Phenol polyethylene glycol derivative as well as preparation method and medical application thereof

Abstract

The invention relates to a phenol polyethylene glycol derivative, a preparation method thereof and application of the phenol polyethylene glycol derivative in medicine. Specifically, the invention relates to a phenol polyethylene glycol derivative as shown in a general formula (A-I) or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof, and application in medicine, the structure of the compound as shown in the general formula (A-I) is shown in the specification, and the group definition of the compound is consistent with that of the specification.

Description

Technical Field

[0001] This invention relates to a phenol polyethylene glycol derivative, its preparation method, and its use in medicine. Specifically, this invention relates to a phenol polyethylene glycol derivative of general formula (I), its stereoisomers or pharmaceutically acceptable salts, its preparation method, pharmaceutical compositions containing them, and their use in the preparation of pharmaceuticals. Background Technology

[0002] Polyethylene glycol (PEG) is composed of repeating oxyethylene groups and possesses excellent water solubility as well as solubility in organic solvents such as dichloromethane, N,N-dimethylformamide, acetonitrile, and ethanol. PEG is a neutral, non-toxic polymer with unique physicochemical properties and good biocompatibility. It is also one of the very few synthetic polymers approved by the FDA for in vivo injection and is widely used in drug modification. Its components exhibit minimal interaction with blood (low plasma protein binding) and high biocompatibility. When coupled with drug molecules, it can impart its superior properties to the modified drug molecule, altering drug solubility, creating a steric barrier around the modified drug, reducing enzymatic degradation, preventing rapid elimination during metabolism, and simultaneously reducing drug toxicity.

[0003] Therefore, polyethylene glycol prodrugs effectively solve the problem of low water solubility of the parent drug, while reducing the toxic side effects of the drug, prolonging the half-life of the drug in the blood, improving targeting and increasing efficacy. Compared with some other prodrug carriers, polyethylene glycol has its unique advantages.

[0004] Cyclopofol is a novel intravenous anesthetic, belonging to the short-acting GABAA receptor agonist class. Its mechanism of action involves enhancing GABAA-mediated chloride ion influx, thereby producing sedation or anesthesia. It is suitable for sedation or anesthesia in various examination procedures, general anesthesia in surgical procedures, and ICU sedation. Currently approved indications include sedation for gastrointestinal endoscopy and induction of general anesthesia in adult patients. Cyclopofol exhibits high selectivity for the two competitive binding targets of the GABAA receptor chloride channel, TBPS and TBOB, and its affinity for the GABAA receptor is approximately five times that of propofol. Clinical studies have shown that within the dose range of 0.3–0.9 mg / kg, the higher the plasma drug concentration of propofol, the deeper the sedation or anesthesia, manifested by a gradual decrease in the Modified Alertness / Sedation Score (MOAA / S) until loss of consciousness and a weakened response to noxious stimuli; the BIS value decreases with increasing dose and reaches below 60; the sedation or anesthesia time after a single dose of propofol is relatively short, and the MOAA / S score and BIS value recover rapidly with drug distribution and metabolism, with the recovery time being dose-dependent; the sedative or anesthetic effects produced by propofol at 0.4–0.6 mg / kg are comparable to those of propofol at 1.5–2.5 mg / kg, and the recovery times are similar. Propofol is widely distributed after a single intravenous administration, and the plasma drug concentration in humans is directly proportional to the dose. The plasma protein binding rate is approximately 95%, and it easily crosses the blood-brain barrier. Common adverse reactions associated with propofol (incidence ≥1%) are similar to those of propofol. Among these, adverse reactions requiring special attention include hypotension, bradycardia, apnea, respiratory depression, hypoxia, and injection pain. The incidence of pain during propofol injection is significantly lower than that of propofol injection. Summary of the Invention

[0005] This invention combines the advantages of polyethylene glycol and phenol derivatives by modifying phenol derivatives with polyethylene glycol of different chain lengths, providing a new phenol-polyethylene glycol derivative that can improve its water solubility, enhance the characteristics of drug absorption, metabolism and distribution in vivo, improve oral bioavailability, reduce the influence of food, reduce the dosage and frequency of administration, improve patient compliance, enhance safety, and prolong the duration of action.

[0006] Specifically, the present invention relates to a compound of general formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] R 1 and R 2 Each is independently selected from alkyl groups, wherein the alkyl groups are optionally further substituted with cycloalkyl groups;

[0010] R 3 Selected from hydrogen atoms;

[0011] Or, R 2 With R 3 Together with the carbon atoms connected thereto, they form a 4- or 5-membered ring, wherein the 4- or 5-membered ring is optionally further substituted with one or more alkyl groups;

[0012] n is 1 to 16; preferably n is 2 to 16; more preferably n is 11 to 16;

[0013] The condition is that when R 1 and R 2 When it is isopropyl, n is 11 to 16.

[0014] A preferred embodiment of the present invention relates to a compound of general formula (AI) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein the compound is of general formula (I) or its stereoisomers or pharmaceutically acceptable salts thereof.

[0015]

[0016] in:

[0017] R 1 and R 2 Each is independently selected from alkyl groups, wherein the alkyl groups are optionally further substituted with cycloalkyl groups;

[0018] n is 1 to 16; preferably n is 2 to 16; more preferably n is 11 to 16;

[0019] The condition is that when R 1 and R 2 When it is isopropyl, n is 11 to 16.

[0020] A preferred embodiment of the present invention is a compound of formula (AI) or (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 It is isopropyl, R 2 It is 1-cyclopropylethyl.

[0021] A preferred embodiment of the present invention is a compound of formula (AI) or (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 It is 1-cyclopropylethyl.

[0022] A preferred embodiment of the present invention is a compound of formula (AI) or (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 It is isopropyl, and n is 12 to 16.

[0023] A preferred embodiment of the present invention is a compound of general formula (AI) or (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0024]

[0025] Where: R 1 The definitions of n are as described in general formula (I).

[0026] A preferred embodiment of the present invention is a compound of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 It is isopropyl or 1-cyclopropylethyl.

[0027] A preferred embodiment of the present invention is a compound of general formula (AI) or (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is of general formula (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0028]

[0029] Wherein: n is defined as described in general formula (I).

[0030] A preferred embodiment of the present invention is a compound of general formula (AI) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of general formula (IV) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0031]

[0032] in:

[0033] R a and R b Each is independently selected from hydrogen atoms or alkyl groups;

[0034] m is 0 or 1;

[0035] R 1 The definitions of and n are as described in general formula (AI). Typical compounds of the present invention include, but are not limited to:

[0036]

[0037]

[0038] Or its stereoisomers, tautomers, or medicinal salts.

[0039] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0040] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0041] The present invention provides the use of a compound of general formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, 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 / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy.

[0042] Detailed description of the invention

[0043] The following detailed description of preferred embodiments of the invention, including the included examples, will make the invention more readily understood. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, and in the event of any conflict, the definitions in this specification shall prevail.

[0044] As used herein, the terms “prepared with” and “comprising” are synonymous. The terms “comprising,” “including,” “having,” “containing,” or any other variations thereof, as used herein, are intended to cover exclusive inclusion. For example, elements inherent in a composition, step, method, article, or apparatus that includes the listed elements.

