Pyrazole derivative

Abstract

To provide nitro-vinyl-pyrazole compounds, which are valuable intermediates in the production of agrochemicals and pharmaceuticals, and methods of producing such compounds.SOLUTION: The invention provides compounds of the following formula in the figure, where ring A is one of the lower formulas A1 and A2 in the figure. In the formulas A1 and A2: RB2 is C1-C3 alkyl; and RB3SN is halogen or C1-C3 fluoroalkyl.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to pyrazole derivatives of formula (B) and formula (C) as described herein which are important intermediates in the manufacture of agrochemicals and pharmaceuticals. The invention extends to the manufacture of such pyrazole derivatives and their subsequent use in the manufacture of agrochemicals and / or pharmaceuticals. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0002] In a first aspect, there is provided a compound of formula (B): [ka] (Wherein, ring A is a ring nitrogen atom of R B2 and the ring carbon is R B3 and R is a disubstituted pyrazole substituted with B2 is C1-C3 alkyl or C1-C3 fluoroalkyl, R B3 is halogen, C1-C3 fluoroalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 fluoroalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, or C1-C3 alkyl.

[0003] In a second aspect, there is provided a compound of formula (C): [ka] (Wherein, ring A is a ring nitrogen atom of R B2 and the ring carbon is R B3 and R is a disubstituted pyrazole substituted with B2 is C1-C3 alkyl or C1-C3 fluoroalkyl, R B3 is halogen, C1-C3 fluoroalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 fluoroalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, or C1-C3 alkyl.

[0004] The compounds of formula (B) and (C) can be used as intermediates in the manufacture of pharmaceuticals and agrochemicals containing a pyrazolo-pyrrolidone motif. For example, US 2007 / 0123508 describes 2-oxo-1-pyrrolidone derivatives for use as PAR2 inhibitors, and the compounds of formula (B), (C), (D), and (E) can be used as R-type amines of the compounds of US 2007 / 0123508. 1 The preparation of novel herbicidal compounds using the compounds of formula (B) and (C) can be used to synthesize compounds in which the formula (B) is a substituted pyrazole.

[0005] The compound of formula (B) is a halogenated pyrazole compound of formula (A): [ka] (In the formula, rings A, R B2 , and R B3 is as defined above, and Hal is a halogen selected from iodo, bromo, and chloro. can be prepared from compounds of formula (A) by reaction with isopropylmagnesium chloride-lithium chloride in a suitable solvent such as tetrahydrofuran at -20°C. After 2 hours, 1-dimethylamino-2-nitroethylene is added and the reaction is allowed to warm slowly to room temperature over 1 hour. This gives the desired nitrovinylpyrazole of formula (B) after workup and purification (Reaction Scheme 1). Compounds of formula (A) are known or can be prepared according to methods well known in the art.

[0006] Reaction Scheme 1 [ka] Nitrovinylpyrazole compounds of formula (B) can also be prepared by reacting the corresponding pyrazole aldehyde (x) with nitromethane in a suitable solvent using a suitable base, followed by a dehydration step, as shown in Reaction Scheme 1.1 below. Such methods are reported in WO 2016 / 100050 and WO 2019 / 169153.

[0007] Reaction Scheme 1.1 [ka] The nitrovinylpyrazole compound of formula (B) is then reacted with a malonate, such as diethyl malonate, in a suitable solvent, such as toluene, under enantioselective nickel catalysis as described in J. Am. Chem. Soc. 2005, 127, 9958-9959, as shown in Reaction Scheme 2, to provide the enantioselective malonate addition product, which is a compound of formula (C).

[0008] Reaction Scheme 2 [ka] In the compounds of formula (A), (B), and (C) described herein, ring A is a pyrazole moiety bearing two substituents, one of which (R B2 ) on the ring nitrogen, and the second substituent (R B3 ) on a ring carbon atom. In such a configuration, obviously, A is the carbon attached to the rest of the molecule.

