A synthesis process of cyclohexene antiviral compounds

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically relates to a synthesis process of a cyclohexene antiviral compound. Wherein, the cyclohexene compound has a structure of formula F, and its synthesis route comprises the following steps: (1) a compound of formula A undergoes an azide reduction reaction to obtain a compound of formula B; (2) a compound of formula B undergoes a nucleophilic substitution reaction to obtain a compound of formula C; (3) a compound of formula C undergoes a Tsuji-Trost reaction to obtain a compound of formula D; (4) a compound of formula D undergoes hydrolysis, and the tert-butyloxycarbonyl Boc group is removed to obtain a compound of formula F. The reaction route of the present invention improves the reaction yield and atom economy, reduces costs, can be scaled up for production, and has great commercial production value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis process of a cyclohexene antiviral compound. Background Art

[0002] Influenza is a common respiratory disease caused by influenza virus. It is highly contagious and can easily cause a variety of complications, seriously affecting people's normal life.

[0003] At present, the main means of preventing and treating influenza virus is to use neuraminidase inhibitor drugs, which target neuraminidase (NA) on the surface of influenza virus. Neuraminidase is a mushroom-shaped tetrameric glycoprotein. Neuraminidase plays an important role in the process of influenza virus completing replication and leaving host cells. When influenza virus enters host cells through hemagglutinin and replicates, the hemagglutinin on the surface of mature viral cells is connected to the host cell membrane through sialic acid. Since neuraminidase has enzymatic activity, it can hydrolyze sialic acid residues, eventually causing the virus cell to leave the host. Therefore, effectively inhibiting neuraminidase can prevent the spread of influenza virus in the body.

[0004] Chinese patent (CN106496100A) discloses a cyclohexene compound, specifically (3R, 4R, 5S)-4-acetylamino-5-guanidino-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid and a preparation method thereof. The cyclohexene compound has good inhibitory activity against multiple virus subtypes and drug resistance, good in vivo pharmacokinetics and safety, but its preparation process has the problems of low yield and low atom utilization. Therefore, it is urgent to develop a preparation method for synthesizing cyclohexene compounds with high efficiency and low cost. Summary of the invention

[0005] The technical problem solved by the present invention is that the synthesis of cyclohexene antiviral compounds in the prior art has the problems of low yield and low atomic utilization. In view of the above problems, the purpose of the present invention is to provide a preparation process of cyclohexene compounds, specifically providing a preparation process of 4-acetylamino-5-guanidino-3-(-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid.

[0006] Specifically, the present invention provides the following technical solutions:

[0007] In one aspect, the present invention provides a method for preparing a cyclohexene compound, wherein the cyclohexene compound has a structure of formula F, and the synthesis route thereof comprises the following steps:

[0008] (1) the compound of formula A is subjected to an azide reduction reaction to obtain a compound of formula B;

[0009] (2) the compound of formula B undergoes a nucleophilic substitution reaction to obtain a compound of formula C;

[0010] (3) the compound of formula C undergoes Tsuji-Trost reaction to obtain the compound of formula D;

[0011] (4) The compound of formula D is hydrolyzed to remove the tert-butyloxycarbonyl Boc group to obtain a compound of formula F;

[0012]

[0013] Among them, R1 in the compound of formula A, the compound of formula B, the compound of formula C and the compound of formula D is selected from an alkyl group containing 1 to 10 carbon atoms; R2 in the compound of formula A, the compound of formula B and the compound of formula C is selected from an alkyl group containing 1 to 10 carbon atoms; R3 in the compound of formula A, the compound of formula B, the compound of formula C, the compound of formula D and the compound of formula F is selected from an alkyl group containing 1 to 10 carbon atoms.

[0014] In some embodiments, R1 in the compound of formula A, the compound of formula B, the compound of formula C and the compound of formula D is selected from methyl, ethyl, propyl or isopropyl; R2 in the compound of formula A, the compound of formula B and the compound of formula C is selected from methyl, ethyl, propyl or isopropyl; R3 in the compound of formula A, the compound of formula B, the compound of formula C, the compound of formula D and the compound of formula F is selected from methyl, ethyl, propyl or isopropyl.

[0015] In some embodiments, the compound of formula A is a compound of formula (I), the compound of formula B is a compound of formula (II), the compound of formula C is a compound of formula (III), the compound of formula D is a compound of formula (IV), and the compound of formula F is a compound of formula (VI), and the synthesis route comprises the following steps:

[0016] (1) The compound of formula (I) is subjected to an azide reduction reaction to obtain a compound of formula (II);

[0017] (2) the compound of formula (II) undergoes a nucleophilic substitution reaction to obtain a compound of formula (III);

[0018] (3) the compound of formula (III) is subjected to Tsuji-Trost reaction to obtain the compound of formula (IV);

[0019] (4) The compound of formula (IV) is hydrolyzed to remove the tert-butyloxycarbonyl Boc group to obtain the compound of formula (VI);

[0020]

[0021] In some embodiments, in step (1), the catalytic reducing agent for the azide reduction reaction is selected from palladium-carbon, palladium-barium sulfate, platinum dioxide, Raney nickel, lithium aluminum hydride, sodium borohydride or triphenylphosphine.

[0022] In some embodiments, in step (1), the catalytic reducing agent for the azide reduction reaction is selected from Raney nickel or triphenylphosphine.

[0023] In some embodiments, in step (1), the molar ratio of the catalytic reducing agent to the compound of formula A is (1-3):1.

[0024] In some embodiments, in the azide reduction reaction in step (1), in addition to the catalytic reducing agent, water is also added; wherein the molar ratio of water to the compound of formula A is (3-10):1.

[0025] In some embodiments, in step (1), the reaction solvent is selected from one or more of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dichloromethane and toluene.

[0026] In some embodiments, in step (1), the reaction solvent is selected from acetonitrile or tetrahydrofuran;

[0027] In some embodiments, in step (1), the concentration of the compound of formula A in the reaction solvent is 0.1-0.2 g / mL.

[0028] In some embodiments, in step (1), the compound of formula A, a catalytic reducing agent and water are dispersed in a solvent and reacted at 20-30° C. for 1-3 hours; then the temperature is raised to 35-80° C., preferably 35-60° C., and the reaction is carried out for 3-7 hours.

[0029] In some embodiments, in step (2), a first alkaline reagent and N,N-di-tert-butyloxycarbonyl-1H-1-guanidinopyrazole are added to the solution obtained in step (1). After the reaction is completed, the solution is concentrated and a crystallization reagent is added to precipitate the compound of formula C.

[0030] In some embodiments, in step (2), the crystallization reagent is a mixed system of ethylene glycol dimethyl ether, ethanol and n-hexane.

[0031] In some embodiments, in step (2), the volume ratio of ethylene glycol dimethyl ether to ethanol is 1:1.

[0032] In some embodiments, in step (2), the volume ratio of ethanol to n-hexane is 1:6.

[0033] In some embodiments, the reaction temperature of step (2) is 20-30°C.

[0034] In some embodiments, the reaction time of step (2) is 10 to 15 hours.

[0035] In some embodiments, in step (2), the amount of N,N-di-tert-butyloxycarbonyl-1H-1-guanidinopyrazole is determined based on a molar ratio of (1 to 2):1 to the amount of the initial compound of formula A in step (1).

[0036] In some embodiments, in step (2), the first alkaline reagent is selected from one or more of N-methylmorpholine, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, N,N-diisopropylmethylamine, pyridine, triethylenediamine and ammonia water.

[0037] In some embodiments, in step (2), the first alkaline reagent is N,N-diisopropylethylamine.

