DK148476B - ANALOGY PROCEDURE FOR PREPARING METHYL-6-N-PROPOXYBENZOTHIAZOL-2-CARBAMATE - Google Patents
ANALOGY PROCEDURE FOR PREPARING METHYL-6-N-PROPOXYBENZOTHIAZOL-2-CARBAMATE Download PDFInfo
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- 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
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Description
148476148476
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af methyl-6-n-propoxybenzothiazol-2-carbamat med formlen IThe present invention relates to an analogous process for the preparation of methyl 6-n-propoxybenzothiazole-2-carbamate of formula I
| *^>nh-cooch3 I| * ^> nh-cooch3 I
der er en hidtil ukendt forbindelse med anthelminthisk virkning.there is a novel compound with anthelminthic effect.
Fra DE-offentliggørelsesskrift nr. 24 33 982 kendes beslægtede forbindelser, bl.a. den tilsvarende ethylester: ethyl-6-n-propoxy-benzothiazol-2-carbamat.Related publication DE 24 33 982 discloses related compounds, including the corresponding ethyl ester: ethyl 6-n-propoxy-benzothiazole-2-carbamate.
148476 2148476 2
Det har imidlertid overraskende vist sig, at forbindelsen med formlen I er væsentligt mere effektiv til bekæmpelse af Para-scaris equorum end den kendte ethylester. Dette vil fremgå af de nedenfor refererede forsøg.However, it has surprisingly been found that the compound of formula I is substantially more effective in controlling Para-scaris equorum than the known ethyl ester. This will be evident from the experiments referred to below.
Ved fremgangsmåden ifølge opfindelsen, der er ejendommelig ved det i kravets kendetegnende del angivne, fremstilles forbindelsen med formlen.I således efter en af de nedenfor beskrevne analogifremgangsmåder (a) - (e) : (a) vv\ L v C-NHp +Z COOCH, -)In the process according to the invention, which is characterized by the characterizing part of the claim, the compound of the formula is prepared. Thus, according to one of the analogous processes described (a) - (e) below: (a) vv \ L v C-NHp + Z COOCH, -)
n-C-,H70—L IL Xn-C-, H70-L IL X
II IIIII III
hvori Z^ betegner en reaktionsdygtig gruppe, såsom halogen eller en let fraspaltelig carbonholdig gruppe.wherein Z 2 represents a reactive group such as halogen or an easily leaving carbonaceous group.
Fremgangsmåden udføres fortrinsvis i et basisk opløsningsmiddel, såsom pyridin, ved en temperatur mellem 0°C og stuetemperatur. Reaktanterne bringes sammen i ækvimolære mængder, hvorefter car-bonatet langsomt tilsættes over et længere tidsrum. Efter at blandingen er fuldendt, omrøres reaktionsblandingen i en længere periode, fortrinsvis natten over, og det ønskede produkt isoleres herefter efter metoder, der er velkendte inden for teknikken. Rensningen udføres fortrinsvis ved omkrystallisation med passende alkoholer. Skønt pyridin er.det foretrukne opløsningsmiddel til denne omsætning, kan andre opløsningsmidler, såsom acetonitril og trimethylamin og blandinger af acetonitril og pyridin, også anvendes.The process is preferably carried out in a basic solvent, such as pyridine, at a temperature between 0 ° C and room temperature. The reactants are brought together in equimolar amounts and then the carbonate is slowly added over a long period of time. After the mixture is complete, the reaction mixture is stirred for a longer period, preferably overnight, and the desired product is then isolated by methods well known in the art. The purification is preferably carried out by recrystallization with appropriate alcohols. Although pyridine is the preferred solvent for this reaction, other solvents such as acetonitrile and trimethylamine and mixtures of acetonitrile and pyridine can also be used.
