NO167387B - PROCEDURE FOR PREPARING 2-GUANIDINOTHIAZOLD DERIVATIVES. - Google Patents
PROCEDURE FOR PREPARING 2-GUANIDINOTHIAZOLD DERIVATIVES. Download PDFInfo
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- NO167387B NO167387B NO874698A NO874698A NO167387B NO 167387 B NO167387 B NO 167387B NO 874698 A NO874698 A NO 874698A NO 874698 A NO874698 A NO 874698A NO 167387 B NO167387 B NO 167387B
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- formula
- compound
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- thiourea
- acetone
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- 238000000034 method Methods 0.000 title claims description 19
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 18
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 13
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 11
- OKGXJRGLYVRVNE-UHFFFAOYSA-N diaminomethylidenethiourea Chemical compound NC(N)=NC(N)=S OKGXJRGLYVRVNE-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 235000009518 sodium iodide Nutrition 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 238000002955 isolation Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 150000008327 2-guanidinothiazoles Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 15
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 6
- CSVFWMMPUJDVKH-UHFFFAOYSA-N 1,1-dichloropropan-2-one Chemical compound CC(=O)C(Cl)Cl CSVFWMMPUJDVKH-UHFFFAOYSA-N 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 5
- -1 isothiourea compound Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 2
- 229960001596 famotidine Drugs 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000003918 potentiometric titration Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 2
- BPCROVNHEMFQOD-UHFFFAOYSA-N 3-[[2-(diaminomethylideneamino)-1,3-thiazol-4-yl]methylsulfanyl]-n-sulfamoylpropanamide Chemical compound NC(N)=NC1=NC(CSCCC(=O)NS(N)(=O)=O)=CS1 BPCROVNHEMFQOD-UHFFFAOYSA-N 0.000 description 1
- GNHMRTZZNHZDDM-UHFFFAOYSA-N 3-chloropropionitrile Chemical compound ClCCC#N GNHMRTZZNHZDDM-UHFFFAOYSA-N 0.000 description 1
- NMAKJOWVEDTHOA-UHFFFAOYSA-N 4-(chloromethyl)-1,3-thiazol-2-amine;hydron;chloride Chemical compound Cl.NC1=NC(CCl)=CS1 NMAKJOWVEDTHOA-UHFFFAOYSA-N 0.000 description 1
- 206010022714 Intestinal ulcer Diseases 0.000 description 1
- XXFFVVWAHDVWFQ-UHFFFAOYSA-N O.Cl.Cl.N(C(=N)N)C=1SC=C(N1)CSC(N)=N Chemical compound O.Cl.Cl.N(C(=N)N)C=1SC=C(N1)CSC(N)=N XXFFVVWAHDVWFQ-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000002009 allergenic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 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
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003549 thiazolines Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
Description
Foreliggende oppfinnelse angår en ny fremgangsmåte for fremstilling av 2-guanidinothiazolderivat av formel (I) The present invention relates to a new process for the production of 2-guanidinothiazole derivative of formula (I)
såvel som salter derav. as well as salts thereof.
Dette derivat er et viktig mellomprodukt for fremstilling av famotidin (kjemisk N-sulfamyl-3-(2-guanidino-thiazol-4-ylmethylthio)propionamid som har vist seg å være et glimrende legemiddel ved behandling av mage- og tarmsår. This derivative is an important intermediate for the production of famotidine (chemical N-sulfamyl-3-(2-guanidino-thiazol-4-ylmethylthio)propionamide which has proven to be an excellent drug in the treatment of stomach and intestinal ulcers.
Forbindelsen fremstilt ifølge oppfinnelsen er kjent fra litteraturen. The compound produced according to the invention is known from the literature.
