3-(1H-pyrazol-1-yl) azetidine compound and synthesis method thereof

Abstract

The invention discloses a synthesis method of a 3-(1H-pyrazol-1-yl) azetidine compound, which comprises the following steps: by taking a 3-azetidinone compound as an initial raw material, reacting nitromethane with ketone under the action of alkali to generate a 3-hydroxy-3-(nitromethyl) azetidine compound; then, under the action of sulfonyl chloride compounds, the hydroxyl groups are derived into easy-to-leave groups, elimination reaction is carried out, and the 3-(nitromethylene) azetidine compounds are obtained. And then carrying out Michael addition reaction with a pyrazole compound or carrying out further hydrogenation reduction to generate the 3-(1H-pyrazol-1-yl) azetidine compound. The synthetic method has the advantages of short steps, low cost and simplicity and convenience in operation, is suitable for large-scale industrial production, and can be used as a drug intermediate or used for researching potential drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediates, and in particular to a 3-(1H-pyrazole-1-yl)azetidine compound and a synthesis method thereof. Background Art

[0002] Pyrazole compounds are widely present in drug molecules. Due to their unique structure and good pharmacological activity, they are used in the research and development of anticancer, antibacterial, anti-inflammatory and other drugs. At the same time, the azetidine ring also shows important drug activity, especially in the development of enzyme inhibitors and neuromodulators. Therefore, compounds combining pyrazole and azetidine structures are expected to play an important role in biological activity and drug development. At present, there are some strategies for synthesizing such 3-(1H-pyrazol-1-yl)azetidine compounds. The literature review is as follows:

[0003] Classical synthesis method: by introducing an easily leaving group (Br, I, OMs or OTs) into the azetidine compound, and then reacting with the pyrazole compound under the action of a base to generate 3-(1H-pyrazol-1-yl)azetidine compounds. The main modification site of the structure of this type of compound is R 1 and R 3 However, these compounds often face some problems, such as poor pharmacokinetic properties, low bioavailability or insufficient specificity. In addition, although azetidine, as a representative of four-membered nitrogen-containing heterocycles, shows good activity in drug molecules, its chemical stability and difficulty in structural modification limit further development.

[0004]

[0005] Therefore, the development of a new compound with pyrazole and azetidine and a diverse structure has become an urgent need in the current field of chemistry and drug research and development. In order to overcome the above problems, it is necessary to provide a 3-(1H-pyrazol-1-yl)azetidine compound with a diverse structure, safety, environmental protection and easy to scale up production. Summary of the invention

[0006] In order to overcome the problems existing in the prior art, the present invention has developed a method for synthesizing 3-(1H-pyrazole-1-yl)azetidine compounds with shorter steps, higher yield, better quality and simple operation.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] The synthetic route of 3-(1H-pyrazole-1-yl)azetidine compounds in the present invention is as follows:

[0009]

[0010] The above-mentioned synthetic route uses 3-azetidinone compound 1 (Formula I) as the starting material. First, under the action of the first base, nitromethane and ketone react to generate 3-hydroxy-3-(nitromethyl)azetidine compound 2 (Formula II); then, under the action of a sulfonyl chloride compound, the hydroxyl group is derivatized into an easy leaving group, and then an elimination reaction occurs to obtain a 3-(nitromethylene)azetidine compound 3 (Formula III); then, a Michael addition reaction is carried out with a pyrazole compound to prepare a compound 4 (Formula IV); and finally, hydrogenation reduction is performed to generate a 3-(1H-pyrazol-1-yl)azetidine compound 5 (Formula V).

[0011] In the above synthetic route, R 1 Any one selected from hydrogen (H), tert-butyloxycarbonyl (Boc), benzyl (Bn) and benzyloxycarbonyl (Cbz); R 2 Any one selected from hydrogen (H), fluorine (F), chlorine (Cl) and bromine (Br); R 3 Any one selected from hydrogen (H), fluorine (F), chlorine (Cl) and bromine (Br); R 4 Any one selected from nitro (NO2), amino (NH2), hydroxylamine (NHOH) and azaalkane compounds.

