A method for synthesizing daclatasvir hydrochloride

Abstract

The application discloses a synthesis method of daclatasvir hydrochloride. The daclatasvir hydrochloride is obtained from biphenyl as a starting material through a Friedel-Crafts acylation reaction, a condensation cyclization reaction, an amide hydrolysis reaction, a condensation reaction, salt formation and the like. The synthesis method has the advantages of low synthesis cost, simple post-treatment method, high yield, industrial production, reduced solvent and catalyst use, reduced reaction by-products and pollution, conformity to the development trend of green chemistry, maximized reduction of the production cost of the overall process and high application value.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a method for synthesizing daclatasvir hydrochloride. Background Technology

[0002] Hepatitis C is a global public health problem, and the demand for its treatment is increasing. It is estimated that tens of millions of people worldwide are infected with the hepatitis C virus (HCV). Traditional treatment regimens, based on pegylated interferon combined with ribavirin, have significant limitations, including a cure rate of less than 50%, numerous adverse reactions, and long treatment courses. With the advent of direct-acting antiviral agents (DAAs), hepatitis C treatment has made groundbreaking progress. Among them, daclatasvir hydrochloride, the first NS5A replication complex inhibitor developed by Bristol-Myers Squibb, has shown excellent inhibitory effects on HCV genotypes 1-6. When used in combination with drugs such as sofosbuvir, the cure rate can reach over 97%, providing a safer and more effective treatment option for hepatitis C patients. Since its approval for marketing in Japan, the European Union, and the United States in 2014, daclatasvir has rapidly become a core drug in hepatitis C treatment combination regimens.

[0003] The conventional synthetic method for daclatasvir hydrochloride is the method reported in US7728027B2. This route uses 4,4'-diacetylbiphenyl (compound A1) as a starting material, which undergoes a bromination reaction to obtain intermediate A2. Then, intermediate A2 undergoes an O-alkylation reaction with BOC-L-proline (compound A3) to obtain intermediate A4. Next, intermediate A4 reacts with sodium acetate to form a nitrogen-containing heterocycle to obtain intermediate A5. Intermediate A5 undergoes an amidation hydrolysis reaction in ethanol and hydrochloric acid to remove BOC and obtain intermediate A6. Finally, intermediate A6 and MOC-L-valine undergo an amidation reaction in the combined action of hydrochloric acid, DIPEA, and the condensing agents HOBt and EDCI to form a salt, yielding daclatasvir hydrochloride. The specific route is shown below:

[0004]

[0005] The starting material 4,4'-diacetylbiphenyl is expensive, the first step of the reaction requires harsh conditions and takes too long, increasing the reaction cycle. Furthermore, the bromine used as a reagent is volatile, highly corrosive, and difficult to store. In addition, DIPEA, which is also expensive, was used twice, leaving room for optimization. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a method for synthesizing daclatasvir hydrochloride. Using biphenyl as a starting material, the method sequentially proceeds through Friedel-Crafts acylation, condensation cyclization, amide hydrolysis, condensation, and salt formation to obtain daclatasvir hydrochloride. This method is low-cost, simple in post-processing, and yields high results, facilitating industrial production. It reduces the use of solvents and catalysts, minimizes reaction byproducts and pollution, aligns with the trend of green chemistry, and minimizes overall production costs, demonstrating significant application value.

[0007] The method for synthesizing daclatasvir hydrochloride according to the present invention includes the following steps:

[0008] Step 1: Dissolve chloroacetic anhydride in 1,2-dichloroethane, lower the system temperature to 0-5℃, and slowly add anhydrous aluminum trichloride in batches, strictly controlling the temperature below 10℃ during this process. After the addition is complete, maintain this temperature and stir for 15 minutes for later use. Add biphenyl to 1,2-dichloroethane and stir to dissolve it completely. Control the temperature at 5-10℃ and add it dropwise to the above reaction system. After the addition is complete, raise the temperature to 40-45℃ and monitor the reaction until it is complete. Control the temperature at 0-10℃ and add dilute hydrochloric acid, stir, filter, wash, and dry to obtain 4,4'-bis(2-chloroacetyl)biphenyl.

[0009] Step 2: Dissolve 4,4'-bis(2-chloroacetyl)biphenyl and N-BOC-L-proline in DMF, slowly add triethylamine dropwise while controlling the temperature at 0-5℃, stir at room temperature for 3 hours, add ammonium carbonate, raise the temperature to 60℃ and monitor the reaction until complete. Add water to the reaction solution, filter, and wash to obtain (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diylbis-1H-imidazol-5,2-diyl)bis-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester.

