JP2006008556A - Method for producing optically active thiazolidine-4-carboxylic acid amide or salt thereof - Google Patents
Method for producing optically active thiazolidine-4-carboxylic acid amide or salt thereof Download PDFInfo
- Publication number
- JP2006008556A JP2006008556A JP2004186005A JP2004186005A JP2006008556A JP 2006008556 A JP2006008556 A JP 2006008556A JP 2004186005 A JP2004186005 A JP 2004186005A JP 2004186005 A JP2004186005 A JP 2004186005A JP 2006008556 A JP2006008556 A JP 2006008556A
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- optically active
- carboxylic acid
- represented
- acid amide
- 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
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
Description
本発明は、一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造方法に関する。詳しくは、一般式（２）で示される光学活性２−アルキル−D−システインアミドに一般式（３）で示されるアルデヒド又はケトン、或いは一般式（４）で示されるケタール（アセタール）を反応させて得られる一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造方法に関する。一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩は、各種工業薬品、農薬、及び医薬品の製造中間体として重要な物質である。
（一般式（１）、（２）中のＲは炭素数１〜４の低級アルキル基、一般式（１）、（３）、（４）中のＲ１及びＲ２は各々独立した水素、炭素数１〜４の低級アルキル基、又は両者が互いに結合した員数５〜８の脂環構造を示す。但しＲ１及びＲ２が同時に水素である場合を除く。また、一般式（４）中のＲ３及びＲ４は炭素数１〜３の低級アルキル基を示す。）
The present invention relates to a method for producing an optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof. Specifically, an optically active 2-alkyl-D-cysteine amide represented by the general formula (2) is reacted with an aldehyde or ketone represented by the general formula (3) or a ketal (acetal) represented by the general formula (4). It is related with the manufacturing method of the optically active thiazolidine-4-carboxylic acid amide shown by General formula (1) obtained by this, or its salt. The optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof is an important substance as a production intermediate for various industrial chemicals, agricultural chemicals, and pharmaceuticals.
(R in the general formulas (1) and (2) is a lower alkyl group having 1 to 4 carbon atoms, R 1 and R 2 in the general formulas (1), (3) and (4) are each independently hydrogen, A lower alkyl group having 1 to 4 carbon atoms or an alicyclic structure having 5 to 8 carbon atoms bonded to each other, except when R 1 and R 2 are simultaneously hydrogen, and in the general formula (4) R 3 and R 4 in C 1 represent a lower alkyl group having 1 to 3 carbon atoms.)
４−アルキルチアゾリジン−４−カルボン酸アミド誘導体の４−アルキルチアゾリジン−４−カルボン酸は、ハロゲン化メチルアルキルケトンとカルボニル化合物を水硫化アルキル及びアンモニアと反応させ、得られたチアゾリンにＨＣＮを付加してチアゾリジンニトリルとし、次いでこれを加水分解することによって得られる（例えば、非特許文献１参照）。しかし、この方法で合成される４−アルキルチアゾリジン−４−カルボン酸はラセミ体であり光学活性を持たない。一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミドそのものも、各種工業薬品、農薬及び医薬品の製造原料として広範な活用が期待される化合物であり、産業上、非常に有用な化合物であるが、この光学活性チアゾリジン−４−カルボン酸アミドを加水分解することによって得られる光学活性２−アルキル−D−システインアミド、さらには光学活性２−アルキル−D−システインも、分子内にメルカプト基、アミノ基、及びカルボキシルアミド基又はカルボキシル基を有し、各種工業薬品、農薬及び医薬品の製造原料として重要である。このように非常に重要な化合物であるにもかかわらず、一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミドの製造法は知られていない。 4-alkylthiazolidine-4-carboxylic acid amide derivative, 4-alkylthiazolidine-4-carboxylic acid, reacts a halogenated methyl alkyl ketone and a carbonyl compound with alkyl hydrosulfide and ammonia, and adds HCN to the resulting thiazoline. To thiazolidinenitrile and then hydrolyzed (see, for example, Non-Patent Document 1). However, 4-alkylthiazolidine-4-carboxylic acid synthesized by this method is racemic and has no optical activity. The optically active thiazolidine-4-carboxylic acid amide itself represented by the general formula (1) is also a compound that is expected to be widely used as a raw material for producing various industrial chemicals, agricultural chemicals, and pharmaceuticals. However, an optically active 2-alkyl-D-cysteine amide obtained by hydrolyzing this optically active thiazolidine-4-carboxylic acid amide, and further an optically active 2-alkyl-D-cysteine is also included in the molecule. It has a group, amino group, and carboxylamide group or carboxyl group and is important as a raw material for producing various industrial chemicals, agricultural chemicals and pharmaceuticals. In spite of such a very important compound, a method for producing an optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) is not known.
