Gamma-aminobutyric acid derivatives containing polycyclic structures, processes for their preparation and uses thereof

Abstract

The present application relates to the field of medicine. In particular, the present application relates to a class of voltage-gated calcium channel α2δ subunit ligands containing polycyclic gamma-aminobutyric acid structures of general formula I, to methods for their preparation, and to their use in the treatment of chronic neuropathic pain, epilepsy and anxiety.

Description

Technical Field

[0001] This application belongs to the field of pharmaceuticals. Specifically, this application relates to a class of voltage-gated calcium ion channel α2δ subunit ligands containing a polycyclic γ-aminobutyric acid structure, their preparation methods, pharmaceutical compositions containing them, and their uses in medicine. Background Technology

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

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

[0004] The α2δ subunit of voltage-gated calcium channels is an important target for drugs treating this disease. Pregabalin, one of the four FDA-approved drugs for diabetic peripheral neuropathy (pregabalin, duloxetine, fluoxetine, and tapentadol), targets this subunit (Field, MJ; et al. Proc. Natl. Acad. Sci. USA 2006, 103, 17537-17542). In addition to treating chronic neuropathic pain, voltage-gated calcium channel α2δ subunit ligands, such as gabapentin, pregabalin, and mirogabalin, can also be used for anti-epileptic purposes (pregabalin, FDA-approved indication) and anti-anxiety purposes (pregabalin, EMA-approved indication).

[0005] This application discloses a γ-aminobutyric acid derivative containing a polycyclic structure, which is related to […]. 3 The binding of H] gabapentin has a strong inhibitory effect on the α2δ subunit of human voltage-gated calcium ion channels, and can be used to prepare drugs for the treatment of chronic neuropathic pain, epilepsy and anxiety. Summary of the Invention

[0006] One object of this application is to provide a voltage-gated calcium ion channel α2δ subunit ligand having general formula I, its chiral isomers, and their pharmaceutically acceptable salts.

[0007] Another object of this application is to provide a method for preparing the above-described voltage-gated calcium ion channel α2δ subunit ligand having general formula I, its chiral isomers, and pharmaceutically acceptable salts.

[0008] Another object of this application is to provide the use of compounds of the above general formula I, their chiral isomers, and pharmaceutically acceptable salts in the treatment of chronic neuropathic pain, epilepsy, and anxiety.

[0009] Another object of this application is to provide a pharmaceutical composition comprising a compound of general formula I, its chiral isomer and a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers, excipients, diluents or combinations thereof.

[0010] Another object of this application is to provide the use of the above-described pharmaceutical composition in the treatment of chronic neuropathic pain, epilepsy, and anxiety.

[0011] The contents of this application will now be described in detail in conjunction with the purpose of this application.

[0012] The compounds of general formula I in this application have the following structural formula:

[0013]

[0014] in,

[0015] R 1 and R 2 Independently selected from H, halogens, and C1–C6 alkyl groups;

[0016] Each R 3 R 4 R 5 R 6 Independently selected from H, halogens, C1-C6 alkyl groups and C1-C6 alkoxy groups; or R 3 R 4 And the C atoms that are connected to them form C3 to C6 cycloalkyl groups, or R 5 R 6 Together with the C atoms they are connected to, they form C3–C6 cycloalkyl groups;

[0017] Each R 7 R 8 R 9 R 10 Independently selected from H, halogens, and C1–C6 alkyl groups;

[0018] Chemical bonds between atoms can be single or double bonds; when it represents a double bond, R 7 and R 9 This indicates that it does not exist;

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

[0020] Or, when n>=1, R 8 The C atoms and R atoms connected 10 The C atom connected to it and adjacent to it can interact with R. 8 R 10 Together they form C3-C6 cycloalkyl groups;

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

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

[0023] R 1 and R 2 Alkyl groups independently selected from H and C1–C3;

[0024] R 3 R 4 Independently selected from H, halogens, and C1-C3 alkyl groups; or R 3 R 4 The C atoms that are connected to them together form a cyclopropyl group;

[0025] R 7 R 8 R 9 R 10 Independently selected from H and C1-C6 alkyl groups; or R 8 The C atoms and R atoms connected 10 The C atom connected to R 8 R 10 Composed of cyclopropyl;

[0026] R 8 The connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R. 8 The connected C atoms and R 10 The chemical bond between the C atoms can be a single bond or a double bond; when it represents a double bond, R 7 and R 9 This indicates that it does not exist;

[0027] m = 0; n = 1.

[0028] According to this application, more preferably are compounds having general formula I, their chiral isomers or pharmaceutically acceptable salts thereof, wherein...

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

[0030] R 3 R 4 Independently selected from H and methyl; or R 3 R 4 The C atoms that are connected to them together form a cyclopropyl group;

[0031] R 7 R 8 R 9 R 10 Independently selected from H or methyl; or R 8 The C atoms and R atoms connected 10 The C atom connected to R 8 R 10 Composed of cyclopropyl;

[0032] R 8 The connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R. 8 The connected C atoms and R 10 The chemical bond between the C atoms can be a single bond or a double bond; when it represents a double bond, R 7 and R 9 This indicates that it does not exist;

[0033] m = 0; n = 1.

[0034] According to this application, more preferably are compounds having general formula I, their chiral isomers or pharmaceutically acceptable salts thereof, wherein...

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

[0036] R 3 R 4 The C atoms that are connected to them together form a cyclopropyl group;

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

[0038] m = 0; n = 1.

[0039] According to this application, more preferably are compounds having general formula I, their chiral isomers or pharmaceutically acceptable salts thereof, wherein...

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

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

[0042] R 7 R 9 Independently selected from H or methyl; R 8 The C atoms and R atoms connected 10 The C atom connected to R 8 R 10 Composed of cyclopropyl;

[0043] m = 0; n = 1.

[0044] According to this application, more preferably are compounds having general formula I, their chiral isomers or pharmaceutically acceptable salts thereof, wherein...

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

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

[0047] R 7 R 9 Independently selected from H or methyl; R 8 The C atoms and R atoms connected 10 The C atom connected to R 8 R 10 Composed of cyclopropyl;

[0048] m = 0; n = 1.

[0049] According to this application, the following compounds are preferred:

[0050]

[0051] The compounds having general formula I described in this application can be synthesized by the following methods:

[0052] In a typical case, ketone K reacts with phosphorylate W1 in the presence of a base to undergo a Wittig condensation reaction, yielding α,β-unsaturated acetate L-1, wherein the base is selected from inorganic and organic bases, wherein R... 11 and R 12 Selected from C1 to C6 alkyl groups; R 1 ~R10 m and n have the definitions described above; L-1 is a mixture of two cis- and anti-geometric configurations.

[0053]

[0054] When R in L-1 8 The connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R. 8 The connected C atoms and R 10 When the chemical bond between the C atoms is a double bond, L⁻¹ is L⁻¹⁻¹. In this case, L⁻¹⁻¹ can be converted to L⁻¹⁻² using the Simmons-Smith reaction or a similar reaction. At this point, R⁻¹⁻² contains R⁻¹. 8 The C atoms and R atoms connected 10 The C atom connected to R 8 R 10 The product is composed of a cyclopropyl group, with L-1-2 being a specific case of L-1. Simmons-Smith reactions or similar reactions involve treating substrates containing C=C double bonds with CH2I2 / Et2Zn, CH2I2 / Et2Zn / trifluoroacetic acid, or CH2I2 / Cu-Zn to obtain the cyclopropyl product.

[0055]

[0056] L-1 reacts with nitromethane in the presence of a base to undergo a Michael addition reaction to give M-1. The newly generated chiral center in M-1 is influenced by the chiral center originating from K. To distinguish it from the configuration of the chiral center at the corresponding position generated by other methods described below, the configuration of the newly generated chiral center in M-1 is marked as R*. The base is selected from various inorganic and organic bases.

[0057]

[0058] For M-1, there are three possible cases:

[0059] M-1-1: R 8 The connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R. 8 The connected C atoms and R 10 The chemical bond between the connected C atoms is a double bond;

[0060] M-1-2: R 8 The C atoms and R atoms connected 10 The C atom connected to R 8 -R 10 Composed of cyclopropyl;

[0061] M-1-3: R 8 The connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R. 8 The connected C atoms and R 10 The chemical bonds between the connected C atoms are single bonds.

[0062] For M-1-1: M-1-1 is hydrolyzed using an acid or base to obtain N-1-1. N-1-1 is then catalytically hydrogenated to simultaneously reduce the nitro group and the C=C double bond, yielding (R*)-I-1-3. (R*)-I-1-3 is a specific form of the compound having general formula I described in this application. (R*)-I-1-3 reacts with acid HA to give the corresponding salt (R*)-I-1-3·HA, where acid HA is selected from various inorganic and organic acids. M-1-1 is first reduced with iron powder to obtain P-1-1. P-1-1 is then hydrolyzed with acid to obtain (R*)-I-1-1. (R*)-I-1-1 is a specific form of the compound having general formula I described in this application. (R*)-I-1-1 reacts with acid HA to give the corresponding salt (R*)-I-1-1·HA, where acid HA is selected from various inorganic and organic acids.

[0063]

[0064] For M-1-2: M-1-2 undergoes hydrolysis of its ester bond using an acid or base to yield N-1-2. N-1-2 is then reduced to its nitro group via catalytic hydrogenation to give (R*)-I-1-2. (R*)-I-1-2 is a specific form of the compound having general formula I described in this application. (R*)-I-1-2 reacts with acid HA to give the corresponding salt (R*)-I-1-2·HA, where acid HA is selected from various inorganic and organic acids. M-1-2 is first reduced to its nitro group using iron powder to give P-1-2. P-1-2 can also be hydrolyzed to yield (R*)-I-1-2 by acid hydrolysis of its ester bond. (R*)-I-1-2 is a specific form of the compound having general formula I described in this application.

[0065]

[0066] (R*)-I-1-2 reacts with acid HA to give the corresponding salt (R*)-I-1-2·HA, wherein the acid HA is selected from various inorganic and organic acids.

[0067] For M-1-3: M-1-3 is hydrolyzed using an acid or base to obtain N-1-3. N-1-3 is then reduced by catalytic hydrogenation to obtain (R*)-I-1-3. (R*)-I-1-3 is a specific form of the compound having general formula I described in this application. (R*)-I-1-3 reacts with acid HA to give the corresponding salt (R*)-I-1-3·HA, where acid HA is selected from various inorganic and organic acids. M-1-3 is first reduced by iron powder to obtain P-1-3. P-1-3 can also be hydrolyzed by acid to obtain (R*)-I-1-3. (R*)-I-1-3 is a specific form of the compound having general formula I described in this application. (R*)-I-1-3 reacts with acid HA to give the corresponding salt (R*)-I-1-3·HA, where acid HA is selected from various inorganic and organic acids.

[0068]

[0069] In another typical case, ketone K undergoes a Knoevenagel condensation reaction with nitromethane in the presence of a catalyst selected from various inorganic and organic bases to give α,β-unsaturated nitro compounds L-2. L-2 is a mixture of two cis-trans geometries.

[0070]

[0071] L-2 and acetate W2 undergo a Michael-like addition reaction in the presence of a strong base to give M-2. The newly formed chiral center in M-2 is influenced by the chiral center originating from K. To distinguish it from the configuration of the corresponding chiral center formed in the reaction from L-1 to M-1, the configuration of the newly formed chiral center in M-2 is labeled as S*. The strong base is selected from tert-butyllithium, diisopropylaminolithium, bis(trimethylsilyl)aminolithium, bis(trimethylsilyl)aminosodium, and bis(trimethylsilyl)aminopotassium; R 13 Alkyl groups selected from C1 to C6, wherein S* and R* represent opposite configurations of the labeled chiral centers.

[0072]

[0073] For M-2, there are three possible scenarios:

[0074] M-2-1: R 8 The connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R. 8 The connected C atoms and R 10 The chemical bond between the connected C atoms is a double bond;

[0075] M-2-2: R8 The C atoms and R atoms connected 10 The C atom connected to R 8 -R 10 Composed of cyclopropyl;

[0076] M-2-3: R 8 The connected C atoms and R 10 The solid and dashed lines between the connected C atoms represent R. 8 The connected C atoms and R 10 The chemical bonds between the connected C atoms are single bonds.

[0077] For M-2-1: M-2-1 is hydrolyzed using an acid or base to obtain N-2-1. N-2-1 is then catalytically hydrogenated to simultaneously reduce the nitro group and the C=C double bond, yielding (S*)-I-2-3. (S*)-I-2-3 is a specific form of the compound having general formula I described in this application. (S*)-I-2-3 reacts with acid HA to give the corresponding salt (S*)-I-2-3·HA, where acid HA is selected from various inorganic and organic acids. M-2-1 is first reduced with iron powder to obtain P-2-1. P-2-1 is then hydrolyzed with acid to obtain (S*)-I-2-1. (S*)-I-2-1 is a specific form of the compound having general formula I described in this application. (S*)-I-2-1 reacts with acid HA to give the corresponding salt (S*)-I-2-1·HA, where acid HA is selected from various inorganic and organic acids.

[0078]

[0079] For M-2-2: M-2-2 is hydrolyzed using an acid or base to obtain N-2-2. N-2-2 is then reduced to a nitro group via catalytic hydrogenation to obtain (S*)-I-2-2. (R*)-I-2-2 is a specific form of the compound having general formula I described in this application. (S*)-I-2-2 reacts with acid HA to give the corresponding salt (S*)-I-2-2·HA, where acid HA is selected from various inorganic and organic acids. M-2-2 is first reduced to a nitro group with iron powder to obtain P-2-2. P-2-2 can also be hydrolyzed to obtain (S*)-I-2-2 by acid hydrolysis of the ester bond. (S*)-I-2-2 is a specific form of the compound having general formula I described in this application. (S*)-I-2-2 reacts with acid HA to give the corresponding salt (S*)-I-2-2·HA, where acid HA is selected from various inorganic and organic acids.

[0080]

[0081] For M-2-3: M-2-3 is hydrolyzed using an acid or base to obtain N-2-3. N-2-3 is then catalytically hydrogenated to simultaneously reduce the nitro group, yielding (S*)-I-2-3. (S*)-I-2-3 is a specific form of the compound having general formula I described in this application. (S*)-I-2-3 reacts with acid HA to give the corresponding salt (S*)-I-2-3·HA, where acid HA is selected from various inorganic and organic acids. M-2-3 is first reduced with iron powder to obtain P-2-3. P-2-3 can also be hydrolyzed with acid to obtain (S*)-I-2-3. (S*)-I-2-3 is a specific form of the compound having general formula I described in this application. (S*)-I-2-3 reacts with acid HA to give the corresponding salt (S*)-I-2-3·HA, where acid HA is selected from various inorganic and organic acids.

[0082]

[0083] To prepare the optically pure final product I, it can be separated using a racemic intermediate consisting of a pair of enantiomers with the same relative configuration.

[0084] In a typical example, the racemic intermediate (±)-N-acid, consisting of a pair of enantiomers with the same relative configuration in the above synthetic route, is salted and resolved in a suitable solvent using suitable chiral bases A and B, respectively, to obtain precipitated salts of sufficient optical purity: (+)-N-acid·chiral base A and (-)-N-acid·chiral base B. After removing chiral bases A and B by dilute hydrochloric acid treatment, (+)-N-acid and (-)-N-acid are obtained, respectively. The (+)-N-acid and (-)-N-acid are then subjected to catalytic hydrogenation to reduce the nitro group, yielding optically pure products (+)-IA and (+)-IA. (+)-IA and (+)-IA are specific forms of the compounds having general formula I described in this application. (+)-IA and (-)-IA react with acid HA to give the corresponding salts (+)-IA·HA and (-)-IA·HA, respectively, wherein the acid HA is selected from various inorganic and organic acids.

[0085]

[0086] 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 salted in a suitable solvent using suitable chiral acids A and B, respectively, to obtain precipitated salts (+)-P-NH2·chiral acid-A and (-)-P-NH2·chiral acid-B with sufficient optical purity. After removing chiral acids A and B by treating with an aqueous sodium bicarbonate solution, (+)-P-NH2 and (-)-P-NH2 are obtained, respectively. (+)-P-NH2 and (-)-P-NH2 are then acid-hydrolyzed with tert-butyl ester to obtain optically pure products (+)-I-A1 and (-)-I-A1. (+)-I-A1 and (+)-I-A1 are specific forms of the compounds having general formula I described in this application. (+)-I-A1 and (-)-I-A1 react with acid HA to give the corresponding salts (+)-I-A1·HA and (-)-I-A1·HA, respectively, wherein the acid HA is selected from various inorganic and organic acids.

[0087]

[0088] In a typical example, K-1, a specific form of the aforementioned compound having the general formula K, can be synthesized as follows: Compound CDE reacts with compound Q-1 via a Diels-Alder reaction to give compound R, where Z is selected from NH, O, and S. 14 Selected from H and C1-C6 alkyl groups, or -ZR 14 -R 14 Z-=O, at this point, compound Q-1 is maleic anhydride. Compound R reacts with alcohol R under acid catalysis. 15 The reaction with OH yields compounds S and R. 15 The compounds are selected from C1 to C6 alkyl groups. Compound S reacts with metallic sodium and trimethylchlorosilane in a refluxing inert solvent (hydroxyketone condensation reaction), and the product is hydrolyzed with acid to give compound T. Compound T is treated with PPh3 in refluxing CX4 to give compound U-1, wherein X is selected from Cl, Br, and I. Compound U-1 is treated with Zn powder in an acidic medium to give compound K-1.

[0089]

[0090] In another typical example, K-1 can be synthesized as follows: Compound CDE reacts with compound Q-2 via a Diels-Alder reaction to give compound K-1.

[0091]

[0092] Compound ALE reacts with dichlorovinyl ketone to give compound U-2. Dichlorovinyl ketone can be prepared by reacting trichloroacetyl chloride with activated zinc powder or by reacting dichloroacetyl chloride with triethylamine. U-2 is treated with Zn powder in an acidic medium to give compound K-2, which is a specific form of the aforementioned compound having the general formula K.

[0093]

[0094] Compound K-1 was reduced by catalytic hydrogenation to yield compound K-3. K-1 was then converted to K-4 using the Simmons-Smith reaction. The Simmons-Smith reaction and similar reactions involve treating substrates containing C=C double bonds with CH₂I₂ / Et₂Zn, CH₂I₂ / Et₂Zn / trifluoroacetic acid, or CH₂I₂ / Cu-Zn to obtain cyclopropyl products. K-3 and K-4 are specific forms of the aforementioned compounds having the general formula K.

[0095]

[0096] The term "halogen" as used in this application refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0097] In this application, "alkyl" refers to a branched or straight-chain saturated aliphatic alkane with a specified number of carbon atoms, minus one hydrogen-derived group. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, and C6 alkyl groups; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, and 1,1-dimethylbutyl.

[0098] The term "alkoxy" as used in this application refers to an alkyl group as defined herein, connected to another group via an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C 1-4 "Alkoxy" is a molecule containing, but is not limited to, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, and 1,2-dimethylpropoxy. Preferably, the "alkoxy" in this application is C1. 1-4 Alkoxy, more preferably C 1-3 Alkyl group.

[0099] The term "cycloalkyl" as used in this application refers to a saturated cyclic alkyl group derived from a cycloalkane by removing one hydrogen atom. The cycloalkyl group includes "3-6 membered cycloalkyl" and "3-5 membered cycloalkyl". Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0100] Pharmaceutically acceptable salts of compounds having general formula I as described in this application include, but are not limited to, compounds of general formula I with various inorganic bases, such as NaOH, KOH, Mg(OH)2, Ca(OH)2, Sr(OH)2, Al(OH)3, etc., or inorganic carbonates, such as Na2CO3, K2CO3, MgCO3, CaCO3, SrCO3, etc., or organic bases, such as amino acids, 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., forming pharmaceutically acceptable salts.

[0101] The compounds having general formula I described in this application can be co-formed with one or more pharmaceutically acceptable excipients to create pharmaceutical compositions. These pharmaceutical compositions can be formulated into dosage forms such as solid oral preparations, liquid oral preparations, and injections. The solid and liquid oral preparations include: tablets, dispersible tablets, sugar-coated tablets, granules, dry powders, capsules, and solutions. The injections include: small injections, large-volume infusions, water-for-injection injections, and lyophilized powder injections.

[0102] The compounds of this application exist as chiral isomers, such as enantiomers, diastereomers, racemic mixtures and other mixtures, all of which are within the scope of this application.

[0103] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0104] The term "diastereomer" refers to a stereoisomer of a molecule that has two or more chiral centers and is not a mirror image of the molecule.

[0105] (±) indicates that a compound is a racemic mixture, and the configuration in the chemical structure of this compound is a relative configuration. (+) or (-) indicates that a compound is optically pure, and the optical rotation symbols represent dextrorotatory or levorotatory, respectively, and the configuration in the chemical structure of this compound is an absolute configuration.

[0106] Chiral isomers of the compounds described in this application can be prepared using the chiral synthesis or chiral reagents described above, or other conventional techniques. The separation of optically pure compounds in this application is typically accomplished using chiral resolution. This involves forming a salt with a racemic base using an optically pure chiral acid, followed by crystallization in a suitable solvent to obtain an optically pure salt of the base and chiral acid, thus achieving the separation of the chiral compounds.

[0107] The term "optically pure" means that the content of the isomer or enantiomer is greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0108] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction can be used, and the absolute configuration of a compound can also be confirmed by examining the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis.

[0109] According to the compositions of this application, the pharmaceutically or food-grade excipients are selected from: carriers, excipients, diluents, binders, fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, and coating materials.

[0110] According to the compositions of this application, the excipient is a non-toxic substance that is compatible with the active ingredient and otherwise biologically suitable for use in organisms. The selection of a specific excipient will depend on the route of administration or the type and state of disease for treating a particular patient. Examples of such excipients include, but are not limited to, solvents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, antioxidants, etc., commonly used in the pharmaceutical field. The filler comprises one or more of lactose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, dicalcium phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; the binder comprises one or more of sucrose, povidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, ethanol, and water; and the disintegrant comprises one or more of crospovidone, crospovidone, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and effervescent disintegrants.

[0111] The compound having general formula I described in this application has a binding effect on the voltage-gated calcium ion channel α2δ and can be used as an active ingredient in the preparation of drugs for treating chronic neuropathic pain, epilepsy, and anxiety. The activity of the compound having general formula I described in this application is demonstrated at the in vitro level by inhibiting the human recombinant calcium ion channel Ca2+ expressed on CHO cells. v 2.2 / β3 / α2δ-1 receptor and [ 3 The efficacy of gabapentin was verified at the in vivo level through its analgesic effect in an animal model of chronic pain and its antiepileptic effect in an animal model of epilepsy.

[0112] The compounds of general formula I described in this application are effective over a fairly wide dosage range. For example, the daily dose ranges from approximately 1 mg to 3000 mg per person, divided into one or several administrations. The actual dosage of the compounds of general formula I described in this application can be determined by the physician based on the patient's specific condition. Attached Figure Description

[0113] The present application will be further described below with reference to the accompanying drawings, wherein:

[0114] Figure 1 This is the chemical structure (ORTEP diagram) of the compound (+)-32-LAC obtained by single-crystal diffraction.

[0115] Figure 2 This is the chemical structure (ORTEP diagram) of the compound (+)-22-LAC obtained by single-crystal diffraction.

[0116] Figure 3A The mechanical pain threshold time-course plots are the pharmacodynamic evaluation results of compounds (±)-I-7, (±)-I-3 and (±)-I-4 in a rat sciatic nerve branch injury model. Figure 3B This is the area under the mechanical pain threshold-time curve of the efficacy evaluation results of compounds (±)-I-7, (±)-I-3 and (±)-I-4 in a rat sciatic nerve branch injury model;

[0117] Figure 4A This is a time-course graph of the mechanical pain threshold for evaluating the efficacy of compounds (-)-I-3, (+)-I-3, (-)-I-4 and (+)-I-4 in a rat model of sciatic nerve branch injury; Figure 4B This is the area under the mechanical pain threshold-time curve for evaluating the efficacy of compounds (-)-I-3, (+)-I-3, (-)-I-4 and (+)-I-4 in a rat model of sciatic nerve branch injury.

[0118] Figure 5 The median effective dose (EDT) of the compound for animal protection in a mouse model of maximal electric shock. 50 The fitted curve was obtained by calculating the dose-protection rate curve using the least squares method (Graphpad Prism 5).

[0119] Figure 6 The antiepileptic effects of compounds (+)-I-3 and (+)-I-4 in a mouse epilepsy model (maximum electroshock model (MES));

[0120] Figure 7 This is a graph showing the effects of compounds (+)-I-3-p-toluenesulfonate and (+)-I-4-p-toluenesulfonate) on animal locomotion, measured by a rotarod test. Detailed Implementation

[0121] The following specific embodiments further illustrate the content of this application in detail. It should be noted that the following embodiments are for illustrative purposes only and are not intended to limit the scope of this application. Various modifications made by those skilled in the art based on the teachings of this application should be within the scope of protection claimed in the claims of this application.

[0122] Melting point measurements were performed using an SGW X-4A micro melting point apparatus (Shanghai Instrument & Electronics Physical Optical Instrument Co., Ltd., Shanghai, China). The thermometer was not calibrated. 1 H NMR and 13 C NMR was performed using a Bruker Ascend 500 NMR spectrometer (Bruker Swiss AG). (Switzerland) Detection, using CDCl3, DMSO-d6, CD3OD or D2O as solvents, TMS (for...) 1 H NMR) or deuterated solvents (used for 13 The known chemical shifts of the carbon signal in the C10 NMR spectrum were used as internal standards. High-resolution mass spectrometry was performed using electrospray ionization (ESI) on a Thermo Q Exactive Plus mass spectrometer (Thermo Fisher Scientific, Bremen, Germany). Optical rotation was determined using an Anton Paar MCP4100 polarimeter.

