TWI755667B - Preparation method of fused tricyclic derivatives and intermediates thereof - Google Patents

Abstract

。The invention provides a preparation method and an intermediate of a fused tricyclic derivative. The fused tricyclic derivative has the structure represented by formula (I). The preparation method has easy-to-obtain raw materials and simple steps, and is suitable for large-scale industrial production.

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Description

Preparation method of fused tricyclic derivatives and intermediates thereof

The present invention relates to the field of medicine, in particular to a preparation method and an intermediate of a fused tricyclic derivative.

Voltage-gated calcium channels are composed of α1 subunit and accessory protein α2δ, β, γ subunits. α2δ proteins can modulate calcium channel density and calcium channel voltage-dependent kinetics (Felix et al (1997) J. Neuroscience 17:6884-6891; Klugbauer et al (1999) J. Neuroscience 19:684-691; Hobom et al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496). Compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α2δ have been shown to be effective in the treatment of pain, such as pregabalin and gabapentin. In mammals, there are four isoforms of α2δ proteins, each encoded by a different gene. α2δ isoforms 1 and 2 showed high affinity for pregabalin, while α2δ isoforms 3 and 4 showed no significant drug binding.

However, for gabapentin, the proportion of patients with diabetic peripheral neuropathy is about 60% improved (Acta Neurol. Scand. 101: 359-371, 2000), for pregabalin, although it is better tolerated than gabapentin , but its safety is lower, and there is the possibility of abuse or dependence of patients (Am J Health Syst Pharm. 2007; 64 (14): 1475-1482).

There remains a great need to develop new compounds that exhibit high-affinity binding to the voltage-dependent calcium channel subunit α2δ.

式(I)。 The PCT/CN2017/101364 patent application discloses a fused tricyclic γ-amino acid derivative and its preparation method and application in medicine, which have good biological activity, and also discloses the intermediate formula (I) for preparing the derivative. ) compounds and methods for their preparation,

Formula (I).

The object of the present invention is to provide a method for preparing a fused tricyclic derivative of formula (I).

Another object of the present invention is to provide a method for preparing intermediates of the fused tricyclic derivatives of formula (I).

Another object of the present invention is to provide intermediates for preparing the compounds of formula (I) and their stereoisomers or their pharmaceutically acceptable salts.

The present invention relates to a preparation method of a compound of formula (I) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is prepared from a compound of formula (3-10);

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by reaction with chlorine.

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or The compound of formula (I) is prepared by reacting acyl chloride, and the acid anhydride is selected from trifluoromethanesulfonic anhydride and trifluoroacetic anhydride; the acyl chloride is selected from phosphorus oxychloride, oxalyl chloride, triphosgene or thionous chloride.

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by chlorine reaction, and the base is selected from organic bases, preferably Collidine, 2,4,6-trimethylpyridine, 2-fluoropyridine, 2,6-di-tert-butyl- 4-methylpyridine, 2,6-di-tert-butylpyridine, hexamethylphosphine triamine, triethylamine, N,N-diisopropylethylamine or DBU(1,8-diazepine bicyclo[5.4.0]undec-7-ene).

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. Chlorine reaction is prepared to obtain the compound of formula (I), wherein the reaction is further performed under alkaline conditions, and the base is selected from inorganic bases, preferably metal bases, further preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, Sodium Phosphate, Lithium Hydroxide, Sodium Hydroxide, Potassium Hydroxide, Sodium Bicarbonate or Potassium Bicarbonate.

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by chlorine reaction, and the molar ratio of compound (3-10) to acid anhydride or acyl chloride is selected from 1:1-1:4, preferably 1:1.5-1:2. Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by chlorine reaction, and the solvent used in the reaction is selected from water, dichloromethane, acetone or 1,2-dichloroethane.

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or acyl anhydride under basic conditions. The compound of formula (I) is prepared by chlorine reaction, and the reaction temperature is selected from 0°C to reflux.

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-10) is combined with acid anhydride or amide in the presence of an organic base Chlorine reacts to obtain the intermediate imide salt, and then reacts under alkaline conditions to prepare the compound of formula (I), and the acid anhydride is selected from trifluoromethanesulfonic anhydride or trifluoroacetic anhydride; Oxalyl chloride, triphosgene or sulfite chloride; the organic base is selected from Collidine, 2,4,6-collidine, 2-fluoropyridine, 2,6-di-tert-butyl-4-methyl Pyridine, 2,6-di-tert-butylpyridine, hexamethylphosphoric triamine, triethylamine, N,N-diisopropylethylamine or DBU(1,8-diazabicyclo[5.4. 0]undec-7-ene); The base is selected from inorganic bases, preferably metal bases, further preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate or Potassium bicarbonate.

The present invention relates to a preparation method of the compound of formula ((3-10) and its stereoisomers or pharmaceutically acceptable salts thereof, which comprises preparing the compound of formula (3-9) to obtain the compound of formula (3-10) ,

Some specific embodiments of the present invention, a preparation method of the compound of formula ((3-10) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine, a condensing agent The compound of formula (3-10) can be obtained by reacting under basic conditions.

Some specific embodiments of the present invention, a preparation method of the compound of formula ((3-10) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine, a condensing agent The compound of formula (3-10) is prepared by reacting under basic conditions; the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), carbonyl diimide Imidazole (CDI), Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), Methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), p-nitrobenzenesulfonic acid Acyl chloride (NsCl), O-(7-azabenzotriazole-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazole- 1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate Phosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-butanediimidinyl)- Bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbodiimide)-bis(dimethylamino)carbon Onium tetrafluoroborate (TNTU), phenylphosphonium chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiodimethylphosphonium azide Nitrogen (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphonium chloride (BOP-Cl).

Some specific embodiments of the present invention, a preparation method of the compound of formula ((3-10) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine, a condensing agent The compound of formula (3-10) is prepared by reacting under basic conditions, and the base used in the reaction is selected from organic bases or inorganic bases, preferably triethylamine, N,N-diisopropylethylamine, 4- N , N -lutidine (DMAP), 1-hydroxybenzotriazole (HOBt), sodium carbonate or potassium carbonate.

Some specific embodiments of the present invention, a preparation method of the compound of formula ((3-10) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine, a condensing agent The compound of formula (3-10) is prepared by reacting under basic conditions, and the solvent used in the reaction is selected from dichloromethane, ethyl acetate Any one or any of several in nitrile, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and N-methylpyrrolidone proportion of the mixture.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-10) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine and condensing agent are in The compound of formula (3-10) is prepared by the reaction under basic conditions, and the molar ratio of the compound of formula (3-9) to pyrrolidine is 1:1-1:3, preferably 1:1-1:2.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-10) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-9), pyrrolidine and condensing agent are in The compound of formula (3-10) is prepared by reacting under basic conditions, and the reaction temperature is selected from 0°C to reflux, preferably 0-40°C.

