CH403749A - Process for the preparation of 1-cyclohexyl-3- (p-trifluoromethyl-benzenesulfonyl) -urea - Google Patents

Process for the preparation of 1-cyclohexyl-3- (p-trifluoromethyl-benzenesulfonyl) -urea

Info

Publication number
CH403749A
CH403749A CH442865A CH442865A CH403749A CH 403749 A CH403749 A CH 403749A CH 442865 A CH442865 A CH 442865A CH 442865 A CH442865 A CH 442865A CH 403749 A CH403749 A CH 403749A
Authority
CH
Switzerland
Prior art keywords
trifluoromethyl
cyclohexyl
urea
preparation
benzenesulfonyl
Prior art date
Application number
CH442865A
Other languages
German (de)
Inventor
Cannon Cheney Lee
Gaston Perron Yvon
Original Assignee
Bristol Myers Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Co filed Critical Bristol Myers Co
Publication of CH403749A publication Critical patent/CH403749A/en

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Classifications

    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms

Description

  

  



   Verfahren zur Herstellung von   1-Cyclohexyl-3- (p-trifluormethyl-benzolsulfonyl)-harnstoff   
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von l-Cyclohexyl-3- (p-trifluor  methyl-benzolsulfonyl)-harnstoff.    Diese neue Verbindung der Formel
EMI1.1     
 weist   hypoglykämische    Wirksamkeit auf und eignet sich zur Behandlung gewisser Diabetiker.



   Das erfindungsgemässe Verfahren verläuft in zwei Stufen und ist dadurch gekennzeichnet, dass man   4-Trifluormethyl-benzolsulfonamid    mit einem Alkylchlorformiat in das entsprechende Carbamat überführt und letzteres mit Cyclohexylamin umsetzt.



  Vorzugsweise lässt man hierbei das Sulfonamid mehrere Stunden lang mit dem Chlorformiat reagieren und verwendet einen Chlorameisensäureester mit niedriger Alkylgruppe.



   Das als Ausgangssubstanz für das erfindungsgemässe Verfahren verwendete   4-Trifluormethyl-    benzolsulfonamid ist eine neue Substanz, die sich nach einer im Schweiz. Patent Nr. 399 434 beschriebenen Arbeitsweise herstellen lässt.



   Beispiel
Zu 225 g (1,0 Mol) 4-Trifluormethyl-benzolsulfonamid und 358 g (2,6 Mol) einer wasserfreien Lösung von Kaliumcarbonat in 1,2 Liter Aceton wird langsam unter Rühren 163 g (1,32 Mol) Äthylchlorformiat im Verlauf von 3 Stunden zugegeben. Nach dem Abkühlen in einem Eisbad wird das Reaktionsgemenge filtriert und das Filtrat unter vermindertem Druck eingeengt. Der Rückstand wird in 3 Liter Wasser aufgenommen. Die erhaltene Lösung wird filtriert und langsam unter Kühlen angesäuert, wobei das weisse kristalline Carbamat entsteht.



   Zu 29,7 g (0,1 Mol) des getrockneten derart hergestellten Carbamats werden 29,0 g (0,3 Mol) Cyclohexylamin zugefügt. Das Gemisch wird in Benzol auf dem Wasserbad während ungefähr 10 Minuten erhitzt, worauf Auflösung eintritt. Das Benzol wird hierauf aus dem Gemenge bei 120 bis   140  C    unter vermindertem Druck abgetrieben und der Rückstand aus einem Wachsbad während unge  fähr    3 Stunden auf 135 bis   140     erwärmt. Der Rückstand wird aufgelöst in ungefähr 175 ml siedenden Isopropanols und die Lösung hierauf filtriert, wonach das Filtrat auf 500 ml mit Wasser bei unge  fähr      100     verdünnt wird.

   Das erhaltene verdünnte Filtrat, welches das gewünschte Produkt enthält, wird abkühlen und über Nacht stehengelassen, worauf das ausgefallene feste Produkt abfiltriert wird. Die kristalline Substanz wird hierauf in 500 ml einer wässrigen Lösung von Natriumcarbonat (5 %) gelöst und die Lösung filtriert, wonach die unlösliche feste Substanz mit zwei Portionen von je 100 ml Wasser gewaschen wird. Das Filtrat wird angesäuert und abgekühlt, worauf das Produkt ausfällt, abfiltriert wird und aus   Isopropanol/Wasser    umkristallisiert wird. Man   erhältfarbloseKristalledes l-Cyclohexyl-3-      (p-trifluormethyl-benzolsulfonyl)-harnstoffs    mit einem Smp. von 181 bis   183 .   



  Analyse :
Berechnet für   CsgHi7FsNS03S    (Molekulargewicht
350,36) : C 48,00% H 4,90%   %   
Gefunden : C 47,94% H 4,81%
Das erhaltene Präparat, das ebenfalls als   l- (p-      Trifluormethyl-benzolsulfonyl)-3-cyclohexyl-harnstoff    bezeichnet werden kann, erweist sich bei oraler Verabreichung als wirksames   hypoglykämisches    Agens von geringer Toxizität.



