A process for the synthesis of dydrogesterone and intermediates thereof

Abstract

The present invention provides a method for the synthesis of a dydrogesterone intermediate, and a method for the further synthesis of dydrogesterone from the intermediate.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic chemistry. Specifically, this invention relates to a method for synthesizing a dydrogesterone compound. Background Technology

[0002] Dydrogesterone is an oral synthetic progestin widely used clinically to treat various conditions associated with insufficient endogenous progesterone. Compared to natural progesterone, dydrogesterone exhibits more favorable oral administration characteristics and higher progesterone receptor (PR) selectivity. Its typical... retro -progesterone configuration (C9 / C10 configuration inversion) and C6-C7 double bond (Δ 6 This results in a molecular conformational characteristic different from natural progesterone, leading to differences in pharmacodynamics and receptor selectivity. It should be noted that oral dydrogesterone still undergoes first-pass metabolism, but its main metabolite, 20α-dihydrodydrogesterone (20α-DHD), is the active metabolite, and its in vivo exposure is usually significantly higher than that of the parent drug, thus supporting its overall oral efficacy. In contrast, progesterone is more easily reduced and further metabolized during hepatic first-pass metabolism, limiting its oral bioavailability.

[0003] The development of dydrogesterone dates back to the 1950s, with its initial synthesis by the Dutch company Duphar. In early process studies, Duphar reported a route for synthesizing dydrogesterone using photosterol as a starting material. This route suffered from high photosterol costs and low yields due to multiple oxidation reactions, limiting its scale-up and application. In 1961, Duphar further reported a route for synthesizing dydrogesterone using the more readily available pregnenolone acetate as a starting material. Although this strategy was more direct, the efficiency of the key electrocyclization tandem reaction was low, limited by two main factors: poor stereoselectivity in the electrocyclization ring-closing stage and the tendency for the side-chain carbonyl group to undergo the Norrish-Yang side reaction under photochemical conditions. To suppress the photochemical Norrish-Yang side reaction of the side-chain carbonyl group, in 1971, Duphar improved the key photochemical steps based on the previous route. Given the stable clinical demand for dydrogesterone, subsequent research has continued to focus on process improvements around its key photochemical steps. Key improvements include introducing continuous flow reactions to optimize light conditions and employing photosensitizer systems to enhance conversion efficiency. While these methods have improved yields to some extent, the limited stereoselectivity control during the electrocyclization ring-closing process remains unresolved. In 2018, Samir et al. reported a route for synthesizing dydrogesterone from progesterone, which requires a large amount of oxidant for degradation and lacks the advantages of green chemistry. In 2023, Tang Wenjun's research group at the Shanghai Institute of Organic Chemistry reported a route for synthesizing dydrogesterone from 9-OH-4-AD, but this route involves a long reaction time.

[0004] Therefore, developing efficient methods for synthesizing dydrogesterone is of great significance. Summary of the Invention

[0005] The purpose of this invention is to provide a new method for the efficient synthesis of dydrogesterone intermediates.

[0006] In a first aspect of the invention, a method for synthesizing compound 10 is provided, characterized by comprising the steps of: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7; e) (e-1) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by an enol silyl etherification reaction with a silicon reagent to generate an enol silyl ether intermediate. Then, in a polar solvent, a Pd metal catalyst is added, and a palladium-catalyzed reaction occurs to give compound 8; or... (e-2) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by a dehydrogenation reaction with a dehydrogenating reagent to give compound 8; or, (e-3) When X is Br, I or Cl, in an aprotic solvent, compound 7 undergoes an elimination reaction with a base to give compound 8; f) In an aprotic solvent, compound 8 undergoes a boronization reaction with a boron reagent, followed by the addition of a base and hydrogen peroxide for oxidation to give compound 9; g) In an aprotic solvent, under the action of an oxidizing agent, compound 9 undergoes an oxidation reaction to give compound 10.

[0007] In some embodiments, the method has one or more technical features selected from the group consisting of: (1) In step a), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkanes solvents, or combinations thereof; (2) In step a), the volume molar ratio of the aprotic solvent to compound 2 is 10~30 L: 1 mol; (3) In step a), the alkali is selected from the group consisting of: sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, n-butyllithium, potassium hexamethyldisilamide (KHMDS), sodium hexamethyldisilamide (NaHMDS), lithium hexamethyldisilamide (LiHMDS), lithium diisopropylamino, or combinations thereof; (4) In step a), the molar ratio of the base to compound 2 is 1~5:1; (5) In step a), the Wittig reagent is PPh3EtX or AsPh3EtX, where X is Br, I or Cl; (6) In step a), the molar ratio of Wittig reagent to compound 2 is 1~5:1; (7) In step a), the reaction is carried out at 0~80°C, preferably at 20~50°C; (8) In step b), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (9) In step b), the volume molar ratio of the aprotic solvent to compound 3 is 10~30 L: 1 mol; (10) In step b), the catalyst is selected from the group consisting of ZnCl2, AlCl3, EtAlCl2, Et2AlCl, SnCl4, Sc(OTf)3, TiCl4, Me2AlCl or BF3•OEt2; (11) In step b), the molar ratio of the catalyst to compound 3 is 0.05 to 0.5:1; (12) In step b), the molar ratio of compound 4 to compound 3 is 1~2:1; (13) In step b), the reaction is carried out at -20 to 50°C, preferably at -20 to 20°C; (14) In step c), the alcohol solvent is selected from the group consisting of ethylene glycol, glycerol, diethylene glycol, or combinations thereof; (15) In step c), the volume molar ratio of the alcohol solvent to compound 5 is 10~30 L: 1 mol; (16) In step c), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium ethoxide, potassium ethoxide, or combinations thereof; (17) In step c), the molar ratio of the base to compound 5 is 5~12:1; (18) In step c), the hydrazine compound is selected from the group consisting of hydrazine, hydrazine hydrate, hydrazine salt, sulfonyl hydrazine, or combinations thereof; preferably, the hydrazine compound is selected from the group consisting of hydrazine hydrochloride, hydrazine sulfate, anhydrous hydrazine, hydrazine hydrate, TsNHNH2, or combinations thereof; (19) In step c), the molar ratio of the hydrazine compound to compound 5 is 10~30:1; (20) In step c), the reaction is carried out at 120~200°C; preferably 140~190°C; (21) In step d), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, ketone solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (22) In step d), the volume molar ratio of the aprotic solvent to compound 6 is 10~30 L: 1 mol; (23) In step d), the acid is selected from the group consisting of: HCl, H2SO4, HClO4, PTSA•H2O, TiCl4, BF3•OEt2, trifluoroacetic acid, or a combination thereof; (24) In step d), the molar ratio of the acid to compound 6 is 0.5 to 3:1; (25) In step d), the reaction is carried out at 0~60°C, preferably at 10~30°C; (26) In step (e-1), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (27) In step (e-1), the volume molar ratio of the aprotic solvent to compound 7 is 10~30 L: 1 mol; (28) In step (e-1), the inorganic salt is selected from the group consisting of lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, potassium iodide, sodium iodide, or combinations thereof; (29) In step (e-1), the molar ratio of the inorganic salt to compound 7 is 1 to 5:1; (30) In step (e-1), the lithium reagent is n-butyllithium, LiHMDS, tert-butyllithium, or a combination thereof; (31) In step (e-1), the molar ratio of the lithium reagent to compound 7 is 1 to 5:1; (32) In step (e-1), the amine reagent is selected from the group consisting of: , , , , , , or a combination thereof; (33) In step (e-1), the silicon reagent is selected from the group consisting of: trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, trimethylsilyltrifluoromethanesulfonate, or combinations thereof; (34) In step (e-1), the molar ratio of the silicon reagent to compound 7 is 1 to 5:1; (35) In step (e-1), the enolization reaction is carried out at -78 to -40°C, preferably at -78 to -60°C; (36) In step (e-1), the polar solvent is acetonitrile, dimethyl sulfoxide (DMSO) or N,N-dimethylformamide (DMF). (37) In step (e-1), the volume molar ratio of the polar solvent to compound 7 is 10~30 L: 1 mol; (38) In step (e-1), the metal Pd catalyst is selected from the group consisting of: Pd(OAc)2, PdCl2, Pd(TFA)2, Pd(acac)2, Pd(PPh3)4, Pd2(dba)3, or a combination thereof; (39) In step (e-1), the molar ratio of the metal Pd catalyst to compound 7 is 1-3:1; (40) In step (e-1), the palladium-catalyzed reaction is carried out at 0~60°C, preferably at 10~30°C; (41) In step (e-2), the dehydrogenating agent is selected from the group consisting of: benzeneselenic anhydride, 2-iodobenzoic acid (IBX), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). or a combination thereof; (42) In step (e-2), the molar ratio of the dehydrogenating agent to compound 7 is 1 to 5:1; (43) In step (e-2), when the dehydrogenating agent is The dehydrogenation reaction is carried out at -120 to -50°C, preferably at -110 to -78°C. (44) In step (e-2), when the dehydrogenating agent is benzeneselenic anhydride, 2-iodobenzoic acid (IBX) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the dehydrogenation reaction is carried out at a temperature of 10~100℃, preferably at 20~60℃. (45) In step (e-3), the alkali is selected from the group consisting of: DBU, Et3N, t -BuOK、 t-BuONa, NaH, KH, CaH2, NaHMDS, KHMDS, LiHMDS, NaOMe, KOMe, NaOEt, KOEt, LiCO3 / LiCl, Na2CO3 / LiCl, K2CO3 / LiCl, or combinations thereof; (46) In step (e-3), the elimination reaction is carried out at 20~100°C, preferably at 20~50°C; (47) In step f), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (48) In step f), the volume molar ratio of the aprotic solvent to compound 8 is 10~30 L: 1 mol; (49) In step f), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof; (50) In step f), the molar ratio of the base to compound 8 is 10~20:1; (51) In step f), the volume molar ratio of hydrogen peroxide to compound 8 is 0.1~0.5 L: 1 mol; (52) In step f), the boron reagent is selected from the group consisting of: BH3•Me2S, diisopentylborane (Sia2BH), tert-hexylborane (ThxBH2), dicyclohexylborane (Cy2BH), 9-boronbicyclo[3.3.1]nonane (9-BBN), or combinations thereof; (53) In step f), the molar ratio of the boron reagent to compound 8 is 3~8:1; (54) In step f), the borohydride reaction is carried out at 0~60°C, preferably at 0~30°C; (55) In step g), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (56) In step g), the volume molar ratio of the aprotic solvent to compound 9 is 10~30 L: 1 mol; (57) In step g), the oxidant is selected from the group consisting of: pyridine chlorochromate (PCC), pyridine dichromate (PDC), Dysmart oxidant (DMP), (COCl)2 / DMSO / Et3N, Al( i -PrO)3 / acetone, N-methylmorpholine-N-oxide / tetrapropylammonium perruthenate (NMO / TPAP), or combinations thereof; (58) In step g), the molar ratio of the oxidant to compound 9 is 0.5 to 3:1; (59) In step g), the oxidation reaction is carried out at 0~60°C, preferably at 10~30°C.