本発明の目的は、各種工業薬品、農薬及び医薬品の製造原料として広範な活用が期待され、産業上、非常に有用な化合物である一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造法を提供することにある。 An object of the present invention is to provide an optically active thiazolidine-4-carboxylic acid represented by the general formula (1), which is expected to be widely used as a raw material for producing various industrial chemicals, agricultural chemicals, and pharmaceuticals, and is an industrially very useful compound. It is to provide a method for producing an amide or a salt thereof.
かかる実状に鑑み、本発明者らは一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造方法について鋭意研究を行ったところ、一般式（２）で示される光学活性２−アルキル−D−システインアミドを、一般式（３）で示されるアルデヒド又はケトン、或いは一般式（４）で示されるケタール（アセタール）と反応させることにより、一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩を効率よく製造できることを見出し、本発明を完成するに至った。即ち、本発明は、以下の１）〜４）に示す、一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造方法に関する。
１）一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造法であって、一般式（２）で示される光学活性２−アルキル−D−システインアミドに一般式（３）で示されるアルデヒド又はケトン、或いは一般式（４）で示されるケタール（アセタール）を反応させることを特徴とする、一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造方法。
（一般式（１）、（２）中のＲは炭素数１〜４の低級アルキル基、一般式（１）、（３）、（４）中のＲ１及びＲ２は各々独立した水素、炭素数１〜４の低級アルキル基、又は両者が互いに結合した員数５〜８の脂環構造を示す。但しＲ１及びＲ２が同時に水素である場合を除く。また、一般式（４）中のＲ３及びＲ４は炭素数１〜３の低級アルキル基を示す。）
２）一般式（２）で示される光学活性２−アルキル−D−システインアミドに一般式（３）で示されるアルデヒド又はケトン、或いは一般式（４）で示されるケタール（アセタール）を反応させる際に塩基触媒を用いる、１）記載の一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造方法。
３）一般式（１）、（２）中のＲがメチル基である、１）又は２）記載の一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造方法。
４）一般式（１）、（２）中のＲ、並びに一般式（１）、（３）、（４）中のＲ１及びＲ２がともにメチル基である、１）〜３）の何れかに記載の一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩の製造方法。
In view of the actual situation, the present inventors conducted extensive research on a method for producing the optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof, and found that the optical represented by the general formula (2). The active 2-alkyl-D-cysteine amide is represented by the general formula (1) by reacting with an aldehyde or ketone represented by the general formula (3) or a ketal (acetal) represented by the general formula (4). The inventors have found that optically active thiazolidine-4-carboxylic acid amide or a salt thereof can be efficiently produced, and have completed the present invention. That is, the present invention relates to a process for producing an optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof shown in the following 1) to 4).
1) A process for producing an optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof, wherein the optically active 2-alkyl-D-cysteine amide represented by the general formula (2) has the general formula An optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1), wherein the aldehyde or ketone represented by the formula (3) or a ketal (acetal) represented by the general formula (4) is reacted. A method for producing the salt.
(R in the general formulas (1) and (2) is a lower alkyl group having 1 to 4 carbon atoms, R 1 and R 2 in the general formulas (1), (3) and (4) are each independently hydrogen, A lower alkyl group having 1 to 4 carbon atoms or an alicyclic structure having 5 to 8 carbon atoms bonded to each other, except when R 1 and R 2 are simultaneously hydrogen, and in the general formula (4) R 3 and R 4 in C 1 represent a lower alkyl group having 1 to 3 carbon atoms.)
2) When the optically active 2-alkyl-D-cysteine amide represented by the general formula (2) is reacted with the aldehyde or ketone represented by the general formula (3) or the ketal (acetal) represented by the general formula (4) A method for producing an optically active thiazolidine-4-carboxylic acid amide or a salt thereof represented by the general formula (1) described in 1), using a base catalyst.
3) Method for producing optically active thiazolidine-4-carboxylic acid amide or a salt thereof represented by general formula (1) according to 1) or 2), wherein R in general formulas (1) and (2) is a methyl group .
4) R in the general formulas (1) and (2), and R 1 and R 2 in the general formulas (1), (3) and (4) are both methyl groups, and any of 1) to 3) A method for producing an optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof.
