Purification method

FIELD: chemistry.

SUBSTANCE: present invention relates to versions of a method of purifying terbinafine from nonmetallic impurities, primarily a substance A of formula

, as well as to use of said methods to obtain purified terbinafine. One of the versions of the method involves molecular distillation of crude terbinafine in form of a free base and extraction the obtained purified terbinafine in form of a free base or acid-addition salt (method A). In another version (method B), crude terbinafine in form a free base undergoes molecular distillation combined with formation of a salt of the obtained product with simultaneous deposition of a purified trans-isomer, and the obtained highly pure terbinafine is extracted in form of a free base or acid addition salt.

EFFECT: method enables to obtain terbinafine containing less than approximately 5 ppm of substance A.

13 cl, 2 dwg, 6 ex

 

The present invention relates to a method of cleaning elelmentary pharmaceuticals. The invention relates to a method of purification of crude terbinafine in free base and purified terbinafine.

Terbinafine, primarily in the form of an acid additive salts (hydrochloride), described, for example, in patent EP 24587. It belongs to the class allylamine antifungal medication and is available in the form of commercial products with the trade name lamisilR. Terbinafine is effective both at local and oral administration in a wide range of fungal infections. Terbinafine is used primarily against dermatophytes, contagious fungi that infect the dead skin tissue or its derivatives, such as stratum corneum, nails and hair.

The use of terbinafine is an outstanding achievement in the field of antifungal therapy, due to its high fungicidal activity in vitro and rapid clinical effect in the treatment of infections of various dermatophytes as oral, and the local administration. He is a highly effective inhibitor of the biosynthesis of ergosterol (Ann. NY Acad. Sci. 544, 46-62 (1988)), blocks the action of scaleability thus inhibits the conversion of squalene to squalene epoxide. Although the synthesis of ergosterol inhibited the nose part, cell growth is completely suppressed. Assume that the fungicidal effect terbinafine is associated with the accumulation of squalene, which in high concentrations is toxic to fungi. The spectrum of action of terbinafine in vitro includes all dermatophytes of the genus Trichophyton, Epidermophyton, and Microsporum. The average minimum inhibitory concentration for these dermatophytes is from 0.001 μg/ml to 0.01 μg/ml (Science 224, 1239-1241 (1984)). Terbinafine is also active in vitro against mould and fungi, dimorphic fungi, and many pathogenic yeasts of the genus Pityrosporum, Candida and Rhodotorula.

The structure of terbinafine is characterized by the formula I

methanamine (E)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthalene.

Terbinafine may exist in free base form or in the form of an acid additive salt. An acid additive salt is obtained from the free base by standard methods and Vice versa. Examples of suitable acid additive salts are the hydrochloride, lactate, ascorbate and malate, such as L-(-)-gidromolot. Preferred are the free base, hydrochloride and malate, especially the hydrochloride and L-(-)-gidromolot.

As shown above (formula I), the terbinafine is derived allylamine containing in the side chain of the triple bond, condensed with a double bond. Although terbinafine patented mn is years ago (see, for example, EP 24587, example 16), such condensed uninpressed still very rarely used in pharmaceuticals and characterized by a new structural characteristic in medicinal chemistry.

The presence of both double and triple links gives the molecule an extremely high reactivity. Despite the fact that in the chemical literature does not exclude the possibility of existence of stable compounds with such a structure, some compounds are unstable and may decompose during storage or processing, such as heating, for example, distillation at elevated temperature.

For example, as described in article E.R.H.Jones etc., J. Chem. Soc. 341-346 (1960), simple distillation of pure Penta-1,2-Dien-4-in at the boiling temperature of 57°C in normal conditions leads to its decomposition. Similarly, the dimer of 1-alkene-4-in (unfused)

[CH2=CH-CH2-C≡C-C(CH3)(OH)-]2

6,7-dimethylbutene-1,11-diene-4,8-Dien-6,7-diol (compound V in article .Disselnkötter and .Kurtz, Ann. Chem. 26-34 (1964)) significantly decomposes when distilled at low temperature (85-90°C) and pressure (0.05 mm Hg), as well as distillation under other conditions when 81-85°C and 0.03 mm Hg in Addition, Indien (Z,Z)was 3.7-decadien-1,5,9-Triin polymerized at high speed, and its solutions are thermally decomposed at a temperature of 170-190°SS the formation of naphthalene, while at thermolysis of the corresponding (E,Z) and (e,E) isomers have different products or polymers (J. Am. Chem. Soc. 114, 3120-3121 (1992)).

In addition, isomerization of condensed Anisovich compounds, such as ether CH3CH=CH-C=C-CH2OS2H5in the corresponding 1,3,5-triene, accompanied by the formation of considerable polymeric distillation residue due to the 1,6-elimination of ethanol, while replacing the group-OC2H5the amino group leads to the formation of aromatic rings (Van-Dongen, J. and others, Recueil Trav. Chim. Pays-Bas 86, 1077-1081 (1967)).

In addition, as described, for example, in the above articles, the distillation is practically all derived Enina usually carried out at a temperature of less than or slightly more than 100°C, first of all, less than about 125°C, since it is known that compounds with high reactivity when heated, decompose or polymerize or decomposition even accompanied by an explosion. This also applies to most alkenylboronic described, for example, articles Recueil Trav. Chim. Pays-Bas, 85, 952-965 (1966) and Zh. Org. Khim, 3, 1792-1793 (1967) (SA 68, 12370 (1968)), while the two intermediate compounds to obtain pheromones that are described in the collection of Czech Author's Certificate No. 232843 (SA 106, 213632b (1984)), purified by distillation under reduced pressure at 102-115°C and 118-125°C, respectively.

In addition, the temperature to the singing terbinafine-shaped base is 140°C at a pressure of 0.3 mbar, moreover, at this temperature, its thermal stability is limited and there is a decomposition (according to gas chromatography, the peak area of one compound relative to the sum of all peaks is denoted as area-%, in the case of Z-isomer value in area-% corresponds roughly to the amount in wt.%), the data obtained is presented below.

The duration of heating (h)A by-product 1 (area-%)Z-isomer (area-%)Undecomposed E-isomer (area-%)
00,090,2597,6
70,570,3496,6
230,920,4594,7
321,200,5292,0
A by-product 1: (methyl)(naphthalene-1-ylmethyl)Amin

On the other hand, the product solidifies at a temperature of less than 43°C. Therefore, when processing the e chemical compounds with this unusual structure is generally recommended not to use extended heating, first of all, if the connection is characterized by limited thermal stability, especially when processing in preparative scale, for example, in industrial production of pharmaceutical preparations. For example, in patent EP 0421302 A2 (Banyu, example 13), which describes the obtaining of terbinafine, the crude mixture (free base), obtained after the reaction, purified by chromatography on silica gel.

However, unexpectedly, it was found that terbinafine in free base can distill without any adverse effects. Moreover, it was found that the distillation can be conducted at elevated temperature, for example even at temperatures significantly above 100°C., for example from about 110°to about 170°C., preferably from about 125°to about 165°C., especially approximately 160°C, and the corresponding reduced pressure, for example, at 0.2 mbar at 160°C (the temperature of the shirt).

