TW202409000A - A new and efficient process for preparing 3-halo-4,5-dihydro-1h-pyrazoles - Google Patents

Abstract

An improved method is disclosed for preparing a 3-halo-4,5-dihydro-1H-pyrazole compound of Formula I comprising reacting a compound of Formula II with a halide salt and a mineral acid to form the compound of Formula I. wherein X1, R1, R2, R<SP>x</SP>, k, Z and X2 are as defined in the disclosure. Also disclosed are methods for preparing compounds of Formula III and Formula IV wherein R1, X1, R2, R<SP>x</SP>, k, R<SP>6A</SP>, R<SP>6B</SP>, R<SP>6C</SP>, R<SP>6D</SP> and R7 are as defined in the disclosure, using a compound of Formula I characterized by preparing the compound of Formula I by the method disclosed above or using a compound of Formula I prepared by the method disclosed above.

Description

A new and efficient method for preparing 3-halogenated-4,5-dihydro-1H-pyrazole

The present disclosure relates to an improved method for preparing 3-halo-4,5-dihydro- 1H -pyrazoles. Such compounds prepared by the methods disclosed herein can be used to prepare diamide crop protection agents which are of interest as insecticides.

Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylate is an intermediate in the preparation of diamide crop protection agents such as the insecticides cyanamide, chloranilamide and their derivatives. The conventional process for the production of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylate using hydrogen bromide as a gas or solution is affected by several industrial problems associated with the storage, handling and use of steel cylinders and solutions containing corrosive gases (e.g., hydrogen bromide). Compared to conventional methods, halides reduce environmental hazards, high costs, reagent reactivity, the need for necessary specialized equipment, and limitations in operating the method on a commercial scale.

The present disclosure provides novel methods for preparing 3-halogenated-4,5-dihydro- 1H -pyrazoles. Benefits of the disclosed methods include significant improvements in the process for commercial scale operation compared to previous methods, using relatively low cost, milder reaction conditions, and less hazardous reagents that are commercially available in industrial quantities.

The present disclosure relates to a method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound having Formula I Wherein R ¹ is C(O)R ³ , halogen, cyano, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl or C ₁ -C ₄ hydroxyalkyl; X ¹ is halogen; R ² is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; each ^R C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; Z is N or CR ^z ; R ³ is H, OH, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ^z is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; and k is 0, 1, 2 or 3; the method includes: making (1) 4,5- having formula II Dihydro- 1H -pyrazole compound Where X ² is OS(O) _m R ⁴ , OP ₍ O ⁾ _n (OR ⁵ ) ₂ or ^halogen other than ₄ alkyl or C ₁ -C ₄ haloalkyl; or phenyl optionally substituted with 1 to 3 substituents selected from C ₁ -C ₄ alkyl and halogen; and each R ⁵ is independently C ₁ - C ₄ alkyl or C ₁ -C ₄ haloalkyl; or phenyl optionally substituted by 1 to 3 substituents selected from C ₁ -C ₄ alkyl and halogen; with (2) halide salt, wherein the halogen The ^halogen series of the salt,

The present disclosure also relates to a method of preparing a compound of formula III Wherein R ¹ is C(O)R ³ , halogen, cyano, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl or C ₁ -C ₄ hydroxyalkyl; X ¹ is halogen; R ² is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; each ^R C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; Z is N or CR ^z ; R ³ is H, OH, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ^z is Hydrogen, halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; and k is 0, 1, 2 or 3; the method is characterized in that it is prepared by the method disclosed above 3-halo-4,5-dihydro- 1H -pyrazole compounds of formula I.

The present disclosure also relates to a method for preparing a diamide compound having formula IV wherein ^X1 is halogen; ^R2 is hydrogen, halogen, cyano, _C1 - _C4 alkyl or _C1 - _C4 halogenated alkyl; each ^Rx is independently halogen, cyano, _C1 - _C4 alkyl or _C1 - _C4 halogenated alkyl; Z is N or ^CRz ; ^Rz is hydrogen, halogen, cyano, _C1 - _C4 alkyl or _C1 -C4 halogenated alkyl; k is 0, 1, 2 or 3; ^R6A is halogen, cyano, _C1 - _C4 alkyl or _C1 - _C4 halogenated alkyl ^{; R6B} is hydrogen, halogen, cyano, _C1 - _C4 alkyl or _C1 - _C4 halogenated alkyl; _R6C is halogen, cyano, _C1 - _C4 alkyl or _C1 - _C4 halogenated alkyl; R ^6D is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ halogenated alkyl; and R ⁷ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₈ cycloalkylalkyl, C ₄ -C ₈ alkylcycloalkyl, or C ₅ -C ₈ alkylcycloalkylalkyl; the method uses a compound having formula Ia wherein R ³ is OH or C ₁ -C ₄ alkoxy; the method is characterized in that the compound having formula Ia is prepared by the method disclosed above.

The methods of the present disclosure are generally applicable to a variety of starting compounds of Formula II and product compounds of Formula I. In the description herein, although the R ¹ substituent is attached to the backbone of the 4,5-dihydro-1 H -pyrazole ring, the R ¹ substituent is separated from the reaction center. The R ¹ substituents can include a variety of carbon-based groups that can be prepared by modern organic synthetic chemistry methods. Those skilled in the art will recognize that certain groups are sensitive to the reagents of this method and can be transformed under the reaction conditions. Those skilled in the art will also recognize that certain groups are basic and can form salts when contacted with reagents of the method, and therefore the methods of the present disclosure may require additional halide salts and inorganic acids.

As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any other variations thereof, are intended to cover a non-exclusive inclusion, subject to any limitation expressly stated. For example, a composition, mixture, process, or method that comprises a list of elements is not necessarily limited to those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

The transitional phrase "consisting of" excludes any unspecified element, step, or ingredient. If in a claim, the phrase renders the claim closed, excluding materials other than those expressly listed, except for impurities normally associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than in the immediate preceding clause, the phrase limits only the elements specified in that clause; the claim as a whole does not exclude other elements.

The linking phrase "consisting essentially of" is used to define a composition, process or method that includes materials, steps, features, components, or elements in addition to those literally disclosed, provided that such additional materials, steps , features, components, or elements do not materially affect the basic and novel characteristics of the present disclosure. The term "consisting essentially of" falls somewhere between "includes" and "consisting of."

When the applicant has defined an embodiment or a part thereof with an open-ended term such as "comprising", it should be readily understood that (unless otherwise stated) the description should be interpreted as also using the term "consisting essentially of" or “consisting of” describes the embodiment.

In addition, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive or. For example, condition A or B is satisfied by any of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

Similarly, the indefinite article "a/an" before an element or component of the present disclosure is intended to be non-restrictive with respect to the number of instances (i.e., occurrences) of the element or component. Therefore, "a or an" should be understood to include one or at least one, and the singular word form of an element or component also includes the plural, unless the number obviously means the singular.

As used herein, the term "about" means plus or minus 10% of the value. It should also be understood that any numerical ranges listed herein include all values from the lower limit to the upper limit. For example, if the numerical range is specified as 1 to 10, it is expected that values such as 2 to 9, 2.5 to 8.1, or 1 to 1.6 are clearly listed in this specification. These are only examples of specific intent, and all possible combinations of numerical values between (and including) the lowest and highest values listed will be considered to be clearly stated in this application. It should be further understood that if a range is listed in a "from/to" or "from about/to about" format, such as from 10: 1 to 1: 10, the range includes endpoints ( i.e. , 10: 1 and 1: 10).

In any of the various aspects of the present disclosure, the molar ratio of the halide to the compound of Formula II is 20:1, 15:1, 10:1, 9:1, 8:1, 7.9:1, 7.8:1, 7.7:1, 7.6:1, 7.5:1, 7.4:1, 7.3:1, 7.2:1, 7.1:1, 7:1, 6.9:1, 6.8:1, 6.7:1, 6.6:1, 6.5:1, 6.4:1, 6.3:1, 6.2:1, 6.1:1, 6:1, 5.9:1, 5.8:1, 5.7:1, 5.6:1 1, 5.5 : 1, 5.4 : 1, 5.3 : 1, 5.2 : 1, 5.1 : 1, 5.1, 4.9 : 1, 4.8 : 1, 4.7 : 1, 4.6 : 1, 4.5 : 1, 4.4 : 1, 4.3 : 1, 4.2 : 1, 4.1 : 1, 4 : 1, 3.9 : 1, 3.8 : 1, 3.7 : 1, 3.6 : 1, 3.5 : 1, 3.4 : 1, 3.3 : 1, 3.2 : 1, 3.1 : 1, 3 : 1, 2.9 : 1, 2.8 : 1, 2.7 : 1, 2.6 : 1, 2.5 : 1, 2.4 : 1, 2.3:1, 2.2:1, 2.1:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, 0.9:1, 0.8:1, 0.7:1, 0.6:1, 0.5:1, 0.4:1, 0.3:1, 0.2:1 or 0.1:1, and any ranges consisting of the above values, such as about 1:1 to about 6:1, about 1:1 to about 5:1, about 2:1 to about 5:1, about 3.5:1 to about 4.5:1 1, or about 3.9:1 to about 4.1:1.

In any of the various aspects of the present disclosure, the molar ratio of the inorganic acid to the compound of Formula II is 20:1, 15:1, 12:1, 10:1, 9:1, 8:1, 7.9: 1, 7.8 : 1, 7.7 : 1, 7.6 : 1, 7.5 : 1, 7.4 : 1, 7.3 : 1, 7.2 : 1, 7.1 : 1, 7 : 1, 6.9 : 1, 6.8 : 1, 6.7 : 1, 6.6: 1, 6.5: 1, 6.4: 1, 6.3: 1, 6.2: 1, 6.1: 1, 6: 1, 5.9: 1, 5.8: 1, 5.7: 1, 5.6: 1, 5.5: 1, 5.4: 1, 5.3 : 1, 5.2 : 1, 5.1 : 1, 5.1, 4.9 : 1, 4.8 : 1, 4.7 : 1, 4.6 : 1, 4.5 : 1, 4.4 : 1, 4.3 : 1, 4.2 : 1, 4.1 : 1, 4: 1, 3.9: 1, 3.8: 1, 3.7: 1, 3.6: 1, 3.5: 1, 3.4: 1, 3.3: 1, 3.2: 1, 3.1: 1, 3: 1, 2.9: 1, 2.8 : 1, 2.7 : 1, 2.6 : 1, 2.5 : 1, 2.4 : 1, 2.3 : 1, 2.2 : 1, 2.1 : 1, 2 : 1, 1.9 : 1, 1.8 : 1, 1.7 : 1, 1.6 : 1, 1.4 : 1, 1.3 : 1, 1.2 : 1, 1.1 : 1, 1 : 1, 0.9 : 1, 0.8 : 1, 0.7 : 1, 0.6 : 1, 0.5 : 1, 0.4 : 1, 0.3 : 1, 0.2:1 or 0.1:1, and any range consisting of such values, such as about 0.5:1 to about 12:1, about 0.5:1 to about 6:1, about 2:1 to about 4:1, about 2.5:1 to about 3.5:1, or about 2.9:1 to about 3.1:1.

