JPH06247948A - Production of 1,3-thiazolidine-4-carboxylic acid derivative or its salt - Google Patents
Production of 1,3-thiazolidine-4-carboxylic acid derivative or its saltInfo
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- JPH06247948A JPH06247948A JP19265492A JP19265492A JPH06247948A JP H06247948 A JPH06247948 A JP H06247948A JP 19265492 A JP19265492 A JP 19265492A JP 19265492 A JP19265492 A JP 19265492A JP H06247948 A JPH06247948 A JP H06247948A
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- JP
- Japan
- Prior art keywords
- salt
- chemical formula
- amino acid
- thiazolidine
- carboxylic acid
- Prior art date
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- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、１，３−チアゾリジン
−４−カルボン酸誘導体の製造法に関する。本発明のカ
ルボン酸誘導体は、保護アミノ酸としてヒト免疫不全ウ
イルスのプロテアーゼ阻害剤として有効なペプチド誘導
体、その他の生理活性ペプチド製造の中間体として有用
である。FIELD OF THE INVENTION The present invention relates to a method for producing a 1,3-thiazolidine-4-carboxylic acid derivative. INDUSTRIAL APPLICABILITY The carboxylic acid derivative of the present invention is useful as a protected amino acid, a peptide derivative effective as a protease inhibitor of human immunodeficiency virus, and an intermediate for producing other physiologically active peptides.
【０００２】[0002]
【従来の技術】本発明者らは、後天性免疫不全症候群(A
IDS)の治療あるいはその病原体であるヒト免疫不全ウイ
スル(HIV) の感染予防の試みとして、該ウイルスのプロ
テアーゼ阻害剤として有効なペプチド誘導体またはその
薬理的に許容される塩を提唱した (特願平3-348705号明
細書) 。そして、このペプチド誘導体の製造には、下記
（化４）で示される１，３−チアゾリジン−４−カルボ
ン酸誘導体が合成中間体として用いられる。BACKGROUND OF THE INVENTION The present inventors have found that the acquired immunodeficiency syndrome (A
As an attempt to treat (IDS) or prevent infection of its pathogen, human immunodeficiency virus (HIV), a peptide derivative effective as a protease inhibitor of the virus or a pharmacologically acceptable salt thereof was proposed (Japanese Patent Application No. Heisei 7-96 3-348705). Then, in the production of this peptide derivative, a 1,3-thiazolidine-4-carboxylic acid derivative represented by the following (Chemical Formula 4) is used as a synthetic intermediate.
【化４】 従来、この保護アミノ酸を製造するには、下記（化５）
で示されるアミノ酸を公知の方法、例えば、R. Neer ら
のHelv. Chim. Acta, 29, 1874 (1946) に記載された方
法で環化して下記（化６）で示される環状アミノ酸を製
造し、これを単離した後、この環状アミノ酸を、さらに
公知の方法、例えば、T. W. Greeneらの"Protective Gr
oups in Organic Synthesis" Chap 7, JOHN WILEY & SO
NS, NewYork(1981)に記載される方法でｔ−ブトキシカ
ルボニル化して製造されていた。[Chemical 4] Conventionally, the following (chemical formula 5) has been used to produce this protected amino acid.
A cyclic amino acid represented by the following (Chemical Formula 6) is produced by cyclizing the amino acid represented by the following formula by a known method, for example, the method described in Helv. Chim. Acta, 29 , 1874 (1946) of R. Neer et al. , This cyclic amino acid, after isolation, can be further isolated by known methods, eg, TW Greene et al., "Protective Gr.
oups in Organic Synthesis "Chap 7, JOHN WILEY & SO
It was produced by t-butoxycarbonylation by the method described in NS, New York (1981).
