CN1083447C - 苯并噻唑酮类化合物的制备方法 - Google Patents
苯并噻唑酮类化合物的制备方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- BXQNSPXDWSNUKE-UHFFFAOYSA-N 1,3-benzothiazole 1-oxide Chemical class C1=CC=C2S(=O)C=NC2=C1 BXQNSPXDWSNUKE-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 4
- 230000026030 halogenation Effects 0.000 claims description 4
- 238000005658 halogenation reaction Methods 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- -1 2-aminobenzothiazole compound Chemical class 0.000 claims description 3
- BSQLQMLFTHJVKS-UHFFFAOYSA-N 2-chloro-1,3-benzothiazole Chemical class C1=CC=C2SC(Cl)=NC2=C1 BSQLQMLFTHJVKS-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 claims description 3
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- XVTVJNXKVZQUSM-UHFFFAOYSA-N n-nitroacetamide Chemical compound CC(=O)N[N+]([O-])=O XVTVJNXKVZQUSM-UHFFFAOYSA-N 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- PMDCZENCAXMSOU-UHFFFAOYSA-N N-ethylacetamide Chemical compound CCNC(C)=O PMDCZENCAXMSOU-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UHGULLIUJBCTEF-UHFFFAOYSA-N 2-aminobenzothiazole Chemical compound C1=CC=C2SC(N)=NC2=C1 UHGULLIUJBCTEF-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 229960003280 cupric chloride Drugs 0.000 description 2
- 229940045803 cuprous chloride Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241001635574 Sabatia angularis Species 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- XJHOSWBRTBAQJU-UHFFFAOYSA-N acetamide;nitrobenzene Chemical compound CC(N)=O.[O-][N+](=O)C1=CC=CC=C1 XJHOSWBRTBAQJU-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- DQMWMUMCNOJLSI-UHFFFAOYSA-N n-carbamothioylbenzamide Chemical compound NC(=S)NC(=O)C1=CC=CC=C1 DQMWMUMCNOJLSI-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000007738 vacuum evaporation 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
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C335/20—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
- C07C335/26—Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/82—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明说明制备式(I)化合物的方法，以及制备过程中的新中间体。
Description
本发明涉及苯并噻唑酮类化合物的制备方法，以及本发明方法中的新型中间体。
苯并噻唑酮类化合物是熟知的化合物。例如，WO93/24473说明了下列通式的7-(2-氨基乙基)-苯并噻唑酮化合物及其药学上可接受的衍生物
其中
X和Y独立代表-S(O)n-或-O-，
n代表0、1或2，
p、q或r独立代表2或3，
Z代表任选由卤素、-OR1、NO2或NR2R3取代的苯基；或5-或6-元含有N、O或S的杂环，
R1、R2和R3独立代表氢或烷基C1-6。
WO93/24473的化合物可通过数种方法制备，例如，通过式I的苯并噻唑酮化合物
