Cycloalkene derivative preparation method

Abstract

The present invention relates to a cycloalkene derivative preparation method. The method of the present invention overcomes problems in the prior art, greatly reduces costs, improves process operability and yield, and has high process safety. Thus, the present invention is suitable for industrial application.

Description

Process for the preparation of a cycloalkene derivative TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a process for the preparation of a cycloalkene derivative. BACKGROUND

[0002] Diabetes mellitus is a common endocrine and metabolic disease, which is caused by metabolic disorder due to various reasons and leads to damage of multiple systems and multiple organs. The incidence is high, and there are about 425 million diabetic patients worldwide. The incidence of diabetes in China is about 10%, of which type II diabetes accounts for 90%, and the prevalence rate is still increasing, and the age of onset is becoming younger and younger.

[0003] At present, there are many types of drugs for the treatment of type II diabetes, including insulin, biguanides, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase (DPP-IV) inhibitors, sodium-glucose co-transporter 2 (SGLT-2) inhibitors, and alpha-glucosidase inhibitors, among which GLP-1 receptor agonists are the most concerned.

[0004] GLP-1 is a peptide hormone secreted by human intestinal L cells, and its receptor is distributed in islet cells, various gastrointestinal cells, central nervous system and neurons of peripheral nervous system. After the activation of GLP-1 receptor, it has physiological effects such as promoting insulin secretion, inhibiting glucagon secretion, inhibiting appetite and delaying gastric emptying. Clinical evidence shows that compared with other hypoglycemic drugs, GLP-1 receptor agonists have better hypoglycemic effect and are less likely to cause side effects such as hypoglycemia. In addition, it also has additional cardiovascular benefits, and can reduce food intake and delay gastric emptying, which is beneficial to weight control.

[0005] The currently marketed GLP-1 receptor agonists are all polypeptide drugs, most of which need to be administered subcutaneously, and the compliance of patients is not good. The bioavailability of oral polypeptides is very low. Therefore, there is a great clinical demand for the development of oral small molecule GLP-1 receptor agonists.

[0006] At present, there is no small molecule GLP-1 receptor agonist approved, and there are three small molecule GLP-1 receptor agonists in the clinical research stage, such as PF-06882961 and PF-07081532 developed by Pifzer Company, and TTP273 developed by vTv Company, which are currently in the clinical I / II phase research stage. Among them, PF-06882961 has shown significant hypoglycemic and weight loss effects in early clinical trials, and the safety is similar to that of polypeptide GLP-1 receptor agonists, and it is expected that in the future it can bring more treatment options for patients with diabetes, obesity and NASH.

[0007] There is a great clinical need for GLP-1 receptor agonists. Oral small molecule GLP-1 receptor agonists with lower cost and better compliance have the potential to treat a variety of metabolic diseases and have broad market prospects.

[0008] A series of GLP-1 receptor agonists are disclosed in patent WO2023011539, which have good effects. The present application further studies the preparation process of GLP-1 receptor agonist compounds to meet the needs of industrial amplification. SUMMARY

[0009] The present application provides a compound as shown in formula (VII), a stereoisomer thereof or a salt thereof,

[0010] wherein X1 and X2 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl; preferably, X1 and X2 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl or C 2-4 alkynyl; more preferably, X1 and X2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, vinyl or ethynyl;

[0011] PG1 is an amino protecting group; preferably, the amino protecting group is selected from Ns, Cbz, Boc, Fmoc, Alloc, Teoc, Meoc, Etoc, Pht, Tos, Tfa, Trt, DMB, PMB or Bn; more preferably, the amino protecting group is selected from Cbz, Boc, Fmoc, Alloc, Teoc or Meoc; further preferably Boc;

[0012] PG2 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-6 alkyl, C1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl or an alkynyl protecting group; preferably, PG2is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, TMS, TES, TBS, TIPS or TBDPS; more preferably, PG2is selected from hydrogen or TMS.

[0013] The present application also provides a compound as shown in formula (VII-1), a stereoisomer thereof or a salt thereof,

[0014] wherein PG1, PG2, X1and X2are as previously described.

[0015] The present application provides a compound as shown in general formula (VII) or (VII-1), a stereoisomer thereof or a salt thereof, and the structure of the compound is specifically shown as follows,

[0016] The present application also provides a preparation method of a compound as shown in formula (VII-1), wherein a compound as shown in formula (VI) and a reaction reagent compound as shown in formula (IV) are reacted to obtain a compound as shown in formula (VII-1),

[0017] wherein PG1, PG2, X1and X2are as previously described.

[0018] In a further preferred embodiment of the present application, in the preparation method of the compound as shown in formula (VII-1), the reaction is carried out in an organic solvent; preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; more preferably, the organic solvent is selected from isopropyl ether.

[0019] In a further preferred embodiment of the present application, the reaction in the process for preparing the compound of formula (VII-1) is carried out under inert gas protection, preferably nitrogen protection.

[0020] In a further preferred embodiment of the present application, the reaction in the process for preparing the compound of formula (VII-1) is carried out in the presence of a phosphine-containing catalyst; preferably, the phosphine-containing catalyst is selected from one or more of diphenylmethylphosphine, methylphosphine, triethylphosphine, tripropylphosphine, tri-tert-butylphosphine, triphenylphosphine or tributylphosphine; more preferably, the phosphine-containing catalyst is selected from triphenylphosphine or tributylphosphine; further preferably, the phosphine-containing catalyst is triphenylphosphine.

[0021] In a further preferred embodiment of the present application, the reaction in the process for preparing the compound of formula (VII-1) is carried out in the presence of an azo reagent; preferably, the azo reagent is selected from one or more of Tsunoda reagent, DEAD, DIAD, TMAD, TMAD, DBAD, ADDP or TIPA; more preferably, the azo reagent is selected from DEAD, DIAD, TMAD or ADDP; further preferably, the azo reagent is TMAD.

