JPH0429990A - Production of optically active cis-thiazolidin-4-one derivative - Google Patents
Production of optically active cis-thiazolidin-4-one derivativeInfo
- Publication number
- JPH0429990A JPH0429990A JP13632890A JP13632890A JPH0429990A JP H0429990 A JPH0429990 A JP H0429990A JP 13632890 A JP13632890 A JP 13632890A JP 13632890 A JP13632890 A JP 13632890A JP H0429990 A JPH0429990 A JP H0429990A
- Authority
- JP
- Japan
- Prior art keywords
- thiazolidin
- cis
- optically active
- salt
- derivative
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 230000003287 optical effect Effects 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 18
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 16
- FZXAQGVGSAANBR-XCBNKYQSSA-N (2s,5r)-3,5-dimethyl-2-pyridin-3-yl-1,3-thiazolidin-4-one Chemical compound CN1C(=O)[C@@H](C)S[C@H]1C1=CC=CN=C1 FZXAQGVGSAANBR-XCBNKYQSSA-N 0.000 claims description 11
- 238000000354 decomposition reaction Methods 0.000 claims description 4
- NOLHRFLIXVQPSZ-UHFFFAOYSA-N 1,3-thiazolidin-4-one Chemical class O=C1CSCN1 NOLHRFLIXVQPSZ-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-ZDFGOMNRSA-N [2,2,3,3,4,5,5-heptadeuterio-7-methyl-6-oxo-7-(trideuteriomethyl)-1-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C12(C(=O)C(C(C(C1([2H])[2H])([2H])[2H])(C2(C([2H])([2H])[2H])C)[2H])([2H])[2H])CS(=O)(=O)O MIOPJNTWMNEORI-ZDFGOMNRSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 2
- 239000002904 solvent Substances 0.000 abstract description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 4
- 238000009835 boiling Methods 0.000 abstract description 3
- 208000026935 allergic disease Diseases 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 206010061218 Inflammation Diseases 0.000 abstract 1
- 230000004054 inflammatory process Effects 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 5
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 4
- -1 dioxane Chemical compound 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- PLBVNSJJNYHVDG-UHFFFAOYSA-N 2-pyridin-3-yl-1,3-thiazolidin-4-one Chemical compound N1C(=O)CSC1C1=CC=CN=C1 PLBVNSJJNYHVDG-UHFFFAOYSA-N 0.000 description 2
- LCTZAVXIVLCKMH-UHFFFAOYSA-N 2-pyridin-3-ylethenamine Chemical compound NC=CC1=CC=CN=C1 LCTZAVXIVLCKMH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HDAOSBOZJLANJQ-UHFFFAOYSA-N (7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methylsulfonyl (7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonate Chemical compound C1CC(C2(C)C)CC(=O)C12CS(=O)(=O)OS(=O)(=O)CC1(C(=O)C2)CCC2C1(C)C HDAOSBOZJLANJQ-UHFFFAOYSA-N 0.000 description 1
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical class CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- ULKGGIRPUMAXMP-UHFFFAOYSA-N 5,5-dimethyl-2-pyridin-3-yl-1,3-thiazolidin-4-one Chemical compound N1C(=O)C(C)(C)SC1C1=CC=CN=C1 ULKGGIRPUMAXMP-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- JQQHKTPQFWSNBC-UHFFFAOYSA-J hydrogen carbonate thorium(4+) Chemical compound [Th+4].OC([O-])=O.OC([O-])=O.OC([O-])=O.OC([O-])=O JQQHKTPQFWSNBC-UHFFFAOYSA-J 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明は式〔I〕
で表されるシス−チアゾリジン−4−オン誘導体のd体
とβ体からなる混合物を光学分割することにより、上記
式〔工〕で表される化合物の光学活性体を製造法に関す
る。Detailed Description of the Invention <Industrial Application Field> The present invention provides the above-mentioned This invention relates to a method for producing an optically active compound of the formula [E].
