KR20070106739A - Purification process - Google Patents

Abstract

Process for the purification from non-metal contaminants of the allylamine pharmaceutical terbinafine of formula (I) in free base form or acid addition salt form, by distilling crude terbinafine base, preferably by short path distillation, e.g. at a temperature above 100°C and reduced pressure, e.g. 0.2 mbar (method A), optionally together with salt formation of the resultant product under simultaneous precipitation of pure trans isomer (method B), and recovering the pure product in free base or acid addition salt form. Detection of non-metal contaminants such as substance A of formula (II) is preferably effected by RP HPLC analysis with UV detection.

Description

Purification Method {PURIFICATION PROCESS}

The present invention relates to a process for purifying allylamine pharmaceuticals. The present invention relates to a process for the purification of crude terbinafine base and the resulting pure terbinafine.

Terbinafine, in particular terbinafine in the form of hydrochloride acid addition salts, is known from EP 24587, for example. Terbinafine belongs to the group of allylamine antimicrobials. Terbinafine is marketed under the trade name Lamisil®. Terbinafine is effective for both topical and oral administration in a wide range of fungal infections. Terbinafine is particularly useful for dermatophytes as contact infectious bacteria that infiltrate the skin or its appendages such as the stratum corneum, nails and necrotic tissue of the hair.

Terbinafine represents a significant advance in antimicrobial therapy based on its potent bactericidal action in vitro and secondary clinical efficacy in various dermatitis infections upon oral and topical presentation. Terbinafine is a potent inhibitor of ergosterol biosynthesis (Ann. NY Acad. Sci. 544 [1988] 46-62), which blocks the action of squalene epoxidase to inhibit the transformation of squalene into squalene epoxide . Ergosterol synthesis is only partially inhibited, but cell growth is completely stopped. This suggests that the bactericidal effect of terbinafine may be associated with the accumulation of squalene, which can be toxic to fungi at high concentrations. The activity spectrum of terbinafine in vitro covers all dermatophytes in Trichophyton , Epidermophyton and Microsporum . Average minimum inhibitory concentrations for these dermatophytes range from 0.001 μg / ml to 0.01 μg / ml (Science 224 [1984] 1239-1241). Terbinafine is also active against fungi, and dimorphic fungi in vitro, and Petey Los Forum (Pityrosporum), candidiasis (Candida) and also for a number of pathogenic yeast in the torulra (Rhodotorula).

The structure of terbinafine is as shown by the following formula (I), and the chemical name thereof is (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene methanamine.

Terbinapine may be in free base form or in acid addition salt form. Acid addition salt forms can be prepared from the free base form in a conventional manner and vice versa. Examples of suitable acid addition salt forms are hydrochloride, lactate, ascorbate and malate, for example L-(-)-hydromalemaleate. Free bases and hydrochloride and maleate salts, in particular hydrochloride and L-(-)-hydromalemaleate, are preferred.

As can be seen from the above formula (I), terbinafine is an allylamine compound having a triple bond conjugated with a double bond in the side chain. Terbinafin was invented many years ago (see, eg, Example 16 of EP 24587), and this conjugated enyne structure is very specific in the pharmaceutical field and has constituted novel structural features in medicinal chemistry, and even today It is still so.

Both double bonds and triple bonds typically have high reactivity. Although the chemical literature does not exclude that compounds having such a structure may be stable, some are unstable and may decompose upon storage or processing when heat is applied, for example distillation at elevated temperatures.

Thus, for example, EHR Jones et al., J. Chem. Soc. (1960) 341-346, it is shown that a simple distillation of pure penta-1,2-diene-4-yne at its standard boiling point of 57 ° C. already causes decomposition. Likewise, (non-conjugated) 1-alkene-4- dimers [CH ₂ = CH-CH ₂ -C≡CC (CH ₃ ) (OH)-] ₂ , ie 6,7-dimethyl-dodeca- 1,11-diene-4,8-diene-6,7-diol (Compound V in H. Disselnkoetter and P. Kurtz, Ann. Chem. [1964] 26-34) was reduced in temperature (85-90 ° C.). ) And distillation under reduced pressure (0.05 mmHg) as well as complementary distillation at 81-85 ° C. and 0.03 mmHg. In addition, endyne (Z, Z) -3,7-decadiene-1,5,9-triyne is readily polymerized and its solution is pyrolyzed at 170 to 190 ° C. to give naphthalene, while the corresponding (E , Z) and pyrolysis of the (E, E) isomers provide other products or polymers (J. Am. Chem. Soc. 114 [1992] 3120-3121).

Isomerization of the conjugated enine compounds, for example the isomerization of ether CH ₃ CH═CH—C—C—CH ₂ OC ₂ H _{5 to} the corresponding 1,3,5-triene compound, includes The 6-removal can result in significant polymer residues after distillation and the -OC ₂ H ₅ group being replaced by an amino group resulting in aromatization (Van-Dongen, J. et al., Recueil Trav. Chim. Pays -Bas 86 [1967] 1077-1081].

