A process for the synthesis of blz945

Abstract

The application belongs to the technical field of pharmaceutical chemistry and organic synthesis, and particularly relates to a process method for synthesizing BLZ945. The method is to use p-methoxyaniline as a starting material to synthesize BLZ945 through five steps. Specifically, 2-amino-6-methoxybenzothiazole is prepared through thiocyanate esterification / potassium persulfate oxidation cyclization in an aqueous phase; then, a mild Sandmeyer chlorination reaction is performed on the organic nitrous ester diazotization reagent and cuprous chloride in acetonitrile; subsequently, nucleophilic substitution, demethylation through aluminum trichloride, and finally etherification with N-methyl-4-chloro-2-pyridine carboxamide are sequentially performed to obtain the target product. The process of the application fundamentally solves the defects of the original route, such as expensive raw materials, dangerous operation and low yield, through complete replacement of the starting material and key innovation of the diazotization step, and has the significant advantages of low cost, mild conditions, safe operation, high yield and environmental friendliness, and is very suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical chemistry and organic synthesis technology, and in particular to a process for synthesizing BLZ945. Background Technology

[0002] BLZ945 is a highly efficient and selective small molecule inhibitor of CSF-1R. By targeting the CSF-1 / CSF-1R signaling pathway in tumor-associated macrophages (TAMs), it remodels the tumor immune microenvironment and shows great potential in the treatment of solid tumors such as breast cancer, pancreatic cancer, and glioblastoma. Currently, BLZ945 has entered the clinical research stage, and its efficient and economical synthesis process is crucial for reducing drug costs and promoting its clinical application.

[0003] The synthesis of BLZ945 in the prior art mainly relies on the route disclosed by Novartis AG in patent US2007066898W. This route uses 2-mercapto-5-hydroxybenzothiazole as the key starting material and constructs the target molecule through multiple reaction steps. However, this route has the following significant drawbacks, which seriously restrict its industrial production: First, the raw materials are expensive, have a foul odor, and are in limited supply. The key raw material is an expensive specialty chemical, and its synthesis steps are cumbersome, resulting in high overall costs. At the same time, the raw material has a strong thiol odor, which poses a threat to the production environment and human health, does not meet the requirements of green production, and easily generates sulfur-containing byproducts during the reaction, increasing the burden of environmental treatment. Second, the key process steps have defects. The diazotization reaction involved in the route usually uses the traditional hydrochloric acid / sodium nitrite system. This system is violent, exothermic, difficult to control precisely, and easily generates various byproducts such as phenols and azo compounds, resulting in low purity of the final product, difficulty in separation, and unsatisfactory overall yield.

[0004] Therefore, developing a new synthetic route for BLZ945 that avoids the use of odorous and expensive raw materials, is mild, easy to operate, has a high total yield, and is environmentally friendly is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0005] In view of this, the present invention proposes a process for synthesizing BLZ945. This process uses inexpensive, readily available, and odorless p-methoxyaniline as the starting material and efficiently constructs BLZ945 through a rationally designed and mild linear synthetic route. Furthermore, it innovatively employs an organic nitrite diazotizing reagent, fundamentally solving the raw material, safety, and environmental protection problems of the original process.

[0006] The technical solution of this invention is implemented as follows: This invention provides a process for synthesizing BLZ945, comprising the following steps: S1. React p-methoxyaniline with potassium thiocyanate in an aqueous phase, followed by the addition of persulfate to obtain 2-amino-6-methoxybenzothiazole; S2. The 2-amino-6-methoxybenzothiazole obtained in step S1 is reacted with an organic nitrite diazotizing agent and cuprous chloride in an organic solvent to obtain 2-chloro-6-methoxybenzothiazole. S3. The 2-chloro-6-methoxybenzothiazole obtained in step S2 is reacted with (1R,2R)-2-aminocyclohexanol in the presence of an organic base to give (1R,2R)-2-[(6-methoxy-2-benzothiazole)amino]cyclohexanol; S4. React the (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol obtained in step S3 with aluminum trichloride to give 2-[[(1R,2R)-2-hydroxycyclohexanol]amino]-6-benzothiazolyl alcohol; S5. The 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolyl obtained in step S4 is reacted with N-methyl-4-chloro-2-pyridinecarboxamide in the presence of an inorganic base to obtain the BLZ945.

[0007] The synthesis route is shown below: .

