CH457404A - Process for the production of new acetylene derivatives - Google Patents

Description

  

      Process for the production of new acetylene derivatives D.'le present invention relates to a process for the production of new acetylene derivatives of the formula I,
EMI0001.0010
    in which, A denotes the trimethylene chain or the radical -CH = CH-O-, and its acid addition salts.



  The inventive method is characterized in that a compound of the formula II
EMI0001.0017
    a) monomethylated and the N-methyl-aminomethyl compound obtained is reacted with a propargylic acid or b) reacted with a propargylic acid, the resulting mixture of N-monopropargyl and N , N-di- propa # rgyl-aminomethyl-verb'mdu:

  ugen separates and the monopropargyl compound monomethylated and the end product, if desired, converted into the corresponding salt by reaction with an inorganic or organic acid.



  Compounds of formula 1I are used, for. B. 6 - aminomethylbenzo [b] furan., 4 - am'uvomethylindane, 5-aminomethylindane etc.



  The process is carried out, for example, by reacting the amiuzomethylverbi: ndung II with ethyl chloroformate in a mixture of aqueous alkali and a water-immiscible organic solvent, such as chloroform, and the urethane obtained in an inert one Solvent,

      like abs. Ether, tetrahydrofuran or dioxane, reduced to the N-methylamino compound by means of lithium ad, ammonium hydride.

   The methylation also succeeds. Formamides formed by formylation of the compound 1I with formic acid and reduction 6-es by means of lithium aluminum hydride. The N-methylamine:

  Overbinding goes on heating with Propargylbromi @ d in an inert solvent, preferably methylene chloride, and in the presence of an acid-binding agent, for. B. a trialkyl amine or potash, into the desired N-methy'1 N-propargyl-aminomethyl compound.



  However, the reverse procedure can also be used by first treating the aminomethyl compound 1I with the propargyl halide, which results in a mixture of derivatives which are mono- and disubstituted on the nitrogen atom. The mixture is separated into the component by distillation, adsorption chromatography or fractional crystallization of a suitable salt; the N-monopropargyl aminomethyl compound is then methylated, e.g.

   B. by reaction with methyljo: did, methyl bromide, etc., in the presence of an acid-binding agent.



  Compounds of the formula I have not yet been described in the literature. At room temperature, they are oily, colorless to pale yellow bases which are slightly soluble in water and slightly soluble in most organic solvents. With inorganic and organic acids they form stable, mostly nicely crystallized salts, e.g. B.

   Hydrochloride, hydrobromide, sulfate or methane sulfonate, ethane @ sudfonate, p-toluene sulfonate, succinate, hydrogen maleate, fumarate, malate, tartrate, benzoate, hexahydrobenzoate and so on.



  The new compounds develop a blood pressure on the hypertonic test animal (Gro'llmann rat). They suppress the initial pressor effect (sympathetic homimetic effect) produced by guanethidine [N- (2- Gua @ nid'inoethyl) -octahydro-l-azocine], which means that they inhibit the release of sympathetic carrier substances ( z.

   B. norepinephrine). Furthermore, they have a strong inhibitory effect on monoamine oxidase in vivo and in vitro and are more central antagonists, in particular of the convulsive and depressive effects of reserpine. Compared to their effectiveness, they show low toxicity.



  The new compounds can therefore be used for the therapy of hypertension and pectangiose conditions, but are also suitable for the drug treatment of mental illnesses, especially the depressive type. They can be used as remedies - preferably in the form of their water-soluble,

   physiologically acceptable acid addition salts - can be used alone or in appropriate dosage forms for enteral or parenteral administration.



  The amino methyl compounds of the formula II used as starting materials can, depending on the meaning of A, be prepared as follows: 1. Benzofuran derivatives (A = -CH = CH-O-): One starts from a nitrobenzo [b] furan from which one to go through.

   Hydrogenation in the presence of: Raney nickel reduced to the corresponding amino compound; the 5- and 6-aminobenzo [b] furan have already been described.

