Phenol derivatives and their use in medicine

Abstract

This invention provides a novel GABA structure with better efficacy, reduced side effects, and greater safety for clinical use. A This invention relates to receptor agonists, specifically a phenol derivative, its preparation method, and its use in the central nervous system. The phenol derivative provided by this invention offers more and better drug options for inducing or maintaining anesthesia in animals or humans, promoting sedation and hypnosis, and treating and / or preventing anxiety, nausea, vomiting, migraines, seizures, epilepsy, neurodegenerative diseases, and other central nervous system-related disorders.

Description

Phenol derivatives and their applications in medicine Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to a phenol derivative, its stereoisomers, pharmaceutically acceptable salts, and the use of the compounds of this invention in the preparation of central nervous system drugs. Background Technology

[0002] GABA A GABA receptors are the main inhibitory neurotransmitter receptors in the central nervous system. They are composed of pentamers of transmembrane polypeptide subunits, with 19 different subunits forming various GABA groups. A Receptor subtype. GABA A GABA receptors are involved in the pathogenesis, diagnosis, and treatment of various diseases, including anesthesia, depression, anxiety, epilepsy, memory impairment, and drug dependence. Therefore, GABA... A Receptors are important drug targets in pharmacology and clinical practice. Propofol and its derivatives are an important class of GABA-based receptors. A Compounds that are targets.

[0003] Propofol can activate various GABAs A Propofol, a receptor subtype, is widely used for the induction and maintenance of general anesthesia. Its significant pharmacokinetic and pharmacodynamic properties include rapid onset of action, short duration of action, and rapid reversibility. After intravenous administration, propofol rapidly enters hyperperfusion areas such as the heart, lungs, and liver from the bloodstream. Its high lipid solubility allows propofol to easily cross the blood-brain barrier and enter the brain to exert its general anesthetic effect.

[0004] As the clinical application of propofol has deepened, numerous limitations and drawbacks have been reported. It has been reported that approximately 70% of patients experience some degree of pain or discomfort when receiving propofol injections. Propofol has been shown to lower systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure, thus clinically causing hypotension. Simultaneously, respiratory depression is another significant risk that cannot be ignored when using propofol. These adverse reactions have largely hindered the application of propofol in certain clinical cases, such as cardiovascular disease, brain injury, and chronic hypotension.

[0005] Sodium fospropofol is a water-soluble prodrug of propofol. It is rapidly hydrolyzed by alkaline phosphatase, releasing propofol, phosphate, and formaldehyde. Although sodium fospropofol relieves pain at the intravenous injection site of propofol, it still carries the risk of respiratory depression and adverse hemodynamic effects because it acts as the original form of propofol. Sodium fospropofol can also cause paresthesia and itching.

[0006] To address the limitations and drawbacks of propofol and fospropofol, there is a need to develop new GABA derivatives with better pharmacokinetic and pharmacodynamic properties and fewer side effects. AReceptor agonists.

[0007] US patent 20050032753A1 describes phenol derivatives for anesthesia and sedation, wherein R 1 and R 2 Independently selected from C 1-8 Alkyl, C 1-8 cycloalkyl, where L is selected from covalent bonds, C 1-12 R-alkylene group 3 Selected from -C(=O)ORa; where Ra is selected from C 1-12 Hydroxyl group;

[0008]

[0009] Patent CN104507899A discloses a phenol derivative and its preparation method, as well as its use in the central nervous system field, and discloses the following general formula. The compound structure of this patent is significantly different from that of the present invention, and the specific description in this patent is not considered part of the present invention.

[0010]

[0011] Patent CN104507898A discloses a phenol derivative and its preparation method, as well as its use in the central nervous system field, and discloses the following general formula. The compound structure of this patent is significantly different from that of the present invention, and the specific description in this patent is not considered part of the present invention.

[0012] Summary of the Invention

[0013] The purpose of this invention is to provide a GABA with a novel structure, better efficacy, reduced side effects, and greater safety for clinical use. A The use of receptor agonist phenol derivatives, and all their stereoisomers, in the central nervous system, to provide more and better drug options for inducing or maintaining anesthesia in animals or humans, promoting sedation and hypnosis, and treating and preventing anxiety, nausea, vomiting, migraine, seizures, epilepsy, neurodegenerative diseases, and other central nervous system-related diseases.

[0014] This invention provides a compound of general formula (I) or a chiral isomer thereof, and a pharmaceutically acceptable salt thereof:

[0015]

[0016] in:

[0017] R1 is selected from C 1-6Alkyl groups, 3 to 6-membered cycloalkyl groups; wherein the alkyl or cycloalkyl groups may optionally be further substituted with R;

[0018] R2 and R3 are independently selected from H, hydroxyl group, F, and C. 1-6 Alkyl, C 1-6 Alkoxy, CN, NH2, 3 to 6 membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be further substituted with R, or R2 and R3 may form (=O);

[0019] R4 is selected from H, F, Cl, Br, I, hydroxyl group, C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 5-membered cycloalkyl, or 3- to 5-membered heterocyclic group;

[0020] Alternatively, R1, together with R4 and the atoms they are attached to, can form a 4- to 6-membered cycloalkyl or heterocyclic group fused with the benzene ring, wherein the cycloalkyl or heterocyclic group may optionally be further substituted with R;

[0021] R5 is selected from C 1-6 Alkyl, 3- to 6-membered cycloalkyl, wherein the alkyl or cycloalkyl may optionally be further substituted with R;

[0022] R6 is selected from C 1-6 Alkoxy, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkoxy, OCD3, OH, ONa, OK, NR7Ra, wherein the alkoxy, cycloalkyl, or cycloalkoxy may optionally be further substituted with R;

[0023] The R7, R a Independently selected from H, C 1-6 alkyl, C 1-6 Alkoxy, 3 to 6-membered cycloalkyl, wherein the alkyl or cycloalkyl group may optionally be further substituted with R;

[0024] Or R7 and R a Together with the N linked to it, it forms a 3- to 6-membered heterocyclic group;

[0025] Y is selected from H, Na, K, -(CH2) m COOR 12 , C 1-10 Alkyl groups, wherein the alkyl groups may optionally be further substituted with R;

[0026] Alternatively, Y and R6, together with the atoms they are attached to, can form a 6- to 8-membered ring fused with the benzene ring;

[0027] R8 and R9 are each independently selected from H and C. 1-6 Alkyl, C 1-6Alkoxy, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl;

[0028] Alternatively, R8 and R9 together with the atoms they are attached to form a 5- to 8-membered ring, which may contain 0 to 4 heteroatoms selected from N, O, and S.

[0029] R 10 and R 11 Each is independently selected from H and C 1-6 Alkyl groups, alkali metal ions, alkaline earth metal ions, protonated amines or protonated amino acids, wherein the alkali metal ions are selected from Na+. + K + Li + The alkaline earth metal ions mentioned are selected from Be. 2+ Mg 2+ Or Ca 2+ The amine is selected from tromethamine, triethanolamine, ethanolamine, triethylamine, or N-methylglucosamine, and the amino acid is selected from arginine or lysine.

[0030] R 12 Independently selected from H and C 1-6 Alkyl, 3- to 8-membered cycloalkyl or 4- to 8-membered heterocyclic group, wherein the alkyl, cycloalkyl or heteroalkyl group may optionally be further substituted with R;

[0031] The R is selected from F, Cl, Br, I, deuterium, hydroxyl, carbonyl, CN, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 5-membered cycloalkyl, or 3- to 5-membered heterocyclic group;

[0032] n is selected from 0, 1, 2, and 3;

[0033] m is selected from 0, 1, 2, 3, 4.

[0034] In some embodiments, the present invention provides a compound of general formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0035]

[0036] Where: L represents 1, 2, or 3; Y is selected from H.

[0037] In some preferred embodiments, L is 1 or 2;

[0038] R2 and R3 are independently selected from H and C. 1-3 alkyl, C 1-3 Alkoxy, CN;

[0039] R5 is selected from methyl or cyclopropyl;

[0040] R6 is selected from C. 1-6 Alkyl groups, OCD3, ONa, OK, NR7R a .

[0041] In some embodiments, R6 is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkoxy, OCD3, ONa, OK, NR7R. a The cycloalkyl and cycloalkoxy groups may optionally be further substituted with R;

[0042] The R7, R a Independently selected from H, C 1-6 alkyl, C 1-6 Alkoxy, 3 to 6-membered cycloalkyl, wherein the alkyl or cycloalkyl group may optionally be further substituted with R;

[0043] Or R7 and R a Together with the N linked to it, it forms a 3- to 6-membered heterocyclic group.

[0044] In some preferred embodiments, R6 is selected from NR7R. a ;

[0045] The R7, R a Independently selected from H, C 1-6 alkyl, C 1-6 Alkoxy, 3 to 6-membered cycloalkyl, wherein the alkyl or cycloalkyl group may optionally be further substituted with R;

[0046] Or R7 and R a Together with the N linked to it, it forms a 3- to 6-membered heterocyclic group.

[0047] In some preferred embodiments, the present invention provides a compound of formula (IV), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0048]

[0049] Another aspect of this invention provides a compound of general formula (III) or a chiral isomer thereof, or a pharmaceutically acceptable salt thereof:

[0050]

[0051] in:

[0052] W is selected from 5- to 6-membered cycloalkyl or 5- to 6-membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be further substituted by R;

[0053] R b Selected from C 1-6Alkyl, 3 to 6-membered cycloalkyl, F, wherein the alkyl or cycloalkyl may optionally be further substituted with R;

[0054] R c Selected from C 1-6 alkoxy, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkoxy, OCD3, NR d Re, F, the alkyl, alkoxy, cycloalkyl, cycloalkoxy groups may optionally be further substituted with R;

[0055] The R d R e Independently selected from H, C 1-6 alkyl, C 1-6 Alkoxy, 3 to 6-membered cycloalkyl, wherein the alkyl or cycloalkyl group may optionally be further substituted with R;

[0056] Or R d and R e Together with the N linked to it, it forms a 3- to 6-membered heterocyclic group;

[0057] Y and R are as defined in general formula (Ⅰ).

[0058] The preferred embodiments of the present invention, wherein the compounds of the present invention are selected from, but not limited to:

[0059]

[0060]

[0061] The preferred embodiments of the present invention, wherein the compounds of the present invention are selected from, but not limited to:

[0062]

[0063] The present invention provides a pharmaceutical composition comprising the compound described herein or its stereoisomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0064] The pharmaceutical compositions involved in this invention are any pharmaceutically acceptable dosage form, such as tablets, capsules, dispersible tablets, granules, injections, lipid emulsions, aerosols, powder inhalers, sprays, oral solutions, oral suspensions, etc.

[0065] The present invention also provides the use of the compounds described herein, or their stereoisomers, or pharmaceutically acceptable salts, in the preparation of drugs for inducing and maintaining anesthesia in animals or humans, promoting sedation and hypnosis in animals or humans, and treating and preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.

[0066] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0067] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, etc.

[0068] "Alkoxy" refers to -O-alkyl. Examples include methoxy, ethoxy, n-propoxy, and isopropoxy.

[0069] "Cycloalkoxy" refers to the aforementioned cycloalkyl group formed by the bonding of oxygen atoms. Examples of 3- to 6-membered cycloalkoxy groups include cyclopropyloxy and cyclohexyloxy.

[0070] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 (e.g., 3, 4, 5, or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0071] "Heterocyclic group" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (Where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include azirmonobutyl, pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0072] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, corresponding isomers, and conformational isomers.

[0073] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "selectively alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0074] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help those skilled in the art better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0075] Example 1 Synthesis of methyl 3-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)butyrate (1)

[0076]

[0077] (1) Intermediate 1-2: Synthesis of (E)-(but-2-en-1-propoxy)benzene:

[0078] Compound 1-1 (2 g, 21.3 mmol, 1 eq) was dissolved in anhydrous DMF (30 mL). Sodium hydroxide (1.7 g, 42.54 mmol, 2 eq) was added under nitrogen protection. The reaction mixture was stirred at 25 °C for 30 minutes. Subsequently, a mixture of cis and trans-chloro-2-butene (2.3 g, 25.6 mmol, 1.2 eq) was slowly added at 0 °C. After the addition was complete, the reaction mixture was continued to react at 25 °C for 2 hours. TLC (V1) was performed. hexane V EA =1:0) The reaction ended after the raw materials were completely consumed. The reaction solution was slowly added dropwise to ice water (100 mL). The aqueous phase became turbid. After the addition was completed, it was diluted with n-hexane (100 mL), stirred evenly, and extracted three times with n-hexane (100 mL * 3). The organic phases were combined, washed with saturated brine (100 mL), separated, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a colorless oily mixture of cis and trans 1-2 (2.5 g, yield: 79.2%).

[0079] 1HNMR (400MHz, CDCl3) δ7.32-7.26(m,2H), 6.96-6.91(m,3H), 5.91-5.70(m,2H), 4.60-4.45(m,2H); 1.77-1.72(m,3H).

[0080] (2) Synthesis of intermediate 1-3: 2-(but-3-en-2-yl)phenol:

[0081] The cis-trans mixture 1-2 (12.5 g, 84.4 mmol) was purged 3-5 times under nitrogen protection, and the reaction solution was heated to 210 °C and reacted for 4-5 hours. TLC (V hexane V EA =10:1) Once most of the raw materials have been consumed, stop the reaction and allow the reaction solution to cool naturally to room temperature. Dilute the reaction solution with n-hexane, concentrate it, and purify the crude product by column chromatography using eluent polarity V. 正己烷 V 乙酸乙酯 The ratio of 20:1 to 15:1 yielded target compounds 1-3 as yellow oils (2.34 g, yield: 18.4%).

[0082] 1 HNMR (400MHz, CDCl3), δ7.18-7.13(m,2H),6.84-6.82(m,2H),6.16-6.07(m,1 H),5.24-5.18(m,2H),5.13(s,1H),3.75-3.72(m,1H),1.44(d,J=8.0Hz,3H).

[0083] (3) Synthesis of intermediate 1-4: 2-(1-cyclopropylethyl)phenol:

[0084] Under nitrogen protection, the 100 mL three-necked flask was purged 3-5 times, and DCM (40 mL) was added. The reaction system was cooled to -5 to 0 °C, and diethylzinc (46.5 mL, 1.0 M, 46.5 mmol, 3 eq.) was slowly added dropwise over approximately 10 minutes. Then, trifluoroacetic acid (5.3 g, 46.5 mmol, 3 eq.) was added in an ice-cold ethanol bath. After approximately 5 minutes, diiodomethane (16.6 g, 62.0 mmol, 4 eq.) was dissolved in DCM (15 mL) and added to the reaction solution using a syringe, maintaining the system temperature at -5 to 0 °C. After 40 minutes, compounds 1-3 (2.3 g, 15.5 mmol, 1 eq.) were dissolved in DCM (10 mL) and slowly added dropwise to the reaction. After the addition was complete, the ice bath was removed, and the reaction was heated to room temperature (25 °C) and stirred for 48 hours. TLC (V Hexane V EA=10:1) After most of the raw materials were consumed, the reaction was stopped. The reaction solution was diluted with dichloromethane (50 mL), washed with saturated ammonium chloride solution, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography with a polarity of V. 正己烷 V 乙酸乙酯 The ratio of 50:1 to 15:1 yielded target compounds 1-4 as pale yellow solids (0.83 g, yield: 32.8%).

[0085] 1 HNMR(400MHz, CDCl3), δ7.33-7.27(m,2H),6.94-6.90(m,2H),4.54(s,1H),2.43-2.39(m,1H),1. 32(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.58-0.56(m,1H),0.44-0.42(m,1H),0.21-0.14(m,2H).

[0086] (4) Synthesis of intermediate 1-5: 2-(1-cyclopropylethyl)phenylacetic acid ester:

[0087] Compounds 1-4 (1.65 g, 10.2 mmol, 1.0 eq.), DCM (15 mL), DMAP (1.50 g, 12.2 mmol, 1.2 eq.), and acetic anhydride (1.35 g, 13.2 mmol, 1.3 eq.) were added sequentially to a reaction flask at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in 25 mL of diethyl ether. The solution was washed with 2N hydrochloric acid (15 mL), saturated sodium bicarbonate solution (15 mL), and saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a colorless oily substance 1-5 (1.48 g, yield 71.0%).

[0088] 1 HNMR(400MHz, CDCl3), δ7.36-7.30(m,2H),6.96-6.90(m,2H),2.46-2.42(m,1H),2.33(s,3H),1. 34(d,J=8.0Hz,3H),1.08-1.06(m,1H),0.56-0.54(m,1H),0.43-0.41(m,1H),0.23-0.17(m,2H).

[0089] (5) Synthesis of intermediates 1-6: 1-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)ethyl ketone:

[0090] At room temperature, a solution of compound 1-5 (1.48 g, 7.2 mmol, 1.0 eq.) in carbon disulfide (5 mL) was added dropwise to a reaction flask containing aluminum chloride (1.08 g, 7.2 mmol, 1.0 eq.) and carbon disulfide (10 mL). The reaction mixture was stirred at room temperature for 1 h, then refluxed for 2 h. The solvent was evaporated to dryness, and the mixture was heated to 70 °C and reacted for another 6 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and dilute hydrochloric acid solution was added. The mixture was extracted with diethyl ether, and the organic phase was separated and washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase. The target product was collected as an off-white solid 1-6 (1.38 g, yield 93.8%).

[0091] 1 HNMR(400MHz, CDCl3), δ7.35-7.20(m,2H),6.90-6.85(m,1H),4.57(s,1H),2.43-2.39(m,1H),2.36(s, 3H), 1.31 (d, J = 8.0Hz, 3H), 1.06-1.04 (m, 1H), 0.57-0.53 (m, 1H), 0.44-0.42 (m, 1H), 0.25-0.18 (m, 2H).

[0092] (6) Intermediates 1-7: Synthesis of 1-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)ethyl ketone:

[0093] Compounds 1-6 (1.35 g, 6.6 mmol, 1.0 eq), potassium carbonate (1.82 g, 13.2 mmol, 2.0 eq), benzyl bromide (1.47 g, 8.6 mmol, 1.3 eq), and acetonitrile (1 mL) were added sequentially to a reaction flask. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, washed with acetonitrile, concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 ratio as the eluent, product 1-7 (1.59g, yield 82.3%) was obtained as a yellow, transparent, oily substance.

[0094] 1HNMR(400MHz, CDCl3), δ7.49(m,2H),7.44-7.39(m,3H),7.37(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),5.32(s,2H ),2.43-2.39(m,1H),2.35(s,3H),1.31(d,J=8.0Hz,3H),1.08-1.04(m,1H),0.56-0.54(m,1H),0.42-0.421(m,1H),0.23-0.16(m,2H).