式〔I〕で表されるシス−チアゾリジン−4オン誘導体
は優れた血小板活性化因子(以後PAFと略称する)拮
抗作用を有し、PAF誘発病、たとえば種々の炎症・ア
レルギー性疾患、循環器系疾患、消化器系疾患などの予
防治療薬として極めて有用なものであることが知られて
いる(特開平1−279882号公報)。The cis-thiazolidin-4one derivative represented by formula [I] has excellent platelet activating factor (hereinafter abbreviated as PAF) antagonistic activity, and is effective against PAF-induced diseases such as various inflammatory and allergic diseases, cardiovascular diseases, etc. It is known to be extremely useful as a prophylactic and therapeutic drug for systemic diseases, digestive system diseases, etc. (Japanese Patent Application Laid-open No. 1-279882).
〈従来の技術および問題点〉
式CI)で表されるシス−チアゾリジン−4−オン誘導
体の光学活性体の取得法としては、光学活性なα−メル
カプトプロピオン酸と、N−ニコチニリデンメチルアミ
ンを縮合して取得する方法が知られている(特開平1−
279882号公報)。しかし、この方法は、原料であ
る光学活性なα−メルカプトプロピオン酸の入手に問題
があるなど、現状では実用的な方法とはいいがたい。<Prior art and problems> As a method for obtaining an optically active form of cis-thiazolidin-4-one derivative represented by formula CI), optically active α-mercaptopropionic acid and N-nicotinylidenemethylamine are used. There is a known method to obtain it by condensing the
279882). However, this method cannot be said to be a practical method at present, as there are problems in obtaining optically active α-mercaptopropionic acid as a raw material.
〈発明が解決しようとする課題〉
本発明は、式〔I〕で表されるシス−チアゾリジン−4
−オン誘導体の光学活性体の実用的な製造法を確立する
ことを目的とする。<Problems to be Solved by the Invention> The present invention provides cis-thiazolidine-4 represented by formula [I]
The purpose of this study is to establish a practical method for producing optically active -one derivatives.
く課題を解決するための手段〉
工業的に入手が容易な、α−メルカプトプロピオン酸の
d体と1体からなる混合物とN−ニコチニリデンメチル
アミンから製造される前記式〔I〕で表されるシス−チ
アゾリジン−4−オン誘導体のd体とβ体からなる混合
物を、光学活性な10−カンファースルホン酸で光学分
割することにより、目的が達成されることがわかった。Means for Solving the Problem> A compound represented by the above formula [I] produced from a mixture of the d-mercaptopropionic acid and the 1-mercaptopropionic acid and N-nicotinylidenemethylamine, which is industrially easily available. It has been found that the objective can be achieved by optically resolving a mixture of the d-form and the β-form of the cis-thiazolidin-4-one derivative with optically active 10-camphorsulfonic acid.
すなわち、本発明は式〔I〕で表されるシス−チアゾリ
ジン−4−オン誘導体のd体とβ体からなる混合物を、
光学分割剤として光学活性な10−カンファースルホン
酸を用いて光学分割し、光学活性な式〔I〕のシス−チ
アゾリジン−4−オン誘導体を取得する方法に関する。That is, the present invention provides a mixture of the d-form and the β-form of the cis-thiazolidin-4-one derivative represented by formula [I],
The present invention relates to a method for obtaining an optically active cis-thiazolidin-4-one derivative of formula [I] by optically resolving using optically active 10-camphorsulfonic acid as an optical resolving agent.
更に詳しくは、本発明は、式〔I〕で表されるシス−チ
アゾリジン−4−オン誘導体のd体と1体からなる混合
物とD−又はL−10−カンファースルホン酸とを適当
な溶媒中で反応させ、2種類のジアステレオマー塩を生
成させ、これらの塩の溶媒に対する溶解度差を利用して
分離し、得られる所望のジアステレオマー塩を分解して
所望の配位を有する式〔I〕で表される光学活性なシス
−チアゾリジン−4−オン誘導体を得る方法である。More specifically, the present invention provides a method for preparing a mixture of a d-form and a cis-thiazolidin-4-one derivative represented by formula [I] and D- or L-10-camphorsulfonic acid in an appropriate solvent. to generate two types of diastereomeric salts, which are separated by utilizing the difference in solubility of these salts in the solvent, and the resulting desired diastereomeric salt is decomposed to form the formula [ This is a method for obtaining an optically active cis-thiazolidin-4-one derivative represented by [I].
本発明は、具体的には次の方法により実施する。Specifically, the present invention is carried out by the following method.