[0012] R 4 When selected from azaalkane compounds, preferably the structural formula is:

[0013]

[0014] To achieve the above object, the present invention adopts the following technical solution:

[0015] Step S1, using 3-azetidinone compound 1 (Formula I) as a starting material, under the action of a first base, nitromethane and ketone react in a first solvent to generate 3-hydroxy-3-(nitromethyl)azetidinone compound 2 (Formula II);

[0016] Step S2, in a second solvent, reacting a 3-hydroxy-3-(nitromethyl)azetidine compound 2 (Formula II), a sulfonyl chloride compound and a second base to derivatize the hydroxyl group into an easy leaving group, and then undergoing an elimination reaction to obtain a 3-(nitromethylene)azetidine compound 3 (Formula III);

[0017] Step S3, under the action of a third base, the 3-(nitromethylene)azetidine compound 3 (Formula III) and the pyrazole compound undergo Michael addition reaction in a third solvent to obtain a compound 4 (Formula IV);

[0018] Step S4: Under the action of a catalyst, compound 4 is subjected to hydrogenation reduction in a fourth solvent to generate 3-(1H-pyrazol-1-yl)azetidine compound 5 (Formula V).

[0019]

[0020] R 1 Any one selected from hydrogen (H), tert-butyloxycarbonyl (Boc), benzyl (Bn) and benzyloxycarbonyl (Cbz); R 2 Any one selected from hydrogen (H), fluorine (F), chlorine (Cl) and bromine (Br); R 3 Any one selected from hydrogen (H), fluorine (F), chlorine (Cl) and bromine (Br); R 4 Any one selected from nitro (NO2), amino (NH2), hydroxylamine (NHOH) and azaalkane compounds.

[0021] Furthermore, the specific operation steps of step S1 include: under the promotion of the first base, the 3-azetidinone compound 1 (Formula I) and nitromethane react, the reaction temperature is -10-60°C, and after the reaction, a solution of a 3-hydroxy-3-(nitromethyl)azetidine compound 2 (Formula II) is obtained or a 3-hydroxy-3-(nitromethyl)azetidine compound 2 (Formula II) is obtained after post-treatment and purification.

[0022] Furthermore, in step S1, the compound 1 (Formula I) is selected from any one of 3-oxoazetidinone, 1-Boc-3-azetidinone, 1-Bn-3-azetidinone and 1-Cbz-3-azetidinone; preferably, the compound 1 (Formula I) is 1-Boc-3-azetidinone.

[0023] Further, in step S1, the first base is selected from any one or more of triethylamine, trimethylamine, N,N-diisopropylethylamine, diisopropylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), pyridine, potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH) and sodium bicarbonate (NaHCO3); preferably, the first base is triethylamine.

[0024] Furthermore, in step S1, the first solvent is selected from any one or more of ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, tetrahydrofuran, toluene and no solvent; preferably, the first solvent is toluene.

[0025] Furthermore, in the step S1, the molar ratio of the 3-azetidinone compound 1 (Formula I), nitromethane and the first base is 1:0.5-10:0.5-5.

[0026] Furthermore, in the step S1, the reaction temperature is between -10-60°C, and the reaction time is 1 to 48 hours; preferably, the temperature is 25°C, and the reaction time is 24 hours.

[0027] Furthermore, the specific operation steps of step S2 include: in a second solvent, reacting a 3-hydroxy-3-(nitromethyl)azetidine compound 2 (Formula II), a sulfonyl chloride compound and a second base to derivatize the hydroxyl group into an easy leaving group, and then undergoing an elimination reaction, the reaction temperature is -30-60°C, and after the reaction, a solution of a 3-(nitromethylene)azetidine compound 3 (Formula III) is obtained or a 3-(nitromethylene)azetidine compound 3 (Formula III) is obtained after post-treatment and purification.

[0028] Furthermore, in step S2, the sulfonyl chloride compound is selected from any one or more of methanesulfonyl chloride (MsCl) and p-toluenesulfonyl chloride (TsCl); preferably, the sulfonyl chloride compound is MsCl.

[0029] Further, in step S2, the second base is selected from any one or more of triethylamine, trimethylamine, N,N-diisopropylethylamine, diisopropylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), pyridine, potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH) and sodium bicarbonate (NaHCO3); preferably, the second base is diisopropylamine.

