A method for preparing a benzoxazolone amide compound
By adopting a simplified three-step synthetic route, the problems of long synthetic routes and low yields of benzoxazolone amide compounds in existing technologies have been solved, enabling efficient and convenient industrial production.
Patent Information
- Application Number
- CN202411940474.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-26
- Publication Date
- 2025-12-26
- Estimated Expiration
- 2044-12-26
AI Technical Summary
The existing synthetic routes for benzoxazolone amide compounds 5 are long, have low yields, and are cumbersome to operate, making them unsuitable for commercial production.
A simplified three-step synthetic route was adopted, including Suzuki coupling, catalytic hydrogenation and isocyanate reaction, which avoids nitro reduction, ring closure and deprotection steps and optimizes reaction conditions and post-processing.
The synthesis steps were shortened, the overall yield was increased to over 36.8%, the operation process was simplified, and it is suitable for industrial production.
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Figure CN119751431B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the technical field of drug development, and particularly relates to a preparation method of a benzoxazolone amide compound. BACKGROUND
[0002] Acid ceramidase (AC, ASAH-1) is a ubiquitously expressed enzyme and one of the key enzymes regulating ceramide and glycosphingolipid metabolism. It releases fatty acids and sphingosine from ceramide, and its deficiency causes a progressive lysosomal storage disorder, commonly known as Farber disease (FD). At the same time, inhibiting AC is considered a potential target for anti-cancer drugs. Abnormal AC activity also occurs in several other common diseases, including inflammation, pain and various pulmonary diseases.
[0003] Benzoxazolone amide compound 5 (Acid-Ceramidase-IN-1) is a new oral acid ceramidase inhibitor (hAC IC50 = 0.166 μM) developed by Fondazione Istituto Italiano di Tecnologia and Lysosomal Therapeutics, and its structural formula is as follows:
[0004]
[0005] Acid-Ceramidase-IN-1 has good brain penetration in mice, can significantly reduce the levels of toxic lipid glucosylsphingosine (GluSph) and galactosylsphingosine (GalSph) in the mouse brain, and has the potential to be further developed for correcting severe neurological LSD.
[0006] At present, there is only one reported synthesis route of Acid-Ceramidase-IN-1 in the prior art, which is as follows:
[0007]
[0008] This route needs to go through six steps of suzuki coupling, nitro reduction, ring closure, deprotection, methylation and substitution to obtain the final compound. The route has a long step number, the total yield is less than 29.5%, and needs to go through steps of catalytic hydrogenation, intramolecular carbonylation ring formation, deprotection group, etc. The operation is complicated, the atom utilization rate is low, the yield is low, and it is not conducive to commercial production. Therefore, it is urgent to develop a real and feasible, economical and fast, simple and easy to operate, simple post-treatment, high yield, high atom utilization rate preparation method of compound 5.
[0009] The application provides a preparation method of a benzoxazolone amide compound 5, which does not need the steps of nitro reduction, ring closure, deprotection and methylation, greatly shortens a reaction route, and has the advantages of economy, quickness, simple operation, simple post-treatment, high conversion rate and high atom utilization rate, is suitable for industrial production, and thus has good market value and far-reaching practical significance.
[0010] Technical scheme
[0011] In view of the above technical background, the application provides a preparation method of a benzoxazolone amide compound, which has the advantages of simple process operation, short route, high atom utilization rate, high reproducibility, high yield, low cost, green environmental protection, and is beneficial to industrial production.
[0012] A first aspect of the application provides a preparation method of compound 5, and the reaction is as follows:
[0013]
[0014] X is Br or Cl;
[0015] The method comprises the following steps:
[0016] Step 1: compound 1 and compound 2 are coupled by Suzuki to obtain compound 3;
[0017] Step 2: compound 3 is reacted in the presence of a catalyst and a hydrogen source to obtain compound 4;
[0018] Step 3: compound 4 is reacted with isocyanate and an organic base to obtain compound 5;
[0019] As a further improvement of the application, the compound 1 and the compound 2 in the step 1 are reacted in the presence of a palladium catalyst, a base, an organic solvent and water to obtain the compound 3.
[0020] As a further improvement of the application, the palladium catalyst in the step 1 is selected from one or more of Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2 and Pd2(dba)3, and is preferably Pd(PPh3)4.
