NO140102B - PROCEDURE FOR THE PREPARATION OF 4-CHLORO-2-HYDROXYBENZO-THIAZOLE, AND CORRESPONDING PRODUCTS SUBSTITUTED IN 3-POSITION - Google Patents
PROCEDURE FOR THE PREPARATION OF 4-CHLORO-2-HYDROXYBENZO-THIAZOLE, AND CORRESPONDING PRODUCTS SUBSTITUTED IN 3-POSITION Download PDFInfo
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- NO140102B NO140102B NO4587/73A NO458773A NO140102B NO 140102 B NO140102 B NO 140102B NO 4587/73 A NO4587/73 A NO 4587/73A NO 458773 A NO458773 A NO 458773A NO 140102 B NO140102 B NO 140102B
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- chloro
- diazotization
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- formula
- ester
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- 238000000034 method Methods 0.000 title claims description 23
- MBFOZAKOORJAMK-UHFFFAOYSA-N 4-chloro-3h-1,3-benzothiazol-2-one Chemical compound C1=CC=C2SC(O)=NC2=C1Cl MBFOZAKOORJAMK-UHFFFAOYSA-N 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title description 4
- 238000006193 diazotization reaction Methods 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical group 0.000 claims description 12
- 150000003839 salts Chemical group 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- OEQQFQXMCPMEIH-UHFFFAOYSA-N 4-chloro-1,3-benzothiazol-2-amine Chemical compound C1=CC=C2SC(N)=NC2=C1Cl OEQQFQXMCPMEIH-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- -1 trichloroethylene, perchloroethylene, 1,1,1-trichloroethane Chemical class 0.000 claims description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical group 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HYJSGOXICXYZGS-UHFFFAOYSA-N benazolin Chemical compound C1=CC=C2SC(=O)N(CC(=O)O)C2=C1Cl HYJSGOXICXYZGS-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 229960002939 metizoline Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 230000007306 turnover Effects 0.000 description 6
- YZUKKTCDYSIWKJ-UHFFFAOYSA-N (2-chlorophenyl)thiourea Chemical compound NC(=S)NC1=CC=CC=C1Cl YZUKKTCDYSIWKJ-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- JJWANONAOYNRME-UHFFFAOYSA-N 2,4-dichloro-1,3-benzothiazole Chemical compound C1=CC=C2SC(Cl)=NC2=C1Cl JJWANONAOYNRME-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OYBFKJFWVAZRMI-UHFFFAOYSA-N 2-bromo-4-chloro-1,3-benzothiazole Chemical compound ClC1=CC=CC2=C1N=C(Br)S2 OYBFKJFWVAZRMI-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 235000010288 sodium nitrite Nutrition 0.000 description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 2
- DXXACNSRSDYMOR-UHFFFAOYSA-N 4-chloro-1,3-benzothiazol-2-amine;hydron;bromide Chemical compound Br.C1=CC=C2SC(N)=NC2=C1Cl DXXACNSRSDYMOR-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000011928 denatured alcohol Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 description 1
- SXOCCTHWTPGZHT-UHFFFAOYSA-N 2-(2-oxo-1,3-benzothiazol-3-yl)acetic acid Chemical compound C1=CC=C2SC(=O)N(CC(=O)O)C2=C1 SXOCCTHWTPGZHT-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LSRDBSOMEBHGMO-UHFFFAOYSA-N 4-chloro-2-phenyl-1,3-benzothiazole Chemical compound N=1C=2C(Cl)=CC=CC=2SC=1C1=CC=CC=C1 LSRDBSOMEBHGMO-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical class [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- 238000004448 titration 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
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
- A01N57/10—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-oxygen bonds or phosphorus-to-sulfur bonds
- A01N57/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-oxygen bonds or phosphorus-to-sulfur bonds containing heterocyclic radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Forbindelsen 4-klor-2-oksobenzotiazolin-3-yleddiksyre (ofte referert til som benazolin) og estere og salter derav med formelen: The compound 4-chloro-2-oxobenzothiazolin-3-ylacetic acid (often referred to as benazoline) and its esters and salts with the formula:
hvor B er en karboksylgruppe eller et salt eller en ester derav, where B is a carboxyl group or a salt or ester thereof,
