CH506531A - Process for the preparation of new heterocyclic nitrogen compounds - Google Patents

Abstract

Cpds. of general formulae (I) and (II) and pharmaceutical compns. contg. them. where R=H, hydrocarbyl opt. substd. by is not > 6F, Cl or Br and/or at least 1 group chosen from; OH, NH2, HO/amino-hydrocarbyl (hydrocarbyl chain may contain O or N)and/or substd. by: OH, NH2, COOH COOM (M=alkali or alk. earth metal), F, Cl, Br. X=R, -COR, -COOR; but R + X do not contain >30 C Z's = H, F. Espec. the cpds. in which: R = H, X=C(CF3)2NH2, H, CH2OH, CH2NMe2, CH2OCH2OH, Z's = F R=H;X=CF(CF2H)NH2, H, Z=Z2=F Z1=Z3=H R=Et, X=H, Z's=F. The cpds. are CNS-depressants. Useful in treating neurological and psychiatric disorders and in obtaining relaxation under general anaesthesia.

Description

  

  
 



  Process for the preparation of new heterocyclic nitrogen compounds
The invention relates to a process for the preparation of N-acyl derivatives of 4-imino-2,2,5,5-tetrakis (polyhalomethyl) imidazolines or their tautomers. The method of the invention is characterized in that one compounds of the formula
EMI1.1
 in which Z, Zt, Z2 and ZS are hydrogen or fluorine atoms, the alkali metal salts of such compounds are acylated.



   The compounds of the formulas (Ia) and (Ib) have extremely acidic properties. For example, the hydrogen atoms in the N position quickly exchange with deuterium when D2O is added to an acetone solution of the compound, as evidenced by the disappearance of the NH absorption band in the nuclear magnetic resonance spectrum. The exchange of the N hydrogen atoms against each other takes place so quickly that only a single absorption band at 250C from these protons is detected in the nuclear magnetic resonance spectrum.



   Since the compounds of the formulas (Ia) and (Ib) have acidic properties, they can form salts with bases. The salts of the two tautomers are identical.



   For example, 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine is a weak acid. The compound can be treated with a strong base, e.g. Tetramethylammonium hydroxide, can be titrated in a non-aqueous solvent such as pyridine to give a sharp end point. The salt formed during this titration can be represented by the following resonance structures:
EMI1.2
  
4 -acetylimino 2,2,5,5-tetrakis (trifluoromethyl) -imidazolidine (R = H, X = CHsCO- and all Z radicals are F) is a stronger acid.

  The compound can be titrated in water with sodium hydroxide to form a salt that can be represented by the following resonance structures:
EMI2.1

EMI2.2

The compounds of the formulas (Ia) and (Ib) used as starting materials can be prepared by means of the process described in the British patent.



   The compounds obtainable by the process according to the invention have surprising pharmacological effects which are therapeutically valuable in the treatment of neurotic and psychological disorders. They are central depressants that decrease skeletal muscle tone. This is a desirable property for the treatment of hypertension and hyperkinesis. This property is also valuable as it induces relaxation in general anesthesia.



   Preferred compounds of the formulas (Ia) and (Ib) correspond to the formulas:
EMI2.3

The above-mentioned compounds are as such preferred pharmacological agents and additionally serve as precursors for other compounds which are prepared by conventionally known chemical processes.



   The preparation of the compounds of the formulas (Ia) and (Ib) can be represented by the following scheme
EMI3.1

The polyfluoromethylethylamino-substituted intermediate can be isolated.



   If more than two Z radicals are to be different in the reaction zone, more than one imine must of course be used in the reaction mixture, with more than one product being obtained. Furthermore, of course, the stoichiometry of the intermediate compound requires that 3 moles of the imine react with 1 mole of the inorganic cyanide, but the proportions of the reactants in the reaction mixture are relatively unimportant except for saving or preserving material.



  The order in which the reactants are mixed is not essential.



   The process for the preparation of compounds (Ia) and (Ib) is preferably carried out in an inert reaction medium, e.g. in dimethylformamide, dimethyl sulfoxide, liquid nitriles, e.g. Acetonitrile and benzonitrile, glycol ethers, e.g. B. Dimethyl ethers of ethylene and in diethylene glycols.



   The reaction is exothermic and the addition of the imine to the alkali metal cyanide or of the cyanide to the imine is regulated in such a way that the reaction temperature remains in the range from about -400C to about 1000C. The temperature is preferably kept in the lower part of this possible range in order to largely eliminate the formation of by-products. After the reactants have been added, the reaction mixture is treated with a dilute aqueous solution of a mineral acid, e.g.



     10% of hydrochloric acid, acidified. If hexafluoroisopropylidenimine is used as the imine reaction component, 4- [l -amino-2,2,2-trifluoro- - I - (trifluoromethyl) ethylaminol -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline is obtained . This intermediate is dissolved in concentrated sulfuric acid and left for a few minutes, e.g. 10 minutes, held at a temperature of about 100-1500C. After cooling to 200 ° C., the solution is poured onto crushed ice, whereupon solid 4-imino -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine is precipitated. This product is isolated and purified in the usual way.



   The imines of the formula
EMI3.2
 used as starting materials in the above-described process can be prepared in various ways. Halofluoroisopropylidenimine can be prepared by the methods described in US Pat. No. 3,226,439 by the applicant and in J. Org. Chem. 30, 1938 (1965). The imines in which Z or Z1 or both are hydrogen can be prepared by a modification of the method of Zeifman et al., Akad. Nauk S.S.S.R. Doklady, 153, 1334 (1963) for the preparation of hexafluoroisopropylidenimine.

  In the process for the preparation of pentafluoroisopropylidenimine, pentafluoroacetone is first reacted with phenyl isocyanate at about 2000C in the presence of a catalytic amount of a triarylphosphine oxide to form - N-phenylpentafluoroisopropylidenimine, which is then treated with ammonia to form N-phenyl-2,2-diamino-pentafluoropropane becomes. This product, which does not have to be isolated or purified before the next and last stage, is then reacted with phosphorus pentoxide, whereby it splits off aniline with the formation of pentafluoroisopropylidenimine.

 

   Suitable acylating agents are acyl halides and anhydrides or substituted acyl halides and anhydrides and ketenes. In the special case in which oxalyl chloride is used as the acylating agent, 4-isocyanate-2,2,5,5-tetrakis (polyfluoromethyl) 3-imidazolines are formed, and these isocyanates can be further reacted with alcohols to form carbamates.



   Example I A. Preparation of 4- [1-amino-2,2,2-trifluoro-1 - (trifluoromethyl) ethylamino] -2,2,5,5-tetrakis (trifluoromethyl) -3 imidazoline
R = H; X = -C (CF3) 2NH2; all remainders Z = F)
EMI4.1

At −100 ° C., 20 ml of hexafluoroisopropylidenimine (about 30.8 g, 0.187 mol) were slowly distilled into a stirred suspension of 3.06 g (0.0625 mol) of powdered sodium cyanide in 50 ml of dimethyl sulfoxide. An exothermic reaction began. The addition of the imine was regulated so that the temperature of the reaction mixture did not rise above 650.degree. After the addition, which took about 20 minutes, the reaction mixture became homogeneous. The mixture was cooled to 200 ° C. and then poured into 500 ml of water containing 100 ml of 10% hydrochloric acid.

  The oil which formed was separated off by decanting the aqueous phase. After adding 500 ml of fresh water, the oil and the water were shaken vigorously. The oil froze. The solid was separated on a filter and pressed dry and then dried over phosphorus pentoxide in a vacuum desiccator. Here, 24.1 g (74% of theory) 4- [1-amino-2,2,2-trifluoro- 1 - (trifluoromethyl) - ethylamino] 2,2,5,5-tetrakis (trifluoromethyl) - 3 - -imidazoline as a hydrophobic white solid of melting point.



  45-460C were obtained. A sample was recrystallized from pentane for analysis. The FI9-NMR spectrum in CDC13 showed two septets (J = 5.0 Hz) centered at 72.8 and 77.9 ppm from trichlorofluoromethane, which served as an internal standard, and one singlet at 79.8 ppm, all of the same Surface. The proton spectrum in CDC13 showed two very broad singlets at 5.55 and 3.57 ppm (each area 1) and one broad singlet at 3.08 ppm (area 2) from tetramethylsilane, which served as the internal standard. The infrared spectrum showed a band at 5.97 u.



  Analysis for C1oH4Fl8N4:
Calculated: C 23.00 H 0.77 F 65.49
Found: C 23.21 H 0.91 F 65.23 B. Preparation of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine
R = X = H: all Z = F radicals
EMI4.2

4- [1-amino-2,2,2-trifluoro- - 1 - (trifluoromethyl) - ethylaminoj 2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline prepared according to Part A in an amount of 47.1 g was dissolved in 100 ml of concentrated sulfuric acid. The solution was slowly heated to 1500 ° C. while stirring and held at this temperature for 10 minutes. The solution foamed during the heating. The solution was then cooled to 200 ° C. and poured onto 1 liter of crushed ice.

  The white solid that formed was separated on a filter after the ice had melted and washed with water. Recrystallization from an alcohol-water mixture (1: 2) gave 31.5 g (98% yield) of 4-imino-2,2,5,5-tetrakis (trifluoro methy]) imidazoline in the form of long, colorless Needles with a melting point of 158-1,590C were obtained.



   Example 2 Preparation of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) - -imidazoline R = X = H; all residues Z = F
The removal of the polyfluoromethylethylamino substituent from the intermediate is described
The effectiveness of this compound, 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine, as a muscle relaxant can be seen from the fact that it stimulates the righting reflex in mice (Domino et al., J. Pharmacol, Exptl.



  Therap., 105, 486-497 (1952)] and the elimination of rigorous decerebration in cats [Goodman, L., Bull. New.



  England Med. Center 5, 97-100 (1943)]. The compound has 10 to 60 times the activity of chlordiazepoxide, an agent widely used in the treatment of musculoskeletal disorders. It also has a therapeutic quotient of 12 in the mouse relaxation test compared to 6.5 for chlordiazepoxide.



   Example 3 4-Imino-2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl) imidazolidine R = X = H; Z = Z2 = F; Z1 = Z3 = H
EMI5.1
 manure, i.e. Step 2 of the process by heating the reaction mixture of the first step while removing the solvent by distillation at normal pressure.



