A method for the synthesis of adagrasyl by convergent approach

Abstract

The application provides a method for synthesizing adagrasyl by a convergent method. The adagrasyl is obtained through only five reaction steps from a starting material, and the route is shortened by nearly half the time compared with other patents. The application avoids the use of a high-cost palladium catalyst, and the cost of raw materials is greatly reduced. The route of the application has a huge cost advantage.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and relates to an anticancer targeted drug that precisely inhibits KRAS G12C mutations, and particularly to a highly efficient, mild, and green polymerization method for synthesizing adagracib. Background Technology

[0002] After reviewing relevant patents and literature, only a few methods for synthesizing adagaratesib were found so far: 1) Starting with benzylamine, the mixture first undergoes substitution with ethyl bromoethyl, then with methyl 4-bromobutyrate, followed by urea ring closure to obtain a pyrimidine compound. This compound is then chlorinated with phosphonotrichloroisocyanuric acid, followed by methoxy substitution of the chlorine at the 4-position with sodium methoxide, and then N-methylprolyl is attached at the 2-position via palladium-catalyzed coupling. Hydrogenation and debenzylation are then performed, followed by palladium-catalyzed coupling to 8-chloro-1-bromonaphthalene, followed by demethylation, and then trifluoromethanesulfonate via trifluoromethanesulfonic anhydride. This is followed by substitution with (S)-2-(piperazin-2-yl)acetonitrile hydrochloride, and finally condensation with 2-fluoroacrylic acid to obtain adagarate. This approach has high raw material costs and a lengthy 13-step route, making it unsuitable for commercial production. The route is shown below: .

[0003] 2) Similar to the previous route, this route uses benzylamine as the starting material, but the order of debenzylation and addition of (S)-2-(piperazin-2-yl)acetonitrile, N-methylprolyl, and 8-chloro-1-bromonaphthalene differs. This type of route is also a linear synthesis, but it is quite long, requiring up to 13 steps. It also uses palladium-catalyzed coupling twice, posing significant challenges to cost control and making it unsuitable for commercial production. The route is shown below: .

[0004] 3) Starting with 8-chloro-1-aminonaphthalene, the reaction proceeds first with methyl 4-bromobutyrate, then with 2-chloro-acetylmorpholine, followed by cyclization via LiHMDS, then cyclization with isopropylthiourea, oxidation with hydrogen peroxide, then substitution with N-methylprolyl, followed by substitution with (S)-2-(piperazin-2-yl)acetonitrile hydrochloride under the action of 2-nitrosulfonyl chloride, and finally condensation with 2-fluoroacrylic acid to obtain adagarate. This route involves a total of 8 steps, which is shorter than the previous two routes, but it is still a long-chain synthesis with a long production time, which is not conducive to industrialization. The route is shown below: . Summary of the Invention

[0005] To address the shortcomings of existing synthetic methods for adagrasibab, such as high cost, long routes, and unsuitability for commercial production, this invention provides a convergent synthesis method for adagrasibab. This invention yields adagrasibab in just five reaction steps from the starting materials, reducing the time by nearly half compared to other patented routes. It also avoids the drawback of known synthetic strategies that use palladium-catalyzed coupling, which makes large-scale production difficult.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a method for synthesizing adagogracib via a convergence method, the method comprising the following steps: 1) Dissolve the compound shown in formula 1 in a solvent, then add alkali and the compound shown in formula 2 and heat to react until the reaction is complete. Then add the compound shown in formula 4 and heat to react until the reaction is complete. The reaction solution is extracted, washed, dried and concentrated to obtain the intermediate compound shown in formula 5. The intermediate compound shown in formula 5 is added to LiHMDS solution and should be completely added. Then it is extracted, washed, concentrated and crystallized to obtain the intermediate compound shown in formula 6. 2) Dissolve the compound shown in formula 7 in a solvent, add chlorosulfonyl chloride, add water after the reaction is complete, extract and concentrate with solvent to obtain the intermediate compound shown in formula 8, add thiourea and solvent, heat to 80℃ and react, and after post-treatment, obtain the intermediate compound shown in formula 9. 3) The compound shown in intermediate formula 6 and the compound shown in intermediate formula 9 are mixed, alkali is added, solvent is added and the reaction is heated to complete. After extraction, washing, concentration and crystallization, the compound shown in intermediate formula 10 is obtained. 4) The compound shown in formula 11 was dissolved in a solvent and added to a mixed solution of EDC.HCl and sodium 2-fluoroacrylate. After the reaction was completed, water was added for extraction and layering. The organic phase was dried and concentrated to obtain the intermediate compound shown in formula 12. The intermediate compound shown in formula 12 was dissolved in an organic solvent and a solution of hydrogen chloride was added dropwise. After precipitation, the compound was filtered to obtain the intermediate compound shown in formula 13. 5) Dissolve the compound shown in intermediate formula 10 in an organic solvent, add a base and a condensing agent, then add the compound shown in intermediate formula 13. After the reaction is complete, extract, wash, dry and concentrate to obtain the compound shown in Adagorasibb formula 14. The compound shown in Formula 1: ; The compound shown in Formula 2: ; The compound shown in Formula 3: ; The compound shown in Formula 4: ; The compound shown in Formula 5: ; The compound shown in Formula 6: ; The compound shown in Formula 7: ; The compound shown in Formula 8: ; The compound shown in Formula 9: ; The compound shown in Formula 10: ; The compound shown in Formula 11: ; The compound shown in Formula 12: ; The compound shown in Formula 13: ; The compound shown in Formula 14: ; Wherein, R1 is methoxy, ethoxy, isopropoxy, benzyloxy, or morpholine, and R2 is methyl, ethyl, or benzyl.

