DE1618476B1 - Process for the separation of an isomer mixture composed of 3c-dimethylamino-4-phenyl-4c-carbethoxy-Delta1-cyclohexene and 3t-dimethylamino-4-phenyl-4t-carbethoxy-Delta1-cyclohexene into the individual compounds - Google Patents

Description

Patent 1,518,959 describes a process for the preparation of basic substituted cyclohexenes by means of which 3-dimethylamino-4-phenyl-4-carbethoxy- A ¹ -cyclohexene can also be prepared. The compound mentioned is obtained as a mixture of the corresponding 3-cis-4-cis and the corresponding 3-trans-4-trans compounds. The separation of the isomers by the process of this patent is tedious and expensive and it is very difficult to obtain a pure product. The separation process according to the above patent proceeds as follows: The solution of the base mixture in ethyl acetate is treated while hot with an equivalent amount of HCl dissolved in ethyl acetate. Then with stirring, simultaneous careful and constant cooling and inoculation with pure ice compound, 75% of the amount of water corresponding to _{the IV 2 hydrate is added.} The iy ₂ hydrate of the hydrochloride, the cis compound, is usually separated out initially in an oily state, and only after prolonged stirring, after 1 to 2 hours, does the product crystallize. Once crystallization has started, it progresses very quickly. The point in time must now be adjusted at which a maximum amount of cis compound hydrate is present in crystalline form, but the trans compound does not yet begin to precipitate. This point in time is extremely difficult to determine, so that usually the cis compound is interspersed with 10 to 15% trans compound and the ethyl acetate phase still contains considerable amounts of cis compound. This separation process becomes more problematic and difficult to handle the larger the batches, and is accordingly unsuitable for carrying out the isometric separation on an industrial scale.

The present invention now enables the separation of the cis and trans isomers of S-dimethylamino ^ phenyl ^ carbäthoxy-J ¹ -cyclohexene in a simple manner. It has been surprisingly found that the cis compound in question of 3 c - dimethylamino - 4 - phenyl -4c-carbäthoxy-J ¹ -cyclohexene in aqueous solution containing chlorine ions with a pH of 2.5 to 4.0 with ZnCl ₂ forms a sparingly soluble zinc complex, which enables an effortless and almost quantitative separation of the cis-components.

The present invention therefore relates to a process for the separation of a 3 c-dimethylamino-4-phenyl-4c-carbäthoxy- A ^{1-cyclohexene} and 3t-dimethylamino - 4 - phenyl - 4t - carbethoxy - A ¹ - cyclohexen composite isomeric mixture into the individual compounds , characterized in that the isomer mixture is treated in an aqueous solution containing chlorine ions at a pH of 2.5 to 4.0 with zinc chloride, the forming zinc complex of Sc-dimethylamino ^ -phenyl ^ c-carbäthoxy- /! ¹ -cyclohexene is separated from the aqueous phase, both the zinc complex and the aqueous 3t-dimethylamino-4-phenyl-4t-carbethoxy / ¹ -cyclohexene-containing phase are treated with a base, such as strong NaOH or KOH, or preferably ammonia, and the free bases are obtained in pure form in the usual way by extraction with advantageously chloroform or methylene chloride. The total amount of the trans compound remains in the aqueous phase. The isolation of the trans compound from the aqueous phase and the recovery of the cis compound from the complex are carried out in a simple manner by adding aqueous ammonia, which on the one hand almost pure trans base deposited, on the other hand the zinc complex of the cis compound quantitatively with release of the cis base is cleaved.
The complex formation of the cis compound with Zn ²⁺ ions in chloride-containing solution seems to be specific, since no other heavy metal investigated so far results in a precipitation with the cis compound in the aqueous phase. The presence of chloride ions is necessary because the exchange of chloride ion for another anion leads to failure of the reaction.

The complex of zinc chloride and cis compound

is composed of one molecule of zinc chloride and two molecules of 3c-dimethylamino-4-phenyl-4c - carbethoxy - A ¹ - cyclohexene - hydrochloride; the gross formula of the complex is

C ₃₄ H ₄₈ Cl ₄ N ₂ O ₄ Zn

the molecular weight is 755.3. An analysis sample provides the following elementary analysis:

Calculated:

C = 54.06, H = 6.41, Cl = 18.79, N = 3.74,

Zn = 8.68%;
found:

C = 54.40, H = 6.28, Cl = 17.59, N = 3.81,

C = 53.90, H = 6.11, Cl = 18.31, N = 3.98,

Zn = 8.57%.