[0030] Furthermore, in step S2, the second solvent is selected from any one or more of ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, tetrahydrofuran, dichloromethane, chloroform and toluene; preferably, the second solvent is ethyl acetate.

[0031] Furthermore, in step S2, the molar ratio of the 3-hydroxy-3-(nitromethyl)azetidine compound 2 (Formula II), the sulfonyl chloride compound and the second base is 1:0.5-6.0:0.5-6.0.

[0032] Furthermore, in the step S2, the reaction temperature is between -30-60°C, and the reaction time is 0.5-12h; preferably, the temperature is 0°C, and the reaction time is 1h.

[0033] Furthermore, the specific operation steps of step S3 include: under the action of a third base, 3-(nitromethylene)azetidine compound 3 (Formula III) and a pyrazole compound undergo Michael addition reaction in a third solvent, the reaction temperature is -10-90°C, and after the reaction is completed, a solution of compound 4 (Formula IV) is obtained or compound 4 (Formula IV) is obtained after post-treatment.

[0034] Furthermore, in step S3, the third solvent is selected from any one or more of ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, tetrahydrofuran, dichloromethane, chloroform and toluene; preferably, the third solvent is ethyl acetate.

[0035] Further, in step S3, the third base is selected from any one or more of triethylamine, trimethylamine, N,N-diisopropylethylamine, diisopropylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), pyridine, potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bicarbonate (NaHCO3) and no alkali; preferably, the third base is any one or more of diisopropylamine and no alkali.

[0036] Furthermore, in the step S3, the molar ratio of the 3-(nitromethylene)azetidine compound 3 (Formula III) to the pyrazole compound is 1:0.5-3.0.

[0037] Furthermore, in the step S3, the reaction temperature is -10-90°C, and the reaction time is 12-48h; preferably, the reaction temperature is 45°C, and the reaction time is 24h.

[0038] Furthermore, the specific operation steps of step S4 include: under the action of a catalyst, compound 4 (Formula IV) undergoes a hydrogenation reduction reaction in a fourth solvent, the reaction temperature is 0-130°C, and after the reaction is completed, post-treatment and purification are performed to obtain 3-(1H-pyrazole-1-yl)azetidine compound 5 (Formula V).

[0039] Furthermore, in step S4, the catalyst is selected from any one or more of palladium carbon (Pd / C), rhodium carbon (Ru / C), platinum carbon (Pt / C), palladium hydroxide carbon (Pd(OH)2 / C) and Raney nickel (Raney); preferably, the catalyst is palladium carbon.

[0040] Furthermore, in step S4, the fourth solvent is selected from any one or more of isopropanol, methanol, ethanol, toluene, ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane and tetrahydrofuran; preferably, the fourth solvent is toluene.

[0041] Furthermore, in the step S4, the molar ratio of the compound 4 (Formula IV) to the catalyst is 1:0.01-1.0.

[0042] Furthermore, in the step S4, the reaction temperature is 0-110°C, the reaction time is 12-72h, and the hydrogen pressure is 0.2-1.0MPa; preferably, the reaction temperature is 55°C, the reaction time is 18h, and the hydrogen pressure is 0.5MPa.

[0043] Compared with the prior art, the present invention adopts the above technical solution to have the following beneficial effects:

[0044] (1) In the presence of a base, nitromethane reacts with 3-azetidinone compounds to generate 3-hydroxy-3-(nitromethyl)azetidinone compounds, with high reaction efficiency and a wide substrate range.

[0045] (2) The hydroxyl group is first activated and then eliminated to obtain 3-(nitromethylene)azetidine compounds, which provide modification sites for azetidine compounds and overcome the problem that traditional methods cannot modify azetidine compounds.