[0038] In some embodiments, in step (2), the amount of the first alkaline reagent used is determined based on a molar ratio of (2 to 5):1 to the amount of the compound of the initial formula A used in the reaction in step (1).

[0039] In some embodiments, in step (3), (S)-3-(2-methoxyethoxy)piperidine, a second alkaline reagent, a palladium catalyst and a solvent are added to the compound of formula C, and after the reaction is completed, a compound of formula D is prepared.

[0040] In some embodiments, in step (3), the reaction temperature is 40-90°C.

[0041] In some embodiments, in step (3), the reaction temperature is 60-70°C.

[0042] In some embodiments, in step (3), the reaction time is 3 to 7 hours.

[0043] In some embodiments, in step (3), the molar ratio of (S)-3-(2-methoxyethoxy)piperidine to the compound of formula C is (1-3):1.

[0044] In some embodiments, in step (3), the second alkaline reagent is selected from one or more of N-methylmorpholine, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, N,N-diisopropylmethylamine, pyridine, triethylenediamine and ammonia water.

[0045] In some embodiments, in step (3), the second alkaline agent is selected from N,N-diisopropylethylamine.

[0046] In some embodiments, in step (3), the molar ratio of the second alkaline reagent to the compound of formula C is (1-3):1.

[0047] In some embodiments, in step (3), the palladium catalyst is selected from palladium acetate, diphenylphosphinoferrocenepalladium dichloride, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate or palladium pivalate.

[0048] In some embodiments, in step (3), the palladium catalyst is selected from tetrakis(triphenylphosphine)palladium.

[0049] In some embodiments, the molar ratio of the palladium catalyst in step (3) to the compound of formula C is (0.01-0.1):1.

[0050] In some embodiments, in step (3), the solvent is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, diethyl ether or methyl tert-butyl ether.

[0051] In some embodiments, in step (3), the solvent is selected from acetonitrile.

[0052] In some embodiments, in step (3), the molar concentration of the compound of formula C in the solvent is 0.1 to 0.2 g / mL.

[0053] In some embodiments, step (4) comprises the following reaction steps:

[0054]

[0055] Wherein, R3 in the compound of formula E is selected from an alkyl group containing 1 to 10 carbon atoms; preferably methyl, ethyl, propyl or isopropyl;

[0056] Wherein, step (4) comprises the following steps:

[0057] (4a) subjecting the compound of formula D to saponification to obtain the compound of formula E;

[0058] (4b) The tert-butyloxycarbonyl Boc protecting group of the compound of formula E is removed under high temperature conditions to obtain a compound of formula F.

[0059] In some embodiments, the compound of formula D is a compound of formula (IV), the compound of formula E is a compound of formula (V), the compound of formula F is a compound of formula (VI), and step (4) comprises the following reaction steps:

[0060]

[0061] In some embodiments, in step (4a), the reaction temperature is 0 to 25°C.

[0062] In some embodiments, in step (4a), the reaction temperature is 15-25°C.

[0063] In some embodiments, in step (4a), the reaction time is 10 to 15 hours.

[0064] In some embodiments, in step (4a), the reaction solvent contains ethylene glycol dimethyl ether.

[0065] In some embodiments, in step (4a), the alkaline reagent used in the reaction is potassium hydroxide or sodium hydroxide aqueous solution.

[0066] In some embodiments, in step (4a), the amount of potassium hydroxide or sodium hydroxide used is determined based on a molar ratio of (0.5 to 1.5):1 to the amount of the compound of formula (III) initially used in step (3).

[0067] In some embodiments, step (4a) further comprises the step of adjusting the pH of the solution after the saponification reaction to 4-5, concentrating the solution, and adding a crystallization reagent to precipitate the compound of formula E.

[0068] In some embodiments, the crystallization reagent in step (4a) is selected from one or more of ethylene glycol dimethyl ether, ethanol, n-hexane, ethyl acetate, methanol, ethanol, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, diethyl ether, n-heptane and acetone.

[0069] In some embodiments, the crystallization reagent in step (4a) is a mixed system of ethyl acetate, water and n-heptane.

[0070] In some embodiments, the crystallization reagents in step (4a) are ethyl acetate and water in a volume ratio of 130:11.5; and water and n-heptane in a volume ratio of 11.5:130.

[0071] In some embodiments, in step (4b), the compound of formula E is dissolved in water, the temperature is adjusted to 50-100° C., and the tert-butyloxycarbonyl Boc protecting group is removed to obtain a compound of formula F.

[0072] In some embodiments, in step (4b), the compound of formula E is dissolved in water, the temperature is adjusted to 60-80° C., and the tert-butyloxycarbonyl Boc protecting group is removed to obtain a compound of formula F.

[0073] In some embodiments, in step (4b), the compound of formula E is dissolved in water, the temperature is adjusted to 50-100° C., the reaction is carried out for 3-7 hours, and the tert-butyloxycarbonyl Boc protecting group is removed to obtain a compound of formula F.

[0074] In some embodiments, step (4b) further comprises the step of adding activated carbon after the reaction is completed, cooling, separating, and adding a crystallization reagent to the filtrate to precipitate the compound of formula F.

[0075] In some embodiments, in step (4b), the crystallization reagent is a mixed system of isopropanol and methyl tert-butyl ether.

[0076] In some embodiments, in step (4b), the volume ratio of isopropanol to methyl tert-butyl ether is 5.9:6.

[0077] In a second aspect, the present invention provides a cyclohexene compound, which is prepared by the preparation method of the cyclohexene compound.

[0078] In a third aspect, the use of the cyclohexene compound or its pharmaceutically acceptable salt and ester prodrug or stereoisomer in the preparation of drugs for preventing and treating influenza.

[0079] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the cyclohexene compound or a pharmaceutically acceptable salt and ester prodrug or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.

[0080] Beneficial effects of the present invention

[0081] In the synthesis process of the present invention, (3R, 4R, 5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester is used as a raw material. In the first step, the azide in the raw material is reduced to an amino group, and then directly reacted with a guanidine fragment, which not only completes the fragment splicing, but also can be used as an amino protecting group, and then the other side chain (piperidine) is connected by Tsuji-Trost reaction to obtain a compound of formula IV, avoiding the reaction steps of amino protection-deprotection, improving the reaction yield and atom economy, reducing costs, and can be scaled up for production, which has great commercial production value. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 The compound of formula (III) in Example 1 1 H-NMR spectrum.

[0083] Figure 2 It is the mass spectrum of the compound of formula (III) in Example 1.

[0084] Figure 3The compound of formula (VI) in Example 1 1 H-NMR spectrum.

[0085] Figure 4 The compound of formula (VI) in Example 1 1 C-NMR spectrum.

[0086] Figure 5 The invention discloses a synthetic route diagram of the cyclohexene compounds. DETAILED DESCRIPTION

[0087] As described above, the purpose of the present invention is to provide a preparation process of cyclohexene compounds, specifically providing a preparation process of (3R, 4R, 5S)-4-acetylamino-5-guanidino-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid. The preparation process improves the reaction yield and atom economy, reduces the cost, and has great commercial production value.

[0088] In the first aspect, the synthesis route of the cyclohexene compound of the present invention, i.e., 4-acetylamino-5-guanidino-3-(-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid is as follows:

[0089]

[0090] Wherein, R1 in the compound of formula A, the compound of formula B, the compound of formula C and the compound of formula D is selected from an alkyl group containing 1 to 10 carbon atoms; R1 includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl.

[0091] R2 in the compound of formula A, formula B and formula C is selected from an alkyl group containing 1 to 10 carbon atoms; R2 includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl.

