JP2012176960A - Purification method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for performing purification of allylamine medicinal, terbinafine in a free base form or in an acid addition salt form, from a nonmetal contaminant.SOLUTION: Crude terbinafine base of formula (I) is distilled, preferably by short path distillation, for example, at a temperature above 100°C and reduced pressure, for example, 0.2 mbar (method A), if desired, salt formation of the product obtained under simultaneous precipitation with a pure trans isomer is also obtained (method B), and pure terbinafine in a free base form or in an acid addition salt form is recovered.

Description

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

In particular, terbinafine in the form of an acid addition salt which is the hydrochloride is known, for example, from EP 24587. It belongs to the class of allylamine antifungals. It is marketed under the trademark Lamisil ^R. It is effective for a wide range of fungal infections, both topically and orally. Terbinafine is particularly effective against skin dead tissue or its appendages, such as dermatophytes, which are infectious fungi that invade the stratum corneum, nails and hair.

Terbinafine represents a significant advance in antifungal therapy based on its powerful bactericidal action in vitro and its rapid clinical effect on various dermatophyte infections when administered orally and topically. It is a potent inhibitor of ergosterol biosynthesis ( Ann. NY Acad. Sci. 544 [1988] 46 62), which blocks the action of squalene epoxidase and thus inhibits the conversion of squalene to squalene epoxide. Ergosterol synthesis is only partially inhibited, but cell growth is completely blocked. This suggests that the bactericidal action of terbinafine may be related to the accumulation of squalene, which may be toxic to fungi at high concentrations. The spectrum of terbinafine activity in vitro includes all dermatophytes of the genera Trichophyton, Epidermophyton and Microsporum. Mean 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 in vitro against molds and dimorphic fungi, and against a number of pathogenic yeasts of the genus Pityrosporum, Candida and Rhodotorula.

で示されるとおりであり、そしてその化学名はとりわけ（Ｅ）−Ｎ−（６，６−ジメチル−２−ヘプテン−４−イニル）−Ｎ−メチル−１−ナフタレン−メタンアミンである。 The structure of terbinafine has the formula I

And its chemical name is inter alia (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalene-methanamine.

  It can be in the free base form or the acid addition salt form. The 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 such as L-(−)-malate. The free base and the hydrochloride and malate are preferred, especially the hydrochloride and L-(-)-malate.

  As apparent from the above formula I, terbinafine is an allylamine compound having a triple bond conjugated to a double bond in the side chain. Terbinafine was invented long ago (see, for example, EP 24587, Example 16), and such conjugated enyne structures were very rare at the time and still in the field of medicine, and have new structural features in medicinal chemistry. Constitute.

  Both double and triple bonds are usually very reactive. The chemical literature does not exclude the possibility that a compound with such a structure is stable, but some are unstable and when stored or processed, for example, when heat is applied, e.g. Sometimes it can be broken down.

It is already known that subjecting pure penta-1,2-dien-4-yne to simple distillation at its normal boiling temperature of 57 ° already results in decomposition, for example ERH Jones et al., J. Chem. Soc . (1960) 341-346. Similarly, (non-conjugated) 1-alkene-4-yn-dimer _{[CH 2 = CH-CH 2} -C≡C-C (CH 3) (OH) -] 2, i.e., 6,7-dimethyl - dodeca - 1,11-diene-4,8-diyne-6,7-diol (compound V of H. Disselnkoetter and P. Kurtz, Ann. Chem. [1964] 26-34) at low temperature (85-90 ° C.) and pressure Considerable degradation occurs by distillation at (0.05 mmHg) and by fresh distillation at 81-85 ° C. and 0.03 mmHg. Furthermore, enediyne, (Z, Z) -3,7-decadiene-1,5,9-triene polymerizes easily, and the solution is pyrolyzed at 170-190 ° C. to naphthalene, while corresponding (E , Z) and (E, E) isomers lead to other products or polymers ( J. Am. Chem. Soc. 114 [1992] 3120 3121).

Furthermore, the isomerization of conjugated eneyne compounds, such as ether CH ₃ CH═CH—C≡C—CH ₂ OC ₂ H ₅ , to the corresponding 1,3,5-triene compound can be achieved by the accompanying ethanol 1,6 -. obtained with a large quantity of polymer residue after distillation, resulting from removal, whereas, substituted at the amino group of OC ₂ H ₅ group results in aromatization (Van Dongen, J. et al, Recueil Trav. Chim. Pays-Bas 86 [1967] 1077 1081).

Furthermore, if distillation is carried out with an enyne derivative, it is expected to be a highly reactive compound that can decompose or disintegrate or polymerize on heating, and even explode, so it is usually below 100 ° C or slightly above, especially Performing at temperatures below about 125 ° C. is, for example, quite obvious from the above publication. This is also the case with most of the alkene derivatives described for example in Recueil Trav.Chim.Pays-Bas 85 (1966) 952 965 and Zh.Org.Khim 3 (1967) 1792 3 (CA 68 [1968] 12370). The two intermediates for the pheromone described in Czech Author's Certificate No. 232843 (CA 106 [1984] 213632b) are purified by distillation at 102-115 ° C and 118-125 ° C, respectively, under reduced pressure.

