The method of obtaining triazoles, final and intermediate products of the way

 

(57) Abstract:

Describes how to obtain triazoles of the formula (I) or its salt additive acid or base, where R is phenyl, optionally substituted by 1-3 substituents, each of which is independently selected from halogen and trifloromethyl; R1- C1-C6-alkyl and Het is pyrimidinyl, optionally substituted by 1-3 substituents, each of which is independently selected from C1-C4-alkyl, C1-C4-alkoxy, halogen, oxo, benzyl and benzyloxy, comprising the reaction of compounds of formula (II), where R is previously defined for compounds of formula (I) with the compound of the formula (III), where R1and Het are defined previously for compounds of formula (I), X is chlorine, bromine or iodine, in the presence of zinc, iodine and/or Lewis acid and an aprotic organic solvent with subsequent optional conversion of the compounds of formula (I) in its additive salt of the acid or base. Also describes the final and intermediate products. The technical result is an increase in the yield of the target product and stereoselectivity. 5 C. and 34 C.p. f-crystals.

The invention relates to a method for producing alcohols by attaching ORGANOMETALLIC reagents to ka with ORGANOMETALLIC compounds, derived from alpha-halogensilberemulsionen with the formation of tertiary alcohols.

In the field of organic chemistry well known reaction of ORGANOMETALLIC compounds, derivatives of alkylhalogenide, with aldehydes and ketones with secondary and tertiary alcohols, respectively. It was reported that for this type of reactions suitable for many different metals and derivatives of metals, including lithium, magnesium, aluminum, tin and zinc, together with their salts. For example, A. R. Gangloff, etc., J. Org. Chem., 57, 4797-4799 (1992) describe that 2-(methyl bromide)-4-carbethoxy-1,3-oxazol reacts with zinc dust with education tsinkorganicheskih derived, which takes nucleophilic attach to aldehydes and ketones. In addition, Chollet, etc., Synth. Comm. , 19 (11 and 12), 2167-2173 (1989), have reported reactions tsinkorganicheskih derivatives brominated esters with aldehydes and ketones.

Certain compounds obtained by the present method described in published European patent application No. 0357241 C 07 D 249/08 and 0440372 C 07 D 403/06.

It was unexpectedly discovered that certain derivatives of 1-phenyl-2-(1H-1,2,4-triazole-1-yl)ethanone can react with ORGANOMETALLIC compounds derived from the op is the principal output and with high stereoselectivity, using the reaction conditions, which are particularly suitable for the synthesis of the product in mass.

It was found that this discovery is particularly suitable for the synthesis of (2R, 3S/2S, 3R)-3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)butane-2-ol, the main intermediate product to obtain (2R, 3S)-2-(2,4-differenl)-3-(5 - ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, compounds with antifungal activity. The synthesis of both of these compounds are described in published European patent application number 0440372. In this application (2R,3S/2S,3R)-3-(4-chloro-5-ftorpirimidinu-6-yl)- 2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol obtained by chromatographic separation of the two pairs of enantiomers, obtained as a result of the merger of organolithium derivative 4-chloro-6-ethyl-5-ftorpirimidinu 1-(2,4-differenl)-2-(1H-1,2,4 - triazole-1-yl)ethanone at a temperature of from -70 to -50oC. the Best stereoselectivity, which was achieved in this connection, is the molar ratio of 1.1:1 in favor 2R,3S/2S,3R-enantiomeric pairs with a total output of all selected four stereoisomers, constituting only about 50%, and believe that the low yield is due to the competitive reaction enolizatsii. These factors, instead of diluting and together with the difficulty in the separation of approximately equimolar amounts of the two pairs of enantiomers at the end of the reaction, moreover, 2R, 3R/2S, 3S-enantiomeric pair is undesirable, means that the method is extremely unsuitable for cheap obtain the desired 2R,3S/2S,3R-intermediate on a large scale.

On the contrary, it has been found, for example, that the molar ratio of 2R, 3S/2S, 3R-enantiomeric pair to 2R,3R/2S,3S-enantiomeric pair of 3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol, equal to 9: 1, and the total output of all selected enantiomers (in the form of cleaners containing hydrochloride salts), equal to 65%, can be achieved under the reaction conditions of the present invention, which is very convenient for large-scale synthesis of the product.

However, by varying the reaction conditions in accordance with the present invention have been achieved higher yields of the selected substance and a higher molar ratio (as for [the reaction] in situ, and in respect of the selected product).

Similar results were achieved for a number of alpha-halogensilberemulsionen substrates.

The achieved outputs and stereospecificity lead to significant economic benefits.

In the present invention proposes a method of obtaining compounds of the formula:

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or age, each of which is independently selected from halogen and trifloromethyl;

R1represents C1-C6-alkyl; and

Het is pyrimidinyl, optionally substituted by 1-3 substituents, each of which is independently selected from C1-C4-alkyl, C1-C4-alkoxy, halogen, oxo, benzyl and benzyloxy,

comprising the reaction of the compound of the formula:

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where R is previously defined for compounds of formula (I) with the compound of the formula:

< / BR>
where R1and Het are defined previously for compounds of formula (I), and X represents chlorine, bromine or iodine, in the presence of zinc, iodine and/or Lewis acid and an aprotic organic solvent, and after this process is not necessarily followed by the formation of additive acidic or basic salt of the product.

In addition, the reaction may not necessarily be the lead or as the metal itself or in the form of a suitable salt, for example, the halide of lead (II). It can be added separately or it may initially be present in the zinc.

In the above definitions, the alkyl and alkoxy groups containing three or more carbon atoms may be linear or branched chain, and "halogen" sachlage-substituents.

More preferably, R is phenyl, substituted by 1 or 2 substituents, each of which is independently selected from fluorine and chlorine.

Even more preferably, R is phenyl, substituted by 1 or 2 fluorine substituents.

Most preferably, R is 2,4-differenial.

Preferably, R1represents C1-C4-alkyl.

More preferably, R1represents methyl or ethyl.

Most preferably, R1represents methyl.

Preferably, Het is pyrimidinyl, optionally substituted by 1-3 substituents, each of which is independently selected from halogen, oxo or benzyl.

More preferably, Het is pyrimidinyl, optionally substituted by 1-3 substituents, each of which is independently selected from fluorine, chlorine, oxo or benzyl.

Even more preferably, Het is pyrimidinyl, substituted by 1-3 substituents, each of which is independently selected from fluorine and chlorine.

It is preferable examples of Het include pyrimidine-4-yl, 4-chloro-5-ftorpirimidinu-6-yl, 5-ftorpirimidinu-4-yl, 2-chloro-5-ftorpirimidinu-6-yl, 2,4-dichloro-5-ftorpirimidinu-6-yl, 4-chloro-pyrimidine-6-yl and 1-nl.

Preferably, X represents bromine or iodine.

Most preferably, X represents bromine.

The compound of formula (II) may be able to enolizatsii ketone. Most preferably, the compound of formula (II) is 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)atenonol.

The compound of formula (III), preferably selected from 6-(1-bromacil)-2,4-dichloro-5-ftorpirimidinu, 6-(1-bromacil)-4-chloro-5-ftorpirimidinu, 6-(1-bromacil)-2-chloro-5-fluoro-pyrimidine, 4-(1-bromacil)pyrimidine, 4-(1-bromacil)-6-chloropyrimidine, 4-(1-bromacil)-5-ftorpirimidinu and 1-benzyl-4-(1-bromacil)-5-ftorpirimidinu-6-it.

Most preferably, the compound of formula (III) is 6-(1-bromacil)-4-chloro-5-torpedinidae.

The reaction is carried out in the presence of a suitable aprotic organic solvent, such as tetrahydrofuran, toluene, 1,2-dimethoxyethane or methylene chloride, or a mixture of two or more of these solvents. It is desirable to drain the solvent before use, to remove essentially all traces of water. Drying can be achieved by use of such driers as magnesium sulfate, sodium sulfate or molecular sieves, by distillation over such a metal as lithium, sodium, and what I tetrahydrofuran.

It is also preferred to conduct the reaction in a dry inert atmosphere, for example, using gaseous dry nitrogen or argon.

Used in the reaction of zinc can be zinc powder, obtained from a commercial product, or can be freshly prepared in situ by raising the recovery of zinc halide (e.g. zinc chloride) with the use of lithium, sodium or potassium (see, for example, R. D. Rieke, Acc. Chem. Res., 10, 301 (1977)). Before using zinc powder can be activated by mixing suspensions of powder for several hours in a suitable solvent, e.g. tetrahydrofuran.

