Preparation method of compound containing bi-azetidine subunit structure

Abstract

The invention belongs to the technical field of medicines, and particularly relates to synthesis of a novel compound containing a di-azetidine subunit structure. According to the invention, the industrial synthesis method of a novel compound (S)-4-((1 '-(3-hydroxy-2-phenylpropionyl)-1', 4 '-dihydro-2H, 2' H-[3, 3 '-biazetidine subunit]-1 (4H)-yl) sulfonyl) cyanobenzene is systematically researched for the first time, and a synthesis route and process parameter selection suitable for industrial application are explored; the provided new route or new parameter technology suitable for industrialization has the technical advantages that the comprehensive yield is high, the reaction condition is mild, an expensive Grubbs catalyst is avoided, and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of small molecule drugs, and in particular relates to a method for preparing a compound containing a diazetidine subunit structure. Background Art

[0002] The related application compound patent WO2023 / 116774A1 of the present invention provides a new compound containing a diazetidinyl subunit structure - (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinyl subunit]-1(4H)-yl)sulfonyl)benzonitrile, as shown in the following formula A:

[0003]

[0004] It has been verified that the novel compound of formula A has good PKR agonist and / or USP9X inhibitory activity, and is expected to be used for the prevention and treatment of PKR and / or USP9X-mediated related diseases, such as sickle cell anemia, β-thalassemia, colorectal cancer, renal cancer, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, melanoma, lymphoma, glioblastoma or multiple myeloma.

[0005] A method for synthesizing a compound of formula A is provided in the prior compound patent application WO2023 / 116774A1, and the reaction route is as follows:

[0006]

[0007] The synthesis method of formula A described in the above compound patent has any one or more of the following deficiencies:

[0008] First, the purpose of synthesis in the prior compound patents was only to obtain a small amount of the target compound for the first time for use in early drug discovery research. However, no systematic applicability research was conducted on the industrial synthesis of the compound of formula A, which emphasized efficiency, simplicity, convenience, etc., and therefore no synthetic route suitable for industrial application was proposed.

[0009] Secondly, when removing the benzyloxycarbonyl protecting group (-Cbz), the method of stirring overnight with trifluoroacetic acid at 60°C was adopted, which has a high reaction temperature and a long reaction time. This will place high demands on production equipment in industrial production and is not conducive to scale-up production.

[0010] Third, the product yield obtained by relying on its current specific synthesis step parameters is very low, resulting in high commercial production costs. The overall yield of the last four steps alone is as low as 14%.

[0011] Fourth, the reaction conditions provided are relatively harsh, for example, the expensive Grubbs catalyst needs to be used, and the post-processing is difficult, which is not suitable for industrial scale-up production. Summary of the invention

[0012] In order to solve the above problems existing in the prior art, the object of the present invention is to provide a method for preparing a compound containing a diazetidinyl subunit structure suitable for industrial application (i.e., the compound shown in formula A - (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinyl subunit]-1(4H)-yl)sulfonyl)benzonitrile).

[0013] The new preparation method provided by the present invention has made a systematic study on the industrial synthesis of the compound of formula A for the first time. According to different route or reaction condition selections, any one or more of the following technical effects can be achieved: first, a new synthesis route suitable for industrialization different from the compound is provided; second, the application of some extreme reaction conditions, such as long-term high-temperature reaction, is optionally avoided, thereby reducing the requirements for the conditions of production equipment; third, the overall yield is optionally improved; fourth, the use of expensive Grubbs catalyst is optionally avoided, thereby reducing the difficulty of post-processing; and so on.

[0014] The technical solution adopted by the present invention is:

[0015] The first synthetic route of the compound represented by formula A provided by the present invention is as follows:

[0016]

[0017] The compound represented by Formula 1 or the compound represented by Formula 3 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate. The compound represented by Formula 1 is preferably in the form of p-toluenesulfonate, and the compound represented by Formula 3 is preferably in the form of sulfate;

[0018] R is an amino protecting group, and R can be selected from -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc.

[0019] In the first synthetic route, the preparation method of the intermediate compound of formula 2 comprises the following reactions:

[0020]

[0021] The compound represented by Formula 1 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 1 is preferably p-toluenesulfonate;

[0022] R is an amino protecting group, which can be -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc;

[0023] In the reaction:

[0024] The solvent may be selected from tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, acetonitrile and acetone, or a combination of two or more thereof, preferably tetrahydrofuran, N,N-dimethylformamide, toluene, acetonitrile and acetone, or a combination of two or more thereof, particularly preferably acetonitrile and / or toluene;

[0025] A base may be optionally added, and the base may be selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N-ethyldiisopropylamine and pyridine, preferably one or a combination of two or more of triethylamine, N-ethyldiisopropylamine and pyridine, and particularly preferably triethylamine and / or N-ethyldiisopropylamine; the amount of the base added may be selected from 2 equivalents or more of the compound of formula 1, preferably 2 to 5 equivalents, and particularly preferably 2.5 equivalents;

[0026] The reaction time can be optionally controlled to be 3 to 24 hours, preferably 3 hours;

[0027] The reaction temperature can be optionally controlled at above 0°C, preferably 0 to 45°C, particularly preferably 0°C.

[0028] In the first synthetic route, the preparation method of the intermediate compound of formula 3 comprises the following reactions:

[0029]

[0030] The compound represented by Formula 3 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 3 is preferably in the form of a sulfate;

[0031] R is an amino protecting group, which can be -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc;

[0032] In the post-treatment after the reaction is completed:

[0033] A reaction quencher may be optionally added, and the reaction quencher may be selected from hydrochloric acid, trifluoroacetic acid, acetic acid, anhydrous methanol, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid and water, or a combination of two or more thereof, preferably hydrochloric acid, acetic acid, anhydrous methanol, sulfuric acid and water, or a combination of two or more thereof, and particularly preferably sulfuric acid; the sulfuric acid may be concentrated sulfuric acid, and the amount of concentrated sulfuric acid added may be selected from 0.6 to 1.5 equivalents of the compound of formula 2, preferably 1.15 equivalents;

[0034] Optionally, a dispersant is also added, and the dispersant can be acetonitrile, isopropanol, ethanol and / or methanol, preferably methanol.

[0035] When R is -Cbz, the reagent for removing the amino protecting group in the reaction is TMSI, and the reaction solvent is dichloromethane.

[0036] In the first synthetic route, the method for preparing the compound represented by formula A comprises the following reactions:

[0037]

[0038] The compound represented by Formula 3 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 3 is preferably in the form of a sulfate;

[0039] In the reaction:

[0040] The type or type combination of the added condensing agent can be selected from HATU, HBTU, EDCI+HOBt, DIC+HOBt, DCC+HOBt, PyBOP, EEDQ or DMT-MM, preferably a DMT-MM condensation system;

[0041] The solvent may be selected from one or more of dichloromethane, ethyl acetate, isopropanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone and N-methylpyrrolidone, or a combination of two or more thereof; or the solvent may be selected from any one of dichloromethane, ethyl acetate, isopropanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone and N-methylpyrrolidone and any one of water, methanol and ethanol, preferably N,N-dimethylformamide or N-methylpyrrolidone, or the solvent may be selected from one of the following combinations in a volume ratio of 1:1: N,N-dimethylformamide:ethanol, N,N-dimethylformamide:isopropanol, N-methylpyrrolidone:ethanol, N-methylpyrrolidone:isopropanol;

[0042] A base may be added optionally, and the base may be selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N-ethyldiisopropylamine, pyridine and N-methylpyrrole, preferably one or a combination of two or more of triethylamine, N-ethyldiisopropylamine, sodium carbonate and potassium carbonate, and particularly preferably N-ethyldiisopropylamine; the amount of the base added may be selected to be 1.25 equivalents or more of the compound of formula 3, preferably 1.25 to 2.5 equivalents, and particularly preferably 2.0 equivalents.