一方、生成物は４３℃未満で既に凝固する。 In addition, the free base form of terbinafine is boiled at 140 ° C. with a pressure of 0.3 mbar and at that temperature its thermal stability is limited: therefore the following decomposition can be observed (analysis by gas chromatography; all peaks The area of the peak of one compound that is compared to the sum is named area%; for the Z isomer, area% should be approximately equal to weight%):

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

  Therefore, especially in large-scale operations such as in the industrial manufacture of pharmaceuticals, when post-processing a compound having such an unusual structure, especially when the structure is associated with limited thermal stability, Will refrain from performing operations that require substantial application of. For example, in Example 13 of Banyu EP 0 421302 A2, which describes the preparation of terbinafine, the crude mixture (free base) obtained after the reaction is subjected to purification by silica gel chromatography.

  However, contrary to intuition, it has been found by the present invention that terbinafine base can be subjected to distillation without particularly adverse effects. Furthermore, such distillation can be carried out at elevated temperatures, for example, temperatures significantly exceeding 100 ° C., for example from about 110 ° C. to about 170 ° C., preferably from about 125 ° C. to about 165 ° C., especially about 160 ° C. and corresponding reduced pressures. It has been found that it can be achieved, for example, at 160 ° C. (jacket temperature) at 0.2 mbar.

  The yield achieved thereby is usually about 95% starting from the crude product.

  The above invention is a novel method for the purification of terbinafine comprising subjecting the free base form of crude terbinafine to distillation and recovering the resulting free base or acid addition salt form product. / EP2004 / 9587 (WO 2005/21483) and its corresponding patents.

The process is especially notable for separating terbinafine from, for example, catalysts, such as copper and / or especially palladium contaminants, especially from metal contaminants resulting from its chemical synthesis, in particular for example Banyu EP 421302 and / or Dipharma EP 1 For example, (E) -N- (3-halo-2-propenyl) -N-methyl-N- (1-naphthylmethyl) amine (R ¹¹ ) for obtaining terbinafine base is described in '236'709. Is a compound of formula IV of EP 421302 where R ²¹ is 1-naphthylmethyl and W is a halogen such as bromo, preferably chloro, and 3,3-dimethyl-1-butyne (R ⁷ Resulting from a method according to or similar to the reaction of a compound of the above formula V wherein is tert-butyl) in the presence of palladium and / or copper catalyst It is emphasized therein that contaminants are useful to reduce or eliminate that. The catalyst is, for example, copper (I) iodide, or copper (I) iodide and bis (triphenylphosphine) palladium (II) dichloride or tetrakis (triphenylphosphine) palladium, or even EP 421302 A2, for example on page 7 Palladium, copper or palladium / copper containing catalyst selected from those described on line 54 to line 18 on line 54.

  The method is by conventional means, preferably as a so-called “mild” distillation method, for example as a batch distillation, or preferably in a continuous or semi-continuous method, and especially the path between the heating mantle and the cooler is as short as eg 10 cm. Thus, it is performed as a “short path” distillation that minimizes the time for terbinafine to remain at high temperatures, eg, above 100 ° C.

  The term “short path distillation” should be understood as high vacuum distillation to separate a mixture of organic (or silicon) compounds that cannot withstand prolonged heating without undue structural change or degradation. This utilizes the heat of condensation as the main body for radioactive heat release to the evaporator surface film. The path between the evaporator and the cooler is not blocked. Due to the short residence time and low distillation temperature, the thermal hazard to organic substances is greatly reduced.

  The method using short path distillation can be carried out in accordance with the description of WO 2005/21483, for example using convenient equipment as illustrated in the figure, whereby distillation is preferred and cyclic processing is carried out. While allowing a short heating time of the mixture intended for purification, the yield of the product to be purified is correspondingly improved. Furthermore, the thickness of the material on the evaporator wall is reduced, allowing a lower evaporation temperature and a shorter residence time. Thereby, very efficient separation from contaminants is achieved without the need for further purification steps such as by chromatography or recrystallization or the use of large amounts of charcoal.

  However, prior to the present invention, the greatest potential and use derived from the ability of terbinafine base to be able to carry out distillation at high temperatures without decomposition or with little decomposition was not understood. Other non-metallic contaminants, especially organic compounds such as (methyl) (naphthalen-1-ylmethyl) amine (byproduct 1); 2,2,7,7-tetramethylocta-3,5-diyne (formation) It was believed that the Z isomer of terbinafine, if present, could be removed, for example, only partially or not at all, by-product 1 and the terbinafine Z isomer.

  However, thorough research and refinement of methods that can be used to detect pollutants is now unexpected, and further organic pollutant compounds can be removed using the above method or similar conditions or are highly It was shown that it can be reduced.

  From the physicochemical properties of terbinafine base and such organic contaminants, it is very surprising and surprising that this simple distillation means can separate most of these contaminants from the pharmaceutical end product. Met.

