RU2317983C2 - Substituted dihydro-3-halogen-1h-pyrazol-5-carboxylates, their preparing and using - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel compounds of the formula (I):

wherein R¹ represents halogen atom; R² represents halogen atom; R³ represents (C₁-C₄)-alkyl; X represents nitrogen atom (N) or -CH; n = 0-3 under condition that when X represents -CH then n= 1 at least. Also, invention relates to novel compounds of the formula (II):

wherein R¹ represents halogen atom; R² represents halogen atom; R³ represents hydrogen atom (H) or (C₁-C₄)-alkyl; X represents N or -CH; n = 0-3 under condition that when X represents -CH then n = 1 at least. Also, invention relates to a method for synthesis of compound of the formula (I), a method for synthesis of compound of the formula (II) and to a method for synthesis of compound of the formula (III) given in the invention description. Also, invention describes intermediate compounds of the formula (4) given in the invention description. Invention provides synthesis of novel biologically active compounds that can be used as insecticides, and a method for their synthesis.

EFFECT: valuable properties of compounds.

24 cl, 3 tbl, 19 ex

Description

FIELD OF THE INVENTION

The present invention relates to new compounds of 3-halogen-1-aryl-substituted dihydro-1H-pyrazoles and pyrazoles based on carboxylic acids. These compounds are suitable for the preparation of certain compounds based on anthranyl amides that are of interest as insecticides (see, for example, PCT publication WO 01/070671).

BACKGROUND OF THE INVENTION

Tetrahedron Letters, 1999, 40, 2605-2606 describes the preparation of 1-phenyl-3-bromopyrazole-5-carboxylic acid compounds, including the preparation of the reactive intermediate bromnitrilimine. Cycling of this intermediate with an acrylic ester gives 1-phenyl-3-bromo-2-pyrazoline-5-carboxylate ester, which can then be oxidized to the desired 1-phenyl-3-bromo-2-pyrazole-5-carboxylate complex ether. Alternatively, cycloaddition of the propiolate ester directly gives the 1-phenyl-3-bromo-2-pyrazole-5-carboxylate ester.

US 3,153,654 describes the condensation of certain optionally substituted aryl (e.g. phenyl or naphthyl, which are optionally substituted with lower alkyl, lower alkoxy or halogen) hydrazines with certain fumaric or maleic esters to give 3-pyrazolidinone carboxylic acid derivatives.

Japanese Unexamined Patent Publications 9-316055 and 9-176124 describe the preparation of pyrazole ester compounds of carboxylic acids and pyrazoline derivatives, respectively, which are substituted with 1-position alkyl.

J. Med. Chem. 2001, 44, 566-578 describes the preparation of 1- (3-cyanophenyl) -3-methyl-1H-pyrazole-5-carboxylic acid and its use in the preparation of blood coagulation factor Xa inhibitors.

The present invention provides methods suitable for conveniently preparing 3-halogen-5-carboxylate-1-aryl-substituted dihydro-1H-pyrazoles and pyrazoles.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula I

Where

R ¹ represents halogen;

each R ² is independently C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ haloalkynyl, C ₃ -C ₆ halogenocycloalkyl, halogen, CN, NO ₂ , C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkylamino, C ₂ -C ₈ dialkylamino, C ₃ -C ₆ cycloalkylamino, C ₃ -C ₆ (alkyl) cycloalkylamino, C ₂ -C ₄ alkylcarbonyl, C ₂ -C ₆ alkoxycarbonyl , C ₂ -C ₆ alkylaminocarbonyl, C ₃ -C ₈ dialkylaminocarbonyl or C ₃ -C ₆ trialkylsilyl;

R ³ represents H or C ₁ -C ₄ alkyl;

X represents N or CR ⁴ ;

R ⁴ represents H or R ² ; and

n is from 0 to 3, provided that when X represents CH, n is at least 1.

The present invention also relates to a method for producing a compound of formula I, comprising (1) treating a compound of formula 4

(where X, R ² and n are as described above for formula I, and R ³ is C ₁ -C ₄ alkyl) a halogenating agent to give a compound of formula I; and then, in the case of obtaining compounds of formula I, where R ³ represents H, (2) the conversion of the compound obtained in (1) into a compound where R ³ represents H.

The present invention also relates to a compound of formula II

where R ¹ represents halogen (and X, R ² , R ³ and n are as defined above for formula I), and to a method for producing a compound of formula II. The method includes (3) treating the compound of formula I with an oxidizing agent, optionally in the presence of an acid, to obtain a compound of formula II; and when the compound of formula I, where R ³ is C ₁ -C ₄ alkyl, is used to obtain a compound of formula II, where R ³ is H, (4) the conversion of the compound obtained in (2) into a compound of formula II, where R ³ represents H.

The present invention also provides compounds of formula 4, where X is N, and their use in the preparation of compounds of formulas I and II, where X is N (and R ² , R ³ and n are as defined above for formula I) .

The present invention also includes a process for preparing a compound of formula III.

where X, R ¹ , R ² , and n are as defined above for formula II; R ⁶ represents CH ₃ , Cl or Br; R ⁷ represents F, Cl, Br, I or CF ₃ ; and R ⁸ is C ₁ -C ₄ alkyl using a compound of formula II, where R ⁶ is H. This process is distinguished by the preparation of a compound of formula II using the method as described above.

DETAILED DESCRIPTION OF THE INVENTION

In the above enumerations, the term “alkyl”, used either alone or in compound words, such as “alkylthio” or “haloalkyl”, includes straight or branched chain alkyl such as methyl, ethyl, n-propyl, iso propyl, or various isomers of butyl, pentyl or hexyl. “Alkenyl” may include straight or branched chain alkenes, such as 1-propenyl, 2-propenyl, and various isomers of butenyl, pentenyl, and hexenyl. "Alkenyl" also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includes straight or branched chain alkynes, such as 1-propynyl, 2-propynyl, and various isomers of butynyl, pentynyl, and hexynyl. "Alkynyl" may also include residues containing many triple bonds, such as 2,5-hexadiinyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and various butoxy, pentoxy and hexyloxy isomers. “Alkoxyalkyl” means an alkoxy substitution of an alkyl group. Examples of “alkoxyalkyl” include CH ₃ OCH ₂ , CH ₃ OCH ₂ CH ₂ , CH ₃ CH ₂ OCH ₂ , CH ₃ CH ₂ CH ₂ CH ₂ OCH ₂ and CH ₃ CH ₂ OCH ₂ CH ₂ . “Alkylthio” includes straight or branched chain alkylthio radicals such as methylthio, ethylthio, and various isomers of propylthio, butylthio, pentylthio, and hexylthio. "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. “Cycloalkylalkyl” refers to an alkyl group substituted with a cycloalkyl group, and includes, for example, cyclopropylmethyl, cyclobutylethyl, cyclopentylpropyl and cyclohexylmethyl. “Cycloalkylamino” means that an amino nitrogen atom is attached to a cycloalkyl radical and a hydrogen atom and includes groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino. “(Alkyl) cycloalkylamino” means a cycloalkylamino group wherein the hydrogen atom is substituted with an alkyl radical; examples include groups such as (alkyl) cyclopropylamino, (alkyl) cyclobutylamino, (alkyl) cyclopentylamino and (alkyl) cyclohexylamino. Preferably, the alkyl in (alkyl) cycloalkylamino is C ₁ -C ₄ alkyl, while the cycloalkyl in cycloalkylamino and (alkyl) cycloalkylamino is C ₃ -C ₆ cycloalkyl.

As used herein, the term “aryl” refers to an aromatic ring, or a ring system, or a heteroaromatic ring, or a ring system, with each ring or ring system being optionally substituted. The term "aromatic ring system" refers to completely unsaturated carbocycles and heterocycles in which at least one ring of the polycyclic ring system is aromatic. Aromatic indicates that each of the ring atoms is essentially in the same plane and has a p-orbital perpendicular to the plane of the ring, and in which (4n + 2) π electrons, where n is 0 or a positive integer, are associated with the ring, in accordance with the Hückel rule. The term “aromatic carbocyclic ring system” includes fully aromatic carbocycles and carbocycles in which at least one ring of the polycyclic ring system is aromatic (eg, phenyl and naphthyl). The term “heteroaromatic ring or ring system” includes fully aromatic heterocycles and heterocycles in which at least one ring of the polycyclic ring system is aromatic, and in which at least one atom of the ring is not carbon, and which may contain from 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, provided that each heteroaromatic ring contains no more than 4 nitrogen atoms, no more than 2 oxygen atoms and no more than 2 se ry (where aromatic indicates that the Hückel rule is true). Heterocyclic ring systems can be connected via any available carbon or nitrogen atom, by replacing hydrogen on the specified carbon or nitrogen atom. More specifically, the term “aryl” refers to a residue

where R ² and n are as defined above, and “3” denotes the 3rd position for the substituents on the residue.

