JPH04224569A - Thiazolidine derivative and preparation thereof - Google Patents
Thiazolidine derivative and preparation thereofInfo
- Publication number
- JPH04224569A JPH04224569A JP3067755A JP6775591A JPH04224569A JP H04224569 A JPH04224569 A JP H04224569A JP 3067755 A JP3067755 A JP 3067755A JP 6775591 A JP6775591 A JP 6775591A JP H04224569 A JPH04224569 A JP H04224569A
- Authority
- JP
- Japan
- Prior art keywords
- mol
- dithiocarbamate
- thiazoline
- compound
- 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.)
- Granted
Links
- 150000003548 thiazolidines Chemical class 0.000 title 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012990 dithiocarbamate Substances 0.000 claims abstract description 20
- 150000003549 thiazolines Chemical class 0.000 claims abstract description 9
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 5
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 24
- 238000004519 manufacturing process Methods 0.000 claims description 16
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 13
- 229910015900 BF3 Inorganic materials 0.000 claims description 8
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 4
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 230000010512 thermal transition Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 229930186147 Cephalosporin Natural products 0.000 abstract description 3
- 229940124587 cephalosporin Drugs 0.000 abstract description 3
- 150000001780 cephalosporins Chemical class 0.000 abstract description 3
- OOLYTKUVAPWWTO-UHFFFAOYSA-N 5-methoxy-2-methylsulfanyl-4,5-dihydro-1,3-thiazole Chemical compound COC1CN=C(SC)S1 OOLYTKUVAPWWTO-UHFFFAOYSA-N 0.000 abstract description 2
- 230000009466 transformation Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- -1 allyl N-(2,2-dimethoxyethyl)dithiocarbamate Chemical compound 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000002904 solvent Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 7
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 3
- JLPUISACQXFVRC-UHFFFAOYSA-N 2,5-dihydro-1,3-thiazole Chemical class C1SCN=C1 JLPUISACQXFVRC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- HJKLEAOXCZIMPI-UHFFFAOYSA-N 2,2-diethoxyethanamine Chemical compound CCOC(CN)OCC HJKLEAOXCZIMPI-UHFFFAOYSA-N 0.000 description 1