  Thus, convenient means can be used according to the present invention to produce highly purified terbinafine from organic contaminants on a large, industrial scale.

  “Pure terbinafine” in free base form or acid addition salt form is defined herein as terbinafine free of non-metallic contaminants, eg, containing less than about 2% w / w of non-metallic, especially organic contaminants in total. Yes. Conversely, “crude terbinafine” is generally about 2% w / w or more, such as about 2% to about 10%, especially about 2% to about 5% w / w of such non-metallic contaminants, and substances With respect to A (defined below), it should be understood that it has about 5 ppm or more, eg, about 5 ppm to about 200 ppm, especially about 5 ppm to about 100 ppm of substance A.

  In a first aspect, therefore, the present invention is subjecting the free base form of crude terbinafine to distillation under conditions that result in a substantial reduction in the concentration of non-metallic contaminants, and the resulting free base form or acid addition salt form of pure terbinafine. Relates to a new method for the purification of terbinafine from non-metallic contaminants, including the recovery of the following: “Method A” for short.

  The detection of non-metallic contaminants is preferably below the conventional quantitation limit of about 0.05% w / w (500 ppm) normally achieved by conventional detection methods such as reverse phase high pressure liquid chromatography (RP-HPLC). Preferably achieved using commercially available equipment, for example HP 1100 (Agilent) and Alliance 2695 (Waters) as described in Example 4 below and as described in Example 4 below, for example UV Performed using analytical methods that are sensitive to concentrations of the lower limit of quantification as low as about 0.0001% (1 ppm) of RP HPLC with detection. Typical results are, for example, as illustrated in the chromatogram below.

  “Large-scale” or “industrial scale” production of purified terbinafine base or acid addition salt herein is at least about 5 kg, preferably at least about 50 kg, especially at least about 50 kg, based on the free base form, per distillation batch or run. It means an amount of product of about 200 kg, for example about 500 kg to about 2 tons, more preferably about 600 kg to about 900 kg, more preferably about 800 kg to about 900 kg, especially about 850 kg.

  “Substantial reduction in non-metallic contaminant concentration” is determined by, for example, RP-HPLC (reverse phase high performance liquid chromatography) with UV detection analysis, resulting in an overall initial concentration of about 2% to about 10 total. Starting from crude terbinafine base with% w / w detectable organic contaminants, total less than about 0.5% to about 2% w / w, especially less than about 0.5% detectable non-metallic, It should be understood as obtaining a concentration of essentially organic pollutants.

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

  The distillation is preferably at a temperature of about 100 ° C. to about 170 ° C., such as about 110 ° C. to about 170 ° C., preferably about 125 ° C. to about 165 ° C., especially about 160 ° C. (jacket temperature) and correspondingly reduced pressure. Under, for example, about 0.2 mbar and 160 ° C.

すなわち、６，６−ジメチル−２−ヘプテン−４−イナル（ｙｎａｌ）；
ｂ）

すなわち、（メチル）（ナフタレン−１−イルメチル）アミン；Ｎ−メチル−Ｎ−（１−ナフチルメチル）アミン；Ｎ−メチル−１−ナフタレンメタンアミン（副生成物１）；
ｃ）

すなわち、（Ｚ）−Ｎ−（６，６−ジメチル−２−ヘプテン−４−イニル）−Ｎ−メチル−１−ナフタレンメタンアミン（＝Ｚ異性体）；
ｄ）

すなわち、（Ｅ）−Ｎ−（３−クロロ−２−プロペニル）−Ｎ−メチル−１−ナフチルメタンアミン；
および特に
ｅ）

すなわち
（Ｅ）−４−［４，４−ジメチルペンチン−（Ｅ）−イリデン］−Ｎ^１，Ｎ^５−ジメチル−Ｎ^１，Ｎ^５−ビスナフタレン−１−イルメチル−ペント−２−エン−１，５−ジアミン
または
２（Ｅ），４（Ｚ）−Ｎ−（４−［（Ｎ’−メチル−Ｎ’−１−ナフチルメチル）アミノメチル］−８，８−ジメチル−２，４−ノナ−ジエン−６−イニル）−Ｎ−メチル−１−ナフチルメタンアミン（物質Ａ）。 These additional non-metallic contaminants are usually organic compounds, such as one or more of the following compounds:
a)

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

(Methyl) (naphthalen-1-ylmethyl) amine; N-methyl-N- (1-naphthylmethyl) amine; N-methyl-1-naphthalenemethanamine (byproduct 1);
c)

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

(E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthylmethanamine;
And especially e)

That is, (E) -4- [4,4-dimethylpentyne- (E) -ylidene] -N ¹ , N ⁵ -dimethyl-N ¹ , N ⁵ -bisnaphthalen-1-ylmethyl-pent-2-ene- 1,5-diamine or 2 (E), 4 (Z) -N- (4-[(N′-methyl-N′-1-naphthylmethyl) aminomethyl] -8,8-dimethyl-2,4- Nonadiene-6-ynyl) -N-methyl-1-naphthylmethanamine (Substance A).

