DE1096351B - Process for the preparation of therapeutically active substituted 4-dimethylaminocyclohexylcarbinols - Google Patents

Description

GERMAN

The present invention relates to a modification or improvement of the German Auslegeschrift 1016705 described process for the production of therapeutically effective substituted 4-dimethylaminocyclohexylcarbinols, in which the preparation of therapeutically valuable compounds of general formula I.

HO-CR ₉

H ₃ CN-CH ₃

is described and claimed, and their nontoxic addition and quaternary salts, in which R ₁ and R _{2 are} saturated or unsaturated carbocyclic radicals, for example a cycloalkyl radical (e.g. cyclohexyl), aryl radicals (e.g. phenyl, substituted phenyl) or heterocyclic Radicals (e.g. thionyl) in which the heteroatom is nitrogen or sulfur, X is a lower alkyl radical, e.g. B. methyl, ethyl or propyl, and η is a number between 0 and 3. The improvement of the process described in German Auslegeschrift 1016705 by the present invention lies in the isolation of the cis isomers of the aforementioned compounds of the general formula I, where in particular R ₁ and R _{2 are} 2-thienyl, phenyl or a substituted phenyl (ζ. B . Tolyl), partly from solvent residues. The trans isomers can be derived from their mixtures with the cis isomers as crystalline compounds by precipitation with a hydrocarbon solvent, ζ. Β. a saturated aliphatic, saturated cycloaliphatic or aromatic solvent or mixtures thereof with petroleum ether (preferably not more than 80 percent by weight of the latter), especially if the substituted cyclohexylamine product contains thienyl or phenyl substituents. The cis isomer, which is soluble in the hydrocarbon solvent, is recovered after isolation of the trans isomer by evaporating the aforementioned solution to dryness at a temperature below the boiling point of the cis isomer. The cis isomer can then, if appropriate, be purified further by customary distillation processes.

Examples of the liquid hydrocarbon solvents used to dissolve the isomeric mixtures are pentane, isopentane, octane, heptane, decane, nonane, toluene, cyclohexane, cycloheptane and preferably hexane or benzene.

Method of manufacture

of therapeutically effective

substituted 4-dimethylaminocyclo-

hexyl carbinols

Applicant:

Schering Corporation,
Bloomfield, NJ (V. St. A.)

Representative: Dipl.-Chem. Dr. W. Koch,

Hamburg 4, Simon-von-Utrecht-Str. 43,

and Dr.-Ing. R. Glawe, Munich 27, patent attorneys

Claimed priority:
V. St. v. America December 19, 1957

Frank J. Villani, Essex, NJ (V. St. Α.),
has been named as the inventor

The starting material for the preparation of the cis isomers, e.g. B. cis-a, a-Di- (2-thienyl) -4-dimethylaminocyclohexylcarbinol, e.g. B. have been manufactured according to the following process:
For example, p-aminobenzoic acid in the presence of a suitable catalyst, e.g. B. platinum oxide, according to the method described by Gerhard Wen dt in reports of the German Chemical Society, Vol. 75, 1942, pp. 425 to 429, or rhodium on alumina, are hydrogenated. At the end of the reaction, cis-4-aminocyclohexanecarboxylic acid is separated off. This can be done conveniently by filtering off the catalyst, removing the water in vacuo and dissolving the residue in an aqueous medium, to which alcohol is then added in order to precipitate the desired cis-cyclohexanecarboxylic acid. An alcoholic solution of this product is then heated in the reflux condenser in the presence of sulfuric acid in order to effect the esterification to ethyl cis-4-aminocyclohexanecarboxylate. Dimethylation of the amino group is conveniently carried out by standard procedures known as the methods previously described. For example, the amino group can be dimethylated by reacting the ester obtained and described above with formic acid and formaldehyde (cf. Organic Synthesis, Vol. 3.1955, p. 723).

