JPH0460975B2 - - Google Patents
Info
- Publication number
- JPH0460975B2 JPH0460975B2 JP14615983A JP14615983A JPH0460975B2 JP H0460975 B2 JPH0460975 B2 JP H0460975B2 JP 14615983 A JP14615983 A JP 14615983A JP 14615983 A JP14615983 A JP 14615983A JP H0460975 B2 JPH0460975 B2 JP H0460975B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- ethyl
- melting point
- same
- group
- 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.)
- Expired
Links
- -1 disulfide compound Chemical class 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 29
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 150000002019 disulfides Chemical class 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- SMTOKHQOVJRXLK-UHFFFAOYSA-N butane-1,4-dithiol Chemical compound SCCCCS SMTOKHQOVJRXLK-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229960000344 thiamine hydrochloride Drugs 0.000 description 3
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 3
- 239000011747 thiamine hydrochloride Substances 0.000 description 3
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- APAUAYLVDHNFBF-UHFFFAOYSA-N 2-(2-hydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound N1C(C(=O)O)CSC1C1=CC=CC=C1O APAUAYLVDHNFBF-UHFFFAOYSA-N 0.000 description 2
- YCLSOMLVSHPPFV-UHFFFAOYSA-N 3-(2-carboxyethyldisulfanyl)propanoic acid Chemical compound OC(=O)CCSSCCC(O)=O YCLSOMLVSHPPFV-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 229950001139 timonacic Drugs 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 1
- SRZXCOWFGPICGA-UHFFFAOYSA-N 1,6-Hexanedithiol Chemical compound SCCCCCCS SRZXCOWFGPICGA-UHFFFAOYSA-N 0.000 description 1
- AKYZXEVLLDNHDZ-UHFFFAOYSA-N 2-bromo-2-(4-chlorophenyl)acetonitrile Chemical compound ClC1=CC=C(C(Br)C#N)C=C1 AKYZXEVLLDNHDZ-UHFFFAOYSA-N 0.000 description 1
- IJYFABMVKOPOKF-UHFFFAOYSA-N 2-bromo-3-ethoxy-3-oxopropanoic acid Chemical compound CCOC(=O)C(Br)C(O)=O IJYFABMVKOPOKF-UHFFFAOYSA-N 0.000 description 1
- IETIFJSFKTVJSL-UHFFFAOYSA-N 2-bromo-3-oxo-3-phenylpropanoic acid Chemical compound OC(=O)C(Br)C(=O)C1=CC=CC=C1 IETIFJSFKTVJSL-UHFFFAOYSA-N 0.000 description 1
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VUAFHZCUKUDDBC-BYPYZUCNSA-N Bucillamine Chemical compound CC(C)(S)C(=O)N[C@@H](CS)C(O)=O VUAFHZCUKUDDBC-BYPYZUCNSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 108010053070 Glutathione Disulfide Proteins 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- FNJVDWXUKLTFFL-UHFFFAOYSA-N diethyl 2-bromopropanedioate Chemical compound CCOC(=O)C(Br)C(=O)OCC FNJVDWXUKLTFFL-UHFFFAOYSA-N 0.000 description 1
