CN102177138A - Method for the synthesis of substituted pyrazoles - Google Patents

Abstract

Processes for preparing 4, 5-disubstituted pyrazole 3-carboxylic acid esters and 2, 4, 5-trisubstituted pyrazole 3-carboxylic acid esters from 3-acyloxirane-2-carboxylic acid esters and hydrazine compounds.

Description

Method for the synthesis of substituted pyrazoles

technical field

The present invention relates to a process for the preparation of 4,5-disubstituted pyrazole 3-carboxylates and 2,4,5-trisubstituted pyrazole 3-carboxylates.

Background technique

JP-A 2001-342178 discloses the reaction of alkyl α, γ-diketoalkanoates with substituted hydrazines to give 2,5-disubstituted pyrazole 3-carboxylates, wherein in the second step by Chloromethylation introduces a substituent at the 4-position. Alkyl α,γ-diketoalkanoates with alkyl substituents in both β and δ positions are unstable or even absent, such as "ethyl 3-methyl 2,4-dioxo Valeric acid esters", which can only be isolated in the form of the corresponding lactones. See Becht J.-M. et al, Tetrahedron 2006, 62, 4430-4434.

Contents of the invention

The object of the present invention is to provide a further process for the preparation of 4,5-disubstituted pyrazole 3-carboxylates and 2,4,5-trisubstituted pyrazole 3-carboxylates.

What is claimed is a process for the preparation of compounds of formula I

Wherein ^R is hydrogen or is selected from alkyl, alkenyl, alkynyl, aryl and aralkyl, each of which optionally has one or more selected from halogen, cyano, nitro, C _1-6 alkane Substituents of radical, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl, and R ² , R ³ and R ⁴ are independently selected from from alkyl, alkenyl, alkynyl, aryl and aralkyl, each of which optionally has one or more selected from halogen, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl substituents, or R ³ and R ⁴ together form a C _3-5 alkenyl, so 5 to 7 Part of a membered ring optionally having one or more substituents selected from the group consisting of halogen, cyano, nitro, C _1-6 alkyl and C _1-6 alkoxy,

Including such that wherein R ² , R ³ and R ⁴ are compounds of formula II as defined above

Reaction with hydrazine of formula III where ^R is defined above

^R1NH - _NH2III .

In a preferred embodiment of the method, each alkyl group is independently a C _1-20 alkyl group, more preferably a C _1-8 alkyl group, and each alkenyl group is independently a C _2-20 alkenyl group, more preferably is C _2-8 alkenyl, and each alkynyl is independently C _2-20 alkynyl, more preferably C _2-8 alkynyl.

Particularly preferred is a method wherein R ^{and R} are selected from alkyl, alkenyl, alkynyl, aryl or aralkyl, each of which optionally also has one or more members selected from halogen, cyano, Substituents of nitro, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl, R ³ and R ^R4 is preferably alkyl or aryl, each of which is substituted as described above; or ^R3 and ^R4 together are _C4 alkenyl and are thus part of a 6-membered ring. Each of the alkyl or aryl substituent and C _alkenyl is optionally substituted as described above.

The reaction is preferably carried out in the presence of an acid.

In a preferred embodiment, the acid is an organic acid. The organic acid is more preferably an alkanoic acid, preferably a C _2-5 alkanoic acid, more preferably selected from acetic acid, propionic acid, butyric acid, trifluoroacetic acid, 2-chloropropionic acid and tert-butyric acid.