[0092] R3 in the compound of formula A, formula B, formula C, formula D and formula F is selected from an alkyl group containing 1 to 10 carbon atoms; R3 includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl.

[0093] In the compound of formula (A), the compound of formula (B), the compound of formula (C), the compound of formula (D), the compound of formula (E) and the compound of formula (F), R1 is selected from ethyl; R2 is selected from ethyl; and R3 is selected from ethyl.

[0094] In some embodiments, the present invention provides a method for preparing a cyclohexene compound, wherein the cyclohexene compound has a structural formula (IV), and its synthesis route comprises the following steps:

[0095] (1) The compound of formula (I) is subjected to an azide reduction reaction to obtain a compound of formula (II);

[0096] (2) the compound of formula (II) undergoes a nucleophilic substitution reaction to obtain a compound of formula (III);

[0097] (3) the compound of formula (III) is subjected to Tsuji-Trost reaction to obtain the compound of formula (IV);

[0098] (4) The compound of formula (IV) is hydrolyzed to remove the tert-butyloxycarbonyl Boc protecting group to obtain the compound of formula (VI);

[0099]

[0100] Wherein, R1 in the compound of formula (I), the compound of formula (II), the compound of formula (III) and the compound of formula (IV) is selected from an alkyl group containing 1 to 10 carbon atoms, and R1 includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl; preferably methyl, ethyl, propyl or isopropyl; R2 in the compound of formula (I), the compound of formula (II) and the compound of formula (III) is selected from an alkyl group containing 1 to 10 carbon atoms, and R2 includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl; preferably methyl, ethyl, propyl or isopropyl; Not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl; preferably methyl, ethyl, propyl or isopropyl; R3 in the compound of formula (I), the compound of formula (II), the compound of formula (III), the compound of formula (IV) and the compound of formula (VI) is selected from an alkyl group containing 1 to 10 carbon atoms, and R3 includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl; preferably methyl, ethyl, propyl or isopropyl.

[0101] Preferably, step (4) comprises the following reaction steps:

[0102]

[0103] Wherein, R3 in the compound of formula (V) is selected from an alkyl group containing 1 to 10 carbon atoms; R3 includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl; preferably methyl, ethyl, propyl or isopropyl;

[0104] Wherein, step (4) comprises the following steps:

[0105] (i) subjecting the compound of formula (IV) to saponification to obtain a compound of formula E;

[0106] (ii) removing the tert-butyloxycarbonyl Boc protecting group from the compound of formula (V) at high temperature to obtain a compound of formula (VI).

[0107] Preferably, in step (i), the reaction temperature is 0-25°C.

[0108] Preferably, in step (i), the reaction temperature is 15-25°C.

[0109] Preferably, step (i) further comprises the step of adjusting the pH of the solution after the saponification reaction to 4-5, concentrating, and adding a crystallization reagent to precipitate the compound of formula E.

[0110] Preferably, the crystallization reagent in step (i) is selected from one or more of ethylene glycol dimethyl ether, ethanol, n-hexane, ethyl acetate, methanol, ethanol, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, ether, n-heptane and acetone.

[0111] Preferably, the crystallization reagent in step (i) is a mixture of ethyl acetate, water and n-heptane.

[0112] Preferably, in the step (i), the crystallization reagents are ethyl acetate and water in a volume ratio of 130:11.5; and water and n-heptane in a volume ratio of 11.5:130.

[0113] Preferably, in step (ii), the compound of formula E is dissolved in water, the temperature is adjusted to 50-100° C., preferably 60-80° C., and the tert-butyloxycarbonyl Boc protecting group is removed to obtain a compound of formula F.

[0114] Preferably, step (ii) further comprises the step of adding activated carbon after the reaction is completed, cooling, separating, and adding a crystallization reagent to the filtrate to precipitate the compound of formula F.

[0115] Preferably, in step (ii), the crystallization reagent is a mixed system of isopropanol and methyl tert-butyl ether.

[0116] Preferably, in step (ii), the volume ratio of isopropanol to methyl tert-butyl ether is 5.9:6.

[0117] Preferably, the present invention provides a synthetic route of (3R, 4R, 5S)-4-acetylamino-5-guanidino-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid as shown below:

[0118]

[0119] Wherein, the preparation method of cyclohexene comprises the following steps:

[0120] (1) using (3R,4R,5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (Formula I) as a starting material, adding triphenylphosphine, water and a solvent, and performing a reduction reaction at a temperature of 20 to 80° C. to reduce the azido group to the amino group, thereby obtaining a solution containing (3R,4R,5S)-4-acetylamino-5-amino-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (Formula II);

[0121] (2) cooling the solution obtained in step (1) to 20-30° C., then adding N,N′-di-Boc-1H-1-guanidinopyrazole and the first alkaline reagent. After the reaction is completed, the solution is concentrated under reduced pressure, a crystallization solvent (ethylene glycol dimethyl ether, ethanol and n-hexane) is added, and the solution is filtered to obtain (3R,4R,5S)-4-acetylamino-5-((Z)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (Formula III);

[0122] (3) dissolving the compound of formula (III) obtained in step (2) in an organic solvent, then adding (S)-3-(2-methoxyethoxy)piperidine, a second alkaline reagent and a palladium catalyst, reacting at a temperature of 40 to 90° C., concentrating under reduced pressure after the reaction, adding methyl tert-butyl ether and an aqueous sodium bisulfite solution, stirring at room temperature, filtering and standing to separate the liquids, separating the organic layer (containing the compound of formula IV) for later use;

[0123] (4) The organic layer solution obtained in step (3) is concentrated under reduced pressure, ethylene glycol dimethyl ether and water are added, and the mixture is cooled to 0-25° C., and an inorganic base solution is slowly added dropwise to carry out a saponification reaction. After the reaction is completed, dichloromethane is added, and the pH value is adjusted to acidic with an acid. The mixture is allowed to stand for separation, and the aqueous layer is extracted with dichloromethane. The organic layers are combined and concentrated under reduced pressure, and a crystallization reagent (ethyl acetate, water and n-heptane) is added. The mixture is stirred and filtered to obtain (3R, 4R, 5S)-4-acetylamino-5-((E)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid pentahydrate (Formula V);

[0124] (5) Dissolve the compound of formula V obtained in step (4) in a solvent, adjust the temperature to 50-100° C., remove the Boc protecting group, add activated carbon after the reaction is completed, cool, separate and filter, add crystallization reagents (isopropanol and methyl tert-butyl ether) and a small amount of seed crystals to the filtrate, and filter to obtain (3R, 4R, 5S)-4-acetylamino-5-guanidino-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid.

[0125] The crystallization reagent of the present invention refers to a solvent that can be added to the reaction system to precipitate the product.

[0126] Compared with the comparative document (patent application number: 201610814412.8), the technical scheme of the present invention is different in the synthesis route and the reaction conditions of each step. Here, the advantages and significance of the present invention using this synthesis route are briefly described. The final product (VI) in the present invention and the comparative document is obtained by synthesizing the intermediate of formula (IV). The biggest difference is that the routes for synthesizing the compound of formula (IV) are different. In the first step of the present invention, the azide group in the starting material (Formula I) is first reduced to an amino group, then reacted with a guanidine fragment, and finally connected to another side chain (connected to the N atom on the piperidine ring) to obtain the compound of formula (IV), while the first step of the comparative document is to first connect the starting material (Formula I) to another side chain (connected to the N atom on the piperidine ring), then reduce the azide to an amino group, and finally react with a guanidine fragment to obtain the compound of formula (IV).