与下式的烷基化剂的烷基化作用
L-(CH2)p-X-(CH2)q-Y-(CH2)r-Z其中p、q、r、X、Y和Z定义同上，L代表离去基团，或者在还原剂存在下，用下式化合物使式I化合物烷基化制备，
O＝CH-(CH2)p-1-X-(CH2)q-Y-(CH2)r-Z其中p、q、r、X、Y和Z定义同上。
本发明特别涉及合成化合物I的新方法。
合成该化合物的路线是熟知的，例如Weinstock等，J.Med.Chem.，1987，30，1166-1176。
根据本发明制备式I化合物
的方法包括将式II的氯代苯并噻唑化合物
转化成式I化合物，如使用浓氢溴酸。
式II化合物是新化合物，可通过使式III的2-氨基苯并噻唑化合物卤化而制备，例如使用氯化铜(II)和氯化亚铜(I)及任选乙醇在HCl中，如在20％HCl中，并向其中加入亚硝酸钠制备：
式III化合物是新化合物，可用卤化/氧化剂，如N-溴代琥珀酰亚胺、溴或N-氯代琥珀酰亚胺，在酸性溶剂中，如混合酸性溶剂如MeSO3H/AcOH中由式IV的硫脲制备，
式IV化合物是新化合物，可通过例如在水中用碱如K2C03或碱金属的氢氧化物，如NaOH或KOH水解式V化合物制备：
式V化合物是新化合物，可通过如在丙酮或甲基异丁基酮(MIBK)中使式VI的苯胺盐酸盐
与苯甲酰基异硫代氰酸盐反应制备。
式VI化合物是新化合物，可在任何适当的溶剂中，如在乙醇或2-丙醇中，在钯碳存在下，通过使式VII的硝基乙酰胺氢化，再用HCl处理制备
式VII化合物是新化合物，可通过在乙酸中如用HNO3使式VIII的乙酰胺硝基化制备，
式VIII化合物可通过如用乙酸酐或乙酰氯作为溶剂和试剂，或者在二氯甲烷和三乙胺存在下由式IX化合物制备：
另一方面，本发明提供制备式I化合物的方法，包括(i)例如用乙酸酐或乙酰氯作为溶剂和试剂，或者在二氯甲烷和三乙胺存在下进行，使式IX化合物转化成式VIII化合物，(ii)将式VIII化合物转化成式I化合物，例如如上所述通过逐步制备的化合物VII、VI、V、IV、III和II进行。
本发明的方法提供简易制备化合物II的方法，不需使用不理想的原料而得到较好收率的产物化合物。
本发明还提供新的式II、III、IV、V、VI和VII化合物。
以下实施例说明，但不限制本发明。
(a)通氮气下，使2-(4-甲氧基苯基)乙胺(100g)溶于二氯甲烷中。向其中加入三乙胺(92.18ml)，将得到的溶液冷却至0℃。向该冷溶液中在35分钟内滴加乙酸酐(62.40ml)。观察到最高外温升至6℃。将反应混合液于室温下搅拌40分钟。T1c表明加入完成后无痕量的原料。
将反应混合液用稀盐酸(2×1L)和饱和NaHCO3溶液(2×1L)洗涤，再用无水MgSO4干燥，过滤，真空浓缩得到灰白色固体。真空干燥(T＝40℃)。
(b)将2-(4-甲氧基苯基)乙基乙酰胺(70g)的冰醋酸(350ml)溶液用25分钟加入到20℃的浓硝酸(339.6ml)中。冷却以保持温度在18-20℃之间。将得到的溶液于室温下(24℃)搅拌45分钟。通过HPLC监察反应过程。
将反应混合液倾入冰水(2.7L)中形成沉淀/混悬液。产物在室温搅拌下油状析出。将混合液用二氯甲烷(2×1L)提取。将提取的样本用NaHCO3洗涤、干燥，浓缩用于分析。将提取液用饱和Na2CO3溶液(2×1L)洗涤，以使该提取液用水饱和。将该提取液用少量二氯甲烷(～100ml)稀释，然后用无水MgSO4干燥，过滤，真空浓缩。
(c)将2-(4-甲氧基-3-硝基苯基)乙基乙酰胺(4.82g)溶于热乙酸乙酯(9.5ml)中，然后放冷至室温。冷却至0℃，形成黄色结晶。过滤结晶，用冷乙酸乙酯洗涤，真空干燥(T＝40℃)。
(d) 将2-(4-甲氧基-3-硝基苯基)乙基乙酰胺(5.98g)溶于乙醇(150ml)中，加入10％钯碳(0.18g)，将得到的混合液在3巴下氢化，过夜。
滤掉催化剂，浓缩滤液至约其体积的三分之一。然后将溶液用氯化氢充气直至冷却下沉淀出淡棕色固体。将混合液搅拌过夜。过滤灰白色固体，用乙醚洗涤，然后真空干燥(T＝50℃)。
(e)将苯胺盐酸盐(40.0g)溶于水(200ml)中，用氢氧化钠水溶液(25％w/v)碱化至pH≈11，用二氯甲烷(100ml×3)提取，干燥(Na2SO4)，真空蒸发至干得到淡粉红色固体。将该固体溶于丙酮(140ml)中。
将硫氰酸铵(12.35g)溶于丙酮(分析纯，120ml)中，搅拌下2分钟并滴加苯甲酰氯(17.3ml)。滴加中，温度由22℃升至38℃，形成白色沉淀。将反应在室温下再搅拌75分钟，然后过滤，用丙酮(20ml)洗涤得到苯甲酰异硫氰酸盐。用40分钟将此盐搅拌下滴加至该胺溶液中。滴加过程中，温度由23℃升至36℃。形成浓膏状沉淀。将反应室温下搅拌16小时，然后过滤收集产物，用水(30ml)洗涤，吸干，然后在60℃下真空干燥。
(f)将N-苯甲酰硫脲(45.0g)悬浮于水(330ml)中。加入氢氧化钠溶液(25％w/v，58ml)，将该搅拌的混合液加热至75-80℃20分钟。
将混合液在冷水浴中冷却至室温，然后用盐酸(～4N，80ml)酸化至pH7-8。
将混合液再在冰浴中冷却内温至5℃，将该冷溶液搅拌15分钟，过滤收集产物，用水(50ml)洗涤，吸干。50℃下真空干燥。