   Hexafluoroisopropylidenimine (25 g, 0.15 mol) was slowly distilled into a stirred suspension of 10 g (0.2 mol) of sodium cyanide in 50 ml of acetonitrile. An exothermic reaction began. The temperature of the mixture was kept below 350C by cooling. After the addition, the reaction mixture was stirred for 30 minutes at room temperature, after which 50 ml of water were added. The pH of the solution was adjusted to 7 by adding a small amount of hydrochloric acid.



  The organic layer was separated, washed twice with water and dried with anhydrous magnesium sulfate. The liquid was distilled off at normal pressure and the solid residue was recrystallized twice from benzene using decolorizing charcoal. 4.1 g (15% of theory) of 4-imino -2,2,5,5-tetrakis- (trifluoromethyl) -imidazoline were obtained as colorless needles with a melting point of 159-1600 ° C. The proton NMR spectrum in dimethyl sulfoxide contained a broad singlet at + 7.2 ppm (area 2) and a sharp singlet at + 6.06 ppm (area 1). The 15F resonance spectrum in acetone contained a pair of septets (J = 4.7 Hz) at 71.5 and 76.5 ppm from trichlorofluoromethane, which was used as an internal standard.

  The infrared spectrum contained bands at 2.85, 2.9, 2.96, 3.04, 3.10, 3.16, 5.9 and 6.2. The very strong band at 5.9 shows that the 4-iminotautomer is present in larger quantities.



  Analysis for C; H3F12N3:
Calculated: C 23.55 H 0.85 F 63.85 N 11.77
Found: C 23.77 H 1.35 F 64.05 N 12.05
A solution of 24.1 g (0.163 mol) of pentafluoroisopropylidenimine (prepared in the manner described below) in 50 ml of dimethylformamide was cooled to OOC and 4.9 g (0.1 mol) of powdered sodium cyanide were added in portions over 30 minutes. By cooling, it was ensured that the temperature did not rise above 50C. The reaction mixture was stirred for 2 hours at 250 ° C. and then poured into 200 ml of 10C hydrochloric acid.

  The oil that parted, namely crude 4- [1-amino-2,2-difluoro- 1 - (trifluoromethyl) ethylamino] -2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl) -3- imidazoline, was washed with 200 ml of water and then dissolved in 25 ml of 20% fuming sulfuric acid.



  The sulfuric acid solution was heated to 1500C, cooled and poured over 25 g of ice. The solid which formed was filtered off and washed with water.



  Sublimation at 100 ° C. (10 mm Hg) gave 2.9 g of a white crystalline powder with a melting point of 118-1195 ° C. (closed capillary, product A).

 

   The filtrate was further diluted with 200 ml of water and made slightly basic with 50% aqueous potassium hydroxide. The precipitate that formed was filtered off, washed with water, air-dried and sublimed at 1000 ° C. (10 mm Hg). This gave 5.79 g of 4-imino-2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl) (imidazalidine as a white crystalline powder with a melting point of 142-1440 ° C. (closed capillary, product B) 19F resonance spectrum of product B in acetone showed that it was a mixture of two isomers, one of which was predominant.

  The CF3 area showed a complex multiplet at +72.8 ppm (3F) and complex multiplets in a ratio of about 1: 2 at 77.1 and 77.7 ppm (both together 3F); the CF2H region showed two doublets (J = 54 Hz) that were further split into complex multiplets centered at + 127.0 and + 131.0 ppm. The H resonance spectrum showed two triplets (J = 54 Hz) with shoulders centered at X 3.56 and X 3.98 (each 1 H), one broad absorption at w 5.12 (1 H) and one very broad absorption at -3.0 (2H). The infrared absorption spectrum showed a band at 5.91 tt for C = N.



  Analysis for CTHsF1oN3
Calculated: C 26.18 H 1.57 F 59.17 N 13.08
Found: C 26.49 H 1.45 F 59.15 N 12.92
The pentafluoroisopropylidenimine used as starting material can be prepared as follows: Phenyl isocyanate is reacted with pentafluoroacetone in the presence of triphenylphosphine oxide at 2000C to form N-phenylpentafluoroisopropylidenimine. This product is reacted first with ammonia and then with phosphorus pentoxide to give the desired pentafluoroisopropylidenimine.



   Example 4 3-methyl and 3-methyl-4-methylimino derivatives of 4 -imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine R = CH,; X = H and -CH3; all residues Z = F
EMI6.1

A solution of 10.0 g of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 20 ml of dimethyl sulfate was heated rapidly to the boil (about 180 ° C.). 50 ml of water were added dropwise to the hot reaction mixture in order to decompose the excess dimethyl sulfate. The resulting solution was then cooled and neutralized with about 135 ml of 10% aqueous sodium hydroxide. The white solid which separated out was filtered off, washed thoroughly with water and air-dried. This gave 9.42 g of a crude mixture of methylated derivatives.

  Gas chromatographic analysis in a column filled with chamotte that had been impregnated with the petroleum fat aApiezon L at 95-C showed that the mixture of 73% of the dimethyl derivative (second eluted component) and 23% of the monomethyl derivative (first eluted Component) existed.



   The two compounds were separated by fractional crystallization from pentane. The progress of the recrystallizations was followed by gas chromatography and each component was recrystallized until its purity was higher than 99%.



   The component with the lowest solubility was pure 4-imino-3-methyl-2,2,5-tetrakis (trifluoromethyl) - imidazolidine (the original, 23% component) in the form of colorless needles with a melting point of 121-1220C (closed capillary ) receive. The infrared spectrum showed a band at 5.95 u for C = N.



  The 2 "F resonance spectrum in acetone showed a septet (J = 4.6 Hz) centered at 73.6 ppm and a multiplet at 75.4 ppm in CCI3F as an internal standard.



  The 1H resonance spectrum in (CD3) 2CO showed a septet (JHF = 0.85 Hz) at 3.12 ppm (area 3) and two broad absorptions at 8.1 u. 5.95 ppm (both area 1).



  Analysis for C8HsF12N3
Calculated: C 25.89 H 1.36 F 61.43 N 11.32
Found: C 25.92 H 1.54 F 60.73 N 11.92
Pure 3-methyl -4-methylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine was obtained as the most soluble component (the original component of 73%) in the form of a white crystalline powder with a melting point of 48490C. The infrared spectrum showed a band at 5.92 Z for C = N. The 19F resonance spectrum in acetone showed a pair of septets (J = 46 Hz) at 73.6 and 75.4 ppm from CCI3F as the internal standard. The 1H resonance spectrum in (CD,) - CO showed singlets at 3.33 and 3.02 ppm (both area 3) and a broad absorption at 6.25 ppm (area 1) from (CH3) 4Si as internal standard.



  Analysis for C0H7F13N3:
Calculated: C 28.06 H 1.83 F 59.20 N 10.91
Found: C 28.30 H 1.89 F 58.51 N 10.65
Example 5 3-Ethyl-4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine R = -C.H! I; X = H; all residues Z = F
EMI6.2
  
A mixture of 5.0 g of 4-imino-2,2,5,5-tetrakis- (trifluoromethyl) imidazoline and 10 ml of diethyl sulfate was heated to the boil for 5 minutes (about 200 ° C.). Water was carefully added to the hot reaction mixture in order to decompose the excess diethyl sulfate. After adding 1.0 g of activated charcoal, the mixture was filtered. The filtrate was neutralized with 10% aqueous sodium hydroxide and the precipitated solid was filtered off and recrystallized from pentane.

  This gave 2.48 g of 3-ethyl-4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in the form of colorless needles with a melting point of 113-1 140 ° C. (closed capillary). The infrared spectrum contained a band at 5.96 't.



  The 1'F resonance spectrum in acetone showed two septets (J = 4.6 Hz) at 73.7 and 75.4 ppm centered from CCI3F, which served as an internal standard. The 'H resonance spectrum showed two broad absorptions at 6.30 and 7.75 ppm (both area 1), a quartet (J = 7 Hz) centered at 3.54 ppm (area 2) and a triplet (J = 7 Hz ) centered at 1.15 ppm (area 3) from (CH4) 4Si; that served as an internal standard.



  Analysis for C9HTF12N3:
Calculated: C 28.06 H 1.83 F 59.20 N 10.91
Found: C 28.40 H 2.16 F 58.96 N 11.16
Example 6 4-Dimethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline
R = X = -CH3; all residues Z = F phie analyzed. The two main components, excluding the solvent, were isolated from the escaping gases using a trap filled with liquid nitrogen. The compound, which was first eluted on a silicone column, gave 3-methyl-4-methylimino -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine (about 1 g was isolated).

  The compound eluted second (0.8 g isolated) with a melting point of 30-330 ° C. was identified as 4-dimethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline according to the following analytical values: 'H resonance spectrum : sharp line for (CH) 2N at 3.19 ppm and NH at 6.05 ppm; 19F resonance spectrum: septet pair (J = 4 Hz) at +69.4 and +7.78 ppm from FCCIS as internal standard at 56.4 MHz. Infrared spectrum: in the ring C = N at 6.12 u and sharp line for NH at 2.88 u.



  Analysis for Cl, H, NsFl2 (385.17):
Calculated: C 28.06 H 1.83 F 59.20 N 10.91
Found: C 28.51 H 2.28 F 59.33 N 10.85
Example 7 A. 3-Ethyl-4-ethylamino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine and (B. 4-ethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3- imid azoline
A. R = -C2H>; X = -C2H3; all residues Z = F
B. R = H; X = -C2H5; all residues Z = F
EMI7.1

10.0 g of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine and 30 ml of dimethyl sulfate (excess) were placed in an 80 ml autoclave, which was lined with the corrosion-resistant alloy of the trade name (<Hastelloy) given and held at 2000C for 8 hours.

  The autoclave was cooled to OOC and vented. Excess dimethyl sulfate in the dark residue obtained (44 g) was decomposed at the boiling point by adding 10 ml of water dropwise under reflux over the course of 0.5 hours. The mixture was cooled and neutralized with dilute sodium hydroxide solution. A white semi-solid was obtained by extraction with ether and subsequent washing with water, drying over magnesium sulphate and evaporation of the ether extracts. The semi-solid was dissolved in a hot ether-pentane mixture, cooled and. filtered.