式〔I〕のシス−チアゾリジン−4−オン誘導体のd体
とβ体からなる混合物とD−10−カンファースルホン
酸あるいはL−10−カンファースルホン酸とを溶媒中
に溶解して塩を形成せしめる。A mixture of the d-form and β-form of the cis-thiazolidin-4-one derivative of formula [I] and D-10-camphorsulfonic acid or L-10-camphorsulfonic acid are dissolved in a solvent to form a salt. .
次いで、生ずる2種のジアステレオマー塩のうち一方を
優先的に晶出せしめる。Next, one of the two resulting diastereomeric salts is preferentially crystallized.
d体と1体からなる混合物としては例えばラセミ体が挙
げられる。An example of a mixture consisting of the d-form and the 1-form is a racemate.
溶媒としては例えば、ベンゼン、トルエン、クロロベン
ゼンなどの芳香族系溶媒、例えばテトラヒドロフラン、
ジオキサンなどのエーテル系溶媒、例えばアセトン、2
−ブタノンなどのケトン系溶媒、例えばアセトニトリル
、ジメチルホルムアミド、ジメチルスルホキシドなどの
高極性非プロトン性溶媒、例えばジクロロメタン、クロ
ロホルム、■、2−ジクロロエタンなどのハロゲン系溶
媒、例えばメタノール、エタノール、イソプロピルアル
コール、t−ブチルアルコールなどのアルコール系溶媒
等を挙げることができる。特に好ましい溶媒としては、
例えばテトラヒドロフラン、ベンゼン、イソプロピルア
ルコール等の溶媒が挙げられる。また、これらを任意の
割合で混合して用いることもできる。Examples of the solvent include aromatic solvents such as benzene, toluene, and chlorobenzene, such as tetrahydrofuran,
Ether solvents such as dioxane, e.g. acetone, 2
- Ketone solvents such as butanone, highly polar aprotic solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, halogen solvents such as dichloromethane, chloroform, 2-dichloroethane, e.g. methanol, ethanol, isopropyl alcohol, t -Alcoholic solvents such as butyl alcohol can be mentioned. Particularly preferred solvents include:
Examples include solvents such as tetrahydrofuran, benzene, and isopropyl alcohol. Moreover, these can also be mixed and used in arbitrary ratios.
溶解し塩を形成せしめる際の温度としては、室温から溶
媒の沸点までの範囲で行うことができるが、塩の形成を
容易に行うこと及び溶解度差により一方のジアステレオ
マー塩を優先的に析出させ易くすることから、溶媒の沸
点近くまで加温する− 6 =
ことが好ましい。析出した塩を分離する前に必要に応じ
冷却し、析出晶を増加させることもできる。The temperature for dissolving and forming a salt can be in the range from room temperature to the boiling point of the solvent, but it is possible to form the salt easily and preferentially precipitate one diastereomeric salt due to the difference in solubility. In order to facilitate the reaction, it is preferable to heat the solvent to a temperature close to its boiling point. Before separating the precipitated salt, it is possible to cool the precipitated salt as necessary to increase the number of precipitated crystals.
分割剤としてのD−10−カンファースルホン酸あるい
はL−10−カンファースルホン酸の使用量は、基質に
対して0.5〜2.0当量、好ましくは1当量前後が適
当である。The appropriate amount of D-10-camphorsulfonic acid or L-10-camphorsulfonic acid used as a resolving agent is 0.5 to 2.0 equivalents, preferably around 1 equivalent, relative to the substrate.
なお、予め用意しておいた光学純度の高い塩を結晶化時
に接種することも可能である。Note that it is also possible to inoculate a previously prepared salt with high optical purity at the time of crystallization.
得られた結晶を、先に挙げた溶媒中で再結晶、または同
溶媒中に懸濁攪拌した後濾過することにより、光学純度
をより向上させることも可能である。この時に用いる溶
媒は最初の塩の形成に用いたのと同じ溶媒でも良く、ま
た、別の溶媒を用いてもよい。It is also possible to further improve optical purity by recrystallizing the obtained crystals in the above-mentioned solvent, or by suspending and stirring the crystals in the same solvent and filtering them. The solvent used at this time may be the same as that used for the initial salt formation, or a different solvent may be used.