- KUSGATRNQCYALG-UHFFFAOYSA-N dithiepane Chemical compound C1CCSSCC1 KUSGATRNQCYALG-UHFFFAOYSA-N 0.000 description 1
- LMBQHCNXCQCXGQ-UHFFFAOYSA-N dithiocane Chemical compound C1CCCSSCC1 LMBQHCNXCQCXGQ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- NGJKQTAWMMZMEL-UHFFFAOYSA-N ethyl 2-bromo-3-oxobutanoate Chemical compound CCOC(=O)C(Br)C(C)=O NGJKQTAWMMZMEL-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- GFEGEDUIIYDMOX-BMJUYKDLSA-N n-[(4-amino-2-methylpyrimidin-5-yl)methyl]-n-[(z)-3-[[(z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-hydroxypent-2-en-3-yl]disulfanyl]-5-hydroxypent-2-en-2-yl]formamide Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(\C)=C(CCO)/SSC(/CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N GFEGEDUIIYDMOX-BMJUYKDLSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- YPZRWBKMTBYPTK-UHFFFAOYSA-N oxidized gamma-L-glutamyl-L-cysteinylglycine Natural products OC(=O)C(N)CCC(=O)NC(C(=O)NCC(O)=O)CSSCC(C(=O)NCC(O)=O)NC(=O)CCC(N)C(O)=O YPZRWBKMTBYPTK-UHFFFAOYSA-N 0.000 description 1
- KMTUBAIXCBHPIZ-UHFFFAOYSA-N pentane-1,5-dithiol Chemical compound SCCCCCS KMTUBAIXCBHPIZ-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- SIXLXDIJGIWWFU-UHFFFAOYSA-N pyritinol Chemical compound OCC1=C(O)C(C)=NC=C1CSSCC1=CN=C(C)C(O)=C1CO SIXLXDIJGIWWFU-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- BSHDUMDXSRLRBI-JOYOIKCWSA-N rentiapril Chemical compound SCCC(=O)N1[C@H](C(=O)O)CS[C@@H]1C1=CC=CC=C1O BSHDUMDXSRLRBI-JOYOIKCWSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960001385 thiamine disulfide Drugs 0.000 description 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
本発明はチオール化合物に式（）で表わされ
る化合物を反応させることを特徴とするジスルフ
イド化合物の製造法に関する。
式中、R1およびR2は同一かまたは異なつて、
アシル基（アセチル基で代表される低級アルカノ
イル基またはベンゾイル基で代表されるアリール
カルボニル基を含む）、低級アルコキシカルボニ
ル基（メトキシカルボニル基、エトキシカルボニ
ル基、ブトキシカルボニル基など）、シアノ基ま
たはアリール基（ニトロ基、塩素等の電子吸引性
の基で置換されたフエノル基）を示す。
Ｘはハロゲン原子（塩素、臭素等）を示す。
以下の説明および実施例から明らかなように、
チオール化合物については特に制限はなく、ほと
んど全てのチオール化合物を用いることができ
る。
その一例として使用したチオール化合物と得ら
れたジスフイド化合物を表に示す。
ジスルフイド化合物の製法としては、チオール
化合物を空気、ハロゲン、塩化第二鉄等で酸化す
る方法などが知られている。本発明者らは、活性
メチレン基を有する化合物の特性に注目し、それ
らのハロゲン化物を使用しチオール化合物をジス
ルフイド化合物に導く新規な方法を見い出した。
本方法は従来の方法とは発想を全く異にしてお
り、ほとんど全てのチオール化合物を容易にジス
ルフイド化合物とする事ができる。従来の酸化法
では用いるチオール化合物によつては、ジスルフ
イドの段階で酸化が止まらず、さらに酸化が進行
しスルフイン酸等まで酸化される場合があるが、
本方法ではジスルフイド化合物が選択的に得られ
る。特にチオール基が２個存在するチオール化合
物の場合、従来の酸化法では多くの混合物からな
る分子間ジスルフイドおよび分子内ジスルフイド
が生成物に混在し、単離等が非常に困難である。
本方法では、チオール基を２個有するチオール化
合物の場合にも分子内ジスルフイドを選択的に得
る事ができる。分子内ジスルフイド化合物を収率
良く製造する方法は今まで知られておらず、本発
明者らが初めて見い出したものである。
本方法を反応式で表わすと下記の様になる。
〔式中、R1、R2およびＸは前記と同義。
チオール化合物はＲ−SHまたはHS−Ｒ−SH
と総称する。〕
本方法は、有機塩基（トリエチルアミン、モル
ホリン等）または無機塩基（水酸化ナトリウム、
炭酸カリウム等）の存在下、有機溶媒（塩化メチ
レン、テトラヒドロフラン、エタノール等）また