[0008] In a second aspect of the invention, a method for synthesizing compound 9 is provided, characterized by comprising the steps of: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7; e) (e-1) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by an enol silyl etherification reaction with a silicon reagent to generate an enol silyl ether intermediate. Then, in a polar solvent, a Pd metal catalyst is added, and a palladium-catalyzed reaction occurs to give compound 8; or... (e-2) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by a dehydrogenation reaction with a dehydrogenating reagent to give compound 8; or, (e-3) When X is Br, I or Cl, in an aprotic solvent, compound 7 undergoes an elimination reaction with a base to give compound 8; f) In an aprotic solvent, compound 8 undergoes a boronization reaction with a boron reagent, followed by the addition of a base and hydrogen peroxide for oxidation, to obtain compound 9.

[0009] In a third aspect of the invention, a method for synthesizing compound 8 is provided, characterized by comprising the steps of: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7; e) (e-1) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by an enol silyl etherification reaction with a silicon reagent to generate an enol silyl ether intermediate. Then, in a polar solvent, a Pd metal catalyst is added, and a palladium-catalyzed dehydrogenation reaction occurs to give compound 8; or... (e-2) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by a dehydrogenation reaction with a dehydrogenating reagent to give compound 8; or, (e-3) When X is Br, I or Cl, in an aprotic solvent, compound 7 undergoes an elimination reaction with a base to give compound 8.

[0010] In a fourth aspect of the invention, a method for synthesizing compound 7 is provided, characterized by comprising the steps of: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7.

[0011] In a fifth aspect of the invention, a method for synthesizing compound 6 is provided, characterized by comprising the steps of: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6.

[0012] In a sixth aspect of the invention, a method for synthesizing compound 5 is provided, characterized by comprising the steps of: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5.

[0013] In a seventh aspect of the invention, a method for synthesizing compound 3 is provided, characterized by comprising the steps of: a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3.

[0014] In an eighth aspect of the present invention, a method for synthesizing dydrogesterone is provided, characterized by comprising the steps of: 1) The intermediate compound 10 is prepared by the method as described in any one of the first to seventh aspects of the present invention; 2) In an alcohol solvent, under the action of acid, compound 10 undergoes a double bond isomerization reaction to give compound 1, dydrogesterone.

[0015] In another preferred embodiment, in step 2), the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, or combinations thereof; In another preferred embodiment, in step 2), the volume molar ratio of the alcohol solvent to compound 10 is 10~30L:1 mol; In another preferred embodiment, in step 2), the acid is HCl, HBr, HClO4, PTSA, or TFA; In another preferred embodiment, in step 2), the molar ratio of the acid to compound 10 is 0.5 to 3:1; In another preferred embodiment, in step 2), the double bond isomerization reaction is carried out at 0~60°C, preferably at 10~30°C.

[0016] In a ninth aspect of the invention, a dydrogesterone intermediate compound is provided, characterized in that it is selected from the group consisting of: , , , , , ; Wherein, R is a C1-C6 alkylene group; X is H, Br, I, or Cl.

[0017] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0018] Through extensive and in-depth research, the inventors discovered a dydrogesterone intermediate and its synthesis method, and based on this, completed the present invention.

[0019] Compound 3 and its preparation method This invention provides compound 3, which can be used as an intermediate for the preparation of non-natural steroidal skeleton compounds of the dydrogesterone type.

[0020] Furthermore, the present invention also provides a method for preparing compound 3: a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3.

[0021] In another preferred embodiment, step a) further comprises one or more technical features selected from the group consisting of: (1) In step a), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkanes solvents, or combinations thereof; (2) In step a), the volume molar ratio of the aprotic solvent to compound 2 is 10~30 L: 1 mol; (3) In step a), the alkali is selected from the group consisting of: sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, n-butyllithium, potassium hexamethyldisilamide (KHMDS), sodium hexamethyldisilamide (NaHMDS), lithium hexamethyldisilamide (LiHMDS), lithium diisopropylamino, or combinations thereof; (4) In step a), the molar ratio of the base to compound 2 is 1~5:1; (5) In step a), the Wittig reagent is PPh3EtX or AsPh3EtX, where X is Br, I or Cl; (6) In step a), the molar ratio of Wittig reagent to compound 2 is 1~5:1; (7) In step a), the reaction is carried out at 0~80°C, preferably at 20~50°C.

[0022] Compound 5 and its preparation method This invention provides compound 5, which can be used as an intermediate for the preparation of non-natural steroidal skeleton compounds of the dydrogesterone type.

[0023] Furthermore, the present invention also provides a method for preparing compound 5: b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5, wherein R is a C1-C6 alkylene group; and X is H, Br, I or Cl.

[0024] In another preferred embodiment, step b) further comprises one or more technical features selected from the group consisting of: (8) In step b), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (9) In step b), the volume molar ratio of the aprotic solvent to compound 3 is 10~30 L: 1 mol; (10) In step b), the catalyst is selected from the group consisting of ZnCl2, AlCl3, EtAlCl2, Et2AlCl, SnCl4, Sc(OTf)3, TiCl4, Me2AlCl or BF3•OEt2; (11) In step b), the molar ratio of the catalyst to compound 3 is 0.05 to 0.5:1; (12) In step b), the molar ratio of compound 4 to compound 3 is 1~2:1; (13) In step b), the reaction is carried out at -20 to 50°C, preferably at -20 to 20°C.

[0025] Compound 6 and its preparation method This invention provides compound 6, which can be used as an intermediate for the preparation of non-natural steroidal skeleton compounds of the dydrogesterone type.

[0026] Furthermore, the present invention also provides a method for preparing compound 6: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6.

[0027] In another preferred embodiment, step c) further comprises one or more technical features selected from the group consisting of: (14) In step c), the alcohol solvent is selected from the group consisting of ethylene glycol, glycerol, diethylene glycol, or combinations thereof; (15) In step c), the volume molar ratio of the alcohol solvent to compound 5 is 10~30 L: 1 mol; (16) In step c), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium ethoxide, potassium ethoxide, or combinations thereof; (17) In step c), the molar ratio of the base to compound 5 is 5~12:1; (18) In step c), the hydrazine compound is selected from the group consisting of hydrazine, hydrazine hydrate, hydrazine salt, sulfonyl hydrazine, or combinations thereof; preferably, the hydrazine compound is selected from the group consisting of hydrazine hydrochloride, hydrazine sulfate, anhydrous hydrazine, hydrazine hydrate, TsNHNH2, or combinations thereof; (19) In step c), the molar ratio of the hydrazine compound to compound 5 is 10~30:1; (20) In step c), the reaction is carried out at 120~200℃; preferably 140~190℃.

