RU2039050C1 - Derivatives of 1,2,4-triazole, optically inert or containing r- or s-configuration at c-2 and c-3 asymmetric centers, or their salts showing fungicide activity, and a method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: derivative of 1,2,4-triazole of the formula (I)

where R^°, R¹ and R²-, are similar or different, hydrogen or lower alkyl group; A a group of the formula (II)

where X chemical bond or a group of the formula (III)

where X¹ chemical bond or C₁-C₅-alkylene group which can contain sulfur atom; R⁵ and R⁶ are similar or different, hydrogen or lower alkyl group; R³ aromatic heterocycle in which heteroatom is nitrogen, sulfur or oxygen atom and which can be substituted with lower alkyl (unsubstituted or fluorine-substituted), C₃-cycloalkyl, amini, lower alkylmercapto-group or oxo-group; n 0, 1 or 2; or A a group of the formula S-R⁴ where R⁴ as indicated above, R^o or R¹ lower alkyl-group. Reagent 1: compound of the formula IV

where R^°, R¹ and R² as indicated above. Reagent 2: HS-X-R³ where X and R³ as indicated above. Reaction conditions: at temperature from -20 to 150 C at oxidation of reaction product if necessary. Synthesized compounds were used as antifungal agents. EFFECT: improved method of synthesis. 3 cl, 18 tbl

Description

 The invention relates to triazole compounds, their preparation and use as antifungal agents or intermediates for the manufacture of antifungal medicinal herbs, as well as agrochemicals.

 There are many compounds that can be classified as antifungal agents.

 Derivatives of triazole with antifungal activity are known (Japanese Patent Laid-open No. 189173/83, 98072/84). However, it is not clear from these publications whether these compounds are sufficiently effective as medicines, if we consider them in terms of their antifungal activity, side effects in absorbent capacity.

 As for the existing standard antifungal agents, they are not effective enough and have certain disadvantages, such as side effects.

 To eliminate these drawbacks, it is desirable to use compounds with stronger antifungal activity and greater reliability as medicines.

 Figure 1 shows a powder x-ray of the hydrochloride of compound 43; figure 2 the same, the hydrobromide of compound 43.

_A (I) где R^o, R¹ и R² являются одинаковыми или различными и представляют собой атом водорода или алкильную группу;
А группа формулы
-

X R³ где Х химическая связь или группа формулы

- X¹- где Х¹ химическая связь или алкиленовая группа с 1-5 атомами углерода, которая может содержать атом серы или кислорода в качестве составляющих атомов; R⁵ и R⁶ являются одинаковыми или различными и означают атом водорода или низшую алкильную группу;
R³ ароматическая гетероциклическая группа, которая может быть замещенной; n означает 0, 1 или 2,
или А является группой формулы
-S-R⁴, где R⁴ атом водорода, алканоильная группа, если Х и Х¹ в радикале А являются химической связью или А является группой формулы
-S-R⁴, где R⁴ указан выше,
то R⁰ или R¹ низшая алкильная группа, или к соли описанного соединения формулы I.The present invention relates to:
1. To the compound of the formula

_A (I) where R ^o , R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group;
A group of formula
-

XR ³ where X is a chemical bond or a group of the formula

- X ¹ - where X ^{1 is a} chemical bond or alkylene group with 1-5 carbon atoms, which may contain a sulfur or oxygen atom as constituent atoms; R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a lower alkyl group;
R ^{3 is an} aromatic heterocyclic group which may be substituted; n means 0, 1 or 2,
or A is a group of the formula
-SR ⁴ , where R ^{4 is} a hydrogen atom, an alkanoyl group, if X and X ¹ in radical A are a chemical bond or A is a group of the formula
-SR ⁴ , where R ⁴ is indicated above,
then R ⁰ or R ¹ lower alkyl group, or to a salt of the described compounds of formula I.

 2. To a method for producing a compound of formula I.

 3. To antifungal agents containing a compound of formula I.

_{x ____ R}3 (I') где R⁰,R¹,R²,R³,x,n определены выше,
и общей формулой

_{S ____ R}4 (I'') где R⁰,R¹,R² и R⁴ определены выше.The compound of the present invention may also be represented by the general formula

_{x ____ R} 3 (I ') where R ⁰ , R ¹ , R ² , R ³ , x, n are as defined above,
and the general formula

_{S ____ R} 4 (I '') where R ⁰ , R ¹ , R ² and R ^{4 are} defined above.

In compounds (I), the lower alkyl groups represented by R ⁰ , R ¹ or R ² are straight chain or branched C _1-3 alkyl groups such as methyl, ethyl, propyl and isopropyl; or R ¹ and R ² in combination are lower alkylene groups, for example ethylene, propylene, compounds in which R ^{1 is a} methyl group and R ⁰ and R ² are hydrogen atoms are preferred.

- X¹- то предпочтительно, чтобы R⁵ представлял собой атом водорода или низшую алкильную группу, например метил, этил, пропил, или чтобы R⁶ представлял собой атом водорода или метил, а Х представлял собой алкиленовую группу с 1-5 атомами углерода, которая может содержать в качестве составляющих атомов атомы серы или кислорода и примерами которой могут служить следующие группы:
CH₂, CH₂CH₂,

,

,

H₂CH₂
CH

H₂, CH₂CH₂CH₂CH₂, CH₂CH₂CH₂CH₂CH₂ СН₂S, CH₂SCH₂, CH₂SCH₂S, CH₂SCH₂CH₂, CH₂SCH₂CH₂S, CH₂SCH₂CH₂CH₂, CH₂CH₂S, CH₂CH₂SCH₂, CH₂CH₂SCH₂S, CH₂CH₂SCH₂CH₂,
CH

CH₂, CH₂CH₂CH₂S, CH₂CH₂CH₂SCH₂

CH₂OCH₂CH₂S, CH₂SCH₂CH₂O, CH₂OCH₂CH₂O, CH₂OCH₂CH₂, CH₂OCH₂CH₂CH₂, CH₂CH₂CH₂O.If in the compounds of formula I, X in A represents a group of the formula

- X ¹ - it is preferable that R ⁵ represents a hydrogen atom or a lower alkyl group, for example methyl, ethyl, propyl, or that R ⁶ represents a hydrogen atom or methyl, and X represents an alkylene group with 1-5 carbon atoms, which may contain sulfur or oxygen atoms as constituent atoms and examples of which are the following groups:
CH ₂ , CH ₂ CH ₂ ,

,

,

H ₂ CH ₂
CH

H ₂ , CH ₂ CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ S, CH ₂ SCH ₂ , CH ₂ SCH ₂ S, CH ₂ SCH ₂ CH ₂ , CH ₂ SCH ₂ CH ₂ S, CH ₂ SCH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ S, CH ₂ CH ₂ SCH ₂ , CH ₂ CH ₂ SCH ₂ S, CH ₂ CH ₂ SCH ₂ CH ₂ ,
CH

CH ₂ , CH ₂ CH ₂ CH ₂ S, CH ₂ CH ₂ CH ₂ SCH ₂

CH ₂ OCH ₂ CH ₂ S, CH ₂ SCH ₂ CH ₂ O, CH ₂ OCH ₂ CH ₂ O, CH ₂ OCH ₂ CH ₂ , CH ₂ OCH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ O.

If X is an alkylene group containing sulfur atoms as constituent atoms, then said sulfur atoms can be oxidized to form sulfoxide or sulfone. If these groups having chemical bonds on both sides have a sulfur or oxygen atom at the end, then these atoms are bonded to R ³ .

X R³ то ароматическая гетероциклическая группа, которая может быть замещенной, может быть также конденсированной с ядром, имеющим 5-7 членов. При этом примерами таких конденсированных ароматических гетероциклических групп могут служить 1-бензимидазолил, 2-бензимидазолил, 5Н-6,7-дигидропиролло[1,2-a] имидазол-2-ил, 5Н-6,7-дигидропиролло[1,2-c]имидазол-3-ил, 2-имидазо[1,2-a]пиримидинил, 5,6,7,8-тетрагидроимидазо[1,2-a]пиридин-2-ил, 2-имидазо[1,2-a]пиридинил, 3-имидазо [1,5-a]пиразинил, 2-имидазо[1,2-a]пиразинил, 6-имидазо[1,2-b] пиридазинил, 2-имидазо[1,2-b] пиридазинил, 3-имидазо[1,2-b] пиридазинил, 5-имидазо[1,5-a]пиридинил, 6-имидазо[1,5-a]пиридинил, 7-имида- зо[1,5-b] пиридазинил, 2-бензотиазолил, 4,5,6,7-тетра- гидробензотиазол-2-ил, 4Н-5,6-дигидроциклопента[d] тиазол-2-ил, 4Н-5,6,7,8-тетрагидроциклогепта [d] тиазол-2-ил, хинолил, изохинолил, хиназолинил, индолизинил и индолил.If in the compounds of formula I A represents
-

XR ³ is an aromatic heterocyclic group which may be substituted, may also be fused to a nucleus having 5-7 members. In this case, examples of such condensed aromatic heterocyclic groups include 1-benzimidazolyl, 2-benzimidazolyl, 5H-6,7-dihydropyrrolo [1,2-a] imidazol-2-yl, 5H-6,7-dihydropyrolo [1,2- c] imidazol-3-yl, 2-imidazo [1,2-a] pyrimidinyl, 5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-2-yl, 2-imidazo [1,2- a] pyridinyl, 3-imidazo [1,5-a] pyrazinyl, 2-imidazo [1,2-a] pyrazinyl, 6-imidazo [1,2-b] pyridazinyl, 2-imidazo [1,2-b] pyridazinyl, 3-imidazo [1,2-b] pyridazinyl, 5-imidazo [1,5-a] pyridinyl, 6-imidazo [1,5-a] pyridinyl, 7-imidazo [1,5-b] pyridazinyl, 2-benzothiazolyl, 4,5,6,7-tetrahydrobenzothiazol-2-yl, 4 H-5,6-dihydrocyclopenta [d] thiazol-2-yl, 4H-5,6,7,8-tetrahydrocyclohepta [d] thiazol-2-yl, quinolyl, isoquinolyl, quinazolinyl, indolisinyl and indolyl.

Examples of non-condensed heterocyclic groups in aromatic heterocyclic groups represented by the radical R ³ that may be substituted are 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (H) -1,2,4-tri- azolyl, 3- (4H) -1,2,4-triazolyl, 3- (1H) -1,2,4-triazolyl, 5- (1H) = 1,2,4-triazolyl, 4- (4H) - 1,2,4-triazolyl, 1,2,3-triazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 4-pyridyl, 2-pyridyl, 3-pyridyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-thienyl, 2-furyl, 1-pyrrolyl, 2-pyrazinyl, 3-pyrimisinyl, 2-pyrimide ynyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-ozoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-tetrazolyl, 5-tetrazolyl and 2-oxo-1,3-dioxol-4-yl.

 Substituents which may have fused or non-fused aromatic heterocyclic groups are halogen atoms, amino, hydroxy, alkyl, alkenyl, aryl, aralkyl, halogenated alkyl, alkylthio, cycloalkyl and cycloalkylalkyl groups, the indicated halogen atoms being chlorine atoms, fluorine, bromine and iodine.

 Said alkyl groups having preferably 1-4 carbon atoms are straight or branched chain groups such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

 The indicated alkenyl groups having 2-4 carbon atoms are vinyl, allyl and 1,3-butadienyl.

 Said aryl group may be phenyl and naphthyl.

 Said aralkyl group may be benzyl, phenethyl and phenylpropyl.

 Examples of said halogenated alkyl group are alkyl groups having 1-4 carbon atoms, each of which is substituted with 1-5 halogen atoms, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl and tetrafluoropropyl.

 Examples of the indicated alkylthio group having 1-4 carbon atoms are methylthio, ethylthio, propylthio and butylthio groups, and in these alkylthio groups, the sulfur atom can be oxidized to form sulfoxide or sulfone.

 Examples of a cycloalkyl group having 3-6 carbon atoms are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

 Examples of cycloaralkyl groups having 1-4 carbon atoms, each of which is substituted by cycloalkyl groups having 3-6 carbon atoms, are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylbutyl.

If A is —SR ⁴ in the compounds of formula I, then the alkanoyl group represented by R ⁴ is an acyl group derived from carboxylic acids, for example a C _2-5 alkanoyl group such as propionyl, buturyl, isobuturyl, valeryl and acetyl, and aryl C _1-3 alkanoyl group such as phenylacetyl and phenylpropionyl. A preferred acyl group is a group that has the ability to hydrolyze in the body.

 Specific compounds of the present invention are presented in tables 1-4.

If compounds (I) have one or more asymmetric carbon atoms, the present invention includes stereoisomers of the R and S configurations and mixtures thereof. Preferred compounds are compounds (I) having a methyl group as R ¹ and a hydrogen atom as R ² , the absolute configuration of which is the R configuration.

 Compounds (I) can also be prepared in the form of salts, for example, salts of inorganic acids, such as hydrochlorides, hydrobromides, sulfates, nitrates and phosphates, and salts of organic acids, such as acetates, tartrates, citrates, fumarates, maleates, toluenesulfonates and methanesulfonates.

N-

(II)
с соединением общей формулы
HS X R³. (III)
Указанную реакцию обычно проводят в присутствии воды или органического растворителя, например, ацетонитрила, диметилформамида, диметилсульфоксида, тетрагидрофурана, метилового спирта, этилового спирта, которые могут быть использованы как отдельно, так и в сочетании друг с другом, или без какого-либо растворителя при температуре от -20 до 150^оС. В целях ускорения реакции в реакционную систему может быть добавлено основание, например, такое как карбонат калия, гидроксид калия, гидроксид натрия, гидрид натрия, метилат натрия, этилат натрия или фторид тетрабутиламмония.If n is 0 in the formula (I ′) of the compounds of the present invention, then these compounds can be obtained, for example, by reaction of a compound of the formula

N-

(Ii)
with a compound of the general formula
HS XR ³ . (III)
The specified reaction is usually carried out in the presence of water or an organic solvent, for example, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl alcohol, ethyl alcohol, which can be used either separately or in combination with each other, or without any solvent at a temperature from -20 to 150 ^C. in order to accelerate the reaction in the reaction system may be added a base, e.g., such as potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide yl tetrabutylammonium fluoride.

N

SH (IV) с соединением общей формулы
W X R³, (V) где Х и R³ определены выше; W атом галогена или группа формулы R³-SO₂-O-, где R³ низший С_1-4-алкил, трифторoметил, фенил или р-толуол.If n is 0 in the formula (I) of the compounds of the present invention, such compounds can also be obtained, for example, by reaction of a compound of the formula

N

SH (IV) with a compound of the general formula
WXR ³ , (V) where X and R ^{3 are as} defined above; W is a halogen atom or a group of the formula R ³ —SO ₂ —O—, where R ^{3 is} lower C _1-4 alkyl, trifluoromethyl, phenyl or p-toluene.

Typically, this reaction is carried out in the presence of water or an organic solvent, for example acetonitrile, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl alcohol, ethyl alcohol, which can be used either separately or in combination with each other, or without any solvent a temperature of from -20 to 150 ^C. in order to accelerate the reaction in the reaction system may be added a base, e.g., such as potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methoxide, ethoxide, atria or tetrabutylammonium fluoride.

N

SH с соединением формулы
R^4' W', (VI) где R^4' является алканоильной группой; W' атом галогена или -О-R^4'', где R^4'' ацильная группа.If in formula (I ") of the present invention, R ⁴ is an alkanoyl group, then such compounds can be prepared by reaction of a compound of the formula

N

SH with a compound of the formula
R ^{4 '} W', (VI) where R ^{4 '} is an alkanoyl group; W 'is a halogen atom or —O — R ^{4 ″} , where R ^{4 ″ is an} acyl group.

Typically, said reaction is carried out in water or an organic solvent such as methylene chloride, chloroform, ethyl acetate, benzene, dioxane, tetrahydrofuran, which may be used both separately and in combination with each other, at a temperature of from -20 to 100 ^C. In order to In order to accelerate the reaction, an inorganic base such as potassium carbonate, sodium hydrogen carbonate or sodium hydroxide, or an organic base such as triethylamine, pyridine, or picoline may be added to the reaction system.

N

SH
Реакцию окисления обычно проводят в присутствии воды или органического растворителя, например метиленхлориде, хлороформе, изопропиловом спирте, бензоле уксусной кислоте, которые могут быть использованы как отдельно, так и в сочетании друг с другом, при температуре от -20 до 50^оС с оксидантом, например m-хлоропербензойной кислотой, перуксусной кислотой, перекисью водорода, бензоилпероксидом. Количество оксиданта, эквивалентного соединению (8), может быть соответственно скорректировано так, что соединение формулы (I'), в котором n равно 1, и соединение, в котором n равно 2, могут быть получены отдельно или в смеси. Реакционная температура и время прохождения реакции могут быть откорректированы так, что соединения формулы (I'), в которых n равно 1 и 2, могут быть получены отдельно или в смеси. Для указанной реакции предпочтительным оксидантом является m-хлорбензойная кислота.If n is 1 or 2 in the formula (I ′) of the compounds of the present invention, then such compounds can be obtained, for example, using a compound of the formula

N

SH
The oxidation reaction is typically conducted in the presence of water or an organic solvent, such as methylene chloride, chloroform, isopropyl alcohol, benzene acetic acid that can be used both separately and in combination with each other, at a temperature of from -20 ^to 50 ° C with an oxidizing reagent, for example m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, benzoyl peroxide. The amount of oxidant equivalent to compound (8) can be adjusted accordingly so that a compound of formula (I ′) in which n is 1 and a compound in which n is 2 can be obtained separately or in a mixture. The reaction temperature and the reaction time can be adjusted so that the compounds of formula (I '), in which n is 1 and 2, can be obtained separately or in a mixture. For this reaction, m-chlorobenzoic acid is the preferred oxidant.

N

S ___ R_p (XXIX)
где R⁰, R¹ и R² определены выше; R_р бензил, n-метоксибензил, n-метилбензил или тритил. Указанная реакция разблокирования может быть проведена, например, путем воздействия кислоты, такой как фтороводород, трифторуксусная кислота, трифторметансульфоновая кислота и т.п. на субстратное соединение (XXIX) в присутствии или отсутствия анизола или триазола, путем воздействия металлического натрия на соединение XXIX в жидком аммиаке или путем обработки субстратного соединения тяжелым металлом, например нитратом серебра, ацетатом ртути, трифторoацетатом ртути и т.п. с последующей реакцией этого соединения с меркаптосоединением, например сероводородом, β-меркаптоэтанолом и т.п. Указанная реакция разблокирования обычно протекают в присутствии или отсутствии органического растворителя, например уксусной кислоты, метиленхлорида, хлороформа, трифторуксусной кислоты и т.п. при температуре приблизительно от -10 до 60^о.The compound (I ") of the present invention, where R ^{4 is} hydrogen, can also be obtained using the unlock reaction of the compounds of formula

N

S ___ R _p (XXIX)
where R ⁰ , R ¹ and R ^{2 are} defined above; R _p benzyl, n-methoxybenzyl, n-methylbenzyl or trityl. Said unlocking reaction can be carried out, for example, by exposure to an acid such as hydrogen fluoride, trifluoroacetic acid, trifluoromethanesulfonic acid and the like. on the substrate compound (XXIX) in the presence or absence of anisole or triazole, by exposing the compound XXIX in liquid ammonia to sodium metal or by treating the substrate compound with a heavy metal, for example silver nitrate, mercury acetate, mercury trifluoroacetate, and the like. followed by reaction of the compound with a mercapto compound, for example, hydrogen sulfide, β-mercaptoethanol and the like. Said unlocking reaction usually proceeds in the presence or absence of an organic solvent, for example, acetic acid, methylene chloride, chloroform, trifluoroacetic acid, and the like. at a temperature of from about -10 to 60 ^about .

 Compound (I) resulting from these reactions can be isolated from the reaction mixture using standard purification procedures such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and thin layer chromatography.

 Compound (I) can exist in at least two stereoisomers. These isomers, as well as mixtures thereof, if necessary, can be obtained separately. This can be accomplished, for example, using the described corresponding reaction of a particular isomer of the starting compound (II), (III), (V), (VI), (VII), (VIII) or (XXIX), which can be obtained the corresponding isomer of compound (I). If the reaction product is a mixture of two or more isomers, it can be fractionated into the corresponding isomers by standard separation or fractionation techniques, such as salt formation with an optically active acid, for example camphorosulfonic acid, tartaric acid, and the like. several types of chromatography, fractionation, recrystallization, etc.

 Physiologically acceptable salts of compound (I) can be obtained by adding the indicated inorganic acids and organic acids.

Among the synthetic intermediates (II) used in the present invention, compound (IX), where R ⁰ and R ² are hydrogen, can be prepared by a method as illustrated in the reaction scheme below.

Способ получения соединения (IX) подробно описан ниже. Так, например, 2,4-дифторoбензол (Х) подвергают реакции Фриделя-Крафтса с пропионилхлоридом с получением соединения (XI), которое затем обрабатывают бромидом, в результате чего получают бромид (XII). Указанное соединение (XII) может быть также получено с помощью реакции Фриделя-Крафтса соединения (Х) и 2-бромопропионилхлорида. Реакция (XII) (XIII) является реакцией гидролиза, которая может быть легко осуществлена в присутствии формата натрия в метаноле. С помощью обычной реакции тетрагидропиранилирования соединения (XIII) получают соединение (XIV). Если указанное соединение (XIV) подвергают реакции с триметилсульфоксонийиодидом в присутствии гидрида натрия, то в результате получают соединение (XV), в котором ТНР является 2-(2Н)-3,4,5,6-тетрагидропиранилом. Реакция (XV)-(XVI) является реакцией размыкания эпоксикольца с помощью триазолнатриевой соли, образованной из триазола и гидрида натрия, и может быть легко осуществлена в диметилформамиде при 60-90^оС. При воздействии n-толуолсульфонатом пиридиния на соединение (XVI) в этаноле имеет место реакция разблокирования с образованием соединения (XVII). В результате взаимодействия этого соединения (XVII) с метансульфонилхлоридом получают соединение (XVIII), которое затем обрабатывают основанием, например метоксидом натрия, в целях получения соединения (IX).

The method of obtaining compound (IX) is described in detail below. Thus, for example, 2,4-difluoro-benzene (X) is subjected to a Friedel-Crafts reaction with propionyl chloride to give compound (XI), which is then treated with bromide, whereby bromide (XII) is obtained. The specified compound (XII) can also be obtained using the Friedel-Crafts reaction of compound (X) and 2-bromopropionyl chloride. Reaction (XII) (XIII) is a hydrolysis reaction that can be easily carried out in the presence of a sodium format in methanol. Using the usual tetrahydropyranylation reaction of compound (XIII), compound (XIV) is obtained. If said compound (XIV) is reacted with trimethyl sulfoxonium iodide in the presence of sodium hydride, the result is a compound (XV) in which THP is 2- (2H) -3,4,5,6-tetrahydropyranyl. Reaction of (XV) - (XVI) is an epoxy ring opening reaction using triazolnatrievoy salt formed from the triazole and sodium hydride, and can be easily carried out in dimethylformamide at 60-90 ° ^C. Under the influence of n-toluenesulfonate to the pyridinium compound (XVI) in ethanol unlocking reaction takes place with the formation of compound (XVII). By reacting this compound (XVII) with methanesulfonyl chloride, a compound (XVIII) is obtained, which is then treated with a base, for example sodium methoxide, in order to obtain compound (IX).

 In the described synthesis method, compounds (XVII), (XVIII) and (IX) are prepared as a mixture of two diastereoisomers. If desired, each compound from (XVII), (XVIII) and (IX) can be fractionated into the diastereomers of the component by fractional recrystallization, chromatography, etc., or each of the preceding compounds (XV) and (XVI) can be fractionated before the corresponding reaction. by fractional recrystallization, chromatography or the like, which leads to the production of diastereomers (XVII), (XVIII) and (IX). In addition, diastereomer (XVIII) or (IX) can be obtained by using the corresponding diastereomer (XVII) or (XVIII).

