CH629188A5 - Process for the preparation of pyrrolidine derivatives - Google Patents

Description

The present invention relates to a process for the preparation of heterocyclic compounds, namely compounds of the formula

R4

HN

in the R1 2-thienyl or phenyl substituted by a lower tertiary amino group, R2 and R3 independently of one another are hydrogen or lower alkyl and R4 phenyl which can be substituted by halogen, lower alkyl, lower alkoxy or primary, lower-secondary or lower-tertiary amino may represent, where if R4 is phenyl or halogen-substituted phenyl, R1 is phenyl substituted by a lower tertiary amino group,

as well as acid addition salts thereof.

According to the invention, the compounds of the formula I and their acid addition salts are prepared by

that a compound of the formula in which R4 'is nitro-substituted phenyl or a radical R4, or an N-oxide of a compound of the formula II is reduced and, if desired, a base obtained is converted into an acid addition salt.

Lower alkyl groups are to be understood as straight-chain or branched alkyl groups with up to 7 carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl, the methyl group being preferred.

Chlorine is preferred among the halogen atoms fluorine, chlorine, bromine and iodine.

Lower alkoxy groups are to be understood as meaning those with 1-7 carbon atoms, for example methoxy, ethoxy, propoxy, butoxy and the like, the methoxy group being preferred.

Lower secondary amino groups are understood to mean a lower aliphatic radical, e.g. B. by a lower alkyl radical, substituted amino groups. Lower tertiary amino groups are substituted by two such radicals or they consist of 5- or 6-membered, saturated N-He-terocycles, which optionally contain an additional nitrogen, oxygen or sulfur atom and also by z. B. lower alkyl or hydroxy lower alkyl may be substituted, e.g. Pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, picolinyl, N'-methyl and N'-hydroxyethylpiperazinyl.

The compounds of the above formula I have at least one basic nitrogen atom and can accordingly be combined with inorganic or organic acids, for example with hydrogen chloride, hydrogen bromide, sulfuric acid,

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Acetic acid, succinic acid, maleic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like form acid addition salts, the hydrochlorides being particularly preferred.

The salts of the compounds of formula I can also be in hydrated form, for example in the form of their mono- or polyhydrates, e.g. B. their trihydrates.

For the preparation of the compounds of formula I, the compounds of formula II are reduced. The reduction can be carried out catalytically using noble metal catalysts, for example using platinum, or using Raney nickel catalysts, in the latter case expediently under increased pressure, for example under a pressure of more than 2 atmospheres. When the reduction is carried out with the above reducing agents, the process products of the formula I are predominantly (to more than 90%) formed in cis form.

However, the compounds of the formula II can also be reduced by means of nascent hydrogen, produced by the action of acids on metals. The hydrogen can be generated, for example, by the action of a lower alkane carboxylic acid, preferably formic acid, on zinc, in particular zinc dust, or on iron, in particular iron powder. The reduction with zinc or iron and acid can be carried out at temperatures between about 0 and about 80 ° C., preferably at about 60 ° C. With this type of reduction, the end products of the formula I are predominantly obtained in the trans configuration.

However, the compounds of the formula II can also be reduced using complex hydrides, such as sodium borohydride or lithium aluminum hydride, the end products of the formula I being obtained predominantly in the cis configuration.

If a compound of the formula II in which R4 'denotes a nitro-substituted phenyl radical is used as starting point in the preparation of a compound of the formula I, the nitro group is converted into the amino group in the reduction of such a compound.

If one wishes to obtain a compound of the formula I which has a nitro-substituted phenyl radical R4, the nitro group is subsequently introduced into the phenyl radical. This can be done with a nitrating agent such as nitric acid, the procedure being appropriately such that the nitration is carried out by means of a mixture of concentrated nitric acid and concentrated sulfuric acid, preferably with cooling.

Acid addition salts of the compounds of formula I can be obtained from these compounds by treatment with the corresponding acids.

An optionally obtained mixture of ice and trans isomers of the end products of formula I can, if desired, be separated into the individual isomers, for example by means of fractional crystallization. The cis isomers are particularly preferred.

If desired, the undesired isomer obtained can be isomerized on the route via a compound of the formula II, specifically the isomerization can be carried out both on the isomer mixture and after the separation of this mixture. This isomerization consists in a dehydrogenation of a compound of general formula I and a subsequent hydrogenation. The dehydrogenation can be carried out, for example, by N-halogenation, in particular N-chlorination (e.g. with an alkali metal hypochlorite) and subsequent elimination of hydrogen halide using a base, e.g. with sodium methylate. The pyrroline obtained in this way is then reduced to the desired isomer of the formula I as described above.