[0021] As a further improvement of the application, the base in the step 1 is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide and potassium acetate, and is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate.
[0022] As a further improvement of the present application, including but not limited to, in the 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 application, including but not limited to, the reaction temperature of the step 1 is 70-140℃, preferably 80-130℃.
[0024] As a further improvement of the present application, including but not limited to, the reaction time of the step 1 is 4-24h, preferably 5-20h.
[0025] As a further improvement of the present application, including but not limited to, the organic solvent in the step 1 is selected from one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, toluene, xylene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), preferably one or more of dioxane, toluene, xylene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO).
[0026] As a further improvement of the present application, in some embodiments, after the completion of the step 1 reaction, the reaction solution is filtered, extracted, separated, washed, dried, and concentrated to obtain compound 3;
[0027] As a further improvement of the present application, in some embodiments, the above 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 application, including but not limited to, the catalyst in the step 2 is selected from one of palladium on carbon, palladium hydroxide, platinum on carbon, platinum dioxide, Raney nickel, preferably palladium on carbon.
[0029] As a further improvement of the present application, including but not limited to, the hydrogen source in the step 2 is selected from one or more of hydrogen, ammonium formate, hydrazine hydrate, formic acid, preferably one of hydrogen and ammonium formate.
[0030] As a further improvement of the present application, including but not limited to, when the hydrogen source is hydrogen, the reaction pressure is 1-10Mpa, preferably 1-6Mpa, for example 2Mpa, 3Mpa, 4Mpa, 5Mpa.
[0031] As a further improvement of the present application, including but not limited to, the reaction temperature of the step 2 is 20-100℃, preferably 50-90℃.
[0032] As a further improvement of the present application, including but not limited to, the reaction time of step 2 is 2-24h, preferably 5-18h.
[0033] As a further improvement of the present application, including but not limited to, the reaction solvent of step 2 is any one or more of methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide, preferably one or more of methanol, ethanol.
[0034] As a further improvement of the present application, in some embodiments, after the completion of the reaction of step 2, the reaction solution is filtered and concentrated to obtain compound 4, which can be further purified by column chromatography, and the eluent of column chromatography is, for example, dichloromethane / methanol = 30:1.
[0035] As a further improvement of the present application, including but not limited to, the isocyanate in step 3 can be prepared by the presence of triphosgene, isobutylamine and organic base.
[0036] As a further improvement of the present application, including but not limited to, the molar ratio of compound 4 to organic base in step 3 is (0.5-1.5), preferably 1:(0.7-1.3);
[0037] As a further improvement of the present application, including but not limited to, the reaction temperature of step 3 is 0-40℃, preferably 10-35℃.
[0038] As a further improvement of the present application, including but not limited to, the reaction time of step 3 is 2-24h, preferably 5-18h.
[0039] As a further improvement of the present application, including but not limited to, 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 (DMAP), N,N-diisopropylethylamine (DIPEA), pyridine, preferably triethylamine.
[0040] As a further improvement of the present application, including but not limited to, the reaction solvent in step 3 and the solvent used in the preparation of isocyanate in step 3 are independently selected from one or more of dichloromethane (DCM), dichloroethane, chloroform, preferably dichloromethane.
[0041] As a further improvement of the present application, including but not limited to, the isocyanate in step 3 can be obtained by the reaction of triphosgene, isobutylamine and triethylamine in dichloromethane.
[0042] Further, 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] Further, the mole ratio of triphosgene to base used in the isocyanate preparation process in step 3 is 1:(1-6), preferably 1:(1.5-5);
[0044] Further, the reaction temperature for preparing the isocyanate in step 3 is 0-40℃, preferably 10-35℃;
[0045] Further, the reaction time for preparing the isocyanate in step 3 is 0.5-5h, preferably 1-4h.
[0046] As a further improvement of the present application, in some embodiments, after the reaction in step 3 is complete, the reaction solution is filtered, the filtrate is adjusted to pH 7-10 with a base, and extracted and separated, the organic phase is washed, dried, and concentrated to obtain compound 5;
[0047] As a further improvement of the present application, the above-mentioned base is selected from one or more of the following: 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 application, in some embodiments, the above-mentioned compound 5 can be further purified by column chromatography, and the column chromatography eluent is, for example, dichloromethane / methanol=50:1.