[0028] Compound 7 and its preparation method This invention provides compound 7, which can be used as an intermediate for the preparation of non-natural steroidal skeleton compounds of the dydrogesterone type.

[0029] Furthermore, the present invention also provides a method for preparing compound 7: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7.

[0030] In another preferred embodiment, step d) further comprises one or more technical features selected from the group consisting of: (21) In step d), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, ketone solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (22) In step d), the volume molar ratio of the aprotic solvent to compound 6 is 10~30 L: 1 mol; (23) In step d), the acid is selected from the group consisting of: HCl, H2SO4, HClO4, PTSA•H2O, TiCl4, BF3•OEt2, trifluoroacetic acid, or a combination thereof; (24) In step d), the molar ratio of the acid to compound 6 is 0.5 to 3:1; (25) In step d), the reaction is carried out at 0~60°C, preferably at 10~30°C.

[0031] Compound 8 and its preparation method This invention provides compound 8, which can be used as an intermediate for the preparation of non-natural steroidal skeleton compounds of the dydrogesterone type.

[0032] Furthermore, the present invention also provides a method for preparing compound 8: in, X is H, Br, I, or Cl; e) (e-1) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by an enol silyl etherification reaction with a silicon reagent to generate an enol silyl ether intermediate. Then, in a polar solvent, a Pd metal catalyst is added, and a palladium-catalyzed reaction occurs to give compound 8; or... (e-2) In an aprotic solvent, an organolithium reagent and an amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and an inorganic salt, compound 7 undergoes deprotonation, followed by a dehydrogenation reaction with a dehydrogenating reagent to give compound 8; or, (e-3) When X is Br, I or Cl, in an aprotic solvent, compound 7 undergoes an elimination reaction with a base to give compound 8.

[0033] In another preferred embodiment, step e) further comprises one or more technical features selected from the group consisting of: (26) In step (e-1), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (27) In step (e-1), the volume molar ratio of the aprotic solvent to compound 7 is 10~30 L: 1 mol; (28) In step (e-1), the inorganic salt is selected from the group consisting of lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, potassium iodide, sodium iodide, or combinations thereof; (29) In step (e-1), the molar ratio of the inorganic salt to compound 7 is 1 to 5:1; (30) In step (e-1), the lithium reagent is n-butyllithium, LiHMDS, tert-butyllithium, or a combination thereof; (31) In step (e-1), the molar ratio of the lithium reagent to compound 7 is 1 to 5:1; (32) In step (e-1), the amine reagent is selected from the group consisting of: , , , , , , or a combination thereof; (33) In step (e-1), the silicon reagent is selected from the group consisting of: trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, trimethylsilyltrifluoromethanesulfonate, or combinations thereof; (34) In step (e-1), the molar ratio of the silicon reagent to compound 7 is 1 to 5:1; (35) In step (e-1), the enolization reaction is carried out at -78 to -40°C, preferably at -78 to -60°C; (36) In step (e-1), the polar solvent is acetonitrile, dimethyl sulfoxide (DMSO) or N,N-dimethylformamide (DMF). (37) In step (e-1), the volume molar ratio of the polar solvent to compound 7 is 10~30 L: 1 mol; (38) In step (e-1), the metal Pd catalyst is selected from the group consisting of: Pd(OAc)2, PdCl2, Pd(TFA)2, Pd(acac)2, Pd(PPh3)4, Pd2(dba)3, or a combination thereof; (39) In step (e-1), the molar ratio of the metal Pd catalyst to compound 7 is 1-3:1; (40) In step (e-1), the palladium-catalyzed reaction is carried out at 0~60°C, preferably at 10~30°C; (41) In step (e-2), the dehydrogenating agent is selected from the group consisting of: benzeneselenic anhydride, 2-iodobenzoic acid (IBX), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). or a combination thereof; (42) In step (e-2), the molar ratio of the dehydrogenating agent to compound 7 is 1 to 5:1; (43) In step (e-2), when the dehydrogenating agent is The dehydrogenation reaction is carried out at -120 to -50°C, preferably at -110 to -78°C. (44) In step (e-2), when the dehydrogenating agent is benzeneselenic anhydride, 2-iodobenzoic acid (IBX) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the dehydrogenation reaction is carried out at a temperature of 10~100℃, preferably at 20~60℃. (45) In step (e-3), the alkali is selected from the group consisting of: DBU, Et3N, t -BuOK、 t -BuONa, NaH, KH, CaH2, NaHMDS, KHMDS, LiHMDS, NaOMe, KOMe, NaOEt, KOEt, LiCO3 / LiCl, Na2CO3 / LiCl, K2CO3 / LiCl, or combinations thereof; (46) In step (e-3), the elimination reaction is carried out at 20~100°C, preferably at 20~50°C.

[0034] Compound 9 and its preparation method This invention provides compound 9, which can be used as an intermediate for the preparation of non-natural steroidal skeleton compounds of the dydrogesterone type.

[0035] Furthermore, the present invention also provides a method for preparing compound 9: f) In an aprotic solvent, compound 8 undergoes a boronization reaction with a boron reagent, followed by the addition of a base and hydrogen peroxide for oxidation, to obtain compound 9.

[0036] In another preferred embodiment, step f) further comprises one or more technical features selected from the group consisting of: (47) In step f), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (48) In step f), the volume molar ratio of the aprotic solvent to compound 8 is 10~30 L: 1 mol; (49) In step f), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof; (50) In step f), the molar ratio of the base to compound 8 is 10~20:1; (51) In step f), the volume molar ratio of hydrogen peroxide to compound 8 is 0.1~0.5 L: 1 mol; (52) In step f), the boron reagent is selected from the group consisting of: BH3•Me2S, diisopentylborane (Sia2BH), tert-hexylborane (ThxBH2), dicyclohexylborane (Cy2BH), 9-boronbicyclo[3.3.1]nonane (9-BBN), or combinations thereof; (53) In step f), the molar ratio of the boron reagent to compound 8 is 3~8:1; (54) In step f), the borohydride reaction is carried out at 0~60°C, preferably at 0~30°C.

[0037] Preparation method of compound 10 This invention provides a method for preparing compound 10: g) In an aprotic solvent, under the action of an oxidizing agent, compound 9 undergoes an oxidation reaction to give compound 10.

[0038] In another preferred embodiment, step g) further comprises one or more technical features selected from the group consisting of: (55) In step g), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (56) In step g), the volume molar ratio of the aprotic solvent to compound 9 is 10~30 L: 1 mol; (57) In step g), the oxidant is selected from the group consisting of: pyridine chlorochromate (PCC), pyridine dichromate (PDC), Dysmart oxidant (DMP), (COCl)2 / DMSO / Et3N, Al( i -PrO)3 / acetone, N-methylmorpholine-N-oxide / tetrapropylammonium perruthenate (NMO / TPAP), or combinations thereof; (58) In step g), the molar ratio of the oxidant to compound 9 is 0.5 to 3:1; (59) In step g), the oxidation reaction is carried out at 0~60°C, preferably at 10~30°C.

[0039] Preparation method of compound 1 This invention provides a novel method for preparing compound 1, dydrogesterone: 1) The intermediate compound 10 is prepared by the method according to any one of claims 1-8; 2) In an alcohol solvent, under the action of acid, compound 10 undergoes a double bond isomerization reaction to give compound 1, dydrogesterone.

[0040] In another preferred embodiment, step 2) further comprises one or more technical features selected from the group consisting of: In step 2), the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, or combinations thereof; In step 2), the volume molar ratio of the alcohol solvent to compound 10 is 10~30 L: 1 mol; In step 2), the acid is HCl, HBr, HClO4, PTSA, or TFA; In step 2), the molar ratio of the acid to compound 10 is 0.5 to 3:1; In step 2), the double bond isomerization reaction is carried out at 0~60℃, preferably at 10~30℃.

[0041] Any step in this invention may also include a post-processing step.

[0042] The main advantages of this invention include: 1. This invention provides a novel method for preparing a key intermediate of dydrogesterone.

[0043] 2. The method of the present invention uses inexpensive and readily available raw materials, has a simple route, mild conditions, and a high yield, making it very suitable for industrial production.

[0044] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0045] Example In the following embodiments, unless otherwise specified, the operation is carried out at room temperature. The room temperature is 0℃~35℃, preferably 20℃~30℃.