A racemate obtained can be split into the optical antipodes, for example using optically active acids such as dibenzoyl tartaric acid, camphor sulfonic acid and the like.

5 Particularly preferred compounds of the formula I are obtained if a compound is used as starting material in which R1 is the 2-thienyl radical.

In addition, preferred compounds are obtained if a starting material is used in which the substituents R2 and R3 are methyl groups.

It is further preferred to use a starting material in which R4 is p-methoxyphenyl. 5- (p-Methoxyphenyl) -2,2-dimethyl-3- (2-thienyl) pyrrolidine and its acid addition salts are very particularly preferred.

i5 The starting materials of the formula II, and also their acid addition salts and their N-oxides can be obtained by adding a compound of the formula

R4

30th

cyclized under reducing conditions and that a compound of the formula II obtained in this way is optionally converted into an N-oxide or into an acid addition salt of one of these compounds.

35 The reducing cyclization of the compounds of the formula III can be carried out using tin and glacial acetic acid, preferably at the boiling point of the reaction mixture. Depending on the reaction conditions, a compound of formula II or the corresponding N-oxide is obtained. The reducing cyclization of the compounds of the formula III to give the compounds of the formula II can, however, also take place under certain reaction conditions by means of zinc and a lower alkane carboxylic acid, preferably formic acid, and it is in this case if a further reduction to the compounds of the formula I should be prevented, required to use little zinc and short reaction times. The compounds of the formula II are also obtained by reducing the amount of acid or lowering the temperature.

The compounds of the formula II obtained by one of the two process variants can be converted into acid addition salts or into N-oxides in a manner known per se. The N-oxides can be obtained, for example, by treating the compounds of the formula II with peracids 55 or hydrogen peroxide.

The starting materials of the formula II must and cannot be used in isolated cases in all cases; rather, it is possible that in the reducing cyclization of a compound of the formula III an end product 60 of the formula I is obtained directly.

The starting materials of formula III are close analogues of known compounds (J. Am. Chem. Soc. 69, 1947, pages 2271-5) and can be prepared in a conventional manner, e.g. B. be-65 as described in the literature mentioned.

The compounds of formula I and their acid addition salts have a pharmacodynamic effect and can therefore be used as active ingredients in pharmaceutical preparations

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be used separately. The compounds mentioned can be used as medicinal products in the form of pharmaceutical preparations, which they mix with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. Contain water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, rubber, polyalkylene glycols, petroleum jelly etc. The pharmaceutical preparations can be in solid form, for. B. as tablets, dragées, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

The compounds of formula I and their acid addition salts have analgesic effects without being addictive. They can therefore be used to combat pain. For example, the rac-cis-5- (p-methoxyphenyl) -2,2-dimethyl-3- (2-thienyl) pyrrolidine hydrochloride in the writhing test when administered orally to the mouse has an ED50 of 30 (60 minutes) mg / kg. The acute oral toxicity of this substance in the mouse is 250-500 mg / kg (24-hour value). An ED50 of 153 (60 minutes) mg / kg was found for this substance in the hotplate test.

Compounds corresponding to formula I, wherein R1 is 2-thienyl and R4 is phenyl or halogen-substituted phenyl, are analgesically ineffective.

As analgesic active substances, the compounds of formula I and their pharmaceutically acceptable acid addition salts can be administered to humans in individual doses of about 50-200 mg 1-3 times a day. Oral administration is preferred.

example 1

17 g of 2- (p-methoxyphenyl) -5,5-dimethyl-4- (2-thienyl) -1-pyrroline are dissolved in 250 ml of absolute ethanol and mixed with 10 g of sodium borohydride. The mixture is stirred for 6 hours under a nitrogen atmosphere, evaporated under reduced pressure, the residue is taken up in water and extracted with ether. The organic phase is dried with sodium sulfate and evaporated under reduced pressure. The remaining pyrrolidine is dissolved in ethanol and converted into the hydrochloride by adding concentrated hydrochloric acid. The latter is recrystallized from acetone-diisopropyl ether after the solvent has been stripped off under reduced pressure. This gives cis-5- (p-methoxyphenyl) -2,2-dimethyl-3- (2-thienyl) -pyrroli-dinhydrochloride with a melting point of 181 ° C.

