A process for the preparation of a diazabicyclooctene compound

Abstract

The application discloses a preparation method of a diazabicyclooctene compound. Specifically, the method comprises the following steps: performing ring formation reaction of compound 3 and triphosgene in a solvent under the action of a base, as shown in the following formula, and the solvent is a halogenated alkane solvent, and the base is triethylamine. The preparation method has a short synthesis route, reduces consumption of raw materials, and improves overall yield.

Description

Technical Field

[0001] The present invention provides a method for preparing a diazabicyclooctene compound. Background Art

[0002] The closest method to the present invention is a report by JMC (Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C and D Serine β-lactamases) on the synthesis of a diazabicyclooctane compound (ETX0282). Using ethyl glyoxylate (B-1) as a raw material, intermediate B was synthesized through 11 steps of reaction. Ethyl bromofluoroacetate (A-1) was then used as a raw material to synthesize intermediate A through three steps of hydrolysis, resolution, and esterification. The specific synthesis route is shown below. This synthetic route involves condensing compound B-1 with S-tert-butylsulfenamide to produce compound B-2, which is then subjected to a Diels-Alder reaction (DA cyclization) with isoprene to produce compound B-3. The tert-butylsulfenamide is removed under acidic conditions, followed by Boc protection of the secondary amine to produce compound B-4. This is hydrolyzed under alkaline conditions to produce compound B-5, which is then converted to an amide with ammonium acetate under the action of carbonyldiimidazole (CDI) to produce compound B-6. This amide then reacts with BocNHOH via oxygen to produce compound B-7. The hydroxyl group is then protected to produce compound B-8, which is then deprotected with the Boc protecting group under zinc bromide to produce compound B-9. This is then cyclized with triphosgene to produce compound B-10, and the tert-butyldimethylsilyl (TBS) protecting group is removed to produce intermediate B. Finally, intermediates A and B are joined to produce the finished product, ETX0282. This synthetic route is lengthy and has a low yield.

[0003] Summary of the Invention

[0004] The present invention addresses the drawback of the existing preparation method for ETX0282, which suffers from a long reaction route and results in low yields. The present invention provides a method for preparing a diazabicyclooctene compound. The method has a shorter synthesis route, reduces raw material consumption, and improves overall yield.

[0005] The present invention provides a method for preparing a diazabicyclooctene compound, comprising the following steps: in a solvent, in the presence of a base, compound 3 and triphosgene undergo a cyclization reaction as shown below to obtain compound ETX0282; the base is triethylamine;

[0006]

[0007] In the present application, the ring-forming reaction is preferably carried out in the presence of an inert gas, which is a gas that is chemically inert and hardly reacts with other substances in the art, for example, one or more selected from nitrogen, argon and helium, preferably nitrogen.

[0008] In the present application, the solvent in the ring-forming reaction can be a halogenated alkane solvent, preferably dichloromethane.

[0009] In the present application, the molar volume ratio of the compound 3 to the solvent in the ring-forming reaction is the conventional molar volume ratio in the art for such a reaction, for example, 1:(7-22) mol / L, preferably 1:14 mol / L.

[0010] In the present application, the molar ratio of the base to the compound 3 in the ring-forming reaction is the conventional molar ratio in the art for such a reaction, for example, (1-3):1, preferably 2:1.

[0011] In the present application, the molar ratio of the triphosgene to the compound 3 in the ring-forming reaction is the conventional molar ratio in the art for such a reaction, for example, 1:(2.5-3.5), preferably 1:2.9. The triphosgene is preferably applied to the ring-forming reaction in the form of a solution. The solvent of the triphosgene solution is preferably the solvent in the above ring-forming reaction. The concentration of the triphosgene solution is preferably 0.05-0.2 mol / L, more preferably 0.118 mol / L.

[0012] In the present application, the feeding sequence of the ring-forming reaction is preferably to add the base to the compound 3 first, and then add the triphosgene. The feeding operation of the ring-forming reaction is preferably carried out at 0°C.