  The filtrate was determined by preparative gas chromatography
A solution of 20.0 g of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 50 ml of diethyl sulfate was
Heated to reflux for 75 minutes. 20 ml of water were carefully added to the hot reaction mixture in order to decompose any excess diethyl sulfate.

 

   The black reaction mixture was diluted with 300 ml of water and neutralized with 6N sodium hydroxide.



   The organic phase was separated by steam distillation (total volume 100 ml) and subsequent extraction of the distillate with ether. Concentration gave 23.8 g of a mixture of solid and oil. The whole sample was again with 40 ml
Treated diethyl sulfate under reflux and isolated in the manner described above, 21.5 g of an oil were obtained. The gas chromatographic analysis showed that the oil consists of 56% of a substance with a retention time of 10.9 minutes, 33% of a substance with a retention time of 12.6 minutes, 7% 3-ethyl-4-imino '.', 5.5 -tetrakis (trifluoromethyl) imidazolidine and 2% unreacted starting material.



   Pure samples of the two main components were obtained by preparative gas chromatography. The first eluted compound (A) was 3-ethyl-4-ethylimino-1 5 5-tetrakis (trifluoromethyl) imidazolidine, which was isolated as an oil with a refractive index nx, 23 of 1.3624.



  An analytical sample was obtained by distillation with a short path column: H1 nuclear magnetic resonance spectrum 6.7 z - wt. 5, multiplet of approximately two quartets with a further overlapping peak and 9.0 wt. 6, two overlapping triplets with focal points at 9.01 (J = 7.5 Hz) and 9.03 (J = 6.0 Hz).



  In CDCI, the 6.7 peak was changed to a pure quartet (weight 4) and the 9.0 peak to a triplet (weight 6) by the addition of trifluoroacetic acid and deuterium (two-phase). The mass spectrum showed a peak of the original sample (parent peak) at nile 413.



  Infrared spectrum: 3480 (NH) and 1705 cm-l (C = N).



  Analysis for C @@ H11F12N3:
Calculated: C 32.0 H 2.7 F 55.2 N 10.2
Found: C 32.0 H 2.8 F 55.7 N 10.3
55.7
The second eluted compound was 4-ethylamino-2,2.5,5-tetrakis (trifluoromethyl) -3-imidazoline.



  which was isolated as an oil of refractive index ND23 of 1.3541. An analytical sample was obtained by distillation with a short path column. HI resonance spectrum: 5.12 r wt. 1, broad triplet; 6.6 T - wt. 3, multiplet which turned out to be an approximate quartet split into doublets with an overlying triplet, and 8.08 - wt. 3, triplet (J = 7.2 Hz). The addition of trifluoroacetic acid and deuterium oxide in (: DCI3 had the consequence that the spectrum was simplified to a quartet (wt. 2) at 6.6 W and a triplet (wt. 3) at 8 i together with a sharp DOH exchange peak .

  The mass spectrum showed a peak of the original sample at nile 385 and the base peak at m / e 316 (parent-CF3 +).



  Analysis for C., H, F, 2Ns:
Calculated: C 28.1 H 1.8 F 59.2 N 10.9
Found: C 28.0 H 2.2 F 58.7 N 11.2
59.0
Example 8 3-Ethyl-4-methylimino-2,2,5,5-tetrakis (trifluoromethyl) -imidazolidine R = -C.H,: X = -CH:.; all residues Z = F
A solution of 5.0 g of 3-ethyl-4-imino-2,2,5,5-tetra kis (trifluoromethyl) inidazolidine in 5 ml of dimethyl sulfate was refluxed for 2 minutes and treated with 1 nil of water while hot to remove the excess to decompose ge dimethyl sulfate. After adding a further 15 ml of water, the mixture was neutralized with 6N sodium hydroxide.

  The organic phase was separated by extraction with ether (3 × 10 ml) and concentration. The yellow oil obtained (5.3 g) was separated into two main compounds by preparative gas chromatography. The larger component (76'7c) was 3-ethyl - T - methylimino 2.2.5,5-tetn "kis (trifluoromethyl) imidazolidine, which was isolated as an oil. Nuclear magnetic resonance spectrum:

  : 6.6 - 6.9 T - weight-6, multiplet consisting of a quartet (J = 7 Hz) at 6.68 T, a sharp singlet at 6.88 9 and a broad NH line with a focus at 6.62 C, and 9.03 T - wt. 3, triplet (J = 7 Hz). The mass spectrum contained a peak of the original sample at m / e 399 with a base peak at m / e 302 (parent -CF, and C! H;).



  Infrared analysis: 3520 (NH) and 1710 cm- '(C = N).



  Analysis for C10H9F12N3:
Calculated: C 30.1 H 2.3 F 57.1 N 10.5
Found: C 30.8 H 2.5 F 57.0 N 10.6
30.7 2.6 57.1 10.2
The second major component (15%) was found to be identical to 4-dimethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline.



   Example 9 4-Ethylimino-3-methyl-2,2,5,5-tetrakis (trifluoromethyl) -imidazolidine R = -CH5; X = -C2H5; all residues Z = F
A solution of 5.0 g of 3-methyl-4-imino-2,2,5,5-tetra kis (trifluoromethyl) imidazolidine in 12.5 ml of diethyl sulfate was refluxed for 15 minutes. While the black mixture was hot, it was carefully treated with 5 ml of water in order to decompose the excess diethyl sulfate. After adding a further 30 ml of water, the mixture was neutralized with 6N sodium hydroxide. A drop of silicone antifoam was added and the mixture distilled until 20 ml of distillate was collected. The organic phase (4.2 ml) was extracted into ether (20 ml and 2 X 10 ml).

  The ether extracts were dried over magnesium sulfate and concentrated, 5.5 g of an oil being obtained. The crude mixture was subjected to preparative gas chromatography (butanediosuccinate at 750C), an oil which was identical to 4-ethyl imino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline, and 1.81 g of one Oil was obtained which consisted of 4-ethylimino-3-methyl -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine with a refractive index nn 1.3615.



  This material had an infrared spectrum very similar to that of the 3-tthyl-4-methylimino isomer. The mass spectra were very different, however, with the 4-ethylimino-3-methyl isomer containing the Parz of the original sample at m / e 399 and its base peak at m / e 384 (parent-CH, +).

 

  Analysis for C10H9F12N3:
Calculated: C 30.1 H 2.3 F 57.1 N 10.5
Found: C 30.5 H 2.5 F 57.0 N 10.3
30.8 2.6 57.0
If the experiments described in Examples 4-9 are repeated, but the dimethyl and diethyl sulfates used here are replaced by corresponding dialkyl sulfates or alkyl p-toluene sulfonates. in which the alkyl radicals contain up to 15 carbon atoms, the following alkyl derivatives of 4-imino-2,2, 5,5-tetrakis (trifluoromethyl) imidazolidines or their tau isomers can be obtained: 3-butyl-4-imino-2.2 , 5,5, -terakis (trifluoromethyl) imidazolidine 4-dioctylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline 3-decyl-4-decylamino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine and 3-dodecyl-4-imino-2,2,5,5-etrakis (trifluoromethyl) -imidazolidine.



   Likewise, when the experiments described in Examples 4-9 are repeated, the respective 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidines are replaced by corresponding imidazolidines with difluoromethyl groups instead of the trifluoromethyl groups and similar alkylating agents are used, the following derivatives are obtained: 4-n-propylamino-2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl) -3-imidazoline 3-butyl-4-imino-2,2, 5,5-tetrakis (difluoromethyl) imidazolidine and 4-n-hexyl-2,2,5,5-tetrakis (difluoromethyl) imidazolidine.



   The alkylation of the alkali salts of 4-imino-2,2,5,5-tetrakis (polyfluoroalkyl) imidazolidines with halides as alkylating agents is described in Examples 10-13.



   Example 10 4-Benzylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline R = H; X = -CH2C6H5; all residues Z = F
Example 11 4- (Allylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline R = H; X = -CH2CH = CH2; all residues Z = F
This compound, which boiled at 870 ° C./25 mm Hg, was prepared in the manner described in Example 10, but using 3.0 g of 3-bromopropene in place of the benzyl bromide. The H'-nuclear magnetic resonance spectrum shows a complex absorption at T 3.7-5.1 for -CH = CH2 and an absorption for NH, a three-peak absorption at n 5.9 for a CH2 group by NH and -CH = split, and an absorption for NH at t 6.4.

  The 19F nuclear magnetic resonance spectrum shows a pair of septets at 72.8 and 78.0 ppm from CFCl3. The mass spectrum shows a parent ion (43%) at m / e 397 with the base peak at m / e 41 (CH2 = CHCH2-).



  Analysis for C1oHTN3Fo2
Calculated: C 30.24 H 1.78 F 57.40 N 10.58
Found: C 30.19 H 2.16 F 56.87 N 10.42
EMI9.1

A solution of 7 g (0.02 mol) of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 10 ml of 1,2-dimethoxy ethane was at a temperature below 100C to 1 g of 54%. Sodium hydride in mineral oil (0.02 mol) is added to 50 ml of 1,2-dimethoxyethane. The suspension was refluxed with stirring for 2 hours, cooled and 4.0 g (0.023 mol) of benzyl bromide were added at a temperature below 100 ° C. The mixture was refluxed for 22 hours (yellow precipitate), cooled and filtered to remove the sodium bromide. By distilling the filtrate in a spinning band column, 6.3 g (70%) of 4-benzylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline were obtained as a colorless liquid with a boiling point of 1,200 ° C./10 mm Hg.

  The H1 nuclear magnetic resonance spectrum showed NH at T 2.35 and C 3.85, aromatic-H at 2.68 and a doublet (J = 6) for -CH2-, split by NH. The 19F resonance spectrum showed a pair of septets (J = 5) at 72.7 and 78.1 ppm in CFCl3. The mass spectrum showed a parent ion at m / e 447 which accounted for 42% of the base peak at m / e 91 (CH2CfiHs +).



  Analysis for C14H9N3F12:
Calculated: C 37.60 H 2.03 F 51.10 N 9.40
Found: C 37.59 H 2.13 F 50.87 N 9.42
Example 12 4-Methylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline
R = H; X = -CH3; all residues Z = F
A. This compound was isolated along with other alkylated products in 40% yield in a reaction which was carried out in the manner described in Example 10, but with
3.5 g of methyl iodide were used in place of the benzyl bromide.



