A process for the synthesis of 3-hydroxy-7-fluoro-1-naphthol, synthesis intermediates and uses thereof

Abstract

This invention relates to a method for synthesizing 3-hydroxy-7-fluoro-1-naphthol, comprising: protecting the hydroxyl group of methyl 4-hydroxy-6-fluoro-2-naphthyl carboxylate with a benzyl group; then hydrolyzing the ester group of the product to a carboxyl group to obtain a hydrolysate; mixing the hydrolysate, diphenyl azidophosphate, triethylamine, and toluene, heating for a predetermined time, adding hydrochloric acid, and continuing heating to perform rearrangement to obtain a rearranged product; dissolving the rearranged product in dilute sulfuric acid, adding an aqueous sodium nitrite solution to perform a diazotization reaction, and then heating the reaction product to perform diazotization hydroxylation; after the reaction is complete, 3-hydroxy-7-fluoro-1-naphthol is obtained. The synthesis method provided in this application achieves high yield and low cost through the selection of raw materials and routes; the provided intermediates are stable and can be sold as finished products, lowering the preparation threshold for the synthesis of 3-hydroxy-7-fluoro-1-naphthol and the synthesis of G12D inhibitors.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis, specifically relating to a method for synthesizing 3-hydroxy-7-fluoro-1-naphthol, the synthetic intermediate, and its uses. Background Technology

[0002] The RAS gene is an oncogene, mainly comprising three subtypes: HRAS, NRAS, and KRAS. KRAS gene mutations account for over 85% of all RAS gene mutations and are a common mutated gene in various human cancers. Among KRAS gene mutations, G12 mutations are predominant, and within G12 mutations, G12D mutations account for a relatively high proportion.

[0003] Regarding inhibitors for G12D gene mutations, existing technology reports include Amgen's disclosure of a class of pyridopyrimidine compounds as G12D inhibitors, and Taiho's disclosure of a class of G12D inhibitors containing a pyrimidine ring, but the activity of these inhibitors needs further improvement.

[0004] Existing technologies also disclose polysubstituted pyrimidine aryl ring derivatives (CN116102559) or bicyclic heteroaryl compounds (CN116253748A) as G12D inhibitors, which have higher activity than the aforementioned technologies, but the raw material price is high, resulting in higher costs.

[0005] There is a need in this field to develop an intermediate for preparing the above-mentioned compounds, in order to provide a new synthetic approach and explore the possibility of reducing costs. Summary of the Invention

[0006] To address the shortcomings of existing technologies, one objective of this invention is to provide a method for synthesizing 3-hydroxy-7-fluoro-1-naphthol, the method comprising the following steps:

[0007] (1) Protect the hydroxyl group of methyl 4-hydroxy-6-fluoro-2-naphthoic acid by benzyl group to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid;

[0008] (2) The ester group of methyl 4-benzyloxy-6-fluoro-2-naphthoic acid was hydrolyzed to a carboxyl group to obtain the hydrolysis product 4-benzyloxy-6-fluoro-2-naphthoic acid;

[0009] (3) The hydrolysis products 4-benzyloxy-6-fluoro-2-naphthoic acid, diphenyl azidophosphate, triethylamine and toluene were mixed, heated for a predetermined time, hydrochloric acid was added and heated continuously to carry out the rearrangement. After the reaction was completed, the reaction solution was post-treated to obtain the rearranged product 3-amino-7-fluoro-1-naphthol.

[0010] (4) The rearranged product 3-amino-7-fluoro-1-naphthol was dissolved in dilute sulfuric acid, and sodium nitrite aqueous solution was added to carry out a diazotization reaction. Then the reaction product was heated to carry out diazotization hydroxylation. After the reaction was completed, 3-hydroxy-7-fluoro-1-naphthol was obtained after post-treatment.

[0011] The synthetic route for the intermediate 3-hydroxy-7-fluoro-1-naphthol provided in this application can be illustrated as follows:

[0012]

[0013] In the aforementioned synthesis method, methyl 4-hydroxy-6-fluoro-2-naphthylcarboxylate can be obtained commercially or through existing technology. The synthetic route for the intermediate 3-hydroxy-7-fluoro-1-naphthol provided in this application offers a new synthetic approach for the synthesis of G12D inhibitors, and it is expected that the selection of raw materials and routes will result in high yield and low cost.

[0014] Preferably, the benzyl protection step in step (1) includes dissolving the methyl 4-hydroxy-6-fluoro-2-naphthoic acid in N,N-dimethylformamide, adding triethylamine, potassium carbonate and benzyl bromide, heating to 110-130°C and reacting for more than 8 hours. After the reaction is completed, the reaction solution is post-treated to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0015] Preferably, in the benzyl protection process, the mass ratio of benzyl bromide to methyl 4-hydroxy-6-fluoro-2-naphthoate is 1.65:1 to 1.75:1; the mass ratio of triethylamine to methyl 4-hydroxy-6-fluoro-2-naphthoate is 1.15:1 to 1.25:1; the mass ratio of potassium carbonate to methyl 4-hydroxy-6-fluoro-2-naphthoate is 1.2:1 to 1.3:1; and the mass-volume ratio of methyl 4-hydroxy-6-fluoro-2-naphthoate to N,N-dimethylformamide is 4.3 to 4.5 g of methyl 4-hydroxy-6-fluoro-2-naphthoate per 100 mL of N,N-dimethylformamide.