The reaction may optionally be carried out if additional presence of lead.

Obtained from a commercial product zinc powder may contain small quantities of lead as an impurity, and the lead content can reach about 2000 parts per million (0.20 wt.%) depending on the source. However, it is generally preferable to increase the lead content by adding it in the form of a lead powder to the reaction mixture. Lead powder is available for sale.

Preferably, when using a lead, the quantity present in the More preferable, the number of present lead is from 2,000 to 100,000 parts per million (0.2 to 10 wt.%). Most preferably, the amount present of lead is about 50,000 ppm (5% wt.).

Typically, iodine is used in its commercially available crystalline form. There is an assumption that his role in the reaction is the generation in situ of iodide of zinc, possibly in conjunction with iodide lead (II), when also present lead, both of them can act as catalysts.

When using iodine, it can be introduced into the reaction vessel before add compounds of formulas (II) and (III), during it or after. Alternatively it can be added in at least two stages, for example, one part can be added to the reaction vessel before, and the second part can be added when the add connection formulas (II) and (III).

The Lewis acids suitable for use in the reaction include zinc chloride, zinc bromide, zinc iodide, isopropoxide titanium (IV), triisopropoxide, titanium tetrachloride, trimethylboron, boron TRIFLUORIDE (athirat), iron chloride (III) and diethylaluminium.

Preferred Lewis acids are brough shall be separately Lewis acid.

In the above method, you do not have to use and iodine, and a Lewis acid.

The reaction can be from -15oC to the temperature of reflux distilled mixture. Preferably, it is conducted from -10oC to +30oC and most preferably from -10oC to +15oC.

Almost safe to say that the reaction proceeds through the formation of tsinkorganicheskih particles obtained in the reaction in situ between zinc and a compound of formula (III), which is used as the starting material.

The reaction may be conducted by the following General method.

Iodine and/or a suitable Lewis acid is added to stir the mixture of zinc, optionally, lead and a suitable aprotic organic solvent. The mixture is cooled and add a solution of the compounds of formula (II), the compounds of formula (III) and, optionally, additional iodine in a suitable aprotic organic solvent, cooling the mixture during the addition. The mixture is stirred additionally a short time, and then warmed to room temperature. The reaction is quenched by adding glacial acetic acid and then water, and then you can use conventional techniques to highlight the desired selling the product. Preferably the formation of acid additive salts, and suitable salts include cleaners containing hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, methanesulfonate, camphorsulfonate, R-(-)-10-camphorsulfonate, (+)-3-bromo-10-camphorsulfonate, (-)-3-bromo-8-camphorsulfonate, phosphate, para-toluensulfonate and benzosulfimide salt. Especially preferred cleaners containing hydrochloride salt.

The compound of formula (I) obtained by the method according to the invention contains two or more asymmetric carbon atoms and therefore exists in four or more stereoisomeric forms.

Generally, the reaction proceeds with high stereoselectivity in favor of (2R,3S/2S,3R)-enantiomeric pairs of compounds of formula (I), that is,

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where the asterisk (*) indicate asymmetric carbon atoms, referred to.

Division of diastereoisomers can be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or HPLC stereoisomeric mixtures of compounds of formula (I) or a suitable salt or derivative. Separation of enantiomers of compounds of formula (I) can be achieved by HPLC of the corresponding racemate using podhodyaschego of the racemate with a suitable optically active acid, for example, R-(-)-10-camphorsulfonic acid.

The method is preferably used to obtain 3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol from the source material - 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone and 6-(1-bromacil)-4-chloro-5-ftorpirimidinu. High stereoselectivity can be achieved, for example, in the reaction with a molar ratio of 9: 1 between 2R,3S/2S,3R and 2R,3R/2S,3S-enantiomeric pairs, which is obtained, if carefully controlled reaction conditions. In addition, there has, for example, 65% of the total output of all selected enantiomers (in the form of cleaners containing hydrochloride salts).

The reaction product, which contains a much higher proportion hydrochloride (2R, 3S/2S, 3R)-3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4 - differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, can be restored to obtain (2R, 3S/2S, 3R)-2-(2,4-differenl)-3-(5 - ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, which can be divided to obtain (2R,3S)-2-(2,4-differenl)-3-(5 - ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol according to the method described in published European patent application number 0440372.

According to another aspect of the present invention proposes a method of obtaining compounds of the formula:

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(a) reaction of a compound of the formula:

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where R is defined for the compounds of formula (IV) with the compound of the formula:

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where X is chlorine, bromine or iodine, R1and R2previously defined for compounds of formula (IV), and either each of R3and R4independently selected from chlorine or bromine, or one of R3and R4is chlorine or bromine and the other is H, in the presence of zinc, iodine and/or Lewis acid and an aprotic organic solvent, to obtain the compounds of formula:

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where R, R1, R2, R3and R4previously defined for a given stage (a);

(b) optional conversion of the compounds of formula (IA) in its acid additive salt;

(c) recovery of the compounds of formula (IA) or its acid salt additive with obtaining the compounds of formula (IV); and

(d) optional conversion of the compounds of formula (IV) in its acid additive salt.

Reaction conditions, including preferred terms that are used in stage (a), are the same as described previously, to obtain the compounds of formula (I). Again, at the stage (a) can also optionally be present in the lead.

Recovery stage (c) can be carried out if any is 4 is chlorine or bromine.

Recovery can be accomplished under normal conditions of hydrogenation using a suitable catalyst, e.g. palladium on charcoal, optionally in the presence of a suitable base, such as sodium acetate, in a suitable solvent, for example ethanol, in an atmosphere of hydrogen.

Recovery is preferably carried out under conditions of hydrogenation with the transfer, using a suitable catalyst, e.g. palladium or rhodium, a suitable donor of hydrogen, for example, ammonium formate or potassium hydroxide, in a suitable solvent, e.g. methanol. The reaction is preferably carried out at a temperature reflux distilled solvent and in nitrogen atmosphere.

Examples of the acid additive salts on the stage (b) are cleaners containing hydrochloride, nitrate, methanesulfonate, p-toluensulfonate, camphorsulfonate, R-(-)-10-camphorsulfonate, (+)-3-bromo-10-camphorsulfonate and (-)-3-bromo-8-camphorsulfonate salt. The preferred acid additive salts at the stage (b) are cleaners containing hydrochloride, methanesulfonate and p-toluensulfonate salt.

The preferred acid additive salt on stage (d) is R-(-)-10-camphorsulfonate that mo is to use S-(+)-10-camphorsulfonate salt.

In this method of obtaining compounds of formula (IV):

(I), R preferably is a phenyl, optionally substituted by 1-3 halogen substituents.

More preferably, R is phenyl, substituted by 1 or 2 substituents, each of which is independently selected from fluorine and chlorine.

Even more preferably, R is phenyl, substituted by 1 or 2 fluorine substituents.

Most preferably, R is 2,4-differenl.

(II) Preferably, R1represents C1-C4-alkyl.

More preferably, R1represents methyl or ethyl.

Most preferably, R1represents methyl.

(III) Preferably, X represents bromine or iodine.

Most preferably X is bromine.

(IV) Preferably, R2is fluoride.

(V) Preferably, R3represents chlorine and R4represents H, R3is H and R4represents chlorine, or R3and R4both are chlorine.

(VI) To the preferred compounds of the formula (IIIA) include: 6-(1-bromacil)-2,4-dichloro-5-ftorpirimidinu, 6-(1-bromacil)-4-chloro-5-ftorpirimidinu, 6-(1-bromacil)-2 is tocada:

3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol,

3-(2-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol,

3-(2,4-dichloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H - 1,2,4-triazole-1-yl)butane-2-ol and

3-(4-chloropyrimidine-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol,

and their acid additive salts, in particular, cleaners containing hydrochloride, methanesulfonate and p-toluensulfonate salt.

(VIII) To the preferred compounds of the formula (IV) include:

2-(2,4-differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol and

2-(2,4-differenl)-3-(pyrimidine-4-yl)-1-(1H-1,2,4-triazole-1 - yl)butane-2-ol

and their acid additive salts, in particular, S-(+)- or R-(-)-10-camphorsulfonate salt.

Syntheses of starting materials used in the method according to the present invention, are conventional and appropriate reagents and reaction conditions for their production, and methods of selection of desired products is well known in the art with reference to literature and the examples of synthesis described in the description.

