WO2015058272A1 - Process for selectively preparing (1h-1,2,4-triazol-1-yl)alkanols, hydrazinyl alkanol compound produced by said process and use thereof - Google Patents

Abstract

The present invention describes a process for selectively preparing (1H-1,2,4-triazol-1-yl)alkanols that can be used as synthesis intermediates and as pharmaceutical, veterinary and agrochemical active ingredients, and also the use of intermediates thereof, and process conditions. According to the present invention, oxiranes and halohydrins react with hydrazine (in any form, hydrates or salts) to form hydrazinyl alkanol intermediates, which are converted into (1H-1,2,4-triazol-1-yl)alkanols by reacting same with a reagent that forms 1,2,4-triazolyl. The technique discovered represents an improvement over the prior art by not allowing isomers substituted in position 4 of the triazole ring to be formed, the (1H-1,2,4-triazol-4-yl)alkanols. The methods described in the present invention are particularly advantageous over the prior art due to higher yields, shorter process times, simplification of individual processes, greater ease in recovering unreacted auxiliary materials, and complete selectivity for the formation of regioisomers.

Description

 Process for the selective preparation of (1,2,4-triazoM-yl) alkanols, hydrazinyl afkanyl compound obtained by such process and its use.

Field of the invention

 The present invention describes a process for the selective preparation of 2,4-triazol-1-yl) alkanols useful as synthesis intermediates and as pharmaceutical, veterinary and agrochemical active ingredients, as well as the use of their intermediates, processing conditions. .

Fundamentals of the invention

 Large amounts of pharmaceutical, veterinary and agrochemical active ingredients containing the substrate (1 # -1,2,4-triazol-1-yl) alkanol are known, especially the analogues riazol-1-yl) ethanol.

 Formula (I)

 Fluconazole, Voriconazole and, more recently, Ravuconazole are just a few examples of antifungal medicines for human use. Among others, Triticonazole has already been prescribed for veterinary treatments. A number of other (1H-1,2,4-triazol-1-yl) alkanols are of high importance in the treatment of plant fungal diseases such as Cyproconazole, Diclobutrazol, Flutriafol, Hexacohazole, Ipconazole, Metconazole and Tebuconazole.

The strategies for the synthesis of these substrates containing the (1H-1,2,4-triazoyl-1-yl) alkanol substrate are very similar to each other and have always been based on the opening of an oxirane ring (main intermediate, commonly limiting reagent) by reaction with 1H-1,2,4-triazole (secondary intermediate), often mediated by a proton acceptor. Optionally, a halohydrin may be employed in place of oxirane. Reaction temperatures may vary but are preferably low in order to favor the formation of the 1H-1,2,4-triazol-1-yl regioisomer over the biologically inactive species 1H-1,2,4-triazoI. -4-il. The term "principal intermediary" used herein refers to the most economically relevant intermediary because it was the intellectual property of its inventors (at the time of its publication).

Conventional route via reaction of (H-1,2,4-triazol-1- (1H-1,2,4-triazol-4-oxirane + 1H-1,2,4-triazolyl) alkanol yl) alkanol

 Examples of traditional (1 H -1,2,4-triazoyl-1-yl) alkanols synthesis processes will be readily found by those skilled in the art. Still, by way of illustration, the preparation processes for Fluconazole and Cyproconazole are presented.

 The synthesis of Fluconazole (R3 = R4 = H; R1 = 2,4-difluorophenyl;

R 2 = (1H-1,2,4-triazol-1-yl) methyl) was first described in the patent family containing US4404216 by the reaction of 1- [2- (2,4-difluorophenyl) - 2,3-epoxypropyl] -1H-1,2,4-triazole with 100% molar excess of 1H-1,2,4-triazole in dimethylformamide at 90 ° C and with anhydrous potassium carbonate as proton acceptor . After 4.5h of reaction and a laborious isolation process, the product was obtained in 44% yield.

 The synthesis of Cyproconazole (R3 = R4 = H; R1 = 4-chlorophenyl; R2 = 1-cyclopropylethyl) was introduced by the patent family containing US4664696 proposing the preparation of an oxirane from 1- (4). -chlorophenyl) -2-cyclopropylpropan-1-one, followed by reaction with 1 H -1,2,4-triazole in dimethylformamide with potassium carbonate at 90 ° C for 2h. Neither the purity nor the yield of the product is stated in the example.

