SI8911369A - New process for preparing n-(1-naphtylmethyl)-heptene amine - Google Patents

Description

New process for the preparation of N- (1-naphthylmethyl) heptenamine *

The invention relates to a novel process for the preparation of (E) -Nmethyl-6,6-dimethyl-N- (1-naphthylmethyl) -hept-2-en-4-yn-1-amine of the formula

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

The compound of formula I and its use as an antifungal agent for the treatment of mycosis caused especially by dermatophytes "are known e.g. from European {presit ¹ 24 587.

In Example 16 of EP 24 587, the aforementioned compound of formula I is specifically described and is said to be prepared according to the procedures a), c) and e) of EP 24 587, analogous to examples 1, and 6 / which are described in detail in EP 24 587, which further clarifies procedures a), c) and e).

According to Examples 1, 3 and 6 in EP 24 587, the product is each obtained as a base and in the form of a mixture consisting of the cis (Z) and trans (E) isomers ·, and from this mixture of isomers a trans (E) compound is obtained by chromatography using quartz gel, each using toluene / ethyl acetate as the eluent, for the processes a) (example 1) and e) (example 6) in the ratio 4/1 and for process c) (example 3) in the ratio 95/5.

According to EP 24 587, the trans (E) isomer is first eluted followed by the cis (Z) isomer. They then convert the base as desired into an acid addition salt.

This method of preparation has the disadvantage that a portion of the undesirable cis-isomer must be included in the chromatography in each case together with any by-products present. Furthermore, it is undesirable, even though chromatography for the preparation of large quantities, that the resulting base solutions for the subsequent salt formation are inappropriate and therefore need to be re-evaporated and the residue redissolved. The thermal load on the base resulting from this is undesirable.

In J.Med. Chem. 27 (1984) 1539-1543 discloses that isomers can also be separated by fractional crystallization of hydrochloride salts, but are necessary to obtain

- 3 purify the trans (E) -isomer two recrystallizations in 2-propanol / diethyl ether. This path is very complex and is done using ether.

Now we have surprisingly found that the difficult chromatographic separation of the bases or the. the adverse recrystallization of the hydrochlorides is absent and can be replaced by a single, single-step salt formation with simultaneous precipitation of the trans (E) -isomer, starting from a mixture of the two isomers in the form of bases. In addition, all the impurities present in the mother liquors of the precipitate remain to produce a very pure product.

The process of the invention consists in forging a crude mixture containing the compound of formula I and its cis (Z) -isomer in free form as a base, simultaneously precipitating the trans (E) -isomer, and optionally subsequently obtaining the compound thus obtained of the Formula I salt is converted to the free base form or to the further acid addition salt.

The crude mixture, which, in addition to the trans (E) - and cis (Z) -isomers, can be metabolized in large proportions, e.g. about 15 to about 30% (w / w) of any further impurities and by-products. The starting material contains e.g. about 15 to about 30% (w / w) of the cis (E) -isomer and about 70 to about 40% (w / w) of the trans (E) -isomer. The trans / cis ratio is about 4: 3 to about 7: 1.5, preferably about 3: 1.

In order to carry out the process of the invention, we work in an organic acid ester or in a mixture of an organic acid ester with further organic solvents.

The ester is preferably an acetic acid ester, e.g. Acetic acid C 1-6 alkylester such as methyl-, ethyl-, n-butyl- or i-butyl ester, in particular acetic acid ethyl ester.

As further organic solvents which can be used in admixture with the above organic acid esters, particularly suitable alcohols are those which are appropriate to the ester, e.g. ethanol together with acetic acid ethyl ester, i-propanol together with acetic acid isopropyl ester, etc., preferably ethanol together with acetic acid ethyl ester.

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

Preferably, salts with mineral acids, especially hydrochloride, are used as salt forms.

Other reaction conditions are analogous to similar known methods. Preferably, it is operated at a temperature from about -25 ° to about 100 ° C, preferably at room temperature from about 20 to 25 ° C.

The process of the invention enables the separation of cis / transisomers by a single operation. Like other than that (

it is advantageous that all impurities remain in the mother liquor in a single precipitate, and thus a very pure product is obtained in the required trans (E) form. Hydrochloride is preferred for this purpose.

Thus, it is surprising that three different effects can be achieved in a single, one-step operation, namely salt formation, isomer separation and purification.

- 5 The starting material is a crude product from the previous step with a given mixture of isomers and any impurities present, e.g. with a trans (E) / cis (Z) ratio of 3: 1 in the form of bases.