[0049] In a second aspect of the present application, a compound is provided, and the structure is shown as follows:
[0050]
[0051] The advantages of the method of the present application mainly include:
[0052] 1. The present inventors have found through a large number of experiments that the method in the prior art has poor reproducibility and a complicated procedure, and needs to be prepared in 6 steps; the present application provides a method for preparing compound 5 in only 3 steps, which is 3 steps shorter than the prior art, and the total yield of the three steps is higher than 36.8%, which is at least 7.3% higher than the total yield of the prior art. The present application has the advantages of short steps, simple operation, high yield, and good reproducibility, and is suitable for industrial production.
[0053] 2. More importantly, in the route development, the inventors have found that the last step in the prior art cannot stably prepare the target product; through a large amount of creative labor, the inventors finally determined the important process parameters of triphosgene, isobutylamine, and triethylamine in the third step of the reaction route, which greatly improved the synthesis efficiency of the target product. On this basis, further creative post-treatment methods are used, and sodium hydroxide is used to make the reaction solution weakly alkaline, which can effectively avoid the salification of the product under acidic conditions, reduce the difficulty of post-treatment, and significantly improve the reaction yield.
[0054] 3、The present inventors found that the molar ratio of triphosgene and isobutylamine is critical in the preparation of isocyanate, too much or too little will affect the reaction, the present inventors finally confirmed that the molar ratio of triphosgene and isobutylamine is controlled at 1: (2.5-3.5), preferably 1:3.
[0055] 4、The present application provides a novel method for preparing compound 5, which uses a new intermediate, avoids the steps of nitro reduction, ring closure, deprotection and methyl addition in the original route, has better atom economy, short reaction time, and is beneficial to industrial scale-up production, and therefore has good market value and far-reaching practical significance. DETAILED DESCRIPTION
[0056] The beneficial effects of the present application will be further described by the following examples, which should be understood as being for illustrative purposes only, and the changes and modifications made by those skilled in the art according to the present application are also included within the scope of the present application.
[0057] The novel synthesis method of fezolinetant and the advantages of the method will be further described below in combination with the examples of the present application.
[0058] The experimental methods not specified in the following examples are generally carried out under conventional conditions or under the conditions recommended by the manufacturers. The raw materials or reagents used in the examples are commercially available unless otherwise specified. Unless otherwise specified, the reagents described are used directly without purification. All solvents are purchased from commercial suppliers and can be used without treatment.
[0059] Example 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, stirred at room temperature for 15 min, and protected by argon. Pd(PPh3)4 (1 g, 865 umol) was added and reacted at 110°C overnight. The reaction solution was filtered, extracted and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain compound 3 (5.7 g, yield 53%) as a 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] Example 2:
[0064]
[0065] Compound 3 (15 g, 65.1 mmol) was dissolved in methanol (200 mL), 10% palladium carbon (1.5 g) was added, hydrogenated to 4 MPa, and reacted at 70 °C overnight. After the reaction was completed, it was filtered under suction, and the obtained crude product was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain compound 4 (14 g, yield 92.5%) as a white solid, MS: 233.0 [M+1] + .
[0066] 1 H 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).
[0067] Example 3:
[0068]
[0069] Compound 4 (20.27 g, 87.37 mmol) was added to a reaction bottle, DCM (250 mL) and triethylamine (10 mL, 72 mmol) were mixed and prepared. Take triphosgene (28.53 g, 96 mmol), dissolve in DCM (250 mL), add isobutylamine (28.7 mL, 288.9 mmol) dropwise under ice bath, triethylamine (51 mL, 366.9 mmol), stir at room temperature for 2 h, and then drop the prepared isocyanate solution into the mixed solution of compound 4, and react at room temperature overnight. After the reaction was completed, it was filtered under suction, and the filtrate was washed with dilute sodium hydroxide aqueous solution until the pH was 8-9, extracted, dried, and concentrated to obtain the crude product. The crude product 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 (400 MHz, CCI3D): δ 8.10 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.13 (t, J = 2.2 Hz, 2H), 3.25 (t, J = 6.3 Hz, 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 = 13.4 Hz, 5H), 0.99 (d, J = 6.7 Hz, 6H).
