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NO139086B - R PROCEDURE FOR THE PREPARATION OF BENZENESULPHONYLURINE SUBSTANCE - Google Patents

R PROCEDURE FOR THE PREPARATION OF BENZENESULPHONYLURINE SUBSTANCE Download PDF

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Publication number
NO139086B
NO139086B NO4443/73A NO444373A NO139086B NO 139086 B NO139086 B NO 139086B NO 4443/73 A NO4443/73 A NO 4443/73A NO 444373 A NO444373 A NO 444373A NO 139086 B NO139086 B NO 139086B
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methyl
benzenesulfonyl
urea
lower alkyl
cyclohexyl
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NO4443/73A
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Norwegian (no)
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NO139086C (en
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Walter Aumueller
Volker Hitzel
Rudi Weyer
Heinz Herr
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Hoechst Ag
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Publication of NO139086C publication Critical patent/NO139086C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/59—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Saccharide Compounds (AREA)

Description

Benzensulfonylurinstoffer kan fremstilles etter forskjellige metoder. En i lengre tid kjent fremgangsmåte består i at man behandler benzensulfonylisourinstoffeter med hydrogen-halogenider, eksempelvis slike med den generelle formel I Benzenesulfonylureas can be prepared by various methods. A method known for a long time consists of treating benzenesulfonylisourea ethers with hydrogen halides, for example those with the general formula I

idet R-^ og Rp betyr hydrogen, alkyl-, aryl- eller aralkylrester, Alk betyr en alkyl- eller aralkylgruppe, under avspaltning av alkylhalogenider (tysk patent nr. 741.533). Benzensulfonylisourinstoffeterne fåes ved omsetning av benzensulfonylsyreklorider med tilsvarende isourinstoff-etere. Senere ble det funnet at benzensulfonylisourinstoffetere med den generelle formel II wherein R-^ and Rp mean hydrogen, alkyl, aryl or aralkyl residues, Alk means an alkyl or aralkyl group, during cleavage of alkyl halides (German patent no. 741,533). The benzenesulfonyl isourea ethers are obtained by reacting benzenesulfonyl acid chlorides with corresponding isourea ethers. Later it was found that benzenesulfonylisourea ethers of the general formula II

hvor substituentenes betydning er som angitt ovenfor, også ved alkalisk hydrolyse lar seg overføre i tilsvarende benzensulfonylurinstoffer (japansk patent nr. 272.556). where the significance of the substituents is as indicated above, also by alkaline hydrolysis can be transferred into corresponding benzenesulfonylureas (Japanese patent no. 272,556).

En annen vanlig fremgangsmåte til fremstilling av benzensulfonylurinstoffer går ut fra 2-arylsulfonylimino-1,3~som med forskjellige aminer over mellomtrinn gir benzensulfonyl-merkaptoetylisourinstoffeter (IV) Another common method for the production of benzenesulfonylureas starts from 2-arylsulfonylimino-1,3~, which with various amines over intermediate stages gives benzenesulfonyl-mercaptoethylureas (IV)

som spaltes til benzensulfonylurinstoffer. which breaks down into benzenesulfonylureas.

Herved reagerer aminet med produktet med formel IV under dannelse av et sterkt nukleofilt merkaptidion, hvoretter det inntrer nedbrytning (Seigo Suzue og Tutomu Irikuro, Chemisches und Pharmazeutisches Bulletin, bind 17, nr. 8(1969), DOS 1.668.339)• Thereby, the amine reacts with the product of formula IV to form a strong nucleophilic mercaptide, after which decomposition occurs (Seigo Suzue and Tutomu Irikuro, Chemisches und Pharmazeutisches Bulletin, Vol. 17, No. 8(1969), DOS 1,668,339)•

Det ble nå Tunnet at man rent generelt kan spalte benzensulfonylisourinstoffetere med formel V It was now discovered that one can generally cleave benzenesulfonyl isourin ethers of formula V

ved behandling med aminer eller alkalimetallforbindelser av svakt sure organiske forbindelser til benzensulfonylurinstoffer med formel: by treatment with amines or alkali metal compounds of weakly acidic organic compounds to benzenesulfonylureas of formula:

Substituentene har følgende betydninger: The substituents have the following meanings:

R betyr lavere alkyl, lavere alkoksy, halogen, NH~2i CP^» acetyl eller en acylaminoalkylgruppe, hvori acyl betyr resten av en alifatisk, cykloalifatisk, aromatisk eller en heterocyklisk karboksylsyre resp. resten av en karbaminsyre og alkylgruppen har 1 til 4 C-atomer. R means lower alkyl, lower alkoxy, halogen, NH~2i CP^» acetyl or an acylaminoalkyl group, in which acyl means the residue of an aliphatic, cycloaliphatic, aromatic or a heterocyclic carboxylic acid resp. the residue is a carbamic acid and the alkyl group has 1 to 4 C atoms.

betyr lavere alkyl, cykloalkyl, cykloalkylalkyl og cykloalkenyl, som kan være substituert med en lavere alkyl- eller alkoksygruppe, videre en polyciklisk rest, som kan være bundet til nitrogenatomet over en lavere alkylgruppe. means lower alkyl, cycloalkyl, cycloalkylalkyl and cycloalkenyl, which may be substituted with a lower alkyl or alkoxy group, further a polycyclic residue, which may be bound to the nitrogen atom via a lower alkyl group.

R^ betyr H eller sammen med R^ og naboplassert N-atomdel av en 5- til 7-leddet ring, som eventuelt er substituert med en endoalkylengruppe eller med en lavere alkylgruppe . R^ means H or together with R^ and neighboring N atom part of a 5- to 7-membered ring, which is optionally substituted with an endoalkylene group or with a lower alkyl group.

R^ betyr alkyl med 1 til 3 C-atomer. R 1 means alkyl with 1 to 3 carbon atoms.

I ovennevnte og følgende definisjoner betyr en lavere alkyl resp. lavere alkoksy alltid et slikt med 1 til 4 C-atomer i rettlinjet eller forgrenet kjede og acyl en organisk syrerest. In the above and following definitions, a lower alkyl means resp. lower alkoxy always one with 1 to 4 C atoms in a straight or branched chain and acyl an organic acid residue.

Med organiske baser innen oppfinnelsens ramme for-stås primære, sekundære og tertiære aminer, samt alkalimetallforbindelser av svakt sure organiske forbindelser. Organic bases within the scope of the invention are understood to mean primary, secondary and tertiary amines, as well as alkali metal compounds of weakly acidic organic compounds.

