Preparation method of 6-hydroxy-1-naphthoic acid

Abstract

The invention relates to the technical field of organic synthesis, and aims at solving the problems that an existing 6-hydroxy-1-naphthoic acid preparation method is low in reaction yield, extremely difficult to purify and not suitable for industrial production. The invention provides a preparation method of 6-hydroxy-1-naphthoic acid, which comprises the following steps: taking 2-acetophenone as an initial raw material, and brominating to obtain an intermediate I; then the intermediate I and cyanide are subjected to a nitrile reaction in a reaction solvent to generate an intermediate II; reacting the intermediate II with peroxide cyanide in a reaction solvent to generate an intermediate III; the intermediate III is subjected to hydrolytic acidification to generate 6-hydroxy-1-naphthoic acid, the preparation process is simpler, the raw materials are low in price and easy to obtain, the product yield is higher, and the method is suitable for industrial mass production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 6-hydroxy-1-naphthoic acid. Background Art

[0002] 6-Hydroxy-1-naphthoic acid is widely used as an organic synthesis intermediate and an important raw material for the production of medicines and dyes. In recent years, tyrosine kinase targeted drugs (including monoclonal antibodies and small molecule compounds) have been actively developed and applied in a variety of cancers such as hematological malignancies, lung cancer, kidney cancer, colorectal cancer, gastric cancer, and liver cancer. Delitinib is a small molecule multi-target tyrosine kinase inhibitor targeting VEGFR1, VEGFR2, FGFR1, PDGFRβ, c-Kit, and c-Src. Similar drugs have been successfully used in clinical anti-tumor treatment. In non-clinical studies, Delitinib has good efficacy, safety, and pharmacokinetic characteristics, and 6-hydroxy-1-naphthoic acid is a key raw material for a new class of drugs, Delitinib.

[0003] In the prior art, the preparation methods of 6-hydroxy-1-naphthoic acid mostly use furoic acid and anisole as starting materials, and obtain 6-hydroxy-1-naphthoic acid through Diels-Alder reaction, cyclization, demethylation and other reactions.

[0004] For example, a Chinese patent with publication number CN108863775A discloses a method for preparing 6-hydroxy-1-naphthoic acid, which belongs to the field of organic synthesis technology. The method uses furoic acid and anisole as starting materials, and reacts under the catalysis of Lewis acid to prepare 6-methoxy-1-naphthoic acid; without separation, Lewis acid is used to eliminate and remove the methyl group to prepare 6-methoxy-1-naphthoic acid.

[0005] The above method has a low reaction yield of only 12%, and is extremely difficult to purify, and is not suitable for industrial production. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing 6-hydroxy-1-naphthoic acid, which has a simpler preparation process, low-cost and easily available raw materials, a higher product yield and is suitable for large-scale industrial production.

[0007] The embodiments of the present invention are achieved through the following technical solutions:

[0008] A preparation method of 6-hydroxy-1-naphthoic acid, the reaction formula of which is as follows:

[0009]

[0010] The preparation method uses 2-naphthyl acetonide as a starting material, undergoes bromination, cuprous cyanide cyanation, and then undergoes Baeyer-Villiger oxidation under the action of peroxide to convert the naphthyl acetonide into naphthyl acetate, and finally hydrolyzes to generate 6-hydroxy-1-naphthoic acid.

[0011] Specifically, the preparation method comprises the following steps:

[0012] The first step is to react 2-naphthyl acetonide as a starting material with a brominating agent to obtain an intermediate I (5-bromo-2-naphthyl acetonide); the brominating agent includes but is not limited to bromine, dibromohydantoin, NBS and other in-situ brominating agents; preferably, the in-situ brominating agent is ammonium bromide / potassium monopersulfate composite salt; wherein the molar ratio of 2-naphthyl acetonide to the brominating agent is 1:3-4, more specifically, when the brominating agent is ammonium bromide / potassium monopersulfate composite salt, the molar ratio of 2-naphthyl acetonide to the ammonium bromide / potassium monopersulfate composite salt is 1:(1.1-1.4):(2.0-2.5).