 acid)例如氢溴酸、盐酸或硼酸，或路易斯酸例如二氯化锡、四氯化锡、二溴化锡、四溴化锡、三氟化硼、三氟化硼醚络合物、三氯化硼、三溴化硼、三烷基铝、二烷基铝氯化物、烷基铝二氯化物、三氯化铝、氯化钪、溴化钪、碘化钪、氯化钛、溴化钛、三氯化铁、钒氯化物、铬氯化物、锰氯化物、氯化锆、溴化锆、氯化锌、溴化锌、钇氯化物、钼氯化物或钌氯化物，或稀土氯化物例如三氯化镧、三氯化铈或三氯化镱。In another preferred embodiment, the acid is a non-oxidizing mineral acid. Preferably the inorganic acid is a Bronsted acid (

acid) such as hydrobromic acid, hydrochloric acid or boric acid, or Lewis acids such as tin dichloride, tin tetrachloride, tin dibromide, tin tetrabromide, boron trifluoride, boron trifluoride ether complex, trifluoride Boron chloride, boron tribromide, trialkylaluminum, dialkylaluminum chloride, alkylaluminum dichloride, aluminum trichloride, scandium chloride, scandium bromide, scandium iodide, titanium chloride, bromine Titanium chloride, ferric chloride, vanadium chloride, chromium chloride, manganese chloride, zirconium chloride, zirconium bromide, zinc chloride, zinc bromide, yttrium chloride, molybdenum chloride, or ruthenium chloride, or rare earths Chlorides such as lanthanum trichloride, cerium trichloride or ytterbium trichloride.

Although the process can be carried out without the addition of solvent, in a preferred embodiment the reaction can be carried out in a solvent such as alkanoic acid, alcohol, ether, thioether, sulfone, sulfoxide, dimethylformaldehyde Amides, N-alkylpyrrolidones, furans, thiophenes, benzene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, methylene chloride, toluene, hexanes, cyclohexane, pentane , cyclohexane or a mixture thereof). More preferably, the solvent is a polar solvent selected from alkanoic acid, alcohol, ether, thioether, sulfone, sulfoxide, dimethylformamide and N-alkylpyrrolidone.

In another preferred embodiment, the alcohol is a straight chain C _1-12 alcohol or a branched C _1-12 alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec- Butanol, tert-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, 2,2,2-trifluoroethanol, 1,2-ethylene glycol, 1,2-propanediol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2,3-propanetriol, 1,2,6-hexanetriol, Diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoacetate, triethylene glycol, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, three Glycol monobutyl ether or triethylene glycol monoacetate. Particularly preferred are _C1-6 alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol, 2,2-dimethylpropanol, 3,3-Dimethyl-2-butanol, 2,2,2-trichloroethanol, 2,2,2-trifluoroethanol, 2-propenol or 2-dimethylaminoethanol.

In another preferred embodiment, the alcohol is benzyl alcohol or phenol, each of which is optionally substituted. Suitable examples are phenol, benzyl alcohol, trityl alcohol, 4-chlorophenol and 4-nitrophenol.

Suitable ethers and thioethers are, for example, dialkylethers and dialkylsulfides; cyclic ethers and thioethers containing 1 or 2 oxygen atoms or sulfur atoms; and alkylaryl ethers and alkylarylthioethers. Ether, comprising a linear or branched alkyl moiety that is independently a C _1-6 alkyl group, and an aryl moiety that is a phenyl group optionally substituted by one or more halogen atoms.

In another preferred embodiment, ethers and thioethers are selected from dimethyl ether, diethyl ether, ethyl methyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, dimethyl sulfide, diethyl methyl sulfide, ethyl methyl sulfide and tert-butyl methyl sulfide, 1,4-dithiane, tetrahydrothiophene and mixtures thereof.

Suitable sulfones and sulfoxides are, for example, sulfolane and dimethylsulfoxide.

All solvents can be used as a mixture, optionally in the presence of water.

In another preferred embodiment, the reaction is carried out under reflux conditions, optionally in a pressurized vessel, more preferably at a temperature of 20 to 180°C.

The term alkyl means a straight or branched chain alkyl group, while "C _1-n alkyl" means an alkyl group having 1 to n carbon atoms. C _1-18 Alkyl represents, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl Alkyl and octadecyl.

