CH426808A - Process for the preparation of new piperidine derivatives - Google Patents

Description

  

  



  Process for the preparation of new piperidine derivatives
The present invention relates to a process for the preparation of new P-iperidine derivatives with valuable pharmacological properties.



   It has surprisingly been found that piperidine derivatives of the formula I,
EMI1.1
 in which Ri is hydrogen, an alkyl radical with at most 12
Carbon atoms, an alkenyl radical with 3-5
Carbon atoms, the cyclopropylmethyl radical or a phenylalkyl radical with 7-9 carbon atoms, Ra is hydrogen or the methyl radical, R3 is hydrogen or an alkyl radical with at most
3 carbon atoms, the phenyl radical, one
Phenylalkyl radical with 7-8 carbon atoms, and R4 denotes hydrogen or the methyl radical, and their salts with inorganic and organic acids have valuable pharmacological properties, in particular excellent analgesic effectiveness in oral and parenteral administration and strong antitussive effectiveness.

   At the same time, they are relatively less toxic and are therefore suitable for. B. to relieve and eliminate pain of various origins and also the cough stimulus.



   In the compounds of formula I and the associated starting materials mentioned below, Ri is z. B. by hydrogen, alkyl radicals, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-amyl, isoamyl, n-hexyl, n-octyl, n-decyl or n-dodecyl radical; by alkenyl radicals, such as the allyl, crotyl, methallyl or y, y-dimethylallyl radical; by the Cyclopropylmethylrest or by Phenyl alkylrestc, like the
Benzyl, -Phcnyläthyl- or γ-Phenylpropylrest embodied.



     R8 is e.g. B. hydrogen, the methyl, ethyl, n-propyl, isopropyl, phenyl, benzyl, a-phenyl ethyl or ss-phenylethyl radical
As has also been found, the compounds of the formula I can be prepared in a surprisingly simple manner by adding a compound of the formula II,
EMI1.2
 in which Ri, R2, R3 and Ri have the meaning given above, treated with an aqueous mineral acid containing mercury ions at room temperature of moderately elevated temperature. As an aqueous mineral acid for performing the Hy dratisierung is, for example, 10-84% sulfuric acid, further z.

   B. about 15% to 36% (concentrated) hydrochloric acid can be used. The reaction temperature is chosen to be lower with increasing acid concentration; when using 84% sulfuric acid, the reaction is preferably carried out at room temperature, with 10% sulfuric acid or approximately 1: 1 dilute hydrochloric acid at 50-60.



   Individual representatives of starting materials of the formula II with hydrogen as R2 and R3 are described in French patent specification No. 665 M, and others are also in the manner indicated there, that is, by reacting propargyl bromide with amalgamated magnesium, zinc or aluminum in a mixture of tetrahydrofuran and toluene, and condensation of the organometallic compound formed with a 4-piperidone substituted according to the definition of Ri and R4. Instead of the propargyl bromide, analog compounds, such as. Example, 3-bromo-1-butyne or 1-bromo-2-butyne can be used, which supply starting materials of the formula II with a radical R2 and / or R3 other than hydrogen.

   The method described in the French patent specification mentioned is modified with Orteil by using instead of aluminum grit amalgamated merely with mercury chloride, which was first amalgamated with metallic mercury and then treated with mercury chloride.



   The preparation of starting materials of the formula II which contain a hydrogen atom as Ri can, for. B. be carried out by the above-mentioned method using twice the molar amount of propargyl bromide or an analog and a correspondingly increased amount of metal. The preparation of starting materials which contain a keto, cyano or ester group in Ri can, for. B. by partial reaction of the organometallic compounds with appropriately substituted 4-piperidones with respect to their more reactive, 4-position keto group of the piperidine ring, while maintaining the second reactive group.



   It is used to decompose the reaction mixture resulting from the organometallic reaction together with ice. instead of acetic acid, a mineral acid, e.g. B. conc. Hydrochloric acid, an organic and a mineral acid aqueous phase are obtained. The latter contains the reaction components for the process according to the invention, that is to say the desired compound of formula II and mercury ions in mineral acid, e.g. B. hydrochloric acid solution, and if provided by a suitable mixing ratio of ice and acid, z. B. equal parts ice and conc. Hydrochloric acid, if a suitable acid concentration has been ensured, is already the starting mixture for the process according to the invention, the end product of the formula I being formed when it is heated.