【化５】 [Chemical 5]
【化６】 [Chemical 6]
【０００３】[0003]
【発明が解決しようとしている課題】しかし、上記の方
法によると（化６）で示される環状アミノ酸を工程の途
中で単離しているため、製造工程が繁雑となる問題があ
り、より簡便な製造方法の開発が望まれていた。本発明
は、このような現状に鑑みてなされたもので、上記（化
４）で示される１，３−チアゾリジン−４−カルボン酸
誘導体を、簡便かつ安価に製造する方法を提供すること
を目的とする。However, according to the above method, the cyclic amino acid represented by the chemical formula (6) is isolated in the middle of the process, so that there is a problem that the production process is complicated, and a simpler production is possible. Development of a method was desired. The present invention has been made in view of the above circumstances, and an object thereof is to provide a method for simply and inexpensively producing the 1,3-thiazolidine-4-carboxylic acid derivative represented by the above (Chemical Formula 4). And
【０００４】[0004]
【課題を解決するための手段】本発明者らは、上記（化
５）で示されるアミノ酸から（化４）で示される１，３
−チアゾリジン−４−カルボン酸誘導体を簡便に製造す
る方法を開発すべく検討した結果、工程の途中で生成さ
れる中間生成物の（化６）で示される環状アミノ酸また
はその塩を単離せずに、そのまま反応を行って（化４）
で示される化合物に導く方法を見出して、本発明の完成
に至った。Means for Solving the Problems The present inventors have changed from the amino acid shown in (Chemical formula 5) to the 1,3 shown in (Chemical formula 4).
As a result of studies to develop a method for simply producing a thiazolidine-4-carboxylic acid derivative, a cyclic amino acid represented by the chemical formula (6) or a salt thereof, which is an intermediate product formed in the process, was not isolated. , Carry out the reaction as it is (chemical formula 4)
The present invention has been completed by finding a method leading to a compound represented by.
【０００５】すなわち、本発明は、下記（化７）で示さ
れるアミノ酸またはその塩とホルムアルデヒドとを反応
させて（化８）で示される環状アミノ酸またはその塩を
生成せしめ、これを単離することなくこの環状アミノ酸
またはその塩を含む反応混合物をジ−ｔ−ブチルジカル
ボナートと反応させて（化９）で示される１，３−チア
ゾリジン−４−カルボン酸誘導体を製造する方法に関す
る。ただし、（化７），（化８）及び（化９）中、R1及
びR2は同一または異なった、水素原子または低級アルキ
ル基を示す。このような低級アルキル基には、炭素数１
〜５のアルキル基、例えばメチル、エチル、プロピル、
iso −プロピル、ｎ−ブチル、sec −ブチル、ｔ−ブチ
ル、アミル等を例示することができる。That is, according to the present invention, an amino acid represented by the following (Chemical formula 7) or a salt thereof is reacted with formaldehyde to produce a cyclic amino acid represented by the following (Chemical formula 8) or a salt thereof, and isolated. The present invention relates to a method for producing a 1,3-thiazolidine-4-carboxylic acid derivative represented by (Chemical Formula 9) by reacting a reaction mixture containing this cyclic amino acid or a salt thereof with di-t-butyldicarbonate. However, in (Chemical formula 7), (Chemical formula 8) and (Chemical formula 9), R 1 and R 2 represent the same or different hydrogen atoms or lower alkyl groups. Such a lower alkyl group has a carbon number of 1
~ 5 alkyl groups such as methyl, ethyl, propyl,
Examples include iso-propyl, n-butyl, sec-butyl, t-butyl, amyl and the like.
【化７】 [Chemical 7]
【化８】 [Chemical 8]
【化９】 [Chemical 9]
【０００６】そして、このような上記（化７）で示され
るアミノ酸としてはシステイン、ペニシラミン等を例示
することができる。またそれらの塩としては、例えば塩
酸塩、硫酸塩等の無機塩や酢酸塩、乳酸塩等の有機酸の
塩類等が用いられる。またこれは、不斉炭素に基づく光
学活性体を用いることもできる。[0006] Examples of the amino acid represented by the above (Chemical formula 7) include cysteine and penicillamine. As the salts thereof, for example, inorganic salts such as hydrochlorides and sulfates, salts of organic acids such as acetates and lactates, and the like are used. It is also possible to use optically active substances based on asymmetric carbons.