は水中、室温または冷却下（必要に応じて加温し
てもよい）で行うことができる。
本発明は降圧剤、免疫調節剤等医薬として有用
なジスルフイド化合物の新規な製造法を提供する
ものである。
以下に実施例を示すが、本発明は以下の実施例
に限定されるものではない。
実施例 １
（4R，4′R）−３，3′−〔（2S，2′S）−３，3′−ジ
チオビス（２−メチルプロピオニル）〕ビス
（４−チアゾリジンカルボン酸）……化合物１
（4R）−〔（2S）−３−メルカプト−２−メチル
プロピオニル〕−４−チアゾリジンカルボン酸
（3.1ｇ）およびトリエチルアミン（2.9ml）の塩
化メチレン（30ml）溶液に、食塩−氷浴で冷却下
攪拌しながらα−プロモマロン酸エチル（1.6ｇ）
を滴下する。滴下終了後30分間銅温度で攪拌す
る。室温にもどし、さらに30分間攪拌後反応液を
飽和炭酸水素ナトリウム水溶液で抽出する。水層
を分取し、2N塩酸で酸性とし析出する結晶を
取して標記化合物2.8ｇ（91％）を得る。
融点208〜209℃（分解）（エタノール−水）
実施例 ２
（2R，2′R，4R，4′R）−３，3′−（２，2′−ジ
チオジアセチル）ビス〔２−（２−ヒドロキシ
フエニル）−４−チアゾリジンカルボン酸〕…
…化合物２
実施例１における（4R）−〔（2S）−３−メルカ
プト−２−メチルプロピオニル〕−４−チアゾリ
ジンカルボン酸のかわりに（2R，4R）−２−（２
−ヒドロキシフエニル）−３−（メルカプトアセチ
ル）−４−チアゾリジンカルボン酸（2.0ｇ）を用
い、実施例１と同様に操作して標記化合物1.6ｇ
（80％）を得る。
融点128〜129℃（分解）メタノール−水）
実施例 ３
（2R，2′R，4R，4′R）−３，3′−（３，3′−ジ
チオジプロピオニル）ビス〔２−（２−ヒドロ
キシフエニル）−４−チアゾリジンカルボン酸〕
……化合物３
実施例１における（4R）−〔（2S）−３−メルカ
プト−２−メチルプロピオニル〕−４−チアゾリ
ジンカルボン酸のかわりに（2R，4R）−２−（２
−ヒドロキシフエニル）−３−（３−メルカプトプ
ロピオニル）−４−チアゾリジンカルボン酸（3.2
ｇ）を用い、実施例１と同様に操作して標記化合
物1.8ｇ（56％）を得る。
融点187℃（分解）（酢酸エチル）
実施例 ４
３，3′−ジチオジプロピオン酸……化合物４
β−メルカプトプロピオン酸（2.1ｇ）および
トリエチルアミン（６ml）の塩化メチレン（40
ml）溶液に、食塩−氷浴で冷却下攪拌しながらα
−ブロモマロン酸エチル（2.8ｇ）を滴下する。
滴下終了後30分間同温度で攪拌する。室温にもど
し、さらに30分間攪拌後反応液にＮ塩酸（30ml）
を加え析出する結晶を取して標記化合物1.5ｇ
（72％）を得る。
融点152〜154℃
実施例 ５
実施例４におけるα−ブロモマロン酸エチルの
かわりにα−ブロモ（ｐ−ニトロフエニル）酢酸
エチル（2.9ｇ）を用い、実施例４と同様に操作
して化合物４ 1.8ｇ（87％）を得る。
融点は実施例４で得られた結晶のものと同じで
あつた。
実施例 ６
実施例４におけるα−ブロモマロン酸エチルの
かわりにα−ブロモ（ｐ−クロロフエニル）アセ
トニトリル（2.3ｇ）を用い、実施例４と同様に
操作して化合物４ 1.4ｇ（67％）を得る。
融点は実施例４で得られた結晶のものと同じで
あつた。
実施例 ７
実施例４におけるα−ブロモマロン酸エチルの
かわりにα−ブロモベンゾイル酢酸エチル（2.7
ｇ）を用い、実施例４と同様に操作して化合物４
1.6ｇ（77％）を得る。
融点は実施例４で得られた結晶のものと同じで
あつた。
実施例 ８
実施例４におけるα−ブロモマロン酸エチルの
かわりにα−ブロモシアノ酢酸エチル（1.9ｇ）
を用い、実施例４と同様に操作して化合物４
1.4ｇ（67％）を得る。
融点は実施例４で得られた結晶のものと同じで
あつた。
実施例 ９
実施例４におけるα−ブロモマロン酸エチルの
かわりにα−クロロマロン酸エチル（1.9ｇ）を
用い、実施例４と同様に操作して化合物４ 1.2
ｇ（58％）を得る。
融点は実施例４で得られた結晶のものと同じで
あつた。
実施例 10
チアミンジスルフイド……化合物５
チアミン塩酸塩（0.9ｇ）をＮ水酸化ナトリウ
ム水溶液（８ml）とエタノール（５ml）の混液に
溶解し、食塩−氷浴で冷却下攪拌しながらα−ブ
ロモマロン酸エチル（0.32ｇ）のエタノール（３
ml）溶液を滴下する。滴下終了後同温度で30分間
攪拌する。室温にもどし、さらに30分間攪拌後、
反応液にＮ塩酸（１ml）を加え中和しエーテルで
洗浄する。水層を減圧濃縮し、残渣にエタノール
を加え過する。液にエーテルを加え析出する
結晶を取し標記化合物0.65ｇ（87％）を得る。
融点173〜174℃
実施例 11
酸化型グルタチオン……化合物６
実施例９におけるチアミン塩酸塩のかわりにグ
ルタチオン（0.82ｇ）を用い、実施例10と同様に
操作して標記化合物0.74ｇ（91％）を得る。
融点120〜125℃
実施例 12
ピリチオキシン……化合物７
実施例９におけるチアミン塩酸塩のかわりに４
−ヒドロキシメチル−５−ヒドロキシ−６−メチ
ル−３−ビリジルメチルメルカプタン（0.50ｇ）
を用い、実施例10と同様に操作して標記化合物
0.44ｇ（88％）を得る。
融点217〜219℃（分解）
実施例 13
（4R）−７，７−ジメチル−６−オキソ−3H
−１，２，５−パ−ヒドロジチアゼピン−４−
カルボン酸……化合物８
Ｎ−（２−メルカプト−２−メチルプロピオニ
ル）−Ｌ−システイン（80ｇ）およびトリエチル
アミン（105ml）の塩化メチレン（４）溶液に、
食塩−氷浴で冷却下攪拌しながらα−ブロモマロ
ン酸エチル（94ｇ）の塩化メチレン（100ml）溶
液を滴下する。滴下終了後同温度で２時間攪拌す
る。室温にもどし、さらに１時間攪拌後2N塩酸
（350ml）を加える。有機層を分取し、水、飽和食
塩水の順で洗浄後、無水硫酸マグネシウムで乾燥
する。この溶液を減圧濃縮し、残渣にエーテルを