各種工業薬品、農薬及び医薬品の製造原料として広範な活用が期待され、産業上、非常に有用な化合物である一般式（１）で示される光学活性チアゾリジン−４−カルボン酸アミド又はその塩を製造するための、経済的で工業的に実施可能な方法を提供する。 Produced optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof, which is expected to be widely used as a raw material for producing various industrial chemicals, agricultural chemicals and pharmaceuticals, and is an industrially very useful compound. To provide an economical and industrially feasible method for achieving this.
以下に本発明の詳細について説明する。本発明の一般式（１）、（２）中のＲは、炭素数１〜４の低級アルキル基でありそれ以外に特に制限はないが、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、secブチル及びtertブチルなどの直鎖又は分枝した低級アルキル基が好適であり、メチル基が特に好適である。一般式（１）、（３）、（４）中のＲ１及びＲ２は各々独立した水素（但しＲ１及びＲ２が同時に水素である場合を除く）、炭素数１〜４の低級アルキル基、又は両者が互いに結合した員数５〜８の脂環構造を示しそれ以外に特に制限はないが、アルキル基としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、secブチル及びtertブチルなどの直鎖又は分枝した低級アルキル基、脂環としてはシクロペンタン環やシクロヘキサン環、シクロヘプタン環等が好適であり、R1及びR2が互いにメチル基の場合が特に好適である。また、一般式（４）中のＲ３及びＲ４は炭素数１〜３の低級アルキル基を示しそれ以外に特に制限はないが、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、secブチル及びtertブチルなどの直鎖又は分枝した低級アルキル基が好適であり、メチル基が特に好適である。 Details of the present invention will be described below. R in the general formulas (1) and (2) of the present invention is a lower alkyl group having 1 to 4 carbon atoms and is not particularly limited. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl A straight or branched lower alkyl group such as sec butyl and tert butyl is preferred, and a methyl group is particularly preferred. R 1 and R 2 in the general formulas (1), (3) and (4) are each independently hydrogen (except when R 1 and R 2 are simultaneously hydrogen), lower alkyl having 1 to 4 carbon atoms Group, or an alicyclic structure having 5 to 8 members bonded to each other and not particularly limited. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl and tert. As the linear or branched lower alkyl group such as butyl and the alicyclic ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring and the like are preferable, and a case where R 1 and R 2 are each a methyl group is particularly preferable. R 3 and R 4 in the general formula (4) represent a lower alkyl group having 1 to 3 carbon atoms and are not particularly limited. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec Linear or branched lower alkyl groups such as butyl and tertbutyl are preferred, and methyl groups are particularly preferred.
また、一般式（１）の光学活性チアゾリジン−４−カルボン酸アミドは塩を形成することもできる。その種類は、実用上許容できる塩であれば特に制限はないが、例えば塩酸、硫酸、燐酸等の無機酸、ギ酸や酢酸等の有機酸等が上げられ、特に扱いやすさの点で塩酸塩が好適である。 Moreover, the optically active thiazolidine-4-carboxylic acid amide of the general formula (1) can also form a salt. The type of the salt is not particularly limited as long as it is a practically acceptable salt, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid and acetic acid. Is preferred.
本発明で使用する一般式（２）で示される２−アルキル−Ｄ−システインアミドは、その製法等に特に制限はない。例えば、該当する４−アルキルチアゾリジン−４−カルボン酸アミド誘導体を加水分解して２−アルキルシステインアミドのラセミ体を得、そのうちのＬ体のみを、生化学的不斉加水分解等により選択的に加水分解して、対応する２−アルキル−Ｌ−システインと未反応の２−アルキル−Ｄ−システインアミドの混合物となし、そのまま或いは両者を分離して用いることができる。 The 2-alkyl-D-cysteine amide represented by the general formula (2) used in the present invention is not particularly limited in its production method. For example, the corresponding 4-alkylthiazolidine-4-carboxylic acid amide derivative is hydrolyzed to obtain a racemic 2-alkylcysteine amide, and only the L-form thereof is selectively obtained by biochemical asymmetric hydrolysis or the like. It is hydrolyzed to form a mixture of the corresponding 2-alkyl-L-cysteine and unreacted 2-alkyl-D-cysteine amide, which can be used as they are or separately.