  Substance A uses, for example, the method a) of EP 24587 for the preparation of terbinafine, ie N-methyl-N- (1-naphthylmethyl) amine (compound of formula IV of the above EP) is 1-A-6. , 6-Dimethyl-2-hepten-4-yne (a compound of formula V of the above EP where A is a leaving group, especially bromo) is present as a non-metallic contaminant.

  Terbinafine has a trans configuration and is usually sold in pharmaceutical compositions such as tablets, where the active ingredient is in the hydrochloride salt form. Thus, the free base should be converted to an acid addition salt, such as the hydrochloride salt, which, when a crude mixture of terbinafine free base contains a substantial amount of, for example, a cis isomer impurity, the pure trans isomer is subject to simultaneous salt precipitation conditions. Can be obtained by salt formation with an acid such as hydrochloric acid. 678527. Preferably this is an ester of an organic acid, for example ethyl acetate, or an ester of an organic acid, for example a mixture of ethyl acetate and a further organic solvent, or for example using the conditions described in WO 01/28976 Performed with hydrochloric acid solution and an organic solvent such as methyl isobutyl ketone.

  Surprisingly, such salt formation under co-precipitation conditions of pure trans isomers can be advantageously used with the above method of the present invention for further removal of the above non-metallic contaminants, This time it also found the production of terbinafine.

  For example, when starting from a crude terbinafine base with organic contaminants detectable from a total of less than 2% to about 10% w / w at an overall initial concentration, as measured by RP-HPLC analysis, for example, UV detection Such exceptionally pure terbinafine has a total detectable concentration of organic contaminants of less than about 0.2% to about 1% w / w, as measured by RP-HPLC having.

  Thus, for example, starting from a crude product containing about 60 to about 80 ppm of substance A, a particularly pure product in salt form containing less than the detection limit, ie less than about 1 ppm of substance A is distilled and salted / It can be obtained after precipitation (see Example 5).

  Thus, for excellent results, distillation of the crude terbinafine base can be advantageously combined with salt formation under simultaneous precipitation of pure trans isomers.

  In a further aspect, therefore, the present invention is subjecting the free base form of crude terbinafine to distillation under conditions that result in a substantial reduction in the concentration of non-metallic contaminants and simultaneously under the simultaneous precipitation of the pure trans isomer of the resulting product. A new method for purifying terbinafine from non-metallic contaminants, including salt formation and recovery of the resulting free base or acid addition salt form of exceptionally pure terbinafine, hereinafter "Method B" for short .

Salt formation and precipitation are accomplished in one step. Suitable solvents are, for example, esters of organic acids or mixtures of organic acid esters and further organic solvents. Preferred esters of organic acids are, for example, esters of acetic acid, such as C _1-4 alkyl esters of acetic acid, such as methyl, ethyl, n-butyl or isobutyl esters, especially ethyl acetate.

  Further organic solvents are, for example, alcohols and the corresponding esters, such as ethanol and ethyl acetate, isopropanol and isopropyl acetate, especially ethanol and ethyl acetate.

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

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

  Salt formation and coprecipitation is preferably, for example, when the solvent is methyl isobutyl ketone having a pH of 1-3 and having a hydrochloric acid aqueous solution of about 5% to about 40% at a temperature of about 10 ° to about 30 °, for example a gas or It is carried out with an inorganic acid as an aqueous solution, preferably hydrochloric acid.

  For example, terbinafine products obtained from Method A or Method B in free base form or hydrochloride form can be prepared in a conventional manner by further acid addition salt forms, such as malates, for example L-(-)-hydrogen malate. And vice versa.

  Methods A and B can be carried out using large amounts of crude terbinafine base, ie, on a large scale production as defined above, eg, in an industrial environment of purified terbinafine base and acid addition salts.

Accordingly, the present invention further includes, among other things:
-Method A or B as defined above comprising short path distillation;
Method A or B as defined above, wherein the distillation is carried out at a temperature above 100 ° C. and under reduced pressure;
Method A or B as defined above, wherein the crude terbinafine is produced using a palladium and / or copper containing catalyst;
The compound 1-A-6,6-dimethyl-2-hepten-4-yne, especially 1-bromo-6, wherein the crude terbinafine is N-methyl-N- (1-naphthylmethyl) amine and A is a leaving group , Method A or B as defined above, prepared using the reaction of 1,6-dimethyl-2-hepten-4-yne;
Method A or B as defined above, wherein at least 5 kg, preferably at least 50 kg, in particular at least 200 kg of pure product in free base form are produced per distillation batch or run;
The crude terbinafine and (E) -N- (3-halo-2-propenyl) -N-methyl-N- (1-naphthylmethyl) amine in the presence of a palladium- and / or copper-containing catalyst, 3,3 -Process A or B as defined above, prepared using the reaction of dimethyl-1-butyne;