[0022] In a further preferred embodiment of the present application, the molar ratio of the compound of formula (VI) to the compound of formula (IV) in the process for preparing the compound of formula (VII-1) is 1:0.8-1:3; preferably 1:0.8-1:1.5; more preferably 1:1.

[0023] In a further preferred embodiment of the present application, the molar ratio of the compound of formula (VI) to the azo reagent in the process for preparing the compound of formula (VII-1) is 1:0.8-1:3; preferably 1:1-1:1.5; more preferably 1:1.3.

[0024] In a further preferred embodiment of the present application, the molar ratio of the compound of formula (IV) to the azo reagent in the process for preparing the compound of formula (VII-1) is 1:0.8-1:3; preferably 1:1-1:1.5; more preferably 1:1.3.

[0025] In a further preferred embodiment of the present application, the molar ratio of the compound of formula (VI) to the catalyst in the process for preparing the compound of formula (VII-1) is 1:0.8-1:3; preferably 1:1-1:1.5; more preferably 1:1.3.

[0026] In a further preferred embodiment of the present application, in the preparation method of the compound of formula (VII-1), the molar ratio of the compound of formula (IV) to the catalyst is 1:0.8-1:3; preferably 1:1-1:1.5; more preferably 1:1.3.

[0027] In a further preferred embodiment of the present application, in the preparation method of the compound of formula (VII-1), the molar ratio of the catalyst to the azo reagent is 1:0.8-1:3; preferably 1:0.8-1:1.5; more preferably 1:1.

[0028] In a further preferred embodiment of the present application, in the preparation method of the compound of formula (VII-1), the ratio of the compound of formula (IV) to the organic solvent is 1:5-1:20 (g:mL); more preferably 1:8-1:15 (g:mL); further preferably 1:10 (g:mL).

[0029] In a further preferred embodiment of the present application, in the preparation method of the compound of formula (VII-1), the reaction time is 1-10 hours, preferably 4-6 hours.

[0030] In a further preferred embodiment of the present application, in the preparation method of the compound of formula (VII-1), the reaction temperature is 5-60°C, preferably 15-25°C.

[0031] The present application also provides a preparation method of a compound of formula (VIII), which further comprises the following step: the compound of formula (VII-1) is further reacted to obtain the compound of formula (VIII),

[0032] wherein PG2is selected from an alkynyl protecting group; preferably, PG2is selected from TMS, TES, TBS, TIPS or TBDPS; more preferably, PG2is selected from TMS; PG1, X1and X2are as previously described.

[0033] In a further preferred embodiment of the present application, in the process for preparing the compound of formula (VIII), the reaction is carried out in the presence of a base; preferably, the base is selected from one or more of tetrabutylammonium fluoride, TEA / LiCl, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, potassium carbonate, tetrabutylammonium fluoride, TEA / LiCl; more preferably, the base is lithium hydroxide, sodium hydroxide, cesium hydroxide; further preferably, the base is lithium hydroxide; more preferably, the lithium hydroxide is lithium hydroxide monohydrate dissolved in aqueous solution and added to the reaction.

[0034] In a further preferred embodiment of the present application, in the process for preparing the compound of formula (VIII), the reaction is carried out in an organic solvent; preferably, the organic solvent is selected from one or more of water, methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; more preferably, the organic solvent is a mixture of tetrahydrofuran and water; further preferably, the ratio of the organic solvent is tetrahydrofuran: water = 1:1 to 8:1; more preferably, the ratio of the organic solvent is tetrahydrofuran: water = 7:3.

[0035] In a further preferred embodiment of the present application, in the process for preparing the compound of formula (VIII), the ratio of the compound of formula (VII) to the mixed organic solvent is 1:5 to 1:20 (g:mL); preferably, 1:8 to 1:15 (g:mL); more preferably, 1:10 (g:mL).

[0036] In further preferred embodiments of the present application, the reaction time in the process for the preparation of the compound of formula (VIII) is 5 to 15 hours, preferably 8 to 10 hours.

[0037] In further preferred embodiments of the present application, the reaction temperature in the process for the preparation of the compound of formula (VIII) is 0 to 15 °C, more preferably 2 to 8 °C, preferably 5 °C.

[0038] In further preferred embodiments of the present application, the present application also provides a process for the preparation of a compound of formula (XI), wherein the compound of formula (VIII) is further reacted to obtain a compound of formula (XI),

[0039] wherein PG1, X1and X2are as defined above.

[0040] In further preferred embodiments of the present application, the reaction in the process for the preparation of the compound of formula (XI) is carried out in an organic solvent; preferably, the organic solvent is selected from one or more of water, methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethyleneglycol dimethyl ether, methyl-tert-butyl ether, isopropyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide; more preferably, the organic solvent is selected from dichloromethane.

[0041] In further preferred embodiments of the present application, the reaction in the process for the preparation of the compound of formula (XI) is carried out under inert gas protection, preferably nitrogen protection.

[0042] In further preferred embodiments of the present application, the reaction in the process for the preparation of the compound of formula (XI) is carried out in the presence of a catalyst; preferably, the catalyst is selected from one or more of scandium trifluoromethanesulfonate, europium trifluoromethanesulfonate, indium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate or zinc trifluoromethanesulfonate; more preferably, the catalyst is selected from indium trifluoromethanesulfonate.

[0043] In a further preferred embodiment of the present application, the process for the preparation of a compound of formula (XI) is carried out in the presence of a catalyst; more preferably, the catalyst is selected from the group consisting of Ph3PclAu, chloro[tris(o-tolyl)phosphine]gold(I), gold trichloride, AuCl3, DMSAuCl, PPh3AuCl, ArPR2AuCl, XPhosAuCl, JohnphosAu(MeCN)SbF6, (PhO)3PauCl; further preferably, the catalyst is selected from Ph3PclAu. In a further preferred embodiment of the present application, the process for the preparation of a compound of formula (XI) is carried out at a ratio of the compound of formula (VIII) to the organic solvent of 1 :5 to 1 :20 (g:mL); preferably of 1 :8 to 1 :15 (g:mL); more preferably of 1 :10 (g:mL).