[0009] A is disubstituted and R B3 is on a ring carbon atom adjacent to a substituted ring nitrogen atom, B3 The substituent is R B3SN For the avoidance of doubt, R B3SN R is used purely to indicate the location of a position within the pyrazole moiety B3 Since it is a definition of a sub-concept of R B3SNis also selected from the group consisting of halogen, C1-C3 fluoroalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, and C1-C3 alkyl. Thus, when A is disubstituted, the group A 1 , A 2 , A 3 , A 4 , or A 5 In the formula, R B2 , R B3 , and R B3SN is as defined above, and the jagged line indicates the point of attachment to the remainder of the associated molecule. [ka]

[0010] Base A 1 and A 2 is particularly preferred, and A 2 is the most preferred disubstituted pyrazole.

[0011] Preferably, R B2 is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. More preferably, R B2 is selected from the group consisting of methyl, ethyl, n-propyl, trifluoromethyl, and difluoroethyl. More preferably, R B2 is selected from the group consisting of methyl, ethyl, and difluoroethyl.

[0012] Preferably, R B3 (and as a result R B3SN (Also) is selected from chloro, fluoro, bromo, methyl, ethyl, difluoromethyl, trifluoromethyl, C1-C3 haloalkoxy, C1-C3 alkoxy, or C1-C3 alkyl.

[0013] Tables 1 and 2 below provide specific examples of compounds of formulae (B) and (C) for use in the present invention.

[0014] [Table 1]

[0015] [Table 2]

[0016] The compounds of formula (B) and (C) described herein are pyrazolo-lactam-carboxylates of formula (D) [ka] (In the formula, rings A, R B2 , and R B3 are defined herein) and pyrazolo-lactam-carboxylic acid derivatives of formula (E) [ka] (In this formula, rings A and R B2 , and R B3 are defined herein) These novel compounds form a further aspect of the present invention.

[0017] Reductive cyclization of compounds of formula (C) using a suitable reducing agent, such as sodium borohydride, with a suitable catalyst, such as nickel chloride, in a suitable solvent, such as ethanol, provides pyrazole-lactam-carboxylates of formula (D) (Reaction Scheme 3 below).

[0018] Reaction Scheme 3 [ka] Compounds of formula (D) can then be hydrolyzed in an aqueous hydroxide / ethanol mixture to give the appropriate pyrazolo-lactam-3-carboxylic acid derivatives of formula (E), as shown in Reaction Scheme 4.

[0019] Reaction Scheme 4 [ka] The compounds of formula (D) and formula (E) are also important intermediates in the manufacture of pyrazolo-lactam herbicides, particularly since they yield the preferred herbicidal enantiomers. Tables 3 and 4 below provide specific examples of compounds of formula (D) and (E) for use in the present invention.

[0020] [Table 3]

[0021] [Table 4]

[0022] Processes for the preparation of novel pyrazolo-lactam herbicides of formula (G) from compounds of formula (E) are illustrated below in general terms in Reaction Schemes 5 and 6, and with respect to specific herbicidal compounds in the Examples.

[0023] Reaction Scheme 5 [ka] Compounds of formula (E) are methylated on the lactam nitrogen using methyl iodide or an alternative methylating reagent in a suitable solvent such as tetrahydrofuran using an excess of base such as potassium tertbutoxide (reaction scheme 5 above).

[0024] 3-carboxyl substituted N-methyl lactams of formula (F) can be converted to aryl esters of formula R using standard amide coupling conditions, such as propanephosphonic anhydride, in a suitable solvent, such as dichloromethane, with a suitable base. 2 -NH2 aniline (R 2 is defined below) to give the herbicidal pyrazolo-lactam carboxamides of formula (G) (Reaction Scheme 6).