[0046] (3) 3-(1H-pyrazol-1-yl)azetidine compounds can be obtained in one pot, which reduces the post-processing and purification operations, improves the reaction efficiency, and overcomes the problems of complex post-processing and functional group intolerance in traditional methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is the compound 2 of Example 1 of the present invention 1 H NMR spectrum;

[0048] Figure 2 is the compound 2 of Example 1 of the present invention 13 C NMR spectrum;

[0049] Figure 3 is the compound 3 of Example 2 of the present invention 1 H NMR spectrum;

[0050] Figure 4 is the compound 3 of Example 2 of the present invention 13 C NMR spectrum;

[0051] Figure 5 is the compound 4 of Example 3 of the present invention 1 H NMR spectrum;

[0052] Figure 6 is the compound 4 of Example 3 of the present invention 13 C NMR spectrum;

[0053] Figure 7 is the compound 6 of Example 5 of the present invention 1 H NMR spectrum;

[0054] Figure 8 is the compound 6 of Example 5 of the present invention 13 C NMR spectrum;

[0055] Fig. 9 is the compound 7 of Example 6 of the present invention 1 H NMR spectrum;

[0056] Fig.10 is the compound 7 of Example 6 of the present invention 13 C NMR spectrum;

[0057] Fig.11 is the compound 8 of Example 7 of the present invention 1 H NMR spectrum;

[0058] Fig.12 is the compound 8 of Example 7 of the present invention 13 C NMR spectrum;

[0059] Fig.13 is the compound 9 of Example 8 of the present invention 1 H NMR spectrum;

[0060] Fig.14 is the compound 9 of Example 8 of the present invention 13 C NMR spectrum. DETAILED DESCRIPTION

[0061] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work belong to the scope of protection of the present invention. The experimental methods without specific conditions in the following embodiments are usually measured according to national standards. The experimental materials without the source indicated in the following embodiments are all commercially available raw materials. The equipment used in each step in the following embodiments is conventional equipment. If there is no corresponding national standard, it is carried out according to the general international standards, conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, all parts are weight parts and all percentages are mass percentages. Unless otherwise defined or specified, all professional and scientific terms used in the present invention have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar to or equal to the recorded contents can be applied to the method of the present invention. It should be noted that, in the absence of conflict, the features in the embodiments and embodiments of the present invention can be combined with each other. The present invention is further described below in conjunction with specific embodiments, but it is not intended to be limited to the present invention.

[0062] Embodiment 1:

[0063]

[0064] 100.00 g 1-Boc-3-azetidinone (Compound 1, 584.13 mmol, 1.0 eq.), 57.05 g nitromethane (93.81 mmol, 1.6 eq.) and 100.00 g toluene were added to the reaction flask and stirred at 25±5°C until dissolved. A solution of 11.82 g triethylamine (116.83 mmol, 0.2 eq.) in 100.00 g toluene was added dropwise, and the temperature was controlled at 25±5°C during the addition process. After 24 hours of reaction, 300 g of n-heptane was added dropwise to the reaction solution. After the addition was complete, the temperature was lowered to 0-5°C, the mixture was stirred for 1 hour at this temperature, and the filter cake was rinsed with 60 g of a mixed solution of (n-heptane: toluene = 5:1) and dried to obtain 130.23 g of tert-butyl 3-hydroxy-3-(nitromethyl)azetidine-1-carboxylate (compound 2, 560.76 mmol) as an off-white solid (yield: 96%, purity ≥98%).

[0065] get Figure 1 The hydrogen spectrum data of compound 2 shown are as follows:

[0066] 1H NMR (400MHz, Chloroform-d): δ4.69(s,2H),4.26(s,1H),4.09-3.91(m,4H),1.43(s,9H).

[0067] get Figure 2 The carbon spectrum data of compound 2 shown are as follows:

[0068] 13 C NMR (100MHz, Chloroform-d): δ156.44, 80.83, 80.26, 67.80, 28.43.

[0069] Embodiment 2:

[0070]

[0071] Add 100g of tert-butyl 3-hydroxy-3-(nitromethyl)azetidine-1-carboxylate (Compound 2, 430.60mmol, 1.0eq.), 300g of EA (3.0X) and 73.98g of MsCl (645.89mmol, 1.5eq.) to the reaction bottle, protect with nitrogen, and cool to 0-10°C. After cooling, control the temperature at 0-10°C, and add a solution of 104.58g of DIPA (1.03mol, 2.4eq.) in EA (200g) dropwise. After the reaction is completed, filter, add 300g of n-heptane dropwise to the filtrate, cool to 0-5°C, keep warm and stir for 1h, and filter. The filter cake was rinsed with 60 g of a mixed solution (n-heptane: ethyl acetate = 5:1) and dried to obtain 82.10 g of tert-butyl 3-(nitromethylene)azetidine-1-carboxylate (Compound 3) as a light yellow solid (yield: 89%, purity ≥98%).