The term alkenyl denotes a straight-chain alkenyl group which in this application is part of a carbocycle. "C _3-5 alkenyl" means an alkenyl group having 3 to 5 carbon atoms, i.e. -C ₃ H _6-P -, -C ₄ H _8-P - or -C ₅ H _10-P -, where p is an integer representing the maximum possible number of independent substituents different from hydrogen, said independent substituents being attached to said alkenyl, said alkenyl being attached to two residues, preferably attached to ^R3 and ^R4 , Thus a cyclic compound is formed.

The term alkenyl herein means a straight or branched chain group having at least one carbon-carbon double bond, while "C2 _-n alkenyl" means an alkenyl group having 2 to n carbon atoms. C _2-6 alkenyl represents, for example, vinyl (vinyl), propen-1-yl, propen-2-yl (allyl), buten-1-yl or hexen-1-yl.

The term alkynyl herein means a straight chain or linear group having at least one carbon-carbon triple bond, wherein "C2 _-n alkynyl" means an alkynyl group having 2 to n carbon atoms. C _2-6 alkynyl represents, for example, ethynyl, 1-propynyl, 2-propynyl or 1-hexynyl.

The term alkoxy means straight or branched chain alkoxy, and "C ₁ -C _n alkoxy" means alkoxy having 1 to n carbon atoms. C _1-6 alkoxy represents, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, Pentoxy or hexyloxy.

The term aryl means an aromatic group, optionally substituted by one or more halogen atoms, amino and/or optionally substituted C _1-6 alkyl or C _1-6 alkoxy or diC _1-6 alkyl Amino substitution, wherein the alkyl moiety or alkoxy moiety is optionally substituted by one or more halogen atoms. C _6-20 Aryl represents, for example, phenyl or naphthyl and derivatives thereof as defined above.

The term aryloxy means an aromatic group attached through an oxygen atom, which is optionally substituted by one or more halogen atoms, amino groups and/or optionally substituted C _1-6 alkyl or C _{1- 6} alkoxy or diC _1-6 alkylamino, wherein the alkyl moiety or alkoxy moiety is optionally substituted by one or more than one halogen atom. C _6-20 Aryloxy represents, for example, phenoxy or naphthyloxy and derivatives thereof as defined above.

The term aralkyl denotes an aromatic group wherein the alkyl portion of the aralkyl residue is a straight chain C _1-8 alkyl and the aryl portion is preferably selected from phenyl, naphthyl, furyl, thiophene benzo[b]furyl, benzo[b]thienyl, optionally substituted by one or more halogen atoms, amino and/or optionally substituted C _1-6 alkyl or C _1-6 alkoxy Base or diC _1-6 alkylamino substitution.

The main object of the present invention is the reaction of compounds of formula II and of formula III. However, the use of compounds of the formula II as starting compounds for the preparation of pyrazoles has not been disclosed so far. Possible routes are shown in Scenario 1:

plan 1:

Residues R ^a and R ^b each represent residues R ³ and R ⁴ or R ⁴ and R ³ as defined above. If Ra and ^Rb are different and do not together form an asymmetrically substituted alkenyl, the compound of formula II may consist of two isomers, wherein ^R3 and ^R4 are interchangeable ^.

The reaction sequence for the preparation of compounds of formulas IV, V and II is known from Payne GB, J. Org. Chem. 1968, 33, 3517-3523, which however has not disclosed the synthesis involving pyrazoles. Residues R ⁵ and R ⁶ are independently C _1-6 alkyl optionally substituted by one or more halogen atoms, or R ⁵ , R ⁶ and a sulfur atom together form a 5-, 6-, or 7-membered saturated or unsaturated A heterocycle, which optionally has one or more substituents selected from halogen, cyano, nitro, C _1-6 alkyl and C _1-6 alkoxy.

An important route to prepare compounds of formula II is the method of scheme 1, so another aspect of the present invention is to provide compounds of formula II prepared from inexpensive starting materials.