[0016] Preferably, the post-treatment includes terminating the reaction by introducing the reaction solution into ice water, extracting with ethyl acetate, washing the organic phase with water and hydrochloric acid, and drying the organic phase to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0017] Preferably, step (2) of hydrolyzing the ester group into a carboxyl group includes dissolving the methyl 4-benzyloxy-6-fluoro-2-naphthoic acid in methanol, adding an alkaline solution, heating to about 65°C and reacting for more than 6 hours. After the reaction is completed, the reaction solution is post-treated to obtain 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0018] Preferably, the alkali comprises sodium hydroxide and potassium hydroxide, and the mass-to-volume ratio of the alkali solution is 8.5 to 10.0 mg / mL, for example, 8.2 mg / mL, 8.5 mg / mL, 8.8 mg / mL, 9.4 mg / mL, 9.9 mg / mL, etc.

[0019] Preferably, the mass-to-volume ratio of the methyl 4-benzyloxy-6-fluoro-2-naphthoic acid ester dissolved in methanol is 65-68 mg / mL, for example, 66 mg / mL, 67 mg / mL, etc.

[0020] Preferably, the mass ratio of methyl 4-benzyloxy-6-fluoro-2-naphthoic acid to the base is 7:1 to 8:1, for example, 7.2:1, 7.5:1, 7.9:1, etc.

[0021] Preferably, the post-treatment in step (2) includes concentrating the reaction solution, adding water to replenish the solution volume, washing with toluene, adjusting the pH value to 5-6, extracting with dichloromethane, and drying the organic phase to obtain 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0022] Preferably, hydrochloric acid is used to adjust the pH value.

[0023] Preferably, the mass ratio of 4-benzyloxy-6-fluoro-2-naphthoic acid, diphenyl azidophosphate, and triethylamine in step (3) is 1:(0.9-1.1):(0.5-0.6).

[0024] Preferably, the mass-to-volume ratio of 4-benzyloxy-6-fluoro-2-naphthoic acid to toluene is 0.3–0.35 g of 4-benzyloxy-6-fluoro-2-naphthoic acid per 100 mL of toluene.

[0025] Preferably, step (3) includes the following specific steps:

[0026] The hydrolysis products 4-benzyloxy-6-fluoro-2-naphthoic acid, diphenyl azidophosphate, triethylamine and toluene were mixed and heated to about 110°C for 7-8 hours. Then hydrochloric acid was added and the mixture was heated continuously to maintain the temperature at about 100°C for 16 hours for rearrangement. After the reaction was completed, the reaction solution was post-treated to obtain the rearranged product 3-amino-7-fluoro-1-naphthol.

[0027] Preferably, the post-treatment includes water extraction, adjusting the pH to 7-8, extraction with ethyl acetate, and concentration of the organic phase to obtain the rearranged product 3-amino-7-fluoro-1-naphthol.

[0028] Preferably, the temperature of the diazotization reaction in step (4) is 0-5°C and the reaction time is 30-40 min.

[0029] Preferably, in the diazotization reaction described in step (4), the molar ratio of 3-amino-7-fluoro-1-naphthol to sodium nitrite is 1:1.04 to 1:1.06, and the concentration of the sodium nitrite aqueous solution is 30 to 32 wt%.

[0030] Preferably, the reaction temperature for hydroxylation of the diazo group in step (4) is 70-80°C, and the reaction time is 2-2.3 h.

[0031] Preferably, the post-treatment in step (4) includes extraction with toluene, decolorization of the organic phase with activated carbon, concentration, and fine reduction to obtain 3-hydroxy-7-naphthol.

[0032] Preferably, the methyl 4-hydroxy-6-fluoro-2-naphthoic acid ester described in step (1) is prepared by the following method:

[0033] (1a) In a tetrahydrofuran solution containing potassium tert-butoxide, a tetrahydrofuran solution of p-fluorobenzaldehyde and dimethyl succinate was added dropwise to carry out the condensation of dimethyl succinate with the carbonyl group of the aldehyde. After the reaction was completed, the reaction solution was post-treated to obtain the carbonyl ester condensation product.

[0034] (1b) After mixing the carbonyl ester condensation product and acetic anhydride, anhydrous sodium acetate was added and heated to carry out the acetic acid cyclization reaction. After the reaction was completed, the reaction solution was post-treated to obtain the acetic acid cyclization product methyl 4-acetoxy-6-fluoro-2-naphthoic acid.

[0035] (1c) A methanol aqueous solution of methyl 4-acetoxy-6-fluoro-2-naphthoic acid, the cyclization product of acetic acid, was mixed with sodium bicarbonate, heated to carry out hydrolysis, and filtered to obtain methyl 4-hydroxy-6-fluoro-2-naphthoic acid.