где заместитель R является С_1-4-алкильной группой. Реакция сложного эфира (R)-молочной кислоты с (2Н)-3,4-дигидрофураном в присутствии n-толуолсульфоновой кислоты дает соединение (R)-(XX). Указанную реакцию проводят в растворителе, таком как метиленхлорид, хлороформ и т.п. в основном при температуре от -10 до 30^оС. Реакция (R) (XX) ->> (R) (XXI) является обычной гидролизной реакцией, которая легко осуществляется в присутствии основания, например гидроокиси натрия, гидроокиси калия и т.п. в воде или в органическом растворителе, например метаноле, этаноле, иди в их смеси при температуре в пределах 0 40^оС. Реакция конденсации между полученным соединением (R) (XXI) и морфолином может быть предпочтительно проведена в присутствии стандартного дегидратирующего агента конденсации в целях получения соединения (R) (XXII). Дегидрирующим агентом конденсации, используемым в указанной реакции, является, например, дициклогексилкарбодиимид, карбонилдимидазол, диэтилцианофосфат и т. п. В качестве растворителя может быть использован, например, тетрагидрофуран, диоксан или ацетонитрил. Указанную реакцию обычно проводят при температуре от -10^оС до 40^оС. Реакция (R) (XXII) ->> (R) (XIV) является реакцией Гриньяра и может быть осуществлена с помощью реакции соединения (R) (XXIII) с бромидом 2,4-дифторофенилмагния, полученным из 2,4-дифторобромбензола и металлического магния, в органическом растворителе, например тетрагидрофуране, этиловом эфире и т.п. и при температуре от -10 до 40^оС. Амидное соединение (R) (XXII), используемое в реакции Гриньяра, вместо морфолиногруппы может иметь другую циклическую аминогруппу, например, 1-пирролидинил, пиперидино и т.п. или вторичную аминогруппу, например диметиламино, диэтиламино, дибутиламино и т.п. и указанные амиды могут быть синтезированы путем конденсации соответствующих аминов с (R) (XXI). Кроме того, реакция сложного эфира (S)-молочной кислоты, проводимая тем же способом, как описано выше, [(S) (XIX) ->> (S) (XX) ->> (S) (XXI) ->> (S) (XXII) ->> (S) (XIV)] приводит к получению (S) (XIV).You can also use the optically active ester of (R) -lactic acid [(R) - (XIX)] or the ester of (S) -lactic acid [(S) (XIX)] as a starting material for the synthesis of the corresponding optically active compound ( XIV) [(R) (XIV)] or (S) (XIV)] in accordance with the reaction scheme below, and then using the reaction in accordance with the reaction scheme above, followed by (if necessary) separation of the diastereoisomers, the result is optionally active compounds (XVII) [(2R, 3R) (XVII), (2R, 3S) (XVII), (2S, 3S) (XVII)] (XVIII), [(2S, 3RS) (XVIII) (2R, 3S (XVIII), (2S, 3S) (XVIII), (2S, 3R) (XVIII)] and (IX) [(2R, 3R) (IX), (2R, 3S) (IX), ( 2S, 3S) (IX), (2S, 3R) (IX)]

where the substituent R is a C _1-4 alkyl group. Reaction of an (R) -lactic acid ester with (2H) -3,4-dihydrofuran in the presence of n-toluenesulfonic acid gives compound (R) - (XX). Said reaction is carried out in a solvent such as methylene chloride, chloroform and the like. generally at temperatures from -10 to 30 ° ^C. Reaction (R) (XX) - >> (R) (XXI) is a conventional hydrolysis reaction, which is readily accomplished in the presence of a base such as sodium hydroxide, potassium hydroxide, etc. . in water or in an organic solvent such as methanol, ethanol, go in their mixture at a temperature in the range 0 to 40 ^C. The condensation reaction between the resulting compound (R) (XXI) and morpholine may be carried out preferably in presence of a conventional dehydrating condensation agent in order to for the preparation of compound (R) (XXII). The dehydrogenating condensation agent used in this reaction is, for example, dicyclohexylcarbodiimide, carbonyldimidazole, diethyl cyanophosphate, etc. As a solvent, for example, tetrahydrofuran, dioxane or acetonitrile can be used. This reaction is typically conducted at a temperature of from ^-10 ° C to 40 ° ^C. Reaction (R) (XXII) - >> (R) (XIV) is a Grignard reaction and may be carried out by reacting the compound (R) (XXIII) with 2,4-difluorophenylmagnesium bromide derived from 2,4-difluorobromobenzene and magnesium metal in an organic solvent, for example tetrahydrofuran, ethyl ether and the like. and at a temperature of from -10 to 40 ^C. The amide compound (R) (XXII), used in the Grignard reaction, instead of a morpholino group may have a different cyclic amino group, e.g., 1-pyrrolidinyl, piperidino, etc. or a secondary amino group, for example dimethylamino, diethylamino, dibutylamino, and the like. and said amides can be synthesized by condensation of the corresponding amines with (R) (XXI). In addition, the reaction of the ester of (S) -lactic acid, carried out in the same manner as described above, [(S) (XIX) - >> (S) (XX) - >> (S) (XXI) - >> (S) (XXII) - >> (S) (XIV)] yields (S) (XIV).

где заместитель R имеет значения, определенные выше. Реакция конверсии сложного эфира (R)-молочной кислоты (R) (XIX) в амид (R) (XXIII) может быть проведена предпочтительно путем нагревания соединения (R) (XIX) и морфолина в присутствии или в отсутствии растворителя, например бензола, толуола и т.п. при 60 100^оС. Реакция соединения (R) (XXIII) ->> соединение (R) (XXII) может быть проведена тем же способом, что и реакция (R) (XIX) ->> (R) (XX). В указанной реакционной схеме использование циклического амина, не являющегося морфолином, например пирролидина, пиперидина и т.п. или вторичного амина, например диметиламина, диэтиламина, дибутиламина и т.п. вместо морфолина при прочих равных условиях позволяет получить соединение, в котором морфолиногруппа является замененной соответствующей циклической аминогруппой или вторичной аминогруппой. Указанное соединение может быть использовано так же, как и соединение (R) (XXII), в реакции Гриньяра с бромидом 2,4-дифторофенилмагния. Кроме того, с помощью реакции сложного эфира (S)-молочной кислоты (S) (XIX), аналогичной описанной, получают соединение (S) (XXII) по схеме [(S) (XIX) ->> (S) (XIII) ->> (S) (XXII)]
Оптически активное промежуточное соединение (R) (XIV) может быть получено с использованием производного (R)-молочной кислоты (R) (XXIV) в качестве исходного материала в соответствии со следующей реакционной схемой

Использование соответствующих диастереомеров соединений (XVII), (XVIII) и (IX) или их оптически активных форм, полученных указанным способом, в качестве промежуточных соединений позволяет получить соответствующий диастереомер соединения (I) или его оптически активной формы в зависимости от обстоятельств.In the synthesis of an optically active compound according to the present invention, an optically active intermediate (XXII) can also be synthesized in accordance with the following reaction scheme

where the substituent R has the meanings defined above. The reaction for the conversion of the (R) -lactic acid ester (R) (XIX) to the amide (R) (XXIII) can preferably be carried out by heating the compound (R) (XIX) and morpholine in the presence or absence of a solvent, for example benzene, toluene etc. at 60 100 ° ^C. Reaction compound (R) (XXIII) - >> compound (R) (XXII) may be carried out in the same manner as the reaction of (R) (XIX) - >> (R) (XX). In the reaction scheme indicated, the use of a cyclic amine other than morpholine, for example pyrrolidine, piperidine, and the like. or a secondary amine, for example dimethylamine, diethylamine, dibutylamine, and the like. instead of morpholine, ceteris paribus allows to obtain a compound in which the morpholino group is replaced by the corresponding cyclic amino group or a secondary amino group. The specified compound can be used in the same way as the compound (R) (XXII) in the Grignard reaction with 2,4-difluorophenylmagnesium bromide. In addition, using the reaction of the ester of (S) -lactic acid (S) (XIX), similar to that described, compound (S) (XXII) is prepared according to the scheme [(S) (XIX) - >> (S) (XIII) - >> (S) (XXII)]
An optically active intermediate (R) (XIV) can be prepared using a (R) -lactic acid derivative (R) (XX) as a starting material according to the following reaction scheme

The use of the corresponding diastereomers of compounds (XVII), (XVIII) and (IX) or their optically active forms obtained by the indicated method as intermediates allows to obtain the corresponding diastereomer of compound (I) or its optically active form, depending on the circumstances.

Синтетические промежуточные соединения (XXIX) настоящего изобретения могут быть получены, например, следующим образом

N-

R²

(XXIX)
Среди синтетических промежуточных соединений (XXIX) настоящего изобретения соединение (XXX), в котором R⁰ водород, а R¹ и R² вместе взятые представляют собой этиленовую группу, может быть получено, например, способом, проиллюстрированным в следующей реакционной схеме

N__CH

R_p
Если в соединениях формулы (I") настоящего изобретения R⁴ является атомом водорода, то такие соединения могут быть получены, например, с помощью реакции соединения формулы
Az

-

C

(XXIV) (XXXIV) где R⁷, R⁸, R⁹, R¹⁰ и R¹¹ являются одинаковыми или различными и представляют собой атом водорода или остаток углеводорода, который может быть замещенным; А триазолил, имидазолил, с соединением формулы
HS CH₂ CH

где по меньшей мере один из Z и Y является цианогруппой или карбоксильной группой, которая может быть эстерифицированной или амидированной, а другой является атомом водорода, низшей алкильной группой или аминогруппой, которая может быть ацилированной.As for the synthetic intermediate compound (II), the compound (XXVI), in which R ^{o is} methyl and R ¹ and R ^{2 is} hydrogen, can be obtained, for example, by the method illustrated by the following scheme

Synthetic intermediates (XXIX) of the present invention can be obtained, for example, as follows

N-

R ²

(Xxix)
Among the synthetic intermediates (XXIX) of the present invention, compound (XXX) in which R ^{0 is} hydrogen and R ¹ and R ² together represent an ethylene group can be obtained, for example, by the method illustrated in the following reaction scheme

N__ch

R _p
If in the compounds of formula (I ") of the present invention R ⁴ is a hydrogen atom, such compounds can be obtained, for example, by reaction of a compound of the formula
Az

-

C

(XXIV) (XXXIV) where R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are the same or different and represent a hydrogen atom or a hydrocarbon residue which may be substituted; A triazolyl, imidazolyl, with a compound of the formula
HS CH ₂ CH

where at least one of Z and Y is a cyano group or a carboxyl group, which may be esterified or amidated, and the other is a hydrogen atom, a lower alkyl group or an amino group, which may be acylated.

 This reaction can be carried out in one step, the reagents used in this reaction are inexpensive and easy to handle, and the target compounds of general formula (I ") can be obtained in large quantities; thus, the described method can be successfully used in industrial production .

 The reaction between the compound of general formula (XXXIV) and the compound of general formula (IV) is preferably carried out in the presence of an organic or inorganic base, examples of which are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methylate, ethylate sodium, potassium methylate, potassium ethylate, potassium tert-butylate, sodium hydride, potassium hydride, butyl lithium, lithium diisopropylamide, triethylamine, N-methylmorpholine, dimethylaminopyridine, lutidine, tetrabutylammonium fluoride, tetrabut hydroxide tilammoniya; N-benzyltrimethylammonium hydroxide, 1,8-diazabicyclo [5.4.0] und-7-prices; 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, with sodium hydride and sodium methylate being the preferred base.

 In the formula (XXXIV) described above, the triazole designated by AZ may be 1,2,4-triazole.

The hydrocarbon radicals indicated in the formula (XXXIV) R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ can be substituted and represent alkyl, cycloalkyl, alkenyl and aryl groups.

 Examples of these alkyl groups having 1-12 carbon atoms each are straight or branched chain groups such as methyl, ethyl, propyl, butyl, heptyl, octyl, nonyl, decyl and dodecyl.

 Said cycloalkyl groups can be groups containing 3-7 carbon atoms, for example, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

 Said alkenyl groups can be groups comprising 2-6 carbon atoms, for example, such as allyl, vinyl, 1,3-butadienyl, isoprenyl and 2,4-pentadienyl.

 Said aryl groups may be phenyl, naphthyl, biphenyl, antryl and indenyl.

 Said hydrocarbon residues may have substituents, such as a hydroxyl group, carboxyl groups which can be esterified, for example, carboxy, ethoxycarbonyl, methoxycarbonyl, butoxycarbonyl, amino groups, acylamino groups, for example acetylamino, propionylamino, buturylamino, alkylamino groups, for example methylamino, dimethylaminoamino, dimethylaminoamino, alkoxy groups, for example methoxy, ethoxy, butoxy, halogen atoms, for example fluorine, chlorine, bromine, oxo, thio, mercapto, for example methylthio, ethylthio, butylthio, cyan the groups, in addition, the alkyl cycloalkyl, alkenyl and aryl groups described above. These hydrocarbon residues may have from 1 to 3 substituents, which are either the same or different.

The lower C _1-4 alkyl groups represented by X and Y in the formula (IV) may be methyl, propyl, ethyl, butyl, isopropyl and tert-butyl. Examples of amino groups represented by X or Y which may be acylated are acetylamino, benzoylamino, tosylamino and melylamino.

 Examples of carboxyl groups represented by X and Y in formula (IV) that can be esterified or amidated are carboxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, carbamoyl, dimethylaminocarbonyl, diethylaminocarbonyl, morpholinocarbonyl, piperidinecarbonyl, and 1.

 Each of the mercapto compounds represented by the general formula (IX) has one or more asymmetric atoms and two or more stereoisomers. The present invention relates to a method for producing all stereoisomers.

 The method can be carried out as follows.

To a suitable solvent, for example methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide, acetone, toluene, benzene, ethyl acetate, dioxane, tetrahydrofuran and water, which can be used separately or in combination with each other, add a compound of the general formula (XXXIV), and then one or more equivalents, preferably 2-10 equivalents, of the indicated base relative to the amount of compound (XXXIV). Then add one or more equivalents, preferably 2-20 equivalents, of a compound of general formula (IV) with respect to the amount of compound (XXXIV). The resulting mixture was kept at a temperature of from -10 ^to 100 ° C, preferably from 0 to ⁸⁰ ° C, in order to conduct the reaction. After completion of the reaction, a compound of general formula (IX) is obtained by isolation in a manner known per se, for example, by concentration, neutralization, extraction, recrystallization, filtration or various chromatographic methods.

 The most preferred starting compound (IV) of the process of the present invention is a compound in which X is a methoxycarbonyl group and Y is a hydrogen atom (3-mercaptopropionic acid methyl ester).

Preferred starting compounds (XXXIV) are compounds in which AZ 1,2,4-triazolyl; R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are hydrogen atoms or lower alkyl groups, R ^{11 is a} substituted aryl group, with compounds in which R ⁷ , R ⁸ and R ⁹ are hydrogen atoms are particularly preferred; R ^{10 is a} methyl group; R ^{11 is} 2,4-difluorophenyl.

Among the starting compounds of formula (XXXIV) are compounds (IX) in which AZ 1,2,4-triazolyl; R ⁷ , R ⁸ and R ⁹ are hydrogen atoms; R ¹⁰ methyl; R ¹¹ 2,4-difluorophenyl can be synthesized, for example, in accordance with these schemes.

The antifungal activity of the compounds (I) was evaluated as follows: a sheet of filter paper disc (8 mm in diameter) manufactured by Toyo Seisakusho, impregnated by dipping in 1000 ug / ml solution of the compound (I) in methanol was placed on an agar plate and incubated at ²⁸ C for 2 days. then, around the filter paper disk, the diameter of the growth inhibition zone was measured. The following culture media were used:
A yeast agar medium with a nitrogen base;
In a nitrogen base yeast agar medium (pH 7.0);
With agar medium Saburoda.

 The antifungal spectrum of compounds (I) is presented in table 5.

 The antifungal activity of compounds (I) against the fungus Candida albicans are presented in tables 6 and 7.

 The infection-preventing effect of compounds I, evaluated in experimental infection of mice, is shown in Tables 8 and 9.

Method 1 (table. 8): mice of strain Crj: CDF ₁ at the age of 5 weeks were administered an intravenous minimum lethal dose of Candida albicans. The test compound was administered twice: 0 and 2 hours after infection. The efficacy of the drug, expressed in ED ₅₀ values, was calculated by the Reed-Mench method (based on calculating the degree of survival 7 days after infection). ED ₅₀ values were calculated taking into account the total dose administered in these two cases.

Method 2 tab. 9: Mice (Crj CDF1 strain, 5 weeks old) were injected intravenously with a threshold lethal dose of Candida albicans. The test compound was administered immediately after infection. The efficacy of the drug, expressed in ED ₅₀ values, was calculated by the Reed-Mench method according to the degree of survival after 7 days. after infection.

ED ₅₀ values were calculated based on the total dose administered in two cases.

 The compounds of the present invention have low toxicity and high antifungal activity with a wide spectrum of antifungal activity and can be used to prevent and treat fungal infections of humans, domestic animals and birds.

 In the treatment of humans, the compounds of the present invention can be administered orally or parenterally in the form of pharmaceutical compositions formulated in unit dosage forms, such as powders, granules, tablets, capsules and injections, by admixing the active compounds with pharmaceutically acceptable carriers, excipients or diluents. The dose of the active compound may vary depending on the degree of infection and the route of administration, for example, the oral dose for an adult infected with candida is from 0.1 to 100 mg / kg per day, preferably from 1 to 50 mg / kg per day.

 The compound of the present invention can also be used as an antifungal drug for external use. For example, mucous membranes and skin membranes can be sterilized and sanitized by applying an ointment containing 0.1 to 100 mg, preferably 1 to 50 mg, of the compound of the present invention per gram.

 The following are comparative examples and examples illustrating in detail the implementation of the present invention.

 Comparison Example 1. A mixture of benzimidazole (4.72 g, 40 mmol), bromochloroethane (3.4 ml, 41 mmol), potassium carbonate (5.52 g, 40 mM) and dimethylformamide (60 ml) were stirred at room temperature for 20 hours. Ethyl acetate and water were added to this reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. After which the solvent was distilled off, and the residue was chromatographed on silica gel (3.0 x 40 cm), eluting with a mixture of ethyl acetate and hexane (2: 1), whereby 1- (2-chloroethyl) benzimidazole (5.56 gb, 38%) was obtained ) as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.78 (2H, t. I 6 Hz); 4.45 (2H, t, I 6 Hz); 7.19-7.40 (3H, m); 7.76 7.95 (1H, m); 7.90 (1H, s).

To a solution tritilmerkaptana (9.7 g, 35 mmol) in ethanol (90 ml) was added at ⁰ C a solution of sodium methoxide and methanol (28%, 7.1 ml). 1- (2-Chloroethyl) benzimidazole (6.32 g, 35 mmol) was added to the reaction mixture and heated for 2 hours under reflux. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resulting concentrate was chromatographed on silica gel columns (3.0 x 40 cm, ethyl acetate: hexane 1: 1 - >> 2: 1) to obtain 1-2-tritylthioethyl benzimidazole (5.6 g, 38%).

¹ H-NMR (CDCl ₃ ) δ ppm: 2.69 (2H, t, I 6.5 Hz); 3.76 (2H, t, I 6.5 Hz); 6.90-7.90 (21H, m).

To a solution of 1- (2-tritylthioethyl) benzimidazole (7.0 g, 16.6 mmol) in a mixture of methanol (50 ml) and chloroform (80 ml) was added pyridine (1.32 ml, 16.3 mmol), and then silver nitrate (2.9 g, 17.1 mmol). The resulting mixture was stirred for 3 hours at room temperature. The precipitate was isolated and washed with methanol and then with ethyl ether, whereby a silver salt of 1- (2-mercaptoethyl) benzimidazole (4.73 g, 99%) was obtained. Said silver salt was suspended (4.73 g, 16.6 mmol) in dichloromethane (250 mL) and bubbled with hydrogen sulfide at ⁰ ° C for 1 hour. The precipitates were filtered off and the filtrate was concentrated, thereby obtaining 1- (2-mercaptoethyl ) benzimidazole (2.35 g, 79%) as a colorless powder (2.35 g, 79%).

¹ H-NMR (DMCO-d ₆ -CDCl ₃ ) δ ppm: 2.25 (1H, t, I 7.5 Hz); 3.07 (2H, q, I 7.5 Hz); 4.73 (2H, t, I 7.5 Hz); 7.40-8.10 (4H, m); 9.69 (1H, s).

 PRIORITY 2. A mixture of 1H-1,2,4-triazole (10.3 g), 1,3-oxathiolan-2-one (5, 2 g) and toluene (100 ml) were heated in a flask under reflux for 4 days. Then, the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium chloride (50 ml) was added to the residue, and then extracted 4 times with methylene chloride (50 ml). The extract was dried with anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate - >> ethyl acetate: acetone 2: 1) to obtain 2- (1,2,4-triazol-1-yl) ethanethiol (2.5 g) as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.35 (1H, t, I 8.8 Hz); 3.01 (2H, m); 4.37 (2H, t, I 6.6 Hz); 7.99 (1H, s); 8.18 (1H, s).

Example 3: Methanesulfone (1.03 ml, 16 mmol) was added to imidazole (2.16 g, 32 mmol) and the resulting mixture was stirred for 5 min To the reaction mixture was added ethylene sulfide (1.04 ml, 18 mmol) and stirred ^at 55 ° C for 17 h The reaction mixture was chromatographed on a silica gel column (3.0 x 30, ethyl acetate: methanol 10: 1). And 2- (1-imidazolio) ethanethiol (0.85 g, 38%) was obtained as a pale yellow oily substance.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.75 (1H, t, I 8 g Hz); 2.84 (2H, t, I 7.5 Hz); 4.13 (2H, t, I 7.5 Hz); 7.10 (2H, s); 7.51 (1H, s).

 Comparison Example 4. A mixture of imidazole (13.6 g, 0.2 M), bromochloroethane (16.6 ml, 0.2 M), potassium carbonate (0.2 M) and dimethylformamide (100 ml) was stirred for 20 hours at room temperature. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure, whereby 1- (2-chloroethyl) imidazole was obtained as a yellow liquid.

¹ H-NMR (CDCl ₃ ) δ ppm: 3.76 (2H, t, I 6 Hz); 4.29 (2H, t, I 6 Hz); 7.01 (1H, s); 7.07 (1H, s); 7.57 (1H, s).

 1- (2-chloroethyl) imidazole was dissolved in ethanol (30 ml), and then 1,2-ethanedithiol (25 ml) and sodium methoxide (28% methanol solution, 16.6 ml) were added to the solution, the resulting mixture was heated in a flask under reflux for 30 minutes Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. Then dichloromethane (300 ml) was added to the concentrate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride and dried with sodium sulfate. The solvent was distilled off, and the residue was chromatographed on silica gel columns (3.0 x 40 cm, ethyl acetate -> ethyl acetate: methanol 10: 1), whereby 2- [2- (1-imidazolyl) ethylthio] ethanediol was obtained (3, 0 g) in the form of an oily substance pale yellow.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.70 (1H, t, I 7.8 Hz); 2.55-2.70 (4H, m); 2.89 (2H, t, I 6.8 Hz); 4.15 (2H, t, I 6.8 Hz); 6.97 (1H, s); 7.08 (1H, s); 7.55 (1H, s).

 Comparison Example 5. To ethanol (100 ml) containing ethanedithiol (5 ml) and a 28% methanol solution of sodium methylate (11.5 g), 2-chloromethyl-1-methylimidazole hydrochloride (2 g) was added. The resulting mixture was stirred for 15 minutes. Then ethanol was distilled off under reduced pressure. The residue was neutralized with 5 N. aqueous hydrochloric acid (9.5 ml), and then subjected to distillation under reduced pressure. The resulting residue was chromatographed on silica gel (3.5 x 15 cm), eluting with a mixture of methanol and ethyl acetate (5:95). The target fraction was concentrated to give 2- (1-methyl-2-imidazolylthio) ethanethiol (1.4 g) as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ: 1.62 (1H, t, I 7.8 Hz); 2.55-2.80 (4H, m); 3.69 (3H, s); 3.81 (2H, s); 6.87 (1H, d, I 1.4 Hz); 6.91 (1H, d, I = 1.4 Hz).

 COMPARISON EXAMPLE 6. To an acetone solution (40 ml) containing 2-mercapto-1-methylimidazole (4 g) and anhydrous potassium carbonate (20 g), 1-bromo-2-chloroethane (5 ml) was added dropwise and under ice-cooling. The resulting mixture was stirred at room temperature for 2 hours, then methylene chloride (40 ml) was added thereto, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give 2- (2-chloroethylthio) -1-methylimidazole (6.2 g) as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ: 3.35 (2H, t, I 7.0 Hz); 3.63 (3H, s); 3.75 (2H, t, I 7.0 Hz); 6.94 (1H, d, I 1.2 Hz); 7.05 (1H, d, I 1.2 Hz).

 Comparison Example 7. 1H-1,2,4-triazole (13.8 g) and 1-bromo-2- were dissolved in dimethylformamide (100 ml). chloroethane (28.7 g). Potassium carbonate (27.6 g) was added to the resulting solution, and the mixture was stirred for 4 days. The solvent was distilled off under reduced pressure. Dichloromethane (100 ml) was added to the residue. Insoluble materials were filtered off, the filtrate was concentrated, and 1- (2-chloroethyl) -1H-1,2,4-triazole (23.3 g) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.90 (2H, t, I 5.7 Hz); 4.51 (2H, t, I 5.7 Hz); 7.99 (1H, s); 8.17, s).

 The resulting chloroethyl compound (2.8 g) and 1,2-ethanedithiol (4.2 g) were dissolved in ethanol (30 ml), and then a 28% tetraol sodium methylate solution (3.6 ml) and the resulting the mixture was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate) to give 2- [2- (1H-1,2,4-triazol-1-yl) ethylthio] ethanethiol (2.03 g) as a colorless oily substance .

¹ H-NMR (CDCl ₃ ) δ: 1.67 (1H, t, H); 2.62 (4H, m); 3.02 (2H, t, I 6.5 Hz); 4.36 (2H, t, I 6.5 Hz); 7.97 (1H, s); 8.14 (1H, s).

Comparison Example 8. To a solution of dimethylformamide (160 ml), 2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-yl-methyl) oxirane (8 g) and 3-mercaptopropionic acid methyl ester were added, ice-cooling, 60% sodium hydride (4 g). The resulting mixture was stirred for 15 minutes, and then 1N was added dropwise to this mixture. an aqueous solution of hydrochloric acid (101 ml) to bring the pH to 7, after which dimethylformamide and water were distilled off. Water (20 ml) was added to the residue, and then extracted with ethyl acetate (50 ml x 3). The extract was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was chromatographed on silica gel (6.0 x 9.0 cm), eluting with a mixture of ethyl acetate and hexane (3: 1). The target fraction was concentrated, diethyl ether was added to give 2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) propan-2-ol (6.44 g ) in the form of colorless needle crystals with so pl. 112-113 ^about S.

Elemental analysis for C ₁₁ H ₁₁ F ₂ N ₃ OS.

 Calculated, C 48.70; H 4.09; N, 15.49.

 Found, C, 48.96; H 4.11; N, 15.62.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (1H, dd, I 6.80 Hz, 10.8 Hz); 2.84 (1H, dd, I 10.8 Hz, 13.8 Hz); 3.27 (1H, dd, I 6.80 Hz, 13.8 Hz); 4.53 (1H, s); 4.72 (2H, s); 6.74-6.88 (2H, m); 7.42-7.55 (1H, m); 7.83 (1H, s); 8.00 (1H, s).