[0013] In the present application, the reaction temperature of the ring-forming reaction is the conventional reaction temperature in the art for such a reaction, for example, -40-25°C, preferably 0°C.

[0014] In the present application, the reaction progress of the ring-forming reaction can be detected by using the conventional monitoring method in the art (for example, TLC, HPLC or NMR), and the reaction end point is generally when the compound 3 disappears or no longer reacts. The time of the ring-forming reaction is preferably 1-8 hours, for example, 1 hour.

[0015] In the present application, the ring-forming reaction is preferably quenched with ice water.

[0016] In the present application, the ring-forming reaction preferably includes the following post-treatment steps: extraction (for example, using DCM), washing (for example, using water and saturated brine), drying (for example, using anhydrous sodium sulfate), filtration, concentration (for example, concentration under reduced pressure) and purification (for example, column chromatography using ethyl acetate and petroleum ether in a volume ratio of 1:1).

[0017] Preferably, the preparation method of the diazabicyclooctene compound further includes a preparation method of compound 3, which comprises the following steps: in a solvent, in the presence of a deprotection reagent, compound 2 undergoes a deprotection reaction as shown below to form compound 3;

[0018]

[0019] In the present invention, the deprotection reaction is preferably carried out in the presence of an inert gas, which is a gas that is chemically inactive and difficult to react chemically with other substances in the art, such as one or more selected from nitrogen, argon and helium, preferably nitrogen.

[0020] In the present invention, in the deprotection reaction, the solvent is a conventional organic solvent used in this type of reaction in the art, for example, one or more selected from nitrile solvents (such as acetonitrile), amide solvents (such as N,N-dimethylformamide), ether solvents (such as methyltetrahydrofuran and / or dioxane) and halogenated alkane solvents (such as dichloromethane), preferably a halogenated alkane solvent (such as dichloromethane).

[0021] In the present invention, in the deprotection reaction, the deprotection reagent is a conventional deprotection reagent that can be used in the art to remove the Boc protecting group, for example, one or more selected from organic acids, inorganic acids, silane reagents (for example, one or more of iodosilane SiH3I, chlorosilane SiH3Cl and trifluoromethanesulfonic acid silane CF3SO3SiH3) and inorganic salts (for example, one or more of aluminum trichloride, magnesium perchlorate, tin tetrachloride, ceric ammonium nitrate and zinc bromide), preferably an inorganic salt (for example, zinc bromide).

[0022] In the present invention, in the deprotection reaction, the molar volume ratio of the compound 2 to the solvent is a conventional molar volume ratio for such reactions in the art, for example, 1:(13-20) mol / L, preferably 1:16 mol / L.

[0023] In the present invention, in the deprotection reaction, the molar ratio of the deprotection reagent to the compound 2 is a conventional molar ratio for such reactions in the art, for example (1-7):1, preferably 5:1.

[0024] In the present invention, the progress of the deprotection reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). The reaction endpoint is generally determined when compound 2 disappears or ceases to react. The deprotection reaction time is preferably 48 to 56 hours, for example, 52 hours.

[0025] In the present invention, the reaction temperature of the deprotection reaction is the conventional reaction temperature of this type of reaction in the art, such as room temperature, preferably 0-25°C.

[0026] In the present invention, in the deprotection reaction, when the deprotection reagent is zinc bromide, the addition order of the deprotection reaction is preferably to add the zinc bromide to the compound 2 in batches.

[0027] In the present invention, the deprotection reaction preferably further comprises the following post-treatment steps: neutralization (e.g., using sodium bicarbonate), filtration, extraction (e.g., using DCM extraction), washing (e.g., washing with water and saturated brine), drying (e.g., using anhydrous sodium sulfate drying), filtration, concentration (e.g., concentration under reduced pressure), and purification (e.g., using column chromatography with a volume ratio of dichloromethane to methanol of 50:1).

