Preparation method and intermediate of chiral pyrrole derivative

Abstract

The invention relates to a preparation method and an intermediate of a chiral pyrrole derivative.

Description

A preparation method of chiral pyrrole derivatives and intermediates thereof Technical Field

[0001] The present invention relates to a method for synthesizing chiral pyrrole derivatives. Background Art

[0002] Toll-like receptors (TLRs) are a class of molecular pattern recognition receptors that are widely distributed in different tissues. They monitor and recognize different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and play an important role in both innate and adaptive immunity.

[0003] TLRs belong to type I transmembrane proteins. So far, 13 TLR family members have been discovered, 10 of which exist in humans. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10 and TLR11 are located on the cell membrane and can recognize lipids, lipoproteins and other substances of microorganisms; while TLR3, TLR7, TLR8 and TLR9 are located in intracellular vesicle structures (such as lysosomes, endosomes and endoplasmic reticulum) and recognize the nucleic acids of microorganisms.

[0004] TLR7 and TLR8 are most similar in sequence and function. Numerous studies have shown that activation of TLR7 / 8 can trigger type I interferon responses and various inflammatory reactions. In autoimmune disorders such as systemic lupus erythematosus (SLE), abnormal and persistent activation of TLR7 / 8 leads to worsening of the disease state. Therefore, the development of compounds with selective and potent inhibitory activity to inhibit overactivated immune responses by antagonizing TLR7 / 8 is expected to become a new approach for treating autoimmune diseases.

[0005] Summary of the Invention

[0006] The present invention provides a preparation method of a chiral pyrrole derivative and an intermediate thereof. The chiral pyrrole derivative can be used for the synthesis of TLR inhibitors.

[0007] In one or more embodiments of the present invention, a method for preparing a compound represented by formula (I) or a stereoisomer thereof is provided, wherein:

[0008] A chiral amine is added to a reaction solvent to prepare a compound of formula (I); the reaction solvent is selected from one or more of the group consisting of ethyl acetate, methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, 1,2-dichloroethane, methyl tert-butyl ether, toluene, acetonitrile, tetrahydrofuran, and 1,4-dioxane, preferably ethyl acetate; the chiral amine is selected from (1R,2S)-(-)-2-amino-1,2-diphenylethanol, (R)-1-(1-naphthyl)ethanamine, (1S,2R)-(-)-1-amino-2-indanol, (R)-1-(1-naphthyl)ethanamine, (R)-1-(2-naphthyl)ethanamine, cinchonidine, or quinidine;

[0009] in:

[0010] R1 is selected from C 1-6 Alkyl or 3-10 membered cycloalkyl, the C 1-6 The alkyl or 3-10 membered cycloalkyl group is optionally further substituted by one or more halogens; preferably, R1 is CF3.

[0011] In one or more embodiments of the present invention, a method for preparing a compound of formula (Ia) or a stereoisomer is provided, wherein:

[0012] A strong base is added to the reaction solvent of the compound of formula (Ib), and the pH is adjusted using at least one selected from the group consisting of concentrated hydrochloric acid, tartaric acid, citric acid, potassium hydrogen sulfate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid and trifluoroacetic acid, preferably concentrated hydrochloric acid, to prepare a compound of formula (Ia); the reaction solvent is selected from a mixed solvent of THF / H2O / methanol; the strong base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium trimethylsilanol and potassium triethylsilanol, preferably lithium hydroxide (LiOH).

[0013] In one or more embodiments of the present invention, a method for preparing a pyrrole derivative represented by formula (I) or a stereoisomer thereof is provided, wherein:

[0014] The first step: Compounds of formula (I-d1) and (I-d2) are reacted in a solution containing one or more solvents selected from the group consisting of dichloromethane, chloroform, 1.2-dichloroethane, tetrahydrofuran and 1,4-dioxane, preferably a dichloromethane (DCM) solution, with trifluoroacetic acid, acetic acid or hydrochloric acid (preferably trifluoroacetic acid) to obtain a compound of formula (Ic).