- FKSZAUQNBPEMQG-UHFFFAOYSA-N 2,2-dimethoxyethylcarbamodithioic acid Chemical compound COC(OC)CNC(S)=S FKSZAUQNBPEMQG-UHFFFAOYSA-N 0.000 description 1
- IZRGNCRSPNGTBX-UHFFFAOYSA-N 2-[(5-methoxypyridin-2-yl)methylsulfanyl]-4,5-dihydro-1,3-thiazole Chemical compound COC=1C=CC(=NC=1)CSC=1SCCN=1 IZRGNCRSPNGTBX-UHFFFAOYSA-N 0.000 description 1
- LYIIBVSRGJSHAV-UHFFFAOYSA-N 2-aminoacetaldehyde Chemical compound NCC=O LYIIBVSRGJSHAV-UHFFFAOYSA-N 0.000 description 1
- IKRWYPHSXWMUJT-UHFFFAOYSA-N 2-benzylsulfanyl-5-methoxy-4,5-dihydro-1,3-thiazole Chemical compound S1C(OC)CN=C1SCC1=CC=CC=C1 IKRWYPHSXWMUJT-UHFFFAOYSA-N 0.000 description 1
- IQDNHISMVASYQS-UHFFFAOYSA-N 2-ethylsulfanyl-5-methoxy-4,5-dihydro-1,3-thiazole Chemical compound CCSC1=NCC(OC)S1 IQDNHISMVASYQS-UHFFFAOYSA-N 0.000 description 1
- 229910003556 H2 SO4 Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- YTTXBYUDRNBKSF-UHFFFAOYSA-N benzyl n-(2,2-dimethoxyethyl)carbamodithioate Chemical compound COC(OC)CNC(=S)SCC1=CC=CC=C1 YTTXBYUDRNBKSF-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- LZUJFSSGTLNBLF-UHFFFAOYSA-N methyl n-(2,2-diethoxyethyl)carbamodithioate Chemical compound CCOC(OCC)CNC(=S)SC LZUJFSSGTLNBLF-UHFFFAOYSA-N 0.000 description 1
- SFKZZPIYNUISOH-UHFFFAOYSA-N methyl n-(2,2-dimethoxyethyl)carbamodithioate Chemical compound COC(OC)CNC(=S)SC SFKZZPIYNUISOH-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/16—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
【０００１】
【産業上の利用分野】本発明は、セフアロスポリン誘導
体の中間体である新規な５−アルコキシ−２−置換チオ
−１，３−チアゾリン誘導体及びその製造方法に関する
。
【０００２】
【従来の技術及び発明が解決しようとする課題】Ｊ．
Ｏｒｇ． Ｃｈｅｍ．，３０，４９１（１９６５）及び
同誌３６，１０６８（１９７１）には、一般式 （ＩＩ
Ｉ）のチアゾリン誘導体が、次の反応式で製造されるこ
とが開示されている。
【０００３】
【化４】
（式中、Ｒはメチル基であり、Ｒ’及びＲ”はそれぞれ
水素原子、アルキル基又はフェニル基である）。本発明
者らは、上記の方法により後記一般式（Ｉ）のチアゾリ
ン誘導体を製造しようとしたが、一般式（ＩＶ）又は（
Ｖ）においてＲ’又はＲ”がアルコキシ基である原料化
合物を製造することができなかった。
【０００４】
【課題を解決するための手段】本発明は、鋭意研究の結
果、ジチオカーバメート（ＩＩ）を分子内環化反応させ
ることにより、チアゾリン誘導体（Ｉ）を製造すること
に成功した。
【０００５】本発明は、一般式（Ｉ）で示される新規な
チアゾリン誘導体である。
【化５】
（式中、Ｒは水素原子、炭素数１〜６のアルキル基、ア
リル基、２−プロピニル基、ベンジル基又は２−ピリジ
ルメチル基を表し、Ｒ１ はメチル、エチルのような低
級アルキル基を表す）。一般式（Ｉ）のチアゾリン誘導
体は、一般式（ＩＩ）のジチオカーバメート【化６】
（式中、Ｒ及びＲ１ は前述と同じ）を熱転移又は酸の
存在下で環化反応させることによって製造される。
【０００６】本発明の製造方法をより詳細に説明すれば
、ジチオカーバメート（ＩＩ）を５ｍｍＨｇ以下の減圧
で約２００±１０℃で分子内熱転移反応させることによ
り得られる。
