Synthesis process of 6-hydroxy-1-naphthoic acid

Abstract

The invention relates to the technical field of organic synthesis, and aims to solve the problems that an existing 6-hydroxy-1-naphthoic acid synthesis process is low in reaction yield and not suitable for industrial production. The invention provides a synthesis process 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; oxidizing the intermediate I under the action of peroxide, and converting 2-acetophenone into an intermediate II; carrying out alkaline hydrolysis and dimethyl sulfate methylation on the intermediate II to generate an intermediate III; reacting the intermediate III with Mg, and then reacting with carbon dioxide to generate an intermediate IV; finally, the intermediate IV is demethylated under the action of hydrobromic acid / acetic acid, and 6-hydroxy-1-naphthoic acid is generated, the preparation process is simpler, the product yield is higher, raw materials are low in price and easy to obtain, the production cost is low, generation of by-products can be remarkably inhibited, excessive pollution to the environment is avoided, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a synthesis process of 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 preparation method of 6-hydroxy-1-naphthoic acid, the synthesis process of which is simpler, the raw materials are cheap and readily available, the product yield is higher, and the method is suitable for large-scale industrial production.

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

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

[0009]

[0010] The synthesis process of the invention uses 2-acetonapthone as a starting material, and obtains an intermediate I (5-bromo-2-acetonapthone) through bromination; then the intermediate I undergoes Baeyer-Villiger oxidation under the action of peroxide to convert the 2-acetonapthone into an intermediate II (6-acetoxy-1-bromonaphthalene); the intermediate II undergoes alkaline hydrolysis and dimethyl sulfate methylation to generate an intermediate III (6-methoxy-1-bromonaphthalene); the intermediate III reacts with Mg to obtain a Grignard reagent, and then reacts with carbon dioxide to generate an intermediate IV (6-methoxy-1-naphthoic acid); finally, the intermediate IV is demethylated to generate 6-hydroxy-1-naphthoic acid.

[0011] Specifically, the synthesis process comprises the following steps:

[0012] 1) Preparation of intermediate I (5-bromo-2-naphthyl acetonide)

[0013] 2-naphthyl acetonide is used as a starting material to react with a brominating agent to generate an intermediate I; the brominating agent includes but is not limited to any one or more of 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 and potassium monopersulfate composite salt, the molar ratio of 2-naphthyl acetonide to ammonium bromide and potassium monopersulfate composite salt is 1:(1.1-1.4):(2.0-2.5).

[0014] 2) Preparation of intermediate II (6-acetyl-1-bromonaphthalene)

[0015] The intermediate I reacts with the peroxide in a reaction solvent at 0-10° C. to generate the intermediate II; wherein the peroxide may be m-chloroperbenzoic acid or peracetic acid, preferably m-chloroperbenzoic acid; wherein the molar ratio of the intermediate I to the peroxide is 1:(2.0-3.0); the reaction solvent may be any one or more of acetonitrile, tetrahydrofuran, dichloromethane, and dichloroethane; preferably dichloromethane.

[0016] 3) Preparation of intermediate III (6-methoxy-1-bromonaphthalene)

[0017] The intermediate II reacts with a base and dimethyl sulfate at 10-40° C., and is subjected to alkaline hydrolysis and dimethyl sulfate methylation to generate the intermediate III (6-methoxy-1-bromonaphthalene); wherein the base used can be sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., preferably sodium hydroxide; the reaction temperature is 10-40° C.; the molar ratio of the intermediate II to the dimethyl sulfate is 1:1-2; and the ratio of the base to the intermediate II is 1:1.5-2.5 (ml / mmol).

[0018] 4) Preparation of intermediate IV (6-methoxy-1-naphthoic acid)

[0019] When intermediate III is used to prepare intermediate IV, the following methods can be used:

[0020] ① Grignard reaction: intermediate III and Mg undergo Grignard reaction in a reaction solvent to generate a Grignard reagent, which is then reacted with carbon dioxide to generate intermediate IV (6-methoxy-1-naphthoic acid); the reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran, preferably tetrahydrofuran; the reaction temperature with carbon dioxide is -5 to 10°C, preferably 0-5°C; the molar ratio of intermediate III to Mg is 1:1.2-2;

[0021] ② After reacting the intermediate III with butyl lithium in a reaction solvent, the intermediate III is reacted with carbon dioxide; the reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran, preferably tetrahydrofuran; the reaction temperature with carbon dioxide is -60 to -80°C, preferably -78°C. The molar ratio of the intermediate III to butyl lithium is 1:1.1-1.5;

[0022] The first Grignard reaction is preferred.