[0046] In the following examples, calcd for refers to the calculated value, and found refers to the actual value.

[0047] The raw material compound 2 of this invention was synthesized according to the method described in the literature. J. Am. Chem. Soc. 1999, 121 ,8237-8245).

[0048] Example 1: Synthesis of Compound 3 PPh3EtBr (2.52 g, 6.8 mmol, 3.0 equiv) was dissolved in 15 mL of dry THF, and then added... t-BuOK (6.8 mL, 1 M in THF, 6.8 mmol, 3.0 equiv) was added, and the reaction was carried out at room temperature for 40 min. Compound 2 (400.0 mg, 2.3 mmol, 1.0 equiv) in THF (10 mL) solution was added. The mixture was heated to 50 °C and reacted for 3 h. The system was cooled to room temperature, and the reaction was quenched with saturated NH4Cl (5 mL) aqueous solution. Extraction with EtOAc (3 × 30 mL) was performed, and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and compound 3 (413.1 mg, 97%) was purified by column chromatography (PE:EtOAc = 50:1).

[0049] Compound 3: 1 H NMR (400 MHz, CDCl3) δ 6.23 (dd, J = 17.7, 11.1 Hz, 1H), 5.70 (q, J = 3.6 Hz, 1H), 5.25 (d, J = 17.5 Hz, 1H), 5.19 (qt, J = 7.2, 2.1Hz, 1H), 4.87 (d, J = 11.2 Hz, 1H), 2.54 - 2.23 (m, 6H), 2.08 - 1.96 (m, 1H), 1.83 - 1.72 (m, 1H), 1.69 (dt, J = 7.1, 1.9 Hz, 3H), 1.60 - 1.44 (m, 1H), 0.87 (s, 3H). Example 2 Synthesis of Compound 3 PPh3EtCl (1.50 g, 4.6 mmol, 2.0 equiv) was dissolved in 15 mL of dry THF, and NaH (110 mg, 4.6 mmol, 2.0 equiv) was added. The reaction was carried out at room temperature for 40 min. A THF (10 mL) solution of compound 2 (400.0 mg, 2.3 mmol, 1.0 equiv) was added. The mixture was heated to 60 °C and reacted for 3 h. The system was cooled to room temperature, and the reaction was quenched with saturated NH4Cl (5 mL) aqueous solution. Extraction was performed with EtOAc (3 × 30 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and compound 3 (362.0 mg, 85%) was purified by column chromatography (PE:EtOAc = 50:1).

[0050] Example 3 Synthesis of Compound 3 AsPh3EtBr (3.8 g, 9.2 mmol, 4.0 equiv) was dissolved in 15 mL of dry THF, and KHMDS (9.2 mL, 1 M in THF, 9.2 mmol, 4.0 equiv) was added. The reaction was carried out at room temperature for 40 min. Compound 2 (400.0 mg, 2.3 mmol, 1.0 equiv) in THF (10 mL) solution was added. The mixture was heated to 60 °C and reacted for 3 h. The system was cooled to room temperature, and the reaction was quenched with saturated NH4Cl (5 mL) aqueous solution. Extraction with EtOAc (3 × 30 mL) was performed. The organic phases were combined and washed with saturated brine, then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and compound 3 (383.3 mg, 90%) was purified by column chromatography (PE:EtOAc = 50:1).

[0051] Example 4 Synthesis of compound 5a Compound 4a was synthesized from commercially available 1,4-cyclohexanedione monoethylene glycol ketal using the method described in the literature. J. Med. Chem. 2017, 60 , 2780-2789. and J. Org. Chem. 2021, 86 , 5463-5476.).

[0052] Compound 3 (700.0 mg, 3.7 mmol, 1.0 equiv) and compound 4a (1.2 g, 7.4 mmol, 2.0 equiv) were dissolved in 25 mL of dry THF. ZnCl2 (1.9 mL, 1 M in THF, 1.9 mmol, 0.5 equiv) was added at 0 °C, and the reaction was maintained at 0 °C for 3 h. The reaction was quenched with saturated NaHCO3 (5 mL) aqueous solution, extracted with ethyl acetate (3 × 30 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 20:1) to give compound 5a (738.6 mg, 70%).

[0053] Compound 5a: 1 H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 5.32 (q, J = 3.3 Hz,1H), 5.20 - 5.09 (m, 1H), 3.99 - 3.92 (m, 4H), 2.76 (d, J = 13.2 Hz, 1H),2.60 - 2.52 (m, 1H), 2.46 - 2.34 (m, 3H), 2.30 - 2.21 (m, 2H), 1.93 - 1.75(m, 5H), 1.74 - 1.57 (m, 9H), 1.47 - 1.34 (m, 1H), 0.94 (s, 3H). Example 5 Synthesis of compound 5a Compound 3 (700.0 mg, 3.7 mmol, 1.0 equiv) and compound 4a (938.6 mg, 5.6 mmol, 1.5 equiv) were dissolved in 25 mL of dry DCM. EtAlCl2 (0.56 mL, 2 M in hexanes, 1.1 mmol, 0.3 equiv) was added at 0 °C, and the reaction was maintained at 0 °C for 2.5 h. The reaction was quenched with saturated NaHCO3 (5 mL) aqueous solution, extracted with DCM (3 × 30 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and compound 5a (801.9 mg, 76%) was purified by column chromatography (PE:EtOAc = 20:1).

[0054] Example 6 Synthesis of compound 5a Compound 3 (700.0 mg, 3.7 mmol, 1.0 equiv) and compound 4a (938.6 mg, 5.6 mmol, 1.5 equiv) were dissolved in 25 mL of dry chloroform. BF3•OEt2 (52.5 mg, 0.37 mmol, 0.1 equiv) was added at 10 °C, and the reaction was maintained at 10 °C for 2.5 h. The reaction was quenched with saturated NaHCO3 (5 mL) aqueous solution, extracted with DCM (3 × 30 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and compound 5a (738.6 mg, 70%) was purified by column chromatography (PE:EtOAc = 20:1).

[0055] Example 7 Synthesis of Compound 5b Compound 4b was synthesized using the method described in the reference ( Chem. Eur. J. 2007, 13, 3739-3756. and Angew. Chem. Int. Ed. 2024, 63 (e202314800).

[0056] Compound 3 (700.0 mg, 3.7 mmol, 1.0 equiv) and compound 4b (1.65 g, 6.6 mmol, 1.8 equiv) were dissolved in 25 mL of dry THF. AlCl3 (98.7 mg, 0.74 mmol, 0.2 equiv) was added at 0 °C, and the reaction was maintained at 0 °C for 2 h. The reaction was quenched by adding saturated NaHCO3 (5 mL) aqueous solution, extracted by DCM (3 × 30 mL), the organic phases were combined and washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and compound 5b (1.05 g, 65%) was purified by column chromatography (PE:EtOAc = 20:1).

[0057] Compound 5b: 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 5.31 (q, J = 3.4 Hz,1H), 5.20 - 5.09 (m, 1H), 3.98 - 3.90 (m, 4H), 2.75 (d, J= 13.5 Hz, 1H),2.61 - 2.53 (m, 1H), 2.44 - 2.35 (m, 3H), 2.31 - 2.23 (m, 2H), 1.94 - 1.77(m, 5H), 1.72 - 1.62 (m, 8H), 1.46 - 1.33 (m, 1H), 0.92 (s, 3H). Example 8 Synthesis of compound 5c The synthesis method of compound 4c is the same as that of 4b.

[0058] Compound 3 (700.0 mg, 3.7 mmol, 1.0 equiv) and compound 4c (1.50 g, 7.4 mmol, 2 equiv) were dissolved in 25 mL of dry n-hexane. Me₂AlCl (1.85 mL, 1 M hexane solution, 1.85 mmol, 0.5 equiv) was added at 20 °C, and the reaction was maintained at 20 °C for 3 h. The reaction was quenched with saturated NaHCO₃ (5 mL) aqueous solution, extracted with DCM (3 × 30 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 20:1) to give compound 5c (867.7 mg, 62%).

[0059] Compound 5c: 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 5.30 (q, J = 3.4 Hz,1H), 5.21 - 5.12 (m, 1H), 3.40 - 3.93 (m, 4H), 2.75 (d, J = 13.2 Hz, 1H),2.59 - 2.50 (m, 1H), 2.45 - 2.35 (m, 3H), 2.29 - 2.24 (m, 2H), 1.92 - 1.75(m, 5H), 1.73 - 1.60 (m, 9H), 1.48 - 1.35 (m, 1H), 0.94 (s, 3H). Example 9 Synthesis of Compound 6a Compound 5a (600.0 mg, 1.7 mmol, 1.0 equiv) and TsNHNH2 (6.3 g, 34 mmol, 20.0 equiv) were dissolved in 25 mL of ethylene glycol, and the mixture was heated to 140 °C and reacted for 2 h. K2CO3 (2.3 g, 17 mmol, 10.0 equiv) was added, and the mixture was then heated to 185 °C and reacted for 4.5 h. The system was cooled to room temperature, diluted with 150 mL of EtOAc, washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 80:1) to give compound 6a (457.9 mg, 80%).