[0045] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0046] The singular form includes the plural objects of discussion unless the context clearly indicates otherwise. "Optional" or "any one" means that the matter or event described thereafter may or may not occur, and the description includes both the possibility that the event occurs and the possibility that the event does not occur.

[0047] The approximate terms used in the specification and claims to modify quantities indicate that the invention is not limited to that specific quantity, but also includes acceptable modifications close to that quantity that do not alter the relevant essential function. Correspondingly, a numerical value modified by "about," "approximately," etc., means that the invention is not limited to a precise numerical value. In some instances, approximate terms may correspond to the precision of the instrument used to measure the value. In this application's specification and claims, scope definitions can be combined and / or interchanged, unless otherwise stated, these scopes include all subscopes contained therein.

[0048] Furthermore, the indefinite articles “a” and “an” preceding the elements or components of this invention do not impose any limitation on the quantity requirement (i.e., the number of times) of the elements or components. Therefore, “an” or “a” should be interpreted as including one or at least one, and the singular form of an element or component also includes the plural form, unless the quantity clearly refers to the singular form.

[0049] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0050] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. Preferably, it is C3-C. 12 Cycloalkyl groups, more preferably C3-C8 cycloalkyl groups, and most preferably C3-C6 cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., with cyclopropyl and cyclohexenyl being preferred. The cycloalkyl group may be substituted or unsubstituted. Attached Figure Description

[0051] Figure 1 RASS score for Beagle. Detailed Implementation

[0052] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0053] Example

[0054] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions.

[0055] The room temperature mentioned in the examples refers to 10–25°C.

[0056] Unless otherwise specified, the reagents described are used directly without purification. All solvents were purchased from commercial suppliers, such as Shanghai Titan Technology Co., Ltd. and Shanghai Haohong Biomedical Technology Co., Ltd., and are ready for use without further processing.

[0057] The termination of the reaction was determined by the consumption of starting materials, as analyzed by TLC and / or LCMS.

[0058] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for TLC have a diameter of 0.15 mm to 0.2 mm, while those used for TLC separation and purification have a diameter of 0.4 mm to 0.5 mm. Imaging is performed using UV light (254 nm) and / or iodine on the silica gel, and / or heating is performed with TLC staining agents such as alcohol-modified phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or cerium persulfate solution.

[0059] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 HNMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0060] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0061] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0062] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercially available manufacturers include, but are not limited to, Shanghai Titan Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd., Bid Pharmaceutical Technology Co., Ltd., and Aladdin Biochemical Technology Co., Ltd.

[0063] CD3OD: Deuterated methanol

[0064] CDCl3: Deuterated chloroform

[0065] DMSO-d6: Deuterated dimethyl sulfoxide

[0066] Argon atmosphere refers to a reaction flask connected to an argon balloon with a volume of approximately 1L.

[0067] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0068] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0069] The compound was purified by silica gel column chromatography and thin-layer chromatography. The eluent or developing solvent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system. The volume ratio of the solvent varied depending on the polarity of the compound. Small amounts of acidic or basic reagents, such as acetic acid or triethylamine, could also be added for adjustment.

[0070] The abbreviations used in this invention have their conventional meanings in the art, such as:

[0071] "TLC" stands for Thin Layer Chromatography.

[0072] "THF" stands for tetrahydrofuran.

[0073] “EA” stands for ethyl acetate.

[0074] “PE” stands for petroleum ether.

[0075] “DCM” stands for dichloromethane.

[0076] “MeOH” indicates methanol.

[0077] “MTBE” stands for methyl tert-butyl ether.

[0078] “TBAF” stands for tetrabutylammonium fluoride.

[0079] “NBS” stands for N-bromosuccinimide.

[0080] “SEM-Cl” represents 2-(trimethylsilyl)ethoxymethyl chloride.

[0081] “SEM” stands for 2-(trimethylsilyl)ethoxymethyl.

[0082] “DIPEA” stands for N,N-diisopropylethylamine.

[0083] "TFA" stands for trifluoroacetic acid.

[0084] Example 1

[0085] (R)-2-(1-Cyclopropylethyl)-6-isopropylphenyl-methyl polyethylene glycol 12-carboxylate (1)

[0086]

[0087] first step

[0088] 4-Nitrochlorophenyl ester (11.32 g, 56.175 mmol, 1.05 eq) was dissolved in 150 mL of tetrahydrofuran and cooled to 0 °C in an ice bath under a nitrogen atmosphere. Separately, dodecyl glycol monomethyl ether 1-1 (30.0 g, 53.5 mmol, 1.0 eq) and triethylamine (5.5 g, 54.57 mmol, 1.02 eq) were dissolved in 150 mL of dichloromethanetetrahydrofuran and slowly added dropwise to the above raw materials. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight (the experimental procedure was slightly modified according to the previously reported reference WO 2004 / 082620). TLC showed that the reaction was basically complete. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with 100 mL of MTBE for 20 minutes. After filtration, the filter cake was washed with 50 mL of MTBE, and the filtrates were combined and concentrated under reduced pressure to obtain crude product 1-2 (a colorless oily substance), which was used directly in the next step.

[0089] Step 2

[0090] (R)-2-(1-cyclopropylethyl)-6-isopropylphenol 1a (8.0 g, 39.16 mmol, 1.1 eq, according to the synthesis method in WO2016026459A1) was dissolved in 120 mL of dry THF and cooled to 0 °C under a nitrogen atmosphere. Potassium tert-butoxide solid (4.59 g, 40.94 mmol, 1.15 eq) was added in portions, and the mixture was stirred at 0 °C for 1 hour after the addition was complete. Separately, crude product 1-2 (25.8 g, 35.6 mmol, 1.0 eq) was dissolved in 80 mL of dry THF and slowly added dropwise to the above reaction solution under an ice bath. After the addition was complete, the mixture was stirred under an ice bath for 30 minutes (the experimental procedure was slightly modified according to the reported reference WO 2004 / 082620). TLC analysis showed that the intermediate raw material had basically reacted completely (the color at 254 nm wavelength had almost disappeared). 200 mL of ethyl acetate was added for dilution, followed by 100 mL of water for quenching. The mixture was separated, and the organic layer was washed three times with 100 mL of saturated sodium chloride aqueous solution. The mixture was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% DCM-5% MeOH / DCM as the eluent, yielding the target product 1 (20.5 g, colorless oil, yield 72.8%).

[0091] 1 HNMR(400MHz,Chloroform-d)δ7.30-7.14(m,3H),4.39(t,J=4.7Hz,2H),3.78-3.55(m,46H),3.38(s,3H),3.07-2.9 4(m,1H),2.14(t,J=7.7Hz,1H),1.31-1.16(m,9H),0.98(s,1H),0.60-0.49(m,1H),0.42-0.32(m,1H),0.16(m,2H).