[0044] In a further preferred embodiment of the present application, the process for the preparation of a compound of formula (XI) is carried out at a molar ratio of the compound of formula (VIII) to the catalyst of 1 :0.8 to 1 :3; preferably of 1 :0.8 to 1 :1.5; more preferably of 1 :1.

[0045] In a further preferred embodiment of the present application, the process for the preparation of a compound of formula (XI) is carried out for a reaction time of 5 to 35 hours, preferably of 16 to 20 hours.

[0046] In a further preferred embodiment of the present application, the process for the preparation of a compound of formula (XI) is carried out at a reaction temperature of 0 to 50 °C, preferably of 20 to 30 °C.

[0047] In a further preferred embodiment of the present application, the present application also provides a process for the preparation of a compound of formula (IV), which further comprises the step of

[0048] wherein X3is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, C 2-6 alkenyl or C 2-6 alkynyl; preferably, X1and X2are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1- 3halogenated alkyl, C1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl or C 2-4 alkynyl; more preferably, X1and X2are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, ethenyl or ethynyl;

[0049] PG1, PG2, X1and X2are as previously described, and the preparation methods of the compounds shown in each formula are as previously described.

[0050] The present application also provides a preparation method of a compound shown in formula (VI), which comprises the following steps:

[0051] wherein, PG2, X1and X2are as previously described, and the preparation methods of the compounds shown in each formula are as previously described.

[0052] The present application also provides a preparation method of a compound shown in formula (X), which comprises the following steps:

[0053] wherein, X1and X2are as previously described, and the preparation methods of the compounds shown in each formula are as previously described.

[0054] The present application also provides a preparation method of a compound shown in formula (VIII), which comprises the following steps:

[0055] wherein, PG1, PG2, X1and X2are as previously described, and the preparation methods of the compounds shown in each formula are as previously described. The present application also provides a preparation method of a compound shown in formula (IX), which comprises the following steps:

[0056] wherein, PG1, PG2, X1and X2are as previously described, and the preparation methods of the compounds shown in each formula are as previously described. The present application also provides a preparation method of a compound shown in formula (X), which comprises the following steps:

[0057] wherein, X3is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1- alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 2-4 alkyl, C 2-4 alkyl, C

[0058] PG1, PG2, X1and X2are as previously described, and the compounds of each formula are prepared as previously described.

[0059] Compared with the prior art, the present patent uses inexpensive raw materials and reaction reagents, constructs different intermediate states, obtains intermediates with configurations, reduces the generation of reaction byproducts, improves the operability of the process, and finally improves the yield and purity.

[0060] Detailed description of the invention

[0061] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0062] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate, with methyl, ethyl, i-propyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl being preferred.

[0063] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc.

[0064] The term "alkenyl" refers to an alkenyl group in which one hydrogen atom is further substituted, for example, "vinylene" refers to -CH2=CH2-, and "propenylene" refers to -CH2-=CH2-CH2-, etc. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0065] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms, and even more preferably alkyl containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0066] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. The alkenyl group can be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0067] "Alkynyl" means (CH≡C-), preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 3 carbon atoms. The alkynyl group as mentioned can be further substituted by other relevant groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

[0068] "Haloalkyl" means an alkyl group as defined above, substituted by one or more halogen.

[0069] "Haloalkoxy" means an alkoxy group as defined above, substituted by one or more halogen.

[0070] "Hydroxyalkyl" means an alkyl group as defined above, substituted by a hydroxy group.

[0071] "C 1-6 "Cyanoalkyl" means -C 1-6 alkyl CN, such as -CH2CN, -CH2CH2CN, etc.

[0072] "C 1-6 "Carboxy" means -C 1-5 alkyl COOH.

[0073] "Hydroxy" means an -OH group.

[0074] "Halogen" means fluorine, chlorine, bromine or iodine.

[0075] "Amino" means -NH2.

[0076] "Cyano" means -CN.

[0077] "Nitro" means -NO2.

[0078] "Carboxy" means -C(O)OH.

[0079] "DMF" means N,N-dimethylformamide;

[0080] "TFA" means trifluoroacetic acid;

[0081] "DCM" means dichloromethane;

[0082] "K2CO3" means potassium carbonate;

[0083] "KOAc" means potassium acetate;

[0084] "Cbz" means carbobenzyloxy

[0085] "Boc" means tert-butyloxycarbonyl

[0086] "Fmoc" means fluorenylmethyloxycarbonyl

[0087] "Alloc" means allyloxycarbonyl

[0088] "Teoc" means trimethylsilylethoxycarbonyl

[0089] "Meoc" means methyloxycarbonyl

[0090] "Etoc" means ethyloxycarbonyl

[0091] "Pht" means phthaloyl

[0092] "Tos" means p-toluenesulfonyl

[0093] "Tfa" means trifluoroacetyl

[0094] "Trt" means trityl

[0095] "DMB" means 2,4-dimethoxybenzyl

[0096] "PMB" means p-methoxybenzyl

[0097] "Bn" means benzyl

[0098] "TMS" means trimethylsilyl

[0099] "TES" means triethylsilyl

[0100] "TBDMS or TBS" means tert-butyldimethylsilyl

[0101] "TIPS" means triisopropylsilyl

[0102] "TBDPS" means tert-butyldiphenylsilyl

[0103] "DEAD" means diethyl azodicarboxylate

[0104] "DIAD" means diisopropyl azodicarboxylate

[0105] "TMAD" means azodicarboxamide

[0106] "DBAD" means di-tert-butyl azodicarboxylate

[0107] "ADDP" means 1,1'-(azodicarbonyl)dipiperidine

[0108] "TIPA" means N,N,N',N'-tetraisopropylazodicarboxamide

[0109] "DMPU" means 1,3-dimethylpropyleneurea

[0110] "(S)-BINOL" means S-1,1 '-bi-2-naphthol. DETAILED DESCRIPTION

[0111] The present application is further described in detail by the following examples. However, the present application should in no way be limited to only the examples, but rather can also extend to equivalents thereof.