(b) yV"2 < *(b) yV "2 <*
+ , J>N-d0CH., -:-* I+, J> N-d0CH., -: - * I
n-C,H70—L i Jn-C, H70-L in J
IV VIV V
2 3 Z og Z betegner labile grupper såsom -SCH-^-OCH^ eller-N(CH3)2/ der kan fjernes sammen med et hydrogenatom.Z and Z represent labile groups such as -SCH - ^ - OCH ^ or -N (CH3) 2 which can be removed together with a hydrogen atom.
Reaktionen udføres fortrinsvis ved at omrøre og opvarme reak- 3 148476 tanterne ved tilbagesvalingstemperatur i et passende opløsningsmiddel såsom ethanol. Reaktionsblandingen holdes i en inert atmosfære, fortrinsvis nitrogen.The reaction is preferably carried out by stirring and heating the reactants at reflux temperature in a suitable solvent such as ethanol. The reaction mixture is kept in an inert atmosphere, preferably nitrogen.
(c)(C)
SS
_ HH-^HH-COOCH, I intramolekylær n-CnHyO—L O -> kondensation_ HH- ^ HH-COOCH, In intramolecular n-CnHyO-L O -> condensation
VIWE
Også denne fremgangsmåde udføres ved standardmetoder. En foretrukken fremgangsmåde består i at opvarme thiourinstofforbindelsen i et passende opløsningsmiddel, såsom chloroform, ved tilbagesvalingstempe-ratur i nærværelse af brom. I stedet for opvarmning kan man også anvende bestråling af reaktionsblandingen. Isolering af produktet udføres også ved standardmetoder. Blandingen bringes op på stuetemperatur, vaskes med vandig Na2C03 og vandig NaCl og tørres over natriumsulfat. Opløsningsmidlet fjernes ved afdampning, hvorved man opnår det ønskede produkt.This method is also performed by standard methods. A preferred process consists of heating the thiourea compound in a suitable solvent, such as chloroform, at reflux temperature in the presence of bromine. Instead of heating, irradiation of the reaction mixture can also be used. Isolation of the product is also carried out by standard methods. The mixture is brought to room temperature, washed with aqueous Na 2 CO 3 and aqueous NaCl and dried over sodium sulfate. The solvent is removed by evaporation to give the desired product.
Intramolekylær kondensation kan også udføres ved at tilsætte en vandig opløsning af kaliumferricyanid til en omrørt og svagt opvarmet blanding af thiourinstofforbindelsen, natriumhydroxid og vand. Efter at tilsætningen af kaliumferricyanid er tilendebragt, tilsættes kaliumcarbonat, og omrøringen fortsættes. Herefter eks-traheres reaktionsblandingen med et passende opløsningsmiddel, fortrinsvis chloroform. Ekstrakterne tørres over natriumsulfat, og opløsningsmidlet afdampes til opnåelse af det ønskede produkt.Intramolecular condensation can also be carried out by adding an aqueous solution of potassium ferricyanide to a stirred and slightly heated mixture of the thiourea compound, sodium hydroxide and water. After the addition of potassium ferricyanide is complete, potassium carbonate is added and stirring is continued. Then, the reaction mixture is extracted with a suitable solvent, preferably chloroform. The extracts are dried over sodium sulfate and the solvent is evaporated to give the desired product.
(d) f^^V'^NH-COOCH, η'ΡΓ°Ρ^-^-> 1 // f.eks. med n-C.3H.7Br(d) f ^^ V '^ NH-COOCH, η'ΡΓ ° Ρ ^ - ^ -> 1 // e.g. with n-C.3H.7 Br
Etherificeringen udføres fortrinsvis ved at opvarme en blanding af methyl-6-hydroxybenzothiazol-2-carbamat,vandfrit kaliumcarbonat, n-propylbromid og et passende opløsningsmiddel, f.eks. acetone, ved tilbagesvalingstemperatur. Opløsningsmidlet fjernes ved destillation, 4 148476 resten tages op i vand og filtreres. Det rene produkt opnås ved om-krystallisation med ethanol..The etherification is preferably carried out by heating a mixture of methyl 6-hydroxybenzothiazole-2-carbamate, anhydrous potassium carbonate, n-propyl bromide and a suitable solvent, e.g. acetone, at reflux temperature. The solvent is removed by distillation, the residue is taken up in water and filtered. The pure product is obtained by recrystallization with ethanol.