[0025] Reaction Scheme 6 [ka] formula R 2 For the anilines of -NH2 and herbicidal compounds of formula (G), R 2 The substituents include hydrogen, C1-C6 alkyl, -C r Alkoxy C s Alkyl, C1-C6 haloalkyl, -C r Alkoxy C s Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and -(CR 21 R 22 ) t R 20 Each R 20 are independently -C(O)OR 23 , -OC(O)R 23 , -C3-C6 cycloalkyl, or an -aryl, -aryloxy, -heteroaryl, -heteroaryloxy, or -heterocyclyl ring, the ring being selected from 1 to 3 independent R 25 r is an integer of 1, 2, 3, 4, or 5, s is an integer of 1, 2, 3, 4, or 5, and the sum of r+s is 6 or less; t is an integer of 0, 1, 2, 3, 4, 5, or 6, and each R 21 are independently hydrogen or C1-C2 alkyl; each R 22 are independently hydrogen or C1-C2 alkyl; R 23 is hydrogen or C1-C4 alkyl.

[0026] In certain embodiments, R 2 1 to 3 R 25 When the aryl or heteroaryl ring is an optionally substituted aryl or heteroaryl ring selected from the group consisting of phenyl, pyridinyl, and thienyl ring systems, it can be represented by the following general structure: [ka] in which ring B is a phenyl, pyridinyl, or thienyl ring, p is an integer or 0, 1, 2, or 3, and the jagged line represents the point of attachment of the ring to the remainder of the molecule, in this case via the amide nitrogen.

[0027] In certain embodiments, R 2 is R 2 -1, R 2 -2, R 2 -3, R 2 -4, R 2 -5, and R 2 -6: [ka] wherein p and the jagged line are as defined above, and each R 25 are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, nitro, C1-C6 alkylthio, C1-C6 alkylsulfinyl, or C1-C6 alkylsulfonyl.

[0028] More preferably, each R 25 are independently halogen, C1-C4 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy; more preferably, chloro, fluoro, bromo, C1-C2 haloalkyl, C1-C2 haloalkoxy, or C1-C2 alkoxy; more preferably, fluoro, ethyl, trifluoromethyl, difluoroethyl, methoxy, difluoromethoxy, or trifluoromethoxy. As described herein, the value of p is 1, 2, or 3. Preferably, p is 0, 1, or 2, and each R 25 is carried by the ring carbon atom.

[0029] formula R 2 The -NH2 anilines are known or can be prepared according to methods well known in the art.

[0030] Reaction Schemes 1a, 2a, 3a, 4a, and 5a shown below illustrate the compounds and methods of the invention described above for one preferred set of embodiments in which the pyrazole ring in the compound of formula (A) has the structure described above as A2. B2 , R B3 , Hal, and R 2 is as defined herein above. Reaction Scheme 1a [ka] Reaction Scheme 2a [ka] Reaction Scheme 3a [ka] Reaction Scheme 4a [ka] Reaction Scheme 5a [ka] Reaction Scheme 6a [ka]

[0031] Various aspects and embodiments of the invention will now be described in more detail by way of example, it being understood that modifications of detail can be made without departing from the scope of the invention.

[0032] For the avoidance of doubt, where any reference, patent application, or patent is cited within the text of this application, said cited documents are incorporated herein by reference in their entirety. EXAMPLES

[0033] Example 1: Preparation of the herbicidal compound (3S,4R)-N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide [ka] The nickel catalyst used in step 3 to catalyze the addition of asymmetric malonate esters to nitroolefins can be prepared as in J. Am. Chem. Soc. 2005, 127, 9958-9959.

[0034] Step 1: 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole In a 500 mL beaker, the compound 1-methyl-5-(trifluoromethyl)pyrazol-3-amine (5.00 g, 30.3 mmol) was stirred in 9 M sulfuric acid (818 mmol, 91 mL) using an overhead stirrer at 0° C. (ice bath) until a homogenous mixture was obtained. Sodium nitrite (60.6 mmol, 4.18 g) in 10 mL of water was then added dropwise over 5 minutes to give a colorless solution. The reaction was stirred at 0° C. for an additional 20 minutes. Potassium iodide (75.7 mmol, 12.6 g) in 20 mL of water was added dropwise to the reaction, after which the mixture was stirred for an additional 4 hours. The reaction was quenched with saturated sodium thiosulfate until the mixture was clear. The mixture was then diluted with dichloromethane and the phases were separated. The aqueous phase was further extracted with dichloromethane and the combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated under vacuum to give a pale yellow oil. The crude product was purified by column chromatography (eluting with a gradient of EtOAc / hexanes) to give 3.9 g (47%) of 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole as a colorless oil. 1 H NMR(400MHz, CDCl3)δ=6.76(s,1H)4.01(d,J=0.61Hz,3H).