 Comparison Example 9. To an acetone solution (50 ml) containing 2-mercapto-1-methyltetrazole (4 g) and anhydrous potassium carbonate (20 g), 1-bromo-2-chloroethane (5 ml) was added while cooling with ice. The resulting mixture was stirred at room temperature for 90 minutes, and then methylene chloride (50 ml) was added. The mixture was filtered, the filtrate was concentrated under reduced pressure, and 2- (chloroethylthio) -1-methyltetrazole (6 g) was obtained as a yellow oily substance.

¹ H-NMR (CDCl ₃ ) δ: 3.69 (2H, t, I 6.8 Hz); 3.92 (2H, t, I 6.8 Hz); 3.96 (3H, s).

 Example 10: A methanol solution (2 ml) containing (2RS, 3RS) -2- (2,4-difluorophenyl) -3-methyl-2 - (1H-1,2,4-triazol-1-yl-methyl) -oxyran (0.05 g), methyl 3-mercaptopropionate (0.11 ml) and a 28% solution of sodium methylate and methanol were heated in the flask under reflux for 1 h. Then the reaction mixture was cooled and water (10 ml) was added. The mixture was neutralized with 1N. aqueous hydrochloric acid, after which it was extracted with methylene chloride (5.0 ml x 2 times). The extract solution was dried with anhydrous sodium sulfate, and then the solvent was distilled off.

 The residue was chromatographed on silica gel (2.5 cm x 5 cm), eluting with a mixture of ethyl acetate and hexane (1: 2). The target fraction was concentrated, and then ethyl acetate was added to give (2RS, 3RS) -2- (2,4-difluorophenyl) -3-mercapto-1 - [(1H) -1, 2,4-triazole-1- silt] 2-butanol (0.03 g) in the form of colorless needle crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, I 7.0 Hz); 1.96 (1H, d, I 10.2 Hz); 3.45 (1H, d, q, I 7.0 Hz, 10.2 Hz); 4.77 (1H, s); 4.82 (1H, d, I 14.4 Hz); 5.01 (1H, d, I 14.4 Hz); 5.01 (1H, d, I 14.4 Hz); 6.70-6.81 (2H, m); 7.33-7.45 (1H, m); 7.79 (1H, s); 7.80 (1H, s).

The resulting product was recrystallized from ethyl acetate and a colorless substance was obtained in the form of prismatic crystals, so pl. 145-147 ^about S.

C p and n and m o m e n d s n d and Example 11 To a ethanol (20 ml) containing 28% methanol solution of sodium methoxide was added at 80 ° ^C ethanol solution (20 ml) 2-chloromethylimidazo 1,2-a pyridine hydrochloride (2 g). The resulting mixture was heated under reflux for 2.5 hours. Then the reaction mixture was cooled and dilute hydrochloric acid was added to adjust the pH to 1, after which it was washed three times with toluene (30 ml x 3). After that, an aqueous solution of sodium hydroxide was added to the aqueous layer to adjust the pH to 10, and then was extracted 3 times with methylene chloride (30 ml x 3). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on silica gel (3 cm x 15 cm), eluting with a mixture of ethyl acetate and hexane (2: 1). The target fraction was concentrated under reduced pressure to give 2- (4-methoxybenzylthiomethylimidazo [1,2-a] pyridine (2.5 g) as a colorless oily product.

¹ H-NMR (CDCl ₃ ) δ: 3.73 (2H, s); 3.78 (2H, s); 3.78 (2H, s); 3.79 (3H, s); 6.75 (1H, m); 6.83 (2H, d, I 6.6 Hz); 7.13 (1H, m); 7.25 (2H, d, I 6.6 Hz); 7.46 (1H, s); 7.55 (1H, d, I 9.0 Hz); 8.04 (1H, dd, I = 1.0 Hz, 5.6 Hz).

Silver [II] acetate (3.2 g) was added to a mixture of the obtained product (2.5 g), anisole (20 ml) and trifluoroacetic acid (50 ml), and then stirred at room temperature for 4 hours. After this, the reaction the mixture was concentrated under reduced pressure. Petroleum ether was added to the concentrate. The resulting colorless powder was separated, collected by filtration and washed with diethyl ether. The resulting powder (5 g) was suspended in N, N-dimethylformamide (60 ml). Hydrogen sulfide was blown into the suspension until it turned black. Then the reaction mixture was bubbled with nitrogen gas in order to remove excess hydrogen sulfide, and then filtered. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel (2 cm x 15 cm), eluting with a mixture of methanol and methylene chloride (1: 19). The desired fraction was concentrated under reduced pressure. Methanol and methylene chloride were added to the concentrate, and 2-mercaptomethylimidazo [1,2-a] pyridine (1.3 g) was obtained as colorless needle crystals, m.p. 168-178 ^about S.

¹ H NMR (DMCO-d ₆ ) δ: 3.30 (1H, t, I 8.0 Hz); 4.00 (2H, d, I 8.0 Hz); 7.36 (1H, dt. I 1.8 Hz, 6.6 Hz); 7.75-7.89 (2H, m); 8.16 (1H, s); 8.82 (1H, d, I 7.2 Hz).

EXAMPLE 12 To a suspension of imidazole-2-carboxyaldehyde (2.5 g) in N, N-dimethylformamide (25 ml) was added 60% hydride sodium in oil (1.2 g) at room temperature, the resulting mixture was stirred for 30 minutes To this solution at room temperature was added 2,2,3,3-tetraftoropropil-n-toluenesulfonate (11.2 g) and the mixture was stirred at ¹¹⁰ ° C for 2.5 hours. The mixture was cooled, added water (100 ml) and toluene (30 ml) for extraction. Then the aqueous layer was again extracted with toluene 3 times (30 ml x 3). The toluene layers were combined, washed with saturated aqueous sodium chloride (30 ml) and dried with anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (3.0 cm x 10 cm), eluting with a mixture of ethyl acetate and hexane (1: 1). The target fraction was concentrated to give 1- (2,2,3,3-tetrafluoropropyl) imidazole-2-carboxyaldehyde (2.7 g) as colorless plates with mp. 51-54 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 5.15 (2H, t, I 12.6 Hz); 5.92 (1H, t, t, I 54 Hz, 2.6 Hz); 7.27 (1H, s); 7.38 (1H, s); 9.84 (1H, s).

Elemental analysis for C ₇ H ₆ F ₄ N ₂ O.

 Calculated, C 40.01; H 2.99; N, 13.33.

 Found, C 39.68; H 2.86; N, 13.11.

To a solution of 1- (2,2,3,3-tetraftoropropil) imidazole-2-carboxyaldehyde (1.5 g) in methanol (15 ml) was added sodium borohydride (0,08g g) at ⁰ ° C, the resulting mixture was stirred at ⁰ ° C for 40 min. After this, a saturated aqueous solution of sodium chloride (5 ml) was added to the mixture, and the mixture was again stirred for 50 min, and then extracted with ethyl acetate (30 ml x 4 times). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After adding ethyl acetate and hexane to the residue, 2-hydroxymethyl-1- (2,2,3,3-tetrafluoropropyl) imidazole (1.5 g) was obtained as colorless needle crystals, mp. 91-92 ^about S.

Elemental analysis for C ₇ H ₈ F ₄ N ₂ O.

 Calculated, C 39.63; H 3.80; N, 13.20.

 Found, C 39.79; H 3.78; N, 13.20.

¹ H-NMR (CDCl ₃ ) δ: 4.68 (2H, t, I 12.4 Hz); 4.68 (2H, s); 5.88 (1H, t, t, I 53.2 Hz, 2.6 Hz); 6.93 (1H, s); 6.96 (1H, s).

To thionyl chloride (7 ml) was gradually added 2-hydroxymethyl-1- (2,23,3-tetraftoropropil) imidazole (0.7 g) at 0 ° ^C, and the resulting mixture was heated at reflux for 45 min. The mixture was then concentrated under reduced pressure, diethyl ether was added, and the precipitated crystals were collected by filtration. These crystals were dissolved in ethanol and recrystallized from diethyl ether to give 2-chloromethyl-1- (2,2,3,3-tetrafluoropropyl) imidazole hydrochloride (0.9 g) as colorless needle crystals with mp 104-107 ^about S.

Elemental analysis for C ₇ H ₈ Cl ₂ F ₄ N ₂ .

 Calculated, C 31.48; H 3.02; N, 10.49.

 Found, C, 31.74; H 2.94; N, 10.44.

¹ H-NMR (DMCO-d ₆ ) δ: 5.13 (2H, s); 5.17 (2H, t, I 16.2 Hz); 6.76 (1H, t, t. I 51.8 Hz, 5 Hz); 7.66 (1H, d, I 1.8 Hz); 7.69 (1H, broad s).

C p and n and m o m e n d s n p EXAMPLE 13 A mixture of 1H-1,2,4-triazole (20 g) and paraformaldehyde (9 g) was heated at ¹⁷⁰ ° C for 1, 5 hours, and then another 9 g of paraformaldehyde was added to this mixture. The resulting mixture was heated at 170 ° ^C for 1.5 hours and then distilled under reduced pressure to remove remaining triazole. The residue was cooled and dimethylformamide (150 ml) was added. Then, with ice-cooling, tert-butyl dimethyl chloride (25 g) was added to the mixture, after which the mixture was stirred at room temperature for 1.25 hours. The reaction mixture was concentrated under reduced pressure, aqueous saturated sodium bicarbonate solution (100 ml) was added, and extracted with methylene chloride (30 ml) x 3 times). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on silica gel (5 x 20 cm), eluting with a mixture of ethyl acetate and hexane (3: 1). The target fraction was concentrated to give 3-tert-butyldimethylsiloxymethyl-1n-1,2,4-triazole (15 g) as a colorless oily product.

¹ H-NMR (CDCl ₃ ) δ: 0.13 (6H, s), 0.93 (9H, s); 4.94 (2H, s); 8.03 (1H, s).

A solution of 3-tretbutildimetilsiloksimetil-1H-1,2,4-triazole (8 g) in N, N-dimethylformamide (20 ml) was added dropwise at ⁰ C to a mixture of 60% sodium hydride in oil (1.5 g), methyl iodide (2.8 ml) and N, N-dimethylformamide (80 ml) for 10 minutes. The resulting mixture was stirred for 10 minutes, after which water (300 ml) was added to this mixture and extracted with ethyl acetate (100 ml x 3 times). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on silica gel, eluting first with a mixture of ethyl acetate and hexane (1: 1), and then with ethyl acetate. The desired fractions were concentrated under reduced pressure to give 5-tert-butyldimethylsiloxymethyl-1-methyl-1H-1,2,4-triazole (4.4 g), 3-tert-butyldimethylsiloxymethyl-1-methyl-1H-1,2,4-triazole ( 2.4 g) and 3-tert-butyldimethylsiloxymethyl-4-methyl-4H-1,2,4-triazole (0.5 g).

 5-tert-butyldimethylsiloxymethyl-1-methyl-1H-1,2,4-triazole is a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ: 0.09 (6H, s); 0.90 (9H, s); 3.96 (3H, s); 4.85 (2H, s); 7.79 (1H, s);
3-tert-butyldimethylsiloxymethyl-1-methyl-1H-1,2,4-triazole is a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ: 0.13 (6H, s); 0.93 (9H, s); 3.90 (3H, s); 4.77 (2H, s); 7.97 (1H, s).

 2-tert-butyldimethylsiloxymethyl-4-methyl-4H-1,2,4-triazole colorless needle crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.09 (6H, s); 0.89 (9H, s); 3.76 (3H, s); 4.90 (2H, s); 8.08 (1H, s).

Mp (crystallized from diethyl ether) 94-95 ^about C.

 A mixture of 5-tert-butyldimethylsiloxymethyl-1-methyl-1H-1,2,4-triazole (3 g), ethanol (20 ml), 5N aqueous sodium hydroxide solution (4 ml) and methanol (30 ml) was stirred for 24 hours at room temperature. Then the reaction mixture was concentrated under reduced pressure, and the concentrate was chromatographed on silica gel (3.0 x 15 cm), eluting with a mixture of methanol and methylene chloride (1: 9). The target fraction was concentrated under reduced pressure, whereby 5-hydroxymethyl-1-methyl-1H-1,2,4-triazole (1.2 g) was obtained as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s); 4.76 (2H, br s), 5.33 (1H, br s), 7.78 (1 H, s).

To thionyl chloride (8 mL) slowly at ⁰ ° C was added 5-hydroxymethyl-1-methyl-1H-1,2,4-triazole (0.8 g) and the mixture was heated under reflux for 3 hours. The reaction the mixture was concentrated under reduced pressure. Diethyl ether was added to the concentrate and the resulting product in powder form was collected by filtration. This product was then dissolved in ethanol, diethyl ether was added to crystallize, and 5-chloro-1-methyl-1H-1,2,4-triazole hydrochloride (1.1 g) was obtained as colorless crystalline plates with mp. 77-78 ^about S.

Elemental analysis for C ₄ H ₇ Cl ₂ N ₃ x x 1 / 2H ₂ O.

 Calculated, C 27.14; H 4.55; N, 23.74.

 Found, C, 27.60; H 3.98; N, 23.66.

¹ H-NMR (DMCO-d ₆ ) δ: 3.92 (3H, s); 5.01 (2H, s); 8.01 (1H, s).

A mixture of 3-tert-butyldimethylsiloxymethyl-1-methyl-1H-1,2,4-triazole (2 g), ethanol (10 ml), methanol (20 ml) and a 5N aqueous sodium hydroxide solution (2.6 ml) was stirred at room temperature for 27 hours, and then stirred an additional 21 hours at 45 ^C. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (2 x 10 cm), eluting with a mixture of methanol and methylene chloride (1: 9). The target fraction was concentrated under reduced pressure to give 3-hydroxymethyl-1-methyl-1H-1,2,4-triazole (1 g) as colorless needle crystals.

¹ H-NMR (CDCl ₃ ) δ: 3.91 (3H, s); 4.75 (2H, d, I 4.6 Hz); 4.06 (1H, br s), 8.02 (1H, s).

Mp 72-75 ^about S.

To thionyl chloride (8 mL) slowly at ⁰ ° C was added 3-hydroxy-1-methyl-1H-1,2,4-triazole (0.6 g) and the resulting mixture was heated at reflux for 3 hours. The reaction the mixture was concentrated under reduced pressure, after which diethyl ether was added to the mixture. The resulting powder was crystallized from a mixture of ethanol and diethyl ether and 3-chloromethyl-1-methyl-1H-1,2,4-triazole hydrochloride (1 g) was obtained as colorless needle crystals with mp. 69-70 ^about S.

Elemental analysis for C ₄ H ₇ Cl ₂ N ₃ .

 Calculated, C 28.59; H 4.20; N, 25.01.

 Found, C 28.16; H 4.08; N, 24.51.

¹ H NMR (DMCO-d ₆ ) δ: 3.87 (3H, s); 4.72 (2H, s); 8.57 (1H, s).

 A mixture of 3-tert-butyldimethylsiloxymethyl-4-methyl-4H-1,2,4-triazole (0.4 g), ethanol (12 ml) and 5N. hydroxides (0.53 ml) were stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the resulting concentrate was chromatographed on silica gel (2 x 10 cm), eluting with a mixture of methanol and methylene chloride (1: 4). The target fraction was concentrated under reduced pressure to obtain 3-hydroxymethyl-4-methyl-4H-1,2,4-triazole (0.2 g) as a colorless solid.

¹ H-NMR (DMCO-d ₆ ) δ: 3.66 (3H, s); 4.59 (2H, d, I 5.6 Hz); 5.52 (1H, t, I 5.6 Hz), 8.40 (1H, s).

To thionyl chloride (2 ml) was added (at ⁰ ° C) of 3-hydroxymethyl-4-methyl-4-1,2,4-triazole (0.15 g) and the resulting mixture was heated to reflux for 1.5 h. Then the mixture was concentrated under reduced pressure, after which diethyl ether was added. The obtained crystals were collected by filtration and dissolved in ethanol, and then diethyl ether was added to this solution to recrystallize, whereby 3-chloromethyl-4-methyl-4H-1,2,4-triazole hydrochloride (0.22 g) was obtained in the form of colorless prismatic crystals with so pl. 96-97 ^about S.

Elemental analysis for C ₄ H ₇ Cl ₂ N ₃ .

 Calculated, C 28.59; H 4.20; N, 25.01.

 Found, C, 28.70; H 4.18; N, 24.91.

¹ H-NMR (DMCO-d ₆ ) δ: 3.81 (3H, s); 5.11 (2H, s); 9.26 (1H, s).

Example 14. 3-Hydroxymethyl-5-mercapto-4-methyl-4H-1, 2,4-triazole (1.5 g) was added at ⁰ ° C for 1 hour to a mixture of concentrated nitric acid (d 1.38, 2.3 ml), water (6 ml) and sodium nitrite (0.005 g). The reaction mixture was warmed to room temperature, after which it was kept at this temperature for 1 h, and then an aqueous solution of sodium hydroxide was added in order to bring the pH to 8. Water was distilled off under reduced pressure, and the residue was chromatographed (2.5 cm x 10 cm ), eluting with a mixture of methanol and methylene chloride (1: 4). The target fraction was concentrated, and the concentrate was recrystallized from ethyl acetate, whereby 3-hydroxy-4-methyl-4H-1,2,4-triazole (1.1 g) was obtained as colorless needle crystals.

¹ H-NMR (DMCO-d ₆ ) δ: 3.66 (3H, s); 4.59 (2H, g, I 5.6 Hz); 5.52 (1H, t, I 5.6 Hz); 8.40 (1H, s).

Mp 81-82 ^about S.

EXAMPLE 15 A mixture of 6,7-dihydro-5H-pyrrolo [1,2-c] imidazole (7 g) and paraformaldehyde (4 g) was heated at 160 ^C, then after 20 min was added paraformaldehyde (2 g), and after 20 minutes, 1 g of paraformaldehyde was added and the resulting mixture was heated for 45 min. Then the reaction mixture was chromatographed (4 x 15 cm) on silica gel, eluting with a mixture of methanol and methylene chloride (1: 9). The desired fraction was concentrated. Ethanol and diethyl ether were added to the concentrate, and 6,7-dihydro-3-hydroxymethyl-5H-pyrrolo [1,2-c] imidazole (3.4 g) was obtained as colorless needle crystals with mp 110-120 ^about C.

Elemental analysis for C ₇ H ₁₀ N ₂ O.

 Calculated, C 60.85; H, 7.29; N, 20.27.

 Found, C, 61.08; H, 7.30; N, 20.27.

¹ H-NMR (CDCl ₃ ) δ: 2.5-2.7 (2H, m); 2.81 (2H, t, I 7.4 Hz); 4.01 (2H, t, I 7.0 Hz); 4.56 (2H, s); 6.2 (1H, broad s); 6.54 (1H, s).

By tienilhloridu (0.8 ml) at ⁰ ° C was gradually added 6,7-dihydro-3-hydroxymethyl-5-pyrrolo [1,2-c) imidazole (0.8 g) and the resulting mixture was heated under reflux for 40 min, after which thionyl chloride was distilled off under reduced pressure. Diethyl ether was added to the residue, and the resulting solid was collected by filtration. Then this substance was dissolved in ethanol, and after diethyl ether was added, 3-chloromethyl-6,7-dihydro-5H-pyrrolo [1,2-c] imidazole hydrochloride (0.7 g) was obtained in the form of needle-shaped crystals of pale yellow color, t .pl. 120-140 ^about C.

Elemental analysis for C ₇ H ₁₀ Cl ₂ N ₂ .

 Calculated, C 43.55; H 5.22; N, 14.51.

 Found, C, 43.74; H, 5.21; N, 14.31.

¹ H-NMR (DMCO-d ₆ ) δ: 2.5-2.7 (2H, m); 2.96 (2H, t, I 6.8 Hz); 4.28 (2H, t, I 7.0 Hz); 5.16 (2H, s); 7.43 (1H, s).

EXAMPLE 16 A mixture of 2-acetoxythioacetamide (10 g), 2-chlorocyclopentanone (10.6 g) and dimethylformamide (100 ml) was stirred for 24 hours at ⁸⁰ ° C, then the reaction mixture was cooled and poured into ice water (500 ml) and then extracted twice with ethyl acetate (200 mL). The extract was washed twice with water (100 ml) and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (2.5 x 50 cm), eluting with a mixture of ethyl acetate and hexane (3: 7). The target fraction was concentrated to give 2-acetoxymethyl-5,6-dihydro-4H-cyclopenta-thiazole (5 g) as a yellow oily product.

To the resulting product (5 g) was added 5N. sodium hydroxide (10 ml), the mixture was stirred at 80 ^about C for 2 hours. Then the reaction mixture was cooled, neutralized with 2N. hydrochloric acid and was extracted with ethyl acetate (200 ml). The extract was washed with water (50 ml) and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (2.5 x 30 cm), eluting with a mixture of acetate and dichloromethane (3: 2). The target fraction was concentrated to give 2-hydroxymethyl-5,6-dihydro-4H-cyclopentathiazole (3.5 g) as a yellow oily product.

¹ H-NMR (CDCl ₃ ) δ: 2.40-2.59 (4H, m); 2.74-2.99 (4H, m); 3.49 (1H, broad s); 4.85 (2H, s).

 The resulting product (0.17 g) was dissolved in methylene chloride (4 ml); thionyl chloride (1.52 ml) was added dropwise to the resulting solution, after which the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain 2-chloromethyl-5,6-dihydro-4H-cyclopentathiazole hydrochloride (0.22 g) as a reddish oily product.

Example 17: To a mixture of m-difluorobenzene (75 ml) and anhydrous aluminum chloride (115 g) was added dropwise, while stirring, for 50 min 2-bromopropionyl chloride (100 g). The mixture was then stirred in an oil bath at 50-55 ^{° C} for 2 hours. The reaction mixture was cooled and methylene chloride (500 mL). Next, the resulting solution was mixed with it, was added in limited quantities in ice water (1.5 l). Then, the methylene chloride layer was separated, and the aqueous layer was extracted twice with methylene chloride (100 ml). After that, the methylene chloride layers were combined and washed with 500 ml of water, and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-bromo-2 ′, 4′-difluoropropiophenone (142.5 g) as a yellow oily product.

¹ H-NMR (CDCl ₃ ) δ: 1.90 (3H); 5.25 (1H); 6.85-7.06 (2H); 7.93-8.05 (1H).

Example 18: To a mixture of m-difluorobenzene (100 ml) and anhydrous aluminum chloride (114 g) was added dropwise over 45 minutes, and stirred at this, propionyl chloride (66 ml). The mixture was then stirred on an oil bath at 50-55 ^{° C} for 2 hours. The reaction mixture was cooled and added to it methylene chloride (300 mL). The resulting solution was added in portions to ice water (1 L) while stirring. Then the methylene chloride layers were combined, washed with water (200 ml) and dried with anhydrous magnesium sulfate. The solvent was distilled off to obtain 2 ', 4'-difluoropropiophenone (111.4 g) as a yellow oily product.

¹ H-NMR (CDCl ₃ ) δ: 1.17-1.24 (3H); 2.92-3.05 (2H); 6.82-7.02 (2H); 7.89-8.03 (1H).

 EXAMPLE 19: 2 ', 4'-difluoropropiophenone (55 g) was dissolved in methylene chloride (300 ml), and then dropwise over 30 minutes at while stirring, bromine (50 g) was added. The mixture was stirred at room temperature for 30 minutes. Then, water (200 ml) was added to this reaction mixture, and the methylene chloride layer was washed 3 times and dried with anhydrous magnesium sulfate. The solvent was distilled off, and 2-bromo-2 ′, 4′-difluoropropiophenone (77 g) was obtained as a pale yellow oily product.

Comparison Example 20. 2-Bromo-2 ', 4'-difluoropropiophenone (141 g) was dissolved in methanol (1100 g), the sodium format was added to the solution ( 176.2 g) and the resulting mixture was stirred at 50 ^about C for 2 days. Then methanol was distilled off under reduced pressure. The residue was extracted by adding ethyl acetate (700 ml) and water (500 ml). The ethyl acetate layer was dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane (200 ml) to give 2 ', 4'-difluoro-2-hydroxypropiophenone (50.5 g) as colorless prismate crystals with mp 49-51 ^about S.

NMR (CDCl ₃ ) δ: 1.40, 1.41 (3H, d x 2, I 7 Hz); 3.74 (1H, d, I 6.2 Hz); 4.96-5.11 (1H, m); 6.87-7.27 (2H, m); 7.69-8.09 (1H, m).

 Example 21. 2 ', 4'-Difluoro-2-hydroxypropiophenone (61 g) was dissolved in methylene chloride (500 ml), and then added, cooling with ice , n-toluenesulfonic acid hydrate (1 g). To the resulting mixture, 3,4-dihydro-2H-pyran (41.4 g) was added under ice cooling and stirring for 10 minutes. The mixture was stirred under ice-cooling for 1 h, and then 5% aqueous sodium bicarbonate solution (240 ml) was added to this mixture. The mixture was stirred for 10 minutes while cooling with ice. The methylene chloride layer was separated and dried with anhydrous magnesium sulfate, and the solvent was distilled off. The residual oily product was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (5: 1), to give 2 ', 4'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2 -yloxy) propiophenone (86.5 g) as a yellow oily product.

 Comparison Example 22. To dimethyl sulfoxide (650 ml) was added at room temperature in portions over 10 minutes, 60% sodium hydrate in oil (15.2 g). The mixture was stirred at room temperature for 10 minutes, and then trimethylsulfoxonium iodide (83.7 g) was added in portions over the course of 1 hour. To the resulting mixture, a solution of 2 ', 4'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone (86.5 g) in dimethyl sulfoxide ( 150 ml). The mixture was stirred for 3 hours at room temperature, and then the reaction mixture was poured into ice water (1.5 L) and extracted 5 times with ethyl acetate (300 ml). The ethyl acetate layer was washed 4 times with water (300 ml), and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2- [1- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) ethyl] -2- (2,4-difluorophenyl) oxirane (83.4 g) in the form of an oily yellow product.

