SK283454B6 - Process for the production of terbinafine and intermediate for its preparation, (E)-N-(3-chloro-2-propenyl)-N-methyl- 1-naphtalenemethylamine tosylate salt E-isomer - Google Patents

Abstract

Disclosed is a process for the production of pharmaceutical substance terbinafine, i. e. (E)-N-(6,6-dimethyl-2-heptene- 4-inyl)-N-methyl-naphtalenemethylamine through the novel intermediate the pure N-(3-chloro-2-propenyl)-N-methyl- 1-naphtalenemethylamine tosylate acid E-isomer, which is obtained by novel dividing of the mixture of E and Z isomers. The said salt is used as an initial substance for preparation of pharmaceutical substance terbinafine in human medicine.

Description

Technical field

The present invention relates to a process for the preparation of (R) - N - (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine (terbinafine) of formula (V), respectively. its hydrochloride.

Scheme 1.

Furthermore, the present invention relates to a novel intermediate of the E-isomer of the tosylate salt of N '- (3-chloro-2-propenyl) - N' -methyl-1-naphthalenemethylamine of formula (III) used in the preparation of terbinafine

and a novel method for separating the E and Z isomers of N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine to give the pure E-isomer of the tosylate salt N - (3-chloro-2-propenyl) N-methyl-1-naphthalenemethylamines of formula (III).

In another manner (J. Med. Chem., 27, 1539 (1984) and J. Med. Chem., 36, 2820 (1993), from which European Patent Specification No. 24587 (Sandoz) is based), 6,6-dimethylheptene is prepared. -4-ynyl-1-bromide in a ratio of E: Z = 3: 1, which is subsequently reacted with N-methyl-1-naphthalenemethylamine to form an isomeric mixture (E / Z = 3: 1) of terbinafine. The desired E-isomer is isolated by silica gel chromatography (Scheme 2).

Later, Sandoz described a process for separating the E and Z isomers of terbinafine via its addition salt with an inorganic acid, especially hydrochloric acid in Czech patent 280412 and the analogous Slovak patent 279896. A mixture of E and Z isomers (about 3.1) of terbinafine hydrochloride in ethyl acetate only pure E isomer. In this way, Sandoz is currently industrially preparing terbinafine hydrochloride.

Scheme 2.

BACKGROUND OF THE INVENTION

Terbinafine belongs to the group of allylamine fungistatic antifungals with a relatively broad spectrum including dermatophyses, yeasts, dimorphic fungi and aspergils. The mechanism of action is to inhibit the synthesis of ergosterol independently of cytochrome P-450 (inhibits squalene epoxidase). It has favorable pharmacokinetic properties (long half-life) and very good penetration into adipose tissue (skin and nails). Its preparation is described in patent application and publication: A. Stuetz, Eur. pat. Appl. 24,587 (1981 Sandoz), A. Stuetz, G. Petranyi et al., J. Med. Chem. 27.1539 (1984).

As a specific inhibitor of squalene epoxidase, a key enzyme in ergosterol biosynthesis in fungi, is described in G. Petranyi et al., Science, 224, 1239 (1984) and N. S. Ryder, Animicrob. Ag. Chemother. 27, 252 (1985).

Terbinafine can be prepared in various ways.

The first method (J. Med. Chem., 27, 1539 (1984), Tetrahedron Lett., 3145 (1979) and Tetrahedron, 41, 5685 (1985)) describes the partial reduction of 1,3-diinyl amines with diisobutylaluminium hydride with good selective and high yield (scheme 1). 1,3-Diinyl amines are obtained by reaction with acetylene propargyl amine derivative and bromoacetylene in the presence of copper (I) chloride, or by Manich reaction of a secondary amine, 1,3-diin compound and paraformaldehyde. This method cannot be used on an industrial scale.

Tetrahedron, 47, 4591 (1991), JP 257310 (Banyu), ES 8605761 (Inke, SA) and Tetrahedron Lett., 37, 56 (1996) describe in various ways the preparation of (E) -6,6-dimethylhepten-4-ynyl. 1-methylamine (Scheme 3), which in the next step reacts with chloromethylnaphthalene.

