Propofol analogues, methods of making and use in non-narcotic fields

Abstract

The present application provides a propofol analogue, a preparation method thereof and application thereof in non-narcotic field. The propofol analogue has a structure as shown in general formula (G). The propofol analogue of the present application can greatly reduce or eliminate the affinity to GABA receptor, i.e. weaken or eliminate the narcotic property. It targets specific targets and shows effects in improving sleep, regulating blood pressure, relieving vomiting, resisting depression, protecting heart and brain, etc. (G).

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically, to a propofol analogue, its preparation method, and its application in non-anesthetic fields. Background Technology

[0002] Propofol (2,6-diisopropylphenol) is an alkylphenol intravenous general anesthetic, widely used clinically for anesthesia induction, maintenance, and sedation of critically ill ICU patients undergoing mechanical ventilation. Compared to other anesthetics and benzodiazepines, propofol has advantages such as rapid onset, high clearance rate, rapid awakening, and quick recovery of neurophysiological function. After routine injection, patients fall asleep within 15-30 seconds, with a rapid onset and smooth course, without side effects such as involuntary muscle movements, coughing, or hiccups. Its duration of action is short, with patients fully awakening within 5-10 minutes without any agitation, making it a relatively ideal hypnotic intravenous general anesthetic.

[0003] The mechanism of propofol's action on the central nervous system has been extensively studied. Propofol exerts its anesthetic effect by enhancing central inhibitory neurotransmission (γ-aminobutyric acid receptors, i.e., GABA receptors and glycine receptors) and inhibiting central excitatory neurotransmission (N-methyl-D-aspartate receptors, i.e., NMDA receptors, etc.). Propofol primarily acts on synapses, regulating the release of presynaptic neurotransmitters and the function of presynaptic and postsynaptic receptors to achieve its anesthetic effect. Propofol inhibits the release of excitatory neurotransmitters, mainly by inhibiting Na+... ＋ The channel reduces glutamate release. For norepinephrine, propofol non-competitively inhibits K+. ＋ Ca caused 2+ Inflow, inhibiting K ＋ Propofol induces the release of norepinephrine; its inhibition of acetylcholine is regionally selective in the brain, with varying degrees of inhibition in different areas. For the inhibitory neurotransmitter, propofol concentration-dependently enhances K+. ＋ The release of γ-aminobutyric acid induced by propofol can also enhance the release of glycine. Propofol regulates many receptors, but its primary site of action is the centrally inhibitory GABA receptor. A Receptor. Propofol for GABA A There are three types of receptor effects: low concentration (2~100 µmol•L) -1 Propofol enhances GABA-induced whole-cell currents; intermediate concentrations (100~2000 µmol•L) -1 It can directly activate GABA. A Receptors; extremely high concentrations (>2,000 µmol•L) -1Propofol exerts a non-competitive inhibitory effect on GABA receptors. Within the clinical concentration range, the enhancing effect of propofol on GABA currents primarily increases the channel opening frequency, rather than increasing the channel's average opening time.

[0004] Based on the research on the anesthetic mechanism of propofol, different doses may also be used for sedation, hypnosis, anticonvulsant / epilepsy, etc.

[0005] In addition to its anesthetic effects, propofol has been found to be an effective neuroprotective agent in some in vivo and in vitro models of cerebral ischemia, possibly due to its ability to inhibit and reduce the expression of the apoptosis protein Bax. Furthermore, propofol has protective effects on multiple organs, including the heart, liver, and kidneys, which may be due to its antioxidant and free radical scavenging properties.

[0006] In summary, propofol can act on multiple targets throughout the body simultaneously, thus exhibiting different activities. Although there has been progress in understanding the mechanism of propofol's action on the central nervous system, it remains incomplete. The current consensus is that its anesthetic effect is a result of the synergistic effect of different targets. In addition to its anesthetic effects, further research and application of propofol to its non-anesthetic targets may uncover new pharmacological properties, expanding its clinical applications.

[0007] Although propofol has proven successful in surgical anesthesia, its transport and formulation remain key challenges due to its high lipophilicity. Existing emulsion formulations have several drawbacks, such as emulsion instability, the need to add antibacterial agents to inhibit microbial growth, the potential for hyperlipidemia from excessive emulsion intake, and injection site pain.

[0008] Therefore, since its market launch, researchers worldwide have conducted extensive and in-depth studies on the structure-activity relationship of propofol, aiming to improve the shortcomings of propofol formulations. Early studies investigated the effects of different alkyl groups at the 2,6-positions of propofol on its anesthetic effect; however, no significant overall structural improvements to propofol were found. Currently, propofol produced by Sichuan Haisco Pharmaceutical Co., Ltd. is marketed and used clinically. However, its formulation remains an emulsion, with only a slight increase in efficacy. Subsequent studies have involved adding water-soluble groups to the phenolic hydroxyl group of propofol to prepare prodrugs, such as certain amino acid ester derivatives and phosphate ester derivatives (e.g., FDA-approved propofol phosphopropofol); and introducing halogen atoms or other groups at the para-position of the phenolic hydroxyl group of propofol, all aimed at increasing its water solubility to facilitate formulation preparation or improving bioavailability for oral administration. Currently, there are successful cases of propofol modification addressing the water solubility issue, but the improved products have reduced the overall superiority of propofol, thus limiting its clinical application. In the non-anesthetic field, propofol lacks in-depth research, either because its basic anesthetic properties have not changed, or because structural modifications have increased toxicity and side effects, which greatly limits its clinical application. Summary of the Invention

[0009] One object of the present invention is to provide a propofol analogue; the propofol analogue of the present invention has weak or even absent anesthetic and sedative effects, but has new uses in improving sleep, regulating blood pressure, antiemetic, antidepressant, and cardiocerebrovascular protection.

[0010] Another object of the present invention is to provide a method for preparing the propofol analogue;

[0011] Another object of the present invention is to provide a pharmaceutical composition containing the propofol analogue;

[0012] Another object of the present invention is to provide the use of the propofol analogue in non-anesthetic fields.

[0013] To achieve the above objectives, in one respect, the present invention provides a propofol analog of general formula (G), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof:

[0014]

[0015] (G)

[0016] in,

[0017] R1 and R2 are each independently selected from C1-10 straight-chain or branched alkyl groups or 3- to 12-membered cycloalkyl groups; optionally, the alkyl or cycloalkyl group is substituted by 1, 2, 3, 4 or 5 substituents selected from H, halogen, OH, CN, NH2, nitro, carboxyl or C1-5 alkyl groups;

[0018] R3 is selected from 4- to 12-membered saturated or unsaturated heterocyclic groups; optionally, the heterocyclic group is surrounded by 1, 2, 3, 4, or 5 R3 groups. 31 Replaced; each R 31 Each is independently selected from H, halogen, OH, CN, NH2, nitro, carboxyl or C1-10 alkyl; the heterocyclic group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0019] According to some specific embodiments of the present invention, wherein,

[0020] R3 is selected from , , , or ;Optional, the aforementioned , , , or By 1, 2 or 3 R 31 Replaced; each R31 Each is independently selected from H, halogen, OH, CN, NH2, nitro, carboxyl or C1-10 alkyl.

[0021] According to some specific embodiments of the present invention, wherein,

[0022] R1 and R2 are each independently selected from C1-5 straight-chain or branched alkyl groups or 3- to 8-membered cycloalkyl groups; optionally, the alkyl or cycloalkyl group is substituted by 1, 2, 3, 4 or 5 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-3 alkyl groups;

[0023] R3 is selected from 5- to 6-membered heteroaryl groups; optionally, the heteroaryl group is surrounded by 1, 2, 3, 4, or 5 R groups. 31 Replaced; each R 31 Each is independently selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-5 alkyl; the heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0024] According to some specific embodiments of the present invention, wherein,

[0025] R1 and R2 are each independently selected from C1-5 straight-chain or branched alkyl groups or 3- to 8-membered cycloalkyl groups; optionally, the alkyl or cycloalkyl group is substituted by 1, 2, 3, 4 or 5 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-3 alkyl groups;

[0026] R3 is selected from , , , or ;Optional, the aforementioned , , , or By 1, 2 or 3 R 31 Replaced; each R 31 Each group is independently selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl, or C1-3 alkyl.

[0027] According to some specific embodiments of the present invention, wherein,

[0028] R1 is selected from C1-5 straight-chain or branched alkyl or 3- to 8-membered cycloalkyl; optionally, the alkyl or cycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-3 alkyl;

[0029] R2 is selected from C1-5 straight-chain or branched alkyl groups; optionally, the alkyl group is substituted by 1, 2, 3, 4 or 5 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-3 alkyl groups;

[0030] R3 is selected from 5- to 6-membered heteroaryl groups; optionally, the heteroaryl group is surrounded by 1, 2, 3, 4, or 5 R groups. 31 Replaced; each R 31 Each is independently selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-3 alkyl; the heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0031] According to some specific embodiments of the present invention, wherein,

[0032] R1 is selected from C1-5 straight-chain or branched alkyl or 3- to 8-membered cycloalkyl; optionally, the alkyl or cycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-3 alkyl;

[0033] R2 is selected from C1-5 straight-chain or branched alkyl groups; optionally, the alkyl group is substituted by 1, 2, 3, 4 or 5 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-3 alkyl groups;

[0034] R3 is selected from , , , or ;Optional, the aforementioned , , , or By 1, 2 or 3 R 31 Replaced; each R 31 Each group is independently selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl, or C1-3 alkyl.

[0035] According to some specific embodiments of the present invention, wherein,

[0036] R1 and R2 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is substituted by 1, 2, or 3 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl, methyl, ethyl, or propyl.

[0037] R3 is selected from , , , or ;Optional, the aforementioned , , , or By 1 or 2 R 31 Replaced; each R 31 Each is independently selected from H, F, Cl, Br, I, methyl, ethyl, or propyl; the heterocyclic group contains one or two heteroatoms selected from N, O, and S.

[0038] According to some specific embodiments of the present invention, wherein,

[0039] R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is substituted by 1, 2, or 3 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl, methyl, ethyl, or propyl.

[0040] R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; optionally, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl groups are substituted by 1, 2, or 3 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl, methyl, ethyl, or propyl.

[0041] According to some specific embodiments of the present invention, the propofol analogues are as follows:

[0042] .

[0043] According to some specific embodiments of the present invention, wherein,

[0044] Propofol analogues are selected from one of the following structures:

[0045]

[0046] Optional, of which R3 and R 31 What it replaced.

[0047] According to some specific embodiments of the present invention, R3 is selected from... , , , or ;Optional, R3 is controlled by 1, 2 or 3 R 31 What it replaced.

[0048] According to some specific embodiments of the present invention, wherein,

[0049] Propofol analogues are selected from one of the following structures:

[0050] .

[0051] According to some specific embodiments of the present invention, the salt is selected from hydrochloride, sulfate or phosphate.

[0052] According to some specific embodiments of the present invention, the propofol analogue is selected from one of the following structures:

[0053] .

[0054] On the other hand, the present invention also provides a method for preparing the aforementioned propofol analogue, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof, wherein,

[0055] When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-1), the method comprises preparing the compound of formula (G-1) from compounds of formula (G-1-1) and compounds of formula (G-1-2):

[0056]

[0057] R4 is a hydroxyl protecting group;

[0058] Optional, compounds of formula (G-1-2) By 1, 2 or 3 R 31 What it replaced.

[0059] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (G-1-1) and the compound of formula (G-1-2) is 0-10°C.

[0060] According to some specific embodiments of the present invention, the reaction time of the compound of formula (G-1-1) and the compound of formula (G-1-2) is 3-4 hours.

[0061] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-1-1) to the compound of formula (G-1-2) is 1:(3-8). Preferably, it is 1:5.

[0062] According to some specific embodiments of the present invention, the compounds of formula (G-1-1) and (G-1-2) are prepared in the presence of a Lewis acid, wherein the compound of formula (G-1) is prepared.

[0063] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-1-1) to the Lewis acid is 1:(3-8). Preferably, it is 1:4.5.

[0064] According to some specific embodiments of the present invention, the Lewis acid is selected from titanium tetrachloride and / or titanium tetraisopropoxy. Titanium tetrachloride is preferred.

[0065] According to some specific embodiments of the present invention, the compounds of formula (G-1-1) and (G-1-2) are prepared by reacting them in an organic solvent to produce the compound of formula (G-1); said organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and dichloromethane. Dichloromethane is preferred.

[0066] According to some specific embodiments of the present invention, the mass-to-volume ratio of the compound of formula (G-1-1) to the organic solvent is 1:(8-20). Preferably, it is 1:10.

[0067] According to some specific embodiments of the present invention, wherein when the propofol analog represented by general formula (G) is selected from compounds of formula (G-1), the method comprises preparing a compound of formula (G-1-1) from a compound of formula (G-1-3):

[0068] .

[0069] According to some specific embodiments of the present invention, the compound of formula (G-1-3) is prepared in the presence of an alkylating agent as the compound of formula (G-1).

[0070] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-1-3) to the alkylating agent is 1:(1.2-1.6). Preferably, it is 1:1.4.

[0071] According to some specific embodiments of the present invention, the alkylating agent is selected from one or more of methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium bromide and methyl lithium; preferably methyl magnesium bromide.

[0072] According to some specific embodiments of the present invention, the organic solvent of the alkylating agent is tetrahydrofuran.

[0073] According to some specific embodiments of the present invention, the molar concentration of the alkylating agent is 1-2 mol / L.

[0074] According to some specific embodiments of the present invention, the reaction temperature of formula (G-1-3) is 0-5°C.

[0075] According to some specific embodiments of the present invention, the reaction time of formula (G-1-3) is 3-5 hours.

[0076] According to some specific embodiments of the present invention, the compound of formula (G-1-3) is prepared by reacting it in an organic solvent to form the compound of formula (G-1-1); said organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, and methyl tert-butyl methyl ether. Anhydrous tetrahydrofuran is preferred.

[0077] According to some specific embodiments of the present invention, the weight-to-volume ratio of the compound of formula (G-1-3) to the organic solvent is 1:(8-20). Preferably, it is 1:10.

[0078] According to some specific embodiments of the present invention, the method further includes SFC resolution of the (G-1) compound to obtain the (G-1-R) compound and the (G-1-S) compound:

[0079] .

[0080] According to some specific embodiments of the present invention, the conditions for SFC separation include: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35 ℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0081] According to some specific embodiments of the present invention, the method further includes preparing the hydrochloride salt form of the compound of formula (G-1), the compound of formula (G-1-R), or the compound of formula (G-1-S) by performing a salting reaction on the compound of formula (G-1), the compound of formula (G-1-R), or the compound of formula (G-1-S) using a salting reagent.

[0082] According to some specific embodiments of the present invention, the salt-forming reagent is selected from one or more of methanol hydrochloride, ethanol hydrochloride, dioxane hydrochloride, ethyl acetate hydrochloride, diethyl ether hydrochloride, and isopropyl ether hydrochloride. Ethyl acetate hydrochloride is preferred.

[0083] According to some specific embodiments of the present invention, the molar volume concentration of the salt-forming reagent is 2-6 mol / L, preferably 4 mol / L.

[0084] According to some specific embodiments of the present invention, the weight-to-volume ratio of the compound of formula (G-1), the compound of formula (G-1-R), or the compound of formula (G-1-S) to the salt-forming reagent is 1:(5.7-10).

[0085] According to some specific embodiments of the present invention, the salt-forming reaction is carried out in an organic solvent; the organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, methanol, ethanol, diethyl ether, and isopropyl ether. Ethyl acetate is preferred.

[0086] According to some specific embodiments of the present invention, the reaction temperature of the salt-forming reaction is 20-30°C, preferably 20-25°C.

[0087] According to some specific embodiments of the present invention, the reaction time of the salt formation reaction is 1-2 hours.

[0088] According to some specific embodiments of the present invention, wherein the compound of formula (G-1) It cannot be replaced.

