SK5202000A3 - Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4- inyl)-n-methyl-1-naphthalenemethylamine (terbinaphin) - Google Patents

Abstract

The method for the preparation of <i>(E)-N</i>-(6,6-dimethyl-2-hepten-4-ynyl)-<i>N</i>-methyl-1-naphthalenemethanamine (terbinafine) from N-methyl-1-naphthalenemethanamine and <i>(E)</i>-1,3-dichloropropene and by subsequent reaction with 3,3-dimethylbut-1-yne characterized in that the whole reaction sequence is carried out without any isolation of intermediates. All sequential reactions are carried out in the solvent system common for the whole reaction sequence and inert to the reactants and intermediates present in the process. The method according to the present invention may also include additional purification steps.

Description

Title of the invention:

Method for the preparation of (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene-methylamine (terbinafine)

Inventors of the invention: KAKALÍK IVAN, Ing., ŠENKVICE

OREMUS VLADIMIR, Ing. CSc., BRATISLAVA ŠMAHOVSKÝ VENDEL, Ing., PEZINOK ŠNUPÁREK VLADISLAV, Ing., RIŠŇOVCE VANDÁK DUŠAN, Ing. ., BLUE

Reported

PV

Method for the preparation of (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene-methylamine (terbinafine)

Technical field:

The present invention relates to a process for the preparation of (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine (terbinafine) of formula V, wherein the two-step preparation process is free of any isolation or . purification of intermediates (so-called one pot reaction). Further, a method of optimum cleaning operations resulting in pharmaceutically useful terbinafine hydrochloride is described.

BACKGROUND OF THE INVENTION;

Terbinafine belongs to the group of allylamine fungistatic antifungals. It blocks the synthesis of ergosterol by inhibiting squalene epoxidase, has a fungicidal effect on dermatophytes, yeasts, dimorphic fungi and micromicetes. It has a broad antifungal spectrum. It is also available for oral administration. It has advantageous pharmacokinetic properties (long half-life) and very good penetration into adipose tissue (skin and nails). Its preparation is described in the patent application and subsequently in 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, Antimicrob. Ag. Chemother. 27,252 (1985).

The preparation of terbinafine from N-methyl-1-naphthalenemethylamine is described in several publications. Patent EP 24587 and subsequently J. Med. Chem., 2Π, 1539 (1984) and J. Med. Chem., 36, 2820 (1993) disclose the preparation of terbinafine as follows: first, 6,6-dimethylhepten-4-ynyl-bromide is prepared ( 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 1).

Later, Sandoz described a process for separating the E and Z isomers of terbinafine through its addition salt with an inorganic acid, especially hydrochloric acid in Swiss patent CH 678527. Starting from a mixture of E and Z isomers (3: 1) of terbinafine hydrochloride in ethyl acetate only pure E isomer.

Scheme 1

Canadian Patent CA 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 2).

Scheme 2

In New Zealand Patent NZ 280065, it is based on 2,3-epoxipropane or with (3alkyl-1-propargyl) triphenylphosphonium bromide (Scheme 3). In the first case, N-methyl-1-naphthalenemethylamine reacts with epichlorohydrin in a basic medium to form N-methyl-1-naphthylmethyl-2,3-epoxipropane. 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 a second process, V-methyl-1-naphthalenemethylamine is reacted with bromoacetaldehyde in a dialkyl acetal in a basic medium to form an amine acetal which is hydrolyzed in an acidic environment to form an aldehyde from which a Wittig reaction is prepared to form an isomeric terbinafine mixture. An isomeric mixture of terbinafine is prepared by both methods. which is not desirable.

Scheme 3

MsCl / Et 3 N 2.DBU / tol

In Tetrahedron Lett., 29, 1509 (1988), the preparation begins with the lithium salt of N-methyl-1-naphthalenemethylamine, which is further reacted with propargyl bromide to form 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 4).