In any of the various aspects of the disclosure, the weight to volume ratio of the compound of Formula II to the solvent is 1:500, 1:50, 1:40, 1:35, 1:30, 1:25, 1: 24, 1:23, 1:22, 1:21, 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9.9, 1:9.8, 1:9.7, 1:9.6, 1:9.5, 1:9.4, 1:9.3, 1:9.2, 1:9.1, 1:9, 1: 8.9, 1 : 8.8, 1 : 8.7, 1 : 8.6, 1 : 8.5, 1 : 8.4, 1 : 8.3, 1 : 8.2, 1 : 8.1, 1 : 8, 1 : 7.9, 1 : 7.8, 1 : 7.7, 1:7.6, 1:7.5, 1:7.4, 1:7.3, 1:7.2, 1:7.1, 1:7, 1:6.9, 1:6.8, 1:6.7, 1:6.6, 1:6.5, 1: 6.4, 1 : 6.3, 1 : 6.2, 1 : 6.1, 1 : 6, 1 : 5.9, 1 : 5.8, 1 : 5.7, 1 : 5.6, 1 : 5.5, 1 : 5.4, 1 : 5.3, 1 : 5.2, 1:5.1, 1:5, 1:4.9, 1:4.8, 1:4.7, 1:4.6, 1:4.5, 1:4.4, 1:4.3, 1:4.2, 1:4.1, 1:4, 1: 3.9, 1 : 3.8, 1 : 3.7, 1 : 3.6, 1 : 3.5, 1 : 3.4, 1 : 3.3, 1 : 3.2, 1 : 3.1, 1 : 3, 1 : 2.9, 1 : 2.8, 1 : 2.7, 1:2.6, 1:2.5, 1:2.4, 1:2.3, 1:2.2, 1:2.1, 1:2, 1:1.9, 1:1.8, 1:1.7, 1:1.6, 1:1.5, 1: 1.4, 1:1.3, 1:1.2, 1:1.1, 1:1, 1:0.9, 1:0.8, 1:0.75, 1:0.7, 1:0.6, 1:0.5 or 1:0.05, and by the same Any range of values, such as about 0.5:1 to about 12:1, about 0.5:1 to about 6:1, about 2:1 to about 4:1, about 2.5:1 to about 3.5:1, or about 2.9 :1 to approximately 3.1 :1.

As used herein, the term "alkyl" used alone or in compound words such as "haloalkyl", "alkylcycloalkyl", "cycloalkylalkyl" or "alkylcycloalkylalkyl" includes straight or branched alkyl groups having one to four carbon atoms, such as methyl, ethyl, n -propyl, isopropyl , or different butyl isomers. "Alkenyl" includes straight or branched alkenes, such as vinyl, 1-propenyl, 2-propenyl, and different butenyl isomers. "Alkenyl" also includes polyenes, such as 1,2-propadienyl and 1,3-butadienyl. "Alkynyl" includes straight or branched alkynes, such as ethynyl, 1-propynyl, 2-propynyl, and different butynyl isomers. "Alkynyl" may also include moieties consisting of multiple triple bonds, such as 1,3-butadiynyl.

As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine. The term "halogen", alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Furthermore, when used in compound words such as "haloalkyl", the alkyl group may be partially substituted or fully substituted by 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 CCl ₂ .

The term "alkoxy" refers to an alkyl group attached to and linked through an oxygen atom, such as, for _example , methoxy, ethoxy, n _- propoxy, isopropoxy , and the different butoxy isomers. "Hydroxyalkyl" refers to _an alkyl group substituted with _a terminal _hydroxyl group. Examples of "hydroxyalkyl" include _HOCH2CH2 , _CH3CH2 (OH)CH, and _{HOCH2CH2CH2CH2} .

"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "alkylcycloalkyl" refers to alkyl substitution on the cycloalkyl portion, and includes, for example, ethylcyclopropyl, isopropylcyclobutyl, 3-methylcyclopentyl, and 4-methylcyclohexyl. The term "cycloalkylalkyl" refers to cycloalkyl substitution on the alkyl portion. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, and other cycloalkyl portions bonded to straight or branched alkyl groups. "Alkylcycloalkylalkyl" refers to alkylcycloalkyl substitution on the alkyl group. Examples of "alkylcycloalkylalkyl" include methylcyclohexylmethyl and ethylcyclopropylmethyl.

The chemical abbreviations S(O) and S(=O) as used herein represent a sulfinyl moiety. The chemical abbreviations SO ₂ , S(O) ₂ and S(=O) ₂ as used herein represent sulfonyl moieties. The chemical abbreviations C(O) and C(=O) as used herein represent carbonyl moieties. The chemical abbreviations C(S) and C(=S) as used herein represent thiocarbonyl moieties. The chemical abbreviations _CO2 , C(O)O and C(=O)O as used herein represent the oxycarbonyl moiety. "CHO" means nail base.

_A "-" at the beginning of a fragment definition indicates the point of attachment of the fragment to the rest of the molecule; for example, " _-CH2CH2OMe " indicates the fragment 2-methoxyethyl.

Cyclic fragments are represented by the use of two "-"s within parentheses; for example, the fragment 1 _- methylcyclopropyl is represented by "-C( _CH3 )(- _CH2CH2- )" where the carbon atoms are bonded to the two terminal carbon atoms of a di-carbon chain, as shown below.

The total number of carbon atoms in a substituent is indicated by the "C _h -C _i " prefix, where h and i are numbers from 1 to 8. For example, C ₃ -C ₆ cycloalkyl represents cyclopropane to cyclohexane; C ₅ alkylcycloalkylalkyl represents, for example, -CH ₂ C(CH ₃ )(-CH ₂ CH ₂ -) or -CH ₂ C (-CH(CH ₃ )CH ₂ -); C ₆ alkylcycloalkylalkyl represents for example -CH ₂ CH ₂ C(CH ₃ )(-CH ₂ CH ₂ -), -CH ₂ CH ₂ C(- CH(CH ₃ )CH ₂ -), -CH ₂ C(CH ₂ CH ₃ )(-CH ₂ CH ₂ -), -CH ₂ C(-CH(CH ₂ CH ₃ )CH ₂ -), -CH ₂ C(CH ₃ )(-CH ₂ CH ₂ CH ₂ -), -CH ₂ C(-CH(CH ₃ )CH ₂ CH ₂ -) or -CH ₂ C(-CH ₂ CH(CH ₃ )CH ₂ - ); and C ₈ alkylcycloalkylalkyl represents the various isomers of alkyl substituted by alkylcycloalkyl containing a total of eight carbon atoms.

When a compound is substituted by a substituent with a subscript (which indicates that the number of said substituents may exceed 1), said substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g. (R ^x ) _k , where k is 0, 1, 2 or 3. When a group contains a substituent which may be hydrogen, for example ^R2 or ^R6B , then when the substituent is hydrogen it is recognized that this is equivalent to the group being unsubstituted. When a variable group is shown to be optionally attached to a position, such as (R ^x ) _k where k may be 0, then a hydrogen may be located at that position even if not mentioned in the variable group definition. When one or more positions on a group are said to be "unsubstituted" or "unsubstituted," a hydrogen atom is attached to occupy any free valence.

As used herein, the term "suitable" indicates that the entity so described is suitable for use in the situation or environment shown. The term "reaction" and the like refer to the addition, contact or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction to produce the indicated and/or desired product does not necessarily arise directly from the combination of the two reagents initially added, i.e., one or more intermediates may be produced in the mixture that ultimately leads to the formation of the indicated and/or desired product. The reaction can be carried out in the presence or absence of a solvent, at a temperature above or below room temperature, under an inert atmosphere, etc.

The term "optional" when used herein means that an optional condition may or may not be present. For example, when the reaction is optionally carried out in the presence of an organic acid, the organic acid may or may not be present. The term "optionally substituted" refers to a group that is unsubstituted or has at least one non-hydrogen substituent that does not eliminate the chemical or biological activity possessed by the unsubstituted analogue. As used herein, the following definitions will apply unless otherwise specified. The term "optionally substituted" is used interchangeably with the phrase "unsubstituted or substituted" or with the term "(not) substituted." Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.

As used herein, the term "salt" or "salts" refers to any complex of anions and cations. The term "halide" refers to anions of halogens. The term "halide" refers to a salt having one or more halogen anions and at least one other atom that is not a halogen. Halides may include but are not limited to inorganic halides. The term "inorganic halides" means salts of inorganic cations and one or more halogen anions. The inorganic cations may be selected from alkali metals and/or alkaline earth metals. As used herein, the term "alkali" refers to the alkali metals of the periodic table (i.e., lithium, sodium, potassium, cadmium, cesium, and cobalt). As used herein, the term "alkaline earth" refers to the alkali earth metals of the periodic table (i.e., palladium, magnesium, calcium, strontium, barium, and ferrum). The term "organic halide" means a salt of an organic cation and one or more halogen anions. Non-limiting examples of organic cations include, for example, ammonium, quaternary ammonium, and amine cations, such as ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, and ethylammonium, etc.

As used herein, the term "inorganic acid" refers to an acid derived from one or more inorganic compounds that dissociates in water to produce hydrogen ions (H ⁺ ). Non-limiting examples of inorganic acids include, for example, hydroiodic acid, hydrobromic acid, hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, sulfurous acid, phosphoric acid, boric acid, and combinations thereof.

As used herein, the term "organic acid" refers to an organic compound that is characterized by weak acid properties and does not completely dissociate in the presence of water. Examples of organic acids include, but are not limited to, carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, lactic acid, butyric acid, fumaric acid, apple acid, maleic acid, succinic acid, tartaric acid, sorbic acid, citric acid, benzoic acid, and combinations thereof.

As used herein, the term "weight to volume ratio" refers to the weight of the reactants compared to the amount of solvent used in the reaction. Unless otherwise stated, weight to volume ratios are expressed in grams (g) per milliliter (mL). For example, a 1:5 weight to volume ratio of compound of formula II to solvent means 1 gram of compound of formula II compared to 5 mL of solvent.

Implementations of the present disclosure as described in the Summary include those described below. In the following embodiments, references to "a compound of formula I " include the definition of the substituents specified in the Summary of the Invention, unless further defined in the embodiments.

Embodiment 1. A method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound having formula I , wherein R ¹ is C(O)R ³ , halogen, cyano, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or C ₁ -C ₄ hydroxyalkyl.

Embodiment 2. The method of Embodiment 1, wherein R ¹ is C(O)R ³ , halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ hydroxyalkyl.

Embodiment 3. The method as described in Embodiment 1, wherein R ¹ is C(O)R ³ , cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ hydroxyalkyl.

Embodiment 3a. The method of Embodiment 3, wherein R ¹ is C(O)R ³ , cyano, methyl or hydroxymethyl.

Embodiment 3b. The method as described in Embodiment 1, wherein R ¹ is C(O)R ³ .

Embodiment 4. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein ^X1 is Cl, Br , or I.

Embodiment 5. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of Embodiments 1 to 3, wherein X ¹ is Cl, Br or F.

Embodiment 6. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein ^X1 is Cl or Br .

Embodiment 7. The method according to embodiment 6, wherein X ¹ is Cl.

Embodiment 8. The method according to embodiment 6, wherein X ¹ is Br.

Embodiment 9. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein R ² is halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ halogenated alkyl.

Embodiment 10. The method of embodiment 9, wherein R ² is halogen, cyano, methyl, ethyl or C ₁ -C ₄ haloalkyl.

Embodiment 11. The method according to embodiment 9, wherein R ² is halogen, cyano, methyl, ethyl or CF ₃ .

Embodiment 12. The method according to embodiment 9, wherein R ² is F, Cl, Br, cyano, methyl, ethyl or CF ₃ .

