A preparation method of an avibactam intermediate

Abstract

The present invention discloses a preparation method of an avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid. The method is as follows: Selecting cheap and easily available L-camphorsulfonamide as a chiral auxiliary group, using diphenyl imidate and homoallylic halide as the main starting materials, and obtaining the avibactam intermediate through amidation, asymmetric alkylation, deprotection, intramolecular iodocyclization, N-alkylation and hydrolysis. The raw materials of the present invention are cheap and easily available, the route is short, the yield is high, and the stereoselectivity is good. The diphenyl imidate shown in formula (II) forms a complex with trimethylaluminum, which can improve the nucleophilic ability of the amino group in camphorsultam and reduce the generation of by-products. It has good market prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of an intermediate of the antibiotic avibactam, (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid ethyl ester oxalate. Background Art

[0002] Avibactam (Avibactam, NXL-104) belongs to diazabicyclooctanone compounds and is currently the most promising new type of β-lactamase inhibitor. Compared with the three marketed β-lactamase inhibitors, it has a long duration and a reversible covalent binding with the enzyme, and does not induce the production of β-lactamase. On February 25, 2015, the US FDA approved the new antibiotic combination drug Avibactam-Ceftazidime of Allergan, with the trade name Avycaz. Avibactam-ceftazidime combined with metronidazole is used to treat complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI).

[0003] Avibactam sodium, also known as NXL-104, belongs to diazabicyclooctane compounds. Its chemical name is sodium [(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] sulfate monoester, and the specific chemical structure is shown in the structural formula. This compound has a penta- and hexacyclic ring system as the backbone and contains two chiral centers, 2S and 5R. The amide bond in the five-membered ring is the action site of β-lactamase, which can be opened and closed, so it can play a long-term enzyme inhibition effect.

[0004]

[0005] Currently, the synthetic route of avibactam sodium can be roughly divided into:

[0006] (1) Synthesizing avibactam sodium using L-pyroglutamic acid derivatives as the starting material. As shown in Scheme 1, Patent WO2012086241A1 reported using Cbz-protected L-pyroglutamic acid 1 as the starting material, through electrophilic addition, sulfur ylide ring-opening and carbon chain elongation, catalytic ring closure, reduction with sodium borohydride, deprotection of Cbz to obtain the key intermediate 6, and then through acyl protection of the amino group, substitution with benzyloxyamine, deprotection, intramolecular ureas ring formation, hydrolysis, ammonolysis, debenzylation, sulfonation, quaternary ammonium salt complexation, and sodium salt formation, a total of 15 steps to obtain avibactam sodium, with a total reaction yield of 9.8%. This route has many reaction steps, requires a long reaction time, and each intermediate needs to be separated and purified by column chromatography, with cumbersome operations and a low total yield, so it is not suitable for industrial production.

[0007]

[0008] WO2009090320A1 developed another synthetic route starting from L - pyroglutamic acid derivatives, as shown in Scheme 2. This route uses double - protected L - pyroglutamic acid as the starting material. First, it uses sulfur ylide to open the ring and increase carbon, then chlorinates with lithium chloride, adds benzyloxyamine with benzyloxyamine hydrochloride to obtain 17. After that, it removes the Boc protection with methanesulfonic acid, closes the ring with potassium bicarbonate, reduces the carbon - nitrogen double bond with sodium triacetoxyborohydride, separates with oxalic acid to obtain the key intermediate 19. It forms a five - and six - membered ring system by reacting with triphosgene to form a urea ring, hydrolyzes the ester bond with lithium hydroxide to obtain the desired 5R - configuration compound 12. Finally, it removes the benzyl protection by hydrogenation, sulfonates to add a sulfonic acid group, then complexes with a quaternary ammonium salt and exchanges with sodium isooctanoate to obtain the final product avibactam sodium 14.

[0009]

[0010] Chinese Patent CN1468242 reported that using chiral piperidine ring derivative 21 as the starting material, through acylation protection with trifluoroacetic anhydride, trans - nucleophilic substitution with benzyloxyamine, reduction and de - protection with sodium borohydride, formation of a urea ring with triphosgene, removal of the allyl group catalyzed by tetrakis(triphenylphosphine)palladium, substitution with ammonia to obtain the key intermediate 12, then hydrogenation with Pd / C, sulfonation with pyridine sulfur trioxide, complexation with tetrabutylammonium salt, and finally forming the sodium salt to obtain the final product 14, as shown in Scheme 3.

[0011]

[0012] In summary, (2S,5R) - benzyloxyamino - piperidine - 2 - carboxylic acid is the key intermediate for the preparation of avibactam. Therefore, it is necessary to develop a method with simple operation, high yield and good stereoselectivity for the synthesis of (2S,5R) - benzyloxyamino - piperidine - 2 - carboxylic acid. Summary of the Invention

[0013] The present invention provides a method for preparing the avibactam intermediate (2S,5R) - benzyloxyamino - piperidine - 2 - carboxylic acid using inexpensive and readily available L - camphorsulfonamide as a chiral source, through condensation, asymmetric alkylation, hydrolysis, and removal of the chiral auxiliary group.

[0014] A method for preparing the avibactam intermediate (2S,5R) - benzyloxyamino - piperidine - 2 - carboxylic acid, the method comprising the following steps:

[0015]

[0016] Wherein: in formula (IV), X is selected from Cl, Br or I. The present invention adopts the following technical solutions:

[0017] A method for preparing the avibactam intermediate (2S,5R) - benzyloxyamino - piperidine - 2 - carboxylic acid is carried out according to the following steps:

[0018] Step A: The L-camphorsulfonamide shown in formula (I) is dissolved in organic solvent A1. Under a protective atmosphere A (nitrogen in the examples of the present invention), a hexane solution of trimethylaluminum is added dropwise at 10 - 30 °C (preferably 20 - 25 °C). After the addition is complete, the mixture is stirred and reacted for 10 - 30 minutes to obtain reaction solution A1. The diphenyl imidate shown in formula (II) is dissolved in organic solvent A2 and added to the reaction solution A1, and the reaction is carried out at 20 - 80 °C (preferably 40 - 50 °C) for 10 - 40 hours (preferably 15 - 20 hours). After the reaction is completed, the obtained reaction solution A is subjected to post-treatment A to obtain the compound shown in formula (III) (with chirality).

[0019] The molar ratio of the L-camphorsulfonamide shown in formula (I), the diphenyl imidate shown in formula (II) to trimethylaluminum in the hexane solution of trimethylaluminum is 1.0:1.0 - 1.5:1.0 - 1.5 (preferably 1.0:1.1:1.2).

[0020]

[0021] Step B: The compound shown in formula (III) obtained in Step A is dissolved in organic solvent B. Under -78 °C and protective atmosphere B, a basic substance B is added, and then the mixture is stirred and reacted at -78 °C for 10 - 60 minutes (preferably 20 - 30 minutes). At -78 °C, the homoallylic halide shown in formula (IV) is added. After the addition is complete, the temperature is naturally raised to room temperature (20 - 25 °C) and the reaction is carried out for 3 - 8 hours (preferably 4 - 6 hours). The obtained reaction solution B is subjected to post-treatment B to obtain the compound shown in formula (V).