The term “halogen”, either by itself or in compound words such as “haloalkyl,” includes fluoro, chloro, bromo or iodo. Furthermore, when used in compound words such as “haloalkyl,” said alkyl may be partially or completely substituted with halogen atoms, which may be the same or different. Examples of “haloalkyl” include F ₃ C, ClCH ₂ , CF ₃ CH ₂ and CF ₃ CC1 ₂ . The terms “haloalkenyl”, “haloalkynyl”, “haloalkoxy”, and the like, are defined by analogy with the term “haloalkyl”. Examples of "haloalkenyl" include (C1) ₂ C = CHCH ₂ and CF ₃ CH ₂ CH = CHCH ₂ . Examples of “haloalkynyl” include HC ≡ CCHCl, CF ₃ C ≡ C, CC1 ₃ C ≡ C and FCH ₂ C ≡ CCH ₂ . Examples of “haloalkoxy” include CF ₃ O, CC1 ₃ CH ₂ O, HCF ₂ CH ₂ CH ₂ O and CF ₃ CH ₂ O.

Examples of “alkylcarbonyl” include C (O) CH ₃ , C (O) CH ₂ CH ₂ CH ₃ and C (O) CH (CH ₃ ) ₂ . Examples of “alkoxycarbonyl” include CH ₃ OC (= O), CH ₃ CH ₂ OC (= O), CH ₃ CH ₂ CH ₂ OC (= O), (CH ₃ ) ₂ CHOC (= O) and various butoxy- isomers or pentoxycarbonyl. The terms "alkylaminocarbonyl" and "dialkylaminocarbonyl" include, for example, CH ₃ NHC (= O), CH ₃ CH ₂ NHC (= O) and (CH ₃ ) ₂ NC (= O).

The total number of carbon atoms in the substituent group is indicated by the prefix "C _i -C _j ", where i and j are numbers from 1 to 8. For example, C ₁ -C ₃ alkylsulfonyl refers to methylsulfonyl to propylsulfonyl compounds. In the above enumerations, when a compound of formula I contains a heteroaromatic ring, all substituents are connected to this ring through any available carbon or nitrogen atom, by replacing hydrogen on the specified carbon or nitrogen atom.

When a group contains a substituent, which may be hydrogen, for example R ⁴ , then when this substituent is taken as a hydrogen atom, then it is obvious that this is equivalent to the fact that said group is unsubstituted.

Certain compounds of the present invention may exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One of skill in the art should remember that one of the stereoisomers may be more active and / or may have beneficial effects when enriched with it relative to another stereoisomer (stereoisomers), or when it is separated from another stereoisomer (stereoisomers). In addition, the person skilled in the art knows how to isolate, increase the content and / or selectively obtain these stereoisomers. Accordingly, the compounds of the present invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.

From the point of view of cost, ease of synthesis and / or greatest utility, the following compounds are preferred:

1. The compounds of formula I, where R ¹ represents Cl or Br;

each R ² is independently Cl or Br, and one R ² is in the 3rd position; and

X represents N.

2. The compounds of formula I, where

R ¹ represents Cl or Br;

X represents N; and

n is 0.

Of particular note are compounds of formula I (including, but not limited to preferred compounds 1), where n is from 1 to 3.

3. The compounds of formula II, where

X represents N.

4. The compounds of formula II, where

R ¹ represents Cl or Br;

each R ² is independently Cl or Br, and one R ² is in the 3rd position; and

X represents N.

5. The compounds of formula II, where

R ¹ represents Cl or Br;

X represents N; and

n is 0.

Of particular note are compounds of formula II (including, but not limited to preferred compounds 3 and 4), where n is from 1 to 3.

6. The compounds of formula 4 (where R ³ represents C ₁ -C ₄ alkyl), where each R ² represents independently Cl or Br, and one R ² is in the 3rd position.

7. The compounds of formula 4 (where R ³ represents C ₁ -C ₄ alkyl), where

X represents N; and

n is 0.

Particularly noteworthy are compounds of formula 4 (where R ³ is C ₁ -C ₄ alkyl), including but not limited to preferred compounds 6, where n is from 1 to 3.

The 3rd position is determined using the number “3” shown in the aryl residue included above in Formula I, Formula II, and Formula 4.

Particularly preferred are compounds of formula II, wherein when R ¹ is Cl or Br, n is 1, and R ² selected from Cl or Br is in the 3rd position; then X represents N. Compounds are included, where n is from 1 to 3.

Particularly preferred are compounds of formula II, wherein when R ¹ is Cl or Br, n is 1, and R ² selected from Cl or Br is in the 3rd position; then X represents CR ⁴ . Compounds are included, where n is from 1 to 3.

Preferred methods are those that contain the preferred compounds described above. The methods mentioned are those which include the compounds noted above. Particularly noted are a process for preparing a compound of formula I, wherein n is from 1 to 3; and a method for producing a compound of formula II, wherein n is from 1 to 3.

The multi-step process for preparing compounds of formula I and formulas II provided herein includes (a) treating a compound of formula 2

compound of formula 3

where R ³ represents C ₁ -C ₄ alkyl,

in the presence of a base to give a compound of formula 4

where X, R ² and n are as defined above, and R ³ represents H or C ₁ -C ₄ alkyl.

A compound of formula 4, where R ³ is C ₁ -C ₄ alkyl, may then (1) be treated with a halogenating agent to give a compound of formula I; a, in the case of obtaining a compound of formula I, where R ³ represents H, and (2) the compounds obtained in (1) are converted to a compound where R ³ represents H.

The compound of formula I obtained in (1) or (2) can then (3) be treated with an oxidizing agent, optionally in the presence of an acid, to give a compound of formula II; and when compounds of formula I, where R ³ is C ₁ -C ₄ alkyl, are used to prepare compounds of formula II, where R ³ is H, (4), the compound obtained in (3) is converted to a compound of formula II where R ³ represents H

Scheme 1 illustrates stage (a).

Scheme 1

In step (a), a compound of formula 2 is treated with a compound of formula 3, wherein R ³ is C ₁ -C ₄ alkyl (fumarate or maleate esters or a mixture thereof can be used), in the presence of a base and a solvent. The base is typically a metal alkoxide salt such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, and the like. More than 0.5 equivalents of base must be used with respect to the compound of formula 2, preferably in the range between 0.9 and 1.3 equivalents. More than 1.0 equivalent of a compound of formula 3 should be used, preferably between 1.0 and 1.3 equivalents. Polar protic and polar aprotic organic solvents such as alcohols, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, and the like can be used. Preferred solvents are alcohols, such as methanol and ethanol. It is particularly preferred that the alcohol be the same as that used in the preparation of the fumarate or maleate ester and alkoxide base. Typically, the reaction is carried out by mixing a compound of formula 2 and a base in a solvent. The mixture may be heated or cooled to the desired temperature, and the compound of formula 3 is added over a period of time. Typical reaction temperatures are between 0 ° C and the boiling point of the solvent used. The interaction can be carried out at a pressure greater than atmospheric pressure to increase the boiling point of the solvent. Generally preferred are temperatures in the range of between about 30 ° and 90 ° C. The addition time can be as fast as the temperature change allows (heat transfer). Typical addition times are between 1 minute and 2 hours. The optimal reaction temperature and the time of addition vary depending on the nature of the compounds of formula 2 and formula 3. After addition, the reaction mixture can be maintained, for some time, at the reaction temperature. Depending on the reaction temperature, the required holding time may range from 0 to 2 hours. Typical holding times are from about 10 to 60 minutes. Then the reaction mass can be acidified by adding an organic acid, such as acetic acid, and the like, or an inorganic acid, such as hydrochloric acid, sulfuric acid, and the like. Depending on the reaction conditions and the means of isolation, compounds of formula 4 where R ³ is H or compounds of formula 4 where R ³ is C ₁ -C ₄ alkyl can be prepared. For example, a compound of formula 4 where R ³ is C ₁ -C ₄ alkyl may be hydrolyzed in situ to a compound of formula 4 where R ³ is H when water is present in the reaction mixture. Compounds of formula 4 where R ³ is H can easily be converted to compounds of formula 4 where R ³ is C ₁ -C ₄ alkyl using esterification methods well known in the art. Compounds of formula 4 wherein R ³ is C ₁ -C ₄ alkyl are preferred. The desired product, a compound of formula 4, can be isolated using methods known to one skilled in the art, such as crystallization, extraction or distillation.

In step (1), as illustrated in Scheme 2, the compound of formula 4 is treated with a halogenating reagent, typically in the presence of a solvent. Halogenating reagents that can be used include oxyhalides, trihalides and pentahalides of phosphorus, thionyl chloride, dihalo trialkyl phosphoranes, dihalogen diphenyl phosphorans, oxalyl chloride and phosgene. Preferred are oxyhalides and phosphorus pentahalides. To obtain complete conversion, it is necessary to use at least 0.33 equivalents of phosphorus oxyhalide, with respect to the compound of formula 4, preferably in the range between 0.33 and 1.2 equivalents. To obtain complete conversion, it is necessary to use at least 0.20 equivalents of phosphorus pentahalide with respect to the compound of formula 4, preferably in the range of between about 0.20 and 1.0 equivalents. Compounds of formula 4 wherein R ³ is C ₁ -C ₄ alkyl are preferred for this reaction.