[0112] The structure of the compounds of the present application were determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) or deuterated chloroform (CDCI3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0113] LC-MS measurements were performed on an Agilent 1260 Infinity Series Mass Spectrometer. HPLC measurements were performed on a YMC-Triart C18 column (4.6 x 250 mm, 5 μm). Other information is shown in the following table:

[0114] The starting materials in the examples of the present application are known and either commercially available or can be synthesized using or adapting methods known in the art.

[0115] Example 1

[0116] A-1 (100.0 g, 1.0 eq), A-2 (188.0 g, 1.05 eq), and toluene (1 L) were mixed and stirred at room temperature; potassium carbonate (123.0 g, 2.0 eq) & water (200 ml, 2V) were added into the reaction flask, replaced with N2 for 3 times, then tri-tert-butylphosphine tetrafluoroborate (6.4 g, 0.04 eq) and palladium acetate (2.6 g, 0.02 eq) were added into the reaction flask, replaced with N2 for 3 times, then the temperature was raised to 80-90 °C and stirred for 16-20 h, the reaction was cooled to room temperature and monitored by HPLC; after the reaction was completed, dimethyl tetrahydrofuran (500 ml, 5V) and water (1 L, 10V) were added into the reaction, stirred at 20-30 °C for 0.5-1 h, then the reaction was allowed to stand, the upper organic phase was collected by liquid-liquid separation; the organic phase was concentrated to 1-2V at 40 °C; petroleum ether (1 L, 10V) was added into the reaction flask, concentrated to 1-2V at 40 °C; petroleum ether (1 L, 10V) was added into the reaction flask, concentrated to 1-2V at 40 °C; petroleum ether (1 L, 10V) was added into the reaction flask, stirred at 20-30 °C for 16-20 h; filtered, the filter cake was rinsed with petroleum ether (200 ml, 2V), and the solid was collected; the solid was dried at 40 °C for 4-6 h; solid A-3 (151 g) was obtained, with a purity of 96.6%, a content of 95.1%, and a molar content yield of 90%.

[0117] LCMS: MS m / z (ESI): 176.1 [M+1]

[0118] 1H NMR (400 MHz, CDCl3) δ 7.19 - 7.13 (m, 1H), 7.09 (dd, J = 7.9, 1.7 Hz, 1H), 6.90 (ddd, J = 8.0, 5.5, 1.3 Hz, 2H), 5.85 (dt, J = 3.3, 1.7 Hz, 1H), 4.08 (q, J = 2.9 Hz, 2H), 3.65 (t, J = 5.7 Hz, 2H), 2.52 - 2.37 (m, 2H), 1.50 (s, 9H)

[0119] Example 2

[0120] A-3 (100.0 g, 1.0 eq), methanol (500 ml, 5V) and tetrahydrofuran (300 ml, 3V) were added to the reaction flask; 10% wet Pd / C (1 g, 0.01X) was added to the reaction flask; H2was replaced for three times; the reaction was warmed to 30-40 °C and stirred for 24-36 h; the sample was detected for complete conversion from the raw material; after cooling to 20-30 °C, it was filtered through diatomite, the filter cake was rinsed with tetrahydrofuran (500 ml, 5V), and the filtrate was collected; the filtrate was concentrated at 40 °C to 1-2V; petroleum ether (500 ml, 5V) was added to the reaction flask, stirred at 20-30 °C for 1-2 h, filtered, the filter cake was rinsed with petroleum ether (1-2V), and the filter cake was collected; the filter cake was dried at 40-50 °C for 4-5 h to obtain 102 g of solid, purity 95.3%, content: 98.5%, molar yield of content: 100%.

[0121] LCMS: MS m / z (ESI): 178.3 [M+1]

[0122] 1H NMR (400 MHz, CDCl3) δ 7.15 - 7.02 (m, 2H), 6.89 (td, J = 7.5, 1.2 Hz, 1H), 6.77 (dd, J = 8.0, 1.2 Hz, 1H), 5.91 (s, 1H), 4.23 (s, 2H), 3.04 (tt, J = 12.2, 3.5 Hz, 1H), 2.83 (s, 2H), 1.96 - 1.79 (m, 2H), 1.61 (qd, J = 12.6, 4.2 Hz, 2H), 1.49 (s, 9H).

[0123] Example 3

[0124] Under nitrogen protection, add diethyl zinc solution in toluene (2.5 L, 25 V, 1.0 M) into the reaction flask, add trimethyl ethyl acetylene group (248 g, 4.0 eq.) and DMPU (242 g, 3.0 eq.) into the reaction flask in turn, replace three times of nitrogen; after the reaction is heated to 95-105 °C and stirred for 2-3 h, the reaction is cooled to 20-30 °C, slowly add (S)-BINOL (72 g, 0.40 eq.) solution in 25 V DCM into the reaction flask, stir at 20-30 °C for 0.2-0.5 h; add Ti(OiPr)4(180 g, 1.0 eq.) into the reaction flask, stir at 20-30 °C for 0.5-1.0 h; add A-5 (100 g, 1.0 eq.) into the reaction flask, stir at 20-30 °C for 3-4 h, sample detection, after the reaction is completed, control the temperature at 20-30 °C, slowly add potassium sodium tartrate (133.0 g, 1.33X) solution in water (1 L, 10 V), stir at 20-30 °C for 1-2 h, stand and separate, collect the organic phase, filter through diatomite (100 g, 1X), collect the filtrate; concentrate the filtrate at 40 °C to 1-2 V; add petroleum ether (2.5 L, 25 V) into the reaction flask, filter, rinse the filter cake with petroleum ether (200 ml, 2 V), collect the filtrate; wash the filtrate with water (1 L, 10 V), stand and separate, collect the organic phase; continue to wash the filtrate with water (1 L, 10 V), stand and separate, collect the organic phase; continue to wash the filtrate with water (1 L, 10 V), stand and separate, collect the organic phase; continue to wash the filtrate with water (1 L, 10 V), stand and separate, collect the organic phase; concentrate the organic phase at 40 °C to 2-3 V; collect the product A-7 210.0 g, purity 94.15%, content: 70%, molar yield of content: 91%; chiral purity: D / R: 93 / 7.