The output is usually about 95%, based on the quantity of the crude product.

The specified invention and its equivalents are described and claimed in the pending application PCT/EP 2004/9587 (WO 2005/21483), and also described a new method of purification of terbinafine, which includes a distillation of the crude terbinafine in free base form and you the bookmark of the final product in free base form or acid additive salt.

It should be noted that this method is primarily used to separate terbinafine primarily from metallic impurities present after the chemical synthesis of terbinafine, for example after addition of catalysts, impurities such as copper and/or, especially, palladium impurities, primarily for the reduction or removal of impurities present after completion of the synthesis, which is described, for example, in patents EP 421302 (Banyu) and/or EP 1236709 (Dipharma), for example, by the reaction of (E)-N-(3-halogen-2-propenyl)-N-methyl-N-(1-naphthylmethyl)amine (compound of formula IV, as described in patent EP 421302, where R11means methyl, R21mean 1-naphthylmethyl and W stands for halogen, for example bromine, preferably chlorine), 3,3-dimethyl-1-Butina (compound of formula V, where R7means tert-butyl) in the presence of a catalyst based on palladium and/or copper, as a result get terbinafine in free base form. The catalyst means, for example, copper iodide (I)or copper iodide (I) in the mixture with the dichloride bis(triphenylphosphine)palladium (II) or tetrakis(triphenylphosphine)palladium, or another catalyst containing palladium, copper or palladium/copper, which are selected from catalysts described in patent EP 421302 A2, for example, page 7, line 54 to page 8, line 18.

This method is carried out according to standard methods, preferably using the receiving of the so-called distillation under mild conditions, for example, such as periodic distillation or preferably using a continuous or semi-continuous distillation, and above all, molecular distillation, which is characterized by a short distance from the heater casing to the refrigerator, for example a distance of approximately 10 cm, which allows to minimize the time spent terbinafine at elevated temperature, for example, more than 100°C.

The term "molecular distillation" means a distillation in high vacuum, designed for the separation of mixtures of organic (or organosilicon compounds that are unstable during prolonged heating, which leads to significant structural changes or decomposition. In this distillation uses heat of condensation, such as the warmth of the original body, coming to the surface of the evaporator. A pair of freely pass through the area between the evaporator and the refrigerator. A short time contacting and low temperature distillation to substantially reduce the possibility of thermal decomposition of organic compounds.

Molecular distillation is conducted according to the method described in the application WO 2005/21483, i.e. using the standard installation, as shown in the figure, and molecular distillation is preferred and provides intermittent heat with the art, designed for cleaning, and also allows the use of a cyclical process, which in turn allows to increase the yield of the pure product. In addition, this decreases the thickness of the film material on the wall of the evaporator, thereby reducing the evaporation temperature and the residence time in the apparatus. This provides efficient separation of impurities and does not require additional stages of purification, such as chromatography or recrystallization, or the use of large quantities of coal.

To date, however, it was considered impossible to expose terbinafine in free base distillation at elevated temperature with slight decomposition, or when its full absence. It was assumed that other non-metallic impurities, if present, primarily organic compounds, such as (methyl)(naphthalene-1-ylmethyl)Amin (a by-product 1), 2,2,7,7-tetramethylene-3,5-Dien (by-product 2), and Z-isomer terbinafine only partially biodegradable or not biodegradable, such as a by-product 1 and Z-isomer terbinafine.

However, as a result of more detailed research and improvement of methods of analysis of impurities it has been unexpectedly found that when using the above method or similar machining conditions can be separated organic is such impurities or significantly reduce their content.

In addition, it has been unexpectedly found that despite the physicochemical properties terbinafine in free base and these organic impurities using direct distillation can largely remove these impurities from the final pharmaceutical product.

Therefore, currently there is a simple way of obtaining high-purity organic impurities terbinafine in industrial scale.

"Purified terbinafine in free base form or acid additive salts used in this context, means terbinafine, not containing non-metallic impurities, for example, containing less than about 2 wt.% non-metallic impurities, especially organic impurities. On the contrary, "the crude terbinafine" means containing about 2 wt.% or more, for example, from about 2 wt.% to about 10 wt.%, first of all, from about 2 wt.% to about 5 wt.% these non-metallic impurities and substances (as defined below), approximately 5 ppm million or more, for example, from about 5 ppm million to approximately 200 ppm million, primarily from about 5 ppm million up to about 100 ppm million substances A.

One object of the present invention thus relates to a new the way to clean terbinafine from non-metallic impurities, moreover, the method consists in the fact that the distillation of the crude terbinafine in free base form is carried out in conditions which ensure a significant reduction in the level of non-metallic impurities and produce a purified terbinafine in free base form or acid-salt additive (in this context "method A").

The definition of non-metallic impurities is preferably carried out by a method of analysis that is sensitive at concentrations below the normal detection limit of about 0.05 wt.% (500 ppm million), typically using standard methods of analysis, such as reversed-phase liquid chromatography high pressure (PF-GHUR), preferably the detection limit of approximately of 0.0001% (1 ppm million), such as OFF-GHUR with detection by UV and using commercial chromatographs, such as the HP 1100 (Agilent) and Alliance 2695 (Waters), as well as the system described below in example 4. Typical results are presented below, for example, on the chromatogram.

Terms getting in "preparative" or "industrial scale" purified terbinafine in the form of a base or an acid additive salt used in this context means getting at least approximately 5 kg, preferably at least about 50 kg, especially at least approximately the nutrient 200 kg, 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, especially about 850 kg of purified product in free base form in a single distillation or for one cycle of distillation.

"A significant reduction in the level of non-metallic impurities" means the concentration of non-metallic impurities, especially organic detectable impurities from less than about 0.5 wt.% to about 2 wt.%, first of all, less than about 0.5 wt.%, in relation to the number of untreated terbinafine in free base form, which is characterized by initial level detected organic contaminants from about 2 wt.% to about 10 wt.% according to the analysis, for example, by the method OF GHUR with UV detector.

Thus, from the crude terbinafine containing, for example, from about 60 ppm million to approximately 80 ppm million substances (as defined in this context), receive the purified product containing only about 5 ppm million of compound a (see example 4), while the total number of other detectable impurities is approximately two times lower.

The distillation is preferably carried out at temperature the re from approximately 100°to approximately 170°C, for example, from about 110°to about 170°C., preferably from about 125°to about 165°C., especially approximately 160°C (the temperature of the shirt), and the corresponding reduced pressure, for example, about 0.2 mbar at 160°C.

Such non-metallic impurities typically include organic compounds, such as one or more of the following compounds:

a)

that is, 6,6-dimethyl-2-hepten-4-Inal,

b)

that is, (methyl)(naphthalene-1-ylmethyl)amine, that is,

N-methyl-N-(1-naphthylmethyl)amine,

N-methyl-1-naphthalenemethanamine (a by-product 1),

C)

that is, (Z)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthalenemethanamine (Z-isomer),

d)

that is, (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthylmethyl,

and, above all,

e)

that is,

(E)-4-[4,4-dimethylpentan-(E)-ilidene]-N1N5-dimethyl-N1N5-binaphthalene-1-ylmethylene-2-EN-1,5-diamine

or

2(E),4(Z)-N-(4-[(N'-methyl-N'-1-naphthylmethyl)aminomethyl]-8,8-dimethyl-2,4-nonadien-6-inyl)-N-methyl-1-naphthylmethyl

(substance A).