[0089] According to some specific embodiments of the present invention, wherein the compound of formula (G-1) When not substituted, the method further includes preparing compound (G-1') from compounds of formula (G-1) and formula (G-1-4):

[0090] R 31 I (G-1-4) (G-1')

[0091] R 31 It is selected from C1-10 alkyl; or from C1-5 alkyl; or from C1-3 alkyl; preferably methyl, ethyl or propyl.

[0092] According to some specific embodiments of the present invention, the molar ratio of compound (G-1) to compound (G-1-4) is 1:(1.1-1.5).

[0093] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (G-1) and the compound of formula (G-1-4) is 20-30°C; preferably 20-25°C.

[0094] According to some specific embodiments of the present invention, the reaction time of the compound of formula (G-1) and the compound of formula (G-1-4) is 2-5 h; preferably 2-3 h.

[0095] According to some specific embodiments of the present invention, the compound of formula (G-1) and the compound of formula (G-1-4) react in the presence of an inorganic base; the inorganic base is selected from one or more of potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and cesium bicarbonate.

[0096] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-1) to the inorganic base is 1:(1-1.5); preferably 1:(1.2-1.4).

[0097] According to some specific embodiments of the present invention, the compound of formula (G-1) and the compound of formula (G-1-4) are reacted in an organic solvent; said organic solvent is selected from one or more of tetrahydrofuran, acetonitrile, dichloromethane, acetone and N,N-dimethylformamide.

[0098] According to some specific embodiments of the present invention, the method further includes using the preceding SFC resolution method to perform SFC resolution on the (G-1') compound to obtain the (G-1'-R) compound and the (G-1'-S) compound:

[0099] .

[0100] According to some specific embodiments of the present invention, the method further includes preparing the hydrochloride salt form of the (G-1'-R) compound or the (G-1'-S) compound by performing a salting reaction on the (G-1'-R) compound or the (G-1'-S) compound using a salting reagent.

[0101] The conditions for salt formation reactions can be referenced from the salt formation reaction conditions of compounds of formula (G-1), (G-1-R), or (G-1-S).

[0102] When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-2), the method comprises preparing the compound of formula (G-2) from a compound of formula (G-2-1) or a compound of formula (G-2-2):

[0103]

[0104] Optionally, R3 can be divided by 1, 2, 3, 4, or 5 Rs. 31 What it replaced.

[0105] According to some specific embodiments of the present invention, the compound of formula (G-2-1) is prepared by reacting at -60°C to -80°C to obtain the compound of formula (G-2).

[0106] According to some specific embodiments of the present invention, the reaction time of the compound of formula (G-2-1) is 2-2.5 h.

[0107] According to some specific embodiments of the present invention, the compound of formula (G-2-1) is prepared as the compound of formula (G-2) in the presence of a deprotecting agent; said deprotecting agent is selected from one or more of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, boron trichloride, boron tribromide, and aluminum trichloride. Trimethylchlorosilane or boron tribromide is preferred.

[0108] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-2-1) to the deprotecting agent is 1:(1.5-3). Preferably, it is 1:2.

[0109] According to some specific embodiments of the present invention, the compound of formula (G-2-1) is prepared by reacting it in an organic solvent to form the compound of formula (G-2); said organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, diethyl ether, and isopropyl ether. Preferably, it is anhydrous tetrahydrofuran or dichloromethane.

[0110] According to some specific embodiments of the present invention, the weight-to-volume ratio of the compound of formula (G-2-1) to the organic solvent is 1:(10-20). Preferably, it is 1:15.

[0111] According to some specific embodiments of the present invention, when preparing a compound of formula (G-2) using a compound of formula (G-2-2) as a raw material, the compound of formula (G-2-2) is prepared by reacting at 35°C to 45°C.

[0112] According to some specific embodiments of the present invention, the reaction time of the compound of formula (G-2-2) is 7-10 h.

[0113] According to some specific embodiments of the present invention, the compound of formula (G-2-2) is prepared in the presence of a reducing agent; said reducing agent is selected from one or more of lithium borohydride, sodium borohydride, potassium borohydride, palladium on carbon, palladium hydroxide on carbon, and palladium on carbon. Preferably, it is a wet palladium on carbon with a palladium content of 10% by mass.

[0114] According to some specific embodiments of the present invention, the weight ratio of the compound of formula (G-2-2) to the reducing agent is (5-10):1.

[0115] According to some specific embodiments of the present invention, the compound of formula (G-2-2) is prepared under a hydrogen atmosphere.

[0116] According to some specific embodiments of the present invention, the pressure of the hydrogen atmosphere is 0.5-0.7 MPa.

[0117] According to some specific embodiments of the present invention, the compound of formula (G-2-2) is prepared by reaction in an organic solvent; the organic solvent is selected from anhydrous ethanol.

[0118] According to some specific embodiments of the present invention, the weight-to-volume ratio of the compound of formula (G-2-2) to the organic solvent is 1:(10-20). Preferably, it is 1:15.

[0119] According to some specific embodiments of the present invention, wherein,

[0120] When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-2), the method comprises preparing a compound of formula (G-2-1) from a compound of formula (G-2-2):

[0121] .

[0122] According to some specific embodiments of the present invention, the compound of formula (G-2-2) is prepared by reacting at 20-45°C to prepare the compound of formula (G-2-1).

[0123] According to some specific embodiments of the present invention, the reaction time of the compound of formula (G-2-2) is 5-7 h.

[0124] According to some specific embodiments of the present invention, the compound of formula (G-2-2) is prepared as the compound of formula (G-2-1) in the presence of a reducing agent; said reducing agent is selected from one or more of lithium borohydride, sodium borohydride, potassium borohydride, palladium on carbon, palladium hydroxide on carbon, and platinum on carbon. Preferably, it is a wet palladium on carbon with a palladium content of 10% by mass.

[0125] According to some specific embodiments of the present invention, the weight ratio of the compound of formula (G-2-2) to the reducing agent is (5-10):1.

[0126] According to some specific embodiments of the present invention, the compound of formula (G-2-2) is prepared as the compound of formula (G-2-1) under a hydrogen atmosphere.

[0127] According to some specific embodiments of the present invention, the pressure of the hydrogen atmosphere is 0.5-0.7 MPa.

[0128] According to some specific embodiments of the present invention, the compound of formula (G-2-2) is prepared by reaction in an organic solvent; said organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol and isopropanol. Preferably, it is anhydrous tetrahydrofuran or ethanol.

[0129] According to some specific embodiments of the present invention, the weight-volume ratio of the compound of formula (G-2-2) to the organic solvent is 1:(25-35).

[0130] According to some specific embodiments of the present invention, wherein,

[0131] When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-2), the method comprises preparing a compound of formula (G-2-2) from a compound of formula (G-2-3):

[0132] .

[0133] According to some specific embodiments of the present invention, the compound of formula (G-2-3) is prepared by reacting at 20-30°C to prepare the compound of formula (G-2-2). Preferably, the temperature is 20-25°C.

[0134] According to some specific embodiments of the present invention, the reaction time of the compound of formula (G-2-3) is 2-3 h.

[0135] According to some specific embodiments of the present invention, the compound of formula (G-2-3) is prepared as a compound of formula (G-2-2) in the presence of an olefinizing agent; said olefinizing agent is selected from one or more of methyltriphenylphosphine bromide, methyltriphenylphosphine chloride, and methyltriphenylphosphine iodide. Methyltriphenylphosphine bromide is preferred.

[0136] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-2-3) to the olefinic reagent is 1:(2-3). Preferably, it is 1:(2-2.7).

[0137] According to some specific embodiments of the present invention, the compound of formula (G-2-3) is prepared as a compound of formula (G-2-2) in the presence of an olefinic reagent and an organic base; said organic base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, sec-butyllithium, and tert-butyllithium. Potassium tert-butoxide is preferred.

[0138] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-2-3) to the olefinic reagent and the organic base is 1:(2-3):(1.5-3). Preferably, it is 1:(2-2.7):(1.7-2.4).

[0139] According to some specific embodiments of the present invention, the compound of formula (G-2-3) is prepared in an organic solvent as the compound of formula (G-2-2); said organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, and methyl tert-butyl methyl ether. Anhydrous tetrahydrofuran is preferred.

[0140] According to some specific embodiments of the present invention, the weight-to-volume ratio of the compound of formula (G-2-3) to the organic solvent is 1:(6-20). Preferably, it is 1:(6.5-14).

[0141] According to some specific embodiments of the present invention, wherein,

[0142] When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-2), the method comprises preparing a compound of formula (G-2-3) from compounds of formula (G-2-4) and formula (G-2-5):

[0143] .

[0144] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (G-2-4) and the compound of formula (G-2-5) is 20-30°C. Preferably, it is 20-25°C.

[0145] According to some specific embodiments of the present invention, the reaction time of the compound of formula (G-2-4) and the compound of formula (G-2-5) is 2-3 hours.

[0146] According to some specific embodiments of the present invention, the molar ratio of compound (G-2-4) to compound (G-2-5) is 1:(0.8-1.2).

[0147] According to some specific embodiments of the present invention, the compounds of formula (G-2-4) and (G-2-5) are reacted in the presence of a Grignard reagent or a lithium reagent.

[0148] According to some specific embodiments of the present invention, the Grignard reagent is obtained by reacting a compound of formula (G-2-4) with metallic magnesium in the presence of an initiator.

[0149] According to some specific embodiments of the present invention, the initiator is selected from I2.

[0150] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-2-4) to magnesium is 1:(1.1-2.0); preferably 1:(1.15-1.8).

[0151] According to some specific embodiments of the present invention, the method includes preparing solutions of compound (G-2-4) and compound (G-2-5) respectively, and then sequentially adding the solutions of compound (G-2-4) and compound (G-2-5) to a Grignard reagent initiated by a small amount of compound (G-2-4) and metallic magnesium in the presence of an initiator.

[0152] According to some specific embodiments of the present invention, the Grignard reagent is obtained by initiation under an inert gas atmosphere.

[0153] According to some specific embodiments of the present invention, the inert gas is selected from nitrogen or argon.

[0154] According to some specific embodiments of the present invention, the compound of formula (G-2-4) used to initiate the Grignard reaction accounts for 3-10% of the total amount of compound of formula (G-2-4); preferably 3.2-6.5%.

[0155] According to some specific embodiments of the present invention, the method includes adding a solution of the compound of formula (G-2-4) to an initiating Grignard reagent and stirring at 75-85°C for 2-3 hours, then controlling the temperature of the reaction system to -20°C to -10°C, and then adding a solution of the compound of formula (G-2-5).

[0156] According to some specific embodiments of the present invention, after adding the solution of the compound of formula (G-2-5), the reaction system is controlled to react at 20-30°C for 2-4 hours. Preferably, the reaction is carried out at 25-30°C for 3-4 hours.

[0157] According to some specific embodiments of the present invention, the solution of the compound of formula (G-2-4) is added dropwise to the initiating Grignard reagent at 75°C to 85°C.

[0158] Alternatively, according to some specific embodiments of the present invention, the compounds of formula (G-2-4) and (G-2-5) are reacted in the presence of a lithium reagent, wherein the lithium reagent is an alkyllithium.

[0159] According to some specific embodiments of the present invention, the lithium reagent is selected from one or more of n-butyllithium, sec-butyllithium and tert-butyllithium.

[0160] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-2-4) to the lithium reagent is 1:(1-1.5).

[0161] According to some specific embodiments of the present invention, the compounds of formula (G-2-4) and (G-2-5) are reacted in the presence of a lithium reagent under an inert gas atmosphere.

[0162] According to some specific embodiments of the present invention, the inert gas is selected from nitrogen or argon.

[0163] According to some specific embodiments of the present invention, the lithium reagent is added dropwise to the reaction system at a temperature of -85°C to -75°C.

[0164] According to some specific embodiments of the present invention, the method includes cooling the reaction system to -90°C to -80°C and then adding lithium reagent dropwise.

[0165] According to some specific embodiments of the present invention, the method includes adding a lithium reagent to a reaction system containing a compound of formula (G-2-4), controlling the temperature of the reaction system at -90°C to -80°C, adding an organic solvent containing a compound of formula (G-2-5) dropwise, and placing the reaction system at room temperature (the reaction system naturally warms up) for 2-3 hours after the addition is complete.

[0166] According to some specific embodiments of the present invention, the method includes adding a lithium reagent dropwise to the reaction system, stirring at -85°C to -75°C for 1-2 hours, and then adding an organic solvent containing a compound of formula (G-2-5) dropwise.

[0167] According to some specific embodiments of the present invention, the organic solvent for the reaction of the compound of formula (G-2-4) and the compound of formula (G-2-5) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, and methyl tert-butyl methyl ether. Anhydrous tetrahydrofuran is preferred.

[0168] According to some specific embodiments of the present invention, the weight-volume ratio of the compound of formula (G-2-4) to the organic solvent is 1:(6.5-10).

[0169] According to some specific embodiments of the present invention, the method further includes SFC resolution of the (G-2) compound to obtain the (G-2-R) compound and the (G-2-S) compound:

[0170] .

[0171] According to some specific embodiments of the present invention, the conditions for SFC separation include: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35 ℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0172] According to some specific embodiments of the present invention, wherein,

[0173] When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-3), the method comprises preparing the compound of formula (G-3) from a compound of formula (G-3-1):

[0174] .

[0175] According to some specific embodiments of the present invention, the compound of formula (G-3-1) is prepared by reaction in the presence of a deprotecting agent to form the compound of formula (G-3).

[0176] According to some specific embodiments of the present invention, the deprotecting agent is a deetherified methylating agent or a debenzyloxyating agent.

[0177] According to some specific embodiments of the present invention, the deetherifying methylating agent is selected from one or more of trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, boron trichloride, boron tribromide, and aluminum trichloride, or a mixture thereof. Trimethylchlorosilane and / or boron tribromide are preferred.

[0178] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-3-1) and the deetherified methylating agent is 1:(1.9-2.1).

[0179] According to some specific embodiments of the present invention, the compound of formula (G-3-1) and the deetherified methylating agent are reacted at -80°C to -60°C to prepare the compound of formula (G-3).

[0180] According to some specific embodiments of the present invention, the compound of formula (G-3-1) is reacted in the presence of a deetherifying methylating agent for 2-2.5 h to obtain the compound of formula (G-3).

[0181] According to some specific embodiments of the present invention, the compound of formula (G-3-1) and the deetherifying methylating agent are reacted in an organic solvent to prepare the compound of formula (G-3); said organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, diethyl ether, and isopropyl ether. Preferably, it is anhydrous tetrahydrofuran and / or dichloromethane.

[0182] According to some specific embodiments of the present invention, the debenzyloxy reagent is selected from palladium on carbon, palladium hydroxide on carbon, or platinum on carbon. Preferably, it is wet palladium on carbon with a palladium content of 10% by mass.

[0183] According to some specific embodiments of the present invention, the compound of formula (G-3-1) and the debenzyloxy reagent are reacted at 45-55°C to prepare the compound of formula (G-3). Preferably, the temperature is 50°C.

[0184] According to some specific embodiments of the present invention, the compound of formula (G-3-1) is reacted in the presence of a debenzyloxy reagent for 2-4 hours to obtain the compound of formula (G-3). Preferably, the reaction time is 3 hours.

[0185] According to some specific embodiments of the present invention, the compound of formula (G-3-1) and the debenzyloxy reagent are reacted in an organic solvent to prepare the compound of formula (G-3); said organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol and isopropanol. Preferably, it is anhydrous tetrahydrofuran and / or ethanol.

[0186] According to some specific embodiments of the present invention, wherein,

[0187] When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-3), the method comprises preparing the compound of formula (G-3-1) from compounds of formula (G-1-1) and compounds of formula (G-3-2):

[0188]

[0189] Optionally, the compound of formula (G-3-2) is separated by 1, 2 or 3 R 31 What it replaced.

