26 | Chiroad Incorporate | Synthetic method of optically pure (S)-3-hydroxypyrrolidine |
EP4382529A1 (en) | 2022-12-07 | 2024-06-12 | Bayer Consumer Care AG | A process for preparing pure (3s)-pyrrolidin-3-ol and pure (3s)-pyrrolidin-3-ol hydrochloride |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101643469B (en) * | 2008-12-27 | 2012-11-21 | 武汉百科药物开发有限公司 | Synthesis process of barnidipine hydrochloride |
-
1985
- 1985-09-26 FI FI853697A patent/FI83517C/en not_active IP Right Cessation
- 1985-10-08 ES ES547696A patent/ES8607284A1/en not_active Expired
- 1985-10-11 CN CN85107590A patent/CN1023483C/en not_active Expired - Lifetime
- 1985-10-14 AT AT0297085A patent/AT390613B/en not_active IP Right Cessation
- 1985-10-14 DK DK468385A patent/DK468385A/en not_active Application Discontinuation
- 1985-10-14 MX MX260A patent/MX260A/en unknown
- 1985-10-14 NO NO854062A patent/NO166643C/en not_active IP Right Cessation
- 1985-10-14 KR KR1019850007554A patent/KR900002342B1/en not_active IP Right Cessation
- 1985-10-15 GR GR852497A patent/GR852497B/el unknown
- 1985-10-15 IT IT22489/85A patent/IT1221762B/en active
- 1985-10-15 CA CA000492966A patent/CA1273931A/en not_active Expired
-
1986
- 1986-01-22 JP JP61012358A patent/JPS61267577A/en active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002010399A1 (en) * | 2000-08-01 | 2002-02-07 | Kaneka Corporation | Novel carbonyl reductase, gene thereof and method of using the same |
US7033808B2 (en) | 2000-08-01 | 2006-04-25 | Kaneka Corporation | Carbonyl reductase, gene thereof and method of using the same |
US7652152B2 (en) | 2005-07-20 | 2010-01-26 | Chiroad Incorporate | Synthetic method of optically pure (S)-3-hydroxypyrrolidine |
EP4382529A1 (en) | 2022-12-07 | 2024-06-12 | Bayer Consumer Care AG | A process for preparing pure (3s)-pyrrolidin-3-ol and pure (3s)-pyrrolidin-3-ol hydrochloride |
WO2024121219A1 (en) | 2022-12-07 | 2024-06-13 | Bayer Consumer Care Ag | A process for preparing pure (3s)-pyrrolidin-3-ol and pure (3s)-pyrrolidin-3-ol hydrochloride |
Also Published As
Publication number | Publication date |
---|---|
KR860005637A (en) | 1986-08-11 |
CN85107590A (en) | 1986-07-23 |
NO166643B (en) | 1991-05-13 |
CN1023483C (en) | 1994-01-12 |
FI853697L (en) | 1986-07-25 |
CA1273931A (en) | 1990-09-11 |
FI83517C (en) | 1991-07-25 |
FI83517B (en) | 1991-04-15 |
NO166643C (en) | 1991-08-21 |
IT8522489A0 (en) | 1985-10-15 |
DK468385D0 (en) | 1985-10-14 |
ES8607284A1 (en) | 1986-05-16 |
GR852497B (en) | 1986-02-18 |
ES547696A0 (en) | 1986-05-16 |
NO854062L (en) | 1986-07-25 |
FI853697A0 (en) | 1985-09-26 |
IT1221762B (en) | 1990-07-12 |
DK468385A (en) | 1986-07-25 |
MX260A (en) | 1995-01-31 |
ATA297085A (en) | 1989-11-15 |
AT390613B (en) | 1990-06-11 |
KR900002342B1 (en) | 1990-04-12 |
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