In addition, the present invention offers the following new compounds:

(I) (2R, 3S)-3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-deltorphin is(2,4-differenl)-1-(1H - 1,2,4-triazole-1-yl)butane-2-ol and preferably, cleaners containing hydrochloride, nitrate, methanesulfonate, p-toluensulfonate, camphorsulfonate, R-(-)-10-camphorsulfonate, (+)-3-bromo-10-camphorsulfonate or (-)-3-bromo-8-camphorsulfonate salt;

(III) 3-(2,4-dichloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)- 1-(1H-1,2,4-triazole-1-yl)butane-2-ol or (2R,3S/2S,3R)- or (2R,3S)-form, or acid additive salt of any of them;

(IV) 3-(2-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H - 1,2,4-triazole-1-yl)butane-2-ol or (2R,3S/2S,3R)- or (2R,3S)-form, or acid additive salt of any of them;

(V) 3-(1-benzyl-5-ftorpirimidinu-6-on-4-yl)-2-(2,4-differenl)- 1-(1H-1,2,4-triazole-1-yl)butane-2-ol or (2R,3S/2S,3R)- or (2R,3S)-form, or acid additive salt of any of them;

(VI) 3-(4-chloropyrimidine-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol or (2R,3S/2S,3R)- or (2R,3S)-form, or acid additive salt of any of them;

(VII) 6-(1-bromacil)-2,4-dichloro-5-ftorpirimidinu;

(VIII) 4-(1-bromacil)-6-chloropyrimidine;

(IX) 6-(1-bromacil)-4-chloro-5-ftorpirimidinu;

(X) 1-benzyl-4-(1-bromacil)-5-ftorpirimidinu-6-he;

(XI) 6-(1-bromacil)-2-chloro-5-ftorpirimidinu;

(XII) 4-(1-bromacil)-5-ftorpirimidinu;

(XIII) 2-chloro-6-ethyl-5-fluoro-4-hydroxypyrimidine, ammonium salt.

The following example is eremein-6-yl)- 2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol hydrochloride

(* the ratio of the in situ)

< / BR>
Stir a mixture of zinc powder (Britannia Alloys) (9.35 kg), lead (325 mesh, Aldrich) and tetrahydrofuran (53 l) is heated under reflux in nitrogen atmosphere for 3 hours. After that, the mixture is cooled to 25oC and continue stirring for 16 hours. For 80 minutes, add a solution of iodine (7.24 kg) in tetrahydrofuran (21 l) and allow the rise of the reaction temperature during the addition of up to 45oC. the mixture is Then cooled from 0 to -5oC. Then add a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (6,53 kg) and 6-(1-bromacil)-4-chloro-5-ftorpirimidinu (see synthesis 1) (7,01 kg) in tetrahydrofuran (53 l), maintaining during the addition the reaction temperature below +5oC. the Mixture is heated to 25oC and add glacial acetic acid (8,84 kg) and water (84 l). Solid metal residues separated by decantation and 60 liters of tetrahydrofuran is removed by distillation under reduced pressure. Add ethyl acetate (76 kg) and the distillation continued until the removal of 165 l of solvent. The mixture is cooled and extracted with ethyl acetate (2 x 84 l). The combined extracts are washed with a solution of the dihydrate of dinitrilotetraacetic (3,22 kg) in water (161 l) and then with saturated saline solution (30 l).

With the use of 25-cm column with reversed phase C18 Dynamax 60 angstroms, moreover, the mobile phase consists of a mixture of acetonitrile:water 65:35 by volume and has a flow rate of 1 ml/min Detector set at 254 nm. This analysis shows the molar ratio of 9: 1 between 2R, 3S/2S, 3R- (WU = of 5.53 min) and 2R,3R/2S,3S- (WU = 4,47 minutes) enantiomeric pair of free base specified in the connection header.

The organic layer is concentrated to a volume of 56 litres and 25oC add a solution of hydrogen chloride (1.2 kg) in isopropanol (6 l). Specified in the title compound precipitates in the form of solids. It is collected by filtration, washed with ethyl acetate (5 l) and dried (7,89 kg, 65%), so pl. 126-130oC.

Example 2

10,3: 1*(2R, 3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloro-5-ftorpirimidinu - 6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol

(* the ratio of the in situ)

< / BR>
To a stirred suspension of zinc (Britannia Alloys) (3.00 g) and lead (0.15 g) in tetrahydrofuran (19 ml) under nitrogen atmosphere at 25oC added dropwise a solution of iodine (2.25 g) in tetrahydrofuran (6 ml). Allow the rise of the reaction temperature during the addition. The mixture is then cooled to 2oC. is added dropwise within 10 minutes, add a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (2.00 g), 6-(1-bromacil)-4-chloro-5-ftorpirimidinu (see synthesis 1) (2,84 g) and iodine (0 C cooling. Then further cooled to a temperature below +5oC. the Reaction mixture is stirred at a temperature below +5oC for 30 minutes. Select a sample of the reaction mixture and subjecting it to analysis HPLC in accordance with the conditions shown in example 1. The analysis shows the molar ratio of 10.3:1 between 2R,3S/2S,3R and 2R,3R/2S,3S-enantiomeric pair specified in the connection header. Output 2R,3S/2S,3R-enantiomeric pair is calculated as 90% using an internal standard.

Example 3

11,2: 1*(2R, 3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloro-5-ftorpirimidinu - 6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol hydrochloride

(* attitude in the selected product [attitude in situ = 6,7:1])

< / BR>
Zinc dust (Britannia Alloys) or 37.9 g), lead (1.9 grams) and zinc chloride (16.2 g) was stirred with 2oC in nitrogen atmosphere in tetrahydrofuran (320 ml). Within 5 minutes added dropwise a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (26,6 g) and 6-(1-bromacil)-4-chloro-5-ftorpirimidinu (see synthesis 1) (40 g) in tetrahydrofuran (215 ml). The reaction temperature is supported below the 12oC using cooling. The reaction mixture is stirred at a temperature below +10oC for 3 hours and at ambient temperature over but the AET molar ratio of 6.7: 1 between 2R,3S/2S,3R and 2R,3R/2S,3S-enantiomeric pair of free base specified in the connection header. Then add glacial acetic acid (8 g) and water (400 ml), maintaining the reaction temperature below 25oC, and the mixture is stirred for 15 minutes. Solid metal residue are removed by decantation. The mixture is alkalinized to pH 10 with saturated aqueous solution of sodium carbonate (600 ml) and was adjusted back to pH 8.0 with 5 M aqueous solution of hydrochloric acid (15 ml). The solid substance is filtered off and the tetrahydrofuran is removed by distillation under reduced pressure. The mixture is extracted with ethyl acetate (2 x 400 ml). The combined organic phases washed with water (400 ml), 2% (weight/volume) solution of disodium salt of ethylenediaminetetraacetic acid in water (800 ml) and then water (400 ml). An ethyl acetate layer is concentrated to oil. The oil is dissolved in ethyl acetate (225 ml) and add 5,75 M solution of hydrogen chloride in isopropanol (20 ml). Suspension granularit at 20oC for 1 hour and at 0oC for 1 hour. The crude compound indicated in the title, isolated by filtration and dried under reduced pressure at 50oC (39.9 g). Analysis of HPLC in accordance with the conditions shown in example 1, shows that the proportion specified in the connection header in the raw product is 93.9 wt.%.

Example 4

< / BR>
A mixture of zinc dust (Britannia Alloys) (3.00 g) and terriitory (20 ml) is stirred overnight at room temperature and then added dropwise within 3 minutes, add a solution of iodine (2,27 g) in tetrahydrofuran (6 ml). During the addition the reaction temperature rises to approximately 45oC, cooled to 5-10oC before adding a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (2.00 g) and 6-(1-bromacil)-4-chloro-5-ftorpirimidinu (see synthesis 1) (2.9 g) in tetrahydrofuran (16 ml) (using the dropping funnel, which was used previously to add iodine) for 40 minutes.

After two hours stirring select a sample of the reaction mixture and subjecting it to analysis HPLC using the conditions described in example 1. Comparison with standards (see example 1) shows that the reaction mixture contains a molar ratio of 10.2:1 between 2R,3S/2S,3R and 2R,3R/2S,3S-enantiomeric pair specified in the connection header. Calculated the total yield is approximately 72%.

Additional research after one hour shows a small deviation from the above situation. At this point the reaction stops and no longer appreciate.

