DE1923620C3 - Process for the preparation of basic substituted cyclohexenes or their salts - Google Patents

Description

The invention relates to a process for the preparation of basic substituted cyclohexenes with a compound of the general formula
general Formci Ri Rj

N

CH

j COORj

cn

cti

wherein R ₁ and R _{2 are} a lower alkyl radical, such as methyl. Ethyl, propyl, isopropyl, butvi or isobutyl, is or together with the nitrogen atom that they are bonded, a heterocyclic ring. such as a pyrrolidine, morpholine or piperidine ring, ujid R _{3 is} a lower alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl "" or isobutyl, or their salts, which is characterized in that 0 , 5 mol of a compound of the general formula CH ₂

converts, in which R ₁ , R ₂ and R _{3 have} the above meaning.

This implementation would run! t a product that consists of a mixture of two isomers, 3-cis-dialkylamino - 4 - phenyl - 4 - cis - carbalkoxy - I '- cyclohexene and .i-trans-Dialkyiamino ^ -phenyM-trans-carbalkoxy-I'-cyclohexene.

The cis-lsomcre of this compound can go through the following general forms can be represented:

R ₁

H-N

Il

in which R _{1 and R 2 have} the above meaning, reacted with 1 mol of C'rotonaldehyde at temperatures of about 3 to 5 C, optionally in the presence of an inert solvent and a Kalalytisclien amount of a Chiuons as activator, reacted / 1, the reaction geniisch then 0 , 45 moles of a compound of the general »formula

and since*
Formula:

COOR., Irans-Isomcre durcli the following general

Π Ν

COOR ₁

CH,

Ii '

C COOK,

III

in which H ₁ denotes a lower alkyl radical, / usel / t, the eili-iltene in Finnish washes an alkali sulfite with an aqueous solution and the eiliallette is optionally after separation, which is known via the / iiikcbioridkoniplcxvcrbiniliiiiu j-a'WüüsUilenfalK πι S.il/i.· with, uiorganisdieii columns, except S, il / -., iim "del orgi!" iM, JHii Siiuren iilteifülnl.

I ■, .ind already veii.iliren for the production of li.i-.Si.il.nhsiiiiücrleii ('VLl hl

ii

u. ah willows new b.isi, Ui - »iihslilinerle (yclii lh tk'i all {. 'L'ineineii I miiiel I eili.iflni if ni.iii V .IJd ll I l

the .illf-'i'iiieiiK'n I minel

These compounds are inherent in mammals and have good general properties. Because of their relatively low Toxi / iläl and the absence of side effects they represent valuable remedies. For example / do not have any paralyzing ones in the Mngeii-Daini-Trakl

ν » Effects and do not impair the Atnuingssyslein. These changes are generally observed when narcotic anal gels, such as I-methyl-4-phenyl-piperidine-4-carboxylic acid-ethylenic hydrochloride, are administered.

¹ SS Dm to use these compounds as analgesics /.u -.ic with pharnia / etilisciieii carriers, such as 1 aklose. Water or alcohol, combined and administered as a derivate, Injeklioiislösiingen oiler lixirs. how

(·· ■, in Kalten. K.iiiiiulien. Kai / en or dogs. On; l in a dom · »from eiw.i IS ηιμ kg hi> / u elwa SO mg / kg. Mii / 111'.wei- .i · ilw.i '. *> nie kg KorneigewiLlil, ν · .τ-.ibiri.lii uiiilin ileispieisweisi; / ομΙ a Dusis from i'hv ι Dim kf bi · »-K) mg kg sUnke .ιιυΙμι-ΐΐΗΐκ ' ΆιιΙιΐιημ I) .ι. li.iiivlioiueit '/ cigl the stiiiksie an.il ^ e H th ·· Wnkim.i

I hu Ιΐιΐιιιιιιιμ iliι ii <uiul Ir ₁ ItIi Isoiiieien, in · il.i I .ιιίικΊΐΊΐιιΐΜίΙιιιιιμ can over the IIhIhhIiIhihIi

or the 1,5 hydrate of the cis isomer can be achieved. Pa this in the solvent mixture of ethyl acetate and Meihylüthylketon is less soluble than the irans isomer, the ice isomers from the solution in the form of its 1,5-hydrate «. The trans isomer remains in solution and can be removed by removing the solvent can be obtained from the solution.