[0008] Based on the above technical solution, preferably, in step S1, the molar ratio of p-methoxyaniline, potassium thiocyanate, and persulfate is 1:(1.2~2.0):(1.2~1.8). This step uses p-methoxyaniline and potassium thiocyanate as starting materials and is carried out in an aqueous phase. First, a thiocyanate esterification reaction occurs, followed by the addition of persulfate for oxidative cyclization, yielding the key intermediate 2-amino-6-methoxybenzothiazole in a one-pot reaction. The reaction temperature is 20~30℃, and the reaction time is 2~16 hours.

[0009] More preferably, in step S2, after adding the 2-amino-6-methoxybenzothiazole to the organic solvent, an organic nitrite diazotizing agent is added first, followed by cuprous chloride. The organic solvent includes acetonitrile.

[0010] More preferably, in step S2, the organic nitrite diazotizing agent includes one of tert-butyl nitrite, isoamyl nitrite, and isobutyl nitrite.

[0011] More preferably, the molar ratio of the 2-amino-6-methoxybenzothiazole, the organic nitrite diazotizing agent, and cuprous chloride is 1:(1.2~2.0):(1.0~2.0).

[0012] More preferably, the reaction in step S2 is carried out at 20-40°C for 8-20 hours.

[0013] More preferably, in step S3, the organic base includes N-ethyldiisopropylamine; the reaction is carried out in DMSO; the molar ratio of 2-chloro-6-methoxybenzothiazole, (1R,2R)-2-aminocyclohexanol and the organic base is 1:1.1:3; this step is a nucleophilic substitution reaction, introducing a chiral amine fragment into the molecule, and reacting at 60°C for 16 hours.

[0014] More preferably, in step S4, the molar ratio of (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol to aluminum trichloride is 1:(2.0~4.0). The reaction temperature is 20~30℃, and the reaction time is 2 hours.

[0015] More preferably, in step S5, the inorganic base includes cesium carbonate; the reaction is carried out in DMSO; the molar ratio of 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolyl alcohol, N-methyl-4-chloro-2-pyridinecarboxamide and the inorganic base is 1:1:3; after mixing 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolyl alcohol and N-methyl-4-chloro-2-pyridinecarboxamide and pre-stirring at 20~30°C for 30 minutes, cesium carbonate is added all at once, and the reaction is carried out at 70°C for 12 hours.

[0016] More preferably, after the reaction in step S5 is completed, the crude product is purified by column chromatography, wherein the eluent for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.

[0017] The process for synthesizing BLZ945 in this invention has the following advantages over existing technologies: (1) It completely abandons the expensive and foul-smelling 2-mercapto-5-hydroxybenzothiazole in the existing technology and uses p-methoxyaniline, which is cheap, readily available and widely available in the market, as the starting material. The raw material cost is significantly reduced, breaking through the primary bottleneck of industrial production.

[0018] (2) An organic nitrite diazotizing reagent is used instead of the traditional hydrochloric acid / sodium nitrite system. The traditional system is violent, difficult to control, and prone to producing various byproducts, resulting in low product purity. The method of this invention has mild and controllable conditions, significantly suppresses side reactions, improves product purity, and makes post-processing safer and simpler.

[0019] (3) The entire route is reasonably designed, with mild conditions at each step and simple operation. It avoids the large-scale use of malodorous raw materials and highly corrosive reagents, generates less waste, and is more in line with the requirements of green chemistry and safe production, possessing good potential for industrial scale-up. The total yield from p-methoxyaniline meets the needs of industrial development, and its overall economic efficiency is significantly better than existing technologies. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 The 1H NMR spectrum of 2-amino-6-methoxybenzothiazole, the intermediate synthesized in Example 1 of this invention (…). 1 H NMR spectrum; Figure 2 The 1H NMR spectrum of the intermediate 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolol synthesized in Example 1 of this invention ( 1 H NMR spectrum; Figure 3 The proton nuclear magnetic resonance spectrum of the final product BLZ945 synthesized in Example 1 of this invention (… 1 (H NMR) image. Detailed Implementation

[0022] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0023] All materials used in this invention were purchased from the market, specifically: p-methoxyaniline was purchased from Shanghai Titan Technology Co., Ltd.; tert-butyl nitrite was purchased from Shanghai Titan Technology Co., Ltd.; (1R,2R)-2-aminocyclohexanol hydrochloride was purchased from Bid Pharmaceutical Co., Ltd.; and N-methyl-4-chloro-2-pyridinecarboxamide was purchased from Shanghai Titan Technology Co., Ltd.