Further claimed are processes for the preparation of compounds of formula I

Wherein ^R is hydrogen or is selected from alkyl, alkenyl, alkynyl, aryl and aralkyl, each of which optionally has one or more selected from halogen, cyano, nitro, C _1-6 alkane Substituents of radical, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl, and R ² , R ³ and R ⁴ are independently selected from from alkyl, alkenyl, alkynyl, aryl and aralkyl, each of which optionally has one or more selected from halogen, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl substituents; or R ³ and R ⁴ together form C _3-5 alkenyl, so 5 to 7 Part of a membered ring optionally having one or more substituents selected from the group consisting of halogen, cyano, nitro, C _1-6 alkyl and C _1-6 alkoxy,

Including such that wherein R ² , R ³ and R ⁴ are compounds of formula II as defined above

Reaction with hydrazine of formula III where ^R is defined above

R ¹ NH-NH ₂ III,

and wherein the compound of formula II is obtained by making the compound of formula V

Wherein R ² is as defined above, and wherein R ⁵ and R ⁶ are independently selected from C _1-6 alkyl optionally substituted by one or more halogen atoms, or R ⁵ , R ⁶ and a sulfur atom jointly form 5, 6 or 7 membered saturated or unsaturated heterocyclic rings, which optionally have one or more than one selected from halogen, cyano, nitro, C _1-6 alkyl and C _1-6 alkoxy Substituent, with wherein R ³ and R ⁴ are compounds of formula VI as defined above

prepared by the reaction.

In a preferred embodiment, R ³ and R ⁴ are the same, each of R ³ and R ⁴ optionally has one or more members selected from the group consisting of halogen, cyano, nitro, C _1-6 alkyl and C _1-6 alkane or ^R3 and ^R4 together form a _C3-5alkenyl group and are therefore part of a 5 to 7 membered ring which optionally has one or more members selected from the group consisting of halogen, cyano, nitro Substituents of radical, C _1-6 alkyl and C _1-6 alkoxy.

In a preferred embodiment, the R ⁵ -SR ⁶ moieties of the sulfonium compound of formula V are derived from corresponding compounds such as dimethyl sulfide, diethyl sulfide, ethyl methyl sulfide and tetrahydrothiophene.

Thus, emphasis is placed on 2,4,5-trisubstituted pyrazole 3-carboxylates in which ^R is a substituent other than hydrogen, which can be obtained by making 4,5-disubstituted pyrazole 3-carboxylates ( That is, a compound of formula I wherein R ¹ is hydrogen) is conveniently prepared by reacting an N-substituted hydrazine.

Detailed ways

Example

The following examples illustrate how to practice the method of the invention without limiting it.

Example 1: Compound IVa (Compound IV: R ² = ethyl, R ⁵ = R ⁶ = methyl)

A solution of ethyl bromoacetate (106 g, 635 mmol, 1.0 equiv) and dimethyl sulfide (45.6 g, 734 mmol, 1.16 equiv) in acetone (200 mL) was stirred for 3 days (d), during which time a white solid precipitation. The resulting precipitate was collected by filtration and dried under vacuum to afford Compound IVa (120.0 g, 82.6%) as a white solid.

Example 2: Compound IVb (Compound IV: R ² = ethyl, R ⁵ = R ⁶ = -(CH ₂ ) ₄ -)

A solution of tetrahydrothiophene (10.70 g, 122 mmol) and ethyl bromoacetate (16.70 g, 100 mmol) in acetone (40 mL) was stirred for 3 days. The precipitate was collected, washed with acetone (60 mL) and collected by filtration to give compound IVb (21.4 g, 84%) as a white solid. The product can be used directly for the preparation of compound Vb without further purification.

Example 3: Compound Va (Compound V: R ² = ethyl, R ⁵ = R ⁶ = methyl)

To a solution of compound IV in chloroform (75 mL) were added 12.5N NaOH (4 mL) and saturated K ₂ CO ₃ solution (60 mL) at 0° C., respectively. The resulting mixture was warmed to room temperature (RT) within 15 min and stirred at RT for 20 min. The organic phase was separated and the aqueous phase was washed with chloroform (2 x 30 mL). The combined organic phases were dried over _K2CO3 and concentrated under reduced pressure to give compound Va (11.18 g, 75.5%) _in liquid state.