(e) En yderligere fremgangsmåde består i at omsætte det tilsvarende benzothiazol-2-isocyanat med formlen(e) A further process consists of reacting the corresponding benzothiazole-2-isocyanate of the formula
.C-N=C=0 X.C-N = C = 0 X
n-C3U70-\^jK.^ eller et reaktionsdygtigt derivat heraf med methanol. Reaktionen udføres fortrinsvis ved at omrøre en blanding af de vandfri reaktanter i et opløsningsmiddel, f.eks. et overskud af methanol eller benzen, ved stuetemperatur. Foretrukne reaktionsdygtige derivater af forbindelsen med formlen X er sådanne, hvor gruppen -N=C=0 er erstattet af gruppen -NH-§-halogen.or a reactive derivative thereof with methanol. The reaction is preferably carried out by stirring a mixture of the anhydrous reactants in a solvent, e.g. an excess of methanol or benzene, at room temperature. Preferred reactive derivatives of the compound of formula X are those wherein the group -N = C = 0 is replaced by the group -NH-§-halogen.
Udgangsmaterialerne til fremgangsmåderne (a) - (e) kan opnås ved metoder, der er. velkendte inden for teknikken. 2-Amino-benzo-thiazol med formlen II kan opnås ved cyclisering af det tilsvarende thiourinstof ved opvarmning af thiourinstoffet med flydende brom i kogende chloroform eller chlorbenzen. Thiourinstoffet fremstilles ved at kondensere den tilsvarende anilin med et alkalimetalisothio-- cyanat: · Y BrCN NH-C-NH2 n-C3H70 — (Hydrolyse) n_SH70“^^J*The starting materials for processes (a) - (e) can be obtained by methods which are. well known in the art. 2-Amino-benzothiazole of formula II can be obtained by cyclization of the corresponding thiourea by heating the thiourea with liquid bromine in boiling chloroform or chlorobenzene. The thiourea is prepared by condensing the corresponding aniline with an alkali metal isothiocyanate: · Y BrCN NH-C-NH2 n-C3H70 - (Hydrolysis) n_SH70
VIII IXVIII IX
Br~/CHC1-.Br ~ / CHC1-.
-éf-> 5^||/SN:-nh2-if-> 5 ^ || / SN: -nh2
IIII
Udgangsforbindelsen med formlen VI kan opnås efter følgende reaktionsskema:.The starting compound of formula VI can be obtained according to the following reaction scheme:
5 U8476 + SCN-COOCH,-» V1, n-C3H70—U8476 + SCN-COOCH, - »V1, n-C3H70—
Udgangsforbindelserne med formlerne IV og V er velkendte af fagmanden.The starting compounds of formulas IV and V are well known to those skilled in the art.