er meget anvendt som herbicider. Typiske salter er alkalimetall-salter, f.eks. natrium- eller fortrinnsvis kaliumsalter og amin-salter, f.eks. trietylamin- eller dietanolamin- eller fortrinnsvis dimetylamin-salter. Typiske estere er C1_7-alkylestere, f.eks. metyl-, isopropyl- eller fortrinnsvis etyl-estere. Benazolin og dens estere og salter ble opprinnelig beskrevet i britisk patentskrift nr. 86 2.226. Den fremgangsmåte for dens fremstilling som der er beskrevet omfatter å kondensere 4-klor- (eller 4-brom-) 2- oksobenzotiazolin (alternativt kjent som 4-klor-2-hydroksy-benzotiazol) med en forbindelse som gir eddiksyre-andelen, f.eks. • etyl-bromacetat. En annen fremgangsmåte som er beskrevet i dette patentskrift omfatter å klorere eller bromere 2-okso-benzotiazolin-3- yleddiksyre. Den førstnevnte fremgangsmåte var generelt den kommersielt mest tilfredsstillende, men den led av den omstendighet at det var heller vanskelig å oppnå det nødvendige utgangs- are widely used as herbicides. Typical salts are alkali metal salts, e.g. sodium or preferably potassium salts and amine salts, e.g. triethylamine or diethanolamine or preferably dimethylamine salts. Typical esters are C1-7 alkyl esters, e.g. methyl, isopropyl or preferably ethyl esters. Benazolin and its esters and salts were originally described in British Patent Specification No. 86 2226. The process for its preparation described there comprises condensing 4-chloro- (or 4-bromo-) 2-oxobenzothiazoline (alternatively known as 4-chloro-2-hydroxy-benzothiazole) with a compound which gives the acetic acid moiety, f .ex. • ethyl bromoacetate. Another method described in this patent includes chlorinating or brominating 2-oxo-benzothiazolin-3-ylacetic acid. The former method was generally the most commercially satisfactory, but it suffered from the circumstance that it was rather difficult to achieve the necessary output
materiale med tilstrekkelig høyt utbytte og renhet.. material with sufficiently high yield and purity..
4-klor-2-hydroksybenzotiazol med formelen: 4-chloro-2-hydroxybenzothiazole with the formula:
har blitt beskrevet i et tidsskrift has been described in a journal
av Elderfield og Short (J.Org.Chem. 1953 18 1092) hvor den ble fremstilt ved en fremgangsmåte som medfører diazotering av 2-amino-4-klorbenzotiazol i en blanding av brom og hydrobromsyre for å gi 2-brom-4-klorbenzotiazol, efterfulgt av hydrolyse av denne for å gi det krevde produkt. De erholdte utbytter var 72% i første trinn og 77% i andre trinn, og utgjorde et samlet utbytte på 56% for syntesen av 4-klor-2-hydrobenzotiazol fra 2-amino-4-klorbenzotiazol. Fremgangsmåten var ikke særlig tilfredsstillende for kommersiell produksjon. by Elderfield and Short (J.Org.Chem. 1953 18 1092) where it was prepared by a process involving the diazotization of 2-amino-4-chlorobenzothiazole in a mixture of bromine and hydrobromic acid to give 2-bromo-4-chlorobenzothiazole , followed by hydrolysis thereof to give the required product. The yields obtained were 72% in the first step and 77% in the second step, and amounted to a total yield of 56% for the synthesis of 4-chloro-2-hydrobenzothiazole from 2-amino-4-chlorobenzothiazole. The procedure was not particularly satisfactory for commercial production.
I britisk patentskrift nr. 966.496 ble det beskrevet fremgangsmåter hvorved 2-amino-4-klorbenzotiazol kunne omdannes til 2,4-diklorbenzotiazol med høyt utbytte, og denne kunne derefter omdannes til 4-klor-2-hydroksybenzotiazol med høyt utbytte, og med et ganske tilfredsstillende samlet utbytte for hele omsetningen på minst 80%, Fremgangsmåten omfattet diazotering av 2-amino-4-klorbenzotiazol i saltsyre, efterfulg; av hydrolysering av diklor-forbindelsen. Det ble angitt at omsetningen kunne gjøres letter ved nærvær av et med vann blandbart oppløsningsmidde1, og det blir oppnådd spesielt ønskelige forhold dersom benzen eller toluen er inkludert, og benzen gir de mest tilfredsstillende resultater. Varigheten av diazoteringen var lang, f.eks. over 16 timer. In British patent document no. 966,496, methods were described by which 2-amino-4-chlorobenzothiazole could be converted into 2,4-dichlorobenzothiazole with a high yield, and this could then be converted into 4-chloro-2-hydroxybenzothiazole with a high yield, and with a quite satisfactory total yield for the entire turnover of at least 80%, The procedure comprised diazotization of 2-amino-4-chlorobenzothiazole in hydrochloric acid, followed; of hydrolysis of the dichloro compound. It was stated that the reaction could be facilitated by the presence of a water-miscible solvent1, and particularly desirable conditions are obtained if benzene or toluene is included, and benzene gives the most satisfactory results. The duration of the diazotization was long, e.g. over 16 hours.