[0043] The second synthetic route of the compound represented by formula A provided by the present invention is as follows:

[0044]

[0045] The compound represented by Formula 1 or the compound represented by Formula 5 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate. The compound represented by Formula 1 is preferably in the form of p-toluenesulfonate, and the compound represented by Formula 5 is preferably in the form of sulfate;

[0046] R is an amino protecting group, and R can be selected from -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc.

[0047] In the second synthetic route, the preparation method of the intermediate compound of formula 4 comprises the following reactions:

[0048]

[0049] The compound represented by Formula 1 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 1 is preferably p-toluenesulfonate;

[0050] R is an amino protecting group, which can be -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc;

[0051] In the reaction:

[0052] The type or type combination of the added condensing agent can be selected from HATU, HBTU, EDCI+HOBt, DIC+HOBt, DCC+HOBt, EEDQ or DMT-MM, preferably a DMT-MM condensation system;

[0053] The solvent may be selected from one or a combination of two or more of isopropanol, N,N-dimethylformamide, acetone, N-methylpyrrolidone, tetrahydrofuran and dichloromethane, preferably dichloromethane;

[0054] A base may be added optionally, and the base may be selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N-ethyldiisopropylamine, pyridine and N-methylpyrrole, preferably triethylamine, N-ethyldiisopropylamine or pyridine, particularly preferably triethylamine or N-ethyldiisopropylamine; the amount of the base added may be selected to be 1.0 equivalent or more of the compound of formula 1, preferably 1.0 to 2.0 equivalents, particularly preferably 1.0 equivalent.

[0055] In the second synthetic route, the preparation method of the intermediate compound of formula 5 comprises the following reactions:

[0056]

[0057] The compound represented by Formula 5 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 5 is preferably in the form of a sulfate;

[0058] R is an amino protecting group, which can be -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc;

[0059] In the post-treatment after the reaction is completed:

[0060] A reaction quencher may be added optionally, and the reaction quencher may be selected from hydrochloric acid, trifluoroacetic acid, acetic acid, anhydrous methanol, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid and water, or a combination of two or more thereof, preferably hydrochloric acid, acetic acid, anhydrous methanol, methanesulfonic acid, sulfuric acid and water, or a combination of two or more thereof, and particularly preferably sulfuric acid; the sulfuric acid may be concentrated sulfuric acid, and the amount of concentrated sulfuric acid added may be selected from 0.6 equivalents or more of the compound of formula 4, preferably 0.6 to 1.5 equivalents, and particularly preferably 1.15 equivalents.

[0061] When R is -Cbz, the reagent for removing the amino protecting group in the reaction is TMSI, and the reaction solvent is dichloromethane.

[0062] In the second synthetic route, the preparation method of the compound represented by formula A comprises the following reactions:

[0063]

[0064] The compound represented by Formula 5 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 5 is preferably in the form of a sulfate;

[0065] In the reaction:

[0066] The solvent may be selected from tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, acetonitrile and acetone, or a combination of two or more thereof, preferably tetrahydrofuran, toluene, acetonitrile and acetone, and particularly preferably acetonitrile;

[0067] A base may also be added optionally, and the base may be selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N-ethyldiisopropylamine and pyridine, preferably one or a combination of two or more of triethylamine, N-ethyldiisopropylamine and pyridine, and particularly preferably triethylamine.

[0068] In the first and second synthetic routes, the starting reaction material compound of formula 1 can be prepared by the following route:

[0069]

[0070] R 1 , R is a different type of amino protecting group, the amino protecting group can be selected from -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc; R 1 -Boc is particularly preferred, and R is particularly preferred to be -Cbz;

[0071] R 2 for R 2 Preferably

[0072] W is -Cl, -Br or -I, and W is preferably -I.

[0073] The compound of formula A obtained by the new synthetic route and process provided by the present invention has a higher yield and purity, and the purity detected by HPLC can reach more than 99%. Therefore, the compound of formula A prepared by the provided method has a special advantage when used to prepare a pharmaceutical composition. On this basis, a pharmaceutical composition is provided, comprising the compound of formula A prepared by the aforementioned preparation method and a pharmaceutically acceptable excipient, wherein the HPLC content purity of the compound of formula A is not less than 99%. DETAILED DESCRIPTION

[0074] The present invention will be further explained below in conjunction with specific embodiments.

[0075] Unless otherwise specified, the abbreviations or terms in the present invention have the following meanings:

[0076] Grubbs means Grubbs catalyst;

[0077] -Cbz represents a benzyloxycarbonyl protecting group;

[0078] -Boc represents a tert-butyloxycarbonyl protecting group;

[0079] -Fmoc represents a 9-fluorenylmethoxycarbonyl protecting group;

[0080] -PMB represents a p-methoxybenzyl protecting group;

[0081] -Bn represents a benzyl protecting group;

[0082] -Trt represents a trityl protecting group;

[0083] -Tos represents a p-toluenesulfonyl protecting group;

[0084] -Pht represents a phthaloyl protecting group;

[0085] -Alloc represents an allyloxycarbonyl protecting group;

[0086] -TBDPS means tert-butyldiphenylsilyl

[0087] Et3N represents triethylamine;

[0088] MeCN means acetonitrile;

[0089] DIPEA means N,N-diisopropylethylamine;

[0090] DMF stands for N,N-dimethylformamide;

[0091] MeOH means methanol;

[0092] eq. stands for equivalent, which is the abbreviation of equivalent;

[0093] TMSX stands for trimethyl X-silane, which is a general term for various trimethylsilanes and their derivatives. When X is replaced by Cl, Br, I, or OTs, it refers to a specific substance of trimethylsilane or its derivatives. For example, TMSCl stands for trimethyl chlorosilane, TMSBr stands for trimethyl bromosilane, TMSI stands for trimethyl iodosilane, and TMSOTf stands for trimethylsilyl trifluoromethanesulfonate.

[0094] HATU stands for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0095] HBTU stands for benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0096] PyBOP stands for 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate;

[0097] T3P represents 1-propylphosphoric anhydride;

[0098] EEDQ stands for 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline;

[0099] DMT-MM represents 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride;

[0100] EDCI+HOBt represents a condensation agent system composed of EDCI and HOBt, EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and HOBt represents 1-hydroxybenzotriazole;

[0101] DIC+HOBt represents a condensation agent system composed of DCI and HOBt, DCI represents N,N'-diisopropylcarbodiimide, and HOBt represents 1-hydroxybenzotriazole;

[0102] DCC+HOBt represents a condensation agent system composed of DCC and HOBt, DCC represents N,N'-dicyclohexylcarbodiimide, and HOBt represents 1-hydroxybenzotriazole. BRIEF DESCRIPTION OF THE DRAWINGS

[0103] Figure 1 This is the hydrogen spectrum signal diagram of the compound of formula A prepared in Example 3 of the present invention.

[0104] Figure 2 This is the carbon spectrum signal diagram of the compound of formula A prepared in Example 3 of the present invention.

[0105] Figure 3 This is the HPLC detection chart of the compound of formula A prepared in Example 3 of the present invention.

[0106] Example 1: Exemplary Synthesis of Specific Compounds of Intermediate Formula 2

[0107]

[0108] 400.0 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate and 194.0 g (1.0 eq.) of 4-cyanobenzenesulfonyl chloride were added to 4 L of acetonitrile, the mixture was stirred and cooled at 0°C, and 243.0 g (2.5 eq.) of triethylamine were added dropwise; after the addition was completed, stirring was continued at 0°C for 3 hours, 4 L of purified water was added to quench the reaction, and a white solid was obtained by suction filtration, which was dried at 45°C to obtain 364.7 g of a white solid 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine, with a yield of 93% and a purity of 99.5%.

[0109] 1 H NMR(400MHz,d6-DMSO)δ7.756–7.691(m,2H),7.533–7.468(m,2H),7.396–7.2 57(m,5H),5.016(s,2H),4.354(s,4H),4.289–4.232(m,4H),2.433(s,3H)ppm.