[0028] Preferably, the preparation method of the diazabicyclooctene compound further includes a preparation method of compound 2, which comprises the following steps: in a solvent, in the presence of a catalyst, compound A and compound B-7 undergo a substitution reaction as shown below to form compound 2;

[0029]

[0030] In the present invention, the substitution reaction is preferably carried out in the presence of an inert gas, which is a gas that is chemically inactive and difficult to react chemically with other substances in this field, such as one or more selected from nitrogen, argon and helium, preferably nitrogen.

[0031] In the present invention, in the substitution reaction, the solvent is a conventional organic solvent used in the art for such reactions, for example, one or more selected from amide solvents (for example, N,N-dimethylformamide), halogenated alkane solvents (for example, dichloromethane), ester solvents (for example, acetate solvents) and ether solvents (for example, one or more of tetrahydrofuran, methyltetrahydrofuran and 1,4-dioxane), preferably an ether solvent and / or an amide solvent (for example, 1,4-dioxane and / or N,N-dimethylformamide, for example, 1,4-dioxane and N,N-dimethylformamide in a volume ratio of 4:1).

[0032] In the present invention, in the substitution reaction, the catalyst is a conventional catalyst used in the art for such reactions, such as an organic base (for example, one or more of diisopropylethylamine, triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene), preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0033] In the present invention, in the substitution reaction, the molar volume ratio of the compound B-7 to the solvent is a conventional molar volume ratio for such reactions in the art, for example, 1:(6-9) mol / L, preferably 1:7 mol / L.

[0034] In the present invention, in the substitution reaction, the molar ratio of compound A to compound B-7 is a conventional molar ratio for such reactions in the art, for example (1-2):1, preferably 2:1.

[0035] In the present invention, in the substitution reaction, the molar ratio of the catalyst to the compound B-7 is a conventional molar ratio for such reactions in the art, for example (1-2):1, preferably 2:1.

[0036] In the present invention, the preferred order of adding the materials for the substitution reaction is to first add compound A to compound B-7 and then add the catalyst. The addition operation for the substitution reaction is preferably carried out at 0°C.

[0037] In the present invention, the reaction temperature of the substitution reaction is the conventional reaction temperature of this type of reaction in the art, such as room temperature, preferably -5 to 20°C.

[0038] In the present invention, the progress of the substitution reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). The reaction endpoint is generally determined when compound B-7 disappears or ceases to react. The reaction time of the substitution reaction is preferably 1 to 30 minutes, for example, 20 minutes.

[0039] In the present invention, the substitution reaction preferably includes the following post-treatment steps: washing (e.g., washing with ethyl acetate and saturated brine (1:1)), drying (e.g., drying with anhydrous sodium sulfate), filtration, concentration (e.g., concentration under reduced pressure) and purification (e.g., column chromatography purification using a volume ratio of ethyl acetate to petroleum ether of 1:1).

[0040] The present invention also provides a method for preparing compound 3, which comprises the following steps: in a solvent, in the presence of a deprotection reagent, subjecting compound 2 to a deprotection reaction as shown below to form compound 3;

[0041]

[0042] Wherein, the reaction conditions of the deprotection reaction are as described above;

[0043] Preferably, the preparation method of compound 3 further includes the preparation method of compound 2.

[0044] The present invention also provides a method for preparing compound 2, comprising the following steps: in a solvent, in the presence of a catalyst, compound A and compound B-7 undergo a substitution reaction as shown below to form compound 2;

[0045]

[0046] Wherein, the reaction conditions of the substitution reaction are as described above.