Methyl-6-n-propoxybenzothiazol-2-carbamat er velegnet til bekæmpelse af nematoder, dvs. til behandling af mennesker og dyr, der antages at være, eller som er inficeret i mavetarmkanalen med endo-parasitter, ved til værtsdyret at give en prophylaktisk og/eller terapeutisk mængde af forbindelsen, der forbinder en høj grad af an-thelmintisk virkning mod parasitterne med en lav toxicitet over for værtsorganismen. Forbindelsen er særlig enestående og derfor meget værdifuld, da den er virksom over for de tre mest forekommende nematoder, der angriber pattedyr, idet forbindelsen udviser en effektiv anthelmintisk virkning over for ormetyper, såsom Ascaridia (f.eks. rundorm), Ancylostoma (f.eks. hageorm) og Trichuris (f.eks. piskeorm). Den anthelmintiske virkning af forbindelserne kan efterprøves ved standard- og velkendte metoder, såsom den modificerede McMaster ægtællingsteknik, således som beskrevet af H.B.Whitlock og H.McL. Gordon? J.Council Scientific Industrial Research (Australia) 12, s. 50, 1939 og H.B.Whitlock J. Council Scientific Research (Australia) 21, s. 177, 1948. Ved disse (og lignende prøver) efterprøves den anthelmintiske virkning ved at bestemme antallet af æg i faeces, der passerer på de dage, der følger efter behandlingen med forbindelsen.Methyl 6-n-propoxybenzothiazole-2-carbamate is suitable for the control of nematodes, i.e. for the treatment of humans and animals believed to be or infected in the gastrointestinal tract with endo-parasites, by providing to the host animal a prophylactic and / or therapeutic amount of the compound which associates a high degree of anthelmintic action against the parasites with a low toxicity to the host organism. The compound is particularly unique and therefore very valuable as it is effective against the three most common mammalian nematodes in that the compound exhibits an effective anthelmintic effect against worm types such as Ascaridia (e.g. roundworm), Ancylostoma (f. eg hookworm) and Trichuris (eg whip). The anthelmintic effect of the compounds can be verified by standard and well known methods, such as the modified McMaster egg counting technique, as described by H.B. Whitlock and H.McL. Gordon? J.Council Scientific Industrial Research (Australia) 12, pp. 50, 1939 and HBWhitlock J. Council Scientific Research (Australia) 21, pp. 177, 1948. In these (and similar tests), the anthelmintic effect is tested by determining the number of eggs in faeces that pass on the days following treatment with the compound.
Ved disse forsøg er det påvist, at den omhandlede forbindelse udviser signifikante anthelmintiske virkninger, når den administreres til en vært (f.eks. en hest) i en dosismængde på 30-100 mg/kg pr.dag, enten i en enkelt daglig dosis eller i en dosering over flere dage efter metoder, der er velkendte inden for teknikken. Den omhandlede forbindelse kan administreres i suspensioner, i kapsler, som præparater, der sættes til foderet, og som tabletter, således som det er velkendt for fagmanden inden for klinisk og veterinær medicin. Yderligere kan forbindelsen også anvendes som injicerbare anthelmintiske præparater. Til dette formål blandes den aktive ingrediens med et passende sterilt bærestof, såsom sterilt vand og en isotonisk 6 148476 saltopløsning.In these experiments, it has been demonstrated that the subject compound exhibits significant anthelmintic effects when administered to a host (e.g., a horse) at a dosage rate of 30-100 mg / kg per day, either in a single daily dose. or in a dosage over several days according to methods well known in the art. The subject compound can be administered in suspensions, in capsules, as preparations added to the feed, and as tablets, as is well known to those of ordinary skill in clinical and veterinary medicine. Further, the compound can also be used as injectable anthelmintic preparations. For this purpose, the active ingredient is mixed with a suitable sterile carrier such as sterile water and an isotonic saline solution.
Forbindelsen har lav toxicitet og udviser derfor et udmærket terapeutisk indeks. Doseringer til mus og til hunde er ikke lethale ved 200 mg/kg.The compound has low toxicity and therefore exhibits an excellent therapeutic index. Dosages for mice and dogs are not lethal at 200 mg / kg.
Velegnede kliniske præparater, der indeholder det omhandlede benzothiazol, kan administreres peroralt i form af tabletter, kapsler og eliksirer.Suitable clinical preparations containing the subject benzothiazole can be administered orally in the form of tablets, capsules and elixirs.
Forbindelsens overlegenhed i forhold til den tilsvarende ethylester mod Parascaris equorum fremgår af nedenstående forsøg, ved hvilke aktiviteten af følgende forbindelser blev vurderet: I: Methyl-6-n-propoxybenzothiazol-2-carbamat II: Ethyl-6-n-propoxybenzothiazol-2-carbamat.The superiority of the compound to the corresponding ethyl ester against Parascaris equorum is evident from the following experiments in which the activity of the following compounds was assessed: I: Methyl 6-n-propoxybenzothiazole-2-carbamate II: Ethyl-6-n-propoxybenzothiazole-2 carbamate.