[0023] 5) Preparation of 6-hydroxy-1-naphthoic acid

[0024] Intermediate IV is demethylated by hydrolysis to generate 6-hydroxy-1-naphthoic acid; wherein the reaction temperature is above 80°C, preferably reflux temperature; the hydrolysis can be carried out under acidic conditions or under alkaline conditions; if it is carried out under acidic conditions, the acid used can be HBr or HBr / acetic acid; if it is carried out under alkaline conditions, the base used can be a combination of long-chain thiol / sodium methoxide, etc., preferably under acidic conditions, preferably, using HBr / acetic acid.

[0025] The technical solution of the embodiment of the present invention has at least the following advantages and beneficial effects:

[0026] The starting raw materials used in the preparation method of 6-hydroxy-1-naphthoic acid are low in price and easy to obtain, and 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

[0027] 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.

[0028] Example 1: Preparation of Intermediate I (5-bromo-2-naphthyl acetonide)

[0029] 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 evenly. Cool the suspension to 3 ° C, add potassium monopersulfate (43.4 g, 70.5 mmol, 2.40 equivalent) in batches, and 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, and concentrated under reduced pressure. 20 ml of ethanol was added, and the mixture was cooled, stirred, crystallized, filtered, and dried to give 5-bromo-2-naphthacetone as a yellow crystalline solid (8.05 g, 32.3 mmol). The yield was 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).

[0030] Example 2: Preparation of Intermediate II (6-acetyl-1-bromonaphthalene)

[0031] At 0°C, add intermediate I (24.7g, 100mmol) and 200ml dichloromethane into a 500ml reaction bottle and stir evenly. 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 turn, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 22g of intermediate II (6-acetyl-1-bromonaphthalene), with a yield of 83%.

[0032] Example 3: Preparation of Intermediate III (6-methoxy-1-bromonaphthalene)

[0033] Add intermediate II (26.5g, 100mmol) and 200ml 10% sodium hydroxide solution and 50ml ethanol to a 500ml reaction bottle and stir. Heat to 50℃ and continue stirring for 3 hours. Then cool to room temperature, add dimethyl sulfate (16.7g, 150mmol) dropwise, and stir at room temperature for 5 hours. Then add ethyl acetate (100ml*3) for extraction, wash with 100ml water, dry over anhydrous sodium sulfate, filter and concentrate to obtain 20.1g of intermediate III (6-methoxy-1-bromonaphthalene) with a yield of 85%. HNMR (400MHz, CDCl3): δ (ppm) 8.12 (dJ = 9.2Hz.1H). 7.71 (d, J = 8.4Hz, 1H), 7.62 (d, J = 7.6Hz 1H), 7.23-7.20 (m, 2H), 7.10 (d, J = 2.4Hz.1H). 3.92 (s.3H).

[0034] Example 4: Preparation of Intermediate IV (6-methoxy-1-naphthoic acid)

[0035] In a nitrogen-protected four-necked bottle, under anhydrous and oxygen-free conditions, magnesium metal (5g) and 50ml of anhydrous tetrahydrofuran were added and the temperature was raised to reflux temperature. Then intermediate III (54g) and anhydrous tetrahydrofuran (200ml) solution were added dropwise. About 10ml was added dropwise to confirm that the reaction was initiated. If it was not initiated, two drops of bromoethane were added dropwise, and the reaction was confirmed to be completely initiated and then continued to be added dropwise. After the addition was completed, reflux was continued for 3 hours. Then the temperature was lowered to 5°C, carbon dioxide was introduced for about 4 hours, and the reaction was terminated. Then 20ml of dilute hydrochloric acid solution was added dropwise to the reaction solution to adjust the pH to 1.5, and then ethyl acetate was added for extraction, washed with water, dried over anhydrous sodium sulfate, and spin-dried to obtain intermediate IV (6-methoxy-1-naphthoic acid) yellow solid about 45g, with a yield of 70%.