In addition, for example, from the above literature, even if distillation is carried out with any enine derivative, it is typically less than 100 ° C. or as expected in highly reactive compounds that are susceptible to degradation or degradation or polymerization upon heating or even exploding. It is generally noted that it is carried out at temperatures slightly above 100 ° C., in particular below about 125 ° C. It is also described, for example, in Recueil Trav. Chim. Pays-Bas 85 (1966) 952-965 and Zh. Org. The same is true for most alkenine derivatives disclosed in Khim 3 (1967) 1792-3 (CA 68 [1968] 12370), see Czech Author's Certificate No. 232843]. Two intermediates of pheromones disclosed in (CA 106 [1984] 213632b) are purified by distillation under reduced pressure at 102-115 ° C and 118-125 ° C, respectively.

In addition, terbinafine in free base form boils at 140 ° C. at a pressure of 0.3 mbar, and its thermal stability is limited at this temperature: the following degradation products can thus be observed (in analysis by gas chromatography, all The area under the peak of one compound relative to the sum of the peaks is called area-%; for the Z isomer the area-% should be approximately equal to the weight-%).

Heating time (hours) By-product 1 (area-%) Z isomer (area-%) E isomer without change (area-%) 0 0.09 0.25 97.6 7 0.57 0.34 96.6 23 0.92 0.45 94.7 32 1.20 0.52 92.0 By Product 1 = (methyl) (naphthalen-1-ylmethyl) amine

On the other hand the product is already solidified below 43 ° C.

Therefore, when working-up chemicals with such unusual structures, it is usually avoided to perform operations that require the application of substantial heat, especially when associated with limited thermal stability in large scale operations, such as in industrial production of pharmaceuticals. do. For example, in Example 13 of EP 0 421302 A2 (Banyu), which discloses the preparation of terbinafine, the crude mixture (free base) obtained after the reaction is purified by silica gel chromatography.

However, contrary to the idea, it has been found that terbinafine base can be distilled without particularly adverse effects. Furthermore, such distillation can be carried out at elevated temperatures, for example at temperatures much higher than 100 ° C., for example at about 110 ° C. to about 170 ° C., preferably at about 125 ° C. to about 165 ° C., especially at about 160 ° C. It has been found that it can be carried out under 0.2 mbar, for example, at 160 ° C. (jacket temperature).

The yield thus obtained is usually about 95% starting from the crude product.

The invention provides a novel process for the purification of terbinafine, comprising distilling crude terbinafine in free base form and recovering the product in free base or acid addition salt form, wherein the co-pending application PCT / EP2004 / 9587 (WO 2005/21483) and equivalents thereof, and claimed.

The method of the above application is particularly useful for separating terbinafine from its chemical synthesis, for example from metal contaminants, such as copper and / or palladium contaminants produced from catalysts, in particular for example EP 421302 (Banau) and (Or (E) in the presence of a palladium and / or copper catalyst to obtain a synthesis according to the method disclosed in EP 1'236'709 (Dipharma) or a similar synthesis, for example terbinafine base. -N- (3-halo-2-propenyl) -N-methyl-N- (1-naphthylmethyl) amine (compound of formula IV of EP 421302; wherein R ¹¹ is methyl and R ²¹ is 1- Naphthylmethyl and W is halogen, for example bromo, preferably chloro) and 3,3-dimethyl-1-butyne (compound of formula V of EP 421302; wherein R ⁷ is tert-butyl) It is emphasized as being useful for reducing or eliminating contaminants generated from synthesis by reactions. All. The catalyst is, for example, copper iodide (I), or bis- (triphenylphosphine) palladium- (II) -dichloride or tetrakis (triphenylphosphine) palladium and copper iodide (I), or further EP 421302 A2 is, for example, a palladium-, copper- or palladium / copper-containing catalyst selected from those disclosed in lines 7 to 54 on page 8.

 The process of this application is carried out by conventional means, preferably as a so-called "gentle" distillation method, for example as batch distillation, or preferably continuously or semi-continuously, in particular heating mantle The path between the heating mantle and the condenser is so short that, for example, about 10 cm, it is carried out as a "short path" distillation which minimizes the time the terbinafin stays at elevated temperatures, for example above 100 ° C.

The term "short path distillation" is understood as high vacuum distillation for separating mixtures of organic (or silicon) compounds that will not withstand extended heating without excessive structural changes or decomposition. Short path distillation utilizes heat of condensation as a subject for radiant heat release to the surface film of the evaporator. There is no obstruction in the path between the evaporator and the condenser. Due to the short residence times and low distillation temperatures, the thermal hazards to organic materials are significantly reduced.

The method of using short-path distillation is carried out similarly to that disclosed in WO 2005/21483, for example using a convenient setup illustrated in the figures, whereby short-circuit times of the mixtures for which short-path distillation is preferred and to be purified are circulated as well. Along with processing, it is possible to improve the yield of the corresponding purified product. In addition, the thickness of the material on the evaporator wall is reduced to allow lower evaporation temperatures and shorter residence times. Thus very efficient separation from contaminants is achieved by chromatography or recrystallization, or without the need for further purification steps such as using large amounts of gum charcoal.