[0024] Example 1: Synthesis of BLZ945 Step S1: Synthesis of 2-amino-6-methoxybenzothiazole To a 2L single-necked flask, p-methoxyaniline (123.2 g, 1.00 mol) and potassium thiocyanate (194.4 g, 2.00 mol) were added, followed by 1.0 L of deionized water. The mixture was stirred at room temperature for 1 hour. Subsequently, potassium persulfate (405.4 g, 1.50 mol) was added in portions, with the temperature controlled to not exceed 30°C. After the addition was complete, the mixture was stirred at 25°C for 12 hours. The reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate = 5:1). The reaction solution was cooled, adjusted to neutral with sodium carbonate, and extracted with ethyl acetate (300 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from water / ethanol to give 125 g of a white solid, 2-amino-6-methoxybenzothiazole, with a yield of 69.4% and an HPLC purity of 93%.

[0025] like Figure 1 The following is the 1H NMR spectrum data of 2-amino-6-methoxybenzothiazole: 1 H NMR (400 MHz, DMSO- d 6) delta 7.28 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 8.8, 2.4Hz, 1H), 5.50 (br s, 2H, NH2), 3.75 (s, 3H).

[0026] Step S2: Synthesis of 2-chloro-6-methoxybenzothiazole The product from step S1 (18.0 g, 0.100 mol) and acetonitrile (150 mL) were added to a 500 mL three-necked flask and stirred to dissolve. Tert-butyl nitrite (15.5 g, 0.150 mol) was slowly added dropwise at 25°C. Subsequently, cuprous chloride (11.9 g, 0.120 mol) was added in portions. After the addition was complete, the reaction mixture was stirred at 30°C for 12 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 40:1). The reaction mixture was filtered while hot, and the filtrate was poured into ice water and extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to give 20.1 g of crude 2-chloro-6-methoxybenzothiazole, a light brown solid, with a yield of 70.3% and an HPLC purity of approximately 71%. This crude product was used directly in the next step.

[0027] Step S3: Synthesis of (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol Add the crude product from step S2 (14.3 g, approximately 0.050 mol), (1R,2R)-2-aminocyclohexanol hydrochloride (8.3 g, 0.055 mol), and DMSO (100 mL) to a 250 mL three-necked flask. Add N-ethyldiisopropylamine (19.4 g, 0.150 mol) dropwise and react at 60°C for 16 hours. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 3:1). Pour the reaction mixture into ice water, filter, and wash with water. Recrystallize the solid from ethyl acetate to give 10.3 g of light brown crystals of (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol, yield 74.1%, HPLC purity 98%.

[0028] Step S4: Synthesis of 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolol Add the product from step S3 (2.78 g, 0.0100 mol), dichloromethane (20 mL), and aluminum trichloride (4.00 g, 0.0300 mol) to a 100 mL three-necked flask and react at room temperature for 2 hours. Monitor the reaction by TLC (dichloromethane / methanol = 10:1). Quench the reaction solution in ice water, adjust to acidity with 2 M hydrochloric acid, and filter. Dissolve the solid in ethyl acetate, wash with alkali, water, and brine, dry and concentrate to give 2.1 g of white powder 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolyl alcohol, yield 79.5%, HPLC purity 96%.

[0029] like Figure 2 The following is the 1H NMR spectrum data for 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolyl: 1 H NMR (400 MHz, DMSO- d 6) delta 9.71 (s, 1H, OH), 7.34 (d, J = 8.7 Hz, 1H), 7.23(d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.7, 2.5 Hz, 1H), 4.78 (d, J = 5.1 Hz, 1H, OH),3.62-3.58 (m, 1H), 3.40-3.30 (m, 2H), 2.01 (t, J = 7.8 Hz, 1H), 1.90 (s, 1H), 1.66 (d, J = 9.1 Hz, 2H), 1.38-1.19 (m, 4H).

[0030] Step S5: Synthesis of BLZ945 Add the product from step S4 (1.33 g, 5.00 mmol), N-methyl-4-chloro-2-pyridinecarboxamide (0.85 g, 5.00 mmol), DMSO (10 mL), and cesium carbonate (4.89 g, 15.0 mmol) to a 50 mL three-necked flask, and react at 70°C for 12 hours. Monitor the reaction mixture by HPLC. Pour the reaction mixture into ice water and extract with ethyl acetate (30 mL × 3). Wash the organic phase with water and brine, dry to anhydrous magnesium sulfate, and concentrate. Purify the crude product by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient from 2:1 to 1:2), and concentrate to give a pale yellow solid. Recrystallize from acetonitrile to give 0.63 g of white powder BLZ945, with an average yield of 31.5% and an HPLC purity of 97%.