   B. This material was also prepared by reducing 4-isocyanate-2,2,5,5-tetrakis (trifluoromethyl) -3-imid-azoline. To 0.70 g (0.0184 mol) of lithium aluminum hydride in 100 ml of ether were 6.15 g (0.0159 mol) of the isocyanate in 20 ml of ether dropwise at a
Temperature given below 1 OOC. The mixture became
Stirred for 24 hours at 250C u. then with 200 ml 50/4
Hydrochloric acid decomposes at a temperature below 100C. The
Layers were separated and the aqueous layer extracted with ether. The combined ether layers were washed with water and dried over magnesium sulfate.

  The ether was distilled off and the residue was distilled under reduced pressure, with 2.3 g (38%) of 4- methylamino-2,2,5,5-tetrakis (trifluoromethyl) -3- -imidazoline as a colorless liquid with a boiling point of 750C / 10 mm Hg were obtained. The H1 nuclear magnetic resonance spectrum showed a doublet (J = 5.9) at b 6.90 for CH3 split by NH, and singlets at 5 5.05 and 6.50 for NH absorption. The mass spectrum showed a base peak at m / e 302 (parent -CF3) and was consistent with the structure.



  Analysis for C8HsF, 2N3:
Calculated: C 25.89 H 1.36 N 11.32 F 61.43
Found: C 25.88 H 1.51 N 11.16 F 60.89
Example 13 4-Dimethylaminoethylamino-2,2,5,5-tetrakis (trifluoromethyl) 3-imidazoline R = H; X = CH2CH2N (CH3) 2; all residues Z = F
The sodium salt of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline was based on the 4-cyclohexylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline 4 - (2-chloroethylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3 - -imidazoline 4- (2-methoxyethylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline 4 - (2-Cyclohexenylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline.



   The alkylation of the original compounds with formaldehyde to give hydroxymethyl and hydroxymethoxymethyl derivatives is described in Examples 14 and 15.



   Example 14 4-Hydroxymethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline R = H; X = CH2OH; all residues Z = F
EMI10.1
 prepared in the manner described. Another equivalent (1 g) of 54% sodium hydride mineral oil and 4.85 g of 3-dimethylaminoethyl bromide hydrobromide were added successively at a temperature below 100 ° C. The mixture was refluxed for 24 hours and filtered. The filtrate was distilled, 5.0 g (58%) of 4-dimethylaminoethylamino -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline being obtained as a colorless liquid with a boiling point of 80-850C / 7 mm Hg. This compound solidified to a white solid with a melting point.



     47-530C if left standing. A sample purified by the hydrochloride had a melting point of 58-61 ° C. The H 'resonance spectrum of the free base showed NH bands at N 3.4 and 3.9, triplets at 6.5 (J = 6, further split) and at T 7.46 for the NCH, CH, N group and a singlet at n 7.78 for the N (CH3) 2 group. The tbF resonance spectrum showed a pair of septets (J = 5) at 75.5 and 78.6 ppm from CFCIs.



  The mass spectrum showed a peak of the original sample at m / e 428 with a base peak at m / e 58 [(CH3) 2NcH2 +].



  Analysis for CllH, 2N, Fl2:
Calculated: C 30.85 H 2.83 F 53.24 N 13.08
Found: C 30.37 H 2.63 F 53.40 N 13.94
If the experiments described in Examples 10-13 are repeated, but the alkylating agents used there are replaced by appropriate hydrocarbyl halides or substituted hydrocarbyl halides, the following derivatives of 4-imino-2,2,5,5-tetrakis (polyfluoromethyl) imidazolidines can be used (or their tautomers) are prepared: 4-propargylamino-2,2,5,5-tetrakis (trifluoromethyl) -3- -imidazoline
A mixture of 10 g of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine and 50 ml of 37% aqueous formaldehyde was heated to the boil.

  The resulting clear solution was cooled to OOC, diluted with 200 ml of cold water and made strongly basic with 100 ml of 10% sodium hydroxide. The white precipitate that formed was filtered off and recrystallized from a mixture of ether and pentane (10:90). This gave 6.1 g of 4-hydroxymethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline as a white crystalline powder with a melting point of 90-920C. The infrared spectrum showed a band at 6.00 St for C = N and a strong band at 6.44! L for NH bending.

  The 19F resonance spectrum in acetone showed two septets (J = 4.8) with focal points at 72.1 and 77.1 ppm from CFCl3. The H1 nuclear magnetic resonance spectrum in (CDs) 2CO showed a very broad signal at r 2.3 (NH), a singlet at T 3.9 (NH) and a doublet (J = 5.4), which gave a broader signal ( 3H) superimposed at X 4.97 for CH20H.



  Analysis for C8H5F12N3O:
Calculated: C 24.82 H 1.31 F 58.89 N 10.86
Found: C 25.37 H 1.47 F 58.57 N 11.25
Example 15 4- (hydroxymethoxymethylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3.imidazoline R = H; X = -CH2OCH3OH; all residues Z = F
EMI11.1

A 10 g sample of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine was dissolved in 50 ml of boiling 37% aqueous formaldehyde. The resulting solution was cooled and diluted with 100 ml of water. The oil which separated out was washed several times with water until it solidified. Recrystallization of the solid from an ether-pentane mixture gave 8.7 g of 4 - (hydroxymethoxymethylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline as colorless crystals with a melting point of 106-1080C.

  The infrared spectrum showed a band at 6.00 u for C = N and a strong band at 6.44 u for NH diffraction. The 13F resonance spectrum in acetone showed two septets (J = 4.8) with focal points at 72.3 and 77.2 ppm from CFCl3. The H 'resonance spectrum in (CD3) 2CO showed a broad signal at t 2.13 (NH), a singlet at T 3.72 (NH), a triplet (J = 7.5) at n 4.57 (OH ), one doublet (J = 6) at T 4.92 (NCH, O) and one doublet (J = 7.5) at T 5.15 (OCH2O).



  Analysis for Cs) HTF12N302:
Calculated: C 25.91 H 1.69 F 54.65 N 10.07
Found: C 25.88 H 1.51 F 54.56 N 9.89
If the experiments described in Examples 14 and 15 with 4-imino-2,2,5,5-tetrakis (polyfluoromethyl) -imidazolidines are repeated, which contain difluoromethyl groups instead of the trifluoromethyl groups in the imidazolidines used there, the following compounds can be prepared 4-hydroxymethylamino-2,2,5,5-tetrakis (difluoromethyl) -3-imidazoline 4-hydroxymethylamino-2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl) -3-imidazoline 4 - (Hydroxymethoxymethylamino) -2,2,5,5-tetrakis (difluoromethyl) -3-imidazoline.



   The dialkylaminomethyl derivatives of the original compounds (ie compounds in which X and R in the general formula are H) can be obtained by condensation of 4-imino-2,2,5,5-tetrakis (polyfluoromethyl) imidazolidines with formaldehyde and ammonia, a primary or a secondary amine can be prepared by the known Mannich reaction. These reactions can be carried out by simply heating a mixture containing the 4-iminoimidazolidine, the amine and the formaldehyde (or a formaldehyde precursor, e.g. paraformaldehyde) in water or an alcohol solvent e.g. Contains ethanol or isoamyl alcohol. This procedure is used in Examples 16, 18,
19, 20 and 23.

  The preparation of salts of these dialkylamino derivatives with inorganic acids and with alkyl halides is described in Examples 17, 21 and 22.



   Example 16 4- (N-pyrrolidylmethylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline R = H; X = N-pyrrolidylmethyl; all residues Z = F
EMI11.2

EMI11.3
  
10 ml of pyrrolidine were added to a hot solution (90CC) of 10 g of 4-imino -2.2.5.5-tetrakis (trifluoromethyl) imidazolidine in 50 ml of 37Sc- a formaldehyde (aqueous solution). The resulting reaction mixture was cooled. The solid which separated out was filtered off, washed with water and dried. Recrystallization from pentane gave 9.6 ff 4- (pyrrolidylmethyl amino) - 2,2.5.5 - tetrakis (trifluoromethyl) -3-imidazoline as colorless needles with a melting point of 127-128 ° C.



  The H2-KMR spectrum in (CD,), CO showed a broad signal at w 2.73 (NH), a broad singlet at n 3.90 (NH), a singlet at T 5.45 (N-CH2- N) and multiplets at T 7.3 (% H) and T 8.3 (4H). The 19F resonance spectrum showed two septets (J = 4.8) with emphases at 71.0 and 77.2 ppm from CFCI3.



  Analysis for C12H2F12N4:
Calculated: C 32.74 H 2.75 F 51.79 N 12.73
Found: C 32.58 H 3.02 F 52.30 N 12.75
Example 17 4- (N-pyrrolidylmethylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline hydrochloride
EMI12.1

A solution of 3.0 g of 4- (N-pyrrolidylmethylamino) -2.2.5.5-tetrakis (trifluoromethyl) -3-imidazoline in 50 ml of ether was saturated with dry hydrogen chloride gas. The white precipitate that formed was filtered off and washed with ether. This gave 3.1 g of the hydrochloride as a white crystalline powder with a melting point of 123-126dC.



  Analysis for C, 2H, 3Fl2NçCl:
Calculated: Cl 7.44
Found: Cl 7.00
Example 18 4- (N-piperidylmethylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline R = H; X = N-piperidiylmethyl; all residues Z = F
EMI12.2

EMI12.3

10 ml of piperidine were added to a hot solution (900C) of 10 g of 4-imino -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 50 ml of 37% formaldehyde (aqueous solution). The reaction mixture was cooled, 100 ml of water were added and the mixture was left to stand overnight, during which the oil which separated out solidified. The solid was filtered off, washed with water and recrystallized from pentane. This gave 8.9 g of 4- (N-piperidylmethylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3- imidazoline as colorless prisms with a melting point of 87-880C.

  The H'-nuclear magnetic resonance spectrum in (CD3) 2CO showed a broad signal at X 2.83 (NH), a broad singlet at T 3.92, a doublet (J = 6) at X 5.57 (N-CH3- N) and multiplets at n 7.4 (4H) and z 8.55 (6H).



  The 19F resonance spectrum showed two septets (J = 4.8) with focal points at 71.8 and 77.1 ppm from CFCI3.