It has also been suggested that the mixture of isomers of the basic substituted cyclohexenes in a strong mineral acid, such as hydrogen chloride * acid, to dissolve (pH about 2.5 to 3.5) and add an aqueous solution to this acidic solution, which is about Contains 15 to 40%, preferably about 20% zinc chloride, Add slowly until crystals of a zinc chloride complex salt begin to separate out. The cis-lsomerc reacts specifically with the zinc chloride to form a complex salt, which is derived from the Solution containing the isomer mixture separates out. The trans-Lsomcre does not react with the zinc chloride and therefore remains dissolved in the acidic solution. Man The insoluble complex salt of zinc chloride and the cis-isomer can therefore be removed by filtration of Separate the trans isomer.

In order to isolate the pure trans isomer from the acidic solution, one adds to the solution the these isomers contains an organic solvent, preferably chloroform, and makes the solution alkaline, preferably with concentrated aqueous ammonia. The pure trans isomer is obtained from the alkaline mixture by adding the organic jo residue in a mixture of allyl acetate and Diiiiethylketon dissolves and one with a concentrated solution of gaseous hydrogen chloride Adjusts a pH value of around .1.5 to around 4. The hydrochloride of the pure trans-. »5 Isomers from the acidic solution. It is filtered off and recrystallized.

The present invention is concerned with a / wide new process for the preparation of basic substituted cyclohexenes of the general formula.

Hei the already proposed process for the preparation of the new basic substituted cyclohexenes becomes I-dimethylaininohutadiene- (U) as the starting material used. This connection is not commercially available and can only be used at high costs and are made with great difficulty. In addition, this method has the disadvantage that in the Use of aminobutadiene as a starting material during the reaction a considerable proportion 5 » a propional impurity is formed, which is difficult to obtain from the isolated cis and trans isomers can be removed This lowers the yield of the active trans isomer.

The process according to the invention uses readily accessible starting materials, and the amount of propion powder contamination formed is significantly less than in the case of the already defeated case 'U'"'Iran's hoiiieien better.

The Reaklionieiliiehmer can [! C (! Cl>cni'iil.ills in a direct solvent such as benzene luhiol or '\ lliL-t. Be dissolved, and the first I Ίιιμ, -Ι / ιιιι! Can be done by / iigalie a ( hiiioiis. ivic l'luii.iiillm 11 '"ihiiioii imu (hiysenchiiiuii. kat.iiy-.ici! weiden ί > w ith condensation is at Tempel <iItuen from t In. ί ι' ιΙύΐι.ΙψιΙπΙιι! and after the / uu .il'i ', k-, final reaction participant the mixture to about 50 to about 150 "C, preferably to about 90" C heated and held at this temperature for 2 hours. A dehydrating agent such as potassium carbonate is added to the reaction solution in amounts that the molar concentration, the amine ratio are the same, added, the dehydrating agent removes that during the reaction of the compound formed water and at the same time reduces the formation of propionate impurities.

During the reaction a product is formed which

from a mixture of the two isomeric compounds 3 ■ ice - dialkylumino - 4 - phenyl - 4 - ice - carballkoxy-

l'-cyclohexene and 3-trans-dialkylamino-4-phcnyl-

4-trans-carbalkoxy-l'-cyclohexene.

The isomer mixture obtained according to the invention can then, if appropriate, after separation of the stereoisomers via the zinc chloride complexes per se be converted into salts in a known manner. The isomer separation is carried out in the manner described above.