Som eksempler for substituentene R kan nevnes: CH-j-, Cl-, CH-jO-, NH2-, CH^CO og acylaminoalky 1-gruppen, hvori alkylgruppen fortrinnsvis danner en dimetylen-gruppe med formel -CH^-C}^-. Følgelig kommer det som acylamino-alkylgrupper eksempelvis i betraktning Examples of the substituents R can be mentioned: CH-j-, Cl-, CH-jO-, NH2-, CH^CO and the acylaminoalky 1 group, in which the alkyl group preferably forms a dimethyl group with the formula -CH^-C}^ -. Accordingly, acylamino-alkyl groups, for example, come into consideration

CHj-CO-NH-CH^-CH^, CHj-CO-NH-CH^-CH^,

Av de betydninger som kommer på tale for substituentene kan det eksempelvis nevnes: Of the meanings that come up for the substituents, the following can be mentioned, for example:

Som heterocykliske ringer, som R2 kan danne med R-^ og det naboplasserte nitrogenatom, skal det eksempelvis nevnes: As heterocyclic rings, which R2 can form with R-^ and the neighboring nitrogen atom, the following should be mentioned, for example:

Som aminer kan det ved isourinstoffeterspaltningen fungere: lavmolekylære primære alifatiske og cykloalifatiske og ar-alifatiske aminer, sekundære aminer som f.eks. As amines, the following can function in the isourea ether cleavage: low molecular weight primary aliphatic and cycloaliphatic and ar-aliphatic amines, secondary amines such as e.g.

idet de cykliske aminer er foretrukket. Som tertiære aminer kommer det eksempelvis på tale lavmolékylæré trialkylaminer som f.eks. trietylamin og cykliske aminer som f.eks. N-etylpiperidin. Som svakt sure organiske forbindelser egner det seg spesielt karboksyl-syrer som f.eks. eddiksyre, propionsyre eller benzosyre, fenol, sulfonamider og CH-acide forbindelser, som f.eks. aceteddikester. the cyclic amines being preferred. Tertiary amines include, for example, low molecular weight trialkylamines such as triethylamine and cyclic amines such as N-ethylpiperidine. As weakly acidic organic compounds, carboxylic acids such as e.g. Acetic acid, propionic acid or benzoic acid, phenol, sulfonamides and CH-acide compounds, such as e.g. acetic acid esters.

Dette funn er overraskende. This finding is surprising.

Ifølge litteraturangivelser (hollandsk søknad nr. 6.500.013, Chem. Abstr. 64, 2007 (1966)) får man ved omsetning av N-benzyl-N'-metyl-isourinstoffmetyletere med metylamin 1-benzyl-2,3-dimetyl-guanidin. Således var det ved den tilsvarende omsetning av benzensulfonylisourinstoffetere med aminer å vente dannelsen av benzensulfonylguanidiner. According to literature information (Dutch application no. 6,500,013, Chem. Abstr. 64, 2007 (1966)), reaction of N-benzyl-N'-methyl-isourea methyl ethers with methylamine yields 1-benzyl-2,3-dimethyl-guanidine . Thus, in the corresponding reaction of benzenesulfonylisourea ethers with amines, the formation of benzenesulfonylguanidines was to be expected.

Ifølge Robert F. Meyer Journ. Org. Chemistry 28, side According to Robert F. Meyer Journ. Org. Chemistry 28, p

2902 (1963) ble det av p-tolylsulfonylimidoetylkarbonat og pyrrolidin i molforhold 1 : 2 bare oppnådd N-_/—4-metyl-benzensulfonyl7-N'-N'-tetrametylenisourinstoffetyleter. 2902 (1963), from p-tolylsulfonylimidoethyl carbonate and pyrrolidine in a molar ratio of 1:2, only N-_/-4-methyl-benzenesulfonyl-7-N'-N'-tetramethylene isourea ethyl ether was obtained.

Fremgangsmåten ifølge oppfinnelsen er også uventet med hensyn til reaksjonen ifølge Seigo Suzue og Tutomu Irikura. Her foreligger spesielle forhold. Som allerede anført reagerer her aminet med en spesiell forbindelse, nemlig med et sterkt nukleofilt merkaptidion, som nedbrytes i etylensulfid og sulfonylurinstoff. The method according to the invention is also unexpected with respect to the reaction according to Seigo Suzue and Tutomu Irikura. There are special conditions here. As already mentioned, the amine reacts here with a special compound, namely with a strong nucleophilic mercaptidium, which decomposes into ethylene sulphide and sulphonylurea.

Videre er det overraskende at omsetningen av benzensulf onylisourinstoff etere med formel V spesielt med sekundære cykliske aminer forløper overordentelig lett, skånende og med meget godt utbytter. Således kan omsetningen eksempelvis med piperidin på enkel måte foregå således åt man oppløser N-4-metyl-benzensulfonyl-N'-cykloheksyl-isourinstoff--metyleter i tørr piperidin og lar opp-løsningen stå natten over. Etter fortynning med vann og surgjøring får man med en gang et krystallisat av N-4-metylbenzensulfonyl-N'-cykloheksyl-urinstoff i tilnærmet kvantitativt utbytte. Furthermore, it is surprising that the reaction of benzenesulfonyl urea ethers of formula V, especially with secondary cyclic amines, proceeds extremely easily, gently and with very good yields. Thus, for example, the reaction with piperidine can be carried out in a simple way by dissolving N-4-methyl-benzenesulfonyl-N'-cyclohexyl-isourea methyl ether in dry piperidine and leaving the solution overnight. After dilution with water and acidification, a crystallisate of N-4-methylbenzenesulfonyl-N'-cyclohexylurea is immediately obtained in approximately quantitative yield.

Man kan imidlertid også komme til samme resultat når man oppvarmer reaksjonskomponentene kort på dampbad. However, you can also reach the same result when you heat the reaction components briefly in a steam bath.

At det ved reaksjonen dreier seg om en ny fremgangsmåte fremgår av at det eksempelvis ved omsetning av N-4-metylbenzensulfo-nyI-N'-cykloheksyl-isourinstoff-metyleter med piperidin kunne det påvises den (tilnærmet kvantitative) dannelse av en tertiær base (N-metylpiperidin). That the reaction involves a new method is evident from the fact that, for example, by reacting N-4-methylbenzenesulfonyl-N'-cyclohexyl isourea methyl ether with piperidine, the (almost quantitative) formation of a tertiary base could be demonstrated ( N-methylpiperidine).

Det har således funnet sted en transmetylering. Reaksjonen ifølge oppfinnelsen kan gjennomføres uten spesielt oppløsningsmiddel med et overskudd av organisk base, men også under hjelp av oppløsningsmidler, idet det er foretrukket med vann blandbare oppløsningsmidler som alkohol, dioksan, dimetylformamid. Som reaksjonstemperatur kommer det på tale temperaturer mellom værelsestemperatur og ca. 150°C. A transmethylation has thus taken place. The reaction according to the invention can be carried out without a special solvent with an excess of organic base, but also with the help of solvents, water-miscible solvents such as alcohol, dioxane, dimethylformamide being preferred. The reaction temperature refers to temperatures between room temperature and approx. 150°C.