Ifølge forfatterne av Europa-patentskrift 87 274 ble isothiourea av formel (I) erholdt i et utbytte over 90 % ved omsetning av en forbindelse av formel (III) According to the authors of European patent specification 87 274, isothiourea of formula (I) was obtained in a yield of over 90% by reacting a compound of formula (III)
hvori X er halogen, med thiourea i alkohol. wherein X is halogen, with thiourea in alcohol.
En ulempe ved denne fremgangsmåte består imidlertid i at klormethylutgangsforbindelsen er et allergenisk middel som irriterer hud og slimhinner. A disadvantage of this method, however, is that the chloromethyl starting compound is an allergenic agent that irritates the skin and mucous membranes.
Isothioureaforbindelsen erholdt på den ovenfor angitte måte ble omsatt med 3-klorpropionitril i nærvær av natrium-hydroxyd i vandig alkohol under avkjøling, under dannelse av nitrilet i 89,8 % utbytte. Denne fremgangsmåte er besværlig idet den krever meget tid og arbeide ettersom produktet må isoleres under anvendelse av ekstraksjon, azeotropisk tørking og omkrystallisering fra en løsningsmiddelblanding. The isothiourea compound obtained in the above manner was reacted with 3-chloropropionitrile in the presence of sodium hydroxide in aqueous alcohol under cooling, forming the nitrile in 89.8% yield. This process is cumbersome as it requires a lot of time and labor as the product must be isolated using extraction, azeotropic drying and recrystallization from a solvent mixture.
Forskerne hos Yamanouchi Co. forsøkte å eliminere ulempene ved de ovenfor angitte metoder ved å utvikle en annen fremgangsmåte beskrevet i Europa-patentsøknad 128 736. Dikloraceton ble kondensert med amidinothiourea under 0° C i flere dager, under dannelse av thiazolinet av formel (iv) The researchers at Yamanouchi Co. tried to eliminate the disadvantages of the above methods by developing another method described in European patent application 128 736. Dichloroacetone was condensed with amidinothiourea below 0° C for several days, forming the thiazoline of formula (iv)
i 96,4 % utbytte. Det således erholdte thiazolin ble oppvar-met med thiourea i alkohol, under dannelse av forbindelsen av formel (I) i 75,9 % utbytte (83,8 % som beregnet for thiourea). in 96.4% yield. The thiazoline thus obtained was heated with thiourea in alcohol, forming the compound of formula (I) in 75.9% yield (83.8% as calculated for thiourea).
Den mest betydningsfulle ulempe ved den ovenfor angitte metode synes å være at den teknologiske prosedyre er besværlig og langvarig, cykliseringen krever avkjøling i hele reaksjonsperioden og den således erholdte thiazolinforbindelse av formel (IV) er relativt ustabil. Ifølge foretatte under-søkelser er dette thiazolinderivat meget ustabilt ved romtemperatur. The most significant disadvantage of the above-mentioned method seems to be that the technological procedure is cumbersome and lengthy, the cyclization requires cooling throughout the reaction period and the thus obtained thiazoline compound of formula (IV) is relatively unstable. According to investigations carried out, this thiazoline derivative is very unstable at room temperature.
Den hud-irriterende klormethyl-mellomproduktforbin-delse av formel (IV) hvori X betegner klor, ble for første gang beskrevet i belgisk patentskrift 866 156, ifølge hvilket dikloraceton ble omsatt med amidinothiourea ved omrøring i acetonløsning over natten ved romtemperatur. Imidlertid er utbyttet av den rene klormethylforbindelse erholdt ved omkrystallisering fra" alkohol ikke angitt. Ifølge egne bestemmelser er dette utbytte mindre enn 80 %. Andre fremstillingsmetoder er ikke kjent fra litteraturen, eller er ekvivalente eller varianter av den ovenfor angitte fremgangsmåte. The skin-irritating chloromethyl intermediate compound of formula (IV) in which X represents chlorine was first described in Belgian patent document 866 156, according to which dichloroacetone was reacted with amidinothiourea by stirring in acetone solution overnight at room temperature. However, the yield of the pure chloromethyl compound obtained by recrystallization from alcohol is not stated. According to own regulations, this yield is less than 80%. Other production methods are not known from the literature, or are equivalent or variants of the above-mentioned method.