Example 4: Compound Vb (Compound V: R ⁵ and R ⁶ =-(CH ₂ ) ₄ -)

To a solution of compound IVb (8.30 g, 33 mmol) in chloroform (20 mL) were added 12.5N NaOH (2.6 mL) and saturated K ₂ CO ₃ solution (19.6 mL), respectively. The resulting mixture was stirred for an additional 15 min under ice-bath cooling, and for an additional 15 min at 15 to 17 °C. The organic phase was separated and the aqueous phase was washed with chloroform (2 x 30 mL). The organic phases were combined, dried over _K2CO3 , and concentrated under reduced pressure to give compound Vb (5.30 g, 93%) _as a yellow liquid.

Example 5: Compound IIa (Compound II: R ² = ethyl, R ³ = R ⁴ = methyl)

To a solution of compound Va (10.1 g, 68 mmol, 1.0 equiv) in toluene (68 mL) was added dropwise a solution of 2,3-butanedione (5.87 g, 68 mmol, 1.0 equiv) in toluene (17 mL) at 48 °C within 2 h. After the addition was complete, the resulting solution was stirred at the same temperature for 1 h, then cooled to RT and further stirred at RT for 18 h. Residual toluene was removed under reduced pressure, and the residue was washed again with toluene (3 x 30 mL). Removal of the toluene under reduced pressure gave an oil which was then vacuum distilled to give Compound IIa (5.0 g, 42.6%) as a light yellow oil boiling at 104-106° C. (1 mbar).

Example 6: Compound IIb (Compound II: R ² = ethyl, R ³ = R ⁴ = phenyl)

To a solution of compound Vb (2.10 g, 12 mmol, 1.2 equiv) in toluene (8 mL) was added 1,2-diphenylethane-1,2-dione (diphenylethane) dropwise at 45 to 46° C. within 2 h Diketone, 2.10 g, 10 mmol) in toluene (8 mL). The resulting mixture was further heated at 45 to 46 °C for 1 h and stirred at RT for 18 h. The reaction mixture was concentrated, and the residue was subjected to flash chromatography (petroleum ether:ethyl acetate; 12:1; v:v) to obtain compound IIb (2.2 g, yield: 74%) as a yellow liquid.

Example 7: Compound IIb (Compound II: R ² = ethyl, R ³ = R ⁴ = phenyl)

To a solution of compound Va (6.80 g, 45 mmol, 1.0 equiv) in toluene (50 mL) was added dropwise a solution of diphenylethylenedione (9.65 g, 45 mmol) in toluene (23 mL) at 45 to 46° C. within 2 h and heated to 45°C. The reaction was stirred for an additional 2 h at 45 to 46 °C and for 18 h at RT. The reaction mixture was concentrated, and the residue was subjected to flash chromatography (petroleum ether:ethyl acetate; 12:1; v:v) to obtain compound IIb (9.80g, yield: 72%, purity :>95%).

Example 8: Compound IIc (Compound II: R ² =R ³ =R ⁴ =Ethyl)

To a solution of compound Vb (2.10 g, 12 mmol, 1.2 equiv) in toluene (8 mL) was added dropwise a solution of 3,4-hexanedione (1.14 g, 10 mmol) in toluene (5 mL) within 2 h and heated to 45 to 46 °C . The resulting mixture was heated in this temperature range for 1 h and stirred for a further 18 h at RT. The reaction mixture was concentrated under reduced pressure to obtain Compound IIc (2.0 g, 95%) as a yellow liquid.

Example 9: Compound IIc (Compound II: R ² =R ³ =R ⁴ =Ethyl)

To a solution of compound Va (5.06 g, 35 mmol, 1.17 equiv) in toluene (30 mL) was added dropwise a solution of 3,4-hexanedione (3.42 g, 30 mmol) in toluene (8 mL) within 2 h and heated at 46 to 47 °C . The resulting mixture was heated in this temperature range for 1 h and stirred for a further 24 h at RT. The reaction mixture was concentrated under reduced pressure to obtain Compound IIc (5.3 g, yield: 88%, purity: >97.9%) in brown liquid state.