[0072] get Figure 3 The hydrogen spectrum data of compound 3 shown are as follows:

[0073] 1 H NMR (400MHz, Chloroform-d): δ7.04(s,1H),5.09-4.96(m,2H),4.70(m,2H),1.46(s,9H).

[0074] get Figure 4 The carbon spectrum data of compound 3 shown are as follows:

[0075] 13 C NMR (100MHz, Chloroform-d): δ156.00,149.23,132.50,81.04,59.87,55.67,28.41.

[0076] Embodiment 3:

[0077]

[0078] Add 50g of tert-butyl 3-(nitromethylene)azetidine-1-carboxylate (Compound 3, 233.40mmol, 1.0eq.), 100g of ethyl acetate and 24.11g of 4-fluoropyrazole (280.08mmol, 1.2eq.) to the reaction bottle, heat to 45-50°C, keep warm for 24h, and after the reaction is completed, cool to room temperature, add 250g of 15% NaCl aqueous solution, stir for 30±5min, stand for stratification, and take the organic phase. Add 250g of 15% NaCl aqueous solution, stir for 30±5min, and stand for stratification. After the organic phase was concentrated, 150 g of isopropanol was added and the temperature was raised to 55±5°C. After stirring to dissolve, the temperature was lowered to 30-35°C. After cooling, 100 g of water was added dropwise and stirred until a solid precipitated. Stirring was continued for 1 to 2 h. 100 g of water (2X) was added dropwise and the temperature was lowered to 0-5°C. Stirring was continued for 1 to 2 h. After stirring was completed, the mixture was filtered and the filter cake was rinsed with 10 g of an ice mixed solvent (isopropanol: water = 1:2) and dried to obtain 58.87 g of tert-butyl 3-(nitromethyl)-3-(4-fluoro-1-H-pyrazol-1-yl)azetidine-1-carboxylate (compound 4, 196.06 mmol) as an off-white solid (yield: 84%, purity ≥98%).

[0079] get Figure 5 The hydrogen spectrum data of compound 4 shown are as follows:

[0080] 1 H NMR (400MHz, Chloroform-d): δ7.58(d,J=4.7Hz,1H),7.45(d,J=4.3Hz,1H),5.12(s,2H),4.45-4.34(m,4H),1.49(s,9H).

[0081] get Figure 6 The carbon spectrum data of compound 4 shown are as follows:

[0082] 13 C NMR (100MHz, Chloroform-d): δ155.83, 150.05 (d, J = 247.5Hz), 128.52 (d, J = 13.9Hz), 114.44 (d, J = 28.1Hz), 81.24, 57.98, 57.51, 28.36.

[0083] Embodiment 4:

[0084]

[0085] Add 100g of tert-butyl 3-hydroxy-3-(nitromethyl)azetidine-1-carboxylate (Compound 2, 430.60mmol, 1.0eq.), 300g of EA and 73.98g of MsCl (645.89mmol, 1.5eq.) to the reaction bottle, protect with nitrogen, and cool to 0-10°C. After cooling, control the temperature at 0-10°C, and add dropwise a solution of 104.58g of DIPA (1.03mol, 2.4eq.) in EA (200g). After the reaction is completed, concentrate to 200g-250g to obtain a solution of tert-butyl 3-(nitromethylene)azetidine-1-carboxylate. Then, 44.47 g of 4-fluoropyrazole (516.70 mmol, 1.2 eq.) was added, the temperature was raised to 45-50°C, and the reaction was kept at this temperature for 24 hours. After the reaction was completed, the temperature was lowered to room temperature, 500 g of 15% NaCl aqueous solution was added, the mixture was stirred for 30±5 min, and the mixture was allowed to stand for stratification, and the organic phase was taken. Another 500 g of 15% NaCl aqueous solution was added, the mixture was stirred for 30±5 min, and the mixture was allowed to stand for stratification. After the organic phase was concentrated, 300 g of isopropanol was added and the temperature was raised to 55±5°C. After stirring to dissolve, the temperature was lowered to 30-35°C. After cooling, 200 g of water was added dropwise and stirred until a solid precipitated. Stirring was continued for 1 to 2 h. 200 g of water (2X) was added dropwise and the temperature was lowered to 0-5°C. Stirring was continued for 1 to 2 h. After stirring was completed, the mixture was filtered and the filter cake was rinsed with 20 g of an ice mixed solvent (isopropanol: water = 1:2) and dried to obtain tert-butyl 3-(nitromethyl)-3-(4-fluoro-1-H-pyrazol-1-yl)azetidine-1-carboxylate 94.39 g (compound 4, 314.33 mmol) as an off-white solid (yield: 73%, purity ≥98%).