The compound of Formula I in free form can be converted into further acid addition salts in a known manner and vice versa. Hydrochloride is preferred. Thus, the pure trans-form acid addition salts of the invention can, in a known manner, be prepared in a free form as a base and further acid addition salts of the compound of formula I. However, the salt so originally obtained can also be recrystallized to produce crystalline forms and granules which can be further used galenically. In addition to the solvents mentioned above, solvents and mixtures of solvents can also be used, including with water, such as e.g. ethanol / water mixtures.

In a preferred embodiment of the process of the invention, a crude mixture consisting of the two trans (E) / cis (Z) isomers in the free form is used as the base obtained by the metabolism of the compound of formula II

Me

with a compound of formula III z-ch ₂ -ch = ch-c = cc (ch ₃ ) ₃

III

- 6 in which Z stands for outgoing group.

Metabolism is done analogously to known methods. The compound of formula II is preferably used in the form of an acid addition salt, e.g. as hydrochloride, but of course it is reacted with a compound of formula III under normally used alkaline conditions as a base. The compounds of formula III act as an E / Z mixture. We work in an aqueous solution, preferably under alkaline conditions, e.g. using sodium hydroxide. Optionally an inert organic solvent is added, e.g. toluene or ethanol. The temperature varies between about room temperature and boiling point, preferably about 100 ° C.

Z means e.g. a halogen, preferably chlorine, bromine or iodine, preferably chlorine or bromine, or an organic sulfonyloxy group of 1 to 10 carbon atoms, e.g. alkylsulphonyloxy having preferably 1 to 4 carbon atoms, preferably mesyloxy, or alkylphenylsulfonyloxy having preferably 7 to 10 carbon atoms, preferably tosyloxy.

Z means especially bromine.

There would be no separation of cis / trans isomers - or only under difficult circumstances, e.g. by demanding derivatization and re-conversion - it can be performed at the stage of the compounds of formula III, because on one side they act as liquids and on the other side exhibit thermal instabilities and further inappropriate physical properties, such as e.g. toxicity and over reactivity.

The process of the invention, which represents a significant advantage in terms of yields, technical scale (Scale Up) and environmental portability in the preparation of the compounds of Formula I used therein, can be detailed as described in the following example.

- 8 EXAMPLE: (E) -N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) -hept-2en-4-ynyl-1-amine hydrochloride

a) Preparation of crude base

To the 1000 l reactor was added under nitrogen 200 l of water, 85.0 kg of N-methyl-naphthalene-1-methylamine hydrochloride were added (J. Am.Chem.Soc. 65/1943/1984; J.Org.Chem. Γ2 / 1947 / 760), and while stirring for 10 minutes at an internal temperature of about 20 ° to 30 ° C, make up to 10 1 30% sodium hydroxide. Addition is only weakly exothermic. The reaction mixture is then heated to reflux (internal temperature about 100 ° C to 105 ° C). Add 94.4 kg of 1-bromo-6,6-dimethyl-2-hepten-4-yne (A. Stiitz and G. Petranyi, J. Med. Chem. 27/1984/1539) over reflux for 90 minutes (mixture E / Z around 3: 1). After the reaction lasts for 3 hours, cool the reaction mixture to an internal temperature of 30 ° C for about 90 minutes. Cooling may result in a suspension which, after the addition of 565 1 toluene, is converted into a separable, 2-phase mixture. The mixture was stirred for an additional 10 minutes at an internal temperature of 30 ° C, separated the lower aqueous phase (about 325 l, pH about 12), and released the upper toluene phase (about 700 l) into another tank. The lower aqueous phase was stirred for 5 minutes with 115 l of toluene, allowing the phases to separate for about 30 minutes, and this second toluene phase was also added to the upper second tank. The combined toluene phases were mixed four times for 5 minutes with 140 liters of water each time and allowed to separate for 15 minutes each time. After separation of the lower aqueous phase, the upper, toluene phase (about 810 l) is filtered using a filter aid, such as e.g.

p

Cellflok, under gentle nitrogen pressure, the filter is washed with 95 l of toluene and the combined filtrates (about 835 l) in a 630 l reactor by ration (first ration about 400 l) at an internal temperature of about 40 ° to 55 ° C and partial vacuum of about 120 to Evaporate 40 mbar for about 5 hours. The distilled toluene is recycled. The liquid residue is degassed (about 40 mbar, 60 ° C) and cooled to 40 ° C. The N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) -hept-2en-4-ynyl-1-amine is obtained as a mixture (mixture of (E) - and (Z) -: isomers about 3: 1 ) as a brown yellow viscous oil.