【０００７】これらの化合物とホルムアルデヒドとの反
応は、（化７）で示されるアミノ酸またはその塩の水溶
液中に少なくとも１当量、好ましくは1.2 〜２当量のホ
ルムアルデヒドを加えて混合すると環化反応が進行す
る。ホルムアルデヒドとしてはホルマリンを用いるのが
簡便で好ましい。反応温度は−１０〜５０℃、特には０
〜３０℃が好ましい。反応の終結は薄相クロマトグラフ
ィー等により環状アミノ酸の生成を確認することによっ
て知ることができる。Regarding the reaction between these compounds and formaldehyde, the cyclization reaction proceeds when at least 1 equivalent, preferably 1.2 to 2 equivalents of formaldehyde is added to an aqueous solution of the amino acid represented by the chemical formula (7) or a salt thereof and mixed. To do. It is preferable to use formalin as the formaldehyde because it is simple and convenient. The reaction temperature is -10 to 50 ° C, especially 0.
-30 degreeC is preferable. The termination of the reaction can be known by confirming the production of cyclic amino acid by thin-layer chromatography or the like.
【０００８】次に、反応生成物から（化８）で示される
環状化合物を単離することなく、この反応混合物にジ−
ｔ−ブチルジカルボナートを加えて反応させる。この
際、適当な塩基を加えて、反応液を中性ないしは弱アル
カリ性に保ち、さらに、極性有機溶媒を共存させるのが
好ましい。このような塩基としては、トリエチルアミ
ン、Ｎ−メチルモルホリン等の有機三級アミン、水酸化
ナトリウム、水酸化カリウム等の無機塩基を用いること
ができる。また有機溶媒としては、テトラヒドロフラ
ン、ジオキサン等を用いることができる。反応温度は−
１０〜５０℃、特には０〜３０℃が好ましい。Next, di- was added to the reaction mixture without isolation of the cyclic compound represented by the chemical formula (8) from the reaction product.
Add t-butyl dicarbonate and react. At this time, it is preferable to add a suitable base to keep the reaction solution neutral or weakly alkaline, and to coexist with a polar organic solvent. As such a base, organic tertiary amines such as triethylamine and N-methylmorpholine, and inorganic bases such as sodium hydroxide and potassium hydroxide can be used. Further, as the organic solvent, tetrahydrofuran, dioxane or the like can be used. The reaction temperature is −
10-50 degreeC, especially 0-30 degreeC are preferable.
【０００９】このようにして得られた反応混合物を酸性
化すると、（化９）で示される１，３−チアゾリジン−
４−カルボン酸誘導体が遊離する。酸性化に使用する酸
としては、クエン酸等の水溶性有機酸または塩酸等の鉱
酸を使用することができる。特に、塩酸が簡便に使用さ
れ、かつ安価であるので好ましい。この１，３−チアゾ
リジン−４−カルボン酸誘導体を遊離させるに先立ち、
まず反応液から有機溶媒を留去し、有機溶媒で洗浄を行
ない、その後にこれを遊離させると効率よく遊離でき
る。有機溶媒による洗浄には、トルエン、酢酸エチル、
ジエチルエーテル等を用いることができる。When the reaction mixture thus obtained is acidified, 1,3-thiazolidine-
The 4-carboxylic acid derivative is released. As the acid used for acidification, a water-soluble organic acid such as citric acid or a mineral acid such as hydrochloric acid can be used. In particular, hydrochloric acid is preferable because it is conveniently used and is inexpensive. Prior to releasing the 1,3-thiazolidine-4-carboxylic acid derivative,
The organic solvent can be efficiently released by first distilling off the organic solvent from the reaction solution, washing with the organic solvent, and then liberating the organic solvent. To wash with an organic solvent, use toluene, ethyl acetate,
Diethyl ether or the like can be used.