[0022] The basic substance B is selected from one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, tert-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium bis(trimethylsilyl)amide, lithium hexamethyldisilazide, and is preferably lithium hexamethyldisilazide.

[0023] The molar ratio of the compound shown in formula (III), the homoallylic halide shown in formula (IV) to the basic substance B is 1.0:1.0 - 1.5:1.0 - 1.5 (preferably 1.0:1.2:1.2).

[0024]

[0025] In formula IV, X is a halogen, such as Cl, Br or I, and is chlorine in one embodiment of the present invention.

[0026] Step C: The compound shown in formula (V) obtained in Step B is dissolved in organic solvent C, and an aqueous solution of an acidic substance is added thereto at -10°C to 30°C (preferably 0°C to 20°C) for reaction for 1 to 8 hours (preferably 3 to 4 hours), and then naturally warmed to room temperature. The pH of the reaction solution is adjusted to 8 to 9 with saturated sodium bicarbonate solution. The obtained reaction solution C is subjected to post-treatment C to obtain the compound shown in formula (VI); herein, adding acid for hydrolysis can obtain the hydrochloride salt of the product, and adjusting the pH is mainly to neutralize hydrochloric acid to obtain a free amino group.

[0027] The molar ratio of the compound shown in formula (V) to the acidic substance in the aqueous solution of the acidic substance is 1.0:1.0 - 2.0 (preferably 1.0:1.5);

[0028]

[0029] Step D: The compound shown in formula (VI) obtained in Step C is dissolved in organic solvent D, elemental iodine is added thereto, and the reaction is carried out at 0°C to 70°C (preferably 10°C to 30°C) for 3 to 10 hours (preferably 5 to 7 hours). The obtained reaction solution D is subjected to post-treatment D to obtain the compound shown in formula (VII);

[0030] The molar ratio of the compound shown in formula (VI) to elemental iodine is 1.0:1.0 - 2.0 (preferably 1.0:1.2);

[0031]

[0032] Step E: The compound shown in formula (VII) obtained in Step D is dissolved in organic solvent E, benzyloxyhydroxylamine hydrochloride and organic base E are added thereto, and the reaction is carried out at 20°C to 100°C (preferably 40°C to 50°C) for 2 to 8 hours (preferably 3 to 5 hours). The obtained reaction solution E is subjected to post-treatment E to obtain the compound shown in formula (VIII);

[0033] The molar ratio of the compound shown in formula (VII), benzyloxyhydroxylamine hydrochloride to organic base E is 1.0:1.0 - 2.0:1.0 - 2.0 (preferably 1.0:1.5:1.5);

[0034]

[0035] Step F: The compound shown in formula (VIII) is dissolved in organic solvent F. At -10°C to 30°C (preferably 0 - 20°C), a basic substance F is added and the reaction is carried out for 1 - 10 hours (preferably 2 - 5 hours). It is naturally warmed to room temperature (20 - 25°C), and hydrochloric acid (with a concentration of 1.0 mol / L in an embodiment of the present invention) is added to adjust the pH to 4 - 5. After post-treatment F of the reaction solution F, the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid shown in formula (IX) is obtained;

[0036]

[0037] The preferred basic substance F is an inorganic base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, and most preferably lithium hydroxide. The basic substance F is added in the form of an aqueous solution of the basic substance F. In an embodiment of the present invention, the concentration of the basic substance F is 2.0 mol / L;

[0038] The molar ratio of the compound shown in formula (VIII) to the basic substance F is 1.0:1.0 - 5.0, preferably 1.0:3.0.

[0039] Furthermore, in step A, the organic solvents A1 and A2 are each independently one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dimethyl sulfoxide, and are preferably toluene.

[0040] Furthermore, in step A, the volume of the organic solvent A1 is 10 - 15 mL / g based on the mass of L-camphorsulfonamide shown in formula (I); the volume of the organic solvent A2 is 5 - 10 mL / g based on the mass of diphenyl imidate shown in formula (II).

[0041] Furthermore, in the embodiments of the present invention, the concentration of the n-hexane solution of trimethylaluminum is 1.0 mol / L - 2.0 mol / L.

[0042] Furthermore, in step A, the post-treatment A is: cooling the reaction solution A to room temperature, successively adding saturated sodium bicarbonate solution and water, separating the layers, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing with water (three times), concentrating the organic phase, and performing column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 4:1 as the eluent, collecting the eluent containing the target product, and evaporating the solvent to obtain the compound shown in formula (III).

[0043] Furthermore, in step B, the organic solvent B is one or more of toluene, anhydrous tetrahydrofuran, 1,4-dioxane, and is preferably anhydrous tetrahydrofuran.

[0044] Further, in step B, the volume of the organic solvent B is 5 - 10 mL / g based on the mass of the compound represented by the formula (III).

[0045] Further, in step B, the post-treatment B is as follows: water is added to the reaction solution B, liquid separation is performed, the obtained aqueous phase is extracted with ethyl acetate (3 times), the organic phases are combined, washed with saturated ammonium chloride, the obtained organic phase is concentrated, column chromatography separation is performed using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent, the eluent containing the target product is collected, and the solvent is evaporated to obtain the compound represented by the formula (V).

[0046] Further, in step C, the acidic substance is preferably hydrogen chloride or sulfuric acid, and most preferably hydrogen chloride.

[0047] Furthermore, in an embodiment of the present invention, the acidic substance is added in the form of an aqueous solution of the acidic substance, and the concentration of the aqueous solution of the acidic substance is 1.0 mol / L.

[0048] Further, in step C, the organic solvent C is one or a mixture of two or more of methanol, tetrahydrofuran, and N,N-dimethylformamide, and preferably tetrahydrofuran.

[0049] Further, in step C, the volume of the organic solvent C is 10 - 15 mL / g based on the mass of the compound represented by the formula (V).

[0050] Further, in step C, the post-treatment C is as follows: the reaction solution C is extracted with ethyl acetate, the organic phase is concentrated, column chromatography separation is performed using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent, the eluent containing the target product is collected, and the solvent is evaporated to obtain the compound represented by the formula (VI).

[0051] Further, in step D, the organic solvent D is one or a mixture of two or more of dichloromethane, chloroform, 1,2-dichloroethane, and toluene, and preferably dichloromethane.

[0052] Further, in step D, the volume of the organic solvent D is 10 - 15 mL / g based on the mass of the compound represented by the formula (VI).

[0053] Further, in step D, the post-treatment D is as follows: an aqueous solution of saturated sodium bisulfite is added to the reaction solution D, extraction is performed with ethyl acetate, the obtained organic phase is concentrated under reduced pressure, column chromatography separation is performed using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent, the eluent containing the target product is collected, and the solvent is evaporated to obtain the compound represented by the formula (VII).

[0054] Further, in step E, the organic solvent E is one or a mixture of two or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, and ethyl acetate, preferably 1,2-dichloroethane.

[0055] Further, in step E, the volume of the organic solvent E is 10 - 15 mL / g based on the mass of the compound represented by formula (VII).

[0056] Further, in step E, the organic base E is selected from one or a mixture of two of triethylamine, diisopropylethylamine, pyridine, and 2,6-dimethylpyridine, preferably triethylamine.