【０００７】また、酸の存在下で分子内環化反応させる
には、酸として三フッ化ホウ素、無水マグネシウム・ブ
ロマイド又は濃硫酸等を用いることができ、三フッ化ホ
ウ素が最も好ましい。反応はジクロロメタン、ジクロロ
エタン、クロロホルム、四塩化炭素のようなハロゲン化
炭化水素溶媒中で行うことができ、反応温度は１０±５
℃で行うのが好ましい。本発明の方法によれば、容易に
入手し得るジチオカーバメート（ＩＩ）から９５％以上
の高収率で目的のチアゾリン誘導体（Ｉ）を得ることが
できる。
【０００８】また、ジチオカーバメート（ＩＩ）は、Ｓ
ｙｎｔｈｅｓｉｓ，６３８（１９８９）に記載された次
の反応式に示すように、アミノアセトアルデヒドジアル
キルアセタール（ＶＩＩ） からトリエチルアミンの存
在下に二硫化炭素と０〜２０℃で反応させ、一般式（Ｖ
ＩＩＩ）の化合物を得、継続してハロゲン化アルキルを
同温度で反応させて容易に製造することができる。
【化７】
【０００９】
【発明の効果】本発明のチアゾリン誘導体（Ｉ）は、例
えば次の反応式に示す方法によりセフアロスポリン誘導
体に導くことができる。
【化８】
（式中、Ｒ２ はカルボキシル基の保護基である）【０
０１０】
【実施例】以下に本発明の製造例を示し、詳細に説明す
る。ただし、本発明は、実施例にだけ限定されるもので
はなく、本発明の保護範囲内でこの分野の熟練者により
修正及び変更が可能であることを理解しなければならな
い。
【００１１】参考例１
メチルＮ−（２，２−ジメトキシエチル）ジチオカーバ
メート（ＩＩ，Ｒ＝Ｒ１ ＝メチル）の製造アミノアセ
トアルデヒドジメチルアセタール２１ｇ （０．２モル
）をエタノール１５０ｍｌと水１０ｍｌに溶かした後、
トリエチルアミン２４．３ｇ （０．２４モル）を加え
、二硫化炭素１６．８ｇ （０．２２モル）を０〜５℃
で少量ずつ加えた。同じ温度で１時間撹拌反応後、沃化
メチル３１．２ｇ （０．２２モル）を少量ずつ滴下し
た後、１５±５℃で１時間撹拌反応させた。反応液は減
圧（３０ｍｍＨｇ）下で溶媒を留去し、水を加えた後、
酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した後
、ろ過し、減圧（３０ｍｍＨｇ）下で溶媒を除去し、目
的の液体化合物３６．９ｇ （９５％収率）を得た。１
Ｈ−ＮＭＲ δ （ＣＤＣｌ３）：２．３１（Ｓ，
３Ｈ）， ３．１１（ｓ， ６Ｈ）， ３．５７（ｔ，
Ｊ＝５．１， ２Ｈ），４．２８（ｔ， Ｊ＝５．１
， １Ｈ）， ７．５０（ｂｒ ｓ， １Ｈ）【００１
２】参考例２
メチルＮ−（２，２−ジエトキシエチル）ジチオカーバ
メート（ＩＩ，Ｒ＝メチル、Ｒ１ ＝エチル）の製造ア
ミノアセトアルデヒドジエチルアセタール４ｇ （０．
０３モル）をテトラヒドロフラン６０ｍｌに溶かした後
、トリエチルアミン３．３ｇ （０．０３３モル）と二
硫化炭素２．５ｇ （０．０３３モル）を加え、０〜５
℃で１時間撹拌後、沃化メチル４．７ｇ （０．０３３
モル）を徐々に加え、１５±５℃で１時間撹拌した。反
応液は減圧（３０ｍｍＨｇ）下で溶媒を留去し、水を加
えた後、酢酸エチルで抽出し、無水硫酸ナトリウムで乾
燥した後、ろ過し、減圧（３０ｍｍＨｇ）下で溶媒を除
去し、目的の液体化合物６．５４ｇ （９８％収率）を
得た。１Ｈ−ＮＭＲ δ （ＣＤＣｌ３）：１．２３
（ｔ， Ｊ＝７．０， ６Ｈ）， ２．６３（ｓ， ６
Ｈ）， ３．４１ 〜４．０４（ｍ， ６Ｈ）， ４．
７０（ｔ， Ｊ＝６．０， １Ｈ）， ７．３１（ｂｒ
ｓ， １Ｈ）
【００１３】
【参考例３】エチルＮ−（２，２−ジメトキシエチル）
ジチオカーバメート（ＩＩ，Ｒ＝エチル、Ｒ１ ＝メチ
ル）の製造
アミノアセトアルデヒドジメチルアセタール１０．５ｇ
（０．１モル）を用いて、参考例１の方法に準じてエ
チルブロマイド１２ｇ （０．１１モル）と２時間反応
させ、目的の液体化合物１９．９ｇ （９５％収率）を
得た。１Ｈ−ＮＭＲ δ （ＣＤＣｌ３）：１．３３
（ｔ， Ｊ＝７．５， ３Ｈ）， ３．２７（ｑ， Ｊ
＝７．５， ２Ｈ）， ３．４３（ｓ， ６Ｈ）， ３
．８７（ｔ， Ｊ＝５．０， ２Ｈ）， ４．５７（ｔ
， Ｊ＝５．０， １Ｈ）， ７．４３（ｂｒ ｓ，
１Ｈ） 【００１４】参考例４
アリルＮ−（２，２−ジメトキシエチル）ジチオカーバ
メート（ＩＩ，Ｒ＝アリル、Ｒ１ ＝メチル）の製造ア
ミノアセトアルデヒドジメチルアセタール１０．５ｇ
（０．１モル）を用いて、参考例１の方法に準じてアリ
ルブロマイド１３．３ｇ （０．１１モル）と３０分間
反応させ、目的の液体化合物２１．２ｇ （９６％収率
）を得た。１Ｈ−ＮＭＲ δ （ＣＤＣｌ３）：３．
４３（ｓ， ６Ｈ）， ３．８０ 〜４．０３（ｍ，
４Ｈ）， ４．６０（ｔ， Ｊ＝５．０， １Ｈ），
５．０７ 〜５．６３（ｍ， ２Ｈ）， ５．６７ 〜
６．２３（ｍ，１Ｈ）， ７．４３（ｂｒ ｓ， １Ｈ
） 【００１５】参考例５
２−プロピニルＮ−（２，２−ジメトキシエチル）ジチ
オカーバメート（ＩＩ，Ｒ＝２−プロピニル、Ｒ１ ＝
メチル）の製造
アミノアセトアルデヒドジメチルアセタール１０．５ｇ
（０．１モル）をテトラヒドロフラン１００ｍｌに溶