Embodiment 13. The method of embodiment 9, wherein R ² is F, Cl, Br, cyano or CF ₃ .

Embodiment 14. The method of embodiment 9, wherein R ² is F, Cl or Br.

Embodiment 15. The method of embodiment 9, wherein R ² is F.

Embodiment 16. The method as described in Embodiment 9, wherein R ² is Cl.

Embodiment 17. The method of embodiment 9, wherein R ² is Br.

Embodiment 18. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein each R ^x is independently F, Cl, Br, cyano or CF ₃ .

Embodiment 19. The method according to embodiment 18, wherein each R ^x is independently F, Cl or Br.

Embodiment 20. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein R ³ is OH or C ₁ -C ₄ alkoxy.

Embodiment 20a. The method according to Embodiment 20, wherein R ³ is OH, OCH ₃ or OCH ₂ CH ₃ .

Embodiment 20b. The method of embodiment 20, wherein R ³ is OH or OCH ₃ .

Embodiment 20c. The method according to Embodiment 20, wherein R ³ is OH.

Embodiment 20d. The method of embodiment 20, wherein R ³ is OCH ₃ .

Embodiment 21. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein R ^z is hydrogen, F, Cl, Br, cyano, methyl or CF ₃ .

Embodiment 22. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of Embodiments 1 to 20, wherein Z is N.

Embodiment 23. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein k is 0, 1 or 2.

Embodiment 24. The method of embodiment 23, wherein k is 0 or 1.

Implementation method 25. The method as described in implementation method 23, wherein k is 0.

Embodiment 26. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein ^X is OS(O ) _m R ⁴ , or halogen other than X ¹ .

Embodiment 26a. The method of embodiment 26, wherein X ² is Cl or OS(O) _m R ⁴ .

Embodiment 27. The method of embodiment 26, wherein X ² is OS(O) _m R ⁴ .

Embodiment 28. The method of embodiment 26, wherein X ² is a halogen other than X ¹ .

Embodiment 29. The method according to embodiment 28, wherein X ² is Cl.

Embodiment 30. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of Embodiments 1 to 25, wherein X ² is OP(O) _n (OR ⁵ ) ₂ .

Embodiment 31. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of embodiments 1 to 27, wherein m is 2.

Embodiment 32. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of embodiments 1 to 27, wherein R ⁴ is C ₁ -C ₄ alkyl; or phenyl optionally substituted with 1 to 3 substituents selected from C ₁ -C ₄ alkyl and halogen.

Embodiment 33. The method as described in Embodiment 32, wherein R ⁴ is methyl or ethyl; or phenyl which is optionally substituted with 1 to 3 substituents selected from methyl, ethyl and halogen.

Embodiment 34. The method as described in Embodiment 32, wherein R ⁴ is methyl or ethyl; or phenyl which is optionally substituted with one substituent selected from methyl, ethyl and halogen.

Embodiment 35. The method of embodiment 32, wherein R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl.

Embodiment 35a. The method according to Embodiment 32, wherein R ⁴ is methyl, phenyl or 4-methylphenyl.

Embodiment 35b. The method as described in Embodiment 35, wherein R ⁴ is methyl.

Embodiment 35c. The method of embodiment 35, wherein R ⁴ is phenyl or 4-methylphenyl.

Embodiment 35d. The method as described in Embodiment 35, wherein R ⁴ is phenyl.

Embodiment 35e. The method of embodiment 35, wherein R ⁴ is 4-methylphenyl.

Embodiment 36. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of embodiments 1 to 25, wherein n is 1.

Embodiment 37. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of embodiments 1 to 25, wherein each R ⁵ is independently C ₁ -C ₄ alkyl; or phenyl optionally substituted with 1 to 3 substituents selected from C ₁ -C ₄ alkyl and halogen.

Embodiment 38. The method as described in Embodiment 37, wherein R ⁵ is methyl or ethyl; or phenyl which is optionally substituted with 1 to 3 substituents selected from methyl, ethyl and halogen.

Embodiment 39. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of Formula I as described in any one of the preceding embodiments, wherein the halide salt is selected from the group consisting of bases Metal halides, alkaline earth metal halides, ammonium halides, quaternary ammonium halides and combinations thereof.

Embodiment 40. The method for preparing a 3-halogenated-4,5-dihydro-1H-pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the halide is selected from alkali metal halides, alkali earth metal halides and combinations thereof.

Embodiment 41. The method of embodiment 40, wherein the halide salt is selected from alkali metal halides and combinations thereof.

Embodiment 42. The method of embodiment 40, wherein the halide salt is selected from alkaline earth metal halides and combinations thereof.

Embodiment 43. The method as described in embodiment 39, wherein the halide is selected from alkali metal bromides, alkali earth metal bromides, ammonium bromide, quaternary ammonium bromide, alkali metal chlorides, alkali earth metal chlorides, ammonium chloride, quaternary ammonium chlorides and combinations thereof.

Embodiment 44. The method of embodiment 39, wherein the halide salt is selected from the group consisting of alkali metal bromide, alkaline earth metal bromide, ammonium bromide, quaternary ammonium bromide and combinations thereof.

Embodiment 45. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of Formula I as described in any one of Embodiments 1 to 40, wherein the halide is selected from alkali metal bromides, alkaline earth metal bromides and combinations thereof.

Embodiment 46. The method of embodiment 45, wherein the halide salt is selected from the group consisting of lithium bromide, sodium bromide, potassium bromide, cesium bromide, magnesium bromide, calcium bromide and combinations thereof.

Embodiment 47. The method as described in embodiment 45, wherein the halide is selected from alkali metal bromides and combinations thereof.

Embodiment 47a. The method according to embodiment 45, wherein the halide is selected from lithium bromide, sodium bromide, potassium bromide, cesium bromide and combinations thereof.

Embodiment 47b. The method of embodiment 45, wherein the halide salt is selected from the group consisting of sodium bromide, potassium bromide and combinations thereof.

Embodiment 47c. The method according to Embodiment 45, wherein the halide is sodium bromide or potassium bromide.

Embodiment 48. The method of embodiment 45, wherein the halide salt is sodium bromide.

Embodiment 49. The method of embodiment 45, wherein the halide salt is potassium bromide.

Embodiment 50. The method of embodiment 45, wherein the halide salt is selected from alkaline earth metal bromides and combinations thereof.

Embodiment 50a. The method according to embodiment 45, wherein the halide is selected from magnesium bromide, calcium bromide and combinations thereof.

Embodiment 51. The method of embodiment 39, wherein the halide salt is selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, ammonium chloride, quaternary ammonium chlorides, and combinations thereof.

Embodiment 51a. The method as described in Embodiment 51, wherein the halide is selected from alkali metal chlorides, alkaline earth metal chlorides and combinations thereof.

Embodiment 51b. The method of embodiment 51, wherein the halide salt is selected from alkali metal chlorides and combinations thereof.

Embodiment 52. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound having Formula I as described in any of the preceding embodiments, wherein the inorganic acid is selected from hydroiodic acid, hydrobromic acid, hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, sulfurous acid, phosphoric acid, boric acid, and combinations thereof.

Embodiment 53. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of Embodiments 1 to 51, wherein the inorganic acid is not hydroiodic acid, hydrobromic acid, hydrochloric acid or hydrofluoric acid.

Embodiment 53a. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of Embodiments 1 to 51, wherein the inorganic acid is not hydrobromic acid or hydrochloric acid.

Embodiment 53b. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of Formula I as described in any one of Embodiments 1 to 51, wherein the inorganic acid is not hydrochloric acid.

Embodiment 53c. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of Formula I as described in any one of Embodiments 1 to 51, wherein the inorganic acid is not hydrobromic acid.

Embodiment 54. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the inorganic acid is selected from the group consisting of Chloroic acid, sulfuric acid, nitric acid, sulfurous acid, phosphoric acid, boric acid and combinations thereof.

Embodiment 54a. The method of embodiment 54, wherein the inorganic acid is selected from the group consisting of perchloric acid, sulfuric acid, nitric acid, oxalic acid, sulfurous acid, and combinations thereof.

Embodiment 54b. The method according to embodiment 54, wherein the inorganic acid is perchloric acid, sulfuric acid, nitric acid, oxalic acid or sulfurous acid.

Embodiment 54c. The method of embodiment 54, wherein the inorganic acid is sulfuric acid or nitric acid.

Embodiment 54d. The method as described in Embodiment 54, wherein the inorganic acid is sulfuric acid.

Embodiment 55. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound having Formula I as described in any one of the preceding embodiments, wherein the solvent is selected from nitriles, esters, alcohols, amides, ketones, halogenated alkanes, ethers, aromatic hydrocarbons, water; and combinations thereof.

Embodiment 55a. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the solvent is selected from dichloro Methane, dichloroethane, dibromomethane, dibromoethane, ethyl acetate, acetonitrile, ethanol, methanol, N , N -dimethylformamide, ethyl lactate, water, propionitrile, methyl acetate, acetic acid Butyl ester, acetone, methyl ethyl ketone (MEK), methyl butyl ketone, chloroform; diethyl ether, methyl tertiary butyl ether, benzene, p-dichlorobenzene, toluene, chlorobenzene, dichlorobenzene and its combination.

Embodiment 55b. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the solvent is selected from dichloro Methane, dichloroethane, dibromomethane, dibromoethane, ethyl acetate, acetonitrile, ethanol, methanol, N , N -dimethylformamide, ethyl lactate, water, and combinations thereof.

Embodiment 55c. The method according to embodiment 55, wherein the solvent is selected from dichloromethane, dichloroethane, dibromomethane, dibromoethane, ethyl acetate, acetonitrile, ethyl lactate, water, and combinations thereof.

Embodiment 55d. The method of embodiment 55, wherein the solvent is dichloromethane, dichloroethane, ethyl acetate or ethyl lactate.

Embodiment 55e. The method according to Embodiment 55, wherein the solvent is dichloromethane, dichloroethane or ethyl acetate.

Embodiment 55f. The method of embodiment 55, wherein the solvent is ethyl acetate or ethyl lactate.

Embodiment 55g. The method of embodiment 55, wherein the solvent is ethyl acetate.

Embodiment 55h. The method as described in Embodiment 55, wherein the solvent is dichloromethane.

Embodiment 55i. The method as described in Embodiment 55, wherein the solvent is ethylene dichloride.

Embodiment 56. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the organic acid is selected from carboxylic acid Acids and their combinations.

Embodiment 56a. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the organic acid is selected from formic acid , acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, lactic acid, butyric acid, fumaric acid, malic acid, maleic acid, succinic acid, tartaric acid, sorbic acid, citric acid, benzoic acid and combinations thereof.

Embodiment 56b. The method as described in Embodiment 56a, wherein the organic acid is formic acid, acetic acid or trifluoroacetic acid.

Embodiment 56c. The method as described in Embodiment 56a, wherein the organic acid is formic acid or acetic acid.

Embodiment 56d. The method of embodiment 56a, wherein the organic acid is acetic acid.

Embodiment M1. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the reaction is performed at a temperature higher than Performed at a temperature of -10°C.

Embodiment M1a. The method of embodiment M1, wherein the reaction is carried out at a temperature higher than 0°C.

Embodiment M2. The method as described in Embodiment M1, wherein the reaction is carried out at a temperature of about 0°C to about 100°C.