[0123] Enantiomeric excess (%ee) determination (chiral HPLC): The determination was performed using a Daicel Chiralpak AS-RH 4.6 mm × 250 mm column (5 μm) on an Agilent 1260 Infinity II liquid chromatograph with a detector wavelength of 220 nm. The mobile phase was acetonitrile / 0.1% KH2PO4-KOH buffer solution (pH = 7.0) = 70 / 30, the flow rate was 1 mL / min, the sample concentration was 0.5 mg / mL, and the injection volume was 3 μL.

[0124] Single crystal diffraction method: Cu Kα diffraction was performed at 100.00(10) K using a Rigaku XtaLAB Pro single crystal diffractometer. Diffraction data were collected and restored using CrysAlisPro 1.171.39.33c (Rigaku OD, 2017). The structure was analyzed and refined using the SHELXL program.

[0125] The drying solvent is prepared from the corresponding analytical grade solvent using standard drying methods.

[0126] Example 1: Synthesis of compound (±)-I-1

[0127]

[0128] Step 1: Synthesis of compound (±)-3

[0129] The preparation of activated zinc powder is as follows: 40.00 g (0.25 mol) of dry CuSO4 is added to 1 L of water and stirred until dissolved. 600.00 g (9.17 mol) of zinc powder is added, and the mixture is stirred at room temperature for 3-4 hours and then filtered. The filter cake is washed successively with water (300 mL × 2) and acetone (750 mL × 2), and then dried in a vacuum drying oven at 50 °C (approximately 10 mmHg) for 24-48 hours.

[0130] Under N2 conditions and an ice-water bath, compound 2 (14.00 g, 0.15 mol) and activated zinc powder (14.00 g, 0.21 mol) were added sequentially to dry tetrahydrofuran (140 mL) with stirring. A solution of trichloroacetyl chloride (12.00 g, 66 mmol) in dry tetrahydrofuran (20 mL) was added dropwise. The system was exothermic during the addition, and the temperature was maintained between 35 °C and 40 °C by controlling the dropping rate. After the addition was complete, the reaction system was stirred overnight at 35 °C. TLC monitoring showed the reaction was complete, and the reaction solution was cooled to room temperature. The solution was filtered with diatomaceous earth as an aid, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance. This was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→9 / 91] to obtain the target product (±)-3. A pale yellow oily substance; 6.00 g; this product does not require characterization and can be used directly in the next reaction.

[0131] Step 2: Synthesis of compound (±)-4

[0132] Zinc powder (12.00 g, 0.18 mol) and glacial acetic acid (65 mL) were mixed and stirred. A freshly prepared solution of compound (±)-3 (6.00 g, 29 mmol) in glacial acetic acid (12 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction mixture was placed in an oil bath at 55 °C and stirred for 2 h under N2 conditions. TLC monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was poured into ice water (350 mL) and extracted with CH2Cl2 (200 mL × 2). The organic phases were combined, washed with water (300 mL × 3), dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a brown oily substance. This substance was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-4. Pale yellow oily substance; 3.00 g (2→(±)-4 combined yield 15%);

[0133] 1H NMR (CDCl3, 500MHz) δ: 3.08-3.10 (m, 1H), 3.03 (ddd, 1H, J = 3.8Hz, 8.8Hz and 18.5Hz), 2.53 (dt, 1H, J = 3.5Hz and 18.5Hz),2.43-2.45(m,1H),2.39-2.41(m,1H),2.25-2.28(m,1H),1.58-1.65(m,1H),1.53 -1.56(m,1H),1.46-1.53(m,1H),1.24-1.27(m,1H),1.18-1.24(m,1H),1.10-1.13(m,1H).

[0134] 13 C NMR (CDCl3, 126MHz) δ: 213.08, 68.21, 50.44, 39.70, 37.41, 32.62, 31.38, 28.46, 26.87.

[0135] Step 3: Synthesis of compound (±)-5

[0136] Under N2 atmosphere, potassium tert-butoxide (t-BuOK) (3.8 g, 34 mmol) was added to 25 mL of dry THF and stirred in an ice-water bath to form a suspension. Then, tert-butyl diethylphosphonoacetate (7.00 g, 28 mmol) was added dropwise. After the addition was complete, the reaction was carried out in an ice-water bath for 40 min. Then, a freshly prepared solution of compound (±)-4 (3.00 g, 22 mmol) in 10 mL of dry THF was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 2 h, and TLC monitoring showed that the reaction was complete. The reaction solution was poured into 200 mL of water and extracted with EtOAc (120 mL × 2). The organic phases were combined, dried (MgSO4), filtered to remove the desiccant, and concentrated under reduced pressure on a rotary evaporator to obtain a deep yellow oil. This oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-5. Pale yellow oily substance; 3.70 g; This product does not require characterization and can be used directly in the next reaction.

[0137] Step 4: Synthesis of compound (±)-6

[0138] At room temperature, (±)-5 (3.70 g, 16 mmol) was dissolved in CH3NO2 (22 mL), stirred, and 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 N2 atmosphere. TLC monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, it was poured into water (200 mL) and extracted with CH2Cl2 (150 mL × 2). After combining the organic phases, the mixture was dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brownish-black oil. The oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-6. Pale yellow oil; 3.80 g (combined yield of (±)-4→(±)-6 58%).

[0139] 1 H NMR (CDCl3, 500MHz) δ: 4.74 (dd, 1H, J = 1.0Hz and 11.5Hz), 4.68 (d, 1H, J = 11.5Hz), 2.57 (d, 1H, J = 17.0Hz), 2.52 (d, 1H, J = 17.0Hz), 2. 31-2.35(m,1H),2.12-2.13(m,1H),2.03-2.05(m,2H),1.99(ddd,1H,J=2.0Hz,9.0Hz and 14.0Hz),1.87-1.90(m,1H),1.57-1.61(m,1H),1.45-1.50(m,11H),1.29-1.32(m,1H),1.02-1.06(m,2H).

[0140] 13 C NMR (CDCl3, 126MHz) δ: 170.83, 82.52, 81.10, 48.40, 39.78, 37.97, 37.43, 36.35, 35.03, 34.25, 32.03, 28.88, 28.23, 27.52.

[0141] ESI-HRMS:(m / z)calcd.for C 16 H 26 NO4([M+H)) + )296.1856,found:296.1852.

[0142] Step 5: Synthesis of compound (±)-7

[0143] Compound (±)-6 (1.70 g, 5.8 mmol) was dissolved in CH2Cl2 (18 mL), and trifluoroacetic acid (TFA) (10 mL) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred at room temperature until TLC monitoring showed that the reaction was complete (usually 2-4 hours). The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→17 / 33] to obtain a pale yellow oil. 1 mL of n-hexane was added to the oil, and the mixture was ultrasonically pulverized to precipitate a solid. After stirring at room temperature for 1 h, the mixture was filtered, the solid was collected, and dried to obtain the target product (±)-7. White solid; 1.00 g (72%); melting point 93.7℃-95.5℃;

[0144] 1 H NMR (CDCl3, 500MHz) δ: 4.76 (d, 1H, J = 12.0Hz), 4.71 (d, 1H, J = 12.0Hz), 2.77 (d, 1H, J = 18.0Hz), 2.72 (d, 1H,J=18.0Hz),2.34-2.38(m,1H),2.15-2.16(m,1H),2.03-2.07(m,2H),1.99(ddd,1H,J=2.0Hz,8.5Hz and14.0Hz),1.86-1.88(m,1H),1.62(dd,1H,J=6.0Hz and 14.0Hz),1.48-1.52(m,2H),1.32-1.34(m,1H),1.02-1.08(m,2H).

[0145] 13 C NMR (DMSO-d6, 126MHz) δ: 172.30, 82.18, 47.56, 38.90, 37.26, 36.77, 35.60, 33.76, 33.59, 31.27, 28.38, 27.06.

[0146] ESI-HRMS:(m / z)calcd.for C 12 H 18 NO4([M+H)) + )240.1230,found:240.1227.

[0147] Step 6: Synthesis of compound (±)-I-1

[0148] (±)-7 (1.00 g, 4.2 mmol) was dissolved in CH3OH (10 mL), and 10% Pd(OH)2 / C (0.27 g) was added. The air in the reaction vessel was replaced with hydrogen (by a balloon) according to standard procedures, and the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete (the reaction usually takes 12 h to complete). The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain an oily residue. EtOAc (10 mL) was added and stirred, and a solid precipitated. The mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried to obtain the target product (±)-I-1. White solid; 0.30 g (34%); melting point 180.2℃-184.0℃;

[0149] 1 H NMR (CD3OD, 500MHz) δ: 3.04 (s, 2H), 2.63 (d, 1H, J = 16.0Hz), 2.45 (d, 1H, J = 16.0Hz), 2.29-2.34 (m,1H),2.21-2.22(m,2H),2.01-2.06(m,2H),1.86-1.87(m,1H),1.79(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.49-1.55(m,3H),1.30-1.32(m,1H),1.03-1.07(m,2H).

[0150] 13 C NMR (CD3OD+D2O(1drop), 126MHz) δ: 180.68, 51.20, 49.46, 42.56, 39.00, 38.90, 37.88, 37.29, 34.69, 32.76, 29.48, 28.39.

[0151] ESI-HRMS:(m / z)calcd.for C 12 H 20 NO2([M+H] + )210.1489,found:210.1483.

[0152] Compound (±)-I-1 is a specific form of the compound having general formula I in this application.

[0153] Example 2 Synthesis of compound (±)-I-2

[0154]

[0155] Step 1: Synthesis of compound (±)-9

[0156] Under N2 atmosphere and ice-water bath conditions, compound 8 (42.00 g, 0.46 mol) and activated zinc powder (42.00 g, 0.64 mol) were added sequentially to dry tetrahydrofuran (350 mL) with stirring. A solution of trichloroacetyl chloride (36.00 g, 0.20 mol) in dry tetrahydrofuran (150 mL) was added dropwise. The reaction system was exothermic during the addition, and the internal temperature was maintained at 32℃-38℃. After the addition was complete, the internal temperature was maintained at 34.5℃ and stirred overnight. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered with diatomaceous earth as an aid, and the residue obtained by vacuum concentration of the filtrate on a rotary evaporator was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→2 / 23] to obtain the target product (±)-9. A pale yellow oily substance; 10.54 g; this product does not require characterization and can be used directly in the next reaction.

[0157] Step 2: Synthesis of compound (±)-10

[0158] Zinc powder (21.00 g, 0.32 mol) and glacial acetic acid (120 mL) were mixed and stirred. A freshly prepared solution of compound (±)-9 (10.54 g, 52 mmol) in glacial acetic acid (25 mL) was added dropwise under ice-water bath cooling. After the addition was complete, the reaction mixture was placed in an oil bath at 55 °C and stirred overnight under N2 conditions. TLC monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (400 mL) and extracted with CH2Cl2 (300 mL). The organic phase was washed successively with water (400 mL × 3) and saturated NaHCO3 solution (400 mL) until the pH of the aqueous phase was >7. The solution was dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a brown oily substance. This substance was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23] to obtain the target product (±)-10. Pale yellow oily substance; 2.73 g (4% combined yield of 8→(±)-10);

[0159] 1 H NMR(CDCl3,500MHz)δ:6.29-6.31(m,1H),6.12-6.14(m,1H),3.05-3.08(m,2H),3.00-3.01(m,1H),2.84(ddd,1H,J=3.3Hz,9.0Hz and 19.3Hz),2.28-2.33(m,2H),1.54-1.56(m,1H),1.40-1.43(m,1H).

[0160] 13C NMR (CDCl3, 126MHz) δ: 211.83, 139.86, 136.19, 66.31, 45.70, 44.17, 43.18, 41.06, 30.28.

[0161] ESI-HRMS:(m / z)calcd.for C9H 11 O([M+H] + )135.0804,found:135.0803.

[0162] Step 3: Synthesis of compound (±)-11

[0163] Under N2 atmosphere, t-BuOK (4.52 g, 40 mmol) was added to dry THF (90 mL), and stirred into a suspension in an ice-water bath. Then, tert-butyl diethylphosphonoacetate (10.16 g, 40 mmol) was added dropwise. After the addition was complete, the reaction was carried out in an ice-water bath for 1 h. A freshly prepared solution of compound (±)-10 (2.70 g, 20 mmol) in dry THF (30 mL) was then added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete. The reaction solution was poured into water (400 mL), extracted with EtOAc (300 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (300 mL), dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a deep yellow oil. The oil was purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 2 / 23] to obtain the target product (±)-11. Pale yellow oily substance; 3.91 g; This product does not require characterization and can be used directly in the next reaction.

[0164] Step 4: Synthesis of compound (±)-12

[0165] At room temperature, (±)-11 (3.91 g, 17 mmol) was dissolved in CH3NO2 (40 mL), stirred, and DBU (7.76 g, 51 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred overnight in an oil bath at 50 °C under N2 atmosphere. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and poured into water (250 mL), and extracted with CH2Cl2 (200 mL × 2). After combining the organic phases, the mixture was dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure in a rotary evaporator to obtain a brownish-black oil. The oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→2 / 23] to obtain the target product (±)-12. Pale yellow oil; 3.06 g (combined yield of (±)-10→(±)-12 52%).

[0166] 1H NMR (CDCl3, 500MHz) δ: 6.02-6.04 (m, 1H), 5.99-5.01 (m, 1H), 4.74 (d, 1H, J = 11.5Hz), 4.70 (d, 1 H,J=11.5Hz),2.72-2.74(m,2H),2.55(s,2H),2.09-2.14(m,1H),2.04(ddd,1H,J=2.0Hz,8.5Hz and 13.5Hz),1.87-1.88(m,1H),1.71-1.73(m,1H),1.36-1.48(m,11H).

[0167] 13 C NMR (CDCl3, 126MHz) δ: 170.87, 136.29, 136.18, 82.78, 81.22, 44.44, 43.34, 41.94, 41.90, 36.16, 34.70, 32.56, 30.46, 28.24.

[0168] ESI-HRMS:(m / z)calcd.for C 16 H 24 NO4([M+H)) + )294.1700,found:294.1693.

[0169] Step 5: Synthesis of compound (±)-13 p-toluenesulfonate

[0170] At room temperature, compound (±)-12 (0.70 g, 2.4 mmol) was dissolved in EtOH (10 mL), and water (5 mL) was added with stirring. Then, iron powder (0.67 g, 12 mmol) and NH4Cl (0.26 g, 4.9 mmol) were added sequentially. The air in the reaction vessel was replaced with nitrogen (using a balloon) according to standard procedures, and the mixture was stirred in an oil bath at 85 °C for 6–7 hours. TLC monitoring showed 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), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily residue. At room temperature, EtOAc (8 mL) was added to dilute the residue, followed by p-TsOH·H2O (0.49 g, 2.6 mmol) and stirring to dissolve. The system was then transferred to an ice-water bath and stirred until a white solid precipitated. Stirring continued for 1 h in the ice-water bath. The filter cake was collected by filtration and dried using a vacuum oil pump to obtain (±)-13 p-toluenesulfonate. White solid; 0.66 g (64%).

[0171] 1H NMR(DMSO-d6,500MHz)δ:7.75(brs,3H),7.48(d,2H,J=8.0Hz),7.11(d,2H,J=8.0Hz),6.03-6.05(m,1H),6.00-6.02(m,1H ),3.04-3.08(m,2H),2.65-2.67(m,2H),2.43-2.44(m,2H),2.29(s,3H),1.98-2.02(m,1H),1.82(ddd,1H,J=1.8Hz,8.5Hz and 13.3Hz),1.41(s,9H),1.22-1.27(m,2H).

[0172] 13 C NMR(DMSO-d6,126MHz)δ:170.40,145.70,137.63,135.92,135.89,128.06,125.50,8 0.33,47.12,43.51,42.79,41.55,41.32,34.16,33.97,31.69,29.31,27.78,20.79.

[0173] ESI-HRMS:(m / z)calcd.for C 16 H 26 NO2([M(free base)+H]) + )264.1958,found:264.1953.

[0174] Step 6: Synthesis of compound (±)-I-2

[0175] At room temperature, (±)-13 p-toluenesulfonate (0.66 g, 1.5 mmol) was stirred with saturated NaHCO3 solution (100 mL) for 20 min (in suspension), and then extracted with EtOAc (30 mL × 3). After combining the organic phases, the mixture was dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was then dissolved in CH2Cl2 (5 mL). TFA (2.5 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. TLC monitoring showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil. The oil was dried and solidified using a vacuum oil pump, and then methyl tert-butyl ether (5 mL) was added. The mixture was then crushed and pulped at room temperature for 30 min, filtered to collect the solid, and dried using a vacuum oil pump to obtain compound (±)-I-2. White solid; 0.20 g (64%); melting point 141.8℃-146.6℃;

[0176] 1H NMR (CD3OD, 500MHz) δ: 6.02-6.05 (m, 2H), 3.24 (d, 1H, J = 13.0Hz), 3.21 (d, 1H, J = 13.0Hz), 2.76-2.77 (m, 1H), 2.7 0-2.71(m,1H),2.64(d,1H,J=17.0Hz),2.55(d,1H,J=16.5Hz),2.09-2.14(m,1H),1.89(ddd,1H,J=2.0Hz,8.5Hz and 13.5Hz),1.78-1.80(m,1H),1.73-1.75(m,1H),1.41(dd,1H,J=5.5Hz and 13.5Hz),1.35-1.38(m,1H).

[0177] 13 C NMR (CD3OD, 126MHz) δ: 175.47, 137.19, 137.05, 49.86, 45.37, 44.46, 42.88, 42.60, 35.34, 35.19, 33.43, 30.99.

[0178] ESI-HRMS:(m / z)calcd.for C 12 H 18 NO2([M+H] + )208.1332,found:208.1327.

[0179] Compound (±)-I-2 is a specific form of the compound having general formula I in this application.

[0180] Example 3 Synthesis of compound (±)-I-3

[0181]

[0182] Step 1: Synthesis of Compound 15

[0183] Compound 14 (30.00 g, 0.18 mol) was dissolved in dry CH3OH (300 mL), and concentrated H2SO4 (3 mL) was added. The mixture was refluxed for 24 h. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to 1 / 3 of its original volume using a rotary evaporator, then poured into ice water (400 mL). The resulting mixture was extracted with CH2Cl2 (300 mL × 2), the organic phases were combined, washed with saturated NaHCO3 solution (400 mL), dried (MgSO4), filtered to remove the desiccant, and concentrated under reduced pressure using a rotary evaporator to obtain target compound 15. Yellow oily substance; 37.00 g (96%); 1H NMR (CDCl3, 500MHz) δ: 6.26-6.27(m,2H), 3.61(s,6H), 3.29-3.30(m,2H), 3.16-3.17(m,2H), 1.47-1.49(m,2H), 1.32-1.35(m,2H).

[0184] Step 2: Synthesis of compound (±)-16

[0185] Sodium metal (19.00 g, 0.83 mol) was added to dry toluene (370 mL). The mixture was heated under N2 atmosphere until the sodium was completely melted, and stirred for 20 min while maintaining an internal temperature of 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. The addition process was exothermic, and the internal temperature of the reaction system was maintained at 103-106 °C. After the addition was complete, the reaction system was stirred overnight while maintaining an internal temperature of 103-106 °C. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature. The solution was filtered with diatomaceous earth as an aid, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance. The oily substance was dissolved in THF (200 mL), and 1 M HCl (20 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 h. TLC monitoring showed the reaction was complete. The reaction solution was poured into water (400 mL), and EtOAc (300 mL × 2) was added for extraction. After combining the organic phases, the mixture was dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→2 / 3] to obtain the target product (±)-16. It was a white solid; 14.3 g (54%); melting point 74.7℃-77.5℃. This product did not require characterization and was used directly in the next reaction.

[0186] Step 3: Synthesis of compound (±)-17

[0187] 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. The air in the reactor was replaced with nitrogen (using a balloon) according to standard operating procedures, and the reactor was stirred overnight in a 75°C oil bath. TLC monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brownish-black oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 9 / 91] to obtain the target product (±)-17. A pale yellow oil; 4.40 g; this product does not require characterization and can be used directly in the next reaction.

[0188] Step 4: Synthesis of compound (±)-18

[0189] Zinc powder (8.00 g, 0.12 mol) and glacial acetic acid (40 mL) were mixed and stirred. Then, a freshly prepared solution of compound (±)-17 (4.40 g, 26 mmol) in glacial acetic acid (6 mL) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred in an oil bath at 55 °C for 1.5 h under N2 atmosphere. TLC monitoring showed 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 CH2Cl2 (70 mL × 2). The combined organic phases were washed with water (100 mL × 3), dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a yellow oil. This oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-18. Pale yellow semi-solid; 1.30 g (29% combined yield of (±)-16→(±)-18);

[0190] 1 H NMR(CDCl3,500MHz)δ:6.16-6.17(m,2H),3.71-3.75(m,1H),3.12-3.14(m,1H ),3.04-3.06(m,1H),2.79-2.84(m,1H),2.72(dddd,1H,J=1.0Hz,3.0Hz,8.5Hz and18.0Hz),2.15(dt,1H,J=3.8Hz and 18.5Hz),1.75-1.77(m,1H),1.45-1.47(m,1H).

[0191] 13 C NMR (CDCl3, 126MHz) δ: 211.48, 135.81, 132.74, 66.65, 54.50, 46.42, 46.21, 44.13, 26.93.

[0192] Step 5: Synthesis of compound (±)-19

[0193] Under N2 atmosphere, t-BuOK (1.90 g, 17 mmol) was added to 15 mL of dry THF and stirred in an ice-water bath to form a suspension. Then, tert-butyl diethylphosphonoacetate (3.50 g, 14 mmol) was added dropwise. After the addition was complete, the reaction was carried out in an ice-water bath for 40 min. Then, a freshly prepared solution of compound (±)-18 (1.40 g, 10 mmol) in 5 mL of dry THF was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1.5 h. TLC monitoring showed that the reaction was complete. The reaction solution was poured into 100 mL of water and extracted with EtOAc (70 mL × 2). The organic phases were combined, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a deep yellow oil. The oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→2 / 23] to obtain the target product (±)-19. Pale yellow oily substance; 2.42 g; This product does not require characterization and can be used directly in the next reaction.

[0194] Step 6: Synthesis of compound (±)-20

[0195] At room temperature, the crude product (±)-19 (2.42 g, based on 10 mmol) was dissolved in CH3NO2 (15 mL), stirred, and DBU (3.00 g, 20 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred overnight in an oil bath at 80 °C under N2 atmosphere. TLC monitoring showed that the starting material was not completely reacted. The reaction solution was cooled to room temperature and poured into water (150 mL), and extracted with CH2Cl2 (70 mL × 2). After combining the organic phases, the mixture was dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a brownish-black oil. The oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-20. Pale yellow oil; 1.00 g (combined yield of (±)-18→(±)-20 33%).

[0196] 1H NMR (CDCl3, 500MHz) δ: 6.40-6.41 (m, 1H), 6.28-6.29 (m, 1H), 4.82 (dd, 1H, J = 1.0Hz and 11.5Hz), 4.60 (dd, 1H, J = 1.0Hz and 11.5Hz),2.94-2.96(m,1H),2.81-2.87(m,2H),2.52-2.56(m,1H),2.47(dd,1H,J=0.8Hz and17.8H),2.38(d,1H,J=17.5Hz),2.04(ddd,1H,J=1.5Hz,8.0Hz and 13.0Hz),1.56-1.60(m,1H),1.47(s,9H),1.32-1.36(m,1H),1.11-1.13(m,1H).

[0197] 13 C NMR (CDCl3, 126MHz) δ: 170.92, 137.50, 136.91, 83.36, 80.92, 53.22, 47.71, 45.82, 44.83, 38.78, 36.17, 34.10, 32.83, 28.24.

[0198] ESI-HRMS:(m / z)calcd.for C 16 H 24 NO4([M+H)) + )294.1700,found:294.1777.

[0199] Step 7: Synthesis of compound (±)-21

[0200] Compound (±)-20 (1.00 g, 3.4 mmol) was dissolved in CH2Cl2 (10 mL), and TFA (6 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a yellow oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→2 / 3] to obtain a light yellow oil. 1 mL of n-hexane was added to the oil, and the mixture was sonicated. The oil solidified and then slurryed at room temperature for 30 min. The solid was collected by filtration, and the filter cake was dried using a vacuum oil pump to obtain compound (±)-21. White solid; 0.80 g (99%); melting point 84.6℃-87.7℃;

[0201] 1H NMR(CDCl3,500MHz)δ:6.43-6.44(m,1H),6.31-6.32(m,1H),4.79(dd,1H,J=1.0Hz and 11.5Hz),4.65(d,1H,J=11.5Hz),2.97-2.99(m,1H),2.86-2.89(m,2H),2.67(d,1H,J=18.5Hz),2.5 7(d,1H,J=18.5Hz),2.54-5.56(m,1H),2.03-2.07(m,1H),1.61-1.63(m,1H),1.38(dd,1H,J=6.0Hz and 13.5Hz),1.13-1.15(m,1H). 13 C NMR (CDCl3, 126MHz) δ: 177.12, 137.88, 136.78, 83.09, 53.34, 47.56, 45.68, 44.84, 38.34, 34.58, 34.17, 32.70. ESI-HRMS:(m / z)calcd.for C 12 H 16 NO4([M+H)) + )238.1074,found:238.1071.