The present invention relates to a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, which comprises preparing the compound of formula (3-8) to obtain the compound of formula (3-9)

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared; the oxidant is selected from NaClO ₂ , pyridinium dichromate (PDC), potassium permanganate, sodium periodate/ruthenium trichloride, hydrogen peroxide/formic acid or iodine diacetate Benzene/2,2,6,6-tetramethylpyridine oxide.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared; the oxidant is 2-methyl-2-butene/NaClO ₂ /NaH ₂ PO ₄ .

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared, and the solvent used in the reaction is selected from any one of water, tert-butanol, dichloromethane, acetone, dioxane and toluene, or a mixture of any of them in any proportion.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared, and the molar ratio of the compound of formula (3-8) to the oxidant is 1:1-1:4, preferably 1:3.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared, and the reaction temperature is selected from 0-40°C.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-9) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-8) is reacted with an oxidizing agent under acidic conditions The compound of formula (3-9) is prepared, and the oxidant is selected from NaClO ₂ , pyridinium dichromate (PDC), potassium permanganate, sodium periodate/ruthenium trichloride, hydrogen peroxide/formic acid, iodine diacetate Benzene/2,2,6,6-tetramethylpyridine oxide, preferably 2-methyl-2-butene/NaClO ₂ /NaH ₂ PO ₄ ; the solvent used in the reaction is selected from water, tert-butylene Any one of alcohol, dichloromethane, acetone, dioxane and toluene or a mixture of any of them in any ratio.

The present invention relates to a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (3-8) by preparing the compound of formula (3-7),

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compounds.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compound, the oxidant is selected from o-iodobenzoic acid (IBX), pyridinium chlorochromate (PCC), sulfur trioxide pyridine, Dess-Martin oxidant, Jones reagent, dimethylsulfite/ Oxalyl chloride or TPAP([n- _Pr4N ][ _RuO4 ])/N-methylmorpholine.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compound, the solvent used in the reaction is selected from ethyl acetate, dichloromethane, acetone and dimethylsulfite, or any mixture in any proportion.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compound, the reaction temperature is selected from 0°C to reflux.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) The compound, the molar ratio of the compound of formula (3-7) to the oxidizing agent is selected from 1:1-1:3.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-8) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-7) is reacted with an oxidizing agent to prepare formula ( 3-8) Compound, the oxidant is selected from o-iodobenzoic acid (IBX), pyridinium chlorochromate (PCC), sulfur trioxide pyridine, Dess-Martin oxidant, Jones reagent, dimethylsulfite/ Oxalyl chloride or TPAP([n-Pr ₄ N][RuO ₄ ])/N-methylmorpholine; the solvent used in the reaction is selected from any of ethyl acetate, dichloromethane, acetone and dimethylsulfoxide. One or any mixture in any ratio; the molar ratio of the compound of formula (3-7) to the oxidant is selected from 1:1-1:3; the reaction temperature is selected from 0°C to reflux.

；P選自羥基保護基，較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 The present invention relates to a preparation method of the compound of formula (3-7) and its stereoisomers or pharmaceutically acceptable salts thereof, which comprises preparing the compound of formula (3-6) to obtain the compound of formula (3-7)

; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-7) and a stereoisomer or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (3-6) to obtain formula (3- 7) Compound wherein, the catalyst used in the reaction is selected from 2,3-dichloro-5,6-dicyano-p _- benzoquinone (DDQ), cerium ammonium nitrate, cerium trifluoromethanesulfonate, Pd/C/H or tetrakis Zirconium chloride.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-7) and a stereoisomer or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (3-6) to obtain formula (3- 7) Compound, the buffer solvent used in the reaction is selected from pH=7 buffer solution, preferably pH=7 potassium phosphate buffer solution, pH=7 sodium phosphate buffer solution.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-7) and a stereoisomer or a pharmaceutically acceptable salt thereof, comprising preparing the compound of formula (3-6) to obtain formula (3- 7)ization The solvent used in the reaction is selected from any one or a mixture of any of several in any ratio among dichloromethane, acetonitrile, chlorobenzene, toluene, ethylene glycol diethyl ether and nitromethane.

；P選自羥基保護基，較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 The present invention relates to a preparation method of the compound of formula (3-6) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises preparing the compound of formula (3-4) to obtain the compound of formula (3-6)

; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl.

；式(3-4)化合物與式(3-5)化合物在催化劑存在下反應製備得到式(3-6)化合物。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein,

The compound of formula (3-4) is reacted with the compound of formula (3-5) in the presence of a catalyst to prepare the compound of formula (3-6).

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) The compound of formula (3-6) is prepared by reacting in the presence of a catalyst, the catalyst is selected from metal reagents, preferably dilithium tetrachlorocuprate, cuprous iodide, cerium trichloride, lithium chloride or dichloride Zinc.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) The compound of formula (3-6) is prepared by reacting in the presence of a catalyst, and the solvent used in the reaction is selected from tetrahydrofuran, any one of toluene, dioxane, diethyl ether, chlorobenzene and dimethyl sulfite in any proportion or in any proportion. mixture.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) in the catalyst The compound of formula (3-6) is prepared in the following reaction, and the molar ratio of the compound of formula (3-4) to the compound of formula (3-5) is 1:1-1:4.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) The compound of formula (3-6) is prepared by reacting in the presence of a catalyst, and the reaction temperature is -78°C-40°C.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-6) and a stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (3-4) and the compound of formula (3-5) The compound of formula (3-6) is prepared by reacting in the presence of a catalyst, the catalyst is selected from metal reagents, preferably dilithium tetrachlorocuprate, cuprous iodide, cerium trichloride, lithium chloride or dichloride Zinc oxide; the solvent used in the reaction is selected from tetrahydrofuran, toluene, dioxane, diethyl ether, chlorobenzene and dimethyl sulfite or any mixture in any proportion; the compound of formula (3-4) and the formula (3-5) The molar ratio of the compound is 1:1-1:4; the reaction temperature is -78°C-40°C.

；P選自羥基保護基，較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 Some specific embodiments of the present invention, a preparation method of the compound of formula (3-4) and a stereoisomer or a pharmaceutically acceptable salt thereof, which comprises preparing the compound of formula (3-3) to obtain formula (3) -4) Compounds

; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-3) is reacted with metal magnesium in the presence of a catalyst The compound of formula (3-4) is prepared.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-4) and stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-3) and metal magnesium are in the presence of a catalyst The compound of formula (3-4) is prepared by the reaction, and the catalyst is selected from iodine, 1,2-dichloroethane or isopropylmagnesium bromide.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-4) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-3) and metal magnesium are in the presence of a catalyst The compound of formula (3-4) is prepared by the reaction, and the solvent used in the reaction is selected from ether solvents, preferably any one of tetrahydrofuran and diethyl ether or a mixture of any of them in any proportion.