I motsetning til spaltning av sulfonylisourinstoffetere med konsentrert HC1 ifølge Haack (tysk patent nr. 741-533) er fremgangsmåten ifølge oppfinnelsen teknisk lett gjennomførbar, mens derimot håndteringen av større mengder av den nevnte isourinstoffeter med konsentrert saltsyre teknisk ikke ville være fordelaktig. In contrast to the cleavage of sulfonylureas with concentrated HCl according to Haack (German patent no. 741-533), the method according to the invention is technically easily feasible, while, on the other hand, the handling of larger quantities of the aforementioned isoureas with concentrated hydrochloric acid would not be technically advantageous.

Fremgangsmåteproduktene finner anvendelse som Phårmaka til nedsettelse av blodsukkerspeilet. The process products are used as Phårmaka for lowering the blood sugar level.

Eksempel 1. Example 1.

N-/~ 4- metyl- benzensulfonyl7- N'- cykloheksyl- urinstoff. N-/~ 4- methyl- benzenesulfonyl7- N'- cyclohexyl- urea.

1,0 g N-_/—4-metyl-benzensulfonyl/-N'-cykloheksyl-isourinstof fmetyleter, smeltepunkt 114 til 115°C (fra isopropanol) oppløses i 10 ml tørr piperidin. Man lar det stå i 2 dager. Uaktet en ved rysting iakttatt krystalldannelse (piperidinsalt av N-_/ 4- 1.0 g of N-_/—4-methyl-benzenesulfonyl/-N'-cyclohexyl-isourea methyl ether, melting point 114 to 115°C (from isopropanol) is dissolved in 10 ml of dry piperidine. You let it stand for 2 days. Despite a crystal formation observed upon shaking (piperidine salt of N-_/ 4-

metyl-benzensulfonylV-N'-cykloheksyl-urinstoff) fortynner man med vann og surgjør den dannede oppløsning. Man får i tilnærmet kvantitativt utbytte en krystallinsk utfelling av N-_/—4-metyl-benzensul-fonyl/-N'-cykloheksyl-urinstoff)7<;> Etter frasugning, vasking med vann og tørkning omkrystalliseres produktet av metanol. Smeltepunkt 172 til 173°C. Til det samme produkt kommer man likeledes i tilnærmet kvantitativt utbytte, når man oppvarmer nevnte reaksjonskom-ponent i 30 minutter på dampbad og opparbeider den avkjølte reak-sjonsoppløsning deretter på omtalte måte. methyl-benzenesulfonyl V-N'-cyclohexyl-urea) is diluted with water and the resulting solution acidified. A crystalline precipitate of N-_/-4-methyl-benzenesulfonyl/-N'-cyclohexyl-urea)7<;> is obtained in approximately quantitative yield. After extraction, washing with water and drying, the product is recrystallized from methanol. Melting point 172 to 173°C. The same product is also obtained in approximately quantitative yield, when the said reaction component is heated for 30 minutes on a steam bath and the cooled reaction solution is then worked up in the manner described.

På analog måte vil man av N-/ 4-metyl-benzensulfonylV-N'-n-butyl-isourinstoffmetyleter (smeltepunkt 79°C) og piperidin få N-_/ 4-metyl-benzensulfonyl7-N1 -n-butyl-urinstoff av smeltepunkt In an analogous way, from N-/ 4-methyl-benzenesulfonyl V-N'-n-butyl isourea methyl ether (melting point 79°C) and piperidine one will get N-_/ 4-methyl-benzenesulfonyl7-N1 -n-butyl-urea of melting point

127 til 129°C (fra eddikestér). 127 to 129°C (from acetic acid).

Eksempel 2. Example 2.

N-/ 4- metyl- benzensulfonyl7- N'- cykloheksyl- urinstoff. N-/ 4- methyl- benzenesulfonyl7- N'- cyclohexyl- urea.

3,1 g N-/—4-metyl-benzensulfonyl/-N'-cykloheksyl-iso- 3.1 g of N-/-4-methyl-benzenesulfonyl/-N'-cyclohexyl-iso-

r urinstoffmetyleter (1/100 mol) med 4,3 g absolutt piperidin (5/100 r urea methyl ether (1/100 mol) with 4.3 g of absolute piperidine (5/100

mol) oppvarmes kort på dampbad. Den dannede oppløsning lar man stå natten over. Det inntrer krystallutskillelse. Man oppvarmer igjen på dampbad, oppløser krystallisatet i vann og behandler med for- mol) is heated briefly in a steam bath. The resulting solution is allowed to stand overnight. Crystal precipitation occurs. It is heated again in a steam bath, the crystallisate is dissolved in water and treated with

tynnet saltsyre. Det dannede N-/_ 4-metyl-benzensulfony^-N'-cykloheksyl-urinstoff adskilles ved frasugning fra filtratet I. Det fåes ved oppløsning i fortynnet vandig ammoniakk, gjenutfelling med fortynnet syre, frasugning og tørkning i tilnærmet kvantitativt utbytte. (Smeltepunkt etter omkrystallisering fra metanol 172 til 173°C). dilute hydrochloric acid. The formed N-/_ 4-methyl-benzenesulfonyl-N'-cyclohexyl-urea is separated by suction from the filtrate I. It is obtained by dissolution in dilute aqueous ammonia, reprecipitation with dilute acid, suction and drying in approximately quantitative yield. (Melting point after recrystallization from methanol 172 to 173°C).

Filtrat I inndampes og det dannede krystallisat tørkes Filtrate I is evaporated and the crystallisate formed is dried

med P2°5 i eksikator. Ved titrering med HCIO^ i iseddik under til-setning av Hg-acetat for binding av Cl-ioner ble det i en prøve fastslått et samlet basenitrogen på 8,54$, et tertiært basenitrogen på 1,58%; dette tilsvarer 42, 2% piperidin (mol 85) og 11,2? N-metylpiperidin (mol 99). with P2°5 in a desiccator. By titration with HCIO^ in glacial acetic acid while adding Hg acetate to bind Cl ions, a total base nitrogen of 8.54% was determined in one sample, a tertiary base nitrogen of 1.58%; this corresponds to 42.2% piperidine (mol 85) and 11.2? N-methylpiperidine (mol 99).