[0086] Embodiment 5:

[0087]

[0088] Add 50g 3-oxoazetidine hydrochloride (compound 5, 464.96mmol, 1.0eq.) and 99.33g nitromethane (1.63mol, 3.5eq.) to the reaction bottle, cool to 0-5°C, add 56.46g triethylamine (557.95mmol, 1.2eq.) dropwise, and concentrate after the reaction. Add 300g EA and 79.89g MsCl (697.44mmol, 1.5eq.) to the concentrate, protect with nitrogen, and cool to 0-10°C. After cooling, control the temperature at 0-10°C, and add a solution of 112.92g DIPA (1.12mol, 2.4eq.) in EA (200g) dropwise. After the reaction, the mixture was concentrated to 200 g to 250 g, and then 48.02 g of 4-fluoropyrazole (577.91 mmol, 1.2 eq.) was added, and the temperature was raised to 45-50°C. The mixture was kept warm for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, 300 g of 15% NaCl aqueous solution was added, and the mixture was stirred for 30 ± 5 min, and the mixture was allowed to stand for stratification. The organic phase was taken, and 300 g of 15% NaCl aqueous solution was added, and the mixture was stirred for 30 ± 5 min, and the mixture was allowed to stand for stratification. After the organic phase is concentrated, 100 g of isopropanol is added and the temperature is raised to 55±5°C. After stirring to dissolve, the temperature is lowered to room temperature and stirred for 1 to 2 h. 300 g of n-heptane is added dropwise and stirring is continued for 1 to 2 h. The temperature is lowered to 0-5°C and stirring is continued for 1 to 2 h. After stirring is completed, the mixture is filtered and the filter cake is rinsed with 20 g of an ice mixed solvent (isopropanol: n-heptane = 1:3) and dried to obtain 43.74 g of 3-(nitromethyl)-3-(4-fluoro-1-H-pyrazol-1-yl)azetidine (compound 6, 218.52 mmol) as a light yellow solid (yield: 47%, purity ≥95%).

[0089] get Figure 7 The hydrogen spectrum data of compound 6 shown are as follows:

[0090] 1 H NMR (400MHz, DMSO-d6): δ8.24(d,J=4.5Hz,1H),7.56(d,J=4.4Hz,1H),5.37(s,2H),3.96-3.76(m,4H),3.22(s,1H).

[0091] get Figure 8 The carbon spectrum data of compound 6 shown are as follows:

[0092] 13 C NMR (100MHz, DMSO-d6): δ149.2(d,J=241.9Hz), 126.40(d,J=13.6Hz), 115.24(d,J=28.6Hz), 78.34, 62.63, 54.34.

[0093] Embodiment 6:

[0094]

[0095] 30g of tert-butyl 3-nitro-3-(4-fluoro-1-H-pyrazol-1-yl)azetidine-1-carboxylate (Compound 4, 99.90mmol, 1.0eq.), 150.0g of methanol and 3g of Raney Ni were reacted at 35°C under H2 (0.5MPa) atmosphere. The reaction was completed by spot plate detection, filtered, the filter cake was rinsed with 20g of methanol, and the filtrate was concentrated. Column chromatography (n-hep:EA=2:1) ​​gave 22.60g of tert-butyl 3-(hydroxyamino)methyl)-3-(4-fluoro-1-H-pyrazol-1-yl)azetidine-1-carboxylate (Compound 7), a light brown solid (yield: 79%, purity ≥98%).