Scheme 2

Typical solvents for such halogenation include halogenated alkanes such as dichloromethane, chloroform, chlorobutane, and the like, aromatic solvents such as benzene, xylene, chlorobenzene, and the like, ethers such as tetrahydrofuran, p-dioxane, diethyl ether , and the like, and polar aprotic solvents such as acetonitrile, N, N-dimethylformamide, and the like. Optionally, an organic base may be added, such as triethylamine, pyridine, N, N-dimethylaniline, or the like. The addition of a catalyst, such as N, N-dimethylformamide, is also optional. Preferred is a method in which the solvent is acetonitrile and the base is absent. Typically, when acetonitrile is used as a solvent, neither a base nor a catalyst is required. A preferred method is carried out by mixing a compound of formula 4 with acetonitrile. Then, at a convenient time, a halogenating reagent is added, and then the mixture is kept at the desired temperature until the reaction is complete. The reaction temperature is usually between 20 ° C and the boiling point of acetonitrile, and the reaction time is usually less than 2 hours. Then the reaction mass is neutralized with an inorganic base, such as sodium bicarbonate, sodium hydroxide, and the like, or an organic base, such as sodium acetate. The desired product, a compound of formula I, can be isolated using methods known to those skilled in the art, including crystallization, extraction and distillation.

In step (2), a compound of formula I where R ³ is C ₁ -C ₄ alkyl ester can be hydrolyzed to a compound of formula I where R ³ is H to a carboxylic acid. Hydrolysis can be catalyzed by acids, metal ions, and enzymes. Iodtrimethylsilane is noted as an example of an acid that can be used to catalyze hydrolysis (see Advanced Organic Chemistry, Third Ed., Jerry March, John Wiley & Sons, Inc. New York, 1985, pp. 334-338, review of methods). Base catalyzed hydrolysis processes are not recommended for the hydrolysis of compounds of formula I and can lead to decomposition. Carboxylic acid can be isolated using methods known to those skilled in the art, including crystallization, extraction, and distillation.

In step (3), as illustrated in Scheme 3, the compound of formula I is treated with an oxidizing agent, optionally in the presence of an acid. A compound of formula I, wherein R ³ is C ₁ -C ₄ alkyl (i.e., the preferred product of step (1)), is preferred as a starting material for step (3). The oxidizing agent may be hydrogen peroxide, organic peroxides, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate (e.g., Oxone®) or potassium permanganate. In order to achieve complete conversion, it is necessary to use at least one equivalent of an oxidizing agent with respect to the compound of formula I, preferably from about one to two equivalents. This oxidation is usually carried out in the presence of a solvent. The solvent may be an ether, such as tetrahydrofuran, p-dioxane, and the like, an organic ester, such as ethyl acetate, dimethyl carbonate, and the like, or a polar aprotic organic solvent, such as N, N-dimethylformamide, acetonitrile, and things like that. Acids suitable for use in the oxidation step include inorganic acids such as sulfuric acid, phosphoric acid, and the like, and organic acids such as acetic acid, benzoic acid, and the like. The acid, when used, should be used in a proportion greater than 0.1 equivalent, with respect to the compound of formula I. To achieve complete conversion, one to five equivalents of acid can be used. For compounds of formula I, where X is CR ² , the preferred oxidizing agent is hydrogen peroxide, and the oxidation is preferably carried out in the absence of acid. For compounds of formula I where X is N, the preferred oxidizing agent is potassium persulfate, and the oxidation is preferably carried out in the presence of sulfuric acid. The reaction can be carried out by stirring the compound of formula I in the desired solvent and in the acid, if used. An oxidizing agent may then be added at a convenient rate. The reaction temperature typically varies, at least, from about 0 ° C to the boiling point of the solvent, in order to obtain a reasonable reaction time, to complete the reaction, preferably in less than 8 hours. The desired product, a compound of formula II, wherein R ³ is C ₁ -C ₄ alkyl, can be isolated using methods known to those skilled in the art, including crystallization, extraction and distillation.

Scheme 3

In step (4), as illustrated in Scheme 4, a compound of formula II, wherein R ³ is C ₁ -C ₄ alkyl, i.e. an ester, can be converted to a compound of formula II, where R ³ is H, i.e. carboxylic acid. Methods for converting esters to carboxylic acids are well known to those skilled in the art. Compounds of formula II (R ³ is C ₁ -C ₄ alkyl) can be converted to compounds of formula II (R ³ is H) using numerous methods, including nucleophilic cleavage under anhydrous conditions, or hydrolytic methods, including the use of either acids, or bases (see TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991, pp. 224-269, review of methods). For the method of Scheme 4, alkaline catalysis hydrolysis methods are preferred. Suitable bases include alkali metal hydroxides (such as lithium, sodium or potassium). For example, an ester can be dissolved in a mixture of water and an alcohol, such as ethanol. When treated with sodium hydroxide or potassium hydroxide, the ester is saponified to produce the sodium or potassium salt of the carboxylic acid. Acidification with a strong acid such as hydrochloric acid or sulfuric acid gives carboxylic acid. Carboxylic acid can be isolated by methods known to those skilled in the art, including crystallization, extraction, and distillation.

Scheme 4

It should be noted that certain compounds of formula I, where R ¹ is halogen, can be obtained from other compounds of formula I, where R ¹ is another halogen or is a sulfonate group such as p-toluenesulfonate, benzenesulfonate and methanesulfonate. For example, a compound of formula I, where R ¹ is Br, can be prepared by treatment with hydrogen bromide, the corresponding compound of formula I, where R ¹ is Cl or p-toluenesulfonate. The reaction is carried out in an appropriate solvent, such as dibromomethane, dichloromethane or acetonitrile. The interaction can be carried out at or near atmospheric pressure, or at a pressure exceeding atmospheric pressure, in a high pressure vessel. When R ¹ , in the starting compound of formula I, is a halogen such as Cl, the reaction is preferably carried out in such a way that the hydrogen halide generated in the reaction is removed by blowing or other suitable means. The interaction can be carried out at a temperature in the range between about 0 and 100 ° C, most conveniently, around the ambient temperature (for example, about 10-40 ° C), and more preferably in the range between about 20 and 30 ° C. The addition of a Lewis acid catalyst (e.g., aluminum tribromide, to produce a compound of formula I, where R ¹ is Br) can accelerate the reaction. The product of formula I can be isolated using conventional methods known to those skilled in the art, including extraction, distillation and crystallization.

The starting compounds of formula I, where R ¹ is halogen, can be prepared as described for Scheme 2. The starting compounds of formula I, where R ¹ is a sulfonate group, can likewise be prepared from the corresponding compounds of formula 4 using standard methods such as treatment with a sulfonyl chloride (e.g. p-toluenesulfonyl chloride) and a base such as a tertiary amine (e.g. triethylamine) in an appropriate solvent such as dichloromethane.

Without further explanation, it is assumed that a person skilled in the art, using the preceding description, can use the present invention in its fullest extent. For this reason, the following examples should be considered solely as illustrative and not limiting the description in any way. The source material for the following examples may not necessarily be prepared using a specific production method, the procedure of which is described in other examples. Percentages are percentages by weight (mass), excluding mixtures of chromatographic solvents or where otherwise indicated. Fractions and percentages for mixtures of chromatographic solvents are indicated by volume unless otherwise indicated. ¹ H NMR spectra are indicated in ppm, in the direction of a weak field, from tetramethylsilane; “s” means a singlet, “d” means a doublet, “t” means a triplet, “q” means a quartet, “m” means a doublet, “dd” means a doublet of doublets, “dt” means a doublet of triplets, and “br s” means widened singlet.

EXAMPLE 1

Obtaining ethyl 5-oxo-2-phenyl-3-pyrazolidinecarboxylate (alternative name for ethyl 1-phenyl-3-pyrazolidinone-5-carboxylate) using diethyl maleate

In a 300 ml four-necked flask equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and nitrogen inlet, 80 ml of absolute ethanol, 80.0 ml (0.214 mol) of 21% sodium ethoxide in ethanol and 20.0 are charged ml (0.203 mol) of phenylhydrazine. An orange solution was treated dropwise with 40.0 ml (0.247 mol) of diethyl maleate for about 18 minutes. The temperature of the reaction mass rises from 25 to 38 ° C during the first 5 minutes of addition. A water bath was used alternately with continued addition to maintain the reaction temperature between 38-42 ° C. The resulting orange-red solution was incubated at ambient conditions for 30 minutes. Then it is transferred to a separatory funnel containing 20.0 ml (0.349 mol) of glacial acetic acid and 700 ml of water. The mixture was extracted with 250 ml of dichloromethane. The extract is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The resulting black-yellow oil (52.7 g) was diluted with 100 ml of ether, while the crystallization of the product was fast enough to cause a slight boil. The suspension is incubated for 2 hours at ambient conditions. Then it is cooled to about 0 ° C. The product was separated by filtration, washed with 2 x 20 ml of cold ether, and then dried in air on a filter for about 15 minutes. The product consists of 29.1 g (61%) of a high crystallinity white powder. By ¹ H NMR, no significant impurities were detected. The filtrate was concentrated to 20.8 g of a brown oil. An analysis of the oil shows the presence of an additional 6.4 g (13%) of the desired product. Therefore, the total reaction yield is 74%.

¹ H NMR (DMSO-d ₆ ) δ 10.25 (s, 1H), 7.32 (t, 2H), 7.15 (d, 2H), 7.00 (t, 1H), 4.61 ( dd, 1H), 4.21 (q, 2H), 2.95 (dd, 1H), 2.45 (dd, 1H), 1.25 (t, 3H).