  



   Process for the preparation of 1-cyclohexyl-3- (p-trifluoromethyl-benzenesulfonyl) -urea
The present invention relates to a process for the preparation of l-cyclohexyl-3- (p-trifluoro methylbenzenesulfonyl) urea. This new compound of formula
EMI1.1
 has hypoglycemic activity and is suitable for the treatment of certain diabetics.



   The process according to the invention runs in two stages and is characterized in that 4-trifluoromethylbenzenesulfonamide is converted with an alkyl chloroformate into the corresponding carbamate and the latter is reacted with cyclohexylamine.



  The sulfonamide is preferably allowed to react with the chloroformate for several hours and a chloroformic acid ester with a lower alkyl group is used.



   The 4-trifluoromethylbenzenesulfonamide used as the starting substance for the process according to the invention is a new substance that is based on one in Switzerland. Patent No. 399,434 can produce the operation described.



   example
To 225 g (1.0 mol) of 4-trifluoromethyl-benzenesulfonamide and 358 g (2.6 mol) of an anhydrous solution of potassium carbonate in 1.2 liters of acetone, 163 g (1.32 mol) of ethyl chloroformate are slowly added with stirring over the course of Added 3 hours. After cooling in an ice bath, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 3 liters of water. The resulting solution is filtered and slowly acidified with cooling, the white crystalline carbamate being formed.



   29.0 g (0.3 mol) of cyclohexylamine are added to 29.7 g (0.1 mol) of the dried carbamate produced in this way. The mixture is heated in benzene on the water bath for approximately 10 minutes, after which dissolution occurs. The benzene is then driven off from the mixture at 120 to 140 C under reduced pressure and the residue is heated from a wax bath to 135 to 140 for about 3 hours. The residue is dissolved in approximately 175 ml of boiling isopropanol and the solution is then filtered, after which the filtrate is diluted to 500 ml with water at approximately 100%.

   The dilute filtrate obtained, which contains the desired product, is cooled and left to stand overnight, whereupon the precipitated solid product is filtered off. The crystalline substance is then dissolved in 500 ml of an aqueous solution of sodium carbonate (5%) and the solution is filtered, after which the insoluble solid substance is washed with two 100 ml portions of water. The filtrate is acidified and cooled, whereupon the product precipitates, is filtered off and is recrystallized from isopropanol / water. Colorless crystals of l-cyclohexyl-3- (p-trifluoromethylbenzenesulfonyl) urea with a melting point of 181 to 183 are obtained.



  Analysis:
Calculated for CsgHi7FsNS03S (molecular weight
350.36): C 48.00% H 4.90%%
Found: C 47.94% H 4.81%
The preparation obtained, which can also be referred to as l- (p-trifluoromethylbenzenesulfonyl) -3-cyclohexylurea, proves to be an effective hypoglycemic agent of low toxicity when administered orally.

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von l-Cyclohexyl-3- (p-trifluormethyl-benzolsulfonyl)-harnstoff, dadurch gekennzeichnet, dal3 man 4-Trifluormethyl-benzolsulfonamid mit einem Alkylchlorformiat in das entsprechende Carbamat überführt und letzteres mit Cyclohexylamin umsetzt. PATENT CLAIM Process for the preparation of l-cyclohexyl-3- (p-trifluoromethyl-benzenesulfonyl) -urea, characterized in that 4-trifluoromethyl-benzenesulfonamide is converted with an alkyl chloroformate into the corresponding carbamate and the latter is reacted with cyclohexylamine. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man das Sulfonamid mehrere Stunden lang mit dem Chlorameisensäureester reagieren lässt. SUBCLAIMS 1. The method according to claim, characterized in that the sulfonamide is allowed to react with the chloroformic acid ester for several hours. 2. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man ein niedriges Alkylchlorformiat verwendet. 2. The method according to claim, characterized in that a lower alkyl chloroformate is used.
CH442865A 1959-02-24 1960-02-24 Process for the preparation of 1-cyclohexyl-3- (p-trifluoromethyl-benzenesulfonyl) -urea CH403749A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US79483259A 1959-02-24 1959-02-24

Publications (1)

Publication Number Publication Date
CH403749A true CH403749A (en) 1965-12-15

Family

ID=25163812

Family Applications (2)

Application Number Title Priority Date Filing Date
CH442865A CH403749A (en) 1959-02-24 1960-02-24 Process for the preparation of 1-cyclohexyl-3- (p-trifluoromethyl-benzenesulfonyl) -urea
CH209860A CH399434A (en) 1959-02-24 1960-02-24 Process for the preparation of therapeutically active sulfonylureas

Family Applications After (1)

Application Number Title Priority Date Filing Date
CH209860A CH399434A (en) 1959-02-24 1960-02-24 Process for the preparation of therapeutically active sulfonylureas

Country Status (5)

Country Link
CH (2) CH403749A (en)
ES (1) ES256000A1 (en)
FR (1) FR611M (en)
GB (2) GB899583A (en)
SE (1) SE302964B (en)

Also Published As

Publication number Publication date
SE302964B (en) 1968-08-12
CH399434A (en) 1965-09-30
FR611M (en) 1961-06-19
GB899584A (en) 1962-06-27
ES256000A1 (en) 1960-09-01
GB899583A (en) 1962-06-27

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