CN1072651C - 用于制备2－咪唑啉－5－酮的中间体 - Google Patents
用于制备2－咪唑啉－5－酮的中间体 Download PDFInfo
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- CN1072651C CN1072651C CN97196640A CN97196640A CN1072651C CN 1072651 C CN1072651 C CN 1072651C CN 97196640 A CN97196640 A CN 97196640A CN 97196640 A CN97196640 A CN 97196640A CN 1072651 C CN1072651 C CN 1072651C
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- 238000002360 preparation method Methods 0.000 title claims description 10
- 239000000543 intermediate Substances 0.000 title abstract description 7
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical class O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- -1 amino, hydroxyl Chemical group 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 150000001721 carbon Chemical group 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 239000011877 solvent mixture Substances 0.000 claims description 3
- ATANCPFXUICFMN-UHFFFAOYSA-N 1,3-thiazolidine-2-sulfonic acid Chemical compound S1C(NCC1)S(=O)(=O)O ATANCPFXUICFMN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 230000000855 fungicidal effect Effects 0.000 abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000126 substance Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940031815 mycocide Drugs 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical class NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- HTCSFFGLRQDZDE-VIFPVBQESA-N (2s)-2-azaniumyl-2-phenylpropanoate Chemical compound OC(=O)[C@](N)(C)C1=CC=CC=C1 HTCSFFGLRQDZDE-VIFPVBQESA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- HGKUPDZBTAQFGJ-UHFFFAOYSA-N 2-amino-2-phenylpropanamide Chemical compound NC(=O)C(N)(C)C1=CC=CC=C1 HGKUPDZBTAQFGJ-UHFFFAOYSA-N 0.000 description 1
- UGWULZWUXSCWPX-UHFFFAOYSA-N 2-sulfanylideneimidazolidin-4-one Chemical compound O=C1CNC(=S)N1 UGWULZWUXSCWPX-UHFFFAOYSA-N 0.000 description 1
- VOZAKIVKZSKOHM-UHFFFAOYSA-N CC1(C=C(N=C1)S(=O)(=O)O)C2=CC=CC=C2 Chemical class CC1(C=C(N=C1)S(=O)(=O)O)C2=CC=CC=C2 VOZAKIVKZSKOHM-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 240000005109 Cryptomeria japonica Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- AFVLVVWMAFSXCK-VMPITWQZSA-N alpha-cyano-4-hydroxycinnamic acid Chemical group OC(=O)C(\C#N)=C\C1=CC=C(O)C=C1 AFVLVVWMAFSXCK-VMPITWQZSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940095054 ammoniac Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000019628 coolness Nutrition 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- ZAMCTDDIJFNXOH-UHFFFAOYSA-N tributylazanium;acetate Chemical compound CC(O)=O.CCCCN(CCCC)CCCC ZAMCTDDIJFNXOH-UHFFFAOYSA-N 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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