Eksempel 3- Example 3-

N-/_—4-mety 1-benzensulf ony l7-N' -cykloheksyl-urinstoff. 31 g (1/10 mol) N-/-4-metyl-benzensulfony^/-N' -cyklo-heksy1-isourinstoff-metyleter bringes til oppløsning på dampbad med 43 g (5/10 mol) piperidin ved oppvarmning. Etter ca. 1 time iakttar man krystallutskillelse. Man lar det henstå natten over og oppvarmer deretter kort på dampbad (vetd avpresning på leire og omkrystallisering fra eddikester isolerer man eri. prøve av krystallisatet av smeltepunkt 151 til 152°C. Stoffet ér etter.smeltepunkt og blandingssmeltepunkt identisk med et piperidinsalt av N-/_ 4-metyl-benzensulfony]/7-N'-cykloheksylurinstoff, dannet ved behandling av urinstoff med piperidin. N-/_—4-methyl 1-benzenesulfony 17-N' -cyclohexylurea. 31 g (1/10 mol) of N-/-4-methyl-benzenesulfonyl-/-N'-cyclohexyl-isourea methyl ether are dissolved on a steam bath with 43 g (5/10 mol) of piperidine by heating. After approx. Crystal precipitation is observed for 1 hour. It is left overnight and heated then briefly on a steam bath (by pressing on clay and recrystallization from acetic acid, one isolates a sample of the crystallisate with a melting point of 151 to 152°C. The substance is, by melting point and mixture melting point, identical to a piperidine salt of N-/_ 4-methyl-benzenesulfony] /7-N'-cyclohexylurea, formed by treating urea with piperidine.

Blandingens hovedmengde blandes under omrøring med vann The main quantity of the mixture is mixed with water while stirring

og fortynnet saltsyre til kongosur reaksjon. Man frasuger på denne måte dannet krystallisat av N-/_ 4-metyl-benzensulfonyl/-N»-cykloheksyl-urinstoff , vasker med vann og tørker. Utbyttet av råstoff . er tilnærmet kvantitativt. Etter omkrystallisering i metanol smelter sulfonylurinstoffet ved 172 til 173°C. and dilute hydrochloric acid to Congo acid reaction. The crystallisate of N-/_ 4-methyl-benzenesulfonyl/-N-cyclohexyl-urea formed in this way is filtered off with suction, washed with water and dried. The yield of raw material. is approximately quantitative. After recrystallization from methanol, the sulfonylurea melts at 172 to 173°C.

Den etter isolering av N-/_ 4-metyl-benzensulfony]1/-N'-cykloheksylurinstoff dannede vandige saltsyreoppløsning inndampes. The aqueous hydrochloric acid solution formed after isolation of N-/_ 4-methyl-benzenesulfonyl]1/-N'-cyclohexylurea is evaporated.

Det inntrer krystallutskillelse. Ved frasugning isolerer man 11,5 g piperidin-hydroklorid. Moderluten blander man med konsentrert natron-lut og utetrer igjen. Eteroppløsningen tørkes med kaliumkarbonat og inndampes. Crystal precipitation occurs. By suction, 11.5 g of piperidine hydrochloride are isolated. The mother liquor is mixed with concentrated caustic soda and filtered again. The ether solution is dried with potassium carbonate and evaporated.

Ved destillering får man en baseblanding, idet det i mas-sespektrogram lar seg påvise N-metyl-piperidin ved siden av piperidin. ... Eksempel 4. By distillation, a base mixture is obtained, as it is possible to detect N-methyl-piperidine next to piperidine in the mass spectrogram. ... Example 4.

N-A<->4-metyl-benzensulfonyl7-N'-cykloheksyl-urinstoff. N-A<->4-methyl-benzenesulfonyl7-N'-cyclohexylurea.

En-blanding av 1 g N-/<->4-metyl-benzensulfonyl/-N'-cykloheksyl-isourinstoff-metyleter og 10 ml pyrrolidin oppvarmes 30 minutter på dampbad. Den dannede oppløsning fortynnes med vann A mixture of 1 g of N-/<->4-methyl-benzenesulfonyl/-N'-cyclohexyl isourea methyl ether and 10 ml of pyrrolidine is heated for 30 minutes on a steam bath. The resulting solution is diluted with water

og surgjøres med fortynnet saltsyre. Etter krystallisatets frasugning isolerer man i tilnærmet kvantitativt utbytte N-/ 4-metylbenzen-sulfonyl7-N'-cykloheksyl-urinstoff av smeltepunkt 172 til 173°C etter omkrystallisering fra metanol. and acidified with dilute hydrochloric acid. After suctioning off the crystallisate, N-/4-methylbenzenesulfonyl7-N'-cyclohexylurea of melting point 172 to 173°C is isolated in approximately quantitative yield after recrystallization from methanol.

På analog måte får man av det samme utgangsmaterial det samme sluttprodukt, når man istedenfor pyrrolidin anvender N-benzyl-piperazin eller cykloheksylamin. In an analogous way, the same starting material gives the same final product, when N-benzyl-piperazine or cyclohexylamine is used instead of pyrrolidine.

Eksempel 5-N- benzensulfonyl- N'- isobuty1- urinstoff. ' Example 5-N-benzenesulfonyl-N'-isobuty1-urea. '

En blanding av 1 g N-benzensulfonyl-N'-isobutyl-iso-urinstoffmetyleter (smeltepunkt 75 til 76°C) og 10 ml morfolin oppvarmes 30 minutter på dampbad. Man fortynner med vann, surgjør med fortynnet saltsyre og isolerer den dannede utfelling ved frasugning. A mixture of 1 g of N-benzenesulfonyl-N'-isobutyl-iso-urea methyl ether (melting point 75 to 76°C) and 10 ml of morpholine is heated for 30 minutes on a steam bath. Dilute with water, acidify with dilute hydrochloric acid and isolate the formed precipitate by suction.

Det i godt utbytte dannede N-benzensulfonyl-N'-isobuty1-urinstoff smelter etter omkrystallisering fra metanol ved 132 til 133°C. The N-benzenesulfonyl-N'-isobutyl urea formed in good yield melts after recrystallization from methanol at 132 to 133°C.

På analog måte får man N-benzensulfonyl-N'-isobutyl-urinstoff fra den innledningsvis "nevnte isourinstoffeter ved anvendelse av piperidin istedenfor morfolin. Istedenfor å oppvarme reaksjonskomponentene på dampbad kan man la deres blanding stå noen dager ved værelsestemperatur og på den nevnte måte isolere det dannede N-benzensulfonyl-N'-isobuty1-urinstoff. In an analogous way, N-benzenesulfonyl-N'-isobutylurea is obtained from the initially "mentioned isourea ether by using piperidine instead of morpholine. Instead of heating the reaction components on a steam bath, you can let their mixture stand for a few days at room temperature and isolate it in the aforementioned manner it formed N-benzenesulfonyl-N'-isobuty1-urea.

Eksempel 6. Example 6.