[0035] Step 2: 1-Methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole Isopropylmagnesium chloride-lithium chloride in THF (23.55 mmol, 1.3 mol / L) was added dropwise to 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole (5.0 g, 18.12 mmol) in THF (90 mL) at -20°C and the mixture was stirred for 2 h. 1-Dimethylamino-2-nitroethylene (27.17 mmol, 3.321 g) was added and the reaction was allowed to warm slowly to room temperature over 1 h. The reaction mixture was then carefully quenched with 2 M HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography (eluting with a gradient of EtOAc / cyclohexane) to give 2.99 g (74.6%) of 1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole as a yellow oil. 1 H NMR(400MHz, CDCl3)δ=7.89(d,J=13.7Hz,1H),7.63(d,J=13.7Hz,1H),6.88(s,1H),4.05(d,J=0.6Hz,3H).

[0036] Step 3 Diethyl 2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate To a solution of 1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (0.650 g, 2.94 mmol) in toluene (19.5 mL) was added diethyl malonate (0.676 mL, 4.41 mmol) followed by nickel(II) bis[(1R,2R)-N1,N2-bis(phenylmethyl)-1,2-cyclohexanediamine-N1,N2]dibromide (0.0588 mmol, 0.0472 g) and the mixture was stirred at ambient temperature for 20 h.

[0037] The reaction mixture was washed with water (2×10 mL) and the organic phase was separated, concentrated and purified by chromatography (eluting with a gradient of EtOAc / cyclohexane) to give 1.07 g (95%) of diethyl 2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ=6.53(s,1H),5.01(dd,1H),4.88(dd,J=4.3,13.9Hz,1H),4.35(ddd,J=4.4,7.7,9.0 Hz,1H),4.22(q,2H),4.16(q,J=7.1Hz,2H),3.90(s,3H),3.89(d,1H),1.26(t,3H),1.20(t,J=7.2Hz,3H).

[0038] Step 4: Ethyl (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate A solution of diethyl 2-[(1R)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate (1.07 g, 2.81 mmol) in ethanol (42.1 mL) was cooled to 0-5 °C (ice bath) under nitrogen and dichloronickel hexahydrate (2.95 mmol, 0.700 g) was added. Sodium borohydride (8.42 mmol, 0.325 g) was then added portionwise to the pale greenish blue solution. After 30 min, the cooling was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring at ambient temperature for 5 h, the reaction mixture was cooled to 5-10 °C in an ice-water bath and slowly quenched with ammonium chloride solution and the mixture was stirred for an additional 20 min. The mixture was then diluted with EtOAc (20 mL) and filtered through a bed of Celite, rinsing with water and portions of EtOAc. The combined biphasic mixture was concentrated to remove most of the solvent, the residue was transferred to a separatory funnel, diluted with EtOAc (20 mL), and the organic phase was separated. The aqueous phase was further extracted with EtOAc (2×25 mL), and all organic extracts were combined, passed through a phase separator, concentrated, and purified by chromatography (eluting with a gradient of EtOAc / hexanes) to give 0.61 g (77%) of a pale yellow oil that crystallized on standing. 1H NMR (400MHz, CDCl3)δ=6.91(br s,1H),6.47(s,1H),4.28(q,J=7.2Hz,2H),4.14(q,1H),3.94(d,3H),3.80(dt,J=1.0, 9.0Hz,1H),3.63(d,J=9.3Hz,1H),3.52(dd,J=8.2,9.5Hz,1H),1.32(t,J=7.2Hz,3H).