[0015] Step 2: Adding a compound of formula (Ic) to a reaction system of a cyclopropanation reagent, a strong base, and a reaction solvent to prepare a compound of formula (Ib); the cyclopropanation reagent is selected from trimethylsulfoxide iodide or trimethylsulfide iodide; the strong base is selected from potassium tert-butoxide or sodium hydride; and the reaction solvent is selected from one or more of the group consisting of dimethylsulfoxide, tetrahydrofuran, and 1,4-dioxane, preferably dimethylsulfoxide (DMSO);

[0016] Step 3: Add a strong base to the reaction solvent of the compound of formula (Ib), and adjust the pH with one or more selected from the group consisting of concentrated hydrochloric acid, tartaric acid, citric acid, potassium hydrogen sulfate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid and trifluoroacetic acid, preferably concentrated hydrochloric acid, to prepare a compound of formula (Ia); the reaction solvent is selected from a mixed solvent of THF / H2O / methanol; the strong base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium trimethylsilanol and potassium triethylsilanol, preferably lithium hydroxide (LiOH);

[0017] Step 4: Adding a chiral amine to a reaction solvent to obtain a compound of formula (I); the reaction solvent is selected from one or more of the group consisting of ethyl acetate, methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, 1,2-dichloroethane, methyl tert-butyl ether, toluene, acetonitrile, tetrahydrofuran and 1,4-dioxane, preferably ethyl acetate; the chiral amine is selected from (1R,2S)-(-)-2-amino-1,2-diphenylethanol, (R)-1-(1-naphthyl)ethanamine, (1S,2R)-(-)-1-amino-2-indanol, (R)-1-(1-naphthyl)ethanamine, (R)-1-(2-naphthyl)ethanamine, cinchonidine or quinidine;

[0018] in:

[0019] R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

[0020] In one or more embodiments of the present invention, a method for preparing a pyrrole derivative represented by formula (Ih) or a stereoisomer thereof is provided, wherein:

[0021] Step 5: Adding an acyl chloride reagent to a reaction solvent to prepare compound (Ie); the reaction solvent is selected from one or more of the group consisting of dichloromethane, chloroform and 1,2-dichloroethane, preferably dichloromethane (DCM); the acyl chloride reagent is selected from thionyl chloride or oxalyl chloride;

[0022] Step 6: Adding a metal catalyst and a reducing agent to the compound (Ie) in a reaction solvent to react to obtain compound (If); the reaction solvent is selected from one or more of the group consisting of methanol, ethanol, and isopropanol, preferably methanol; the metal catalyst is selected from palladium carbon or palladium hydroxide; and the reducing agent is selected from hydrogen or ammonium formate;

[0023] Step 7: Add p-toluenesulfonyl chloride to the compound of formula (If) in a reaction solvent in the presence of an organic base to prepare compound (Ig); the organic base is selected from one or more of the group consisting of triethylamine, diisopropylethylamine, potassium carbonate and cesium carbonate, preferably triethylamine; the reaction solvent is selected from one or more of the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran and 1,4-dioxane, preferably dichloromethane (DCM);

[0024] Step 8: Add a strong base to the compound of formula (Ig) in a reaction solvent to react to obtain a compound of formula (Ih); the reaction solvent is selected from one or more of the group consisting of tetrahydrofuran / water, tetrahydrofuran, 1,4-dioxane, water, methanol, ethanol and isopropanol, preferably a mixed solvent of tetrahydrofuran / water (THF / H2O); the strong base is selected from one or more of the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium trimethylsilanol and potassium triethylsilanol, preferably lithium hydroxide (LiOH);

[0025] in:

[0026] R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

[0027] In one or more embodiments of the present invention, a method for preparing a compound represented by formula (I) or a stereoisomer thereof is provided, wherein:

[0028] A chiral amine is added to a reaction solvent to prepare a compound of formula (I); the reaction solvent is selected from ethyl acetate; the chiral amine is selected from (1R, 2S)-(-)-2-amino-1,2-diphenylethanol, (R)-1-(1-naphthyl)ethylamine, (1S, 2R)-(-)-1-amino-2-indanol, (R)-1-(1-naphthyl)ethylamine, (R)-1-(2-naphthyl)ethylamine, cinchonidine or quinidine;

[0029] in:

[0030] R1 is selected from C 1-6 Alkyl or 3-10 membered cycloalkyl, the C1-6 The alkyl or 3-10 membered cycloalkyl is optionally further substituted with one or more halogens; preferably, R1 is CF3.