However, prior to the present invention the full potential and use of the terbinafine base to distill at elevated temperatures without degradation or with only limited degradation is not understood. Thus other non-metallic contaminants, especially (methyl) (naphthalen-1-ylmethyl) amine ( byproduct 1 ); 2,2,7,7-tetramethylocta-3,5-diyne ( byproduct 2 ); And organic compounds, such as Z-isomers of terbinafine , may be only partially removed or not removed at all (eg, by-product 1 and Z-isomers of terbinafine).

However, it has now been found that further studies and improvements in the methods available for the detection of contaminants have led to the invention that, in anticipation, additionally, organic contaminants can be removed or significantly reduced using the method or similar conditions.

It is very surprising and unexpected in terms of terbinafine base and the physicochemical characteristics of these organic contaminants that a direct distillation procedure can almost separate these contaminants from the pharmaceutical end product.

Thus, convenient procedures are now available for the production of terbinafine, which is highly purified of organic contaminants on a huge industrial scale.

“Pure terbinafine” in free base or acid addition salt form herein refers to terbinafine free of non-metal contaminants, for example comprising less than about 2 w / w% of non-metal, especially organic contaminants. It is defined as In contrast, “crude terbinafine” is such a non-metal contamination, with at least about 5 ppm, for example from about 5 ppm to about 200 ppm, in particular from about 5 ppm to about 100 ppm of material A (defined below). It is to be understood that the material has at least about 2 w / w% in total, for example from about 2 w / w% to about 10 w / w%, in particular from about 2 w / w% to about 5 w / w%.

Thus, in one aspect, the present invention provides a method for preparing a free base terbinafine, comprising distilling crude terbinafine in free base form under conditions that substantially reduce the level of non-metal contaminants , and pure terbinafine in form of free base or acid addition salts. And a novel method for purifying terbinafine from non-metallic contaminants , comprising recovering the same, hereinafter referred to simply as " Method A ".

Detection of non-metallic contaminants is preferably at a concentration below the conventional quantitative limit of about 0.05 w / w% (500 ppm), which is typically achieved by conventional detection methods such as reverse phase high pressure liquid chromatography (RP-HPLC), 0.0001% preferably achieved with commercially available devices such as HP 1100 (Agilent) and Alliance 2695 (Waters) and as achieved in RP-HPLC, for example in parallel with UV detection, as described in Example 4 below. It is carried out using an analytical method that is sensitive to concentrations below the limit of quantitation of the order of (1 ppm). Typical results are for example as illustrated in the chromatogram below.

“Large scale” or “industrial scale” preparation of the purified terbinafine base or acid addition salts can be used herein to provide at least about 5 kg, preferably at least about 50 kg, of purified product on a free base form per one distillation batch or operation, In particular from about 200 kg or more, for example from about 500 kg to about 2 tons, more preferably from about 600 kg to about 900 kg, most preferably from about 800 kg to about 900 kg, in particular about 850 kg. .

"Substantial reduction of non-metallic contaminant levels" means a total of about 2 w / w% to about 10 w / w% of detectable, as measured by RP-HPLC (reverse phase high pressure liquid chromatography) analysis in combination with UV detection. A total of about 0.5 w / w% to less than about 2 w / w%, in particular less than about 0.5%, of a detectable non-metal, essentially organic contamination, starting from a crude terbinafine base with an overall initial level of organic contaminants It should be understood that this results in a concentration of the substance.

Thus starting from the crude terbinafine product comprising, for example, about 60 to about 80 ppm of substance A (defined below), a purified product comprising only about 5 ppm of substance A can be obtained (Example 4), the total amount of other impurities detected is about half.

Distillation is preferably performed under a corresponding reduced pressure at a temperature of about 100 ° C. to about 170 ° C., for example about 110 ° C. to about 170 ° C., preferably about 125 ° C. to about 165 ° C., in particular about 160 ° C. (jacket temperature). For example, it is carried out at about 0.2 mbar at 160 ℃.

Such additional non-metallic contaminants are typically organic compounds, for example one or more of the following compounds:

a)

That is, 6,6-dimethyl-2-hepten-4-ynal;

b)

Namely, (methyl) (naphthalen-1-ylmethyl) amine; Ie, N-methyl-N- (1-naphthylmethyl) amine;

That is, N-methyl-1-naphthalenemethanamine ( byproduct 1 );

c)

Namely, (Z) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethanamine (= Z-isomer );

d)

Namely, (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthylmethanamine; And

E)

Ie, (E) -4- [4,4-dimethylpentin- (E) -ylidene] -N ¹ , N ⁵ -dimethyl-N ¹ , N ⁵ -bisnaphthalen-1-ylmethyl-pent-2- En-1,5-diamine or

2 (E), 4 (Z) -N- (4-[(N'-methyl-N'-1-naphthylmethyl) aminomethyl] -8,8-dimethyl-2,4-nona-diene-6 -Ynyl) -N-methyl-1-naphthylmethanamine ( Material A ).