[0202] Step 8: Synthesis of compound (±)-I-3

[0203] Compound (±)-21 (0.23 g, 0.97 mmol) was dissolved in CH3OH (9 mL), and 10% Pd(OH)2 / C (0.15 g) was added. The air in the reaction vessel was replaced with hydrogen (using a balloon) according to standard procedures, and the mixture was stirred overnight at room temperature. TLC monitoring showed the reaction was complete (the reaction typically takes 12 hours to complete). The mixture was filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a white solid. CH3OH (1 mL) / EtOAc (2 mL) was added, and the mixture was stirred and slurried at room temperature for 5 min. The solid was collected by filtration and dried to obtain the target product (±)-I-3. White solid; 0.12 g (60%); melting point 186.2℃-190.5℃;

[0204] 1H NMR (CD3OD, 500MHz) δ: 3.07 (d, 1H, J = 12.5Hz), 2.98 (d, 1H, J = 12.5Hz), 2.71 (d, 1H, J = 16.0Hz), 2.65 (d, 1H, J =16.0Hz),2.50-2.55(m,1H),2.44-2.46(m,1H),2.22-2.26(m,2H),1.99-2.05(m,1H),1.91(dd,1H,J=7.5Hz and 13.0Hz),1.75-1.81(m,2H),1.54-1.61(m,1H),1.46-1.53(m,1H),1.40-1.43(m,1H),1.24-1.27(m,1H). 13 C NMR (CD3OD, 126MHz) δ: 180.05, 52.82, 49.93, 47.58, 42.78, 41.02, 40.22, 37.39, 34.81, 33.73, 26.23, 25.26. ESI-HRMS:(m / z)calcd.for C 12 H 20 NO2([M+H] + )210.1489,found:210.1484.

[0205] Compound (±)-I-3 is a specific form of the compound having general formula I in this application.

[0206] Example 4: Synthesis of compound (±)-I-4 and its p-toluenesulfonate

[0207]

[0208] Step 1: Synthesis of compound (±)-22 p-toluenesulfonate

[0209] At room temperature, compound (±)-20 (1.50 g, 5.1 mmol) was dissolved in EtOH (15 mL), and water (7 mL) was added. After stirring, iron powder (1.50 g, 27 mmol) and NH4Cl (0.50 g, 9.3 mmol) were added sequentially. The air in the reactor was replaced with nitrogen (by a balloon) according to standard operating procedures, and the reactor was stirred in an oil bath at 85 °C for 4 h. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was added to a saturated NaHCO3 solution (100 mL) and extracted with EtOAc (40 mL × 3). The organic phases were combined, dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oily substance. At room temperature, 15 mL of EtOAc was added to dilute the oily substance, followed by the addition of p-TsOH·H2O (0.97 g, 5.1 mmol). After stirring and dissolving, a large amount of solid precipitated. The system was transferred to an ice-water bath and stirred for another 1 hour. The solid was collected by filtration and dried using a vacuum oil pump to obtain (±)-22 p-toluenesulfonate. White solid; 1.60 g (72%); melting point 184.4℃-187.1℃;

[0210] 1 H NMR(DMSO-d6,500MHz)δ:7.71(brs,3H),7.48(d,2H,J=8.0Hz),7.12(d,2H,J=8.0Hz),6.35-6.37(m,1H),6.28-6.30(m,1H),3.05-3.1 1(m,1H),2.94-3.00(m,1H),2.79-2.82(m,2H),2.71-2.77(m,1H),2.40-2.43(m,1H),2.26-2.33(m,5H),1.79(ddd,1H,J=1.5Hz,8.5Hz and 13.0Hz),1.45-1.48(m,1H),1.43(s,9H),1.11(dd,1H,J=6.0Hz and13.0Hz),1.04-1.06(m,1H).

[0211] 13 C NMR(DMSO-d6,126MHz)δ:170.51,145.64,137.69,137.19,136.49,128.08,125.50,8 0.09,52.46,47.71,46.62,45.25,44.08,36.54,36.07,33.20,32.20,27.74,20.79.

[0212] ESI-HRMS:(m / z)calcd.for C 16 H 26NO2([M(free base)+H]) + )264.1958,found:264.1954.

[0213] Step 2: Synthesis of compound (±)-I-4 and its p-toluenesulfonate

[0214] At room temperature, (±)-22 p-toluenesulfonate (1.60 g, 3.7 mmol) was stirred with saturated NaHCO3 solution (100 mL) for 20 min (in suspension), and then extracted with EtOAc (60 mL × 3). The combined organic phases were dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a pale yellow oil, which was then dissolved in CH2Cl2 (10 mL). TFA (7 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4–6 hours. TLC monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was then concentrated again with CH2Cl2 (20 mL). The oil was dried under vacuum until the solid completely precipitated, which was (±)-I-4. The solid was dissolved in CH3OH (2 mL), and then EtOAc (4 mL) was added and stirred. p-TsOH·H2O (0.65 g, 3.4 mmol) was added to the reaction solution. After stirring and dissolving, a large amount of solid precipitated out. The mixture was stirred and slurried at room temperature for 2 hours. The solid was collected by filtration, and the filter cake was dried using a vacuum oil pump to obtain compound (±)-I-4 p-toluenesulfonate. White solid; 0.50 g (36%); melting point 197.0℃-198.7℃;

[0215] 1 H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.5Hz), 7.23 (d, 2H, J = 8.0Hz), 6.43-6.4 4(m,1H),6.30-6.31(m,1H),3.25(d,1H,J=13.0Hz),3.12(d,1H,J=12.5Hz),2 .84-2.93(m,3H),2.58(d,1H,J=17.5Hz),2.51-2.53(m,1H),2.34-2.38(m,4H ),1.75-1.80(m,1H),1.57-1.59(m,1H),1.32-1.35(m,1H),1.14-1.16(m,1H).

[0216] 13C NMR(CD3OD,126MHz)δ:175.74,143.53,141.72,138.51,137.90,129.83,126 .97,53.83,50.47,48.15,46.90,45.86,37.93,37.16,35.08,34.08,21.31.

[0217] ESI-HRMS:(m / z)calcd.for C 12 H 18 NO2([M(free base)+H]) + )208.1332,found:208.1328.

[0218] Compound (±)-I-4 is a specific form of the compound having general formula I in this application.

[0219] Example 5: Synthesis of compound (±)-I-5

[0220]

[0221] Step 1: Synthesis of Compound 23

[0222] Maleic anhydride (68.00 g, 0.69 mol) was dissolved in CHCl3 (400 mL), and a CHCl3 (50 mL) solution of 1,4-cyclohexadiene (78.00 g, 0.97 mol) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain an oily substance, which was then added to an EtOAc / n-hexane mixture (100 mL / 400 mL) and stirred at room temperature. The solid was collected by filtration and dried to obtain compound 23; 54.50 g (44%). 1 H NMR (CDCl3, 500MHz) δ: 6.31-6.33(m,2H), 3.22-3.24(m,2H), 3.127-3.134(m,2H), 1.59-1.62(m,2H), 1.40-1.43(m,2H).

[0223] Step 2: Synthesis of Compound 24

[0224] Compound 23 (17.00 g, 95 mmol) was dissolved in CH3OH (170 mL), stirred, and concentrated sulfuric acid (1.7 mL) was added. The mixture was heated under reflux overnight. TLC monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to 1 / 3 of its original volume using a rotary evaporator and then poured into ice water (200 mL). The resulting mixture was extracted with CH2Cl2 (100 mL × 3), and the combined organic phases were washed successively with saturated NaHCO3 solution (200 mL) and saturated brine (200 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure using a rotary evaporator to give solid compound 24. White solid; 20.00 g (93%); 1 H NMR (CDCl3, 500MHz) δ: 6.31-6.35(m,2H), 3.60(s,6H), 3.02-3.03(m,2H), 2.89-2.91(m,2H), 1.53-1.57(m,2H), 1.30-1.33(m,2H).

[0225] Step 3: Synthesis of compound (±)-25

[0226] Sodium metal (10.00 g, 0.43 mol) was added to dry toluene (200 mL). The mixture was heated under N2 atmosphere until the sodium was completely melted. Stirring was then started, and the internal temperature was maintained at 103℃-106℃ for 20 min. A solution of compound 24 (20.00 g, 89 mmol) and TMSCl (48.00 g, 0.44 mol) in dry toluene (30 mL) was added dropwise. The dropwise addition was exothermic, and the internal temperature of the reaction system was controlled by the dropwise addition rate to maintain it at 103℃-106℃. After the addition was complete, the reaction system was stirred overnight at 103℃-106℃. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature. The solution was filtered with diatomaceous earth as an aid, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance. The oily substance was dissolved in THF (100 mL), and 1M HCl (16 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 h. TLC monitoring showed the reaction was complete. The reaction solution was poured into water (100 mL), and EtOAc (100 mL × 2) was added for extraction. After combining the organic phases, the mixture was dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance, which solidified after being left at room temperature. Hexane (15 mL) was added to the solidified system, and the mixture was heated to reflux. EtOAc was added dropwise until the solid was completely dissolved. The mixture was cooled to room temperature and stirred to precipitate crystals. Stirring was continued for 5 hours. The mixture was filtered, and the filter cake was dried using a vacuum oil pump to obtain the target compound (±)-25. White solid; 7.60 g (52%); melting point 106.1℃-110.4℃; this product does not require characterization and can be used directly in the next reaction.

[0227] Step 4: Synthesis of compound (±)-26

[0228] Compound (±)-25 (2.00 g, 12 mmol) was dissolved in CH2Cl2 (20 mL). Pyridine (1.93 g, 24 mmol) and 4-dimethylaminopyridine (DMAP) (0.74 g, 6.1 mmol) were added sequentially to the system. The air in the reaction vessel was replaced with nitrogen (by a balloon) according to standard procedures. Phenyl thiochloroformate (3.15 g, 18 mmol) was slowly added dropwise to the system under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. TLC monitoring showed that the reaction was complete. The reaction solution was poured into ice water (100 mL) and extracted with CH2Cl2 (50 mL × 2). The organic phases were combined and washed sequentially with 1 M HCl (100 mL) and saturated brine (100 mL). The mixture was dried (MgSO4), filtered to remove the drying agent, and concentrated under reduced pressure on a rotary evaporator to obtain crude compound (±)-26. Yellow solid; 3.66 g; This product did not require characterization and was used directly in the next reaction.

[0229] Step 5: Synthesis of compound (±)-27

[0230] Compound (±)-26 (3.66 g, 12 mmol) was added to benzene (40 mL), and the air in the reactor was replaced with nitrogen (by a balloon) according to standard procedures. The mixture was heated to 90 °C and refluxed, and a benzene (15 mL) solution of n-Bu3SnH (5.30 g, 18 mmol) and azobisisobutyronitrile (AIBN) (0.20 g, 1.2 mmol) was slowly added dropwise. After the addition was complete, the mixture was kept in an oil bath at 90 °C overnight. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure using a rotary evaporator to obtain an oily substance, which was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-27. Pale yellow oily substance; 1.20 g (66% combined yield of (±)-25→(±)-27);

[0231] 1 H NMR(CDCl3,500MHz)δ:6.20-6.25(m,2H),3.31-3.34(m,1H),2.89-2.95(m,1H),2.85-2.89(m,1H ),2.78-2.81(m,1H),2.40-2.47(m,1H),1.47-1.53(m,1H),1.37-1.44(m,2H),1.23-1.29(m,1H).

[0232] 13C NMR (CDCl3, 126MHz) δ: 212.49, 133.54, 131.54, 64.18, 50.49, 32.04, 31.01, 26.48, 24.54, 22.54.

[0233] Step 6: Synthesis of compound (±)-28

[0234] Under N2 atmosphere, t-BuOK (0.90 g, 8.0 mmol) was added to 10 mL of dry THF and stirred in an ice-water bath to form a suspension. Then, tert-butyl diethylphosphonoacetate (1.70 g, 6.7 mmol) was added dropwise. After the addition was complete, the reaction was carried out in an ice-water bath for 40 min. Then, a freshly prepared solution of compound (±)-27 (0.60 g, 4.0 mmol) in 5 mL of dry THF was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1.5 h. TLC monitoring showed that the reaction was complete. The reaction solution was poured into 100 mL of ice water and extracted with EtOAc (50 mL × 2). The organic phases were combined, dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a deep yellow oil. The oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-28. Pale yellow oily substance; 0.90 g; This product does not require characterization and can be used directly in the next reaction.

[0235] Step 7: Synthesis of compound (±)-29

[0236] At room temperature, compound (±)-28 (0.90 g, 3.7 mmol) was dissolved in CH3NO2 (9 mL), and DBU (2.00 g, 13 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred overnight in an oil bath at 80 °C under N2 conditions. TLC monitoring showed that the reaction was basically complete. The reaction solution was cooled to room temperature and poured into water (100 mL), and extracted with CH2Cl2 (50 mL × 2). After combining the organic phases, the mixture was dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a brownish-black oil. The oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-29. Pale yellow oil; 0.50 g (combined yield of (±)-27→(±)-29 40%).

[0237] 1H NMR(CDCl3,500MHz)δ:6.45-6.49(m,1H),6.26-6.30(m,1H),4.78(dd,1H,J=0.5Hz and 11.5Hz),4.65(d,1H,J=11.5Hz),2.60(d,1H,J=17.5Hz),2.52-2.61(m,3H ),2.54(d,1H,J=17.5Hz),2.27-2.30(m,1H),1.94(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.64(dd,1H,J=7.3Hz and 13.3Hz),1.45(s,9H),1.35-1.40(m,2H),1.25-1.30(m,1H),1.18-1.23(m,1H).

[0238] 13 C NMR (CDCl3, 126MHz) δ: 171.17, 134.53, 134.32, 82.57, 80.94, 46.80, 40.89, 36.38, 34.74, 33.09, 32.50, 30.96, 28.24, 25.21, 23.61.

[0239] ESI-HRMS:(m / z)calcd.for C 17 H 26 NO4([M+H)) + )308.1856,found:308.1852.

[0240] Step 8: Synthesis of compound (±)-30

[0241] Compound (±)-29 (0.50 g, 1.6 mmol) was dissolved in CH2Cl2 (5 mL), and TFA (3 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oily substance. Then, n-hexane (3 mL) was added to the oily substance, and the mixture was sonicated. The oily substance turned into a solid, and the mixture was stirred and slurried at room temperature for 1 h. The solid was collected by suction filtration and dried using a vacuum oil pump to obtain compound (±)-30. White solid; 0.33 g (80%); melting point 120.0℃-123.6℃;

[0242] 1H NMR(CDCl3,500MHz)δ:6.47-6.50(m,1H),6.28-6.32(m,1H),4.78(dd,1H,J=0.8Hz and 5.9Hz),4.68(d,1H,J=11.5Hz),2.80(d,1H,J=18.0Hz),2.73(d,1H,J=18.0Hz),2.53-2.65(m,3H),2.27-2.30(m,1H),1.95(ddd,1H,J=2.0Hz,8.5Hz and13.5Hz),1.66(dd,1H,J=2.3Hz and 13.3Hz),1.32-1.42(m,2H),1.25-1.31(m,1H),1.17-1.24(m,1H).

[0243] 13 C NMR (CDCl3, 126MHz) δ: 176.37, 134.66, 134.33, 82.31, 46.58, 40.37, 34.65, 32.97, 32.78, 30.85, 25.17, 23.55. ESI-HRMS:(m / z)calcd.for C 13 H 18 NO4([M+H)) + )252.1230,found:252.1229.

[0244] Step 9: Synthesis of compound (±)-I-5

[0245] Compound (±)-30 (0.30 g, 1.2 mmol) was dissolved in CH3OH (10 mL), and 10% Pd(OH)2 / C (0.20 g) was added. The air in the reaction vessel was replaced with hydrogen (using a balloon) according to standard procedures, and the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete (the reaction typically takes 12 h to complete). The solid was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a white solid. CH3OH (2 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 to obtain the target product (±)-I-5. White solid; 0.13 g (49%); melting point 176.6℃-178.2℃;

[0246] 1H NMR (CD3OD, 500MHz) δ: 3.16 (d, 1H, J = 13.0Hz), 3.07 (d, 1H, J = 13.0Hz), 2.74 (d, 1H, J = 16.5Hz), 2.67 (d, 1H, J = 16. 0Hz),2.45-2.52(m,1H),2.20-2.27(m,2H),2.01-2.04(m,1H),1.90-1.96(m,1H),1.85(ddd,1H,J=3.0Hz,8.5Hz and 12.5Hz),1.74-1.76(m,1H),1.46-1.70(m,6H),1.36-1.43(m,1H).

[0247] 13 C NMR (CD3OD, 126MHz) δ: 180.15, 51.74, 46.55, 44.33, 40.14, 33.41, 33.09, 27.72, 26.94, 26.50, 23.84, 22.75. ESI-HRMS:(m / z)calcd.for C 13 H 22 NO2([M+H] + )224.1645,found:224.1641.

[0248] Compound (±)-I-5 is a specific form of the compound having general formula I in this application.

[0249] Example 6: Synthesis of compound (±)-I-6 and its p-toluenesulfonate

[0250]

[0251] Step 1: Synthesis of compound (±)-31 p-toluenesulfonate

[0252] At room temperature, compound (±)-29 (1.10 g, 3.6 mmol) was dissolved in EtOH (10 mL), and water (5 mL) was added and stirred. Iron powder (1.30 g, 23 mmol) and NH4Cl (0.45 g, 8.4 mmol) were added sequentially. The air in the reactor was replaced with nitrogen (using a balloon) according to standard operating procedures, and the mixture was refluxed with stirring for 5 h. TLC monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was washed with saturated NaHCO3 solution (120 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil. At room temperature, EtOAc (15 mL) was added to dilute the oil, and then p-TsOH·H2O (0.70 g, 3.7 mmol) was added and stirred until dissolved. A large amount of solid precipitated. The system was transferred to an ice-water bath and stirred for 1 h. The solid was collected by filtration and dried under vacuum oil pump to obtain (±)-31 p-toluenesulfonate. White solid; 1.30 g (81%); melting point 190.1℃-192.5℃;

[0253] 1 H NMR(DMSO-d6,500MHz)δ:7.69(brs,3H),7.48(d,2H,J=6.5Hz),7.12(d,2H,J=8.0Hz),6.44-6.46(m,1H),6.25-6.28(m,1H ),3.07-3.11(m,1H),2.96-3.00(m,1H),2.40-2.54(m,5H),2.29(s,3H),2.12-2.14(m,1H),1.74(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.38-1.42(m,10H),1.31-1.33(m,2H),1.17-1.21(m,1H),1.09-1.14(m,1H).

[0254] 13 C NMR(DMSO-d6,126MHz)δ:170.55,145.64,137.66,134.31,133.80,128.07,125.49,80.0 9,46.72,45.55,38.85,35.92,33.77,32.38,31.83,30.37,27.74,24.67,23.21,20.78.

[0255] ESI-HRMS:(m / z)calcd.for C 17 H 28 NO2([M(free base)+H]) +)278.2115,found:278.2111.

[0256] Step 2: Synthesis of compound (±)-I-6 and its p-toluenesulfonate

[0257] At room temperature, (±)-31 p-toluenesulfonate (1.30 g, 2.9 mmol) was stirred with saturated NaHCO3 solution (100 mL) for 20 min (in suspension), and then extracted with EtOAc (60 mL × 3). After combining the organic phases, the mixture was dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a pale yellow oil, which was then dissolved in CH2Cl2 (10 mL). TFA (7 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was then concentrated again with CH2Cl2 (20 mL). The oil was dried using a vacuum oil pump until the solid completely precipitated, which was (±)-I-6. The solid was dissolved in CH3OH (3 mL), and then EtOAc (8 mL) was added and stirred. p-TsOH·H₂O (0.60 g, 3.2 mmol) was added to the reaction solution and stirred until dissolved. A large amount of solid precipitated out. Stirring was continued at room temperature for 0.5 h. The solid was collected by filtration and dried under vacuum to give compound (±)-I-6 p-toluenesulfonate. White solid; 0.70 g (62%); melting point 192.7℃-194.0℃;

[0258] 1 H NMR (CD3OD, 500MHz) δ: 7.71 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.5Hz), 6.48-6.52 (m, 1H), 6 .28-6.32(m,1H),3.26(d,1H,J=12.5Hz),3.14(d,1H,J=13.0Hz),2.66(d,1H,J=17.0Hz) ,2.56(d,1H,J=17.0Hz),2.56-2.67(m,2H),2.51-2.53(m,1H),2.19-2.22(m,1H),1.74- 1.79(m,1H),1.58-1.64(m,1H),1.40-1.43(m,2H),1.27-1.32(m,1H),1.19-1.24(m,1H).

[0259] 13C NMR(CD3OD,126MHz)δ:175.74,143.57,141.67,135.55,135.31,129.80,126.97 ,49.41,47.40,40.12,36.92,35.65,33.98,33.67,32.16,25.98,24.39,21.30.

[0260] ESI-HRMS:(m / z)calcd.for C 13 H 20 NO2([M(free base)+H]) + )222.1489,found:222.1485.

[0261] Compound (±)-I-6 is a specific form of the compound having general formula I in this application.

[0262] Example 7 Synthesis of compounds (-)-I-3, (+)-I-3 and their p-toluenesulfonates

[0263]

[0264] Step 1: Synthesis of compound (±)-32 p-toluenesulfonate

[0265] Compound (±)-20 (140.00 g, 0.48 mol) was dissolved in CH3OH (800 mL), and 10% Pd(OH)2 / C (22.00 g) was added. The air in the reaction vessel was replaced with hydrogen gas (using a balloon) according to standard procedures, and the mixture was stirred at room temperature for 12 h. TLC monitoring showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain crude compound (±)-32. Compound (±)-32 was diluted with CH2Cl2 (800 mL), washed with saturated NaHCO3 solution (2 L), and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 (500 mL × 2). The combined organic phases were dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oily substance. At room temperature, the oily substance was diluted with EtOAc (800 mL), and then p-TsOH·H2O (70.00 g, 0.37 mol) was added and stirred to dissolve. A large amount of solid precipitated out. The mixture was stirred at room temperature for 3 h. The solid was collected by filtration and dried under vacuum to obtain (±)-32 p-toluenesulfonate. White solid; 75.20 g (36%); melting point 170.1℃-174.4℃;

[0266] 1H NMR(DMSO-d6,500MHz)δ:7.73(brs,3H),7.48(d,2H,J=8.0Hz),7.12(d,2H,J=7.5Hz), 3.02-3.07(m,1H),2.91-2.95(m,1H),2.61(d,1H,J=17.0Hz),2.57(d,1H,J=17.0Hz), 2.39-2.46(m,1H),2.27-2.29(m,4H),2.18-2.20(m,1H),2.10-2.13(m,1H),1.83-1.8 8(m,1H),1.68-1.79(m,3H),1.41-1.53(m,11H),1.31-1.33(m,1H),1.13-1.16(m,1H).

[0267] 13 C NMR(DMSO-d6,126MHz)δ:170.59,145.54,137.76,128.11,125.51,80.17,48.51,48 .43,48.23,41.52,38.50,35.42,35.39,33.04,30.92,27.74,24.64,23.74,20.80.

[0268] 3,5-Dinitrobenzoylation: Synthesis of the 3,5-dinitrobenzoylation derivative of compound (±)-32

[0269] At room temperature, compound (±)-32 p-toluenesulfonate (1.00 g, 2.3 mmol) was added to saturated NaHCO3 solution (200 mL) and stirred to form a suspension. The suspension was extracted with EtOAc (100 mL). The organic phase was washed again with saturated NaHCO3 solution (200 mL), and the organic phase was extracted and separated. The aqueous phase was extracted with EtOAc (50 mL). The organic phases were combined, dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a pale yellow oily compound (±)-32. The oily compound was dissolved in CH2Cl2 (7 mL), stirred, and 3,5-dinitrobenzoyl chloride (0.6 g, 2.6 mmol) was added. Triethylamine (0.6 mL) was then added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. TLC monitoring showed that the reaction was complete. The reaction solution was directly purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 4] to obtain a pale yellow oil. 10 mL of n-hexane was added to the oil, precipitating a solid. The mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to obtain a 3,5-dinitrobenzoyl derivative of (±)-32. White solid; 0.70 g (67%); melting point 113.9℃-115.4℃; 1H NMR (CDCl3, 500MHz) δ: 9.40 (brs, 1H), 9.20 (d, 2H, J = 2.0Hz), 9.15 (t, 1H, J = 2.0Hz), 3.70 (dd, 1H, J = 4.5Hz and 13.5Hz), 3.43 (dd, 1H, J = 3.3Hz and 13.3Hz),2.84(dd,1H,J=1.0Hz and 12.0Hz),2.71(d,1H,J=17.0Hz),2.54-2.60(m,1H),2.36-2.38(m,1H),2.30-2.33(m,1H),2.26-2.28( m,1H),1.86-1.94(m,2H),1.75-1.82(m,2H),1.50-1.62(m,11H),1.38-1.40(m,1H),1.21-1.24(m,1H).

[0270] ESI-HRMS:(m / z)calcd.for C 23 H 28 N3O7([MH)) - )458.1933,found:458.1939.

[0271] The 3,5-dinitrobenzoyl derivative of (±)-32 is used as a reference standard for chiral HPLC to determine the optical purity of (-)-32 and (+)-32 after chiral acid resolution of (±)-32 in steps 2 and 3.

[0272] Step 2: Synthesis of (R)-(-)-O-acetylmandelate of compound (-)-32

[0273] (±)-32 p-toluenesulfonate (22.80 g, 52 mmol) was added to a saturated NaHCO3 solution (200 mL × 2) and stirred. Extraction was performed using EtOAc (200 mL × 2). After combining the organic phases, the mixture was dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a pale yellow oil. At room temperature, 100 mL of THF was added to dilute the oil, followed by dropwise addition of a 50 mL THF solution of (R)-(-)-O-acetylmandelic acid (5.00 g, 26 mmol). After the addition was complete, a large amount of solid gradually precipitated. 8 mL of THF was added, and the mixture was stirred overnight at room temperature. The solid was collected by suction filtration (filtrate was recovered), and the filter cake was dried using a vacuum oil pump to obtain a white solid (7.35 g, 16 mmol), which is the (R)-(-)-O-acetylmandelic acid salt of compound (-)-32.