[0031] In one or more embodiments of the present invention, a method for preparing a compound of formula (Ia) or a stereoisomer is provided, wherein:

[0032] A strong base is added to the reaction solvent of the compound of formula (Ib) for reaction, and the pH is adjusted with concentrated hydrochloric acid to prepare the compound of formula (Ia); the reaction solvent is selected from a mixed solvent of THF / H2O / methanol; and the strong base is selected from LiOH.

[0033] In one or more embodiments of the present invention, a method for preparing a pyrrole derivative represented by formula (I) or a stereoisomer thereof is provided, wherein:

[0034] Step 1: Add trifluoroacetic acid to a DCM solution of the compounds of formula (I-d1) and (I-d2) to react and obtain a compound of formula (Ic).

[0035] Step 2: Adding a compound of formula (Ic) to a reaction system of a cyclopropanation reagent, a strong base, and a reaction solvent to prepare a compound of formula (Ib); the cyclopropanation reagent is selected from trimethylsulfoxide iodide or trimethylsulfide iodide; the strong base is selected from potassium tert-butoxide or sodium hydride; and the reaction solvent is selected from DMSO;

[0036] Step 3: Add a strong base to the reaction solvent of the compound of formula (Ib) and adjust the pH with concentrated hydrochloric acid to prepare the compound of formula (Ia); the reaction solvent is selected from a mixed solvent of THF / H2O / methanol; the strong base is selected from LiOH;

[0037] Step 4: Adding a chiral amine to a reaction solvent to obtain a compound of formula (I); the reaction solvent is selected from ethyl acetate; the chiral amine is selected from (1R, 2S)-(-)-2-amino-1,2-diphenylethanol, (R)-1-(1-naphthyl)ethylamine, (1S, 2R)-(-)-1-amino-2-indanol, (R)-1-(1-naphthyl)ethylamine, (R)-1-(2-naphthyl)ethylamine, cinchonidine or quinidine;

[0038] in:

[0039] R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

[0040] In one or more embodiments of the present invention, a method for preparing a pyrrole derivative represented by formula (Ih) or a stereoisomer thereof is provided, wherein:

[0041] Step 5: Add an acyl chloride reagent to the reaction solvent of formula (I) to prepare compound (Ie); the reaction solvent is selected from DCM; the acyl chloride reagent is selected from thionyl chloride or oxalyl chloride;

[0042] Step 6: Adding a metal catalyst and a reducing agent to the compound (Ie) in a reaction solvent to react to obtain compound (If); the reaction solvent is selected from methanol; the metal catalyst is selected from palladium carbon or palladium hydroxide; and the reducing agent is selected from hydrogen or ammonium formate;

[0043] Step 7: Add p-toluenesulfonyl chloride to the compound (If) in a reaction solvent in the presence of an organic base to prepare compound (Ig); the organic base is selected from triethylamine; the reaction solvent is selected from DCM;

[0044] Step 8: Add a strong base to the compound of formula (Ig) in a reaction solvent to react and obtain a compound of formula (Ih); the reaction solvent is selected from a mixed solvent of THF / H2O; and the strong base is selected from LiOH;

[0045] in:

[0046] R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

[0047] In one or more embodiments of the present invention, an intermediate for preparing a compound of formula (I) or formula (Ih) or a stereoisomer thereof is provided, wherein the intermediate is selected from:

[0048] wherein R1 is as defined above,

[0049] Provided that the intermediate is not

[0050] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0051] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0052] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group.

[0053] Base refers to a compound that ionizes OH- in aqueous solution; or a compound that can accept protons; the strong base described in the present invention includes cesium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, lithium hydroxide, etc.

[0054] The organic bases described in the present invention refer to compounds containing nitrogen atoms, such as amine compounds and nitrogen-containing heterocyclic compounds. Non-limiting examples include sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, phenyllithium, Grignard reagents, quaternary ammonium hydroxides, pyridine, and lithium amide compounds (such as lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS)). Organic bases selected in the present invention include sodium tert-butoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, and sodium tert-amyloxide. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG1 shows the X-ray single crystal diffraction pattern of compound 2. DETAILED DESCRIPTION

[0056] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0057] DMSO: dimethyl sulfoxide;

[0058] DCM: dichloromethane;

[0059] THF: tetrahydrofuran.