The compounds prepared according to the invention easily form other jellies by known methods, ζ. B. in the implementation of stoichiomctnschcn amounts of the base and the desired acid in one customary inert solvent. Examples of acids, which are suitable for the formation of the acid addition salts of the bases according to the invention are inorganic Acids, excluding hydrochloric acid, for example nitric acid, sulfuric acid or phosphoric acid and organic acids, for example benzoic acid, acetic acid, salicylic acid, maleic acid, tartaric acid or Citric acid. The preferred salts are those which are pharmaceutically acceptable, e.g. h "it is Acid addition salts that are not more toxic than that Bases ai's which they are made and which do have the necessary physical properties that make them suitable for processing into pharmaceutical preparations.

example

a) Implementation of crotonaldehyde. Dimcthylamiu and Ethyl ethyl ester

Into a 22 liter three-necked flask. equipped with a stirrer and a thermometer, I ¹ Xi) g (42.1 MdI) of anhydrous Crotonaidchyd are added. 2-120 ml anhydrous benzene, 10.6 μ phenanthrenequinone and 2020 g (21.15MoI) anhydrous potassium carbonate. In this mixture, at 5 ° C., 055 g (21.2 mol) of anhydrous diniethylamine condensed within 2 hours. When the reaction is over, there will be. After a period of 15 minutes, the apparatus is flushed with nitrogen. Then all at once U) W) μ (1Κ, ') 5 mol) aliopus acid ether ( ¹ > | .2% purity by C / .ischromalogr.iphie) are added and. iiif 75 C Ii minutes heated removing the außeie heating and allowing the Reaklionstemperalui aiii ¹ JO '■' .iiisieigen and koiiliollieil it by cooling N.uli the Re.iklion zeroes more exothermic veil.mit. and the rempei.itiii! hours at ¹ Ht to <)> (held

The Rc.iklionMiiisihuiii · is in 21 I Was, ei 111 an it) I Dieili.ilskollien. that with linen »Rühiir .iiisjxsi.iiiel is given and with Hl.5 I llenzol eiti ι Inert. Dk Ikn / nl .lIikIiI wild .ilipclii-nut and dl: wanr ^ e Schithi vwinwifci! The! K'H / siiv.hith! winl with! ! rush I 11 t hlorwa ^ erslolfviurc (2. ¹ or 11) ι · \ ΐι, linen D <e ΗιίιλιΙ-.ιΙικΙιΙ wild vctwoifcn The

Süurccxiraklc are combined and washed with 4.5 l of benzene, The Benzolschicni is separated and discarded.

The aqueous layer is 1.4! 50% aqueous sodium hydroxide made basic and extracted with 2 parts of Pelroluther (11.5 or 6 l). The wiißrigc layer is discarded, the Pciroläthcrcxtraktc are combined and washed with 31 I S0% aqueous sodium bisulfite igcm l '/ vigorously stirred for ₄ hours.

The organic layer is separated and the aqueous layer is extracted with 4.7 liters of petroleum ether. the aqueous layer is discarded. The Pctroläthcrextraktc are combined and twice with 51 Water washed. The aqueous layer is discarded. The polyether layer is covered over magnesium sulphate dried, nitrated and in a vacuum (steam bath, i 5 mm Hg) for the complete removal of the Pctrolaelhcrs concentrated. 4135 g of residue are obtained (80% of theory). Gas-liquid chromatographic indicates that the mixture of 60% cis-isomercm, 40% trans isomer cream and less than 0.1% ethyl 2-phcnyl-3-dimethylaminopropionate.

Similarly, heterocyclic amines such as pyrrolidine, morpholine or piperidine can be substituted of dimethylamine can be used, the corresponding heterocyclic cyclohexene compounds are formed.

b) Isomer separation

17.71 liters of N-hydrochloric acid are placed in a 50-1 three-necked flask equipped with a stirrer and thermometer. The mixture is heated to 65 ° C. and 4.13 kg of 3-dimethylamino-4-phenyl-4-carbethoxy are added all at once - I ¹ - cyclohexene (60% cis and 40% trans-isomer) is added The solution 3s is heated at 70 ° C Γ / ₂ hours, it cools' at 35 C, and extracted with 3.151 Pctroläther The... Aqueous layer is separated, the petroleum ether extract is discarded, the aqueous layer is treated with 108 g of activated charcoal and stirred for a few minutes, then the charcoal is removed by filtration, the filtrate is diluted to 241 and poured into a 50 l flask fitted with a Stirrer and a dropping funnel is equipped.