[0127] Compared with the synthetic route of comparative document 1, the synthetic route of the present invention has three advantages:

[0128] On the one hand, the yield of the product obtained by the synthesis route of the present invention is relatively high; while the catalyst used in the first step of the comparative document to connect the starting material to the other side chain is Pd(PPh3)4, and the azide in the starting material will oxidize the triphenylphosphine contained in the catalyst, producing by-products and also causing the catalyst to be deactivated, so the yield of the product obtained by the synthesis route of the comparative document is relatively low. Second, the amount of catalyst used in the first step of the synthetic route of the comparative document is relatively high, so the production input cost is relatively high. Third, the operation of the present invention is simple, the conditions are mild, it is suitable for industrial scale-up production, and it has great commercial production value; while the comparative document is not suitable for industrial scale-up production.

[0129] Unless otherwise specified, various reagents / instruments used in the examples and comparative examples of the present invention are conventional commercially available products.

[0130] Among them, the manufacturer of the starting material (3R, 4R, 5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester in the present invention is Zhuhai Hairuide Biotechnology Co., Ltd. The manufacturer of the (S)-3-(2-methoxyethoxy)piperidine described in the present invention is Levi Pharmaceuticals (Tianjin) Co., Ltd. The manufacturer of the N,N'-di-BOC-1H-1-guanidinopyrazole described in the present invention is Suzhou Haofan Biotechnology Co., Ltd. The instrument model of the nuclear magnetic resonance hydrogen spectrometer used in the present invention is QUANTUM-Iplus AS400, and the manufacturer is China Science Oxford Spectroscopy Technology Co., Ltd.

[0131] In order to better understand the technical solution of the present invention, the technical solution of the present invention is described in detail below in conjunction with specific embodiments.

[0132] Example 1

[0133] (1) Under room temperature, 50 g (0.161 mol) of (3R, 4R, 5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula I) was dissolved in 500.0 mL of tetrahydrofuran and stirred. 55 g (0.210 mol) of triphenylphosphine and 8.7 g (0.483 mol) of water were added. The mixture was stirred at 20-30° C. for 2 h, and then the temperature was raised to 55° C. and stirred for 5 h.

[0134] (2) The reaction solution obtained in the above step was cooled to 25°C, 60 g (0.193 mol) of N, N'-di-BOC-1H-1-guanidinopyrazole and 62.5 g (0.483 mol) of N, N-diisopropylethylamine were added, and the mixture was stirred for 12 h. The mixture was concentrated under reduced pressure, 100.0 mL of ethylene glycol dimethyl ether and 100.0 mL of ethanol were added, and 600.0 mL of n-hexane was slowly added dropwise, and the mixture was stirred for 12 h. The mixture was filtered, and the filter cake was rinsed with 100.0 mL of n-hexane. The filter cake was dried in a forced air drying oven at 40°C for 10 h to obtain 55.2 g of a white solid with a yield of 65.1%. The liquid chromatography purity was 98.33%.

[0135] Figure 1 The compound of formula (III) 1 HNMR spectrum: 1HNMR(400MHz, CDCl3)δ / ppm=11.3854(s,1H),8.6285(m,1H),6.6722(m,1H),6.6596(m,1H),5.6425(m,1H),4.5109(m,1H), 4.2318(m,3H),2.8949(m,1H),2.4024(m,1H),2.0997(s,3H),1.8949(s,3H),1.5079(s,9H),1.5027(s,9H),1.3027(m,3H).

[0136] Figure 2 The MS spectrum of the structure of formula (III): MS (ESI): m / z [M+H] +: 527.27.

[0137] (3) Under room temperature, 50.0 g (0.095 mol) of (3R, 4R, 5S)-4-acetylamino-5-((Z)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula III) was dissolved in 500.0 mL of acetonitrile and stirred. 15.1 g (0.095 mol) of (S)-3-(2-methoxyethoxy)piperidine, 13.5 g (0.104 mol) of N,N-diisopropylethylamine and 1.1 g (0.95 mmol) of tetrakis(triphenylphosphine)palladium were added and the atmosphere was replaced with nitrogen. The mixture was heated to 60°C and stirred for 4 hours, then concentrated under reduced pressure at 45°C. 500.0 mL of methyl tert-butyl ether was added to the concentrate and stirred to dissolve. Then, 100.0 g of 10% aqueous sodium bisulfite solution was added and stirred at room temperature for 0.5 hours. After filtration, the mixture was allowed to stand for separation. The organic layer was concentrated under reduced pressure. 380.0 mL of ethylene glycol dimethyl ether was added to the concentrate and stirred to dissolve. The solution was clear and set aside.

[0138] (4) Add 125.0 mL of water to the solution in step (3), cool to below 15°C with stirring, slowly drop 116.0 mL of 1 mol / L KOH aqueous solution, and stir for 12 h. Add 1000.0 mL of dichloromethane, cool to 10°C, drop 2 mol / L HCl aqueous solution to adjust the pH value to 5, let stand for about 78 mL, separate the liquids, extract the water layer with 500.0 mL of dichloromethane, combine the organic layers, concentrate under reduced pressure, add 130.0 mL of ethyl acetate and 11.5 mL of water, stir at room temperature, drop 130.0 mL of n-heptane, and continue stirring for 8 h. Filter, and rinse the filter cake with 146.0 mL of n-heptane. Dry the filter cake in a forced air drying oven at 45°C for 8 h to obtain 42.5 g of a white solid, with a yield of 65.0% and a liquid chromatography purity of 99.61%.

[0139] (5) Under room temperature, 40.0 g (0.058 mol) of (3R, 4R, 5S)-4-acetylamino-5-((E)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid pentahydrate (compound of formula V) obtained in step (4) was dissolved in 120.0 mL of water, heated to 70° C. and stirred for 5 h. 1.0 g of activated carbon was added, and the temperature was lowered to 25° C. and stirred for 0.5 h. After filtering, 236.0 mL of isopropanol was added to the filtrate, and the temperature was raised to 35° C. and stirred. 240.0 mL of methyl tert-butyl ether and a small amount of seed crystals were slowly added, and the mixture was filtered after continued stirring for 8 h. The filter cake was rinsed with 100.0 mL of methyl tert-butyl ether to obtain 20.8 g of a white solid with a yield of 90.0% and a liquid phase purity of 99.93%.

[0140] Figure 3 The compound of formula (VI) 1 H-NMR spectrum, 1 H-NMR (400MHz, D2O) δ = 6.38 (t, 1H), 4.02 (dd, J1 = 10.3, J2 = 8.9Hz, 1H), 3.67 ~ 3.52 (m, 4H), 3.51 ~ 3.41 (m, 3H), 3.27 (m, 3H), 2.81 (d d, J1=10.8, J2=3.8Hz,1H), 2.72~2.59(m,2H), 2.35~2.16(m,3H), 1.92(m,4H), 1.64(m,1H), 1.43~1.31(m,1H), 1.18~1.13(m,1H).

[0141] Figure 4 The compound of formula (VI) 1 C-NMR spectrum, 13 C-NMR(100MHz,D2O)δ=174.30,174.11,156.79,136.02,132.15,75.17,71.31, 67.00,64.17,58.02,52.46,52.15,49.75,49.67,30.71,29.49,22.62,22.14.

[0142] Example 2

[0143] (1) Dissolve 50 g (0.161 mol) of (3R, 4R, 5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula I) in 500.0 mL of tetrahydrofuran at room temperature and stir. Add 50.7 g (0.193 mol) of triphenylphosphine and 8.7 g (0.483 mol) of water. Stir at 20-30° C. for 2 h, then raise the temperature to 55° C. and stir for 5 h.