Scheme 4

The simplest preparation utilizes the reaction of (E) -1,3-dichloropropene with N-methyl-1-naphthalenemethylamine and the resulting product (N, N-(3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine further reacts with tert-butylacetylene in the presence of palladium). catalyst, base and CuI (Scheme 5).

The preparation of a mixture of E and Z (9: 1) isomers of N - (3-chloro-2-propenyl) - N -methyl-lnaphthalenemethylamine is described in detail in patents EP 0421302 and US 5231183 (JP).

257310/89), starting from a mixture of the E and Z isomers of 1,3-dichloropropene and subsequent chromatographic purification over a silica gel column, afforded the pure E isomer from which the pure E-isomer of terbinafine was prepared in the second step.

Scheme 5

Sandoz has also reported a simplified preparation of terbinafine by the same synthetic route, but using pure (E) -1,3,3- (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 Lett., 37, 57, (1996), where also isomerically pure ( - 1,3-dichloropropene.

SUMMARY OF THE INVENTION

In the following, the process of the invention will be described. Scheme 6 describes the reaction sequence in the preparation of terbinafine. Starting materials and all reagents are commercially available.

θ '(E) -isomer

CH ₃ CH ₃ ^CH ₃

2nd grade Piperidine Et ₃ N

Cul, Pd ²⁺

The advantages of the described process are summarized in the following points - the present invention describes a process for preparing terbinafine in the two reaction steps described in Scheme 6 without any isolation and purification of the intermediates (the so-called one pot reaction)

The process is carried out in a single solvent system common to the entire reaction sequence

the process thus eliminates the time required in the intermediate isolation and purification steps, respectively. eliminates the need to change the solvent system and thus becomes much more efficient than the stepwise preparation process, thereby increasing production capacity

surprisingly in the process described in the invention, the terbinafine prepared is qualitatively the same as in the stepwise preparation, and the big surprise is the quantitative yield of terbinafine

the use of the pure (E) -1,3-dichloropropene isomer makes it possible to prepare crude terbinafine without impurity of the other isomer (Z).

The crude terbinafine obtained by the present invention can be purified and / or converted into pharmaceutically acceptable salts in a further step. The method of optimum terbinafine purification steps is described below.

DETAILED DESCRIPTION OF THE INVENTION.

In a first step, N-methyl-1-naphthalenemethylamine hydrochloride is reacted with a slight excess of (E) -1,3-dichloropropene in the presence of a base and a sodium iodide catalyst in an inert solvent.

Excess (E) -1,3-dichloropropene can be used from 0 to 100%, with an optimal excess of 10%.

However, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, n-butylamine, Ν, dim-dimethylaniline, diisopropylamine may also be used as the most preferred base in this step.

The amount of sodium iodide catalyst may be between 1 and 20%, most preferably 10%. As an inert solvent, acetone, ethyl methyl ketone, methyl isobutyl ketone and the like can be used. dimethylformamide, most preferably using acetone.

The reaction temperature may be between room temperature and the reflux temperature of the solvent used. Most preferably, the reflux temperature is for acetone and ethyl methyl ketone and the temperature is 80 ° C for dimethylformamide.

The reaction time depends on the reaction temperature and may range from 1 to 48 hours, for the most preferred temperatures of the solvents used, the reaction time is two hours.

In the second step, catalyst and co-catalyst are added to the reaction mixture along with a slight excess of 3,3-dimethylbut-1-yne and an excess of base. The solvent system is retained as the solvent after the first step.

As the catalysts of this step, palladium complexes with tertiary phosphines or combinations of palladium salts or palladium complexes with tertiary phosphines can be used.

Palladium complex with tertiary phosphines means a complex of zero-powerful palladium or bivalent palladium with tertiary amines such as trialkyl or triaryl phosphines and may be, for example, bis (triphenylphosphine) palladium chloride, bis (trimethylphosphine) palladium chloride, bis (triphenylphosphine) palladium bromide ) palladium.