[0060] Example

[0061] Example 1

[0062] (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 1

[0063] (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0064] first step:

[0065] 1-Benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester 1c

[0066] ethyl 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate

[0067] Compound 4,4,4-trifluoro-2-butynoic acid ethyl ester 1d-1 (200 g, 1.2 mol) was added to a clean three-necked flask, mixed with dichloromethane (2 L), and then trifluoroacetic acid (1.36 g, 12 mmol) was added. Compound N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine 1d-2 (284 g, 1.2 mol) was mixed with dichloromethane (400 ml) and added dropwise to the above solution at room temperature (about 2 h to complete the addition). After the addition was completed, the reaction was continued at room temperature for 1 h. After the reaction was complete as monitored by LC-MS, water (2 L) was added to the reaction system, stirred and mixed, allowed to stand for stratification, and separated using a separatory funnel. The organic phase was collected, and the aqueous phase was extracted with dichloromethane (1 L). The organic phases were combined, dried, and concentrated under reduced pressure to obtain compound 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester 3 (crude product 361 g, yellow liquid).

[0068] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.24(m,5H),4.19(q,2H),3.79-3.78(m,6H),1.20(t,3H).

[0069] LC-MS m / z(ESI)=300.1[M+1].

[0070] Step 2:

[0071] 3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 1b

[0072] ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0073] The compound trimethylsulfoxide iodide (264 g, 1.2 mol) was added to a clean three-necked flask, mixed with DMSO (1.5 L), replaced with nitrogen three times, and potassium tert-butoxide (142 g, 1.26 mol) was added at room temperature, and stirring was continued for 30 min. The compound 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester 1c (361 g, 1.2 mol) was mixed with DMSO (500 ml) and added dropwise to the above solution (about 1 h). After the addition was completed, the reaction was continued for 1 h. After the reaction was complete as monitored by LC-MS, saturated ammonium chloride solution (500 ml) was added to the reaction system and stirred for 10 min. Water (500 ml) and ethyl acetate (2 L) were then added, stirred and mixed, and the mixture was allowed to stand for stratification. The mixture was separated using a separatory funnel, the aqueous phase was removed, and the organic phase was washed twice with water (1 L * 2); the aqueous phases were combined, and then back-extracted once with ethyl acetate (1 L). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 1b (crude product 347 g, brown liquid).

[0074] 1 H NMR(400MHz,DMSO-d6)δ7.34-7.24(m,5H),4.11(q,2H),3.66(s,2H), 3.08-3.01(m,2H),2.86-2.82(m,1H),2.65-2.62(m,1H),1.82-1.79(m,2H),1.15(t,3H).

[0075] LC-MS m / z(ESI)=314.1[M+1].

[0076] Step 3:

[0077] 3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 1a

[0078] 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0079] Compound 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 1b (347 g, 1.1 mol) was mixed with tetrahydrofuran (600 ml), water (600 ml), and methanol (60 ml). Lithium hydroxide monohydrate (185 g, 4.4 mol) was then added and the mixture was allowed to react at 60°C for 1 h. After completion of the reaction as monitored by LC-MS, the mixture was cooled to room temperature, the organic solvent was removed under reduced pressure, and the aqueous phase was extracted with dichloromethane (1 L). The organic phase was back-extracted once with water (500 ml). The combined aqueous phases were adjusted to pH 3-4 with concentrated hydrochloric acid, and then the aqueous phases were extracted with ethyl acetate (1 L x 6). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield compound 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 1a (crude product, 245 g, brown liquid).

[0080] LC-MS m / z (ESI) = 286.10 [M+1].

[0081] Step 4:

[0082] (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 1

[0083] (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0084] 3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 1a (24.0 g, 0.084 mol) was added to the reaction flask and dissolved with ethyl acetate (500 mL). (1R, 2S)-(-)-2-amino-1,2-diphenylethanol (18.0 g, 0.084 mol) was added at room temperature and stirred for 10 min. A large amount of white solid precipitated. The mixture was heated to reflux and ethyl acetate (600 mL) was added. ) until the solution is completely clear, and then cooled to room temperature naturally. Solid precipitates and is filtered to obtain 19 g of a white solid. The obtained solid is then dissolved in ethyl acetate, and 2N hydrochloric acid is added to adjust the pH to 3-4. The organic phase is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-aza-azacyclo[3.1.0]hexane-1-carboxylic acid compound 1 (10.8 g, white solid, 45% yield, 96% ee). Analysis method: The ee value is obtained by chiral HPLC analysis. The chiral column is AD, the mobile phase is V n-hexane / V methanol = 95 / 5, the flow rate is 1 mL / min, and the retention time is t minor =2.032min, t major=2.607min

[0085] LC-MS m / z (ESI) = 286.10 [M+1].