Scheme 3.

Canadian Patent 1 157023 relates to a method for preparing terbinafine by reductive amination of naphthylamine with (E) -6,6-dimethylhept-2-en-4-yn-1-al in the presence of formaldehyde and sodium borohydride (Scheme 4).

Scheme 4.

b, HCHO MaBH, and NaBH,

In New Zealand Patent 280065, starting with 2,3-epoxipropane or with (3-alkyl-1-propargyl) triphenylphosphonium bromide (Scheme 5). In the first case, N'-methyl-1-naphthalenemethylamine reacts with epichlorohydrin in a basic medium to form N ¹ -methyl-1-naphthylmethyl-2,3-epoxypropane. The resulting epoxide is further opened with lithium tert-butylacetylene in the presence of boron trifluoride etherate to give the secondary alcohol. The free hydroxy group is protected by a readily leaving group such as methanesulfonate or tosylate. In the last step, the easily leaving group is removed with a strong base of 1,8-diazabicyclo [5.4.0] undecan-7-ene to form a mixture of terbinafine isomers.

In the second process, N-methyl-1-naphthalenemethylamine is reacted with bromoacetaldehyde in a basic medium to form an amine acetal which is hydrolyzed in an acidic medium to form an aldehyde from which a Wittig reaction is prepared to form an isomeric mixture of terbinafine. An isomeric mixture of terbinafine is prepared by both methods, which is not desired.

Scheme 5.

In Tetrahedron Leti., 29, 1509 (1988), the preparation begins with the lithium salt of N'-methyl-1-naphthalenemethylamine, which is further reacted with propargyl bromide to give the propargyl amine derivative. The resulting product undergoes hydro-zirconization with zirconocene chlorohydride and upon addition of iodine there is formed a (E) -3-iodalyl amine which is reacted with the zinc salt of 3,3-dimethyl-1-butine using a divalent palladium catalyst (Scheme 6). This preparation is commercially demanding and especially expensive.

Scheme 6.

The simplest preparation utilizes the reaction of (E) -1,3-dichloropropene with N-methyl-1-naphthalenemethylamine and the resulting product (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine is further reacted with tert-butylacetylene in the presence of palladium catalyst, base and CuI (Scheme 7).

The preparation of a mixture of E and Z (9: 1) N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine isomers is described in detail in patents EP 0421302 A2 and US 5231183 (JP 257310/89), where Starting from a mixture of E and Z isomers of 1,3-dichloropropene and subsequent chromatographic purification over a silica gel column, the pure E isomer was obtained from which the pure E-isomer of terbinafine was prepared in the second step.

This method of preparation has the disadvantage of purifying the prepared reaction isomeric mixture by chromatography. Chromatography is unsuitable for the preparation of larger quantities in terms of cost and purity of the product. The base solutions obtained by chromatography are also unsuitable for the preparation of terbinafine base and must be re-evaporated and the residue must be redissolved. Such a thermal load of the (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine base that is present is undesirable.

Scheme 7.

Sandoz also reported a simplified preparation of terbinafine by the same synthetic route, but using pure (E) -1,3- to prepare (E ') - X- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine dichloropropene (Chimia 50, No. 4, 154, (1996)).

The preparation of (E) - N - (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine is also described in Tetrahedron Leti., 37, 57, (1996), which is also based on isomeric pure ( (R) -1,3-dichloropropene, which is a very expensive and unavailable starting material.

SUMMARY OF THE INVENTION

The above-mentioned drawbacks of terbinafine preparation are largely overcome by the terbinafine preparation process of the present invention which utilizes the separation of the E and Z mixture of the geometric isomers of N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine via the addition salt of ara -toulenesulfonic acid (compound III), of which the very pure E isomer is precipitated from a solution of ethyl acetate in the form of crystals, in which, in a second step, the crystalline tosylate is reacted with 3,3-dimethyl-1-butine (compound IV) using palladium catalyst an organic base, preferably piperidine and triethylamine, to form terbinafine ((E) - N - (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine) according to reaction scheme (8).

