CH370767A - Process for the preparation of ethanolamines with a triple bond - Google Patents

Description

  

  Process for the preparation of ethanolamines having a triple bond The present invention relates to a process for the preparation of new ethanolamines having a triple bond of the formula
EMI0001.0005
    In this formula, R, and R3 to R6 are hydrogen or an alkyl, aryl,

          Alkaryl or aralkyl group and R2 an alkyl, oxyalkyl, aryl, alkaryl or aralkyl group.



       R7 can be hydrogen, an al'kyl, alkenyl, aryl, aral'kyl, alkaryl or oxyalkyl group.

    
EMI0001.0029
    In general, the reaction conditions for this reaction are as follows: The oxazolidine is preferably dissolved in a suitable solvent, such as, preferably, dioxane or, in particular, dimethylformamide, brought to the reaction.

   Although the above reaction also takes place in the absence of a solvent, it has been found that it is quieter and better. The new compounds are prepared according to the invention by adding a compound with a triple bond which has at least one active hydrogen atom,

      with an oxazo 1'id # in. This reaction takes place according to the following equation: it can be regulated and the temperature control is easier if a solvent is present. The required amount of solvent used depends largely on. the equipment used.

   In general, however, about 1 to 5 parts of solvent are used per part of oxazolid'in. If dioxane is chosen as the solvent, 2 to 3 parts of dioxane are preferably used per part of oxazolidine. If 'dimethylformamide is used as a solvent, the preferred amount is 1 to 5 parts per part of oxazolidline.



  The reaction is exothermic, which is why temperatures between 0 and 60 C are used. A preferred temperature range is between 5 and 30 C.



  The implementation according to the invention can be carried out within a wide pressure range, from negative pressure to positive pressure. There seems to be a certain dependency between the speed and the smooth course of the reaction on the one hand and the pressure on the other hand, but this problem has not yet been fully clarified. In general, the reaction proceeds smoothly at a slight excess pressure between about 127 and 356 mm Hg; a pressure of 203-254 mm is especially preferred.



  Since the starting compound with a triple bond is mostly: gaseous, diluent gases such as nitrogen and other inert gases can be used to prevent an explosion or dangerous overloading of the unsaturated compound.



  An essential feature of the process according to the invention is the presence of a source of cuprous ions. These cupro ions form a catalytic copper complex with the unsaturated compound.

   The source: the cuprous ions can consist of any copper salt, which breaks down in the reaction mixture to form the desired cuprous ions. For example, copper chloride, copper (I) sulfate and the like can be used.



       After the oxazolidine is dissolved in the desired solvent, cuprous ions are present and the temperature and pressure have been adjusted to the required value, the compound with three-fold bond is added to the aforementioned mixture with constant stirring. Usually a brightly colored precipitate is formed from the copper complex with the unsaturated compound.

   This substance is filtered off from the reaction mixture. The hydrogen sulfide gas is preferably passed into the reaction mixture in this way in order to precipitate all remaining cuprous ions. However, any other means can also be used to bind and remove the excess cuprous ions.



  After the excess cupric ions have been removed, the reaction mixture is distilled in order to free it from the solvent. After, the solvent becomes the desired product at a certain temperature, which is mostly not more than 2-10 C
EMI0002.0069
    sways, distilled off. The work-up of the crude product can be carried out using one of the known methods, such as renewed distillation, recrystallization, etc., he followed.

   The product obtained is tested by means of a water-free titration, a hydrogenation to determine the amount of absorbed hydrogen and other known methods.



  The ethanolamines with triple bonds obtained by the process according to the invention are versatile. They are valuable intermediates in the manufacture of large numbers of. Industrial products due to the presence of three highly active groups in the molecule, namely the acetylene group, the amino group and the hydroxyl group, all of which can be reacted with numerous known substances and result in the classic reactions of these compounds.



  If, for example, R7 in the above formula is hydrogen, the ethanolamines with a triple bond can enter into all classic acetylene reactions, such as ethynylation, vinylation, carbonylation, etc.

   If R8 is an organic radical such as methyl, ethyl, propyl and the like, the compounds can enter into addition reactions, such as halogenation, hydrogenation, etc. If desired, the compounds can also be used to carry out the classic reactions of tertiary amines, such as salt formation, formation of quaternary ammonium compounds, etc.



  The Hydroxylgru.ppe can be used to form esters, ethers, metal alcohols, etc. The ethanolamines with triple bond obtained according to the invention can be used as medicinal products.

   Certain derivatives, such as the hydrochlorides in particular, have hypnotic and sedative effects when administered to animals. Furthermore, the compounds prepared according to the invention are valuable hardening agents and can be used, for example, for hardening epoxy resins and other such Har zen.



  The oxazolidines used as starting materials for the inventive preparation of ethanolamines with a triple bond can be obtained by known methods.

   One of these syntheses is briefly described, for example, as follows: A primary amine is reacted with a 1,2-epoxide in the presence of water to form an ethanolamine. This ethanolamine is condensed with an aldehyde or ketone with elimination of one mole of water to give the desired oxazolidine. This synthesis takes place according to the following scheme: Those shown in the formula above.

    monosubstituted monoethanolamine can also be obtained by reductive alkylation of a monoethanolamine with an aldehyde or ketone in the presence of hydrogen and a hydrogenation catalyst.