また、本発明方法では、2種のジアステレオマー塩の混
合物を予め単離しておき、これを前述の溶媒を用い再結
晶するか、または同溶媒中に懸濁攪拌した後濾過して、
ジアステレオマー塩の一方だけを取り出すこともできる
。In addition, in the method of the present invention, a mixture of two types of diastereomer salts is isolated in advance, and this is recrystallized using the above-mentioned solvent, or suspended in the same solvent, stirred, and then filtered.
It is also possible to extract only one of the diastereomeric salts.
これらの方法で得られたジアステレオマー塩は通常の塩
分解法を経て光学活性なシス−チアゾリジン−4−オン
誘導体を単離することができる。The diastereomeric salts obtained by these methods can be subjected to conventional salt decomposition methods to isolate optically active cis-thiazolidin-4-one derivatives.
即ち、例えばジアステレオマー塩を塩基により中和し、
光学活性な10−カンファースルホン酸は塩基との塩と
して水層に移行させ、光学活性なシス−チアゾリジン−
4−オン誘導体を水と分離する適当な有機溶媒、例えば
ジクロロメタン、1゜2−ジクロロエタン、トルエン、
酢酸エチル、エーテル等で抽出することにより、これを
分離し、単離することができる。塩基としては無機塩基
、及び有機塩基が挙げられる。無機塩基としては例えば
炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム等
のアルカリ金属の炭酸塩、例えば水酸化ナトリウム、水
酸化カリウム等の水酸化アルカリ金属などがあげられる
。有機塩基としては例えばトリエチルアミン等のアミン
類が挙げられる。That is, for example, by neutralizing the diastereomeric salt with a base,
Optically active 10-camphorsulfonic acid is transferred to the aqueous layer as a salt with a base, and optically active cis-thiazolidine-
A suitable organic solvent for separating the 4-one derivative from water, such as dichloromethane, 1°2-dichloroethane, toluene,
It can be separated and isolated by extraction with ethyl acetate, ether, etc. Examples of the base include inorganic bases and organic bases. Examples of the inorganic base include alkali metal carbonates such as sodium hydrogen carbonate, sodium carbonate, and potassium carbonate, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Examples of the organic base include amines such as triethylamine.
さらに、一方のジアステレオマー塩を得た際の濾液から
その対掌体を得ることもできる。Furthermore, the enantiomer can also be obtained from the filtrate obtained when one diastereomeric salt is obtained.
即ち、濾液の濃縮残渣を上記の方法で塩分解し、得られ
る式CI)で表されるシス−チアゾリジン4−オン誘導
体に、先に使用した光学活性な10−カンファースルホ
ン酸と逆の旋光性を有する光学活性10−カンファース
ルホン酸を作用させ、以下、上述の方法を適用すること
により光学活性なシス−チアゾリジン−4−オン誘導体
を得ることができる。従って本発明の方法によって、−
形成〔I〕で表されるシス−チアゾリジン−4−オン誘
導体の6体とβ体の混合物から、光学純度の高い6体及
び1体をそれぞれ高収率で得ることが可能である。That is, the concentrated residue of the filtrate is subjected to salt decomposition by the above method, and the resulting cis-thiazolidin 4-one derivative represented by formula CI) has an optical rotation opposite to that of the optically active 10-camphorsulfonic acid used previously. An optically active cis-thiazolidin-4-one derivative can be obtained by reacting optically active 10-camphorsulfonic acid having 10-camphorsulfonic acid and applying the above-mentioned method. Therefore, by the method of the invention, -
From a mixture of the 6-isomer and the β-isomer of the cis-thiazolidin-4-one derivative represented by Formation [I], it is possible to obtain the 6-isomer and the 1-isomer with high optical purity in high yields, respectively.
次に、本発明を以下の実施例によって説明するが、これ
はその−例にすぎないものであって、これに何ら限定さ
れるものではない。Next, the present invention will be explained with reference to the following examples, but these are merely examples and are not intended to limit the invention in any way.
なお、実施例中、光学純度は次のようにして測定したも
のを示す。In addition, in the examples, the optical purity is measured as follows.