Example 23. To N, N-dimethylformamide (700 ml) at room temperature and stirring for 10 minutes, 60% sodium hydride in oil was added in portions. (35.2 g). The mixture was stirred for 5 minutes at room temperature, and then 1H-1,2,4-triazole (25 g) was added portionwise over 20 minutes at room temperature. The reaction mixture was ice-cooled, and 1N-1,2,4-triazole (44.6 g) was added to the mixture over 30 minutes, after which the mixture was stirred at room temperature for another 10 minutes. To the resulting mixture, 2- [1- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) ethyl] -2- (2,4-difluorophenyl) oxirane (83, 4 g) and the mixture was stirred at ⁹⁰ ° C for 4 hours. The reaction mixture was cooled, poured into ice water (1.5 l) and extracted with ethyl acetate (500 mL) 4 times. The ethyl acetate layer was washed 3 times with water (300 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain a light yellow oily product. This product was purified by silica gel column chromatography, eluting with a mixture of hexane and acetone (4: 1 - >> 1: 1). The resulting oily product was crystallized from hexane to give 2- (2,4-difluorophenyl) -3- (3,4,5,6-tetrahydro-2H-pyran-2-yl) oxy-1- (1H-1,2, 4-triazol-1-yl) -2-butanol (51.4 g) as a colorless powder with a melting point of 93-95 ^about S.

Elemental analysis for C ₁₇ H ₂₁ F ₂ N ₃ O ₃ .

 Calculated, C 57.78; H 5.99; N, 11.89.

 Found, C 57.82; H, 6.04; N, 11.77.

Example 24. 2- (2,4-Difluorophenyl) -3- (3,4,5,6-tetrahydro) was dissolved in ethanol (500 ml) -2H-pyran-2-yl) oxy-1- (1H-1,2,4-triazol-1-yl) -2-butanol (51.4 g), then pyridinium n-toluenesulfonate was added to the resulting solution (13 , 2 g) and the mixture was stirred ^at 55 ° C for 6 hours. Thereafter, the resultant mixture was further added 2 g of n-toluenesulfonate, and the mixture was stirred ^at 55 ° C for 1.5 hours. The mixture was then cooled and the solvent was distilled off under reduced pressure. Ethyl acetate (900 ml) was added to the residue, and the mixture was washed 3 times with water (50 ml). The ethyl acetate layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off. Ethyl acetate (50 ml) and ethyl ether (100 ml) were added to the residue. Precipitated crystals were collected by filtration to obtain a pure compound (99% purity): (2RS, 3RS) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) - 2,3-butanediol (29 g) as diastereomer, mp. 154-156 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, d, I 6.2 Hz); 4.26-4.39 (1H, m); 4.82 (2H, s); 6.71-6.83 (2H, m); 7.35-7.51 (1H, m); 7.84 (1H, s); 7.87 (1H, s).

Elemental analysis for C ₁₂ H ₁₃ F ₂ N ₃ O ₂ .

 Calculated, C 53.53; H 4.87; N, 15.61.

 Found, C, 53.35; H 4.90; N, 15.49.

Example 25. (2RS, 3RS) -2- (2,4-difluorophenyl) was dissolved in a mixture of ethyl acetate (200 ml) and methylene chloride (50 ml). -1- (1H-1,2,4-triazol-1-yl) -2, 3-butanediol (11 g), triethylamine (6.21 ml) was added to the resulting mixture under ice-cooling. Methanesulfonyl chloride (3.46 ml) was added dropwise to this mixture over 3 minutes while stirring and cooling with ice, and then stirred at room temperature for 45 minutes. Water (100 ml) was added to the reaction mixture, then the organic layer was separated, washed with water and dried with anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure to obtain (2RS, 3RS) -2- (2,4-difluorophenyl) -3- methanesulfonyloxy-1- (1H-1,2,4-triazol-1-yl) -2-butanol as an oily product. The product was then dissolved in methanol (200 ml), and a 28% methanol solution of sodium methylate (8.84 g) was added to the solution under ice cooling, after which the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. Ethyl acetate (200 ml) and water (100 ml) were added to the residue for extraction. The ethyl acetate layer was washed with water and dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and methylene chloride (4: 1), and after crystallization from hexane (2RS, 3RS) -2- (2,4-difluorophenyl) -3-methyl-2- (1H- 1,2,4-triazol-1-yl) methyloxyran (8.3 g) as a single diastereomer of colorless crystals, mp. 66-68 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.65 (3H, d, I 5.6 Hz); 3.20 (1H, q, I 5.6 Hz); 4.42 (1H, d, I 14.6 Hz); 4.89 (1H, d, I 14.6 Hz); 6.68-6.83 (2H, m); 6.93-7.08 (1H, m); 7.82 (1H, s); 7.97 (1H, s).

Elemental analysis for C ₁₂ H ₁₁ F ₂ N ₃ O.

 Calculated, C 57.37g; H 4.41; N, 16.73.

 Found, C 57.31. H 4.44; N, 16.62.

 Example 26. In dichloromethane (200 ml) was dissolved (S) - (-) - ethyl lactate (35.4 g), to the solution, cooling with ice, n-toluenesulfonic acid hydrate (570 mg) was added. Then, 3,4-dihydro-2H-pyran (30.2 g) was added dropwise to the mixture over 30 minutes, and the resulting mixture was stirred under ice cooling for 1 h. A 5% aqueous solution of sodium bicarbonate was added to the reaction mixture ( 50 ml), stirring vigorously, after which the organic layer was separated. Then, the organic layer was washed with a 5% aqueous sodium bicarbonate solution and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure to obtain ethyl (2S) -2- (3,4,5,6-tetrahydro-2H-pyran-2 yloxy) propionate (61 g) as a yellow oily product.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, I 7.0 Hz); 1.40-1.46 (3H, d, I 6.8 Hz); 1.40-2.00 (6H, m); 3.40-3.60 (2H, m); 3.80-4.00 (2H, m); 4.10-4.44 (3H, m); 4.68-4.76 (1H, m).

Comparative Example 27. Ethyl (2S) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionate was dissolved in ethanol (450 ml), and 2N was added to the solution under ice cooling. sodium hydroxide solution (150 ml) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was cooled with ice, and then added to this mixture at 27 ^{° C} aqueous solution of acetic acid (100 ml) and extracted 3 times with dichloromethane (200 ml ) The dichloromethane layers were combined, washed twice with saturated solution and brine (100 ml), and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain (2S) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionic acid (29.5 g) as a colorless waxy product.

 Anhydrous tetrahydrofuran (250 ml) was added to (2S) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionic acid (29.5 g). While stirring at room temperature, 1,1-carbonyl-diimidazole (33.1 g) was added to the mixture over 10 minutes. The resulting mixture was stirred at room temperature for 30 minutes, cooled with ice, and then morpholine (34.8 g) was added dropwise over 15 minutes. The resulting mixture was stirred for 15 minutes in an ice bath, and then concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (300 ml), washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (1: 4), and N - [(2S) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy] propionyl was obtained morpholine (17.5 g).

¹ H-NMR (CDCl ₃ ) δ: 1.39-1.44 (3H, d, I 6.8 Hz); 1.45-1.96 (6H, m); 3.40-3.95 (10H, m); 4.52, 4.68 (1H, qI, 6.8 Hz); 4.60 (1H, m).

IR (film): 2945, 2855, 1662, 1650, 1460, 1435, 1370, 1270, 1230, 1110, 1020, 980 cm ^-1 .

Example 28. 1-bromo-2,4-difluorobenzene (7.72 g) was dissolved in anhydrous tetrahydrofuran (40 ml). Magnesium (flakes, 972 mg) and a very small amount of iodine were added to the solution at room temperature, then the mixture was stirred vigorously for approximately 2 hours, resulting in a 1M solution of 2,4-difluorophenyl magnesium bromide. A portion of 9.5 ml was taken from this solution, 9.5 ml of anhydrous tetrahydrofuran was diluted in it, and then this solution was added dropwise to an anhydrous solution of tetrahydrofuran (25 ml) and N - [(2S) -2- (3.4 , 5-tetrahydro-2H-pyran-2-yloxy) propionyl] morpholine (2.26 g) for 25 min at a temperature of (-30) (-20) ^о С. Upon completion of the addition, the temperature of the mixture was raised to 20 ^о С in for 1 h. The mixture was stirred at ²⁰ ° C for an additional 2 hours. The reaction mixture was cooled with ice and to this mixture was added a saturated aqueous ammonium chloride solution (20 ml) followed eq tragirovaniem ethyl acetate (100 mL). The extract was dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (10: 1), to give (2S) -2 ', 4'-difluoro-2- (3,4,5,6-tetrahydro-2H- pyran-2-yloxy) propiophenone (1.02 g) as a pale yellow oily product.

IR (film): 3075, 2950, 2875, 1695, 1605, 1500, 1422, 1370, 1265, 1230, 1132, 1090, 1030, 970, 848 cm ^-1 .

 The optical purity of this compound was determined as follows.

(2S) -2 ', 4'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone (95 mg) was dissolved in ethanol (3 ml), and to the resulting solution was added n-pyridinium toluenesulfonate (21 mg), and the mixture was stirred at 55 ^{° C} for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL) and dried over anhydrous magnesium sulfate, after which the solvent was distilled off. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (5: 1), whereby (2S) -2 ', 4'-difluoro-2-hydroxypropiophenone (40 mg) was obtained as a pale yellow oily product .

0,46 см х 25 см, изготовлена Daicel Chemical Industries, Ltd]
Избыток энантиомера составлял 98,4%
¹Н-ЯМР (CDCl₃) δ: 1,41 (3Н, дд, I 7,0 Гц); I 1,6 Гц); 3,74 (1Н, д); 5,01 (1Н, м); 6,86-7,08 (2Н, м); 7,96-8,08 (1Н, м).The resulting product was analyzed by high resolution liquid chromatography (mobile phase: hexane, 9: 1 isopropyl alcohol) using an optical isomer separation column (CHIRALCEL

0.46 cm x 25 cm manufactured by Daicel Chemical Industries, Ltd]
The excess enantiomer was 98.4%
¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, dd, I = 7.0 Hz); I 1.6 Hz); 3.74 (1H, d); 5.01 (1H, m); 6.86-7.08 (2H, m); 7.96-8.08 (1H, m).

IR (film): 3450, 1690, 1612, 1500, 1430, 1270, 1145, 1100, 1030, 980, 858 cm ^-1 .

EXAMPLE 29. To dimethyl sulfoxide (5 ml) was added 60% sodium hydride in oil (85 mg), followed by trimethyl sulfoxonium iodide (0.49 g ) with stirring at ¹⁵ ° C, the mixture was stirred for another 15 minutes at room temperature. The reaction mixture was ice-cooled and dimethyl sulfoxide solution [1.2 ml] (2S) -2 ', 4'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionphenone ( 0.5 g), after which the resulting mixture was stirred at room temperature for 2 hours. Then, water (10 ml) and ethyl acetate (50 ml) were added to the reaction mixture, and the resulting mixture was shaken. The organic layer was washed with a saturated aqueous solution of sodium chloride 2 times (10 ml), dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: 10: 1 mixture of hexane and ethyl acetate), whereby 2 - [(1S) -1- (3,4,5,6-tetrahydro- 2H-pyran-2-yloxy) ethyl] -2- (2, 4-difluorophenyl) oxirane (0.4 g) as a pale yellow oily product.

¹ H-NMR (CDCl ₃ ) δ: 1.10-1.26 (3H, m); 1.40-1.95 (6H, m); 2.83 (1H, m); 3.05, 3.32 (1H, d, I 5.2 Hz); 3.42-3.59 (1H, m); 3.76-4.12 (2H, m); 4.74-4.96 (1H, m); 6.72-6.95 (2H, m); 7.32-7.60 (1H, m).

Comparison Example 30. 60% sodium hydride in oil (0.23 g) was dispersed in dimethylformamide (5 ml), and this dispersion was added while cooling at this ice, triazole (0.59 g), after which the mixture was stirred for 15 minutes. To the resulting mixture was added a dimethylformamide solution (1 ml) 2 - [(1S) -1- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) ethyl] -2- (2,4-difluorophenyl) oxirane (0.4 g) and heated at ⁸⁰ ° C for 3 hours. The reaction mixture was cooled and cold water (1 ml) and ethyl acetate (50 ml) then the mixture was shaken. The aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with a saturated solution of aqueous sodium chloride and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of dichloromethane, ethyl acetate and acetone (6: 1: 1). The resulting waxy product was reprecipitated twice from ethyl acetate and hexane, whereby (3S) -2- (2,4-difluorophenyl) -3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) - 1- (1H-1,2 4-t-2-butanol (0.22 g) as a colorless waxy product.

¹ H-NMR (CDCl ₃ ) δ: 0.99, 1.12 (3H, d, I 6.4 Hz); 1.40-2.00 (6H, m); 3.40-3.65 (1H, m); 3.80-4.06 (1H, m); 4.25-4.45 (1H, m); 4.31 (1H, s); 4.63 (1H, d, I 14.2 Hz); 4.71 (1H, m); 4.90 (1H, d, I 14.2 Hz); 6.65-6.85 (2H, m); 7.35-7.50 (1H, m); 7.72, 7.73 (1H, s); 7.93, 7.96 (1H, s).

EXAMPLE 31. In ethanol (4 ml), (3S) -2- (2,4-difluorophenyl) -3- (3,4,5) was dissolved , 6-tetrahydro-2H-pyran-2-yl) oxy-1- (1H-1,2,4-triazol-1-yl) -2-butanol (0.22 g) and pyridinium n-toluenesulfonate (47 mg ) and the resulting solution was stirred at 55 ^{° C} for 2 hours. Then, to the solution was added an additional 10 mg of n-toluenesulfonate and the resulting solution was stirred ^at 55 ° C for another 2 hours. The reaction mixture was cooled and the solvent was distilled off. Ethyl acetate (30 ml) was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium chloride (10 ml). The ethyl acetate layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue, and the precipitated crystals were collected by filtration, whereby (2S, 3S) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) - 2,3-butanediol (60 mg), mp 115-117 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, d, I 6.4 Hz); 4.32 (1H, m); 4.82 (2H, s); 6.69-6.82 (2H, m); 7.35-7.48 (1H, m); 7.83 (1H, s); 7.84 (1H, s).

Example 32. In a mixture of ethyl acetate (2 ml) and dichloromethane (0.5 ml), (2S, 3S) -2- (2,4- difluorophenyl-1- (1H-1,2,4-triazol-1-yl) -2,3-butanediol (58 g). To the resulting solution, triethylamine (66 ml) and methanesulfonyl chloride (37 ml) were added while cooling with ice. The mixture was stirred at room temperature for 2 hours, then ethyl acetate (30 ml) was added to this reaction mixture, the resulting mixture was washed with water, dried with anhydrous magnesium sulfate and concentrated to give (2S, 3S) -2- (2 , 4-difluorophenyl) -3-methanesulfonyloxy-1- (1H- 1,2,4-triazol-1-yl) -2-butanol as an oily product This product was dissolved in methanol (2 ml), after which 28% sodium methylate (116 ml) was added under ice-cooling, and the resulting mixture stirred at room temperature for 30 minutes, then dichloromethane (30 ml) was added to the reaction mixture, the resulting mixture was washed with water and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and dichloromethane (4: 1), whereby (2S, 3S) -2- (2,4-difluorophenyl) -3-methyl-2- ( 1H-1,2,4-triazol-1-yl) methyloxyran (42 ml) as colorless needle crystals, mp. 89-90 ^about S.

[α] _D ²³ 7.8 ^about (with 1.0 in Meon).

¹ H-NMR (CDCl ₃ ) δ: 1.65 (3H, d, I 5.6 Hz); 3.20 (1H, qI, 5.5 Hz); 4.43 (1H, d, I 14.6 Hz); 4.88 (1H, d, I 14.6 Hz); 6.68-6.83 (2H, m); 6.93-7.08 (1H, m); 7.82 (1H, s); 7.96 (1H, s).

Elemental analysis for C ₁₂ H ₁₁ F ₂ N ₃ O.

 Calculated, C 57.37; H 4.41; N, 16.73.

 Found, C 56.98; H 4.40; N, 16.53.

0,46 см х 25 см, изготовлена Daicel Chemical Industries, Ltd. Избыток энантиомера составлял 97,9%
С р а в н и т е л ь н ы й п р и м е р 33. Метил (R)-(+)-лактат (25 г) растворяли в дихлорoметане (250 мл), к раствору при охлаждении льдом добавляли гидрат n-толуол- сульфоновой кислоты (456 мг). Затем к смеси по каплям в течение 30 мин добавляли 3,4-дигидро-2Н-пиран (24,2 г) и полученную смесь перемешивали при охлаждении льдом в течение 1 ч. После этого к реакционной смеси добавляли 5%-ный водный раствор бикарбоната натрия (50 мл), смесь энергично перемешивали с последующим отделением органического слоя. Органический слой промывали 5%-ным водным раствором бикарбоната натрия, высушивали безводным сульфатом магния с последующей отгонкой растворителя при пониженном давлении и получали метил (2R)-2-(3,4,5,6-тетрагидро-2Н-пиран-2-илокси)пропионат (42,7 г) в виде маслянистого продукта желтого цвета.The resulting product was analyzed by high resolution liquid chromatography (mobile phase: hexane isopropanol 9: 1) using a column for the separation of optical isomers [CHIRALCEL

0.46 cm x 25 cm manufactured by Daicel Chemical Industries, Ltd. The excess enantiomer was 97.9%
EXAMPLE 33. Methyl (R) - (+) - lactate (25 g) was dissolved in dichloromethane (250 ml), hydrate was added to the solution under ice cooling n-toluenesulfonic acid (456 mg). Then, 3,4-dihydro-2H-pyran (24.2 g) was added dropwise to the mixture over 30 minutes, and the resulting mixture was stirred under ice cooling for 1 hour. After that, a 5% aqueous bicarbonate solution was added to the reaction mixture. sodium (50 ml), the mixture was vigorously stirred, followed by separation of the organic layer. The organic layer was washed with a 5% aqueous sodium bicarbonate solution, dried with anhydrous magnesium sulfate, followed by distillation of the solvent under reduced pressure, and methyl (2R) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) was obtained ) propionate (42.7 g) as a yellow oily product.

 EXAMPLE 34. Methyl (2R) -2- (3,4,5,6-tetrahydro-2H-pyran-) was dissolved in ethanol (510 ml) 2-yloxy) propionate (42.7 g), sodium hydroxide solution (170 ml) was added to the resulting solution, cooling with ice, after which the mixture was stirred at room temperature for 1 h. Then the reaction mixture was cooled with ice, 26 was added to it aqueous solution of acetic acid (120 ml) and extracted 3 times with dichloromethane (200 ml). The dichloromethane layers were combined, washed with a saturated aqueous solution of sodium chloride (100 ml) 2 times and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, whereby (2R) -2- (3,4,5,6-tetrahydro- 2H-pyran-2-yloxy) propionic acid (32 g) as a colorless waxy product.

 Anhydrous tetrahydrofuran (250 ml) was added to (2R) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionic acid (32 g). Then 1,1'-carbonyl-diimidazole (35.8 g) was added portionwise to the mixture over 10 minutes. The resulting mixture was stirred at room temperature for 30 minutes, and then, after cooling with ice, morpholine (38.3 g) was added dropwise to it over 15 minutes, after which the mixture was stirred in an ice bath for another 15 minutes. The reaction mixture was then concentrated under reduced pressure, and the concentrate was dissolved in dichloromethane (300 ml). The solution was washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (1: 4), whereby N - [(2R) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) was obtained ) propionyl] morpholine (25.7 g).

¹ H-NMR (CDCl ₃ ) δ: 1.39 (1.44, 3H, d, I 6.8 Hz); 1.45-1.96 (6H, m); 3.40-3.95 (10H, m); 4.52, 4.68 (1H, q, I 6.8 Hz); 4.59-4.65 (1H, m).

IR (film): 2945, 2855, 1662, 1650, 1462, 1438, 1370, 1270, 1230, 1112, 1030, 980 cm ^-1 .

Comparison Example 35. 1-Bromo-2,4-difluorobenzene (9.69 g) was dissolved in anhydrous tetrahydrofuran (50 ml). Then, magnesium (1.22 g) and a small amount of iodine were added to the solution at room temperature, after which the resulting mixture was vigorously stirred for 2 hours to obtain a 1M solution of 2,4-difluorophenyl magnesium bromide. This solution was diluted with 50 ml of anhydrous tetrahydrofuran and added to anhydrous tetrahydrofuran solution (125 ml) of N - [(2R) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionyl] morpholine (12 , 7 g) at (-30) - (- 20) ^C for 45 min. After the addition, the temperature of the mixture was raised ^to 20 ° C for 1 h. The mixture was stirred at this temperature for 1 hour. The reaction mixture was cooled with ice and added to a saturated aqueous solution of ammonium chloride (40 mL) followed by extraction with ethyl acetate (300 ml ) The extract was dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (10; 1), to give (2R) -2 ', 4'-difluoro-2- (3,4,5,6-tetrahydro-2H- pyran-2-yloxy) propiophenone (5.03 g) as a pale yellow oily product.

IR (film): 3075, 2950, 2875, 1695, 1605, 1500, 1422, 1370, 1266, 1235, 1138, 1090, 1030, 970, 850 cm ^-1 .

 The optical purity of this compound was determined as follows.

In ethanol (3 ml), (2R) -2 ', 4'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone (121 mg) was dissolved and to the resulting solution was added n-pyridinium toluenesulfonate (25 mg), and the mixture was stirred at 55 ^{° C} for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water and dried with anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dried by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (5: 1), whereby (2R) -2 ', 4'-difluoro-2-hydroxypropiophenone (62 mg) was obtained as a pale yellow oily product .

 [d] + 68.7 (from 1.8 in chloroform).

This product was analyzed by high performance liquid chromatography (mobile phase: hexane isopropanol 9: 1) using a column for the separation of optical isomers [CHIRALCEL 0.46 cm x 25 cm, manufactured by Daicel Chemical Industries, Ltd]
An enantiomer with a (2R) configuration was not found.

¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, d, I 7.0 Hz, I 1.6 Hz); 3.74 (1H, d, I 7.0 Hz); 5.01 (1H, m); 6.86-7.08 (2H, m); 7.96-8.08 (1H, m).

IR (film): 3450, 1690, 1610, 1500, 1430, 1268, 1140, 1095, 1030, 980, 855 cm ^-1 .

Comparative Example 36. To dimethyl sulfoxide (50 ml) was added 60% sodium hydride (0.833 g) in mineral oil. The resulting mixture was stirring at ¹⁵ ° C, was added trimetilsulfoksoniyiodid (4.80 g), and the mixture was stirred at room temperature for 15 min. The reaction mixture was ice-cooled and a solution of 10 ml of (2R) -2 ', 4'-difluoro-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone (4.90 g) was added to it. ) The resulting mixture was stirred at room temperature for 2 hours. Then the reaction mixture was poured into ice water (120 ml) and extracted with ethyl acetate (150, 100, 100 ml). The ethyl acetate layers were combined and washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml), and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (10: 1), to give 2 - [(1R) -1- (3,4,5,6-tetrahydro- 2H-pyran-2-yloxy) ethyl] -2- (2,4-difluorophenyl) - oxirane (4.7 g) as a pale yellow oily product.

¹ H-NMR (CDCl ₃ ) δ: 1.10-1.30 (3H, m); 1.40-1.95 (6H, m); 2.83 (1H, m); 3.05, 3.32 (1H, d, I 5.2 Hz); 3.42-3.60 (1H, m); 3.76-4.14 (2H, m); 4.76, 4.93 (1H, m); 6.72-6.95 (2H, m); 7.32-7.60 (1H, m).

IR (film): 2950, 1618, 1600, 1510, 1425, 1270, 1140, 1120, 1075, 1020, 990, 985, 850 cm ^-1 .

Comparison Example 37. In dimethylformamide (50 ml), 60% sodium hydride (2.64 g) was dispersed in mineral oil, and then into this dispersion, while cooling with ice, triazole (6.84 g) was added and the mixture was stirred for 15 minutes. Then, a solution of 10 ml of 2 - [(1R) -1- (3,4,5,6-tetrahydro-2H-pyran-2-yl-hydroxy) ethyl] -2- (2,4-difluorophenyl) was added to this mixture oxirane (4.7 g) in dimethylformamide. The resulting mixture was heated at ⁸⁰ ° C for 3 hours. The reaction mixture was cooled, poured into cold water (200 ml) and extracted 3 times with ethyl acetate (150 mL). The ethyl acetate layers were combined, washed with water (100 ml × 3) and a saturated aqueous solution of sodium chloride (100 ml), dried with anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography, eluting with a mixture of dichloromethane, ethyl acetate and acetone (6: 1: 1), and (3R) -2-2,4-difluorophenyl-3- (3,4,5,6-tetrahydro- 2H-pyran-2-yloxy) -1- (1H-1,2,4-triazol-1-yl) -2-butanol (4.4 g) as a colorless viscous oily substance.

¹ H-NMR (CFCl ₃ ) δ: 0.99-1.12 (3H, d, I 6.4 Hz); 1.40-2.00 (6H, m); 3.40-3.65 (1H, m); 3.80-4.06 (1H, m); 4.25-4.45 (1H, m); 4.29 (1H, s); 4.62 (1H, d, I 14.2 Hz); 4.71 (1H, m); 4.90 (1H, d, I 14.2 Hz); 6.65-6.83 (2H, m); 7.35-7.50 (1H, m); 7.71, 7.72 (1H, s); 7.91, 7.94 (1H, s).