N-/_ 4 - ( B-N ' -metyl-N ' -2-pyridy 1-ureidoetyl)-benzensulf ony 1./-N' - cykloheksyl- urinstoff. 1 g N-/_ 4-(B-N'-metyl-N'-2-pyridy1-ureidoetyl)-benzensulfony]V-N'-cykloheksy1-isourinstoff-metyleter (smeltepunkt 117 til 118°C fra isopropanol) oppløses i 20 ml tørr piperidin. Etter hen-stand natten over ved værelsestemperatur fortynner man med vann og surgjør den dannede oppløsning med eddiksyre. Det utfelte produkt oppløses i meget fortynnet vandig ammoniakk. Man surgjør igjen med eddiksyre og isolerer det i tilnærmet kvantitativt utbytte dannede N-/_ 4- ( B-N ' -metyl-N ' -2-pyridyl-ureidoety 1 )-benzensulf ony l7-N ' - cykloheksyl-urinstoff ved frasugning. Stoffet smelter etter omkrystallisering fra metanol ved 167 til l69°C. N-/_ 4 - (B-N'-methyl-N'-2-pyridy 1-ureidoethyl)-benzenesulfony 1./-N'-cyclohexyl-urea. 1 g of N-/_ 4-(B-N'-methyl-N'-2-pyridy1-ureidoethyl)-benzenesulfony]V-N'-cyclohexy1-isourea methyl ether (melting point 117 to 118°C from isopropanol) is dissolved in 20 ml of dry piperidine. After standing overnight at room temperature, dilute with water and acidify the resulting solution with acetic acid. The precipitated product is dissolved in very dilute aqueous ammonia. It is again acidified with acetic acid and isolated in approximately quantitative yield formed N-/_ 4-(B-N'-methyl-N'-2-pyridyl-ureidoety 1 )-benzenesulfony l7-N'-cyclohexyl-urea by suction. The substance melts after recrystallization from methanol at 167 to 169°C.

Eksempel 7. Example 7.

N-/_ 4- (B-<5-klor-2-metoksy-benzamido>-ety1)-benzensulfony1/-N'-cykloheksyI- urinstoff. 1 g N-/ 4-(3-<5-klor-2-metoksy-benzarnido>-etyl )-benzensulfony_l/-N '-cykloheksy 1-isourinstof f-metyleter (smeltepunkt 99 til 101°C fra metanol) oppløses i 10 ml ren piperidin. Man lar det henstå natten over, oppvarmer deretter ennå i 10 minutter på dampbad. N-/_ 4-(B-<5-chloro-2-methoxy-benzamido>-ethyl)-benzenesulfonyl/-N'-cyclohexyl-urea. 1 g of N-[4-(3-<5-chloro-2-methoxy-benzarnido>-ethyl)-benzenesulfonyl]-N'-cyclohexy 1-isourea f-methyl ether (melting point 99 to 101°C from methanol) is dissolved in 10 ml pure piperidine. You let it stand overnight, then reheat for another 10 minutes in a steam bath.

Man iakttar en krystallutskillelse. (De isolerte krystaller viser Crystal precipitation is observed. (The isolated crystals show

seg som piperidindalt av N-/_—4-(3-<5-klor-2-metoksy-benzamido>-ety 1)-benzensulfony_l/-N'-cykloheksyl-urinstoff, smeltepunkt 105 til 1D8°C (fra eddikester)). Etter fortynning med vann får man ved surgjøring av den dannede oppløsning i tilnærmet kvantitativt utbytte N-/_ 4-(B-<5-klor-2-rnetoksy-benzamido>-ety1)-benzensulfonyl/-N'-cykloheksyl-urinstoff, som etter oppløsning i meget fortynnet vandig ammoniakk, gjenutfelling med saltsyre, frasugning og omkrystallisering fra metanol smelter ved 172 til 174°C. as the piperidine alt of N-[-4-(3-<5-chloro-2-methoxy-benzamido>-ethyl)-benzenesulfonyl-1/-N'-cyclohexylurea, mp 105 to 1D8°C (from acetic ester) ). After dilution with water, by acidifying the resulting solution, N-/_ 4-(B-<5-chloro-2-rnetoxy-benzamido>-ethyl)-benzenesulfonyl/-N'-cyclohexyl-urea is obtained in approximately quantitative yield, which after dissolution in very dilute aqueous ammonia, reprecipitation with hydrochloric acid, suction and recrystallization from methanol melts at 172 to 174°C.

På analog måte vil man av samme utgangsmaterial få det nevnte sulfonylurinstoff under anvendelse av pyrrolidon (idet pyrro-lidinsaltet av N-/_ 4-(B-<5-klor-2-metoksy-benzamido>-etyl)-benzen-sulfonyl7-N'-cykloheksyl-urinstoff, smeltepunkt 100 til 102°C oppstår som mellomprodukt) og under anvendelse•av morfolin (over morfolin-•saltet av N-/_ 4-(3-<5-klor-2-metoksy-benzamido>-etyl )-benzensulfony_l/-N'-cykloheksy luri nst off. In an analogous way, the aforementioned sulfonylurea will be obtained from the same starting material using pyrrolidone (wherein the pyrrolidine salt of N-/_ 4-(B-<5-chloro-2-methoxy-benzamido>-ethyl)-benzene-sulfonyl7- N'-cyclohexyl-urea, m.p. 100 to 102°C occurs as intermediate) and using•morpholine (over the morpholine-•salt of N-/_ 4-(3-<5-chloro-2-methoxy-benzamido> -ethyl )-benzenesulfonyl_l/-N'-cyclohexy luri nst off.

Eksempel 8. Example 8.

N-/_ 4-met<y>l-benzensulfony_l/-N'-cykloheksyl-urinstoff. N-/_ 4-met<y>l-benzenesulfony_l/-N'-cyclohexylurea.

1 g N-/_ <4>-met<y>l-benzensulfon<y>_l/-N '-cykloheksyl-iso-urinstoff-metyleter, 5 g piperazin og 5 ml dimetylformamid oppvarmes 1 g of N-/_ <4>-meth<y>l-benzenesulfon<y>__l/-N '-cyclohexyl-iso-urea-methyl ether, 5 g of piperazine and 5 ml of dimethylformamide are heated

1 time på dampbad. 1 hour in a steam bath.

Man fortynner med vann og surgjør den klare oppløsning. Dilute with water and acidify the clear solution.

Den dannede utfelling frafiltreres, oppløses i fortynnet ammoniakk. Ved surgjøring med fortynnet saltsyre får man i godt utbytte en utfelling av praktisk talt rent N-/_ 4-metyl-benzensulf onyl/-N' - cykloheksyl-urinstoff. The formed precipitate is filtered off, dissolved in dilute ammonia. By acidifying with dilute hydrochloric acid, a precipitation of practically pure N-/_ 4-methyl-benzenesulfonyl/-N'-cyclohexyl-urea is obtained in good yield.

Man suger fra og tørker. Etter omkrystallisering fra metanol smelter produktet ved 172 til 173°C. You vacuum and dry. After recrystallization from methanol, the product melts at 172 to 173°C.

Eksempel 9» Example 9»

N-/_ 4-klor-benzensulf onyl/—N' -n-propy 1-urinstof f (klorpropamid). N-/_ 4-Chloro-benzenesulfonyl/—N' -n-propyl 1-urea f (chloropropamide).