Forsøgene blev udført med naturligt inficerede ponyer, der blev udvalgt på basis af det store antal P. equorum-æg, der blev fundet i deres faeces. Efter tilvending til forsøgsomstændighederne blev der til ponyerne administreret den forbindelse, som skulle prøves, i et passende bæremiddel. Det fækalmateriale, der blev afgi-. vet efter behandlingen, blev undersøgt dagligt for orm, der var afgivet som reaktion på behandlingen med stoffet. Denne procedure blev fortsat i syv dage, og hvis der var afgivet orm og antallet af æg pr. g faeces var faldet, blev dyret underkastet necropsi, og fordøjelseskanalens indhold undersøgt for parasitter. Hvis der var minimal ændring i antallet af æg, og der kun blev afgivet få eller ingen orm, lod man dyret hvile i syv døgn og gentog cyclus med samme stof. Ved denne prøve tjente hvert forsøgsdyr som sin egen kontrol.The experiments were conducted with naturally infected ponies selected on the basis of the large number of P. equorum eggs found in their faeces. After application to the experimental conditions, the compound to be tested was administered to the ponies in a suitable carrier. The faecal material that was released. after treatment, were tested daily for worms released in response to treatment with the drug. This procedure was continued for seven days and if worms were released and the number of eggs per g faeces had decreased, the animal was subjected to necropsy, and the digestive tract content was examined for parasites. If there was minimal change in the number of eggs and only few or no worms were released, the animal was allowed to rest for seven days and repeated cycles with the same substance. In this test, each experimental animal served as its own control.
Til prøvning af forbindelse II blev der opnået to dyr, der havde infektioner af P. equorum-orm, vurderet ved tælning af æg.For testing Compound II, two animals that had P. equorum worm infections were assessed by egg counting.
Efter tilpasning af dyrene blev stoffet suspenderet i vegetabilsk olie og anbragt i maven på dyret ved hjælp af en maveslange, der var nedført gennem næse og hals. Ved hvert forsøg androg mængden af stof 100 mg/kg af dyrets vægt. Ved det første forsøg med pony A blev der ikke fundet P. equorum-orm i faeces, og der blev ikke iagttaget nogen ændring i ægantallet syv døgn efter behandlingen. Forsøget blev gentaget som beskrevet ovenfor, og dyret underkastet autopsi syv dage efter den anden behandling.After adjusting the animals, the substance was suspended in vegetable oil and placed in the stomach of the animal by means of a gastric tube down through the nose and throat. In each experiment, the amount of substance was 100 mg / kg of animal weight. In the first trial of pony A, no P. equorum worm was found in faeces, and no change in egg number was observed seven days after treatment. The test was repeated as described above and the animal underwent autopsy seven days after the second treatment.
Denne prøvecyclus med forbindelse II i samme dosis blev gentaget med pony B. Efter hvileperioden blev cyclus gentaget. Re- 7 148476 sultaterne af disse to forsøg med forbindelse II er anført i tabel II.This test cycle of compound II at the same dose was repeated with pony B. After the rest period, the cycle was repeated. The results of these two experiments with Compound II are listed in Table II.
Tabel IITable II
Pony Forsøg Dosis Antal P. equorum Antal P.equorum % nr. mg/kg afgivet efter fundet ved effektivitet _behandling_autopsi_ A 1 100 0 (3)* 0 A 2 100 0 3 0 B 1 100 1 (5)* 16,6 B 2 100 0 5 0 *Pony Trial Dose No. of P. equorum No. of P. equorum% No. mg / kg delivered after found by efficacy _treatment_autopsy_ A 1 100 0 (3) * 0 A 2 100 0 3 0 B 1 100 1 (5) * 16.6 B 2 100 0 5 0 *
Autopsi efter anden behandling.Autopsy after other treatment.