En modifikasjon av denne6 fremgangsmåte har blitt anvendt kommersielt i stor utstrekning. Ved denne modifiserte fremgangsmåte blir 2-amino-4-klorbenzotiazol-hydrobromid omdannet til en blanding av 2,4-diklorbenzotiazol og 2-brom-4-klorbenzotiazol, og blandingen blir hydrolysert for å gi 4-klor-2-hydroksybenzo-tiazol. Samlede utbytter på f.eks. 70-80%, som blir oppnådd ved denne fremgangsmåte, er meget bedre enn de tidligere utbytter på 56%, men fremgangsmåten mangler enda mye på å være kommersielt ønsket. Det er således nødvendig med lange omsetningstider for å oppnå disse utbytter. Dessuten er 4-klor-2-hydroksybenzotiazol forurenset med betydelige mengder av uaksep-table biprodukter som må fjernes, vanligvis i et senere trinn ved den samlede fremgangsmåte for å danne benazolin eller dens estere eller salter. Dette medfører et ekstra rensetrinn som er klart tidsforbrukende og kostbart og som det ville være øns-kelig å unngå. Dessuten representerer dannelsen av disse uøns-kede biprodukter et tap av utgangsmateriale. A modification of this method has been used commercially to a large extent. In this modified procedure, 2-amino-4-chlorobenzothiazole hydrobromide is converted to a mixture of 2,4-dichlorobenzothiazole and 2-bromo-4-chlorobenzothiazole, and the mixture is hydrolyzed to give 4-chloro-2-hydroxybenzothiazole. Total dividends on e.g. 70-80%, which is obtained by this method, is much better than the previous yields of 56%, but the method is still far from being commercially desirable. Long turnover times are therefore necessary to achieve these dividends. Also, 4-chloro-2-hydroxybenzothiazole is contaminated with significant amounts of unacceptable by-products that must be removed, usually at a later stage in the overall process to form benazoline or its esters or salts. This entails an additional cleaning step which is clearly time-consuming and expensive and which it would be desirable to avoid. Moreover, the formation of these unwanted by-products represents a loss of starting material.
Hensikten med oppfinnelsen har derfor vært å finne på en metode til å danne 4-klor-2-hydroksybenzotiazol med en høyere renhetsgrad og med bedre utbytte og/eller kortere omsetningstid enn det som tidligere har vært oppnåelig i kommersiell skala, som et mellomprodukt ved fremstillingen av benazolin og dens estere og salter. The purpose of the invention has therefore been to come up with a method to form 4-chloro-2-hydroxybenzothiazole with a higher degree of purity and with a better yield and/or shorter turnover time than what has previously been achievable on a commercial scale, as an intermediate product in the preparation of benazoline and its esters and salts.
Det har nå overraskende blitt funnet at det i virkeligheten kan oppnås forbedret renhet og forbedret utbytte og/eller kortere omsetningstid ved anvendelse ar spesielle oppløsningsmidler som ikke er blandbare med vann, ved diazoteringen. Det er således nå mulig å danne benazolin og dens estere og salter med en slik høy renhetsgrad at hvilke som helst forurensninger som er til-stede er i så små mengder og er slik at det ikke lenger er vesen-tlig å utføre ovennevnte rensetrinn. Det er dessuten nå mulig å oppnå utbytte som ved samme omsetningstider som ble anvendt ved de tidligere fremgangsmåter, er bedre enn de som tidligere var oppnåelig, eller å oppnå et tilfredsstillende utbytte ved mye kortere omsetningstider enn det kunne anvendes tidligere for å oppnå tilfredsstillende utbytte, og/eller nedsette tapet av utgangsmateriale . It has now surprisingly been found that improved purity and improved yield and/or shorter turnover time can in fact be achieved by using special solvents which are not miscible with water during the diazotization. It is thus now possible to form benazoline and its esters and salts with such a high degree of purity that whatever impurities are present are in such small quantities that it is no longer essential to carry out the above-mentioned purification step. It is also now possible to achieve yields which, with the same turnover times used in the previous methods, are better than those previously achievable, or to achieve a satisfactory yield with much shorter turnover times than could be used previously to achieve satisfactory yields, and/or reduce the loss of starting material.