一般式（２）で示される光学活性２−アルキル−D−システインアミドを一般式（３）で示されるアルデヒド又はケトン、或いは一般式（４）で示されるケタール（アセタール）と反応させることによって、一般式（１）で示されるチアゾリジン−４−カルボン酸アミドが誘導される。ここで使用する一般式（３）で示されるアルデヒド又はケトン、一般式（４）で示されるケタール（アセタール）のR1及びR2は各々独立して水素又は炭素数１から４の低級アルキル基、或いは互いに一つの環を形成する炭素数３から８の脂環化合物であればよく、特に制限はないが、アルキル基としては例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、secブチル及びtertブチルなどの直鎖又は分枝した低級アルキル基、シクロペンタン環やシクロヘキサン環等の脂環が好適であり、Ｒ１及びＲ２が互いにメチル基である場合が特に好適である。また一般式（４）のＲ４、Ｒ５は炭素数１から３のアルキル基であれば良く、メチル、エチル等がその例として挙げられる。このような化合物として、具体的にはアセトン、メチルエチルケトン、アセトアルデヒド、シクロペンタノン、シクロヘキサノン、アセトンジメチルアセタール等が挙げられ、特にアセトンが好適に使用される。用いるケトン又はアルデヒド、或いはケタール（アセタール）の量は、２−アルキル−Ｄ−システインアミドの1モル倍以上あればよく、特に上限はないが、反応速度の促進効果と、加熱や溶媒回収に掛かるコスト等を考慮して適宜決定されれば良い。 By reacting the optically active 2-alkyl-D-cysteine amide represented by the general formula (2) with an aldehyde or ketone represented by the general formula (3) or a ketal (acetal) represented by the general formula (4), Thiazolidine-4-carboxylic acid amide represented by the general formula (1) is derived. The aldehyde or ketone represented by the general formula (3) and the R 1 and R 2 of the ketal (acetal) represented by the general formula (4) are each independently hydrogen or a lower alkyl group having 1 to 4 carbon atoms. Or an alicyclic compound having 3 to 8 carbon atoms which forms one ring with each other, and is not particularly limited. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl and A straight-chain or branched lower alkyl group such as tertbutyl or an alicyclic ring such as a cyclopentane ring or a cyclohexane ring is preferred, and a case where R 1 and R 2 are each a methyl group is particularly preferred. R 4 and R 5 in the general formula (4) may be any alkyl group having 1 to 3 carbon atoms, and examples thereof include methyl and ethyl. Specific examples of such a compound include acetone, methyl ethyl ketone, acetaldehyde, cyclopentanone, cyclohexanone, acetone dimethyl acetal, and acetone is particularly preferably used. The amount of the ketone or aldehyde or ketal (acetal) to be used should be at least 1 mol times that of 2-alkyl-D-cysteine amide, and there is no particular upper limit. However, it depends on the effect of promoting the reaction rate, heating and solvent recovery. What is necessary is just to determine suitably in consideration of cost etc.
一般式（２）で示される光学活性な２−アルキル−Ｄ−システインアミド又はその塩を溶媒に溶かし、一般式（３）で示されるケトン又はアルデヒド、若しくは一般式（４）で示されるケタール（アセタール）を１モル倍以上加えて加熱攪拌すると反応が進行し、反応後に溶媒と未反応のケトン又はアルデヒド、或いはケタール（アセタール）を除去すると、目的とする光学活性チアゾリジン−４−カルボン酸アミドが得られる。反応に用いられる溶媒は特に制限されず、２−アルキル−Ｄ−システインアミド又はその塩と、ケトン又はアルデヒド、或いはケタール（アセタール）を溶解する溶媒を適宜選択して用いればよく、例えば、水、メタノールやエタノール等のアルコール類、ジエチルエーテルやテトラヒドロフラン等のエーテル類、ジメチルホルムアミド等のアミド類等の極性溶媒、さらにはこれらの混合溶媒等が好適に用いられる。なお、２−アルキル−Ｄ−システインアミド又はその塩が、反応に用いるケトン又はアルデヒド、或いはケタール（アセタール）に溶解する場合には、そのケトン又はアルデヒド、或いはケタール（アセタール）を反応溶媒とするのが最も好ましい。反応は室温でも進むが、より速く反応を行なうためには、加熱還流下で反応を行なうのが実際的で好ましい。また、さらに好ましくは、反応によって生成する水を脱水剤を使用する等して除去しながら行なうのが望ましい。 An optically active 2-alkyl-D-cysteine amide represented by general formula (2) or a salt thereof is dissolved in a solvent, and a ketone or aldehyde represented by general formula (3) or a ketal represented by general formula (4) ( (Acetal) is added 1 mol times or more and heated and stirred, and the reaction proceeds. After the reaction, the solvent and unreacted ketone or aldehyde, or ketal (acetal) is removed, and the desired optically active thiazolidine-4-carboxylic acid amide can get. The solvent used in the reaction is not particularly limited, and a solvent that dissolves 2-alkyl-D-cysteine amide or a salt thereof, a ketone or an aldehyde, or a ketal (acetal) may be appropriately selected and used. Polar solvents such as alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran, amides such as dimethylformamide, and mixed solvents thereof are preferably used. In addition, when 2-alkyl-D-cysteine amide or a salt thereof is dissolved in a ketone or aldehyde or ketal (acetal) used in the reaction, the ketone or aldehyde or ketal (acetal) is used as a reaction solvent. Is most preferred. Although the reaction proceeds even at room temperature, in order to carry out the reaction faster, it is practical and preferable to carry out the reaction under heating and reflux. More preferably, the water produced by the reaction is removed while using a dehydrating agent.