[0057] Further, in step E, the post-treatment E is as follows: water is added to the reaction solution E, followed by extraction with ethyl acetate. The obtained organic phase is concentrated, and column chromatography separation is performed using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. The eluate containing the target product is collected, and the solvent is evaporated to obtain the compound represented by formula (VIII).

[0058] Further, the basic substance F is added in the form of an aqueous solution of the basic substance F, and the concentration of the aqueous solution of the basic substance F is 2.0 mol / L.

[0059] Further, in step F, the basic substance F is selected from one or a mixture of two of sodium hydroxide, lithium hydroxide, potassium hydroxide, and calcium hydroxide, preferably lithium hydroxide.

[0060] Further, in step F, the organic solvent F is one or a mixture of two or more of methanol, ethanol, 1,4-dioxane, and tetrahydrofuran, preferably tetrahydrofuran.

[0061] Further, in step F, the volume of the organic solvent F is 10 - 15 mL / g based on the mass of the compound represented by formula (VI).

[0062] Further, in step F, the method for post-treatment F of the reaction solution F is as follows: the solvent in the obtained reaction solution F is removed by distillation under reduced pressure, and column chromatography separation is performed using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent. The eluate containing the target product is collected, and the solvent is evaporated to obtain the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid represented by formula (IX).

[0063] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0064] The raw materials of the present invention are cheap, readily available, have a short route, high yield, and good stereoselectivity. The diphenyl imidate shown in formula (II) forms a complex with trimethylaluminum, which can improve the nucleophilic ability of the amino group in camphorsulfonyl lactam and reduce the generation of by-products. Currently, (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid is an important chiral intermediate of avibactam and has good market prospects. Detailed implementation manners

[0065] The present invention will be further illustrated by specific examples below, but the protection scope of the present invention is not limited thereto.

[0066] In the examples, trimethylaluminum was purchased from Sigma-Aldrich Chemical Technology (Shanghai) Co., Ltd., with a specification of 1.0 mol / L n-hexane solution and a CAS number of 75-24-1;

[0067] Sodium hydride was purchased from Sigma-Aldrich Chemical Technology (Shanghai) Co., Ltd., with a specification of 60% mineral oil and a CAS number of 7646-69-6;

[0068] Potassium tert-butoxide was purchased from Sigma-Aldrich Chemical Technology (Shanghai) Co., Ltd., with a specification of 98% and a CAS number of 865-47-4;

[0069] n-Butyllithium was purchased from Sigma-Aldrich Chemical Technology (Shanghai) Co., Ltd., with a specification of 2.5 mol / L n-hexane solution and a CAS number of 109-72-8;

[0070] Lithium diisopropylamide was purchased from Sigma-Aldrich Chemical Technology (Shanghai) Co., Ltd., with a specification of 2.0 mol / L n-hexane solution and a CAS number of 4111-54-0;

[0071] Lithium hexamethyldisilazide was purchased from Sigma-Aldrich Chemical Technology (Shanghai) Co., Ltd., with a specification of 1.0 mol / L tetrahydrofuran solution and a CAS number of 4039-32-1.

[0072] Example 1: Synthesis of compound (Ⅲ)

[0073] The following reaction was carried out according to the molar ratio of L-camphorsulfonamide, diphenyl imidate to trimethylaluminum of 1.0:1.0:1.0:

[0074] Dissolve 0.43 g (2.0 mmol) of L-camphorsulfonamide in 5 mL of toluene. Under nitrogen protection, dropwise add 2.0 mL (2.0 mmol) of trimethylaluminum n-hexane solution (1.0 mol / L) at room temperature. Stir the system at room temperature for another 15 minutes, then add 0.534 g (2.0 mmol) of the toluene solution (5 mL) of diphenyl imidate. Heat the temperature to 40 °C and react for 20 hours. Cool the reaction solution to room temperature (20 - 25 °C), successively add 10 mL of saturated sodium bicarbonate and 10 mL of water, separate the layers, extract the aqueous phase with 20 mL of ethyl acetate, combine the organic phases, wash with water (10 mL) three times, concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 4:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.698 g of the compound shown in formula (III) with a yield of 80% and a product purity of 96% (HPLC).

[0075] Example 2: Synthesis of Compound (III)

[0076] Carry out the following reaction according to the molar ratio of L-camphorsulfonamide, diphenyl imidate to trimethylaluminum of 1.0:1.5:1.0:

[0077] Dissolve 0.5 g (2.32 mmol) of L-camphorsulfonamide in 5 mL of toluene. Under nitrogen protection, dropwise add 2.4 mL (2.4 mmol) of trimethylaluminum n-hexane solution (1.0 mol / L) at room temperature. After continuously stirring the above reaction solution at room temperature for 15 minutes, add 0.93 g (3.48 mmol) of the toluene solution (5 mL) of diphenyl imidate to the reaction solution, heat the temperature to 40 °C, and react for 20 hours.. Cool the reaction solution to room temperature (20 - 25 °C), successively add 10 mL of saturated sodium bicarbonate and 10 mL of water, separate the layers, extract the aqueous phase with 20 mL of ethyl acetate, combine the organic phases, wash with water (10 mL) three times, concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 4:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.84 g of the compound shown in formula (III) with a yield of 83% and a product purity of 97% (HPLC).

[0078] Example 3: Synthesis of Compound (III)

[0079] Carry out the following reaction according to the molar ratio of L-camphorsulfonamide, diphenyl imidate to trimethylaluminum of 1.0:1.1:1.0:

[0080] Dissolve 0.5 g (2.32 mmol) of L-camphorsulfonamide in 5 mL of toluene. Under nitrogen protection, add 2.4 mL (2.4 mmol) of trimethylaluminum n-hexane solution (1.0 mol / L) dropwise at room temperature. After continuously stirring the above reaction solution at room temperature for 15 minutes, add a toluene solution (5 mL) of 0.68 g (2.55 mmol) of diphenyl imidate to the reaction solution, heat up to 40 °C, and react for 20 hours. Cool the reaction solution to room temperature (20 - 25 °C), successively add 10 mL of saturated sodium bicarbonate and 10 mL of water, separate the layers, extract the aqueous phase with 20 mL of ethyl acetate, combine the organic phases, wash three times with water (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 4:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.86 g of the compound shown in formula (III) with a yield of 85.6% and a product purity of 96% (HPLC).

[0081] Example 4: Synthesis of Compound (III)

[0082] Carry out the following reaction according to the molar ratio of L-camphorsulfonamide, diphenyl imidate to trimethylaluminum of 1.0:1.1:1.5:

[0083] Dissolve 0.538 g (2.5 mmol) of L-camphorsulfonamide in 6 mL of toluene. Under nitrogen protection, add 3.8 mL (3.8 mmol) of trimethylaluminum n-hexane solution (1.0 mol / L) dropwise at room temperature. After continuously stirring the above reaction solution at room temperature for 20 minutes, add a toluene solution (5 mL) of 0.735 g (2.75 mmol) of diphenyl imidate to the reaction solution, heat up to 40 °C, and react for 20 hours. Cool the reaction solution to room temperature (20 - 25 °C), successively add 10 mL of saturated sodium bicarbonate and 10 mL of water, separate the layers, extract the aqueous phase with 20 mL of ethyl acetate, combine the organic phases, wash three times with water (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 4:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.916 g of the compound shown in formula (III) with a yield of 84% and a product purity of 97% (HPLC).