かした後、トリエチルアミン１２．２ｇ （０．１２モ
ル）と二硫化炭素８．４ｇ （０．１１モル）を加え、
０〜５℃で１時間撹拌後、反応温度を−７８℃に冷却し
た後、２−プロピニルブロマイド１３．１ｇ （０．１
１モル）を少量ずつ滴加した。１０分後、反応中に析出
したアミン塩をろ過して除去し、ろ液は減圧（３０ｍｍ
Ｈｇ）下で溶媒を留去し、目的の液体化合物２０．１ｇ
（９２％収率）を得た。１Ｈ−ＮＭＲ δ （ＣＤ
Ｃｌ３）：２．２９（ｔ， Ｊ＝２．５， １Ｈ），
３．４７（ｓ， ６Ｈ）， ３．８９（ｔ， Ｊ＝５．
７， ２Ｈ）， ４．０９（ｄ， Ｊ＝２．５， ２Ｈ
）， ４．６７（ｔ， Ｊ＝５．５，１Ｈ）， ７．４
２（ｂｒ ｓ， １Ｈ） 【００１６】参考例６
ベンジルＮ−（２，２−ジメトキシエチル）ジチオカー
バメート（ＩＩ，Ｒ＝ベンジル、Ｒ１ ＝メチル）の製
造アミノアセトアルデヒドジメチルアセタール１０．５
ｇ （０．１モル）を用いて、参考例１の方法に準じて
ベンジルクロライド１３．９ｇ （０．１１モル）と２
時間反応させ、目的の液体化合物２６．３ｇ （９７％
収率）を得た。１Ｈ−ＮＭＲ δ （ＣＤＣｌ３）：
３．４０（ｓ， ６Ｈ）， ３．９０（ｔ， Ｊ＝５．
１， ２Ｈ）， ４．５３ 〜４．６３（ｍ， ３Ｈ）
， ７．２３ 〜７．５３（ｍ， ６Ｈ）
【００１７】参考例７
２−ピリジルメチルＮ−（２，２−ジメトキシエチル）
ジチオカーバメート（ＩＩ，Ｒ＝２−ピリジルメチル、
Ｒ１ ＝メチル）の製造
アミノアセトアルデヒドジメチルアセタール１０．５ｇ
（０．１モル）を用いて、参考例１の方法に準じて２
−クロロメチルピリジン塩酸塩１８．０ｇ （０．１１
モル）と２時間反応させ、目的の固体化合物２５．８ｇ
（９５％収率）を得た。１Ｈ−ＮＭＲ δ （ＣＤ
Ｃｌ３）：３．４４（ｓ， ６Ｈ）， ３．９３（ｔ，
Ｊ＝５．５， ２Ｈ）， ４．３０（ｓ， ２Ｈ），
５．６８（ｔ， Ｊ＝５．５， １Ｈ）， ７．１３〜
８．６３（ｍ， ４Ｈ）， １０．８３（ｂｒ ｓ，
１Ｈ） 【００１８】参考例８
Ｎ−（２，２−ジメトキシエチル）ジチオカーバメート
（ＩＩ，Ｒ＝水素、Ｒ１ ＝メチル）の製造アミノアセ
トアルデヒドジメチルアセタール１０．５ｇ （０．１
モル）をテトラヒドロフラン１００ｍｌに溶かした後、
トリエチルアミン１１．１ｇ （０．１１モル）と二硫
化炭素７．６ｇ （０．１１モル）を加え、０〜５℃で
１時間撹拌した。反応液に濃塩酸９ｍｌを加え、無水硫
酸ナトリウムで乾燥した後、ろ過し、ろ液は減圧（３０
ｍｍＨｇ）下で溶媒を留去し、目的の液体化合物１３．
０ｇ （７２％収率）を得た。１Ｈ−ＮＭＲ δ （
ＣＤＣｌ３）：３．４１（ｓ， ６Ｈ）， ３．５７（
ｄ， Ｊ＝５．２， ２Ｈ）， ４．４７（ｔ， Ｊ＝
５．０， １Ｈ）， ６．７９（ｂｒ ｓ， １Ｈ）
【００１９】実施例１
５−メトキシ−２−メチルチオ−１，３−チアゾリン（
Ｉ，Ｒ＝Ｒ１ ＝メチル）の製造
１）熱転移方法参考例１の方法で得たジチオカーバメー
ト１９．５ｇ （０．１モル）を、２００±１０℃で徐
々に減圧蒸留（１．５ｍｍＨｇ）し、目的のチアゾリン
化合物１２．２ｇ （７５％収率）を得た。１Ｈ−ＮＭ
Ｒ δ （ＣＤＣｌ３）：２．５３（ｓ， ３Ｈ），
３．２６（ｓ， ３Ｈ）， ４．０４（ｄｄ， Ｊ＝
１６．２， ５．６２， １Ｈ）， ４．４５（ｄ，
Ｊ＝１６．２， １Ｈ）， ５．６２（ｄ， Ｊ＝５．
６２， １Ｈ）
【００２０】２）ＢＦ３ 方法参考例１の方法で得たジ
チオカーバメート４．８８ｇ （０．０２５モル）を、
ジクロロメタン５０ｍｌに溶かした後、１０±５℃で三
フッ化ホウ素・エーテル３．９ｇ （０．０２７５モル
）を少量ずつ滴加した後、同じ温度で１０分間撹拌した
。反応溶液を炭酸水素ナトリウム飽和水溶液で中和して
ｐＨ８〜９に調整した後、ジクロロメタン５０ｍｌで２
回抽出し、無水硫酸ナトリウムで乾燥した後、減圧（３
０ｍｍＨｇ）下で溶媒を留去し、目的のチアゾリン化合
物４．０ｇ （９８％収率）を得た。
【００２１】３）ＭｇＢｒ２ 方法参考例１の方法で得
たジチオカーバメート４．８８ｇ （０．０２５モル）
をジクロロメタン５０ｍｌに溶かした後、１０±５℃で
無水マグネシウムブロマイド・エーテル７．１ｇ （０
．０２７５モル）を加え、同じ温度で２０分間撹拌した
後、実施例１−２）の方法と同様に処理して、目的のチ
アゾリン化合物４．０（９８％収率）を得た。
【００２２】４）Ｈ２ ＳＯ４ 方法参考例１の方法で
得たジチオカーバメート４．８８ｇ （０．０２５モル
）を、四塩化炭素５０ｍｌに溶かした後、９５％濃硫酸
２．５８ｇ （０．０２５モル）を加え、３時間還流し
た。反応溶液を冷却（〜５℃）して析出する固体をろ過
した後、固体を水に溶かし、５％水酸化ナトリウム水溶
液で中和後、ジクロロメタン５０ｍｌで２回抽出し、無
水硫酸ナトリウムで乾燥した後、減圧（３０ｍｍＨｇ）
下で溶媒を留去し、目的のチアゾリン化合物３．１ｇ（
７６％収率）を得た。
【００２３】実施例２
５−メトキシ−２−エチルチオ−１，３−チアゾリン（
Ｉ，Ｒ＝エチル、Ｒ１ ＝メチル）の製造１）熱転移方
法参考例３の方法で得たジチオカーバメート２０．９ｇ