EXAMPLE 38. In ethanol (50 ml), (3R) -2- (2,4-difluorophenyl) -3- (3,4,5 , 6-tetrahydro-2H-pyran-2-yl) oxy-1- (1H-1,2,4-triazol-1-yl) -2-butanol (4.4 g) and pyridinium n-toluenesulfonate (0, 93 g). The solution was stirred ^at 55 ° C for 2 hours and then added to a solution of 0.20 g of n-toluenesulfonate and stirred ^at 55 ° C for another 2 hours. The reaction mixture was cooled and the solvent was distilled off. Ethyl acetate (250 ml) was added to the residue and washed with water (50 ml) and then with a saturated aqueous solution of sodium chloride (50 ml). The ethyl acetate layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue, and the precipitated crystals were collected by filtration, whereby (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1-yl) was obtained ) -2,3-butanediol (1.37 g), mp 115-117 ^about S.

[α] _D -80,3 ^{° C} (c = 1.0 in methanol).

¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, d, I 6.4 Hz); 4.33 (1H, m); 4.82 (2H, s); 6.69-6.82 (2H, m); 7.35-7.48 (1H, m); 7.84 (1H, s); 7.85 (1H, s).

Example 39. (2R, 3R) -2- (2,4-difluorophenyl) was dissolved in a mixture of ethyl acetate (40 ml) and dichloromethane (10 ml). -1- (1H-1,2,4-triazol-1-yl) -2,3-butanediol (1.25 g). Triethylamine (0.84 ml) and methanesulfonyl chloride (0.48 ml) were added to the solution under ice-cooling, after which the mixture was stirred at room temperature for 30 minutes. Then ethyl acetate (50 ml) was added to the reaction mixture, the resulting mixture was washed with water, dried with anhydrous magnesium sulfate and concentrated, whereby (2R, 3R) -2- (2,4-difluorophenyl) -3-methanesulfonyloxy-1 was obtained - (1H-1,2,4-triazol-1-yl) -2-butanol as an oily product. This product was dissolved in methanol (40 ml), and then a 28% methanol solution of sodium methylate (1.16 ml) was added thereto under ice-cooling. The mixture was stirred at room temperature for 30 minutes. After that, the reaction mixture was concentrated under reduced pressure to a volume of 10 ml. Ethyl acetate (100 ml) was added to the concentrate, the resulting mixture was washed with water and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and dichloromethane (4: 1), and after recrystallization from a mixture of ethyl acetate and hexane, (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl) methyl oxirane (520 mg) as colorless needle crystals, mp. 89-90 ^about S.

[α] ²³ -8.3 (c 1.0 in MeOH).

¹ H-NMR (CDCl ₃ ) δ: 1.65 (3H, d, I 5.6 Hz); 3.20 (1H, q, 5.6 Hz); 4.43 (1H, d, I 14.6 Hz); 4.88 (1H, d, I 14.6 Hz); 6.68-6.83 (2H, m); 6.93-7.08 (1H, m); 7.82 (1H, s); 7.97 (1H, s).

Elemental analysis for C ₁₂ H ₁₁ F ₂ N ₃ O.

 Calculated, C 57.37; H 4.41; N, 16.73.

 Found, C 57.27; H 4.43; N, 16.83.

The resulting product was analyzed by high resolution liquid chromatography (mobile phase: 9: 1 hexane isopropyl alcohol) using an optical isomer separation column [CHIRALCEL 0.46 cm x 25 cm, manufactured by Daicel Chemical Industries, Ltd. The excess enantiomer was 99.2%
C p and n and m o m e n d s n d and m EXAMPLE 40 A mixture of methyl (R) -lactate (104 g) and morpholine (260 ml) was heated at 85 ^{° C} for 60 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel chromatography (800 g silica gel, eluent: hexane ethyl acetate 1: 1 - >> ethyl acetate), whereby N - [(2R) -2-hydroxypropionyl] morpholine (141 g ) as an oily product of pale yellow color.

¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, d, I 6.6 Hz); 3.43 (2H, t, I 4.8 Hz); 3.55-3.80 (6H, m); 3.79 (1H, d); 4.45 (1H, m).

[α] _D + 0.98 (from 5.24 in CHCl ₃ ).

 Comparison Example 41. To a solution of dichloromethane (500 ml) and N - [(2R) -2-hydroxypropionyl] morpholine (141 g) was added n-toluenesulfonic monohydrate acid (1.67 g). Then, 3,4-dihydro-2H-pyran (89.3 g) was added dropwise to the mixture over 30 minutes while cooling with ice, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with 5% aqueous sodium bicarbonate (150 ml x 2), dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 800 g, eluent: hexane ethyl acetate 8: 1 - >> ethyl acetate) to obtain N - [(2R) -2- (3,4,5,6-tetrahydro-2H-pyran) -2-yloxy) propionyl] morpholine (184 g) as a pale yellow oily product.

¹ H-NMR (CDCl ₃ ) δ: 1.39, 1.44 (3H, d, I 6.8 Hz); 1.40-1.95 (6H, m); 3.40-3.95 (10H, m); 4.48-4.75 (2H, m).

[α] _D +34.9 ^about (from 6.3 in CHCl ₃ ).

Comparison Example 42. The mother liquor obtained after recrystallization of (2RS, 3RS) -2- (2,4-difluorophenyl) -1- (1H-1, 2,4-triazol-1-yl) -2,3-butanediol (see comparative example 24) was distilled under reduced pressure. The residue was purified by column chromatography, eluting with a mixture of ethyl acetate and methanol (30: 1), and (2RS, 3RS) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1) was obtained -yl) -2,3-butanediol (in the form of the first eluate fraction), after recrystallization of which colorless prismate crystals (1.9 g) were obtained from methanol as a diastereomer with a purity of 98%, and so on. 146-148 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, d, I 5.8 Hz), 2.41-2.52 (1H, m); 3.92-4.07 (1H, m); 4.57 (1H, d, I 14 Hz); 5.03 (1H, s); 5.04 (1H, d, I 14 Hz); 6.68-6.87 (2H, m); 7.50-7.68 (1H, m); 7.79 (1H, s); 8.05 (1H, s).

Elemental analysis for C ₁₂ H ₁₃ F ₂ O ₂ .

 Calculated, C 55.53; H 4.87; N, 15.61.

 Found, C, 53.70; H 4.97; N, 15.59.

 Comparison Example 43. The compound (2RS, 3RS) -2- (2,4-difluorophenyl) -1- (1H-1, obtained in comparative example 42) 2,4-triazol-1-yl) -2,3-butadiol (1.1 g) was reacted with methanesulfonyl chloride (0.35 ml) by the method described in comparative example 25, after treatment with 28% methanol Sodium methylate solution gave (2RS, 3RS) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxyran. The resulting product was purified by column chromatography, eluting with a mixture of ethyl acetate and methylene chloride (4: 1), and a yellow oily product (0.8 g g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, I 5.4 Hz); 3.18 (2H, q, I 5.4, 10.7 Hz); 4.42 (1H, d, I 15 Hz); 4.81 (1H, d, I 15 Hz); 6.76-6.92 (2H, m); 7.07-7.20 (1H, m); 7.86 (1H, s); 8.07 (1H, s).

 Comparison Examples 44-50. By a method similar to that described in comparative example 12, imidazole-2-carboxyaldehyde was reacted with an alkylating agent indicated in Table 10 (step 1), and then, without purification, the product was subjected to a reduction reaction with sodium borohydride (step 2), followed by chlorination using thionyl chloride (step 3), whereby a 2-chloromethylimidazole derivative was obtained.

Comparative Example 51. To an ethanol solution (100 ml) of 3- (n-methoxybenzylthio) propionaldehyde (5.7 g) was added a 40% aqueous solution of glyoxal (4.3 g), followed by a 30% aqueous solution of ammonium (4.1 mL) at -10 ^C. The mixture was stirred at room temperature for 1 h, then thereto was added 40% aqueous glyoxal solution (4 ml) and 30% aqueous ammonia solution (4.1 ml), the resulting mixture was stirred for another 1 hour. Then the reaction mixture was concentrated under reduced pressure. The concentrate was acidified with hydrochloric acid and washed with methylene chloride (30 ml x 2), the pH of the aqueous layer was adjusted to 8 with an aqueous solution of sodium hydroxide, and then extracted with methylene chloride (30 ml x 3). The solution was dried with anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of ethanol and ethyl acetate was added to the concentrate, whereby 2- [2- (n-methoxybenzylthio) ethyl] imidazole (2.7 g) was obtained in the form of crystals. The mother liquor was chromatographed on silica gel (3 cm x 15 cm column), eluting with a mixture of methanol and methylene chloride (1: 9). The desired fraction was concentrated under reduced pressure to obtain 1.1 g of the product as crystals. Mp 116-118 ^about With (colorless plates).

¹ H-NMR (DMCO-d ₆ ) δ: 2.68 (2H, t, I 7.0 Hz); 2.85 (2H, t, I 7.0 Hz); 3.65 (2H, s); 3.73 (3H, s); 6.87 (2H, d, I 8.8 Hz); 7.23 (2H, d, I 8.8 Hz); 6.7-7.1 (2H, broad s); 11.73 (1H, broad s).

Elemental analysis for C ₁₃ H ₁₆ N ₂ OS.

 Calculated, C 62.87; H, 6.49; N, 11.28.

 Found, C, 62.86; H 6.45; N, 11.29.

To a solution (15 ml) 2- [2- (n-methoxybenzylthio) ethyl] imidazole (1.5 g) in dimethylformamide was added 60% sodium hydride (0.29 g) in mineral oil at 0 ° ^C. Then after 15 min the mixture was added methyl iodide (0.41 ml) at ^-20 ° C after which the mixture was stirred for 10 min. The reaction mixture was poured into water (60 ml) and extracted with methylene chloride (20 ml x 3). The organic layer was washed with water (20 ml), dried with anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on silica gel columns (3 cm x 15 cm), eluting with a mixture of methanol and methylene chloride (5.95). The target fraction was concentrated under reduced pressure to give 1-methyl-2- [2- (n-methoxybenzylthio) ethyl] imidazole (1.6 g) as a colorless oily product.

¹ H-NMR (CDCl ₃ ) δ: 2.8-2.95 (4H, m); 3.54 (3H, s); 3.65 (2H, s); 3.79 (3H, s); 6.78 (1H, d, I 1.4 Hz); 6.54 (2H, d, I 8.6 Hz); 6.94 (1H, d, I 1.4 Hz); 7.24 (2H, d, I 8.6 Hz).

1-methyl-2- [2- (n-methoxybenzylthio) ethyl] imidazole (1.4 g) was dissolved in a mixture of trifluoroacetic acid (25 ml) and anisole (10 ml). To this solution at ⁰ ° C was added mercuric acetate (1.9 g) and the resulting mixture was stirred for 1 h 45 min. Then the reaction mixture was concentrated under reduced pressure. Petroleum ether (50 ml) was added to the concentrate. The supernatant was removed. Diethyl ether (30 ml) was added to the precipitate, and a white powder (2.6 g) was obtained after filtration. This powder (1 g) was dissolved in N, N-dimethylformamide (5 ml) and to this solution was bubbled with hydrogen sulfide at ⁰ ° C for 10 min. Then, in order to remove excess hydrogen sulfide, nitrogen was bubbled into the reaction mixture. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure, whereby 1-methyl-2- (2-mercaptoethyl) imidazole (0.5 g) was obtained as a colorless oily product.

¹ H-NMR (DMCO-d ₆ ) δ: 2.74 (1H, t, I 7.0 Hz); 2.88 (2H, d, I 7.0 Hz, d, I 12 Hz); 3.1-3.4 (2H, m); 3.82 (3H, s); 7.61 (1H, d, I 2 Hz); 7.63 (1H, d, I 2 Hz).

Comparison Example 52. To a methanol solution (31 ml) containing a 37% aqueous formaldehyde solution (8.9 g) and a 40% glycosal solution (16 g), a methanol solution (5 ml) containing cyclopropylamine (6.3 g) and a 28% aqueous solution of ammonium (7.6 g) was added over 25 minutes while cooling with ice. The resulting mixture was stirred at 0 ^C for 1 h, and then concentrated under reduced pressure to a volume of about 10 ml. Insoluble substances were filtered off. Water (200 ml) was added to the filtrate. The aqueous solution was washed with hexane (100 ml x 4) and then with a mixture of hexane (50 ml) and diethyl ether (30 ml). The resulting aqueous solution was saturated with sodium chloride and extracted with ethyl acetate (100 ml x 8). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride (50 ml), dried with anhydrous magnesium sulfate, and, after distilling off the solvent under reduced pressure, the crude 7-cyclopropylimidazole compound (4.2 g) was obtained as a colorless powder. A mixture of this crude product (3.5 g) and paraformaldehyde (3 g) was heated at 170 ° ^C for 30 minutes and then thereto was added an additional 2 g of paraformaldehyde. The resulting mixture was heated at 170 ^C for 20 min. To this mixture was added an additional 2 g of paraformaldehyde, and then again heated at ¹⁷⁰ ° C for 20 min. After this, the reaction mixture was ice-cooled and dissolved in methanol (20 ml), a saturated aqueous solution of sodium chloride (20 ml) was added to the resulting solution, followed by extraction with ethyl acetate (40 ml x 2). The ethyl acetate layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on silica gel columns (3 x 13 cm), eluting with a mixture of methanol and dichloromethane (1: 9), and the target fraction was concentrated under reduced pressure. A mixture of ethyl acetate and diethyl ether was added to the concentrate, whereby 1-cyclopropyl-2-hydroxymethylimidazole (0.7 g) was obtained as colorless crystals. The resulting compound (0.7 g) was added to thionyl chloride (7 ml) at ⁰ ° C and then the mixture was stirred for 5 min. Then, the reaction mixture was heated under reflux for 15 minutes. Excess thionyl chloride was distilled off under reduced pressure. Diethyl ether was added to the residue, and the resulting powder was collected by filtration. Recrystallization from a mixture of ethanol and diethyl ether gave 1-cyclopropyl-2-chloromethylimidazole hydrochloride (0.75 g).

1-Cyclopropyl-2-hydroxymethylimidazole, m.p. 90-95 ^about With, colorless needle crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.9-1.2 (4H, m); 3.25-3.40 (1H, m); 4.76 (2H, s); 5.9 (1H, broad s); 6.86 (2H, s).

Elemental analysis for C ₇ H ₁₀ N ₂ O.

 Calculated, C 60.85; H, 7.29; N, 20.27.

 Found, C, 60.83; H, 7.29; N, 20.24.

1-Cyclopropyl-2-chloromethylimidazole hydrochloride, mp 100-101 ^about With colorless prismatic crystals.

¹ H-NMR (DMCO-d ₆ ) δ: 1.1-1.3 (4H, m); 3.65-3.80 (1H, m), 5.21 (2H, s), 7.72 (1H, d, I 2.0 Hz); 7.80 (1H, d, I = 2.0 Hz).

Elemental analysis for C ₇ H ₉ ClN ₂ HCl.

 Calculated, C 43.55; H 5.22; N, 14.51.

 Found, C, 43.61; H 5.22; N, 14.37.

C p and n and m o m e n d s n p EXAMPLE 53 To a methanol solution (50 mL) hydrazine glycolic acid (5 g) was added cyclopropyl isothiocyanate (5.6 g) at 20 ^C. The mixture was stirred for 1 h, then thereto was added water (30 ml) at 0 ^C. Then, to the resulting mixture dropwise 5N. aqueous NaOH solution (11 ml), the solution temperature was raised to 20 ° ^C and stirred at this temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to a volume of about 10 ml. The concentrate was diluted with ethanol (100 ml), after which 5N was added dropwise to it, cooling with ice. HCl aqueous solution (11 ml). Insoluble materials were filtered off, and the filtrate was concentrated to dryness under reduced pressure, whereby crude crystals (6.4 g) of 4-cyclopropyl-5-hydroxymethyl-3-mercapto-4H-1,2,4-triazole were obtained. This compound (3 g) was added to a mixture of concentrated nitric acid (d 1,38 4,6 ml), water (12 ml) and sodium nitrite (10 mg) at 60 ° ^C. Then 1 ml concentrated nitric acid. When a portion of nitric acid has interacted with a small amount of triazole compound on the inner wall of the reaction vessel, the reaction started and the temperature reached 90-100 ^{° C,} whereupon the reaction was complete. Then the reaction mixture was cooled with ice, neutralized with an aqueous NaOH solution and concentrated under reduced pressure. The concentrate was chromatographed on silica gel (3 x 10 cm), eluting with a mixture of methanol and dichloroethane (1: 4). The desired fraction was concentrated to give 4-cyclopropyl-3-hydroxymethyl-4H-1,2,4-triazole (2 g). This product (1 g) was added to thionyl chloride (10 ml) at ⁰ ° C after which the mixture was heated under reflux for 20 minutes. The mixture was cooled, and an excess of thionyl chloride was distilled off under reduced pressure. Diethyl ether was added to the residue, and the resulting powder was collected by filtration. This product was recrystallized from a mixture of ethanol and ethyl acetate to give 4-cyclopropyl-3-chloromethyl-1,2,4-triazole hydrochloride (1.34 g).

4-Cyclopropyl-5-hydroxymethyl-3-mercapto-4H-1,2,4-triazole, m.p. 159-160 ^о С, colorless prismatic crystals.

¹ H-NMR (DMCO-d ₆ ) δ: 1.0-1.2 (4H, m); 2.9-3.0 (1H, m); 3.37 (1H, broad s); 4.51 (2H, s); 5.60 (1H, broad s).

Elemental analysis for C ₆ H ₉ N ₃ OS.

 Calculated, C 42.09; H, 5.30; N, 24.54.

 Found, C, 42.11; H 5.34; N, 24.50.

 4-Cyclopropyl-3-hydroxymethyl-4H-1, 2,4-triazole.

¹ H-NMR (DMCO-d ₆ ) δ: 1.01 (4H, d, I 5.4 Hz); 3.3-3.5 (1H, m); 4.64 (2H, d, I 5.8 Hz); 5.50 (1H, t, I 5.8 Hz); 8.42 (1H, s).

Mass spectrum (m / z): 140 (MH) ⁺ .

4-Cyclopropyl-3-chloromethyl-1,2,4-triazole hydrochloride, mp. 60-65 ^about With, colorless needle crystals.

¹ H-NMR (DMCO-d ₆ ) δ: 1.0-1.3 (4H, m); 3.5-3.7 (1H, m); 5.12 (2H, s); 9.51 (1H, s).

Elemental analysis for C ₆ H ₈ ClN ₃ HCl xx 0.5 H ₂ O.

 Calculated, C 35.49; H 4.96; N, 20.69.

 Found, C 35.86; H 4.55; N, 20.30.

 EXAMPLE 54. A mixture of ethyl bromopyruvate (6.82 g), 2,2,2-trifluorothioacetamide (4.52 g) and ethanol (30 ml) was heated under reflux for 3 hours. Then the reaction mixture was cooled, and ethanol was distilled off under reduced pressure. Water (40 ml) was added to the residue and extracted with ethyl acetate (60 ml x 2). The extract solution was washed with water (40 ml) and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (2.5 x 45 cm), eluting with a mixture of ethyl acetate and hexane (1: 5). The desired fraction was concentrated to give ethyl 2-trifluoromethyl-4-thiazole carboxylate (2.2 g) as pale yellow needle crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, I 7 Hz); 4.48 (2H, q, I 7 Hz); 8.40 (1H, s).

 Lithium aluminum hydride (0.33 g) was added to anhydrous ether (40 ml). Anhydrous ether solution (20 ml) of ethyl 2-trifluoromethyl-4-thiazolecarboxylate (2 g) was added dropwise to this mixture. The mixture was stirred at room temperature for 3 hours. Then, water (20 ml) was added dropwise to the reaction mixture, cooling with ice, in order to decompose the excess amount of the reducing agent. Ethyl acetate (50 ml) and water (25 ml) were added to the resulting reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water (25 ml) and then with a saturated aqueous solution of sodium chloride (25 ml) and dried with magnesium sulfate. The solvent was distilled off, and the residue was chromatographed on silica gel (2.5 x 30 cm), eluting with ethyl acetate and hexane (3: 1). The target fraction was concentrated to give 2-trifluoromethyl-4-hydroxymethylthiazole (1.1 g) as an oily pale yellow product.

¹ H-NMR (CDCl ₃ ) δ: 2.50 (1H, s); 4.87 (2H, d, I 5 Hz); 7.50 (1H, s).

 2-trifluoromethyl-4-hydroxymethylthiazole (1 g) was dissolved in chloroform (10 ml), and thionyl chloride (2 ml) was added dropwise to the resulting solution. The mixture was then refluxed for 4 hours. The reaction mixture was cooled and an excess of thionyl chloride was distilled off under reduced pressure. Dichloromethane (30 ml) was added to the residue, then washed successively with aqueous sodium bicarbonate (20 ml) and water (20 ml) and dried with magnesium sulfate. The solvent was distilled off, and the residue was chromatographed on silica gel (2.5 x 20 cm), eluting with a mixture of ethyl acetate and hexane (1: 3). The target fraction was concentrated to give 2-trifluoromethyl-4-chloromethylthiazole (0.66 g) as a reddish oily product.

¹ H-NMR (CDCl ₃ ) δ: 4.62 (2H, s); 7.57 (1H, s).

 Example 55. A mixture of ethyl boropyruvate (3.6 g), cyclopropanethioamide (2.2 g) and ethanol (30 ml) was heated under reflux for 2 h. Then the reaction mixture was cooled, and ethanol was distilled off under reduced pressure. Water (30 ml) was added to the residue and extracted twice with ethyl acetate (50 ml). The extract solution was washed with water (30 ml) and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (2.5 x 30 cm), eluting with a mixture of ethyl acetate and hexane (1: 3). The desired fraction was concentrated to give 2-cyclopropyl-4-thiazole carboxylate (0.84 g) as pale yellow needle crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.01-1.24 (4H, m); 1.40 (3H, t, I 7 Hz); 2.32-2.50 (1H, m); 4.41 (2H, q, I 7 Hz); 7.95 (1H, s).

 Anhydrous ether solution (10 ml) of ethyl 2-cyclopropyl-4-thiazole carboxylate (1.65 g) was added dropwise to a mixture of lithium aluminum hydride (0.32 g) and anhydrous ether (40 ml), and the resulting mixture was stirred at room temperature in for 1 h. Then, water (20 ml) was added dropwise to the reaction mixture, cooling with ice, to decompose the excess amount of the reducing agent. Ethyl acetate (50 ml) and water (25 ml) were added to the resulting mixture, and extracted with ethyl acetate. The organic layer was washed with water (25 ml) and saturated aqueous sodium chloride (25 ml), and then dried with magnesium sulfate. The solvent was distilled off, and the residue was chromatographed on silica gel (2.5 x 30 cm), eluting with a mixture of ethyl acetate and hexane (2: 1). The target fraction was concentrated to give 2-cyclopropyl-4-hydroxymethylthiazole (0.94 g) as pale yellow needle crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.98-1.18 (4H, m); 2.24-2.39 (2H, m); 3.20 (1H, s); 4.70 (2H, d, I 5 Hz); 6.93 (1H, s).

2-cyclopropyl-4-hydroxymethylthiazole (0.9 g) was dissolved in chloroform (10 ml), and then thionyl chloride (0.68 g ml) was added dropwise to this solution, while cooling with ice, after which the mixture was stirred at room temperature within 30 minutes Excess thionyl chloride was distilled off under reduced pressure. Diethyl ether was added to the residue to give 2-cyclopropyl-4-chloromethylthiazole hydrochloride (1.1 g) as a brown powder, mp. 108-110 ^about C.

¹ H-NMR (DMCO-d ₆ ) δ: 0.93-1.18 (4H, m); 2.32-2.48 (1H, m); 4.72 (2H, s); 7.47 (1H, s).

 Comparison Example 56. The mother liquor obtained after recrystallization of (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H- 1,2,4-triazol-1-yl) -2,3-butanediol, as described in comparative example 31, was concentrated under reduced pressure. The concentrate was purified by silica gel chromatography (eluent: ethyl acetate), whereby (2S, 3R) -2- (2,4-difluoromethyl) -1- (1H-1,2,4-triazol-1-yl) -2 was obtained , 3-butanediol as the first eluate fraction.

Mp 154-156 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, dd, I 6.4 Hz, I 1.6 Hz); 2.44 (1H, d, OH); 3.99 (1H, m); 4.56 (1H, dd, I 14 Hz, I 1.6 Hz); 5.05 (1H, dd, I14 Hz); 1.6 Hz); 6.65-6.86 (2H, m); 7.50-7.62 (1H, m); 7.80 (1H, s); 8.05 (1H, s).

IR (KBr), cm ^-1 : 3400, 1615, 1500, 1420, 1275, 1200, 1135.

Example 57. (2S, 3R) -2- (2,4-difluorophenyl) -1- (1H-1) was dissolved in ethyl acetate (40 ml). 2,4-triazol-1-yl) -2,3-butanediol (2.5 g). To the solution, ice-cold was added triethylamine 1.82 ml and methanesulfonyl chloride (1.51 g). The mixture was stirred at room temperature for 30 minutes. Then, ethyl acetate (40 ml) was added to the reaction mixture, after which the mixture was washed with water, dried with anhydrous magnesium sulfate, and after concentration, (2S, 3R) -2- (2,4-difluorophenyl) -3-methanesulfonyloxy-1- (1H, 1,2,4-triazol-1-yl) -2-butanol as an oily product. This product was dissolved in methanol (40 ml), and then, under ice-cooling, a 28% methanol solution of sodium methylate (2.04 g) was added thereto. The resulting mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. Ethyl acetate (100 ml) was added to the concentrate, the mixture was washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (4: 1), whereby (2S, 3S) -2- (2,4-difluorophenyl) -3-methyl-2- ( 1H-1,2,4-triazol-1-yl) methyl oxirane (1.62 g) as a colorless oily product. Upon freezing, this product became a colorless solid with a melting point of 41-43 ^about S.