[0274] 3,5-Dinitrobenzoylation Derivatization: Synthesis of the 3,5-dinitrobenzoylation derivative of compound (-)-32. The above white solid (0.1 g, 0.22 mmol) was added to a saturated NaHCO3 solution (50 mL × 2) and stirred. Extraction was performed with EtOAc (25 mL × 2). The organic phases were combined, dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a pale yellow oil. At room temperature, CH2Cl2 (3 mL) was added to the above oil, followed by 3,5-dinitrobenzoyl chloride (0.1 g, 0.43 mmol) and stirred. Triethylamine (2-3 drops) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 10 min. TLC monitoring showed that the reaction was complete. The reaction solution was directly purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 4] to obtain a pale yellow oily substance. After vacuum drying, a white foamy solid of (-)-32 3,5-dinitrobenzoyl derivative was obtained. The derivative was determined by chiral HPLC to have an ee value of 80.54%.

[0275] Enantiomeric excess (%ee) determination (chiral HPLC): The determination was performed using a Daicel Chiralpak AS-RH 4.6 mm × 250 mm column (5 μm) on an Agilent 1260 Infinity II liquid chromatograph with a detector wavelength of 220 nm. The mobile phase was acetonitrile / 0.1% KH2PO4-KOH buffer solution (pH = 7.0) = 70 / 30, the flow rate was 1 mL / min, the sample concentration was 0.5 mg / mL, and the injection volume was 3 μL.

[0276] At room temperature, the white solid (6.35 g, 14 mmol) of (R)-(-)-O-acetylmandelate of compound (-)-32 obtained from the first separation was thoroughly stirred with THF (65 mL), then transferred to an oil bath at 40 °C and stirred for 10 min (the system was slightly soluble). The system was then placed at room temperature, and THF (30 mL) was added, followed by stirring overnight. The solid was collected by filtration and dried under vacuum to obtain a white solid (4.90 g, 11 mmol). Recrystallization was repeated to obtain the (R)-(-)-O-acetylmandelate of compound (-)-32. Following the 3,5-dinitrobenzoyl derivatization procedure described above, its ee value was determined to be 99.34% by chiral HPLC. White solid; 4.40 g (37%); This product did not require characterization and was used directly in the next reaction.

[0277] Step 3: Synthesis of (S)-(+)-O-acetylmandelate of compound (+)-32

[0278] The filtrate from the separation and crystallization filtration in step 2 was concentrated, and saturated NaHCO3 solution (100 mL × 2) was added and stirred. Extraction was performed using EtOAc (100 mL × 2). After combining the organic phases, the mixture was dried (MgSO4), filtered, and concentrated under reduced pressure using a rotary evaporator to obtain a pale yellow oil (12.85 g, based on 48 mmol). At room temperature, THF (100 mL) was added to dilute the oil, followed by dropwise addition of a THF (50 mL) solution of (S)-(+)-O-acetylmandelic acid (4.70 g, 24 mmol) (a large amount of solid began to precipitate gradually when half of the solution was added). After the addition was complete, THF (30 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filter cake was dried using a vacuum oil pump to obtain a white solid (+)-32 (S)-(+)-O-acetylmandelic acid salt (6.00 g, 13 mmol). Following the above-described 3,5-dinitrobenzoyl derivatization steps and measuring its ee value by chiral HPLC, it was found to be 90.77%.

[0279] At room temperature, the above white solid was thoroughly stirred with THF (60 mL), then transferred to a 40°C oil bath and stirred for 10 min (the system was slightly soluble). The system was then placed at room temperature, and THF (30 mL) was added, followed by stirring overnight. The solid was collected by filtration and dried under vacuum to obtain (S)-(+)-O-acetylmandelate of compound (+)-32. Following the 3,5-dinitrobenzoyl derivatization procedure described above, its ee value was determined by chiral HPLC to be 99.17%. White solid; 4.40 g (40%); This product does not require characterization and can be used directly in the next reaction.

[0280] Step 4: Synthesis of compound (-)-I-3 and its p-toluenesulfonate

[0281] At room temperature, (R)-(-)-O-acetylmandelate (1.50 g, 3.3 mmol) of compound (-)-32 was added to saturated NaHCO3 solution (100 mL) and stirred for 20 min (in suspension). EtOAc (50 mL × 3) was then added for extraction. The combined organic phases were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil. The oil was then dissolved in CH2Cl2 (10 mL), and TFA (7 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4–6 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil. CH2Cl2 (10 mL) was added again for further concentration. The resulting oil was dried using a vacuum oil pump to obtain (-)-32. The above (-)-32 sample was dissolved in CH3OH (2.5 mL), and then EtOAc (12 mL) was added. The mixture was stirred, and p-TsOH·H2O (0.70 g, 3.7 mmol) was added to the solution. After stirring and dissolving, a large amount of solid precipitated. Stirring was continued at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to obtain compound (-)-I-3 p-toluenesulfonate. White solid; 1.00 g (80%); melting point 180.6℃-183.5℃; [α] D 20 = -22.8 (c = 2.50, CH3OH);

[0282] 1 H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.0Hz), 3.20 (d, 1H, J = 13.0Hz), 3.10(d,1H,J=13.0Hz),2.79(d,1H,J=17.5Hz),2.70(d,1H,J=17.5Hz),2.49-2.57(m,1H),2 .41-2.43(m,1H),2.37(s,3H),2.22-2.27(m,2H),1.92-1.97(m,1H),1.84-1.89(m,2H),1.7 6-1.81(m,1H),1.57-1.63(m,1H),1.49-1.55(m,1H),1.41-1.44(m,1H),1.25-1.28(m,1H).

[0283] 13C NMR(CD3OD,126MHz)δ:177.10,143.14,140.84,130.31,126.34,50.73,49. 15,42.42,40.52,40.21,39.64,36.05,34.47,32.47,25.62,24.79,21.41.

[0284] Compound (-)-I-3 is a specific form of the compound having the general formula I in this application, and is also an optically pure compound with levorotatory optical properties that has the same relative configuration as (±)-I-3.

[0285] Step 5: Synthesis of compound (+)-I-3 and its p-toluenesulfonate

[0286] At room temperature, (S)-(+)-O-acetylmandelate (1.40 g, 3.0 mmol) of compound (+)-32 was added to saturated NaHCO3 solution (100 mL) and stirred for 20 min (in suspension). EtOAc (50 mL × 3) was then added for extraction. The combined organic phases were dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil. This oil was then dissolved in CH2Cl2 (10 mL), and TFA (7 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4–6 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil. CH2Cl2 (10 mL) was added again for further concentration. The resulting oil was dried using a vacuum oil pump to obtain (+)-I-3. The above (+)-I-3 sample was dissolved in CH3OH (2 mL), and then EtOAc (6 mL) was added and stirred. p-TsOH·H2O (0.60 g, 3.2 mmol) was added to the solution, and after stirring and dissolving, a large amount of solid precipitated. Stirring was continued at room temperature for 1 h. The solid was collected by filtration and dried using a vacuum oil pump to obtain p-toluenesulfonate of compound (+)-I-3. White solid; 0.85 g (73%); melting point 179.5℃-181.8℃; [α] D 20 = +25.09 (c = 2.55, CH3OH);

[0287] 1H NMR (CD3OD, 500MHz) δ: 7.71 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.0Hz), 3.20 (d, 1H, J = 13.0Hz), 3.10(d,1H,J=13.0Hz),2.78(d,1H,J=17.5Hz),2.70(d,1H,J=17.5Hz),2.48-2.55(m,1H),2 .40-2.42(m,1H),2.37(s,3H),2.21-2.26(m,2H),1.90-1.95(m,1H),1.83-1.88(m,2H),1.7 6-1.80(m,1H),1.56-1.62(m,1H),1.49-1.54(m,1H),1.40-1.42(m,1H),1.24-1.27(m,1H).

[0288] 13 C NMR(CD3OD+D2O(1drop),126MHz)δ:176.94,142.97,141.11,130.25,126.38,50. 74,49.21,42.44,40.56,40.17,39.67,36.10,34.50,32.47,25.65,24.81,21.40.

[0289] Compound (+)-I-3 is a specific form of the compound having general formula I in this application, and is also an optically pure compound with dextrorotatory optical properties having the same relative configuration as (±)-I-3.

[0290] The absolute configuration of compound (+)-I-3 is determined as follows: the (S)-(+)-O-acetylmandelate of (+)-32, which has the same absolute configuration, is converted to its lactam (+)-32-LAC. The absolute configuration of (+)-32-LAC is then determined using X-ray single-crystal diffraction, and this absolute configuration is identical to that of (+)-32. This method can indirectly determine the absolute configuration of (+)-I-3.

[0291] The specific experimental method is as follows:

[0292] Synthesis of (+)-32-LAC: (+)-32-(S)-(+)-O-acetylmandelate (1.00 g, 2.2 mmol) with an ee value of 99.17% was added to a saturated NaHCO3 solution (100 mL), stirred for 10 min, and then extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with brine, dried (MgSO4), filtered to remove the drying agent, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was dissolved in toluene (7 mL), refluxed overnight, and TLC showed the reaction was complete. The reaction system was cooled to room temperature, the solvent was evaporated on a rotary evaporator, and the residue was mixed with EtOAc / n-hexane (1 / 10 by v / v, total 3 mL), collected by vacuum filtration, and dried to obtain (+)-32-LAC. 0.28 g (67%); melting point 189.3-191.5°C, [α] D 20 = +62.6° (c = 1.15, CH3OH). 1 H NMR (CDCl3, 500MHz) δ: 6.05 (brs, 1H), 3.45 (d, 1H, J = 9.5Hz), 3.36 (d, 1H, J = 9.5Hz), 2.47-2.52 (m, 1H), 2. 43(d,1H,J=17.0Hz),2.39-2.42(m,1H),2.34(d,1H,J=17.0Hz),2.23-2.27(m,2H),2.02(dd,1H,J=7.0Hz and 13.0Hz),1.93-1.98(m,1H),1.70-1.75(m,1H),1.60-1.66(m,1H),1.51 -1.58(m,1H),1.42-1.49(m,1H),1.39-1.41(m,1H),1.20-1.23(m,1H).

[0293] 13 C NMR (CDCl3, 126MHz) δ: 178.29, 58.68, 51.24, 41.99, 41.78, 39.62, 39.51, 38.99, 35.31, 33.54, 25.59, 23.95. ESI-HRMS:(m / z)calcd.for C 12 H 18 NO([M+H] + )192.1383,found:192.1380.

[0294] Cultivation and X-ray diffraction of (+)-32-LAC single crystals: 10 mg of (+)-32-LAC sample was weighed and dissolved in CH2Cl2 (1 mL), then n-hexane (2 mL) was added, shaken well, filtered, and the filtrate was placed in a small glass Erlenmeyer flask. After slow evaporation at room temperature for 2-3 days, a single crystal suitable for X-ray diffraction was obtained. A single crystal with a size of 0.12×0.1×0.08 mm was taken and diffracted with Cu Kα rays at 100.00(10) K on a RigakuXtaLAB Pro single crystal diffractometer. Diffraction data were collected and restored using CrysAlisPro1.171.39.33c (Rigaku OD, 2017), and the structure was analyzed and refined using the SHELXL program.

[0295] The chemical structure of compound (+)-32-LAC by single-crystal diffraction (ORTEP diagram) is shown below. Figure 1 As shown.

[0296] The crystallography and structural refinement parameters of (+)-32-LAC are shown in the table below:

[0297]

[0298]

[0299] Example 8 Synthesis of compounds (-)-I-4, (+)-I-4 and their p-toluenesulfonates

[0300]

[0301] Step 1: Synthesis of compound (±)-22

[0302] At room temperature, 60.00 g (0.14 mol) of (±)-22 p-toluenesulfonate was added to saturated NaHCO3 solution (600 mL × 2), stirred, and extracted with EtOAc (400 mL × 2). The combined organic phases were dried (MgSO4), filtered to remove the drying agent, and concentrated under reduced pressure using a rotary evaporator to obtain compound (±)-22. A yellow oily substance was obtained; 36 mL was prepared. This product did not require characterization and was used directly in the next reaction.

[0303] 3,5-Dinitrobenzoylation: Synthesis of the 3,5-dinitrobenzoylation derivative of compound (±)-22

[0304] At room temperature, p-toluenesulfonate (1.00 g, 2.3 mmol) of compound (±)-22 was added to saturated NaHCO3 solution (200 mL) and stirred, then extracted with EtOAc (100 mL × 2). The organic phases were combined, dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a pale yellow oily compound (±)-22. The above oily substance was dissolved in CH2Cl2 (7 mL), stirred, and then 3,5-dinitrobenzoyl chloride (0.60 g, 2.6 mmol) was added. Triethylamine (0.6 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h after the addition was complete. TLC monitoring showed that the reaction was complete. The reaction solution was directly purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 4] to obtain a pale yellow oily substance. The above oily substance was added to n-hexane (10 mL), and the mixture was stirred at room temperature for 1 h. The solid was collected by suction filtration and dried under vacuum to obtain the 3,5-dinitrobenzoyl derivative of the target product (±)-22. White solid; 0.60 g (57%); melting point 118.9℃-119.8℃;

[0305] 1 H NMR (CDCl3, 500MHz) δ: 9.46 (brs, 1H), 9.19 (d, 2H, J = 2.0Hz), 9.16 (t, 1H, J = 2.0Hz), 6.40-6.42 (m, 1H), 6.31-6.33 (m, 1H), 3.82 (dd, 1H, J = 5.5Hz and 13.5Hz),3.36(dd,1H,J=3.3Hz and 13.8Hz),2.86-2.90(m,3H),2.69(dd,1H,J=1.0Hz and 17.0Hz),2.58-2.60(m,1H),2.37(d,1H,J=17.5Hz),1.77-1.81(m,1H),1.58-1.61(m,10H),1.30(dd,1H,J=5.8Hz and 12.3Hz),1.11-1.13(m,1H).

[0306] 13 C NMR(CDCl3,126MHz)δ:175.42,162.99,148.82,138.26,138.12,136.52,127.59,12 0.86,82.84,54.11,53.02,46.82,45.87,44.76,42.21,37.02,35.75,34.57,28.14.

[0307] ESI-HRMS:(m / z)calcd.for C 23 H 27N3NaO7([M+Na)) + )458.1741,found:458.1735.

[0308] The 3,5-dinitrobenzoyl derivative of (±)-22 is used as a reference standard for chiral HPLC to determine the optical purity of (-)-22 and (+)-22 after chiral acid resolution of (±)-22 in steps 2 and 3.

[0309] Step 2: Synthesis of (R)-(-)-mandelate of compound (-)-22

[0310] At room temperature, compound (±)-22 (18.14 g, 69 mmol) was dissolved in THF (90 mL), and then a THF (90 mL) solution of (R)-(-)-mandelic acid (4.50 g, 30 mmol) was added dropwise. After the addition was complete, stirring was continued for 30 min, followed by the addition of isopropyl ether (180 mL). The mixture was stirred overnight at room temperature, and crystals precipitated. If no solid precipitated, a suitable amount of seed crystals was added to the system, and solid gradually precipitated. Then, a THF (9 mL) solution of R-(-)-mandelic acid (2.25 g, 15 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 h, followed by the addition of isopropyl ether (180 mL). After the addition was complete, the amount of solid in the system increased, and the mixture was stirred at room temperature for 1 h. The solid was collected by filtration (filtrate was recovered), and dried using a vacuum oil pump to obtain a white solid (8.60 g, 21 mmol), which was the (R)-(-)-mandelic acid salt of (-)-22. A small sample was derivatized using the 3,5-dinitrobenzoyl method described above, and its ee value was determined to be 87.05% by chiral HPLC. At room temperature, the above-mentioned (-)-22 (R)-(-)-mandelate white solid (8.40 g, 20 mmol) was thoroughly stirred with a mixed solvent of THF (40 mL) / isopropyl ether (40 mL), then transferred to a 65°C oil bath for stirring. The mixed solvent of THF (10 mL) / isopropyl ether (10 mL) was added dropwise. The system was slightly soluble. Stirring was continued for 30 min, and then the system was placed at room temperature and stirred overnight. The solid was collected by filtration and dried under vacuum to obtain a white solid (6.60 g, 16 mmol). This solid was recrystallized again using THF / isopropyl ether = 1 / 2 (v / v) as solvent to obtain pure R-(-)-mandelate of compound (-)-22. A small sample was derivatized using the 3,5-dinitrobenzoyl method described above, and its ee value was determined by chiral HPLC to be 99.10%. White solid; 6.00 g (43%); This product does not require characterization and can be used directly in the next reaction.

[0311] Step 3: Synthesis of (S)-(+)-mandelate of compound (+)-22

[0312] At room temperature, compound (±)-22 (18.14 g, 69 mmol) was dissolved in isopropanol (45 mL), 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 and no significant change was observed, stirring was continued for 30 min, followed by the dropwise addition of isopropyl ether (270 mL). The addition was continued until a large amount of solid was produced; if no crystals were produced, a suitable amount of seed crystals was added to the system. The crystallization system was stirred overnight at room temperature. The crystals were collected by filtration (filtrate was recovered), and dried under vacuum to obtain a white solid (9.00 g, 22 mmol) of (+)-22 (S)-(+)-mandelic acid salt. A small amount was derivatized using the above-described 3,5-dinitrobenzoyl method, and its ee value was determined by chiral HPLC to be 30.88%. At room temperature, the (S)-(+)-mandelate of (+)-22 (9.00 g, 22 mmol) was thoroughly stirred with a mixed solvent of isopropanol / isopropyl ether = 1 / 2 (v / v, 50 mL total). The mixture was then transferred to a 60°C oil bath and stirred (the system was slightly soluble) for 10 min. The system was then placed at room temperature, and a large amount of white solid gradually precipitated. The mixed solvent of isopropanol / isopropyl ether = 1 / 2 (v / v, 15 mL total) was added dropwise, and stirring continued for 1-2 h. The solid was collected by filtration and dried under vacuum to obtain a white solid (5.40 g, 13 mmol). The recrystallization operation was repeated twice to obtain the (S)-(+)-mandelate of compound (+)-22. A small amount was derivatized using the 3,5-dinitrobenzoyl method described above, and its ee value was determined by chiral HPLC to be 98.34%. White solid; 2.40 g (17%); This product does not require characterization and can be used directly in the next reaction.

[0313] Step 4: Synthesis of compound (-)-I-4 and its p-toluenesulfonate

[0314] At room temperature, (R)-(-)-mandelate (3.00 g, 7.2 mmol) of compound (-)-22 was added to saturated NaHCO3 solution (100 mL), stirred for 20 min, and extracted with EtOAc (80 mL × 3). After combining the organic phases, the mixture was dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil, which was then dissolved in CH2Cl2 (20 mL). TFA (15 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4–6 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was then concentrated again with CH2Cl2 (20 mL). The resulting oil was dried using a vacuum oil pump to obtain (-)-I-4. The above-mentioned (-)-I-4 was dissolved in CH3OH (2.5 mL), and then EtOAc (12 mL) was added and stirred thoroughly. p-TsOH·H2O (1.40 g, 7.4 mmol) was added to the solution, and after stirring to dissolve, a large amount of solid precipitated. Stirring was continued at room temperature for 1 h. The solid was collected by suction filtration, and the filter cake was dried using a vacuum oil pump to obtain compound (-)-I-4 p-toluenesulfonate. White solid; 1.80 g (66%); melting point 180.3℃-183.5℃; [α] D 20 = -35.47 (c = 2.65, CH3OH);

[0315] 1 H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.5Hz), 7.23 (d, 2H, J = 8.0Hz), 6.42-6.44 (m, 1H),6.29-6.31(m,1H),3.24(d,1H,J=13.0Hz),3.12(d,1H,J=13.0Hz),2.92-2.94( m,1H),2.81-2.87(m,2H),2.57(d,1H,J=17.5Hz),2.49-2.53(m,1H),2.37(s,3H), 2.36(d,1H,J=17.5Hz),1.75-1.80(m,1H),1.57-1.59(m,1H),1.34(dd,1H,J=4.5Hz and13.5Hz),1.14-1.15(m,1H).

[0316] 13 C NMR(CD3OD,126MHz)δ:175.72.143.52,141.71,138.50,137.88,129.82,126 .96,53.81,50.45,48.14,46.89,45.84,37.91,37.15,35.07,34.06,21.31.

[0317] Compound (-)-I-4 is a specific form of the compound having the general formula I in this application, and is also an optically pure compound with the same relative configuration as (±)-I-4 and having levorotatory optical properties.

[0318] Step 5: Synthesis of compound (+)-I-4 and its p-toluenesulfonate

[0319] At room temperature, compound (+)-22(S)-(+)-mandelate (2.40 g, 5.8 mmol) was added to saturated NaHCO3 solution (100 mL), stirred for 20 min, and extracted with EtOAc (60 mL × 3). The combined organic phases were dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil, which was then dissolved in CH2Cl2 (18 mL). TFA (14 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4–6 h. TLC monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil, which was then concentrated again with CH2Cl2 (20 mL). The resulting oil was dried using a vacuum oil pump to obtain (+)-I-4. The dried oil was dissolved in CH3OH (2 mL), and EtOAc (8 mL) was added with stirring. p-TsOH·H₂O (1.10 g, 5.8 mmol) was added to the reaction solution and stirred until dissolved. A large amount of solid precipitated out. Stirring was continued at room temperature for 1 h. The solid was collected by vacuum filtration, and the filter cake was dried using a vacuum oil pump to obtain compound (+)-I-4-toluenesulfonate. White solid; 1.60 g (73%); melting point 182.1 °C–184.7 °C; [α] D 20 = +37.81 (c = 2.75, CH3OH);

[0320] 1 H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.0Hz), 6.42-6.44 (m, 1H),6.29-6.31(m,1H),3.24(d,1H,J=13.0Hz),3.12(d,1H,J=13.0Hz),2.92-2.94( m,1H),2.81-2.87(m,2H),2.57(d,1H,J=17.5Hz),2.50-2.53(m,1H),2.37(s,3H), 2.36(d,1H,J=17.5Hz),1.75-1.80(m,1H),1.57-1.59(m,1H),1.34(dd,1H,J=6.0Hz and13.5Hz),1.13-1.16(m,1H).

[0321] 13 C NMR(CD3OD,126MHz)δ:175.73,143.53,141.70,138.50,137.89,129.82,126 .96,53.81,50.45,48.14,46.89,45.85,37.92,37.15,35.07,34.07,21.30.

[0322] Compound (+)-I-4 is a specific form of the compound having general formula I in this application, and is also an optically pure compound with dextrorotatory optical properties having the same relative configuration as (±)-I-4.

[0323] The absolute configuration of compound (+)-I-4 was determined as follows: the (S)-(+)-mandelate of (+)-22, which has the same absolute configuration, was converted to its lactam (+)-22-LAC. The absolute configuration of (+)-22-LAC was determined by X-ray single-crystal diffraction, and this absolute configuration was the same as that of (+)-32. This method can indirectly determine the absolute configuration of (+)-I-4.

[0324] The specific experimental method is as follows:

[0325] Synthesis of (+)-22-LAC: (+)-22-(S)-(+)-mandelate (1.00 g, 2.4 mmol) with an ee value of 98.34% was added to a saturated NaHCO3 solution (100 mL), stirred for 10 min, and then extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with brine, dried (MgSO4), filtered to remove the drying agent, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was dissolved in toluene (7 mL), refluxed overnight, and TLC showed the reaction was complete. The reaction system was cooled to room temperature, the solvent was evaporated on a rotary evaporator, and the residue was mixed with EtOAc / n-hexane (1 / 10 by v / v, total 5 mL), collected by vacuum filtration, and dried to obtain (+)-32-LAC. 0.40 g (88%); melting point 178.7-180.5°C; [α] D 20 = +30.2° (c = 1.03, CH3OH).

[0326] 1H NMR (CDCl3, 500MHz) δ: 6.27-6.29 (m, 1H), 6.22-6.24 (m, 1H), 5.89 (brs, 1H), 3.40 (dd, 1H, J = 1.0Hz and9.5Hz),3.36(d,1H,J=9.5Hz),2.97-2.99(m,1H),2.81-2.83(m,1H),2.69-2.74(m,1H),2. 54-2.57(m,1H),2.13(d,1H,J=17.0Hz),2.05(d,1H,J=17.0Hz),1.91(ddd,1H,J=1.0Hz,8.5Hz and 12.5Hz),1.57-1.60(m,1H),1.42(dd,1H,J=0.8Hz and 12.8Hz),1.08-1.10(m,1H).

[0327] 13 C NMR (CDCl3, 126MHz) δ: 178.22, 136.71, 136.25, 58.19, 52.34, 48.58, 45.59, 44.50, 40.90, 40.74, 37.63, 33.04. ESI-HRMS:(m / z)calcd.for C 12 H 16 NO([M+H] + )190.1226,found:190.1224.

[0328] Cultivation and X-ray diffraction of (+)-22-LAC single crystals: 10 mg of (+)-22-LAC sample was weighed and dissolved in CH2Cl2 (1 mL), then n-hexane (2 mL) was added, shaken well, filtered, and the filtrate was placed in a small glass Erlenmeyer flask. After slow evaporation at room temperature for 2-3 days, a single crystal suitable for X-ray diffraction was obtained. A single crystal with a size of 0.3 × 0.09 × 0.08 mm was taken and diffracted with Cu Kα rays at 100.00 (10) K on a RigakuXtaLAB Pro single crystal diffractometer. Diffraction data were collected and restored using CrysAlisPro1.171.39.33c (Rigaku OD, 2017). The structure was analyzed and refined using the SHELXL program.