（０．１モル）を、２００±１０℃で徐々に減圧蒸留
（１〜５ｍｍＨｇ）し、目的のチアゾリン化合物１２．
４ｇ （７０％収率）を得た。１Ｈ−ＮＭＲ δ （
ＣＤＣｌ３）：１．３５（ｔ， Ｊ＝７．４， ３Ｈ）
， ３．１０（ｑｄ， Ｊ＝７．４， ３．２， ２Ｈ
），３．２５（ｓ， ３Ｈ）， ４．０８（ｄｄ， Ｊ
＝１６．１， ５．５， １Ｈ）， ４．４３（ｄ，
Ｊ＝１６．１， １Ｈ）， ５．６０（ｄ， Ｊ＝５．
４， １Ｈ） 【００２４】２）ＢＦ３ 方法参考例３
の方法で得たジチオカーバメート５．２３ｇ （０．０
２５モル）を、実施例１−２）の方法に準じて反応させ
、目的のチアゾリン化合物４．２５ｇ （９６％収率）
を得た。
【００２５】実施例３
５−メトキシ−２−アリルチオ−１，３−チアゾリン（
Ｉ，Ｒ＝アリル、Ｒ１ ＝メチル）の製造１）熱転移方
法参考例４で得たジチオカーバメート２２．１ｇ （０
．１モル）を、２００±１０℃で徐々に減圧蒸留（１．
５ｍｍＨｇ）し、目的のチアゾリン化合物１１．７ｇ
（６２％収率）を得た。１Ｈ−ＮＭＲ δ （ＣＤＣ
ｌ３）：３．２７（ｓ， ３Ｈ）， ３．７５ 〜３．
８１（ｍ， ２Ｈ）， ４．１１（ｄｄ， Ｊ＝１６．
２， ５．６， １Ｈ）， ４．４７（ｄ， Ｊ＝１６
．２， １Ｈ）， ５．１４（ｄ， Ｊ＝８．７， １
Ｈ）， ５．２８（ｄ， Ｊ＝１７．１， １Ｈ），
５．６２（ｄ， Ｊ＝５．６， １Ｈ）， ６．８４〜
６．００（ｍ， １Ｈ）
【００２６】２）ＢＦ３ 方法参考例４で得たジチオカ
ーバメート５．５３ｇ （０．０２５モル）を、実施例
１−２）の方法に準じて反応させ、目的チアゾリン化合
物４．６８ｇ （９９％収率）を得た。
【００２７】実施例４
５−メトキシ−２−（２−プロピニルチオ）−１，３−
チアゾリン（Ｉ，Ｒ＝２−プロピニル、Ｒ１ ＝メチル
）の製造
参考例５で得たジチオカーバメート５．４８ｇ （０．
０２５モル）を、実施例１−２）の方法に準じて反応さ
せ、目的のチアゾリン化合物４．５８ｇ （９８％収率
）を得た。１Ｈ−ＮＭＲ δ （ＣＤＣｌ３）：２．
２７（ｔ， ２．６， １Ｈ）， ３．２７（ｓ， ３
Ｈ）， ３．８９（ｄｄ， Ｊ＝９．４，２．６， ２
Ｈ）， ４．１１（ｄｄ， Ｊ＝１６．３， ５．５，
１Ｈ）， ４．４８（ｄ， Ｊ＝１６．３， １Ｈ）
， ５．６７（ｄ， Ｊ＝５．４， １Ｈ）
【００２８】実施例５
５−メトキシ−２−ベンジルチオ−１，３−チアゾリン
（Ｉ，Ｒ＝ベンジル、Ｒ１ ＝メチル）の製造参考例６
で得たジチオカーバメート６．７８ｇ （０．０２５モ
ル）を、実施例１−２）の方法に準じて反応させ、目的
のチアゾリン化合物５．８０ｇ （９７％収率）を得た
。１Ｈ−ＮＭＲ δ （ＣＤＣｌ３）：３．２０（ｓ
， ３Ｈ）， ４．０５（ｄｄ， Ｊ＝１６．２， ５
．４， １Ｈ）， ４．３０（ｄ， Ｊ＝１３．０，
１Ｈ）， ４．３９（ｄ， Ｊ＝１３．０， １Ｈ），
４．４５（ｄ， Ｊ＝１６．２， １Ｈ）， ５．５
４（ｄ， Ｊ＝５．４，１Ｈ）， ７．２０ 〜７．３
５（ｍ， ５Ｈ） 【００２９】実施例６
５−メトキシ−２−ピリジルメチルチオ−１，３−チア
ゾリン（Ｉ，Ｒ＝２−ピリジルメチル、Ｒ１ ＝メチル
）の製造
参考例７で得たジチオカーバメート６８．１ｇ （０．
０２５モル）を、三フッ化ホウ素・エーテル８．５１ｇ
（０．０６モル）を用いて、実施例１−２）の方法に
準じて反応させ、目的のチアゾリン化合物５．８２ｇ
（９７％）を得た。１Ｈ−ＮＭＲ δ （ＣＤＣｌ３
）：３．３８（ｓ， ３Ｈ），４．２３（ｄｄ， Ｊ＝
１６．２， ５．５， １Ｈ）， ４．６０（ｄ， Ｊ
＝１６．２， １Ｈ）， ４．６４（ｄ， Ｊ＝４．６
， ２Ｈ）， ５．７５（ｄ， Ｊ＝５．５， １Ｈ）
， ７．２５ 〜７．７８（ｍ， ３Ｈ），５．６４
〜８．６７（ｍ， １Ｈ） 【００３０】実施例７
５−メトキシ−２−メルカプト−１，３−チアゾリン（
Ｉ，Ｒ＝水素、Ｒ１ ＝メチル）の製造参考例８で得た
ジチオカーバメート４．５３ｇ （０．０２５モル）を
、実施例１−２）の方法に準じて反応させ、固体化合物
を得た。これをエーテルで再結晶し、目的のチアゾリン
化合物２．７６ｇ（７４％収率）を得た。融点：７７℃
１Ｈ−ＮＭＲ δ （ＣＤＣｌ３）：３．４０（ｓ，
３Ｈ）， ４．０５（ｄｄ， Ｊ＝１４．０， ０．
９， １Ｈ）， ４．１９（ｄｄ， Ｊ＝１３．０，
５．２， １Ｈ）， ５．５４（ｄｄ， Ｊ＝５．０，
０．９， １Ｈ）， ８．７９（ｂｒ ｓ， １Ｈ）
【００３１】実施例８Description: [0001] The present invention relates to a novel 5-alkoxy-2-substituted thio-1,3-thiazoline derivative, which is an intermediate for cephalosporin derivatives, and a method for producing the same. . [Prior art and problems to be solved by the invention] J.