[0084] Example 5: Synthesis of Compound (III)

[0085] Carry out the following reaction according to the molar ratio of L-camphorsulfonamide, diphenyl imidate to trimethylaluminum of 1.0:1.1:1.2:

[0086] Dissolve 0.6 g (2.8 mmol) of L-camphorsulfonamide in 8 mL of toluene. Under nitrogen protection, add 3.4 mL (3.4 mmol) of trimethylaluminum n-hexane solution (1.0 mol / L) dropwise at room temperature. After continuously stirring the above reaction solution at room temperature for 15 minutes, add a toluene solution (5 mL) of 0.822 g (3.08 mmol) of diphenyl imidate to the reaction solution, heat up to 40 °C, and react for 20 hours. Cool the reaction solution to room temperature (20 - 25 °C), successively add 10 mL of saturated sodium bicarbonate and 10 mL of water, separate the layers, extract the aqueous phase with 20 mL of ethyl acetate, combine the organic phases, wash with water (10 mL) three times, concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 4:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent to obtain 1.087 g of the compound shown in formula (III), with a yield of 89% and a product purity of 98% (HPLC). 1 1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 5.2, 3.3 Hz, 2H), 7.49 - 7.42 (m, 3H), 7.38 (dd, J = 4.9, 3.6 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.25–7.15 (m, 2H), 4.63 (d, J = 4.5 Hz, 2H), 3.90 (dd, J = 7.8, 4.9 Hz, 1H), 3.42 (d, J = 12.4 Hz, 2H), 2.14 - 2.03 (m, 1H), 1.41 - 1.38 (m, 1H), 1.35 (d, J = 6.7 Hz, 1H), 1.13 (s, 4H), 0.95 (s, 6H) ppm.

[0087] Example 6: Synthesis of Compound (V)

[0088] Carry out the following reaction according to the molar ratio of compound (III), homoallyl chloride (IV) and sodium hydride of 1.0:1.0:1.0:

[0089] Add 1.05 g (2.4 mmol) of compound (III), 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 97 mg (2.4 mmol, mineral oil with a mass fraction of 60%) of sodium hydride at -78 °C. Stir the reaction solution at -78 °C for 20 minutes, then add homoallyl chloride (IV) (216 mg, 2.4 mmol) dropwise at -78 °C. After addition, let the reaction solution warm up to room temperature (20 - 25 °C) and react for 5 hours. Add 10 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated ammonium chloride (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.823 g of the compound shown in formula (V) with a yield of 70.0% and a product purity of 97% (HPLC).

[0090] Example 7: Synthesis of compound (V)

[0091] Carry out the following reaction according to the molar ratio of compound (III), homoallyl chloride (IV) to potassium tert-butoxide of 1.0:1.0:1.0:

[0092] Add 1.05 g (2.4 mmol) of compound (III), 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 0.27 g (2.4 mmol) of potassium tert-butoxide at -78 °C. Stir the reaction solution at -78 °C for 30 minutes, then add homoallyl chloride (IV) (216 mg, 2.4 mmol) dropwise at -78 °C. After addition, let the reaction solution warm up to room temperature (20 - 25 °C) and react for 6 hours. Add 10 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated ammonium chloride (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.764 g of the compound shown in formula (V) with a yield of 65% and a product purity of 98% (HPLC).

[0093] Example 8: Synthesis of compound (V)

[0094] Carry out the following reaction according to the molar ratio of compound (III), homoallyl chloride (IV) to n-butyllithium of 1.0:1.0:1.0:

[0095] Add 1.05 g (2.4 mmol) of compound (III) and 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 0.96 mL of n-butyllithium n-hexane solution (2.5 mol / L) at -78 °C. Stir the reaction solution at -78 °C for an additional 20 minutes, then add homoallyl chloride (IV) (216 mg, 2.4 mmol) dropwise at -78 °C. After addition, let the reaction solution warm to room temperature (20 - 25 °C) and react for 5 hours. Add 10 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated ammonium chloride (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent to obtain 0.964 g of the compound shown in formula (V), with a yield of 82% and a product purity of 98% (HPLC).

[0096] Example 9: Synthesis of Compound (V)

[0097] Carry out the following reaction according to the molar ratio of compound (III), homoallyl chloride (IV) to lithium diisopropylamide of 1.0:1.0:1.0:

[0098] Add 1.05 g (2.4 mmol) of compound (III) and 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 1.21 mL of lithium diisopropylamide n-hexane solution (2.0 mol / L) at -78 °C. Stir the reaction solution at -78 °C for an additional 20 minutes, then add homoallyl chloride (IV) (216 mg, 2.4 mmol) dropwise. After addition, let the reaction solution warm to room temperature (20 - 25 °C) and react for 4 hours. Add 10 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated ammonium chloride (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent to obtain 0.976 g of the compound shown in formula (V), with a yield of 83% and a product purity of 97.8% (HPLC).

[0099] Example 10: Synthesis of Compound (V)

[0100] Carry out the following reaction according to the molar ratio of compound (III), homoallyl chloride (IV) to lithium hexamethyldisilazide of 1.0:1.0:1.0:

[0101] Add 1.05 g (2.4 mmol) of compound (III) and 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 2.41 mL of lithium hexamethyldisilazide tetrahydrofuran solution (1.0 mol / L) at -78 °C. The reaction mixture is stirred at -78 °C for an additional 20 minutes, and then allyl chloride (IV) (216 mg, 2.4 mmol) is added dropwise at -78 °C. After addition, the reaction mixture is allowed to warm to room temperature (20 - 25 °C) and react for 5 hours. When the reaction is completed as detected by TLC, add 10 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated ammonium chloride (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 1.0 g of the compound shown in formula (V) with a yield of 85% and a product purity of 98.3% (HPLC).

[0102] Example 11: Synthesis of Compound (V)

[0103] Carry out the following reaction according to the molar ratio of compound (III), allyl chloride (IV) to lithium hexamethyldisilazide of 1.0:1.2:1.2:

[0104] Add 1.05 g (2.4 mmol) of compound (III) and 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 2.88 mL (2.88 mmol) of lithium hexamethyldisilazide tetrahydrofuran solution (1.0 mol / L) at -78 °C. The reaction mixture is stirred at -78 °C for an additional 20 minutes, and then allyl chloride (IV) (260 mg, 2.88 mmol) is added dropwise at -78 °C. After addition, the reaction mixture is allowed to warm to room temperature (20 - 25 °C) and react for 5 hours. Add 10 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated ammonium chloride (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 1.047 g of the compound shown in formula (V) with a yield of 89% and a product purity of 98% (HPLC).