光学純度:
シスー3,5−ジメチル−2−(3−ピリジル)−チア
ゾリジン−4−オンはジクロルメタンに溶解し、又、シ
ス−3,5−ジメチル−2(3−ピリジル)−チアゾリ
ジン−4−オンのカンファースルホン酸塩は炭酸水素ナ
トリウム水溶液で塩分解後にジクロロメタンで抽出した
。この溶液について、次の肝LC条件で分析し、光学純
度(%e、 e、 )を求めた。HPLC条件カラム:
Chiralcel OD■(ダイセル社製)4.6
X260mm
移動相゛n−ヘキサン/IPA=9/1 1.0ml/
minカラム温度: 室温
検出:uv−264nm
保持時間:(+)シス−3,5−ジメチル−2(3−ピ
リジル)チアゾリジン
4−オン 16.6m1n
(−)−シス−3,5ジメチル−2
(3−ピリジル)チアゾリジン
4−オン 31.2m1n
実施例I
5.0gのラセミ体のシス−3,5−ジメチル2−(3
−ピリジル)チアゾリジン−4−オン5.58gのD−
カンファースルホン酸(無水物)にテトラヒドロフラン
25m1を加え室温で溶解した。Optical purity: cis-3,5-dimethyl-2-(3-pyridyl)-thiazolidin-4-one is dissolved in dichloromethane, and cis-3,5-dimethyl-2(3-pyridyl)-thiazolidin-4-one is dissolved in dichloromethane. The camphor sulfonate of 100% was salt-decomposed with an aqueous sodium bicarbonate solution, and then extracted with dichloromethane. This solution was analyzed under the following liver LC conditions to determine the optical purity (%e, e, ). HPLC condition column:
Chiralcel OD■ (manufactured by Daicel) 4.6
X260mm Mobile phase n-hexane/IPA=9/1 1.0ml/
min Column temperature: Room temperature detection: UV-264 nm Retention time: (+)cis-3,5-dimethyl-2(3-pyridyl)thiazolidin-4-one 16.6mln (-)-cis-3,5dimethyl-2 ( 3-pyridyl)thiazolidin-4-one 31.2 m1n Example I 5.0 g of racemic cis-3,5-dimethyl 2-(3
-pyridyl)thiazolidin-4-one 5.58g D-
25 ml of tetrahydrofuran was added to camphorsulfonic acid (anhydride) and dissolved at room temperature.
この溶液に(十)−シス−3,5−ジメチル−2(3−
ピリジル)チアゾリジン−4−オンのDカンファースル
ホン酸塩を種晶として少量加え、室温で5時間攪拌した
。析出品を濾取しテトラヒドロフラン6−で洗浄し、減
圧乾燥して(+)シス−3,5−ジメチル−2−(3−
ピリジル)チアゾリジン−4−オンのD−カンファース
ルホン酸塩4.61gを得た。Add (10)-cis-3,5-dimethyl-2(3-
A small amount of D camphorsulfonate of pyridyl)thiazolidin-4-one was added as a seed crystal, and the mixture was stirred at room temperature for 5 hours. The precipitated product was collected by filtration, washed with tetrahydrofuran 6-, and dried under reduced pressure to give (+)cis-3,5-dimethyl-2-(3-
4.61 g of D-camphorsulfonate of pyridylthiazolidin-4-one was obtained.
融点 145〜150°C
〔α〕乙’−十34.5° (c = 1.0.メタノ
ール)光学純度 85,0%e、 e。Melting point 145-150°C [α] Otsu'-134.5° (c = 1.0.methanol) Optical purity 85.0% e, e.
実施例2
5.0gのラセミ体のシス−3,5−ジメチル2−(3
−ピリジル)チアゾリジン−4−オン、5、58 gの
D−カンファースルホン酸(無水物)にベンゼン50m
1を加え室温で溶解した。この溶液に(+)−シス−3
,5−ジメチル−2−(3ピリジル)チアゾリジン−4
−オンのD−カンファースルホン酸塩を種晶として少量
加え、室温で5時間攪拌した。析出品を濾取しベンゼン
10mgで洗浄し、減圧乾燥して(+)−シス−3,5
ジメチル−2−(3−ピリジル)チアゾリジン4−オン
のD−カンファースルホン酸塩4.55gを得た。Example 2 5.0 g of racemic cis-3,5-dimethyl 2-(3
-pyridyl)thiazolidin-4-one, 5.58 g of D-camphorsulfonic acid (anhydride) and 50 m of benzene
1 was added and dissolved at room temperature. Add (+)-cis-3 to this solution.