[0036] HNMR (400MHz, CDCl3): δ (ppm) 8.79 (d, J = 9.1Hz, 1H); 8.05 (d, J = 8.1Hz, 1H), 7.98 (d, J = 6.1Hz ,1H),7.53(t,J=7.8Hz,1H),7.41(d,J=2.4Hz,1H),7.29(dd,J=6.9,2.4Hz,1H),3.89(s,3H).

[0037] Example 5: Preparation of Intermediate IV (6-methoxy-1-naphthoic acid)

[0038] In a nitrogen-protected four-necked bottle, under anhydrous and oxygen-free conditions, the intermediate III (54g) was dissolved in anhydrous tetrahydrofuran (200ml) and cooled to -78°C. Then, n-butyl lithium solution (2.2M hexane solution, 135mL) was slowly added dropwise at this temperature. After the addition was complete, it was stirred for 20 minutes, and then carbon dioxide was introduced for 15 minutes, and the temperature was naturally raised to room temperature. 30ml of tetrahydrofuran solution with a water content of 50% was added dropwise to the reaction solution to quench the unreacted butyl lithium, and then 20ml of dilute hydrochloric acid solution was added dropwise to the reaction solution to adjust the pH to 1.5, and then ethyl acetate was added for extraction, washed with water, dried over anhydrous sodium sulfate, and spin-dried to obtain about 51g of intermediate IV (6-methoxy-1-naphthoic acid) as a yellow solid with a yield of 79.3%.

[0039] HNMR (400MHz, CDCl3): δ (ppm) 8.79 (d, J = 9.1Hz, 1H); 8.05 (d, J = 8.1Hz, 1H), 7.98 (d, J = 6.1Hz ,1H),7.53(t,J=7.8Hz,1H),7.41(d,J=2.4Hz,1H),7.29(dd,J=6.9,2.4Hz,1H),3.89(s,3H).

[0040] Example 6: Preparation of 6-hydroxy-1-naphthoic acid

[0041] Add intermediate IV (92.4 g, 546 mmol), 48% hydrobromic acid (500 g) and glacial acetic acid (500 g) to the reaction flask, heat to reflux temperature, stir and react overnight, and the reaction is complete. Cool the reaction solution to room temperature, filter with suction, add 500 g of water to the filter cake, adjust the pH to 2.5 with 150 g of potassium carbonate, precipitate solid, filter with suction, wash, and dry to obtain 82.2 g of 6-hydroxy-1-naphthoic acid as a white solid, with a yield of 80%. 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).

[0042] 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 synthesis process for 6-hydroxy-1-naphthoic acid, characterized in that: The reaction formula is as follows:

2. The synthesis process of 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 undergoes an oxidation reaction with a peroxide in a reaction solvent to obtain an intermediate II; the intermediate II reacts with a base and dimethyl sulfate, and undergoes alkaline hydrolysis and methylation to generate an intermediate III; the intermediate III reacts with Mg to prepare a Grignard reagent, and then reacts with carbon dioxide to generate an intermediate IV; finally, the intermediate IV is demethylated to generate 6-hydroxy-1-naphthoic acid.

3. The synthesis process of 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 synthesis process of 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 synthesis process of 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that, When preparing intermediate II: the peroxide is m-chloroperbenzoic acid and / or peracetic acid; the reaction solvent is any one or more of acetonitrile, tetrahydrofuran, dichloromethane, and dichloroethane.

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

7. The synthesis process of 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate III: the base is any one or more of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; the reaction temperature is 10-40°C.

8. The synthesis process of 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate III: the molar ratio of intermediate II to dimethyl sulfate is: 1:1-2.

9. The synthesis process of 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When preparing intermediate IV, the following methods can be used: ① Intermediate III reacts with Mg in a reaction solvent to undergo a Grignard reaction, and then reacts with carbon dioxide to generate intermediate IV; ② After the intermediate III reacts with butyl lithium, it reacts with carbon dioxide to generate the intermediate IV.

10. The synthesis process of 6-hydroxy-1-naphthoic acid according to claim 2, characterized in that: When 6-hydroxy-1-naphthoic acid is prepared from intermediate IV: the hydrolysis can be carried out under acidic conditions or alkaline conditions; if it is under acidic conditions, the acid used is HBr or HBr / acetic acid; if it is under alkaline conditions, the base used is long-chain thiol and sodium methoxide.

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