またこの反応は塩基性条件でより好適に行なうことができる。用いる２−アルキルシステインアミドがアルカリ金属、有機アルカリ等の強塩基と塩を形成している場合には、そのまま使用すればよいが、塩酸塩や硫酸塩等のように酸との塩を形成している場合には、この酸分に対してやや過剰となる塩基を用いることにより、反応を速やかに進行させることができる。その際に用いることのできる塩基としては、水酸化ナトリウムや水酸化カリウム等の水酸化アルカリ、炭酸ナトリウムや炭酸水素カリウム等のアルカリ金属炭酸塩、水酸化テトラメチルアンモニウムや炭酸テトラエチルアンモニウム等の有機アルカリ等、一級アミンよりも強い塩基性を示す塩基であれば使用可能であるが、反応液の後処理の容易さやコスト的観点から、水酸化ナトリウムや炭酸ナトリウムがより好適に用いられる。 Moreover, this reaction can be more suitably performed on basic conditions. When the 2-alkylcysteine amide used forms a salt with a strong base such as an alkali metal or organic alkali, it can be used as it is, but it forms a salt with an acid such as hydrochloride or sulfate. In this case, the reaction can be rapidly advanced by using a base that is slightly excessive with respect to this acid content. Bases that can be used include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium hydrogen carbonate, and organic alkalis such as tetramethylammonium hydroxide and tetraethylammonium carbonate. For example, sodium hydroxide and sodium carbonate are more preferably used from the viewpoint of ease of post-treatment of the reaction solution and cost.
反応後の反応液から有機溶媒を除去した後、これを最少量の水に溶かし、ｐＨ８から１４、好ましくはｐＨ９から１３に調節すると、目的とする光学活性チアゾリジン−４−カルボン酸アミドが析出するので、これを取得する。濾液を非極性有機溶媒で抽出して溶媒を留去すると、さらに光学活性チアゾリジン−４−カルボン酸アミドが回収できる。得られた光学活性チアゾリジン−４−カルボン酸アミドは、物性に合わせて再結晶やクロマトグラフィー等の定法によって適宜精製できる。 After removing the organic solvent from the reaction solution after the reaction, it is dissolved in a minimum amount of water and adjusted to pH 8 to 14, preferably pH 9 to 13, to precipitate the target optically active thiazolidine-4-carboxylic acid amide. So get this. When the filtrate is extracted with a nonpolar organic solvent and the solvent is distilled off, further optically active thiazolidine-4-carboxylic acid amide can be recovered. The obtained optically active thiazolidine-4-carboxylic acid amide can be appropriately purified by conventional methods such as recrystallization and chromatography according to physical properties.
本発明の方法によって、具体的には、例えば２，２，４Ｒ−トリメチルチアゾリジン−4−カルボン酸アミドを製造することができる。 Specifically, for example, 2,2,4R-trimethylthiazolidine-4-carboxylic acid amide can be produced by the method of the present invention.
本発明を実施例により更に具体的に説明するが、本発明はこれによって」限定されるものではない。 The present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.