[0047] The present invention also provides compound 2 or compound 3 as shown below:

[0048]

[0049] The present invention also provides a method for preparing a diazabicyclooctene compound, which comprises the following steps:

[0050] (1) In a solvent, in the presence of a catalyst, compound A and compound B-7 undergo a substitution reaction as shown below to form compound 2;

[0051]

[0052] (2) In a solvent, under the action of a deprotection reagent, compound 2 undergoes a deprotection reaction as shown below to form compound 3;

[0053]

[0054] (3) In a solvent, under the action of a base, compound 3 and triphosgene undergo a cyclization reaction as shown below to obtain compound ETX0282;

[0055]

[0056] In step (1), the reaction conditions of the substitution reaction are as described above;

[0057] In step (2), the reaction conditions of the deprotection reaction are as described above;

[0058] In step (3), the reaction conditions of the cyclization reaction are as described above.

[0059] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0060] The reagents and raw materials used in the present invention are commercially available.

[0061] The positive progress effect of the present invention is that the preparation method of the present invention has a short synthesis route, reduces the consumption of raw materials, and improves the overall yield. DETAILED DESCRIPTION

[0062] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0063] In Example 1, the compound A and the compound B-7 are prepared according to the reference "Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C and D Serine β-lactamases".

[0064] It is well known in the art that the following preparation methods have no effect on the configuration of chiral carbon atoms.

[0065] Example 1

[0066]

[0067] N2 protection, raw material B-7 (5 g, 13.48 mmol) was dissolved in 1,4-dioxane / N,N- dimethylformamide (80 mL / 20 mL), compound A (5.33 g, 26.96 mmol) was first added at 0 °C, then DBU (4.1 g, 26.96 mmol) was added, and the reaction was allowed to rise to room temperature (20 °C) for 20 minutes. The reaction solution was washed with ethyl acetate and saturated brine (1:1 by volume) (3 x 100 mL), the combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether = 1:1 (v / v)) to obtain white solid compound 2 (4.05 g, 8.28 mmol) with a yield of 61.42% and a purity of 95.61%.

[0068] MS (ESI + )[M+Na] + :512 (C 22 H 36 FN3O8Na).

[0069] 1 HNMR (400MHz, DMSO-d6) δ: 1.24-1.47 (m, 24H), 1.78 (s, 3H), 3.26 (d, 1H), 4.07 (m, J = 10.4 Hz, 1H), 4.12-4.38 (m, 1H), 4.66 (d, J = 67.7 Hz, 1H), 4.95 (qt, J = 18.7, 6.0 Hz, 1H), 5.44-5.73 (m, 1H), 5.82 (d, J = 53.7 Hz, 1H), 7.05 (s, 1H), 7.46 (s, 1H).

[0070] Example 2

[0071]

[0072] Compound 2 (3 g, 6.13 mmol) was dissolved in dichloromethane (100 mL) under N2protection, ZnBr2(6.91 g, 30.67 mmol) was added in batches, the reaction was carried out at room temperature for 52 h, then the reaction solution was reduced to 0 °C, a solution of NaHCO3(5.15 g, 61.3 mmol) in water (20 mL) was added and stirred for 1 h, filtered, extracted with DCM (3 x 50 mL), washed with water and saturated brine (3 x 100 mL), the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 50 / 1 (v / v)) to obtain white solid compound 3 (1.40 g, 4.86 mmol) with a yield of 79.23% and a purity of 99.56%.

[0073] MS (ESI + [M+H] + : 290 (C 12 H 20 FN3O4).

[0074] 1 HNMR (600 MHz, DMSO-d6+D2O) δ: 1.18-1.29 (m, 6H), 1.68 (s, 3H), 2.51-2.69 (m, 1H), 2.85-3.10 (m, 1H), 3.17 (d, J = 43.6 Hz, 1H), 3.62 (d, J = 2.0 Hz, 1H), 4.96 (qt, J = 70.4, 35.0 Hz, 1H), 5.33-5.81 (m, 1H), 5.83 (d, J = 46.0, 33.6 Hz, 1H).

