WO2001077064A1

WO2001077064A1 - Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine)

Info

Publication number: WO2001077064A1
Application number: PCT/SK2001/000008
Authority: WO
Inventors: Ivan Kakalík; Vladimír Oremus; Vendel ŠMAHOVSKÝ; Vladislav ŠNUPÁREK; Dušan VANDÁK; Ivan Varga; Marián Zemánek; Valdemar ŠTALMACH; Ladislav JEŽEK
Original assignee: Slovakofarma A.S.
Priority date: 2000-04-07
Filing date: 2001-04-05
Publication date: 2001-10-18
Also published as: HUP0302919A3; LT5051B; EE200200583A; AU2001248998A1; LV12955B; LT2002103A; WO2001077064A8; HUP0302919A2; SK5202000A3

Abstract

The method for the preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine (terbinafine) from N-methyl-1-naphthalenemethanamine and (E)-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

Method for the preparation of E>-N-(6,6-di ethyl-2-hepten-4-ynyl)-N-methyI-l- naphthalenemethanamine (terbinafme)

Technical Field

Present invention relates to the method for the manufacture of (2ζ/-JV^r-(6,6-dimethyi-2-hepten- 4-ynyl)-N-methyl-l-naphthalenemethanamine (terbinafme) of formula V, wherein the process of the preparation in two steps is without any isolation or purification of intermediates (so called one pot reaction). Furthermore the method of optimal purification operations leading to the pharmaceutically usable terbinafme hydrochloride is described.

Background Art

Terbinafme belongs to the group of allylamine fungistatic antimycotics. Terbinafme blocks ergosterol synthesis by squalene epoxidase inhibition, affects fungicidaily upon dermatophytes, yeasts, dimorphous fungi and micromycetes. It possesses with a wide antimycotic spectrum and is accessible also for peroral application. Its pharmacokinetic characteristics are very advantageous (a long biological half-life) and has a very good passage into adipose tissue (skin and nails).

The preparation of terbinafme has been described in patent application and subsequently, in publication by A. Stuetz.( A. Stuetz: Eur. Pat. Appl. 24,587 (1981 Sandoz), A. Stuetz, G. Petranyi et al: J. Med. Chem. 27, 1539 (1984).

Terbinafme as specific inhibitor of squalene epoxidase, the key enzyme in ergosterol biosynthesis in fungi, has been described by G. Petranyi et al in Science, 224, 1239 (1984) and by N. S. Ryder in Antimicrob. Ag. Chemother. 27, 252 (1985). Preparation of terbinafme from N-m ethyl- 1-naphthalenemethanamine has been described in number of documents.

In European Patent Appl. 24587 and subsequently in J. Med. Chem., 27, 1539 (1984) and J. Med. Chem., 36, 2820 (1993) the preparation of terbinafme has been described as follows: at first 6,6-dimethylhepten-4-ynyl-l -bromide (E:Z = 3:1) is prepared, which subsequently reacts with N-methyl- 1-naphthalenemethanamine to afford the isomeric mixture (E:Z = 3:1) of terbinafme. Desired E-isomer is isolated by chromatography on silica gel (Scheme 1).

Later in the Swiss patent CH 678527 of Sandoz Company was disclosed the method for the separation of E and Z terbinafme isomers via its addition salt with inorganic acid, preferably hydrochloric acid. Starting from the mixture of E and Z isomers (3:1) of terbinafme hydrochtoride in ethylacetate, only pure E isomer was precipitated.

Scheme 1

Canadian patent CA 1 157023 relates to the method for preparation of terbinafme by reduction amination of naphthylamine with fE 6,6-dimethylhept-2-ene-4-yne-l-al in the presence of formaldehyde and borohydride natrium (Scheme 2).

Scheme 2

In the New Zealand patent NZ 280065 is starting compound 2,3-epoxypropane or (3-alkyl-l- propargyl)triphenylphosphonium bromide (Scheme 3). In the first case N-methyl-1- naphthalenemethanamine reacts with epichlorhydrin in the basic medium to afford N^"-methyl-I-naphthylmethyl-2,3-epoxypropane. The epoxide formed is subsequently with lithium tert-butylacetylene in the presence of boron trifluoride etherate opened to form secondary alcohol. Free hydroxy group is protected by easy leaving group such as methansulfσnate or tosylate. In the last step easy leaving group is removed by strong base of l,8-diazabicyclo[5.4.0]undecan-7-ene to give the mixture of terbinafme isomers.