実施例１
２−メチル−Ｄ−システインアミド塩酸塩１０．０ｇ（０．０６mol）を１００ｍLのメタノールに溶解させ、５０ｍLのアセトン、１２．７ｇ（０．１２ｍｏｌ）の炭酸ナトリウムを加え、これを窒素気流下で１２時間加熱還流した。反応液を濃縮後、２０ｍLの水を加えて析出した沈殿を濾取した。得られた沈殿をメタノールより再結晶して、無色立方晶８．１ｇ（０．０５ｍｏｌ）の２,２,４Ｒ−トリメチルチアゾリジン−4−カルボン酸アミドを得た。２−メチル−Ｄ−システインアミドからの収率は７９％であった。この２,２,４Ｒ−トリメチルチアゾリジン−4−カルボン酸アミドの結晶を光学異性体分離カラムを用いた液体クロマトグラフィーによって分析した結果、光学純度は９７％ｅ．ｅ．以上であった。
２,２,４Ｒ−トリメチルチアゾリジン−4−カルボン酸アミド；無色立方晶（融点８３℃）
［α］Ｄ −３７．４ｄｅｇ ０．９５％水溶液
質量スペクトル（ＣＩ法） ｍ／ｚ １７５ （Ｍ＋１）
１Ｈ−ＮＭＲ（９０MHｚ，ＣＤＣｌ３）δ［ｐｐｍ］ ７．３（１Ｈ，ｓ,ｂｒ），５．９（１Ｈ，ｓ,ｂｒ），３．７９（１Ｈ，ｄ，Ｊ＝１２．０Ｈｚ），２．９９（１Ｈ，ｄ，Ｊ＝１２．０Ｈｚ），２．１２（１Ｈ，ｓ，ｂｒ），１．６４（３Ｈ，ｓ），１．５３（３Ｈ，ｓ），１．５０（３Ｈ，ｓ）
ＩＲ［ｃｍ−１］（ＫＢｒ） Ｎ−Ｈ ３４２９，３３９０，３３０７，３１７８，１５７９，１５７４ Ｃ−Ｈ ２９７６，２９２７，２８６６，１４９５，１４７９，１４６０，１４５４ Ｃ＝Ｏ １６７８
元素分析 （測定値）C；４８．６４，H；８．１３，N；１６．２４，（計算値）Ｃ；４８．２５，Ｈ；８．１０，Ｎ；１６．０８
さらに、２,２,４Ｒ−トリメチルチアゾリジン−4−カルボン酸アミド８．０ｇ（０．０５mol）を５０ｍＬの水に分散し、塩酸１０ｍＬを加えて撹拌し、濃縮乾固することにより無色立方晶の２,２,４Ｒ−トリメチルチアゾリジン−4−カルボン酸アミド塩酸塩９．６ｇ（０．０５mol）が当量的に得られた。この塩酸塩は、光学異性体分離カラムを用いた液体クロマトグラフィーによって分析した結果、光学純度は９７％e.e.以上であった。
２,２,４Ｒ−トリメチルチアゾリジン−4−カルボン酸アミド塩酸塩；無色立方晶（２６４℃にて分解）
［α］Ｄ ＋５８．０ｄｅｇ ０．８６％水溶液
１Ｈ−ＮＭＲ（９０MHｚ，Ｄ２Ｏ）δ［ｐｐｍ］ ３．７２（１Ｈ，ｄ，J=１３．５Ｈｚ），３．４５（Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），1.82(3Ｈ，ｓ)，１．８３（３Ｈ，ｓ），１．７５（３Ｈ，ｓ）
ＩＲ［ｃｍ−１］（ＫＢｒ） Ｎ−Ｈ ３２０９，３１８２，３１１１，３０７４，１５５６ Ｃ−Ｈ ２９９３，２８９１，２７６０，１４５０，１４４６ Ｃ＝Ｏ １６８２
元素分析 （測定値）C；４０．１１，H；７．１９，N；１３．４０，（計算値）Ｃ；３９．９０，Ｈ；７．１７，Ｎ；１３．２９
Example 1
10.0 g (0.06 mol) of 2-methyl-D-cysteine amide hydrochloride was dissolved in 100 mL of methanol, 50 mL of acetone and 12.7 g (0.12 mol) of sodium carbonate were added, and this was added under a nitrogen stream. Heated to reflux for 12 hours. After the reaction solution was concentrated, 20 mL of water was added and the deposited precipitate was collected by filtration. The obtained precipitate was recrystallized from methanol to obtain 8.1 g (0.05 mol) of colorless cubic crystals of 2,2,4R-trimethylthiazolidine-4-carboxylic acid amide. The yield based on 2-methyl-D-cysteine amide was 79%. As a result of analyzing the 2,2,4R-trimethylthiazolidine-4-carboxylic acid amide crystals by liquid chromatography using an optical isomer separation column, the optical purity was 97% e.e. e. That was all.