The 2- (p-methoxy-phenyl) -5,5-dimethyl-4- (2-thienyl) -l-pyrroline used as the starting compound can be prepared as follows:

180 g of zinc powder are added in portions over a period of 5 hours to a solution of 194 g of 4'-methoxy-4-methyl-4-nitro-3- (2-thienyl) valerophenone in 400 ml of ethanol and 400 ml of formic acid. The reaction temperature is kept at 48-50 ° C. Then the zinc sludge is filtered off and the filtrate is strongly concentrated under reduced pressure. The residue is taken up in water and made alkaline with 3N sodium hydroxide solution. The mixture is then extracted with methylene chloride and the organic is washed Phase with water, dried over sodium sulfate and evaporated under reduced pressure, the oily residue is chromatographed on silica gel, eluting first with pure benzene, then with benzene / acetone mixtures with increasing acetone content (up to 50% acetone) 2- (pM ethoxy phenyl) -5,5-dimethyl-4- (2-th ienyl) -1-pyrr-oline, which melts at 84 C after recrystallization from n-hexane.

The above-mentioned 4-methoxy-4-methyl-4-nitro-3- (2-thienyl) valerophenone can be prepared as follows:

a) 300 g of acetanisole (4-methoxy-acetophenone) and 300 ml of thienyl-2-aldehyde are finely distributed in 21 water with vigorous stirring and mixed with 200 ml of 10% aqueous sodium hydroxide solution. The emulsion thus obtained is stirred for 60 hours at room temperature with nitrogen gas. The mixture is then extracted with ether, the organic phase is dried over sodium sulphate and the solvent is evaporated off. The remaining brown oil is distilled in a high vacuum. The distillate solidifies in the receiver and is recrystallized from methanol. 4-Methoxy-3- (2-thienyl) acrylophenone with a melting point of 104 ° C. is obtained.

b) 168 g of 4-methoxy-3- (2-thienyl) acrylophenone are heated to boiling together with 267 g of 2-nitropropane and 400 ml of anhydrous methanol. A solution of 43 g of sodium methylate in anhydrous methanol is added dropwise to this mixture in the course of 60 minutes and the mixture is then boiled for 3 hours under reflux conditions. After cooling, the reaction mixture is mixed with 43 ml of glacial acetic acid, largely concentrated and the residue is taken up in 1500 ml of dichloromethane. This solution is washed twice with 500 ml of water, dried over sodium sulphate and evaporated to dryness. The residue is crystallized from ethanol to give 4'-methoxy-4-methyl-4-nitro-3- (2-thienyl) valerophenone, melting point 90 ° C.

Example 2

47 g of 4- (p-dimethylaminophenyl) -5,5-dimethyl-2-phenyl-1-pyrroline-l-oxide are dissolved in a mixture of 400 ml of ethanol and 400 ml of formic acid, and 80 g of zinc powder are added in portions with stirring. The reaction temperature is kept at 43 ° C. The mixture is then stirred for a further 2 hours, then the zinc sludge is filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in water, neutralized with 3N sodium hydroxide solution and extracted with ether. The ether phase is then dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel, starting with pure benzene, then with benzene-acetone mixtures with increasing acetone content (up to 50% acetone)

eluted. In this way, trans-3- (p-dimethylaminophenyl) -2,2-dimethyl-5-phenylpyrrolidine is obtained, which melts at 108-109 ° C. after crystallization from n-hexane.

Chromatography also gives 5,5-dimethyl-2-phenyl-4- (p-dimethylaminophenyl) -1-pyrroline, which is processed according to Example 3.

The 4- (p-dimethylaminophenyl) -5,5-dimethyl-2-phenyl-1-pyrroline-1-oxide used as the starting compound can be prepared as follows:

120 g of 4-methyl-4-nitro-3- (p-dimethylaminophenyl) -va-lerophenone are dissolved in a mixture of 1 liter of ethanol and 1 liter of formic acid. 50 g of zinc powder are added in portions to this solution with stirring over the course of 8 hours, and care is taken to ensure that the reaction temperature does not exceed 58.degree. The mixture is stirred for a further 12 hours and 50 g of zinc powder are again added in the same manner. The zinc sludge is then filtered off, the filtrate is diluted with water and neutralized with sodium hydroxide solution while cooling with ice. The mixture is then extracted with methylene chloride, the organic phase is dried over sodium sulfate and the solvent is stripped off under reduced pressure.

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The residue is refluxed for a short time in high-boiling petroleum ether (fraction 80-105). Then decant from the undissolved dark oil and decolorize the petroleum ether solution with activated carbon. On cooling, 4- (p-dimethylaminophenyl) -5,5-dimethyl-2-phenyl-1-pyrroline-1-oxide crystallized.

Example 3

16 g of 5,5-dimethyl-2-phenyl-4- (p-dimethylaminophenyl) -1-pyrroline are dissolved in 300 ml of absolute ethanol and 16 g of sodium borohydride are added. The solution is stirred at room temperature for 14 hours under nitrogen. The mixture is then evaporated to dryness under reduced pressure and the residue is suspended in water by vigorous stirring. The undissolved portion is filtered off, dried and recrystallized first from n-hexane and then from diisopropyl ether. This gives cis-3- [p- (dimethylamino) phenyl] -2,2-dimethyl-5-phenyl-pyrrolidine with a melting point of 117-118 ° C.