Material A, for example, if method a) of EP 24587 is used for the preparation of terbinafine, ie N-methyl-N- (1-naphthylmethyl) amine (compound of formula IV of EP 24587) is 1- A-6,6-dimethyl-2-hepten-4-yne (compound of formula V of EP 24587; wherein A is a leaving group, in particular bromo), is present as a non-metallic contaminant.

Terbinapine has a trans structure and is typically commercialized in pharmaceutical compositions such as tablets, wherein the active ingredient is in the form of hydrochloride acid addition salts. Thus, the free base must be converted to an acid addition salt such as hydrochloride, for example if the crude mixture of terbinafine free base in Swiss Patent No. 678527 contains for example significant amounts of cis isomeric impurities, the pure trans isomer It is known that it can be obtained by forming a salt with an acid such as hydrochloric acid simultaneously with salt precipitation. Preferably it is hydrochloric acid and organic in aqueous solution in the presence of an ester of an organic acid, such as ethyl acetate, or an ester of an organic acid, such as ethyl acetate, with a further organic solvent, or using, for example, the conditions described in WO 01/28976. It is carried out using a solvent such as methyl isobutyl ketone.

It has also been surprisingly reached in the present invention for the preparation of very pure terbinafine using such salt formation which coincides with the precipitation of pure trans isomers advantageously in combination with the above method of the invention for the further removal of the non-metallic contaminants described above. It has also been found that can lead to.

For example, starting from crude terbinapine bases having a total initial level of detectable organic contaminants in total from about 2 w / w% to about 10 w / w% as measured by RP-HPLC analysis. Very pure terbinafine has a total level of detectable residual organic contaminants totaling from about 0.2 w / w% to less than about 1 w / w%, for example as measured by RP-HPLC in parallel with UV detection.

Thus, starting from a crude product comprising, for example, about 60 ppm to about 80 ppm of substance A, the salt form contains a very small amount of substance A below the detection limit, ie less than about 1 ppm (see Example 5). Pure product can be obtained after distillation and salt formation / precipitation.

Thus, for good results, it may be advantageous to combine the distillation of the crude terbinafine base with salt formation which coincides with the precipitation of pure trans isomers.

Thus, in a further aspect, the present invention provides a method of distilling crude terbinafine in free base form under conditions that substantially reduce non-metallic contaminant levels, with salt formation of the product concurrently with precipitation of the pure trans isomers. and generating the free base or acid addition salt form of very pure Terre rain and recovering the pin, non-of the metal contaminants comprises a novel method for the purification of terbinafine, which hereinafter simply as "method B" It is called.

Salt formation taking place simultaneously with precipitation is carried out in one step. Suitable solvents are, for example, esters of organic acids or mixtures of esters of organic acids with further organic solvents. A preferred ester of an organic acid, for example, esters of acetic acid, for example acetic acid C _{1 - 4} alkyl ester is, for example, methyl, ethyl, n- butyl or isobutyl ester, especially ethyl acetate.

Further organic solvents are, for example, alcohols corresponding to esters, such as ethanol with ethyl acetate, isopropanol with acetic acid isopropyl ester, and the like, in particular with ethanol.

Further organic solvents are, for example, aliphatic ketones, preferably methyl isobutyl ketone.

The temperature is preferably conventional, preferably about -25 ° C to about 100 ° C, preferably about room temperature.

Salt formation, which occurs concurrently with precipitation, is preferably carried out using an inorganic acid, preferably hydrochloric acid, for example as a gas or an aqueous solution, for example from about 5% to about 40% aqueous when the solvent is methyl isobutyl ketone Hydrochloric acid is carried out at pH 1 to 3 and at a temperature of about 10 ° C to about 30 ° C.

The terbinafine product produced from Method A or Method B, for example the terbinafine product in free base or hydrochloride form, is in another manner in the form of another acid addition salt, for example L-(-)-hydrogenmal It can be converted to maleate salts such as rate and vice versa.

Methods A and B can be carried out using large amounts of crude terbinafine bases, ie in industrial settings, for example in the large scale preparations defined above for the purified terbinafine bases and acid addition salts.

Therefore, the present invention

Method A or Method B as defined above comprising short path distillation;

Method A or method B as defined above, wherein the distillation is carried out under reduced pressure at a temperature above 100 ° C .;

Process A or method B as defined above, wherein the crude terbinafine is prepared using a palladium- and / or copper-containing catalyst;

The crude terbinafine is N-methyl-N- (1-naphthylmethyl) amine and compound 1-A-6,6-dimethyl-2-hepten-4-, wherein A is a leaving group, in particular 1 Method A or Method B as defined above, prepared using the reaction of Bromo-6,6-dimethyl-2-hepten-4-yne;

Process A or Method B as defined above, wherein the pure product in free base form is prepared at least 5 kg, preferably at least 50 kg, in particular at least 200 kg per distillation batch or operation;

Crude terbinafine is (E) -N- (3-halo-2-propenyl) -N-methyl-N- (1-naphthylmethyl) amine and 3,3-dimethyl-1-butyne palladium and Method A or Method B as defined above, which is prepared using a reaction in the presence of a copper catalyst;

Terbinafine in the form of a free base or acid addition salt purified to remove non-metal contaminants;