[0110] Example 2: Exemplary Synthesis of Specific Compounds of Intermediate Formula 3

[0111]

[0112] 400 g of 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 2 L of dichloromethane, and 234.6 g (1.5 eq.) of trimethylsilyl iodide was added dropwise; after stirring at room temperature for 1 h, the mixture was moved to an ice-water bath, and 110.1 g (1.15 eq.) of sulfuric acid was added dropwise to quench the reaction. After stirring for 1 hour, methanol was added to disperse the solid, and a light yellow solid was obtained by suction filtration. The solid was washed twice with 95% ethanol (500 ml), and dried at 45° C. to obtain 270.3 g of light yellow solid 1-(4-cyanobenzenesulfonyl)-3-[3'-azetidinylidene]azetidine monosulfate, with a yield of 85% and a purity of 98.7%.

[0113] 1 H NMR (400MHz, d4-methanol) δ8.165–8.107(m,2H),8.105–8.058(m,2H),4.627(p,J=2.8Hz,4H),4.488(p,J=2.8Hz,4H)ppm.

[0114] Example 3: Exemplary method for synthesizing the compound of formula A via the routes of formula 2 and formula 3

[0115]

[0116] 400 g of 1-(4-cyanobenzenesulfonyl)-3-[3'-azetidinylidene]azetidine monosulfate was added to 4 L of N,N-dimethylformamide, and 214.8 ml (1.0 eq.) of N-ethyldiisopropylamine was added dropwise. After stirring at room temperature for 30 min, 307.4 g (1.5 eq.) of (S)-tropic acid and 545.2 g (1.5 eq.) of DMT-MM were added. After stirring at room temperature for 3 h, 4 L of 10% NaCl aqueous solution and 2 L of ethyl acetate were added. After stirring, the mixture was allowed to stand for separation. The separated aqueous layer was extracted with another 2 L of ethyl acetate. After combining the organic layers, the organic layer was washed with 4 L of 10% citric acid aqueous solution, 4 L of 10% sodium bicarbonate aqueous solution, and 4 L of 10% NaCl aqueous solution. All the aqueous layers were discarded, and the organic layer was concentrated to obtain a crude product. The crude product was added into 2.5 L of anhydrous ethanol for recrystallization, heated under reflux to dissolve, then the heating was stopped, cooled and stirred to precipitate a solid, cooled to 25° C. and stirred for 20 hours, filtered to obtain a white solid, dried at 45° C., and collected to obtain 444.0 g of a white solid (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazotidine subunit]-1(4H)-yl)sulfonyl)benzonitrile, with a yield of 85% and a purity of 99.67%. 1 H NMR(400MHz,d6-DMSO)δ8.190–8.124(m,2H),8.039–7.973(m,2H),7.329–7.183(m,5H),4.793(s,1H),4.702(d,J=13.4Hz,1H),4.4 21–4.260(m,6H),4.194(d,J=13.4Hz,1H),3.888(t,J=9.5Hz,1H),3.619(dd,J=8.8,5.5Hz,1H),3.458(dd,J=10.1,5.5Hz,1H)ppm. 13 C NMR(100MHz,d6-DMSO)δ171.77,138.37,137.47,134.18,129.47,128.90,128.60 ,127.46,121.64,118.25,118.04,116.60,64.01,58.95,57.37,55.20,50.37ppm.

[0117] LC-MS (ESI+) m / z: [M+H] + C 22 H 21 The calculated value of N3O4S is 424.1326; the measured value is 424.1335.

[0118] Example 4: Exemplary Synthesis of Specific Compounds of Intermediate Formula 4

[0119]

[0120] 400.0 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate was added to 4 L of dichloromethane, and 133.5 ml (1.0 eq.) of triethylamine was added dropwise. After stirring at room temperature for 30 min, 239.5 g (1.5 eq.) of (S)-tropic acid and 424.6 g (1.5 eq.) of DMT-MM were added. After stirring at room temperature for 3 h, 4 L of isopropyl ether was added, and a white solid was obtained by filtration. The white solid was dried at 45° C. to obtain 328.2 g of white solid (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine, with a yield of 87% and a purity of 99.2%.

[0121] 1 H NMR(400MHz,d6-DMSO)δ7.366–7.232(m,10H),5.289(t,J=6.2Hz,1H),5.114(s,2H),4.163–4.122(m ,1H),4.120–4.102(m,4H),4.071(s,4H),3.865(dt,J=12.0,6.1Hz,1H),3.775(t,J=5.9Hz,1H)ppm.

[0122] Example 5: Exemplary Synthesis of Specific Compounds of Intermediate Formula 5

[0123]

[0124] 400 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 2 L of dichloromethane, and 305.9 g (1.5 eq.) of trimethylsilyl iodide was added dropwise; after stirring at room temperature for 1 h, the mixture was moved to an ice-water bath, and 115.0 g (1.15 eq.) of sulfuric acid was added dropwise to quench the reaction. 200 mL of methanol was added, and after stirring for 30 min, a yellow solid was obtained by suction filtration. The solid was washed twice with dichloromethane / methanol (v / v) = 10:1 (500 ml), and dried at 45° C. to obtain 194.6 g of yellow solid (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[3'-azetidinylidene]azetidine monosulfate, with a yield of 62% and a purity of 96.0%.

[0125] 1H NMR (400MHz, d4-methanol) δ7.364–7.315(m,4H),7.288–7.234(m,1H),4.246–4.144(m,4H),4.150(dt,J =12.0,6.0Hz,1H),3.878(dt,J=12.0,5.8Hz,1H),3.777(t,J=5.9Hz,1H),3.513–3.458(m,4H)ppm.

[0126] Example 6: Exemplary method for synthesizing the compound of formula A via the routes of formula 4 and formula 5

[0127]

[0128] 400.0 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[3'-azetidinylidene]azetidine monosulfate and 262.5 g (1.0 eq.) of 4-cyanobenzenesulfonyl chloride were added to 4 L of acetonitrile, the mixture was stirred and cooled at 0°C, and 329.2 g (2.5 eq.) of triethylamine was added dropwise. After the addition was completed, the mixture was stirred at 0°C for 3 hours, 4 L of purified water was added to quench the reaction, and a white solid was obtained by suction filtration. The mixture was dried at 45°C to obtain 507.0 g of a white solid (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile, with a yield of 92% and a purity of 95.2%.

[0129] Example 7-34: Synthesis process screening study of specific compounds of intermediate formula 2

[0130] Embodiment 7-18:

[0131]

[0132] 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate 4g, 4-cyanobenzenesulfonyl chloride 1.94g (1.0eq.) were added to 40mL solvent, stirred at room temperature, and 3.4ml (2.5eq.) of triethylamine was added dropwise; after the addition was completed, stirring was continued for 3 hours or 24 hours, and samples were taken for HPLC testing to detect the content of 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine in the reaction solution.

[0133] The effects of solvent type and reaction time on the product content in the reaction solution are shown in the following table:

[0134] Example Solvents Reaction time Product content in the reaction solution 7 Tetrahydrofuran 3 hours 88.74％ 8 Tetrahydrofuran 24 hours 90.10％ 9 N,N-Dimethylformamide 3 hours 86.62％ 10 N,N-Dimethylformamide 24 hours 91.64％ 11 Dichloromethane 3 hours 65.77％ 12 Dichloromethane 24 hours 87.77％ 13 Toluene 3 hours 95.16％ 14 Toluene 24 hours 96.00％ 15 Acetonitrile 3 hours 96.75％ 16 Acetonitrile 24 hours 88.38％ 17 acetone 3 hours 92.10％ 18 acetone 24 hours 85.43％

[0135] Conclusion: The reaction can be carried out in most types of organic solvents. Solvents represented by dichloromethane require a long reaction time of up to 24 hours, and the industrial production efficiency is low. Most reactions can be completed in 3 hours in solvents represented by acetonitrile and toluene, and the reaction rate is fast. In particular, acetonitrile as a reaction solvent can react quickly and the product purity is good. Acetonitrile is preferred.