[0010] Step 3: Dissolve (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diylbis-1H-imidazolium-5,2-diyl)bis-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester in methanol, stir at room temperature for 1 hour, and slowly add concentrated hydrochloric acid while maintaining the temperature. After the addition is complete, raise the temperature to 50°C and monitor the reaction until complete. Filter and wash to obtain 1H-imidazolium, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride (1:4).

[0011] Step 4: Dissolve oxalyl chloride in tetrahydrofuran, add DMF catalyst dropwise at 0℃, and add MOC-L-valine while maintaining the temperature. After the addition is complete, heat to room temperature and stir for 1 hour. Then, add triethylamine dropwise while maintaining the temperature at 0-5℃ and stirring for 30 minutes. Set aside. Dissolve 1H-imidazolium, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride (1:4) in tetrahydrofuran and add it dropwise to the above solution while maintaining the temperature at 0-5℃. After the addition is complete, stir for 2 hours while maintaining the temperature. Then, heat to room temperature and react for 8 hours. After the reaction is complete as monitored by HPLC, wash and concentrate to obtain daclatasvir.

[0012] Step 5: Dissolve daclatasvir in methanol, add concentrated hydrochloric acid dropwise at room temperature under controlled temperature, and after the addition is complete, raise the temperature to 50°C and react for 4 hours. Add methyl tert-butyl ether, cool and crystallize, filter, wash, and dry to obtain daclatasvir hydrochloride.

[0013] In step 1, the molar ratio of biphenyl, chloroacetic anhydride, and aluminum trichloride is 1:2.1:5, and the volume of 1,2-dichloroethane is 18 times that of biphenyl.

[0014] In step 2, the molar ratio of 4,4'-bis(2-chloroacetyl)biphenyl, N-BOC-L-proline, triethylamine, and ammonium carbonate is 1:2.1:2.1:10, and the volume of DMF is 8 times that of 4,4'-bis(2-chloroacetyl)biphenyl.

[0015] In step 3, the molar ratio of (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diyldi-1H-imidazolium-5,2-diyl)di-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester to HCl is 1:10, and the volume of methanol is 10 times that of (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diyldi-1H-imidazolium-5,2-diyl)di-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester.

[0016] In step 4, the molar ratio of 1H-imidazolium, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride (1:4), MOC-L-valine, oxaloyl chloride, triethylamine, and DMF is 1:2:2:4.5:0.2, and the volume of tetrahydrofuran is 6 times that of 1H-imidazolium, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride (1:4).

[0017] In step 5, the molar ratio of daclatasvir to HCl is 1:3, and the volume of methanol is 5 times that of daclatasvir.

[0018] The synthetic route of this invention is shown in the figure below:

[0019]

[0020] This invention discloses a method for synthesizing daclatasvir hydrochloride. Using biphenyl (compound B1) as a starting material, it first undergoes a Friedel-Crafts acylation reaction with chloroacetic anhydride (compound B2) in 1,2-dichloroethane to obtain compound B3. Next, compound B3 undergoes a condensation reaction with ammonium carbonate in DMF in the presence of triethylamine to form a ring, yielding compound B5. Then, compound B5 undergoes an amide hydrolysis reaction in methanol and hydrochloric acid to remove BOC, yielding compound B6. Subsequently, compound B6 reacts with oxalyl chloride and MOC-L-valine (compound B7) in tetrahydrofuran under the catalysis of N,N-dimethylformamide to generate compound B8. Finally, compound B8 reacts with hydrochloric acid in methanol to obtain daclatasvir hydrochloride (compound B9). This method has low synthesis cost, simple post-processing, high yield, and is suitable for industrial production. It reduces the use of solvents and catalysts, minimizes reaction byproducts and pollution, aligns with the trend of green chemistry, and minimizes the overall production cost, demonstrating high application value. Attached Figure Description

[0021] Figure 1 The 1H NMR spectrum of the raw material (compound B1) is shown.

[0022] Figure 2 This is the 1H NMR spectrum of compound B4.

[0023] Figure 3 This is the 1H NMR spectrum of compound B9 (daclatasvir hydrochloride).

[0024] Figure 4 This is the mass spectrum of compound B9 (daclatasvir hydrochloride). Detailed Implementation

[0025] The technical solution of the present invention is further illustrated below through specific embodiments. These embodiments are only for illustrative purposes and are not intended to limit the scope of the invention.