I henhold til oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av 4-klor-2-hydroksybenzotiazol ved å diazotere 2-amino-4-klorbenzotiazol-hydrohalogenid med formelen: According to the invention, a method is provided for the production of 4-chloro-2-hydroxybenzothiazole by diazotizing 2-amino-4-chlorobenzothiazole hydrohalide with the formula:
og hydrolysere produktet. Fremgangsmåten karakteriseres ved at diazoteringen blir utført i nærvær av et halogenert alifatisk hydrokarbon i hvilket hovedproduktene fra diazoteringsreaksjonen er oppløselige i en utstrekning på minst 10% vekt/volum ved 20°C. Hovedproduktet fra diazoteringsreaksjonen er 2-halogen-4-klor-benzotiazoler. Når 2-amino-4-klorbenzotiazolen er i den foretrukne form som hydrobromid, er hovedproduktet 2-brom-4-klor-benzotiazol. 2,4-diklorbenzotiazol blir også vanligvis dannet. and hydrolyzing the product. The method is characterized by the fact that the diazotization is carried out in the presence of a halogenated aliphatic hydrocarbon in which the main products from the diazotization reaction are soluble to an extent of at least 10% weight/volume at 20°C. The main product from the diazotization reaction is 2-halo-4-chloro-benzothiazoles. When the 2-amino-4-chlorobenzothiazole is in the preferred form as the hydrobromide, the major product is 2-bromo-4-chlorobenzothiazole. 2,4-Dichlorobenzothiazole is also usually formed.
Foretrukne halogenerte alifatiske hydrokarboner for anvendelse ved oppfinnelsen, er klorerte hydrokarboner, f.eks. etylendiklorid som er spesielt foretrukket, metylenklorid, kloroform, karbontetraklorid, tetrakloretan, trikloretylen, perkloretylen, 1,2-diklorpropan og 1,1,1-trikloretan. Andre halogenerte hydrokarboner innbefatter bromholdige hydrokarboner, f.eks. etylendibromid. Det foretrekkes at oppløsningsmidlet er et som har et kokepunkt på mellom 40-90°C, fortrinnsvis 60-90°C. Preferred halogenated aliphatic hydrocarbons for use in the invention are chlorinated hydrocarbons, e.g. ethylene dichloride being particularly preferred, methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane, trichloroethylene, perchloroethylene, 1,2-dichloropropane and 1,1,1-trichloroethane. Other halogenated hydrocarbons include brominated hydrocarbons, e.g. ethylene dibromide. It is preferred that the solvent is one which has a boiling point of between 40-90°C, preferably 60-90°C.
Diazoteringsreaksjonen blir fortrinnsvis utført ved en temperatur under 30°C, f.eks. ved 20-25°c, vanligvis i saltsyre som har en konsentrasjon som er høyere enn IN, fortrinnsvis mellom 5,5 og 6,5N. Omsetningen blir også fortrinnsvis utført i nærvær av eddiksyre. Mengden med organisk oppløsningsmiddel er ikke kritisk, men den er fortrinnsvis minst 20 volum% av den samlede reaksjons-blanding, f.eks. 25-60 volum%. The diazotization reaction is preferably carried out at a temperature below 30°C, e.g. at 20-25°c, usually in hydrochloric acid having a concentration higher than IN, preferably between 5.5 and 6.5N. The reaction is also preferably carried out in the presence of acetic acid. The amount of organic solvent is not critical, but it is preferably at least 20% by volume of the overall reaction mixture, e.g. 25-60% by volume.
Diazoteringsreaksjonen blir vanligvis foretatt i minst 2, men The diazotization reaction is usually carried out for at least 2 but
ofte mindre enn 7 eller endog 5 timer. Den holder vanligvis på inntil det i det vesentlige ikké er noe fast materiale tilbake suspendert i den vandige fase. Den organiske fase blir så fra-skilt og den blir fortrinnsvis inndampet til tørrhet før den blir hydrolysert. Hydrolysen kan utføres ved å omsette med en mineralsyre, f.eks. konsentrert saltsyre, fortrinnsvis i nær- often less than 7 or even 5 hours. It usually continues until there is essentially no solid material left suspended in the aqueous phase. The organic phase is then separated and it is preferably evaporated to dryness before being hydrolysed. The hydrolysis can be carried out by reacting with a mineral acid, e.g. concentrated hydrochloric acid, preferably in close
vær av et med vann blandbart oppløsningsmiddel, f.eks. metanol, etanol eller industriell metylert sprit. Hydrolysen blir passende utført ved en temperatur på 50-150°C og fortrinnsvis under tilbake løpskjøling. Produktet kan isoleres ved konvensjonelle be of a water-miscible solvent, e.g. methanol, ethanol or industrial methylated spirits. The hydrolysis is conveniently carried out at a temperature of 50-150°C and preferably under reflux. The product can be isolated by conventional
midler, og kan så om ønskes omdannes til benazolin, f.eks. ved den fremgangsmåte som er beskrevet i britisk patentskrift nr. 966.496. Fremgangsmåten beskrevet i dette patentskrift, som også benyttes ifølge foreliggende oppfinnelse, omfatter å kondensere 4-klor-2-hydroksybenzotiazolen med en forbindelse valgt fra ACH2B eller RjOCI^CN hvor A er et halogenatom, B er en karboksylgruppe eller et salt, en ester, et amid eller et nitril derav, og ^ er en alkylsulfonyl- eller en aromatisk sulfonylgruppe, i nærvær av et alkalisk kondenseringsmiddel, for å danne en forbindelse med formel I agents, and can then, if desired, be converted into benazoline, e.g. by the method described in British patent document no. 966,496. The method described in this patent document, which is also used according to the present invention, comprises condensing the 4-chloro-2-hydroxybenzothiazole with a compound selected from ACH2B or RjOCI^CN where A is a halogen atom, B is a carboxyl group or a salt, an ester, an amide or a nitrile thereof, and ^ is an alkylsulfonyl or an aromatic sulfonyl group, in the presence of an alkaline condensing agent, to form a compound of formula I
og eventuelt omdanne B for å danne en ønsket gruppe valgt fra karboksyl eller salter eller estere derav, slik som dem som er beskrevet ovenfor. and optionally converting B to form a desired group selected from carboxyl or salts or esters thereof, such as those described above.