[0092] Example 2

[0093] 2,6-Diisopropylphenol-methyl polyethylene glycol 12-carboxylate (2)

[0094]

[0095]

[0096] first step

[0097] 2,6-Diisopropylphenol 1b (3.49 g, 19.58 mmol, 1.1 eq) was dissolved in 60 mL of dry THF and cooled to 0 °C under a nitrogen atmosphere. Potassium tert-butoxide solid (2.30 g, 20.47 mmol, 1.15 eq) was added in portions, and stirring was continued at 0 °C for 1 hour after the addition was complete. Separately, crude intermediate 1-2 (12.92 g, 17.8 mmol, 1.0 eq) from Example 1 was dissolved in 40 mL of dry tetrahydrofuran and slowly added dropwise to the above reaction solution under ice bath conditions. After the addition was complete, stirring was continued under ice bath conditions for 30 minutes (the experimental procedure was slightly modified based on the reported reference WO 2004 / 082620). TLC analysis showed that the intermediate raw material had basically reacted completely (the color at 254 nm wavelength had almost disappeared). 100 mL of ethyl acetate was added for dilution, followed by 70 mL of water for quenching. The mixture was separated, and the organic layer was washed three times with 70 mL of saturated sodium chloride aqueous solution. The mixture was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% DCM-5% MeOH / DCM as the eluent, yielding the target product 2 (11.5 g, colorless oil, yield 84.5%).

[0098] 1 HNMR (400MHz, Chloroform-d) δ7.24-7.19 (m, 1H), 7.15 (d, J = 7.4Hz, 2H), 4.41 (t, J = 4. 8Hz, 2H), 3.83-3.51 (m, 46H), 3.38 (s, 3H), 3.08-2.97 (m, 2H), 1.21 (d, J = 6.9Hz, 12H).

[0099] Example 3

[0100] (R)-2-(1-Cyclopropylethyl)-6-isopropylphenyl-methyl polyethylene glycol 10-carboxylate (3)

[0101]

[0102] first step

[0103] 4-Nitrochlorophenyl ester (0.90 g, 4.46 mmol, 1.05 eq) was dissolved in 25 mL of tetrahydrofuran and cooled to 0 °C in an ice bath under a nitrogen atmosphere. Separately, decaethylene glycol monomethyl ether 3-1 (2.0 g, 4.25 mmol, 1.0 eq) and triethylamine (0.44 g, 4.33 mmol, 1.02 eq) were dissolved in 25 mL of tetrahydrofuran and slowly added dropwise to the above-mentioned starting material. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight (the experimental procedure was slightly modified based on the previously reported reference WO 2004 / 082620). TLC analysis showed that the reaction was essentially complete. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with 30 mL of MTBE for 20 minutes. After filtration, the filter cake was washed with 10 mL of MTBE, and the combined filtrates were concentrated under reduced pressure to obtain crude product 3-2 (a colorless oily substance), which was used directly in the next step.

[0104] Step 2

[0105] (R)-2-(1-cyclopropylethyl)-6-isopropylphenol 1a (0.95 g, 4.67 mmol, 1.1 eq, according to the synthesis method in WO2016026459A1) was dissolved in 30 mL of dry THF and cooled to 0 °C under a nitrogen atmosphere. Potassium tert-butoxide solid (0.55 g, 4.89 mmol, 1.15 eq) was added in portions, and the mixture was stirred at 0 °C for 1 hour after the addition was complete. Separately, crude product 3-2 (2.71 g, 4.25 mmol, 1.0 eq) was dissolved in 20 mL of dry THF and slowly added dropwise to the above reaction solution under an ice bath. After the addition was complete, the mixture was stirred under an ice bath for 30 minutes (the experimental procedure was slightly modified according to the reported reference WO 2004 / 082620). TLC analysis showed that the intermediate raw material had basically reacted completely (the color at 254 nm wavelength had almost disappeared). 50 mL of ethyl acetate was added for dilution, followed by 50 mL of water for quenching. The mixture was separated, and the organic layer was washed three times with 50 mL of saturated sodium chloride aqueous solution. The mixture was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% DCM-5% MeOH / DCM as the eluent, yielding the target product 3 (1.7 g, colorless oil, yield 57%).

[0106] 1H NMR (400MHz, Chloroform-d) δ7.30-7.22(m,2H),7.17(dd,J=7.4,2.0Hz,1H),4.39(dd,J=5.7,3.7Hz,2H),3.83-3.52(m,38H),3.38(s ,3H),3.07-2.95(m,1H),2.18-2.05(m,1H),1.30-1.17(m,9H),1.03-0.93(m,1H),0.59-0.50(m,1H),0.38(m,1H),0.24-0.07(m,2H).

[0107] Example 4

[0108] (R)-2-(1-Cyclopropylethyl)-6-isopropylphenyl-methyl polyethylene glycol 9-carboxylate (4)

[0109]

[0110]

[0111] first step

[0112] 4-Nitrochlorophenyl ester (0.99 g, 4.90 mmol, 1.05 eq) was dissolved in 25 mL of tetrahydrofuran and cooled to 0 °C in an ice bath under a nitrogen atmosphere. Separately, nonaethylene glycol monomethyl ether 4-1 (2.0 g, 4.67 mmol, 1.0 eq) and triethylamine (0.48 g, 4.76 mmol, 1.02 eq) were dissolved in 25 mL of tetrahydrofuran and slowly added dropwise to the above-mentioned starting material. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight (the experimental procedure was slightly modified based on the previously reported reference WO 2004 / 082620). TLC analysis showed that the reaction was essentially complete. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with 30 mL of MTBE for 20 minutes. After filtration, the filter cake was washed with 10 mL of MTBE, and the combined filtrates were concentrated under reduced pressure to obtain crude product 4-2 (a colorless oily substance), which was used directly in the next step.

[0113] Step 2

[0114] (R)-2-(1-cyclopropylethyl)-6-isopropylphenol 1a (1.05 g, 5.14 mmol, 1.1 eq, according to the synthesis method in WO2016026459A1) was dissolved in 30 mL of dry THF and cooled to 0 °C under a nitrogen atmosphere. Potassium tert-butoxide solid (0.60 g, 5.37 mmol, 1.15 eq) was added in portions, and the mixture was stirred at 0 °C for 1 hour after the addition was complete. Separately, crude product 4-2 (2.77 g, 4.67 mmol, 1.0 eq) was dissolved in 20 mL of dry THF and slowly added dropwise to the above reaction solution under an ice bath. After the addition was complete, the mixture was stirred under an ice bath for 30 minutes (the experimental procedure was slightly modified according to the reported reference WO 2004 / 082620). TLC analysis showed that the intermediate raw material had basically reacted completely (the color at 254 nm wavelength had almost disappeared). 50 mL of ethyl acetate was added for dilution, followed by 50 mL of water for quenching. The mixture was separated, and the organic layer was washed three times with 50 mL of saturated sodium chloride aqueous solution. The mixture was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% DCM-5% MeOH / DCM as the eluent, yielding the target product 4 (1.0 g, colorless oil, yield 32.5%).

[0115] 1 H NMR(400MHz,Chloroform-d)δ7.29-7.21(m,2H),7.17(dd,J=7.4,2.0Hz,1H),4.39(dd,J=5.7,3.7Hz,2H),3.86-3.45(m,34H),3.38 (s,3H),3.01(p,J=6.9Hz,1H),2.14(dd,J=8.8,6.8Hz,1H),1.35-1.15(m,9H),0.98(m,1H),0.55(m,1H),0.37(m,1H),0.16(m,2H).