[0026] Synthesis of compound B3:

[0027]

[0028] Example 1:

[0029] Dissolve chloroacetic anhydride (23.4 g, 136.08 mmol) in 1,2-dichloroethane (150 mL) in a reaction flask. After the temperature drops to 0-5℃, slowly add anhydrous aluminum trichloride (43.2 g, 324 mmol) in portions. During this process, strictly control the temperature below 10℃. After the addition is complete, maintain this temperature and stir for 15 minutes before use. Compound B1 (10 g, 64.8 mmol) was added to 30 mL of 1,2-dichloroethane in a reaction flask and stirred until fully dissolved. The solution was then added dropwise at a controlled temperature of 5-10 °C. After the addition was complete, the temperature was raised to 40-45 °C and the reaction was carried out for 4 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to 0 °C and filtered. The filter cake was then slowly added in portions to 100 mL of 2% hydrochloric acid at a controlled temperature of 0-10 °C. After the addition was complete, the mixture was stirred for 2 hours and filtered. The filter cake was washed with water and 1,2-dichloroethane and dried to obtain 15.9 g of compound B3, with a yield of 80% and an HPLC purity of 98.2%.

[0030] Example 2:

[0031] Dissolve chloroacetic anhydride (23.4 g, 136.08 mmol) in carbon disulfide (150 mL) in a reaction flask. After the temperature drops to 0-5℃, slowly add anhydrous aluminum trichloride (43.2 g, 324 mmol) in batches. During this process, strictly control the temperature below 10℃. After the addition is complete, maintain this temperature and stir for 15 minutes before use. Compound B1 (10 g, 64.8 mmol) was added to carbon disulfide (30 mL) in a reaction flask and stirred until fully dissolved. The solution was then added dropwise at a controlled temperature of 5-10 °C. After the addition was complete, the temperature was raised to 40-45 °C and the reaction was carried out for 4 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to 0 °C and filtered. The filter cake was then slowly added in batches to 2% hydrochloric acid (100 mL) at a controlled temperature of 0-10 °C. After the addition was complete, the mixture was stirred for 2 hours and filtered. The filter cake was washed with water and carbon disulfide and dried to obtain 15.5 g of compound B3, with a yield of 78% and an HPLC purity of 98.1%.

[0032] Example 3:

[0033] Dissolve chloroacetic anhydride (23.4 g, 136.08 mmol) in 1,2-dichloroethane (150 mL) in a reaction flask. After the temperature drops to 0-5 °C, slowly add anhydrous ferric chloride (52.6 g, 324 mmol) in portions. During this process, strictly control the temperature below 10 °C. After the addition is complete, maintain this temperature and stir for 15 minutes before use. Compound B1 (10 g, 64.8 mmol) was added to 30 mL of 1,2-dichloroethane in a reaction flask and stirred until fully dissolved. The solution was then added dropwise at a controlled temperature of 5-10 °C. After the addition was complete, the temperature was raised to 40-45 °C and the reaction was carried out for 4 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to 0 °C and filtered. The filter cake was then slowly added in portions to 100 mL of 2% hydrochloric acid at a controlled temperature of 0-10 °C. After the addition was complete, the mixture was stirred for 2 hours and filtered. The filter cake was washed with water and 1,2-dichloroethane and dried to obtain 8.3 g of compound B3, with a yield of 42% and an HPLC purity of 91.2%.

[0034] Example 4:

[0035] Dissolve chloroacetic anhydride (23.4 g, 136.08 mmol) in 1,2-dichloroethane (150 mL) in a reaction flask. After the temperature drops to 0-5℃, slowly add anhydrous aluminum trichloride (43.2 g, 324 mmol) in portions. During this process, strictly control the temperature below 10℃. After the addition is complete, maintain this temperature and stir for 15 minutes before use. Compound B1 (10 g, 64.8 mmol) was added to 30 mL of 1,2-dichloroethane in a reaction flask and stirred until fully dissolved. The solution was then added dropwise at 5-10 °C. After the addition was complete, the mixture was refluxed for 4 hours. Once the reaction was complete as monitored by TLC, the solution was cooled to 0 °C and filtered. The filter cake was then slowly added in portions to 100 mL of 2% hydrochloric acid at 0-10 °C. After the addition was complete, the mixture was stirred for 2 hours and filtered. The filter cake was washed with water and 1,2-dichloroethane and dried to obtain 13 g of compound B3, with a yield of 65.4% and an HPLC purity of 88.3%.

