SK4302002A3 - Method for the preparation of (E)-N-(6,6-dimethylhept-2-en-4- ynyl)-N-methyl-1-naphthalenemethanamine from a geometric isomers mixture - Google Patents

Abstract

Method for obtaining (E)-N-(6,6-dimethylhept-2-en-4-ynyl)-N- methyl-1-naphthalenemethanamine, i. e., terbinafine, from a mixture of geometric isomers consists in that terbinafine is precipitated in the form of hydrochloride salt from the C1-5 alcohol solution by addition of an aliphatic C5-7 saturated hydrocarbon or a mixture of C5-7 saturated hydrocarbons in the amount of 0.25 to 3 times of the alcohol volume and under the temperature from -10 °C to boiling point temperature of the employed solvent mixture, wherein (Z)-isomer along with impurities remain in the mother liquor.

Description

Technical field

The invention relates to a novel process for obtaining (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-naphthalenemethanamine of the formula I from a mixture of geometric isomers by precipitation in the form of an acid addition salt.

BACKGROUND OF THE INVENTION (E) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (I, terbinafine) belongs to the group of allylamine fungistatic antifungals with a relatively broad spectrum of activity including dermatophytes , yeasts, molds and dimorphic fungi. 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 (J. Med. Chem. 27, 1539 (1984)).

In most of the processes described for the preparation of terbinafine, this compound is formed in a mixture of (E) - and (Z) -isomers from which the desired (E) -isomer must be isolated. In European patent no. 0 024 587 describes the recovery of the (E) -isomer by silica gel chromatography, which is not very advantageous for industrial use. In Swiss patent no. 678 527, or in its Slovak equivalent no. 279 896 discloses a process for resolving (E) - and (Z) isomers of terbinafine via its hydrochloride acid addition salt. From the mixture of (E) - and (Z) isomers (about 3: 1) of terbinafine hydrochloride in ethyl acetate, only the pure (E) -isomer crystallizes. In addition to ethyl acetate, another acetic acid C 1-4 ester or a mixture thereof with an alcohol can be used for crystallization. In patent application WO 0128976, (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine is isolated from a mixture of geometric isomers by crystallizing its hydrochloride from methyl isobutyl ketone using an aqueous hydrochloric acid solution.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a novel process for obtaining (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -Nmethyl-1-naphthalenemethanamine of formula I from a mixture of geometric isomers by precipitation of its acid addition salt in an alcohol mixture. and an aliphatic saturated hydrocarbon,

optionally mixtures of aliphatic saturated hydrocarbons, wherein the (Z) -isomer together with the other impurities remains in the mother liquors.

The starting material is (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine containing (Z) -N- (6,6-dimethylhept-2-en-4- (nyl) -N-methyl-lnaphthalenemethanamine in an amount of 0.5 to 50% (kg / kg), but most often 10 to 25% (kg / kg) and other impurities in an amount of 0.5 to 50% (kg / kg), most often 15 to 30% (kg / kg). In a preferred embodiment, the free base mixture is dissolved in an alcohol, addition salts of both isomers are added by addition of an inorganic or organic acid, and after addition of the aliphatic saturated hydrocarbon, the (E) -isomer is precipitated from the mixture filtration, or centrifugation. The obtained (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-naphthalenemethanamine salt can be converted to the free base or to an acid addition salt with another acid.

In another preferred embodiment, the (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-naphthalenemethanamine addition salt comprises the (Z) -N- (6,6-dimethylhept- 2-en-4-ynyl) -N-methyl-lnaphthalenemethanamine in an amount of 0.5 to 50% (kg / kg), but most often 10 to 25% (kg / kg) and other impurities in an amount of 0.5 to 50% (kg / kg), most commonly 15 to 30% (kg / kg) is dissolved in an alcohol at elevated temperature, an aliphatic saturated hydrocarbon is added to the solution and upon cooling the mixture precipitates the (E) -isomer which is separated by filtration or centrifugation.

In an embodiment of the invention, a C 1-5 alcohol, in particular 2-propanol, is used.

The (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine salt is precipitated from the mixture by the addition of a C 5 - 7 alkane, which may be linear or branched, or C 5. Or a mixture of C 5-7 alkanes, most preferably n-heptane or cyclohexane.

The volume of aliphatic saturated hydrocarbon added to precipitate the (E) -isomer is 0.25- to 3-fold the volume of alcohol used to prepare or dissolve the addition salts, preferably 1- to 2-fold the volume of alcohol is used.