[0086] The resolution results of other chiral amines are shown in Table 1.

[0087] Table 1 Resolution results of other chiral amines

[0088] Example 2

[0089] (1S,5R)-3-methanesulfonyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 2

[0090] (1S,5R)-3-tosyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0091] first step:

[0092] (1S,5R)-3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 2a

[0093] (1S,5R)-ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0094] (1S,5R)-3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 1 (350 mg, 1.23 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of thionyl chloride (5 mL). The mixture was stirred under heating and reflux for 30 min, and the solvent was then concentrated. Ethanol (10 mL) was added, and the reaction solution was extracted with ethyl acetate, washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by silica gel column chromatography to obtain the target (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 2a (colorless oily liquid, 300 mg, yield: 78%).

[0095] LC-MS m / z (ESI) = 314.13 [M+1].

[0096] Step 2:

[0097] (1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 2b

[0098] Ethyl-(1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0099] Dissolve (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 2a (300 mg, 0.96 mmol) in 5 mL of methanol, add palladium carbon (30 mg, 0.19 mmol) and ammonium formate (241.5 mg, 3.83 mmol) in sequence, and heat under reflux for 6 h. After the reaction is completed, monitor the reaction by TLC. Concentrate the reaction solution to obtain the target (1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 2b, which is used directly in the next step.

[0100] LC-MS m / z (ESI) = 224.08 [M+1].

[0101] Step 3:

[0102] (1S,5R)-3-Trimethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester 2c

[0103] Ethyl-(1S,5R)-3-tosyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 9

[0104] Ethyl (1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 2b was dissolved in dichloromethane (20 mL), and triethylamine (0.4 mL, 2.88 mmol) and p-toluenesulfonyl chloride (273.6 mg, 1.44 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain ethyl (1S,5R)-3-trimethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 2c (colorless oil, 258 mg, two-step yield: 72%).

[0105] LC-MS m / z (ESI) = 378.09 [M+1].

[0106] Step 4:

[0107] (1S,5R)-3-methanesulfonyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 2

[0108] (1S,5R)-3-tosyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0109] Ethyl (1S,5R)-3-trimethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 2c (258 mg, 0.69 mmol) was dissolved in tetrahydrofuran (10 mL). An aqueous solution of anhydrous lithium hydroxide (165 mg, 6.9 mmol) (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. After the reaction, the tetrahydrofuran was dried and extracted with ethyl acetate. The aqueous phase was retained and the pH was adjusted to 3-4 with 2M hydrochloric acid. The phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purification by silica gel column chromatography afforded (1S,5R)-3-methylsulfonyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 2 (white solid, 158 mg, yield: 66%).

[0110] LC-MS m / z (ESI) = 350.06 [M+1].

[0111] 1 H NMR (400MHz, DMSO) δ = 13.34 (s, 1H), 7.74 (d, 2H), 7.50 (d, 2H), 3.73 (d, 1H), 3 .66(d,1H),3.39(d,1H),3.24(d,1H),2.43(s,3H),1.93(d,1H),1.32(d,1H).

[0112] Determination of the absolute configuration of compound 2

[0113] Compound 2 (100 mg) was dissolved in 6 mL of solvent (petroleum ether:ethyl acetate = 5:1) and allowed to evaporate naturally at room temperature until a single crystal was grown. The absolute configuration was determined using a Rigaku Xtalab Synergy single crystal diffractometer. The single crystal data are shown in Table 2:

[0114] Table 2 Single crystal data of compound 2

[0115] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a compound represented by formula (I) or a stereoisomer thereof, characterized in that: A chiral amine is added to a reaction solvent to prepare a compound of formula (I); the reaction solvent is selected from one or more of the group consisting of ethyl acetate, methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, 1,2-dichloroethane, methyl tert-butyl ether, toluene, acetonitrile, tetrahydrofuran, and 1,4-dioxane, preferably ethyl acetate; the chiral amine is selected from (1R,2S)-(-)-2-amino-1,2-diphenylethanol, (R)-1-(1-naphthyl)ethanamine, (1S,2R)-(-)-1-amino-2-indanol, (R)-1-(1-naphthyl)ethanamine, (R)-1-(2-naphthyl)ethanamine, cinchonidine, or quinidine; in: R1 is selected from C 1-6 Alkyl or 3-10 membered cycloalkyl, the C 1-6 The alkyl or 3-10 membered cycloalkyl group is optionally further substituted by one or more halogens; preferably, R1 is CF3.