Scheme 8.

^C ^ ^Cl to a mixture of E and Z

2. p-TSA

EtOAc

1. K ₂ CO ₃ , 10% Na 1 acetone

(III) (H (H) CH ₃ N R

(Hl)

Piperidine Et ₃ N

Cul, Pd ² *

(IN)

A key step in the process is the preparation of the pure E isomer of the tosylate salt of the N- (3-chloro-2-propenyl) N-methyl-1-naphthalenemethylamine of formula (III), which is isolated in crystalline form from a mixture of E and Z isomers in ethyl acetate solution.

We have surprisingly found that the expensive chromatographic separation of the isomeric mixture of the base A ¹ - (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine mentioned in JP 257310/98 or the use of a very expensive pure E isomer In its preparation, 1,3-dichloropropene can be completely replaced by a one-step, one-step formation of the para-toluenesulfonic acid addition salt with the precipitation of only the pure trans (E) -isomer of the salt using a mixture of the two isomers as a base. In addition, all impurities present remain after precipitation in the mother liquor to give a very pure product.

Our proposed method for obtaining the pure E-isomer of N- (3-chloro-2-propenyl) - N -methyl-1-naphthalenemethylamine tosylate salt will ultimately make the preparation of terbinafine more commercially efficient.

The process for the preparation of the very pure E isomer of the (E ') - N- (3-chloro-2-propenyl) -N'-methyl-1-naphthalenemethylamine tosylate salt according to the present invention is characterized in that the crude mixture containing both isomers in the form of a base, as well as other reaction impurities, is converted in the presence of a C ₁₄ acetic acid ester or a mixture of C ₁₄ . ₄ ester of an acetic acid with an alcohol of the corresponding ester, to the addition salt while precipitating the tosylate salt of the trans (E) isomer.

The preparation may be based on a crude mixture which, in addition to the trans (E) - and cis (Z) isomers, also contains high proportions of other impurities or by-products (e.g. 5 to 40% by weight).

In the process, acetic esters such as methyl, ethyl, isopropyl, n-butyl or isobutyl ester are used, with ethyl acetate being most preferred. Mixtures of the above-mentioned acetic acid esters with alcohols corresponding to the respective ester can also be used. Such as methyl acetate together with methanol or isopropyl acetate with isopropanol, etc. Most preferably, ethanol is used together with ethyl acetate. It is also possible to use a combination of isopropanol with isohexane, which is a suitable mixture for further purification of the addition salt.

The salt form used is exclusively a salt with an organic acid, in particular para-toluenesulfonic acid or methanesulfonic acid.

EP 0421302 A2 and US 5231183 disclose addition salts of N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine with inorganic acids such as hydrochloride, sulfate or nitrate, but which cannot be prepared because 7V - (3-Chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine decomposes into polymeric products in the presence of inorganic acids.

The reaction conditions are analogous to those known in the art. The reaction is carried out at a temperature of from 20 to 100 ° C, but most preferably at a temperature of from 50 to 80 ° C.

The process according to the invention allows the separation of the cis / / trans isomer mixture in one operating step. It has proven to be advantageous that all impurities remain in the mother liquor in a single precipitation, thereby obtaining a very pure product in the desired trans (E) form. It is preferred to use a tosylate for this purpose.

This way we will achieve three effects:

(a) salt preparation;

b) separation of geometric isomers,

(c) purification of the crude mixture.

In the preparation of the pure E isomer of the N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt (compound III), starting from a crude mixture consisting of both the trans (E) and cis (Z) isomers in free form as the base obtained by the reaction of <RTI ID = 0.0> N-methyl-1-naphthalenemethylamine </RTI> of formula (I)

with a mixture of E and Z geometric isomers of 1,3-dichloropropene of formula (II).

d (II)

This reaction is carried out analogously to known methods. The compound of formula (I) is used as the free base or in the form of an acid addition salt, for example in the form of the hydrochloride.