[0116] Example 5

[0117] (R)-2-(1-Cyclopropylethyl)-6-isopropylphenyl-methyl polyethylene glycol 7-carboxylate (5)

[0118]

[0119] first step

[0120] 4-Nitrochlorophenyl ester (1.24 g, 6.17 mmol, 1.05 eq) was dissolved in 25 mL of tetrahydrofuran and cooled to 0 °C in an ice bath under a nitrogen atmosphere. Separately, heptaethylene glycol monomethyl ether 5-1 (2.0 g, 5.88 mmol, 1.0 eq) and triethylamine (0.61 g, 6.0 mmol, 1.02 eq) were dissolved in 25 mL of tetrahydrofuran and slowly added dropwise to the above raw materials. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight (the experimental procedure was slightly modified according to the previously reported reference WO 2004 / 082620). TLC showed that the reaction was basically complete. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with 30 mL of MTBE for 20 minutes. After filtration, the filter cake was washed with 10 mL of MTBE, and the filtrates were combined and concentrated under reduced pressure to obtain crude product 5-2 (a colorless oily substance), which was used directly in the next step.

[0121] Step 2

[0122] (R)-2-(1-cyclopropylethyl)-6-isopropylphenol 1a (1.32 g, 6.49 mmol, 1.1 eq, according to the synthesis method in WO2016026459A1) was dissolved in 30 mL of dry THF and cooled to 0 °C under a nitrogen atmosphere. Potassium tert-butoxide solid (0.76 g, 6.76 mmol, 1.15 eq) was added in portions, and the mixture was stirred at 0 °C for 1 hour after the addition was complete. Separately, crude product 5-2 (2.97 g, 5.88 mmol, 1.0 eq) was dissolved in 20 mL of dry THF and slowly added dropwise to the above reaction solution under an ice bath. After the addition was complete, the mixture was stirred under an ice bath for 30 minutes (the experimental procedure was slightly modified according to the reported reference WO 2004 / 082620). TLC analysis showed that the intermediate raw material had basically reacted completely (the color at 254 nm wavelength had almost disappeared). 50 mL of ethyl acetate was added for dilution, followed by 50 mL of water for quenching. The mixture was separated, and the organic layer was washed three times with 50 mL of saturated sodium chloride aqueous solution. The mixture was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% DCM-5% MeOH / DCM as the eluent, yielding the target product 5 (1.9 g, colorless oil, yield 56.6%).

[0123] 1 H NMR (400MHz, Chloroform-d) δ7.30-7.21(m,2H),7.17(dd,J=7.5,2.0Hz,1H),4.39(t,J=4.7Hz,2H),3.82-3.52(m,26H),3. 38(s,3H),3.01(p,J=6.9Hz,1H),2.18-2.09(m,1H),1.30-1.16(m,9H),0.98(m,1H),0.54(m,1H),0.37(m,1H),0.16(m,2H).

[0124] Example 6

[0125] (R)-2-(1-Cyclopropylethyl)-6-isopropylphenyl-methyl polyethylene glycol 4-carboxylate (6)

[0126]

[0127] first step

[0128] 4-Nitrochlorophenyl ester (5.08 g, 25.2 mmol, 1.05 eq) was dissolved in 75 mL of tetrahydrofuran and cooled to 0 °C in an ice bath under a nitrogen atmosphere. Separately, tetraethylene glycol monomethyl ether 6-1 (5.0 g, 24.0 mmol, 1.0 eq) and triethylamine (2.47 g, 24.5 mmol, 1.02 eq) were dissolved in 75 mL of tetrahydrofuran and slowly added dropwise to the above-mentioned starting material. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight (the experimental procedure was slightly modified based on the previously reported reference WO 2004 / 082620). TLC analysis showed that the reaction was essentially complete. The reaction solution was concentrated under reduced pressure, and the crude product was pulped with 50 mL of MTBE for 20 minutes. The mixture was filtered, and the filter cake was washed with 40 mL of MTBE. The combined filtrates were concentrated under reduced pressure to obtain crude product 6-2 (a colorless oily substance), which was used directly in the next step.

[0129] Step 2

[0130] (R)-2-(1-cyclopropylethyl)-6-isopropylphenol 1a (5.4 g, 26.4 mmol, 1.1 eq, according to the synthesis method in WO2016026459A1) was dissolved in 80 mL of dry THF and cooled to 0 °C under a nitrogen atmosphere. Potassium tert-butoxide solid (3.1 g, 27.6 mmol, 1.15 eq) was added in portions, and the mixture was stirred at 0 °C for 1 hour after the addition was complete. Crude product 6-2 (8.96 g, 24.0 mmol, 1.0 eq) was dissolved in 70 mL of dry THF and slowly added dropwise to the above reaction solution under an ice bath. After the addition was complete, the mixture was stirred under an ice bath for 30 minutes (the experimental procedure was slightly modified according to the reported reference WO 2004 / 082620). TLC analysis showed that the intermediate raw material had basically reacted completely (the color at 254 nm wavelength had almost disappeared). 50 mL of ethyl acetate was added for dilution, followed by 50 mL of water for quenching. The mixture was separated, and the organic layer was washed three times with 50 mL of saturated sodium chloride aqueous solution. The mixture was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% DCM-5% MeOH / DCM as the eluent, yielding the target product 6 (5.0 g, colorless oil, yield 47.5%).

[0131] 1H NMR(400MHz,Chloroform-d)δ7.30-7.20(m,2H),7.17(dd,J=7.4,2.0Hz,1H),4.43-4.36(m,2H),3.82-3.53(m,14H),3.38(s,3H),3.0 6-2.95(m,1H),2.14(dd,J=8.8,6.8Hz,1H),1.28-1.18(m,9H),1.05-0.93(m,1H),0.60-0.50(m,1H),0.38(m,1H),0.25-0.08(m,2H).

[0132] Example 7

[0133] 2,6-Bis((R)-1-cyclopropylethyl)phenol-methyl polyethylene glycol 12-carboxylate (7)

[0134]

[0135] first step

[0136] 2,6-Bis((R)-1-cyclopropylethyl)phenol-methyl polyethylene glycol 12-carboxylate (7)

[0137] 2,6-Bis((R)-1-cyclopropylethyl)phenol (1e) (0.41 g, 1.78 mmol, 1 eq, synthetic method referred to WO2014180305A1) was dissolved in 10 mL of dry THF and cooled to 0 °C under a nitrogen atmosphere. Potassium tert-butoxide solid (0.23 g, 2.05 mmol, 1.15 eq) was added in portions, and the mixture was stirred at 0 °C for 1 hour after the addition was complete. Separately, crude compounds 1-2 (1.29 g, 1.78 mmol, 1.0 eq) prepared by the same method in Example 1 were dissolved in 10 mL of dry THF and slowly added dropwise to the above reaction solution under an ice bath. After the addition was complete, the mixture was stirred under an ice bath for 30 minutes (the experimental procedure was slightly modified according to the reported reference WO 2004 / 082620). TLC analysis showed that the intermediate raw material had basically reacted completely (the color at 254 nm wavelength had almost disappeared). 20 mL of ethyl acetate was added for dilution, followed by 20 mL of water for quenching. The mixture was separated, and the organic layer was washed three times with 10 mL of saturated sodium chloride aqueous solution. The mixture was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 100% DCM-5% MeOH / DCM as the eluent, yielding the target product 9 (1.04 g, colorless oil, yield 71.4%). 1H NMR(400MHz,Chloroform-d)δ7.31-7.22(m,3H),4.40-4.33(m,2H),3.80-3.51(m,46H),3.38(s,3 H),2.12(m,2H),1.25(d,J=7.0Hz,6H),0.98(m,2H),0.61-0.49(m,2H),0.37(m,2H),0.16(m,4H).