[0036] Example 5:

[0037] Chloroacetic anhydride (23.4 g, 136.08 mmol) was dissolved in 1,2-dichloroethane (150 mL) in a reaction flask. Anhydrous aluminum trichloride (43.2 g, 324 mmol) was slowly added in portions at room temperature. After the addition was complete, the mixture was stirred at this temperature for 15 minutes. Compound B1 (10 g, 64.8 mmol) was added to 1,2-dichloroethane (150 mL) in a reaction flask and stirred until fully dissolved. The solution was then added dropwise to the above reaction solution at room temperature. After the addition was complete, the temperature was raised to 40-45 °C and the reaction was carried out for 4 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to 0 °C, filtered, and the filter cake was slowly added in portions to 2% hydrochloric acid (100 mL) at 0-10 °C. After the addition was complete, the mixture was stirred for 2 hours, filtered, and the filter cake was washed with water and 1,2-dichloroethane and dried to obtain 11.71 g of compound B3, with a yield of 58.9% and an HPLC purity of 86.5%.

[0038] NMR data of the raw material (compound B1): 1H NMR (400 MHz, DMSO) δ 7.70-7.63 (m, 2H), 7.47 (dd, J = 8.4, 6.9 Hz, 2H), 7.41-7.33 (m, 1H).

[0039] Synthesis of compound B5:

[0040]

[0041] Example 6:

[0042] Compound B3 (10 g, 32.6 mmol) and compound B4 (13.7 g, 68.4 mmol) were dissolved in DMF (80 mL) and placed in a reaction flask. Triethylamine (6.9 g, 68.4 mmol) was slowly added dropwise at 0-5 °C. After stirring at room temperature for 3 hours, ammonium carbonate (31.3 g, 326 mmol) was added, and the mixture was heated to 60 °C and reacted for 4 hours. After the reaction was complete as monitored by TLC, water was added, and the mixture was filtered. The filter cake was washed with methanol and dried to obtain 16.9 g of compound B5, with a yield of 82.8% and an HPLC purity of 95.6%.

[0043] Example 7:

[0044] Compound B3 (10 g, 32.6 mmol) and compound B4 (13.7 g, 68.4 mmol) were dissolved in DMF (80 mL) and placed in a reaction flask. N,N-diisopropylethylamine (8.2 g, 68.4 mmol) was slowly added dropwise at 0-5 °C. After stirring at room temperature for 3 hours, ammonium carbonate (31.3 g, 326 mmol) was added, and the mixture was heated to 60 °C and reacted for 4 hours. After the reaction was completed by TLC monitoring, water was added, and the mixture was filtered. The filter cake was washed with methanol and dried to obtain 14.7 g of compound B5, with a yield of 72% and an HPLC purity of 94.5%.

[0045] Example 8:

[0046] Compound B3 (10 g, 32.6 mmol) and compound B4 (13.7 g, 68.4 mmol) were dissolved in DMF (80 mL) and placed in a reaction flask. Triethylamine (6.9 g, 68.4 mmol) was slowly added dropwise at 0-5 °C. After stirring at room temperature for 3 hours, ammonium carbonate (31.3 g, 326 mmol) was added, and the mixture was heated to 90 °C and reacted for 4 hours. After the reaction was complete as monitored by TLC, water was added, and the mixture was filtered. The filter cake was washed with methanol and dried to obtain 15.2 g of compound B5, with a yield of 74.4% and an HPLC purity of 92.9%.

[0047] Example 9:

[0048] Compound B3 (10 g, 32.6 mmol) and compound B4 (13.7 g, 68.4 mmol) were dissolved in DMF (80 mL) and placed in a reaction flask. Triethylamine (6.9 g, 68.4 mmol) was slowly added dropwise at 0-5 °C. After stirring at room temperature for 3 hours, ammonium acetate (50.2 g, 652 mmol) was added, and the mixture was heated to 60 °C and reacted for 4 hours. After the reaction was complete as monitored by TLC, water was added, and the mixture was filtered. The filter cake was washed with methanol and dried to obtain 16.5 g of compound B5, with a yield of 80.8% and an HPLC purity of 93.3%.

[0049] NMR data for compound B4: 1H NMR (400 MHz, CHLOROFORM-D) δ 9.48 (dd, J =38.8, 2.6 Hz, 1H), 4.22–3.93 (m, 1H), 3.55–3.41 (m, 2H), 1.86 (dt, J = 13.7, 6.4 Hz, 2H), 1.42 (d, J = 20.1 Hz, 9H).