,5-dimethyl-2-(3pyridyl)thiazolidine-4
A small amount of D-camphorsulfonate of -one was added as a seed crystal, and the mixture was stirred at room temperature for 5 hours. The precipitated product was collected by filtration, washed with 10 mg of benzene, and dried under reduced pressure to obtain (+)-cis-3,5
4.55 g of D-camphorsulfonate of dimethyl-2-(3-pyridyl)thiazolidin-4-one was obtained.
融点 144〜148°C
〔α〕乙’= +33.6° (c=1.0.メタノ
ール)光学純度 83.6%e、 e。Melting point 144-148°C [α] Otsu' = +33.6° (c = 1.0.methanol) Optical purity 83.6% e, e.
実施例3
5、Ogのラセミ体のシス−3,5−ジメチル2−(3
−ピリジル)チアゾリジン−4−オン、5、58 gの
D−カンファースルホン酸(無水物)にイソプロピルア
ルコール15m1を加え、約50°Cに加温し溶解した
。この溶液を室温まで冷却し、(+)−シス−3,5−
ジメチル−2−(3−ピリジル)チアソリジン−4−オ
ンのD−カンファースルホン酸塩を種晶として少量加え
、室温にて5時間攪拌した。析出品を濾取し5°Cに冷
却したイソプロピルアルコール3 mlで洗浄し、減圧
乾燥■
して(+)−シス−3,5−ジメチル−2−(3ピリジ
ル)チアゾリジン−4−オンのD−カンファースルホン
酸塩4.14gを得た。Example 3 Racemic cis-3,5-dimethyl 2-(3
-pyridyl)thiazolidin-4-one, 15 ml of isopropyl alcohol was added to 58 g of D-camphorsulfonic acid (anhydride) and dissolved by heating to about 50°C. This solution was cooled to room temperature and (+)-cis-3,5-
A small amount of D-camphorsulfonate of dimethyl-2-(3-pyridyl)thiazoridin-4-one was added as a seed crystal, and the mixture was stirred at room temperature for 5 hours. The precipitate was collected by filtration, washed with 3 ml of isopropyl alcohol cooled to 5°C, and dried under reduced pressure. - 4.14 g of camphorsulfonate were obtained.
融点 145〜150°C
〔α〕乙’−+34.1° (c=1.0.メタノール
) 光学純度 8.6.4%e、 e。Melting point 145-150°C [α] Otsu'-+34.1° (c=1.0.methanol) Optical purity 8.6.4% e, e.
実施例4
D−カンファースルホン酸の代りにL−カンファースル
ホン酸を用いて、実施例1と同様に処理し、(−)−シ
ス−3,5−ジメチル−2−(3ピリジル)チアシリジ
ン−4−オンのし一カンファースルホン酸塩4.48g
を得た。Example 4 Using L-camphorsulfonic acid instead of D-camphorsulfonic acid, the same treatment as in Example 1 was performed to obtain (-)-cis-3,5-dimethyl-2-(3pyridyl)thiacyridine-4. -onoshiichi camphor sulfonate 4.48g
I got it.
融点 145〜148°C
〔α〕乙0= −34,1° (c=1.0.メタツ
ル) 光学純度 82.6%e、 e。Melting point 145-148°C [α] Otsu0=-34.1° (c=1.0.Metatsuru) Optical purity 82.6%e, e.
実施例5
実施例1の分割濾洗液を減圧濃縮し溶媒を留去した。残
渣に水30m1と5%炭酸水素ナトリウム水溶液34.
7gを加え塩を分解し、ジクロロメタン25艷で2回抽
出した。有機層を減圧濃縮し残渣2、81 gを得た。Example 5 The divided filtration and washing liquid of Example 1 was concentrated under reduced pressure to remove the solvent. Add 30ml of water and 34% 5% sodium bicarbonate aqueous solution to the residue.
7 g was added to decompose the salt, and the mixture was extracted twice with 25 g of dichloromethane. The organic layer was concentrated under reduced pressure to obtain 81 g of residue 2.
