A method for preparing a key intermediate of darcitinib

Abstract

The application discloses a preparation method of a key intermediate of dacomitinib, and comprises the following steps: (1) a cyclization reaction of compound 2 and compound 3 is generated under catalysis of a catalyst 1 to obtain compound 4; the catalyst 1 is CuI supported by modified mesoporous material MCM-41; (2) an amination reaction of compound 4 and 4-fluoro-3-chloroaniline is directly generated under the action of a catalyst 2, an oxidizing agent and DMF to obtain compound 5; the catalyst 2 is a copper compound, and the oxidizing agent is a peroxide; (3) a reduction reaction of compound 5, hydrazine hydrate and activated carbon is generated to obtain the target compound 1, i.e. 7-methoxy-6-amino-4-(3-chloro-4-fluoroanilino) quinazoline; the method uses cheap compound 2 and compound 3 as starting materials, and compound 1 is prepared through three steps, and the total yield can reach more than 76%; the reaction condition is mild, the catalyst can be recycled, the production cost is low, and the method is safe and environmentally friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of a key intermediate of dacotinib, in particular to a preparation method of a key intermediate 7-methoxy-6-amino-4-(3-chloro-4-fluoroanilino) quinazoline of dacotinib. BACKGROUND

[0002] Dacomitinib (Formula A), chemically named as N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-4-(piperidin-1-yl)-2-butenoic amide, is a second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by Pfizer. It was approved by FDA in September 2018 for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer carrying EGFR activating mutations. It is also a potential treatment drug for head and neck cancer, brain tumor, skin squamous cell carcinoma and pulmonary arterial hypertension, etc. It is an orally available high-selectivity quinazoline multi-kinase inhibitor targeting HER1, 2 and 3. The structural formula is:

[0003]

[0004] The preparation of dacomitinib has been reported in many literatures, among which the representative one is to prepare it by amidation reaction of 7-methoxy-6-amino-4-(3-chloro-4-fluoroanilino) quinazoline (Compound 1) with (E)-4-(1-piperidinyl)-2-butenoic acid. Therefore, Compound 1 is a key intermediate for the synthesis of dacomitinib, which is of great significance for the preparation of dacomitinib.

[0005] For Compound 1, there are many literatures reporting its synthesis methods, mainly including the following:

[0006] Route 1: The synthesis method reported in patent US7772243 B2: This method is to use 2-amino-4-fluorobenzoic acid as the raw material, to form a ring with formamidine acetate, then to nitrate with nitric acid / sulfuric acid, to chlorinate with SOCl2, to undergo nucleophilic substitution with 3-chloro-4-fluoroaniline, then to methoxylate with sodium methoxide, and to catalyze hydrogenation with Raney Ni, etc. to obtain Compound 1. The synthetic route is:

[0007]

[0008] This method has long steps and complicated operation, needs to use column chromatography twice for separation, has high cost and low yield; toxic and harmful SOCl2 is used in the chlorination reaction, which is easy to produce harmful waste gas and is not friendly to the environment; in addition, the catalysts used in the nitration reaction and the reduction reaction also have safety hazards, which are not suitable for industrial production.

[0009] Route 2: The synthesis method reported in Journal of China Pharmaceutical University, 2014, 45(2): 165-169: This method is also to take 2-amino-4-fluorobenzoic acid as raw material, and form a ring with formamide, and then go through nitration, chlorination, amination, methoxylation and reduction steps to obtain compound 1. The synthesis route is:

[0010]

[0011] This method is different from the first step of the ring reaction raw material of route 1, and the other steps are the same as the method of route 1, so it also has the shortcomings of the first method.