Terbinafine in free base form or acid addition salt form purified to remove non-metallic contaminants;
-Pure terbinafine in free base or acid addition salt form, which contains a total of about 0.2% to less than about 1% w / w organic contaminants;
-Pure terbinafine in free base form or acid addition salt form containing about 1 ppm or less of substance A;
-Pure terbinafine in free base form or acid addition salt form produced by method A or B as defined above;
The crude terbinafine contains more than about 5 ppm of non-metallic contaminants selected from one or more compounds defined as a), b), c), d) and / or e) (Substance A) above Including method A or B as defined above;
E) Method A or B as defined above comprising more than about 5 ppm of the compound defined as e) (Substance A);
-Method A as defined above, wherein the crude terbinafine contains more than about 5 ppm of substance A and the purified terbinafine contains less than about 5 ppm of substance A;
A non-metal selected from one or more compounds wherein the crude terbinafine is defined as a non-metallic contaminant; for example greater than about 5 ppm a), b), c), d) and / or e) Contaminant; eg, containing more than about 5 ppm of substance A; eg, method B as defined above, wherein the crude terbinafine base contains more than about 5 ppm of substance A and exceptionally pure terbinafine contains less than about 1 ppm of substance A;
-Method A or B as defined above for the production of pure terbinafine;
Use of method A or B as defined above for the production of pure terbinafine containing less than about 1 ppm of substance A;

Terbinafine in the free base or acid addition salt form produced by method A or B as defined above;
-Containing less than about 5 ppm of substance A prepared by method A as defined above; or pure terbinafine in free base or acid addition salt form 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 form or acid addition salt form produced by method A or B as defined above and one or more pharmaceutically acceptable carriers or diluents;
-A method of producing pure terbinafine having, for example, less than about 1 ppm of substance A, comprising reducing the concentration of substance A present in a crude sample of terbinafine;
-A method for removing substance A from terbinafine comprising distilling terbinafine in free base form;
When using method A as defined above, comprising taking a sample of crude terbinafine base before distillation and a sample of pure terbinafine base after distillation and assessing the concentration of their non-metallic contaminants, eg, substance A A method for monitoring the concentration of non-metallic contaminants such as substance A;
-Taking 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 assessing the concentration of their non-metallic contaminants, e.g. A method of monitoring the concentration of non-metallic contaminants, eg, substance A, when using method B as defined above.

Figure Legend (1/2):
1. 1. Distillate outflow section 2. Connection to vacuum pump 3. Heat inflow part 4. Cooler 5. Space under reduced pressure Rolling wiper (distributes the crude product evenly to form a film)
7). Heating jacket8. 8. Fill liquid, intake port 9. Flange for gear unit 10. Injection part for crude product 11. Heat medium outflow section 12. Outflow portion of residue 13. Inlet for cooling water Outlet for cooling water

Explanation of chromatogram (2/2):
I = Blank chromatogram (solvent)
II = Reference solution 3 (1 ppm of substance A)
III = test solution (pure terbinafine; no substance A detected)
IV = “SST” solution (with pure terbinafine, 5 ppm of substance A)
V = Reference solution 2 (100 ppm of substance A)
1 = drug, terbinafine 2 = RS (ie terbinafine related substance): substance A
WVL = Wavelength 280nm
Abscissa: minutes (minutes)
Ordinate: mAU = absorption unit × 10 ⁻³
(See also Example 4)

Figure Legend (1/2): 1. 1. Distillate effluent; 2. connection to the vacuum pump; 3. Heat inflow part; 4. cooler; 5. space under reduced pressure; 6. Rolling wiper (distributing the crude product uniformly to form a film); 7. heating jacket; 8. Filling liquid, intake; 9. flange for gearing; 10. injection part of the crude product; 11. Heat medium outflow part; 12. Outflow portion of residue; 13. inlet for cooling water; Outlet for cooling water Chromatogram description (2/2): I = blank chromatogram (solvent); II = reference solution 3 (1 ppm of substance A); III = test solution (pure terbinafine; no detected substance A); IV = “ SST ”solution (with pure terbinafine, 5 ppm of substance A); V = reference solution 2 (100 ppm of substance A); 1 = drug, terbinafine; 2 = RS (ie terbinafine related substance): substance A; WVL = wavelength 280 nm Abscissa: minutes (minutes); ordinate: mAU = absorption unit × 10 ⁻³ (see also Example 4)

  The following examples illustrate the invention. All temperatures are in degrees Celsius (° C). 1000 mbar = 750.06 mmHg. Examples 2, 4 and 5 illustrate the positive results obtained (Example 3 is not informative regarding non-metallic contaminant concentrations); Example 1 and the comparative example are (negative) for reference is there.

Example 1 : Batch distillation (Method A; laboratory scale)
( Negative for byproduct 1)
100 g crude terbinafine base containing 0.3 area% (methyl) (naphthalen-1-ylmethyl) amine (product 1) is mixed with 20 g peanut oil and the mixture is heated to 142 ° at 0.3 mbar pressure. (Jacket temperature 190 ° C.). After 2 hours, 96.4 g of purified terbinafine base and 21.4 g of dark brown residue are obtained as a yellowish distillate. Due to the effect of heat during batch distillation (2 hours, 142 ° C.), the distillate was approximately 1 area% (methyl) (naphthalene- 1-ylmethyl) amine (byproduct 1).