Example 10: Compound Ia (Compound I: R ¹ =phenyl, R ² =ethyl, R ³ =R ⁴ =methyl)

To a solution of acetic acid (50 mL, 0.87 mmol, 0.87 equiv) in ethanol (1 mL) was added phenylhydrazine (140.6 mg, 1.3 mmol, 1.3 equiv) at 0°C. The resulting solution was stirred for another 5 min, and then added to a solution of compound IIa (172.20 mg, 1.0 mmol, 1.0 equiv) in ethanol (2 mL) at 25 °C, rinsed with ethanol (1 mL). The resulting solution was heated to reflux for 3h. The resulting solution was cooled and volatiles were removed under reduced pressure. To the resulting mixture were added dichloromethane (25 mL) and saturated Na ₂ CO ₃ (10 mL). The aqueous phase was separated and washed with dichloromethane (2 x 25 mL). The combined organic phases were concentrated to obtain a brown liquid, which was subjected to silica gel column chromatography (hexane:ethyl acetate; 8:1; v:v) to obtain Compound Ia (203 mg, 83%) as a yellow liquid.

Example 11: Compound Ib (Compound I: R ¹ =Hydrogen, R ² =Ethyl, R ³ =R ⁴ =Methyl)

A solution of Ma (303 mg) and hydrazine hydrate (80%, 132 mg) in ethanol (2 mL) was heated to reflux for 3 h. The resulting crude mixture was concentrated and subjected to silica gel column chromatography (hexane:ethyl acetate; 3:1; v:v) to obtain Compound Ib (24.5 mg) as a white solid.

Example 12: Compound Ic (Compound I: R ¹ =R ³ =R ⁴ =methyl, R ² =ethyl)

To a mixture of IIa (172 mg, 1.0 mmol) and ethanol (2 mL) was added a solution of methylhydrazine (60 mg, 1.3 mmol) in ethanol (1 mL) and acetic acid (50 mL, 0.87 mmol) at 0°C. The reaction mixture was diluted with ethanol (1 mL) and heated to reflux for 2 h. The resulting mixture was then cooled and evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (25 mL) and _{saturated Na2CO3} . The phases were separated and the aqueous phase was washed twice with dichloromethane (2 x 25 mL). The combined organic phases were dried over sodium sulfate and concentrated. Compound Ic (90 mg, 49%) was obtained as a yellow oil after separation by column chromatography.

Example 13: Compound Id (Compound I: R ¹ =R ³ =R ⁴ =phenyl, R ² =ethyl)

To a solution of acetic acid (0.8 mL, 14.0 mmol, 0.86 equiv) in ethanol (16 mL) was added phenylhydrazine (3.00 g, 27.7 mmol, 1.70 equiv) over 5 min under an ice-water bath for cooling temperature regulation. The resulting solution was stirred for a further 5 min, then a solution of compound lib (4.80 g, 16.2 mmol) in ethanol (32 mL) was added over 10 min at RT. The resulting solution was refluxed for 7h. The resulting mixture was cooled, and volatiles were removed under reduced pressure. To the _resulting mixture were added dichloromethane (60 mL) and saturated _K2CO3 solution (60 mL). The aqueous phase was separated and washed with dichloromethane (2 x 60 mL). The combined organic phases were concentrated to give a brown liquid which was subjected to flash chromatography (petroleum ether/ethyl acetate; 30:1; v:v) then petroleum ether/ethyl acetate; 15:1; v:v) Purification afforded Compound Id (2.10 g, 36.5%) as a yellow solid. ¹ H-NMR (400MHz, CDCl ₃ ) δ(ppm): 0.93(t, 3H, J=7.2Hz, CH ₃ ), 4.07(d, 2H, J=7.2Hz, OCH ₂ ), 7.26～7.28(m , 3H, Ar-H), 7.35~7.40(m, 5H, Ar-H), 7.43~7.52(m, 7H, Ar-H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ13.4, 61.2 , 125.1, 125.4, 127.6, 127.9, 128.1, 128.2, 128.2, 128.4, 128.8, 130.5, 132.3, 132.3, 132.7, 140.6, 150.2, 160.1.