The compound of formula (II) (1,3-dichloropropene) is present in the reaction in the form of the pure E isomer, or a mixture of both isomers in E: Z ratios of from 95: 5 (w / w) to 45: 55 (w / w) to the detriment of the E isomer, which is a cheap and commercially available mixture of 1,3-dichloropropene.

The reaction is carried out under alkaline conditions of sodium carbonate, potassium carbonate, sodium bicarbonate or potassium in the presence of a catalyst.

The reaction catalyst is sodium or potassium iodide. The amount of catalyst used is in the range of from 1 to 10 mol%, with 10 mol% being most preferred. Without the use of a catalyst, the reaction proceeds with only low conversion.

Suitable solvents are ketones such as acetone, ethyl methyl ketone or methyl isobutyl ketone.

The compound of formula (III) can be isolated and purified by conventional techniques, such as filtration and optionally further crystallization, which is carried out in a mixture of isopropanol and isohexane. By isohexane is meant a mixture of branched and unbranched alkanes with a boiling point of from 50 to 80 ° C.

The pure F. isomer of the (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt is used directly in the preparation of the very pure E isomer of the (E) -N- (6,6-dimethyl) -2-hepten-4-ynyl) -N'-methyl-1-naphthalenemethylamine (terbinafine).

This involves coupling of the tosylate salt of (E) -, N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine of formula (III),

with 3,3-dimethyl-1-butyne of formula (IV),

CH ₃

H, (CH ₃ CH ₃ (IV) using palladium catalysis in an organic amine and the addition of CuI.

Similar types of palladium catalyzed cross-capling reactions are described in review articles: Tetrahedron Lett., 32.6109, (1991), Tetrahedron Lett., 34, 6403, (1993), Tetrahedron, 50, 5335, (1994) and Tetrahedron Lett., 37, 57 (1996).

The following types of palladium catalysts are used in the reaction: tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride and bis (benzonitrile) palladium chloride, with bis (benzonitrile) palladium chloride being preferred. The amount of palladium catalyst used ranges from 0.1 to 5 mol%.

Piperidine and triethylamine are used alone as organic amines, alone or in combination with each other in ratios from 1: 1 to 5: 1 in favor of piperidine.

Suitable solvents include alcohols such as ethanol, methanol or isopropanol, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, chlorinated solvents such as chloroform, dichloromethane and 1,2-dichloroethane or other solvents such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide and dimethylsulfoxide. The organic amines mentioned may also be a solvent.

The reaction temperature is usually from -5 ° C to room temperature and the reaction time from 30 min. up to 24 hours, depending on the amount of palladium catalyst used. The amount of CuI used is from 0.1% to 10% by mole.

The terbinafine prepared can be isolated and purified by conventional techniques such as extraction, filtration and crystallization.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of (E) -N- (3-Chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt

To a solution of 5 g (24.1 mmol) of Λ'-methyl-naphthalenemethylamine hydrochloride in 30 ml of ethyl methyl ketone was added K ₂ CO ₃ powder (7.6 g, 55.4 mmol), NaI (0.18) at room temperature. g, 12 mmol) and 1,3-dichloropropene (E: Z = 3: 1 ratio) (3.2 g, 28.9 mmol) followed by refluxing the mixture with stirring for 7 hours. After suctioning off the inorganic salts, the filtrate is concentrated to dryness in vacuo. The residue was dissolved in 35 mL of ethyl acetate at 50 ° C. Then p-toluenesulfonic acid monohydrate (4.6 g, 24.1 mmol) was added slowly with stirring. The mixture was stirred at room temperature for 1 hour, during which a white crystalline solid precipitated out of the mixture. The suspension was then stirred at 0-5 ° C for 2 hours. The precipitated crystals are filtered off with suction and washed with 10 ml of cold ethyl acetate. 5.4 g (60%) of the E isomer of the tosylate N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine are obtained.