  Analysis for C13H14F12N4:
Calculated: C 34.37 H 3.11 F 50.19 N 12.33
Found: C 34.00 H 3.31 F 50.01 N 12.34
Example 19 4- (N-Morpholinylamino) -2,2,5,5-tetrakis (trifluoromethyl).



  -3-imidazoline R = H; X = N-morpholinylmethyl; all residues Z = F
EMI13.1

10 ml of morpholine were added to a solution of 10 g of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 50 ml of 37% formaldehyde (aqueous solution).



  After adding 100 ml of water, the mixture was cooled. The oil which separated out solidified after cooling for 20 hours. The solid was filtered off, washed with water and recrystallized from a pentane-ether mixture. 3.3 g of 4- (N-morpholinyl methylamino) -2,2,5,5-tetrakis (trifluoromethyl) -3 - imidazoline were obtained as colorless crystals with a melting point of 139-1400C. The H1 resonance spectrum in (CD3) 2CO showed a broad signal at ç 2.57 (NH), a singlet at T 3.80 (NH), a lublet (J = 6) at T 5.54 (NCH2N) and multiplets at T 6.38 (4H) and T 7.38 (4H).



  The 19F resonance spectrum showed two septets (J = 4.8) at 71.0 and 77.1 ppm from CFCl3.



  Analysis for Cl2H12Fl2NlO:
Calculated: C 31.59 H 2.65 F 49.97 N 12.28
Found: C 31.22 H 2.74 F 49.89 N 12.12
Example 20 4-Dimethylaminomethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline R = H; X = dimethylaminomethyl: all Z = F radicals
EMI13.2

A 10 g sample of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine was dissolved in 50 ml of boiling 37% formaldehyde (aqueous solution). The solution was cooled to 250 ° C. with stirring, whereupon 10 ml of dimethylamine were distilled into the solution within 10 minutes. The solid which formed was filtered off and washed with water.

  Recrystallization from pentane gave 9.3 g of 4-dimethylaminomethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline as colorless needles with a melting point of 113-1 140 ° C. The Hl nuclear magnetic resonance spectrum in (CD3) 2CO showed a broad absorption at T 2.76 (NH), a singlet at r 3.87 (NH), a doublet (J = 5) at x5.60 (NCH2N) and a Singlet at T 7.70 (2CH3). The lt'F resonance spectrum showed two septets (J = 4.8) at 72.2 and 77.2 ppm from CFCln.

 

  Analysis for CloH1oFl2N4
Calculated: C 29.00 H 2.44 F 55.04 N 13.57
Found: C 29.04 H 2.28 F 54.74 N 12.94
Example 21 4-Dimethylaminomethylamino-2,2.5,5 tetrakis (trifluoromethyl) -3-imidazoline hydrochloride
EMI14.1

A solution of 2.5 g of 4-dimethylaminomethylamino -2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline in 50 ml of ether was saturated with dry hydrogen chloride gas. The white precipitate that formed was filtered off and washed with ether. 2.4 g of the hydrochloride were obtained as colorless crystals with a melting point of 160-165 ° C.



  Analysis for CioHllFl2N4Cl:
Calculated: Cl 7.87
Found: Cl 7.24
Example 22 4- (N-methylpyrrolidiniummethylamino) -2,2,5,5-tetrakis- - (trifluoromethyl) -3-imidazoline iodide
EMI14.2

EMI14.3

25 ml of methyl iodide were added to a solution of 5.0 g of 4- (pyrrolidylmethylamino) -2,2 5,5-tetrakis (trifluoromethyl) -3-imidazoline in 25 ml of ether. The solution was left to stand at 25 ° C. for 3 hours. The solid which separated out during this time was filtered off and washed with ether. The solid (5.85 g) was dissolved in acetone and fractionally precipitated by adding ether: the first fraction contained no fluorine and was discarded.

  The last fraction obtained was 3.0 g of 4 - (N-methylpyrrolidinium / methylamino) -2,2,5,5-tetrakis- (trifluoromethyl) -3-imidazoline with a melting point of 190.193 ° C. The H 'nuclear magnetic resonance spectrum in (CD) .CO showed a broad signal at T 1.15 (NH), a singlet at # 3.34 (NH), a doublet (J = 5.5) at X 4.60 (NCH2N), one multiplet at # 6.0 (4H), one singlet at T 6.61 (CHg) and one multiplet at r 7.62 (4H).



  The 10F resonance spectrum showed a pair of septets (J = 4.7) at 70.9 and 76.8 ppm from CFCls.



  Analysis for C19H15F12N4J:
Calc .: C 26.82 H 2.60 F 39.16 J 21.80 N 9.62
Found: C 27.01 H 2.87 F 38.73 J 22.13 N 9.25
Example 23 4- (N-Pyrrolidylmethylamino) -2,5-bis (difluoromethyl) -2,5 -bis (trifluoromethyl) -3-imidazoline R = H; X = N-pyrrolidylmethyl, Z = Z3 = H; Z1 = Z2 = F
EMI14.4
  
EMI15.1

2.0 g of 4-imino-2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl) imidazolidine were dissolved in 5 ml of hot 37% strength aqueous formaldehyde. The solution was cooled and mixed with 2 ml of pyrrolidine. After adding 100 ml of water, the solid which separated out was filtered off and washed with water.

  Recrystallization from pentane gave 1.15 g of 4- (N-pyrrolidyl methylamino) -2,5 '- bis (difluoromethyl) -2,5-bis (trifluoromethyl) -3-imidazoline as colorless crystals with a melting point of 97-990C receive. The H 'nuclear magnetic resonance spectrum in fCD.) ICO showed a triplet (J = 54) at X 3.54 (2H), a broad signal at S 3.06 (NH), a singlet at 9 3.95, a doublet (J = 4.5) at W 5.54 and multiplets at r 7.34 (4H) and W (4H). The @@ F -KMR spectrum showed multiplets at 73.9 (3F), 77.8 (3F), 126.2 (2F) and 131.6 ppm (2F).



  Analysis for CroH "FloN4:
Calculated: C 35.65 H 3.49 F 47.00 N 13.86
Found: C 35.76 H 3.53 F 46.90 N 13.53
Example 24 4-Acetylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine R = H; X = -COCH3; all residues Z = F
EMI15.2

A solution of 5.0 g (0.014 mol) of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 25 ml of acetyl chloride was refluxed for 20 hours. The reaction mixture was then cooled and poured into 300 ml of cold water to decompose the excess acetyl chloride. The solid that formed was filtered off and air dried. This gave 5.32 g (yield 95%) of crude 4-acetylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine as a white powder.

  Colorless needles with a melting point of 154 to 1550 ° C. (closed capillary) were obtained by recrystallization from an alcohol-water mixture. The infrared spectrum contained bands at 5.79, 6.00 and 6.61 u.



  The t9F nuclear magnetic resonance spectrum in acetone showed two septets (J = 4.6 Hz) with emphases at 71.7 and 76.5 ppm from CClsF, which was used as an internal standard. The Hl resonance spectrum in (CD3) ..- -CO showed a sharp singlet at 2.37 ppm (area 3) and two broad absorptions at 6.54 and 9.20 ppm (both area 1) from (CH,), Si, which was used as an internal standard. The ultraviolet spectrum has a band at Bs, t101 223 with (± = 13500) with a shoulder at about 265 mu, which indicates the presence of a tautomeric form in ethanolic solution.



  Analysis for C9H @ F12N3O:
Calculated: C 27.08 H 1.26 F 57.12 N 10.53
Found: C 27.52 H 1.41 F 58.14 N 11.30
Example 25 Tetramethylammonium salt of 4-acetylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine
EMI15.3

A 106Xc aqueous sodium hydroxide solution was added dropwise to a suspension of 5.0 g of 4-acetylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 25 ml
Given water until completely dissolved. The solution was filtered and the filtrate with a solution of
5.0 g of tetramethylammonium chloride mixed in 10 ml of water. The precipitate which formed on cooling to 0> C was filtered off and then recrystallized from a mixture of alcohol and ether.

  4.1 g of the tetramethylammonium salt were obtained as colorless crystals with a melting point of 225-227GC. The infrared spectrum showed a strong absorption at 6.44.



     "Analysis for Cl H"; FI2N.lO:
Calculated: C 33.06 H 3.42 F 48.28 N 11.86
Found: C 33.43 H 3.69 F 47.74 N 11.55
Example 26 4-Chloroacetylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine R = H: X = -COCH2Cl; all residues Z = F
EMI16.1

A 5.0 g sample of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine and 25 ml (excess) chloroacetyl chloride were refluxed for three days. The resulting reaction mixture was poured into ice water (using pentane to facilitate transfer) and a solid (4 g) was separated by suction filtration.

  The solid was recrystallized from an ether-pentane mixture, 1.87 g of 4-chloroacetylimino -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine having a melting point of 143-1440C.



  Evaporation of the mother liquor gave a further 1.98 g of product. The mass spectrum showed a peak of the original sample at m / e 433 and the expected fragmentation. The H nuclear magnetic resonance spectrum showed bands at 4.62 ppm (-CH5-), 6.6 ppm (-NH- in the ring) and 9.6 ppm (-NHCO) from (CH) lSi, which was used as an internal standard . The 'rjF nuclear magnetic resonance spectrum revealed a characteristic pair of septets (J = 5 Hz) at +72.2 and 77.5 ppm from FCCl3 as the external standard at 56.4 MHz.



  Analysis for Ct, HsN30F1oCl (432.60):
Calc .: C 24.88 H 0.93 N 9.73 F 52.6 Cl 8.20
Found: C 25.03 H 1.07 N 9.48 F 53.04 Cl 8.75
Example 27 4-Benzoylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine
0 | H = -C-CfiHs; R = H; all residues Z = F
EMI16.2

A 1.00 g sample of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine, 0.410 g benzoyl chloride (1 equivalent) and 15 ml diethylene glycol dimethyl ether (Digly island were refluxed for 3 days (the Most of the hydrogen chloride was given off within a few minutes. The reaction mixture was poured onto ice, diluted with water and extracted with ether.



  The combined ether extracts were washed with water and dried over magnesium sulfate. Evaporation of the ether gave 85 g of a solid which was recrystallized from ethanol-water, 0.60 g of 4-benzoylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in the form of white Crystals having a melting point of 157.5 to 159 C were obtained. The mass spectrum showed a peak of the original sample at m / e 461 and the base peak at mle 105 for (COC3H5) +. The H1 nuclear magnetic resonance spectrum was consistent with the assumed structure, and the '9F resonance spectrum showed two multiplets at 72.5 and 77.6 ppm from FCCl5, which served as an external standard, at 56.4 MHz.