      <I> Example 1 </I> N-Isobutyl-N- (2-propynyl) -ethanolamine In a one-liter three-necked flask, which is fitted with a stirrer, a thermometer and a Dean-Starke trap for removing the water A reflux condenser was provided, 200 cubic meters of benzene, 122 g of monoethanolamine and 144 g of isobutyraldehyde were added.

   The mixture was refluxed with stirring for 5 hours, during which time 36 cm3 of water were separated out in the Dean-Starke trap.

   The flask was subjected to distillation and all of the solvent benzene was distilled off. The residue was then. 300 cm3 of methanol and 0.2 g of platinum catalyst were added and the mixture was hydrogenated in a Parr shaking apparatus at room temperature.

       After the theoretical amount of hydrogen had been absorbed, the catalyst was filtered off from the solution, the methanol was distilled off and the residue was subjected to distillation. 181 g of N-isobutylethanolamine were obtained. This material was placed in a flask equipped as described above. Then 250 cm- 'benzene were added and finally 46.5 g of paraformaldehyde were introduced.

   The mixture was refluxed for 6 hours, during which time 21 cm3 of water was collected in the Dean-stark trap. The mineral spirits were removed by distillation and the residue was subjected to vacuum distillation. 124 g of 3-isobutyloxazolidine with a boiling point of 61; 20 mm were obtained.



  In a one-liter flask, which was provided with a stirrer, a feed pipe for introducing acetylene and a discharge pipe in connection with an open U-tube mercury manometer, the 109 g of 3-isobutyloxazolidine, 250 cm3 of dioxane and 5 g of powdered copper chloride were added.

   The mixture was stirred and acetylene was introduced under a pressure of 50-76 mm Hg above atmospheric pressure. The temperature was kept at about 20-25 ° C. with the aid of an ice bath while the acetylene was being fed in. A total of 20 g of acetylene were absorbed within a period of 2 hours.

   The catalyst was then filtered off from the reaction mixture, the dioxane was removed by distillation under reduced pressure and the residue was fractionated. 59 g of a product boiling at 59 ° C./7 mm were obtained; ND = 1.4545. The anhydrous titration showed that 98.8 / o of the product consisted of the desired compound N isobutyl'-N- (2-propynyl) -ethanolamine.

      <I> Example 2 </I> N-t-ButylL-N- (2-propynyl) -ethanolamine The oxazolidine was prepared in the usual way from t-butylethanolamine, paraformaldehyde) and benzene.



       A suitable flask was charged with 65 g of 3-t-butyloxazolidine, 200 cm3 of dimethylformamide and 5 g of copper chloride. 16 g of acetylene were passed in at 15-25 ° C. in the course of 6 hours. The filtrate was treated with hydrogen sulfide, activated charcoal and filter cel and filtered.

   The filtrate was then freed from dimethylformamide using a water pump and the residue was distilled off. 41 g of Nt-butyl-N- (2-propynyl-ethanolamine, which passed over at 63-70 ° C./0.24 mm) are obtained. Another distillation of the material gave a product with a boiling point of 98-101 ° C./15 mm .

   This material gave a purity of 97.3 "/ o with anhydrous titration and had an ND of 1.4665. <I> Example 3 </I> Nt-] 3utyl-N- (1-n-propyl -2-propy! Nyl)

  -ethanolamine The oxazolidine was prepared from t.Butylethanolamine and butyraldehyde using benzene as the azeotropic agent according to the method described above. In a suitable.

   The flasks were filled with 86 g of the oxazolidine, 200 cm3 of dimethylformamide, and 10 g of copper chloride. Acetylene was introduced into this mixture with stirring, with 8.5 g of acetylene being absorbed in 3 hours.

   After this time, a further 100 cm3 of di'methylformamide were added and acetylene was again introduced. The mixture took up a further 7.5 g of acetylene over the course of 5 hours, so that the total amount of acetylene taken up was 16 g.

   The mixture was filtered to remove the copper catalyst and the remaining copper was removed by bubbling hydrogen sulphide into the filtrate, adding filter cel and again filtering; away. The thin ethyl formamide was removed with the water jet pump, and after its complete removal a solid separated out in the still.

   This solid was filtered off and washed with Skellysolve. . Washed and, this washing liquid combined with the filtrate.

   The filtrate was then freed from Skellysolve and the residue was distilled. 28.5 g of N-t-butyl were obtained! N- (1- n-propyl-2rpropynyl) -ethanolamine with a boiling point of 80-83 CI0.5 man. The,

       The material examined showed a content of 1001/0 of the above compound on anhydrous titration and had an ND of 1.4635. <I> Example 4 </I> N t-Butyl N- (2-propynyl) -beta-phenylethanolamine In a flask which was provided with a reflux condenser, a Dean-Starke® trap, a stirrer and a thermometer ,

       79 g of t-butyl-ss phenylethanolamine, prepared according to the in J. Am. Chem. Soc. <I> 78, </I> 4039 (1956) described method, filled with 122 g of paraformaldehyde and 150 cmss of benzene. This mixture was refluxed with stirring and the water formed during the reaction was deposited in the Dean Starke trap.

   The benzene was removed in vacuo and the residue was distilled in a high vacuum. He held 77 g of 3-t butyl 5-phenyl-oxazolidine, bp.

   88 C 0.3 mm, N 1.5138. D A suitable flask was filled with 77 g of the above-described oxazolidin, 250 cm3 of dimethylformamide and 5 g of copper chloride. Then acetylene was introduced over 8 hours at room temperature.