[0060] Compound 6a: 1 H NMR (400 MHz, CDCl3) δ 5.24 - 5.18 (m, 1H), 5.12 (qt, J =7.1, 2.1 Hz, 1H), 3.99 - 3.91 (m, 4H), 2.56 (d, J = 13.5 Hz, 1H), 2.46 - 2.29(m, 4H), 2.20 (dd, J = 13.6, 8.1 Hz, 1H), 1.88 - 1.76 (m, 2H), 1.75 - 1.65(m, 5H), 1.64 (dt, J = 7.1, 2.1 Hz, 3H), 1.60 - 1.49 (m, 2H), 1.48 - 1.31 (m,4H), 0.93 (s, 3H), 0.78 (s, 3H). Example 10 Synthesis of Compound 6a Compound 5a (600.0 mg, 1.7 mmol, 1.0 equiv) and 85% aqueous solution of N₂H₄·H₂O (2.4 mL, 42 mmol, 25.0 equiv) were dissolved in 17 mL of diethylene glycol, and the mixture was heated to 140 °C and reacted for 2 h. KOH (848.0 mg, 15.1 mmol, 9.0 equiv) was added, and the mixture was then heated to 190 °C and reacted for 4.5 h. The system was cooled to room temperature, diluted with EtOAc (150 mL), washed with saturated brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 80:1) to give compound 6a (492.3 mg, 86%).

[0061] Example 11 Synthesis of Compound 6a Compound 5a (600.0 mg, 1.7 mmol, 1.0 equiv) and hydrazine hydrochloride (2.5 g, 37.4 mmol, 22.0 equiv) were dissolved in 25 mL of glycerol, and the mixture was heated to 140 °C and reacted for 2 h. NaH (60%, 408.0 mg, 10.2 mmol, 6.0 equiv) was added, followed by heating to 190 °C and reacting for 4.5 h. The system was cooled to room temperature, diluted with 150 mL of EtOAc, washed with saturated brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 80:1) to give compound 6a (446.5 mg, 78%).

[0062] Example 12 Synthesis of Compound 6b Compound 5b (600.0 mg, 1.4 mmol, 1.0 equiv) and 85% aqueous solution of N₂H₄·H₂O (2.0 mL, 35 mmol, 25.0 equiv) were dissolved in 20 mL of diethylene glycol, and the mixture was heated to 150 °C and reacted for 2 h. Sodium ethoxide (952.7 mg, 14.0 mmol, 10 equiv) was added, and the mixture was then heated to 200 °C and reacted for 5 h. The system was cooled to room temperature, diluted with 150 mL of EtOAc, washed with saturated brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 80:1) to give compound 6b (472.0 mg, 80%).

[0063] Compound 6b: 1 H NMR (400 MHz, CDCl3) δ 5.25 - 5.20 (m, 1H), 5.14 (qt, J =7.1, 2.1 Hz, 1H), 3.40 - 3.92 (m, 4H), 2.58 (d, J = 13.5 Hz, 1H), 2.48 - 2.30(m, 4H), 2.21 (dd, J = 13.6, 8.1 Hz, 1H), 1.90 - 1.77 (m, 2H), 1.76 - 1.66(m, 4H), 1.64 (dt, J= 7.1, 2.1 Hz, 3H), 1.61 - 1.51 (m, 2H), 1.50 - 1.32 (m,4H), 0.95 (s, 3H), 0.80 (s, 3H). Example 13 Synthesis of Compound 6c Compound 5c (600.0 mg, 1.5 mmol, 1.0 equiv) and 85% aqueous solution of N₂H₄·H₂O (1.7 mL, 30 mmol, 20.0 equiv) were dissolved in 20 mL of diethylene glycol, and the mixture was heated to 150 °C and reacted for 2 h. NaOH (600.0 mg, 15.0 mmol, 10 equiv) was added, and the mixture was then heated to 180 °C and reacted for 5 h. The system was cooled to room temperature, diluted with 150 mL of EtOAc, washed with saturated brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 80:1) to give compound 6c (451.2 mg, 80%).

[0064] Compound 6c: 1 H NMR (400 MHz, CDCl3) δ 5.25 - 5.19 (m, 1H), 5.13 (qt, J =7.1, 2.1 Hz, 1H), 3.40 - 3.92 (m, 4H), 2.57 (d, J = 13.5 Hz, 1H), 2.47 - 2.30(m, 4H), 2.21 (dd, J = 13.6, 8.1 Hz, 1H), 1.89 - 1.77 (m, 2H), 1.76 - 1.67(m, 4H), 1.65 (dt, J = 7.1, 2.1 Hz, 3H), 1.61 - 1.51 (m, 2H), 1.49 - 1.32 (m,4H), 0.94 (s, 3H), 0.79 (s, 3H). Example 14 Synthesis of Compound 7a Compound 6a (300.0 mg, 0.90 mmol, 1.0 equiv) was dissolved in 6 mL of acetone, and PTSA•H2O (154.3 mg, 0.90 mmol, 1.0 equiv) was added at room temperature. The reaction was allowed to proceed for 4 h at room temperature. The reaction was quenched with saturated NaHCO3 (5 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 30:1) to give compound 7a (270.4 mg, >99%).

[0065] Compound 7a: 1 H NMR (400 MHz, CDCl3) δ 5.29 - 5.23 (m, 1H), 5.14 (tdt, J = 7.2, 5.1, 2.2 Hz, 1H), 2.71 (d, J = 13.1 Hz, 1H), 2.52 - 2.33 (m, 6H), 2.30- 2.21 (m, 2H), 2.17 (ddd, J = 15.5, 4.6, 2.3 Hz, 1H), 2.03 (ddd, J = 14.1,6.5, 2.1 Hz, 1H), 1.95 - 1.77 (m, 3H), 1.75 - 1.57 (m, 2H), 1.65 (dt, J =7.1, 2.1 Hz, 3H), 1.57 - 1.34 (m, 3H), 0.96 (s, 3H), 0.86 (s, 3H). Example 15 Synthesis of Compound 7a Compound 6a (300.0 mg, 0.9 mmol, 1.0 equiv) was dissolved in 7 mL THF, and TiCl4 (89.4 μL, 0.54 mmol, 0.6 equiv) was added at room temperature. The reaction was allowed to proceed for 4 h at room temperature. The reaction was quenched with saturated NaHCO3 (5 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 30:1) to give compound 7a (234.5 mg, 90%).

[0066] Example 16 Synthesis of Compound 7a Compound 6a (300.0 mg, 0.90 mmol, 1.0 equiv) was dissolved in 7 mL THF, and BF3•OEt2 (0.22 mL, 1.80 mmol, 2 equiv) was added at room temperature. The reaction was allowed to proceed for 4 h at room temperature. The reaction was quenched with saturated NaHCO3 (5 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 30:1) to give compound 7a (234.5 mg, 90%).

[0067] Example 17 Synthesis of Compound 7b Compound 6b (300.0 mg, 0.71 mmol, 1.0 equiv) was dissolved in 6 mL of CH2Cl2, and PTSA•H2O (154.3 mg, 0.90 mmol, 1.3 equiv) was added at room temperature. The reaction was allowed to proceed for 4 h at room temperature. The reaction was quenched with saturated NaHCO3 (5 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 30:1) to give compound 7b (254.3 mg, 95%).

[0068] Compound 7b: 1 H NMR (400 MHz, CDCl3) δ 5.28 - 5.22 (m, 1H), 5.13 (tdt, J = 7.1, 5.2, 2.3 Hz, 1H), 2.70 (d, J = 13.2 Hz, 1H), 2.51 - 2.35 (m, 5H), 2.31- 2.23 (m, 2H), 2.16 (ddd, J = 15.5, 4.6, 2.3 Hz, 1H), 2.02 (ddd, J = 14.1,6.5, 2.1 Hz, 1H), 1.94 - 1.78 (m, 3H), 1.74 - 1.58 (m, 2H), 1.66 (dt, J=7.1, 2.1 Hz, 3H), 1.55 - 1.33 (m, 2H), 0.95 (s, 3H), 0.85 (s, 3H). Example 18 Synthesis of Compound 7c Compound 6c (300.0 mg, 0.80 mmol, 1.0 equiv) was dissolved in 6 mL of chloroform, and PTSA (154.3 mg, 0.90 mmol, 1.1 equiv) was added at room temperature. The reaction was allowed to proceed for 4 h at room temperature. The reaction was quenched with saturated NaHCO3 (5 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 30:1) to give compound 7c (239.0 mg, 95%).