[0050] Synthesis of compound B6:

[0051]

[0052] Example 10:

[0053] Compound B5 (10 g, 16 mmol) was dissolved in methanol (100 mL) in a reaction flask and stirred at room temperature for 1 hour. Concentrated hydrochloric acid (16.2 g, 160 mmol) was slowly added dropwise while maintaining the temperature. After the addition was complete, the temperature was raised to 50 °C and the reaction was carried out for 5 hours. After the reaction was monitored by HPLC to be complete, the mixture was filtered, the filter cake was washed with methanol, and dried to give 8.5 g of compound B6, with a yield of 93.6% and an HPLC purity of 98.5%.

[0054] Example 11:

[0055] Compound B5 (10 g, 16 mmol) was dissolved in methanol (100 mL) in a reaction flask and stirred at room temperature for 1 hour. Concentrated hydrochloric acid (16.2 g, 160 mmol) was slowly added dropwise while maintaining the temperature. After the addition was complete, the mixture was heated to reflux and reacted for 5 hours. After the reaction was monitored by HPLC to ensure it was complete, the mixture was filtered. The filter cake was washed with methanol and dried to obtain 8 g of compound B6, with a yield of 88.2% and an HPLC purity of 96.6%.

[0056] Example 12:

[0057] Compound B5 (10 g, 16 mmol) was dissolved in methanol (100 mL) in a reaction flask and stirred at room temperature for 1 hour. While maintaining the temperature, 10% hydrochloric acid (58.2 g, 160 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 50 °C and the reaction was carried out for 5 hours. After the reaction was monitored by HPLC to be complete, the mixture was filtered, the filter cake was washed with methanol, and dried to give 8.2 g of compound B6, with a yield of 90.3% and an HPLC purity of 98.2%.

[0058] Synthesis of compound B8:

[0059]

[0060] Example 13:

[0061] Oxaloyl chloride (4.5 g, 35.1 mmol) was dissolved in tetrahydrofuran (20 mL) in a reaction flask. Catalyst DMF (0.25 g, 3.5 mmol) was added dropwise at 0 °C. Compound B7 (6.14 g, 35.1 mmol) was added while maintaining this temperature. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. Then, triethylamine (8.0 g, 78.9 mmol) was added dropwise at 0-5 °C while maintaining the temperature and stirring for 30 minutes. Compound B6 (10 g, 17.5 mmol) was dissolved in tetrahydrofuran (40 mL) in a reaction flask and added dropwise to the above solution while maintaining the temperature at 0-5 °C. After the addition was complete, the mixture was stirred while maintaining the temperature for 2 hours. The mixture was then heated to room temperature and reacted for 8 hours. After the reaction was complete as monitored by HPLC, the mixture was washed successively with 5% hydrochloric acid and 5% sodium hydroxide aqueous solution. The organic phase was concentrated to obtain 12.1 g of compound B8, with a yield of 93.5% and an HPLC purity of 98.4%.

[0062] Example 14:

[0063] Oxaloyl chloride (4.7 g, 36.9 mmol) was dissolved in tetrahydrofuran (20 mL) in a reaction flask. Catalyst DMF (0.25 g, 3.5 mmol) was added dropwise at 0 °C. Compound B7 (6.4 g, 36.9 mmol) was added while maintaining this temperature. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. Then, triethylamine (8.0 g, 78.9 mmol) was added dropwise at 0-5 °C while maintaining the temperature and stirring for 30 minutes. Compound B6 (10 g, 17.5 mmol) was dissolved in tetrahydrofuran (40 mL) in a reaction flask and added dropwise to the above solution while maintaining the temperature at 0-5 °C. After the addition was complete, the mixture was stirred while maintaining the temperature for 2 hours. The mixture was then heated to room temperature and reacted for 8 hours. After the reaction was complete as monitored by HPLC, the mixture was washed successively with 5% hydrochloric acid and 5% sodium hydroxide aqueous solution. The organic phase was concentrated to obtain 11.4 g of compound B8, with a yield of 88.1% and an HPLC purity of 90.2%.