；P選自羥基保護基，較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基。 The present invention relates to a preparation method of the compound of formula (3-3) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises preparing the compound of formula (3-2) to obtain the compound of formula (3-3)

; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-3) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-2) and a brominating reagent are present in the presence of a catalyst The compound of formula (3-3) can be obtained by the following reaction.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-3) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-2) and a brominating reagent are present in the presence of a catalyst The compound of formula (3-3) is prepared by the following reaction, and the solvent used in the reaction is selected from any one of acetonitrile, dichloromethane, water, tetrahydrofuran, toluene, ether and ethyl acetate or a mixture of any of them in any proportion.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-3) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-2) and a brominating reagent are present in the presence of a catalyst The compound of formula (3-3) is prepared by the following reaction, and the catalyst is selected from phosphine compounds, preferably triphenylphosphine or tributylphosphine and the like.

Some specific embodiments of the present invention, a preparation method of the compound of formula (3-3) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of formula (3-2) and a brominating reagent are present in the presence of a catalyst The compound of formula (3-3) is prepared by the lower reaction, and the bromination reagent is selected from carbon tetrabromide, hydrobromic acid, sodium bromide/sulfuric acid, cyanogen bromide, liquid bromine, phosphorus tribromide, 1-butane 3-methylimidazolium bromide or dibromohydantoin.

The present invention relates to a preparation method of the compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which comprises preparing the compound of formula (3-1) to obtain the compound of formula (3-2)

The present invention relates to a preparation method of a compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare formula (3-2) ) compound.

The present invention relates to a preparation method of a compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare formula (3-2) ) compound. The base used in the reaction is selected from sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine or 4- N , N -lutidine (DMAP).

The present invention relates to a preparation method of a compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare formula (3-2) ) compound, and the solvent used in the reaction is selected from any one or a mixture of any of several in any ratio among tetrahydrofuran, acetone, ether, N-methylpyrrolidone, N,N-dimethylformamide and toluene.

The present invention relates to a preparation method of a compound of formula (3-2) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare formula (3-2) ) compound The catalyst used in the reaction is selected from tetrabutylammonium iodide, sodium iodide, potassium iodide, sodium bromide, potassium bromide or tetrabutylammonium bromide.

，P選自羥基保護基，較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基或苄基；a：以式(3-1)化合物為原料，與羥基保護劑反應製備得到式(3-2)化合物；b：以式(3-2)化合物為原料，與溴化試劑反應製備得到式(3-3)化合物；c：以式(3-3)化合物為原料，與金屬鎂反應製備得到式(3-4)化合物；d：以式(3-4)化合物為原料，與式(3-5)化合物製備得到式(3-6)化合物； e：以式(3-6)化合物為原料，與脫保護反應製備得到式(3-7)化合物；f：以式(3-7)化合物為原料，與氧化劑反應製備得到式(3-8)化合物；g：以式(3-8)化合物為原料，與氧化劑反應製備得到式(3-9)化合物；h：以式(3-9)化合物為原料，與吡咯烷在縮合劑存在下，在鹼性條件下反應製備得到式(3-10)化合物；i以式(3-10)化合物為原料，在鹼性條件下與三氟甲磺酸酐反應製備得到式(I)化合物。 The present invention relates to a preparation method of the compound of formula (I) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

, P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl; a: take the compound of formula (3-1) as a raw material, react with a hydroxyl protecting agent to prepare a compound of formula (3-2); b: take the compound of formula (3-2) as a raw material, react with a bromination reagent to prepare a compound of formula ( 3-3) compound; c: using the compound of formula (3-3) as a raw material, and reacting with metal magnesium to prepare the compound of formula (3-4); d: using the compound of formula (3-4) as a raw material, and the compound of formula (3) -5) The compound of the formula (3-6) is obtained by preparing the compound; e: the compound of the formula (3-6) is used as the raw material, and the compound of the formula (3-7) is prepared by the deprotection reaction; f: the compound of the formula (3-7) is obtained The compound is used as a raw material, and the compound of formula (3-8) is prepared by reacting with an oxidizing agent; g: the compound of formula (3-8) is prepared by reacting with an oxidizing agent as a raw material; h: the compound of formula (3-9) is prepared by reacting with the oxidizing agent; 9) The compound is a raw material, reacts with pyrrolidine in the presence of a condensing agent under basic conditions to prepare the compound of formula (3-10); i takes the compound of formula (3-10) as a raw material, reacts with three The compound of formula (I) can be obtained by the reaction of fluoromethanesulfonic anhydride.

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein a: the hydroxyl protecting agent used in the reaction is selected from p-methoxybenzyl Chlorine, the base is selected from sodium hydride, the solvent is selected from tetrahydrofuran, the catalyst is selected from tetrabutylammonium iodide; b: the brominating reagent used in the reaction is selected from carbon tetrabromide, the solvent is selected from acetonitrile, and the catalyst is selected from triphenylphosphine c: the catalyst used in the reaction is selected from iodine, and the solvent used is selected from tetrahydrofuran; d: the catalyst used in the reaction is selected from dilithium tetrachlorocuprate, and the solvent is selected from tetrahydrofuran; e: the catalyst used in the reaction is selected from 2,3 -Dichloro-5,6-dicyano-p-benzoquinone (DDQ), the solvent is selected from dichloromethane, the buffer solvent is selected from potassium phosphate buffer solution with pH=7; f: the oxidant used in the reaction is selected from o-iodobenzoic acid (IBX), the solvent is selected from ethyl acetate; g: the oxidation system used in the reaction is selected from 2-methyl-2-butene/NaClO ₂ /NaH ₂ PO.2H ₂ O, and the solvent is selected from water and tert-butanol Any one or any mixture in any ratio; h: the condensation reagent used in the reaction is selected from O-(7-azabenzotriazole-1-yl)-bis(dimethylamino)carbonium hexa Fluorophosphate (HATU), the base is selected from triethylamine, and the solvent is selected from dichloromethane; i: the acid anhydride used in the reaction is trifluoromethanesulfonic anhydride, and the base is 2,4,6-trimethylpyridine, and further in the base The reaction was carried out under neutral conditions, and the base was potassium carbonate.