[α] ²³ + 5.8 ^about (with 1.0 in methanol).

NMR (CDCl ₃ ) δ: 1.06 (3H, d, I 5.4 Hz), 3.18 (1H, q, I 5.4 Hz); 4.42 (1H, d, I 15 Hz); 4.80 (1H, d, 15 Hz); 6.76-6.90 (2H, m); 7.07-7.20 (1H, m); 7.85 (1H, s); 8.06 (1H, s).

IR (KBr), cm ^-1 : 3150, 1615, 1595, 1502, 1420, 1270, 1130.

 Comparison Example 58. The mother liquor obtained after recrystallization of (2S, 3S) -2- (2,4-difluorophenyl) -1- (1H-1, 2,4-triazol-1-yl) -2,3-butanediol, as described in comparative example 38, was concentrated under reduced pressure. The concentrate was purified by silica gel chromatography (eluent: ethyl acetate) to obtain (2R, 3S) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2, 3-butanediol as a first eluate fraction.

Mp 156-157 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, dd, I 6.4 Hz, I 1.6 Hz); 2.42 (1H, d, OH); 3.99 (1H, m); 4.57 (1 H, doublet of doublets, I 14 Hz, I 1.6 Hz); 5.05 (1H, dd, I 14 Hz, 1.6 Hz); 6.67-6.86 (2H, m); 7.50-7.62 (1H, m); 7.80 (1H, s); 8.04 (1H, s).

IR (KBr), cm ^-1 : 3350, 1615, 1510, 1420, 1275, 1200, 1130.

 EXAMPLE 59. (2R, 3S) -2- (2,4-difluorophenyl) -1- (1H-1) was dissolved in ethyl acetate (4 ml). 2,4-triazol-1-yl) -2,3-butanediol (0.18 g). Triethylamine (0.1 ml) and methanesulfonyl chloride (84 mg) were added to the resulting solution, while cooling with ice. The mixture was stirred at room temperature for 30 minutes, after which ethyl acetate (10 ml) was added. The reaction mixture was washed with water, dried with anhydrous magnesium sulfate, and after concentration, (2R, 3S) -2- (2,4-difluorophenyl) -3-methanesulfonyloxy-1- (1H-1,2,4-triazole-1-) was obtained sludge) -2-butanol as an oily product. This product was dissolved in methanol (6 ml), and a 5.6% methanol solution of sodium methylate was added to the resulting solution while cooling with ice. The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. Ethyl acetate (30 ml) was added to the concentrate, washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography eluting with a mixture of hexane and ethyl acetate (1: 2), whereby (2R, 3R) -2- (2,4-difluorophenyl) -3-methyl-2- ( 1H-1,2,4-triazol-1-yl) methyl oxiran (0.15 g) as a colorless oily product.

NMR (CDCl ₃ ) δ: 1.06 (3H, d, I 5.4 Hz); 3.18 (1H, q, I, 5.4 Hz); 4.42 (1H, d, I 15 Hz); 4.80 (1H, d, I 15 Hz); 6.76-6.90 (2H, m); 7.07-7.20 (1H, m); 7.85 (1H, s); 8.06 (1H, s).

IR (film), cm ^-1 : 1615, 1595, 1505, 1420, 1270, 1140.

Example 60. 2 ', 4'-Difluoro-2-hydroxypropiophenone (2.8 g) was dissolved in methylene chloride (28 ml), and then to this solution was added at ⁰ ° C triethylamine (2.5 ml) and methanesulfonyl chloride (1.3 ml). After stirring for 15 minutes, the mixture was washed with water (30 ml), and the organic layer was dried and concentrated under reduced pressure. The residue was chromatographed on silica gel columns (3 cm x 10 cm), eluting with methylene chloride. The target fraction was concentrated to give 2 ', 4'-difluoro-2-methanesulfonyloxypropiophenone (3 g) as a colorless oily product. This product (3 g) was dissolved in 30 ml of N, N-dimethylformamide, after which 1H-1,2,4-triazole (0.94 g) was added to this solution, followed by a 60% suspension of sodium hydride in oil (0 , 5 g) at -10 ^C. After stirring at ⁰ ° C for 50 minutes, the reaction mixture was added to a mixture of ethyl acetate (100 ml) and water (200 ml) for extraction. The aqueous layer was extracted with ethyl acetate (100 ml), the ethyl acetate layers were combined, washed with a saturated aqueous solution of sodium chloride (30 ml x 2), dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel columns (3 x 10 cm), eluting with ethyl acetate. The target fraction was concentrated to give 2 ', 4'-difluoro-2- (1H-1,2,4-triazol-1-yl) propiophenone (1.5 g) as a colorless oily product. This product (1.24 g) was added to a mixture of dimethylsulfoxide (30 ml), 60% sodium hydride suspension in oil (0.25 g) and trimethylsulfoxonium iodide (1.38 g) at 10 ^{° C,} after which the temperature was raised up to 25 ^° C. After 2 hours, the reaction mixture was added to a mixture of diethyl ether (100 ml) and water (150 ml), the diethyl ether layer was separated, and the aqueous layer was extracted with diethyl ether (100 ml x 2). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride (50 ml × 2), dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel columns (3 x 10 cm) and eluted with a mixture of ethyl acetate and hexane (3: 1) to give 2- (2,4-difluorophenyl) -2-1- (1H-1,2,4 -triazol-1-yl) ethyl-oxiran as a colorless oily product (0.87 g).

¹ H-NMR (CDCl ₃ ) δ: 1.61 (3H, d, I 7.0 Hz); 1.62 (3H, d, I = 6.0 Hz); 2.64 (1H, d, I 4.6 Hz); 2.81 (1H, d, I 5.6 Hz); 2.87 (1H, d, I 4.6 Hz); 3.18 (1H, d, I 4.6 Hz); 4.92 (2H, qI, 7.0 Hz); 6.7-7.2 (6H, m); 7.87 (1H, s); 7.94 (1H, s); 8.04 (1H, s); 8.12 (1H, s).

Comparison Example 61. To a solution of 2- (2,4-difluorophenyl) -2 - [(1R) -1- (3,4,5,6 - tetrahydro-2H-pyran-2-yloxy) ethyl] oxirane (1.7 g) and imidazole (0.49 g) in N, N-dimethylformamide (17 ml) were added portionwise 60% oily sodium hydride in mineral oil (0 , 29 g), while constantly stirring at 20 ^C. After 5 minutes, the mixture was heated at ⁷⁰ ° C for 3 hours. The reaction mixture was cooled, poured into water (50 ml) and extracted with ethyl acetate (20 ml x 3). The ethyl acetate layers were combined, washed with a saturated aqueous solution of sodium chloride (20 ml), dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (3 cm x 15 cm), eluting with a mixture of methanol and ethyl acetate (5:95). The target fraction was concentrated under reduced pressure to obtain (3R) -2- (2,4-difluorophenyl) -1- (1-imidazoyl) -3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy ) -2-butanol (1.8 g) as a colorless syrup.

¹ H-NMR (CDCl ₃ ) δ: 0.92 (1.03 3H, d, I 6.2 Hz, I 6.4 Hz); 1.5-2.0 (6H, m); 3.5-4.8 (6H, m); 6.6-7.5 (6H, m).

IR (neat), cm ^-1 : 3300, 2900, 1650, 1650, 1600, 1490.

MSWI (mass spectroscopy of secondary ions m / z): 353 (MH ⁺ ).

In ethanol (8.5 ml) was dissolved (3R) -2- (2,4-difluorophenyl) -1- (1-imidazolyl) -3- (3,4,5,6-tetrahydro-2H-pyran- 2-yloxy) -2-butanol (1.7 g) was added to the resulting solution at ⁰ ° C, trifluoroacetic acid (8.5 mL). After 10 minutes, the temperature was adjusted ^to 20 ° C, and the mixture was allowed to stand for 1 hour then the reaction mixture was concentrated under reduced pressure and the residue chromatographed on silica gel (2 x 10 cm), eluting with methanol-methylene chloride (1: 9).. The target fraction was concentrated to give (3) -2- (2,4-difluorophenyl) -1- (1-imidazolyl) -2,3-butanediol (1.7 g).

¹ H-NMR (DMCO-d ₆ ) δ: 0.83, 1.03 (3H, d, I 6.2 Hz, I 6.4 Hz); 4.15-4.35 (1H, m); 4.62 (1H, d, I 14.2 Hz); 4.71 (1H, d, I 14.2 Hz); 5.5 (1H, broad s); 5.71 (1H, s); 6.9-7.0 (1H, m); 7.15-8.8 (5H, m).

IR (neat), cm ^-1 : 3300, 1660, 1495, 1410, 1190, 1120.

MSWI (m / z): 269 (MH ⁺ ).

To a methylene chloride solution (60 ml) containing (3R) -2- (2,4-difluorophenyl) -1- (1-imidazole) -2,3-butanediol (1.7 g), triethylamine (0.88 ml) and tetrahydrofuran (2 ml) was added dropwise at ⁰ C methanesulfonyl chloride (0.5 mL) while stirring constantly. After 10 minutes, the temperature was adjusted to 20 ° ^C and the mixture was stirred for another 50 min. Then methanesulfonyl chloride (0.50 ml) and triethylamine (0.88 ml) were added, after which the reaction mixture was stirred for 1 h, poured into water (100 ml) and extracted with methylene chloride (30 ml x 3). The ethyl acetate layers were combined, washed with a saturated aqueous solution of sodium chloride (20 ml), dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (3 cm x 15 cm), eluting with ethyl acetate. The desired fraction was concentrated under reduced pressure. Isopropyl ether-n-hexane was added to the residue, with which (2R, 3S) -2- (2,4-difluorophenyl) -2- (1-imidazolyl) methyl-3-methyloxyran (0.14 g) was crystallized prismatic colorless crystals with so pl. 73-76 ^about S.

Comparison Example 62. To N, N-dimethylformamide solution (35 ml) containing (2R, 3S) -3- (2,4-difluorophenyl) - 3,4-epoxy-2-butyl methanesulfonate (3.5 g) and imidazole (1.2 g) was added 60% sodium hydride in mineral oil (0.7 g) under constant agitation at 0 ° ^C. After 10 minutes, the temperature was adjusted to 20 ° ^C and the mixture was stirred for 20 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (30 ml x 4). The ethyl acetate layers were combined, washed with a saturated aqueous solution of sodium chloride (30 ml), dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3 x 15 cm), eluting with a mixture of methanol and ethyl acetate (5:95). The target fraction was concentrated under reduced pressure, the residue was crystallized by adding isopropyl ether and n-hexane to obtain (2R, 3S) -2- (2,4-difluorophenyl) -2- (1-imidazoyl) methyl-3-methyloxyran ( 1.7 g) in the form of colorless prismatic crystals, so pl. 73-76 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.61 (3H, d, I 5.6 Hz); 3.16 (1H, q, 5.6 Hz); 4.13 (1H, d, I 14.8 Hz); 4.63 (1H, d, I 14.8 Hz); 6.66-6.78 (2H, m); 6.83 (1H, s); 6.94 (1H, s); 6.92-7.04 (1H, m); 7.29 (1H, s).

Elemental analysis for C ₁₃ H ₁₂ F ₂ N ₂ O xx 1/4 H ₂ O.

 Calculated, C 61.29; H 4.95; N, 11.00.

 Found, C 61.46; H 4.73; N, 10.89.

IR (KBr), cm ^-1 : 1600, 1585, 1495, 1415, 1270, 1260, 1210, 1110, 1090.

PRI me R 1. In dimethylformamide (20 ml) was dissolved 2- (2,4-difluorophenyl) -2- (1H-1,2,4, -triazol-1-yl-methyl) oxirane (1,2 g) and 1- (2-mercaptoethyl) benzimidazole (1.1 g). To this solution was added, while cooling with ice, 60% sodium hydride in oil (0.36 g) and the resulting mixture was stirred for 90 minutes. Then dimethylformamide was distilled off under reduced pressure, the residue was diluted with water (50 ml) and extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous solution of sodium chloride and dried with MgSO ₄ , and the solvent was distilled off. The residue was chromatographed on silica gel (2.5 x 40 cm), eluting with a mixture of ethyl acetate, acetone and methanol (6: 2: 1). The target fraction was concentrated to give compound 1 (1.1 g) as a colorless powder.

Elemental analysis for C ₂₀ H ₁₉ F ₂ N ₅ OS xx 0.5 H ₂ O.

 Calculated, C 56.59; H 4.75; N, 16.50.

 Found, C 57.07; H 4.96; N, 15.98.

¹ H-NMR (CDCl ₃ ) δ: 2.81-3.12 (4H, m); 4.30-4.37 (2H, m); 4.64 (2H, s); 6.74-6.82 (2H, m); 7.28-7.50 (5H, m); 7.71-7.83 (1H, broad s); 7.81 (1H, s); 7.88 (1H, s); 7.93 (1H, s).

MSWI (m / z): 416 (M + H) ⁺ .

PRI me R 2. A mixture of 2- (1H-1,2,4-triazol-1-yl) ethanethiol (4.5 g), 2- (2,4-difluorophenyl) -2- (1H-1 , 2,4-triazol-1-yl-methyl) oxy ranmetasulfonata (4 g), potassium carbonate (6.5 g) and dimethylformamide (20 ml) was stirred at ⁷⁰ ° C for 1 hour. After cooling, the reaction mixture was diluted water (150 ml) and saturated sodium chloride and was extracted with ethyl acetate (150 ml x 3). The extract was washed with water (50 ml x 3) and dried with sodium sulfate, and the solvent was distilled off, resulting in a yellow oily substance. The resulting product was purified by silica gel chromatography, eluting with a mixture of ethyl acetate, acetone and methanol (6: 2: 1), the resulting oily product was crystallized from a mixture of ethyl ether and ethyl acetate, whereby compound 2 (0.85 g) was obtained as colorless prismate crystals .

Mp 114-115 ^about S.

Elemental analysis for C ₁₅ H ₁₆ F ₂ N ₆ OS.

 Calculated, C 49.17; H 4.40; N, 22.94.

 Found, C, 48.93; H 4.40; N, 22.87.

Example 3. Compound 2 (0.2 g) was dissolved in methylene chloride (10 ml), and m-chlorobenzoic acid (85% purity 0.29 g) was added while stirring at room temperature. The mixture was then stirred at room temperature for 16 hours. The mixture was washed with a 5% aqueous sodium bicarbonate solution, the organic layer was dried with MgSO _4, and concentrated under reduced pressure. The residue was chromatographed on silica gel columns (1.5 x x 15 cm), eluting with a mixture of ethyl acetate, acetone and methanol (8: 2: 1). The desired fraction was concentrated to give compound 3 (0.12 g) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 3.36-3.79 (4H, m); 4.63-4.79 (3H, m); 4.89 (1H, d, I 14.2 Hz); 5.61 (1H, s); 6.78-6.92 (2H, m); 7.38-7.53 (1H, m); 7.86 (1H, s); 7.91-7.95 (2H, m); 8.18 (1H, s).

MSWI (m / z): 399 (M + H) ⁺ .

Example 4. Compound 2 (0.3 g) was dissolved in methylene chloride (15 ml), and m-chlorobenzoic acid (85% purity 0.22 g) was added while stirring with ice cooling. The mixture was stirred while cooling with ice, and washed with 5% aqueous sodium bicarbonate. The organic layer was dried with MgSO ₄ and concentrated under reduced pressure. The residue was chromatographed on silica gel columns (1.5 x 20 cm), eluting with a mixture of ethyl acetate, acetone and methanol (5: 4: 1). The desired fraction was concentrated to give compound 4 (0.07 g) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 2.87-3.48 (4H, m); 4.36-4.72 (4H, m); 5.48 (1H, broad s); 6.81-7.02 (2H, m); 7.59-7.75 (1H, m); 7.85-7.99 (2H, m); 8.11 (1H, s); 8.15 (1H, s).

PRI me R 5. A mixture of 2- (1-imidazolyl) ethanethiol (4.5 g), 2- (2,4-dichloro-phenyl-2- (1H-1,2,4-triazol-1-yl- methyl) oksiranmetansulfonata (4 g), potassium carbonate (6.5 g) and dimethylformamide (30 ml) was stirred at ⁷⁰ ° C for 1 hour. After cooling, the reaction mixture was diluted with water (100 ml), saturated with sodium chloride and extracted with ethyl acetate ( 100 ml x 3). The extract was washed with water (30 ml x 3) and dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain a colorless oily substance. This product was purified by chromatography on silica barely, eluting with ethyl acetate, acetone, methanol (6: 2: 1), and poluchali oily product, which after crystallization from ethyl ether to give Compound 5 (1.28 g) as a colorless powder with a m.p. ^of 103-105 WITH.

Elemental analysis for C ₁₆ H ₁₇ F ₂ N ₅ OS.

 Calculated, C 52.59; H 4.69; N, 19.17.

 Found, C, 52.32; H 4.69; N, 19.03.

 PRI me R 6. In a similar manner to that described in example 3, compound 5 (0.3 g) was oxidized with m-chlorobenzoic acid, whereby compound 6 (0.17 g, 51%) was obtained as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 3.51-3.73 (4H, m); 4.37-4.43 (2H, m); 4.59 (1H, d, I 14.2 Hz); 4.80 (1H, d, I 14.2 Hz); 6.44 (1H, broad s); 6.80-6.99 (4H, m); 7.40-7.54 (2H, m); 7.81 (1H, s); 8.11 (1H, s).

MSWI (m / z): 398 (M + H) ⁺ .

 PRI me R s 7-12. By a method similar to that described in example 1, a reaction was carried out of the interaction of 2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-yl-methyl) oxirane (epoxy compound in Table 11) with various the thiols shown in table 11, with the result that the obtained compounds 7,8,9,10,11,11,19,19 and 21.

PRI me R 13. A mixture of (2RS, 3SR) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl-methyl) oxirane ( 0.5 g), 2-mercapto-5,6-dihydro-4H-cyclopentathiazole (0.38 g) and 1M tetrabutylammonium fluoride (2.2 ml) in ethanol (15 ml) were heated under reflux for 4 h. Then ethanol was distilled off under reduced pressure, and the residue was diluted with water (25 ml) and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride and dried with MgSO ₄ , and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel columns (2.5 x 40 cm), eluting with a mixture of ethyl acetate and n-hexane (3: 2). The target fraction was concentrated, a mixture of ether and hexane (2: 1) was added to the residue, and compound 12 (0.34 g) was obtained as colorless prismatic crystals. Mp 70-72 ^about S.

Elemental analysis for C ₁₈ H ₁₈ F ₂ N ₄ OS.

 Calculated, C 52.93; H 4.44; N, 13.72.

 Found, C, 52.65; H 4.38; N, 13.70.

¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, I 7.2 Hz); 2.43-2.62 (2H, m); 2.87-2.99 (2H, m); 4.02 (1H, q, I, 7.2 Hz); 4.98 (2H, s); 6.64-6.82 (2H, m); 7.08 (1H, s); 7.39-7.52 (1H, m); 7.67 (1H, s); 8.06 (1H, s).

 PRI me R 14. A mixture of (2RS, 3SR) -2- (2,4-difluoromethyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl-methyl) oxirane ( 0.5 g), 1- (2-mercaptoethyl) - 1H-1,2,3-triazole (0.31 g) and 1M tetrabutylammonium fluoride (2.2 ml) in ethanol (20 ml) were heated in a flask with reverse refrigerator for 12 hours. Ethanol was then distilled off under reduced pressure, and the residue was diluted with water (25 ml) and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel columns (2.5 x 40 cm), eluting with a mixture of ethyl acetate, acetone and methanol (10: 2: 1). The target fraction was concentrated to give compound 13 (0.4 g) as an oily substance.

¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, d, I 7.2 Hz); 3.09-3.38 (3H, m); 4.37-4.59 (2H, m); 4.73 (1H, d, I 14 Hz); 4.93 (1H, d, I 14 Hz); 5.03 (1H, broad s); 6.69-6.78 (2H, m); 7.29-7.41 (1H, m); 7.78 (1H, s); 7.79 (1H, s); 8.02 (1H, s); 8.19 (1H, s).

 After treating this product (0.14 g) with hydrogen chloride in ethyl acetate, the hydrochloride salt of the title compound (0.11 g) was obtained as a colorless powder.

Mp 179-181 ^about S.

Elemental analysis for C ₁₆ H ₁₈ F ₂ N ₆ OS xx 2HCl ˙ 0.5 H ₂ O.

 Calculated, C 41.57; H 4.58; N, 18.18.

 Found, C, 41.87; H 4.41; N, 18.45.

 PRI me R 15. In a similar manner to that described in example 3, compound 13 (0.2 g) was oxidized with m-chloroperbenzoic acid (0.28 g), whereby compound 14 (0.8 g, 37%) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, I 7.2 Hz); 3.56-4.08 (3H, m); 4.76-4.82 (2H, m); 4.91 (1H, d, I 14.2 Hz); 5.36 (1H, d, I 14.2 Hz); 5.36 (1H, d, I 14.2 Hz); 5.71 (1H, s); 6.71-6.81 (2H, m); 7.18-7.32 (1H, m); 7.75 (1H, s); 7.77 (1H, s); 8.00 (1H, s); 8.25 (1H, s).

MSWI (m / z): 413 (M + H ⁺ ).

 PRI me R 16. A mixture of a solution of (2RS, 3SR) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1, 2,4-triazol-1-yl-methyl) oxirane (0.6 g), pyridin-4-methanethiol (0.45 g) and 28% sodium methoxide and methanol (0.55 g) in ethanol (12 ml) were heated in a flask under reflux for 1 h. Then ethanol drove away under reduced pressure, and the residue was chromatographed on silica gel columns (2.5 x 15 cm), eluting with a mixture of methanol and ethyl acetate (5:95). The target fraction was concentrated, and a mixture of ethyl acetate and diethyl ether was added to the residue, whereby compound 15 (0.67 g) was obtained as colorless needle crystals.

Mp 98-99 ^about S.

Elemental analysis for C ₁₈ H ₁₈ F ₂ N ₄ OS.

 Calculated, C 57.43; H 4.82; N, 14.88.

 Found, C, 57.12; H 4.70; N, 14.78.

¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, d, I 6.8 Hz); 3.16 (1H, q, 6.80 Hz); 3.80 (1H, d, I 13.8 Hz); 3.92 (1H, d, I 13.8 Hz); 4.57 (1H, d, I 14.2 Hz); 4.97 (1H, d, I 14.2 Hz); 5.04 (1H, s); 6.64-6.77 (2H, m); 7.28-7.40 (1H, m); 7.31 (2H, d, I 6.0 Hz); 7.74 (1H, s); 7.76 (1H, s); 8.59 (2H, d, I 6.0 Hz).

 PRI me R s 17-19. In a manner similar to that described in example 16, the reaction of interaction (2RS-3SR) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1, 2,4-triazol-1-yl-methyl) was carried out oxirana (methyloxy compound in table 12) with various thiols shown in table. 12, whereby compounds 16, 22 and 23 were obtained.

PRI me R 20. A mixture of a solution of 2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) propan-2-ol (1 , 2 g), 2- (2-chloroethylthio) -1-methylimidazole (1.2 g) and 28% sodium methanol methoxide (0.94 g) in ethanol (30 ml) were heated in a flask under reflux for 2 h. Then, ethanol was distilled off under reduced pressure, and the residue was chromatographed on silica gel (3.5 x 15 cm), eluting with a mixture of methanol and ethyl acetate (5:95). The target fraction was concentrated, and dichloromethane and diethyl ether were added to the residue, whereby compound 18 (0.9 g) was obtained as colorless needle crystals. Mp 92-93 ^about S.

Elemental analysis for C ₁₇ H ₁₉ F ₂ N ₅ OS ₂ .

 Calculated, C 49.62; H 4.65; N, 17.02.

 Found, C, 49.45; H 4.71; N, 16.84.

¹ H-NMR (CDCl ₃ ) δ: 2.89 (2H, broad t, I, 7.4 Hz); 3.22-3.30 (2H, m); 3.20 (1H, d, I 14.8 Hz); 3.39 (1H, d, I 14.8 Hz); 3.57 (3H, s); 4.65 (1H, d, I 14.2 Hz); 4.75 (1H, d, I 14.2 Hz); 6.19 (1H, s); 6.74-6.85 (2H, m); 6.92 (1H, s); 6.98 (1H, s); 7.47-7.60 (1H, m); 7.76 (1H, s); 8.07 (1H, s).

 EXAMPLES 21 and 22. By a method similar to that described in example 20, the reaction of interaction 2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1 -yl) propan-2-ol, (shown in Table 13 as a thiol derivative with the chlorine derivative shown in Table 13, whereby compounds 20 and 24 were obtained.

Example 23 Compound 16 (0.52 g), prepared as described in Example 17, was dissolved in diethyl ether (30 ml), after which hydrogen chloride in ethyl acetate was added to this solution. The resulting mixture was allowed to settle and the supernatant was removed by decantation. The residue was diluted with diethyl ether (30 ml), settled, and the supernatant was removed by decantation. The residue was dissolved in ethanol (10 ml), and then ethyl acetate (100 ml) was added thereto, and the resulting mixture was kept for one day for crystallization. The resulting crystals were collected by filtration and dried under reduced pressure, whereby a 16-hydrochloride compound (0.49 g) was obtained. Mp 114-116 ^about S.

Elemental analysis for C ₁₇ H ₁₉ F ₂ N ₅ OS xx 2HCl ˙ H ₂ O.

 Calculated, C 43.41; H 4.93; N, 14.89.

 Found, C, 43.76; H 4.72; N, 14.96.

¹ H-NMR (DMCO-d ₆ ) δ: 1.05 (3H, d, I 6.6 Hz); 3.43 (1H, q, I 6.6 Hz); 3.90 (3H, s); 4.32 (1H, d, I 15.4 Hz); 4.45 (1H, d, I 15.4 Hz); 4.56 (1H, d, I 14.4 Hz); 4.86 (1H, d, I 14.4 Hz); 6.95 (1H, m); 7.10-7.40 (2H, m); 7.68 (1H, s); 7.73 (1H, s); 7.82 (1H, s); 8.54 (1H, s).