Example 5

9,4: 1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloro-5-ftorpirimidinam (6 ml) was added dropwise to a stirred suspension of zinc (Britannia Alloys) (3.00 g) in tetrahydrofuran (19 ml) under nitrogen atmosphere at 25oC. During the addition allow the growth temperature. After that, the mixture is cooled to 2oC. is added dropwise within 10 minutes, add a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (2.00 g), 6-(1-bromacil)-4-chloro-5-ftorpirimidinu (see synthesis 1) (3.00 g) and iodine (0,23 g) in tetrahydrofuran (16 ml), keeping the temperature below +5oC using cooling. The reaction mixture is stirred at a temperature below +5oC for 30 minutes. Select a sample of the reaction mixture and subjecting it to analysis HPLC in accordance with the conditions shown in example 1. The analysis shows the molar ratio of 9.4:1 between 2R,3S/2S,3R and 2R,3R/2S, 3S-enantiomeric pair specified in the connection header. Output 2R,3S/2S, 3R-enantiomeric pair is calculated as 77% using an internal standard.

Example 6

10,2: 1*(2R, 3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloro-5-ftorpirimidinu - 6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol

(* the ratio of the in situ)

< / BR>
A solution of iodine (2.20 g) in tetrahydrofuran (6 ml) was added dropwise to a stirred suspension of zinc (Britannia Alloys) (3.00 g) in tetrahydrofuran (19 ml) under nitrogen atmosphere at 25oC. During the addition allow the growth temperature. After that, the mixture is cooled to 2oC. is added dropwise in the course is on (see synthesis 1) (2,84 g) in tetrahydrofuran (16 ml). Within the first 2 minutes of this addition also add a solution of iodine (0.07 g) in tetrahydrofuran (4 ml). To maintain the reaction temperature below +5oC using cooling. The reaction mixture is stirred at a temperature below +5oC for 30 minutes. Select a sample of the reaction mixture and subjecting it to analysis HPLC in accordance with the conditions shown in example 1. The analysis shows the molar ratio of 10.2:1 between 2R, 3S/2S, 3R and 2R,3R/2S,3S-enantiomeric pair specified in the connection header. Output 2R,3S/2S,3R-enantiomeric pair is calculated as 87% with the use of an internal standard.

Example 7

64: 1*(2R, 3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloro-5-ftorpirimidinu - 6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol hydrochloride

(* the ratio of the in situ)

< / BR>
A solution of iodine (to 20.52 g) in tetrahydrofuran (65 ml) was added dropwise to a stirred suspension of zinc dust (28.6 g) in tetrahydrofuran (160 ml) under nitrogen atmosphere at 20oC. Allow the increase in the reaction temperature to 25oC. then the mixture is cooled to 0-5oC. dropwise over 75 minutes, add a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (20,0 g), 6-(1-bromacil)-4-chloro-5-ftorpirimidinu (see synthetic is the use of cooling. The reaction mixture is stirred at a temperature below +5oC for 30 minutes. At the end of the reaction is ascertained by HPLC using the conditions shown in example 1. The analysis shows that the stoichiometric output 2R,3S/2S,3R-enantiomeric pair is 88%. Then add glacial acetic acid (5.4 ml) and water (260 ml), keeping the temperature below 25oC. Solid metal residue are removed by decantation. The mixture is alkalinized to pH 10 with saturated aqueous solution of sodium carbonate (180 ml) and then adjusted to pH 8.0 5M aqueous solution of hydrochloric acid. The solid substance is filtered off and the tetrahydrofuran is removed by distillation under reduced pressure. Add ethyl acetate (260 ml) and the mixture is stirred for 10 minutes. The organic layer is separated and the aqueous phase extracted with ethyl acetate (86 ml). The combined organic phases are washed with 2% (weight/volume) solution of disodium salt of ethylenediaminetetraacetic acid in water (286 ml), water (139 ml) and saturated salt solution (52 ml). An ethyl acetate layer is concentrated to a volume of 150 ml Add a solution of sulfosalicylic acid (1.86 g) in isopropanol (5 ml) and the suspension granularit at 20oC for 2 hours. The solid is filtered off and washed with the 1.1 for the amount of product and 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone in the filtrate and the suspension granularit at 25oC for 2 hours and another hour at 0 to 2oC. the Crude compound indicated in the title, isolated by filtration, washed with ethyl acetate (20 ml) and dried under reduced pressure at 50oC. the Yield by weight is 30 g Analysis by HPLC in accordance with the conditions shown in example 1, shows that the product contains 2R,3S/2S,3R-enantiomeric pair is specified in the header of the connection stoichiometric output to 75.7 wt.%.

Example 8

5,5: 1*(2R, 3S/2S, 3R)-:(2R,3R/2S,3S)-3-(2,4-dichloro-5-ftorpirimidinu - 6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol

(* attitude in the selected product).

< / BR>
Stir a mixture of zinc powder (Britannia Alloys) (78,6 g), lead powder (Aldrich) (3,9 g) and tetrahydrofuran (450 ml) maintained at 20oC for 17 hours, and then treated with a solution of iodine (153 g) in tetrahydrofuran (450 ml), keeping the temperature below 45oC using cooling. The mixture is then cooled to 30oC and add a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (134,7 g) and 6-(1-bromacil)-2,4-dichloro-5-ftorpirimidinu (see synthesis of 3) (82,4 g) in tetrahydrofuran (300 ml), maintaining the temperature between -3 to -5oC. the Mixture is heated to 30oC and maintained at dancoyote decanted from the metal residue and the tetrahydrofuran is removed by concentration under reduced pressure. Add ethyl acetate (2.5 l) and the mixture is alkalinized by addition of a saturated aqueous solution of sodium carbonate (1.5 l). The mixture granularit at 20oC for 30 minutes and the precipitated precipitated zinc carbonate is removed by filtration. The organic layer in the filtrate was separated, washed with water (2 2.0 l) and concentrated under reduced pressure. The resulting solution is treated with a solution dihydrate 5-sulfosalicylic acid (107,5 g) in isopropanol (215 ml). After granulation for 1 hour at 20oC precipitated in the sediment sulfosalicylate 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone removed by filtration. The filtrate is washed with 5% (V/o) aqueous solution of disodium salt dihydrate ethylenediaminetetraacetic acid (2 x 500 ml), water (500 ml) and then concentrated under reduced pressure to get crude product in the form of syrup (123,8 g).

Analysis by HPLC using the conditions shown in example 1, shows that the product contains a molar ratio of 5.5:1 between 2R,3S/2S, 3R- (WU = min 7,1) and (2R,3R/2S,3S- (WU = 5,6 minutes) enantiomeric pair specified in the connection header.

1H-NMR (300 MHz, CDCl3): = of 1.06 (d, 3H), of 3.95 (q, 1H), 4,34 (d, 1H), 4,70 (d, 1H), 5,55 (Shir., 1H), 6,65-to 6.80 (m, 2H), 7,45-7,56 (m, 1H), 7,55 (s, 1H), to 7.93 (s, 1H) M. D.


(* attitude in the selected product)

< / BR>
Stir a mixture of zinc dust (Pasminco) (573 mg), lead powder (29 mg) and tetrahydrofuran (6 ml) was kept at room temperature for 18 hours, and then add a solution of iodine (370 mg) in tetrahydrofuran (2 ml). Then to the mixture for 10 minutes, added dropwise a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (653 mg) and 1-benzyl-4-(1-bromacil)-5-ftorpirimidinu-6-it (see the synthesis of 5) (of 1.00 g) in tetrahydrofuran (7 ml). The reaction mixture is heated to approximately 40oC for 1 h, and then cooled and quenched with glacial acetic acid (1 ml) and water (10 ml). The mixture is partitioned between water and ethyl acetate, the organic layer is separated and washed with an aqueous solution of potassium bicarbonate, and then brine, then dried (MgSO4) and concentrate under reduced pressure. The remainder chromatographic on silica gel, elwira a mixture of hexane:ethyl acetate (using a gradient of solvent from 4:1 to 1:1 to 0:1 by volume), and receive the product as a white solid (519 mg, 39%).

Analysis by HPLC using the conditions shown in example 1, shows that the product contains a molar ratio of 9.2:1 between 2R,3S/2S, 3R- (WU = 3,78 min) and 2R,3R/2S,3S- (WU = 5,28 mi is, ,91 (kV, 1H), 4,30 (d, 1H), 4,78 (d, 1H), 5,12 (d, 1H), 5,19 (d, 1H), 5,95 (s, 1H), 6,72-6,86 (m, 2H), 7,30-7,56 (m, 7H), 7,89 (s, 1H), 8,00 (s, 1H) M. D.