Some specific embodiments of the present invention, a preparation method of the compound of formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof, wherein a: using the compound of formula (3-1) as a raw material, and protecting it with a hydroxyl group The compound of formula (3-2) is prepared by reacting with an agent; the base used in the reaction is selected from sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine or 4- N , N -lutidine (DMAP); the solvent used in the further reaction is selected from any one or several of tetrahydrofuran, acetone, diethyl ether, N-methylpyrrolidone, N,N-dimethylformamide and toluene A mixture in any proportion; the catalyst used in the further reaction is selected from tetrabutylammonium iodide, sodium iodide, potassium iodide, sodium bromide, potassium bromide or tetrabutylammonium bromide; b: with formula (3-2 ) compound is a raw material, and reacts with a brominating reagent to prepare a compound of formula (3-3); the further described brominating reagent is selected from carbon tetrabromide, hydrobromic acid, sodium bromide/sulfuric acid, cyanogen bromide, liquid bromine , phosphorus tribromide, 1-butyl-3-methylimidazolium bromide or dibromohydantoin; further the catalyst is selected from phosphine compounds, preferably triphenylphosphine or tributylphosphine, etc.; The solvent used for further reaction is selected from any one or any mixture of any ratio in acetonitrile, dichloromethane, water, tetrahydrofuran, toluene, ether and ethyl acetate; c: take the compound of formula (3-3) as a raw material , and react with metal magnesium to prepare the compound of formula (3-4); further the catalyst is selected from iodine, 1,2-dichloroethane or isopropyl magnesium bromide; the solvent used in the further reaction is selected from ether solvents , preferably any one of tetrahydrofuran or diethyl ether or a mixture of several arbitrary proportions; d: using the compound of formula (3-4) as a raw material, and the compound of formula (3-5) to prepare the compound of formula (3-6) Further, the catalyst is selected from metal reagents, preferably dilithium tetrachlorocuprate, cuprous iodide, cerium trichloride, lithium chloride or zinc dichloride; the solvent used in the further reaction is selected from tetrahydrofuran, Any one of toluene, dioxane, diethyl ether, chlorobenzene and dimethyl sulfite or a mixture of any of several arbitrary proportions; e: take the compound of formula (3-6) as a raw material, and prepare the formula with deprotection reaction (3-7) Compound; the catalyst used in the further reaction is selected from 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), cerium ammonium nitrate, cerium trifluoromethanesulfonate, Pd/C/H _2. Zirconium tetrachloride; the buffer solvent used in the further reaction is selected from the buffer solution of pH=7, preferably the potassium phosphate buffer solution of pH=7 or the sodium phosphate buffer solution of pH=7; the solvent used in the further reaction be selected from any one or any mixture of any ratio in dichloromethane, acetonitrile, chlorobenzene, toluene, ethylene glycol diethyl ether and nitromethane; f: take the compound of formula (3-7) as a raw material, and an oxidant The compound of formula (3-8) is prepared by the reaction; further the oxidant is selected from o-iodobenzoic acid (IBX), pyridinium chlorochromate (PCC), sulfur trioxide pyridine, Dess-Martin oxidant, Jones reagent, Dimethyl sulfite / oxalate Chlorine, TPAP([n-Pr ₄ N][RuO ₄ ])/N-methylmorpholine; the solvent used in the further reaction is selected from any of ethyl acetate, dichloromethane, acetone and dimethylsulfoxide. One or several mixtures in arbitrary proportions; g: take the compound of formula (3-8) as a raw material, and react with an oxidant to prepare a compound of formula (3-9); further, the oxidant is selected from NaClO ₂ , pyridinium dichromate Salt (PDC), potassium permanganate, sodium periodate/ruthenium trichloride, hydrogen peroxide/formic acid or iodobenzene diacetate/2,2,6,6-tetramethylpyridine oxide, preferably 2- Methyl-2-butene/NaClO ₂ /NaH ₂ PO ₄ ; the solvent used in the further reaction is selected from any one or several of water, tert-butanol, dichloromethane, acetone, dioxane and toluene a mixture of any proportion.

h: The compound of formula (3-9) is used as a raw material, and the compound of formula (3-10) is prepared by reacting with pyrrolidine in the presence of a condensing agent under basic conditions; further the condensing agent is selected from 1-(3 - Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), Carbonyldiimidazole (CDI), Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC) , Methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), p-nitrobenzenesulfonyl chloride (NsCl), O-(7-azabenzotriazol-1-yl)-bis(bis) Methylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU), O-(5- Chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino) Carbonium tetrafluoroborate (TBTU), O-(N-butadiamido)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-nor Camphene-2,3-dicarbodiimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), phenylphosphonium chloride (DPP-Cl), diethyl cyanophosphate ( DECP), diphenylphosphoryl azide (DPPA, thiodimethylphosphoryl azide (MPTA), or bis(2-oxo-3-oxazolidinyl)phosphonium chloride (BOP-Cl); furthermore The base used in the reaction is selected from organic bases or inorganic bases, preferably triethylamine, N,N-diisopropylethylamine, 4- N , N -lutidine (DMAP), 1-hydroxybenzotrimine Azole (HOBt), sodium carbonate, potassium carbonate; the solvent used for further reaction is selected from dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylformamide Any one of acetamide, dimethyl sulfoxide and N-methylpyrrolidone or a mixture of any of several arbitrary proportions; i: wherein the compound of formula (3-10) reacts with acid anhydride or acyl chloride in the presence of an organic base to obtain The intermediate imide salt is then reacted under alkaline conditions to prepare the compound of formula (I); the acid anhydride is further selected from trifluoromethanesulfonic anhydride or trifluoroacetic anhydride; Acrylic chloride, triphosgene or sulfite chloride; the organic base is selected from Collidine, 2,4,6-collidine, 2-fluoropyridine, 2,6-di-tert-butyl-4-methylpyridine , 2,6-di-tert-butylpyridine, hexamethylphosphoric triamine, triethylamine, N,N-diisopropylethylamine or DBU (1,8-diazabicyclo[5.4.0 ]undec-7-ene); the base is selected from inorganic bases, preferably metal bases, further preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, hydroxide Sodium, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.

、

、

或

；P選自羥基保護基，較佳為對甲氧基苄基、甲基、甲氧基甲基、第三丁基二甲基矽基、第三丁基二苯基矽基；條件是P不為苄基或三氟乙基。 The present invention relates to an intermediate for preparing the compound of formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of

,

,

or

; P is selected from hydroxyl protecting groups, preferably p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl; Condition is P Not benzyl or trifluoroethyl.

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

When the compound of the general formula involved in the present invention has a chiral center, the compound of the general formula may be a racemate or an optical isomer unless clearly indicated.

When the present invention relates to substitution with multiple substituents, each substituent may be the same or different.

When the present invention involves the inclusion of multiple heteroatoms, the heteroatoms may be the same or different.

The elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopic conditions, and the elements carbon, hydrogen, oxygen involved in the groups and compounds of the present invention , sulfur or nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, and hydrogen isotopes include protium (H), deuterium (D, also known as deuterium ), tritium (T, also known as super heavy hydrogen), the isotopes of oxygen include ¹⁶ O, ¹⁷ O and ¹⁸ O, the isotopes of sulfur include ³² S, ³³ S, ³⁴ S and ³⁶ S, and the isotopes of nitrogen include ¹⁴ N and ¹⁵ N , the isotope of fluorine is ¹⁹ F, the isotope of chlorine includes ³⁵ Cl and ³⁷ Cl, and the isotope of bromine includes ⁷⁹ Br and ⁸¹ Br.