Med forbindelse I blev udført samme prøvecyclus, blot blev dyrene underkastet autopsi ved afslutningen af den første cyclus som følge af afgivelse af P. equorum. Resultaterne af forsøgene med forbindelse I er anført i tabel I.With compound I, the same test cycle was performed, only the animals were subjected to autopsy at the end of the first cycle due to delivery of P. equorum. The results of the experiments with Compound I are listed in Table I.
Tabel ITable I
Pony Dosis Antal P.equo'rum Antal P.equorum % nr. mg/kg afgivet efter fundet ved effektivitet behandling autopsi 3 100 71 0 100Pony Dose No. of P.equo'rum No. of P.equorum% No. mg / kg given after found by efficacy treatment autopsy 3 100 71 0 100
Det fremgår af ovenstående forsøgsresultater, at ethyl-6-n-propoxybenzothiazol-2-carbamat er praktisk taget inaktivt overfor Parascaris equorum ved en dosis på 100 mg/kg af dyrets vægt, medens methyl-6-n-propoxybenzothiazol-2-carbamat er særdeles effektivt ved samme prøve.It is clear from the above test results that ethyl 6-n-propoxybenzothiazole-2-carbamate is virtually inactive against Parascaris equorum at a dose of 100 mg / kg of animal weight, while methyl-6-n-propoxybenzothiazole-2-carbamate is very effective in the same test.
De følgende eksempler belyser fremgangsmåderne nærmere: Eksempel 1 I en rundbundet 1 liter kolbe udstyret med tilbagesvaler, en magnetisk omrører og en varmekappe anbringes 45,75 g 2-mercapto-4-propoxyanilin, 45,25 g methyl-N-[di(methylthio)-methylen]carbamat og 250 ml absolut ethanol. Blandingen opvarmes til kogning i en inert atmosfære af nitrogen i 12 timer. Herefter afkøles den, og det hvide krystallinske faste stof, der er dannet, isoleres ved filtrering, vaskes med kold ethanol og tørres. Smp.: 178-180°C.The following examples illustrate the procedures in more detail: Example 1 A 45.75 g of 2-mercapto-4-propoxyaniline, 45.25 g of methyl N- [di (methylthio) is placed in a round bottom 1 liter flask equipped with a reflux condenser, a magnetic stirrer and a heating sheath. ) -methylene] carbamate and 250 ml of absolute ethanol. The mixture is heated to boil in an inert atmosphere of nitrogen for 12 hours. It is then cooled and the white crystalline solid formed is isolated by filtration, washed with cold ethanol and dried. Mp: 178-180 ° C.
8 1484768 148476
Eksempel 2Example 2
En opløsning af 26,8 g l-carbomethoxy-3-(p-n-propoxyphenyl)-thiourinstof i chloroform og 16 g brom opvarmes med tilbagesvaling i 5 timer. Herefter bringes opløsningen op på stuetemperatur og vaskes med 100ml vandig 10% Na2SO^, 200 ml vandig 10% ^200^ og vandig mættet natriumchlorid. Den tørres over vandfrit natriumsulfat, og herefter fjernes opløsningsmidlet ved fordampning til opnåelse af 25 g af et hvidt fast stof. Smp.: 178-180°C.A solution of 26.8 g of 1-carbomethoxy-3- (p-n-propoxyphenyl) thiourea in chloroform and 16 g of bromine are refluxed for 5 hours. Then the solution is brought to room temperature and washed with 100ml aqueous 10% Na2SO4, 200ml aqueous 10% ^ 200 ^ and aqueous saturated sodium chloride. It is dried over anhydrous sodium sulfate and then the solvent is removed by evaporation to give 25 g of a white solid. Mp: 178-180 ° C.
Eksempel 3Example 3
En opløsning af 26,8 g l-carbomethoxy~3-(p-n-propoxyphenyl)-thiourinstof Og 16 g brom i 700 ml chloroform bestråles i en kvartsbeholder med en 450 W middeltrykskviksølvlampe, indtil bromets farve forsvinder. Reaktionsblandingen oparbejdes herefter ved fremgangsmåden beskrevet i eksempel 2 til opnåelse af den ønskede forbindelse. Smp.: 178-180°C.A solution of 26.8 g of l-carbomethoxy ~ 3- (p-n-propoxyphenyl) thiourea And 16 g of bromine in 700 ml of chloroform are irradiated in a quartz vessel with a 450 W medium-pressure mercury lamp until the color of the bromine disappears. The reaction mixture is then worked up by the procedure described in Example 2 to obtain the desired compound. Mp: 178-180 ° C.