[0096] get Fig. 9 The hydrogen spectrum data of compound 7 shown are as follows:

[0097] 1 H NMR (400MHz, DMSO-d6): δ8.07(d,J=4.5Hz,1H),7.56(d,J=4.3Hz,1H),7.34(s,1H),5.89(s,1H),4.21(d,J=7.3Hz,4H),3.24(s,2H),1.38(s,9H).

[0098] get Fig.10 The carbon spectrum data of compound 7 shown are as follows:

[0099] 13 C NMR (100MHz, Chloroform-d): δ156.33, 150.06 (d, J = 246.3Hz), 127.39 (d, J = 13.6Hz), 114.53 (d, J = 27.6Hz), 80.52, 59.52, 59.26, 58.62, 28.44.

[0100] Embodiment 7:

[0101]

[0102] To the reaction bottle, 30 g of tert-butyl 3-(nitromethylene)azetidine-1-carboxylate (compound 2, 140.04 mmol, 1.0 eq.), 11.44 g of pyrazole (168.05 mmol, 1.2 eq.) and 60 g of ethyl acetate were added dropwise, and a solution of 14.17 g of DIPA (140.04 mmol, 1.0 eq.) in ethyl acetate (30 g) was added, the temperature was raised to 45-50° C., and the reaction was kept warm for 24 h. After the reaction was completed, the temperature was lowered to room temperature, 150 g of 15% NaCl was added, and the mixture was stirred for 30±5 min, and the mixture was allowed to stand for stratification. The organic phase was taken, 150 g of 15% NaCl was added, and the mixture was stirred for 30±5 min, and the mixture was allowed to stand for stratification. The organic phase was taken, 4 g of 10% Pd / C (3.38 mmol, 0.02 eq.) was added, and the mixture was reacted at 50° C. for 24 h under H2 (0.6-0.8 MPa) atmosphere. After the reaction was completed, the reaction was filtered, 180 g of n-heptane was added to the filtrate, stirred for 1 to 2 h, the temperature was lowered to 0-5 ° C, and stirring was continued for 1 to 2 h. After the stirring was completed, the reaction was filtered, and the filter cake was rinsed with 5 g of an ice mixed solvent (ethyl acetate: n-heptane = 1:2) and dried to obtain 25.44 g of tert-butyl 3-(aminomethyl)-3-(pyrazole)azetidine-1-carboxylate (compound 8, 100.82 mmol) as an off-white solid (yield: 72%, purity ≥98%).

[0103] get Fig.11 The hydrogen spectrum data of compound 8 shown are as follows:

[0104] 1 H NMR (400MHz, DMSO-d6): δ7.91(d,J=2.4Hz,1H),7.53(d,J=1.7Hz,1H),6.31(t,J=2.1Hz,1H),4.12(s,4H),3.02(s,2H),1.39(s,9H).

[0105] get Fig.12 The carbon spectrum data of compound 8 shown are as follows:

[0106] 13 C NMR (100MHz, Chloroform-d): δ155.66,139.07,128.68,105.49,78.92,60.49,47.87,28.00.

[0107] Embodiment 8:

[0108]

[0109] 30g of tert-butyl 3-nitro-3-(4-fluoro-1-H-pyrazol-1-yl)azetidine-1-carboxylate (Compound 4, 99.90mmol, 1.0eq.), 150.0g of toluene and 30g of Pd / C (27.33mmol, 0.25eq.) were reacted at 130°C for 48h under H2 (0.8MPa) atmosphere. The reaction was completed by spot plate detection, filtered, the filter cake was rinsed with 5g of toluene, and the filtrate was concentrated. Column chromatography (n-hep:EA=3:1) gave 24.06g of 3,3'-(azadiylbis(methylene))bis(3-(4-fluoro-1H-pyrazol-1-yl)azetidine-1-carboxylate) (Compound 9) as a light yellow solid (yield: 46%, purity ≥95%).

[0110] get Fig.13 The hydrogen spectrum data of compound 9 shown are as follows:

[0111] 1 H NMR (400MHz, DMSO-d6): δ7.98 (d, J = 4.7Hz, 2H), 7.54 (d, J = 4.3Hz, 2H), 4.13-3.97 (m, 8H), 2.97 (d, J = 7.1Hz, 4H), 1.99 (s, 1H), 1.38 (s, 18H).