   The aminobenzo- [b] furan obtained is converted into the corresponding cyanobenzo [b] furan under the conditions of the Sandmeyer reaction, ie by diazotitration and replacement of the diazonium group for the cyano radical by means of copper-I-cyanide.

       The latter is in an inert solvent, e.g. B. dioxane or Tetrahyd @ rofuran, by means of lithium aluminum hydride, reduced to the corresponding aminomethyl bond.



  2. Indane derivatives (A = trimethylene chain): The already known farmyl-indanes are converted into their oximes using hydroxylamine and these are reduced, for example, using lithium aluminum hydride in abs. Ether, dioxane or tetrahydrofuran.



  In the following examples, all temperatures are given in degrees Celsius; the melting points are corrected. <I> Example 1 </I> 6- (N-methyl-N-propargyl-aminomethyl)

  - benzo [b] furan 10 g of 6-aminomethyl! benzo [b] furan are dissolved in 300 ml of chloroform and the solution is covered with 140 m4 of water. While stirring vigorously at a temperature of 0-5, 11.5 mil chloroformic acid ethyl ester and then a solution of 4,

  7g sodium hydroxide in 100 ml water was added dropwise. The mixture is stirred for 45 minutes at room temperature, the chloroform phase is separated off, the aqueous phase is shaken out twice with chloroform,

      the combined chloroform extracts extracted 4 times' with 2N hydrochloric acid, dried over magnesium sulfate and evaporated. The 6 - (N-ethoxycarbounyl-aminomethyl) obtained as a light yellow oil

  Benzo [b] furan is dissolved in 50 ml of tetrahydrofuran and this solution is slowly added dropwise at a temperature of 80 to a suspension of 8.9 g of lithium aluminum hydride in 90 mil. tetrahydrofuran. The mixture is refluxed for 45 min.

          Excess lithium aluminum hydride decomposed with methanol and the whole thing after adding sat. Shake out sodium sulfate solution with ChAoroform. After drying over magnesium sulfate and distillation! i fiering the chloroform is obtained

  the 6- (N-methyl-amihomethyl) -benzo [b] furan lpight yellow Ö <B> l </B>. The bimaleate crystallizes from ethyl acetate in long, colorless needles of melting point 122-123.

      To a solution of 4.5 g of 6- (N-methyl! -Amnomethyl) = benzo [b] furan in 50 ml of methylene chloride are added 5 mil of trimethylamine and then 3.65 g of propargy-1-bromide are added dropwise; the temperature rises to 35 to 40.

   When the dropwise addition is complete, the mixture is heated to boiling under reflux for 2 hours, then cooled and mixed with 100 × nf water. After adding 100 ml of 10% tartaric acid solution, it is shaken, the tartaric acid phase is separated off, filtered over highly purified soil:

  and placed in alkaline condition with cooling with 2N Nafirone lye. The alkaline solution is shaken out with chloroform, the chloroform extracts are dried over magnesium sulfate and concentrated.

   The residue is chromatographed on silica gel with chloroform / ethyl acetate. The 6- (N-methyl-N-propaurgyl-amiro: omethyd) = benzo [b] furan is obtained as a pale yellow oil. Its hydrochloride, crystallized from ethanal / ether in the form of fine needles from Sm # p. 197-198.



  The starting product can be produced, for example, as follows: 6-Amino-b:

  enzo [b] furan is suspended in half-concentrated hydrochloric acid RTI ID = "0002.0240" WI = "6" HE = "4" LX = "1456" LY = "1006"> and with the corresponding amount of sodium hydroxide (dissolved in Water)

   diazotized at 0-5. The almost neutralized diazonium salt solution is allowed to drip into an aqueous solution of copper-I-dhoride and sodium cyanide at the same temperature. After brief heating, the mixture is extracted with ether, the organic phase is separated off and evaporated and the residue is purified by chromatography.