[0144] (2) The reaction solution obtained in the above step was cooled to 25°C, 60 g (0.193 mol) of N, N'-di-BOC-1H-1-guanidinopyrazole and 41.7 g (0.322 mol) of N, N-diisopropylethylamine were added, and the mixture was stirred for 12 h. The mixture was concentrated under reduced pressure, 100.0 mL of ethylene glycol dimethyl ether and 100.0 mL of ethanol were added, and 600.0 mL of n-hexane was slowly added dropwise, and the mixture was stirred for 12 h. The mixture was filtered, and the filter cake was rinsed with 100.0 mL of n-hexane. The filter cake was dried in a forced air drying oven at 40°C for 10 h to obtain 50.9 g of a white solid with a yield of 60.0% and a liquid chromatography purity of 97.33%.

[0145] (3) Under room temperature, 50.0 g (0.095 mol) of (3R, 4R, 5S)-4-acetylamino-5-((Z)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula III) was dissolved in 500.0 mL of acetonitrile and stirred. 15.1 g (0.095 mol) of (S)-3-(2-methoxyethoxy)piperidine, 13.5 g (0.104 mol) of N,N-diisopropylethylamine and 1.1 g (0.95 mmol) of tetrakis(triphenylphosphine)palladium were added and the atmosphere was replaced with nitrogen. The mixture was heated to 60°C and stirred for 4 hours, then concentrated under reduced pressure at 45°C. 500.0 mL of methyl tert-butyl ether was added to the concentrate and stirred to dissolve. Then, 100.0 g of 10% aqueous sodium bisulfite solution was added and stirred at room temperature for 0.5 hours. After filtration, the mixture was allowed to stand for separation. The organic layer was concentrated under reduced pressure. 380.0 mL of ethylene glycol dimethyl ether was added to the concentrate and stirred to dissolve. The solution was clear and set aside.

[0146] (4) Add 125.0 mL of water to the solution in step (3), cool to 15°C with stirring, slowly drop 116.0 mL of 1 mol / L KOH aqueous solution, and stir for 12 h. Add 1000.0 mL of dichloromethane, cool to 10°C, and drop 2 mol / L -1Adjust the pH value to 5 with HCl aqueous solution, about 78.0 mL, stand and separate, extract the water layer with 500.0 mL of dichloromethane, combine the organic layers, concentrate under reduced pressure, add 130.0 mL of ethyl acetate and 11.5 mL of water, stir at room temperature, add 130.0 mL of n-heptane dropwise, and continue stirring for 8 hours. Filter, rinse the filter cake with 146.0 mL of n-heptane. Dry the filter cake in a forced air drying oven at 45°C for 8 hours to obtain 39.2 g of white solid, with a yield of 60.0% and a liquid chromatography purity of 99.03%.

[0147] (5) Under room temperature, 35.0 g (0.058 mol) of (3R, 4R, 5S)-4-acetylamino-5-((E)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid pentahydrate (compound of formula V) obtained in step (4) was dissolved in 105.0 mL of water, heated to 70° C. and stirred for 5 h. 1.0 g of activated carbon was added, and the temperature was lowered to 25° C. and stirred for 0.5 h. After filtering, 206.5 mL of isopropanol was added to the filtrate, and the temperature was raised to 35° C. and stirred. 210 mL of methyl tert-butyl ether and a small amount of seed crystals were slowly added, and the mixture was filtered after continued stirring for 8 h. The filter cake was rinsed with 87.0 mL of methyl tert-butyl ether to obtain 17.2 g of a white solid with a yield of 85.0% and a liquid phase purity of 99.87%.

[0148] Example 3

[0149] (1) Dissolve 100 g (0.322 mol) of (3R, 4R, 5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula I) in 500.0 mL of tetrahydrofuran at room temperature and stir. Add 110 g (0.420 mol) of triphenylphosphine and 17.4 g (0.966 mol) of water. Stir at 20-30° C. for 2 h, then heat to 55° C. and stir for 5 h.

[0150] (2) The reaction solution obtained in the above step was cooled to 25°C, 120 g (0.386 mol) of N, N'-di-BOC-1H-1-guanidinopyrazole and 125.0 g (0.966 mol) of N, N-diisopropylethylamine were added, and the mixture was stirred for 12 h. The mixture was concentrated under reduced pressure, 200.0 mL of ethylene glycol dimethyl ether and 200.0 mL of ethanol were added, and 1200.0 mL of n-hexane was slowly added dropwise, and the mixture was stirred for 12 h. The mixture was filtered, and the filter cake was rinsed with 200.0 mL of n-hexane. The filter cake was dried in a forced air drying oven at 40°C for 10 h to obtain 122.2 g of a white solid with a yield of 72.0% and a liquid chromatography purity of 98.87%.

[0151] (3) Under room temperature, 100.0 g (0.19 mol) of (3R, 4R, 5S)-4-acetylamino-5-((Z)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula III) was dissolved in 500.0 mL of acetonitrile and stirred. 30.2 g (0.19 mol) of (S)-3-(2-methoxyethoxy)piperidine, 27.0 g (0.209 mol) of N,N-diisopropylethylamine and 2.2 g (1.9 mmol) of tetrakis(triphenylphosphine)palladium were added and the atmosphere was replaced with nitrogen. The mixture was heated to 60°C and stirred for 4 hours, then concentrated under reduced pressure at 45°C. 1000.0 mL of methyl tert-butyl ether was added to the concentrate and stirred to dissolve. Then, 200.0 g of 10% aqueous sodium bisulfite solution was added and stirred at room temperature for 0.5 hours. The mixture was filtered and allowed to stand for separation. The organic layer was concentrated under reduced pressure. 760.0 mL of ethylene glycol dimethyl ether was added to the concentrate and stirred to dissolve. The solution was clear and set aside.

[0152] (4) Add 250.0 mL of water to the solution in step (3), cool to 15°C, slowly drop 232.0 mL of 1 mol / L KOH aqueous solution, and stir for 12 h. Add 2000.0 mL of dichloromethane, stir, cool to 10°C, drop 2 mol / L HCl aqueous solution to adjust the pH value to 5, about 160.0 mL, stand and separate, extract the water layer with 1000.0 mL of dichloromethane, combine the organic layers, concentrate under reduced pressure, add 260.0 mL of ethyl acetate and 23.0 mL of water, stir at room temperature, drop 260.0 mL of n-heptane, and continue stirring for 8 h. Filter, and rinse the filter cake with 292.0 mL of n-heptane. Dry the filter cake in a forced air drying oven at 45°C for 8 h to obtain 101.9 g of a white solid, with a yield of 78.0% and a liquid chromatography purity of 99.73%.

[0153] (5) Under room temperature, 100.0 g (0.145 mol) of (3R, 4R, 5S)-4-acetylamino-5-((E)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid pentahydrate (compound of formula V) obtained in step (4) was dissolved in 300.0 mL of water, heated to 70° C. and stirred for 5 h. 2.5 g of activated carbon was added, and the temperature was lowered to 25° C. and stirred for 0.5 h. After filtering, 590.0 mL of isopropanol was added to the filtrate, and the temperature was raised to 35° C. and stirred. 600.0 mL of methyl tert-butyl ether and a small amount of seed crystals were slowly added, and the mixture was filtered after continued stirring for 8 h. The filter cake was rinsed with 250.0 mL of methyl tert-butyl ether to obtain 53.2 g of a white solid with a yield of 92.0% and a liquid phase purity of 99.95%.

[0154] Example 4

[0155] (1) Under room temperature, 50 g (0.161 mol) of (3R, 4R, 5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula I) was dissolved in 500.0 mL of tetrahydrofuran and stirred. 126.8 g (0.483 mol) of triphenylphosphine and 29.0 g (1.611 mol) of water were added. The mixture was stirred at 20-30° C. for 2 h, and then the temperature was raised to 60° C. and stirred for 3 h.