I tillegg til å gi fordeler med høye utbytter og raskere reak-sjonstider enn det som har vært mulig ved anvendelse av oppløs-ningsmidler som tidligere er beskrevet, har anvendelsen av de halogenerte alifatiske hydrokarboner som oppløsningsmidler ved oppfinnelsen en ytterligere viktig fordel. Det er at 2-amino-4-klorbenzotiazol-hydrohalogenidet kan dannes ved å cyklisere N-2-klorfenyltiourinstoff i det samme organiske oppløsnings-middel -system som det som anvendes ved den efterfølgende dia-zoteringsreaks jon , med det resultat at 2-amino-4-klorbenzotiazol-hydrohalogenidet kan fremstilles og omsettes i det samme organiske oppløsningsmiddel-system uten at det er nødvendig å isolere det før diazoteringstrinnet. Som et resultat av at man unngår å separere forbindelsen før diazoteringen, blir det totale utbytte og den totale tid som kreves for å utføre fremstilligen av bena-zoling fra N-2-klorfenyltiourinstoff enda ytterligere forbedret. In addition to providing advantages with high yields and faster reaction times than has been possible using solvents previously described, the use of the halogenated aliphatic hydrocarbons as solvents in the invention has a further important advantage. It is that the 2-amino-4-chlorobenzothiazole hydrohalide can be formed by cyclizing N-2-chlorophenylthiourea in the same organic solvent system as that used in the subsequent diazotization reaction, with the result that 2-amino The -4-chlorobenzothiazole hydrohalide can be prepared and reacted in the same organic solvent system without the need to isolate it prior to the diazotization step. As a result of avoiding separating the compound prior to diazotization, the overall yield and total time required to carry out the preparation of benazoling from N-2-chlorophenylthiourea is even further improved.
Foretrukne forhold for å cyklisere N-2-klorfenyltiourinstoff Preferred conditions for cyclizing N-2-chlorophenylthiourea
for å danne 2-amino-4-klorbenzotiazol-hydrohalogenid omfatter å omsette tiourinstoffet med en kilde for klor- eller bromatomer i to form 2-amino-4-chlorobenzothiazole hydrohalide involves reacting the thiourea with a source of chlorine or bromine atoms in
et halogenert alifatisk hydrokarbon-oppløsningsmiddel, slik som dem som er omtalt ovenfor. Den foretrukne kilde for kloratomer er sulfurylklorid, mens den foretrukne kilde for bromatomer er brom. Reaksjonstemperaturen er fortrinnsvis 30 til 100°C. a halogenated aliphatic hydrocarbon solvent, such as those discussed above. The preferred source for chlorine atoms is sulfuryl chloride, while the preferred source for bromine atoms is bromine. The reaction temperature is preferably 30 to 100°C.
Oppfinnelsen blir belyst i de følgende eksempler i hvilke "pro-senter" er "vektprosenter". Utbyttene er av ren substans, slik at de tilsynelatende utbytter (av urenset materiale) er noe høyere enn vist. The invention is illustrated in the following examples in which "per cent" is "weight percentage". The yields are of pure substance, so that the apparent yields (of impure material) are somewhat higher than shown.