Et mål med foreliggende oppfinnelse er å tilveie-bringe en fremgangsmåte hvori mellomproduktet av formel (I) for famotidin kan fremstilles i et enkelt kar, slik at isolering av de andre mellomprodukter som utviser uhensikts-messige egenskaper blir unødvendig. An aim of the present invention is to provide a method in which the intermediate product of formula (I) for famotidine can be produced in a single vessel, so that isolation of the other intermediate products which exhibit inappropriate properties becomes unnecessary.
Oppfinnelsen er basert på den erkjennelse at S-alkylering utført ved omsetning av et dihaloaceton med amidinothiourea av formel (II) og den etterfølgende cyklisering kan selektivt oppnås under anvendelse av en jodidkatalysator i et løsningsmiddel, som fører til separasjon av halomethylforbindelsen av generell formel (III) i krystallinsk form fra reaksjonsblandingen. Etter tilsetning av vann og thiourea kan denne forbindelse overføres til målproduktet, dvs. forbindelsen av formel (I), som ut-skilles i en ren krystallinsk tilstand fra reaksjonsblandingen. The invention is based on the recognition that S-alkylation carried out by reacting a dihaloacetone with amidinothiourea of formula (II) and the subsequent cyclization can be selectively achieved using an iodide catalyst in a solvent, which leads to the separation of the halomethyl compound of general formula (III ) in crystalline form from the reaction mixture. After addition of water and thiourea, this compound can be transferred to the target product, i.e. the compound of formula (I), which separates out in a pure crystalline state from the reaction mixture.
Nye og overraskende trekk er også involvert i den ovenfor angitte erkjennelse. Det kunne ikke forventes at en slik grad av selektivitet ville kunne oppnås ved cykliseringen ved anvendelse av en jodidkatalysator i et aceton-medium. Dette understøttes av det faktum at uten en jodidkatalysator ved omsetningen av dikloraceton med amidinothiourea, etterfulgt av omsetning med thiourea, var de erholdte utbytter 25 til 30 % lavere sammenlignet med utbyttet ved reaksjonen basert på denne erkjennelse, selv om den eneste forskjell besto i katalysen. New and surprising features are also involved in the above-mentioned realization. It could not be expected that such a degree of selectivity could be achieved in the cyclization using an iodide catalyst in an acetone medium. This is supported by the fact that without an iodide catalyst in the reaction of dichloroacetone with amidinothiourea, followed by reaction with thiourea, the yields obtained were 25 to 30% lower compared to the yield of the reaction based on this finding, although the only difference was in the catalysis.
Den selektivitets-økende rolle av jodidkatalysen ble i tillegg også bekreftet når det gjelder 2-amino-4-klormethyl-thiazol-hydroklorid av formel (v) The selectivity-enhancing role of iodide catalysis was additionally also confirmed in the case of 2-amino-4-chloromethyl-thiazole hydrochloride of formula (v)
en forbindelse kjent fra litteraturen. Ved omsetning av thiourea med dikloraceton i et 1:1 molarforhold, ble forbindelsen av formel (V) erholdt i 58,5 % utbytte, og den etterfølgende reaksjon med thiourea resulterte i forbindelsen av formel (VI) a connection known from the literature. By reacting thiourea with dichloroacetone in a 1:1 molar ratio, the compound of formula (V) was obtained in 58.5% yield, and the subsequent reaction with thiourea resulted in the compound of formula (VI)
i et utbytte på 22,2 % (J.Am. Chem. Soc. 68. 2156 (1946). I motsetning til disse utbytter ble forbindelsen av formel (V) erholdt i et utbytte på 86 % under anvendelse av jodidkatalysen erholdt i foreliggende forsøk. in a yield of 22.2% (J.Am. Chem. Soc. 68. 2156 (1946). In contrast to these yields, the compound of formula (V) was obtained in a yield of 86% using the iodide catalysis obtained in the present attempt.