   With inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,
Nitric acid, phosphoric acid, methanesulphonic acid, ethane disulphonic acid, ss-hydroxyethanesulphonic acid,
Acetic acid, propionic acid, maleic acid,
Fumaric acid, lactic acid, malic acid, tartaric acid,
Citric acid, benzoic acid, salicylic acid,
Phenylacetic acid and mandelic acid form the compounds of the formula I salts, some of which are readily soluble in water.



   The following examples explain the implementation of the process according to the invention, but by no means represent the only embodiments thereof. The temperatures are given in degrees Celsius.



   Example 1 a) 4.05 g of aluminum powder are mixed with 10 g of mercury and mixed well with a stirrer. Then the unused mercury is decanted off. The amalgamated aluminum is in 25 ml abs. Tetrahydrofuran and 15 ml of abs. Benzene briefly boiled with 15 mg of mercury chloride and then stirred for a further 15 minutes. Then at 50-60 of a total of 20.5 ml of propargyl bromide are added without solvent until the reaction starts and the temperature rises to 70; then the remaining propargyl bromide is diluted with 35 ml abs. Benzene, added. The mixture is stirred for 30 minutes.

   Then at 20-25 50 g of l- (-phenyl-ethyl) -4-piperidone in 150 ml of abs. Benzene is slowly added dropwise while cooling with ice and the mixture is stirred for a further 15 hours. Then it is decomposed with ice and 2N hydrochloric acid, the aqueous phase is separated off, washed with chloroform and concentrated with conc. Sodium hydroxide solution made alkaline, and the released base was taken up in chloroform. The chloroform solution is dried and evaporated and the residue is distilled, whereby the 1- (ss-phenyl-ethyl) 4 (2'-propynyl) + piperidinol of boiling point 0.03 130-140 is obtained.



   In an analogous way one obtains z. B.: l-Benzyl-4- (2'-propynyl) -4-piperidinol,
Kp.0. o3128-135;
1-methyl-4- (2'-propynyl) -4-piperidinol,
M.p. 91-93;
1-methyl-4- (l'-methyl-2'-propynyl) -4-piperidinol,
Bp. O. Oi 75-78;
1-ethyl-4- (2'-propynyl) -4-piperdinol; 1-n-butyl-4- (2'-propynyl) -4-piperidinol;
1-n-dodecyl-4- (2'-propynyl) -4-piperidinol;
1- (1-methyl-ss-phenyl-ethyl) -4- (2'-propynyl)
4-piperidinol; 1- (γ-phenyl-propyl) -4- (2'-propynyl) -4-piperidinol. b) 5.3 g of 1- (ß-phenyl-ethyl) -4- (2'-propynyl) -4-piperidinol are stirred with 21 ml of 10% sulfuric acid and 300 mg of mercury sulfate at 60 for 5 hours.

   The mixture is then concentrated with. Sodium hydroxide solution made alkaline and extracted with chloroform. The chloroform solution is washed with saturated sodium chloride solution, dried and evaporated. Distillation of the residue yields the 1- [l '- (ss-phenyl-ethyl) -4'-hydroxy-4'-piperidyl] -2-propanone of bp o, or 135-140.



   The hydrochloride precipitated from a solution of the base in isopropanol / ether by means of an ethereal hydrogen chloride solution melts at 127-129 after recrystallization from isopropanol.