  Due to the large scale production, the effects of distillation time and heat will be quite high. As a result, it is expected that by-product 1 will be at a fairly high concentration unless the distillation time is short, such as for example a “short path” distillation.

  The crude terbinafine base used as starting material is, for example, as described in Example 13 of EP 421302 A2, but without subjecting the resulting product to silica gel chromatography, catalytic amounts of copper (I) iodide and bis (triphenyl). (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethanamine and 3,3-dimethyl- in n-butylamine and water in the presence of phosphine) palladium (II) dichloride Produced by reaction of 1-butyne.

Example 2 : Short path distillation (Method A; laboratory scale)
(Unclear for byproduct 1 and Z isomer; positive for product 2)
In a commercially available thin film evaporator (Leybold Heraeus GmbH, Hanau, Germany: heated drum with a diameter of 7 cm; length 25 cm; cooling finger 50 ° C .; pressure 0.2 mbar; Teflon ^R rotor 450 rpm) 179 g of crude terbinafine base (for example above Prepared as described in Example 1) with 8.9 g peanut oil and the mixture is heated to 50 ° C. After evacuating the entire system to 0.2 mbar, the distillation is started by slowly dropping the mixture into a hot zone (jacket temperature, 160 ° C.) where terbinafine base is heated to the boiling point for only a few seconds. After 2 hours, 171 g (95%) of pure terbinafine base was obtained as a yellowish distillate, which was contaminated with 1 ppm palladium and less than 1 ppm copper. Gas chromatography (HP-1 column; crosslinked methylsiloxane; length 30 m; film thickness 2.65 μm; column internal diameter 0.53 mm; thermal ionization detector (FID) temperature 300 ° C .; injection temperature 250 ° C .; temperature gradient 50 The chemical purity of the distillate is 98.6% w / w terbinafine base (ie, E isomer) as measured by ° to 270 ° C; heating rate 20 ° C / min). 10.5 g of distillation residue was added to obtain 0.4 g of oily sublimate. The sublimate is mainly composed of 2,2,7,7-tetramethylocta-3,5-diyne (byproduct 2).

When measured by gas chromatography, the overall purity of terbinafine base is as follows:

Example 3 : Short path distillation (Method A; industrial scale)
(Positive for metallic contaminants; no information value for non-metallic contaminants)
Distillation of the crude terbinafine base is performed in a high performance vacuum distillation apparatus (UIC GmbH HKD 150) using short path distillation with two serial evaporators. This always sends and distributes the material to the internal surface of the vertical directional evaporator. As the liquid flows downward, the axially arranged roller wiper system dispenses this liquid as a thin film that is always mixed (see figure). This gentle distillation method thus reduces both the maximum evaporation temperature and the residence time at high temperatures.

The starting temperature is generally as follows:
The internal limit of the supply tank: 70 ° C .;
-Internal limit of product receiver: 80 ° C; Jacket limit of residue tank: 80 ° C;
The upper and lower internal limits of evaporators 1 and 2: 100 ° C .;
-Jacket limit for evaporators 1 and 2: 160 ° C.

After controlling the entire equipment for emptyness and cleanliness, the maximum vacuum of both evaporators that can be achieved by the diffusion pump is as follows:
Before and after the evaporator 1: 1.6 × 10 ⁻¹ mbar;
In front of the evaporator 2: 2.6 × 10 ⁻² mbar;
-After evaporator 2: 4.7 x ^10-3 mbar.

A mixture of 872.5 kg crude terbinafine base (prepared as described in Example 1 above) and 120 kg peanut oil is then transferred to the feed tank. Peanut oil ensures that the skin does not accumulate inside the evaporator. Fill the cooling port with a mixture of 20 to 30 kg of dry ice and about 30 l of ethanol (94%) and adjust the temperature as follows:
-Jacket for residue receiving part: 40 ° C;
-Jacket of the evaporator 1: 120 ° C;
The evaporator 1 cooler: 50 ° C .;
-Jacket of the evaporator 2: 155 ° C;
-Cooler of evaporator 2: 45 ° C.

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

  When all temperatures have been reached, the crude product is transferred to the evaporator 1 at a flow rate of about 1.5 l / min. Since the volume is small, the distillate of the evaporator 1 (the remainder of the solvent) can be collected in the meter. The residue of evaporator 1 is transferred to evaporator 2 and the crude base is distilled, which is recovered in the heated main vessel as a yellow liquid (1.4 l / min).

  When all the crude mixture has been distilled (about 11 hours), the residue of the evaporator 2 is transferred to the feed tank and distilled again. Thereby, the jacket temperature of the evaporator 1 is lowered to 110 ° C., and the jacket temperature of the evaporator 2 is lowered to 140 ° C.

  After the distillation of the residue is complete (about 2 hours), fresh residue is circulated through the evaporator until the product flow rate reaches about 0.2 l / hour. Before the circulation can start, the jacket temperature of the evaporator 1 drops to 100 ° C. and the cooler temperature of the evaporator 2 rises to 60 ° C. During the circulation, the distillate contained is darkened.