[0013] Step 2: reacting the intermediate I with cyanide in a reaction solvent at 160-200°C to generate the intermediate II; wherein the molar ratio of the intermediate I to the cyanide is 1:(1.8-2.2); the reaction solvent may be N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone; preferably N-methylpyrrolidone; the cyanide may be cuprous cyanide, sodium cyanide, potassium cyanide, etc., preferably, the cyanide is cuprous cyanide.

[0014] Step 3: reacting the intermediate II with a peroxide in a reaction solvent at 0-10°C to generate an intermediate III; the peroxide may be m-chloroperbenzoic acid or peracetic acid, preferably m-chloroperbenzoic acid; wherein the molar ratio of the intermediate II to the peroxide is 1:(2.0-3.0); the reaction solvent may be acetonitrile, tetrahydrofuran, dichloromethane, or dichloroethane, preferably dichloromethane.

[0015] Step 4: The intermediate III is hydrolyzed and acidified at 60-80°C to generate 6-hydroxy-1-naphthoic acid. During the hydrolysis and acidification, a strong base such as sodium hydroxide, potassium hydroxide, etc., preferably sodium hydroxide, can be added; then the pH value is adjusted to 2-3 by hydrochloric acid or sulfuric acid; wherein the molar ratio of the intermediate III to the strong base is 1:(3.5-4.5).

[0016] The technical solution of the embodiment of the present invention has at least the following advantages and beneficial effects:

[0017] The preparation method of the invention can prepare 6-hydroxy-1-naphthoic acid through only four steps of reaction; the starting raw material 2-naphthone is low in price and easy to obtain; the reaction conditions are relatively mild, the single-step yield and the total yield are both high, and the method is suitable for industrial production. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0019] Example 1: Preparation of Intermediate I (5-bromo-2-naphthyl acetonide)

[0020] Put 2-naphthone (10.0 g, 58.8 mmol, 1.00 equivalent) into a 500 ml reaction bottle, add 50 ml of water, 100 ml of acetonitrile, and ammonium bromide (6.91 g, 70.5 mmol, 1.20 equivalent) and stir. Cool the suspension to 0-5 ° C, add potassium monopersulfate (43.4 g, 70.5 mmol, 2.40 equivalent) in batches, keep the temperature at 3 ° C for 1 hour after the addition is completed, and then naturally warm to room temperature. React at room temperature for 3.5 hours, and the reaction is complete. Filter the precipitate and wash with ethyl acetate (30 mL). Remove acetonitrile under reduced pressure, and extract the mother liquor with ethyl acetate (2×100 mL). Wash the combined ethyl acetate phase with sodium thiosulfate solution (100 ml) and water (100 mg). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, 20 ml of ethanol was added, cooled and stirred for crystallization, filtered, and dried to obtain a yellow crystalline solid of 5-bromo-2-naphthacetone (8.05 g, 32.3 mmol), with a yield of 55%. HNMR (400 MHz, CDCl3): δ (ppm) 8.29 (1H), 8.13-8.09 (1H), 7.97 (1H), 7.77 (2H), 7.27 (1H), 2.65 (3H).

[0021] Example 2: Preparation of Intermediate II (6-acetyl-1-naphthocarbonitrile)

[0022] Add 5-bromo-2-naphthyl acetonide (12.5 g, 50.2 mmol) and 100 ml N-methylpyrrolidone (NMP) to a 500 ml reaction bottle, stir, and add 9 g (100.5 mmol) of cuprous cyanide. Heat to 200 °C and react for 8 hours until the reaction is complete. Cool to 45 °C and filter to remove the solid. Then add 200 ml of water and extract with dichloromethane (150 ml*3), combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate. Recrystallize with anhydrous ethanol to obtain 7.4 g of intermediate II (6-acetyl-1-naphthylcarbonitrile), with a yield of 76%. HNMR (400 MHz, CDCl3): δ (ppm) 8.27 (1H), 8.13-8.10 (1H), 8.01 (1H), 7.85 (2H), 7.35 (1H), 2.65 (3H).