[0190] According to some specific embodiments of the present invention, the compound of formula (G-1-1) and the compound of formula (G-3-2) are prepared by reacting at 20-30°C. Preferably, the temperature is 20-25°C.

[0191] According to some specific embodiments of the present invention, the reaction time of the compound of formula (G-1-1) and formula (G-3-2) is 4-5 h.

[0192] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-1-1) to that of formula (G-3-2) is 1:(1.1-2). Preferably, it is 1:1.5.

[0193] According to some specific embodiments of the present invention, the compounds of formula (G-1-1) and (G-3-2) are prepared by reaction in the presence of a phosphorus reagent to prepare the compound of formula (G-3-1); the phosphorus reagent is selected from tributylphosphine and / or triphenylphosphine. Tributylphosphine is preferred.

[0194] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-1-1) and the phosphorus reagent is 1:(1.5-2.5). Preferably, it is 1:2.

[0195] According to some specific embodiments of the present invention, the compounds of formula (G-1-1) and (G-3-2) are prepared by reacting a compound of formula (G-3-1) in the presence of a phosphorus reagent and an azo reagent; the azo reagent is selected from one or more of diethyl azodicarbonate, dicarboxamide azodicarbonate, and diisopropyl azodicarbonate. Dicarboxamide azodicarbonate is preferred.

[0196] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (G-1-1), the phosphorus reagent, and the azo reagent is 1:(1.5-2.5):(1.5-2.5). Preferably, it is 1:2:2.

[0197] According to some specific embodiments of the present invention, the compounds of formula (G-1-1) and (G-3-2) are prepared by reacting them in an organic solvent to produce the compound of formula (G-3-1); said organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran. Anhydrous tetrahydrofuran is preferred.

[0198] According to some specific embodiments of the present invention, the method further includes SFC resolution of the (G-3) compound to obtain the (G-3-R) compound and the (G-3-S) compound:

[0199] .

[0200] According to some specific embodiments of the present invention, the conditions for SFC separation include: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35 ℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0201] According to some specific embodiments of the present invention, the method further includes preparing the hydrochloride salt form of the compound of formula (G-3), the compound of formula (G-3-R), or the compound of formula (G-3-S) by performing a salting reaction on the compound of formula (G-3), the compound of formula (G-3-R), or the compound of formula (G-3-S) using a salting reagent.

[0202] According to some specific embodiments of the present invention, the salt-forming reagent is selected from one or more of methanol hydrochloride, ethanol hydrochloride, dioxane hydrochloride, ethyl acetate hydrochloride, diethyl ether hydrochloride, and isopropyl ether hydrochloride. Ethyl acetate hydrochloride is preferred.

[0203] According to some specific embodiments of the present invention, the weight-to-volume ratio of the compound of formula (G-3), the compound of formula (G-3-R), or the compound of formula (G-3-S) to the salt-forming reagent is 1:(7.6-8.3).

[0204] According to some specific embodiments of the present invention, the salt-forming reaction is carried out in an organic solvent; the organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, methanol, ethanol, diethyl ether, and isopropyl ether. Ethyl acetate is preferred.

[0205] According to some specific embodiments of the present invention, the reaction temperature of the salt-forming reaction is 20-30°C, preferably 20-25°C.

[0206] According to some specific embodiments of the present invention, the reaction time of the salt formation reaction is 1-2 hours.

[0207] In another aspect, the present invention also provides a pharmaceutical composition comprising a propofol analogue as described in any one of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer or polymorph thereof, and a pharmaceutically acceptable carrier and / or diluent.

[0208] In another aspect, the present invention also provides the use of any of the propofol analogues described in any of the preceding claims, or pharmaceutically acceptable salts, stereoisomers, tautomers or polymorphs thereof, or the pharmaceutical compositions thereof, in the preparation of sleep-improving drugs, blood pressure regulating drugs, antiemetic drugs, antidepressant drugs or cardioprotective drugs.

[0209] According to some specific embodiments of the present invention, the depression is acute depression (anxiety).

[0210] According to some specific embodiments of the present invention, the propofol analogue, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph, improves sleep, regulates blood pressure, relieves nausea, has antidepressant effects, or provides cardioprotection by acting simultaneously with 5-HT2C and nAChRα7 / RIC3, ​​or simultaneously with 5-HT2A, 5-HT2C, and nAChRα7 / RIC3, ​​or simultaneously with alpha1A, alpha2A, and 5-HT3A.

[0211] In summary, this invention provides a propofol analogue, its preparation method, and its application in non-anesthetic fields. The technical solution of this invention has the following advantages:

[0212] The propofol analogues of this invention can significantly reduce or eliminate their affinity for GABA receptors, thus weakening or eliminating their anesthetic properties. Targeting specific sites, they exhibit effects in improving sleep, regulating blood pressure, relieving nausea, combating depression, and protecting the heart and brain. Attached Figure Description

[0213] Figure 1 This is a schematic diagram illustrating the effect of intraperitoneal injection of physiological saline or compound IV(R) at 3, 10, or 20 mg / kg during the dark period (20:00) of Experiment 3 on total daytime, nighttime, and 24-hour sleep-wake cycles. Data are expressed as Means ± SEM (n=8 per group). *p<0.05, **p<0.01, ***p<0.01.

[0214] Figure 2 This is a schematic diagram showing the effect of intraperitoneal injection of saline or 3, 10, or 20 mg / kg compound IV (R) during the dark period (20:00) of Experiment Example 3 on the total hourly sleep-wake cycle. The data are expressed as Means ± SEM (n=8 per group).

[0215] Figure 3 This is a schematic diagram illustrating the effect of intraperitoneal injection of saline or compound IV (R) at 3, 10, and 20 mg / kg during the dark period (20:00) of Experiment 3 on NREM sleep and REM sleep latency. Data are expressed as Means ± SEM (n=8 per group). **p<0.01, ***p<0.01.

[0216] Figure 4 The graphs show the analysis of daytime 12h, nighttime 12h, and 24h sleep-wake structures after intraperitoneal injection of saline or compound IV (R) at 3, 10, and 20 mg / kg during the dark period (20:00) in Experiment 3. Data are expressed as Means ± SEM (n=8 per group). *p<0.05, **p<0.01, ***p<0.01.

[0217] Figure 5 The following are cortical EEG spectra at 2 h (21:00h–22:00h) after intraperitoneal injection of normal saline or compound IV (R) at the dark period (20:00) in Experiment 3. Data are expressed as Means ± SEM (n=8 per group). *p 0.05, **p<0.01, ***p<0.01.

[0218] Figure 6 The figure shows the effect of compound IV (R) and compound IV on reserpine-induced ptosis in C57 mice in Experiment Example 5. In the figure, *p<0.05,**p<0.01, ****p<0.0001 vs Model; ####p<0.0001 vs Cotrol.

[0219] Figure 7 The figure shows the effect of compound IV (R) and compound IV on the immobility time of swimming induced by reserpine in Experiment 5. In the figure, * p < 0.05 vs Model; # p < 0.01 vs Cotrol. Detailed Implementation

[0220] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0221] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 Units (ppm) are given. NMR measurements were performed using a JEOL 400MHz NMR spectrometer with deuterated DMSO-d6 as the solvent and tetramethylsilane (TMS) as the internal standard. HRMS measurements were performed using a high-resolution mass spectrometer (Thermo Scientific Q Exactive Orbitrap, manufacturer: Thermo Fisher Scientific, USA); MS measurements were performed using a liquid chromatography-mass spectrometry system (Agilent Technologies 1100, USA). Chiral preparations were performed using a Shimadzu preparative chromatograph (LC-20AD, manufacturer: Shimadzu, Japan), Column: CHIRALPAK IG (IG00CE-XL022; Column size: 0.46cm I.D. × 25cm L; Mobilephase: Hexane / EtOH = 95 / 5 (V / V); Flow rate: 1 ml / min; Wave length: UV 220 nm; Temperature: 35℃.

[0222] The reaction process was monitored using thin-layer chromatography (TLC). TLC used Yantai Huanghai GF254 silica gel plates with a diameter of 0.15-0.2 mm. Silica gel column chromatography typically used Yantai Huanghai 200-300 mesh silica gel as the carrier. The eluent system used for the reaction and for purifying the compounds included n-hexane / ethyl acetate, with the volume ratio adjusted according to the polarity of the compounds.

[0223] The chiral structure of the compounds of this invention was confirmed with reference to dexmedetomidine hydrochloride (S-type, structural formula shown below). The chemical structure of the compounds of this invention is similar to that of dexmedetomidine hydrochloride, both possessing the same chiral center and a similar core skeleton. Given that the absolute configuration of dexmedetomidine hydrochloride has been confirmed by authoritative methods such as single-crystal X-ray diffraction and is included in the standard pharmacopoeia as a known drug, its optical rotation properties (including direction and value of optical rotation) have become a reliable reference standard for this chiral series.

[0224] Based on the principle of "similar structure and similar optical rotation properties", the chiral configuration of the compounds in this invention is confirmed using the following method:

[0225] (1) Preparation and determination of reference objects:

[0226] Accurately weigh high-purity dexmedetomidine hydrochloride reference standard and prepare an aqueous solution with a concentration of 1 g / 100 ml. At room temperature, measure its optical rotation using a polarimeter (Autopol IV) to a value of +52.4 degrees; this value will be used as the reference standard.

[0227] (2) Determination of the test sample:

[0228] Solutions of the compounds of the present invention were precisely prepared under identical experimental conditions, and their optical rotation values ​​were measured using the same polarimeter.

[0229] (3) Configuration determination:

[0230] Configuration is determined by comparing the optical rotation values ​​of the compounds of this invention with the optical rotation values ​​of the reference compound dexmedetomidine hydrochloride, using both the sign (positive / negative direction) and magnitude.

[0231] If both have the same optical rotation direction (e.g., both are dextrorotatory or both are levorotatory) and their values ​​are similar within a reasonable range considering purity error, then it can be determined that the compound of the present invention and dexmedetomidine hydrochloride have the same absolute chiral configuration. If the optical rotation directions are opposite, it indicates that they are a pair of enantiomers.

[0232] (Dexmedetomidine hydrochloride)

[0233] Example 1: Preparation of compounds II, II(R), and II(S)

[0234] Step 1:

[0235]

[0236] Under nitrogen protection, 30.5 g of 2-benzyloxy-3-isopropylbenzaldehyde and 300 ml of anhydrous tetrahydrofuran were added to a 1 L three-necked flask. The mixture was cooled to 0 °C, and 72 ml of a 2 mol / L ethyl magnesium bromide solution was added dropwise. Stirring continued for 3 h at this temperature. TLC showed that the reactants had reacted completely (EA / PE = 1 / 5). 120 ml of saturated ammonium chloride was added dropwise to quench the reaction. After the addition was complete, 100 ml of water and 200 ml of ethyl acetate were added to extract the reaction mixture, and the ethyl acetate phase was collected. The aqueous phase was extracted with 100 ml of ethyl acetate, and the two ethyl acetate phases were combined. The mixture was washed once with 100 ml of water and once with 100 ml of saturated brine, respectively. The solution was dried over anhydrous sodium sulfate for at least 0.5 h, and concentrated to obtain 32.15 g of a yellow oily crude product. The crude product was purified by column chromatography using hexane / ethyl acetate = 100 / 1-50 / 1-30 / 1 as the eluent to obtain 24.5 g of pure, light yellow, oily compound II-INT1.

[0237] Step 2:

[0238]

[0239] Under nitrogen protection, 160 ml of dichloromethane was added to a 1 L three-necked flask, followed by the rapid addition of 42.9 ml of titanium tetrachloride. The mixture was stirred and cooled to approximately 0 °C. A solution of 60.5 g of trimethylsilylimidazolium dissolved in 160 ml of dichloromethane was added dropwise, and the mixture was kept at this temperature and stirred for 30 min. Then, 24.5 g of compound II-INT1 dissolved in 160 ml of dichloromethane solution was added dropwise. After the addition was complete, the temperature was raised to approximately 10 °C, and the reaction was allowed to proceed for about 3-4 h. TLC showed that the reactants had largely reacted (PE / EA = 2 / 1). The mixture was cooled to approximately 0 °C, and 250 ml of an ice-water solution was added dropwise. After the addition was complete, the mixture was stirred for 10 min, and the aqueous phase was collected after separation. 200 ml of water was added to the dichloromethane phase, and the mixture was stirred and collected. The two aqueous phases were combined. The pH of the aqueous phase was adjusted to approximately 8 using a 4 mol / L sodium hydroxide aqueous solution. 400 ml of ethyl acetate was added, and the mixture was stirred thoroughly. After standing, the mixture was allowed to separate into layers, and the ethyl acetate phase was collected. The aqueous phase was extracted twice with 300 ml of ethyl acetate. The three ethyl acetate phases were combined, washed once with 400 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 12.0 g of crude oil. The crude product was purified by column chromatography using n-hexane / ethyl acetate = 30 / 1-20 / 1-10 / 1-5 / 1 as eluent to obtain 8.0 g of pure pure compound II-INT2 in oil.

[0240] Step 3: Compound II

[0241]

[0242] 2.8 g of the racemic mixture of compound II-INT2 and 20 ml of 4 mol / L ethyl hydrochloride were added to a 50 ml three-necked flask and stirred at room temperature for 1-2 h. TLC showed that all the starting materials had formed salt. The reaction solution was transferred to a -10 °C cold pump, and 100 ml of methyl tert-butyl ether was slowly added dropwise. A solid precipitated out. After stirring at this temperature for 1 h, the mixture was filtered. The filter cake was washed with 15 ml of n-hexane three times. The wet solid was placed in a vacuum drying oven at 50 °C and dried to constant weight to obtain 2.65 g of pure compound II as a white solid.

[0243] LCMS: MS m / z (ESI): [M+H + [-HCl]=245.16570; Chemical purity: 98.38%.

[0244] 1HNMR (400 MHz, DMSO-d6): δ14.463 (br, 1H), 8.980(s, 1H), 7.436(s,1H), 7.040-7.020(m, 1H), 6.892- 6.889(m, 1H), 6.813-6.795(m, 1H), 4.493-4.455(m, 1H), 3.348-3.281(m, 1H), 2.048-2.020(m, 1H), 1.902-1.884(m, 1H), 1.143-1.090(d, 6H), 0.836-0.800(d, 3H).

[0245] 13 CNMR (100MHz, DMSO-d6): δ151.613, 136.941, 136.731, 134.095, 129.956,125.298, 124.714, 120.766, 116.147, 36.629, 27.497, 26.577, 23.549, 23.491,12.653.

[0246] Step 4: Compound II(R) and Compound II(S)

[0247]

[0248] 5.2g of compound II-INT2 was chirally resolved to yield 2.6g of free compound II(R) and 2.5g of free compound II(S).

[0249] The separation conditions were as follows: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0250] 2.6 g of free compound II(R) and 15 ml of ethyl acetate were added to a 100 ml three-necked flask. The temperature was lowered to 0 °C, and 15 ml of 4 mol / L ethyl hydrochloride was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and stirred at room temperature for 1-2 h. TLC showed that the raw material had completely formed a salt (EA / PE = 1 / 2), and a white solid precipitated out. The mixture was filtered, and the filter cake was washed with a small amount of ethyl acetate and then washed three times with 15 ml of n-hexane. The filter cake was collected and dried in a vacuum drying oven at 50 °C until constant weight, yielding 2.2 g of pure compound II(R, optical rotation -202.3 °C), a white solid.

[0251] LCMS: MS m / z (ESI): [M+H+ [-HCl]=245.16546; Chemical purity: 99.10%.

[0252] Chiral HPLC: RT=1.050 min, ee=99.42%.