Example 10

12,5: 1*(2R, 3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloropyrimidine-6-yl)- 2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol

(* the ratio of the in situ)

< / BR>
A mixture of zinc dust (Britannia Alloys) (249 g), lead powder (12.3 g) and tetrahydrofuran (760 ml) is stirred overnight at room temperature and then added dropwise a solution of iodine (203,4 g) in tetrahydrofuran (650 ml). During the addition the reaction temperature rises to approximately 45oC. Then it is cooled to 5-10oC for 30 minutes, keeping the temperature below 55oC, add a solution of 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (199 g), 4-(1-bromacil)-6-chloropyrimidine (293 g of the crude product from the synthesis of 6: estimated content of 217 g of pyrimidine), and iodine (22,6 g) in tetrahydrofuran (1600 ml). After 1 hour, take a sample of the reaction mixture and subjecting it to analysis by HPLC using the conditions shown in example 1. It was determined that the molar ratio between 2R, 3S/2S, 3R- (retention time to 4.23 min) and 2R,3R/2S,3S- (retention time of 3.4 min) enantiomeric pair is 12.5:1.

The reaction mixture is cooled to 20oC and quenched with an Addendum is one solution of sodium carbonate until until the mixture reaches a pH of 10. Then reduce pH to 7.5 with diluted aqueous solution of hydrochloric acid and usageprice zinc carbonate is removed by filtration. The solution is concentrated under reduced pressure to remove most of the solvent of tetrahydrofuran and receiving water suspension, which is extracted with dichloromethane (2 x 500 ml). The organic phases are combined and washed with 5% (V/V) aqueous solution of disodium salt of ethylenediaminetetraacetic acid (2 x 500 ml). After concentrating the organic phase under reduced pressure, the residue is recrystallized from isopropanolamide alcohol (2.5 liters) and the solid collected by filtration. After drying at 50oC under reduced pressure the product (140 g) analyzed by HPLC, and it was shown that it contains 91 weight. % (2R,3S/2S,3R)-enantiomeric pairs specified in the connection header.

1H-NMR (300 MHz, CDCl3): 1,1 (d, 3H), of 3.65 (q, 1H), 4,15 (d, 1H), and 4.8 (d, 1H), x 6.15 (s, 1H), 6,8 (m, 2H), and 7.5 (s, 1H), 7,55 (m, 1H), 7,65 (s, 1H), and 7.9 (s, 1H), 8,9 (s, 1H) M. D.

The following syntheses illustrate the obtaining of certain raw materials used in the previous examples, together with the additional processing of certain compounds according to the examples.

Synthesis of 1

6-cyl (111,5 kg) and phosphorus oxychloride (394,6 kg) is heated to 95oC and add N,N-dimethylaniline (207 kg) for 1 hour, during which celebrated the release of heat. The mixture was kept at 95oC for 15 hours, then cooled to room temperature and carefully quenched in ice 3 n aqueous solution of hydrochloric acid (450 l) for 4 hours, maintaining during this operation the temperature below 30oC. the Mixture is extracted with dichloromethane (2 x 390 l), the combined extracts washed with water (280 l) up until the aqueous wash is not reached pH 7 and concentrated under reduced pressure. The rest contribute to dimethoxyethan (190 l) and a solution of the product used directly in the next stage.

1H NMR (300 MHz, CDCl3): = 8,5 (s, 1H) M. D.

(ii) 2,4-Dichloro-6-ethyl-5-ftorpirimidinu

To a stirred mixture of magnesium turnings (12.1 kg) in tetrahydrofuran (161 l) add a solution of brometane (54,3 kg) in tetrahydrofuran (53 l), maintaining the reaction temperature below the 50oC during the addition. The solution of Grignard reagent is cooled to 0oC and add a solution of the compound from section (i) (56 kg) dimethoxyethane (170 l), maintaining during the addition the reaction temperature below 15oC. the Reaction mixture was stirred for 1 hour at 15oC and cooled to a 5oC and then a solution of iodine (85 kg) in tetrahydrofuran (256 l), maintaining the reaction temperature below 15oC. then the reaction quenched with water (840 l), maintaining the reaction temperature below 25oC. Adjusted the pH to 1 with 5 n aqueous hydrochloric acid solution (50 l), and the mixture is extracted with toluene (1 x 490 l, then 1 x 210 l). The combined organic layers washed with 2% (W/V) aqueous solution of sodium metabisulfite (700 l), then add water (700 l) and the remaining tetrahydrofuran is removed by distillation under reduced pressure. The mixture is cooled, the organic layer separated, washed with water (425 liters), and then concentrated under reduced pressure to obtain product as oil (50 kg).

(iii) 2-Chloro-6-ethyl-5-fluoro-4-hydroxypyrimidine, ammonium salt

The mixture of compounds from section (ii) (40 kg) and water (10 kg) is heated to 90oC and added 4 n aqueous solution of sodium hydroxide (127 l). Heating is continued at 80oC for 30 minutes and then the mixture is cooled to 25oC. the Mixture is washed with toluene (124 l), the aqueous layer was separated and to it add dichloromethane (162 l). To this mixture, add concentrated hydrochloric acid until then, until the pH reached 1. The organic layer is separated and the aqueous layer was extracted with dichloromethane (162 lrout and the filtrate is treated with a concentrated aqueous solution of ammonia until until you reach a pH of 9. The product precipitates as a solid substance and it is collected by filtration (34 kg), so pl. 125-131oC.

(iv) 6-Ethyl-5-fluoro-4-hydroxypyrimidine

To a mixture of compound from section (iii) (34 kg), ethanol (170 l) and water (5 kg) add 5% (V/C), palladium on coal (water content 50%) (3.4 kg) and the mixture hydronaut at 50oC and 345 kPa (50 psi) until completion of the reaction. Add water (10.5 l) and the catalyst removed by filtration. The filtrate is concentrated under reduced pressure to a small volume and extracted with dichloromethane (2 x 58 l). The combined organic extracts are concentrated under reduced pressure and add toluene (150 l). The mixture is concentrated under reduced pressure to a volume of 50 l, add toluene (50 l) and cooled to 4oC for 4 hours. Precipitated precipitated product is collected by filtration, washed with toluene (10 l) and dried (yield = 20 kg), so pl. 112-4oC.

1H NMR (300 MHz, CDCl3): = 1,25 (m, 3H), by 2.73 (m, 2H), 8,00 (s, 1H) M. D.

(v) 4-Chloro-6-ethyl-5-ftorpirimidinu

To a mixture of compounds of the section (iv) (40 kg), dichloromethane (120 l) and triethylamine (28.4 g) is added slowly over 3 hours of phosphorus oxychloride (to 47.2 kg), maintaining during the addition the temperature of the reaction h is ASAT a 3 n aqueous solution of hydrochloric acid (176 l), supporting during this operation the temperature below 20oC. the Layers are separated, the aqueous phase is extracted with dichloromethane (50 l) and the combined organic layers washed with water (50 l). The organic layer is concentrated under reduced pressure and get the product in the form of oil (40,69 kg).

1H NMR (300 MHz, CDCl3): = of 1.30 (t, 3H), 2,87 (kV, 2H), 8,65 (s, 1H) M. D.

(vi) 6-(1-Bromacil)-4-chloro-5-ftorpirimidinu

Stir a mixture of compounds of the section (v) (38,5 kg), azoisobutyronitrile (AIBN) (1,92 kg), N-bromosuccinimide (49 kg) and dichloromethane (198 l) is heated under reflux in nitrogen for 12 hours. The mixture is cooled to 25oWith and add water (239 l). The layers are separated and the aqueous layer was extracted with dichloromethane (120 l). The combined organic layers washed with a solution of sodium metabisulfite (22,8 kg) in water (239 l) and then water (239 l). The organic layer is concentrated under reduced pressure, add toluene (240 l) and the final solution is concentrated under reduced pressure to obtain product as oil (for 61.7 kg).

1H NMR (300 MHz, CDCl3): = 2,08 (d, 3H), 5,35 (kV, 1H), 8,80 (s, 1H) M. D.