Eksempel 4Example 4
Til en omrørt suspension af 2,1 g 1-carbomethoxy-(p-n-propoxy)-thiourinstof i en opløsning af 2,4 g natriumhydroxid i 35 ml vand anbragt i er erlenmeyerkolbe ved 64°c (vandbad) sættes en opløsning af 8,8 g kaliumferricyanid i 20 ml vand. Omrøringen fortsættes i yderligere 2 timer. Herefter tilsættes kaliumcarbonat, 6 g, til blandingen, og omrøringen fortsættes i yderligere 2 timer. Herefter ekstraheres den med 2 x 50 ml chloroform. Chloroformekstrakterne tørres over vandfrit Na2S0^, og opløsningsmidlet fjernes ved fordampning til opnåelse af produktet. Smp.: 178 - 180°C.To a stirred suspension of 2.1 g of 1-carbomethoxy (pn-propoxy) -thiourea in a solution of 2.4 g of sodium hydroxide in 35 ml of water placed in erlenmeyer flask at 64 ° C (water bath) is added a solution of 8 8 g of potassium ferricyanide in 20 ml of water. Stirring is continued for another 2 hours. Then potassium carbonate, 6 g, is added to the mixture and stirring is continued for another 2 hours. It is then extracted with 2 x 50 ml of chloroform. The chloroform extracts are dried over anhydrous Na 2 SO 4 and the solvent is removed by evaporation to give the product. Mp: 178 - 180 ° C.
Eksempel 5Example 5
Til en omrørt og afkølet (0°C) opløsning af 24,45 g 2-amino- 6-n-propoxybenzothiazolhydrochlorid i 100 ml tør pyridin sættes dråbevis 9,45 g methylchloroformat. Herefter henstår blandingen ved stuetemperatur i 8 timer. Den udhældes i 300 g isvand. Det faste stof fraskilles ved filtrering og tørres. Omkrystallisation med ethanol giver 20 g af produktet. Smp.: 178-180°C.To a stirred and cooled (0 ° C) solution of 24.45 g of 2-amino-6-n-propoxybenzothiazole hydrochloride in 100 ml of dry pyridine is added dropwise 9.45 g of methyl chloroformate. The mixture is then left at room temperature for 8 hours. It is poured into 300 g of ice water. The solid is separated by filtration and dried. Recrystallization with ethanol gives 20 g of the product. Mp: 178-180 ° C.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/775,006 US4093731A (en) | 1976-03-30 | 1977-03-07 | Methyl-6-n-propoxybenzothiazole-2-carbamate and anthelmintic pharmaceutical compositions thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57187575 | 1975-04-25 | ||
| US05/571,875 US4006242A (en) | 1973-07-18 | 1975-04-25 | Certain benzothiazoles used in the treatment of helminthiasis |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK146076A DK146076A (en) | 1976-10-26 |
| DK148476B true DK148476B (en) | 1985-07-15 |
| DK148476C DK148476C (en) | 1985-12-16 |
Family
ID=24285412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK146076A DK148476C (en) | 1975-04-25 | 1976-03-30 | ANALOGY PROCEDURE FOR PREPARING METHYL-6-N-PROPOXYBENZOTHIAZOL-2-CARBAMATE |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS51128966A (en) |
| AR (1) | AR211611A1 (en) |
| AU (1) | AU501493B2 (en) |
| BE (1) | BE840945A (en) |
| CA (1) | CA1085297A (en) |
| CH (1) | CH619940A5 (en) |