 For reasons of confidentiality, most publications related to this traditional technique (always starting from 1H-1, 2,4-triazole) do not have their main disadvantages, which fall so much in the generally high reaction times required for an economic yield (such as as a result of the low temperatures), as well as the laborious processes of separating the isomer that is always formed (even in small proportions), sometimes using several cycles of recrystallization and washing. Many publications do not even mention the formation of this 1 H-1,2,4-triazol-4-yl isomer, which compromises the yield of the reaction, as it can statistically lead to the loss of up to one third of the major intermediate.

Proposals to solve this problem were presented. For example, BR8807554 proposes the isomerization of the 4-substituted triazoles to their 1-substituted equivalents. However, it requires drastic temperature conditions and the presence of a catalyst, although it has not been proven effective for all compounds. Nevertheless, this technique represents an additional step in the overall process of preparing (1H-1,2,4-triazol-1-yl) alkanols.

 Bulger and Contributors (Tetrahedron Letters 41 (2000)

1297-1301) found that the problem of selectivity of 1 -1,2,4-triazole alkylations is not solved by changes in the solvent or base.

 Faced with this inability to control selectivity in the preparation of (1H-1,2,4-triazol-1-yl) alkanols within the current state of the art, the inventors developed the novel process object of this invention by constructing cycle 1. -1,4,4-triazol-1-yl directly over the major intermediate via hydrazine alkylation and subsequent cyclization.

 The present innovative process is inspired by the conventional process of preparing unsubstituted 1W-1,2,4-triazole based on the reaction of hydrazine with formic acid, formamide and / or ammonia as exemplified by US4490539. However, the innovation is not an obvious derivation, as, so far, no publications have been found describing the process of preparing (1H-1,2,4-triazol-1-yl) alkanols by reacting hydrazinylalkanols with forming reagents. 1 H-1,2,4-triazophyll as object of the present invention, much less foreseeing the use of its products and intermediates in the preparation of pharmaceutical, veterinary and agrochemical active ingredients. Furthermore, publications describing the preparation of unsubstituted 1H-1,2,4-triazole have never envisioned the possibility of constructing the triazole ring directly on the structure of an oxirane or halohydrin intermediate in order to form the cycle exclusively / exclusively. 1W-1,2,4-triazole substituted at position 1 only, as object of the present invention.

Objectives of the invention

 This invention introduces a novel process for obtaining (1H-1,2,4-triazol-1-yl) alkanols to meet the following objectives:

a) completely prevent formation of substituted isomers at position 4 of the triazole ring, as these isomers (1H-1,2,4-triazol-4-yl) alkanols are not biologically active, which implies full selectivity for regioisomer formation substituted exclusively at position 1 of cycle 1, 2,4-triazolyl;

b) presenting higher overall yield in obtaining said high purity (1H-1,2,4-triazol-1-yl) alkanols;

c) use shorter processing times, simplifying unit operations; d) more easily recover unreacted and auxiliary materials; and Such advantages will be covered in more detail in the following sections.

 Brief Description of the Invention

 According to the process of the present invention, oxiranes and halphydrias react with hydrazine (in any presentation form, hydrates or salts) to yield hydrazinylalkanol type intermediates which are converted to (1H-1,2,4-triazol-1-yl ) alkanols by reaction with some 1,2,4-triazolyl forming reagent.

The present invention describes a process for the preparation of (1H-1,2,4-triazol-1-yl) alkanols comprising the steps of: a) reaction of halohydrin of formula (II) or oxirane compound of formula (III) , below:

 Formula (II) Formula (III)

 where X is halogen; R1, R2, R3 and R4 are independently hydrogen, heteroatoms or carbon chains substituted or not substituted by heteroatoms, especially aliphatic, cyclic, heterocyclic, aromatic and heteroaromatic substituent groups, even halogenated, oxygenated, sulfonated and nitrated; with hydrazine or its salts, hydrates and derivatives to obtain a hydrazinylalkanole intermediate of formula (IV), given below:

HO R ³

R ² NH-NH ₂

 Formula (IV)

b) reacting the hydrazinyl alkanol intermediate compound of formula (IV) obtained in the previous step with a 1,2,4-triazolyl forming reagent to obtain at the end compounds (1- -1,4,4-triazol-1 -yl) alkanols of formula (I) as indicated below:

Formula (I) Detailed Description of the Invention

 The present invention describes a method for preparing (1H-1,2,4-triazol-1-yl) alkanols via alkylation of hydrazine (in any presentation, hydrate or salt) with oxiranes or halohydrins, followed by cyclization. with some 1H-1,2,4-triazolyl forming reagent according to the following steps:

1) Hydrazine alkylation:

1.1 with a halohydrin:

1.2 or with an oxirane

 2) followed by cyclization with some 1 H -1,2,4-triazolyl forming reagent, resulting in the formation of (1 W -1,2,4-triazol-1-yl) ethanol:

 where X is a halogen (fluorine, chlorine, bromine or iodine) and R1, R2, R3 and R4 are independently hydrogen, heteroatoms or heteroatom-substituted carbon chains, especially aliphatic, cyclic, heterocyclic, aromatic substituent groups and heteroaromatic, even halogenated, oxygenated, sulfonated and nitrated (R 1 and R 2 are preferably alkyl or aryl groups, whether or not independently substituted by heteroatoms; R3 and R4 may be aryl or alkyl groups, whether or not independently substituted by heteroatom, or preferably H).

1,2,4-triazolyl forming reagent is any reagent containing a carbon atom bonded to a hydrogen by single covalent bonding, also to a single covalent bonding heteroatom and to an additional double covalent bonding heteroatom reaction with ammonia and / or already combined with an unsubstituted nitrogen atom. Unlimited examples of the 1,2,4-triazoiyl forming reagent are 1,3,5-triazine, formamidine, formamidinium salts or derivatives, formamide, and combinations of formic acid and / or ammonium derivatives thereof. Combinations of these reagents are still possible.

 The formation reactions of the hydrazinylalkanol intermediate are preferably conducted in the absence of solvent, or in solution with short chain alcohols, up to 4 carbon atoms, or in the presence of glycols, or in the presence of a phase transfer catalyst. Temperatures may range from room temperature to reflux temperature, atmospheric pressure or positive pressure.

 The triazole ring formation step is preferably conducted in the absence of solvent, or in solution with a solvent compatible with the 1,2,4-triazolyl forming reagent or in excess of the 1,2,4-triazolyl forming reagent. solvent paper at temperatures preferably above 100 ° C, the upper limit being the decomposition temperature of the reaction medium components. The reaction may be conducted at atmospheric pressure, positive pressure or vacuum, may be catalyzed by mineral acids, organic acids or bases, or may occur in the absence of catalysts.

 The discovery technique represents an advance over the state of the art by not allowing the formation of 4-position substituted isomers of the triazole ring, the (1H-1,2,4-triazol-4-yl) alkanols.

 The present invention proposes a novel process for the selective preparation of (1 H -1,2,4-triazol-1-yl) alkanols (known sterol biosynthesis inhibitors) which differs from the state of the art mainly by preventing the formation of (1 H-1, 2,4-triazol-4-yl) alkanis isomers, which have no biological activity or economic value, and whose formation (unavoidable by conventional synthesis routes) compromises process yields and creates the need for laborious and complex purification processes.

 The new process also allows process conditions where solvents and excess unreacted materials can be easily recovered and recycled for use in successive batches,

 The complete process presented herein consists of 2 synthesis steps, each of which is separately and as a whole, object of this invention.

Step 1: Synthesis of a hidrazinilalcanol (comprising two alternative synthesis routes)

 Where X, R1, R2, R3 and R4 are substituents as described above. X is preferably chlorine, bromine or iodine, more preferably chlorine or bromine, even more preferably chlorine; R 1 and R 2 are preferably alkyl or aryl, whether or not independently substituted by heteroatoms. R3 and R4 are preferably hydrogen.