Org. Chem. , 30, 491 (1965) and the same magazine 36, 1068 (1971), the general formula (II
It is disclosed that the thiazoline derivative of I) is prepared by the following reaction scheme. [0003] In the formula, R is a methyl group, and R' and R'' are each a hydrogen atom, an alkyl group, or a phenyl group. An attempt was made to produce a thiazoline derivative of (I), but the general formula (IV) or (
It has not been possible to produce a raw material compound in which R' or R'' in V) is an alkoxy group. [Means for Solving the Problem] As a result of extensive research, the present invention We succeeded in producing thiazoline derivative (I) by intramolecular cyclization reaction of (In the formula, R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an allyl group, a 2-propynyl group, a benzyl group, or a 2-pyridylmethyl group, and R1 represents a lower alkyl group such as methyl or ethyl.) The thiazoline derivative of the general formula (I) can be obtained by subjecting the dithiocarbamate of the general formula (II) to a cyclization reaction in the presence of a thermal transfer or an acid. To explain the production method of the present invention in more detail, it is obtained by subjecting dithiocarbamate (II) to an intramolecular thermal transfer reaction at about 200±10° C. under reduced pressure of 5 mmHg or less. ] Furthermore, to perform an intramolecular cyclization reaction in the presence of an acid, boron trifluoride, anhydrous magnesium bromide, concentrated sulfuric acid, etc. can be used as the acid, and boron trifluoride is most preferred.The reaction is carried out using dichloromethane, It can be carried out in a halogenated hydrocarbon solvent such as dichloroethane, chloroform, or carbon tetrachloride, and the reaction temperature is 10±5
Preferably, it is carried out at .degree. According to the method of the present invention, the desired thiazoline derivative (I) can be obtained from easily available dithiocarbamate (II) in a high yield of 95% or more. Furthermore, dithiocarbamate (II) is S
Synthesis, 638 (1989), aminoacetaldehyde dialkyl acetal (VII) is reacted with carbon disulfide at 0 to 20°C in the presence of triethylamine to form the general formula (V
It can be easily produced by obtaining the compound III) and subsequently reacting an alkyl halide at the same temperature. embedded image The thiazoline derivative (I) of the present invention can be converted into a cephalosporin derivative, for example, by the method shown in the following reaction formula. embedded image (wherein R2 is a carboxyl group protecting group) 0
[Example] Production examples of the present invention will be shown below and explained in detail. However, it should be understood that the present invention is not limited only to the embodiments, but that modifications and changes can be made by those skilled in the art within the protection scope of the present invention. Reference Example 1 Production of methyl N-(2,2-dimethoxyethyl)dithiocarbamate (II, R=R1 = methyl) 21 g (0.2 mol) of aminoacetaldehyde dimethyl acetal was dissolved in 150 ml of ethanol and 10 ml of water. rear,
Add 24.3 g (0.24 mol) of triethylamine and 16.8 g (0.22 mol) of carbon disulfide at 0 to 5°C.
I added it little by little. After the reaction was stirred for 1 hour at the same temperature, 31.2 g (0.22 mol) of methyl iodide was added dropwise little by little, and the reaction was stirred for 1 hour at 15±5°C. After distilling off the solvent from the reaction solution under reduced pressure (30 mmHg) and adding water,
After extraction with ethyl acetate and drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was removed under reduced pressure (30 mmHg) to obtain 36.9 g (95% yield) of the desired liquid compound. 1
H-NMR δ (CDCl3): 2.31 (S,
3H), 3.11(s, 6H), 3.57(t,
J=5.1, 2H), 4.28(t, J=5.1
, 1H), 7.50(br s, 1H) 001
2] Reference Example 2 Production of methyl N-(2,2-diethoxyethyl)dithiocarbamate (II, R = methyl, R1 = ethyl) Aminoacetaldehyde diethyl acetal 4g (0.
After dissolving 0.03 mol) in 60 ml of tetrahydrofuran, 3.3 g (0.033 mol) of triethylamine and 2.5 g (0.033 mol) of carbon disulfide were added.
After stirring for 1 hour at ℃, 4.7 g of methyl iodide (0.033
mol) was gradually added and stirred at 15±5°C for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure (30 mmHg), water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure (30 mmHg). 6.54 g (98% yield) of a liquid compound was obtained. 1H-NMR δ (CDCl3): 1.23
(t, J=7.0, 6H), 2.63(s, 6
H), 3.41 to 4.04 (m, 6H), 4.
70 (t, J=6.0, 1H), 7.31 (br
s, 1H) [Reference Example 3] Ethyl N-(2,2-dimethoxyethyl)
Production of dithiocarbamate (II, R = ethyl, R1 = methyl) Aminoacetaldehyde dimethyl acetal 10.5g
(0.1 mol) was reacted with 12 g (0.11 mol) of ethyl bromide for 2 hours according to the method of Reference Example 1 to obtain 19.9 g (95% yield) of the target liquid compound. 1H-NMR δ (CDCl3): 1.33
(t, J=7.5, 3H), 3.27(q, J
=7.5, 2H), 3.43(s, 6H), 3
．． 87 (t, J=5.0, 2H), 4.57 (t
, J=5.0, 1H), 7.43(br s,
1H) Reference Example 4 Production of allyl N-(2,2-dimethoxyethyl)dithiocarbamate (II, R = allyl, R1 = methyl) Aminoacetaldehyde dimethyl acetal 10.5 g
(0.1 mol) was reacted with 13.3 g (0.11 mol) of allyl bromide for 30 minutes according to the method of Reference Example 1 to obtain 21.2 g (96% yield) of the target liquid compound. Ta. 1H-NMR δ (CDCl3): 3.
43 (s, 6H), 3.80 ~ 4.03 (m,
4H), 4.60 (t, J=5.0, 1H),
5.07 ~5.63 (m, 2H), 5.67 ~
6.23 (m, 1H), 7.43 (br s, 1H
) Reference Example 5 2-Propynyl N-(2,2-dimethoxyethyl)dithiocarbamate (II, R=2-propynyl, R1=
10.5g of aminoacetaldehyde dimethyl acetal
(0.1 mol) was dissolved in 100 ml of tetrahydrofuran, then 12.2 g (0.12 mol) of triethylamine and 8.4 g (0.11 mol) of carbon disulfide were added.
After stirring at 0 to 5°C for 1 hour, the reaction temperature was cooled to -78°C, and 13.1 g of 2-propynyl bromide (0.1
1 mol) was added dropwise little by little. After 10 minutes, the amine salt precipitated during the reaction was removed by filtration, and the filtrate was placed under reduced pressure (30 mm
The solvent was distilled off under Hg) to obtain 20.1 g of the desired liquid compound.
(92% yield). 1H-NMR δ (CD
Cl3): 2.29 (t, J=2.5, 1H),
3.47 (s, 6H), 3.89 (t, J=5.
7, 2H), 4.09(d, J=2.5, 2H
), 4.67 (t, J=5.5, 1H), 7.4
2(br s, 1H) Reference Example 6 Production of benzyl N-(2,2-dimethoxyethyl)dithiocarbamate (II, R=benzyl, R1=methyl) Aminoacetaldehyde dimethyl acetal 10.5
g (0.1 mol), 13.9 g (0.11 mol) of benzyl chloride and 2
26.3 g (97%
Yield) was obtained. 1H-NMR δ (CDCl3):
3.40 (s, 6H), 3.90 (t, J=5.