Embodiment M2a. The method of embodiment M1, wherein the reaction is performed at a temperature of about 0°C to about 60°C.

Embodiment M3. The method of embodiment M1, wherein the reaction is performed at a temperature of about 10°C to about 50°C.

Embodiment M3a. The method of embodiment M1, wherein the reaction is performed at a temperature of about 10°C to about 40°C.

Embodiment M4. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the halide salt and the compound having The compounds of formula II have a molar ratio of at least 0.1 : 1.0.

Embodiment M4a. The method as described in Embodiment M4, wherein the molar ratio of the halide to the compound of Formula II is about 0.2:1 to about 20:1.

Embodiment M4b. The method of embodiment M4, wherein the molar ratio of the halide salt to the compound of formula II is from about 0.5:1 to about 10:1.

Embodiment M4c. The method of embodiment M4, wherein the molar ratio of the halide salt to the compound of formula II is from about 1:1 to about 6:1.

Embodiment M4d. The method as described in Embodiment M4, wherein the molar ratio of the halide to the compound of Formula II is about 1:1 to about 5:1.

Embodiment M4e. The method of embodiment M4, wherein the molar ratio of the halide salt to the compound of formula II is from about 1:1 to about 4:1.

Embodiment M4f. The method as described in Embodiment M4, wherein the molar ratio of the halide to the compound of Formula II is about 4:1.

Embodiment M5. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the inorganic acid and the compound having The compounds of formula II have a molar ratio of at least 0.1 : 1.0.

Embodiment M5a. The method as described in Embodiment M5, wherein the molar ratio of the inorganic acid to the compound having Formula II is from about 0.1:1.0 to about 20.0:1.0.

Embodiment M5b. The method of embodiment M5, wherein the molar ratio of the inorganic acid to the compound of formula II is about 0.5:1 to about 12:1.

Embodiment M5c. The method of embodiment M5, wherein the molar ratio of the inorganic acid to the compound of formula II is about 0.5:1 to about 6:1.

Embodiment M5d. The method of embodiment M5, wherein the molar ratio of the inorganic acid to the compound of formula II is from about 1:1 to about 6:1.

Embodiment M5e. The method of embodiment M5, wherein the molar ratio of the inorganic acid to the compound of formula II is from about 2:1 to about 4:1.

Embodiment M5f. The method of embodiment M5, wherein the molar ratio of the inorganic acid to the compound of formula II is about 3:1.

Embodiment M6. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the inorganic acid and the halogen The molar ratio of salt to the compound of formula II is about 3:4:1.

Embodiment M7. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any of the preceding embodiments, wherein the compound of formula II The weight to volume ratio with the solvent is about 1:0.05 to about 1:500.

Embodiment M7a. The method as described in Embodiment M7, wherein the weight to volume ratio of the compound having Formula II to the solvent is about 1:0.5 to about 1:50.

Embodiment M7b. The method of embodiment M7, wherein the weight and volume ratio of the compound of formula II to the solvent is from about 1:0.75 to about 1:25.

Embodiment M7c. The method of embodiment M7, wherein the weight and volume ratio of the compound of formula II to the solvent is from about 1:1 to about 1:15.

Embodiment M7d. The method of embodiment M7, wherein the weight and volume ratio of the compound of formula II to the solvent is from about 1:1 to about 1:10.

Embodiment M7e. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any of the preceding embodiments, wherein the compound of formula II The weight to volume ratio with the solvent is approximately 1:5.

Embodiment P1. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any of the preceding embodiments, wherein the average particle size of the halide salt is less than 1000 μm.

Embodiment P2. The method of embodiment P1, wherein the halide salt has an average particle size of about 0.1 µm to about 1000 µm.

Embodiment P3. The method of embodiment P1, wherein the halide salt has an average particle size of about 1.0 µm to about 1000 µm.

Embodiment P4. The method as described in embodiment P1, wherein the average particle size of the halide salt is less than 500 μm.

Embodiment P5. The method according to embodiment P1, wherein the average particle size of the halide salt is about 0.1 µm to about 500 µm.

Embodiment P6. The method as described in Embodiment P1, wherein the average particle size of the halide is about 1.0 μm to about 500 μm.

Embodiment P7. The method of embodiment P1, wherein the halide salt has an average particle size of about 5.0 µm to about 500 µm.

Embodiment P8. The method as described in Embodiment P1, wherein the average particle size of the halide is about 10.0 μm to about 500 μm.

Embodiment P9. The method according to embodiment P1, wherein the average particle size of the halide salt is less than 389 μm.

Embodiment P10. The method of embodiment P1, wherein the halide salt has an average particle size of about 0.1 µm to about 389 µm.

Embodiment P11. The method as described in Embodiment P1, wherein the average particle size of the halide is about 1.0 μm to about 389 μm.

Embodiment P12. The method as described in Embodiment P1, wherein the average particle size of the halide is about 5.0 μm to about 389 μm.

Embodiment P13. The method as described in Embodiment P1, wherein the average particle size of the halide is about 10.0 μm to about 389 μm.

Implementation method P14. The method as described in Implementation method P1, wherein the average particle size of the halide is less than 300 µm.

Embodiment P15. The method of embodiment P1, wherein the halide salt has an average particle size of about 0.1 µm to about 300 µm.

Embodiment P16. The method of embodiment P1, wherein the halide salt has an average particle size of about 1.0 µm to about 300 µm.

Embodiment P17. The method of embodiment P1, wherein the halide salt has an average particle size of about 5.0 µm to about 300 µm.

Embodiment P18. The method of embodiment P1, wherein the halide salt has an average particle size of about 10.0 µm to about 300 µm.

Implementation method P19. The method as described in Implementation method P1, wherein the average particle size of the halide is less than 250 μm.

Embodiment P20. The method of embodiment P1, wherein the halide salt has an average particle size of about 0.1 µm to about 250 µm.

Embodiment P21. The method of embodiment P1, wherein the halide salt has an average particle size of about 1.0 µm to about 250 µm.

Embodiment P22. The method of embodiment P1, wherein the halide salt has an average particle size of about 5.0 µm to about 250 µm.

Embodiment P23. The method as described in Embodiment P1, wherein the average particle size of the halide is about 10.0 μm to about 250 μm.

Embodiment P24. The method of embodiment P1, wherein the halide salt has an average particle size of about 20.0 µm to about 250 µm.

Implementation method P25. The method as described in Implementation method P1, wherein the average particle size of the halide is less than 200 µm.

Embodiment P26. The method of embodiment P1, wherein the halide salt has an average particle size of about 0.1 µm to about 200 µm.

Embodiment P27. The method of embodiment P1, wherein the halide salt has an average particle size of about 1.0 µm to about 200 µm.

Embodiment P28. The method as described in Embodiment P1, wherein the average particle size of the halide is about 5.0 μm to about 200 μm.

Embodiment P29. The method of embodiment P1, wherein the halide salt has an average particle size of about 10.0 µm to about 200 µm.

Embodiment P30. The method according to embodiment P1, wherein the average particle size of the halide salt is about 20.0 µm to about 200 µm.

Implementation method P31. The method as described in Implementation method P1, wherein the average particle size of the halide is less than 150 µm.

Embodiment P32. The method of embodiment P1, wherein the halide salt has an average particle size of about 0.1 µm to about 150 µm.

Embodiment P33. The method as described in Embodiment P1, wherein the average particle size of the halide is about 1.0 μm to about 150 μm.

Embodiment P34. The method of embodiment P1, wherein the halide salt has an average particle size of about 5.0 µm to about 150 µm.

Embodiment P35. The method of embodiment P1, wherein the halide salt has an average particle size of about 10.0 µm to about 150 µm.

Embodiment P36. The method of embodiment P1, wherein the halide salt has an average particle size of about 20.0 µm to about 150 µm.

Embodiment P37. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any of the preceding embodiments, wherein the average particle size of the halide salt is less than 100 μm.

Embodiment P38. The method of embodiment P1, wherein the halide salt has an average particle size of about 0.1 µm to about 100 µm.

Embodiment P39. The method of embodiment P1, wherein the halide salt has an average particle size of about 1.0 µm to about 100 µm.

Embodiment P40. The method of embodiment P1, wherein the halide salt has an average particle size of about 5.0 µm to about 100 µm.

Embodiment P41. The method of embodiment P1, wherein the halide salt has an average particle size of about 10.0 µm to about 100 µm.

Implementation method P42. The method as described in implementation method P1, wherein the average particle size of the halide is about 20.0 μm to about 100 μm.

Embodiment P43. The method as described in Embodiment P1, wherein the average particle size of the halide is about 30.0 μm to about 100 μm.

Embodiment P44. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the halide salt has an average particle size Less than 80 µm.

Embodiment P45. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the halide salt has an average particle size is about 30.0 µm to about 80 µm.

Embodiment P46. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the halide salt has an average particle size Less than 75 µm.

Embodiment P47. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of Formula I as described in any one of the preceding embodiments, wherein the halide salt has an average particle size is about 35.0 µm to about 75 µm.

Embodiment S1. A method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of the preceding embodiments, wherein the inorganic acid is added last.

Embodiment S2. The method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of Embodiments 1 to P47, wherein the inorganic acid is first reacted with the halide salt.

Embodiment S3. The method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of formula I as described in any one of embodiments 1 to P47, wherein the inorganic acid is first React with a mixture consisting of the halide salt and the organic acid.

Embodiment X1. A method for preparing a compound of formula IV as described in the Summary of the Invention, wherein ^R6A is F, Cl, Br, I, cyano, _CH3 or _CF3 .

Embodiment X2. The method as described in Embodiment X1, wherein R ^6A is F, Cl, Br or CH ₃ .

Embodiment X3. The method of embodiment X1, wherein R ^6A is Cl or CH ₃ .

Embodiment X4. The method as described in Embodiment X1, wherein R ^6A is CH ₃ .

Embodiment X5. The method of any one of embodiments X1 to X4, wherein R ^6B is hydrogen, F, Cl or Br.

Embodiment X6. The method as described in Embodiment X5, wherein R ^6B is hydrogen, Cl or Br.

Embodiment X7. The method as described in Embodiment X5, wherein R ^6B is hydrogen or Cl.

Embodiment X8. The method according to Embodiment X5, wherein R ^6B is hydrogen.

Embodiment X9. The method of any one of embodiments X1 to X8, wherein R ^6C is F, Cl, Br, I, cyano, CH ₃ or CF ₃ .

Embodiment X10. The method as described in Embodiment X9, wherein R ^6C is F, Cl, Br, I or cyano.

Embodiment X11. The method of embodiment X9, wherein R ^6C is Cl, Br, I or cyano.

Embodiment X12. The method as described in Embodiment X9, wherein R ^6C is Cl or cyano.

Embodiment X13. The method of embodiment X9, wherein R ^6C is Cl.

Embodiment X14. The method as described in Embodiment X9, wherein R ^6C is cyano.

Embodiment X15. The method according to any one of Embodiments X1 to X14, wherein R ^6D is hydrogen, F, Cl or Br.

Embodiment X16. The method according to Embodiment X15, wherein R ^6D is hydrogen, Cl or Br.

Embodiment X17. The method according to Embodiment X15, wherein R ^6D is hydrogen or Cl.

Embodiment X18. The method according to embodiment X15, wherein R ^6D is hydrogen.

Embodiment X19. The method according to any one of embodiments X1 to X18, wherein R ⁷ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₈ cycloalkylalkyl Or C ₅ -C ₈ alkylcycloalkyl.