[0125] LCMS: MS m / z (ESI): 257.1 [M+1] +

[0126] 1H NMR (400 MHz, CDCl3) δ 7.40 (t, J = 8.1 Hz, 1H), 6.98 (ddd, J = 8.3, 2.1, 0.9 Hz, 1H), 6.90 (dd, J = 9.9, 2.0 Hz, 1H), 5.48 (s, 1H), 0.00 (s, 9H).

[0127] Example 4

[0128] Into a reaction flask was placed A-4 (90 g, 1.0 eq.), A-7 (85.5 g, 1.03 eq.), triphenylphosphine (110.7 g, 1.30 eq.) and isopropyl ether (900 ml, 10V); the reaction temperature was adjusted to 15-25 °C, 1.1-azodicarboxamide (72.9 g, 1.30 eq.) was added to the reaction flask in portions while maintaining the temperature at 15-25 °C, and the reaction was stirred at 15-25 °C for 4-6 h under nitrogen protection. The reaction was sampled and determined to be complete. Ethyl acetate (450 ml, 5V) was added to the reaction, and the mixture was stirred at 15-25 °C for 0.5-1 h. The mixture was filtered, the filter cake was rinsed with ethyl acetate (2-3V), and the filtrate was collected. The filtrate was stirred with saturated sodium bicarbonate aqueous solution (900 ml, 10V) at 20-30 °C for 1-2 h, and the mixture was allowed to stand and separate into two phases. The organic phase was retained. The organic phase was stirred with saturated sodium chloride aqueous solution (900 ml, 10V) at 20-30 °C for 1-2 h, and the mixture was allowed to stand and separate into two phases. The organic phase was retained. The organic phase was concentrated at 40 °C to 1-2V. Petroleum ether (900 ml, 10V) was added to the reaction flask, and the mixture was stirred at 20-30 °C for 1-2 h. The mixture was filtered, the filter cake was rinsed with petroleum ether (3-5V), and the filtrate was collected. The filtrate was concentrated at 40 °C to 2-3V. The silica gel was brushed (900 g, 10X) and rinsed with petroleum ether (40V), then rinsed with petroleum ether / ethyl acetate (50 / 1) (20V), then rinsed with petroleum ether / ethyl acetate (30 / 1) (20V), then rinsed with petroleum ether / ethyl acetate (20 / 1) (10V), then rinsed with petroleum ether / ethyl acetate (10 / 1) (10V). Fractions with a purity of more than 70% were collected. The fractions were concentrated at 40 °C to dryness to obtain A-8 product 142 g, with a purity of 91.1%, a content of 85%, and a molar yield of 67%.

[0129] LCMS: MS m / z (ESI): 416.6 [M+1]

[0130] 1H NMR (400 MHz, CDCl3) δ 7.71 (t, J = 8.1 Hz, 1H), 7.25-7.21 (m, 1H), 7.20-7.08 (m, 4H), 7.01 (ddd, J = 8.0, 6.5, 2.0 Hz, 1H), 6.02 (s, 1H), 4.22-4.12 (m, 2H), 3.08 (tt, J = 12.2, 3.5 Hz, 1H), 2.76 (dtd, J = 20.0, 12.8, 2.8 Hz, 2H), 2.07 (dq, J = 13.0, 2.7 Hz, 1H), 1.67 (dt, J = 12.8, 2.7 Hz, 1H), 1.56 (tdt, J = 12.5, 7.8, 4.1 Hz, 2H), 1.49 (s, 9H), 0.12 (s, 9H).

[0131] Example 5

[0132] A-8 (50 g, 1.0 eq.), tetrahydrofuran (350 ml, 7V) and water (150 ml, 3V) were sequentially added into a reaction flask, the temperature of the reaction flask was adjusted to 2-8 °C (target temperature 5 °C), a solution of lithium hydroxide monohydrate (4 g, 1.0 eq.) in water (200 ml, 4V) was slowly added dropwise, and stirring was performed at 2-8 °C for 8-10 h. The conversion of the raw material was detected by sampling. Ethyl acetate (500 ml, 10V) was added into the reaction flask, the temperature of the reaction flask was adjusted to 20-30 °C, and stirring was performed. The organic phase was collected after standing and separation. Saturated ammonium chloride aqueous solution (250 ml, 5V) was added into the organic phase, stirring was performed at 20-30 °C for 0.3-0.5 h, and the organic phase was collected after standing and separation. Saturated sodium chloride aqueous solution (250 ml, 5V) was added into the organic phase, stirring was performed at 20-30 °C for 0.3-0.5 h, and the organic phase was collected after standing and separation. The organic phase was concentrated to 1-2V at 40 °C. A-9 product 51.6 g was obtained, with a purity of 86.6%, a content of 75%, and a molar yield of 90%.