[0069] Compound 7c: 1 H NMR (400 MHz, CDCl3) δ 5.27 - 5.21 (m, 1H), 5.15 (tdt, J = 7.3, 5.2, 2.4 Hz, 1H), 2.73 (d, J = 13.3 Hz, 1H), 2.55 - 2.40 (m, 5H), 2.29- 2.20 (m, 2H), 2.18 (ddd, J = 15.5, 4.7, 2.3 Hz, 1H), 2.04 (ddd, J = 14.1,6.5, 2.1 Hz, 1H), 1.96 - 1.79 (m, 3H), 1.73 - 1.60 (m, 2H), 1.63 (dt, J =7.1, 2.1 Hz, 3H), 1.55 - 1.36 (m, 3H), 0.97 (s, 3H), 0.87 (s, 3H). Example 19 Synthesis of Compound 8 Compound 11 was synthesized by a conventional method: an organolithium reagent and an amine reagent were used to form a base in situ in an aprotic solvent.

[0070] Compound 11a (2 mL, 0.12 M in THF, 0.24 mmol, 1.2 equiv) was added to the reaction tube. LiCl (0.48 mL, 0.5 M in THF, 0.24 mmol, 1.2 equiv) was added at 0 °C. Compound 7a (1 mL, 0.2 M in THF, 0.20 mmol, 1.0 equiv) was added at -116 °C, and the reaction was allowed to proceed for 10 min. Subsequently, compound 12a (0.4 mL, 1 M in THF, 0.40 mmol, 2.0 equiv) was added. The reaction was maintained at -116 °C for 15 min, followed by increasing the temperature to -78 °C and reacting for 30 min. The reaction was quenched with saturated NH4Cl (2 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined, washed with water, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the compound was purified by column chromatography (PE:EtOAc = 15:1) to obtain compound 8 (40.2 mg, 68%).

[0071] Compound 8: 1 H NMR (500 MHz, CDCl3) δ 5.82 (s, 1H), 5.35 - 5.30 (m, 1H), 5.15 (qt, J = 7.2, 2.2 Hz, 1H), 3.16 - 3.05 (m, 1H), 3.02 - 2.93 (m, 1H),2.52 - 2.43 (m, 2H), 2.43 - 2.34 (m, 3H), 2.30 - 2.21 (m, 2H), 2.06 - 1.98(m, 1H), 1.89 - 1.74 (m, 3H), 1.69 - 1.51 (m, 3H), 1.63 (dt, J = 7.1, 2.1 Hz, 3H), 1.43 (tdd, J = 11.9, 10.6, 9.0 Hz, 1H), 1.06 (s, 3H), 0.87 (s, 3H). Example 20 Synthesis of Compound 8 Compound 11a (1.2 mL, 0.5 M in THF, 0.60 mmol, 3.0 equiv) was added to the reaction tube. LiCl (1.2 mL, 0.5 M in THF, 0.60 mmol, 3.0 equiv) was added at 0 °C, followed by TMSCl (77.0 μL, 0.60 mmol, 3.0 equiv) at -78 °C, and then compound 7a (1 mL, 0.2 M in THF, 0.20 mmol, 1.0 equiv). The reaction was maintained at -78 °C for 80 min. The reaction was quenched with saturated NaHCO3 (2 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined, washed with water, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain the crude product. The crude product was dissolved in 3.0 mL of CH3CN, and Pd(OAc)2 (44.8 mg, 0.20 mmol, 1 equiv) was added at room temperature. After reacting at room temperature for 3 h, the mixture was filtered through silica gel and eluted with EtOAc. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 15:1) to give compound 8 (25.2 mg, 42% for 2 steps).

[0072] Example 21 Synthesis of Compound 8 Compound 11b (2 mL, 0.2 M in THF, 0.40 mmol, 2.0 equiv) was added to the reaction tube. LiCl (0.88 mL, 0.5 M in THF, 0.44 mmol, 2.2 equiv) was added at 0 °C. Compound 7a (1 mL, 0.2 M in THF, 0.20 mmol, 1.0 equiv) was added at -116 °C, and the reaction was allowed to proceed for 10 min. Subsequently, IBX (0.4 mL, 1 M in THF, 0.40 mmol, 2.0 equiv) was added. The reaction was maintained at -116 °C for 15 min, followed by increasing the temperature to 50 °C and reacting for 30 min. The reaction was quenched with saturated NH4Cl (2 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined, washed with water, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the compound was purified by column chromatography (PE:EtOAc = 15:1) to obtain compound 8 (40.2 mg, 68%).

[0073] Example 22 Synthesis of Compound 8 Compound 11c (2 mL, 0.2 M in THF, 0.40 mmol, 2.0 equiv) was added to the reaction tube. LiCl (1.2 mL, 0.5 M in THF, 0.60 mmol, 3.0 equiv) was added at 0 °C, followed by TMSBr (66.0 μL, 0.50 mmol, 2.5 equiv) at -70 °C, and then compound 7a (1 mL, 0.2 M in THF, 0.20 mmol, 1.0 equiv). The reaction was maintained at -70 °C for 100 min. The reaction was quenched with saturated NaHCO3 (2 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined, washed with water, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain the crude product, which was then dissolved in 3.0 mL of DMF. PdCl2 (70.8 mg, 0.40 mmol, 2 equiv) was added at room temperature. After reacting at room temperature for 3 h, the mixture was filtered through silica gel and eluted with EtOAc. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 15:1) to give compound 8 (28.4 mg, 48% for 2 steps).

[0074] Example 23 Synthesis of Compound 8 Compound 7b (300.0 mg, 0.80 mmol, 1.0 equiv) was dissolved in 6 mL THF, and NaH (38.4 mg, 1.60 mmol, 2 equiv) was added at room temperature. The reaction was allowed to proceed for 5 h at room temperature. The reaction was quenched with saturated ammonium chloride (5 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 15:1) to give compound 8 (213.1 mg, 90%).

[0075] Example 24 Synthesis of Compound 8 Compound 7b (300.0 mg, 0.80 mmol, 1.0 equiv) was dissolved in 6 mL of toluene, and DBU (0.6 mL, 4.0 mmol, 5 equiv) was added at room temperature. The reaction was allowed to proceed for 3 h at room temperature. The reaction was quenched with saturated ammonium chloride (5 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 15:1) to give compound 8 (215.4 mg, 91%).

[0076] Example 25 Synthesis of Compound 8 Compound 7b (300.0 mg, 0.90 mmol, 1.0 equiv) was dissolved in 6 mL THF, and NaOMe (146.3 mg, 2.7 mmol, 3 equiv) was added at room temperature. The reaction was allowed to proceed for 3 h at room temperature. The reaction was quenched with saturated ammonium chloride (5 mL) aqueous solution, extracted with EtOAc (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 15:1) to give compound 8 (215.4 mg, 91%).

[0077] Example 26 Synthesis of Compound 9 Compound 8 (15.0 mg, 0.05 mmol, 1.0 equiv) was dissolved in 1.5 mL of dry THF, and 9-BBN (0.4 mL, 0.5 M in THF, 0.20 mmol, 4.0 equiv) was added at room temperature. The reaction was allowed to proceed for 13 h at room temperature. The mixture was then placed in an ice-water bath, and NaOH (0.3 mL, 3.0 M in H2O) and 30% H2O2 aqueous solution (0.2 mL) were added sequentially. After reacting at room temperature for 0.5 h, the mixture was diluted with EA (20 mL), washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 5:1) to obtain compound 9 (13.3 mg, 83%).