[0253] 1 HNMR (400 MHz, DMSO-d6): δ14.456 (br, 1H), 8.997(s, 1H), 7.458(s,1H), 7.055-7.037(m, 1H), 6.919-6.901(m, 1H), 6.828-6.809(m, 1H), 4.504-4.466(m, 1H), 3.346-3.311(m, 1H), 2.048-2.032(m, 1H), 1.915-1.897(m, 1H), 1.158-1.129(d, 6H), 0.890-0.833 (d, 3H).

[0254] 13 CNMR (100 MHz, DMSO-d6): δ151.622, 136.941, 136.711, 134.124,129.946, 125.298, 124.733, 120.766, 116.156, 36.658, 27.497, 26.577, 23.549, 23.491, 12.663.

[0255] 2.5 g of free compound II (S) and 15 ml of ethyl acetate were added to a 100 ml three-necked flask, and the mixture was cooled to 0 °C. The same preparation process as for compound II (R) was used to obtain 2.7 g of pure compound II (S, optical rotation of +202.3 degrees), a white solid.

[0256] LCMS: MS m / z (ESI): [M+H + [-HCl]=245.16576; Chemical purity: 99.60%.

[0257] Chiral HPLC: RT=1.271min, ee=98.70%.

[0258] 1HNMR(400 MHz, DMSO-d6): δ14.457 (br, 1H), 8.998(s, 1H), 7.458(s, 1H),7.058-7.039(m, 1H), 6.920-6.901(m, 1H), 6.829-6.790(m, 1H), 4.504-4.466(m,1H), 3.345-3.311(m, 1H), 1.915-1.881(m, 2H), 1.158-1.129(d, 6H), 0.850-0.833(d, 3H).

[0259] 13 CNMR(100 MHz, DMSO-d6): δ151.622, 136.941, 136.702, 134.124, 129.946,125.298, 124.733, 120.756, 116.156, 36.668, 27.497, 26.577, 23.559, 23.491,12.663.

[0260] Example 2: Preparation of compounds III, III(R), and III(S)

[0261] Step 1:

[0262]

[0263] Under nitrogen protection, 26.3 g of 2-benzyloxy-3-cyclohexylbenzaldehyde and 260 ml of anhydrous tetrahydrofuran were added to a 500 ml three-necked flask. The mixture was stirred until dissolved, cooled to 0 °C, and 44 ml of methyl magnesium bromide (3 mol / L) was added dropwise, controlling the temperature to not exceed 5 °C. The addition was completed in approximately 30 minutes, and the reaction was maintained at this temperature for 4–5 hours. TLC showed that the reactants had reacted completely (PE / EA = 5 / 1). 125 ml of saturated ammonium chloride aqueous solution was slowly added dropwise, followed by 200 ml of ethyl acetate and 150 ml of water. After thorough stirring, the mixture was extracted, and the ethyl acetate phase was collected. The aqueous phase was extracted again with 200 ml of ethyl acetate, and the ethyl acetate phase was collected and combined. The ethyl acetate phase was washed once with 150 ml of water and once with 200 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 29.03 g of crude solid. The crude product was purified by column chromatography using hexane / ethyl acetate = 50 / 1-30 / 1-20 / 1 as the eluent, yielding 26.0 g of pure compound III-INT1 as a white solid.

[0264] Step 2:

[0265]

[0266] Under nitrogen protection, 160 ml of dry dichloromethane was added to a 1 L three-necked flask, followed by the rapid addition of 41.5 ml of titanium tetrachloride. The mixture was cooled to 0 °C, and a dichloromethane solution of trimethylsilylimidazolium (58.7 g dissolved in 160 ml of dichloromethane) was added dropwise. The mixture was stirred for 30 min. Then, 26.0 g of compound III-INT1 dissolved in 160 ml of dichloromethane solution was added dropwise, and the reaction was continued at 0 °C for 3–4 h. TLC showed that the reactants had reacted completely (PE / EA = 2:1). The reaction was then quenched slowly with 200 ml of ice water (internal temperature not exceeding 10 °C). 200 ml of water was added, and the mixture was thoroughly stirred and extracted, collecting the aqueous phase. 400 ml of water was added to the dichloromethane phase, and the mixture was thoroughly stirred and extracted, collecting the aqueous phase. The two aqueous phases were combined, and the pH of the combined aqueous phase was adjusted to 7-8 with 4 mol / L sodium hydroxide aqueous solution. After thorough stirring, the mixture was extracted three times with 400 ml of dichloromethane. The three dichloromethane phases were combined and dried over anhydrous sodium sulfate. After concentration, 15.0 g of oily crude product was obtained. The crude product was solidified and slurried with a hexane / ethyl acetate mixed solvent to obtain 13.0 g of pure compound III-INT2, a white solid.

[0267] Step 3: Compound III

[0268]

[0269] In a 50 ml three-necked flask, 2.5 g of the racemic mixture of compound III-INT2 and 20 ml of 4 mol / L ethyl hydrochloride were added, and the mixture was stirred at room temperature for 1–2 h. TLC showed that all the starting material had formed a salt (PE / EA = 1:5). The reaction solution was concentrated to dryness. 8 ml of ethyl acetate was added to a single-necked flask to dissolve the sample, followed by 20 ml of n-hexane. The mixture was stirred at 0 °C for 30 min. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected, and the wet material was dried in a vacuum drying oven at 50 °C to constant weight, yielding 2.2 g of pure compound III as a white solid.

[0270] LCMS: MS m / z (ESI): [M+H + [-HCl]=271.18095; Chemical purity: 99.97%.

[0271] 1HNMR (400 MHz, DMSO-d6): δ14.403 (br, 1H), 9.028(s, 1H), 7.385(s,1H), 7.022-6.990(m, 1H), 6.793 -6.761(m, 2H), 4.679-4.625(m, 1H), 2.956-2.928(m, 1H), 1.766-1.701(m, 5H), 1.517-1.449 (m, 3H), 1.372-1.284(m, 5H).

[0272] 13 CNMR (100 MHz, DMSO-d6): δ151.287, 138.034, 135.964, 134.201,131.326, 125.413, 124.867, 120.718, 115.965, 36.358, 33.659, 33.611, 29.883, 27.047, 26.328, 20.329.

[0273] Step 4: Compound III(R) and Compound III(S)

[0274]

[0275] 10.5g of compound III-INT2 was chirally resolved to yield 4.0g of free compound III(R) and 3.9g of free compound III(S).

[0276] The separation conditions were as follows: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0277] 4.0 g of free compound III(R) and 40 ml of 4 mol / L ethyl hydrochloride were added to a 50 ml three-necked flask, and the reaction was carried out at room temperature for 1-2 h. TLC showed that the starting material was completely salted (PE / EA = 2:1). The solution was concentrated, and the solvent was replaced with 15 ml × 3 dichloromethane solutions. The solution was then concentrated again to give 4.3 g of pure compound III(R, optical rotation -198.4 degrees), a white solid.

[0278] LCMS: MS m / z (ESI): [M+H + [-HCl]=271.18116; Chemical purity: 97.48%.

[0279] Chiral HPLC: RT=1.314 min, ee=99.98%.

[0280] 1 HNMR (400 MHz, DMSO-d6): δ14.357 (br, 1H), 9.020(s, 1H), 7.409(s,1H), 7.029-7.016(m, 1H), 6.789-6.778(m, 2H), 4.699-4.647(m, 1H), 2.975-2.946(m, 1H), 1.783-1.719(m, 5H), 1.534-1.516(m, 3H), 1.389-1.301(m, 5H).

[0281] 13 CNMR (100 MHz, DMSO-d6): 151.277, 138.015, 135.983, 134.182,131.345, 125.241, 124.896, 120.718, 116.128, 36.840, 33.755, 33.508, 29.835,27.114, 26.462, 20.463.

[0282] 3.9 g of free compound III (S) and 40 ml of 4 mol / L ethyl hydrochloride were added to a 50 ml three-necked flask. The same preparation process as for compound III (R) was used to obtain 4.0 g of pure compound III (S, optical rotation of +198.4 degrees), a white solid.

[0283] LCMS: MS m / z (ESI): [M+H + [-HCl]=271.18118; Chemical purity: 100.0%.

[0284] Chiral HPLC: RT=1.983min, ee=99.74%.

[0285] 1HNMR (400 MHz, DMSO-d6): δ14.468 (br, 1H), 9.048(s, 1H), 7.405(s,1H), 7.035-7.013(m, 1H), 6.844-6.785(m, 2H), 4.739-4.687(m, 1H), 3.023-2.968(m, 1H), 1.753-1.726(m, 5H), 1.546-1.528(m, 3H), 1.392-1.329(m, 5H).

[0286] 13 CNMR (100 MHz, DMSO-d6): 151.277, 138.034, 136.041, 134.134,131.374, 125.375, 124.867, 120.727, 115.927, 36.677, 33.659, 33.611, 29.816, 27.056, 26.347, 20.367.

[0287] Example 3: Preparation of compounds IV, IV(R), and IV(S)

[0288] Step 1:

[0289]

[0290] ① Under nitrogen protection, 40.0 g of 2-benzyloxy-3-isopropylbenzaldehyde and 400 ml of anhydrous tetrahydrofuran were added to a 1 L three-necked flask. The temperature was lowered to approximately -3 °C, and 220.2 ml of 1 mol / L methyl magnesium bromide was added dropwise. The mixture was kept at this temperature and stirred for 3 h. TLC analysis showed that the reaction was complete (EA / PE = 1 / 10, color development at 254 nm). The reaction was quenched by adding saturated ammonium chloride aqueous solution. After the addition was complete, 200 ml of water and 100 ml of ethyl acetate were added, and the ethyl acetate phase was collected. The aqueous phase was extracted once again with 100 ml of ethyl acetate. The two ethyl acetate phases were combined and washed once with 100 ml × 2 water and once with 100 ml of saturated brine, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 41.1 g of crude yellow oily compound IV-INT1.

[0291] ② Under nitrogen protection, in a 1L three-necked flask, add 210ml of dichloromethane, then quickly add 44.20ml of titanium tetrachloride, cool to 0℃, and slowly add dropwise 62.3g of trimethylsilylimidazolium dissolved in 210ml of dichloromethane solution, keeping the internal temperature below 5℃ throughout, and stir for 30min. Dissolve 24.0g of compound IV-INT1 in 210ml of dichloromethane and slowly add it dropwise to the above solution. After the addition is complete, react at 0℃ for about 3-4h. TLC detection (PE / EA=1:2) indicates that the starting material has basically reacted. Quench the reaction dropwise with 280ml of ice water, and stir for 10min after the addition is complete. Transfer the reaction solution to a separatory funnel for extraction and collect the aqueous phase. The dichloromethane phase was washed once with 280 ml of water, and the two aqueous phases were combined. The aqueous phase was carefully adjusted to pH 7-8 with 6 mol / L NaOH aqueous solution, and extracted with 250 ml × 4 ethyl acetate solutions. The four ethyl acetate phases were combined, washed once with 300 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily crude product. The crude product was purified by column chromatography, eluting with n-hexane / ethyl acetate in a ratio of 40 / 1-30 / 1-20 / 1-10 / 1 to give 9.0 g of pure, colorless oily compound IV-INT2.

[0292] ③ Under nitrogen protection, 10.9 g of compound IV-INT2, 218 ml of acetonitrile, and 18.6 g of cesium carbonate were added to a 500 ml three-necked flask. 7.40 g of iodomethane was added dropwise, and the reaction was maintained at room temperature for 2 hours. TLC showed that the reaction was complete (PE / EA = 2:1). The reaction solution was transferred to a 1 L conical flask, and 200 ml of ethyl acetate and 200 ml of purified water were added. After thorough stirring, the mixture was extracted and separated into layers. The ethyl acetate phase was collected. The aqueous phase was extracted again with 200 ml of ethyl acetate, and the two ethyl acetate phases were combined. The ethyl acetate phase was washed once with 200 ml of water and once with 200 ml of saturated brine. It was dried over anhydrous sodium sulfate for at least 30 minutes and concentrated to dryness to obtain 11.0 g of a yellow crude product. The crude product was purified by column chromatography using n-hexane / ethyl acetate = 30 / 1-20 / 1-15 / 1-10 / 1 as the eluent to obtain 9.9 g of pure compound IV-INT3, a yellow oil.

[0293] Step 2: Compound IV

[0294]

[0295] In a 50 ml three-necked flask, 2.90 g of compound IV-INT3 and 20 ml of 4 mol / L ethyl hydrochloride were added, and the mixture was stirred at room temperature for 1–2 h. TLC showed that all the starting material was converted to salt (PE / EA = 2:1). The reaction solution was concentrated to dryness, and a small amount (about 16 ml) of ethyl acetate was added, resulting in a large amount of solid. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected, and the wet material was dried in a vacuum drying oven at 50 °C to constant weight, yielding a pale yellow crude solid. 12 ml of a mixed solvent of ethyl acetate / n-hexane was added, and the mixture was stirred and slurried for 1 h. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected, and the wet material was dried in a vacuum drying oven at 50 °C to constant weight, yielding 2.4 g of pure compound IV, a pale yellow solid.

[0296] LCMS: MS m / z (ESI): [M+H + [-HCl]=245.16545; Chemical purity: 98.75%.

[0297] 1 HNMR (400 MHz, DMSO-d6): δ9.034(s, 1H), 7.415(s, 1H), 7.078-7.055(m,1H), 6.878-6.793(m, 2H), 4.703 -4.649 (m, 1H), 3.811(s, 3H), 3.366-3.332(m,1H), 1.550-1.510(d, 3H), 1.159-1.138(d, 6H).

[0298] 13 CNMR (100 MHz, DMSO-d6): 151.287, 138.417, 136.846, 135.792,131.038, 124.973, 124.896, 120.785, 119.970, 35.882, 29.787, 26.548, 23.587, 23.530, 20.387.

[0299] Step 3: Compound IV(R) and Compound IV(S)

[0300]

[0301] 7.0g of compound IV-INT1 was chirally resolved to yield 2.8g of free compound IV(R) and 2.4g of free compound IV(S).

[0302] The separation conditions were as follows: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0303] In a 50 ml three-necked flask, 2.8 g of free compound IV(R) and 20 ml of 4 mol / L ethyl hydrochloride were added, and the mixture was stirred at room temperature for 1–2 h. TLC showed that all the starting material was converted to salt (PE / EA = 2:1). The reaction solution was concentrated to dryness, and a small amount (about 16 ml) of ethyl acetate was added, resulting in a large amount of solid. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected, and the wet material was dried in a vacuum drying oven at 50 °C to constant weight, yielding a pale yellow crude solid. 12 ml of the mixed solvent ethyl acetate / n-hexane was added, and the mixture was stirred and slurried for 1 h. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected, and the wet material was dried in a vacuum drying oven at 50 °C to constant weight, yielding 2.6 g of pure compound IV(R, optical rotation -205.0 °C), a pale yellow solid.

[0304] LCMS: MS m / z (ESI): [M+H + [-HCl]=245.16565; Chemical purity: 100.0%.

[0305] Chiral HPLC: RT=1.219 min, ee=99.04%.

[0306] 1 HNMR (400 MHz, DMSO-d6): δ9.000(s, 1H), 7.398(s, 1H), 7.060-7.046(m,1H), 6.849-6.778(m, 2H), 4.673-4.621(m, 1H), 3.853(s, 3H), 3.348-3.296(m,1H), 1.551-1.495(d, 3H), 1.180-1.126(d, 6H).

[0307] 13 CNMR (100 MHz, DMSO-d6): 151.277, 138.417, 136.769, 135.801,130.991, 124.953, 124.906, 120.766, 119.970, 35.863, 29.826, 26.520, 23.568,23.511, 20.358.

[0308] In a 50ml three-necked flask, 2.4g of free compound IV(S) and 20ml of 4mol / L ethyl hydrochloride were added. Following the same preparation process as compound IV(R) above, 2.2g of pure compound IV(S, optical rotation of +205.0 degrees) was obtained as a pale yellow solid.

[0309] LCMS: MS m / z (ESI): [M+H + [-HCl]=245.16528; Chemical purity: 99.75%.

[0310] Chiral HPLC: RT=1.351 min, ee=98.52%.

[0311] 1 HNMR (400 MHz, DMSO-d6): δ9.005(s, 1H), 7.416(s, 1H), 7.076-7.061(m,1H), 6.856-6.790(m, 2H), 4.647-4.640(m, 1H), 3.807(s, 3H), 3.390-3.307(m,1H), 1.522-1.505(d, 3H), 1.157-1.140(d, 6H).

[0312] 13 CNMR(100 MHz, DMSO-d6): 151.287, 138.398, 136.740, 135.830, 130.971,124.963, 124.934, 120.775, 120.018, 35.891, 29.854, 26.520, 23.587, 23.530,20.348.

[0313] Example 4: Preparation of compounds V, V(R), and V(S)

[0314] Step 1:

[0315]

[0316] Under nitrogen protection, 30.0 g of compound IV-INT1, 180 ml of anhydrous tetrahydrofuran, 44.9 g of tributylphosphine, and 11.3 g of pyrazole were added sequentially to a 1 L three-necked flask. The temperature was lowered to 0-5 °C, and a solution of 25.8 g of azodicarbonamide dissolved in 450 ml of anhydrous tetrahydrofuran was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 4-5 hours. TLC showed that the reaction of the starting materials was complete (PE / EA = 30:1). 250 ml of water was added to the reaction solution, and the mixture was extracted three times with 400 ml, 200 ml, and 150 ml of ethyl acetate, respectively. The three ethyl acetate phases were combined. The ethyl acetate phase was washed once with 300 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 90 g of a red oily crude product. The crude product was purified by column chromatography, eluting with hexane / ethyl acetate = 200 / 1-100 / 1-60 / 1-50 / 1 to obtain 23.0 g of pure compound V-INT1, which was a light yellow oil.

[0317] Step 2:

[0318]

[0319] 36.6 g of compound V-INT1 and 350 ml of anhydrous methanol were added to a 1 L three-necked flask. 9.15 g of 5% palladium on carbon catalyst was added with stirring. The flask was filled with hydrogen gas through two layers of balloons, and the mixture was purged three times. Heating was then initiated, and the temperature was raised to 50 °C. The reaction was carried out at 50 °C for 3 hours, followed by overnight reaction at room temperature with stirring. TLC showed that the reactants had completely reacted (PE / EA = 30 / 1). The mixture was filtered, and the filter cake was washed with a small amount of anhydrous methanol. All the filtrate was collected and evaporated to dryness to obtain 22.7 g of a yellow crude oil. The crude product was purified by column chromatography using n-hexane / ethyl acetate = 200 / 1-100 / 1-50 / 1 as eluent to obtain 14.1 g of pure compound V-INT2 as a colorless oil.

[0320] Step 3: Compound V

[0321]

[0322] In a 50 ml three-necked flask, 3.0 g of the racemic mixture of compound V-INT2 and 25 ml of 4 mol / L ethyl hydrochloride were added, and the mixture was stirred at room temperature for 1–2 h. TLC showed that the starting material was completely salted (PE / EA = 20:1). The reaction solution was concentrated to dryness, and 12 ml of a mixed solvent of ethyl acetate / methyl tert-butyl ether was added. The mixture was stirred and slurried for 1 h. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected, and the wet material was dried in a vacuum drying oven at 50 °C to constant weight to obtain 2.2 g of pure compound V, an off-white solid.

[0323] LCMS: MS m / z (ESI): [M+H +[-HCl]=231.14996; Chemical purity: 100.0%.

[0324] 1 HNMR (400 MHz, DMSO-d6): δ7.856(s, 1H), 7.695(s, 1H), 7.058-7.052(m,1H), 6.762-6.744(m, 2H), 6.285-6.281 (d, 1H), 5.956-5.897(m, 1H), 3.382-3.263(m, 1H), 1.752-1.699(d, 3H), 1.169-1.114(d, 6H).

[0325] 13 CNMR(100 MHz, DMSO-d6): 151.355, 138.530, 136.750, 130.042, 129.927,125.749, 124.733, 120.421, 105.606, 56.676, 26.424, 23.491, 23.424, 20.741.

[0326] Step 4: Compound V(R) and Compound V(S)

[0327]

[0328] 11.1g of compound V-INT2 was chirally resolved to yield 4.6g of free compound V(R) and 4.3g of free compound V(S).

[0329] The separation conditions were as follows: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0330] In a 50 ml three-necked flask, 4.6 g of free compound V(R) and 35 ml of 4 mol / L ethyl hydrochloride were added, and the mixture was stirred at room temperature for 1–2 h. TLC showed that the starting material was completely salted (PE / EA = 20:1). The reaction solution was concentrated to dryness, and 20 ml of a mixed solvent of ethyl acetate / methyl tert-butyl ether was added. The mixture was stirred and slurried for 1 h. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected, and the wet material was dried in a vacuum drying oven at 50 °C to constant weight to obtain 4.8 g of pure compound V(R, optical rotation -203.6 degrees), an off-white solid.

[0331] LCMS: MS m / z (ESI): [M+H +[-HCl]=231.14930; Chemical purity: 100.0%.

[0332] Chiral HPLC: RT=0.711 min, ee=99.70%.

[0333] 1 HNMR (400 MHz, DMSO-d6): δ7.857(s, 1H), 7.543(s, 1H), 7.060-7.050(m,1H), 6.776-6.759(m, 2H), 6.290-6.288(d, 1H), 5.947-5.894(m, 1H), 3.378-3.275(m, 1H), 1.765-1.748(d, 3H), 1.151-1.096(d, 6H).

[0334] 13 CNMR (100 MHz, DMSO-d6): 151.316, 138.676, 136.711, 130.071,129.802, 125.710, 124.762, 120.411, 105.510, 56.667, 26.433, 23.501, 23.434, 20.770.

[0335] In a 50 ml three-necked flask, 4.3 g of free compound V(S) and 35 ml of 4 mol / L ethyl hydrochloride were added. Following the same preparation process as compound V(R) above, 4.4 g of pure compound V(S, optical rotation of +203.6 degrees) was obtained as a white solid.

[0336] LCMS: MS m / z (ESI): [M+H + [-HCl]=231.14930; Chemical purity: 100.0%.

[0337] Chiral HPLC: RT=0.849 min, ee=98.42%.

[0338] 1HNMR (400 MHz, DMSO-d6): δ7.866(s, 1H), 7.554(s, 1H), 7.072-7.069(m,1H), 6.778-6.762(m, 2H), 6.300-6.290(d, 1H), 5.958-5.950(m, 1H), 3.364-3.296(m, 1H), 1.768-1.750(d, 3H), 1.207-1.134(d, 6H).

[0339] 13 CNMR (100 MHz, DMSO-d6): 151.325, 138.638, 136.721, 130.032,129.860, 125.720, 124.752, 120.411, 105.529, 56.667, 26.433, 23.491, 23.434, 20.760.

[0340] Example 5: Preparation of compounds VI, VI(R), and VI(S)

[0341] Step 1:

[0342]

[0343] Under nitrogen protection, 52.5 g of 2-benzyloxy-3-sec-butylbenzaldehyde and 520 ml of anhydrous tetrahydrofuran were added to a 1 L three-necked flask. The mixture was cooled to 0 °C, and 91.3 ml of 3 mol / L magnesium methyl bromide solution was added dropwise. After the addition was complete, the mixture was kept at approximately 0 °C for 3–4 h. TLC showed that the reactants had reacted completely (PE / EA = 10:1). The reaction was quenched by slowly adding 200 ml of saturated ammonium chloride aqueous solution to the three-necked flask. After quenching, the reaction solution was transferred to a 2 L conical flask, and 200 ml of water and 130 ml of ethyl acetate were added. After thorough stirring, the mixture was allowed to stand for separation and extraction, and the ethyl acetate phase and aqueous phase were collected separately. The aqueous phase was extracted once more with 130 ml of ethyl acetate, and the two ethyl acetate phases were combined. The organic phase was washed twice with 130 ml of water, once with 130 ml of saturated brine, dried over anhydrous sodium sulfate for at least 0.5 h, and then evaporated to dryness to obtain 54.64 g of a colorless oily crude product. The crude product was purified by column chromatography using hexane / ethyl acetate = 100 / 1-40 / 1 as the eluent, yielding 44.4 g of pure compound VI-INT1 as a yellow oil.

[0344] Step 2:

[0345]

[0346] Under nitrogen protection, 260 ml of dichloromethane was added to a 2 L three-necked flask at room temperature, followed by the rapid addition of 77.2 ml of titanium tetrachloride. The temperature was lowered to 0 °C, and 109.5 g of trimethylsilylimidazolium (dissolved in 260 ml of dichloromethane) solution was added dropwise. After the addition was complete, the mixture was kept at 0 °C and stirred for 30 min. Then, 44.4 g of compound VI-INT1 dissolved in 260 ml of dichloromethane solution was added dropwise, and the reaction was continued at 0 °C for 3–4 h. TLC showed that most of the reactants had reacted (PE / EA = 2:1, iodine powder for color development). 520 ml of ice water was added to quench the reaction, and the mixture was stirred thoroughly for 10 min. The reaction mixture was then transferred to a separatory funnel, and the layers were extracted statically, collecting the aqueous and dichloromethane phases. The dichloromethane phase was washed once with 400 ml of water, and the two aqueous phases were combined. The pH of the aqueous phase was adjusted to 5–6 with 4 mol / L sodium hydroxide aqueous solution, and then adjusted to 8 with saturated sodium bicarbonate aqueous solution. Adjust the pH to 8, add 800 ml of ethyl acetate to the reaction solution, stir thoroughly, and allow to stand (separation is difficult). Collect the first ethyl acetate phase. Extract the aqueous phase three more times with 600 ml, 600 ml, and 400 ml of ethyl acetate, and combine the four ethyl acetate phases. Wash once with 800 ml of saturated brine, dry with anhydrous sodium sulfate for at least 0.5 h, and evaporate to dryness to obtain 16.9 g of crude oil. Purify the crude product by column chromatography using hexane / ethyl acetate = 40 / 1-30 / 1-20 / 1-10 / 1-5 / 1 as eluent to obtain 13 g of pure compound VI-INT2, a yellow oil.

[0347] Step 3: Compound VI

[0348]

[0349] 3.0 g of the racemic mixture of compound VI-INT2 and 30 ml of 4 mol / L ethyl hydrochloride were added to a 50 ml three-necked flask and stirred at room temperature for 1–2 h. TLC showed that the raw material was completely salted (PE / EA = 2:1). The mixture was filtered, and the filter cake was washed once with a small amount of ethyl acetate and then washed three times with 15 ml of n-hexane. The filter cake was collected to obtain 2.3 g of a white, off-white solid. The crude product was added to 12 ml of a mixed solvent of n-hexane and ethyl acetate and stirred. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected and dried in a vacuum drying oven at 50 °C to constant weight to obtain 2.15 g of pure compound VI, a white solid.

[0350] LCMS: MS m / z (ESI): [M+H + [-HCl]=245.16678; Chemical purity: 99.53%.

[0351] 1HNMR (400 MHz, DMSO-d6): δ14.454 (br, 1H), 9.034(s, 1H), 7.399-7.372(d, 1H), 7.022-6.999(m, 1H), 6.813 -6.778(m, 2H), 4.772-4.669(m, 1H), 3.171-3.119(m, 1H), 1.544-1.526(m, 5H), 1.130-1.113 (d, 3H), 0.828-0.806(t, 3H).

[0352] 13 CNMR (100 MHz, DMSO-d6):151.613, 138.043, 135.638, 134.191, 131.297,125.346, 124.838, 120.708, 115.955, 33.199, 33.141, 30.190, 30.094, 29.797, 21.230, 20.435, 20.396, 12.577, 12.519.

[0353] Step 4: Compound VI(R) and Compound VI(S)

[0354]

[0355] 9.0g of compound VI-INT2 was chirally resolved to yield 3.0g of free compound VI(R) and 3.1g of free compound VI(S).

[0356] The separation conditions were as follows: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0357] 3.0 g of free compound VI(R) and 30 ml of 4 mol / L ethyl hydrochloride were added to a 50 ml three-necked flask and stirred at room temperature for 1–2 h. TLC showed that the raw material was completely salted (PE / EA = 2:1). The mixture was filtered, and the filter cake was washed once with a small amount of ethyl acetate and then washed three times with 15 ml of n-hexane. The filter cake was collected to obtain 2.3 g of a white solid crude product. The crude product was added to 12 ml of a mixed solvent of n-hexane and ethyl acetate and stirred. The mixture was filtered, and the filter cake was washed three times with 15 ml of n-hexane. The filter cake was collected and dried in a vacuum drying oven at 50 °C to constant weight to obtain 3.2 g of pure compound VI(R, optical rotation -195.2 degrees), a white solid.

[0358] LCMS: MS m / z (ESI): [M+H + [-HCl]=245.16545; Chemical purity: 99.59%.

[0359] Chiral HPLC: RT=1.070 min, ee=99.14%.

[0360] 1 HNMR (400 MHz, DMSO-d6): δ14.454 (br, 1H), 9.028(s, 1H),

[0361] 7.401-7.374(d, 1H), 7.011-7.000(m, 1H), 6.808-6.790(m, 2H), 4.710-4.658(m, 1H), 3.149-3.131 (m, 1H), 1.541-1.523(m, 5H), 1.134-1.113(d, 3H), 0.811-0.806(t, 3H).

[0362] 13 CNMR (100 MHz, DMSO-d6): 151.622, 138.024, 135.600, 134.230,131.268, 125.536, 124.838, 120.708, 115.984, 33.189, 33.132, 30.190, 30.094, 29.826, 21.230, 20.387, 20.396, 12.577, 12.519.

[0363] Add 3.1 g of free compound VI(S) and 30 ml of 4 mol / L ethyl hydrochloride to a 50 ml three-necked flask, and proceed in the same manner as compound VI(R) to obtain 3.1 g of pure compound VI(S, optical rotation of +195.2 degrees), a white solid.

[0364] LCMS: MS m / z (ESI): [M+H + [-HCl]=245.16545; Chemical purity: 99.59%.

[0365] Chiral HPLC: RT=1.277 min, ee=98.22%.

[0366] 1HNMR (400 MHz, DMSO-d6): δ14.425 (br, 1H), 9.021(s, 1H),

[0367] 7.403-7.379(d, 1H), 7.024-7.001(m, 1H), 6.802-6.785(m, 2H), 4.699-4.647(m, 1H), 3.144-3.118(m, 1H), 1.538-1.520(m, 5H), 1.129-1.112(d, 3H), 0.841-0.787(t, 3H).

[0368] 13 CNMR (100 MHz, DMSO-d6): 151.622, 138.015, 135.522, 134.268,131.240, 125.375, 124.829, 120.699, 116.013, 33.180, 33.122, 30.199, 30.094, 29.854, 21.239, 20.367, 20.367, 12.577, 12.519.

[0369] Example 6: Preparation of compounds VII, VII(R) and VII(S)

[0370] Step 1:

[0371]

[0372] Solution 1: 176g of 1-bromo-3-isopropyl-2-(benzoxy)-benzene dissolved in 500g of tetrahydrofuran; Solution 2: 122g of N-methoxy-N-methyl-1,3-thiazolyl-4-carboxamide dissolved in 1200ml of tetrahydrofuran.