Synthesis of 2

(2R, 3S)-2-(2,4-differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H - 1,2,4-triazole-1-yl)butane-2-ol

< / BR>
(i) (2R,3S/2S,3R)-2-the i.i.d. according to the method of example 1 (26,5 kg), dichloromethane (400 l) and water (184 liters) was adjusted to pH 11 with 40% (V/V) aqueous solution of sodium hydroxide (10 l). The organic layer was separated, washed with a solution of disodium salt dihydrate ethylenediaminetetraacetic acid (a total of 8.74 kg) in water (183,5 l), then water (184 l) and then concentrated under reduced pressure to an oil. It is dissolved in ethanol (134 l), add sodium acetate (8 kg) and 5% (V/C), palladium on coal (water content 50% in/in) (3,34 kg) and the mixture hydronaut at 103 kPa (15 psi) and 25oC to complete the reaction. The catalyst was removed by filtration and the filtrate concentrated to a volume of 51 litre. Add dichloromethane (152 l) and water (152 l) and the pH adjusted to 11 to 40% (weight/weight) aqueous solution of sodium hydroxide. The layers are separated and the aqueous layer was extracted with dichloromethane (61 l). The combined organic extracts washed with water (61 l), concentrated under reduced pressure, add isopropanol (70 l) and concentrate to a volume of 62 liters of a Mixture granularit for 3 hours at 20oC, collected by filtration, washed with isopropanol (2 5 l) and dried to obtain specified in the title compounds as the main enantiomeric pairs in the product (19 kg), so pl. 127oC.

(ii) (2R, 3S)-2-(2,4-Differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H - 1,2,4-triazole-1-yl)buta is Oh acid (12,57 kg) in methanol (142 l) and the mixture heated under reflux until until the "homogeneous solution. The solution is cooled to 20oC and granularit during the night. The solid is collected by filtration, washed with acetone (9.35 kg) and dried to obtain R-(-)-10-camphorsulfonate (2R,3S)-2-(2,4-differenl)- 3-(5-ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol as a white solid (12.3 kg).

The above camphorsulfonate salt (12,3 kg) is placed in dichloromethane (61,5 l) and water (61,5 l) and the pH adjusted to 11 by addition of 40% (V/V) aqueous sodium hydroxide solution (2.5 liters). The layers are separated and the aqueous layer was extracted with dichloromethane (14 l). The combined organic extracts washed with water (3 x 45 l), filtered and the solvents removed by distillation under reduced pressure. Add isopropanol (30 l) and the distillation continued until, until you reach a volume of 22 liters. The mixture is cooled to 0oC and granularit within 2 hours. The product is collected by filtration and washed with isopropanol (2 4 l) to obtain the specified title compound as a white solid (7.6 kg).

Synthesis of 3

6-(1-Bromacil)-2,4-dichloro-5-ftorpirimidinu

< / BR>
(i) 2,4-Dichloro-6-ethyl-5-ftorpirimidinu

To a stirred mixture of magnesium turnings (90,4 g) in tetrahydrofuran (1,04 l) dobster Grignard reagent is stirred for 30 minutes at 20oC, cooled to 0oC and add a solution of the compound of synthesis 1 (i) (420 g) dimethoxyethane (600 ml), maintaining the reaction temperature below 15oC. the Mixture is stirred for 1 hour at 15oC and cooled to 0oC. In 5oTo add a solution of triethylamine (254 g) in tetrahydrofuran (510 ml), and then a solution of iodine (632 g) in tetrahydrofuran (1,92 l), keeping the temperature below 15oC. the Reaction is quenched with water (6 l), keeping the temperature below 25oC. the Mixture is acidified to pH 1 with 5 n aqueous solution of hydrochloric acid and extracted with ethyl acetate (2 x 6 l). The combined organic extracts are washed with 10% (V/o) aqueous solution of sodium metabisulfite (12 l). Add water (4 l) and the main part of the organic solvent is removed by evaporation under reduced pressure. The layers are separated and the aqueous layer was extracted with ethyl acetate (2 liters). The combined organic extracts treated with glacial acetic acid (400 ml) and concentrate under reduced pressure at 80oC. the Mixture is cooled to 20oC and oil partitioned between dichloromethane (3 l) and 1 n aqueous sodium hydroxide solution (3 l). The organic layer was separated, washed with water (3.0 l) and concentrated under reduced pressure to obtain product as oil (carperitide

The mixture of compounds of the section (i) (400 g), N-bromosuccinimide (730 g), azoisobutyronitrile (33,7 g), bromine (65,5 g) and water (6.4 l) heated at 80-85oC for 5 hours. Add an additional amount of N-bromosuccinimide (183 g), continue heating for 2 hours and then add more azoisobutyronitrile (33,7 g). After heating for 2 hours at 85oC adds extra azoisobutyronitrile (33,7 g) and heating continued for 3 hours. The reaction mixture is cooled, diluted with water (4 l) and extracted with dichloromethane (2 x 3 l). The combined organic extracts are washed with a solution of sodium metabisulfite (600 g) in water (2.5 l) and then water (3 l). The solvent is removed by evaporation under reduced pressure, add toluene (1.0 l) and the solution concentrated under reduced pressure to obtain product as oil (534 g).

1H NMR (300 MHz, CDCl3): = 2,05 (d, 3H), of 5.06 (q, 1H) M. D.

Synthesis of 4

(2R, 3S)-2-(2,4-Differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol

< / BR>
(i) (2R,3S/2S,3R)-2-(2,4-Differenl)-3-(5-ftorpirimidinu-4-yl)- 1-(1H-1,2,4-triazole-1-yl)butane-2-ol

Stir a mixture of the product obtained by the method of example 8 (123,8 g), sodium acetate (27.4 g), 5% (V/V) is for 19 hours. The reaction mixture is cooled to 25oC and the catalyst is filtered off and washed with ethanol (100 ml). The filtrate is concentrated under reduced pressure to dryness and the residue partitioned between dichloromethane (1.0 l) and 10% (V/o) aqueous solution of potassium bicarbonate (1.0 l). The organic layer is separated and washed with water, and then evaporated under reduced pressure to dryness to obtain specified in the title compounds as the main enantiomeric pairs in the product. It is directly used in the next stage.

1H NMR (300 MHz, d6-DMSO): = 1,1 (d, 3H), 3,90 (kV, 1H), 4,33 (d, 1H), 4,80 (d, 1H), 6.87 in-6,93 (m, 1H), 7,10-7,20 (m, 1H), 7,21-7,34 (m, 1H), 7,60 (s, 1H), 8,21 (s, 1H), 8,82 (s, 1H), of 9.02 (s, 1H) M. D.

(ii) (2R, 3S)-2-(2,4-Differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H - 1,2,4-triazole-1-yl)butane-2-ol

The product of section (i) was placed in acetone (383 ml) and add a solution of (R)-(-)-camphor-10-sulfonic acid (42,1 g) in acetone (300 ml). The mixture granularit at 20oC for 18 hours and then cooled to 0oC for 1 hour. The solid is filtered off and washed with cold acetone (100 ml) and then dried to obtain crude camphorsulfonate product (35.4 g).

Analysis by HPLC (column reversed-phase 25 cm x 4.6 mm C18 Dynamax 60 angstroms, on the purity of 91% and contains a molar ratio 2R,3S and 2S,3R-enantiomeric pairs, 63: 37.

This is partially divided salt (34 g) dissolved in a mixture of methanol (110 ml) and acetone (329 ml) which is heated under reflux. The solution is slowly cooled to 20oC and granularit during the night. The solid is collected by filtration, washed with acetone (50 ml) and dried to obtain R-(-)-camphor-10-sulfonate (2R,3S)-2-(2,4-differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol as white crystals (17.1 g), so pl. 187oC. Analysis by HPLC shows that this material has an optical purity of 100%.

Salt (17 g) partitioned between dichloromethane (85 ml) and water (85 ml) and the pH adjusted to 11 by addition of 40% (V/V) aqueous solution of sodium hydroxide. The layers are separated and the aqueous phase is extracted with dichloromethane (20 ml). The combined organic extracts washed with water (2 x 80 ml), filtered and the solvent is removed by evaporation under reduced pressure. Add isopropanol (26 ml), the solution is cooled to 0oC and granularit for 1 hour. The solid is collected by filtration, washed with cold isopropanol (5 ml) and dried under reduced pressure at 50oC product (8,4 g), so pl. 133oC.

