A process for the preparation of 4-acetyl-1-naphthoic acid

Abstract

The application relates to a method for preparing 4-acetyl-1-naphthalene carboxylic acid and belongs to the technical field of pharmacy. The method provided by the application takes 1,4-naphthalene dicarboxylic acid which is cheap and easy to obtain as raw material, decarboxylates after taking the form of methyl acid, carboxymethylates, and finally hydrolyzes to prepare 4-acetyl-1-naphthalene carboxylic acid. The method provided by the application can obtain high-purity products, the process avoids using flammable metal reagent methyl zinc, the reaction condition is mild, the operation is simple, and the method is suitable for industrial amplification production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing 4-acetyl-1-naphthoic acid. Background Technology

[0002] Afoxolaner, CAS: 1093861-60-9, chemical name: 4-{(5R)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}naphthalene-1-carboxamide, molecular formula: C 26 H 17 ClF9N3O3 has a molecular weight of 625.87. Afranal is a pet medication, primarily used clinically as an oral external parasite treatment for dogs.

[0003] The chemical structural formula of afranal is shown in formula (I):

[0004]

[0005] 4-Acetyl-1-naphthoic acid and its derivatives are key intermediates in the synthesis of afolanar. The chemical structural formula of 4-acetyl-1-naphthoic acid is shown in formula (II):

[0006]

[0007] In the prior art, patent documents AU2005319305 and ChemCatChem,9(16),3121-3124 both disclose the preparation process of afolanar intermediate (Formula II). Among them, the method disclosed in AU2005319305 has the disadvantages of low product yield, use of the hazardous reagent methyl zinc, and the need for an anhydrous environment for some post-processing. The method disclosed in ChemCatChem,9(16),3121-3124 has the disadvantages of using the noble metal catalyst palladium acetate and seven times the equivalent of formic acid, resulting in high cost and low yield, making it unsuitable for large-scale production.

[0008] This invention provides a method for preparing the afolanar intermediate 4-acetyl-1-naphthoic acid (Formula II). The method uses inexpensive and readily available raw materials, has simple reaction steps, mild reaction conditions, is environmentally friendly, and is suitable for industrial production. Summary of the Invention

[0009] The present invention provides a method for preparing the afolanar intermediate 4-acetyl-1-naphthoic acid as shown in formula (II).

[0010] On one hand, a method for preparing 4-acetyl-1-naphthoic acid includes: step (d): adding an acid to the reaction solvent of compound (6) and reacting under certain temperature conditions to prepare compound (7), the reaction formula of which is shown below:

[0011]

[0012] In step (d), the reaction solvent is one or a combination of toluene, xylene, benzene, or ethylbenzene.

[0013] In step (d), the acid is one or a combination of hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid.

[0014] In step (d), the specified temperature is 60℃-120℃.

[0015] The aforementioned compound (7) can be hydrolyzed to prepare 4-acetyl-1-naphthoic acid. The hydrolysis reaction may include: dissolving compound (7) in toluene, adding water, NaOH and TBAB, stirring the reaction at 60℃-120℃, cooling the reaction solution to room temperature after the reaction is complete, separating the liquids, washing the aqueous phase with toluene, and then slowly adding HCl dropwise to the aqueous phase until the solid is completely precipitated, filtering, and drying to obtain 4-acetyl-1-naphthoic acid.

[0016] On one hand, a method for preparing 4-acetyl-1-naphthoic acid includes: step (c): reacting compound (4) or its salt with compound (5) in the presence of a reaction solvent, a catalyst, a base and a condensing agent at a certain temperature to prepare compound (6), as shown in the following reaction formula:

[0017]

[0018] In step (c), the reaction solvent is at least one of DCM, dichloroethane, DMSO, or DMF.

[0019] In step (c), the catalyst is at least one of DMAP, HOBt, or 4-PPy.

[0020] In step (c), the base is at least one of triethylamine or DIPEA.

[0021] In step (c), the condensing agent is at least one of EDCI, DCC, or CDI.

[0022] In step (c), the specified temperature is -10℃ to 30℃.