(g)通氮气下，将冰醋酸(112ml)加入到甲磺酸(823ml)中。需要冷却以保持温度在30℃以下。将硫脲(93.5g)加入到28℃下的该溶液中。将得到的溶液冷却至2℃，用30分钟加入N-溴代琥珀酰亚胺(59.14g)的甲磺酸(187ml)溶液。保持温度在2-5℃之间。将得到的溶液在～2℃下搅拌1小时，然后在室温(观测到最高温度30℃)下搅拌22小时。通过HPLC监察反应过程。将反应混合液转移至滴液漏斗中，然后用3.5小时加入到4℃下的25％氢氧化钠溶液(4.675L)中。整个滴加过程中保持温度低于11℃。灰白色固体从反应终止液中沉淀出。将该混合液在7-10℃之间搅拌1.25小时，然后过滤。将固体用水(2×200ml)洗涤，吸干，然后真空干燥(T＝50℃)得到灰白色固体。
(h)通氮气下，将2-氨基-苯并噻唑(5g)溶于22℃下的浓盐酸中。向其中加入氯化铜(II)(1.26g)、氯化亚铜(I)(0.93g)和乙醇(0.32g)。观察到氨基苯并噻唑完全溶解。将该溶液冷却至15℃，用1.75小时通过注射器吸筒将亚硝酸钠(3.9g)的水溶液逐渐加入到反应混合液的液面下。保持温度在13-18℃之间。观察到放出N2。通过HPLC监察反应过程。室温下搅拌1.75小时后，将反应混合液在5分钟内加入到室温下搅拌的水中。形成奶黄色溶液，其中产物在将加入完毕时以油状物析出。将混合液搅拌～60小时。过滤固体，用水(250ml)洗涤，空气干燥，然后真空干燥(T＝55℃)得到橙色固体。
(i)通氮气下，将氯代苯并噻唑(15.0g)混悬于浓氢溴酸(165ml)中，将混合液加热回流7.5小时。将该混合液冷却过夜，过滤收集沉淀的产物，用异丙醇(20ml)洗涤，吸干得到黄棕色粉末，45℃下真空干燥。
(j)将该氢溴酸盐(13.3g)混悬于水(130ml)中，再通氮气下温热至80-90℃。再加入水(20ml)。加入活性炭(1.1g)，在～70℃下搅拌该溶液/混悬液15分钟，然后热过滤得到澄清溶液。
将浓盐酸(18ml)加入到该滤液中，将该混合液通氮气下搅拌过夜。过滤收集固体，用异丙醇(20ml)洗涤，吸干得到黄色粉末，45℃下真空干燥。
通氮气下，将该产物(5.0g)混悬于水(50ml)中，再温热至～70℃。加入活性炭(0.3g)，将混合液搅拌10分钟，然后慢慢过滤得到浅黄色溶液。通氮气下加入浓盐酸(7ml)，搅拌混合液，并使冷却。过滤收集沉淀的产物，用异丙醇(10ml)洗涤，吸干得到浅黄色粉末，45℃下真空干燥。
Claims (9)
1.制备式I化合物的方法：
包括将式II的氯代苯并噻唑化合物
转化成式I化合物。
2.权利要求1的方法，其中式II化合物通过将式III的2-氨基苯并噻唑化合物卤化而制备。
3.权利要求2的方法，其中式III化合物用卤化/氧化剂由式IV的硫脲制备，
4.权利要求3的方法，其中式IV化合物通过式V化合物的水解制备。
5.权利要求4的方法，其中式V化合物通过使式VI的苯胺盐酸盐
与异硫氰酸苯甲酰酯反应制备。
6.权利要求5的方法，其中式VI化合物通过将式VII的硝基乙酰胺氢化，再用HCl在任何适当的溶剂中处理而制备。
7.权利要求6的方法，其中式VII化合物通过将式VIII的乙酰胺硝化而制备。
8.权利要求7的方法，其中式VIII化合物由式IX化合物：例如用乙酸酐或乙酰氯作为溶剂和试剂，或者在二氯甲烷和三乙胺存在下制备。
9.式II化合物
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| SE9700706A SE9700706D0 (sv) | 1997-02-27 | 1997-02-27 | Process for the preparation of benzothiazoline compounds |
| SE97007066 | 1997-02-27 | ||
| SE9700706-6 | 1997-02-27 |
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| EP (1) | EP0970064A1 (zh) |
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| TW200738658A (en) | 2005-08-09 | 2007-10-16 | Astrazeneca Ab | Novel compounds |
| TW200745067A (en) | 2006-03-14 | 2007-12-16 | Astrazeneca Ab | Novel compounds |
| US7270805B1 (en) * | 2006-03-30 | 2007-09-18 | Conopco, Inc. | Skin lightening agents, compositions and methods |
| TW200833670A (en) | 2006-12-20 | 2008-08-16 | Astrazeneca Ab | Novel compounds 569 |
| GB0702458D0 (en) | 2007-02-08 | 2007-03-21 | Astrazeneca Ab | Salts 668 |
| WO2009154557A1 (en) | 2008-06-18 | 2009-12-23 | Astrazeneca Ab | Benzoxazinone derivatives acting as beta2-adrenoreceptor agonist for the treatment of respiratory disorders |
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| EP0529600A1 (de) * | 1991-08-30 | 1993-03-03 | Hoechst Aktiengesellschaft | Verfahren zur Herstellung von 2-Aminobenzthiazolen |