   A total of 17 g of acetylene was absorbed. The mixture was worked up in the usual way and, after distillation, gave 50 g of a material boiling at 130 ° C./0.25 mm. The test showed a content of 96.3%. ND was 1.5185.



  <I> Example </I> S N-Benzyl-N- (2-propynyl) -ethanolamine In a 3-liter flask equipped with a stirrer, Dean-Starke trap with attached reflux condenser and thermometer, 755 g of benzylethanolamine, 800 cm3 of benzene and 180 g of paraformaldehyde are filled.

   The mixture was refluxed with stirring, with 95 m3 of water being separated out in the Dean-Starke trap. The benzene was at
EMI0004.0070
  
    <I> a) <SEP> Acute <SEP> intraperitoneal <SEP> toxicity <SEP> in <SEP> mice </I>
<tb> Effect <SEP> Intraperitoneal <SEP> dose <SEP> mortality
<tb> Calming <SEP> Subhypnosis <SEP> Hypnosis <SEP> mg / kg <SEP> D / U <SEP> Time <SEP> (number of <SEP> mice)
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 577 <SEP> 0.5 *
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 751 <SEP> 0.5 *
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 976 <SEP> 5.5 * <SEP> 20 <SEP> min.

   <SEP> (5)
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 1269 <SEP> 5.5 * <SEP> 10 <SEP> min. <SEP> (5)
<tb> 7/30/56 <SEP> A-LD50 <SEP> = <SEP> 856 <SEP> mg / kg <SEP> (5/20 <SEP> Mou <SEP> IP; <SEP> 28 <SEP > g)
<tb> <I> b) <SEP> Acute <SEP> oral <SEP> toxicity <SEP> in <SEP> rats </I>
<tb> Effect <SEP> TP <SEP> Oral <SEP> dose <SEP> mortality
<tb> Calming <SEP> Subhypnosis <SEP> Hypnosis <SEP> Vo <SEP> Mon <SEP> mg / kg <SEP> D / U <SEP> Time <SEP> (number of <SEP> rats)
<tb> 0/5 <SEP> 0/5 <SEP> 0/5 <SEP> 0/5 <SEP> 0/5 <SEP> 400 <SEP> 0.5
<tb> <I> 4/5 <SEP> 1/5 </I> <SEP> 0/5 <SEP> 0/5 <SEP> 0/5 <SEP> 600 <SEP> 0.5
<tb> 5/5 <SEP> 5/5 <SEP> <I> 5/5 <SEP> 5/5 </I> <SEP> 5/5 <SEP> 900 <SEP> 0.5
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 1350 <SEP> 0.5 *
<tb> 5/5 <SEP> 5/5 <SEP> 5 <B> <I> 1 </I> </B> 5 <SEP> 5/5 <SEP> 5/5 <SEP> 2025 <SEP > 0,

  5 *
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 3040 <SEP> 4.5 * <SEP> 12 <SEP> min. <SEP> (4)
<tb> 4550 <SEP> (5.5) <SEP> * <SEP> accepted
<tb> 7/30/56 <SEP> A <SEP> LD5o <SEP> - <SEP> 2690 <SEP> 219 <SEP> SD <SEP> mg / kg <SEP> (5/30 <SEP> advice < SEP> 0R; <SEP> 11l-20 <SEP> gm)
<tb> 48.5 <SEP> SE <SEP> mg / kg With non-conductive doses, all rats were placed in hypnosis within 10 minutes and woke up again after 30 minutes.

   The rats were distilled off under ordinary pressure and the obtained product was subjected to distillation under reduced pressure. There were a practical, quantitative yield of 3-benzyloxazolidine, bp-. 125-127 C 18 mm received.



  A. Reaction of 3-benzyloxazolidine with Acety len at room temperature.



  A suitable flask equipped as in Example 1 was filled with 83 g of 3-benzyloxazolidin, 200.3 m3 of dioxane and 5 g of copper chloride. Acetylene was passed into this mixture at 20-30C. 15g of acetylene were taken up in 3 hours.

   The mixture was then left to stand for 2 days, the catalyst was filtered off, the dioxane was removed by distillation under reduced pressure and the residue was distilled. 54 g of a fraction boiling at 124 ° C./1.5 mm and 20 g of a fraction boiling at 124-150 ° C. 11.5 mm with decomposition were obtained. The anhydrous titration of the first fraction showed that the product was N-benzyl-N- (2-propynyl) -ethanolamine.



  This compound, a base in liquid form, has been shown to produce brief hypnosis when administered intraperitoneally to mice (W.R.

         7-4-56). A chlorohydrate was therefore prepared in order to be able to test its effectiveness when administered intravenously. The salt was obtained in the form of a 9.18% aqueous solution. The results obtained are as follows: anesthetized at 900 mg! Kg.

   The estimated oral anesthetic dose (Anes D 50) is 735 mg / kg or 27% A-LD50 (Rat 0R). B. Implementation of 3-Ben @ zyloxazolidine with Acety len at low temperature.



  83 g of 3-benzyloxazolidine, 200 cm3 of dioxane and 5 g of copper chloride were placed in a one-liter flask equipped as in Example 2. The mixture was cooled to about 10 ° C. in an ice bath and the acetylene was passed in at this temperature. Within 5 hours 16 g of acetylene were absorbed.

   The catalyst was removed by filtration, the dioxane was distilled off by distillation under reduced pressure and the product was distilled. It. 68.5 g of a product boiling at 124-128 C / 1.5 min were obtained.



