Патент USA US2558071код для вставки
Patented June 26, 1951 2,558,068 UNITED STATES ‘PATENT OFFICE 2,558,068 PROCESS OF PRODUCING 3,4-DIMETHYL-5 PHENYL-Z-IMINOTHIAZOLIDINES Anton Wolf, Heidelberg, Germany 1 N0 Drawing. Application August 23, 1949, Serial No. 111,979 10 Claims. (Cl. 260—306.7) . The present invention relates to organic com 2 an organic solvent, e. g. methanol, ethanol, vdi pounds being useful for therapeutic application. butyl ether, the chlorine-substitution products of More speci?cally the invention relates to a new ‘hydrocarbons, such as chlorofrom or ethylene di chloride, furthermore'benzene or pyridine, can be process of producing substituted 2-iminothiazoli dines, exactly speaking 3,4-dimethyl-5-phenyl-2 used apart from water. In the above described process the reaction products are produced as salts of the thiocyanic acid. The thiocyanates can be transformed into iminothiazolidines these compounds representing chemotherapeutic substances of high value. 3,4-dimethyl-5-phenyl-2-iminothiazolidines are produced by causing a thiocyanic acid salt to act upon l-phenyl-l-chloro-2-methylamino-propane hydrochloride in the presence of a solvent or sus 'a salt of any other acid according to known 10 methods. > The following examples are inserted in order to pension medium. The reaction takes place in two illustrate the above describedinvention. , well distinguishable stages the ?rst one compris (1.) 1.5 kg. of racemic l-phenyl-1-chloro—2 ing heating both reaction components in an acid methylamino-propane hydrochloride I are sus reactive medium having a pH of 1—2.5 this stage 15 pended in 6 liters of ethyl alcohol together with leading to the formation of l-phenyl-l-thiocyan 1.15 kg. of ammonium thiocyanate and 25- g. of _2-methylamino-propane, the second one compris dry caustic potash or caustic soda and the reac ing the further heating of the reaction product tion mixture is heated at a re?ux condenser for of the ?rst stage in an alkaline reactive medium two hours. The reaction product having cooled having a pH of 5.4-8.5 this stage leading to 3,4 20 down the precipitate which has formed and is dimethyl-5-phenyl-2-iminothiazolidine_ a nucleus having been formed. Advantageously both phases composed of 3,4-dimethyl-5-phenyl-2-iminothi azolidine thiocyanate and ammonium chloride is of the reaction are combined into one single stage extracted with water in order to remove the am monium chloride. The remaining vsalt of the itial products in an alkaline reactive medium from 25 thiazolidine is recrystallized from hot water. The the combination being realized by heating the in the beginning of the reaction; 3,4-dimethyl-5 pheny1-2-iminothiazolidine is the immediate re action product. l-phenyl-1-thiocyan-2-methyl thiocyanate of the'base melts in the pure'state at 190-192“ C. The yield amounts toabout 80% of the theoretical yield. - amino-propane, however, can also be used as in itial material and can be converted into 3,4-di The free base is precipitated by adding an al 30 kali to the aqueous solution of the ‘dimethyl methyl-5-phenyl-2-iminothiazolidine by being phenyl-iminothiazolidine thiocyanate. The free heated in an alkaline reactive medium. base is an oil which can be converted into its If the above named two reaction components hydrochloride by dissolving the oil in ‘ethyl alco are caused to react with each other in a neutral hol, drying the solution and treating it with hy organic solvent, heating at a re?ux condenser for 35 drochloric acid dissolved-in ethyl alcohol; the hy 8 hours is necessary. But if an alkaline agent, drochloride has the melting point of 222°-224° C. e. g. a caustic alkali, ammonia, methylamine, aniline, ephedrin, pyridine or quinoline, are added to the organic solvent, the reaction is ?nished after a short time. Instead of l-phenyl-1-chloro-2-methylamino propane hydrochloride the analogously consti tuted l-phenyl-1-bromo-2-methylamino-propane hydrobromide can be used as starting material. If the levorotatory l-phenyl-l-chloro-Z-meth ylamino-propane hydrochloride is used as start ing