[0156] (2) The reaction solution obtained in the above step was cooled to 25°C, 100.0 g (0.322 mol) of N, N'-di-BOC-1H-1-guanidinopyrazole and 104.1 g (0.806 mol) of N, N-diisopropylethylamine were added, and the mixture was stirred for 10 h. The mixture was concentrated under reduced pressure, 100.0 mL of ethylene glycol dimethyl ether and 100.0 mL of ethanol were added, and 600.0 mL of n-hexane was slowly added dropwise, and the mixture was stirred for 10 h. The mixture was filtered, and the filter cake was rinsed with 100.0 mL of n-hexane. The filter cake was dried in a forced air drying oven at 40°C for 10 h to obtain 55.2 g of a white solid with a yield of 65.1% and a liquid chromatography purity of 97.33%.

[0157] (3) Under room temperature, 50.0 g (0.095 mol) of (3R, 4R, 5S)-4-acetylamino-5-((Z)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula III) was dissolved in 500.0 mL of acetonitrile and stirred. 45.4 g (0.285 mol) of (S)-3-(2-methoxyethoxy)piperidine, 24.6 g (0.190 mol) of N,N-diisopropylethylamine and 11.0 g (9.5 mmol) of tetrakis(triphenylphosphine)palladium were added and the atmosphere was replaced with nitrogen. The mixture was heated to 60°C and stirred for 3 h, then concentrated under reduced pressure at 45°C. 500.0 mL of methyl tert-butyl ether was added to the concentrate and stirred to dissolve. Then, 100.0 g of 10% aqueous sodium bisulfite solution was added and stirred at room temperature for 0.5 h. After filtration, the mixture was allowed to stand for separation. The organic layer was concentrated under reduced pressure. 380.0 mL of ethylene glycol dimethyl ether was added to the concentrate and stirred to dissolve. The solution was clear and set aside.

[0158] (4) Add 125.0 mL of water to the solution in step (3), cool to below 15°C with stirring, slowly drop 116.0 mL of 1 mol / L KOH aqueous solution, and stir for 12 h. Add 1000.0 mL of dichloromethane, cool to 10°C, drop 2 mol / L HCl aqueous solution to adjust the pH value to 5, let stand for about 78 mL, separate the liquids, extract the water layer with 500.0 mL of dichloromethane, combine the organic layers, concentrate under reduced pressure, add 130.0 mL of ethyl acetate and 11.5 mL of water, stir at room temperature, drop 130.0 mL of n-heptane, and continue stirring for 8 h. Filter, and rinse the filter cake with 146.0 mL of n-heptane. Dry the filter cake in a forced air drying oven at 45°C for 8 h to obtain 40.5 g of a white solid, with a yield of 62.0% and a liquid chromatography purity of 98.61%.

[0159] (5) Under room temperature, 40.0 g (0.058 mol) of (3R, 4R, 5S)-4-acetylamino-5-((E)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid pentahydrate (compound of formula V) obtained in step (4) was dissolved in 120.0 mL of water, heated to 70° C. and stirred for 5 h. 1.0 g of activated carbon was added, and the temperature was lowered to 25° C. and stirred for 0.5 h. After filtering, 236.0 mL of isopropanol was added to the filtrate, and the temperature was raised to 35° C. and stirred. 240.0 mL of methyl tert-butyl ether and a small amount of seed crystals were slowly added, and the mixture was filtered after continued stirring for 8 h. The filter cake was rinsed with 100.0 mL of methyl tert-butyl ether to obtain 20.8 g of a white solid with a yield of 90.0% and a liquid phase purity of 99.0%.

[0160] Example 5

[0161] (1) Dissolve 50 g (0.161 mol) of (3R, 4R, 5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula I) in 500.0 mL of tetrahydrofuran at room temperature and stir. Add 126.8 g (0.483 mol) of triphenylphosphine and 17.4 g (0.966 mol) of water. Stir at 20-30° C. for 2 h, then raise the temperature to 35° C. and stir for 7 h.

[0162] (2) The reaction solution obtained in the above step was cooled to 25°C, 100.0 g (0.322 mol) of N, N'-di-BOC-1H-1-guanidinopyrazole and 104.1 g (0.806 mol) of N, N-diisopropylethylamine were added, and the mixture was stirred for 15 h. The mixture was concentrated under reduced pressure, 100.0 mL of ethylene glycol dimethyl ether and 100.0 mL of ethanol were added, and 600.0 mL of n-hexane was slowly added dropwise, and the mixture was stirred for 10 h. The mixture was filtered, and the filter cake was rinsed with 100.0 mL of n-hexane. The filter cake was dried in a forced air drying oven at 40°C for 10 h to obtain 54.2 g of a white solid with a yield of 63.9% and a liquid chromatography purity of 97.33%.

[0163] (3) Under room temperature, 50.0 g (0.095 mol) of (3R, 4R, 5S)-4-acetylamino-5-((Z)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester (compound of formula III) was dissolved in 500.0 mL of acetonitrile and stirred. 45.4 g (0.285 mol) of (S)-3-(2-methoxyethoxy)piperidine, 36.8 g (0.285 mol) of N,N-diisopropylethylamine and 5.5 g (4.75 mmol) of tetrakis(triphenylphosphine)palladium were added and the atmosphere was replaced with nitrogen. The mixture was heated to 60°C and stirred for 3 h, then concentrated under reduced pressure at 45°C. 500.0 mL of methyl tert-butyl ether was added to the concentrate and stirred to dissolve. Then, 100.0 g of 10% aqueous sodium bisulfite solution was added and stirred at room temperature for 0.5 h. After filtration, the mixture was allowed to stand for separation. The organic layer was concentrated under reduced pressure. 380.0 mL of ethylene glycol dimethyl ether was added to the concentrate and stirred to dissolve. The solution was clear and set aside.

[0164] (4) Add 125.0 mL of water to the solution in step (3), cool to below 15°C with stirring, slowly drop 116.0 mL of 1 mol / L KOH aqueous solution, and stir for 12 h. Add 1000.0 mL of dichloromethane, cool to 10°C, drop 2 mol / L HCl aqueous solution to adjust the pH value to 5, let stand for about 78 mL, separate the liquids, extract the water layer with 500.0 mL of dichloromethane, combine the organic layers, concentrate under reduced pressure, add 130.0 mL of ethyl acetate and 11.5 mL of water, stir at room temperature, drop 130.0 mL of n-heptane, and continue stirring for 8 h. Filter, and rinse the filter cake with 146.0 mL of n-heptane. Dry the filter cake in a forced air drying oven at 45°C for 8 h to obtain 38.5 g of a white solid, with a yield of 59.0% and a liquid chromatography purity of 97.61%.

[0165] (5) Under room temperature, 38.0 g (0.055 mol) of (3R, 4R, 5S)-4-acetylamino-5-((E)-2,3-di(tert-butyloxycarbonyl)guanidino)-3-((S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid pentahydrate (compound of formula V) obtained in step (4) was dissolved in 114.0 mL of water, heated to 70° C. and stirred for 5 h. 1.0 g of activated carbon was added, and the temperature was lowered to 25° C. and stirred for 0.5 h. After filtering, 224.2 mL of isopropanol was added to the filtrate, and the temperature was raised to 35° C. and stirred. 240.0 mL of methyl tert-butyl ether and a small amount of seed crystals were slowly added, and the mixture was filtered after continued stirring for 8 h. The filter cake was rinsed with 95.0 mL of methyl tert-butyl ether to obtain 18.8 g of a white solid with a yield of 81.0% and a liquid phase purity of 98.0%.