[0373] Under argon protection (0.5 L / min) at room temperature (25℃~30℃), 24 g of magnesium shavings, 150 ml of THF, 3 iodine granules (approximately 0.3 g), and 6 g of 1-bromo-3-isopropyl-2-(benzoxy)-benzene were added sequentially to a 3 L three-necked flask equipped with a mechanical stirrer and thermometer. The temperature was raised to 60℃~80℃, and then stirring was started. The system was kept under weak reflux (75℃~85℃) while adding the prepared solution 1 dropwise. After the addition was completed, the system was kept at 75℃~85℃ and stirred for 2 h. The system became brownish-yellow and turbid. Tetrahydrofuran was added to the system, and the temperature was lowered to -10℃~-20℃. Solution 2 was added dropwise. The temperature was raised during the addition process and controlled at -10℃~-20℃. The addition took approximately 20 min. After the addition was completed, the system was allowed to return to room temperature (25℃~30℃) and the reaction was timed for 3 h. Under controlled temperature of 0℃~10℃, the reaction system was slowly poured into 700ml of saturated ammonium chloride aqueous solution with stirring. 1L of ethyl acetate was added, and the mixture was stirred and separated. The organic phase was temporarily set aside. The aqueous phase was extracted once with 1L of ethyl acetate and separated. The aqueous phase was discarded. The combined organic phases were added to 500ml of saturated sodium chloride aqueous solution, allowed to stand, and separated. Anhydrous sodium sulfate was added to the organic phase for drying. The sodium sulfate was removed by filtration. 205g of crude product was concentrated from the filtrate. Column chromatography was performed using hexane / ethyl acetate as eluent to obtain 46.5g of pure compound VII-INT1, a pale yellow oil.

[0374] Step 2:

[0375]

[0376] Under argon atmosphere (0.5 L / min) protection at room temperature (25℃~30℃), 900 ml of tetrahydrofuran, 138 g of methyltriphenylphosphine bromide, and 41 g of potassium tert-butoxide were added sequentially with stirring. The system turned yellow and turbid. The reaction was stirred at room temperature (25℃~30℃) for 1.5 h. Then, 46.5 g of compound VII-INT1 dissolved in 250 ml of THF was added dropwise at room temperature (25℃~30℃). After the addition was complete, the reaction was allowed to proceed for 3 h at room temperature (25℃~30℃). The reaction system was poured into 500 ml of water with stirring, 1 L of ethyl acetate was added, stirred, and allowed to stand for separation. The organic phase was temporarily set aside. 250 ml of ethyl acetate was added to the aqueous phase, stirred, and allowed to stand for separation. The organic phases were combined, and 500 ml of saturated sodium chloride aqueous solution was added. The mixture was stirred, allowed to stand for separation, and anhydrous sodium sulfate was added to the organic phase for drying. Sodium sulfate was removed by filtration. The filtrate was concentrated until no liquid distilled off to obtain 140 g of crude brown-black oil. The crude product was purified by column chromatography using ethyl acetate / n-hexane as the eluent to obtain 40 g of pure compound VII-INT2, a pale yellow oil.

[0377] Step 3: Compound VII

[0378]

[0379] At room temperature (25℃~28℃), 1.4L of anhydrous ethanol, 40g of compound VII-INT2, and 4g of 10% wet Pd / C were added sequentially to a 2L high-pressure hydrogenation reactor. After the addition was complete, the system was sealed, purged with nitrogen three times, and pressurized with hydrogen to 0.5MPa~0.7MPa. The temperature was then raised to 35℃~45℃. The reaction was carried out for 7 hours, cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography using ethyl acetate / n-hexane as the eluent to obtain 15g of pure racemic compound VII, a pale yellow oil.

[0380] MS: MS m / z (ESI): [M+H + =248.2, Chemical purity: 97.66%.

[0381] 1 HNMR (400 MHz, DMSO-d6): δ9.063(s, 1H), 8.920(s, 1H), 7.358-7.353(s,1H), 6.996-6.978(m, 1H), 6.847-6.709 (m, 2H), 4.688-4.635(m, 1H), 3.331-3.270(m, 1H), 1.578-1.542(m, 3H), 1.182-1.109(d, 6H).

[0382] 13 CNMR (100 MHz, DMSO-d6): 161.416, 153.108, 152.753, 138.273, 130.339, 125.001, 124.994, 120.200, 112.132, 38.709, 27.008, 23.031, 18.326.

[0383] Step 4: Compound VII(R) and Compound VII(S)

[0384]

[0385] 7.0 g of compound VII was chirally resolved to yield 2.9 g of compound VII (R, optical rotation of -145.1 degrees) and 2.9 g of compound VII (S, optical rotation of +145.1 degrees).

[0386] The separation conditions were as follows: column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; column temperature: 35℃; back pressure: 2200 psi; mobile phase: methanol (containing 10 mM ammonia).

[0387] Compound VII (R): MS: MS m / z (ESI): [M+H + =248.2, Chemical purity: 98.12%.

[0388] Chiral HPLC: RT=4.909 min, ee=99.50%.

[0389] 1 HNMR (400 MHz, DMSO-d6): δ9.056-9.035(m, 2H), 7.341-7.322(s, 1H), 7.019-6.997(m, 1H), 6.894-6.872(m, 1H), 6.769-6.730(m, 1H), 4.721-4.668 (m,1H), 3.395-3.326 (m, 1H), 1.598-1.580 (d, 3H), 1.175-1.155(d, 6H).

[0390] 13 CNMR (100 MHz, DMSO-d6): 161.540, 154.468, 151.795, 136.481, 132.294, 125.595, 124.311, 120.344, 114.106, 36.045, 26.730, 23.444, 20.588.

[0391] Compound VII(S): MS: MS m / z (ESI): [M+H + =248.2, Chemical purity: 95.65%.

[0392] Chiral HPLC: RT=5.288 min, ee=99.72%.

[0393] 1 HNMR (400 MHz, DMSO-d6): δ9.055-9.050(m, 2H), 7.340-7.336(s, 1H), 7.020-6.999(m, 1H), 6.897-6.789(m, 1H), 6.771-6.733(m, 1H), 4.724-4.671 (m,1H), 3.417-3.314 (m, 1H), 1.601-1.583(d, 3H), 1.175-1.158(d, 6H).

[0394] 13CNMR (100 MHz, DMSO-d6): 161.549, 154.459, 151.814, 136.501, 132.275, 125.605, 124.311, 120.354, 114.057, 36.074, 26.740, 23.444, 20.569.

[0395] Example 7: Preparation of Compound VIII

[0396] Step 1:

[0397]

[0398] Solution 1: 94g of 2-isopropyl-6-bromoanisole dissolved in 200ml of tetrahydrofuran; Solution 2: 22.7g of N-methoxy-N-methyl 1,3-oxazol-4-carboxamide dissolved in 500ml of tetrahydrofuran.

[0399] Under argon protection (0.5 L / min) at room temperature (25℃~30℃), 12.2 g magnesium shavings, 100 ml THF, 3 iodine granules (approximately 0.3 g), and 6 g 2-isopropyl-6-bromoanisole were added sequentially to a 3 L three-necked flask equipped with a mechanical stirrer and thermometer. The temperature was raised to 60℃~80℃ to initiate the Grignard reaction (a large number of bubbles were produced after initiation; to prevent spraying), and stirring was started. The system was kept under weak reflux (75℃~85℃), and the prepared solution 1 was added dropwise. After the addition was completed, the system was kept at 75℃~85℃ and stirred for 2 hours. The system became brownish-yellow and turbid. Tetrahydrofuran was added to the system, and the temperature was lowered to -10℃~-20℃. Solution 2 was added dropwise. The temperature was raised during the addition process and controlled at -10℃~-20℃. The addition took approximately 20 minutes. After the addition was completed, the system was allowed to return to room temperature (25℃~30℃), and the reaction was timed for 3 hours. Under controlled temperature of 0℃~10℃, the reaction system was slowly poured into 600ml of saturated ammonium chloride aqueous solution with stirring. 1L of ethyl acetate was added, and the mixture was stirred and separated. The organic phase was temporarily set aside. The aqueous phase was extracted once with 1L of ethyl acetate and separated. The aqueous phase was discarded. The combined organic phases were added to 500ml of saturated sodium chloride aqueous solution, allowed to stand, and separated. Anhydrous sodium sulfate was added to the organic phase for drying. The sodium sulfate was removed by filtration. 84g of crude product, a reddish-black oily substance, was obtained by concentrated filtration. Column chromatography using hexane / ethyl acetate as eluent yielded pure compound VIII-INT1, a pale yellow oily substance.

[0400] Step 2:

[0401]

[0402] Under argon atmosphere (0.5 L / min) protection at room temperature (25℃~30℃), 900 ml of tetrahydrofuran, 64.1 g of methyltriphenylphosphine bromide, and 19.1 g of potassium tert-butoxide were added sequentially with stirring. The system turned yellow and turbid. The reaction was stirred at room temperature (25℃~30℃) for 1.5 h. Then, 22 g of compound VIII-INT1 dissolved in 100 ml of THF was added dropwise at room temperature (25℃~30℃). After the addition was completed, the reaction was allowed to proceed for 3 h at room temperature (25℃~30℃). The reaction system was poured into 500 ml of water with stirring, 1 L of ethyl acetate was added, stirred, allowed to stand and separated, the organic phase was temporarily set aside, 250 ml of ethyl acetate was added to the aqueous phase, stirred, allowed to stand and separated, the organic phases were combined, 500 ml of saturated sodium chloride aqueous solution was added, stirred, allowed to stand and separated, anhydrous sodium sulfate was added to the organic phase and dried, the sodium sulfate was removed by filtration, the filtrate was concentrated until no liquid distilled off to obtain 140 g of crude brown-black oily product, the crude product was purified by column chromatography using ethyl acetate / n-hexane system as eluent to obtain 13 g of pure compound VIII-INT2, a pale yellow oily product.

[0403] Step 3:

[0404]

[0405] At room temperature (25℃~28℃), 400mL of anhydrous ethanol, 13g of compound VIII-INT2, and 2g of 10% wet d / C were added sequentially to a 1L high-pressure hydrogenation reactor. After the addition was completed, the system was sealed, purged with nitrogen three times, and the system was pressurized with hydrogen to 0.5MPa~0.7MPa. The reaction was carried out at room temperature for 5 hours. The mixture was filtered, and the filtrate was concentrated to obtain 12.1g of pure compound VIII-INT3, which was a pale yellow oil.

[0406] Step 4: Compound VIII

[0407]

[0408] Under argon protection (0.5 L / min) at room temperature (25℃~30℃), 155 ml of dichloromethane and 10.3 g of compound VIII-INT3 were added sequentially to a 1 L three-necked flask equipped with a mechanical stirrer and thermometer. The system was pale yellow and transparent. The temperature was lowered to -70℃~-80℃, and 84 ml of boron tribromide dichloromethane solution was added dropwise. The temperature rose significantly. The temperature was controlled at -60℃~-80℃ during the process. After the addition was completed, the temperature was maintained at -70℃~-80℃ and stirred for 0.5 h. The reaction was then allowed to return to the ambient temperature for 2 h. The reaction system was cooled to -30℃ to -40℃, and 500ml of methanol was added dropwise. The temperature was controlled at -30℃ to -40℃, and the mixture was stirred for 10 minutes. The mixture was then poured into 1L of methanol at room temperature (25℃ to 30℃). 250ml of 5% sodium carbonate aqueous solution was added to the system, and the pH was adjusted to 6 to 7. The mixture was concentrated until no solvent distilled out. 100ml of water and 200ml of ethyl acetate were added to the concentrated system, and the mixture was stirred. The mixture was allowed to stand and separated. The organic phase was temporarily set aside, and the aqueous phase was extracted once with 200ml of ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, and filtered to remove sodium sulfate. The filtrate was concentrated until no liquid distilled out to obtain 10g of a brownish-red oily crude product. The crude product was purified by column chromatography using an ethyl acetate / n-hexane system as the eluent to obtain 7.9g of compound VIII, a brownish-yellow oily substance.

[0409] LCMS: MS m / z (ESI): [M+H + =232.1, Chemical purity: 99.31%.

[0410] 1 HNMR (400 MHz, DMSO-d6): 8.546(s, 1H), 8.278(s, 1H), 7.251-7.229(m,1H), 7.066-7.043(m, 1H), 6.924-6.856 (m, 1H), 3.359-3.290(m, 1H), 2.507-2.460(m, 1H), 1.330-1.192(m, 9H).

[0411] 13 CNMR (100 MHz, DMSO-d6): 150.846, 149.552, 142.573, 138.625, 136.347, 127.646, 126.611, 120.507, 114.317, 27.162, 22.773, 19.821, 13.247.

[0412] Example 8: Preparation of compounds IX, IX(R) and IX(S)

[0413] Step 1:

[0414]

[0415] Solution preparation: Dissolve 50g of N-methoxy-N-methylfuran-2-carboxamide in 270ml of tetrahydrofuran and set aside.

[0416] Under argon (0.5 L / min) protection at room temperature (25℃~30℃), 1.5 L of tetrahydrofuran and 118 g of 1-bromo-3-isopropyl-2-(benzoxy)-benzene were added sequentially to a 3 L three-necked flask equipped with a mechanical stirrer and thermometer. The system was pale yellow and transparent. The temperature was lowered to -80℃~-90℃, and 168 mL of 2.5 mol / L n-butyllithium solution was added dropwise. The temperature rose during the dropwise addition, and the process temperature was controlled at -75℃~-85℃. After the dropwise addition was completed, the temperature was maintained at -75℃~-85℃ and stirred for 1 h. Then, the prepared N-methoxy-N-methylfuran-2-carboxamide solution was added dropwise, and the process temperature was controlled at -80℃~-90℃. The system turned reddish-brown. After the dropwise addition was completed, the system was allowed to return to the temperature naturally and the reaction was timed for 2 h. The reaction system was slowly poured into 500 ml of saturated ammonium chloride aqueous solution under stirring, while maintaining a temperature of 0℃ to 10℃. The system produced a large amount of white solid salt. 500 ml of water was added and stirred. 1 L of ethyl acetate was added and stirred. The mixture was allowed to stand and separated. The organic phase was temporarily set aside. The aqueous phase was extracted once with 1 L of ethyl acetate. The organic phases were combined and washed with 1 L of saturated sodium chloride aqueous solution. Anhydrous sodium sulfate was added to the organic phase for drying. Sodium sulfate was removed by filtration. The filtrate was concentrated until no liquid distilled off to obtain 120 g of brown oily crude product. The crude product was purified by column chromatography using an ethyl acetate / n-hexane system as the eluent to obtain 110 g of compound IX-INT1, a brownish-yellow oily substance.

[0417] Step 2:

[0418]

[0419] Under argon atmosphere (0.5 L / min) protection at room temperature (25℃~30℃), 900 ml of tetrahydrofuran, 107.1 g of methyltriphenylphosphine bromide, and 32 g of potassium tert-butoxide were added sequentially with stirring. The system turned yellow and turbid. The reaction was stirred at room temperature (25℃~30℃) for 1.5 h. Then, 48 g of compound IX-INT1 dissolved in 120 ml of THF was added dropwise at room temperature (25℃~30℃). After the addition was completed, the reaction was allowed to proceed for 3 h at room temperature (25℃~30℃). The reaction system was poured into 1L of water with stirring, and 1L of ethyl acetate was added. The mixture was stirred, allowed to stand, and separated. The organic phase was temporarily set aside. 1L of ethyl acetate was added to the aqueous phase, and the mixture was stirred, allowed to stand, and separated. The organic phases were combined, and 1L of saturated sodium chloride aqueous solution was added. The mixture was stirred, allowed to stand, and separated. Anhydrous sodium sulfate was added to the organic phase for drying. Sodium sulfate was removed by filtration. The filtrate was concentrated until no liquid distilled off to obtain 122g of crude brown-black oil. The crude product was purified by column chromatography using ethyl acetate / n-hexane as the eluent to obtain 40g of pure compound IX-INT2, a pale yellow oil.