  C. Reaction of acetylene with 3-benzyloxazolidine using acetone as the solvent.



  83 g of 3-benzyloxazolidine, 250 cm, 3 of acetone and 5 g of copper chloride were placed in a one-liter flask equipped as in Example 2. The reaction mixture was cooled in an ice bath before acetylene was introduced. 15 g of acetylene WUR absorbed within 6 hours.

   The catalyst was removed by filtration in the usual way, the acetone was a-bdistilled under reduced pressure and the product d'istilled. 41 g of the product were obtained.



  D. Reaction of acetylene with 3-benzyl-oxazolidine; Removal of the catalyst with H2S In a one-liter flask equipped as in Example '2 were 83 g of 3-benzyloxazolidine,

      200 cm3 of dioxane and 5 g of copper chlorine were poured in. The mixture was cooled to about 10 ° C. in an ice bath and acetylene at 5-10 ° C. for 4 hours
EMI0005.0059
  
    IP <SEP> dose <SEP> mortality
<tb> Effect <SEP> mg / kg <SEP> DIU <SEP> time <SEP> (number of <SEP> mice)
<tb> Ataxia <SEP>; <SEP> pseudohypnosis; <SEP> convulsions
<tb> - <SEP>; <SEP> - <SEP> - <SEP> 100 <SEP> 0/5
<tb> - <SEP>; <SEP> - <SEP> - <SEP> 372 <SEP> 0/5
<tb> - <SEP>; <SEP> - <SEP> - <SEP> 629 <SEP> 0/5
<tb> <SEP> - <SEP> - <SEP> 818 <SEP> 0/5
<tb> <SEP>;

   <SEP> - <SEP> - <SEP> 1063 <SEP> 2/5 <SEP> 10 <SEP> min. <SEP> (1); <SEP> 24 <SEP> hours <SEP> (1)
<tb> <SEP>; <SEP> - <SEP>; <SEP> - <SEP> 1382 <SEP> 1/5 <SEP> 10 <SEP> min. <SEP> (1)
<tb>;> <SEP>; <SEP> - <SEP> - <SEP> 1797 <SEP> 1/5 <SEP> 10 <SEP> min. <SEP> (1)
<tb> <SEP>; <SEP> 415 <SEP> - <SEP> 2326 <SEP> 2/5 <SEP> 30 <SEP> min. <SEP> (2)
<tb> - <SEP>; <SEP> 415 <SEP> 215 <SEP> 3024 <SEP> 3/5 <SEP> 30 <SEP> min. <SEP> (3)
<tb> - <SEP>; <SEP> - <SEP> 515 <SEP> 3913 <SEP> 5/5 <SEP> 10 <SEP> min. <SEP> (5)
<tb> 7/23/56 <SEP> A-LD5o <SEP> = <SEP> 2576-311 <SEP> SD <SEP> mgikg <SEP> (5/40 <SEP> Mou <SEP> IP;

   <SEP> 23.9 <SEP> gm)
<tb> 68 <SEP> SE <SEP> mg / kg <I> Example? </I> N-Benzyl-N- (1-n-propyl-2-propynyl) -ethanolamine According to the method described in Example 4, obtained from 129 g of benzylethanolamine, 300 em3 of benzene and 72 g of n-butyraldehyde, 150 g of 2-N-propyl = 3-benzyl'oxazolidine with a boiling point of 143 'to 1450C112 mm; ND 1.5076.

           paid. The mixture was left to stand at room temperature overnight. 15.5 g of acetylene were taken up. The catalyst was then filtered off using an auxiliary filter bed:

      The catalyst cake was washed with dioxane, the wash liquid combined with the filtrate, and the filtrate treated with hydrogen sulfide to form a copper sulfide precipitate.

    The copper sulfide was filtered off. However, the film obtained was not clear; Hydrogen sulphide was therefore passed in further, activated charcoal was added and the filtration was again carried out. In this way a pale orange colored filtrate was obtained.

   The dioxane was removed by distillation under reduced pressure and the residue was distilled off in vacuo, 70 g of a product boiling at 104-106 ° C./0.27 mm being obtained. No decomposition was observed during this distillation.

    <I> Example 6 </I> N-benzyl = N- (1-phenyl-, 2-propynyl) -lethanolamine was prepared as described in Example 1, where 151 g of benzylethane alamine, 300 cm3 of benzene and 106 g of benzaldehyde were used . 200 g of the desired: Oxazolid'ins were obtained, which melts at 130 Cl 1 mm; ND 1.5075.



  The reaction was carried out as in Example 1 using 119 g of 2 phem.yl: -3-bevzyl-oxazolidine, 250 cm3 of dioxane, 10 g of copper chloride and 12 g of acetylene.

   The batch was processed in the usual way and gave 75 g of the desired product; Bp 151-155 C / 0.25 mm; Nl, 5695. D This compound had the following pharmacological properties:

              Following the procedure of Example 4, 95 g of the desired product were obtained from 103 g of oxazolidine, 200 cm 3 of dioxane, 10 g of copper chloride and 15 g of acetylene; Bp 115-117 C / 3 mm;

          N1,5155. D This compound had the following pharmacological effects:

      
EMI0006.0000
  
    IP <SEP> dose <SEP> mortality
<tb> mg / kg <SEP> D / U <SEP> time <SEP> (number of <SEP> mice)
<tb> Calming <SEP> 5/5 <SEP> 1063 <SEP> 0/5
<tb> <SEP>; <SEP> subhyp. <SEP> 5/5; <SEP> Hyp. <SEP> 3/5 <SEP> 1382 <SEP> 1/5 * <SEP> 48 <SEP> hours <SEP> (1)
<tb> - <SEP> <SEP>; <SEP> <SEP> 5/5 <SEP> 1797 <SEP> 1/5 * <SEP> 24 <SEP> hours <SEP> (1)
<tb> - <SEP> <SEP> <SEP> 5/5 <SEP> 2326 <SEP> 5/5 * <SEP> 3 <SEP> hours <SEP> (2); <SEP> 24 <SEP> hours <SEP> (2)
<tb> 48 <SEP> hours <SEP> (1)
<tb> - <SEP> <SEP>; <SEP> <SEP> 5/5 <SEP> 3024 <SEP> 4/5 * <SEP> 3 <SEP> hours <SEP> (2); <SEP> 24 <SEP> hours <SEP> (2)
<tb> 7/30/56 <SEP> AOLD5o <SEP> = <SEP> 1877-216 <SEP> SD <SEP> mg / kg <SEP> (5j25 <SEP> MouIP;

   <SEP> 27.7 <SEP> gm)
<tb> 48 <SEP> SE <SEP> mg / kg <I> Example 8 </I> A. Reaction of acetylene with 3-benzyloxazolidine using dimethylformamide as solvent.



  87 g of 3-benzyl oxazolidine, 250 cubic meters of dimethylformamide and 5 g of copper chloride were placed in a suitable vessel. Acety len was passed into this mixture with rapid stirring at an excess pressure of 7.5-15 cm Hg.

   The temperature was kept between 5 and 10 ° C. There was an extremely rapid absorption of acetylene, and after one hour 22 g of acetylene had been absorbed by the mixture.

   A filter aid known from the Filter-Cel brand was then added to this mixture, the mixture was filtered and the filter cake was washed with a small amount of acetone.

    The filtrate was treated with hydrogen sulfide, activated carbon added and filtered again to remove the carbon and copper sulfide. A clear, colorless filtrate was obtained. was freed from acetone and dimethylformamide under reduced pressure. The high boiling material was then distilled to give 82 g of a product boiling at 106 to 11011C / 0.25 mm.

   This corresponds to a yield of 82% of theory. <I> Example 9 </I> N-Benzyl N- (4-acetoxy-4methyl-2-pentynyl) - ethanolamine acetate In a one-liter three-necked flask with thermometer, reflux condenser,

      The dropping funnel and stirrer were 85 g of 3-Benzyloxazol'i d '! , 200 cm-dioxane and 10 g copper chloride filled.

   50 g of dimethylethynylcarbinol were then added dropwise with stirring. , This addition caused a slightly exothermic reaction,

      and the temperature rose to 4811 C and was at that altitude. kept at 45-47 ° C. by cooling slightly in an ice bath. The required dimethylethynylearbinol was added within 40 minutes. The mixture was stirred for a further 2 hours, during which it became very viscous,

      so that another 200 cm- 'dioxane was added for dilution. The mixture was then left to stand overnight, then hydrogen sulfide was passed through it, activated charcoal and filter cell were added and filtered. A clear solution was obtained from which the dioxane was removed under reduced pressure and the residue was treated as follows:

    To this residue, in a suitable vessel with a stirrer, thermometer and dropping funnel, 300 cm3 of benzene, 80 g of pyridine and, with stirring, 180 g of acetyl chloride were added over the course of 30 minutes and keeping the temperature constant at about 75 ° C. using an ice bath. The mixture was stirred for a further 30 minutes and then slowly with a solution of 92 g

  Sodium hydroxide in 150% water was added, the temperature being kept below 20 ° C. with the aid of the ice bath. The mixture was then filtered through filter cel, neutralized with sodium carbonate, the upper layer separated and the lower layer extra hard with benzene. The benzene extracts were combined with the top layer and dried over anhydrous potassium carbonate. The benzene was removed under reduced pressure and the residue was distilled.

   There was 125 g of one at 167 C; 0.26 mm of boiling substance. This substance was identified by anhydrous titration as N-benzyl N- (4-acetoxy-4-methyl-2-pentynyl) -ethanolamine acetate.



  <I> Example 10 </I> N-Benzyl-N- (4-oxy-4-methyl-2-hexynyl) -ethanolamine In a similar experiment, 48 g of 3-benzyloxazol'id'in, 200 cm3 of dioxane and 5 g of copper chloride are placed in a flask and 25 g of methylethylethylcarbine are added at 35 ° C. The mixture was stirred and stirred for 2 hours

  then left to stand overnight. Hydrogen sulfide was then passed in, activated carbon was added and the mixture was filtered. The dioxane was drawn off at the water jet pump and the residue was distilled. 54 g of the desired substance were obtained; 175-180 Ci0.26 mm.

   This material was titrated by the anhydrous method and was found to be 99.8% N benzyl-N- (4-oxy-4-methyl-2-hexynyl) -ethanolamine; ND = 1.5366.

      <I> Example 11 </I> N-Benzyl- (2-heptynyl) -ethanolamine. 86 g of 3-benzyloxazolidine, 250 cm3 of dioxane and 5 g of copper chloride were placed in a one-liter three-necked flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser, and inside 46 g of n-butyl acetylene were added for 20 minutes. A slightly exothermic reaction resulted.

   The reaction mixture was stirred for 5 hours, left to stand overnight, then heated to 500.degree. C. and stirred at 40-50.degree. C. for a further 60 hours. Then the mixture was filtered, the filtrate treated with H.S., added filter cel and filtered again. The filtrate was freed from dioxane in vacuo and the residue was distilled.

   86 g of N-benzyl-N- (2-heptynyl) -ethanolamine were obtained. The ND of this substance was 1.5202 and its content was determined to be 97% by anhydrous titration.



       Example <I> 12 </I> N-Isopropyl-N- (2-propynyl) -ethanolamine In a one-liter three-necked flask with a Dean-Starke trap and attached reflux condenser, stirrer and thermometer, 103 g of N-isopropyl'ethanolamine,

       Filled with 200 cm-3 benzene and 30 g paraformaldehyde. The mixture was refluxed and 20 cm- 'of water deposited in the Dean Starke trap. The benzene was then distilled off at ordinary pressure and the residue was the

  Subjected to vacuum distillation. 82 g of 3-isopropyloxazol'idine with a boiling point of 450 ° C./30 mm were obtained.



  77.5 g of 3-isopropyloxazolidine, 200 cm ?, dioxane and: 5 g of copper chloride were placed in a suitable flask. Acetylene was then passed through the mixture at 10-20 ° C., 17 g of acetylene being absorbed within 8 hours (theoretical amount 19 g).

   The catalyst was filtered off, this filtrate was saturated with HZS, Norit activated carbon was added and the mixture was again filtered. The dioxane was then removed in vacuo and the product d'estill'iert in vacuo. 46.5 g of the desired compound were obtained, boiling point.

       96-980C / '0.1.6 mm-. Another, higher-boiling fraction with a boiling point of 64-1450C / 1.5 mm was not investigated further.



  <I> Example 13 </I> N-Isopropyl-N- (4-oxy-4-methyl-2-hexynyl) -ethanolamine In a similar experiment, 74 g of 3-isopropyl oxazolidine with a content of 80 / o, 200 cm3 of dioxane and 10 g of copper chloride were poured into a flask and 50 g of methylethylaphynylearbinol were added dropwise over the course of 30 minutes, the temperature being kept below 400 ° C. with the aid of an ice bath.

   The mixture was stirred for 2 hours and left to stand overnight. Then it was worked up in the usual way. After removing the dioxane on the water jet pump, the residue was distilled and gave 65 g of N-isopropyl-N- (4-oxy-4-methyl-2-hexynyl)

  -ethanolamine. With anhydrous titration this material showed a content of 99.7% and had an N25 D of 1.4821. Example <I> 14 </I> N-Isopropyl-N- [3- (2-cyclohexanol) -2-propynyl:

  ] - äthanolamiu In a similar experiment, 85 g of 3-isopropyloxazolidine, 200 cm:

  3 dioxane and 5 g copper chlorine are poured into a flask and a solution of 62 g ethynyl cyclohexanol in 20 cm 3 dioxane is added through the dropping funnel while stirring. The drawing album of EthynylcycIohexanols required 20 minutes,

          and the maximum temperature occurring was 380 C. The mixture was then. Praised for 2½ hours and then worked up as usual. 65 g of N-isopropyl-N- [3- (2-cyclohexanol) -2-propynyl] -abhanolamine of bp.

   1580- C 0.5 mm. The material had an ND of 1.5057 and anhydrous titration showed a content of 990/0.



  <I> Example 15 </I> N-isopropyl N- (2 butynyl) -ethanolamine. 60 g of 3-isopropyloxazold'ine were added to a similar flask as was used for the acetylene reactions.

      250 cm3 of dioxane and 5 g of copper chlorine were poured in. Methylacetylene (1-propyne) was passed into this mixture at 25 to 300 ° C. for 10 hours, during which time 34 g of mer thylacetylene were absorbed.

   The mixture: Was separated from the catalyst, treated with H.S as usual, freed from dioxane using a water jet pump and the residue was distilled. 63 g of N-isopropyl - N - (2 - bwtynyl) - ethanolamine of bp.

    640 C / 0; 6 mm; the content was determined by anhydrous titration and gave 97.3% ND = 1.4728. <I> Example 16 </I> N-isopropyT N- (2 methyI 1-buten-3-yn) reaction of 3-isopropyloxazalidine with isopropyl acetylene.



  The experiment was carried out in a similar way to that with butyl / acetylene. 120 g of 3 isopropyloxazolidhn, 200 cubic meters of dioxane and 7.5 g of copper chloride were placed in a one-liter flask.

       Then it got slow. a solution of 68 g of isopropenyl'acetylene in 100 cm3 of dioxane was added. An exothermic reaction resulted, which led to a temperature of 350 C. The temperature was then, by cooling during,

   the addition, which took 25 minutes, was kept at 30-35 ° C. The mixture was stirred for 3 hours and gradually cooled.

       It was then left to stand overnight and worked up in the usual way by filtration, treatment with H2S and removal of the boiling solvent on the water jet pump.

   136 g of a product boiling at 720 ° C./0.25 mm were obtained, the anhydrous titration of which gave 98% N-isopropyl-N- (2-methyl-1-buten-3-yn) ethanolamine.



  Example 17 N-isopropyl-N- (2-heptynyl) ethanolamine As described above, 120 g of 3-isopropyloxazolidihu, 400 cubic meters of dioxane and 10 g of copper chloride were reacted with 86 g of butylacetylene. The temperature was 33 to 400 ° C. during the addition of the butyl acetylene.

   The mixture was stirred for 2 hours, heated to 60.degree. C. over the course of 20 minutes and rose to 68.degree. C. over 45 minutes. The heat source was then removed and the mixture was allowed to cool to room temperature with stirring. The catalyst was filtered off and the filtrate treated with hydrogen sulphide and Darco G-60 and then filtered again. The doxan was removed from the water jet pump and the residue was distilled in a high vacuum.

   165 g of N-isopropyl-N- (2-heptyryl) -ethanolamine, boiling point 88-90 C0.5 mm were obtained; N = D 1.4678. Example 18 a) In a one-liter three-necked flask equipped with a stirrer, thermometer, Dean-Starke = trap and reflux condenser, 210 g of diethanolamine,

      250 cms of benzene and 120 g of propionaldehyde are added. The mixture was stirred and refluxed, separating 40 cm -1 of water.

   The benzene was distilled off at ordinary pressure and the residue was distilled in vacuo. 1.97 g of 3- (ss-oxyethyl) -2-ethyl'oxazolidine of boiling point 108-112a C were obtained! 15 mm. The <B> N21 </B> was 1.4665, and the material examined had a content of 100.25% in the anhydrous titration.



       143 g of the above oxazolidin, 350 cm.J of methylformamide and 8 g of copper chloride were placed in a flask equipped with a thermometer, stirring, gas inlet pipe and gas escape pipe in connection with an open mercury manometer.

   The mixture was cooled to 311 ° C. with stirring and, after flushing with acetylene, acetylene was passed into the mixture and the reaction was carried out at a temperature of -3 to 4 ° C. for 4 hours. A total of 24 g of acetylene was absorbed. The mixture was filtered to filter off the copper catalyst, the filtrate was diluted with 500 cm ?, acetone and saturated with H.S.

   The solution was filtered off from the sulfide and the acetone and dimethylformamide removed on the water jet pump. The residue was distilled in vacuo and gave 85 g of N-oxy-ethyl-N- (1-ethyl-2-propyne) -ethanolamine, b.p. 122-128 "C, - '1.3 mm; ND - 1 , 4895.

   Yield according to anhydrous titration: 102.8 / a.
EMI0008.0083
  
    Effect <SEP> IP <SEP> dose <SEP> mortality
<tb> mg / kg <SEP> D / U <SEP> time <SEP> (number of <SEP> mice)
<tb> reassurance
<tb> 3/5 <SEP> 1382 <SEP> 0/5
<tb> 5/5 <SEP> 1797 <SEP> 0/5
<tb> 5/5 <SEP> 2326 <SEP> 3/5 * <SEP> 24 <SEP> hours <SEP> (1); <SEP> 48 <SEP> hours <SEP> (2)
<tb> 5/5 <SEP> 3024 <SEP> 3/5 * <SEP> 24 <SEP> hours <SEP> (2); <SEP> 72 <SEP> hours <SEP> (1)
<tb> 10/12/56 <SEP> A-LDSO <SEP> = <SEP> 2527-230 <SEP> SD <SEP> mg / kg <SEP> (5/20 <SEP> MoulP;

   <SEP> 26.5 <SEP> gm)
<tb> 51 <SEP> SE <SEP> mg / kg b) A two-liter flask with a stirring condenser, thermometer and dropping funnel was charged with 800 cm of dioxane and 130 g (1.13 mol) of N-isopropyloxazolidine. When 40 g of copper chloride were added, the temperature rose slightly to <B> 350 </B> C. 125 g (2.23 moles) of propargylic alcohol were added from the dropping funnel over a period of 45 minutes. The reaction was exothermic and the highest temperature was 490 C.

   The mixture was stirred for 2 hours, then filtered to remove the yellow solid (copper salt of propargylic alcohol). The filtrate was treated with H2S and filtered from the deposited copper sulfide. The orange-red colored filtrate was freed from dioxane and excess propargyl alcohol. The distillation under vacuum gave a: small forerunner of unreacted propargyl alcohol. The main fraction passed over 0.75 mm at 147-150 C.

   It was 91 g of N-isopropyl-N- (4-oxy-2-bu: tynyl) -ethanolamine; ND = 1.4974. 48 g of a resinous residue remained in the distillation flask. <I> Example 19 </I> N-methyl-N- (1-phenyl-2-propynyl) -ethanol: min According to the procedure described above, 65g of monomebhylethanolamine, 200 cm- 'benzene and 106 g of benzaldehyde' , 106 g of 2-phenyl-3-methyl-oxazolide! In with a boiling point of 110-115 ° C; 18 mm.



  According to the process described above, 41 g of the desired product with a boiling point of 103 ° C., 0.26 mm were obtained from 81 g of oxazolidine, 200 g of dioxane, 10 g of copper chloride and 8.5 g of acetylene.

      <I> Example 20 </I> N-Oxyethyl-N- (2-propynyl) -ethanolamine 100.5 g of 3 - (/ 3-oxyethyl) - oxazalidine of oxazolidine were made from 105 g of diethanolamine, 200 cm3 of benzene and 30 g of paraformaldehyde Obtained from bp 680 C, 0.5 mm; ND - 1.4775.



  According to the process described above, 32 g of the product boiling at 113-116 ° C. / 0.5 mm were obtained from 58.5 g of the oxazolidin, 200 cms of dioxane, 7 g of copper chloride and 14.5 g of acetylene.

    The material solidified on standing and was found to be 960% pure on anhydrous titration. This compound had the following pharmacological effects:

        <I> Example 21 </I> N-Phenyl N- (2 propynyl) -ethanol'amine From 139 g of phenylethanolamine, 200 cms of benzene and 30 g of paraformaldehyde, 135 g of 3-phenyl-oxazolidine were obtained by the method described above
EMI0009.0007
  
    IP <SEP> dose <SEP> mortality
<tb> Effect <SEP> mg / kg <SEP> D / U <SEP> time <SEP> (number of <SEP> mice)
<tb> reassurance; <SEP> hypnosis
<tb> 4/5 <SEP>; <SEP> 3/5 <SEP> 372 <SEP> 1/5 * <SEP> 24 <SEP> hours <SEP> (1)
<tb> 5/5 <SEP>; <SEP> 3/5 <SEP> 484 <SEP> 2/5 * <SEP> 24 <SEP> hours <SEP> (1);

   <SEP> 48 <SEP> hours <SEP> (1)
<tb> 5/5 <SEP> 3/5 <SEP> 629 <SEP> 3/5 * <SEP> 24 <SEP> hours <SEP> (3)
<tb> 5/5 <SEP>; <SEP> 5/5 <SEP> <B> 818 </B> <SEP> 5/5 * <SEP> 6 <SEP> min. <SEP> (5)
<tb> 5/5 <SEP> 5/5 <SEP> 1063 <SEP> 5/5 * <SEP> 5 <SEP> min. <SEP> (5)
<tb> 10/8/56 <SEP> A-LD5o <SEP> - <SEP> 534 <SEP> - <SEP> 64 <SEP> SD <SEP> mg / kg <SEP> (5/25 <SEP> Mou <SEP> IP;

   <SEP> 28.1 <SEP> gm)
<tb> -14 <SEP> SE <SEP> mg / kg <I> Example 22 </I> Nt-octyl-N- (2-propynyl) -ethanolamine In a similar experiment <B> 100 </ B> g of t-octylethanolamine, 200 cm3 of paint and 18.5 g of paraformaldehyde boiled under reflux, separating 11 cms of water in the trap.

   The benzene was removed on the water aspirator and the residue, which weighed 136.5 g, was considered to consist entirely of 3-t-octyloxazolidine.



  In a similar experiment, the 136.5 g of the oily residue, 250 cm3 of dioxane and 5 g of copper chloride were reacted with acetylene at room temperature with stirring. After 8 hours, 15 g of acetylene had been absorbed. The mixture was worked up in the usual way.

   The distillation. yielded 78.5 g of N-t-octyl-N- (2-propynyl) -ethanolamine of D, bp 104-112 CJl, 7-2.0 mm; N = 1.4722; Purity (anhydrous titration) 1010/9.
EMI0009.0035
    with an acetylenically unsaturated compound of the formula R7 C - CH in which formulas R1 and R3 to RG are hydrogen, alkyl, aryl, alkaryl or aralkyl groups,

       R2 is an alkyl, oxyalkyl, aryl, alkaryl or aralkyl group, R7 is hydrogen or an alkyl, alkenyl, aryl, aralkyl, alkaryl or oxyalkyl group,

   Reacts in the presence of a source of cuprous ions at a temperature between 0 and 60 ° C, which does not have a bp of 87 ° C / 0.28 mm; N = D 1.5730.



  The material showed a purity of 104% by anhydrous titration.



  The compound produced therefrom with acetylene had the following pharmacological effect: Example 23 Nt-octyl-N- (1-n-propyl-2-propyn) -ethanolamine. This oxazolide was given off in the usual way t-octylethanolamine, n-butyraldehyde and benzene are produced as azeotropic agents.



  114 g of 2-n-propyl-3-t-octyloxazolidine, 300 cm of dimethylformamide and 7 g of copper chlorine are treated with acetylene in the usual way. In the course of 4 hours, 16 g of acetylene were absorbed at 15-25 C.

   The catalyst was filtered off and the filtrate was used without further purification, dpa no discoloration indicated any remaining copper. The dimethylformamide was sucked off using the water jet pump and the residue was distilled. 76 g of the product boiling at 81-85 ° C./0.75 mm were obtained;

      N D = 1.4561.

 

Claims (1)

PATENT CLAIM Process for the production of new ethanolamines with a triple bond, thereby: characterized in that an oxazol'idin of the formula reacted reactant is removed from the reaction mixture and the desired end product is distilled off from the residue. SUBClaims 1. Method according to claim, characterized in that N-isobutyl-N- (2-propynyl) -ethanolamine is produced. 2. The method according to claim, characterized in that N-benzyl-N- (2-propynyl) -ethanol- amine. will be produced. 3. The method according to claim, characterized in that N-isopropyl-N- (2-propynyl) -ethanolamine is produced. 4th Process according to patent claim, characterized in that: ss N oxyethyl-N- (2-propynyl) -ethanolamine is produced. 5. The method according to patent claim, characterized in that N-isopropyl-N- (4-oxy-methyl-2-hexenyl) -ethanolamine is produced. 6. The method according to claim, characterized in that one works at 5-30 ° C. 7th Process according to claim, characterized in that one works in the presence of a solvent means.