[0012] Route 3: The synthesis method reported in Chinese Pharmaceutical Industry Journal, 2014, (2): 107-109: This method is to take 7-fluoro-6-nitro-4(3H)-quinazolinone as raw material, and go through methoxylation, chlorination with POCl3 / SOCl2, nucleophilic substitution with 3-chloro-4-fluoroaniline, and then catalytic hydrogenation with Raney Ni to obtain compound 1. The synthesis route is:

[0013]

[0014] This method directly uses 7-fluoro-6-nitro-4(3H)-quinazolinone as raw material, which saves the ring-forming and nitration steps of the first method. Although the steps are reduced, the starting material is expensive, and in the chlorination reaction, POCl3 and SOCl2 are used as chlorination reagents, which can produce a large amount of waste acid and waste gas in industrialization, and are also toxic, which is not friendly to the environment. The hydrogenation catalyst also has safety hazards, so it is not suitable for industrial production.

[0015] Route 4: The synthesis method reported in document CN107698524: This method is to take 7-chloro-4-hydroxyquinazoline as the starting material, and go through nitration, amination and reduction, hydrolysis, substitution, etherification and chlorination reactions to obtain compound 1. The synthesis route is:

[0016]

[0017] This method has long steps and complicated operation; in addition to the safety hazards of the nitration reaction, it also uses toxic and harmful reagents such as ammonia, chlorine gas, and reagents such as concentrated sulfuric acid that can corrode equipment. In addition, the last step of chlorination reaction needs to use excess anhydrous aluminum chloride as catalyst, which requires strict anhydrous reaction, and will also produce isomers of chlorinated products that are difficult to separate, so it is also not suitable for industrial production.

[0018] Route 5: The synthesis method reported in Chinese Journal of Pharmaceuticals, 2021, (11): 1464-1467: This method is to take 2-bromo-4-methoxy-5-nitrobenzonitrile as the starting material, and compound 1 is obtained through addition, cyclization and reduction steps. The synthesis route is:

[0019]

[0020] This synthesis method has a short route and a high total yield, but the starting material is not easy to obtain, and the cyan group in the starting material is a genetic toxicity warning structure, which should be avoided as much as possible in the production of drugs. Therefore, it is also difficult to realize large-scale production. SUMMARY

[0021] The purpose of the application is to provide a synthesis method of the key intermediate 7-methoxy-6-amino-4-(3-chloro-4-fluoroanilino) quinazoline of daratumumab, which has easy-to-obtain raw materials, mild reaction conditions, recyclable catalysts, low production cost and safety and environmental protection.

[0022] Technical scheme: The synthesis method of 7-methoxy-6-amino-4-(3-chloro-4-fluoroanilino) quinazoline according to the application comprises the following steps:

[0023] (1) Compound 2 and compound 3 are reacted under the catalysis of catalyst 1 to obtain compound 4; wherein the catalyst 1 is CuI supported by modified mesoporous material MCM-41;

[0024] (2) Compound 4 and 4-fluoro-3-chloroaniline directly undergo amination reaction under the action of catalyst 2, oxidant and DMF to obtain compound 5, wherein the catalyst 2 is a copper compound, and the oxidant is a peroxide;

[0025] (3) Compound 5 and hydrazine hydrate and activated carbon undergo a reduction reaction under the action of a catalyst to obtain compound 1, 7-methoxy-6-amino-4-(3-chloro-4-fluoroanilino) quinazoline; The specific synthesis route is as follows:

[0026]

[0027] Wherein, X is chlorine, bromine or iodine.

[0028] In step (1), the catalyst 1 is CuI supported by mesoporous material MCM-41, and the structure is:

[0029]

[0030] The structure and preparation method of the catalyst 1 have been reported in the literature, which are relatively simple.

[0031] The catalyst 1 has high catalytic efficiency, and the amount of the catalyst 1 is 4-10% of the amount of substance of the compound 2.

[0032] The catalyst 1 is easy to recycle and has high utilization rate, and the yield only decreases by not more than 4% after 10 cycles.

[0033] In step (1), the reaction temperature is 40-100℃.

[0034] In step (1), the solvent is one or a mixture of several of DMF, acetonitrile, DMSO, DMAC, toluene, ethanol, isopropanol and the like polar solvents, and DMF is preferred.