| EP0622362A1 (de) * | 1993-04-28 | 1994-11-02 | Hoechst Aktiengesellschaft | Verfahren zur Herstellung von 2(3H)-Benzothiazolonen |
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| US3832365A (en) * | 1972-03-14 | 1974-08-27 | Hoffmann La Roche | Quinone intermediates for synthesis of 6-hydroxydopamine |
| CH592644A5 (zh) * | 1975-01-22 | 1977-10-31 | Lonza Ag | |
| DE2631163B2 (de) * | 1976-07-10 | 1978-06-29 | Basf Ag, 6700 Ludwigshafen | Verfahren zur Herstellung von 2-Iminobenzothiazolen |
| DE3231885A1 (de) * | 1982-08-27 | 1984-03-01 | Hoechst Ag, 6230 Frankfurt | Verfahren zur herstellung halogensubstituierter 2-aminobenzthiazole |
| DE3507824A1 (de) * | 1985-03-06 | 1986-09-11 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von substituierten styrolen |
| DE3522941A1 (de) * | 1985-06-27 | 1987-01-08 | Hoechst Ag | Verfahren zur herstellung von 2-aminobenzthiazolen |
| JPH0558998A (ja) * | 1991-09-06 | 1993-03-09 | Taisho Pharmaceut Co Ltd | カルバゾール誘導体 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0529600A1 (de) * | 1991-08-30 | 1993-03-03 | Hoechst Aktiengesellschaft | Verfahren zur Herstellung von 2-Aminobenzthiazolen |
| EP0622362A1 (de) * | 1993-04-28 | 1994-11-02 | Hoechst Aktiengesellschaft | Verfahren zur Herstellung von 2(3H)-Benzothiazolonen |
Also Published As
| Publication number | Publication date |
|---|---|
| IS5162A (is) | 1999-08-23 |
| IL131121A0 (en) | 2001-01-28 |
| EP0970064A1 (en) | 2000-01-12 |
| NO994131D0 (no) | 1999-08-26 |
| WO1998038180A1 (en) | 1998-09-03 |
| AU6640798A (en) | 1998-09-18 |
| KR20000075720A (ko) | 2000-12-26 |
| HUP0000766A2 (hu) | 2000-10-28 |
| US6114578A (en) | 2000-09-05 |
| SE9700706D0 (sv) | 1997-02-27 |
| BR9807785A (pt) | 2000-02-22 |
| ID22430A (id) | 1999-10-14 |
| CN1248252A (zh) | 2000-03-22 |
| HUP0000766A3 (en) | 2001-12-28 |
| NO994131L (no) | 1999-08-26 |
| US6118024A (en) | 2000-09-12 |
| US6124468A (en) | 2000-09-26 |
| EE9900373A (et) | 2000-04-17 |
| US6194614B1 (en) | 2001-02-27 |
| US6147219A (en) | 2000-11-14 |
| CA2280010A1 (en) | 1998-09-03 |
| JP2001513770A (ja) | 2001-09-04 |
| NZ336877A (en) | 2001-07-27 |
| AU724616B2 (en) | 2000-09-28 |
| SK111499A3 (en) | 2000-05-16 |
| PL334901A1 (en) | 2000-03-27 |
| TR199902057T2 (xx) | 2000-02-21 |
| US6087508A (en) | 2000-07-11 |
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