EKSEMPEL 1 EXAMPLE 1
2-amino-4-klorbenzotiazol-hydrobromid (79 g) og etylendiklorid (300 ml) ble satt til en blanding av konsentrert saltsyre 2-Amino-4-chlorobenzothiazole hydrobromide (79 g) and ethylene dichloride (300 ml) were added to a mixture of concentrated hydrochloric acid
(114 ml), iseddik (78 ml) og vann (114 ml) i en 1 liters kolbe. Hele blandingen ble rørt og holdt ved 20-25 oC med vannavkjøling mens en oppløsning av natriumnitritt (41 g) i vann (67 ml) ble tilsatt ved konstant hastighet i løpet av 2 timer. Blandingen ble rørt i ytterligere 2 timer. Vann (100 ml) ble tilsatt og det nedre sjikt ble fraseparert og inndampet til tørrhet. Resten ble oppløst i varm industriell metylert sprit og oppløsningen ble holdt ved en livlig tilbakeløpskjøling og rørt mens det i løpet av 2 1/2 timer ble tilsatt konsentrert saltsyre (182 ml) . Rør-ing og oppvarming ble fortsatt i ytterligere 2 timer. Blandingen ble så avkjølt under 30°C og det ble tilsatt vann (182 ml) . (114 ml), glacial acetic acid (78 ml) and water (114 ml) in a 1 liter flask. The entire mixture was stirred and maintained at 20-25°C with water cooling while a solution of sodium nitrite (41 g) in water (67 ml) was added at a constant rate over 2 hours. The mixture was stirred for an additional 2 hours. Water (100 mL) was added and the lower layer was separated and evaporated to dryness. The residue was dissolved in hot industrial methylated spirit and the solution was kept under vigorous reflux and stirred while concentrated hydrochloric acid (182 ml) was added over 2 1/2 hours. Stirring and heating were continued for a further 2 hours. The mixture was then cooled below 30°C and water (182 ml) was added.
Det faste.stoff ble samlet, vasket fri for syre og tørret i. vakuum ved 60°C. Det således erholdte 4-klor-2-hydroksybenzo-tiazol viste ved titrering med tetrabutylammonium-hydroksyd i aceton å ha en renhet på 95%. Utbytte = 83%. The solid was collected, washed free of acid and dried in vacuum at 60°C. The 4-chloro-2-hydroxybenzothiazole thus obtained was shown by titration with tetrabutylammonium hydroxide in acetone to have a purity of 95%. Yield = 83%.
EKSEMPEL 2 EXAMPLE 2
Eksempel 1 ble gjentatt ved å erstatte etylendikloridet med et ekvivalent volum med metylenklorid. Det viste seg at det således erholdte 4-klor-2-hydroksybenzotiazol hadde en renhet på 95%. Utbytte = 87%. Example 1 was repeated by replacing the ethylene dichloride with an equivalent volume of methylene chloride. It turned out that the 4-chloro-2-hydroxybenzothiazole thus obtained had a purity of 95%. Yield = 87%.
EKSEMPEL 3 EXAMPLE 3
N-2-klorfenyltiourinstoff (65 g) ble satt til en blanding av iseddik (48 ml) og etylendiklorid (195 ml) i en 1 liters kolbe. Blandingen ble rørt krafig og det ble tilsatt brom (61,5 g) i N-2-chlorophenylthiourea (65 g) was added to a mixture of glacial acetic acid (48 ml) and ethylene dichloride (195 ml) in a 1 liter flask. The mixture was stirred vigorously and bromine (61.5 g) was added i
en porsjon. Da temperaturen hadde holdt opp med å stige, ble a portion. When the temperature had stopped rising,
blandingen kokt under tilbakeløpskjøling i 4 timer. Den ble så avkjølt til mellom 15 og 20°C, og det ble tilsatt en blanding av konsentrert saltsyre (115 ml) og vann (115 ml). Temperaturen ble holdt ved 20 til 25°C mens det i løpet av 2 timer ble tilsatt en oppløsning av natriumnitritt (41 g) i vann. Forsøket ble så fortsatt som i eksempel 1, for å danne 4-klor-2-hydroksy-benzotiazol som viste seg å ha en renhet på 95%. Utbytte = 83%. the mixture was boiled under reflux for 4 hours. It was then cooled to between 15 and 20°C and a mixture of concentrated hydrochloric acid (115 ml) and water (115 ml) was added. The temperature was maintained at 20 to 25°C while a solution of sodium nitrite (41 g) in water was added over 2 hours. The experiment was then continued as in Example 1, to form 4-chloro-2-hydroxy-benzothiazole which was found to have a purity of 95%. Yield = 83%.