EXAMPLE 2

Obtaining ethyl 5-oxo-2-phenyl-3-pyrazolidinecarboxylate (alternative name for ethyl 1-phenyl-3-pyrazolidinone-5-carboxylate) using diethyl fumarate

150 ml of absolute ethanol, 15.0 g (0.212 mol) of 96% sodium ethoxide in ethanol and 20.0 are charged into a 500 ml four-necked flask equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and nitrogen inlet. ml (0.203 mol) of phenylhydrazine. The orange mixture was dropwise treated with 40.0 ml (0.247 mol) of diethyl fumarate over a period of 75 minutes. During the addition, the temperature of the reaction mass increases from 28 to 37 ° C as much as possible, and the final temperature is 32 ° C. The resulting somewhat cloudy orange solution was incubated at ambient conditions for 135 minutes. Then the reaction mixture was poured into a separatory funnel containing 15.0 ml (0.262 mol) of glacial acetic acid and 700 ml of water. The mixture was extracted with 150 ml of dichloromethane. The extract is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The resulting brown-yellow oil (41.3 g) was diluted with 100 ml of ether. A few seed crystals are added. The mixture was incubated for 30 minutes at ambient conditions. Then it is cooled to about 0 ° C. The product was separated by filtration, washed with 2 x 10 ml of cold ether, and then dried in air on a filter for about 15 minutes. The product consists of 9.5 g (20%) of a high crystallinity white powder. By ¹ H NMR, no significant impurities were detected. The filtrate was concentrated to 31 g of a brown oil. An analysis of the oil shows the presence of an additional 7.8 g (16%) of the desired product. Therefore, the overall selectivity of the reaction is 36%.

EXAMPLE 3

Preparation of ethyl 5-oxo-2- (2-pyridinyl) -3-pyrazolidinecarboxylate (alternative name for ethyl 1- (2-pyridinyl) -3-pyrazolidinone-5-carboxylate)

In a 200 ml four-necked flask equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and nitrogen inlet, 18 ml of absolute ethanol, 18.0 ml (0.0482 mol) of 21% sodium ethoxide in ethanol and 5 are charged , 00 g (0.0458 mol) of 2-hydrazinopyridine. The solution is heated to 34 ° C. Then it is treated dropwise with 9.0 ml (0.056 mol) of diethyl maleate over a period of 20 minutes. During the addition, the temperature of the reaction mixture rises to a maximum of 48 ° C. The resulting orange solution was kept at ambient conditions for 85 minutes. Then it is poured into a separatory funnel containing 4.0 ml (0.070 mol) of glacial acetic acid and 300 ml of water. The mixture was extracted with 2 x 50 ml of dichloromethane. The extract is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The resulting orange oil (10.7 g) was flash chromatographed on a column of 200 g silica gel using 4% methanol in chloroform as eluent (50 ml fraction). Fractions 9-12 are evaporated on a rotary evaporator to give 3.00 g of an orange oil that contains 77% of the desired product, 15% of chloroform and 8% of diethyl 2-ethoxybutanedioate. Fractions 13-17 are concentrated to give 4.75 g of an orange-yellow oil, which contains 94% of the desired product and 6% of chloroform. Fractions 18-21 are concentrated to give 1.51 g of olive green oil, which contains 80% of the desired product and 20% chloroform. The total yield of the desired product is 8.0 g (74%).

¹ H NMR (DMSO-d ₆ ) δ 10.68 (br, 1H), 8.22 (d, 1H), 7.70 (t, 1H), 6.90 (m, 2H), 5.33 (dd, 1H), 4.17 (q, 2H), 3.05 (dd, 1H), 2.48 (dd, 1H), 1.21 (t, 3H).

EXAMPLE 4

Preparation of ethyl 2- (2-chlorophenyl) -5-oxo-3-pyrazolidinecarboxylate (alternative name for ethyl 1- (2-chlorophenyl) -3-pyrazolidinone-5-carboxylate)

40 ml absolute ethanol, 40.0 ml (0.107 mol) 21% sodium ethoxide in ethanol and 14.5 are charged into a 250 ml four-necked flask equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and nitrogen inlet. g (0.102 mol) (2-chlorophenyl) hydrazine. The purple solution is heated to 35 ° C. Then it is treated dropwise with 19.0 ml (0.117 mol) of diethyl maleate over a period of about 23 minutes. A water / ice bath is used interchangeably with continued addition to maintain the reaction temperature between 35-40 ° C. The reaction mixture was kept at this temperature for 30 minutes. Then it is added to a separatory funnel containing 10.0 ml (0.175 mol) of glacial acetic acid and 400 ml of water. The mixture was extracted with 2 x 100 ml dichloromethane. The extract is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The resulting dark brown oil (31.0 g) crystallizes upon standing. The material was suspended in 100 ml of ether and the suspension was stirred for about 1 hour. The product was separated by filtration, washed with 50 ml of ether, and then dried overnight at room temperature in vacuo. The product consists of 12.5 g (46%) of crystalline powder. By ¹ H NMR, no significant impurities were detected. The filtrate was concentrated to 16.3 g of a brown oil. An analysis of the oil shows the presence of an additional 6.7 g (25%) of the desired product. Therefore, the overall selectivity of the reaction is 71%.

¹ H NMR (DMSO-d ₆ ) δ 10.14 (s, 1H), 7.47 (6, 1H), 7.32 (m, 2H), 7.14 (t, 1H), 4.39 ( d, 1H), 4.19 (q, 2H), 3.07 (dd, 1H), 2.29 (d, 1H), 1.22 (t, 3H).

EXAMPLE 5

Preparation of ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (alternative name ethyl 1- (3-chloro-2-pyridinyl) -3-pyrazolidinone-5-carboxylate).

250 ml of absolute ethanol and 190 ml (0.504 mol) of 21% sodium ethoxide in ethanol are charged into a 2-liter, four-necked flask equipped with a mechanical stirrer, a thermometer, a dropping funnel for adding reagent, a reflux condenser and a nitrogen inlet. The mixture was refluxed at about 83 ° C. Then, 68.0 g (0.474 mol) of 3-chloro-2 (1H) -pyridinone hydrazone (alternative name for 3-chloro-2-hydrazinopyridine) is treated. The mixture was refluxed for a period of 5 minutes. The yellow suspension is then treated dropwise with 88.0 ml (0.544 mol) of diethyl maleate over a period of 5 minutes. During the addition, the boiling speed increases markedly. By the end of the addition, all of the starting material is dissolved. The resulting orange-red solution was kept under reflux for 10 minutes. After cooling to 65 ° C., the reaction mixture was treated with 50.0 ml (0.873 mol) of glacial acetic acid. A precipitate forms. The mixture is diluted with 650 ml of water, while the precipitate dissolves. The orange solution is cooled in an ice bath. The product begins to precipitate at 28 ° C. The suspension is maintained at about 2 ° C for 2 hours. The product was separated by filtration, washed with 3 x 50 ml of a 40% aqueous ethanol solution, and then dried in air on a filter for about 1 hour. The product consists of 70.3 g (55%) of a light orange powder with a high degree of crystallinity. By ¹ H NMR, no significant impurities were detected.

¹ H NMR (DMSO-d ₆ ) δ 10.18 (s, 1H), 8.27 (d, 1H), 7.92 (d, 1H), 7.20 (dd, 1H), 4.84 ( d, 1H), 4.20 (q, 2H), 2.91 (dd, 1H), 2.35 (d, 1H), 1.22 (t, 3H).

EXAMPLE 6

Obtaining ethyl 3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate (alternative name for ethyl 1-phenyl-3-chloro-2-pyrazoline-5-carboxylate)

EXAMPLE 6A

The use of phosphorus oxychloride in acetonitrile, in the absence of a base

150 ml acetonitrile, 25.0 g (0.107 mol) ethyl 5-oxo-2-phenyl-3- are charged into a 500 ml four-necked flask equipped with a mechanical stirrer, thermometer, dropping funnel for adding reagent, reflux condenser and nitrogen inlet. pyrazolidine carboxylate and 11.0 ml (0.118 mol) of phosphorus oxychloride. The light yellow solution is heated to 78-80 ° C, over a period of 45 minutes. After cooling to 54 ° C, the resulting blue-green mixture was treated dropwise with a solution of 25.0 g (0.298 mol) of sodium bicarbonate in 250 ml of water. An orange oil is separated during a 15 minute addition. After stirring for about 5 minutes, the pH of the mixture is about 1. An additional 10.0 g (0.119 mol) of sodium bicarbonate is added as a solid over a period of about 3 minutes, resulting in a final pH of about 6. The mixture is diluted 400 ml of water, while the orange oil crystallizes. The crystalline mass is crushed using a spatula. The product was separated by filtration, washed with 4 x 100 ml of water, and then dried in air on a filter for about 2 hours. The product consists of 24.5 g (91%) of loose crystalline light yellow powder. By ¹ H NMR, no significant impurities were detected.

¹ H NMR (DMSO-d ₆ ) δ 2.74 (t, 2H), 6.88 (d, 2H), 6.83 (t, 1H), 5.02 (dd, 1H), 4.14 ( q, 2H), 3.68 (dd, 1H), 3.34 (d, 1H), 1.16 (t, 3H).