   6-Cya @ no-benzo [b] fwran is obtained as a deep red oil with a boiling point of 73 to 75 / 0.01 mm Hg.



  By reducing the 6-cyano-benzo [b] fura @ us with lith # i, uma, llumin # iumhydrid in abs. Tetrahydrofuran gives 6-aminomethylbenzo [b] furan. in the form of colorless needles with a melting point of 95-98 (after crystallization from ligromine). M.p. des bitartrate 191-193 (massive prisms made of methanol / ether).



  <I> Example 2 </I> 5- (N-methyll \ Np \ ro'pargyl'-aminomethyl) -indane A solution of 3.05 g of 5-aminomethyl'-indane in 80 ml of chloroform is covered with 38 ml of water . While stirring vigorously at a temperature of 0-5, 3.75 ml of ethyl chloroformate and then its own solution of 1,

  55 g of sodium hydroxide in 33 ml of water were added dropwise. The mixture is stirred for 30 minutes at room temperature, the chloroform phase is separated off and the aqueous phase is extracted twice with chloroform;

          the combined chloroform extracts are extracted 4 times with 2N hydrochloric acid, dried over magnesium sulfate and evaporated. The 5- (N-Äth.oxycarbonyl-aminomethyl) -indane obtained (m.p. 59-60, needles from pefirolether)

      is dissolved in 65 ml of tetrahydrofuran and this solution is slowly added dropwise at a temperature of 70 to a suspension of 3.7 g of lithium aluminum hydride in 65 ml of tetrahydrofuran. The mixture is 1 hour.

   Heated to boiling under reflux, excess lithium aluminum hydride is decomposed with methanol and the whole is shaken out with chloroform after addition of saturated sodium sulfate solution. To.

   Drying over magnesium sulfate and distilling off the chloro form gives 5-methylaminomethyl-indane as a pale yellow oil with a boiling point of 115-120 / 12 mm Hg.



  To a solution of 2.9 g of 5-methylaminomethylindane in 5 ml of methylene chloride is a solution of 1 g of propargyl bromide in 8 ml of meth:

  ylene chloride was added dropwise, the temperature rising to 35-40. The mixture is then refluxed for 11/2 hours, cooled, and the unconverted 5-methylaminomethylindane precipitates by adding ether as hydroboromide.

   It is filtered, the filtrate is evaporated, chromatograph: the residue is broken up on silica gel with chloroform and the 5- (N-methyi-N propargyl-aminomethyl) -indane is obtained as a light yellow oil, bp.100-105 / < B> 0.01 </B> mm Hg. Its Bimafelnat crystallizes out.

       Methanol / ethyl acetate is a prism with a melting point of 112-113 '.



  The 5-amimomethyl-indane required as starting material is obtained as follows: Ind'a) n-5-alde'hyd is converted into indane-5-al'dehyde oxime with hydroxylamine hydrochloride (bp 110-115 / 0.01 mm Hg), which is then reduced to 5-aminomethylindane with lithium aluminum hydride. 100-105 / 0.01 mm Hg.



  <I> Example 3 </I> 4- (N-Methyl-N-2-propynyl-aminomethyl) -indane A solution of 3.7 g of 4-aminomethyl-indane in 100 ml of chloroform is covered with 45 ml of water - tet. While stirring vigorously at a temperature of 0-5, 4.6 ml / 1 chilli oroformic acid ethyls:

  ter and then a solution of 1.9 g of sodium hydroxide in 40 ml of water was added dropwise. The mixture is stirred for 30 minutes at room temperature, the chloroform phase is separated off and the aqueous phase is extracted twice with chloroform;

   the combined chloroform extracts are shaken out 4 times with 2N hydrochloric acid, dried over magnesium sulfate and evaporated.

   The 4- (N-ethoxycarbonyl-aminomethyl) -ind'an obtained is dissolved in 80 ml of tetrahydrofuran and this solution is slowly added dropwise at a temperature of 70 to a suspension of 4.55 g of lithium aluminum hydride in 80 ml of tetrahydrofuran. The mixture is 1 hour.