Thus prepared cis- or trans-4-dimethylaminocyclohexanecarboxylic acid ethyl ester is added to an ether solution of 2-thienyllithium and brought to reflux, d. H. about 40 ° C if diethyl ether is used,

O09 697/511

3 4

heated. While diethyl ether contains the preferred solution, hydrochloric acid, is dissolved, is medium, other ethers, such as dibutyl ether, 3.50 kg / cm ² hydrogen pressure in the presence of 2 g can be used. The organohthium complex platinum oxide obtained is hydrogenated. The theoretical amount of hydrogen compound is hydrolyzed and the trans-a, a-di- (2-thi- is absorbed within several hours, the enyl) -4-dimethylaminocyclohexylcarbinol preferably 5 catalyst is filtered off and the filtrate in vacuo from an inert liquid Hydrocarbon concentrated to dryness as a solution. The residue is dissolved in water, for example an aromatic hydrocarbon, made alkaline with ammonium hydroxide and extracted with chloroform as above, such as hexane, toluene, xylene or benzene. After removal of the solution it was mentioned that it was recrystallized. The remaining oil is distilled using the appropriate means. Obtained cis-isomers is achieved if it is introduced 114 to the hydrocarbon solvent in such a io 4-Aminocyclohexancarbonsäureäthylester, Kp. _Lo. By 117 ° C.

Evaporation of this solution becomes essentially pure. Mixture of 49 g of this ester, 76 g of 98% strength

cis-a, a-Di- (2-thienyl) -4-dimethylaminocyclohexylcarbinol formic acid and 68 ml of aqueous formaldehyde solution

obtain. is heated under reflux for 8 hours. The solution

Another method comprises heating a medium then in vacuo on a steam bath ent-4-Dimethylaminocyclohexanecarbonsäurealkyl-, preferably removed, the residue dissolved in water, with ammonium-ethyl ester, which is made alkaline mainly as the cis-isomer hydroxide and with chloroform extra, ie about 80% or more, during the hiert. By removing the solvent and distile residue, the corresponding trans isomer is, with a lation in vacuo, 4-dimethylaminocyclohexane alkali metal alcoholate, eg. B. sodium ethylate, for example in 20 carboxylic acid ethyl ester, b.p. _lo 122 to 125 ° C, obtained,
a suitable solvent, reaction of the product obtained with a suitable inorganic _m 50 ecm of absolute ether becomes a cooled, good acid, for example a hydrohalic acid, such as a stirred ethereal solution of phenylmagnesium bromide hydrochloric acid, adding a suitable anorga- (0.8 mol), which was prepared in the usual way, nischem alkali or ammonium hydroxide added to the so 25. The mixture is heated to room temperature reaction mixture is formed around the p _H value of the _un d it is stirred for another 6 hours. Adjust the reaction mixture mixture to about 7 or above. The then -is with dilute ammonium chloride solution zererhaltene product, trans-4-Dimethylaminocyclohexan- _se TZT and extracted with ether. The combined Äthercarbonsäureäthylester is, after cleaning with a extracts are carefully with 10 ° / ₀ hydrochloric organic lithium or magnesium halide extracted in the 30 acid and the acidic solution with ammonium Previously, and in the following examples described made alkaline hydroxide. The aqueous solution is reacted in such a way that the desired trans-carbinol is extracted with chloroform, which is then obtained with water, that of remaining cis-isomers (which, if washed, dried and concentrated in vacuo, this process is carried out, in amounts up to, but by recrystallizing the residue, a mixture not exceeding 20 percent by weight is present through 35 _{V of} isomers, from hexane trans-diphenyl-4-di-recrystallization from a suitable liquid carbo-methylaminocyclohexylcarbinol, m.p. 150, 5 to 151 ⁰ C, hydrogen, as described above, purified and obtained. Can be isolated by evaporation of the remaining. Hexane solvent to dryness will be the appropriate

The compounds which can be prepared according to the invention contain cis isomers. Kp. _2187-193 ° C.

are pharmacologically, preferably in the form of their 40 B "t> '1 2

Salts, as in the procedure of the German Auslegeschrift ^
1016705, is best used as
quaternary salts, such as halomethylates, preferred

wise as bromomethylates, and are described there- To a solution of thienylmagnesium bromide, the

by heating the tertiary substituted 45 from 21.4 g of magnesium and 144 g of 2-bromothiophene.

