Preparation method of benzoxazolone amide compound

Abstract

The invention relates to a preparation method of a benzoxazolone amide compound, and belongs to the technical field of medicines and chemistry. The invention provides a preparation method of a compound 5, and the reaction is as follows: # imgabs0 #, in which X is Br or Cl; the preparation method comprises the following steps: 1, carrying out Suzuki coupling on a compound 1 and a compound 2 to obtain a compound 3; 2, reacting the compound 3 in the presence of a catalyst and a hydrogen source to obtain a compound 4; and 3, reacting the compound 4 with isocyanate and organic alkali to obtain a compound 5. The invention provides a brand-new preparation method of a compound 5, which is a new intermediate, has the advantages of short steps, high yield, high atom utilization rate and good reproducibility, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug development, and specifically relates to a method for preparing a benzoxazolone amide compound. Background Art

[0002] Acid ceramidase (AC, ASAH-1) is a ubiquitously expressed enzyme and one of the key enzymes regulating ceramide and glycosphingolipid metabolism. It can release fatty acids and sphingosine from ceramide, and its deficiency leads to a progressive lysosomal storage disorder, commonly known as Farber disease (FD). At the same time, inhibition of AC is considered a potential anticancer drug target. Aberrant AC activity is also seen in several other common diseases, including inflammation, pain, and various lung diseases.

[0003] Benzoxazolone amide compound 5 (Acid-Ceramidase-IN-1) is a novel oral acid ceramidase inhibitor (hACIC50 = 0.166 μM), developed by Fondazione Istituto Italiano di Tecnologia and Lysosomal Therapeutics, and its structural formula is shown below:

[0004]

[0005] Acid-Ceramidase-IN-1 has good brain penetration in mice and can significantly reduce the levels of toxic lipids glucose sphingosine (GluSph) and galactosylsphingosine (GalSph) in the mouse brain. It has the potential to be further developed for the correction of severe neurological LSD.

[0006] At present, there is only one synthetic route reported about Acid-Ceramidase-IN-1 in the prior art, which is as follows:

[0007]

[0008] This route requires six steps of Suzuki coupling, nitro reduction, ring closure, deprotection, methylation and substitution to obtain the final compound. This route has a long number of steps, the total yield is less than 29.5%, and it requires catalytic hydrogenation, intramolecular carbonylation reaction to form a ring, deprotection and other steps. The operation is cumbersome, the atomic utilization rate is low, the yield is low, and it is not conducive to commercial production. Therefore, it is urgent to develop a preparation method for compound 5 that is truly feasible, economical and fast, easy to operate, simple to post-process, high in yield, and high in atomic utilization.

[0009] The present invention provides a method for preparing a benzoxazolone amide compound 5, which does not require the steps of nitro reduction, ring closure, deprotection, and methylation, greatly shortens the reaction route, and has the advantages of being economical, fast, easy to operate, simple to post-process, high conversion rate, and high atomic utilization rate. It is suitable for industrial production and therefore has good market value and far-reaching practical significance.

[0010] Technical Solution

[0011] In view of the above technical background, the present invention provides a method for preparing benzoxazolone amide compounds, which has simple process operation, short route, high atomic utilization, high reproducibility, high yield, low cost, green and environmental protection, and is conducive to industrial production.

[0012] The first aspect of the present invention provides a method for preparing compound 5, the reaction is as follows:

[0013]

[0014] Wherein, X is Br or Cl;

[0015] The following steps are included:

[0016] Step 1: Compound 1 and compound 2 are reacted by Suzuki coupling to obtain compound 3;

[0017] Step 2: Compound 3 reacts in the presence of a catalyst and a hydrogen source to obtain compound 4;

[0018] Step 3: Compound 4 reacts with isocyanate and an organic base to obtain compound 5;

[0019] As a further improvement of the present invention, including but not limited to, in step 1, compound 1 and compound 2 react in the presence of a palladium catalyst, a base, an organic solvent and water to obtain compound 3.

[0020] As a further improvement of the present invention, including but not limited to, the palladium catalyst in step 1 is selected from one or more of Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, preferably Pd(PPh3)4.

[0021] As a further improvement of the present invention, including but not limited to, the base in step 1 is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, and potassium acetate, preferably one or more of sodium carbonate, potassium carbonate, and cesium carbonate.

[0022] As a further improvement of the present invention, including but not limited to, in step 1, the molar ratio of compound 1, compound 2, base and palladium catalyst is 1: (1-5): (1-10): (0.01-0.8), preferably 1: (1-3): (1.1-5): (0.01-0.6).