1,45 g N-/_ 4-klor-benzensulfony 1/-N '-n-propy 1-isourinstof f-metyleter (smeltepunkt 75 til 77°C fra isopropanol) oppløses i .15 ml piperidin. Man lar det stå 2 dager ved værelsestemperatur. Ved utrivning får man et krystallisat, som man frasuger og etter-vasker med eter. Smeltepunkt 137 til 139°C. (Etter omkrystallisering fra eddikester, smeltepunkt 137 til 139°C). Det dreier seg om piperi dinsaltet av klorpropamid. (Identifisering ved smeltepunkt og blandingssmeltepunkt med en fra klorpropamid og piperidin dannet prøve 1.45 g of N-/_ 4-chloro-benzenesulphonyl/-N'-n-propyl 1-isourea f-methyl ether (melting point 75 to 77° C. from isopropanol) are dissolved in .15 ml of piperidine. Let it stand for 2 days at room temperature. During extraction, a crystallisate is obtained, which is suctioned off and then washed with ether. Melting point 137 to 139°C. (After recrystallization from acetic ester, melting point 137 to 139°C). It concerns piperi salted with chlorpropamide. (Identification by melting point and mixture melting point with a sample formed from chlorpropamide and piperidine

av smeltepunkt 137 til 139°C). Man oppløser det dannede piperidinsalt av klorpropamid i vann. Ved surgjøring får man i meget godt utbytte N-_/ 4-klor-benzensulf ony_l/-N '-n-propy 1-urinstof f av smeltepunkt 129°C (fra vandig etanol). of melting point 137 to 139°C). The formed piperidine salt of chlorpropamide is dissolved in water. By acidification, N-_/ 4-chloro-benzenesulfony_l/-N '-n-propy 1-urea of melting point 129°C (from aqueous ethanol) is obtained in very good yield.

Eksempel 10. Example 10.

N-/__4-mety 1-benzensulf ony l7-N '-cykloheksyl-urinstoff. N-/__4-methyl 1-benzenesulfony 17-N'-cyclohexyl-urea.

En blanding av 1 g N-/_~4-metyl-benzensulfonyl/-N '-cykloheksylisourinstoff-etyleter (smeltepunkt 75 til 76°C, fra etanol) og 10 ml piperidin oppvarmes 2 timer på dampbad. Etter fortynning med vann og filtrering under kulltilsetning surgjøres med fortynnet saltsyre. Det derved utfelte N-/_ 4-mety1-benzensulfonyl/- A mixture of 1 g of N-/_~4-methyl-benzenesulfonyl/-N'-cyclohexylurea ethyl ether (melting point 75 to 76° C., from ethanol) and 10 ml of piperidine is heated for 2 hours on a steam bath. After dilution with water and filtration under charcoal addition, acidify with dilute hydrochloric acid. The thereby precipitated N-/_ 4-methyl-benzenesulfonyl/-

.N'-cykloheksylurinstoff frasuges og smelter etter omkrystallisering fra metanol ved 172 til T73°C: Eksempel 11. .N'-cyclohexylurea is sucked off and melts after recrystallization from methanol at 172 to T73°C: Example 11.

N- £ 4-metyl-benzensulfonyl/-N',Nr-tetrametylen-urinstoff. N- £ 4-methyl-benzenesulfonyl/-N',Nr-tetramethylene-urea.

1 g N-_/ 4-metyl-benzensulfony_l/-N' ,N'-tetrametylen-iso-urinstoffetyleter og 10 ml pyrrolidin oppvarmes 30 minutter på dampbad. Etter fortynning med vann og filtrering surgjøres med fortynnet saltsyre. Det etterhvert utkrystalliserende N-/~4-metyl-benzensulfony JL/-N ' ,N '-tetramety len-urinstof f . fraf iltreres og smelter etter omkrystallisering fra etanol ved 212 til 2l4°C. 1 g of N-_/ 4-methyl-benzenesulfonyl_1/-N',N'-tetramethylene-iso-urea ethyl ether and 10 ml of pyrrolidine are heated for 30 minutes on a steam bath. After dilution with water and filtration, acidify with dilute hydrochloric acid. The eventually crystallising N-/~4-methyl-benzenesulfony JL/-N ' ,N '-tetramethylene-urea f . is filtered off and melts after recrystallization from ethanol at 212 to 214°C.

På analog måte vil man av In an analogous way, one wants off

N-/_ 4-metyl-benzensulfony31/~N ' ,N '-pentametylen-iso-urinstoffetyleter med piperidin få N-/_ 4-methyl-benzenesulfony31/~N ' ,N '-pentamethylene-iso-urea ethyl ether with piperidine get

N-/_ 4-metyl-benzensulf ony_l/-N' ,N '-pentametylen-urinstof f av smeltepunkt 149 til 151°C (fra metanol), N-/_ 4-methyl-benzenesulfonyl-1/-N',N'-pentamethylene-urea of melting point 149 to 151°C (from methanol),

av N-/_ 4-metyl-benzensulf ony ]./-N' -buty 1-isourinstof f-etyleter med piperidin få of N-/_ 4-methyl-benzenesulfony ]./-N'-buty 1-isourea f-ethyl ether with piperidine get

N-/_ 4-metyl-benzensulf onyl/-N '-buty 1-urinstof f av N-/_ 4-methyl-benzenesulfonyl/-N '-buty 1-urea f av

smeltepunkt 127 til 129°C (fra metanol). mp 127 to 129°C (from methanol).

Eksempel 12. Example 12.

N-/<_> 4-(B-<5-klor-2-metyl-benzoksazol-7-karboksamido>-ety1)-benzensulf ony JL/-N ' - cykloheksyl-urinstoff. 1 g N-/_ 4-(3-<5-klor-2-metyl-benzoksazol-7-karboksamido>-e ty 1)- benzensulf ony 1./-N '-cykloheksy 1-isourinstof f-metyleter, (smeltepunkt 119_121°C fra isopropanol) oppløses i 10 ml rent piperidin ved 30°C. N-[<_> 4-(B-<5-chloro-2-methyl-benzoxazole-7-carboxamido>-ethyl)-benzenesulfony JL/-N '-cyclohexyl-urea. 1 g N-/_ 4-(3-<5-chloro-2-methyl-benzoxazole-7-carboxamido>-e ty 1)-benzenesulfony 1./-N '-cyclohexy 1-isourea f-methyl ether, ( melting point 119-121°C from isopropanol) is dissolved in 10 ml of pure piperidine at 30°C.

