BE533997A - - Google Patents

Description

       

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   The present invention relates to improvements in the preparation of quaternary ammonium compounds and their corresponding tertiary amines.



   Quaternary ammonium compounds having the general formula (I) and their corresponding tertiary amines possess useful spasmolytic properties.
 EMI1.1
 



  In this formula, R1 and R2 are the same or different and are alkyl groups having 1 to 3 carbon atoms or else the NRIR group is a piperidino or pyrrolidino ring R is an alkyl group having 1 to 3 carbon atoms and X is an anion.



   Belgian Patent No. 482,556 describes the preparation of quaternary ammonium compounds corresponding to the general formula (I) by treating the corresponding tertiary amine with a quaternizing agent R3X.



   It has now been found that the quaternary ammonium compounds of the general formula (I) and their corresponding tertiary amines can be prepared by reacting a carbinql of the general formula (II).
 EMI1.2
 with, as the case may be, a tertiary or secondary amine of the general formula RIR2R4N (where R1 and R2 are taken in the same sense as above, R4 is an alkyl group having 1 to 3 carbon atoms or hy- drogen and Y is halogen, for example chlorine or bromine).



   The carbinols of the general formula (II) can be prepared by subjecting a ketone of the general formula C6H5COCH2CH2Y to a reaction with a Grignard cyclohexl reagent C6H1MgY (where Y is taken in the same sense as above), then by hydro -lysant the reaction product.

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   The present invention therefore comprises the preparation of quaternary ammonium compounds of the general formula (I) and their corresponding tertiary amines in which a carbinol of the general formula (II) is reacted with, depending on the case, a tertiary amine. or secondary of the general formula RR R4N where RI, R2 and R are taken in the sense indicated above.



   The invention also includes the novel compound of formula (II) useful as an intermediate in the preparation of valuable quaternary ammonium compounds.



   The invention will be described with reference to the accompanying drawings where all temperatures are given in degrees Centigrade.



  EXAMPLE 1.-
 EMI2.1
 Preparation of l-cyclohexyl-l-phenyl-3-chloropropan-l-ol
42.5 g of cyclohexyl chloride in 225 cm3 of dehydrated sodium ether are slowly added to a refluxed mixture of 13 g of magnesium turnings, 75 cm of ether, 16.5 g of cyclohexyl chloride and a iodine crystal. When the reaction is complete, the solution of c-clohexyl-magnesium chloride thus obtained is cooled to -40 ° C., then a solution of 25 g of beta-chloropropiophenone in 100 cm3 of dehydrated sodium ether is slowly added while cooling to maintain temperature at 40 ° Ce. When the addition is complete, the mixture is kept at 40 for 2 hours, then poured onto a mixture of 200 g of ice and 52 g of ammonium chloride.

   The ether layer is separated, dried over anhydrous sodium sulfate, and the ether is removed by evaporation in a vacuum at room temperature. 36 g of a pale yellow liquid remain, containing chloropropanol. This product is not purified, but is used as it is for the next phase.
 EMI2.2
 



  Preparation of l-cyclohexyl-l-phenyl-3-pyrrolidinopropan-1-ol hydrochloride
8.5 g of crude 1-cyclohexyl-l-phenyl-3-chloropropan-l-ol, 5.93 g of pyrrolidine and 100 cm3 of benzene are refluxed for 6 hours. After cooling, the mixture is washed with water and the benzene layer is evaporated to dryness in vacuum in a water bath. The residue is dissolved in ether and made acidic to Congo red with hydrochloric acid in alcoholic solution. The solid part is separated by filtration and washed with acetone to give 2.1 g of pyrrolidino-propanol hydrochloride, mp 220-222. Another small amount of this compound is obtained from the mother liquors.



  EXAMPLE 2.- # '#####' # "#
 EMI2.3
 Preparation of N-methyl-3-crclohexyl-3-phenyl-3-hydroxy-propyl-pyrrolidinium chloride 8.5 g of 1-cyclohexyl- are heated under reflux for 8 hours.
 EMI2.4
 Crude I-phenyl-3-chloropropan-1-ol, 10.7 g of N-methylpyrrolidine and 100 cm3 of isobutanol. The mixture is then evaporated to dryness in a vacuum in a water bath. The residue is first stirred with ether which is then decanted. Acetone is then added and the solid part is filtered off. The latter is recrystallized from a mixture of methyl ethyl ketone and chloroform and 0.87 g of a quaternary salt identical to an authentic sample prepared by another route is obtained (melting point, melting point in mixture, physiological action).

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   The process of the invention makes it possible to react compounds of the general formula (II) with secondary and tertiary amines, to obtain the corresponding dialkylamino, piperidino and pyrrolidino derivatives, their acid addition compounds and quaternary ammonium with a good performance. In the case of quaternary compounds, this process eliminates the need to form tertiary amines from compounds of formula (II} and then to quaternize them to obtain the desired products.



   The following can be prepared by a similar process: 3 1-Cyclohexyl-1-phenyl-3-piperidinopropan-1-ol hydrochloride, melting point 255 with decomposition.
 EMI3.1
 



  4. N-ethyl-3-cyclohexyl-3-phenyl-3-hydroxypropyl-piperidinium iodide, mp 179-180 with decomposition.



  5. N-n-propyl-3-cycI¯ohexyl-3-phenyl-3-hydroxypropyl-pipéT ridinium iodide, melting point 196-1970 with decomposition.



  6. N-methyl-N iodide: N-diethyl-3-cyclohexyl-3-'phenyl-3-hydro-xypropylammonium, melting point 160-182.



   CLAIMS
1.- Process for the preparation of compounds of the formula
 EMI3.2
 where R1R2 and R3a are alkyl groups having 1 to 3 carbon atoms, R and R are piperidino and pyrrolidino rings and X is a therapeutically acceptable anion, and corresponding tertiary amines of these compounds, characterized in that one makes react a compound of the formula
 EMI3.3
 where Y is a halogen with an amine of the formula R1R2R4N, where R4 is chosen from the class formed by alkyl groups of 1 to 3 pod atoms and hydrogen, and the product obtained is separated.

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Claims (1)

2e- Process for preparing a compound selected from EMI3.4 class formed by 1-c elohexyl-1-phenyl-¯3-pyrrolidinopropan-1ol and its salts, characterized in that l-cyclohexyll-phenyl-3-chloropropan-l-ol is reacted with pyrrolidine and separates the product obtained. <Desc / Clms Page number 4> 3.- Process for the preparation of 3-cyclohexyl-3- phenyl-3-hydroxy-propylmethylpyrrolidinium chloride, characterized in that the beta-chloropropiophenone is reacted with a Grignard cyclohexyl reagent to form 3-chloro-1-cyclohexy1 -1-phenylpropan-1-01 and the latter substance is reacted with N-methylpyrrolidine.