[0064] Example 15:

[0065] Phosphorus oxychloride (5.4 g, 35.1 mmol) was dissolved in tetrahydrofuran (20 mL) in a reaction flask. Catalyst DMF (0.25 g, 3.5 mmol) was added dropwise at 0 °C. Compound B7 (6.14 g, 35.1 mmol) was added while maintaining this temperature. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. Then, triethylamine (8.0 g, 78.9 mmol) was added dropwise at 0-5 °C while maintaining the temperature and stirring for 30 minutes. Compound B6 (10 g, 17.5 mmol) was dissolved in tetrahydrofuran (40 mL) in a reaction flask and added dropwise to the above solution while maintaining the temperature at 0-5 °C. After the addition was complete, the mixture was stirred while maintaining the temperature for 2 hours. The mixture was then heated to room temperature and reacted for 8 hours. After the reaction was complete as monitored by HPLC, the mixture was washed successively with 5% hydrochloric acid and 5% sodium hydroxide aqueous solution. The organic phase was concentrated to obtain 11.1 g of compound B8, with a yield of 85.8% and an HPLC purity of 84.3%.

[0066] Example 16:

[0067] Oxaloyl chloride (4.5 g, 35.1 mmol) was dissolved in tetrahydrofuran (20 mL) in a reaction flask. Catalyst DMF (0.25 g, 3.5 mmol) was added dropwise at 0 °C. Compound B7 (6.14 g, 35.1 mmol) was added while maintaining this temperature. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. Then, N,N-diisopropylethylamine (10.2 g, 78.9 mmol) was added dropwise at 0-5 °C while maintaining the temperature and stirring for 30 minutes. Compound B6 (10 g, 17.5 mmol) was dissolved in tetrahydrofuran (40 mL) in a reaction flask and added dropwise to the above solution while maintaining the temperature at 0-5 °C. After the addition was complete, the mixture was stirred while maintaining the temperature for 2 hours. The mixture was then heated to room temperature and reacted for 8 hours. After the reaction was complete as monitored by HPLC, the mixture was washed successively with 5% hydrochloric acid and 5% sodium hydroxide aqueous solution. The organic phase was concentrated to obtain 12 g of compound B8, with a yield of 92.8% and an HPLC purity of 98.1%.

[0068] Example 17:

[0069] Oxaloyl chloride (4.5 g, 35.1 mmol) was dissolved in tetrahydrofuran (20 mL) in a reaction flask. Catalyst DMF (0.25 g, 3.5 mmol) and compound B7 (6.14 g, 35.1 mmol) were added sequentially at room temperature. The mixture was stirred for 1 hour after the addition was complete. Then, triethylamine (8.0 g, 78.9 mmol) was added dropwise, and the mixture was stirred for 30 minutes. Compound B6 (10 g, 17.5 mmol) was dissolved in tetrahydrofuran (40 mL) in a reaction flask and added dropwise to the above solution at room temperature. After the addition was complete, the mixture was stirred for 8 hours while maintaining the temperature. After the reaction was monitored by HPLC to be complete, the mixture was washed sequentially with 5% hydrochloric acid and 5% sodium hydroxide aqueous solution. The organic phase was concentrated to give compound B8 (11.2), with a yield of 86.6% and an HPLC purity of 91.7%.

[0070] Synthesis of daclatasvir hydrochloride (compound B9):

[0071]

[0072] Example 18:

[0073] Compound B8 (10 g, 13.5 mmol) was dissolved in methanol (50 mL) and placed in a reaction flask. Concentrated hydrochloric acid (4.1 g, 40.6 mmol) was added dropwise at room temperature. After the addition was complete, the temperature was raised to 50 °C and reacted for 4 hours. The temperature was then lowered to 40 °C and 100 mL of methyl tert-butyl ether was added. After the addition was complete, the temperature was maintained at 5 °C and stirred for 2 hours. The mixture was then filtered, and the filter cake was washed with methyl tert-butyl ether and dried to obtain 9.5 g of daclatasvir hydrochloride (compound B9), with a yield of 87% and an HPLC purity of 99.2%.

[0074] 1H NMR (600 MHz, DMSO-D6) δ 8.20-7.84 (m, 10H), 7.26 (d, J = 8.5 Hz, 2H), 5.13 (t, J = 7.1 Hz, 2H), 4.09 (t, J = 7.8 Hz, 2H), 3.86 (dq, J = 56.7,8.3 Hz, 4H), 3.50 (s, 6H), 2.39-1.95 (m, 10H), 0.77 (dd, J = 37.0, 6.7 Hz,12H).