Det er også kjent at cykliseringen av forbindelsen av formel (II) innbefatter minst tre trinn. Da det kan forventes at det første trinn, dvs. S-alkyleringen bare akselereres av jodidkatalysen, er det også overraskende at i tillegg til økningen i selektiviteten, akselereres hele thiazoldannel-sen. It is also known that the cyclization of the compound of formula (II) involves at least three steps. As it can be expected that the first step, i.e. the S-alkylation, is only accelerated by the iodide catalysis, it is also surprising that in addition to the increase in selectivity, the whole thiazole chain is accelerated.
Foreliggende oppfinnelse angår således en ny fremgangsmåte for fremstilling av 2-guanidinothiazolderivat av formel (I), såvel som salter derav, kjennetegnet ved cyklisering av amidinothiourea av formel (II) The present invention thus relates to a new process for the production of 2-guanidinothiazole derivative of formula (I), as well as salts thereof, characterized by cyclization of amidinothiourea of formula (II)
med et 1,3-dihaloaceton i et løsningsmiddel, fortrinnsvis i aceton, og i nærvær av en jodidkatalysator som er løselig i angitte løsningsmiddel, fortrinnsvis natriumjodid, og omsetning uten isolering av det således erholdte halogenderivat av formel (III) with a 1,3-dihaloacetone in a solvent, preferably in acetone, and in the presence of an iodide catalyst which is soluble in specified solvents, preferably sodium iodide, and reaction without isolation of the halogen derivative of formula (III) thus obtained
hvori X betegner halogen, med thiourea i nærvær av vann. wherein X represents halogen, with thiourea in the presence of water.
Ifølge en foretrukket utførelsesform av fremgangsmåten ifølge oppfinnelsen anvendes jodidkatalysatoren i en mengde på fra 1 til 10 mol%, fortrinnsvis 4-6 mol%. According to a preferred embodiment of the method according to the invention, the iodide catalyst is used in an amount of from 1 to 10 mol%, preferably 4-6 mol%.
Ved fremgangsmåten ifølge oppfinnelsen dannes forbindelsen av formel (I) ved en temperatur mellom 20 og 60 C. In the method according to the invention, the compound of formula (I) is formed at a temperature between 20 and 60 C.
Ved fremgangsmåten ifølge oppfinnelsen tilsettes amidinothioureaforbindelsen av formel (u) porsjonsvis til det egnede dihaloaceton, fortrinnsvis dikloraceton, i et løsnings-middel, fortrinnsvis i aceton også inneholdende natriumjodid. Vann og thiourea tilsettes til den således dannede krystallsuspensjon, og etter kokning og avkjøling filtreres den således erholdte forbindelse av formel (I), vaskes med vandig aceton og tørkes. In the method according to the invention, the amidinothiourea compound of formula (u) is added portionwise to the suitable dihaloacetone, preferably dichloroacetone, in a solvent, preferably in acetone also containing sodium iodide. Water and thiourea are added to the crystal suspension thus formed, and after boiling and cooling, the thus obtained compound of formula (I) is filtered, washed with aqueous acetone and dried.
Fordelene med fremgangsmåten ifølge oppfinnelsen kan oppsummeres som følger. The advantages of the method according to the invention can be summarized as follows.
a) På grunn av jodidkatalysen vil utførelsen av en cyklisering som varer i flere dager under 0° C, såvel som isoleringen av de ustabile mellomprodukter bli unødvendig. a) Due to the iodide catalysis, the performance of a cyclization that lasts for several days below 0° C, as well as the isolation of the unstable intermediates will become unnecessary.