[0035] In step (1), the base is triethylamine, tributylamine, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium acetate, potassium acetate and the like, and cesium carbonate is preferred.

[0036] In step (2), the catalyst 2 is a copper compound such as CuCl2, CuBr2, CuI2, Cu(OAc)2, Cu(acac)2 and CuI, and Cu(acac)2 is preferred.

[0037] The catalyst 2 has high catalytic efficiency, and the amount of the catalyst is 3-8% of the amount of substance of the compound 4.

[0038] In step (2), the oxidant is a peroxide such as tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP), cumyl hydroperoxide (CHP), meta-chloro-peroxybenzoic acid (m-CPBA), benzoyl peroxide (BPO) and hydrogen peroxide, and DTBP is preferred.

[0039] In step (2), DMF is both a reactant and a reaction solvent.

[0040] In step (2), the reaction temperature is 80-130℃.

[0041] In step (3), the catalyst is a mixture of ferric chloride hexahydrate, aluminum chloride hexahydrate and copper dichloride dihydrate.

[0042] Advantages: Compared with the prior art, the present application has the following remarkable advantages: (1) the present method uses cheap compound 2 and compound 3 as starting materials, and compound 1 is prepared in three steps, and the total yield can reach more than 76%; (2) the reaction conditions are mild, the catalyst can be recycled, the production cost is low, and it is safe and environmentally friendly. DETAILED DESCRIPTION

[0043] The application will be described in detail below with reference to examples for the convenience of those skilled in the art to understand the application.

[0044] Example 1 Preparation of Catalyst 1

[0045] Catalyst 1 is prepared by loading CuI onto mesoporous material MCM-41 modified with bipyridine ligand (BTESBPY), and the synthetic route of BTESBPY is as follows:

[0046]

[0047] In a reaction bottle, 20 g of 4,4'-dibromomethyl-2,2'-bipyridine is added, and 80 mL of 3-aminopropyltriethoxysilane, 120 mL of triethylamine, and 400 mL of THF are added, and the mixture is stirred at 50°C for 6 h under nitrogen protection. After the reaction solution is cooled, it is passed through a magnesium sulfate column, and is washed with ethyl acetate twice, and the solvent is evaporated to obtain BTESBPY.

[0048] In a reaction bottle, 18.8 g of MCM-41 and 0.8 L of anhydrous toluene are added, and the mixture is stirred at room temperature until it becomes a paste. 200 mL of toluene and 24 g of BTESBPY are mixed and added, and the mixture is stirred under reflux for 48 h under argon protection. After cooling, the mixture is suction filtered, the filter cake is washed with 200 mL of dichloromethane twice, and then the filter cake is vacuum dried at 150°C for 5 h to obtain 28 g of a light yellow powder.

[0049] The dried ligand powder is added to a three-necked flask, 1 L of toluene and 35 mL of trimethylsilyl chloride are added, and the mixture is stirred at room temperature for 24 h under nitrogen protection, and then the mixture is suction filtered, the filter cake is washed with 500 mL of acetone and 500 mL of anhydrous diethyl ether three times, and then the filter cake is vacuum dried at 150°C for 5 h to obtain 30 g of a solid. Elemental analysis: N content is 2.91 mmol / g.

[0050] In a reaction bottle, 40 g of the dried powder, 6 g of CuI, and 400 mL of DMF are sequentially added, and the mixture is stirred at room temperature for 7 h under nitrogen protection. After cooling, the mixture is filtered, the filter cake is washed with 250 mL of DMF, 250 mL of distilled water, and 250 mL of acetone three times, and then the filter cake is vacuum dried at 60°C to obtain 40 g of a light green catalyst 1. Elemental analysis: N content is 2.67 mmol / g, and copper content is 0.63 mmol / g.