 PRI me R 24. A mixture of (2RS-3SR) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxyran (0, 3 g), 2-methyl-1,3,4-thiadiazole-5-thiol (0.19 g) and 1M tetrabutylammonium fluoride (1.3 ml) in ethanol (10 ml) were heated in a flask under reflux for 4 , 5 hours. Then ethanol was distilled off under reduced pressure, and the residue was diluted with water (15 ml) and extracted with ethyl acetate.

The extract was washed with water and a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel columns (2.5 x 30 cm), eluting with a mixture of ethyl acetate and dichloromethane (3: 2). The target fraction was concentrated, and a mixture of ether and isopropyl ether (1: 2) was added to the residue, whereby compound 26 (0.07 g) was obtained as colorless prismate crystals. Mp 130-131 ^about S.

Elemental analysis for C ₁₅ H ₁₅ F ₂ N ₅ OS.

 Calculated, C 46.99; H 3.94; N, 18.26.

 Found, C 46.77; H 3.86; N, 18.06.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, I 7 Hz); 2.77 (3H, s); 4.62 (1H, q, I 7 Hz); 4.89 (1H, d, I 13.8 Hz); 5.12 (1H, d, I 13.8 Hz); 5.97 (1H, s); 6.72-6.86 (2H, m); 7.41-7.52 (1H, m), 7.75 (1H, s), 7.91 (1H, s).

PRI me R 25. A mixture of (2RS, 3SR) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxyran (0, 25 g), 2-imidazo [1,2-a] pyridinomethanethiol (0.25 g), 28% sodium methoxide and methanol (0.25 ml) and ethanol (7.5 ml) were heated under reflux for 2 hours The reaction mixture was concentrated under reduced pressure, and the residue was diluted with methylene chloride (20 ml) and water (20 ml), and then extracted with methylene chloride. The methylene chloride layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was chromatographed on silica gel (2.5 x 7.0 cm), eluting with ethyl acetate. The target fraction was concentrated to give compound 27 (0.25 g) as a syrup. This syrup (0.19 g) was dissolved in diethyl ether (30 ml), and then hydrogen chloride in ethyl acetate was added thereto. The resulting mixture was sedimented and the supernatant was removed by decantation. The residue was diluted with 30 ml of diethyl ether, and the supernatant was removed by decantation. A mixture of diethyl ether and ethanol was added to the residue to crystallize, and compound 27 hydrochloride (0.17 g) was obtained. Mp 123-125 ^about S.

Elemental analysis for C ₂₀ H ₁₉ F ₂ N ₅ OS xx 2HCl ˙ 1 / 2H ₂ O.

 Calculated, C 48.30; H 4.46; N, 14.08.

 Found, C 48.38; H 4.44; N 13.92.

¹ H-NMR (DMCO-d ₆ ) δ: 1.08 (3H, d, I 8.2 Hz); 3.43 (1H, q, I, 8.2 Hz); 4.22 (1H, d, I 14.4 Hz); 4.32 (1H, d, I 14.4 Hz); 4.68 (1H, d, I 14.6 Hz); 4.99 (1H, d, I 14.6 Hz); 6.92 (1H, m); 7.12 (1H, m), 7.29 (1H, m), 7.50 (1H, m); 7.77 (1H, s); 7.97 (2H, m); 8.37 (1H, s); 8.64 (1H, s); 8.98 (1H, d, I 6.6 Hz).

PRI me R 26. To a solution of (2RS, 3SR) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2- butanol (0.30 g) in ethanol (3 ml) was added 28% sodium methoxide-ethanol (0.98 ml) at room temperature. After adding 1-methyl-5-chloromethylimidazole hydrochloride (0.48 g), the mixture was stirred for 10 minutes. This reaction mixture was diluted with diethyl ether (30 ml) and water (30 ml) and extracted with diethyl ether (30 ml x 3). The diethyl ether layers were combined, washed with a saturated aqueous solution of sodium chloride (20 ml), dried with anhydrous sodium sulfate and concentrated under reduced pressure. Diethyl ether was added to the residue to give (2RS, 3SR) -2- (2,4-difluorophenyl) -3- (1-methylimidazol-5-yl) methylthio-1- (1H-1, 2,4-triazol-1 -yl) -2-butanol compound 29 (0.30 g) as crystals. These crystals were recrystallized from a mixture of ethanol and diethyl ether, whereby colorless needle crystals (0.27 g) were obtained. Mp 159-160 ^about C.

Elemental analysis for C ₁₇ H ₁₉ F ₂ N ₅ OS.

 Calculated, C 53.81; H 5.05; N, 18.46.

 Found, C, 53.40; H 5.23; N, 18.22.

¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, d, I 7.0 Hz); 3.20 (1H, q, I, 7.0 Hz); 3.73 (3H, s); 3.82 (1H, d, I 14.8 Hz); 3.91 (1H, d, I 14.8 Hz); 4.45 (1H, d, I 14.2 Hz); 4.83 (1H, d, I 14.2 Hz); 5.00 (1H, broad s); 6.72 (2H, m); 7.01 (1H, s); 7.35 (1H, m); 7.48 (1H, s); 7.72 (1H, s); 7.77 (1H, s).

 PRI me R s 27-37. In a manner similar to that described in example 26, the reaction of interaction (2RS, 3SR) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2 was carried out -butanol, indicated in the table. 14 with a methylthiol derivative, with chlorine compounds shown in Table 14, whereby compounds 25, 28 and 30-38 were obtained.

 PRI me R 38. A mixture of (2RS, 3SR) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxyran (7 g ), methyl 3-mercaptopropionate (30.8 ml) and 28% sodium methoxide methanol (19.6 ml) in methanol (210 ml) were heated under reflux for 2 hours. Then 28% sodium methanol methoxide was added. (9.8 ml) and the mixture was heated under reflux for another 1 hour. After this, methyl 3-mercaptopropionate was added and the mixture was heated under reflux for another 2 hours. Then the reaction mixture was cooled, diluted with water (100 ml), neutralized with 5% aqueous phosphoric acid They were extracted with methylene chloride (200 ml × 2). The extract was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (4 x 50 cm), eluting with a mixture of ethyl acetate and hexane (3: 1), and the target fraction was concentrated. Ether was added to the residue to give compound 39 (5.5 g) as colorless needle crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, I 7.0 Hz); 1.96 (1H, d, I 10.2 Hz); 3.45 (1 H, doublet. Q. I 7.0 Hz, I 10.2 Hz); 4.77 (1H, s); 4.82 (1H, d, I 14.4 Hz); 5.01 (1H, d, I 14.4 Hz); 6.70-6.81 (2H, m); 7.33-7.45 (1H, m); 7.79 (1H, s); 7.80 (1H, s). Mp 145-147 ^about S.

Example 39. To dichloromethane (5 ml) was added (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1- il) -2-butanol (0.3 g), and then triethylamine (0.16 ml) was added under ice-cooling. Then, acetyl chloride (0.082 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. Then, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (2.5 x 20 cm), eluting with a mixture of ethyl acetate and hexane (2: 1). The target fraction was concentrated, hexane was added to the residue, whereby compound 40 (0.2 g) was obtained as colorless needle crystals. Mp 73-75 ^about S.

Elemental analysis of C ₁₄ H ₁₅ F ₂ N ₃ O ₂ .

 Calculated, C 51.37; H 4.62; N, 12.84.

 Found, C, 51.19; H 4.53; N, 12.84.

¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, d, I 7.2 Hz); 2.42 (2H, s); 4.29 (1H, q, I, 7.2 Hz); 4.67 (1H, d, I 15.2 Hz); 4.91 (1H, d, I 15.2 Hz); 5.09 (1H, s); 6.69-6.88 (2H, m); 7.26-7.43 (1H, m); 7.77 (1H, s); 7.78 (1H, s).

 PRI me R 40. A mixture of (2S, 3R) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxiran (30 il ), methyl 3-mercaptopropionate (0.09 ml) and 28% sodium methoxide-methanol (0.08 ml) in methanol (2 ml) were heated under reflux for 2 hours, after which a mixture of 28% sodium methoxide was added and methanol (0.04 ml) and the resulting mixture was heated under reflux for another 1 hour. Then methyl 3-mercaptopropionate (0.04 ml) was added and the mixture was heated under reflux for another 2 hours. The reaction mixture was cooled diluted with water (2 ml), not a centrally 5% aqueous solution of phosphoric acid and extracted with methylene chloride (3 ml x 2). The extract was dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (1 x 5 cm), eluting with a mixture of ethyl acetate and hexane (3: 1). The target fraction was concentrated, and the residue was crystallized from a mixture of ethyl acetate and isopropyl ether to give (2S, 3S) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2, 4-triazole -1-yl) -2-butanol (compound 42 11 g) as colorless prismatic crystals.

[α] _D ²⁵ + 55.7 ^° (s 1.0, methanol).

¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, I 6.8 Hz); 1.96 (1H, d, I 10.4 Hz); 3.39-3.54 (1H, m); 4.75 (1H, s); 4.81 (1H, d, I 14.4 Hz); 5.01 (1H, d, I 14.4 Hz); 6.69-6.81 (2H, m); 7.33-7.46 (1H, m); 7.79 (1H, s); 7.80 (1H, s). T.pl. 175-178 ^about S.

 To determine the excess of the enantiomer, the resulting product S was acetylated (compound 44 in Example 43) and analyzed by high-resolution liquid chromatography using a chiral column (Chiralcel OF, 0.46 cm x 25 cm, Daicel Chemical, mobile phase: 7: 3 hexanisopropyl alcohol ) At a flow rate of 1 ml / min, compound 44 had basically one peak at a retention time of 10 minutes and the excess of enantiomer was 97.4%. The corresponding racemic compound (compound 40 in Example 39) had two peaks at a ratio of 1: 1 at a retention time of 10 and 17 min under the same conditions.

PRI me R 41. In methanol (10 ml) was dissolved (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazole-1- il) methyloxyran (0.40 g), methyl 3-mercaptopropionate (1.42 ml) and 28% sodium methoxide methanol (1.25 ml). The resulting solution was heated under reflux. Then after 2 hours, and then after 3.5 hours, methyl 3-mercaptopropionate (0.53 and 0.32 ml) was added, and after 2.5 minutes 28% sodium methoxide methanol (0.63 ml) was added. 4.5 hours after the start of heating, the oil bath was removed, and the reaction mixture was cooled, neutralized 1N. hydrochloric acid (9.6 ml) and was extracted with dichloromethane (100 ml). The extract was washed with a saturated aqueous solution of sodium chloride (20 ml) and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (1: 3). The target fraction was concentrated and the resulting crystals were collected and washed with isopropyl ether, whereby (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole) was obtained -1-yl) -2-butanol (compound 43, 0.22 g) as colorless needle crystals. Mp 176-178 ^about S.

[α] _D ²⁵ -56.8 ^about (s 0.7, methanol).

Elemental analysis for C ₁₂ H ₁₃ F ₂ N ₃ OS
Calculated, C 50.52; H 4.59; N, 14.73.

 Found, C, 50.81; H 4.64; N, 14.64.

¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, I 7.0 Hz); 1.96 (1H, d, I 10.2 Hz); 3.45 (1H, m); 4.76 (1H, s); 4.82 (1H, d, I 14.4 Hz); 5.01 (1H, d, I 14.4 Hz); 6.74 (2H, m); 7.33-7.45 (1H, m); 7.79 (2H, s).

OF, 0,46 х 25 см, Daicel Chemical, подвижная фаза: гексанизопропиловый спирт 7,3). При скорости потока 1 мл/мин соединение 45 имело в основном один пик при времени удерживания 17 мин, а избыток энантиомера составлял 99,7% Соответствующее рацемическое соединение (соединение 40 в примере 39) имело два пика в отношении (1:1) при времени удерживания 10 и 17 мин при тех же условиях.In order to determine the excess of the enantiomer, the resulting product S was acetylated (compound 45 in Example 44) and analyzed by high resolution liquid chromatography using a chiral column (Chiralce

OF, 0.46 x 25 cm, Daicel Chemical, mobile phase: hexanisopropyl alcohol 7.3). At a flow rate of 1 ml / min, compound 45 had basically one peak at a retention time of 17 minutes, and the excess of the enantiomer was 99.7%. The corresponding racemic compound (compound 40 in Example 39) had two peaks at a ratio of (1: 1) at time holding for 10 and 17 minutes under the same conditions.

 PRI me R 42. To dichloromethane (1 ml) was added (2S, 3S) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1- il) -2-butanol (3 mg), then a triethylamine dichloromethane solution (10% 16 μl) was added under ice-cooling. After this, a dichloromethane solution of acetyl chloride (10% 8.2 μl) was added and the resulting mixture was stirred at room temperature for 30 minutes. Then, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (1 x 1 cm), eluting with a mixture of ethyl acetate and hexane (2: 1). The target fraction was concentrated to give (2S, 3S) -3-acetylthio-2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol (compound 44, 1.2 mg) as a colorless solid.

 PRI me R 43. In dichloromethane (1.5 ml) was dissolved (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole- 1-yl) -2-butanol (60 mg), after which triethylamine (33 ml) and acetyl chloride (13 ml) were added to the solution, cooling with ice. The mixture was then stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (1: 2), and the target fraction was concentrated, whereby (2R, 3R) -3-acetylthio-2- (2,4-difluorophenyl) -1- was obtained (1H-1,2,4-triazol-1-yl) -2-butanol (compound 45, 59 mg) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, d, I 7.2 Hz); 2.42 (3H, s); 4.31 (1H, d, I 7.2 Hz); 4.67 (1H, d, I 14.4 Hz); 4.92 (1H, d, I 14.4 Hz); 5.11 (1H, d, I 1.8 Hz); 6.69-6.88 (2H, m); 7.27-7.43 (1H, m); 7.78 (2H, s).

The excess enantiomer of this product was 99.7%
PRI me R s 44-53. In a manner similar to that described in example 26, the reaction of interaction (2RS, 3SR) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl-2- butanol) [(2R 3R) methyl derivative in Table 15] with the chloro compounds shown in Table 15, whereby compounds 46-49, 51-55 and 59 were obtained.

PRI me R 54. A mixture of (2RS, 3RS) -2- (2,4-difluorophenyl) -1-methyl-2- (1H-triazol-1-yl-methyl) oxirane (0.18 g), 1-methyl-2- (2-mercaptoethyl) imidazole (0.1 g), 28% sodium methanol methoxide (0.20 ml) and ethanol (5.4 ml) were heated under reflux for 1 h. Then the reaction mixture was diluted with water (10 ml) and was extracted with diethyl ether (20 ml x 3). The extract was washed with a saturated aqueous solution of sodium chloride (10 ml), dried with anhydrous sodium sulfate and concentrated under reduced pressure. Diethyl ether was added to the residue, and crude crystals (2RS, 3RS) -2- (2,4-difluorophenyl) -3- [2- (1-methylimidazol-2-yl) ethyl] thio-1- (1H-1, 2,4-triazol-1-yl) -2-butanol (0.088 g). The crystals were recrystallized from ethyl acetate to give 0.050 g of a compound (compound 50). Mp 175-176 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, I 6.6 Hz); 2.7-3.6 (5H, m); 3.60 (3H, s); 4.71 (1H, d, I14.2 Hz); 5.03 (1H, d, I 14.2 Hz); 6.87-6.77 (2H, m); 6.87 (1H, s); 7.08 (1H, s); 7.43-7.55 (1H, m); 7.69 (1H, s); 7.82 (1H, s); 8.03 (1H, s).

Elemental analysis for C ₁₈ H ₂₁ F ₂ N ₅ OS.

 Calculated, C 54.95; H 5.38; N, 17.80.

 Found, C, 55.04; H 5.39; N, 17.62.

PRI me R 55. To a solution of (2RS, 3RS) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2- butanol (0.060 g), 4-bromomethyl-5-methyl-2-oxo-1,3-dioxol (0.049 g) in N, N-dimethylformamide (2 ml) was added anhydrous carbonate (0.2 g) at -20 ^about C and the resulting mixture was stirred for 10 minutes. Ethyl acetate (10 ml) and water (10 ml) were added to the reaction mixture, and the organic layer was separated. The mixture was then extracted with ethyl acetate (10 ml x 2). The organic layers were combined, washed with saturated aqueous sodium chloride (10 ml), dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (1 x 5 cm), eluted with a mixture of ethyl acetate and hexane (1: 1). The target fraction was concentrated and the residue was crystallized from a mixture of chloroform and diethyl ether to give (2RS, 3RS) -2- (2,4-difluorophenyl) -3- (5-methyl-2-oxo-1,3-dioxole -4-yl) methylthio-1- (1H-1,2,4-triazol-1-yl) -2-butanol (compound 56, 0.065 g), mp 173-174 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, I 7.0 Hz); 2.15 (3H, s); 3.32 (1H, q, I, 7.0 Hz); 3.67 (1H, d, I 15.4 Hz); 3.77 (1H, d, I 15.4 Hz); 4.83 (1H, d, I 14.2 Hz); 5.04 (1H, d, I 14.2 Hz); 5.11 (1H, d, I 1.6 Hz); 6.68-6.79 (2H, m); 7.30-7.42 (1H, m); 7.79 (1H, s); 7.80 (1H, s).

Elemental analysis for C ₁₇ H ₁₇ F ₂ N ₃ O ₄ S.

 Calculated, C 51.38; H 4.31; N, 10.57.

 Found, C, 51.39; H 4.30; N, 10.55.

 Example 56. N- (2-pyrazinylmethyl) chloroacetamide (0.5 g) was dissolved in 1,2-dichloroethane (5 ml), and then phosphorus oxychloride (5 ml) was added at room temperature. The mixture was refluxed for 40 minutes and then concentrated under reduced pressure. The residue was dissolved in methanol (1 ml) and diethyl ether was added, whereby crude 3-chloromethylimidazo [1,5-a] pyrazine hydrochloride was obtained in powder form (0.46 g). This powder (0.18 g) was added to a mixture of (2RS, 3RS) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H, 2,4-triazol-1-yl) -2-butanol (0.25 g), ethanol (2.5 ml) and 28% sodium methoxide and methanol (0.36 ml) at room temperature. The resulting mixture was stirred for 7 minutes.

 Then the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 3). The organic layers were combined, washed with saturated aqueous sodium chloride (10 ml), dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed (2 x 8 cm), eluting with methanol-methylene chloride (5:95). The desired fractions were combined and then chromatographed on silica gel (2 x 8 cm), eluting with a mixture of methylene chloride and ethyl acetate (1: 2). The desired fractions were combined and concentrated. A mixture of diethyl ether and hexane was added to the residue, whereby (2RS, 3RS) -2- (2,4-difluorophenyl) -3- (imidazo [1,5-a] pyradin-3-yl) methylthio-1- was obtained (1H-1,2,4-triazol-1-yl) -2-butanol (compound 57, 0.02 g) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, d, I 7.0 Hz), 3.34 (1H, q, I 7.0 Hz); 4.28 (1H, d, I 15 Hz); 4.38 (1H, d, I 15 Hz); 4.49 (1H, d, I 14.4 Hz); 4.86 (1H, d, I 14.4 Hz); 5.56 (1H, broad s); 6.66-6.77 (2H, m); 7.27-7.44 (1H, m); 7.62 (1H, d, I 5.0 Hz); 7.74 (1H, s); 7.77 (1H, s); 7.80 (1H, s); 7.86 (1H, d, I 5.0 Hz); 9.01 (1H, d, I 1.4 Hz).

MSWI (m / z): 417 (MH ⁺ ).

 PRI me R 57. A methanol solution (25 ml) containing (2RS, 3RS) -2- (2,4-difluorophenyl) -3-methyl-2- (1H-1,2,4-triazole-1 -yl) methyloxyran (1.1 g), methyl 3-mercaptopropionate (2.5 ml), 28% sodium methanol methoxide (2.4 ml), was heated under reflux for 3 hours. After addition of 28% sodium methoxide methanol (1.2 ml), the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was diluted with water (25 ml), neutralized with a 5% aqueous phosphoric acid solution, and extracted with methylene chloride (25 ml x 3 ) The extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (4 x 50 cm), eluting with a mixture of ethyl acetate and hexane (3: 1). The target fraction was concentrated, ether was added to the residue, and compound 60 (0.5 g) was obtained as colorless needle crystals.

The resulting product (0.5 g) was recrystallized from ethyl acetate (40 ml), whereby colorless prismatic crystals (2 g) of compound 60 were obtained. 107-109 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, I Hz); 2.11 (1H, d, I 8.4 Hz); 3.61 (1H, q, I 7 Hz); 6.42 (1H, d, I 14.2 Hz); 4.71 (1H, d, I 14.2 Hz); 5.84 (1H, s); 6.81-6.92 (1H, m); 6.99-7.15 (1H, m); 7.21-7.37 (1H, m); 7.65 (1H, m); 8.23 (1H, s).

Elemental analysis for C ₁₂ H ₁₃ F ₂ N ₃ OS.

 Calculated, C 50.52; H 4.59; N, 14.73.

 Found, C, 50.31; H 4.59; N, 14.60.

Example 58. To dichloromethane (5 ml) was added (2RS, 3RS) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1- il) -2-butanol (0.35 g), and then triethylamine (0.18 ml) was added by cooling with ice. Then acetyl chloride (0.1 ml) was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. After that, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (2.5 x 20 cm), eluting with a mixture of ethyl acetate and hexane (2: 1). The target fraction was concentrated, and hexane was added to the residue, whereby compound 61 (0.22 g) was obtained as colorless needle crystals. Mp 128-130 ^about C.

¹ H-NMR (CDCl ₃ ) δ: 1.57 (3H, d, I 7 Hz); 2.14 (3H, s); 4.22 (1H, q, I 7 Hz); 4.55 (1H, d, I 14 Hz); 4.99 (1H, d, I 14 Hz); 5.13 (1H, s); 6.62-6.79 (2H, m); 7.31-7.42 (1H, m); 7.77 (1H, s); 7.87 (1H, s).

Elemental analysis for C ₁₄ H ₁₅ F ₂ N ₃ O ₂ S.

 Calculated, C 51.37; H 4.62; N, 12.84.

 Found, C 51.32; H 4.61; N, 12.71.

Example 59. (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1-) was dissolved in dichloromethane (5 ml). il) -2-butanol (143 mg), followed by cooling with ice, triethylamine (0.076 ml) and isobuturyl chloride (58.6 mg) were added. The mixture was stirred at room temperature for 15 minutes, after which the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (1: 2). The target fraction was concentrated to give (2R, 3R) -2- (2,4-difluorophenyl) -3-isobuturylthio-1- (1H-1,2,4-triazol-1-yl) -2-butanol (compound 62, 140 mg) as a colorless syrup. This product was treated with 4n hydrochloric acid in ethyl acetate, whereby the hydrochloride salt of compound 62 (156 mg) was obtained as a colorless powder. Mp 129-138 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, d, I 7.0 Hz); 1.18 (6H, dd, I 6.8 Hz, I 4.0 Hz); 2.84 (1H, m); 4.33 (1H, q, I, 7.0 Hz); 4.67 (2H, s); 6.92 (1H, m); 7.08-7.30 (2H, m); 7.76 (1H, s); 8.42 (1H, s).

 PRI me R 60. Methyl 3-mercaptopropionate (0.88 ml) was added to N, N-dimethylformamide (14 ml) containing 60% sodium hydride in oil (0.32 g), while cooling ice. Then, after 5 minutes, a solution of 2- (2,4-difluorophenyl) -2- [1- (1H-1,2,4-triazol-1-yl) ethyl] oxirane (0, 67 g) in N, N-dimethylformamide (3.5 ml). After 15 minutes, the reaction mixture was poured into water (150 ml), neutralized with hydrochloric acid and extracted with ethyl acetate (50 ml x 3). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride (30 ml × 2), dried with sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (3 x 10 cm), eluting with a mixture of ethyl acetate and hexane (1: 1). The target fraction was concentrated and diethyl ether was added to the residue, whereby crude crystals (0.25 g) of 2- (2,4-difluorophenyl) -1-mercapto-3 - [(1H-1,2,4-) were obtained triazol-1-yl) -2-butanol] low polarity, compound 116, diastereomer B. The crystals were recrystallized from a mixture of chloroform and diethyl ether and 0.21 g of compound 116 was obtained. The mother liquor of the obtained crude crystals was chromatographed on silica gel (2 x 12 cm ), eluting with a mixture of ethyl acetate and hexane (1: 1). The target fraction was concentrated and diethyl ether and hexane were added to the residue, whereby crude crystals (0.25 g) of 2- (2,4-difluorophenyl) -1-mercapto-3 - [(1H-1,2,4- triazol-1-yl) -2-butanol] high polarity; compound 115, diastereomer A. These crystals were recrystallized from a mixture of chloroform and diethyl ether to give crystals of compound 115 (0.611 g).

 Compound 115 (diastereomer A).

Mp 112-117 ^about With, colorless prismatic crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.19 (1H, t, I 8.2 Hz; 1.69 (3H, d, I 7.0 Hz); 3.05 (1H, d, I 8, 2 Hz, d, I 14.0 Hz); 3.31 (1H, d, I 8.2 Hz, d, I 14 Hz); 4.55 (1H, s); 5.06 (1H, q, I 7.0 Hz); 6.68-6.79 (2H, m); 7.23-7.35 (1H, m); 7.73 (1H, s); 7.88 (1H, s) .

 Compound 116 (diastereomer B).

Mp 183-184 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 0.93 (1H, d, I 6.8 Hz, d, I 10.2 Hz); 1.36 (3H, d, I 7.0 Hz); 2.18 (1H, d, I 14 Hz, d, I 10.2 Hz); 3.28 (1H, d, I 6.8 Hz, d, I 14 Hz); 4.19 (1H, s); 5.09 (1H, q, I, 7.0 Hz); 6.80-7.04 (2H, m); 7.67-7.79 (1H, m); 7.99 (1H, s); 8.29 (1H, s).