Example 14: Compound Ie (Compound I: R ¹ =Hydrogen, R ² =Ethyl, R ³ =R ⁴ =Phenyl)

To a solution of acetic acid (0.2 mL, 3.50 mmol, 0.83 equiv) in ethanol (2 mL) was added hydrazine (80%, 180 mg, 2.88 mmol, 1.37 equiv) over 5 min under an ice water bath for cooling temperature regulation. The resulting solution was stirred for an additional 5 min, then a solution of compound lib (1.20 g, 4.05 mmol) in ethanol (4 mL) was added at RT over 15 min. The resulting solution was heated to reflux for 6h. It was then stirred at RT for 18h. The volatiles were removed under reduced pressure to give a brown liquid (900 mg). The resulting brown liquid was purified by flash chromatography (dichloromethane:triethylamine; 3:1; v:v) to afford compound Ie (90 mg, 9.86%) as a white solid. ¹ H-NMR (400MHz, CDCl ₃ ) δ(ppm): 1.22(t, 3H, J=7.20Hz, CH ₃ ), 4.28(q, 2H, J=7.20Hz, OCH ₂ ), 7.28-7.39(m , 10H, Ar-H). ¹³ C-NMR (100MHz, CDCl ₃ ): δ12.9, 60.1, 126.5, 126.9, 126.93, 127.2, 127.4, 129.6, 130.1, 130.9, 159.5.

Example 15: Compound If (Compound I: R ¹ =Phenyl, R ² =R ³ =R ⁴ =Ethyl)

To a solution of acetic acid (0.5 mL, 8.75 mmol, 0.86 equiv) in ethanol (10 mL) was added phenylhydrazine (1.40 g, 13.1 mmol, 1.30 equiv) over 5 min under an ice water bath for cooling temperature regulation. The resulting solution was stirred for an additional 5 min, then a solution of compound IIf (2.00 g, 10.1 mmol) in ethanol (20 mL) was added over 10 min at RT. The resulting solution was refluxed for 6 h, then cooled to RT. Volatiles were removed under reduced pressure. To the _resulting mixture were added dichloromethane (30 mL) and saturated _K2CO3 solution (30 mL). The aqueous phase was separated and washed with dichloromethane (2 x 30 mL). The combined organic phases were concentrated to obtain a brown liquid, which was then subjected to two silica gel column chromatography (first time: petroleum ether:ethyl acetate; 30:1; v:v, second time: petroleum ether/acetic acid Ethyl ester; 15:1; v:v) was purified to obtain compound If (1.05 g, 38.6%) in brown liquid state.

Example 16: Compound If (Compound I: R ¹ =Phenyl, R ² =R ³ =R ⁴ =Ethyl)

To a solution of acetic acid (0.1 mL, 1.75 mmol, 0.70 equiv) in ethanol (2 mL) was added hydrazine (80%, 180 mg, 2.88 mmol, 1.37 equiv) over 5 min under an ice-water bath for cooling temperature regulation. The resulting solution was stirred for an additional 5 min, then a solution of compound IIf (0.50 g, 2.50 mmol) in ethanol (8 mL) was added over 15 min at RT. The resulting solution was refluxed for 3 h, then cooled to RT. Volatiles were removed under reduced pressure. The resulting brown liquid (650 mg) was purified by silica gel column chromatography (petroleum ether: ethyl acetate: triethylamine; 46:15:2; v:v:v) to obtain a small amount of compound If.