【００１０】このようにして遊離させた（化９）で示さ
れる１，３−チアゾリジン−４−カルボン酸誘導体は、
そのまま水系から晶析させるか、トルエン、酢酸エチ
ル、エーテル等の有機溶媒によって抽出し濃縮すること
によって単離できる。また、本発明の（化７）で示され
るアミノ酸として光学活性体を用いると、ラセミ化する
ことなく、（化９）で示される化合物の光学活性体を得
ることができる。The 1,3-thiazolidine-4-carboxylic acid derivative represented by Chemical formula 9 thus liberated is
It can be isolated by crystallization as it is from the aqueous system or by extraction with an organic solvent such as toluene, ethyl acetate, ether and the like and concentration. When an optically active substance is used as the amino acid represented by (Chemical formula 7) of the present invention, the optically active substance of the compound represented by (Chemical formula 9) can be obtained without racemization.
【００１１】このようにして得られる（化９）で示され
る１，３−チアゾリジン−４−カルボン酸誘導体は、ア
ミノ基が保護されており、これを中間体として用いてHI
V ウイルスのプロテアーゼ阻害剤となるペプチド誘導体
を製造することができる。このペプチド誘導体は、特願
平3-348705号明細書に記載したように１，３−チアゾリ
ジン−４−カルボン酸誘導体を、例えば、ｔ−ブチルア
ミンと縮合させ、脱保護した後、３−Ｎ−ｔ−ブトキシ
カルボニルアミノ−２−ヒドロキシ−４−フェニルブタ
ン酸と縮合し、脱保護し、２−Ｎ−ｔ−ブトキシカルボ
ニルアミノ−３−メチルチオプロピオン酸と縮合させ、
さらに脱保護し、イソキノリン−５−イルオキシ酢酸と
縮合させることにより製造できる。The thus obtained 1,3-thiazolidine-4-carboxylic acid derivative represented by Chemical formula 9 has an amino group protected, and this is used as an intermediate to obtain HI.
It is possible to produce a peptide derivative which is a protease inhibitor of V virus. This peptide derivative is prepared by condensing a 1,3-thiazolidine-4-carboxylic acid derivative with, for example, t-butylamine as described in Japanese Patent Application No. 3-348705, followed by deprotection and then 3-N-. condensed with t-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid, deprotected and condensed with 2-Nt-butoxycarbonylamino-3-methylthiopropionic acid,
It can be produced by further deprotection and condensation with isoquinolin-5-yloxyacetic acid.
【００１２】[0012]
【発明の効果】本発明の方法によると、（化７）で示さ
れるアミノ酸またはその塩から（化９）で示される１，
３−チアゾリジン−４−カルボン酸誘導体またはその塩
を製造するに当り、中間生成物の（化８）で示される環
状アミノ酸またはその塩を単離することなく１，３−チ
アゾリジン−４−カルボン酸誘導体またはその塩を直接
得ることができるので、反応工程を簡便化することがで
き、経済的に有利な製造法である。According to the method of the present invention, from the amino acid represented by (Chemical formula 7) or its salt,
In producing a 3-thiazolidine-4-carboxylic acid derivative or a salt thereof, 1,3-thiazolidine-4-carboxylic acid can be obtained without isolating the cyclic amino acid represented by the chemical formula (8) or a salt thereof. Since the derivative or its salt can be directly obtained, the reaction process can be simplified and the production method is economically advantageous.