In the second process N-methyl- 1-naphthalenemethanamine reacts with bromoacetaldehyde dialkylacetal in the basic medium to give amine acetal, which is hydrolyzed in acidic medium, whereby aldehyde is formed, from which by Wittig reaction isomeric mixture of terbinafme is prepared. Both mentioned methods afford isomeric mixture of terbinafme what is undesirable.

Scheme 3

According to the method described in Tetrahedron Lett., 29, 1509 (1988), the preparation starts with lithium salt of N-methyl- 1-naphthalenemethanamine, which subsequently reacts with propargyl bromide to give propargyl amine derivative. The product obtained is hydrozirconated by treating with zirconocene chlorohydride and after adding iodine (Ej-3-iodoalIyl amine is formed which reacts with zinc salt of 3,3-dimethylbut-l-yne using bivalent palladium catalyst (Scheme 4). Scheme 4

The most simple preparation utilized the reaction of (E)- 1,3-dichloropropene with /N-methyl- 1-naphthalenemethanamine and the product obtained, f ⁾-N-(3-chloro-2-propenyl)-7N-methyl- 1-naphthalenemethanamine further reacts with tert-butylacetylene in the presence of palladium catalyst, base and Cul (Scheme 5).

The preparation of the mixture E and Z (9:1) isomers of N- (3-chloro-2-propenyl)-N-methyl- 1-naphthalenemethanamine has been described in detail in patents EP 0421302 and US 5231183 (JP 257310/89), wherein the starting reactant was the mixture of E and Z isomers of 1,3-dichloropropene and by subsequent purification by colon chromatography on silica gel pure E isomer was obtained, from which in the second step pure E-isomer of terbinafme was prepared.

Scheme 5

Sandoz company also introduced the simplificated preparation of terbinafme by the same synthetic way but for the preparation of (E -N-(3-chloro-2-propenyl)-N-methyI-l- naphthalenemethanamine pure (E)- 1,3-dichloropropene was used {Chimia 50, No. 4, 154, (1996)).

The preparation of (7ii⁾-N-(3-chloro-2-propenyl)-N-methyl-l-naphthalenemethanamine also in another publication: Tetrahedron Lett., 37, 57, (1996) has been described, wherein the isomeric pure (Ej-l,3-dichloropropene was usmg as starting reactant, too.

Disclosure of the Invention

In the following, the process according to the present invention will be described. In the Scheme 6 reaction sequence of terbinafme preparation in the preferred embodiment of the invention is described. Starting materials as well as all reactants are commercially available.

Scheme 6

The advantages of the process described in present invention can be summarized into following points: present invention discloses the process for the preparation of terbinafme in two reaction steps, described in Scheme 6, without any isolation and purification of intermediates (so called one pot reaction);

the process is carried out in one solvent system common for the whole reaction sequence;

the process by this way eliminates a time needed in steps of intermediates isolation and purification and eliminates the necessity for change of solvent system, resp., and therefore is far more effective than a process of step-by-step (stepped) preparation, what permits to enhance the capacity of manufacture;

surprisingly terbinafme prepared by the process according to the present invention is qualitatively same as terbinafme prepared by step-by-step process, and a great surprise is quantitative yield of terbinafme;

utilisation of pure isomer t2ζ -l,3-dichloropropene enables to prepare raw terbinafme without impurities of second isomer (Z).

Raw terbinafme obtained by the process of present invention may be purified in additional step and/or may be transformed into pharmaceutically acceptable salts. Method of optimal purification steps for terbinafme is described below.

Detailed Description of the Invention

In the first step N-methyl-1-naphthalenemethanamine reacts with (E)- 1,3-dichloropropene, which is preferably in moderate excess, in the presence of base and catalyst natrium iodide in an inert solvent.

The excess of f--ζ -l,3-dichloropropene can be used from 0 to 100 %, wherein the optimum excess of this reactant is 10 % (mole percent).

The most preferable base in this step used is potassium carbonate, but natrium carbonate, natrium hydroxide, potassium hydroxide, natrium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, n-butylamine, N,N-dimethylaniline, diisopropylamine or a mixture thereof can be used, too.

The amount of catalyst used natrium iodide can be in the range of 1 to 20 %, preferably is 10 % (mole percent).