[0075] Example 3

[0076]

[0077] Compound 3 (1 g, 3.46 mmol) was dissolved in dichloromethane (50 mL) under N2protection, triethylamine (0.7 g, 6.92 mmol) was added at 0 °C, then triphosgene (0.35 g, 1.18 mmol) was diluted with dichloromethane (10 mL) and added, the reaction was carried out at this temperature for 1 h, then ice water (20 mL) was added to quench, extracted with DCM (3 x 20 mL), washed with water and saturated brine (3 x 20 mL), the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1 (v / v)) to obtain white solid ETX0282 (0.56 g, 1.79 mmol) with a yield of 51.77% and a purity of 98.13%.

[0078] MS (ESI +)[M+H] + :316(C 13 H 18 FN3O5).

[0079] 1 HNMR(300MHz,DMSO-d6)δ:1.24(m,6H),1.82(t,3H,J=1.79Hz),3.21(m,1H),3.33(m,1H),3.95(d,1H,J= 2.1Hz),4.22(m,1H),5.01(m,1H),5.52(m,1H),6.15-6.33(d,1H,J=55.8Hz),7.32(s,1H),7.55(s,1H); 13 C NMR (300MHz, DMSO-d6) δ: 21.62, 21.76, 23.00, 46.49, 62.56, 64.16, 70.66, 104.37, 107.49, 120.98, 138.69, 162.63, 163.07, 169.45, 169.90.

[0080] Comparative Example 1

[0081] Compound ETX0282 was prepared by the same method as in Example 3, except that "triethylamine" was replaced by "diisopropylethylamine". Compound ETX0282 was not found in the product.

[0082] Comparative Example 2

[0083] Compound ETX0282 was prepared by the same method as in Example 3, except that "triethylamine" was replaced by "DBU". Compound ETX0282 was not found in the product.

[0084] Comparative Example 3

[0085] Compound ETX0282 was prepared by the same method as in Example 3, except that "triethylamine" was replaced by "DIPEA". Compound ETX0282 was not found in the product.

[0086] Comparative Example 4

[0087] Compound ETX0282 was prepared by the same method as in Example 3, except that "dichloromethane" was replaced by a mixed solvent of acetonitrile and dichloromethane (v:v = (3:4)). The yield was only 25-30%.

[0088] Comparative Example 5

[0089] Compound ETX0282 was prepared using the same method as in Example 3, except that "dichloromethane" was replaced by "acetonitrile". The yield was measured to be only 20%.

Claims

1. A method for preparing a diazabicyclooctene compound, comprising the following steps: in a solvent, in the presence of a base, compound 3 and triphosgene undergo a cyclization reaction as shown below to obtain compound ETX0282; the base is triethylamine; and the solvent is dichloromethane; 2. The preparation method according to claim 1, wherein It meets one or more of the following conditions: (1) The cyclization reaction is carried out in the presence of an inert gas; (2) In the cyclization reaction, the molar volume ratio of the compound 3 to the solvent is 1:(7-22) mol / L; (3) In the cyclization reaction, the molar ratio of the base to the compound 3 is (1-3):1; (4) In the cyclization reaction, the molar ratio of triphosgene to compound 3 is 1:(2.5-3.5); (5) In the cyclization reaction, the triphosgene is applied to the cyclization reaction in the form of a solution; (6) The order of adding materials in the cyclization reaction is to first add the base to the compound 3 and then add the triphosgene; (7) the addition operation of the cyclization reaction is carried out at 0°C; and (8) The reaction temperature of the cyclization reaction is -40 to 25°C.

3. The preparation method according to claim 1, wherein It meets one or more of the following conditions: (1) When the cyclization reaction is carried out in the presence of an inert gas, the inert gas is selected from one or more of nitrogen, argon and helium; (2) In the cyclization reaction, the molar volume ratio of the compound 3 to the solvent is 1:14 mol / L; (3) In the cyclization reaction, the molar ratio of the base to the compound 3 is 2:1; (4) In the cyclization reaction, the molar ratio of triphosgene to compound 3 is 1:2.9; (5) In the cyclization reaction, when the triphosgene is applied to the cyclization reaction in the form of a solution, the concentration of the triphosgene solution is 0.05 to 0.2 mol / L; (6) The reaction temperature of the cyclization reaction is 0°C; (7) quenching the cyclization reaction with ice water; and (8) The cyclization reaction includes the following post-processing steps: extraction, washing, drying, filtration, concentration and purification.