The preparation of addition salts and precipitation of the (E) -isomer takes place at a temperature of from -10 ° C to the boiling point of the solvents used, preferably at room temperature.

In carrying out the process according to the invention, addition salts of inorganic and organic acids, preferably hydrochloride, are prepared.

The following examples describe the embodiment of the invention in more detail, but do not limit its scope in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 23 mL of 2-propanol. To the solution was added 7 mL of a solution of hydrogen chloride in 2-propanol (20% (kg / kg)) followed by 60 mL of n-heptane, stirred for 3 h at room temperature, then filtered and the filter cake washed with nheptane. 6.14 g (91.9%) of product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 99.84%) was obtained. (Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.13%) and other impurities (HPLC content 0.03%).

'3

Example 2 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 23 mL of 2-propanol. To the solution was added 7 mL of a solution of hydrogen chloride in 2-propanol (20% (kg / kg)) followed by 30 mL of n-heptane, stirred for 3 h at room temperature, then filtered and the filter cake washed with nheptane. 5.78 g (86.5%) of product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 99.79%) is obtained. (Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.11%) and other impurities (HPLC content 0.10%).

Example 3 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 23 mL of 2-propanol. To the solution was added 7 mL of a solution of hydrogen chloride in 2-propanol (20% (kg / kg)) followed by 60 mL of n-heptane, and the mixture was cooled to 5 ° C and stirred at this temperature for 3 h. and the filter cake was washed with n-heptane and dried to give 6.29 g (94.0%) of the product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1 -naphthalenemethanamine (HPLC content 99.62%), (Z) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.16%) and other impurities ( HPLC content 0.22%).

Example 4 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 23 mL of 2-propanol. To the solution was added 7 mL of a solution of hydrogen chloride in 2-propanol (20% (kg / kg)) followed by 30 mL of n-heptane, and the mixture was cooled to 5 ° C and stirred at this temperature for 3 h. and the filter cake was washed with n-heptane and dried to give 6.12 g (91.6%) of the product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1 -naphthalenemethanamine (HPLC content 99.41%), (Z) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0,27%) and other impurities (HPLC content 0.32%).

Example 5 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 23 mL of 2-propanol. To the solution was added 7 mL of a solution of hydrogen chloride in 2-propanol (20% (kg / kg)) followed by 15 mL of n-heptane, and the mixture was cooled to 5 ° C and stirred at this temperature for 3 h. and the filter cake was washed with n-heptane and dried to give 5.97 g (89.2%) of the product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1 -naphthalenemethanamine (HPLC content 99.67%), (Z) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0,28%) and other impurities ( HPLC content 0.05%).

- Example 6 ιο g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59,4% (kg / kg)) and (Z) 1 - N - (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalerethanamine (13.3% (kg / kg)) was dissolved in 23 mL of 2-propanol. To the solution was added 7 mL of a solution of hydrogen chloride in 2-propanol (20% (kg / kg)) followed by 60 mL of cyclohexane, and the mixture was stirred at room temperature for 3 h, filtered and washed with cyclohexane and dried. 5.38 g (80.7%) of a product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 99.54%), ( Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.15%) and other impurities (HPLC content 0.31%).

Example 7 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-Dimethyl-hept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 23 mL of 2-propanol. To the solution was added 7 mL of a solution of hydrogen chloride in 2-propanol (20% (kg / kg)) followed by 30 mL of cyclohexane, stirred for 3 h at room temperature, then filtered and the filter cake was washed with cyclohexane and dried. 4.78 g (71.6%) of a product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 99.96%) and ( Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.04).

Example 8 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 23 mL of 2-propanol. To the solution was added 7 mL of a solution of hydrogen chloride in 2-propanol (20% (kg / kg)) followed by 60 mL of cyclohexane, and the mixture was cooled to 5 ° C and stirred at this temperature for 3 h, filtered and filtered. the cake was washed with cyclohexane and dried to give 5.90 g (89.5%) of the product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (content HPLC 99.54%), (Z) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.14%) and other impurities (HPLC content 0, 32%).

Example 9 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 30 mL of 2-butanol. Hydrogen chloride gas (1.5 g) was added to the solution with stirring, followed by the addition of 60 mL of cyclohexane. The mixture was stirred for 3 h at room temperature, then filtered and the filter cake was washed with cyclohexane and dried. 5.66 g (84.7%) of a product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-naphthalenemethanamine (HPLC content 99.86%) is obtained, (Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.05%) and other impurities (content 0.09%).

