JPH08319280A - Production of thiazolidine derivative - Google Patents

Production of thiazolidine derivative

Info

Publication number
JPH08319280A
JPH08319280A JP7146907A JP14690795A JPH08319280A JP H08319280 A JPH08319280 A JP H08319280A JP 7146907 A JP7146907 A JP 7146907A JP 14690795 A JP14690795 A JP 14690795A JP H08319280 A JPH08319280 A JP H08319280A
Authority
JP
Japan
Prior art keywords
compound
thioproline
formula
solution
thiazolidine
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
Application number
JP7146907A
Other languages
Japanese (ja)
Inventor
Katsuo Shinozaki
勝雄 篠崎
Masaaki Eda
正明 江田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zeria Pharmaceutical Co Ltd
Original Assignee
Zeria Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zeria Pharmaceutical Co Ltd filed Critical Zeria Pharmaceutical Co Ltd
Priority to JP7146907A priority Critical patent/JPH08319280A/en
Priority to PCT/JP1996/001021 priority patent/WO1996037487A1/en
Priority to AU52891/96A priority patent/AU5289196A/en
Publication of JPH08319280A publication Critical patent/JPH08319280A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

PURPOSE: To efficiently obtain the subject compound for medicines (intermediates) having prolylenedopeptidase-inhibiting action and improving actions on antihypoxia, cerebral circulation and cerebral metabolism by reacting a specific indanylcarboxylic acid derivative, etc., with L-thioproline. CONSTITUTION: A methylene chloride solution of L-thioproline and triethylamine, etc., is dropped into a compound expressed by formula I [A is methylene or ethylene; B is a halogen, a lower alkoxy or hydroxy; (n) is an integer of 0-5] (e.g. 2-indanylacetyl chloride) under ice cooling and the solutions are stirred at ambient temperature for 30min to react the compound of formula I with L-thioproline and the reacted solution is poured into ice water, stirred and the reaction solution is separated and the organic layer is washed with 1N hydrochloric acid and a saturated common salt water solution and dried with anhydrous magnesium sulfate, and the solvent is distilled away under reduced pressure and a mixed liquid of ethyl acetate with n-hexane is added to the residual material and the deposited crystal is filtered to provide the objective thiazolidine derivative expressed by formula II, which has prolylendopeptidase inhibiting action and improving actions on cerebral circulation and cerebral metabolism.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は、医薬及び医薬の製造中
間体の製造法に関し、特にプロリルエンドペプチダーゼ
阻害作用、抗低酸素作用、脳循環・脳代謝改善作用を併
せ持つチアゾリジン誘導体及びその製造中間体の製造法
に関する。TECHNICAL FIELD The present invention relates to a method for producing a medicine and an intermediate for producing a medicine, and particularly to a thiazolidine derivative having a prolyl endopeptidase inhibitory action, an anti-hypoxia action, a cerebral circulation / cerebral metabolism improving action and its production. It relates to a method for producing an intermediate.

【０００２】[0002]

【従来の技術】（４Ｒ）−３−（インダン−２−イル）
アセチル−４−（１−ピロリジニルカルボニル）チアゾ
リジン（別名：１−［３−（２−インダニルアセチル）
−Ｌ−チオプロリル］ピロリジン）に代表されるチアゾ
リジン誘導体の製造方法としては、特開平２−２６２５
５７号公報にその製造法が開示されている。それによれ
ば、チアゾリジン誘導体はインダニル誘導体にＬ−チオ
プロリン誘導体を反応させ、次いでピロリジン誘導体を
反応させて製造できることが示されているが、Ｌ−チオ
プロリン誘導体としてはＬ−チオプロリンアルキルエス
テルを用いた製造法が例示されており、Ｌ−チオプロリ
ンを用いた具体的な製造法は未記載である。2. Description of the Related Art (4R) -3- (Indan-2-yl)
Acetyl-4- (1-pyrrolidinylcarbonyl) thiazolidine (alias: 1- [3- (2-indanylacetyl))
As a method for producing a thiazolidine derivative typified by -L-thioprolyl] pyrrolidine), there is disclosed in JP-A-2-2625.
No. 57 discloses the manufacturing method. It is shown that the thiazolidine derivative can be produced by reacting an indanyl derivative with an L-thioproline derivative, and then with a pyrrolidine derivative. The method is illustrated, and the specific production method using L-thioproline is not described.