  The ultraviolet spectrum showed bands at i * ", ax245 (= 12,700), 263 (11,100) ml.



  Analysis for C1EHTN3OF, 2 (461,22):
Calculated: C 36.45 H 1.53 N 9.12 F 49.50
Found: C 36.67 H 1.59 N 9.49 F 49.85
Example 28 4-Acetylimino-3-methyl-2,2,5,5-tetrakis (trifluoromethyl) -imidazolidine R = -CH5; X = -COCH3; all residues Z = F
EMI16.3
  
A mixture of 2.0 g (0.0054 mol) of 4-imino-3-methyl-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine and 5 ml of acetyl chloride was refluxed for 30 hours and then cooled and heated Poured ice. The solid which formed was filtered off, washed with water and recrystallized from alcohol-water. 1.85 g (83%) of 4-acetylimino-3-methyl-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine were obtained as colorless crystals of mp.



     137-1 390C obtained. The 19F nuclear magnetic resonance spectrum in CD3CN showed a septet (J = 4.2 Hz) at 73.1 ppm and a multiplet at 75.1 ppm from CCI3F, which was used as an internal standard. The H1 nuclear magnetic resonance spectrum in CD3C> N showed a singlet (area 3) at 2.17 ppm, a singlet (area 1, NH) at 2.33 ppm and a septet (JHF = 1Hz) (area 3) with a focus at 3.02 ppm lower panel of (CH3) 4Si used as an internal standard. The ultraviolet spectrum showed B; A, e; 'x "at' 217 u (z = 8300). The infrared spectrum showed bands at 5.75 u and 6.00 u.



  Analysis for C1oH7F12N3O
Calculated: C 29.07 H 1.71 F 55.18 N 10.17
Found: C 29.37 H 2.01 F 54.92 N 10.22
Example 29 Preparation of 4- (p-chlorobenzoylimino) -2; .2,5,5-tetrakis- (trifluoromethyl) imidazolidine R = H; X = -COC; H.s-CI-p; all residues Z = F
EMI17.1

A solution containing 5.0 g (14.0 millimoles) of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine and the like. Containing 2.5 g (14.3 millimoles) of p-chlorobenzoyl chloride in 50 ml of diethylene glycol dimethyl ether, the mixture was refluxed under nitrogen until no more hydrogen chloride was detected when the condenser outlet was kept in silver nitrate solution. This took 15 hours.



  The cooled reaction solution was poured into 150 ml of water and the solid obtained was filtered off, dissolved in methanol and precipitated with water. The filtered product was dissolved in 75 ml of diethyl ether and extracted with 5 ml of 5% sodium bicarbonate. The ether layer was washed with water, dried over anhydrous magnesium sulfate and then filtered. By recrystallization from a mixture of ether and petroleum ether (3: 1), filtration and drying in a vacuum oven at 600C for a period of 12 hours, 3.3 g of 4- (p-chlorobenzoylimino) -2,2,5, 5-tetrakis (trifluoromethyl) imidazolidine was obtained in the form of white crystals with a melting point of 139-1400C.



  Analysis for Cl4H6CIFl2N3O:
Calculated: C 33.93 H 1.22 Cl 7.15 F 46.06 N 8.48
Found: C 34.29 H 1.52 Cl 7.85 F 45.33 N 8.44
Molecular weight 495.57
The mass spectrum contained the peak for the original sample at 495 m / e. The 19F nuclear magnetic resonance spectrum in deuteroacetone with (CH), Si as the internal standard and FCCl3 as the external standard contained four broad bands of equal intensity with emphases at 73.3, 74.5, 79.1 and 79.5 ppm. The proton resonance spectrum contained a broad line at 6.8 ppm [H-N- (1)].

  The A2B2 pattern for aromatics had a focus at 7.78 ppm and the A2 part at 7.55 ppm (J = 8.5 Hz) (2H). The B, part had the center of gravity at 8.05 ppm (J = 8.5 Hz) and was distorted by (NH), giving a broad band of 7.8-10.15 ppm (3H). When trifluoroacetic acid was added, the high field (NH) was shifted and appeared as a sharp singlet at 6.72 ppm. The low field (NH) was removed and the aromatics gave a typical A2B2 pattern with emphasis at 7.78 ppm (J = 8.5 Hz) (4H).



  The ultraviolet spectrum in acetonitrile showed one band at À \ aX = 250 my (E = 19330), and in ethanol the spectrum contained two bands at Xlxiax 253, 270 mu.



   Example 30 Preparation of 4- (2,4-dichlorobenzylimino) -2,2,5,5-tetra kis (trifluoromethyl) imidazolidine R = H; X = -COC6H5Cl2-2.4; all residues Z = F
EMI17.2
  
The experiment described in Example 29 was repeated with the exception that 3.0 g (14.3 millimoles) of 2,4-dichlorobenzoyl chloride were used in place of p-chlorobenzoyl chloride and the reaction mixture was refluxed for 40 hours. This gave 4.5 g of 4- (2.4-Vichlorbenzoylimino) -2,2,5,5-tetrakis (trifluoroniethyl) imidazolidine as white needles with a melting point of 153.4-153.80 ° C.



  Analysis for C1 4H5Cl2F12N3O:
Calc .: C 31.72 H 0.95 Cl 13.38 F 43.02 N 7.93
Found: C 32.40 H 1.16 Cl 14.00 F 42.23 N 7.79
Molecular weight 530.02.



   The mass spectrum contained the peak of the original at 529 m / e, based on the most abundant C1S ion.



  The l 'F-KMR spectrum in deuteroacetone with (CH.) ISi as the internal standard and with FCCI3 as the external standard contained two broad bands of the same intensity with emphasis at 73.2 and 78.7 ppm. The proton KMR spectrum contained a singlet at 6.56 ppm [HN - (1)], a multiplet typical of an ABC pattern for aromatics with a focus at 7.5 ppm (3H) and a broad band at 10.1 ppm (NH), which exchanged with trifluoroacetic acid. The ultraviolet spectrum in acetonitrile showed a band at) #max = 216 mln. (± = 23400).



   Example 31 Preparation of 4- (p-Methoxybenzoylimino) -2,2,5,5-tetra kis (t trifluoromethyl) imidazolidine R = H; X = -COC @ H4OCH3-p; all residues Z = F focus at 6.7 ppm [H-N- (I)]. The A2B pattern for aromatics was distorted by the low field (near) which appeared distorted at 7.25 to 9.3 ppm (= 11) and contained the B2 part, the broad band with a focus at 8.0 ppm appeared. The A2 part had the focus at 7.04 ppm (J = 9 Hz) (211). When trifluoroacetic acid was added, the high field (NH) was shifted and appeared as a sharp inglet at 5.65 ppm.



  The low field (NH) was removed and the aromatics gave a typical A <B, pattern with emphasis at 7.5 ppm (J = 9 Hz) (4H). The ultraviolet spectrum in acetonitrile showed bands at amine = 220 with (e = 16800); #nixa = 278 nt (e = 17100).



   Example 32 4- (Crotonylimino) -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine R = 11, X = -COCH = CHCH3; all radicals Z = F (with isomers and tautomers)
The experiment described in Example 29 was repeated with the exception that 7.0 g (19.6 millimoles) of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine were used and the p-chlorobenzoyl was replaced by 2, 0 g (20.0 millimoles) of crotonyj chloride was replaced and the reaction mixture was refluxed for 63 hours.

  Fractional recrystallization of 4.8 g of the solid product from chloroform gave cis and trans isomers and 0.7 g of a cis-trans mixture of 4- (crotonylimino) -2,2,5,5-tetrakis (trifluoromethyl) imidazo-
EMI18.1

The experiment described in Example 29 was repeated with the exception that 2.5 g (14.3 millimoles) of p-methoxybenzoyl chloride were used instead of p-chlorobenzoyl chloride and the reaction mixture was refluxed for 24 hours. The product obtained was 2.5 g of 4- (p -methoxybenzoylimino) -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine as white crystals with a melting point of 122.8-124.20C.



  Analysis for C13H @ F12N3O2 (molar weight 491.16):
Calculated: C 36.76 H 1.85 F 46.54 N 8.56
Found: C 37.05 H 1.89 F 45.20 N 8.80
The mass spectrum contained the peak of the original sample at 491 m / e. The 19F KMR spectrum. recorded in the manner described in Example 30 contained four broad lines: two lines of equal intensity with emphasis at 72.1 and 77.3 ppm and two lines of equal intensity with emphasis at 73.8 and 78.4 ppm. The ratio of the low field set to the high field set was about 5: 4.



   The proton CMR spectrum contained a sharp singlet at 3.9 ppm (CH, O) and a broad line with lidine obtained as white crystals with a melting point of 208.8-213.80C.

 

  Analysis for C11H @ F12N3O:
Calculated: C 31.08 H 1.66 F 53.64 N 9.89
Found: C 30.86 H 1.73 F 53.13 N 9.68 * * for cis / trans mixture
The infrared, proton and fluorine CMR spectra gave consistent results.



   Example 33 4- (Heptanoylimino) -2,2,55-tetrakis (trifluoromethyl) imidazolidine (and tautomers) R = H; X == -CO (CH) sCHg all radicals Z = F
The experiment described in Example 32 was repeated with the exception that 3 g (20 millimoles) of n-heptanoyl chloride were used in place of the crotonyl chloride. Recrystallization of 5.5 g of the solid product from chloroform gave 1.6 ra 4- (heptanoylimino) -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine as white needles with a melting point of 87.5-88.00C.



  Analysis for C14Hl5Fl2N3O:
Calculated: C 35.85 H 3.22 F 48.82 N 8.96
Found: C 35.49 H 3.13 F 48.06 N 8.69
The results of the infrared, proton and fluorine NMR spectra were consistent.



   Example 34 4- (dichloroacetylimino) -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine (and tautomers) R = 11; X = COCHCl2; all residues Z = F
The experiment described in Example 32 was repeated with the exception that 25 ml of dichloroacetyl chloride were used in place of the crotonyl chloride.