[0051] Example 2 Preparation of Compound 4

[0052] Into a reaction flask, 50 mmol of compound 2 (X = Br), 75 mmol of compound 3, 4 mmol of catalyst 1, 100 mmol of cesium carbonate and 300 mL of DMF were sequentially added, and the reaction was stirred at 70 °C under nitrogen protection for 12 h. The reaction was stopped, and the reaction liquid was cooled to room temperature. 500 mL of ethyl acetate was added to the reaction flask, and the catalyst was filtered out. The filtrate was extracted with 1.2 L of distilled water in three portions, and the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain yellow compound 4 with a yield of 94%. The structure of the compound was characterized by MS, ESI-LRMS m / z: 222.1 [M+H] + .

[0053] Preparation of compound 4 in Example 3

[0054] Into a reaction flask, 50 mmol of compound 2 (X = Br), 75 mmol of compound 3, 4 mmol of catalyst 1, 100 mmol of cesium carbonate and 300 mL of DMF were sequentially added, and the reaction was stirred at 70 °C under nitrogen protection for 12 h. The reaction was stopped, and the reaction liquid was cooled to room temperature. 500 mL of ethyl acetate was added to the reaction flask, and the catalyst was filtered out. The filtrate was extracted with 1.2 L of distilled water in three portions, and the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain yellow compound 4 with a yield of 94%. The structure of the compound was characterized by MS, ESI-LRMS m / z: 222.1 [M+H]

[0055] Preparation of compound 4 in Example 4

[0056] Into a reaction flask, 50 mmol of compound 2 (X = Br), 75 mmol of compound 3, 4 mmol of catalyst 1, 100 mmol of cesium carbonate and 300 mL of DMF were sequentially added, and the reaction was stirred at 70 °C under nitrogen protection for 12 h. The reaction was stopped, and the reaction liquid was cooled to room temperature. 500 mL of ethyl acetate was added to the reaction flask, and the catalyst was filtered out. The filtrate was extracted with 1.2 L of distilled water in three portions, and the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain yellow compound 4 with a yield of 94%. The structure of the compound was characterized by MS, ESI-LRMS m / z: 222.1 [M+H]

[0057] Preparation of compound 4 in Example 5

[0058] Into a reaction flask, 50 mmol of compound 2 (X = Br), 75 mmol of compound 3, 4 mmol of catalyst 1, 100 mmol of cesium carbonate and 300 mL of DMF were sequentially added, and the reaction was stirred at 70 °C under nitrogen protection for 12 h. The reaction was stopped, and the reaction liquid was cooled to room temperature. 500 mL of ethyl acetate was added to the reaction flask, and the catalyst was filtered out. The filtrate was extracted with 1.2 L of distilled water in three portions, and the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain yellow compound 4 with a yield of 94%. The structure of the compound was characterized by MS, ESI-LRMS m / z: 222.1 [M+H]

[0059] Preparation of compound 4 in Example 6

[0060] Into a reaction flask, 50 mmol of compound 2 (X = Br), 75 mmol of compound 3, 5 mmol of catalyst 1, 100 mmol of cesium carbonate and 300 mL of DMF were sequentially added, and the reaction was stirred at 70°C under nitrogen protection for 12 h. The reaction was stopped, and the reaction solution was cooled to room temperature. 500 mL of ethyl acetate was added to the reaction flask, and the catalyst was filtered out. The filtrate was extracted with 1.2 L of distilled water in three portions, and the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain yellow compound 4 with a yield of 95%.

[0061] Based on the reaction conditions of Example 2 (i.e., the molar ratio of compound 2, compound 3, base and catalyst is 1:1.5:2:0.08), the base cesium carbonate in the reaction can be replaced with triethylamine, tributylamine, potassium carbonate, sodium carbonate, potassium phosphate, sodium acetate, potassium acetate, etc.; the reaction system temperature can be adjusted between 40°C and 100°C; the solvent DMF can be replaced with acetonitrile, DMSO, DMAC, toluene, ethanol, isopropanol, etc. polar solvents, and other reaction conditions remain unchanged. Part of the experimental results are shown in Table 1.