【０００３】[0003]

【発明が解決しようとする課題】しかしながら、上記の
方法においてはエステルの加水分解が必要であり、この
工程による収量の低下が懸念されていた。However, in the above-mentioned method, hydrolysis of the ester is necessary, and there is a concern that the yield may be reduced by this step.

【０００４】[0004]

【課題を解決するための手段】本発明者らは、その後さ
らなる研究を行なった結果、インダニル酢酸誘導体にＬ
−チオプロリンを反応させてＬ−チオプロリン誘導体を
製造し、さらにピロリジンを反応させてチアゾリジン誘
導体を製造する方法が、前記特許公報の実施例の方法に
比べて工程の短縮、原料コストの低下の点で優れてお
り、また同一容器内で連続して反応を行うことにより高
収率で製造できることを見いだし、（４Ｒ）−３−（イ
ンダン−２−イル）アセチル−４−（１−ピロリジニル
カルボニル）チアゾリジンに代表されるチアゾリジン誘
導体を安全かつ経済的に得ることができる方法として、
本製造法を完成した。As a result of further researches conducted by the present inventors, the indanyl acetic acid derivative was found to have L
-The method of reacting thioproline to produce an L-thioproline derivative, and further reacting pyrrolidine to produce a thiazolidine derivative is shorter in process and lower in raw material cost than the method of Examples of the above patent publications. It has been found that it is excellent and that it can be produced in high yield by continuously performing the reaction in the same container, and (4R) -3- (indan-2-yl) acetyl-4- (1-pyrrolidinylcarbonyl ) As a method for safely and economically obtaining a thiazolidine derivative represented by thiazolidine,
This manufacturing method was completed.

【０００５】即ち、本発明は一般式（Ｉ）That is, the present invention has the general formula (I)

【０００６】[0006]

【化６】 [Chemical 6]

【０００７】（式中、Ａはメチレン基又はエチレン基を
示し、Ｂはハロゲン原子、低級アルコキシ基又はヒドロ
キシ基を示し、ｎは０〜５の整数を示す。）で表される
化合物とＬ−チオプロリンを反応させ一般式（II）(Wherein A represents a methylene group or an ethylene group, B represents a halogen atom, a lower alkoxy group or a hydroxy group, and n represents an integer of 0 to 5) and L-. Reaction with thioproline General formula (II)

【０００８】[0008]

【化７】 [Chemical 7]

【０００９】（式中、Ａ、ｎは前記と同意義を示す。）
で表されるチアゾリジン化合物とし、さらにピロリジン
と反応させることを特徴とする、一般式（III）(In the formula, A and n have the same meanings as described above.)
A thiazolidine compound represented by the formula (III), which is further reacted with pyrrolidine

【００１０】[0010]

【化８】 Embedded image

【００１１】（式中、Ａ、ｎは前記と同意義を示す。）
で表されるチアゾリジン誘導体の製造法に関する。(In the formula, A and n have the same meanings as described above.)
Relates to a method for producing a thiazolidine derivative represented by

【００１２】また、本発明は一般式（Ｉ）The present invention also has the general formula (I)

【００１３】[0013]

【化９】 [Chemical 9]

【００１４】（式中、Ａ、Ｂ、ｎは前記と同意義を示
す。）で表される化合物とＬ−チオプロリンを反応させ
ることを特徴とする、一般式（II）(Wherein A, B and n have the same meanings as defined above) and L-thioproline is reacted with the compound of the general formula (II).