2. A method for preparing a compound represented by formula (I) or a stereoisomer thereof, characterized in that: A chiral amine is added to a reaction solvent to prepare a compound of formula (I); the reaction solvent is selected from ethyl acetate; the chiral amine is selected from (1R, 2S)-(-)-2-amino-1,2-diphenylethanol, (R)-1-(1-naphthyl)ethylamine, (1S, 2R)-(-)-1-amino-2-indanol, (R)-1-(1-naphthyl)ethylamine, (R)-1-(2-naphthyl)ethylamine, cinchonidine or quinidine; in: R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

3. The method for preparing the compound of formula (Ia) or its stereoisomer according to claim 1, characterized in that: In the reaction solvent of the compound of formula (Ib), a strong base is added to react, using a mixture selected from concentrated hydrochloric acid, tartaric acid, citric acid, The compound of formula (Ia) is prepared by adjusting the pH with one or more of the group consisting of potassium hydrogen sulfate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid and trifluoroacetic acid, preferably concentrated hydrochloric acid; the reaction solvent is selected from a mixed solvent of THF / H2O / methanol; the strong base is selected from one or more of the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium trimethylsilanol and potassium triethylsilanol, preferably lithium hydroxide (LiOH).

4. The method for preparing the compound of formula (Ia) or its stereoisomer according to claim 2, wherein: A strong base is added to the reaction solvent of the compound of formula (Ib) for reaction, and the pH is adjusted with concentrated hydrochloric acid to prepare the compound of formula (Ia); the reaction solvent is selected from a mixed solvent of THF / H2O / methanol; and the strong base is selected from LiOH.

5. A method for preparing a pyrrole derivative represented by formula (I) or a stereoisomer thereof, characterized in that: Step 1: Compounds of formula (I-d1) and (I-d2) are reacted in a solution comprising one or more solvents selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, and 1,4-dioxane, preferably a dichloromethane (DCM) solution, with trifluoroacetic acid, acetic acid, or hydrochloric acid, preferably trifluoroacetic acid, to obtain a compound of formula (Ic); Step 2: Adding a compound of formula (Ic) to a reaction system of a cyclopropanation reagent, a strong base, and a reaction solvent to prepare a compound of formula (Ib); the cyclopropanation reagent is selected from trimethylsulfoxide iodide or trimethylsulfide iodide; the strong base is selected from potassium tert-butoxide or sodium hydride; and the reaction solvent is selected from one or more of the group consisting of dimethylsulfoxide, tetrahydrofuran, and 1,4-dioxane, preferably dimethylsulfoxide (DMSO); Step 3: Add a strong base to the reaction solvent of the compound of formula (Ib), and adjust the pH with one or more selected from the group consisting of concentrated hydrochloric acid, tartaric acid, citric acid, potassium hydrogen sulfate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid and trifluoroacetic acid, preferably concentrated hydrochloric acid, to prepare a compound of formula (Ia); the reaction solvent is selected from a mixed solvent of THF / H2O / methanol; the strong base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium trimethylsilanol and potassium triethylsilanol, preferably lithium hydroxide (LiOH); Step 4: Adding a chiral amine to a reaction solvent to obtain a compound of formula (I); the reaction solvent is selected from one or more of the group consisting of ethyl acetate, methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, 1,2-dichloroethane, methyl tert-butyl ether, toluene, acetonitrile, tetrahydrofuran and 1,4-dioxane, preferably ethyl acetate; the chiral amine is selected from (1R,2S)-(-)-2-amino-1,2-diphenylethanol, (R)-1-(1-naphthyl)ethanamine, (1S,2R)-(-)-1-amino-2-indanol, (R)-1-(1-naphthyl)ethanamine, (R)-1-(2-naphthyl)ethanamine, cinchonidine or quinidine; in: R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