[0007] In a preferred embodiment of the present invention, in step 1), the solvent used is toluene, and the base used is N,N-diisopropylethylamine or sodium bicarbonate.

[0008] In a preferred embodiment of the present invention, in step 2), the post-processing is concentration and recrystallization.

[0009] As a preferred embodiment of the present invention, the recrystallization is carried out by dissolving methanol at 60°C, cooling it to 0°C, and then filtering it.

[0010] In a preferred embodiment of the present invention, in step 2), the solvent is dichloromethane, 2-methyltetrahydrofuran, or dichloroethane.

[0011] In a preferred embodiment of the present invention, in step 3), the solvent is dichloromethane, 2-methyltetrahydrofuran, or dichloroethane.

[0012] As a preferred embodiment of the present invention, in step 3), the reaction temperature is first kept at 0-10℃ for a period of time, and then reacted at 40-50℃.

[0013] As a preferred embodiment of the present invention, in step 3), the base used is triethylamine or N,N-diisopropylethylamine.

[0014] As a preferred embodiment of the present invention, in step 3) and step 5), the condensation reagent is p-toluenesulfonic acid, p-toluenesulfonyl chloride, p-nitrobenzenesulfonic acid, o-nitrobenzenesulfonic acid, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, oxaloyl chloride or T4P.

[0015] As a preferred embodiment of the present invention, in step 5), the base used is N,N-diisopropylethylamine or sodium bicarbonate.

[0016] Compared with the prior art, the present invention has the following beneficial effects: 1) The process route of the present invention is different from the existing process routes. The present invention provides a highly efficient, mild and green, aggregated synthesis method for adagograsibu. Adagograsibu is obtained in only five steps from the starting raw materials. Compared with other patent routes, it is nearly shortened, making the process production more efficient.

[0017] 2) This invention avoids the use of high-cost palladium catalysts, resulting in a significant reduction in raw material costs. The cost advantage of this invention is substantial. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of this application 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 this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is the roadmap for the present invention.

[0020] Figure 2 This is the HPLC chromatogram of the compound shown in Formula 6 in Example 1.

[0021] Figure 3 This is the hydrogen spectrum of the compound shown in Formula 6 in Example 1.

[0022] Figure 4 This is the mass spectrum of the compound shown in Formula 6 in Example 1.

[0023] Figure 5 This is the mass spectrum of the compound shown in Formula 9 in Example 1.

[0024] Figure 6 This is the HPLC chromatogram of the compound shown in Formula 10 in Example 1.

[0025] Figure 7 This is the hydrogen spectrum of the compound shown in Formula 10 in Example 1.

[0026] Figure 8 This is the mass spectrum of the compound shown in Formula 10 in Example 1.

[0027] Figure 9 This is the mass spectrum of the compound shown in Formula 13 in Example 1.

[0028] Figure 10This is the HPLC chromatogram of the compound shown in Formula 14 in Example 1.

[0029] Figure 11 This is the hydrogen spectrum of the compound shown in Formula 14 in Example 1.

[0030] Figure 12 This is the mass spectrum of the compound shown in Formula 14 in Example 1.

[0031] Figure 13 This is the HPLC chromatogram of the compound shown in Formula 6 in Example 2.

[0032] Figure 14 This is the mass spectrum of the compound shown in Formula 6 in Example 2.

[0033] Figure 15 This is the HPLC chromatogram of the compound shown in Formula 10 in Example 2.

[0034] Figure 16 This is the HPLC chromatogram of the compound shown in Formula 14 in Example 2.

[0035] Figure 17 This is the HPLC chromatogram of the compound shown in Formula 6 in Example 3.

[0036] Figure 18 This is the HPLC chromatogram of the compound shown in Formula 10 in Example 3.

[0037] Figure 19 This is the HPLC chromatogram of the compound shown in Formula 14 in Example 3.

[0038] Figure 20 This is the HPLC chromatogram of the compound shown in Formula 6 in Example 4.

[0039] Figure 21 This is the mass spectrum of the compound shown in Formula 6 in Example 4.

[0040] Figure 22 This is the HPLC chromatogram of the compound shown in Formula 10 in Example 4.

[0041] Figure 23 This is the HPLC chromatogram of the compound shown in Formula 14 in Example 4.

[0042] Figure 24 This is the HPLC chromatogram of the compound shown in Formula 6 in Example 5.

[0043] Figure 25 This is the HPLC chromatogram of the compound shown in Formula 10 in Example 5.

[0044] Figure 26 This is the HPLC chromatogram of the compound shown in Formula 14 in Example 5. Detailed Implementation

[0045] To further understand the content of this invention, the invention will be described in detail with reference to the embodiments.