【００１３】[0013]
【実施例１】Ｌ−システイン塩酸塩一水和物5.00g(28.5
mmol) を水２５mlに溶解させ、３７％ホルマリン（８％
メタノール含有）５ml(2.3当量) を加えて室温で終夜撹
拌した。これに氷冷下でジ−ｔ−ブチルジカルボナート
7.50g(1.2当量) のテトラヒドロフラン（２５ml) 溶
液、トリエチルアミン11.9ml(3.0当量) を加え、室温で
１０時間撹拌した。反応混合物に水２０mlを加えて、酢
酸エチル２０mlで洗浄し、水層を減圧濃縮した。これに
クエン酸を加えてpH４として酢酸エチルで抽出し、有機
層を５％クエン酸水溶液、飽和食塩水で順に洗浄、硫酸
ナトリウムで乾燥、溶媒を減圧留去、ヘキサンを加えて
結晶化、濾取、真空乾燥してＲ−３−ｔ−ブトキシカル
ボニル−１，３−チアゾリジン−４−カルボン酸6.03g
(収率９１％）を得た。1 H NMR(CDCl3) ：δ 1.48(S, 9H, t-Bu)、3.31(bs, 2
H)、4.3-4.9(m, 3H)、8.27(b, 1H, OH) なお、この生成物の一部を４Ｍ塩化水素、ジオキサン溶
液で脱保護した後、キラルHPLC（ダイセル社製、キラル
パックWH）で分析したところ、Ｓ体は全く検出されなか
った。Example 1 5.00 g (28.5 L-cysteine hydrochloride monohydrate
mmol) in 25 ml of water, and 37% formalin (8%
5 ml (2.3 equivalents) (containing methanol) was added, and the mixture was stirred at room temperature overnight. Di-t-butyl dicarbonate was added to this under ice cooling.
A tetrahydrofuran (25 ml) solution of 7.50 g (1.2 eq) and 11.9 ml (3.0 eq) of triethylamine were added, and the mixture was stirred at room temperature for 10 hours. 20 ml of water was added to the reaction mixture and the mixture was washed with 20 ml of ethyl acetate, and the aqueous layer was concentrated under reduced pressure. To this, citric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous citric acid solution and saturated brine, dried over sodium sulfate, the solvent was distilled off under reduced pressure, hexane was added for crystallization, and filtration was performed. It was taken and dried in vacuum, and R-3-t-butoxycarbonyl-1,3-thiazolidine-4-carboxylic acid 6.03 g
(Yield 91%) was obtained. 1 H NMR (CDCl 3 ): δ 1.48 (S, 9H, t-Bu), 3.31 (bs, 2
H), 4.3-4.9 (m, 3H), 8.27 (b, 1H, OH) In addition, after deprotecting a part of this product with 4M hydrogen chloride and dioxane solution, chiral HPLC (manufactured by Daicel, Chiralpack) WH), S form was not detected at all.
【００１４】[0014]
【実施例２】Ｌ−システイン塩酸塩一水和物20.0g(114m
mol)を水８０mlに溶解させ、３７％ホルマリン（８％メ
タノール含有）１２ml(1.4当量) を加えて室温で終夜撹
拌した。これに氷冷下で２Ｎ水酸化ナトリウム水溶液 1
14ml(2.0当量) 、ジ−ｔ−ブチルジカルボナート 24.9g
(1.0当量) のテトラヒドロフラン（８０ml) 溶液を加え
て2.5 時間撹拌した。これに２Ｎ水酸化ナトリウム水溶
液２０ml (0.35当量)を加え、室温で終夜撹拌した。反
応混合物にトルエン８０mlを加えて洗浄し、水層にクエ
ン酸一水和物16.6g(８０mmol) を加えてpH３とし、減圧
濃縮して析出した結晶を濾取、水洗、真空乾燥してＲ−
３−ｔ−ブトキシカルボニル−１，３−チアゾリジン−
４−カルボン酸20.0g(収率７５％）を得た。Example 2 20.0 g (114 m) of L-cysteine hydrochloride monohydrate
mol) was dissolved in 80 ml of water, 12 ml (1.4 equivalents) of 37% formalin (containing 8% methanol) was added, and the mixture was stirred at room temperature overnight. Add 2N sodium hydroxide solution under ice cooling 1
14 ml (2.0 equivalents), di-t-butyl dicarbonate 24.9 g
A solution of (1.0 equivalent) in tetrahydrofuran (80 ml) was added and the mixture was stirred for 2.5 hours. To this, 20 ml (0.35 equivalent) of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 80 ml of toluene, and the aqueous layer was adjusted to pH 3 with 16.6 g (80 mmol) of citric acid monohydrate, concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with water, and vacuum dried to form R-.
3-t-butoxycarbonyl-1,3-thiazolidine-
20.0 g of 4-carboxylic acid (yield 75%) was obtained.