[0095] (7) Intermediates 1-8: Synthesis of methyl (E)-3-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)but-2-enoate:

[0096] Under nitrogen protection at 0°C, trimethylphosphonoacetate (1.48 g, 8.1 mmol, 1.5 eq.) was added dropwise to a reaction flask containing sodium hydride (0.26 g, 10.7 mmol, 1.0 eq.) and THF (15 mL). The mixture was stirred at 0°C for 30 min. Then, a THF solution of compound 1-7 (1.58 g, 5.4 mmol, 1.0 eq.) in 3 mL was slowly added using a syringe. The reaction mixture was stirred at this temperature for 30 min, then slowly heated to 60°C and reacted overnight. After the reaction was complete as detected by TLC, EA (50 mL) was added to the reaction mixture. The organic phase was separated and washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase. The target product was collected as an off-white solid 1-8 (1.40 g, yield 74.0%).

[0097] 1 HNMR(400MHz, CDCl3), δ7.49(m,2H),7.44-7.39(m,3H),7.36(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),6.83(d,J=4.0Hz,1H),5.92(s,1H),5.3 2(s,2H),3.85(s,3H),2.44-2.40(m,4H),1.31(d,J=8.0Hz,3H),1.07- 1.05(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.22-0.14(m,2H).

[0098] (8) Synthesis of intermediates 1-9: methyl 3-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)butyrate:

[0099] Under nitrogen protection at room temperature, 50 mg, 0.2 mmol, and 0.05 eq. of titanium dioxide dichloroethylene (0.65 g, 10.0 mmol, and 2.5 eq.), 2.75 g, 20.0 mmol, and 5.0 eq. of triethylamine hydrochloride, and 100 mL of DCM were added sequentially to a reaction flask. The mixture was stirred at room temperature until the color of the reaction solution changed from red to green. Compounds 1-8 (1.40 g, 4.0 mmol, and 1.0 eq.) were dissolved in 100 mL of DCM and injected into the above reaction solution. The mixture was stirred at room temperature. After the reaction was monitored by TLC (anisaldehyde color development), the reaction was quenched with saturated ammonium chloride (100 mL). The reaction mixture was filtered through diatomaceous earth, and the mother liquor was extracted with DCM (3 x 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography with petroleum ether / ethyl acetate as the mobile phase. The target product was collected as an off-white solid 1-9 (1.26 g, yield 89.4%).

[0100] 1 HNMR(400MHz, CDCl3), δ7.49(m,2H),7.43-7.37(m,3H),7.32(d,J=8.0Hz,1H) ,7.11(d,J=8.0Hz,1H),6.81(d,J=4.0Hz,1H),5.32(s,2H),3.51-3.62(m,4H), 2.47-2.66(m,2H),2.42-2.31(m,1H),1.33(d,J=8.0Hz,3H),1.20-1.24(m,3H ),1.06-1.04(m,1H),0.58-0.56(m,1H),0.45-0.43(m,1H),0.23-0.16(m,2H).

[0101] (9) Synthesis of compound 1: methyl 3-(3-(1-cyclopropylethyl)-2-ylphenyl)butyrate:

[0102] Compounds 1-9 (200 mg, 0.57 mmol, 1.0 eq), palladium / carbon (15 mg, palladium content w / w = 10%), potassium carbonate (11.8 mg, 0.09 mmol, 0.15 eq), and methanol (4 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 1 (48 mg, yield 32.1%) was obtained as a pale yellow solid.

[0103] 1HNMR(400MHz, CDCl3), δ7.37-7.21(m,2H),6.90-6.85(m,1H),4.57(s,1H),3.51-3.62(m,4H),2.45-2.64(m,2H),2.42-2.31( m,1H),1.33(d,J=8.0Hz,3H),1.21-1.25(m,3H),1.07-1.04(m,1H),0.56-0.52(m,1H),0.45-0.43(m,1H),0.23-0.16(m,2H).

[0104] Example 2 Synthesis of methyl 3-(4-hydroxy-2,3-dihydro-1-hydro-inden-5-yl)butyrate (2)

[0105]

[0106] (1) Synthesis of intermediate 2-2: 2,3-dihydro-1-hydro-inden-4-yl-acetate:

[0107] Compound 2-1 (1.00 g, 7.5 mmol, 1.0 eq.), DCM (10 mL), DMAP (1.10 g, 8.94 mmol, 1.2 eq.), and acetic anhydride (1.00 g, 9.8 mmol, 1.3 eq.) were added sequentially to a reaction flask at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether (25 mL). The solution was washed with 2N hydrochloric acid (15 mL), saturated sodium bicarbonate solution (15 mL), and saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a colorless oily substance 2-2 (1.08 g, yield 81.7%).

[0108] 1 HNMR(400MHz, CDCl3), δ7.36(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),6.82(d,J=4.0H z,1H),2.95(t,J=8.0Hz,2H),2.81(d,J=8.0Hz,2H),2.33(s,3H),2.16-2.09(m,2H).

[0109] (2) Synthesis of intermediate 2-3: 1-(4-hydroxy-2,3-dihydro-1-hydro-inden-5-yl)acetone:

[0110] At room temperature, a solution of compound 2-2 (1.00 g, 5.7 mmol, 1.0 eq.) in carbon disulfide (5 mL) was added dropwise to a reaction flask containing aluminum chloride (0.85 g, 5.7 mmol, 1.0 eq.) and carbon disulfide (10 mL). The reaction mixture was stirred at room temperature for 1 h, then refluxed for 2 h. The solvent was evaporated to dryness, and the mixture was heated to 70 °C and reacted for another 6 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and 10 mL of dilute hydrochloric acid solution was added. The mixture was extracted with ether (3 x 20 mL), and the organic phase was separated and washed with saturated sodium bicarbonate solution (10 mL) and saturated brine solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase. The target product, 2-3 (0.93 g, yield 93.0%), was collected as an off-white solid.

[0111] 1 HNMR(400MHz, CDCl3), δ7.17(d,J=8.0Hz,1H),6.85(d,J=4.0Hz,1H),4.58(s,1H ),2.95(t,J=8.0Hz,2H),2.84(d,J=8.0Hz,2H),2.62(s,3H),2.18-2.11(m,2H).

[0112] (3) Synthesis of intermediate 2-4: 1-(4-(benzyloxy)-2,3-dihydro-1-hydro-inden-5-yl) ethyl ketone:

[0113] Compounds 2-3 (0.9 g, 5.1 mmol, 1.0 eq), potassium carbonate (1.40 g, 10.2 mmol, 2.0 eq), benzyl bromide (1.47 g, 8.6 mmol, 1.3 eq), and acetonitrile (1 mL) were added sequentially to the reaction flask. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, washed with acetonitrile, concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 When the eluent is diluted 1:10, product 2-4 (1.19g, yield 87.6%) is obtained as a yellow, transparent oily substance.

[0114] 1 HNMR(400MHz, CDCl3), δ7.49(m,2H),7.44-7.38(m,2H),7.35(d,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),6.83( d,J=4.0Hz,1H),5.31(s,2H),2.92(t,J=8.0Hz,2H),2.83(d,J=8.0Hz,2H),2.62(s,3H),2.16-2.08(m,2H).

[0115] (4) Intermediate 2-5: Synthesis of methyl (E)-3-(4-(benzyloxy)-2,3-dihydro-1-hydro-inden-5-yl)but-2-enoate:

[0116] Under nitrogen protection at 0°C, trimethylphosphonoacetate (1.21 g, 6.6 mmol, 1.5 eq.) was added dropwise to a reaction flask containing sodium hydride (0.11 g, 4.4 mmol, 1.0 eq.) and THF (10 mL). The mixture was stirred at 0°C for 30 min. Then, a THF solution of compound 2-4 (1.18 g, 4.4 mmol, 1.0 eq.) in 2 mL was slowly added using a syringe. The reaction mixture was stirred at this temperature for 30 min, and then slowly heated to 60°C and reacted overnight. After the reaction was complete as detected by TLC, EA (50 mL) was added to the reaction mixture. The organic phase was separated and washed with saturated sodium bicarbonate solution (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase. The target product was collected as an off-white solid 2-5 (1.04 g, yield 73.3%).

[0117] 1 HNMR(400MHz, CDCl3), δ7.47(m,2H),7.44-7.38(m,2H),7.33(d,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),6.83(d,J=4.0Hz,1H) ,5.94(s,1H),5.31(s,2H),3.85(s,3H),2.85(t,J=8.0Hz,2H),2.82(d,J=8.0Hz,2H),2.42-2.38(m,3H),1.99-1.94(m,2H).

[0118] (5) Synthesis of intermediate 2-6: methyl 3-(4-(benzyloxy)-2,3-dihydro-1-hydro-inden-5-yl)butyrate:

[0119] Under nitrogen protection at room temperature, 39 mg, 0.2 mmol, and 0.05 eq. of titanium dioxide dichloroethylene, 0.50 g, 7.75 mmol, and 2.5 eq. of zinc powder, 2.13 g, 15.5 mmol, and 5.0 eq. of triethylamine hydrochloride, and 75 mL of DCM were added sequentially to the reaction flask. The mixture was stirred at room temperature until the color of the reaction solution changed from red to green. Compound 2-5 (1.00 g, 3.1 mmol, and 1.0 eq.) was dissolved in 50 mL of DCM and injected into the above reaction solution. The mixture was stirred at room temperature. After the reaction was monitored by TLC (anisaldehyde color development), the reaction was quenched with saturated ammonium chloride (50 mL). The reaction mixture was filtered through diatomaceous earth, and the mother liquor was extracted with DCM (3 x 100 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography with petroleum ether / ethyl acetate as the mobile phase. The target product was collected as an off-white solid 2-6 (0.43 g, yield 42.8%).

[0120] 1 HNMR(400MHz, CDCl3), δ7.47(m,2H),7.44-7.39(m,2H),7.33(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),5.33(s,2H),3.5 1-3.62(m,4H),2.82(t,J=8.0Hz,2H),2.80(d,J=8.0Hz,2H),2.47-2.65(m,1H),2.44-2.33(m,1H),1.99-1.92(m,2H),1.32(d,J=8.0Hz,3H).

[0121] (6) Synthesis of compound 2: methyl 3-(4-hydroxy-2,3-dihydro-1-hydro-inden-5-yl)butyrate:

[0122] Compounds 2-6 (200 mg, 0.62 mmol, 1.0 eq), palladium / carbon (15 mg, palladium content w / w = 10%), potassium carbonate (11.8 mg, 0.09 mmol, 0.15 eq), and methanol (4 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 2 (91 mg, yield 62.6%) was obtained as a pale yellow solid.

[0123] 1HNMR(400MHz, CDCl3), δ7.34-7.20(m,1H),6.92-6.85(m,1H),4.58(s,1H),3.51-3.62(m,4H),2.85(t,J=8.0H z,2H),2.81(d,J=8.0Hz,2H),2.44-2.63(m,1H),2.42-2.31(m,1H),1.97-1.91(m,2H),1.30(d,J=8.0Hz,3H).

[0124] Example 3 Synthesis of methyl 3-(3-(1-cyclopropylethyl)-2-((2-oxo-4-hydro-benzo-[1,3,2]-dioxophosphoric acid-2-yl)-methoxy)phenylbutyrate (3)

[0125]

[0126] (1) Synthesis of intermediate 3-2: 2-chloro-4-hydro-benzo-[1,3,2]dioxophosphate:

[0127] Phosphorus oxychloride (270 mg, 1.76 mmol, 1.1 eq), tetrahydrofuran (5 mL), and triethylamine (340 mg, 3.36 mmol, 2.1 eq) were added sequentially to a reaction flask. Under nitrogen protection, the mixture was heated to -70°C in a dry ice-ethanol bath. Compound 3-1 (200 mg, 1.6 mmol, 1.0 eq) was then added (keeping the temperature below -50°C). After the addition was complete, the reaction mixture was allowed to react at -50°C for 1 h, and then slowly raised to room temperature for 4 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a brownish liquid crude product 3-2. This crude product was added directly to the next reaction without further purification, and the yield was calculated as 100%.

[0128] (2) Synthesis of intermediate 3-3: 2-hydroxy-4-hydro-benzo-[1,3,2]-dioxophosphate:

[0129] Compound 3-2 (327 mg, 1.6 mmol) and water (5 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 2 h, and the organic layer was washed with ethyl acetate until it was colorless. The aqueous phase was collected and concentrated under reduced pressure to give crude white solid 3-3. This crude solid was added directly to the next reaction without further purification, and the yield was calculated as 100%.

[0130] (3) Intermediate 3-4: Synthesis of methyl-3-(2-(chloromethyl)-3-(1-cyclopropylethyl)phenylbutyrate:

[0131] Compound 1 (200 mg, 0.76 mmol, 1.0 eq), tetrahydrofuran (3 mL), and sodium hydroxide (61 mg, 1.52 mmol, 2.0 eq) were added sequentially to a reaction flask. The mixture was heated under reflux for 0.5 h, followed by the addition of bromochloromethane (2.95 g, 22.8 mmol, 30 eq). The reaction mixture was reacted at 70 °C for 2 h, after which stirring was stopped. The reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography with V polarity eluent. 正己烷 V 乙酸乙酯 The ratio of 50:1 to 15:1 yielded target compounds 3-4 as a pale yellow liquid crude product (125 mg, yield: 52.9%), which was directly added to the next reaction without further purification.

[0132] (4) Synthesis of compound 3: methyl 3-(3-(1-cyclopropylethyl)-2-((2-oxo-4-hydro-benzo-[1,3,2]-dioxophosphoric acid-2-yl)-methoxy)phenylbutyrate:

[0133] Compound 3-3 (150 mg, 0.8 mmol, 1.0 eq.), triethylamine (0.66 g, 6.5 mmol, 8.0 eq.), and acetonitrile (10 mL) were added sequentially to a reaction flask. The mixture was heated to 50 °C and reacted for 0.5 h. Then, compound 3-4 (0.9 g, 2.9 mmol, 3.6 eq.) was added, and the mixture was reacted at 70 °C for 24 h. After the reaction was completed as detected by TLC, the reaction mixture was evaporated to dryness under reduced pressure. Water (25 mL) was added to the residue, and the mixture was extracted with ethyl acetate (3 x 50 mL). The residue was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a pale yellow solid 3 (48 mg, yield 13.5%).

[0134] 1 HNMR(400MHz, CDCl3), δ7.42-7.37(m,2H),7.36-7.21(m,2H),7.14-7.01(m ,2H),6.90-6.85(m,1H),5.29(s,2H),4.42(s,2H),3.51-3.62(m,4H),2.46 -2.65(m,2H),2.42-2.31(m,1H),1.31(d,J=8.0Hz,3H),1.21-1.25(m,3H), 1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0135] Example 4 Synthesis of methyl 3-(2-hydroxy-8-methoxy-8-methylbicyclo[4.2.0]oct-1,3,5-trien-3-yl)butyrate (4)

[0136]

[0137] (1) Synthesis of intermediate 4-2: 1-(benzyloxy)-2-bromobenzene:

[0138] Compound 4-1 (5.0 g, 28.9 mmol, 1.0 eq), potassium carbonate (8.0 g, 57.8 mmol, 2.0 eq), benzyl bromide (4.95 g, 28.9 mmol, 1.0 eq), and acetonitrile (100 mL) were added sequentially to a reaction flask, and the mixture was heated to 80 °C and stirred for 4 h. After cooling to room temperature, the mixture was filtered, washed with acetonitrile, concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 ratio as the eluent, product 4-2 (6.95g, yield 91.4%) was obtained as a pale yellow, transparent oily substance.

[0139] (2) Synthesis of intermediate 4-3: 5-(benzyloxy)bicyclo[4.2.0]oct-1,3,5-trien-7-one:

[0140] Under nitrogen protection, compound 4-2 (6.9 g, 26.2 mmol, 1.0 eq), 1,1-diethoxyethylene (6.1 g, 52.4 mmol, 2.0 eq), sodium amide (2.04 g, 52.4 mmol, 2.0 eq), and tetrahydrofuran (70 mL) were added sequentially to the reaction flask, and the mixture was heated to reflux and stirred overnight. After cooling to room temperature, ice water (70 mL) and concentrated hydrochloric acid (10 mL) were added, and the mixture was stirred at room temperature for 2 h. The mixture was extracted with ethyl acetate (100 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 When the eluent is diluted 1:50, product 4-3 (3.55g, yield 60.4%) is obtained as a pale yellow, transparent oily substance.

[0141] 1 HNMR (400MHz, CDCl3), δ7.51-7.29(m,6H),7.02(m,2H),5.50(s,2H),3.88(s,2H).

[0142] (3) Synthesis of intermediate 4-4: 5-(benzyloxy)-7-methylbicyclo[4.2.0]oct-1,3,5-trien-7-ol:

[0143] Compound 4-3 (3.5 g, 15.6 mmol, 1.0 eq) was added to 40 mL of tetrahydrofuran, and 3 mol / L methylmagnesium chloride (13.0 mL, 39.0 mmol, 2.5 eq) was added dropwise at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 8 h. The reaction solution was then poured into 60 mL of ammonium chloride solution and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 ratio as the eluent, the target compound 4-4 (1.55 g, yield: 41.3%) was obtained as a pale yellow solid.

[0144] 1 HNMR(400MHz, CDCl3), δ7.51-7.29(m,6H),7.02(m,2H),5.50(s,2H),3.64(s,2H),1.78(s,3H).

[0145] (4) Synthesis of intermediate 4-5: 2-(benzyloxy)-8-methoxy-8-methylbicyclo[4.2.0]octyl-1,3,5-triene:

[0146] Compound 4-4 (400 mg, 1.66 mmol, 1.0 eq), p-toluenesulfonic acid (441 mg, 2.50 mmol, 1.5 eq), and methanol (10 mL) were added sequentially to the reaction flask. The mixture was heated to 70 °C and stirred for 3 h. After cooling to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to >7. The mixture was extracted with ethyl acetate (3 x 30 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent yields product 4-5 (325 mg, yield 89.3%), a yellow, transparent oily substance.

[0147] 1 HNMR(400MHz, CDCl3), δ7.51-7.29(m,6H),7.02(m,2H),5.50(s,2H),3.64(s,2H),3.31(s,3H),1.78(s,3H).

[0148] (5) Synthesis of intermediates 4-6: oct-1,3,5-trien-2-ol (8-methoxy-8-methylbicyclo[4.2.0]oct-1,3,5-trien-2-ol):

[0149] Compounds 4-5 (320 mg, 1.34 mmol, 1.0 eq), palladium / carbon (30 mg, palladium content w / w = 10%), potassium carbonate (27.8 mg, 0.20 mmol, 0.15 eq), and methanol (8 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 4-6 (191 mg, yield 86.8%) was obtained as a pale yellow solid.

[0150] 1 HNMR (400MHz, CDCl3), δ7.34-7.20(m,2H),6.92-6.85(m,1H),4.58(s,1H),3.64(s,2H),3.31(s,3H),1.78(s,3H).

[0151] (6) Synthesis of intermediates 4-7: 8-methoxy-8-methylbicyclo[4.2.0]octyl-1,3,5-trien-2-acetate:

[0152] Compounds 4-6 (190 mg, 1.16 mmol, 1.0 eq.), DCM (5 mL), DMAP (171 mg, 1.39 mmol, 1.2 eq.), and acetic anhydride (154 mg, 1.51 mmol, 1.3 eq.) were added sequentially to a reaction flask at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether (10 mL). The solution was washed with 2N hydrochloric acid (3 mL), saturated sodium bicarbonate solution (5 mL), and saturated brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a colorless oily substance 4-7 (188 mg, yield 78.6%).