Substance And is non-metallic impurity, formed by carrying out, for example, method a), as described in patent EP 24587, when si is Teze terbinafine, that is, when the interaction of N-methyl-N-(1-naphthylmethyl)amine (compound of formula IV in this context) with 1-And-6,6-dimethyl-2-hepten-4-other (compound of formula V in this context, where a represents a leaving group, especially bromine).

Terbinafine in transconformation usually included in commercial pharmaceutical compositions such as tablets, in which the active ingredient is in the form of an acid additive salt is hydrochloride. Therefore, the free surface must turn in an acid additive salt, such as hydrochloride, for example, as described in the patent CH No. 678527, if the crude mixture terbinafine in free base contains a significant amount, for example, CIS-isomeric impurities, the pure TRANS-isomer can be isolated in the form of a salt by adding acid, such as adding hydrochloric acid salt precipitates. Preferably this reaction is carried out in the presence of an ester of an organic acid, such as ethyl acetate, or in the presence of a mixture of ether organic acids, such as ethyl acetate, other organic solvents or other conditions, as described, for example, in the application WO 01/28976, in a mixture with hydrochloric acid in aqueous solution and organic solvent such as methylisobutylketone.

In addition, it has been unexpectedly found that the formation of salts with the simultaneous precipitation of purified transisomer in the sludge can be successfully used in combination with the above-described method according to the present invention for additional separation of non-metallic impurities, as described above, and thus obtain highly purified terbinafine.

The initial level of all detected organic impurities in the original crude terbinafine in free base is from about 2 wt.% to about 10 wt.% according to, for example, OF GHUR, and the total residual levels of all detected organic impurities in the obtained highly purified the terbinafine is from about 0.2 wt.% to about 1 wt.% according to, for example, OF GHUR with UV detector.

Thus, from the source of the crude product containing, for example, from about 60 to about 80 ppm million substances And, after distillation and the formation/deposition of salts obtain a highly purified product in the form of a salt containing the substance in quantities below the limit of sensitivity, that is, approximately less than 1 part./million (see example 5).

Therefore, to improve the treatment efficiency of the distillation of the crude terbinafine in free base preferably be combined with the formation of the salt of purified transisomer, which precipitates.

Another object of the present invention includes a new method of purification of terbinafine from non-metallic impurities, the method consists in the fact that the distillation of the crude terbinafine in free base form is carried out in in the circumstances, which provide a significant reduction in the level of non-metallic impurities in combination with the formation of the salt of the obtained product, and purified transisomer simultaneously precipitated, and conduct the selection of the obtained high-purity terbinafine in free base form or acid-salt additive (in this context, a "way In").

The salt formation and the deposition is carried out in one stage. Suitable solvent is, for example, ether, organic acid, or a mixture of the ester of the organic acid with other organic solvents. The preferred ester of the organic acid is, for example, ether acetic acid, for example, With1-C4alkilany ester of acetic acid, such as methyl, ethyl, n-butyl or isobutyl esters, especially ethyl acetate.

As another organic solvent used, for example, the alcohol corresponding to the ester, for example a mixture of ethanol with ethyl acetate, isopropanol with isopropyl ether acetic acid, and the like, and, above all, of ethanol with ethyl acetate.

As another organic solvent used, for example, aliphatic ketone, preferably methyl isobutyl ketone.

The cleaning process is preferably carried out at a standard temperature, preferably from about -25°C up rough is about 100°C, preferably at approximately room temperature.

The formation of salts during its deposition is preferably carried out by adding an inorganic acid, preferably by adding hydrochloric acid, for example, in a gaseous state or in aqueous solution, for example, if the solvent is methyl isobutyl ketone, add approximately 5% to approximately 40% aqueous solution of hydrochloric acid, pH 1-3 at a temperature from about 10°to about 30°C.

Obtained by the method a or method In the product terbinafine, for example, in free base form or in the form of a salt of hydrochloric acid, is transformed into another form of acid additive salts, such as malate, such as L-(-)-gidromolot, standard methods and Vice versa.

Methods a and b can be effectively used for the purification of large quantities of crude terbinafine in free base, i.e. in an industrial environment, for example, to obtain purified terbinafine in free base and an acid additive salt in preparative scale, as defined above.

Thus, the present invention includes:

- method a or b, as defined above, which includes molecular distillation,

- method a or b, as defined above, including distillation at a temperature of over 100°C and lowered the second pressure

- method a or b, as defined above, in which the crude terbinafine obtained using catalysts based on palladium and/or copper,

- method a or b, as defined above, in which the crude terbinafine get the reaction of N-methyl-N-(1-naphthylmethyl)amine with 1-And-6,6-dimethyl-2-hepten-4-otherwise, where a represents a leaving group, especially with 1-bromo-6,6-dimethyl-2-hepten-4-other

- method a or b, as defined above, in which at least 5 kg of purified product in free base form get one distillation or cycle, preferably at least 50 kg, especially at least 200 kg,

- method a or b, as defined above, in which the crude terbinafine get reactions

(E)-N-(3-halogen-2-propenyl)-N-methyl-N-(1-naphthylmethyl)amine with 3,3-dimethyl-1-Butina in the presence of catalysts based on palladium and/or copper,

- terbinafine in free base form or acid additive salt, purified from non-metallic impurities,

purified terbinafine in free base form or acid additive salts mainly containing from about 0.2 wt.% to about 1 wt.% organic impurities,

purified terbinafine in free base form or acid additive salts containing approximately 1 part./million or less substance And,

- cleaned terbin the fin in the form of a free base or an acid additive salt, obtained by method a or b, as defined above,

- method a or b, as defined above, in which the crude terbinafine contains more than about 5 ppm million of non-metallic impurities, which are selected from one or more compounds as defined above in paragraphs a), b), C), (d) and/or (e) (substance A)

- method a or b, as defined above, in which the crude terbinafine contains more than about 5 ppm million compounds as defined above in paragraph (e) (substance A)

the method as defined above, in which the crude terbinafine contains more than about 5 ppm million substances And purified terbinafine contains less than about 5 ppm million substances And,

the method, as defined above, in which the crude terbinafine contains non-metallic impurities, for example, more than about 5 ppm million of non-metallic impurities, which are selected from one or more compounds as defined above in paragraphs a), b), C), (d) and/or (e), for example, more than about 5 ppm million substances And, for example, in which the crude terbinafine in free base contains more than about 5 ppm million substances And and highly terbinafine contains less than about 1 part./million substances And,

- method a or b, as defined above, to obtain a purified terbinafine,

- use method a or b, the AK defined above, to obtain purified terbinafine containing less than about 1 part./million substances And,