 Hydrazine is preferably employed in hydrate or salt form, more preferably in hydrate form. The hydrazine content of the hydrate may range from 1 to 80%, preferably from 20 to 70%, more preferably from 60 to 70%. The reaction may proceed in stoichiometric proportion. However, molar excess of hydrazine is preferable to accelerate the reaction, consume the formed hydrogen halide and prevent formation of disubstituted hydrazines. Thus, the molar ratio of hydrazine to halohydrin may range from 1 to 50, preferably from 2 to 20, more preferably from 5 to 15.

 When necessary the use of solvent can be selected from the group of short chain alcohols, from 1 to 4 carbons, preferably from 2 to 3 carbons, more preferably isopropanol. Alternatively, glycols and alkylglycols may be employed, preferably alkyl (di) glycols, more preferably ethyl and butyl (di) glycols, even more preferably ethylglycol.

 Catalysts are not essential for the progress of the reaction, but alkalines may be employed as non-limited examples: alkali metal hydrides, hydroxides, carbonates and borates, tertiary amines, pyridines and pyrimidines, diazabicycloundecene (DBU), or still base transfer catalyst, among others. In any case, the molar ratio of catalyst to limiting reagent may range from 0.0001 to 1, preferably from 0.005 to 0.5, more preferably from 0.01 to 0.20.

For most reagents, the reaction occurs from room temperature, but may be accelerated by increasing the temperature. Temperatures of 25 to 200 ° C are acceptable, preferably 40 to 150 ° C, more preferably from 60 to 120 ° C, depending on the vapor pressures of the selected components.

 For reagents and liquid solvents at reaction temperature, the effect of pressure variations is irrelevant. For high vapor pressure reagents and solvents, the pressurization of the reaction medium is favorable. Ideal pressures range from 0.5 to 200 bar, preferably from 0.9 to 60 bar, more preferably from 1 to 10 bar.

 The process allows and contemplates the accomplishment of this synthesis step in batch, continuous or semi-batch mode, in any equipment design available in the art: agitated tank, tubular reactor, microreactor, among others. In all cases, especially for semi-battered processes, the present process contemplates any order of addition of reagents and auxiliaries.

 Reaction times depend on the physicochemical properties of the selected halohydrin, its reactivity, steric effects, temperature and pressure conditions, stoichiometric ratios, dilution ratio, stirring efficiency, among other factors, but according to The present invention for complete consumption of the limiting reagent may range from 10 min to 50 h. Under conditions closer to ideal for safe operation and better yields, reaction times preferably range from 1 to 20h, more preferably from 2 to 10h.

b) Oxirane route:

Oxiranes, prepared by any means described in the art, are reacted with hydrazine, its hydrate or salts thereof, to form a hydrazinylalkanol by opening the oxirane ring via attack of one of the least-carbon hydrazine nitrogen atoms.

Where R1, R2, R3 and R4 are as defined above. The same considerations made for the alternative (a) of ^the first stage are valid for the alternative (b) with regard to: Preferably the substituents R1, R2, R3 and R4; presentation form, concentration and stoichiometric proportion of hydrazine; solvent selection; catalyst selection and ratio; temperature and pressure conditions; equipment types and designs; order of addition; and reaction times.

Step 2: Synthesis of (1 H-1,2,4-triazol-1 -iltelcanol

A compound of the type (1/1M, 2,4-triazol-1-yl) alkanol is hidrazinilalcanol prepared by the reaction produced in the first forming step with a reagent 1, 2,4-triazolyl. Possible reagents include, but are not limited to: 1,2,5-triazine, formamidine, formamidine salts or derivatives, formamide, and combinations of formic acid and / or ammonium derivatives thereof, preferably formamide and combination of formic acid with ammonia, more preferably formamide only. This process further permits and contemplates possible combinations of these reagents with each other.

 When formamide is employed to form cycle 1,2,4-triazolyl on the hydrazinylalcanol structure, the overall reaction proceeds in parallel and / or successive steps, forming several detectable intermediate species, which eventually converge to the formation of a Single molecule. Amid the reaction, there is release of water and ammonia. Eventually release of formic acid may also occur as a decomposition product of formamide.