[0071] Example 4:
[0072]
[0073] Compound 4 (500 mg, 2.15 mmol) was added to a reaction flask, DCM (5 mL) and triethylamine (0.3 ml, 2.16 mmol) were mixed and ready for use. To a solution of triphosgene (700 mg, 2.36 mmol) in DCM (15 mL), isobutylamine (0.7 mL, 7.1 mmol) and triethylamine (1.2 mL, 8.6 mmol) were added dropwise under ice bath. The mixture was stirred at room temperature for 2 h. The prepared isocyanate was added dropwise to the solution of compound 4. The reaction was carried out at room temperature for 30 min and overnight. After the reaction was completed, water was added to extract the organic phase. The organic phase was dried and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to give compound 5 (0.42 g, yield 58.9%) as a white solid.
[0074] Example 5:
[0075] Compound 4 (20.27 g, 87.37 mmol) was added to a reaction flask, DCM (250 mL) and triethylamine (12 mL, 87.37 mmol) were mixed and ready for use. To a solution of triphosgene (28.53 g, 96 mmol) in DCM (250 mL), isobutylamine (28.7 mL, 288.2 mmol) and triethylamine (49 mL, 349.5 mmol) were added dropwise under ice bath. The mixture was stirred at room temperature for 2 h. The prepared isocyanate was added dropwise to the solution of compound 4. The reaction was carried out at room temperature overnight. After the reaction was completed, the mixture was filtered. The filtrate was washed with dilute sodium hydroxide aqueous solution until the pH was 8-9. The organic phase was dried and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to give 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 a reaction flask, DCM (20 mL) and triethylamine (1.7 mL, 12 mmol) were mixed and ready for use. Take the triphosgene (1.2 g, 4 mmol) and dissolve in DCM (15 mL), drop isobutylamine (3.6 mL, 36 mmol) and triethylamine (4.9 mL, 36 mmol) in ice bath, stir for 2 h at room temperature. The above prepared isocyanate was added dropwise to the system where compound 4 was located, and reacted at room temperature overnight. TLC showed that a large amount of raw materials remained, and there was no obvious change after prolonging the reaction time. 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, DCM (20 mL) and triethylamine (1.7 mL, 12 mmol) were mixed and ready for use. Take the triphosgene (1.2 g, 4 mmol) and dissolve in DCM (15 mL), drop isobutylamine (3.6 mL, 36 mmol) and triethylamine (4.9 mL, 36 mmol) in ice bath, stir for 2 h at room temperature. The above prepared isocyanate was added dropwise to the system where compound 4 was located, and reacted at room temperature overnight. TLC showed that a large amount of raw materials remained, and there was no obvious change after prolonging the reaction time. A large amount of raw materials remained.
[0080] Comparative Example 3:
[0081] Compound 4 (500 mg, 2.15 mmol) was added to a reaction flask, DCM (5 mL) and triethylamine (0.3 mL, 2.15 mmol) were mixed and ready for use. Take the triphosgene (213 mg, 0.72 mmol) and dissolve in DCM (15 mL), drop isobutylamine (0.64 mL, 6.44 mmol) and triethylamine (0.9 mL, 6.47 mmol) in ice bath, stir for 30 min at room temperature. The above prepared isocyanate was added dropwise to the system where compound 4 was located, and reacted at room temperature for 30 min. TLC showed that the reaction was incomplete, and after prolonging to overnight, TLC detection showed that a small amount of raw materials remained, and the reaction was relatively impure. Water was added for extraction, and the organic phase was dried and concentrated to obtain the 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 is only a preferred embodiment of the present application, and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.
Claims
1. A method for preparing compound 5, the reaction is as follows: wherein X is Br or Cl; characterized in comprising the following steps: Step 1: compound 1 and compound 2 are coupled by Suzuki to obtain compound 3; Step 2: compound 3 is reacted in the presence of a catalyst and a hydrogen source to obtain compound 4; Step 3: compound 4 is reacted with isocyanate and organic base to obtain compound 5; the catalyst in step 2 is selected from one of palladium on carbon, palladium hydroxide, platinum on carbon, platinum dioxide, Raney nickel; the isocyanate in step 3 is prepared in the presence of triphosgene, isobutylamine and organic base; the molar ratio of triphosgene to isobutylamine used in the preparation of isocyanate in step 3 is 1: (2.5-3.5); after the reaction in step 3 is complete, the reaction solution is filtered, the filtrate is adjusted to pH 7-10 with a base, extracted and separated, the organic phase is washed, dried, and concentrated to obtain compound 5.