EXAMPLE 6B

The use of phosphorus oxychloride in chloroform in the absence of base

In a 100 ml two-necked flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen inlet, 50 ml of chloroform, 5.00 g (0.0213 mol) of ethyl 5-oxo-2-phenyl-3-pyrazolidinecarboxylate, 2, are charged. 10 ml (0.0225 mol) of phosphorus oxychloride and 2 drops of N, N-dimethylformamide. The red-orange solution was refluxed at 64 ° C for a period of 60 minutes. The resulting mixture, a tan liquid and a dark green gummy solid, was kept at the boil under reflux for 140 minutes. Then diluted with 100 ml of dichloromethane and transferred to a separatory funnel. The solution is washed twice with 50 ml of a 6% aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, then concentrated on a rotary evaporator. The crude product consists of 1.50 g of orange oil, which crystallizes upon standing. Analysis of the crude product using ¹ H NMR shows that it represents approximately 65% of the desired product and 35% of the starting material. The yield of the desired product is therefore approximately 18%.

EXAMPLE 6C

The use of phosphorus oxychloride in chloroform in the presence of triethylamine

In a 100 ml two-necked flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen inlet, 20 ml of chloroform, 2.00 g (0.00854 mol) of ethyl 5-oxo-2-phenyl-3-pyrazolidine carboxylate, 1, 30 ml (0.00933 mol) of triethylamine, 2 drops of N, N-dimethylformamide and 0.0850 ml (0.00912 mol) of phosphorus oxychloride. When phosphorus oxychloride is added, an instantaneous and violent reaction takes place. The mixture was refluxed at 64 ° C for 25 minutes. The resulting yellow solution was diluted with 50 ml of water, and then treated with 3.0 g (0.036 mol) of solid sodium bicarbonate. The biphasic mixture is stirred for 50 minutes at ambient conditions. Then transferred to a separatory funnel and diluted with 100 ml of dichloromethane. The organic layer is separated and then washed, in turn, with 50 ml of a 5.5% aqueous solution of hydrochloric acid and 50 ml of a 3.8% aqueous solution of sodium carbonate. The washed organic layer is dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The crude product consists of 1.90 g of yellow oil, which crystallizes upon standing. Analysis of the crude product using ¹ H NMR shows that it is approximately 94% of the desired product, 2% of the starting material and 2% of an undefined impurity. The yield of the desired product, therefore, is approximately 83%.

EXAMPLE 7

Obtaining ethyl 3-chloro-4,5-dihydro-1- (2-pyridinyl) -1H-pyrazole-5-carboxylate (alternative name ethyl 1- (2-pyridinyl) -3-chloro-2-pyrazoline-5-carboxylate )

In a 250 ml four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet, 50 ml of acetonitrile, 4.70 g (0.0188 mol) of 5-oxo-2- (2-pyridinyl) -3-pyrazolidinecarboxylate are charged and 2.00 ml (0.0215 mol) of phosphorus oxychloride. The mixture heats itself from 22 to 33 ° C. After aging for 60 minutes at ambient conditions, a sample is taken. Analysis using ¹ H NMR shows 70% conversion of the starting material to the desired product. The mixture was refluxed at 85 ° C for 80 minutes. The heating casing is removed. The resulting yellow-orange solution was diluted with 50 ml of water. Then, 3.9 g (0.049 mol) of a 50% aqueous solution of caustic soda are treated dropwise to obtain a pH of about 7.5. After stirring for 20 minutes, the pH of the mixture drops to about 3. An additional 3.0 g (0.038 mol) of a 50% aqueous solution of caustic soda is added, with the pH increasing to about 9.0. A small amount of concentrated hydrochloric acid is added to adjust the pH to about 7.5. The neutralized mixture is transferred to a separatory funnel containing 300 ml of water and 100 ml of dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The product consists of 4.10 g (84%) of a pale yellow oil, which crystallizes upon standing. The only noticeable impurities detected by ¹ H NMR are 1.0% starting material and 0.6% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 8.18 (d, 1H), 8.63 (t, 1H), 8.13 (d, 1H), 7.80 (t, 1H), 5.08 ( dd, 1H), 4.11 (m, 2H), 3.65 (dd, 1H), 3.27 (dd, 1H), 1.14 (t, 3H).

EXAMPLE 8

Preparation of ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (alternative name for ethyl 1- (3-chloro-2-pyridinyl) -3-chloro -2-pyrazoline-5-carboxylate)

1000 ml of acetonitrile, 91.0 g (0.337 mol) of ethyl 2- (3-chloro-2-pyridinyl) -5-oxo- are charged into a 2-liter four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet. 3-pyrazolidinecarboxylate and 35.0 ml (0.375 mol) of phosphorus oxychloride. When phosphorus oxychloride is added, the mixture heats itself from 22 to 25 ° C and a precipitate forms. The light yellow suspension was refluxed at 83 ° C. for a period of 35 minutes, and the precipitate dissolved. The resulting orange solution is kept at the boil under reflux for 45 minutes, while it becomes black and green. The reflux condenser was replaced with a distillation head and 650 ml of solvent was removed by distillation. Into a second 2-liter four-necked flask equipped with a mechanical stirrer, 130 g (1.55 mol) of sodium bicarbonate and 400 ml of water are charged. The concentrated reaction mixture was added to a suspension of sodium bicarbonate over a period of 15 minutes. The resulting two-phase mixture is stirred vigorously for 20 minutes, during which time gas evolution ceases. The mixture was diluted with 250 ml of dichloromethane and then stirred for 50 minutes. The mixture is treated with 11 g of Celite 545® diatomaceous earth and then filtered to remove a black gum that interferes with phase separation. Since the filtrate is slowly separated into various phases, it is diluted with 200 ml of dichloromethane and 200 ml of water and treated with an additional 15 g of Celite 545®. The mixture was filtered and the filtrate was transferred to a separatory funnel. The heavier dark green organic layer is separated. 50 ml of the coarse layer is re-filtered and then added to the organic layer. An organic solution (800 ml) was treated with 30 g of magnesium sulfate and 12 g of silica gel and the suspension was stirred using a magnetic stirrer for 30 minutes. The suspension is filtered to remove magnesium sulfate and silica gel, while it becomes blue-green. The filter cake was washed with 100 ml of dichloromethane. The filtrate was concentrated on a rotary evaporator. The product consists of 92.0 g (93%) of dark amber oil. The only noticeable impurities detected by ¹ H NMR are 1% starting material and 0.7% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 8.12 (d, 1H), 7.84 (d, 1H), 7.00 (dd, 1H), 5.25 (dd, 1H), 4.11 ( q, 2H), 3.58 (dd, 1H), 3.26 (dd, 1H), 1.15 (t, 3H).

EXAMPLE 9

Preparation of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (alternative name for ethyl 1- (3-chloro-2-pyridinyl) -3-bromo -2-pyrazoline-5-carboxylate)

EXAMPLE 9A

Use of phosphorus oxybromide

400 ml of acetonitrile, 50.0 g (0.185 mol) of ethyl 2- (3-chloro-2-pyridinyl) -5-oxo- are charged into a 1-liter four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet. 3-pyrazolidinecarboxylate and 34.0 g (0.119 mol) of phosphorus oxybromide. The orange suspension was refluxed at 83 ° C. for a period of 20 minutes. The resulting cloudy orange solution was kept at the boil under reflux for 75 minutes, during which time a dense tan crystalline precipitate formed. The reflux condenser was replaced with a distillation head and 300 ml of an opaque colorless distillate was collected. In a second 1-L four-necked flask equipped with a mechanical stirrer, 45 g (0.54 mol) of sodium bicarbonate and 200 ml of water are charged. The concentrated reaction mixture was added to a suspension of sodium bicarbonate over a period of 5 minutes. The resulting two-phase mixture is stirred vigorously for 5 minutes, during which time gas evolution ceases. The mixture was diluted with 200 ml of dichloromethane and then stirred for 75 minutes. The mixture is treated with 5 g of Celite 545® and then filtered to remove a brown gum. The filtrate is transferred to a separatory funnel. The brown organic layer (400 ml) was separated and then treated with 15 g of magnesium sulfate and 2.0 g of Darco G60 activated carbon. The resulting suspension was stirred with a magnetic stirrer for 15 minutes, and then filtered to remove magnesium sulfate and coal. The green filtrate is treated with 3 g of silica gel and thickened in a few minutes. The blue-green silica gel was removed by filtration and the filtrate was concentrated on a rotary evaporator. The product consists of 58.6 g (95%) of light amber oil, which crystallizes upon standing. The only noticeable impurity observed using ¹ H NMR is 0.3% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 8.12 (d, 1H), 7.84 (d, 1H), 6.99 (dd, 1H), 5.20 (dd, 1H), 4.11 ( q, 2H), 3.60 (dd, 1H), 3.29 (dd, 1H), 1.15 (t, 3H).