[0133] LCMS: MS m / z (ESI): 344.04 [M+1]

[0134] 1H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 8.1 Hz, 1H), 7.25-7.15 (m, 5H), 7.15-7.08 (m, 1H), 6.08 (s, 1H), 4.16-4.06 (m, 2H), 3.04 (tt, J = 12.2, 3.5 Hz, 1H), 2.73-2.66 (m, J = 20.0, 12.8, 2.8 Hz, 2H), 2.09 (m, J = 13.0, 2.7 Hz, 4H), 1.46 (s, 9H),

[0135] Example 6

[0136] A-9 (30 g, 1.0 eq.) and dichloromethane (300 ml, 10V) were added to the reaction bottle, and indium trifluoromethanesulfonate (38.1 g, 1.0 eq.) and Ph3PClAu (0.618 g, 0.005 eq.) were added to the reaction bottle, and the reaction bottle was replaced with nitrogen three times, and stirred at 20-30 °C for 16-20 h. After the reaction was completed by sampling, saturated aqueous sodium bicarbonate solution (300 ml, 10V) was added to the reaction bottle, and stirred at 20-30 °C for 2-3 h, and then allowed to stand to separate the layers, and the organic phase was collected. The aqueous phase was added with dichloromethane (150 ml, 5V), stirred at 20-30 °C for 0.5-1 h, allowed to stand to separate the layers, and the organic phase was collected. The organic phases were combined, and the organic phase was filtered through diatomite to collect the filtrate. The filtrate was concentrated to dryness at 40 °C to obtain A-10 product 33.3 g, purity 83.8%, content: 60%, content molar yield: 86%, chirality: D / R: 91 / 9.

[0137] LCMS: MS m / z (ESI): 344.4 [M+1]

[0138] 1H NMR (400 MHz, CDCl3) δ 7.37 (t, J = 8.0 Hz, 1H), 7.19-7.04 (m, 3H), 6.94-6.79 (m, 2H), 6.60 (dd, J = 9.8, 1.7 Hz, 1H), 6.22 (dd, J = 3.8, 1.7 Hz, 1H), 5.76 (dd, J = 9.8, 3.7 Hz, 1H), 3.30-3.16 (m, 2H), 3.07-2.91 (m, 1H), 2.77 (dtd, J = 15.0, 12.2, 3.5 Hz, 2H), 2.53 (s, 1H), 1.90-1.78 (m, 1H), 1.76-1.57 (m, 3H).

[0139] Example 7

[0140] A-10 (20 g) and 2-butanone (100 ml, 5V) were added to the reaction bottle, and the temperature of the reaction bottle was adjusted to 35-45 °C, N-acetyl-D-leucine (2 g, 1.0X) was added to the reaction bottle, and a seed crystal (0.06 g, 0.003X) was added, and stirred at 35-45 °C for 1-2 h, N-acetyl-D-leucine (10.2 g, 0.51X) was added to the reaction bottle, and n-heptane (100 ml, 5V) was slowly added dropwise to the reaction bottle; the reaction was controlled to slowly cool to 5-10 °C for 6 h, and stirred at 8-10 °C for 10-12 h, and filtered, the filter cake was rinsed with n-heptane (40 ml, 2V), and the solid was collected; the solid was dried at 40 °C for 3-5 h to obtain the product 23.7 g, purity 96.1%, content: 60%, content molar yield 71%, chirality: D / R: 99 / 1.

[0141] LCMS: MS m / z (ESI): 344.4 [M+1]

[0142] 1H NMR (400 MHz, CDC13) δ 7.35 (t, J = 8.1 Hz, 1H), 7.16 - 7.03 (m, 3H), 6.96 - 6.86 (m, 2H), 6.62 (dd, J = 9.9, 1.7 Hz, 1H), 6.43 (d, J = 7.8 Hz, 2H), 6.22 (dd, J = 3.8, 1.7 Hz, 1H), 5.77 (dd, J = 9.8, 3.7 Hz, 1H), 4.40 (td, J = 8.4, 4.4 Hz, 2H), 3.96 - 3.84 (m, 1H), 3.71 (td, J = 8.1, 6.4 Hz, 1H), 3.50 (dd, J = 20.6, 13.0 Hz, 2H), 3.13 - 2.89 (m, 3H), 1.95 - 1.80 (m, 3H), 1.75 - 1.65 (m, 5H), 1.58 - 1.49 (m, 2H), 1.41 (dq, J = 11.6, 7.9 Hz, 1H).

[0143] Example 8

[0144] SM04 (90 g, 1.0X, 1.0 eq) was taken in a reaction flask, dichloromethane (1350 ml, 15V) was added, stirred, nitrogen purging was done for three times, temperature was maintained at 0-5°C, to the reaction flask oxalyl chloride (74 g, 0.82X, 1.2 eq), DMF (1.78 g, 0.02X, 0.05 eq) was added, temperature was maintained at 25-30°C, stirred for 1-2 h, HPLC monitoring was done for completion of reaction (methanol quenching), temperature was maintained at 0-5°C, to the reaction flask triethylamine (127.9 g, 1.42X, 2.6 eq) was added, temperature was maintained at 0-5°C, to the reaction flask 3-hydroxypropionitrile (41.5 g, 0.46X, 1.2 eq) was added, temperature was maintained at 25-30°C, stirred for 2-3 h, HPLC monitoring was done for completion of reaction (methanol quenching), to the reaction flask process water (180 ml, 2V) was added, allowed to stand for separation of layers, the organic layer was washed with saturated aqueous sodium bicarbonate solution (900 ml, 10V), allowed to stand for separation of layers, the organic layer was washed with saturated aqueous sodium chloride solution (450 ml, 5V), allowed to stand for separation of layers, the organic phase was concentrated to dryness, to get the product 121 g, purity 91.42%, content 84.9%, yield 89% by considering the content.

[0145] LCMS: MS m / z (ESI): 393.10 [M+H]+

[0146] 1H NMR (400 MHz, CDCl3) δ 8.21-8.07 (m, 1H), 8.06-7.88 (m, 2H), 4.61 (t, 2H), 2.91 (t, 2H).