At 25 to 30 C all at once 5.25 l of zinc chloride solution, made up of 2.06 kg of zinc chloride. 10.41 of water and 108 ecm of concentrated hydrochloric acid has been prepared, was added. It is inoculated with the zinc chloride complex compound of cis-isomercn and the remainder of the zinc chloride solution is added within 2 hours. When the addition is complete, the mixture is stirred at 25 ° C. for 1 hour and kept at 0 ° to 5 ° C. overnight (i 5 hours).

The zinc chloride complex compound is separated off by filtration and is not washed. the moist filter cake weighs 3.65 kg and after drying at 60 to 65 ° C 3.4 kg.

4.321 ammonium hydroxide, 1.77 l of water and 75 ml of 50% aqueous sodium hydroxide are placed in a 50 l three-necked flask equipped with a stirrer. The filtrate from the separation of the zinc chloride complex compound is added and the mixture is stirred at 25 CV for ₂ hours. The aqueous layer is separated off and treated with 2 to 3 liters of Pcirofüihcr cxtia- r »s. The aqueous layer is discarded, the combined petroleum ether oils are: Washed twice with 4.5 and 2.3 liters of water each time. The pctrolether is dried with magnesium sulphate, evaporated IHtricl and hqi 40 to 50C / 15 mm Hg, whereby 1.63 kg residue is obtained. The gas liquid chromatography shows a content of 80% trans-isomers. 20% cis-isomer and 0.25% ethyl-2-phcrtyl-3-dimethylaminopropionate,

c) salt formation

273 g (1 mol) of 3-dimethylamino-4-phcnyl-4-carbiilhoxy-I ¹ -cyclohexene (at least 80% Iran) are dissolved in 1 l of ethyl acetate and slowly mixed with a solution of 102 g (1 mol) with stirring and cooling. 96% sulfuric acid in 21 ethyl acetate was added. After standing for several hours, the crystalline precipitate is filtered off with suction, washed with Athylacclal and dried until constant. Yield 342 g: melting point 118 to 119 ° C.: water content according to K. Fischer 0.2%.

Claims (1)

Palent claims: I. Process for the preparation of basic substituted cyclohexenes of the general Forn.cl COOR ₃ wherein R ₁ and R ₂ denote a lower alkyl radical or together with the nitrogen atom to which they are bonded form a heterocyclic ring and R ₃ denotes a lower alkyl radical or salts thereof, characterized in that 0.5 mol of a compound of general formula H-N in which R, and R _{2 have} the above meaning, with 1 mole of crotonaldchyd at temperatures of about 3 to about 5 C, optionally in the presence of an inert solvent and a catalytic! Amount of a chinchin as activator, converts the reaction mixture 0.45 mol of a compound of the general formula C -COOR, in which R _{3 means} a lower Aikylrcsl, /whaben.''/ '. this c; i ;;:! '. e: ie ί; c: t !! kc! j to a TcKipirnilur of elwa 50 to about 150 C crhit / t. Washed with an aqueous solution of an alkali metal silicone filament and the isomer mixture obtained, optionally 2, process according to claim I, characterized in after separation of the stereoisomers, the zinc indicates that a * s quinone phananthrenequinone chloride complex compound »if desired is used in / In a manner known per se, in salts with inorganic acids. The process according to claim 1, characterized in that genetic acids, with the exception of hydrochloric acid, or S indicates that the last stage converts the cyclic organic acids. tion is performed at 90 to 95 'C ^J.