2. The production method according to claim 1, characterized by, the Suzuki coupling in step 1 includes: compound 1 and compound 2 are reacted in the presence of a palladium catalyst, a base, an organic solvent and water to obtain compound 3.
3. The preparation method according to claim 2, characterized in that, the preparation method of step 1 meets one or more of the following conditions: (1) the palladium catalyst is selected from one or more of Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3; (2) the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, potassium acetate; (3) the molar ratio of compound 1, compound 2, base and palladium catalyst is 1: (1-5): (1-10): (0.01-0.8); (4) the reaction temperature is 70-140℃; (5) the reaction time is 4-24h; (6) the organic solvent is selected from one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, toluene, xylene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide; (7) after the reaction is complete, the reaction solution is filtered, extracted and separated, washed, dried, and concentrated to obtain compound 3.
4. The production method according to claim 3, characterized by, the preparation method of step 1 meets one or more of the following conditions: (1) the reaction temperature is 80-130℃; (2) the molar ratio of compound 1, compound 2, base and palladium catalyst is 1: (1-3): (1.1-5): (0.01-0.6); (3) the reaction time is 5-20h; (4) the organic solvent is selected from one or more of dioxane, toluene, xylene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide; (5) after the reaction is complete, compound 3 is further purified by column chromatography.
5. The preparation method according to claim 1, characterized in that, the preparation method of step 2 meets one or more of the following conditions: (1) the catalyst is selected from palladium on carbon; (2) the hydrogen source is selected from one or more of hydrogen, ammonium formate, hydrazine hydrate, formic acid; (3) step 2 is carried out in a solvent selected from any one or more of methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide; (4) the reaction temperature is 20-100℃; (5) the reaction time is 2-24h; (6) After the reaction is completed, the reaction solution is filtered and concentrated to obtain compound 4.
6. The preparation method according to claim 5, characterized in that, The preparation method of step 2 meets one or more of the following conditions: (1) When the hydrogen source is hydrogen, the pressure of the reaction is 1-10 Mpa; (2) The reaction temperature is 50-90℃; (3) The reaction time is 5-18h; (4) The solvent is selected from one or both of methanol and ethanol; (5) After the reaction is completed, compound 4 is further purified by column chromatography.
7. The production method according to claim 6, wherein When the hydrogen source is hydrogen, the pressure of the reaction is 1-6 Mpa.
8. The method of claim 1, wherein, The preparation method of step 3 meets one or more of the following conditions: (1) The molar ratio of compound 4 to organic base is 1:(0.5-1.5); (2) The reaction temperature is 0-40℃; (3) The reaction time is 2-24h; (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; (5) The molar ratio of triphosgene to organic base used in the preparation of isocyanate in step 3 is 1:(1-6); (6) Steps 3 and the preparation of isocyanate in step 3 are carried out in a solvent selected from one or more of dichloromethane, dichloroethane, and chloroform; (7) The molar ratio of triphosgene to isobutylamine used in the preparation of isocyanate in step 3 is 1:3; (8) The reaction temperature for preparing isocyanate in step 3 is 0-40℃; (9) The reaction time for preparing isocyanate in step 3 is 0.5-5h.
9. The production method according to claim 8, characterized by, The preparation method of step 3 meets one or more of the following conditions: (1) The molar ratio of compound 4 to organic base is 1:(0.7-1.3); (2) The molar ratio of triphosgene to organic base used in the preparation of isocyanate in step 3 is 1:(1.5-5); (3) The reaction temperature is 10-35℃; (4) The reaction time is 5-18h; (5) The organic base in step 3 and the organic base used in the preparation of isocyanate in step 3 are independently selected from triethylamine; (6) The solvent for steps 3 and the preparation of isocyanate in step 3 is dichloromethane; (7) The reaction temperature for preparing isocyanate in step 3 is 10-35℃; (8) The reaction time for preparing isocyanate in step 3 is 1-4h.
10. The method of claim 1, wherein, The compound 5 prepared in step 3 is further purified by column chromatography.
Citation Information
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