[0023] In some embodiments, a method for preparing 4-acetyl-1-naphthoic acid includes: step (b): reacting compound (2) with a base in a reaction solvent to obtain compound (3), followed by post-treatment, and then hydrolyzing compound (3) under the action of an acid to prepare compound (4), as shown in the following reaction formula:

[0024]

[0025] in,

[0026] M is a lithium, sodium, or potassium ion;

[0027] The reaction solvent is one or a combination of DMF, toluene, methanol, or benzene;

[0028] The alkali is one or a combination of KOH, lithium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, or potassium carbonate;

[0029] The acid is one or a combination of hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid.

[0030] In some embodiments, in step (b), the post-treatment involves adding water and toluene for extraction, collecting the organic phase, and removing the solvent.

[0031] In some embodiments, a method for preparing 4-acetyl-1-naphthoic acid further includes step (a): adding thionyl chloride to the reaction solvent of compound (1) and reacting it under certain temperature conditions to prepare compound (2), as shown in the following reaction formula:

[0032]

[0033] in,

[0034] The reaction solvent is selected from at least one of methanol and ethanol;

[0035] The specified temperature is 60℃-90℃.

[0036] In some embodiments, a method for preparing 4-acetyl-1-naphthoic acid includes any one, any two, any three, or all four steps of the aforementioned steps (a), (b), (c), and (d). In some embodiments, a method for preparing 4-acetyl-1-naphthoic acid includes the aforementioned steps (c) and (d).

[0037] In some embodiments, the method for preparing 4-acetyl-1-naphthoic acid includes: reacting compound (1) in a solvent with the addition of thionyl chloride to obtain compound (2); reacting compound (2) with a base in the reaction solvent to obtain compound (3); hydrolyzing compound (3) under the action of acid to obtain compound (4); reacting compound (4) with compound (5) to obtain compound (6); and reacting compound (6) to obtain compound (7). The reaction route is shown in the following formula:

[0038]

[0039] Compound (7) was hydrolyzed to prepare 4-acetyl-1-naphthoic acid.

[0040] In some embodiments of the aforementioned method, in step (c), the reaction solvent is preferably DCM (dichloromethane), which is beneficial for the reaction and post-processing operations.

[0041] In some embodiments of the aforementioned method, in step (c), the catalyst is preferably DMAP.

[0042] In some embodiments of the aforementioned method, in step (c), the condensing agent is preferably EDCI.

[0043] In the aforementioned method, in some embodiments, the reaction temperature in step (c) is -10°C to 0°C. In some embodiments, the reaction temperature in step (c) is 0°C to 30°C. In some embodiments, the reaction temperature in step (c) is 20°C to 30°C.

[0044] In some embodiments of the aforementioned method, in step (c), the amount of compound (5) fed for every 1.0 mole of compound (4) or its salt is 1.0-1.5 moles, preferably 1.1-1.4 moles, and more preferably 1.3 moles, which is beneficial for obtaining the product.

[0045] In some embodiments of the aforementioned method, the reaction time in step (c) can be from 2 hours to 10 hours. In some embodiments, the reaction time is from 3 hours to 8 hours.

[0046] In some embodiments of the aforementioned method, in step (c), compound (4) or its salt is reacted with compound (5) in dichloromethane or dichloroethane in the presence of DMAP, triethylamine, and EDCI at -10°C to -40°C to prepare compound (6).

[0047] In some embodiments of the aforementioned method, in step (c), compound (4) or its salt is reacted with compound (5) in dichloromethane in the presence of DMAP, triethylamine, and EDCI at -10°C to -40°C to prepare compound (6).

[0048] In some embodiments of the aforementioned method, in step (d), the reaction solvent is preferably toluene, which is beneficial for the reaction to proceed and for post-processing operations.

[0049] In some embodiments of the aforementioned method, hydrochloric acid is preferred in step (d).

[0050] In the aforementioned method, in some embodiments, the reaction temperature in step (d) is 60°C-120°C. In some embodiments, the reaction temperature in step (d) is 65°C-100°C. In some embodiments, the reaction temperature in step (d) is 105°C-120°C. In some embodiments, the reaction temperature in step (d) is 100°C.