1H NMR (300 MHz, d6-DMSO): 1,10 (d, 3H), 3,90 (the 5

1-Benzyl-4-(1-bromacil)-5-ftorpirimidinu-6-he

< / BR>
(i) 1-Benzyl-4-ethyl-5-ftorpirimidinu-6-he

Sodium hydride (60% in/in dispersion in oil, 928 mg) was triturated with hexane and then add dimethylformamide (30 ml). To this mixture add a connection from the synthesis of 1 (iv) (3 g), and after cessation of gas - benzylbromide (of 2.51 ml). The mixture is stirred for 1 hour and then quenched with water. The mixture is partitioned between diethyl ether and water, the ether layer is separated and washed successively with dilute sodium hydroxide solution, brine and water, after which it concentrate under reduced pressure to obtain the desired product as white crystals (Android 4.04 g). On ICSD m/z = 232,9 (m)+.

1H NMR (300 MHz, CDCl3): = 1,22 (t, 3H), 2.63 in (DV kV, 2H), 5,14 (s, 2H), 7,32-7,40 (m, 5H), to 7.93 (s, 1H) M. D.

(ii) 1-Benzyl-4-(1-bromacil)-5-ftorpirimidinu-6-he

The mixture of compounds from synthesis 5 (i) (2 g), N-bromosuccinimide (1,76 g), azoisobutyronitrile (71 mg) and dichloromethane (20 ml) is heated under reflux in nitrogen for 20 hours. The reaction mixture is cooled, washed successively with diluted aqueous solution of sodium metabisulfite, water, then brine, then dried (MgSO4) and concentrate under reduced Yes is the product as a white syrup (1.60 g). On ICSD m/z = 310,9/312,9 (m)+.

1H NMR (300 MHz, CDCl3): = 1,94 (d, 3H), 5,07 (d, 1H), 5,17 (d, 1H), and 5.30 (q, 1H), 7,30-7,41 (m, 5H), of 8.00 (s, 1H) M. D.

Synthesis of 6

4-(1-Bromacil)-6-chloropyrimidine

< / BR>
(i) 4-Ethyl-6-hydroxypyrimidine

Formamidine (500 g) and methyl 3-oxopentanoate (500 g) are added to a solution of sodium methoxide (500 g) in methanol (4 l) at 20oC and the mixture is stirred for 15 hours. Add water (1 l) and acetic acid (500 ml) to achieve a pH of 7. The solvent is removed by evaporation under reduced pressure and the aqueous residue diluted with water (1 l) and extracted with ethyl ketone (4 x 2.5 l). The combined organic phases are concentrated by evaporation under reduced pressure to obtain an orange syrup. The syrup was dissolved in ethyl acetate (1 l) and the solution stirred for 15 hours to obtain a solid substance. The solid is collected by filtration, washed with ethyl acetate (200 ml at 10oC) and dried at 50oC under reduced pressure to obtain specified in the connection header (183 g). After concentrating the mother solutions under reduced pressure, add diethyl ether (3 l) and get a solid substance. This solid is collected by filtration, washed with tert-butyle the head connection. The total yield specified in the connection header is approximately 79% (195 g).

1H NMR (300 MHz, D2O): = 1,02 by 1.12 (m, 3H), 1,89 (s, 1H), 2,41 is 2.55 (m, 2H), 6,21 (s, 1H), 8,16 (s, 1H) M. D.

(ii) 4-Chloro-6-ethylpyrimidine

The product of the synthesis of 6 (i) (348 g) was transferred to a suspension in dichloromethane (2.5 l) and add triethylamine (284 g). To the mixture is added phosphorus oxychloride (473 g) and heat bring the reaction mixture to a temperature of distillation. The distillation temperature is maintained for 4 hours after which the reaction mixture is cooled to 20oC and quenched with a 1 n aqueous solution of hydrochloric acid (2.2 l) cooling (maintaining the reaction temperature at about 10oC). After separation of the organic phase the aqueous layer was extracted with dichloromethane (1 l). The combined organic phases washed with water (2 x 3 l). The solution is concentrated under reduced pressure and get the product (272 g, 80% purity according to calculations based1H NMR) as a dark oil.

1H NMR (300 MHz, CDCl3): = is 1.31 (t, 3H), 2,80 (kV, 2H), 7.23 percent (s, 1H), 8,88 (s, 1H) M. D.

(iii) 4-(1-Bromacil)-6-chloropyrimidine

The product of the synthesis of 6 (ii) (212 g) was dissolved in dichloromethane (2.1 liters). Add N-bromosuccinimide (305,3 g) and azoisobutyronitrile (10.6 g) and the mixture is heated Lieut another 1 hour before cooling the mixture to 20oC. the Organic phase is separated, washed with an aqueous solution of sodium metabisulfite (1 l) and then washed with water (1 l), the organic phase is dried with magnesium sulfate (20 g) and evaporated under reduced pressure to get crude product, specified in the header, in the form of a dark oil (312 g, purity approximately 74% according to the calculation based on the 1H NMR), which is directly used in example 10.

1H NMR (300 MHz, CDCl3): 2,03 (d, 3H), 5,04 (kV, 1H), 7,51 (s, 1H), of 8.95 (s, 1H) M. D.

Synthesis of 7

R-(-)-10-Camphorsulfonate (2R,3S/2S,3R)-2-(2,4-differenl)-3-(5 - ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol

< / BR>
Hydrochloride 119: 1 (2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloro-6 - ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (40 g) dissolved in methanol (360 ml). In an atmosphere of nitrogen was added 10% (V/C), palladium on coal (water content 50%) (5.6 g) and ammonium formate (24 g). The reaction mixture is heated under reflux for 2 hours and cooled to 25oC. Filtration to remove the catalyst and washed with methanol (120 ml). The filtrate is divided into two parts (2 x approximately 245 ml).

One part concentrated under reduced pressure and the residue is dissolved in methylene chloride (95 ml) and water (95 ml) and Pern pressure to oil. Add isopropanol (100 ml) and the mixture is concentrated under reduced pressure. Add isopropanol (90 ml) and the mixture is heated to 55oC with obtaining a solution. To this solution was added a solution of R-(-)-10-camphorsulfonic acid (10,75 g) in isopropanol (21,5 ml). The resulting suspension is cooled to 25oC, granularit for 1 hour, cooled to 0oC and granularit another 2 hours. The product distinguish by filtration, washed with cold isopropanol (2 20 ml) and dried under reduced pressure to obtain specified in the connection header (23.7 g). Analysis by HPLC using the conditions described in example 1, shows that the product is a clear connection specified in the header.

Synthesis of 8

(2R, 3S/2S, 3R)-2-(2,4-Differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H - 1,2,4-triazole-1-yl)butane-2-ol

< / BR>
Hydrochloride 16,36: 1 (2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloro-5 - ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (1.7 kg solvent; calculated the proportion of (2R,3S/2S,3R)-enantiomeric pair is 1.08 kg) is added to methylene chloride (8.5 l) and water (8.5 l) under stirring. The mixture is alkalinized to pH 11 with 40% aqueous sodium hydroxide solution and the layers separated. The aqueous phase is extracted with chloride of methylene raucously acid (425 g) in water (8.5 l), and then water (2 x 5 l). Solution in methylene chloride is divided into two unequal parts. Both parts of concentrated under reduced pressure to obtain oil (containing 198 g 980 g of the free bases with regard to the solvent, according to the calculation based on the1H NMR). Analysis by HPLC using the conditions described in example 1, shows that the oils contain, respectively, 76 and 69 weight. % (2R,3S/2S,3R)-3-(4-chloro-5-ftorpirimidinu - 6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol.

Sample "980 g dissolved in methanol (10 l) and in nitrogen atmosphere, add 10% (V/C), palladium on coal (water content 50% in/in) (Johnson Matthey type 87L) (69 g) and ammonium formate (322 g). The reaction mixture is heated under reflux for 3 hours and cooled to 40oC. the Catalyst is removed by filtration and the filtrate concentrated to oil. To the oil is added methylene chloride (5 l) and water (5 l) and the mixture vigorously stirred. The layers are separated and the aqueous layer was extracted with methylene chloride (1 liter). The combined organic phases are washed with water (2 x 3 l), concentrated under reduced pressure, add isopropanol and again concentrated under reduced pressure. Add isopropanol (3 l) and the suspension granularit at 0oC during the> during the night, getting mentioned in the title compound (547 g). Analysis by HPLC using the conditions described in example 1, shows that the product is listed in the title compound with a purity of 97%.