[0036] Preferably, in the tetrahydrofuran solution of p-fluorobenzaldehyde and dimethyl succinate described in step (1a), the mass ratio of p-fluorobenzaldehyde to dimethyl succinate is 1:1.6 to 1:1.7.

[0037] In the tetrahydrofuran solution of p-fluorobenzaldehyde and dimethyl succinate described in this application, the ratio of the added mass of tetrahydrofuran to the sum of the masses of p-fluorobenzaldehyde and dimethyl succinate is 1:0.95:1.05.

[0038] Preferably, the mass ratio of p-fluorobenzaldehyde and potassium tert-butoxide in step (1a) is 1:1.01 to 1:1.10;

[0039] Preferably, the temperature at which the dropping is performed in step (1a) is 25–30°C;

[0040] Preferably, the condensation temperature of dimethyl succinate and aldehyde carbonyl group in step (1a) is 35-45°C, and the reaction time is 2-3 hours.

[0041] Preferably, the post-treatment in step (1a) includes terminating the reaction by pouring the reaction solution into ice water, then washing with toluene, adjusting the pH to 3-4, extracting with dichloromethane, and drying the organic phase to obtain the carbonyl ester condensation product.

[0042] Preferably, the mass ratio of the carbonyl ester condensation product to acetic anhydride in step (1b) is 1:4.5 to 1:4.6, and the mass ratio of the carbonyl ester condensation product to anhydrous sodium acetate is 2.4:1 to 2.5:1.

[0043] Preferably, the acetic acid ring-closure reaction in step (1b) is carried out at a temperature of about 120°C for 4 to 4.5 hours.

[0044] Preferably, the post-processing in step (1b) includes concentrating the reaction solution, dissolving it in ethyl acetate, washing it with water and / or an aqueous sodium bicarbonate solution, drying the organic phase, filtering, and concentrating it to obtain the acetic acid cyclization product.

[0045] Preferably, the mass ratio of methyl 4-acetoxy-6-fluoro-2-naphthoic acid ester to sodium bicarbonate in step (1c) is 2.0:1 to 2.2:1.

[0046] Preferably, the methanol aqueous solution of methyl 4-acetoxy-6-fluoro-2-naphthoic acid ester in step (1c) has a mass-volume concentration of 6-8%.

[0047] Preferably, the volume ratio of methanol to water in step (1c) is 0.9 to 1.1:1.

[0048] Preferably, the hydrolysis temperature in step (1c) is about 65°C, and the hydrolysis reaction time is 6 to 8 hours.

[0049] The second objective of this application is to provide a synthetic intermediate for 3-hydroxy-7-fluoro-1-naphthol, the synthetic intermediate having the following structure:

[0050]

[0051] The intermediate described in this application addresses performance issues, enables mass production, shortens the synthetic route of 3-hydroxy-7-fluoro-1-naphthol, and reduces the synthetic difficulty of G12D inhibitors.

[0052] The third objective of this application is to provide the use of the synthesis method described in the first objective, or the use of 3-hydroxy-7-fluoro-1-naphthol as described in the second objective, wherein the synthesis method described in the first objective, or the 3-hydroxy-7-fluoro-1-naphthol as described in the second objective, is used to prepare a target drug against KRAS subtype gene mutations.

[0053] Compared with the prior art, this application has the following beneficial effects:

[0054] (1) This application provides a new synthetic method for 3-hydroxy-7-fluoro-1-naphthol, which achieves high yield and low cost through the selection of raw materials and routes;

[0055] (2) The intermediate provided in this application has stable properties and can be sold as a finished product, which lowers the preparation threshold for the synthesis of 3-hydroxy-7-fluoro-1-naphthol and the synthesis of G12D inhibitors. Attached Figure Description

[0056] Figure 1 The mass spectrum of the product of step (3) in Example 1 is given;

[0057] Figure 2 The NMR spectrum of the product of step (3) in Example 1 is given;

[0058] Figure 3 The mass spectrum of the product of step (5) in Example 1 is given;

[0059] Figure 4 The mass spectrum of the product from step (6) of Example 1 is given.

[0060] Figure 5 The mass spectrum of the product 3-hydroxy-7-fluoro-1-naphthol from step (7) of Example 1 is given;

[0061] Figure 6 The NMR spectrum of the product 3-hydroxy-7-fluoro-1-naphthol from step (7) of Example 1 is given. Detailed Implementation

[0062] The technical solution of the present invention will be further explained and described below with reference to specific embodiments. However, it should be noted that the specific embodiments are only a specific implementation and explanation of the essence of the technical solution of the present invention, and should not be construed as a limitation on the scope of protection of the present invention.

[0063] The reagents and instruments used in the examples are all commercially available, and the detection methods are conventional methods well known in the art.