[0039] Step 5: (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid To a solution of ethyl (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate (0.61 g, 2.0 mmol) in ethanol (6.0 mL) and water (2.0 mL) was added 2 M sodium hydroxide (3 mL, 6.0 mmol) at 0° C. (ice bath). The reaction mixture was stirred at 0° C. for 30 min, then diluted with water (15 mL) and extracted with EtOAc (25 mL). The organic extract was washed with water (10 mL) and the aqueous extracts were combined and acidified to pH 2 with dilute HCl. The acidified aqueous extract was then re-extracted with EtOAc (3×20 mL) and these organic extracts were passed through a phase separation cartridge and concentrated to give 0.54 g (quantitative) of a pale yellow oil that crystallized on standing. 1 H NMR(400MHz, CDCl3)δ=6.59(s,1H),4.09(q,1H),3.94(s,3H),3.85-3.77(m,1H),3.72(d,J=10.0Hz,1H),3.66-3.58(m,1H).

[0040] Step 6: (3R,4R)-1-Methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid To a stirred solution of (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid (0.57 g, 2.1 mmol, 0.57 g) in tetrahydrofuran (16 mL) at room temperature under nitrogen atmosphere was added potassium tertbutoxide (1.0 M in THF) (4.5 mL, 4.5 mmol) to give a pale yellow fine suspension. To this suspension was added iodomethane (0.19 mL, 3.1 mmol) and stirring was continued at room temperature for 20 h. The stirred reaction mixture was acidified to pH 2 with dilute HCl, the mixture was diluted with water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (15 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated to give 0.63 g (quantitative) of a clear amber gum. 1H NMR:(400MHz,CDCl3)δ=6.68(s,1H),3.97(q,1H),3.94(s,3H),3.76-3.68(m,3H),2.99(s,3H).

[0041] Step 7 (3S,4R)-N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide To a solution of (3R,4R)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid (0.61 g, 2.1 mmol) in dichloromethane (15 mL) was added 2,3-difluoroaniline (0.21 mL, 2.1 mmol). Propylphosphonic anhydride (50% by weight) in ethyl acetate (2.3 g, 3.6 mmol, 2.1 mL) was then added, after which the reaction mixture was immersed in a room temperature water bath. N,N-diisopropylethylamine (1.1 mL, 6.3 mmol) was added dropwise and the reaction was stirred at room temperature for 2.5 hours. The reaction mixture was quenched by the addition of water (15 mL) and transferred to a phase separation cartridge. The aqueous phase was further extracted with DCM (2×10 mL) and the combined organic extracts were concentrated and purified by chromatography (eluting with a gradient of EtOAc / hexanes) to give a pink oil. Trituration with isohexane gave 398 mg (47%) of a pale pink solid. 1H NMR:(400MHz,CDCl3)δ=10.16(br s,1H),8.08-8.01(m,1H),7.02(ddt,J=2.1,5.9,8.3Hz,1H),6.93-6.84(m,1H),6.69(s ,1H),4.09(q,1H),3.94(s,3H),3.78(d,J=9.5Hz,1H),3.76-3.65(m,2H),2.98(s,3H).

[0042] Chiral HPLC analysis by the method described above confirmed an enantiomeric ratio of 97:3.

[0043] Example 2 Preparation of (3S,4S)-N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxamide The herbicidal compound (3S,4S)-N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-oxo-pyrrolidine-3-carboxamide was prepared in direct analogy to that described above for (3S,4R)-N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide in Example 1 above. The NMR data for the single enantiomers are as follows: 1HNMR(CDCl3)δ=10.05(br s,1H),8.04-7.97(m,1H),7.46(s,1H),7.01(ddt,J=2.1,5.9,8.3Hz,1H),6.93-6.84(m,1H),4.21(q,J=8.8 Hz,1H),4.00(s,3H),3.75(t,J=9.5Hz,1H),3.64(d,J=9.4Hz,1H),3.27(dd,J=8.1,9.9Hz,1H),2.97(s,3H).