1, 2H), 4.53 ~ 4.63 (m, 3H)
, 7.23 to 7.53 (m, 6H) Reference Example 7 2-pyridylmethyl N-(2,2-dimethoxyethyl)
dithiocarbamate (II, R=2-pyridylmethyl,
Production of R1 = methyl) 10.5 g of aminoacetaldehyde dimethyl acetal
(0.1 mol) according to the method of Reference Example 1.
-Chloromethylpyridine hydrochloride 18.0g (0.11
mol) for 2 hours to obtain 25.8 g of the desired solid compound.
(95% yield). 1H-NMR δ (CD
Cl3): 3.44 (s, 6H), 3.93 (t,
J=5.5, 2H), 4.30(s, 2H),
5.68 (t, J=5.5, 1H), 7.13~
8.63 (m, 4H), 10.83 (br s,
1H) Reference Example 8 Production of N-(2,2-dimethoxyethyl)dithiocarbamate (II, R=hydrogen, R1=methyl) Aminoacetaldehyde dimethyl acetal 10.5g (0.1
After dissolving mol) in 100 ml of tetrahydrofuran,
11.1 g (0.11 mol) of triethylamine and 7.6 g (0.11 mol) of carbon disulfide were added, and the mixture was stirred at 0 to 5°C for 1 hour. 9 ml of concentrated hydrochloric acid was added to the reaction solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was heated under reduced pressure (30
The solvent was distilled off under 13.mmHg) to obtain the desired liquid compound 13.
0 g (72% yield) was obtained. 1H-NMR δ (
CDCl3): 3.41 (s, 6H), 3.57 (
d, J=5.2, 2H), 4.47(t, J=
5.0, 1H), 6.79 (br s, 1H) Example 1 5-Methoxy-2-methylthio-1,3-thiazoline (
1) Heat transfer method 19.5 g (0.1 mol) of the dithiocarbamate obtained by the method of Reference Example 1 was gradually distilled under reduced pressure (1.5 mmHg) at 200±10°C. 12.2 g (75% yield) of the desired thiazoline compound was obtained. 1H-NM
R δ (CDCl3): 2.53 (s, 3H),
3.26 (s, 3H), 4.04 (dd, J=
16.2, 5.62, 1H), 4.45(d,
J=16.2, 1H), 5.62(d, J=5.
62, 1H) 2) BF3 4.88 g (0.025 mol) of dithiocarbamate obtained by the method of Method Reference Example 1,
After dissolving in 50 ml of dichloromethane, 3.9 g (0.0275 mol) of boron trifluoride ether was added dropwise little by little at 10±5° C., followed by stirring at the same temperature for 10 minutes. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate to adjust the pH to 8 to 9, and then diluted with 50 ml of dichloromethane.
After extracting twice and drying with anhydrous sodium sulfate, the mixture was extracted under reduced pressure (3
The solvent was distilled off under 0 mmHg) to obtain 4.0 g (98% yield) of the desired thiazoline compound. 3) MgBr2 4.88 g (0.025 mol) of dithiocarbamate obtained by the method of Method Reference Example 1
was dissolved in 50 ml of dichloromethane, and then 7.1 g of anhydrous magnesium bromide ether (0
．． After stirring at the same temperature for 20 minutes, the mixture was treated in the same manner as in Example 1-2) to obtain the desired thiazoline compound 4.0 (98% yield). 4) H2 SO4 Method 4.88 g (0.025 mol) of the dithiocarbamate obtained by the method of Reference Example 1 was dissolved in 50 ml of carbon tetrachloride, and then 2.58 g (0.025 mol) of 95% concentrated sulfuric acid was added. ) and refluxed for 3 hours. After cooling the reaction solution (~5°C) and filtering the precipitated solid, the solid was dissolved in water, neutralized with a 5% aqueous sodium hydroxide solution, extracted twice with 50 ml of dichloromethane, and dried over anhydrous sodium sulfate. After that, reduce the pressure (30mmHg)
The solvent was distilled off and 3.1 g of the desired thiazoline compound (
76% yield) was obtained. Example 2 5-methoxy-2-ethylthio-1,3-thiazoline (
Production of I, R = ethyl, R1 = methyl) 1) Heat transfer method 20.9 g of dithiocarbamate obtained by the method of Reference Example 3
(0.1 mol) was gradually distilled under reduced pressure (1 to 5 mmHg) at 200±10°C to obtain the desired thiazoline compound 12.
4g (70% yield) was obtained. 1H-NMR δ (
CDCl3): 1.35 (t, J=7.4, 3H)
, 3.10 (qd, J=7.4, 3.2, 2H
), 3.25 (s, 3H), 4.08 (dd, J
=16.1, 5.5, 1H), 4.43(d,
J=16.1, 1H), 5.60(d, J=5.
4, 1H) 2) BF3 Method Reference Example 3
Dithiocarbamate 5.23g (0.0
25 mol) was reacted according to the method of Example 1-2) to obtain 4.25 g (96% yield) of the desired thiazoline compound.
I got it. Example 3 5-methoxy-2-allylthio-1,3-thiazoline (
Production of I,R=allyl, R1=methyl) 1) Heat transfer method 22.1 g of dithiocarbamate obtained in Reference Example 4 (0
．． 1 mol) was gradually distilled under reduced pressure (1.
5 mmHg) and 11.7 g of the desired thiazoline compound.
(62% yield). 1H-NMR δ (CDC
l3): 3.27 (s, 3H), 3.75 to 3.