[0153] (7) Synthesis of intermediate 4-8:1-(2-hydroxy-8-methoxy-8-methylbicyclo[4.2.0]oct-1,3,5-trien-3-yl)acetone:

[0154] At room temperature, a solution of compound 4-7 (180 mg, 0.91 mmol, 1.0 eq.) in carbon disulfide (2 mL) was added dropwise to a reaction flask containing aluminum chloride (0.85 g, 0.91 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 1 h, then refluxed for 2 h. The solvent was evaporated to dryness, and the mixture was heated to 70 °C and reacted for another 6 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and 2 mL of dilute hydrochloric acid solution was added. The mixture was extracted with ether (3 x 10 mL), and the organic phase was separated and washed with saturated sodium bicarbonate solution (5 mL) and saturated brine solution (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was then subjected to silica gel column chromatography. 石油醚 V 乙酸乙酯 Using the mobile phase, the target product was collected as an off-white solid 4-8 (156 mg, yield 75.6%).

[0155] 1 HNMR(400MHz, CDCl3), δ7.34-7.30(d,1H),6.92-6.87(d,1H),4.58(s,1H),3.64(s,2H),3.31(s,3H),2.62(s,3H),1.78(s,3H).

[0156] (8) Intermediate 4-9: Synthesis of 1-(2-(benzyloxy)-8-methoxy-8-methylbicyclo[4.2.0]oct-1,3,5-trien-3-yl) ethyl ketone:

[0157] Compounds 4-8 (155 mg, 0.75 mmol, 1.0 eq), potassium carbonate (207 mg, 1.50 mmol, 2.0 eq), benzyl bromide (167 mg, 0.98 mmol, 1.3 eq), and acetonitrile (3 mL) were added sequentially to the reaction flask. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, washed with acetonitrile, concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 ratio as the eluent, product 4-9 (179 mg, yield 80.5%) was obtained as a yellow, transparent oily substance.

[0158] (9) Intermediate 4-10: Synthesis of methyl (E)-3-(2-(benzyloxy)-8-methoxy-8-methylbicyclo[4.2.0]oct-1,3,5-trien-3-yl)but-2-enoate:

[0159] Under nitrogen protection at 0°C, trimethylphosphonoacetate (162 mg, 0.89 mmol, 1.5 eq.) was added dropwise to a reaction flask containing sodium hydride (14.2 mg, 0.59 mmol, 1.0 eq.) and THF (3 mL). The mixture was stirred at 0°C for 30 min. A THF solution of compound 4-9 (175 mg, 0.59 mmol, 1.0 eq.) in 1 mL was slowly added using a syringe. The reaction mixture was stirred at this temperature for 30 min, and then slowly heated to 60°C and reacted overnight. After the reaction was complete as detected by TLC, EA (10 mL) was added to the reaction mixture. The organic phase was separated and washed with saturated sodium bicarbonate solution (5 mL) and saturated brine solution (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase. The target product was collected as an off-white solid, 4-10 (170 mg, yield 81.6%).

[0160] 1 HNMR(400MHz, CDCl3), δ7.50-7.28(m,5H),7.02(m,2H),5.94(s,1H),5.50(s ,2H),3.85(s,3H),3.64(s,2H),3.31(s,3H),2.42-2.38(m,3H),1.78(s,3H).

[0161] (10) Synthesis of compound 4: methyl 3-(2-hydroxy-8-methoxy-8-methylbicyclo[4.2.0]oct-1,3,5-trien-3-yl)butyrate:

[0162] Compound 4-10 (170 mg, 0.48 mmol, 1.0 eq), palladium / carbon (15 mg, palladium content w / w = 10%), potassium carbonate (10.0 mg, 0.07 mmol, 0.15 eq), and methanol (3 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 4 (26 mg, yield 20.5%) was obtained as a pale yellow solid.

[0163] 1 HNMR(400MHz, CDCl3), δ7.39-7.35(d,1H),6.94-6.89(d,1H),4.56(s,1H),3.85(s,3H) ,3.51-3.62(m,3H),3.31(s,3H),2.38-2.67(m,2H),1.78(s,3H),1.30(d,J=8.0Hz,3H).

[0164] Example 5: Synthesis of methyl 3-(8-cyano-2-hydroxy-8-methylbicyclo[4.2.0]oct-1,3,5-trien-3-yl)butyrate (5)

[0165]

[0166] (1) Synthesis of intermediate 5-1: 5-(benzyloxy)-7-methylbicyclo[4.2.0]oct-1,3,5-trien-7-ol:

[0167] Under nitrogen protection, compound 4-4 (400 mg, 1.66 mmol, 1.0 eq), dichloromethane (10 mL), and trimethylcyanosilane (213 mg, 2.16 mmol, 1.3 eq) were added sequentially to the reaction flask. Boron trifluoride diethyl ether solution (2356 mg, 16.6 mmol, 10 eq) was slowly added dropwise at 0 °C, and the reaction was stirred overnight. The reaction was quenched by slow addition of saturated sodium bicarbonate solution (10 mL). The organic phase was separated, and the aqueous phase was extracted with DCM (20 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 When the eluent is diluted 1:50, product 5-1 (365 mg, yield 88.2%) is obtained as a pale yellow solid.

[0168] 1 HNMR(400MHz, CDCl3), δ7.47-7.12(m,5H),7.02-6.89(m,3H),5.16(s,2H),3.27(s,2H),1.79(s,3H).

[0169] (2) Synthesis of intermediate 5-2: 5-(benzyloxy)-7-methylbicyclo[4.2.0]octyl-1,3,5-trien-7-nitrile:

[0170] Compound 5-1 (360 mg, 1.44 mmol, 1.0 eq), palladium / carbon (30 mg, palladium content w / w = 10%), potassium carbonate (29.9 mg, 0.20 mmol, 0.15 eq), and methanol (8 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 5-2 (190 mg, yield 82.9%) was obtained as a pale yellow solid.

[0171] (3) Synthesis of intermediate 5-3: 8-cyano-8-methylbicyclo[4.2.0]octyl-1,3,5-trien-2-yl acetate:

[0172] Compound 5-2 (190 mg, 1.19 mmol, 1.0 eq.), DCM (5 mL), DMAP (176 mg, 1.43 mmol, 1.2 eq.), and acetic anhydride (158 mg, 1.55 mmol, 1.3 eq.) were added sequentially to a reaction flask at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether (10 mL). The solution was washed with 2N hydrochloric acid (3 mL), saturated sodium bicarbonate solution (5 mL), and saturated brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a colorless oily substance 5-3 (190 mg, yield 79.3%).

[0173] (4) Synthesis of intermediate 5-4: 4-acetyl-5-hydroxy-7-methylbicyclo[4.2.0]octyl-1,3,5-trien-7-nitrile:

[0174] At room temperature, a solution of compound 5-3 (180 mg, 0.89 mmol, 1.0 eq.) in carbon disulfide (2 mL) was added dropwise to a reaction flask containing aluminum chloride (0.84 g, 0.89 mmol, 1.0 eq.) and carbon disulfide (2 mL). The reaction mixture was stirred at room temperature for 1 h, then refluxed for 2 h. The solvent was evaporated to dryness, and the mixture was heated to 70 °C and reacted for another 6 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and 2 mL of dilute hydrochloric acid solution was added. The mixture was extracted with diethyl ether (3 x 10 mL), and the organic phase was separated and washed with saturated sodium bicarbonate solution (5 mL) and saturated brine solution (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase. The target product, 5-4 (156 mg, yield 60.1%), was collected as an off-white solid.

[0175] 1 HNMR(400MHz, CDCl3), δ7.36-7.32(d,1H),6.94-6.89(d,1H),4.58(s,1H),3.68(s,2H),2.60(s,3H),1.79(s,3H).

[0176] (5) Synthesis of intermediate 5-5: 4-acetyl-5-(benzyloxy)-7-methylbicyclo[4.2.0]octyl-1,3,5-trien-7-nitrile:

[0177] Compound 5-4 (150 mg, 0.77 mmol, 1.0 eq), potassium carbonate (213 mg, 1.55 mmol, 2.0 eq), benzyl bromide (171 mg, 1.00 mmol, 1.3 eq), and acetonitrile (3 mL) were added sequentially to the reaction flask. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, washed with acetonitrile, concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 ratio as the eluent yields product 5-5 (191 mg, yield 85.1%), a yellow, transparent oily substance.

[0178] (6) Intermediate 5-6: Synthesis of methyl (E)-3-(2-(benzyloxy)-8-cyano-8-methylbicyclo[4.2.0]oct-1,3,5-trien-3-yl)but-2-enoate:

[0179] Under nitrogen protection at 0°C, trimethylphosphonoacetate (168 mg, 0.93 mmol, 1.5 eq.) was added dropwise to a reaction flask containing sodium hydride (14.8 mg, 0.62 mmol, 1.0 eq.) and THF (3 mL). The mixture was stirred at 0°C for 30 min. Then, a THF solution of compound 5-5 (180 mg, 0.62 mmol, 1.0 eq.) in 1 mL was slowly added using a syringe. The reaction mixture was stirred at this temperature for 30 min, and then slowly heated to 60°C and reacted overnight. After the reaction was complete as detected by TLC, EA (10 mL) was added to the reaction mixture. The organic phase was separated and washed with saturated sodium bicarbonate solution (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase. The target product was collected as an off-white solid 5-6 (166 mg, yield 77.1%).

[0180] 1 HNMR(400MHz, CDCl3), δ7.56-7.32(m,5H),7.05(m,2H),5.94(s,1H),5.50(s,2H),3.80(s,3H),3.27(s,2H),2.42-2.38(m,3H),1.79(s,3H).

[0181] (7) Synthesis of compound 5: methyl 3-(8-cyano-2-hydroxy-8-methylbicyclo[4.2.0]oct-1,3,5-trien-3-yl)butyrate:

[0182] Compounds 5-6 (160 mg, 0.46 mmol, 1.0 eq), palladium / carbon (15 mg, palladium content w / w = 10%), potassium carbonate (9.8 mg, 0.07 mmol, 0.15 eq), and methanol (3 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 5 (19 mg, yield 15.9%) was obtained as a pale yellow solid.

[0183] 1 HNMR(400MHz, CDCl3), δ7.39-7.35(d,1H),6.94-6.89(d,1H),4.56(s,1H),3.85( s,3H),3.51-3.62(m,3H),2.38-2.67(m,2H),1.78(s,3H),1.30(d,J=8.0Hz,3H).

[0184] Example 6: Synthesis of sodium ((2-(1-cyclopropylethyl)-6-(4-methoxy-4-oxobutane-2-yl)phenoxy)methyl)phosphonate (6)

[0185]

[0186] Phosphoric acid (251 mg, 2.56 mmol, 1.0 eq.), triethylamine (324 mg, 3.2 mmol, 10.0 eq.), and acetonitrile (3 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and reacted for 0.5 h. Then, compound 3-4 (100 mg, 0.32 mmol, 1.0 eq.) was added, and the mixture was reacted at 70 °C for 24 h. After the reaction was completed as detected by TLC, the reaction mixture was evaporated to dryness under reduced pressure. 1.5 mL of water was added, and the pH was adjusted to 1 with 1 N hydrochloric acid. The mixture was extracted with methyl tert-butyl ether (10 mL * 3), and the organic phase was evaporated to dryness. 5 mL of ethanol was added to dissolve the organic phase, and 10% (w / w) sodium hydroxide aqueous solution (0.32 mL, 0.64 mmol, 2.0 eq.) was added using a pipette. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and 95% isopropanol aqueous solution (2 mL) was added to the residue. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. A pale yellow powdery solid was obtained by pumping. Add acetonitrile (3 mL), beat at 50 °C for 4 h, and filter while hot to obtain the target product 6 (45 mg, 35.1%), which is a light yellow powder.

[0187] 1HNMR(400MHz, CDCl3), δ7.42-7.37(m,2H),7.31-7.27(m,1H),4.42(s,2H),3.51-3.62(m,4H),2.46-2.65(m,2H),2.42-2.31( m,1H),1.31(d,J=8.0Hz,3H),1.21-1.25(m,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0188] Example 7 Synthesis of methyl 3-(2-hydroxy-3-isopropylphenyl)butyrate (7)

[0189]

[0190] (1) Synthesis of intermediate 7-2: 2-isopropylphenyl acetate:

[0191] At 0°C, DCM (20 mL) and 2-isopropylphenol (5 g, 36.71 mmol) were added sequentially to a single-necked flask, followed by dropwise addition of Ac₂O (4.5 g, 44.05 mmol). The mixture was slowly heated to room temperature and stirred for 2 h. After the reaction was complete, 20 mL of water was added, and the pH of the reaction solution was adjusted to 3-4 with 2 M HCl aqueous solution. The solution was then extracted with DCM (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6.56 g of a colorless oily liquid, which proceeded directly to the next step.

[0192] 1 H NMR (400MHz, CDCl3) δ7.36-7.32(m,1H),7.27-7.17(m,2H),7.10-6.96(m,1H),3.05(m,1H),2.35(s,3H),1.24(d,J=6.9Hz,6H).

[0193] (2) Synthesis of intermediate 7-3: 1-(2-hydroxy-3-isopropylphenyl)ethyl ketone:

[0194] Compound 7-2 (6.56 g, 36.8 mmol) and AlCl3 (5.89 g, 44.16 mmol) were added sequentially to a single-necked flask. The mixture was heated to 120 °C and stirred for 75 min. The system became viscous, and the reaction was stopped. 80 mL of DCM was added for dilution. The reaction solution was poured into 50 mL of aqueous sodium sulfate, and the mixture was separated. The aqueous phase was then extracted with DCM (30 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether) to give 1.3 g of a colorless oily liquid, with a yield of 20.00%.

[0195] 1 H NMR(400MHz, CDCl3) δ12.71(s,1H),7.62(dd,J=8.0,1.4Hz,1H),7.44(d,J=7.4Hz,1H), 6.89(t,J=7.7Hz,1H),3.41(dt,J=13.7,6.9Hz,1H),2.66(s,3H),1.26(d,J=6.9Hz,6H).

[0196] (3) Synthesis of intermediate 7-4: 1-(2-(benzyloxy)-3-isopropylphenyl)ethyl ketone:

[0197] 1-(2-hydroxy-3-isopropylphenyl)ethyl-1-one (2.13 g, 12 mmol), DCM (40.0 mL), Bu4NBr (386.8 mg, 1.2 mmol), and 10% sodium hydroxide (9 mL) were added sequentially to a single-necked flask. Benzyl bromide (2.25 g, 13.2 mmol) was added under vigorous stirring, and the mixture was stirred overnight at room temperature. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with DCM (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM The ratio of the two solutions was 3:1, yielding 3.2 g of a pale yellow oily liquid. Yield: 99%.

[0198] 1 H NMR (400MHz, CDCl3) δ7.47-7.37(m,7H),7.20(t,J=8Hz,1H),5.16(s,2H),3.45-3.40(m,1H),2.62(s,3H),1.24(d,J=4Hz,6H).

[0199] (4) Intermediate 7-5: Synthesis of methyl (E)-3-(2-(benzyloxy)-3-isopropylphenyl)but-2-enoate:

[0200] Add NaH (592 mg, 14.8 mmol) and THF (100.0 mL) to the reaction flask, under nitrogen protection, and cool in an ice-water bath. Add methyl 2-(dimethoxyphosphoryl)acetate (2.7 g, 14.8 mmol) dropwise, and incubate for 0.5 h. Then add 7-4(2-(benzyloxy)-3-isopropylphenyl)ethyl-1-one 7-4 (2.0 g, 7.4 mmol) dropwise, slowly heat, and reflux overnight. Add 100 mL of saturated ammonium chloride solution, extract with EA (100 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (V). 石油醚 V DCM =3:1), yielding 760mg of a pale yellow oily liquid. Yield 31%.

[0201] 1 H NMR (400MHz, CDCl3) δ7.42-7.38(m,4H),7.37-7.32(m,1H),7.30-7.28(m,1H),7.13(t,J=7.6Hz,1H),7.05(dd,J=7.5,1.8 Hz,1H),6.07(q,J=1.4Hz,1H),4.77(s,2H),3.77(s,3H),3.44-3.38(m,1H),2.59(d,J=1.4Hz,3H),1.22(d,J=7.0Hz,6H).

[0202] (5) Synthesis of compound 7: methyl 3-(2-hydroxy-3-isopropylphenyl)butyrate:

[0203] Compound 7-5 (136 mg, 0.4 mmol), Pd(OH)₂ (Pd: 10%, 14 mg), and THF (5.0 mL) were added to a reaction flask. The mixture was purged with hydrogen three times, and the reaction was allowed to proceed overnight with the addition of a hydrogen balloon. After the reaction was complete, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =3:1), yielding 35 mg of a colorless oily liquid. Yield 35%.

[0204] 1 H NMR(400MHz, CDCl3)δ7.11(dd,J=7.4,1.8Hz,1H),7.05(dd,J=7.7,1.7Hz,1H),6.98–6.92(m,1H),6.92(s,1H), 3.67(s,3H),3.65–3.59(m,1H),3.43–3.34(m,1H),2.72–2.65(m,2H),1.36(d,J=7.1Hz,3H),1.29–1.26(m,6H).

[0205] Example 8 Synthesis of methyl 3-(3-(1-cyclopropylethyl)-2-(2-ethoxy-2-oxoethoxy)phenyl)butyrate (8)

[0206]

[0207] Compound 1 (50 mg, 0.19 mmol, 1.0 eq.), potassium carbonate (26.3 mg, 0.38 mmol, 2.0 eq.), and acetonitrile (2 mL) were added sequentially to the reaction flask. The mixture was heated to 40 °C and reacted for 1 h. Then, ethyl bromoacetate (35.7 mg, 0.21 mmol, 1.1 eq.) was added, and the reaction was continued at 40 °C for 24 h. After the reaction was complete as detected by TLC, the mixture was filtered, the mother liquor was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting apparatus: V). Pe V EA =100 / 1-25 / 1), yielding a colorless liquid compound 8 (38 mg, yield 57.4%).

[0208] 1 HNMR(400MHz, CDCl3), δ7.37-7.21(m,2H),6.90-6.85(m,1H),4.99(s,2H),4.19-4.23(m,2H),3.51-3.62(m,4H),2.45-2.64(m,2H),2. 42-2.31(m,1H),1.33(d,J=8.0Hz,3H),1.20-1.275(m,6H),1.07-1.04(m,1H),0.55-0.52(m,1H),0.45-0.43(m,1H),0.25-0.16(m,2H).