[0105] Example 12: Synthesis of Compound (V)

[0106] Carry out the following reaction according to the molar ratio of compound (III), allyl bromide (IV) to lithium hexamethyldisilazide of 1.0:1.2:1.2:

[0107] Add 1.05 g (2.4 mmol) of compound (III) and 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 2.88 mL (2.88 mmol) of lithium hexamethyldisilazide tetrahydrofuran solution (1.0 mol / L) at -78 °C. Stir the reaction solution at -78 °C for an additional 20 minutes, then add homoallyl bromide (IV) (386 mg, 2.88 mmol) dropwise at -78 °C. After addition, allow the reaction solution to warm to room temperature (20 - 25 °C) and react for 4 hours. Add 10 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated ammonium chloride (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 1.058 g of the compound shown in formula (V) with a yield of 90% and a product purity of 98% (HPLC).

[0108] Example 13: Synthesis of compound (V)

[0109] Carry out the following reaction according to the molar ratio of compound (III), homoallyl iodide (IV) to lithium hexamethyldisilazide being 1.0:1.2:1.2:

[0110] Add 1.05 g (2.4 mmol) of compound (III) and 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 2.88 mL (2.88 mmol) of lithium hexamethyldisilazide tetrahydrofuran solution (1.0 mol / L) at -78 °C. Stir the reaction solution at -78 °C for an additional 20 minutes, then add homoallyl iodide (IV) (524 mg, 2.88 mmol) dropwise at -78 °C. After addition, allow the reaction solution to warm to room temperature (20 - 25 °C) and react for 4 hours. Add 10 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated ammonium chloride (10 mL), concentrate the organic phase, and perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 1.082 g of the compound shown in formula (V) with a yield of 92% and a product purity of 98% (HPLC).

[0111] Example 14: Synthesis of compound (VI)

[0112] Carry out the following reaction according to the molar ratio of compound (V) to hydrochloric acid being 1.0:1.0:

[0113] Dissolve 0.49 g (1.0 mmol) of compound (V) in 5 mL of tetrahydrofuran, add 1.0 mL (1.0 mol / L) of aqueous hydrochloric acid at 0 °C, and maintain the reaction at 0 °C for 4 hours. The reaction solution is allowed to rise to room temperature (20 - 25 °C) naturally, the pH of the aqueous phase is adjusted to 8 - 9 with saturated sodium bicarbonate, and then extracted with ethyl acetate. The organic phase is concentrated, and column chromatography is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. The eluate containing the target product is collected, the solvent is evaporated, and 0.274 g of the compound shown in formula (VI) is obtained, with a yield of 84% and a product purity of 98.5% (HPLC).

[0114] Example 15: Synthesis of compound (VI)

[0115] Carry out the following reaction according to the molar ratio of compound (V) to hydrochloric acid of 1.0:1.5:

[0116] Add 0.49 g (1.0 mmol) of compound (V) and 5 mL of tetrahydrofuran, add 1.5 mL (1.0 mol / L) of aqueous hydrochloric acid at 0 °C, and maintain the reaction at 0 °C for 4 hours. The reaction solution is allowed to rise to room temperature (20 - 25 °C) naturally, the pH of the aqueous phase is adjusted to 8 - 9 with saturated sodium bicarbonate, extracted with ethyl acetate, the organic phase is concentrated, and column chromatography is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. The eluate containing the target product is collected, the solvent is evaporated, and 0.293 g of the compound shown in formula (VI) is obtained, with a yield of 90% and a product purity of 97.6% (HPLC).

[0117] Example 16: Synthesis of compound (VI)

[0118] Carry out the following reaction according to the molar ratio of compound (V) to sulfuric acid of 1.0:1.0:

[0119] Add 0.49 g (1.0 mmol) of compound (V) and 5 mL of tetrahydrofuran, add 1.0 mL of sulfuric acid aqueous solution (1.0 mol / L) at 0 °C, and maintain the reaction at 0 °C for 4 hours. The reaction solution is allowed to rise to room temperature (20 - 25 °C) naturally, the pH of the aqueous phase is adjusted to 8 - 9 with saturated sodium bicarbonate, then extracted with ethyl acetate, the organic phase is concentrated, and column chromatography is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. The eluate containing the target product is collected, the solvent is evaporated, and 0.267 g of the compound shown in formula (VI) is obtained, with a yield of 82% and a product purity of 98% (HPLC).

[0120] Example 17: Synthesis of compound (VII)

[0121] Carry out the following reaction according to the molar ratio of compound (VI) to elemental iodine of 1.0:1.2:

[0122] Dissolve 0.489 g (1.5 mmol) of compound (VI) in dichloromethane (5 mL), add 0.457 g (1.8 mmol) of elemental iodine, react at 25 °C for 6 hours, add saturated sodium bisulfite (5 mL), add ethyl acetate (30 mL) for extraction, separate the layers, concentrate the organic phase under reduced pressure, perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent, collect the eluate containing the target product, evaporate the solvent, and obtain 0.596 g of the compound shown in formula (VII) with a yield of 88% and a product purity of 97% (HPLC).

[0123] Example 18: Synthesis of compound (VII)

[0124] Carry out the following reaction according to the molar ratio of compound (VI) to elemental iodine of 1.0:1.0:

[0125] Dissolve 0.587 g (1.8 mmol) of compound (VI) in dichloromethane (6 mL), add 0.457 g (1.8 mmol) of elemental iodine, react at 25 °C for 8 hours, add saturated sodium bisulfite (5 mL), add ethyl acetate (30 mL) for extraction, separate the layers, concentrate the organic phase under reduced pressure, perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent, collect the eluate containing the target product, evaporate the solvent, and obtain 0.642 g of the compound shown in formula (VII) with a yield of 79% and a product purity of 95% (HPLC).

[0126] Example 19: Synthesis of compound (VII)

[0127] Carry out the following reaction according to the molar ratio of compound (VI) to elemental iodine of 1.0:2.0:

[0128] Dissolve 0.326 g (1.0 mmol) of compound (VI) in dichloromethane (4 mL), add 0.508 g (2.0 mmol) of elemental iodine, react at 25 °C for 4 hours, add saturated sodium bisulfite (6 mL), add ethyl acetate (30 mL) for extraction, separate the layers, concentrate the organic phase under reduced pressure, perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent, collect the eluate containing the target product, evaporate the solvent, and obtain 0.380 g of the compound shown in formula (VII) with a yield of 84% and a product purity of 95% (HPLC).

[0129] Example 20: Synthesis of compound (VII)

[0130] Carry out the following reaction according to the molar ratio of compound (VI) to elemental iodine of 1.0:1.2:

[0131] Dissolve 0.489 g (1.5 mmol) of compound (VI) in 1,2-dichloroethane (5 mL), add 0.457 g (1.8 mmol) of elemental iodine, react at 25 °C for 6 hours, add saturated sodium bisulfite (5 mL), add ethyl acetate (30 mL) for extraction, separate the layers, concentrate the organic phase under reduced pressure, perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent, collect the eluate containing the target product, evaporate the solvent, and obtain 0.556 g of the compound shown in formula (VII) with a yield of 82% and a product purity of 96% (HPLC).

[0132] Example 21: Synthesis of compound (VII)

[0133] Carry out the following reaction according to the molar ratio of compound (VI) to elemental iodine of 1.0:1.2:

[0134] Dissolve 0.489 g (1.5 mmol) of compound (VI) in 1,2-dichloroethane (5 mL), add 0.457 g (1.8 mmol) of elemental iodine, react at 60 °C for 6 hours, add saturated sodium bisulfite (5 mL), add ethyl acetate (30 mL) for extraction, separate the layers, concentrate the organic phase under reduced pressure, perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent, collect the eluate containing the target product, evaporate the solvent, and obtain 0.488 g of the compound shown in formula (VII) with a yield of 72% and a product purity of 94% (HPLC).

[0135] Example 22: Synthesis of compound (VII)

[0136] Carry out the following reaction according to the molar ratio of compound (VI) to elemental iodine of 1.0:1.2:

[0137] Dissolve 0.326 g (1.0 mmol) of compound (VI) in dichloromethane (4 mL), add 0.305 g (1.2 mmol) of elemental iodine, react at 0 °C for 10 hours, add saturated sodium bisulfite (5 mL), add ethyl acetate (30 mL) for extraction, separate the layers, concentrate the organic phase under reduced pressure, perform column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent, collect the eluate containing the target product, evaporate the solvent, and obtain 0.316 g of the compound shown in formula (VII) with a yield of 70% and a product purity of 95% (HPLC).

[0138] Example 23: Synthesis of compound (VIII)

[0139] Carry out the following reaction according to the molar ratio of compound (VII), O-benzylhydroxylamine hydrochloride to triethylamine of 1.0:1.5:1.5:

[0140] Dissolve 0.452 g (1.0 mmol) of compound (VII) in 1,2-dichloroethane (5.0 mL), add 0.239 g (1.5 mmol) of benzyloxyhydroxylamine hydrochloride and 0.152 g (1.5 mmol) of triethylamine, react at 45 °C for 4 hours. After the reaction solution cools to room temperature (20 - 25 °C), add water (20 mL), extract with ethyl acetate. The organic phase is concentrated under reduced pressure to remove the solvent. Column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.375 g of the compound shown in formula (VIII), with a yield of 84% and a product purity of 97% (HPLC).

[0141] Example 24: Synthesis of compound (VIII)

[0142] Carry out the following reaction according to the molar ratio of compound (VII), benzyloxyhydroxylamine hydrochloride to triethylamine of 1.0:1.0:1.0:

[0143] Dissolve 0.452 g (1.0 mmol) of compound (VII) in 1,2-dichloroethane (5.0 mL), add 0.159 g (1.0 mmol) of benzyloxyhydroxylamine hydrochloride and 0.101 g (1.0 mmol) of triethylamine, react at 50 °C for 7 hours. After the reaction solution cools to room temperature (20 - 25 °C), add water (20 mL), extract with ethyl acetate. The organic phase is concentrated under reduced pressure to remove the solvent. Column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.322 g of the compound shown in formula (VIII), with a yield of 72% and a product purity of 95% (HPLC).

[0144] Example 25: Synthesis of compound (VIII)

[0145] Carry out the following reaction according to the molar ratio of compound (VII), benzyloxyhydroxylamine hydrochloride to triethylamine of 1.0:2.0:2.0:

[0146] Dissolve 0.452 g (1.0 mmol) of compound (VII) in 1,2-dichloroethane (5.0 mL), add 0.320 g (2.0 mmol) of benzyloxyhydroxylamine hydrochloride and 0.203 g (2.0 mmol) of triethylamine, react at 45 °C for 3 hours. After the reaction solution cools to room temperature (20 - 25 °C), add water (20 mL), extract with ethyl acetate. The organic phase is concentrated under reduced pressure to remove the solvent. Column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent, and obtain 0.367 g of the compound shown in formula (VIII), with a yield of 82% and a product purity of 95% (HPLC).

[0147] Example 26: Synthesis of Compound (VIII)

[0148] The following reaction was carried out according to the molar ratio of compound (VII), O-benzylhydroxylamine hydrochloride to triethylamine of 1.0:1.5:1.5:

[0149] Dissolve 0.452 g (1.2 mmol) of compound (VII) in tetrahydrofuran (5.0 mL), add 0.287 g (1.8 mmol) of O-benzylhydroxylamine hydrochloride and 0.182 g (1.8 mmol) of triethylamine, react at 45 °C for 5 hours, cool the reaction solution to room temperature (20 - 25 °C), add water (20 mL), extract with ethyl acetate, concentrate the organic phase under reduced pressure to remove the solvent, carry out column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent, collect the eluate containing the target product, evaporate the solvent, and obtain 0.429 g of the compound shown in formula (VIII), with a yield of 80% and a product purity of 95% (HPLC).

[0150] Example 27: Synthesis of Compound (VIII)

[0151] The following reaction was carried out according to the molar ratio of compound (VII), O-benzylhydroxylamine hydrochloride to triethylamine of 1.0:1.5:1.5:

[0152] Dissolve 0.452 g (1.0 mmol) of compound (VII) in dichloromethane (5.0 mL), add 0.239 g (1.5 mmol) of O-benzylhydroxylamine hydrochloride and 0.152 g (1.5 mmol) of triethylamine, react at 40 °C for 7 hours, cool the reaction solution to room temperature (20 - 25 °C), add water (20 mL), extract with ethyl acetate, concentrate the organic phase under reduced pressure to remove the solvent, carry out column chromatography separation using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent, collect the eluate containing the target product, evaporate the solvent, and obtain 0.349 g of the compound shown in formula (VIII), with a yield of 78% and a product purity of 94% (HPLC).

[0153] Example 28: Synthesis of Compound (VIII)

[0154] The following reaction was carried out according to the molar ratio of compound (VII), O-benzylhydroxylamine hydrochloride to diisopropylethylamine of 1.0:1.5:1.5:

[0155] Dissolve 0.452 g (1.0 mmol) of compound (VII) in 1,2-dichloroethane (5.0 mL), add 0.239 g (1.5 mmol) of benzyloxyhydroxylamine hydrochloride and 0.194 g (1.5 mmol) of diisopropylethylamine, react at 40 °C for 5 h. After the reaction solution is cooled to room temperature (20 - 25 °C), add water (20 mL), extract with ethyl acetate. The organic phase is concentrated under reduced pressure to remove the solvent. Column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent to obtain 0.362 g of the compound shown in formula (VIII), with a yield of 81% and a product purity of 96% (HPLC).

[0156] Example 29: Synthesis of compound (VIII)

[0157] Carry out the following reaction according to the molar ratio of compound (VII), benzyloxyhydroxylamine hydrochloride to pyridine of 1.0:1.5:1.5:

[0158] Dissolve 0.452 g (1.0 mmol) of compound (VII) in 1,2-dichloroethane (5.0 mL), add 0.239 g (1.5 mmol) of benzyloxyhydroxylamine hydrochloride and 0.119 g (1.5 mmol) of pyridine, react at 45 °C for 4 h. After the reaction solution is cooled to room temperature (20 - 25 °C), add water (20 mL), extract with ethyl acetate. The organic phase is concentrated under reduced pressure to remove the solvent. Column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent to obtain 0.353 g of the compound shown in formula (VIII), with a yield of 79% and a product purity of 94% (HPLC).

[0159] Example 30: Synthesis of compound (IX)

[0160] Carry out the following reaction according to the molar ratio of compound (VIII) to sodium hydroxide of 1.0:3.0: Add 0.447 g (1.0 mmol) of compound (VIII) and 5 mL of tetrahydrofuran. Add 1.5 mL (3.0 mmol) of NaOH aqueous solution (2.0 mol / L) at 0 °C and maintain this temperature for 3 h. The reaction solution is naturally warmed to room temperature (20 - 25 °C), add 1.0 mol / L hydrochloric acid to adjust the pH of the reaction solution to 4 - 5, concentrate under reduced pressure, and carry out column chromatography separation using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent. Collect the eluate containing the target product, evaporate the solvent to obtain 0.21 g of the compound shown in formula (IX), with a yield of 84% and a product purity of 98% (HPLC). 1H-NMR(400MHz, D2O) δ 7.45 - 7.40 (m, 5H), 4.74 (s, 2H), 3.60 - 3.53 (m, 2H), 3.27 - 3.24 (m, 1H), 2.84 - 2.80 (m, 1H), 2.34 - 2.31 (m, 1H), 2.03 - 1.97 (m, 1H), 1.73 - 1.67 (m, 1H), 1.51 - 1.47 (m, 1H); ESI-MS C 13 H 18 N2O3 [M + H] + : 251.1。

[0161] Example 31: Synthesis of Compound (IX)

[0162] The following reaction was carried out according to the molar ratio of compound (VI) to lithium hydroxide of 1.0:3.0:

[0163] 0.447 g (1.0 mmol) of compound (VI) and 5 mL of tetrahydrofuran were added. 1.5 mL (3.0 mmol) of an aqueous LiOH solution (2.0 mol / L) was added at 0 °C, and the reaction was maintained at this temperature for 5 hours. The reaction solution was allowed to rise to room temperature (20 - 25 °C) naturally, and 1.0 mol / L hydrochloric acid was added to adjust the pH of the reaction solution to 4 - 5. The solvent was removed by distillation under reduced pressure, and column chromatography separation was carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent. The eluate containing the target product was collected, and the solvent was evaporated to obtain 0.237 g of the compound shown in formula (IX), with a yield of 95% and a product purity of 98% (HPLC).

[0164] Example 32: Synthesis of Compound (IX)

[0165] The following reaction was carried out according to the molar ratio of compound (VI) to lithium hydroxide of 1.0:3.0: 0.447 g (1.0 mmol) of compound (VI) and 5 mL of methanol were added. 1.5 mL (3.0 mmol) of an aqueous LiOH solution (2.0 mol / L) was added at 0 °C, and the reaction was maintained at this temperature for 5 hours. The reaction solution was allowed to rise to room temperature (20 - 25 °C) naturally, and 1.0 mol / L hydrochloric acid was added to adjust the pH of the reaction solution to 4 - 5. The solvent was concentrated under reduced pressure, and column chromatography separation was carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent. The eluate containing the target product was collected, and the solvent was evaporated to obtain 0.228 g of the compound shown in formula (IX), with a yield of 91% and a product purity of 98% (HPLC).

[0166] Example 33: Synthesis of Compound (IX)

[0167] The following reaction was carried out according to the molar ratio of compound (VI) to lithium hydroxide of 1.0:1.0: 0.671 g (1.5 mmol) of compound (VI) and 8 mL of tetrahydrofuran were added. 0.75 mL (1.5 mmol) of an aqueous LiOH solution (2.0 mol / L) was added at 0 °C, and the reaction was carried out at this temperature for 8 hours. The reaction solution was allowed to rise to room temperature (20 - 25 °C) naturally, and 1.0 mol / L hydrochloric acid was added to adjust the pH of the reaction solution to 4 - 5. The solution was concentrated under reduced pressure, and column chromatography separation was carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent. The eluate containing the target product was collected, the solvent was evaporated, and 0.281 g of the compound shown in formula (IX) was obtained, with a yield of 75% and a product purity of 95% (HPLC).

[0168] Example 34: Synthesis of compound (IX)

[0169] The following reaction was carried out according to the molar ratio of compound (VI) to lithium hydroxide of 1.0:2.0: 0.671 g (1.5 mmol) of compound (VI) and 8 mL of tetrahydrofuran were added. 1.5 mL (3.0 mmol) of an aqueous LiOH solution (2.0 mol / L) was added at 0 °C, and the reaction was carried out at this temperature for 6 hours. The reaction solution was allowed to rise to room temperature (20 - 25 °C) naturally, and 1.0 mol / L hydrochloric acid was added to adjust the pH of the reaction solution to 4 - 5. The solution was concentrated under reduced pressure, and column chromatography separation was carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent. The eluate containing the target product was collected, the solvent was evaporated, and 0.334 g of the compound shown in formula (IX) was obtained, with a yield of 89% and a product purity of 97% (HPLC).

[0170] Example 35: Synthesis of compound (IX)

[0171] The following reaction was carried out according to the molar ratio of compound (VI) to lithium hydroxide of 1.0:3.0: 0.447 g (1.0 mmol) of compound (VI) and 5 mL of tetrahydrofuran were added. 1.5 mL (3.0 mmol) of an aqueous LiOH solution (2.0 mol / L) was added at -10 °C, and the reaction was carried out at this temperature for 10 hours. The reaction solution was allowed to rise to room temperature (20 - 25 °C) naturally, and 1.0 mol / L hydrochloric acid was added to adjust the pH of the reaction solution to 4 - 5. The solution was concentrated under reduced pressure, and column chromatography separation was carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent. The eluate containing the target product was collected, the solvent was evaporated, and 0.175 g of the compound shown in formula (IX) was obtained, with a yield of 70% and a product purity of 95% (HPLC).

[0172] Example 36: Synthesis of compound (IX)

[0173] The following reaction was carried out according to the molar ratio of compound (VI) to lithium hydroxide of 1.0:3.0: 0.447 g (1.0 mmol) of compound (VI) and 5 mL of tetrahydrofuran were added. 1.5 mL (3.0 mmol) of an aqueous LiOH solution (2.0 mol / L) was added at 30 °C, and the reaction was maintained at this temperature for 6 hours. The reaction solution was allowed to rise to room temperature (20 - 25 °C) naturally, and the pH of the reaction solution was adjusted to 4 - 5 with 1.0 mol / L hydrochloric acid. The solution was concentrated under reduced pressure, and column chromatography separation was carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent. The eluate containing the target product was collected, the solvent was evaporated, and 0.233 g of the compound shown in formula (IX) was obtained, with a yield of 93% and a product purity of 98% (HPLC).

[0174] It should be noted that the above experimental examples are only to illustrate the concept and characteristics of the present invention, and their purpose is to enable those familiar with the present invention to understand this experiment and implement it accordingly, and cannot limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for preparing the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid, characterized in that Proceed as follows: Step A: L-camphorsulfonamide shown in formula (I) is dissolved in organic solvent A1. Under a protective atmosphere A, a n-hexane solution of trimethylaluminum is added dropwise at 10 - 30 °C. After the addition is complete, the mixture is stirred and reacted for 10 - 30 minutes to obtain reaction solution A1; diphenyl imidate shown in formula (II) is dissolved in organic solvent A2 and added to the obtained reaction solution A1. The reaction is carried out at 20 - 80 °C for 10 - 40 hours. After the reaction is completed, the obtained reaction solution A is subjected to post-treatment A to obtain the compound shown in formula (III); The molar ratio of L-camphorsulfonamide shown in formula (I), diphenyl imidate shown in formula (II) to trimethylaluminum in the n-hexane solution of trimethylaluminum is 1.0:1.0 - 1.5:1.0 - 1.5; Step B: The compound shown in formula (III) obtained in Step A is dissolved in organic solvent B. Under a protective atmosphere B at -78 °C, a basic substance B is added, and then the mixture is stirred and reacted at -78 °C for 10 - 60 minutes. At -78 °C, a homoallylic halide shown in formula (IV) is added. After the addition is complete, the temperature is naturally raised to room temperature and the reaction is carried out for 3 - 8 hours. The obtained reaction solution B is subjected to post-treatment B to obtain the compound shown in formula (V); The basic substance B selected from one of the following: sodium hydride, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, tert-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium bis(trimethylsilyl)amide or lithium hexamethyldisilazide; The molar ratio of the compound shown in formula (III), the homoallylic halide shown in formula (IV) to the basic substance B is 1.0:1.0 - 1.5:1.0 - 1.5; In formula (IV), X is a halogen; Step C: The compound shown in formula (V) obtained in Step B is dissolved in organic solvent C. An aqueous solution of an acidic substance is added at -10 °C to 30 °C and the reaction is carried out for 1 - 8 hours. The temperature is naturally raised to room temperature, and the pH of the reaction solution is adjusted to 8 - 9 with saturated sodium bicarbonate solution. The obtained reaction solution C is subjected to post-treatment C to obtain the compound shown in formula (VI); The molar ratio of the compound shown in formula (V) to the acidic substance in the aqueous solution of the acidic substance is 1.0:1.0 - 2.0; Step D: The compound shown in formula (VI) obtained in Step C is dissolved in organic solvent D. Elemental iodine is added and the reaction is carried out at 0 °C - 70 °C for 3 - 10 hours. The obtained reaction solution D is subjected to post-treatment D to obtain the compound shown in formula (VII); The molar ratio of the compound shown in formula (VI) and elemental iodine is 1.0:1.0 - 2.0; Step E: The compound shown in formula (VII) obtained in Step D is dissolved in organic solvent E. Benzyl O-hydroxyamine hydrochloride and organic base E are added, and the reaction is carried out at 20 °C - 100 °C for 2 - 8 hours. The obtained reaction solution E is subjected to post-treatment E to obtain the compound shown in formula (VIII); The molar ratio of the compound shown in formula (VII), benzyl O-hydroxyamine hydrochloride to organic base E is 1.0:1.0 - 2.0:1.0 - 2.0; Step F: The compound shown in formula (VIII) is dissolved in organic solvent F. At -10°C - 30°C, a basic substance F is added and the reaction is carried out for 1 - 10 hours. It is naturally raised to room temperature of 20 - 25°C, and hydrochloric acid is added to adjust the pH to 4 - 5. The resulting reaction solution F is subjected to post-treatment F to obtain the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid shown in formula (IX). The basic substance F is an inorganic base, and the molar ratio of the compound shown in formula (VIII) to the basic substance F is 1.0:1.0 - 5.

0.

2. The method for preparing the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid according to claim 1, characterized in that, The concentration of the n-hexane solution of trimethylaluminum is 1.0 mol / L - 2.0 mol / L.

3. The method for preparing the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid according to claim 1, characterized in that In the said step A, the post-treatment A is as follows: The reaction solution A is cooled to room temperature, saturated sodium bicarbonate solution and water are added successively, and liquid separation is carried out. The aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with water, the organic phase is concentrated, and column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 4:1 as the eluent. The eluent containing the target product is collected, and the solvent is evaporated to obtain the compound shown in formula (III).

4. The method for preparing the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid according to claim 1, characterized in that In the said step B, the post-treatment B is as follows: Water is added to the reaction solution B, and liquid separation is carried out. The resulting aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with saturated ammonium chloride solution, the resulting organic phase is concentrated, and column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the eluent. The eluent containing the target product is collected, and the solvent is evaporated to obtain the compound shown in formula (V).

5. The method for preparing the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid according to claim 1, characterized in that In the said step C, the post-treatment C is as follows: The reaction solution C is extracted with ethyl acetate, the organic phase is concentrated, and column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. The eluent containing the target product is collected, and the solvent is evaporated to obtain the compound shown in formula (VI).

6. The method for preparing the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid according to claim 1, characterized in that In the said step D, the post-treatment D is as follows: An aqueous solution of saturated sodium bisulfite is added to the reaction solution D, and extraction is carried out with ethyl acetate. The resulting organic phase is concentrated under reduced pressure, and column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent. The eluent containing the target product is collected, and the solvent is evaporated to obtain the compound shown in formula (VII).

7. The preparation method of the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid as described in claim 1, wherein In step E, the organic base E is selected from one or a mixture of two of triethylamine, diisopropylethylamine, pyridine, and 2,6-dimethylpyridine.

8. The preparation method of the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid as described in claim 1, wherein In step E, the post-treatment E is as follows: Water is added to the reaction solution E, and then extraction is carried out with ethyl acetate. The resulting organic phase is concentrated, and column chromatography separation is carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 1:1 as the eluent. The eluent containing the target product is collected, and the solvent is evaporated to obtain the compound shown in formula (VIII).

9. The preparation method of the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid as described in claim 1, wherein In step F, the post-treatment method of the reaction solution F is as follows: the reaction solution is naturally raised to room temperature, 1.0 mol / L hydrochloric acid is added to adjust the pH of the reaction solution to 4-5, the solvent is removed by vacuum distillation, column chromatography separation is carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 1:1 as the eluent, the eluent containing the target product is collected, and the solvent is evaporated to obtain the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid shown in formula (IX).

10. The preparation method of the avibactam intermediate (2S,5R)-benzyloxyamino-piperidine-2-carboxylic acid as described in claim 1, characterized in that: In step A, the organic solvents A1 and A2 are each independently one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and dimethyl sulfoxide. The volume of the organic solvent A1 is 10-15 mL / g based on the mass of the L-camphorsulfonamide shown in formula (I); the volume of the organic solvent A2 is 5-10 mL / g based on the mass of the diphenyl imidate shown in formula (II). In step B, the organic solvent B is one or more of toluene, anhydrous tetrahydrofuran, and 1,4-dioxane. The volume of the organic solvent B is 5-10 mL / g based on the mass of the compound shown in formula (III). In step C, the organic solvent C is methanol, tetrahydrofuran, N,N-dimethylformamide. In step C, the volume of the organic solvent C is mL / g based on the mass of the compound shown in formula (V). In step D, the organic solvent D is one or more of dichloromethane, chloroform, 1,2-dichloroethane, and toluene. The volume of the organic solvent D is 10-15 mL / g based on the mass of the compound shown in formula (VI). In step E, the organic solvent E is one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, and ethyl acetate. The volume of the organic solvent E is 10-15 mL / g based on the mass of the compound shown in formula (VII). In step F, the organic solvent F is one or more of methanol, ethanol, 1,4-dioxane, and tetrahydrofuran. The volume of the organic solvent F is 10-15 mL / g based on the mass of the compound shown in formula (VI).

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