[0062] Table 1 Conditions and results of preparing compound 4 in Examples 7-26

[0063]

[0064]

[0065] Preparation of compound 4 in Example 27

[0066] The filtered catalyst 1 in Example 2 was soaked in acetone for 2 h, filtered, and then washed with methanol, distilled water, and acetone, respectively, and placed in a vacuum device for vacuum drying at 60°C. The recovered light green catalyst 1 was obtained.

[0067] Into a reaction flask, 50 mmol of compound 2 (X = Br), 75 mmol of compound 3, 5 mmol of catalyst 1, 100 mmol of cesium carbonate and 300 mL of DMF were sequentially added, and the reaction was stirred at 70°C under nitrogen protection for 12 h. The reaction was stopped, and the reaction solution was cooled to room temperature. 500 mL of ethyl acetate was added to the reaction flask, and the catalyst was filtered out. The filtrate was extracted with 1.2 L of distilled water in three portions, and the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain yellow compound 4 with a yield of 95%.

[0068] Preparation of compound 4 in Example 28

[0069] The filtered catalyst 1 of Example 27 was recovered again according to the recovery method of Example 27, and the recovered catalyst 1 was recycled 9 times according to the method of Example 2. The reaction yield after the 10th cycle of catalysis was 90%.

[0070] Preparation of compound 5 of Example 29

[0071] Into a reaction flask were sequentially added 50 mmol of compound 4, 60 mmol of 4-fluoro-3-chloroaniline, 200 mmol of DTBP, 2.5 mmol of Cu(acac)2, and 300 mL of DMF. The reaction system was heated to 120°C and stirred for 12 h. The reaction was stopped, and the reaction solution was cooled to room temperature. Into the reaction flask was added 1.2 L of saturated sodium carbonate solution, which was stirred for 0.5 h. Then, 0.6 L of ethyl acetate was added in three portions for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation until about 50 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, and the mixture was stirred and left to stand at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain yellow compound 5 in a yield of 88%. The structure was characterized by MS and 1 H NMR characterization, ESI-LRMS m / z: 349.3 [M+H] + , 1 H NMR (500 MHz, CDCl3) δ: 8.60 (s, 1H), 8.48 (s, 1H), 7.87 (s, 1H), 7.62 (s, 1H), 7.41 (s, 1H), 7.30-7.22 (m, 2H), 4.01 (s, 3H).

[0072] Preparation of compound 5 of Example 30

[0073] Into a reaction flask were sequentially added 50 mmol of compound 4, 60 mmol of 4-fluoro-3-chloroaniline, 200 mmol of DTBP, 2.5 mmol of Cu(acac)2, and 300 mL of DMF. The reaction system was heated to 120°C and stirred for 12 h. The reaction was stopped, and the reaction solution was cooled to room temperature. Into the reaction flask was added 1.2 L of saturated sodium carbonate solution, which was stirred for 0.5 h. Then, 0.6 L of ethyl acetate was added in three portions for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation until about 50 mL of solvent remained. After cooling, 200 mL of petroleum ether was added, and the mixture was stirred and left to stand at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain yellow compound 5 in a yield of 88%. The structure was characterized by MS and

[0074] Preparation of compound 5 of Example 31

[0075] Into a reaction flask, 50 mmol of compound 4, 60 mmol of 4-fluoro-3-chloroaniline, 200 mmol of DTBP, 4.0 mmol of Cu(acac)2, and 300 mL of DMF were sequentially added. The reaction system was heated to 120°C and stirred for 12 h. The reaction was stopped and the reaction solution was cooled to room temperature. Into the reaction flask, 1.2 L of saturated sodium carbonate solution was added and stirred for 0.5 h. Then, 0.6 L of ethyl acetate was added in three portions for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation to about 50 mL of solvent. After cooling, 200 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain compound 5 in a yield of 89%.