[0023] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 1 is 70-140°C, preferably 80-130°C.

[0024] As a further improvement of the present invention, including but not limited to, the reaction time of step 1 is 4 to 24 hours, preferably 5 to 20 hours.

[0025] As a further improvement of the present invention, including but not limited to, the organic solvent in step 1 is selected from one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, toluene, xylene, dimethylformamide (DMF), dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO), preferably one or more of dioxane, toluene, xylene, dimethylformamide (DMF), dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO).

[0026] As a further improvement of the present invention, in certain embodiments, after the reaction of step 1 is completed, the reaction solution is filtered, extracted, separated, washed, dried, and concentrated to obtain compound 3;

[0027] As a further improvement of the present invention, in certain embodiments, the compound 3 can be further purified by column chromatography, and the column chromatography eluent is, for example, dichloromethane / methanol = 30:1.

[0028] As a further improvement of the present invention, including but not limited to, the catalyst in step 2 is selected from one of palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide, and Raney nickel, preferably palladium carbon.

[0029] As a further improvement of the present invention, including but not limited to, the hydrogen source in step 2 is selected from one or more of hydrogen, ammonium formate, hydrazine hydrate, and formic acid, preferably one of hydrogen and ammonium formate.

[0030] As a further improvement of the present invention, including but not limited to, when the hydrogen source is hydrogen, the pressure of the reaction is 1-10 MPa, preferably 1-6 MPa, such as 2 MPa, 3 MPa, 4 MPa, 5 MPa.

[0031] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 2 is 20-100°C, preferably 50-90°C.

[0032] As a further improvement of the present invention, including but not limited to, the reaction time of step 2 is 2 to 24 hours, preferably 5 to 18 hours.

[0033] As a further improvement of the present invention, including but not limited to, the reaction solvent in step 2 is any one or more of methanol, ethanol, tetrahydrofuran, dioxane, and dimethylformamide, preferably one or more of methanol and ethanol.

[0034] As a further improvement of the present invention, in certain embodiments, after the reaction of step 2 is completed, the reaction solution is filtered and concentrated to obtain compound 4, and the above compound 4 can be optionally further purified by column chromatography, and the column chromatography eluent is, for example: dichloromethane / methanol = 30:1.

[0035] As a further improvement of the present invention, including but not limited to, the isocyanate in step 3 can be prepared in the presence of triphosgene, isobutylamine and an organic base.

[0036] As a further improvement of the present invention, including but not limited to, the molar ratio of compound 4 to the organic base in step 3 is (0.5-1.5), preferably 1:(0.7-1.3);

[0037] As a further improvement of the present invention, including but not limited to, the reaction temperature of step 3 is 0 to 40°C, preferably 10 to 35°C.

[0038] As a further improvement of the present invention, including but not limited to, the reaction time of step 3 is 2 to 24 hours, preferably 5 to 18 hours.

[0039] As a further improvement of the present invention, including but not limited to, the organic base in step 3 and the organic base used for the preparation of isocyanate in step 3 are independently selected from one or more of triethylamine, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA), pyridine, preferably triethylamine.

[0040] As a further improvement of the present invention, including but not limited to, the reaction solvent in step 3 and the solvent used for preparing the isocyanate in step 3 are independently selected from one or more of dichloromethane (DCM), dichloroethane, and chloroform, preferably dichloromethane.

[0041] As a further improvement of the present invention, including but not limited to, the isocyanate in step 3 can be obtained by reacting triphosgene, isobutylamine and triethylamine in dichloromethane.

[0042] Furthermore, the molar ratio of triphosgene to isobutylamine used in the preparation of isocyanate in step 3 is 1:(2.5-3.5), preferably 1:3;

[0043] Furthermore, the molar ratio of triphosgene to base used in the preparation process of isocyanate in step 3 is 1:(1-6), preferably 1:(1.5-5);

[0044] Furthermore, the reaction temperature for preparing isocyanate in step 3 is 0 to 40° C., preferably 10 to 35° C.;

[0045] Furthermore, the reaction time for preparing isocyanate in step 3 is 0.5 to 5 hours, preferably 1 to 4 hours.

[0046] As a further improvement of the present invention, in certain embodiments, after the reaction of step 3 is completed, the reaction solution is filtered, the filtrate is adjusted to pH 7-10 with alkali, the liquid is extracted and separated, the organic phase is washed, dried, and concentrated to obtain compound 5;

[0047] As a further improvement of the present invention, including but not limited to, the alkali is selected from one or more of sodium bicarbonate aqueous solution, sodium hydroxide aqueous solution, lithium hydroxide aqueous solution, and potassium hydroxide aqueous solution.