[0136] Embodiment 18-23:

[0137] 4 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate and 1.94 g (1.0 eq.) of 4-cyanobenzenesulfonyl chloride were added to different volumes of acetonitrile, stirred at room temperature, and 3.4 ml (2.5 eq.) of triethylamine were added dropwise; after the addition was completed, stirring was continued for 3 hours, 40 mL of purified water was added to quench the reaction, and a white solid was obtained by suction filtration. The mixture was dried at 45°C, and white solid 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was collected and sampled for HPLC inspection.

[0138] The effect of the volume of acetonitrile used on the product is shown in the following table:

[0139] Example Acetonitrile volume Product Quality Yield 19 5V 99.27％ 92.9％ 20 7.5V 99.50％ 96.0％ 21 10V 99.65％ 97.2％ 22 12.5V 99.42％ 99.7％ 23 15V 99.33％ 99.8％

[0140] Note: "V" is the mass (g) to volume (mL) ratio. For example, 4 g of "1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate" is dissolved in 40 mL of solvent, and the volume of the solvent is recorded as 10V. The volume mark "V" appearing elsewhere in the present invention is explained and defined from here.

[0141] Conclusion: The reaction can be achieved at all acetonitrile volumes, and the product quality and yield are better when the acetonitrile volume is above 7.5V, especially 10V acetonitrile.

[0142] Embodiment 24-26:

[0143] 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate 4g, 4-cyanobenzenesulfonyl chloride 1.94g (1.0eq.) were added to 40mL of acetonitrile, stirred at room temperature, and an organic base (2.5eq.) was added dropwise; after the addition was completed, stirring was continued for 3 hours, 40mL of purified water was added to quench the reaction, and a white solid was obtained by suction filtration, which was dried at 45°C to obtain a white solid 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine, and a sample was taken and sent to HPLC for inspection.

[0144] The effects of the organic base used on the product are shown in the following table:

[0145] Example Organic base Product Quality Yield 24 Triethylamine 99.51％ 94.3％ 25 N-Ethyldiisopropylamine 99.44％ 91.8％ 26 Pyridine 87.42％ 72.5％

[0146] Conclusion: All types of organic bases can achieve the reaction, among which triethylamine and N-ethyldiisopropylamine are used as bases, and the product purity and yield are good. Triethylamine is particularly preferred.

[0147] Embodiment 27-31:

[0148] 4 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate and 1.94 g (1.0 eq.) of 4-cyanobenzenesulfonyl chloride were added to 40 mL of acetonitrile, stirred at room temperature, and different amounts of triethylamine were added dropwise; after the addition was completed, stirring was continued for 3 hours, 40 mL of purified water was added to quench the reaction, and a white solid was obtained by suction filtration, which was dried at 45°C to obtain a white solid 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine, and a sample was taken and sent to HPLC for inspection.

[0149] The effect of triethylamine dosage on the product is shown in the following table:

[0150] Example Dosage of triethylamine Product Quality Yield 27 1.0 equivalent 68.71％ 39.7％ 28 2.0 equivalent 98.37％ 78.8％ 29 2.5 equivalent 99.64％ 97.4％ 30 3.0 equivalent 99.52％ 95.9％ 31 5.0 equivalent 99.49％ 96.3％

[0151] Conclusion: More than 1 equivalent of triethylamine can make the reaction proceed, but when the amount of triethylamine is too small, such as 1 equivalent, the product quality and yield are low. When the amount of triethylamine is more than 2 equivalents, the product quality and yield are significantly improved, and 2.5 equivalents of triethylamine are particularly preferred.

[0152] Embodiment 32-34:

[0153] 4 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate and 1.94 g (1.0 eq.) of 4-cyanobenzenesulfonyl chloride were added to 40 mL of acetonitrile, stirred and cooled while maintaining different reaction temperatures, and 3.4 ml (2.5 eq.) of triethylamine were added dropwise; after the addition was completed, stirring was continued for 3 hours, 40 mL of purified water was added to quench the reaction, and a white solid was obtained by suction filtration, which was dried at 45°C to obtain a white solid 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine, and a sample was taken and sent to HPLC for inspection.

[0154] The effect of reaction temperature on the product is shown in the following table:

[0155] Example Reaction temperature Product Quality Yield 32 45℃ 97.83％ 93.1％ 33 25℃ 99.61％ 93.7％ 34 0℃ 99.55％ 94.9％

[0156] Conclusion: Too high temperature will bring more side reactions. The product quality and yield are better when the temperature is below 25℃, especially 0℃ is preferred.

[0157] Examples 35-64: Synthesis screening study of specific compounds of intermediate formula 3

[0158] Examples 35-41:

[0159]

[0160] 2.0 g of 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to a reaction bottle, and 2V of different solvents and 2V of different acids were added, and the mixture was reacted at 0-65°C.

[0161]

[0162]

[0163] Conclusion: When trifluoroacetic acid is used as the -Cbz deprotection reagent, the reaction cannot occur normally at low temperatures or in the presence of organic solvent dilution. When no solvent dilution is used and a higher reaction temperature such as above 60°C is maintained, the removal reaction can proceed, but it still requires a long reaction time and is accompanied by more side reactions, and the product has more impurities.

[0164] Embodiment 42-48:

[0165]

[0166] 3.0 g of 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added into 10 mL of different solvents, and different types of trimethylsilane (TMSX) (1.2 eq.) were added dropwise at 0-30° C. The reaction was monitored after stirring at 0-30° C. for 2 h.

[0167] Example TMSX Solvents Reaction 42 TMSCl Dichloromethane No response 43 TMSBr Dichloromethane No target compound 44 TMSI Dichloromethane The raw material disappears and the product is generated 45 TMSOT Dichloromethane No target compound 46 TMSI Acetonitrile No response 47 TMSCl+NaI Dichloromethane No response 48 TMSCl+NaI Acetonitrile No response

[0168] Conclusion: Only TMSI in dichloromethane can undergo the removal of -Cbz reaction.

[0169] Examples 49-57:

[0170]

[0171] 3.0 g of 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 15 mL of dichloromethane, cooled to 0-5°C, and 1.76 g (1.2 eq.) of trimethylsilyl iodide was added dropwise. After stirring at room temperature for 2 hours, the reaction was complete. Different quenchers were added dropwise to quench the reaction. After stirring for 1 hour, a light yellow solid was obtained by suction filtration, which was rinsed once with the corresponding solvent and dried at 25°C. The solid was collected.

[0172]

[0173]

[0174] Conclusion: Sulfuric acid is preferred as quenching agent

[0175] Examples 58-61:

[0176]

[0177] 3.0 g of 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 15 mL of dichloromethane, cooled to 0-5°C, and 1.76 g (1.2 eq.) of trimethylsilyl iodide was added dropwise. After stirring at room temperature for 2 hours, the reaction was complete, and concentrated sulfuric acid was added dropwise to quench the reaction. After adding different dispersants and stirring for 1 hour, a light yellow solid was obtained by suction filtration, which was rinsed once with the corresponding solvent and dried at 25°C. The solid was collected.

[0178] Example Dispersants Yield Dispersion effect 58 Acetonitrile 54％ Able to obtain dispersed and filterable solids 59 Methanol 85％ Able to obtain dispersed and filterable solids 60 Ethanol 81％ Can obtain dispersed and easily filterable solids, but with low purity 61 Isopropyl alcohol 82％ Can obtain dispersed and easily filterable solids, but with low purity

[0179] Conclusion: Methanol is the preferred dispersant.

[0180] Embodiment 62-64:

[0181]

[0182] 3.0 g of 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 15 mL of dichloromethane, cooled to 0-5°C, and 1.76 g (1.2 eq.) of trimethylsilyl iodide was added dropwise. After stirring at room temperature for 2 hours, the reaction was complete, and different equivalents of concentrated sulfuric acid were added dropwise to quench the reaction. Methanol was added and stirred for 1 hour, and a light yellow solid was obtained by suction filtration, which was rinsed once with the corresponding solvent and dried at 25°C. The solid was collected.