The hydroxyl protecting group is selected from alkyl ether protecting groups, ester protecting groups or silyl ether protecting groups, and hydroxyl protecting groups include but are not limited to methyl, benzyl, p-methoxybenzyl, trityl, third Butyl, methoxymethyl ether, methoxyethoxymethyl, tetrahydrofuranyl, tert-butylcarbonyl, benzyl, acetyl, chloromethylcarbonyl, tert-butoxycarbonyl, benzyloxy Carbonyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, di-tert-butylhydroxysilyl, p-nitrobenzyl group, allyl, benzyloxycarbonyl, tertiary butoxycarbonyl, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl, preferably methyl, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl.

Alkyl ether protecting groups can be removed under basic or acidic conditions, the bases or acids include but are not limited to sodium hydride, sodium methoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, pyridine, trifluoroacetic acid, hydrochloric acid , formic acid or acetic acid; ester protecting groups can be removed under alkaline conditions, the bases include but are not limited to sodium methoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, pyridine or ammonia; silyl ethers The protecting group can be removed under conditions such as hydrogen fluoride, tetrabutylammonium fluoride and the like.

Hydroxyl protecting agents are generally halides, halogens or halides of hydroxyl protecting groups; including but not limited to p-methoxybenzyl chloride, methyl iodide, chloromethyl methyl ether, tert-butyldimethylsilicon chloride, Tributyldiphenylsilicon chloride, benzyl bromide.

PMB: p-methoxybenzyl.

The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present case.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are expressed in units of 10 ⁻⁶ (ppm). NMR was measured using (BrukerAvance III 400 and BrukerAvance 300) nuclear magnetic instruments, and the solvents were deuterated dimethylsulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), Deuterated acetonitrile (CD ₃ CN), the internal standard is tetramethylsilane (TMS).

For MS measurement, Agilent 6120B (ESI) and Agilent 6120B (APCI) were used.

For the HPLC measurement, an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm) was used.

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm, and the specification used for TLC separation and purification products is 0.4 mm~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.

The ratio shown in the silica gel column chromatography of the present invention is the volume ratio.

Example 1

first step

4-[(4-methoxyphenyl)methoxy]butan-1-ol

4-[(4-Methoxyphenyl)methoxy]butyl-1-ol (Compound 3-2 )

At 0 °C, 1,4-butanediol 3-1 (100 mL, 1.1 mol) was added dropwise to a suspension of sodium hydride (142.3 g, 1.1 mol) in tetrahydrofuran (1 L), the addition was completed, and stirred for 10 min, Then, tetrabutylammonium iodide (46 g, 114 mmol) and p-methoxybenzyl chloride (155 mL, 1.14 mol) were added to the reaction system, kept at 0° C. for 30 min, and the temperature was raised to room temperature for 17 h to stop the reaction. Saturated sodium bicarbonate solution (300 mL) was added to the reaction solution to quench the reaction, the organic phase was extracted with ethyl acetate (350 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and separated by column chromatography (Petroleum ether/ethyl acetate=1:1) to obtain compound 3-2 (186 g, 69.3%), which is a colorless liquid.

¹ H NMR (400MHz, Chloroform- d )δ 7.25(d, J =8.7Hz, 2H), 6.92-6.83(m, 2H), 4.45(d, J =1.2Hz, 2H), 3.80d, J =1.3 Hz,3H),3.63(ddd, J =7.8,4.4,1.6Hz,2H),3.49(td, J =5.8,1.3Hz,2H),2.04(d, J =0.9Hz,1H),1.26(td , J =7.1,0.9Hz,1H).

second step

1-(4-bromobutoxymethyl)-4-methoxy-benzene

1-(4-Bromobutoxymethyl)-4-methoxy-benzene (compound 3-3 )

4-[(4-Methoxyphenyl)methoxy]butyl-1-ol 3-2 (186 g, 762 mmol) was dissolved in a mixed solvent of acetonitrile (700 mL) and dichloromethane (300 mL), and cooled To 0°C, triphenylphosphine (301.9 g, 1.2 mol) was added to the reaction solution, followed by addition of carbon tetrabromide (381.6 g, 1.2 mol) to the reaction system in portions. After the reaction, the insolubles were removed by filtration, the reaction solvent was removed under reduced pressure, and column chromatography (petroleum ether/ethyl acetate=50:1~5:1) was performed to isolate compound 3-3 (240 g, 99.6%).

¹ H NMR (400MHz, Chloroform- d )δ 7.24(d, J =8.6Hz, 2H), 6.87(d, J =8.6Hz, 2H), 4.42(s, 2H), 3.79(s, 3H), 3.44 (dt, J =20.8,6.5Hz,4H),2.02-1.89(m,2H),1.80-1.67(m,2H).

third step

bromo-[4-[(4-methoxyphenyl)methoxy]butyl]magnesium

Bromo-[4-[(4-methoxyphenyl)methoxy]butyl]magnesium salt (compound 3-4 )

The activated magnesium chips (1.05g, 43.8mmol) were placed in a 10mL three-necked flask, a magnetic stirrer and a grain of iodine were added, nitrogen was replaced three times, 6mL of anhydrous tetrahydrofuran was injected, and 4-[(4-methoxybenzene was added dropwise. yl)methoxy]butyl-1-ol (compound 3-3 ) (1 g, 3.7 mmol), under stirring, slowly heated until the initiation of Grignard reagent is completed (it can be clearly observed that the color of the reaction solution changes from brown to was colorless), then slowly added dropwise 25 mL of 1-(4-bromobutoxymethyl)-4-methoxy-benzene (compound 3-3 ) (9 g, 33 mmol) tetrahydrofuran solution, the dropwise addition process made the reaction in In a slightly boiling state, the addition was completed in about 30 minutes, and the reflux reaction was continued for 1 hour after the addition. After cooling to room temperature, a total of 20 mL of Grignard reagent was withdrawn from the supernatant with a syringe.

Step 4 (Method A)

1-(4-(cyclopent-3-en-1-yl)butoxymethyl)-4-methoxy-benzene

1-(4-(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 )

(Compound 3-5 ) (0.45 g, 1.90 mmol) was placed in a 50 mL three-necked flask, nitrogen was replaced three times, 10 mL of anhydrous tetrahydrofuran was added, dry ice ethanol was cooled to -78 ° C, and dilithium tetrachlorocuprate (2.0 mL, 0.1M), continue to stir for 0.5h after the addition, and then slowly dropwise add Grignard reagent 3-4 (2.7mL, 5mmol), (the experimental phenomenon changes from dark brown to light blue) and continue to react at -78°C for 1h, The reaction was heated to -20 °C for 3 hours, then overnight at room temperature. The next day, 5 mL of saturated ammonium chloride solution was added to quench the reaction, 15 mL of methyl tert-butyl ether was added, and the organic phase was extracted and separated, and then 30 mL of methyl tertiary butyl ether was added. The aqueous phase was back-extracted twice with ether, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain 600 mg of crude product, which was prepared and separated by high performance liquid phase to obtain 1-(4 -(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 ) (150 mg, 30%).