Isomeric HPLC purity: 98.5% m.p. 154-156 ° C.

IR (KBr) cm ^-1 : 3050, 2700, 1640, 1470, 1440, 1210, 1160, 1000,795,680,560 1 HNMR (200 Hz, DMSO) δ: 2.29 (3H, CH ₃ s), 2.68 ( 3H, CH ₃ N, d, 4.6 Hz), 4.00 (2H, CH ₂ N, m, 4.6 Hz), 4.88 (2H, CH ₂ N, m, 8 Hz), 6, 30 (1H, CH, dt, 8 Hz, 13.3 Hz), 6.82 (1H, CH, d, 13.2 Hz), 7.10-8.31 (11H, CH3, m), 9 , 69 (11 H, SO ₃ H, s)

Example 2

Preparation of (E) -N- (3-Chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt

To a solution of 5 g (24.1 mmol) of N-methyl-naphthalenemethylamine hydrochloride in 30 ml of acetone is added at room temperature powdered NaHCO ₃ (4.6 g, 55.4 mmol), KI (0.4 g, 2, 41 mmol) and 1,3-dichloropropene (Nematocide, ratio E: Z - 45: 55) (3.2 g, 28.9 mmol). The mixture was refluxed for 15 hours with stirring. After suctioning off the inorganic salts, the filtrate is concentrated to dryness in vacuo. The residue was dissolved in 15 mL of ethyl acetate and 5 mL of ethanol at 50 ° C. Then, p-toluenesulfonic acid monohydrate (4.6 g, 24.1 mmol) was added slowly with stirring, and the mixture was stirred at room temperature for 1 hour, during which a white crystalline solid precipitated out of the mixture. The suspension was then stirred at 0-5 ° C for 1 hour. The precipitated crystals are filtered off with suction and washed with 10 ml of cold ethyl acetate. 3.1 g (34.4%) of the E isomer of the tosylate N - (3-chloro-2-propenyl) - N -methyl-1-naphthalenemethylamine are obtained.

Isomeric HPLC purity: 97.1% m.p. 153-156 ° C.

Example 3

Preparation of (E) -N- (3-Chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt

To a solution of 5 g (24.1 mmol) of N'-methyl-naphthalenemethylamine hydrochloride in 30 ml of methyl isobutyl ketone is added at room temperature powdered Na ₂ CO ₃ (5.8 g, 55.4 mmol), NaI (0.4 g). g, 2.41 mmol) and 1,3-dichloropropene (E: Z-9: 1 ratio) (3.2 g, 28.9 mmol) followed by refluxing the mixture for 10 hours with stirring. After suctioning off the inorganic salts, the filtrate is concentrated to dryness in vacuo. The residue was dissolved in 40 mL of isopropyl acetate at 70 ° C. Then p-toluenesulfonic acid monohydrate (4.6 g, 24.1 mmol) was added slowly with stirring. The mixture was stirred at room temperature for 1 hour, during which a white crystalline solid precipitated out of the mixture. The suspension was then stirred at 5 ° C for about 2 hours. The precipitated crystals are filtered off with suction and washed with 10 ml of cold ethyl acetate. 7.1 g (79%) of the E isomer of the N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate are obtained.

Isomeric HPLC purity: 99.4% m.p. 156-157 ° C.

