SK434289A3 - Method for resolving izomers with aim to attain (e)-n-methyl-6,6- -dimethyl-n-(1-naphthylmethyl)-hept-2-en-4-in-1-yl amine - Google Patents

Abstract

Prodn. of the (E)-N- (1-naphthylmethyl)- heptenamine deriv. and its addn. salts comprises sepg. (I) from a crude mixt. of (E) base (I) and corresp. (Z) base by salt formation. The salt formation combined with preparing the crude E/Z base mixt. by reacting 1-methyl aminomethyl-naphthalene (II) with a substd. heptenyne (III) is also claimed. The salt formation is pref. carried out in an organic ester, esp. ethyl acetate,opt. in admixture with another organic solvent, esp. the corresp. alcohol, partic. ethanol. The crude base mixt. has an E:Z ratio of 4:1-7:1.5. In partic. a crude base mixt. contg. (wt./wt.) 70-40% (E) base, 15-30% (Z) base and 15-30% impurities/byprods. is used.

Description

Separation of isomers to give (E) -N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) -hept-2-en-4-yn-1-ylamine

Technical field

The present invention relates to a novel process for the separation of isomers to give (E) -N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) hept-2-en-4-yn-1-ylamine of the free formula I

in the form or in the form of acid addition salts.

BACKGROUND OF THE INVENTION

The compound of formula (I) and its use as an antifungal agent for the treatment of mycoses caused by dermatophytes is known, for example, from European patent specification no. 24 587.

In Example 16 of the cited European patent specification no. No. 24,587 specifically describes the above compound of formula I and is also reported to be prepared according to processes a), c) and e) of this European patent specification no. 24,587, analogously to Examples 1, 3 and 6 described in detail herein, which further illustrate procedures a), c) and e).

According to examples 1, 3 and 6 of European patent specification no.

587, the product is always obtained in the form of a base and in the form of a mixture consisting of the cis (Z) - and trans (E) -isomers and from this mixture of isomers the trans (E) -isomer is obtained by chromatography over silica gel using a solvent system. in each case a mixture of toluene and ethyl acetate, in process a) (example 1) and e) (example 6) in a ratio of 4: 1 and in process c) (example 3) in a ratio of 95: 5.

According to the data contained in European patent specification no. 24 587 elutes first the trans (E) -isomer and then the cis (Z) -isomer. The base is then optionally converted into an acid addition salt.

This production method has the disadvantage that, during the chromatography, a portion of the undesired cis-isomer must always be fed together with the by-products, if any, present. A further disadvantage is that - apart from the fact that chromatography is undesirable for the production of larger quantities - the base solutions obtained are unsuitable for subsequent salt formation and must therefore be re-evaporated and the residue must then be redissolved. The thermal load of the base, which occurs, is undesirable.

J. Med. Chem. 27, p. 1539-1543 (1984) discloses that isomers may also be resolved by fractional crystallization of the hydrochloride salts. However, recrystallization twice from a mixture of 2-propanol and diethyl ether is necessary in order to obtain the pure trans (E) -isomer. This route is very lengthy and is carried out using ether.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that the expensive chromafographic separation of bases or the unfavorable recrystallization of hydrochlorides can be omitted and can be replaced by a one-step, one-step salt formation with simultaneous precipitation of the trans (E) -isomer using a mixture of the two isomers as bases. In addition, all impurities present in the mother liquors will remain after precipitation to give a highly pure product.

It is an object of the present invention to provide a process for resolving isomers in order to obtain (E) -N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) hept-2-en-4-yn-1-ylamine in free form or in the form of acid addition salts, which comprises the crude mixture containing the compound of formula I and the cis (Z) isomer in the free form as a base, is converted in the presence of C _1-4 ester, acetate, or a mixture of C ₁ _ ₄ acetic acid ester with an alcohol corresponding to the ester, the salt precipitation while the trans (E), then the resulting compound of formula I in salt form into the free base or into another acid addition salt.

Here, it is possible to start from a crude mixture which, in addition to the trans (E) - and cis (Z) -isomers, contains still high proportions, for example 15 to 30% (w / w) of possible further impurities or by-products, etc. The starting material contains, for example, 15 to 30 cis (E) -isomers and 70 to 40 trans (E) -isomers. The trans / cis ratio is 4: 3 to 7: 1.5, preferably 3: 1.

% (weight% (weight moves / weight) / weight) from approx

In the method of the invention it operates in a C ₁ _ ₄ ethyl acetate, such as methyl, ethyl, n-butyl or isobutyl acetate, in particular ethyl acetate.

Suitable further organic solvents which can be used in admixture with the above-mentioned organic acid esters are, in particular, alcohols corresponding to said ester, such as ethanol together with ethyl acetate, isopropanol together with isopropyl acetate, etc., preferably ethanol together with ethyl acetate .