[0075] Example 19:

[0076] Compound B8 (10 g, 13.5 mmol) was dissolved in methanol (50 mL) and placed in a reaction flask. Concentrated hydrochloric acid (4.1 g, 40.6 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was refluxed for 4 hours. The temperature was lowered to 40 °C and 100 mL of methyl tert-butyl ether was added. After the addition was complete, the mixture was stirred at 5 °C for 2 hours. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether and dried to give 9.1 g of daclatasvir hydrochloride (compound B9), with a yield of 83.4% and an HPLC purity of 96.8%.

[0077] 1H NMR (600 MHz, DMSO-D6) δ 8.20-7.84 (m, 10H), 7.26 (d, J = 8.5 Hz, 2H), 5.13 (t, J = 7.1 Hz, 2H), 4.09 (t, J = 7.8 Hz, 2H), 3.86 (dq, J = 56.7,8.3 Hz, 4H), 3.50 (s, 6H), 2.39-1.95 (m, 10H), 0.77 (dd, J = 37.0, 6.7 Hz,12H).

[0078] Example 20:

[0079] Compound B8 (10 g, 13.5 mmol) was dissolved in methanol (50 mL) and placed in a reaction flask. Concentrated hydrochloric acid (4.1 g, 40.6 mmol) was added dropwise at room temperature. After the addition was complete, the temperature was raised to 50 °C and reacted for 4 hours. The temperature was then lowered to 40 °C and 100 mL of methyl tert-butyl ether was added. After the addition was complete, the temperature was maintained at 5 °C and stirred for 2 hours. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether and dried to obtain 9.3 g of daclatasvir hydrochloride (compound B9), with a yield of 85.2% and an HPLC purity of 98.3%.

[0080] 1H NMR (600 MHz, DMSO-D6) δ 8.20-7.84 (m, 10H), 7.26 (d, J = 8.5 Hz, 2H), 5.13 (t, J = 7.1 Hz, 2H), 4.09 (t, J = 7.8 Hz, 2H), 3.86 (dq, J = 56.7,8.3 Hz, 4H), 3.50 (s, 6H), 2.39-1.95 (m, 10H), 0.77 (dd, J = 37.0, 6.7 Hz,12H).

[0081] The following conclusions can be drawn from the above examples:

[0082] 1. In the synthesis of compound B3, multiple experiments have shown that 1,2-dichloroethane should be selected as the solvent and aluminum trichloride as the catalyst to ensure that the raw materials react fully. In addition, the temperature should be strictly controlled when adding reagents, and the reaction temperature should not be too high to reduce the generation of impurities, thereby improving the yield and purity.

[0083] 2. In the synthesis of compound B5, multiple experiments have shown that ammonium carbonate should be selected as the ammonia source and triethylamine as the base to reduce costs. Furthermore, the reaction temperature should not be too high to reduce the generation of impurities, thereby improving the yield and purity.

[0084] 3. In the synthesis of compound B6, multiple experiments have shown that concentrated hydrochloric acid should be used and the reaction temperature should not be too high in order to ensure that the reaction can proceed fully and thus improve the yield.

[0085] 4. In the synthesis of compound B8, multiple experiments have shown that oxalyl chloride is the preferred acyl chloride reagent. The amount of oxalyl chloride used must be strictly controlled (excessive amounts are not recommended), and low temperatures should be maintained during the dropwise addition to reduce impurities and improve yield and purity. Furthermore, from a cost-reduction perspective, triethylamine is recommended as the base used in the reaction.

[0086] 3. In the synthesis of compound B9 (daclatasvir hydrochloride), multiple experiments have shown that concentrated hydrochloric acid should be used and the reaction temperature should not be too high in order to ensure that the reaction can proceed fully and thus improve the yield.

[0087] This invention discloses a method for synthesizing daclatasvir hydrochloride. Starting with biphenyl, the method involves sequentially performing Friedel-Crafts acylation, condensation cyclization, amide hydrolysis, condensation, and salt formation to obtain the daclatasvir hydrochloride. This method offers low synthesis cost, simple post-processing, high yield, and industrial-scale production capability. It reduces the use of solvents and catalysts, minimizes reaction byproducts and pollution, aligns with the trend of green chemistry, and minimizes overall process costs, demonstrating significant application value.

[0088] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements without departing from the principle of the present invention, and these improvements are also considered to be within the scope of protection of the present invention.