Example 4

Preparation of (E) -N- (3-Chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt

To a 2-liter three-necked round-bottom flask equipped with a reflux condenser and a thermometer was charged N-methylnaphlanene methylamine hydrochloride (1057 g, 6.172 mol), powdered K ₂ CO ₃ (938 g, 6.789 mol), NaI (92.5 g, 0.617 mol) and acetone (5000 mL). 1,3-Dichloropropene (E: Z-86: 11 ratio) (753.4 g, 6.789 mol) was then added dropwise to the solution at room temperature, followed by refluxing with stirring for 5 hours. After the inorganic salts are filtered off with suction, the filtrate is vacuum-dried. The residue was dissolved in dichloromethane (1000 mL) and then filtered through a pad of Al ₂ O ₃ (300 g), activated carbon (200 g) and again Al ₂ O ₃ (300 g), which was further washed with dichloromethane (2000 mL). After concentration of the combined dichloromethane solutions, the residue is dissolved in 3000 ml of ethyl acetate and heated to 50 ° C. Then, under stirring, p-toluenesulfonic acid monohydrate (1174.1 g, 6.172 mol) dissolved in ethyl acetate (1000 mL) (solution temperature 60 ° C) is slowly added dropwise over 5 min. The mixture is stirred for about 1 hour at room temperature, during which a white crystalline solid precipitates from the mixture. The suspension was then stirred at 0-5 ° C for three hours. The precipitated crystals are filtered off with suction and washed with 500 ml of cold ethyl acetate. 1811 g (70.2%) of pure E isomer of N- (3-chloro-2-propenyl) - N -methyl-1-naphthalenemethylamine tosylate is obtained. Isomeric HPLC purity: 99.8% by weight.

Melting point: 156-158 ° C.

Example 5

Preparation of (E) -N- (6,6-Dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine hydrochloride (Terbinafine)

To a mixture of 14 mL of piperidine and 20 mL of triethylamine is added the (E) - N - (3-chloro-2-propenyl) - N -methyl-1-naphthalenemethylamine tosylate salt (10 g, 24 mmol), CuI (0.046 g, 0). , 24 mmol) and bis (benzonitrile) palladium chloride (0.046 g, 0.11 mmol). The mixture was cooled to 5-10 ° C with stirring, followed by the careful addition of 3,3-dimethyl-1-butyne (2.4 g, 28.8 mmol). The mixture was stirred at room temperature for 15 hours. The precipitated salt is then filtered off, washed with 10 ml of dichloromethane and the filtrate is concentrated under vacuum at a bath temperature of 60-70 ° C. The residue is dissolved in 40 ml of isohexane and extracted with 4 x 20 ml of 1N sodium hydroxide and 10 ml of water. Isohexane layer was filtered through a layer of A1 ₂ O _3, which was which was washed with 20 ml of isohexane. The filtrate is concentrated to dryness under vacuum at a bath temperature of 60 ° C. The residue was dissolved in 20 ml of isopropanol and then added dropwise at 5 ° C to a 10% solution of hydrogen chloride in isopropanol (15 ml). After complete addition, 30 ml of isohexane was added and the solution was allowed to stir at 0-5 ° C for two hours. The precipitated white crystalline solid is filtered off with suction, washed with 10 ml of isohexane and dried. There was thus obtained terbinafine hydrochloride (6.4 g, 82%).

Mp: 206-207 ° C HPLC: 98.7% by weight of IR (KBr) ^cm-1: 2971,2400,1465,1400,1360,955,780 HNMR (200 Hz, _CDCl3) δ: 1.26 (9 H , 3xCH _3, s), 2.63 (3H, CH ₃ N, s), 3.74 (2H, CH ₂ N, d, 8 Hz), 4.62 (2H, CH ₂ N, p), 6 14 (1H, CH, d, 15Hz), 6.38 (1H, CH, dt, 15Hz, 8Hz), 7.30-8.31 (7H, CH3).

Example 6

Preparation of (E) -N- (6,6-Dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine hydrochloride (Terbinafine)