[0138] Example 8

[0139] (S)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octyl-1(6),2,4-trien-2-ol-methylpolyethylene glycol 12-carboxylate

[0140]

[0141] first step

[0142] 2-(1-Cyclopropyl-1-hydroxyethyl)phenol (8-2)

[0143] A 1.0 M tetrahydrofuran solution of cyclopropylmagnesium bromide (3.525 L, 3.525 mmol, 2.4 eq) was added to the reaction flask. Under a nitrogen atmosphere, the mixture was cooled to 0 ± 5 °C, and a tetrahydrofuran solution (1 L) of 1-(2-hydroxyphenyl)ethyl-1-one (20) (200 g, 1469 mmol, 1.0 eq) was added dropwise. After the addition was complete, the mixture was stirred at 0 ± 5 °C for 30 minutes, and then allowed to react naturally overnight. The reaction solution was quenched dropwise in 1.5 L of saturated ammonium chloride aqueous solution at 0–5 °C. 1 L of petroleum ether was added, and the organic phase was separated. The aqueous phase was extracted with 0.5 L of petroleum ether. The combined organic phases were washed with 1 L of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:20) to give 97 g of the title product 2-(1-cyclopropyl-1-hydroxyethyl)phenol (21) (yield 37%).

[0144] 1 H NMR (400MHz, Chloroform-d) δ9.10 (s, 1H), 7.24-7.10 (m, 2H), 6.84 (dd, J=11.4, 7.8Hz, 2H), 2.42 (s, 1H), 1.50 (s, 3H), 1.40 (s, 1H), 0.73-0.31 (m, 4H).

[0145] Step 2

[0146] 2-(1-Cyclopropylethyl)phenol (8-3)

[0147] 2-(1-Cyclopropyl-1-hydroxyethyl)phenol (21) (213 g, 1200 mmol, 1 eq) was dissolved in 2 L of dichloromethane and cooled to -5 to 0 °C. Triethylsilane (209 g, 1800 mmol, 1.5 eq) was added, followed by slow dropwise addition of trifluoroacetic acid (109 g, 960 mmol, 0.8 eq). The mixture was then stirred overnight at room temperature. The reaction solution was washed successively with 1 L of water, 500 mL of saturated sodium bicarbonate solution, and 500 mL of water. Tetrabutylammonium fluoride (156 g, 600 mmol, 0.5 eq) was added to the organic phase, and stirring was continued for 4 h until the intermediate essentially disappeared. The reaction solution was washed successively with 500 mL of water and 500 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 1:20) to give the title product 2-(1-cyclopropylethyl)phenol (22) (162 g, yield 83%).

[0148] 1 H NMR (400MHz, Chloroform-d) δ7.27 (dd, J=8.1, 6.4Hz, 1H), 7.08 (td, J=7.7, 1.7Hz, 1H), 6.97-6.86 (m, 1H), 6.79-6.6 9 (m, 1H), 5.07 (s, 1H), 2.50-2.37 (m, 1H), 1.30 (d, J=7.0Hz, 3H), 1.06 (m, 1H), 0.54-0.38 (m, 2H), 0.27-0.11 (m, 2H).

[0149] Step 3

[0150] 2-Bromo-6-(1-Cyclopropylethyl)phenol (8-4)

[0151] 2-(1-Cyclopropylethyl)phenol (22) (156 g, 962 mmol, 1.0 eq) was added to a reaction flask, followed by diisopropylamine (9.73 g, 96.2 mmol, 0.1 eq). The mixture was cooled to 0 ± 5 °C, and NBS (180 g, 1010 mmol, 1.05 eq) was added. After the addition was complete, the mixture was stirred for 1 h to complete the reaction. Silica gel column chromatography (ethyl acetate: petroleum ether = 1:20) yielded 195 g of the title product 2-bromo-6-(1-cyclopropylethyl)phenol (23) (yield 84%).

[0152] 1H NMR (400MHz, Chloroform-d) δ7.32 (ddd, J=21.5, 7.4, 1.6Hz, 2H), 6.83 (t, J=7.8Hz, 1H), 5.58 (s, 1H), 2.47 (dd, J=9.4, 7.0Hz, 1H), 1 .34 (d, J=7.1Hz, 3H), 1.06 (qd, J=8.4, 6.7, 3.2Hz, 1H), 0.66-0.55 (m, 1H), 0.45 (dd, J=8.6, 4.3Hz, 1H), 0.23 (dt, J=24.9, 4.7Hz, 2H).

[0153] Step 4

[0154] 2-Bromo-6-(1-Cyclopropylethyl)phenyl((S)-1-Phenethyl)carbamate (8-5)

[0155] 2-Bromo-6-(1-cyclopropylethyl)phenol (23) (230 g, 954 mmol, 1 eq) was dissolved in n-heptane (4000 mL) at room temperature, and triethylamine (48.2 g, 476 mmol, 0.5 eq) was added. (S)-1-phenylethyl isocyanate (196.5 g, 1335 mmol, 1.4 eq) was added. The reaction was carried out at 40 °C for half an hour, then heated to 105 °C for 1 hour, and then cooled to room temperature. Filtration yielded the crude product 2-bromo-6-(1-cyclopropylethyl)phenyl((S)-1-phenylethyl)carbamate (24a).

[0156] Step 5

[0157] 2-Bromo-6-((R)-1-cyclopropylethyl)phenyl((S)-1-phenylethyl)carbamate (8-6)

[0158] Crude 2-bromo-6-(1-cyclopropylethyl)phenyl((S)-1-phenylethyl)carbamate (24a) was added to a solution of n-heptane, heated to dissolve, and then cooled to crystallize. This process was repeated several times until the required chiral purity was achieved, yielding the title product 2-bromo-6-((R)-1-cyclopropylethyl)phenyl((S)-1-phenylethyl)carbamate (25a).

[0159] The crystallization temperature and its effect are shown in the table below:

[0160]

[0161] *average value

[0162] Step 6

[0163] (R)-2-bromo-6-(1-cyclopropylethyl)phenol (8-7)

[0164] 2-Bromo-6-((R)-1-cyclopropylethyl)phenyl((S)-1-phenylethyl)carbamate (25a) (60 g, 154.4 mmol, 1.0 eq) was added to a reaction flask, along with 120 mL of methanol, 120 mL of tetrahydrofuran, and 150 mL of 10% sodium hydroxide aqueous solution. The mixture was stirred at room temperature for 2 h. The pH was adjusted to neutral by adding citric acid aqueous solution, and the organic solvent was concentrated. 200 mL of ethyl acetate was added. The reaction solution was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then subjected to silica gel column chromatography (PE:EA = 20:1) to yield the title product (R)-2-bromo-6-(1-cyclopropylethyl)phenol (26a) 35 g (yield 94%).