[0064] Example 1

[0065] A method for synthesizing 3-hydroxy-7-fluoro-1-naphthol, comprising the following steps:

[0066] (1) Add potassium tert-butoxide (13.46 g) and tetrahydrofuran (500 mL) to a 1000 mL three-necked flask. Add a mixed solution of p-fluorobenzaldehyde (12.4 g) and dimethyl succinate (20.45 g) diluted with tetrahydrofuran at 25-30 °C. React at 40 °C for 3 h. Pour the reaction solution into 200 mL of ice water. Wash twice with toluene (100 mL × 2). Adjust the pH of the aqueous phase to 3-4 with 1 N hydrochloric acid. Extract twice with dichloromethane (200 mL × 2). Dry the organic phase with anhydrous sodium sulfate (20 g). After filtration, concentrate the filtrate to obtain the carbonyl ester condensation product.

[0067] (2) Add carbonyl ester condensation product (22.01g) and acetic anhydride (100g) to a 500mL single-necked flask, stir well, add anhydrous sodium acetate (9g), heat to about 120℃ and react for 4h. After the reaction solution is concentrated, add ethyl acetate (300mL) to dissolve, add water (200mL×2) to wash twice, add saturated sodium bicarbonate aqueous solution (200mL×2) to wash twice, add anhydrous sodium sulfate (20g) to dry the organic phase, filter, and concentrate the filtrate to obtain methyl 4-acetoxy-6-fluoro-2-naphthoic acid;

[0068] (3) Add methyl 4-acetoxy-6-fluoro-2-naphthoic acid (21.07 g) to a 500 mL single-necked flask, dissolve in 150 mL of methanol, add water (150 mL) and sodium bicarbonate (10 g), heat to about 65 °C for 7 h, cool to 5-10 °C and filter to obtain methyl 4-hydroxy-6-fluoro-2-naphthoic acid;

[0069] Figure 1 The mass spectrum of the product from step (3) is given. Figure 1 It can be seen that ESI-API m / z: 219.1 [M-1] - ;

[0070] Figure 2 The NMR spectrum of the product from step (3) is given. Figure 2 The NMR results are as follows: 1 H NMR (400MHz, DMSO-d6), δ10.67(s,1H), 8.12-8.09(m,2H), 7.75-7.72(d,1H), 7.47-7.43(m,1H), 7.37(s,1H), 3.84(s,3H).

[0071] (4) Add methyl 4-hydroxy-6-fluoro-2-naphthoic acid (2.20 g) and DMF (50 mL) to a 100 mL three-necked flask and stir until dissolved. Add triethylamine (2.62 g), potassium carbonate (2.76 g), and benzyl bromide injection (3.76 g). Heat to 120 °C and react. After the reaction is complete, pour the reaction solution into ice water (200 mL), add ethyl acetate (200 mL) for extraction, wash the organic phase twice with water (200 mL × 2), wash once with 0.5 N hydrochloric acid (200 mL), and wash once with water (200 mL). Dry and concentrate the organic phase to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0072] (5) Add methyl 4-benzyloxy-6-fluoro-2-naphthoic acid (3.3g) to a 250mL three-necked flask, dissolve it in methanol (50mL) by heating, add sodium hydroxide (0.44g) and water (50mL), heat to about 65℃ and react for 6h. After the reaction is completed, concentrate the reaction solution, add water (50mL) to make up the solution volume, add toluene (50mL) to wash once, add 1N hydrochloric acid to the aqueous phase to adjust the pH to 5-6, add dichloromethane to extract 2-3 times, add anhydrous sodium sulfate to the organic phase to dry, filter and concentrate the filtrate to obtain 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0073] Figure 3 The mass spectrum of the product from step (5) is given. Figure 3 It can be seen that ESI-API m / z: 295.0 [M-1] - ;

[0074] (6) Add 4-benzyloxy-6-fluoro-2-naphtholic acid (0.1 g), toluene (30 mL), DPPA (0.096 g), and triethylamine (0.058 g) to a 100 mL three-necked flask, heat to 110 °C, add 6N hydrochloric acid (0.69 g) after 8 h, and continue heating to about 100 °C for 16 h. After the reaction is completed, add purified water (10 mL × 2) to the reaction solution and extract twice. Add 1N sodium hydroxide to the aqueous phase to adjust the pH to 7-8, add ethyl acetate (10 mL × 2) and extract twice. Concentrate the organic phase to obtain 3-amino-7-fluoro-1-naphthol.

[0075] Figure 4 The mass spectrum of the product from step (6) is given. Figure 4 It can be seen that ESI-API m / z: 178.1 [M-1] - ;

[0076] (7) 3-amino-7-fluoro-1-naphthol was dissolved in 10% dilute sulfuric acid, and 1.05N sodium nitrite aqueous solution (concentration 30%) was added dropwise at 0 to 5℃. After reacting for 30 min, the mixture was heated to 70℃ until the reaction was completed. Toluene was added for extraction, the mixture was separated, the organic phase was decolorized with activated carbon, concentrated, and crystallized to obtain the final product 3-hydroxy-7-fluoro-1-naphthol. The molar yield was calculated to be 24.1%.