[0048] As a further improvement of the present invention, in certain embodiments, the compound 5 can be further purified by column chromatography, and the column chromatography eluent is, for example, dichloromethane / methanol = 50:1.

[0049] The second aspect of the present invention provides a compound, the structural formula of which is shown below:

[0050]

[0051] The advantages of the method of the present invention mainly lie in:

[0052] 1. The inventors have found through a large number of experiments that the methods in the prior art have poor reproducibility and cumbersome steps, and need to go through 6 steps to prepare; the present invention provides a method for preparing compound 5 in only 3 steps, which is 3 steps shorter than the prior art route, and the total yield of the three steps of the present invention is higher than 36.8%, which is at least 7.3% higher than the total yield of the prior art. The present invention has the advantages of short steps, simple operation, high yield, and good reproducibility, and is suitable for industrial production.

[0053] 2. More importantly, during the route development, the inventors found that the last step in the prior art could not stably prepare the target product. The present invention, through a lot of creative work, finally determined the important process parameters of triphosgene, isobutylamine and triethylamine in the third step of the reaction route, greatly improving the synthesis efficiency of the target product. On this basis, a creative post-treatment method is further adopted, using sodium hydroxide to make the reaction solution weakly alkaline, which can effectively avoid the product from forming salts under acidic conditions, reduce the difficulty of post-treatment, and significantly improve the reaction yield.

[0054] 3. The inventors found that the molar ratio of triphosgene to isobutylamine is critical in the preparation of isocyanate. Too much or too little will affect the reaction. The inventors finally confirmed that the molar ratio of triphosgene to isobutylamine is better when it is controlled at 1: (2.5-3.5), and the effect is even better when it is 1:3.

[0055] 4. The present invention provides a new method for preparing compound 5, which passes through a new intermediate and avoids the steps of nitro reduction, ring closure, deprotection and methylation in the original route. It is more atom-economical, has a short reaction time, and is conducive to industrial scale-up production. Therefore, it has good market value and far-reaching practical significance. DETAILED DESCRIPTION

[0056] The beneficial effects of the present invention are now further described by the following examples. It should be understood that these examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention.

[0057] The novel synthesis method of fezonetant and the advantages of the method will be further described below in conjunction with the embodiments of the present invention.

[0058] The experimental methods in the following examples without specifying specific conditions are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, the raw materials or reagents used in the examples are commercially available. Unless otherwise specified, the reagents are used directly without purification. All solvents are purchased from commercial suppliers and used without treatment.

[0059] Embodiment 1:

[0060]

[0061] Compound 1A (10 g, 46.7 mmol) and compound 2 (11.47 g, 51.5 mmol) were dissolved in a mixture of water (60 mL) and dioxane (90 mL), sodium carbonate (12.38 g, 116.8 mmol) was added, and the mixture was stirred at room temperature for 15 min under argon protection. Pd(PPh3)4 (1 g, 865 umol) was added, and the mixture was reacted at 110°C overnight. The reaction solution was filtered, extracted, and concentrated to obtain a crude product, which was then chromatographed on a silica gel column (dichloromethane / methanol = 30:1) to obtain compound 3 (5.7 g, yield 53%) as an off-white solid, MS: 231 [M+1] + .

[0062] 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.13 (s, 1H), 3.16 (s, 2H), 2.71 (s, 2H), 2.51 (s, 2H, overlapped with DMSO signal), 2.38 (s, 3H).

[0063] Embodiment 2:

[0064]

[0065] Compound 3 (15 g, 65.1 mmol) was dissolved in methanol (200 mL), 10% palladium carbon (1.5 g) was added, hydrogenation was added to 4 MPa, and the reaction was continued at 70°C overnight. After the reaction was completed, the crude product was filtered and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol=30:1) to obtain compound 4 (14 g, yield 92.5%) as an off-white solid, MS: 233.0 [M+1] + .

[0066] 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.47 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 6.17 (s, 1H), 3.82 (s, 2H), 3.39 (s, 2H), 2.85 (s, 3H), 2.76 (s, 2H), 2.51 (s, 2H, overlapped with DMSO signal).

[0067] Embodiment 3:

[0068]

[0069] Compound 4 (20.27 g, 87.37 mmol) was added to the reaction bottle, and DCM (250 mL) and triethylamine (10 mL, 72 mmol) were added and mixed for use. Triphosgene (28.53 g, 96 mmol) was taken and dissolved with DCM (250 mL), and isobutylamine (28.7 mL, 288.9 mmol) and triethylamine (51 mL, 366.9 mmol) were added dropwise under an ice bath, and stirred at room temperature for 2 h. The prepared isocyanate solution was added dropwise to the mixed solution of compound 4, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was washed with a dilute aqueous sodium hydroxide solution until the pH was 8-9. The crude product obtained by extraction, drying and concentration of the organic phase was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain compound 5 (21.7 g, yield 75%) as a white solid.