加え析出する結晶を取し標記化合物42.3ｇ（53
％）を得る。
融点175.5〜177℃（酢酸エチル−ヘキサン）
実施例 14
実施例13におけるα−ブロモマロン酸エチルの
かわりにα−ブロモベンゾイル酢酸エチル（100
ｇ）を用い、実施例13と同様に操作して化合物８
32.5ｇ（41％）を得る。
融点は実施例13で得られた結晶のものと同じで
あつた。
実施例 15
実施例13におけるα−ブロモマロン酸エチルの
かわりにα−ブロモアセト酢酸エチル（76ｇ）を
用い、実施例13と同様に操作して化合物８ 22.2
ｇ（28％）を得る。
融点は実施例13で得られた結晶のものと同じで
あつた。
実施例 16
実施例13におけるα−ブロモマロン酸エチルの
かわりにα−ブロモシアノ酢酸エチル（70ｇ）を
用い、実施例13と同様に操作して化合物８ 25.4
ｇ（32％）を得る。
融点は実施例13で得られた結晶のものと同じで
あつた。
実施例 17
実施例13におけるα−ブロモマロン酸エチルの
かわりにα−ブロモ（ｐ−ニトロフエニル）酢酸
エチル（105ｇ）を用い、実施例13と同様に操作
して化合物８ 31.7ｇ（40％）を得る。
融点は実施例13で得られた結晶のものと同じで
あつた。
実施例 18
実施例13におけるα−ブロモマロン酸エチルの
かわりにα−クロロマロン酸エチル（71ｇ）を用
い、実施例13と同様に操作して化合物８ 23.8ｇ
（30％）を得る。
融点は実施例13で得られた結晶のものと同じで
あつた。
実施例 19
１，２−ジチアン……化合物９
１，４−ブタンジチオール（2.1ｇ）およびト
リエチルアミン（2.7ml）の塩化メチレン（150
ml）溶液に、食塩−氷浴で冷却下攪拌しながら、
α−ブロモマロン酸エチル（4.1ｇ）の塩化メチ
レン（10ml）溶液を滴下する。滴下終了後室温に
もどしつつさらに１時間攪拌する。反応液を水、
Ｎ水酸化ナトリウム水溶液、0.1N塩酸の順で洗
浄する。有機層を無水硫酸ナトリウムで乾燥後減
圧濃縮し得られる油状物をシリカゲルカラムクロ
マトで精製して標記化合物1.7ｇ（82％）を得る。
沸点110℃（18mmHg）（浴温）
実施例 20
１，２−ジチエパン……化合物10
実施例19における１，４−ブタンジチオールの
かわりに１，５−ジメルカプトペンタン（2.3ｇ）
用い、実施例19と同様に操作して標記化合物0.8
ｇ（35％）を得る。
沸点115〜120℃（13mmHg）（浴温）
実施例 21
１，２−ジチオカン……化合物11
実施例19における１，４−ブタンジチオールの
かわりに１，６−ジメルカプトヘキサン（2.6ｇ）
を用い、実施例19と同様に操作して標記化合物
0.7ｇ（27％）を油状物として得る。
The present invention relates to a method for producing a disulfide compound, which is characterized by reacting a thiol compound with a compound represented by the formula (). In the formula, R 1 and R 2 are the same or different,
Acyl group (including lower alkanoyl group represented by acetyl group or arylcarbonyl group represented by benzoyl group), lower alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, etc.), cyano group or aryl group (a phenol group substituted with an electron-withdrawing group such as a nitro group or chlorine). X represents a halogen atom (chlorine, bromine, etc.). As is clear from the description and examples below,
There are no particular restrictions on the thiol compound, and almost all thiol compounds can be used. As an example, the thiol compound used and the obtained disulfide compound are shown in the table. Known methods for producing disulfide compounds include methods in which thiol compounds are oxidized with air, halogen, ferric chloride, and the like. The present inventors have focused on the properties of compounds having active methylene groups and have discovered a new method of converting thiol compounds into disulfide compounds using their halides.
The concept of this method is completely different from conventional methods, and almost all thiol compounds can be easily converted into disulfide compounds. Depending on the thiol compound used in conventional oxidation methods, oxidation does not stop at the disulfide stage and may proceed further to oxidize to sulfinic acid, etc.