Embodiment X20. The method as described in Embodiment X19, wherein R ⁷ is methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl or (1-methyl)cyclopropyl.

Embodiment X21. The method of embodiment X19, wherein R ⁷ is methyl or ethyl.

Embodiment X22. The method as described in Embodiment X19, wherein R ⁷ is methyl.

The embodiments of the present disclosure (including the above embodiments 1-X22 and any other embodiments described herein) can be combined in any way, and the description of the variables in the embodiments is not only about compounds with formula I , III and IV , but also about starting compounds and intermediate compounds that can be used to prepare compounds with formula I , III and IV . In addition, the embodiments of the present disclosure (including the above embodiments 1-X22 and any other embodiments described herein) and any combination thereof are about the methods of the present disclosure.

The combination of implementation mode 1-X22 is shown below:

Embodiment A. A method for preparing a 3-halo-4,5-dihydro- 1H -pyrazole compound of Formula I as described in the Summary of the Invention, wherein m is 2; and n is 1 .

Embodiment A1. The method of embodiment A, wherein X ¹ is Cl or Br; and X ² is OS(O) _m R ⁴ , or a halogen other than X ¹ .

Embodiment A1A. The method as described in Embodiment A or Embodiment A1, wherein R ¹ is C(O)R ³ , cyano, methyl or hydroxymethyl; X ¹ is Cl or Br; X ² is OS (O) _m R ⁴ , or a ^halogen other than , ammonium chloride, quaternary ammonium chloride and combinations thereof.

Embodiment A1B. The method as described in Embodiment A or Embodiment A1, wherein R ¹ is C(O)R ³ , cyano, methyl or hydroxymethyl; X ¹ is Cl or Br; X ² is OS(O) _m R ⁴ , or a halogen other than X ¹ ; k is 0 or 1; and the halogen salt is selected from alkali metal bromides, alkali earth metal bromides, ammonium bromide, quaternary ammonium bromides, alkali metal chlorides, alkali earth metal chlorides, ammonium chloride, quaternary ammonium chlorides and combinations thereof.

Embodiment A1C. The method as described in Embodiment A or Embodiment A1, wherein R ¹ is C(O)R ³ , cyano, methyl or hydroxymethyl; X ¹ is Cl or Br; X ² is OS (O) _m R ^{4 ,} or ^halogen other than phenyl; and the halide salt is selected from alkali metal bromide, alkaline earth metal bromide, ammonium bromide, quaternary ammonium bromide, alkali metal chloride, alkaline earth metal chloride, ammonium chloride, quaternary ammonium chloride and combinations thereof .

Embodiment A2. The method according to any one of embodiments A to A1C, wherein R ¹ is C(O)R ³ ; R ² is halogen; Z is N; R ³ is OH or C ₁ -C ₄ alkoxy; k is 0; and R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl.

Embodiment A3. The method of any one of embodiments A to A2, wherein R ² is Cl or Br; and R ³ is OH, OCH ₃ or OCH ₂ CH ₃ .

Embodiment A3A. The method of any one of embodiments A to A3, wherein R ² is Cl; and R ³ is OH, OCH ₃ or OCH ₂ CH ₃ .

Embodiment A4. The method of any one of embodiments A to A3, wherein R ² is Cl; X ¹ is Br; X ² is Cl or OS(O) _m R ⁴ ; and the halide salt is selected from Alkali metal bromides, alkaline earth metal bromides and combinations thereof.

Embodiment A4A. The method of any one of Embodiments A to A4, wherein R ² is Cl; X ¹ is Br; X ² is Cl or OS(O) _m R ⁴ ; and the halide is selected from alkali metal bromides and combinations thereof.

Embodiment A5. The method according to any one of embodiments A to A4, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OH, OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ , or Cl; m is 1; R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl; and The halide salt is selected from sodium bromide, potassium bromide and combinations thereof.

Embodiment A5A. The method according to Embodiment A5, wherein R ³ is OCH ₃ or OCH ₂ CH ₃ ; and X ² is OS(O) _m R ⁴ .

Embodiment A5B. The method as described in Embodiment A5 or Embodiment A5A, wherein R ⁴ is 4-methylphenyl.

Implementation A5C. The method as described in any one of Implementations A5 to A5B, wherein, the inorganic acid is perchloric acid, sulfuric acid, nitric acid, oxalic acid or sulfurous acid; and the optional organic acid is formic acid or acetic acid.

Embodiment A5D. The method of any one of embodiments A5 to A5C, wherein, The halide salt is sodium bromide or potassium bromide.

Embodiment A6. The method as described in any one of Embodiments A to A5, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ ; m is 1; R ⁴ is 4-methylphenyl; the halogen salt is sodium bromide or potassium bromide; the inorganic acid is sulfuric acid; and the optional organic acid is formic acid or acetic acid.

Embodiment A6A. The method as described in embodiment A6, wherein, The organic acid is acetic acid.

Implementation A7. A method as described in any one of Implementations A to A6A, wherein the solvent is dichloromethane, dichloroethane or ethyl acetate.

Embodiment A8. The method according to any one of embodiments A to A6A, wherein, The solvent is ethyl acetate.

Implementation A9. The method as described in any one of Implementation A to A6A, wherein the solvent is dichloromethane.

Embodiment A10. The method according to any one of embodiments A to A6A, wherein, The solvent is dichloroethane.

Embodiment B. A method for preparing a compound of formula III as described in the invention, wherein R ¹ is C(O)R ³ ; X ¹ is Cl or Br; R ² is a halogen; Z is N; R ³ is OH or C ₁ -C ₄ alkoxy; k is 0; X ² is OS(O) _m R ⁴ , or a halogen other than X ¹ ; m is 2; R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl; and the halogen salt is selected from alkali metal bromides, alkali earth metal bromides, ammonium bromide, quaternary ammonium bromides, alkali metal chlorides, alkali earth metal chlorides, ammonium chlorides, quaternary ammonium chlorides and combinations thereof.

Implementation B1. The method as described in Implementation B, wherein ^X1 is _Br ; ^R2 is Cl; ^R3 is OH, _OCH3 or _OCH2CH3 ; ^X2 is Cl or OS(O) _mR4 ; and the halide is selected from alkali metal bromides and combinations ^thereof .

Implementation method B2. The method as described in implementation method B or implementation method B1, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OH, OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ , or Cl; m is 1; R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl; and the halide is selected from sodium bromide, potassium bromide and a combination thereof.

Embodiment B2A. The method of embodiment B2, wherein R ³ is OCH ₃ or OCH ₂ CH ₃ ; and X ² is OS(O) _m R ⁴ .

Embodiment B2B. The method as described in Embodiment B2 or Embodiment B2A, wherein R ⁴ is 4-methylphenyl.

Embodiment B2C. The method as described in any one of Embodiments B2 to B2B, wherein, the inorganic acid is perchloric acid, sulfuric acid, nitric acid, oxalic acid or sulfurous acid; and the optional organic acid is formic acid or acetic acid.

Embodiment B2D. The method according to any one of embodiments B2 to B2C, wherein, The halide salt is sodium bromide or potassium bromide.

Embodiment B3. The method as described in any one of Embodiments B to B2, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ ; m is 1; R ⁴ is 4-methylphenyl; the halide is sodium bromide or potassium bromide; the inorganic acid is sulfuric acid; and the optional organic acid is formic acid or acetic acid.

Implementation method B3A. The method as described in Implementation method B3, wherein, the organic acid is acetic acid.

Embodiment C. A method for preparing a compound of formula IV as described in the Summary of the Invention, wherein R ^6A is F, Cl, Br or CH ₃ ; R ^6B is hydrogen, F, Cl or Br; R ^6C is F, Cl, Br, I, or cyano; and R ^6D is hydrogen, F, Cl, or Br.

Embodiment C1. The method as described in Embodiment C, wherein R ¹ is C(O)R ³ ; X ¹ is Cl or Br; R ² is a halogen; Z is N; R ³ is OH or C ₁ -C ₄ alkoxy; k is 0; X ² is OS(O) _m R ⁴ , or a halogen other than X ¹ ; m is 2; R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl; the halogen salt is selected from alkali metal bromides, alkali earth metal bromides, ammonium bromide, quaternary ammonium bromides, alkali metal chlorides, alkali earth metal chlorides, ammonium chlorides, quaternary ammonium chlorides and combinations thereof; and R ⁷ is methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl or (1-methyl)cyclopropyl.

Embodiment C2. The method according to any one of embodiments C to CA1, wherein X ¹ is Br; R ² is Cl; R ³ is OH, OCH ₃ or OCH ₂ CH ₃ ; X ² is Cl or OS (O) _m R ⁴ ; and the halide salt is selected from alkali metal bromides and combinations thereof.

Embodiment C2A. The method according to Embodiment C1 or C2, wherein R ^6B is hydrogen or Cl; and R ^6D is hydrogen or Cl.

Embodiment C3. The method according to any one of embodiments C to C2, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OH, OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ , or Cl; m is 1; R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl; and The halide salt is selected from sodium bromide, potassium bromide and combinations thereof.

Embodiment C3A. The method according to embodiment C3, wherein R ³ is OCH ₃ or OCH ₂ CH ₃ ; and X ² is OS(O) _m R ⁴ .

Embodiment C3B. The method as described in Embodiment C3 or Embodiment C3A, wherein R ⁴ is 4-methylphenyl.

Implementation C3C. The method as described in any one of Implementations C3 to C3B, wherein, the inorganic acid is perchloric acid, sulfuric acid, nitric acid, oxalic acid or sulfurous acid; and the optional organic acid is formic acid or acetic acid.

Embodiment C3D. The method of any one of embodiments C3 to C3C, wherein, The halide salt is sodium bromide or potassium bromide.

Embodiment C3E. The method of any one of embodiments C3 to C3D, wherein R ^6A is Cl or CH ₃ ; R ^6B is hydrogen or Cl; R ^6C is Cl, Br, I or cyano; and R ^6D is hydrogen or Cl.

Embodiment C4. The method according to any one of embodiments C to C3, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OCH _{3 Or} OCH ₂ CH ₃ ^; k is ^{0 ;} is sulfuric acid; and the optional organic acid is formic acid or acetic acid.

Embodiment C4A. The method of Embodiment C4, wherein R ^6A is CH ₃ ; R ^6B is hydrogen; R ^6C is Cl or cyano; and R ^6D is hydrogen.

Embodiment C4B. The method as described in embodiment C4 or embodiment C4A, wherein, The organic acid is acetic acid.

Compounds of formula I can be prepared by one or more of the following methods and variants as described in Scheme 1. Unless otherwise stated, the substituents in compounds of formula I - IV are defined as above in the context of the invention. Compounds of formula Ia are a subset of compounds of formula I. Compounds of formula IIa are a subset of compounds of formula II . Unless otherwise stated, the substituents of each subset formula are defined as the parent formula. Ambient temperature or room temperature is defined as about 20°C-25°C.