[0077] Figure 5 The mass spectrum of the product 3-hydroxy-7-fluoro-1-naphthol from step (7) is given. Figure 5 It can be seen that ESI-API m / z: 177.1 [M-1] - ;

[0078] Figure 6 The NMR spectrum of the product 3-hydroxy-7-fluoro-1-naphthol from step (7) is given. Figure 6 The NMR results are as follows: 1 HNMR (400MHz, DMSO-d6), δ10.23(s,1H), 9.53(s,1H), 7.67-7.57(m,2H), 7.26(t,1H), 6.66(s,1H), 6.58(s,1H).

[0079] Example 2

[0080] A method for synthesizing 3-hydroxy-7-fluoro-1-naphthol, comprising the following steps:

[0081] (1) Add potassium tert-butoxide (13.05 g) and tetrahydrofuran (500 mL) to a 1000 mL three-necked flask. Add a mixed solution of p-fluorobenzaldehyde (12.9 g) and dimethyl succinate (20.64 g) diluted with tetrahydrofuran at 25-30 °C. React at 35 °C for 3 h. Pour the reaction solution into 200 mL of ice water. Wash twice with toluene (100 mL × 2). Adjust the pH of the aqueous phase to 3-4 with 1 N hydrochloric acid. Extract twice with dichloromethane (200 mL × 2). Dry the organic phase with anhydrous sodium sulfate (20 g). After filtration, concentrate the filtrate to obtain the carbonyl ester condensation product.

[0082] (2) Add carbonyl ester condensation product (22.2g) and acetic anhydride (100g) to a 500mL single-necked flask, stir well, add anhydrous sodium acetate (9.05g), heat to about 120℃ and react for 4h. After the reaction solution is concentrated, add ethyl acetate (300mL) to dissolve, add water (200mL×2) to wash twice, add saturated sodium bicarbonate aqueous solution (200mL×2) to wash twice, add anhydrous sodium sulfate (20g) to dry the organic phase, filter, and concentrate the filtrate to obtain methyl 4-acetoxy-6-fluoro-2-naphthoic acid;

[0083] (3) Add methyl 4-acetoxy-6-fluoro-2-naphthoic acid (21.96 g) to a 500 mL single-necked flask, dissolve in 150 mL of methanol, add water (150 mL) and sodium bicarbonate (10.51 g), heat to about 65 °C for 7 h, cool to 5-10 °C and filter to obtain methyl 4-hydroxy-6-fluoro-2-naphthoic acid;

[0084] (4) Add methyl 4-hydroxy-6-fluoro-2-naphthoic acid (2.50 g) and DMF (50 mL) to a 100 mL three-necked flask and stir until dissolved. Add triethylamine (3.13 g), potassium carbonate (3.25 g), and benzyl bromide injection (4.38 g). Heat to 125 °C and react. After the reaction is complete, pour the reaction solution into ice water (200 mL), add ethyl acetate (200 mL) for extraction, wash the organic phase twice with water (200 mL × 2), wash once with 0.5 N hydrochloric acid (200 mL), and wash once with water (200 mL). Dry and concentrate the organic phase to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0085] (5) Add methyl 4-benzyloxy-6-fluoro-2-naphthoic acid (3.2 g) to a 250 mL three-necked flask, dissolve in methanol (48 mL) by heating, add sodium hydroxide (0.44 g) and water (50 mL), heat to about 65 °C and react for 6 h. After the reaction is complete, concentrate the reaction solution, add water (50 mL) to replenish the solution volume, add toluene (50 mL) to wash once, add 1 N hydrochloric acid to the aqueous phase to adjust the pH to 5-6, add dichloromethane to extract 2-3 times, add anhydrous sodium sulfate to the organic phase to dry, filter and concentrate the filtrate to obtain 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0086] (6) Add 4-benzyloxy-6-fluoro-2-naphtholic acid (0.1 g), toluene (30 mL), DPPA (0.091 g), and triethylamine (0.051 g) to a 100 mL three-necked flask, heat to 110 °C, add 6N hydrochloric acid (0.69 g) after 8 h, and continue heating to about 100 °C for 16 h. After the reaction is completed, add purified water (10 mL × 2) to the reaction solution and extract twice. Add 1N sodium hydroxide to the aqueous phase to adjust the pH to 7-8, add ethyl acetate (10 mL × 2) and extract twice. Concentrate the organic phase to obtain 3-amino-7-fluoro-1-naphthol.

[0087] (7) 3-amino-7-fluoro-1-naphthol was dissolved in 10% dilute sulfuric acid, and 1.04N sodium nitrite aqueous solution (concentration 30%) was added dropwise at 0 to 5°C. After reacting for 30 min, the mixture was heated to 70°C until the reaction was complete. Toluene was added for extraction, the mixture was separated, the organic phase was decolorized with activated carbon, concentrated, and crystallized. The final product 3-hydroxy-7-fluoro-1-naphthol was determined by NMR and mass spectrometry, and the molar yield was calculated to be 23.4%.