Yield: about 140 kg (content of about 79.3 kg trans (E) isomer = 66.5% of theory.)

Quality: bromide content of about 100 ppm.

Thin-layer chromatographically demonstrable ¢ 2% of the starting product.

b) Salt formation and isomer separation

About 50 kg of base obtained as described in a) containing 30 kg of trans (E) isomer, 10 kg of cis (Z) isomer and 10 kg of by-products, impurities and residual solvents are added together with 10 l of ethyl ester _t of acetic acid in a 400 l reactor and 205 l of ethyl ester of acetic acid were added. At an internal temperature of 20 ° C, it is stirred until complete dissolution. The filter is then filtered through a 2 µm Pall filter into another 400 l reactor, which is set to an internal temperature of 20 ° C and 0.5 bar of vacuum. Then, at an internal temperature of 20 ° C to 25 ° C, 6.2 kg of hydrogen chloride gas were incubated. The pressure does not rise above 0.3 bar. After the addition is complete, the waste air is passed through an alkaline washer and then checked with water moistened indicator paper to make the pH suspension about 2.

The suspension (about 280 l) was stirred for an additional 4 to 15 hours at an internal temperature of 20 ° C and then centrifuged and the reactor was rinsed with 5 l of ethyl acetate. The wet product in the centrifuge was washed in four portions with 80 l of acetic acid ethyl ester and centrifuged at about 1000 rpm. (ethyl acetate filtrates are evaporated and the solvent is recycled). About 40 kg of wet product is obtained, which is dried for 10 hours at an external temperature of 5O ° C / 66.66 mbar and 5 hours at an external temperature of 6O ° C / 6.66 to 13.33 mbar. Pure trans (E) -N-methyl6,6-dimethyl-N- (1-naphthylmethyl) -hept-2-en-4-ynyl-1-amine hydrochloride is thus obtained.

Yield: 29.1 kg trans (E) -isomer (= 86.2% theory) Quality: Thin layer chromatography:

a maximum of about 0.3% by-products incl. cis (Z) -isomer.

Content (HCIO ^ titration): 100 + 2.0% Bromide content: <500 ppm Melting point: 203-205 ° C

Drying loss: <0.5%.

Claims (11)

PATENT APPLICATIONS A process for the preparation of (E) -N-methyl-6,6-dimethylN- (1-naphthylmethyl) -hept-2-en-4-ynyl-1-amine of formula I tBu in free or acid addition form salts, characterized in that the crude mixture containing the compound of formula I and its cis (Z) -isomer in free form as a base is salified while simultaneously precipitating the trans (E) -isomer and, if desired, the compound of formula I thus obtained. in the form of salts, it is converted into the form of the free base or in the form of a further acid addition salt. Process according to claim 1, characterized in that the reaction is carried out in the presence of an organic acid ester or a mixture of an organic acid ester and further organic solvents. Process according to claim 1, characterized in that the reaction is carried out in the presence of an organic acid ester or a mixture of an organic acid ester and a suitable alcohol. A process according to claim 1, characterized in that the reaction is carried out in the presence of ethyl ester ^! acetic acid and ethanol. A process according to claim 1, characterized in that the reaction is carried out in the presence of acetic acid ethyl ester. Process according to claim 1, characterized in that the reaction is carried out with a crude mixture containing the trans (E) - and cis (Z) -isomer in a ratio of from about 4: 1 to about 7: 1.5. Process according to claim 1, characterized in that the reaction is carried out with a crude mixture containing the trans (E) - and cis (Z) -isomer in a ratio of about 3: 1. Process according to claim 1, characterized in that the reaction is carried out with a crude mixture containing about 70 to about 40% (w / w) trans (E) -isomer, about 15 to about 30% (w / w) by weight) of the cis (Z) isomer and about 15 and up to about 30% (w / w) of further impurities or by-products. Process according to claim 1, characterized in that the reaction is carried out with a crude mixture containing about 60% (w / w) trans (E) -isomer, about 20% (w / w) cis (Z ) isomer and about 20% (w / w) of further impurities or by-products. A process according to any one of claims 1 to 9, characterized in that the compound of formula II Me II 13 III is reacted with a compound of formula III z-ch ₂ -ch = ch-c = cc (ch ₃ ) ₃ in which Z stands for the leaving group and then a crude mixture is obtained containing the compound of formula I and its cis (Z The free-form isomer as a base is salified while simultaneously precipitating the trans (E) -isomer and, if desired, then the salt of formula I thus obtained is converted into the free base form or to a further acid addition salt.