  Recrystallization of 6 g of the solid product from ether-pentane gave 1 g of 4- (dichloroacetylimino) -2,2,5,5- -tetrakis (trifluoromethyl) imidazolidine as white crystals.



  obtained from melting point 100.2 to 101.20C (closed capillary).



  Analysis for CoH3Fj2CI2NsO
Calc .: C 23.10 H 0.64 Cl 15.15 F 48.72 N 8.98
Found: C 22.95 H 0.63 Cl 14.91 F 47.71 N 8.95
Molecular weight 468.06.



   The mass spectrum contained the peak of the original sample at 467 m / e, based on the most common C135 ion.



   The infrared, ultraviolet and CMR spectra were consistent and indicated tautomers.



   Example 35 4- (2,4-dichlorophenoxyacetylimino) -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine (and tautomers)
R = H; X = COCH2OC6H3Cl-2.4; all leftovers
Z = F
The experiment described in Example 29 was repeated with the exception that 3.5 g (14.6 millimoles)
2,4-dichloro-phenoxyacetyl chloride is used instead of p-chloro benzoyl chloride and the reaction mixture 24
Was heated on the reflux condenser for hours. This gave 2.0 g of 4- (2,4-dichlorophenoxyacetyl) -2,2,5,5-etrakis (trifluoromethyl) imidazolidine in the form of white crystals with a melting point of 197-197.90C.



  Analysis for C16H, Cl2Fl2N302 (molar weight 560.051):
Calculated: C 32.17 H 1.26 F 40.72 N 7.50
Found: C 32.36 H 1.32 F 39.69 N 7.02
The mass spectrum contained the peak of the original sample at 559 m / e, based on the most abundant Cl35 ion. The infrared and NMR spectra agreed. The ultraviolet spectrum indicated tautomerization.



   The following acyl derivatives of 4 - imino -2,2,5,5 - tetrakis (polyfluoromethyl) imidazolidines can be prepared in the manner described in Examples 24 and 26 to 35, but using appropriate acid chlorides instead of the special acid chlorides used there: 4-propionylimino-2,2,5,5-tetrakis (difluoromethyl) -imidazolidine 4-octanoylimino-3-methyl-2,2,5,5-tetrakis (trifluoromethyl) -imidazolidine 4-undecanoylimino -2,2, 5,5-tetrakis (trifluoromethyl) imide - azolidine 4-trifluoroacetylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 4- (3-chlorobutyryl) imino-2,2,5,5-tetrakis (difluoromethyl) - imidazolodine 4- (2-bromopropionyl) imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine <RTI

    ID = 19.16> 4-methoxyacetylimino-2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl) imidazolidine 4-butoxyacetylimino-2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl ) imidazolidine 4 (p-ethoxypropionyl) imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 4-naphthoylimino-2,2,5,5-tetrakis (trifluoromethyl) .imidazolidine 4- (p-fluorobenzoyl ) imino-2,2,5,5-tetrakis (trifluoromethyl) - imidazolidine 4- (2,4,6-trichlorobenzoyl) imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 4- (p- Bromobenzoyl) imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 4- (2,4-diethylbenzoyl) imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 4-cumoylimino-2,2,5 , 5-tetrakis (trifluoromethyl) imidazolidine <RTI

    ID = 19.25> 4- (p-methoxybenzoyl) imino-2,2,5,5-tetrakis (trifluorme.



  thyl) imidazolidine 4- (p-butoxybenzoyl) imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine.



   If amino- or alkyl-substituted aminoacyl derivatives are desired, they can be prepared as follows: First, the 4-imino-2,2,5,5-tetrakis (polyfluoromethyl) imidazolidine is converted with a nitroacyl chloride to the corresponding 4-nitroacylimino-2,2,5 , 5-tetrakis (polyfluoromethyl) imidazolidine implemented. This nitroacyl derivative can then be reduced to the aminoacylimino-2,2,5,5-tetrakis (polyfluoromethyl) imidazolidine by treatment with hydrogen in the presence of a hydrogenation catalyst such as platinum. The alkyl- and dialkylaminoacylimidazolidine can be prepared by alkylating 4-aminoacylimino-2,2,5,5-tetrakis (polyfluoromethyl) imidazolidine with alkylating agents which contain alkyl components with 1-4 C atoms, e.g. Dimethyl sulfate.

  The following aminoacyl derivatives of 4-imino -2,2,5,5-tetrakis (polyfluoromethyl) imidazolidine can be prepared in this way: 4- (Aminoacetylimino) -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 4- ( α-aminopropionyl) imino -2.2.5,5-tetrakis (difluoromethyl) imidazolidine 4-butylaminoacetylimino -2,2,5,5-tetrakis (difluoromethyl) - imidazolidine 4 - [, oc- (dipropylamino) propionyl] imino -2,2,5,5-tetrakis- (trifluoromethyl) imidazolidine 4- (p-aminobenzoyl) imino-2,5-bis (difluoromethyl) -2,5-trifluoromethyl) imidazolidine 4- (p-butylaminobenzoyl) imino- 2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 4- (p-diethylaminobenzoyl) imino-2,5-bis (difluoromethyl) -2,5-bis (trifluoromethyl) imidazolidine.



   Example 36 4- (Carbethoxyimino) -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine R = H; X = COO-CH3CH3, all Z = F
EMI20.1

EMI20.2

A solution of 5.0 g of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 20 ml of ethylene glycol dimethyl ether was added to 4.0 ml of oxolyl chloride (excess) in 20 ml of ethylene glycol dimethyl ether within 30 minutes (yellow COLOUR). After the addition, the infrared spectrum of the reaction mixture showed no bands in the isocyanate range.

  After stirring for 20 minutes at room temperature, a faint band appeared at 4.41 it in the infrared spectrum, an indication of the formation of 4-isocyanate-2,2,5,5-tetra kis (trifluoromethyl) -3-imidazoline. After refluxing for half an hour, the yellow color had completely disappeared and the infrared spectrum now showed a strong isocyanate band at 4.41. After further heating for 15 minutes on the reflux condenser, 10 ml of absolute ethanol were added (the infrared analysis showed no isocyanate band, a sign that the isocyanate had reacted with ethanol).

  Evaporation of the ethylene glycol methyl ether and the excess ethanol under reduced pressure gave a white semi-solid, from which 4.82 g of a white solid with a melting point of 70-120 ° C. were obtained by washing with pentane.



   The solid, washed with pentane, was recrystallized from ether-pentane, 0.86 g of carbethoxyimine being obtained as a white solid with a melting point of 122-1240C. The H1-KMR spectrum showed a CH3 triplet (J = 7.0) at 1.27 ppm and a CH2 quartet (J = 7.0) at 4.23 ppm and NH bands at 6.48 ppm u . 9.22 ppm lower panel from (CH3) 4Si as internal standard.



  Analysis for C1oHTNsO2Fl2
Calculated: C 27.99 H 1.64 N 9.80 F 53.1
Found: C 28.25 H 1.95 N 9.87 F 53.24
Molecular weight 429.18.



   The 4-isocyanate 2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline formed as an intermediate in the experiment described in Example 36 can optionally be isolated by carrying out the first step of the procedure of this example as follows becomes:
EMI20.3

Essentially anhydrous conditions were maintained. A three-necked flask which was attached to the foot of a spinning band column used for fractionation was equipped with a magnetic stirrer, nitrogen inlet and the like.



  Provide dropping funnel. The apparatus was flame dried and cooled. 15 ml of oxalyl chloride and 75 ml of anhydrous diethyl ether were introduced into the flask under positive pressure of nitrogen. Then a solution of 30 g of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine in 100 ml of ether was added over the course of 30 minutes with vigorous stirring. After stirring for a further 20 minutes, the ether was distilled off at a moderate rate and the residue was distilled at 75 mm Hg. The product, 25.7 g of 4-Isocya nat-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline, boiling point 780 ° C. (75 mm Hg), was found in oven-dried vials (as it reacts with moist air).

 

  The H1 CMR spectrum shows a singlet (broad) at 3.6 ppm. The 19F-NMR spectrum showed two septets (J = 5) at +73.2 and +78.0 ppm from FCCI3, which was used as an external standard, at 56.7 M.



  Analysis for C8HN3OF14 (383.12):
Calculated: C 25.08 H 0.26 N 10.96
Found: C 25.58 H 0.77 N 11.51
If other alcohols are used instead of ethanol for reaction with the isocyanate formed as an intermediate compound in the experiment described in Example 36, the following carbalkoxyiminoimidazolidines can be prepared: 4-Carbocyclohexoxyimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 4-carbobutoxyimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine.



   Example 37 4- (Carbomethoxyimino) -2,2,5,5-tetrakis (trifluoromethyl) -imidazolidine R = H; X = -COOCH2; all residues Z = F
EMI21.1

25 ml (excess) of methanol were mixed at room temperature with a solution of 6.2 g of 4-isocyanate-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline in 100 ml of ether. By evaporation; of the reaction mixture to dryness, 6.98 g of a white solid with a melting point of 116-1200 ° C. were obtained. Recrystallization of one half of this material from methanol-water gave 2.56 g (76%) of the urethane product, melting point 125-1290C. This material showed no absorption in the ultraviolet spectrum above 210 mj.

  The H1-KMR spectrum showed -OCH2 absorption at T 6.20 and NH bands at X 3.5 and C 0.2. The 19F-CMR spectrum showed two septets (J = 5) at 72.1 and 75.6 ppm from FCCI3, which served as an external standard.



  Analysis for CsH2N2O2F1 (415.15):
Calculated: C 26.04 11 1.21 N 10.13 F 54.92
Found: C 26.30 H 1.39 N 10.44 F 53.65
Example 38 4- (2-Dimethylaminoethoxycarbonylimina) -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine R = H; X = COOCH2CH2N (CH3) 2; all residues Z = F
EMI21.2
 and / or tautomeres
6.2 g of 4-isocyanate-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline were added at room temperature to a solution of 1.44 g (1 equivalent) of dimethylaminoethanol in 100 ml of ether. An exothermic reaction took place and a white precipitate formed in a few minutes.