In this method, disulfide compounds are selectively obtained. Particularly in the case of a thiol compound having two thiol groups, conventional oxidation methods result in a mixture of many intermolecular disulfides and intramolecular disulfides in the product, making isolation etc. extremely difficult.
In this method, even in the case of a thiol compound having two thiol groups, intramolecular disulfide can be selectively obtained. A method for producing intramolecular disulfide compounds with good yield has not been known so far, and the present inventors have discovered this method for the first time. This method can be expressed as a reaction formula as follows. [In the formula, R 1 , R 2 and X have the same meanings as above. Thiol compound is R-SH or HS-R-SH
Collectively called. ] This method uses organic bases (triethylamine, morpholine, etc.) or inorganic bases (sodium hydroxide,
The reaction can be carried out in the presence of potassium carbonate (potassium carbonate, etc.), an organic solvent (methylene chloride, tetrahydrofuran, ethanol, etc.) or water, at room temperature or under cooling (it may be heated if necessary). The present invention provides a novel method for producing disulfide compounds useful as medicines such as antihypertensive agents and immunomodulators. Examples are shown below, but the present invention is not limited to the following examples. Example 1 (4R,4'R)-3,3'-[(2S,2'S)-3,3'-dithiobis(2-methylpropionyl)]bis(4-thiazolidinecarboxylic acid)...Compound 1 (4R)-[(2S)-3-mercapto-2-methylpropionyl]-4-thiazolidinecarboxylic acid (3.1 g) and triethylamine (2.9 ml) were added to a solution of methylene chloride (30 ml) under cooling in a salt-ice bath. While stirring, add ethyl α-promomalonate (1.6 g).
drip. Stir at copper temperature for 30 minutes after completion of addition. After returning to room temperature and stirring for an additional 30 minutes, the reaction mixture was extracted with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer is separated, acidified with 2N hydrochloric acid, and the precipitated crystals are removed to obtain 2.8 g (91%) of the title compound. Melting point: 208-209℃ (decomposition) (ethanol-water) Example 2 (2R, 2′R, 4R, 4′R)-3,3′-(2,2′-dithiodiacetyl)bis[2-(2 -hydroxyphenyl)-4-thiazolidinecarboxylic acid]...
... Compound 2 (2R,4R)-2-(2
Using -hydroxyphenyl)-3-(mercaptoacetyl)-4-thiazolidinecarboxylic acid (2.0 g), the same procedure as in Example 1 was carried out to obtain 1.6 g of the title compound.