EKSEMPEL 4- 9 EXAMPLES 4-9
Eksempel 1 ble gjentatt ved å erstatte etylendikloridet med efter tur ekvivalente volumer av kloroform (eksempel 4), tetra-kloretylen (eksempel 5), 1,1,1-trikloretan (eksempel 6), 1,2-diklorpropan (eksempel 7), etylendibromid (eksempel 8), og det dobbelte av det ekvivalente volum med karbontetraklorid (eksempel 9). Det i hvert av disse eksempler erholdte 4-klor-2-hydroksy-benzotiazol hadde en renhet i området 93 til 95%, og ga utbytter på henholdsvis 73%, 66%, 65%, 72%, 61% og 71%. Det kan oppnås høyere utbytter ved å utføre diazoteringen i en lengre tids-periode . Example 1 was repeated by replacing the ethylene dichloride with successively equivalent volumes of chloroform (Example 4), tetrachloroethylene (Example 5), 1,1,1-trichloroethane (Example 6), 1,2-dichloropropane (Example 7), ethylene dibromide (Example 8), and twice the equivalent volume of carbon tetrachloride (Example 9). The 4-chloro-2-hydroxy-benzothiazole obtained in each of these examples had a purity in the range of 93 to 95%, and gave yields of 73%, 66%, 65%, 72%, 61% and 71% respectively. Higher yields can be achieved by carrying out the diazotization for a longer period of time.
EKSEMPEL 10 EXAMPLE 10
En oppslemning av N-2-klorfenyltiourinstoff (65 g) i en blanding av iseddik (48 ml) og etylendiklorid (36 ml) ble sakte satt til en rørt oppløsning av brom (61,5 g) i etylendiklorid (9 7 ml) mens temperaturen ble holdt under 55°C med vannavkjøling. Blandingen ble omhyggelig oppvarmet til tilbakeløpog holdt ved den temperaturen i 4 timer. Den ble så avkjølt til mellom 15 og 20°C, og forsøket fortsatte som i eksempel 3 for å danne 4-klor-2-hydroksybenzotiazol som har en renhet på 95%. Utbytte = 84%. A slurry of N-2-chlorophenylthiourea (65 g) in a mixture of glacial acetic acid (48 mL) and ethylene dichloride (36 mL) was slowly added to a stirred solution of bromine (61.5 g) in ethylene dichloride (97 mL) while the temperature was kept below 55°C with water cooling. The mixture was carefully heated to reflux and held at that temperature for 4 hours. It was then cooled to between 15 and 20°C and the experiment continued as in Example 3 to form 4-chloro-2-hydroxybenzothiazole having a purity of 95%. Yield = 84%.
EKSEMPEL 11 EXAMPLE 11
4-klor-2-hydroksybenzotiazol (185,5 g) erholdt fra eksempel 1 ble blandet med vannfritt kaliumkarbonat (138,5 g) ', natriumjodid (5 g) og metyletylketon (1 L). Blandingen ble rørt og tilbake-løpsbehandlet under tilsetning av etylkloracetat (135 g). Blan-dingen ble behandlet under tilbakeløp i ytterligere 4 timer, det ble tilsatt vann (280 ml) og blandingen ble avkjølt til 70°C. Det vandige sjikt ble kassert og det organiske sjikt ble inndampet for å gi en olje som ble oppløst i tilbakeløpende indus- 4-Chloro-2-hydroxybenzothiazole (185.5 g) obtained from Example 1 was mixed with anhydrous potassium carbonate (138.5 g), sodium iodide (5 g) and methyl ethyl ketone (1 L). The mixture was stirred and refluxed with the addition of ethyl chloroacetate (135 g). The mixture was refluxed for a further 4 hours, water (280 ml) was added and the mixture was cooled to 70°C. The aqueous layer was discarded and the organic layer was evaporated to give an oil which was dissolved in refluxing indus-
triell metylert sprit (200 ml). Det ble tilsatt vandig natriumhydroksyd (2,5N, 440 ml) og tilbakeløpsbehandlingen fortsatt i 1/2 time. Oppløsningen ble så avkjølt og surgjort til en pH på 1 til 2 med saltsyre. Det resulterende produkt ble frafiltrert, vasket med vann og tørret for å gi benazolin, s.p. 185-8°C. trial methylated spirit (200 ml). Aqueous sodium hydroxide (2.5N, 440 mL) was added and refluxing continued for 1/2 hour. The solution was then cooled and acidified to a pH of 1 to 2 with hydrochloric acid. The resulting product was filtered off, washed with water and dried to give benazoline, m.p. 185-8°C.