[0031] like Figure 3 The following is the 1H NMR spectrum data of BLZ945: 1 H NMR (400 MHz, DMSO- d 6) delta 8.78 (q, J = 4.8 Hz, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 2.5Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 5.6, 2.6Hz, 1H), 7.05 (dd, J = 8.6, 2.5 Hz, 1H), 5.76 (s, 1H), 4.78 (d, J = 5.1 Hz, 1H), 3.58 (d, J = 8.9 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.08 (d, J = 11.1 Hz, 1H), 1.90(d, J = 11.3 Hz, 1H), 1.65 (s, 2H), 1.34-1.18 (m, 4H).

[0032] Example 2: Step S1: Synthesis of 2-amino-6-methoxybenzothiazole To a 2L single-necked flask, p-methoxyaniline (123.2 g, 1.00 mol), potassium thiocyanate (116.6 g, 1.20 mol), and 1.0 L of deionized water were added, and the mixture was stirred at room temperature for 1 hour. Subsequently, potassium persulfate (324.3 g, 1.20 mol) was added in portions, maintaining the temperature above 30°C. After the addition was complete, the mixture was stirred at 20°C for 16 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled, adjusted to neutral with sodium carbonate, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized to give 117.1 g of a white solid, 2-amino-6-methoxybenzothiazole, in approximately 65% ​​yield, with an HPLC purity >92%.

[0033] Step S2: Synthesis of 2-chloro-6-methoxybenzothiazole Add the product from step S1 (18.0 g, 0.100 mol) and acetonitrile (150 mL) to a 500 mL three-necked flask and stir to dissolve. At 20°C, slowly add isoamyl nitrite (12.4 g, 0.120 mol). Then, add cuprous chloride (9.9 g, 0.100 mol) in portions. After the addition is complete, stir the reaction mixture at 40°C for 8 hours. Monitor the reaction mixture by TLC. Filter the reaction mixture while hot, pour the filtrate into ice water, and extract with dichloromethane. Dry and concentrate the organic phase to obtain 13.6 g of crude 2-chloro-6-methoxybenzothiazole, a light brown solid, with a yield of approximately 68% and an HPLC purity of approximately 82%. This crude product was used directly in the next step.

[0034] Step S3: Synthesis of (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol The procedure is carried out according to step S3 of Example 1, and will not be repeated here.

[0035] Step S4: Synthesis of 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolol Add (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol (2.78 g, 0.0100 mol), dichloromethane (20 mL), and aluminum trichloride (2.67 g, 0.0200 mol) to a 100 mL three-necked flask. Place the reaction mixture in a 20°C water bath and stir for 2 hours. TLC (developing solvent: dichloromethane / methanol = 10:1) showed the disappearance of the starting material spot. Quench the reaction mixture in 50 mL of ice water, adjust the pH to 2-3 with 2 M hydrochloric acid, and a solid precipitates. Filter the mixture, and wash the filter cake with water until neutral. Dissolve the solid in 30 mL of ethyl acetate, and wash successively with saturated sodium bicarbonate solution, water, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2.1 g of 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolol, a white powder. The calculated yield was approximately 78%, and the HPLC purity was >95%.

[0036] Step S5: Synthesis of BLZ945 The procedure was carried out under the same conditions as in Example 1 (S3), which will not be repeated here. The final product was BLZ945 (0.63 g, calculated yield approximately 31.5%, HPLC purity >95%), whose structure was confirmed by 1H NMR spectroscopy.

[0037] Example 3: Step S1: Synthesis of 2-amino-6-methoxybenzothiazole To a 2L single-necked flask, p-methoxyaniline (123.2 g, 1.00 mol), potassium thiocyanate (194.4 g, 2.00 mol), and 1.0 L of deionized water were added, and the mixture was stirred at room temperature for 1 hour. Subsequently, potassium persulfate (486.4 g, 1.80 mol) was added in portions, maintaining the temperature below 30°C. After the addition was complete, the mixture was stirred at 30°C for 2 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled, adjusted to neutral with sodium carbonate, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized to give 133.3 g of a white solid, 2-amino-6-methoxybenzothiazole, with a yield of approximately 74% and an HPLC purity >94%.