[0070] 1HNMR (400MHz, CCl3D): δ8.10 (s, 1H), 7.96 (d, J=8.6Hz, 1H), 7.13 (t, J=2.2Hz, 2H), 3.25 (t, J=6.3Hz, 2H), 3.02 ( d, 2H), 2.66-2.54 (m, 1H), 2.36 (s, 3H), 2.14-2.07 (t, 2H), 1.95-1.77 (m, J=13.4Hz, 5H), 0.99 (d, J=6.7Hz, 6H).

[0071] Embodiment 4:

[0072]

[0073] Compound 4 (500 mg, 2.15 mmol) was added to the reaction bottle, and DCM (5 mL) and triethylamine (0.3 ml, 2.16 mmol) were added and mixed for later use. Triphosgene (700 mg, 2.36 mmol) was taken and dissolved with DCM (15 mL), and isobutylamine (0.7 mL, 7.1 mmol) and triethylamine (1.2 mL, 8.6 mmol) were added dropwise under an ice bath, and stirred at room temperature for 2 h. The prepared isocyanate was added dropwise to the system where compound 4 was located, and the reaction was carried out at room temperature for 30 min. TLC showed that the reaction was incomplete, and the reaction was carried out overnight. After the reaction was complete, water was added for extraction, and the organic phase was dried and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol=50:1) to obtain compound 5 (0.42 g, yield 58.9%) as a white solid.

[0074] Embodiment 5:

[0075] Compound 4 (20.27 g, 87.37 mmol) was added to the reaction bottle, and DCM (250 mL) and triethylamine (12 mL, 87.37 mmol) were added and mixed for later use. Triphosgene (28.53 g, 96 mmol) was taken and dissolved with DCM (250 mL), and isobutylamine (28.7 mL, 288.2 mmol) and triethylamine (49 mL, 349.5 mmol) were added dropwise in an ice bath, and stirred at room temperature for 2 h. The prepared isocyanate was added dropwise to the system where 4 was located, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was washed with a dilute aqueous sodium hydroxide solution until the pH was 8-9. The organic phase was dried and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain compound 5 (21.7 g, yield 75%) as a white solid.

[0076] Comparative Example 1:

[0077] Compound 4 (2.78 g, 12 mmol) was added to the reaction bottle, and DCM (20 mL) and triethylamine (1.7 mL, 12 mmol, 1 eq) were added and mixed for later use. Triphosgene (1.2 g, 4 mmol) was taken and dissolved in DCM (15 mL), and isobutylamine (3.6 mL, 36 mmol) and triethylamine (4.9 mL, 36 mmol) were added dropwise in an ice bath, and stirred at room temperature for 2 h. The prepared isocyanate was added dropwise to the system where compound 4 was located, and the reaction was allowed to proceed overnight at room temperature. TLC showed that a large amount of raw materials remained. There was no significant change in the reaction time, and a large amount of raw materials remained.

[0078] Comparative Example 2:

[0079] Compound 4 (2.78 g, 12 mmol) was added to a reaction flask, and DCM (20 mL) and triethylamine (1.7 mL, 12 mmol) were added and mixed for later use. Triphosgene (1.2 g, 4 mmol) was taken and dissolved in DCM (15 mL), and triethylamine (4.9 mL, 36 mmol) was added dropwise under an ice bath, stirred in an ice bath for 2 h, and isobutylamine (3.6 mL, 36 mmol) was added dropwise, and stirred at room temperature for 30 min. The above reaction solution was added to the system where compound 4 was located, and the reaction was allowed to proceed overnight at room temperature. TLC showed that a large amount of raw materials remained, and there was no obvious change in the reaction time, and a large amount of raw materials still remained.

[0080] Comparative Example 3:

[0081] Compound 4 (500 mg, 2.15 mmol) was added to the reaction bottle, and DCM (5 mL) and triethylamine (0.3 mL, 2.15 mmol) were added and mixed for use. Triphosgene (213 mg, 0.72 mmol) was taken and dissolved with DCM (15 mL), and isobutylamine (0.64 mL, 6.44 mmol) and triethylamine (0.9 mL, 6.47 mmol) were added dropwise in an ice bath, and stirred at room temperature for 30 min. The prepared isocyanate was added dropwise to the system where compound 4 was located, and the reaction was reacted at room temperature for 30 min. TLC showed that the reaction was incomplete, and the reaction was extended to overnight. TLC detection showed that a small amount of raw materials remained, and the reaction was more complicated. Water was added for extraction, and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain compound 5 (0.21 g, yield 30%) as a white solid.