-
- 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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/36—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Cosmetics (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及新颖的2-硫代-噻唑烷-5-酮化合物，它用作制备杀真菌剂的2-咪唑啉-5-酮的中间体。
Description
本发明涉及用于制备杀真菌剂用的2-咪唑啉-5-酮的中间体新产品。它还涉及这些新产品的制备方法以及从这些新颖的中间体开始获得2-咪唑啉-5-酮的有效方法。
通过欧洲专利EP551048,EP599749,EP629616和国际专利WO93/24467，人们已了解用作杀真菌剂的2-咪唑啉-5-酮。
本发明的一个目的是提出制取2-咪唑啉-5-酮中使用的新颖中间体。
本发明的另一目的是提出一种具有改进安全性得到2-咪唑啉-5-酮的杀真菌剂的新途径。
因此，本发明首次提出了通式(Ⅰ)的2-硫代-噻唑烷-5-酮：
其中：
-R1是C1-C3烷基或苯基
-R2是选自苯基或吡啶基的任意被选自卤素，硝基，氰基，C1-C3烷基，C1-C3烷氧基的1-3个取代基所取代的芳基；
在Tetrahedron Letters,16,(1977),1351-1354里揭示的4-乙基-4-苯基-硫代-噻唑烷-5-酮除外。
本发明还涉及式(Ⅰ)化合物的盐以及立体异构体形式。本发明特别涉及到由不对称碳的存在而得到的光学异构体，以及特别是当R1和R2不同时，载有R1和R2的不对称碳的存在能引出光学异构体。这些光学异构体是纯的光学化合物或富集形式的对映体。如下所述，人们通过光学活性形式的化合物来测量对映体，在化合物中含有至少80％的对映体，较好的是至少90％的对映体。所有这些化合物被认为包括在前述定义的式(Ⅰ)内。
在式(Ⅰ)化合物中，优选的是其中：
-R1表示C1-C3烷基；
-R2表示任意被卤原子，氰基，硝基，甲基或甲氧基取代的苯基。
更好的是在式(Ⅰ)的化合物中，R2为苯基，R1为甲基。
根据本发明的很有利的变体，式(Ⅰ)化合物中
-R1是甲基，和
-R2是苯基，
该化合物是关于载有R1和R2的不对称碳的对映体。
在本说明书中，所有出现在下式(Ⅰ)化合物中的基团，已在通式(Ⅰ)里规定的基团，保持相同的定义，只有当明确表示时，可以不一样。本文中所述的烷基可以是直链或支链的。
现在叙述通式(Ⅰ)化合物的制备方式，该制备方式表现在化合物相对于载有R1和R2的碳是外消旋的情况下。虽然，本技术领域人员希望可以使用相同的反应来获得关于载有R1和R2的碳的式(Ⅰ)的对映体化合物。事实上，后面所述的反应完全是立体选择性的，从道理上说，反应不会导致同一个碳的绝对构型发生改变。
这样得到式(Ⅰ)的化合物：在溶剂或溶剂混合物中，任意地在碱存在的情况下，在0℃到+50℃的温度下，使化学式(Ⅱ)的化合物与二硫化碳反应得到式(Ⅰ)化合物，反应流程如下：其中：
R3是氨基，羟基或有1～6个碳原子，较佳地有1～3个碳原子的直链或支链的烷氧基，或者是任意被卤原子所取代的苄氧基。
可能使用的碱是无机碱，诸如氢氧化物，碱金属或碱土金属的碳酸盐，或者是有机碱，诸如伯胺，仲胺，叔胺。碱可以按碱/化合物比率(按摩尔数表示之)使用，比率包括在0.05和1.2之间，较佳的包括在0.1和1之间。
在此方案中，作为中间体的式(Ⅲ)的化合物在使用碱后呈盐状情况下是可以分离出来的。
作为溶剂可使用水，醚，环醚，烷基酯，诸如乙腈的偶极溶剂，有1～4个碳原子的醇类，芳香溶剂，较佳的是甲苯，二氯甲烷或氯仿。作为溶剂混合物可使用一种或多种醇和上述的一种或多种溶剂的混合物。
当R3是羟基时，较佳的是使用水作为溶剂。
当R3不是羟基时，较佳的是使用醇类/水的混合物作为溶剂。
如果分离得到式(Ⅲ)化合物，可通过将温度从25℃增加到所用溶剂的回流度以直接将式(Ⅲ)化合物转变成化合物(Ⅰ)。中间化合物(Ⅲ)还可通过强酸处理得以转变成化合物(Ⅰ)，强酸可以是无机酸，诸如盐酸或硫酸，也可以是有机酸，诸如三氟乙酸。
优选的是无碱存在的情况和温度在20℃到40℃下采用此方法。在此情况下，无需分离式(Ⅲ)化合物。
按A.C.DAVIS和AJLEVY在化学学会杂志2419-25页(1951)或由K HOFMANN等人在美国化学学会杂志，74卷，470-476页(1952)描述，它揭示了从化合物(Ⅱ)开始制取化合物(Ⅰ)的另一些方法的模式。
这样得到R3是烷氧基的化合物(Ⅱ)的α-氰基酯：按照类似于由M.Brenne和W.Huber在HelvCh.Acta(1953),36卷，1109-1115页所描述的方法，通过使相应的α-烷基酸酯化而获得。