[0165] Step 7

[0166] (R)-2-(benzyloxy)-1-bromo-3-(1-cyclopropylethyl)benzene (8-8)

[0167] (R)-2-bromo-6-(1-cyclopropylethyl)phenol (10) (6.0 g, 24.88 mmol, 1 eq), benzyl bromide (6.38 g, 37.32 mmol, 1.5 eq), and potassium carbonate (10.32 g, 74.65 mmol, 3 eq) were added to a reaction flask. The mixture was purged with nitrogen three times and reacted overnight at 45–50 °C. The reaction solution was cooled to room temperature, and 1 g of glycine ethyl ester hydrochloride was added. The mixture was stirred for 1 h to remove excess benzyl bromide. The reaction solution was poured into 200 mL of water, extracted with 100 mL of petroleum ether (3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to give 7.9 g of the title product (95% yield).

[0168] Step 8

[0169] (R)-5-(benzyloxy)-4-(1-cyclopropylethyl)-bicyclo[4.2.0]oct-1(6),2,4-trien-7-one)(8-9)

[0170] (S)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]oct-1(6),2,4-trien-2-ol(1) (7.50 g, 22.64 mmol, 1 eq) was added to the reaction flask, followed by 50 mL of anhydrous tetrahydrofuran and 1,1-diethoxyethylene (7.89 g, 67.92 mmol, 3 eq). The mixture was purged with nitrogen three times, and sodium amino acid (2.65 g, 67.92 mmol, 3 eq) was added. The mixture was refluxed at 70 °C for 3.5 h. At this point, the solution was blackish-yellow, and the solid had almost disappeared. TLC showed that the starting material had disappeared. After cooling, the reaction solution was diluted with 50 mL of anhydrous ethanol, and the remaining sodium amino acid was quenched dropwise with water. The reaction solution was poured into 200 mL of water, extracted with 100 mL of ethyl acetate twice, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in 20 mL of tetrahydrofuran, and 20 mL of 6N hydrochloric acid aqueous solution was added. The mixture was reacted at room temperature for 2 h, and TLC showed that the intermediate disappeared. The pH was adjusted to neutral with sodium bicarbonate aqueous solution, and the mixture was extracted with 50 mL of ethyl acetate (2 times). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography was used to purify the product, yielding 4.2 g of the title product (63% yield).

[0171] 1 H NMR(400MHz,Chloroform-d)δ7.54(d,J=7.3Hz,1H),7.46-7.41(m,2H),7.41-7.29(m,3H),7.04(d,J=7.3Hz,1H),5.51(d,J=1.2Hz, 2H),3.89(s,2H),2.48(m,1H),1.27(d,J=7.0Hz,3H),1.07-0.93(m,1H),0.55(m,1H),0.38(m,1H),0.20(m,1H),0.14-0.03(m,1H).

[0172] Step 9

[0173] (R)-2-(benzyloxy)-3-(1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octyl-1(6),2,4-triene(8-10)

[0174] Methyltriphenylphosphine bromide (9.77 g, 27.36 mmol, 2 eq) was added to a reaction flask, followed by 40 mL of anhydrous tetrahydrofuran. The mixture was purged with nitrogen three times, cooled to 0 °C, and then 1 N potassium tert-butoxide tetrahydrofuran solution (20.52 mL, 20.52 mmol, 1.5 eq) was added. The mixture was stirred for 1 h until the solution turned lemon yellow. A tetrahydrofuran solution of (R)-5-(benzyloxy)-4-(1-cyclopropylethyl)-bicyclo[4.2.0]oct-1(6),2,4-trien-7-one)(12) (4.0 g, 13.68 mmol, 1 eq) was added, and the mixture was allowed to react naturally overnight. The reaction was quenched with ammonium chloride aqueous solution, and the reaction mixture was poured into 100 mL of water. The mixture was extracted with 50 mL of ethyl acetate twice, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to give 2.0 g of the title product (50% yield).

[0175] 1 H NMR(400MHz,Chloroform-d)δ7.45-7.30(m,5H),7.29-7.25(m,1H),6.86(d,J=7.3Hz,1H),5.32(s,2H),5.24(d,J=1.3Hz,1H),4.95(d, J=1.2Hz,1H),3.56(s,2H),2.43(m,1H),1.23(d,J=7.0Hz,3H),1.02-0.93(m,1H),0.51(m,1H),0.34(m,1H),0.15(m,1H),0.04(m,1H).

[0176] Step 10

[0177] 3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]oct-1(6),2,4-trien-2-ol(8-11)

[0178] (R)-2-(benzyloxy)-3-(1-cyclopropylethyl)-8-methylbicyclo[4.2.0]oct-1(6),2,4-triene(13) (800 mg, 2.75 mmol, 1 eq) and 5 mL of isopropanol were added to a reaction flask. 80 mg of 10% palladium on carbon was added, and the mixture was purged with hydrogen three times. The reaction was carried out overnight at room temperature. The reaction solution was filtered through a diatomaceous earth liner. The filter cake was washed with 30 mL of dichloromethane, the organic phase was concentrated, and purified by column chromatography to give 340 mg of the title product (61% yield).

[0179] 1H NMR(400MHz,Chloroform-d)δ7.14(dd,J=7.5,1.7Hz,1H),6.68(d,J=7.3Hz,1H),4.54(s,1H),3.56(dd,J=9.8,4.6Hz,1H),3.29(dd,J=13.8,5.2Hz,1H),2 .62(dd,J=13.7,2.1Hz,1H),2.40(dt,J=8.3,6.9Hz,1H),1.45(m,3H),1.33- 1.27(m,3H),1.04(s,1H),0.59-0.51(m,1H),0.48-0.36(m,1H),0.19(m,2H).

[0180] Step 11

[0181] (S)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]octyl-1(6),2,4-trien-2-ol-methylpolyethylene glycol 12-carboxylate (8-12)

[0182] 3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]oct-1(6),2,4-trien-2-ol was subjected to chiral resolution under the following conditions:

[0183] Column model: Chiralpak AD-3;

[0184] Mobile phase: A: Supercritical carbon dioxide; B: Methanol (containing 0.05% diethylamine)

[0185] Gradient: Phase B 5%–40% 4 min; 40%–5% 0.2 min; 5% 1.8 min

[0186] Flow rate: 3 mL / min, column temperature: 35 °C, ABPR: 1500 psi

[0187] The title product was obtained (Peak2 is the target product with S configuration).

[0188] Peak1(R) 1H NMR(400MHz,Chloroform-d)δ7.13(d,J=7.4Hz,1H),6.67(d,J=7.3Hz,1H),4.54(s,1H),3.61-3.51(m,1H),3.28(dd,J=13.8,5.2Hz,1H),2.61(dd,J=13.7, 2.4Hz,1H),2.39(dd,J=8.3,6.8Hz,1H),1.45(d,J=7.0Hz,3H),1.28(d,J=7.0 Hz,3H),1.05(m,1H),0.60-0.48(m,1H),0.48-0.36(m,1H),0.28-0.11(m,2H).

[0189] Peak2(S) 1 H NMR(400MHz,Chloroform-d)δ7.14(d,J=7.4Hz,1H),6.67(d,J=7.4Hz,1H),4.52( s,1H),3.56(ddd,J=7.2,5.1,2.3Hz,1H),3.29(dd,J=13.7,5.2Hz,1H),2.61(dd,J =13.7,2.4Hz,1H),2.41(dd,J=8.3,6.8Hz,1H),1.44(d,J=7.0Hz,3H),1.29(d,J= 7.0Hz,3H),1.03(m,1H),0.59-0.51(m,1H),0.45-0.37(m,1H),0.25-0.11(m,2H).

[0190] Step Twelve

[0191] (S)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]oct-1(6),2,4-trien-2-ol-methylpolyethylene glycol-12-carboxylic acid

[0192] Ester (8)

[0193] (S)-3-((R)-1-cyclopropylethyl)-8-methylbicyclo[4.2.0]oct-1(6),2,4-trien-2-ol(1) (0.5 g, 2.47 mmol, 1.1 eq) was dissolved in 20 mL of anhydrous tetrahydrofuran, purged with nitrogen three times, cooled to 0 °C, and 1N potassium tert-butoxide tetrahydrofuran solution (2.58 mL, 2.58 mmol, 1.15 eq) was added. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. Separately, 4-nitrophenyl-methyl polyethylene glycol 12-carboxylate (1.63 g, 2.25 mmol, 1.0 eq) was dissolved in 20 mL of anhydrous tetrahydrofuran and slowly added dropwise to the above reaction solution under ice bath conditions. After the addition was complete, the mixture was stirred under ice bath conditions for 30 minutes and then allowed to react overnight at room temperature. Dilute with 50 mL of ethyl acetate, then quench with 50 mL of water, separate the layers, wash the organic layer three times with 50 mL of saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain 1.2 g of the title product (yield 67%).

[0194] 1 H NMR(400MHz,Chloroform-d)δ7.23(d,J=7.5Hz,1H),6.95(d,J=7.5Hz,1H),5.30(s, 1H),4.43-4.37(m,2H),3.83-3.53(m,46H),3.38(s,3H),3.35-3.29(m,1H),2.65(dd ,J=14.0,2.6Hz,1H),2.25(m,1H),1.34(d,J=7.1Hz,3H),1.27(d,J=7.0Hz,3H),1.03 -0.89(m,1H),0.57-0.48(m,1H),0.40-0.31(m,1H),0.19(m,1H),0.11-0.03(m,1H).

[0195] Example 9

[0196] (R)-2-Cyclopropyl-6-(1-Cyclopropylethyl)phenol-methyl polyethylene glycol 12-carboxylate

[0197]

[0198] first step

[0199] (R)-2-Cyclopropyl-6-(1-Cyclopropylethyl)phenol

[0200] (R)-2-bromo-6-(1-cyclopropylethyl)phenol (8-7) (5.0 g, 20.74 mmol, 1 eq), potassium cyclopropyltrifluoroborate (2.67 g, 31.10 mmol, 1.5 eq), and potassium phosphate (13.20 g, 62.21 mmol, 3 eq) were added to the reaction flask. Toluene (80 mL), water (16 mL), palladium acetate (0.46 g, 2.07 mmol, 0.1 eq), and tricyclohexylphosphine fluoroborate (1.53 g, 4.15 mmol, 0.2 eq) were added. The mixture was purged with nitrogen three times and heated at 95 °C for 16 h until no starting material remained. The mixture was diluted with 100 mL of water, extracted with ethyl acetate (80 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 3.0 g of the product (71% yield).

[0201] 1 H NMR (400MHz, Chloroform-d) δ7.19 (dd, J=7.6, 1.7Hz, 1H), 6.97 (ddd, J=7.5, 1.7, 0.9Hz, 1H), 6.83 (t, J=7.6Hz, 1H), 5.61 (s, 1H), 2.46 (m, 1H), 1.8 2-1.70(m,1H),1.30(d,J=7.1Hz,3H),1.12-1.00(m,1H),1.01-0.93(m,2 H),0.65(m,2H),0.59-0.49(m,1H),0.44-0.34(m,1H),0.26-0.12(m,2H).

[0202] Step 2

[0203] (R)-2-Cyclopropyl-6-(1-Cyclopropylethyl)phenol-methyl polyethylene glycol 12-carboxylate

[0204] (R)-2-cyclopropyl-6-(1-cyclopropylethyl)phenol (3) (1.01 g, 5.00 mmol, 1.1 eq) was dissolved in 30 mL of anhydrous tetrahydrofuran, purged with nitrogen three times, cooled to 0 °C, and 1 N potassium tert-butoxide tetrahydrofuran solution (5.22 mL, 5.22 mmol, 1.15 eq) was added. After the addition was complete, stirring was continued at 0 °C for 1 hour. Separately, 4-nitrophenyl-methyl polyethylene glycol 12-carboxylate (3.30 g, 4.54 mmol, 1.0 eq) was dissolved in 20 mL of anhydrous tetrahydrofuran and slowly added dropwise to the above reaction solution under ice bath conditions. After the addition was complete, stirring was continued under ice bath conditions for 30 minutes, and the reaction was allowed to proceed overnight at room temperature. Dilute with 50 mL of ethyl acetate, then quench with 50 mL of water, separate the layers, wash the organic layer three times with 50 mL of saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain 2.87 g of the title product (yield 80%). 1 H NMR(400MHz,Chloroform-d)δ7.24(dd,J=7.7,1.7Hz,1H),7.15(t,J=7.7Hz,1H ),6.85(dd,J=7.6,1.7Hz,1H),4.43-4.37(m,2H),3.84-3.52(m,46H),3.38(s, 3H),2.24-2.15(m,1H),1.87(m,1H),1.26(d,J=7.0Hz,3H),1.04-0.94(m,1H), 0.88(m,2H),0.66(m,2H),0.55(m,1H),0.37(m,1H),0.21(m,1H),0.13(m,1H).

[0205] Test Example 1: Stability Test

[0206] Compound 1 of the present invention was tested to be stable in PBS solution and aqueous solution at room temperature.

[0207] 0.2 g of compound 1 with a purity of 99.11% was dissolved in 0.01 M PBS buffer at pH 6.5 and left at room temperature for 17 hours. The purity was retested and found to be 99.32%, with no obvious impurity peaks. It has good water solubility and solution stability.

[0208] Test Example 2: Drug Efficacy Test: Mouse Righting Reflex Experiment

[0209] ICR mice, SPF grade, 100 mice, half male and half female, provided by Chengdu Vital River Laboratory Animal Technology Co., Ltd.

[0210] Test substance preparation: 5% DMSO + 5% HS-15 + 90% physiological saline.

[0211] LD50 solvent: diluted with 20% soybean oil blank emulsion.

[0212] The general anesthetic effects of the test compounds were studied using a well-established mouse anesthesia model (Ratnakumari Lingamaneni et al. (2001). Anesthesiology, 2001, 94, 1050-7). The anesthetic efficacy and safety were evaluated using indicators such as median effective dose (ED50), median lethal dose (LD50), therapeutic index (TI, i.e., LD50 / ED50), safety index (SI, i.e., LD50 / ED95), induction time, maintenance time, and maximum tolerated dose (MTD).

[0213] Before the experiment, a preliminary test was conducted to determine the approximate dose (administered volume) that would induce anesthesia in animals. This dose was then used as the intermediate dose for the formal experiment. Two to three additional dose groups were established, one above and one below the intermediate dose group. The disappearance of the righting reflex was used as the indicator of efficacy. The test animals were fasted overnight before administration. The following day, the drug was administered at a volume of 10 mL / kg via intravenous injection. The time from drug administration to the disappearance of the righting reflex was recorded as the anesthesia induction time, and the time from the disappearance of the righting reflex to its recovery was recorded as the duration of anesthesia. The strength of the anesthetic effect was represented by the anesthesia induction time and the duration of anesthesia. Details are shown in Table 1 below.

[0214] Table 1. LORR results in mice

[0215]

[0216] Conclusion: The intravenous injection of the prodrug of cyclopropofol (compound 1) of the present invention provides anesthesia for ED. 50 =21 mg / kg (5.38 mg / kg based on propofol), LD50 50 = 81.5 mg / kg (20.9 mg / kg based on propofol), 30 mg / kg anesthetizes all animals (7.7 mg / kg based on propofol); onset time is about 1 minute (2 seconds for propofol), anesthesia time is 2-10 minutes (5-8 minutes for propofol).

[0217] Test Example 3: Drug Efficacy Test: Evaluation of Anesthesia and Sedation Efficacy in Beagle Dogs

[0218] 1. Laboratory animals

[0219] Six males that were not first-time test subjects were selected. Ordinary Beagles of similar weight and in good health were provided by the Sichuan Musk Deer Research Institute. All animals were acclimatized to a standard breeding environment for 5-7 days before the trial and passed quarantine before being included in this trial.

[0220] 2. Preparation of the test substance

[0221] Accurately weigh compound 1 or compound 9 and prepare the drug solution as follows: First, add 10% dimethyl sulfoxide (DMSO) to the final volume and mix thoroughly until the compound is completely dissolved; then add 10% hydroxypropyl-β-cyclodextrin (HS-15) and vortex mix; finally, add 80% physiological saline, and after sonication and vortexing, obtain a clear and transparent drug solution for intravenous injection.

[0222] 3. Dosing regimen

[0223] Prior to the trial, all beagles were fasted and deprived of water for more than 12 hours. Two hours after administration, the animals were allowed to recover before being fed again.

[0224] Compound 1: Three beagle dogs received single intravenous injections of 10 mg / kg and 20 mg / kg, respectively (two animals in the 20 mg / kg group);

[0225] Compound 9: Three beagle dogs received single intravenous injections of 20 mg / kg, 30 mg / kg, and 40 mg / kg, respectively.

[0226] 4. Observation and detection indicators

[0227] (1) General clinical observation

[0228] Systematic clinical observations were conducted on all animals before and after administration, including their mental state, behavior, reflexes, skin, coat, eyes, ears, nose, abdomen, external genitalia, anus, limbs, injection site, feet, and respiration, to assess drug safety and adverse reactions.

[0229] (2) Measurement of onset and duration of anesthesia

[0230] Anesthesia latency period (onset time): Record the time from the start of intravenous injection to the animal losing its righting reflex;

[0231] Duration of anesthesia: Record the time from the onset of anesthesia to the beginning of the animal’s awakening (such as opening its eyes, raising its head, and other voluntary movements);

[0232] Walking recovery time: The time from awakening to when the animal is able to stand and walk independently is recorded.

[0233] (3) Sedation depth assessment (RASS score)

[0234] The modified Richmond Agitation-Sedation Scale (RASS) was used to quantitatively assess the degree of sedation. Scoring time points included: before drug administration (0 min), 1, 2, 3, 5, 10, 20, and 30 min after drug administration, and at awakening, for a total of 9 time points. The scoring criteria are shown in Table 2.

[0235] Table 2 RASS Sedation Criteria

[0236] 0 sober and calm Awake and natural state -1 sleepy Not fully conscious, motor incoordination, inability to balance on the hind limbs -2 Mild sedation Upon opening eyes and hearing a sound, the righting reflex is lost, but the eyelash reflex is present. -3 Moderate sedation Loss of righting reflex and absence of eyelash reflex -4 Deep sedation Responding to bodily stimuli -5 coma No response to bodily stimuli

[0237] 5. Test Results

[0238] The RASS scores are summarized in Table 3, and are further detailed in Appendix 3. Figure 1 To provide a visual presentation.

[0239] Table 3. RASS scores of compounds 1 and 9 in beagles.

[0240]

[0241] Note: " / " indicates that the time point was not recorded or that the animal has awakened / not reached that stage.

[0242] 6. Conclusion

[0243] The experimental results showed that compound 1, administered intravenously at a dose of 20 mg / kg, rapidly induced deep sedation and even coma in beagle dogs (RASS score of -5), exhibiting rapid onset, sufficient sedation depth, and moderate duration of action. Animals typically recovered to a mild sedation state (RASS score of approximately -2) approximately 45 minutes after administration, indicating controllable metabolism and clearance processes, which is beneficial for smooth postoperative recovery. In contrast, compound 9, even at the same or higher doses, induced weaker sedation depth and shorter duration of action. In conclusion, compound 1 demonstrated excellent combined anesthesia-sedation performance in canine models, making it particularly suitable for experimental or clinical anesthesia scenarios requiring rapid onset and controllable recovery.

[0244] Furthermore, based on the results of the LORR experiment in mice and the pharmacological studies in beagle dogs, the compounds of this invention exhibited good anesthetic and sedative activities in both rodents and non-rodent mammals, demonstrating their potential as novel anesthetic drugs.

Claims

1. A compound of general formula (AI) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof: in: R 1 and R 2 Each is independently selected from alkyl groups, wherein the alkyl groups are optionally further substituted with cycloalkyl groups; R 3 Selected from hydrogen atoms; Or, R 2 With R 3 Together with the carbon atoms connected thereto, they form a 4- or 5-membered ring, wherein the 4- or 5-membered ring is optionally further substituted with one or more alkyl groups; n is 1 to 16; preferably n is 2 to 16; more preferably n is 11 to 16; The condition is that when R 1 and R 2 When it is isopropyl, n is 11 to 16.

2. The compound according to claim 1, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is a compound of general formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: R 1 and R 2 Each is independently selected from alkyl groups, wherein the alkyl groups are optionally further substituted with cycloalkyl groups; n is 1 to 16; preferably n is 2 to 16; more preferably n is 11 to 16; The condition is that when R 1 and R 2 When it is isopropyl, n is 11 to 16.

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 It is isopropyl, R 2 It is 1-cyclopropylethyl.

4. The compound according to claim 1 or 2, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 1 and R 2 It is 1-cyclopropylethyl.

5. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 It is isopropyl, and n is 12 to 16.

6. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (II), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. in: R 1 The definitions of n are as described in general formula (I).

7. The compound according to claim 6, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 1 It is isopropyl or 1-cyclopropylethyl.

8. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. in: The definition of n is as described in general formula (I).

9. The compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of general formula (IV). in: R a and R b Each is independently selected from hydrogen atoms or alkyl groups; m is 0 or 1; R 1 The definitions of n are as described in the general formula (AI).

10. The compound according to any one of claims 1 to 9, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

11. A pharmaceutical composition comprising the compound or its stereoisomer or pharmaceutically acceptable salt as claimed in any one of claims 1 to 10, and one or more pharmaceutically acceptable carriers and / or excipients.

12. Use of the compounds according to claims 1 to 10, or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the compositions according to claim 11, 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 / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.

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