| DE (1) | DE2617198C2 (en) |
| DK (1) | DK148476C (en) |
| ES (1) | ES447157A1 (en) |
| FR (1) | FR2308363A1 (en) |
| GB (1) | GB1545296A (en) |
| HU (1) | HU174390B (en) |
| IE (1) | IE43095B1 (en) |
| IT (1) | IT1067960B (en) |
| LU (1) | LU74792A1 (en) |
| NL (1) | NL7604149A (en) |
| SE (1) | SE417963B (en) |
| ZA (1) | ZA762331B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI91859C (en) * | 1987-06-17 | 1994-08-25 | Eisai Co Ltd | Analogue method for the preparation of an active benzothiazole derivative as an antiallergic agent |
| JPH0534814Y2 (en) * | 1989-09-22 | 1993-09-03 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH505543A (en) * | 1968-11-01 | 1971-04-15 | Ciba Geigy Ag | Pesticides |
| AR204835A1 (en) * | 1973-07-18 | 1976-03-05 | Scherico Ltd | PROCEDURE FOR PREPARING BENZOTHIAZOLE-2-ETHYL CARBAMATES |
-
1976
- 1976-03-30 DK DK146076A patent/DK148476C/en not_active IP Right Cessation
- 1976-04-14 CH CH494376A patent/CH619940A5/en not_active IP Right Cessation
- 1976-04-20 JP JP51045316A patent/JPS51128966A/en active Granted
- 1976-04-20 SE SE7604543A patent/SE417963B/en not_active IP Right Cessation
- 1976-04-20 ZA ZA762331A patent/ZA762331B/en unknown
- 1976-04-20 ES ES447157A patent/ES447157A1/en not_active Expired
- 1976-04-20 DE DE2617198A patent/DE2617198C2/en not_active Expired
- 1976-04-20 NL NL7604149A patent/NL7604149A/en not_active Application Discontinuation
- 1976-04-20 FR FR7611601A patent/FR2308363A1/en active Granted
- 1976-04-20 GB GB15967/76A patent/GB1545296A/en not_active Expired
- 1976-04-20 LU LU74792A patent/LU74792A1/xx unknown
- 1976-04-21 CA CA250,725A patent/CA1085297A/en not_active Expired
- 1976-04-21 AR AR262946A patent/AR211611A1/en active
- 1976-04-21 BE BE166318A patent/BE840945A/en not_active IP Right Cessation
- 1976-04-21 IT IT22502/76A patent/IT1067960B/en active
- 1976-04-21 IE IE845/76A patent/IE43095B1/en unknown
- 1976-04-21 AU AU13210/76A patent/AU501493B2/en not_active Expired
- 1976-04-22 HU HU76SCHE563A patent/HU174390B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2617198C2 (en) | 1984-12-20 |
| GB1545296A (en) | 1979-05-10 |
| FR2308363B1 (en) | 1978-11-17 |
| HU174390B (en) | 1979-12-28 |
| BE840945A (en) | 1976-10-21 |
| IE43095L (en) | 1976-10-25 |
| JPS51128966A (en) | 1976-11-10 |
| DE2617198A1 (en) | 1976-11-04 |
| CH619940A5 (en) | 1980-10-31 |
| ES447157A1 (en) | 1977-10-01 |
| NL7604149A (en) | 1976-10-27 |
| AU1321076A (en) | 1977-10-27 |
| ZA762331B (en) | 1977-04-27 |
| FR2308363A1 (en) | 1976-11-19 |
| IE43095B1 (en) | 1980-12-17 |
| CA1085297A (en) | 1980-09-09 |
| DK146076A (en) | 1976-10-26 |
| IT1067960B (en) | 1985-03-21 |
| AR211611A1 (en) | 1978-02-15 |
| AU501493B2 (en) | 1979-06-21 |
| SE417963B (en) | 1981-04-27 |
| SE7604543L (en) | 1976-10-26 |
| JPS6117830B2 (en) | 1986-05-09 |
| LU74792A1 (en) | 1977-02-07 |
| DK148476C (en) | 1985-12-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |