BE569576A - - Google Patents

Description

       

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   The present invention relates to new acetylenic compounds, and in particular to acetylenically unsaturated ethanolamines; the invention relates especially to acetylenically unsaturated ethanolamines having the following chemical formula:

   
 EMI1.1
   In the above formula, R1, R2 and R4 to R7 may be hydrogen, alkyl groups, aryl groups, alkaryl groups or aralkyl groups, provided that R1 or R2 are hydrogenated. limiting factors are that R1 and R2 cannot both be an alkyl or aryl group, and that R3 is not hydrogen.
R8 can be hydrogen, an alkyl group, an alkenyl group, an aryl group, an aralkyl group, an alkaryl group, or a hydroxyalkyl group.



   The new compounds of the present invention are prepared by the reaction of any mono-acetylenic compound containing at least one active hydrogen atom, with an oxazolidine. This reaction proceeds according to the following equation:
 EMI1.2
 

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The reaction conditions for the reaction given above are generally as follows.



   The chosen oxazolidine is dissolved in a suitable solvent, preferably dioxane or dimethylformamide, the latter being especially preferred. Although the above reaction can proceed in the absence of the solvent, it has been found that the reaction proceeds more smoothly, and under better control, if a solvent is present. The amount of solvent used will depend to some extent on the plant used. Generally, however, about 1 to 5 parts of solvent per part of oxazolidine is used.

   When dioxane is the solvent used, it is usually preferred to use 2 to 3 parts of dioxane per part of the oxazolidine. When dimethylformamide is the solvent used, it is preferred to use 1 to 5 parts per part of the oxazolidineo
The reaction proceeds exothermically and it is preferred to operate at temperatures varying from about 0o to 60 C. A preferable temperature range is 5 to 10 C. It should be understood, however, that temperature limitations do not apply. are not critical. The reaction is controlled, however, by the proper control of the temperature.



   The reactions of the present invention can be carried out under a wide range of pressures from a pressure below atmospheric pressure to a pressure above atmospheric pressure. Although there appears to be some relationship between speed and smoothness of the reaction with pressure, this point has not yet been fully explored Ordinarily, reactions develop smoothly at pressures varying from about 5 to about 14 inches of mercury, 8 to 10 inches being preferred.
Since the acetylene compound is ordinarily a gaseous material, it is believed that diluent gases, such as nitrogen and other inert gases, can be used, in order to prevent accidental explosion or overcharging of the acetylene compound.



   One of the essential characteristics of the new reactions to which the present invention relates is the presence of a source of cuprous ions. These ouprous ions form a complex of catalytic copper with the acetylene compound. The source of the cuprous ions can be any copper salt which dissociates in the reaction mixture to give the required cuprous ions. For example, cuprous chloride, ouprous sulfate, etc., are usable.



   After the oxazolidine has been dissolved in the desired solvent, the cuprous ions have been introduced and the pressure and temperature have been adjusted to the desired point, the acetylene compound is passed through the mixture of ingredients with stirring. until the desired amount has been added. Normally, a brightly colored precipitate is found which represents the copper-acetylene complex. This material is filtered to separate it from the reaction mixture. It is then preferred to pass hydrogen sulfide through the reaction mixture to precipitate any residual orprous ions.



  It should of course be understood that any other suitable means can be used to remove excess cupreuxo
After removing the residual cuprous ions, the reaction mixture is then distilled to remove the solvent. The desired product is removed by distillation after the solvent, at a determined temperature which usually does not vary more than 2 to 100. The treatment of the product is completed by any of the methods known in the art. These methods are redistillation, recrystallization, etc. The product obtained is monitored by non-aqueous titration, hydrogenation to check the amount of hydrogen attached, and other familiar methods.

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   The acetylenically unsaturated ethanolamines of the present invention have a large number of applications, both in the industrial and pharmaceutical fields. They are of interest in the formation of a large number of industrial compounds due to the presence of three very active groups in the molecule, namely the acetylenic group, the amino group and the hydroxyl group, all capable of reacting with various reagents known to give the conventional reactions of these compounds.



   For example, when R8 of the formula is hydrogen, acetylenically unsaturated ethanolamines undergo all the conventional acetylenic reactions, such as ethynylation, vinylation, carbonylation, etc.



    When R8 is an organic radical, such as methyl, ethyl, propyl, etc., the compounds undergo addition reactions, such as halogenation, hydrogenation, etc. When desired, the compounds can be used to undergo conventional tertiary amine reactions, such as salt formation, formation of quaternary ammonium compounds, etc.
The hydroxyl group can be used to form esters, ethers, metal alcoholates, etc.



   The acetylenically unsaturated ethanolamines of the present invention have utility as pharmacological compounds. Certain derivatives, especially the hydrochlorides, have hypnotic and sedative properties, when administered to animals. The materials of the present invention are also of interest as curing agents and have utility in the curing of materials, such as epoxy resins and other resinous materials of this type.



   The oxazolidines used as raw materials for the formation of the acetylenically unsaturated ethanolamines of the present invention can be suitably prepared by methods known in the art. Such a synthesis can be described in the following general terms.



   A primary amine is reacted with a 1,2-epoxide in the presence of water to form an ethanolamineo The ethanolamine is then condensed with an aldehyde or an oetone, with the elimination of a water molecule, to erode the oxazolidine desired. This synthesis can be represented by the formula given below:
 EMI3.1
 
The mono-ethanolamines, mono-substituted, as represented in the formula above, can also be prepared by the reductive alkylation of a mono-ethanolamine with an aldehyde or a ketone, in the presence

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 hydrogen and a hydrogenation catalyst.



   The new compounds of the invention and their method of preparation can be more clearly explained with reference to the following examples.



  EXAMPLE 1: N-isobutyl-N- (2-propynyl) ethanolamine.



   A. Preparation of 3-isobutyloxazolidineo
It was placed in a three-necked, one liter flask, equipped with a stirring device, a thermometer and a Dean-Starke manifold for water removal, and surmounted by a reflux condenser , 200 ml of benzene, 122 g of mono-ethanolamine and 144 g of isobutyraldehyde. The mixture was stirred and refluxed for 5 hours, during which time 36 ml of water separated in the Dean-Starkeo manifold. The flask was then mounted for distillation and all the benzene solvent was removed by distillation.



  To the residue were then added 300 ml of methanol and 0.2 g of platinum as a catalyst, and the mixture was hydrogenated on a Parr shaker at room temperature. When the theoretical amount of hydrogen was absorbed, the solution was filtered to separate it from the catalyst, the methanol was removed by distillation and the residue was distilled off. 181 g of N-isobutylethanolamine were obtained. This material was loaded into a flask equipped as described above. Then, 250 ml of benzene was added and, finally, 46.5 g of paraformaldehyde was introduced. The mixture was refluxed for 6 hours, during which time 21 ml of water were removed in the Dean-Starke manifold.



  The benzene solvent was removed by distillation and the residue was distilled off in vacuo. 124 g of 3-isobutyloxazolidine were obtained, boiling at 61 C / 20 mm.



   Bo Reaction of acetylene with 3-isobutyloxazolidine.



   It was loaded into a liter flask, fitted with a stirring device, an inlet tube for the introduction of acetylene and an outlet tube connected to a U-tube mercury manometer. of the open type, 109 g of 3-isobutyloxazolidine, 250 ml of dioxane and 5 g of pulverulent cuprous chloride. The mixture was stirred and acetylene was passed through it at a pressure of 2 to 3 inches of mercury, above atmospheric pressure.



  The temperature was maintained at about 20-25 C by means of an ice bath while introducing the acetylene. Over a period of 2 hours, a total of 20 g of acetylene was absorbed. The catalyst was removed from the reaction mixture by filtration, the dioxane was removed by distillation at reduced pressure, and the residue was fractionated. 59 g of product boiling at 59 C / 0.7 mm were obtained.



  The N25 of this material was 1.4545; non-aqueous titration indicated that 98.8% of the product constituted the desired compound, namely N-isobutyl-N- (2-propynyl) ethanolamine.



  EXAMPLE 2: N-t-butyl-N- (2-propynyl) ethanolaminee
A. Preparation of oxazolidineo
The preparation was planned in the usual manner from tbutylethanolamine, paraformaldehyde and benzene.



   Bo Reaction with acetylene.



   In a suitable flask, 65 g of 3-t-butyloxazolidine, 200 ml of dimethylformamide and 5 g of cuprous chloride were charged. 16 g of acetylene were passed through it over a period of 6 hours at 15-25 C. The mixture was treated with hydrogen sulfide, charcoal, Filter-Cel, then filtered The filtrate was liberated from dimethylformamide with a water pump, and the residue was removed at the top give 41 g of Nt-butyl-N- (2-propynyl) ethanolmaine, boiling at 63 -70 C / 0.24 mmo Redistillation of the material gave a pro- milk boiling at 980-101 / 25 mm. This material titrated 97.3% by a non-aqueous titration and had an N25 of 1.46650

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 EMI5.1
 EXAMPLES: NtmbutylNm lnpropyl2-propynyl) ethanolam.neo A Preparation of oxazolidine.



  Oxazolidine was prepared starting from t-butylethsllc --- &, nine and butyraldehyde, using benzene as the azeotropic agent. The process used was as described above.
 EMI5.2
 Bo Reaction of oxazolidine with acetyleneo A suitable flask was loaded with 86 g of 1 oxazolidine, 200 ml of dimethylformamide and 10 g of cuprous chloride. Acetylene was passed through this stirred mixture with an absorption of 8.5 g in 3 hours, after
 EMI5.3
 which was added a further 100 ml of dimethylformamide and OD again passed acetylene. The mixture then removed an additional 7.5 g of acetylene over a 5 hour period, making a total of 16 g of acetylene.

   The mixture was filtered to remove the catalyst copper, and the residual copper was removed by passing hydrogen sulfide through the filtrate, adding Filter-Cel and filtering. The dimethylformamide was removed with the water pump and when it was completely removed a solid separated in the vial. The solid was removed by filtration and washed with Skellysolve, then combined with the filtrate The filtrate was then freed from Skellysolve and the residue was distilled to give 28.5 g of Nt-butyl-N- (1-npropyl-2- propynyl) ethanolamine boiling at 80-83 / 0.5 mmo This material titrated for the above structure 101% by a non-aqueous titration and it had an N25 of 1.46350
 EMI5.4
 EXAMPLE 4: N-t-butyl-N- (2-propynyl) -beta-phenylethanolamine.



  A. Preparation of 3-t-but: l- hp x, y1 oxazolidineo
In a flask equipped with a reflux condenser, a Dean-Starke collector, a stirrer and a thermometer, 79 gr of t-butyl-beta-phenylethanolamine prepared by the process developed in JACS 78 were charged. , 4039 (1956), 122 g of paraformaldehyde and 150 ml of benzene. This mixture was heated with stirring at reflux and the water formed in the reaction was separated in the Dean-Starkeo manifold The benzene was removed with a water pump and the residue was distilled under a high vacuum o 77 g were obtained, boiling at 88 / 0.3 mm, having an N25 of 1.51380
Bo Reaction with acetylene.



   77 g of the above oxazolidine, 250 ml of dimethylformamide and 5 g of oupreux chloride were charged into a suitable flask. Acetylene was passed through it at room temperature over a period of 8 hours. We had a total absorption of 17 g of acetylene. The mixture was treated in the usual manner and, on distillation, gave 50 g of material boiling at 130 / 0.25 mmo. This material assayed 96.3%. The N25 was 1.51850
 EMI5.5
 EXAMPLE 5: -. N-Benzyl-N- (2-propn; Zl) ethanolamine.



  A. Preparation of 3-benzyloxaolidineo
Into a 3 liter flask, equipped with a stirring device, a Dean-Starke collector surmounted by a reflux condenser and a thermometer, 755 gr of benzylethanolamine, 800 ml of benzene and 180 gr of
 EMI5.6
 paraformaldehyde The mixture was stirred and refluxed and 95 cc of water was removed in the Dean-Starkec manifold. Benzene was removed by atmospheric distillation and the product was distilled off under reduced pressure.



  A practically quantitative yield of boiled 3-benzyloxazolidine was obtained.
 EMI5.7
 lant to 125 -127 / 18 mm.



  . i3o Rcaotion â, 3.a low temperature, mbenz loxazol..in aveo 18 Wot ln. o Loaded into an appropriate vial, equipped as described in

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 Example 1, 83 g of 3-benzyloxazolidine, 200 ml of dioxane and 5 g of oupreux chloride. -Acetylene was passed in this mixture at 20-30 C.



   In 3 hours, 15 g of acetylene were absorbed. The mixture was allowed to stand for about 2 days, was filtered from the catalyst, the dioxane was removed by distillation under reduced pressure, and the residue was distilled. 54 g of product boiling at 124 / 1.5 mm and 20 g of material boiling at 124-150 / 1.5 mm with decomposition were obtained. The product in the first fraction was titrated by non-aqueous titration and it was found that 'he matched
 EMI6.1
 with N-benzyi-N- (2-propynyi) ethanolamineo
This compound, which is a base in liquid form, was found to produce short-lived hypnosis, when administered to mice by
 EMI6.2
 intraperitoneal route (9eRoQ.m56) We prepared, therefore,

   a hydrochloride to check its activity by intravenous administration o The salt was collected as a 9.18% aqueous solution. The results are as follows *
 EMI6.3
 (a) Intense intraperitoneal toxicity to mice
 EMI6.4
 
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<tb> E <SEP> f <SEP> f <SEP> e <SEP> t <SEP> Dose <SEP> Mortality
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 EMI6.5
 intrapero 1 Time Number ± l ± 7111 DU Mouse time ------------ -.. - ........ aālil "lIftI:!" ¯1I:; W ---- ¯Y8¯-¯ '& ":. JIII III -----... ¯-¯ -.:- .-;

  ----------
 EMI6.6
 
<tb>
<tb> Sedation <SEP> Sub- <SEP> Hypnosis
<tb> hypnosis
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 577 <SEP> 0.5 <SEP> @
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 751 <SEP> 0.5 <SEP>
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 976 <SEP> 5/5 <SEP> 20 <SEP> mina <SEP> 5
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 1269 <SEP> 5/5 <SEP> 10 <SEP> min. <SEP> 5
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 EMI6.7
 ------... ¯- = à ..... d>: III; II - .. IooaI - ¯-¯W <R¯ ------------ -, *, ---------------- 3007056 A-LD50 - 856 mgr / (5/20 mice intrape .;

   28 gr)
 EMI6.8
 (b) Intense oral toxicity, in rats o
 EMI6.9
 
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<tb> E <SEP> f <SEP> f <SEP> e <SEP> t <SEP> Dose <SEP> Mortality
oral <tb>
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 EMI6.10
 ---- <1 ..... 8: 1.h ... 1 ¯ ..l8CIaEI Sécla- Sous- Eypno- Vo Mo
 EMI6.11
 
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<tb> tion <SEP> hypno- <SEP> se
<tb> se
<tb> 0/5 <SEP> 0/5 <SEP> 0/5 <SEP> 0/5 <SEP> 0/5 <SEP> 400 <SEP> 0/5
<tb> 4/5 <SEP> 1/5 <SEP> 0/5 <SEP> 0/5 <SEP> 0/5 <SEP> 600 <SEP> 0/5
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 5/5 <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 <SEP> #
<tb> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 5/5 <SEP> 2025 <SEP> 0/5 <SEP>
<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> assumed
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 EMI6.12
 3007056 A-LD50 = 2690 219 SD mgr / Kg (5/30 oral rat; 111-20 gr) 48 5 SE mg: r / Kg

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In non-lethal doses, all rats are hypnotized within 10 minutes and return from hypnosis within 30 minutes. it should be noted that the rats were anesthetized at 900 mgr per kg. The estimated oral anesthetic dose (Anes D50) is 735 mgr / Kg or 27% A-LD50 (oral rat).
 EMI7.1
 



  Low temperature coRaction of 3-benzyloxazoliine with aoetyleneo
83 g of 3-benzyloxazolidine, 200 ml of dioxane and 5 g of ouprous chloride were loaded into a one liter flask equipped as described in Example 2. The mixture was cooled in an ice bath to about 10 and there pass the acetylene at this temperature. Over a period of 5 hours, 16 g of acetylene were absorbed. The catalyst was removed by filtration, the dioxane was removed by distillation under reduced pressure, and the product was distilled off.



  68.5 g of product boiling at 124 -128 / 1.5 mmo were obtained
 EMI7.2
 Do Reaction of acetylene with 3 = benzyloxazolidine using acetone as solvent o 83 gr of 3-benzylozazolidine, 250 ml of acetone and 5 gr of chloride- orprous were charged in a 1 liter flask equipped as described in Example 2. The reaction mixture was cooled in an ice bath before passage of acetylene, and over a period of 6 hours, 15 g of acetylene was absorbed.



  The catalyst was removed by filtration in the usual manner, acetone was removed by distillation under reduced pressure, and the product was distilled. 41 g of product were obtained.
 EMI7.3
 o Reaction of acetylene with lā3 = ben loxazolidÀne, ¯ removal of the catalyst with H2S.



   Was charged into a 1 liter reaction flask, equipped as in Example 2, 83 g of 3-benzyloxazolidine, 200 ml of dioxane, and 5 g of cupreuxo chloride The mixture was cooled with an ice bath to about 10%. and we there
 EMI7.4
 changed acetylene over 4 hours to 5-10 ° C. The rigiange was allowed to stand at room temperature overnight.



  15.5 g of acetylene were absorbed. The catalyst was removed by filtration, using a bed of filter aid. The catalyst cake was washed with dioxane, the wash liquor being combined with the filtrate, and the filtrate was treated with H2s to give a precipitate of copper sulfide. This was removed by filtration. The resulting filtrate, however, was not clear; as a result, additional hydrogen sulfide was passed through it, activated carbon was added and 1 filtration operation was repeated. In this way, a light orange colored filtrate was obtained.

   The dioxane was removed by distillation under reduced pressure, and the residue was distilled under
 EMI7.5
 the vacuum to give 70 g of product boiling at 104 = 106% 927 mmo There was no decomposition during this distillation.



  EXAMPLE 6 N-b e n zyl-N- (1-phenyl 2-pro ynl) ethanolaminao A. Preparation of 2-Dhenyl-3-benzyloxazolidine.



  This oxazolidine was prepared as described in part A of Example 1, using 151 g of benzlthanole, lead, 300 cc of benzene and 106 g of benzaldhdeo. 200 g of the desired oxazolidant, boiling at 130/1 mm, were obtained. , with an N25 of 1.50750 Bo Reaction dtAēy, 1in¯with 2 = hn 13benz loazol.di..eo This reaction was developed as in the example part B, using 119 g of phnrlm3'bpnztloxazolidine , 250 gold, dioxane, 10 g of oupreux chloride and 12 g of acetylene.

   The batch was treated in a ha-
 EMI7.6
 common and 75 g of the desired product were obtained, boiling at z-1550 / 0.25 mm, with an N5 of 195695 - This compound showed the following pharmacological effect

 <Desc / Clms Page number 8>

 
 EMI8.1
 
<tb>
<tb> E <SEP> f <SEP> f <SEP> e <SEP> t <SEP> Dose <SEP> M <SEP> o <SEP> r <SEP> t <SEP> a <SEP> lit <SEP > é
<tb> Intrapero <SEP> D / U <SEP> Time <SEP> Number <SEP> of
<tb> mgr / Kg <SEP> mouse
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 EMI8.2
 ------------------------------------> --- ----- L ---
 EMI8.3
 
<tb>
<tb> Ataxia <SEP> Pseudo- <SEP> Convulhypnosis <SEP> sions
<tb> - <SEP> 100 <SEP> 0/5
<tb> - <SEP> - <SEP> 372 <SEP> 0/5
<tb> - <SEP> - <SEP> - <SEP> 629 <SEP> 0/5
<tb> - <SEP> - <SEP> 818 <SEP> 0/5
<tb> - <SEP> - <SEP> - <SEP> 1063 <SEP> 2/5 <SEP> 10 <SEP> min. <SEP> t; <SEP> 24hr:

   <SEP> 1
<tb> - <SEP> - <SEP> - <SEP> 1382 <SEP> 1/5 <SEP> 10 <SEP> "<SEP> 1
<tb> - <SEP> 1797 <SEP> 1/5 <SEP> 10 <SEP> "<SEP> 1
<tb> - <SEP> 4/5 <SEP> - <SEP> 2326 <SEP> 2/5 <SEP> 30 <SEP> "<SEP> 2
<tb> - <SEP> 4/5 <SEP> 2/5 <SEP> 3024 <SEP> 3/5 <SEP> 30 <SEP> "<SEP> 3
<tb> - <SEP> 5/5 <SEP> 3913 <SEP> 5/5 <SEP> 10 <SEP> "<SEP> 5
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 EMI8.4
 2307056 A-LD50. 2576 - 311 SD mgr / Kg (5/40 intrapero mice; 23.9 g) 68 SE "EXAMPLE 7:

   N-benzyl-I! - (ln-propyl-2-pro '!) Ynyl) ethanolamine o Ao Preparation of 2-N-proyl-3-benzyloxazolidineo With a process described in Example 4, part A, above , starting from 129 gr of bensylethanolamine, 300 cc of benzene and 72 gr of N-butyraldehyde, we obtain 150 gr of the desired oxazolidine, boiling at 143-145 /
 EMI8.5
 12 mm, with a Nu5 of 1.5 760 D Bo Béaation¯4e 2z $ -nrōpyi = 3 = be ioxazoiidine with acetylene
By repeating the process of Example 4, part B, we obtained, starting from 103 gr of oxazolidine, 200 cc of dioxane, 10 gr of cuprous chloride and 15 gr of acetylene, 95 gr of the product. desires, boiling at
 EMI8.6
 115 "-117 / 3 mm <with an NJ of 1,

  51550 This compound showed the following pharmaoological effect
 EMI8.7
 
<tb>
<tb> Dose <SEP> '<SEP> Mortality
<tb> Intrapero <SEP> Time <SEP> Number <SEP> of
<tb> mgr / Kg <SEP> D / U <SEP> mouse
<tb> Sedation <SEP> Sub- <SEP> Hypnosis
<tb> hypnosis
<tb> 5/5 <SEP> 1063 <SEP> 0/5
<tb> 5/5 <SEP> 3/5 <SEP> 1382 <SEP> 1/5 <SEP> 48 <SEP> hr. <SEP> 1
<tb> 5/5 <SEP> 5/5 <SEP> 1797 <SEP> 1/5 <SEP> # <SEP> 24 <SEP> 1
<tb> 5/5 <SEP> 5/5 <SEP> 2326 <SEP> 5/5 <SEP> 3 <SEP> "<SEP> 2; <SEP> 24 <SEP> hr <SEP>:
<tb> 248 <SEP> 1
<tb> 5/5 <SEP> 5/5 <SEP> 3024 <SEP> 4/5 <SEP> # <SEP> 3 <SEP> "<SEP> 2; <SEP> 24 <SEP> hr <SEP> :
<tb>
   3007056 AOLD50 = 1877 - 216 SD mgr / Kg (5/25 intrapero mice; 27.7 gr) 48 SE "

 <Desc / Clms Page number 9>

 
 EMI9.1
 EXAMPLE 8: with 3 = benzyloxazolidine using dmti1lformamid as solvent.



  Into a suitable flask were charged 87 g of 3-be-nzvlozazolidineg 250 ml of dimethylformamide and 5 g of cupreux chloride o Acetylene was passed through this mixture with rapid stirring at a pressure of 3-6 inches.
 EMI9.2
 of mercury above atmospheric pressure. The temperature was set at 5%. There was extremely rapid absorption of acetylene and after 1 hour 22 g of acetylene had been removed by this mixture.

   To this was then added a filter aid available commercially under the trademark Filter-Cel, the mixture was filtered and the cake was washed with a small amount of acetone. The filtrate was treated with hydrogen sulfide, Charcoal was added and then filtered again to remove charcoal and drunken sulphide. A clear, colorless filtrate was obtained which was separated under reduced pressure from acetone and du. dimethylformamidao The material
 EMI9.3
 at boiling point.

   high was then distilled and 82 g of product were obtained, boiling at l06 = 110o / 025 memo This constitutes a yield of 82% of the theoretical yield o EXAMPLE 9 a N-benzyl acetate = N - (- aaetoxy - methyl = 2 = entynylJéthanolamineo In a: t1 .-: '.: one to three are of a liter, equipped with a thermometer, a reflux condenser, a funnel with tap, and a stirring device, we loaded 85 g of 3-benzyloxazolidine, 200 ml of dioxane and 10 g of cuprous chloride.

   With stirring, one then added, by the funnel with tap ;, 50 gr of
 EMI9.4
 dimethylethynylearbinolo When adding the carbinol there was a slight exothermic reaction and the temperature was raised to 48 ° C., then maintained at 45-47 with slight cooling by application of an ice bath. The addition time of dimethylethynylcarbinol was 40 minutes. The mixture was stirred for 2 hours, after which it became very thick, and an additional 200 ml of dioxin was added to thin it out somewhat.

   The mixture was left to stand overnight, then the hydrogen was passed
 EMI9.5
 sulphide in this mixture, charcoal and Filter-Ce-1 added. ,, and the mixture was filtered. A clear solution was obtained from which the dioxane was removed at reduced pressure, and the residue was treated as follows.



   Was added to this residue, in a suitable flask equipped with a stirring device, a thermometer and a funnel with a stopcock, 300 ml of benzene, 80 g of pyridine and then with stirring, 180 g of d chloride. acetyl over a period of 30 minutes while maintaining the temperature at. around 75 using an ice bath. The mixture was stirred for an additional 30 minutes, and a solution of 92 g of caustic soda was slowly added to
 EMI9.6
 150 a; carried out, while maintaining the temperature below 20 with an ice bath.

   The mixture was then filtered through ilter0e.lg the pH was adjusted to neutral with sodium carbonate, the upper layer was separated and the lower layer was extracted with benzene. The benzene extracts were combined with the layer. top and dry over anhydrous potassium carbonate. Benzene was removed under reduced pressure and the
 EMI9.7
 residue was distilled to produce 125 g of material, boiling 167% 926 o This material was identified by non-aqueous titration as N = benzyl acetate = N = (4-acetoxy = 4 = methyl-2 = pentynyl) ethanolamineo EXAMPLE 1'0: T 'ben ltm 4h r -4 mth l = mhe i 1 th..o.in.e In a similar experiment, 48 g of 3 = benlooldi2e9 were loaded into 200 ml of dioxane and 5 gr. of euprous chiorure.

   Then added to zus 5 gr of methylethynyloarbinolo The mixture was stirred for 2 hours and then left to stand overnightc Hydrogen sulfide was passed through the mixture, added charcoal and mixture was then filtered. The dioxane was removed with the water pump and the residue was distilled to give 54 g, boiling point of.

 <Desc / Clms Page number 10>

   175 -180%, 26 mmo This material was titrated by the non-aqueous method and it
 EMI10.1
 titrated 998% as N isoproprlN 4mhydroxymQ.methyl2 hezynylthanolaminea The N5 was 1.5366.



  EXAMPLE 11: NbanzylmN (2heptynl) ethanolaminao
In a one-liter three-necked flask, fitted with a stirring device, a thermometer, a funnel with stopcock and a reflux condenser,
 EMI10.2
 86 g of 3 bensrlaazolidine9 were loaded with 250 ml of dioxane and 5 g of opre chloride.

   46 grams of n-butylaoetylene were then added over a period of 20 minutes. There was a slight exotherm when adding the butylacetylene. The reaction mixture was stirred for 5 hours, left to stand overnight, and then heated to at 50 and stirred for an additional 60 hours at 40-50 o The mixture was filtered, the filtrate was treated with hydrogen
 EMI10.3
 sulphide, F'.ltarCel9 was added and filtered again.

   The filtrate was separated from the dioxane with a water pump and the residue was distilled to give 86 g of N-benzyl-N- (2-ootyrlyl) ethanolamineo The N25 of this material was 1.5202 and titrated 97% by titration. non-aqueous o EXAMPLE 12: 1 isopropyl T (2mpropynrl) ethanolaminee Ao Preparation of 3-isopropyloxazolidineo
Into a three-necked one-liter flask, fitted with a Dean-Starke manifold surmounted by a reflux condenser, a stirring device and a thermometer, 103 g of N-isopropylethanolamine, 200 ml of
 EMI10.4
 benzene and 30 gr of paraf'ormaldehyde The mixture was subjected to relfux and 20 gold of water were separated in the Dean-Starkeo collector. Benzene was removed by atmospheric distillation,

   and the residue was distilled under the video
 EMI10.5
 82 g of 3igaproprlaazolidine boiling at 45/30 mmo were obtained. Bo Reactivation of UÊZ-le-ne with 3-isopropyloxasolidineo. of cupreuxo Chloride The acetylene was passed in this mixture at 1020 ° C. and, over an 8 hour period, 17 g were absorbed (theory, 19 g). The catalyst was removed by filtration, the filtrate was saturated with hydrogen sulfide, Norite activated carbon was added, and the mixture was filtered. Dioxane was removed by vacuum distillation, and the product was vacuum distilled. 46.5 g of the desired product were obtained, boiling at 96-98 / 16 mm.

   There was a higher boiling point fraction, which boiled 64 to 145 / 15mm, which was not further characterized.
 EMI10.6
 



  EXAMPLE 13: N-isopropyl-N- (4-hydroxy-4 "methyl-2-hexynyl) ethanolamine
In a similar experiment, 74 g of 3-isopropyloxazolidine, which titrated 80% of matter, 200 ml of dioxane and 10 g of cupreux chloride were charged o 50 g of methylethylethynylcarbinol were then dropped therein dropwise over a period of 30 minutes, keeping the temperature below 40 with an ice bath. The mixture was stirred for 2 hours and then allowed to stand overnight. He was treated in the usual way.



  After removing the dioxane with a water pump, the residue was removed at the top
 EMI10.7
 to give 65 g of N ieoproplN (.hpdro 4mmethr12mhexnyl) ethe.nolamine This material titrated 99.7% by a nonaqueous titration and had an N5 of 1.4821.
 EMI10.8
 



  EXAMPLE 14: N-iso'propylN. / 3 '- (2.oyclohexanol) -2-propynylethanolamine.



  In a similar experiment, 85 g of 3isoproploazol.dina, 200 ml of dioxane and 5 g of cuprous chloride were charged in a flask. A solution consisting of 62 g of ethynyloycslohexanol and 20 cc of dioxane was then added, with stirring, through 1 tap funnel. The addition of the solution

 <Desc / Clms Page number 11>

 
 EMI11.1
 of ethynylcyclohexanol took 20 minutes and the maximum temperature reached 38 The mixture was stirred for 2 and a half hours and then treated in the usual way. 65 g of Nisoprop-.N ..--- (2rcloh: xa oi) 2 propynyl7éthaziolanîiie were obtained. boiling at 158%, 5 mmo The material had run? i ± 5 .e 15 57 and titrated 99% by a non-aqueous titration o EXAMPLE 15¯:

   â Nirop; pl N (4hYdro 4-met, h; l2hen.; i ât, n, olaxnin
60 g of 3-isopropyloxazolidine and 200 ml of dioxane were loaded into a one liter flask, equipped with a reflux condenser, a funnel with stopcock, a stirring device and a thermometer, and the mixture was
 EMI11.2
 heated to 30 "., at which time 50 g of methyletuylethynylcarbinolo were added. No catalyst was used. The mixture was kept at 7L-801 for 7 hours, cooled and distilled. Oproploaol.d, ine9 was recovered. dioxane and metl-tylethylethynylcarbinol There was no formation of high boiling product.



  EXAMPLE 16:.! = Is.9proPzl = N- (2-b tyfoE thygggolamineo In a flask similar to that used for the acetylene reactions, 60 g of 3isopropyloxe, o7 .di.ne 250 ml of dioxane and 5 were charged. g of cupreuxo Chloride Methylacetylene (1-propyne) from a reservoir was passed through this mixture at 25-30 over a period of 10 hours, during which 34 g of methyl acetylene was absorbed.

   The mixture was filtered from the catalyst, treated with hydrogen sulfide in the usual manner, separated from dioxane with a water pump, and the residue was distilled to give 63 g of N-isopropyl-N- (2-butynyl. ) ethanolamine which boiled at 64 / 0.6 mm and titrated 97.3% by non-aqueous titration, with an N25D of 1047280
 EMI11.3
 EXAMPLE 17: 19Z: yl dY (5inet11Y1 "Uténe3ne) .0 3-isopropyloxazolidine aveo ieoropénylaot; lneo This experiment was carried out in a manner similar to that employed for butylacetylene6 In a one liter flask, 120 g of 3mieoproprloaol3dzne 200 ml of dioxane and 75 g of cupreuxo was added slowly a solution consisting of 68 g of. isopropén; ylaè: etylene in 100 mgr of dioxane.

   An exothermic reaction brought the temperature to 35 and this temperature was maintained between 30-35 with cooling, throughout the addition which took 25 minutes. The mixture was stirred for 3 hours while the mixture gradually cooled. The mixture was then allowed to stand for a period of time and treated in the usual manner by filtration, treatment with hydrogen sulfide, and removal of the low boiling solvent at the water pump. We obtained 136 gr. of product boiling at 72%, 25 mmg which, by a non-aqueous titration, titrates 98% of N-isoprepyl-N- (2-methyl-1-butene-2-yne) ethanolamine.
 EMI11.4
 



  EXAMPLE 18 Nie rca 1N b.e t 1 tha, lonarine In the manner described above, 120 g of 3-isopropyloxazolidine, 400 ml of dioxane and 10 g of chloride supr & ne were reacted with 86 g of butylacetylene. The temperature was 33-40 C during the addition of oe brutyla.oôtl6neo The mixture was stirred for 2 hours, heated at 60 for 20 minutes and brought up to 68 for 45 minutes o The heating source was then discarded, the bath was stirred and cooled to room temperature. The catalyst was removed by filtration and the filtrate was treated with hydrogen sulfide, then with Darco G-60g and then filtered again.



  The dioxane was separated at the water pump and the residue was distilled under a
 EMI11.5
 high vacuum to give 165 Ur of lTm.eopropliV (2hept; nl) ethanolawina boiling at bzz, 5 mmo The ND5 was 194678.

 <Desc / Clms Page number 12>

 
 EMI12.1
 



  EXAMPLE 19: N isorrouyl N (4 hrdrox 2mbut¯n.yl) ethanolamine in preparation of 3- (bta-hydroxcthyl) 2-dthyloazolidine:
210 g of diethanolamine, 250 ml of benzene and 120 g were charged in a 3-necked bottle of 1 liter equipped with a stirring device, a thermometer, a Dean-Starke collector and a condenser. gr of propioaldehyde The mixture was stirred and refluxed and 40 ml of water removed. The benzene was removed by atmospheric distillation and the residue was distilled in vacuo.
 EMI12.2
 



  197 g of the desired oxazolidine were obtained, boiling at 108 = 112/15 mmo. The N25 was 1.4665 and the material titrated 100.25% for a non-aqueous titra% ion.



   B. Reaction with acetylene:
In a flask equipped with a stirrer, a gas inlet tube, a gas outlet tube connected to an open type mercury manometer, and a thermometer, 143 g of the gas were charged. oxazolidine above, 350 ml of dimethylformamide and 8 g of oupreux chloride. With stirring, the mixture was cooled to 3 and after flushing with acetylene the concentration of aoetylene was initiated and the reaction was developed for 4 hours at -3 to 40. There was a total absorption of 14. gr of acetylene. The mixture was filtered to remove catalyst copper, the filtrate was diluted with 500 ml of acetone and saturated with hydrogen sulfide.

   The solution was filtered to remove sulfide and acetone and the dimethylformamide was removed with the water pump.
 EMI12.3
 



  The residue was distilled under the vidēet one obtains 85 g of N-% gdroxy-ù- (1-ethyl-2-propyne) ethanolamine, boiling at 122 -128 / 1.3 mmo The N25 was 1.4895 and the material titrated 102.8% for a non-aqueous titration o
A 2 liter flask fitted with a stirrer, condenser, thermometer and stopcock funnel was charged with 800 ml of
 EMI12.4
 dioxane and 130 gr (1.13 mol) of N-Îaopropylozazolidineo When 40 gr of ouprene chloride were then added, a slight exothermic effect was noted, going up to 3500. Through the tap funnel, 125 gr (2 , 23 moles) of propargyl alcohol over a period of 45 minutes.

   The reaction was exothermic; it reached 490 as the maximum temperature o Stirred for 2 hours, and then filtered to remove a yellow solid (copper salt of propargyl alcohol) o The filtrate was treated with hydrogen sulfide and filtered to remove copper sulfide as well precipitate. The filtrate (red-orange in color) was scrubbed to remove dioxane and excess propargyl alcohol. Vacuum pump distillation gave a small pro alcohol distillation head.
 EMI12.5
 pargylic who did not react. The product was collected at 147-150%, 75 mm, and an amount of 91 gr with an N25 of -194974. A resinous residue of 48 g remained in the still tank.



  EXAMPLE 20: lmth.yl-N (1-thénl-2royn.yl) ethanolamine A. Preparation of 2mphny'1 = 3 mthyloxazoliâine: Using the same process as described above, starting with 65 g of monomethylethanola.mine , 200 cc of benzene and 106 g of benzaldehyde, 106 g of the desired oxazolidine were obtained boiling at .10 -115 18 mm Bo Reaction of 2-phenyl-3 mthloxazolidine with aaet lene 6
By the process described above, there was obtained, starting with 81 g of oxazolidine, 200 cc of dioxane, 10 g of cuprous chloride and 8.5 g of acetylene, 41 g of the desired product boiling at 1070 / 0.26 mmo
 EMI12.6
 EXAMPLE 21 N-hydroxyethyl-N- (2-propynyl) ethanolamine Ao Preparation of 3- (beta-hydroxyethyl) -oxazolidine s Starting with 105 g of diethanolamine, 200 cc of benzene and 30 g of paraformaldehyde, we got 100,

  5 gr of boiling oxazolidine

 <Desc / Clms Page number 13>

 
 EMI13.1
 680/095 mm-9 -ie 5 t¯ 194775.



  B. Reaotion at, j ± @% $ ènē¯aveo le 3 4bgtél hg # oqgµt #g% oxyo @@ Ôneo By the process described above, starting from 585 gi- -1, the oxasoli'dinee of 200 co of dioxane of 7 gr of ouprene chloride and 1495 gr of alacatylene, we obtained 32 gr of product boiling at 1130-1160 / 095 illillo L> matter solidified on standing and titrated 96% purity for a non 5, q : aeuse ,,
 EMI13.2
 This compound had the following pharmacological effect:

   
 EMI13.3
 
<tb>
<tb> Effect <SEP> Dose <SEP> Mortality
<tb>
 
 EMI13.4
 internal 0, 1V mg free! ' / 'f4s ID read Time mouse sedation 395 1,382 095 595 1,797 0.5 1 # 2.326 3.5 s 24 hr li 48hr s 2 É # 3.024 3, 5 24 hr 2' (2hr 1 (m.)
 EMI13.5
 12/10/56 à-LD 2527 - 230 SD mgr / Kg (5/20 mice in.trapoj 2695 gr) -51 SE Il EXAMPLE 22 NhénYl = N = (2 = propy11éthanolandneo 4 9gyé% # éltion¯dg¯ 3 = ¯phµ J¯glgzazglj @ j # e Starting with 139 gas of phenylethano1wnine, 100 0 of benzene and 30 gr of paraformaldehydeg we obtained, by the process deorit nt9 135 gr of 3-phéRyloxasolidine bauillaïlt at 87% / 0928 nia and having tin- Jl "5 'le 1.57300 The material titrated 104% by a non-aqueous titration 6e 00mpGfB 3vixnait the following pharmarcological results
 EMI13.6
 Effect Dose Intraperiortality Number of TI1f!, T IKg Diu time mouse Sedaj ;; LcJj, 1;

   1 p 4/5 3/5 372 1/5 x 24- 5/5 EB 484 2/5 s 24 "z 48trr 'B9; BE 629 3/5 s 24?; Vi 5/5 8 8 5/5 s 6 mÜlo If; v "1063 PP 5mino 5
 EMI13.7
 10/8/56 A-LD50 - 534.- 64 SD mg / Kg (5/25 intrapo mice, 2801 gm) 14 SE et / îQ ZKBWLE 23 -me ïU (., WpeyYï) ta, .ï3ie 1 o Px x . ¯. j-o ïï ..z.
 EMI13.8
 



  In ONE. @ 6experienoe ... 9,100 ger of t-C! Tylethala: Jîil1e9 200 e-c of benzene and 18y 5 gr of p & raform & .ld4hyde were refluxed and He cc of water was removed.: V: âJ the collector.



  The benzene was eniei: 1 at the water pump and the residue which p + s, i, t 136.5 ger was oorisid4zé OOmJ1! Ê ';' :: 1 .. t giv-ßrzy de la. t-ocityloxasolidine.



  B 0 - J: 1 ..: h (J..tJ5), - de - "., A; .. rdicâ ... r r.:

 <Desc / Clms Page number 14>

 
In a similar experiment, 136.5 g of the above residue, 250 cc of dioxane and 5 g of cuprene chloride were stirred, while acetylene was passed through the mixture at room temperature. 8 hour period, there was an absorption of 15 g of acetylene.

   The mixture was processed in the usual manner and, on distillation, gave
 EMI14.1
 78.5 gr of N-t-oetyl-N- (2-propynyl) ethanolamine boiling at 104 112 19 72mmo This material had an N25 of 1.4722 and titrated 101% for a non-aqueous titration
 EMI14.2
 EXAMPLE¯24:

   y N tmoct lN hn- ro e ethanolamine A, Preparation of 1 oxazolidinē Lli4 = azolidine was prepared in the usual way starting from t-octylethanolamine, n-butyraldehyde and benzene as air-propellant Bo Reaction with actv 114 g of 2-n-piopyl-3-t-oatyloxazolidine, 300 ml of dimethylformamide and 7 g of cuprous chloride were treated with acetylene in the usual manner. Over a period of 4 hours at a temperature of 15-25, there was an absorption of 16 g of acetylene The catalyst was removed by filtration and the filtrate was used as is, as there was no coloration indicating a residue of copper. The dimethylformamide was removed with a water pump and the residue was distilled off.

   76 g of product boiling at 81-85 /
 EMI14.3
 0.75 noon The material had an N ± 5 of 1.4561a
In summary, the present invention relates to novel acetylenically unsaturated ethanolamines, which are formed by the reaction, with a copper ion catalyst, of the corresponding oxazolidine and an acetylenic compound. The reaction is carried out in the presence of a solvent, such as dioxane or dimethylformamide, at a temperature in the range of 10 to 30 0 and at a pressure of 5 to 10 inches of mercury above. atmospheric pressure.



   CLAIMS. As new compounds, acetylenically unsaturated ethanolamines, having the formula:
 EMI14.4
 wherein "R and R to R are selected from the group consisting of hydro-
 EMI14.5
 gene, akyl groups, aryl groups, alkaryl groups or arailic groups for R 1 or R2 are hydrogen; R is selected from the group consisting of alkyl groups, aryl groups, alkaryl groups or aralkyl groups; Ra is selected from the group consisting of hydrogen, groups ..-. I, uee groups, Lk'i3quess

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

aryl groups, alkaryl groups, aralkyl groups and alkyl hydroxy groups. <Desc / Clms Page number 15> 2. As a new compound, N-isobutyl-N- (2-propynyl) ethanolamine. 3. As a new compound, N-benzyl-N- (2-propynyl) .ethanolamine. 40 As a new compound, N-isopropyl-N- (2-propynyl) ethanolamine. 5. As a new compound, N-hydroxyethyl-N- (2-propynyl) ethanolamine 6. As a new compound, N-isopropyl-N- (4-hydroxy-4-methyl-2-hexynyl) ethanolamine. 7. A process for the preparation of novel acetylenically unsaturated ethanolamines, which comprises reacting an oxazolidine having the formula EMI15.1 with an acetylenically unsaturated compound having the formula: R8C - CH formulas in which R1, R2 and R4 to R7 are selected from the group consisting of hydrogen ;, alkyl groups, aryl groups, alkaryl groups or aralkyl groups, provided that R1 or R2 are hydrogen ; R3 is chosen from the group comprising alkyl groups, aryl groups, alkaryl groups or aralkyl groups - R8 is chosen from the group comprising hydrogen, alkyl groups, alkenyl groups, aryl groups, alkaryl groups, aralkyl groups and alkyl hydroxy groups, in the presence of a solvent for oxazolidine and a source of ouprene ions at a temperature of 0 to 30 C and at a pressure between atmospheric pressure and 14 inches of mercury above this atmospheric pressure, removing unreacted components from the reaction mixture and distilling therefrom the desired end product.