Claims (9)

1. The method for preparing formula I compound Wherein ^R is hydrogen or is selected from alkyl, alkenyl, alkynyl, aryl and aralkyl, each of which optionally has one or more selected from halogen, cyano, nitro, C _1-6 alkane Substituents of radical, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl; and R ² , R ³ and R ⁴ are independently selected from from alkyl, alkenyl, alkynyl, aryl and aralkyl, each of which optionally has one or more selected from halogen, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl substituents; or R ³ and R ⁴ together form C _3-5 alkenyl, so 5 to 7 Part of a membered ring optionally having one or more substituents selected from the group consisting of halogen, cyano, nitro, C _1-6 alkyl and C _1-6 alkoxy, Including such that wherein R ² , R ³ and R ⁴ are compounds of formula II as defined above

Reaction with hydrazine of formula III where ^R is defined above ^R1NH - _NH2III . 2. The method according to claim 1, wherein R ^{and R} are selected from alkyl, alkenyl, alkynyl, aryl or aralkyl, each of which optionally also has one or more selected from halogen, Substituents of cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl, R ³ and R ⁴ are preferably alkyl or aryl; or R ³ and R ⁴ together form a C ₄ alkenyl and thus part of a 6 membered ring. 3. The method according to claim 1 or 2, wherein the reaction is carried out in the presence of an acid. 4. The method according to claim 3, wherein the acid is an alkanoic acid, preferably a _C2-5 alkanoic acid, more preferably selected from acetic acid, propionic acid, butyric acid, trifluoroacetic acid, 2 - Chloropropionic acid and tert-butyric acid. 5. The method according to any one of claims 1 to 4, characterized in that the reaction is carried out in the presence of a solvent, preferably selected from the group consisting of alkanoic acid, alcohol, ether, thioether, sulfone, sulfoxide, Dimethylformamide, N-alkylpyrrolidone, furan, thiophene, benzene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, methylene chloride, toluene, hexanes, cyclic in the presence of polar solvents such as hexane, pentane, cyclohexane or mixtures thereof. 6. according to the described method of any one of claim 1 to 5, it is characterized in that, described reaction is carried out under the existence of alkanoic acid and/or alcohol, and preferably described acid is C _2-5 alkanoic acid, and The alcohol is straight chain C ₁ -C ₁₂ alkyl alcohol or branched C ₁ -C ₁₂ alkyl alcohol. 7. The method according to any one of claims 1 to 8, characterized in that the reaction is carried out under reflux conditions, optionally in a pressurized vessel. 8. The method for preparing the compound of formula I according to any one of claims 1 to 8, wherein ^R is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and aralkyl, each of which is optionally have one or more than one selected from halogen, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryl Substituents of oxy and aralkyl, and R ² , R ³ and R ⁴ are independently selected from alkyl, alkenyl, alkynyl, aryl or aralkyl, each of which optionally also has one or more selected from halogen, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, aryl, aryloxy and aralkyl Substituents, or ^R3 and ^R4 together represent a chain group, the main chain includes 3, 4 or 5 carbon atoms and optionally has one or more than one selected from halogen, cyano, nitro, C _1-6 Alkyl and C _1-6 alkoxy substituents, characterized in that by making the compound of formula V

Wherein R ² is as defined above, and wherein R ⁵ and R ⁶ are independently selected from C _1-6 alkyl optionally substituted by one or more halogen atoms, or R ⁵ , R ⁶ and a sulfur atom jointly form 5, 6 or 7 membered saturated or unsaturated heterocyclic rings, which optionally have one or more substitutions selected from halogen, cyano, nitro, C _1-6 alkyl and C _1-6 alkoxy base, and wherein R ³ and R ⁴ are compounds of formula VI as defined above reaction to prepare the compound of formula II. 9. The method according to claim 8, wherein above-mentioned R ³ and R ⁴ are identical, and each optionally has one or more than one selected from halogen, cyano, nitro, C _1-6 alkyl and C _{1- 6} alkoxy substituents; or R and ^R together form a C _3-5 alkenyl and are therefore part of a 5 to 7 membered ring optionally having ^one or more members selected from the group consisting of halogen, cyano , nitro, C _1-6 alkyl and C _1-6 alkoxy substituents.