The zinc complex has a F. = 146 to 147 ° C. The following structure of the complex is currently being used for probably held:

H CH,

CH ₅ OOC

-N

^X CH ₃
COOC ₂ H ₅

[ZnCl ₂ ]

CH

- 2HCl

The feasibility of the inventive The cleavage of the zinc complex or the free

Fahrens is, however, in no way of the correctness 65 establishment of the trans connection is also with others

depending on the above formula of the zinc complex, bases other than ammonia, for example with strong

The only decisive factor is compliance with the NaOH or KOH described, which can be carried out. At work

procedural measures. however, with ammonia they become perfectly clear

and get easily separable phases, which cannot be achieved with other technical bases, so that the Use of ammonia is highly preferred. The required pH range varies between 8.5 and 9.5.

With regard to the optimal purity and yield of the zinc complex, certain concentration ranges are observed in the production of the zinc complex. 90 mol of isomer mixture are dissolved in 100 to 2001, preferably in 1701, of HCl and reacted _{with 75 to 90 mol, preferably 90 mol, of ZnCl 2.}

example

5.46 kg (20 mol) isomer mixture, consisting of 75% 3 c - dimethylamine - 4 - phenyl -4c- carbäthoxy-J ^ cyclohexene and 25% 3t-dimethylamino-4-phenyl-4t-carbäthoxy-zl ¹ -cyclohexene, are dissolved in 251 HCl (1 to 2N). The solution is then diluted to 35 liters and adjusted to a pH of about 3. The HCl concentration is then 2 to 3 percent by weight. A solution of 2.7 kg of ZnCl ₂ in 15 l of water is slowly added while stirring. Stirring is then continued for 1 hour at room temperature and for 1 hour at 0 ^° C. The colorless crystalline complex formed is pressed off sharply (3 atmospheres of compressed air). The air-dried zinc chloride complex of the cis compound weighs 5.2 kg (92% of theory) and is practically free from the trans compound.

The aqueous filtrate is poured into a mixture of 71 concentrated aqueous ammonia (25 to 27% NH ₃ ) and 5 l of water, with stirring, and 121 of chloroform are then added. It is stirred well. The dried chloroform phase is concentrated, the residue is dissolved in ethyl acetate and precipitated using HCl (10 percent by weight) dissolved in ethyl acetate. Instead of chloroform, methylene chloride or benzene, which contains 10 to 20 percent by weight of ethyl acetate, can also be used to separate the trans compound.

The yield of trans compound is 1.2 kg (88% of theory). The trans connection can too recrystallized from ethyl acetate with 8 to 10% acetone or ethyl acetate with 5 to 10% chloroform will.

The cis compound becomes quantitative by adding the zinc chloride complex to aqueous ammonia recovered as the free base.

The free bases are isolated in the usual way. As a solvent for the extraction of the free bases from aqueous solution, chloroform and methylene chloride have proven particularly beneficial.

The time required to carry out the above example is I ¹ I ₂ days, while 12 to days are required to obtain 1 kg of trans compound by the method described in patent 1518 959.

Claims (2)

Patent claims: 1. A process for separating an isomer mixture composed of 3c-dimethylamino-4-phenyl-4c-carbäthoxy-J ¹ -cyclohexene and St-Dimethylamino ^ -phenyMt-carbäthoxyi ^ -cyclohexene into the individual compounds, characterized in that the isomer mixture is in aqueous Chlorine ion-containing solution treated with zinc chloride at a pH value of 2.5 to 4.0, the zinc complex formed of 3c - dimethylamine - 4 - phenyl-4c-carbäthoxy-. _! d ¹ -cyclohexene separated from the aqueous phase, both the zinc complex and the aqueous 3t-dimethylamino-4-phenyl-41-CaAaUiOXy- /! ¹ -cyclohexene-containing phase is treated with a base, such as strong NaOH or KOH, or preferably ammonia, and the free bases are obtained in pure form in the usual way by extraction with advantageously chloroform or methylene chloride. 2. The method according to claim 1, characterized in that the isomer mixture before the Treatment with zinc chloride dissolves in hydrochloric acid.