Synthesis of 9

(2R, 3S/2S,3R)-2-(2,4-Differenl)-3-(pyrimidine-4-yl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol

< / BR>
A mixture of (2R, 3S/2S, 3R)-:(2R,3R/2S,3S)-3-(4-chloropyrimidine-6-yl)- 2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (the product from example 10) (70 g), ammonium formate (24,1 g) and 10% (V/C), palladium on coal (water content 60% in/in) (Johnson Matthey type 87L) (4.7 g) in methanol (700 ml) is heated under reflux for 2 hours in nitrogen atmosphere. After cooling to 25oC, the reaction mixture was filtered and concentrated under reduced pressure. The residue is dissolved in dichloromethane (500 ml) and washed with water (2 x 500 ml). The organic phase is dried with magnesium sulfate, concentrated under reduced pressure, and the resulting resin is crystallized from isopropanol (250 ml) at -10oC. the Product is collected by filtration to obtain specified in the connection header (38,1 g) after drying at 50oC under reduced pressure.

1H NMR (300 MHz, CDCl3): = 1,1 (d, 3H), of 3.65 (q, 1H), 4,15 (d, 1H), and 4.8 (d, 1H), 6,55 (s, 1H), 6,8 (m, 2H), and 7.4 (d, 1H), 7.5 (m, 1H), and 7.6 (s, 1H), Soli acid or base

where R is phenyl, optionally substituted by 1-3 substituents, each of which is independently selected from halogen and trifloromethyl;

R1- C1-C6-alkyl;

Het - pyrimidinyl, optionally substituted by 1-3 substituents, each of which is independently selected from C1-C4-alkyl, C1-C4-alkoxy, halogen, oxo, benzyl and benzyloxy,

comprising the reaction of compounds of formula II

< / BR>
where R is previously defined for compounds of formula (I),

with the compound of the formula III

< / BR>
where R1and Het are defined previously for compounds of formula (I);

X is chlorine, bromine or iodine,

in the presence of zinc, iodine and/or Lewis acid and kotonoha organic solvent with subsequent optional conversion of the compounds of formula (I) in its additive salt of the acid or base.

2. The method according to p. 1, wherein the process is carried out in the presence of lead.

3. The method according to p. 1 or 2 where the use of iodine.

4. The method according to p. 3, which is carried out by mixing the solution or solutions of compounds of the formula (II) and (III) and iodine in an aprotic organic solvent with a mixture of zinc, iodine, does not necessarily lead optional Lewis acid and aprotic organic use zinc chloride, the zinc bromide or zinc iodide.

6. The method according to any of the preceding paragraphs, in which the aprotic organic solvent is tetrahydrofuran.

7. The method according to any of the preceding paragraphs, in which you receive an acidic additive salt of the compounds of formula (I).

8. The method according to p. 7, in which the acid additive salt is cleaners containing hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, methanesulfonate, camphorsulfonate, R-(-)-10-camphorsulfonate, (+)-3-bromo-10-camphorsulfonate, (-)-3-bromo-8-camphorsulfonate, phosphate, paratoluenesulfonyl or benzosulfimide salt, is preferably cleaners containing hydrochloride salt.

9. The method according to any of the preceding paragraphs, in which R is phenyl, substituted by 1 or 2 substituents, each of which is independently selected from fluorine and chlorine.

10. The method according to p. 9, in which R is phenyl, substituted by 1 or 2 fortuntately.

11. The method according to p. 10, in which R is 2,4-differenl.

12. The method according to any of the preceding paragraphs, in which R1is methyl.

13. The method according to any of the preceding paragraphs, in which Het - pyrimidinyl, optionally substituted by 1-3 substituents, each of which is independently selected from g is estealam, each of which is independently selected from fluorine, chlorine, oxo or benzyl.

15. The method according to p. 14, in which Het - pyrimidinyl, substituted by 1-3 substituents, each of which is independently selected from fluorine and chlorine.

16. The method according to p. 14, in which Het - pyrimidine-4-yl, 4-chloro-5-ftorpirimidinu-6-yl, 5-ftorpirimidinu-4-yl, 2-chloro-5-ftorpirimidinu-6-yl, 2,4-dichloro-5-ftorpirimidinu-6-yl, 4-chloropyridin-6-yl or 1-benzyl-5-ftorpirimidinu-6-on-4-yl.

17. The method according to p. 16, in which Het is 4-chloro-5-ftorpirimidinu-6-yl.

18. The method according to any of the preceding paragraphs, in which X is bromine.

19. The method of obtaining the compounds of formula IV

< / BR>
or its acid salt additive,

where R and R1previously defined for compounds of formula (I) in paragraph (1;

R2- H or fluorine,

characterized in that the compound of General formula II

< / BR>
where R is defined for the compounds of formula (IV),

subjected to interaction with the compound of General formula IIIA

< / BR>
where X is chlorine, bromine or iodine;

R1and R2previously defined for compounds of formula (IV);

of R3and R4either each independently selected from chlorine or bromine, or one of R3and R4is chlorine or bromine and the other is - H,

in prisutstvovali IA

< / BR>
where R, R1, R2, R3and R4previously defined,

if necessary turn in his acid additive salt and restore his or its acid additive salt, followed if necessary by turning the obtained target product IV in his acid additive salt.

20. The method according to p. 19, characterized in that the first stage of the process is carried out in the presence of lead.

21. The method according to p. 19 or 20, characterized in that the first stage of the process using iodine.

22. The method according to any of paragraphs.19 to 21, characterized in that the first stage of the process aprotic organic solvent is tetrahydrofuran.

23. The method according to any of paragraphs.19 - 22, wherein the acid additive salt of the compounds of formula IA is cleaners containing hydrochloride, methanesulfonate or p-toluensulfonate salt.

24. The method according to any of paragraphs.19 to 23, characterized in that the recovery of the compounds of formula (IA) or its acid salt additive is carried out by catalytic hydrogenation or by hydrogenation with the transfer.

25. The method according to p. 24, in which the recovery is carried out by hydrogenation with the transfer.

26. The method according to p. 257. The method according to any of paragraphs.19 to 26, characterized in that the acid additive salt of the compound of formula IV is S -(+)- or R -(-)-10 - camphorsulfonate salt.

28. The method according to any of paragraphs.19 - 27, in which R is 2,4-differenl.

29. The method according to any of paragraphs.19 - 28, in which R1is methyl.

30. The method according to any of paragraphs.19 - 29, in which R2- fluoride.

31. The method according to any of paragraphs.19 - 30, in which:

(I) R3- chlorine and R4- N.;

(III) R3- N and R4- chlorine or

(III) R3and R4both chlorine.

32. The method according to p. 31, in which R3is chlorine, R4- N.

33. The method according to any of paragraphs.19 - 32, in which X is bromine.

34. The method according to any of paragraphs.19 - 27, in which R is 2,4-differenl, R1is methyl, R2- fluorine, R3is chlorine, R4Is h and X is bromine.

35. The method according to any of paragraphs.19 - 27, in which the compound of formula (IA) is: 3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, 3-(2-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, 3-(2,4-dichloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol or acid additive salt of any of them.

36. The method according to any of paragraphs.19 - 27, in which the compound of the formula (the active salt.

37. The compound of formula (I) under item 1, which is:

(I) (2R, 3S)-3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol;

(II) an acid additive salt of (2R, 3S/2S, 3R) - or (2R, 3S)-3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol and, preferably, cleaners containing hydrochloride salt;

(III) 3-(2,4-dichloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, or (2R, 3S/2S, 3R) - or (2R, 3S)-form, or an acid additive salt of any of them;

(IV) 3-(1-benzyl-5-ftorpirimidinu-6-on-4-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, or (2R, 3S/2S, 3R) - or (2R, 3S)-form, or an acid additive salt of any of them, or

(V) 3-(4-chloropyrimidine-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, or (2R, 3S/2S, 3R) - or (2R, 3S)-form, or an acid additive salt of any of them.

38. The compound of formula (III) under item 1, which is:

(I) 6-(1-bromacil)-2,4-dichloro-5-ftorpirimidinu;

(II) 4-(1-bromacil)-6-chloropyrimidine;

(III) 6-(1-bromacil)-4-chloro-5-ftorpirimidinu;

(IV) 1-benzyl-4-(1-bromacil)-5-ftorpirimidinu-6-he.

39. 2-Chloro-6-ethyl-5-fluoro-4-hydroxypyrimidine, ammonium salt.

 

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