Man lar det stå natten over og heller oppløsningen på fortynnet eddiksyre. Man får i tilnærmet kvantitativt utbytte en utfelling av N-/_ 4-( 3-<5-klor-2-metyl-benzoksazol-7-karboksamido>-etyl)-benzensulfonyl/-N'-cykloheksyl-urinstoff som man oppløser#i meget fortynnet vandig ammoniakk og igjen utfeller ved surgjøring med fortynnet eddiksyre. Stoffet smelter etter frasugning og omkrystallisering fra metanol ved 195 til 197°C. One leaves it overnight and pours the solution on diluted acetic acid. One obtains in approximately quantitative yield a precipitate of N-/_ 4-(3-<5-chloro-2-methyl-benzoxazole-7-carboxamido>-ethyl)-benzenesulfonyl/-N'-cyclohexyl-urea which is dissolved# in very dilute aqueous ammonia and again precipitates when acidified with dilute acetic acid. The substance melts after extraction and recrystallization from methanol at 195 to 197°C.

Eksempel 13- Example 13-

N-( 4- me tylbenzensulfonyl)- N'- cykloheksylurinstoff. N-(4-methylbenzenesulfonyl)-N'-cyclohexylurea.

1 g N-(4-metyl-benzensulfonyl)-N'-cykloheksyl-isourin-stoffmetyleter og 10 ml absolutt trietylamin oppvarmes 4 timer under tilbakeløp til kokning. Det overskytende amin avdestiUeres under nedsatt trykk, residuet blandes med fortynnet saltsyre og det uopp-løste frasuges. Det således dannede N-(4-metylbenzensulfonyl)-N'-cykloheksylurinstoff gjenutfelles fra 1%-ig vandig ammoniakk/fortynnet saltsyre. Det smelter etter omkrystallisering fra metanol ved 170-172°C. 1 g of N-(4-methyl-benzenesulfonyl)-N'-cyclohexyl-isourea methyl ether and 10 ml of absolute triethylamine are heated for 4 hours under reflux to boiling. The excess amine is distilled off under reduced pressure, the residue is mixed with dilute hydrochloric acid and the undissolved is sucked off. The N-(4-methylbenzenesulfonyl)-N'-cyclohexyl urea thus formed is reprecipitated from 1% aqueous ammonia/diluted hydrochloric acid. It melts after recrystallization from methanol at 170-172°C.

Eksempel 14. Example 14.

N-( 4- metylbenzensulfony1)- N1- cykloheksylurinstoff. N-(4- methylbenzenesulfony1)- N1- cyclohexylurea.

0,5 g N-(4-mety1-benzensulfony1)-N<1->cykloheksyl-iso-urinstoffmetyleter og 5 ml N-etylpiperidin oppvarmes 4 timer på dampbad. Man fjerner overskytende amin i vakuum, blander residuet med fortynnet saltsyre og frasuger. Det i godt utbytte dannede N-(4-metylbenzensulfony1)-N'-cykloheksylurinstoff gjenutfelles fra fortynnet vandig ammoniakk/fortynnet saltsyre og omkrystalliseres fra metanol. Det smelter ved 170-172°C. 0.5 g of N-(4-methyl-benzenesulfonyl)-N<1->cyclohexyl-iso-urea methyl ether and 5 ml of N-ethylpiperidine are heated for 4 hours on a steam bath. Excess amine is removed in a vacuum, the residue is mixed with dilute hydrochloric acid and suction is applied. The N-(4-methylbenzenesulfonyl)-N'-cyclohexylurea formed in good yield is reprecipitated from dilute aqueous ammonia/diluted hydrochloric acid and recrystallized from methanol. It melts at 170-172°C.

Eksempel 15. Example 15.

N-( 4- metylbenzensulfony1)- N'- cykloheksylurinstoff. N-(4-Methylbenzenesulfonyl)-N'-Cyclohexylurea.

0,5 g N-(4-metyl-benzensulfonyl)-N'-cykloheksyl-iso-urinstoffmetyleter, 5 g natriumacetat vannfri og 100 ml DMP (Prosynthese) oppvarmes 6 timer på dampbad. DMF avdestilleres i vakuum, residuet behandles med fortynnet saltsyre og utfellingen frasuges. Reaksjonsblandingen utrøres med ljS-ig vandig ammoniakk, uoppløst frafiltreres og filtratet surgjøres med fortynnet saltsyre. Det utfelte N-(4-metylbenzensulfony1)-N'-cykloheksylurinstoff frasuges og omkrystalliseres fra metanol. Smeltepunkt 170-172°C. Eksempel 16. 0.5 g N-(4-methyl-benzenesulfonyl)-N'-cyclohexyl-iso-urea methyl ether, 5 g anhydrous sodium acetate and 100 ml DMP (Prosynthesis) are heated for 6 hours on a steam bath. DMF is distilled off in a vacuum, the residue is treated with dilute hydrochloric acid and the precipitate is suctioned off. The reaction mixture is stirred with 100% aqueous ammonia, undissolved is filtered off and the filtrate is acidified with dilute hydrochloric acid. The precipitated N-(4-methylbenzenesulfonyl)-N'-cyclohexylurea is sucked off and recrystallized from methanol. Melting point 170-172°C. Example 16.

N-( 4- metylbenzensulfonyl)- N'- cykloheksylurinstoff. N-(4-methylbenzenesulfonyl)-N'-cyclohexylurea.

0,5 g N-(4-metylbenzensulfonyl)-N'-cykloheksyl-isourin-stoffmetyleter, 3 g benzosyre-natrium og 100 ml dimetylformamid (Prosynthese) oppvarmes 4 timer på dampbad. Oppløsningsmidlet avdestilleres i vakuum, residuet behandles med fortynnet saltsyre, uoppløst frasuges, deretter behandles med eter og frasuges igjen. 0.5 g of N-(4-methylbenzenesulfonyl)-N'-cyclohexyl-isourea methyl ether, 3 g of sodium benzoic acid and 100 ml of dimethylformamide (Prosynthesis) are heated for 4 hours on a steam bath. The solvent is distilled off in a vacuum, the residue is treated with dilute hydrochloric acid, undissolved is filtered off, then treated with ether and filtered off again.

Det således dannede N-(4-metylbenzensulfonyl)-N'-cykloheksylurinstoff gjenutfelles fra vandig ammoniakk/fortynnet saltsyre. Det smelter etter omkrystallisering fra metanol ved 170-172°C. Eksempel 17. The N-(4-methylbenzenesulfonyl)-N'-cyclohexylurea thus formed is reprecipitated from aqueous ammonia/diluted hydrochloric acid. It melts after recrystallization from methanol at 170-172°C. Example 17.

N-( 4- metylbenzensulfony1)- N'- cykloheksylurinstoff. N-(4-Methylbenzenesulfonyl)-N'-Cyclohexylurea.