[0209] Example 9 Synthesis of 7-(1-cyclopropylethyl)-3-methylbenzofuran-2(3-hydro)-one (9)

[0210]

[0211] (1) Synthesis of intermediate 9-1: (3S)-7-(1-cyclopropylethyl)-3-hydroxy-3-methylbenzofuran-2(3-hydro)-one:

[0212] Under nitrogen protection, compounds 1-4 (408 mg, 2.47 mmol, 1.0 eq) and DCM (10.0 mL) were added to a reaction flask. The flask was cooled in an ice-water bath. Pyruvate (302 mg, 2.96 mmol, 1.2 eq) was added, followed by the addition of 3 mL of dichloromethane solution containing TiCl4 (561 mg, 2.96 mmol, 1.2 eq). The mixture was slowly heated to room temperature and reacted for 1 h. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added, followed by extraction with DCM (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =1:1), yielding a colorless oily liquid 9-1 (450 mg, yield 78.4%).

[0213] 1 H NMR (400MHz, CDCl3) δ7.35-7.24(m,2H),7.19(t,J=7.6Hz,1H),3.30-3.06(m,1H),2.43-2.39(m,1H),1.75 (s,3H),1.32(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.58-0.56(m,1H),0.44-0.42(m,1H),0.21-0.14(m,2H).

[0214] (2) Synthesis of intermediate 9-2: 7-(1-cyclopropylethyl)-3-hydroxy-2-oxo-2,3-dihydrobenzofuran-3-yl-acetate:

[0215] Compound 9-1 (450 mg, 1.94 mmol, 1.0 eq) and THF (10.0 mL) were added to a reaction flask, followed by DMAP (23 mg, 0.19 mmol, 0.1 eq) and triethylamine (294 mg, 2.9 mmol, 1.5 eq). Acetic anhydride (297 mg, 2.9 mmol, 1.5 eq) was then added dropwise. After the addition was complete, the mixture was heated to 65 °C and reacted for 2 h. After the reaction was complete, the mixture was washed with 10 mL of 1 M dilute hydrochloric acid, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =3:1), yielding a colorless oily liquid 9-2 (532 mg, 100% yield).

[0216] 1H NMR (400MHz, CDCl3) δ7.35-7.24(m,2H),7.19(t,J=7.6Hz,1H),2.43-2.39(m,1H),2.08(s,3H),1.75(s, 3H), 1.32 (d, J = 8.0Hz, 3H), 1.06-1.04 (m, 1H), 0.58-0.56 (m, 1H), 0.44-0.42 (m, 1H), 0.21-0.14 (m, 2H).

[0217] (3) Synthesis of compound 9: 7-(1-cyclopropylethyl)-3-methylbenzofuran-2(3-hydro)-one:

[0218] Compound 9-2 (530 mg, 1.93 mmol, 1.0 eq), Pd / C (Pd: 10%, 48 mg, 0.10 mmol, 0.05 eq), and MeOH (10.0 mL) were added to a reaction flask. The mixture was purged three times with hydrogen gas, and a hydrogen balloon was added. The reaction was carried out at 60 °C for 1 h. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (V... 石油醚 V DCM Petroleum ether / DCM = 3:1) yielded compound 9 as a colorless oily liquid (63 mg, yield 15.1%) and compound 10 as a colorless oily liquid (23 mg, yield 4.8%).

[0219] 1 H NMR (400MHz, CDCl3) δ7.21 (dd, J=7.2, 2.1Hz, 1H), 7.16-7.08 (m, 2H), 3.75 (q, J=7.6Hz, 1H), 2.43-2.39 (m, 1H), 1.60 (d,J=7.6Hz,3H),1.32(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.58-0.56(m,1H),0.44-0.42(m,1H),0.21-0.14(m,2H).

[0220] Example 10 Synthesis of methyl 2-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)propionate (10)

[0221] The preparation method of compound 10 is described in Example 9.

[0222] 1H NMR (400MHz, CDCl3) δ7.74(s,1H),7.15(dd,J=7.6,1.6Hz,1H),6.96(dd,J=7.6,1.7Hz,1H),6.87(t,J=7.6Hz,1H),3.88(q,J=7.2Hz,1H),3.74(s, 3H),2.43-2.38(m,1H),1.57(d,J=5.6Hz,4H),1.35(d,J=8.0Hz,3H),1.0 7-1.04(m,1H),0.58-0.56(m,1H),0.46-0.44(m,1H),0.23-0.17(m,2H).

[0223] Example 11 Synthesis of deuterated methyl 2-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)propionate (11)

[0224]

[0225] (1) Synthesis of intermediate 11-1: methyl 2-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)propionate:

[0226] Compound 10 (200 mg, 0.81 mmol, 1.0 eq), potassium carbonate (222 mg, 1.61 mmol, 2.0 eq), benzyl bromide (180 mg, 1.05 mmol, 1.3 eq), and acetonitrile (3 mL) were added sequentially to the reaction flask. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, washed with acetonitrile, concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 ratio as the eluent, product 11-1 (259 mg, yield 94.5%) was obtained as a yellow, transparent oily substance.

[0227] 1 H NMR (400MHz, CDCl3) δ7.49(m,2H),7.44-7.39(m,3H),7.15(dd,J=7.6,1.6Hz,1H ),6.96(dd,J=7.6,1.7Hz,1H),6.87(t,J=7.6Hz,1H),5.32(s,2H),3.88(q,J=7.2 Hz,1H),3.74(s,3H),2.43-2.38(m,1H),1.57(d,J=5.6Hz,3H),1.35(d,J=8.0Hz, 3H),1.07-1.04(m,1H),0.58-0.56(m,1H),0.46-0.44(m,1H),0.23-0.17(m,2H).

[0228] (2) Synthesis of intermediate 11-2: 2-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)propionic acid:

[0229] Compound 11-1 (250 mg, 0.74 mmol, 1.0 eq), 6N sodium hydroxide aqueous solution (0.15 mL, 0.89 mmol, 1.2 eq), and 1,4-dioxane (5 mL) were added sequentially to the reaction flask. The reaction solution was heated to 60 °C and reacted for 2 h. After cooling to room temperature, water (10 mL) and ethyl acetate (20 mL) were added. The aqueous phase was separated and the pH was adjusted to 1 with 2N hydrochloric acid. Ethyl acetate was added for extraction (3 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the target product 11-2 as a pale yellow liquid (218 mg, yield 90.8%). This product was directly added to the next reaction without further purification.

[0230] (3) Synthesis of intermediate 11-3: deuterated methyl 2-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)propionate:

[0231] Compound 11-2 (210 mg, 0.65 mmol, 1.0 eq), deuterated methanol (2 mL), and concentrated sulfuric acid (2 drops) were added sequentially to the reaction flask. The reaction solution was heated to 65 °C and reacted for 4 h. After the reaction was completed as shown by TLC, the reaction solution was cooled to room temperature, diluted with MTBE (10 mL), washed with saturated sodium bicarbonate solution (5 mL), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a colorless, transparent, oily liquid, liquid 11-3 (205 mg, yield 92.4%), which was directly added to the next reaction without further purification.

[0232] (4) Synthesis of compound 11: Deuterated methyl 2-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)propionate:

[0233] Compound 11-3 (200 mg, 0.59 mmol, 1.0 eq), Pd / C (Pd: 10%, 10 mg, 0.03 mmol, 0.05 eq), and MeOH (5.0 mL) were added to a reaction flask. The mixture was purged with hydrogen three times, a hydrogen balloon was added, and the reaction was carried out at 60 °C for 1 h. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (V... 石油醚 V DCM =3:1), to obtain compound 11 as a colorless oily liquid (23 mg, yield 15.5%).

[0234] 1H NMR (400MHz, CDCl3) δ7.74(s,1H),7.15(dd,J=7.6,1.6Hz,1H),6.96(dd,J=7.6,1.7Hz,1H),6.87(t,J=7.6Hz,1H),3.88(q,J=7.2Hz,1H),2 .43-2.38(m,1H),1.57(d,J=5.6Hz,4H),1.35(d,J=8.0Hz,3H),1.07-1.04(m,1H),0.58-0.56(m,1H),0.46-0.44(m,1H),0.23-0.17(m,2H).

[0235] Example 12 Synthesis of sodium (2-(1-cyclopropylethyl)-6-(1-methoxy-1-oxopropane-2-yl)phenoxy)methylphosphate (12)

[0236]

[0237] (1) Synthesis of intermediate 12-1: methyl 2-(3-(1-cyclopropylethyl)-2-(hydroxymethoxy)phenyl)propionate:

[0238] Compound 10 (200 mg, 0.81 mmol, 1.0 eq), tetrahydrofuran (3 mL), and sodium hydroxide (64 mg, 1.612 mmol, 2.0 eq) were added sequentially to a reaction flask. The mixture was heated under reflux for 0.5 h, followed by the addition of bromochloromethane (3.14 g, 24.3 mmol, 30 eq). The reaction mixture was reacted at 70 °C for 2 h, after which stirring was stopped. The reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography with V polarity eluent. 正己烷 V 乙酸乙酯 The ratio of 50:1 to 15:1 yielded the target compound 12-1 as a pale yellow liquid crude product (160 mg, yield: 71.0%), which was directly added to the next reaction without further purification.

[0239] (2) Synthesis of compound 12: Sodium (2-(1-cyclopropylethyl)-6-(1-methoxy-1-oxopropane-2-yl)phenoxy)methylphosphate:

[0240] Phosphoric acid (423 mg, 4.32 mmol, 8.0 eq.), triethylamine (5 mg, 3.2 mmol, 10.0 eq.), and acetonitrile (5 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and reacted for 0.5 h. Then, compound 12-1 (150 mg, 0.54 mmol, 1.0 eq.) was added, and the mixture was reacted at 70 °C for 24 h. After the reaction was completed as detected by TLC, the reaction mixture was evaporated to dryness under reduced pressure. 2 mL of water was added, and the pH was adjusted to 1 with 1 N hydrochloric acid. The mixture was extracted with methyl tert-butyl ether (20 mL * 3). The organic phase was evaporated to dryness, and 10 mL of ethanol was added to dissolve it. 10% (w / w) sodium hydroxide aqueous solution (0.54 mL, 1.08 mmol, 2.0 eq.) was added using a pipette. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and 95% isopropanol aqueous solution (4 mL) was added to the residue. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. A pale yellow powdery solid was obtained by pumping. Add acetonitrile (5 mL), beat at 50 °C for 4 h, and filter while hot to obtain the target product 12 (65 mg, 29.9%), a light yellow powder solid.

[0241] 1 H NMR (400MHz, CDCl3) δ7.42-7.37(m,2H),7.31-7.27(m,1H),5.45(s,2H),3.88(q,J=7.2Hz,1H),3.74(s,3H),2.43-2.38(m,1 H), 1.57 (d, J = 5.6Hz, 3H), 1.35 (d, J = 8.0Hz, 3H), 1.07-1.04 (m, 1H), 0.58-0.56 (m, 1H), 0.46-0.44 (m, 1H), 0.23-0.17 (m, 2H).

[0242] Example 13 Synthesis of 3-(2-hydroxy-3-isopropylphenyl)-N-methylbutyramide (13)

[0243]

[0244] 400 mg (1.69 mmol) of methyl 3-(2-hydroxy-3-isopropylphenyl)butyrate and 10.0 mL of methylamine in methanol were added to a reaction flask and reacted at 60 °C for 7 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (V). 石油醚 V DCM The ratio of the extract to the target compound 13 was 1:5, yielding 180 mg of a colorless oily liquid. The yield was 45%.

[0245] 1H NMR (400MHz, CDCl3) δ8.43(s,1H),7.09-7.04(m,1H),6.99(d,J=1.7Hz,1H),6.89(d,J=7.6Hz,1H),5.42(s,1H),3.78-3.66(m,1H) ,3.47-3.37(m,1H),2.71(d,J=4.8,,3H),2.67–2.61(m,1H),2.34(dd,J=16,10Hz,1H),1.32(d,J=7.1Hz,3H),1.22(d,J=6.8,6H).

[0246] Example 14 Synthesis of Compound 14: 8-Isopropyl-4-methylbenzodihydropyran-2-one (14)

[0247]

[0248] methyl 3-(2-hydroxy-3-isopropylphenyl)butyrate 7 (140 mg, 0.59 mmol), TFA (0.5 mL), and DCM (5.0 mL) were added to a reaction flask and reacted at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (V). 石油醚 V DCM The ratio of the extract to the target compound 14 was 3:1, yielding 110 mg of a colorless oily liquid. The yield was 91%.

[0249] 1 H NMR(400MHz, CDCl3)δ7.20(dd,J=7.6,1.9Hz,1H),7.13-7.01(m,2H),3.49-3.34(m,1H),3.21-3.11(m,1H),2 .82(dd,J=15.6,5.4Hz,1H), 2.58(dd,J=15.6,7.2Hz,1H), 1.33(d,J=7.2Hz,3H), 1.24(dd,J=7.0,4.2Hz,6H).

[0250] Example 15 Synthesis of Compound 15: 7-Isopropyl-3-methylbenzofuran-2(3-hydro)-one (15)

[0251]

[0252] (1) Synthesis of intermediate 15-2: (S)-3-hydroxy-7-isopropyl-3-methylbenzofuran-2(3-hydro)-one:

[0253] 2-Isopropylphenol 15-1 (408 mg, 3 mmol) and DCM (10.0 mL) were added to a reaction flask. Under nitrogen protection and cooling in an ice-water bath, pyruvate (367.2 mg, 3.6 mmol) was added, followed by the dropwise addition of TiCl4 (682.8 mg, 3.6 mmol) in dichloromethane solution (3 mL). The mixture was slowly heated to room temperature and reacted for 1 h. After the reaction was complete, 10 mL of saturated ammonium chloride solution was added, followed by extraction with DCM (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =1:1), yielding 15-2 (450 mg, yield 73%) of a colorless oily liquid.

[0254] 1 H NMR (400MHz, CDCl3) δ7.35-7.24(m,2H),7.19(t,J=7.6Hz,1H),3.30-3.06(m,1H),1.75(s,3H),1.31(dd,J=7.0,2.6Hz,6H).

[0255] (2) Synthesis of intermediate 15-3: 7-isopropyl-3-methyl-2-oxo-2,3-dihydrobenzofuran-3-yl-acetate:

[0256] 3-Hydroxy-7-isopropyl-3-methylbenzofuran-2(3H)-one 15-2 (300 mg, 1.45 mmol) and THF (10.0 mL) were added to a reaction flask, followed by DMAP (18 mg, 0.15 mmol) and Et3N (212 mg, 2.1 mmol), and then acetic anhydride (214 mg, 2.1 mmol) was added dropwise. After the addition was complete, the temperature was raised to 65 °C and the reaction was carried out for 2 h. After the reaction was complete, the mixture was washed with 10 mL of 1 M dilute hydrochloric acid, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =3:1), yielding 15-3 (360 mg, 100% yield) of a colorless oily liquid.

[0257] 1 H NMR (400MHz, CDCl3) δ7.26-7.23(m,1H),7.14-7.05(m,2H),3.23(p,J=7.0Hz,1H),2.06(s,3H),1.72(s,3H),1.29(d,J=7.0Hz,6H).

[0258] (3) Synthesis of compound 15: 7-isopropyl-3-methylbenzofuran 2(3-hydro)-one:

[0259] 15-3 methyl-2-oxo-2,3-dihydrobenzofuran-3-yl acetate (360 mg, 1.44 mmol), Pd / C (Pd: 10%, 36 mg), and MeOH (10.0 mL) were added to a reaction flask. The mixture was purged with hydrogen three times, a hydrogen balloon was added, and the reaction was carried out at 60 °C for 1 h. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =3:1), yielding compound 15 as a colorless oily liquid (210 mg, yield 77%) and compound 16 as a colorless oily liquid (63 mg, yield 20%).

[0260] 1 H NMR (400MHz, CDCl3) δ7.21-7.15(m,1H),7.14-7.05(m,2H),3.72(q,J=7.6Hz ,1H),3.26-3.13(m,1H),1.57(d,J=7.6Hz,3H),1.28(dd,J=7.0,2.3Hz,6H).

[0261] Example 16 Synthesis of methyl 2-(2-hydroxy-3-isopropylphenyl)propionate (16)

[0262] The preparation method of compound 16 is described in Example 15.

[0263] 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.15(dd,J=7.6,1.6Hz,1H),6.96(dd,J=7.6,1.6Hz,1H),6.87(t,J=7.6Hz, 1H), 3.88 (q, J = 7.2Hz, 1H), 3.74 (s, 3H), 3.40-3.31 (m, 1H), 1.57 (d, J = 5.6Hz, 3H), 1.24 (dd, J = 7.0, 4.0Hz, 6H).

[0264] Example 17 Synthesis of 1-cyclopropyl-2-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)-1-propanone (17)

[0265]

[0266] (1) Synthesis of intermediate 17-1: 2-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)propionic acid:

[0267] Compound 11-1 (5.0 g, 14.8 mmol, 1.0 eq), lithium hydroxide monohydrate (682 mg, 16.3 mmol, 1.1 eq), 10 mL of water, and 20 mL of methanol were added sequentially to the reaction flask. The mixture was stirred overnight at room temperature. The reaction solution was concentrated, and the pH of the residue was adjusted to 2 with 1 M dilute hydrochloric acid. The residue was then extracted with ethyl acetate (15 mL × 3), and the organic phase was concentrated. The residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:5 ratio as the eluent, product 17-1 (4.7g, yield 97.9%) was obtained as a colorless, transparent oily substance.

[0268] 1 H NMR(400MHz, CDCl3)δ7.50(m,2H),7.46-7.41(m,3H),7.14(dd,J=7.6,1.6Hz, 1H),6.96(dd,J=7.6,1.6Hz,1H),6.87(t,J=7.6Hz,1H),5.34(s,2H),3.86(q, J=7.2Hz,1H),2.44-2.38(m,1H),1.56(d,J=5.6Hz,3H),1.34(d,J=8.0Hz,3H) ,1.07-1.04(m,1H),0.58-0.56(m,1H),0.46-0.44(m,1H),0.23-0.16(m,2H).

[0269] (2) Synthesis of intermediate 17-2: 2-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)-N-methoxy-N-methylpropionamide:

[0270] Compound 17-1 (4.6 g, 14.2 mmol, 1.0 eq), dimethylhydroxylamine hydrochloride (1.52 g, 15.62 mmol, 1.1 eq), and triethylamine (1.58 g, 15.62 mmol, 1.1 eq) were added to 25 mL of DMF. 10 mL of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0 g, 15.62 mmol, 1.1 eq) solution was added dropwise at 0 °C. After 1 h of reaction, the mixture was allowed to stand at room temperature for 8 h. The reaction mixture was then poured into 90 mL of water and extracted with EA (25 mL × 3). The organic phases were combined, washed once with 50 mL of water, concentrated, and purified by column chromatography (V). 石油醚 V DCM =3:1), yielding a colorless oily liquid 17-2 (4.9 g, yield 94.2%).