 The overall reaction of this step can be presented as:

Carbonylated species that form rapidly at temperatures above 130 ° C have been detected via LCMSSQ, as observed by the strong

By reaction with the in situ or possibly added ammonia or by reaction with formamide itself, the dicarbonylated species is fatally converted to (1 H -1,2,4-triazol-1-it) alkanol, as shown, without any possibility of formation of the (1H-N-triazo N-alkanol isomer).

The elevated temperature significantly increases the reaction rate, being the preferred range according to the invention 100-220 ^* 0, more preferably 130-200 ° C, most preferably 150-180 ° C. Higher temperatures are possible, but subject the reagents to decomposition, especially formamide.

 Formamide is a preferred reagent as it also acts as a reaction solvent. In this case (reactive solvent), the higher the dilution of hydrazinylalkanol, the faster and more efficient the reaction will be. This process recommends and contemplates formamide to hydrazinylalkane molar ratios of between 2 and 500, preferably between 3 and 50, more preferably between 5 and 20.

 Catalysts are not essential to the progress of the reaction, but alkalines can be employed as non-limited examples: alkali metal hydrides, hydroxides, carbonates and borates, ammonia, tertiary amines, pyridines and pyrimidines, diazabicycloundecene (DBU). ), or base transfer catalyst, among others. In any case, the molar ratio of catalyst to limiting reagent may range from 0.0001 to 1, preferably from 0.005 to 0.5, more preferably from 0.01 to 0.20.

 Pressurization of the reaction medium is not required. Ammonia generated as a reaction by-product may be removed at atmospheric pressure or by vacuum, or may be contained in the reaction medium by generating positive pressure. Optionally, the reaction medium may be pressurized with inert gas or ammonia gas.

This invention provides that the second step may be carried out after isolation of the intermediate generated in the first step by distillation / evaporation of excess and auxiliary materials, or by solvent extraction followed by evaporation, or followed by washing crystallization, or by any another means of isolation. Nevertheless, the process allows the step 2 may occur subsequently to ^the first, since the materials employed are compatible with each other and with the provisos that provided that the molar ratios are balanced to correct for possible losses with parallel reactions (as might occur with traces of hydrazine consuming formamide to generate 1 H-1, 2,4-triazole and / or 4-aminp-4H-1, 2,4-triazole).

 Preferred, non-limiting examples of the scope of this invention are the processes for preparing (1 H -1,2,4-triazoM-yl) alkanols of formula (I) comprised of the group containing: Fiuconazole, Voriconazole, Ravuconazole, Triticonazole , Cyproconazole, Diclobutrazol, Flutriafol, Hexaconazole, Ipconazole, Etconazole and Tebuconazole. Preferred, non-limiting examples of the scope of this invention are those processes which use as main intermediates halohydrins and oxiranes which give rise to the products mentioned above. Preferred, non-limiting examples of the scope of this invention are the processes that generate and use the hydrazinylanitic intermediates for the purpose of preparing the products mentioned above. In short, preferred, non-limiting examples of the scope of this invention are the processes which employ in their respective steps (depending on the class of compound) the molecules shown in Table 1, as well as their

 invention, without limitation of its scope, the use of oxiranes (III) 2- (2-fluorophenyl) -2- (4-fluorophenyl) oxirane and 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane; the preparation and use of the respective (IV) 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2-hydrazinylethanol and 2- (4-chlorophenyl) -3-cyclopropyl-1-hydrazinylbutanecarboxylicides. 2-ol; successive obtaining of (1W-1,2,4-triazol-1-yl) α-canols (I) 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2- (1 H-1,2) , 4-triazol-1-yl) ethanol (Flutriafol) and 2- (4-chlorophenyl) -3-cyclopropyl-1- (1H-1,2,4-triazol-1-yl) -2-butanol (Cyproconazole ).

After complete consumption of hydrazinylalkanol, the excess of formamide is evaporated under reduced pressure in the temperature range 100 to 180 ^° C, preferably 110 to 150 ° C, leaving a crude product based on (1 / - / - 1,2 ₍ 4-Triazol-1-yl) alkane, solid or liquid, depending on the physicochemical properties determined by their substituents.

Products with melting temperature below 150 ° C may be obtained in liquid form at the end of this process. Of these, those which are normally solid at room temperature may further be purified and crystallized according to techniques described in the art.