【００１５】[0015]
【実施例３】Ｌ−システイン塩酸塩一水和物20.0g(114m
mol)を水８０mlに溶解させ、３７％ホルマリン（８％メ
タノール含有）１２ml(1.4当量) を加えて室温で終夜撹
拌した。これに氷冷下でトリエチルアミン４８ml(3.0当
量) 、ジ−ｔ−ブチルジカルボナート24.9g (1.0当量)
のテトラヒドロフラン (８０ml) 溶液を加えて、室温で
終夜撹拌した。反応混合物にトルエン８０mlを加えて洗
浄し、水層にクエン酸−水和物４３ｇを加えて酸性化、
水２０mlを加えて酢酸エチル１６０mlで抽出した。有機
層を硫酸ナトリウムで乾燥、減圧濃縮、乾固させ、真空
乾燥してＲ−３−ｔ−ブトキシカルボニル−１，３−チ
アゾリジン−４−カルボン酸22.2g(収率８４％）を得
た。Example 3 L-Cysteine hydrochloride monohydrate 20.0 g (114 m
mol) was dissolved in 80 ml of water, 12 ml (1.4 equivalents) of 37% formalin (containing 8% methanol) was added, and the mixture was stirred at room temperature overnight. Under ice cooling, 48 ml of triethylamine (3.0 equivalents) and 24.9 g of di-t-butyl dicarbonate (1.0 equivalents) were added.
Tetrahydrofuran solution (80 ml) was added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 80 ml of toluene, and the aqueous layer was acidified with 43 g of citric acid monohydrate.
20 ml of water was added and the mixture was extracted with 160 ml of ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, dried to dryness, and dried under vacuum to obtain 22.2 g (yield 84%) of R-3-t-butoxycarbonyl-1,3-thiazolidine-4-carboxylic acid.
【００１６】[0016]
【実施例４】ジ−ｔ−ブチルジカルボナート添加時にテ
トラヒドロフランに代えてジオキサン（８０ml) を用
い、その他は実施例２と同様の操作を行って、Ｒ−３−
ｔ−ブトキシカルボニル−１，３−チアゾリジン−４−
カルボン酸19.4g(収率７３％）を得た。Example 4 Dioxane (80 ml) was used in place of tetrahydrofuran when di-t-butyl dicarbonate was added, and otherwise the same operation as in Example 2 was carried out to carry out R-3-
t-Butoxycarbonyl-1,3-thiazolidine-4-
19.4 g (yield 73%) of carboxylic acid was obtained.
【００１７】[0017]
【実施例５】ジ−ｔ−ブチルジカルボナート添加時にテ
トラヒドロフランに代えてジオキサン（８０ml) を用
い、その他は実施例３と同様の操作を行って、Ｒ−３−
ｔ−ブトキシカルボニル−１，３−チアゾリジン−４−
カルボン酸22.3g(収率８４％）を得た。Example 5 Dioxane (80 ml) was used in place of tetrahydrofuran when di-t-butyl dicarbonate was added, and otherwise the same operation as in Example 3 was carried out to carry out R-3-
t-Butoxycarbonyl-1,3-thiazolidine-4-
22.3 g (yield 84%) of carboxylic acid was obtained.