【００１５】[0015]

【化１０】 [Chemical 10]

【００１６】（式中、Ａ、ｎは前記と同意義を示す。）
で表されるチアゾリジン化合物の製造法に関する。(In the formula, A and n have the same meanings as described above.)
Relates to a method for producing a thiazolidine compound represented by

【００１７】一般式（III）の化合物は、プロリルエン
ドペプチダーゼ阻害作用、抗低酸素作用、脳循環・脳代
謝改善作用を併せ持つ医薬として有用であり、一般式
（II）の化合物はその製造中間体として有用である。The compound of the general formula (III) is useful as a drug having both a prolyl endopeptidase inhibitory action, an anti-hypoxia action, and a cerebral circulation / cerebral metabolism improving action. It is useful as a body.

【００１８】本発明の製造法によると、一般式（Ｉ）の
化合物から一般式（III）の化合物を約８４％の高収率
で製造することができ、またラセミ化の心配も全くない
という特徴を有する。According to the production method of the present invention, the compound of the general formula (III) can be produced from the compound of the general formula (I) in a high yield of about 84%, and there is no fear of racemization. It has characteristics.

【００１９】本発明において、「低級」とは炭素数１〜
４の意味を表し、「低級アルキル基」としては、例えば
メチル基、エチル基、プロピル基、イソプロピル基、ブ
チル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−
ブチル基等が挙げられる。In the present invention, "lower" has 1 to 1 carbon atoms.
4, which means, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-group.
Examples thereof include a butyl group.

【００２０】本発明の製造法は、下記の式で表される。The manufacturing method of the present invention is represented by the following formula.

【００２１】[0021]

【化１１】 [Chemical 11]

【００２２】（式中、Ａ、Ｂ、ｎは前記と同意義を示
す。）(In the formula, A, B and n have the same meanings as described above.)

【００２３】工程１ 化合物（Ｉ）とＬ−チオプロリンを反応させることによ
り、化合物（II）を製造することができる。反応は通
常、塩基の存在又は非存在下で行うことができる。反応
に用いられる溶媒としては、反応に影響を及ぼさないも
のであればよく、例えば塩化メチレン、クロロホルム、
１，２−ジクロロエタン等のハロゲン系溶媒、アセト
ン、メチルエチルケトン等のジアルキルケトン系溶媒、
Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド
等の極性非プロトン性溶媒、エーテル、テトラヒドロフ
ラン、ジオキサン等のエーテル系溶媒、トルエンなどの
ベンゼン系溶媒等が挙げられ、特にハロゲン系溶媒を用
いることが好ましい。塩基としては、例えば炭酸ナトリ
ウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カ
リウム等のアルカリ金属炭酸塩、水酸化ナトリウム、水
酸化カリウム、水酸化リチウム等のアルカリ金属水酸化
物、トリエチルアミン、ジイソプロピルエチルアミン等
のトリアルキルアミン類、ピリジン、ルチジン、４−ジ
メチルアミノピリジン等のピリジン類が挙げられるが、
トリアルキルアミン類が好ましく、特にトリエチルアミ
ンが好ましい。また、反応は通常、室温又は加温下で行
うことができる。化合物（Ｉ）においてＢがヒドロキシ
基である場合には、縮合剤を用いて反応を行うことが好
ましく、縮合剤としては１−（３−ジメチルアミノプロ
ピル）−３−エチルカルボジイミドやジシクロヘキシル
カルボジイミド等が挙げられる。Step 1 Compound (II) can be produced by reacting compound (I) with L-thioproline. The reaction can usually be performed in the presence or absence of a base. The solvent used in the reaction may be one that does not affect the reaction, for example, methylene chloride, chloroform,
Halogen-based solvents such as 1,2-dichloroethane, dialkyl ketone-based solvents such as acetone and methyl ethyl ketone,
Examples thereof include polar aprotic solvents such as N, N-dimethylformamide and dimethylsulfoxide, ether solvents such as ether, tetrahydrofuran and dioxane, benzene solvents such as toluene and the like, and halogen solvents are particularly preferable. Examples of the base include alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, triethylamine and diisopropylethylamine. Examples of pyridines include trialkylamines, pyridine, lutidine, and 4-dimethylaminopyridine.
Trialkylamines are preferable, and triethylamine is particularly preferable. In addition, the reaction can usually be performed at room temperature or under heating. When B is a hydroxy group in compound (I), it is preferable to carry out the reaction using a condensing agent, and examples of the condensing agent include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and dicyclohexylcarbodiimide. Can be mentioned.