PRI me R 61. To ethanol (25 ml) was added (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1- il) -2-butanol (0.9 g) and 4-chloromethyl-2-methylthiazole hydrochloride (0.7 g), and then, with constant stirring at room temperature, a 28% mixture of sodium ethoxide and ethanol was added (1, 3 ml). After this, the mixture was stirred at room temperature for 30 minutes, and then ethyl acetate (100 ml) and water (100 ml) were added. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml). The ethyl acetate layers were combined, washed with water (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2.9 x 100 cm), eluting with a mixture of ethyl acetate and acetone (4: 1). The target fraction was concentrated to give compound 107 (0.8 g) as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, I 7.2 Hz); 2.79 (3H, s); 3.49 (1H, q, I, 7.2 Hz); 3.82 (1H, d, I 14.6 Hz); 4.06 (1H, d, I 14.6 Hz); 4.68 (1H, d, I 14.6 Hz); 5.08 (1H, d, I 14.6 Hz); 6.25 (1H, s); 6.69-6.78 (2H, m); 6.93 (1H, s); 7.36-7.50 (1H, m); 7.72 (1H, s); 7.83 (1H, s).

This product (0.8 g) was treated with 4 N. HCl-ethyl acetate and received the hydrochloride salt of the compound as colorless crystals (0.64 g). Mp 165-167 ^about S.

[α] _D ²³ 83.1 ^about (s 1.0, methanol).

Elemental analysis for C ₁₇ H ₁₈ F ₂ N ₄ OS ₂ x x 2HCl ˙ 1/2 H ₂ O.

 Calculated, C 42.68; H 4.42; N, 11.71.

 Found, C, 42.64; H 4.37; N, 11.59.

 PRI me R 62. In ethanol (7.5 ml) was dissolved (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole- 1-yl) -2-butanol (0.74 g), and then, stirring at room temperature, 28% sodium methoxide-methanol (1.06 ml) and 2-chloromethyl-1-cyclopropylimidazole hydrochloride ( 0.5 g). The mixture was stirred at room temperature for 10 minutes, then diluted with water (20 ml) and extracted with ethyl ether (20 ml x 3). The extract was washed with a saturated aqueous solution of sodium chloride, dried with magnesium sulfate and concentrated under reduced pressure.

 The residue was purified by chromatography on silica gel, eluting with a mixture of: ethyl acetate-ethyl acetate-methanol = 95: 5 and crystallized from ethyl ether to give compound 110 (0.82 g) as colorless prismate crystals.

[α] _D ²³ 119.5 ^about (s 1.0, methanol).

Mp 127-128 ^about S.

Elemental analysis for C ₁₉ H ₂₁ F ₂ N ₅ O ₁ S ₁ .

 Calculated, C 56.28; H 5.22; N, 17.27.

 Found, C 56.34; H 5.26; N, 17.14.

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.17 (4H, m); 1.26 (3H, d, I 7.0 Hz); 3.20-3.33 (1H, m); 3.60 (1H, q, I, 7.0 Hz); 3.94 (1H, d, I 15.4 Hz); 4.03 (1H, d, I 15.4 Hz); 4.62 (1H, d, I 14.2 Hz); 4.88 (1H, d, I 14.2 Hz); 6.67-6.80 (2H, m); 6.87 (1H, s); 6.93 (1H, s); 7.40-7.53 (1H, m); 7.65 (1H, s); 7.68 (1H, s); 8.03 (1H, s).

PRI me R 63. In N, N-dimethylformamide (30 ml) was dissolved (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4- triazol-1-yl) -2-butane (1 g) and 4-bromomethyl-5-methyl-1,3-dioxol-2-one (0.81 g), and then, while stirring at room temperature, potassium carbonate was added (3 g). After this, the mixture was stirred for 7 minutes, and then water (100 ml) was added and extracted with ethyl acetate (50 ml x 3). The organic layers were combined, washed with a saturated aqueous solution of chloride (30 ml x 2), dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and hexane (1: 1 - >> 2: 1), and the resulting oily substance was crystallized from a mixture of chloroform and ethyl acetate, whereby compound 111 (1 g) was obtained as a colorless needle crystals. Mp 133-134 ^about S.

[α] _D ²³ 77g, 8 ^o (c = 1.0, methanol).

Elemental analysis for C ₁₇ H ₁₇ F ₂ N ₃ O ₄ S ₁ .

 Calculated, C 51.38; H 4.31; N, 10.57.

 Found, C 51.20; H 4.35; N, 10.52.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, I 7.2 Hz); 2.15 (3H, s); 3.32 (1H, q, I, 7.2 Hz); 3.67 (1H, d, I 15.2 Hz); 3.77 (1H, d, I 15.2 Hz); 4.83 (1H, d, I 14.2 Hz); 5.04 (1H, d, I 14.2 Hz); 5.11 (1H, d, I 1.4 Hz); 6.68-6.79 (2H, m); 7.30-7.42 (1H, m); 7.79 (1H, s); 7.80 (1H, s).

 PRI me R 64. (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2-butanol ( 0.25 g) was dissolved in ethanol (2.5 ml), and then, with stirring at room temperature, 28% sodium methoxide-methanol (0.36 ml) and 3-chloromethyl-4-cyclopropyl-4H-1 were added. 2,4-triazole hydrochloride (0.17 g). The mixture was stirred for 10 minutes and then diluted with saturated aqueous sodium chloride (3 ml) and extracted with ethyl acetate (10 ml x 3). The organic layers were combined and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of methylene chloride and methanol (98: 2 - >> 1: 9), whereby compound 114 (0.29 g) was obtained as a colorless oily product.

¹ H-NMR (CDCl ₃ ) δ: 1.01-1.1 (4H, m); 1.18 (3H, d, I 6.8 Hz); 3.28-3.40 (1H, m); 3.57 (1H, q, I, 6.8 Hz); 4.04 (1H, d, I 15 Hz); 4.16 (1H, d, I 15 Hz); 4.64 (1H, d, I 14.2 Hz); 4.84 (1H, d, I 14.2 Hz); 5.58 (1H, s); 6.66-6.80 (2H, m); 7.30-7.43 (1H, m); 7.73 (1H, s); 7.86 (1H, s); 8.12 (1H, s).

 The resulting product was dissolved in ethyl acetate, and then a mixture of hydrogen chloride and ethyl acetate was added. The precipitate was crystallized from a mixture of ethanol and ethyl acetate to give the compound 114 dihydrochloride (0.31 g) as a colorless powder.

[α] _D ²³ 75.6 ^about (s 1.0, methanol).

 PRI me R s 65-75. In a manner similar to that described in example 64, the reaction of interaction (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) was carried out -2-butanol indicated in Table 16 2R, 3R-methylthiol, derivatives. with chloro compounds shown in table 16, resulting in the obtained compounds 78, 97, 99, 108, 112, 121-125.

Example 76. (2S, 3S) -2- (2,4-difluorophenyl) -3-methyl-2 - [(1H) -1,2,4-triazole- was dissolved in methanol (25 ml). 1-yl) methyl] oxyran (1 g), methyl 3-mercaptopropionate (3.5 ml) and 29% sodium methoxide-methanol (3.07 g). The resulting solution was heated under reflux in an oil bath. After 2 and 3 hours, methyl 3-methylpropionate (1.75 ml) and 28% sodium methoxide-methanol (1.5 g) were added. After heating for 4 hours, the oil bath was removed, and the reaction mixture was neutralized with cold 1N. hydrochloric acid (32 ml) and was extracted with dichloroethane (200 ml). The extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (1: 3). The target fraction was concentrated and the obtained crystals were recrystallized from a mixture of ethyl acetate and hexane, whereby (2S, 3S) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4- triazol-1-yl) -2-butanol (compound 117, 472 mg) as colorless needle crystals. T. pl. 141-144 ^about S.

[α] _D ²⁵ + 61.1 ^about (s 1.0, in methanol).

Elemental analysis for C ₁₂ H ₁₃ F ₂ N ₃ OS.

 Calculated, C 50.52; H 4.59; N, 14.73.

 Found, C, 50.51; H 4.59; N, 14.49.

¹ H-NMR (CDCl ₃ ) δ: 1.52 (3H, d, I 7 Hz); 1.54 (1H, d, I 6 Hz); 3.69 (1H, m); 4.56 (1H, s); 4.62 (1H, d, I 14 Hz); 4.94 (1H, dd, I 14 Hz, I 1.8 Hz); 6.68-6.81 (2H, m); 7.30-7.43 (1H, m); 7.73 (1H, s); 7.95 (1H, s).

IR (KBr), cm ^-1 : 3260, 1615, 1500, 1420, 1260, 1200, 1125.

PRI me R 77. In trifluoroacetic acid (75 ml) was dissolved [1- (1,2,4-difluorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl-1- (4-label sibecyclopropane (4.26 g), anisole (26 ml) and mercury acetate [II] (3.58 g). The resulting solution was stirred at room temperature for 2 hours. Then the reaction mixture was concentrated under reduced pressure, and the residue was diluted with petroleum ether (50 ml) and the supernatant was removed. Ether (30 ml) was added to the residue, resulting in a mercury compound as a colorless powder. The powder was collected by filtration and washed a small amount (10 ml) of ether.The resulting product (6.2 g) was suspended in dichloromethane (150 ml) and hydrogen sulfide was bubbled into the suspension at room temperature for 30 minutes, the resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel (2.5 x 40 ml), eluting with a mixture of ethyl acetate and hexane (3: 1). The target fraction was concentrated and the residue was treated with isopropyl ether, whereby compound 120 (2 g) was obtained as colorless needle crystals. Mp 92-94 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 0.72-1.28 (4H, m); 2.26 (1H, s); 4.80 (1H, dd, I 1.6 Hz, 14 Hz); 5.19 (1H, broad s); 5.31 (1H, dd, I 1.6, 14 Hz); 6.63-6.88 (2H, m); 7.54-7.66 (1H, m); 7.81 (1H, s); 8.14 (1H, dd, I = 1.6 Hz).

Elemental analysis for C ₁₃ H ₁₃ F ₂ N ₃ OS.

 Calculated, C 52.52; H 4.41; N, 14.13.

 Found, C, 52.41; H 4.45; N, 13.97.

PRI me R 78. In methanol (25 ml) was dissolved (2R, 3R) -2- (2,4-difluorophenyl) -3-methyl-2 - [(1H-1,2,4-triazole-1 -yl) methyl] oxyran (0.98 g), methyl 3-mercaptopropionate (3.3 ml) and 28% sodium methoxide-methanol (3 g). The resulting solution was heated under reflux in an oil bath. After 2 and then after 3 hours, methyl 3-methyl propionate (0.83 ml) and 28% sodium methoxide-methanol (0.75 g) were respectively added. After heating for 4 hours, the oil bath was removed, and the reaction mixture was neutralized with cold 1N. HCl (23 ml) and was extracted with dichloromethane (200 ml). The extract was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography, eluting with a mixture of hexane and ethyl acetate (1: 3). The target fraction was concentrated and the obtained crystals were recrystallized from ethyl acetate and hexane, whereby (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1) was obtained -yl) -2-butanol (compound 118, 461 mg) as colorless needle crystals. T, pl. 141-143 ^about S.

[α] _D ²⁵ 63.4 ^about (s 1.0, methanol).

Elemental analysis of C ₁₂ H ₁₃ F ₂ N ₃ OS.

 Calculated, C 50.52; H 4.59; N, 14.73.

 Found, C, 50.51; H 4.68; N, 14.53.

¹ H-NMR (CDCl ₃ ) δ: 1.52 (3H, d, I 7.0 Hz); 1.54 (1H, d, I 6 Hz); 3.69 (1H, m); 4.55 (1H, s); 4.62 (1H, d, I 14 Hz); 4.93 (1 H, doublet of doublets, I 14 Hz, I 1.8 Hz); 6.68-6.82 (2H, m); 7.29-7.45 (1H, m); 7.72 (1H, s); 7.95 (1H, s).

IR (KBr), cm ^-1 : 3260, 1615, 1500, 1420, 1200, 1120.

Example 79. 3- (4-Methoxybenzylthio) -2- (2,4-difluorophenyl) -3-methyl-1- (1H-1,2,4-triazole) was dissolved in trifluoroacetic acid (20 ml). -1-yl) -2-butanol (1.23 g), anisole (7.5 ml) and mercury [II] acetate (1.03 g). The resulting solution was stirred at room temperature for 2 hours. Then the reaction mixture was concentrated under reduced pressure, the residue was diluted with petroleum ether (20 ml), and the supernatant layer was removed. Ether (20 ml) was added to the residue. The resulting colorless powder was collected by filtration, washed with a small amount (5 ml) of ether, and a mercury compound (1.6 g) was obtained. This product (1.6 g) was suspended in dichloromethane (50 ml) and a suspension of hydrogen chloride was bubbled at room temperature for 20 minutes. Then the precipitate was filtered off, N ₂ gas was bubbled into the filtrate for 15 minutes, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel columns (2.5 x 20 cm), eluting with a mixture of ethyl acetate and hexane (3: 1). The target fraction was concentrated, isopropyl ether was added to the residue, whereby (compound 119, 0.6 g) was obtained as colorless needle crystals. Mp 95-96 ^about S.

¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, s); 1.42-1.48 (3H, m); 2.39 (1H, s); 4.93 (1H, d, d, I 2.6 Hz, I 14 Hz); 5.32 (1H, dd, I 2.6 Hz, 14 Hz); 5.44 (1H, s); 6.59-6.85 (2H, m); 7.62-7.71 (1H, m); 7.75 (1H, s); 8.08 (1H, d, I 2.6 Hz).

Elemental analysis of C ₁₃ H ₁₅ F ₂ N ₃ OS.

 Calculated, C 52.16; H 5.05; N, 14.04.

 Found, C, 52.13; H 5.10; N, 14.03.

 PRI me R s 80-85. In a manner similar to that described in example 64, the reaction of interaction (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2 was carried out - butanol (indicated in Table 17 by the 2R, 3R-methylthiol derivative) with chloro compounds shown in Table 17, whereby compounds 90, 91, 126-129 were obtained.

b 13,771 (2)

с 9,069 (1)

Объем ячейки 1343,2 (3)

Пространственная группа Р2₁2₁2₁ Число формульных единиц в элементарной ячейке 4 Вычисленная плотность 1,411 г/см³ Излучение Мо-Ка (λ=0,71069

) Конечная Р-величина 0,041
П р и м е р 87. В этилацетате (10 мл) растворяли (2R, 3R)-2-(2,4-дифторофенил)-3-меркапто-1-(1Н-1,2,4-триазол-1-ил)-2-бута- нол (соединение 43, 0,2 г), а затем к полученному раствору добавляли 4н. HCl-этилацетат (1 мл). Смесь концентрировали при пониженном давлении до получения объема около 1 мл, в результате чего получали кристаллы. Затем добавляли этиловый эфир (2 мл), смесь фильтровали и получили гидрохлорид соединения 43 (0,15 г) в виде игольчатых кристаллов. Т.пл. 155-162^оС.PRI me R 86. In ethyl acetate (20 ml) was dissolved (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1- il) -2-butanol (compound 43, 0.2 g). The resulting solution was concentrated to a volume of 10 ml under reduced pressure. The concentrate was then left at room temperature, whereby compound 43 was obtained as colorless prismate crystals. Analysis by x-ray crystallography showed the following results: Crystallographic data Formula C ₁₂ H ₁₃ N ₃ OF ₂ Formula mass 285.31 Crystallographic system Orthorhombic Cell dimensions a 10.754 (1)

b 13,771 (2)

s 9,069 (1)

Cell Volume 1343.2 (3)

Spatial group P2 ₁ 2 ₁ 2 ₁ Number of formula units in a unit cell 4 Calculated density 1.411 g / cm ³ Mo-Ka radiation (λ = 0.71069

) The final P-value of 0.041
PRI me R 87. In ethyl acetate (10 ml) was dissolved (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1- il) -2-butanol (compound 43, 0.2 g), and then 4N was added to the resulting solution. HCl-ethyl acetate (1 ml). The mixture was concentrated under reduced pressure to a volume of about 1 ml, whereby crystals were obtained. Ethyl ether (2 ml) was added, the mixture was filtered and hydrochloride of compound 43 (0.15 g) was obtained in the form of needle crystals. Mp 155-162 ^about S.

Elemental analysis of C ₁₂ H ₁₃ F ₂ N ₃ OS ˙ HCl.

 Calculated, C 44.79; H 4.39; N 13.06.

 Found, C 44.77; H 4.48; N, 12.85.

 Figure 1 presents a powder x-ray.

PRI me R 88. In ethyl acetate (20 ml) was dissolved (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazole-1- il) -2-butanol (compound 43, 0.48 g), and then a 25% mixture of hydrogen bromide and acetic acid (0.7 ml) was added to the resulting solution. After this, the mixture was diluted with 100 ml of hexane and the resulting powder was collected by filtration, and then dissolved in ethyl acetate (10 ml). After adding ethyl ether (20 ml), the solution was aged and the resulting crystals were collected by filtration (0.35 g, hydrobromide of compound 43) in the form of plate crystals. Mp 180-175 ^about S.

Elemental analysis of C ₁₂ H ₁₃ F ₂ N ₃ OS ˙ HBr.

 Calculated, C 39.36; H 3.85; N, 11.47.

 Found, C 39.28; H 3.85; N, 11.32.

 Figure 2 presents a powder x-ray of the compound.

 PRI me R s 89-93. In a manner similar to that described in example 64, the reaction of interaction (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2 was carried out -butanol, indicated in Table 18 by the 2R, 3R-methylthiol derivative, with chloro compounds shown in Table 18, whereby compounds 95, 101, 102, 130, 131 were obtained.

PRI me R 94. To a solution of 2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-yl-methyl) oxirane (8 g) and 3- methyl ester mercaptopropionic acid (11.2 ml) in dimethylformamide (160 ml) was added a 60% suspension of sodium hydride in oil (4 g). The resulting mixture was stirred for 15 minutes. Then, 1N was added dropwise to adjust the pH to 7. an aqueous solution of hydrochloric acid (101 ml), and dimethylformamide and water were evaporated under reduced pressure. 20 ml of water was added to the residue and extracted with ethyl acetate (50 ml x 3). The extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was chromatographed on silica gel columns (6.0 x 9.0 cm), eluting with a mixture of ethyl acetate and hexane (3: 1). The target fraction was concentrated and diethyl ether was added to the residue. As a result, 2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) propan-2-ol (6.44 g) was obtained as colorless needles crystals. Mp 112-113 ^about S.

Elemental analysis of C ₁₁ H ₁₁ F ₂ N ₃ OS.

 Calculated, C 48.70; P 4.09; N, 15.49.

 Found, C, 48.96; H 4.11; N, 15.62.

 PRI me R 95. A solution of methanol (75 ml) containing (2R, 3S) -2- (2,4-difluorophenyl) -2- (1-imidazolyl) methyl-3-methyloxyran (2.5 g ), methyl 3-mercaptopropionate (5.5 ml) and a 28% solution of sodium methoxide and methanol (8.1 ml) were heated under reflux for 1.5 h. Then, 1-mercaptopropionate was added to the solution (5, 5 ml) and 28% sodium methoxide-methanol (8.1 ml) and the resulting mixture was heated under reflux for another 2 hours. Then the reaction mixture was cooled with ice, neutralized with 5N hydrochloric acid (16 ml) was diluted with saturated aqueous sodium chloride (100 ml) and extracted with ethyl acetate (200 ml x 3). The extract was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (40 ml), and then 1N was added to it. an aqueous solution of sodium hydroxide (8 ml) and water (100 ml). Next, the aqueous layer was extracted with methylene chloride (40 ml x 3). The methylene chloride layers were combined and extracted 5 times with water (30 ml) containing 1N hydrochloric acid (8 ml). The aqueous layers were combined, neutralized with sodium hydroxide and extracted with methylene chloride (40 ml x 4). The extract was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel columns (4 cm x 15 cm) using a mixture of methanol and methylene chloride (5:95) as eluent. The target fraction was concentrated, and after adding diethyl ether to the residue, (2R, 3R) -2- (2,4-difluorophenyl) -1- (1-imidazolyl) -3-mercapto-2-butanol (0.84 g) was obtained as colorless prismatic crystals.

¹ H-NMR (CDCl ₃ ) δ 1.12 (3H, d, I 7.0 Hz); 1.69 (1H, d, I 6.0 Hz); 3.68 (1H, m); 4.45 (1H, dd, I 1.4 Hz, 14.2 Hz); 4.59 (1H, d, I 14.2 Hz); 6.57 (1H, s); 6.71 (1H, s); 6.7-6.85 (1H, m); 7.28 (1H, s); 7.3-7.5 (1H, m).

Mp 125-135 ^about S.

Elemental analysis of C ₁₃ H ₁₄ F ₂ N ₂ OS.

 Calculated, C 54.92; H 4.96; N, 9.85.

 Found, C 54.94; H 5.10; N, 9.62.

IR (KBr), cm ^-1 : 3000, 1610, 1590, 1500, 1420, 1260, 1200, 1130.

 The resulting compound was dissolved in diethyl ether and a mixture of hydrochloric acid and diethyl ether was added thereto. The resulting powder was recrystallized from a mixture of ethanol and diethyl ether, whereby the hydrochloride was obtained in the form of prismatic crystals.

¹ H-NMR (DMCO-d ₆ ) δ: 1.06 (3H, d, I 6.8 Hz); 2.95 (1H, d, I = 9.2 Hz); 3.63 (1H, m); 4.65 (1H, d, I 14.6 Hz); 4.92 (1H, d, I 14.6 Hz); 6.31 (1H, s); 6.98 (1H, d, I 2.8 Hz, 8.8 Hz); 7.20-7.37 (2H, m); 7.29 (1H, s); 7.45 (1H, s); 8.85 (1H, s).

Elemental analysis of C ₁₃ H ₁₅ F ₂ N ₂ OS ˙ ˙ HCl ˙ 1 / 2H ₂ O.

 Calculated, C 47.34; H 4.89; N, 8.49.

 Found, C 46.74; H 4.43; N, 8.44.

 IR (KBr), cm -1: 3270, 3000, 1600, 1490, 1410, 1260, 1120.

Claims (4)

1. Derivatives of 1,2,4-triazole of the general formula I

where R ₀ , R ₁ and R ₂ are the same or different, hydrogen or a lower alkyl group;
A group of General formula II

where X is a chemical bond or a group of the general formula III

where X _{1 is a} chemical bond or a C ₁ C ₅ alkylene group which may contain a sulfur atom among the constituent atoms;
R ₅ and R ₆ , the same or different, hydrogen or a lower alkyl group;
R _{3 is an} aromatic heterocyclic group in which the heteroatom is a nitrogen, sulfur or oxygen atom and which may be substituted by lower alkyl (unsubstituted or fluoro-substituted), C ₃ -cycloalkyl, amino, lower alkyl mercapto or oxo;
n 0,1 or 2,
or
A group of General formula IV
SR ₄ ,
where R _{4 is} hydrogen or a lower alkanoyl group,
moreover, when X or X ₁ in the radical A is a chemical bond or A is a group of the general formula IV, where R ₄ is as defined, R ₀ or R _{1 is a} lower alkyl group;
optically inert or having R- or S-configurations of C-2 and C-3 asymmetric centers, or their salts having fungicidal activity. 2. A method of obtaining a compound of General formula I

where R ₀ , R ₁ and R ₂ are the same or different, hydrogen or a lower alkyl group;
A group of General formula II

where X is a chemical bond or a group of the general formula III

where X _{1 is a} chemical bond or a C ₁ C ₅ alkylene group which may contain a sulfur or oxygen atom as constituent atoms;
R ₅ and R ₆ , the same or different, hydrogen or a lower alkyl group;
R _{3 is an} aromatic heterocyclic group in which the heteroatom is a nitrogen, sulfur or oxygen atom and which may be substituted by unsubstituted or fluoro-substituted lower alkyl, C ₃ -cycloalkyl, amino, lower alkyl mercapto or oxo;
n is 0.1 or 2;
or
A group of General formula IV
SR ₄ ,
where R _{4 is} hydrogen or a lower alkanoyl group,
wherein when X or X ₁ in A is a chemical bond or A is a group of general formula IV, where R ₄ is as defined above, R ₀ or R _{1 is a} lower alkyl group,
optically inert or having an R- or S-configuration, C-2 and C-3 asymmetric centers, or a salt thereof, characterized in that the compound of general formula V

where R ₀ , R ₁ and R ₂ have the indicated meanings,
reacted with a compound of general formula VI
HS XR ₃ ,
where X and R ₃ have the indicated meanings,
at a temperature of from -20 to 150 ^o C, and if necessary, subject the reaction product to oxidation. Priority by signs:
09/26/89 at R ₀ hydrogen; R ₁ and R _{2 are} hydrogen; lower alkyl; A group of the general formula

where XC ₁ C _{5 is an} alkylene group which may contain sulfur as a substituent; R _{3 is an} aromatic heterocycle in which the heteroatom is a nitrogen, sulfur or oxygen atom and which may be substituted with lower alkyl (unsubstituted or fluoro-substituted), C ₃ -cycloalkyl, amino, lower alkyl mercapto or oxo, n 0.1 or 2. 12/14/89 when A is a group of general formula SR ₄ , where R ₄ is hydrogen, acyl, or a group of general formula

where R ₁ and R _{2 are} hydrogen, lower alkyl. 03/07/90 at R ₀ lower alkyl, A group of the general formula

where X is a chemical bond, or of general formula SR ₄ , where R _{4 is} alkanoyl, excluding acyl, a group of general formula

where R ₁ and R _{2 are} hydrogen, lower silkyl.

Images