   In an analogous way z. B. received:
1- {l'-Benzyl4'-hydroxy-4'-piperidyl) -2-propanone,
Kp. O, oi 130-135,
Hydrochloride m.p. 166-168; 1- (l'-methyl-4'-hydroxy-4'-piperidyl) -2-propanone, b.p. o, oi 75; Kp. X2125-130,
Hydrochloride m.p. 125-127 (from isopropanol), citrate m.p. 103-105;
3- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-butanone,
B.p. o, oi 78-80, citrate m.p. 125-126; 1- (1'-ethyl-4'-hydroxy-4'-piperidyl) -2-propanone;
1- (1'-n-butyl-4'-hydroxy-4'-piperidyl) -2-propanone;

      1- (l'-n-dodecyl-4'-hydroxy-4'-piperidyl) -
2-propanone, b.p. 0.09 135-138; 1- [l '- (a-MethylnB-phenyl-ethyl) -4'-hydroxy-4'-piperidyl] -2-propanone; 1- [l'- (y-phenyl-propyl) -4'-hydroxy-4'-piperidyl] -
2-propanone.



   Example 2 a) 4.05 g of aluminum powder are mixed with 10 g of mercury and mixed well with a stirrer.



  Then the unused mercury is decanted off. The amalgamated aluminum is dissolved in 25 ml of absolute tetrahydrofuran and 15 ml of abs. Benzene briefly boiled with 15 mg mercury chloride and then stirred for 15 minutes. Then at 50-60 of a total of 20.5 ml of propargyl bromide are added so much solvent until the reaction starts and the temperature rises to 70; then the remaining propargyl bromide, diluted with 35 ml of abs. Benzene, added.



  The mixture is stirred for 30 minutes. Then at 20-25 50 g of 1- (ss-phenyl-ethyl) -4-piperidone in 150 ml of abs. Benzene was added dropwise with ice cooling and the mixture was stirred for a further 15 hours. Then the reaction mixture is concentrated with about 150 g of ice and 150 ml. Hydrochloric acid decomposed and the benzene phase separated. b) The hydrochloric acid solution obtained is stirred for 4-6 hours at 40-60. Then it is washed with chloroform, with conc. Sodium hydroxide solution made alkaline and extracted with chloroform.

   The chloroform solution is dried and evaporated and the residue is distilled, the 1- [1'- (-phenyl-ethyl) -4'-hydroxy-4'-piperidyl] -
2-propanone of bp o, oi 135-140 is obtained.



   Analogously to the procedure of Example 1 or 2, z. B. the following compounds can also be obtained:
1- (1'-Merthyl-4'-hdyroxy'-4-piperidyl) -2-butanone,
B.p. 0195, citrate m.p. 145-146; 1- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-pentanone, KP. o, oos 119-121, citrate m.p. 126-128;
1- (1'-methyl-4'-hydroxy-4'-piperidyl) -2-hexanone, b.p. o, or 11g118;
1- (1'-methyl-4'-hydroxy-4'-piperidyl) -3-phneyl
2-propanone, b.p. 0.003 132-135;
2- (1'-methyl-4'-hydroxy-4'-piperidyl) -3-pentanone,
B.p. 008 95-100, citrate 130-132;

  
1- (1'-n-propyl-4'-hydroxy-4'-piperidyl)
2-propanone, bp. 0180-82, hydrochloride
137-139.



   Example 3 a) 12 g of finely powdered hydrochloride of 4-piperidinol are added to 20 g of finely powdered sodium hydroxide in 80 ml of chloroform at −20.



  Then 2 ml of water are slowly added, whereupon the temperature rises. Cooling ensures that it does not rise above 10.



  Sodium sulfate is then added, the reaction mixture is filtered and the filtrate is evaporated in a rotary evaporator, finally for 5 minutes under high vacuum, the 4-piperidinol remaining behind. 9 g of magnesium are in 20 ml of abs. Submitted ether, 0.1 g of mercury chloride added and at -10 to -5 44.5 g of propargyl bromide in 100 ml of abs. Ether added dropwise. The mixture is then stirred for a further 20 minutes at -5. At -5 to 0, 28.95 g of 4-piperidinol in 250 ml of abs.



  Benzene was added dropwise, the reaction mixture heating up. Stirring is continued for 30 minutes at 0 and then for about 14 hours at room temperature. Ice and glacial acetic acid are then added, the benzene phase is separated off and extracted with 2N acetic acid. The acetic acid solutions are combined, shaken with ether and then made alkaline.