[0112] get Fig.14 The carbon spectrum data of compound 9 shown are as follows:

[0113] 13 C NMR (100MHz, DMSO-d6): δ155.52, 149.02 (d, J = 241.8Hz), 126.07 (d, J = 13.3Hz), 115.55 (d, J = 28.4Hz), 79.00, 60.17, 54.70, 27.95.

Claims

1. A method for synthesizing a 3-(1H-pyrazole-1-yl)azetidine compound, characterized in that: Its synthetic route is as follows: The specific steps include: (1) Step S1, using compound 1 as a starting material, under the action of a first base, nitromethane and a ketone react in a first solvent to generate compound 2; (2) Step S2, in a second solvent, reacting compound 2, a sulfonyl chloride compound and a second base to derivatize the hydroxyl group into an easy leaving group, and then undergoing an elimination reaction to obtain compound 3; (3) Step S3, under the action of a third base, compound 3 and a pyrazole compound undergo Michael addition reaction in a third solvent to obtain compound 4; (4) Step S4: Compound 4 is hydrogenated and reduced in a fourth solvent under the action of a catalyst to generate Compound 5: R 1 Any one selected from hydrogen (H), tert-butyloxycarbonyl (Boc), benzyl (Bn) and benzyloxycarbonyl (Cbz); R 2 Any one selected from hydrogen (H), fluorine (F), chlorine (Cl) and bromine (Br); R 3 Any one selected from hydrogen (H), fluorine (F), chlorine (Cl) and bromine (Br); R 4 Any one selected from nitro (NO2), amino (NH2), hydroxylamine (NHOH) and azaalkane compounds.

2. The method for synthesizing 3-(1H-pyrazol-1-yl)azetidine compounds according to claim 1, characterized in that: In step S1, the compound 1 is selected from any one of 3-oxoazetidinone, 1-Boc-3-azetidinone, 1-Bn-3-azetidinone and 1-Cbz-3-azetidinone.

3. The method for synthesizing 3-(1H-pyrazol-1-yl)azetidine compounds according to claim 1, characterized in that: In step S1, the first base is selected from any one or more of triethylamine, trimethylamine, N,N-diisopropylethylamine, diisopropylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), pyridine, potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH) and sodium bicarbonate (NaHCO3).

4. The method for synthesizing 3-(1H-pyrazol-1-yl)azetidine compounds according to claim 1, characterized in that: The sulfonyl chloride compound in step S2 is selected from any one or more of methanesulfonyl chloride (MsCl) and p-toluenesulfonyl chloride (TsCl).

5. The method for synthesizing 3-(1H-pyrazol-1-yl)azetidine compounds according to claim 1, characterized in that: In step S2, the second base is selected from any one or more of triethylamine, trimethylamine, N,N-diisopropylethylamine, diisopropylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), pyridine, potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH) and sodium bicarbonate (NaHCO3).

6. The method for synthesizing 3-(1H-pyrazol-1-yl)azetidine compounds according to claim 1, characterized in that: The third solvent in step S3 is selected from any one or more of ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, tetrahydrofuran, dichloromethane, chloroform and toluene.

7. The method for synthesizing 3-(1H-pyrazol-1-yl)azetidine compounds according to claim 1, characterized in that: The third base in step S3 is selected from any one or more of triethylamine, trimethylamine, N,N-diisopropylethylamine, diisopropylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), pyridine, potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bicarbonate (NaHCO3) and no alkali.

8. The method for synthesizing 3-(1H-pyrazol-1-yl)azetidine compounds according to claim 1, characterized in that: The catalyst described in step S4 is selected from any one or more of palladium carbon (Pd / C), rhodium carbon (Ru / C), platinum carbon (Pt / C), palladium hydroxide carbon (Pd(OH)2 / C) and Raney nickel (Raney).

9. The method for synthesizing 3-(1H-pyrazol-1-yl)azetidine compounds according to claim 1, characterized in that: The fourth solvent in step S4 is selected from any one or more of isopropanol, methanol, ethanol, toluene, ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane and tetrahydrofuran.

10. A 3-(1H-pyrazol-1-yl)azetidine compound, synthesized according to the method for synthesizing a 3-(1H-pyrazol-1-yl)azetidine compound according to any one of claims 1 to 9.

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