material, the above described method results 40 in the formation of the thiocyanic acid salt of d-3,4-dimethyl-5-phenyl-2-iminothiaz0lidine, the thiocyanate having the melting point of 1'70'-171° C., and a 5% methanol solution of this thiocya nate shows the speci?c rotationof [a]D2°°=—|-124=°. If the optically active 3,4-dimethyl-5-phenyl-2 By dlSSOlVillg the resulting thiocyanate in Water iminothiazolidines are intended to be produced, and adding an alkali to the aqueous solution the the levorotatory - l - phenyl - l-chloro-Z-methyl free base is precipitated as an oil which is con amino-propane hydrochloride is used as starting verted into the hydrochloride of the base by treat material for producing the dextrorotatory com ing. the oil with hydrochloric acid dissolved in pound from which by being acted upon with a 50 ethyl alcohol. The hydrochloride melts at thiocyanic acid salt the thiocyanic acid salt of 235-238° C. It is likewise dextrorotatory the d-3,4-dimethyl-5-phenyl-2-iminothiazolidine can speci?c rotation of . a 5% aqueous solution, be produced. In an analogous manner d-l phenyl-1-chloro-2-methylamino~propane hydro chloride leads to the thiocyanate of 1-3,4—di methyl-5-phenyl-2-iminothiazolidine. Preferably the alkali salts of thiocyanic acid are used in the process of the present invention, e. g. the sodium salt, the potassium salt or the ammonium salt. As solvent or suspension medium amounting to [a]D2°°=+l56.4°. In an analogous manner the hydrochloric acid salt‘ of l-3,4-dimethyl-5-phenyl-2-iminothiazoli dine is formed, if the dextrorotatory l-phenyl-l chloro-2-methylamino-propane hydrochloride is used as-starting material in the above ‘described process. The l-3,4-dimethyl-5-phenyl-2-imino thiazolidine hydrochloride has the melting point 2,558,068 4 3. 2. The process of producing 3,4-dimethy1-5 of 235-238° C. and shows in a 5% aqueous solu tion the speci?c rotation of . . phenyl-Z-iminothiazolidine which process com prises causing a salt of thiocyanic acid to act upon 1-phenyl-1-chloro-2-methylamino-propane hy (2.) 26.6 g. of the thiocyanic acid salt of 1-. phenyl-l-thiocyan-Z-methylamino-propane are dissolved in 150 com. of water while heating and drochloride suspended in a diluent vehicle in which the reactive materials are at least partly soluble while making alkaline the pH of the 5 com. of concentrated caustic soda solution are reaction mixture. - 3. The process of producing 3,4-dimethyl-5 added to the solution. Crystals of the thiocyanic acid salt of dimethyl-phenyl-iminothiazolidine 10 phenyl-Z-iminothiazolidine which process com begin to separate very soon. The yield amounts prises causing the ammonium salt of thiocyanic to 23.5 g., that are 88% of the theoretical yield. acid to act upon 1-phenyl-l-halogen-Z-methyl (3.) 18.75 g. of racemic 1-phenyl-1-chloro-2 amino-propane hydrohalide suspended in a dil methylamino~propane hydrochloride and 14.5 g. uent vehicle in which the reactive materials are of ammonium thiocyanate are suspended in a 15 at least partly soluble while making alkaline the .mixture being composed of 450 ccm. of ethylene pH of the reaction mixture. dichloride and 50 ccm. of pyridine and heated at 4. The process of producing 3A-dimethyl-5 ' a reflux condenser on the water bath for 1/2 hour. phenyl-2-iminothiazo1idine which process com The reaction product is further treated as has prises causing the ammonium salt of thiocyanic been described in Example 1. The yield amounts 20 acid to act upon 1-phenyl-l-chloro-2-methyl to 12.8 g. corresponding to 61.2% of the theoretical amino-propane hydrochloride suspended in a dil yield. ' uent vehicle in which the reactive materials are (4.) 