Gamma-aminobutyric acid derivative containing polycyclic structure as well as preparation method and application thereof

Abstract

The invention relates to the field of medicines. Specifically, the invention relates to a voltage-gated calcium channel alpha2delta subunit ligand containing a polycyclic gamma-aminobutyric acid structure as shown in a general formula I, a preparation method of the voltage-gated calcium channel alpha2delta subunit ligand and application of the voltage-gated calcium channel alpha2delta subunit ligand to treatment of chronic neuropathic pain, epilepsy and anxiety. # imgabs0 #

Description

Gamma-aminobutyric acid derivatives containing polycyclic structures, preparation methods and uses thereof Technical Field

[0001] The present application belongs to the field of medicine. Specifically, the present application relates to a class of voltage-gated calcium channel α2δ subunit ligands containing a polycyclic γ-aminobutyric acid structure, a preparation method thereof, a pharmaceutical composition containing the same, and its use in medicine. Background Art

[0002] Chronic neuropathic pain (CNP) is pain caused by nerve damage due to various causes, such as long-term diabetes, certain viral infections, cancer, central nervous system damage, and the use of certain chemotherapy drugs. Diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) are the two most common types of chronic neuropathic pain. Untreated or poorly treated chronic neuropathic pain can cause significant physical pain and negatively impact patients' moods, leading to psychological problems such as insomnia, anxiety, and depression. This can significantly reduce patients' quality of life and place a heavy burden on their families and society.

[0003] The main medications currently used to treat chronic neuropathic pain include antidepressants, anticonvulsants (antiepileptics), and analgesics. Antidepressants used to treat chronic neuropathic pain can be broadly divided into tricyclic antidepressants and other antidepressants. Tricyclic antidepressants include amitriptyline, maprotiline, clomipramine, doxepin, etc. Tricyclic antidepressants are associated with numerous side effects, including anticholinergic effects (dry mouth, constipation, blurred vision, drowsiness, weight gain), central nervous system toxicity (difficulty concentrating, seizures, social behavior disturbances, hallucinations), and cardiovascular toxicity (hypotension, tachycardia, arrhythmias). The combined use of these drugs carries numerous precautions, and drug interactions are complex. Other antidepressants are mostly selective serotonin and / or norepinephrine reuptake inhibitors, such as imipramine, paroxetine, fluoxetine, escitalopram, duloxetine, bupropion, venlafaxine, and sertraline. The combined use of antidepressants also carries numerous precautions and complex drug interactions, posing significant challenges to clinical use and patient compliance. Antiepileptic drugs used to treat chronic neuropathic pain primarily involve sodium and calcium channel blockers, such as gabapentin, pregabalin, lamotrigine, topiramate, carbamazepine, oxcarbazepine, and sodium valproate. Gabapentin requires a very high dose, requiring a daily dose of 1800-3600 mg to achieve optimal results. High doses experience absorption saturation and a slow onset of action (onset of action may take two weeks after oral administration). Sodium channel blockers, such as lamotrigine and topiramate, are associated with numerous adverse reactions, such as rash, nausea and vomiting, dizziness, fatigue, and blurred vision. Furthermore, combined use requires numerous precautions and complex drug interactions. Analgesics used to treat chronic neuropathic pain include opioids, tramadol, and tapentadol, the latter two of which have a significant mechanism of action similar to that of opioids. Opioids have a certain effect on nerve pain, but the effect is not strong, they have many side effects, and they are addictive.Studies have shown that when duloxetine 60 mg / day and 120 mg / day are used to treat diabetic peripheral neuropathy, the clinical efficacy is only 49% and 52%, respectively (Goldstein, DJ; et al. Pain, 2005, 116(1-2), 109-118.); when gabapentin is used at daily doses of up to 1800 mg / day, 2400 mg / day and 3600 mg / day, the clinical efficacy for postherpetic neuralgia is 32%, 34% and 43%, respectively (Rice, ASC; et al. Pain, 2001, 94(2), 215-224; Rowbotham, M.; et al. al.JAMA, 1998, 280(21), 1837-1842.); the clinical efficacy of pregabalin at 150-600 mg per day for postherpetic neuralgia is 26%-50% (Dworkin, RH; et al. Neurology, 2003, 60(8), 1274-1283; Sabatowski, R.; et al. Pain, 2004, 109(1-2), 26-35.). These very low clinical efficacy data reflect the dilemma of the current marketed drugs in terms of therapeutic effect: there is currently no specific drug for this type of disease, and there is no simple treatment plan that can prevent or reverse neurological lesions or completely relieve pain.

[0004] The voltage-gated calcium channel α2δ subunit is an important target for drugs treating this disease. Pregabalin, one of the four drugs approved by the US FDA for diabetic peripheral neuropathy (pregabalin, duloxetine, fluoxetine, and tapentadol), acts on this target (Field, MJ; et al. Proc. Natl. Acad. Sci. USA 2006, 103, 17537-17542). Ligands for the voltage-gated calcium channel α2δ subunit, such as gabapentin, pregabalin, and mirogabalin, are not only used to treat chronic neuropathic pain but also for anti-epileptic (pregabalin, US FDA-approved indication) and anxiolytic (pregabalin, European EMA-approved indication).

[0005] The present application discloses a γ-aminobutyric acid derivative containing a polycyclic structure. 3 The binding of [H] gabapentin has a strong inhibitory effect on the α2δ subunit of the human voltage-gated calcium channel and can be used to prepare therapeutic drugs for chronic neuropathic pain, epilepsy and anxiety.

[0006] Summary of the Invention

[0007] One object of the present application is to provide a voltage-gated calcium ion channel α2δ subunit ligand having a general formula I, its chiral isomers and pharmaceutically acceptable salts thereof.

[0008] Another object of the present application is to provide a method for preparing the voltage-gated calcium ion channel α2δ subunit ligand having the general formula I, its chiral isomers and pharmaceutically acceptable salts.

[0009] Another object of the present application is to provide the use of the compound of the above-mentioned general formula I, its chiral isomers and pharmaceutically acceptable salts thereof in the treatment of chronic neuropathic pain, epilepsy and anxiety.

[0010] Another object of the present application is to provide a pharmaceutical composition comprising a compound of formula I, its chiral isomers and pharmaceutically acceptable salts thereof as active ingredients, and one or more pharmaceutically acceptable carriers, excipients, diluents or a combination thereof.

[0011] Another object of the present application is to provide the use of the above-mentioned pharmaceutical composition in treating chronic neuralgia, epilepsy and anxiety.

[0012] The contents of this application are now described in detail in conjunction with the purpose of this application.

[0013] The compound of the present invention having the general formula I has the following structural formula:

[0014] in,

[0015] R 1 and R 2 Independently selected from H, halogen and C1-C6 alkyl;

[0016] Each R 3 、R 4 、R 5 、R 6 independently selected from H, halogen, C1-C6 alkyl and C1-C6 alkoxy; or R 3 、R 4 and the C atoms they are connected to form a C3-C6 cycloalkyl group, or R 5 、R 6 and the C atoms they are connected to together form a C3-C6 cycloalkyl group;

[0017] Each R 7 、R 8 、R 9 、R 10 Independently selected from H, halogen and C1-C6 alkyl;

[0018] The chemical bonds between atoms can be single or double; when it represents a double bond, R7 and R 9 Indicates non-existence;

[0019] m and n are independently selected from 0, 1, 2, 3;

[0020] Or, when n>=1, R 8 The connected C atom and R 10 The adjacent C atoms can be connected to R 8 、R 10 Together they form a C3-C6 cycloalkyl group;

[0021] When n>=1, R 8 Connected C atoms and R 10 The solid and dashed lines connecting the adjacent C atoms represent R 8 Connected C atoms and R 10 The chemical bond between the connected C atoms can be a single bond or a double bond; when it represents a double bond, the corresponding R 7 and R 9 Indicates that it does not exist.

[0022] According to the present application, the following compounds having the general formula I, chiral isomers thereof or pharmaceutically acceptable salts thereof are preferred, wherein:

[0023] R 1 and R 2 independently selected from H and C1-C3 alkyl;

[0024] R 3 、R 4 independently selected from H, halogen and C1-C3 alkyl; or R 3 、R 4 Together with the C atom to which they are commonly attached, they form a cyclopropyl group;

[0025] R 7 、R 8 、R 9 、R 10 independently selected from H and C1-C6 alkyl; or R 8 The connected C atom and R 10 The C atom connected to R 8 、R 10 Composition of cyclopropyl;

[0026] R 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8 Connected C atoms and R 10 The chemical bond between the connected C atoms can be a single bond or a double bond; when it represents a double bond, R 7 and R 9Indicates non-existence;

[0027] m=0; n=1.

[0028] According to the present application, more preferred are the following compounds having the general formula I, their chiral isomers or pharmaceutically acceptable salts thereof, wherein:

[0029] R 1 and R 2 independently selected from H or methyl;

[0030] R 3 、R 4 are independently selected from H and methyl; or R 3 、R 4 Together with the C atom to which they are commonly attached, they form a cyclopropyl group;

[0031] R 7 、R 8 、R 9 、R 10 are independently selected from H or methyl; or R 8 The connected C atom and R 10 The C atom connected to R 8 、R 10 Composition of cyclopropyl;

[0032] R 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8 Connected C atoms and R 10 The chemical bond between the connected C atoms can be a single bond or a double bond; when it represents a double bond, R 7 and R 9 Indicates non-existence;

[0033] m=0; n=1.

[0034] According to the present application, more preferred are the following compounds having the general formula I, their chiral isomers or pharmaceutically acceptable salts thereof, wherein:

[0035] R 1 and R 2 independently selected from H or methyl;

[0036] R 3 、R 4 Together with the C atom to which they are commonly attached, they form a cyclopropyl group;

[0037] R 7 、R 8 、R 9 、R 10 independently selected from H or methyl;

[0038] m=0; n=1.

[0039] According to the present application, more preferred are the following compounds having the general formula I, their chiral isomers or pharmaceutically acceptable salts thereof, wherein:

[0040] R 1 and R 2 independently selected from H or methyl;

[0041] R 3 、R 4 independently selected from H and methyl;

[0042] R 7 、R 9 R is independently selected from H or methyl; 8 The connected C atom and R 10 The C atom connected to R 8 、R 10 Composition of cyclopropyl;

[0043] m=0; n=1.

[0044] According to the present application, more preferred are the following compounds having the general formula I, their chiral isomers or pharmaceutically acceptable salts thereof, wherein:

[0045] R 1 and R 2 independently selected from H or methyl;

[0046] R 3 、R 4 independently selected from H and methyl;

[0047] R 7 、R 9 R is independently selected from H or methyl; 8 The connected C atom and R 10 The C atom connected to R 8 、R 10 Composition of cyclopropyl;

[0048] m=0; n=1.

[0049] According to the present application, the following compounds are more preferred,

[0050] The compounds of the general formula I described in the present application can be synthesized by the following method:

[0051] In a typical case, ketone K undergoes Wittig condensation reaction with phosphoacetic acid ester W1 in the presence of a base to obtain α,β-unsaturated acetate L-1, wherein the base is selected from an inorganic base and an organic base, wherein R 11 and R 12 An alkyl group selected from C1 to C6; R 1 ~R10 , m and n have the definitions given above; L-1 is a mixture of two cis and trans geometric configurations.

[0052] When R in L-1 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8 Connected C atoms and R 10 When the chemical bond between the connected C atoms is a double bond, L-1 is L-1-1. In this case, L-1-1 can be converted to L-1-2 using Simmons-Smith reaction or similar reaction. In this case, R in L-1-2 is 8 The connected C atom and R 10 The C atom connected to R 8 、R 10 The Simmons-Smith reaction or similar reaction comprises treating a substrate containing a C=C double bond with CH2I2 / Et2Zn, CH2I2 / Et2Zn / trifluoroacetic acid or CH2I2 / Cu-Zn to give a cyclopropyl product.

[0053] L-1 undergoes Michael addition reaction with nitromethane in the presence of a base to obtain M-1. The newly generated chiral center in M-1 is affected by the chiral center derived from K. In order to distinguish it from the configuration of the chiral center at the corresponding position generated by other methods described below, the configuration of the newly generated chiral center in M-1 is marked as R* here. The base is selected from various inorganic bases and organic bases.

[0054] For M-1, there are three situations:

[0055] M-1-1: R 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8 Connected C atoms and R 10 The chemical bonds between the connected C atoms are double bonds;

[0056] M-1-2: R 8 The connected C atom and R 10 The C atom connected to R 8 -R 10 Composition of cyclopropyl;

[0057] M-1-3: R 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8Connected C atoms and R 10 The chemical bonds between the connected C atoms are single bonds.

[0058] For M-1-1: M-1-1 is hydrolyzed with an acid or base to obtain N-1-1, and N-1-1 is simultaneously reduced to the nitro group and the C=C double bond by catalytic hydrogenation to obtain (R*)-I-1-3, (R*)-I-1-3 is a specific form of the compound having the general formula I described in the present application, and (R*)-I-1-3 reacts with an acid HA to obtain the corresponding salt (R*)-I-1-3·HA, wherein the acid HA is selected from various inorganic acids and organic acids. M-1-1 is first reduced with iron powder to obtain P-1-1, and P-1-1 is hydrolyzed with an acid to obtain (R*)-I-1-1, (R*)-I-1-1 is a specific form of the compound having the general formula I described in the present application, and (R*)-I-1-1 reacts with an acid HA to obtain the corresponding salt (R*)-I-1-1·HA, wherein the acid HA is selected from various inorganic acids and organic acids.

[0059] For M-1-2: M-1-2 is hydrolyzed with an acid or base to obtain N-1-2. N-1-2 is reduced to the nitro group using catalytic hydrogenation to obtain (R*)-I-1-2. (R*)-I-1-2 is a specific form of the compound having the general formula I described herein. (R*)-I-1-2 reacts with an acid HA to obtain the corresponding salt (R*)-I-1-2·HA. The acid HA is selected from various inorganic acids and organic acids. M-1-2 is first reduced to the nitro group using iron powder to obtain P-1-2. P-1-2 is also hydrolyzed with an acid to obtain (R*)-I-1-2. (R*)-I-1-2 is a specific form of the compound having the general formula I described herein.

[0060] (R*)-I-1-2 reacts with an acid HA to obtain the corresponding salt (R*)-I-1-2·HA, wherein the acid HA is selected from various inorganic acids and organic acids.

[0061] For M-1-3: The ester bond in M-1-3 is hydrolyzed using an acid or base to obtain N-1-3. The nitro group in N-1-3 is reduced using catalytic hydrogenation to obtain (R*)-I-1-3. (R*)-I-1-3 is a specific form of the compound having the general formula I described in the present application. (R*)-I-1-3 reacts with an acid HA to obtain the corresponding salt (R*)-I-1-3·HA. The acid HA is selected from various inorganic acids and organic acids. M-1-3 is first reduced with iron powder to obtain P-1-3. The ester bond in P-1-3 is also hydrolyzed using an acid to obtain (R*)-I-1-3. (R*)-I-1-3 is a specific form of the compound having the general formula I described in the present application. (R*)-I-1-3 reacts with an acid HA to obtain the corresponding salt (R*)-I-1-3·HA. The acid HA is selected from various inorganic acids and organic acids.

[0062] In another typical case, ketone K undergoes a Knoevenagel condensation reaction with nitromethane in the presence of a catalyst selected from various inorganic and organic bases to give an α,β-unsaturated nitro compound L-2. L-2 is a mixture of two cis and trans geometric configurations.

[0063] L-2 reacts with acetate W2 in the presence of a strong base to undergo a Michael-like addition reaction to obtain M-2. The newly generated chiral center in M-2 is affected by the chiral center originating from K. In order to distinguish it from the configuration of the chiral center at the corresponding position generated in the above reaction of L-1 to generate M-1, the configuration of the newly generated chiral center in M-2 is marked as S*. The strong base is selected from tert-butyl lithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. The R 13 An alkyl group selected from C1 to C6, wherein S* and R* represent that the configurations of the marked chiral centers are opposite.

[0064] For M-2, there are three situations:

[0065] M-2-1: R 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8 Connected C atoms and R 10 The chemical bonds between the connected C atoms are double bonds;

[0066] M-2-2: R 8 The connected C atom and R 10 The C atom connected to R 8 -R 10 Composition of cyclopropyl;

[0067] M-2-3: R 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8 Connected C atoms and R 10 The chemical bonds between the connected C atoms are single bonds.

[0068] For M-2-1: M-2-1 is hydrolyzed with an acid or base to obtain N-2-1. N-2-1 is simultaneously reduced to the nitro group and the C=C double bond using catalytic hydrogenation to obtain (S*)-I-2-3. (S*)-I-2-3 is a specific form of the compound having the general formula I described in the present application. (S*)-I-2-3 reacts with an acid HA to obtain the corresponding salt (S*)-I-2-3·HA. The acid HA is selected from various inorganic acids and organic acids. M-2-1 is first reduced to the nitro group using iron powder to obtain P-2-1. P-2-1 is hydrolyzed to obtain (S*)-I-2-1. (S*)-I-2-1 is a specific form of the compound having the general formula I described in the present application. (S*)-I-2-1 reacts with an acid HA to obtain the corresponding salt (S*)-I-2-1·HA. The acid HA is selected from various inorganic acids and organic acids.

[0069] Regarding M-2-2: The ester bond in M-2-2 is hydrolyzed using an acid or base to obtain N-2-2. The nitro group in N-2-2 is reduced using catalytic hydrogenation to obtain (S*)-I-2-2. (R*)-I-2-2 is a specific form of the compound having the general formula I described herein. (S*)-I-2-2 reacts with an acid HA to obtain the corresponding salt (S*)-I-2-2·HA. The acid HA is selected from various inorganic acids and organic acids. The nitro group in M-2-2 is first reduced using iron powder to obtain P-2-2. The ester bond in P-2-2 is also hydrolyzed using an acid to obtain (S*)-I-2-2. (S*)-I-2-2 is a specific form of the compound having the general formula I described herein. (S*)-I-2-2 reacts with an acid HA to obtain the corresponding salt (S*)-I-2-2·HA. The acid HA is selected from various inorganic acids and organic acids.

[0070] For M-2-3: The ester bond in M-2-3 is hydrolyzed using an acid or base to obtain N-2-3. The nitro group of N-2-3 is simultaneously reduced using catalytic hydrogenation to obtain (S*)-I-2-3. (S*)-I-2-3 is a specific form of the compound having the general formula I described herein. (S*)-I-2-3 reacts with an acid HA to obtain the corresponding salt (S*)-I-2-3·HA. The acid HA is selected from various inorganic acids and organic acids. M-2-3 is first reduced with iron powder to obtain P-2-3. The ester bond of P-2-3 is also hydrolyzed using an acid to obtain (S*)-I-2-3. (S*)-I-2-3 is a specific form of the compound having the general formula I described herein. (S*)-I-2-3 reacts with an acid HA to obtain the corresponding salt (S*)-I-2-3·HA. The acid HA is selected from various inorganic acids and organic acids.

[0071] In order to prepare optically pure final product I, a racemic intermediate consisting of a pair of enantiomers having the same relative configuration can be used for resolution.

[0072] In a typical example, a racemic intermediate (±)-N-acid, a pair of enantiomers with the same relative configuration in the above synthetic route, is subjected to salt separation using appropriate chiral bases A and B in a suitable solvent, respectively, to obtain precipitated salts (+)-N-acid·chiral base A and (-)-N-acid·chiral base B of sufficient optical purity. Both salts are then treated with dilute hydrochloric acid to remove chiral base A and chiral base B, respectively, to obtain (+)-N-acid and (-)-N-acid. The nitro group of (+)-N-acid and (-)-N-acid is reduced using catalytic hydrogenation to obtain optically pure products (+)-IA and (+)-IA. (+)-IA and (+)-IA are each a specific form of the compound of formula I described herein. (+)-IA and (-)-IA react with acid HA to obtain the corresponding salts (+)-IA·HA and (-)-IA·HA, respectively. The acid HA is selected from various inorganic acids and organic acids.

[0073] In another typical example, a racemic intermediate (±)-P-NH2, which is a pair of enantiomers with the same relative configuration in the above synthetic route, is subjected to salt separation using appropriate chiral acid-A and chiral acid-B in a suitable solvent to obtain precipitated salts (+)-P-NH2·chiral acid-A and (-)-P-NH2·chiral acid-B of sufficient optical purity. Both salts are treated with aqueous sodium bicarbonate to remove chiral acid-A and chiral acid-B, respectively, to obtain (+)-P-NH2 and (-)-P-NH2. (+)-P-NH2 and (-)-P-NH2 are hydrolyzed with acid to obtain the optically pure products (+)-I-A1 and (-)-I-A1. (+)-I-A1 and (+)-I-A1 are each a specific form of the compound of formula I described herein. (+)-I-A1 and (-)-I-A1 react with acid HA to obtain the corresponding salts (+)-I-A1·HA and (-)-I-A1·HA, respectively. The acid HA is selected from various inorganic acids and organic acids.

[0074] In a typical example, K-1 can be synthesized according to the following method. K-1 is a specific form of the compound having the general formula K. Compound CDE undergoes a Diels-Alder reaction with compound Q-1 to obtain compound R, wherein Z is selected from NH, O and S, and R 14 Selected from H and C1-C6 alkyl, or -ZR 14 -R 14 Z-=O, in this case, compound Q-1 is maleic anhydride. Compound R reacts with alcohol R under acid catalysis. 15 OH reacts to give compound S, R 15 An alkyl group selected from C1 to C6. Compound S is reacted with sodium metal and trimethylsilyl chloride in a refluxing inert solvent (hydroxyketone condensation reaction), and the resulting product is hydrolyzed with acid to produce compound T. Compound T is treated with PPh3 in refluxing CX4 to produce compound U-1, wherein X is selected from Cl, Br, and I. Compound U-1 is treated with Zn powder in an acidic medium to produce compound K-1.

[0075] In another typical example, K-1 can be synthesized according to the following method: Compound CDE and compound Q-2 undergo Diels-Alder reaction to obtain compound K-1.

[0076] Compound ALE reacts with dichloroethenone to produce compound U-2. Dichloroethenone can be prepared by reacting trichloroacetyl chloride with activated zinc powder or dichloroacetyl chloride with triethylamine. U-2 is treated with zinc powder in an acidic medium to produce compound K-2, a specific form of the compound of formula K.

[0077] Compound K-1 is reduced by catalytic hydrogenation to yield compound K-3. K-1 is converted to K-4 using the Simmons-Smith reaction. The Simmons-Smith reaction and similar reactions involve treating a substrate containing a C=C double bond with CH2I2 / Et2Zn, CH2I2 / Et2Zn / trifluoroacetic acid, or CH2I2 / Cu-Zn to yield a cyclopropyl product. K-3 and K-4 are each a specific form of the compound of formula K.

[0078] The "halogen" mentioned herein refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0079] The "alkyl" mentioned in this application refers to a group derived from a branched or straight chain saturated aliphatic alkane with a specified number of carbon atoms by removing one hydrogen. For example, "C 1-6 “Alkyl” refers to C1, C2, C3, C4, C5, and C6 alkyl groups; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, and 1,1-dimethylbutyl.

[0080] The "alkoxy" mentioned in this application refers to an alkyl group defined herein connected to another group through an oxygen atom, i.e. "alkyl-O-". 1-6 Alkoxy" (structure is C 1-6 Alkyl-O-), "C 1-4 "alkoxy", specific examples include but are not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" described in this application is C 1-4 Alkoxy, more preferably C 1-3 Alkoxy.

[0081] As used herein, a "cycloalkyl" refers to a saturated cyclic alkyl group derived from a cycloalkane by removing a hydrogen atom. Examples of cycloalkyl groups include "3-6 membered cycloalkyl" and "3-5 membered cycloalkyl." Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0082] Pharmaceutically acceptable salts of the compounds of Formula I described herein include, but are not limited to, pharmaceutically acceptable salts formed by the compounds of Formula I and various inorganic bases, such as NaOH, KOH, Mg(OH)2, Ca(OH)2, Sr(OH)2, Al(OH)3, etc., or inorganic carbonates, such as Na2CO3, K2CO3, MgCO3, CaCO3, SrCO3, etc., or organic bases, such as amino acids, or inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, etc., or organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, malic acid, citric acid, etc.

[0083] The compounds of Formula I described herein can be formulated with one or more pharmaceutically acceptable excipients to form pharmaceutical compositions. These pharmaceutical compositions can be formulated into solid oral preparations, liquid oral preparations, injections, and other dosage forms. These solid and liquid oral preparations include tablets, dispersible tablets, sugar-coated tablets, granules, dry powders, capsules, and solutions. Injections include small injections, large infusions, water for injection, and freeze-dried powder for injection.

[0084] The compounds of the present application exist in chiral isomers, such as enantiomers, diastereomers, racemic mixtures and other mixtures, all of which fall within the scope of the present application.

[0085] The term "enantiomer" refers to stereoisomers that are mirror images of one another.

[0086] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0087] (±) indicates that a compound is a racemic mixture. In this case, the configuration in the chemical structure of the compound is relative. (+) or (-) indicates that a compound is optically pure. The optical rotation sign indicates right-handed or left-handed respectively. In this case, the configuration in the chemical structure of the compound is absolute.

[0088] Chiral isomers of the compounds of the present application can be prepared by the chiral synthesis or chiral reagents described above, or other conventional techniques. The separation of optically pure compounds in the present application is typically accomplished using chiral resolution, employing an optically pure chiral acid to form a salt with a racemic base, followed by crystallization in a suitable solvent to obtain a salt of the optically pure base and chiral acid, thereby achieving the purpose of separating the chiral compound.

[0089] The term "optically pure" means that the content of the isomer or enantiomer is greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0090] The absolute stereo configuration of a compound can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction, or by the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis.

[0091] According to the composition of the present application, the pharmaceutically or food-related acceptable excipients are selected from the group consisting of: carriers, excipients, diluents, adhesives, fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, and coating materials.

[0092] According to the compositions of the present application, the excipient is a substance that is non-toxic, compatible with the active ingredient, and otherwise biologically suitable for use in an organism. The choice of a particular excipient will depend on the mode of administration or the type and condition of disease to be treated for a particular patient. Examples of the excipient include, but are not limited to, conventional solvents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, antioxidants, and the like, which are conventional in the pharmaceutical field. The filler includes one or a combination of lactose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; the binder includes one or a combination of sucrose, povidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyethylene glycol, ethanol, and water; the disintegrant includes one or a combination of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and an effervescent disintegrant.

[0093] The compound of formula I described in the present application has a binding effect on voltage-gated calcium ion channel α2δ and can be used as an active ingredient in the preparation of a drug for treating chronic neuropathic pain, epilepsy and anxiety. The activity of the compound of formula I described in the present application is demonstrated in vitro by inhibiting the human recombinant calcium ion channel Ca expressed in CHO cells. v 2.2 / β3 / α2δ-1 receptor and [ 3 H]gabapentin, and its analgesic effect in animal chronic pain models and antiepileptic effect in animal epilepsy models were verified at the in vivo level.

[0094] The compounds of Formula I of the present application are effective over a wide dosage range. For example, a daily dosage range is approximately 1 mg to 3000 mg per person, administered once or several times. The actual dosage of the compounds of Formula I of the present application can be determined by the physician based on the patient's specific needs. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] The present application is further described below with reference to the accompanying drawings, in which:

[0096] FIG1 is the chemical structure of compound (+)-32-LAC by single crystal diffraction (ORTEP diagram);

[0097] FIG2 is the chemical structure of compound (+)-22-LAC by single crystal diffraction (ORTEP diagram);

[0098] FIG3A is a graph showing the mechanical pain threshold time course of the efficacy evaluation results of compounds (±)-I-7, (±)-I-3, and (±)-I-4 in a rat sciatic nerve branch injury model; FIG3B is a graph showing the area under the mechanical pain threshold-time curve of the efficacy evaluation results of compounds (±)-I-7, (±)-I-3, and (±)-I-4 in a rat sciatic nerve branch injury model;

[0099] Figure 4A is a graph showing the mechanical pain threshold time course of the efficacy evaluation of compounds (-)-I-3, (+)-I-3, (-)-I-4, and (+)-I-4 in a rat sciatic nerve branch injury model; Figure 4B is a graph showing the area under the mechanical pain threshold-time curve of the efficacy evaluation of compounds (-)-I-3, (+)-I-3, (-)-I-4, and (+)-I-4 in a rat sciatic nerve branch injury model;

[0100] Figure 5 shows the half effective dose (ED) of the compound for protecting animals in the maximum electric shock model in mice 50 ) The fitted curve of the dose-protection rate curve was calculated using the least squares method (Graphpad Prism 5);

[0101] Figure 6 shows the anti-epileptic effects of compounds (+)-I-3 and (+)-I-4 in a mouse epilepsy model (maximal electroshock model (MES));

[0102] FIG7 is a graph showing the effects of compound (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate on the motor function of animals as measured by rotarod test. DETAILED DESCRIPTION

[0103] The present invention is further described in detail below by means of specific examples. It should be noted that the following examples are intended to illustrate, but not to limit, the present invention. Various modifications made by those skilled in the art based on the teachings of the present invention should fall within the scope of protection required by the claims of the present invention.

[0104] Melting points were measured using an SGW X-4A micromelting point apparatus (Shanghai Yidian Physical Optical Instrument Co., Ltd., Shanghai, China), and the thermometer was uncalibrated. 1 H NMR and 13 C NMR was performed on a Bruker Ascend 500 NMR spectrometer (Bruker Swiss AG, Switzerland) detection, using CDCl3, DMSO-d6, CD3OD or D2O as solvent, TMS (for 1 H NMR) or deuterated solvents (for 13 C NMR (carbon) signals with known chemical shifts were used as internal standards. High-resolution mass spectrometry was performed using electrospray ionization (ESI) on a Thermo Q Exactive Plus mass spectrometer (Thermo Fisher Scientific, Bremen, Germany). Optical rotations were determined using an Anton Paar MCP4100 polarimeter.

[0105] Enantiomeric excess (%ee) determination method (chiral HPLC method): Daicel Chiralpak AS-RH 4.6 mm × 250 mm chromatographic column (5 μm) was used on an Agilent 1260 Infinity II liquid chromatograph with a detector wavelength of 220 nm. The mobile phase was acetonitrile / 0.1% KH2PO4-KOH buffer solution (pH = 7.0) = 70 / 30, with a flow rate of 1 mL / min. The injected sample concentration was 0.5 mg / mL and the injection volume was 3 μL.

[0106] Single crystal diffraction determination method: Rigaku XtaLAB Pro single crystal diffractometer, diffraction with Cu Kα rays at 100.00 (10) K, using CrysAlisPro 1.171.39.33c (Rigaku OD, 2017) to collect diffraction data and perform data reduction, and the SHELXL program was used for structure analysis and refinement.

[0107] Drying solvents were prepared from the corresponding analytical grade solvents using standard drying methods.

[0108] Example 1 Synthesis of Compound (±)-I-1

[0109] Step 1: Synthesis of compound (±)-3

[0110] Prepare activated zinc powder as follows: Add dry CuSO₄ (40.00 g, 0.25 mol) to water (1 L) and stir until dissolved. Add zinc powder (600.00 g, 9.17 mol), stir at room temperature for 3-4 hours, and filter. Wash the filter cake with water (300 mL x 2) and acetone (750 mL x 2), followed by drying in a vacuum oven at 50°C (approximately 10 mmHg) for 24-48 hours.

[0111] Under N₂ atmosphere and an ice-water bath, compound 2 (14.00 g, 0.15 mol) and activated zinc powder (14.00 g, 0.21 mol) were added sequentially to dry tetrahydrofuran (140 mL) with stirring. A solution of trichloroacetyl chloride (12.00 g, 66 mmol) in dry tetrahydrofuran (20 mL) was added dropwise. During the addition, the system exothermed; the reaction temperature was maintained at 35°C-40°C by controlling the addition rate. After the addition was complete, the reaction system was maintained at 35°C and stirred overnight. TLC monitoring indicated the reaction was complete, and the reaction solution was cooled to room temperature. Filtering was performed with celite, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield a brown oil. The target product (±)-3 was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 9 / 91) to yield 6.00 g of a pale yellow oil. This product was used directly in the next step without further characterization.

[0112] Step 2: Synthesis of compound (±)-4

[0113] Zinc powder (12.00 g, 0.18 mol) and glacial acetic acid (65 mL) were mixed and stirred. A freshly prepared solution of compound (±)-3 (6.00 g, 29 mmol) in glacial acetic acid (12 mL) was then added dropwise under an ice-water bath. After the addition was complete, the reaction mixture was stirred in an oil bath at 55°C for 2 h under a nitrogen atmosphere. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was poured into ice water (350 mL) and extracted with CH2Cl2 (200 mL x 2). The combined organic phases were washed with water (300 mL x 3), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a brown oil, which was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9) to afford the desired product (±)-4. Pale yellow oil; 3.00 g (combined yield of 2→(±)-4: 15%);

[0114] 1H NMR (CDCl3, 500MHz) δ: 3.08-3.10 (m, 1H), 3.03 (ddd, 1H, J = 3.8Hz, 8.8Hz and 18.5Hz), 2.53 (dt, 1H, J = 3.5Hz and 18.5Hz),2.43-2.45(m,1H),2.39-2.41(m,1H),2.25-2.28(m,1H),1.58-1.65(m,1H),1.53 -1.56(m,1H),1.46-1.53(m,1H),1.24-1.27(m,1H),1.18-1.24(m,1H),1.10-1.13(m,1H).

[0115] 13 C NMR (CDCl3, 126MHz) δ: 213.08, 68.21, 50.44, 39.70, 37.41, 32.62, 31.38, 28.46, 26.87.

[0116] Step 3: Synthesis of compound (±)-5

[0117] Under N₂ atmosphere, potassium tert-butoxide (t-BuOK) (3.8 g, 34 mmol) was added to dry THF (25 mL). After stirring in an ice-water bath to form a suspension, tert-butyl diethylphosphonoacetate (7.00 g, 28 mmol) was added dropwise. After the addition was complete, the mixture was reacted in an ice-water bath for 40 min. A freshly prepared solution of compound (±)-4 (3.00 g, 22 mmol) in dry THF (10 mL) was then added dropwise. After the addition was complete, the mixture was reacted at room temperature for 2 h. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (200 mL) and extracted with EtOAc (120 mL x 2). The combined organic phases were dried (MgSO₄), filtered to remove the desiccant, and concentrated under reduced pressure on a rotary evaporator to yield a dark yellow oil. The product was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9) to obtain the desired product (±)-5. Pale yellow oil; 3.70 g; the product does not require characterization and is used directly in the next reaction.

[0118] Step 4: Synthesis of compound (±)-6

[0119] At room temperature, (±)-5 (3.70 g, 16 mmol) was dissolved in CH3NO2 (22 mL) and stirred, followed by the dropwise addition of 1,8-diazabicycloundec-7-ene (DBU) (4.80 g, 32 mmol). After the addition was complete, the reaction mixture was stirred in an oil bath at 65°C overnight under a nitrogen atmosphere. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and poured into water (200 mL). The mixture was extracted with CH2Cl2 (150 mL x 2). The combined organic phases were dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure on a rotary evaporator to afford a brown-black oil. The target product (±)-6 was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9) to afford 3.80 g of a pale yellow oil (combined yield of (±)-4 → (±)-6: 58%).

[0120] 1 H NMR (CDCl3, 500MHz) δ: 4.74 (dd, 1H, J = 1.0Hz and 11.5Hz), 4.68 (d, 1H, J = 11.5Hz), 2.57 (d, 1H, J = 17.0Hz), 2.52 (d, 1H, J = 17.0Hz), 2. 31-2.35(m,1H),2.12-2.13(m,1H),2.03-2.05(m,2H),1.99(ddd,1H,J=2.0Hz,9.0Hz and 14.0Hz),1.87-1.90(m,1H),1.57-1.61(m,1H),1.45-1.50(m,11H),1.29-1.32(m,1H),1.02-1.06(m,2H).

[0121] 13 C NMR (CDCl3, 126MHz) δ: 170.83, 82.52, 81.10, 48.40, 39.78, 37.97, 37.43, 36.35, 35.03, 34.25, 32.03, 28.88, 28.23, 27.52.

[0122] ESI-HRMS: (m / z) calcd. for C 16 H 26 NO4([M+H] + )296.1856,found:296.1852.

[0123] Step 5: Synthesis of compound (±)-7

[0124] Compound (±)-6 (1.70 g, 5.8 mmol) was dissolved in CH2Cl2 (18 mL) and trifluoroacetic acid (TFA) (10 mL) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred at room temperature until TLC monitoring showed that the reaction was complete (usually within 2-4 hours). The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→17 / 33] to obtain a light yellow oil. n-Hexane (1 mL) was added to the oil and ultrasonically crushed to precipitate a solid. After stirring at room temperature for 1 hour, the solid was filtered, collected, and dried to obtain the target product (±)-7. White solid; 1.00 g (72%); melting point 93.7°C-95.5°C;

[0125] 1 H NMR (CDCl3, 500MHz) δ: 4.76 (d, 1H, J = 12.0Hz), 4.71 (d, 1H, J = 12.0Hz), 2.77 (d, 1H, J = 18.0Hz), 2.72 (d, 1H,J=18.0Hz),2.34-2.38(m,1H),2.15-2.16(m,1H),2.03-2.07(m,2H),1.99(ddd,1H,J=2.0Hz,8.5Hz and14.0Hz),1.86-1.88(m,1H),1.62(dd,1H,J=6.0Hz and 14.0Hz),1.48-1.52(m,2H),1.32-1.34(m,1H),1.02-1.08(m,2H).

[0126] 13 C NMR (DMSO-d6, 126MHz) δ: 172.30, 82.18, 47.56, 38.90, 37.26, 36.77, 35.60, 33.76, 33.59, 31.27, 28.38, 27.06.

[0127] ESI-HRMS: (m / z) calcd. for C 12 H 18 NO4([M+H] + )240.1230,found:240.1227.

[0128] Step 6: Synthesis of compound (±)-I-1

[0129] (±)-7 (1.00 g, 4.2 mmol) was dissolved in CH3OH (10 mL) and 10% Pd(OH)2 / C (0.27 g) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature overnight. TLC monitoring showed that the reaction was complete (the reaction generally takes 12 h to complete). The reaction mixture was filtered through celite and the filtrate was concentrated on a rotary evaporator under reduced pressure to obtain an oily residue. EtOAc (10 mL) was added and stirred to precipitate a solid. The mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried to obtain the desired product (±)-I-1. White solid; 0.30 g (34%); melting point 180.2°C-184.0°C;

[0130] 1 H NMR (CD3OD, 500MHz) δ: 3.04 (s, 2H), 2.63 (d, 1H, J = 16.0Hz), 2.45 (d, 1H, J = 16.0Hz), 2.29-2.34 (m,1H),2.21-2.22(m,2H),2.01-2.06(m,2H),1.86-1.87(m,1H),1.79(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.49-1.55(m,3H),1.30-1.32(m,1H),1.03-1.07(m,2H).

[0131] 13 C NMR (CD3OD+D2O(1drop), 126MHz) δ: 180.68, 51.20, 49.46, 42.56, 39.00, 38.90, 37.88, 37.29, 34.69, 32.76, 29.48, 28.39.

[0132] ESI-HRMS: (m / z) calcd. for C 12 H 20 NO2([M+H] + )210.1489,found:210.1483.

[0133] Compound (±)-I-1 is a specific form of the compound of formula I of the present application.

[0134] Example 2 Synthesis of Compound (±)-I-2

[0135] Step 1: Synthesis of compound (±)-9

[0136] Under N₂ atmosphere and an ice-water bath, compound 8 (42.00 g, 0.46 mol) and activated zinc powder (42.00 g, 0.64 mol) were added sequentially to dry tetrahydrofuran (350 mL) with stirring. A solution of trichloroacetyl chloride (36.00 g, 0.20 mol) in dry tetrahydrofuran (150 mL) was added dropwise. The reaction system exothermed during the addition, maintaining the internal temperature at 32°C-38°C. After the addition was complete, the reaction system was stirred overnight while maintaining the internal temperature at 34.5°C. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated on a rotary evaporator under reduced pressure to obtain a residue, which was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23) to afford the desired product (±)-9. A pale yellow oil (10.54 g) was obtained. This product did not require characterization and was used directly in the next step.

[0137] Step 2: Synthesis of compound (±)-10

[0138] Zinc powder (21.00 g, 0.32 mol) and glacial acetic acid (120 mL) were stirred and then a freshly prepared solution of compound (±)-9 (10.54 g, 52 mmol) in glacial acetic acid (25 mL) was added dropwise under ice-water cooling. After the addition was complete, the reaction mixture was stirred overnight in an oil bath at 55°C under a nitrogen atmosphere. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (400 mL) and extracted with CH2Cl2 (300 mL). The organic phase was washed sequentially with water (400 mL × 3) and saturated NaHCO3 solution (400 mL) until the aqueous phase reached a pH > 7. The phase was then dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to yield a brown oil, which was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23) to afford the desired product (±)-10. Pale yellow oil; 2.73 g (combined yield of 8→(±)-10 4%);

[0139] 1 H NMR(CDCl3,500MHz)δ:6.29-6.31(m,1H),6.12-6.14(m,1H),3.05-3.08(m,2H),3.00-3.01(m,1H),2.84(ddd,1H,J=3.3Hz,9.0Hz and 19.3Hz),2.28-2.33(m,2H),1.54-1.56(m,1H),1.40-1.43(m,1H).

[0140] 13C NMR (CDCl3, 126MHz) δ: 211.83, 139.86, 136.19, 66.31, 45.70, 44.17, 43.18, 41.06, 30.28.

[0141] ESI-HRMS:(m / z)calcd.for C9H 11 O([M+H] + )135.0804,found:135.0803.

[0142] Step 3: Synthesis of compound (±)-11

[0143] Under N₂ atmosphere, t-BuOK (4.52 g, 40 mmol) was added to dry THF (90 mL). After stirring in an ice-water bath to form a suspension, tert-butyl diethylphosphonoacetate (10.16 g, 40 mmol) was added dropwise. After the addition was complete, the mixture was reacted in an ice-water bath for 1 h. A freshly prepared solution of compound (±)-10 (2.70 g, 20 mmol) in dry THF (30 mL) was then added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (400 mL) and extracted with EtOAc (300 mL x 3). The organic phases were combined, washed with saturated brine (300 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a dark yellow oil, which was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23) to afford the desired product (±)-11. Pale yellow oil; 3.91 g; the product does not require characterization and is used directly in the next reaction.

[0144] Step 4: Synthesis of compound (±)-12

[0145] (±)-11 (3.91 g, 17 mmol) was dissolved in CH₃NO₂ (40 mL) at room temperature and stirred, followed by the dropwise addition of DBU (7.76 g, 51 mmol). After the addition was complete, the reaction mixture was stirred in an oil bath at 50°C overnight under a nitrogen atmosphere. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, poured into water (250 mL), and extracted with CH₂Cl₂ (200 mL x 2). The combined organic phases were dried (MgSO₄), filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield a brown-black oil. The target product (±)-12 was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23) to yield 3.06 g of the pale yellow oil (combined yield of (±)-10 → (±)-12: 52%).

[0146] 1H NMR (CDCl3, 500MHz) δ: 6.02-6.04 (m, 1H), 5.99-5.01 (m, 1H), 4.74 (d, 1H, J = 11.5Hz), 4.70 (d, 1 H,J=11.5Hz),2.72-2.74(m,2H),2.55(s,2H),2.09-2.14(m,1H),2.04(ddd,1H,J=2.0Hz,8.5Hz and 13.5Hz),1.87-1.88(m,1H),1.71-1.73(m,1H),1.36-1.48(m,11H).

[0147] 13 C NMR (CDCl3, 126MHz) δ: 170.87, 136.29, 136.18, 82.78, 81.22, 44.44, 43.34, 41.94, 41.90, 36.16, 34.70, 32.56, 30.46, 28.24.

[0148] ESI-HRMS: (m / z) calcd. for C 16 H 24 NO4([M+H] + )294.1700,found:294.1693.

[0149] Step 5: Synthesis of compound (±)-13 p-toluenesulfonate

[0150] Compound (±)-12 (0.70 g, 2.4 mmol) was dissolved in EtOH (10 mL) at room temperature. Water (5 mL) was added and stirred, followed by the addition of iron powder (0.67 g, 12 mmol) and NH₄Cl (0.26 g, 4.9 mmol). The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures, and the mixture was stirred in an 85°C oil bath for 6-7 hours. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was washed with saturated NaHCO₃ solution (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were dried (MgSO₄), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield a brown oily residue. At room temperature, the residue was diluted with EtOAc (8 mL), followed by the addition of p-TsOH·H₂O (0.49 g, 2.6 mmol) and stirring to dissolve. The mixture was then transferred to an ice-water bath and stirred. A white solid precipitated, and stirring was continued in the ice-water bath for 1 h. The filter cake was collected by filtration and dried using a vacuum oil pump to obtain the p-toluenesulfonate salt of (±)-13 as a white solid; 0.66 g (64%).

[0151] 1H NMR(DMSO-d6,500MHz)δ:7.75(brs,3H),7.48(d,2H,J=8.0Hz),7.11(d,2H,J=8.0Hz),6.03-6.05(m,1H),6.00-6.02(m,1H ),3.04-3.08(m,2H),2.65-2.67(m,2H),2.43-2.44(m,2H),2.29(s,3H),1.98-2.02(m,1H),1.82(ddd,1H,J=1.8Hz,8.5Hz and 13.3Hz),1.41(s,9H),1.22-1.27(m,2H).

[0152] 13 C NMR(DMSO-d6,126MHz)δ:170.40,145.70,137.63,135.92,135.89,128.06,125.50,8 0.33,47.12,43.51,42.79,41.55,41.32,34.16,33.97,31.69,29.31,27.78,20.79.

[0153] ESI-HRMS: (m / z) calcd. for C 16 H 26 NO2([M(free base)+H] + )264.1958,found:264.1953.

[0154] Step 6: Synthesis of compound (±)-I-2

[0155] (±)-13-p-Toluenesulfonate (0.66 g, 1.5 mmol) was stirred with saturated NaHCO₃ solution (100 mL) at room temperature for 20 min (to a suspension state), then extracted with EtOAc (30 mL x 3). The combined organic phases were dried (MgSO₄) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a brown oil, which was then dissolved in CH₂Cl₂ (5 mL). TFA (2.5 mL) was slowly added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 2 h. TLC monitoring indicated the reaction was complete, and the reaction solution was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil. The oil solidified after drying with a vacuum pump. Methyl tert-butyl ether (5 mL) was added and the mixture was triturated and slurried at room temperature for 30 min. The solid was collected by filtration and dried with a vacuum pump to yield compound (±)-I-2. White solid; 0.20 g (64%); melting point 141.8°C-146.6°C;

[0156] 1H NMR (CD3OD, 500MHz) δ: 6.02-6.05 (m, 2H), 3.24 (d, 1H, J = 13.0Hz), 3.21 (d, 1H, J = 13.0Hz), 2.76-2.77 (m, 1H), 2.7 0-2.71(m,1H),2.64(d,1H,J=17.0Hz),2.55(d,1H,J=16.5Hz),2.09-2.14(m,1H),1.89(ddd,1H,J=2.0Hz,8.5Hz and 13.5Hz),1.78-1.80(m,1H),1.73-1.75(m,1H),1.41(dd,1H,J=5.5Hz and 13.5Hz),1.35-1.38(m,1H).

[0157] 13 C NMR (CD3OD, 126MHz) δ: 175.47, 137.19, 137.05, 49.86, 45.37, 44.46, 42.88, 42.60, 35.34, 35.19, 33.43, 30.99.

[0158] ESI-HRMS: (m / z) calcd. for C 12 H 18 NO2([M+H] + )208.1332,found:208.1327.

[0159] Compound (±)-I-2 is a specific form of the compound having the general formula I of the present application.

[0160] Example 3 Synthesis of Compound (±)-I-3

[0161] Step 1: Synthesis of compound 15

[0162] Compound 14 (30.00 g, 0.18 mol) was dissolved in dry CH3OH (300 mL), and concentrated H2SO4 (3 mL) was added. The mixture was heated and refluxed for 24 h. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and directly concentrated to 1 / 3 of its original volume on a rotary evaporator under reduced pressure and poured into ice water (400 mL). The resulting mixture was extracted with CH2Cl2 (300 mL × 2), and the organic phases were combined, washed with saturated NaHCO3 solution (400 mL), dried (MgSO4), filtered to remove the desiccant, and concentrated on a rotary evaporator under reduced pressure to obtain the target compound 15. Yellow oil; 37.00 g (96%); 1H NMR (CDCl3, 500MHz) δ: 6.26-6.27(m,2H), 3.61(s,6H), 3.29-3.30(m,2H), 3.16-3.17(m,2H), 1.47-1.49(m,2H), 1.32-1.35(m,2H).

[0163] Step 2: Synthesis of compound (±)-16

[0164] Sodium metal (19.00 g, 0.83 mol) was added to dry toluene (370 mL). Under a nitrogen atmosphere, the mixture was heated until the sodium was completely melted, maintaining an internal temperature of 103°C-106°C with stirring for 20 min. A solution of compound 15 (37.00 g, 0.18 mol) and trimethylsilyl chloride (TMSCl) (85.00 g, 0.78 mol) in dry toluene (100 mL) was then added dropwise with stirring. During the addition, the system exothermed, maintaining an internal temperature of 103°C-106°C. After the addition was complete, the reaction system was stirred overnight while maintaining an internal temperature of 103°C-106°C. TLC monitoring indicated completion of the reaction, and the reaction solution was cooled to room temperature. Filtering was performed with celite, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield a brown oil. The oil was dissolved in THF (200 mL), and 1M HCl (20 mL) was added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 0.5 h. TLC monitoring indicated the reaction was complete. The reaction mixture was poured into water (400 mL) and extracted with EtOAc (300 mL x 2). The combined organic phases were dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to yield a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 3] to afford the desired product (±)-16 as a white solid (14.3 g, 54%); melting point 74.7°C-77.5°C. This product was used directly in the next reaction without further characterization.

[0165] Step 3: Synthesis of compound (±)-17

[0166] Compound (±)-16 (5.00 g, 33 mmol) was dissolved in CCl₄ (60 mL). Triphenylphosphine (10.00 g, 38 mmol) and NaHCO₃ (0.40 g, 4.8 mmol) were added sequentially with stirring. The air in the reactor was replaced with nitrogen (balloon) according to standard procedures, and the mixture was stirred overnight in a 75°C oil bath. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a brown-black oil. The target product (±)-17 was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 9 / 91) to yield a pale yellow oil (4.40 g). This product was used directly in the next step without further characterization.

[0167] Step 4: Synthesis of compound (±)-18

[0168] Zinc powder (8.00 g, 0.12 mol) and glacial acetic acid (40 mL) were stirred and mixed. A freshly prepared solution of compound (±)-17 (4.40 g, 26 mmol) in glacial acetic acid (6 mL) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred in an oil bath at 55°C under a nitrogen atmosphere for 1.5 h. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ice water (150 mL) and extracted with CHCl (70 mL x 2). The combined organic phases were washed with water (100 mL x 3), dried (MgSO), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil, which was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9) to afford the desired product (±)-18. Pale yellow semisolid; 1.30 g (combined yield of (±)-16 → (±)-18 29%);

[0169] 1 H NMR(CDCl3,500MHz)δ:6.16-6.17(m,2H),3.71-3.75(m,1H),3.12-3.14(m,1H ),3.04-3.06(m,1H),2.79-2.84(m,1H),2.72(dddd,1H,J=1.0Hz,3.0Hz,8.5Hz and 18.0Hz), 2.15 (dt, 1H, J = 3.8Hz and 18.5Hz), 1.75-1.77 (m, 1H), 1.45-1.47 (m, 1H).

[0170] 13 C NMR (CDCl3, 126MHz) δ: 211.48, 135.81, 132.74, 66.65, 54.50, 46.42, 46.21, 44.13, 26.93.

[0171] Step 5: Synthesis of compound (±)-19

[0172] Under N₂ atmosphere, t-BuOK (1.90 g, 17 mmol) was added to dry THF (15 mL). After stirring in an ice-water bath to form a suspension, tert-butyl diethylphosphonoacetate (3.50 g, 14 mmol) was added dropwise. After the addition was complete, the mixture was reacted in an ice-water bath for 40 min. A freshly prepared solution of compound (±)-18 (1.40 g, 10 mmol) in dry THF (5 mL) was then added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1.5 h. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (100 mL) and extracted with EtOAc (70 mL x 2). The organic phases were combined, dried (MgSO₄), and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a dark yellow oil, which was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23) to afford the desired product (±)-19. Pale yellow oil; 2.42 g; The product does not require characterization and is used directly in the next reaction.

[0173] Step 6: Synthesis of compound (±)-20

[0174] At room temperature, the crude product (±)-19 (2.42 g, calculated as 10 mmol) was dissolved in CH3NO2 (15 mL), stirred, and DBU (3.00 g, 20 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred in an oil bath at 80°C overnight under a N2 atmosphere. TLC monitoring showed that the starting material had not reacted completely. The reaction solution was cooled to room temperature and poured into water (150 mL) and extracted with CH2Cl2 (70 mL×2). After combining the organic phases, they were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a brown-black oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-20. Pale yellow oil; 1.00 g (combined yield of (±)-18→(±)-20: 33%);

[0175] 1H NMR (CDCl3, 500MHz) δ: 6.40-6.41 (m, 1H), 6.28-6.29 (m, 1H), 4.82 (dd, 1H, J = 1.0Hz and 11.5Hz), 4.60 (dd, 1H, J = 1.0Hz and 11.5Hz),2.94-2.96(m,1H),2.81-2.87(m,2H),2.52-2.56(m,1H),2.47(dd,1H,J=0.8Hz and17.8H),2.38(d,1H,J=17.5Hz),2.04(ddd,1H,J=1.5Hz,8.0Hz and 13.0Hz),1.56-1.60(m,1H),1.47(s,9H),1.32-1.36(m,1H),1.11-1.13(m,1H).

[0176] 13 C NMR (CDCl3, 126MHz) δ: 170.92, 137.50, 136.91, 83.36, 80.92, 53.22, 47.71, 45.82, 44.83, 38.78, 36.17, 34.10, 32.83, 28.24.

[0177] ESI-HRMS: (m / z) calcd. for C 16 H 24 NO4([M+H] + )294.1700,found:294.1777.

[0178] Step 7: Synthesis of compound (±)-21

[0179] Compound (±)-20 (1.00 g, 3.4 mmol) was dissolved in CH2Cl2 (10 mL), and TFA (6 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 2 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a yellow oil, which was then purified by column chromatography [V (EtOAc) / V (n-hexane) = 0 / 1 → 2 / 3] to obtain a light yellow oil. N-hexane (1 mL) was added to the oil, and ultrasonication was performed. The oil solidified and then slurried at room temperature for 30 min. The solid was collected by filtration, and the filter cake was dried with a vacuum oil pump to obtain compound (±)-21. White solid; 0.80 g (99%); melting point 84.6°C-87.7°C;

[0180] 1H NMR(CDCl3,500MHz)δ:6.43-6.44(m,1H),6.31-6.32(m,1H),4.79(dd,1H,J=1.0Hz and 11.5Hz),4.65(d,1H,J=11.5Hz),2.97-2.99(m,1H),2.86-2.89(m,2H),2.67(d,1H,J=18.5Hz),2.5 7(d,1H,J=18.5Hz),2.54-5.56(m,1H),2.03-2.07(m,1H),1.61-1.63(m,1H),1.38(dd,1H,J=6.0Hz and 13.5Hz),1.13-1.15(m,1H). 13 C NMR (CDCl3, 126MHz) δ: 177.12, 137.88, 136.78, 83.09, 53.34, 47.56, 45.68, 44.84, 38.34, 34.58, 34.17, 32.70. ESI-HRMS:(m / z)calcd.for C 12 H 16 NO4([M+H] + )238.1074,found:238.1071.

[0181] Step 8: Synthesis of compound (±)-I-3

[0182] Compound (±)-21 (0.23 g, 0.97 mmol) was dissolved in CH3OH (9 mL) and 10% Pd(OH)2 / C (0.15 g) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature overnight. TLC monitoring showed that the reaction was complete (the reaction generally took 12 hours to complete). The filtrate was filtered and concentrated on a rotary evaporator under reduced pressure to obtain a white solid. CH3OH (1 mL) / EtOAc (2 mL) was added and stirred at room temperature for 5 minutes. The solid was collected by filtration and dried to obtain the target product (±)-I-3. White solid; 0.12 g (60%); melting point 186.2℃-190.5℃;

[0183] 1H NMR (CD3OD, 500MHz) δ: 3.07 (d, 1H, J = 12.5Hz), 2.98 (d, 1H, J = 12.5Hz), 2.71 (d, 1H, J = 16.0Hz), 2.65 (d,1H,J=16.0Hz),2.50-2.55(m,1H),2.44-2.46(m,1H),2.22-2.26(m,2H),1.99-2.05(m,1H),1.91(dd,1H,J=7.5Hz and 13.0Hz),1.75-1.81(m,2H),1.54-1.61(m,1H),1.46-1.53(m,1H),1.40-1.43(m,1H),1.24-1.27(m,1H). 13 C NMR (CD3OD, 126MHz) δ: 180.05, 52.82, 49.93, 47.58, 42.78, 41.02, 40.22, 37.39, 34.81, 33.73, 26.23, 25.26. ESI-HRMS:(m / z)calcd.for C 12 H 20 NO2([M+H] + )210.1489,found:210.1484.

[0184] Compound (±)-I-3 is a specific form of the compound having the general formula I of the present application.

[0185] Example 4 Synthesis of Compound (±)-I-4 and its p-toluenesulfonate

[0186] Step 1: Synthesis of compound (±)-22 p-toluenesulfonate

[0187] At room temperature, compound (±)-20 (1.50 g, 5.1 mmol) was dissolved in EtOH (15 mL). Water (7 mL) was added and stirred, followed by the addition of iron powder (1.50 g, 27 mmol) and NH₄Cl (0.50 g, 9.3 mmol). Following standard procedures, the air in the reactor was replaced with nitrogen (balloon) and stirred in an 85°C oil bath for 4 h. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was added to a saturated NaHCO₃ solution (100 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were dried (MgSO₄), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield a yellow oil. At room temperature, EtOAc (15 mL) was added to dilute the oil, followed by the addition of p-TsOH·H₂O (0.97 g, 5.1 mmol) and stirring to dissolve. A large amount of solid precipitated, and the system was transferred to an ice-water bath and stirred for 1 hour. The solid was collected by filtration and dried using a vacuum pump to obtain (±)-22-toluenesulfonate. A white solid (1.60 g, 72%) was obtained; the melting point was 184.4°C-187.1°C.

[0188] 1 H NMR(DMSO-d6,500MHz)δ:7.71(brs,3H),7.48(d,2H,J=8.0Hz),7.12(d,2H,J=8.0Hz),6.35-6.37(m,1H),6.28-6.30(m,1H),3.05-3.1 1(m,1H),2.94-3.00(m,1H),2.79-2.82(m,2H),2.71-2.77(m,1H),2.40-2.43(m,1H),2.26-2.33(m,5H),1.79(ddd,1H,J=1.5Hz,8.5Hz and 13.0Hz),1.45-1.48(m,1H),1.43(s,9H),1.11(dd,1H,J=6.0Hz and 13.0Hz),1.04-1.06(m,1H).

[0189] 13 C NMR(DMSO-d6,126MHz)δ:170.51,145.64,137.69,137.19,136.49,128.08,125.50,8 0.09,52.46,47.71,46.62,45.25,44.08,36.54,36.07,33.20,32.20,27.74,20.79.

[0190] ESI-HRMS: (m / z) calcd. for C 16 H 26NO2([M(free base)+H] + )264.1958,found:264.1954.

[0191] Step 2: Synthesis of compound (±)-I-4 and its p-toluenesulfonate

[0192] (±)-22 p-toluenesulfonate (1.60 g, 3.7 mmol) was stirred with saturated NaHCO₃ solution (100 mL) at room temperature for 20 min (to a suspension state), then extracted with EtOAc (60 mL x 3). The combined organic phases were dried (MgSO₄) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a pale yellow oil, which was then dissolved in CH₂Cl₂ (10 mL). TFA (7 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 4-6 hours. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to yield a brown oil, which was then concentrated again with CH₂Cl₂ (20 mL). The oil was dried under vacuum oil pump until a solid was completely precipitated, resulting in (±)-I-4. The solid was dissolved in CH₃OH (2 mL) and EtOAc (4 mL) was added and stirred. p-TsOH·H2O (0.65 g, 3.4 mmol) was added to the reaction solution and stirred to dissolve. A large amount of solid precipitated. Stirring was continued at room temperature for 2 h. The solid was collected by filtration and the filter cake was dried using a vacuum oil pump to obtain compound (±)-I-4 p-toluenesulfonate. It was a white solid; 0.50 g (36%); melting point: 197.0°C-198.7°C.

[0193] 1 H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.5Hz), 7.23 (d, 2H, J = 8.0Hz), 6.43-6.4 4(m,1H),6.30-6.31(m,1H),3.25(d,1H,J=13.0Hz),3.12(d,1H,J=12.5Hz),2 .84-2.93(m,3H),2.58(d,1H,J=17.5Hz),2.51-2.53(m,1H),2.34-2.38(m,4H ),1.75-1.80(m,1H),1.57-1.59(m,1H),1.32-1.35(m,1H),1.14-1.16(m,1H).

[0194] 13C NMR(CD3OD,126MHz)δ:175.74,143.53,141.72,138.51,137.90,129.83,126 .97,53.83,50.47,48.15,46.90,45.86,37.93,37.16,35.08,34.08,21.31.

[0195] ESI-HRMS: (m / z) calcd. for C 12 H 18 NO2([M(free base)+H] + )208.1332,found:208.1328.

[0196] Compound (±)-I-4 is a specific form of the compound having the general formula I of the present application.

[0197] Example 5 Synthesis of Compound (±)-I-5

[0198] Step 1: Synthesis of compound 23

[0199] Maleic anhydride (68.00 g, 0.69 mol) was dissolved in CHCl3 (400 mL), and a solution of 1,4-cyclohexadiene (78.00 g, 0.97 mol) in CHCl3 (50 mL) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain an oil, which was then slurried in an EtOAc / n-hexane mixture (100 mL / 400 mL) at room temperature. The solid was collected by filtration and dried to obtain compound 23; 54.50 g (44%); 1 H NMR (CDCl3, 500MHz) δ: 6.31-6.33(m,2H), 3.22-3.24(m,2H), 3.127-3.134(m,2H), 1.59-1.62(m,2H), 1.40-1.43(m,2H).

[0200] Step 2: Synthesis of compound 24

[0201] Compound 23 (17.00 g, 95 mmol) was dissolved in CH3OH (170 mL), stirred, and concentrated sulfuric acid (1.7 mL) was added. Heated under reflux overnight. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated on a rotary evaporator under reduced pressure to 1 / 3 of its original volume and then poured into ice water (200 mL). The resulting mixture was extracted with CH2Cl2 (100 mL×3), and the organic phases were combined and washed with saturated NaHCO3 solution (200 mL) and saturated brine (200 mL) in sequence, dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to obtain solid compound 24. White solid; 20.00 g (93%); 1 H NMR (CDCl3, 500MHz) δ: 6.31-6.35(m,2H), 3.60(s,6H), 3.02-3.03(m,2H), 2.89-2.91(m,2H), 1.53-1.57(m,2H), 1.30-1.33(m,2H).

[0202] Step 3: Synthesis of compound (±)-25

[0203] Sodium metal (10.00 g, 0.43 mol) was added to dry toluene (200 mL) and heated under a nitrogen atmosphere until the sodium was completely melted. Stirring was initiated and the internal temperature maintained at 103-106°C for 20 min. A solution of compound 24 (20.00 g, 89 mmol) and TMSCl (48.00 g, 0.44 mol) in dry toluene (30 mL) was added dropwise. The addition was exothermic, and the internal temperature of the reaction system was maintained at 103-106°C by controlling the addition rate. After the addition was complete, the reaction system was stirred at 103-106°C overnight. TLC monitoring indicated completion of the reaction, and the reaction solution was cooled to room temperature. Filtering was performed with celite, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield a brown oil. The oil was dissolved in THF (100 mL), and 1M HCl (16 mL) was added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 3 h. TLC monitoring showed that the reaction was complete. The reaction solution was poured into water (100 mL) and extracted with EtOAc (100 mL×2). After combining the organic phases, they were dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which solidified after standing at room temperature. Add n-hexane (15 mL) to the above solidification system, heat to reflux, and add EtOAc dropwise until the solid is completely dissolved. Cool to room temperature and stir to precipitate crystals, and continue stirring for 5 hours. Filter and dry the filter cake with a vacuum oil pump to obtain the target compound (±)-25. White solid; 7.60 g (52%); melting point 106.1°C-110.4°C; the product does not need to be characterized and is used directly in the next reaction.

[0204] Step 4: Synthesis of compound (±)-26

[0205] Compound (±)-25 (2.00 g, 12 mmol) was dissolved in CH2Cl2 (20 mL). Pyridine (1.93 g, 24 mmol) and 4-dimethylaminopyridine (DMAP) (0.74 g, 6.1 mmol) were added sequentially. The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. Phenyl chlorothioformate (3.15 g, 18 mmol) was slowly added dropwise under an ice-water bath. After the addition was complete, the mixture was allowed to react at room temperature for 1 h. TLC monitoring indicated the reaction was complete. The reaction solution was poured into ice water (100 mL) and extracted with CH2Cl2 (50 mL x 2). The organic phases were combined, washed sequentially with 1 M HCl (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered to remove the desiccant, and concentrated on a rotary evaporator under reduced pressure to afford crude compound (±)-26. A yellow solid (3.66 g) was obtained. This product did not require characterization and was used directly in the next step.

[0206] Step 5: Synthesis of compound (±)-27

[0207] Compound (±)-26 (3.66 g, 12 mmol) was added to benzene (40 mL), and the air in the reactor was replaced with nitrogen (balloon) according to standard procedures. The temperature was raised to 90°C and refluxed. A solution of n-Bu3SnH (5.30 g, 18 mmol) and azobisisobutyronitrile (AIBN) (0.20 g, 1.2 mmol) in benzene (15 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at 90°C in an oil bath overnight. TLC monitoring indicated that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure using a rotary evaporator to obtain an oil. The target product (±)-27 was purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to obtain a light yellow oil; 1.20 g (combined yield of (±)-25 → (±)-27: 66%).

[0208] 1 H NMR(CDCl3,500MHz)δ:6.20-6.25(m,2H),3.31-3.34(m,1H),2.89-2.95(m,1H),2.85-2.89(m,1H ),2.78-2.81(m,1H),2.40-2.47(m,1H),1.47-1.53(m,1H),1.37-1.44(m,2H),1.23-1.29(m,1H).

[0209] 13C NMR (CDCl3, 126MHz) δ: 212.49, 133.54, 131.54, 64.18, 50.49, 32.04, 31.01, 26.48, 24.54, 22.54.

[0210] Step 6: Synthesis of compound (±)-28

[0211] Under N₂ atmosphere, t-BuOK (0.90 g, 8.0 mmol) was added to dry THF (10 mL). After stirring in an ice-water bath to form a suspension, tert-butyl diethylphosphonoacetate (1.70 g, 6.7 mmol) was added dropwise. After the addition was complete, the mixture was reacted in an ice-water bath for 40 min. A freshly prepared solution of compound (±)-27 (0.60 g, 4.0 mmol) in dry THF (5 mL) was then added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1.5 h. TLC monitoring indicated the reaction was complete. The reaction solution was poured into ice water (100 mL) and extracted with EtOAc (50 mL x 2). The organic phases were combined, dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a dark yellow oil, which was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9) to afford the desired product (±)-28. Pale yellow oil; 0.90 g; The product does not require characterization and is used directly in the next reaction.

[0212] Step 7: Synthesis of compound (±)-29

[0213] At room temperature, compound (±)-28 (0.90 g, 3.7 mmol) was dissolved in CH3NO2 (9 mL), and DBU (2.00 g, 13 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred in an 80°C oil bath under N2 overnight. TLC monitoring indicated that the reaction was essentially complete. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with CH2Cl2 (50 mL x 2). The organic phases were combined, dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a brown-black oil. The target product (±)-29 was purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to obtain a light yellow oil; 0.50 g (combined yield of (±)-27 → (±)-29: 40%).

[0214] 1H NMR(CDCl3,500MHz)δ:6.45-6.49(m,1H),6.26-6.30(m,1H),4.78(dd,1H,J=0.5Hz and 11.5Hz),4.65(d,1H,J=11.5Hz),2.60(d,1H,J=17.5Hz),2.52-2.61(m,3H ),2.54(d,1H,J=17.5Hz),2.27-2.30(m,1H),1.94(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.64(dd,1H,J=7.3Hz and 13.3Hz),1.45(s,9H),1.35-1.40(m,2H),1.25-1.30(m,1H),1.18-1.23(m,1H).

[0215] 13 C NMR (CDCl3, 126MHz) δ: 171.17, 134.53, 134.32, 82.57, 80.94, 46.80, 40.89, 36.38, 34.74, 33.09, 32.50, 30.96, 28.24, 25.21, 23.61.

[0216] ESI-HRMS: (m / z) calcd. for C 17 H 26 NO4([M+H] + )308.1856,found:308.1852.

[0217] Step 8: Synthesis of compound (±)-30

[0218] Compound (±)-29 (0.50 g, 1.6 mmol) was dissolved in CH2Cl2 (5 mL) and TFA (3 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a yellow oil. Then, n-hexane (3 mL) was added to the oil and ultrasonicated. The oil turned into a solid and was stirred and slurried at room temperature for 1 h. The solid was collected by filtration and dried with a vacuum oil pump to obtain compound (±)-30. White solid; 0.33 g (80%); melting point: 120.0°C-123.6°C;

[0219] 1H NMR(CDCl3,500MHz)δ:6.47-6.50(m,1H),6.28-6.32(m,1H),4.78(dd,1H,J=0.8Hz and 5.9Hz), 4.68(d,1H,J=11.5Hz),2.80(d,1H,J=18.0Hz),2.73(d,1H,J=18.0Hz),2.53-2.65(m,3H),2.27-2.30(m,1H),1.95(ddd,1H,J=2.0Hz,8.5Hz and 13.5Hz),1.66(dd,1H,J=2.3Hz and 13.3Hz),1.32-1.42(m,2H),1.25-1.31(m,1H),1.17-1.24(m,1H).

[0220] 13 C NMR (CDCl3, 126MHz) δ: 176.37, 134.66, 134.33, 82.31, 46.58, 40.37, 34.65, 32.97, 32.78, 30.85, 25.17, 23.55. ESI-HRMS:(m / z)calcd.for C 13 H 18 NO4([M+H] + )252.1230,found:252.1229.

[0221] Step 9: Synthesis of compound (±)-I-5

[0222] Compound (±)-30 (0.30 g, 1.2 mmol) was dissolved in CH3OH (10 mL) and 10% Pd(OH)2 / C (0.20 g) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature overnight. TLC monitoring showed that the reaction was complete (the reaction generally required 12 h to complete). The solid was removed by filtration and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a white solid. CH3OH (2 mL) / EtOAc (3 mL) was added and stirred at room temperature for 0.5 h. The solid was collected by filtration and dried to obtain the target product (±)-I-5. White solid; 0.13 g (49%); melting point 176.6°C-178.2°C;

[0223] 1H NMR (CD3OD, 500MHz) δ: 3.16 (d, 1H, J = 13.0Hz), 3.07 (d, 1H, J = 13.0Hz), 2.74 (d, 1H, J = 16.5Hz), 2.67 (d, 1H, J = 16. 0Hz),2.45-2.52(m,1H),2.20-2.27(m,2H),2.01-2.04(m,1H),1.90-1.96(m,1H),1.85(ddd,1H,J=3.0Hz,8.5Hz and 12.5Hz),1.74-1.76(m,1H),1.46-1.70(m,6H),1.36-1.43(m,1H).

[0224] 13 C NMR (CD3OD, 126MHz) δ: 180.15, 51.74, 46.55, 44.33, 40.14, 33.41, 33.09, 27.72, 26.94, 26.50, 23.84, 22.75. ESI-HRMS:(m / z)calcd.for C 13 H 22 NO2([M+H] + )224.1645,found:224.1641.

[0225] Compound (±)-I-5 is a specific form of the compound having the general formula I of the present application.

[0226] Example 6 Synthesis of Compound (±)-I-6 and its p-toluenesulfonate

[0227] Step 1: Synthesis of compound (±)-31 p-toluenesulfonate

[0228] At room temperature, compound (±)-29 (1.10 g, 3.6 mmol) was dissolved in EtOH (10 mL). Water (5 mL) was added and stirred, followed by the addition of iron powder (1.30 g, 23 mmol) and NH₄Cl (0.45 g, 8.4 mmol). The air in the reactor was replaced with nitrogen (balloon) according to standard procedures, and the mixture was stirred and refluxed for 5 h. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered to remove solids. The filtrate was washed with saturated NaHCO₃ solution (120 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were dried (MgSO₄), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield a yellow oil. EtOAc (15 mL) was added to dilute the oil at room temperature, and p-TsOH·H₂O (0.70 g, 3.7 mmol) was added and stirred to dissolve. A large amount of solid precipitated, and the system was transferred to an ice-water bath and stirred for 1 h. The solid was collected by filtration and dried under vacuum oil pump to obtain (±)-31 p-toluenesulfonate. White solid; 1.30 g (81%); melting point: 190.1°C-192.5°C;

[0229] 1 H NMR(DMSO-d6,500MHz)δ:7.69(brs,3H),7.48(d,2H,J=6.5Hz),7.12(d,2H,J=8.0Hz),6.44-6.46(m,1H),6.25-6.28(m,1H ),3.07-3.11(m,1H),2.96-3.00(m,1H),2.40-2.54(m,5H),2.29(s,3H),2.12-2.14(m,1H),1.74(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.38-1.42(m,10H),1.31-1.33(m,2H),1.17-1.21(m,1H),1.09-1.14(m,1H).

[0230] 13 C NMR(DMSO-d6,126MHz)δ:170.55,145.64,137.66,134.31,133.80,128.07,125.49,80.0 9,46.72,45.55,38.85,35.92,33.77,32.38,31.83,30.37,27.74,24.67,23.21,20.78.

[0231] ESI-HRMS: (m / z) calcd. for C 17 H 28 NO2([M(free base)+H] +)278.2115,found:278.2111.

[0232] Step 2: Synthesis of compound (±)-I-6 and its p-toluenesulfonate

[0233] (±)-31 p-toluenesulfonate (1.30 g, 2.9 mmol) was stirred with saturated NaHCO₃ solution (100 mL) at room temperature for 20 min (to a suspension state), then extracted with EtOAc (60 mL x 3). The combined organic phases were dried (MgSO₄) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a pale yellow oil, which was then dissolved in CH₂Cl₂ (10 mL). TFA (7 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the mixture was allowed to react at room temperature for 4 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to yield a brown oil, which was then concentrated again with CH₂Cl₂ (20 mL). The oil was dried under vacuum until a solid, (±)-I-6, was completely precipitated. The solid was dissolved in CH₃OH (3 mL) and EtOAc (8 mL) was added and stirred. p-TsOH·H2O (0.60 g, 3.2 mmol) was added to the reaction solution and stirred to dissolve. A large amount of solid precipitated. Stirring was continued at room temperature for 0.5 h. The solid was collected by filtration and dried under vacuum to obtain compound (±)-I-6 p-toluenesulfonate. It was a white solid; 0.70 g (62%); melting point: 192.7°C-194.0°C.

[0234] 1 H NMR (CD3OD, 500MHz) δ: 7.71 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.5Hz), 6.48-6.52 (m, 1H), 6 .28-6.32(m,1H),3.26(d,1H,J=12.5Hz),3.14(d,1H,J=13.0Hz),2.66(d,1H,J=17.0Hz) ,2.56(d,1H,J=17.0Hz),2.56-2.67(m,2H),2.51-2.53(m,1H),2.19-2.22(m,1H),1.74- 1.79(m,1H),1.58-1.64(m,1H),1.40-1.43(m,2H),1.27-1.32(m,1H),1.19-1.24(m,1H).

[0235] 13C NMR(CD3OD,126MHz)δ:175.74,143.57,141.67,135.55,135.31,129.80,126.97 ,49.41,47.40,40.12,36.92,35.65,33.98,33.67,32.16,25.98,24.39,21.30.

[0236] ESI-HRMS: (m / z) calcd. for C 13 H 20 NO2([M(free base)+H] + )222.1489,found:222.1485.

[0237] Compound (±)-I-6 is a specific form of the compound having the general formula I of the present application.

[0238] Example 7 Synthesis of Compounds (-)-I-3, (+)-I-3 and Their p-Toluenesulfonates

[0239] Step 1: Synthesis of compound (±)-32 p-toluenesulfonate

[0240] Compound (±)-20 (140.00 g, 0.48 mol) was dissolved in CH3OH (800 mL) and 10% Pd(OH)2 / C (22.00 g) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature for 12 h. TLC monitoring indicated the reaction was complete. The mixture was filtered and the filtrate was concentrated on a rotary evaporator under reduced pressure to obtain crude compound (±)-32. Compound (±)-32 was diluted with CH2Cl2 (800 mL) and washed with saturated NaHCO3 solution (2 L). The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (500 mL x 2). The combined organic phases were dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator under reduced pressure to obtain a yellow oil. At room temperature, EtOAc (800 mL) was added to dilute the oil. p-TsOH·H₂O (70.00 g, 0.37 mol) was then added and stirred to dissolve. A large amount of solid precipitated. The mixture was stirred at room temperature for 3 h. The solid was collected by filtration and dried under vacuum to obtain (±)-32-toluenesulfonate. It was a white solid; 75.20 g (36%); melting point: 170.1°C-174.4°C.

[0241] 1H NMR(DMSO-d6,500MHz)δ:7.73(brs,3H),7.48(d,2H,J=8.0Hz),7.12(d,2H,J=7.5Hz), 3.02-3.07(m,1H),2.91-2.95(m,1H),2.61(d,1H,J=17.0Hz),2.57(d,1H,J=17.0Hz), 2.39-2.46(m,1H),2.27-2.29(m,4H),2.18-2.20(m,1H),2.10-2.13(m,1H),1.83-1.8 8(m,1H),1.68-1.79(m,3H),1.41-1.53(m,11H),1.31-1.33(m,1H),1.13-1.16(m,1H).

[0242] 13 C NMR(DMSO-d6,126MHz)δ:170.59,145.54,137.76,128.11,125.51,80.17,48.51,48 .43,48.23,41.52,38.50,35.42,35.39,33.04,30.92,27.74,24.64,23.74,20.80.

[0243] 3,5-Dinitrobenzoyl Derivatization: Synthesis of 3,5-Dinitrobenzoyl Derivatives of Compound (±)-32

[0244] At room temperature, compound (±)-32 p-toluenesulfonate (1.00 g, 2.3 mmol) was added to a saturated NaHCO₃ solution (200 mL), stirred to form a suspension, and extracted with EtOAc (100 mL). The organic phase was washed again with saturated NaHCO₃ solution (200 mL), separated by extraction, and the aqueous phase was extracted with EtOAc (50 mL). The organic phases were combined, dried (MgSO₄), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield compound (±)-32 as a pale yellow oil. The oil was dissolved in CH₂Cl₂ (7 mL), stirred, and 3,5-dinitrobenzoyl chloride (0.6 g, 2.6 mmol) was added. Triethylamine (0.6 mL) was then added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 1 h. TLC monitoring indicated the reaction was complete. The reaction mixture was directly purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 4] to afford a pale yellow oil. n-Hexane (10 mL) was added to the oil to precipitate a solid, which was then stirred at room temperature for 1 hour. The solid was collected by filtration and dried under vacuum to afford the 3,5-dinitrobenzoylated derivative of (±)-32. The product was a white solid; 0.70 g (67%); melting point: 113.9°C-115.4°C. 1H NMR (CDCl3, 500MHz) δ: 9.40 (brs, 1H), 9.20 (d, 2H, J = 2.0Hz), 9.15 (t, 1H, J = 2.0Hz), 3.70 (dd, 1H, J = 4.5Hz and 13.5Hz), 3.43 (dd, 1H, J = 3.3Hz and 13.3Hz),2.84(dd,1H,J=1.0Hz and 12.0Hz),2.71(d,1H,J=17.0Hz),2.54-2.60(m,1H),2.36-2.38(m,1H),2.30-2.33(m,1H),2.26-2.28( m,1H),1.86-1.94(m,2H),1.75-1.82(m,2H),1.50-1.62(m,11H),1.38-1.40(m,1H),1.21-1.24(m,1H).

[0245] ESI-HRMS: (m / z) calcd. for C 23 H 28 N3O7([MH] - )458.1933,found:458.1939.

[0246] The 3,5-dinitrobenzoylated derivative of (±)-32 is used as a reference substance for the chiral HPLC test of the optical purity of (-)-32 and (+)-32 after chiral acid resolution of (±)-32 in steps 2 and 3.

[0247] Step 2: Synthesis of (R)-(-)-O-acetylmandelate salt of compound (-)-32

[0248] (±)-32 p-toluenesulfonate (22.80 g, 52 mmol) was added to a saturated NaHCO₃ solution (200 mL x 2) with stirring and extracted with EtOAc (200 mL x 2). The combined organic phases were dried (MgSO₄), filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure on a rotary evaporator to yield a pale yellow oil. The oil was diluted with THF (100 mL) at room temperature, followed by the dropwise addition of a solution of (R)-(-)-O-acetylmandelic acid (5.00 g, 26 mmol) in THF (50 mL). Upon completion of the addition, a large amount of solid gradually precipitated. Additional THF (8 mL) was added, and the mixture was stirred at room temperature overnight. The solid was collected by filtration (the filtrate was recovered), and the filter cake was dried using a vacuum pump to yield a white solid (7.35 g, 16 mmol), the (R)-(-)-O-acetylmandelic acid salt of compound (-)-32.

[0249] 3,5-Dinitrobenzoyl Derivatization: Synthesis of the 3,5-dinitrobenzoyl derivative of compound (-)-32. The above white solid (0.1 g, 0.22 mmol) was added to a saturated NaHCO₃ solution (50 mL x 2) with stirring and extracted with EtOAc (25 mL x 2). The combined organic phases were dried (MgSO₄), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield a pale yellow oil. At room temperature, CH₂Cl₂ (3 mL) was added to the above oil, followed by 3,5-dinitrobenzoyl chloride (0.1 g, 0.43 mmol) with stirring. Triethylamine (2-3 drops) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 10 minutes. TLC monitoring showed that the reaction was complete. The reaction solution was directly purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 4] to obtain a light yellow oil. After vacuum drying, the 3,5-dinitrobenzoyl derivative of (-)-32 was obtained as a white foamy solid. The ee value of the derivative was determined to be 80.54% by chiral HPLC.

[0250] Enantiomeric excess (%ee) determination method (chiral HPLC method): Daicel Chiralpak AS-RH 4.6 mm × 250 mm chromatographic column (5 μm) was used on an Agilent 1260 Infinity II liquid chromatograph with a detector wavelength of 220 nm. The mobile phase was acetonitrile / 0.1% KH2PO4-KOH buffer solution (pH = 7.0) = 70 / 30, with a flow rate of 1 mL / min. The injected sample concentration was 0.5 mg / mL, and the injection volume was 3 μL.

[0251] The (R)-(-)-O-acetylmandelate salt of compound (-)-32, obtained in the first resolution, was thoroughly stirred with THF (65 mL) at room temperature. The mixture was then moved to a 40°C oil bath and stirred for 10 minutes (the solution was slightly soluble). The solution was then returned to room temperature, and THF (30 mL) was added and stirred overnight. The solid was collected by filtration and dried under vacuum to afford a white solid (4.90 g, 11 mmol). The above recrystallization method was repeated to afford the (R)-(-)-O-acetylmandelate salt of compound (-)-32. Following the above 3,5-dinitrobenzoyl derivatization procedure, chiral HPLC analysis revealed an ee value of 99.34%. The product was a white solid (4.40 g, 37%). This product was used directly in the next reaction without further characterization.

[0252] Step 3: Synthesis of (S)-(+)-O-acetylmandelate salt of compound (+)-32

[0253] The filtrate from the crystallization and filtration of step 2 was concentrated, stirred with saturated NaHCO₃ solution (100 mL x 2), and extracted with EtOAc (100 mL x 2). The combined organic phases were dried (MgSO₄), filtered, and concentrated under reduced pressure on a rotary evaporator to yield a pale yellow oil (12.85 g, 48 mmol). THF (100 mL) was added to dilute the oil at room temperature, followed by the dropwise addition of a solution of (S)-(+)-O-acetylmandelic acid (4.70 g, 24 mmol) in THF (50 mL). A large amount of solid began to precipitate halfway through the addition. Upon completion of the addition, additional THF (30 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filter cake dried using an oil vacuum pump to yield the (S)-(+)-O-acetylmandelic acid salt of (+)-32 as a white solid (6.00 g, 13 mmol). The ee value of the product was determined by chiral HPLC according to the above 3,5-dinitrobenzoyl derivatization procedure and was 90.77%.

[0254] The white solid was thoroughly stirred with THF (60 mL) at room temperature, then moved to a 40°C oil bath and stirred for 10 minutes (the solution was slightly soluble). The solution was then brought to room temperature, and THF (30 mL) was added and stirred overnight. The solid was collected by filtration and dried under vacuum to afford the (S)-(+)-O-acetylmandelate salt of compound (+)-32. Following the 3,5-dinitrobenzoyl derivatization procedure described above, chiral HPLC analysis revealed an ee value of 99.17%. The product yielded 4.40 g (40%) of white solid. This product was used directly in the next reaction without further characterization.

[0255] Step 4: Synthesis of compound (-)-I-3 and its p-toluenesulfonate

[0256] At room temperature, (R)-(-)-O-acetylmandelate salt of compound (-)-32 (1.50 g, 3.3 mmol) was added to a saturated NaHCO₃ solution (100 mL) and stirred for 20 minutes (to a suspension state). EtOAc (50 mL x 3) was then added for extraction. The organic phases were combined, dried (MgSO₄), and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil. This oil was then dissolved in CH₂Cl₂ (10 mL) and TFA (7 mL) was slowly added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 4-6 hours. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to yield a brown oil. CH₂Cl₂ (10 mL) was then added and concentrated again. The resulting oil was dried using a vacuum pump to obtain (-)-32. The (-)-32 sample was dissolved in CH3OH (2.5 mL), and EtOAc (12 mL) was added with stirring. p-TsOH·H2O (0.70 g, 3.7 mmol) was added to the solution and stirred until dissolved. A large amount of solid precipitated. Stirring was continued at room temperature for 1 hour. The solid was collected by filtration and dried under vacuum to obtain the p-toluenesulfonate salt of compound (-)-I-3. It was a white solid; 1.00 g (80%); melting point: 180.6°C-183.5°C; [α] D 20 =-22.8 (c = 2.50, CH3OH);

[0257] 1 H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.0Hz), 3.20 (d, 1H, J = 13.0Hz), 3.10(d,1H,J=13.0Hz),2.79(d,1H,J=17.5Hz),2.70(d,1H,J=17.5Hz),2.49-2.57(m,1H),2 .41-2.43(m,1H),2.37(s,3H),2.22-2.27(m,2H),1.92-1.97(m,1H),1.84-1.89(m,2H),1.7 6-1.81(m,1H),1.57-1.63(m,1H),1.49-1.55(m,1H),1.41-1.44(m,1H),1.25-1.28(m,1H).

[0258] 13C NMR(CD3OD,126MHz)δ:177.10,143.14,140.84,130.31,126.34,50.73,49. 15,42.42,40.52,40.21,39.64,36.05,34.47,32.47,25.62,24.79,21.41.

[0259] Compound (-)-I-3 is a specific form of the compound of the general formula I of the present application, and is also an optically pure compound of (±)-I-3 that has the same relative configuration as (±)-I-3 and has left-handed optical rotation.

[0260] Step 5: Synthesis of compound (+)-I-3 and its p-toluenesulfonate

[0261] At room temperature, (S)-(+)-O-acetylmandelate salt of compound (+)-32 (1.40 g, 3.0 mmol) was added to a saturated NaHCO₃ solution (100 mL) and stirred for 20 min (to a suspension state). EtOAc (50 mL x 3) was then added for extraction. The combined organic phases were dried (MgSO₄) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil. This oil was then dissolved in CH₂Cl₂ (10 mL) and TFA (7 mL) was slowly added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 4-6 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to yield a brown oil. CH₂Cl₂ (10 mL) was added and the mixture was concentrated again. The resulting oil was dried using a vacuum pump to obtain (+)-I-3. The (+)-I-3 sample was dissolved in CH3OH (2 mL), followed by the addition of EtOAc (6 mL) and stirring. p-TsOH·H2O (0.60 g, 3.2 mmol) was added to the solution and stirred to dissolve. A large amount of solid precipitated. Stirring was continued at room temperature for 1 hour. The solid was collected by filtration and dried using a vacuum oil pump to obtain the p-toluenesulfonate salt of compound (+)-I-3. It was a white solid; 0.85 g (73%); melting point: 179.5°C-181.8°C; [α] D 20 =+25.09 (c=2.55, CH3OH);

[0262] 1H NMR (CD3OD, 500MHz) δ: 7.71 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.0Hz), 3.20 (d, 1H, J = 13.0Hz), 3.10(d,1H,J=13.0Hz),2.78(d,1H,J=17.5Hz),2.70(d,1H,J=17.5Hz),2.48-2.55(m,1H),2 .40-2.42(m,1H),2.37(s,3H),2.21-2.26(m,2H),1.90-1.95(m,1H),1.83-1.88(m,2H),1.7 6-1.80(m,1H),1.56-1.62(m,1H),1.49-1.54(m,1H),1.40-1.42(m,1H),1.24-1.27(m,1H).

[0263] 13 C NMR(CD3OD+D2O(1drop),126MHz)δ:176.94,142.97,141.11,130.25,126.38,50. 74,49.21,42.44,40.56,40.17,39.67,36.10,34.50,32.47,25.65,24.81,21.40.

[0264] Compound (+)-I-3 is a specific form of the compound of the general formula I of the present application, and is also an optically pure compound of (±)-I-3 that has the same relative configuration as (±)-I-3 and has dextrorotatory optical properties.

[0265] The absolute configuration of compound (+)-I-3 was determined by converting the (S)-(+)-O-acetylmandelate salt of (+)-32, which has the same absolute configuration, into its lactam (+)-32-LAC. The absolute configuration of (+)-32-LAC was determined using single crystal X-ray diffraction, and the absolute configuration was the same as that of (+)-32. This method can indirectly determine the absolute configuration of (+)-I-3.

[0266] The specific experimental methods are as follows:

[0267] Synthesis of (+)-32-LAC: (S)-(+)-O-acetylmandelate (1.00 g, 2.2 mmol), the (+)-32 salt with an ee of 99.17%, was added to a saturated NaHCO₃ solution (100 mL) and stirred for 10 min. The mixture was then extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried (MgSO₄), and filtered to remove the desiccant. The filtrate was evaporated to dryness on a rotary evaporator. The resulting residue was dissolved in toluene (7 mL) and refluxed overnight. TLC indicated the reaction was complete. The reaction system was cooled to room temperature, the solvent was evaporated on a rotary evaporator, and the residue was slurried in EtOAc / hexane (1 / 10 by v / v, 3 mL total). The crystals were collected by filtration and dried to yield (+)-32-LAC (0.28 g, 67%); m.p. 189.3-191.5°C, [α] D 20 =+62.6°(c=1.15,CH3OH). 1 H NMR (CDCl3, 500MHz) δ: 6.05 (brs, 1H), 3.45 (d, 1H, J = 9.5Hz), 3.36 (d, 1H, J = 9.5Hz), 2.47-2.52 (m, 1H), 2. 43(d,1H,J=17.0Hz),2.39-2.42(m,1H),2.34(d,1H,J=17.0Hz),2.23-2.27(m,2H),2.02(dd,1H,J=7.0Hz and 13.0Hz),1.93-1.98(m,1H),1.70-1.75(m,1H),1.60-1.66(m,1H),1.51 -1.58(m,1H),1.42-1.49(m,1H),1.39-1.41(m,1H),1.20-1.23(m,1H).

[0268] 13 C NMR (CDCl3, 126MHz) δ: 178.29, 58.68, 51.24, 41.99, 41.78, 39.62, 39.51, 38.99, 35.31, 33.54, 25.59, 23.95. ESI-HRMS:(m / z)calcd.for C 12 H 18 NO([M+H] + )192.1383,found:192.1380.

[0269] Cultivation and X-ray diffraction of (+)-32-LAC single crystals: Weigh 10 mg of (+)-32-LAC sample and dissolve it in CH2Cl2 (1 mL). Then add n-hexane (2 mL), shake well, filter, and place the filtrate into a small glass conical flask. After slowly evaporating at room temperature for 2-3 days, a single crystal suitable for X-ray diffraction was obtained. A single crystal with a size of 0.12×0.1×0.08 mm was taken and diffracted with Cu Kα rays at 100.00 (10) K on a Rigaku XtaLAB Pro single crystal diffractometer. Diffraction data were collected and reduced using CrysAlisPro 1.171.39.33c (Rigaku OD, 2017). The structure was solved and refined using the SHELXL program.

[0270] The chemical structure (ORTEP pattern) of the single crystal diffraction of compound (+)-32-LAC is shown in FIG1 .

[0271] The relevant parameters of (+)-32-LAC crystal testing and structure refinement are shown in the table:

[0272] Example 8 Synthesis of Compounds (-)-I-4, (+)-I-4 and Their p-Toluenesulfonates

[0273] Step 1: Synthesis of compound (±)-22

[0274] At room temperature, (±)-22 p-toluenesulfonate (60.00 g, 0.14 mol) was added to a saturated NaHCO solution (600 mL x 2), stirred, and extracted with EtOAc (400 mL x 2). The combined organic phases were dried (MgSO), filtered to remove the desiccant, and concentrated on a rotary evaporator under reduced pressure to yield compound (±)-22 as a yellow oil (36 mL). This product was used directly in the next reaction without characterization.

[0275] 3,5-Dinitrobenzoyl Derivatization: Synthesis of 3,5-Dinitrobenzoyl Derivatives of (±)-22

[0276] At room temperature, the p-toluenesulfonate salt of compound (±)-22 (1.00 g, 2.3 mmol) was added to a saturated NaHCO₃ solution (200 mL) with stirring and extracted with EtOAc (100 mL x 2). The organic phases were combined, dried (MgSO₄), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator under reduced pressure to yield compound (±)-22 as a pale yellow oil. The oil was dissolved in CH₂Cl₂ (7 mL) and stirred, followed by the addition of 3,5-dinitrobenzoyl chloride (0.60 g, 2.6 mmol). Triethylamine (0.6 mL) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 1 h. TLC monitoring indicated the reaction was complete. The reaction solution was directly purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 4) to yield a pale yellow oil. To the oil was added n-hexane (10 mL) and the mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to obtain the target product (±)-22, a 3,5-dinitrobenzoylated derivative. White solid; 0.60 g (57%); melting point: 118.9°C-119.8°C;

[0277] 1 H NMR (CDCl3, 500MHz) δ: 9.46 (brs, 1H), 9.19 (d, 2H, J = 2.0Hz), 9.16 (t, 1H, J = 2.0Hz), 6.40-6.42 (m, 1H), 6.31-6.33 (m, 1H), 3.82 (dd, 1H, J = 5.5Hz and 13.5Hz),3.36(dd,1H,J=3.3Hz and 13.8Hz),2.86-2.90(m,3H),2.69(dd,1H,J=1.0Hz and 17.0Hz),2.58-2.60(m,1H),2.37(d,1H,J=17.5Hz),1.77-1.81(m,1H),1.58-1.61(m,10H),1.30(dd,1H,J=5.8Hz and 12.3Hz),1.11-1.13(m,1H).

[0278] 13 C NMR(CDCl3,126MHz)δ:175.42,162.99,148.82,138.26,138.12,136.52,127.59,12 0.86,82.84,54.11,53.02,46.82,45.87,44.76,42.21,37.02,35.75,34.57,28.14.

[0279] ESI-HRMS: (m / z) calcd. for C 23 H 27N3NaO7([M+Na] + )458.1741,found:458.1735.

[0280] The 3,5-dinitrobenzoylated derivative of (±)-22 is used as a reference substance for the chiral HPLC test of the optical purity of (-)-22 and (+)-22 after chiral acid resolution of (±)-22 in steps 2 and 3.

[0281] Step 2: Synthesis of (R)-(-)-mandelate salt of compound (-)-22

[0282] At room temperature, compound (±)-22 (18.14 g, 69 mmol) was dissolved in THF (90 mL), and a solution of (R)-(-)-mandelic acid (4.50 g, 30 mmol) in THF (90 mL) was added dropwise. Stirring was continued for 30 minutes after the addition was complete. Isopropyl ether (180 mL) was then added dropwise. Stirring was continued at room temperature overnight until crystals precipitated. If no solid precipitated, an appropriate amount of seed crystals was added to the system, which would gradually cause solid precipitation. A solution of R-(-)-mandelic acid (2.25 g, 15 mmol) in THF (9 mL) was then added dropwise. Stirring was continued at room temperature for 1 hour, followed by the addition of isopropyl ether (180 mL). Upon completion of the addition, the amount of solid in the system increased, and stirring was continued at room temperature for 1 hour. The solid was collected by filtration (the filtrate was recovered) and dried using a vacuum oil pump to yield a white solid (8.60 g, 21 mmol), the (R)-(-)-mandelate salt of (-)-22. A small sample was taken and subjected to the 3,5-dinitrobenzoyl derivatization procedure described above, and chiral HPLC analysis revealed an ee value of 87.05%. The (R)-(-)-mandelate salt of (-)-22 (8.40 g, 20 mmol) was thoroughly stirred with a THF (40 mL) / isopropyl ether (40 mL) mixture at room temperature. The mixture was then stirred in a 65°C oil bath. Additional THF (10 mL) / isopropyl ether (10 mL) mixture was added dropwise, causing slight dissolution. Stirring was continued for 30 minutes, and the mixture was then allowed to stand at room temperature and stirred overnight. The solid was collected by filtration and dried under vacuum to yield a white solid (6.60 g, 16 mmol). This solid was recrystallized again using THF / isopropyl ether = 1 / 2 (v / v) as a solvent, yielding the pure R-(-)-mandelate salt of compound (-)-22. A small sample was taken and subjected to the above 3,5-dinitrobenzoyl derivatization procedure, and chiral HPLC analysis revealed an ee value of 99.10%. The product was used directly in the next reaction without further characterization.

[0283] Step 3: Synthesis of (S)-(+)-mandelate salt of compound (+)-22

[0284] Compound (±)-22 (18.14 g, 69 mmol) was dissolved in isopropanol (45 mL) at room temperature, followed by the dropwise addition of a solution of (S)-(+)-mandelic acid (9.00 g, 59 mmol) in isopropanol (45 mL). Upon completion of the addition, if no significant change was observed, stirring was continued for 30 min, followed by the dropwise addition of isopropyl ether (270 mL). The mixture was stirred until a large amount of solid formed; if no crystals formed, an appropriate amount of seed crystals was added. The crystallization system was stirred overnight at room temperature. The crystals were collected by filtration (the filtrate was recovered) and dried under vacuum to afford the (S)-(+)-mandelate salt of (+)-22 as a white solid (9.00 g, 22 mmol). A small amount was then subjected to the above 3,5-dinitrobenzoyl derivatization procedure, and chiral HPLC analysis revealed an ee value of 30.88%. At room temperature, the (S)-(+)-mandelate salt of (+)-22 (9.00 g, 22 mmol) was thoroughly stirred with a mixture of isopropyl alcohol and isopropyl ether (1 / 2 v / v, 50 mL total) and then transferred to a 60°C oil bath for stirring (the solution was slightly soluble). Stirring was continued for 10 minutes, and the mixture was then allowed to stand at room temperature, whereupon a large amount of white solid gradually precipitated. A mixture of isopropyl alcohol and isopropyl ether (1 / 2 v / v, 15 mL total) was added dropwise, and stirring was continued for 1-2 hours. The solid was collected by filtration and dried under vacuum to afford a white solid (5.40 g, 13 mmol). This recrystallization procedure was repeated twice to afford the (S)-(+)-mandelate salt of (+)-22. A small amount was then used in the 3,5-dinitrobenzoyl derivatization procedure described above, and chiral HPLC analysis revealed an ee value of 98.34%. The product was a white solid (2.40 g, 17%). This product was used directly in the next reaction without further characterization.

[0285] Step 4: Synthesis of compound (-)-I-4 and its p-toluenesulfonate

[0286] At room temperature, the (R)-(-)-mandelate salt of compound (-)-22 (3.00 g, 7.2 mmol) was added to a saturated NaHCO solution (100 mL), stirred for 20 min, and extracted with EtOAc (80 mL x 3). The combined organic phases were dried (MgSO), and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil, which was then dissolved in CH2Cl2 (20 mL). TFA (15 mL) was slowly added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 4-6 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to yield a brown oil, which was then concentrated again by adding CH2Cl2 (20 mL). The resulting oil was dried using a vacuum pump to yield (-)-I-4. The above (-)-I-4 was dissolved in CH3OH (2.5 mL), and EtOAc (12 mL) was added and stirred thoroughly. p-TsOH·H2O (1.40 g, 7.4 mmol) was added to the solution and stirred until dissolved. A large amount of solid precipitated. Stirring was continued at room temperature for 1 hour. The solid was collected by filtration and the filter cake was dried using a vacuum oil pump to obtain the p-toluenesulfonate salt of compound (-)-I-4. It was a white solid; 1.80 g (66%); melting point 180.3°C-183.5°C; [α] D 20 =-35.47 (c = 2.65, CH3OH);

[0287] 1 H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.5Hz), 7.23 (d, 2H, J = 8.0Hz), 6.42-6.44 (m, 1H),6.29-6.31(m,1H),3.24(d,1H,J=13.0Hz),3.12(d,1H,J=13.0Hz),2.92-2.94( m,1H),2.81-2.87(m,2H),2.57(d,1H,J=17.5Hz),2.49-2.53(m,1H),2.37(s,3H), 2.36(d,1H,J=17.5Hz),1.75-1.80(m,1H),1.57-1.59(m,1H),1.34(dd,1H,J=4.5Hz and 13.5Hz),1.14-1.15(m,1H).

[0288] 13 C NMR(CD3OD,126MHz)δ:175.72.143.52,141.71,138.50,137.88,129.82,126 .96,53.81,50.45,48.14,46.89,45.84,37.91,37.15,35.07,34.06,21.31.

[0289] Compound (-)-I-4 is a specific form of the compound of the general formula I of the present application, and is also an optically pure compound of (±)-I-4 that has the same relative configuration as (±)-I-4 and has left-handed optical rotation.

[0290] Step 5: Synthesis of compound (+)-I-4 and its p-toluenesulfonate

[0291] Compound (+)-22(S)-(+)-mandelate salt (2.40 g, 5.8 mmol) was added to a saturated NaHCO solution (100 mL) at room temperature and stirred for 20 minutes. The mixture was then extracted with EtOAc (60 mL x 3). The combined organic phases were dried (MgSO) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil, which was then dissolved in CHCl (18 mL). TFA (14 mL) was slowly added dropwise in an ice-water bath. After the addition was complete, the mixture was allowed to react at room temperature for 4-6 hours. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to yield a brown oil. CHCl (20 mL) was added and the mixture was concentrated again. The resulting oil was dried using a vacuum pump to yield (+)-I-4. The dried oil was dissolved in CHOH (2 mL) and stirred with EtOAc (8 mL). p-TsOH·H2O (1.10 g, 5.8 mmol) was added to the reaction solution and stirred to dissolve. A large amount of solid precipitated. Stirring was continued at room temperature for 1 hour. The solid was collected by filtration and the filter cake was dried using a vacuum oil pump to obtain compound (+)-I-4 p-toluenesulfonate. It was a white solid; 1.60 g (73%); melting point: 182.1°C-184.7°C; [α] D 20 =+37.81 (c=2.75, CH3OH);

[0292] 1H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.0Hz), 6.42-6.44 (m, 1H),6.29-6.31(m,1H),3.24(d,1H,J=13.0Hz),3.12(d,1H,J=13.0Hz),2.92-2.94( m,1H),2.81-2.87(m,2H),2.57(d,1H,J=17.5Hz),2.50-2.53(m,1H),2.37(s,3H), 2.36(d,1H,J=17.5Hz),1.75-1.80(m,1H),1.57-1.59(m,1H),1.34(dd,1H,J=6.0Hz and 13.5Hz),1.13-1.16(m,1H).

[0293] 13 C NMR(CD3OD,126MHz)δ:175.73,143.53,141.70,138.50,137.89,129.82,126 .96,53.81,50.45,48.14,46.89,45.85,37.92,37.15,35.07,34.07,21.30.

[0294] Compound (+)-I-4 is a specific form of the compound of the general formula I of the present application, and is also an optically pure compound of (±)-I-4 that has the same relative configuration as (±)-I-4 and has dextrorotatory optical properties.

[0295] The absolute configuration of compound (+)-I-4 was determined by converting the (S)-(+)-mandelate salt of (+)-22, which has the same absolute configuration, into its lactam (+)-22-LAC. The absolute configuration of (+)-22-LAC was determined using single crystal X-ray diffraction, and the absolute configuration was the same as that of (+)-32. This method can indirectly determine the absolute configuration of (+)-I-4.

[0296] The specific experimental methods are as follows:

[0297] Synthesis of (+)-22-LAC: The (S)-(+)-mandelate salt of (+)-22 (1.00 g, 2.4 mmol), with an ee of 98.34%, was added to a saturated NaHCO₃ solution (100 mL) and stirred for 10 min. The mixture was then extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried (MgSO₄), and filtered to remove the desiccant. The filtrate was evaporated to dryness on a rotary evaporator. The resulting residue was dissolved in toluene (7 mL) and refluxed overnight. TLC indicated the reaction was complete. The reaction system was cooled to room temperature, the solvent was evaporated on a rotary evaporator, and the residue was slurried in EtOAc / hexane (1 / 10 v / v, 5 mL total). The crystals were collected by filtration and dried to yield (+)-32-LAC, 0.40 g (88%); m.p. 178.7-180.5°C; [α] D 20 =+30.2°(c=1.03,CH3OH).

[0298] 1 H NMR (CDCl3, 500MHz) δ: 6.27-6.29 (m, 1H), 6.22-6.24 (m, 1H), 5.89 (brs, 1H), 3.40 (dd, 1H, J = 1.0Hz and9.5Hz),3.36(d,1H,J=9.5Hz),2.97-2.99(m,1H),2.81-2.83(m,1H),2.69-2.74(m,1H),2. 54-2.57(m,1H),2.13(d,1H,J=17.0Hz),2.05(d,1H,J=17.0Hz),1.91(ddd,1H,J=1.0Hz,8.5Hz and 12.5Hz),1.57-1.60(m,1H),1.42(dd,1H,J=0.8Hz and 12.8Hz),1.08-1.10(m,1H).

[0299] 13 C NMR (CDCl3, 126MHz) δ: 178.22, 136.71, 136.25, 58.19, 52.34, 48.58, 45.59, 44.50, 40.90, 40.74, 37.63, 33.04. ESI-HRMS:(m / z)calcd.for C 12 H 16 NO([M+H] + )190.1226,found:190.1224.

[0300] Cultivation and X-ray diffraction of (+)-22-LAC single crystals: Weigh 10 mg of (+)-22-LAC sample and dissolve it in CH2Cl2 (1 mL). Then add n-hexane (2 mL), shake well, filter, and place the filtrate in a small glass conical flask. After slowly evaporating at room temperature for 2-3 days, a single crystal suitable for X-ray diffraction is obtained. A single crystal with a size of 0.3×0.09×0.08 mm is taken and diffracted with Cu Kα rays at 100.00 (10) K on a Rigaku XtaLAB Pro single crystal diffractometer. Diffraction data are collected and reduced using CrysAlisPro 1.171.39.33c (Rigaku OD, 2017). The structure is solved and refined using the SHELXL program.

[0301] The chemical structure of compound (+)-22-LAC by single crystal diffraction (ORTEP pattern) is shown in FIG2 .

[0302] The parameters related to the crystal testing and structure refinement of (+)-22-LAC are shown in the following table:

[0303] Example 9 Synthesis of Compound (±)-I-7

[0304] Step 1: Synthesis of compound (±)-33

[0305] Add dry CH2Cl2 (200 mL) to a dry flask, and replace the air in the reaction vessel with nitrogen (balloon) according to standard procedures. Under ice-water cooling, slowly add Et2Zn (1M in n-hexane, 298 mL) and TFA (33.99 g, 0.30 mol) in dry CH2Cl2 (30 mL) dropwise to the system, yielding a white slurry. After the additions are complete, continue stirring in an ice-water bath for 0.5 h, then add a solution of CH2I2 (79.84 g, 0.30 mol) in dry CH2Cl2 (80 mL) dropwise. (During the addition, a white viscous solid gradually dissolves and becomes clear, followed by precipitation of a white solid to form a suspension.) After the additions are complete, continue stirring in an ice-water bath for 0.5 h, then add a solution of compound (±)-18 (10.00 g, 75 mmol) in dry CH2Cl2 (20 mL) dropwise. After the addition was complete, the reaction system was stirred at room temperature for 4-6 hours and then heated to reflux overnight. TLC monitoring showed that the reaction was complete, and the reaction was stopped. After the reaction system cooled to room temperature, it was added to a saturated aqueous NH4Cl solution (300mL×2), stirred, and extracted with CH2Cl2 (200mL×2). After the organic phases were combined, they were washed with saturated brine (400mL) and separated. The organic phases were combined, dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated using a rotary evaporator to obtain a brown oil, which was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target compound (±)-33. Yellow oil (slightly impure); 3.15g (29%);

[0306] 1 H NMR (CDCl3, 500MHz) δ: 3.48-3.52 (m, 1H), 2.95 (dt, 1H, J = 3.5Hz and 18.5Hz),2.65-2.77(m,2H),2.55-2.56(m,1H),2.51-2.53(m,1H),1.32-1.35(m,1H),1.01 -1.05(m,1H),0.97-1.00(m,1H),0.87-0.90(m,1H),0.54-0.57(m,1H),0.03-0.08(m,1H).

[0307] Step 2: Synthesis of compound (±)-34

[0308] Under a nitrogen atmosphere, t-BuOK (11.92 g, 0.11 mol) was added to dry THF (30 mL). After stirring in an ice-water bath to form a suspension, tert-butyl diethylphosphonoacetate (26.81 g, 0.11 mol) was added dropwise. After the addition was complete, the mixture was reacted in an ice-water bath for 1 h. A freshly prepared solution of compound (±)-33 (3.15 g, 21 mmol) in dry THF (10 mL) was then added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring indicated the reaction was complete. The reaction solution was poured into ice water (80 mL x 2) and extracted with CH2Cl2 (60 mL x 2). The combined organic phases were washed once with saturated brine (150 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to yield a dark yellow oil. This oil was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to afford the desired product (±)-34 as a light yellow oil (3.15 g). This product was used directly in the next reaction without further characterization.

[0309] Step 3: Synthesis of compound (±)-35

[0310] Compound (±)-34 (3.60 g, 15 mmol) was dissolved in CH₃NO₂ (120 mL) at room temperature and stirred, followed by the dropwise addition of DBU (24.47 g, 0.16 mol). After the addition was complete, the reaction mixture was refluxed for 48 h under N₂. TLC monitoring indicated a significant amount of unreacted starting material, so the reaction was terminated. The reaction solution was cooled to room temperature and poured into ice water. Extraction was performed with CH₂Cl₂ (50 mL x 2). The combined organic phases were washed sequentially with ice water (100 mL) and saturated brine (150 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to afford a brownish-black oil, which was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9) to afford the desired product (±)-35. A pale yellow oil; 0.74 g (combined yield of (±)-33 → (±)-35: 10%).

[0311] 1H NMR (CDCl3, 500MHz) δ: 4.83 (dd, 1H, J = 1.3Hz and 11.3Hz),4.55(d,1H,J=11.0Hz),2.73(s,2H),2.52-2.58(m,1H),2.48-2.49 (m,1H),2.30-2.32(m,1H),2.15-2.19(m,2H),2.11(ddd,1H,J=2.3Hz,8.5Hz and13.3Hz),1.48(s,9H),1.23-1.27(m,1H),1.13-1.17(m,2H),0.58-0.60(m,1H),0.43-0.46(m,1H),0.06-0.10(m,1H).

[0312] 13 C NMR (CDCl3, 126MHz) δ: 170.79, 83.55, 81.08, 49.08, 39.87, 39.61, 38.64, 37.19, 34.59, 29.94, 29.14, 28.26, 12.23, 11.14, 2.58.

[0313] ESI-HRMS: (m / z) calcd. for C 17 H 26 NO4([M+H] + )308.1856,found:308.1853.

[0314] Step 4: Synthesis of compound (±)-36

[0315] Compound (±)-35 (0.28 g, 0.91 mmol) was dissolved in CH2Cl2 (5 mL). Et3SiH3 (0.16 g, 1.4 mmol) and TFA (2 mL) were added dropwise in an ice-water bath. After the addition was complete, the mixture was allowed to react at room temperature for 4 h. TLC monitoring indicated the reaction was complete. The reaction mixture was poured into ice water (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator at low temperature (25°C) to afford a yellow oil. CH2Cl2 (10 mL × 3) was added to the oil and the mixture was further concentrated. The mixture was dried under vacuum for 10 min, resulting in the precipitation of a white solid. The solid was crushed and added with n-hexane (4 mL). The mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to afford compound (±)-36. White solid; 0.09 g (39%); melting point 105.7°C-109.3°C;

[0316] 1H NMR (DMSO-d6, 500MHz) δ: 12.31 (brs, 1H), 4.78 (d, 1H, J = 12.0Hz), 4.71 (d, 1H, J = 12.0Hz), 2.74 (d, 1H, J = 17.5Hz), 2.56 (d, 1H,J=17.5Hz),2.52-2.55(m,1H),2.36-2.37(m,1H),2.21-2.23(m,1H),2.12-2.17(m,2H),2.00(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.21-1.23(m,1H),1.17-1.20(m,1H),1.09-1.12(m,1H),0.54-0.56(m,1H),0.37-0.39(m,1H),-0.01-0.03(m,1H).

[0317] 13 C NMR (CDCl3, 126MHz) δ: 176.63, 83.22, 48.89, 39.71, 38.20, 37.95, 37.13, 34.63, 29.81, 29.14, 12.42, 11.33, 2.66.

[0318] ESI-HRMS: (m / z) calcd. for C 13 H 18 NO4([M+H] + )252.1230,found:252.1228.

[0319] Step 5: Synthesis of compound (±)-I-7

[0320] Compound (±)-36 (0.18 g, 0.72 mmol) was dissolved in CH3OH (4 mL) and 10% Pd(OH)2 / C (0.06 g) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature overnight. TLC monitoring showed that the reaction was complete (the reaction generally took 12 hours to complete). The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a white solid. CH3OH (1 mL) / EtOAc (3 mL) was added and stirred at room temperature for 1-2 hours. Filter and dry to obtain the target product (±)-I-7. White solid; 0.04 g (25%); melting point 184.5℃-190.0℃;

[0321] 1H NMR (CD3OD, 500MHz) δ: 3.10 (dd, 1H, J = 1.5Hz and 13.0Hz), 2.96 (d, 1H, J = 13.0Hz), 2.78 (dd, 1H, J = 1.3Hz and 16.8Hz),2.60(d,1H,J=16.5Hz),2.51-2.55(m,1H),2.48-2.49(m,1H),2.23-2.27(m,2H),2.18(dd,1H,J=6.8Hz and 12.8Hz),1.69(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.50-1.53(m,1H),1.14-1.20(m,2H),0.56-0.58(m,1H),0.45-0.48(m,1H),0.03-0.07(m,1H).

[0322] 13 C NMR (D2O, 126MHz) δ: 179.55, 49.53, 46.11, 44.30, 37.56, 35.01, 34.80, 32.58, 29.65, 26.94, 10.37, 9.02, 0.01. ESI-HRMS:(m / z)calcd.for C 13 H 20 NO2([M+H] + )222.1489,found:222.1487.

[0323] Compound (±)-I-7 is a specific form of the compound having the general formula I of the present application.

[0324] Example 10 Synthesis of Compound (±)-I-8

[0325] Step 1: Synthesis of compound 37

[0326] Maleic anhydride (27.79 g, 0.28 mol) was dissolved in a mixed solvent of benzene (50 mL) / methyl tert-butyl ether (150 mL). The air in the reactor was replaced with nitrogen (balloon) according to standard procedures. A solution of 1,2,3,4,5-pentamethylcyclopentadiene (20.00 g, 0.15 mol) in benzene / methyl tert-butyl ether = 1 / 3 (v / v, 50 mL in total) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction was stopped and the reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a purple-red oil. The oil was placed in an ice-water bath for low-temperature crystallization. After crystals precipitated, n-hexane (100 mL) was added and stirred at room temperature for 1 hour. The solid was collected by suction filtration and the filter cake was dried using a vacuum oil pump to obtain a crude product of compound 37. White solid (containing a certain amount of impurities); 40.00 g (>100%, because it contains a certain amount of unreacted maleic anhydride); the product was not further purified and was directly used in the next reaction.

[0327] 1 H NMR (CDCl3, 500MHz) δ: 3.18 (s, 2H), 1.55-1.59 (m, 7H), 1.35 (s, 6H), 0.62 (d, 3H, J = 6.5Hz).

[0328] Step 2: Synthesis of compound 38

[0329] Compound 37 (40.00 g, calculated as 0.17 mol) was dissolved in 1,4-dioxane (400 mL). 50% aqueous NaOH solution (68 mL) was slowly added dropwise under an ice bath, and a white solid gradually precipitated during the addition. After the addition was complete, 1,4-dioxane (300 mL) was added to the system and stirred at room temperature for 1 hour. TLC monitoring showed that the reaction was complete. Under ice cooling, 1M HCl was slowly added dropwise to the reaction system until the pH was <2. The mixture was saturated with sodium chloride and extracted with EtOAc (300 mL × 3). The organic phases were combined, dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator to obtain a residue. n-Hexane (100 mL) was added to the residue and stirred at room temperature for 1 hour. The solid was collected by suction filtration and dried under vacuum oil pump to obtain compound 38. White solid; 20.86 g (combined yield of 1,2,3,4,5-pentamethylcyclopentadiene→38: 56%); the product was used directly in the next reaction without further purification. 1 H NMR (DMSO-d6, 500MHz) δ: 2.90 (s, 2H), 1.54 (s, 6H), 1.37 (q, 1H, J = 6.3Hz), 1.08 (s, 6H), 0.52 (d, 3H, J = 6.5Hz).

[0330] Step 3: Synthesis of compound 39

[0331] Compound 38 (20.86 g, 83 mmol) was dissolved in N,N-dimethylformamide (DMF) (210 mL). The air in the reactor was replaced with nitrogen (balloon) according to standard procedures. K2CO3 (34.28 g, 0.25 mol) was added under ice-water cooling, followed by the slow dropwise addition of CH3I (46.94 g, 0.33 mol). After the addition was complete, the reaction was allowed to react at room temperature for 5-6 hours. TLC monitoring indicated the reaction was complete. EtOAc (200 mL) was added to the reaction solution, the solid was removed by filtration, and the filtrate was washed with water (300 mL x 5). All aqueous phases were combined and back-extracted with EtOAc (200 mL x 2). All organic phases were combined, washed with saturated brine (500 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator to yield a yellow oil, which was purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to afford the desired product 39 as a colorless, transparent oil (22.10 g, 95%, containing some impurities). This product was used directly in the next reaction without further purification.

[0332] 1 H NMR (CDCl3, 500MHz) δ: 3.57 (s, 6H), 3.00 (s, 2H), 1.60 (s, 6H), 1.37 (q, 1H, J = 6.3Hz), 1.15 (s, 6H), 0.60 (d, 3H, J = 6.5Hz).

[0333] Step 4: Synthesis of compound (±)-40

[0334] Sodium metal (9.97 g, 0.43 mol) was added to dry toluene (220 mL). Under a nitrogen atmosphere, the mixture was heated until the sodium was completely melted. Stirring was initiated, and the reaction system was maintained at an internal temperature of 103°C-106°C for 20 min. A solution of compound 39 (22.10 g, 79 mmol) and TMSCl (45.39 g, 0.42 mol) in dry toluene (15 mL) was then added dropwise. The addition was exothermic, and the reaction system temperature was maintained at 103°C-106°C by controlling the addition rate. After the addition was complete, the reaction system was stirred overnight while maintaining an internal temperature of 103°C-106°C. TLC monitoring indicated the reaction was complete, and the reaction solution was cooled to room temperature. Filtering was performed using celite, and the filtrate was concentrated under reduced pressure on a rotary evaporator to yield a brown oil. The oil was dissolved in THF (100 mL), and 1M HCl (15 mL) was added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 30 min. TLC monitoring showed that the reaction was complete. The reaction solution was poured into water (100 mL) and extracted with EtOAc (100 mL×2). After combining the organic phases, the mixture was washed with saturated brine (300 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which solidified at low temperature. N-hexane (10 mL) was added to the above solid and stirred at room temperature for 1 hour. The solid was collected by filtration and dried with a vacuum oil pump to obtain the target compound (±)-40. White solid; 3.60 g (21%); melting point 124.0℃-128.0℃;

[0335] 1 H NMR (CDCl3, 500MHz) δ: 4.44 (dd, 1H, J = 3.5Hz and 9.0Hz), 3.16 (dd, 1H, J = 3.5Hz and 7.5Hz), 2.91 (dd, 1H, J = 7.5Hz and 9.0Hz), 1.640-1.643 (m, 3H), 1.58-1.62 (m, 2H), 1.499-1.504 (m, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 0.57 (d, 3H, J = 6.5Hz).

[0336] Step 5: Synthesis of compound (±)-41

[0337] Compound (±)-40 (2.61 g, 12 mmol) was dissolved in CCl₄ (20 mL), and triphenylphosphine (3.41 g, 13 mmol) and NaHCO₃ (0.04 g, 0.48 mmol) were added sequentially with stirring. The air in the reactor was replaced with nitrogen (balloon) according to standard procedures, and the mixture was stirred and refluxed overnight. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure. Methyl tert-butyl ether (12 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h. The solid was removed by filtration, and the filtrate was concentrated on a rotary evaporator under reduced pressure to obtain a brown-black oil. The target product (±)-41 was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 9 / 91) to obtain a light yellow oil (slightly impure); 2.20 g. This product did not require characterization and was used directly in the next step.

[0338] Step 6: Synthesis of compound (±)-42

[0339] Zinc powder (2.06 g, 32 mmol) and glacial acetic acid (10 mL) were stirred and mixed. A freshly prepared solution of compound (±)-41 (2.20 g, 9.2 mmol) in glacial acetic acid (5 mL) was then added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred in an oil bath at 55°C overnight under a nitrogen atmosphere. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ice water (50 mL) and extracted with CHCl (40 mL x 2). The combined organic phases were washed sequentially with water (80 mL x 3) and saturated brine (100 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil. This was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 20) to yield a pale yellow oil. The oil was dried using a vacuum pump to a solid. Add n-hexane (5 mL) to the above solid and stir at room temperature for 1 hour. Filter and dry the filter cake using a vacuum pump to obtain the target compound (±)-42. 1.08 g (combined yield of (±)-40 and (±)-42, 45%) as a white solid; melting point: 101.0°C-103.0°C.

[0340] 1H NMR(CDCl3,500MHz)δ:3.34-3.37(m,1H),2.62(ddd,1H,J=3.0Hz,8.5Hz and 18.5Hz),2.49-2.52(m,1H),2.14(dt,1H,J=3.5Hz and 18.5Hz), 1.616-1.624 (m, 3H), 1.51-1.52 (m, 3H), 1.48 (q, 1H, J = 6.5Hz), 1.14 (s, 3H), 1.13 (s, 3H), 0.58 (d, 3H, J = 6.5Hz).

[0341] 13 C NMR (CDCl3, 126MHz) δ: 211.60, 134.45, 133.12, 73.07, 66.04, 56.64, 55.52, 45.28, 36.90, 15.97, 15.29, 12.49, 11.11, 8.19.

[0342] ESI-HRMS: (m / z) calcd. for C 14 H 21 O([M+H] + )205.1587,found:205.1587.

[0343] Step 7: Synthesis of compound (±)-43

[0344] Under N₂ atmosphere, t-BuOK (2.35 g, 21 mmol) was added to dry THF (10 mL). After stirring in an ice-water bath to form a suspension, tert-butyl diethylphosphonoacetate (5.28 g, 21 mmol) was added dropwise. After the addition was complete, the mixture was reacted in an ice-water bath for 30 min. A freshly prepared solution of compound (±)-42 (0.86 g, 4.2 mmol) in dry THF (7 mL) was then added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring indicated the reaction was complete. The reaction solution was poured into ice water (80 mL) and extracted with CH₂Cl₂ (30 mL x 3). The combined organic phases were washed sequentially with 1M HCl (20 mL) and saturated brine (100 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to yield a dark yellow oil. This oil was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 20] to afford the desired product (±)-43 as a pale yellow oil (0.97 g). This product was used directly in the next reaction without further characterization.

[0345] Step 8: Synthesis of compound (±)-44

[0346] Compound (±)-43 (0.97 g, 3.2 mmol) was dissolved in CH₃NO₂ (12 mL) at room temperature, and DBU (4.40 g, 29 mmol) was added dropwise. After the addition was complete, the reaction mixture was refluxed for 48 h under N₂. TLC monitoring showed approximately 60% of the starting material was unreacted, so the reaction was terminated. The reaction solution was cooled to room temperature, poured into ice water (100 mL), and extracted with CH₂Cl₂ (50 mL x 2). The combined organic phases were washed sequentially with 1M HCl (50 mL) and saturated brine (100 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a brown-black oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to yield a pale yellow oil. The oil solidified at low temperature. Hexane (2 mL) was added and stirred at -18°C for 30 min. The solid was collected by filtration and dried under vacuum to obtain the desired product (±)-44. ((±)-42 → (±)-44) was a white solid (0.10 g, 7% yield). The melting point was 78.6°C-81.5°C.

[0347] 1 H NMR (CDCl3, 500MHz) δ: 4.82 (d, 1H, J = 11.5Hz), 4.66 (d, 1H, J = 11.5Hz), 2.47-2.52 (m, 1H), 2.3 6(d,1H,J=17.5Hz),2.28(d,1H,J=17.5Hz),2.24-2.26(m,1H),1.91(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.73-1.74(m,3H),1.605-1.612(m,3H),1.44(s,9H),1.17-1.24(m,2H),1.00(s,3H),0.97(s,3H),0.55(d,3H,J=6.0Hz).

[0348] 13 C NMR(CDCl3,126MHz)δ:171.17,137.15,134.49,82.91,80.86,66.54,56.45,55. 96,55.78,42.49,39.08,36.58,31.59,28.25,16.22,15.25,13.26,12.84,8.12.

[0349] ESI-HRMS: (m / z) calcd. for C 21 H 32 NO4([MH] - )362.2337,found:362.2343.

[0350] Step 9: Synthesis of compound (±)-45

[0351] Compound (±)-44 (0.10 g, 0.28 mmol) was dissolved in CH2Cl2 (5 mL) and TFA (1 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 2-3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 7] to obtain a light yellow solid. N-hexane (3 mL) was added to the solid and stirred at room temperature for 1 hour. The solid was collected by filtration and dried under vacuum to obtain compound (±)-45. White solid; 0.05 g (63%); melting point 122.8℃-126.4℃;

[0352] 1 H NMR (CDCl3, 500MHz) δ: 4.78 (d, 1H, J = 12.0Hz), 4.74 (d, 1H, J = 11.5Hz), 2.55 (d, 1H, J = 18.0Hz) ,2.50-2.54(m,1H),2.51(d,1H,J=18.0Hz),2.26-2.28(m,1H),1.91(ddd,1H,J=2.0Hz,8.5Hz and 13.5Hz),1.75-1.76(m,3H),1.61-1.62(m,3H),1.22-1.26(m,2H),0.99(s,3H),0.98(s,3H),0.56(d,3H,J=6.5Hz);

[0353] 13 C NMR(CDCl3,126MHz)δ:176.32,137.65,134.32,82.69,66.66,56.44,56.10,55.55,42.44,38.57,34.98,31.74,16.34,15.23,13.31,12.88,8.11;

[0354] ESI-HRMS: (m / z) calcd. for C 17 H 26 NO4([M+H] + )308.1856,found:308.1850.

[0355] Step 10: Synthesis of compound (±)-I-8

[0356] Compound (±)-45 (0.05 g, 0.16 mmol) was dissolved in CH3OH (3 mL) and 10% Pd(OH)2 / C (0.03 g) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature overnight. TLC monitoring showed that the reaction was complete (the reaction generally required 12 h to complete). The mixture was filtered and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a white solid. CH3OH (1 mL) / EtOAc (3 mL) was added and stirred at room temperature for 0.5 h. The solid was collected by filtration and dried under vacuum to obtain the target product (±)-I-8. White solid; 0.02 g (53%); melting point: 180.0°C-184.0°C;

[0357] 1 H NMR (CD3OD, 500MHz) δ: 3.09 (dd, 1H, J = 0.8Hz and 13.3Hz), 2.97 (d, 1H, J = 13.0Hz), 2.48-2.53 (m, 1H), 2.43 (dd, 1H, J = 1.3Hz and 17.3Hz),2.27(d,1H,J=17.0Hz),2.20-2.22(m,1H),1.81-1.82(m,3H),1.61-1.62(m,3H),1.59(ddd,1H,J=2.0Hz,8.0Hz and 12.5Hz),1.24(q,1H,J=6.3Hz),1.14(dd,1H,J=6.5Hz and 12.5Hz),1.08(s,3H),0.99(s,3H),0.58(d,3H,J=6.5Hz);

[0358] 13 C NMR(CD3OD,126MHz)δ:180.23,137.15,136.15,67.72,57.44,56.85,55.52,51.85,45.39,43.50,38.85,34.01,16.90,15.51,13.16,12.83,8.44;

[0359] ESI-HRMS: (m / z) calcd. for C 17 H 28 NO2([M+H] + )278.2115,found:278.2111.

[0360] Compound (±)-I-8 is a specific form of the compound having the general formula I of the present application.

[0361] Example 11 Synthesis of Compound (±)-I-9 and its p-toluenesulfonate

[0362] Step 1: Synthesis of compound 46

[0363] Tetrabutylammonium bromide (TBAB) (32.64 g, 0.10 mol) was added to a 50% aqueous NaOH solution (1.2 L) with stirring. The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. Freshly distilled cyclopentadiene (167.13 g, 2.5 mol) and 1,2-dichloroethane (250.50 g, 2.5 mol) were mixed uniformly in an ice-water bath and added dropwise to the reaction system. (The reaction is exothermic; the addition rate was controlled to maintain an internal temperature of 30°C-40°C. During the addition, the color of the system gradually changed from colorless and transparent to dark reddish-brown, and the system became viscous.) After the addition was complete, the reaction apparatus was moved to an oil bath, maintained at an internal temperature of 30°C-40°C, and stirred for 2 h. The reaction was terminated, the reaction solution was cooled to room temperature, poured into ice water (1.0 L), and extracted with n-pentane (300 mL x 2). The organic phases were combined and washed sequentially with water (500 mL x 2), 1 M HCl (300 mL), and saturated brine (500 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was subjected to atmospheric distillation, and the fractions at 108°C-109°C were collected to obtain the target compound 46 (containing a certain amount of n-pentane). 46.24 g (20%) of the compound was obtained as a colorless, transparent liquid. 1 H NMR (CDCl3, 500MHz) δ: 6.50-6.52 (m, 2H), 6.11-6.13 (m, 2H), 1.65 (s, 4H).

[0364] Step 2: Synthesis of compound 47

[0365] Maleic anhydride (11.28 g, 0.12 mol) was dissolved in a benzene (30 mL) / methyl tert-butyl ether (90 mL) solvent mixture. Following standard procedures, the air in the reactor was replaced with nitrogen (balloon). Compound 46 (13.24 g, 0.14 mol) in a 1 / 3 (v / v, 50 mL) benzene / methyl tert-butyl ether solution was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred overnight at room temperature and then refluxed in a 45°C oil bath for 2 h. The reaction was stopped, the temperature of the reaction system was lowered to room temperature, and the mixture was concentrated under reduced pressure on a rotary evaporator to yield a colorless, transparent oil. Hexane (100 mL x 4) was added, and the mixture was concentrated multiple times to yield a white solid. Hexane (120 mL) was added to the white solid, and the mixture was stirred and slurried at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to yield compound 47. White solid; 21.03 g (77%); melting point 92.7°C-96.9°C;

[0366] 1H NMR(CDCl3,500MHz)δ:6.386-6.394(m,2H),3.70-3.71(m,2H),2.88-2.90(m,2H),0.64-0.68(m,2H),0.51-0.54(m,2H);

[0367] 13 C NMR (CDCl3, 126MHz) δ: 171.25, 135.62, 51.11, 49.12, 47.54, 8.26, 7.12;

[0368] ESI-HRMS: (m / z) calcd. for C 11 H 11 O3([M+H] + )191.0703,found:191.0701.

[0369] Step 3: Synthesis of compound 48

[0370] Compound 47 (21.00 g, 0.11 mol) was dissolved in 1,4-dioxane (500 mL), stirred under ice cooling, and 50% aqueous NaOH solution (44 mL) was slowly added dropwise. A white solid gradually precipitated during the addition. After the addition was complete, stirring was continued at room temperature for 0.5-1 hour. TLC monitoring showed that the reaction was complete. Under ice bath, 1M HCl was added dropwise to adjust the pH of the reaction solution to <2, saturated with sodium chloride, and extracted with EtOAc (400 mL×3). The organic phases were combined, dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated using a rotary evaporator to obtain a residue. N-hexane (120 mL) was added to the residue and stirred at room temperature for 1 hour. The solid was collected by filtration and dried with a vacuum oil pump to obtain compound 48. White solid; 22.33 g (97%); melting point 163.3℃-166.3℃; 1 H NMR(CDCl3,500MHz)δ:6.345-6.352(m,2H),3.50-3.51(m,2H),2.53-2.55(m,2H),0.56-0.59(m,2H),0.42-0.45(m,2H);

[0371] 13 C NMR (CDCl3, 126MHz) δ: 179.21, 135.10, 51.32, 49.66, 44.86, 7.91, 6.55;

[0372] ESI-HRMS: (m / z) calcd. for C 11 H 13 O4([M+H] +)209.0808,found:209.0805.

[0373] Step 4: Synthesis of compound 49

[0374] Compound 48 (42.34 g, 0.20 mol) was dissolved in DMF (500 mL), and the air in the reactor was replaced with nitrogen (balloon) according to standard procedures. Dry K2CO3 (84.32 g, 0.61 mol) was added under an ice-water bath, followed by the slow dropwise addition of CH3I (115.44 g, 0.81 mol). After the addition was complete, the reaction was moved to a 55°C oil bath and stirred overnight. TLC monitoring indicated the reaction was complete. The reaction system was cooled to room temperature, and EtOAc (500 mL) was added. The mixture was stirred, and the solid was removed by filtration. The filtrate was washed with water (600 mL x 5). All aqueous phases were combined and back-extracted with EtOAc (300 mL x 2). All organic phases were then combined, washed with saturated brine (1.0 L), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated using a rotary evaporator to yield a brownish-black oil, which was purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 10] to yield a white solid. n-Hexane (150 mL) was added to the solid, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration and dried under vacuum to yield the title compound 49. White solid; 40.09 g (83%); melting point: 71.4°C-74.2°C.

[0375] 1 H NMR(CDCl3,500MHz)δ:6.34-6.35(m,2H),3.62(s,6H),3.45(m,2H),2.52-2.53(m,2H),0.54-0.57(m,2H),0.41-0.44(m,2H);

[0376] 13 C NMR (CDCl3, 126MHz) δ: 172.88, 135.07, 51.67, 51.37, 49.01, 44.46, 7.86, 6.51;

[0377] ESI-HRMS: (m / z) calcd. for C 13 H 17 O4([M+H] + )237.1121,found:237.1118.

[0378] Step 5: Synthesis of compound (±)-50

[0379] Sodium metal (21.41 g, 0.93 mol) was added to dry toluene (300 mL). Under a nitrogen atmosphere, the mixture was heated until the sodium was completely melted. Stirring was initiated and the internal temperature maintained at 103-106°C for 20 min. A solution of compound 49 (40.00 g, 0.17 mol) and TMSCl (97.48 g, 0.90 mol) in dry toluene (200 mL) was then added dropwise. The addition was exothermic; the addition rate was controlled to maintain the internal temperature of the reaction system at 103-106°C. After the addition was complete, stirring was continued for 3-4 hours while maintaining the internal temperature at 103-106°C. TLC monitoring indicated completion of the reaction, and the reaction solution was cooled to room temperature. Filtering was performed using celite, and the filtrate was concentrated under reduced pressure on a rotary evaporator to yield a dark reddish-brown oil. The oil was dissolved in THF (300 mL), and 1M HCl (20 mL) was added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was poured into water (300 mL) and extracted with EtOAc (300 mL × 2). After combining the organic phases, the mixture was washed with saturated brine (500 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a residue. A mixed solvent of EtOAc (15 mL) / n-hexane (90 mL) was added to the residue and stirred at room temperature for 1 hour. The solid was collected by filtration and dried with a vacuum oil pump to obtain the target compound (±)-50. Brown solid; 20.34 g (68%); The product did not require characterization and was used directly in the next reaction.

[0380] Step 6: Synthesis of compound (±)-51

[0381] Compound (±)-50 (20.34 g, 0.12 mol) was dissolved in CCl₄ (150 mL) and stirred. Triphenylphosphine (34.51 g, 0.13 mol) and NaHCO₃ (1.36 g, 16 mmol) were added sequentially. The air in the reactor was replaced with nitrogen (balloon) according to standard procedures, and the mixture was refluxed overnight. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered to remove solids. The filtrate was concentrated under reduced pressure on a rotary evaporator. A mixture of EtOAc (30 mL) and n-hexane (60 mL) was added to the residue, and stirring was continued at room temperature for 1 hour. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure on a rotary evaporator to yield a brown-black oil. The target product (±)-51 was purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97) to obtain the target product (±)-51. Light yellow oil (slightly impure); 7.36 g; the product does not require characterization and is used directly in the next reaction.

[0382] Step 7: Synthesis of compound (±)-52

[0383] Zinc powder (8.50 g, 0.13 mol) and glacial acetic acid (40 mL) were stirred and then a freshly prepared solution of compound (±)-51 (7.36 g, 38 mmol) in glacial acetic acid (30 mL) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred overnight in an oil bath at 55°C under a nitrogen atmosphere. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and poured into ice water (100 mL). Stirring was performed, and the solids were removed by filtration. The filtrate was extracted with EtOAc (80 mL x 3). The combined organic phases were washed sequentially with water (200 mL x 3), saturated NaHCO₃ solution (200 mL), and saturated brine (200 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to yield a yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97] to afford the desired product (±)-52 as a pale yellow oil; 4.87 g (combined yield of (±)-50 → (±)-52: 26%).

[0384] 1 H NMR(CDCl3,500MHz)δ:6.23-6.28(m,2H),3.84-3.88(m,1H),2.92-2.97(m,1H),2.74(ddd,1H,J=3.0Hz,8.5Hz and 18.5Hz),2.50-2.52(m,1H),2.42-2.45(m,1H),2.22(dt,1H,J=3.8Hz and 18.5Hz),0.50-0.56(m,2H),0.42-0.46(m,1H),0.35-0.39(m,1H);

[0385] 13 C NMR (CDCl3, 126MHz) δ: 211.22, 135.61, 132.91, 66.90, 51.52, 50.64, 49.45, 46.10, 27.03, 7.70, 5.60;

[0386] ESI-HRMS: (m / z) calcd. for C 11 H 13 O([M+H] + )161.0961,found:161.0960.

[0387] Step 8: Synthesis of compound (±)-53

[0388] Under N₂ atmosphere, t-BuOK (3.71 g, 33 mmol) was added to dry THF (6 mL). After stirring in an ice-water bath to form a suspension, tert-butyl diethylphosphonoacetate (8.35 g, 33 mmol) was added dropwise. After the addition was complete, the reaction was continued in an ice-water bath for 1 h. A freshly prepared solution of compound (±)-52 (1.06 g, 6.6 mmol) in dry THF (4 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring indicated the reaction was complete. The reaction solution was poured into ice water (50 mL) and extracted with CH₂Cl₂ (40 mL x 2). The organic phases were combined and washed sequentially with ice water (80 mL x 2) and saturated brine (150 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to yield a dark yellow oil. Purification by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97] afforded the desired product (±)-53 as a light yellow oil (1.62 g). This product was used directly in the next reaction without further characterization.

[0389] Step 9: Synthesis of compound (±)-54

[0390] At room temperature, compound (±)-53 (1.62 g, 6.3 mmol) was dissolved in CH3NO2 (20 mL), and DBU (7.64 g, 50 mmol) was added dropwise. After the addition was complete, the mixture was refluxed under N2 for 48 h. TLC monitoring showed that approximately 60% of the starting material had not reacted. The reaction was stopped, and the reaction solution was cooled to room temperature and poured into ice water (30 mL). It was then extracted with CH2Cl2 (30 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a brown-black oil, which was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→2 / 23] to obtain the target compound (±)-54. 0.59 g of light brown oil (combined yield of (±)-52→(±)-54: 28%) was obtained.

[0391] 1H NMR (CDCl3, 500MHz) δ: 6.49-6.51 (m, 1H), 6.38-6.40 (m, 1H), 4.84 (dd, 1H, J = 1.0Hz and 11.5Hz), 4.63 (dd, 1H, J = 1.0Hz and 11.5Hz),2.95-3.01(m,1H),2.66-2.70(m,1H),2.53(dd,1H,J=0.8Hz and 17.8Hz),2.42(d,1H,J=17.5Hz),2.28-2.30(m,1H),2.22-2.24(m,1H),2.06(ddd,1H,J=1.8Hz,8.5Hz and 13.3Hz),1.46(s,9H),1.41-1.44(m,1H),0.44-0.47(m,2H),0.25-0.33(m,2H).

[0392] 13 C NMR (CDCl3, 126MHz) δ: 170.98, 137.31, 136.84, 83.29, 80.91, 51.09, 50.24, 49.20, 47.98, 39.28, 36.43, 34.55, 32.34, 28.24, 7.83, 4.74.

[0393] ESI-HRMS: (m / z) calcd. for C 18 H 26 NO4([M+H] + )320.1856,found:320.1854.

[0394] Step 10: Synthesis of compound (±)-55 p-toluenesulfonate

[0395] At room temperature, compound (±)-54 (0.59 g, 1.8 mmol) was dissolved in EtOH (10 mL). Water (5 mL) was added and stirred. Iron powder (0.52 g, 9.3 mmol) and NH₄Cl (0.20 g, 3.7 mmol) were added sequentially. The air in the reactor was replaced with nitrogen (balloon) according to standard procedures, and the mixture was refluxed overnight. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and the solid was removed by filtration. The filtrate was added to saturated NaHCO₃ solution (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried (MgSO₄), and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a light brown oil. At room temperature, EtOAc (5 mL) was added to dilute the oil, followed by p-TsOH·H₂O (0.38 g, 2.0 mmol). Stirring dissolved the mixture was then transferred to an ice-water bath and stirred. A white flocculent solid gradually precipitated. EtOAc (7.5 mL) was added to the mixture to allow for thorough stirring. Stirring was continued at room temperature overnight. The solid was collected by filtration and dried under vacuum to afford the target compound (±)-55 p-toluenesulfonate. The product was a white solid (0.60 g, 70%). The melting point was 171.6°C-175.8°C.

[0396] 1 H NMR (DMSO-d6, 500MHz) δ: 7.69 (brs, 3H), 7.47 (d, 2H, J = 8.0Hz), 7.11 (d, 2H, J = 8.0Hz), 6.43-6.45 (m, 1 H),6.36-6.38(m,1H),3.08-3.13(m,1H),2.97-3.02(m,1H),2.84-2.90(m,1H),2.55(dd,1H,J=4.5Hz and 9.0Hz),2.37(d,1H,J=17.5Hz),2.31(d,1H,J=17.0Hz),2.29(s,3H),2.17-2.21(m,2H),1.79(ddd,1H,J=1.8Hz,8.5Hz and 12.8Hz),1.41(s,9H),1.19-1.23(m,1H),0.36-0.42(m,2H),0.27-0.31(m,1H),0.21-0.25(m,1H);

[0397] 13C NMR(DMSO-d6,126MHz)δ:170.55,145.60,137.71,137.00,136.45,128.09,125.51,80.05, 50.56,49.42,48.59,47.70,46.97,37.08,36.34,33.71,31.86,27.75,20.80,7.48,4.45;

[0398] ESI-HRMS: (m / z) calcd. for C 18 H 28 NO2([M(free base)+H] + )290.2115,found:290.2112.

[0399] Step 11: Synthesis of compound (±)-I-9 p-toluenesulfonate

[0400] Compound (±)-55 p-toluenesulfonate (0.56 g, 1.2 mmol) was added to a saturated NaHCO₃ solution (100 mL) at room temperature and stirred for 20 minutes (to a suspension state). EtOAc (60 mL x 3) was then added for extraction. The organic phases were combined, dried (MgSO₄), and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil. CH₂Cl₂ (20 mL x 3) was added and concentrated several times, and the oil was dissolved in CH₂Cl₂ (5 mL). TFA (3 mL) was slowly added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 6 hours. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a brown oil. CH2Cl2 (20 mL × 3) was added and concentrated several times, and then dried with a vacuum oil pump (a small amount of solid precipitated during the drying process). EtOAc (3 mL) was then added to dissolve the solution. A solution prepared by dissolving p-TsOH·H2O (0.25 g, 1.3 mmol) in EtOAc (3 mL) was added dropwise to the reaction solution. An off-white solid gradually precipitated from the system. After the addition was complete, the mixture was stirred at room temperature overnight. The solid was collected by filtration, and the filter cake was washed with EtOAc (1 mL) and dried with a vacuum oil pump to obtain compound (±)-I-9 p-toluenesulfonate. White solid; 0.38 g (77%); melting point 187.5°C-188.5°C;

[0401] 1H NMR (CD3OD, 500MHz) δ: 7.71 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.0Hz), 6.50-6.52 ( m,1H),6.38-6.40(m,1H),3.27(d,1H,J=13.0Hz),3.13(d,1H,J=13.0Hz),2.95- 3.01(m,1H),2.66-2.69(m,1H),2.63(d,1H,J=17.5Hz),2.40(d,1H,J=17.5Hz), 2.37(s,3H),2.26-2.28(m,1H),2.20-2.22(m,1H),1.78(ddd,1H,J=1.5Hz,8.5Hz and 13.0Hz),1.44(dd,1H,J=6.5Hz and 13.0Hz),0.40-0.46(m,2H),0.30-0.34(m,1H),0.25-0.29(m,1H);

[0402] 13 C NMR(CD3OD,126MHz)δ:175.76,143.51,141.71,138.32,137.84,129.82,126.96,5 2.26,51.30,50.45,49.93,48.37,38.43,37.52,35.51,33.66,21.31,8.27,5.20;

[0403] ESI-HRMS: (m / z) calcd. for C 14 H 20 NO2([M(free base)+H] + )234.1489,found:234.1486.

[0404] Compound (±)-I-9 is a specific form of the compound of formula I of the present application.

[0405] Example 12 Synthesis of Compound (±)-I-10

[0406] Step 1: Synthesis of compound (±)-56

[0407] Compound (±)-54 (0.21 g, 0.66 mmol) was dissolved in CH2Cl2 (2 mL), and TFA (1.5 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 2-3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator, and CH2Cl2 (20 mL×4) was added and concentrated several times to obtain a brown-black oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 7] to obtain a yellow solid. N-hexane (1 mL) was added to the above solid, and the mixture was stirred and slurried at room temperature overnight. The solid was collected by filtration and dried by a vacuum oil pump to obtain compound (±)-56. White solid; 0.11 g (64%); melting point 141.3℃-144.5℃;

[0408] 1 H NMR(DMSO-d6,500MHz)δ:12.23(s,1H),6.47-6.49(m,1H),6.36-6.38(m,1H),4.79(s,2H),2.91-2.97(m,1H),2.63-2.66( m,1H),2.45(d,1H,J=17.5Hz),2.27(d,1H,J=17.5Hz),2.24-2.25(m,1H),2.20-2.21(m,1H),1.96(ddd,1H,J=1.8Hz,8.5Hz and 13.0Hz),1.36(dd,1H,J=6.5Hz and 13.0Hz),0.36-0.41(m,2H),0.22-0.30(m,2H);

[0409] 13 C NMR (DMSO-d6, 126MHz) δ: 172.26, 136.94, 136.57, 82.95, 50.35, 49.40, 48.77, 47.08, 38.50, 35.06, 33.94, 31.69, 7.44, 4.43;

[0410] ESI-HRMS: (m / z) calcd. for C 14 H 18 NO4([M+H] + )264.1230,found:264.1225.

[0411] Step 2: Synthesis of compound (±)-I-10

[0412] Compound (±)-56 (0.11 g, 0.42 mmol) was dissolved in CH3OH (3 mL) and 10% Pd(OH)2 / C (0.04 g) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature overnight. TLC monitoring showed that the reaction was complete (the reaction generally took 12 h to complete). The solid was removed by filtration and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a white solid. EtOAc (2 mL) was added and stirred at room temperature for 1 h. The solid was collected by filtration and dried in vacuo to obtain the target product (±)-I-10. White solid; 0.03 g (31%); melting point 197.3°C-201.1°C;

[0413] 1 H NMR (CD3OD, 500MHz) δ: 3.14 (d, 1H, J = 13.0Hz), 3.01 (d, 1H, J = 12.5Hz), 2.75 (dd, 1H, J = 1.0Hz and16.5Hz),2.63-2.78(m,1H),2.66(d,1H,J=16.0Hz),2.53-2.57(m,1H),2.10-2.17(m,1H),2.01(dd,1H,J=7.5Hz and 13.0Hz),1.79-1.90(m,4H),1.60-1.62(m,1H),1.42-1.44(m,1H),0.42-0.51(m,4H);

[0414] 13 C NMR (CD3OD, 126MHz) δ: 180.04, 52.77, 49.79, 47.72, 46.30, 45.63, 39.39, 38.20, 35.05, 33.87, 26.24, 25.76, 6.33, 5.15;

[0415] ESI-HRMS: (m / z) calcd. for C 14 H 22 NO2([M+H] + )236.1645,found:236.1642.

[0416] Compound (±)-I-10 is a specific form of the compound having the general formula I of the present application.

[0417] Example 13 Synthesis of Compound (±)-I-11 and its p-toluenesulfonate

[0418] Step 1: Synthesis of compound (±)-58

[0419] Compound (±)-18 (3.00 g, 22 mmol) was dissolved in benzene (40 mL). CH₃NO₂ (20 mL) and piperidine (0.95 g, 11 mmol) were added sequentially with stirring. The mixture was heated to reflux and separated using a Dean-Stark trap for 2 h. TLC monitoring indicated the reaction was complete, and the reaction was stopped. The reaction mixture was cooled to room temperature and poured into ice water (100 mL). Extraction was performed with CH₂Cl₂ (50 mL x 2). The organic phases were combined and washed sequentially with 1M HCl (20 mL), saturated NaHCO₃ solution (100 mL), and saturated brine (100 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a dark brown oil, which was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97) to yield the target compound (±)-58. Yellow oil; 0.78 g; the product consists of a Z / E mixture and is used directly in the next reaction.

[0420] Step 2: Synthesis of compound (±)-59

[0421] Add dry THF (5 mL) to the reactor, and replace the air in the reaction vessel with nitrogen (balloon) according to standard procedures. Add diisopropylamine (0.86 g, 8.5 mmol) with stirring, and cool to -78°C (liquid nitrogen-alcohol system). Add n-butyllithium (1.6 M in hexane, 5.3 mL, 8.5 mmol) dropwise. After completion of the addition, react at -78°C for 0.5 h. Then, add a solution of tert-butyl acetate (0.99 g, 8.5 mmol) in dry THF (1 mL) dropwise. After completion of the addition, react at -78°C for another 0.5 h. Then, add a solution of compound (±)-58 (0.50 g, 2.8 mmol) in dry THF (1 mL) dropwise. After completion of the addition, react at -78°C for an additional 1-2 h. TLC monitoring indicates the reaction is complete. After returning the reaction mixture to room temperature, pour it into ice water (15 mL) and extract with CH2Cl2 (20 mL). The organic phase was washed sequentially with 1M HCl (40 mL), saturated NaHCO₃ solution (40 mL), and saturated brine (40 mL), dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to afford a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97] to afford the target compound (±)-59 as a light yellow oil; 0.51 g (combined yield of (±)-18 → (±)-59: 12%).

[0422] 1H NMR (CDCl3, 500MHz) δ: 6.41-6.43 (m, 1H), 6.32-6.34 (m, 1H), 4.59 (d, 1H, J = 13.0Hz) ,4.54(d,1H,J=13.0Hz),3.02-3.05(m,1H),2.84-2.90(m,2H),2.69(dd,1H,J=1.0Hz and 16.5Hz),2.59(dd,1H,J=0.5Hz and 16.5Hz),2.50-2.53(m,1H),1.82-1.88(m,1H),1.60-1.62(m,1H),1.45-1.49(m,10H),1.11-1.14(m,1H);

[0423] 13 C NMR (CDCl3, 126MHz) δ: 170.65, 138.31, 136.61, 81.21, 76.29, 53.54, 49.17, 45.75, 44.86, 44.48, 37.98, 34.36, 32.85, 28.27;

[0424] ESI-HRMS: (m / z) calcd. for C 16 H 24 NO4([M+H] + )294.1700,found:294.1698.

[0425] Step 3: Synthesis of compound (±)-60 p-toluenesulfonate

[0426] At room temperature, compound (±)-59 (0.51 g, 1.7 mmol) was dissolved in EtOH (10 mL). Water (5 mL) was added and stirred, followed by the addition of iron powder (0.47 g, 8.4 mmol) and NH4Cl (0.18 g, 3.4 mmol). The air in the reactor was replaced with nitrogen (balloon) according to standard procedures, and the mixture was stirred and refluxed overnight. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and the solid was removed by filtration. The filtrate was added to saturated NaHCO3 solution (50 mL) and extracted with EtOAc (40 mL x 3). The organic phases were combined, washed sequentially with saturated NaHCO3 solution (80 mL) and saturated brine (100 mL), dried (MgSO4), filtered to remove the desiccant, and concentrated under reduced pressure on a rotary evaporator to yield a brown oil. The brown oil was dissolved in EtOAc (5 mL) and p-TsOH·H2O (0.35 g, 1.8 mmol) was added. After stirring and dissolving, a white solid gradually precipitated. EtOAc (3 mL) was added to the system to allow for thorough stirring. Stirring was continued at room temperature for 1-2 hours. The solid was collected by filtration and dried under vacuum to obtain the target compound (±)-60 p-toluenesulfonate. It was a white solid; 0.39 g (52%); melting point: 194.9°C-196.7°C.

[0427] 1 H NMR (DMSO-d6, 500MHz) δ: 7.52 (brs, 3H), 7.48 (d, 2H, J = 8.5Hz), 7.12 (d, 2H, J = 8.0Hz), 6 .40-6.42(m,1H),6.26-6.28(m,1H),2.99-3.00(m,1H),2.83-2.89(m,1H),2.76-2.82(m ,3H),2.58(d,1H,J=16.0Hz),2.53(d,1H,J=16.0Hz),2.33-2.35(m,1H),2.29(s,3H),1 .63-1.68(m,1H),1.47-1.49(m,1H),1.42(s,9H),1.27-1.31(m,1H),1.05-1.07(m,1H);

[0428] 13 C NMR(DMSO-d6,126MHz)δ:170.22,145.63,137.66,137.30,136.31,128.06,125.48,8 0.39,53.06,47.38,44.67,43.98,43.20,40.12,36.87,32.62,31.58,27.82,20.78;

[0429] ESI-HRMS: (m / z) calcd. for C 16 H 26 NO2([M(free base)+H] + )264.1958,found:264.1956.

[0430] Step 4: Synthesis of compound (±)-I-11 and its p-toluenesulfonate

[0431] Compound (±)-60 p-toluenesulfonate (0.39 g, 0.90 mmol) was added to a saturated NaHCO₃ solution (50 mL) at room temperature and stirred for 20 min (to a suspension state). EtOAc (40 mL x 3) was then added for extraction. The combined organic phases were dried (MgSO₄) and the desiccant removed by filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a yellow oil. CH₂Cl₂ (20 mL x 3) was added and concentrated repeatedly. The oil was then dissolved in CH₂Cl₂ (4 mL). TFA (3 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 5-6 hours. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to yield a brown oil. CH₂Cl₂ (20 mL x 3) and EtOAc (20 mL x 3) were then added and concentrated repeatedly. The oil was dried using a vacuum pump to yield (±)-I-11. The (±)-I-11 sample was dissolved in EtOAc (2 mL) and a solution of p-TsOH·H₂O (0.19 g in 2.5 mL of EtOAc, 1.0 mmol) was added dropwise (gradually forming an off-white solid). Upon completion of the addition, EtOAc (2.5 mL) was added to allow for smooth stirring. Stirring was continued at room temperature for 1 hour. The solid was collected by filtration and dried under vacuum to obtain the p-toluenesulfonate salt of compound (±)-I-11. This product was a white solid (0.26 g, 77%) with a melting point of 193.0°C-188.5°C.

[0432] 1H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.5Hz), 7.23 (d, 2H, J = 8.0Hz), 6.43-6.44 (m, 1H), 6.31-6.33 (m, 1H), 3.07 (d, 1H, J = 13.0Hz), 3.02-3.03 (m, 1H),2.99(d,1H,J=13.0Hz),2.89-2.95(m,1H),2.84-2.86(m,1H),2.74(d,1H,J=17.0Hz),2.70(d,1H,J=17.0Hz),2.46(ddd,1H,J=1.5Hz,4.5Hz and 9.0Hz),2.37(s,3H),1.75(ddd,1H,J=1.8Hz,8.5Hz and 12.8Hz),1.61-1.63(m,1H),1.44(dd,1H,J=6.5Hz and 12.5Hz),1.16-1.18(m,1H);

[0433] 13 C NMR(CD3OD,126MHz)δ:175.29,143.52,141.69,139.13,137.18,129.81,126 .96,54.43,49.46,46.36,45.74,44.77,42.50,37.95,34.42,33.32,21.30;

[0434] ESI-HRMS: (m / z) calcd. for C 12 H 18 NO2([M(free base)+H] + )208.1332,found:208.1331.

[0435] Compound (±)-I-11 is a specific form of the compound having the general formula I of the present application.

[0436] Example 14 Synthesis of Compound (±)-I-12

[0437] Step 1: Synthesis of compound (±)-61

[0438] Compound (±)-59 (0.50 g, 1.7 mmol) was dissolved in CH2Cl2 (3 mL), and TFA (3 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to react at room temperature for 3-4 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a brown oil, which was then added with CH2Cl2 (20 mL×5) and concentrated several times. The obtained oil was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 7] to obtain an off-white solid. N-hexane (3 mL) was added to the solid and slurried at room temperature for 1 hour. The solid was collected by filtration and dried with a vacuum oil pump to obtain compound (±)-61. White solid; 0.32 g (79%); melting point 91.4℃-93.8℃;

[0439] 1 H NMR(DMSO-d6,500MHz)δ:12.33(brs,1H),6.47-6.49(m,1H),6.32-6.34(m,1H),4.58(d,1H,J=13.0Hz),4.52(d,1H,J=13.0Hz),2.91-2.93(m ,1H),2.84-2.88(m,1H),2.80-2.82(m,1H),2.59(d,1H,J=16.5Hz),2.55(d,1H,J=17.0Hz),2.44-2.47(m,1H),1.76(ddd,1H,J=1.8Hz,8.3Hz and 12.8Hz),1.47-1.49(m,1H),1.40(dd,1H,J=6.5Hz and 13.0Hz),1.06-1.09(m,1H);

[0440] 13 C NMR (DMSO-d6, 126MHz) δ: 172.14, 137.79, 136.27, 76.46, 52.74, 48.32, 45.10, 44.08, 42.66, 37.14, 33.58, 32.16;

[0441] ESI-HRMS: (m / z) calcd. for C 12 H 16 NO4([M+H] + )238.1074,found:238.1072.

[0442] Step 2: Synthesis of compound (±)-I-12

[0443] Compound (±)-61 (0.30 g, 1.3 mmol) was dissolved in CH3OH (5 mL) and 10% Pd(OH)2 / C (0.08 g) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature overnight. TLC monitoring showed that the reaction was complete (the reaction generally required 12 hours to complete). The solid was removed by filtration and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a white solid. A mixed solvent of CH3OH / EtOAc = 1 / 3 (v / v) (3 mL) was added and stirred at room temperature for 1 hour. The solid was collected by filtration and dried to obtain the target product (±)-I-12. White solid; 0.05 g (19%); melting point 153.2°C-157.3°C;

[0444] 1 H NMR (CD3OD, 500MHz) δ: 3.17 (d, 1H, J = 13.5Hz), 3.14 (d, 1H, J = 13.5Hz), 2.68 (s, 2H), 2.57-2 .64(m,1H),2.49-2.51(m,1H),2.25-2.27(m,1H),2.13-2.16(m,1H),2.01(dd,1H,J=7.5Hz and 12.5Hz),1.73-1.82(m,3H),1.61-1.67(m,1H),1.50-1.55(m,1H),1.43-1.45(m,1H),1.27-1.30(m,1H);

[0445] 13 C NMR (CD3OD, 126MHz) δ: 180.18, 53.17, 53.31, 47.14, 43.23, 40.81, 40.06, 36.72, 34.78, 32.43, 26.51, 25.22; ESI-HRMS: (m / z)calcd.for C 12 H 20 NO2([M+H] + )210.1489,found:210.1485.

[0446] Compound (±)-I-12 is a specific form of the compound of formula I of the present application.

[0447] Example 15 Synthesis of Compound (±)-I-13

[0448] Step 1: Synthesis of compound 62

[0449] Under ice-water cooling and stirring, SnCl2·2H2O (1299.93 g, 5.76 mol), KI (956.29 g, 5.76 mol), and allyl bromide (696.94 g, 5.76 mol) were added sequentially to deionized water (8.25 L) with stirring (the solution turned orange-red). After the internal temperature stabilized at 10°C, a solution of acrolein diethyl acetal (500.00 g, 3.84 mol) in THF (768 mL) was slowly added dropwise (monitoring the internal temperature to not exceed 20°C; the color of the system changed from orange-red to light yellow). After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitoring indicated the reaction was complete. The reaction was stopped, and the reaction mixture was poured into CH2Cl2 (8 L) with stirring. The organic phase was separated, and the aqueous phase was extracted once more with CH2Cl2 (8 L). The combined organic phases were washed with saturated brine (5 L), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure (30°C) on a rotary evaporator to give a pale yellow oil, which was purified by vacuum distillation. The fractions with a top temperature of approximately 60°C / 30 mmHg were collected to obtain the desired product 62. 183.50 g (49%) of colorless, transparent oil. 1 H NMR (CDCl3, 500 MHz) δ: 5.78-5.93 (m, 2H), 5.24-5.28 (m, 1H), 5.13-5.18 (m, 3H), 4.17-4.21 (m, 1H), 2.33-2.39 (m, 1H), 2.26-2.32 (m, 1H). The product was used directly in the next reaction without further purification.

[0450] Step 2: Synthesis of compound 63

[0451] Preparation of Jones reagent: Add water (267 mL) to a reaction vessel, cool in an ice-water bath, add CrO3 (122.83 g, 1.23 mol) in batches with stirring to form an orange-red suspension, then slowly add concentrated H2SO4 (131 mL) dropwise. After the addition is complete, set aside.

[0452] Compound 62 (120.56 g, 1.23 mol) was dissolved in acetone (430 mL) and stirred in an ice-water bath. Jones reagent was slowly added dropwise (a green solid was produced during the addition, and the solution color changed from bluish-green to dark green). TLC was monitored during the addition. The addition was stopped once the reaction was complete. The reaction system was diluted with n-pentane (400 mL) and washed with water (400 mL). The aqueous phase was back-extracted with n-pentane (250 mL x 2). The organic phases were combined and washed sequentially with 10% sodium sulfite solution (200 mL) and saturated brine (200 mL x 3), dried (MgSO4), and filtered to remove the desiccant. The filtrate was first fractionally distilled at atmospheric pressure to remove the n-pentane (top temperature 36°C-38°C), then distilled under reduced pressure. The fractions at 58°C-60°C / 30 mmHg were collected (the receiving flask was placed in liquid nitrogen for cryogenic protection) to obtain the target compound 63. Pale yellow oil; 26.42 g (22%); 1 H NMR (CDCl3, 500 MHz) δ: 6.39 (dd, 1H, J = 10.5 Hz and 18.0 Hz), 6.26 (dd, 1H, J = 1.3 Hz and 17.8 Hz), 5.92-6.00 (m, 1H), 5.87 (dd, 1H, J = 1.0 Hz and 10.5 Hz), 5.15-5.23 (m, 2H), 3.37-3.39 (m, 2H). This product contained a certain amount of n-pentane and was used directly in the next reaction without further purification.

[0453] Step 3: Synthesis of compound 64

[0454] Compound 63 (26.42 g, 0.27 mol) was dissolved in n-pentane (1.5 L) in a quartz container. The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. The reaction apparatus was placed in a dark environment, stirred, and irradiated with UV light (365 nm; 15 W x 6) at room temperature for 7-14 days (the solution color changed from colorless and transparent to purple-red and then faded to light purple). During the reaction, a small amount of viscous polymer byproduct adhered to the inner wall of the reaction vessel. Activated carbon (10 g) and diatomaceous earth (10 g) were added every 2-3 days, stirred for 10 minutes, and the polymer was removed by filtration. The filtrate was then re-introduced into the reaction according to the above procedure. The reaction was stopped when TLC showed a small amount of starting material. The reaction solution was concentrated to half of its original volume under reduced pressure (<30°C) on a rotary evaporator. Br2 was then slowly added dropwise until the Br2 discoloration ceased (the solution turned light orange). Next, 10% sodium thiosulfate solution (200 mL) was added and stirred to destroy the excess Br2, at which point the solution turned colorless. The organic phase was separated, dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure (<30°C) to yield an oil. CH3OH (20 mL) was then added and concentrated to afford crude target compound 64. This pale yellow oil (6.61 g) was not characterized and used directly in the next reaction.

[0455] Step 4: Synthesis of compound 65

[0456] Compound 64 (16.00 g, 0.17 mol) was dissolved in CH3OH (320 mL), and 4-methylbenzenesulfonylhydrazide (31.00 g, 0.17 mol) was added. The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures, and the mixture was refluxed overnight. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated on a rotary evaporator under reduced pressure to obtain a yellow oil. The oil was dissolved in CH2Cl2 (500 mL), washed sequentially with 1M HCl (400 mL × 6) and saturated brine (200 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated on a rotary evaporator under reduced pressure to obtain a yellow oil. After adding n-hexane (50 mL × 2), the mixture was concentrated several times to obtain a yellow solid. EtOAc (3 mL) / n-hexane (30 mL) was added to the solid and the mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to obtain compound 65. Pale yellow solid; 17.09 g (63 → 65 combined yield 10%); melting point 174.7°C-177.6°C;

[0457] 1H NMR (CDCl3, 500MHz) δ: 7.86 (d, 2H, J = 8.0Hz), 7.32 (d, 2H, J = 8.0Hz), 7.21 (brs, 1H), 2.98-3.00 ( m,1H),2.65-2.68(m,1H),2.43(s,3H),2.16-2.17(m,2H),1.98-2.04(m,2H),1.31-1.32(m,2H);

[0458] 13 C NMR (CDCl3, 126MHz) δ: 168.36, 144.10, 135.67, 129.74, 128.18, 49.53, 42.05, 36.29, 32.91, 21.76.

[0459] Step 5: Synthesis of compound 66

[0460] Compound 65 (4.23 g, 19 mmol) was dissolved in dry THF (50 mL). The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. CH3Li (1.6 M in diethoxymethane, 42 mL, 67.2 mmol) was slowly added dropwise to the mixture while stirring in an ice-water bath. After the addition was complete, the mixture was allowed to react at room temperature overnight. TLC monitoring indicated the reaction was complete. Water (10 mL) was added dropwise to the mixture under an ice-water bath to quench the reaction. The reaction mixture was poured into ice water (200 mL) and extracted with n-pentane (100 mL x 3). The organic phases were combined, washed sequentially with 1 M HCl (100 mL x 2) and saturated brine (100 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was fractionally distilled at atmospheric pressure to remove the solvent, yielding crude target compound 66 (1.52 g), which was used directly in the next step without further purification.

[0461] Step 6: Synthesis of compound (±)-67

[0462] At room temperature, compound 66 (1.52 g, calculated as 19 mmol) and dichloroacetyl chloride (3.72 g, 25 mmol) were dissolved in dry n-hexane (20 mL). The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. A solution of triethylamine (2.80 g, 28 mmol) in dry n-hexane (10 mL) was slowly added dropwise with stirring at room temperature. Heat was released during the addition, and the rate of addition was controlled to maintain an internal temperature of 30°C-35°C. After the addition was complete, the reactor was placed in a 35°C oil bath and stirred for 2 h. Additional dry n-hexane (50 mL) was added to allow for sufficient stirring, and the reaction was allowed to proceed overnight at room temperature. TLC monitoring indicated the reaction was complete. After cooling the reaction solution to room temperature, it was poured into ice water (200 mL). The organic phase was separated and washed sequentially with 1M HCl (50 mL), water (200 mL), saturated NaHCO₃ solution (100 mL x 2), and saturated brine (100 mL). The mixture was dried (MgSO₄), filtered to remove the desiccant, and the filtrate was concentrated on a rotary evaporator under reduced pressure to afford crude compound (±)-67 as a dark red oil (1.89 g). This product was used directly in the next reaction without further purification.

[0463] Step 7: Synthesis of compound (±)-68

[0464] Zinc powder (3.23 g, 49 mmol) and glacial acetic acid (20 mL) were stirred and mixed. A freshly prepared solution of compound (±)-67 (1.89 g, 9.9 mmol) in glacial acetic acid (5 mL) was then added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred overnight in an oil bath at 55°C under a nitrogen atmosphere. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with CH2Cl2 (200 mL) and washed sequentially with water (200 mL × 3), saturated NaHCO3 solution (200 mL), and saturated brine (200 mL). The mixture was then dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a dark brown oil. The crude product of compound (±)-68 was obtained by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 20). Dark brown oil; 0.31 g; the product was used directly in the next reaction without further purification.

[0465] Step 8: Synthesis of compound (±)-69

[0466] Under N₂ atmosphere, t-BuOK (1.42 g, 13 mmol) was added to dry THF (5 mL). After stirring in an ice-water bath to form a suspension, tert-butyl diethylphosphonoacetate (3.20 g, 13 mmol) was added dropwise. After the addition was complete, the mixture was reacted in an ice-water bath for 1 h. A freshly prepared solution of compound (±)-68 (0.31 g, 2.5 mmol) in dry THF (10 mL) was then added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC monitored the reaction completion. The reaction mixture was poured into ice water (100 mL), stirred, and extracted with CH₂Cl₂ (30 mL x 3). The organic phases were combined, washed with saturated brine, dried (MgSO₄), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to yield a dark brown oil. This was then purified by column chromatography (V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 12) to afford crude compound (±)-69. Dark brown oil; 0.40 g; the product was used directly in the next reaction without further purification.

[0467] Step 9: Synthesis of compound (±)-70

[0468] At room temperature, compound (±)-69 (0.40 g) was dissolved in CH3NO2 (10 mL), stirred, and DBU (3.0 g) was added dropwise. After the addition was complete, the reaction mixture was refluxed for one week under N2. TLC monitoring showed that a large amount of raw materials were still unreacted, so the reaction was stopped. The reaction solution was cooled to room temperature and poured into ice water (100 mL), extracted with CH2Cl2 (50 mL×2), and the combined organic phases were washed with ice water (100 mL) and saturated brine (150 mL) in sequence, dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a brown-black oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-70. Pale yellow oil; 0.10 g;

[0469] 1 H NMR (acetone-d6, 500MHz) δ: 4.77 (d, 1H, J = 12.0Hz), 4.65 (d, 1H, J = 12.0Hz), 2.65 (d, 1H, J = 18.5Hz), 2.57 (d, 1H, J = 18.5Hz), 2.33-2.36 (m,1H),2.00-2.04(m,1H),1.98-1.99(m,2H),1.81-1.83(m,1H),1.41(s,9H),1.32-1.36(m,1H),1.23-1.28(m,2H),1.01-1.04(m,2H);

[0470] ESI-HRMS: (m / z) calcd. for C15 H 24 NO4([M+H] + )282.1700,found:282.1702.

[0471] Step 10: Synthesis of compound (±)-71

[0472] Compound (±)-70 (78 mg, 0.28 mmol) was dissolved in CH2Cl2 (1 mL) and TFA (0.5 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. TLC monitoring showed that the reaction was complete. The reaction mixture was poured into ice water (5 mL) and extracted with CH2Cl2 (2 mL×3). After combining the organic phases, the mixture was washed with saturated brine (2 mL×2), dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated using a rotary evaporator to obtain a yellow oil. Purification by column chromatography [V(EtOAc) / V(n-hexane)=1 / 5→1 / 0] gave the target product (±)-71. Colorless oil, 32 mg (51%);

[0473] 1 H NMR(acetone-d6+D2O(1drop),500MHz)δ:4.70(d,1H,J=11.5Hz), 4.53(d,1H,J=11.5Hz), 2.61(d,1H,J=19.0Hz), 2.55(d,1H,J=18.5Hz ),2.42-2.46(m,1H),2.12-2.16(m,1H),1.99-2.03(m,2H),1.84-1.86(m,1H),1.51-1.56(m,1H),1.20-1.22(m,2H),1.13-1.15(m,2H);

[0474] ESI-HRMS: (m / z) calcd. for C 11 H 16 NO4([M+H] + )226.1074,found:226.1070.

[0475] Step 11: Synthesis of compound (±)-I-13

[0476] Compound (±)-71 (25 mg, 0.11 mmol) was dissolved in CH3OH (0.5 mL) and 10% Pd(OH)2 / C (5 mg) was added. The air in the reaction vessel was replaced with hydrogen (balloon) according to standard procedures and stirred at room temperature overnight. TLC monitoring showed that the reaction was complete (the reaction generally took 12 hours to complete). The desiccant was filtered off and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a white solid. EtOAc (0.5 mL) was added and the mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and dried to obtain the target product (±)-I-13. White solid; 11 mg (51%);

[0477] 1 H NMR(CD3OD+D2O(1drop),500MHz)δ:3.06(s,2H),2.67(d,1H,J=18.0Hz),2.43(d,1H,J=18.0Hz),2.31-2.32(m,1H) ,2.20-2.22(m,1H),1.97-2.02(m,1H),1.88-1.89(m,2H),1.40-1.51(m,2H),1.16-1.21(m,1H),1.00-1.06(m,2H);

[0478] ESI-HRMS: (m / z) calcd. for C 11 H 18 NO2([M+H] + )196.1332,found:196.1341.

[0479] Compound (±)-I-13 is a specific form of the compound having the general formula I of the present application.

[0480] Examples 16-21

[0481] The compounds shown in the following table were synthesized by referring to the methods of Examples 1 to 15.

[0482] Example 22

[0483] Preparation process: Crush and sieve the (±)-I-3 sample for later use. Add the (±)-I-3 sample, lactose, and pregelatinized starch according to the above formula and premix for 15 minutes. Add disodium hydrogen phosphate and polyvinylpyrrolidone according to the formula and mix for 10 minutes. Add talc according to the formula and mix for 30 minutes. Fill the mixed material into (±)-I-3 capsules according to the capsule size.

[0484] Example 23

[0485] Preparation process: Separately sieve the (±)-I-4 sample and pregelatinized starch and mix thoroughly. Add the polyvinyl pyrrolidone solution, mix, and prepare a soft material. Sieve and prepare wet granules. Dry at 80°C. Separately sieve the sodium carboxymethyl starch, microcrystalline cellulose, and magnesium stearate, then add them to the granules, mix thoroughly, and compress into tablets.

[0486] Example 24

[0487] Preparation process: First add water for injection and (+)-I-3 sample, stir and dissolve, adjust the pH to 5.0-7.0 with NaOH and hydrochloric acid, add 0.3g activated carbon, stir at room temperature for 30 minutes, filter with a microporous filter membrane, and measure the concentration of the filtrate in the central control. Package 5mL per ampoule, and sterilize at 100°C for 30 minutes to obtain the injection solution.

[0488] Example 25

[0489] Preparation: Pass (-)-I-3 sample, sucrose, crospovidone, and carboxymethyl cellulose through a 100-mesh sieve. Prepare a 25% concentrated solution of sucrose laurate in 60°C ethanol. Weigh the prescribed amount and thoroughly mix under fluidized conditions. Add 25% sucrose laurate to form a soft base, dry at 55°C, and granulate into 20-mesh granules. Sieve through a 12-mesh sieve, add silicon dioxide, aspartame, and apple flavoring, and measure the bag weight before packaging.

[0490] Example 26

[0491] Preparation process: Take 80 mL of water for injection, add (+)-I-4 sample, mannitol, and lactose, stir until dissolved, add 1 mol / L citric acid and 1 mol / L sodium hydroxide, adjust the pH to 5.0-7.0, and add water to 100 mL. Add 0.5 g of activated carbon, stir at 30°C for 20 minutes to remove the carbon, filter through a microporous filter to sterilize, and divide the filtrate into 1 mL vials. After pre-freezing at -40°C for 5 hours, freeze-dry under reduced pressure for 12 hours (pressure <20 Pa). After the freeze-drying is complete, let the sample cool to room temperature and then dry for another 5 hours to obtain a white, loose mass, which is then sealed.

[0492] Example 27

[0493] Preparation process: Dissolve the above-mentioned malic acid in 25mL of purified water, add the above-mentioned chitosan, stir thoroughly to dissolve it completely, take an appropriate amount of 1mol / L sodium bicarbonate solution and add it to the above-mentioned solution for rapid neutralization, adjust the pH value of the chitosan solution to 5.0-7.0, and set aside. Then add the above-mentioned acesulfame potassium and strawberry essence in 40mL of purified water, stir to dissolve, then add the above-mentioned (+)-I-3 sample in the above-mentioned amount, stir to dissolve, then add the above-mentioned standby chitosan solution, stir evenly, make up the remaining purified water in the above-mentioned amount to the mixed liquid, stir to mix evenly, and obtain a (+)-I-3 oral solution with a pH of 5.0-7.0.

[0494] Example 28 Binding of the Compound to Human Recombinant Calcium Channel Cav2.2 / β3 / α2δ-1 in Vitro

[0495] There are four subtypes of the voltage-gated calcium channel α2δ subunit, α2δ-1, α2δ-2, α2δ-3 and α2δ-4, among which α2δ-1 is the subtype that mediates chronic neuropathic pain (Field, MJ; et al. Proc. Natl. Acad. Sci. USA 2006, 103, 17537-17542). Therefore, the binding strength of a compound to α2δ-1 is a direct indicator of its analgesic effect on chronic neuropathic pain (Calandre, EP; et al. Expert Rev. Neurother. 2016, 16, 1263-1277).

[0496] The binding strength of the compounds of the present application to the human recombinant calcium channel Cav2.2 / β3 / α2δ-1 in vitro was basically operated according to the reported method (Gee, NS; et al. J. Biol. Chem. 1996, 271, 5768-5776; Marais, E.; et al. Mol. Pharmacol. 2001, 59, 1243-1248.). The test used CHO cells expressing the human recombinant calcium channel Cav2.2 / β3 / α2δ-1. After the cell membrane was isolated according to the conventional method, 3 μg of cell membrane was added to each well. Modified HEPES / KOH buffer (pH 7.4) was used as the solution of the test system, and then 5 nM [ 3 [H] gabapentin and six concentrations of the test compound (3, 9, 27, 81, 243, and 729 nM) were incubated at 25°C for 120 min. Nonspecific binding was achieved by replacing the test compound in the above test system with 10 μM gabapentin. After incubation, the cell membranes were collected by filtration and washed with 50 mM Tris-HCl (pH 7.4). The cell membranes were then assayed for [H] gabapentin binding using liquid scintillation.3 H] gabapentin radioactivity. The compounds of the present application and [ 3 H] Gabapentin competitively binds to the human recombinant calcium channel Cav2.2 / β3 / α2δ-1. The compounds of the present application are effective against [ 3 The inhibition rate of gabapentin binding to the human recombinant calcium channel Cav2.2 / β3 / α2δ-1 was calculated according to the following formula: Inhibition rate = [(II U ) / (I0-I U )]×100%

[0497] in,

[0498] I is the compound to be tested and [ 3 The radioactivity corresponding to the co-incubation of gabapentin with human recombinant calcium channel Cav2.2 / β3 / α2δ-1 was

[0499] I0 is [ 3 H] The corresponding radioactivity when gabapentin was co-incubated with human recombinant calcium channel Cav2.2 / β3 / α2δ-1, without adding the test compound to the incubation system.

[0500] I U is 10 μM gabapentin with [ 3 [H] The radioactivity corresponding to the co-incubation of gabapentin with recombinant human calcium channel Cav2.2 / β3 / α2δ-1.

[0501] The test compound inhibited 50% of [ 3 The concentration of [H] gabapentin combined with human recombinant calcium channel Cav2.2 / β3 / α2δ-1 was defined as the IC 50 , IC 50 The inhibition rate was calculated using nonlinear least squares regression analysis (MathIQ TM ,ID Business Solutions Ltd.,UK). The test results are shown in the table below:

[0502] From the activity data of this example, it can be seen that the compound of the present application having the general formula I has good activity in binding to the human recombinant calcium channel Cav2.2 / β3 / α2δ-1, and can be used to prepare drugs for treating chronic neuropathic pain, epilepsy and anxiety.

[0503] γ-aminobutyric acid drugs such as gabapentin and pregabalin, which act on the voltage-gated calcium channel α2δ-1 ligand, have not only analgesic effects on chronic neuropathic pain, but also anti-epileptic (pregabalin, an indication approved by the US FDA) and anxiolytic (pregabalin, an indication approved by the European EMA) effects. These effects are related to the binding of the drug to the voltage-gated calcium channel α2δ-1 ligand. Therefore, the compounds of the general formula I of the present application can also be used to prepare drugs for the treatment of epilepsy and anxiety.

[0504] Example 29 Analgesic Effect of Compound in Chronic Neuropathic Pain Rat Model

[0505] The efficacy of the representative compounds of the present application, 30 mg / kg (±)-I-7, (±)-I-3 and (±)-I-4 p-toluenesulfonate, administered orally by gavage in the sciatic nerve branch injury (SNI) model of Sprague Dawley (SD) rats was evaluated.

[0506] Establishment of the SNI model: Surgery was performed according to aseptic techniques, and all surgical instruments, including scalpels, forceps, suture needles / threads, and surgical cotton, were sterilized preoperatively. After anesthesia with an intraperitoneal injection of 50 mg / kg of Zotai 50 solution, the animals were placed in the lateral decubitus position. The hair in the surgical area of ​​the lower body was shaved and disinfected alternately with iodine and 75% alcohol. The skin was incised at the upper edge of the left hind limb, and the muscles were bluntly dissected to expose the sciatic nerve trunk and its three branches: the tibial nerve, the common peroneal nerve, and the sural nerve. The tibial nerve and the common peroneal nerve were ligated and transected, while the sural nerve was preserved and maintained intact. Postoperatively, the wound was sutured in layers, and 25% ampicillin (1 mL / kg) was injected intraperitoneally to prevent infection. Routine care was then provided. In the sham group, only the sciatic nerve and its branches were exposed, without ligation or transecting. All other procedures were the same as those in the model group.

[0507] Mechanical pain threshold detection: The mechanical pain threshold of the surgical side of each animal was detected using Von-frey test fibers on the 1st, 3rd, and 7th days after surgery. The mechanical pain threshold detection method adopted the "up-and-down" method, and the stimulation intensity included 0.4, 0.6, 1, 2, 4, 6, 8, and 15g. During the test, the test fiber vertically stimulated the center of the left hind foot of the rat near the outside, each time for 6-8 seconds, with an interval of 5 seconds. The pain response was manifested as obvious paw withdrawal, licking, or paw lifting behavior in each test. Starting from the 11th day after surgery, the animals were placed in the experimental environment for adaptation, adapting for 15 minutes every day for 3 consecutive days. After the adaptation was completed on the 13th day, the basal value of mechanical allodynia was detected. Mechanical allodynia is expressed by the 50% paw withdrawal threshold (PWT), and the calculation formula is 50% PWT (g) = 10xf+kδ , where xf is the log value of the fiber test force, k is the table value, and δ is the average value of the interval of the log value of the fiber test force.

[0508] Efficacy evaluation: Based on the baseline threshold test results on the 13th day after surgery, animals in the model group that did not show mechanical allodynia, i.e., a paw withdrawal threshold (PWT) greater than 4g, were eliminated. The remaining animals with successful modeling were used for formal testing. On the 14th day after surgery, each test compound was freshly prepared. Pregabalin at a dose of 30 mg / kg was directly dissolved in 0.9% sodium chloride to form a solution of the desired concentration. (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate at a dose of 30 mg / kg (calculated as free base) was also completely dissolved in 0.9% sodium chloride solution. The successfully modeled animals were randomly divided into 5 groups, with 8 animals in each group, and 7 animals in the sham operation group. After marking and weighing the animals, the test drug and vehicle (0.9% sodium chloride) were administered orally at a volume of 10 mL / kg. Mechanical allodynia in the left hind paw was measured 1, 2, 4, 6, 8, 10, and 24 hours after administration. The animals were blindly evaluated using the same testing methods as above. The area under the curve (AUC) of the mechanical pain threshold-time relationship was calculated using GraphPad Prism Version 8.0.1 software. The analgesic effect in the SNI model was expressed as the maximum possible effect (MPE): %MPE = [(AUC of the drug group - AUC of the vehicle group) / (AUC of the sham group - AUC of the vehicle group)] × 100.

[0509] Results and Discussion: Data are expressed as mean ± standard error of the mean (SEM) and plotted using GraphPad Prism Version 8.0.1 software. Data between groups were compared using one-way ANOVA, followed by Dunnett's test for multiple comparisons. *(p < 0.05) indicates significant differences, ** indicates p < 0.01, and *** indicates p < 0.001. Statistical results are detailed in the mechanical pain threshold time course graph (Figure 3A) and the area under the mechanical pain threshold-time curve graph (Figure 3B). As shown in the figure below, like the positive drug pregabalin, (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate salts at a dose of 30 mg / kg (as the free base) all inhibited mechanical allodynia in SNI rats to varying degrees. The area under the mechanical pain threshold-time curve in the (±)-I-7 and (±)-I-4 p-toluenesulfonate salt groups was significantly higher than that in the vehicle control group. The maximum possible analgesic effects (%MPE) of the four positive compounds, pregabalin, (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate, were 110.90%, 73.63%, 44.80%, and 95.95%, respectively. These results demonstrate that the representative compounds (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate exhibited moderate analgesic activity in the SNI model at a dose of 30 mg / kg (as free base) and are potentially useful in the preparation of drugs for the treatment of chronic neuropathic pain.

[0510] Analgesic effect of the compound of Example 30 in a rat model of chronic neuropathic pain

[0511] The efficacy of (-)-I-3-toluenesulfonate, (+)-I-3-toluenesulfonate, (-)-I-4-toluenesulfonate and (+)-I-4-toluenesulfonate administered orally at 10 mg / kg (as free base) in the sciatic nerve branch injury (SNI) model of SD rats was evaluated.

[0512] The model construction method and mechanical pain threshold detection method are the same as Example 29.

[0513] Efficacy evaluation: The specific detection method is the same as that in Example 29. On the 14th day after surgery, freshly prepare each test compound. Pregabalin at a dose of 10 mg / kg was directly dissolved in 0.9% sodium chloride to form a solution of the desired concentration. The representative compounds of this application (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate at a dose of 10 mg / kg (as free base) were dissolved in a solvent of 5% PEG 400 (polyethylene glycol 400) + 95% (0.9% sodium chloride), that is, first dissolve in 5% PEG 400, then add 95% 0.9% sodium chloride solution to a final volume, and vortex to fully dissolve. The animals with successful modeling were randomly divided into 5 groups, with 6 animals in each group, and 5 animals in the sham operation group. After marking and weighing the animals, the test drug and vehicle (5% PEG 400 + 95% (0.9% sodium chloride) were administered orally at a dose volume of 10 mL / kg. Mechanical allodynia in the left hind paw was measured 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration. The test was performed in a blinded manner, using the same method as above. The area under the curve (AUC) of the mechanical pain threshold-time relationship and the maximum possible analgesic effect (MPE) were calculated using the same method as in Example 29.

[0514] Results and Discussion: Data are expressed as mean ± standard error (SEM) and plotted using GraphPad Prism Version 8.0.1 software. Data between groups were compared using one-way ANOVA, followed by post hoc Dunnett's test for multiple comparisons. *(p < 0.05) indicates a significant difference, ** indicates p < 0.01, and *** indicates p < 0.001. Statistical results are detailed in the mechanical pain threshold time course graph (Figure 4A) and the area under the mechanical pain threshold-time curve graph (Figure 4B). As can be seen from Figures 4A and 4B, the representative compounds of the present application (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate were administered orally at a dose of 10 mg / kg (as free base) on the mechanical allodynia in rats with sciatic nerve branch injury model. The area under the mechanical pain threshold-time curve of the (+)-I-4 p-toluenesulfonate group was significantly increased compared with the vehicle control group, and its effect was significantly stronger than that of the 10 mg / kg positive drug pregabalin. The maximum possible analgesic effects (MPEs) of pregabalin, (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate were calculated to be 23.04%, 30.22%, 48.50%, 18.53%, and 69.09%, respectively. The above results indicate that: (1) the representative compounds of the present application, (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate, exhibited good analgesic effects in the rat SNI model and can be used to prepare drugs for treating chronic neuropathic pain; (2) the analgesic activity of the compound (+)-I-3 p-toluenesulfonate was stronger than that of the (-)-I-3 p-toluenesulfonate, and the analgesic activity of the compound (+)-I-4 p-toluenesulfonate was stronger than that of the (-)-I-4 p-toluenesulfonate, indicating that the analgesic activity of the compounds of the present application is stereochemically dependent. The results of the in vitro binding assays of the (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate in Example 28 are consistent with this conclusion.

[0515] Antiepileptic effect of the compound in the mouse epilepsy model (maximal electroshock model (MES))

[0516] Set up test groups such as solvent negative control, positive drug control group (pregabalin and gabapentin) and compound of the present application. Male ICR mice weighing 22±2g were selected. The test drug and control drug were dissolved in DMSO (5% v / v) + 10% 1,2-propylene glycol saline solution (95% v / v), and the administration method was gavage with a dosing volume of 10mL / kg. The mice were first fasted for 12 hours, and then given the compound of the present application or the control drug according to their body weight, and then electrically stimulated to induce generalized tonic-clonic seizure behavior after a certain time interval (2 hours for pregabalin, 1 hour for gabapentin, and 3 hours for the compound of the present application). A YLS-9A electrophysiological stimulator (Shanghai Xinruan Information Technology Co., Ltd.) was used in the induced model, and the parameters were set to: configuration 8, stimulation voltage of 160V, and wave number 90. To administer electrical stimulation, wipe both ears of the mouse with saline solution. Then, administer electrical stimulation once using ear clip electrodes. The onset of an epileptic seizure was determined by the onset of hind limb rigidity. Animals experiencing hind limb rigidity were considered unprotected by the drug, while animals without hind limb rigidity were considered protected by the drug. The animal's response was observed and recorded, and the resulting data were compiled to calculate the compound protection rate.

[0517] The test results are shown in the table below:

[0518] *Note: Calculated based on the drug prototype (free base).

[0519] The half effective dose (ED) of the test compound for protecting animals 50 ) was calculated using the least squares method (Graphpad Prism 5) using the dose-protection rate curve. The fitting curve is shown in Figure 5.

[0520] After calculation, the ED of (+)-I-3 50 =6.52 mg / kg, ED of (+)-I-4 50 =21.51mg / kg, the ED of pregabalin 50 =11.99 mg / kg. The above results show that the representative compounds (+)-I-3 and (+)-I-4 of the present application exhibit strong anti-epileptic seizure effects in the mouse maximal electric shock model and can be used to prepare anti-epileptic drugs.

[0521] Antiepileptic effect of the compound of Example 32 in a mouse epilepsy model (6-Hz psychomotor seizure model)

[0522] A solvent negative control, a positive drug control group (pregabalin and gabapentin) and a test group of the compound of the present application were set up. Male C57BL / 6 mice weighing 20±2g were selected. The test drug and the control drug were dissolved in DMSO (5% v / v) + 10% 1,2-propylene glycol saline solution (95% v / v), and the administration method was gavage with a dosing volume of 10mL / kg. The mice were first fasted for 12 hours, and then given the compound of the present application or the control drug, and then after a certain time interval (2 hours for pregabalin, 1 hour for gabapentin, 1 hour for levetiracetam, and 3 hours for the compound of the present application), 6-Hz electrical stimulation was performed to induce epileptic seizure behavior. In the induced model, while stimulating with a Model 4100 stimulator (AM Systems, USA), the mouse was manually secured at the back of the neck in the home cage. A corneal electrode moistened with saline was gently placed on both corneas of the mouse. Stimulation was then administered using a foot-operated electrical stimulator. Stimulation parameters were 6 Hz, a unidirectional square wave of 32 mA, a pulse width of 0.2 ms, and a stimulation duration of 3 seconds. A stopwatch was used to time the stimulation. If seizure-like behavior persisted for no more than 7 seconds after the end of the stimulation, the mouse was considered drug-protected. If it persisted for more than 7 seconds, the drug was considered unprotected. The animal's responses were observed and recorded, and the resulting data were statistically analyzed to calculate the compound protection rate.

[0523] Statistical method: The protection ratios of different drug-administered groups were compared with those of the vehicle control group using Fisher's exact test.

[0524] The test results are shown in the following table:

[0525] # Note: The dosage is based on the original drug form (free base).

[0526] The above results show that the representative compounds of the present application (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate exhibit strong anti-epileptic effects in the mouse 6-Hz electrical stimulation-induced epileptic seizure model and can be used to prepare anti-epileptic drugs.

[0527] Antiepileptic effect of the compound of Example 33 in a mouse epilepsy model (subcutaneous injection of pentylenetetrazol model (sc-PTZ))

[0528] A negative control of the solvent, a positive drug control group (pregabalin and gabapentin) and a test group of the compound of the present application were set up. Male ICR mice weighing 22±2g were selected. The test drug and the control drug were dissolved in DMSO (5% v / v) + 10% 1,2-propylene glycol saline solution (95% v / v), and the administration method was intraperitoneal injection with a dosage volume of 10mL / kg. The mice were first fasted for 12 hours, and then given the compound of the present application or the control drug, and then after a certain time interval (2 hours for pregabalin, 1 hour for gabapentin, and 3 hours for the compound of the present application), pentylenetetrazol (PTZ) was subcutaneously injected to induce epileptic seizure behavior. In the induced model, pentylenetetrazol (PTZ) was dissolved in saline and administered to mice by subcutaneous injection (10 mL / kg, a dose of 100 mg / kg). The mice were behaviorally observed for 1 hour after PTZ injection, and the number and latency of convulsions, clonic seizures, tonic seizures, and death after PTZ injection were recorded.

[0529] Statistical methods: The protection ratio and mortality rate of different drug-treated groups were compared with those of the vehicle control group using Fisher's exact test. The onset time and latency were analyzed using one-way ANOVA.

[0530] Test results:

[0531] Note: Fisher's exact test, compared with the solvent control group, *p<0.05, **p<0.01 indicates significant difference. # The dosages are based on the original drug form (free base).

[0532] Subcutaneous injection of pentylenetetrazol (PTZ) induces strong convulsive behavior in mice: in the vehicle control group, 8 / 8 (100%) experienced generalized clonus, 6 / 8 (75%) experienced generalized tonic-clonic seizures, and 6 / 8 (75%) died. The positive control, pregabalin (PGB), showed a trend toward reducing generalized clonus (100% → 62.5%) and significantly reduced the incidence of tonicity (75% → 12.5%) and mortality (75% → 12.5%). (+)-I-3-toluenesulfonate also showed a trend toward reducing generalized clonus (100% → 60%) and significantly reduced the incidence of tonicity (75% → 0%) and mortality (75% → 0%). (+)-I-4-toluenesulfonate also showed a trend toward reducing generalized clonus (100% → 60%) and also showed a trend toward reducing the incidence of tonicity (75% → 20%) and mortality (75% → 30%). Gabapentin (GBP) at this dose had no significant improvement on the incidence of convulsions and mortality.

[0533] In the above-mentioned experiments, the time from subcutaneous injection of pentylenetetrazol to the onset of different epilepsy-related phenomena for the representative compounds of the present application (+)-I-3 p-toluenesulfonate, (+)-I-4 p-toluenesulfonate, and control drugs was defined as the latency period of a certain stage. As can be seen from Figure 6, pregabalin (PGB), (+)-I-3 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate at 30 mg / kg (calculated as free base) significantly prolonged the latency period of generalized clonus, tonic seizures, and death, but gabapentin (GBP) was ineffective at this dose.

[0534] The above results show that the representative compounds of the present application (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate have a strong inhibitory effect on epileptic seizures and epilepsy-induced death in mice in the subcutaneous injection of pentylenetetrazol model, and can be used to prepare anti-epileptic drugs.

[0535] Example 34 Pharmacokinetics of the compound in rats

[0536] Male SD rats were fasted for 12 hours before the experiment and had free access to water. The compound (+)-I-3 p-toluenesulfonate or (+)-I-4 p-toluenesulfonate of the present application was dissolved in 10% 1,2-propylene glycol distilled water and administered orally or intravenously to male SD rats, with 3 rats in each group. 0.2 mL of blood was collected from the retroocular venous plexus 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after oral administration, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after intravenous administration. The blood was placed in an EDTA-K2 test tube, centrifuged at 11000 rpm for 5 minutes, the plasma was separated, and the blood was frozen in a -20°C refrigerator. The concentration of the drug prototype was determined using a validated HPLC-ESI-MS method, and the pharmacokinetic parameters were calculated using WinNonLin. The results are shown in the table below:

[0537] *Both compounds were administered as p-toluenesulfonate salts. Test data are based on the prototype drug (free base).

[0538] From the above data, it can be seen that the representative compounds of the present application (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate are rapidly absorbed after oral administration and have very high bioavailability, and are suitable for oral administration.

[0539] Example 35 Effect of Compounds on Motor Function in Rats

[0540] All test drugs were dissolved in DMSO (5% v / v) + 10% 1,2-propylene glycol in saline (95% v / v) and administered by oral gavage at a volume of 10 mL / kg. A vehicle negative control and a positive control group (pregabalin (PGB) at 10 mg / kg and 30 mg / kg) were set up. Experimental groups included (+)-I-3-toluenesulfonate (10 mg / kg, calculated as the free base), (+)-I-4-toluenesulfonate (10 mg / kg, calculated as the free base), (+)-I-3-toluenesulfonate (30 mg / kg, calculated as the free base), and (+)-I-4-toluenesulfonate (30 mg / kg, calculated as the free base). Male Sprague-Dawley rats weighing 200-250 g were selected, with 10 animals per treatment group. Rotarod testing was performed using a YLS-31A rotarod apparatus (Shanghai Xinruan Information Technology Co., Ltd.) at a constant speed of 6 rpm. On the first day, a screening test was first performed. The tip of the rat's tail was pinched and placed on a rotating rod. After it maintained balance on the rotating rod and walked around, it was released and the number of times the rat fell within 1 minute was recorded and counted. Rats that fell 3 times within 1 minute were eliminated and not used for subsequent drug evaluation. A drug evaluation experiment was carried out on the second day. Rats fasted for 8 hours before the experiment, and then a rotating rod test was performed as the pre-dose time point (BL). Then, oral administration was performed. A rotating rod test was performed at 1h, 2h, 4h, 6h, 8h, 10h, and 24 hours after administration. The number of falls of the rat within 1 minute was recorded and counted. If the rat fell 3 times within one minute, it was considered that drug toxicity caused the rat's "motor function impairment". The degree of "motor function impairment" (rotarod fall) of each drug administration group at a specific time point was calculated based on the ratio of the number of "motor function impairment" animals in the group to the total number of animals in the group.

[0541] The test results are shown in Figure 7.

[0542] The rotarod test is a classic experiment to measure the damage of compounds on animal motor function. We used the rat rotarod test to evaluate the effects of the representative compounds (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate of the present application on rat motor function. As can be seen from Figure 7, at a dose of 10 mg / kg (as free base), (+)-I-3 p-toluenesulfonate, (+)-I-4 p-toluenesulfonate and pregabalin (PGB) control did not significantly affect the rotarod performance of rats; at a dose of 30 mg / kg (as free base), the PGB group showed obvious toxic reactions, and the effect on the rat rotarod reached its maximum 4 hours after administration. The proportion of rats whose rotarod performance was affected in the (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate groups was less than that in the PGB group.

[0543] Acute toxicity test of compound in Example 36 in rats

[0544] Preliminary acute toxicity evaluation of (±)-I-7, (+)-I-3 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate in male SD rats.

[0545] SD rats were acclimated for one week before preliminary acute toxicity testing. Compounds were prepared fresh on the day of testing. Pregabalin and (±)-I-7 were dissolved directly in 0.9% sodium chloride to the desired concentration. (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate were dissolved in 5% PEG 400 + 95% (0.9% sodium chloride) as the solvent. This was accomplished by first dissolving the compounds in 5% PEG 400 at a final volume, then adding 95% 0.9% sodium chloride solution and vortexing thoroughly to dissolve the compounds. Animals were then labeled and weighed and randomly divided into groups of 2-4 animals per group. The animals were administered the test compound and vehicle (5% PEG 400 + 95% (0.9% sodium chloride)) via oral gavage at a dose volume of 10 mL / kg. Clinical symptoms were observed and recorded 0.5, 1, 2, 4, 6, and 24 hours after administration. The clinical symptom codes are as follows: 0 no abnormality, 1 mild tremor, 2 unsteady gait, 3 prone position, 4 startle reflex, 5 dyspnea, 6 loss of righting reflex, 7 closed eyelids, 8 tachypnea, × animal death.

[0546] Results and Discussion: The results are shown in the following table. When the compound (+)-I-3 p-toluenesulfonate was administered at a dose of 164.5 mg / kg (as free base) and (+)-I-4 p-toluenesulfonate was administered at a dose of 163.8 mg / kg (as free base) by oral gavage, all animals in the two groups were consistent with the animals in the vehicle control group from 0 to 24 hours after administration, and no obvious abnormal manifestations were observed. When the (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate were administered at a dose of 300 mg / kg (as free base) by oral gavage, two animals in the (+)-I-3 p-toluenesulfonate group fell prone only 1 hour after administration, and one of them was also accompanied by mild tremor and eyelid closure symptoms, while one animal in the (+)-I-4 group fell prone only 1 hour after administration, and the other animal was found to fall prone at both 1 hour and 3 hours after administration. Another compound, (±)-I-7, was administered orally at a dose of 300 mg / kg (as free base). All animals developed prone positions within 1 and 2 hours of dosing, with two animals also exhibiting mild tremors. Twenty-four hours after dosing, similar to the vehicle control group, no significant abnormalities were observed in animals administered (±)-I-7, (+)-I-3 p-toluenesulfonate, or (+)-I-4 p-toluenesulfonate. The test results show that the representative compounds of the present application, (+)-I-3 p-toluenesulfonate, at a dose of 164.5 mg / kg (as free base) and (+)-I-4 p-toluenesulfonate, at a dose of 163.8 mg / kg (as free base) in male rats, did not exhibit neurotoxicity when orally administered. Combined with the analgesic and antiepileptic efficacy doses disclosed in Examples 29 to 33 of the present application, it can be inferred that the representative compounds of the present application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, have a wide safety window. The representative compounds of the present application, (±)-I-7, (+)-I-3 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate, at a high dose of 300 mg / kg (as free base), can cause animals to experience relatively obvious acute toxic reactions, but no animal deaths occur.

Claims

1. A compound of formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof, in, R 1 and R 2 Independently selected from H, halogen or C1-C6 alkyl; Each R 3 、R 4 、R 5 、R 6 independently selected from H, halogen, C1-C6 alkyl and C1-C6 alkoxy; or R 3 、R 4 and the C atoms they are connected to form a C3-C6 cycloalkyl group, or R 5 、R 6 and the C atoms they are connected to together form a C3-C6 cycloalkyl group; Each R 7 、R 8 、R 9 、R 10 Independently selected from H, halogen and C1-C6 alkyl; m and n are independently selected from 0, 1, 2, 3; Or, when n>=1, R 8 The connected C atom and R 10 The adjacent C atoms can be connected to R 8 、R 10 Together they form a C3-C6 cycloalkyl group; When n>=1, R 8 Connected C atoms and R 10 The solid and dashed lines connecting the adjacent C atoms represent R 8 Connected C atoms and R 10 The chemical bond between the connected C atoms can be a single bond or a double bond; when it represents a double bond, the corresponding R 7 and R 9 Indicates that it does not exist.

2. The compound of claim 1 having the general formula I, its chiral isomer or a pharmaceutically acceptable salt thereof, in, R 1 and R 2 independently selected from H and C1-C3 alkyl; R 3 、R 4 independently selected from H, halogen and C1-C3 alkyl; or R 3 、R 4 Together with the C atom to which they are commonly attached, they form a cyclopropyl group; R 7 、R 8 、R 9 、R 10 independently selected from H and C1-C6 alkyl; or R 8 The connected C atom and R 10 The C atom connected to R 8 、R 10 Composition of cyclopropyl; R 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8 Connected C atoms and R 10 The chemical bond between the connected C atoms can be a single bond or a double bond; when it represents a double bond, R 7 and R 9 Indicates non-existence; m=0; n=1.

3. The compound of formula I according to claim 1 or 2, its chiral isomer or a pharmaceutically acceptable salt thereof, in, R 1 and R 2 independently selected from H or methyl; R 3 、R 4 are independently selected from H and methyl; or R 3 、R 4 Together with the C atom to which they are commonly attached, they form a cyclopropyl group; R 7 、R 8 、R 9 、R 10 are independently selected from H or methyl; or R 8 The connected C atom and R 10 The C atom connected to R 8 、R 10 Composition of cyclopropyl; R 8 Connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R 8 Connected C atoms and R 10 Between connected C atoms The chemical bond of can be a single bond or a double bond; when it represents a double bond, R 7 and R 9 Indicates non-existence; m=0; n=1.

4. The compound of claim 1 having the general formula I, its chiral isomer or a pharmaceutically acceptable salt thereof, in, R 1 and R 2 independently selected from H or methyl; R 3 、R 4 are independently selected from H and methyl; or R 3 、R 4 Together with the C atom to which they are commonly attached, they form a cyclopropyl group; R 7 、R 8 、R 9 、R 10 independently selected from H or methyl; m=0; n=1.

5. The compound of formula I according to claim 1 or 2, wherein the chiral isomers thereof or pharmaceutically acceptable salts thereof are selected from the following compounds:

6. The method for preparing a compound of formula I according to any one of claims 1 to 5, wherein: The following steps are involved: 1) Ketone K reacts with phosphoacetate W1 in the presence of a base to undergo Wittig condensation to obtain α,β-unsaturated acetate L-1. L-1 reacts with nitromethane in the presence of a base to undergo Michael addition reaction to obtain M-1. or 2) Ketone K reacts with nitromethane in the presence of a catalyst to undergo Knoevenagel condensation reaction to obtain an α,β-unsaturated nitro compound L-2. L-2 reacts with acetate W2 in the presence of a strong base to undergo a Michael-like addition reaction to give M-2. where R 11 、R 12 and R 13 An alkyl group selected from C1 to C6; R 1 ~R 10 , m and n have the meanings as defined in any one of claims 1-5.

7. Use of the compound of formula I according to any one of claims 1 to 5, its chiral isomers and pharmaceutically acceptable salts thereof in the preparation of drugs for treating chronic neuropathic pain, epilepsy and anxiety.

8. A pharmaceutical composition, characterized in that The invention comprises a compound of general formula I according to any one of claims 1 to 5, a chiral isomer thereof and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; the excipient is selected from one or more of a carrier, a diluent and an excipient.

9. The pharmaceutical composition according to claim 8, wherein The composition is a solid oral preparation, a liquid oral preparation or an injection.

10. The pharmaceutical composition according to claim 9, wherein the solid and liquid oral preparations comprise: Dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, granules, oral solutions; the injection preparations include water injection, freeze-dried powder injection, large infusion, and small injection.

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