[0046] The present application will be further described in detail below with reference to embodiments. It is understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it. Furthermore, it should be noted that, for ease of description, only the parts relevant to the invention are shown in the accompanying drawings. The terms "first," "second," etc., used in this invention are for the convenience of describing the technical solutions of the invention and have no specific limiting effect; they are all general terms and do not constitute a limitation on the technical solutions of the invention. It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of this application can be combined with each other. Multiple technical solutions in the same embodiment, as well as multiple technical solutions in different embodiments, can be arranged and combined to form new technical solutions that do not contradict or conflict, all of which are within the scope of protection claimed by this invention.

[0047] See Figure 1 This invention provides a method for synthesizing adagogracib using a convergence method, the method comprising the following steps: 1) Dissolve the compound shown in formula 1 in a solvent, then add alkali and the compound shown in formula 2 and heat to react until the reaction is complete. Then add the compound shown in formula 4 and heat to react until the reaction is complete. The reaction solution is extracted, washed, dried and concentrated to obtain the intermediate compound shown in formula 5. The intermediate compound shown in formula 5 is added to LiHMDS solution and should be completely added. Then it is extracted, washed, concentrated and crystallized to obtain the intermediate compound shown in formula 6. 2) Dissolve the compound shown in formula 7 in a solvent, add chlorosulfonyl chloride, add water after the reaction is complete, extract and concentrate with solvent to obtain the intermediate compound shown in formula 8, add thiourea and solvent, heat to 80℃ and react, and after post-treatment, obtain the intermediate compound shown in formula 9. 3) The compound shown in intermediate formula 6 and the compound shown in intermediate formula 9 are mixed, alkali is added, solvent is added and the reaction is heated to complete. After extraction, washing, concentration and crystallization, the compound shown in intermediate formula 10 is obtained. 4) The compound shown in formula 11 was dissolved in a solvent and added to a mixed solution of EDC.HCl and sodium 2-fluoroacrylate. After the reaction was completed, water was added for extraction and layering. The organic phase was dried and concentrated to obtain the intermediate compound shown in formula 12. The intermediate compound shown in formula 12 was dissolved in an organic solvent and a solution of hydrogen chloride was added dropwise. After precipitation, the compound was filtered to obtain the intermediate compound shown in formula 13. 5) Dissolve the compound shown in intermediate formula 10 in an organic solvent, add a base and a condensation reagent, then add the compound shown in intermediate formula 13. After the reaction is complete, extract, wash, dry and concentrate to obtain the compound shown in Adagorasibb formula 14.

[0048] In this invention, all raw materials, reagents, or equipment used can be purchased from the market.

[0049] Raw material source: 1-Amino-8-chloronaphthalene: Shanghai Bide Pharmaceutical Technology Co., Ltd.

[0050] Ethyl bromoacetate: Aladdin.

[0051] Methyl bromoacetate: Aladdin.

[0052] Isopropyl bromoacetate: Aladdin.

[0053] Benzyl bromoacetate: Aladdin.

[0054] 2-Bromo-1-(4-morpholino)ethyl ketone: Shanghai Bide Pharmaceutical Technology Co., Ltd.

[0055] 4-Bromobutyrate ethyl ester: Aladdin.

[0056] 4-Bromobutyrate methyl ester: Aladdin.

[0057] 4-Bromobutyrate benzyl ester: Shanghai Bide Pharmaceutical Technology Co., Ltd.

[0058] N-Methyl-L-proline: Aladdin.

[0059] Chlorosulfonyl chloride: Aladdin.

[0060] Thiourea: Aladdin.

[0061] Raw material 11 ((S)-3-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester): Nanjing Yaoshi Technology Co., Ltd.

[0062] 4-Nitrobenzenesulfonyl chloride: Aladdin.

[0063] o-Nitrobenzenesulfonyl chloride: Titan.

[0064] Sodium 2-fluoroacrylate: Shandong Polar Pharmaceutical.

[0065] Example 1

[0066] See Figure 1 This embodiment provides a method for synthesizing adagograss (taking R1: OMe, R2: Me as an example), including: 1) Add 177 g of 1-amino-8-chloronaphthalene, 1770 mL of toluene, 387 g of N,N-diisopropylethylamine, and 167 g of methyl bromoacetate to a reaction flask. Heat to approximately 100°C and maintain this temperature for 18 hours. After cooling to room temperature, add 217 g of methyl 4-bromobutyrate. React at 100°C for 15 hours. Add the reaction solution to 1770 mL of water, allowing the layers to separate. Desolventize the organic phase to 5°C. In another reaction flask, add 1 M, 2 L of LiHMDS, cool to -10°C, and dropwise add the concentrated organic phase from the first step. After the addition is complete, react at -10°C for 2 hours. Add the solution to 2 L of 2 M hydrochloric acid, allowing the layers to separate. Concentrate the organic phase to dryness, add 1 L of methanol, and slurry. Filter to obtain 225 g of the intermediate compound of formula 6, yield 71%, HPLC purity: 99.9%. See [link to relevant documentation]. Figure 2 ; 1 H NMR (CDCl3) δ11.94(s,1H),7.72(dd,1H,J=8.2Hz,1.3Hz) , 7.57(dd,1H, J=8.2Hz,1.3Hz), 7.52(dd,1H, J=7.5Hz,1.3Hz), 7.42(m,1H), 7.32(dd,1H, J=8.2Hz,7.5Hz), 7.20(dd,1H, J=7.5Hz, 1.3Hz), 3.90 (dd, 1H, J=17.4Hz, 1.3Hz), 3.87 (s, 3H), 3.81 (s, 3H), 3.50 (dt, 1H, J=17.4Hz, 2.0Hz), 3.40 (m, 1H) 3.05 (m, 1H), 2.70 (m, 1H), 2.34 (m, 1H), see [reference] Figure 3 ESI + =318, 320, see also Figure 4 .