[0329] The chemical structure of compound (+)-22-LAC by single-crystal diffraction (ORTEP diagram) is shown below. Figure 2 As shown.

[0330] The relevant parameters for crystal testing and structural refinement of (+)-22-LAC are shown in the table below:

[0331]

[0332]

[0333] Example 9 Synthesis of compound (±)-I-7

[0334]

[0335] Step 1: Synthesis of compound (±)-33

[0336] Add 200 mL of dry CH2Cl2 to a dry flask, and replace the air in the reaction vessel with nitrogen gas (using a balloon) according to standard procedures. Under ice-water bath cooling, slowly add dropwise a solution of 298 mL of dry CH2Cl2 containing 1 M Et2Zn in n-hexane and 30 mL of TFA (33.99 g, 0.30 mol), resulting in a white slurry. After the addition is complete, continue stirring under ice-water bath conditions for 0.5 h, then add dropwise a solution of 80 mL of dry CH2Cl2 containing 79.84 g, 0.30 mol of CH2I2 (during the addition, the white viscous solid gradually dissolves and becomes clear, then precipitates out as a suspension). After the addition is complete, continue stirring under ice-water bath conditions for 0.5 h, then add dropwise a solution of 20 mL of dry CH2Cl2 containing 10.00 g, 75 mmol of compound (±)-18. After the addition was complete, the reaction system was stirred at room temperature for 4-6 hours and then refluxed overnight. TLC monitoring showed the reaction was complete, and the reaction was stopped. After the reaction system cooled to room temperature, saturated NH4Cl aqueous solution (300 mL × 2) was added, stirred, and extracted with CH2Cl2 (200 mL × 2). The organic phases were combined and washed with saturated brine (400 mL) to separate the organic phases. The combined organic phases were dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated using a rotary evaporator to obtain a brown oily substance. This substance was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target compound (±)-33. Yellow oily substance (slightly impure); 3.15 g (29%);

[0337] 1 H NMR (CDCl3, 500MHz) δ: 3.48-3.52 (m, 1H), 2.95 (dt, 1H, J = 3.5Hz and 18.5Hz),2.65-2.77(m,2H),2.55-2.56(m,1H),2.51-2.53(m,1H),1.32-1.35(m,1H),1.01 -1.05(m,1H),0.97-1.00(m,1H),0.87-0.90(m,1H),0.54-0.57(m,1H),0.03-0.08(m,1H).

[0338] Step 2: Synthesis of compound (±)-34

[0339] Under a nitrogen atmosphere, t-BuOK (11.92 g, 0.11 mol) was added to 30 mL of dry THF and stirred in an ice-water bath to form a suspension. Then, tert-butyl diethylphosphonoacetate (26.81 g, 0.11 mol) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 1 h in an ice-water bath. Then, a freshly prepared solution of compound (±)-33 (3.15 g, 21 mmol) in 10 mL of dry THF was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete. The reaction solution was then poured into ice water (80 mL × 2) and extracted with CH2Cl2 (60 mL × 2). After combining the organic phases, wash once more with saturated brine (150 mL), dry (MgSO4), filter to remove the desiccant, and concentrate the filtrate under reduced pressure using a rotary evaporator to obtain a deep yellow oil. Purify by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-34. Pale yellow oil; 3.15 g; This product does not require characterization and can be used directly in the next reaction.

[0340] Step 3: Synthesis of compound (±)-35

[0341] At room temperature, compound (±)-34 (3.60 g, 15 mmol) was dissolved in CH3NO2 (120 mL), stirred, and DBU (24.47 g, 0.16 mol) was added dropwise. After the addition was complete, the reaction mixture was refluxed for 48 h under N2. TLC monitoring showed that a large amount of starting material remained unreacted, so the reaction was stopped. The reaction solution was cooled to room temperature and poured into ice water, extracted with CH2Cl2 (50 mL × 2), and the combined organic phases were 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 using a rotary evaporator to obtain a brownish-black oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-35. Pale yellow oil; 0.74 g (combined yield of (±)-33→(±)-35 10%).

[0342] 1H NMR (CDCl3, 500MHz) δ: 4.83 (dd, 1H, J = 1.3Hz and 11.3Hz),4.55(d,1H,J=11.0Hz),2.73(s,2H),2.52-2.58(m,1H),2.48-2.49 (m,1H),2.30-2.32(m,1H),2.15-2.19(m,2H),2.11(ddd,1H,J=2.3Hz,8.5Hz and13.3Hz),1.48(s,9H),1.23-1.27(m,1H),1.13-1.17(m,2H),0.58-0.60(m,1H),0.43-0.46(m,1H),0.06-0.10(m,1H).

[0343] 13 C NMR (CDCl3, 126MHz) δ: 170.79, 83.55, 81.08, 49.08, 39.87, 39.61, 38.64, 37.19, 34.59, 29.94, 29.14, 28.26, 12.23, 11.14, 2.58.

[0344] ESI-HRMS:(m / z)calcd.for C 17 H 26 NO4([M+H)) + )308.1856,found:308.1853.

[0345] Step 4: Synthesis of compound (±)-36

[0346] Compound (±)-35 (0.28 g, 0.91 mmol) was dissolved in CH2Cl2 (5 mL), and Et3SiH (0.16 g, 1.4 mmol) and TFA (2 mL) were added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. TLC monitoring showed that the reaction was complete. The reaction mixture was poured into ice water (10 mL) and extracted with CH2Cl2 (10 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated at low temperature (25 °C) using a rotary evaporator to obtain a yellow oil. CH2Cl2 (10 mL × 3) was added to the oil for further concentration, and the mixture was dried under vacuum for 10 min, precipitating a white solid. The solid was crushed and then hexane (4 mL) was added, and the mixture was stirred at room temperature for 1 h. The solid was collected by suction filtration and dried under vacuum to obtain compound (±)-36. White solid; 0.09 g (39%); melting point 105.7℃-109.3℃;

[0347] 1H NMR (DMSO-d6, 500MHz) δ: 12.31 (brs, 1H), 4.78 (d, 1H, J = 12.0Hz), 4.71 (d, 1H, J = 12.0Hz), 2.74 (d, 1H, J = 17.5Hz), 2.56 (d, 1H,J=17.5Hz),2.52-2.55(m,1H),2.36-2.37(m,1H),2.21-2.23(m,1H),2.12-2.17(m,2H),2.00(ddd,1H,J=2.0Hz,8.5Hz and13.0Hz),1.21-1.23(m,1H),1.17-1.20(m,1H),1.09-1.12(m,1H),0.54-0.56(m,1H),0.37-0.39(m,1H),-0.01-0.03(m,1H).

[0348] 13 C NMR (CDCl3, 126MHz) δ: 176.63, 83.22, 48.89, 39.71, 38.20, 37.95, 37.13, 34.63, 29.81, 29.14, 12.42, 11.33, 2.66.

[0349] ESI-HRMS:(m / z)calcd.for C 13 H 18 NO4([M+H)) + )252.1230,found:252.1228.

[0350] Step 5: Synthesis of compound (±)-I-7

[0351] Compound (±)-36 (0.18 g, 0.72 mmol) was dissolved in CH3OH (4 mL), and 10% Pd(OH)2 / C (0.06 g) was added. The air in the reaction vessel was replaced with hydrogen (using a balloon) according to standard procedures, and the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete (the reaction typically takes 12 hours to complete). The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a white solid. CH3OH (1 mL) / EtOAc (3 mL) was added, and the mixture was stirred and slurried at room temperature for 1-2 hours. The mixture was then filtered and dried to obtain the target product (±)-I-7. White solid; 0.04 g (25%); melting point 184.5℃-190.0℃;

[0352] 1H NMR (CD3OD, 500MHz) δ: 3.10 (dd, 1H, J = 1.5Hz and 13.0Hz), 2.96 (d, 1H, J = 13.0Hz), 2.78 (dd, 1H, J = 1.3Hz and 16.8Hz),2.60(d,1H,J=16.5Hz),2.51-2.55(m,1H),2.48-2.49(m,1H),2.23-2.27(m,2H),2.18(dd,1H,J=6.8Hz and 12.8Hz),1.69(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.50-1.53(m,1H),1.14-1.20(m,2H),0.56-0.58(m,1H),0.45-0.48(m,1H),0.03-0.07(m,1H).

[0353] 13 C NMR (D2O, 126MHz) δ: 179.55, 49.53, 46.11, 44.30, 37.56, 35.01, 34.80, 32.58, 29.65, 26.94, 10.37, 9.02, 0.01. ESI-HRMS:(m / z)calcd.for C 13 H 20 NO2([M+H] + )222.1489,found:222.1487.

[0354] Compound (±)-I-7 is a specific form of the compound having general formula I in this application.

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

[0356]

[0357] Step 1: Synthesis of Compound 37

[0358] 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). Following standard operating procedures, the air in the reactor was replaced with nitrogen (using a balloon). 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, total 50 mL) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was stopped, and the reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a purplish-red oil. The oil was placed in an ice-water bath for low-temperature crystallization. After crystals precipitated, n-hexane (100 mL) was added, and the mixture was stirred and slurried at room temperature for 1 hour. The solid was collected by suction filtration, and the filter cake was dried using a vacuum oil pump to obtain the crude product of compound 37. White solid (containing a certain amount of impurities); 40.00 g (>100%, because it contains a certain amount of unreacted maleic anhydride); this product is not further purified and is used directly in the next reaction.

[0359] 1 H NMR (CDCl3, 500MHz) δ: 3.18 (s, 2H), 1.55-1.59 (m, 7H), 1.35 (s, 6H), 0.62 (d, 3H, J = 6.5Hz).

[0360] Step 2: Synthesis of Compound 38

[0361] Compound 37 (40.00 g, based on 0.17 mol) was dissolved in 1,4-dioxane (400 mL). Under ice bath conditions, 50% NaOH aqueous solution (68 mL) was slowly added dropwise, during which a white solid gradually precipitated. After the addition was complete, 1,4-dioxane (300 mL) was added to the system, and the mixture was stirred at room temperature for 1 hour. TLC monitoring showed that the reaction was complete. Under ice bath cooling, 1M HCl was slowly added dropwise to the reaction system until the pH < 2. The mixture was saturated with sodium chloride and extracted with EtOAc (300 mL × 3). The organic phases were combined, dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated using a rotary evaporator to obtain the residue. Hexane (100 mL) was added to the residue, and the mixture was stirred and slurried at room temperature for 1 hour. The solid was collected by suction filtration and dried under vacuum to obtain compound 38. White solid; 20.86 g (combined yield of 56% for 1,2,3,4,5-pentamethylcyclopentadiene → 38); the product was used directly in the next reaction without further purification. 1 HNMR (DMSO-d6, 500MHz) δ: 2.90 (s, 2H), 1.54 (s, 6H), 1.37 (q, 1H, J = 6.3Hz), 1.08 (s, 6H), 0.52 (d, 3H, J = 6.5Hz).

[0362] Step 3: Synthesis of Compound 39

[0363] Compound 38 (20.86 g, 83 mmol) was dissolved in N,N-dimethylformamide (DMF) (210 mL). The air in the reactor was replaced with nitrogen (using a balloon) according to standard operating procedures. K₂CO₃ (34.28 g, 0.25 mol) was added under ice-water bath cooling, followed by slow dropwise addition of CH₃I (46.94 g, 0.33 mol). After the addition was complete, the reaction was allowed to proceed at room temperature for 5–6 hours. TLC monitoring showed the reaction was complete. EtOAc (200 mL) was added to the reaction mixture, and the solid was removed by filtration. 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), filtered to remove the desiccant, and the filtrate was concentrated using a rotary evaporator to obtain a yellow oily substance. This was purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 9] to obtain the target product 39. 22.10 g (95%, containing certain impurities) of a colorless, transparent oily substance was obtained. This product was not further purified and was used directly in the next reaction step.

[0364] 1 H NMR (CDCl3, 500MHz) δ: 3.57 (s, 6H), 3.00 (s, 2H), 1.60 (s, 6H), 1.37 (q, 1H, J = 6.3Hz), 1.15 (s, 6H), 0.60 (d, 3H, J = 6.5Hz).

[0365] Step 4: Synthesis of compound (±)-40

[0366] Sodium metal (9.97 g, 0.43 mol) was added to dry toluene (220 mL). The mixture was heated under N2 atmosphere until the sodium was completely melted. Stirring was started, and the reaction system temperature was maintained at 103 °C–106 °C for 20 min. A solution of compound 39 (22.10 g, 79 mmol) and TMSCl (45.39 g, 0.42 mol) in dry toluene (15 mL) was added dropwise. The dropwise addition was exothermic, and the reaction system temperature was controlled by adjusting the dropwise addition rate to maintain it at 103 °C–106 °C. After the addition was complete, the reaction system temperature was maintained at 103 °C–106 °C and stirred overnight. TLC monitoring showed the reaction was complete, and the reaction solution was cooled to room temperature. The solution was filtered with diatomaceous earth as an aid, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance. The oily substance was dissolved in THF (100 mL), and 1 M HCl (15 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. TLC monitoring showed the reaction was complete. The reaction solution was poured into water (100 mL), and EtOAc (100 mL × 2) was added for extraction. After combining the organic phases, the mixture was washed with saturated brine (300 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance, which solidified at low temperature. 10 mL of n-hexane was added to the solid, and the mixture was stirred and slurried at room temperature for 1 h. The solid was collected by filtration and dried under vacuum using an oil pump to obtain the target compound (±)-40. White solid; 3.60 g (21%); melting point 124.0℃-128.0℃;

[0367] 1 H NMR (CDCl3, 500MHz) δ: 4.44 (dd, 1H, J = 3.5Hz and 9.0Hz), 3.16 (dd, 1H, J = 3.5Hz and 7.5Hz), 2.91 (dd, 1H, J = 7.5Hz and 9.0Hz), 1.640-1.643 (m, 3H), 1.58-1.62 (m, 2H), 1.499-1.504 (m, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 0.57 (d, 3H, J = 6.5Hz).

[0368] Step 5: Synthesis of compound (±)-41

[0369] Compound (±)-40 (2.61 g, 12 mmol) was dissolved in CCl4 (20 mL). Triphenylphosphine (3.41 g, 13 mmol) and NaHCO3 (0.04 g, 0.48 mmol) were added sequentially with stirring. The air in the reactor was replaced with nitrogen (using a balloon) according to standard operating procedures, and the mixture was refluxed overnight with stirring. TLC monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. Methyl tert-butyl ether (12 mL) was added to the concentrated residue, and the mixture was stirred at room temperature for 1 h. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brownish-black oil. This oil was purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 9 / 91] to obtain the target product (±)-41. A pale yellow oil (slightly impure); 2.20 g; this product does not require characterization and can be used directly in the next reaction.

[0370] Step 6: Synthesis of compound (±)-42

[0371] Zinc powder (2.06 g, 32 mmol) and glacial acetic acid (10 mL) were mixed and stirred. A freshly prepared solution of 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 N2 atmosphere. TLC monitoring showed 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 CH2Cl2 (40 mL × 2). The combined organic phases were washed successively with water (80 mL × 3) and saturated brine (100 mL), dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a yellow oil. This oil was then purified by column chromatography [V(EtOAc) / V(n-hexane) = 0 / 1 → 1 / 20] to obtain a pale yellow oil. The oil was dried using a vacuum oil pump to become a solid. Add 5 mL of n-hexane to the above solid and stir at room temperature for 1 h. Filter, and dry the filter cake with a vacuum oil pump to obtain the target compound (±)-42. White solid; 1.08 g ((±)-40→(±)-42 combined yield 45%); melting point 101.0℃-103.0℃;

[0372] 1H NMR(CDCl3,500MHz)δ:3.34-3.37(m,1H),2.62(ddd,1H,J=3.0Hz,8.5Hz and18.5Hz),2.49-2.52(m,1H),2.14(dt,1H,J=3.5Hz and 18.5Hz), 1.616-1.624 (m, 3H), 1.51-1.52 (m, 3H), 1.48 (q, 1H, J = 6.5Hz), 1.14 (s, 3H), 1.13 (s, 3H), 0.58 (d, 3H, J = 6.5Hz).

[0373] 13 C NMR (CDCl3, 126MHz) δ: 211.60, 134.45, 133.12, 73.07, 66.04, 56.64, 55.52, 45.28, 36.90, 15.97, 15.29, 12.49, 11.11, 8.19.

[0374] ESI-HRMS:(m / z)calcd.for C 14 H 21 O([M+H] + )205.1587,found:205.1587.

[0375] Step 7: Synthesis of compound (±)-43

[0376] Under N2 atmosphere, t-BuOK (2.35 g, 21 mmol) was added to 10 mL of dry THF and stirred in an ice-water bath to form a suspension. Then, tert-butyl diethylphosphonoacetate (5.28 g, 21 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed for 30 min in an ice-water bath. Then, a freshly prepared solution of compound (±)-42 (0.86 g, 4.2 mmol) in 7 mL of dry THF was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete. The reaction solution was then poured into 80 mL of ice water and extracted with CH2Cl2 (30 mL × 3). The organic phases were combined and washed successively with 1M HCl (20 mL) and saturated brine (100 mL), dried (MgSO4), filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a deep yellow oil. This oil was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 20] to obtain the target product (±)-43. A pale yellow oil; 0.97 g; this product does not require characterization and can be used directly in the next reaction.

[0377] Step 8: Synthesis of compound (±)-44

[0378] At room temperature, compound (±)-43 (0.97 g, 3.2 mmol) was dissolved in CH3NO2 (12 mL), and DBU (4.40 g, 29 mmol) was added dropwise. After the addition was complete, the reaction mixture was refluxed for 48 h under N2 atmosphere. TLC monitoring showed that approximately 60% of the starting material remained unreacted, so the reaction was stopped. The reaction solution was cooled to room temperature and poured into ice water (100 mL), and extracted with CH2Cl2 (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 using a rotary evaporator to obtain a brownish-black oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain a pale yellow oil. The oily substance solidified at low temperature, and hexane (2 mL) was added. The mixture was stirred and slurried at -18℃ for 30 min. The solid was collected by suction filtration and dried by vacuum oil pump to obtain the target product (±)-44. White solid; 0.10 g ((±)-42→(±)-44 combined yield 7%); melting point 78.6℃-81.5℃;

[0379] 1 H NMR (CDCl3, 500MHz) δ: 4.82 (d, 1H, J = 11.5Hz), 4.66 (d, 1H, J = 11.5Hz), 2.47-2.52 (m, 1H), 2.3 6(d,1H,J=17.5Hz),2.28(d,1H,J=17.5Hz),2.24-2.26(m,1H),1.91(ddd,1H,J=2.0Hz,8.5Hz and 13.0Hz),1.73-1.74(m,3H),1.605-1.612(m,3H),1.44(s,9H),1.17-1.24(m,2H),1.00(s,3H),0.97(s,3H),0.55(d,3H,J=6.0Hz).

[0380] 13 C NMR(CDCl3,126MHz)δ:171.17,137.15,134.49,82.91,80.86,66.54,56.45,55. 96,55.78,42.49,39.08,36.58,31.59,28.25,16.22,15.25,13.26,12.84,8.12.

[0381] ESI-HRMS:(m / z)calcd.for C 21 H 32 NO4 ([MH)) - )362.2337,found:362.2343.

[0382] Step 9: Synthesis of compound (±)-45

[0383] Compound (±)-44 (0.10 g, 0.28 mmol) was dissolved in CH2Cl2 (5 mL), and TFA (1 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 2-3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a brown oily substance, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 7] to obtain a pale yellow solid. 3 mL of n-hexane 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 vacuum to obtain compound (±)-45. White solid; 0.05 g (63%); melting point 122.8℃-126.4℃;

[0384] 1 H NMR (CDCl3, 500MHz) δ: 4.78 (d, 1H, J = 12.0Hz), 4.74 (d, 1H, J = 11.5Hz), 2.55 (d, 1H, J = 18.0Hz) ,2.50-2.54(m,1H),2.51(d,1H,J=18.0Hz),2.26-2.28(m,1H),1.91(ddd,1H,J=2.0Hz,8.5Hz and 13.5Hz),1.75-1.76(m,3H),1.61-1.62(m,3H),1.22-1.26(m,2H),0.99(s,3H),0.98(s,3H),0.56(d,3H,J=6.5Hz);

[0385] 13 C NMR(CDCl3,126MHz)δ:176.32,137.65,134.32,82.69,66.66,56.44,56.10,55.55,42.44,38.57,34.98,31.74,16.34,15.23,13.31,12.88,8.11;

[0386] ESI-HRMS:(m / z)calcd.for C 17 H 26 NO4([M+H)) + )308.1856,found:308.1850.

[0387] Step 10: Synthesis of compound (±)-I-8

[0388] Compound (±)-45 (0.05 g, 0.16 mmol) was dissolved in CH3OH (3 mL), and 10% Pd(OH)2 / C (0.03 g) was added. The air in the reaction vessel was replaced with hydrogen (using a balloon) according to standard procedures, and the mixture was stirred overnight at room temperature. TLC monitoring showed the reaction was complete (the reaction typically takes 12 h to complete). The mixture was filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain 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 vacuum to obtain the target product (±)-I-8. White solid; 0.02 g (53%); melting point 180.0℃-184.0℃;

[0389] 1 H NMR (CD3OD, 500MHz) δ: 3.09 (dd, 1H, J = 0.8Hz and 13.3Hz), 2.97 (d, 1H, J = 13.0Hz), 2.48-2.53 (m, 1H), 2.43 (dd, 1H, J = 1.3Hz and 17.3Hz),2.27(d,1H,J=17.0Hz),2.20-2.22(m,1H),1.81-1.82(m,3H),1.61-1.62(m,3H),1.59(ddd,1H,J=2.0Hz,8.0Hzand 12.5Hz),1.24(q,1H,J=6.3Hz),1.14(dd,1H,J=6.5Hz and 12.5Hz),1.08(s,3H),0.99(s,3H),0.58(d,3H,J=6.5Hz);

[0390] 13 C NMR(CD3OD,126MHz)δ:180.23,137.15,136.15,67.72,57.44,56.85,55.52,51.85,45.39,43.50,38.85,34.01,16.90,15.51,13.16,12.83,8.44;

[0391] ESI-HRMS:(m / z)calcd.for C 17 H 28 NO2([M+H] + )278.2115,found:278.2111.

[0392] Compound (±)-I-8 is a specific form of the compound having general formula I in this application.

[0393] Example 11 Synthesis of compound (±)-I-9 and its p-toluenesulfonate

[0394]

[0395] Step 1: Synthesis of Compound 46

[0396] Tetrabutylammonium bromide (TBAB) (32.64 g, 0.10 mol) was added to 1.2 L of 50% NaOH aqueous solution and stirred. The air in the reaction vessel was replaced with nitrogen gas (using a balloon) according to standard operating procedures. Under an ice-water bath, freshly distilled cyclopentadiene (167.13 g, 2.5 mol) and 1,2-dichloroethane (250.50 g, 2.5 mol) were mixed thoroughly and added dropwise to the reaction system (the reaction is exothermic; the dropping rate was controlled to maintain an internal temperature of 30℃-40℃. During the dropping process, the system color gradually changed from colorless and transparent to dark reddish-brown, and the system became viscous). After the dropping was complete, the reaction apparatus was moved to an oil bath and stirred for 2 hours to maintain an internal temperature of 30℃-40℃. The reaction was stopped, and the reaction solution was cooled to room temperature and poured into 1.0 L of ice water. Extraction was performed with n-pentane (300 mL × 2). The organic phases were combined and washed successively with water (500 mL × 2), 1 M HCl (300 mL), and saturated brine (500 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was fractionally distilled at atmospheric pressure, and the fraction collected at 108 °C–109 °C was used to obtain the target compound 46 (containing a certain amount of n-pentane). It is a colorless, transparent liquid; 46.24 g (20%). 1 H NMR (CDCl3, 500MHz) δ: 6.50-6.52 (m, 2H), 6.11-6.13 (m, 2H), 1.65 (s, 4H).

[0397] Step 2: Synthesis of Compound 47

[0398] 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). Following standard operating procedures, the air in the reactor was replaced with nitrogen (using a balloon). 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 under an ice-water bath. After the addition was complete, the mixture was stirred overnight at room temperature, and then refluxed in an oil bath at 45 °C for 2 h. The reaction was stopped, and the temperature of the reaction system was lowered to room temperature. The mixture was then concentrated under reduced pressure using a rotary evaporator to obtain a colorless, transparent oil. Hexane (100 mL × 4) was added to this oil, and the mixture was concentrated several times to obtain a white solid. Hexane (120 mL) was added to the white solid, and the mixture was stirred and slurried at room temperature for 1 h. The solid was collected by filtration and dried under vacuum using an oil pump to obtain compound 47. White solid; 21.03 g (77%); melting point 92.7℃-96.9℃;

[0399] 1H NMR(CDCl3,500MHz)δ:6.386-6.394(m,2H),3.70-3.71(m,2H),2.88-2.90(m,2H),0.64-0.68(m,2H),0.51-0.54(m,2H);

[0400] 13 C NMR (CDCl3, 126MHz) δ: 171.25, 135.62, 51.11, 49.12, 47.54, 8.26, 7.12;

[0401] ESI-HRMS:(m / z)calcd.for C 11 H 11 O3([M+H)) + )191.0703,found:191.0701.