EKSEMPEL 12 EXAMPLE 12
på en lignende måte som den som er beskrevet i eksempel 11, ble benazolin efter tur erholdt fra 4-klor-2-hydroksybenzotiazol fremstilt som i eksemplene 2 til 9. in a similar manner to that described in Example 11, benazoline was obtained in turn from 4-chloro-2-hydroxybenzothiazole prepared as in Examples 2 to 9.
SAMMENLIGNENDE EKSEMPEL COMPARATIVE EXAMPLE
Eksempel 1 ble gjentatt bortsett fra at det ble anvendt benzen Example 1 was repeated except that benzene was used
i stedet for etylendiklorid, at natriumnitritt-tilsetningen tok 5 timer i stedet for 2 og at røringen ble fortsatt i 16 timer i stedet for 2 timer. 4-klor-2-hydroksybenzotiazolen ble erholdt i et utbytte på 77% og den var bare 87% ren og var forurenset blant annet med 8,3% 4-klor-2-fenylbenzotiazol som var vanskelig å fraskille i dette trinn. Da produktet ble omdannet til benazolin som beskrevet i eksempel 11, var det nødvendig å fjerne denne forurensning ved å utføre en ekstrahering med metylenklorid efter hydrolysen med natriumhydroksyd. instead of ethylene dichloride, that the sodium nitrite addition took 5 hours instead of 2 and that stirring was continued for 16 hours instead of 2 hours. The 4-chloro-2-hydroxybenzothiazole was obtained in a yield of 77% and it was only 87% pure and was contaminated, among other things, with 8.3% 4-chloro-2-phenylbenzothiazole which was difficult to separate in this step. When the product was converted to benazoline as described in example 11, it was necessary to remove this contamination by performing an extraction with methylene chloride after the hydrolysis with sodium hydroxide.
Claims (4)
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GB5568472A GB1397089A (en) | 1972-12-01 | 1972-12-01 | Preparation of benzothiazoles |
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- 1973-11-23 IL IL43690A patent/IL43690A/en unknown
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- 1973-11-27 CS CS8171A patent/CS175468B2/cs unknown
- 1973-11-28 AT AT997673A patent/AT331240B/en not_active IP Right Cessation
- 1973-11-28 AU AU63005/73A patent/AU473940B2/en not_active Expired
- 1973-11-29 FR FR7342591A patent/FR2208907B1/fr not_active Expired
- 1973-11-29 PL PL1973166924A patent/PL89548B1/pl unknown
- 1973-11-29 CA CA186,985A patent/CA1023749A/en not_active Expired
- 1973-11-29 IT IT7353972A patent/IT1000168B/en active
- 1973-11-30 FI FI3690/73A patent/FI56004C/en active
- 1973-11-30 NO NO4587/73A patent/NO140102C/en unknown
- 1973-11-30 CH CH1687473A patent/CH587259A5/xx not_active IP Right Cessation
- 1973-11-30 LU LU68895A patent/LU68895A1/xx unknown
- 1973-11-30 SE SE7316243A patent/SE415098B/en unknown
- 1973-11-30 ES ES420999A patent/ES420999A1/en not_active Expired
- 1973-12-01 JP JP48134828A patent/JPS5824437B2/en not_active Expired
- 1973-12-03 DE DE2360202A patent/DE2360202C2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
SE415098B (en) | 1980-09-08 |
US3888871A (en) | 1975-06-10 |
IL43690A0 (en) | 1974-03-14 |
AU473940B2 (en) | 1976-07-08 |
IT1000168B (en) | 1976-03-30 |
FI56004C (en) | 1979-11-12 |
NO140102C (en) | 1979-07-11 |
GB1397089A (en) | 1975-06-11 |
BE807856A (en) | 1974-05-27 |
JPS5824437B2 (en) | 1983-05-20 |
JPS4986364A (en) | 1974-08-19 |
IE39320B1 (en) | 1978-09-13 |
CA1023749A (en) | 1978-01-03 |
IL43690A (en) | 1976-02-29 |
IE39320L (en) | 1974-06-01 |
ATA997673A (en) | 1975-11-15 |
DE2360202A1 (en) | 1974-06-06 |
AT331240B (en) | 1976-08-10 |
CH587259A5 (en) | 1977-04-29 |
DE2360202C2 (en) | 1983-11-24 |
ES420999A1 (en) | 1976-04-01 |
ZA738920B (en) | 1974-10-30 |
CS175468B2 (en) | 1977-05-31 |
LU68895A1 (en) | 1974-02-11 |
NL7315862A (en) | 1974-06-05 |
FI56004B (en) | 1979-07-31 |
PL89548B1 (en) | 1976-11-30 |
FR2208907A1 (en) | 1974-06-28 |
FR2208907B1 (en) | 1976-10-08 |
AU6300573A (en) | 1975-05-29 |
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