Claims

1. A method for synthesizing daclatasvir hydrochloride, characterized in that... Includes the following steps: Step 1: Using biphenyl as the starting material, it undergoes a Friedel-Crafts reaction with chloroacetic anhydride under the catalysis of aluminum trichloride to generate 4,4'-bis(2-chloroacetyl)biphenyl; Step 2: 4,4'-bis(2-chloroacetyl)biphenyl undergoes a cyclization reaction with ammonium carbonate and N-BOC-L-proline to generate (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diylbis-1H-imidazol-5,2-diyl)bis-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester; Step 3: (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diylbis-1H-imidazol-5,2-diyl)bis-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester reacts with hydrochloric acid to generate 1H-imidazol, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride; Step 4: 1H-imidazolium, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride reacts with oxalyl chloride and MOC-L-valine in the presence of N,N-dimethylformamide to generate daclatasvir; Step 3: Daclatasvir reacts with hydrochloric acid to produce 1H-imidazol, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride; The reaction route is shown below: 。 2. The synthesis method according to claim 1, characterized in that: In step 1, chloroacetic anhydride is dissolved in 1,2-dichloroethane, and the system temperature is lowered to 0-5℃. Anhydrous aluminum trichloride is added slowly in batches, and the temperature is strictly controlled below 10℃ during this process. After the addition is complete, the mixture is stirred at this temperature for 15 minutes for later use. Biphenyl is added to 1,2-dichloroethane and stirred until it is fully dissolved. It is then added dropwise to the above reaction system at a controlled temperature of 5-10℃. After the addition is complete, the temperature is raised to 40-45℃ to react and obtain 4,4'-bis(2-chloroacetyl)biphenyl.

3. The synthesis method according to claim 2, characterized in that: In step 1, the molar ratio of biphenyl, chloroacetic anhydride, and aluminum trichloride is 1:2.1:

5.

4. The synthesis method according to claim 1, characterized in that: In step 2, 4,4'-bis(2-chloroacetyl)biphenyl and N-BOC-L-proline are dissolved in DMF, and triethylamine is slowly added dropwise at a controlled temperature of 0-5℃. After stirring at room temperature for 3 hours, ammonium carbonate is added, and the temperature is raised to 60℃ to react and obtain (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diylbis-1H-imidazol-5,2-diyl)bis-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester.

5. The synthesis method according to claim 4, characterized in that: In step 2, the molar ratio of 4,4'-bis(2-chloroacetyl)biphenyl, N-BOC-L-proline, triethylamine, and ammonium carbonate is 1:2.1:2.1:

10.

6. The synthesis method according to claim 1, characterized in that: In step 3, (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diylbis-1H-imidazolium-5,2-diyl)bis-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester was dissolved in methanol and stirred at room temperature for 1 hour. Concentrated hydrochloric acid was slowly added dropwise while maintaining the temperature constant. After the addition was complete, the temperature was raised to 50°C to react and obtain 1H-imidazolium, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride (1:4).

7. The synthesis method according to claim 6, characterized in that: In step 3, the molar ratio of (2S,2'S)-2,2'-([1,1'-biphenyl]-4,4'-diylbis-1H-imidazol-5,2-diyl)bis-1-pyrrolidinecarboxylic acid 1,1'-di-tert-butyl ester to HCl is 1:

10.

8. The synthesis method according to claim 1, characterized in that: In step 4, oxalyl chloride was dissolved in tetrahydrofuran, and DMF catalyst was added dropwise at 0°C. MOC-L-valine was added while maintaining the temperature. After the addition was complete, the temperature was raised to room temperature and stirred for 1 hour. Then, triethylamine was added dropwise at 0-5°C while maintaining the temperature and stirring for 30 minutes. The solution was then set aside. 1H-imidazolium, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride was dissolved in tetrahydrofuran and added dropwise to the above solution while maintaining the temperature at 0-5°C. After the addition was complete, the temperature was maintained and stirred for 2 hours. Then, the temperature was raised to room temperature to react and obtain daclatasvir.

9. The synthesis method according to claim 8, characterized in that: In step 4, the molar ratio of 1H-imidazolium, 5,5'-[1,1'-biphenyl]-4,4'-bis[2-(2S)-2-pyrrolidine hydrochloride (1:4), MOC-L-valine, oxalyl chloride, triethylamine, and DMF is 1:2:2:4.5:0.

2.

10. The synthesis method according to claim 1, characterized in that: In step 5, daclatasvir is dissolved in methanol, and concentrated hydrochloric acid is added dropwise at room temperature under controlled temperature. After the addition is complete, the temperature is raised to 50°C to react and obtain daclatasvir hydrochloride.

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