【００２４】工程２ 化合物（II）とピロリジンを反応させることにより、チ
アゾリジン誘導体（III）を製造することができる。反
応は、化合物（II）のカルボン酸を常法にしたがってカ
ルボン酸エステル、酸ハライド、酸無水物など反応性の
高い置換基に変換した後、工程１と同様の操作により行
うことができる。Step 2 The thiazolidine derivative (III) can be produced by reacting the compound (II) with pyrrolidine. The reaction can be carried out by the same operation as in step 1 after converting the carboxylic acid of the compound (II) into a highly reactive substituent such as a carboxylic acid ester, an acid halide and an acid anhydride according to a conventional method.

【００２５】工程３ 化合物（Ｉ）とＬ−チオプロリンを反応させ、生成する
化合物（II）を単離、精製することなく、引き続き次の
反応に供することによりチアゾリジン誘導体（III）を
製造することができる。反応は通常、工程１と同様の操
作により得られた化合物（II）を含む反応液に、エステ
ル化剤、ハロゲン化剤、縮合剤などを加え、化合物（I
I）のカルボン酸部分を工程２と同様にして反応性の高
い置換基に変換し、工程１又は２と同様の操作によりピ
ロリジンと反応させることにより行うことができる。Step 3 A thiazolidine derivative (III) can be produced by reacting compound (I) with L-thioproline and subjecting the resulting compound (II) to the next reaction without isolation and purification. it can. The reaction is usually carried out by adding an esterifying agent, a halogenating agent, a condensing agent, etc. to the reaction solution containing the compound (II) obtained by the same operation as in step 1
It can be carried out by converting the carboxylic acid moiety of I) into a highly reactive substituent in the same manner as in step 2 and reacting it with pyrrolidine by the same operation as in step 1 or 2.

【００２６】本発明の製造法は、前記特許公報の実施例
の方法に比べて製造工程が短縮され、原料コストも低く
なるという利点を有している。さらに本発明は同一容器
内で連続して反応が行え、また収率・純度も高いので、
化合物（Ｉ）から化合物（III）を操作性良く、経済的
に、安全に製造することができる。The manufacturing method of the present invention has the advantages that the manufacturing process is shortened and the raw material cost is reduced as compared with the method of the embodiment of the above patent publication. Furthermore, the present invention allows continuous reaction in the same container, and since the yield and purity are high,
The compound (III) can be produced from the compound (I) with good operability, economically and safely.

【００２７】[0027]

【実施例】以下に本発明の製造法を実施例をあげて詳述
するが、本発明はこれに限定されるものではない。EXAMPLES The production method of the present invention is described in detail below with reference to examples, but the present invention is not limited thereto.

【００２８】実施例１ （４Ｒ）−３−（インダン−２−イル）アセチルチアゾ
リジン−４−カルボン酸の製造Example 1 Preparation of (4R) -3- (indan-2-yl) acetylthiazolidine-4-carboxylic acid

【００２９】[0029]

【化１２】 [Chemical 12]