[0088] Example 3

[0089] A method for synthesizing 3-hydroxy-7-fluoro-1-naphthol, comprising the following steps:

[0090] (1) Add potassium tert-butoxide (13.97 g) and tetrahydrofuran (500 mL) to a 1000 mL three-necked flask. Add a mixed solution of p-fluorobenzaldehyde (12.7 g) and dimethyl succinate (21.58 g) diluted with tetrahydrofuran dropwise at 25-30 °C. React at 45 °C for 2 h. Pour the reaction solution into 200 mL of ice water and wash twice with toluene (100 mL × 2). Adjust the pH of the aqueous phase to 3-4 with 1 N hydrochloric acid. Extract twice with dichloromethane (200 mL × 2). Dry the organic phase with anhydrous sodium sulfate (20 g). After filtration, concentrate the filtrate to obtain the carbonyl ester condensation product.

[0091] (2) Add carbonyl ester condensation product (22.16 g) and acetic anhydride (100 g) to a 500 mL single-necked flask, stir well, add anhydrous sodium acetate (8.87 g), heat to about 120 °C and react for 4 h. After the reaction solution is concentrated, add ethyl acetate (300 mL) to dissolve, add water (200 mL × 2) to wash twice, add saturated sodium bicarbonate aqueous solution (200 mL × 2) to wash twice, add anhydrous sodium sulfate (20 g) to dry the organic phase, filter, and concentrate the filtrate to obtain methyl 4-acetoxy-6-fluoro-2-naphthoic acid;

[0092] (3) Add methyl 4-acetoxy-6-fluoro-2-naphthoic acid (21.42 g) to a 500 mL single-necked flask, dissolve it in 150 mL of methanol, then add water (150 mL) and sodium bicarbonate (10.3 g), heat to about 65 °C for 7 h, cool to 5-10 °C and filter to obtain methyl 4-hydroxy-6-fluoro-2-naphthoic acid;

[0093] (4) Add methyl 4-hydroxy-6-fluoro-2-naphthoic acid (2.22 g) and DMF (50 mL) to a 100 mL three-necked flask and stir until dissolved. Add triethylamine (2.55 g), potassium carbonate (2.66 g), and benzyl bromide injection (3.66 g). Heat to 125 °C and react. After the reaction is complete, pour the reaction solution into ice water (200 mL), add ethyl acetate (200 mL) for extraction, wash the organic phase twice with water (200 mL × 2), wash once with 0.5 N hydrochloric acid (200 mL), and wash once with water (200 mL). Dry and concentrate the organic phase to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0094] (5) Add methyl 4-benzyloxy-6-fluoro-2-naphthoic acid (3.07 g) to a 250 mL three-necked flask, dissolve in methanol (46 mL) by heating, add sodium hydroxide (0.44 g) and water (50 mL), heat to about 65 °C and react for 6 h. After the reaction is complete, concentrate the reaction solution, add water (50 mL) to make up the solution volume, add toluene (50 mL) to wash once, add 1 N hydrochloric acid to the aqueous phase to adjust the pH to 5-6, add dichloromethane to extract 2-3 times, add anhydrous sodium sulfate to the organic phase to dry, filter and concentrate the filtrate to obtain 4-benzyloxy-6-fluoro-2-naphthoic acid.

[0095] (6) Add 4-benzyloxy-6-fluoro-2-naphtholic acid (0.1g), toluene (30mL), DPPA (0.107g), and triethylamine (0.059g) to a 100mL three-necked flask, heat to 110℃, add 6N hydrochloric acid (0.69g) after 8h, continue heating to about 100℃ and react for 16h. After the reaction is completed, add purified water (10mL×2) to the reaction solution and extract twice. Add 1N sodium hydroxide to the aqueous phase to adjust the pH to 7-8, add ethyl acetate (10mL×2) and extract twice. Concentrate the organic phase to obtain 3-amino-7-fluoro-1-naphthol.

[0096] (7) 3-amino-7-fluoro-1-naphthol was dissolved in 10% dilute sulfuric acid, and 1.06N sodium nitrite aqueous solution (concentration 30%) was added dropwise at 0 to 5°C. After reacting for 30 min, the mixture was heated to 70°C until the reaction was complete. Toluene was added for extraction, the mixture was separated, the organic phase was decolorized with activated carbon, concentrated, and crystallized. The final product 3-hydroxy-7-fluoro-1-naphthol was determined by NMR and mass spectrometry, and the molar yield was calculated to be 22.6%.

[0097] In the synthesis methods of 3-hydroxy-7-fluoro-1-naphthol provided in Examples 1 to 3, the materials can be adjusted within a small range, but this will have some impact on the yield. However, the molar yield can be above 22%.

[0098] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing 3-hydroxy-7-fluoro-1-naphthol, characterized in that, The method includes the following steps: (1) The hydroxyl group of methyl 4-hydroxy-6-fluoro-2-naphthoic acid is protected with benzyl group to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid; (2) The ester group of methyl 4-benzyloxy-6-fluoro-2-naphthoic acid is hydrolyzed to a carboxyl group to obtain the hydrolysis product 4-benzyloxy-6-fluoro-2-naphthoic acid; (3) The hydrolysis products 4-benzyloxy-6-fluoro-2-naphthoic acid, diphenyl azidophosphate, triethylamine and toluene were mixed and heated for a predetermined time. Hydrochloric acid was added and the mixture was heated continuously to carry out the rearrangement. After the reaction was completed, the reaction solution was post-treated to obtain the rearranged product 3-amino-7-fluoro-1-naphthol. (4) Dissolve the rearranged product 3-amino-7-fluoro-1-naphthol in dilute sulfuric acid, add sodium nitrite aqueous solution to carry out diazotization reaction, and then heat the reaction product to carry out diazotization hydroxylation. After the reaction is completed, 3-hydroxy-7-fluoro-1-naphthol is obtained after post-treatment.