2,2,4R-trimethylthiazolidine-4-carboxylic acid amide; colorless cubic (melting point 83 ° C.)
[Α] D −37.4 deg 0.95% aqueous solution mass spectrum (CI method) m / z 175 (M + 1)
1 H-NMR (90 MHz, CDCl 3 ) δ [ppm] 7.3 (1 H, s, br), 5.9 (1 H, s, br), 3.79 (1 H, d, J = 12.0 Hz) , 2.99 (1H, d, J = 12.0 Hz), 2.12 (1H, s, br), 1.64 (3H, s), 1.53 (3H, s), 1.50 (3H) , S)
IR [cm-1] (KBr) N-H 3429, 3390, 3307, 3178, 1579, 1574 C-H 2976, 2927, 2866, 1495, 1479, 1460, 1454 C = O 1678
Elemental analysis (measured value) C; 48.64, H; 8.13, N; 16.24, (calculated value) C; 48.25, H; 8.10, N; 16.08
Furthermore, 8.0 g (0.05 mol) of 2,2,4R-trimethylthiazolidine-4-carboxylic acid amide was dispersed in 50 mL of water, added with 10 mL of hydrochloric acid, stirred and concentrated to dryness to give colorless cubic crystals. 9.6 g (0.05 mol) of 2,2,4R-trimethylthiazolidine-4-carboxylic acid amide hydrochloride was obtained equivalently. As a result of analyzing the hydrochloride by liquid chromatography using an optical isomer separation column, the optical purity was 97% ee or higher.
2,2,4R-trimethylthiazolidine-4-carboxylic acid amide hydrochloride; colorless cubic (decomposes at 264 ° C.)
[Α] D +58.0 deg 0.86% aqueous solution
1 H-NMR (90 MHz, D 2 O) δ [ppm] 3.72 (1H, d, J = 13.5 Hz), 3.45 (H, d, J = 13.5 Hz), 1.82 (3H, s ), 1.83 (3H, s), 1.75 (3H, s)
IR [cm-1] (KBr) N-H 3209, 3182, 3111, 3074, 1556 C-H 2993, 2891, 2760, 1450, 1446 C = O 1682
Elemental analysis (Measured value) C; 40.11, H; 7.19, N; 13.40, (Calculated value) C; 39.90, H; 7.17, N; 13.29
Claims (4)
（一般式（１）、（２）中のＲは炭素数１〜４の低級アルキル基、一般式（１）、（３）、（４）中のＲ１及びＲ２は各々独立した水素、炭素数１〜４の低級アルキル基、又は両者が互いに結合した員数５〜８の脂環構造を示す。但しＲ１及びＲ２が同時に水素である場合を除く。また、一般式（４）中のＲ３及びＲ４は炭素数１〜３の低級アルキル基を示す。） A method for producing an optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof, wherein the optically active 2-alkyl-D-cysteine amide represented by the general formula (2) is represented by the general formula (3 The optically active thiazolidine-4-carboxylic acid amide represented by the general formula (1) or a salt thereof, wherein the aldehyde or ketone represented by the formula (4) or a ketal (acetal) represented by the general formula (4) is reacted. Manufacturing method.