Cyclohexylamine with the appropriate alkyl halide, 39.8 g of 4-dimethylaminocyclohexane

z. B. methyl bromide, with or without a solvent, added carboxylic acid ethyl ester. According to the procedure

posed. from Example 1 is a mixture of isomers of

These compounds and their corresponding salts, a.a-Dithienyl ^ -dimethylaminocylohexylcarbinol, are obtained

especially their di- (2-thienyl) -substituted members, 50 of which the trans isomer with a melting point

like cis-a, a-di- (2-thienyl) -4-dimethylaminocyclohexyl- from 156 to 157 ° C by recrystallization from hexane

carbinol, are, as is isolated in the German edition. By subsequent evaporation of the

1016705 is executed, valuable spasmolytic and hexane solution to dryness is the corresponding cis-

parasympathetic blocking agents. Isomers, b.p. _x 195 to 205 ° C, obtained.

The cis compounds 55 methyl bromide which can be prepared according to the invention are immersed in a cooled solution for 4 hours

are in inhibiting the mobility of 91 g of cis-a, a-di- (2-thienyl) -4-dimethylaminocyclo-

Gastric perhaps a little less active than the correspon- ding hexylcarbinol, which is dissolved in 1.5 liters of anhydrous benzene

corresponding trans compounds, however, they show themselves at has been directed. Soon a white solid precipitates,

Application of large doses is not the undesirable and the mixture is left overnight at room temperature

Side effects like the trans compounds, which 60 left standing. The product is filtered off and off

a much larger mydriatic and antisialogogical mixture of absolute methanol - absolute

Show activity. . Ether re-crystallized. This product is cis-a, cc-di-

The inventive method is based on the (2-thienyl) -4-dimethylaminocyclohexylcarbinolbromme-

the following examples are explained in more detail. Ethylate with a melting point of 239 to 241 ° C.

Example 1 ^e 5 Example 3

cis-aja-diphenyl- ^ l-dimethylaminocyclohexylcarbinol cis-a, a- (p, p'-ditolyl) -4-dimethylaminocyclohexyl-

The required starting material is carbinol as follows

prepared: 33 g of ethyl p-aminobenzoate, the in By using the Grignard reagent used in Example 1

300 ecm of absolute ethanol, the 16.8 ecm concentrated 7 ° by an equivalent amount of p-tolyhnagnesium bromide

is replaced, cis-a, cc- (p, p'-ditolyl) -4-dimethylaminocyclohexylcarbinol is obtained in the manner described in Example 1 in an analogous manner. Bp _x 192 to 195 ° C.

The cis compounds can also be prepared in such a way that after the hydrogenation of the s p-aminobenzoic acid ester the cis-p-aminocyclohexanecarboxylic acid ester isolated and then the method described in German Auslegeschrift 1016 705 with the pure cis compounds.

Example 4

cis-a, a-Di (2-thienyl) -4-dimethylaminocyclohexylcarbinol

137 g of p-aminobenzoic acid are suspended in 2.5 liters of water in a 4.7-1 bomb and 10 g of platinum oxide are added. The reduction is carried out in a closed vessel at room temperature and an initial hydrogen pressure of 14 to 21 kg / cm ² . The reduction is complete after 12 to 15 hours (cf. Ber. Dtsch. Chem. Ges., Vol. 75, 1942, pp. 425 to 429). ao

The catalyst is filtered off and the water is removed in vacuo. The residue is in 630 ecm of water dissolved, and 31 ethanol are added, whereby the cis form of 4-aminocyclohexanecarboxylic acid precipitated will. The acid is filtered off and air-dried. F. 323 to 325 ° C.

A solution of 52 g of the cis acid, 500 ecm of ethanol and 50 ecm of concentrated sulfuric acid is under Stirring heated under the reflux condenser for 6 hours. The excess solvents are removed in vacuo and the residue dissolved in water, made basic with sodium hydroxide and extracted with chloroform. After removing the chloroform, the residue is distilled.

The product obtained is ethyl cis-4-aminocyclohexanecarboxylate and has the following parameters: Κρ. _µ 117 to 118 ° C; <= 1.4660.

A mixture of 52 g of the ethyl cis-4-aminocyclohexanecarboxylate thus obtained, 80 g of 85 weight percent formic acid and 69 ecm of 37 weight percent aqueous formaldehyde solution is heated on a steam bath for 8 hours. The excess solvent are removed in vacuo, the residue dissolved in water, made basic with sodium hydroxide and with Chloroform extracted. After the chloroform is distilled, the desired ester becomes a colorless liquid obtain.