[0402] Step 3: Synthesis of Compound 48

[0403] Compound 47 (21.00 g, 0.11 mol) was dissolved in 1,4-dioxane (500 mL), stirred under ice bath cooling, and 50% NaOH aqueous solution (44 mL) was slowly added dropwise. A white solid gradually precipitated during the addition. After the addition was complete, stirring was continued at room temperature for 0.5–1 hour. TLC monitoring showed the reaction was complete. Under ice bath cooling, 1 M HCl was added dropwise to adjust the pH of the reaction solution to <2. The solution was saturated with sodium chloride and extracted with EtOAc (400 mL × 3). The organic phases were combined, dried (MgSO4), and the desiccant was removed by vacuum filtration. The filtrate was concentrated using a rotary evaporator to obtain the residue. Hexane (120 mL) was added to the residue, and the mixture was stirred and slurried at room temperature for 1 hour. The solid was collected by vacuum filtration and dried under vacuum oil pump to obtain compound 48. White solid; 22.33 g (97%); melting point 163.3 °C–166.3 °C; 1 H NMR(CDCl3,500MHz)δ:6.345-6.352(m,2H),3.50-3.51(m,2H),2.53-2.55(m,2H),0.56-0.59(m,2H),0.42-0.45(m,2H);

[0404] 13 C NMR (CDCl3, 126MHz) δ: 179.21, 135.10, 51.32, 49.66, 44.86, 7.91, 6.55;

[0405] ESI-HRMS:(m / z)calcd.for C 11 H 13 O4([M+H)) +)209.0808,found:209.0805.

[0406] Step 4: Synthesis of Compound 49

[0407] Compound 48 (42.34 g, 0.20 mol) was dissolved in DMF (500 mL), and the air in the reactor was replaced with nitrogen (by a balloon) according to standard operating procedures. Dry K₂CO₃ (84.32 g, 0.61 mol) was added under an ice-water bath, followed by the slow dropwise addition of CH₃I (115.44 g, 0.81 mol). After the addition was complete, the reaction apparatus was transferred to a 55°C oil bath and stirred overnight. TLC monitoring showed that the reaction was complete. The reaction system was cooled to room temperature, and EtOAc (500 mL) was added. The mixture was stirred, filtered to remove the solid, 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 the desiccant was removed by filtration. The filtrate was concentrated using a rotary evaporator to obtain a brownish-black oily substance, which was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 10] to obtain a white solid. n-Hexane (150 mL) was added to the solid, and the mixture was stirred and slurried at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to obtain the target compound 49. White solid; 40.09 g (83%); melting point 71.4℃-74.2℃;

[0408] 1 H NMR(CDCl3,500MHz)δ:6.34-6.35(m,2H),3.62(s,6H),3.45(m,2H),2.52-2.53(m,2H),0.54-0.57(m,2H),0.41-0.44(m,2H);

[0409] 13 C NMR (CDCl3, 126MHz) δ: 172.88, 135.07, 51.67, 51.37, 49.01, 44.46, 7.86, 6.51;

[0410] ESI-HRMS:(m / z)calcd.for C 13 H 17 O4([M+H)) + )237.1121,found:237.1118.

[0411] Step 5: Synthesis of compound (±)-50

[0412] Sodium metal (21.41 g, 0.93 mol) was added to dry toluene (300 mL). The mixture was heated under N2 atmosphere until the sodium was completely melted. Stirring was started, and the internal temperature was maintained at 103℃-106℃ for 20 min. A solution of compound 49 (40.00 g, 0.17 mol) and TMSCl (97.48 g, 0.90 mol) in dry toluene (200 mL) was added dropwise. The dropwise addition was exothermic; the rate of addition was controlled to maintain the internal temperature of the reaction system at 103℃-106℃. After the addition was complete, the internal temperature of the reaction system was maintained at 103℃-106℃ and stirring continued for 3-4 hours. TLC monitoring showed the reaction was complete, and the reaction solution was cooled to room temperature. The solution was filtered with diatomaceous earth as an aid, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a dark reddish-brown oil. The oil was dissolved in THF (300 mL), and 1M HCl (20 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. TLC monitoring showed the reaction was complete. The reaction solution was poured into water (300 mL), and EtOAc (300 mL × 2) was added for extraction. After combining the organic phases, the mixture was washed with saturated brine (500 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain the residue. A mixed solvent of EtOAc (15 mL) / n-hexane (90 mL) was added to the residue, and the mixture was stirred and slurried at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to obtain the target compound (±)-50. Brown solid; 20.34 g (68%); This product does not require characterization and can be used directly in the next reaction.

[0413] Step 6: Synthesis of compound (±)-51

[0414] Compound (±)-50 (20.34 g, 0.12 mol) was dissolved in CCl4 (150 mL) and stirred. Triphenylphosphine (34.51 g, 0.13 mol) and NaHCO3 (1.36 g, 16 mmol) were added sequentially. The air in the reactor was replaced with nitrogen (by a balloon) according to standard operating procedures, and then the mixture was refluxed overnight. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure using a rotary evaporator. A mixed solvent of EtOAc (30 mL) and n-hexane (60 mL) was added to the concentrated residue, and the mixture was stirred for 1 h at room temperature. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brownish-black oily substance. The product (±)-51 was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 97]. Pale yellow oily substance (slightly impure); 7.36 g; This product does not require characterization and can be used directly in the next reaction.

[0415] Step 7: Synthesis of compound (±)-52

[0416] Zinc powder (8.50 g, 0.13 mol) and glacial acetic acid (40 mL) were mixed and stirred. Then, a freshly prepared solution of compound (±)-51 (7.36 g, 38 mmol) in glacial acetic acid (30 mL) was added dropwise at room temperature. After the addition was complete, the reaction mixture was placed in an oil bath at 55 °C and stirred overnight under N2 atmosphere. TLC monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and poured into ice water (100 mL), stirred, and filtered to remove the solids. The filtrate was extracted with EtOAc (80 mL × 3). After merging the organic phases, the mixture was washed sequentially with water (200 mL × 3), saturated NaHCO3 solution (200 mL), and saturated brine (200 mL), dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oily substance. This was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 97] to obtain the target product (±)-52. Pale yellow oily substance; 4.87 g ((±)-50→(±)-52 combined yield 26%).

[0417] 1 H NMR(CDCl3,500MHz)δ:6.23-6.28(m,2H),3.84-3.88(m,1H),2.92-2.97(m,1H),2.74(ddd,1H,J=3.0Hz,8.5Hz and 18.5Hz),2.50-2.52(m,1H),2.42-2.45(m,1H),2.22(dt,1H,J=3.8Hz and 18.5Hz),0.50-0.56(m,2H),0.42-0.46(m,1H),0.35-0.39(m,1H);

[0418] 13 C NMR (CDCl3, 126MHz) δ: 211.22, 135.61, 132.91, 66.90, 51.52, 50.64, 49.45, 46.10, 27.03, 7.70, 5.60;

[0419] ESI-HRMS:(m / z)calcd.for C 11 H 13 O([M+H] + )161.0961,found:161.0960.

[0420] Step 8: Synthesis of compound (±)-53

[0421] Under N2 atmosphere, t-BuOK (3.71 g, 33 mmol) was added to dry THF (6 mL), and stirred into a suspension in an ice-water bath. Then, tert-butyl diethylphosphonoacetate (8.35 g, 33 mmol) was added dropwise. After the addition was complete, the reaction was continued in an ice-water bath for 1 h. A freshly prepared solution of compound (±)-52 (1.06 g, 6.6 mmol) in dry THF (4 mL) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete. The reaction solution was poured into ice water (50 mL) and extracted with CH2Cl2 (40 mL × 2). The organic phases were combined and washed successively with ice water (80 mL × 2) and saturated brine (150 mL), dried (MgSO4), and the desiccant was removed by suction filtration. The filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a deep yellow oily substance, which was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 97] to obtain the target product (±)-53. A pale yellow oily substance; 1.62 g; this product does not require characterization and can be used directly in the next reaction.

[0422] Step 9: Synthesis of compound (±)-54

[0423] At room temperature, compound (±)-53 (1.62 g, 6.3 mmol) was dissolved in CH3NO2 (20 mL), and DBU (7.64 g, 50 mmol) was added dropwise. After the addition was complete, the mixture was refluxed under N2 for 48 h. TLC monitoring showed that approximately 60% of the starting material did not react. The reaction was stopped, and the reaction solution was cooled to room temperature and poured into ice water (30 mL), and extracted with CH2Cl2 (30 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a brownish-black oil, which was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→2 / 23] to obtain the target compound (±)-54. A light brown oil; 0.59 g ((±)-52→(±)-54 combined yield 28%).

[0424] 1H NMR (CDCl3, 500MHz) δ: 6.49-6.51 (m, 1H), 6.38-6.40 (m, 1H), 4.84 (dd, 1H, J = 1.0Hz and 11.5Hz), 4.63 (dd, 1H, J = 1.0Hz and 11.5Hz),2.95-3.01(m,1H),2.66-2.70(m,1H),2.53(dd,1H,J=0.8Hz and 17.8Hz),2.42(d,1H,J=17.5Hz),2.28-2.30(m,1H),2.22-2.24(m,1H),2.06(ddd,1H,J=1.8Hz,8.5Hz and 13.3Hz),1.46(s,9H),1.41-1.44(m,1H),0.44-0.47(m,2H),0.25-0.33(m,2H).

[0425] 13 C NMR (CDCl3, 126MHz) δ: 170.98, 137.31, 136.84, 83.29, 80.91, 51.09, 50.24, 49.20, 47.98, 39.28, 36.43, 34.55, 32.34, 28.24, 7.83, 4.74.

[0426] ESI-HRMS:(m / z)calcd.for C 18 H 26 NO4([M+H)) + )320.1856,found:320.1854.

[0427] Step 10: Synthesis of compound (±)-55 p-toluenesulfonate

[0428] At room temperature, compound (±)-54 (0.59 g, 1.8 mmol) was dissolved in EtOH (10 mL), water (5 mL) was added, and the mixture was stirred. Iron powder (0.52 g, 9.3 mmol) and NH4Cl (0.20 g, 3.7 mmol) were added sequentially. The air in the reactor was replaced with nitrogen (using a balloon) according to standard operating procedures, and the mixture was refluxed overnight. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was added to a saturated NaHCO3 solution (50 mL) and extracted with EtOAc (40 mL × 3). After combining the organic phases, the mixture was washed with saturated brine (100 mL), dried (MgSO4), and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a light brown oily substance. At room temperature, 5 mL of EtOAc was added to dilute the oily substance, followed by 0.38 g of p-TsOH·H₂O (2.0 mmol). The mixture was stirred until dissolved, and then transferred to an ice-water bath for further stirring. A white flocculent solid gradually precipitated out. 7.5 mL of EtOAc was added to the mixture to ensure thorough stirring, and stirring was continued overnight at room temperature. The solid was collected by suction filtration and dried under vacuum to obtain the target compound (±)-55 p-toluenesulfonate. White solid. 0.60 g (70%). Melting point: 171.6℃–175.8℃.

[0429] 1 H NMR (DMSO-d6, 500MHz) δ: 7.69 (brs, 3H), 7.47 (d, 2H, J = 8.0Hz), 7.11 (d, 2H, J = 8.0Hz), 6.43-6.45 (m, 1 H),6.36-6.38(m,1H),3.08-3.13(m,1H),2.97-3.02(m,1H),2.84-2.90(m,1H),2.55(dd,1H,J=4.5Hz and 9.0Hz),2.37(d,1H,J=17.5Hz),2.31(d,1H,J=17.0Hz),2.29(s,3H),2.17-2.21(m,2H),1.79(ddd,1H,J=1.8Hz,8.5Hz and 12.8Hz),1.41(s,9H),1.19-1.23(m,1H),0.36-0.42(m,2H),0.27-0.31(m,1H),0.21-0.25(m,1H);

[0430] 13C NMR(DMSO-d6,126MHz)δ:170.55,145.60,137.71,137.00,136.45,128.09,125.51,80.05, 50.56,49.42,48.59,47.70,46.97,37.08,36.34,33.71,31.86,27.75,20.80,7.48,4.45;

[0431] ESI-HRMS:(m / z)calcd.for C 18 H 28 NO2([M(free base)+H]) + )290.2115,found:290.2112.

[0432] Step 11: Synthesis of compound (±)-I-9 p-toluenesulfonate

[0433] At room temperature, compound (±)-55 p-toluenesulfonate (0.56 g, 1.2 mmol) was added to saturated NaHCO3 solution (100 mL) and stirred for 20 min (in suspension). EtOAc (60 mL × 3) was then added for extraction. The combined organic phases were dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil. CH2Cl2 (20 mL × 3) was added and concentrated several times, dissolving the oil in CH2Cl2 (5 mL). TFA (3 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 6 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance. CH2Cl2 (20 mL × 3) was added and the solution was concentrated multiple times. Then, the solution was dried using a vacuum oil pump (a small amount of solid precipitated during drying). EtOAc (3 mL) was added to dissolve the solid. A solution of p-TsOH·H2O (0.25 g, 1.3 mmol) dissolved in EtOAc (3 mL) was added dropwise to the reaction solution. A creamy-white solid gradually precipitated from the system. After the addition was complete, the mixture was stirred overnight at room temperature. The solid was collected by filtration, and the filter cake was washed with EtOAc (1 mL). The mixture was then dried using a vacuum oil pump to obtain compound (±)-I-9 p-toluenesulfonate. White solid; 0.38 g (77%); melting point 187.5℃-188.5℃;

[0434] 1H NMR (CD3OD, 500MHz) δ: 7.71 (d, 2H, J = 8.0Hz), 7.23 (d, 2H, J = 8.0Hz), 6.50-6.52 ( m,1H),6.38-6.40(m,1H),3.27(d,1H,J=13.0Hz),3.13(d,1H,J=13.0Hz),2.95- 3.01(m,1H),2.66-2.69(m,1H),2.63(d,1H,J=17.5Hz),2.40(d,1H,J=17.5Hz), 2.37(s,3H),2.26-2.28(m,1H),2.20-2.22(m,1H),1.78(ddd,1H,J=1.5Hz,8.5Hz and 13.0Hz),1.44(dd,1H,J=6.5Hz and 13.0Hz),0.40-0.46(m,2H),0.30-0.34(m,1H),0.25-0.29(m,1H);

[0435] 13 C NMR(CD3OD,126MHz)δ:175.76,143.51,141.71,138.32,137.84,129.82,126.96,5 2.26,51.30,50.45,49.93,48.37,38.43,37.52,35.51,33.66,21.31,8.27,5.20;

[0436] ESI-HRMS:(m / z)calcd.for C 14 H 20 NO2([M(free base)+H]) + )234.1489,found:234.1486.

[0437] Compound (±)-I-9 is a specific form of the compound having general formula I in this application.

[0438] Example 12 Synthesis of compound (±)-I-10

[0439]

[0440] Step 1: Synthesis of compound (±)-56

[0441] Compound (±)-54 (0.21 g, 0.66 mmol) was dissolved in CH2Cl2 (2 mL), and TFA (1.5 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 2-3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator, and then concentrated multiple times with CH2Cl2 (20 mL × 4) to obtain a brownish-black oily substance. This substance was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 7] to obtain a yellow solid. 1 mL of n-hexane was added to the solid, and the mixture was stirred and slurried overnight at room temperature. The solid was collected by filtration and dried under vacuum to obtain compound (±)-56. White solid; 0.11 g (64%); melting point 141.3℃-144.5℃;

[0442] 1 H NMR(DMSO-d6,500MHz)δ:12.23(s,1H),6.47-6.49(m,1H),6.36-6.38(m,1H),4.79(s,2H),2.91-2.97(m,1H),2.63-2.66( m,1H),2.45(d,1H,J=17.5Hz),2.27(d,1H,J=17.5Hz),2.24-2.25(m,1H),2.20-2.21(m,1H),1.96(ddd,1H,J=1.8Hz,8.5Hz and13.0Hz),1.36(dd,1H,J=6.5Hz and 13.0Hz),0.36-0.41(m,2H),0.22-0.30(m,2H);

[0443] 13 C NMR (DMSO-d6, 126MHz) δ: 172.26, 136.94, 136.57, 82.95, 50.35, 49.40, 48.77, 47.08, 38.50, 35.06, 33.94, 31.69, 7.44, 4.43;

[0444] ESI-HRMS:(m / z)calcd.for C 14 H 18 NO4([M+H)) + )264.1230,found:264.1225.

[0445] Step 2: Synthesis of compound (±)-I-10

[0446] Compound (±)-56 (0.11 g, 0.42 mmol) was dissolved in CH3OH (3 mL), and 10% Pd(OH)2 / C (0.04 g) was added. The air in the reaction vessel was replaced with hydrogen (using a balloon) according to standard procedures, and the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete (the reaction typically takes 12 h to complete). The solid was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a white solid. EtOAc (2 mL) was added, and the mixture was stirred and slurried at room temperature for 1 h. The solid was collected by filtration and dried under vacuum to obtain the target product (±)-I-10. White solid; 0.03 g (31%); melting point 197.3℃-201.1℃;

[0447] 1 H NMR (CD3OD, 500MHz) δ: 3.14 (d, 1H, J = 13.0Hz), 3.01 (d, 1H, J = 12.5Hz), 2.75 (dd, 1H, J = 1.0Hz and16.5Hz),2.63-2.78(m,1H),2.66(d,1H,J=16.0Hz),2.53-2.57(m,1H),2.10-2.17(m,1H),2.01(dd,1H,J=7.5Hz and 13.0Hz),1.79-1.90(m,4H),1.60-1.62(m,1H),1.42-1.44(m,1H),0.42-0.51(m,4H);

[0448] 13 C NMR (CD3OD, 126MHz) δ: 180.04, 52.77, 49.79, 47.72, 46.30, 45.63, 39.39, 38.20, 35.05, 33.87, 26.24, 25.76, 6.33, 5.15;

[0449] ESI-HRMS:(m / z)calcd.for C 14 H 22 NO2([M+H] + )236.1645,found:236.1642.

[0450] Compound (±)-I-10 is a specific form of the compound having general formula I in this application.

[0451] Example 13 Synthesis of compound (±)-I-11 and its p-toluenesulfonate

[0452]

[0453] Step 1: Synthesis of compound (±)-58

[0454] Compound (±)-18 (3.00 g, 22 mmol) was dissolved in benzene (40 mL). CH3NO2 (20 mL) and piperidine (0.95 g, 11 mmol) were added sequentially with stirring. The mixture was heated to reflux and water was separated using a Dean-Stark separator for 2 h. TLC monitoring showed the reaction was complete, and the reaction was stopped. The reaction solution was cooled to room temperature and poured into ice water (100 mL). CH2Cl2 (50 mL × 2) was added for extraction. The organic phases were combined and washed sequentially with 1 M HCl (20 mL), saturated NaHCO3 solution (100 mL), and saturated brine (100 mL). The solution was dried (MgSO4) and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 97] to obtain the target compound (±)-58. Yellow oily substance; 0.78 g; This product consists of a Z / E mixture and can be used directly in the next reaction step.

[0455] Step 2: Synthesis of compound (±)-59

[0456] Add 5 mL of dry THF to the reactor and replace the air in the reaction vessel with nitrogen (using a balloon) according to standard operating procedures. While stirring, add 0.86 g (8.5 mmol) of diisopropylamine and cool to -78 °C (liquid nitrogen-alcohol system). Add 5.3 mL (8.5 mmol) of 1.6 M hexane solution dropwise, and after the addition is complete, react at -78 °C for 0.5 h. Then add 1 mL of dry THF solution containing 0.99 g (8.5 mmol) of tert-butyl acetate dropwise, and continue reacting at -78 °C for another 0.5 h. Next, add 1 mL of dry THF solution containing 0.50 g (2.8 mmol) of compound (±)-58 dropwise, and react at -78 °C for another 1-2 hours. TLC monitoring showed the reaction was complete. After the reaction solution returned to room temperature, pour it into 15 mL of ice water and extract with 20 mL of CH2Cl2. The organic phase was washed successively with 1M HCl (40 mL), saturated NaHCO3 solution (40 mL), and saturated brine (40 mL), dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a dark brown oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 97] to obtain the target compound (±)-59. A light yellow oil; 0.51 g ((±)-18→(±)-59, combined yield 12%).

[0457] 1H NMR (CDCl3, 500MHz) δ: 6.41-6.43 (m, 1H), 6.32-6.34 (m, 1H), 4.59 (d, 1H, J = 13.0Hz) ,4.54(d,1H,J=13.0Hz),3.02-3.05(m,1H),2.84-2.90(m,2H),2.69(dd,1H,J=1.0Hz and 16.5Hz),2.59(dd,1H,J=0.5Hz and 16.5Hz),2.50-2.53(m,1H),1.82-1.88(m,1H),1.60-1.62(m,1H),1.45-1.49(m,10H),1.11-1.14(m,1H);

[0458] 13 C NMR (CDCl3, 126MHz) δ: 170.65, 138.31, 136.61, 81.21, 76.29, 53.54, 49.17, 45.75, 44.86, 44.48, 37.98, 34.36, 32.85, 28.27;

[0459] ESI-HRMS:(m / z)calcd.for C 16 H 24 NO4([M+H)) + )294.1700,found:294.1698.

[0460] Step 3: Synthesis of compound (±)-60 p-toluenesulfonate

[0461] At room temperature, compound (±)-59 (0.51 g, 1.7 mmol) was dissolved in EtOH (10 mL), water (5 mL) was added, and the mixture was stirred. Iron powder (0.47 g, 8.4 mmol) and NH4Cl (0.18 g, 3.4 mmol) were added sequentially. The air in the reactor was replaced with nitrogen (using a balloon) according to standard operating procedures, and the mixture was stirred and refluxed overnight. TLC monitoring showed the reaction was complete. The reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was added to a saturated NaHCO3 solution (50 mL) and extracted with EtOAc (40 mL × 3). The organic phases were combined, washed sequentially with a saturated NaHCO3 solution (80 mL) and a saturated brine solution (100 mL), dried (with MgSO4), filtered to remove the drying agent, and concentrated under reduced pressure using a rotary evaporator to obtain a brown oily substance. The above-mentioned brown oily substance was dissolved in EtOAc (5 mL), and then p-TsOH·H2O (0.35 g, 1.8 mmol) was added. After stirring and dissolving, a white solid gradually precipitated out. EtOAc (3 mL) was added to the system to ensure thorough stirring, and the mixture was stirred and slurried at room temperature for 1-2 hours. The solid was collected by suction filtration and dried under vacuum to obtain the target compound (±)-60 p-toluenesulfonate. White solid; 0.39 g (52%); melting point 194.9℃-196.7℃;

[0462] 1 H NMR (DMSO-d6, 500MHz) δ: 7.52 (brs, 3H), 7.48 (d, 2H, J = 8.5Hz), 7.12 (d, 2H, J = 8.0Hz), 6 .40-6.42(m,1H),6.26-6.28(m,1H),2.99-3.00(m,1H),2.83-2.89(m,1H),2.76-2.82(m ,3H),2.58(d,1H,J=16.0Hz),2.53(d,1H,J=16.0Hz),2.33-2.35(m,1H),2.29(s,3H),1 .63-1.68(m,1H),1.47-1.49(m,1H),1.42(s,9H),1.27-1.31(m,1H),1.05-1.07(m,1H);

[0463] 13 C NMR(DMSO-d6,126MHz)δ:170.22,145.63,137.66,137.30,136.31,128.06,125.48,8 0.39,53.06,47.38,44.67,43.98,43.20,40.12,36.87,32.62,31.58,27.82,20.78;

[0464] ESI-HRMS:(m / z)calcd.for C 16 H 26 NO2([M(free base)+H]) + )264.1958,found:264.1956.

[0465] Step 4: Synthesis of compound (±)-I-11 and its p-toluenesulfonate

[0466] At room temperature, compound (±)-60 p-toluenesulfonate (0.39 g, 0.90 mmol) was added to saturated NaHCO3 solution (50 mL) and stirred for 20 min (in suspension). EtOAc (40 mL × 3) was then added for extraction. The combined organic phases were dried (MgSO4) and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oil. CH2Cl2 (20 mL × 3) was added and concentrated several times, and the oil was dissolved in CH2Cl2 (4 mL). TFA (3 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 5-6 hours. TLC monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure using a rotary evaporator to obtain a brown oil. CH2Cl2 (20 mL × 3) and EtOAc (20 mL × 3) were added sequentially and concentrated several times. The oil was dried using a vacuum oil pump to obtain (±)-I-11. The above (±)-I-11 sample was dissolved in EtOAc (2 mL), and p-TsOH·H2O (0.19 g in 2.5 mL EtOAc, 1.0 mmol) solution was added dropwise (a white solid gradually precipitated). After the addition was complete, EtOAc (2.5 mL) was added to ensure smooth stirring, and stirring was continued at room temperature for 1 h. The solid was collected by suction filtration and dried under vacuum to obtain compound (±)-I-11 p-toluenesulfonate. White solid; 0.26 g (77%); melting point 193.0℃-188.5℃;

[0467] 1H NMR (CD3OD, 500MHz) δ: 7.70 (d, 2H, J = 8.5Hz), 7.23 (d, 2H, J = 8.0Hz), 6.43-6.44 (m, 1H), 6.31-6.33 (m, 1H), 3.07 (d, 1H, J = 13.0Hz), 3.02-3.03 (m, 1H),2.99(d,1H,J=13.0Hz),2.89-2.95(m,1H),2.84-2.86(m,1H),2.74(d,1H,J=17.0Hz),2.70(d,1H,J=17.0Hz),2.46(ddd,1H,J=1.5Hz,4.5Hz and 9.0Hz),2.37(s,3H),1.75(ddd,1H,J=1.8Hz,8.5Hz and 12.8Hz),1.61-1.63(m,1H),1.44(dd,1H,J=6.5Hz and 12.5Hz),1.16-1.18(m,1H);

[0468] 13 C NMR(CD3OD,126MHz)δ:175.29,143.52,141.69,139.13,137.18,129.81,126 .96,54.43,49.46,46.36,45.74,44.77,42.50,37.95,34.42,33.32,21.30;

[0469] ESI-HRMS:(m / z)calcd.for C 12 H 18 NO2([M(free base)+H]) + )208.1332,found:208.1331.