(R in the general formulas (1) and (2) is a lower alkyl group having 1 to 4 carbon atoms, R 1 and R 2 in the general formulas (1), (3) and (4) are each independently hydrogen, A lower alkyl group having 1 to 4 carbon atoms or an alicyclic structure having 5 to 8 carbon atoms bonded to each other, except when R 1 and R 2 are simultaneously hydrogen, and in the general formula (4) R 3 and R 4 in C 1 represent a lower alkyl group having 1 to 3 carbon atoms.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004186005A JP2006008556A (en) | 2004-06-24 | 2004-06-24 | Method for producing optically active thiazolidine-4-carboxylic acid amide or salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004186005A JP2006008556A (en) | 2004-06-24 | 2004-06-24 | Method for producing optically active thiazolidine-4-carboxylic acid amide or salt thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2006008556A true JP2006008556A (en) | 2006-01-12 |
Family
ID=35776191
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004186005A Pending JP2006008556A (en) | 2004-06-24 | 2004-06-24 | Method for producing optically active thiazolidine-4-carboxylic acid amide or salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2006008556A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100753251B1 (en) | 2006-02-16 | 2007-08-30 | 신호상 | Preparing method of liquor, food or water eliminated aldehyde compounds and product thereby |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000309572A (en) * | 1999-04-27 | 2000-11-07 | Consortium Elektrochem Ind Gmbh | Hydrolytic ring-opening for thiazolidine derivatives, production of cysteine, cysteine methyl ester or cysteine ethyl ester and production of penicillamine |
| JP2002034593A (en) * | 2000-07-26 | 2002-02-05 | Mitsubishi Gas Chem Co Inc | METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-AMINO ACID |
| WO2005049557A1 (en) * | 2003-11-18 | 2005-06-02 | Mitsubishi Gas Chemical Company, Inc. | Process for producing optically active 2-alkylcysteine, derivative thereof, and processes for production |
-
2004
- 2004-06-24 JP JP2004186005A patent/JP2006008556A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000309572A (en) * | 1999-04-27 | 2000-11-07 | Consortium Elektrochem Ind Gmbh | Hydrolytic ring-opening for thiazolidine derivatives, production of cysteine, cysteine methyl ester or cysteine ethyl ester and production of penicillamine |
| JP2002034593A (en) * | 2000-07-26 | 2002-02-05 | Mitsubishi Gas Chem Co Inc | METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-AMINO ACID |
| WO2005049557A1 (en) * | 2003-11-18 | 2005-06-02 | Mitsubishi Gas Chemical Company, Inc. | Process for producing optically active 2-alkylcysteine, derivative thereof, and processes for production |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100753251B1 (en) | 2006-02-16 | 2007-08-30 | 신호상 | Preparing method of liquor, food or water eliminated aldehyde compounds and product thereby |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20050113292A (en) | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidineacetamide | |
| JPH06234715A (en) | Production of alanylglutamine | |
| CN102906064B (en) | The manufacture method of (1R, 2S)-1-amino-2-vinylcyclopropanecaracidlic acidlic ester that optical purity has been improved | |
| JP5647790B2 (en) | Process for producing N-carbamoyl-tert-leucine | |
| JP5168830B2 (en) | Method for producing tetrahydropyran-4-one compound | |
| JP2006008556A (en) | Method for producing optically active thiazolidine-4-carboxylic acid amide or salt thereof | |
| CN104557583A (en) | Method for synthesizing gamma-aminobutyric acid chiral compound | |
| JP2009242244A (en) | Method for producing pyrazine derivative and intermediate of the same | |
| US20100185012A1 (en) | Method for producing optically active trans-2-aminocyclohexanol and intermediate of optically active trans-2-aminocyclohexanol | |
| JPH0978277A (en) | Production of 3-amino-2-hydroxy-1,1,1-trifluoromethyl compound | |
| JP4899385B2 (en) | Method for producing 3-aminomethyloxetane compound | |
| KR100625649B1 (en) | The method of preparing ?-hydroxybutyric acid alkyl esters | |
| EP0902011B1 (en) | Gamma-oxo-homophenylalanine derivatives and process for producing homophenylalanine derivatives by reducing the same | |
| KR20070110510A (en) | Process for preparing enantiopure e-(2s)-alkyl-5-halopent-4-enoic acids and esters | |
| JP3981996B2 (en) | Ketooxazolidinone and process for producing amidoindanol from the compound | |
| JP2009242243A (en) | alpha-HYDROXYIMINO CARBOXYLIC ACID ESTER DERIVATIVE AND METHOD FOR PRODUCING alpha-AMINO-alpha-HALOALKYL CARBOXYLIC ACID ESTER DERIVATIVE BY USING THE SAME | |
| JP2002371060A (en) | Method for producing optically active aminopiperidine derivative | |
| JP4929717B2 (en) | Process for producing N, N'-dialkoxy-N, N'-dialkyloxamide | |
| KR100597259B1 (en) | A Process for Optical Pure R-2-Phenoxypropionic acid derivatives | |
| KR100503267B1 (en) | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid | |
| JPS6210500B2 (en) | ||
| KR100638171B1 (en) | Preparation method of 2,N-dimethyl-N-3,3-diphenylpropyl-1-amino-2-propanol | |
| JP4560309B2 (en) | Method for producing optically active amino acid derivative | |
| JPH01100153A (en) | Production of n-(alpha-alkoxyethyl)carbonamide | |
| JPH11106363A (en) | Production of optically active 2-hydroxymethyl-3-phenylpropionic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Effective date: 20070525 Free format text: JAPANESE INTERMEDIATE CODE: A621 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20100616 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A132 Effective date: 20100630 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20110119 |