EXAMPLE 9B

Use of phosphorus pentabromide

330 ml of acetonitrile, 52.0 g (0.193 mol) of ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3- are charged into a 1-liter four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet. pyrazolidine carboxylate and 41.0 g (0.0952 mol) of phosphorus pentabromide. The orange slurry was refluxed at 84 ° C for a period of 20 minutes. The resulting brick-red mixture is kept at the boil under reflux for 90 minutes, during which time a dense yellow-brown crystalline precipitate forms. The reflux condenser was replaced with a distillation head and 220 ml of an opaque colorless distillate was collected. In a second 1-L four-necked flask equipped with a mechanical stirrer, 40 g (0.48 mol) of sodium bicarbonate and 200 ml of water are charged. The concentrated reaction mixture was added to a suspension of sodium bicarbonate over a period of 5 minutes. The resulting two-phase mixture is stirred vigorously for 10 minutes, during which time gas evolution ceases. The mixture was diluted with 200 ml of dichloromethane and then stirred for 10 minutes. The mixture is treated with 5 g of Celite 545® and then filtered to remove the purple gum. The filter cake was washed with 50 ml of dichloromethane. The filtrate is transferred to a separatory funnel. The purple-red organic layer (400 ml) is separated, then 15 g of magnesium sulfate and 2.2 g of activated carbon Darco G60 are treated. The suspension is stirred with a magnetic stirrer for 40 minutes. The suspension is filtered to remove magnesium sulfate and coal. The filtrate was concentrated on a rotary evaporator. The product consists of 61.2 g (95%) of dark amber oil, which crystallizes upon standing. The only noticeable impurity observed using ¹ H NMR is 0.7% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 8.12 (d, 1H), 7.84 (d, 1H), 6.99 (dd, 1H), 5.20 (dd, 1H), 4.11 ( q, 2H), 3.60 (dd, 1H), 3.29 (dd, 1H), 1.15 (t, 3H).

EXAMPLE 10

Obtaining ethyl 3-chloro-1-phenyl-1H-pyrazole-5-carboxylate (alternative name for ethyl 1-phenyl-3-chloropyrazole-5-carboxylate)

EXAMPLE 10A

Use of hydrogen peroxide

1.50 g (0.00594 mol) of ethyl 3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole - are charged into a 100 ml two-necked flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen inlet. 5-carboxylate and 15 ml of acetonitrile. The mixture is heated to 80 ° C. Then it is treated with 0.700 ml (0.00685 mol) of a 30% aqueous hydrogen peroxide solution. The mixture is kept at 78-80 ° C for 5 hours. Then the reaction mass is added to 70 ml of water. The precipitated product is separated by filtration, and then washed with 15 ml of water. The wet cake of the precipitate is dissolved in 100 ml of dichloromethane. The solution was dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The product consists of 1.24 g (approximately 79%) of orange oil, which crystallizes upon standing. As ¹ H NMR shows, the resulting material contains approximately 95% pure product.

¹ H NMR (DMSO-d ₆ ) δ 7.50 (s, 5H), 7.20 (s, 1H), 7.92 (d, 1H), 4.18 (q, 2H), 1.14 ( t, 3H).

EXAMPLE 10B

Use of Manganese Dioxide

3.00 g (0.0119 mol) of ethyl 3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole - are charged into a 100-ml two-necked flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen inlet. 5-carboxylate, 25 ml of chloroform and 2.50 g (0.0245 mol) of activated manganese dioxide. The mixture is heated at the boil under reflux at 62 ° C for a period of 1 hour. Analysis of a sample of the reaction mass using ¹ H NMR shows an approximately 6% conversion of the starting material mainly to the desired ethyl 1-phenyl-3-chloropyrazole-5-carboxylate. The mixture was kept at the boil under reflux for an additional 5 hours. Analysis of the second sample shows approximately 9% conversion.

EXAMPLE 10C

Use of sodium hypochlorite

1.00 g (0.00396 mol) of ethyl 3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole - are charged into a 100-ml two-necked flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen inlet. 5-carboxylate, 10 ml of acetonitrile, 0.55 g (0.0040 mol) of sodium dihydrogen phosphate monohydrate and 5.65 g (0.00398 mol) of 5.25% aqueous sodium hypochlorite solution. The orange solution is maintained at ambient conditions for 85 minutes. Analysis of a sample of the reaction mass using ¹ H NMR shows approximately 71% conversion of the starting material into two main products. The solution was heated to 60 ° C for 60 minutes. Analysis of the second sample does not show any conversion growth relative to the first sample. The reaction mixture was treated with an additional 3.00 g (0.00211 mol) of 5.25% aqueous sodium hypochlorite solution. After keeping for 60 minutes at 60 ° C, the reaction mass is added to 100 ml of water. The mixture is extracted with 100 ml of dichloromethane. The extract is separated, dried over magnesium sulfate, filtered, and then concentrated on a rotary evaporator. The crude product consists of 0.92 g of red-orange oil. ¹ H NMR indicates that the crude product consists mainly of ethyl 3-chloro-1- (4-chlorophenyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (alternative name is ethyl 1- (4-chlorophenyl ) -3-chloro-2-pyrazoline-5-carboxylate) and ethyl 3-chloro-1- (2-chlorophenyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (alternative name is ethyl 1- (2- chlorophenyl) -3-chloro-2-pyrazoline-5-carboxylate), in a 2: 1 ratio. The isomer can be isolated by silica gel chromatography using 10% ethyl acetate in hexane as the eluent. ¹ H NMR for ethyl 3-chloro-1- (4-chlorophenyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (DMSO-d ₆ ) δ 7.28 (d, 2H), 6.89 ( d, 2H), 5.08 (dd, 1H), 4.14 (q, 2H), 3.71 (dd, 1H), 3.37 (dd, 1H), 1.16 (t, 3H). ¹ H NMR for ethyl 3-chloro-1- (2-chlorophenyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (DMSO-d ₆ ) δ 7.41 (d, 1H), 7.30 ( m, 2H), 7.14 (m, 1H), 5.22 (dd, 1H), 3.90 (q, 2H), 3.68 (dd, 1H), 3.38 (dd, 1H), 0.91 (t, 3H).

EXAMPLE 11

Obtaining ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (alternative name for ethyl 1- (3-chloro-2-pyridinyl) -3-chloropyrazole-5-carboxylate)

In a 2-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet, 99.5 g (0.328 mol) of ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4.5- are charged dihydro-1H-pyrazole-5-carboxylate, 1000 ml of acetonitrile with a purity of 95% and 35.0 ml (0.661 mol) of 98% sulfuric acid. The mixture is heated on its own from 22 to 35 ° C with the addition of sulfuric acid. After stirring for several minutes, the mixture is treated with 140 g (0.518 mol) of potassium persulfate. The suspension is heated under reflux at 84 ° C for 4.5 hours. The resulting orange suspension is filtered while it is still warm (50-65 ° C) to remove a finely divided white precipitate. The filter cake was washed with 50 ml of acetonitrile. The filtrate was concentrated on a rotary evaporator to about 500 ml. In a second 2-L four-necked flask equipped with a mechanical stirrer, 1250 ml of water was charged. Concentrated reaction mass was added to water over a period of about 5 minutes. The product was separated by filtration, washed with 3 x 125 ml of a 25% aqueous acetonitrile solution, washed once with 100 ml of water, and then dried overnight in vacuo at room temperature. The product consists of 79.3 g (82%) of crystalline orange powder. The only noticeable impurities detected by ¹ H NMR are approximately 1.9% water and 0.6% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 8.59 (d, 1H), 8.38 (d, 1H), 7.71 (dd, 1H), 7.31 (s, 1H), 4.16 ( q, 2H), 1.09 (t, 3H).

EXAMPLE 12

Obtaining ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylate (alternative name for ethyl 1- (3-chloro-2-pyridinyl) -3-bromopyrazole-5-carboxylate)

40.2 g (0.121 mol) of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5- are charged into a 1-liter four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen inlet. dihydro-1H-pyrazole-5-carboxylate, 300 ml of acetonitrile and 13.0 ml (0.245 mol) of 98% sulfuric acid. The mixture is heated on its own from 22 to 36 ° C, with the addition of sulfuric acid. After stirring for several minutes, the mixture was treated with 48.0 g (0.178 mol) of potassium persulfate. The suspension is heated at the boil under reflux at 84 ° C for 2 hours. The resulting orange suspension is filtered while it is still warm (50-65 ° C) to remove a white precipitate. The filter cake was washed with 2 x 50 ml of acetonitrile. The filtrate was concentrated on a rotary evaporator to about 200 ml. In a second 1-liter four-necked flask equipped with a mechanical stirrer, 400 ml of water was charged. Concentrated reaction mass was added to water over a period of about 5 minutes. The product is separated by filtration, washed with 100 ml of a 20% aqueous acetonitrile solution, washed with 75 ml of water, and then dried in air on the filter for 1 hour. The product consists of 36.6 g (90%) of crystalline orange powder. The only noticeable impurities detected by ¹ H NMR are approximately 1% unknown product and 0.5% acetonitrile.

¹ H NMR (DMSO-d ₆ ) δ 8.59 (d, 1H), 8.39 (d, 1H), 7.72 (dd, 1H), 7.35 (s, 1H), 4.16 ( q, 2H), 1.09 (t, 3H).