Example 4

A solution of 7 g of 2- (p-methoxyphenyl) -5,5-dimethyl-4- (p-dimethylaminophenyl) -1-pyrroline hydrochloride in water is made alkaline with 3N sodium hydroxide solution and extracted with methylene chloride. The organic phase is washed with water and dried over sodium sulfate. The oil remaining after the solvent has been stripped off is taken up in 150 ml of absolute ethanol and the solution is mixed with 5 g of sodium borohydride. Then the mixture is stirred under nitrogen at room temperature for 12 hours. The mixture is then evaporated to dryness under reduced pressure and the residue is suspended in water by vigorous stirring. The undissolved portion is filtered off, dried and recrystallized from n-pentane. The base thus purified is taken up in ethanolic hydrochloric acid, evaporated to dryness under reduced pressure and the residue is recrystallized from ethanol-acetone. This gives cis-3- [p- (dimethylamino) phenyl] -2,2-dimethyl-5- (p-methoxyphenyl) pyrrolidine dihydrochloride with a melting point of 180 ° C.

The 2- (p-methoxy-phenyl) -5,5-dimethyl-4- (p-dimethylaminophenyl) -1-pyrr-oline hydrochloride used as the starting compound can be prepared as follows:

70 g of 4'-methoxy-4-methyl-4-nitro-3- (p-dimethylamino-lo phenyl) valerophenone are dissolved in a mixture of 600 ml of ethanol and 600 ml of formic acid. 120 g of zinc powder are added in portions to this solution over the course of 30 hours with stirring, and the reaction mixture is kept at 60 ° C. for part of the time, partly by cooling and partly by heating. Then the zinc sludge is filtered off, the filtrate is diluted with water and made alkaline with sodium hydroxide solution while cooling with ice. The mixture is then extracted with methylene chloride, the organic phase is dried over sodium sulfate and the solvent is stripped off under reduced pressure. The residue is slurried in acetone at 0 ° C. by vigorous stirring. The undissolved portion of 2- (p-methoxyphenyl) -5,5-dimethyl-4- (p-dimethylaminophenyl) -l-pyrroline oxide is filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in dilute hydrochloric acid and extracted with methylene chloride until the organic phase remains colorless. Now the aqueous phase is made alkaline with 3N sodium hydroxide solution and extracted again with methylene chloride. The organic phase is washed with water and dried over sodium sulfate. After the solvent has been evaporated off under reduced pressure, an oil remains which is taken up in ethanolic hydrochloric acid. At - 18 ° C 2- (p-methoxyphenyl) -5,5-dimethyl-4- (p-dimethylaminophenyl) -1-pyrroline hydrochloride crystallized from it with a melting point of 35 ° C (decomposition).

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Claims (8)

629 188 PATENT CLAIMS 1. Process for the preparation of pyrrolidine derivatives of the formula R4 HN in the R1 2-thienyl or phenyl substituted by a lower tertiary amino group, R2 and R3 independently of one another are hydrogen or lower alkyl and R4 phenyl which is substituted by halogen, lower alkyl, lower alkoxy or primary, lower-secondary or lower-tertiary amino may be substituted, wherein if R4 is phenyl or halogen-substituted phenyl, R1 is phenyl substituted by a lower tertiary amino group, and acid addition salts thereof, characterized in that a compound of the formula in which R4 'is nitro-substituted phenyl or a radical R4 means or an N-oxide of a compound of formula II is reduced and, if desired, a base obtained is converted into an acid addition salt. 2. A process for the preparation of compounds of the formula I in which R4 is nitro-substituted phenyl, characterized in that a compound of the formula II in which R4 is phenyl or an N-oxide thereof is reduced and the compound of the formula I obtained is nitrided. 3. The method according to claim 1, characterized in that one separates a mixture of ice and trans isomers obtained. 4. The method according to claim 1, characterized in that one splits a racemate obtained in the optical antipodes. 5. The method according to claim 1, characterized in that one uses a starting material, wherein R1 is 2-thienyl. 6. The method according to claim 1, characterized in that one uses a starting material, wherein the two substituents R2 and R3 represent methyl groups. 7. The method according to claim 1, characterized in that one uses a starting material, wherein R4 is p-methoxy-phenyl. 8. The method according to claim 1, characterized in that 5- (p-methoxyphenyl) -2,2-dimethyl-3- (2-thienyl) pyrrolidine or an acid addition salt thereof, in particular in cis form, is prepared.