【００３０】Ｌ−チオプロリン７．３２ｇをトリエチル
アミン１６．６mlと塩化メチレン１００mlの混合溶液に
溶解し、水冷下、２−インダニルアセチルクロリド９．
７３ｇの塩化メチレン５０ml溶液を滴下し、室温で３０
分間攪拌した。反応液を氷水に注ぎ攪拌した後分液し、
有機層を１Ｎ塩酸、飽和食塩水で洗浄し、無水硫酸マグ
ネシウムで乾燥した。溶媒を減圧留去し、残留物に酢酸
エチルとｎ−ヘキサンの混合液を加え析出した結晶を濾
取して標記化合物１３．７ｇを得た。収率９４．０％。 融点：１０８〜１０９℃ 旋光度［α］D：−９２°（c=1.0,MeOH）1 Ｈ−ＮＭＲ（CDCl3）δ：2.56(2H,d),2.59〜2.70(2H,
m),2.93〜3.05(1H,m),3.14〜3.37(4H,m),4.50(1H,d),4.
57(1H,d),5.12(1H,dd),7.11〜7.21(4H,m),10.1(1H,brs)7.32 g of L-thioproline was dissolved in a mixed solution of 16.6 ml of triethylamine and 100 ml of methylene chloride, and 2-indanylacetyl chloride was added under water cooling.
73 g of 50 ml of methylene chloride solution was added dropwise at room temperature for 30 minutes.
Stir for minutes. The reaction solution was poured into ice water, stirred, and then separated,
The organic layer was washed with 1N hydrochloric acid and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, a mixed solution of ethyl acetate and n-hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 13.7 g of the title compound. Yield 94.0%. Melting point: 108 to 109 ° C. Optical rotation [α] D: −92 ° (c = 1.0, MeOH) 1 H-NMR (CDCl 3 ) δ: 2.56 (2H, d), 2.59 to 2.70 (2H,
m), 2.93 to 3.05 (1H, m), 3.14 to 3.37 (4H, m), 4.50 (1H, d), 4.
57 (1H, d), 5.12 (1H, dd), 7.11〜7.21 (4H, m), 10.1 (1H, brs)

【００３１】実施例２ （４Ｒ）−３−（インダン−２−イル）アセチル−４−
（１−ピロリジニルカルボニル）チアゾリジンの製造Example 2 (4R) -3- (indan-2-yl) acetyl-4-
Production of (1-pyrrolidinylcarbonyl) thiazolidine

【００３２】[0032]

【化１３】 [Chemical 13]

【００３３】３−（インダン−２−イルアセチル）−Ｌ
−チオプロリン７２８mgをトリエチルアミン０．４２ml
と塩化メチレン１０mlの混合溶液に溶解し、氷冷下、塩
化ピバロイル３０２mgの塩化メチレン２．５ml溶液を滴
下し、同温で１時間攪拌した。この反応液にトリエチル
アミン０．４２mlを加え、次いで氷冷下でピロリジン１
７７mgの塩化メチレン２．５ml溶液を滴下し、室温で１
時間攪拌した。反応液を１Ｎ塩酸、水、飽和重曹水、飽
和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し
た。溶媒を減圧留去し、残留物に酢酸エチルとｎ−ヘキ
サンの混合液を加え析出した結晶を濾取することにより
標記化合物６３８mgを得た。収率７４．１％。 融点：８３〜８４℃ 旋光度［α］D：−１０６°（c=5.0,MeOH）1 Ｈ−ＮＭＲ（CDCl3）δ：1.79〜2.08(4H,m),2.56(2H,
d),2.59〜2.71(2H,m),2.91〜3.01(1H,m),3.11〜3.33(4
H,m),3.40〜3.48(2H,m),3.53〜3.63(1H,m),3.82〜3.90
(1H,m),4.65(1H,d),4.67(1H,d),5.10(1H,dd),7.11〜7.2
0(4H,m)3- (indan-2-ylacetyl) -L
-Thioproline 728 mg triethylamine 0.42 ml
It was dissolved in a mixed solution of 10 ml of methylene chloride and methylene chloride, and a solution of 302 mg of pivaloyl chloride in 2.5 ml of methylene chloride was added dropwise under ice cooling, followed by stirring at the same temperature for 1 hour. To this reaction solution, 0.42 ml of triethylamine was added, and then pyrrolidine 1 was added under ice cooling.
A solution of 77 mg of methylene chloride in 2.5 ml was added dropwise at room temperature to 1
Stir for hours. The reaction mixture was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, a mixed solution of ethyl acetate and n-hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 638 mg of the title compound. Yield 74.1%. Melting point: 83 to 84 ° C. Optical rotation [α] D: −106 ° (c = 5.0, MeOH) 1 H-NMR (CDCl 3 ) δ: 1.79 to 2.08 (4H, m), 2.56 (2H,
d), 2.59 to 2.71 (2H, m), 2.91 to 3.01 (1H, m), 3.11 to 3.33 (4
H, m), 3.40 ~ 3.48 (2H, m), 3.53 ~ 3.63 (1H, m), 3.82 ~ 3.90
(1H, m), 4.65 (1H, d), 4.67 (1H, d), 5.10 (1H, dd), 7.11-7.2
0 (4H, m)