- terbinafine in free base form or acid additive salts obtained by method a or b, as defined above,

purified terbinafine in free base form or acid additive salt, contains less than about 5 ppm million substances And obtained by the method as defined above, or containing less than about 1 part./million substances and obtained by the method as defined above,

pharmaceutical composition comprising purified terbinafine in free base form or acid-salt additive in a mixture with one or more pharmaceutically acceptable carrier or diluent obtained by method a or b, as defined above,

the method of obtaining purified terbinafine, for example, containing less than about 1 part./million substances And in a way is that to reduce the level of the substance As compared to the untreated sample terbinafine,

- method of removing substances And terbinafine, which includes distillation terbinafine in free base form,

- a way to control the level of non-metallic impurities, such as substance And, when using method A, as defined above, which is that a sample is taken of the crude terbin the fin in the form of a free base before distillation and the sample purified terbinafine in free base after distillation, and then determine the level of non-metallic impurities, such as substance And,

- a way to control the level of non-metallic impurities, such as substance And, when using the method, as defined above, which is that a sample is taken of the crude terbinafine in free base before distillation and the sample purified terbinafine in free base after distillation, and the sample of salt terbinafine after the formation/deposition of salt, and then determine the level of non-metallic impurities, such as substance A.

Description 1:

1. The output stream of distillate

2. Connection to the vacuum pump

3. The input stream of coolant

4. Refrigerator

5. The area of low pressure

6. Roller partitions (evenly distribute the crude product with the formation of the film)

7. The heating jacket

8. The sealing liquid

9. A flange for connection to drive

10. The supply of the crude product

11. The output flow of coolant

12. Outlet for VAT residue

13. The input stream of cooling water

14. The output flow rate of the cooling water

Description chromatogram (figure 2):

I baseline (solvent)

II Standard solution 3(1 part./million substances (A)

III Control solution (purified terbinafine, the substance is not detected)/p>

IV Solution "SST" (purified terbinafine containing 5 ppm million substances (A)

V Standard solution 2 (100 ppm million substances (A)

1 Drug, terbinafine

2 RS (i.e. related terbinafine substance: substance And

WVL wavelength of 280 nm

The x-axis: min (minutes)

The y-axis: meladinine absorption = unit absorption ×10-3

(see also example 4)

The following examples are provided to illustrate the present invention. Temperatures are in degrees Celsius (°C). 1000 mbar = 750,06 mm Hg In examples 2, 4 and 5 show positive results (example 3 not informative as to the level of non-metallic impurities), in example 1 and in example compares the results of the analysis of standards (negative control).

Example 1: Periodic distillation (method A, at laboratory scale)

a negative result against a side product 1)

The crude terbinafine in free base (100 g)containing 0.3 area% (methyl)(naphthalene-1-ylmethyl)amine (a by-product 1) was mixed with peanut butter (20 g) and the mixture was heated to 142°C at a pressure of 0.3 mbar (temperature shirts 190°C). After 2 h was obtained purified terbinafine in free base (96.4 g) as yellowish distillate and the residue is dark brown (21,4 g). Due to prolonged exposure t is mperature during periodic distillation (2 h at 142°C.) distillate contains approximately 1 area-% (methyl)(naphthalene-1-ylmethyl)amine (a by-product 1) according to gas chromatography (conditions of the experiment described in example 2).

When distilled in a preparative scale, duration and thermal effects increase significantly. Therefore, we can expect a significant increase in the concentration of by-product 1, i.e. you want to reduce the duration of the distillation, for example the use of molecular distillation.

The crude terbinafine in free base, which is used as a source of material gain, for example by the reaction of (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine with 3,3-dimethyl-1-Butina in n-butylamine and water in the presence of catalytic amounts of copper iodide (I) dichloride and bis(triphenylphosphine)palladium (II), as described in patent EP 421302 A2, example 13, but without purification of the obtained product by chromatography on silica gel.

Example 2: Molecular distillation (method A, at laboratory scale)

a negative result against a side product 1 and Z-isomer, a positive result against a by-product, 2)

The crude terbinafine in free base (179 g, obtained, for example, as described above in example 1) was mixed with peanut butter (8,9 g) and the mixture was heated to 50°C in a commercial film evaporator (firm Leybold-Heraeus GmbH, Hanau, Germany): the diameter of the cylinder is 7 cm, length 25 cm, the cooling finger 50°C, a pressure of 0.2 mbar, the rotor TeflonR, 450 rpm). After acquirement the entire system to a pressure of 0.2 mbar began the slow distillation at adding dropwise the mixture in the high temperature zone (temperature shirt 160°C), where terbinafine in free base was heated to boiling point in just a few seconds. After 2 h was obtained purified terbinafine in free base (171 g, 95%) as yellowish distillate containing impurities palladium (1 part./million) and copper (less than 1 part./million). The chemical purity of the distillate terbinafine in free base amounted to 98.6 wt.% (that is, E-isomer) according to gas chromatography (column HP-1, made methylsiloxane, length 30 m, film thickness to 2.65 μm; inner diameter column 0.53 mm, detector, flame ionization (FID) temperature 300°C, injector temperature 250°C; the temperature gradient from 50 to 270°C, heating rate 20°C/min). In addition, received VAT residue (10.5 g) and oily sublimat (0.4 g). Basically sublimat contains 2,2,7,7-tetramethylene-3,5-Dien (by-product 2).

General cleanliness terbinafine in free base according to gas chromatography is presented below:

Prior to distillation (crude product)After distillation (purified product)
A by-product 1 (area-%)0,10,1
By-product 2 (area%) 0,70,2
Z-isomer (area-%)0,30,3
E-isomer (wt.%)95,698,6
Pd (part./million)1771
C (part./million)19<1

Example 3: Molecular distillation (method A, on an industrial scale)

(a positive result in respect to metallic impurities, not informative in respect of non-metallic impurities)

Distillation of the crude terbinafine in free base was carried out in the apparatus under high vacuum (UIC GmbH K.D 150) using molecular distillation in two successive evaporators. Thus, the material was continuously applied and distributed on the inner surface of a vertically oriented evaporator. As the liquid flows down system along the axis of the roller partitions distributes the liquid into a thin film, which is continuously mixed (see figure). Consequently, when such distillation under mild conditions reduced the maximum evaporation temperature and time is of an unforgettable elevated temperature.

Initial temperature in the system were set as follows:

- the maximum internal temperature in the supply tank: 70°C,

- the maximum internal temperature in the receiving tank for product: 80°C, the maximum temperature of the jacket inlet tank to collect the balance: 80°C,

- upper and lower limits of the internal temperature of the evaporator 1 and 2: 100°C

the maximum temperature shirt evaporators 1 and 2: 160°C.

After testing all hardware for tightness and cleanliness of the system both evaporators were acquirable using diffusion pumps, the magnitude of the vacuum is:

- at the entrance and at the exit of the evaporator 1: 1,6×10-1mbar;

- at the entrance of the evaporator 2: 2,6×10-2mbar;

- on the outlet of the evaporator 2: 4,7×10-3mbar.