[0067] 2) Add 115 g of the starting compound (Formula 7) and 1000 mL of dichloromethane to a reaction flask. After dissolving, cool to 0°C, add 101 g of triethylamine, cool to 0°C, and add 67.5 g of chlorosulfonyl chloride dropwise. After reacting for 2 hours, remove the solvent, add 30 g of urea, then add 14.4 g of water and 25.5 g of concentrated sulfuric acid, keep warm for 2 hours, then add 115 g of water and 37 g of calcium hydroxide. After the solid precipitates, filter, then dissolve in 100 mL of methanol at 60°C. Cool to 0°C and filter to obtain the sulfate of the intermediate compound (Formula 9). Yield: 85.1%, ESI + =158, see also Figure 5 .

[0068] 3) Dissolve 159g of the intermediate compound (Formula 6) in 1590mL of 2-methyltetrahydrofuran, add 77.4g of N,N-diisopropylethylamine, cool to 0℃, then add 123g of the intermediate compound (Formula 9). After the addition is complete, stir at 0-10℃ for 5 hours. After the reaction is complete, add trifluoromethanesulfonic acid, heat to 50℃ and react for 3 hours. Add 1590mL of water, separate the layers, remove the organic phase to dryness, add 1590mL of acetonitrile and slurry, filter, and dry to obtain 191g of the intermediate compound (Formula 10), a yellow solid. Yield: 90%, HPLC purity: 99.9%. See [link to relevant documentation]. Figure 6 ; 1 H NMR (DMSO) δ 7.92 (dd, 1H, J=8.2Hz, 1.3Hz), 7.71 (dd, 1H, J=8.2Hz, 1.3Hz), 7.56 (dd, 1H, J=7.4Hz, 1.3Hz), 7.52(t, 1H, J=7.8Hz), 7.44(t, 1H, J=7.8Hz), 7.35(dt, 1H, J=7.6Hz, 1.2Hz), 4.19(t,2H,J=4.7Hz,2Hz), 3.88(d,1H,J=17.5Hz), 3.69(m,1H), 3.43(m,1H), 3.04(m,1H), 2.92(m,1H,), 2.68(m,1H), 2.53 (m, 1H), 2.43 (m, 1H), 2.30 (s, 3H), 2.17 (m, 1H), 1.89 (m, 1H), 1.64 (m, 3H), see [reference]. Figure 7 ESI + =425, 427, see also Figure 8 .

[0069] 4) Add 2240 mL of acetonitrile to a solution containing 224 g of sodium 2-fluoroacrylate, then add 7.4 g of DMF. After cooling to 0°C, add 117 g of methanesulfonyl chloride. After stirring for one hour, add dropwise a solution containing 225 g of the compound shown in Formula 11 in acetonitrile. After the addition is complete, maintain the temperature at 0°C for 2 hours. After the reaction is complete, add 20 wt% K3PO4 (2250 mL). Separate the layers. Extract the organic phase with 2250 mL of isopropyl acetate. Reduce the organic phase to 1125 mL, add dropwise an isopropyl hydrochloride solution, precipitate the solid, filter, and dry the filter cake to obtain 200 g of the intermediate compound shown in Formula 13. Yield: 85.7%. ESI + =198, see Figure 9 .

[0070] 5) Add 212 mL of N,N-dimethylacetamide to 42.5 g of the intermediate compound of formula 10, cool to 0°C, add 38.7 g of N,N-diisopropylethylamine, then add 26.5 g of 2-nitrobenzenesulfonyl chloride, heat to 20-30°C and stir for one hour, add 23.4 g of the intermediate compound of formula 13, add 636 mL of water dropwise, precipitate the solid, filter, and dry the filter cake to obtain 55.6 g of the compound of formula 14, adagarate. Yield: 92.1%, HPLC purity: 99.4%, see [reference missing]. Figure 10 ; 1 H NMR (DMSO) δ 7.91 (dd, 1H, J=8.2Hz, 1.3Hz), 7.74 (dt, 1H, J=7.4Hz, 1.1Hz), 7.57 (q, 1H, J=7.7Hz), 7.55 (m, 1H,) , 7.45(t,1H,J=7.8Hz), 7.36(m,1H), 5.40(dd,1H,J=18Hz,4.1Hz), 5.32(m,1H), 4.87(brs,1H), 4.22(m,1H), 4.18(m, H), 4.03(m,3H) ,3.75(m,1H) ,3.49(q,J=7.3Hz,1H) 3.24 (dd, 1H, J=13.7Hz, 3.7Hz), 3.10 (m, 3H), 2.94 (m, 2H), 2.70 (m, 1H), 2.32 (m, 3H), 2.16 (dq, 1H, J=8.7Hz, 2.2Hz), 1.92 (dq, 1H, J=12.1Hz, 8.2Hz), 1.66 (m, 2H), 1.57 (m, 1H), see also Figure 11 ESI + =604, see also Figure 12 .