   Heated to the boil under reflux, excess lithium aluminum hydride is decomposed with methanol and the whole thing is extracted with chloroform after adding saturated sodium sulfate solution. After drying over magnesium sulfate and distilling off this chloro forms, one obtains the

  4-Methy lanminomethyl-indane as a light yellow <B> oil </B> with a bp. 113-120 / 11 mm Hg (temperature measured in an air bath).



  A solution of 1.47 g of propargyl bromide in 12 times methylene chloride is added dropwise to a solution of 4.25 g of 4-methylamnoineihhyl- i, nda'n in 7.5 ml of methylene chloride, the temperature increasing to about 40% increases.

         The mixture is then refluxed for 11/2 hours, cooled and the unconverted 4-methylaminome, thyl-indane is precipitated as hydrobromide by adding ether.

   It is filtered, the filtrate is evaporated, chromatographed, the residue is graphed on silica gel with chloroform and the 4- (N-methyl-N-pro; pargyl-aminomethyl) -inda # n is obtained as a pale yellow oil from Sd'p . 98 to 106 / 0.01 mm Hg (temperature measured in an air bath). Its methanesulfonate crystallizes from ethyl acetate in prisms with a melting point of 163-165.



  The 4-ami (nometh @ yl-ind'ane required as starting material is obtained as follows: indane-4-al'dehyde is converted into indane-4-aldehyde-oxime with 1-hydroxylamine-'hydrochloride, d (Bp. 120-125 / 0.1 mm Hg) implemented,

      which is then reduced to 4-amimomethylindane with lithium aluminum hydride. Sd! P. 103-105 / 0.05 mm Hg.



  <I> Example 4 </I> 5- (N-Mothyl-N-propargy'1-aminomethy'1) -indane To a solution of 16.2 g of 5-aminomethylndane in 50 ml of methylene chloride is added a solution of 6.45 g of propargyl bromide in 25 ml of methylene chloride were added dropwise. Main, leaves 4 hours

   stir at room temperature, the unreacted 5-amino-methyl-indane then precipitates out as a hydrobromide by adding ether, filtered: and the filtrate is evaporated.

   Chromatography of the residue on silica gel with chloroform gives 5- (N-propargyl-aminomethyl) -in @ dan as a yellowish oil with a boiling point of 105-110 / 0.1 mm Hg.



  20 g of 5- (N-propargyl-anminomethyl) -indane are dissolved in 50 ml of methylene chloride and a solution of 7.1 g of methyl iodide in 50 ml of methylene chloride is added dropwise, while stirring and cooling with ice.

   The mixture is then stirred for 5 hours at room temperature, then the non-urinary 5- (N-propargyd-aminomethyl) -indane precipitates out as hydroiodide and filtered. The filtrate is evaporated and the oily residue is chromatographed on silica gel with chloroform. The 5- (N-Me, t'hyl-N-propargyl-aminomethyl) -in is obtained,

  then as a light yellow oil with a boiling point of 100 to 105 / 0.01 mm Hg. Its Bim @ alone crystallizes from Met'han: ol / ethyl acetate in prisms with a melting point of 112-113.

 

Claims (1)

PATENT CLAIM Process for the preparation of new acetylene derivatives of the formula I, EMI0003.0217 wherein A denotes the trimethylene chain or the radical -CH = CH-O-, and its acid addition salts, characterized in that a compound of the formula II EMI0003.0226 a) mon: omethylated and the N-methyl-aminomethyl compound obtained is reacted with a propargyl halide or b) with a propargylic, alogenidic reaction, the corresponding mixture of N-monopropargyl = and N, N-di-propargyl-aminomethyl compounds, separated and the monopropargyl compound monomethylated and the end product desired: s - converted into the corresponding salt by reaction with an inorganic or organic acid.