¹ H NMR (400MHz, CDCl ₃ )δ 7.26(d, J =8.6Hz, 2H), 6.87(d, J =8.6Hz, 2H), 5.65(s, 2H), 4.43(s, 2H), 3.80( s, 3H), 3.44(t, J =6.6Hz, 2H), 2.53-2.38(m, 2H), 2.21(dd, J =10.9, 4.1Hz, 1H), 1.94(dd, J =13.7, 6.6Hz ,2H),1.74-1.51(m,2H),1.47-1.27(m,4H).

Step 4 (Method B)

1-(4-(cyclopent-3-en-1-yl)butoxymethyl)-4-methoxy-benzene

1-(4-(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 )

(Compound 3-5 ) (7.1 g, 30.0 mmol) was placed in a 500 mL three-necked flask, nitrogen was replaced three times, 150 mL of anhydrous tetrahydrofuran was added, dry ice ethanol was cooled to -78 ° C, and dilithium tetrachlorocuprate (31.6 mL, 0.1M), continue to stir for 0.5h after the addition, and then slowly dropwise add Grignard reagent 3-4 (19.4mL, 36mmol), (the experimental phenomenon changed from dark brown to light blue) and continue to react at -78°C for 1h, The reaction was heated to -20°C for 3 hours, then overnight at room temperature. The next day, 50 mL of saturated ammonium chloride solution was added to quench the reaction, 150 mL of methyl tert-butyl ether was added, and the organic phase was extracted and separated, and then 300 mL of methyl tert-butyl ether was added. The aqueous phase was back-extracted with ether in two times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography to obtain a crude product of 5.8 g, which was prepared and separated by high performance liquid phase to obtain 1-( 4-(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 ) (1.5 g, 19%).

¹ H NMR (400MHz, CDCl ₃ )δ 7.26(d, J =8.6Hz, 2H), 6.87(d, J =8.6Hz, 2H), 5.65(s, 2H), 4.43(s, 2H), 3.80( s, 3H), 3.44(t, J =6.6Hz, 2H), 2.53-2.38(m, 2H), 2.21(dd, J =10.9, 4.1Hz, 1H), 1.94(dd, J =13.7, 6.6Hz ,2H),1.741.51(m,2H),1.47-1.27(m,4H).

the fifth step

4-(cyclopent-3-en-1-yl)butan-1-ol

4-(Cyclopentyl-3-en-1-yl)butyl-1-ol (Compound 3-7 )

1-(4-(Cyclopentyl-3-en-1-yl)butoxymethyl)-4-methoxy-benzene (compound 3-6 ) (135 mg, 0.52 mmol) was placed in a 25 mL round bottom In the flask, add 4.5 mL of dichloromethane and potassium phosphate buffer solution (0.5 mL) of pH=7, add DDQ (147 mg, 0.65 mmol), and react at room temperature for 1 h. TLC detected, the reaction was complete, 5 mL of saturated sodium bicarbonate solution and saturated sodium thiosulfate solution (volume ratio of 1:1) were added to quench the reaction, the organic phase was separated, and the aqueous phase was reversed with 30 mL of dichloromethane three times. Extract, combine the organic phases, and dry over anhydrous sodium sulfate. Filtration, concentrated under reduced pressure at room temperature, the crude product was separated and purified by column chromatography, and the eluent was PE/EA=4/1 to obtain the target product 4-(cyclopentyl-3-en-1-yl)butyl- 1-ol (compound 3-7 ) was a colorless liquid (70 mg, 96%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.66 (s, 2H), 3.65 (t, J = 6.6 Hz, 2H), 2.57-2.38 (m, 2H), 2.28-2.14 (m, 1H), 1.96 (dd , J =13.6,6.6Hz,2H),1.63-1.53(m,2H),1.50(s,1H),1.46-1.33(m,4H).

Step 6

4-(cyclopent-3-en-1-yl)butanal

4-(Cyclopentyl-3-en-1-yl)butanal (Compound 3-8 )

4-(Cyclopentyl-3-en-1-yl)butyl-1-ol (compound 3-7 ) (25 mg, 0.18 mmol) was placed in a 25 mL round bottom flask, 6 mL of ethyl acetate was added, and IBX was added (76 mg, 0.27 mmol), and the reaction was refluxed for 4 hours with stirring. TLC detected that most of the raw materials disappeared, and the product was light yellow with nitrophenylhydrazine, cooled to room temperature, filtered off with a sand core funnel, and the filter residue was washed with 5 mL of ethyl acetate. Most of the solvent was removed under pressure, and the crude product 4-(cyclopentyl-3-en-1-yl)butanal (compound 3-8 ) was directly used in the next reaction.

Step 7

4-(cyclopent-3-en-1-yl)butanoic acid

4-(Cyclopentyl-3-en-1-yl)butanoic acid (compound 3-9 )

The crude product 4-(cyclopentyl-3-en-1-yl)butanal (compound 3-8 ) (25 mg, 0.18 mmol) was placed in a 25 mL round bottom flask, and 5 mL of a mixed solvent of tertiary butanol and water was added (3/1 by volume), lowered to 0°C, added 2-methyl-2-butene (0.4 mL, 3.8 mmol), NaClO ₂ (48 mg, 0.54 mmol) and NaH ₂ PO ₄ . 2H ₂ O (140 mg, 0.9 mmol), and continued to stir for 1 hour, TLC detected that the reaction of the raw materials was complete, 5 mL of saturated sodium thiosulfate solution was added to quench the reaction, 20 mL of ethyl acetate was added, and the organic phase was extracted and separated. The aqueous phase was back-extracted with methyl chloride twice, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at room temperature. The crude product was separated and purified by column chromatography, and the eluent was PE/EA (4/1- 2/1), isolated to obtain 4-(cyclopentyl-3-en-1-yl)butanoic acid (compound 3-9 ) (18mg, 65%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.66 (s, 2H), 2.48 (dd, J = 14.1, 8.7 Hz, 2H), 2.40-2.31 (m, 2H), 2.30-2.18 (m, 1H), 1.97 (dd, J =13.7,6.4Hz,2H),1.66(dt, J =12.2,7.5Hz,2H),1.51-1.39(m,2H).

Step 8

4-(cyclopent-3-en-1-yl)-1-(pyrrolidin-1-yl)butan-1-one

4-(Cyclopentyl-3-en-1-yl)-1-(pyrrol-1-yl)butyl-1-one (Compound 3-10 )

After (compound 3-9 ) (0.50 g, 3.20 mol) was dissolved in dichloromethane (25 mL), triethylamine (0.82 g, 8.10 mol) and HATU (1.80 g, 4.90 mol) were sequentially added at 0°C. Pyrrolidine (0.35 g, 4.90 mol) was slowly added dropwise, the addition was completed, and the temperature was raised to room temperature to react for 10 hours. The reaction was complete as monitored by TLC, and water (200 mL x 2) was added to wash. The organic layer was separated, washed successively with NH ₄ Cl solution (200 mL×2), and then with saturated brine (200 mL×2); dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the intermediate was obtained after column chromatography (Compound 3-10 ) (0.40 g, 60%).