[0147] Example 9

[0148] B01 (81 g, 1.0X, 1.0 eq), (S)-oxetan-2-methanamine p-toluenesulfonate (105.8 g, 1.31X, 1.2 eq), potassium carbonate (188 g, 2.32X, 4.0 eq) were placed in a reaction flask, tetrahydrofuran (810 ml, 10V), process water (81 ml, 1V) were added, stirred, replaced with nitrogen for three times, controlled temperature at 25-30 °C, stirred for 16-20 h, detected reaction completion by HPLC, concentrated to 1-2V, ethyl acetate (1620 ml, 20V), process water (1620 ml, 2V) were added into the reaction flask, stirred for 1-2 h, settled to separate the layers, the organic layer was washed with saturated sodium chloride aqueous solution (810 ml, 10V), settled to separate the layers, the organic phase was concentrated to 2-3V, petroleum ether (810 ml, 10V) was added into the reaction flask, stirred for 1-2 h, filtered, the filter cake was rinsed with petroleum ether (405 ml, 5V), dried to get solid 90.2 g, content 97.9%, yield 85.1% based on content.

[0149] LCMS: MS m / z (ESI): 305.85 [M+H] +

[0150] 1 1H NMR (400 MHz, CDCl3) δ 8.21-8.07 (m, 1H), 8.06-7.88 (m, 2H), 4.61 (t, 2H), 2.91 (t, 2H).

[0151] Example 10

[0152] Tetrahydrofuran (920 ml, 10V), B02 (92 g, 1.0X, 1.0 eq), 10% wet Pd-C (4.6 g, 0.05X), replace hydrogen three times, control temperature 25-30 °C, stir 18-25 h, HPLC detection reaction completion, filter with diatomite, rinse with tetrahydrofuran (460 ml, 5V), concentrate the filtrate to dryness, get solid 81.5 g, purity 98.8%, content 98.7%, yield 96.9% by content.

[0153] LCMS: MS m / z (ESI): 276.09 [M+H] +

[0154] 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, 1.9 Hz, 1H), 7.40 (d, 1H), 6.71 (d, 1H), 5.13 (qd, 3.5 Hz, 1H), 4.83-4.70 (m, 1H), 4.68-4.56 (m, 1H), 4.50 (t, 2H), 4.12-3.84 (m, 2H), 3.46 (dd, 6.6 Hz, 1H), 3.37 (dd, 3.5 Hz, 1H), 2.88-2.81 (m, 2H), 2.81-2.72 (m, 1H), 2.62 (ddt, 1H).

[0155] Example 11

[0156] Tetrahydrofuran (780 ml, 10V), B03 (78 g, 1.0X, 1.0 eq), stir, replace nitrogen three times, cool to 0-5 °C, control temperature 0-5 °C, drop chloroacetic anhydride (51.2 g, 0.67X, 1.1 eq) in 0-5 °C into the reaction bottle, stir 2-3 h, HPLC detection raw material reaction completion, warm to 65-75 °C, stir 16-18 h, HPLC detection intermediate reaction completion, drop to room temperature, concentrate to 1-2 V, add ethyl acetate (1560 ml, 20V), saturated aqueous sodium bicarbonate solution (2340 ml, 30V) into the reaction bottle, stir 1-2 h, stand to separate, wash the organic layer with saturated aqueous sodium chloride solution (780 ml, 10V), stand to separate, concentrate the organic phase to 2-3 V, warm to 50-55 °C, drop petroleum ether (780 ml, 10V) into the reaction bottle, stir at 50-55 °C for 2-3 h, filter, rinse the filter cake with petroleum ether (390 ml, 5V), dry to get solid 87.5 g, purity 97.5%, content 96.8%, yield 89.6% by content.

[0157] LCMS: MS m / z (ESI): 334.01 [M+H] +

[0158] 1 H NMR (400 MHz, CDC13) δ 8.17 (d, 1H), 8.04 (dd, 1.4 Hz, 1H), 7.83 (d, 1H), 5.24 (qd, 2.6 Hz, 1H), 5.05 (s, 2H), 4.73 - 4.49 (m, 5H), 4.37 (dt, 6.0 Hz, 1H), 2.96 - 2.84 (m, 2H), 2.83 - 2.69 (m, 1H), 2.55 - 2.33 (m, 1H), 1.67 (s, 1H).

Claims

1. A compound represented by the following formula (VII), a stereoisomer thereof, or a salt thereof, ###0001### (VII) ​ wherein, X1and X2are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl; preferably, X1and X2are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, or C 2-4 alkynyl; more preferably, X1and X2are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, ethenyl, or ethynyl; PG1is an amino protecting group; preferably, the amino protecting group is selected from Ns, Cbz, Boc, Fmoc, Alloc, Teoc, Meoc, Etoc, Pht, Tos, Tfa, Trt, DMB, PMB or Bn; more preferably, the amino protecting group is selected from Cbz, Boc, Fmoc, Alloc, Teoc or Meoc; further preferably Boc; PG2is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, or an alkynyl protecting group; preferably, PG2is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, TMS, TES, TBS, TIPS, or TBDPS; more preferably, PG2is selected from hydrogen or TMS.

2. The compound of formula (VII) as claimed in claim 1, its stereoisomers or salts thereof, characterized in that, Further as shown in general formula (VII-1), wherein PG1, PG2, X1and X2are as defined in claim 1.

3. The compound of formula (VII) as claimed in claim 1, its stereoisomers or salts thereof, characterized in that, The compound structure is shown as follows, 4. The method for preparing the compound of formula (VII-1) as described in claim 2, characterized in that, The compound shown in formula (VI) reacts with the compound shown in formula (IV) to give the compound shown in formula (VII-1). wherein PG1, PG2, X1and X2are as defined in claim 1.