[0076] Based on the reaction conditions of Example 29 (i.e., the molar ratio of compound 4, oxidant, and catalyst was 1:4:0.05), the oxidant DTBP in the reaction can be replaced with TBHP, CHP, m-CPBA, BPO, H2O2, etc.; the reaction system temperature can be adjusted between 80°C and 130°C; the catalyst Cu(acac)2 in the reaction can be replaced with copper compounds CuCl2, CuBr2, CuI2, Cu(OAc)2, CuI, etc., and other reaction conditions remain unchanged. Some experimental results are shown in Table 2.

[0077] Table 2: Conditions and results for preparing compound 5 in Examples 32-46

[0078]

[0079]

[0080] Example 47: Preparation of compound 1

[0081] Into a reaction flask, 50 mmol of compound 5 prepared in Example 29, 75 mL of ethanol, and 50 mL of water were sequentially added. The reaction system was heated to 60°C, and 2.0 g of activated carbon, 5 mmol of iron trichloride hexahydrate, 0.5 mmol of aluminum trichloride hexahydrate, and 0.5 mmol of copper dichloride dihydrate were added. The temperature was increased to reflux, and 100 mmol of 80% hydrazine hydrate was slowly added dropwise within 0.5 h. After the dropwise addition was completed, the reflux reaction was continued for 2 h. Filtration was performed, and the filter residue was washed with 15 mL of ethanol in three portions. The filtrate and washings were combined, and the solvent was removed by reduced pressure evaporation. The residue was extracted with 30 mL of ethyl acetate in three portions, and the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. Drying was performed to obtain gray-white solid 1 in a yield of 92%. The structure was characterized by MS and 1 H NMR characterization, ESI-LRMS m / z: 319.2 [M+H] + , 1H NMR (500 MHz, CDC13) δ: 8.71 (s, 2H), 8.49 (s, 1H), 7.40 (s, 1H), 7.32-7.19 (m, 3H), 7.16 (s, 1H), 4.85 (s, 1H), 3.86 (s, 3H).

Claims

1. A method for preparing a key intermediate of dacomitinib, characterized in that: The following steps are involved: (1) Compound 2 and 3 undergo cyclization reaction under the catalysis of catalyst 1 to obtain compound 4; (2) Compound 4 reacts with 4-fluoro-3-chloroaniline in the presence of catalyst 2, an oxidant, and DMF to directly undergo amination reaction to obtain compound 5; (3) Compound 5 undergoes a reduction reaction with hydrazine hydrate and activated carbon in the presence of a catalyst to obtain the target compound 1 7-methoxy-6-amino-4-(3-chloro-4-fluoroanilino)quinazoline. The specific synthetic route is as follows: ； Wherein, X is chlorine, bromine or iodine; The catalyst 1 in step (1) is CuI supported by the mesoporous material MCM-41, and its structure is: ； Catalyst 1 The catalyst 2 in step (2) is selected from copper compounds CuCl2, CuBr2, CuI2, Cu(OAc)2, Cu(acac)2, and CuI; the oxidant in step (2) is selected from TBHP, DTBP, CHP, m-CPBA, BPO, and H2O 2； In the step (1), a base and a solvent are also required to be added.

2. The method for preparing a key intermediate of dacomitinib according to claim 1, wherein In step (1), the amount of the catalyst 1 is 4-10% of the amount of compound 2.

3. The method for preparing a key intermediate of dacomitinib according to claim 1, wherein In step (1), the reaction temperature is 40-100°C.

4. The method for preparing a key intermediate of dacomitinib according to claim 1, wherein In step (1), the solvent is DMF, acetonitrile, DMSO, DMAC, toluene, ethanol, or isopropanol.

5. The method for preparing a key intermediate of dacomitinib according to claim 1, characterized in that: In step (1), the base is triethylamine, tributylamine, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium acetate, or potassium acetate.

6. The method for preparing a key intermediate of dacomitinib according to claim 1, characterized in that: In step (2), the amount of catalyst 2 is 3-8% of the amount of compound 4.

7. The method for preparing a key intermediate of dacomitinib according to claim 1, characterized in that: In step (2), the reaction temperature is 80~130°C.

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