[0071] Example 2

[0072] See Figure 1 This embodiment provides a method for synthesizing adagarate (taking R1: OEt, R2: Et as an example), including: 1) Add 177 g of 1-amino-8-chloronaphthalene, 1770 mL of toluene, and 387 g of N,N-diisopropylethylamine to a reaction flask, followed by 200 g of ethyl bromoethylamine. Heat to approximately 110 °C and maintain this temperature for 10 hours. After cooling to room temperature, add 234 g of ethyl 4-bromobutyrate and react at 110 °C for 8 hours. Add the reaction solution to 1770 mL of water, allowing for separation. Desolventize the organic phase to 5°C. In another reaction flask, add 1 M, 2 L of LiHMDS and cool to -10 °C. Add the concentrated organic phase from the first step dropwise. After the addition is complete, react at -10 °C for 2 hours. Add the solution to 2 L of 2 M hydrochloric acid, allowing for separation. Concentrate the organic phase to dryness, add 1 L of methanol, and slurry. Filter to obtain 238 g of the intermediate compound of formula 6, yield 72%. HPLC purity: 99.8%. See [link to relevant documentation]. Figure 13 ESI + =332, 334, see also Figure 14 .

[0073] 2) Add 115 g of the compound shown in Formula 7 to a reaction flask, along with 1000 mL of dichloromethane. After dissolving, cool to 0°C, add 129 g of N,N-diisopropylethylamine, cool to 0°C, and dropwise add 67.5 g of chlorosulfonyl chloride. After reacting for 2 hours, remove the solvent, add 30 g of urea, then 14.4 g of water and 25.5 g of concentrated sulfuric acid. Maintain the temperature for 2 hours, then add 115 g of water and 37 g of calcium hydroxide. After the solid precipitates, filter the solution and dissolve it in 100 mL of methanol heated to 60°C. Cool to 0°C and filter to obtain the sulfate of the intermediate compound shown in Formula 9. Yield: 85.1%, ESI + =158.

[0074] 3) Dissolve 166g of the intermediate compound (Formula 6) in 1660mL of dichloromethane, add 77.4g of triethylamine, cool to 0℃, then add 123g of the intermediate compound (Formula 9). After the addition is complete, maintain the temperature at 0-10℃ and stir for 5 hours. After the reaction is complete, add trifluoromethanesulfonic acid, heat to 40℃ and react for 16 hours. Add 1660mL of water, separate the layers, remove the organic phase to dryness, add 1660mL of acetonitrile and slurry, filter, and dry to obtain 193g of the intermediate compound (Formula 10), a yellow solid. Yield: 91%, HPLC purity: 99.5%. See [link to relevant documentation]. Figure 15 .

[0075] 4) Add 2240 mL of acetonitrile to a solution containing 224 g of sodium 2-fluoroacrylate, then add 7.4 g of DMF. After cooling to 0°C, add 285 g of p-toluenesulfonyl chloride. After stirring for one hour, add dropwise a solution containing 225 g of the compound shown in Formula 11 in acetonitrile. After the addition is complete, maintain the temperature at 0°C for 2 hours. After the reaction is complete, add 20 wt% K3PO4 (2250 mL). The mixture separates into layers. Extract the organic phase with 2250 mL of isopropyl acetate. After removing the organic phase to 1125 mL, add dropwise an isopropyl hydrochloride solution. After the solid precipitates, filter the mixture. Dry the filter cake to obtain 191 g of the intermediate compound shown in Formula 13. Yield: 81.7%.

[0076] 5) Add 212 mL of N,N-dimethylacetamide to 42.5 g of the intermediate compound of formula 10. After cooling to 0°C, add 38.7 g of N,N-diisopropylethylamine, followed by 26.5 g of 4-nitrobenzenesulfonyl chloride. Heat to 20-30°C and stir for one hour. Add 23.4 g of the intermediate compound of formula 13. React for 12 hours, add 636 mL of water dropwise, precipitate the solid, filter, and dry the filter cake to obtain 54.5 g of the compound of formula 14, adagaratesib. Yield: 90.3%, HPLC purity: 99.9%, see [link to relevant documentation]. Figure 16 .

[0077] Example 3

[0078] See Figure 1 This embodiment provides a method for synthesizing adagarate (taking R1: OIpr, R2: Me as an example), including: 1) Add 177 g of 1-amino-8-chloronaphthalene, 531 mL of toluene, 252 g of sodium bicarbonate, and 217 g of isopropyl bromoacetate to a reaction flask. Raise the internal temperature to approximately 110 °C and separate the water using a separator for 16 hours. Then add 217 g of methyl 4-bromobutyrate dropwise and continue separating the water at 110 °C for another 16 hours. Add the reaction solution to 1770 mL of water, allowing the layers to separate. Desolventize the organic phase to 5°C. In another reaction flask, add 1 M, 2 L of LiHMDS and cool to -10 °C. Add the concentrated organic phase from the first step dropwise. After the addition is complete, react at -10 °C for 2 hours. Add the solution to 2 L of 2 M hydrochloric acid, allowing the layers to separate. Concentrate the organic phase to dryness, add 1 L of methanol, and slurry. Filter to obtain 232 g of the intermediate compound shown in Formula 6, with a yield of 73%. HPLC purity: 99.2%. See [link to relevant documentation]. Figure 17 .