5. The method of claim 4, wherein the compound of formula (VII-1) is prepared by the reaction of a compound of formula (VII-2) with a compound of formula (VIII) in the presence of a catalyst. The reaction is carried out in an organic solvent; preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; more preferably, the organic solvent is selected from isopropyl ether; Preferably, the reaction is carried out in the presence of a phosphine-containing catalyst; more preferably, the phosphine-containing catalyst is selected from one or more of diphenylmethylphosphine, methylphosphine, triethylphosphine, tripropylphosphine, tri-tert-butylphosphine, triphenylphosphine or tributylphosphine; further preferably, the phosphine-containing catalyst is selected from triphenylphosphine or tributylphosphine; more further preferably, the phosphine-containing catalyst is triphenylphosphine; Preferably, the reaction is carried out in the presence of an azo reagent; more preferably, the azo reagent is selected from one or more of Tsunoda reagent, DEAD, DIAD, TMAD, TMAD, DBAD, ADDP or TIPA; further preferably, the azo reagent is selected from DEAD, DIAD, TMAD or ADDP; more further preferably, the azo reagent is TMAD; Preferably, the molar ratio of the compound of formula (VI) to the compound of formula (IV) is 1:0.8 to 1:3; more preferably, 1:0.8 to 1:1.5; further preferably, 1:1; Preferably, the molar ratio of the compound of formula (VI) to the azo reagent is 1:0.8 to 1:3; more preferably, 1:1 to 1:1.5; further preferably, 1:1.3; Preferably, the molar ratio of the compound of formula (IV) to the azo reagent is 1:0.8 to 1:3; more preferably, 1:1 to 1:1.5; further preferably, 1:1.3; Preferably, the molar ratio of the compound of formula (VI) to the catalyst is 1:0.8 to 1:3; more preferably, 1:1 to 1:1.5; further preferably, 1:1.3; Preferably, the molar ratio of the compound of formula (IV) to the catalyst is 1:0.8 to 1:3; more preferably, 1:1 to 1:1.5; further preferably, 1:1.3; Preferably, the molar ratio of the catalyst to the azo reagent is 1:0.8-1:3; more preferably 1:0.8-1:1.5; further preferably 1:

1. Preferably, the ratio of the compound of formula (IV) to the organic solvent is 1:5-1:20 (g:mL); more preferably 1:8-1:15 (g:mL); further preferably 1:10 (g:mL).

6. The process according to claim 4, for the preparation of a compound of formula (VII-1) ###00011### (VII-1) characterized in that, Further comprising the step of further reacting the compound of formula (VII-1) to obtain a compound of formula (VIII), wherein PG2is selected from an alkynyl protecting group; preferably PG2is selected from TMS, TES, TBS, TIPS or TBDPS; more preferably PG2is selected from TMS; PG1, X1and X2are as defined in claim 1; Preferably, the reaction is carried out in the presence of a base; more preferably, the base is selected from one or more of tetrabutylammonium fluoride, TEA / LiCl, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, potassium carbonate, tetrabutylammonium fluoride, TEA / LiCl; further preferably, the base is lithium hydroxide; still further preferably, the lithium hydroxide is lithium hydroxide monohydrate dissolved in aqueous solution added to the reaction; Preferably, the reaction is carried out in an organic solvent; more preferably, the organic solvent is selected from one or more of water, methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; further preferably, the organic solvent is a mixture of tetrahydrofuran and water; still further preferably, the ratio of the organic solvent is tetrahydrofuran:water = 1:1-8:1; still further preferably, the ratio of the organic solvent is tetrahydrofuran:water = 7:3; Preferably, the ratio of the compound of formula (VII-1) to the mixed organic solvent is 1:5-1:20 (g:mL); more preferably 1:8-1:15 (g:mL); further preferably 1:10 (g:mL).

7. The process according to claim 6 for the preparation of a compound of formula (VIII) ###00015### (VIII) characterized in that, It further comprises the step of further reacting the compound of formula (VIII) wherein PG1, X1and X2are the same as defined in claim 1; Preferably, the reaction is carried out in an organic solvent; more preferably, the organic solvent is selected from one or more of water, methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; further preferably, the organic solvent is selected from dichloromethane; Preferably, the reaction is carried out in the presence of a catalyst; more preferably, the catalyst is selected from one or more of scandium trifluoromethanesulfonate, europium trifluoromethanesulfonate, indium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate or zinc trifluoromethanesulfonate; further preferably, the catalyst is selected from indium trifluoromethanesulfonate; Preferably, the reaction is carried out in the presence of a catalyst; more preferably, the catalyst is selected from Ph3PclAu, chloro[tris(o-tolyl)phosphine]gold(I), gold trichloride, AuCl3, DMSAuCl, PPh3AuCl, ArPR2AuCl, XPhosAuCl, JohnphosAu(MeCN)SbF6, (PhO)3PauCl; further preferably, the catalyst is selected from Ph3PclAu; Preferably, the ratio of the compound of formula (VIII) to the organic solvent is 1:5 to 1:20 (g:mL); more preferably, 1:8 to 1:15 (g:mL); further preferably, 1:10 (g:mL); Preferably, the molar ratio of the compound of formula (VIII) to the catalyst is 1:0.8 to 1:3; more preferably, 1:0.8 to 1:1.5; further preferably, 1:

1.

8. The process according to claim 4, for the preparation of a compound of formula (VII-1) ###0009### (VII-1) characterized in that, The preparation of the compound of formula (IV) further comprises the following steps: wherein X3is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, or C 2-6 alkynyl; preferably, X1and X2are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, carboxyl, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1- 3haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, or C 2-4 alkynyl; more preferably, X1and X2are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, ethenyl, or ethynyl; PG1, PG2, X1and X2are the same as defined in claim 1.

9. The process according to claim 4, for the preparation of a compound of formula (VII-1) ###00016### (VII-1) characterized in that, The preparation of the compound of formula (VI) further comprises the following steps: wherein PG2, X1and X2are the same as defined in claim 1.

10. The process according to claim 7 for the preparation of a compound of formula (XI) ###00016### (XI) characterized in that, It also comprises the further step of reacting the compound of formula (XI) wherein X1and X2are the same as defined in claim 1.

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