[0082] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing compound 5, the reaction is as follows: in, X is Br or Cl; It is characterized by comprising the following steps: Step 1: Compound 1 and compound 2 are reacted by Suzuki coupling to obtain compound 3; Step 2: Compound 3 reacts in the presence of a catalyst and a hydrogen source to obtain compound 4; Step 3: Compound 4 reacts with isocyanate and an organic base to obtain compound 5.

2. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) in step 1, compound 1 and compound 2 react in the presence of a palladium catalyst, a base, an organic solvent and water to obtain compound 3; (2) The isocyanate in step 3 can be prepared in the presence of triphosgene, isobutylamine and an organic base.

3. The preparation method according to claim 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) the palladium catalyst in step 1 is selected from one or more of Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, preferably Pd(PPh3)4; (2) The base in step 1 is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, and potassium acetate, preferably one or more of sodium carbonate, potassium carbonate, and cesium carbonate; (3) In step 1, the molar ratio of compound 1, compound 2, base and palladium catalyst is 1:(1-5):(1-10): (0.01~0.8), preferably 1:(1~3):(1.1~5):(0.01~0.6).

4. The preparation method according to any one of claims 2 to 3, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The reaction temperature of step 1 is 70 to 140° C., preferably 80 to 130° C.; (2) The reaction time of step 1 is 4 to 24 hours, preferably 5 to 20 hours; (3) The organic solvent in step 1 is selected from one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, toluene, xylene, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, preferably one or more of dioxane, toluene, xylene, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide; (4) After the reaction of step 1 is completed, the reaction solution is filtered, extracted, separated, washed, dried, and concentrated to obtain compound 3, which can be further purified by column chromatography.

5. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The catalyst in step 2 is selected from one of palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide, and Raney nickel, preferably palladium carbon; (2) The hydrogen source in step 2 is selected from one or more of hydrogen, ammonium formate, hydrazine hydrate and formic acid, preferably one of hydrogen and ammonium formate.

6. The preparation method according to claim 1 or 5, characterized in that: The preparation method satisfies one or more of the following conditions: (1) When the hydrogen source is hydrogen, the reaction pressure is 1 to 10 MPa, preferably 1 to 6 MPa; (2) The reaction temperature of step 2 is 20 to 100° C., preferably 50 to 90° C.; (3) The reaction time of step 2 is 2 to 24 hours, preferably 5 to 18 hours; (4) The reaction solvent in step 2 is any one or more of methanol, ethanol, tetrahydrofuran, dioxane, and dimethylformamide, preferably one or more of methanol and ethanol; (5) After the reaction of step 2 is completed, the reaction solution is filtered and concentrated to obtain compound 4, which can be further purified by column chromatography.

7. The preparation method according to claim 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) In step 3, the molar ratio of compound 4 to the organic base is 1:(0.5-1.5), preferably 1:(0.7-1.3); (2) The reaction temperature of step 3 is 0 to 40° C., preferably 10 to 35° C.; (3) The reaction time of step 3 is 2 to 24 hours, preferably 5 to 18 hours; (4) The organic base in step 3 and the organic base used in the preparation of isocyanate in step 3 are independently selected from one or more of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and pyridine, preferably triethylamine; (5) The reaction solvent in step 3 and the solvent used for preparing the isocyanate in step 3 are independently selected from one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane.

8. The preparation method according to claim 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The molar ratio of triphosgene to isobutylamine used in the isocyanate preparation process in step 3 is 1:(2.5-3.5), preferably 1:3; (2) The molar ratio of triphosgene to base used in the isocyanate preparation process in step 3 is 1:(1-6), preferably 1: (1.5～5)； (3) The reaction temperature for preparing isocyanate in step 3 is 0 to 40° C., preferably 10 to 35° C.; (4) The reaction time for preparing isocyanate in step 3 is 0.5 to 5 hours, preferably 1 to 4 hours.

9. The preparation method according to claim 1, 2, 7 or 8, characterized in that: After the reaction of step 3 is completed, the reaction solution is filtered, the pH of the filtrate is adjusted to 7-10 with alkali, extraction is performed, and the organic phase is washed, dried, and concentrated to obtain compound 5. The compound 5 can be further purified by column chromatography.

10. A compound having the following structure:

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