  At the end of the distillation (total about 22.5 hours), the apparatus is released with nitrogen. The product from the main vessel is drummed at about 50 ° C. Take a sample and weigh the drum. The chemical purity of the free base is 97% w / w or higher (here it was 98.4%) as determined by gas chromatography. The yield was 856.1 kg. The amount of copper and / or palladium remaining is very small or not detectable (less than 1 ppm).

  Combine the remaining residue (about 120 kg of peanut oil; here it was 128 kg), the distillate of evaporator 1 and the condensate of the cold trap and incinerate. After 5 to 6 treatments, the device is cleaned.

Comparative Example : Charcoal refining (laboratory scale)
( Negative for metallic and non-metallic contaminants)
10 g in a 404 g solution of crude terbinafine base in cyclohexane (produced from 100 g of (E) -N- (3-chloro-2-propenyl) -N-methyl 1-naphthalene-methanamine as described in the above example) Add the activated carbon (Norit Supra ^R). The mixture is stirred for 17 hours at 20-25 ° C. and then filtered. After evaporation of the solvent under reduced pressure, 110.5 g (89%) of terbinafine base contaminated with 14 ppm palladium is obtained. The chemical purity of the oily residue is 95% as determined by gas chromatography (experimental conditions: same as in Example 2).

Example 4 : RP-HPLC with short path distillation and UV detection
(Method A; industrial scale)
( Positive for non-metallic contaminants, especially Substance A)
80 ppm (other batches: 62 ppm each) of Substance A (measured from a sample of crude terbinafine base by RP HPLC analysis with UV detection) and 2.45% w / w other detectable non-metallic contaminants overall (Other batches: 2.40% each) from two batches containing industrial quantities (872.5 kg) of crude terbinafine base for short path distillation as described in Example 3 (both combined batches). A sample of crude terbinafine base is taken from the distillate and again subjected to RP HPLC analysis. It shows that the sample still contains only 5 ppm of substance A and a total of 1.14% w / w other detectable non-metallic contaminants.

−流速：１．０ｍｌ／分
−検出波長：２８０ｎｍでＵＶ吸収
−温度：５２℃
−注入量：２０μｌの試験溶液および参考溶液
−実施時間：１６分
−サンプル濃度：４０ｍｇ／ｍｌ RP HPLC with UV detection is performed as follows:
Reagent :
-Acetonitrile: for example LiChrosolv ^R (Merck);
-Water: e.g. LiChrosolv ^R (Merck);
-Triethylamine: for example puriss. p. a. (Fluka);
-Solvent: acetonitrile or acetonitrile / water 8: 2 (v / v);
-Substance A for comparison (for example from about 11 mg isolated as a by-product from terbinafine synthesis by silica gel chromatography according to EP 24587, method a) with spectroscopic confirmation of its chemical structure).
Apparatus : HP 1100 (Agilent), Alliance 2695 (Waters)
Column : XTerra RP18, 3.5 μm particle size, length 150 mm, internal diameter 3.0 mm
Chromatographic conditions :
Mobile phase: A: water / triethylamine 1000: 1 (v / v);
B: Acetonitrile / triethylamine 1000: 1 (v / v)
-Gradient:

-Flow rate: 1.0 ml / min-Detection wavelength: UV absorption at 280 nm-Temperature: 52 ° C
-Injection volume: 20 μl of test solution and reference solution-Run time: 16 minutes-Sample concentration: 40 mg / ml

System suitability is calibrated with reference solutions for:
-Reproducibility (Reference solution 2 containing 100 ppm of substance A prepared by diluting 2.0 ml of reference solution 1 to 20.0 ml with a solvent; reference solution 1 containing 1000 ppm of substance A into a 50 ml volumetric flask ± Obtained by weighing out about 2 mg of substance A with an accuracy of 0.001 mg, dissolved in a solvent and then diluted to 50 ml);
Recording limit (comprising 1 ppm of substance A, prepared by diluting 2.0 ml of reference solution 2 to 20.0 ml with solvent and diluting 2.0 ml aliquots of the solution to 20.0 ml with solvent) Reference solution 3); and -selectivity (prepared by weighing approximately 200 mg of test substance with a precision of ± 0.1 mg into a 5.0 ml volumetric flask, adding 250 μl of reference solution 2 and diluting to volume with solvent. "SST" solution: it contains 100% drug with 5 ppm substance A added).

  Solvent alone is used for the blank chromatogram. Two test solutions are prepared by weighing about 200 mg of test substance with a precision of ± 0.1 mg into a 5.0 ml volumetric flask and dissolving it and diluting to volume with solvent.

  It is preferred to use amber glass flasks and vials.

  The peak area for substance A in the chromatogram of the test solution and reference solution 2 is determined.