EXAMPLE 13

Preparation of 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (alternative name 1- (3-chloro-2-pyridinyl) -3-chloropyrazole-5-carboxylic acid)

79.3 g (0.270 mol) of 97.5% ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -1H-pyrazole are charged into a 1-liter four-necked flask equipped with a mechanical stirrer, thermometer and nitrogen inlet -5-carboxylate, 260 ml of methanol, 140 ml of water and 13.0 g (0.325 mol) of sodium hydroxide granules. The mixture heats itself from 22 to 35 ° C, and the starting material begins to dissolve when sodium hydroxide is added. After stirring for 45 minutes at ambient conditions, all of the starting material is dissolved. The resulting orange-brown solution was concentrated on a rotary evaporator to approximately 250 ml. Then the concentrated reaction mixture was diluted with 400 ml of water. The aqueous solution was extracted with 200 ml of ether. The aqueous layer was transferred to a 1 L Erlenmeyer flask equipped with a magnetic stirrer. The solution is then treated dropwise with 36.0 g (0.355 mol) of concentrated hydrochloric acid over a period of about 10 minutes. The product is separated by filtration, resuspended in 2 x 200 ml of water, the top layer is washed once with 100 ml of water, and then air-dried on the filter for 1.5 hours. The product consists of 58.1 g (83%) of crystalline light brown powder. About 0.7% of the ether is the only noticeable impurity detected by ¹ H NMR.

¹ H NMR (DMSO-d ₆ ) δ 13.95 (br s, 1H), 8.56 (d, 1H), 8.25 (d, 1H), 7.68 (dd, 1H), 7, 20 (s, 1H).

EXAMPLE 14

Preparation of 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (alternative name 1- (3-chloro-2-pyridinyl) -3-bromopyrazole-5-carboxylic acid)

25.0 g (0.0756 mol) of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5 are charged into a 300-ml four-necked flask equipped with a mechanical stirrer, thermometer and nitrogen inlet -carboxylate with a purity of 98.5%, 75 ml of methanol, 50 ml of water and 3.30 g (0.0825 mol) of sodium hydroxide granules. The mixture heats itself from 29 to 34 ° C, and the starting material begins to dissolve with the addition of sodium hydroxide. After stirring for 90 minutes at ambient conditions, all of the starting material is dissolved. The resulting dark orange solution was concentrated to approximately 90 ml on a rotary evaporator. Then the concentrated reaction mixture was diluted with 160 ml of water. The aqueous solution was extracted with 100 ml of ether. The aqueous layer was transferred to a 500 ml Erlenmeyer flask equipped with a magnetic stirrer. The solution is then treated dropwise with 8.50 g (0.0839 mol) of concentrated hydrochloric acid over a period of about 10 minutes. The product was separated by filtration, resuspended in 2 x 40 ml of water, the top layer was washed once with 25 ml of water, and then dried in air on the filter for 2 hours. The product consists of 20.9 g (91%) of a crystalline tan powder. The only noticeable impurities detected by ¹ H NMR are approximately 0.8% of the unknown product and 0.7% of ether. ¹ H NMR (DMSO-d ₆ ) δ 13.95 (br s, 1H), 8.56 (d, 1H), 8.25 (d, 1H), 7.68 (dd, 1H), 7, 25 (s, 1H).

EXAMPLE 15

Preparation of ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate from ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4 , 5-dihydro-1H-pyrazole-5-carboxylate using hydrogen bromide

Hydrogen bromide is passed through a solution of ethyl 3-chloro-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate (8.45 g, 29.3 mmol) in dibromomethane (85 ml). After 90 minutes, the gas flow was stopped and the reaction mixture was washed with an aqueous solution of sodium bicarbonate (100 ml). The organic phase was dried and evaporated under reduced pressure to obtain the title product as an oil (9.7 g, 99% yield), which crystallized upon standing.

¹ H NMR (CDC1 ₃ ) δ 8.07 (dd, J = 1.6, 4.8Hz, 1H), 7.65 (dd, J = 1.6, 7.8Hz, 1H), 6.85 ( dd, J = 4.7, 7.7Hz, 1H), 5.25 (X of ABX, 1H, J = 9.3, 11.9Hz), 4.18 (q, 2H), 3.44 (1 / 2 AB in the ABX series, J = 11.7, 17.3Hz, 1H), 3.24 (1/2 AB in the ABX series, J = 9.3, 17.3Hz, 1H), 1.19 (t , 3H).

The following Example 16 illustrates the preparation of ethyl 1- (3-chloro-2-pyridinyl) -4,5-dihydro-3 - [[(4-methylphenyl) sulfonyl] oxy] -1H-pyrazole-5-carboxylate, which can be used to obtain ethyl 3-bromo-1- (3-chloro-2-pyridinyl) -4,5-dihydro-1H-pyrazole-5-carboxylate, using procedures similar to those described in example 15.

EXAMPLE 16

Preparation of ethyl 1- (3-chloro-2-pyridinyl) -4,5-dihydro-3 - [[4-methylphenyl) sulfonyl] oxy] -1H-pyrazole-5-carboxylate

Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture of ethyl 2- (3-chloro-2-pyridinyl) -5-oxo-3-pyrazolidinecarboxylate (10.0 g, 37.1 mmol) and p -toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 ml), at 0 ° C. Additional portions of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) are added. Then the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was then diluted with dichloromethane (200 ml) and washed with water (3 x 70 ml). The organic phase is dried and evaporated to give the title product as an oil (13.7 g, 87% yield), which slowly forms crystals. The product recrystallized from ethyl acetate / hexane melts at 99.5-100 ° C.

IR (nujol): 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084, 1027.948, 969, 868, 845 cm ^-1 .

¹ H NMR (CDC1 ₃ ) δ 8.01 (dd, J = 1.4, 4.6Hz, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.56 (dd, J = 1.6, 7.8Hz, 1H), 7.36 (d, J = 8.4Hz, 2H), 6.79 (dd, J = 4.6, 7.7Hz, 1H), 5.72 (X from ABX, J = 9, 11.8Hz, 1H), 4.16 (q, 2H), 3.33 (1/2 AB in the ABX series, J = 17.5, 11.8 Hz, 1H), 3 12 (1/2 AB in the ABX series, J = 17.3, 9Hz, 1H), 2.45 (s, 3H), 1.19 (t, 3H).

Using the procedures described herein, together with methods known in the art, the following compounds of Tables 1-3 can be obtained. The following abbreviations are used in the tables: t is tertiary, s is secondary, n is normal, i is iso, Me is methyl, Et is ethyl, Pr is propyl, i-Pr is isopropyl and t- Bu is tertiary butyl.

Table 1

R ¹ represents Cl X represents N X represents CH X is CCl X represents CBr R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl n-bu Br n-bu Cl n-bu Br n-bu Cl n-bu Br n-bu Cl n-bu Br n-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl t-bu Br t-bu Cl t-bu Br t-bu Cl t-bu Br t-bu Cl t-bu Br t-bu

R ¹ represents Br X represents N X represents CH X is CCl X represents CBr R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl n-bu Br n-bu Cl n-bu Br n-bu Cl n-bu Br n-bu Cl n-bu Br n-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl t-bu Br t-bu Cl t-bu Br t-bu Cl t-bu Br t-bu Cl t-bu Br t-bu

table 2

R ¹ represents Cl X represents N X represents CH X is CCl X represents CBr R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl n-bu Br n-bu Cl n-bu Br n-bu Cl n-bu Br n-bu Cl n-bu Br n-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl t-bu Br t-bu Cl t-bu Br t-bu Cl t-bu Br t-bu Cl t-bu Br t-bu R ¹ represents Br X represents N X represents CH X is CCl X represents CBr R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl i-pr Br i-pr Cl n-bu Br n-bu Cl n-bu Br n-bu Cl n-bu Br n-bu Cl n-bu Br n-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl i-bu Br i-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl s-bu Br s-bu Cl t-bu Br t-bu Cl t-bu Br t-bu Cl t-bu Br t-bu Cl t-bu Br t-bu

Table 3

R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ R ² R ³ Cl H Cl n-Pr Cl i-bu Br H Br n-Pr Br i-bu Cl Me Cl i-pr Cl s-bu Br Me Br i-pr Br s-bu Cl Et Cl n-bu Cl t-bu Br Et Br n-bu Br t-bu

Applicability

The compounds of formulas I, II and 4 are suitable for use as synthetic intermediates for preparing a compound of formula III

where X, R ¹ , R ² and n are as defined above; R ⁶ represents CH ₃ , Cl or Br; R ⁷ represents F, Cl, Br, I or CF ₃ ; and R ⁸ represents C ₁ -C ₄ alkyl.

The compounds of formula III are suitable for use as insecticides.

Compounds of formula III can be prepared from compounds of formula II (and, in turn, from compounds of formula 4 and I) using the methods depicted in schemes 5-7.

A pyrazolecarboxylic acid compound of formula IIa (a compound of formula II where R ³ is H) with anthranilic acid of formula 5 gives benzoxazinone of formula 6. In Scheme 5, benzoxazinone of formula 6 is prepared directly by sequentially adding methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to pyrazolecarboxylic acid of formula IIa, followed by the addition of anthranilic acid of formula 5, followed by a second addition of a tertiary amine and methanesulfonyl chloride. This procedure, as a rule, gives a good yield of benzoxazinone.

Scheme 5

Scheme 6 depicts an alternative preparation for benzoxazinones of formula 6, comprising a compound of pyrazolyl chloride of formula 8 with isotonic anhydride of formula 7, with direct preparation of benzoxazinone of formula 6.

Scheme 6

Solvents such as pyridine or pyridine / acetonitrile are suitable for use in this reaction. Chlorides of formula 8 are available from the corresponding acids of formula IIa by known procedures, such as chlorination with thionyl chloride or oxalyl chloride.