 The following examples are merely illustrative of the invention and should not be taken to limit the scope of the invention.

 Examples

 Example 1.a. - 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2-hydrazinylethanol

 10g of 95% hydrous ethanol and 12g of 67.8% hydrazine hydrate were heated to 70 ° C. 20g of 98.2% 2- (2-fluorophenyl) -2- (4-fluorophenyl) oxirane was added over 1.5h. The reaction proceeded for a further 40 min at 70 ° C and continued for a further 30h at room temperature. LCMSSQ analysis revealed total oxirane consumption and major formation of 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2-hydrazini) ethanol (C 14 H 14 F 2 O 2, m / z = 265, LCMSSQ positive mode). The reaction medium was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate and evaporated, yielding 19.1 g of a viscous yellow liquid (yield 85.5%).

 Example 1b. - 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanoyl

 The intermediate was transferred to a reactor containing 40g formamide and 10g ammonium acetate, and the temperature was set to 150 ° C. The reaction continued for 12h. The product was treated at 75-80 ° C by dilution with 200g of water, 30g of toluene and 60g of cyclohexane. After crystallization, filtration and drying, 14.8g of 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2- (1 / - / - 1,2,4-triazoyl-1-yl) product remained. ) ethano (C16H13F2O, m / z = 302, LCMSSQ positive mode, overall yield 68%, purity 95%). The isomer containing structure 1 H-1,2,4-triazol-4-H was not detected.

 Example 2.a. - 2- (4-chlorophenyl) -3-cyclopropyl-1-hydrazinylbutan-2-ol

 49g of 85% hydrated isopropanol and 47.5g of 67.8% hydrazine hydrate were heated to 80 ° C. 27 g of 98% 2- (4-chlorophenyl) -2- (1-cyclopropyl) oxirane was added over 1h and reaction continued for a further 5h. LCMSSQ analysis revealed total oxirane consumption and major formation of 2- (4-chlorophenyl) -3-cyclopropyl-1-hydrazinylbutan-2-ol (C13H19CIN2O, m / z 255, LCMSSQ positive mode), which proceeded to step next without isolation.

 Example 2.b. - 2- (4-chlorophenyl) -3-cyclopropyl-1- (1- -1,4,4-triazol-1-yl) butan-2-ol

Excess isopropanol, water and hydrazine hydrate from the process described in example 2. a. recovered by fractional distillation leaving the intermediate as a residue, on which 93.4g of formamide was added at 130 ° C. The temperature was then raised to 175 ° C for 6h. Ammonia was continuously removed from the reaction medium at atmospheric pressure.

 Excess formamide was recovered by vacuum distillation at 110 to 140 ° C. The residue was diluted with 30g of toluene and 60g of cyclohexane and the solution was cooled to 2-5 ° C for 1h under stirring to crystallize.

30g of water was added and the mixture was kept cool and stirred for a further 1h.

The suspension was then vacuum filtered and dried with hot air circulation resulting in 26.5 g of a 2- (4-chlorophenyl) -3-cyclopropyl-1- (1H-1,2,4) white powder. -triazof-1-yl) -2-butanol (C15H18CIN30, m / z = 292, positive mode LCMSSQ, overall yield 75%, purity 98.5%). The isomer containing structure 1 H-1,2,4-triazol-4-yl was not detected.

 Example 3. a. - 2- (4-chlorophenyl) -3-cyclopropyl-1-hydrazinylbutan-2-ol

 60g of 85% hydrated isopropanol, 50.93g of hydrazine hydrate at

67.8% (1.0776 mol) and 3.74 g of anhydrous 99.6% K2 CO3 (0.0269 mol) were heated to 80 ° C. Then 30.00g of 99.9% 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane (0.1347 mol) was dripped for 1h and reaction continued for a further 2h. LCMSSQ analysis revealed total oxirane consumption and major formation of 2- (4-chlorophenyl) -3-cyclopropyl

1-Hydrazinylbutan-2-ol (C13 HigCIN20, m / z 255, LCMSSQ positive mode), which proceeded to the next step without isolation.