[0166] Comparative Example 1

[0167] The applicant prepared a cyclohexene compound of structural formula X according to the preparation steps of (3R, 4R, 5S)-4-acetylamino-5-guanidino-3-((3S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylic acid trifluoroacetate described in Examples 1 and 11 of the Chinese patent (patent application number: 201610814412.8), and the specific steps are as follows:

[0168] (1) Preparation of ethyl (3R,4S,5S)-4-acetylamino-5-azido-3-((3S)-3-(2-methoxyethoxy)piperidinyl)-1-cyclohexene-1-carboxylate

[0169]

[0170] According to the above reaction formula, 20 mmol of (3R, 4R, 5S)-4-acetylamino-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester and 1 mmol of tetrakistriphenylphosphine palladium were placed in a dry double-necked bottle. After nitrogen replaced the air in the system twice, 40 mL of redistilled DMF (dimethylformamide) was added with a syringe and stirred evenly. 40 mmol of DIPEA (N, N-diisopropylethylamine) was added and stirred and cooled to 0 ° C. Slowly Add a DMF (40 mL) solution of (3S)-3-(2-methoxyethoxy)piperidine trifluoroacetate dropwise, continue stirring at 0°C for 20 minutes after addition, move to an oil bath at 70°C for reaction for 1 hour, thin layer chromatography TLC (DCM:MeOH=10:1, i.e., dichloromethane:methanol=10:1) shows that the reaction is complete, slowly cool to 0°C, slowly add an equal volume of water dropwise, stir evenly, extract with EA (ethyl acetate), directly evaporate to dryness and remove DMF with an oil pump to obtain a brown viscous substance. Column purification (MeOH:DCM=1:50) eluted to obtain 3.8 g of yellow-white powder solid, with a yield of 46.4%.

[0171] (2) Preparation of ethyl (3R,4R,5S)-4-acetylamino-5-amino-3-((3S)-3-(2-methoxyethoxy)piperidinyl)-1-cyclohexene-1-carboxylate

[0172]

[0173] According to the above reaction formula, ethyl (3R, 4S, 5S)-4-acetylamino-5-azido-3-((3S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylate was placed in a single-necked bottle, a catalytic amount of Raney nickel and 40 mL of anhydrous ethanol were added and stirred evenly, and then the air in the system was replaced with hydrogen. The mixture was stirred at room temperature for 2 hours. TLC (DCM: MeOH = 10: 1) showed that the reaction was completed. The Raney nickel was filtered off with diatomaceous earth, and the solvent was evaporated. The mixture was purified by column (DCM: MeOH = 5: 1) to obtain 2.85 g of a white foamy solid with a yield of 75.0%.

[0174] (3) Preparation of ethyl (3R,4R,5S)-4-acetylamino-5-(2,3-di(tert-butyloxycarbonyl)guanidino)-3-((3S)-3-(2-methoxyethoxy)piperidinyl)-1-cyclohexene-1-carboxylate

[0175]

[0176] According to the above reaction formula, 0.5 mmol of ethyl (3R, 4R, 5S)-4-acetylamino-5-amino-3-((3S)-3-(2-methoxyethoxy)piperidine)-1-cyclohexene-1-carboxylate was placed in a single-mouth bottle, 10 mL of acetonitrile was added and stirred at room temperature, 1.5 mmol of DIPEA and 0.5 mmol of N, N'-di-BOC-1H-1-guanidinopyrazole were added, and stirring at room temperature was continued for 3 h. TLC (PE:EA=1:1) showed that the reaction was completed, 20 mL of water was added, EA was extracted, dried over anhydrous sodium sulfate and evaporated to dryness, and column purification (PE:EA=3:1) was performed to obtain 0.23 g of a white solid with a yield of 70.0%.

[0177] (4) Preparation of (3R, 4R, 5S)-4-acetylamino-5-(2,3-di(tert-butyloxycarbonyl)guanidino)-3-((3S)-3-(2-methoxyethoxy)piperidinyl)-1-cyclohexene-1-carboxylic acid

[0178]

[0179] 0.368mmol of (3R, 4R, 5S)-4-acetylamino-5-(2,3-di(tert-butyloxycarbonyl)guanidino)-3-((3S)-3-(2-methoxyethoxy)piperidinyl)-1-cyclohexene-1-carboxylic acid ethyl ester was placed in a single-mouth bottle, 5.5mL of 1,4-dioxane and 0.55mL of water, 0.55mL of 1N KOH aqueous solution were added, and stirred at room temperature overnight. TLC TLC (PE:EA=1:1) showed that the reaction was complete, the solvent was evaporated, and 5mL of methanol was added after the oil pump was dried, and the pH was adjusted to 5 by acidic resin, and the mixture was filtered and evaporated to dryness for column purification, and 1.65g of white solid was obtained by elution with DCM:MeOH=10:1, with a yield of 75.0%.

[0180] (5) Preparation of (3R, 4R, 5S)-4-acetylamino-5-guanidino-3-((3S)-3-(2-methoxyethoxy)piperidinyl)-1-cyclohexene-1-carboxylic acid trifluoroacetate (compound of formula X)

[0181]

[0182] 0.8 g of (3R, 4R, 5S)-4-acetylamino-5-(2,3-di(tert-butyloxycarbonyl)guanidino)-3-(3S)-3-(2-methoxy)ethoxy)piperidine)-1-cyclohexene-1-carboxylic acid was placed in a single-necked bottle, and a 50% TFA solution in DCM was added. The mixture was stirred at room temperature for 1 h. TLC (DCM:MeOH=10:1) showed that the reaction was completed. The solvent was evaporated and the excess TFA was pumped away with an oil pump. Ether was added for slurrying and the reaction was filtered. TLC (DCM:MeOH=10:1) showed that the reaction was completed. The solvent was evaporated and the excess TFA was pumped away with an oil pump. Ether was added for slurrying and the reaction was filtered to obtain 0.66 g of a white solid product with a yield of 80.0%.

[0183] The above is a specific description of a feasible embodiment of the present invention, but the embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the technical spirit of the present invention should be included in the patent scope of the present invention.

Claims

1. A method for preparing a cyclohexene compound, characterized in that: The cyclohexene compound has a structure of formula F, and its synthesis route comprises the following steps: (1) A compound of formula A is subjected to an azide reduction reaction to obtain a compound of formula B; the compound of formula A, a catalytic reducing agent and water are dispersed in a solvent, reacted at 20-30° C. for 1-3 hours; then the temperature is raised to 35-80° C. and reacted for 3-7 hours; the molar ratio of the catalytic reducing agent to the compound of formula A is (1-3):1; the molar ratio of water to the compound of formula A is (3-10):1; the catalytic reducing agent is triphenylphosphine; (2) the compound of formula B undergoes a nucleophilic substitution reaction to obtain a compound of formula C; a first alkaline reagent and N,N-di-tert-butyloxycarbonyl-1H-1-guanidinopyrazole are added to the solution obtained in step (1); after the reaction is completed, the solution is concentrated, and a crystallization reagent is added to precipitate the compound of formula C; the reaction temperature is 20 to 30° C.; the reaction time is 10 to 15 hours; the amount of the N,N-di-tert-butyloxycarbonyl-1H-1-guanidinopyrazole is determined based on the molar ratio of the N,N-di-tert-butyloxycarbonyl-1H-1-guanidinopyrazole to the initial amount of the compound of formula A in step (1) being (1 to 2):1; the first alkaline reagent is N,N-diisopropylethylamine; (3) The compound of formula C undergoes Tsuji-Trost reaction to obtain a compound of formula D; (S)-3-(2-methoxyethoxy)piperidine, a second alkaline reagent, a palladium catalyst and a solvent are added to the compound of formula C to obtain a compound of formula D after the reaction is completed. The reaction temperature is 40 to 90° C. and the reaction time is 3 to 7 hours. The molar ratio of (S)-3-(2-methoxyethoxy)piperidine to the compound of formula C is (1 to 3):1; the molar ratio of the palladium catalyst to the compound of formula C is (0.01 to 0.1):1; the second alkaline reagent is N,N-diisopropylethylamine; and the palladium catalyst is tetrakis(triphenylphosphine)palladium; (4) The compound of formula D is hydrolyzed to remove the tert-butyloxycarbonyl Boc group to obtain a compound of formula F; Wherein, R1 in the compound of formula A, the compound of formula B, the compound of formula C and the compound of formula D is selected from methyl, ethyl, propyl or isopropyl; R2 in the compound of formula A, the compound of formula B and the compound of formula C is selected from methyl, ethyl, propyl or isopropyl; R3 in the compound of formula A, the compound of formula B, the compound of formula C, the compound of formula D and the compound of formula F is selected from methyl, ethyl, propyl or isopropyl.