1,5 g N-(4-metylbenzensulfonyl)-N'-cykloheksylisourin-stoff-metyleter og 0,97 g p-toluensulfonamidnatrium blandes godt 1.5 g of N-(4-methylbenzenesulfonyl)-N'-cyclohexylurea methyl ether and 0.97 g of p-toluenesulfonamide sodium are mixed well

og oppvarmes 2 timer ved 125°C i oljebad. Reaksjonsblandingen behandles etter avkjøling med fortynnet saltsyre og frasuges. Deretter utrører man med 155-ig vandig ammoniakk, frafiltrerer og surgjør filtratet med fortynnet saltsyre. Det utfelte N-(4-metyl-benzensulfonyl)-N'-cykloheksylurinstoff frasuges og omkrystalliseres fra metanol, smp. 170-172°C. and heated for 2 hours at 125°C in an oil bath. After cooling, the reaction mixture is treated with dilute hydrochloric acid and suctioned off. The mixture is then stirred with 155 µg of aqueous ammonia, filtered off and the filtrate acidified with dilute hydrochloric acid. The precipitated N-(4-methyl-benzenesulfonyl)-N'-cyclohexylurea is filtered off with suction and recrystallized from methanol, m.p. 170-172°C.

Eksempel 18- Example 18-

Nll4 r?}§ tY lbenzensulf onyl 2zN^2cy_kloheksy_lurinstof f Nll4 r?}§ tY lbenzenesulf onyl 2zN^2cy_clohexy_lurinstof f

1,5 g N-(4-metylbenzensulfonyl)-N'-cykloheksyl-isourinstoffmetyleter og 0,6 g fenol-natrium blandes godt og oppvarmes 2 timer ved 125°C i oljebad. Reaksjonsblandingen behandles etter avkjølingen med fortynnet saltsyre og frasuges. Deretter utrører man med vandig ammoniakk, frafiltrerer, surgjør filtratet med fortynnet saltsyre og frasuger. 1.5 g of N-(4-methylbenzenesulfonyl)-N'-cyclohexyl isourea methyl ether and 0.6 g of phenol-sodium are mixed well and heated for 2 hours at 125°C in an oil bath. After cooling, the reaction mixture is treated with dilute hydrochloric acid and suctioned off. The mixture is then stirred with aqueous ammonia, filtered off, the filtrate acidified with dilute hydrochloric acid and filtered off with suction.

Det i godt utbytte dannede N-'( 4-metylbenzensulfonyl)-N'-cykloheksylurinstoff omkrystalliseres fra metanol og smelter ved 170-172°C. The N-'(4-methylbenzenesulfonyl)-N'-cyclohexylurea formed in good yield is recrystallized from methanol and melts at 170-172°C.

Claims (1)

Fremgangsmåte til fremstilling av benzensulfony1-urinstoffer med formel:Process for the preparation of benzenesulfony1-ureas of formula: hvori R betyr lavere alkyl, lavere alkoksy, halogen, -NH"2, trifluormety 1, acetyl eller acylaminoalkylgruppen, hvori, acyl betyr resten av en alifatisk, cykloalifatisk, aromatisk eller en heterocyklisk karboksylsyre resp. resten av en karbaminsyre og alkylgruppen har 1 til 4 C-atomer, R^ betyr lavere alkyl, cykloalkyl, cykloalkylalkyl, eller cykloalkeny1 som kan være substituert med en lavere alkyl-eller alkoksygruppe eller betyr en polycyklisk rest, som over en lavere alkylgruppe kan være bundet til nitrogenatomet, R2 betyr hydrogen eller sammen med R-, og det naboplasserte N-atom en 5- til 7-leddet ring, som eventuelt er substituert med en lavere alkylgruppe eller endoalkylengruppen, samt deres salter, karakterisert ved at man behandler benzensulfonylisourinstoffetere med formel: hvori R, R-^ og R2 har ovennevnte betydning og R^. betyr alkyl med 1 til 3 C-atomer med aminer eller alkalimetallforbindelser av r;vakt sure organiske forbindelser og isolerer reaksjonsproduktene enten som salter eller frie syrer.in which R means lower alkyl, lower alkoxy, halogen, -NH"2, trifluoromethyl 1, acetyl or the acylaminoalkyl group, in which, acyl means the residue of an aliphatic, cycloaliphatic, aromatic or a heterocyclic carboxylic acid or the residue of a carbamic acid and the alkyl group has 1 to 4 C atoms, R^ means lower alkyl, cycloalkyl, cycloalkylalkyl, or cycloalkeny1 which can be substituted with a lower alkyl or alkoxy group or means a polycyclic residue, which via a lower alkyl group can be bound to the nitrogen atom, R2 means hydrogen or together with R- and the neighboring N-atom a 5- to 7-membered ring, which is optionally substituted with a lower alkyl group or the endoalkylene group, as well as their salts, characterized by treating benzenesulfonylisourea ethers with the formula: in which R, R-^ and R 2 have the above-mentioned meaning and R^. means alkyl with 1 to 3 C atoms with amines or alkali metal compounds of weakly acidic organic compounds and isolates the reaction products either as salts or free acids.
NO4443/73A 1972-11-21 1973-11-20 R PROCEDURE FOR THE PREPARATION OF BENZENESULPHONYLURINE SUBSTANCE NO139086C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE2256979A DE2256979C3 (en) 1972-11-21 1972-11-21 Process for the preparation of benzenesulfonylureas

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NO139086B true NO139086B (en) 1978-09-25
NO139086C NO139086C (en) 1979-01-03

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JP (1) JPS5735713B2 (en)
AT (1) AT336630B (en)
CA (1) CA1024986A (en)
CH (1) CH592054A5 (en)
DE (1) DE2256979C3 (en)
DK (1) DK139427C (en)
ES (1) ES420557A1 (en)
NO (1) NO139086C (en)
SE (1) SE402281B (en)
YU (1) YU300573A (en)

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Publication number Priority date Publication date Assignee Title
EP0031088A1 (en) * 1979-12-19 1981-07-01 Hoechst Aktiengesellschaft Benzene-sulfonyl ureas, processes for their preparation, pharmaceutical compositions based on these compounds and their use
JPS5936813U (en) * 1982-08-31 1984-03-08 吉田　得一郎 Filtration device in bathtub
JPH0415291Y2 (en) * 1987-02-24 1992-04-07
JPH0212410U (en) * 1988-07-08 1990-01-25
US7803786B2 (en) * 2004-06-17 2010-09-28 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions and related methods of use

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YU300573A (en) 1982-06-18
DK139427C (en) 1979-07-30
DE2256979B2 (en) 1980-08-28
DE2256979C3 (en) 1981-05-21
JPS5735713B2 (en) 1982-07-30
SE402281B (en) 1978-06-26
ATA972173A (en) 1976-09-15
CA1024986A (en) 1978-01-24
CH592054A5 (en) 1977-10-14
DE2256979A1 (en) 1974-05-30
ES420557A1 (en) 1976-04-16
NO139086C (en) 1979-01-03
DK139427B (en) 1979-02-19
AT336630B (en) 1977-05-10
JPS4981344A (en) 1974-08-06

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