这样得到其中R3是氨基的式(Ⅱ)的α-氨基酰胺：根据J.A.Garbarino在意大利化学年鉴，59卷，841-849页(1969)所叙述的方法，从氨基酯开始通过氨的(ammoniac)作用而获得的。
α-氨基酸是通过已知的反应和方法来制得的。
当化学式化合物(Ⅱ)是氨基酯对映体时，它特别可通过下列方式制得：
-根据R.S.ATKINSON等人在Tetrahedron,(1992),48卷，7713-30页所描述的，随着手性偶合物的去保护，前手性化合物进行非对映选择性胺化作用，或通过
-根据Y.SUGI和S.MITSUI日本化学学会通报(1989),42卷，2984～89页所描述的，将具有旋光化合物的相应的外消旋化合物分成两份，或通过
-使手性的氨基酸酯化，这是由D.J.CRAM等人在美国化学学会杂志，1961,.83卷2183-89页所叙述的。
当化学式化合物(Ⅱ)是氨基酰胺对映体时，它可以按照由H.DAHN等人在Helv.Chim.Acta,53卷，1370-1378页(1970)所描述的，从旋光的氨基酯开始或者通过将相应的外消旋物分成两份而制得。
式(Ⅰ)的2-硫代-噻唑烷-5-酮可用于制取化学式(Ⅳ)的2-咪唑啉-5-酮杀真菌剂，
其中-M表不氧原子或硫原子，
-R30表示含有1～6个碳原子的直链或支链烷基，或含有i～6个碳原子的直链或直链卤代烷基
-R4表示氢原子或酰基
-R5表示选自苯基，萘基，吡啶基，嘧啶基，哒嗪基，吡嗪基，噻吩基，苯并噻吩基，呋喃基，苯并呋喃基，喹啉基，异喹啉基，或亚甲基二氧基苯基的芳基或杂芳基，它们可任意地被相同或不同的1～7个，较佳的是1-3个取代基所取代，所述取代基选自R51的定义；
-R51表示：
-卤原子，或
-有1～6个碳原子的直链或支链烷基，卤代烷基，烷氧基，卤代烷氧基，硫代烷基硫代，卤代烷基硫代或烷基磺酰基，或
-有3～6个碳原子的环烷基，卤代环烷基，烯基氧基(alcenyloxy)，炔基氧基(alcynyloxy)，硫代烯基(alcenylthio)，硫代炔基(alcynylthio)，或
-硝基或氰基，或
-任意被有1～6个碳原子的烷基或酰基、或有2～6个碳原子的烷氧基羰基单取代或双取代的氨基；
及其这些化合物在农业上可接受的盐形式和它们的立体异构体，特别是当R1和R2不同时，旋光异构体是由于载有R1和R2的不对称碳的存在而引起的。
现在揭示一种既可用于外消旋系列也可用于对映体系列的方法，该叙述涉及到本发明的从式(Ⅰ)的2-硫代-噻唑烷-5-酮开始制取化学式(Ⅳ)杀真菌剂化合物。
在溶剂里，在+20℃到+100℃，优选的是在40-80℃温度下，使式(Ⅰ)化合物与式(Ⅴ)化合物反应，反应如下：
作为溶剂，可使用诸如二噁烷的醚类，非质子传递的偶极溶剂，特别是N-甲基吡咯烷酮，二甲基亚砜或乙腈，含有1～4个碳原子的醇，特别的是甲醇，芳烃溶剂，更明确地说是吡啶或单氯苯。
优选地使用选自叔胺，例如三乙胺或三丁胺，或该胺的有机盐，例如三丁胺乙酸盐的催化剂来进行反应。此催化剂的催化剂/化合物(Ⅰ)(由摩尔数表示之)比率为0.05～1，较佳的为0.1-0.5，从而获得改善的纯度。
按照EP551048,EP599749，或EP629616专利申请之一所描述的方法，化学式(Ⅵ)的硫代海因被转化成式(Ⅳ)的2-咪唑啉-5酮。
下面所提供的实施例仅仅作为本发明涉及的化合物和制备方法的说明，并非用作限定。借助于至少下述光谱技术之一来建立所述衍生物构形：质子的RMN光谱测定法，碳13的RMN光谱测定法，红外线光谱测定法和质谱测定法，以及测量旋光能力的常规方法。
实施例1：从氨基酰胺中制备(4-S)4-甲基-4-苯基-2-硫代-唑噻烷-5-酮
在装有机械搅拌器的50毫升的圆底烧瓶里加入3.26克(20毫摩尔)的(2-S)2-氨基-2-苯基丙酰胺，6毫升(100亳摩尔)二硫化碳和4毫升乙腈。非均匀介质在20℃下激烈搅拌20小时。在真空下蒸馏除去过量的二硫化碳和乙腈后，经提纯和过滤得到呈白色固体状的3.70克(4-S)4-甲基-4-苯基-2-硫代-噻唑烷-5-酮，熔点为104℃。
实施例2：从氨基酯中制备(4-S)4-甲基-4-苯基-2-硫代-噻唑烷-5-酮：
在配置有磁搅拌的25毫升试管内加入2克(11.1毫摩尔)的(2-S)2-氨-2-苯基丙酸甲酯，15毫升的四氢化呋喃，1.82毫升(13毫摩尔)的三乙胺和0.78毫升(13毫摩尔)的二硫化碳。真空密封后，将试管保持在45℃温度下，使均匀介质在该温度搅拌下保持4小时，经冷却和提纯之后，获得呈白色粉末状、收率为80％的2克(4-S)4-甲基-4-苯基-2-硫代-噻唑烷-5-酮。
实施例.3：制备(4-S)4-甲基-1-苯基氨基-2-硫代海因(thiohydantioine)：
在配置有磁搅拌的25毫升圆底烧瓶内加入893毫克(4毫摩尔)的(4-S)4-甲基-4-苯基-2-硫代-噻唑烷-5-酮，8毫升乙腈和100微升(0.4毫摩尔)的三丁胺。混合物被加热到70℃，继而在2小时内将520毫克(4.8毫摩尔)的苯肼溶液倾倒在4.5毫升的乙腈内。用6小时将反应介质加热到80℃冷却后，通过减压蒸馏除去乙腈。经提纯后，得到呈白色固化状的975毫克的(4-S)4-甲基-4-苯基-1-苯基氨基-2-硫代海因，熔点为167℃。其纯度通过HPLC测定为100％，收率为82％。
实施例4：从(2S)-2-氨基-2-苯丙酸制备(4-S)4-甲基-4-苯基-2-硫代-噻唑烷-5-酮：
在配置有磁搅拌的50毫升圆底烧瓶内，连续地注入11克(10-2摩尔)的(2-S)-2-氨基-2-苯丙酸(15重量％混合物形式，在固态NaCl内的氨基酸)，10毫升的N-甲基吡咯烷酮，0.8克(2×10-2摩尔)氢氧化钠片剂，继而注入1.8毫升(3×10-2摩尔)的二硫化碳，经真空密封后，在剧烈的搅拌下用5个小时将反应介质加热到60℃，冷却后，将50毫升的水，然后将5.4毫升的浓硫酸加进反应介质中。萃取有机相，清洗，干燥，接着浓缩有机相。得到(4-S)4-甲基-4-苯基-2-硫代-噻唑烷-5-酮，收率为84％。