The identified as cis-4-Dimethylaminocyclohexancarbonsäureäthylester product has the following characteristics: Kp _lo 125 to 127 ° C;. <= 1.3490; F. of the picrat 117 to 118 ° C.

2 moles (314 g) of bromobenzene in an equal volume of anhydrous ether are added dropwise with stirring added to a suspension of 27.5 g (4 moles) of granular lithium in about 21 anhydrous ether. Man allows the reaction to take place under reflux during the addition and 1 hour thereafter. 2 moles of thiophene (168 g) are added rapidly with stirring and reflux and the mixture is allowed to continue for an additional 2 hours heated to reflux. 100 g of the ethyl cis-4-dimethylaminocyclohexanecarboxylate obtained above are added to the 2-thienyllithium thus produced ether added in an equal volume; the mixture is refluxed on the water bath for 6 hours and over Left to stand overnight at room temperature. Approximately 11% of water is added and the layers are separated. The aqueous layer is extracted with chloroform and the combined organic layers are washed with saturated saline and distilled.

The product obtained is cis-a, a-di- (2-thienyl-4-dimethylaminocyclohexylcarbinol with the following parameters: bp ₁₁ 195 ° C; mp 93 to 96 ° C from hexane.

Claims (2)

Patent claims: 1. Process for the preparation of therapeutically effective substituted 4-dimethylaminocyclohexylcarbinols the general formula HO Xn + H ₃ CN-CH ,, and their non-toxic acid addition and quaternary salts, in which R ₁ and R _{2 are} saturated or unsaturated carbocyclic radicals, such as cycloalkyl or aryl radicals, such as phenyl, heterocyclic radicals in which the heteroatom is nitrogen or sulfur, X is a lower alkyl radical and η is a Number between 0 and 3, according to a process in which a p-amino or p-dimethylaminobenzoic _{acid ester is hydrogenated in a known manner with hydrogen in the presence of PtO 2} and hydrogen chloride or acetic acid, the optionally obtained 4-aminocyclohexanecarboxylic acid ester in the customary manner with formaldehyde and Dimethylated formic acid, the 4-dimethylaminocyclohexanecarboxylic acid ester obtained either a) in a known manner with an organometallic compound, preferably a Grignard compound of the general formula _{R x} - · Mg - Br or R ₁ - Mg - J, reacted and the organometallic compound obtained in the usual way hydrolyzed or b) first with ammonia at 50 to 100 ° C and increased htem pressure converted into the 4-dimethylaminocyclohexanecarboxamide, this _{dehydrated with P 2} O ₅ in a known manner, the resulting 4-dimethylaminocyclohexanecarboxamide reacted in the usual way according to Grignard with a compound R ₁ -Mg-Br or R ₁ -Mg-J, hydrolyzed, the 4-dimethylaminocyclohexyl-Rj-substituted ketone obtained is subjected to a second Grignard reaction with a compound R ₂ —Mg — Br or R ₂ —Mg — J, the organometallic intermediate obtained is likewise hydrolyzed and finally the obtained, by R ₁ - and or or R ₂ radicals substituted 4-dimethylaminocyclohexylcarbinol, if desired, converted in a known manner into salts or quaternary ammonium compounds, the isomer mixture of 4-dimethylaminocyclohexylcarbinols obtained is treated with a hydrocarbon, such as a saturated aliphatic, saturated cycloaliphatic or aromatic hydrocarbon, and the transprecipitated isomers are treated be separated, thereby characterized in that the cis-isomers are separated off from the mother liquor in a customary manner, such as distillation, if desired converted into salts or quaternary ammonium compounds, if desired, after the hydrogenation of the p-aminobenzoic acid esters, the cis-p-aminocyclohexanecarboxylic acid esters in a customary manner, such as crystallization and filtration , separates, if desired, instead of the p-aminocyclohexanecarboxylic acid ester, the free p-amino- 7 8 reaction mixture containing cyclohexanecaxboxylic acid 2. The method according to claim 1, characterized used, from this the cis-isomer in the usual draws that cis-a, a-di- (2-thienyl) -4-dimethylamino- Way, how crystallization and filtration, separates, cyclohexylcarbinol is reacted with methyl bromide. esterified in a manner known per se and the rest Procedural stages. with the pure cis compounds 5 Publications considered: performs. German publication No. 1016705. © 009 697/511 12. 60