[0038] Step S2: Synthesis of 2-chloro-6-methoxybenzothiazole Add the product from step S1 (18.0 g, 0.100 mol) and acetonitrile (150 mL) to a 500 mL three-necked flask and stir to dissolve. Slowly add isobutyl nitrite (20.6 g, 0.200 mol) dropwise at 40°C. Then, add cuprous chloride (19.8 g, 0.200 mol) in portions. After the addition is complete, stir the reaction mixture at 20°C for 20 hours. Monitor the reaction mixture by TLC. Filter the reaction mixture while hot, pour the filtrate into ice water, and extract with dichloromethane. Dry and concentrate the organic phase to obtain 14 g of crude 2-chloro-6-methoxybenzothiazole, a light brown solid, with a yield of approximately 70% and an HPLC purity of approximately 80%. This crude product was used directly in the next step.

[0039] Step S3: Synthesis of (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol The procedure is carried out according to step S3 of Example 1, and will not be repeated here.

[0040] Step S4: Synthesis of 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolol Add (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol (2.78 g, 0.0100 mol), dichloromethane (20 mL), and aluminum trichloride (5.34 g, 0.0400 mol) to a 100 mL three-necked flask. Place the reaction mixture in a 30°C water bath and stir for 2 hours. TLC (developing solvent: dichloromethane / methanol = 10:1) monitoring showed the disappearance of the starting material spot. Quench the reaction mixture in 50 mL of ice water, adjust the pH to 2-3 with 2 M hydrochloric acid, and a solid precipitates. Filter, and wash the filter cake with water until neutral. Dissolve the solid in 30 mL of ethyl acetate, and wash successively with saturated sodium bicarbonate solution, water, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2.1 g of 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolol, a white powder. The calculated yield was approximately 80%, and the HPLC purity was >95%.

[0041] Step S5: Synthesis of BLZ945 The procedure was carried out under the same conditions as in Example 1 (S3), which will not be repeated here. The final product was BLZ945 (0.63 g), whose structure was confirmed by proton nuclear magnetic resonance spectroscopy.

[0042] Comparative Example 4: Unlike Example 1, in step S2, tert-butyl nitrite was replaced with an aqueous solution of sodium nitrite (8.3 g NaNO2 dissolved in 20 mL of water). The solution was slowly added dropwise while maintaining an internal temperature of 0-5°C. After the addition was complete, the mixture was stirred for another 30 minutes at 0-5°C to ensure complete diazotization.

[0043] After the reaction was completed, TLC (petroleum ether / ethyl acetate = 40:1) was performed. The TLC chromatograms showed multiple distinct byproduct spots above and below the main spot of the target product (Rf≈0.6), indicating the formation of considerable amounts of impurities such as phenols and azo compounds. The reaction mixture was post-treated to obtain a dark brown, viscous, oily crude product. This was then solidified at low temperature to obtain crude 2-chloro-6-methoxybenzothiazole, with a yield of 58.5% and an HPLC purity of approximately 72%.

[0044] Comparative Example 5: Unlike Example 1, tert-butyl nitrite (10.3 g, 0.100 mol) was added in step S2. The remaining steps were the same as in Example 1 and will not be repeated here.

[0045] After 12 hours of reaction, obvious spots were still visible on the TLC plate at the starting material location (Rf≈0.1), indicating that a considerable amount of 2-amino-6-methoxybenzothiazole starting material had not reacted completely. Following post-processing, 14.5 g of crude 2-chloro-6-methoxybenzothiazole was obtained, with a calculated yield of approximately 50.8%.

[0046] This comparative example confirms that when the amount of organic nitrite reagent is 1.0 equivalent (feed ratio 1:1.0), the insufficient diazotizing reagent leads to incomplete diazotization of the aromatic amine feedstock, resulting in a large amount of feedstock residue. This not only significantly reduces the yield of the target chlorinated product (by approximately 20 percentage points), but may also affect subsequent steps due to the contamination of the product with unreacted feedstock.

[0047] Comparative Example 6: Unlike Example 1, tert-butyl nitrite (25.8 g, 0.250 mol) was added in step S2. The remaining steps were the same as in Example 1 and will not be repeated here.

[0048] The reaction process resulted in a significant increase in the generation of nitrogen oxides, placing higher demands on the experimental environment and personal protective equipment, thus increasing safety risks. Excessive reagent decomposition led to the generation of more nitrogen oxide-containing byproducts in the post-processing stage, increasing the complexity of waste treatment and environmental pressure. After post-processing, 20.8 g of crude 2-chloro-6-methoxybenzothiazole was obtained, with a yield of approximately 72.8%, which was not significantly improved compared to the yield in Example 1 (71.7%). The HPLC purity was approximately 83%, even slightly lower than that in Example 1 (85%).