To a mixture of 14 mL of piperidine and 10 mL of ethanol is added the (E) - N - (3-chloro-2-propenyl) -, N -methyl-1-naphthalenemethylamine tosylate salt (10 g, 24 mmol), Cul (0.46) g, 2.4 mmol) and bis (triphenylphosphine) palladium chloride (0.84 g, 1.2 mmol). The mixture was cooled to 5 ° C with stirring, followed by the careful addition of 3,3-dimethyl-1-butyne (2.4 g, 28.8 mmol). The mixture was stirred at room temperature for 5 hours. The precipitated salt is then filtered off, washed with 10 ml of isohexane and the filtrate is concentrated under vacuum at a bath temperature of 60-70 ° C. The residue is dissolved in 40 ml of isohexane and extracted with 4 x 20 ml of 1N sodium hydroxide and 10 ml of water. Isohexane layer was filtered through a layer of A1 ₂ O _3, which was which was washed with 20 ml of isohexane. The filtrate is concentrated to dryness under vacuum at a bath temperature of 60 ° C. The residue was dissolved in 20 ml of isopropanol and then added dropwise at 5 ° C to a 10% solution of hydrogen chloride in isopropanol (15 ml). After complete addition, 30 ml of isohexane was added and the solution was allowed to stir at 0 ° C for two hours. The precipitated white crystalline solid is filtered off with suction, washed with 10 ml of isohexane and dried. 5.9 g (76%) of terbinafine hydrochloride are thus obtained.

Mp .: 209-211 ° C. HPLC: 99.1%

Example 7

Preparation of (E) -N- (6,6-Dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine hydrochloride (Terbinafine)

To a mixture of 10 mL triethylamine and 15 mL DMSO was added the (E) - N - (3-chloro-2-propenyl) - N -methyl-1-naphthalenemethylamine tosylate salt (10 g, 24 mmol), Cul (0.46) g, 0.24 mmol) and tetrakis (triphenylphosphine) palladium (1.4 g, 1.2 mmol). The mixture was cooled to 10 ° C with stirring, and 3,3-dimethyl-1-butyne (2.4 g, 28.8 mmol) was then added. The mixture was stirred at room temperature for 15 hours. The mixture was poured into 50 ml of water and extracted 3 times with 20 ml of diethyl ether. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was dissolved in 20 ml of isopropanol and then added dropwise at 10 ° C to a 10% solution of hydrogen in isopropanol (15 ml). After complete addition, 30 ml of diethyl ether was added and the solution was allowed to stir at 0-5 ° C for two hours. The precipitated white crystalline solid is filtered off with suction, washed with 10 ml of diethyl ether and dried. There was thus obtained terbinafine hydrochloride (4.3 g, 55%). Melting point: 205 - 207 ° C HPLC: 98.6% by weight

Example 8

Preparation of (E) -N- (6,6-Dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine hydrochloride (Terbinafine)

To a mixture of 13 mL of triethylamine and 14 mL of piperidine was added the (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt (10 g, 24 mmol), Cul (0.46 g). , 2.4 mmol) and bis (benzonitrile) palladium chloride (0.46 g, 0.12 mmol). The mixture was cooled to 10 ° C with stirring and 3,3-dimethyl-1-butyne (2.4 g, 28.8 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture is poured into 70 ml of water and extracted 3 times with 20 ml of diethyl ether. The organic layer was washed with brine, dried over MgSO ₄ , filtered, and concentrated to dryness in vacuo. The residue was dissolved in 20 ml of isopropanol and then added dropwise at 10 ° C to a 10% solution of hydrogen in isopropanol (15 ml). After complete addition, 30 ml of diethyl ether was added and the solution was allowed to stir at 5 ° C for two hours. The precipitated white crystalline solid is filtered off with suction, washed with 10 ml of diethyl ether and dried. There was thus obtained terbinafine hydrochloride (7.2 g, 92%). Melting point: 205 - 207 ° C HPLC: 98.3% by weight

Example 9

Preparation of (E) -N- (6,6-Dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine hydrochloride (Terbinafine)