As shown in Scheme 1, according to the method of the present disclosure, 4,5-dihydro- 1H -pyrazoles of Formula II are contacted with halide salts and inorganic acids to form different 3-halo-1H-pyrazoles of Formula I. 4,5-dihydro- 1H -pyrazole compound, wherein the halogen of the halide salt is X ¹ . ^Unless otherwise specified ^{, X 1 ,} plan 1

The reaction is typically carried out in a suitable solvent, however, in some cases, except for the compound of formula II , the halide, the inorganic acid and, if necessary, the organic acid, the reaction can be carried out in the absence of a solvent. In order to obtain the best results, the solvent should be non-nucleophilic, relatively inert to the reagents, and capable of dissolving the compound of formula II . A variety of solvents can be used to form a suitable solvent for the method. In a suitable solvent, the compound of formula II is preferably completely or at least substantially (e.g., at least about 10%) soluble in the volume of the solvent used. Examples of suitable solvents for use in the process include nitriles such as acetonitrile and propionitrile; esters such as methyl acetate, ethyl acetate, ethyl lactate and butyl acetate; alcohols such as ethanol and methanol; amides such as N , N -dimethylformamide; halides such as dichloromethane, dichloroethane, dibromomethane, dibromoethane and trichloromethane; ethers such as tetrahydrofuran (THF); water; and mixtures of the foregoing. Solvents of note include dichloromethane, dichloroethane, dibromomethane, dibromoethane and ethyl acetate. The total volume of solvent used in the process of Scheme 1 is preferably between about 1 mL/g and about 10 mL/g relative to the weight of the compound of Formula II .

The solvent may be added in various ways and times during the reaction process, such as in one batch at the beginning of the reaction sequence, in batches during the reaction sequence, or intermittently during the addition of one or more reagents. For example, one or more reagents can be dispersed, dissolved or partially dissolved in a suitable solvent and then added to a reaction mixture containing the one or more reagents and a suitable solvent. Regardless of the order of addition, the total amount of reagents added during the course of the reaction is as described herein and in the Examples.

In one embodiment, the order of addition includes first forming a slurry of the halide and optionally an organic acid, then adding the inorganic acid to the slurry, and then adding the compound of Formula II in a suitable solvent to the mixture comprising the halide, the inorganic acid, and optionally an organic acid. This order of addition is shown in Examples 1-5.

In another embodiment, the sequence of addition involves first forming a mixture of the compound of formula II in a suitable solvent, optionally adding the organic acid, then the halide salt, and subsequently the inorganic acid. This order of addition is shown in Example 6-18.

The reaction is typically between about 10°C and 50°C, most conveniently between about 10°C and 40°C, and most preferably at near ambient temperature (e.g., about 20°C-25 °C). Reaction times are typically less than 72 h.

In the method of Option 1, the halide salt is typically an alkali metal halide or an alkaline earth metal halide, preferably an alkali metal halide, more preferably a potassium halide or a sodium halide, and most preferably Potassium bromide or sodium bromide. When the halide anion provided by the halide salt becomes ^X1 of formula I , the stoichiometry of the reaction requires at least one molar equivalent of the halide anion relative to the sum of the moles of the compounds of formula II . Typically, the molar ratio of the halide salt relative to the compound of Formula II is from about 1:1 to about 6:1. Although higher levels of brine salts can be used, there is no particular advantage to doing so and higher levels increase feedstock and waste disposal costs. The highest product yields are typically achieved with a molar ratio of sodium bromide to compound of formula II of about 4:1.

Those skilled in the art will understand that increasing solid reagent surface area can exhibit beneficial effects (eg, increased reactivity, increased yield, decreased reaction time, and decreased reagent molar ratio). In one embodiment, the halide salt particle size can be reduced to increase the yield of compounds of Formula I. Typically, higher product yields are achieved with average halide salt particle sizes (i.e., Dv(50) values) of less than 100 µm.

Typically, the molar ratio of the mineral acid to the compound of Formula II is about 0.5: 1 to about 12: 1. Although other levels of the mineral acid may be used, there is no particular advantage in doing so. The highest product yields are generally achieved with a molar ratio of sulfuric acid to the compound of Formula II of about 3: 1.

The addition of an optional organic acid to the process can also affect the optimal ratio of the process of the present invention. For example, the most favorable reaction rate that provides the highest yield of the compound of Formula I is typically obtained at a lower ratio of the halide and the inorganic acid relative to the compound of Formula II when acetic acid is added compared to when acetic acid is not added (i.e., in the presence of acetic acid, the ratio of both the halide and the inorganic acid relative to the compound of Formula II is preferably about 2:1).

The product of Formula I can be isolated by standard techniques known in the art, including pH adjustment, extraction, evaporation, crystallization, and chromatography. For example, the reaction medium can be diluted with about 10 to 75 parts by weight of water relative to the starting compound of formula II , the pH can be adjusted with acid or base as necessary to optimize the removal of acid or base impurities, the aqueous phase can be separated as needed, And most of the solvent can be removed by distillation or evaporation under reduced pressure. Typically, acid impurities in the reactions of the present disclosure are removed by using saturated aqueous sodium bicarbonate solution or 10% aqueous sodium hydroxide solution.

Although the solvent can be removed from compounds of Formula I by such methods as evaporation or distillation of the solvent under reduced pressure, concentrating and purifying the compounds of Formula I is typically not necessary. The solvents used for the preparation of compounds of formula I are generally compatible with the method of the invention for the preparation of compounds of formula III , and the method of the invention therefore works well starting from a composition of a compound of formula I , in which the concentration of the compound of formula I Less than 100%. Thus, compositions of compounds of formula I which can be used in the process of the present invention for the preparation of compounds of formula III typically further comprise a solvent, in particular a solvent used for the preparation of compounds of formula I. Typical solvents include dichloromethane, dichloroethane or ethyl acetate. Typically, the composition contains from about 20% to 99% by weight of a compound of formula I.

4,5-dihydro- 1H -pyrazoles of formula II can be prepared by a variety of methods known in the art, see, for example, WO 2004/011453 A2, and the references cited therein.

Depending on the reaction conditions and the mode of separation, the ester functional group on the compound having Formula Ia (wherein ^R3 is _C1 - _C4 alkoxy) can be hydrolyzed to a carboxylic acid, where ^R3 is OH. For example, the presence of water in the reaction mixture can promote this hydrolysis. If a carboxylic acid is formed, it can be converted back to an ester (i.e., -C(=O) ^R3 , where ^R3 is _C1 - _C4 alkoxy) using esterification methods well known in the art. The desired product (compound having Formula Ia ) can be isolated by methods known to those skilled in the art, such as crystallization, extraction or distillation.

It will be appreciated that some of the reagents and reaction conditions described above for preparing compounds of formula I , III and IV may not be compatible with certain functional groups present in the intermediates. In such cases, incorporating protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired product. The use and selection of protecting groups will be readily apparent to those skilled in the art of chemical synthesis (see, e.g., Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis , 2nd ed.; Wiley: New York, 1991). Those skilled in the art will recognize that, in some cases, additional conventional synthetic steps not described in detail may be required to complete the synthesis of compounds of formula I , III and IV after the reagents described in the various schemes are introduced.

Those skilled in the art will also recognize that the compounds of formulas I , II , III and IV described herein can undergo various electrophilic, nucleophilic, free radical, organometallic, oxidation and reduction reactions to add Substituents or modification of existing substituents. For example, compounds of formula I may contain a cyano group, which may be converted to a carboxylic acid via hydrolysis conditions. Likewise, alcohols, aldehydes and alkyl groups can be oxidized to provide carboxylic acid compounds of formula Ia , wherein ^R3 is OH. Reactions of this type are well documented in the literature; see, for example, March and Smith, March's Advanced Organic Chemistry , 5th ed., John Wiley & Sons, Inc., New York, 2001, and references cited therein.

Without further elaboration, it is believed that one skilled in the art can utilize the present disclosure to its maximum extent using the foregoing description. Therefore, the following examples should be interpreted as being illustrative only and not limiting the present disclosure in any way. The steps in the following examples illustrate the procedures for each step in the overall synthetic transformation, and the starting materials used for each step are not necessarily prepared by specific preparative experiments whose procedures are described in other examples or steps. Ambient temperature or room temperature is defined as about 20°C-25°C. Unless otherwise indicated, percentages are by weight. All patents and publications cited herein are fully incorporated by reference in their entirety. ¹ H NMR spectra are reported in ppm downfield from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, and "dd" means two doublets.

As can be observed in Examples 9 to 18, as the particle size of the halogen salt in the comparative examples decreases, the yield of the compound of Formula I increases. The particle size distribution data of Dv50, Dv10 and Dv90 were determined using a Malvern Mastersizer MS3000. The Dv50 particle size distribution data of the halogen salt samples used in Examples 9 to 18 are shown in Table A, using a Retsch MM400 mixer mill to grind the samples. The abbreviation "rpm." stands for revolutions per minute. The Dv50 value indicates the particle size at which 50% of the sample contains particles of this size or smaller. The Dv10 value indicates the particle size at which 10% of the sample contains particles of this size or smaller. The Dv90 value indicates the particle size at which 90% of the sample contains particles of this size or smaller. [Table A] Halogen Sample Description Dv (50) NaBr (unmilled) 389 µm 20 g NaBr (10 g in each support) was milled at 1200 rpm for 1.5 h, followed by milling at 1800 rpm for 2 h. 73 µm 20 g NaBr (10 g in each support) was milled at 1200 rpm for 1.5 h, followed by milling at 1800 rpm for 4 h. 40 µm Example 1 Preparation of ethyl 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro- 1H -pyrazole-5-carboxylate using a compound of formula II, a halide, an inorganic acid and an organic acid in a ratio of 1:2:2:73

To a slurry of sodium bromide (1.51 g, 14.64 mmol) in acetic acid (30.5 mL) was added sulfuric acid (1.43 g, 14.64 mmol) over a period of 15 min. The reaction mixture was stirred at ambient temperature for 30 min. Ethyl 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylate (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in dichloromethane (25 mL) was added to the reaction mixture and stirred at ambient for 24 h. Sodium hydroxide (10% aqueous solution, 222.53 g, 556.32 mmol) was added to the resulting mixture at 15°C. The organic layer was separated and concentrated under vacuum to give the title compound as a brown oil (2.21 g, 91% yield).