b) Det erholdte hud-irriterende produkt av formel (III) kan ytterligere overføres uten isolering i samme reaksjons-kar. c) Det anvendte løsningsmiddelsystem tilveiebringer separering av forbindelsene av formel (I) og deres salter i en ren tilstand,, mens forurensningene forblir i modervæsken. b) The obtained skin-irritating product of formula (III) can be further transferred without isolation in the same reaction vessel. c) The solvent system used provides separation of the compounds of formula (I) and their salts in a pure state, while the impurities remain in the mother liquor.
d) På grunn av den beskjedne medgåtte arbeidstid og glimrende utbytter er fremgangsmåten ifølge oppfinnelsen meget anvendbar for industriell utnyttelse. Volumutnyttelsen er også meget fordelaktig: 240 kg av forbindelsen av formel (I) kan fremstilles i et driftsvolum på lm<3>. d) Due to the modest working time and excellent yields, the method according to the invention is very applicable for industrial use. The volume utilization is also very advantageous: 240 kg of the compound of formula (I) can be produced in an operating volume of lm<3>.
Fremgangsmåten ifølge oppfinnelsen illustreres i detalj i de etterfølgende eksempler. The method according to the invention is illustrated in detail in the following examples.
Eksempel 1 Example 1
Fremstilling av S-(2-guanidinothiazol-4-yl-methyl)-isothiourea-dihydroklorid-monohydrat [forbindelse av formel (I) hvori Y er gruppen av formel (II)]. Preparation of S-(2-guanidinothiazol-4-yl-methyl)-isothiourea dihydrochloride monohydrate [compound of formula (I) in which Y is the group of formula (II)].
Eksempel 1. 1 Example 1. 1
11,8 g (0,5 1 mol) amidinothiourea ble tilsatt til en omrørt løsning inneholdende 12,7 g (0,1 mol) 1,3-diklor-acetori og 0,75 g (0,005 mol) natriumjodid i 92 ml aceton i løpet av 2 timer. Etter omøring i ytterligere 2 timer ble 9,2 g vann tilsatt, og en løsning ble dannet etter kokning i kort tid. Til denne løsning ble tilsatt 7,6 g (0,1 mol) thiourea, hvorpå blandingen ble kokt i 1 time. Reaksjonsblandingen inneholdende det oljeaktige reaksjonsprodukt fikk avkjøles under omrøring. Den således dannede krystallsuspensjon ble avkjølt til 0° C og ble deretter filtrert, vasket to ganger med aceton og tørket under dannelse av tittelproduktet med smeltepunkt 209 - 213° C (under spaltning), i et utbytte på 27,86 g (85 %) med et innhold av aktiv bestanddel på 98 % som bestemt ved potensiometrisk titrering. 11.8 g (0.51 mol) of amidinothiourea was added to a stirred solution containing 12.7 g (0.1 mol) of 1,3-dichloroacetori and 0.75 g (0.005 mol) of sodium iodide in 92 ml of acetone. within 2 hours. After stirring for a further 2 hours, 9.2 g of water was added, and a solution was formed after boiling for a short time. To this solution was added 7.6 g (0.1 mol) of thiourea, after which the mixture was boiled for 1 hour. The reaction mixture containing the oily reaction product was allowed to cool while stirring. The crystal suspension thus formed was cooled to 0°C and then filtered, washed twice with acetone and dried to give the title product, mp 209-213°C (with cleavage), in a yield of 27.86 g (85%) with an active ingredient content of 98% as determined by potentiometric titration.