A mixture of the crude terbinafine in free base (and 872.5 kg, obtained similarly as described above in example 1) and peanut butter (120 kg) was transferred into the supply tank. Thanks to the peanut butter mixture does not solidify inside the evaporators. A cooling trap was filled with a mixture of dry ice (20 to 30 kg) with ethanol (approximately 30 l, 94%), it was established the following temperatures:

- the temperature of the jacket inlet tank for collecting residue: 40°C,

- the temperature of the jacket of the evaporator 1: 120°C

- temperature holodilny is and evaporator 1: 50°C,

- the temperature of the jacket of the evaporator 2: 155°C

- the temperature of the refrigerator evaporator 2: 45°C.

The internal temperature of the main receiving tank for product support at 50°C., since the melting point of the product is approximately 42°C.

After heating all tanks up to these temperatures, the crude product is fed into the evaporator 1 with a flow rate of approximately 1.5 l/min Distillate (residual solvents) from the evaporator 1 is collected in a measuring Cup, as the volume of distillate small. The residue from the evaporator 1 is transferred into the evaporator 2 for the distillation of the crude base, which are collected mainly receiving the heating tank (1.4 l/min) liquid yellow color.

After completion of the distillation of all of the crude mixture (approximately 11 hours) residue from the evaporator 2 is transferred into the supply tank and again subjected to distillation. The temperature of the jacket of the evaporator 1 is reduced to 110°C., and the temperature of the jacket of the evaporator 2 is reduced to 140°C.

After distillation of the residue (about 2 hours) new balance comes in the cyclic system of evaporators and distillation continued until the rate of flow of the product reaches approximately 0.2 l/h Before the beginning of the cyclic process, the temperature of the jacket of the evaporator 1 is reduced to 100°C., and the temperature of the refrigerator in the COI is the 2 raises to 60°C. During cyclic distillation colour of the distillate in the receiving tank dark.

At the completion of distillation (mostly about 22,5 h) the apparatus was purged with nitrogen for cleaning. The product from the main receiving tank enters the barrel at a temperature of approximately 50°C, which was selected sample of the product and the barrel weighed. Chemical purity free base was 97 wt.% or more (in this case to 98.4 wt.%) according to gas chromatography. The product yield was 856,1, the Number of impurities of copper and/or palladium is little or netdetective number (less than 1 part./million).

The remainder (approximately 120 kg of peanut butter, in this case 128 kg), the distillate from the evaporator 1 and the condensate from the cooling traps were combined and burned. The apparatus was cleaned after holding five or six cycles of distillation.

An example for comparison: clean coal (at laboratory scale)

a negative result against metal and namecalling impurities)

In the solution of the crude terbinafine in free base (404 g) in cyclohexane (obtained in the same way as described above in example 1 from (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (100 g)was added activated charcoal (10 g) (Norit SupraR). The mixture was stirred for 17 h at 20-25°C and then filtered. Polyproylene solvent under reduced pressure was obtained terbinafine in free base (110,5 g, 89%)containing impurities of palladium (14 frequent./million). Chemical purity oily residue was 95% according to gas chromatography (conditions of the experiment described in example 2).

Example 4: Molecular distillation and OF GHUR with UV detector

(method And, on an industrial scale)

(a positive result in respect of non-metallic impurities, primarily substance (A)

Industrial quantity (and 872.5 kg) of the two batches of crude terbinafine in free base obtained after two cycles of distillation, the first of which contained 80 ppm million, and another 62 part./million substances As defined in comparison with the untreated sample terbinafine in free base by the method OF GHUR with UV detector) and 2.45 wt.% all other detected non-metallic impurities (the second party respectively 2,40 wt.%) was subjected to molecular distillation (the first and second batches were combined as described above in example 3, and selected a sample of the crude terbinafine in free base of the distillate and again analyzed its method OF GHUR. It was found that the sample of the distillate contains only 5 frequent./million substances And and 1.14 wt.% all other detected non-metallic impurities.

Conditions OF GVHR with UV detector:

Reagents:

- acetonitrile: for example, LiChrosolvR(Meck),

- water: for example, LiChrosolvR(Merck),

- triethylamine: for example, pure for analysis (Fluka),

- solvent: acetonitrile or acetonitrile/water 8:2 (about./vol.),

- the substance And for comparison (for example, from about 11 mg selected by chromatography on silica gel in the form of by-product formed during the synthesis of terbinafine according to the method (a), the patent EP 24587, chemical structure determined by the spectroscopic method).

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

Column: XTerra RP18, the particle size of 3.5 μm, a length of 150 mm, an inner diameter of 3.0 mm

The chromatography conditions:

- Mobile phase: a: water/triethylamine 1000:1 (vol./vol.);

In: acetonitrile/triethylamine 1000:1 (vol./about.)

- gradient:

Time (min)Phase A (%)Phase (%)
04357
83367
12595
13595
13,13357
3357
Input sample

- flow rate: 1.0 ml/min

- detection: absorption in the ultraviolet region at a wavelength of 280 nm

- temperature: 52°C

- volume of sample: 20 ál sample and standard solutions

- duration of the cycle chromatography: 16 min

concentration of sample: 40 mg/ml

The system is calibrated using standard solutions:

to assess reproducibility (standard solution 2 containing 100 ppm million of compound a, was obtained by dilution with a solvent standard solution of 1 (2.0 ml) to 20.0 ml of standard solution 1, containing 1000 ppm million substances And has been weighing approximately 2 mg of compound a with an accuracy of ±0.001 mg in a volumetric flask of 50 ml volume, followed by dissolving in a solvent and dilute to 50 ml),

- determine the limit of sensitivity (standard solution 3 containing 1 part./million of compound a, was obtained by dilution of a standard solution 2 (2.0 ml) solvent to 20.0 ml and dilute 2.0 ml of the resulting solution with a solvent to 20.0 ml), and

to assess selectivity (solution "SST" received weighing approximately 200 mg of the analyte with an accuracy of ±0.1 mg in a volumetric flask with a volume of 5.0 ml, followed by adding 250 ál of the standard process is as 2 and diluted with solvent to the desired volume: contains 100% of the medicinal product, containing 5 ppm million substances).

Used pure solvent to determine the baseline. Two of the investigated solution was obtained weighing approximately 200 mg of the compounds with an accuracy of ±0.1 mg in a volumetric flask with a volume of 5.0 ml, and then dissolved and diluted to the desired volume of solvent.

It is preferable to use flasks and test tubes of bottle glass.

Determined the peak areas of the substance And on the chromatogram of the investigated solution and standard solution 2.

The calculation was carried out according to the following formula (peaks below the limit of sensitivity of 1 part./million not included):

where

RS = related terbinafine substance, for example, substance And

RAT= the peak area RS in the studied solution

RAR2= the peak area RS in standard solution 2

mR= mass RS standard solution 1 (mg)

mT= mass of the compounds in the test solution (mg)

CR= RS content in percent, used for standard solutions

f=0,01 = dilution factor

10000 = conversion factor unit of measure ppm million

Results a typical chromatogram is shown in the chromatogram (see figure 2) (WVL = wavelength of 280 nm; x-axis = min, y-axis = millied. absorption = unit absorption ×10-3 ). The relative retention time for the drug terbinafine in free base and compound a were respectively 1.00 and approximately 1,73.