【００３４】実施例３ （４Ｒ）−３−（インダン−２−イル）アセチル−４−
（１−ピロリジニルカルボニル）チアゾリジンの製造Example 3 (4R) -3- (indan-2-yl) acetyl-4-
Production of (1-pyrrolidinylcarbonyl) thiazolidine

【００３５】[0035]

【化１４】 Embedded image

【００３６】Ｌ−チオプロリン９．９９ｇをトリエチル
アミン２１．５mlと塩化メチレン１５０mlの混合溶液に
溶解し、水冷下、２−インダニルアセチルクロリド１
４．６ｇの塩化メチレン５０ml溶液を滴下し、同温で３
０分間攪拌した。この反応液を−５℃まで冷却し塩化ピ
バロイル９．０４ｇを滴下した後、氷冷下で１時間攪拌
した。この液にトリエチルアミン１０．４mlを加え、次
いで氷冷下にてピロリジン５．３４ｇの塩化メチレン２
５ml溶液を滴下し、室温で１時間攪拌した。反応液を１
Ｎ塩酸、水、飽和重曹水、飽和食塩水で順次洗浄し、無
水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残
留物に酢酸エチルとｎ−ヘキサンの混合液を加え析出し
た結晶を濾取することにより標記化合物２１．８ｇを得
た。収率８４．４％。 融点：８３〜８４℃ 旋光度［α］D：−１０６°（c=5.0,MeOH）1 Ｈ−ＮＭＲ（CDCl3）δ：1.79〜2.08(4H,m),2.56(2H,
d),2.59〜2.71(2H,m),2.91〜3.01(1H,m),3.11〜3.33(4
H,m),3.40〜3.48(2H,m),3.53〜3.63(1H,m),3.82〜3.90
(1H,m),4.65(1H,d),4.67(1H,d),5.10(1H,dd),7.11〜7.2
0(4H,m)L-thioproline (9.99 g) was dissolved in a mixed solution of triethylamine (21.5 ml) and methylene chloride (150 ml), and 2-indanylacetyl chloride 1 was added under water cooling.
A solution of 4.6 g of methylene chloride in 50 ml was added dropwise, and the mixture was heated to 3 at the same temperature.
Stirred for 0 minutes. The reaction solution was cooled to -5 ° C, 9.04 g of pivaloyl chloride was added dropwise, and the mixture was stirred under ice cooling for 1 hour. To this solution was added 10.4 ml of triethylamine, and then while cooling with ice, pyrrolidine (5.34 g) in methylene chloride 2 was added.
A 5 ml solution was added dropwise and the mixture was stirred at room temperature for 1 hour. 1 reaction mixture
It was washed successively with N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, a mixed solution of ethyl acetate and n-hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 21.8 g of the title compound. Yield 84.4%. Melting point: 83 to 84 ° C. Optical rotation [α] D: −106 ° (c = 5.0, MeOH) 1 H-NMR (CDCl 3 ) δ: 1.79 to 2.08 (4H, m), 2.56 (2H,
d), 2.59 to 2.71 (2H, m), 2.91 to 3.01 (1H, m), 3.11 to 3.33 (4
H, m), 3.40 ~ 3.48 (2H, m), 3.53 ~ 3.63 (1H, m), 3.82 ~ 3.90
(1H, m), 4.65 (1H, d), 4.67 (1H, d), 5.10 (1H, dd), 7.11-7.2
0 (4H, m)

【００３７】[0037]

【発明の効果】本発明はチアゾリジン誘導体の製造法に
関し、操作性がよく、また高価な試薬を使うこともなく
高収率・高純度で製造を実施できるため、操作性、経済
性、安全性に優れ、工業的に有利である。INDUSTRIAL APPLICABILITY The present invention relates to a method for producing a thiazolidine derivative, which has good operability and can be produced in a high yield and a high purity without using an expensive reagent. And is industrially advantageous.