[0470] Compound (±)-I-11 is a specific form of the compound having general formula I in this application.

[0471] Example 14 Synthesis of compound (±)-I-12

[0472]

[0473] Step 1: Synthesis of compound (±)-61

[0474] Compound (±)-59 (0.50 g, 1.7 mmol) was dissolved in CH2Cl2 (3 mL), and TFA (3 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 3-4 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure on a rotary evaporator to obtain a brown oily substance, which was then concentrated multiple times with CH2Cl2 (20 mL × 5). The resulting oily substance was purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→3 / 7] to obtain a white solid. n-hexane (3 mL) was added to the solid, and the mixture was stirred at room temperature for 1 hour. The solid was collected by suction filtration and dried with a vacuum oil pump to obtain compound (±)-61. White solid; 0.32 g (79%); melting point 91.4℃-93.8℃;

[0475] 1 H NMR(DMSO-d6,500MHz)δ:12.33(brs,1H),6.47-6.49(m,1H),6.32-6.34(m,1H),4.58(d,1H,J=13.0Hz),4.52(d,1H,J=13.0Hz),2.91-2.93(m ,1H),2.84-2.88(m,1H),2.80-2.82(m,1H),2.59(d,1H,J=16.5Hz),2.55(d,1H,J=17.0Hz),2.44-2.47(m,1H),1.76(ddd,1H,J=1.8Hz,8.3Hz and 12.8Hz),1.47-1.49(m,1H),1.40(dd,1H,J=6.5Hzand 13.0Hz),1.06-1.09(m,1H);

[0476] 13 C NMR (DMSO-d6, 126MHz) δ: 172.14, 137.79, 136.27, 76.46, 52.74, 48.32, 45.10, 44.08, 42.66, 37.14, 33.58, 32.16;

[0477] ESI-HRMS:(m / z)calcd.for C 12 H 16 NO4([M+H)) + )238.1074,found:238.1072.

[0478] Step 2: Synthesis of compound (±)-I-12

[0479] Compound (±)-61 (0.30 g, 1.3 mmol) was dissolved in CH3OH (5 mL), and 10% Pd(OH)2 / C (0.08 g) was added. The air in the reaction vessel was replaced with hydrogen (using a balloon) according to standard procedures, and the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete (the reaction typically takes 12 h to complete). The solid was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a white solid. A mixed solvent of CH3OH / EtOAc = 1 / 3 (v / v) (3 mL) was added, and the mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried to obtain the target product (±)-I-12. White solid; 0.05 g (19%); melting point 153.2℃-157.3℃;

[0480] 1 H NMR (CD3OD, 500MHz) δ: 3.17 (d, 1H, J = 13.5Hz), 3.14 (d, 1H, J = 13.5Hz), 2.68 (s, 2H), 2.57-2 .64(m,1H),2.49-2.51(m,1H),2.25-2.27(m,1H),2.13-2.16(m,1H),2.01(dd,1H,J=7.5Hz and 12.5Hz),1.73-1.82(m,3H),1.61-1.67(m,1H),1.50-1.55(m,1H),1.43-1.45(m,1H),1.27-1.30(m,1H);

[0481] 13 C NMR (CD3OD, 126MHz) δ: 180.18, 53.17, 53.31, 47.14, 43.23, 40.81, 40.06, 36.72, 34.78, 32.43, 26.51, 25.22; ESI-HRMS: (m / z)calcd.for C 12 H 20 NO2([M+H] + )210.1489,found:210.1485.

[0482] Compound (±)-I-12 is a specific form of the compound having general formula I in this application.

[0483] Example 15 Synthesis of compound (±)-I-13

[0484]

[0485] Step 1: Synthesis of Compound 62

[0486] Under ice-water bath cooling and stirring, SnCl2·2H2O (1299.93 g, 5.76 mol), KI (956.29 g, 5.76 mol), and allyl bromo (696.94 g, 5.76 mol) were added sequentially 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 THF solution of acrolein diethanol(500.00 g, 3.84 mol) in 768 mL was slowly added dropwise (monitoring the internal temperature to not exceed 20 °C, the system color changed from orange-red to pale yellow). After the addition was complete, the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete. The reaction was stopped, and the reaction solution was poured into CH2Cl2 (8 L), stirred, and the organic phase was separated. The aqueous phase was extracted once again with CH2Cl2 (8 L). After combining the organic phases, saturated brine (5 L) was added for washing, and the mixture was dried (MgSO4), and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure (30℃) using a rotary evaporator to obtain a pale yellow oily substance. This substance was purified by vacuum distillation, and the fraction with a top temperature of approximately 60℃ / 30mmHg was collected to obtain the target product 62. A colorless, transparent oily substance; 183.50 g (49%). 1 ¹H NMR (CDCl₃, 500MHz) 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). This product was used directly in the next reaction without further purification.

[0487] Step 2: Synthesis of Compound 63

[0488] Preparation of Jones reagent: Add water (267 mL) to the reaction vessel, place it in an ice-water bath to cool, and add CrO3 (122.83 g, 1.23 mol) in batches while stirring to form an orange-red suspension. Then slowly add concentrated H2SO4 (131 mL) dropwise. After the addition is complete, set aside for later use.

[0489] Compound 62 (120.56 g, 1.23 mol) was dissolved in acetone (430 mL), and then stirred in an ice-water bath. Jones' reagent was slowly added dropwise (a green solid was produced during the addition, and the solution color changed from blue-green to dark green). TLC monitoring was performed during the addition, and the addition was stopped once the TLC reading showed the reaction was complete. The reaction system was diluted with n-pentane (400 mL) and washed with water (400 mL); the aqueous phase was back-extracted with n-pentane (250 mL × 2). After combining the organic phases, the organic phases were washed successively with 10% sodium sulfite solution (200 mL) and saturated brine (200 mL × 3), dried (MgSO4), and filtered to remove the drying agent. The filtrate was first fractionated at atmospheric pressure to remove n-pentane (top temperature 36℃-38℃), and then distilled under reduced pressure. The fraction collected at 58℃-60℃ / 30 mmHg (the receiving flask was placed in liquid nitrogen for cryogenic protection) yielded the target compound 63. Pale yellow oily substance; 26.42g (22%); 1 ¹H NMR (CDCl₃, 500MHz) δ: 6.39 (dd, ¹H, J = 10.5Hz and 18.0Hz), 6.26 (dd, ¹H, J = 1.3Hz and 17.8Hz), 5.92–6.00 (m, ¹H), 5.87 (dd, ¹H, J = 1.0Hz and 10.5Hz), 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 reaction without further purification.

[0490] Step 3: Synthesis of Compound 64

[0491] Compound 63 (26.42 g, 0.27 mol) was dissolved in 1.5 L of n-pentane in a quartz container. The air in the reaction vessel was replaced with nitrogen (using a balloon) according to standard procedures. The reaction apparatus was placed in a dark environment and stirred. It was then irradiated with UV light (365 nm; 15 W × 6) at room temperature for 7-14 days (the solution color changed from colorless and transparent to purplish-red, then faded to pale purple). During the reaction, a small amount of viscous polymer byproducts adhered to the inner wall of the reaction vessel. Every 2-3 days, activated carbon (10 g) and diatomaceous earth (10 g) were added and stirred for 10 minutes. The polymer was removed by filtration, and the filtrate was returned to the reaction vessel following the same procedure. The reaction was stopped when TLC monitoring showed a small amount of starting material. The reaction solution was concentrated under reduced pressure (<30 °C) to half its original volume using a rotary evaporator. Br2 was then slowly added dropwise until the Br2 no longer faded (the solution turned pale orange). Next, add 200 mL of 10% sodium thiosulfate solution and stir to destroy excess Br2, at which point the solution becomes colorless. Separate the organic phase, dry (MgSO4), and filter to remove the drying agent. Concentrate the filtrate under reduced pressure (<30℃) using a rotary evaporator to obtain an oily substance, then add 20 mL of CH3OH to concentrate and obtain the crude target compound 64. Pale yellow oily substance; 6.61 g; This product is not characterized and is used directly in the next reaction.

[0492] Step 4: Synthesis of Compound 65

[0493] Compound 64 (16.00 g, 0.17 mol) was dissolved in CH3OH (320 mL), and 4-methylbenzenesulfonyl hydrazine (31.00 g, 0.17 mol) was added. The air in the reaction vessel was replaced with nitrogen (using a balloon) according to standard procedures, and then refluxed overnight. TLC monitoring showed the reaction was complete. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oily substance. This substance was dissolved in CH2Cl2 (500 mL), then washed successively with 1M HCl (400 mL × 6) and saturated brine (200 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a yellow oily substance, and then concentrated multiple times with n-hexane (50 mL × 2) to obtain a yellow solid. EtOAc (3 mL) / n-hexane (30 mL) was added to the solid, and the mixture was stirred at room temperature for 1 h. The solid was collected by filtration and dried under vacuum using an oil pump to obtain compound 65. Pale yellow solid; 17.09 g (63→65, combined yield 10%); melting point 174.7℃-177.6℃;

[0494] 1H NMR (CDCl3, 500MHz) δ: 7.86 (d, 2H, J = 8.0Hz), 7.32 (d, 2H, J = 8.0Hz), 7.21 (brs, 1H), 2.98-3.00 ( m,1H),2.65-2.68(m,1H),2.43(s,3H),2.16-2.17(m,2H),1.98-2.04(m,2H),1.31-1.32(m,2H);

[0495] 13 C NMR (CDCl3, 126MHz) δ: 168.36, 144.10, 135.67, 129.74, 128.18, 49.53, 42.05, 36.29, 32.91, 21.76.

[0496] Step 5: Synthesis of Compound 66

[0497] 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 (by a balloon) according to standard procedures. CH3Li (1.6 M diethoxymethane solution, 42 mL, 67.2 mmol) was slowly added dropwise to the system under ice-water bath and stirring. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. TLC monitoring showed that the reaction was complete. The reaction was quenched by adding water (10 mL) dropwise to the system under ice-water bath, and the reaction solution was poured into ice water (200 mL) and extracted with n-pentane (100 mL × 3). The organic phases were combined and washed successively with 1 M HCl (100 mL × 2) and saturated brine (100 mL), dried (MgSO4), and filtered to remove the drying agent. The filtrate was fractionated at atmospheric pressure to remove the solvent, yielding crude target compound 66 (1.52 g). This product was used directly in the next reaction without further purification.

[0498] Step 6: Synthesis of compound (±)-67

[0499] At room temperature, compound 66 (1.52 g, based on 19 mmol) and dichloroacetyl chloride (3.72 g, 25 mmol) were dissolved sequentially in 20 mL of dry n-hexane. The air in the reaction vessel was replaced with nitrogen (using a balloon) according to standard operating procedures. A solution of triethylamine (2.80 g, 28 mmol) in 10 mL of dry n-hexane was slowly added dropwise at room temperature with stirring. The system was exothermic during the addition, and the dropping rate was controlled to maintain an internal temperature of 30-35°C. After the addition was complete, the reactor was placed in a 35°C oil bath and stirred for 2 hours. 50 mL of dry n-hexane was added to ensure thorough stirring, and the reaction was allowed to proceed overnight at room temperature. TLC monitoring showed the reaction was complete. The reaction solution was cooled to room temperature and then poured into 200 mL of ice water. The organic phase was separated and washed successively with 1M HCl (50 mL), water (200 mL), saturated NaHCO3 solution (100 mL × 2), and saturated brine (100 mL). The solution was dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain the crude compound (±)-67. It was a deep red oily substance; 1.89 g. This product was used directly in the next reaction without further purification.

[0500] Step 7: Synthesis of compound (±)-68

[0501] Zinc powder (3.23 g, 49 mmol) and glacial acetic acid (20 mL) were mixed and stirred. Then, a freshly prepared glacial acetic acid solution of compound (±)-67 (1.89 g, 9.9 mmol) in 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 N2 atmosphere. TLC monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered with diatomaceous earth as an aid. The filtrate was diluted with CH2Cl2 (200 mL), and washed successively with water (200 mL × 3), saturated NaHCO3 solution (200 mL), and saturated brine (200 mL). The solution was dried (MgSO4), filtered to remove the drying agent, and concentrated under reduced pressure on a rotary evaporator to obtain a dark brown oily substance. This substance was then subjected to column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 20] to obtain crude compound (±)-68. Dark brown oily substance; 0.31 g; This product is used directly in the next reaction without further purification.

[0502] Step 8: Synthesis of compound (±)-69

[0503] Under N2 atmosphere, t-BuOK (1.42 g, 13 mmol) was added to dry THF (5 mL), and the mixture was 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 mixture was reacted in an ice-water bath for 1 h. A freshly prepared solution of compound (±)-68 (0.31 g, 2.5 mmol) in dry THF (10 mL) was then added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was monitored by TLC to indicate completion. The reaction mixture was poured into ice water (100 mL), stirred, and extracted with CH2Cl2 (30 mL × 3). The extracted organic phases were combined, washed with saturated brine, dried (MgSO4), and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a dark brown oil, which was then subjected to column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 12] to obtain crude compound (±)-69. Dark brown oily substance; 0.40 g; This product is used directly in the next reaction without further purification.

[0504] Step 9: Synthesis of compound (±)-70

[0505] At room temperature, compound (±)-69 (0.40 g) was dissolved in CH3NO2 (10 mL), stirred, and DBU (3.0 g) was added dropwise. After the addition was complete, the reaction mixture was refluxed for one week under N2. TLC monitoring showed that a large amount of raw material remained unreacted, so the reaction was stopped. The reaction solution was cooled to room temperature and poured into ice water (100 mL), extracted with CH2Cl2 (50 mL × 2), and the combined organic phases were washed 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 using a rotary evaporator to obtain a brownish-black oil, which was then purified by column chromatography [V(EtOAc) / V(n-hexane)=0 / 1→1 / 9] to obtain the target product (±)-70. Pale yellow oil; 0.10 g;

[0506] 1 H NMR (acetone-d6, 500MHz) δ: 4.77 (d, 1H, J = 12.0Hz), 4.65 (d, 1H, J = 12.0Hz), 2.65 (d, 1H, J = 18.5Hz), 2.57 (d, 1H, J = 18.5Hz), 2.33-2.36 (m,1H),2.00-2.04(m,1H),1.98-1.99(m,2H),1.81-1.83(m,1H),1.41(s,9H),1.32-1.36(m,1H),1.23-1.28(m,2H),1.01-1.04(m,2H);

[0507] ESI-HRMS:(m / z)calcd.for C15 H 24 NO4([M+H)) + )282.1700,found:282.1702.

[0508] Step 10: Synthesis of compound (±)-71

[0509] Compound (±)-70 (78 mg, 0.28 mmol) was dissolved in CH2Cl2 (1 mL), and TFA (0.5 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. TLC monitoring showed that the reaction was complete. The reaction mixture was poured into ice water (5 mL) and extracted with CH2Cl2 (2 mL × 3). The combined organic phases were washed with saturated brine (2 mL × 2), dried (MgSO4), filtered to remove the drying agent, and the filtrate was concentrated by rotary evaporation to obtain a yellow oil. The target product (±)-71 was purified by column chromatography [V(EtOAc) / V(n-hexane)=1 / 5→1 / 0] to obtain a colorless oil, 32 mg (51%).

[0510] 1 H NMR(acetone-d6+D2O(1drop),500MHz)δ:4.70(d,1H,J=11.5Hz), 4.53(d,1H,J=11.5Hz), 2.61(d,1H,J=19.0Hz), 2.55(d,1H,J=18.5Hz ),2.42-2.46(m,1H),2.12-2.16(m,1H),1.99-2.03(m,2H),1.84-1.86(m,1H),1.51-1.56(m,1H),1.20-1.22(m,2H),1.13-1.15(m,2H);

[0511] ESI-HRMS:(m / z)calcd.for C 11 H 16 NO4([M+H)) + )226.1074,found:226.1070.

[0512] Step 11: Synthesis of compound (±)-I-13

[0513] Compound (±)-71 (25 mg, 0.11 mmol) was dissolved in CH3OH (0.5 mL), and 10% Pd(OH)2 / C (5 mg) was added. The air in the reaction vessel was replaced with hydrogen (using a balloon) according to standard procedures, and the mixture was stirred overnight at room temperature. TLC monitoring showed that the reaction was complete (the reaction typically takes 12 hours to complete). The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a white solid. EtOAc (0.5 mL) was added, and the mixture was stirred and slurried at room temperature for 2 hours. The solid was collected by vacuum filtration and dried to obtain the target product (±)-I-13. White solid; 11 mg (51%).

[0514] 1 H NMR(CD3OD+D2O(1drop),500MHz)δ:3.06(s,2H),2.67(d,1H,J=18.0Hz),2.43(d,1H,J=18.0Hz),2.31-2.32(m,1H) ,2.20-2.22(m,1H),1.97-2.02(m,1H),1.88-1.89(m,2H),1.40-1.51(m,2H),1.16-1.21(m,1H),1.00-1.06(m,2H);

[0515] ESI-HRMS:(m / z)calcd.for C 11 H 18 NO2([M+H] + )196.1332,found:196.1341.

[0516] Compound (±)-I-13 is a specific form of the compound having general formula I in this application.

[0517] Examples 16-21

[0518] The compounds listed in the table below were synthesized according to the methods described in Examples 1 to 15.

[0519]

[0520]

[0521] Example 22

[0522]

[0523] Preparation process: Crush and sieve the (±)-I-3 sample for later use. Add the (±)-I-3 sample, lactose, and pregelatinized starch according to the above formula and premix for 15 minutes. Add disodium hydrogen phosphate and polyvinylpyrrolidone according to the formula and mix for 10 minutes. Add talc according to the formula and mix for 30 minutes. Fill the mixed material into (±)-I-3 capsules according to the specified specifications to obtain the final product.

[0524] Example 23

[0525]

[0526] Preparation process: The (±)-I-4 sample and pregelatinized starch were sieved separately and thoroughly mixed. A polyvinylpyrrolidone solution was added, mixed, and the mixture was formed into a soft mass. This mass was then sieved again, and the mixture was made into wet granules, which were dried at 80°C. Sodium carboxymethyl starch, microcrystalline cellulose, and magnesium stearate were pre-sieved and then added to the granules. The mixture was then mixed thoroughly and compressed into tablets.

[0527] Example 24

[0528]

[0529] Preparation process: 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 0.3g activated carbon, stir at room temperature for 30 minutes, filter with microporous membrane, measure the concentration of the filtrate, dispense 5mL into each ampoule, sterilize at 100°C for 30 minutes to obtain the injection solution.

[0530] Example 25

[0531]

[0532] Preparation process: The (-)-I-3 sample, sucrose, crospovidone, and carboxymethyl cellulose were each passed through a 100-mesh sieve. Sucrose laurate was prepared as a 25% concentrated solution using 60°C ethanol. The prescribed amounts were weighed and thoroughly fluidized. Then, 25% sucrose laurate was added to form a soft mass, dried at 55°C, and granulated through a 20-mesh sieve. The granules were then sieved through a 12-mesh sieve, and silica, aspartame, and apple flavoring were added. The weight of the granules was then measured before packaging.

[0533] Example 26

[0534]

[0535] Preparation process: Take 80 mL of water for injection, add (+)-I-4 sample, mannitol and lactose, stir to dissolve, then add 1 mol / L citric acid and 1 mol / L sodium hydroxide to adjust the pH to 5.0-7.0, and add water to 100 mL. Add 0.5 g of activated carbon, stir at 30 °C for 20 minutes to remove carbon, filter sterilize using a microporous membrane, dispense the filtrate into 1 mL vials, pre-freeze at -40 °C for 5 hours, then freeze-dry under reduced pressure for 12 hours (pressure <20 Pa). After freeze-drying, allow the sample temperature to reach room temperature and then dry for another 5 hours to obtain a white, loose, blocky substance, which is then sealed.

[0536] Example 27

[0537]

[0538] Preparation process: Dissolve the malic acid in 25 mL of purified water according to the above formula, add the chitosan according to the formula, and stir thoroughly until completely dissolved. Add an appropriate amount of 1 mol / L sodium bicarbonate solution to the above solution for rapid neutralization, and adjust the pH of the chitosan solution to 5.0-7.0. Set aside. Then add the acesulfame potassium and strawberry flavoring according to the formula to 40 mL of purified water, stir to dissolve, then add the (+)-I-3 sample according to the prescription, stir to dissolve, then add the prepared chitosan solution, stir evenly, add the remaining purified water according to the prescription to the mixed solution, stir to mix evenly, and obtain an (+)-I-3 oral solution with pH 5.0-7.0.

[0539] Example 28: In vitro binding of the compound to human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1

[0540] There are four subtypes of voltage-gated calcium ion channels with α2δ subunits: α2δ-1, α2δ-2, α2δ-3, and α2δ-4. Among them, α2δ-1 is the subtype that mediates chronic neuropathic pain (Field, MJ; et al. Proc. Natl. Acad. Sci. USA 2006, 103, 17537-17542). Therefore, the binding strength of a compound to α2δ-1 is a direct indicator of its analgesic effect on chronic neuropathic pain (Calandre, EP; et al. Expert Rev. Neuroother. 2016, 16, 1263-1277).

[0541] The binding strength of the compound in vitro to the human recombinant calcium channel Cav2.2 / β3 / α2δ-1 was performed in accordance with previously reported methods (Gee, NS; et al. J. Biol. Chem. 1996, 271, 5768-5776; Marais, E.; et al. Mol. Pharmacol. 2001, 59, 1243-1248.). The assay used CHO cells expressing the human recombinant calcium channel Cav2.2 / β3 / α2δ-1. After routine cell membrane separation, 3 μg of cell membrane was added to each well. Modified HEPES / KOH buffer (pH 7.4) was used as the test solution, followed by the addition of 5 nM of […]. 3 [H] Gabapentin and six concentrations of the analyte (3, 9, 27, 81, 243, and 729 nM) were incubated at 25°C for 120 min. Nonspecific binding was obtained by replacing the analyte with 10 μM gabapentin. After incubation, cell membranes were collected by filtration and washed with 50 mM Tris-HCl (pH 7.4), followed by liquid scintillation analysis to detect the binding of [H] gabapentin on the cell membrane. 3 The radioactivity of H] gabapentin. The compounds in this application are related to [ 3 [H] Gabapentin competitively binds to human recombinant calcium ion channels Cav2.2 / β3 / α2δ-1, and the compounds of this application [ 3 The inhibition rate of gabapentin binding to recombinant human calcium channel Cav2.2 / β3 / α2δ-1 was calculated using the following formula:

[0542] Inhibition rate = [(II U ) / (I0-I U )]×100%

[0543] in,

[0544] I is the compound to be tested and [ 3 The radioactivity corresponding to the simultaneous co-incubation of H]gabapentin with human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1.

[0545] I0 is [ 3 The radioactivity corresponding to [H] gabapentin co-incubated with human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1, without the analyte compound added to the incubation system.

[0546] I U It is 10μM gabapentin and [ 3 The radioactivity corresponding to the simultaneous co-incubation of H] gabapentin with human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1.

[0547] The test compound inhibited 50% of [ 3 The concentration of gabapentin in recombinant human calcium channel Cav2.2 / β3 / α2δ-1 was defined as IC50. 50 IC 50 The inhibition rate described above is calculated using nonlinear least squares regression analysis (MathIQ). TM IDBusiness Solutions Ltd. (UK). The test results are shown in the table below:

[0548]

[0549] As can be seen from the activity data of this embodiment, the compound of general formula I of this application has good binding activity with human recombinant calcium ion channel Cav2.2 / β3 / α2δ-1, and can be used to prepare drugs for treating chronic neuropathic pain, epilepsy and anxiety.

[0550] Gamma-aminobutyric acid (GABA) drugs that act on the α2δ-1 ligand of voltage-gated calcium ion channels, such as gabapentin and pregabalin, not only have analgesic effects for chronic neuropathic pain, but also have anti-epileptic (pregabalin, an indication approved by the US FDA) and anti-anxiety (pregabalin, an indication approved by the European EMA) effects. These effects are related to the binding of the drug to the α2δ-1 ligand of the voltage-gated calcium ion channel. Therefore, the compound of general formula I in this application can also be used to prepare drugs for treating epilepsy and anxiety.

[0551] Example 29: Analgesic effect of the compound in a rat model of chronic neuropathic pain

[0552] The efficacy of oral administration of 30 mg / kg (±)-I-7, (±)-I-3 and (±)-I-4 p-toluenesulfonates of the representative compounds of this application in a sciatic nerve injury (SNI) model in Sprague Dawley (SD) rats was evaluated.

[0553] Establishment of the SNI model: Surgery was performed using aseptic techniques. Preoperatively, all surgical instruments, including scalpels, forceps, sutures / needles, and surgical cotton, were sterilized. Animals were anesthetized with an intraperitoneal injection of 50 mg / kg of a 50% styrax solution and placed in a lateral recumbent position. Hair in the surgical area of ​​the lower body was shaved. The area was disinfected alternately with povidone-iodine and 75% alcohol. The skin was incised at the upper edge of the left hind limb, and the muscles were bluntly dissected to expose the main trunk of the sciatic nerve and its three branches: the tibial nerve, common peroneal nerve, and sural nerve. The tibial and common peroneal nerves were ligated and cut, while the sural nerve was preserved and kept intact. Postoperatively, the wound was sutured in layers. 25% ampicillin (1 mL / kg) was injected intraperitoneally to prevent infection, and routine nursing care was provided. In the sham group, only the sciatic nerve and its branches were exposed; the nerve was not ligated or cut. All other procedures were the same as in the model group.