[0183] Example Sulfuric acid equivalent Yield Experimental results 62 0.6 57％ The quenching process is normal 63 1.15 85％ The quenching process is normal 64 1.5 86％ The quenching process is normal

[0184] Conclusion: 1.15 equivalents of sulfuric acid quenching is preferred.

[0185] Examples 65-135: Screening of synthetic processes for compounds of Formula A via routes of Formula 2 and Formula 3

[0186] Examples 65-84:

[0187]

[0188] 4 g of 1-(4-cyanobenzenesulfonyl)-3-[3'-azetidinylidene]azetidine monosulfate was added to 40 ml of solvent, 2.2 ml (1.0 eq.) of N-ethyldiisopropylamine was added dropwise, and the mixture was stirred at room temperature for 30 min. Then, 3.07 g (1.5 eq.) of (S)-tropic acid and condensing agent (1.5 eq.) were added. After stirring at room temperature for 3 hours, samples were taken and sent to HPLC for detection of the content of (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile in the reaction solution.

[0189] The effects of condensation agent types and different solvent systems on the product content in the reaction solution are shown in the following table:

[0190] Example Condensation agent Solvents Product content in the reaction solution 65 HATU N,N-Dimethylformamide 26.55％ 66 HATU Tetrahydrofuran 34.56％ 67 HBTU N,N-Dimethylformamide 33.99％ 68 EDCI+HOBt N,N-Dimethylformamide 43.87％ 69 EDCI+HOBt Tetrahydrofuran 26.08％ 70 DIC+HOBt N,N-Dimethylformamide 47.16％ 71 DIC+HOBt Tetrahydrofuran 24.91％ 72 DCC+HOBT N,N-Dimethylformamide 55.09％ 73 DCC+HOBT Tetrahydrofuran 35.15％ 74 PyBOP N,N-Dimethylformamide 55.82％ 75 T3P Acetonitrile No target compound 76 T3P Ethyl acetate No target compound 77 EEDQ Dichloromethane 33.80％ 78 EEDQ Ethyl acetate 57.07％ 79 EEDQ Acetonitrile 27.63％ 80 EEDQ Tetrahydrofuran 31.95％ 81 DMT-MM water No reaction 82 DMT-MM Methanol No reaction 83 DMT-MM Ethanol No reaction 84 DMT-MM Isopropyl alcohol 65.70％

[0191] Conclusion: Multiple condensation systems are suitable for this reaction, and the DMT-MM system combined with isopropanol as solvent is preferred.

[0192] Embodiment 85-124:

[0193] 4 g of 1-(4-cyanobenzenesulfonyl)-3-[3'-azetidinylidene]azetidine monosulfate was added to 40 ml of solvent, and 2.2 ml (1.0 eq.) of N-ethyldiisopropylamine was added dropwise. After stirring at room temperature for 30 min, 3.07 g (1.5 eq.) of (S)-tropic acid and 5.45 g (1.5 eq.) of DMT-MM were added. After stirring at room temperature for 3 hours, samples were taken and sent to HPLC for detection of the content of (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile in the reaction solution.

[0194] The effects of different solvent systems on the product content in the reaction solution are shown in the table:

[0195]

[0196]

[0197] Conclusion: Multiple solvent systems are suitable for this reaction, and N,N-dimethylformamide, N,N-dimethylformamide:ethanol (v:v=1:1), N,N-dimethylformamide:isopropanol (v:v=1:1), N-methylpyrrolidone, N-methylpyrrolidone:ethanol (v:v=1:1), and N-methylpyrrolidone:isopropanol (v:v=1:1) systems are preferred. The target product with high purity can be obtained by post-treatment with water washing, extraction, and concentration.

[0198] Embodiment 125-129:

[0199] 4 g of 1-(4-cyanobenzenesulfonyl)-3-[3'-azetidinylidene]azetidine monosulfate was added to 40 ml of N,N-dimethylformamide, and a base (1.0 eq.) was added. After stirring at room temperature for 30 min, 3.07 g (1.5 eq.) of (S)-tropic acid and 5.45 g (1.5 eq.) of DMT-MM were added. After stirring at room temperature for 3 hours, a sample was taken and sent to HPLC for detection of the content of (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile in the reaction solution.

[0200] Example Alkali Product Quality 125 Triethylamine 76.73％ 126 N-Ethyldiisopropylamine 79.48％ 127 Pyridine 28.17％ 128 Sodium carbonate 73.77％ 129 N-Methylpyrrole 18.75％

[0201] Conclusion: Triethylamine, N-ethyldiisopropylamine and sodium carbonate can be optionally added, preferably N-ethyldiisopropylamine, and the target product with high purity can be obtained through post-treatment such as washing, extraction and concentration.

[0202] Embodiment 130-135:

[0203] 4 g of 1-(4-cyanobenzenesulfonyl)-3-[3'-azetidinylidene]azetidine monosulfate was added to 40 ml of N,N-dimethylformamide, and different amounts of N-ethyldiisopropylamine were added. After stirring at room temperature for 30 minutes, 3.07 g (1.5 eq.) of (S)-tropic acid and 5.45 g (1.5 eq.) of DMT-MM were added. After stirring at room temperature for 3 hours, samples were taken and sent to HPLC for detection of the content of (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile in the reaction solution.

[0204]

[0205]

[0206] Conclusion: 2.0 equivalents of N-ethyldiisopropylamine are preferred, and the target product with high purity can be obtained by post-treatment with water washing, extraction and concentration.

[0207] Examples 136-156: Synthesis screening study of specific compounds of intermediate formula 4

[0208] Examples 136-142:

[0209]

[0210] 4 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate was added to 40 mL of the corresponding solvent, and 1.34 ml (1.0 eq.) of triethylamine was added dropwise. After stirring at room temperature for 30 min, 2.40 g (1.5 eq.) of (S)-tropic acid and condensing agent (1.5 eq.) were added. After stirring at room temperature for 3 h, a sample was taken and sent to HPLC for detection of the content of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine in the reaction solution.

[0211] The effects of condensation agent types and different solvent systems on the product content in the reaction solution are shown in the table:

[0212] Example Condensation agent Solvents Product content in the reaction solution 136 HATU N,N-Dimethylformamide 27.22％ 137 HBTU N,N-Dimethylformamide 34.28％ 138 EDCI+HOBt N,N-Dimethylformamide 40.07％ 139 DIC+HOBt N,N-Dimethylformamide 45.12％ 140 DCC+HOBT N,N-Dimethylformamide 50.08％ 141 EEDQ Dichloromethane 58.10％ 142 DMT-MM Isopropyl alcohol 68.90％

[0213] Conclusion: Multiple condensation systems are applicable to this reaction, and the DMT-MM system is preferred.

[0214] Examples 143-151:

[0215] 4 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate was added to 40 mL of the corresponding solvent, and 1.34 ml (1.0 eq.) of triethylamine was added dropwise. After stirring at room temperature for 30 min, 2.40 g (1.5 eq.) of (S)-tropic acid and 4.25 g (1.5 eq.) of DMT-MM were added. After stirring at room temperature for 3 h, a sample was taken and sent to HPLC for detection of the content of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine in the reaction solution.

[0216] The effects of different solvent systems on the product content in the reaction solution are shown in the following table:

[0217] Example Solvents Product content in the reaction solution 143 water No reaction 144 Methanol No reaction 145 Ethanol No reaction 146 Isopropyl alcohol 66.88％ 147 N,N-Dimethylformamide 63.42％ 148 acetone 62.98％ 149 N-Methylpyrrolidone 69.78％ 150 Tetrahydrofuran 41.32％ 151 Dichloromethane 72.45％

[0218] Conclusion: Multiple solvent systems are suitable for this reaction, and dichloromethane system is preferred.

[0219] Embodiment 152-154:

[0220] 4 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate was added to 40 mL of dichloromethane, and different types of organic bases (1.0 eq.) were added dropwise. After stirring at room temperature for 30 min, 2.40 g (1.5 eq.) of (S)-tropic acid and 4.25 g (1.5 eq.) of DMT-MM were added. After stirring at room temperature for 3 h, 40 ml of isopropyl ether was added and the mixture was filtered to obtain a white solid product (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine.

[0221] Example Organic base Product Quality Yield 152 Triethylamine 99.2％ 87％ 153 N-Ethyldiisopropylamine 99.0％ 83％ 154 Pyridine 78.5％ 42％

[0222] Conclusion: Triethylamine and N-ethyldiisopropylamine can be selected to obtain better product quality and higher yield, and triethylamine is more preferred.

[0223] Embodiment 152, 155, 156:

[0224] 4 g of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate was added to 40 mL of dichloromethane, and different amounts of triethylamine were added dropwise. After stirring at room temperature for 30 min, 2.40 g (1.5 eq.) of (S)-tropic acid and 4.25 g (1.5 eq.) of DMT-MM were added. After stirring at room temperature for 3 h, 40 ml of isopropyl ether was added at room temperature for 3 hours, and the mixture was filtered to obtain a white solid product (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine.

[0225] Example equivalent Product Quality Yield 152 1.0 equivalent 99.2％ 87％ 155 1.5 equivalent 98.8％ 85％ 156 2.0 equivalent 98.3％ 88％

[0226] Conclusion: The reaction can be achieved with an amount of triethylamine above 1.0 equivalent, and 1.0 equivalent of triethylamine is preferred.

[0227] Examples 157-172: Synthesis screening study of specific compounds of intermediate formula 5

[0228]

[0229] Examples 157-160:

[0230] 4.0 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 20 mL of different solvents, and different types of trimethylsilane X reagents (TMSX) (1.5 eq.) were added dropwise at 0-30°C. After stirring at 0-30°C for 2 h, the reaction was monitored.

[0231] Example TMSX Solvents Reaction 157 TMSI Dichloromethane The raw material disappears and the product is generated 158 TMSI Acetonitrile No response 159 TMSCl+NaI Dichloromethane No response 160 TMSCl+NaI Acetonitrile No response

[0232] Conclusion: Only TMSI in dichloromethane can undergo the reaction of removing Cbz.

[0233] Examples 161-169:

[0234] 4.0 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 20 mL of dichloromethane, cooled to 0-5°C, and 3.06 g (1.5 eq.) of trimethylsilyl iodide was added dropwise. After stirring at room temperature for 1 hour, the reaction was complete, and different quenchers were added dropwise to quench the reaction. After stirring for 1 hour, a light yellow solid was obtained by suction filtration, which was rinsed once with the corresponding solvent and dried at 25°C. The solid was collected.

[0235] Example Quencher Yield Quenching 161 Dilute hydrochloric acid 43％ Dispersed solid obtained upon quenching 162 Trifluoroacetic acid 36％ Dispersed solid obtained upon quenching 163 Acetic acid 56％ Dispersed solid obtained upon quenching 164 Anhydrous methanol 48％ Dispersed solid obtained upon quenching 165 p-Toluenesulfonic acid 42％ The solid turns black when baking 166 Methanesulfonic acid 52％ There is a phenomenon of violent precipitation during quenching, add methanol to disperse 167 sulfuric acid 62％ There is a phenomenon of violent precipitation during quenching, add methanol to disperse 168 Phosphoric acid 59％ There is a phenomenon of violent precipitation during quenching, add methanol to disperse 169 water 52％ After quenching, the solid agglomerates and methanol is added to disperse

[0236] Conclusion: Sulfuric acid is preferred as quenching agent.

[0237] Embodiment 170-172:

[0238] 4.0 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 20 mL of dichloromethane, cooled to 0-5°C, and 3.06 g (1.5 eq.) of trimethylsilyl iodide was added dropwise. After stirring at room temperature for 1 hour, the reaction was complete, and different equivalents of concentrated sulfuric acid were added dropwise to quench the reaction. After adding methanol and stirring for 1 hour, a light yellow solid was obtained by suction filtration, which was rinsed once with the corresponding solvent and dried at 25°C. The solid was collected.

[0239]

[0240]

[0241] Conclusion: 1.15 to 1.5 equivalents of sulfuric acid can be used to quench the reaction, which can achieve a higher yield, and 1.15 equivalents of sulfuric acid is preferred.

[0242] Examples 173-183: Screening of synthetic processes for compounds of Formula A via routes of Formula 4 and Formula 5

[0243]

[0244] Embodiments 173-178:

[0245] 4 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[3'-azetidinylidene]azetidine monosulfate and 2.63 g (1.0 eq.) of 4-cyanobenzenesulfonyl chloride were added to 40 mL of solvent, the mixture was stirred and cooled at 0°C, and 3.3 g (2.5 eq.) of triethylamine was added dropwise. After the addition was completed, stirring was continued at 0°C for 3 hours, and samples were taken and sent to HPLC for testing to detect the content of (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile in the reaction solution.

[0246] The effects of solvent type and reaction time on the product content in the reaction solution are shown in the table:

[0247] Example Solvents Product content in the reaction solution 173 Tetrahydrofuran 78.55％ 174 N,N-Dimethylformamide 45.37％ 175 Dichloromethane 65.62％ 176 Toluene 75.14％ 177 Acetonitrile 92.28％ 178 acetone 89.48％

[0248] Conclusion: All solvents can achieve the reaction, acetonitrile is preferred.

[0249] Embodiment 179-181:

[0250] 4 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[3'-azetidinylidene]azetidine monosulfate and 2.63 g (1.0 eq.) of 4-cyanobenzenesulfonyl chloride were added to different volumes of acetonitrile, moved to 0°C, stirred and cooled, and 3.3 g (2.5 eq.) of triethylamine were added dropwise; after the addition was completed, stirring was continued at 0°C for 3 hours, 40 mL of purified water was added to quench the reaction, and a white solid was obtained by suction filtration. The white solid was dried at 45°C to obtain (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile, and a sample was taken and sent to HPLC for inspection.

[0251] The effect of the volume of acetonitrile used on the product is shown in the following table:

[0252] Example Acetonitrile volume Product Quality Yield 179 5V 90.20％ 93.9％ 180 7.5V 93.22％ 92.5％ 181 10V 93.50％ 92.4％

[0253] Conclusion: 10V acetonitrile, the product has good purity and good yield.

[0254] Embodiment 181-183:

[0255] 4 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[3'-azetidinylidene]azetidine monosulfate and 2.63 g (1.0 eq.) of 4-cyanobenzenesulfonyl chloride were added to 40 mL of acetonitrile, the mixture was stirred and cooled at 0°C, and an organic base (2.5 eq.) was added dropwise. After the addition was completed, stirring was continued at 0°C for 3 hours, 40 mL of purified water was added to quench the reaction, and a white solid was obtained by suction filtration. The mixture was dried at 45°C to obtain a white solid (S)-4-((1'-(3-hydroxy-2-phenylpropionyl)-1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-yl)sulfonyl)benzonitrile, and a sample was taken and sent to HPLC for inspection.

[0256] Example Organic base Product Quality Yield 181 Triethylamine 93.50％ 92.4％ 182 N-Ethyldiisopropylamine 92.85％ 92.0％ 183 Pyridine 78.45％ 70.5％

[0257] Conclusion: Triethylamine is preferred.

[0258] Example 184: Exemplary Synthesis of Specific Compounds of Intermediate Formula 1

[0259] Step 1: Preparation of 1-benzyl 1'-(tert-butyl) 3'-hydroxy-3-iodo-[3,3'-diazetidine]-1,1'-dicarboxylic acid:

[0260]

[0261] 3-(1-azabicyclo[1.1.0]butan-3-yl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2.41 g, 10.65 mmol) and sodium iodide (3.19 g, 21.30 mmol) were dissolved in acetonitrile (30 mL), the reaction system was cooled to 0°C, and then benzyl chloroformate (2.18 g, 12.78 mmol) was slowly added dropwise. After the addition was completed, the reaction was stirred at 0°C for 30 minutes. After the reaction was completed, the compound (4.58 g, yield was 88%) was purified.

[0262] MS (ESI) m / z 389.1 (M+H-100) +

[0263] Step 2: Preparation of 1-benzyl 1'-(tert-butyl) 3-iodo-3'-((methylsulfonyl)oxy)-[3,3'-diazetidine]-1,1'-dicarboxylic acid:

[0264]

[0265] 1-Benzyl 1'-(tert-butyl) 3'-hydroxy-3-iodo-[3,3'-diazetidine]-1,1'-dicarboxylic acid (2.12 g, 4.34 mmol) was dissolved in dichloromethane (50 mL). After cooling the reaction system to 0°C, triethylamine (878 mg, 8.68 mmol) and 4-dimethylaminopyridine (1.06 g, 8.68 mmol) were added, followed by slow dropwise addition of methylsulfonyl chloride (995 mg, 8.68 mmol). After the addition was complete, the reaction was stirred at 0°C for 30 minutes. After the reaction was complete, the compound (1.82 g, yield 74%) was obtained by purification.

[0266] MS (ESI) m / z 467.1 (M+H-100) +

[0267] Step 3: Preparation of 1-benzyl 1'-(tert-butyl) 2H, 2'H-[3,3'-diazetidinylidene]-1,1'(4H, 4'H)-dicarboxylic acid:

[0268]

[0269] 1-Benzyl 1'-(tert-butyl) 3-iodo-3'-((methylsulfonyl)oxy)-[3,3'-diazetidine]-1,1'-dicarboxylic acid (1.8 g, 3.18 mmol) was dissolved in acetic acid (20 mL). Zinc powder (1.04 g, 15.89 mmol) was then added. After the addition was completed, the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, the compound was purified to obtain the compound (980 mg, yield 88%).

[0270] MS (ESI) m / z 245.2 (M+H-100) +

[0271] 1 H NMR (400MHz, Chloroform-d) δ7.35 (d, J = 3.8Hz, 5H), 5.11 (s, 2H), 4.49 (m, 4H), 4.43–4.38 (m, 4H), 1.44 (s, 9H).

[0272] Step 4: Preparation of 1',4'-dihydro-2H,2'H-[3,3'-diazetidinylidene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate

[0273]

[0274] 1-Benzyl 1'-(tert-butyl) 2H, 2'H-[3,3'-diazetidinylidene]-1, 1'(4H, 4'H)-dicarboxylate (980 mg, 2.80 mmol) was dissolved in ethanol (32 mL), and then p-toluenesulfonic acid (1.6 g, 9.29 mmol) was added, and the reaction system was stirred at 50°C for 6 hours. After the reaction was completed, the compound was purified (1.16 g, yield was 100%).

[0275] MS (ESI) m / z 245.1 (M+H) + .

[0276] The present invention is not limited to the above optional implementations, and anyone can derive other various forms of products under the enlightenment of the present invention. The above specific implementations should not be understood as limiting the scope of protection of the present invention. The scope of protection of the present invention should be based on the definition in the claims, and the description can be used to interpret the claims.

Claims

1. A method for preparing the compound of formula A, comprising the following synthetic route: The compound represented by Formula 1 or the compound represented by Formula 3 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate. The compound represented by Formula 1 is preferably in the form of p-toluenesulfonate, and the compound represented by Formula 3 is preferably in the form of sulfate; R is an amino protecting group, and R can be selected from -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc.

2. A method for preparing the intermediate compound of formula 2, comprising the following reactions: The compound represented by Formula 1 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 1 is preferably p-toluenesulfonate; R is an amino protecting group, which can be -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc; In the reaction: The solvent may be selected from tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, acetonitrile and acetone, or a combination of two or more thereof, preferably tetrahydrofuran, N,N-dimethylformamide, toluene, acetonitrile and acetone, or a combination of two or more thereof, particularly preferably acetonitrile and / or toluene; A base may be optionally added, and the base may be selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N-ethyldiisopropylamine and pyridine, preferably one or a combination of two or more of triethylamine, N-ethyldiisopropylamine and pyridine, and particularly preferably triethylamine and / or N-ethyldiisopropylamine; the amount of the base added may be selected from 2 equivalents or more of the compound of formula 1, preferably 2 to 5 equivalents, and particularly preferably 2.5 equivalents; The reaction time can be optionally controlled to be 3 to 24 hours, preferably 3 hours; The reaction temperature can be optionally controlled at above 0°C, preferably 0-45°C, particularly preferably 0°C.

3. The method for preparing the intermediate compound of formula 2 according to claim 2, comprising the following steps: 400.0 g of 1',4'-dihydro-2H,2'H-[3,3'-diazotidine]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate and 194.0 g of 4-cyanobenzenesulfonyl chloride were added to 4 L of acetonitrile, the mixture was stirred and cooled at 0°C, and 243.0 g of triethylamine was added dropwise; after the addition was completed, stirring was continued at 0°C for 3 hours, 4 L of purified water was added to quench the reaction, and a white solid was obtained by suction filtration, which was dried at 45°C to obtain a white solid intermediate compound of formula 2.

4. A method for preparing the intermediate compound of formula 3, comprising the following reactions: The compounds shown in Formula 3 all include free base form or any acceptable salt form, and the acceptable salts include hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate. The compound shown in Formula 3 is preferably in the form of sulfate; R is an amino protecting group, which can be -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc; In the post-treatment after the reaction is completed: A reaction quencher may be optionally added, and the reaction quencher may be selected from hydrochloric acid, trifluoroacetic acid, acetic acid, anhydrous methanol, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid and water, or a combination of two or more thereof, preferably hydrochloric acid, acetic acid, anhydrous methanol, sulfuric acid and water, or a combination of two or more thereof, and particularly preferably sulfuric acid; the sulfuric acid may be concentrated sulfuric acid, and the amount of concentrated sulfuric acid added may be selected from 0.6 to 1.5 equivalents of the compound of formula 2, preferably 1.15 equivalents; Optionally, a dispersant is also added, and the dispersant can be acetonitrile, isopropanol, ethanol and / or methanol, preferably methanol.

5. The method for preparing the intermediate compound of formula 3 according to claim 4, characterized in that: R is -Cbz, the reagent for removing the amino protecting group in the reaction is TMSI, and the reaction solvent is dichloromethane.

6. The method for preparing the intermediate compound of formula 3 according to claim 4, comprising the following steps: 400 g of 1-(4-cyanobenzenesulfonyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 2 L of dichloromethane, and 234.6 g of trimethylsilyl iodide was added dropwise; after stirring at room temperature for 1 hour, the mixture was transferred to an ice-water bath, and 110.1 g of sulfuric acid was added dropwise to quench the reaction. After stirring for 1 hour, methanol was added to disperse the solid, and a light yellow solid was obtained by suction filtration. The solid was washed twice with 95% ethanol, and dried at 45°C to obtain a light yellow solid intermediate compound of formula 3.

7. A method for preparing a compound of formula A, comprising the following reactions: The compound represented by Formula 3 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 3 is preferably in the form of a sulfate; In the reaction: The type or type combination of the added condensing agent can be selected from HATU, HBTU, EDCI+HOBt, DIC+HOBt, DCC+HOBt, PyBOP, EEDQ or DMT-MM, preferably a DMT-MM condensation system; The solvent may be selected from one or more of dichloromethane, ethyl acetate, isopropanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone and N-methylpyrrolidone, or a combination of two or more thereof; or the solvent may be selected from any one of dichloromethane, ethyl acetate, isopropanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone and N-methylpyrrolidone and any one of water, methanol and ethanol, preferably N,N-dimethylformamide or N-methylpyrrolidone, or the solvent may be selected from one of the following combinations in a volume ratio of 1:1: N,N-dimethylformamide:ethanol, N,N-dimethylformamide:isopropanol, N-methylpyrrolidone:ethanol, N-methylpyrrolidone:isopropanol; A base may be added optionally, and the base may be selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N-ethyldiisopropylamine, pyridine and N-methylpyrrole, preferably one or a combination of two or more of triethylamine, N-ethyldiisopropylamine, sodium carbonate and potassium carbonate, and particularly preferably N-ethyldiisopropylamine; the amount of the base added may be selected to be 1.25 equivalents or more of the compound of formula 3, preferably 1.25 to 2.5 equivalents, and particularly preferably 2.0 equivalents.

8. The method for preparing the compound of formula A according to claim 7, comprising the following steps: 400 g of 1-(4-cyanobenzenesulfonyl)-3-[3'-azetidinylidene]azetidine monosulfate was added to 4LN,N-dimethylformamide, 214.8 ml of N-ethyldiisopropylamine was added dropwise, and after stirring at room temperature for 30 min, 307.4 g of (S)-tropic acid and 545.2 g of DMT-MM were added; after stirring at room temperature for 3 h, the reaction was quenched, and the compound shown in formula A was obtained after post-treatment.

9. The method for preparing the compound of formula A according to claim 8, characterized in that: The post-processing comprises the following steps: Add 4L of 10% NaCl aqueous solution and 2L of ethyl acetate, stir and let stand to separate; use another 2L of ethyl acetate to extract the separated water layer, combine the organic layers, wash the organic layer with 4L of 10% citric acid aqueous solution, wash the organic layer with 4L of 10% sodium bicarbonate aqueous solution, wash the organic layer with 4L of 10% NaCl aqueous solution, discard all the water layers, and concentrate the organic layer to obtain the crude compound represented by formula A.

10. The method for preparing the compound of formula A according to claim 9, characterized in that: The post-treatment further includes a recrystallization treatment, and the recrystallization includes the following steps: The crude product was added to 2.5 L of anhydrous ethanol for recrystallization, heated under reflux to dissolve, then the heating was stopped, cooled and stirred to precipitate a solid, cooled to 25°C and stirred for 20 hours, filtered to obtain a white solid, dried at 45°C, and collected to obtain the compound represented by white solid formula A.

11. A method for preparing the compound of formula I, comprising the following synthetic route: The compound represented by Formula 1 or the compound represented by Formula 5 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate. The compound represented by Formula 1 is preferably in the form of p-toluenesulfonate, and the compound represented by Formula 5 is preferably in the form of sulfate; R is an amino protecting group, and R can be selected from -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc.

12. A method for preparing a compound of intermediate formula 4, comprising the following reaction: The compound represented by Formula 1 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 1 is preferably p-toluenesulfonate; R is an amino protecting group, which can be -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc; In the reaction: The type or type combination of the added condensing agent can be selected from HATU, HBTU, EDCI+HOBt, DIC+HOBt, DCC+HOBt, EEDQ or DMT-MM, preferably a DMT-MM condensation system; The solvent may be selected from one or a combination of two or more of isopropanol, N,N-dimethylformamide, acetone, N-methylpyrrolidone, tetrahydrofuran and dichloromethane, preferably dichloromethane; A base may be added optionally, and the base may be selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N-ethyldiisopropylamine, pyridine and N-methylpyrrole, preferably triethylamine, N-ethyldiisopropylamine or pyridine, particularly preferably triethylamine or N-ethyldiisopropylamine; the amount of the base added may be selected to be 1.0 equivalent or more of the compound of formula 1, preferably 1.0 to 2.0 equivalents, particularly preferably 1.0 equivalent.

13. The method for preparing the intermediate compound of formula 4 according to claim 12, comprising the following steps: 400.0 g of 1',4'-dihydro-2H,2'H-[3,3'-diazotidine]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate was added to 4 L of dichloromethane, and 133.5 ml of triethylamine was added dropwise. After stirring at room temperature for 30 min, 239.5 g of (S)-tropic acid and 424.6 g of DMT-MM were added. After stirring at room temperature for 3 h, 4 L of isopropyl ether was added, and a white solid was obtained by filtration. The mixture was dried at 45° C. to obtain the compound shown in Formula 4 as a white solid.

14. A method for preparing a compound of intermediate formula 5, comprising the following reaction: The compound represented by Formula 5 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 5 is preferably in the form of a sulfate; R is an amino protecting group, which can be -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc; In the post-treatment after the reaction is completed: A reaction quencher may be added optionally, and the reaction quencher may be selected from hydrochloric acid, trifluoroacetic acid, acetic acid, anhydrous methanol, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid and water, or a combination of two or more thereof, preferably hydrochloric acid, acetic acid, anhydrous methanol, methanesulfonic acid, sulfuric acid and water, or a combination of two or more thereof, and particularly preferably sulfuric acid; the sulfuric acid may be concentrated sulfuric acid, and the amount of concentrated sulfuric acid added may be selected from 0.6 equivalents or more of the compound of formula 4, preferably 0.6 to 1.5 equivalents, and particularly preferably 1.15 equivalents.

15. The method for preparing the intermediate compound of formula 5 according to claim 14, characterized in that: R is -Cbz, the reagent for removing the amino protecting group in the reaction is TMSI, and the reaction solvent is dichloromethane.

16. The method for preparing the intermediate compound of formula 5 according to claim 14, comprising the following steps: 400 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[N-(benzyloxycarbonyl)-3'-azetidinylidene]azetidine was added to 2 L of dichloromethane, and 305.9 g of trimethylsilane iodide was added dropwise; after stirring at room temperature for 1 h, the mixture was moved to an ice-water bath, 115.0 g of sulfuric acid was added dropwise to quench the reaction, 200 mL of methanol was added, and after stirring for 30 min, a yellow solid was obtained by suction filtration, which was washed twice with dichloromethane / methanol (v / v) = 10:1, and dried at 45° C. to obtain the yellow solid compound shown in Formula 5.

17. A method for preparing a compound of formula A, comprising the following reaction: The compound represented by Formula 5 includes a free base form or any acceptable salt form, wherein the acceptable salt includes hydrochloride, hydrobromide, sulfate, oxalochlorate, acetate, trifluoroacetate, phosphate, methanesulfonate or p-toluenesulfonate, and the compound represented by Formula 5 is preferably in the form of a sulfate; In the reaction: The solvent may be selected from tetrahydrofuran, N,N-dimethylformamide, dichloromethane, toluene, acetonitrile and acetone, or a combination of two or more thereof, preferably tetrahydrofuran, toluene, acetonitrile and acetone, and particularly preferably acetonitrile; A base may also be added optionally, and the base may be selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N-ethyldiisopropylamine and pyridine, preferably one or a combination of two or more of triethylamine, N-ethyldiisopropylamine and pyridine, and particularly preferably triethylamine.

18. The method for preparing the compound of formula A according to claim 17, comprising the following reaction: 400.0 g of (S)-3'-(3-hydroxy-2-phenylpropionyl)-3-[3'-azetidinylidene]azetidine monosulfate and 262.5 g of 4-cyanobenzenesulfonyl chloride were added to 4 L of acetonitrile, the mixture was stirred and cooled at 0°C, and 329.2 g of triethylamine was added dropwise; after the addition was completed, stirring was continued at 0°C for 3 hours, 4 L of purified water was added to quench the reaction, and a white solid was obtained by suction filtration, which was dried at 45°C to obtain the compound represented by the white solid formula A.

19. The preparation method according to claim 1, 2, 11 or 12, characterized in that: The compound described in formula 1 is prepared by the following route: R 1 , R is a different type of amino protecting group, the amino protecting group can be selected from -Cbz, -Boc, -Fmoc, -PMB, -Bn, -Trt, -Tos, -Pht or -Alloc, preferably -Cbz or -Boc; R 1 -Boc is particularly preferred, and R is particularly preferred to be -Cbz; R 2 for R 2 Preferably W is -Cl, -Br or -I, and W is preferably -I.

20. A pharmaceutical composition, characterized in that It comprises a compound of formula A product prepared by the preparation method of claim 1, 7, 11 or 17 and pharmaceutically acceptable excipients, wherein the HPLC content purity of the compound of formula A product is not less than 99%.

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