2. The method for preparing cyclohexene compounds according to claim 1, wherein In step (1), the reaction solvent is selected from one or more of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dichloromethane and toluene.

3. The method for preparing cyclohexene compounds according to claim 1, wherein In step (1), the reaction solvent is selected from acetonitrile or tetrahydrofuran.

4. The method for preparing cyclohexene compounds according to claim 1, wherein In step (1), the concentration of the compound of formula A in the reaction solvent is 0.1 to 0.2 g / mL.

5. The method for preparing cyclohexene compounds according to claim 2, wherein: In step (1), the concentration of the compound of formula A in the reaction solvent is 0.1 to 0.2 g / mL.

6. The method for preparing cyclohexene compounds according to claim 1, wherein: In step (1), the compound of formula A, a catalytic reducing agent and water are dispersed in a solvent and reacted at 20 to 30° C. for 1 to 3 hours; then the temperature is raised to 35 to 60° C. and reacted for 3 to 7 hours.

7. The method for preparing cyclohexene compounds according to claim 1, wherein: In step (2), the crystallization reagent is a mixed system of ethylene glycol dimethyl ether, ethanol and n-hexane.

8. The method for preparing cyclohexene compounds according to claim 2, wherein: In step (2), the crystallization reagent is a mixed system of ethylene glycol dimethyl ether, ethanol and n-hexane.

9. The method for preparing cyclohexene compounds according to claim 1, wherein: In step (2), the amount of the first alkaline agent is determined based on the molar ratio of the first alkaline agent to the initial compound of formula A in step (1) being (2-5):

1.

10. The method for preparing cyclohexene compounds according to claim 1, wherein: In step (3), the reaction temperature is 60-70°C.

11. The method for preparing a cyclohexene compound according to any one of claims 1 to 10, wherein: In step (3), the molar ratio of the second alkaline reagent to the compound of formula C is (1-3):

1.

12. The method for preparing a cyclohexene compound according to any one of claims 1 to 10, wherein: In step (3), the solvent is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, diethyl ether or methyl tert-butyl ether.

13. The method for preparing cyclohexene compounds according to claim 11, wherein: In step (3), the solvent is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, diethyl ether or methyl tert-butyl ether.

14. The method for preparing a cyclohexene compound according to any one of claims 1 to 10, wherein: In step (3), the solvent is selected from acetonitrile.

15. The method for preparing a cyclohexene compound according to any one of claims 1 to 10, wherein: In step (3), the molar concentration of the compound of formula C in the solvent is 0.1 to 0.2 g / mL.

16. The method for preparing cyclohexene compounds according to claim 12, wherein: In step (3), the molar concentration of the compound of formula C in the solvent is 0.1 to 0.2 g / mL.

17. The method for preparing a cyclohexene compound according to any one of claims 1 to 10, wherein: Step (4) comprises the following reaction steps: Wherein, R3 in the compound of formula E is selected from methyl, ethyl, propyl or isopropyl; Wherein, step (4) comprises the following steps: (4a) subjecting the compound of formula D to saponification to obtain the compound of formula E; (4b) The tert-butyloxycarbonyl Boc protecting group is removed from the compound of formula E to obtain a compound of formula F.

18. The method for preparing cyclohexene compounds according to claim 11, wherein: Step (4) comprises the following reaction steps: Wherein, R3 in the compound of formula E is selected from methyl, ethyl, propyl or isopropyl; Wherein, step (4) comprises the following steps: (4a) subjecting the compound of formula D to saponification to obtain the compound of formula E; (4b) The tert-butyloxycarbonyl Boc protecting group is removed from the compound of formula E to obtain a compound of formula F.

19. The method for preparing cyclohexene compounds according to claim 12, wherein: Step (4) comprises the following reaction steps: Wherein, R3 in the compound of formula E is selected from methyl, ethyl, propyl or isopropyl; Wherein, step (4) comprises the following steps: (4a) subjecting the compound of formula D to saponification to obtain the compound of formula E; (4b) The tert-butyloxycarbonyl Boc protecting group is removed from the compound of formula E to obtain a compound of formula F.

20. The method for preparing cyclohexene compounds according to claim 17, wherein: In step (4a), the reaction temperature is 0 to 25°C.

21. The method for preparing cyclohexene compounds according to claim 17, wherein: In step (4a), the reaction temperature is 10-25°C.

22. The method for preparing cyclohexene compounds according to claim 17, wherein: Step (4a) further comprises the step of adjusting the pH of the solution after the saponification reaction to 4-5, concentrating, and adding a crystallization reagent to precipitate the compound of formula E.

23. The method for preparing cyclohexene compounds according to claim 20, wherein: Step (4a) further comprises the step of adjusting the pH of the solution after the saponification reaction to 4-5, concentrating, and adding a crystallization reagent to precipitate the compound of formula E.

24. The method for preparing cyclohexene compounds according to claim 22, wherein: In the step (4a), the crystallization reagent is selected from one or more of ethylene glycol dimethyl ether, ethanol, n-hexane, ethyl acetate, methanol, ethanol, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, ether, n-heptane and acetone.

25. The method for preparing cyclohexene compounds according to claim 22, wherein: The crystallization reagent in step (4a) is a mixture of ethyl acetate, water and n-heptane.

26. The method for preparing cyclohexene compounds according to claim 17, wherein: In step (4b), the compound of formula E is dissolved in water, the temperature is adjusted to 50-100° C., and the tert-butyloxycarbonyl Boc protecting group is removed to obtain a compound of formula F; And / or, step (4b) further comprises the step of adding activated carbon after the reaction is completed, cooling, separating, and adding a crystallization reagent to the filtrate to precipitate the compound of formula F.

27. The method for preparing cyclohexene compounds according to claim 22, wherein: In step (4b), the compound of formula E is dissolved in water, the temperature is adjusted to 50-100° C., and the tert-butyloxycarbonyl Boc protecting group is removed to obtain a compound of formula F; And / or, step (4b) further comprises the step of adding activated carbon after the reaction is completed, cooling, separating, and adding a crystallization reagent to the filtrate to precipitate the compound of formula F.

28. The method for preparing cyclohexene compounds according to claim 26, wherein: In step (4b), the compound of formula E is dissolved in water and the temperature is adjusted to 60-80°C.

29. The method for preparing cyclohexene compounds according to claim 26, wherein: In step (4b), the crystallization reagent is a mixed system of isopropanol and methyl tert-butyl ether.

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