Pure terbinafine in free base or acid addition salt form comprising organic contaminants in total from about 0.2 w / w% to less than about 1 w / w%;

Pure terbinafine in free base or acid addition salt form containing up to about 1 ppm of substance A;

Pure terbinafine in free base or acid addition salt form prepared by Method A or Method B as defined above;

The crude terbinafine comprises more than about 5 ppm non-metallic contaminants selected from one or more compounds defined as a), b), c), d) and / or e) (substance A) , Method A or Method B as defined above;

Process A or Method B as defined above, wherein the crude terbinafine comprises more than about 5 ppm of the compound defined by e) (Material A) above;

Process A as defined above, wherein the crude terbinafine comprises more than about 5 ppm of material A and the purified terbinafine comprises less than about 5 ppm of material A;

Crude terbinafine is non-metallic contaminant; More than about 5 ppm non-metallic contaminants selected from, for example, at least one compound defined as a), b), c), d) and / or e); For example, greater than about 5 ppm of substance A; Method B as defined above, for example, wherein the crude terbinapine base comprises more than about 5 ppm of material A and the very pure terbinafine comprises less than about 1 ppm of material A;

Method A or Method B as defined above for the preparation of pure terbinafine;

The use of Method A or Method B as defined above in the preparation of pure terbinafine comprising less than about 1 ppm of substance A;

Terbinafine in free base or acid addition salt form prepared by Method A or Method B as defined above;

Contains less than about 5 ppm of substance A, prepared by method A as defined above; Pure terbinafine in the form of a free base or acid addition salt containing less than about 1 ppm of substance A, prepared by Method B as defined above;

A pharmaceutical composition comprising pure terbinafine in free base or acid addition salt form prepared by Method A or Method B as defined above with at least one pharmaceutically acceptable carrier or diluent;

A process for preparing pure terbinafine, for example having less than about 1 ppm of substance A, comprising reducing the level of substance A present in a crude sample of terbinafine;

A process for removing substance A from terbinafine, comprising distilling terbinafine in free base form;

Removing the sample of the crude terbinafine base before distillation and the sample of pure terbinafine base after distillation and evaluating the level of non-metallic contaminants such as substance A in the sample. Methods of monitoring non-metallic contaminant levels such as substance A when using A;

Removing a sample of crude terbinafine base before distillation, a sample of terbinafine base after distillation and a sample of terbinafine salt after salt formation / precipitation and evaluating the level of non-metallic contaminants such as substance A in the sample A method of monitoring non-metallic contaminant levels such as material A when using method B as defined above

It further includes.

Description of Figure 1:

1. Distillate outflow

2. End Connection with Vacuum Pump

3. Heat inflow

4. Condenser

5. Space under reduced pressure

6. Rolling wiper (evenly distributes the crude product to form a film)

7. heated jacket

8. Sealant, blown

9. Flange for interlock

10. Crude product inlet

11. Heating medium outlet

12. Residue Spill

13. Cooling water inlet

14. Coolant outlet

Figure 2 ( Chromatogram ) About:

I = blank chromatogram (solvent)

II = control solution 3 (substance A 1 ppm)

III = test solution (pure terbinafine; substance A not detected)

IV = "SST" solution (pure terbinafine; mixed with 5 ppm of substance A)

V = control solution 2 (substance A 100 ppm)

1 = drug terbinafine

2 = RS (ie terbinafine-related substance): substance A

WVL = 280 nm wavelength

Abscissa: minutes

Ordinate: mAU = absorption unit x 10 ^-3

(See also Example 4 )

The following examples illustrate the invention. All temperatures are in degrees Celsius (° C.). 1000 mbar is 750.06 mmHg. Examples 2, 4 and 5 illustrate the positive results obtained (Example 3 is unknown with regard to non-metal contaminant levels); Example 1 and Comparative Example are for (negative) controls.

Example  One: Batch  distillation  (Method A; laboratory scale)

( Negative about byproduct 1)

100 g of crude terbinafine base containing 0.3 area-% of (methyl) (naphthalen-1-ylmethyl) amine ( byproduct 1 ) is mixed with 20 g of peanut oil and the mixture is heated to 142 ° C. at a pressure of 0.3 mbar (Jacket temperature 190 ° C.). After 2 hours, 96.4 g of terbinafine base purified as a yellow distillate and 21.4 g of a dark brown residue were obtained. Due to the thermal shock during batch distillation (2 hours at 142 ° C.), the distillate was about 1 area-% of (methyl) (naphthalene-) as measured by gas chromatography (experimental conditions: the same as in Example 2 ). 1-ylmethyl) amine ( byproduct 1 ).

Distillation times and thermal shocks are quite high for large scale production. As a result, a significantly higher concentration of byproduct 1 can be expected, unless the distillation time is kept short, for example as a "short path" distillation.

The crude terbinafine base used as starting material is according to the method described, for example, in Example 13 of EP 421302 A2, but the catalyst amounts of copper iodide (I) and bis- (triphenylphosphate) are not subjected to silica gel chromatography. (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethanamine and 3,3- in N-butylamine and water in the presence of pin) palladium (II) -dichloride Prepared by reacting dimethyl-1-butyne.