[0078] Compound 9: 1 H NMR (500 MHz, CDCl3) δ 5.41 (dt, J= 3.0, 1.5 Hz, 1H),5.23 - 5.12 (m, 1H), 4.17 (td, J = 5.8, 2.9 Hz, 1H), 3.66 (dq, J = 8.5, 6.3Hz, 1H), 2.95 - 2.86 (m, 1H), 2.67 (dd, J = 20.5, 3.1 Hz, 1H), 2.38 (td, J =8.5, 4.6 Hz, 1H), 2.12 - 1.91 (m, 3H), 1.91 - 1.77 (m, 2H), 1.70 (ddd, J =13.5, 6.0, 2.8 Hz, 1H), 1.63 - 1.51 (m, 3H), 1.51 - 1.41 (m, 3H), 1.41 - 1.31(m, 2H), 1.23 (d, J = 6.2 Hz, 3H), 0.92 (s, 3H), 0.66 (s, 3H). Example 27 Synthesis of Compound 9 Compound 8 (15.0 mg, 0.05 mmol, 1.0 equiv) was dissolved in 1.5 mL of dry THF, and BH3•Me2S (0.12 mL, 2.0 M in THF, 0.25 mmol, 5.0 equiv) was added at room temperature, and the reaction was carried out for 13 h at room temperature. The mixture was then placed in an ice-water bath, and K2CO3 (0.3 mL, 3.0 M in H2O) and 30% H2O2 aqueous solution (0.3 mL) were added sequentially. After reacting at room temperature for 0.5 h, the mixture was diluted with EA (20 mL), washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 5:1) to give compound 9 (13.1 mg, 82%).

[0079] Example 28 Synthesis of Compound 9 Compound 8 (15.0 mg, 0.05 mmol, 1.0 equiv) was dissolved in 1.5 mL of dry THF, and Cy2BH (0.30 mL, 1.0 M in THF, 0.30 mmol, 6.0 equiv) was added at room temperature, and the reaction was allowed to proceed for 13 h at room temperature. Then, KHCO3 (0.4 mL, 3.0 M in H2O) and 30% H2O2 aqueous solution (0.3 mL) were added sequentially at room temperature. After reacting at room temperature for 0.5 h, the mixture was diluted with EA (20 mL), washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 5:1) to give compound 9 (12.8 mg, 80%).

[0080] Example 29 Synthesis of Compound 10 Compound 9 (22.0 mg, 0.07 mmol, 1.0 equiv) was dissolved in 2 mL of dry DCM, followed by the addition of DMP (44.5 mg, 0.11 mmol, 1.5 equiv). After reacting at room temperature for 2 h, the reaction was quenched with saturated sodium bicarbonate solution, diluted with EA (20 mL), washed with saturated brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and compound 10 (15.3 mg, 70%) was purified by column chromatography (PE:EtOAc = 4:1).

[0081] Compound 10: 1 H NMR (600 MHz, CDCl3) δ 5.82 (s, 1H), 5.29 (t, J = 3.4 Hz, 1H), 3.11 (dtt, J = 22.7, 4.2, 2.4 Hz, 1H), 2.97 (dd, J = 22.7, 3.2 Hz, 1H), 2.70 (t, J = 9.2 Hz, 1H), 2.56 - 2.44 (m, 2H), 2.38 (dt, J = 16.7, 4.4 Hz,1H), 2.28 - 2.20 (m, 3H), 2.15 (s, 3H), 2.03 (dt, J = 13.4, 4.7 Hz, 1H), 1.89- 1.67 (m, 5H), 1.65 - 1.60 (m, 1H), 1.49 (qd, J= 11.8, 6.5 Hz, 1H), 1.07(s, 3H), 0.62 (s, 3H). Example 30 Synthesis of Compound 10 Compound 9 (11.0 mg, 0.035 mmol, 1.0 equiv) and NMO (8.2 mg, 0.07 mmol, 2.0 equiv) were dissolved in 1 mL of dry DCM, and 70 mg of 4 Å molecular sieve was added. Then, 0.1 mL of DCM solution containing TPAP (1.2 mg, 0.0035 mmol, 0.1 equiv) was added. After reacting at room temperature for 2 h, the mixture was filtered through silica gel and eluted with EtOAc. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EtOAc = 4:1) to give compound 10 (6.9 mg, 63%).

[0082] Example 31 Synthesis of Compound 1 Compound 10 (50.0 mg, 0.16 mmol, 1.0 equiv) was dissolved in 5 mL of ethanol, followed by the addition of PTSA•H₂O (15.2 mg, 0.080 mmol, 0.5 equiv). After reacting at room temperature for 2 h, the reaction was quenched with saturated sodium bicarbonate solution, diluted with EA (30 mL), washed with saturated brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and compound 1 (34.9 mg, 70%) was purified by column chromatography (PE:EtOAc = 4:1).

[0083] Compound 1: 1 H NMR: (500 MHz, CDCl3) δ 6.21-6.17 (m, 2H), 5.70 (s, 1H), 2.62-2.55 (m, 2H), 2.50-2.45 (m, 2H), 2.30-2.22 (m, 2H), 2.15 (s, 3H), 2.06-1.97 (m, 2H), 1.91-1.84 (m, 2H), 1.81-1.64 (m, 6H), 1.32 (s, 3H). Example 32 Synthesis of Compound 1 Compound 10 (50.0 mg, 0.16 mmol, 1.0 equiv) was dissolved in 5 mL of methanol, followed by the addition of TFA (24 μL, 0.32 mmol, 2 equiv). After reacting at room temperature for 2 h, the reaction was quenched with saturated sodium bicarbonate solution, diluted with EA (30 mL), washed with saturated brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and compound 1 (35.9 mg, 72%) was purified by column chromatography (PE:EtOAc = 4:1).

[0084] Example 33 Synthesis of Compound 1 Compound 10 (50.0 mg, 0.16 mmol, 1.0 equiv) was dissolved in 5 mL of methanol, followed by the addition of HCl (20.0 μL, 12 M, 0.24 mmol, 1.5 equiv). After reacting at room temperature for 2 h, the reaction was quenched with saturated sodium bicarbonate solution, diluted with EA (30 mL), washed with saturated brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and compound 1 (35.9 mg, 72%) was purified by column chromatography (PE:EtOAc = 4:1).

[0085] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for synthesizing compound 10, characterized in that, Including the following steps: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7; e) (e-1) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by an enol silyl etherification reaction with a silicon reagent to generate an enol silyl ether intermediate. Then, in a polar solvent, a Pd metal catalyst is added, and a palladium-catalyzed reaction occurs to give compound 8; or... (e-2) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by a dehydrogenation reaction with a dehydrogenating reagent to give compound 8; or, (e-3) When X is Br, I or Cl, in an aprotic solvent, compound 7 undergoes an elimination reaction with a base to give compound 8; f) In an aprotic solvent, compound 8 undergoes a boronization reaction with a boron reagent, followed by the addition of a base and hydrogen peroxide for oxidation to give compound 9; g) In an aprotic solvent, under the action of an oxidizing agent, compound 9 undergoes an oxidation reaction to give compound 10.