【００１８】[0018]
【実施例６】Ｌ−システイン塩酸塩−水和物20.0g(114m
mol)を水６０mlに溶解させ、３７％ホルマリン（８％メ
タノール含有）１２ml(1.4当量) を加え、室温で６時間
撹拌した。これに氷冷下で３Ｎ水酸化ナトリウム水溶液
７６ml(2.0当量) 、ジ−ｔ−ブチルジカルボナート27.4
g (1.1当量) のテトラヒドロフラン（６０ml) 溶液を加
えて２時間撹拌した。これに３Ｎ水酸化ナトリウム水溶
液８ml(0.2当量) を加え、室温で終夜撹拌した。減圧濃
縮してテトラヒドロフランを留去した後、トルエン８０
mlを加えて洗浄し、６Ｎ塩酸２３mlを徐々に加えて酸性
化し、酢酸エチル１６０mlで抽出した。この酢酸エチル
溶液を減圧濃縮し、トルエン２０mlを加えて減圧下で共
沸脱水し、残渣にヘキサン８０mlを加えて破砕、濾取、
真空乾燥してＲ−３−ｔ−ブトキシカルボニル−１，３
−チアゾリジン−４−カルボン酸25.37g（収率95.3％）
を得た。Example 6 L-Cysteine hydrochloride monohydrate 20.0 g (114 m
Mol) was dissolved in 60 ml of water, 12 ml (1.4 equivalents) of 37% formalin (containing 8% methanol) was added, and the mixture was stirred at room temperature for 6 hours. Under ice cooling, 76 ml of 3N aqueous sodium hydroxide solution (2.0 equivalents), di-t-butyl dicarbonate 27.4
A solution of g (1.1 eq) in tetrahydrofuran (60 ml) was added and stirred for 2 hours. To this, 8 ml (0.2 equivalent) of 3N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. After concentration under reduced pressure to remove tetrahydrofuran, toluene 80
The mixture was acidified by gradually adding 23 ml of 6N hydrochloric acid and extracted with 160 ml of ethyl acetate. The ethyl acetate solution was concentrated under reduced pressure, 20 ml of toluene was added, and the mixture was azeotropically dehydrated under reduced pressure. 80 ml of hexane was added to the residue for crushing and filtration.
Vacuum dried to give R-3-t-butoxycarbonyl-1,3
-Thiazolidine-4-carboxylic acid 25.37 g (yield 95.3%)
Got
【００１９】[0019]
【実施例７】Ｌ−ペニシラミン5.15g(34.5mmol) を水５
０mlに溶解させ、３７％ホルマリン（８％メタノール含
有）3.4ml (1.3当量) を加えて室温で終夜撹拌した。こ
れに氷冷下でジ−ｔ−ブチルジカルボナート 9.07g(1.2
当量) のテトラヒドロフラン（５０ml) 溶液、トリエチ
ルアミン 7.2ml(1.5当量) を加え、室温で８時間撹拌し
た。反応混合物をエーテルで洗浄し、クエン酸を加えて
pH３として酢酸エチルで抽出し、有機層を５％クエン酸
水溶液、飽和食塩水で順に洗浄、硫酸ナトリウムで乾
燥、溶媒を減圧留去、ヘキサンを加えて結晶化、濾取、
真空乾燥してＲ−３−ｔ−ブトキシカルボニル−５，５
−ジメチル−１，３−チアゾリジン−４−カルボン酸8.
39g(収率９２％）を得た。1 H NMR(CDCl3)：δ 1.44(S, 3H, CH3) 、1.49(S, 9H, t
-Bu) 、1.61(S, 3H,CH3) 、4.22及び4.35(b, 1H) 、4.6
3及び4.69(b, 2H) 、7.7(b, 1H, OH)Example 7 5.15 g (34.5 mmol) of L-penicillamine was added to 5 parts of water.
The mixture was dissolved in 0 ml, 37% formalin (containing 8% methanol) 3.4 ml (1.3 equivalent) was added, and the mixture was stirred at room temperature overnight. Under ice-cooling, 9.07 g of di-t-butyl dicarbonate (1.2
Tetrahydrofuran solution (50 ml) and 7.2 ml (1.5 equivalents) of triethylamine were added, and the mixture was stirred at room temperature for 8 hours. Wash the reaction mixture with ether, add citric acid and
The pH was adjusted to 3 and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous citric acid solution and saturated brine, dried over sodium sulfate, the solvent was evaporated under reduced pressure, hexane was added to crystallize, and filtration was performed.
Vacuum dried to R-3-t-butoxycarbonyl-5,5
-Dimethyl-1,3-thiazolidine-4-carboxylic acid 8.