式中、
ＲＳ＝テルビナフィン関連物質、例えば、物質Ａ
ＰＡ_Ｔ＝試験溶液のＲＳのピークエリア
ＰＡ_Ｒ２＝参考溶液２のＲＳのピークエリア
ｍ_Ｒ＝参考溶液１のＲＳの質量（ｍｇ）
ｍ_Ｔ＝試験溶液の試験物質の質量（ｍｇ）
Ｃ_Ｒ＝参考溶液に対して使用されるＲＳの含有％
ｆ＝０．０１＝希釈因子
１００００＝ｐｐｍへの変換係数。 Calculation is performed as follows (peaks below the recording limit of 1 ppm are ignored):

Where
RS = terbinafine related substance, for example substance A
PA _T = RS peak area of test solution PA _R2 = RS peak area of reference solution 2 m _R = RS mass of reference solution 1 (mg)
m _T = mass of test substance in test solution (mg)
C _R =% content of RS used for reference solution
f = 0.01 = dilution factor 10000 = conversion factor to ppm.

A typical run result is as described in the attached chromatogram (WVL = wavelength 280 nm; abscissa = minute; ordinate = mAU = absorption unit × 10 ⁻³ ). The relative retention times for the drug terbinafine base and substance A are 1.00 and about 1.73, respectively.

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

Example 5 : Short path distillation followed by salt formation and precipitation (Method A and Method B; industrial scale)
(Especially positive for substance A)
a) Distillation (Method A):
The terbinafine crude base is subjected to short path distillation as described in Example 4 above. The resulting purified terbinafine base containing 5 ppm of substance A is then subjected to salt formation and precipitation as determined by RP HPLC analysis with UV detection.

b) Further salt formation and precipitation of the trans isomer (Method B):
Ethyl acetate is added to the base product from step a), the mixture is stirred at 20 ° C. until complete dissolution, the resulting solution is filtered (2 μm) and the pressure is reduced to 0.5 bar at a temperature of 20 ° C. Then hydrochloric acid gas is introduced at 20 to 25 ° C. The resulting suspension is stirred for 4 to 15 hours at 20 ° C., centrifuged, the product obtained is washed with ethyl acetate, centrifuged at 1000 rpm and the product obtained is dried. Pure terbinafine hydrochloride is obtained. A sample is taken and subjected to RP HPLC analysis. It is found to contain less than 1 ppm of substance A.

Claims (20)

  Non-metallic contaminants comprising subjecting crude terbinafine in free base form to distillation under conditions that result in a substantial reduction in non-metallic contaminant concentration and recovering the resulting free base or acid addition salt form of pure terbinafine For the purification of terbinafine from sucrose (Method A).   The free base form of crude terbinafine is subjected to distillation under conditions that result in a substantial reduction in the concentration of non-metallic contaminants, at the same time salt formation under the simultaneous precipitation of the pure trans isomer of the product and is exceptionally obtained. For the purification of terbinafine from non-metallic contaminants comprising recovering pure terbinafine in free base form or acid addition salt form obtained (Method B).   3. A process according to claim 1 or 2 comprising short path distillation.   The process according to claim 1 or 2, wherein the distillation is accomplished at a temperature above 100 ° C and under reduced pressure.   Uses the reaction of the compound 1-A-6,6-dimethyl-2-hepten-4-yne in which the crude terbinafine is N-methyl-N- (1-naphthylmethyl) amine and A is a leaving group, especially bromo The method according to claim 1 or 2, wherein the method is produced.   Terbinafine in free base form or acid addition salt form purified by removing non-metallic contaminants.   7. Pure terbinafine according to claim 6, comprising a total of less than about 0.2% to about 1% w / w organic contaminants.   8. Pure terbinafine according to claim 7, comprising about 1 ppm or less of substance A. One or more crude terbinafine compounds a)

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

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

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

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

(Substance A),
3. A method according to claim 1 or 2, comprising more than about 5 ppm non-metallic contaminants selected from: in particular more than about 5 ppm of substance A.   The method of claim 1, wherein the crude terbinafine comprises greater than about 5 ppm of substance A and the pure terbinafine comprises less than about 5 ppm of substance A.   3. The method of claim 2, wherein the crude terbinafine comprises greater than about 5 ppm of substance A and pure terbinafine exceptionally comprises less than about 1 ppm of substance A.   Use of the process according to claim 1 or 2 for the production of pure terbinafine.   13. Use of the process of claim 12 for the production of pure terbinafine containing less than about 1 ppm of substance A.   3. Terbinafine in free base form or acid addition salt form produced by the method according to claim 1 or 2.   15. Pure terbinafine according to claim 14, comprising less than about 5 ppm of substance A produced by the method of claim 1 or comprising less than about 1 ppm of substance A produced by the method of claim 2.   A pharmaceutical composition comprising pure terbinafine in free base form or acid addition salt form and one or more pharmaceutically acceptable carriers or diluents produced by the method according to claim 1 or 2.   A method of producing pure terbinafine having less than about 1 ppm of substance A, comprising reducing the concentration of substance A present in a 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 assessing the concentration of their non-metallic contaminants, eg, substance A. A method of monitoring the concentration of non-metallic contaminants such as substance A.   Taking 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 assessing the concentration of their non-metallic contaminants, for example, substance A. A method for monitoring the concentration of a non-metallic contaminant, for example, the substance A when the method according to Item 2 is used.

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