Step 9

(±)-(1R,3S,6R,8R)-tricyclo[4.2.1.03,8]nonan-2-one

(±)-(1R,3S,6R,8R)-tricyclo[4.2.1.03,8]nonan-2-one (Compound I )

After compound 3-10 (0.30 g, 1.4 mol) was dissolved in dichloromethane (10 mL), 2,4,6-collidine (0.19 g, 1.70 mol) was added. At 0°C, trifluoromethanesulfonic anhydride (0.61 g, 2.2 mol) was dissolved in 2 mL of dichloromethane, and slowly added dropwise to the reaction solution. After the addition was completed, the temperature was raised to 50°C and the reaction was refluxed for 5 hours. The reaction was monitored by LCMS and concentrated under reduced pressure to obtain the intermediate imide salt.

The intermediate imide salt was dissolved in a mixed solvent of water and acetone (8 mL, v/v=1:1), potassium carbonate (0.97 g, 7 mol) was added to the system, the temperature was raised to reflux for 3 hours, and the reaction was monitored by TLC (DCM /MeOH=15:1) until the reaction is complete, add 1M HCl to adjust the pH to about 2-3, extract the reaction solution with methyl tert-butyl ether (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and reduce the pressure. The solvent was removed by concentration, and the crude product was subjected to flash column chromatography (PE/EA=20:1) to obtain a white solid product (compound I ) (0.12 g, 60% volatile).

¹ H NMR (400MHz, CDCl ₃ )δ 3.51-3.28(m,1H), 3.27-3.05(m,1H), 2.89-2.66(m,1H), 2.47-2.25(m,1H), 2.12-1.97( m, 1H), 1.93 (d, J = 12.2Hz, 1H), 1.85-1.61 (m, 1H), 1.62-1.32 (m, 4H), 1.21 (m, 1H).

Claims (31)

A preparation method of a fused tricyclic derivative represented by formula (I) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is prepared from a compound of formula (3-10);

The compound of formula (3-10) reacts with acid anhydride or acyl chloride under the condition of alkali, and the acid anhydride is selected from trifluoromethanesulfonic anhydride or trifluoroacetic anhydride; the acyl chloride is selected from phosphorus oxychloride, oxalic acid Chlorine, triphosgene or thionous chloride; the base is selected from organic bases. The preparation method according to claim 1, wherein the base is Collidine, 2,4,6-trimethylpyridine, 2-fluoropyridine, 2,6-di-tert-butyl-4-methylpyridine , 2,6-di-tert-butylpyridine, hexamethylphosphoric triamine, triethylamine, N,N-diisopropylethylamine or DBU. The preparation method according to claim 1, wherein the reaction is further performed under alkaline conditions, and the base is selected from inorganic bases. According to the preparation method of claim 3, the base is a metal base. According to the preparation method described in claim 3, the alkali is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate. The preparation method according to claim 1, further comprising preparing the compound of formula (3-10) by preparing the compound of formula (3-9),

The compound of formula (3-9), pyrrolidine and condensing agent are reacted under basic conditions to prepare the compound of formula (3-10). The preparation method according to claim 6, wherein the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide Imine, diisopropylcarbodiimide, methanesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, O-(7-azabenzotriazol-1-yl)-di (Dimethylamino)carbonium hexafluorophosphate, O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate, O-(5-chlorobenzotriazole) Azol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate, O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate, O-(N-Butanediimido)-bis(dimethylamino)carbonium tetrafluoroborate, O-(N-endo-5-norbornene-2,3-dicarbodiimide )-bis(dimethylamino)carbonium tetrafluoroborate, phenylphosphonium chloride, diethyl cyanophosphate, diphenylphosphoric azide, thiodimethylphosphonium azide or bis( 2-oxo-3-oxazolidinyl) phosphonium chloride; the base used in the reaction is selected from organic bases or inorganic bases; the solvent used in the reaction is selected from dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, N,N-dimethylformaldehyde Any one or a mixture of any of several in any ratio of carboxymethyl amide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone. The preparation method according to claim 7, wherein the base used in the reaction is triethylamine, N,N-diisopropylethylamine, 4- N , N -lutidine, 1-hydroxybenzotriazepine azole, sodium carbonate or potassium carbonate. The preparation method according to claim 6, further comprising preparing the compound of formula (3-9) by preparing the compound of formula (3-8)

The compound of formula (3-8) is prepared by reacting the compound of formula (3-8) with an oxidant under acidic conditions to obtain the compound of formula (3-9). The preparation method according to claim 9, wherein the oxidant is selected from NaClO ₂ , pyridinium dichromate, potassium permanganate, sodium periodate/ruthenium trichloride, hydrogen peroxide/formic acid or iodobenzene diacetate /2,2,6,6-tetramethylpyridine oxide; the solvent used in the reaction is selected from any one or several of water, tert-butanol, dichloromethane, acetone, dioxane and toluene Mixtures in any ratio. The preparation method according to claim 9, wherein the oxidant is selected from 2-methyl-2-butene/NaClO ₂ /NaH ₂ PO ₄ ; the solvent used in the reaction is selected from water, tert-butanol, dichloride Any one of methane, acetone, dioxane and toluene or a mixture of any of them in any proportion. The preparation method according to claim 9, further comprising preparing the compound of formula (3-8) by preparing the compound of formula (3-7),

The compound of formula (3-7) is prepared by reacting the compound of formula (3-7) with an oxidizing agent to obtain the compound of formula (3-8). The preparation method according to claim 12, wherein the oxidizing agent is selected from the group consisting of o-iodobenzoic acid, pyridinium chlorochromate, sulfur trioxide pyridine, Dess-Martin oxidant, Jones reagent, dimethylsulfite/grass Acyl chloride or TPAP/N-methylmorpholine; the solvent used in the reaction is selected from any one of ethyl acetate, dichloromethane, acetone and dimethylsulfoxide or a mixture of any of them in any proportion. The preparation method according to claim 12, further comprising preparing the compound of formula (3-7) by preparing the compound of formula (3-6)

P is selected from hydroxyl protecting groups, and the catalyst used in the reaction is selected from 2,3-dichloro-5,6-dicyano-p-benzoquinone, cerium ammonium nitrate, cerium trifluoromethanesulfonate, Pd/C/H ₂ or tetrachloride zirconium. The preparation method according to claim 14, wherein P is p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl. The preparation method according to claim 15, wherein the buffer solvent used in the reaction is selected from a buffer solution of pH=7; the solvent used in the reaction is selected from dichloromethane, acetonitrile, chlorobenzene, toluene, ethylene glycol diethyl ether and nitrous Any one or any mixture of any of the base methanes in any proportion. The preparation method according to claim 16, wherein the buffer solvent used in the reaction is a potassium phosphate buffer solution with pH=7 or a sodium phosphate buffer solution with pH=7. The preparation method according to claim 14, further comprising preparing the compound of formula (3-6) by preparing the compound of formula (3-4)