[0079] 2) Add 115 g of the compound shown in Formula 7 to a reaction flask, along with 1000 mL of dichloromethane. After dissolving, cool to 0°C, add 129 g of N,N-diisopropylethylamine, cool to 0°C, and add 67.5 g of chlorosulfonyl chloride dropwise. After reacting for 2 hours, remove the solvent, add 30 g of urea, then 14.4 g of water and 25.5 g of concentrated sulfuric acid, maintain the temperature for 2 hours, then add 115 g of water and 37 g of calcium hydroxide. After the solid precipitates, filter, and dissolve in 100 mL of methanol heated to 60°C. Cool to 0°C and filter to obtain the sulfate of the intermediate compound shown in Formula 9. Yield: 85.1%.

[0080] 3) Dissolve 1660 mL of 2-methyltetrahydrofuran in a reaction flask containing 159 g of the intermediate compound of formula 6. Add 77.4 g of triethylamine, cool to 0°C, and then add 123 g of the intermediate compound of formula 9. After the addition is complete, maintain the temperature at 0-10°C and stir for 5 hours. After the reaction is complete, add trifluoromethanesulfonic acid, heat to 40-50°C and react for 3 hours. Add 1660 mL of water, separate the layers, remove the organic phase to dryness, add 1660 mL of acetonitrile and slurry, filter, and dry to obtain 189 g of the intermediate compound of formula 10, a yellow solid. Yield: 88.9%, HPLC purity: 99.7%. See [link to relevant documentation]. Figure 18 .

[0081] 4) Add 2240 mL of acetonitrile to a solution containing 224 g of sodium 2-fluoroacrylate, then add 7.4 g of DMF. After cooling to 0°C, add 127 g of oxaloyl chloride. After stirring for one hour, add dropwise a solution containing 225 g of the compound shown in Formula 11 in acetonitrile. After the addition is complete, maintain the temperature at 0°C for 2 hours. After the reaction is complete, add 20 wt% K3PO4 (2250 mL). The mixture separates into layers. Extract the organic phase with 2250 mL of ethyl acetate. Reduce the organic phase to 1125 mL, add dropwise ethyl hydrochloride solution, and filter to precipitate the solid. Dry the filter cake to obtain 189 g of the intermediate compound shown in Formula 13. Yield: 81.0%.

[0082] 5) Add 212 mL of acetonitrile to 42.5 g of the intermediate compound of formula 10, cool to -20 °C, add 10.1 g of sodium bicarbonate, then add 33.8 g of trifluoromethanesulfonic anhydride, stir at -20 °C for one hour, then add 23.4 g of the intermediate compound of formula 13 and 10.1 g of sodium bicarbonate, raise the temperature to 20 °C and react for 4 hours, add 636 mL of water dropwise, precipitate the solid, filter, and dry the filter cake to obtain 51.5 g of the compound of formula 14, adagaratesib. Yield: 85.3%, HPLC purity: 99.5%, see [link to relevant documentation]. Figure 19 .

[0083] Example 4

[0084] See Figure 1 This embodiment provides a method for synthesizing adagarate (taking R1: OBn, R2: Bn as an example), including: 1) Add 177 g of 1-amino-8-chloronaphthalene, 531 mL of toluene, 252 g of sodium bicarbonate, and 275 g of benzyl bromoacetate to a reaction flask. Raise the internal temperature to approximately 110 °C and separate the solution using a water separator for 18 hours. Then add 309 g of benzyl 4-bromobutyrate dropwise and continue separating the solution at 110 °C for another 18 hours. Add the reaction solution to 1770 mL of water, allowing the layers to separate. Desolventize the organic phase to 5°C. In another reaction flask, add 1 M, 2 L of LiHMDS and cool to -10 °C. Add the concentrated organic phase from the first step dropwise. After the addition is complete, react at -10 °C for 2 hours. Add the solution to 2 L of 2 M hydrochloric acid, allowing the layers to separate. Concentrate the organic phase to dryness, add 1 L of methanol, and slurry. Filter to obtain 244 g of the intermediate compound of formula 6, yield 62%. HPLC purity: 99.1%, see [link to relevant documentation]. Figure 20 ESI + =394, 396, see Figure 21 .

[0085] 2) Add 115 g of the compound shown in Formula 7 to a reaction flask, along with 1000 mL of dichloromethane. After dissolving, cool to 0°C, add 129 g of N,N-diisopropylethylamine, cool to 0°C, and add 67.5 g of chlorosulfonyl chloride dropwise. After reacting for 2 hours, remove the solvent, add 30 g of urea, then 14.4 g of water and 25.5 g of concentrated sulfuric acid, maintain the temperature for 2 hours, then add 115 g of water and 37 g of calcium hydroxide. After the solid precipitates, filter, and dissolve in 100 mL of methanol heated to 60°C. Cool to 0°C and filter to obtain the sulfate of the intermediate compound shown in Formula 9. Yield: 85.1%.