Compounds of formula III can be prepared by reacting benzoxazinones of formula 6 with C ₁ -C ₄ alkylamines as depicted in Scheme 7. The reaction can be carried out on its own or in a variety of appropriate solvents, including tetrahydrofuran, diethyl ether, dichloromethane or chloroform, with optimal temperatures ranging from room temperature to the reflux temperature of the solvent. The general interaction of benzoxazinones with amines to produce anthranilamides is well known in the chemical literature. For a review of the chemistry of benzoxazinones, see Jakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103 and the references cited therein. See also Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

DIAGRAM 7

Example 17

Preparation of 6.8-Dichloro-2- [1- (3-chloro-2-pyridinyl) -3-bromo-1H-pyrazol-5-yl] -4H-3,1-benzoxazin-4-one

Stage A: Obtaining 6,8-dichloro-2H-3,1-benzoxazine-2,4 (1H) -dione

Trichloromethylchloroformate (70 g, 350 mmol) was added dropwise to a suspension of 2-amino-3,5-dichlorobenzoic acid (104 g, 500 mmol) stirred in dry dioxane (750 ml) at room temperature. The reaction mixture was exothermically slowly heated to 30 ° C, and the solid was almost completely dissolved before again forming a thick suspension. After stirring this suspension at ambient temperature for 2.5 hours, the title compound was isolated by filtration, washed with ethyl ether and dried to obtain the title product compound obtained as a white solid (82 g).

¹ H NMR (DMSO-d ₆ ) δ 7.88 (d, 1H), 8.07 (d, 1H), 11.6 (s, 1H).

Stage B: Obtaining 6,8-dichloro-2- [1- (3-chloro-2-pyridinyl) -3-bromo-1H-pyrazol-5-yl] -4H-3,1-benzoxazin-4-one

To a suspension of 1- (3-chloro-2-pyridinyl) -3-bromo-1H-pyrazole-5-carboxylic acid (i.e., the product of stage C) (118 g, 390 mmol), stirred in dichloromethane (1 l) , N, N-dimethylformamide (8 drops) was added. Oxalyl chloride (63.8 g, 500 mmol) was added dropwise over 1.5 hours. The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The isolated acid chloride was dissolved in dry acetonitrile (200 ml) and 6.8-dichloro-2H-3,1-benzoxazine-2,4 (1H) -dione (i.e., product of stage A) was added to the suspension (82 g, 350 mmol), stirred in dry acetonitrile (200 ml). Pyridine (175 ml) was added and this solution was heated under reflux for reflux for 4 hours. After cooling in an ice bath, a precipitate of white solid (152 g) was collected.

¹ H NMR (CDCl ₃ ) δ 7.27 (d, 1H), 7.38 (q, 1H), 7.72 (s, 1H), 7.9 (d, 1H), 8.05 (s, 1H), 8.55 (d, 1H).

Example 18

Preparation of 2- [3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

To the solution To a solution of methanesulfonyl chloride (0.40 ml, 5.2 mmol) in acetonitrile was added dropwise a mixture of 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (1.5 g, 4.96 mmol) and triethylamine (0.64 ml, 4.96 mmol) in acetonitrile at 0-5 ° C. Then the reaction temperature was maintained at 0 ° C during the sequential addition of reagents. After stirring for 20 minutes, 2-amino-3-methyl-5-chlorobenzoic acid (0.92 g, 4.96 mmol) was added and stirring was continued for an additional 5 minutes. Then, a solution of triethylamine (10.0 mmol) in acetonitrile was added dropwise and the reaction mixture was stirred for 45 minutes, followed by methanesulfonyl chloride (0.40 ml, 5.2 mmol). Then the reaction mixture was warmed to room temperature and stirred overnight.

The title compound was obtained as a solid (1.21 g).

¹ H NMR (CDCl ₃ ) δ 2.01, (s, 3H), 7.29 (s, 1H), 7.42 (d, 1H), 7.95 (d, 1H), 8.04 (m , 1H), 8.25 (s, 1H), 8.26 (d, 1H).

Example 19

Preparation of 3-bromo-N- [4-chloro-2-methyl-6 - [[(1-methylethyl) amino] carbonyl] phenyl] -1- (3-chloro-2-pyridinyl) -1H-pyrazole-5 carboxamide

To a solution of 2- [3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazol-5-yl] -6-chloro-8-methyl-4H-3,1-benzoxazin-4-one ( i.e., the benzoxazinone product obtained above) (0.20 g, 0.44 mmol) in tetrahydrofuran was added isopropylamine (0.122 ml, 1.42 mmol) and the reaction mixture was heated to 60 ° C for 90 minutes and then cooled to room temperature. The solvent tetrahydrofuran was evaporated under reduced pressure and the remaining solid was triturated with ether, filtered and dried to give the title compound, the compound of this invention, as a solid (150 mg), mp. 159-161 ° C.

¹ H NMR (CDCl ₃ ) δ 1.22 (d, 6H), 2.19 (s, 3H), 4.21 (m, 1H), 5.99 (m, 1H), 7.05 (m, 1H), 7.22 (m, 2H), 7.39 (m, 1H), 7.82 (d, 1H), 8.41 (d, 1H).

Claims (24)

1. The compound of formula I

where R ¹ represents a halogen; R ² represents halogen; R ³ represents C ₁ -C ₄ alkyl; X represents N or CH; and n is 0-3, provided that when X is CH, then n is at least 1. 2. The compound according to claim 1, where n is from 1 to 3. 3. The compound according to claim 1, where R ¹ represents Cl or Br; each R ² is independently Cl or Br, and one R ² is in the 3rd position; and X represents N. 4. A method for producing a compound of formula I according to claim 1, comprising processing a compound of formula 4

where R ³ represents C ₁ -C ₄ alkyl; halogenating agent. 5. The method according to claim 4 where n is from 1 to 3. 6. The method according to claim 4, where R ¹ represents Cl or Br; each R ² is independently Cl or Br, and one R ² is in the 3rd position; R ³ represents C ₁ -C ₄ alkyl; and X represents N. 7. The method according to claim 6, where the halogenating agent is a phosphorus oxyhalide or phosphorus pentahalide. 8. The method according to claim 7, where the process is carried out in the absence of a base, using acetonitrile, as a solvent. 9. The compound of formula II

where R ¹ represents halogen; R ² represents halogen; R ³ represents H or C ₁ -C ₄ alkyl; X represents N or CH; and n is from 0 to 3, provided that when X represents CH, then n is at least 1. 10. The compound according to claim 9, where n is from 1 to 3. 11. The compound according to claim 9, where R ¹ represents Cl or Br; each R ² is independently Cl or Br, and one R ² is in the 3rd position; X represents N. 12. The compound according to claim 9, where n = 1; R ¹ represents Cl or Br; R ² represents Cl or Br, and R ² is in the 3rd position and R ³ is N. 13. The compound of formula 4

where each R ² represents halogen; X represents N; R ³ represents C ₁ -C ₄ alkyl; and n is from 0 to 3. 14. The compound according to item 13, where n is from 1 to 3. 15. The compound according to item 13, where each R ² represents, independently, Cl or Br, and one R ² is in the 3rd position. 16. The method of obtaining the compounds of formula II according to claim 9, comprising (3) processing the compounds of formula I

an oxidizing agent, optionally in the presence of an acid, to give a compound of formula II; and when the compound of formula I, where R ³ is C ₁ -C ₄ alkyl, is used to obtain a compound of formula II where R ³ is H, (4) converting the compound obtained in (3) into a compound of formula II, wherein R ³ is H. 17. The method according to clause 16, where n is from 1 to 3. 18. The method according to clause 16, where the oxidizing agent is hydrogen peroxide or persulfate salt. 19. The method according to p, where X represents CH; and the oxidizing agent is hydrogen peroxide. 20. The method according to p, where X represents N; the oxidizing agent is potassium persulfate; and step (3) is carried out in the presence of sulfuric acid. 21. The method according to clause 16, where in the formula I, where R ¹ represents Cl or Br, each R ² represents, independently, Cl or Br, and one R ² is in the 3rd position; R ³ represents C ₁ -C ₄ alkyl; and X represents N. 22. The method according to clause 16, in which the compound of formula I is obtained by a method comprising (1) processing a compound of formula 4

where R ³ represents C ₁ -C ₄ alkyl; halogenating agent to obtain the compounds of formula I. 23. A method of obtaining a compound of formula III

where R ¹ represents halogen; each R ² represents halogen; X represents N or CH; R ⁶ represents CH ₃ , Cl or Br; R ⁷ represents F, Cl, Br, I or CF ₃ ; R ⁸ represents C ₁ -C ₄ alkyl and n is 0, 1, 2 or 3; with the proviso that when X is CH, then n is at least 1; using as an intermediate compound of formula II

where R ³ represents H; characterized in that the method comprises the following steps: (a) obtaining a compound of formula II in accordance with the method described in clause 16; (C) obtaining the compounds of formula 6

or (i) by combining compound II with a compound of formula 5

or (ii) chlorination of a compound of formula II to obtain a compound of formula 8, and a combination of a compound of formula 8 with a compound of formula 7

(c) reacting a compound of formula 6 with a compound of formula R ⁸ NH ₂ . 24. The method according to item 23, where n is from 1 to 3.