Into a 15 liter duplicator kettle was charged the (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt (2000 g, 4.785 mol), CuI (9.11 g, 0, Bis (benzonitrile) palladium chloride (9.18 g, 0.0239 mol), piperidine (2843 mL, 28.7 mol) and triethylamine (1327 mL, 9.570 mol). The mixture was cooled to 5-10 ° C with stirring, and then 3,3-dimethyl-1-butyne (472 g, 5.742 mol) was carefully added dropwise and the kettle sealed well. The mixture was stirred at room temperature for 15 hours. The precipitated salt is then filtered off, washed with 300 ml of piperidine, and the filtrate is concentrated in vacuo at a bath temperature of 60-70 ° C. The residue was dissolved in 4000 ml of isohexane and filtered through a 3 cm pad of A1 ₂ O ₃ (100 g) and the filtrate preextrahuje 4 x 600 ml IN NaOH, followed by 1000 ml of water. The isohexane layer is filtered through a layer consisting of Al ₂ O ₃ (100 g), activated carbon (100 g) and again Al ₂ O ₃ (100 g) and washed with 500 ml of isohexane. The filtrate is concentrated to dryness on an RVO at a bath temperature of 60 ° C. The residue was dissolved in 500 ml of isopropanol and then added dropwise at 5 ° C to a 10% solution of hydrogen chloride in isopropanol (2000 ml). After complete addition, 2000 ml of isohexane was added and the solution was allowed to stir at 0-5 ° C for two hours. The precipitated white crystalline solid is filtered off with suction, washed with 200 ml of isohexane and dried. 1428 g (91%) of terbinafine hydrochloride are thus obtained.

Mp .: 205-208 ° C

HPLC: 99.7%

Industrial usability

The (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine tosylate salt is used as a starting material in the preparation of the pharmaceutical substance terbinafine used in human medicine.

Process according to claims 6 and 7, characterized in that the reaction is further carried out in the presence of a monovalent copper halide, preferably copper (I) iodide.

Process according to claim 1, characterized in that organic amines and / or mixtures thereof, preferably piperidine and / or triethylamine, are used as the organic base.

The intermediate for the preparation of (E) - N - (6,6-dimethyl-2-hepten-4-ynyl) -? - methyl-1-naphthalenemethylamine (terbinafine) according to claim 1, which is the tosylate salt (E) - N - (3-chloro-2-propenyl) - N -methyl-1-naphthalenemethylamine.

Claims (7)

PATENT CLAIMS L A process for producing terbinafine, i. j. (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -7H-methyl-1-naphthalene-methylamine, from N-methyl-1-naphthalenemethylamine and a mixture of (E), (Z) isomers 1, 3-dichloropropene, characterized in that the resulting base, a mixture of (E), (Z) isomers of N - (3-chloro-2-propenyl) -2H-methyl-1-naphthalenemethylamine, is reacted with para-toluenesulfonic acid in from the reaction mixture, in pure form, the pure E isomer of the N- (3-chloro-2-propenyl) -1-N-methyl-1-naphthalenemethylamine tosylate salt is obtained in crystalline form from the reaction mixture, which is subsequently reacted with 3 With 3-dimethyl-1-butyne in the presence of a catalyst and a base to give (E) - N - (6,6-dimethyl-2-hepten-4-ynyl) - N -methyl-1-naphthalenemethylamine (terbinafine) ). Process according to claim 1, characterized in that the terbinafine base formed is converted to the hydrochloride. The process according to claim 1, wherein the organic solvent used in the preparation of the tosylate salt is an acetic acid ester comprising methyl, ethyl, isopropyl, n-butyl, isobutyl or a mixture of said acetic esters with alcohols having a carbon number of carbon atoms. to C ₄ . The process according to claim 3, wherein the organic solvent is ethyl acetate. A process according to claim 1, characterized in that the (E) isomer in the mixture of (E), (Z) isomers of the N '- (3-chloro-2-propenyl) - N -methyl-1-naphthalenemethylamine used in the preparation the tosylate salt is greater than 45% by weight. Process according to claim 1, characterized in that the catalyst used is a palladium catalyst (Pd (0), Pd (II)), preferably tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride and bis (benzonitrile) palladium chloride most preferably bis (benzonitrile) palladium chloride. The process according to claim 6, characterized in that the amount of the catalyst used is from 0.1% to 5 mol%, preferably 0.5 mol%.