2. The method as described in claim 1, characterized in that, The method has one or more technical features selected from the group consisting of: (1) In step a), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkanes solvents, or combinations thereof; (2) In step a), the volume molar ratio of the aprotic solvent to compound 2 is 10~30 L: 1 mol; (3) In step a), the alkali is selected from the group consisting of: sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, n-butyllithium, potassium hexamethyldisilamide (KHMDS), sodium hexamethyldisilamide (NaHMDS), lithium hexamethyldisilamide (LiHMDS), lithium diisopropylamino, or combinations thereof; (4) In step a), the molar ratio of the base to compound 2 is 1~5:1; (5) In step a), the Wittig reagent is PPh3EtX or AsPh3EtX, where X is Br, I or Cl; (6) In step a), the molar ratio of Wittig reagent to compound 2 is 1~5:1; (7) In step a), the reaction is carried out at 0~80°C, preferably at 20~50°C; (8) In step b), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (9) In step b), the volume molar ratio of the aprotic solvent to compound 3 is 10~30 L: 1 mol; (10) In step b), the catalyst is selected from the group consisting of ZnCl2, AlCl3, EtAlCl2, Et2AlCl, SnCl4, Sc(OTf)3, TiCl4, Me2AlCl or BF3•OEt2; (11) In step b), the molar ratio of the catalyst to compound 3 is 0.05 to 0.5:1; (12) In step b), the molar ratio of compound 4 to compound 3 is 1~2:1; (13) In step b), the reaction is carried out at -20 to 50°C, preferably at -20 to 20°C; (14) In step c), the alcohol solvent is selected from the group consisting of ethylene glycol, glycerol, diethylene glycol, or combinations thereof; (15) In step c), the volume molar ratio of the alcohol solvent to compound 5 is 10~30 L: 1 mol; (16) In step c), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium ethoxide, potassium ethoxide, or combinations thereof; (17) In step c), the molar ratio of the base to compound 5 is 5~12:1; (18) In step c), the hydrazine compound is selected from the group consisting of hydrazine, hydrazine hydrate, hydrazine salt, sulfonyl hydrazine, or combinations thereof; preferably, the hydrazine compound is selected from the group consisting of hydrazine hydrochloride, hydrazine sulfate, anhydrous hydrazine, hydrazine hydrate, TsNHNH2, or combinations thereof; (19) In step c), the molar ratio of the hydrazine compound to compound 5 is 10~30:1; (20) In step c), the reaction is carried out at 120~200°C; preferably 140~190°C; (21) In step d), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, ketone solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (22) In step d), the volume molar ratio of the aprotic solvent to compound 6 is 10~30 L: 1 mol; (23) In step d), the acid is selected from the group consisting of: HCl, H2SO4, HClO4, PTSA•H2O, TiCl4, BF3•OEt2, trifluoroacetic acid, or a combination thereof; (24) In step d), the molar ratio of the acid to compound 6 is 0.5 to 3:1; (25) In step d), the reaction is carried out at 0~60°C, preferably at 10~30°C; (26) In step (e-1), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (27) In step (e-1), the volume molar ratio of the aprotic solvent to compound 7 is 10~30 L: 1 mol; (28) In step (e-1), the inorganic salt is selected from the group consisting of lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, potassium iodide, sodium iodide, or combinations thereof; (29) In step (e-1), the molar ratio of the inorganic salt to compound 7 is 1 to 5:1; (30) In step (e-1), the lithium reagent is n-butyllithium, LiHMDS, tert-butyllithium, or a combination thereof; (31) In step (e-1), the molar ratio of the lithium reagent to compound 7 is 1 to 5:1; (32) In step (e-1), the amine reagent is selected from the group consisting of: , , , , , , or a combination thereof; (33) In step (e-1), the silicon reagent is selected from the group consisting of: trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, trimethylsilyltrifluoromethanesulfonate, or combinations thereof; (34) In step (e-1), the molar ratio of the silicon reagent to compound 7 is 1 to 5:1; (35) In step (e-1), the enolization reaction is carried out at -78 to -40°C, preferably at -78 to -60°C; (36) In step (e-1), the polar solvent is acetonitrile, dimethyl sulfoxide (DMSO) or N,N-dimethylformamide (DMF). (37) In step (e-1), the volume molar ratio of the polar solvent to compound 7 is 10~30 L: 1 mol; (38) In step (e-1), the metal Pd catalyst is selected from the group consisting of: Pd(OAc)2, PdCl2, Pd(TFA)2, Pd(acac)2, Pd(PPh3)4, Pd2(dba)3, or a combination thereof; (39) In step (e-1), the molar ratio of the metal Pd catalyst to compound 7 is 1-3:1; (40) In step (e-1), the palladium-catalyzed reaction is carried out at 0~60°C, preferably at 10~30°C; (41) In step (e-2), the dehydrogenating agent is selected from the group consisting of: benzeneselenic anhydride, 2-iodobenzoic acid (IBX), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). or a combination thereof; (42) In step (e-2), the molar ratio of the dehydrogenating agent to compound 7 is 1 to 5:1; (43) In step (e-2), when the dehydrogenating agent is The dehydrogenation reaction is carried out at -120 to -50°C, preferably at -110 to -78°C. (44) In step (e-2), when the dehydrogenating agent is benzeneselenic anhydride, 2-iodobenzoic acid (IBX) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the dehydrogenation reaction is carried out at a temperature of 10~100℃, preferably at 20~60℃. (45) In step (e-3), the alkali is selected from the group consisting of: DBU, Et3N, t -BuOK、 t -BuONa, NaH, KH, CaH2, NaHMDS, KHMDS, LiHMDS, NaOMe, KOMe, NaOEt, KOEt, LiCO3 / LiCl, Na2CO3 / LiCl, K2CO3 / LiCl, or combinations thereof; (46) In step (e-3), the elimination reaction is carried out at 20~100°C, preferably at 20~50°C; (47) In step f), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (48) In step f), the volume molar ratio of the aprotic solvent to compound 8 is 10~30 L: 1 mol; (49) In step f), the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof; (50) In step f), the molar ratio of the base to compound 8 is 10~20:1; (51) In step f), the volume molar ratio of hydrogen peroxide to compound 8 is 0.1~0.5 L: 1 mol; (52) In step f), the boron reagent is selected from the group consisting of: BH3•Me2S, diisopentylborane (Sia2BH), tert-hexylborane (ThxBH2), dicyclohexylborane (Cy2BH), 9-boronbicyclo[3.3.1]nonane (9-BBN), or combinations thereof; (53) In step f), the molar ratio of the boron reagent to compound 8 is 3~8:1; (54) In step f), the borohydride reaction is carried out at 0~60°C, preferably at 0~30°C; (55) In step g), the aprotic solvent is selected from the group consisting of: halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, cycloalkane solvents, or combinations thereof; preferably, the aprotic solvent is selected from the group consisting of: dichloromethane (DCM), chloroform, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether (MTBE), acetone, benzene, toluene, xylene, ethylbenzene, cyclohexane, or combinations thereof; (56) In step g), the volume molar ratio of the aprotic solvent to compound 9 is 10~30 L: 1 mol; (57) In step g), the oxidant is selected from the group consisting of: pyridine chlorochromate (PCC), pyridine dichromate (PDC), Dysmart oxidant (DMP), (COCl)2 / DMSO / Et3N, Al( i -PrO)3 / acetone, N-methylmorpholine-N-oxide / tetrapropylammonium perruthenate (NMO / TPAP), or combinations thereof; (58) In step g), the molar ratio of the oxidant to compound 9 is 0.5 to 3:1; (59) In step g), the oxidation reaction is carried out at 0~60°C, preferably at 10~30°C.

3. A method for synthesizing compound 9, characterized in that, Including the following steps: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7; e) (e-1) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by an enol silyl etherification reaction with a silicon reagent to generate an enol silyl ether intermediate. Then, in a polar solvent, a Pd metal catalyst is added, and a palladium-catalyzed reaction occurs to give compound 8; or... (e-2) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by a dehydrogenation reaction with a dehydrogenating reagent to give compound 8; or, (e-3) When X is Br, I or Cl, in an aprotic solvent, compound 7 undergoes an elimination reaction with a base to give compound 8; f) In an aprotic solvent, compound 8 undergoes a boronization reaction with a boron reagent, followed by the addition of a base and hydrogen peroxide for oxidation, to obtain compound 9.

4. A method for synthesizing compound 8, characterized in that, Including the following steps: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7; e) (e-1) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by an enol silyl etherification reaction with a silicon reagent to generate an enol silyl ether intermediate. Then, in a polar solvent, a Pd metal catalyst is added, and a palladium-catalyzed dehydrogenation reaction occurs to give compound 8; or... (e-2) When X is H, in an aprotic solvent, the organolithium reagent and the amine reagent form a lithium amine base in situ. Under the action of the lithium amine base and the inorganic salt, compound 7 undergoes deprotonation, followed by a dehydrogenation reaction with a dehydrogenating reagent to give compound 8; or, (e-3) When X is Br, I or Cl, in an aprotic solvent, compound 7 undergoes an elimination reaction with a base to give compound 8.

5. A method for synthesizing compound 7, characterized in that, Including the following steps: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6; d) In an aprotic solvent, under the action of acid, compound 6 undergoes a deprotection reaction to give compound 7.

6. A method for synthesizing compound 6, characterized in that, Including the following steps: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5; c) In an alcohol solvent, under the action of a base and a hydrazine compound, compound 5 undergoes a reduction reaction of the aldehyde group to give compound 6.

7. A method for synthesizing compound 5, characterized in that, Including the following steps: in, R is a C1-C6 alkylene group; X is H, Br, I, or Cl; a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3; b) In an aprotic solvent, under the action of a catalyst, compound 3 and compound 4 undergo a cycloaddition reaction to give compound 5.

8. A method for synthesizing compound 3, characterized in that, Including the following steps: a) In an aprotic solvent, under the action of a base, compound 2 reacts with Wittig reagent to give compound 3.

9. A method for synthesizing dydrogesterone, characterized in that, Including the following steps: 1) The intermediate compound 10 is prepared by the method according to any one of claims 1-8; 2) In an alcohol solvent, under the action of an acid, compound 10 undergoes a double bond isomerization reaction to give compound 1, dydrogesterone. In another preferred embodiment, in step 2), the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, or combinations thereof. In another preferred embodiment, in step 2), the volume molar ratio of the alcohol solvent to compound 10 is 10~30 L: 1 mol; In another preferred embodiment, in step 2), the acid is HCl, HBr, HClO4, PTSA, or TFA; In another preferred embodiment, in step 2), the molar ratio of the acid to compound 10 is 0.5 to 3:1; In another preferred embodiment, in step 2), the double bond isomerization reaction is carried out at 0~60°C, preferably at 10~30°C.

10. A dydrogesterone intermediate compound, characterized in that, Selected from the following group: 、 、 、 、 、 ； Wherein, R is a C1-C6 alkylene group; X is H, Br, I, or Cl.

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