  The solid was separated off and washed with ether. The product weighed 4.74 g (62, go) and had a melting point of 136-1410C. The H-KMR spectrum showed NH bands at C 1.0 and 4.48, -OCH, - at. 5.6 and -CH2N at X 6.6 which formed an A2B2 pattern (J = 6) and -N (CH3) 2 at C 7.1. The 10F-KMR spectrum showed two septets (J = 5) at 71.7 and 76.9 ppm for FCCl3 as the internal standard. The ultraviolet spectrum showed a maximum of 252 ml (k = 27.2 in CH3CN and 11.7 in ethanol), a sign of a tautomeric mixture. The hydrochloride was made and was found to be water soluble.



  Analysis for C12Hl2N402Fl2:
Calculated: C 30.52 H 2.56 N 11.87 F 48.4
Found: C 30.92 H 2.82 N 12.14 F 48.91
Example 39 4-Isocyanato-2,2,5,5-tetrakis (trifluoromethyl) -3-imidazoline, cholesterol adduct R = H; X = COCC2TH4s; all residues Z = F
EMI22.1

EMI22.2

7 g of freshly prepared 4-isocyanate 2,2,5,5-tetrakis (trifluoromethyl) -3-imidazolidine were distilled into a solution of 7.7 g of dry cholesterol in 70 ml of ethylene glycol dimethyl ether. The residue was evaporated under reduced pressure. Sublimation of the residue gave 11.3 g (77%) of the adduct with a melting point of 169-1720C. The 1 "> F-KMR spectrum showed two multiplets at 71.8 and 77.1 ppm from FCCI3 as the external standard.



  Analysis for C: -, H47NF1.O (769.76):
Calculated: C 54.61 H 6.14 N 6.26 F 29.6
Found: C 55.58 H 6.25 N 5.54 F 28.13
Many imidazolidines and 3-imidazolines produced according to the invention are stable when they are metal surfaces such as iron, steel, stainless steel. Nickel and copper touch even at elevated temperatures and can therefore be used for purposes where prolonged contact with these metals is an option. Examples of this are applications as heat exchange media and hydraulic fluids. which are used at high temperatures.

  The stability of these tmidazolidines is illustrated by the following experiments:
Example A
A 0.5 g sample of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine was enclosed in a glass tube with an iron wire and a copper wire and kept at 2250 ° C. for 44 hours. No change was found in either the liquid or the metal wires during this time.



   Example B.
A 0.5 g sample of 3-methyl-4-methylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine was sealed in a glass tube with an iron wire and a copper wire and kept at 2250 ° C. for 20 hours. No change was found in either the liquid or the metal wires during this time.



   Example C
In a glass tube, 0.5 g of 4-acetylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine was sealed with a copper wire and kept at 2250 ° C. for 20 hours. During this time, no change was found in either the liquid or the copper wire.



   All compounds prepared according to the invention are valuable modifying agents for polymers.



  The modifications include lowering the deformation temperatures or pressures or plasticizing the polymers. The modification of polymethyl methacrylate is illustrated by the following experiment:
Example D
The following products were made: a) A mixture of 0.5 g of polymethyl methacrylate and
0.1 g of 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine.



  b) A mixture of 0.5 g of polymethyl methacrylate and
0.1 g of 4-acetylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine.



  c) A mixture of 0.5 g of polymethyl methacrylate and
0.1 g of 3-methyl-4-methylimino-2,2,5,5-tetrakis (trifluoromethyl) imidazolidine.



  d) A mixture of 0.5 g of polymethyl methacrylate and
0.1 g of 4-benzylamino-2,2,5,5-tetrakis (trifluoromethyl) -3- imidazoline.



  e) 0.5 g of polymethyl methacrylate without additives.



   Round foils were pressed from a compact pile of each mixture at 1500C, a ram pressure of 2270 kg and a pressing time of 10 seconds. The individual films had the following dimensions: starting mixture thickness, mm diameter, cm
Mixture a) 2.23 12.7
Mixture b) 0.28 4.76
Mixture c) 0.29 4.45
Mixture d) 0.22 5.4
The film pressed from product e) had a thickness of 0.47 mm and a diameter of only 3.5 cm and was only incompletely melted together at the edges.



   These experiments show that the deformation temperatures or pressures for polymethyl methacrylate are lowered by adding the imidazolidines produced according to the invention.



   An excellent method for demonstrating the effectiveness of compounds as muscle relaxants is the L.O. 300 Inclined Screen Test. Randall et al [J. Pharm. Exp. Therap., 129, 163 (1960)]. In this test, the oral dose is determined at which 50 / c of the test animals (mice) fall from their feet on a wire sieve that is inclined at an angle of 300 to the horizontal. This dose is referred to as the analyzing dose "or PD5" value. In this test, low PD "values indicate high effectiveness.



   Another excellent method of demonstrating effectiveness as a muscle relaxant is the Wire Lift Test. The front feet of white mice are placed on a slack wire stretched about 30 cm above a flat surface. Normal animals grab the wire and lift their hind feet onto the wire. where they keep their balance. The inability to lift the hind legs onto the wire is considered a positive response and is considered a measure of muscle relaxation. This test determines the oral dose at which 50ChC the test animals (mice) become unable to lift their hind legs onto the wire. This is known as the effective dose ">) or ED." Value.

  The <(dose-response relationships are determined according to the method of L.C.



  Miller and M.L.Tainter, Proc. Soc. Exp. Biol. Med. 57, 261-264 (1944).



   The ED., "- and EDt," values for representative compounds according to the invention are given in the table below.



   Results of tests to determine the effectiveness as a muscle relaxant Product of compound Siebtest PDso Wire test ED5o Example No. (mg / kg) (mg / kg)
1-B, 2 4-imino-2,2,5,5-tetrakis (trifluoromethyl) imide-10.6 + 0.9 7.0 + 0.51 azolidine
3 4-Imino-2,5-bis (difluoromethyl) -2,5-bis (trifluoro-17.3 + 1.3 10.0 # 0.83 methyl) imidazolidine
4 4-Imino-3-methyl-2,2,5,5-tetrakis (trifluoromethyl) - 20.5 + 1.7 13.0 i 1.3 imidazolidine
4 3-methyl-4-methylimino-2,2,5,5-tetrakis (trifluoro-30.0 + 3.3 19.5 + 2.3 methyl) imidazolidine
5 3-Ethyl-4-imino-2,2,5,5-tetrakis (trifluoromethyl) - 17.0 + 1.4 12.3 # 1.0 imidazolidine
7 <RTI

    ID = 23.29> 3-ethyl-4-ethylimino-2,2,5,5-tetrakis (trifluoro-57.0 + 14.0 30.0 + 3.9 methyl) imidazolidine
7 4-Ethylamino-2,2,5,5-tetrakis (trifluoromethyl) -3-17.5 t 2.4 8.3 + 0.75 -imidazoline
8 3 -ethyl-4-methylimino-2,2,5,5-tetrakis (trifluoro-30.0 + 3.3 methyl) imidazolidine
9 4-Ethylimino-3-methyl-2,2,5,5-tetrakis (trifluoro-22.0 + 1,6 methyl) imidazolidine product of compound Siebtest PD5o Wire test ED5o Example No.

   (mg / kg) (mg / kg) 10 4-Benzylamino-2,2,5,5-tetrakis (trifluoromethyl) -3- 45.0 + 7.6 30.0 i 5.4 -imidazoline 11 4-Allylamino -2,2,5,5-tetrakis (trifluoromethyl) -3- 41.0 i 4.8 28.0 + 3.0 -imidazoline 12 4-methylamino-2,2,5,5-tetrakis (trifluoromethyl) - 18.8 + 1.3 10.8 + 0.86 -3-imidazoline 14 4-hydroxymethylamino-2,2.5,5-tetrakis (trifluoro-13.2 + 1.6 5.6 + 0.85 methyl) - 3 -imidazoline 15 4- (hydroxymethoxymethylamino) -2,2,5,5-tetrakis- 16.0 + 1.3 7.6 + 1.0 (trifluoromethyl) -3-imidazoline 17 4- (N-pyrrolidylmethylamino) - 2,2,5,5-tetrakis (tri 18.8 + 1.7 10.5 + 0.7 fluoromethyl) -3.imidazoline hydrochloride 20 <RTI

    ID = 24.13> 4-dimethylaminomethylamino-2,2,5,5-tetrakis- 22.0 + 1.8 10.0 + 1.1 (trifluoromethyl) -3-imidazoline 21 4-dimethylaminomethylamino-2,2,5, 5-tetrakis-19.2 + 1.2 7.5 + 1.2 (trifluoromethyl) -3-imidazoline hydrochloride 24 4-acetylimino-2,2,5,5-tetrakis (trifluoromethyl) - 24.0 + 1.9 13.4 + 1.1 imidazolidine 25 tetramethylammonium salt of 4-acetylimino-16.0 + 1.6 8.8 i 1.03 -2,2,5,5-tetrakis (trifluoromethyl) imidazolidine 26 4-chloroacetylimino-2, 2,5,5-tetrakis (trifluor- 16.5 + 1.4 9.8 t 0.77 thyl) imidazolidine 27 4-acetylimino-3-methyl-2,2,5,5-tetrakis (trifluor- 24, 0 + 2.5 15.0 + 0.85 methyl) imidazolidine 33 4- (

   Heptanoylimino) -2,2,5,5-tetrakis (trifluorme-28.5 + 2.9 10.0 + 0.6 thyl) -imidazolidine 36 4-carbethoxyimino) .2,2,5,5-tetrakis (trifluorme - 14.5 + 1.4 10.2 + 0.87 thyl) imidazolidine 37 4-carbomethoxyimino) -2,2,5,5-tetrakis (trifluoro-17.0 + 1.0 11.5 + 1.1 methyl) imidazolidine 38 4- (2-dimethylaminoethoxycarbonylimino) -2,2,5,5- 33.5 + 3.2 19.2 + 1.9 -tetrakis (trifluoromethyl) imidazolidine hydrochloride
For pharmaceutical use, the compounds prepared according to the invention and their salts can be administered orally, parenterally or in some other way. They can be incorporated into various forms of preparation with non-toxic carriers and auxiliaries.

 

Claims (1)

PATENT CLAIM Process for the preparation of N-acyl derivatives of 4-imino -2,2,5,5-tetrakis (polyhalomethyl) imidazolidines, or their tautomers, characterized in that compounds of the formula EMI25.1 20 in which Z, Z1, Z2 and Z3 are hydrogen or fluorine atoms, or acylated alkali metal salts of such compounds.