[0023] Example 3: Preparation of Intermediate III (6-acetoxy-1-naphthocarbonitrile)

[0024] At 0-5°C, add intermediate II (19.5g, 100mmol) and 200ml dichloromethane to a 500ml reaction bottle and stir. Then add m-chloroperbenzoic acid (mCPBA 43.1g, 249.76mmol) in batches. Stir for 2 hours, then naturally warm to room temperature, continue stirring and react for 5 hours, and the reaction is complete. Wash with 100ml sodium bicarbonate aqueous solution, 100ml sodium sulfite solution, and 100ml water in sequence, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 17g of intermediate III (6-acetoxy-1-naphthonitrile), with a yield of 80.5%. HNMR (400MHz, CDCl3): δ (ppm) 8.15 (1H), 8.08 (1H), 7.95 (1H), 7.82 (2H), 7.15 (1H), 2.55 (3H).

[0025] Example 4: Preparation of 6-hydroxy-1-naphthoic acid

[0026] Add intermediate III (21.1 g, 100 mmol), 100 ml 15% sodium hydroxide solution and 50 ml ethanol to a 500 ml reaction bottle and stir. Heat to 80 °C, continue stirring and react for 13 hours. After the reaction is complete, heat and evaporate the ethanol. Cool to about 30 °C, adjust the pH to 2.5 with hydrochloric acid, precipitate solid, filter, wash and dry to obtain 15.7 g of white solid, with a yield of 83.3%. HNMR (400 MHz, DMSO-d6): δ (ppm) 12.99 (1H), 9.88 (1H), 8.71 (1H), 7.90 (2H), 7.49–7.41 (1H), 7.20 (1H), 7.20–7.18 (1H).

[0027] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing 6-hydroxy-1-naphthoic acid, characterized in that: The reaction formula is as follows:

2. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 1, characterized in that: The following steps are involved: 2-naphthyl acetonide is used as a starting material to react with a brominating agent to obtain an intermediate I through bromination; then the intermediate I reacts with cyanide in a reaction solvent to generate an intermediate II; the intermediate II reacts with peroxide cyanide in a reaction solvent to generate an intermediate III; and the intermediate III is hydrolyzed and acidified to generate 6-hydroxy-1-naphthoic acid.

3. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate I: the bromination reagent comprises any one or more of bromine, dibromohydantoin, NBS, ammonium bromide or potassium monopersulfate complex salt.

4. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate I: the molar ratio of 2-naphthyl acetonide to the brominating agent is 1:3-4.

5. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate II: the cyanide is any one or more of cuprous cyanide, sodium cyanide, and potassium cyanide; the reaction solvent is any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; and the reaction temperature is 160-200°C.

6. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate II: the molar ratio of intermediate I to cyanide is 1:(1.8-2.2).

7. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate III: the peroxide is any one or more of m-chloroperbenzoic acid and peracetic acid, preferably m-chloroperbenzoic acid; the reaction solvent is any one or more of acetonitrile, tetrahydrofuran, dichloromethane, and dichloroethane; and the reaction temperature is 0-10°C.

8. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate III: the molar ratio of intermediate II to peroxide is 1:(2.0-3.0).

9. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When 6-hydroxy-1-naphthoic acid is prepared from intermediate III: the molar ratio of intermediate III to strong base is 1:(3.5-4.5); the reaction temperature is 60-80°C.

10. The method for preparing 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing 6-hydroxy-1-naphthoic acid from intermediate III: during hydrolysis and acidification, first add a strong base, and then add acid to adjust the pH value to 2-3.

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