6. A method for preparing a pyrrole derivative represented by formula (I) or a stereoisomer thereof, characterized in that: Step 1: Compounds of formula (I-d1) and (I-d2) are reacted in a DCM solution with trifluoroacetic acid to obtain a compound of formula (Ic); Step 2: Adding a compound of formula (Ic) to a reaction system of a cyclopropanation reagent, a strong base, and a reaction solvent to prepare a compound of formula (Ib); the cyclopropanation reagent is selected from trimethylsulfoxide iodide or trimethylsulfide iodide; the strong base is selected from potassium tert-butoxide or sodium hydride; and the reaction solvent is selected from DMSO; Step 3: Add a strong base to the reaction solvent of the compound of formula (Ib) and adjust the pH with concentrated hydrochloric acid to prepare the compound of formula (Ia); the reaction solvent is selected from a mixed solvent of THF / H2O / methanol; the strong base is selected from LiOH; Step 4: Adding a chiral amine to a reaction solvent to obtain a compound of formula (I); the reaction solvent is selected from ethyl acetate; the chiral amine is selected from (1R, 2S)-(-)-2-amino-1,2-diphenylethanol, (R)-1-(1-naphthyl)ethylamine, (1S, 2R)-(-)-1-amino-2-indanol, (R)-1-(1-naphthyl)ethylamine, (R)-1-(2-naphthyl)ethylamine, cinchonidine or quinidine; in: R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

7. A method for preparing a pyrrole derivative represented by formula (Ih) or a stereoisomer thereof, characterized in that: Step 5: Adding an acyl chloride reagent to a reaction solvent to prepare compound (Ie); the reaction solvent is selected from one or more of the group consisting of dichloromethane, chloroform and 1,2-dichloroethane, preferably dichloromethane (DCM); the acyl chloride reagent is selected from thionyl chloride or oxalyl chloride; Step 6: Adding a metal catalyst and a reducing agent to the compound (Ie) in a reaction solvent to react to obtain compound (If); the reaction solvent is selected from one or more of the group consisting of methanol, ethanol, and isopropanol, preferably methanol; the metal catalyst is selected from palladium carbon or palladium hydroxide; and the reducing agent is selected from hydrogen or ammonium formate; Step 7: Add p-toluenesulfonyl chloride to the compound of formula (If) in a reaction solvent in the presence of an organic base to prepare compound (Ig); the organic base is selected from one or more of the group consisting of triethylamine, diisopropylethylamine, potassium carbonate and cesium carbonate, preferably triethylamine; the reaction solvent is selected from one or more of the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran and 1,4-dioxane, preferably dichloromethane (DCM); Step 8: Add a strong base to the compound of formula (Ig) in a reaction solvent to react to obtain a compound of formula (Ih); the reaction solvent is selected from one or more of the group consisting of tetrahydrofuran / water, tetrahydrofuran, 1,4-dioxane, water, methanol, ethanol and isopropanol, preferably a mixed solvent of tetrahydrofuran / water (THF / H2O); the strong base is selected from one or more of the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium trimethylsilanol and potassium triethylsilanol, preferably lithium hydroxide (LiOH); in: R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

8. A method for preparing a pyrrole derivative represented by formula (Ih) or a stereoisomer thereof, characterized in that: Step 5: Add an acyl chloride reagent to the reaction solvent of formula (I) to prepare compound (Ie); the reaction solvent is selected from DCM; the acyl chloride reagent is selected from thionyl chloride or oxalyl chloride; Step 6: Adding a metal catalyst and a reducing agent to the compound (Ie) in a reaction solvent to react to obtain compound (If); the reaction solvent is selected from methanol; the metal catalyst is selected from palladium carbon or palladium hydroxide; and the reducing agent is selected from hydrogen or ammonium formate; Step 7: Add p-toluenesulfonyl chloride to the compound (If) in a reaction solvent in the presence of an organic base to prepare compound (Ig); the organic base is selected from triethylamine; the reaction solvent is selected from DCM; Step 8: Add a strong base to the compound of formula (Ig) in a reaction solvent to react and obtain a compound of formula (Ih); the reaction solvent is selected from a mixed solvent of THF / H2O; the strong base is selected from LiOH; in: R1 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with one or more halogens; preferably, R1 is CF3.

9. An intermediate for preparing a compound of formula (I) or formula (Ih) according to any one of claims 1 to 8, or a stereoisomer thereof, wherein the intermediate is selected from: wherein R1 is as defined in any one of claims 1 to 8, Provided that the intermediate is not

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