[0420] Step 3: Compound IX

[0421]

[0422] At room temperature (25℃~28℃), 1L of anhydrous ethanol, 40g of compound IX-INT2, and 8g of 10% wet Pd / C were added sequentially to a 2L high-pressure hydrogenation reactor. After the addition was complete, the system was sealed, purged with nitrogen three times, and pressurized with hydrogen to 0.5MPa~0.7MPa. The temperature was then raised to 35℃~45℃. The reaction was carried out for 7 hours, cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography using ethyl acetate / n-hexane as the eluent to obtain 36g of the racemic crude product of compound IX, a pale yellow oil. The crude product was then purified by column chromatography using ethyl acetate / n-hexane as the eluent to obtain 22g of pure compound IX, a pale yellow oil.

[0423] MS: MS m / z (ESI): [M+H + =231.3, chemical purity: 99.83%.

[0424] 1HNMR (400 MHz, DMSO-d6): δ8.258 (s, 1H), 7.474(s, 1H), 7.013-6.992(m, 1H), 6.727-6.680 (m, 2H), 6.355- 6.343(m, 1H), 6.139-6.131(s, 1H), 4.597-4.544(m, 1H), 3.338-3.327(m, 1H), 1.433-1.415(m, 3H), 1.183-1.134 (d, 6H).

[0425] 13 CNMR (100 MHz, DMSO-d6): 159.317, 151.134, 141.857, 136.089, 132.064, 125.068, 124.158, 120.411, 110.618, 105.644, 32.078, 26.577, 22.696, 20.205.

[0426] Step 4: Compound IX(R) and Compound IX(S)

[0427]

[0428] 7.0 g of compound IX was chirally resolved to obtain 2.7 g of compound IX (R, optical rotation of -165.4 degrees) and 2.9 g of compound IX (S, optical rotation of +165.4 degrees).

[0429] Compound IX(R): MS: MS m / z (ESI): [M+H + =231.3, Chemical purity: 98.98%.

[0430] Chiral HPLC: RT=2.353 min, ee=99.90%.

[0431] 1 HNMR (400 MHz, DMSO-d6): δ8.317 (s, 1H), 7.465 (s, 1H), 7.044-7.022(m, 1H), 6.792-6.758 (m, 2H), 6.355-6.351 (m, 1H), 6.162- 6.155(s, 1H), 4.710-4.658(m, 1H), 3.439-3.371(m, 1H), 1.507-1.489(m, 3H), 1.136-1.059 (m, 6H).

[0432] 13 CNMR (100 MHz, DMSO-d6): 159.423, 151.258, 141.742, 136.108, 132.083, 125.385, 124.148, 120.421, 110.570, 106.679, 32.193, 26.654, 22.686, 20.195.

[0433] Compound IX(S): MS: MS m / z (ESI): [M+H + =231.3, chemical purity: 99.68%.

[0434] Chiral HPLC: RT=3.123 min, ee=99.92%.

[0435] 1 HNMR (400 MHz, DMSO-d6): δ8.313 (s, 1H), 7.471(s, 1H), 7.050-7.012(m, 1H), 6.783-6.725 (m, 2H), 6.356-6.345 (m, 1H), 6.159-6.151(s, 1H), 4.691-4.638 (m, 1H), 3.421-3.353(m, 1H), 1.493-1.47(d, 3H), 1.205-1.188 (d, 6H).

[0436] 13 CNMR (100 MHz, DMSO-d6): 159.403, 151.229, 141.781, 136.108, 132.083, 125.385, 124.158, 120.430, 110.589, 105.644, 32.173, 26.644, 23.539, 20.214.

[0437] Experimental Example 1. LD50 of compounds II-IX administered via tail vein injection to mice 50 Measurement

[0438] The median lethal dose (LD50) of compounds II-IX administered via tail vein injection in mice was determined using a sequential method. 50 Kunming mice, 18-22g, both male and female, were used. All compounds were prepared by dissolving them in physiological saline. Animal behavior and mortality were observed after tail vein injection. The experimental results are shown in Table 1.

[0439] Table 1. Results of acute toxicity assays for compounds II–IX

[0440]

[0441] Note: Animal behavior is graded as follows: normal; lethargic; weak limbs, lying still; supine reflexes absent.

[0442] Compounds with (R) or (S) following their designation are either (R) or (S) configuration compounds; compounds without (R) or (S) are racemic compounds.

[0443] After administration of compounds II, III, IV, VI and their chiral compounds, as well as compounds VIII and IX, mice initially exhibited erratic limb movements and struggles, followed by slow gait, reduced movement, and slow breathing; they either died within 5 minutes or gradually recovered, fully returning to normal after 1 hour.

[0444] Compound V and its chiral compounds, as well as compound VII, did not cause any animal deaths when administered at the maximum concentration, and the condition of mice was not significantly different from that of normal mice.

[0445] Animal performance may further suggest that the LD50 of propofol administered intravenously in mice is similar to that reported previously. 50 Compared to (approximately 50 mg / kg), the safety range of our newly designed propofol analogue is significantly increased. The corresponding sluggish reaction observed in the animals is different from the disappearance of the righting reaction observed with propofol, indicating that the anesthetic and sedative effects of this type of propofol analogue are significantly reduced or even disappeared.

[0446] This invention, through preliminary observation of animal responses in Experiment 1, examined compounds II, III, IV, VI and their chiral compounds, as well as compounds VIII and IX. This series of compounds exhibits a wide safe dosing range, significantly higher than propofol. Experiment 1 also shows that, after structural modification, some compounds, such as V and VII, no longer possess anesthetic and sedative effects, while simultaneously demonstrating excellent safety.

[0447] Experimental Example 2. Activity evaluation of compounds III, IV, and VII at relevant targets

[0448] Experimental Objectives and Methods: Using compounds III, IV, and VII as representatives, HTRF, patch-clamp, and FLIPR methods were employed to screen the agonistic or inhibitory effects of these compounds on central nervous system targets, such as G protein-coupled receptors (GPCRs), transporters, and ion channels, providing a reference for future research on these compounds.

[0449] A negative control was prepared using DMSO stock solution; compounds III, IV, and VII were dissolved in DMSO to prepare 30 mM stock solutions, aliquoted, and stored at -20°C. The concentration for compound detection was 10 μM.

[0450] Targets M2, M4, 5-HT2A, 5-HT2C, H1, alpha1A, alpha2A, NK1, and NK2 were determined using the FLIPR method; targets D1, A2A, 5-HT1A, 5-HT1B, and NOP were determined using the LANCE Ultra cAMP kit; the ion channel target nAChRα7 / RIC3 was determined using the manual patch-clamp method; targets GABAA (α1β2γ2), 5-HT3A, NR1 / NR2B, and nAChRα4β2 were determined using the FLIPR method; and targets DAT and NET were determined using the transporter target detection method.

[0451] The experimental results are shown in Tables 2, 3, and 4.

[0452] Table 2. Results of target activity assays for Compound III

[0453]

[0454] SB-242084 (CAS: 181632-25-7) is a 5-HT inhibitor.

[0455] Table 3. Results of target activity assays for compound IV

[0456]

[0457] Table 4. Results of target activity assays for compound VII

[0458]

[0459] Conclusions: Compound III, at 10 μM, exhibits agonistic activity against the 5-HT2C target with an activation rate of 94.00%, and inhibitory activity against the nAChRα7 / RIC3 target with an inhibition rate of 67.77%. It shows no significant agonistic or inhibitory activity against the remaining 20 targets, with activation or inhibition rates all less than 50%. Compound IV, at 10 μM, exhibits agonistic activity against the 5-HT2A and 5-HT2C targets with activation rates of 60.11% and 101.59%, respectively, and inhibitory activity against the nAChRα7 / RIC3 target with an inhibition rate of 75.29%. It shows no significant agonistic or inhibitory activity against the remaining 19 targets, with activation or inhibition rates all less than 50%. Compound VII, at 10 μM, inhibits the alpha1A, alpha2A, and 5-HT3A targets with inhibition rates of 98.08%, 98.71%, and 96.74%, respectively. It showed no significant agonist or inhibitory effect on the remaining 19 targets, with agonist or inhibitory rates all less than 50%.

[0460] Clinical studies have confirmed that the main physiological effects of 5-HT2C receptor agonists include appetite suppression, mood regulation, and effects on sleep and cognitive function. 5-HT2A agonists, by activating widely distributed G protein-coupled receptors, produce central effects of perception, mood, and sleep regulation, and peripherally regulate vascular tone, gastrointestinal motility, and coagulation function; their pathological effects are bidirectional—they can exacerbate psychiatric symptoms and inflammatory responses, and may also improve neuropsychiatric disorders through neuroplasticity. 5-HT3 inhibitors exert their antiemetic effect by dually blocking the intestinal chromaffin cell-vagus nerve signal (peripheral) and the area tertiary / nucleus solitarius-vomiting reflex (central). The physiological activity of alpha1A inhibitors is mainly manifested in the selective blocking of alpha1A adrenergic receptor subtypes, thereby producing a smooth muscle relaxation effect, especially significant in the urinary and cardiovascular systems, indicating a certain impact on blood pressure. Alpha2A inhibitors, by selectively antagonizing central and peripheral alpha2A adrenergic receptor subtypes, mainly enhance the activity of the sympathetic nervous system, also indicating a certain impact on blood pressure. The physiological effects of nAChRα7 / RIC3 inhibitors involve interference with cholinergic anti-inflammatory pathways and neuroimmune regulation, mainly manifested as enhanced pro-inflammatory responses and disruption of related physiological processes.

[0461] Compound III showed an activation rate of only 28.06% for GABAA (α1β2γ2); compound IV showed an activation rate of only 34.53% for GABAA (α1β2γ2); and compound VII showed almost no effect on GABAA (α1β2γ2). Compared with propofol, the results suggest that compounds III and IV have significantly reduced effects on the GABA target.

[0462] Among them, 5-HT3A, 5-HT2A, and 5-HT2C are the main subtypes of 5-HT, which are ligand-gated ion channels involved in the regulation of vomiting and pain. They are also major targets for anti-anxiety and antidepressant drugs and important receptors in current research on psychotropic drugs. nAChRα7 / RIC3 plays an important role in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and neuralgia, and is currently an important and effective target for drug discovery. alpha1A and alpha2A are mainly expressed in blood vessels, heart, kidneys, spleen, liver, brain, and lower urinary tract. They are related to changes in blood pressure. GABAA (α1β2γ2) is the main subtype of GABAA and is currently recognized as the main target of propofol, with its main activities being sedation and anesthesia.

[0463] Therefore, compounds III, IV, and VII have different targets than propofol. Their main targets are the 5-HT series, nAChRα7 / RIC3, ​​and alpha1A and alpha2A, while their agonistic rate towards GABAA (α1β2γ2) does not exceed 40%. Furthermore, combined with the results of Experiment 1, it is suggested that compounds III, IV, and VII have significantly different biological activities from propofol.

[0464] Experimental Example 3: Effects of Compound IV(R) on Sleep-Wake Cycle

[0465] Experimental animals: SD rats (260~300g).

[0466] Compound preparation: Compound IV(R) was dissolved in physiological saline to concentrations of 10, 5, and 1.5 mg / ml, and administered at high (20 mg / kg), medium (10 mg / kg), and low (3 mg / kg) doses, respectively, according to animal body weight. Physiological saline served as a control. Eight animals were administered the medication intraperitoneally at 20:00 per group.

[0467] Experimental methods: Rats that had adapted to the laboratory environment were anesthetized and then had EEG and EMG electrodes implanted under stereotaxic guidance. They were given anti-inflammatory treatment and recovered for one week after the operation. Two days in advance, the rats were placed in a sleep recording chamber to adapt. On the day of the experiment, at 20:00, the animals were injected with compound IV(R) via the tail vein or intraperitoneal vein, and polysomnography was started.

[0468] The acquired data was used to determine and analyze sleep-wake phases. Based on the characteristics of cortical electroencephalography (EEG), the brain state was divided into three phases: wakefulness (W), non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep.

[0469] Sleep latency: The time taken for an animal to enter its first NREM sleep lasting more than 20 seconds after drug administration is defined as the NREM latency. The time taken for an animal to enter REM sleep lasting more than 20 seconds from NREM sleep after drug administration is defined as the REM latency.

[0470] Quantitative analysis of wakefulness and sleep depth was performed using power analysis of cortical EEG. Power analysis extracted pure sleep-wake brain waves within 4 hours after drug administration, calculated the area under the curve of power from 0 to 60 Hz, and converted it into the percentage of power in each frequency band for statistical analysis after standardization.

[0471] Statistical analysis: Experimental data were analyzed using SPSS 26.0 statistical software. All data are expressed as Means ± SEM. Data were analyzed using one-way ANOVA. Fisher's least significant difference (LSD) test was used to compare two groups, and p < 0.05 was considered statistically significant.

[0472] Experimental results:

[0473] 1) Effects of different doses of compound IV(R) administered intraperitoneally during the dark period on sleep-wake cycles: Different doses (3, 10, and 20 mg / kg) of compound IV(R) significantly reduced wakefulness and REM sleep and increased NREM sleep during the 12-hour dark period; during the 12-hour light period, it significantly increased wakefulness and decreased NREM sleep. Low-dose compound IVA showed an increase in REM sleep, but medium and high doses still inhibited REM sleep. Analysis of the total 24-hour sleep-wake cycle revealed that only high doses showed inhibition of wakefulness and REM sleep and an increase in NREM sleep. Figure 1 ).

[0474] Different doses of compound IV(R) were injected during the dark period. It was found that each hour after injection, the drug inhibited arousal and REM sleep, and increased NREM sleep. This effect was not only concentration-dependent but also lasted for 12 hours during the dark period. A rebound effect of arousal was observed during the subsequent 12 hours of the light period. However, it is noteworthy that medium and high doses of compound IV(R) consistently showed REM suppression, especially the high dose, which maintained this inhibitory effect for 24 hours without inducing REM sleep. Figure 2 ).

[0475] 2) Changes in sleep-wake structures 24 hours after intraperitoneal injection of compound IV(R)

[0476] Further analysis of its sleep structure revealed that intraperitoneal injection of different doses of compound IV(R) could shorten the NREM sleep latency, showing a concentration-dependent effect, but this did not reach statistical significance. In addition, compound IV(R) significantly prolonged the REM sleep latency; even high doses of compound IV(R) did not induce REM sleep during the statistical period, demonstrating a strong inhibitory effect on REM sleep initiation. Figure 3 Furthermore, analysis of its sleep structure revealed that compound IV(R)'s inhibitory effect on wakefulness during the 12-hour dark period was mainly due to a reduction in its duration; its effect on increasing NREM sleep was due to an increase in the number and duration of sleep segments; its inhibition of REM sleep was mainly due to a shortening of the number and duration of REM sleep segments; its effect on increasing wakefulness during the subsequent light period was mainly due to an increase in the duration of NREM sleep, while its effect on inhibiting REM sleep was mainly due to a decrease in the duration of NREM sleep, and its effect on inhibiting REM sleep was again due to a shortening of the number and duration of REM sleep segments; at a high dose of 24 hours, it showed inhibition of wakefulness due to a shortening of the duration of wakefulness, and its increase in NREM sleep was not due to an increase in duration but rather related to an increase in the number of sleep segments; for REM sleep, it was due to a significant shortening of the number and duration of REM sleep segments. Figure 4 In summary, compound IV(R) exerts its sleep-inducing effect by shortening NREM sleep latency, increasing NREM sleep duration and frequency, while strongly inhibiting REM sleep by prolonging REM sleep latency, reducing the number and duration of REM segments.

[0477] Effects of intraperitoneal injection of compound IV(R) on cortical EEG power: Intraperitoneal injection of different doses of compound IV(R) significantly affected cortical EEG power during wakefulness, NREM sleep, and REM sleep. Specifically, low and medium doses of compound IV(R) slightly increased wakefulness and decreased NREM sleep depth during wakefulness, but high doses resulted in a return to normal levels. Figure 5 ).

[0478] Conclusion: Polysomnography results showed that compound IV(R) had a significant slow-wave sleep-promoting effect, mainly manifested in a decrease in wave size (W) and an increase in normal cerebral eclampsia (NREM). Figure 1 , Figure 2 ), a significant shortening of NREM sleep latency ( Figure 3 ), and the increase in NREM fragments and duration ( Figure 4 The results suggest that compound IV(R) has a significant sleep-improving effect. Cortical EEG power showed an incomplete correspondence with sleep-wake states. Figure 5Combined with specific behavioral manifestations (video recordings), this indicates a dissociation between brain functional state and behavior. Compound IV(R) has a significant inhibitory effect on REM sleep. Figures 1-4 The results suggest that it has a strong deprivation effect on REM sleep, indicating that compound IV(R) has a good antidepressant effect.

[0479] Example 4: Determination of the absolute bioavailability of compound IV(R) orally administered to rats

[0480] Compound: Compound IV(R) was prepared with physiological saline to a concentration of 0.06 mg / ml and administered via IV / ig at a dose of 0.5 ml / 100 g body weight. It should be prepared immediately before use.

[0481] Main instruments: Acquity UPLC liquid chromatography system; Waters BEH-C18 column (2.1mm × 50mm, 1.7µm), Waters Corporation, USA; 6500+ triple quadrupole tandem mass spectrometer (6500+ UPLC-MS / MS), equipped with an electrospray ionization source (ESI source) and Analyst (version 1.7.2) data processing software, AB SCIEX Corporation, USA; 17 / 21 high-speed refrigerated centrifuge, Thermo Fisher Scientific, USA; BT125D 1 / 100,000 electronic analytical balance.

[0482] Experimental animals: SD rats, SPF grade, 8 rats, half male and half female, 259±48g.

[0483] Drug administration and sample collection: Eight SD rats were randomly divided into two groups: gavage (ig) (1 mg / kg) and intravenous injection (iv) (0.3 mg / kg). All rats were fasted for 12 hours before administration, but water was allowed. Before the experiment, rats were anesthetized with pentobarbital 30 mg / kg per injection, and an external jugular vein cannulation was performed for blood collection within 60 minutes. Blood was collected from the external jugular vein at 1, 3, 5, 10, 15, 20, 30, and 60 minutes before and after drug administration, and from the retroorbital venous plexus at 120, 240, 480, 720, and 1440 minutes. Approximately 100 μl of blood was collected and anticoagulated with heparin. Plasma was separated and temporarily stored at -20°C for later analysis.

[0484] Plasma sample processing: Standard curve: Take 190 µl of rat blank plasma, add 10 µl of compound IV(R) standard solution, shake well for 1.5 min, add 800 µl of acetonitrile, shake for 1.5 min to mix thoroughly, centrifuge at 8000 r / min for 10 min, filter through a 0.22 µm organic membrane, take 200 µl of filtrate and place it in the sample inlet tube for LC-MS / MS analysis.

[0485] Plasma sample processing: Take 60 µl of rat plasma to be tested, add 240 µl of acetonitrile, shake for 1.5 min to mix thoroughly, centrifuge at 8000 r / min for 10 min, filter through a 0.22 µm organic membrane, and take 200 µl of the filtrate into the sample inlet tube for LC-MS / MS analysis.

[0486] Chromatographic-mass spectrometry conditions: A Waters BEH-C18 column (2.1 mm × 50 mm, 1.7 μm) was used; column temperature: 35℃; mobile phase (A1): 0.05% formic acid in water, mobile phase (B1): acetonitrile; injection volume: 10 µL; flow rate: 0.4 mL / min gradient elution, elution program as shown in Table 5 below. Mass spectrometry conditions: Electrospray ionization (ESI+) was used, detection was performed in positive ion scanning mode, and the scanning mode was multiple reaction ion detection (MRM); ion source voltage (IS): 5500 V, source temperature (TEM): 500℃, curtain gas (CUR): 30 psi, spray gas (GS1): 50 psi, auxiliary gas (GS2): 50 psi, collision gas (CAD): High. Mass spectrometry parameters were optimized based on the above conditions.

[0487] Table 5. HPLC elution conditions

[0488]

[0489] Data processing: Phoenix 8.1 software was used to process the data and obtain the IV(R) pharmacokinetic parameters of the compound. The area under the CT curve (AUC) was calculated based on the gavage and intravenous administration. ( 0~∞ ) Given the dosage, calculate the absolute bioavailability of the oral administration.

[0490] Experimental results: This method has good specificity and meets the requirements of the guidelines for bioanalytical methods within the assay range.

[0491] The pharmacokinetic parameters and absolute bioavailability are shown in Table 6. The absolute bioavailability (Fabs) of compound IV(R) for oral administration, calculated based on dose, is 34.2%, indicating that compound IV(R) has the potential to be formulated into an oral formulation.

[0492] Table 6. Pharmacokinetic parameters of compound IV(R) administered via IV and ig (mean ± SD, n = 4)

[0493]

[0494] Experimental Example 5: Effects of Compound IV(R) and IV on Reserpine-Induced Acute Depression in C57 Mice

[0495] Compounds / Drugs: Compound IV(R), Compound IV, Fluoxetine, Aladdin, Reserpine.

[0496] Experimental animals: C57BL / 6J mice; SPF grade; 96 mice, half male and half female; 22-25g.

[0497] Drug preparation: 1) Compound IV(R): Prepare solutions at concentrations of 1.8, 0.9, 0.3, and 0.1 mg / ml. 2) Compound IV: Prepare an aqueous solution with a concentration of 0.9 mg / ml. 3) Fluoxetine: Prepare a solution with a final concentration of 0.3 mg / ml. 4) Reserpine: Weigh reserpine, dissolve it in a small amount of 1% acetic acid, then add 99% pure water to prepare a solution with a final concentration of 0.3 mg / ml.

[0498] Animal grouping and administration: Ninety-six mice were randomly divided into eight groups of 12 mice each: a model control group, a positive control group for fluoxetine, four groups receiving compound IV(R) at doses of 1, 3, 9, and 18 mg / kg (ig), and one group receiving compound IV at 9 mg / kg (ig). All medications were administered at a volume of 0.1 ml / 10 g, once daily for seven consecutive days. Model replication: Thirty minutes after the last administration, reserpine 2.5 mg / kg was administered intraperitoneally (ip), while the normal control group received an equivalent volume of saline to replicate the reserpine-induced acute depression model.

[0499] Observation indicators: (1) Ptosis score: 1 hour after reserpine injection, observe the degree of eyelid closure within 30 seconds, and score it as fully closed (4 points), 3 / 4 closed (3 points), 2 / 4 closed (2 points), 1 / 4 closed (1 point), and fully open (0 points). (2) Anal temperature: 1 hour after reserpine injection, measure the anal temperature with a thermometer, and keep the ambient temperature constant at 25℃. (3) Tail suspension test (TST): 1 hour after reserpine modeling, fix the mouse tail tip 1cm upside down, and after 2 minutes of adaptation, record the immobility time within 4 minutes to reflect the despair behavior. (4) Forced swimming test (FST): ① Clean the forced swimming bucket to ensure that there is no animal odor; fill an open cylindrical container with a total volume of 2500mL, a height of 20cm and a diameter of 14cm with 10cm of water at a water temperature of 25℃. ② One hour after reserpine-induced modeling, mice were placed in a cylinder. After acclimatization for 2 minutes, the forced swimming time of 4 minutes was recorded. A mouse remaining motionless was defined as giving up struggling and floating motionless in the water, only making necessary movements to keep its head above water. ③ At the end of the time, the mice were removed, dried, and replaced with another mouse for the experiment.

[0500] Data analysis: Behavioral scores and other data were analyzed using GraphPad Prism 9.0.0 software. One-way ANOVA was used to statistically analyze the differences, with p < 0.05 considered statistically significant. Linear regression analysis was used to evaluate the quantity-effect relationship.

[0501] Experimental results:

[0502] 1) Effect on reserpine-induced ptosis score: Figure 6 The results showed that mice injected with reserpine exhibited decreased activity, lethargy, and inner eyelid closure, graded as follows: complete closure (4 points), 3 / 4 closure (3 points), 2 / 4 closure (2 points), 1 / 4 closure (1 point), to complete opening (0 points). Fluoxetine could improve reserpine-induced ptosis in animals to a certain extent; administration of compound IV at 9 mg / kg also significantly antagonized this ptosis (p<0.05), while administration of different doses of compound IV(R) significantly antagonized reserpine-induced ptosis in mice, with the dose range of 1–18 mg / kg, and this effect showed a clear dose-dependent relationship (p<0.01).

[0503] 2) Effects on reserpine-induced forced swimming behavior in mice: Figure 7 The results showed that 1 hour after reserpine injection, the immobility time of mice forced to swim increased significantly. Compound IV at 9 mg / kg and low doses of 1-9 mg / kg could only partially counteract this behavioral change, while administration of compound IV(R) at 18 mg / kg could significantly counteract the immobility induced by reserpine in mice forced to swim and enhance their vitality (p<0.05).

[0504] Conclusions: Fluoxetine can improve reserpine-induced ptosis in animals to a certain extent; 9 mg / kg of compound IV can also significantly antagonize reserpine-induced ptosis (p<0.05), while different doses of compound IV(R) can significantly antagonize reserpine-induced ptosis in mice, with a clear dose-dependent effect in the 1–18 mg / kg range (p<0.01). 9 mg / kg of compound IV and low doses (1–9 mg / kg) can only partially antagonize the increased immobility time in mice subjected to forced swimming induced by reserpine, while administration of 18 mg / kg of compound IV(R) can significantly antagonize the immobility time in mice subjected to forced swimming induced by reserpine and enhance mouse vitality (p<0.05).

[0505] As demonstrated in Experimental Example 5, compounds IV and IV(R) of this invention have the effect of improving and treating depression. Figure 6 It can be seen that, compared with compound IV, compound IV(R) has a greater effect on ptosis in C57 mice and its biological activity is significantly improved.

Claims

1. A propofol analog of general formula (G), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof: （G） in, R1 and R2 are each independently selected from C1-10 straight-chain or branched alkyl groups or 3- to 12-membered cycloalkyl groups; optionally, the alkyl or cycloalkyl group is substituted by 1, 2, 3, 4 or 5 substituents selected from H, halogen, OH, CN, NH2, nitro, carboxyl or C1-5 alkyl groups; R3 is selected from 4- to 12-membered saturated or unsaturated heterocyclic groups; optionally, the heterocyclic group is surrounded by 1, 2, 3, 4, or 5 R3 groups. 31 Replaced; each R 31 Each is independently selected from H, halogen, OH, CN, NH2, nitro, carboxyl or C1-10 alkyl; the heterocyclic group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S.

2. The propofol analogue according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof, wherein... R1 and R2 are each independently selected from C1-5 straight-chain or branched alkyl groups or 3- to 8-membered cycloalkyl groups; optionally, the alkyl or cycloalkyl group is substituted by 1, 2, 3, 4 or 5 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-3 alkyl groups; R3 is selected from 5- to 6-membered heteroaryl groups; optionally, the heteroaryl group is surrounded by 1, 2, 3, 4, or 5 R groups. 31 Replaced; each R 31 Each is independently selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl or C1-5 alkyl; the heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S.

3. The propofol analogue according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof, wherein... R1 and R2 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group is substituted by 1, 2, or 3 substituents selected from H, F, Cl, Br, I, OH, CN, NH2, nitro, carboxyl, methyl, ethyl, or propyl. R3 is selected from , , , or ;Optional, the aforementioned , , , or By 1, 2 or 3 R 31 Replaced; each R 31 Each is independently selected from H, F, Cl, Br, I, methyl, ethyl, or propyl; the heterocyclic group contains one or two heteroatoms selected from N, O, and S.

4. The propofol analogue, or pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph according to any one of claims 1 to 3, wherein, Propofol analogues are selected from one of the following structures: Optional, of which R3 and R 31 What it replaced.

5. The propofol analogue according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof, wherein, The propofol analogue is selected from one of the following structures: 。 6. A method for preparing a propofol analog of general formula (G) as described in claim 4 or 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof, wherein: When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-1), the method comprises preparing the compound of formula (G-1) from compounds of formula (G-1-1) and compounds of formula (G-1-2): R4 is a hydroxyl protecting group; Optional, compounds of formula (G-1-2) By 1, 2 or 3 R 31 Replaced; or When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-2), the method comprises preparing the compound of formula (G-2) from a compound of formula (G-2-1) or a compound of formula (G-2-2): Optionally, R3 can be divided by 1, 2, 3, 4, or 5 Rs. 31 Replaced; or When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-3), the method comprises preparing the compound of formula (G-3) from a compound of formula (G-3-1): 。 7. The preparation method according to claim 6, wherein... When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-1), the method comprises preparing a compound of formula (G-1-1) from a compound of formula (G-1-3): or When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-2), the method comprises preparing a compound of formula (G-2-1) from a compound of formula (G-2-2): or When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-3), the method comprises preparing the compound of formula (G-3-1) from compounds of formula (G-1-1) and compounds of formula (G-3-2): Optionally, the compound of formula (G-3-2) is separated by 1, 2 or 3 R 31 What it replaced.

8. The preparation method according to claim 7, wherein, When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-2), the method comprises preparing a compound of formula (G-2-2) from a compound of formula (G-2-3): 。 9. The preparation method according to claim 8, wherein, When the propofol analogue represented by general formula (G) is selected from compounds of formula (G-2), the method comprises preparing a compound of formula (G-2-3) from compounds of formula (G-2-4) and formula (G-2-5): 。 10. The preparation method according to claim 8, wherein, Compound of formula (G-1) When not substituted, the method further includes preparing compound (G-1') from compounds of formula (G-1) and formula (G-1-4): R 31 I(G-1-4) (G-1’) R 31 It is selected from C1-10 alkyl; preferably C1-5 alkyl; more preferably methyl, ethyl or propyl.

11. The preparation method according to any one of claims 6 to 10, wherein the method comprises performing SFC resolution on the (G-1) compound, (G-2) compound, (G-3) compound, or (G-1') compound to obtain the (G-1-R) compound, (G-1-S) compound, (G-2-R) compound, (G-2-S) compound, (G-3-R) compound, (G-3-S) compound, (G-1'-R) compound, and (G-1'-S) compound, respectively: The preferred conditions for SFC splitting include: Chromatographic column: Amylose Neo, 100 mm × 4.6 mm, 3.0 μm; Column temperature: 35℃; back pressure: 2200 psi; mobile phase: methanol solution containing 10 mM ammonia.

12. The preparation method according to any one of claims 6 to 11, wherein the method comprises reacting a salt-forming agent with a compound of formula (G-1), formula (G-2), formula (G-3), (G-1'), formula (G-1-R), formula (G-1-S), formula (G-2-R), formula (G-2-S), formula (G-3-R), formula (G-3-S), formula (G-1'-R), or formula (G-1'-S) to prepare the hydrochloride salt form of the above compounds; preferably, the salt-forming agent is selected from one or more of methanol hydrochloride, ethanol hydrochloride, dioxane hydrochloride, ethyl acetate hydrochloride, diethyl ether hydrochloride, and isopropyl ether hydrochloride.

13. A pharmaceutical composition, wherein, The pharmaceutical composition comprises a propofol analogue as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof, and a pharmaceutically acceptable carrier and / or diluent.

14. The use of any propofol analogue of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or polymorph thereof, or the pharmaceutical composition of claim 13, in the preparation of a sleep-improving drug, a blood pressure regulating drug, an antiemetic drug, an antidepressant drug, or a cardioprotective drug.

15. The application according to claim 14, wherein, The propofol analogues, or pharmaceutically acceptable salts, stereoisomers, tautomers, or polymorphs thereof, improve sleep, regulate blood pressure, relieve nausea, have antidepressant or cardioprotective effects by acting simultaneously with 5-HT2C and nAChRα7 / RIC3, ​​or simultaneously with 5-HT2A, 5-HT2C and nAChRα7 / RIC3, ​​or simultaneously with alpha1A, alpha2A and 5-HT3A.

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