残渣をテトラヒドロフラン25m1に溶解し、L−カン
ファースルホン酸(無水物)3.14gを加え、室温で
16時間攪拌した。析出晶を濾取しテトラヒドロフラン
5 rnlで洗浄後減圧乾燥し、(−)−シス−3,5
−ジメチル−2(3−ピリジル)チアゾリジン−4−オ
ンのしカンファースルホン 酸塩4.49gを得た。The residue was dissolved in 25 ml of tetrahydrofuran, 3.14 g of L-camphorsulfonic acid (anhydride) was added, and the mixture was stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration, washed with 5 rnl of tetrahydrofuran, and dried under reduced pressure to give (-)-cis-3,5
4.49 g of camphorsulfonate of -dimethyl-2(3-pyridyl)thiazolidin-4-one was obtained.
融点 149〜153°C
〔α)B’−35,4° (c=1.0.メタノール)
光学純度 94.2%e、 e。Melting point 149-153°C [α)B'-35.4° (c=1.0.methanol)
Optical purity 94.2%e, e.
実施例6
134gのD−カンファースルホン酸°1水和物にトル
エン1700gを加え、加熱を行ない常圧にて水とトル
エンの混合物1250gを留去した。残渣を室温まで冷
却し、これに110gのラセミ体のシス−3,5−ジメ
チル−2−(3−ピリジル)チアゾリジン−4−オンお
よびテトラヒドロフラン820gを加え溶解した。この
溶液に(+)シス−3,5−ジメチル−2−(3−ピリ
ジル)チアゾリジン−4−オンのD−カンファースルホ
ン酸塩を種晶として少量加え、室温で1時間、45〜5
0°Cで1時間、0〜5°Cで2時間保温した。Example 6 1700 g of toluene was added to 134 g of D-camphorsulfonic acid monohydrate and heated to distill off 1250 g of a mixture of water and toluene at normal pressure. The residue was cooled to room temperature, and 110 g of racemic cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one and 820 g of tetrahydrofuran were added and dissolved therein. To this solution, a small amount of D-camphorsulfonate of (+)cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one was added as a seed crystal, and the mixture was incubated at room temperature for 1 hour.
It was kept warm at 0°C for 1 hour and at 0-5°C for 2 hours.
析出晶を濾過し、0〜5°Cに冷却したテトラヒドロフ
ラン300gで洗浄後、乾燥し、(+)−3゜5−ジメ
チル−2−(3−ピリジル)チアゾリジン−4−オンの
D−カンファースルホン酸塩113gを得た。The precipitated crystals were filtered, washed with 300 g of tetrahydrofuran cooled to 0 to 5°C, and dried to form D-camphorsulfone of (+)-3°5-dimethyl-2-(3-pyridyl)thiazolidin-4-one. 113 g of the acid salt was obtained.
光学純度 90.0%e、 e。Optical purity 90.0%e, e.
実施例7
実施例6で得られた(+)−シス−3,5−ジメチル−
2−(3−ピリジル)チアゾリジン−4オンのD−カン
ファースルホン酸塩110gにテトラヒドロフラン49
0gを加え、加熱し環流下に1時間保温、その後0〜5
°Cで2時間保温した。結晶を濾過し、0〜5°Cに冷
却したテトラヒドロフラン140gで洗浄し、(+)−
シス−35−ジメチル−2−(3−ピリジル)チアゾリ
ジン−4−オンのD−カンファースルホン酸塩99gを
得た。Example 7 (+)-cis-3,5-dimethyl- obtained in Example 6
To 110 g of D-camphorsulfonate of 2-(3-pyridyl)thiazolidin-4one was added 49 g of tetrahydrofuran.
Add 0g, heat and keep warm under reflux for 1 hour, then 0 to 5
It was kept warm at °C for 2 hours. The crystals were filtered, washed with 140 g of tetrahydrofuran cooled to 0-5°C, and (+)-
99 g of D-camphorsulfonate of cis-35-dimethyl-2-(3-pyridyl)thiazolidin-4-one was obtained.
融点 151−153°C
〔α]’D = +35.0° (c=1.0.メタ
ノール) 光学純度 98.5%e、 e。Melting point 151-153°C [α]'D = +35.0° (c = 1.0.methanol) Optical purity 98.5% e, e.