  The liberated base is extracted with chloroform, the chloroform solution is dried and evaporated, whereby 9.3 g of an oil remain. The distillation gives a 61 of bp 0.05 100-140 (air bath) which crystallizes. The 4- (2'-propynyl) -4-piperidinol thus obtained melts at 76-78. b) 1.6 g of the product from a) are left to stand for 3 hours at room temperature with 16 ml of 2N sulfuric acid and 200 mg of mercury sulfate. The reaction mixture is made alkaline and extracted with chloroform, the chloroform solution is dried and evaporated.

   The residue is distilled in a bulb tube, whereby 1- (4'-hydroxy 4'-piperidyl) -2-propanone is obtained, boiling point 70, melting point 98-100.



   Example 4 a) In a sulphonation flask, 15.35 g of 4-peridone hydrate hydrochloride are dissolved in 110 ml of sodium bicarbonate solution. While cooling and vibrating, 17.1 g of benzyloxycarbonyl chloride and 110 ml of sodium bicarbonate solution are added dropwise at 5-10, so that the reaction mixture always remains alkaline. It is then vibrated for a further 1 hour and the resulting milky emulsion is extracted with ether. The ether solution is shaken twice with 2N hydrochloric acid and then twice with saturated sodium chloride solution, dried and evaporated and the residue is distilled in a high vacuum.

   The 1-benzyloxycarbonyl-4-piperidone boils at 125-131 / 0.004 torr. b) 4 g of magnesium in 6 ml of abs. Submitted ether and then with stirring between 10-15 19.5 g of propargyl bromide in 35 ml of abs. Ether added dropwise. Then 19.1 g of 1-benzyloxycarbonyl-4-piperidone in 80 ml of abs. Benzene was slowly added dropwise at 2U-25, forming a lump which, however, dissolves again on further stirring. The reaction mixture is then stirred for a further 3 hours. Then it is decomposed with ice and 2N sulfuric acid and extracted with ether.

   The ether solution is shaken well with 2N sulfuric acid, dried and evaporated. The remaining 1-benzyloxycarbonyl-4- (2'-propynyl) + piperidinol boils at 160-163 / 0.01 torr. c) 50 g of 1-benzyloxycarbonyl-4- (2'-propynyl) -4 piperidinol are heated to 35-40 for 1 hour in a mixture of 500 ml of 20% sulfuric acid and 350 ml of dioxane, which contains 5 g of mercury sulfate. The dioxane is then evaporated off in vacuo, the residue is extracted with chloroform, the chloroform extract is washed with saturated sodium chloride solution, dried and evaporated.



  The distillation of the residue gives this
1- (1'-Benzyloxycarbonyl-4'-hydroxy-4'-piperidyl)
2-propanone of bp. 03 180-190 C. d) 30.8 g of (1- (1'-benzyloxycarbonyl-4'-hydroxy-4 'piperidyl) -2-propanone are dissolved in 350 ml of ethanol and dissolved in In the presence of 3 g and later a further 1.5 g of 5% palladium-on-carbon hydrogen passed through until no more carbon dioxide can be detected (about 5 hours). Then the catalyst is filtered off, the solution evaporated, the residue taken up in methylene chloride, the solution dried The 1- (4'-hydroxy-4'-piperidyl) -2-propanone goes below 0.01 Torr at 80-100 air bath temperature with partial decomposition above m.p. 98-100, cf. Example 3.

 

Claims (1)

PATENT CLAIM Process for the preparation of new piperidine derivatives of the formula I, EMI4.1 in which Ri is hydrogen, an alkyl radical with at most 12 Carbon atoms, an alkenyl radical with 3-5 Carbon atoms, the cyclopropylmethyl radical or a phenylalkyl radical with 7-9 carbon atoms, Ra hydrogen or the methyl radical, Ra hydrogen or an alkyl radical with at most 3 carbon atoms, the phenyl radical, one Phenylalkyl radical with 7-8 carbon atoms, and R4 denotes hydrogen or the methyl radical, and their salts with inorganic and organic acids, characterized in that a compound of the formula II, EMI4.2 treated with an aqueous mineral acid containing mercury ions at room temperature at a moderately elevated temperature. SUBClaim Process according to patent claim, characterized in that the compounds of the formula I obtained are converted into salts with inorganic or organic acids.