Eksempel 1. 2 Example 1. 2
35,4 g (0,3 mol) amidinothiourea ble porsjonsvis tilsatt til en omrørt løsning inneholdende 38,1 g (0,3 mol) 1,3-dikloraceton og 2,25 g (0,015 mol) natriumjodid i 240 ml aceton ved 30 til 36° C i løpet av 1 time. Den således erholdte kry-stallsuspens jon ble omrørt ved samme temperatur i ytterligere 1 time, og etter tilsetning av 30 ml vann og 24 g (0,315 mol) thiourea, ble blandingen kokt under tilbakeløpskjøling og under omrøring i 1 time. Blandingen fikk avkjøles til romtemperatur, det krystallinske produkt ble filtrert og vasket to ganger med 40 ml 90 % aceton hver gang, under dannelse av tittelproduktet med smeltepunkt 210 - 214° C (under spalting) 35.4 g (0.3 mol) of amidinothiourea was added portionwise to a stirred solution containing 38.1 g (0.3 mol) of 1,3-dichloroacetone and 2.25 g (0.015 mol) of sodium iodide in 240 ml of acetone at 30 to 36° C within 1 hour. The crystal suspension thus obtained was stirred at the same temperature for a further 1 hour, and after adding 30 ml of water and 24 g (0.315 mol) thiourea, the mixture was boiled under reflux and with stirring for 1 hour. The mixture was allowed to cool to room temperature, the crystalline product was filtered and washed twice with 40 ml of 90% acetone each time, forming the title product with melting point 210 - 214° C (under cleavage)
i et utbytte på 88,02 g (89,7 %) med et innhold av aktiv bestanddel på 98,2 % som bestemt ved potensiometrisk titrering. in a yield of 88.02 g (89.7%) with an active ingredient content of 98.2% as determined by potentiometric titration.
Eksempel 1. 3 Example 1. 3
127,0 kg (500 mol) 1,3-dikloraceton i en 50 vekt% acetonisk løsning ble pumpet inn i en reaktor på 1000 liter. Etter tilsetning av 257 kg aceton og 3,75 kg (25 mol) natriumjodid ble 60,5 kg amidinothiourea med 97,6 % renhet (500 mol) porsjonsvis tilsatt til reaksjonsblandingen i løpet av 1,0 til 1,5 timer under omrøring. Den ønskede indre temperatur på 30 til 40° C ble opprettholdt ved strømning av kaldt vann i mantel. Etter omrøring av reaksjonsblandingen i ytterligere 1 time ble 50 liter vann og 41,2 kg thiourea med 97 % renhet (525 mol) tilsatt, og blandingen ble kokt under omrøring i 1 time. Temperaturen på reaksjonsblandingen ble deretter redu-sert til romtemperatur i løpet av 2 til 3 timer, suspensjonen ble sentrifugert, produktet ble vasket i sentrifugen med en 8:1 blanding av aceton og vann og ble tørket under dannelse av tittelproduktet med smeltepunkt 209 - 214° C (under spaltning) i et utbytte på 148,3 kg (90,0 %) med et innhold av aktiv bestanddel på 97,5 %. 127.0 kg (500 moles) of 1,3-dichloroacetone in a 50% by weight acetone solution was pumped into a 1000 liter reactor. After adding 257 kg of acetone and 3.75 kg (25 mol) of sodium iodide, 60.5 kg of 97.6% purity amidinothiourea (500 mol) was added portionwise to the reaction mixture over 1.0 to 1.5 hours with stirring. The desired internal temperature of 30 to 40°C was maintained by the flow of cold water in the jacket. After stirring the reaction mixture for a further 1 hour, 50 liters of water and 41.2 kg of thiourea of 97% purity (525 mol) were added and the mixture was boiled with stirring for 1 hour. The temperature of the reaction mixture was then reduced to room temperature over 2 to 3 hours, the suspension was centrifuged, the product was washed in the centrifuge with an 8:1 mixture of acetone and water and was dried to give the title product, mp 209-214° C (under cleavage) in a yield of 148.3 kg (90.0%) with an active ingredient content of 97.5%.