[0554] Mechanical pain threshold detection: The mechanical pain threshold of each animal was measured on the surgical side of the sole using Von-Frey test fibers on postoperative days 1, 3, and 7. The "up-and-down" method was employed, with stimulation intensities of 0.4, 0.6, 1, 2, 4, 6, 8, and 15 g. During testing, the test fibers vertically stimulated the lateral part of the center of the left hind paw sole for 6-8 seconds, with a 5-second interval. Pain response was characterized by obvious paw withdrawal, licking, or lifting behaviors during each test. Starting on postoperative day 11, animals were placed in the experimental environment for acclimatization, acclimatizing for 15 minutes daily for 3 consecutive days. After acclimatization on day 13, baseline mechanical hypersensitivity was measured. Mechanical hypersensitivity was expressed as the 50% paw-withdrawal threshold (PWT), calculated using the formula: 50% PWT(g) = 10... xf+kδ , where xf is the fiber test force log value, k is the table value, and δ is the average value of the fiber test force log value interval.

[0555] Efficacy evaluation: Based on the baseline threshold test results on day 13 post-surgery, animals in the model group that did not exhibit mechanoreathia (i.e., a withdrawal threshold PWT greater than 4g) were excluded, and the remaining successfully modeled animals were used for the formal experiment. On day 14 post-surgery, each test compound was freshly prepared. Pregabalin at a dose of 30 mg / kg was directly dissolved in 0.9% sodium chloride to obtain the required concentration. (±)-I-7, (±)-I-3, and (±)-I-4 p-toluenesulfonates at a dose of 30 mg / kg (calculated as free base) were also completely dissolved in 0.9% sodium chloride solution. Successfully modeled animals were randomly divided into 5 groups of 8 animals each, with an additional sham-operated group of 7 animals. After animal marking and weighing, each test drug and solvent (vehicle; 0.9% sodium chloride) were administered orally at a volume of 10 mL / kg. Mechanosensitive hypersensitivity of the left hind paw was assessed at 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h post-administration. A blinded evaluation was conducted using the same testing methods as above. The area under the curve (AUC) of the mechanical pain threshold versus time was calculated using GraphPad Prism Version 8.0.1 software. The analgesic intensity in the rat SNI model was expressed as the Maximum Possible Effect (MPE), %MPE = [(AUC of the drug group - AUC of the solvent group) / (AUC of the sham-operated group - AUC of the solvent group)] × 100.

[0556] Results and Discussion: Data are expressed as mean ± standard error (SEM) and plotted using GraphPad PrismVersion 8.0.1 software. One-way ANOVA was used for comparisons between groups, and Dunnett's analysis was used for post-hoc multiple comparisons. * (p < 0.05) indicates statistical significance, ** indicates p < 0.01, and *** indicates p < 0.001. Detailed statistical results can be found in the mechanical pain threshold time-history graph (…). Figure 3A ) and area under the mechanical pain threshold-time curve ( Figure 3B As shown in the figure below, similar to the positive control drug pregabalin, (±)-I-7, (±)-I-3, and (±)-I-4 tosylate at a dose of 30 mg / kg (as free base) all exhibited varying degrees of inhibitory effects on mechanosensitive hypersensitivity in SNI rats. The areas under the mechanosensitive pain threshold-time curve were significantly higher in the (±)-I-7 and (±)-I-4 tosylate groups compared to the solvent control group. The maximum probable analgesic effects (%MPE) of the four compounds—pregabalin, (±)-I-7, (±)-I-3, and (±)-I-4 tosylate—were 110.90%, 73.63%, 44.80%, and 95.95%, respectively. The results showed that the representative compounds (±)-I-7, (±)-I-3 and (±)-I-4 p-toluenesulfonates of this application at a dose of 30 mg / kg (as free base) all had certain analgesic effects in the SNI model and could be used to prepare drugs for the treatment of chronic neuropathic pain.

[0557] Example 30: Analgesic effect of the compound in a rat model of chronic neuropathic pain

[0558] The efficacy of oral administration of 10 mg / kg (based on free base) of (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate in a sciatic nerve branch injury (SNI) model in SD rats was evaluated.

[0559] The model construction method and the mechanical pain threshold detection method are the same as in Example 29.

[0560] Efficacy evaluation: The specific detection method is the same as in Example 29. On the 14th day after surgery, each test compound was freshly prepared. Pregabalin at a dose of 10 mg / kg was directly dissolved in 0.9% sodium chloride to the required concentration. For the representative compounds of this application (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate at a dose of 10 mg / kg (as free base), the solvent used was 5% PEG 400 (polyethylene glycol 400) + 95% (0.9% sodium chloride), that is, 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 to dissolve completely. The animals that successfully modeled the disease were randomly divided into 5 groups, with 6 animals in each group, and 5 animals in the sham surgery group. After animal tagging and weighing, each test drug and solvent (5% PEG 400 + 95% (0.9% sodium chloride)) were administered orally at a volume of 10 mL / kg. Mechanosensitive hypersensitivity of the left hind paw was assessed at 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h post-administration. A blinded assay was used, following the same testing method as above. The area under the curve (AUC) of the mechanical pain threshold versus time and the maximum probable analgesic effect (MPE) were calculated using the same methods as in Example 29.

[0561] Results and Discussion: Data are expressed as mean ± standard error and plotted using GraphPad Prism Version 8.0.1 software. One-way ANOVA was used for comparisons between groups, and Dunnett's analysis was used for post-hoc multiple comparisons. * (p < 0.05) indicates a significant difference, ** indicates p < 0.01, and *** indicates p < 0.001. Detailed statistical results can be found in the mechanical pain threshold time-history chart (…). Figure 4A ) and the area under the mechanical pain threshold-time curve (4) Figure 4B ).Depend on Figure 4A and Figure 4BIt is known that the representative compounds of this application, (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate, administered orally at a dose of 10 mg / kg (as free base), also showed varying degrees of inhibitory effects on mechanosensitive hypersensitivity in rats with a sciatic nerve branch injury model. Among them, the area under the mechanosensitive pain threshold-time curve in the (+)-I-4 p-toluenesulfonate group was significantly higher than that in the solvent control group, and its effect was significantly stronger than that of the 10 mg / kg positive control drug pregabalin. The maximum probable analgesic 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 this application, (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate, exhibit good analgesic effects in the rat SNI model and can be used to prepare drugs for treating chronic neuropathic pain; (2) the analgesic activity of compound (+)-I-3 p-toluenesulfonate is stronger than that of (-)-I-3 p-toluenesulfonate, and the analgesic activity of compound (+)-I-4 p-toluenesulfonate is stronger than that of (-)-I-4 p-toluenesulfonate, indicating that the analgesic activity of the compounds of this application is stereochemically dependent. The results of the in vitro binding assay of (-)-I-3 p-toluenesulfonate, (+)-I-3 p-toluenesulfonate, (-)-I-4 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate in Example 28 are also consistent with this conclusion.

[0562] Example 31: Antiepileptic effect of the compound in a mouse epilepsy model (maximum electroshock model (MES))

[0563] The experimental groups included a solvent negative control, a positive drug control group (pregabalin and gabapentin), and the compound of this application. Male ICR mice weighing 22±2g were selected. Both the test drug and the control drug were dissolved in DMSO (5% v / v) + 10% 1,2-propanediol saline solution (95% v / v) and administered by gavage at a volume of 10mL / kg. Mice were fasted for 12 hours, then administered the compound of this application or the control drug according to their body weight. After a certain time interval (2 hours for pregabalin, 1 hour for gabapentin, and 3 hours for the compound of this application), electrical stimulation was performed to induce generalized tonic-clonic seizures. The induction model was performed using a YLS-9A electrophysiological stimulator (Shanghai Xinruan Information Technology Co., Ltd.), with the following parameters set: configuration 8, stimulation voltage 160V, and wavenumber 90. Before administering electrical stimulation, the mice's ears were first wiped with saline solution. Then, one electrical stimulation was applied using ear clip electrodes. The standard for a seizure was the rigid extension of the hind limbs. If the animal exhibited hind limb rigidity, it was considered unprotected by the drug; if the hind limbs did not become rigid, it was considered protected by the drug. The animals' responses were observed and recorded, and the data were statistically analyzed to calculate the compound protection rate.

[0564] The test results are shown in the table below:

[0565]

[0566]

[0567] *Note: Calculated based on the original drug (free base).

[0568] The median effective dose (ED) of the test compound for animal protection 50 The dose-protection rate curve was obtained using the least squares method (Graphpad Prism 5). The fitted curve is shown below. Figure 5 As shown.

[0569] After calculation, the ED of (+)-I-3 50 = 6.52 mg / kg, ED of (+)-I-4 50 =21.51 mg / kg, the ED of pregabalin 50 =11.99 mg / kg. The above results show that the representative compounds (+)-I-3 and (+)-I-4 of this application exhibit strong anti-epileptic seizure activity in a mouse maximal electroshock model and can be used to prepare anti-epileptic drugs.

[0570] Example 32: Antiepileptic effect of the compound in a mouse epilepsy model (6-Hz psychomotor seizure model)

[0571] The test groups included a solvent negative control, a positive drug control group (pregabalin and gabapentin), and the compound of this application. Male C57BL / 6 mice weighing 20±2g were selected. Both the test drug and the control drug were dissolved in DMSO (5% v / v) + 10% 1,2-propanediol saline solution (95% v / v) and administered by gavage at a volume of 10mL / kg. Mice were fasted for 12 hours, then given either the compound of this application or the control drug. Seizures were induced by 6-Hz electrical stimulation at specific time intervals (2 hours for pregabalin, 1 hour for gabapentin, 1 hour for levetiracetam, and 3 hours for the compound of this application). In the induction model, when using a Model 4100 stimulator (AM Systems, USA) to administer stimulation, the mice were held upright by the nape of their necks in their cages. Corneal electrodes, moistened with saline, were gently placed on both corneas of the mice. Electrical stimulation was then administered using a foot-operated stimulator with the following parameters: 6 Hz, 32 mA unidirectional square wave, 0.2 ms pulse width, and 3 s stimulation duration. A stopwatch was used to time the stimulation. If the seizure-like behavior of the mouse lasted no more than 7 seconds after the stimulation ended, it was considered that the drug provided protection; if it lasted longer than 7 seconds, it was considered that the drug did not provide epileptic protection. The animals' responses were observed and recorded, and the data were statistically analyzed to calculate the compound's protection rate.

[0572] Statistical methods: Fisher's exact test was performed to compare the protection rates of different drug administration groups with those of the solvent control group.

[0573] The test results are shown in the table below:

[0574]

[0575] # Note: Calculated based on the original form of the drug (free alkali).

[0576] The above results show that the representative compounds (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate of this application exhibit strong anti-epileptic seizure effects in a mouse 6-Hz electrical stimulation-induced seizure model, and can be used to prepare anti-epileptic drugs.

[0577] Example 33: Antiepileptic effect of the compound in a mouse epilepsy model (subcutaneous injection of pentylenetetrazol model (sc-)) PTZ))

[0578] The test groups included a solvent negative control, a positive drug control group (pregabalin and gabapentin), and the compound of this application. Male ICR mice weighing 22±2g were selected. Both the test drug and the control drug were dissolved in DMSO (5% v / v) + 10% 1,2-propanediol saline solution (95% v / v) and administered via intraperitoneal injection at a volume of 10mL / kg. Mice were fasted for 12 hours, then given either the compound of this application or the control drug. Subsequently, at certain time intervals (2 hours for pregabalin, 1 hour for gabapentin, and 3 hours for the compound of this application), pentylenetetrazol (PTZ) was injected subcutaneously to induce epileptic seizures. In the induction model, pentylenetetrazol (PTZ) was dissolved in physiological saline and administered to mice via subcutaneous injection (10 mL / kg, dosage 100 mg / kg). Behavioral observation of mice was conducted 1 hour after PTZ injection, and the number of mice that experienced convulsions, clonic seizures, tonic seizures, and deaths, as well as the latency period, were recorded.

[0579] Statistical methods: Fisher's exact test was performed on the protection rate and mortality rate of different drug administration groups compared with the solvent control group. Onset time and latency were analyzed using one-way ANOVA.

[0580] Experimental results:

[0581]

[0582]

[0583] Note: Fisher's exact test indicates a significant difference compared to the solvent control group (*p<0.05, **p<0.01). # The dosage is based on the original form of the drug (free base).

[0584] Subcutaneous injection of pentylenetetrazol (PTZ) induced strong convulsive behavior in mice: in the solvent control group, 8 / 8 (100%) experienced generalized tonic-clonic seizures, 6 / 8 (75%) experienced generalized tonic-clonic seizures, and 6 / 8 (75%) died. The positive control, pregabalin (PGB), showed a trend towards reducing generalized tonic-clonic seizures (100%→62.5%), and significantly reduced the incidence of tonic seizures (75%→12.5%) and mortality (75%→12.5%). (+)-I-3-tosylate showed a trend towards reducing generalized tonic-clonic seizures (100%→60%), and significantly reduced the incidence of tonic seizures (75%→0%) and mortality (75%→0%). (+)-I-4-tosylate showed a trend towards reducing generalized tonic-clonic seizures (100%→60%), and also showed a trend towards reducing the incidence of tonic seizures (75%→20%) and mortality (75%→30%). Gabapentin (GBP) at this dose did not significantly improve the incidence of seizures or mortality.

[0585] In this application, the representative compounds (+)-I-3 p-toluenesulfonate, (+)-I-4 p-toluenesulfonate, and the control drug, in the above-mentioned tests, define the latency period as the time from subcutaneous injection of pentylenetetrazol to the occurrence of different epilepsy-related phenomena. Figure 6 It can be seen that pregabalin (PGB), (+)-I-3-toluenesulfonate and (+)-I-4-toluenesulfonate at 30 mg / kg (calculated as free base) significantly prolonged the latency of generalized clonic seizures, tonic seizures and death, but gabapentin (GBP) was ineffective at this dose.

[0586] The above results show that the representative compounds (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate of this application have a strong inhibitory effect on seizures and epilepsy-induced death in mice under subcutaneous injection of pentylenetetrazol model, and can be used to prepare antiepileptic drugs.

[0587] Example 34 Pharmacokinetics of the compound in rats

[0588] Male SD rats were fasted for 12 hours before the experiment, but had free access to water. The compounds (+)-I-3-p-toluenesulfonate or (+)-I-4-p-toluenesulfonate of this application were dissolved in a 10% 1,2-propanediol distilled aqueous solution and administered orally or intravenously to male SD rats, with 3 rats per group. Blood samples of 0.2 mL were collected from the posterior ocular venous plexus at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h after oral administration, and at 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h after intravenous administration. The samples were placed in EDTA-K2 tubes, centrifuged at 11000 rpm for 5 min, and the plasma was separated and frozen at -20°C. The concentration of the parent drug was determined using a validated HPLC-ESI-MS method, and pharmacokinetic parameters were calculated using WinNonLin. The results are shown in the table below:

[0589]

[0590] *Both compounds are administered in the form of p-toluenesulfonate, and the test data are based on the original drug (free base).

[0591] As can be seen from the above data, the representative compounds of this application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, are rapidly absorbed and have very high bioavailability after oral administration, making them suitable for oral administration.

[0592] Example 35: Experiment on the effect of compounds on rat motor function

[0593] All test drugs were dissolved in DMSO (5% v / v) + 10% 1,2-propanediol saline solution (95% v / v) and administered by gavage at a volume of 10 mL / kg. A solvent negative control and a positive control group (pregabalin (PGB), 10 mg / kg and 30 mg / kg) were set up. The experimental groups included (+)-I-3 p-toluenesulfonate 10 mg / kg (calculated as free base), (+)-I-4 p-toluenesulfonate 10 mg / kg (calculated as free base), (+)-I-3 p-toluenesulfonate 30 mg / kg (calculated as free base), and (+)-I-4 p-toluenesulfonate 30 mg / kg (calculated as free base). Male SD rats weighing 200-250 g were selected, with 10 animals in each treatment group. The rotarod test was performed using a YLS-31A fatigue rotarod apparatus (Shanghai Xinruan Information Technology Co., Ltd.), with the rotation speed set to a constant 6 rpm. On the first day, a screening test was conducted. Rats were held by the tip of their tails and placed on a rotarod. After they maintained their balance and walked along the rotarod, they were released, and the number of times they fell off within one minute was recorded. Rats that fell off three times within one minute were eliminated and not used for subsequent drug evaluation. On the second day, a drug evaluation experiment was conducted. Rats were fasted for 8 hours before the experiment. A rotarod test was then performed as the pre-drug administration time point, followed by gavage administration. Rotarod tests were performed at 1, 2, 4, 6, 8, 10, and 24 hours after administration, and the number of times the rats fell off within one minute was recorded. Three falls within one minute were considered to indicate drug toxicity causing "rotarod fall" in the rats. The degree of "rotarod fall" at a specific time point in each administration group was calculated as the proportion of animals with "rotarod fall" in that group to the total number of animals in that group.

[0594] The test results are as follows Figure 7 As shown.

[0595] The rotarod test is a classic experiment for measuring the effect of compounds on the motor function of animals. We used the rat rotarod test to evaluate the effects of the representative compounds of this application, (+)-I-3-p-toluenesulfonate and (+)-I-4-p-toluenesulfonate, on the motor function of rats. Figure 7 It can be seen that at a dose of 10 mg / kg (calculated as free base), (+)-I-3 p-tosylate, (+)-I-4 p-tosylate, and pregabalin (PGB) control did not significantly affect the rotator performance of rats; at a dose of 30 mg / kg (calculated as free base), the PGB group showed obvious toxicity, and the effect on the rat rotator reached its maximum 4 h after administration. The proportion of rats whose rotator performance was affected in the (+)-I-3 p-tosylate and (+)-I-4 p-tosylate groups was smaller than that in the PGB group.

[0596] Example 36: Acute toxicity test of the compound in rats

[0597] Preliminary acute toxicity assessment of (±)-I-7, (+)-I-3 and (+)-I-4 toluenesulfonates in male SD rats.

[0598] SD rats were used for preliminary acute toxicity testing one week after acclimatization. Compounds were freshly prepared on the day of the test. Pregabalin and (±)-I-7 were directly dissolved in 0.9% sodium chloride to the required concentration. (+)-I-3 and (+)-I-4 toluenesulfonate were dissolved in 5% PEG 400 + 95% (0.9% sodium chloride) solution, i.e., first dissolved in 5% PEG 400 solution, then added to 95% 0.9% sodium chloride solution, and vortexed until fully dissolved. Animals were marked and weighed, then randomly grouped into groups of 2-4 animals each. Animals were administered each test compound and the solvent (5% PEG 400 + 95% (0.9% sodium chloride)) orally at a volume of 10 mL / kg. Clinical symptoms of each animal were observed and recorded at 0.5 h, 1 h, 2 h, 4 h, 6 h, and 24 h after administration. The clinical symptom codes are as follows: 0 No abnormality, 1 Mild tremor, 2 Unsteady gait, 3 Prone position, 4 Startle reflex, 5 Dyspnea, 6 Loss of orthostatic reflex, 7 Eyelid closure, 8 Rapid breathing, × Animal death.

[0599] Results and Discussion: The results are shown in the table below. When (+)-I-3 p-toluenesulfonate at a dose of 164.5 mg / kg (calculated as free alkali) and (+)-I-4 p-toluenesulfonate at a dose of 163.8 mg / kg (calculated as free alkali) were administered orally, all animals in both groups showed no significant abnormalities compared to the solvent control group within 0-24 hours after administration. When (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate were administered orally at a dose of 300 mg / kg (calculated as free alkali), two animals in the (+)-I-3 p-toluenesulfonate group only developed prone position 1 hour after administration, with one of them also exhibiting mild tremors and eyelid closure symptoms. In contrast, one animal in the (+)-I-4 group only developed prone position 1 hour after administration, while the other animal showed prone position at both 1 hour and 3 hours after administration. Another compound, (±)-I-7, was administered orally at a dose of 300 mg / kg (calculated as free base). All animals were found to be prone at 1 and 2 hours after administration, with two animals also exhibiting mild tremors. 24 hours after administration, consistent with the solvent control group, no significant abnormalities were observed in animals administered (±)-I-7, (+)-I-3 p-toluenesulfonate, and (+)-I-4 p-toluenesulfonate. The test results showed that when the representative compounds of this application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, were orally administered to male rats at a dose of 164.5 mg / kg (calculated as free base) and 163.8 mg / kg (calculated as free base), no neurotoxicity was observed. Combined with the analgesic and antiepileptic dosages disclosed in Examples 29-33 of this application, it can be inferred that the representative compounds of this application, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, have a wide safety window. The representative compounds of this application, (±)-I-7, (+)-I-3 p-toluenesulfonate and (+)-I-4 p-toluenesulfonate, caused relatively significant acute toxic reactions in animals at a high dose of 300 mg / kg (calculated as free base), but no animal deaths occurred.

[0600]

[0601]

Claims

1. A compound having the general formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 and R 2 are independently selected from H, halogen or C1-C6alkyl; each R 3 , R 4 , R 5 , R 6 is independently selected from the group consisting of H, halogen, C1-C6alkyl and C1-C6alkoxy; or R 3 , R 4 and the C-atoms to which they are attached together form a C3-C6cycloalkyl group, or R 5 , R 6 and the C-atoms to which they are attached together form a C3-C6cycloalkyl group; each R 7 , R 8 , R 9 , R 10 is independently selected from H, halogen and C1-C6alkyl; m is 0 or 1; n is 1; R 8 the C atom to which it is attached and R 10 the C atom to which it is attached and R 8 , R 10 together with the C atom to which it is attached and R R 8 connected C atom and R 10 the solid and dashed lines between connected C atoms and R 8 connected C atom and R 10 the chemical bond between connected C atoms can be a single or double bond; when it represents a double bond, the corresponding R 7 and R 9 represents the absence.

2. The compound having the general formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 1 and R 2 are independently selected from H and C1-C3alkyl; and / or R 3 , R 4 are independently selected from H, halogen and C1-C3alkyl; or R 3 , R 4 and the C atom to which they are jointly attached form a cyclopropyl group; and / or R 7 , R 8 , R 9 , R 10 is independently selected from H and C1-C6 alkyl; or R 8 and the C atom to which R 10 is attached and the C atom to which R 8 , R 10 form a cyclopropyl group; and / or R 8 the solid and dashed lines between the C atoms to which R 10 are attached represent R 8 and R 10 attached represent a single or double bond; when it represents a double bond, R 7 and R 9 represent nothing; and / or m = 0; n = 1.

3. The compound having the general formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof according to claim 2, wherein, R 1 and R 2 are independently selected from H or methyl; and / or R 3 , R 4 are independently selected from H and methyl; or R 3 , R 4 and the C atom to which they are jointly attached form a cyclopropyl group; and / or R 7 , R 8 , R 9 , R 10 is independently selected from H or methyl; or R 8 and the C atom to which R 10 is attached and the C atom to which R 8 , R 10 comprise a cyclopropyl group; and / or R 8 the solid and dashed lines between the C atoms to which R 10 are attached represent R 8 and R 10 may be single or double bonds; when it represents a double bond, R 7 and R 9 represent nothing; and / or m = 0; n = 1.

4. The compound having the general formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof according to claim 3, wherein, R 1 and R 2 are independently selected from H or methyl; and / or R 3 , R 4 are independently selected from H and methyl; and / or R 7 , R 8 , R 9 , R 10 is independently selected from H or methyl; or R 8 and the C atom to which R 10 is attached and the C atom to which R 8 , R 10 form a cyclopropyl group; and / or R 8 the C atom to which it is attached is a single or double bond; when it denotes a double bond, R 10 the chemical bond between the C atoms to which it is attached is a single or double bond; when it denotes a double bond, R 7 and R 9 denotes the absence; and / or m = 0; n = 1.

5. The compound having the general formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof according to claim 4, wherein, R 1 and R 2 are independently selected from H or methyl; and / or R 3 , R 4 are independently selected from H and methyl; and / or R 7 , R 8 , R 9 , R 10 are independently selected from H or methyl; and / or m = 0; n = 1.

6. The compound having general formula I according to any one of claims 1 to 5, a chiral isomer thereof or a pharmaceutically acceptable salt thereof, wherein The compound is a racemic mixture.

7. The compound having general formula I according to any one of claims 1 to 5, a chiral isomer thereof or a pharmaceutically acceptable salt thereof, wherein The compound is dextrorotatory.

8. The compound having the general formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, selected from the following compounds:

9. A process for the preparation of a compound of general formula I according to any one of claims 1 to 8, characterized in that, comprising the following steps: 1) Wittig condensation of ketone K with phosphoryl acetic ester W1 in the presence of a base to obtain α,β-unsaturated acetic ester L-1, Michael addition of L-1 with nitromethane in the presence of a base to obtain M-1, 2) Knoevenagel condensation of ketone K with nitromethane in the presence of a catalyst to obtain α,β-unsaturated nitro compound L-2, Michael-like addition of L-2 with acetic ester W2 in the presence of a strong base to obtain M-2, wherein R 11 , R 12 and R 13 are selected from C1-C6 alkyl; R 1 to R 10 , m and n have the definitions as described in any one of claims 1 to 5.

10. Use of the compound having the general formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 for the preparation of a medicament for the treatment of chronic neuropathic pain, epilepsy and anxiety.

11. A pharmaceutical composition, characterized by, The composition comprises a compound having the general formula I, a chiral isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, and a pharmaceutically acceptable adjuvant.

12. The pharmaceutical composition of claim 11, wherein, The adjuvant is selected from one or several of a carrier, a diluent and an excipient.

13. The pharmaceutical composition of claim 11 or 12, wherein, The composition is a solid oral preparation, a liquid oral preparation or an injection.

14. The pharmaceutical composition of claim 13, solid and liquid oral formulations including: The injection is a dispersible tablet, an enteric-coated tablet, a chewable tablet, an oral disintegrating tablet, a capsule, a granule, an oral solution, an injection, a freeze-dried powder for injection, a large volume injection or a small needle.

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