[0271] 1H NMR (400MHz, CDCl3) δ7.53 (m, 2H), 7.44-7.38 (m, 3H), 7.13 (dd, J = 7.6, 1.6Hz, 1H), 6 .96(dd,J=7.6,1.6Hz,1H),6.87(t,J=7.6Hz,1H),5.31(s,2H),3.88(q,J=7.2Hz,1H) ,3.56(s,3H),3.40(s,3H),2.44-2.38(m,1H),1.57(d,J=5.6Hz,3H),1.33(d,J=8.0 Hz,3H),1.07-1.04(m,1H),0.56-0.54(m,1H),0.46-0.44(m,1H),0.23-0.18(m,2H).

[0272] (3) Synthesis of intermediate 17-3: 2-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)-1-cyclopropyl-1-propanone:

[0273] Compound 17-2 (4.5 g, 12.2 mmol, 1.0 eq) was added to 30 mL of anhydrous tetrahydrofuran. Under nitrogen protection, a 1 M tetrahydrofuran solution of cyclopropylmagnesium bromide (12.4 mL, 12.4 mmol, 1.02 eq) was added dropwise at -10 °C. After the addition was complete, the reaction mixture was reacted at 0 °C for 1 h. The reaction solution was then poured into 30 mL of 15% ammonium chloride solution and extracted with EA (25 mL × 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =3:2), yielding a colorless oily liquid 17-3 (1.2 g, yield 28.2%).

[0274] 1 H NMR (400MHz, CDCl3) δ7.48 (m, 2H), 7.44-7.39 (m, 3H), 7.13 (dd, J = 7.6, 1.6Hz, 1H), 6. 97(dd,J=7.6,1.6Hz,1H),6.87(t,J=7.6Hz,1H),5.33(s,2H),3.89(q,J=7.2Hz,1H),2 .43-2.36(m,1H),1.95-1.85(m,1H),1.56(d,J=5.6Hz,3H),1.34(d,J=8.0Hz,3H),1.2 3(m,2H),1.07-1.02(m,3H),0.58-0.56(m,1H),0.46-0.44(m,1H),0.23-0.17(m,2H).

[0275] (4) Synthesis of Compound 17: 1-Cyclopropyl-2-(3-(1-Cyclopropylethyl)-2-hydroxyphenyl)-1-propanone:

[0276] Compound 17-3 (1.0 g, 2.9 mmol, 1.0 eq) was added to 10 mL of anhydrous methanol, followed by palladium on carbon (palladium content w / w = 10%, 0.1 g). The reaction was carried out under a hydrogen atmosphere at room temperature for 24 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (V). 石油醚 V DCM =3:1), yielding a colorless oily liquid (0.40 g, yield 53.4%).

[0277] 1 H NMR (400MHz, CDCl3) δ7.11 (dd, J=7.6, 1.6Hz, 1H), 7.05 (dd, J=7.6, 1.6Hz, 1H ),6.98-6.92(m,1H),6.92(s,1H),3.88(q,J=7.2Hz,1H),2.43-2.38(m,1H), 1.95-1.85(m,1H),1.57(d,J=5.6Hz,3H),1.35(d,J=8.0Hz,3H),1.21(m,2H) ,1.07-1.02(m,3H),0.58-0.56(m,1H),0.46-0.44(m,1H),0.23-0.17(m,2H).

[0278] Example 18 Synthesis of deuterated methyl 3-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)butyrate (18)

[0279]

[0280] (1) Synthesis of intermediate 18-1: deuterated methyl 3-(2-(benzyloxy)-3-(1-cyclopropylethyl)phenyl)butyrate:

[0281] Compounds 1-9 (800 mg, 2.28 mmol, 4.0 eq), THF (20 mL), and 10% sodium hydroxide aqueous solution were added sequentially to the reaction flask. The mixture was stirred at room temperature for 2 hours, and the reaction was confirmed to be complete by TLC. The solution was adjusted to a weakly acidic state (pH = 5) with 1% hydrochloric acid. The reaction solution was poured into 50 mL of water and extracted with EA (25 mL × 3). The organic phases were combined, washed once with 50 mL of water, concentrated, and directly added to the next reaction without further purification. Deuterated methanol (2 mL) and concentrated sulfuric acid (2 drops) were added sequentially to the reaction flask containing the concentrated crude product. The reaction solution was heated to 65 °C and reacted for 4 hours. After the reaction was completed as shown by TLC, the reaction solution was cooled to room temperature. MTBE (10 mL) was added to dilute the reaction solution. The reaction solution was washed with saturated sodium bicarbonate solution (5 mL) and saturated saline solution (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a colorless, transparent, oily liquid, Liquid 18-1 (505 mg, yield 92.4%). This liquid was directly added to the next reaction without further purification.

[0282] (2) Synthesis of compound 18: deuterated methyl ester of 3-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)butyrate

[0283] Compound 18-1 (200 mg, 0.56 mmol, 1.0 eq), palladium / carbon (15 mg, palladium content w / w = 10%), potassium carbonate (11.8 mg, 0.09 mmol, 0.15 eq), and methanol (4 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 18 (60 mg, yield 40.4%) was obtained as a pale yellow solid.

[0284] 1 HNMR(400MHz, CDCl3), δ7.36-7.22(m,2H),6.91-6.88(m,1H),4.58(s,1H),3.51-3.62(m,1H),2.44-2.63(m,2H),2.42-2.31( m,1H),1.33(d,J=8.0Hz,3H),1.21-1.25(m,3H),1.07-1.04(m,1H),0.56-0.52(m,1H),0.45-0.43(m,1H),0.23-0.16(m,2H).

[0285] Example 19 Synthesis of sodium 3-(3-isopropyl-2-phenol sodium)butyrate (19)

[0286]

[0287] Compound 14 (150 mg, 0.79 mmol) and MeOH (5.0 mL) were added to a reaction flask, followed by the addition of a 3.0 mL solution of sodium hydroxide (63 mg, 1.57 mmol) in water. The reaction was carried out at 25 °C for 3 h. After the reaction was complete, the mixture was concentrated and stirred with 2 mL of n-hexane for 0.5 h. The filtrate was discarded, and the mixture was stirred with 2 mL of DCM for 0.5 h. The filtrate was discarded, and the mixture was dried under vacuum to obtain a yellow solid 19 (200 mg, yield: 95%).

[0288] 1 H NMR (400MHz, CDCl3) δ7.25 (dd, J=7.3, 1.9Hz, 1H), 7.13 (dd, J=7.9, 1.7Hz, 1H), 6.99-6.90 (m, 1H), 3.60 –3.52(m,1H),3.10-3.02(m,1H),2.40-2.32(m,2H),1.24(d,J=7.1Hz,3H),1.20-1.14(d,J=6.9Hz,6H).

[0289] Example 20 Synthesis of sodium 2-(3-(1-cyclopropylethyl)-2-phenol sodium)propionate (20)

[0290]

[0291] Compound 11 (150 mg, 0.60 mmol) and MeOH (5.0 mL) were added to a reaction flask, followed by the addition of a 3.0 mL solution of sodium hydroxide (48 mg, 1.57 mmol) in water. The reaction was carried out at 25 °C for 3 h. After the reaction was complete, the mixture was concentrated and stirred with 2 mL of n-hexane for 0.5 h. The filtrate was discarded, and the mixture was stirred with 2 mL of DCM for 0.5 h. The filtrate was discarded, and the mixture was dried under vacuum to give a yellow solid 20 (200 mg, yield: 95%).

[0292] 1 H NMR (400MHz, CDCl3) δ7.19 (dd, J=7.7, 1.8Hz, 1H), 7.05 (dd, J=7.7, 1.8Hz, 1H), 6.91 (t, J=7.7Hz, 1H), 3.78 (q, J=7.2Hz, 1H), 2.43-2. 38(m,1H),1.57(d,J=5.6Hz,4H),1.38(d,J=8.0Hz,3H),1.06-1.01(m,1H),0.58-0.52(m,1H),0.49-0.45(m,1H),0.23-0.19(m,2H).

[0293] Example 21 Synthesis of (2-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)-N,N-dimethylpropionamide)(21)

[0294]

[0295] (1) Synthesis of compound 21-2: (methyl 2-hydroxy-2-(2-hydroxyphenyl)propionate)

[0296] Phenol 21-1 (5.0 g, 53.1 mmol, 1.0 eq) and methyl pyruvate (5.95 g, 58.45 mmol, 1.1 eq) were added to 50 mL of DCM. TiCl4 (11.1 g, 58.45 mmol, 1.1 eq) was added dropwise at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 1 h. After the reaction was complete, 30 mL of saturated ammonium chloride solution was added, followed by extraction with DCM (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a pale yellow oily liquid 21-2 (10.0 g, yield 96.0%), which was used directly in the next step.

[0297] 1 H NMR (400MHz, CDCl3) δ8.38(s,1H),7.24–7.15(m,2H),6.93–6.81(m,2H),4.17(s,1H),3.82(s,3H),1.84(s,3H).

[0298] (2) Synthesis of compound 21-3: (3-hydroxy-3-methylbenzofuran-2(3H)-one)

[0299] Compound 21-2 (10.0 g, 51.0 mmol, 1.0 eq) was added to 80 mL of toluene and 10 mL of trifluoroacetic acid, reacted at 90 °C for 1 h, cooled, concentrated under reduced pressure, and the residue was separated by column chromatography using V... PE V EA Using a 4:1 ratio as the eluent, a colorless liquid product 21-3 (7.5g, yield 89.6%) was obtained.

[0300] 1 H NMR (400MHz, CDCl3) δ7.43 (dd, J=7.5, 0.9Hz, 1H), 7.38 (td, J=8.0, 1.4Hz, 1H) ,7.22(td,J=7.6,0.8Hz,1H),7.13(d,J=8.1Hz,1H),2.89(s,1H),1.73(s,3H).

[0301] (3) Synthesis of compound 21-4: (3-acetoxy-3-methyl-2-oxo-2,3-dihydrobenzofuran)

[0302] Compound 21-3 (7.4 g, 45.1 mmol, 1.0 eq), acetic anhydride (5.53 g, 54.1 mmol, 1.2 eq), DMAP (551 mg, 4.51 mmol, 0.1 eq), and triethylamine (5.47 g, 54.1 mmol, 1.2 eq) were added to 100 mL of DCM and reacted at room temperature for 2 h. Then, 50 mL of water was added, the mixture was separated, and the organic phase was concentrated under reduced pressure to give 9.2 g of a colorless liquid product, with a yield of 98.9%.

[0303] 1 H NMR (400MHz, CDCl3) δ7.37(td,J=7.9,1.3Hz,1H),7.27(dd,J=7.6,1.0Hz,1H),7.20–7.10(m,2H),2.07(s,3H),1.72(s,3H).

[0304] (4) Synthesis of compound 21-5: (3-methylbenzofuran-2(3H)-one)

[0305] Compound 21-4 (9.0 g, 43.6 mmol, 1.0 eq) and Pd / C (Pd: 10%, 900 mg) were added to 100 mL of MeOH and reacted at 60 °C for 3 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (V... 石油醚 V DCM =3:1), yielding a colorless oily liquid 21-5 (6.2 g, yield 95.6%).

[0306] 1 H NMR (400MHz, CDCl3) δ7.32(t,J=7.8Hz,1H),7.27(d,J=7.0Hz,1H),7.18(dd,J=7 .5,0.7Hz,1H),7.13(t,J=7.3Hz,1H),3.77–3.72(m,1H),1.59(d,J=7.6Hz,3H).

[0307] (5) Synthesis of compound 21-6: (methyl 2-(2-hydroxyphenyl)propionate)

[0308] Compound 21-5 (6.0 g, 40.5 mmol, 1.0 eq) was added to 50 mL of MeOH, followed by sodium methoxide (2.19 g, 40.5 mmol, 1.0 eq). The reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete, 3 mL of acetic acid was added to quench the reaction. The reaction mixture was concentrated under reduced pressure. The residue was then added to 50 mL of ethyl acetate and 20 mL of water. The mixture was separated, and the organic phase was concentrated under reduced pressure to give a white solid 21-6 (7.0 g, 95.9% yield).

[0309] 1 H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 7.23–7.16 (m, 2H), 6.90–6.80 (m, 2H), 3.91 (q, J = 7.3Hz, 1H), 3.76 (s, 3H), 1.32 (d, J = 7.0Hz, 3H).

[0310] (6) Synthesis of Compound 21-7: (2-(2-(but-2-enyloxy)phenyl)propionate)

[0311] Compound 21-6 (6.8 g, 37.8 mmol, 1.0 eq), 1-chloro-2-butene (5.13 g, 56.7 mmol, 1.5 eq), potassium carbonate (10.4 g, 75.6 mmol, 2.0 eq), and 0.2 g KI were added to 70 mL of acetone and reacted overnight at room temperature. After the reaction was complete, the reaction solution was poured into 100 mL of water and extracted with n-hexane (5 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was separated by column chromatography. PE V EA Using a 50:1 ratio as the eluent, a colorless liquid 21-7 (4.8 g, yield 54.2%) was obtained.

[0312] 1 H NMR (400MHz, CDCl3) δ7.24–7.17(m,2H),6.93(td,J=7.1,2.5Hz,1H),6.90–6.82(m,1H),5.89–5.74(m,1H),5.72–5.62(m,1H) ,4.61(d,J=5.3Hz,1H),4.47(d,J=5.0Hz,1H),4.10–4.00(m,1H),3.65(s,3H),1.80–1.67(m,3H),1.46(dd,J=7.2,2.0Hz,3H).

[0313] (7) Synthesis of Compound 21-8: (7-(but-3-en-2-yl)-3-methylbenzofuran-2(3H)-one)

[0314] Compound 21-7 (4.8 g, 20.5 mmol, 1.0 eq) was added to a 25 mL reaction flask and reacted at 215 °C for 3 h. After the reaction was complete, the reactants were directly separated by column chromatography. PE V EA Using a 50:1 ratio as the eluent, a colorless liquid 21-8 (3.6 g, yield 86.7%) was obtained.

[0315] 1H NMR (400MHz, CDCl3) δ7.20 (dd, J=7.2, 2.1Hz, 1H), 7.15-7.08 (m, 2H), 6.13-6.05 (m, 1H), 5.21- 5.16(m,2H),3.75(q,J=7.6Hz,1H),3.71(m,1H),1.60(d,J=7.6Hz,3H),1.40(d,J=8.0Hz,3H),.

[0316] (8) Synthesis of Compounds 21-9: ((1-Cyclopropylethyl)-3-methylbenzofuran-2(3H)-one)

[0317] Under nitrogen protection, 50 mL of DCM was added to a 250 mL three-necked flask. The reaction system was cooled to -5 to 0 °C, and then diethylzinc (26.7 mL, 2.0 M, 53.4 mmol, 3.0 eq), trifluoroacetic acid (5.18 g, 53.4 mmol, 3.0 eq), and diiodomethane (19.1 g, 71.2 mmol, 4.0 eq) were slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 1 h. Then, compound 21-8 (3.6 g, 17.8 mmol, 1.0 eq) was dissolved in 10 mL of DCM and slowly added dropwise to the reaction mixture. After the addition was complete, the temperature was slowly raised to 25 °C, and the reaction was stirred for 48 h. The reaction was stopped, and 50 mL of dichloromethane was added to the reaction solution. The mixture was then washed with saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography with a polarity of V. 正己烷 V 乙酸乙酯 Using a 50:1 ratio as the eluent, a yellow oily substance 21-9 (2.8 g, yield 72.7%) was obtained.

[0318] 1 H NMR (400MHz, CDCl3) δ7.21 (dd, J=7.2, 2.1Hz, 1H), 7.16-7.08 (m, 2H), 3.75 (q, J=7.6Hz, 1H), 2.43-2.39 (m, 1H), 1.60 (d,J=7.6Hz,3H),1.32(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.58-0.56(m,1H),0.44-0.42(m,1H),0.21-0.14(m,2H).

[0319] (9) Synthesis of Compound 21: (2-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)-N,N-dimethylpropionamide)

[0320] Compound 21-9 (50 mg, 0.23 mmol, 1.0 eq) and 40% dimethylamine aqueous solution (0.5 mL) were added to 5 mL of tetrahydrofuran solvent, and the mixture was heated to 60 °C for 2 h. The reaction was monitored by TLC (V0.05). PE V EA =5:1), the reactants reacted completely, the reaction solution was cooled to room temperature and diluted with 5 mL of water, 10 mL of ethyl acetate was added for extraction, the liquid was separated, the aqueous phase was extracted again with EA (10 mL × 2), the organic phases were combined, dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and column chromatography was used to obtain a pale yellow oil 21 (35 mg, yield 57.9%).

[0321] 1 H NMR (400MHz, CDCl3) δ10.33(d,J=1.7Hz,1H),7.24(dd,J=6.3Hz,1.6Hz,1H),6.85( dd,J=7.5,1.6Hz,1H),6.78(td,J=7.5,1.0Hz,1H),4.01(q,J=7.1Hz,1H),3.20(s, 3H),3.00(s,3H),2.60–2.53(m,1H),1.56(d,J=7.1Hz,3H),1.28(dd,J=7.0,2.3Hz ,3H),1.04–0.99(m,1H),0.55–0.50(m,1H),0.39–0.34(m,1H),0.22–0.16(m,2H).

[0322] Example 22 Synthesis of (2-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)-N-methylpropionamide)(22)

[0323]

[0324] Compound 21-9 (100 mg, 0.46 mmol, 1.0 eq) and a 30% methylamine methanol solution (1.0 mL) were added to 5 mL of tetrahydrofuran solvent, and the mixture was heated to 60 °C for 2 h. The reaction was monitored by TLC (V0.0). PE V EA =5:1), the reactants reacted completely, the reaction solution was cooled to room temperature and diluted with 5 mL of water, extracted with 10 mL of ethyl acetate, separated, the aqueous phase was extracted again with EA (10 mL × 2), the organic phases were combined, dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and column chromatography was performed to give a pale green oil 22 (100 mg, yield 87.4%).

[0325] 1H NMR (400MHz, CDCl3) δ10.22(d,J=3.6Hz,1H),7.24(d,J=6.4Hz,1H),6.85–6.79(m,2H),5.89(s,1H),3.51(q,J=7.2Hz,1H),2.84(d,J=4.9Hz,3H ),2.61–2.54(m,1H),1.59(d,J=7.2Hz,3H),1.29(d,J=7.0Hz,3H),1.06 –0.99(m,1H),0.56–0.50(m,1H),0.40-0.35(m,1H),0.22–0.14(m,2H).

[0326] Example 23 Synthesis of (1-(aziridin-1-yl)-2-(3-(1-cyclopropylethyl)-2-hydroxyphenyl)prop-1-one)(23)

[0327]

[0328] Compound 21-9 (100 mg, 0.46 mmol, 1.0 eq) and aziridine (30 mg, 0.69 mmol, 1.5 eq) were added to 5 mL of tetrahydrofuran solvent and heated to 60 °C for 2 h. The reaction was monitored by TLC (V0.05). PE V EA =5:1), the reactants reacted completely, the reaction solution was cooled to room temperature and diluted with 5 mL of water, 10 mL of ethyl acetate was added for extraction, the liquid was separated, the aqueous phase was extracted again with EA (10 mL × 2), the organic phases were combined, dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and column chromatography was used to obtain a pale green oil 23 (80 mg, yield 67.2%).