Example  2: Short path  distillation  (Method A; laboratory scale)

(Unknown for by-product 1 and Z-isomer; positive for by- product 2)

Commercially available thin film evaporator (manufactured by Leybold-Heraeus GmbH, Hanoi, Hanoi, Germany: heating drum diameter 7 cm; length 25 cm; cooling finger 50 ° C; pressure 0.2 mbar; Teflon® 179 g of crude terbinafine base (e.g., prepared as described in Example 1 above) at rotator 450 rpm) was mixed with 8.9 g of peanut oil and the mixture was heated to 50 ° C. After the entire system was evacuated to 0.2 mbar, the mixture was slowly added dropwise to the hot zone (jacket temperature 160 ° C.) to initiate distillation where the terbinafine base was heated to boiling point for only a few seconds. After 2 hours, 171 g (95%) of pure terbinafine base as a yellow distillate were obtained, which was contaminated with less than 1 ppm of palladium and less than 1 ppm of copper. Gas chromatography (HP-1 column; cross-linked methyl siloxane; length 30 m; membrane thickness 2.65 μm; column inner diameter 0.53 mm; flame ionization detector (FID) temperature 300 ° C., injector temperature 250 ° C., temperature gradient 50 → 270 ° C .; The chemical purity of the distillate as measured by heating rate 20 ° C./min) was 98.6 w / w% terbinafine base (ie E-isomer). Further 10.5 g of distillation residue and 0.4 g of oil sublimate were obtained. The main component of the sublimate was 2,2,7,7-tetramethylocta-3,5-diyne ( byproduct 2 ).

The overall purity of the terbinafine base measured by gas chromatography was as follows.

Before distillation (crude product) After distillation (pure product) By-product 1 (area-%) 0.1 0.1 By-product 2 (area-%) 0.7 0.2 Z-isomer (area-%) 0.3 0.3 E-isomer (weight-%) 95.6 98.6 Pd (ppm) 177 One Cu (ppm) 19 <1

Example  3: Short path  distillation  (Method A; industrial scale)

(Positive for metal contaminants; unknown for non-metal contaminants)

Distillation of the crude terbinafine base was carried out in a sophisticated vacuum distillation apparatus (UIC GmbH KD 150) using short path distillation using two series of evaporators. This allowed the material to be fed continuously and distributed over the inner surface of the vertically oriented evaporator. As the liquid flowed downward, the axially arranged roller wiper system distributed the liquid as a thin film and continuously mixed it (see figure ). Thus, this mild distillation method reduced both the maximum evaporation temperature and the residence time at high temperatures.

The starting temperature value was typically set as follows:

Internal limit of the supply tank: 70 ° C .;

Internal limit of product receiver: 80 ° C .; Jacket limit of residue tank: 80 ° C;

Upper and lower internal limits of evaporators 1 and 2: 100 ° C .;

Jacket limit of evaporators 1 and 2: 160 ° C.

After adjusting the whole device to empty and purify, the maximum vacuum of the two evaporators that can be reached by the diffusion pump was checked:

Before and after evaporator 1: 1.6 × 10 ⁻¹ mbar;

Before evaporator 2: 2.6 x 10 ^-2 mbar;

After evaporator 2: 4.7 x 10 ^-3 mbar.

A mixture of 872.5 kg of crude terbinafine base (prepared similar to that described in Example 1 above) and 120 kg of peanut oil was then delivered to the feed tank. The peanut oil will prevent hard surfaces from accumulating inside the evaporator. The cold trap was filled with a mixture of 20-30 kg of dry ice and about 30 L of ethanol (94%) and the temperature valve adjusted as follows:

Jacket of residue receiver: 40 ° C .;

Jacket of evaporator 1: 120 ° C .;

Condenser of evaporator 1: 50 ° C .;

Jacket of evaporator 2: 155 ° C .;

Condenser of evaporator 2: 45 ° C.

Since the melting point of the product was about 42 ° C, the internal temperature of the main receiver was set to 50 ° C.

When all temperatures were reached, the crude product was fed to evaporator 1 at a flow of about 1.5 L / min. As the volume of distillate (remaining solvent) of evaporator 1 decreased, it could collect in the gauge. The residue of evaporator 1 was passed to evaporator 2 to distill the crude base, which was collected as a yellow liquid in a heated main receiver (1.4 L / min).

When all the crude mixture was distilled (about 11 hours), the residue of evaporator 2 was transferred to the feed tank and distilled again. The jacket temperature of evaporator 1 was thus reduced to 110 ° C. and the jacket temperature of evaporator 2 was reduced to 140 ° C.

After the distillation of the residue is complete (about 2 hours), the fresh residue will be circulated through the evaporator until the flow of product reaches about 0.2 L / hour. Before the circulation could be initiated, the jacket temperature of evaporator 1 was reduced to 100 ° C. and the condenser temperature of evaporator 2 was raised to 60 ° C. During circulation, the distillate stored became darker.