Claims (6)
1．一种通式(1)的2-硫代-噻唑烷-5-酮化合物，及其盐和对应的立体异构体：其中：
-R1是C1-C3烷基或苯基
-R2是选自苯基或吡啶基的任意被选自卤素，硝基，氰基，C1-C3烷基，C1-C3烷氧基的1-3个取代基所取代的芳基；
当R1和R2不同时，由于载有R1和R2的不对称碳的存在而得到了光学异构体；
4-乙基-4-苯基-硫代-噻唑烷-5-酮除外。
2．根据权利要求1所述的化合物，其特征在于：
-R1表示C1-C3烷基
-R2表示任意被卤原子，氰基，硝基，甲基或甲氧基所取代的苯基。
3．根据权利要求1或2所述的化合物，其特征在于R2是苯基，R1是甲基。
4．根据权利要求1所述的化合物，其特征在于它是关于载有R1和R2的不对称碳的对映体。
5．如权利要求1～4之-所述的式(Ⅰ)化合物的制备方法，其特征在于，在溶剂或溶剂混合物里，任意有碱存在下，于0℃到+50℃温度下，使式(Ⅱ)化合物与二硫化碳反应，反应流程如下：
其中：
R3是氨基，羟基或有1～6个碳原子的直链或支链的烷氧基，或者是任意被卤原子所取代的苄氧基。
6．根据权利要求5所述的制备方法，其特征在于，在无碱和20℃到40℃温度下进行反应。
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| FR9609483A FR2751327A1 (fr) | 1996-07-22 | 1996-07-22 | Intermediaires pour la preparation de 2-imidazoline-5-ones |
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| CNB011166401A Expired - Lifetime CN1136204C (zh) | 1996-07-22 | 2001-04-17 | 2-咪唑啉-5-酮杀真菌剂的制备方法 |
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| FR2778671B1 (fr) * | 1998-05-14 | 2002-07-05 | Rhone Poulenc Agrochimie | Nouveau procede de preparation d'intermediaires de synthese |
| FR2788271B1 (fr) | 1999-01-07 | 2001-02-09 | Rhone Poulenc Agrochimie | Nouveau procede de preparation d'aminoacides chiraux |
| FR2794743A1 (fr) * | 1999-06-09 | 2000-12-15 | Aventis Cropscience Sa | Nouveau procede de preparation d'alpha-aminonitriles optiquement actifs |
| FR2800734B1 (fr) * | 1999-11-05 | 2002-08-23 | Aventis Cropscience Sa | Cristal d'acide amine chiral et son procede de preparation |
| US6759551B1 (en) | 2000-11-03 | 2004-07-06 | Bayer Cropscience S.A. | Chiral (s- or r-methylphenylglycine) amino acid crystal and method for preparing same |
| DE10246310A1 (de) * | 2002-10-04 | 2004-04-22 | Siemens Ag | Gradientenspulensystem und Magnetresonanzgerät mit dem Gradientenspulensystem |
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| FR2685328B1 (fr) | 1991-12-20 | 1995-12-01 | Rhone Poulenc Agrochimie | Derives de 2-imidazoline-5-ones et 2-imidazoline-5-thiones fongicides. |
| WO1993024467A1 (en) | 1992-05-22 | 1993-12-09 | E.I. Du Pont De Nemours And Company | Fungicidal imidazolinones |
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| FR2751327A1 (fr) * | 1996-07-22 | 1998-01-23 | Rhone Poulenc Agrochimie | Intermediaires pour la preparation de 2-imidazoline-5-ones |
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