Other non-metallic impurities can be defined in similar terms, for example, using a reversed-phase column Hypersil ODS (particle size 5 μm, water mobile phase containing 0.1% triethylamine (about./vol.), the methanol phase containing 0.1% of triethylamine (about./vol.), solvent: methanol or methanol/water 80:20 (vol./vol.), concentration of sample: 0.5 mg/ml, column temperature 40°C).

Example 5: Molecular distillation and subsequent salt formation and deposition

(method a and method on an industrial scale)

(a positive result in respect of the first substance (A)

(a) Distillation (method A)

The crude terbinafine in free base was subjected to molecular distillation, as described above in example 4. Purified terbinafine in free base containing 5 ppm million substances And analyzed by the method OF GVHR with UV detector and precipitated in the form of a salt.

b) an Additional stage of formation of salts transisomer and its deposition (method)

To the product in the form of the base obtained in stage a), was added ethyl acetate and the resulting mixture was stirred at 20°C until complete dissolution, then received mesh filter (2 µm) and the pressure was reduced to 0.5 bar at 20°C. Then added gaseous Hcl at a temperature from 20°C to 25°C. the resulting suspension was stirred for 4 to 15 hours at 20°C, centrifuged, and the obtained product was washed with ethyl acetate, centrifuged at 1000 rpm, and the obtained product was dried. When this has been cleared hydrochloride terbinafine. Selected sample and analyzed by the method OF GVHR. It is established that the sample contains less than 1 part./million substances A.

1. The method of purification of terbinafine from non-metallic impurities selected from
a)

i.e. 6,6-dimethyl-2-hepten-4-Inal,
d)

ie (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthylethylene, or
e)

(substance A),
namely, that carried out the molecular distillation of the crude terbinafine in free base form, which significantly reduces the level of non-metallic impurities and produce a purified terbinafine in free base form or acid additive salt (method A).

2. The method of purification of terbinafine from non-metallic impurities selected from
a)

i.e. 6,6-dimethyl-2-hepten-4-Inal,
d)

ie (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthylethylene, or
e)

(substance A),
C is localsize is they spend molecular distillation of the crude terbinafine in free base form, which significantly reduces the level of non-metallic impurities, in combination with the formation of the salt of the obtained product with simultaneous precipitation of purified transisomer, and allocate obtained highly purified terbinafine in free base form or acid additive salt (method).

3. The method according to claim 1 or 2, in which the non-metallic impurity selected from substances And

4. The method according to claim 1 or 2, in which the distillation is carried out at a temperature more than 100°C and under reduced pressure.

5. The method according to claim 1 or 2, in which the crude terbinafine get the reaction of N-methyl-N-(1-naphthylmethyl)amine with 1-A-6,6-dimethyl-2-hepten-4-otherwise, where a represents a leaving group, especially bromine.

6. The method according to claim 1 or 2, in which the crude terbinafine contains more than about 5 hours/million non-metallic impurities selected from one or more compounds
a)

i.e. 6,6-dimethyl-2-hepten-4-Inal,
b)

ie (methyl)(naphthalene-1-ylmethyl)amine, i.e
N-methyl-N-(1-naphthylmethyl)amine, i.e
N-methyl-1-naphthalenemethanamine (a by-product 1),
c)

ie (Z)-N-(6,6-dimethyl-2-hepten-4-inyl)-N-methyl-1-naphthalenemethanamine (Z-some is),
d)

ie (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthylmethyl, and/or
e)

(substance A),
first of all, over approximately 5 hours/million substances A.

7. The method according to claim 1, in which the crude terbinafine contains more than about 5 hours/million substances And purified terbinafine contains less than about 5 hours/million substances A.

8. The method according to claim 2, in which the crude terbinafine contains more than about 5 hours/million substances And and highly terbinafine contains less than about 1 o'clock/million substances A.

9. Application of the method according to claim 1 or 2 for the production of purified terbinafine, which includes distillation terbinafine in free base.

10. Application of the method according to claim 9 for the production of purified terbinafine containing less than approximately 1 hours/million substances A.

11. Method of removing substances And terbinafine, including molecular distillation terbinafine in free base

(substance A).

12. The method according to claim 11, including the selection of the sample of the crude terbinafine in free base before distillation and the sample purified terbinafine in free base after distillation and determination in these samples the level of the substance A.

13. A method of obtaining purified terbinafine containing IU is approximately 1 hour/million substances And, including molecular distillation terbinafine in free base, which leads to a specific decrease in the level of substance And

present in the untreated sample terbinafine.



 

Same patents:

FIELD: analytic chemistry.

SUBSTANCE: invention relates to analytical chemistry and can be used to detect and identify chemical substances in the mixture by their characteristics. Method of detection and identification of components of chemical mixtures by their characteristics include a preliminary identification of indicators traits components to detect and identify these indicators and depending on the operating parameters in the whole range of changes in these parameters. Also method includes measuring of the operating parameters and preliminary identification of indicators of response variations in calibration of measuring devices in the whole range of possible changes in operating parameters. In addition the method includes defining critical limits values of the intensity variations in the subsets of values or ranges of characters in the absence of any of the parts. Then selects a subset of values or characteristic ranges of any of the intensity distribution in excess of the modulus of the critical border of intensity data subsets or ranges of values of attributes. Next, determine the center group parameters and the variation of the intensity distribution observed in selected subsets of values or ranges characteristics. Then the component identification is performed by comparing the values of clustering center of the intensity distributions and values of characteristics in the measured values of operating parameters and values variation of the intensity distributions and values of variations at an incorrect response that measured in operating parameters. In this first in the whole range of possible changes of operating parameters and intensities of the parameter definition of line segments approximating the contour or contour segments gauge responses measuring device. Then determine the relationship between the parameters of these segments and the type of gauge responses contour, and before identification determine sites selected subsets of values or ranges characteristics that can be approximated by line segments with a given deviation. From the values of the parameters of these segments separate the contours of the mixture components are successively subtracted from the subsets of values or ranges of characteristics.

EFFECT: improving the reliability of detection and identification of mixture components.

15 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: biological tissue is crushed, twice for 1 hour is drawn with portions of dioxane, each of which by weight is two times the amount of biomaterial, separate extracts are combined, filtered, filtrate is evaporated in air flow at temperature 18-22°C to small volume, diluted 5 times with water, extracted with ethyl acetate, ethyl acetate extract is separated, dehydrated, evaporated at 18-22°C in air flow to small volume, after which in nitrogen flow until solvent is removed completely, residue is dissolved in mixture of solvents hexane-dioxane-propanol-2 (150:5:1), purified by method of column chromatography in column with size 490×11 mm, filled with 10 g of silica gel L 40/100 mc, with application of mobile phase solvents hexane-dioxane-propanol-2 (150:5:1), eluate fraction, which contain analysed substance, combined, eluate is evaporated in air flow at temperature 18-22°C to small volume, then in nitrogen flow until solvent is removed completely, residue is dissolved in hexane and detection is carried out by method of gas-liquid chromatography with application of capillary column DB-1701, 30 m long, with internal diameter 0.25 mm with stationary phase 0.25 mcm thick, which contains polysiloxane and polyethylene glycol, with application of helium as carrier gas, supplied with velocity 1 ml/min and mass-spectrometric detector, working in mode of electron impact, with registration of mass-spectrum by full ion flow, amount of esphen valerate is calculated by data of chromatogram, obtained by registering intensity of signal induced by charged particles formed during bombardment of analysed substance, which comes from capillary column and gets into source of ions, by ionising beam of electrons with energy 70eV.