18.75 g. of racemic l-phenyl-l-chloro-Z at least partly soluble while making alkaline the methylamino-propane hydrochloride, 14.5 g. of pH of the reaction mixture. ~ ammonium thiocyanate and 10 g. of l-ephedrin 25 5. The process of producing 3,4-dimethyl-5 are suspended in 500 com. ethylene dichloride phenyl-2-iminothiazolidine which process com and heated at a re?ux condenser on the water prises causing a salt of thiocyanic acid to act upon bath for 2 hours. The reaction product is cooled l-phenyl-1-halogen-2-methylamino-propane hy down to 0° C., the separating mass of crystals is drohalide in an aqueous alkaline medium having ?ltered with suction and then carefully washed a pH of 5.4-8.5. out with ethylene dichloride and subsequently 6. The process of producing 3,4-dimethyl-5 with water. The yield amounts to 17.9 g. corre phenyl-2-iminothiazolidine which process com sponding to 85.5% of the theoretical yield. prises causing a salt of thiocyanic acid to act upon (5.) 37.5 g. of raceznic 1-phenyl-1-chloro-2 1-phenyl-1-halogen-2-methylamino-propane hy methylamino-propane hydrochloride are sus drohalide suspended in a diluent vehicle in which pended in 200 com. of water, 29 g. of the am the reactive materials are at least partly soluble monium salt of thiocyanic acid are added to the containing an alkaline reactive agent. suspension and the mixture is heated to about '7. The process of producing 3,4-dimethyl-5 80° C. on the water bath for one hour a pH of phenyl-2-iminothiazolidine which process com 1-2.5 being maintained. The reaction product prises the steps consisting in heating l-phenyl after having cooled down separates as a mass of 1-halogen-2-methylamino-propane hydrohalide crystals and 33 g. of the thiocyanic acid salt of and a salt of thiocyanic acid suspended in a dile l-phenyl-1-thiocyan-2-methylamino-propane of uent vehicle in which the reactive materials are the melting point of 135-139“ C. are obtained; at least partly soluble while maintaining a pH this yield amounts to 81.2% of the theoretical of 1-2.5 in the reaction mixture and subsequent yield. The corresponding free base melts at ly heating the previously formed l-phenyl-l '75-'78° C., the hydrochloride of the base melts at thiocyan-Z-methylamino-propane in an alkaline 208-210° C. reactive medium having a pH of 5.4-8.5. 26.6 g. of the thiocyanic acid salt of l-phenyl 8. The process of producing 3,4-dimethyl-5 1-thiocyan-2-methylamino-propane are dissolved 50 phenyl-2-iminothiazolidine which process com in 150 com. of water while heating and 5 com. of prises the step consisting in heating the thiocyanic concentrated caustic soda solution are added to acid salt of l-phenyl-1-thiocyan-2-methylamino— the solution. Crystals of the thiocyanic acid salt propane suspended in a diluent vehicle in which of dimethyl-phenyl-iminothiazolidine begin to the reactive materials are at least partly soluble. separate very soon. The yield amounts to 23.5 g., i ~ 9. The process of producing 3,4-dimethyl-5 that are 88% of the theoretical yield. phenyl-2-iminothiazolidine which process com After having fully described and disclosed the prises the step consisting in heating the thiocyanic present invention, what I claim is: acid salt of l-phenyl-l-thiocyan-2-methylamino 1. The process of producing substituted 2 iminothiazolidines, chosen from the group con sisting of the racemic, the levorotatory and the propane suspended in a diluent vehicle in which the reactive materials are at least partly soluble while making alkaline the pH of the reaction dextrorotatory 3,4 - dimethyl-5-phenyl—2-imino mixture. thiazolidine which process comprises causing a salt of thiocyanic acid to act upon a compound chosen from the group consisting of the racemic, ‘ 10. The process according to claim 8 in which the heating of the thiocyanic acid salt of l-phen ' yl-1-thiocyan-2-methylamino-propane is carried the levorotatory and the dextrorotatory l-phen out in a diluent vehicle which also contains an yl-l-halogen-2-methylamino-propane hydrohal alkaline agent chosen from the group consisting ide, whilst the reactive materials are suspended in a diluent vehicle in which'they are at least partly of caustic alkali, ammonia, methylamine, aniline, ephedrine, pyridine and quinoline. soluble, said vehicle being chosen from the group 70 consisting of methanol, ethanol, di-butyl ether, a ANTON WOLF. chlorine-substitution product of a lower aliphatic hydrocarbon, benzene, pyridine and water. No references cited.