At the end of the distillation (about 22.5 hours total), the device was released using nitrogen. The product from the main receiver was filled into a drum at about 50 ° C. Samples were collected and drums were weighed. The chemical purity of the free base measured by gas chromatography was at least 97 w / w% (here 98.4%). Yield was 856.1 kg. The residual amount of copper and / or palladium was very small and undetectable (less than 1 ppm).

The residue (approximately 120 kg peanut oil; here 128 kg), the distillate of evaporator 1 and the condensate of the cold trap were combined and incinerated. After 5-6 batches, the apparatus was cleaned.

Comparative example : Sword  Tablet (Laboratory Scale)

( Negative for metal and non-metal contaminants)

404 g of crude terbinafine base solution in cyclohexane (100 g of (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalene-methanamine, similar to that described in Example 1 above) 10 g of activated gum charcoal (Norit Supra®) was added. The mixture was stirred at 20-25 ° C for 17 h and then filtered. After evaporation of the solvent at reduced pressure, 110.5 g (89%) of terbinafine base contaminated with 14 ppm of palladium were obtained. The chemical purity of the oil residue measured by gas chromatography (experimental conditions: same as Example 2 ) was 95% .

Example  4: Short path  RP- in parallel with distillation and UV detection HPLC  (Method A; industrial scale)

( Positive for non-metallic contaminants, especially substance A)

Substance A 80 ppm ( 62 ppm in other batches) (crude terbinafine base sample measured by RP HPLC analysis in parallel with UV detection) and other detectable non-metallic contaminants 2.45 w / w% (in other batches) Industrial scale (872.5 kg) crude terbinafine base from two batches containing 2.40% ) was short-path distilled (combined two batches) as described in Example 3 above, and samples of crude terbinafine base Was collected from the distillate and analyzed again by RP HPLC. The sample was found to still contain 5 ppm of substance A and 1.14 w / w% of other detectable non-metallic contaminants .

RP HPLC in parallel with UV detection was performed as follows:

reagent:

Acetonitrile: for example LiChrosolv® Merck

Water: for example licrosolve (Merck)

Triethylamine: for example puriss p.a. (Fluka);

Solvent: acetonitrile or acetonitrile / water 8: 2 (v / v);

By-product from terbinafine synthesis according to Comparative Material A (e.g., method a of EP 24587) from about 11 mg isolated by silica gel chromatography, whose chemical structure is confirmed by spectroscopy .

Device: HP 1100 (Agilent), Alliance 2695 (Waters)

Column : XTerra RP18, particle size 3.5 μm, length 150 mm, inner diameter 3.0 mm

Chromatography Conditions:

Mobile phase: A: water / triethylamine 1000: 1 (v / v);

          B: acetonitrile / triethylamine 1000: 1 (v / v)

Gradient:

Minutes Phase A (%) Phase B (%) 0 43 57 8 33 67 12 5 95 13 5 95 13.1 33 57 16 33 57 Then inject

Flow rate: 1.0 ml / min

Detection wavelength: UV absorption at 280 nm

Temperature: 52 ℃

Injection volume: 20 μl test solution and control solution

Deployment time: 16 minutes

Sample concentration: 40 mg / ml

System suitability was corrected with the control solution for the following:

Reproducibility ( Control Solution 2 containing 100 ppm of Substance A is prepared by diluting 2.0 ml Control Solution 1 to 20.0 ml with solvent; Control Solution 1 containing 1000 ppm of Substance A has an accuracy of ± 0.001 mg). Obtained by weighing about 2 mg into a 50 ml volumetric flask and dissolving in a solvent to dilute to 50 ml);

Reporting limit ( control solution 3 containing 1 ppm of substance A is prepared by diluting 2.0 mL of control solution 2 to 20.0 mL with solvent and 2.0 mL aliquot of the solution to 20.0 mL with solvent); And

Selectivity ( "SST" solution is prepared by weighing about 200 mg of test substance into a 5.0 ml volumetric flask with an accuracy of ± 0.1 mg, adding 250 μl of Control Solution 2 and then diluting to volume by solvent; It contains 100% of the drug and is mixed with 5 ppm of substance A).

Solvent was also used alone for the blank chromatogram. Two test solutions were prepared by weighing about 200 mg of the test substance into a 5.0 ml volumetric flask with an accuracy of ± 0.1 mg, dissolving with a solvent and diluting to volume.

Preference is given to using amber glass flasks and vials.

The peak areas of material A were determined in the chromatograms of test solution and control solution 2.

Calculated as follows (ignoring peaks below the reporting limit of 1 ppm):

In the formula,

RS = terbinafine-related substance, for example substance A

PA _T = peak area of RS in test solution

PA _R2 = peak area of RS in Control Solution 2

m _R = Amount of RS in control solution 1 (mg)

m _T = amount of test substance in test solution (mg)

C _R = content of RS used in the control solution (%)

f = 0.01 = dilution factor

10000 = conversion factor to ppm

The results from typical developments are as shown in the attached chromatogram (WVL = 280 nm wavelength; abscissa = min; ordinate = mAU = absorption unit x 10 ^-3 ). The relative residence times of the drug terbinafine base and substance A were 1.00 and about 1.73, respectively.