By palladium salts are meant palladium divalent salts such as palladium chloride, palladium bromide, palladium acetate or palladium sulfate.

By palladium complexes are meant the above-mentioned palladium-tertiary phosphine complexes and other complexes 0 and 3, respectively. 2, such as bis (benzonitrile) palladium chloride, bis (benzonitrile) palladium bromide, bis (acetonitrile) palladium chloride, bis (phenylethylamine) palladium chloride.

Most preferred is the use of bis (benzonitrile) palladium chloride or bis (acetonitrile) palladium chloride. The amount of catalyst used can range from 0.2 to 10.0%, most preferably 0.5-1.0% (mole percent).

Copper or cupric salts such as cuprous chloride, cuprous bromide, cuprous iodide, cuprous chloride, cuprous bromide or cuprous iodide may be used as co-catalysts.

Most preferred is the use of copper iodide. The amount of co-catalyst used may range from 0.4 to 20.0%, most preferably the range is 1.0-2.0% (mole percent).

As the base for the second step, organic bases such as triethylamine, pyridine, piperidine, il, dim-dimethylaniline, pirolidine, 1-methylpiperazine, hexamethyleneimine, 4-dimethylaminopyridine and the like can be used. inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and sodium carbonate; potassium carbonate. Most preferred is the use of piperidine in an amount of 1 to 10 equivalents, most preferably 5 equivalents.

The second step may be carried out at a temperature range of from 5 to 40 ° C, most preferably at 20 30 ° C.

Examples:

Example 1

Preparation of (E) -N-methyl-6,6-dimethyl-N- (1-naphthylmethyl) -hept-2-en-4-ynyl-1-amine

Weigh N-methyl-1-naphthalenemethylamine hydrochloride (20.77 g, 0.1 mol), potassium carbonate (29.02 g, 0.21 mol), (E) -1,3-dichloropropene (3) into a three-necked 1 L flask equipped with a magnetic stirrer, thermometer and reflux condenser. 12.21 g, 0.11 mol), sodium iodide (1.50 g, 0.01 mol) and acetone (280 mL). The mixture was then heated to reflux with stirring for two hours. Then, bis (benzonitrile) palladium dichloride (0.38 g, 0.001 mol), copper (I) iodide (0.38 g, 0.002 mol), piperidine (49.5 ml, 0.5 mol) and 3,3-dimethylbutane are added. -l-tin (16.0 mL, 0.13 mol) and the mixture was stirred at room temperature for an additional 18 hours.

Concentrate under reduced pressure and stir the mixture in isohexanes (300 mL) and filter through a layer of alumina (4 cm), then wash with isohexanes (300 mL). The combined filtrates were concentrated under reduced pressure to give about 31 grams of crude terbinafine (quantitative yield). HPLC 96.3% (area).

Example # Change in procedure from Example no. 1 yield (%) HPLC (% area) 2 instead of bis (benzonitrile) palladium chloride (0.38 g, 0.001 mol) used bis (acetonitrile) palladium chloride (0.26 g, 0.001 mol) quantitative 95.1 3 used sodium carbonate (22.26 g, 0.21 mol) instead of potassium carbonate (29.02 g, 0.21 mol) quantitative 96.1

4 triethylamine (29.3 ml, 0.21 mol) used instead of potassium carbonate (29.02 g, 0.21 mol) quantitative 94.8 5 instead of acetone (280 ml, reflux) used ethylmethyl ketone (280 ml, reflux) quantitative 95.3 6 dimethylformamide (280 ml, 80 ° C) used instead of acetone (280 ml, reflux) 85 90.2 7 instead of piperidine (49.5 ml, 0.5 mol) used pirolidine (41.7 ml, 0.5 mol) quantitative 94.7 8 copper bromide (0.29 g, 0.002 mol) used instead of copper iodide (0.38 g, 0.002 mol) quantitative 92.7 9 triethylamine (69.7 ml, 0.5 mol) used instead of piperidine (49.5 ml, 0.5 mol) 23 85.9 10 potassium carbonate (69.1 g, 0.5 mol) used instead of piperidine (49.5 ml, 0.5 mol)