Example 10 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 30 mL of t-butanol. Hydrogen chloride gas (1.5 g) was added to the solution with stirring, followed by the addition of 30 mL of cyclohexane. The mixture was stirred for 3 h at room temperature, then filtered and the filter cake was washed with cyclohexane and dried. 5.95 g (89.2%) of a product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-naphthalenemethanamine (HPLC content 99.73%), (Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.11%) and other impurities (HPLC content 0.16%).

Example 11 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) -N - (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 30 mL of n-butanol. Hydrogen chloride gas (1.5 g) was added to the solution with stirring, followed by the addition of 60 mL of cyclohexane. The mixture was stirred for 3 h at room temperature, then filtered and the filter cake was washed with cyclohexane and dried. 4.84 g (72.5%) of a product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-naphthalenemethanamine (HPLC content 99.93%), (Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.04%) and other impurities (content 0.03%).

Example 12 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (59.4% (kg / kg)) and (Z) - N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (13.3% (kg / kg)) was dissolved in 30 mL isoamyl alcohol. Hydrogen chloride gas (1.5 g) was added to the solution with stirring, followed by the addition of 60 mL of cyclohexane. The mixture was stirred for 3 h at room temperature, then filtered and the filter cake was washed with cyclohexane and dried. 5.00 g (74.9%) of product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 99.98%) is obtained and (Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.02%).

Example 13 g of a mixture containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine hydrochloride (59.8% (kg / kg)) and (Z) N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-naphthalenemethanamine hydrochloride (13.0% (kg / kg)) was dissolved in 23 mL of 2-propanol hot. To the solution was added 30 mL of n-heptane with stirring. The mixture was cooled to room temperature and stirred for 3 h, then filtered and the filter cake was washed with n-heptane and dried. 6.17 g (92.2%) of a product containing (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-naphthalenemethanamine (HPLC content 99.82%) is obtained, (Z) -N- (6,6-Dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine (HPLC content 0.07%) and other impurities (HPLC content 0.11%).

Industrial usability

The invention is useful in the manufacture of a pharmaceutical substance terbinafine.

Claims (8)

PATENT CLAIMS A process for obtaining (E) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine of the formula I from a mixture of geometric isomers in the form of a base or in the form of addition salts with an acid characterized in that the compound of formula I precipitates in the form of an addition salt with an inorganic or organic acid from solution in an alcohol by the addition of an aliphatic saturated hydrocarbon or a mixture of aliphatic saturated hydrocarbons, the (Z) -isomer together with other impurities remaining in the mother liquors. The process according to claim 1, wherein the compound of formula I is obtained from a mixture comprising (Z) -N- (6,6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethanamine in 0.5 to 50% (kg / kg) and other impurities in an amount of 0.5 to 50% (kg / kg), preferably from a mixture comprising (Z) -N- (6,6-dimethylhept-2-ene) 4-ynyl) -N-methyl-1-naphthalenemethanamine in an amount of 10-25% (kg / kg) and other impurities in an amount of 10-25% (kg / kg). A process according to claim 1, characterized in that the compound of formula I present in admixture with its (Z) -isomer and other free base impurities is converted to its acid addition salt in a C 1-5 alcohol medium. The process according to claim 1, characterized in that the starting mixture comprises a compound of formula Ia and its (Z) -isomer in the form of an acid addition salt is dissolved in a C 1-5 alcohol, preferably 2-propanol. The process according to claim 1, characterized in that the precipitation of the compound of formula I present in solution in the form of an acid addition salt occurs after the addition of a C 5-7 alkane or C 5-7 cycloalkane, or the addition of a mixture of C 5-7 alkanes, preferably nheptane. or cyclohexane. The process according to claim 1, characterized in that the volume of the added aliphatic saturated hydrocarbon added to precipitate the compound of formula I in the form of an acid addition salt is 0.25 to 3 times the volume of alcohol used to prepare or dissolve the addition salts, preferably 1- to 2-fold the volume of alcohol used to prepare or dissolve addition salts. Process according to claim 1, characterized in that the preparation of addition salts and the precipitation of the (E) isomer takes place at a temperature of from -10 ° C to the boiling point of the solvents used, preferably at room temperature. A process according to claim 1, wherein the compound of formula Isa precipitates in the form of the hydrochloride.