4. The preparation method according to claim 3, wherein It meets one or more of the following conditions: (1) When the cyclization reaction is carried out in the presence of an inert gas, the inert gas is nitrogen; (2) In the cyclization reaction, when the triphosgene is applied to the cyclization reaction in the form of a solution, the concentration of the triphosgene solution is 0.118 mol / L.

5. The preparation method according to claim 1, wherein The preparation method of the diazabicyclooctene compound further includes a preparation method of compound 3, which comprises the following steps: in a solvent, under the action of a deprotection reagent, compound 2 undergoes a deprotection reaction as shown below to form compound 3; 6. The preparation method according to claim 5, wherein It meets one or more of the following conditions: (1) the deprotection reaction is carried out in the presence of an inert gas; (2) In the deprotection reaction, the solvent is selected from one or more of a nitrile solvent, an amide solvent, an ether solvent, and a halogenated alkane solvent; (3) In the deprotection reaction, the deprotection reagent is selected from one or more of an organic acid, an inorganic acid, a silane reagent and an inorganic salt; (4) In the deprotection reaction, the molar volume ratio of the compound 2 to the solvent is 1:(13-20) mol / L; (5) In the deprotection reaction, the molar ratio of the deprotection reagent to the compound 2 is (1-7):1; and (6) The reaction temperature of the deprotection reaction is room temperature.

7. The preparation method according to claim 6, wherein It meets one or more of the following conditions: (1) In the deprotection reaction, the solvent is a halogenated alkane solvent; (2) In the deprotection reaction, the deprotection reagent is an inorganic salt.

8. The preparation method according to claim 6, wherein It meets one or more of the following conditions: (1) When the deprotection reaction is carried out in the presence of an inert gas, the inert gas is selected from one or more of nitrogen, argon and helium; (2) In the deprotection reaction, when the solvent is a nitrile solvent, the nitrile solvent is acetonitrile; (3) In the deprotection reaction, when the solvent is an amide solvent, the amide solvent is N,N-dimethylformamide; (4) In the deprotection reaction, when the solvent is an ether solvent, the ether solvent is methyltetrahydrofuran and / or dioxane; (5) In the deprotection reaction, when the solvent is a halogenated alkane solvent, the halogenated alkane solvent is dichloromethane; (6) In the deprotection reaction, when the deprotection reagent is a silane reagent, the silane reagent is selected from one or more of iodosilane, chlorosilane and trifluoromethanesulfonic acid silane; (7) In the deprotection reaction, when the deprotection reagent is an inorganic salt, the inorganic salt is selected from one or more of aluminum trichloride, magnesium perchlorate, tin tetrachloride, cerium ammonium nitrate and zinc bromide; (8) In the deprotection reaction, the molar volume ratio of the compound 2 to the solvent is 1:16 mol / L; (9) In the deprotection reaction, the molar ratio of the deprotection reagent to the compound 2 is 5:1; (10) The reaction temperature of the deprotection reaction is 0 to 25°C; (11) In the deprotection reaction, when the deprotection reagent is zinc bromide, the order of adding the materials in the deprotection reaction is to add the zinc bromide to the compound 2 in batches; and (12) The deprotection reaction further includes the following post-processing steps: neutralization, filtration, extraction, washing, drying, filtration, concentration and purification.

9. The preparation method according to claim 8, wherein It meets one or more of the following conditions: (1) When the deprotection reaction is carried out in the presence of an inert gas, the inert gas is nitrogen; (2) In the deprotection reaction, when the deprotection reagent is an inorganic salt, the inorganic salt is zinc bromide.

