Ketone derivative as well as synthesis method and application thereof

Abstract

The invention provides a ketone derivative as well as a synthesis method and application thereof, and belongs to the technical field of medicine synthesis. According to the invention, a halogenated benzene compound and 3-hydroxy-2-pyrazinecarboxylic acid are used as raw materials and are subjected to a specific reaction to obtain the ketone derivative, and the compound is a Nav1.8 inhibitor, has good analgesic activity, quick effect and long analgesic time, and has a good application prospect in preparation of analgesic drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a ketone derivative and a synthesis method and application thereof. Background Art

[0002] Pain is one of the most common clinical symptoms. Pain that lasts for more than 3 months is considered chronic pain. Chronic pain has serious consequences for the body's physical and mental health, social life, and quality of life. According to statistics, about 35%-45% of the general population in the world have suffered from pain, and the incidence of chronic pain in adults is about 30%.

[0003] Analgesics are a class of drugs that mainly act on the nervous system, selectively reduce or eliminate pain and adverse emotional reactions such as mental tension and irritability caused by pain, but do not affect consciousness and other senses. Most of the existing drugs have the disadvantages of poor therapeutic effects and large side effects of long-term use. For example: commonly used opioids have a high risk of addiction and abuse; and non-steroidal anti-inflammatory drugs and tricyclic antidepressants have moderate analgesic effects. At the same time, they can cause a series of adverse reactions, including acute kidney injury, gastroduodenal toxicity and cardiotoxicity. Therefore, the treatment of chronic pain is an unmet health problem, and methods to treat or relieve the pain are urgently needed.

[0004] Different from the mechanism of action of addictive opioids, ion channel drugs mainly affect the formation and conduction of neuroelectrophysiological signals by regulating the ion channels of nerve cells. This difference in mechanism makes them non-addictive.

[0005] The occurrence of pain is closely related to the function of sodium ion channels. Voltage-gated sodium channels are multi-subunit transmembrane glycoproteins expressed on the cell membrane, composed of α and β subunits, and are important determinants of sensory neuron excitability. Nav1.8 is one of the subtypes of voltage-gated sodium channels, encoded by the gene SCN10A, and is mainly expressed in peripheral neurons. Studies on mutations in Nav1.8 have found that it is associated with neuropathic pain and pain sensitivity, and plays an important role in chronic neuropathic pain and chronic inflammatory pain. In some animal pain models, the expression level of Nav1.8 mRNA is increased in dorsal root ganglia. In addition, studies have found that intrathecal injection of Nav1.8 antisense nucleotides not only reduces spontaneous pain and hyperalgesia in animal pain models, but also reduces mechanical allodynia.

[0006] Sodium ion channels can excite the initiation and proliferation of action potentials in cells. By regulating the expression of Nav1.8 and related animal experiments, the role of Nav1.8 in chronic pain has been confirmed. A-803467 is a Nav1.8 selective blocker that has shown promise in preclinical studies for the treatment of chronic pain, but its low bioavailability and poor physicochemical properties limit its application. Currently, there are no selective Nav1.8 inhibitors used in clinical practice. Therefore, the development of new small molecule drugs targeting Nav1.8 is very necessary to address the needs of chronic pain treatment. Summary of the invention

[0007] In view of the deficiencies in the prior art, the present invention aims to provide a ketone derivative and a synthesis method and use thereof.

[0008] The present invention provides a ketone derivative, its stereoisomerism, and its pharmaceutically acceptable salt, wherein the structural formula of the compound is:

[0009]

[0010] Among them, R 1 Selected from C 1-6 Alkyl, halogen, cyano, mercapto, C 1-6 Alkoxy, trifluoromethyl, nitro;

[0011] R 2 Selected from hydrogen, C 1-6 Alkyl, halogen, cyano, hydroxy, trifluoromethyl, nitro;

[0012] R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-6 Alkoxy, halogen, cyano, hydroxy, trifluoromethyl, nitro;

[0013] R 4 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, hydroxy, trifluoromethyl;

[0014] R 5 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, hydroxy.

[0015] Furthermore, the structure of the ketone derivative is shown in Formula II or Formula III:

[0016]

[0017] Among them, R 1 Selected from C 1-3 Alkyl, halogen, trifluoromethyl;

[0018] R 2 Selected from hydrogen, C 1-3 Alkyl, halogen;

[0019] R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, hydroxyl;

[0020] R 4 Selected from hydrogen, C 1-3 Alkyl, hydroxyl;

[0021] R 5 Selected from hydrogen, C 1-3 Alkyl, hydroxyl.

[0022] Furthermore, the ketone derivative includes the following structural formula:

[0023]

[0024] The present invention also provides a method for preparing the above-mentioned ketone derivative, its stereoisomerism, and its pharmaceutically acceptable salt, the method comprising the following steps:

[0025]

[0026] (1) reacting compound A, compound B, a nitrogen nucleophile, a base and a catalyst to obtain an intermediate C;

[0027] (2) reacting intermediate C, a base and an azidating agent to obtain intermediate D;

[0028] (3) reacting the intermediate D, compound E, an alkylating agent and a reducing agent to obtain compound F, i.e., a ketone derivative;

[0029] wherein X is selected from halogen.

[0030] Furthermore, in step (1), the molar ratio of compound A, compound B, nitrogen nucleophile, base and catalyst is 1:0.5-1.5:0.5-1:10-15:0.1-0.5; the nitrogen nucleophile is (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine; the base is an organic base or an inorganic base; the catalyst is a metal catalyst; the solvent of the reaction is an organic solvent; the reaction temperature is 180-220°C, and the reaction time is 10-20 minutes;

[0031] In step (2), the molar ratio of the intermediate C, the base and the azidation reagent is 1:0.1-0.5:1-1.5; the base is an organic base or an inorganic base; the azidation reagent is diphenylphosphoryl azide; the solvent of the reaction is a mixture of an organic solvent and an inorganic solvent; the reaction conditions are: first reacting at 10-40°C for 0.5-1.5 hours, and then reacting at 60-100°C for 0.5-1.5 hours;

[0032] In step (3), the molar ratio of the intermediate D, compound E, alkylating agent and reducing agent is 1:5-7:4-6:8-10; the alkylating agent is magnesium methoxide; the reducing agent is sodium borohydride; the solvent of the reaction is an organic solvent; the reaction conditions are: first react at 50-60°C for 2-4 hours, and then react at 10-40°C for 20-40 minutes.

[0033] Further, in step (1), the molar ratio of compound A, compound B, nitrogen nucleophile, base and catalyst is 1:1:0.7:13:0.3; the base is potassium carbonate; the catalyst is cuprous iodide; the solvent of the reaction is N,N'-dimethylformamide; the reaction temperature is 200°C and the reaction time is 15 minutes;

[0034] In step (2), the molar ratio of the intermediate C, the base and the azidation reagent is 1:0.3:1.1; the base is triethylamine; the solvent of the reaction is a mixture of tetrahydrofuran and water; the reaction conditions are: first reacting at 20-30°C for 1 hour, and then reacting at 80°C for 1 hour;

[0035] In step (3), the molar ratio of the intermediate D, compound E, alkylating agent and reducing agent is 1:6:5:9; the solvent of the reaction is methanol; and the reaction conditions are: first react at 55°C for 3 hours and then react at 20-30°C for 30 minutes.

[0036] Furthermore, after the reaction of step (1) is completed, the following purification step is further included: diluting the reaction solution with ethyl acetate; washing the organic phase with water and a 10% LiCl aqueous solution, drying, filtering, and concentrating to obtain intermediate C;

[0037] In step (2), the reaction is added in the following manner: intermediate C, azidation reagent and base are added to tetrahydrofuran, reacted at 20-30°C for 1 hour, water is added, and then reacted at 80°C for 1 hour;

[0038] In step (3), the reaction is added in the following manner: intermediate D, compound E and alkylating agent are added to methanol, reacted at 55°C for 3 hours, and then reacted at 20-30°C for 30 minutes after adding the reducing agent;

[0039] After the reaction of step (3) is completed, the following purification step is further included: adjusting the pH value to 7 with concentrated hydrochloric acid, removing the solvent, extracting with ethyl acetate, aqueous hydrochloric acid solution, and aqueous potassium hydroxide solution, drying, and concentrating to obtain a ketone derivative.

[0040] The present invention also provides the use of the ketone derivative, its stereoisomerism and its pharmaceutically acceptable salt in the preparation of analgesic drugs.

[0041] Furthermore, the analgesic is a non-addictive analgesic, and the non-addictive analgesic includes chronic neuropathic pain drugs and chronic inflammatory pain drugs.

[0042] The present invention also provides a pharmaceutical composition, which is a preparation prepared by using the above-mentioned ketone derivatives, their stereoisomers, and their pharmaceutically acceptable salts as active ingredients and adding pharmaceutically acceptable excipients.

[0043] In the present invention, the compounds and derivatives provided are named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0044] Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms that are not specifically defined in the present invention, the meanings that can be given to them by those skilled in the art should be given according to the disclosure and context. Among them:

[0045] "Substitution" means that the hydrogen atoms in a molecule are replaced by other different atoms or molecules;

[0046] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. 1～6 Alkyl refers to a straight or branched chain alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms; 1-4 Alkylene refers to straight or branched chain alkylene containing 1, 2, 3 or 4 carbon atoms; and so on.

[0047] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. The alkyl group may be straight or branched, and the alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl).

[0048] "Alkoxy" represents an alkyl group as described above with a specific number of carbon atoms attached through an oxygen bridge, unless otherwise specified. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy.

[0049] "Halogen" is fluorine, chlorine, bromine or iodine.

[0050] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of these compounds are within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0051] Unless otherwise specified, the structures depicted in the present invention are also meant to include solvates of the structures, which refers to the physical association of the compounds of the present invention with one or more solvent molecules; the physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding; non-limiting examples of suitable solvents include, but are not limited to, isopropanol, ethanol, methanol, polyethylene glycol, DMSO, ethyl acetate, acetic acid, and ethanolamine, etc.; "hydrate" is a solvate in which the solvent molecule is H2O;

[0052] The term "pharmaceutically acceptable" means that a carrier, excipient, diluent, adjuvant, and / or applicable salt is generally chemically and physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0053] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after solvent evaporation, or be obtained by freeze-drying after reaction in an aqueous medium. In the present invention, the salt can be a hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0054] Furthermore, the compounds of the present invention may be administered in any convenient form of use, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, colorants, fillers, binders, and additional active agents;

[0055] The compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary and intradermal, and, if necessary for local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, intraocular, intralesional or subcutaneous administration.

[0056] The beneficial technical effects brought about by adopting this technical solution are:

[0057] The invention provides a ketone derivative and a synthesis method thereof. The ketone derivative is used for treating non-addictive chronic pain, has a rapid onset of action, and a long analgesic time, and has broad application prospects in the preparation of non-addictive chronic analgesic drugs.

[0058] In addition, the ketone derivatives synthesized in the present invention have inhibitory activity on Nav1.8 and are Nav1.8 inhibitors. It is well known to those skilled in the art that Nav1.8 inhibitors have good analgesic activity and can be used for a wide range of pain treatments. The ketone derivatives of the present invention have broad application prospects as Nav1.8 inhibitors in the preparation of non-addictive chronic analgesics.

[0059] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0060] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 The mechanical pain threshold-time curves of compounds 1-5 in the CFA pain model.

[0062] Figure 2 The mechanical pain threshold-time curves of compounds 6-9 in the CFA pain model.

[0063] Figure 3 It is the area under the curve (AUC) of the mechanical pain threshold-time curve of compounds 1-9 in the CFA pain model.

[0064] Figure 4 The inhibition rate of compound 1 on resting Nav1.8 current and the time-current response curve.

[0065] Figure 5The inhibition rate of compound 1 on the semi-inactivated Nav1.8 current and the time-current response curve. DETAILED DESCRIPTION

[0066] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0067] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of HT6 (ppm). NMR measurements were performed using a Fcuker NEO (400 MHz) NMR spectrometer, the solvent was deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS). MS measurements were performed using a Waters Q-TOF-Premier. High performance liquid chromatography (HPLC) analysis was performed using Shimadzu's LC-20AD.

[0068] The "room temperature (rt)" referred to in the present invention is 25±5°C.

[0069] Example 1: Method for preparing ketone derivatives of the present invention

[0070] Ketone derivatives were prepared according to the following synthetic route:

[0071]

[0072] The synthetic conditions involved are as follows:

[0073] S1: potassium carbonate, (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine, cuprous iodide, N,N'-dimethylformamide (DMF), 200°C, 15 min;

[0074] S2: triethylamine, diphenylphosphoryl azide, tetrahydrofuran, 80°C~rt, 2h;

[0075] S3: magnesium methoxide, sodium borohydride, methanol, 55°C~rt, 3h~0.5h;

[0076] The specific synthesis process involved is as follows:

[0077] Step 1: Preparation of intermediate 1a

[0078]

[0079] 4-Chloroisopropylbenzene (1 g, 6.47 mmol), 3-hydroxy-2-pyrazinecarboxylic acid (905.98 mg, 6.47 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (643.91 mg, 4.53 mmol), copper (I) iodide (369.48 mg, 1.94 mmol) and potassium carbonate (11.62 g, 84.07 mmol) were added to a microwave reactor and mixed in 10 mL DMF; microwave irradiation was performed at 200 ° C for 15 minutes; the reaction solution was diluted with ethyl acetate (100 mL); the organic phase was washed with water and 10% LiCl aqueous solution; dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain intermediate 1a as a colorless oily liquid (1.43 g). Yield 88%. ESI [M + H] + :259.1038.

[0080] Step 2: Preparation of intermediate 1b

[0081]

[0082] Intermediate 1a (1g, 3.87mmol), diphenylphosphoryl azide (1.23g, 4.45mmol) and triethylamine (117.54mg, 1.16mmol) were dissolved in tetrahydrofuran (35mL), and the mixture was stirred at room temperature for 1 hour; water (6ml) was added to the mixture, and stirred at 80°C for 1 hour; after the reaction solution was cooled to room temperature, it was diluted with saturated aqueous sodium carbonate solution (35mL); the layers were separated, the aqueous layer was extracted with ethyl acetate (35mL×3), and the combined organic extracts were washed with saturated aqueous sodium chloride solution (35mL); the washed organic phase was dried with sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure; the crude residue was purified by flash column chromatography on silica gel. A colorless oily liquid (595mg) was obtained. Yield 67%. ESI[M+H] + :230.1249.

[0083] Step 3: Preparation of compound 1

[0084]

[0085] Intermediate 1b (100 mg, 0.44 mmol) and 3,4-dimethoxybenzaldehyde (434.86 mg, 2.62 mmol) were dissolved in 4 mL of methanol, magnesium methoxide (188.35 mg, 2.18 mmol) was added, and the mixture was stirred at 55 °C for 3 hours; sodium borohydride (148.50 mg, 3.93 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous phase was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 1 was obtained as a white solid (124 mg). Yield 75%, purity 99.7%. ESI [M + H] + :380.1929.

[0086] NMR data of compound 1: 1 H NMR(500MHz,Chloroform-d)δ7.44(d,J=8.1Hz,1H),7.31(t,J=5.3Hz,1H),7.26–7.20(m,3H),7.17–7.14(m,2H),6.89(dt,J=1.8,0.9Hz,1H),6.86(dd t,J=8.5,1.7,0.8Hz,1H),6.82(d,J=8.6Hz,1H),4.72(dt,J=5.2,0.8Hz,2H ),3.86(d,J=1.6Hz,6H),2.85(tt,J=7.3,6.3Hz,1H),1.27(d,J=6.6Hz,6H).

[0087] Example 2: Method for preparing ketone derivatives of the present invention

[0088] Based on Example 1, this example prepared Compound 2 as follows:

[0089]

[0090] The intermediate 1b (100 mg, 0.44 mmol) and p-fluorobenzaldehyde (324.79 mg, 2.62 mmol) in Example 1 were dissolved in 4 mL of methanol, magnesium methoxide (188.35 mg, 2.18 mmol) was added, and the mixture was stirred at 55°C for 3 hours; sodium borohydride (148.50 mg, 3.93 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 2 was obtained as a white solid (122 mg). Yield 83%, purity 99.6%. ESI [M + H] + :338.1624.

[0091] NMR data of compound 2: 1 H NMR(500MHz,Chloroform-d)δ7.44(d,J=8.1Hz,1H),7.35(ddt,J=7.8,3.5,0.9Hz,2H),7.26–7.23(m,2H),7.21(d,J=8.1Hz,1H),7.16(t ,J=1.0Hz,1H),7.15–7.10(m,3H),7.08(t,J=5.2Hz,1H),4.75(dt,J=5.3,0.9Hz,2H),2.85(tt,J=7.3,6.3Hz,1H),1.27(d,J=6.6Hz,6H).

[0092] Example 3: Method for preparing ketone derivatives of the present invention

[0093] Based on Example 1, this example prepared compound 3 as follows:

[0094]

[0095] The intermediate 1b (100 mg, 0.44 mmol) and p-methoxybenzaldehyde (356.28 mg, 2.62 mmol) in Example 1 were dissolved in 4 mL of methanol, magnesium methoxide (188.35 mg, 2.18 mmol) was added, and the mixture was stirred at 55°C for 3 hours; sodium borohydride (148.50 mg, 3.93 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 3 was obtained as a white solid (117 mg). Yield 77%, purity 99.7%. ESI [M + H] + :350.1824.

[0096] NMR data of compound 3: 1 H NMR(500MHz,Chloroform-d)δ7.44(d,J=8.1Hz,1H),7.26–7.20(m,3H),7.20–7.14(m,4H),7.08(t,J=5.2Hz,1H) ,6.86–6.81(m,2H),4.75(dt,J=5.2,0.9Hz,2H),3.80(s,3H),2.85(tt,J=7.3,6.3Hz,1H),1.27(d,J=6.6Hz,6H).

[0097] Example 4: Method for preparing ketone derivatives of the present invention

[0098] This embodiment further provides a method for synthesizing a ketone derivative, and the synthetic route is as follows:

[0099]

[0100] The synthetic conditions involved are as follows:

[0101] S1: potassium carbonate, (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine, cuprous iodide, DMF, 200°C, 15 min;

[0102] S2: triethylamine, diphenylphosphoryl azide, tetrahydrofuran, 80°C~rt, 2h;

[0103] S3: magnesium methoxide, sodium borohydride, methanol, 55°C~rt, 3h~0.5h;

[0104] The specific synthesis process involved is as follows:

[0105] Step 1: Preparation of intermediate 4a

[0106]

[0107] Add 4-chloro-o-xylene (1 g, 7.11 mmol), 3-hydroxy-2-pyrazinecarboxylic acid (996.36 mg, 7.11 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (708.14 mg, 4.98 mmol), copper (I) iodide (406.34 mg, 2.13 mmol) and potassium carbonate (12.78 g, 92.45 mmol) to a microwave reactor and mix in 10 mL DMF; microwave irradiate at 200 ° C for 15 minutes; dilute the reaction solution with ethyl acetate (100 mL); wash the organic phase with water and 10% LiCl aqueous solution; dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent to obtain intermediate 1a as a colorless oily liquid (1.7 g). Yield 90%. ESI [M + H] + :245.0881.

[0108] Step 2: Preparation of intermediate 4b

[0109]

[0110] Intermediate 4a (1.00 g, 4.09 mmol), diphenylphosphoryl azide (1.30 g, 4.71 mmol) and triethylamine (124.29 mg, 1.23 mmol) were dissolved in tetrahydrofuran (35 mL), and the mixture was stirred at room temperature for 1 hour; water (6 ml) was added to the mixture, and stirred at 80°C for 1 hour; after the reaction solution was cooled to room temperature, it was diluted with saturated aqueous sodium carbonate solution (35 mL); the layers were separated, the aqueous layer was extracted with ethyl acetate (35 mL×3), and the combined organic extracts were washed with saturated aqueous sodium chloride solution (35 mL); the washed organic phase was dried with sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure; the crude residue was purified by flash column chromatography on silica gel. A colorless oily liquid (644 mg) was obtained. Yield 73%. ESI[M+H] + :216.1092.

[0111] Step 3: Preparation of compound 4

[0112]

[0113] Intermediate 4b (100 mg, 0.46 mmol) and p-fluorobenzaldehyde (345.95 mg, 2.79 mmol) were dissolved in 4 mL of methanol, magnesium methoxide (200.63 mg, 2.32 mmol) was added, and the mixture was stirred at 55°C for 3 hours; sodium borohydride (158.18 mg, 4.18 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous phase was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 4 was obtained as a white solid (115 mg). Yield 78%, purity 99.7%. ESI [M + H] + :324.1467.

[0114] NMR data of compound 4: 1 H NMR(500MHz,Chloroform-d)δ7.61(d,J=8.2Hz,1H),7.43–7.36(m,2H),7.36–7.30(m,3H),7.22(dd,J=8.1,2.1 Hz,1H),7.10–7.04(m,2H),7.01(dq,J=8.2,1.1Hz,1H),4.66(dt,J=5.3,0.8Hz,2H),2.28(s,3H),2.11(s,3H).

[0115] Example 5: Method for preparing ketone derivatives of the present invention

[0116] Based on Example 4, this example prepared Compound 5 as follows:

[0117]

[0118] The intermediate 4b (100 mg, 0.46 mmol) and 3,4-dimethoxybenzaldehyde (457.70 mg, 2.79 mmol) in Example 4 were dissolved in 4 mL of methanol, magnesium methoxide (200.63 mg, 2.32 mmol) was added, and the mixture was stirred at 55°C for 3 hours; sodium borohydride (158.18 mg, 4.18 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 5 was obtained as a white solid (131 mg). Yield 77%, purity 99.8%. ESI[M+H] + :366.1773.

[0119] NMR data of compound 5: 1 H NMR(500MHz,Chloroform-d)δ7.70(t,J=5.3Hz,1H),7.61(d,J=8.2Hz,1H),7.43–7.39(m,1H),7.35(d,J=8.1Hz,1H),7.22(dd,J=8.1,2.1Hz,1H),7 .01(dq,J=8.2,1.1Hz,1H),6.92–6.85(m,2H),6.81(d,J=8.4Hz,1H),4.6 1(dt,J=5.3,0.8Hz,2H),3.84(d,J=5.3Hz,6H),2.28(s,3H),2.11(s,3H).

[0120] Example 6: Method for preparing ketone derivatives of the present invention

[0121] Based on Example 4, this example prepared Compound 6 as follows:

[0122]

[0123] The intermediate 4b (100 mg, 0.46 mmol) and 4-isopropylbenzaldehyde (413.10 mg, 2.79 mmol) in Example 4 were dissolved in 4 mL of methanol, magnesium methoxide (200.63 mg, 2.32 mmol) was added, and the mixture was stirred at 55°C for 3 hours; sodium borohydride (158.18 mg, 4.18 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 6 was obtained as a white solid (130 mg). Yield 81%, purity 99.6%. ESI[M+H] + :348.2031.

[0124] NMR data of compound 6: 1 H NMR(500MHz,Chloroform-d)δ7.61(d,J=8.2Hz,1H),7.43–7.32(m,3H),7.27–7.19(m,3H),7.17–7.13(m,2H),7.01(d q,J=8.2,1.1Hz,1H),4.66(dt,J=5.3,0.9Hz,2H),2.90–2.78(m,1H),2.28(s,3H),2.11(s,3H),1.28(d,J=6.6Hz,6H).

[0125] Example 7: Method for preparing ketone derivatives of the present invention

[0126] This embodiment further provides a method for synthesizing a ketone derivative, and the synthetic route is as follows:

[0127]

[0128] The synthetic conditions involved are as follows:

[0129] S1: potassium carbonate, (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine, cuprous iodide, DMF, 200°C, 15 min;

[0130] S2: triethylamine, diphenylphosphoryl azide, tetrahydrofuran, 80°C~rt, 2h;

[0131] S3: magnesium methoxide, sodium borohydride, methanol, 55°C~rt, 3h~0.5h;

[0132] The specific synthesis process involved is as follows:

[0133] Step 1: Preparation of intermediate 7a

[0134]

[0135] To a microwave reactor, p-chlorotoluene (1 g, 7.90 mmol), 3-hydroxy-2-pyrazinecarboxylic acid (1.11 g, 7.90 mmol), (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine (786.62 mg, 5.53 mmol), copper (I) iodide (451.37 mg, 2.37 mmol) and potassium carbonate (14.19 g, 102.70 mmol) were added and mixed in 10 mL DMF; microwave irradiation was performed at 200 ° C for 15 minutes; the reaction solution was diluted with ethyl acetate (100 mL); the organic phase was washed with water and 10% LiCl aqueous solution; dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain intermediate 7a as a colorless oil (1.7 g). Yield 93%. ESI [M + H] + :231.0725.

[0136] Step 2: Preparation of intermediate 7b

[0137]

[0138] Intermediate 7a (1.00 g, 4.34 mmol), diphenylphosphoryl azide (1.37 g, 5.00 mmol) and triethylamine (131.86 mg, 1.30 mmol) were dissolved in tetrahydrofuran (35 mL), and the mixture was stirred at room temperature for 1 hour; water (6 ml) was added to the mixture, and stirred at 80°C for 1 hour; after the reaction solution was cooled to room temperature, it was diluted with saturated aqueous sodium carbonate solution (35 mL); the layers were separated, the aqueous layer was extracted with ethyl acetate (35 mL×3), and the combined organic extracts were washed with saturated aqueous sodium chloride solution (35 mL); the washed organic phase was dried with sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure; the crude residue was purified by flash column chromatography on silica gel. Intermediate 7b was obtained as a colorless oily liquid (612 mg). Yield 70%. ESI[M+H] + :202.0936.

[0139] Step 3: Preparation of compound 7

[0140]

[0141] Intermediate 7b (100 mg, 4.47 mmol) and 3,4-dimethylbenzaldehyde (400 mg, 26.84 mmol) were dissolved in 4 mL of methanol, magnesium methoxide (214.61 mg, 2.48 mmol) was added, and the mixture was stirred at 55 °C for 3 hours; sodium borohydride (169.20 mg, 4.47 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 7 was obtained as a white solid (114 mg). Yield 72%, purity 99.6%. ESI [M + H] + :320.1718.

[0142] NMR data of compound 7: 1 H NMR(500MHz,Chloroform-d)δ7.66(t,J=5.2Hz,1H),7.60(d,J=8.2Hz,1H),7.35(d,J=8.0Hz,1H),7.32–7.25(m,2H),7.1 3–7.06(m,3H),7.04–6.98(m,2H),4.58(dt,J=5.3,0.9Hz,2H),2.37(d,J=0.8Hz,3H),2.27(d,J=1.0Hz,3H),2.21(s,3H).

[0143] Example 8: Method for preparing ketone derivatives of the present invention

[0144] Based on Example 7, this example prepared Compound 8 as follows:

[0145]

[0146] The intermediate 7b (100 mg, 0.50 mmol) and 3,4-dimethoxybenzaldehyde (495.48 mg, 2.98 mmol) in Example 7 were dissolved in 4 mL of methanol, magnesium methoxide (214.61 mg, 2.48 mmol) was added, and the mixture was stirred at 55°C for 3 hours; sodium borohydride (169.20 g, 4.47 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 8 was obtained as a white solid (115 mg). Yield 66%, purity 99.8%. ESI[M+H] + :352.1616.

[0147] NMR data of compound 8: 1 H NMR(500MHz,Chloroform-d)δ7.44(d,J=8.1Hz,1H),7.31(t,J=5.3Hz,1H),7.25–7.19(m,3H),7.14–7.08(m,2 H),6.91–6.83(m,2H),6.82(d,J=8.6Hz,1H),4.72(dt,J=5.3,0.9Hz,2H),3.86(d,J=2.2Hz,6H),2.35(s,3H).

[0148] Example 9: Method for preparing ketone derivatives of the present invention

[0149] Based on Example 7, this example prepared compound 9 as follows:

[0150]

[0151] The intermediate 7b (100 mg, 0.50 mmol) and 4-isopropylbenzaldehyde (441.90 mg, 2.98 mmol) in Example 7 were dissolved in 4 mL of methanol, magnesium methoxide (214.61 mg, 2.48 mmol) was added, and the mixture was stirred at 55°C for 3 hours; sodium borohydride (169.20 g, 4.47 mmol) was then slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Compound 9 was obtained as a white solid (133 mg). Yield 80%, purity 99.6%. ESI [M + H] + :334.1875.

[0152] NMR data of compound 9: 1 H NMR(500MHz,Chloroform-d)δ7.44(d,J=8.1Hz,1H),7.25–7.15(m,7H),7.14–7.04(m,3H),4 .75(dt,J=5.3,0.9Hz,2H),2.89–2.82(m,1H),2.35(d,J=0.9Hz,3H),1.27(d,J=6.6Hz,6H).

[0153] The beneficial effects of the present invention are demonstrated by experimental examples below.

[0154] Experimental Example 1: Testing the analgesic activity of ketone derivatives in the complete Freund's adjuvant (CFA)-induced inflammatory pain model

[0155] 1. Experimental methods

[0156] (1) Experimental animal modeling: ICR mice (purchased from Chengdu Dashuo Experimental Animal Co., Ltd., 6-8 weeks old, weighing about 25 g, male, adapted to the experimental environment for three days) were randomly divided into a model group, a positive control group, and a drug group, with 6 mice in each group. 20 μl of CFA was given to the left sole of each group of mice to establish the model and trigger inflammatory pain.

[0157] (2) Treatment: One day after modeling, the mechanical pain threshold of each group before drug administration was measured using an electronic analgesic. The corresponding drugs were dissolved using a solvent combination of DMSO: Tween 80: saline = 1:1:8;

[0158] Among them, the drug group: the above-mentioned solvent combination was used to dissolve compounds 1-9 respectively, and then intraperitoneally injected with a dose of 13mM and 0.2mL;

[0159] Model group: the same dose of DMSO: Tween 80: saline = 1:1:8 solvent combination was given;

[0160] Positive control group: indomethacin was dissolved in the above solvent combination, and then intraperitoneally injected with a dose of 13 mM and 0.2 mL;

[0161] (3) Data statistics: The mechanical pain threshold of the left foot of each mouse was measured at 30 min, 60 min, 120 min, 180 min, 240 min and 300 min after administration. Each time point was measured three times and the average value was included in the statistical data.

[0162] 2. Experimental results

[0163] The results are as follows Figure 1-2 As shown in the figure: Compound 1, Compound 2, and Compound 7 have better analgesic activity than the positive control indomethacin. Among them, Compound 1 achieved the best analgesic effect 60 minutes after administration and lasted for about 5 hours; Compared with indomethacin, Compound 1 has a faster onset, longer duration of action, and higher analgesic intensity; and Figure 3 It can be found that the area under the curve (AUC%) of compound 1 is better than that of indomethacin.

[0164] Therefore, it was concluded that compound 1 has the advantages of rapid onset of action, good analgesic effect and long duration of drug effect in terms of analgesia.

[0165] Experimental Example 2: Effect of ketone derivatives on Nav1.8 current

[0166] 1. Experimental methods

[0167] The effect of compound 1 on Nav1.8 current at concentrations of 10 μM, 3 μM, 1 μM, 0.3 μM and 0.1 μM was determined by manual patch clamp test. The specific process is as follows:

[0168] (1) Before the start of this electrophysiological experiment, Nav1.8 (SCN10A: NP_006505; SCN3B: NP_060870) cell lines should be maintained within 70% of the maximum density in the logarithmic growth phase;

[0169] (2) All reagents were preheated to 37°C before use, and the patch clamp assay was performed after the cells were well attached;

[0170] (3) Nav1.8 sodium current data were collected and stored on a computer using Patchmaster software through an EPC-10 amplifier;

[0171] (4) Use tweezers to remove the cell slide from the cell culture dish, add extracellular fluid, and place it in a bath on the stage of an inverted microscope;

[0172] (5) Use a P-1000 microelectrode puller to pull a glass microtube, fill 1 / 3 of the volume of the glass microtube (recording electrode) with intracellular fluid, and place it in the electrode holder;

[0173] (6) Use an electric micromanipulator (Scientifica-Double 1U) to bring the recording electrode into contact with the cell surface. At this time, due to the sudden increase in electrode resistance, the current value represented by the sealing test pulse displayed in the membrane test window decreases. Remove the positive pressure and apply a negative pressure of 0.5cm H2O. Observe that the sealing resistance rises rapidly until it reaches a gigaohm seal. When the sealing resistance between the recording electrode and the cell membrane is >1GΩ, apply negative pressure to break the membrane to form a whole-cell recording mode. After the membrane is broken and stabilized, compensate for the membrane capacitance (Cs) and series resistance (Rs);

[0174] The stimulation procedure is as follows: 1) The clamping voltage is -120mV, and a square wave train stimulation of -120 to -10mV, 10mV step, and 8000ms duration is given, then step to -10mV, time is 30ms, and finally return to -120mV. The membrane potential is used as the abscissa and the relative current I / Imax is used as the ordinate to draw a graph, and the Boltzmann process I / Imax=1 / {1+exp[(V-V1 / 2) / k]} is used for fitting to obtain the steady-state inactivation curve (V1 / 2 is the conditional pulse voltage when the channel is half inactivated, and k is the slope factor);

[0175] 2) The clamping voltage is -120mV, depolarized to 0mV, the duration is 40ms, the resting current of the sodium channel is stimulated, then the conditional pulse voltage when the inactivation curve V1 / 2 channel is half inactivated is stepped to 8000ms, repolarized to -120mV, the duration is 30ms, then depolarized to 0mV, the duration is 40ms, the half-inactivated current of the sodium channel is stimulated, and finally restored to -120mV, and the current is recorded every 20s. At room temperature, the Nav1.8 sodium channel current is recorded before drug addition. After the control current value reaches a steady state, that is, after the most recent 4 consecutive current recording lines overlap, the cumulative drug addition method is used to detect the effects of negative (0.1% DMSO) and 5 drug concentrations (from low to high) on the current.

[0176] 2. Experimental results

[0177] In two independent repeated experiments, the inhibitory effect of the test compound on the Nav1.8 channel was detected, and the raw data Nav1.8 current peak was extracted from the PatchMaster software. The current inhibition rate was calculated as follows: Peak current inhibition rate = (1-peak current compound / peak current vehicle), the inhibition rate of compound 1 on Nav1.8 current and the time-current response curve. Among them, the inhibition rate of compound 1 on resting Nav1.8 current at a concentration of 10μM was: 80.50±3.88%, and the inhibition rate on semi-inactivated Nav1.8 current was: 85.74±4.66%.

[0178] In summary, the present invention provides a ketone derivative and its synthesis method and use. In the present invention, a halogenated benzene compound and 3-hydroxy-2-pyrazinecarboxylic acid are used as raw materials, and a specific reaction is carried out to obtain the ketone derivative. This compound is a Nav1.8 inhibitor, has good analgesic activity, fast onset, good analgesic effect, long duration of drug effect, and has good application prospects in the preparation of non-addictive analgesics.

Claims

1. A ketone derivative, its stereoisomerism, or its pharmaceutically acceptable salt, characterized in that: The structural formula of the compound is: Among them, R 1 Selected from C 1-6 Alkyl, halogen, cyano, mercapto, C 1-6 Alkoxy, trifluoromethyl, nitro; R 2 Selected from hydrogen, C 1-6 Alkyl, halogen, cyano, hydroxy, trifluoromethyl, nitro; R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-6 Alkoxy, halogen, cyano, hydroxy, trifluoromethyl, nitro; R 4 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, cyano, hydroxy, trifluoromethyl; R 5 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, hydroxy.

2. The ketone derivative, its stereoisomerism, and its pharmaceutically acceptable salt according to claim 1, characterized in that: The structure of the ketone derivative is shown in Formula II or Formula III: Among them, R 1 Selected from C 1-3 Alkyl, halogen, trifluoromethyl; R 2 Selected from hydrogen, C 1-3 Alkyl, halogen; R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, hydroxyl; R 4 Selected from hydrogen, C 1-3 Alkyl, hydroxyl; R 5 Selected from hydrogen, C 1-3 Alkyl, hydroxyl.

3. The ketone derivative, its stereoisomerism, and its pharmaceutically acceptable salt according to claim 1, characterized in that: The ketone derivatives include the following structural formula:

4. A method for preparing the ketone derivative, its stereoisomerism, and its pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: (1) reacting compound A, compound B, a nitrogen nucleophile, a base and a catalyst to obtain an intermediate C; (2) reacting intermediate C, a base and an azidating agent to obtain intermediate D; (3) reacting the intermediate D, compound E, an alkylating agent and a reducing agent to obtain compound F, i.e., a ketone derivative; Wherein, X is selected from halogen.

5. The method according to claim 4, characterized in that In step (1), the molar ratio of compound A, compound B, nitrogen nucleophile, base and catalyst is 1:0.5-1.5:0.5-1:10-15:0.1-0.5; the nitrogen nucleophile is (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine; the base is an organic base or an inorganic base; the catalyst is a metal catalyst; the solvent of the reaction is an organic solvent; the reaction temperature is 180-220°C, and the reaction time is 10-20 minutes; In step (2), the molar ratio of the intermediate C, the base and the azidation reagent is 1:0.1-0.5:1-1.5; the base is an organic base or an inorganic base; the azidation reagent is diphenylphosphoryl azide; the solvent of the reaction is a mixture of an organic solvent and an inorganic solvent; the reaction conditions are: first reacting at 10-40°C for 0.5-1.5 hours, and then reacting at 60-100°C for 0.5-1.5 hours; In step (3), the molar ratio of the intermediate D, compound E, alkylating agent and reducing agent is 1:5-7:4-6:8-10; the alkylating agent is magnesium methoxide; the reducing agent is sodium borohydride; the solvent of the reaction is an organic solvent; the reaction conditions are: first react at 50-60°C for 2-4 hours, and then react at 10-40°C for 20-40 minutes.

6. The method according to claim 5, characterized in that In step (1), the molar ratio of compound A, compound B, nitrogen nucleophile, base and catalyst is 1:1:0.7:13:0.3; the base is potassium carbonate; the catalyst is cuprous iodide; the solvent of the reaction is N,N'-dimethylformamide; the reaction temperature is 200°C and the reaction time is 15 minutes; In step (2), the molar ratio of the intermediate C, the base and the azidation reagent is 1:0.3:1.1; the base is triethylamine; the solvent of the reaction is a mixture of tetrahydrofuran and water; the reaction conditions are: first reacting at 20-30°C for 1 hour, and then reacting at 80°C for 1 hour; In step (3), the molar ratio of the intermediate D, compound E, alkylating agent and reducing agent is 1:6:5:9; the solvent of the reaction is methanol; and the reaction conditions are: first react at 55°C for 3 hours and then react at 20-30°C for 30 minutes.

7. The method according to claim 5, characterized in that After the reaction of step (1) is completed, the following purification step is further included: diluting the reaction solution with ethyl acetate; washing the organic phase with water and a 10% LiCl aqueous solution, drying, filtering, and concentrating to obtain intermediate C; In step (2), the reaction is added in the following manner: intermediate C, azidation reagent and base are added to tetrahydrofuran, reacted at 20-30°C for 1 hour, water is added, and then reacted at 80°C for 1 hour; In step (3), the reaction is added in the following manner: intermediate D, compound E and alkylating agent are added to methanol, reacted at 55°C for 3 hours, and then reacted at 20-30°C for 30 minutes after adding the reducing agent; After the reaction of step (3) is completed, the following purification step is further included: adjusting the pH value to 7 with concentrated hydrochloric acid, removing the solvent, extracting with ethyl acetate, aqueous hydrochloric acid solution, and aqueous potassium hydroxide solution, drying, and concentrating to obtain a ketone derivative.

8. Use of the ketone derivative according to any one of claims 1 to 3, its stereoisomerism, and its pharmaceutically acceptable salt in the preparation of analgesics.

9. The use according to claim 8, characterized in that The analgesic drug is a non-addictive analgesic drug, and the non-addictive analgesic drug includes a chronic neuropathic pain drug and a chronic inflammatory pain drug.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition is a preparation prepared by using the ketone derivative, its stereoisomer, or its pharmaceutically acceptable salt as an active ingredient and adding pharmaceutically acceptable excipients.

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