Other non-metallic impurities also use similar conditions, for example, having a particle size of 5 μm, mobile phase A being water containing 0.1% triethylamine (v / v), and mobile phase B having 0.1% triethylamine ( v / v) using a reversed phase Hypersil ODS with methanol, solvent methanol or methanol / water 80:20 (v / v), sample concentration 0.5 mg / ml and column temperature 40 ° C Could be detected.

Example  5: Short path  Salt formation occurring simultaneously with distillation followed by precipitation  (Method A and Method B; industrial scale)

(Especially positive about substance A)

a) distillation (method A):

The terbinafine crude base was distilled off in a short path as described in Example 4 above. The resulting purified terbinafine base comprising 5 ppm of substance A was then salt formed simultaneously with precipitation as determined by RP HPLC analysis in parallel with UV detection.

b) additionally salt formation coinciding with the precipitation of the trans isomer (method B):

Ethyl acetate was added to the base product from step a) and the mixture was stirred at 20 ° C. until complete dissolution, the resulting solution was filtered (2 μm) and the pressure dropped to 0.5 bar at a temperature of 20 ° C. Hydrochloric acid gas was then introduced at 20 ° C to 25 ° C. The resulting suspension was stirred for 4-15 hours at 20 ° C., centrifuged, the product obtained was washed with ethyl acetate, centrifuged at 1000 rpm and the product dried. Pure terbinafine hydrochloride was obtained. Samples were collected and analyzed by RP HPLC. It was found to contain less than 1 ppm of substance A.

Claims (20)

Distilling the crude terbinafine in free base form under conditions that substantially reduce non-metal contaminant levels, and recovering the non-metallic terbinafine in the form of the resulting free base or acid addition salt. Method for Purifying Terbinapine from Contaminants (Method A). Distilling the crude terbinafine in free base form under conditions that substantially reduce the level of non-metallic contaminants, with salt formation of the product coincident with the precipitation of the pure trans isomer, and the resulting free base or acid addition salt A process for purifying terbinafine from non-metallic contaminants comprising recovering very pure terbinafine in form (Method B). The process of claim 1 or 2 comprising short path distillation. The process according to claim 1 or 2, wherein the distillation is carried out at a temperature above 100 ° C under reduced pressure. 3. The crude terbinafine of claim 1, wherein the crude terbinafine is N-methyl-N- (1-naphthylmethyl) amine and compound 1-A-6,6-dimethyl-2-hepten-4- , A is prepared using the reaction of a leaving group, in particular bromo). Terbinafine in the form of free base or acid addition salt purified to remove non-metal contaminants. The pure terbinafine of claim 6 comprising from about 0.2 w / w% to less than about 1 w / w% total organic contaminants. 8. The pure terbinafine of claim 7 comprising less than about 1 ppm of substance A. 3. The process according to claim 1, wherein the crude terbinafine comprises more than about 5 ppm of non-metallic contaminants selected from one or more of the following compounds, in particular greater than about 5 ppm of material A. 4. a)

That is, 6,6-dimethyl-2-hepten-4-ynal; b)

That is, (methyl) (naphthalen-1-ylmethyl) amine = N-methyl-N- (1-naphthylmethyl) amine = N-methyl-1-naphthalenemethanamine (byproduct 1); c)

Ie, (Z) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethanamine (= Z-isomer); d)

Namely, (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthylmethanamine; And / or e)

(Substance A) The method of claim 1, wherein the crude terbinafine comprises more than about 5 ppm of material A and the pure terbinafine comprises less than about 5 ppm of material A. The method of claim 2, wherein the crude terbinafine comprises more than about 5 ppm of material A and the very pure terbinafine comprises less than about 1 ppm of material A. 4. Use of the method according to claim 1 or 2 for the preparation of pure terbinafine. 13. Use of a method for the preparation of pure terbinafine according to claim 12 comprising less than about 1 ppm of substance A. Terbinafine in free base or acid addition salt form prepared by the process according to claim 1. The method according to claim 14, which contains less than about 5 ppm of substance A prepared by the method according to claim 1, or contains less than about 1 ppm of substance A, prepared by the method according to claim 2. Pure terbinafine. A pharmaceutical composition comprising pure terbinafine in free base or acid addition salt form prepared by the method according to claim 1 together with one or more pharmaceutically acceptable carriers or diluents. A method of making pure terbinafine having less than about 1 ppm of substance A, comprising reducing the level of substance A present in the crude sample of terbinafine. A method of removing substance A from terbinafine comprising distilling terbinafine in free base form. The method of claim 1 comprising removing a sample of crude terbinafine base before distillation and a sample of pure terbinafine base after distillation, and evaluating the level of non-metallic contaminants such as substance A in the sample. Method for monitoring the level of non-metallic contaminants such as substance A when using the method according to the method. Removing a sample of crude terbinapine base before distillation, a sample of terbinafine base after distillation and a sample of terbinafine salt after salt formation / precipitation, and evaluating the level of non-metal contaminants such as substance A in the sample A method of monitoring non-metallic contaminant levels such as substance A when using the method according to claim 2.

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