Example 11

Preparation of (E) -N-methyl-6,6- (methyl-N- (1-naphthylmethyl) -hept-2-en-4-yn-1-ylamine) hydrochloride

The crude terbinafine of Example 1 (31 grams) was dissolved in 10 mL of isopropanol and then added dropwise at 5 ° C to a 10% solution of hydrogen in isopropanol (40 mL). After complete addition, a mixture of isohexanes (40 mL) 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 a mixture of isohexanes (10 ml) and dried. This gives 29.8g (91%) of terbinafine hydrochloride.

Mp .: 205-208 ° C. HPLC: 99.7% by weight.

Industrial usability

In this way, terbinafine, resp. any of its pharmaceutically acceptable salts, in purity and quality, which are used as an active substance in the preparation of medicaments.

Claims (13)

PATENT CLAIMS A process for the preparation of (E) -TV- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene-methylamine (terbinafine) from N-methyl-1-naphthalenemethylamine comprising the following reaction levels N-Methyl-1-naphthalene (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine Cl (E) -1,3-dichloro -propene (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethylamine 3,3-dimethylbut-1- (n catalyst cocatalyst base (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene-methylamine) characterized in that: said reaction steps are carried out in a sequential order without isolation and purification of the intermediate formed during the one-pot reaction using one solvent system common to both reaction steps. Process according to claim 1, characterized in that acetone, ethyl methyl ketone, methyl isobutyl ketone, dimethylformamide or a mixture thereof, preferably acetone, is used as the solvent system for both reaction steps. Method according to claim 1, characterized in that the amount of (E) -1,3-dichloropropene used is preferably in the range of 1.0 to 2.0 molar equivalents, most preferably 1.1 to 1.3 molar equivalents. The process according to claim 1, wherein the base used in the first step is potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, n-butyl amine, N, N-dimethylaniline , diisopropyl amine or a mixture of these bases, preferably potassium carbonate. The process according to claim 1, characterized in that the catalyst in the first stage sodium iodide is preferably in an amount of 0.01 to 0.2 molar equivalent, most preferably 0.1 molar equivalent. T The process according to claim 1, characterized in that the first step of the reaction sequence is carried out at a temperature preferably ranging from room temperature to the reflux temperature of the solvent system used, most preferably at a temperature of 50 to 80 ° C. The process according to claim 1, characterized in that the catalyst in the second stage is a palladium compound containing zero or divalent palladium, preferably palladium complexes with tertiary phosphines, or a combination of palladium salts or palladium complexes with tertiary phosphines, most preferably bis (benzonitrile) palladium chloride or bis (acetonitrile) palladium chloride. The process according to claim 1, characterized in that the second stage co-catalyst of the reaction sequence is a copper (II) halide, preferably copper (I) iodide. The process according to claim 1, wherein the base used in the second step is piperidine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, n-butyl amine, Ν. , Ν-dimethylaniline, pirolidine, 1-methylpiperazine, hexamethylenimine, 4-dimethylaminopyridine or a mixture of these bases in an amount of 1.0 to 10 molar equivalents, preferably 2.5 to 6.0 molar equivalents, most preferably piperidine in an amount of 2 to 5 molar equivalents. The process according to claim 1, characterized in that the second step of the reaction sequence is carried out at a temperature preferably in the range of from + 5 ° C to the reflux temperature of the solvent system used, most preferably at 20-30 ° C. * Process according to claims 1 to 10, characterized in that the resulting (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene-methylamine is further purified in an additional purification step. A pharmaceutical composition comprising (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene-methylamine or a pharmaceutically acceptable salt thereof as an active substance, characterized in that (E) 1) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine is prepared by the process of claims 1 to 10, or 11. (E) -N- (6,6-Dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene-methylamine prepared by the process of claims 1 to 10, or 11.