10. The preparation method according to claim 5, characterized in that The preparation method of the diazabicyclooctene compound further includes a preparation method of compound 2, which comprises the following steps: in a solvent, in the presence of a catalyst, compound A and compound B-7 undergo a substitution reaction as shown below to form compound 2; 11. The preparation method according to claim 10, characterized in that It meets one or more of the following conditions: (1) The substitution reaction is carried out in the presence of an inert gas; (2) In the substitution reaction, the solvent is selected from one or more of an amide solvent, a halogenated alkane solvent, an ester solvent, and an ether solvent; (3) In the substitution reaction, the catalyst is an organic base; (4) In the substitution reaction, the molar volume ratio of the compound B-7 to the solvent is 1:(6-9) mol / L; (5) In the substitution reaction, the molar ratio of the compound A to the compound B-7 is (1-2):1; (6) In the substitution reaction, the molar ratio of the catalyst to the compound B-7 is (1-2):1; (7) The order of adding materials for the substitution reaction is to first add compound A to compound B-7, and then add the catalyst; (8) the addition operation of the substitution reaction is carried out at 0°C; and (9) The reaction temperature of the substitution reaction is room temperature.

12. The preparation method according to claim 11, characterized in that In the substitution reaction, the solvent is an ether solvent and / or an amide solvent.

13. The preparation method according to claim 11, wherein It meets one or more of the following conditions: (1) When the substitution reaction is carried out in the presence of an inert gas, the inert gas is selected from one or more of nitrogen, argon and helium; (2) In the substitution reaction, when the solvent is an amide solvent, the amide solvent is N,N-dimethylformamide; (3) In the substitution reaction, when the solvent is a halogenated alkane solvent, the halogenated alkane solvent is dichloromethane; (4) In the substitution reaction, when the solvent is an ester solvent, the ester solvent is an acetate solvent; (5) In the substitution reaction, when the solvent is an ether solvent, the ether solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran and 1,4-dioxane; (6) In the substitution reaction, when the catalyst is an organic base, the organic base is selected from one or more of diisopropylethylamine, triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene; (7) In the substitution reaction, the molar volume ratio of the compound B-7 to the solvent is 1:7 mol / L; (8) In the substitution reaction, the molar ratio of compound A to compound B-7 is 2:1; (9) In the substitution reaction, the molar ratio of the catalyst to the compound B-7 is 2:1; (10) The reaction temperature of the substitution reaction is -5 to 20°C; and (11) The substitution reaction includes the following post-processing steps: washing, drying, filtration, concentration and purification.

14. The preparation method according to claim 13, wherein It meets one or more of the following conditions: (1) When the substitution reaction is carried out in the presence of an inert gas, the inert gas is nitrogen; (2) In the substitution reaction, when the solvent is an ether solvent, the ether solvent is 1,4-dioxane; (3) In the substitution reaction, when the catalyst is an organic base, the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

15. A method for preparing a diazabicyclooctene compound, comprising the following steps: (1) In a solvent, in the presence of a catalyst, compound A and compound B-7 undergo a substitution reaction as shown below to form compound 2; (2) In a solvent, under the action of a deprotection reagent, compound 2 undergoes a deprotection reaction as shown below to form compound 3; (3) Compound 3 and triphosgene undergo a cyclization reaction in a solvent under the action of a base to obtain compound ETX0282; the base is triethylamine; and the solvent in the cyclization reaction is dichloromethane; 16. The method for preparing the diazabicyclooctene compound according to claim 15, wherein: In step (1), the reaction conditions of the substitution reaction are as described in any one of claims 11 to 14; In step (2), the reaction conditions of the deprotection reaction are as described in any one of claims 6 to 9; In step (3), the reaction conditions of the cyclization reaction are as described in any one of claims 2 to 4.

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