[0329] 1 H NMR (400MHz, CDCl3) δ10.26(d,J=1.8Hz,1H),7.23(d,J=6.8Hz,1H),6.88–6.81(m,2H),3.85(q,J=7.2Hz,1H),2.60–2.54(m,1H),2. 35(s,4H),1.59(d,J=7.2Hz,3H),1.29(d,J=7.0Hz,3H),1.06–1.00(m,1H),0.56–0.50(m,1H),0.40-0.34(m,1H),0.22–0.14(m,2H).

[0330] Synthesis of Example 24 (2-(2-hydroxy-3-isopropylphenyl)-N,N-dimethylpropionamide)(24)

[0331]

[0332] (1) Synthesis of compound 24-2 (3-hydroxy-7-isopropyl-3-methylbenzofuran-2(3H)-one)

[0333] 2-Isopropylphenol 24-1 (408 mg, 3 mmol, 1.0 eq) and DCM (10.0 mL) were added to a reaction flask. Under nitrogen protection and cooling in an ice-water bath, pyruvate (367.2 mg, 3.6 mmol, 1.2 eq) was added, followed by the dropwise addition of a dichloromethane solution (3 mL) of TiCl4 (682.8 mg, 3.6 mmol, 1.2 eq). The mixture was slowly heated to room temperature and reacted for 1 h. After the reaction was complete, 10 mL of saturated ammonium chloride solution was added, followed by extraction with DCM (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. 10 mL of toluene and 1 mL of trifluoroacetic acid were added and stirred for 2 h. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (V). 石油醚 V DCM =1:1), to obtain colorless oily liquid product 24-2 (450mg, yield 73%).

[0334] 1 H NMR (400MHz, CDCl3) δ7.35-7.24(m,2H),7.19(t,J=7.6Hz,1H),3.30-3.06(m,1H),1.75(s,3H),1.31(dd,J=7.0,2.6Hz,6H).

[0335] (2) Synthesis of compound 24-3 (7-isopropyl-3-methyl-2-oxo-2,3-dihydrobenzofuran-3-ylacetate)

[0336] Compound 24-2 (300 mg, 1.45 mmol) and DCM (10.0 mL) were added to a reaction flask, followed by DMAP (18 mg, 0.15 mmol) and Et3N (212 mg, 2.1 mmol). Acetic anhydride (214 mg, 2.1 mmol) was then added dropwise. After the addition was complete, the mixture was heated to 65 °C and reacted for 2 h. After the reaction was complete, the mixture was washed with 1 M dilute hydrochloric acid (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =3:1), yielding a colorless oily liquid product 24-3 (360mg, 100% yield).

[0337] 1H NMR (400MHz, CDCl3) δ7.26-7.23(m,1H),7.14-7.05(m,2H),3.23(p,J=7.0Hz,1H),2.06(s,3H),1.72(s,3H),1.29(d,J=7.0Hz,6H).

[0338] (3) Synthesis of compound 24-4 (7-isopropyl-3-methylbenzofuran-2(3H)-one)

[0339] Compound 24-3 (360 mg, 1.44 mmol), Pd / C (Pd: 10%, 36 mg), and MeOH (10.0 mL) were added to a reaction flask. The mixture was purged with hydrogen three times, a hydrogen balloon was added, and the reaction was carried out at 60 °C for 1 h. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (V). 石油醚 V DCM =3:1), yielding the colorless oily liquid product 24-4 (210 mg, yield 77%).

[0340] 1 H NMR (400MHz, CDCl3) δ7.21-7.15(m,1H),7.14-7.05(m,2H),3.72(q,J=7.6Hz ,1H),3.26-3.13(m,1H),1.57(d,J=7.6Hz,3H),1.28(dd,J=7.0,2.3Hz,6H).

[0341] (4) Synthesis of compound 24 (2-(2-hydroxy-3-isopropylphenyl)-N,N-dimethylpropionamide)

[0342] Compound 24-4 (190 mg, 1.0 mmol, 1.0 eq) and 40% dimethylamine aqueous solution (1 mL) were added to 5 mL of tetrahydrofuran solvent, and the mixture was heated to 60 °C for 2 h. The reaction was monitored by TLC (V0.0). PE V EA =5:1), the reactants reacted completely, the reaction solution was cooled to room temperature and diluted with 5 mL of water, extracted with 10 mL of ethyl acetate, separated, the aqueous phase was extracted again with EA (10 mL × 2), the organic phases were combined, dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and column chromatography was performed to give a pale yellow oil 24 (180 mg, yield 76.6%).

[0343] 1H NMR (400MHz, CDCl3) δ10.30(d,J=1.7Hz,1H),7.23(dd,J=6.0Hz,1.6Hz,1H),6.83(dd,J=7.4,1.6Hz,1H),6.78(td,J=7.8,1.0H z,1H),4.01(q,J=7.2Hz,1H),3.20(s,3H),3.00(s,3H),3.25-3.12(m,1H),1.56(d,J=7.1Hz,3H),1.28(dd,J=7.0,2.3Hz,6H).

[0344] Synthesis of Example 25 (2-(2-hydroxy-3-isopropylphenyl)-N-methylpropionamide)(25)

[0345]

[0346] Compound 24-4 (190 mg, 1.0 mmol, 1.0 eq) and a 30% methylamine methanol solution (1.0 mL) were added to 5 mL of tetrahydrofuran solvent, and the mixture was heated to 60 °C for 2 h. The reaction was monitored by TLC (V0.0). PE V EA =5:1), the reactants reacted completely, the reaction solution was cooled to room temperature and diluted with 5 mL of water, 10 mL of ethyl acetate was added for extraction, the liquid was separated, the aqueous phase was extracted again with EA (10 mL × 2), the organic phases were combined, dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and column chromatography was performed to give 25 (138 mg, yield 55.8%) of a pale green oil.

[0347] 1 H NMR (400MHz, CDCl3) δ10.28(d,J=3.6Hz,1H),7.25(d,J=6.4Hz,1H),6.86–6.80(m,2H),5.87(s,1H),3.50(q ,J=7.2Hz,1H),3.24–3.11(m,1H),2.84(d,J=4.9Hz,3H),1.59(d,J=7.2Hz,3H),1.29(dd,J=7.0,2.1Hz,6H).

[0348] Example 26 (1-(aziridin-1-yl)-2-(2-hydroxy-3-isopropylphenyl)prop-1-one)(26) Synthesis

[0349]

[0350] Compound 24-4 (190 mg, 1.0 mmol, 1.0 eq) and aziridine (430 mg, 10 mmol, 10.0 eq) were added to 5 mL of tetrahydrofuran solvent and heated to 60 °C for 2 h. The reaction was monitored by TLC (V0). PE V EA =5:1), the reactants reacted completely, the reaction solution was cooled to room temperature and diluted with 5 mL of water, extracted with 10 mL of ethyl acetate, separated, the aqueous phase was extracted again with EA (10 mL × 2), the organic phases were combined, dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and column chromatography was performed to give 26 (100 mg, yield 42.9%) of a pale green oil.

[0351] 1 H NMR (400MHz, CDCl3) δ10.24(d,J=1.8Hz,1H),7.25(d,J=6.8Hz,1H),6.87–6.80(m,2H),3.85(q,J =7.2Hz,1H),3.25–3.12(m,1H),2.34(s,4H),1.59(d,J=7.2Hz,3H),1.29(dd,J=7.0,2.2Hz,6H).

[0352] Example 27 Synthesis of 5-(1-cyclopropylethyl)-2,3-dihydro-1-hydro-inden-4-ol (27)

[0353]

[0354] (1) Synthesis of intermediate 27-2: (E)-4-(but-2-en-1-yloxy)-2,3-dihydro-1-hydro-indene:

[0355] Compound 27-1 (3.8 g, 28.32 mmol) was dissolved in anhydrous DMF (60 mL), and sodium hydroxide (2.27 g, 56.64 mmol) was added under nitrogen protection. The reaction mixture was stirred at 25 °C for 30 minutes, followed by the slow addition of a cis-trans mixture of 1-chloro-2-butene (3.08 g, 33.99 mmol) at 0 °C. After the addition was complete, the reaction mixture was continued to react at 25 °C for 2 hours. TLC (V hexane V EA =1:0) to detect the end of the reaction. The reaction solution was slowly added dropwise to ice water (150 mL). The aqueous phase became turbid. After the addition was completed, it was diluted with n-hexane (100 mL), stirred evenly, and extracted three times with n-hexane (100 mL × 3). The organic phases were combined, washed once with saturated brine, separated, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a colorless oily cis-trans mixture 27-2 (5.2 g, yield: 97.5%).

[0356] 1 HNMR(400MHz, CDCl3), δ7.12-7.07(m,1H),6.85-6.84(m,1H),6.68-6.65(m,1H),5.88-5 .71(m,2H),4.63-4.48(m,2H),2.92-2.87(m,4H),2.10-2.03(m,2H),1.76-1.74(m,3H).

[0357] (2) Synthesis of intermediate 27-3: 5-(but-3-en-2-yl)-2,3-dihydro-1-hydro-inden-4-ol:

[0358] The cis-trans mixture 27-2 (3.1 g, 16.47 mmol) was purged 3-5 times under nitrogen protection, and the reaction solution was heated to 210 °C and reacted for 4-5 hours. TLC (V hexane V EA =10:1) Once most of the raw materials have been consumed, stop the reaction and allow the reaction solution to cool naturally to room temperature. Dilute the reaction solution with n-hexane, concentrate it, and purify the crude product by column chromatography using eluent polarity V. 正己烷 V 乙酸乙酯 The ratio of 20:1 to 15:1 yielded the target compound 27-3 as a yellow oil (2.5 g, yield: 80.6%).

[0359] 1 HNMR(400MHz, CDCl3), δ6.96(d,J=8.0Hz,1H),6.81(d,J=8.0Hz,1H),6.14-6.05(m,1H),5.22-5.14(m,2H),4.92( s,1H),3.71-3.67(m,1H),2.92(t,J=8.0Hz,2H),2.86(d,J=8.0Hz,2H),2.14-2.09(m,2H),1.40(d,J=8.0Hz,3H).

[0360] (3) Synthesis of compound 27: 5-(1-cyclopropylethyl)-2,3-dihydro-1-hydro-inden-4-ol:

[0361] Under nitrogen protection, the 100 mL three-necked flask was purged 3-5 times, and 10 mL of DCM was added. The reaction system was cooled to -5 to 0 °C, and diethylzinc (7.97 mL, 1.0 M, 7.97 mmol) was slowly added dropwise over approximately 10 minutes. Trifluoroacetic acid (909 mg, 7.97 mmol) was then added in an ice-cold ethanol bath. After approximately 5 minutes, diiodomethane (2.85 g, 10.62 mmol) was dissolved in 5 mL of DCM and added to the reaction solution using a syringe, maintaining the system temperature at -5 to 0 °C. After 40 minutes, compound 27-3 was dissolved in 5 mL of DCM and slowly added dropwise to the reaction mixture. After the addition was complete, the ice bath was removed, and the reaction was allowed to heat to room temperature (25 °C) and stirred for 48 hours. TLC (V hexane V EA =10:1) After most of the raw materials were consumed, the reaction was stopped. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated ammonium chloride solution, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography with a polarity of V. 正己烷 V 乙酸乙酯 The ratio of crude compound 1 to target compound 27 was increased from 50:1 to 15:1 to obtain a yellow oily substance (400 mg, crude product). The crude product was dissolved in methanol (5 mL) and prepared by reverse phase to obtain target compound 27 (150 mg, yield: 27.9%), which was a grayish-green oily substance.

[0362] 1 HNMR(400MHz, CDCl3), δ7.10(d,1H),6.82(d,1H),4.56(s,1H),2.94(t,2H),2.84(d,2H),2.43-2.39(m,1H), 2.16-2.09(m,2H),1.31(d,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0363] Example 28 Synthesis of 6-(1-cyclopropylethyl)-7-hydroxy-2,3-dihydro-1-hydro-inden-1-one (28)

[0364]

[0365] (1) Synthesis of intermediate 28-2: (E)-7-(but-2-en-1-yloxy)-2,3-dihydro-1-hydro-indanone:

[0366] Compound 28-1 (2.1 g, 13.57 mmol) was dissolved in anhydrous DMF (40 mL), and potassium carbonate (2.81 g, 20.35 mmol) was added under nitrogen protection. The reaction mixture was stirred at 25 °C for 30 minutes, followed by the slow addition of a cis-trans mixture of 1-chloro-2-butene (1.47 g, 16.28 mmol) at 0 °C. After the addition was complete, the reaction mixture was continued to react at 25 °C for 2 hours. TLC (V hexane V EA =20:1) The reaction ended after the raw materials were completely consumed. The reaction solution was slowly added dropwise to ice water (150 mL). The aqueous phase became turbid. After the addition was completed, it was diluted with n-hexane (100 mL), stirred evenly, and extracted three times with n-hexane (100 mL × 3). The organic phases were combined, washed once with saturated brine, separated, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a colorless oily mixture of cis and trans 28-2 (1.2 g, yield: 41.6%).

[0367] 1 HNMR(400MHz, CDCl3), δ7.49-7.45(m,1H),6.97-6.95(m,1H),6.78-6.75(m,1H),5.9 4-5.72(m,2H),4.79-4.62(m,2H),3.08-3.03(t,2H),2.67-2.64(t,2H),1.76(d,3H).

[0368] (2) Synthesis of intermediate 28-3: 6-(but-3-en-2-yl)-7-hydroxy-2,3-dihydro-1-hydro-indanone:

[0369] The cis-trans mixture 28-2 (1.2 g, 5.94 mmol) was purged 3-5 times under nitrogen protection, and the reaction solution was heated to 210 °C and reacted for 4-5 hours. TLC (V hexane V EA =10:1) Once most of the raw materials have been consumed, stop the reaction and allow the reaction solution to cool naturally to room temperature. Dilute the reaction solution with n-hexane, concentrate it, and purify the crude product by column chromatography using eluent polarity V. 正己烷 V 乙酸乙酯 The ratio of 20:1 to 15:1 yielded the target compound 28-3 as a yellow oil (0.5 g, yield: 41.7%).

[0370] 1HNMR(400MHz, CDCl3), δ9.36(s,1H),7.35(d,1H),6.91(d,1H),6.08-5.99(m,1H),5.1 0-5.05(m,2H),3.92-3.89(m,1H),3.09-3.06(m,2H),2.73-2.70(m,2H),1.35(d,3H).

[0371] (3) Synthesis of compound 28: 6-(1-cyclopropylethyl)-7-hydroxy-2,3-dihydro-1-hydro-indanone:

[0372] Under nitrogen protection, the 100 mL three-necked flask was purged 3-5 times, and 10 mL of DCM was added. The reaction system was cooled to -5 to 0 °C, and diethylzinc (7.42 mL, 1.0 M, 7.42 mmol) was slowly added dropwise over approximately 10 minutes. Trifluoroacetic acid (845 mg, 7.42 mmol) was then added in an ice-cold ethanol bath. After approximately 5 minutes, diiodomethane (2.65 g, 9.89 mmol) dissolved in 5 mL of DCM was added to the reaction solution using a syringe, maintaining the system temperature at -5 to 0 °C. After 40 minutes, compound 28-3 (0.5 g, 2.47 mmol) dissolved in 5 mL of DCM was slowly added dropwise to the reaction. After the addition was complete, the ice bath was removed, and the reaction was allowed to heat to room temperature (25 °C) and stirred for 48 hours. TLC (V hexane V EA =10:1) After most of the raw materials were consumed, the reaction was stopped. The reaction solution was diluted with dichloromethane (30 mL), washed with saturated ammonium chloride solution, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography with a polarity of V. 正己烷 V 乙酸乙酯 The ratio of crude compound 2 to target compound 2 was increased from 50:1 to 15:1 to obtain a yellow oily substance (400 mg, crude product). The crude product was dissolved in methanol (5 mL) and prepared by reverse phase to obtain target compound 28 (300 mg, yield: 56.2%), which was a pale yellow solid.

[0373] 1 HNMR(400MHz, CDCl3), δ9.32(s,1H),7.52(d,1H),6.93(d,1H),3.09-3.06(m,2H),2.73-2.71(m,2H),2.4 6-2.38(m,1H),1.32(d,3H),1.04-1.01(m,1H),0.56-0.54(m,1H),0.38-0.36(m,1H),0.23-0.14(m,2H).

[0374] Example 29 Synthesis of 6-(1-cyclopropylethyl)-2,3-dihydro-1-hydro-indene-1,7-diol (29)

[0375]

[0376] Compound 28 (50 mg, 0.23 mmol, 1.0 eq), methanol (5 mL), and sodium borohydride (17.5 mg, 0.462 mmol, 2.0 eq) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 1 h, then added to a saturated ammonium chloride solution, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, the solvent was removed by rotary evaporation, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 When the eluent is diluted 1:10, product 29 (40.0 mg) of white solid is obtained.

[0377] 1 H NMR (400MHz, CDCl3) δ7.22-7.19(m,1H),6.80-6.74(m,2H),5.53-5.47(m, 1H),2.93-2.90(m,1H),2.79-2.76(m,1H),2.65-2.62(m,1H),2.42-2.40( m,1H),1.99(d,J=8.0Hz,1H),1.92-1.89(m,1H),1.31(d,J=8.0Hz,3H),1. 05-1.02(m,1H),0.55-0.52(m,1H),0.40-0.38(m,1H),0.22-0.17(m,2H).

[0378] Example 30 Synthesis of 5-(1-cyclopropylethyl)-3-methyl-1-hydro-inden-4-ol (30)

[0379]

[0380] (1) Synthesis of intermediate 28-a: 7-(benzyloxy)-6-(1-cyclopropylethyl)-2,3-dihydro-1-hydro-indanone:

[0381] Compound 28 (2.0 g, 9.2 mmol, 1.0 eq), potassium carbonate, benzyl bromide, and acetonitrile were added sequentially to a reaction flask, and the mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, washed with acetonitrile, concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 ratio as the eluent, product 28-a (2.5g, yield 88.3%) was obtained as a yellow, transparent, oily substance.

[0382] 1 H NMR(400MHz, CDCl3)δ7.49(m,2H),7.44-7.39(m,2H),7.36(d,1H),7.10(d,1H),6.82(d,1H),5.31(s,2H),3.36-3.27(m,2H),2.43-2 .39(m,1H),1.50-1.41(m,1H),1.31(d,3H),1.29(t,1H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0383] (2) Synthesis of intermediates 30-1: 4-(benzyloxy)-5-(1-cyclopropylethyl)-3-methyl-1-hydro-indene and 31-1: 7-(benzyloxy)-6-(1-cyclopropylethyl)-1-methyl-2,3-dihydro-1-hydro-indene-1-ol:

[0384] Compound 28-a (2.0 g, 6.5 mmol, 1.0 eq) was added to 20 mL of tetrahydrofuran, and 3 mol / L methylmagnesium chloride (5.5 mL, 16.3 mmol, 2.5 eq) was added dropwise at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 8 h. The reaction solution was then poured into 30 mL of ammonium chloride solution and extracted with ethyl acetate (45 mL × 3). The organic phases were combined, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 eluent, a mixture of products 30-1 and 30-2 was obtained as a yellow, transparent, oily substance. The crude product was dissolved in methanol (5 mL), and the target compound 30-1 (255 mg, yield: 12.9%) was prepared by reverse phase chromatography as a pale yellow solid.