81 (m, 2H), 4.11 (dd, J=16.
2, 5.6, 1H), 4.47(d, J=16
．． 2, 1H), 5.14 (d, J=8.7, 1
H), 5.28 (d, J=17.1, 1H),
5.62 (d, J=5.6, 1H), 6.84~
6.00 (m, 1H) 2) BF3 Method 5.53 g (0.025 mol) of the dithiocarbamate obtained in Reference Example 4 was reacted according to the method of Example 1-2) to obtain the desired thiazoline. 4.68 g (99% yield) of the compound was obtained. Example 4 5-methoxy-2-(2-propynylthio)-1,3-
Production of thiazoline (I, R = 2-propynyl, R1 = methyl) 5.48 g of dithiocarbamate obtained in Reference Example 5 (0.
025 mol) was reacted according to the method of Example 1-2) to obtain 4.58 g (98% yield) of the desired thiazoline compound. 1H-NMR δ (CDCl3):2.
27(t, 2.6, 1H), 3.27(s, 3
H), 3.89 (dd, J=9.4, 2.6, 2
H), 4.11(dd, J=16.3, 5.5,
1H), 4.48 (d, J=16.3, 1H)
, 5.67 (d, J=5.4, 1H) Example 5 Reference Example 6 for the production of 5-methoxy-2-benzylthio-1,3-thiazoline (I,R=benzyl, R1=methyl)
6.78 g (0.025 mol) of the dithiocarbamate obtained in Example 1-2) was reacted to obtain 5.80 g (97% yield) of the desired thiazoline compound. 1H-NMR δ (CDCl3): 3.20 (s
, 3H), 4.05(dd, J=16.2, 5
．． 4, 1H), 4.30(d, J=13.0,
1H), 4.39(d, J=13.0, 1H),
4.45 (d, J=16.2, 1H), 5.5
4 (d, J=5.4, 1H), 7.20 ~ 7.3
5(m, 5H) Example 6 Production of 5-methoxy-2-pyridylmethylthio-1,3-thiazoline (I,R=2-pyridylmethyl, R1=methyl) Dithiocarbamate obtained in Reference Example 7 68.1g (0.
025 mol), 8.51 g of boron trifluoride ether
(0.06 mol) was reacted according to the method of Example 1-2) to obtain 5.82 g of the desired thiazoline compound.
(97%). 1H-NMR δ (CDCl3
): 3.38 (s, 3H), 4.23 (dd, J=
16.2, 5.5, 1H), 4.60(d, J
=16.2, 1H), 4.64(d, J=4.6
, 2H), 5.75 (d, J=5.5, 1H)
, 7.25 ~ 7.78 (m, 3H), 5.64
~8.67 (m, 1H) Example 7 5-methoxy-2-mercapto-1,3-thiazoline (
4.53 g (0.025 mol) of the dithiocarbamate obtained in Reference Example 8 was reacted according to the method of Example 1-2) to obtain a solid compound. . This was recrystallized from ether to obtain 2.76 g (74% yield) of the desired thiazoline compound. Melting point: 77℃
1H-NMR δ (CDCl3): 3.40 (s,
3H), 4.05(dd, J=14.0, 0.
9, 1H), 4.19(dd, J=13.0,
5.2, 1H), 5.54(dd, J=5.0,
0.9, 1H), 8.79(br s, 1H)
Example 8
Claims (1)
導体。 【化１】 （式中、Ｒは水素原子、炭素数１〜６のアルキル基、ア
リル基、２−プロピニル基、ベンジル基又は２−ピリジ
ルメチル基を表し、Ｒ１ は低級アルキル基を表す）【
請求項２】 一般式 （ＩＩ） のジチオカーバメー
ト【化２】 （式中、Ｒ及びＲ１ は請求項１と同じ）を熱転移又は
酸の存在下で環化反応させることを特徴とする一般式（
Ｉ）のチアゾリン誘導体の製造方法。 【化３】 （式中、Ｒ及びＲ１ は請求項１と同じ）【請求項３】
酸が三フッ化ホウ素、無水マグネシウム・ブロマイ
ド又は濃硫酸である請求項２の製造方法。[Scope of Claims] [Claim 1] A thiazoline derivative represented by general formula (I). [Formula, R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an allyl group, a 2-propynyl group, a benzyl group, or a 2-pyridylmethyl group, and R1 represents a lower alkyl group]
[Claim 2] A dithiocarbamate of the general formula (II) [Chemical formula 2] (wherein R and R1 are the same as those in claim 1) is subjected to a cyclization reaction in the presence of a thermal transition or an acid. (
I) Method for producing a thiazoline derivative. [Claim 3] (In the formula, R and R1 are the same as in Claim 1) [Claim 3]
3. The method of claim 2, wherein the acid is boron trifluoride, anhydrous magnesium bromide or concentrated sulfuric acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019900010721A KR920008615B1 (en) | 1990-07-14 | 1990-07-14 | Thiazoline derivatives and its method |
| KR10721/1990 | 1990-07-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04224569A true JPH04224569A (en) | 1992-08-13 |
| JPH0645608B2 JPH0645608B2 (en) | 1994-06-15 |
Family
ID=19301278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3067755A Expired - Lifetime JPH0645608B2 (en) | 1990-07-14 | 1991-03-08 | Thiazoline derivative and method for producing the same |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH0645608B2 (en) |
| KR (1) | KR920008615B1 (en) |
-
1990
- 1990-07-14 KR KR1019900010721A patent/KR920008615B1/en not_active IP Right Cessation
-
1991
- 1991-03-08 JP JP3067755A patent/JPH0645608B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| KR920008615B1 (en) | 1992-10-02 |
| KR920002563A (en) | 1992-02-28 |
| JPH0645608B2 (en) | 1994-06-15 |
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