(80%). Melting point 128-129℃ (decomposed) methanol-water) Example 3 (2R, 2′R, 4R, 4′R)-3,3′-(3,3′-dithiodipropionyl)bis[2-(2 -hydroxyphenyl)-4-thiazolidinecarboxylic acid]
... Compound 3 Instead of (4R)-[(2S)-3-mercapto-2-methylpropionyl]-4-thiazolidinecarboxylic acid in Example 1, (2R,4R)-2-(2
-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid (3.2
g) in the same manner as in Example 1 to obtain 1.8 g (56%) of the title compound. Melting point: 187°C (decomposed) (ethyl acetate) Example 4 3,3'-dithiodipropionic acid... Compound 4 β-mercaptopropionic acid (2.1 g) and triethylamine (6 ml) in methylene chloride (40
ml) solution while stirring while cooling in a salt-ice bath.
- Add ethyl bromomalonate (2.8 g) dropwise.
After completion of the dropwise addition, stir at the same temperature for 30 minutes. After returning to room temperature and stirring for an additional 30 minutes, add N-hydrochloric acid (30 ml) to the reaction solution.
Add the crystals that precipitate, and collect 1.5 g of the title compound.
(72%). Melting point: 152-154°C Example 5 1.8 g of compound 4 was prepared in the same manner as in Example 4, except that α-bromo(p-nitrophenyl)ethyl acetate (2.9 g) was used in place of ethyl α-bromomalonate in Example 4. (87%). The melting point was the same as that of the crystals obtained in Example 4. Example 6 1.4 g (67%) of Compound 4 was obtained in the same manner as in Example 4, using α-bromo(p-chlorophenyl)acetonitrile (2.3 g) instead of ethyl α-bromomalonate in Example 4. . The melting point was the same as that of the crystals obtained in Example 4. Example 7 Ethyl α-bromobenzoylacetate (2.7
g) and operated in the same manner as in Example 4 to obtain compound 4.
Obtain 1.6g (77%). The melting point was the same as that of the crystals obtained in Example 4. Example 8 Ethyl α-bromocyanoacetate (1.9 g) instead of ethyl α-bromomalonate in Example 4
Compound 4 was prepared in the same manner as in Example 4 using
Obtain 1.4g (67%). The melting point was the same as that of the crystals obtained in Example 4. Example 9 Compound 4 was prepared in the same manner as in Example 4 except that ethyl α-chloromalonate (1.9 g) was used instead of ethyl α-bromomalonate in Example 4.
g (58%). The melting point was the same as that of the crystals obtained in Example 4. Example 10 Thiamine disulfide... Compound 5 Thiamine hydrochloride (0.9 g) was dissolved in a mixture of N aqueous sodium hydroxide solution (8 ml) and ethanol (5 ml), and α- Ethyl bromomalonate (0.32 g) in ethanol (3
ml) solution dropwise. After the addition is complete, stir at the same temperature for 30 minutes. After returning to room temperature and stirring for an additional 30 minutes,
The reaction solution was neutralized by adding N-hydrochloric acid (1 ml) and washed with ether. The aqueous layer was concentrated under reduced pressure, and ethanol was added to the residue and filtered. Add ether to the liquid and collect the precipitated crystals to obtain 0.65 g (87%) of the title compound. Melting point: 173-174°C Example 11 Oxidized glutathione... Compound 6 Using glutathione (0.82 g) in place of thiamine hydrochloride in Example 9, the same procedure as in Example 10 was performed to obtain 0.74 g (91%) of the title compound. get. Melting point 120-125℃ Example 12 Pyrithioxine... Compound 7 4 in place of thiamine hydrochloride in Example 9
-Hydroxymethyl-5-hydroxy-6-methyl-3-biridylmethylmercaptan (0.50g)
The title compound was prepared in the same manner as in Example 10 using
Obtain 0.44g (88%). Melting point 217-219℃ (decomposition) Example 13 (4R)-7,7-dimethyl-6-oxo-3H
-1,2,5-perhydrodithiazepine-4-
Carboxylic acid... Compound 8 N-(2-mercapto-2-methylpropionyl)-L-cysteine (80 g) and triethylamine (105 ml) in methylene chloride (4) solution,
A solution of ethyl α-bromomalonate (94 g) in methylene chloride (100 ml) was added dropwise while stirring while cooling in a salt-ice bath. After the dropwise addition was completed, the mixture was stirred at the same temperature for 2 hours. After returning to room temperature and stirring for an additional hour, 2N hydrochloric acid (350 ml) was added. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. This solution was concentrated under reduced pressure, ether was added to the residue, and the precipitated crystals were collected to give 42.3 g (53 g) of the title compound.