Claims

1. Compound of formula (B): 【Chemistry 1】 (Wherein, ring A is a ring nitrogen atom of R B2 and a ring carbon is R B3 and R is a disubstituted pyrazole substituted with B2 is C 1 ~C 3 Alkyl or C 1 ~C 3 fluoroalkyl, and each R B3 is halogen, C 1 ~C 3 Fluoroalkyl, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Fluoroalkyl, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkoxy or C 1 ~C 3 (alkyl).

2. Compound of formula (C): 【Chemistry 2】 (Wherein, ring A is R B2 , and R B3 is as defined in claim 1).

3. The compound according to claim 1 or 2, wherein ring A is A1, A2, A3, A4, or A5: 【Chemistry 3】 (In the formula, R B3SN is R B2 R located on the carbon atom immediately adjacent to the nitrogen atom substituted with B3 The substituents are shown in Figure 1, and the jagged line indicates the point of attachment to the nitrovinyl moiety.

4. R B2 The compound of any one of claims 1 to 3, wherein is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

5. R B3 is chloro, fluoro, bromo, methyl, ethyl, difluoromethyl, trifluoromethylC 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkoxy, and C 1 ~C 3 The compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of alkyl.

6. Compound of formula (D) 【Chemistry 4】 (Wherein, ring A is a ring nitrogen atom of R B2 and a ring carbon is R B3 and R is a disubstituted pyrazole substituted with B2 is C 1 ~C 3 Alkyl or C 1 ~C 3 fluoroalkyl, and each R B3 is halogen, C 1 ~C 3 Fluoroalkyl, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Fluoroalkyl, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkoxy or C 1 ~C 3 is alkyl) A process for the enantioselective preparation of (i) in a suitable solvent, 【Chemistry 5】 wherein Hal is a halogen selected from iodo, bromo, and chloro. is reacted with isopropylmagnesium chloride-lithium chloride, followed by addition of 1-dimethylamino-2-nitroethylene to give the compound of formula (B) 【Chemistry 6】 to obtain; (ii) reacting the compound of formula (B) from step (i) with a malonate ester under enantioselective nickel catalysis in a solvent to obtain a compound of formula (C) 【Chemistry 7】 to obtain; and (iii) reacting the compound of formula (C) from step 2 with a reducing agent in a solvent in the presence of a catalyst to obtain a compound of formula (D) 【Chemistry 8】 to get The method includes:

7. Compound of formula (E) 【Chemistry 9】 (Wherein, ring A is a ring nitrogen atom of R B2 and a ring carbon is R B3 and R is a disubstituted pyrazole substituted with B2 is C 1 ~C 3 Alkyl or C 1 ~C 3 fluoroalkyl, and each R B3 is halogen, C 1 ~C 3 Fluoroalkyl, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Fluoroalkyl, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 Alkoxy or C 1 ~C 3 is alkyl) A process for the enantioselective preparation of (i) in a suitable solvent, 【Chemistry 10】 wherein Hal is a halogen selected from iodo, bromo, and chloro. is reacted with isopropylmagnesium chloride-lithium chloride, followed by addition of 1-dimethylamino-2-nitroethylene to give the compound of formula (B) 【Chemistry 11】 to obtain; (ii) reacting the compound of formula (B) from step (i) with a malonate ester under enantioselective nickel catalysis in a solvent to obtain a compound of formula (C) 【Chemistry 12】 to obtain; (iii) reacting the compound of formula (C) from step 2 with a reducing agent in a solvent in the presence of a catalyst to obtain a compound of formula (D) 【Chemistry 13】 to obtain; and (iv) hydrolyzing the compound of formula (D) from step (iii) in an aqueous hydroxide / ethanol mixture to obtain the compound of formula (E) 【Chemistry 14】 to get The method includes: