γ-Aminobutyric acid derivatives containing polycyclic structures, their preparation and use

Abstract

The present invention relates to the pharmaceutical field. Specifically, the present application relates to voltage-gated calcium ion channel α2δ subunit ligands comprising a polycyclic γ-aminobutyric acid structure represented by general formula I, their preparation methods, and their use in the treatment of chronic neuropathic pain, epilepsy, and anxiety. [Formula 1] TIFF2025537126000058.tif32128

Description

[Technical Field]

[0001] The present application relates to the pharmaceutical field. Specifically, the present application relates to a series of voltage-gated calcium ion channel α2δ subunit ligands containing a polycyclic γ-aminobutyric acid structure, methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof in medicine. [Background technology]

[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 injury, and the use of certain chemotherapy drugs. Diabetic peripheral neuropathy pain (DPNP) and postherpetic neuralgia (PHN) are the two most common types of chronic neuropathic pain. Untreated or improperly treated chronic neuropathic pain can cause significant physical pain, have a significant negative impact on the patient's mood, and lead to mental and psychological problems such as insomnia, anxiety, and depression, thereby significantly reducing the patient's quality of life and placing a significant burden on families and society.

[0003] Currently, the three main types of medications used to treat chronic neuropathic pain are 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 have many side effects, such as anticholinergic effects (dry mouth, constipation, blurred vision, hypersomnia, weight gain, etc.), central nervous system toxicity (inattention, epileptic seizures, abnormal social behavior, hallucinations, etc.), and cardiovascular toxicity (hypotension, tachycardia, arrhythmia, etc.). These medications have many precautions for combination therapy, and their drug interactions are relatively complex. Other antidepressants include primarily selective 5-hydroxytryptamine and / or norepinephrine reuptake inhibitors, such as imipramine, paroxetine, fluoxetine, escitalopram, duloxetine, bupropion, venlafaxine, and sertraline. Antidepressants have numerous precautions for combination therapy and complex drug interactions, creating significant challenges in clinical therapy and patient compliance. Antiepileptic drugs used to treat chronic neuropathic pain are primarily sodium and calcium ion channel drugs, such as gabapentin, pregabalin, lamotrigine, topiramate, carbamazepine, oxcarbazepine, and sodium valproate. Gabapentin requires a very high daily dose of 1,800–3,600 mg to achieve optimal efficacy. At higher doses, absorption saturates, resulting in a slow onset of effect (onset occurs after 2 weeks of oral administration). Sodium ion channel blockers, such as lamotrigine and topiramate, have many side effects, such as rash, nausea and vomiting, dizziness and fatigue, and blurred vision. They require careful attention when used in combination with other drugs, and their drug interactions are relatively complex. Painkillers used to treat chronic neuropathic pain include opioids, tramadol, and tapentadol, the latter two of which share a significant portion of the mechanism of action of opioids. Opioid drugs have some, but not strong, effect on neuropathic pain, but they have significant side effects and are addictive.Studies have shown that when duloxetine is used at doses of 60 mg / day and 120 mg / day to treat diabetic peripheral neuropathic pain, the clinical effectiveness rates are only 49% and 52%, respectively (Goldstein, DJ; et al. Pain, 2005, 116(1-2), 109-118.), and when gabapentin is used at daily doses of up to 1,800 mg / day, 2,400 mg / day, and 3,600 mg / day, the clinical effectiveness rates for postherpetic neuralgia are 32%, 34%, and 43%, respectively (Rice, ASC; et al. Pain, 2001, 94(2), 215-224; Rowbotham, M.; et al. JAMA, 1998, 280(21), It has been reported that when pregabalin is used at a dose of 150-600 mg per day, the clinical effectiveness rate 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 extremely low clinical effectiveness data reflect the dilemma of the therapeutic effectiveness of currently available drugs, in that there is currently no specific cure for these diseases and no easy treatment that can prevent or improve neuropathy or completely relieve pain.

[0004] The voltage-gated calcium ion channel α2δ subunit is an important target for therapeutic drugs. Of the four drugs approved by the US FDA for diabetic peripheral neuropathic pain (pregabalin, duloxetine, fluoxetine, and talpentadol), pregabalin acts on this target (Field, MJ; et al. Proc. Natl. Acad. Sci. USA 2006, 103, 17537-17542). Voltage-gated calcium ion channel α2δ subunit ligand drugs, such as gabapentin, pregabalin, and mirogabalin, can be used to treat chronic neuropathic pain as well as epilepsy (pregabalin, US FDA-approved) and anxiety (pregabalin, European Medicines Agency-approved).

[0005] The present invention discloses a γ-aminobutyric acid derivative containing a polycyclic structure, which compound is 3 When combined with [H] gabapentin, it has a strong inhibitory effect on the human voltage-gated calcium ion channel α2δ subunit, and can be used to prepare drugs for the treatment of chronic neuropathic pain, epilepsy, and anxiety. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Goldstein, DJ; et al. Pain, 2005, 116(1-2), 109-118 [Non-patent document 2] Rice, ASC; et al. Pain, 2001, 94(2), 215-224 [Non-patent document 3] Rowbotham, M.; et al. JAMA, 1998, 280(21), 1837-1842 [Non-patent document 4] Dworkin, RH; et al. Neurology, 2003, 60(8), 1274-1283 [Non-Patent Document 5] Sabatowski, R.; et al. Pain, 2004, 109(1-2), 26-35 [Non-patent document 6] Field, MJ; et al. Proc. Natl. Acad. Sci. USA 2006, 103, 17537-17542 Summary of the Invention [Problem to be solved by the invention]

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

[0008] Another object of the present application is to provide methods for preparing voltage-gated calcium ion channel α2δ subunit ligands of general formula I, their chiral isomers, and pharmaceutically acceptable salts thereof.

[0009] Yet another object of the present application is to provide the use of the above compounds of general formula I, their chiral isomers, and their pharmaceutically acceptable salts in the treatment of chronic neuropathic pain, epilepsy, and anxiety.

[0010] Yet another object of the present application is to provide a pharmaceutical composition comprising, as an active ingredient, one or more of the above compounds of general formula I, chiral isomers thereof, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, diluent, or combination thereof.

[0011] Yet another object of the present application is to provide the use of the above pharmaceutical composition in the treatment of chronic neuropathic pain, epilepsy, and anxiety.

[0012] The contents of this application are described in detail in conjunction with the purpose of this application. [Means for solving the problem]

[0013] The compounds of general formula I in this application have the following structural formula: [ka] (In the formula, R 1 and R 2 are independently selected from H, halogen, and C1-C6 alkyl; R 3 , R 4 , R 5 and R 6 are each independently selected from H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, or R 3 and R 4 together with the C atom to which they are attached form a C3-C6 cycloalkyl, or R 5 and R 6 together with the C atom to which they are attached form a C3-C6 cycloalkyl, R 7 , R 8 , R 9 and R 10 are each independently selected from H, halogen, and C1-C6 alkyl; The chemical bond between atoms can be a single bond or a double bond, and when the chemical bond represents a double bond, R 7 and R 9 does not exist, m and n are independently selected from 0, 1, 2, and 3; Alternatively, if n ≥ 1, then R 8 C atoms and R bonded to 10 The adjacent C atom bonded to R 8 and R 10 can be taken together with If n ≥ 1, R 8 C atom and R bonded to 10 The solid and dashed lines between adjacent C atoms bonded to R 8 C atom and R bonded to 10represents that the chemical bond between the C atoms bonded to the 7 and R 9 does not exist).

[0014] According to the application: R 1 and R 2 are independently selected from H and C1-C3 alkyl; R 3 and R 4 are independently selected from H, halogen, and C1-C3 alkyl, or R 3 and R 4 together with the C atom to which they are attached to form a cyclopropyl group, R 7 , R 8 , R 9 and R 10 are independently selected from H and C1-C6 alkyl, or R 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 together to form a cyclopropyl R 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 represents that the chemical bond between the C atom bonded to R may be a single bond or a double bond, and when the chemical bond represents a double bond, R 7 and R 9 does not exist, m=0 and n=1, Compounds of general formula I, their chiral isomers, or pharmaceutically acceptable salts thereof are preferred.

[0015] According to the application: R 1 and R 2 is independently selected from H or methyl; R 3 and R 4 are independently selected from H and methyl, or R 3and R 4 together with the C atom to which they are attached to form a cyclopropyl group, R 7 , R 8 , R 9 and R 10 are independently selected from H or methyl, or R 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 together to form a cyclopropyl R 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 represents that the chemical bond between the C atom bonded to R may be a single bond or a double bond, and when the chemical bond represents a double bond, R 7 and R 9 does not exist, m=0 and n=1, More preferred are compounds of general formula I, chiral isomers thereof, or pharmaceutically acceptable salts thereof.

[0016] According to the application: R 1 and R 2 is independently selected from H or methyl; R 3 and R 4 together with the C atom to which they are attached to form a cyclopropyl group, R 7 , R 8 , R 9 and R 10 is independently selected from H or methyl; m=0 and n=1, More preferred are compounds of general formula I, chiral isomers thereof, or pharmaceutically acceptable salts thereof.

[0017] According to the application: R 1 and R 2 is independently selected from H or methyl; R3 and R 4 is independently selected from H and methyl; R 7 and R 9 is independently selected from H or methyl; R 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 together to form a cyclopropyl m=0 and n=1, More preferred are compounds of general formula I, chiral isomers thereof, or pharmaceutically acceptable salts thereof.

[0018] According to the application: R 1 and R 2 is independently selected from H or methyl; R 3 and R 4 is independently selected from H and methyl; R 7 and R 9 is independently selected from H or methyl; R 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 together to form a cyclopropyl m=0 and n=1, More preferred are compounds of general formula I, chiral isomers thereof, or pharmaceutically acceptable salts thereof.

[0019] According to the present application, the following compounds are more preferred:

[0020] [ka]

[0021] The compounds of general formula I in this application can be synthesized by the following methods.

[0022] In one typical case, ketone K and phosphonoacetate W1 undergo a Wittig condensation reaction in the presence of a base to give α,β-unsaturated acetate L-1, wherein the base is selected from inorganic bases and organic bases, and wherein R 11 and R 12 is selected from C1-C6 alkyl, R 1 ~R 10 , m and n have the definitions above, and L-1 is a mixture of two cis / trans geometric isomers.

[0023] [ka]

[0024] R in L-1 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 When the chemical bond between the C atoms bonded to R is a double bond, L-1 is L-1-1. In this case, L-1-1 can be converted to L-1-2 using the Simmons-Smith reaction or a similar reaction. In this case, R in L-1-2 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 to form a cyclopropyl. L-1-2 is a specific case of L-1. The Simmons-Smith reaction or similar reactions involve treating a substrate containing a C=C double bond with CH2I2 / Et2Zn, CH2I2 / Et2Zn / trifluoroacetic acid, or CH2I2 / Cu-Zn to give the cyclopropyl product.

[0025] [ka]

[0026] M-1 is obtained by Michael addition of L-1 and nitromethane in the presence of a base, and the newly generated chiral center in M-1 is influenced by the chiral center derived from K. In order to distinguish the configuration of the chiral center generated at the corresponding position by other methods described later, in this specification, the configuration of the newly generated chiral center in M-1 is referred to as R * The base is selected from a variety of inorganic and organic bases.

[0027] [ka]

[0028] M-1 is divided into three cases: M-1-1:R 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 indicates that the chemical bond between the C atoms bonded to is a double bond. M-1-2:R 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 together to form cyclopropyl. M-1-3:R 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 indicates that the chemical bond between the C atoms bonded to is a single bond.

[0029] Regarding M-1-1: The ester bond of M-1-1 is hydrolyzed with an acid or a base to obtain N-1-1, and the nitro group and the C=C double bond of N-1-1 are simultaneously reduced using catalytic hydrogenation (R * )-I-1-3 is obtained. (R * )-I-1-3 is a specific form of the compound of general formula I in this application. * )-I-1-3 with an acid HA to give the corresponding salt (R *)-I-1-3·HA, where the acid HA can be selected from a variety of inorganic and organic acids. First, the nitro group of M-1-1 is reduced with iron powder to give P-1-1, and the ester bond of P-1-1 is hydrolyzed with acid to give (R * )-I-1-1 is obtained. (R * )-I-1-1 is a specific form of the compound of general formula I in this application. (R * )-I-1-1 is reacted with an acid HA to give the corresponding salt (R * )-I-1-1·HA is obtained, where the acid HA is selected from a variety of inorganic and organic acids.

[0030] [ka]

[0031] Regarding M-1-2: The ester bond of M-1-2 is hydrolyzed with an acid or a base to obtain N-1-2, and the nitro group of N-1-2 is reduced by catalytic hydrogenation to obtain (R * )-I-1-2 is obtained. (R * )-I-1-2 is a specific form of the compound of general formula I in this application. (R * )-I-1-2 with an acid HA to give the corresponding salt (R * )-I-1-2·HA, where the acid HA can be selected from a variety of inorganic and organic acids. First, the nitro group of M-1-2 is reduced with iron powder to give P-1-2, and the ester bond of P-1-2 is hydrolyzed with acid to give (R * )-I-1-2 is obtained. (R * )-I-1-2 is a specific form of the compound of general formula I in the present application.

[0032] [ka]

[0033] (R * )-I-1-2 with an acid HA to give the corresponding salt (R * )-I-1-2·HA is obtained, where the acid HA is selected from various inorganic and organic acids.

[0034] Regarding M-1-3: The ester bond of M-1-3 is hydrolyzed with an acid or a base to obtain N-1-3, and the nitro group of N-1-3 is reduced by catalytic hydrogenation (R * )-I-1-3 is obtained. (R * )-I-1-3 is a specific form of the compound of general formula I in this application. * )-I-1-3 with an acid HA to give the corresponding salt (R * )-I-1-3·HA, where the acid HA is selected from various inorganic and organic acids. First, the nitro group of M-1-3 is reduced with iron powder to give P-1-3, and the ester bond of P-1-3 is hydrolyzed with acid to give (R * )-I-1-3 is obtained. (R * )-I-1-3 is a specific form of the compound of general formula I in this application. * )-I-1-3 with an acid HA to give the corresponding salt (R * )-I-1-3·HA is obtained, where the acid HA is selected from a variety of inorganic and organic acids.

[0035] [ka]

[0036] In another typical case, ketone K and nitromethane undergo a Knoevenagel condensation reaction in the presence of a catalyst to give α,β-unsaturated nitro compound L-2, where the catalyst is selected from a variety of inorganic and organic bases. L-2 is a mixture of two cis / trans geometric isomers.

[0037] [ka]

[0038] L-2 and acetate W2 undergo a Michael-like addition reaction in the presence of a strong base to give M-2, and the newly generated chiral center in M-2 is influenced by the chiral center derived from K. In the above reaction to produce M-1 from L-1, in order to distinguish the configuration of the chiral center generated at the corresponding position, the configuration of the newly generated chiral center in M-2 is referred to as S in this specification. * The strong base is selected from tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide, and R 13 is selected from C1-C6 alkyl, and S * and R * indicates that the configuration of the depicted chiral center is opposite.

[0039] [ka]

[0040] M-2 can be divided into three cases: M-2-1:R 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 indicates that the chemical bond between the C atoms bonded to is a double bond. M-2-2:R 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 together to form cyclopropyl. M-2-3:R 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 indicates that the chemical bond between the C atoms bonded to is a single bond.

[0041] Regarding M-2-1: The ester bond of M-2-1 is hydrolyzed with an acid or base to obtain N-2-1, and the nitro group and the C=C double bond of N-2-1 are simultaneously reduced using catalytic hydrogenation (S * )-I-2-3 is obtained. (S * )-I-2-3 is a specific form of the compound of general formula I in this application. * )-I-2-3 is reacted with an acid HA to give the corresponding salt (S * )-I-2-3·HA, where the acid HA is selected from various inorganic and organic acids. First, the nitro group of M-2-1 is reduced with iron powder to give P-2-1, and the ester bond of P-2-1 is hydrolyzed with acid to give (S * )-I-2-1 is obtained. (S * )-I-2-1 is a specific form of the compound of general formula I in this application. * )-I-2-1 is reacted with an acid HA to give the corresponding salt (S * )-I-2-1·HA, where the acid HA is selected from a variety of inorganic and organic acids.

[0042] [ka]

[0043] Regarding M-2-2: The ester bond of M-2-2 is hydrolyzed with an acid or base to obtain N-2-2, and the nitro group of N-2-2 is reduced using catalytic hydrogenation to obtain (S * )-I-2-2 is obtained. (S * )-I-2-2 is a specific form of the compound of general formula I in this application. * )-I-2-2 is reacted with an acid HA to give the corresponding salt (S * )-I-2-2·HA, where the acid HA is selected from various inorganic and organic acids. First, the nitro group of M-2-2 is reduced with iron powder to give P-2-2, and the ester bond of P-2-2 is hydrolyzed with acid to give (S * )-I-2-2 is obtained. (S * )-I-2-2 is a specific form of the compound of general formula I in this application. *)-I-2-2 is reacted with an acid HA to give the corresponding salt (S * )-I-2-2·HA is obtained, where the acid HA is selected from a variety of inorganic and organic acids.

[0044] [ka]

[0045] Regarding M-2-3: The ester bond of M-2-3 is hydrolyzed with an acid or a base to obtain N-2-3, and the nitro group of N-2-3 is simultaneously reduced using catalytic hydrogenation (S * )-I-2-3 is obtained. (S * )-I-2-3 is a specific form of the compound of general formula I in this application. * )-I-2-3 is reacted with an acid HA to give the corresponding salt (S * )-I-2-3·HA, where the acid HA is selected from various inorganic and organic acids. First, the nitro group of M-2-3 is reduced with iron powder to give P-2-3, and the ester bond of P-2-3 is hydrolyzed with acid to give (S * )-I-2-3 is obtained. (S * )-I-2-3 is a specific form of the compound of general formula I in this application. * )-I-2-3 is reacted with an acid HA to give the corresponding salt (S * )-I-2-3·HA, where the acid HA is selected from a variety of inorganic and organic acids.

[0046] [ka]

[0047] To prepare the optically pure final product I, a racemic intermediate consisting of a pair of enantiomers of the same relative configuration can be used for resolution.

[0048] In one typical example, the racemic intermediate (±)-N-acid, consisting of a pair of enantiomers with the same relative configuration in the above synthetic route, is chlorinated using a suitable chiral base A and a chiral base B in a suitable solvent to obtain precipitable salts (+)-N-acid·chiral base A and (-)-N-acid·chiral base B, respectively, with sufficient optical purity. These salts are then treated with dilute hydrochloric acid to remove the chiral base A and the chiral base B, yielding the (+)-N-acid and the (-)-N-acid, respectively. The nitro groups of the (+)-N-acid and the (-)-N-acid are reduced using catalytic hydrogenation to obtain the optically pure products (+)-IA and (-)-IA, respectively. (+)-IA and (-)-IA are each specific forms of the compound of general formula I in this application. (+)-IA and (-)-IA are reacted with an acid HA to give the corresponding salts (+)-IA·HA and (-)-IA·HA, respectively, where the acid HA is selected from a variety of inorganic and organic acids.

[0049] [ka]

[0050] In another typical example, the racemic intermediate (±)-P-NH2, consisting of a pair of enantiomers with the same relative configuration in the above synthetic route, is chlorinated using suitable chiral acids A and B in a suitable solvent to obtain precipitable salts (+)-P-NH2·chiral acid-A and (-)-P-NH2·chiral acid-B, respectively, with sufficient optical purity. These salts are then treated with aqueous sodium bicarbonate to remove chiral acids A and B, yielding (+)-P-NH2 and (-)-P-NH2, respectively. The tert-butyl esters of (+)-P-NH2 and (-)-P-NH2 are hydrolyzed with acid to obtain the optically pure products (+)-I-A1 and (-)-I-A1, respectively. (+)-I-A1 and (-)-I-A1 are each specific forms of the compound of general formula I in this application. (+)-I-A1 and (-)-I-A1 are reacted with an acid HA to give the corresponding salts (+)-I-A1·HA and (-)-I-A1·HA, respectively, where the acid HA is selected from a variety of inorganic and organic acids.

[0051] [ka]

[0052] In one typical example, K-1 can be synthesized according to the following method, where K-1 is a specific form of the above compound of general formula K. Compound CDE and compound Q-1 are subjected to a Diels-Alder reaction to obtain compound R, where Z is selected from NH, O and S, and R 14 is H and C1-C6 alkyl, or -ZR 14 -R 14 Z-=O, where compound Q-1 is maleic anhydride. Compound R is converted to alcohol R under acid catalysis. 15 OH to give compound S, where R 15 is selected from C1-C6 alkyl. Compound S is reacted with metallic sodium and trimethylchlorosilane in a refluxing inert solvent (hydroxyketone condensation reaction), and the resulting product is hydrolyzed with an acid to obtain compound T. Compound T is treated with PPh3 in refluxing CX4 to obtain compound U-1, where X is selected from Cl, Br, and I. Compound U-1 is treated with Zn powder in an acidic medium to obtain compound K-1.

[0053] [ka]

[0054] In another typical example, K-1 can be synthesized according to the following method: Compound CDE and compound Q-2 are subjected to a Diels-Alder reaction to obtain compound K-1.

[0055] [ka]

[0056] Compound ALE is reacted with dichloroketene to give compound U-2, which can be prepared by the reaction of trichloroacetyl chloride and activated zinc powder, or by the reaction of dichloroacetyl chloride and triethylamine. Treatment of U-2 with Zn powder in an acidic medium gives compound K-2, which is a specific form of the aforementioned compound of general formula K.

[0057] [ka]

[0058] Compound K-1 is catalytically hydrogenated to reduce the C=C double bond to give compound K-3. K-1 is converted to K-4 using the Simmons-Smith reaction, which involves treating a substrate containing a C=C double bond with CHI / EtZn, CHI / EtZn / trifluoroacetic acid, or CHI / Cu-Zn to give the cyclopropyl product. K-3 and K-4 are each specific forms of the aforementioned compound of general formula K.

[0059] [ka]

[0060] In this application, "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0061] In this application, "alkyl" refers to a group derived from a branched or straight-chain saturated aliphatic alkane having the specified number of carbon atoms after removing one hydrogen atom. For example, "C 1~6 "Alkyl" is intended to include C1, C2, C3, C4, C5, and C6 alkyl, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, and the like.

[0062] In this application, "alkoxy" refers to an alkyl as defined herein attached to another group via an oxygen atom, i.e., "alkyl-O-", and includes "C 1~6 Alkoxy" (C 1~6 alkyl-O-) and "C 1~4 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., and "alkoxy" in this application is preferably C 1~4 Alkoxy, more preferably C 1~3 It is an alkoxy.

[0063] In this application, "cycloalkyl" refers to a saturated cyclic alkyl derived from a cycloalkane after removing one hydrogen atom. Cycloalkyl includes "3- to 6-membered cycloalkyl" and "3- to 5-membered cycloalkyl." Preferably, cycloalkyl has a monocyclic saturated structure, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0064] Pharmaceutically acceptable salts of the compounds of general formula I in the present application include, but are not limited to, pharmaceutically acceptable salts formed from the compounds of general formula I and various inorganic bases, such as NaOH, KOH, Mg(OH), Ca(OH), Sr(OH), Al(OH), etc., or inorganic carbonate bases, such as NaCO, KCO, MgCO, CaCO, SrCO, etc., or organic bases, such as amino acids, etc., 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.

[0065] The compound of general formula I in this application can be combined with one or more pharmaceutically acceptable auxiliary substances to prepare a pharmaceutical composition.The pharmaceutical composition can be prepared into solid oral preparations, liquid oral preparations, injections, and other dosage forms.Solid oral preparations and liquid oral preparations include tablets, dispersible tablets, sugar-coated tablets, granules, dry powders, capsules, and solutions.Injections include small volume parenteral (SVP) solutions, infusion solutions, water for injection, lyophilized powders for injection, etc.

[0066] The compounds of the present application include chiral isomers, such as enantiomers, diastereomers, racemic mixtures and other mixtures, and all of these mixtures are included within the scope of the present application.

[0067] The term "enantiomer" refers to a mirror-image stereoisomer.

[0068] The term "diastereomer" refers to stereoisomers whose molecules have two or more centers of chirality and the molecules are not mirror-images.

[0069] (±) indicates that a compound is a racemic mixture, and the configuration in the chemical structure of the compound is the relative configuration. (+) or (-) indicates that a compound is optically pure, and the optical rotation symbol indicates dextrorotation or levorotation, respectively, and the configuration in the chemical structure of the compound is the absolute configuration.

[0070] Chiral isomers of the compounds of the present application can be prepared according to the chiral synthesis or chiral reagents described above in the present application, or other conventional techniques. The separation of optically pure compounds in the present application is usually completed by chiral resolution. The separation of optically pure compounds is achieved by salifying optically pure chiral acids and racemic bases, followed by crystallization in a suitable solvent to obtain the salts of optically pure bases and chiral acids.

[0071] The term "optically pure" means an isomer or enantiomer content of 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0072] The absolute configuration of a compound can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction. The absolute configuration of a compound can also be confirmed by the chiral structure of the starting material or the reaction mechanism of asymmetric synthesis.

[0073] According to the framework of the present application, the pharmaceutically acceptable auxiliary substance or food science acceptable auxiliary substance is selected from carriers, excipients, diluents, binders, fillers, disintegrants, lubricants, glidants, effervescent agents, flavorings, preservatives, and coating agents.

[0074] According to the present application, an excipient is a substance that is non-toxic, compatible with the active ingredient, and has other biological properties that are biocompatible. The selection of a particular excipient depends on the administration method for treating a particular patient or the type and state of the disease. Examples of excipients include, but are not limited to, solvents, dispersing agents, suspending agents, surfactants, isotonicity agents, thickeners, emulsifiers, stabilizers, hydrating agents, emulsification enhancers, buffers, absorbents, colorants, ion exchange agents, release agents, coating agents, antioxidants, and the like, which are conventional in the pharmaceutical field. The filler includes one or more compositions of lactose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; the binder includes one or more compositions of sucrose, povidone, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, ethanol, and water; and the disintegrant includes one or more compositions of cross-linked povidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, and effervescent disintegrants.

[0075] The compound of general formula I in the present application has a binding activity to the 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 in vitro activity of the compound of general formula I in the present application was measured by measuring the binding activity of the compound to the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1 receptor expressed on CHO cells. 3 It has been demonstrated in vitro by inhibiting the binding of [H]gabapentin, and in vivo by its analgesic effect in animal chronic pain models and its antiepileptic effect in animal epilepsy models.

[0076] The compound of formula I in the present application is effective in a very wide range of dosage. For example, the daily dosage ranges from about 1 to 3000 mg / person, and can be administered once or multiple times. The actual dosage of the compound of formula I in the present application can be determined by a doctor according to the actual condition of the patient.

[0077] The present invention will be further described below in conjunction with the drawings. [Brief explanation of the drawings]

[0078] [Figure 1] FIG. 1 shows the chemical structure of the compound (+)-32-LAC in single crystal diffraction (ORTEP diagram). [Figure 2] FIG. 1 shows the chemical structure of the compound (+)-22-LAC in single crystal diffraction (ORTEP diagram). [Figure 3A] 1 shows a mechanical pain threshold time chart of the pharmacodynamic evaluation results of compounds (±)-I-7, (±)-I-3 and (±)-I-4 in a rat model of partial nerve injury. [Figure 3B] 1 is a chart showing the area under the mechanical pain threshold-time curve of the pharmacodynamic evaluation results of compounds (±)-I-7, (±)-I-3, and (±)-I-4 in a rat model of spared nerve injury. [Figure 4A] 1 is a mechanical pain threshold time chart for the pharmacodynamic evaluation of compounds (-)-I-3, (+)-I-3, (-)-I-4, and (+)-I-4 in a rat spared nerve injury model. [Figure 4B] 1 is a chart of the area under the mechanical pain threshold-time curve for the pharmacodynamic evaluation of compounds (-)-I-3, (+)-I-3, (-)-I-4, and (+)-I-4 in a rat spared nerve injury model. [Figure 5] 1 shows the fitting curve of the median effective dose (ED50) of a compound for animal protection in the maximal electroshock model in mice, calculated by the least squares method (Graphpad Prism5) employing the dose-protection rate curve. [Figure 6]FIG. 1 shows the antiepileptic effects of compounds (+)-I-3 and (+)-I-4 in a mouse epilepsy model (maximal electroshock model (MES)). [Figure 7] FIG. 1 shows the curves of the effects of compounds (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate on the motor function of animals measured by the rotarod test. DETAILED DESCRIPTION OF THE INVENTION

[0079] The present invention will be described in more detail below with specific examples. Please note that the following examples are only used for illustration purposes and are not intended to limit the present invention. Various modifications made by those skilled in the art based on the teachings of the present invention shall fall within the scope of protection claimed by the claims of the present invention.

[0080] Melting points are measured using an SGW X-4A microscopic melting point analyzer (INESA Physico-optical Instrument Co., Ltd, Shanghai, China) without thermometer calibration. 1 H NMR and 13 C NMR was performed on a Bruker Ascend 500 NMR spectrometer (Bruker Swiss AG, Fallanden, Switzerland) using CDCl3, DMSO-d6, CD3OD, or DO as solvents and TMS ( 1 1H NMR) or deuterated solvent ( 13 The known chemical shifts of carbon signals (in the case of C NMR) were detected. High-resolution mass spectra were examined using electrospray ionization (ESI) techniques on a Thermo Q Exactive Plus mass spectrometer (Thermo Fisher Scientific, Bremen, Germany). Optical rotations were measured using an Anton Paar MCP4100 polarimeter.

[0081] Enantiomeric excess (%ee) measurement method (chiral HPLC method): Measurement was performed using a Daicel Chiralpak AS-RH 4.6 mm × 250 mm chromatographic column (5 μm) on an Agilent 1260 infinity Type II liquid chromatograph (detector wavelength 220 nm, mobile phase of acetonitrile / 0.1% KH2PO4-KOH buffer (pH = 7.0) = 70 / 30, flow rate 1 mL / min, sample injection concentration 0.5 mg / mL, sample injection volume 3 μL).

[0082] Single crystal diffraction method: A Rigaku XtaLAB Pro single crystal diffractometer was used for diffraction using Cu Kα radiation at a temperature of 100.00(10) K. CrysAlisPro 1.171.39.33c (Rigaku OD, 2017) was used for diffraction data collection and data reduction processing, and the SHELXL program was used for structure analysis and refinement.

[0083] Dry solvents were prepared from the corresponding analytically pure solvents using standard drying methods.

[0084] [Example 1] Synthesis of compound (±)-I-1

[0085] [ka] Step 1: Synthesis of compound (±)-3 The procedure for preparing activated zinc powder is as follows: dry CuSO4 (40.00 g, 0.25 mol) was added to water (1 L) and stirred to dissolve and clarify. Zinc powder (600.00 g, 9.17 mol) was added, stirred at room temperature for 3-4 hours, and filtered. The filter cake was washed with water (300 mL x 2) and acetone (750 mL x 2) successively and dried in a vacuum drying oven at 50 °C (approximately 10 mmHg) for 24-48 hours.

[0086] Compound 2 (14.00 g, 0.15 mol) and activated zinc powder (14.00 g, 0.21 mol) were sequentially added to dry tetrahydrofuran (140 mL) under a N2 atmosphere and an ice-water bath, and the mixture was stirred. A solution of trichloroacetyl chloride (12.00 g, 66 mmol) in dry tetrahydrofuran (20 mL) was then added dropwise. Heat was generated during the addition, and the internal temperature of the reaction mixture was maintained between 35 and 40 °C by controlling the addition rate. After the addition was completed, the internal temperature of the reaction mixture was maintained at 35 °C and the mixture was stirred overnight. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 9 / 91] to give the desired product (±)-3 (pale yellow oil, 6.00 g). The product was used directly in the next reaction without characterization.

[0087] Step 2: Synthesis of compound (±)-4 Zinc powder (12.00 g, 0.18 mol) and glacial acetic acid (65 mL) were mixed and stirred, and a solution of freshly prepared compound (±)-3 (6.00 g, 29 mmol) in glacial acetic acid (12 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction mixture was placed in an oil bath under a N2 atmosphere and stirred at 55 °C for 2 h. 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 CHCl (200 mL × 2). The organic phases were combined, washed with water (300 mL × 3), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give the desired product (±)-4 (3.00 g of a pale yellow oil). (The combined yield of 2 → (±)-4 was 15%). 1H NMR (CDCl3, 500 MHz) δ: 3.08-3.10 (m, 1H), 3.03 (ddd, 1H, J = 3.8 Hz, 8.8 Hz, and 18.5 Hz), 2.53 (dt, 1H, J = 3.5 Hz and 18.5 Hz), 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). 13 C NMR (CDCl3, 126 MHz) δ: 213.08, 68.21, 50.44, 39.70, 37.41, 32.62, 31.38, 28.46, 26.87.

[0088] Step 3: Synthesis of compound (±)-5 Under a N2 atmosphere, potassium tert-butoxide (t-BuOK) (3.8 g, 34 mmol) was added to dry THF (25 mL) and stirred in an ice-water bath to form a suspension. tert-Butyl diethylphosphonoacetate (7.00 g, 28 mmol) was then added dropwise. After the addition was complete, the reaction was continued in an ice-water bath for 40 min, followed by the dropwise addition of a solution of freshly prepared compound (±)-4 (3.00 g, 22 mmol) in dry THF (10 mL). After the addition was complete, the reaction was continued at room temperature for 2 h, and TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (200 mL) and extracted with EtOAc (120 mL × 2). The combined organic phases were dried (MgSO), filtered to remove the drying agent, and concentrated on a rotary evaporator under reduced pressure to give a dark yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 3.70 g of the desired product (±)-5 (pale yellow oil), which was used directly in the next reaction without further characterization.

[0089] Step 4: Synthesis of compound (±)-6 (±)-5 (3.70 g, 16 mmol) was dissolved in CH3NO2 (22 mL) and stirred at room temperature, to which 1,8-diazabicycloundec-7-ene (DBU) (4.80 g, 32 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred overnight in an oil bath at 65 °C under a N2 atmosphere. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, poured into water (200 mL), and extracted with CHCl2 (150 mL × 2). The organic phases were combined, dried, and purified by HPLC. g The mixture was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 3.80 g of the desired product (±)-6 (a pale yellow oil). The combined yield of (±)-4 → (±)-6 was 58%. 1 H NMR (CDCl3, 500 MHz) δ: 4.74 (dd, 1H, J = 1.0 Hz and 11.5 Hz), 4.68 (d, 1H, J = 11.5 Hz), 2.57 (d, 1H, J = 17.0 Hz), 2.52 (d, 1H, J = 17.0 Hz), 2.31-2.35 (m, 1H), 2.12-2.13 (m, 1H), 2.03-2.05 (m, 2H), 1.99 (ddd, 1H, J = 2.0 Hz, 9.0 Hz and 14.0 Hz), 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). 13 C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 16 H 26 NO4([M+H] +) calculated value: 296.1856, measured value: 296.1852.

[0090] Step 5: Synthesis of compound (±)-7 Compound (±)-6 (1.70 g, 5.8 mmol) was dissolved in CHCl (18 mL) and trifluoroacetic acid (TFA) (10 mL) was added dropwise in an ice-water bath. After the addition was complete, the mixture was stirred at room temperature until TLC monitoring indicated the reaction was complete (usually 2-4 h). The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 17 / 33] to give a pale yellow oil. n-Hexane (1 mL) was added to the oil, and the solid was sonicated to precipitate. After stirring at room temperature for 1 h, the solid was collected and dried to give 1.00 g of the desired product (±)-7 (white solid (72%)), melting at 93.7 °C-95.5 °C. 1 H NMR (CDCl3, 500 MHz) δ: 4.76 (d, 1H, J = 12.0 Hz), 4.71 (d, 1H, J = 12.0 Hz), 2.77 (d, 1H, J = 18.0 Hz), 2.72 (d, 1H, J = 18.0 Hz), 2.34-2.38 (m, 1H), 2.15-2.16 (m, 1H), 2.03-2.07 (m, 2H), 1.99 (ddd, 1H, J = 2.0 Hz, 8.5 Hz and 14.0 Hz), 1.86-1.88 (m, 1H), 1.62 (dd, 1H, J = 6.0 Hz and 14.0 Hz), 1.48-1.52 (m, 2H), 1.32-1.34 (m,1H), 1.02-1.08 (m, 2H). 13 C NMR (DMSO-d6, 126 MHz) 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. ESI-HRMS: (m / z) C 12 H 18NO4([M+H] + ) calculated value: 240.1230, measured value: 240.1227.

[0091] Step 6: Synthesis of compound (±)-I-1 (±)-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 reaction vessel was purged with hydrogen (balloon) according to standard procedures and stirred overnight at room temperature. TLC monitoring indicated the reaction was complete (reactions typically completed within 12 h). The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated on a rotary evaporator under reduced pressure to give an oily residue. EtOAc (10 mL) was added and stirred to precipitate a solid, which was then stirred at room temperature for 1 h. The solid was collected by filtration and dried to give 0.30 g of the desired product (±)-I-1 (white solid, 34%), melting at 180.2 °C–184.0 °C. 1 H NMR (CD3OD, 500 MHz) δ: 3.04 (s, 2H), 2.63 (d, 1H, J = 16.0 Hz), 2.45 (d, 1H, J = 16.0 Hz), 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 = 2.0 Hz, 8.5 Hz and 13.0 Hz), 1.49-1.55 (m, 3H), 1.30-1.32 (m, 1H), 1.03-1.07 (m, 2H). 13 C NMR (CD3OD + D2O (1 drop), 126 MHz) 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. ESI-HRMS: (m / z) C 12 H 20 NO2([M+H] + ) calculated value: 210.1489, measured value: 210.1483.

[0092] Compound (±)-I-1 is a specific form of the compound of general formula I in this application.

[0093] [Example 2] Synthesis of compound (±)-I-2

[0094] [ka] Step 1: Synthesis of compound (±)-9 Compound 8 (42.00 g, 0.46 mol) and activated zinc powder (42.00 g, 0.64 mol) were sequentially added to dry tetrahydrofuran (350 mL) under a N2 atmosphere and an ice-water bath, and the mixture was stirred. A solution of trichloroacetyl chloride (36.00 g, 0.20 mol) in dry tetrahydrofuran (150 mL) was then added dropwise. During the addition, heat was generated from the reaction system, and the internal temperature of the reaction system was maintained at 32–38°C. After the addition was completed, the internal temperature of the reaction system was maintained at 34.5°C, and the mixture was stirred overnight. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a residue, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23] to give 10.54 g of the desired product (±)-9 (a pale yellow oil). The product was used directly in the next reaction without characterization.

[0095] Step 2: Synthesis of compound (±)-10 After stirring, zinc powder (21.00 g, 0.32 mol) and glacial acetic acid (120 mL) were mixed, and then a solution of freshly prepared compound (±)-9 (10.54 g, 52 mmol) in glacial acetic acid (25 mL) was added dropwise to the mixture in an ice-water bath. After the addition was complete, the reaction mixture was placed in a 55 °C oil bath under a N atmosphere and stirred overnight. 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 CHCl (300 mL). The organic phase was washed successively with water (400 mL × 3) and saturated NaHCO solution (400 mL) until the pH of the aqueous phase was >7, dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23] to give 2.73 g of the desired product (±)-10 (a pale yellow oil). (The combined yield of 8 → (±)-10 was 4%). 1 H NMR (CDCl3, 500 MHz) 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 = 3.3 Hz, 9.0 Hz and 19.3 Hz), 2.28-2.33 (m, 2H), 1.54-1.56 (m, 1H), 1.40-1.43 (m, 1H). 13 C NMR (CDCl3, 126 MHz) δ: 211.83, 139.86, 136.19, 66.31, 45.70, 44.17, 43.18, 41.06, 30.28. ESI-HRMS: (m / z) CH 11 O ([M+H] + ) calculated value: 135.0804, measured value: 135.0803.

[0096] Step 3: Synthesis of compound (±)-11 Under a N2 atmosphere, t-BuOK (4.52 g, 40 mmol) was added to dry THF (90 mL) and stirred in an ice-water bath to form a suspension. tert-Butyl diethylphosphonoacetate (10.16 g, 40 mmol) was then added dropwise. After the addition was complete, the reaction was stirred in an ice-water bath for 1 h, and then a solution of freshly prepared compound (±)-10 (2.70 g, 20 mmol) in dry THF (30 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 water (400 mL) and extracted with EtOAc (300 mL x 3). The combined organic phase was washed with saturated brine (300 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23] to give 3.91 g of the desired product (±)-11 (pale yellow oil), which was used directly in the next reaction without further characterization.

[0097] Step 4: Synthesis of compound (±)-12 (±)-11 (3.91 g, 17 mmol) was dissolved in CH3NO2 (40 mL) and stirred at room temperature. DBU (7.76 g, 51 mmol) was added dropwise to the solution. After the addition was complete, the reaction mixture was stirred overnight in a 50 °C oil bath under a N2 atmosphere. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, poured into water (250 mL), and extracted with C2Cl2 (200 mL × 2). The combined organic phases were dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23] to give 3.06 g of the desired product (±)-12 (a pale yellow oil). The combined yield of (±)-10 → (±)-12 was 52%. 1H NMR (CDCl3, 500 MHz) δ: 6.02-6.04 (m, 1H), 5.99-5.01 (m, 1H), 4.74 (d, 1H, J = 11.5 Hz), 4.70 (d, 1H, J = 11.5 Hz), 2.72-2.74 (m, 2H), 2.55 (s, 2H), 2.09-2.14 (m, 1H), 2.04 (ddd, 1H, J = 2.0 Hz, 8.5 Hz and 13.5Hz), 1.87-1.88 (m, 1H), 1.71-1.73 (m, 1H), 1.36-1.48 (m, 11H). 13 C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 16 H 24 NO4([M+H] + ) calculated value: 294.1700, measured value: 294.1693.

[0098] Step 5: Synthesis of compound (±)-13 p-toluenesulfonate Compound (±)-12 (0.70 g, 2.4 mmol) was dissolved in 10 mL of EtOH and stirred in 5 mL of water at room temperature. Iron powder (0.67 g, 12 mmol) and NH₄Cl (0.26 g, 4.9 mmol) were then added sequentially. The reaction vessel was purged with nitrogen (balloon) according to standard procedures, and the mixture was stirred in an oil bath at 85°C for 6–7 h. 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 × 3). The combined organic phases were dried (MgSO₄), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oily residue. The residue was diluted with 8 mL of EtOAc at room temperature, followed by the addition of 0.49 g of p-TsOH HO (2.6 mmol) and stirring to dissolve. The mixture was then transferred to an ice-water bath and stirred to precipitate a white solid. The mixture was then stirred for 1 h under ice-water bath conditions. The filter cake was collected by filtration and dried under oil pump vacuum to give 0.66 g (64%) of the p-toluenesulfonate salt of (±)-13 (white solid). 1 H NMR (DMSO-d6, 500 MHz) δ: 7.75 (brs, 3H), 7.48 (d, 2H, J = 8.0 Hz), 7.11 (d, 2H, J = 8.0 Hz), 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 = 1.8 Hz, 8.5 Hz and 13.3 Hz), 1.41 (s, 9H), 1.22-1.27 (m, 2H). 13C NMR (DMSO-d6, 126 MHz) δ: 170.40, 145.70, 137.63, 135.92, 135.89, 128.06, 125.50, 80.33, 47.12, 43.51, 42.79, 41.55, 41.32, 34.16, 33.97, 31.69, 29.31, 27.78, 20.79. ESI-HRMS: (m / z) C 16 H 26 NO2 ([M(free base) + H] + ) calculated value: 264.1958, measured value: 264.1953.

[0099] Step 6: Synthesis of compound (±)-I-2 (±)-13 p-Toluenesulfonate (0.66 g, 1.5 mmol) and saturated NaHCO3 solution (100 mL) were stirred at room temperature for 20 minutes (suspension), and then extracted with EtOAc (30 mL x 3). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then dissolved in CHCl2 (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 proceed at room temperature for 2 hours. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was dried under vacuum oil pump, then solidified, and methyl tert-butyl ether (5 mL) was added to the mixture, which was then crushed and slurried at room temperature for 30 minutes. The solid was collected by filtration and dried under vacuum oil pump to give 0.20 g of compound (±)-I-2 (white solid (64%)) having a melting point of 141.8°C to 146.6°C. 1H NMR (CD3OD, 500 MHz) δ: 6.02-6.05 (m, 2H), 3.24 (d, 1H, J = 13.0 Hz), 3.21 (d, 1H, J = 13.0 Hz), 2.76-2.77 (m, 1H), 2.70-2.71 (m, 1H), 2.64 (d, 1H, J = 17.0 Hz), 2.55 (d, 1H, J = 16.5 Hz), 2.09-2.14 (m, 1H), 1.89 (ddd, 1H, J = 2.0 Hz, 8.5 Hz and 13.5 Hz), 1.78-1.80 (m, 1H), 1.73-1.75 (m, 1H), 1.41 (dd, 1H, J = 5.5 Hz and 13.5 Hz), 1.35-1.38 (m, 1H). 13 C NMR (CD3OD, 126 MHz) 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. ESI-HRMS: (m / z) C 12 H 18 NO2([M+H] + ) calculated value: 208.1332, measured value: 208.1327.

[0100] Compound (±)-I-2 is a specific form of the compound of general formula I in this application.

[0101] [Example 3] Synthesis of compound (±)-I-3

[0102] [ka] Step 1: Synthesis of compound 15 Compound 14 (30.00 g, 0.18 mol) was dissolved in dry CHOH (300 mL), then concentrated HSO (3 mL) was added and heated to reflux for 24 hours. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated to one-third of its original volume under reduced pressure on a rotary evaporator. It was then poured into ice water (400 mL). The resulting mixture was extracted with CHCl (300 mL x 2). The combined organic phases were washed with saturated NaHCO solution (400 mL), dried (MgSO), filtered to remove the drying agent, and concentrated under reduced pressure on a rotary evaporator to give the desired compound 15 (yellow oil) 37.00 g (96%). 1 H NMR (CDCl3, 500 MHz) 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).

[0103] Step 2: Synthesis of compound (±)-16 Sodium metal (19.00 g, 0.83 mol) was added to dry toluene (370 mL) and heated under a N2 atmosphere until the sodium completely melted. The mixture was stirred for 20 min while maintaining the internal temperature at 103-106 °C. A solution of compound 15 (37.00 g, 0.18 mol) and trimethylchlorosilane (TMSCl) (85.00 g, 0.78 mol) in dry toluene (100 mL) was added dropwise with stirring. Heat was generated during the addition, and the internal temperature of the reaction mixture was maintained at 103-106 °C. After the addition was complete, the internal temperature of the reaction mixture was maintained at 103-106 °C and the mixture was stirred overnight. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oil. The oil was dissolved in THF (200 mL) and 1 M HCl (20 mL) was added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 h. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (400 mL) and extracted with EtOAc (300 mL × 2). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 3] to give 14.3 g (54%) of the desired product (±)-16 (white solid), melting at 74.7 °C–77.5 °C. The product was used directly in the next reaction without further characterization.

[0104] Step 3: Synthesis of compound (±)-17 Compound (±)-16 (5.00 g, 33 mmol) was dissolved in CCl4 (60 mL) and triphenylphosphine (10.00 g, 38 mmol) and NaHCO3 (0.40 g, 4.8 mmol) were added sequentially with stirring. According to standard procedures, the reaction vessel was purged with nitrogen (balloon) and stirred overnight in an oil bath at 75 °C. 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 give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 9 / 91] to give 4.40 g of the desired product (±)-17 (pale yellow oil). The product was used directly in the next reaction without further characterization.

[0105] Step 4: Synthesis of compound (±)-18 After mixing zinc powder (8.00 g, 0.12 mol) and glacial acetic acid (40 mL) with stirring, a solution of freshly prepared 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 a 55 °C oil bath under a N 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 × 2). The organic phases were combined, washed with water (100 mL × 3), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 1.30 g of the desired product (±)-18 (a pale yellow semi-solid). (The combined yield of (±)-16 → (±)-18 was 29%). 1H NMR (CDCl3, 500 MHz) 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 = 1.0 Hz, 3.0 Hz, 8.5 Hz and 18.0 Hz), 2.15 (dt, 1H, J = 3.8 Hz and 18.5 Hz), 1.75-1.77 (m, 1H), 1.45-1.47 (m, 1H). 13 C NMR (CDCl3, 126 MHz) δ: 211.48, 135.81, 132.74, 66.65, 54.50, 46.42, 46.21, 44.13, 26.93.

[0106] Step 5: Synthesis of compound (±)-19 Under a N2 atmosphere, t-BuOK (1.90 g, 17 mmol) was added to dry THF (15 mL) and stirred in an ice-water bath to form a suspension. tert-Butyl diethylphosphonoacetate (3.50 g, 14 mmol) was then added dropwise. After the addition was complete, the reaction was stirred in an ice-water bath for 40 minutes, and then a solution of freshly prepared compound (±)-18 (1.40 g, 10 mmol) in dry THF (5 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1.5 hours. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (100 mL) and extracted with EtOAc (70 mL × 2). The organic phases were combined, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23] to give 2.42 g of the desired product (±)-19 (pale yellow oil), which was used directly in the next reaction without further characterization.

[0107] Step 6: Synthesis of compound (±)-20 The crude product (±)-19 (2.42 g, calculated as 10 mmol) was dissolved in CH3NO2 (15 mL) and stirred at room temperature. DBU (3.00 g, 20 mmol) was added dropwise to the solution. After the addition was complete, the reaction mixture was stirred overnight in an oil bath at 80 °C under a N2 atmosphere. TLC monitoring indicated that the starting material had not completely reacted. After cooling to room temperature, the reaction mixture was poured into water (150 mL) and extracted with CHCl2 (70 mL × 2). The combined organic phases were dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 1.00 g of the desired product (±)-20 (a pale yellow oil). (The combined yield of (±)-18 → (±)-20 was 33%). 1 H NMR (CDCl3, 500 MHz) δ: 6.40-6.41 (m, 1H), 6.28-6.29 (m, 1H), 4.82 (dd, 1H, J = 1.0 Hz and 11.5 Hz), 4.60 (dd, 1H, J = 1.0 Hz and 11.5 Hz), 2.94-2.96 (m, 1H), 2.81-2.87 (m, 2H), 2.52-2.56 (m, 1H), 2.47 (dd, 1H, J = 0.8 Hz and 17.8 H), 2.38 (d, 1H, J = 17.5 Hz), 2.04 (ddd, 1H, J = 1.5 Hz, 8.0 Hz and 13.0 Hz), 1.56-1.60 (m, 1H), 1.47 (s, 9H), 1.32-1.36 (m, 1H), 1.11-1.13 (m, 1H). 13 C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 16 H 24 NO4([M+H] +) calculated value: 294.1700, measured value: 294.1777.

[0108] Step 7: Synthesis of compound (±)-21 Compound (±)-20 (1.00 g, 3.4 mmol) was dissolved in CHCl (10 mL) and TFA (6 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 2 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 3] to give a pale yellow oil. n-Hexane (1 mL) was added to the oil, and the oil was sonicated to solidify, followed by slurrying at room temperature for 30 min. The solid was collected by filtration, and the filter cake was dried under vacuum oil pump to give 0.80 g (99%) of compound (±)-21 (white solid), melting at 84.6 °C–87.7 °C. 1 H NMR (CDCl3, 500 MHz) δ: 6.43-6.44 (m, 1H), 6.31-6.32 (m, 1H), 4.79 (dd, 1H, J = 1.0 Hz and 11.5 Hz), 4.65 (d, 1H, J = 11.5 Hz), 2.97-2.99 (m, 1H), 2.86-2.89 (m, 2H), 2.67 (d, 1H, J = 18.5 Hz), 2.57 (d, 1H, J = 18.5 Hz), 2.54-5.56 (m, 1H), 2.03-2.07 (m, 1H), 1.61-1.63 (m, 1H), 1.38 (dd, 1H, J = 6.0 Hz and 13.5 Hz), 1.13-1.15 (m, 1H). 13 C NMR (CDCl3, 126 MHz) 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) C 12 H 16 NO4([M+H]+ ) calculated value: 238.1074, measured value: 238.1071.

[0109] Step 8: Synthesis of compound (±)-I-3 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 reaction vessel was purged with hydrogen (balloon) according to standard procedures and stirred overnight at room temperature. TLC monitoring indicated the reaction was complete (typically within 12 h). The filtrate was concentrated under reduced pressure on a rotary evaporator to give a white solid. CH3OH (1 mL) / EtOAc (2 mL) was added and slurried at room temperature for 5 min. The solid was collected by filtration and dried to give the desired product (±)-I-3 (white solid), 0.12 g (60%), melting point 186.2 °C–190.5 °C. 1 H NMR (CD3OD, 500 MHz) δ: 3.07 (d, 1H, J = 12.5 Hz), 2.98 (d, 1H, J = 12.5 Hz), 2.71 (d, 1H, J = 16.0 Hz), 2.65 (d, 1H, J = 16.0 Hz), 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 = 7.5 Hz and 13.0 Hz), 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, 126 MHz) 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) C 12 H 20 NO2([M+H] +) calculated value: 210.1489, measured value: 210.1484.

[0110] Compound (±)-I-3 is a specific form of the compound of general formula I in this application.

[0111] [Example 4] Synthesis of Compound (±)-I-4 and its p-Toluenesulfonate

[0112] [ka] Step 1: Synthesis of compound (±)-22 p-toluenesulfonate Compound (±)-20 (1.50 g, 5.1 mmol) was dissolved in EtOH (15 mL) at room temperature, and water (7 mL) was added and stirred. Iron powder (1.50 g, 27 mmol) and NHCl (0.50 g, 9.3 mmol) were then added sequentially. The reaction vessel was purged with nitrogen (balloon) according to standard procedures, and the mixture was stirred in an oil bath at 85 °C 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 saturated NaHCO solution (100 mL) and extracted with EtOAc (40 mL × 3). The organic phases were combined, dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was diluted with 15 mL of EtOAc at room temperature, followed by the addition of 0.97 g of p-TsOH·HO (5.1 mmol) and stirring until a large amount of solid precipitated. The mixture was then transferred to an ice-water bath and stirred for 1 h to form a slurry. The solid was collected by filtration and dried under oil pump vacuum to give 1.60 g (72%) of (±)-22 p-toluenesulfonate (white solid), melting point 184.4 °C–187.1 °C. 1H NMR (DMSO-d6, 500 MHz) δ: 7.71 (brs, 3H), 7.48 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J = 8.0 Hz), 6.35-6.37 (m, 1H), 6.28-6.30 (m, 1H), 3.05-3.11 (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 = 1.5 Hz, 8.5 Hz and 13.0 Hz), 1.45-1.48 (m, 1H), 1.43 (s, 9H), 1.11 (dd, 1H, J = 6.0 Hz and 13.0 Hz), 1.04-1.06 (m, 1H). 13 C NMR (DMSO-d6, 126 MHz) δ: 170.51, 145.64, 137.69, 137.19, 136.49, 128.08, 125.50, 80.09, 52.46, 47.71, 46.62, 45.25, 44.08, 36.54, 36.07, 33.20, 32.20, 27.74, 20.79. ESI-HRMS: (m / z) C 16 H 26 NO2 ([M(free base) + H] + ) calculated value: 264.1958, measured value: 264.1954.

[0113] Step 2: Synthesis of compound (±)-I-4 and its p-toluenesulfonate salt (±)-22-p-toluenesulfonate (1.60 g, 3.7 mmol) and saturated NaHCO3 solution (100 mL) were stirred at room temperature for 20 min (suspension) and extracted with EtOAc (60 mL × 3). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a pale yellow oil, which was then dissolved in CHCl2 (10 mL). TFA (7 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 4–6 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then added with CHCl2 (20 mL) and concentrated again. The oil was dried under vacuum with an oil pump until a solid was obtained, i.e., (±)-I-4 was completely precipitated. The solid was dissolved in CH3OH (2 mL), and EtOAc (4 mL) was added and the mixture was stirred. p-TsOH·HO (0.65 g, 3.4 mmol) was then added to the reaction solution, stirred until a large amount of solid precipitated, and stirred at room temperature for 2 hours to form a slurry. The solid was collected by filtration, and the filter cake was dried under oil pump vacuum to give 0.50 g (36%) of compound (±)-I-4 p-toluenesulfonate (white solid), melting point 197.0 °C-198.7 °C. 1 H NMR (CD3OD, 500 MHz) δ: 7.70 (d, 2H, J = 8.5 Hz), 7.23 (d, 2H, J = 8.0 Hz), 6.43-6.44 (m, 1H), 6.30-6.31 (m, 1H), 3.25 (d, 1H, J = 13.0 Hz), 3.12 (d, 1H, J = 12.5 Hz), 2.84-2.93 (m, 3H), 2.58 (d, 1H, J = 17.5 Hz), 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). 13C NMR (CD3OD, 126 MHz) 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. ESI-HRMS: (m / z) C 12 H 18 NO2 ([M(free base) + H] + ) calculated value: 208.1332, measured value: 208.1328.

[0114] Compound (±)-I-4 is a specific form of the compound of general formula I in the present application.

[0115] [Example 5] Synthesis of compound (±)-I-5

[0116] [ka] Step 1: Synthesis of compound 23 Maleic anhydride (68.00 g, 0.69 mol) was dissolved in CHCl 3( The reaction mixture was dissolved in 1,4-cyclohexadiene (78.00 g, 0.97 mol) in CHCl (50 mL) and added dropwise under ice-water bath. After the addition was complete, the mixture was stirred overnight at room temperature. TLC monitoring showed the reaction was complete. The reaction mixture was concentrated under reduced pressure on a rotary evaporator to give an oily substance, which was then slurried with a mixture of EtOAc / n-hexane (100 mL / 400 mL) at room temperature. The solid was collected by suction filtration and dried to give compound 23, 54.50 g (44%). 1 H NMR (CDCl3, 500 MHz) 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).

[0117] Step 2: Synthesis of compound 24 Compound 23 (17.00 g, 95 mmol) was dissolved in CHOH (170 mL) and stirred. Concentrated sulfuric acid (1.7 mL) was added to the solution. The mixture was heated to reflux overnight. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to one-third of the original volume and then poured into ice water (200 mL). The resulting mixture was extracted with CHCl (100 mL × 3). The combined organic phases were washed with saturated NaHCO solution (200 mL) and saturated brine (200 mL), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure using a rotary evaporator to give compound 24 (white solid) 20.00 g (93%). 1 H NMR (CDCl3, 500 MHz) 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).

[0118] Step 3: Synthesis of compound (±)-25 Sodium metal (10.00 g, 0.43 mol) was added to dry toluene (200 mL) and heated under a N2 atmosphere until the sodium completely melted. Stirring was initiated and continued for 20 min while maintaining the internal temperature at 103-106 °C. 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. Heat was generated during the addition, 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 internal temperature of the reaction system was maintained at 103-106 °C and the system was stirred overnight. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure on a rotary evaporator to give 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 proceed at room temperature for 3 hours. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were dried (MgSO4) and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oil. The oil was allowed to stand at room temperature and then solidified. n-Hexane (15 mL) was added to the solidified mixture, heated to reflux, and EtOAc was added dropwise until the solid was completely dissolved. The mixture was cooled to room temperature and stirred to precipitate crystals, followed by stirring for 5 hours. The mixture was filtered. The filter cake was dried in a vacuum oil pump to give 7.60 g (52%) of the desired compound (±)-25 (white solid), melting at 106.1-110.4 °C. The product was used directly in the next reaction without characterization.

[0119] Step 4: Synthesis of compound (±)-26 Compound (±)-25 (2.00 g, 12 mmol) was dissolved in CHCl (20 mL), and pyridine (1.93 g, 24 mmol) and 4-dimethylaminopyridine (DMAP) (0.74 g, 6.1 mmol) were added sequentially to the system. The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. Phenyl chlorothionocarbonate (3.15 g, 18 mmol) was slowly added dropwise to the system in an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. TLC monitoring indicated the reaction was complete. The reaction solution was poured into ice-water (100 mL) and extracted with CHCl (50 mL × 2). The combined organic phases were washed successively with 1 M HCl (100 mL) and saturated brine (100 mL), dried (MgSO), filtered to remove the drying agent, and concentrated on a rotary evaporator under reduced pressure to give 3.66 g of crude compound (±)-26 (yellow solid), which was used directly in the next reaction without further characterization.

[0120] Step 5: Synthesis of compound (±)-27 Compound (±)-26 (3.66 g, 12 mmol) was added to benzene (40 mL) and the reaction vessel was purged with nitrogen (balloon) according to standard procedures. The mixture was heated to reflux at 90 °C, and a solution of n-Bu3SnH (5.30 g, 18 mmol) and azodiisobutyronitrile (AIBN) (0.20 g, 1.2 mmol) in benzene (15 mL) was added dropwise slowly. After the addition was complete, the reaction was carried out overnight in an oil bath maintained at 90 °C. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure on a rotary evaporator to give an oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 1.20 g of the desired product (±)-27 (a pale yellow oil) (66% yield combined from (±)-25 to (±)-27). 1H NMR (CDCl3, 500 MHz) 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). 13 C NMR (CDCl3, 126 MHz) δ: 212.49, 133.54, 131.54, 64.18, 50.49, 32.04, 31.01, 26.48, 24.54, 22.54.

[0121] Step 6: Synthesis of compound (±)-28 Under a N2 atmosphere, t-BuOK (0.90 g, 8.0 mmol) was added to dry THF (10 mL) and stirred in an ice-water bath to form a suspension. tert-Butyl diethylphosphonoacetate (1.70 g, 6.7 mmol) was then added dropwise. After the addition was complete, the reaction was stirred in an ice-water bath for 40 min, and then a solution of freshly prepared compound (±)-27 (0.60 g, 4.0 mmol) in dry THF (5 mL) was 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 × 2). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 0.90 g of the desired product (±)-28 (pale yellow oil), which was used directly in the next reaction without further characterization.

[0122] Step 7: Synthesis of compound (±)-29 Compound (±)-28 (0.90 g, 3.7 mmol) was dissolved in CH3NO2 (9 mL) at room temperature, and DBU (2.00 g, 13 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred overnight in an 80 °C oil bath under a N2 atmosphere. 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 C2Cl2 (50 mL × 2). The combined organic phases were dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 0.50 g of the desired product (±)-29 (a pale yellow oil). (The combined yield of (±)-27 → (±)-29 was 40%). 1 H NMR (CDCl3, 500 MHz) δ: 6.45-6.49 (m, 1H), 6.26-6.30 (m, 1H), 4.78 (dd, 1H, J = 0.5 Hz and 11.5 Hz), 4.65 (d, 1H, J = 11.5 Hz), 2.60 (d, 1H, J = 17.5 Hz), 2.52-2.61 (m, 3H), 2.54 (d, 1H, J = 17.5 Hz), 2.27-2.30 (m, 1H), 1.94 (ddd, 1H, J = 2.0 Hz, 8.5 Hz and 13.0 Hz), 1.64 (dd, 1H, J = 7.3 Hz and 13.3 Hz). 1.45 (s, 9H), 1.35-1.40 (m, 2H), 1.25-1.30 (m, 1H), 1.18-1.23 (m, 1H). 13 C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 17 H 26 NO4([M+H] +) calculated value: 308.1856, measured value: 308.1852.

[0123] Step 8: Synthesis of compound (±)-30 Compound (±)-29 (0.50 g, 1.6 mmol) was dissolved in CHCl (5 mL) and 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 4 hours. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. After that, n-hexane (3 mL) was added to the oil and sonicated to convert the oil to a solid. The mixture was stirred at room temperature for 1 hour to form a slurry. The solid was collected by suction filtration and dried under a vacuum oil pump to give 0.33 g (80%) of compound (±)-30 (white solid), melting at 120.0 °C–123.6 °C. 1 H NMR (CDCl3, 500 MHz) δ: 6.47-6.50 (m, 1H), 6.28-6.32 (m, 1H), 4.78 (dd, 1H, J = 0.8 Hz and 5.9 Hz), 4.68 (d, 1H, J = 11.5 Hz), 2.80 (d, 1H, J = 18.0 Hz), 2.73 (d, 1H, J = 18.0 Hz), 2.53-2.65 (m, 3H), 2.27-2.30 (m, 1H), 1.95 (ddd, 1H, J = 2.0 Hz, 8.5 Hz and 13.5 Hz), 1.66 (dd, 1H, J = 2.3 Hz and 13.3 Hz). 1.32-1.42 (m, 2H), 1.25-1.31 (m, 1H), 1.17-1.24 (m, 1H). 13 C NMR (CDCl3, 126 MHz) 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) C 13 H 18 NO4([M+H] +) calculated value: 252.1230, measured value: 252.1229.

[0124] Step 9: Synthesis of compound (±)-I-5 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 reaction vessel was purged with hydrogen (balloon) according to standard procedures and stirred overnight at room temperature. TLC monitoring indicated the reaction was complete (reactions typically completed within 12 h). The solid was removed by filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to give 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 suction filtration and dried to give 0.13 g (49%) of the desired product (±)-I-5 (white solid), melting at 176.6 °C–178.2 °C. 1 H NMR (CD3OD, 500 MHz) δ: 3.16 (d, 1H, J = 13.0 Hz), 3.07 (d, 1H, J = 13.0 Hz), 2.74 (d, 1H, J = 16.5 Hz), 2.67 (d, 1H, J = 16.0 Hz), 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 = 3.0 Hz, 8.5 Hz and 12.5 Hz), 1.74-1.76 (m, 1H), 1.46-1.70 (m, 6H), 1.36-1.43 (m, 1H). 13 C NMR (CD3OD, 126 MHz) 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) C 13 H 22 NO2([M+H] + ) calculated value: 224.1645, measured value: 224.1641.

[0125] Compound (±)-I-5 is a specific form of the compound of general formula I in this application.

[0126] [Example 6] Synthesis of Compound (±)-I-6 and its p-Toluenesulfonate

[0127] [ka] Step 1: Synthesis of compound (±)-31 p-toluenesulfonate Compound (±)-29 (1.10 g, 3.6 mmol) was dissolved in EtOH (10 mL) at room temperature, and water (5 mL) was added and stirred. Iron powder (1.30 g, 23 mmol) and NHCl (0.45 g, 8.4 mmol) were then added sequentially. The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures, and the mixture was refluxed under stirring for 5 hours. 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 NaHCO solution (120 mL) and extracted with EtOAc (50 mL × 3). The organic phases were combined, dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was diluted with 15 mL of EtOAc at room temperature, followed by the addition of 0.70 g of p-TsOH·HO (3.7 mmol). The mixture was stirred until a large amount of solid precipitated and dissolved. The mixture was then transferred to an ice-water bath and stirred for 1 h. The solid was filtered and dried under vacuum in an oil pump to give 1.30 g (81%) of (±)-31 p-toluenesulfonate (white solid), melting point 190.1 °C–192.5 °C. 1H NMR (DMSO-d6, 500 MHz) δ: 7.69 (brs, 3H), 7.48 (d, 2H, J = 6.5 Hz), 7.12 (d, 2H, J = 8.0 Hz), 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 = 2.0 Hz, 8.5 Hz and 13.0 Hz), 1.38-1.42 (m, 10H), 1.31-1.33 (m, 2H), 1.17-1.21 (m, 1H), 1.09-1.14 (m, 1H). 13 C NMR (DMSO-d6, 126 MHz) δ: 170.55, 145.64, 137.66, 134.31, 133.80, 128.07, 125.49, 80.09, 46.72, 45.55, 38.85, 35.92, 33.77, 32.38, 31.83, 30.37, 27.74, 24.67, 23.21, 20.78. ESI-HRMS: (m / z) C 17 H 28 NO2 ([M(free base) + H] + ) calculated value: 278.2115, measured value: 278.2111.

[0128] Step 2: Synthesis of compound (±)-I-6 and its p-toluenesulfonate salt (±)-31 p-toluenesulfonate (1.30 g, 2.9 mmol) and saturated NaHCO3 solution (100 mL) were stirred at room temperature for 20 min (suspension) and extracted with EtOAc (60 mL × 3). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a pale yellow oil, which was then dissolved in CHCl2 (10 mL). TFA (7 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 4 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then added with CHCl2 (20 mL) and concentrated again. The oil was dried under vacuum with an oil pump until a solid was obtained, i.e., (±)-I-6 was completely precipitated. The solid was dissolved in CH3OH (3 mL), and EtOAc (8 mL) was added and the mixture was stirred. p-TsOH·HO (0.60 g, 3.2 mmol) was then added to the reaction solution, stirred until a large amount of solid precipitated, and stirred at room temperature for 0.5 h. The solid was collected by filtration and dried under oil pump vacuum to give 0.70 g (62%) of compound (±)-I-6 p-toluenesulfonate (white solid), melting point 192.7 °C-194.0 °C. 1 H NMR (CD3OD, 500 MHz) δ: 7.71 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.5 Hz), 6.48-6.52 (m, 1H), 6.28-6.32 (m, 1H), 3.26 (d, 1H, J = 12.5 Hz), 3.14 (d, 1H, J = 13.0 Hz), 2.66 (d, 1H, J = 17.0 Hz), 2.56 (d, 1H, J = 17.0 Hz), 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). 13C NMR (CD3OD, 126 MHz) 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. ESI-HRMS: (m / z) C 13 H 20 NO2 ([M(free base) + H] + ) calculated value: 222.1489, measured value: 222.1485.

[0129] Compound (±)-I-6 is a specific form of the compound of general formula I in the present application.

[0130] [Example 7] Synthesis of Compounds (-)-I-3 and (+)-I-3 and Their p-Toluenesulfonates

[0131] [ka] Step 1: Synthesis of compound (±)-32 p-toluenesulfonate 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 reaction vessel was purged with hydrogen (balloon) according to standard procedures, and the mixture was stirred at room temperature for 12 hours. TLC monitoring indicated the reaction was complete. The filtrate was concentrated under reduced pressure on a rotary evaporator to give crude compound (±)-32. Compound (±)-32 was diluted with CHCl2 (800 mL) and washed with saturated NaHCO3 solution (2 L). The organic phase was separated, and the aqueous phase was extracted with CHCl2 (500 mL × 2). The combined organic phases were dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was diluted with 800 mL of EtOAc at room temperature, and then p-TsOH HO (70.00 g, 0.37 mol) was added and stirred until a large amount of solid precipitated. The mixture was stirred at room temperature for 3 hours. The solid was collected by suction filtration and dried under oil pump vacuum to give 75.20 g (36%) of (±)-32 p-toluenesulfonate (white solid), melting point 170.1 °C–174.4 °C. 1 H NMR (DMSO-d6, 500 MHz) δ: 7.73 (brs, 3H), 7.48 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J = 7.5 Hz), 3.02-3.07 (m, 1H), 2.91-2.95 (m, 1H), 2.61 (d, 1H, J = 17.0 Hz), 2.57 (d, 1H, J = 17.0 Hz), 2.39-2.46 (m, 1H), 2.27-2.29 (m, 4H), 2.18-2.20 (m, 1H), 2.10-2.13 (m, 1H), 1.83-1.88 (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). 13C NMR (DMSO-d6, 126 MHz) 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.

[0132] 3,5-Dinitrobenzoyl derivatization: Synthesis of the 3,5-dinitrobenzoyl derivative of compound (±)-32 Compound (±)-32 p-toluenesulfonate (1.00 g, 2.3 mmol) was added to saturated NaHCO3 solution (200 mL) at room temperature, stirred to form a suspension, and then 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), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give compound (±)-32 as a pale yellow oil. The above oil was dissolved in CHCl2 (7 mL) and stirred. 3,5-dinitrobenzoyl chloride (0.6 g, 2.6 mmol) was added, followed by dropwise addition of triethylamine (0.6 mL). After the dropwise addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. 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 give a pale yellow oil. n-Hexane (10 mL) was added to the oil to precipitate a solid, which was then slurried at room temperature for 1 hour. The solid was collected by suction filtration and dried in vacuo to give 0.70 g (67%) of the 3,5-dinitrobenzoyl derivative of (±)-32 (white solid), melting at 113.9 °C to 115.4 °C. 1H NMR (CDCl3, 500 MHz) δ: 9.40 (brs, 1H), 9.20 (d, 2H, J = 2.0 Hz), 9.15 (t, 1H, J = 2.0 Hz), 3.70 (dd, 1H, J = 4.5 Hz and 13.5 Hz), 3.43 (dd, 1H, J = 3.3 Hz and 13.3 Hz), 2.84 (dd, 1H, J = 1.0 Hz and 12.0 Hz), 2.71 (d, 1H, J = 17.0 Hz), 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). ESI-HRMS: (m / z) C 23 H 28 N3O7([MH] - ) calculated value: 458.1933, measured value: 458.1939.

[0133] The 3,5-dinitrobenzoylated derivative of (±)-32 was used as a reference substance to test the optical purity of (−)-32 and (+)-32 obtained after chiral acid resolution of (±)-32 in steps 2 and 3 below using a chiral HPLC method.

[0134] Step 2: Synthesis of (R)-(-)-O-acetylmandelate of compound (-)-32 (±)-32 p-Toluenesulfonate (22.80 g, 52 mmol) was added to saturated NaHCO3 solution (200 mL × 2), stirred, and extracted with EtOAc (200 mL × 2). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a pale yellow oil. THF (100 mL) was added at room temperature to dilute the oil, and then a solution of (R)-(-)-O-acetylmandelic acid (5.00 g, 26 mmol) in THF (50 mL) was added dropwise. After the addition was complete, 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 suction filtration (the filtrate was recovered). The filter cake was dried under oil pump vacuum to give a white solid (7.35 g, 16 mmol), namely, (R)-(-)-O-acetylmandelate of compound (-)-32.

[0135] 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 saturated NaHCO3 solution (50 mL × 2), stirred, and extracted with EtOAc (25 mL × 2). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a pale yellow oil. CHCl2 (3 mL) was added to the above oil at room temperature, followed by 3,5-dinitrobenzoyl chloride (0.1 g, 0.43 mmol). Triethylamine (2-3 drops) was added dropwise, and the reaction was allowed to proceed at room temperature for 10 minutes. 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 give a pale yellow oil, which was then dried under vacuum to give the 3,5-dinitrobenzoyl derivative of (-)-32 as a white foamy solid. The ee value of the derivative determined by chiral HPLC was 80.54%.

[0136] Enantiomeric excess (%ee) measurement method (chiral HPLC method): Measurement was performed using a Daicel Chiralpak AS-RH 4.6 mm × 250 mm chromatographic column (5 μm) on an Agilent 1260 infinity Type II liquid chromatograph (detector wavelength 220 nm, mobile phase of acetonitrile / 0.1% KH2PO4-KOH buffer (pH = 7.0) = 70 / 30, flow rate 1 mL / min, sample injection concentration 0.5 mg / mL, and sample injection volume 3 μL).

[0137] The (R)-(-)-O-acetylmandelate of compound (-)-32 (white solid) (6.35 g, 14 mmol) obtained after the primary resolution at room temperature was thoroughly stirred with THF (65 mL) and then transferred to an oil bath and stirred at 40 °C for 10 minutes (the system was slightly dissolved). The system was then returned to room temperature, and THF (30 mL) was added, followed by stirring overnight. The solid was collected by suction filtration and dried under a vacuum oil pump to obtain a white solid (4.90 g, 11 mmol). The above recrystallization method was repeated to obtain the (R)-(-)-O-acetylmandelate of compound (-)-32. The derivative was obtained following the above 3,5-dinitrobenzoylation derivatization step, and its ee value measured by chiral HPLC was 99.34% (4.40 g (37%) of white solid). The product was used directly in the next reaction without characterization.

[0138] Step 3: Synthesis of (S)-(+)-O-acetylmandelate of compound (+)-32 The filtrate obtained after filtering the separated crystals in Step 2 was concentrated, and saturated NaHCO3 solution (100 mL x 2) was added thereto, stirred, and extracted with EtOAc (100 mL x 2). The organic phases were combined, dried (MgSO4), filtered, and concentrated under reduced pressure on a rotary evaporator to give a pale yellow oil (12.85 g, 48 mmol equivalent). THF (100 mL) was added at room temperature to dilute the oil, and a solution of (S)-(+)-O-acetylmandelic acid (4.70 g, 24 mmol) in THF (50 mL) was added dropwise (a large amount of solid gradually precipitated after half of the solution had been added). After the addition was complete, THF (30 mL) was added and the mixture was stirred at room temperature for 2 hours. Filtration was then performed. The filter cake was dried under oil pump vacuum to give (S)-(+)-O-acetylmandelate of (+)-32 (white solid, 6.00 g, 13 mmol). The derivative was obtained following the 3,5-dinitrobenzoylation derivatization step described above, and its ee value determined by chiral HPLC was 90.77%.

[0139] The white solid was thoroughly stirred with THF (60 mL) at room temperature, then transferred to an oil bath and stirred at 40 °C for 10 minutes (the system was slightly dissolved). The system was then returned to room temperature, and THF (30 mL) was added, followed by stirring overnight. The solid was collected by suction filtration and dried under a vacuum oil pump to obtain the (S)-(+)-O-acetylmandelate of compound (+)-32. The derivative was obtained following the 3,5-dinitrobenzoylation derivatization step described above, and its ee value measured by chiral HPLC was 99.17% (4.40 g (40%) of white solid). The product was used directly in the next reaction without further characterization.

[0140] Step 4: Synthesis of compound (-)-I-3 and its p-toluenesulfonate salt The (R)-(-)-O-acetylmandelate of compound (-)-32 (1.50 g, 3.3 mmol) was added to saturated NaHCO3 solution (100 mL) at room temperature, stirred for 20 minutes (suspension), and extracted with EtOAc (50 mL x 3). The organic phases were combined, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was then dissolved in CHCl2 (10 mL) and TFA (7 mL) was added dropwise slowly in an ice-water bath. After the addition was complete, the reaction was allowed to proceed 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 give a brown oil. CHCl2 (10 mL) was added and the mixture was concentrated again. The resulting oil was dried in a vacuum oil pump to give (-)-32. The (-)-32 sample was dissolved in CH3OH (2.5 mL), then EtOAc (12 mL) was added and stirred. p-TsOH HO (0.70 g, 3.7 mmol) was added to the solution, and the solution was stirred until a large amount of solid precipitated. The solution was stirred at room temperature for 1 hour. The solid was collected by suction filtration and dried under a vacuum oil pump. The melting point was 180.6 °C–183.5 °C, [α]D 20 = -22.8 (c = 2.50, CH3OH) compound (-)-I-3 p-toluenesulfonate (white solid) 1.00 g (80%) was obtained. 1H NMR (CD3OD, 500 MHz) δ: 7.70 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0 Hz), 3.20 (d, 1H, J = 13.0 Hz), 3.10 (d, 1H, J = 13.0 Hz), 2.79 (d, 1H, J = 17.5 Hz), 2.70 (d, 1H, J = 17.5 Hz), 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), 1.76-1.81 (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). 13 C NMR (CD3OD, 126 MHz) 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.

[0141] Compound (-)-I-3 is a specific form of the compound of general formula I in the present application, and is also one of the optically pure compounds (±)-I-3, which has the same relative configuration as (±)-I-3 and has levorotatory optical activity.

[0142] Step 5: Synthesis of compound (+)-I-3 and its p-toluenesulfonate salt The (S)-(+)-O-acetylmandelate of compound (+)-32 (1.40 g, 3.0 mmol) was added to saturated NaHCO3 solution (100 mL) at room temperature, stirred for 20 minutes (suspension), and extracted with EtOAc (50 mL x 3). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was then dissolved in CHCl2 (10 mL) and TFA (7 mL) was added dropwise slowly in an ice-water bath. After the addition was complete, the reaction was allowed to proceed 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 give a brown oil. CHCl2 (10 mL) was added and the mixture was concentrated again. The resulting oil was dried under vacuum on an oil pump to give (+)-I-3. The (+)-I-3 sample was dissolved in CHOH (2 mL), and EtOAc (6 mL) was added again and stirred. p-TsOH·HO (0.60 g, 3.2 mmol) was then added to the solution, and the solution was stirred until a large amount of solid precipitated. The solution was then stirred at room temperature for 1 hour. The solid was collected by suction filtration and dried under oil pump vacuum. The melting point was 179.5°C–181.8°C, [α]. D 20 = +25.09 (c = 2.55, CH3OH) to obtain 0.85 g (73%) of p-toluenesulfonic acid salt of compound (+)-I-3 (white solid). 1H NMR (CD3OD, 500 MHz) δ: 7.71 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0 Hz), 3.20 (d, 1H, J = 13.0 Hz), 3.10 (d, 1H, J = 13.0 Hz), 2.78 (d, 1H, J = 17.5 Hz), 2.70 (d, 1H, J = 17.5 Hz), 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), 1.76-1.80 (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). 13 C NMR (CD3OD+D2O (1 drop), 126 MHz) 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.

[0143] Compound (+)-I-3 is a specific form of the compound of general formula I in the present application, and is also one of the optically pure compounds (±)-I-3, which has the same relative configuration as (±)-I-3 and has dextrorotatory optical activity.

[0144] The absolute configuration of compound (+)-I-3 can be determined indirectly by converting the (S)-(+)-o-acetylmandelate of (+)-32, which has the same absolute configuration, into its lactam, (+)-32-LAC, and determining the absolute configuration of (+)-32-LAC, which has the same absolute configuration as (+)-32, using X-ray single crystal diffraction.

[0145] The specific experimental method is as follows: Synthesis of (+)-32-LAC: (S)-(+)-O-acetylmandelate (1.00 g, 2.2 mmol) of the above (+)-32 (ee value 99.17%) was added to saturated NaHCO3 solution (100 mL) and stirred for 10 minutes, followed by extraction with EtOAc (30 mL × 3). The organic phases were combined, washed with saturated brine, dried (MgSO4), and filtered to remove the drying agent. The filtrate was evaporated to dryness on a rotary evaporator. The resulting residue was dissolved in toluene (7 mL) and heated to reflux overnight. TLC showed the reaction was complete. The reaction was cooled to room temperature, and the solvent was removed by rotary evaporation. The residue was slurried with EtOAc / n-hexane (1 / 10 v / v, 3 mL total). The crystals were collected by suction filtration and dried, melting at 189.3-191.5 °C, [α]. D 20 = +62.6° (c=1.15, CH3OH) to obtain 0.28 g (67%) of (+)-32-LAC. 1 H NMR (CDCl3, 500 MHz) δ: 6.05 (brs, 1H), 3.45 (d, 1H, J = 9.5 Hz), 3.36 (d, 1H, J = 9.5 Hz), 2.47-2.52 (m, 1H), 2.43 (d, 1H, J = 17.0 Hz), 2.39-2.42 (m, 1H), 2.34 (d, 1H, J = 17.0 Hz), 2.23-2.27 (m, 2H), 2.02 (dd, 1H, J = 7.0 Hz and 13.0 Hz), 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). 13 C NMR (CDCl3, 126 MHz) 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) C12 H 18 NO ([M+H] + ) calculated value: 192.1383, measured value: 192.1380.

[0146] Cultivation and X-ray diffraction of (+)-32-LAC single crystals: 10 mg of (+)-32-LAC sample was weighed and dissolved in 1 mL of CHCl. ​​Then, 2 mL of n-hexane was added and the mixture was shaken uniformly. The solution was filtered, and the filtrate was placed in a small glass Erlenmeyer flask and allowed to slowly evaporate at room temperature for 2–3 days to obtain single crystals suitable for X-ray diffraction. A single crystal measuring 0.12 × 0.1 × 0.08 mm was selected for diffraction using CuKα radiation at 100.00 (10) K on a Rigaku XtaLAB Pro single crystal diffractometer. CrysAlisPro 1.171.39.33c (Rigaku OD, 2017) was used for diffraction data collection and data reduction, and the SHELXL program was used for structure analysis and refinement.

[0147] The chemical structure of the compound (+)-32-LAC in single crystal diffraction (ORTEP diagram) is shown in Figure 1.

[0148] The parameters associated with the crystallographic study and structure refinement of (+)-32-LAC are shown in the following table.

[0149] [Table 1]

[0150] [Example 8] Synthesis of Compounds (-)-I-4 and (+)-I-4 and Their p-Toluenesulfonates

[0151] [ka] Step 1: Synthesis of compound (±)-22 (±)-22 p-toluenesulfonate (60.00 g, 0.14 mol) was added to saturated NaHCO3 solution (600 mL × 2) at room temperature, stirred, and extracted with EtOAc (400 mL × 2). The organic phases were combined, dried (MgSO4), filtered to remove the drying agent, and concentrated under reduced pressure on a rotary evaporator to give 36 mL of (±)-22 (yellow oil). The product was used directly in the next reaction without characterization.

[0152] 3,5-Dinitrobenzoyl derivatization: Synthesis of 3,5-dinitrobenzoyl derivative of compound (±)-22 Compound (±)-22 p-toluenesulfonate (1.00 g, 2.3 mmol) was added to saturated NaHCO3 solution (200 mL) at room temperature, stirred, and extracted with EtOAc (100 mL × 2). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give compound (±)-22 as a pale yellow oil. The above oil was dissolved in CHCl2 (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, and the reaction was allowed to proceed at room temperature for 1 hour after the dropwise addition. 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 give a pale yellow oil. n-Hexane (10 mL) was added to the oil and slurried at room temperature for 1 hour. The solid was collected by suction filtration and dried under vacuum to give 0.60 g (57%) of the 3,5-dinitrobenzoylated derivative of the desired product (±)-22 (white solid), melting point 118.9°C-119.8°C. 1H NMR (CDCl3, 500 MHz) δ: 9.46 (brs, 1H), 9.19 (d, 2H, J = 2.0 Hz), 9.16 (t, 1H, J = 2.0 Hz), 6.40-6.42 (m, 1H), 6.31-6.33 (m, 1H), 3.82 (dd, 1H, J = 5.5 Hz and 13.5 Hz), 3.36 (dd, 1H, J = 3.3 Hz and 13.8 Hz), 2.86-2.90 (m, 3H), 2.69 (dd, 1H, J = 1.0 Hz and 17.0 Hz), 2.58-2.60 (m, 1H), 2.37 (d, 1H, J = 17.5 Hz). Hz), 1.77-1.81 (m, 1H), 1.58-1.61 (m, 10H), 1.30 (dd, 1H, J = 5.8 Hz and 12.3 Hz), 1.11-1.13 (m, 1H). 13 C NMR (CDCl3, 126 MHz) δ: 175.42, 162.99, 148.82, 138.26, 138.12, 136.52, 127.59, 120.86, 82.84, 54.11, 53.02, 46.82, 45.87, 44.76, 42.21, 37.02, 35.75, 34.57, 28.14. ESI-HRMS: (m / z) C 23 H 27 N3NaO7([M+Na] + ) calculated value: 458.1741, measured value: 458.1735.

[0153] The 3,5-dinitrobenzoyl derivative of (±)-22 was used as a reference substance to test the optical purity of (−)-22 and (+)-22 obtained after chiral acid resolution of (±)-22 in steps 2 and 3 below using a chiral HPLC method.

[0154] Step 2: Synthesis of the (R)-(-)-mandelate of compound (-)-22 Compound (±)-22 (18.14 g, 69 mmol) was dissolved in THF (90 mL) at room temperature, and then a solution of (R)-(-)-mandelic acid (4.50 g, 30 mmol) in THF (90 mL) was added dropwise. After the addition was complete, stirring was continued for 30 minutes. Isopropyl ether (180 mL) was then added dropwise, and the mixture was stirred overnight at room temperature until crystals precipitated. If a solid did not precipitate, an appropriate amount of seed crystals was added to the system until a solid gradually precipitated. Next, a THF solution (9 mL) of (R)-(-)-mandelic acid (2.25 g, 15 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Isopropyl ether (180 mL) was then added dropwise. After the addition was complete, the amount of solid in the system increased, and the mixture was stirred at room temperature for 1 hour. The solid was collected by suction filtration (the filtrate was collected) and dried under a vacuum oil pump to give the (R)-(-)-mandelate of (-)-22 (8.60 g, 21 mmol) (white solid). A small sample was treated according to the 3,5-dinitrobenzoylation derivatization step described above and determined to have an ee value of 87.05% by chiral HPLC. The (R)-(-)-mandelate of (-)-22 (8.40 g, 20 mmol) was thoroughly stirred with a mixture of THF (40 mL) and isopropyl ether (40 mL) (white solid) at room temperature, then transferred to an oil bath and stirred at 65 °C. A mixture of THF (10 mL) and isopropyl ether (10 mL) was added dropwise until the system was slightly dissolved, followed by stirring for 30 minutes. The system was then left at room temperature and stirred overnight. The solid was collected by suction filtration and dried under an oil pump vacuum to give a white solid (6.60 g, 16 mmol). The solid was recrystallized by repeating the above recrystallization method using a THF / isopropyl ether = 1 / 2 (v / v) solvent to give the pure (R)-(-)-mandelate of compound (-)-22. A small amount was treated according to the 3,5-dinitrobenzoylation derivatization step described above, and determined by chiral HPLC to have an ee value of 99.10% (white solid, 6.00 g (43%)). The product was used directly in the next reaction without further characterization.

[0155] Step 3: Synthesis of the (S)-(+)-mandelate of compound (+)-22 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). After the addition was complete, no significant change was observed. Stirring was continued for 30 minutes, and then isopropyl ether (270 mL) was added dropwise. After the addition was complete, stirring was continued until a large amount of solid was formed. If no crystals were formed, an appropriate amount of seed crystals was added to the system. The crystallization system was stirred overnight at room temperature. The crystals were collected by suction filtration (the filtrate was collected) and dried under a vacuum oil pump to obtain 9.00 g (22 mmol) of (S)-(+)-mandelate of (+)-22 (white solid). A small amount of the sample was treated according to the 3,5-dinitrobenzoylation derivatization step described above, and the ee value was determined to be 30.88% by chiral HPLC. The (S)-(+)-mandelate (9.00 g, 22 mmol) of (+)-22 was thoroughly stirred with a 1 / 2 mixture of isopropanol and isopropyl ether (v / v, 50 mL total) at room temperature, then transferred to an oil bath and stirred at 60 °C (the system dissolved slightly). Stirring continued for 10 min. The system was then left at room temperature until a large amount of white solid gradually precipitated. A 1 / 2 mixture of isopropanol and isopropyl ether (v / v, 15 mL total) was added dropwise, and the system was stirred for 1-2 h. The solid was collected by suction filtration and dried under a vacuum oil pump to obtain a white solid (5.40 g, 13 mmol). The above recrystallization procedure was repeated twice to give the (S)-(+)-mandelate of compound (+)-22, a small portion of which was treated according to the 3,5-dinitrobenzoylation derivatization step described above and determined by chiral HPLC to have an ee value of 98.34% (white solid, 2.40 g (17%)). The product was used directly in the next reaction without further characterization.

[0156] Step 4: Synthesis of compound (-)-I-4 and its p-toluenesulfonate salt The (R)-(-)-mandelate of compound (-)-22 (3.00 g, 7.2 mmol) was added to saturated NaHCO3 solution (100 mL) at room temperature, stirred for 20 minutes, and extracted with EtOAc (80 mL x 3). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was then dissolved in CHCl2 (20 mL) and TFA (15 mL) was added dropwise slowly in an ice-water bath. After the addition was complete, the reaction was allowed to proceed 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 give a brown oil. CHCl2 (20 mL) was added and the mixture was concentrated again. The resulting oil was dried in a vacuum oil pump to give (-)-I-4. The (-)-I-4 was dissolved in CHOH (2.5 mL), EtOAc (12 mL) was added, and the mixture was thoroughly stirred. p-TsOH HO (1.40 g, 7.4 mmol) was added to the solution, and the mixture was stirred until a large amount of solid precipitated. The mixture was then stirred at room temperature for 1 h. The solid was collected by suction filtration, and the filter cake was dried under a vacuum oil pump. The melting point was 180.3 °C–183.5 °C, [α]. D 20 = -35.47 (c = 2.65, CH3OH) to obtain 1.80 g (66%) of p-toluenesulfonic acid salt of compound (-)-I-4 (white solid). 1H NMR (CD3OD, 500 MHz) δ: 7.70 (d, 2H, J = 8.5 Hz), 7.23 (d, 2H, J = 8.0 Hz), 6.42-6.44 (m, 1H), 6.29-6.31 (m, 1H), 3.24 (d, 1H, J = 13.0 Hz), 3.12 (d, 1H, J = 13.0 Hz), 2.92-2.94 (m, 1H), 2.81-2.87 (m, 2H), 2.57 (d, 1H, J = 17.5 Hz), 2.49-2.53 (m, 1H), 2.37 (s, 3H), 2.36 (d, 1H, J = 17.5 Hz), 1.75-1.80 (m, 1H), 1.57-1.59 (m, 1H), 1.34 (dd, 1H, J = 4.5 Hz and 13.5 Hz), 1.14-1.15 (m, 1H). 13 C NMR (CD3OD, 126 MHz) δ: 175.72. 37.15, 35.07, 34.06, 21.31.

[0157] Compound (-)-I-4 is a specific form of the compound of general formula I in the present application, and is also one of the optically pure compounds (±)-I-4, which has the same relative configuration as (±)-I-4 and has levorotatory optical activity.

[0158] Step 5: Synthesis of compound (+)-I-4 and its p-toluenesulfonate salt Compound (+)-22 (S)-(+)-mandelate (2.40 g, 5.8 mmol) was added to saturated NaHCO3 solution (100 mL) at room temperature, stirred for 20 minutes, and extracted with EtOAc (60 mL × 3). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was then dissolved in CHCl2 (18 mL) and TFA (14 mL) was added dropwise slowly in an ice-water bath. After the addition was complete, the reaction was allowed to proceed 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 give a brown oil. CHCl2 (20 mL) was added and the mixture was concentrated again. The resulting oil was dried in a vacuum oil pump to give (+)-I-4. The dried oil was dissolved in CH3OH (2 mL), and EtOAc (8 mL) was added again and stirred. p-TsOH·HO (1.10 g, 5.8 mmol) was then added to the reaction solution, and the mixture was stirred until a large amount of solid precipitated. The mixture was then stirred at room temperature for 1 hour. The solid was collected by suction filtration, and the filter cake was dried under a vacuum oil pump to give a melting point of 182.1 °C–184.7 °C, [α] D 20 = +37.81 (c = 2.75, CH3OH) to obtain 1.60 g (73%) of p-toluenesulfonic acid salt of compound (+)-I-4 (white solid). 1H NMR (CD3OD, 500 MHz) δ: 7.70 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0 Hz), 6.42-6.44 (m, 1H), 6.29-6.31 (m, 1H), 3.24 (d, 1H, J = 13.0 Hz), 3.12 (d, 1H, J = 13.0 Hz), 2.92-2.94 (m, 1H), 2.81-2.87 (m, 2H), 2.57 (d, 1H, J = 17.5 Hz), 2.50-2.53 (m, 1H), 2.37 (s, 3H), 2.36 (d, 1H, J = 17.5 Hz), 1.75-1.80 (m, 1H), 1.57-1.59 (m, 1H), 1.34 (dd, 1H, J = 6.0 Hz and 13.5 Hz), 1.13-1.16 (m, 1H). 13 C NMR (CD3OD, 126 MHz) 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.

[0159] Compound (+)-I-4 is a specific form of the compound of general formula I in the present application, and is also one of the optically pure compounds (±)-I-4, which has the same relative configuration as (±)-I-4 and has dextrorotatory optical rotation.

[0160] The absolute configuration of compound (+)-I-4 can be determined indirectly by converting the (S)-(+)-mandelate of (+)-22, which has the same absolute configuration, into the lactam (+)-22-LAC, whose absolute configuration is identical to that of (+)-22, using X-ray single crystal diffraction.

[0161] The specific experimental method is as follows: Synthesis of (+)-22-LAC: (S)-(+)-Mandelate (1.00 g, 2.4 mmol) of the above (+)-22 (ee value 98.34%) was added to saturated NaHCO3 solution (100 mL) and stirred for 10 minutes, followed by extraction with EtOAc (30 mL × 3). The organic phases were combined, washed with saturated brine, dried (MgSO4), and filtered to remove the drying agent. The filtrate was evaporated to dryness on a rotary evaporator. The resulting residue was dissolved in toluene (7 mL) and heated to reflux overnight. TLC showed the reaction was complete. The reaction was cooled to room temperature, and the solvent was removed by rotary evaporation. The residue was slurried with EtOAc / n-hexane (1 / 10 v / v, 5 mL total). The crystals were collected by suction filtration and dried, melting at 178.7-180.5 °C, [α] D 20 = +30.2° (c = 1.03, CH3OH) to obtain 0.40 g (88%) of (+)-22-LAC. 1 H NMR (CDCl3, 500 MHz) δ: 6.27-6.29 (m, 1H), 6.22-6.24 (m, 1H), 5.89 (brs, 1H), 3.40 (dd, 1H, J = 1.0 Hz and 9.5 Hz), 3.36 (d, 1H, J = 9.5 Hz), 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 = 17.0 Hz), 2.05 (d, 1H, J = 17.0 Hz), 1.91 (ddd, 1H, J = 1.0 Hz, 8.5 Hz and 12.5 Hz), 1.57-1.60 (m, 1H), 1.42 (dd, 1H, J = 0.8 Hz and 12.8 Hz), 1.08-1.10 (m, 1H). 13 C NMR (CDCl3, 126 MHz) 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) C 12 H 16 NO ([M+H] + ) calculated value: 190.1226, measured value: 190.1224.

[0162] Cultivation of (+)-22-LAC single crystals and X-ray diffraction: 10 mg of (+)-22-LAC sample was weighed and dissolved in 1 mL of CHCl. ​​Then, 2 mL of n-hexane was added and the mixture was shaken uniformly. The solution was filtered, and the filtrate was placed in a small glass Erlenmeyer flask and allowed to slowly evaporate at room temperature for 2-3 days to obtain single crystals suitable for X-ray diffraction. A single crystal measuring 0.3 x 0.09 x 0.08 mm was selected for diffraction using CuKα radiation at 100.00 (10) K on a Rigaku XtaLAB Pro single crystal diffractometer. CrysAlisPro 1.171.39.33c (Rigaku OD, 2017) was used for diffraction data collection and data reduction, and the SHELXL program was used for structure analysis and refinement.

[0163] The chemical structure of the compound (+)-22-LAC in single crystal diffraction (ORTEP diagram) is shown in Figure 2.

[0164] The parameters associated with the crystallographic study and structure refinement of (+)-22-LAC are shown in the following table.

[0165] [Table 2]

[0166] [Example 9] Synthesis of compound (±)-I-7

[0167] [ka] Step 1: Synthesis of compound (±)-33 A dried flask was charged with dry CHCl (200 mL), and the air in the reaction vessel was purged with nitrogen (balloon) according to standard procedures. Under ice-water bath cooling, a solution of EtZn (1 M in n-hexane, 298 mL) in dry CHCl (30 mL) and TFA (33.99 g, 0.30 mol) were added dropwise to the system, yielding a white slurry. After the addition was complete, the mixture was stirred for 0.5 h in the ice-water bath, followed by the dropwise addition of a solution of CHCl (79.84 g, 0.30 mol) in dry CHCl (80 mL). (During the addition, the white viscous solid gradually dissolved and clarified, and a white solid precipitated in the suspension.) After the addition was complete, the mixture was stirred for 0.5 h in the ice-water bath, followed by the dropwise addition of a solution of compound (±)-18 (10.00 g, 75 mmol) in dry CHCl (20 mL). After the addition was complete, the reaction was stirred at room temperature for 4–6 h and then heated to reflux overnight. TLC monitoring indicated the reaction was complete. The reaction was quenched, cooled to room temperature, added to saturated aqueous NH4Cl (300 mL × 2), stirred, and extracted with C2Cl2 (200 mL × 2). The organic phases were combined, washed with saturated brine (400 mL), and separated. The combined organic phases were dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated on a rotary evaporator to give a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 3.15 g (29%) of the desired compound (±)-33 (yellow oil (slightly impure)). 1 H NMR (CDCl3, 500 MHz) δ: 3.48-3.52 (m, 1H), 2.95 (dt, 1H, J = 3.5 Hz and 18.5 Hz), 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).

[0168] Step 2: Synthesis of compound (±)-34 Under a N2 atmosphere, t-BuOK (11.92 g, 0.11 mol) was added to dry THF (30 mL) and stirred in an ice-water bath to form a suspension. tert-Butyl diethylphosphonoacetate (26.81 g, 0.11 mol) was then added dropwise. After the addition was complete, the reaction was stirred in an ice-water bath for 1 h, and then a solution of freshly prepared compound (±)-33 (3.15 g, 21 mmol) in dry THF (10 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 (80 mL × 2) and extracted with CHCl (60 mL × 2). The combined organic phase was washed once with saturated brine (150 mL), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give the desired product (±)-34 (3.15 g of a pale yellow oil), which was used directly in the next reaction without further characterization.

[0169] Step 3: Synthesis of compound (±)-35 Compound (±)-34 (3.60 g, 15 mmol) was dissolved in CH3NO2 (120 mL) and stirred at room temperature, and DBU (24.47 g, 0.16 mol) was added dropwise to the solution. After the addition was complete, the reaction mixture was refluxed under a N2 atmosphere for 48 hours. TLC monitoring indicated that a large amount of the starting material had not yet reacted. The reaction was stopped. The reaction solution was cooled to room temperature, poured into ice water, and extracted with CHCl2 (50 mL × 2). The organic phases were combined, washed successively with ice water (100 mL) and saturated brine (150 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 0.74 g of the desired product (±)-35 (a pale yellow oil). (The combined yield of (±)-33 → (±)-35 was 10%). 1¹H NMR (CDCl₃, 500 MHz) δ: 4.83 (dd, 1H, J = 1.3 Hz and α11.3 Hz), 4.55 (d, 1H, J = 11.0 Hz), 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 = 2.3 Hz, 8.5 Hz and α13.3 Hz), 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). 13 C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 17 H 26 NO4([M+H)) + ) The calculated value is 308.1856, the measured value is: 308.1853.

[0170] ステップ4:Synthesis of compound (±)-36 Compound (±)-35 (0.28 g, 0.91 mmol) was dissolved in CHCl (5 mL), and EtSiH (0.16 g, 1.4 mmol) and TFA (2 mL) were added dropwise in an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 hours. TLC monitoring indicated the reaction was complete. The reaction mixture was poured into ice-water (10 mL) and extracted with CHCl (10 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated on a rotary evaporator at low temperature (25 °C) to give a yellow oil. CHCl (10 mL × 3) was added to the oil, followed by concentration and drying under a vacuum oil pump for 10 minutes to give a white solid. The solid was crushed, added to n-hexane (4 mL), and slurried at room temperature for 1 hour. The solid was collected by suction filtration and dried under oil pump vacuum to give 0.09 g (39%) of compound (±)-36 (white solid), melting point 105.7°C-109.3°C. 1 H NMR (DMSO-d6, 500 MHz) δ: 12.31 (brs, 1H), 4.78 (d, 1H, J = 12.0 Hz), 4.71 (d, 1H, J = 12.0 Hz), 2.74 (d, 1H, J = 17.5 Hz), 2.56 (d, 1H, J = 17.5 Hz), 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 = 2.0 Hz, 8.5 Hz and 13.0 Hz), 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). 13 C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 13 H 18 NO4([M+H] + ) calculated value: 252.1230, measured value: 252.1228.

[0171] Step 5: Synthesis of compound (±)-I-7 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 reaction vessel was purged with hydrogen (balloon) according to standard procedures and stirred overnight at room temperature. TLC monitoring indicated the reaction was complete (reactions typically completed within 12 h). The reaction was filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a white solid. CH3OH (1 mL) / EtOAc (3 mL) was added and the mixture was stirred at room temperature for 1–2 h to form a slurry. Filtration and drying afforded the desired product (±)-I-7 (white solid), 0.04 g (25%), melting point 184.5–190.0 °C. 1 H NMR (CD3OD, 500 MHz) δ: 3.10 (dd, 1H, J = 1.5 Hz and 13.0 Hz), 2.96 (d, 1H, J = 13.0 Hz), 2.78 (dd, 1H, J = 1.3 Hz and 16.8 Hz), 2.60 (d, 1H, J = 16.5 Hz), 2.51-2.55 (m, 1H), 2.48-2.49 (m, 1H), 2.23-2.27 (m, 2H), 2.18 (dd, 1H, J = 6.8 Hz and 12.8 Hz), 1.69 (ddd, 1H, J = 2.0 Hz, 8.5 Hz and 13.0 Hz), 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). 13C NMR (D2O, 126 MHz) 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) C 13 H 20 NO2([M+H] + ) calculated value: 222.1489, measured value: 222.1487.

[0172] Compound (±)-I-7 is a specific form of the compound of general formula I in this application.

[0173] [Example 10] Synthesis of compound (±)-I-8

[0174] [ka] Step 1: Synthesis of compound 37 Maleic anhydride (27.79 g, 0.28 mol) was dissolved in a mixed solvent of benzene (50 mL) and methyl tert-butyl ether (150 mL). The air in the reaction vessel 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 total) was added dropwise in an ice-water bath. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was then terminated. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a purple-red oil. The oil was placed in an ice-water bath and crystallized at low temperature. After crystals precipitated, n-hexane (100 mL) was added and the mixture was stirred at room temperature for 1 hour to form a slurry. The solid was collected by suction filtration, and the filter cake was dried under oil pump vacuum to give 40.00 g (>100% due to the presence of a certain amount of unreacted maleic anhydride) of crude compound 37 (white solid (with some impurities)). The product was used directly in the next step without further purification. 1H NMR (CDCl3, 500 MHz) δ: 3.18 (s, 2H), 1.55-1.59 (m, 7H), 1.35 (s, 6H), 0.62 (d, 3H, J = 6.5 Hz).

[0175] Step 2: Synthesis of compound 38 Compound 37 (40.00 g, calculated as 0.17 mol) was dissolved in 1,4-dioxane (400 mL), and 50% aqueous NaOH (68 mL) was slowly added dropwise under ice bath conditions. During the addition, a white solid gradually precipitated. After the addition was complete, 1,4-dioxane (300 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. TLC monitoring indicated the reaction was complete. 1 M HCl was slowly added dropwise to the reaction mixture under ice bath cooling until the pH was <2. The reaction mixture was saturated with sodium chloride and extracted with EtOAc (300 mL × 3). The organic phases were combined, dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated on a rotary evaporator to obtain a residue. n-Hexane (100 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour to form a slurry. The solid was collected by suction filtration and dried under oil pump vacuum to give 20.86 g of compound 38 (white solid) (combined yield of 1,2,3,4,5-pentamethylcyclopentadiene → 38 was 56%). The product was used directly in the next reaction without further purification. 1 H NMR (DMSO-d6, 500 MHz) δ: 2.90 (s, 2H), 1.54 (s, 6H), 1.37 (q, 1H, J = 6.3 Hz), 1.08 (s, 6H), 0.52 (d, 3H, J = 6.5 Hz).

[0176] Step 3: Synthesis of compound 39 Compound 38 (20.86 g, 83 mmol) was dissolved in N,N-dimethylformamide (DMF) (210 mL), and the air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. Under ice-water bath cooling, K2CO3 (34.28 g, 0.25 mol) was added, followed by slow, dropwise addition of CHCl (46.94 g, 0.33 mol). After the addition was complete, the reaction was allowed to proceed at room temperature for 5–6 h. TLC monitoring indicated the reaction was complete. EtOAc (200 mL) was added to the reaction solution, filtered to remove solids, and the filtrate was washed with water (300 mL × 5). All aqueous phases were combined and back-extracted with EtOAc (200 mL × 2). All organic phases were combined, washed with saturated brine (500 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated on a rotary evaporator to give a yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 22.10 g (95%, containing some impurities) of the desired product 39 (a colorless, transparent oil), which was used directly in the next step without further purification. 1 H NMR (CDCl3, 500 MHz) δ: 3.57 (s, 6H), 3.00 (s, 2H), 1.60 (s, 6H), 1.37 (q, 1H, J = 6.3 Hz), 1.15 (s, 6H), 0.60 (d, 3H, J = 6.5 Hz).

[0177] Step 4: Synthesis of compound (±)-40 Sodium metal (9.97 g, 0.43 mol) was added to dry toluene (220 mL) and heated under a N2 atmosphere until the sodium completely melted. Stirring was initiated and continued for 20 min while maintaining the internal temperature of the reaction mixture at 103-106 °C. A solution of compound 39 (22.10 g, 79 mmol) and TMSCl (45.39 g, 0.42 mol) in dry toluene (15 mL) was added dropwise. Heat was generated during the addition, and the internal temperature of the reaction mixture was maintained at 103-106 °C by controlling the addition rate. After the addition was complete, the internal temperature of the reaction mixture was maintained at 103-106 °C and the mixture was stirred overnight. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure on a rotary evaporator to give 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 proceed at room temperature for 30 minutes. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with saturated brine (300 mL), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which solidified at low temperature. n-Hexane (10 mL) was added to the solid, and the mixture was stirred and slurried at room temperature for 1 hour. The solid was collected by filtration and dried under oil pump vacuum to give 3.60 g (21%) of the desired compound (±)-40 (white solid), melting at 124.0-128.0 °C. 1 H NMR (CDCl3, 500 MHz) δ: 4.44 (dd, 1H, J = 3.5 Hz and 9.0 Hz), 3.16 (dd, 1H, J = 3.5 Hz and 7.5 Hz), 2.91 (dd, 1H, J = 7.5 Hz and 9.0 Hz), 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 = 6.5 Hz).

[0178] Step 5: Synthesis of compound (±)-41 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. According to standard procedures, the air in the reaction vessel was replaced with nitrogen (balloon) and the mixture was refluxed overnight with stirring. 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. Methyl tert-butyl ether (12 mL) was added to the concentrated residue and stirred at room temperature for 1 hour. The solids were removed by filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 9 / 91] to give 2.20 g of the desired product (±)-41 (pale yellow oil, slightly impure). The product was used directly in the next reaction without characterization.

[0179] Step 6: Synthesis of compound (±)-42 Zinc powder (2.06 g, 32 mmol) and glacial acetic acid (10 mL) were mixed by stirring, and a solution of freshly prepared compound (±)-41 (2.20 g, 9.2 mmol) in glacial acetic acid (5 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 N 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 × 2). The combined organic phases were washed successively with water (80 mL × 3) and saturated brine (100 mL), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 20] to give a pale yellow oil. The oily substance was dried using a vacuum oil pump to obtain a solid. n-Hexane (5 mL) was added to the solid, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered. The filter cake was dried using a vacuum oil pump to obtain 1.08 g of the target compound (±)-42 (white solid) with a melting point of 101.0 °C to 103.0 °C (the combined yield of (±)-40 → (±)-42 was 45%). 1 H NMR (CDCl3, 500 MHz) δ: 3.34-3.37 (m, 1H), 2.62 (ddd, 1H, J = 3.0 Hz, 8.5Hz and 18.5 Hz), 2.49-2.52 (m, 1H), 2.14 (dt, 1H, J = 3.5 Hz and 18.5 Hz), 1.616-1.624 (m, 3H), 1.51-1.52 (m, 3H), 1.48 (q, 1H, J = 6.5 Hz), 1.14 (s, 3H), 1.13 (s, 3H), 0.58 (d, 3H, J = 6.5 Hz). 13 C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 14 H21 O ([M+H] + ) calculated value: 205.1587, measured value: 205.1587.

[0180] Step 7: Synthesis of compound (±)-43 Under a N2 atmosphere, t-BuOK (2.35 g, 21 mmol) was added to dry THF (10 mL) and stirred in an ice-water bath to form a suspension. tert-Butyl diethylphosphonoacetate (5.28 g, 21 mmol) was then added dropwise. After the addition was complete, the reaction was stirred in an ice-water bath for 30 min, and then a solution of freshly prepared compound (±)-42 (0.86 g, 4.2 mmol) in dry THF (7 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 (80 mL) and extracted with CHCl (30 mL × 3). The combined organic phase was washed successively with 1 M HCl (20 mL) and saturated brine (100 mL), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 20] to give 0.97 g of the desired product (±)-43 (a pale yellow oil), which was used directly in the next reaction without further characterization.

[0181] Step 8: Synthesis of compound (±)-44 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 under a N2 atmosphere for 48 h. TLC monitoring indicated that approximately 60% of the starting material was unreacted. The reaction was then quenched. The reaction solution was cooled to room temperature, poured into ice water (100 mL), and extracted with C2Cl2 (50 mL × 2). The combined organic phases were washed successively with 1 M HCl (50 mL) and saturated brine (100 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give a pale yellow oil. The oil solidified at low temperature, and n-hexane (2 mL) was added. The mixture was stirred at −18°C for 30 minutes to form a slurry. The solid was collected by suction filtration and dried under oil pump vacuum to give 0.10 g of the desired product (±)-44 (white solid) having a melting point of 78.6°C to 81.5°C (the combined yield of (±)-42 → (±)-44 was 7%). 1 H NMR (CDCl3, 500 MHz) δ: 4.82 (d, 1H, J = 11.5 Hz), 4.66 (d, 1H, J = 11.5 Hz), 2.47-2.52 (m, 1H), 2.36 (d, 1H, J = 17.5 Hz), 2.28 (d, 1H, J = 17.5 Hz), 2.24-2.26 (m, 1H), 1.91 (ddd, 1H, J = 2.0 Hz, 8.5 Hz and 13.0 Hz), 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 = 6.0 Hz). 13C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 21 H 32 NO4([MH] - ) calculated value: 362.2337, measured value: 362.2343.

[0182] Step 9: Synthesis of compound (±)-45 Compound (±)-44 (0.10 g, 0.28 mmol) was dissolved in CHCl (5 mL) and TFA (1 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 2–3 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 7] to give a pale yellow solid. n-Hexane (3 mL) was added to the solid, and the mixture was stirred at room temperature for 1 h to form a slurry. The solid was collected by suction filtration and dried under oil pump vacuum to give 0.05 g (63%) of compound (±)-45 (white solid), melting at 122.8–126.4 °C. 1H NMR (CDCl3, 500 MHz) δ: 4.78 (d, 1H, J = 12.0 Hz), 4.74 (d, 1H, J = 11.5 Hz), 2.55 (d, 1H, J = 18.0 Hz), 2.50-2.54 (m, 1H), 2.51 (d, 1H, J = 18.0 Hz), 2.26-2.28 (m, 1H), 1.91 (ddd, 1H, J = 2.0 Hz, 8.5 Hz and 13.5 Hz), 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 = 6.5 Hz); 13 C NMR (CDCl3, 126 MHz) 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; ESI-HRMS: (m / z) C 17 H 26 NO4([M+H] + ) calculated value: 308.1856, measured value: 308.1850.

[0183] Step 10: Synthesis of compound (±)-I-8 Compound (±)-45 (0.05 g, 0.16 mmol) was dissolved in CH3OH (3 mL), 10% Pd(OH)2 / C (0.03 g) was added, and the reaction vessel was purged with hydrogen (balloon) according to standard procedures and stirred overnight at room temperature. TLC monitoring indicated the reaction was complete (the reaction was usually complete within 12 h). The mixture was filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a white solid. CH3OH (1 mL) / EtOAc (3 mL) was added and the mixture was stirred at room temperature for 0.5 h. The solid was collected by suction filtration and dried under oil pump vacuum to give 0.02 g (53%) of the desired product (±)-I-8 (white solid), melting point 180.0 °C–184.0 °C. 1 H NMR (CD3OD, 500 MHz) δ: 3.09 (dd, 1H, J = 0.8 Hz and 13.3 Hz), 2.97 (d, 1H, J = 13.0 Hz), 2.48-2.53 (m, 1H), 2.43 (dd, 1H, J = 1.3 Hz and 17.3 Hz), 2.27 (d, 1H, J = 17.0 Hz), 2.20-2.22 (m, 1H), 1.81-1.82 (m, 3H), 1.61-1.62 (m, 3H), 1.59 (ddd, 1H, J = 2.0 Hz, 8.0 Hz and 12.5 Hz), 1.24 (q, 1H, J = 6.3 Hz), 1.14 (dd, 1H, J = 6.5 Hz and 12.5 Hz), 1.08 (s, 3H), 0.99 (s, 3H), 0.58 (d, 3H, J = 6.5 Hz); 13 C NMR (CD3OD, 126 MHz) 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; ESI-HRMS: (m / z) C 17 H 28 NO2([M+H] + ) calculated value: 278.2115, measured value: 278.2111.

[0184] Compound (±)-I-8 is a specific form of the compound of general formula I in this application.

[0185] [Example 11] Synthesis of Compound (±)-I-9 and its p-Toluenesulfonate

[0186] [ka] TIFF2025537126000034.tif94169 Step 1: Synthesis of compound 46 Tetrabutylammonium bromide (TBAB) (32.64 g, 0.10 mol) was added to 50% aqueous NaOH (1.2 L) and stirred. 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 homogeneously in an ice-water bath and then added dropwise to the reaction system. (Heat was generated during the reaction, and the internal temperature was maintained between 30 and 40°C by controlling the addition rate. During the addition, the color of the system gradually changed from colorless to dark reddish-brown and became viscous.) After the addition was complete, the reactor was transferred to an oil bath, and the internal temperature was maintained between 30 and 40°C. The system was stirred for 2 hours. The reaction was then stopped. The reaction solution was cooled to room temperature, poured into ice water (1.0 mL), and extracted with n-pentane (300 mL × 2). The combined organic phases were washed successively with water (500 mL × 2), 1 M HCl (300 mL), and saturated brine (500 mL), dried (MgSO), and filtered to remove the drying agent. The filtrate was separated under atmospheric pressure, and the fraction between 108 °C and 109 °C was collected to obtain 46.24 g (20%) of the target compound 46 (containing a certain amount of n-pentane) as a colorless, transparent liquid. 1 H NMR (CDCl3, 500 MHz) δ: 6.50-6.52 (m, 2H), 6.11-6.13 (m, 2H), 1.65 (s, 4H).

[0187] Step 2: Synthesis of compound 47 Maleic anhydride (11.28 g, 0.12 mol) was dissolved in a mixed solvent of benzene (30 mL) and methyl tert-butyl ether (90 mL). The air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. A solution of compound 46 (13.24 g, 0.14 mol) in benzene / methyl tert-butyl ether (1 / 3, v / v, total 50 mL) was added dropwise in an ice-water bath. After the addition was complete, the mixture was stirred overnight at room temperature. The mixture was then placed in an oil bath and refluxed at 45 °C for 2 hours. The reaction was then stopped. The mixture was cooled to room temperature and then concentrated under reduced pressure on a rotary evaporator to obtain a colorless, transparent oil. n-Hexane (100 mL × 4) was added and concentrated several times to obtain a white solid. n-Hexane (120 mL) was added to the solid, and the mixture was stirred at room temperature for 1 hour to form a slurry. The solid was collected by suction filtration and dried under oil pump vacuum to give 21.03 g (77%) of compound 47 (white solid), melting point 92.7°C-96.9°C. 1 H NMR (CDCl3, 500 MHz) 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); 13 C NMR (CDCl3, 126 MHz) δ: 171.25, 135.62, 51.11, 49.12, 47.54, 8.26, 7.12; ESI-HRMS: (m / z) C 11 H 11 O3([M+H] + ) calculated value: 191.0703, measured value: 191.0701.

[0188] Step 3: Synthesis of compound 48 Compound 47 (21.00 g, 0.11 mol) was dissolved in 1,4-dioxane (500 mL) and stirred under ice bath cooling. 50% aqueous NaOH (44 mL) was slowly added dropwise, resulting in the gradual precipitation of a white solid during the addition. After the addition was complete, stirring was continued at room temperature for 0.5–1 h. TLC monitoring indicated the reaction was complete. The pH of the reaction solution was adjusted to <2 by adding 1 M HCl dropwise under ice bath conditions. The reaction mixture was saturated with sodium chloride and extracted with EtOAc (400 mL × 3). The organic phases were combined, dried (MgSO4), and the drying agent was removed by suction filtration. The filtrate was concentrated on a rotary evaporator to obtain a residue. n-Hexane (120 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h to form a slurry. The solid was collected by suction filtration and dried under oil pump vacuum to give 22.33 g (97%) of compound 48 (white solid), melting point 163.3°C-166.3°C. 1 H NMR (CDCl3, 500 MHz) 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); 13 C NMR (CDCl3, 126 MHz) δ: 179.21, 135.10, 51.32, 49.66, 44.86, 7.91, 6.55; ESI-HRMS: (m / z) C 11 H 13 O4([M+H] + ) calculated value: 209.0808, measured value: 209.0805.

[0189] Step 4: Synthesis of compound 49 Compound 48 (42.34 g, 0.20 mol) was dissolved in DMF (500 mL) and the reaction vessel was purged with nitrogen (balloon) according to standard procedures. Dry K2CO3 (84.32 g, 0.61 mol) was added under ice-water bath conditions, followed by slow, dropwise addition of CHCl (115.44 g, 0.81 mol). After the addition was complete, the reaction was transferred to an oil bath and stirred at 55 °C overnight. TLC monitoring indicated the reaction was complete. The reaction was cooled to room temperature. EtOAc (500 mL) was added to the reaction and stirred. The solids were removed by suction filtration, and the filtrate was washed with water (600 mL × 5). All aqueous phases were combined and back-extracted with EtOAc (300 mL × 2). All organic phases were then combined, washed with saturated brine (1.0 L), dried (MgSO4), and suction filtered to remove the drying agent. The filtrate was concentrated on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 10] to give a white solid. n-Hexane (150 mL) was added to the solid, and the mixture was stirred at room temperature for 1 hour to form a slurry. The solid was collected by suction filtration and dried under oil pump vacuum to give 40.09 g (83%) of the target compound 49 (white solid), melting at 71.4 °C - 74.2 °C. 1 H NMR (CDCl3, 500 MHz) 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); 13 C NMR (CDCl3, 126 MHz) δ: 172.88, 135.07, 51.67, 51.37, 49.01, 44.46, 7.86, 6.51; ESI-HRMS: (m / z) C 13 H 17 O4([M+H] + ) calculated value: 237.1121, measured value: 237.1118.

[0190] Step 5: Synthesis of compound (±)-50 Sodium metal (21.41 g, 0.93 mol) was added to dry toluene (300 mL) and heated under a N2 atmosphere until the sodium completely melted. Stirring was initiated and continued for 20 min while maintaining the internal temperature at 103–106 °C. 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 added dropwise. Heat was generated during the addition, and the internal temperature of the reaction mixture was maintained at 103–106 °C by controlling the addition rate. After the addition was complete, the internal temperature of the reaction mixture was maintained at 103–106 °C and stirring was continued for 3–4 h. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure on a rotary evaporator to give 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 proceed at room temperature for 1 hour. TLC monitoring indicated the reaction was complete. The reaction solution was poured into water (300 mL) and extracted with EtOAc (300 mL × 2). The combined organic phases were washed with saturated brine (500 mL), dried (MgSO), and filtered under suction to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a residue. A mixture of EtOAc (15 mL) and n-hexane (90 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour to form a slurry. The solid was collected by suction filtration and dried under oil pump vacuum to obtain 20.34 g (68%) of the desired compound (±)-50 (brown solid). The product was used directly in the next reaction without further characterization.

[0191] Step 6: Synthesis of compound (±)-51 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 atmosphere 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 filtered under suction to remove the solids. The filtrate was concentrated under reduced pressure on a rotary evaporator, and a mixture of EtOAc (30 mL) and n-hexane (60 mL) was added to the concentrated residue. The mixture was stirred at room temperature for 1 hour. The solids were removed by suction filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97] to give 7.36 g of the desired product (±)-51 (a pale yellow oil (slightly impure)), which was used directly in the next reaction without characterization.

[0192] Step 7: Synthesis of compound (±)-52 Zinc powder (8.50 g, 0.13 mol) and glacial acetic acid (40 mL) were mixed with stirring, and a solution of freshly prepared 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 placed in an oil bath under a N2 atmosphere and stirred at 55 °C overnight. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, poured into ice water (100 mL), stirred, and filtered with suction to remove solids. The filtrate was extracted with EtOAc (80 mL × 3). The organic phases were combined and washed successively with water (200 mL × 3), saturated NaHCO3 solution (200 mL), and saturated brine (200 mL), dried (MgSO4), and filtered with suction to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97] to give 4.87 g of the desired product (±)-52 (a pale yellow oil). (The combined yield of (±)-50 → (±)-52 was 26%). 1H NMR (CDCl3, 500 MHz) δ: 6.23-6.28 (m, 2H), 3.84-3.88 (m, 1H), 2.92-2.97 (m, 1H), 2.74 (ddd, 1H, J = 3.0 Hz, 8.5 Hz and 18.5 Hz), 2.50-2.52 (m, 1H), 2.42-2.45 (m, 1H), 2.22 (dt, 1H, J = 3.8 Hz and 18.5 Hz), 0.50-0.56 (m, 2H), 0.42-0.46 (m, 1H), 0.35-0.39 (m, 1H); 13 C NMR (CDCl3, 126 MHz) δ: 211.22, 135.61, 132.91, 66.90, 51.52, 50.64, 49.45, 46.10, 27.03, 7.70, 5.60; ESI-HRMS: (m / z) C 11 H 13 O ([M+H] + ) calculated value: 161.0961, measured value: 161.0960.

[0193] Step 8: Synthesis of compound (±)-53 Under a N2 atmosphere, t-BuOK (3.71 g, 33 mmol) was added to dry THF (6 mL) and stirred in an ice-water bath to form a suspension. tert-Butyl diethylphosphonoacetate (8.35 g, 33 mmol) was then added dropwise. After the addition was complete, the reaction was continued for 1 hour in an ice-water bath. A solution of freshly prepared 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 CHCl (40 mL × 2). The combined organic phase was washed successively with ice-water (80 mL × 2) and saturated brine (150 mL), dried (MgSO), and filtered under vacuum to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 97] to give 1.62 g of the desired product (±)-53 (pale yellow oil), which was used directly in the next reaction without further characterization.

[0194] Step 9: Synthesis of compound (±)-54 Compound (±)-53 (1.62 g, 6.3 mmol) was dissolved in CH3NO2 (20 mL) at room temperature, and DBU (7.64 g, 50 mmol) was added dropwise. After the addition was complete, the mixture was refluxed under a N2 atmosphere for 48 hours. TLC monitoring indicated that approximately 60% of the starting material had not reacted. The reaction was then stopped. The reaction solution was cooled to room temperature, poured into ice water (30 mL), and extracted with CHCl2 (30 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried (MgSO4), and filtered under vacuum to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23] to give 0.59 g of the target compound (±)-54 (light brown oil). (The combined yield of (±)-52 → (±)-54 was 28%). 1H NMR (CDCl3, 500 MHz) δ: 6.49-6.51 (m, 1H), 6.38-6.40 (m, 1H), 4.84 (dd, 1H, J = 1.0 Hz and 11.5 Hz), 4.63 (dd, 1H, J = 1.0 Hz and 11.5 Hz), 2.95-3.01 (m, 1H), 2.66-2.70 (m, 1H), 2.53 (dd, 1H, J = 0.8 Hz and 17.8 Hz), 2.42 (d, 1H, J = 17.5 Hz), 2.28-2.30 (m, 1H), 2.22-2.24 (m, 1H), 2.06 (ddd, 1H, J = 1.8 Hz). Hz, 8.5 Hz and 13.3 Hz), 1.46 (s, 9H), 1.41-1.44 (m, 1H), 0.44-0.47 (m, 2H), 0.25-0.33 (m, 2H). 13 C NMR (CDCl3, 126 MHz) 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. ESI-HRMS: (m / z) C 18 H 26 NO4([M+H] + ) calculated value: 320.1856, measured value: 320.1854.

[0195] Step 10: Synthesis of p-toluenesulfonate salt of compound (±)-55 Compound (±)-54 (0.59 g, 1.8 mmol) was dissolved in EtOH (10 mL) and added to water (5 mL) at room temperature with stirring. Iron powder (0.52 g, 9.3 mmol) and NH₄Cl (0.20 g, 3.7 mmol) were then added sequentially. 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 filtered under vacuum to remove solids. The filtrate was added to saturated NaHCO₃ solution (50 mL) and extracted with EtOAc (40 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried (MgSO₄), and filtered under vacuum to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a light brown oil. The oil was diluted with 5 mL of EtOAc at room temperature, followed by the addition of 0.38 g (2.0 mmol) of p-TsOH·HO and stirring to dissolve the solid. The mixture was then transferred to an ice-water bath and stirred until a white, fluffy solid gradually precipitated. 7.5 mL of EtOAc was added, and the mixture was thoroughly stirred. Stirring at room temperature continued overnight. The solid was collected by suction filtration and dried under an oil pump vacuum to obtain 0.60 g (70%) of the desired compound (±)-55 p-toluenesulfonate (white solid), melting at 171.6 °C–175.8 °C. 11H NMR (DMSO-d6, 500 MHz) δ: 7.69 (brs, 3H), 7.47 (d, 2H, J = 8.0 Hz), 7.11 (d, 2H, J = 8.0 Hz), 6.43 - 6.45 (m, 1H), 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 = 4.5 Hz and 9.0 Hz), 2.37 (d, 1H, J = 17.5 Hz), 2.31 (d, 1H, J = 17.0 Hz), 2.29 (s, 3H), 2.17 - 2.21 (m, 2H), 1.79 (ddd, 1H, J = 1.8 Hz, 8.5 Hz and 12.8 Hz), 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); 13 13C NMR (DMSO-d6, 126 MHz) 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; ESI-HRMS: (m / z) C 18 H 28 NO2([M(free base)+H] + ) calculated value 290.2115, measured value: 290.2112.

[0196] Step 11: Synthesis of the p-toluenesulfonate salt of compound (±)-I-9 Compound (±)-55 p-toluenesulfonate (0.56 g, 1.2 mmol) was added to saturated NaHCO3 solution (100 mL) at room temperature, stirred for 20 minutes (suspension), and extracted with EtOAc (60 mL x 3). The combined organic phases were dried (MgSO4) and filtered under vacuum to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. CHCl2 (20 mL x 3) was added and concentrated several times. The oil was dissolved in CHCl2 (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 give a brown oil. CHCl2 (20 mL x 3) was added and concentrated several times, and then dried under vacuum with an oil pump (a small amount of solid precipitated during drying). 3 mL of EtOAc was added to dissolve the solid. A solution of p-TsOH·HO (0.25 g, 1.3 mmol) in 3 mL of EtOAc was added dropwise to the reaction mixture until an off-white solid precipitated. After the addition was complete, the mixture was stirred overnight at room temperature. The solid was collected by suction filtration. The filter cake was washed with 1 mL of EtOAc and dried under oil pump vacuum to give 0.38 g (77%) of the p-toluenesulfonate salt of compound (±)-I-9 (white solid), melting at 187.5 °C–188.5 °C. 1H NMR (CD3OD, 500 MHz) δ: 7.71 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0 Hz), 6.50-6.52 (m, 1H), 6.38-6.40 (m, 1H), 3.27 (d, 1H, J = 13.0 Hz), 3.13 (d, 1H, J = 13.0 Hz), 2.95-3.01 (m, 1H), 2.66-2.69 (m, 1H), 2.63 (d, 1H, J = 17.5 Hz), 2.40 (d, 1H, J = 17.5 Hz), 2.37 (s, 3H), 2.26-2.28 (m, 1H), 2.20-2.22 (m, 1H), 1.78 (ddd, 1H, J = 1.5 Hz, 8.5 Hz and 13.0 Hz), 1.44 (dd, 1H, J = 6.5 Hz and 13.0 Hz), 0.40-0.46 (m, 2H), 0.30-0.34 (m, 1H), 0.25-0.29 (m, 1H); 13 C NMR (CD3OD, 126 MHz) δ: 175.76, 143.51, 141.71, 138.32, 137.84, 129.82, 126.96, 52.26, 51.30, 50.45, 49.93, 48.37, 38.43, 37.52, 35.51, 33.66, 21.31, 8.27, 5.20; ESI-HRMS: (m / z) C 14 H 20 NO2 ([M(free base) + H] + ) calculated value: 234.1489, measured value: 234.1486.

[0197] Compound (±)-I-9 is a specific form of the compound of general formula I in this application.

[0198] [Example 12] Synthesis of compound (±)-I-10

[0199] [ka] Step 1: Synthesis of compound (±)-56 Compound (±)-54 (0.21 g, 0.66 mmol) was dissolved in CHCl (2 mL) and TFA (1.5 mL) was slowly added dropwise under ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 2–3 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator. CHCl (20 mL × 4) was then added and concentrated several times to give a dark brown oily substance, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 7] to give a yellow solid. n-Hexane (1 mL) was added to the solid, and the mixture was stirred at room temperature overnight to form a slurry. The solid was collected by suction filtration and dried under oil pump vacuum to give 0.11 g (64%) of compound (±)-56 (white solid), melting at 141.3–144.5 °C. 1 H NMR (DMSO-d6, 500 MHz) 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 = 17.5 Hz), 2.27 (d, 1H, J = 17.5 Hz), 2.24-2.25 (m, 1H), 2.20-2.21 (m, 1H), 1.96 (ddd, 1H, J = 1.8 Hz, 8.5 Hz and 13.0 Hz), 1.36 (dd, 1H, J = 6.5 Hz and 13.0 Hz), 0.36-0.41 (m, 2H), 0.22-0.30 (m, 2H); 13 C NMR (DMSO-d6, 126 MHz) 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; ESI-HRMS: (m / z) C 14 H 18 NO4([M+H] +) calculated value: 264.1230, measured value: 264.1225.

[0200] Step 2: Synthesis of compound (±)-I-10 Compound (±)-56 (0.11 g, 0.42 mmol) was dissolved in CH3OH (3 mL), 10% Pd(OH)2 / C (0.04 g) was added, and the reaction vessel was purged with hydrogen (balloon) according to standard procedures and stirred overnight at room temperature. TLC monitoring indicated the reaction was complete (typically within 12 h). The solid was removed by suction filtration. The filtrate was concentrated on a rotary evaporator under reduced pressure to give a white solid. 2 mL of EtOAc was added and the mixture was stirred at room temperature for 1 h to form a slurry. The solid was collected by suction filtration, dried under vacuum, and collected to give 0.03 g (31%) of the desired product (±)-I-10 (white solid), melting point 197.3 °C–201.1 °C. 1 H NMR (CD3OD, 500 MHz) δ: 3.14 (d, 1H, J = 13.0 Hz), 3.01 (d, 1H, J = 12.5 Hz), 2.75 (dd, 1H, J = 1.0 Hz and 16.5 Hz), 2.63-2.78 (m, 1H), 2.66 (d, 1H, J = 16.0 Hz), 2.53-2.57 (m, 1H), 2.10-2.17 (m, 1H), 2.01 (dd, 1H, J = 7.5 Hz and 13.0 Hz), 1.79-1.90 (m, 4H), 1.60-1.62 (m, 1H), 1.42-1.44 (m, 1H), 0.42-0.51 (m, 4H); 13 C NMR (CD3OD, 126 MHz) 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; ESI-HRMS: (m / z) C 14 H 22 NO2([M+H] + ) calculated value: 236.1645, measured value: 236.1642.

[0201] Compound (±)-I-10 is a specific form of the compound of general formula I in the present application.

[0202] [Example 13] Synthesis of Compound (±)-I-11 and its p-Toluenesulfonate

[0203] [ka] Step 1: Synthesis of compound (±)-58 Compound (±)-18 (3.00 g, 22 mmol) was dissolved in benzene (40 mL), CH3NO2 (20 mL) and piperidine (0.95 g, 11 mol) were added sequentially with stirring, and the mixture was heated to reflux and subjected to water separation using a Dean-Stark water separator for 2 hours. TLC monitoring indicated the reaction was complete. The reaction was then stopped. The reaction solution was cooled to room temperature, poured into ice water (100 mL), and extracted with CHCl2 (50 mL × 2). The combined organic phase was washed sequentially with 1 M HCl (20 mL), saturated NaHCO3 solution (100 mL), and saturated brine (100 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97] to give 0.78 g of the target compound (±)-58 (yellow oil). The product consisted of a Z / E mixture and was used directly in the next reaction.

[0204] Step 2: Synthesis of compound (±)-59 Dry THF (5 mL) was added to the reaction vessel, and the air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. Diisopropylamine (0.86 g, 8.5 mmol) was added under stirring and cooled to -78 °C (liquid nitrogen-alcohol system). n-Butyllithium (1.6 M hexane solution, 5.3 mL, 8.5 mmol) was added dropwise. After the addition was complete, the reaction was carried out at -78 °C for 0.5 h. Next, a solution of tert-butyl acetate (0.99 g, 8.5 mmol) in dry THF (1 mL) was added dropwise. After the addition was complete, the reaction was continued at -78 °C for 0.5 h. A solution of compound (±)-58 (0.50 g, 2.8 mmol) in dry THF (1 mL) was added dropwise. After the addition was complete, the reaction was again carried out at -78 °C for 1 to 2 h. TLC monitoring indicated the reaction was complete. After allowing the mixture to cool to room temperature, the reaction mixture was poured into ice water (15 mL) and extracted with CHCl (20 mL). The organic phase was washed successively with 1 M HCl (40 mL), saturated NaHCO solution (40 mL), and saturated brine (40 mL), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 97] to give 0.51 g of the desired compound (±)-59 (a pale yellow oil). (The combined yield of (±)-18 → (±)-59 was 12%). 1 H NMR (CDCl3, 500 MHz) δ: 6.41-6.43 (m, 1H), 6.32-6.34 (m, 1H), 4.59 (d, 1H, J = 13.0 Hz), 4.54 (d, 1H, J = 13.0 Hz), 3.02-3.05 (m, 1H), 2.84-2.90 (m, 2H), 2.69 (dd, 1H, J = 1.0 Hz and 16.5 Hz), 2.59 (dd, 1H, J = 0.5 Hz and 16.5 Hz), 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); 13C NMR (CDCl3, 126 MHz) 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; ESI-HRMS: (m / z) C 16 H 24 NO4([M+H] + ) calculated value: 294.1700, measured value: 294.1698.

[0205] Step 3: Synthesis of compound (±)-60 p-toluenesulfonate Compound (±)-59 (0.51 g, 1.7 mmol) was dissolved in 10 mL of EtOH and stirred in 5 mL of water. Iron powder (0.47 g, 8.4 mmol) and NH₄Cl (0.18 g, 3.4 mmol) were then added sequentially. The reaction vessel was purged with nitrogen (balloon) according to standard procedures, and the mixture was refluxed overnight under stirring. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered with suction to remove solids. The filtrate was added to saturated NaHCO₃ solution (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic phases were washed with saturated NaHCO₃ solution (80 mL) and saturated brine (100 mL), dried (MgSO₄), filtered with suction to remove the drying agent, and concentrated under reduced pressure on a rotary evaporator to give a brown oil. The brown oil was dissolved in 5 mL of EtOAc, and p-TsOH HO (0.35 g, 1.8 mmol) was added and stirred until a white solid gradually precipitated. 3 mL of EtOAc was added again, and the mixture was stirred thoroughly. Stirring continued at room temperature for 1-2 h. The solid was collected by suction filtration and dried under oil pump vacuum to give 0.39 g (52%) of the desired compound (±)-60 p-toluenesulfonate (white solid), melting point 194.9 °C-196.7 °C. 1H NMR (DMSO-d6, 500 MHz) δ: 7.52 (brs, 3H), 7.48 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 8.0 Hz), 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 = 16.0 Hz), 2.53 (d, 1H, J = 16.0 Hz), 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); 13 C NMR (DMSO-d6, 126 MHz) δ: 170.22, 145.63, 137.66, 137.30, 136.31, 128.06, 125.48, 80.39, 53.06, 47.38, 44.67, 43.98, 43.20, 40.12, 36.87, 32.62, 31.58, 27.82, 20.78; ESI-HRMS: (m / z) C 16 H 26 NO2 ([M(free base) + H] + ) calculated value: 264.1958, measured value: 264.1956.

[0206] Step 4: Synthesis of compound (±)-I-11 and its p-toluenesulfonate salt Compound (±)-60 p-toluenesulfonate (0.39 g, 0.90 mmol) was added to saturated NaHCO3 solution (50 mL) at room temperature, stirred for 20 minutes (suspension), and extracted again with EtOAc (40 mL × 3). The organic phases were combined, dried (MgSO4), and filtered under vacuum to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. CHCl2 (20 mL × 3) was added and concentrated several times. The oil was dissolved in CHCl2 (4 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 5–6 hours. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a brown oil. CHCl2 (20 mL × 3) and EtOAc (20 mL × 3) were added and concentrated several times. The oil was dried under vacuum with an oil pump to give (±)-I-11. The above (±)-I-11 sample was dissolved in 2 mL of EtOAc, and a solution of p-TsOH·HO (0.19 g, 1.0 mmol in 2.5 mL of EtOAc) was added dropwise (an off-white solid gradually precipitated). After the addition was complete, 2.5 mL of EtOAc was added to ensure smooth stirring, and the mixture was stirred at room temperature for 1 h. The solid was collected by suction filtration and dried under vacuum with an oil pump to give 0.26 g (77%) of the p-toluenesulfonic acid salt of compound (±)-I-11 (white solid), melting at 193.0 °C–188.5 °C. 1H NMR (CD3OD, 500 MHz) δ: 7.70 (d, 2H, J = 8.5 Hz), 7.23 (d, 2H, J = 8.0 Hz), 6.43-6.44 (m, 1H), 6.31-6.33 (m, 1H), 3.07 (d, 1H, J = 13.0 Hz), 3.02-3.03 (m, 1H), 2.99 (d, 1H, J = 13.0 Hz), 2.89-2.95 (m, 1H), 2.84-2.86 (m, 1H), 2.74 (d, 1H, J = 17.0 Hz), 2.70 (d, 1H, J = 17.0 Hz), 2.46 (ddd, 1H, J = 1.5 Hz, 4.5 Hz and 9.0 Hz), 2.37 (s, 3H), 1.75 (ddd, 1H, J = 1.8 Hz, 8.5 Hz and 12.8 Hz), 1.61-1.63 (m, 1H), 1.44 (dd, 1H, J = 6.5 Hz and 12.5 Hz), 1.16-1.18 (m, 1H); 13 C NMR (CD3OD, 126 MHz) 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; ESI-HRMS: (m / z) C 12 H 18 NO2 ([M(free base) + H] + ) calculated value: 208.1332, measured value: 208.1331.

[0207] Compound (±)-I-11 is a specific form of the compound of general formula I in the present application.

[0208] [Example 14] Synthesis of compound (±)-I-12

[0209] [ka] Step 1: Synthesis of compound (±)-61 Compound (±)-59 (0.50 g, 1.7 mmol) was dissolved in CHCl (3 mL) and 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 3–4 h. TLC monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to give a brown oil. CHCl (20 mL × 5) was then added and concentrated several times. The resulting oil was purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 3 / 7] to give an off-white solid. n-Hexane (3 mL) was added to the solid and slurried at room temperature for 1 h. The solid was collected by suction filtration and dried under vacuum in an oil pump to give 0.32 g (79%) of compound (±)-61 (white solid), melting at 91.4–93.8 °C. 1 H NMR (DMSO-d6, 500 MHz) δ: 12.33 (brs, 1H), 6.47-6.49 (m, 1H), 6.32-6.34 (m, 1H), 4.58 (d, 1H, J = 13.0 Hz), 4.52 (d, 1H, J = 13.0 Hz), 2.91-2.93 (m, 1H), 2.84-2.88 (m, 1H), 2.80-2.82 (m, 1H), 2.59 (d, 1H, J = 16.5 Hz), 2.55 (d, 1H, J = 17.0 Hz), 2.44-2.47 (m, 1H), 1.76 (ddd, 1H, J = 1.8 Hz, 8.3 Hz and 12.8 Hz), 1.47-1.49 (m, 1H), 1.40 (dd, 1H, J = 6.5 Hz and 13.0 Hz), 1.06-1.09 (m, 1H); 13 C NMR (DMSO-d6, 126 MHz) 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; ESI-HRMS: (m / z) C 12 H 16 NO4([M+H]+ ) calculated value: 238.1074, measured value: 238.1072.

[0210] Step 2: Synthesis of compound (±)-I-12 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 reaction vessel was purged with hydrogen (balloon) according to standard procedures and stirred overnight at room temperature. TLC monitoring indicated the reaction was complete (the reaction was usually completed within 12 h). The solid was removed by suction filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a white solid. A 1 / 3 (v / v) CH3OH / EtOA mixture (3 mL) was added and stirred at room temperature for 1 h. The solid was collected by suction filtration and dried to give the desired product (±)-I-12 (white solid), 0.05 g (19%), melting point 153.2 °C–157.3 °C. 1 H NMR (CD3OD, 500 MHz) δ: 3.17 (d, 1H, J = 13.5 Hz), 3.14 (d, 1H, J = 13.5 Hz), 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 = 7.5 Hz and 12.5 Hz), 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); 13 C NMR (CD3OD, 126 MHz) 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) C 12 H 20 NO2([M+H] + ) calculated value: 210.1489, measured value: 210.1485.

[0211] Compound (±)-I-12 is a specific form of the compound of general formula I in the present application.

[0212] [Example 15] Synthesis of compound (±)-I-13

[0213] [ka] Step 1: Synthesis of compound 62 While cooling and stirring in an ice-water bath, 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 sequentially added to deionized water (8.25 L) and stirred (the solution turned orange-red). After the internal temperature of the system stabilized at 10 °C, a solution of acrolein diethyl acetal (500.00 g, 3.84 mol) in THF (768 mL) was slowly added dropwise (the internal temperature was confirmed to be no higher than 20 °C, and the color of the system changed from orange-red to pale yellow). After the addition was complete, the system was stirred overnight at room temperature. TLC monitoring indicated the reaction was complete. The reaction was then quenched. The reaction solution was poured into CHCl2 (8 L) and stirred. The organic phase was separated, and the aqueous phase was re-extracted with CHCl2 (8 L). The organic phases were combined, washed with saturated brine (5 L), dried (MgSO4), and suction filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator (low temperature 30 °C) to give a pale yellow oil. The oil was purified by vacuum distillation. The fractions with a head temperature of approximately 60 °C / 30 mmHg were collected to give 183.50 g (49%) of the desired product 62 (a clear, colorless oil). 1 H NMR (CDCl, 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 step without further purification.

[0214] Step 2: Synthesis of compound 63 Preparation of Jones Reagent: A reaction vessel was charged with water (267 mL) and cooled in an ice-water bath. CrO (122.83 g, 1.23 mol) was added in small portions under stirring to form an orange-red suspension, and then concentrated HSO (131 mL) was added dropwise slowly. After the addition was complete, the solution was stored for later use.

[0215] 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 (during the addition, a green solid was generated and the solution color changed from blue-green to dark green). TLC monitoring was performed during the addition. After TLC monitoring showed the reaction was complete, the addition was immediately stopped. n-Pentane (400 mL) was added to the reaction mixture to dilute it, and it was washed with water (400 mL). The aqueous phase was back-extracted with n-pentane (250 mL × 2). The combined organic phases were washed sequentially with 10% sodium sulfite solution (200 mL) and saturated brine (200 mL × 3), dried (MgSO4), and filtered under suction to remove the drying agent. The filtrate was first separated under atmospheric pressure to remove n-pentane (top temperature 36 °C–38 °C), and then distilled under reduced pressure. The fraction between 58°C and 60°C / 30 mmHg was collected (the receiving bottle was placed in liquid nitrogen for cryogenic protection) to give 26.42 g (22%) of the target compound 63 (a pale yellow oil). 1 H NMR (CDCl, 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). The product contained a certain amount of n-pentane and was used directly in the next step without further purification.

[0216] Step 3: Synthesis of compound 64 Compound 63 (26.42 g, 0.27 mol) was dissolved in n-pentane (1.5 L) in a quartz vessel, and the air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. The reaction apparatus was placed in a dark place, stirred, and irradiated with a UV lamp (365 nm, 15 W × 6) at room temperature for 7–14 days (the solution color changed from colorless to reddish purple, then faded to light purple). During the reaction, a small amount of viscous polymer by-product was produced and adhered to the inner wall of the reaction vessel. Every 2–3 days, activated carbon (10 g) and diatomaceous earth (10 g) were added, the mixture was stirred for 10 minutes, and the polymer was removed by suction filtration. The filtrate was then reintroduced into the reaction vessel according to the procedure described above. The reaction was stopped when TLC monitoring indicated that a small amount of starting material remained. The reaction solution was concentrated to half its original volume using a rotary evaporator under reduced pressure (<30 °C), and Br2 was slowly added dropwise to the system until Br2 disappeared (the solution was pale orange). A 10% sodium thiosulfate solution (200 mL) was then added and stirred to decompose excess Br2, at which point the solution faded to colorless. The organic phase was separated, dried (MgSO4), and suction filtered to remove the drying agent. The filtrate was concentrated on a rotary evaporator under reduced pressure (<30 °C for concentration) to give an oil, which was then concentrated with CH3OH (20 mL) to give 6.61 g of crude target compound 64 (a pale yellow oil). The product was used directly in the next reaction without further characterization.

[0217] Step 4: Synthesis of compound 65 Compound 64 (16.00 g, 0.17 mol) was dissolved in CH3OH (320 mL) and 4-methylbenzenesulfonhydrazide (31.00 g, 0.17 mol) was added. The reaction vessel was purged with nitrogen (balloon) according to standard procedures and then refluxed overnight. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure on a rotary evaporator to give a yellow oil. The oil was dissolved in CHCl2 (500 mL) and washed sequentially with 1 M HCl (400 mL × 6) and saturated brine (200 mL), dried (MgSO4), and filtered with suction to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a yellow oil. n-Hexane (50 mL × 2) was added and concentrated several times to give a yellow solid. EtOAc (3 mL) / n-hexane (30 mL) was added to the solid and slurried at room temperature for 1 hour. The solid was collected by suction filtration and dried under oil pump vacuum to give 17.09 g of compound 65 (a pale yellow solid) (combined yield of 63→65 was 10%), melting at 174.7° C.-177.6° C. 1 H NMR (CDCl3, 500 MHz) δ: 7.86 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0 Hz), 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); 13 C NMR (CDCl3, 126 MHz) δ: 168.36, 144.10, 135.67, 129.74, 128.18, 49.53, 42.05, 36.29, 32.91, 21.76.

[0218] Step 5: Synthesis of Compound 66 Compound 65 (4.23 g, 19 mmol) was dissolved in dry THF (50 mL), and the air in the reaction vessel was replaced with nitrogen (balloon) according to standard procedures. CH3Li (1.6 M solution in diethoxymethane, 42 mL, 67.2 mmol) was slowly added dropwise to the system while stirring in an ice-water bath. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. TLC monitoring indicated the reaction was complete. Water (10 mL) was added to the system in an ice-water bath to quench the reaction. The reaction solution was poured into ice-water (200 mL) and extracted with n-pentane (100 mL × 3). The combined organic phases were washed with 1 M HCl (100 mL × 2) and saturated brine (100 mL), dried (MgSO4), and filtered under vacuum to remove the drying agent. The filtrate was subjected to atmospheric pressure separation to remove the solvent, thereby yielding the crude product of target compound 66 (1.52 g). The product was used directly in the next reaction without further purification.

[0219] Step 6: Synthesis of compound (±)-67 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) sequentially at room temperature. 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 at room temperature with stirring. Heat was generated from the system during the addition, and the internal temperature was maintained between 30 and 35 °C by controlling the addition rate. After the addition was complete, the reaction vessel was placed in an oil bath and stirred at 35 °C for 2 h. Dry n-hexane (50 mL) was then added, stirred thoroughly, and the reaction was allowed to proceed overnight at room temperature. TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and poured into ice water (200 mL). The organic phase was separated and washed successively with 1 M HCl (50 mL), water (200 mL), saturated NaHCO solution (100 mL × 2), and saturated brine (100 mL), dried (MgSO), and filtered under suction to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give 1.89 g of crude compound (±)-67 (dark red oil). The product was used directly in the next step without further purification.

[0220] Step 7: Synthesis of compound (±)-68 Zinc powder (3.23 g, 49 mmol) and glacial acetic acid (20 mL) were mixed with stirring, and a solution of freshly prepared compound (±)-67 (1.89 g, 9.9 mmol) in glacial acetic acid (5 mL) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred overnight in a 55 °C oil bath under a N atmosphere. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was diluted with CHCl (200 mL) and washed successively with water (200 mL × 3), saturated NaHCO solution (200 mL), and saturated brine (200 mL), dried (MgSO), and filtered under vacuum to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 20] to give 0.31 g of crude compound (±)-68 (dark brown oil), which was used directly in the next reaction without further purification.

[0221] Step 8: Synthesis of compound (±)-69 Under a N2 atmosphere, t-BuOK (1.42 g, 13 mmol) was added to dry THF (5 mL) and stirred in an ice-water bath to form a suspension. Then, tert-butyl diethylphosphonoacetate (3.20 g, 13 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed in an ice-water bath for 1 hour, and then a solution of freshly prepared compound (±)-68 (0.31 g, 2.5 mmol) in dry THF (10 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 mixture was poured into ice-water (100 mL), stirred, and extracted with CHCl (30 mL × 3). The organic phases were combined by extraction, washed with saturated brine, dried (MgSO), and filtered under vacuum to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 12] to give 0.40 g of crude compound (±)-69 (dark brown oil), which was used directly in the next reaction without further purification.

[0222] Step 9: Synthesis of compound (±)-70 Compound (±)-69 (0.40 g) was dissolved in CH3NO2 (10 mL) and stirred at room temperature. DBU (3.0 g) was added dropwise. After the addition was complete, the reaction mixture was refluxed under a N2 atmosphere for 1 week. TLC monitoring indicated that a large amount of unreacted starting material remained. The reaction was then quenched. The reaction solution was cooled to room temperature, poured into ice water (100 mL), and extracted with C2Cl2 (50 mL × 2). The combined organic phases were washed with ice water (100 mL) and saturated brine (150 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to give 0.10 g of the desired product (±)-70 (pale yellow oil). 1 H NMR (acetone-d6, 500 MHz) δ: 4.77 (d, 1H, J = 12.0 Hz), 4.65 (d, 1H, J = 12.0 Hz), 2.65 (d, 1H, J = 18.5 Hz), 2.57 (d, 1H, J = 18.5 Hz), 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); ESI-HRMS: (m / z) C 15 H 24 NO4([M+H] + ) calculated value: 282.1700, measured value: 282.1702.

[0223] Step 10: Synthesis of compound (±)-71 Compound (±)-70 (78 mg, 0.28 mmol) was dissolved in CHCl (1 mL) and TFA (0.5 mL) was added dropwise slowly under ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 hours. TLC monitoring indicated the reaction was complete. The reaction mixture was poured into ice-water (5 mL) and extracted with CHCl (2 mL × 3). The combined organic phases were washed with saturated brine (2 mL × 2), dried (MgSO), and filtered to remove the drying agent. The filtrate was concentrated on a rotary evaporator to give a yellow oil. The oil was purified by column chromatography [V(EtOAc) / V(n-hexane) = 1 / 5 → 1 / 0] to give the desired product (±)-71 (colorless oil) 32 mg (51%). 1 H NMR (acetone-d6+D2O (1 drop), 500 MHz) δ: 4.70 (d, 1H, J = 11.5 Hz), 4.53 (d, 1H, J = 11.5 Hz), 2.61 (d, 1H, J = 19.0 Hz), 2.55 (d, 1H, J = 18.5 Hz), 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); ESI-HRMS: (m / z) C 11 H 16 NO4([M+H] + ) calculated value: 226.1074, measured value: 226.1070.

[0224] Step 11: Synthesis of compound (±)-I-13 Compound (±)-71 (25 mg, 0.11 mmol) was dissolved in CHOH (0.5 mL) and 10% Pd(OH) / C (5 mg) was added. The reaction vessel was purged with hydrogen (balloon) according to standard procedures and stirred overnight at room temperature. TLC monitoring indicated the reaction was complete (typically within 12 h). The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to give a white solid. EtOAc (0.5 mL) was added and the mixture was stirred at room temperature for 2 h to form a slurry. The solid was collected by suction filtration and dried to give the desired product (±)-I-13 (white solid), 11 mg (51%). 1 H NMR (CD3OD+D2O (1 drop), 500 MHz) δ: 3.06 (s, 2H), 2.67 (d, 1H, J = 18.0 Hz), 2.43 (d, 1H, J = 18.0 Hz), 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); ESI-HRMS: (m / z) C 11 H 18 NO2([M+H] + ) calculated value: 196.1332, measured value: 196.1341.

[0225] Compound (±)-I-13 is a specific form of the compound of general formula I in the present application.

[0226] [Examples 16 to 21] The compounds in the following table were synthesized with reference to the methods of Examples 1 to 15.

[0227] [Table 3]

[0228] [Example 22]

[0229] [Table 4] Preparation method: The (±)-I-3 sample was crushed and sieved for later use. The (±)-I-3 sample, lactose, and pregelatinized starch were added according to the above-mentioned proportions and premixed for 15 minutes. Disodium hydrogen phosphate and polyvinylpyrrolidone were added according to the proportions and mixed for 10 minutes. Talc powder was added according to the proportions and mixed for 30 minutes. The mixed material was filled into capsules according to the specifications to prepare (±)-I-3 capsules.

[0230] [Example 23]

[0231] [Table 5] Preparation method: (±)-I-4 sample and pregelatinized starch were sieved and thoroughly mixed. Polyvinylpyrrolidone solution was added and mixed to prepare a soft substance. The soft substance was sieved and dried at 80°C to prepare wet granules. Carboxymethyl starch sodium salt, microcrystalline cellulose, and magnesium stearate were sieved in advance and then added to the above granules, mixed uniformly, and compressed into tablets.

[0232] [Example 24]

[0233] [Table 6] Preparation method: First, add water for injection and (+)-I-3 sample, stir to dissolve, adjust the pH to 5.0-7.0 with NaOH and hydrochloric acid, add 0.3 g of activated carbon, stir at room temperature for 30 minutes, filter through a microporous filter membrane to obtain the filtrate, determine the concentration of the solution by central control, fill the solution into 5 mL per ampoule, and sterilize at 100°C for 30 minutes to obtain the injection.

[0234] [Example 25]

[0235] [Table 7] Preparation process: (-)-I-3 sample, sucrose, cross-linked povidone, and carboxymethylcellulose were each sieved through a 100-mesh sieve, and sucrose laurate was prepared in ethanol at 60°C to a 25% concentrated solution for later use. The above ingredients were weighed according to the formulation amount, thoroughly fluidized, and mixed. 25% sucrose laurate was then added to prepare a soft substance, which was then dried at 55°C and pelletized through a 20-mesh sieve. The mixture was granulated through a 12-mesh sieve, and silica, aspartame, and apple extract were added. The bag was weighed and packaged.

[0236] [Example 26]

[0237] [Table 8] Preparation method: 80 mL of water for injection was weighed, and the (+)-I-4 sample, mannitol, and lactose were added and stirred to dissolve. Then, 1 mol / L citric acid and 1 mol / L sodium hydroxide were added to adjust the pH to 5.0-7.0, and water was added to make 100 mL. 0.5 g of activated carbon was added, and the mixture was stirred at 30°C for 20 minutes to decarbonate. A microporous filter membrane was used for filtration and sterilization. The filtrate was divided into 1 mL aliquots per tube, pre-frozen at -40°C for 5 hours, and lyophilized under reduced pressure (pressure <20 Pa) for 12 hours. After lyophilization was complete, the sample was allowed to return to room temperature and then dried for 5 hours to produce a white, loose mass, which was obtained after sealing.

[0238] [Example 27]

[0239] [Table 9] Preparation method: The above-mentioned amount of malic acid was dissolved in 25 mL of purified water, and the above-mentioned amount of chitosan was added and thoroughly stirred to completely dissolve. An appropriate amount of 1 mol / L sodium bicarbonate solution was weighed and added to the above-mentioned solution to quickly neutralize it, and the pH value of the chitosan solution was adjusted to 5.0-7.0 for later use. Next, the above-mentioned amount of acesulfame and strawberry essence was added to 40 mL of purified water and stirred to dissolve. Next, the above-mentioned amount of (+)-I-3 sample was added and stirred to dissolve. Next, the above-mentioned prepared chitosan solution was added and stirred uniformly. The remaining amount of purified water was added to the mixed solution and stirred to uniformly mix, resulting in a (+)-I-3 oral solution with a pH of 5.0-7.0.

[0240] [Example 28] In vitro binding of compounds to the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1 The voltage-gated calcium ion channel α2δ subunit has four subtypes: α2δ-1, α2δ-2, α2δ-3, and α2δ-4. Of these, 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 provides a direct indicator for measuring the analgesic effect on chronic neuropathic pain (Calandre, EP et al.; Expert Rev. Neurother. 2016, 16, 1263-1277).

[0241] The in vitro binding strength of the compounds of the present application to the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1 was measured essentially according to a previously published method (Gee, NS et al.; J. Biol. Chem. 1996, 271, 5768-5776; Marais, E. et al.; Mol. Pharmacol. 2001, 59, 1243-1248). CHO cells expressing the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1 were used for the test. After the cell membrane was separated by a conventional method, 3 μg of cell membrane was added to each well containing modified HEPES / KOH buffer (pH 7.4) as the test solution. Then, 5 nM [ 3 [H]gabapentin and six concentrations (3, 9, 27, 81, 243, and 729 nM) of test compound were added, and the test system was incubated at 25°C for 120 minutes. Nonspecific binding was obtained by replacing the test compound with 10 μM gabapentin in the above test system. After the incubation was completed, the cell membranes were collected by filtration, washed with 50 mM Tris-HCl (pH 7.4), and then bound to the cell membranes. 3 The radioactivity of [H] gabapentin was tested by liquid scintillation counting. 3 H]gabapentin competitively bound to the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1. 3 The binding inhibition rate of [H]gabapentin to the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1 was calculated according to the following formula: Inhibition rate = [(II U ) / (I0-I U )] × 100% During the ceremony, I is the test compound and 3 H] is the radioactivity corresponding to simultaneous co-incubation of gabapentin with the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1. I0 is the time when the test compound is not added to the incubation system [ 3H] is the radioactivity corresponding to the co-incubation of gabapentin and the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1, I U 10 μM gabapentin and [ 3 H] is the radioactivity corresponding to simultaneous co-incubation of gabapentin with the human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1.

[0242] Human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1 3 The concentration of the test compound that inhibits 50% of the binding of [H]gabapentin is defined as IC 50 The IC was calculated by nonlinear least squares regression analysis using the above inhibition rate. 50 was calculated (MathIQ®, ID Business Solutions Ltd., UK). The test results are shown in the table below.

[0243] [Table 10]

[0244] As can be seen from the activity data of this example, the compound of general formula I in the present application has good activity in binding to human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1, and can be used to prepare therapeutic drugs for chronic neuropathic pain, epilepsy and anxiety.

[0245] Gamma-aminobutyric acid drugs acting on voltage-gated calcium ion channel α2δ-1 ligands, such as gabapentin and pregabalin, have analgesic effects on chronic neuropathic pain, as well as other effects, such as antiepileptic effects (pregabalin, approved by the US FDA) and anxiolytic effects (pregabalin, approved by the European Medicines Agency). These effects are related to the binding of the drug to the voltage-gated calcium ion channel α2δ-1 ligand. Therefore, the compounds of general formula I in the present application can also be used to prepare therapeutic drugs for epilepsy and anxiety.

[0246] [Example 29] Analgesic effects of compounds in a rat model of chronic neuropathic pain Representative compounds of the present application, (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate, were orally administered at 30 mg / kg to Sprague-Dawley (SD) rats in a SNI model, and pharmacodynamic evaluation was performed.

[0247] Establishment of the SNI model: Surgery was performed according to aseptic surgical techniques. Various surgical instruments, including scalpels, tweezers, suture needles / threads, and surgical cotton, were sterilized before surgery. The animals were anesthetized by intraperitoneal injection of 50 mg / kg of Zoletil® 50 solution and positioned in a lateral decubitus position. The surgical site on the animal's lower body was shaved and then disinfected with alternating iodophor and 75% alcohol. The skin at the top of the left hind paw was incised, and the muscles were smoothly separated to expose the sciatic nerve trunk and its three branches: the tibial nerve, common peroneal nerve, and peroneal nerve. The tibial nerve and common peroneal nerve were ligated and severed, while the peroneal nerve was preserved. After surgery, the wound was sutured in layers, and 25% ampicillin (1 mL / kg) was administered intraperitoneally to prevent infection. The animals received standard nursing care. In the sham group, only the sciatic nerve and its nerve branches were exposed, and the nerve was not ligated or cut, but the other operations were the same as those in the model group.

[0248] Mechanical pain threshold detection: Using a von Frey test fiber, the mechanical pain threshold of each animal's plantar paw on the operated side was measured on days 1, 3, and 7 after surgery. The "up-and-down" method was used to detect mechanical pain thresholds at stimulation intensities of 0.4, 0.6, 1, 2, 4, 6, 8, and 15 g. During testing, the test fiber was used to stimulate the lateral mid-plantar area of ​​the rat's left hind paw in a vertical direction for 6–8 seconds at 5-second intervals. Pain responses were indicated by the animal's apparent paw withdrawal, paw licking, or paw lift during each test. Starting on day 11 after surgery, the animals were placed in the experimental environment for acclimation, and the acclimation process was continued for 3 days, 15 minutes per day. On day 13, after acclimation was complete, the baseline mechanical pain hypersensitivity was measured. Mechanical pain hypersensitivity was expressed as the 50% paw withdrawal threshold (PWT), calculated as follows: 50% PWT (g) = 10 xf+kδwhere xf is the logarithm of the fiber test force, k is the nominal value, and δ is the average interval of the logarithm of the fiber test force.

[0249] Pharmacodynamic evaluation: Based on the results of the baseline threshold detection on postoperative day 13, animals in the model group without mechanical pain hypersensitivity (i.e., PWT >4 g) were excluded, and the remaining successfully modeled animals were used for formal testing. On postoperative day 14, various test compounds were newly formulated. Pregabalin was directly dissolved in 0.9% sodium chloride at a dose of 30 mg / kg to obtain a solution of the desired concentration. (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate salts were also completely dissolved in 0.9% sodium chloride at a dose of 30 mg / kg (free base equivalent). Successfully modeled animals were randomly divided into five groups, each with eight animals. Seven additional animals were selected for the sham group. After labeling and weighing, the various test drugs and vehicle (0.9% sodium chloride) were administered orally at a dose of 10 mL / kg. Mechanical hyperalgesia was detected in the left hind paw at 1, 2, 4, 6, 8, 10, and 24 hours after administration. Evaluation was performed blinded, and the detection method was the same as described above. The area under the mechanical pain threshold-time curve (AUC) was calculated using GraphPad Prism version 8.0.1 software. The analgesic intensity of rats in the SNI model was expressed as the maximum possible effect (MPE), where %MPE = [(AUC of the treatment group - AUC of the vehicle group) / (AUC of the sham group - AUC of the vehicle group)] × 100.

[0250] Results and Discussion: Data were expressed as mean ± standard error (SEM) and plotted using GraphPad Prism version 8.0.1 software. Data between groups were compared using one-way analysis of variance, with post-hoc testing performed using Dunnett's test. * is a significant difference (p<0.05), ** p<0.01, ***indicates p<0.001. The statistical results are detailed in the mechanical pain threshold-time chart (Figure 3A) and the area under the mechanical pain threshold-time curve chart (Figure 3B). As can be seen from the figure below, similar to the active drug pregabalin, (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate had varying degrees of inhibitory effects on mechanical pain hypersensitivity in SNI rats after administration at a dose of 30 mg / kg (free base equivalent). The area under the mechanical pain threshold-time curve in the (±)-I-7 and (±)-I-4 p-toluenesulfonate groups was significantly improved compared to the vehicle control group. The maximum possible efficacy (%MPE) of the four compounds, i.e., the positive drugs pregabalin, (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate, was 110.90%, 73.63%, 44.80%, and 95.95%, respectively. The results show that the representative compounds of the present application, (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonate, all have a certain degree of analgesic effect in the SNI model at a dose of 30 mg / kg (free base equivalent), and can be used to prepare therapeutic drugs for chronic neuropathic pain.

[0251] [Example 30] Analgesic effects of compounds in a rat model of chronic neuropathic pain The pharmacodynamics of (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate were evaluated in a Sprague-Dawley rat model of spinal cord injury (SNI) after oral gavage at 10 mg / kg (free base equivalent).

[0252] The model construction method and mechanical pain threshold detection method were the same as those in Example 29.

[0253] Pharmacodynamic evaluation: The specific detection method was the same as in Example 29. Various test compounds were freshly prepared 14 days after animal surgery. Pregabalin was directly dissolved in 0.9% sodium chloride at a dose of 10 mg / kg to obtain a solution of the desired concentration. Representative compounds of the present application, (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate, were used at a dose of 10 mg / kg (calculated as the free base) together with a vehicle containing 5% PEG 400 (polyethylene glycol 400) and 95% 0.9% sodium chloride. That is, they were first dissolved in 5% PEG 400 to a final volume, then added to 95% 0.9% sodium chloride solution to a final volume, and vortexed until fully dissolved. Successful modeling animals were randomly divided into five groups, each containing six animals. Additionally, five animals were selected as a sham group. After labeling and weighing, the animals were given various test drugs and a vehicle (5% PEG 400 + 95% 0.9% sodium chloride) at a volume of 10 mL / kg by oral gavage. Mechanical hyperalgesia was detected in the left hind paw at 1, 2, 4, 6, 8, 10, and 24 hours after administration. The evaluation was performed in a blinded manner, and the detection method was the same as above. The area under the mechanical pain threshold-time curve (AUC) and maximum possible effect (MPE) were calculated using the same method as in Example 29.

[0254] Results and Discussion: Data are expressed as mean ± standard error of the mean and plotted using GraphPad Prism version 8.0.1 software. Data between groups were compared by one-way analysis of variance, followed by post-hoc testing using Dunnett's test. * is a significant difference (p<0.05), ** p<0.01, ***indicates p<0.001. The statistical results are shown in detail in the mechanical pain threshold-time chart (FIG. 4A) and the area under the mechanical pain threshold-time curve chart (FIG. 4B). As can be seen from FIGS. 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, all exhibited varying degrees of inhibitory effects on mechanical pain hypersensitivity in nerve injury-preserved model rats after oral gavage at a dose of 10 mg / kg (free base equivalent). Among these, the area under the mechanical pain threshold-time curve in the (+)-I-4 p-toluenesulfonate group was significantly improved compared to that in the vehicle control group, and this effect was significantly greater than that of the active drug pregabalin at 10 mg / kg. The maximum possible effects (MPE) 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, exhibit superior analgesic effects in the rat SNI model and can be used to prepare therapeutic drugs for chronic neuropathic pain; and (2) the analgesic activity of the compound (+)-I-3 p-toluenesulfonate is higher than that of (-)-I-3 p-toluenesulfonate, and the analgesic activity of the compound (+)-I-4 p-toluenesulfonate is higher than that of (-)-I-4 p-toluenesulfonate, suggesting that the analgesic activity of the compounds of the present application is stereochemically dependent. The results of the in vitro binding studies of (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate in Example 28 are consistent with these conclusions.

[0255] [Example 31] Antiepileptic effects of compounds in a mouse epilepsy model (maximal electroshock model (MES)) A negative vehicle control group, a positive drug control group (pregabalin and gabapentin), and a test group for the compound of the present invention were established. Male ICR mice weighing 22±2 g were selected. Both test and control drugs were dissolved in 10% saline solution of 1,2-propanediol (95% v / v) supplemented with DMSO (5% v / v) and administered orally at a volume of 10 mL / kg. After a 12-hour fast, the mice were administered the compound of the present invention or a control drug according to their body weight. After a set time (2 hours for pregabalin, 1 hour for gabapentin, and 3 hours for the compound of the present invention), electrical stimulation was administered to induce generalized tonic-clonic seizure behavior. The induction model was performed using a YLS-9A electrophysiological stimulator (Shanghai Xinruan Information Technology Co., Ltd.) with the following parameters: configuration 8, stimulation voltage 160 V, and wave number 90. For electrical stimulation, both ears of the mice were first wiped with saline, and then a single electrical stimulation was administered using ear clip electrodes. Tonic extension of the hind paws was used as the criterion for epileptic seizures. Animals showing tonic extension of the hind paws were considered to be unprotected by the drug, while animals without tonic extension of the hind paws were considered to be protected by the drug. The animal's response was observed and recorded, and the data obtained were compiled to calculate the protection rate of the compound.

[0256] The test results are shown in the following table.

[0257] [Table 11]

[0258] Median effective dose (ED) of the test compound for animal protection 50 ) was calculated by the least squares method (Graphpad Prism 5) using the dose-protection rate curve. The fitting curve is shown in Figure 5.

[0259] As a result of calculation, the ED of (+)-I-3 50EDTA of (+)-I-4 was 6.52 mg / kg. 50 was 21.51 mg / kg, and the ED of pregabalin 50 The results above indicate that (+)-I-3 and (+)-I-4, which are representative compounds of the present application, exhibit potent antiepileptic effects in the maximal electroshock model in mice and can be used to prepare antiepileptic drugs.

[0260] [Example 32] Antiepileptic effects of compounds in a mouse epilepsy model (6Hz psychomotor seizure model) A negative vehicle control group, a positive drug control group (pregabalin and gabapentin), and a test group for the compounds of the present application were established. Male C57BL / 6 mice weighing 20±2 g were selected. Both test and control drugs were dissolved in 10% saline solution of 1,2-propanediol (95% v / v) supplemented with DMSO (5% v / v) and administered orally by gavage at a volume of 10 mL / kg. After a 12-hour fast, the mice were administered the compounds of the present application or control drugs. Then, after a set time period (2 hours for pregabalin, 1 hour for gabapentin, 1 hour for levetiracetam, and 3 hours for the compounds of the present application), epileptic seizure behavior was induced by 6 Hz electrical stimulation. In the induction model, stimulation was performed using a Model 4100 stimulator (AM Systems, the United States). The mouse's back of the neck was manually fixed in a feeding cage. Corneal electrodes moistened with saline were lightly contacted to both corneas of the mouse, and the mouse was then electrically stimulated with a foot on the stimulator. Stimulation parameters were 6 Hz, unidirectional square wave 32 mA, pulse width 0.2 ms, and duration 3 s. The stimulation was timed with a stopwatch. After the end of electrical stimulation, mice exhibiting seizure behavior for less than 7 s were considered to be protected from epilepsy by the drug, while mice exhibiting seizure behavior for more than 7 s were considered not to be protected from epilepsy by the drug. The animal's response was observed and recorded, and the data obtained were compiled to calculate the protection rate of the compound.

[0261] Statistical Methods: The protection rates of the various treatment groups were compared with the vehicle control group, respectively, and Fisher's exact probability test was performed.

[0262] The test results are shown in the table below.

[0263] [Table 12]

[0264] The above results indicate that the representative compounds of the present application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, exhibit very strong antiepileptic effects in a mouse epileptic seizure model induced by 6 Hz electrical stimulation, and can be used to prepare antiepileptic drugs.

[0265] [Example 33] Antiepileptic effects of compounds in a mouse epilepsy model (subcutaneous injection of pentylenetetrazole (sc-PTZ) model) A negative vehicle control group, a positive drug control group (pregabalin and gabapentin), and a test group for the compounds of the present application were established. Male ICR mice weighing 22±2 g were selected. Both test and control drugs were dissolved in 10% saline solution of 1,2-propanediol (95% v / v) supplemented with DMSO (5% v / v) and administered intraperitoneally at a dose of 10 mL / kg. After a 12-hour fast, the mice were administered the compounds of the present application or control drugs. Then, after a set time (2 hours for pregabalin, 1 hour for gabapentin, and 3 hours for the compounds of the present application), pentylenetetrazole (PTZ) was subcutaneously injected to induce epileptic seizure behavior. In the induction model, pentylenetetrazole (PTZ) was dissolved in saline and administered to the mice via subcutaneous injection (10 mL / kg, dose 100 mg / kg). After PTZ injection, the behavior of the mice was observed for 1 hour, and the latency and number of mice that developed convulsive seizures, clonic seizures, tonic seizures, and died after PTZ injection were recorded.

[0266] Statistical methods: The protection rate and mortality rate of various treatment groups were compared with the vehicle control group, respectively, using Fisher's exact probability test. The seizure duration and latency were analyzed by one-way analysis of variance.

[0267] The test results are as follows:

[0268] [Table 13]

[0269] Subcutaneous injection of pentylenetetrazole (PTZ) induces severe convulsive behavior in mice. In the vehicle control group, 8 / 8 mice (100%) developed generalized clonic seizures, 6 / 8 mice (75%) developed generalized tonic-clonic seizures, and 6 / 8 mice (75%) died. The positive control, pregabalin (PGB), tended to reduce generalized clonic seizures (100% → 62.5%), significantly reducing the incidence of tonic seizures (75% → 12.5%) and mortality (75% → 12.5%). (+)-I-3 p-toluenesulfonate tended to reduce generalized clonic seizures (100% → 60%), significantly reducing the incidence of tonic seizures (75% → 0%) and mortality (75% → 0%). (+)-I-4 p-toluenesulfonate showed a trend toward a reduction in generalized clonic seizures (100% → 60%), and also a trend toward a reduction in the incidence of tonic seizures (75% → 20%) and mortality (75% → 30%). Gabapentin (GBP) did not significantly improve seizure incidence or mortality at this dose.

[0270] For the representative compounds of this application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, as well as the control drugs, the latency period at a certain stage was defined as the time from subcutaneous injection of pentylenetetrazole to the onset of various epilepsy-related phenomena in the above test. As shown in Figure 6, pregabalin (PGB), (+)-I-3 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate significantly prolonged the latency periods for generalized clonic seizures, tonic seizures, and death at a dose of 30 mg / kg (free base equivalent), while gabapentin (GBP) had no effect at this dose.

[0271] The above results indicate that the representative compounds of the present application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, have potent inhibitory effects on epileptic seizures and death due to epilepsy in a mouse epilepsy model induced by subcutaneous injection of pentylenetetrazole, and can be used to prepare antiepileptic drugs.

[0272] [Example 34] Pharmacokinetic study of compounds in rats Male SD rats were fasted for 12 hours before the test and then allowed to drink water ad libitum. The compounds of the present application, (+)-I-3 p-toluenesulfonate or (+)-I-4 p-toluenesulfonate, were dissolved in 10% distilled water of 1,2-propanediol and administered orally or intravenously to three male SD rats per group. At 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after oral administration, or at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after intravenous administration, 0.2 mL of blood was collected from the retroorbital venous plexus, placed in EDTA-K2 test tubes, and centrifuged at 11,000 rpm for 5 minutes to separate plasma, which was then frozen in a refrigerator at -20°C. The concentrations of the drug prototypes were measured by HPLC-ESI-MS according to a validated method, and pharmacokinetic parameters were calculated using WinNonLin. The results are shown in the table below.

[0273] [Table 14]

[0274] As can be seen from the above data, the representative compounds of the present application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, are rapidly absorbed after oral administration and exhibit very high bioavailability, making them suitable for oral administration.

[0275] [Example 35] Testing the effects of compounds on motor function in rats All test drugs were dissolved in 10% saline solution of 1,2-propanediol (95% v / v) containing DMSO (5% v / v) and administered orally at a volume of 10 mL / kg. A negative vehicle control group, a positive drug control group (pregabalin (PGB) at 10 mg / kg and 30 mg / kg), and test groups ((+)-I-3 p-toluenesulfonate 10 mg / kg (free base equivalent), (+)-I-4 p-toluenesulfonate 10 mg / kg (free base equivalent), (+)-I-3 p-toluenesulfonate 30 mg / kg (free base equivalent), and (+)-I-4 p-toluenesulfonate 30 mg / kg (free base equivalent)) were established. Male SD rats weighing 200–250 g were selected, with 10 rats per treatment group. The rotarod test apparatus used was a YLS-31A fatigue rotarod (Shanghai Xinruan Information Technology Co., Ltd.), with a constant rotation speed of 6 rpm. A screening test was conducted on day 1. The rats were placed on the rotarod by pinching the tip of their tails. After the rats maintained their balance on the rotarod and moved in sync with the rotarod, the tails were released. The number of rats that fell within the next minute was recorded and counted. Rats that fell three times within one minute were excluded and not used for subsequent drug evaluation. A drug evaluation test was conducted on day 2. The rats were fasted for 8 hours before the test, and then a single rotarod test was conducted as a pre-dose time point (BL), followed by drug administration via force-feeding. The rotarod test was conducted once each at 1, 2, 4, 6, 8, 10, and 24 hours after administration. The number of rat falls per minute was recorded and counted. Rats that fell three times within one minute were considered to have "motor dysfunction" due to drug toxicity. The degree of "motor dysfunction" (rotarod falls) at a particular time point in each treatment group was calculated as the number of animals with "motor dysfunction" in the group as a percentage of the total number of animals in the group.

[0276] The test results are shown in Figure 7.

[0277] The rotarod test is a classic test for measuring the impairment of a compound on the motor function of animals. The rat rotarod test was used to evaluate the effects of the representative compounds of the present application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, on rat motor function. As can be seen from Figure 7, at a dose of 10 mg / kg (free base equivalent), (+)-I-3 p-toluenesulfonate, (+)-I-4 p-toluenesulfonate, and the control group, pregabalin (PGB), had no significant effect on the rats' rotarod behavior. At a dose of 30 mg / kg (free base equivalent), the PGB group showed a clear toxic reaction, with the greatest effect on the rats' rotarod behavior 4 hours after administration. The (+)-I-3 p-toluenesulfonate group and the (+)-I-4 p-toluenesulfonate group showed a smaller effect on the rats' rotarod behavior than the PGB group.

[0278] [Example 36] Acute toxicity test of compounds in rats The preliminary acute toxicity of (±)-I-7, (+)-I-3 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate in male SD rats was evaluated.

[0279] After a one-week acclimation period, SD rats were used in preliminary acute toxicity studies. Compounds were prepared fresh on the day of testing. Pregabalin and (±)-I-7 were directly dissolved in 0.9% sodium chloride to obtain solutions of the desired concentrations. (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate were used together with a vehicle of 95% 0.9% sodium chloride plus 5% PEG 400; that is, they were first dissolved in 5% PEG 400 to a final volume, then added to a final volume of 95% 0.9% sodium chloride solution, and vortexed until completely dissolved. Animals were labeled, weighed, and randomly assigned to groups of 2–4. Each test compound and vehicle (5% PEG 400 + 95% 0.9% sodium chloride) were administered orally by gavage at a volume of 10 mL / kg. Clinical signs of each animal were observed and recorded 0.5, 1, 2, 4, 6, and 24 hours after administration. Clinical signs were coded as follows: 0 (no abnormalities), 1 (mild tremor), 2 (unsteady gait), 3 (prone position), 4 (startle reflex), 5 (dyspnea), 6 (loss of righting reflex), 7 (eyelid closure), 8 (shortness of breath), and × (death of the animal).

[0280] Results and Discussion: The results are shown in the table below. When compound (+)-I-3 p-toluenesulfonate was administered by oral gavage at a dose of 164.5 mg / kg (free base equivalent) and (+)-I-4 p-toluenesulfonate at a dose of 163.8 mg / kg (free base equivalent), all animals in the two groups were consistent with the animals in the vehicle control group and showed no obvious abnormal behavior from 0 to 24 hours after administration. When (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate were administered by oral gavage at a dose of 300 mg / kg (free base equivalent), two animals in the (+)-I-3 p-toluenesulfonate group assumed a prone position just 1 hour after administration, one of which also showed mild tremors and closed eyelids. In the (+)-I-4 group, one animal assumed a prone position just 1 hour after administration, and the other animal assumed a prone position both 1 and 3 hours after administration. When another compound, (±)-I-7, was administered by oral gavage at a dose of 300 mg / kg (free base equivalent), each animal assumed a prone position 1 and 2 hours after administration, two of which also showed mild tremors. Twenty-four hours after administration, no obvious abnormalities were observed in any of the animals administered with (±)-I-7, (+)-I-3 p-toluenesulfonate, or (+)-I-4 p-toluenesulfonate, consistent with the results in the vehicle control group. The test results showed that oral administration of (+)-I-3 p-toluenesulfonate, a representative compound of the present application, at a dose of 164.5 mg / kg (free base equivalent), and (+)-I-4 p-toluenesulfonate at a dose of 163.8 mg / kg (free base equivalent) to male rats did not result in neurotoxicity. Combined with the doses for analgesic and antiepileptic effects disclosed in Examples 29-33 of the present application, it can be concluded that the representative compounds of the present application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, have a wide safety margin. Representative compounds of the present application, (±)-I-7, (+)-I-3 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate, can induce relatively obvious acute toxic reactions in animals at a high dose of 300 mg / kg (free base equivalent), but no animals died.

[0281] Table 15

Claims

1. A compound of general formula I, its chiral isomer or a pharmaceutically acceptable salt thereof 【Chemistry 1】 (In the formula, R 1 and R 2 H, halogens, and C 1 ~C 6 independently selected from alkyl, R 3 , R 4、 R 5 and R 6 are H, halogen, and C, respectively. 1 ~C 6 Alkyl, and C 1 ~C 6 alkoxy, or R 3 and R 4 together with the C atoms to which they are attached 3 ~C 6 Form a cycloalkyl or R 5 and R 6 together with the C atoms to which they are attached 3 ~C 6 forming a cycloalkyl, R 7 , R 8 , R 9 and R 10 are H, halogen, and C, respectively. 1 ~C 6 independently selected from alkyl, m and n are independently selected from 0, 1, 2, and 3; Alternatively, if n ≥ 1, then R 8 C atoms and R bonded to 10 The adjacent C atom bonded to R 8 and R 10 Together with C 3 ~C 6 can form a cycloalkyl, If n ≥ 1, R 8 C atom and R bonded to 10 The solid and dashed lines between adjacent C atoms bonded to R 8 C atom and R bonded to 10 represents that the chemical bond between the C atoms bonded to the 7 and R 9 does not exist).

2. R 1 and R 2 H and C 1 ~C 3 independently selected from alkyl, R 3 and R 4 H, halogens, and C 1 ~C 3 alkyl, or R 3 and R 4 together with the C atom to which they are attached to form a cyclopropyl group, R 7 , R 8 , R 9 and R 10 H and C 1 ~C 6 alkyl, or R 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 together to form a cyclopropyl R 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 represents that the chemical bond between the C atom bonded to R may be a single bond or a double bond, and when the chemical bond represents a double bond, R 7 and R 9 does not exist, m=0 and n=1, 2. A compound of general formula I according to claim 1, its chiral isomer, or a pharmaceutically acceptable salt thereof.

3. R 1 and R 2 is independently selected from H or methyl; R 3 and R 4 are independently selected from H and methyl, or R 3 and R 4 together with the C atom to which they are attached to form a cyclopropyl group, R 7 , R 8 , R 9 and R 10 are independently selected from H or methyl, or R 8 C atoms and R bonded to 10 The C atom bonded to R 8 and R 10 together to form a cyclopropyl R 8 C atom and R bonded to 10 The solid and dashed lines between the C atoms bonded to R 8 C atom and R bonded to 10 represents that the chemical bond between the C atom bonded to R may be a single bond or a double bond, and when the chemical bond represents a double bond, R 7 and R 9 does not exist, m=0 and n=1, 3. A compound of general formula I according to claim 1 or 2, a chiral isomer thereof, or a pharmaceutically acceptable salt thereof.

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

5. The following compounds: 【Chemistry 2】 3. A compound of general formula I according to claim 1 or 2, a chiral isomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

6. A method for preparing a compound of general formula I according to any one of claims 1 to 5, comprising: 1) Wittig condensation of ketone K and phosphonoacetate W1 in the presence of a base to give α,β-unsaturated acetate L-1; 【Transformation 3】 and a step of carrying out a Michael addition reaction of L-1 and nitromethane in the presence of a base to obtain M-1. 【Chemistry 4】 or 2) Knoevenagel condensation of ketone K and nitromethane in the presence of a catalyst to obtain α,β-unsaturated nitro compound L-2; 【Transformation 5】 and performing a Michael-like addition reaction of L-2 and acetate W2 in the presence of a strong base to obtain M-2. 【Transformation 6】 (In the formula, R 11 , R 12 and R 13 is C 1 ~C 6 alkyl, and R 1 ~R 10 , m and n have the definitions as set forth in any one of claims 1 to 5). A method comprising:

7. Use of the compounds of general formula I according to any one of claims 1 to 5, their chiral isomers, and their pharmaceutically acceptable salts in the preparation of a medicament for the treatment of chronic neuropathic pain, epilepsy, and anxiety.

8. A pharmaceutical composition comprising a compound of general formula I according to any one of claims 1 to 5, its chiral isomers, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable auxiliary substances, wherein the auxiliary substances are selected from one or more of carriers, diluents, and excipients.

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

10. 10. The pharmaceutical composition according to claim 9, wherein the solid oral formulations and liquid oral formulations include dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, granules, and oral liquids, and the injectable formulations include water for injection, lyophilized powder for injection, infusion solution, and small-volume parenteral solution.

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