2. The synthesis method according to claim 1, characterized in that, The benzyl protection step (1) includes dissolving the methyl 4-hydroxy-6-fluoro-2-naphthoic acid in N,N-dimethylformamide, adding triethylamine, potassium carbonate and benzyl bromide, heating to 110~130℃ and reacting for more than 8 hours. After the reaction is completed, the reaction solution is post-treated to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid.

3. The synthesis method as described in claim 2, characterized in that, In the benzyl protection process, the mass ratio of benzyl bromide to methyl 4-hydroxy-6-fluoro-2-naphthoate is 1.65:1 to 1.75:1; the mass ratio of triethylamine to methyl 4-hydroxy-6-fluoro-2-naphthoate is 1.15:1 to 1.25:1; the mass ratio of potassium carbonate to methyl 4-hydroxy-6-fluoro-2-naphthoate is 1.2:1 to 1.3:1; and the mass-volume ratio of methyl 4-hydroxy-6-fluoro-2-naphthoate to N,N-dimethylformamide is 4.3 to 4.5 g of methyl 4-hydroxy-6-fluoro-2-naphthoate per 100 mL of N,N-dimethylformamide.

4. The synthesis method according to claim 2, characterized in that, The post-treatment includes terminating the reaction by introducing the reaction solution into ice water, extracting with ethyl acetate, washing the organic phase with water and hydrochloric acid, and drying the organic phase to obtain methyl 4-benzyloxy-6-fluoro-2-naphthoic acid.

5. The synthesis method as described in claim 1, characterized in that, Step (2) involves hydrolyzing the ester group into a carboxyl group, which includes dissolving the methyl 4-benzyloxy-6-fluoro-2-naphthoic acid in methanol, adding an alkaline solution, heating to about 65°C and reacting for more than 6 hours. After the reaction is completed, the reaction solution is post-treated to obtain 4-benzyloxy-6-fluoro-2-naphthoic acid.

6. The synthesis method as described in claim 5, characterized in that, The alkali includes sodium hydroxide and potassium hydroxide, and the mass-to-volume ratio of the alkali solution is 8.5~10.0 mg / mL.

7. The synthesis method as described in claim 5, characterized in that, The methyl 4-benzyloxy-6-fluoro-2-naphthoic acid ester is soluble in methanol at a mass-to-volume ratio of 65~68 mg / mL.

8. The synthesis method as described in claim 5, characterized in that, The mass ratio of methyl 4-benzyloxy-6-fluoro-2-naphthoic acid ester to alkali is 7:1 to 8:

1.

9. The synthesis method as described in claim 5, characterized in that, The post-treatment in step (2) includes concentrating the reaction solution, adding water to replenish the solution volume, washing with toluene, adjusting the pH value to 5-6, extracting with dichloromethane, and drying the organic phase to obtain 4-benzyloxy-6-fluoro-2-naphthoic acid.

10. The synthesis method according to claim 9, characterized in that, Use hydrochloric acid to adjust the pH value.

11. The synthesis method according to claim 1, characterized in that, The mass ratio of 4-benzyloxy-6-fluoro-2-naphthoic acid, diphenyl azidophosphate, and triethylamine in step (3) is 1:(0.9~1.1):(0.5~0.6).

12. The synthesis method according to claim 1, characterized in that, The mass-to-volume ratio of 4-benzyloxy-6-fluoro-2-naphthoic acid to toluene is 0.3~0.35g of 4-benzyloxy-6-fluoro-2-naphthoic acid per 100mL of toluene.

13. The synthesis method according to claim 1, characterized in that, The specific steps of step (3) include: The hydrolysis products 4-benzyloxy-6-fluoro-2-naphthoic acid, diphenyl azidophosphate, triethylamine and toluene were mixed and heated to about 110°C for 7-8 hours. Then hydrochloric acid was added and the mixture was heated continuously to maintain the temperature at about 100°C for 16 hours for rearrangement. After the reaction was completed, the reaction solution was post-treated to obtain the rearranged product 3-amino-7-fluoro-1-naphthol.

14. The synthesis method according to claim 13, characterized in that, The post-processing includes water extraction, adjusting the pH to 7-8, extraction with ethyl acetate, and concentration of the organic phase to obtain the rearranged product 3-amino-7-fluoro-1-naphthol.

15. The synthesis method according to claim 1, characterized in that, The temperature of the diazotization reaction in step (4) is 0~5℃ and the reaction time is 30~40min.