Claims (3)

【特許請求の範囲】[Claims] 【請求項１】 一般式（Ｉ） 【化１】 （式中、Ａはメチレン基又はエチレン基を示し、Ｂはハ
ロゲン原子、低級アルコキシ基又はヒドロキシ基を示
し、ｎは０〜５の整数を示す。）で表される化合物とＬ
−チオプロリンを反応させることを特徴とする、一般式
（II） 【化２】 （式中、Ａ、ｎは前記と同意義を示す。）で表されるチ
アゾリジン化合物の製造法。1. A compound of the general formula (I) (Wherein A represents a methylene group or an ethylene group, B represents a halogen atom, a lower alkoxy group or a hydroxy group, and n represents an integer of 0 to 5) and L.
-The compound of the general formula (II): characterized by reacting with thioproline (In the formula, A and n have the same meanings as described above.) A method for producing a thiazolidine compound. 【請求項２】 一般式（Ｉ） 【化３】 （式中、Ａはメチレン基又はエチレン基を示し、Ｂはハ
ロゲン原子、低級アルコキシ基又はヒドロキシ基を示
し、ｎは０〜５の整数を示す。）で表される化合物とＬ
−チオプロリンを反応させ一般式（II） 【化４】 （式中、Ａ、ｎは前記と同意義を示す。）で表されるチ
アゾリジン化合物とし、さらにピロリジンと反応させる
ことを特徴とする、一般式（III） 【化５】 （式中、Ａ、ｎは前記と同意義を示す。）で表されるチ
アゾリジン誘導体の製造法。2. A compound represented by the general formula (I): (Wherein A represents a methylene group or an ethylene group, B represents a halogen atom, a lower alkoxy group or a hydroxy group, and n represents an integer of 0 to 5) and L.
-Reacting with thioproline, the compound of the general formula (II): (Wherein A and n have the same meanings as defined above), and a thiazolidine compound is further reacted with pyrrolidine. (In the formula, A and n have the same meanings as described above.) A method for producing a thiazolidine derivative. 【請求項３】 一般式（II）で表される化合物を単離・
精製することなく一般式（III）で表される化合物を得
る請求項第２項に記載の製造法3. Isolation of the compound represented by the general formula (II)
The production method according to claim 2, wherein the compound represented by the general formula (III) is obtained without purification.
JP7146907A 1995-05-23 1995-05-23 Production of thiazolidine derivative Pending JPH08319280A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7146907A JPH08319280A (en) 1995-05-23 1995-05-23 Production of thiazolidine derivative
PCT/JP1996/001021 WO1996037487A1 (en) 1995-05-23 1996-04-12 Process for producing thiazolidine derivatives
AU52891/96A AU5289196A (en) 1995-05-23 1996-04-12 Process for producing thiazolidine derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP7146907A JPH08319280A (en) 1995-05-23 1995-05-23 Production of thiazolidine derivative

Publications (1)

Publication Number Publication Date
JPH08319280A true JPH08319280A (en) 1996-12-03

Family

ID=15418273

Family Applications (1)

Application Number Title Priority Date Filing Date
JP7146907A Pending JPH08319280A (en) 1995-05-23 1995-05-23 Production of thiazolidine derivative

Country Status (3)

Country Link
JP (1) JPH08319280A (en)
AU (1) AU5289196A (en)
WO (1) WO1996037487A1 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0822847B2 (en) * 1988-12-08 1996-03-06 ゼリア新薬工業株式会社 Fused benzene derivative, pharmaceutical containing the same, and intermediate for producing the compound
JPH02207070A (en) * 1989-02-07 1990-08-16 Zeria Pharmaceut Co Ltd Amide acid imide derivative, drug containing same and intermediate for producing the compound
JPH049367A (en) * 1990-04-26 1992-01-14 Zeria Pharmaceut Co Ltd Arylalkanoyl derivative, production intermediate for the compound and drug containing the same
AU6983894A (en) * 1993-06-30 1995-01-24 Zeria Pharmaceutical Co., Ltd. Thiazolidine derivative and medicine containing the same

Also Published As

Publication number Publication date
AU5289196A (en) 1996-12-11
WO1996037487A1 (en) 1996-11-28

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