¹ H NMR (CDCl ₃ , 400 MHz,) δ 8.07 (dd, J = 4.8, 1.5 Hz, 1H), 7.65 (dd, J = 7.9, 1.5 Hz, 1H), 6.86 (dd, J = 7.9, 4.8 Hz , 1H), 5.25 (dd, J = 11.9, 9.1 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.43 (dd, J = 17.4, 11.9 Hz, 1H), 3.23 (dd, J = 17.4, 9.1 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H). Example 2 Preparation of ethyl 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro- 1H -pyrazole-5 _- carboxylate in _ClCH2CH2Cl

To a slurry of sodium bromide (1.51 g, 14.64 mmol) in acetic acid (30.5 mL) was added sulfuric acid (1.43 g, 14.64 mmol) over a period of 15 min. The reaction mixture was stirred at ambient temperature for 30 min. Add 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyridinyl in dichloroethane (25 mL). Azole-5-carboxylic acid ethyl ester (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) was added to the reaction mixture and stirred at ambient for 24 h. To the resulting mixture was added sodium hydroxide (10% aqueous solution, 222.53 g, 556.32 mmol) at 15°C. The organic layer was separated and concentrated in vacuo to give the title compound as a brown oil (2.20 g, 90% yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 3 Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-4,5-di using a compound of formula II, a halide salt, an inorganic acid and an organic acid in a ratio of 1:2:2:6 Hydrogen- 1H -pyrazole-5-carboxylic acid ethyl ester

To a slurry of sodium bromide (0.15 g, 1.46 mmol) in acetic acid (0.25 mL) was added sulfuric acid (0.14 g, 1.46 mmol) dropwise and stirred at ambient temperature for 30 min. 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylic acid ethyl ester (PCT Patent Publication WO 2004/011453) (0.3 g, 0.73 mmol) in dichloromethane (3 mL) was added to the reaction mixture and stirred at ambient for 3 h. Sodium hydroxide (10% aqueous solution, 2.93 g, 7.32 mmol) was added to the resulting mixture at 15°C. The organic layer was separated and concentrated under vacuum to give the title compound as a brown oil (0.08 g, 33% yield). The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1. Example 4 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester using a compound of Formula II, a halide, an inorganic acid, and an organic acid in a ratio of 1:2:2:17

To a slurry of sodium bromide (0.15 g, 1.46 mmol) in acetic acid (0.71 mL) was added dropwise sulfuric acid (0.14 g, 1.46 mmol) and stirred at ambient temperature for 30 min. Dissolve 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyrazole in dichloromethane (3 mL) -Ethyl 5-formate (PCT Patent Publication WO 2004/011453) (0.3 g, 0.73 mmol) was added to the reaction mixture and stirred at ambient for 3 h. To the resulting mixture was added sodium hydroxide (10% aqueous solution, 5.85 g, 14.64 mmol) at 15°C. The organic layer was separated and concentrated in vacuo to afford the title compound as a brown oil (0.19 g, 78% yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 5 Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-4,5-di using a compound of formula II, a halide salt, an inorganic acid and an organic acid in a ratio of 1:2:2:36 Hydrogen- 1H -pyrazole-5-carboxylic acid ethyl ester

To a slurry of sodium bromide (0.15 g, 1.46 mmol) in acetic acid (1.5 mL) was added dropwise sulfuric acid (0.14 g, 1.46 mmol) and stirred at ambient temperature for 30 min. Dissolve 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyrazole in dichloromethane (3 mL) -Ethyl 5-formate (PCT Patent Publication WO 2004/011453) (0.3 g, 0.73 mmol) was added to the reaction mixture and stirred at ambient for 3 h. To the resulting mixture was added sodium hydroxide (10% aqueous solution, 10.83 g, 27.08 mmol) at 15°C. The organic layer was separated and concentrated in vacuo to afford the title compound as a brown oil (0.19 g, 78% yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 6 Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro- 1H- using a compound of formula II, a halide salt and an inorganic acid in a ratio of 1:4:3.1 Ethyl pyrazole-5-carboxylate

To a solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylate (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in ethyl acetate (15 mL) was added sodium bromide (3.01 g, 29.28 mmol) followed by sulfuric acid (2.20 g, 22.40 mmol) over a period of 5 min. The mixture was stirred at 20 °C for 30 min. Saturated aqueous sodium bicarbonate (170 mL) was added to the resulting mixture. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound as a brown oil (2.27 g, 90% yield). The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1. Example 7 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester using a compound of formula II, a halide and an inorganic acid in a ratio of 1:3:3.1

To a solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylate (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in ethyl acetate (15 mL) was added sodium bromide (2.26 g, 21.96 mmol) followed by sulfuric acid (2.20 g, 22.40 mmol) in one portion. The mixture was stirred at 20°C for 15 h. To the resulting mixture was added saturated aqueous sodium bicarbonate (170 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (2.11 g, 87% yield) as a brown oil. The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1. Example 8 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester using a compound of Formula II, a halide, and an inorganic acid in a ratio of 1:2:12

To a solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylate (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in ethyl acetate (15 mL) was added sodium bromide (1.51 g, 14.64 mmol) followed by sulfuric acid (8.61 g, 87.84 mmol) in one portion. The mixture was stirred at 20°C for 24 h. To the resulting mixture was added saturated aqueous sodium bicarbonate (170 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to give the title compound (2.05 g, 84% yield) as a brown oil. The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1. Example 9 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester using a compound of formula II, a halide (Dv50 = 389 µm), an inorganic acid, and an organic acid in a ratio of 1:1.6:2:3.9

To 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyrazole-5-carboxylic acid at 20°C To a stirred solution of the ethyl ester (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in dichloromethane (7 mL) was added acetic acid (1.62 mL, 28.3 mmol), followed by sodium bromide (Dv50 = 389 µm) (1.21 g, 11.71 mmol). Cool the mixture to 0°C. Concentrated sulfuric acid (1.43 g, 14.64 mmol) was added to the mixture over a period of 5 min. The mixture was stirred at 0°C for 1 h, heated to 20°C, stirred at 20°C for 5 h, and then cooled to 0°C. To the resulting mixture was added sodium hydroxide (10% aqueous solution, 10 g, 25 mmol). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexane) to provide the title compound as a brown oil (0.47 g, 19% yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 10 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl) using a compound of formula II, a halide salt (Dv50 = 389 µm), an inorganic acid and an organic acid in a ratio of 1 : 4 : 3.1 : 0 -4,5-Dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester

To 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyrazole-5-carboxylic acid at 20°C To a stirred solution of ethyl ester (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in ethyl acetate (15 mL) was added sodium bromide (Dv50 = 389 µm) (3.01 g, 29.28 mmol) followed by Concentrated sulfuric acid (2.20 g, 22.40 mmol) was added over a period of 5 min. The mixture was stirred at 20°C for 6 h. To the resulting mixture, saturated aqueous sodium bicarbonate solution (50 mL) was slowly added over a period of 15 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexane) to provide the title compound as a pale yellow oil (0.63 g, 26 % yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 11 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl) using a compound of formula II, a halide salt (Dv50 = 73 µm), an inorganic acid and an organic acid in a ratio of 1 : 1.6 : 2 : 3.9 -4,5-Dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester

To 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyrazole-5-carboxylic acid at 20°C To a stirred solution of the ethyl ester (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in dichloromethane (7 mL) was added acetic acid (1.62 mL, 28.3 mmol), followed by sodium bromide (Dv50 = 73 µm) (1.21 g, 11.71 mmol). Concentrated sulfuric acid (1.43 g, 14.64 mmol) was added to the mixture over a period of 5 min. The mixture was stirred at 20°C for 6 h and then cooled to 0°C. To the resulting mixture was added sodium hydroxide (10% aqueous solution, 10 g, 25 mmol). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexane) to provide the title compound as a pale yellow oil (0.77 g, 32 % yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 12 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl) using a compound of formula II, a halide salt (Dv50 = 73 µm), an inorganic acid and an organic acid in a ratio of 1 : 4 : 3.1 : 0 -4,5-Dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester

To a stirred solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylate (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in ethyl acetate (15 mL) at 20°C was added sodium bromide (Dv50 = 73 µm) (3.01 g, 29.28 mmol) followed by concentrated sulfuric acid (2.20 g, 22.40 mmol) over a period of 5 min. The mixture was stirred at 20°C for 6 h. To the resulting mixture was slowly added saturated aqueous sodium bicarbonate (50 mL) over a period of 15 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexanes) to provide the title compound (1.74 g, 71% yield) as a light yellow oil. The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1. Example 13 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester using a compound of Formula II, a halogen salt (Dv50 = 73 µm), an inorganic acid, and an organic acid in a ratio of 1:1.6:2:3.9.

To 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyrazole-5-carboxylic acid at 20°C To a stirred solution of ethyl ester (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in dichloromethane (7 mL) was added acetic acid (1.62 mL, 28.3 mmol), followed by sodium bromide (Dv50 = 73 µm) (1.21 g, 11.71 mmol). Cool the mixture to 0°C. Concentrated sulfuric acid (1.43 g, 14.64 mmol) was added to the mixture over a period of 5 min. The mixture was stirred at 0°C for 1 h, heated to 20°C, and stirred at 20°C for 5 h. The mixture was cooled to 0 °C and stirred for 17 h. To the resulting mixture was added sodium hydroxide (10% aqueous solution, 10 g, 25 mmol). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexane) to provide the title compound as a pale yellow oil (0.81 g, 33 % yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 14 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl) using a compound of formula II, a halide salt (Dv50 = 73 µm), an inorganic acid and an organic acid in a ratio of 1 : 4 : 3.1 : 0 -4,5-Dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester

To 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyrazole-5-carboxylic acid at 20°C To a stirred solution of ethyl ester (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in ethyl acetate (15 mL) was added sodium bromide (Dv50 = 73 µm) (3.01 g, 29.28 mmol) followed by Concentrated sulfuric acid (2.20 g, 22.40 mmol) was added over a period of 5 min. The mixture was stirred at 20°C for 23 h. To the resulting mixture, saturated aqueous sodium bicarbonate solution (50 mL) was slowly added over a period of 15 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexane) to provide the title compound as a pale yellow oil (2.0 g, 82 % yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 15 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl) using a compound of formula II, a halide salt (Dv50 = 40 µm), an inorganic acid and an organic acid in a ratio of 1 : 1.6 : 2 : 3.9 -4,5-Dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester

To a stirred solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylate (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in dichloromethane (7 mL) at 20°C was added acetic acid (1.62 mL, 28.3 mmol) followed by sodium bromide (Dv50 = 40 µm) (1.21 g, 11.71 mmol). The mixture was cooled to 0°C. Concentrated sulfuric acid (1.43 g, 14.64 mmol) was added to the mixture over a period of 5 min. The mixture was stirred at 0°C for 1 h, heated to 20°C, and stirred at 20°C for 5 h. To the resulting mixture was added sodium hydroxide (10% aqueous solution, 10 g, 25 mmol). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexanes) to provide the title compound (0.85 g, 35% yield) as a light yellow oil. The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1. Example 16 Preparation of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylate using a compound of formula II, a halide (Dv50 = 40 µm), an inorganic acid and an organic acid in a ratio of 1:4:3.1:0

To 1-(3-chloro-2-pyridyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1 H -pyrazole-5-carboxylic acid at 20°C To a stirred solution of ethyl ester (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in ethyl acetate (15 mL) was added sodium bromide (Dv50 = 40 µm) (3.01 g, 29.28 mmol) followed by Concentrated sulfuric acid (2.20 g, 22.40 mmol) was added over a period of 5 min. The mixture was stirred at 20°C for 6 h. To the resulting mixture, saturated aqueous sodium bicarbonate solution (50 mL) was slowly added over a period of 15 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexane) to provide the title compound as a pale yellow oil (1.76 g, 72 % yield). The ¹ H NMR spectrum of this product was identical to that reported for the product of Example 1. Example 17 Preparation of 3-bromo-1-(3-chloro-2-pyridinyl) using a compound of formula II, a halide salt (Dv50 = 40 µm), an inorganic acid and an organic acid in a ratio of 1 : 1.6 : 2 : 3.9 -4,5-Dihydro- 1H -pyrazole-5-carboxylic acid ethyl ester

To a stirred solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylate (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in dichloromethane (7 mL) at 20°C was added acetic acid (1.62 mL, 28.3 mmol) followed by sodium bromide (Dv50 = 40 µm) (1.21 g, 11.71 mmol). The mixture was cooled to 0°C. Concentrated sulfuric acid (1.43 g, 14.64 mmol) was added to the mixture over a period of 5 min. The mixture was stirred at 0°C for 1 h, heated to 20°C, and stirred at 20°C for 5 h. The mixture was cooled to 0 °C and stirred for 17 h. Sodium hydroxide (10% aqueous solution, 10 g, 25 mmol) was added to the resulting mixture. The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexanes) to provide the title compound (0.99 g, 41% yield) as a light yellow oil. The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1. Example 18 Preparation of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro- 1H -pyrazole-5-carboxylate using a compound of formula II, a halide (Dv50 = 40 µm), an inorganic acid and an organic acid in a ratio of 1:4:3.1:0

To a stirred solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy] -1H -pyrazole-5-carboxylate (PCT Patent Publication WO 2004/011453) (3.0 g, 7.32 mmol) in ethyl acetate (15 mL) at 20°C was added sodium bromide (Dv50 = 40 µm) (3.01 g, 29.28 mmol) followed by concentrated sulfuric acid (2.20 g, 22.40 mmol) over a period of 5 min. The mixture was stirred at 20°C for 23 h. To the resulting mixture was slowly added saturated aqueous sodium bicarbonate (50 mL) over a period of 15 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and purified by silica gel chromatography (eluting with 20% ethyl acetate in hexanes) to provide the title compound (2.03 g, 84% yield) as a light yellow oil. The ¹ H NMR spectrum of the product was identical to that reported for the product of Example 1.