16. The synthesis method according to claim 1, characterized in that, In step (4), the molar ratio of 3-amino-7-fluoro-1-naphthol to sodium nitrite in the diazotization reaction is 1:1.04 to 1:1.06, and the concentration of the sodium nitrite aqueous solution is 30 to 32 wt%.

17. The synthesis method according to claim 1, characterized in that, The reaction temperature for the hydroxylation of the diazo group in step (4) is 70~80℃, and the reaction time is 2~2.3h.

18. The synthesis method according to claim 1, characterized in that, The post-processing in step (4) includes extraction with toluene, decolorization of the organic phase with activated carbon, concentration, and fine reduction to obtain 3-hydroxy-7-naphthol.

19. The synthesis method according to any one of claims 1 to 5, characterized in that, The methyl 4-hydroxy-6-fluoro-2-naphthoic acid ester described in step (1) is prepared by the following method: (1a) In a tetrahydrofuran solution containing potassium tert-butoxide, a tetrahydrofuran solution containing p-fluorobenzaldehyde and dimethyl succinate was added dropwise to carry out the condensation of dimethyl succinate with the carbonyl group of the aldehyde. After the reaction was completed, the reaction solution was post-treated to obtain the carbonyl ester condensation product. (1b) After mixing the carbonyl ester condensation product and acetic anhydride, anhydrous sodium acetate is added and heated to carry out the acetic acid cyclization reaction. After the reaction is completed, the reaction solution is post-treated to obtain the acetic acid cyclization product methyl 4-acetoxy-6-fluoro-2-naphthoic acid. (1c) The methanol aqueous solution of methyl 4-acetoxy-6-fluoro-2-naphthoic acid, the cyclization product of acetic acid, was mixed with sodium bicarbonate, heated to carry out hydrolysis reaction, and filtered to obtain methyl 4-hydroxy-6-fluoro-2-naphthoic acid.

20. The synthesis method according to claim 19, characterized in that, In the tetrahydrofuran solution of p-fluorobenzaldehyde and dimethyl succinate described in step (1a), the mass ratio of p-fluorobenzaldehyde to dimethyl succinate is 1:1.6 to 1:1.

7.

21. The synthesis method according to claim 19, characterized in that, The mass ratio of p-fluorobenzaldehyde and potassium tert-butoxide in step (1a) is 1:1.01 to 1:1.

10.

22. The synthesis method according to claim 19, characterized in that, The temperature at which the drop is added in step (1a) is 25~30℃.

23. The synthesis method as described in claim 19, characterized in that, The condensation temperature of dimethyl succinate and aldehyde carbonyl group in step (1a) is 35~45℃, and the reaction time is 2-3h.

24. The synthesis method according to claim 19, characterized in that, The post-treatment in step (1a) includes terminating the reaction by pouring the reaction solution into ice water, then washing with toluene, adjusting the pH to 3-4, extracting with dichloromethane, and drying the organic phase to obtain the carbonyl ester condensation product.

25. The method for synthesizing 3-hydroxy-7-fluoro-1-naphthol as described in claim 19, characterized in that, In step (1b), the mass ratio of the carbonyl ester condensation product to acetic anhydride is 1:4.5 to 1:4.6, and the mass ratio of the carbonyl ester condensation product to anhydrous sodium acetate is 2.4:1 to 2.5:

1.

26. The method for synthesizing 3-hydroxy-7-fluoro-1-naphthol as described in claim 19, characterized in that, The acetic acid ring-closure reaction in step (1b) is carried out at a temperature of about 120°C for 4 to 4.5 hours.

27. The method for synthesizing 3-hydroxy-7-fluoro-1-naphthol as described in claim 19, characterized in that, The post-processing described in step (1b) includes concentrating the reaction solution, dissolving it in ethyl acetate, washing it with water and / or an aqueous sodium bicarbonate solution, drying the organic phase, filtering, and concentrating it to obtain the acetic acid cyclization product.

28. The method for synthesizing 3-hydroxy-7-fluoro-1-naphthol as described in claim 19, characterized in that, The mass ratio of methyl 4-acetoxy-6-fluoro-2-naphthoic acid ester to sodium bicarbonate in step (1c) is 2.0:1 to 2.2:

1.

29. The method for synthesizing 3-hydroxy-7-fluoro-1-naphthol as described in claim 19, characterized in that, The methanol aqueous solution of methyl 4-acetoxy-6-fluoro-2-naphthoic acid in step (1c) has a mass-volume concentration of 6-8%.

30. The method for synthesizing 3-hydroxy-7-fluoro-1-naphthol as described in claim 19, characterized in that, The volume ratio of methanol to water in step (1c) is 0.9 to 1.1:

1.

31. The method for synthesizing 3-hydroxy-7-fluoro-1-naphthol as described in claim 19, characterized in that, The hydrolysis temperature in step (1c) is about 65°C, and the hydrolysis reaction time is 6~8h.

32. Use of the synthesis method according to any one of claims 1 to 31, characterized in that, The synthesis method described in any one of claims 1 to 8 is used to prepare a target drug against KRAS subtype gene mutations.

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