The compound of formula (3-4) is reacted with the compound of formula (3-5) in the presence of a catalyst to prepare the compound of formula (3-6); the catalyst is selected from metal reagents; the solvent used in the reaction is selected from tetrahydrofuran, toluene, dioxygen Any one of hexacyclic ring, diethyl ether, chlorobenzene and dimethyl sulfoxide or a mixture of any of them in any proportion. A preparation method of a compound represented by formula (3-6) and a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is prepared from a compound of formula (3-4),

P is selected from hydroxyl protecting groups; the compound of formula (3-4) is reacted with the compound of formula (3-5) in the presence of a catalyst to prepare the compound of formula (3-6); the catalyst is selected from metal reagents; the solvent used in the reaction is selected from From tetrahydrofuran, any one of toluene, dioxane, diethyl ether, chlorobenzene and dimethyl sulfite or a mixture of any of them in any proportion. The preparation method according to claim 19, wherein P is p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or benzyl. The preparation method according to claim 18 or 19, wherein the catalyst is dilithium tetrachlorocuprate, cuprous iodide, cerium trichloride, lithium chloride or zinc dichloride. The preparation method according to any one of claims 18-20, further comprising preparing the compound of formula (3-4) by preparing the compound of formula (3-3)

The compound of formula (3-3) is reacted with metal magnesium in the presence of a catalyst to prepare the compound of formula (3-4); the catalyst is selected from iodine, 1,2-dichloroethane or isopropylmagnesium bromide; the reaction uses The solvent is selected from ether solvents. The preparation method according to claim 22, wherein the solvent used in the reaction is any one of tetrahydrofuran and diethyl ether or a mixture of any of several in any proportion. The preparation method according to claim 22, further comprising preparing the compound of formula (3-2) to obtain the compound of formula (3-3)

The compound of formula (3-2) is reacted with a brominating reagent in the presence of a catalyst to prepare the compound of formula (3-3); the solvent used in the reaction is selected from acetonitrile, dichloromethane, water, tetrahydrofuran, toluene, ether and ethyl acetate The mixture of any one or any of several arbitrary proportions; Described catalyst is selected from phosphine compounds; Described bromination reagent is selected from carbon tetrabromide, hydrobromic acid, sodium bromide/sulfuric acid, cyanogen bromide, liquid Bromine, phosphorus tribromide, 1-butyl-3-methylimidazolium bromide or dibromohydantoin. The preparation method according to claim 24, wherein the catalyst is triphenylphosphine or tributylphosphine. The preparation method according to claim 24, further comprising preparing the compound of formula (3-1) to obtain the compound of formula (3-2)

The compound of formula (3-1) is reacted with a hydroxyl protecting agent to prepare a compound of formula (3-2); the hydroxyl protecting agent is selected from p-methoxybenzyl chloride, methyl iodide, chloromethyl methyl ether, tert-butyl Dimethylsilicon chloride, tert-butyldiphenylsilicon chloride or benzyl bromide; the base used in the reaction is selected from sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N,N- Diisopropylethylamine or 4- N , N -lutidine; the solvent used in the reaction is selected from tetrahydrofuran, acetone, diethyl ether, N-methylpyrrolidone, N,N-dimethylformamide and toluene Any one or several mixtures in any proportion; the catalyst used in the reaction is selected from tetrabutylammonium iodide, sodium iodide, potassium iodide, sodium bromide, potassium bromide or tetrabutylammonium bromide. A kind of preparation method of compound shown in formula (I) and its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that

P is selected from a hydroxyl protecting group; a: take the compound of formula (3-1) as a raw material, react with a hydroxyl protecting agent to prepare the compound of formula (3-2); b: take the compound of formula (3-2) as a raw material, react with bromine The compound of formula (3-3) is prepared by reacting a chemical reagent; c: the compound of formula (3-3) is used as a raw material, and the compound of formula (3-4) is prepared by reacting with metal magnesium; d: the compound of formula (3-4) is prepared by As a raw material, the compound of formula (3-5) is prepared with the compound of formula (3-5) to obtain the compound of formula (3-6); e: the compound of formula (3-6) is used as a raw material, and the compound of formula (3-7) is prepared by deprotection reaction; f: Using the compound of formula (3-7) as a raw material, react with an oxidant to prepare a compound of formula (3-8); g: use the compound of formula (3-8) as a raw material, react with an oxidant to prepare a compound of formula (3-9); h: The compound of formula (3-9) is used as the raw material, and the compound of formula (3-10) is prepared by reacting with pyrrolidine in the presence of a condensing agent under basic conditions; i: The compound of formula (3-10) is used as the raw material , and react with trifluoromethanesulfonic anhydride under basic conditions to prepare the compound of formula (3-3). The preparation method according to claim 27, wherein P is p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyl. The preparation method according to claim 27, wherein a: the hydroxyl protecting agent used in the reaction is selected from p-methoxybenzyl chloride, the base is selected from sodium hydride, the solvent is selected from tetrahydrofuran, and the catalyst is selected from tetrabutylammonium iodide; b : the brominating reagent used in the reaction is selected from carbon tetrabromide, the solvent is selected from acetonitrile, and the catalyst is selected from triphenylphosphine; c: the catalyst used in the reaction is selected from iodine, and the solvent used is selected from tetrahydrofuran; d: the catalyst used in the reaction is selected from is selected from dilithium tetrachlorocuprate, and the solvent is selected from tetrahydrofuran; e: the catalyst used in the reaction is selected from 2,3-dichloro-5,6-dicyano-p-benzoquinone, the solvent is selected from dichloromethane, and the buffer solvent is selected from From potassium phosphate buffer solution with pH=7; f: the oxidant used in the reaction is selected from o-iodobenzoic acid, and the solvent is selected from ethyl acetate; g: the oxidation system used in the reaction is selected from 2-methyl-2-butene/ NaClO ₂ /NaH ₂ PO. 2H ₂ O, the solvent is selected from any one of water and the third butanol or the mixture of any of them in any ratio; h: the condensation reagent used in the reaction is selected from O-(7-azabenzotriazole-1- base)-bis(dimethylamino)carbonium hexafluorophosphate, the base is selected from triethylamine, and the solvent is selected from dichloromethane; i: the acid anhydride used in the reaction is trifluoromethanesulfonic anhydride, and the base is selected from 2,4 , 6-trimethylpyridine, and further react under basic conditions, and the base is selected from potassium carbonate. A kind of intermediate for preparing compound shown in formula (I) and its stereoisomer or its pharmaceutically acceptable salt, selected from

P is selected from hydroxy protecting groups; provided that P is not benzyl or trifluoroethyl. The preparation method according to claim 30, wherein P is p-methoxybenzyl, methyl, methoxymethyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.