Preferably, the acetic acid ester itself, in particular the ethyl ester thereof, is used.

The salt forms used are preferably salts with inorganic acids, in particular the hydrochloride.

The other reaction conditions are analogous to those of similar known methods. The reaction is preferably at a temperature of about -25 ^e C to about 100 ° C, preferably at about 20 to about 25 ^e C

The process according to the invention allows the separation of cis / trans-isomer mixtures in a single step. This is most surprising. In addition, it has proven to be highly advantageous that all impurities remain in the mother liquor in a single precipitation, thereby obtaining a very pure product in the necessary trans (E) form. Hydrochloride is preferred for this purpose.

Surprisingly, three different effects can thus be achieved in a single, one-off stage, i.e., in a single step. salt formation, isomer separation and purification.

As a starting material, the crude product of the preceding step with said mixture of isomers and any impurities present, for example with a trans (E) / cis (Z) 3: 1 ratio, in the form of bases is used.

The compound of formula I in free form can be converted into acid addition salts in a known manner and vice versa. The preferred salt is the hydrochloride. Thus, a compound of formula I in free form as a base can be prepared from the acid addition salt of the pure trans-form according to the invention in a known manner, and then further acid addition salts can be prepared therefrom. However, it is also possible to recrystallize the salt thus obtained in order to obtain crystalline forms and crystal sizes which would be even more preferred for galenic use. Other solvents and solvent mixtures may also be used, also together with water, such as ethanol-water mixtures.

In a preferred embodiment of the process according to the invention, a crude mixture is used which consists of both the trans (E) and cis (Z) isomers in free form as a base obtained by reaction of a compound of formula II

Me

(II) .NH with a compound of formula III

Z-CH ₂ CH = CH-C 5 -C-C (CH 3) 3 (III) wherein

Z is a cleavage group.

This reaction is carried out analogously to known methods. The compound of formula II is preferably used in the form of an acid addition salt, for example in the form of the hydrochloride, reacted with a compound of formula III under the usual alkaline conditions in the form of a base. The compounds of formula III are present in the form of a mixture of isomers E and Z. It is operated in aqueous solution, preferably under alkaline conditions, for example using aqueous sodium hydroxide. Optionally, an inert organic solvent such as toluene or ethanol is added. The temperature is between room temperature and boiling point and is preferably about 100 ° C. Z represents, for example, a halogen atom, preferably a chlorine or iodine atom, or an organic sulfonyloxy group having 1 to 10 carbon atoms, for example an alkylsulfonyl group having preferably 1 to 4 carbon atoms, preferably mesyloxy, or an alkylphenylsulfonyl group having preferably 7 to 10 carbon atoms, preferably tosyloxy . The substituent Z is in particular a bromine atom.

The separation of cis and trans isomers cannot be carried out or can only be carried out under difficult circumstances, for example by expensive separation and re-conversion, at the stage of the compounds of formula III, since on the one hand these compounds are present in liquid form and on the other hand, they also exhibit thermal instability and other unsuitable physical properties, such as toxicity and excessive reactivity.

The process according to the invention, with respect to the production of the compound of formula I to be used, has a substantial advantage in terms of yields, technical feasibility as well as environmental protection compared to the known process. The process according to the invention can be carried out in detail as described in the following example.

DETAILED DESCRIPTION OF THE INVENTION

Example (E) -N-Methyl-6,6-dimethyl-N- (1-naphthylmethyl) hept-2-en-4-yn-1-ylamine hydrochloride

(a) Production of crude base

To a 1000 L reactor was charged with 200 L of water under a nitrogen atmosphere, then 85.0 kg of N-methylnaphthalene-1-methylamine hydrochloride (cf. J. Am. Chem. Soc. 65 [1943] 1984);

Org. Chem. 12 [1947] 760) and then allowed to flow to the mixture with stirring for 10 minutes with 102 liters of 30% sodium hydroxide at an internal temperature of about 20-30 ° C. As a result of this addition, there is a slight exothermic reaction. The reaction mixture was then heated to reflux (internal temperature about 100-105 ° C). 94.4 kg of 1-bromo-6,6-dimethyl-2-hepten-4-yne are allowed to flow under reflux for 90 minutes (cf. A. Stutz and G. Petrányi, J. Med. Chem. Chem. 27 [1984] 1939) (E / Z ratio of about 3: 1). After a reaction time of 3 hours, the reaction mixture is cooled to an internal temperature of 30 ° C over about 90 minutes. Upon cooling, a slurry may be formed which, upon addition of 565 liters of toluene, is converted into a readily separable biphasic mixture. The mixture is stirred for 10 minutes at 30 ° C (internal temperature), the lower aqueous phase (about 325 liters, pH about 12) is separated, and the upper toluene phase (about 700 liters) is left in the second tank. The lower, aqueous phase is stirred with 115 liters of toluene for 5 minutes, the phases are allowed to separate for about 30 minutes, and the second toluene phase is added to the above second tank. The combined toluene phases are mixed four times with 140 liters of water each for 5 minutes and again allowed to separate for 15 minutes. After separation of the lower, aqueous phases, the upper toluene phase (about 810 liters) is filtered using a filter aid such as Cellflok ^R under low nitrogen pressure, the filter is washed with 25 liters of toluene and the combined filtrates (about 835 liters) are evaporated to a residue. a 630 liter reactor (in portions) (first portion of about 400 liters) at an internal temperature of about 40 ° C and 55 ° C and at a reduced pressure of about 12,000-4,000 Pa over about 5 hours. The distilled toluene is recycled. The liquid residue was degassed (about 4000 Pa, 60 ° C) and cooled to 40 ° C. There was thus obtained N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) hept-2-en-4-yn-1-ylamine as a base (mixture of (E) and (Z) -isomers in ratio of about 3: 1) in the form of a brownish, viscous oil.