EFFECT: increase of detection sensitivity.

3 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention describes a method of determination of ethanol and other metabolites content in human blood by liquid phase chromatography, including preparation of blood distillates by vapour straight distillation and blood component analyis, characterised by the fact that it is combined with one-stage quantitative determination of ethanol, diethyl ester, acetaldehyde, acetone, methylacetate, ethylacetate, propyl alcohol, isobutyl alcohol, butyl alcohol, isoamyl alcohol with the use of capillary chromatographic columns; the concentration of the determined blood components is calculated by formula: where a is chromatographic study results, mg/dm3; V is a distillate volume, cm3; m is a whole blood weight, g.

EFFECT: method can be used in clinical laboratory diagnostics in studies of metabolic disorders caused by alcohol poisoning, and in judicial medical activity for diagnosing of a degree of intoxication of live persons.

1 ex, 1 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method for ion-exchange separation of methionine and glycine and can be used in biochemistry, pharmaceutical and food industry. The method involves separation of methionine and glycine in two steps. At the first step amino acids undergo sorption with enrichment of the sorbent phase with glycine, and the solution at the output enriched with methionine. For this purpose, polyampholyte Purolite S950 in H-form is prepared. The mixture of two aliphatic amino acids undergoes sorption in a countercurrent column with a fixed sorbent layer. For this purpose, a solution containing a mixture of glycine and methionine is fed from below and glycine is undergoes sorption on polyampholyte Purolite S950. Methionine, appears at the output, the aqueous solution of which is sorbed in a receiver at the output of the column and after a certain time - the amino acids. Sorption is stopped. During sorption, samples are collected at defined time intervals. Total concentration of amino acids is controlled using an iodimetric method, and concentration of methionine is controlled using a spectrophotometric method, while glycine concentration is controlled based on concentration difference: between total concentration and methionine concentration. The degree of separation of the initial solution is equal to 60%. At the second step, glycine is eluted with hydrochloric acid solution at pH 1.2 from the sorbent while feeding glycine-containing eluate from the top, and sorbed in the receiver. Concentration of glycine is equal to 70%. After desorption of glycine, the mixture of amino acids undergoes complete desorption. Polyampholyte takes the initial shape and is ready for operation. Samples are collected at defined time intervals and each sample is analysed using iodometric and spectrophotometric methods. For complete separation of glycine from methionine, the two-step process of separating the mixture of amino acids obtained at the output of the column is repeated.

EFFECT: method enables efficient separation of methionine and glycine by combining sorption and desorption processes while excluding the sorbent regeneration step, and reduce the volume of wash water without using considerable amount of auxiliary reactants.

2 dwg, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: analysed sample is infused with an organic insulating agent. The obtained extract is purified through chromatography on a column of silica gel L 40/100 µ, while performing elution with a mixture of organic solvents. The analysed substance is determined using a chromatographic technique using a mobile phase which contains hexane, dioxane and propanol-2. The organic insulating agent is toluene. The toluene extract is dehydrated with anhydrous sodium sulphate. During the purification process, hexane is first passed through the column and elution is then carried out with a hexane-dioxane-propanol-2 solvent mixture (8:3:0.6 by volume). Eluate fractions containing the analysed substance are merged. The eluent is evaporated. The residue is dissolved in the hexane-dioxane-propanol-2 solvent mixture (15:5:1 by volume) and detection is carried out using high-performance liquid chromatography (HPLC) in a 64×2 mm column filled with Silasorb-600 sorbent using a hexane-dioxane-propanol-2 mobile phase (15:5:1 by volume) and a UV detector.

EFFECT: high accuracy and sensitivity of analysis.

3 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: there is described a method of quantitative cyclosporine A evaluation in patients' blood involving blood protein precipitation by adding an aqueous solution of zinc sulphate and methanol, mixing, centrifuging and sampling a centrifugate; separating the centrifugate ingredients by reverse phase high-yield liquid chromatography, mass-spectrometre detecting cyclosporine A and evaluating the cyclosporine A concentration with plotting a calibration curve; blood protein are precipitated with using whole blood; blood protein precipitation is followed by additional salt impurity precipitation by adding methanol to the centrifugate to the general concentration not less than 90 vol. %, mixing again, centrifuging and sampling the centrifugate; separating the centrifugate ingredients, detecting and evaluating the cyclosporine A concentration.

EFFECT: method allows facilitating analysis simplicity and universality with providing adequate sensitivity and selectivity ensured by the absence of necessity for the internal standard and online extraction and lower requirements to specification of the used mass spectrometre by conducting preliminary impurity precipitation.

1 ex

FIELD: physics.

SUBSTANCE: proposed method comprises forcing analysed product into chromatograph first circuit to define carbon sulphide at its concentration exceeding 0.1 wt % and, at a time, into second circuit at carbon sulphide concentration lower than 0.1 wt %. First circuit comprises piston-type metering valve and packed columns arranged in heated temperature-controlled cabinet and filled with polymer adsorbent, 0.1-1.5 m-long precolumn and 0.5-5 m-long main column, and heat conductivity detector. Second circuit comprises piston-type metering valve, packed capillary columns arranged in heated temperature-controlled cabinet and filled with polymer adsorbent, 0.1-1.5 m-long precolumn and 15-50 m-long main column with their ID making 0.23-0.32 mm, and sulfur-selective detector. Metering valves are arranged sequentially in both circuits along sample feed direction.

EFFECT: shorter easier process.

5 cl, 1 dwg, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: urine is sampled, centrifuged that is followed by solid-phase extraction with Oasis HLB sorbent with using 100% acetonitrile as an extraction fluid for dimethyl terephthalate extraction. Said solid-phase extraction is conducted by consequent passing 100% acetonitrile, distilled water, the urine sample after centrifugation, distilled water, 20% aqueous acetonitrile and 100% acetonitrile as the extraction fluid through the sorbent; then the prepared extract is analysed by liquid chromatography with using as a mobile phase mixed acetonitrile and water in the at the varying ratio 25:75 vol. % to 90:10 vol. % respectively in a gradient mode which is enabled with combining chromatography by supplying at first the mobile phase containing mixed acetonitrile and water in the ratio 25:75 vol. % for 10 minutes. Then increasing the acetonitrile concentration in the mobile phase to 90 vol. % for 5 minutes and passing such mobile phase for another 5 minutes is followed by decreasing a volume amount of acetonitrile to 25 vol. % for 5 minutes and passing such mobile phase through a column for 10 minutes, while an amount of dimethyl terephthalate is determined by a calibration chart.

EFFECT: high sensitivity of the method combined with selectivity and availability for routine analyses.

5 cl, 6 tbl

FIELD: medicine.

