CS214312B1 - Method for the production of 3-trans-dimethylamino-4-phenyl-4-trans-carbetoxy-1-cyclohexene - Google Patents

Description

The present invention relates to a process for the preparation of 3-trans-dimethyl-amino / -4-phenyl-4-trans-carbethoxy-1-cyclohexene of the formula I

which is used in medicine as an analgesic.

To date, this compound has been prepared by isolation from a mixture of the trans-isomer of Formula I and the cis-isomer, i. 3-Eis-dimethylamino-4-phenyl-4-cis-carbetoxy-1-cyclohexene of formula II

CH

CH

3 \.

214 312/10 /

2,414,312 by fractional crystallization of their hydrochlorides (DOS 1,923,619), using the cis-isomer complex with zinc chloride (DOS 1,923,620 and Nem.pat. No. 1,618,476], or by using a naphthalene-1,5-disulfonic acid addition salt of transomer I (Nem. Pat. No. 1,768,704 and DOS 2,134,821 /.

The present invention relates to the preparation of the pure trans-isomer of formula I by isolation from a mixture of isomers I and II with aromatic sulfocarboxylic acids, preferably with 5-sulfoisophthalic acid of formula III

with which they form the trans-isomer of formula I in an aliphatic alcohol having a carbon number of 1 to 4, preferably in ethanol, an aliphatic ketone having a carbon number of 3 to 7, preferably acetone, or mixtures thereof with water, aliphatic acid esters with the number of carbons 2 to 6, preferably with ethyl acetate, or with aliphatic or cyclic ethers with a number of carbons of 3 to 8 and a number of yeasts of 1 or 2, preferably with tetrahydrofuran and 3-6, respectively. dioxane, an isolate salt of formula IV

The process according to the invention is carried out by adding a solution of the isomers I and II in an alcohol to a solution of an aromatic sulfocarboxylic acid, preferably 5-sulfoisophthalic acid of the formula III, and an aliphatic alcohol, preferably ethanol or an aliphatic ketone, preferably acetone. , ketone, ester or ether, preferably in ethanol, acetone, ethyl acetate or dioxane, respectively. tetrahydrofuran, the mixture being spontaneously heated to 30-50 ° C. After cooling to -10 to + 25 ° C, preferably to 0 to + 5 ° C, the aromatic sulfocarboxylic acid salt ¹ of the trans-isomer of formula IV crystallizes while the analogous salt of the cis-isomer II remains in solution. The treated salt ¹ is aspirated, suspended in water and the trans-isomer I is liberated from the salt by addition of a strong inorganic or organic base. This is extracted with an inorganic organic solvent, preferably petroleum ether, the extract is dried and the solvent is distilled off. The trans-isomer I is obtained in a yield of 60-65% with a content of cis-isomer II of max. 1% by weight

The advantage of this process over the naphthalene-1,5-disulfonic acid process described above is the use of the acid no. provenance. Compared to the other processes described above, the advantage of this process is to obtain a higher purity of the trans-isomer I.

In the following, the subject of the invention described in the examples has been carried out without being limited thereto.

214 312

Example 1 *

To a previously prepared solution of 3.16 kg (11.97 mol) of 5-sulfoisophthalic acid monohydrate in 4 L of ethanol, a solution of 4.56 kg of a base containing 60% by weight is added under stirring and cooling. of the trans-isomer I (10 mol) in 4.4 L of ethyl acetate. After cooling the solution and partially precipitating the crystal, 4.8 L of ethyl acetate was added and the mixture was allowed to stir for 1.5 hours. The precipitated salt is then filtered off with suction, suspended in a mixture of 41 ethanol and 6 l of ethyl acetate and allowed to stir at room temperature for about 20 minutes. It is then aspirated again, the purified crystal is suspended in 8 l of water and the base is collected. The resulting base is extracted with petroleum ether, the petroleum ether extract is dried freely. sodium sulfate and the petroleum ether was distilled off. 1.67 J < g is obtained. base containing 95.15% by weight. 3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy-1-cyclohexene and less than 1% by weight. 3-cis-dimethylamino-4-phenyl-4-cis-carbetoxy-1-cyclohexene of formula II. The yield was 61.1%. From the mother liquors after distilling off the solvent, 1.16 kg of a base containing 65% by weight are obtained as described above. % Of 3-cis-dimethylamino-4-phenyl-4-cis-carbethoxy-1-cyclohexene; 3-Trans-dimethylamino-4-phenyl-4-trans-carbethoxy-1-cyclohexene of formula I.

Example 2

To the suspension! 28.8 g (0.11 mol) of S-sulfoisophthalic acid monohydrate in 50 ml of acetone and 5 ml of water are added at 30 to 40 ° C with stirring a solution of 40 g of base containing 25 g of the trans-isomer I (0.09 mol). in 30 ml acetone. Upon cooling, the salt of 3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy-1-cyclohexene-5-sulfoisophthalate crystallizes, which is further processed as in Example 1. 13.7 g of base are obtained, containing 96% by weight. trans-isomer I.

Example 3

To a suspension of 28.8 g (0.11 mol) of 5-sulfoisophthalic acid monohydrate in 50 ml of acetone and 15 ml of ethanol at a temperature of 30 to 40 ° C is added, with stirring, a solution of 40 g of base containing 25 g of the trans-isomer I / O. 09 mol / v 30 ml acetone. After cooling the crystallized salt ¹ 3-trans-dimethylamino-4-phenyl-4-carbethoxy-trans-l-cyclohexene 5-sulfoisophthalate to be the aspiration and purification processes as in Example 1 to give 13.3 g of a base consisting of 92% weight of transisomer I.

Example 4

To a solution of 18 g (0.068 mol) of 5-sulfoisophthalic acid monohydrate in 60 ml of dioxane is added a solution of 20 g of base containing 12 g of trans-isomer I (0.044 mol) dissolved in 20 ml of dioxane. After seeding with stirring and cooling crystallized salt of ^3-1 transTdimetylamino-4-phenyl-4-carbethoxy-trans-l-cyclohexene 5-sulfoisophthalate. Sol ¹ was treated in a similar manner to Example 1. 6.2 g of a base containing 98% by weight were obtained. trans-isomer I.

Claims (4)

1. A process for the preparation of 3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy-1-cyclohexene of the formula I 214 312/1 / CH ₃ -x by isolation from a mixture of the trans-isomer of formula I and the cis-isomer of formula II by formation of an addition salt of the trans-isomer of formula I with an aromatic sulfocarboxylic acid, characterized in that 5-sulfoisophthalic acid is used as aromatic sulfocarboxylic acid an aliphatic alcohol having a carbon number of 1 to 4, an aliphatic ketone having a carbon number of 3 to 7, or mixtures thereof with water, an ester of an aliphatic acid having a carbon number of 2 to 6, or an aliphatic resp. cyclic ethers having a carbon number of 3 to 8 and an oxygen number of 1 or 2. 2. A process for the preparation of compound I according to item 1 ₍ characterized in that the isolation of the addition salt is carried out in an ethanol-ethyl acetate medium). 3. A process for the preparation of compound (I) according to claim 1 ₍ characterized in that the isolation of the addition salt is carried out in an acetone-water medium). 4. A process for the preparation of a compound of claim 1, wherein the isolation of the addition salt is carried out in an acetone-ethanol environment.