%). Melting point: 175.5-177°C (ethyl acetate-hexane) Example 14 Instead of ethyl α-bromomalonate in Example 13, α-bromobenzoylacetate (100
g) and operated in the same manner as in Example 13 to obtain compound 8.
Obtain 32.5g (41%). The melting point was the same as that of the crystals obtained in Example 13. Example 15 Compound 8 was prepared in the same manner as in Example 13, using ethyl α-bromoacetoacetate (76 g) instead of ethyl α-bromomalonate in Example 13.
g (28%). The melting point was the same as that of the crystals obtained in Example 13. Example 16 Compound 8 was prepared in the same manner as in Example 13, using ethyl α-bromocyanoacetate (70 g) instead of ethyl α-bromomalonate in Example 13.
g (32%). The melting point was the same as that of the crystals obtained in Example 13. Example 17 Using ethyl α-bromo(p-nitrophenyl)acetate (105 g) in place of ethyl α-bromomalonate in Example 13, the procedure was repeated in the same manner as in Example 13 to obtain 31.7 g (40%) of Compound 8. . The melting point was the same as that of the crystals obtained in Example 13. Example 18 23.8 g of compound 8 was prepared in the same manner as in Example 13, using ethyl α-chloromalonate (71 g) instead of ethyl α-bromomalonate in Example 13.
(30%). The melting point was the same as that of the crystals obtained in Example 13. Example 19 1,2-dithiane...Compound 9 1,4-butanedithiol (2.1 g) and triethylamine (2.7 ml) in methylene chloride (150
ml) solution while stirring while cooling in a salt-ice bath.
A solution of ethyl α-bromomalonate (4.1 g) in methylene chloride (10 ml) is added dropwise. After the dropwise addition was completed, the mixture was stirred for an additional hour while returning to room temperature. Add the reaction solution to water,
Wash with N aqueous sodium hydroxide solution and 0.1N hydrochloric acid in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting oil was purified by silica gel column chromatography to obtain 1.7 g (82%) of the title compound. Boiling point 110℃ (18mmHg) (bath temperature) Example 20 1,2-dithiepane...Compound 10 1,5-dimercaptopentane (2.3g) in place of 1,4-butanedithiol in Example 19
and the title compound was prepared in the same manner as in Example 19 at 0.8
g (35%). Boiling point 115-120℃ (13mmHg) (bath temperature) Example 21 1,2-dithiocane...Compound 11 1,6-dimercaptohexane (2.6g) in place of 1,4-butanedithiol in Example 19
The title compound was prepared in the same manner as in Example 19 using
Obtain 0.7 g (27%) as an oil.
【表】【table】
【表】【table】
【表】【table】
Claims (1)
物を反応させることを特徴とするジスルフイド化
合物の製造法。 〔式中、R1およびR2は同一かまたは異なつて、
アシル基、低級アルコキシカルボニル基、シアノ
基またはアリール基を示す。 Ｘはハロゲン原子を示す。〕[Scope of Claims] 1. A method for producing a disulfide compound, which comprises reacting a thiol compound with a compound represented by the formula (). [In the formula, R 1 and R 2 are the same or different,
Indicates an acyl group, lower alkoxycarbonyl group, cyano group or aryl group. X represents a halogen atom. ]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58146159A JPS6036456A (en) | 1983-08-09 | 1983-08-09 | Preparation of disulfide compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58146159A JPS6036456A (en) | 1983-08-09 | 1983-08-09 | Preparation of disulfide compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6036456A JPS6036456A (en) | 1985-02-25 |
| JPH0460975B2 true JPH0460975B2 (en) | 1992-09-29 |
Family
ID=15401461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58146159A Granted JPS6036456A (en) | 1983-08-09 | 1983-08-09 | Preparation of disulfide compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6036456A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0472084A (en) * | 1990-07-12 | 1992-03-06 | Toshiba Corp | Treating liquid temperature controller |
| ATE182329T1 (en) * | 1995-12-21 | 1999-08-15 | Akzo Nobel Nv | METHOD FOR PRODUCING THIOGLYCOLIC ACID |
| US20060148663A1 (en) | 2003-02-05 | 2006-07-06 | Idemitsu Kosan Co., Ltd. | Additives for lubricating oils and fuel oils, lubricating oil compositions, and fuel oil compositions |
-
1983
- 1983-08-09 JP JP58146159A patent/JPS6036456A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6036456A (en) | 1985-02-25 |
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