SUBSTANCE: invention describes a method of quantitative evaluation of blood acetic, propionic, isobutyric, butyric, valeric, isocapronic and capronic acids by gas chromatography analysis wherein a blood sample is acidified with 1 % sulphuric acid to pH 2-3, evaluated acids are extracted with isobutyl alcohol volume of which is related to the blood sample volume as 1:1. The protein separation is enabled by centrifugation. 2-3 drops of 0.4 % alkali is added, and the extract is evaporated dry, further the solid residue is added consistently with 1 % sulphuric acid and isobutyl alcohol that is followed with gas chromatography separation of the mixed acids in a capillary column with a flame ionisation detector, and the amount of each acid is evaluated by a calibration diagram.

EFFECT: higher sensitivity and accuracy of the method of quantitative evaluation of acetic, propionic, isobutyric, butyric, valeric, isocapronic and capronic acids if found in blood together.

5 cl, 1 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: disclosed is a method of detecting unknown substances in body fluids of patients taking narcotic or psychoactive substances. The method involves preparation of three body fluid samples - the first through extraction with re-solution, the second through acid hydrolysis and the third through enzymatic hydrolysis. The first sample undergoes GC/MS analysis at temperature gradient of 15°C/min and data are analysed by comparing with a data base from which features of the unknown substance are detected, specifically spectra with m/z values which coincide with basic ions of the narcotic or psychoactive substance or metabolites and content of the unknown substance in the sample. The second sample undergoes GC/MS analysis at temperature gradient of 25°C/min and the third sample undergoes GC/MS analysis also at temperature gradient of 15°C/min and, if content of the unknown substances in the last two samples is higher than the in the first, the narcotic or psychoactive substance undergoes GC/MS analysis for presence of the unknown substance also at temperature gradient of 15°C/min, and if also not present in the basic substance. Presence of the unknown substance in intact body fluid is also checked, for which a sample of the intact body fluid is prepared via acid hydrolysis and undergoes GC/MS analysis at temperature gradient of 15°C/min and 25°C/min, and if the unknown substance is detected in the intact body fluid, the substance is classified as endogenous, and in the absence of features, an aliquot of the first sample is mixed with the sample of intact body fluid. The sample is prepared via acid hydrolysis of the mixture. The sample undergoes GC/MS analysis at temperature gradient of 15°C/min and 25°C/min. Further, content of the unknown substance is determined from results of both analysis modes and then compared with content of the known substance in the first sample. If content values of the unknown substance in the said three samples coincide, the unknown substance is classified as a new, previously unknown product of metabolism of the basic narcotic or psychoactive substance.

EFFECT: possibility of unique identification of chemical compounds and their fragments in arbitrary combinations while increasing accuracy and rapidness of detection.

4 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the improved method of purification of terbinafine with formula (I) by distillation of the raw terbinafine base at decreased pressure and temperature in the range 110-170°C. The said distillation is carried out up to temperature which causes only limited product thermal destruction with its segregation in the form of free base or in the form of acid-addition salt. The distillation is preferably carried out at minimal time of increased temperature affect. For implementing of the said method it is desirable to use raw terbinafine obtained by the reaction of (E)-N-(3-halo-2-propenyl)-N-methyl-N-(1-naphtylmethyl)amine with 3,3-dimethyl-1-buthyn in presence of palladium and/or copper catalyst.

EFFECT: decrease of by-products and other admixtures content, increase of pure E-isomer yield.

9 cl, 1 dwg, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a novel terbinafine salt of the formula (I):

with malic acid possessing an antimycotic activity and to a method for its preparing and pharmaceutical composition used in treatment of fungal infection. L-(-)-bimalate is the most preferable form of salt. Method for preparing salt involves interaction of compound of the formula (I) as a free base with the corresponding form of malic acid. Pharmaceutical composition comprises indicated salt in combination with at least one pharmaceutically acceptable carrier or excipient. Pharmaceutical composition can be prepared as a solution or lacquer for nails. Proposed salt shows improved pharmacokinetic properties that makes its to be preferable in preparing pharmaceutical compositions adopted for systemic and topical using.

EFFECT: improved preparing method, improved and valuable properties of salt and pharmaceutical composition.

8 cl, 6 dwg, 5 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to derivatives of allylamines, namely, to a method for preparing terbinafine or its hydrochloride. Method involves interaction of N-methyl-naphth-1-yl-methylamine taken in excess with 1-halogen-6,6-dimethylheptene-2-ene-4-ine in water or inorganic base an aqueous solution followed by, if necessary, treatment of prepared product with hydrochloric acid. As a rule, as the parent reagent both 1-bromo-6,6-dimethylhept-2-ene-4-ine and 1-chloro-6,6-dimethylhept-2-ene-4-ine is used. Usually 5-50% mole excess of N-methyl-naphth-1-yl-methylamine is used in case using inorganic base. Method provides enhancing yield of the end compound, to simplify the process and to expand the raw base by using the more low-priced 1-chloro-6,6-dimethylhept-2-ene-4-ine as an alkylating agent.

EFFECT: improved preparing method.

3 cl, 3 ex

The invention relates to a new method of obtaining (E)-N-methyl-N-(1-naphthylmethyl)-6,6-dimethylheptyl-2-EN-4-inyl-1-amine of the formula (I) or its acid salt additive

The invention relates to new compounds of the formula I or II or compounds selected from the following group, with activity against receptor calcium, pharmaceutical compositions and methods of treating diseases caused by abnormal mineral homeostasis, hyperparathyroidism, hypercalcemia, malignant tumors, osteoporosis, hypertension and renal osteodystrophies

The invention relates to medicinal chemistry, to methods for obtaining compounds of compounds possessing the ability to inhibit holinesterzy and thereby improve the functioning of the brain in older people

FIELD: chemistry.

SUBSTANCE: method involves bringing a crude organic product into contact with a solid adsorbent, where the solid adsorbent is selected from a group consisting of an oxide or hydroxide of magnesium, calcium, strontium and barium, and filtering the crude organic product in order to remove the metal of the residual catalyst. The residual catalyst is selected from a group consisting of a metal halide, metal oxyhalide, alkyl metal, alkoxy metal, where the metal in the residual catalyst is selected from a group consisting of group III and group VIII metals.

EFFECT: method enables more complete removal of catalyst residue.

22 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: method involves hydrogenation of a dinitrile with hydrogen or a hydrogen-containing gas in several steps: first distillation of a stream E0 coming from the hydrogenation medium in order to extract a head fraction E1 containing water and imines present in the medium, and a tail fraction Q1 containing hydrogenated compounds; second distillation of stream Q1 to extract a head fraction E2 containing hydrogenated compounds and a tail fraction Q2 containing compounds with a higher boiling point than that of the primary diamine; third distillation of the head fraction E2 to extract a tail fraction Q3 containing hydrogenated compounds and a head fraction E3 containing compounds with boiling point lower than that of the formed diamine; fourth distillation of the tail fraction Q3 to extract a head fraction E4 containing pure diamine, and a tail fraction Q4 containing heavy impurities.

EFFECT: method enables to carry out separation in third and fourth columns with minimum power consumption and high output, and reduce contamination of elements of the column filling.

5 cl, 1 dwg

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