 Example 3 b. 2- (4-chlorophenyl) -3-cyclopropyl-1- (1 H -1,4,4-triazol-1-yl) butan-2-one;

 Excess isopropanol, water and hydrazine hydrate from the process described in example 3. a. were recovered by fractional distillation, leaving the intermediate as a residue, onto which 91.93g of 99% formamide (2.0206mol) was added at 130 ° C. The temperature was then raised to 170 ° C for 3h. Ammonia was continuously removed from the reaction medium at atmospheric pressure.

 Excess formamide was recovered by vacuum distillation at 110 to 140 ° C. The residue was diluted with 20g toluene, cooled to 5 ° C, crystallized with the addition of 40g hexane, neutralized with 29g 3M HCl and washed with 50g water. The suspension was then vacuum filtered and dried with hot air circulation, resulting in 27.5 g of a light beige 2- (4-chlorophenyl) -3-cyclopropyl-1- (1H-1,2,4- triazol-1-yl) -2-butanol (C15H18CIN30, m / z = 292, LCMSS positive mode, overall yield 70%, purity 96.5%). The isomer containing structure I H-1,2,4-triazol-4-yl was not detected in measurable quantity.

Claims

Claims 1. Process for the selective preparation of (IH-1^^-triazol-1-i alkanols, characterized by comprising the steps below: a) reaction of halohydrin of formula (II) or oxirane compound of formula (III) indicated below:

Formula (II) Formula (III) where sulfonated and nitrated; with hydrazine or its salts, hydrates and derivatives, to obtain the intermediate compound hydrazinylalkanol of formula (IV) indicated below:

Formula (IV) b) reaction of the intermediate hydrazinyl alkanol compound of formula (IV) obtained in the previous step with a 1,2,4,-triazolyl-forming reagent to obtain the final compounds (1W-1,2,4-triazof-1- il)alkanols of formula (I) as indicated below:

Formula (I) 2. Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized in that X is chlorine, bromine or iodine, more preferably chlorine or bromine, even more preferably chlorine; and R3 and R4 are preferably hydrogen. 3. Process for the selective preparation of (1 H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized by being hydrazine preferably employed in the form of a hydrate or salt, more preferably in the form of a hydrate. 4. Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alicanols according to claim 1, characterized by having a molar ratio of hydrazine in relation to halohydrin or oxirane of 1 to 50, preferably of 2 to 20, more preferably 5 to 15. 5. Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized in that no solvent is used in step (a) - formation of hydrazinylalkanol (IV). 6. Process for the selective preparation of (1 H-1, 2,4-triazole- 1-yl)alkanols according to claim 1, characterized by employing in step (a) - formation of hydrazinylalkanol (IV) - a solvent selected from the group comprising: short-chain alcohols, from 1 to 4 carbons, preferably from 2 to 3 carbons , more preferably isopropanol; or glycols and alkylglycols, preferably alkyl(di)glycols, more preferably ethyl- and butyl-(di)glycols, even more preferably ethylglycols. 7. Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized by using at least one catalyst in any of the steps. 8. Process for the selective preparation of (1H-1, 2.4-triazole- 1-yl)alkanols according to claim 7, characterized by employing alkaline catalysts such as those chosen from the group containing: hydrides, hydroxides, carbonates and borates of alkali metals, tertiary amines, pyridines and pyrimidines, diazabicycloundecene (DBU); or base transfer catalyst. 9. Process for the selective preparation of (1 H-1,2,4-triazole- 1-yl) aphenols according to claims 7 or 8, characterized by preferably using sodium hydroxide, potassium hydroxide or potassium carbonate as a catalyst, in a molar ratio for the limiting reagent of 0.0001 to 1, preferably 0.005 to 0.5, more preferably 0.01 to 0.20. 10. Process for the selective preparation of (1H-1, 2,4-triazol-1-i1)alkanols according to claim 1, characterized by employing in step (a) - formation of hydrazinylalkanol (IV) - at room temperature, or temperatures between 25 to 200°C, preferably from 40 to 150°C, more preferably from 60 to 120°C. 11. Process for the selective preparation of (1H-,2,4-triazol-1-yl)alkanols according to claim 1, characterized by employing in step (a) - formation of hydrazinylalkanol (IV) - pressures from 0.5 to 200 bar, preferably 0.9 to 60 bar, more preferably 1 to 10 bar. 12- Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized by recovering solvents and surplus materials from the reaction medium of step (a) - formation of hydrazinylalkanol (IV) - by evaporation and recycling for use in successive batches. 13. Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized by using 1,2,4-triazolyl as a forming reagent in step (b) - preparation of (1 H-1,2,4-triazol-1-yl)alkanol - a reagent containing at least 1 carbon atom linked to a hydrogen by simple covalent bond, also linked to a heteroatom by simple covalent bond and further linked to an additional heteroatom by double covalent bond, capable of reacting with ammonia and/or already combined with an unsubstituted nitrogen atom. 14. Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alkanols according to claim 13, characterized in that the 1,2,4-triazolyl-forming reagent is chosen from the group comprising: 1,3,5-triazine, formamidine, salts or derivatives of formamidinium, formamide, and combinations of formic acid and/or its derivatives with ammonia, preferably formamide and the combination of formic acid with ammonia, more preferably only formamide. 15. Process for the selective preparation of (11-1-1,2,4-triazol-1-i)alkanols according to claim 14, characterized by recovering surplus formamide by evaporation and recycling for use in successive batches. 16. Process for the selective preparation of (I H-1,2,4-triazol-1-yl)alkanols according to claim 14, characterized by employing molar ratios of formamide to hydrazinylalkanol between 2 and 500, preferably between 3 and 50, more preferably between 5 and 20. 17. Process for the selective preparation of (1 H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized by employing in step (b) - preparation of (1 H-1,2,4- triazol-1-yl)alkanol - temperatures from 100 to 220°C, more preferably from 130 to 200°C, even more preferably from 150 to 180°C. 18. Process for the selective preparation of (1 H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized by using in step (b) - preparation of (1 H-1,2,4- triazol-1-yl)alkanol - positive pressure, autogenous or by pressurization with inert gas or ammonia. 19. Process for the selective preparation of (1 H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized in that no solvent is used in step (b) - preparation of (1 H-1,2, 4-triazol-1-yl)alkanol. 20. Process for the selective preparation of (1 H-1,2,4-triazol-1-ii)alkanols according to claim 1, characterized by proceeding with step (b) - preparation of (1 H-1,2,4- triazol-1-yl)alkanol - without isolation of the hydrazinylalkanol formed in step (a). 21. Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized in that the final product is generated (1H-1,2,4-triazol-1-yl) alkanols chosen from the group containing: Fluconazole, Voriconazole, Ravuconazole, Triticonazole, Cyproconazole, Diclobutrazole, Flutriafol, Hexaconazole, Ipconazole, Metconazole and Tebuconazole. 22. Process for the selective preparation of (1H-1,2,4-triazol-1-yl)alkanols according to claim 1, characterized by employing the oxiranes (III) 2-(2-fluorophenyl)-2-(4-fluorophenyl )oxirane and 2-(4-chlorophenyl)-2-(1-cyclopropylethyl)oxirane in the preparation of the respective hydrazinylalkanol intermediates (IV) 1-(2-fluorophenyl)-1-(4-fluorophenyl)-2-hydrazinylethanol and 2- (4-chlorophenyl)-3-cyclopropyl-1-hydrazinylbutan-2-ol, with the successive obtaining of (1H-1,2,4-triazol-1-yl)alkanols (I) 1-(2-fluorophenyl) -1-(4-fluorophenyl)- 2-(1H-1,2,4-triazol-1-yl)ethanol (Flutriafol) and 2-(4-chlorophenyl)-3-cyclopropyl-1-(1H- 1,2,4-triazol-1-yl)-2-butanol (Cyproconazole). 23. Hydrazinylalkanol compound obtained according to any of claims 1 to 22, characterized by having the structure as in formula (IV), as indicated below:

Formula (IV) where X is halogen and R1, R2, R3 and R4 are, independently, hydrogen, heteroatoms or carbon chains substituted or not by heteroatom. 24. Use of the hydrazinylalkanol compound according to claim 23, characterized by being used as a chemical intermediate in the synthesis of pharmaceuticals, agricultural pesticides and veterinary products.