As inert solvent can be acetone, ethyl methyl ketone, methylisobutyl ketone, dimethylformamide or a mixture thereof used, the most preferably acetone is used.

The reaction is carried out at temperature between room temperature and the reflux temperature of solvent used. The most preferably reflux temperature for acetone and ethylmethyl ketone and temperature 80 °C for dimethylformamide is used.

Reaction time depends on reaction temperature and can be in the range from 1 to 48 hours, for the most preferably temperatures of solvents used is optimum reaction time two hours.

In the second step catalyst and co-catalyst together with a moderate excess of 3,3- dimethylbut-l-yne and excess of the base are added into the reaction mixture. As an solvent, the solvent system after the first step is kept.

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

The term "complex of palladium with tertiary phosphines" means the complex of zerovalent palladium or bivalent palladium with tertiary phosphines such as trialkyl or triaryl phosphines, comprising e.g. bis(triphenylphosphine)palladium chloride, bis(trimethylphosphi- ne)palladium chloride, bis(triphenylphosphine)palladium bromide, tetrakis(triphenylphosphi- ne)palladium.

The term "palladium salts" means salts formed by bivalent palladium, as e.g. palladium (II)chloride, palladium(II)bromide, palladium acetate or palladium sulfate.

The term "palladium complexes" means above mentioned complexes of palladium - tertiary phosphine and other complexes of zerovalent or bivalent palladium, as e.g. bis(benzonitrile)palladium chloride, bis(benzonitrile)palladium bromide, bis(acetonitrile)pa- lladium chloride, bis(phenylethylamine)palladium chloride. The most preferably bis(benzonitrile)palladium chloride or bis(acetonitrile)palladium chloride is used. The amount of the catalyst used can be in the range from 0.2 to 10.0 %, the most preferably is the range from 0.5 to 1.0 % (mole percent).

As co-catalysts copper(I) or copper(II) salts are used, e.g. copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(II) chloride, coppertTI) bromide or copper(H) iodide.

The most preferably copper(ϊ) iodide is used. The amount of the co-catalyst used can be in the range from 0.4 to 20.0 %, the range from 1.0 to 2.0 % (mole percent) is the most preferable.

As the base in the second step organic bases such as triethylamine, pyridine, piperidine, N,N- dimethylaniline, pyrrolidine, 1-methylpiperazine, hexamethyleneimine, 4-dimethyl- aminopyridine or inorganic bases such as natrium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or a mixture thereof can be used. The most preferably piperidine is used, in the amount from 1 to 10 molar equivalents, optimally in the amount of 5 molar equivalents.

The second reaction step may be carried out at the temperature range from 5 to 40 °C, optimally at the temperature from 20 to 30 °C.

The following examples are intended to illustrate the invention without limiting its scope.

Examples

Example 1 E)-N-(6,6-dimethyl-2-hepten-4-vnvIVN-methyI-l-ήaphthalenemethanamine

N-methyl- 1-naphthalenemethanamine hydrochloride (20.77 g, 0.1 mol), potassium carbonate (29.02 g, 0.21 mol), (E)- 1,3-dichloropropene (12.21 g, 0.11 mol), natrium iodide (1.50 g, 0.01 mol) and acetone (280 ml) are weighed into one litre three-necked flask equipped with magnetic stirrer, thermometer and reflux cooler. The mixture is then under stirring heated to the reflux temperature during two hours. Thereafter the mixture is cooled to room temperature and 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-dimethylbut-l-yne (16.0 ml, 0.13 mol) are added, and the mixture is stirred for the further 18 hours at room temperature.

Thereafter the mixture is concentrated under reduced pressure and concentrate obtained is stirred in the mixture of isohexanes (300 ml) and filtered through aluminium oxide layer (4 cm), subsequently the layer is once more with the mixture of isohexanes (300 ml) washed. The combined filter liquors are concentrated under reduced pressure to give about 31.0 g of raw terbinafme (quantitative yield). HPLC 96.3% (of area).

Example 11

^g)-N-(6,6-dimethvI-2-hepten-4-vnyl N-methyl-l-naphthalenemethanamine hydrochloride

Raw terbinafme from the Example 1 (31.0 g) is dissolved in isopropylalcohol (10 ml) and subsequently to this solution is added dropwise at temperature 5 °C up 10% solution of hydrogen chloride in isopropylalcohol (40 ml). After the adding is completed, mixture of isohexanes (40 ml) is added and the solution is stirred at temperature from 0 to 5° C for two hours. Precipitated white crystalline product is aspirated, washed with mixture of isohexanes (10 ml) and dried to yield 29.8 g (91%) of terbinafme hydrochloride.

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

Industrial Applicability

The method according to this invention enables to prepare terbinafme or any of pharmaceutically acceptable salts thereof by the high effective and economic manner in the purity and quality used for active substance in medicament preparation.

Claims

C L I S

1. A method for the manufacture of fE -N-(6,6-dimethyl-2-hepten-4-yny{)- V-methyl-l- naphthaienemethana ine (terbinafme) from N-methyl- 1-naphthalenemethanamine comprising the following reaction steps:

Step 1 :

propene fE N 3-cUoro-2-pror«iiyl)-W^'-metb.yl-

W-mettιyl-1-naphthaleιιe- 1-mphthaleιιemethanaπιine methanamiiie

Step 2:

3,3-dimethylbut-l.-yne

₍E -Λ/-(3-chloro-2-propenyl)-iV-πιethyl- 1 -riaphtMenemetli-Lπairiine

_fΕ;-iV 6,6-dirnβthyl-2-hepten-4-ynyl)- W-methyl- l-naphhalenemetbi- --αiune

wherein the said reaction steps are carried out in the consecutive order without isolation and purification of the intermediate formed during the process, as one-pot reaction, using one solvent system common for the both reaction steps.

2. The method according to claim 1 characterized in that the solvent system used for both reaction steps is acetone, ethylmethyl ketone, methyl isobutyl ketone, dimethylformamide or a mixture thereof, preferably acetone.

3. The method according to claim I characterized in that the amount of (E)-l,3- dichloropropene used is preferably in the range from 1.0 to 2.0 molar equivalent, more preferably from 1.1 to 1.3 molar equivalent.

4. The method according to claim 1 characterized in that the base used in the first step is potassium carbonate, natrium carbonate, natrium hydroxide, potassium hydroxide, natrium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, n-butylamine, N,N-dimethylaniline, diisopropylamine or a mixture of these bases, preferably potassium carbonate.

5. The method according to claim 1 characterized in that the catalyst in the first step natrium iodide is preferably in an amount from 0.01 to 0.2 molar equivalent, more preferably in the amount of 0.1 molar equivalent.

6. The method according to claim 1 characterized in that the first step of the reaction sequence is carried out at the temperature preferably in the range from room temperature to reflux temperature of the solvent system used, more preferably at the temperature from 50 to 80 °C.

7. The method according to claim 1 characterized in that the catalyst in the second step is palladium compound containing zerovalent or bivalent palladium, preferably complexes of palladium with tertiary phosphines, or combinations of palladium salts or palladium complexes, the most preferably bis(benzonitrile)palladium chloride or bis(acetonitrile)palladium chloride.

8. The method according to claim 1 characterized in that the co-catalyst of the second step of the reaction sequence is copper(I)halogenide or copper(II) halogenide, preferably copper(I) iodide.

9. The method according to claim 1 characterized in that the base used in the second step is piperidine, natrium carbonate, potassium carbonate, natrium hydroxide, potassium hydroxide, natrium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, n₇butylamine, N,N-dimethylaniline, pyrrolidine, , 1-methylpiperazine, hexamethyleneimine, 4-dimethylaminopyridine or a mixture of these bases, in an amount of 1.0 to 10.0 molar equivalents, preferably of 2.5 to 6.0 molar equivalents, the most preferably piperidine in the amount of 2 to 5 molar equivalents.

10. The method according to claim 1 characterized in that the second step of the reaction sequence is carried out at the temperature preferably in the range from +5 °C to reflux temperature of the solvent system used, more preferably at the temperature from 20 to 30 °C.

11. The method according to claims 1 to 10 characterized in that the resulting (2ζ/-N-(6,6- dimethyI-2-hepten-4-ynyl)-N-methyl- 1-naphthalenemethanamine is further purified in an additional purification step.

12. A pharmaceutical composition comprising as the active substance (2 )-N-(6,6-dimethyl-2- hepten-4-ynyl)-N-methyl-l-naphthaIenemethanamine or pharmaceutically acceptable salt thereof characterized in that this ^-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-l- naphthalenemethanamine is prepared by the method according to claims 1 to 10, or 11.

13. tE^-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-l-naphthaIenemethanamine prepared by the method according to claims 1 to 10, or 11.