実施例8
実施例7で得られた(+)−シス−3,5−ジメチル−
2−(3−ピリジル)チアゾリジン−4オンのD−カン
ファースルホン酸塩5.0gを25 mlの水に溶解し
、5%炭炭酸水素上トリウム水溶液285gを加え塩分
解した。この溶液をジクロロメタン25mfで2回抽出
し、ジクロロメタン層を無水硫酸マグネシウムで乾燥後
溶媒を留去し、(+)−シス−3,5−ジメチル−2−
(3−ピリジル)チアゾリジン−4−オン2.32 g
を得た。Example 8 (+)-cis-3,5-dimethyl- obtained in Example 7
5.0 g of D-camphorsulfonate of 2-(3-pyridyl)thiazolidin-4one was dissolved in 25 ml of water, and 285 g of a 5% thorium bicarbonate aqueous solution was added thereto for salt decomposition. This solution was extracted twice with 25 mf of dichloromethane, the dichloromethane layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and (+)-cis-3,5-dimethyl-2-
(3-pyridyl)thiazolidin-4-one 2.32 g
I got it.
光学純度 99,0%e、 e。Optical purity 99.0%e, e.
融点 66〜67°C
〔α〕乙’−十39.7° (c=1.0.メタノール
)〈本発明の効果〉
本発明により、前記式〔I〕で表される光学活性なシス
−チアゾリジン−4−オン誘導体を工業的に有利な方法
で得ることが可能となった。Melting point 66-67°C [α] Otsu'-139.7° (c=1.0.methanol) <Effects of the present invention> According to the present invention, the optically active cis- It has become possible to obtain thiazolidin-4-one derivatives by an industrially advantageous method.
Claims (4)
とl体からなる混合物に光学活性な10−カンファース
ルホン酸を作用させ、生じる2種のジアステレオマー塩
を溶解度差を利用して分離し、得られる塩を分解するこ
とを特徴とする式〔 I 〕で表される光学活性なシス−
チアゾリゾン−4−オン誘導体の製造法。(1) Formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Optically active 10-camphorsulfonic acid in a mixture consisting of the d-form and l-form of the cis-thiazolidin-4-one derivative represented by [I] The optically active cis-
Method for producing thiazolizon-4-one derivative.
晶出させた残渣中に含まれる他方のジアステレオマー塩
を塩分解した後、塩分解された式〔 I 〕で表されるシ
ス−チアゾリジン−4−オン誘導体に、請求項1で使用
した光学活性な10−カンファースルホン酸とは逆の旋
光性を有する光学活性な10−カンファースルホン酸を
作用させる工程を含むことを特徴とする光学活性なシス
−チアゾリジン−4−オン誘導体の製造法。(2) In claim 1, after salt decomposition of the other diastereomer salt contained in the residue obtained by crystallizing one diastereomer salt, the salt decomposed cis- An optical method comprising the step of acting on a thiazolidin-4-one derivative with optically active 10-camphorsulfonic acid having an optical rotation opposite to that of the optically active 10-camphorsulfonic acid used in claim 1. Method for producing active cis-thiazolidin-4-one derivatives.
活性体と、光学活性な10−カンファースルホン酸との
塩。(3) A salt of an optically active form of a cis-thiazolidin-4-one derivative represented by the formula [I] ▼Mathematical formulas, chemical formulas, tables, etc.▼[I] and optically active 10-camphorsulfonic acid.
リジル)チアゾリジン−4−オンとD−10−カンファ
ースルホン酸との塩。(4) Salt of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one and D-10-camphorsulfonic acid.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13632890A JPH0429990A (en) | 1990-05-24 | 1990-05-24 | Production of optically active cis-thiazolidin-4-one derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13632890A JPH0429990A (en) | 1990-05-24 | 1990-05-24 | Production of optically active cis-thiazolidin-4-one derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0429990A true JPH0429990A (en) | 1992-01-31 |
Family
ID=15172657
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13632890A Pending JPH0429990A (en) | 1990-05-24 | 1990-05-24 | Production of optically active cis-thiazolidin-4-one derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0429990A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR970027075A (en) * | 1995-11-20 | 1997-06-24 | 김준웅 | Separation method of optical isomer |
US8380351B2 (en) | 2008-06-11 | 2013-02-19 | Panasonic Corporation | Manipulator, manipulator collision detecting method and manipulator control method |
-
1990
- 1990-05-24 JP JP13632890A patent/JPH0429990A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR970027075A (en) * | 1995-11-20 | 1997-06-24 | 김준웅 | Separation method of optical isomer |
US8380351B2 (en) | 2008-06-11 | 2013-02-19 | Panasonic Corporation | Manipulator, manipulator collision detecting method and manipulator control method |
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