39 g (yield 92%) was obtained. 1 H NMR (CDCl 3 ): δ 1.44 (S, 3H, CH 3 ), 1.49 (S, 9H, t
-Bu), 1.61 (S, 3H, CH 3 ), 4.22 and 4.35 (b, 1H), 4.6
3 and 4.69 (b, 2H), 7.7 (b, 1H, OH)
───────────────────────────────────────────────────── フロントページの続き (72)発明者 木曽 良明 大阪府茨木市稲葉町15−26 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshiaki Kiso 15-26 Inaba, Ibaraki, Osaka
Claims (1)
塩とホルムアルデヒドとを反応させて（化２）で示され
る環状アミノ酸またはその塩を生成せしめ、これを単離
することなく、該環状アミノ酸またはその塩を含む反応
混合物を、ジ−ｔ−ブチルジカルボナートと反応させて
（化３）で示される１，３−チアゾリジン−４−カルボ
ン酸誘導体またはその塩を生成せしめることを特徴とす
る１，３−チアゾリジン−４−カルボン酸誘導体または
その塩の製造法。〔（化１），（化２）及び（化３）
中、R1及びR2は同一または異なって、水素原子または低
級アルキル基を表す。〕 【化１】 【化２】 【化３】 1. A cyclic amino acid represented by (Chemical formula 1) or a salt thereof is reacted with formaldehyde to form a cyclic amino acid represented by (Chemical formula 2) or a salt thereof, and the cyclic amino acid is isolated without isolation. Alternatively, the reaction mixture containing a salt thereof is reacted with di-t-butyl dicarbonate to form a 1,3-thiazolidine-4-carboxylic acid derivative represented by (Chemical Formula 3) or a salt thereof. A method for producing a 1,3-thiazolidine-4-carboxylic acid derivative or a salt thereof. [(Chemical Formula 1), (Chemical Formula 2) and (Chemical Formula 3)
Wherein R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group. ] [Chemical 1] [Chemical 2] [Chemical 3]
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19265492A JPH06247948A (en) | 1992-05-13 | 1992-05-13 | Production of 1,3-thiazolidine-4-carboxylic acid derivative or its salt |
| EP19930303644 EP0574135B1 (en) | 1992-05-13 | 1993-05-11 | Process for producing peptide derivatives and salts thereof |
| DE1993622127 DE69322127T2 (en) | 1992-05-13 | 1993-05-11 | Process for the preparation of peptide derivatives and their salts |
| US08/364,707 US5644028A (en) | 1992-05-13 | 1994-12-28 | Process for producing peptide derivatives and salts therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19265492A JPH06247948A (en) | 1992-05-13 | 1992-05-13 | Production of 1,3-thiazolidine-4-carboxylic acid derivative or its salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06247948A true JPH06247948A (en) | 1994-09-06 |
Family
ID=16294837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19265492A Pending JPH06247948A (en) | 1992-05-13 | 1992-05-13 | Production of 1,3-thiazolidine-4-carboxylic acid derivative or its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06247948A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002179660A (en) * | 2000-12-11 | 2002-06-26 | Mitsubishi Gas Chem Co Inc | Method for producing 1,3-thiazolidine-4-carboxylic acid amide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63112571A (en) * | 1986-10-28 | 1988-05-17 | Nippon Rikagaku Yakuhin Kk | Racemization of l-thiazolidine-4-carboxylic acid |
| JPH0356462A (en) * | 1989-07-24 | 1991-03-12 | Kissei Pharmaceut Co Ltd | Pyroglutamic acid derivative |
-
1992
- 1992-05-13 JP JP19265492A patent/JPH06247948A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63112571A (en) * | 1986-10-28 | 1988-05-17 | Nippon Rikagaku Yakuhin Kk | Racemization of l-thiazolidine-4-carboxylic acid |
| JPH0356462A (en) * | 1989-07-24 | 1991-03-12 | Kissei Pharmaceut Co Ltd | Pyroglutamic acid derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002179660A (en) * | 2000-12-11 | 2002-06-26 | Mitsubishi Gas Chem Co Inc | Method for producing 1,3-thiazolidine-4-carboxylic acid amide |
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