₍ pvibliicu

Yield: about 140 kg (containing about 79.3 kg of the trans (E) -isomer,

i 66.5% of theory)

Quality: bromide content: about 100 ppm, less than 2% of the starting product; detectable by thin layer chromatography.

b) Salt formation and separation of isomers

About 50 kg of the base obtained as described in a), which contains 30 kg of the trans (E) -isomer, 10 kg of the cis (Z) -isomer and 10 kg of by-products, impurities and solvent residue, are introduced together with 10 liters of ethyl acetate into of a 400-liter reactor and 205 liters of ethyl acetate are added to the mixture. At 20 ° C (internal temperature) the mixture is stirred until complete dissolution, then the solution is filtered through a 2 μη Pallfilter into a second 400 liter reactor, the temperature is adjusted to 20 C (internal temperature) and the pressure to 0.05 MPa. . Thereafter, 6.2 kg of hydrogen chloride gas is injected into the reactor at an internal temperature of 20-25 ° C. The pressure does not exceed 0.03 MPa overpressure. Upon completion of the addition, the off-gas is passed through an aqueous sodium hydroxide scrubber and then checked with a damp indicator paper.

so that the pH of the suspension is about 2.

The slurry (about 280 liters) is stirred for an additional 4-15 hours at an internal temperature of 20 ° C and then centrifuged and the reactor rinsed with about 5 liters of ethyl acetate. The wet product on the centrifuge is washed with four portions of 80 liters of ethyl acetate and again sprayed at about 1000 rpm (the ethyl acetate filtrates are concentrated and the solvent is returned to the circuit). About 40 kg of wet product are obtained, which is dried for 10 hours at an external temperature of 50 ° C / 6665 Pa and for 5 hours at an external temperature of 60 C / 666 to 13330 Pa. Pure trans (E) -N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) hept-2-en-4-ynyl amine hydrochloride is obtained.

Yield: 29.1 kg of the trans (E) -isomer (i.e., 86.2% of theory).

Quality: thin layer chromatography: about 0.3% of maximum by-products including cis (Z) -isomer.

Content (titration with HCl ₄ ): 100% + 2.0%

Bromide content: 500 ppm

Melting point: 203-205 ° C

Loss on drying: 0.5%

Claims (7)

PATENT CLAIMS A process for separating isomers to obtain (E) -N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) hept-2-en-4-yn-1-ylamine of formula I (I) in free form or of addition salts thereof, characterized in that the crude mixture containing the compound of formula I and the cis (Z) isomer in the free form as a base, is converted in the presence of ethyl acetate or a mixture of C ₁ _ ₄ ester of acetic acid with an alcohol corresponding to the ester to the salt while precipitating the trans (E) -isomer, and then optionally converting the compound of formula I so obtained into its free base or other acid addition salt. Process according to claim 1, characterized in that the reaction is carried out in the presence of ethyl acetate and ethanol. The process according to claim 1, wherein the reaction is carried out in the presence of ethyl acetate. The process according to claim 1, wherein the reaction is carried out using a crude mixture comprising the trans (E) -isomer and the cis (Z) -isomer in a ratio of from 4: 1 to 7: 1.5. The process of claim 1, wherein the reaction is carried out using a crude mixture comprising the trans (E) -isomer and the cis (Z) -isomer in a ratio of 3: 1. The process according to claim 1, wherein the reaction is carried out using a crude mixture containing 70 to 40% (w / w) of the trans (E) -isomer, 15 to 30% (w / w) of cis (Z). and 15 to 30% (w / w) of other impurities or by-products. The process of claim 1, wherein the reaction is carried out using a crude mixture containing 60% (w / w) trans (E) -isomer, 20% (w / w) cis (Z) -isomer and 20% (w / w) of other impurities or by-products.