[0086] 3) Dissolve 197g of the intermediate compound (Formula 6) in 1660mL of dichloroethane, add 77.4g of triethylamine, cool to 0℃, then add 123g of the intermediate compound (Formula 9). After the addition is complete, maintain the temperature at 0-10℃ and stir for 6 hours. After the reaction is complete, add trifluoromethanesulfonic acid, heat to 40-50℃ and react for 5 hours. Add 1660mL of water, separate the layers, remove the organic phase to dryness, add 1970mL of acetonitrile and slurry, filter, and dry to obtain 191g of the intermediate compound (Formula 10), a yellow solid. Yield: 90%, HPLC purity: 99.5%. See [link to relevant documentation]. Figure 22 .

[0087] 4) Add 2240 mL of acetonitrile to a solution containing 224 g of sodium 2-fluoroacrylate, then add 7.4 g of DMF. After cooling to 0°C, add 78 g of oxaloyl chloride. After stirring for one hour, add dropwise a solution containing 225 g of the compound shown in Formula 11 in acetonitrile. After the addition is complete, maintain the temperature at 0°C for 2 hours. After the reaction is complete, add 20 wt% K3PO4 (2250 mL). The mixture separates into layers. Extract the organic phase with 2250 mL of isopropyl acetate. The organic phase is reduced to 1125 mL, and a solution of isopropyl hydrochloride is added dropwise. After the solid precipitates, filter the mixture. Dry the filter cake to obtain 189 g of the intermediate compound shown in Formula 13. Yield: 81.0%.

[0088] 5) Add 212 mL of acetonitrile to 42.5 g of the intermediate compound of formula 10, cool to -20 °C, add 10.1 g of sodium bicarbonate, then add 28.5 g of p-toluenesulfonyl chloride, stir at -20 °C for one hour, heat to 20-30 °C and stir for one hour, add 23.4 g of the intermediate compound of formula 13, react for 12 hours, add 636 mL of water dropwise, filter after the solid precipitates, and dry the filter cake to obtain 42.6 g of the compound of formula 14, adagarate. Yield: 70.5%, HPLC purity: 99.5%, see [link to relevant documentation]. Figure 23 .

[0089] Example 5

[0090] See Figure 1 This embodiment provides a method for synthesizing adagogracib (taking R1: OMe, R2: morpholine as an example), including: 1) Add 177 g of 1-amino-8-chloronaphthalene, 531 mL of toluene, 252 g of sodium bicarbonate, and 196 g of 4-(2-chloroacetyl)morpholine to a reaction flask. Raise the internal temperature to approximately 110 °C and separate the solution using a water separator for 16 hours. Then add 217 g of methyl 4-bromobutyrate dropwise and continue separating the solution at 110 °C for another 16 hours. Add the reaction mixture to 1770 mL of water, allowing the layers to separate. Desolventize the organic phase to 5°C. In another reaction flask, add 1 M, 1.5 L of LiHMDS and cool to -10 °C. Add the concentrated organic phase from the first step dropwise. After the addition is complete, react at -10 °C for 2 hours. Add the mixture to 2 L of 2 M hydrochloric acid, allowing the layers to separate. Concentrate the organic phase to dryness and then add 1 L of methanol to slurry. Filter to obtain 223 g of the intermediate compound shown in Formula 6, with a yield of 70.1%. HPLC purity: 99.6%. See [link to relevant documentation]. Figure 24 .

[0091] 2) Add 115 g of the compound shown in Formula 7 to a reaction flask, along with 1000 mL of dichloromethane. After dissolving, cool to 0°C, add 129 g of N,N-diisopropylethylamine, cool to 0°C, and add 67.5 g of chlorosulfonyl chloride dropwise. After reacting for 2 hours, remove the solvent, add 30 g of urea, then 14.4 g of water and 25.5 g of concentrated sulfuric acid, maintain the temperature for 2 hours, then add 115 g of water and 37 g of calcium hydroxide. After the solid precipitates, filter, and dissolve in 100 mL of methanol heated to 60°C. Cool to 0°C and filter to obtain the sulfate of the intermediate compound shown in Formula 9. Yield: 85.1%.

[0092] 3) Dissolve 159g of 2-methyltetrahydrofuran in 1590mL of a reaction flask containing 159g of the intermediate compound of formula 6. Add 77.4g of triethylamine, cool to 0℃, and then add 123g of the intermediate compound of formula 9. After the addition is complete, maintain the temperature at 0-10℃ and stir for 4 hours. After the reaction is complete, add trifluoromethanesulfonic acid, heat to 40-50℃ and react for 5 hours. Add 1660mL of water, separate the layers, remove the organic phase to dryness, add 1590mL of acetonitrile and slurry, filter, and dry to obtain 198g of the intermediate compound of formula 10, a yellow solid. Yield: 93%, HPLC purity: 99.4%. See [link to relevant documentation]. Figure 25 .

[0093] 4) Add 2240 mL of acetonitrile to a solution containing 224 g of sodium 2-fluoroacrylate, then add 720 g of T4P. After stirring for 2 hours, add 225 g of the starting compound (Formula 11). After the addition is complete, maintain the temperature at 20 °C for 12 hours. After the reaction is complete, add 20 wt% K3PO4 (2250 mL). The mixture separates into layers. Extract the organic phase with 2250 mL of isopropyl acetate. After removing the organic phase to 1125 mL, add isopropyl hydrochloride solution dropwise. After the solid precipitates, filter the mixture. Dry the filter cake to obtain 182 g of the intermediate compound (Formula 13). Yield: 80.9%.