Claims (2)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU864658A HU195959B (en) | 1986-11-12 | 1986-11-12 | Process for producing 2-guanidino-thiazole derivatives |
Publications (4)
Publication Number | Publication Date |
---|---|
NO874698D0 NO874698D0 (en) | 1987-11-11 |
NO874698L NO874698L (en) | 1988-05-13 |
NO167387B true NO167387B (en) | 1991-07-22 |
NO167387C NO167387C (en) | 1991-10-30 |
Family
ID=10968597
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO874698A NO167387C (en) | 1986-11-12 | 1987-11-11 | PROCEDURE FOR PREPARING 2-GUANIDINOTHIAZOLD DERIVATIVES. |
Country Status (14)
Country | Link |
---|---|
KR (1) | KR900006556B1 (en) |
AR (1) | AR243874A1 (en) |
AT (1) | AT389510B (en) |
CA (1) | CA1323032C (en) |
CS (1) | CS268693B2 (en) |
DK (1) | DK169966B1 (en) |
ES (1) | ES2005441A6 (en) |
FI (1) | FI84912C (en) |
GR (1) | GR871696B (en) |
HU (1) | HU195959B (en) |
NO (1) | NO167387C (en) |
PT (1) | PT86113B (en) |
SU (1) | SU1678205A3 (en) |
YU (1) | YU46086B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5731442A (en) * | 1997-03-11 | 1998-03-24 | Albemarle Corporation | Synthesis of thiazole derivatives |
US5856500A (en) * | 1997-03-11 | 1999-01-05 | Albemarle Corporation | Synthesis of thiazole derivatives |
-
1986
- 1986-11-12 HU HU864658A patent/HU195959B/en unknown
-
1987
- 1987-10-20 AT AT0277087A patent/AT389510B/en not_active IP Right Cessation
- 1987-10-21 CA CA000549936A patent/CA1323032C/en not_active Expired - Fee Related
- 1987-11-04 GR GR871696A patent/GR871696B/en unknown
- 1987-11-10 AR AR87309242A patent/AR243874A1/en active
- 1987-11-10 DK DK587287A patent/DK169966B1/en not_active IP Right Cessation
- 1987-11-11 PT PT86113A patent/PT86113B/en unknown
- 1987-11-11 NO NO874698A patent/NO167387C/en not_active IP Right Cessation
- 1987-11-12 ES ES8703223A patent/ES2005441A6/en not_active Expired
- 1987-11-12 YU YU204987A patent/YU46086B/en unknown
- 1987-11-12 SU SU874203655A patent/SU1678205A3/en active
- 1987-11-12 CS CS878101A patent/CS268693B2/en not_active IP Right Cessation
- 1987-11-12 FI FI875003A patent/FI84912C/en not_active IP Right Cessation
- 1987-11-19 KR KR1019870013045A patent/KR900006556B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
CS268693B2 (en) | 1990-04-11 |
FI875003A (en) | 1988-06-13 |
PT86113B (en) | 1990-08-31 |
AR243874A1 (en) | 1993-09-30 |
KR890008120A (en) | 1989-07-08 |
SU1678205A3 (en) | 1991-09-15 |
ATA277087A (en) | 1989-05-15 |
DK587287A (en) | 1988-05-13 |
PT86113A (en) | 1987-12-01 |
FI84912C (en) | 1992-02-10 |
GR871696B (en) | 1987-12-08 |
CS810187A2 (en) | 1989-07-12 |
YU46086B (en) | 1992-12-21 |
ES2005441A6 (en) | 1989-03-01 |
NO874698L (en) | 1988-05-13 |
NO874698D0 (en) | 1987-11-11 |
KR900006556B1 (en) | 1990-09-13 |
DK169966B1 (en) | 1995-04-18 |
DK587287D0 (en) | 1987-11-10 |
NO167387C (en) | 1991-10-30 |
HU195959B (en) | 1988-08-29 |
FI84912B (en) | 1991-10-31 |
AT389510B (en) | 1989-12-27 |
CA1323032C (en) | 1993-10-12 |
YU204987A (en) | 1988-10-31 |
FI875003A0 (en) | 1987-11-12 |
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