[0385] (3) Synthesis of compound 30: 5-(1-cyclopropylethyl)-3-methyl-1-hydro-inden-4-ol:

[0386] Compound 30-1 (250 mg, 0.82 mmol, 1.0 eq), palladium / carbon (20 mg, palladium content w / w = 10%), potassium carbonate (11 mg, 0.08 mmol, 0.1 eq), and methanol (3 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 30 (14.5 mg, yield 8.3%) was obtained as a pale yellow solid.

[0387] 1H NMR (400MHz, CDCl3)7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),6.17(d,J=1.6Hz,1H),4.96(s,1H),3.36-3.2 7(m,2H),2.41(m,4H),1.31(m,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0388] Example 31 Synthesis of 1-methyl-2,3-dihydro-1-hydro-inden-1,7-diol (31)

[0389]

[0390] Compound 31-1 (950 mg, 2.95 mmol, 1.0 eq), palladium / carbon (85 mg, palladium content w / w = 10%), potassium carbonate (61 mg, 0.44 mmol, 0.15 eq), and methanol (10 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 The eluent was 1:20, yielding target compound 31 as a pale yellow solid (650 mg, yield 94.8%) and a pale yellow liquid.

[0391] 1 H NMR (400MHz, CDCl3)7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),6.06(d,J=1.6Hz,1H),4.96(s,1H),3.36-3.27(m,2H),2.41(m,4H) ,1.50-1.41(m,1H),1.31(m,3H),1.29(t,J=6.0Hz,1H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0392] Example 32 Synthesis of 5-(1-cyclopropylethyl)-3-methyl-2,3-dihydro-1-hydro-inden-4-ol (32)

[0393]

[0394] (1) Synthesis of intermediate 32-2: 1-methyl-2,3-dihydro-1-hydro-indene-1,7-diol:

[0395] Compound 32-1 (1.0 g, 7.2 mmol, 1.0 eq) was added to 10 mL of tetrahydrofuran, and 3 mol / L methylmagnesium chloride (6 mL, 18 mmol, 2.5 eq) was added dropwise at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 8 h. The reaction solution was then poured into 15 mL of ammonium chloride solution and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, the solvent was removed by rotary evaporation, and the mixture was separated by column chromatography. 乙酸乙酯 V 石油醚 When the eluent is diluted 1:10, product 32-2 (0.6g) is obtained as a yellow, transparent, oily substance.

[0396] 1 H NMR (400MHz, CDCl3) δ7.06(d,J=4.8Hz,2H),6.67(t,J=4.4Hz,1H),6.06(d,J=1.6Hz,1H),4.9 6(s,1H),3.36-3.27(m,2H),2.41(d,J=1.7Hz,3H),1.50-1.41(m,1H),1.29(t,J=6.0Hz,1H).

[0397] (2) Synthesis of intermediate 32-3: 3-methyl-2,3-dihydro-1-hydro-indanol:

[0398] Compound 32-2 (500 mg, 3.0 mmol, 1.0 eq) was added to 10 mL of dichloromethane, followed by the addition of trifluoroacetic acid (350 mg, 31 mmol, 1.02 eq) and triethylsilane (380 mg, 33 mmol, 1.1 eq). The mixture was then slowly heated to room temperature and reacted for 5 hours. The reaction solution was then poured into 10 mL of water, separated, the organic phase was evaporated to remove the solvent, and column chromatography was performed. 二氯甲烷 V 石油醚 Using a 1:3 ratio as the eluent, the product compound 32-3 (350 mg) was obtained as a colorless, transparent oil.

[0399] 1 H NMR (400MHz, CDCl3) δ7.06(t,J=7.6Hz,1H),6.83(d,J=7.6Hz,1H),6.60(d,J=8.0Hz,1H),4.63(s,1H),3.39(ddd,J=14.6,9.2,5.6Hz,1H),3.03(dt,J =16.4,8.4Hz,1H),2.84(ddd,J=16.0,8.8,4.4Hz,1H),2.31(ddd,J=17.2,1 2.8,8.0Hz,1H),1.75(ddd,J=16.6,8.4,4.2Hz,1H),1.31(d,J=7.2Hz,3H).

[0400] (3) Synthesis of intermediate 32-4: (E)-7-(but-2-en-1-propoxy)-1-methyl-2,3-dihydro-1-hydro-indene:

[0401] Compound 32-3 (100 mg, 0.67 mmol, 1.0 eq) was added to 5 mL of LDM, followed by sodium hydroxide (54 mg, 1.34 mmol, 2.0 eq) and 1-chloro-2-butene (73 mg, 0.80 mmol, 1.2 eq). The reaction mixture was reacted at room temperature for 4 hours. The reaction solution was poured into 10 mL of water and extracted with n-hexane (15 mL × 4). The organic phases were combined and the solvent was removed by rotary evaporation to give product 32-4 (110 mg) as a yellow oil.

[0402] 1 H NMR (400MHz, CDCl3) δ7.11(t,J=6.0Hz,1H),6.83(d,J=7.2Hz,1H),6.68(d,J=8.0Hz,1H),5.94-5.69(m,2H),4.50(d,J=5.6Hz,2H),3.4 8-3.35(m,1H),3.01(dt,J=16.0,8.0Hz,1H),2.88-2.75(m,1H),2.27(tt,J=20.0,8.0Hz,1H),1.81-1.67(m,4H),1.27(d,J=2.0Hz,3H).

[0403] (4) Synthesis of intermediate 32-5: 5-(but-3-en-2-yl)-3-methyl-2,3-dihydro-1-hydro-inden-4-ol:

[0404] The cis-trans mixture 32-4 (0.94 g, 4.70 mmol) was purged 3-5 times under nitrogen protection, and the reaction solution was heated to 210 °C and reacted for 4-5 hours. TLC (V hexane V EA =10:1) Once most of the raw materials have been consumed, stop the reaction and allow the reaction solution to cool naturally to room temperature. Dilute the reaction solution with n-hexane, concentrate it, and purify the crude product by column chromatography using eluent polarity V. 正己烷 V 乙酸乙酯 The ratio of 20:1 to 15:1 yielded the target compound 32-5 as a yellow oil (0.64 g, yield: 68.1%).

[0405] 1HNMR (400MHz, CDCl3), δ6.96 (dd, J=8.0, 4.0Hz, 1H), 6.78 (d, J=8.0Hz, 1H), 6.12-6.06 (m, 1H), 5.22-5.15 (m, 2H), 5.04 (d, J=8.0Hz, 1H), 3.67-3.64 ( m,1H),3.36-3.34(m,1H),3.00-2.94(m,1H),2.79-2.78(m,1H),2.30-2.2 5(m,1H),1.76-1.71(m,1H),1.41(d,J=8.0Hz,3H),1.27(d,J=8.0Hz,3H).

[0406] (5) Synthesis of compound 32: 5-(1-cyclopropylethyl)-3-methyl-2,3-dihydro-1-hydro-inden-4-ol:

[0407] Under nitrogen protection, the 100 mL three-necked flask was purged 3-5 times, and 10 mL of DCM was added. The reaction system was cooled to -5 to 0 °C, and diethylzinc (7.97 mL, 1.0 M, 7.97 mmol) was slowly added dropwise over approximately 10 minutes. Then, trifluoroacetic acid (909 mg, 7.97 mmol) was added in an ice-cold ethanol bath. After approximately 5 minutes, diiodomethane (2.85 g, 10.62 mmol) dissolved in 5 mL of DCM was added to the reaction solution using a syringe, maintaining the system temperature at -5 to 0 °C. After 40 minutes, compound 32-5 (500 mg, 2.66 mmol) dissolved in 5 mL of DCM was slowly added dropwise to the reaction. After the addition was complete, the ice bath was removed, and the reaction was allowed to heat to room temperature (25 °C) and stirred for 48 hours. TLC (V hexane V EA =10:1) After most of the raw materials were consumed, the reaction was stopped. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated ammonium chloride solution, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography with a polarity of V. 正己烷 V 乙酸乙酯 The ratio of crude compound 32 was increased from 50:1 to 15:1 to obtain a yellow oily substance (400 mg, crude product). The crude product was dissolved in methanol (5 mL) and the target compound 32 (150 mg, yield: 27.9%) was prepared by reverse phase reaction. The product was a colorless oily substance.

[0408] 1HNMR(400MHz, CDCl3), δ7.10(d,J=8.0Hz,1H),6.80(d,J=8.0Hz,1H),4.68(s,1 H),3.38-3.32(m,1H),3.02-2.98(m,1H),2.82-2.79(m,1H),2.43-2.42(m,1H), 2.30-2.27(m,1H),1.77-1.73(m,1H),1.31(d,J=4.0Hz,3H),1.28(d,J=8.0Hz,3 H),1.06-1.04(m,1H),0.55-0.54(m,1H),0.45-0.43(m,1H),0.22-0.16(m,2H).

[0409] Example 33 Synthesis of 5-(1-cyclopropylethyl)-3-methoxy-3-methyl-2,3-dihydro-1-hydro-inden-4-ol (33)

[0410]

[0411] (1) Synthesis of intermediate 33-1: 7-(benzyloxy)-6-(1-cyclopropylethyl)-1-methoxy-1-methyl-2,3-dihydro-1-hydro-indene:

[0412] Compound 31-1 (200 mg, 0.62 mmol, 1.0 eq), p-toluenesulfonic acid (166 mg, 0.94 mmol, 1.5 eq), and methanol (5 mL) were added sequentially to the reaction flask. The mixture was heated to 70 °C and stirred for 3 h. After cooling to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to >7. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, product 33-1 (155 mg, yield 74.3%) was obtained as a yellow, transparent oily substance.

[0413] 1H NMR (400MHz, CDCl3) δ7.49(m,2H),7.44-7.39(m,2H),7.36(d,J=8.0Hz,1H),7.10(d, J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),5.31(s,2H),3.50(s,3H),3.36-3.27(m,2H),2. 43-2.39(m,1H),1.74(s,3H),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J=6. 0Hz,1H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0414] (2) Synthesis of compound 33: 5-(1-cyclopropylethyl)-3-methoxy-3-methyl-2,3-dihydro-1-hydro-inden-4-ol:

[0415] Compound 33-1 (60 mg, 0.18 mmol, 1.0 eq), palladium / carbon (10 mg, palladium content w / w = 10%), potassium carbonate (2.5 mg, 0.02 mmol, 0.1 eq), and methanol (1 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 33 (35 mg, yield 81.7%) was obtained as a pale yellow solid.

[0416] 1 H NMR (400MHz, CDCl3) δ7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),4.96(s,1H),3.50(s,3H),3.36-3.27(m,2H),2.43-2.39(m,1H),1.74(s,3H) ),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J=6.0Hz,1H),1.06 -1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0417] Example 34 Synthesis of 6-(1-cyclopropylethyl)-7-hydroxy-1-methyl-2,3-dihydro-1-hydro-inden-1-nitrile (34)

[0418]

[0419] (1) Synthesis of intermediate 34-1 7-(benzyloxy)-6-(1-cyclopropylethyl)-1-methyl-2,3-dihydro-1-hydro-inden-1-nitrile:

[0420] Under nitrogen protection, compound 31-1 (200 mg, 0.62 mmol, 1.0 eq), dichloromethane (5 mL), and trimethylcyanosilane (80 mg, 0.81 mmol, 1.3 eq) were added sequentially to the reaction flask. Boron trifluoride diethyl ether solution (880 mg, 6.2 mmol, 10 eq) was slowly added dropwise at 0 °C, and the reaction was stirred overnight. The reaction was quenched by slow addition of saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with DCM (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 When the eluent is diluted 1:50, product 34-1 (165 mg, yield 80.3%) is obtained as a pale yellow solid.

[0421] 1 H NMR (400MHz, CDCl3) δ7.49 (m, 2H), 7.44-7.39 (m, 2H), 7.36 (d, J = 8.0Hz, 1H), 7.10 (d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),5.31(s,2H),3.36-3.27(m,2H),2.43-2.3 9(m,1H),1.80(s,3H),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J=6.0Hz ,1H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0422] (2) Synthesis of compound 34: 6-(1-cyclopropylethyl)-7-hydroxy-1-methyl-2,3-dihydro-1-hydro-inden-1-nitrile:

[0423] Compound 34-1 (160 mg, 0.48 mmol, 1.0 eq), palladium / carbon (25 mg, palladium content w / w = 10%), potassium carbonate (10 mg, 0.07 mmol, 0.15 eq), and methanol (1 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 34 (98 mg, yield 84.6%) was obtained as a pale yellow solid.

[0424] 1 H NMR (400MHz, CDCl3) δ7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),4.96(s,1H),3.36-3.27(m,2H),2.43-2.39(m,1H),1.80(s,3H),1.50 -1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J=6.0Hz,1H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0425] Example 35 Synthesis of 5-(1-cyclopropylethyl)-3-ethoxy-3-methyl-2,3-dihydro-1-hydro-inden-4-ol (35)

[0426]

[0427] The synthesis method is the same as that of compound 33 in Example 33.

[0428] 1 H NMR (400MHz, CDCl3)7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),4.96(s,1H),3.40-3.27(m,4H),2.41(m,4H),1.50-1.41(m,1H) ),1.31(m,3H),1.29(t,J=6.0Hz,1H),1.18(m,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0429] Example 36 Synthesis of 3-cyclopropyl-5-(1-cyclopropylethyl)-2,3-dihydro-1-hydro-inden-4-ol (36)

[0430]

[0431] (1) Synthesis of intermediate 36-1: 7-(benzyloxy)-1-cyclopropyl-6-(1-cyclopropylethyl)-2,3-dihydro-1-hydro-inden-1-ol:

[0432] Under nitrogen protection, compound 28-a (200 mg, 0.65 mmol, 1.0 eq) was added to 5 mL of tetrahydrofuran, and 1 mol / L cyclopropyl magnesium bromide solution (1.0 mL, 1.0 mmol, 1.55 eq) was added dropwise at -78 °C. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 3 h. The reaction mixture was then poured into 10 mL of ammonium chloride solution, stirred at room temperature for 30 min, and extracted with ethyl acetate (25 mL × 3). The organic phases were combined, the solvent was removed by rotary evaporation under reduced pressure, and the mixture was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:10 ratio as the eluent, product 36-1 (112 mg, yield: 49.7%) was obtained as a pale yellow solid.

[0433] (2) Synthesis of compound 36: 3-Cyclopropyl-5-(1-Cyclopropylethyl)-2,3-Dihydro-1-Hydro-Indene-4-ol:

[0434] Compound 36-1 (100 mg, 0.29 mmol, 1.0 eq), palladium / carbon (8 mg, palladium content w / w = 10%), potassium carbonate (6.0 mg, 0.04 mmol, 0.15 eq), and methanol (2 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 36 (55 mg, yield 78.3%) was obtained as a pale yellow solid.

[0435] 1 H NMR (400MHz, CDCl3) δ7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),6.60(d,J=8.0Hz,1H),4.63( s,1H),3.39(ddd,J=14.6,9.2,5.6Hz,1H),3.03(dt,J=16.4,8.4Hz,1H),2.84(ddd,J=16.0,8.8, 4.4Hz,1H),2.43-2.39(m,1H),2.31(ddd,J=17.2,12.8,8.0Hz,1H),1.75(ddd,J=16.6,8.4,4.2H z,1H),1.31(m,3H),1.06-1.01(m,2H),0.54-0.51(m,2H),0.43-0.40(m,2H),0.26-0.16(m,4H).

[0436] Example 37 Synthesis of 5-(1-cyclopropylethyl)-3-methoxy-2,3-dihydro-1-hydro-inden-4-ol (37)

[0437]

[0438] (1) Synthesis of intermediate 37-1: 7-(benzyloxy)-6-(1-cyclopropylethyl)-2,3-dihydro-1-hydro-inden-1-ol:

[0439] Compound 28-a (200 mg, 0.65 mmol, 1.0 eq), methanol (5 mL), and sodium borohydride (44.6 mg, 1.18 mmol, 1.8 eq) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 1 h, then added to a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The solvent was removed by rotary evaporation, and the residue was separated by silica gel column chromatography using V as the eluent. 乙酸乙酯 V 石油醚 =1:10, yield product 37-1 (173mg, yield 86.3%), a white solid.

[0440] 1 H NMR (400MHz, CDCl3) δ7.48(m,2H),7.45-7.40(m,2H),7.37(d,J=8.0Hz,1H),7.12(d,J=8 .0Hz,1H),6.84(d,J=4.0Hz,1H),6.06(d,J=1.6Hz,1H),5.32(s,2H),5.20-4.99(m,1H),3 .46-3.37(m,2H),2.53-2.49(m,1H),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J =6.0Hz,1H),1.06-1.04(m,1H),0.57-0.54(m,1H),0.44-0.41(m,1H),0.23-0.17(m,2H).

[0441] (2) Synthesis of intermediate 37-2: 7-(benzyloxy)-6-(1-cyclopropylethyl)-1-methoxy-2,3-dihydro-1-hydro-indene:

[0442] Compound 37-1 (80 mg, 0.26 mmol, 1.0 eq), p-toluenesulfonic acid (69 mg, 0.39 mmol, 1.5 eq), and methanol (3 mL) were added sequentially to the reaction flask. The mixture was heated to 70 °C and stirred for 3 h. After cooling to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to >7. The mixture was extracted with ethyl acetate (15 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, product 37-2 (65 mg, yield 77.5%) was obtained as a yellow, transparent oily substance.

[0443] 1 H NMR (400MHz, CDCl3) δ7.47(m,2H),7.44-7.39(m,2H),7.37(d,J=8.0Hz,1H),7.12(d,J =8.0Hz,1H),6.83(d,J=4.0Hz,1H),5.33(s,2H),5.20-4.99(m,1H),3.52(s,3H),3.46- 3.38(m,2H),2.53-2.49(m,1H),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J=6 .0Hz,1H),1.08-1.06(m,1H),0.56-0.53(m,1H),0.44-0.41(m,1H),0.23-0.18(m,2H).

[0444] (3) Synthesis of compound 37: 5-(1-cyclopropylethyl)-3-methoxy-2,3-dihydro-1-hydro-inden-4-ol:

[0445] Compound 37-2 (60 mg, 0.18 mmol, 1.0 eq), palladium / carbon (10 mg, palladium content w / w = 10%), potassium carbonate (2.5 mg, 0.02 mmol, 0.1 eq), and methanol (1 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, the target compound 37 (32 mg, yield 74.5%) was obtained as a pale yellow solid.

[0446] 1 H NMR (400MHz, CDCl3) δ7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),5.20-4.99(m,1H),4.96(s,1H),3.52(s,3H),3.46-3.38(m,2H),2.53-2.49(m, 1H),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J=6.0Hz,1H),1.0 8-1.06(m,1H),0.56-0.53(m,1H),0.44-0.41(m,1H),0.23-0.18(m,2H).