By the procedures described herein and methods known in the art, compounds of formula II can be converted to compounds of formula I as shown in Table 1 having formulas Ia and IIa . The following abbreviations are used in the table: Me is methyl, Et is ethyl, n -Pr is n- propyl, i -Pr is isopropyl , t -Bu is tertiary butyl, and Ph is phenyl. [Table 1] ^X1 is Br; ^X2 is OS(O) _2Ph ; k is 0 Z series N Z series CH Z is CCl Z series 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 ^X1 is Br; ^X2 is OS(O) _2Ph -4-Me; k is 0 Z series N Z series CH Z is CCl Z series 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 ^X1 is Br; ^X2 is OS(O) _2Me ; k is 0 Z series N Z series CH Z is CCl Z series 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 ^X1 is Br; ^X2 is Cl; k is 0 Z series N Z series CH Z is CCl Z series 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 ^X1 is Cl; ^X2 is OS(O) _2Ph -4-Me; k is 0 Z series N Z series CH Z is CCl Z series 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 ^X1 is Br; k is 0 R ² R ³ Z X ² R ² R ³ Z X ² Cl H N OS(O) ₂ Et Cl H N OS(O) ₂ CF ₃ Br Me CH OS(O)Me Br Me CH OS(O) ₂ - n -Bu Cl Et N OP(O)(OMe) ₂ Cl Et N OP(O)(O- i -Pr) ₂ Br n -Pr CH OP(OMe) ₂ Br n -Pr CH OS(O) ₂ Ph-2,4,6-Tri-Me Cl i -Pr N OP(O)(OEt) ₂ Cl i -Pr N OP(O)(OPh-4-Me) ₂ Br n -Bu CH OP(O)(OPh) ₂ Br n -Bu CH OS(O) ₂ Ph-4-Cl

The preparation method of the 3-halogenated-4,5-dihydro- 1H -pyrazole of the present invention can be used to prepare a variety of compounds having formula I , and the compounds can be used as intermediates for preparing crop protection agents.

In another aspect of the present invention, the compound of formula I prepared by the method of Scheme 1 can be used as an intermediate for preparing compounds of formula III and formula IV .

As previously disclosed in WO 2003/015518 and WO 2006/055922, compounds of formula IV are useful as insecticides.

By a variety of methods previously disclosed in WO 2003/016283, WO 2004/067528, WO 2004/087689 and WO 2006/062978, compounds of formula IV can be prepared from compounds of formula III , and in turn from compounds of formulas II and I Preparation of compounds.

without

without

without

Claims (21)

A method for preparing a 3-halogenated-4,5-dihydro- 1H -pyrazole compound having formula I wherein ^R1 is C(O) ^R3 , halogen, cyano, _C1 - _C4 alkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl, _C1 - _C4 halogenated alkyl or _C1 - _C4 hydroxyalkyl; ^X1 is halogen; ^R2 is hydrogen, halogen, cyano, _C1 - _C4 alkyl or _C1 - _C4 halogenated alkyl; each ^Rx is independently halogen, cyano, _C1 - _C4 alkyl or _C1 - _C4 halogenated alkyl; Z is N or ^CRz ; ^R3 is H, OH, _C1 - _C4 alkyl or _C1 - _C4 alkoxy; ^Rz is hydrogen, halogen, cyano, _C1 - _C4 alkyl or _C1 - _C4 halogenated alkyl; and k is 0, 1, 2 or 3; the method comprises: (1) a 4,5-dihydro- 1H -pyrazole compound having formula II wherein X ² is OS(O) _m R ⁴ , OP(O) _n (OR ⁵ ) ₂ or a halogen other than X ¹ ; m is 1 or 2; n is 0 or 1; R ⁴ is C ₁ -C ₄ alkyl or C ₁ -C ₄ halogenated alkyl; or phenyl optionally substituted by 1 to 3 substituents selected from C ₁ -C ₄ alkyl and halogen; and each R ⁵ is independently C ₁ -C ₄ alkyl or C ₁ -C ₄ halogenated alkyl; or phenyl optionally substituted by 1 to 3 substituents selected from C ₁ -C ₄ alkyl and halogen; reacting with (2) a halogen salt, wherein the halogen of the halogen salt is X ¹ , and (3) an inorganic acid in the presence of a suitable solvent and optionally in the presence of an organic acid to form the compound of formula I. The method of claim 1, wherein m is 2 and n is 1. The method of claim 2, wherein X ¹ is Cl or Br; and X ² is OS(O) _m R ⁴ , or a halogen other than X ¹ . The method of claim 3, wherein R ¹ is C(O)R ³ ; R ² is halogen; Z is N; R ³ is OH or C ₁ -C ₄ alkoxy; k is 0; and R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl. The method of claim 4, wherein R ² is Cl or Br; and R ³ is OH, OCH ₃ or OCH ₂ CH ₃ . The method as described in claim 5, wherein R ² is ^{Cl; X 1 is Br} _; its combination. The method as described in claim 1, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OH, OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ , or Cl; m is 1; R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl; and the halide is selected from sodium bromide, potassium bromide and a combination thereof. The method of claim 1, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ ; m is 1; R ⁴ is 4-methylphenyl; the halide salt is sodium bromide or potassium bromide; the inorganic acid is sulfuric acid; and the organic acid is optional It is formic acid or acetic acid. The method as described in claim 1, wherein the solvent is dichloromethane, dichloroethane or ethyl acetate. A method for preparing compounds of formula III Wherein, R ¹ is C(O)R ³ , halogen, cyano, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl or C ₁ -C ₄ hydroxyalkyl; X ¹ is halogen; R ² is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; each ^R , C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; Z is N or CR ^z ; R ³ is H, OH, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ^z is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; and k is 0, 1, 2 or 3; the method is characterized by using as by claim 1-9 The 3-halo-4,5-dihydro- 1H -pyrazole compound having formula I prepared by the method described in any one of the above. The method as described in claim 10, wherein R ¹ is C(O)R ³ ; X ¹ is Cl or Br; R ² is a halogen; Z is N; R ³ is OH or C ₁ -C ₄ alkoxy; k is 0; X ² is OS(O) _m R ⁴ , or a halogen other than X ¹ ; m is 2; R ⁴ is methyl, ethyl, phenyl or 4-methylphenyl; and the halogen salt is selected from alkali metal bromides, alkali earth metal bromides, ammonium bromide, quaternary ammonium bromides, alkali metal chlorides, alkali earth metal chlorides, ammonium chloride, quaternary ammonium chlorides and combinations thereof. The method of claim 11, wherein ^X1 is Br; ^{R2 is} Cl; ^R3 is OH, _OCH3 or _OCH2CH3 ; _X2 is Cl or OS(O) _mR4 ; and the halide is selected from alkali metal bromides and combinations ^thereof . The method of claim 12, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OH, OCH ₃ or OCH ₂ CH ₃ ; k is ⁰ _; ^{​ ​} Potash and its combinations. The method of claim 13, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ ; m is 1; R ⁴ is 4-methylphenyl; the halide salt is sodium bromide or potassium bromide; the inorganic acid is sulfuric acid; and the organic acid is optional It is formic acid or acetic acid. A method for preparing a diamide compound having formula IV wherein ^X1 is a halogen; ^R2 is a hydrogen, a halogen, a cyano, a _C1 - _C4 alkyl or a _C1 - _C4 halogenated alkyl; each ^Rx is independently a halogen, a cyano, a _C1 - _C4 alkyl or a _C1 - _C4 halogenated alkyl; Z is N or ^CRz ; ^Rz is a hydrogen, a halogen, a cyano, a _C1 - _C4 alkyl or a _C1 - _C4 halogenated alkyl; k is 0, 1, 2 or 3; ^R6A is a halogen, a cyano, a _C1 - _C4 alkyl or a _C1 - _C4 halogenated alkyl; ^R6B is a hydrogen, a halogen, a cyano, a _C1 - _C4 alkyl or a _C1 - _C4 halogenated alkyl; ^R6C is a halogen, a cyano, a _C1 - _C4 alkyl or a _C1 - _C4 halogenated alkyl; R ^6D is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl or C ₁ -C ₄ halogenated alkyl; and R ⁷ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₈ cycloalkylalkyl, C ₄ -C ₈ alkylcycloalkyl, or C ₅ -C ₈ alkylcycloalkylalkyl; the method uses a compound having formula Ia wherein R ³ is OH or C ₁ -C ₄ alkoxy; the method is characterized in that the compound having formula Ia is prepared by the method as described in any one of claims 1 to 9. The method of claim 15, wherein R ^6A is F, Cl, Br or CH ₃ ; R ^6B is hydrogen, F, Cl or Br; R ^6C is F, Cl, Br, I or cyano; and R ^6D is hydrogen, F, Cl or Br. The method of claim 16, wherein R ¹ is C(O)R ³ ; X ¹ is Cl or Br; R ² is halogen; Z is N; R ³ is OH or C ₁ -C ₄ alkoxy ; k is ⁰ ; X ² is OS(O) _m R ⁴ , or ^halogen other than The salt is selected from the group consisting of alkali metal bromide, alkaline earth metal bromide, ammonium bromide, quaternary ammonium bromide, alkali metal chloride, alkaline earth metal chloride, ammonium chloride, quaternary ammonium chloride and combinations thereof; and R ⁷ is methyl , ethyl, isopropyl, cyclopropyl, cyclopropylmethyl or (1-methyl)cyclopropyl. The method according to claim 17, wherein X ¹ is Br; R ^{2 is} Cl _; R ^{3 is} OH, OCH ₃ or OCH ₂ CH ₃ ; The salt is selected from alkali metal bromides and combinations thereof. The method of claim 18, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OH, OCH ₃ or OCH ₂ CH ₃ ; k is ⁰ _; ^{​ ​} Potash and its combinations. The method as described in claim 19, wherein R ¹ is C(O)R ³ ; X ¹ is Br; R ² is Cl; Z is N; R ³ is OCH ₃ or OCH ₂ CH ₃ ; k is 0; X ² is OS(O) _m R ⁴ ; m is 1; R ⁴ is 4-methylphenyl; the halogen salt is sodium bromide or potassium bromide; the inorganic acid is sulfuric acid; and the optional organic acid is formic acid or acetic acid. The method according to any one of claims 1-20, wherein the average particle size of the brine salt is less than 389 μm.