[0049] This comparative example confirms that when the amount of organic nitrite reagent is as high as 2.5 equivalents (feed ratio 1:2.5), it does not lead to an effective increase in yield. Instead, it causes significant safety and environmental problems (increased release of nitrogen oxides) and increases the burden of post-processing.

[0050] Comparative Example 7: Unlike Example 1, cuprous chloride (7.9 g, 0.080 mol) was added in step S2. The remaining steps were the same as in Example 1 and will not be repeated here.

[0051] After 12 hours of reaction, TLC showed that, in addition to the main spot of the target product, new and more obvious byproduct spots appeared at the origin and at slightly more polar positions, suspected to be biphenyl byproducts generated by aryl radical coupling. Post-processing yielded 15.8 g of crude 2-chloro-6-methoxybenzothiazole, with a calculated yield of approximately 55.4%, significantly lower than the yield of Example 1. Post-processing observation: the reaction mixture was darker in color, and the crude product obtained after post-processing was also darker in color than the product of Example 1.

[0052] This comparative example confirms that when cuprous chloride is used at a dosage of 0.8 equivalents (feed ratio 1:0.8), the insufficient amount of copper(I) in the catalytic diazonium salt conversion (SET process) results in the aryl radicals generated not being captured and converted into chlorinated products in a timely manner. These "idle" aryl radicals undergo coupling side reactions, generating unintended dimer or polymer impurities, thereby diverting the reaction pathway and significantly reducing the yield of the target chlorinated product.

[0053] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for synthesizing BLZ945, characterized in that, Includes the following steps: S1. React p-methoxyaniline with potassium thiocyanate in an aqueous phase, followed by the addition of persulfate to obtain 2-amino-6-methoxybenzothiazole; S2. The 2-amino-6-methoxybenzothiazole obtained in step S1 is reacted with an organic nitrite diazotizing agent and cuprous chloride in an organic solvent to obtain 2-chloro-6-methoxybenzothiazole. S3. The 2-chloro-6-methoxybenzothiazole obtained in step S2 is reacted with (1R,2R)-2-aminocyclohexanol in the presence of an organic base to give (1R,2R)-2-[(6-methoxy-2-benzothiazole)amino]cyclohexanol; S4. React the (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol obtained in step S3 with aluminum trichloride to give 2-[[(1R,2R)-2-hydroxycyclohexanol]amino]-6-benzothiazolyl alcohol; S5. The 2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-6-benzothiazolyl obtained in step S4 is reacted with N-methyl-4-chloro-2-pyridinecarboxamide in the presence of an inorganic base to obtain the BLZ945.

2. The process method as described in claim 1, characterized in that, In step S1, the molar ratio of p-methoxyaniline, potassium thiocyanate and persulfate is 1:(1.2~2.0):(1.2~1.8).

3. The process method as described in claim 1, characterized in that, In step S2, after adding the 2-amino-6-methoxybenzothiazole to the organic solvent, an organic nitrite diazotizing agent is added first, followed by cuprous chloride.

4. The process method as described in claim 3, characterized in that, In step S2, the organic nitrite diazotizing agent includes one of tert-butyl nitrite, isoamyl nitrite, and isobutyl nitrite.

5. The process method as described in claim 3, characterized in that, The molar ratio of 2-amino-6-methoxybenzothiazole, the organic nitrite diazotizing agent, and cuprous chloride is 1:(1.2~2.0):(1.0~2.0).

6. The process method as described in claim 3, characterized in that, The reaction was carried out at 20-40°C for 8-20 hours.

7. The process method as described in claim 1, characterized in that, In step S3, the organic base includes N-ethyldiisopropylamine; the reaction is carried out in DMSO.

8. The process method as described in claim 1, characterized in that, In step S4, the molar ratio of (1R,2R)-2-[(6-methoxy-2-benzothiazolyl)amino]cyclohexanol to aluminum trichloride is 1:(2.0~4.0).

9. The process method as described in claim 1, characterized in that, In step S5, the inorganic base includes cesium carbonate; the reaction is carried out in DMSO.

10. The process method as described in claim 9, characterized in that, After the reaction was completed, the crude product was purified by column chromatography, with the eluent being a mixture of petroleum ether and ethyl acetate.

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