[0447] Example 38 Synthesis of 5-(1-cyclopropylethyl)-3-(2-methoxyethoxy)-3-methyl-2,3-dihydro-1-hydro-inden-4-ol (38)

[0448]

[0449] (1) Synthesis of intermediate 38-1: 7-(benzyloxy)-6-(1-cyclopropylethyl)-1-(2-methoxyethoxy)-1-methyl-2,3-dihydro-1-hydro-indene:

[0450] Compound 31-1 (200 mg, 0.62 mmol, 1.0 eq), p-toluenesulfonic acid (166 mg, 0.94 mmol, 1.5 eq), and ethylene glycol monomethyl ether (6 mL) were added sequentially to the reaction flask. The mixture was heated to 70 °C and stirred for 3 h. After cooling to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to >7. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, product 38-1 (162 mg, yield 68.7%) was obtained as a yellow, transparent oily substance.

[0451] 1 H NMR (400MHz, CDCl3) δ7.49(m,2H),7.44-7.39(m,2H),7.36(d,J=8.0Hz,1H),7.10(d,J=8. 0Hz,1H),6.82(d,J=4.0Hz,1H),5.30(s,2H),3.58-3.53(m,4H),3.39(s,3H),3.36-3.27( m,2H),2.43-2.39(m,1H),1.74(s,3H),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t, J=6.0Hz,1H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0452] (2) Synthesis of compound 38: 5-(1-cyclopropylethyl)-3-(2-methoxyethoxy)-3-methyl-2,3-dihydro-1-hydro-inden-4-ol:

[0453] Compound 38-1 (100 mg, 0.26 mmol, 1.0 eq), palladium / carbon (15 mg, palladium content w / w = 10%), potassium carbonate (6 mg, 0.04 mmol, 0.15 eq), and methanol (2 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚Using a 1:20 ratio as the eluent, the target compound 38 (55 mg, yield 72.8%) was obtained as a pale yellow solid.

[0454] 1 H NMR (400MHz, CDCl3) δ7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),4.96(s,1 H),,3.58-3.53(m,4H),3.39(s,3H),3.36-3.27(m,2H),2.43-2.39(m,1H),1 .74(s,3H),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J=6.0Hz,1H), 1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0455] Example 39 Synthesis of 6-(1-cyclopropylethyl)-3-methyl-1-hydro-inden-7-ol (39)

[0456]

[0457] Compound 41 (100 mg, 0.46 mmol, 1.0 eq), MeCN (5 mL), and concentrated sulfuric acid (1 mL) were added sequentially to the reaction flask, and the mixture was stirred under reflux for 3 h. After cooling to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to approximately neutral. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, product 39 (62 mg, yield 67.3%) was obtained as a pale yellow solid.

[0458] 1 H NMR (400MHz, CDCl3)7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),6.57(d,J=1.6Hz,1H),6.32(d,J=1.6Hz,1H),4.97 (s,1H),3.36-3.27(m,2H),2.42(m,4H),1.06-1.04(m,1H),0.57-0.55(m,1H),0.45-0.43(m,1H),0.24-0.16(m,2H).

[0459] Example 40 Synthesis of 5-(1-cyclopropylethyl)-4-hydroxy-2,3-dihydro-1-hydro-indanone (40)

[0460]

[0461] Refer to the synthesis method of compound 28 in Example 28.

[0462] 1 HNMR(400MHz, CDCl3), δ7.36(d,J=8.0Hz,1H),7.12(d,J=4.0Hz,1H),4.59(s,1H),3.13-3.10(t,2H),2.73-2.70(t,2H) ,2.43-2.39(m,1H),1.31(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0463] Example 41 Synthesis of 5-(1-cyclopropylethyl)-2,3-dihydro-1-hydro-indene-1,4-diol (41)

[0464]

[0465] The synthesis method of compound 41 is the same as that of compound 29 in Example 29.

[0466] 1 H NMR(400MHz, CDCl3) δ7.36(d,J=8.0Hz,1H),7.12(d,J=4.0Hz,1H),6.06(d, J=1.6Hz,1H),5.20-4.99(m,1H),4.96(s,1H),3.46-3.37(m,2H),2.53-2.4 9(m,1H),1.50-1.41(m,1H),1.31(d,J=8.0Hz,3H),1.29(t,J=6.0Hz,1H),1 .06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0467] Example 42 Synthesis of 5-(1-cyclopropylethyl)-2,3-dihydrobenzofuran-4-ol (42)

[0468]

[0469] (1) Synthesis of intermediate 42-2(E)-4-(but-2-en-1-propoxy)-2,3-dihydrobenzofuran:

[0470] Compound 42-1 (200 mg, 1.5 mmol, 1.0 eq.) was dissolved in anhydrous DMF (6 mL). Sodium hydroxide (0.12 g, 2.9 mmol, 2 eq.) was added under nitrogen protection. The reaction mixture was stirred at 25 °C for 30 minutes. Subsequently, a mixture of cis and trans-chloro-2-butene (0.16 g, 1.8 mmol, 1.2 eq.) was slowly added at 0 °C. After the addition was complete, the reaction mixture was continued to react at 25 °C for 2 hours. TLC (V1) was performed. hexane V EA =1:0) The reaction ended after the raw materials were completely consumed. The reaction solution was slowly added dropwise to ice water (15 mL). The aqueous phase became turbid. After the addition was completed, it was diluted with n-hexane (10 mL), stirred evenly, and extracted three times with n-hexane (10 mL × 3). The organic phases were combined, washed once with saturated brine, separated, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a colorless oily cis-trans mixture 42-2 (225 mg, yield: 78.9%).

[0471] 1 HNMR(400MHz, CDCl3), δ7.16-7.11(m,1H),6.75-6.73(m,1H),6.66-6.63(m,1H),5.81-5 .61(m,2H),4.63-4.48(m,2H),4.27-4.23(t,2H),2.93-2.90(t,2H),1.76-1.74(m,3H).

[0472] (2) Synthesis of intermediate 42-3: 5-(but-3-en-2-yl)-2,3-dihydrobenzofuran-4-ol:

[0473] The cis-trans mixture 42-2 (220 mg, 1.16 mmol, 1 eq.) was purged 3-5 times under nitrogen protection, and the reaction solution was heated to 210 °C and reacted for 4 hours. TLC (V hexane V EA =10:1) Once most of the raw materials have been consumed, stop the reaction and allow the reaction solution to cool naturally to room temperature. Dilute the reaction solution with n-hexane, concentrate it, and purify the crude product by column chromatography using eluent polarity V. 正己烷 V 乙酸乙酯 The ratio of 20:1 to 15:1 yielded the target compound 42-3 as a yellow oil (187 mg, yield: 84.7%).

[0474] 1HNMR(400MHz, CDCl3), δ6.96(d,J=8.0Hz,1H),6.81(d,J=8.0Hz,1H),6.14-6.05(m,1H),5.22-5.14( m,2H),4.92(s,1H),4.27-4.23(t,2H),3.71-3.67(m,1H),2.93-2.90(t,2H),1.40(d,J=8.0Hz,3H).

[0475] (3) Synthesis of compound 42: 5-(1-cyclopropylethyl)-2,3-dihydrobenzofuran-4-ol:

[0476] Under nitrogen protection, the 25 mL three-necked flask was purged 3-5 times, and DCM (4 mL) was added. The reaction system was cooled to -5 to 0 °C, and diethylzinc (2.5 mL, 1.0 M, 2.52 mmol, 3 eq.) was slowly added dropwise over approximately 10 minutes. Trifluoroacetic acid (287 mg, 2.52 mmol, 3 eq.) was then added in an ice-cold ethanol bath. After approximately 5 minutes, diiodomethane (900 mg, 3.36 mmol, 4 eq.) dissolved in DCM (2 mL) was added to the reaction solution using a syringe, while maintaining the system temperature at -5 to 0 °C. After 40 minutes, compound 42-3 (160 mg, 0.84 mmol, 1.0 eq.) dissolved in DCM (5 mL) was slowly added dropwise to the reaction. After the addition was complete, the ice bath was removed, and the reaction was allowed to heat to room temperature (25 °C) and stirred for 48 hours. TLC (V hexane V EA =10:1) After most of the raw materials were consumed, the reaction was stopped. The reaction solution was diluted with dichloromethane (5 mL), washed with saturated ammonium chloride solution, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography with a polarity of V. 正己烷 V 乙酸乙酯 The crude product was obtained by mixing 50:1 to 15:1, which was a yellow oily substance. It was dissolved in methanol (5 mL) and prepared by reverse phase reaction to obtain the target compound 42 (57 mg, yield: 28.2%). The product was a pale yellow solid.

[0477] 1HNMR(400MHz, CDCl3), δ7.10(d,J=8.0Hz,1H),6.82(d,J=4.0Hz,1H),4.56(s,1H),4.27-4.23(t,2H),2.93-2.90(t,2H) ,2.43-2.39(m,1H),1.31(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0478] Example 43 Synthesis of 5-(1-cyclopropylethyl)-1,3-dihydroisobenzofuran-4-ol (43)

[0479]

[0480] The synthesis of compound 43 is described in Example 42.

[0481] 1 HNMR (400MHz, CDCl3), δ7.10 (d, J = 8.0Hz, 1H), 6.82 (d, J = 4.0Hz, 1H), 4.56 (s, 1H), 4.47-4.37 (m, 4H), 2.43-2. 39(m,1H),1.31(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0482] Example 44 Synthesis of 6-(1-cyclopropylethyl)-2,3-dihydrobenzofuran-7-ol (44)

[0483]

[0484] The synthesis of compound 44 is described in Example 42.

[0485] 1 HNMR(400MHz, CDCl3), δ7.11(d,J=8.0Hz,1H),6.83(d,J=4.0Hz,1H),4.57(s,1H),4.27-4.24(t,2H),2.97-2.94(t,2H) ,2.43-2.39(m,1H),1.32(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.43-0.41(m,1H),0.23-0.16(m,2H).

[0486] Example 45 Synthesis of 5-(1-cyclopropylethyl)indole-4-ol (45)

[0487]

[0488] (1) Synthesis of intermediate 45-2: (E)-4-(but-2-en-1-oxy)indoline-1-carboxylic acid tert-butyl ester:

[0489] Compound 45-1 (500 mg, 2.1 mmol, 1.0 eq.) was dissolved in anhydrous DMF (10 mL). Sodium hydroxide (0.18 g, 4.2 mmol, 2 eq.) was added under nitrogen protection. The reaction mixture was stirred at 25 °C for 30 minutes. Subsequently, a mixture of cis and trans-chloro-2-butene (0.22 g, 2.5 mmol, 1.2 eq.) was slowly added at 0 °C. After the addition was complete, the reaction mixture was continued to react at 25 °C for 2 hours. TLC (V1) was performed. hexane V EA =1:0) The reaction ended after the raw materials were completely consumed. The reaction solution was slowly added dropwise to ice water (25 mL). The aqueous phase became turbid. After the addition was completed, it was diluted with n-hexane (20 mL), stirred evenly, and extracted three times with n-hexane (20 mL × 3). The organic phases were combined, washed once with saturated brine, separated, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a colorless oily cis-trans mixture 45-2 (398 mg, yield: 65.5%).

[0490] 1 HNMR(400MHz, CDCl3), δ7.16-7.12(m,1H),6.74-6.72(m,1H),6.66-6.63(m,1H),5.81-5.61(m ,2H),4.64-4.49(m,2H),4.26-4.22(t,2H),2.93-2.90(t,2H),1.76-1.74(m,3H),1.42(s,9H).

[0491] (2) Synthesis of intermediate 45-3: 5-(tert-butyl-3-en-2-yl)-4-hydroxyindole-1-carboxylic acid tert-butyl ester:

[0492] The cis-trans mixture 45-2 (390 mg, 1.35 mmol, 1 eq.) was purged 3-5 times under nitrogen protection, and the reaction solution was heated to 210 °C and reacted for 4 hours. TLC (V hexane V EA=10:1) Once most of the raw materials have been consumed, stop the reaction and allow the reaction solution to cool naturally to room temperature. Dilute the reaction solution with n-hexane, concentrate it, and purify the crude product by column chromatography using eluent polarity V. 正己烷 V 乙酸乙酯 The ratio of 20:1 to 15:1 yielded the target compound 45-3 as a yellow oil (347 mg, yield: 88.8%).

[0493] 1 HNMR(400MHz, CDCl3), δ6.96(d,J=8.0Hz,1H),6.81(d,J=8.0Hz,1H),6.14-6.05(m,1H),5.22-5.14(m,2H) ,4.92(s,1H),4.27-4.23(t,2H),3.71-3.67(m,1H),2.93-2.90(t,2H),1.45(s,9H),1.40(d,J=8.0Hz,3H).

[0494] (3) Synthesis of compound 45: 5-(1-cyclopropylethyl)indole-4-ol:

[0495] Under nitrogen protection, the 25 mL three-necked flask was purged 3-5 times, and DCM (5 mL) was added. The reaction system was cooled to -5 to 0 °C, and diethylzinc (3.1 mL, 1.0 M, 3.12 mmol, 3 eq.) was slowly added dropwise over approximately 10 minutes. Trifluoroacetic acid (355 mg, 3.12 mmol, 3 eq.) was then added in an ice-cold ethanol bath. After approximately 5 minutes, diiodomethane (1.11 g, 4.14 mmol, 4 eq.) dissolved in DCM (2 mL) was added to the reaction solution using a syringe while maintaining the system temperature at -5 to 0 °C. After 40 minutes, compound 45-3 (300 mg, 1.04 mmol, 1.0 eq.) dissolved in DCM (5 mL) was slowly added dropwise to the reaction. After the addition was complete, the ice bath was removed, and the reaction was allowed to heat to room temperature (25 °C) and stirred for 48 hours. TLC (V hexane V EA =10:1) After most of the raw materials were consumed, the reaction was stopped. 15 mL of water and 10 mL of dichloromethane were added. The aqueous phase was separated and adjusted to neutral pH with saturated sodium bicarbonate solution. DCM extraction (20 mL × 3) was performed. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography with a polarity of V. 正己烷 V 乙酸乙酯 =20:1 to 5:1 yielded 45 (126 mg, yield: 60.0%), the product being a pale yellow solid.

[0496] 1HNMR(400MHz, CDCl3), δ7.02(d,J=8.0Hz,1H),6.67(d,J=4.0Hz,1H),5.07(s,1H),4.56(s,1H),3.65-3.61(t,2H),2.93-2.90 (t,2H),2.43-2.39(m,1H),1.31(d,J=8.0Hz,3H),1.06-1.04(m,1H),0.56-0.54(m,1H),0.44-0.42(m,1H),0.23-0.16(m,2H).

[0497] Example 46 Synthesis of 5-(1-cyclopropylethyl)isoindole-4-ol (46)

[0498]

[0499] The synthesis of compound 46 is described in Example 45.

[0500] 1 HNMR(400MHz, CDCl3), δ7.13(d,J=8.0Hz,1H),6.85(d,J=4.0Hz,1H),5.08(s,1H),4.56(s,1H),3.81-3.71(m,4H),2 .43-2.39(m,1H),1.31(d,J=8.0Hz,3H),1.05-1.03(m,1H),0.56-0.54(m,1H),0.46-0.44(m,1H),0.23-0.17(m,2H).

[0501] Example 47 Synthesis of 5-(1-cyclopropylethyl)-2-methylisoindole-4-ol (47)

[0502]

[0503] Under nitrogen protection, compound 46 (150 mg, 0.74 mmol, 1.0 eq), potassium carbonate (220 mg, 1.6 mmol, 2.2 eq), DMF (5 mL), and iodomethane (105 mg, 0.74 mmol, 1.0 eq) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 3 h. The reaction solution was poured into 10 mL of ice water, extracted with ethyl acetate (15 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography. 乙酸乙酯 V 石油醚 Using a 1:20 ratio as the eluent, product 47 (32 mg, yield 19.9%) was obtained as a pale yellow solid.

[0504] 1 HNMR(400MHz, CDCl3), δ7.13(d,J=8.0Hz,1H),6.85(d,J=4.0Hz,1H),4.56(s,1H),3.81-3.71(m,4H),2.43-2.39(m, 1H), 2.16 (s, 1H), 1.31 (d, J = 8.0Hz, 3H), 1.05-1.03 (m, 1H), 0.56-0.54 (m, 1H), 0.46-0.44 (m, 1H), 0.23-0.17 (m, 2H).

[0505] Example 48

[0506] Mouse righting reflex test

[0507] SPF-grade ICR mice, 18-22g, half male and half female, were used to study the general anesthetic effect of the compound of this invention using a mature mouse anesthesia model. The compound was prepared to the required concentration using solvents of 10% DMSO, 15% solvent HS15, and 75% saline. After acclimatization to the experimental environment, the experimental animals were fasted for 12 hours but allowed free access to water. Following intravenous injection of 10 ml / kg of the drug, the anesthesia induction time (time from drug administration to the disappearance of the righting reflex) and the duration of anesthesia (time from the disappearance of the righting reflex to the recovery of the righting reflex) were recorded. The median effective dose (ED50) was used. 50 ), median mortality (LD50) 50 Treatment index (TI, i.e., LD) 50 / ED 50 The anesthetic efficacy and safety were evaluated by measuring the anesthesia induction time, duration of anesthesia, and maximum tolerated dose. Control group 1 was propofol, with the structural formula shown in Formula V below; control group 2 was cyclopropofol (racemic mixture), with the structural formula shown in Formula VI below.

[0508]

[0509] Table 1. Data from the righting reflex experiment in mice.

[0510]

[0511] Experimental conclusion: The compound of this invention has a high therapeutic index, a high safety factor, a wider therapeutic window, and a smaller ED. 50 This indicates that these test compounds have a small effective dose and high activity. Their low free concentration in the aqueous phase of the corresponding formulation suggests a predictable effect in avoiding injection pain.

Claims

1. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:

2. A compound of general formula (III) or a chiral isomer thereof, or a pharmaceutically acceptable salt thereof: in: W is selected from cyclopentane, which may optionally be further substituted with R; R b Selected from C 1-6 The alkyl group, wherein the alkyl group may optionally be further substituted with R; R c The alkyl group is selected from 3 to 6-membered cycloalkyl groups, which may optionally be further substituted with R; Y is selected from H; R is selected from F, Cl, Br, I, deuterium, hydroxyl, CN, NH2, C. 1-6 Alkyl, C 1-6 Alkyl group.

3. The compound according to claim 2, or its stereoisomer, or a pharmaceutically acceptable salt, wherein the compound is selected from:

4. A pharmaceutical composition comprising the compound or stereoisomer of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

5. The use of the compound according to any one of claims 1 to 3, or its stereoisomers, or pharmaceutically acceptable salts, and the pharmaceutical composition according to claim 4 in the preparation of drugs for inducing and maintaining anesthesia in animals or humans, promoting sedation and hypnosis in animals or humans, and treating and preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.

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