[0094] 5) Add 212 mL of acetonitrile to 42.5 g of the intermediate compound of formula 10, cool to -20 °C, add 10.1 g of sodium bicarbonate, then add 33.8 g of trifluoromethanesulfonic anhydride, stir at -20 °C for one hour, then add 23.4 g of the intermediate compound of formula 13 and 10.1 g of sodium bicarbonate, raise the temperature to 20 °C and react for 4 hours, add 636 mL of water dropwise, precipitate the solid, filter, and dry the filter cake to obtain 51.5 g of the compound of formula 14, adagaratesib. Yield: 85.3%, HPLC purity: 99.0%, see [link to relevant documentation]. Figure 26 .

[0095] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing adagarate via aggregation, characterized in that, The method includes the following steps: 1) Dissolve the compound shown in formula 1 in a solvent, then add alkali and the compound shown in formula 2 and heat to react until the reaction is complete. Then add the compound shown in formula 4 and heat to react until the reaction is complete. The reaction solution is extracted, washed, dried and concentrated to obtain the intermediate compound shown in formula 5. The intermediate compound shown in formula 5 is added to LiHMDS solution and should be completely added. Then it is extracted, washed, concentrated and crystallized to obtain the intermediate compound shown in formula 6. 2) Dissolve the compound shown in formula 7 in a solvent, add chlorosulfonyl chloride, add water after the reaction is complete, extract and concentrate with solvent to obtain the intermediate compound shown in formula 8, add thiourea and solvent, heat to 80℃ and react, and after post-treatment, obtain the intermediate compound shown in formula 9. 3) The compound shown in intermediate formula 6 and the compound shown in intermediate formula 9 are mixed, alkali is added, solvent is added and the reaction is heated to complete. After extraction, washing, concentration and crystallization, the compound shown in intermediate formula 10 is obtained. 4) The compound shown in formula 11 was dissolved in a solvent and added to a mixed solution of EDC.HCl and sodium 2-fluoroacrylate. After the reaction was completed, water was added for extraction and layering. The organic phase was dried and concentrated to obtain the intermediate compound shown in formula 12. The intermediate compound shown in formula 12 was dissolved in an organic solvent and a solution of hydrogen chloride was added dropwise. After precipitation, the compound was filtered to obtain the intermediate compound shown in formula 13. 5) Dissolve the compound shown in intermediate formula 10 in an organic solvent, add a base and a condensing agent, then add the compound shown in intermediate formula 13. After the reaction is complete, extract, wash, dry and concentrate to obtain the compound shown in Adagorasibb formula 14. The compound shown in Formula 1: ; The compound shown in Formula 2: ; The compound shown in Formula 3: ; The compound shown in Formula 4: ; The compound shown in Formula 5: ; The compound shown in Formula 6: ; The compound shown in Formula 7: ; The compound shown in Formula 8: ; The compound shown in Formula 9: ; The compound shown in Formula 10: ; The compound shown in Formula 11: ; The compound shown in Formula 12: ; The compound shown in Formula 13: ; The compound shown in Formula 14: ; Wherein, R1 is methoxy, ethoxy, isopropoxy, benzyloxy, or morpholine, and R2 is methyl, ethyl, or benzyl.

2. The method for synthesizing adagarate via aggregation according to claim 1, characterized in that, In step 1), the solvent used is toluene, and the base used is N,N-diisopropylethylamine or sodium bicarbonate.

3. The method for synthesizing adagarate via aggregation according to claim 1, characterized in that, In step 2), the post-processing involves concentration and recrystallization.

4. The method for synthesizing adagarate via aggregation according to claim 3, characterized in that, The recrystallization process involves dissolving the substance in methanol at 60°C, cooling it to 0°C, and then filtering it.

5. The method for synthesizing adagarate via aggregation according to claim 1, characterized in that, In step 2), the solvent is dichloromethane, 2-methyltetrahydrofuran, or dichloroethane.

6. The method for synthesizing adagarate via aggregation according to claim 1, characterized in that, In step 3), the solvent is dichloromethane, 2-methyltetrahydrofuran, or dichloroethane.

7. The method for synthesizing adagarate via aggregation according to claim 1, characterized in that, In step 3), the reaction temperature is first kept at 0-10℃ for a period of time, and then reacted at 40-50℃.

8. The method for synthesizing adagarate via aggregation according to claim 1, characterized in that, In step 3), the base used is triethylamine or N,N-diisopropylethylamine.

9. The method for synthesizing adagarate via aggregation according to claim 1, characterized in that, In step 3) and step 5), the condensation reagent is p-toluenesulfonic acid, p-toluenesulfonyl chloride, p-nitrobenzenesulfonic acid, o-nitrobenzenesulfonic acid, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, oxaloyl chloride, or T4P.

10. The method for synthesizing adagarate via aggregation according to claim 1, characterized in that, In step 5), the base used is N,N-diisopropylethylamine or sodium bicarbonate.

Images