[0051] In some embodiments of the aforementioned method, the reaction time in step (d) can be from 8 hours to 24 hours. In some embodiments, the reaction time is from 12 hours to 20 hours.

[0052] In some embodiments of the aforementioned method, in step (d), compound (6) is reacted in toluene in the presence of hydrochloric acid or hydrobromic acid at 100°C to prepare compound (7).

[0053] In some embodiments of the aforementioned method, in step (d), compound (6) is reacted in toluene in the presence of hydrochloric acid at 100°C to prepare compound (7).

[0054] In some embodiments of the aforementioned method, the reaction solvent in step (b) is preferably DMF.

[0055] In some embodiments of the aforementioned method, in step (b), the alkali is preferably KOH (potassium hydroxide).

[0056] In some embodiments of the aforementioned method, in step (b), the acid is preferably hydrochloric acid.

[0057] In some embodiments of the aforementioned method, the reaction temperature in step (a) is 70°C-80°C. In some embodiments, the reaction temperature in step (a) is 75°C.

[0058] In some embodiments of the aforementioned method, in step (a), the amount of thionyl chloride fed per 1.0 mole of compound (1) is 1.0-3.5 moles, preferably 1.5-3 moles, and more preferably 2 moles, which is beneficial for obtaining the product.

[0059] In some embodiments of the aforementioned method, the reaction time in step (a) is 2 to 18 hours. In some embodiments, the reaction time is 5 to 6 hours.

[0060] In some embodiments of the aforementioned method, in step (a), compound (1) is dissolved in methanol or ethanol, thionyl chloride is added, and the reaction is carried out at 60°C-90°C. After the reaction is completed, compound (2) is obtained by post-treatment. The post-treatment is carried out by extraction with water and toluene, collecting the organic phase and removing the solvent.

[0061] In some embodiments of the aforementioned method, in step (a), compound (1) is dissolved in methanol, thionyl chloride is added, and the reaction is carried out at 60°C-90°C. After the reaction is completed, compound (2) is obtained by post-treatment. The post-treatment is carried out by extraction with water and toluene, collecting the organic phase and removing the solvent. Detailed Implementation

[0062] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0063] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0064] The present invention can use TLC or HPLC to monitor the degree of reaction of the raw materials. For example, when using HPLC, the reaction is considered complete when the peak area is less than 1.0%.

[0065] In this invention, room temperature refers to 25℃±5℃.

[0066] In this invention, DCM refers to dichloromethane.

[0067] In this invention, DMAP refers to 4-dimethylaminopyridine.

[0068] In this invention, EDCI refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0069] In this invention, DCC refers to dicyclohexylcarbodiimide.

[0070] In this invention, CDI refers to N,N'-carbonyldiimidazole.

[0071] In this invention, THF refers to tetrahydrofuran.

[0072] In this invention, KOH refers to potassium hydroxide.

[0073] In this invention, SOCl2 refers to thionyl chloride.

[0074] In this invention, NaOH refers to sodium hydroxide.

[0075] In this invention, Et3N refers to triethylamine.

[0076] In this invention, TBAB refers to tetrabutylammonium bromide.

[0077] In this invention, HOBt refers to 1-hydroxybenzotriazole.

[0078] In this invention, 4-PPy refers to 4-pyrrolidinylpyridine.

[0079] In this invention, DIPEA refers to N,N'-diisopropylethylamine.

[0080] Example 1 Preparation of compound (2)

[0081]

[0082] Compound (1), namely 1,4-naphthalenedicarboxylic acid (80 g, 370 mmol) and methanol (560 mL), were added to a 1000 mL round-bottom flask. The temperature was lowered to below 0 °C, and SOCl2 (92.4 g, 777 mmol) was slowly added dropwise with stirring. After the addition was complete, the temperature was raised to 75 °C, and the reaction was refluxed for 12 h. After the reaction was completed, the temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a solid crude product. The crude product was dissolved in 300 mL of toluene, washed twice with 150 mL of 10% K2CO3 (mass fraction), and then washed with 150 mL of water. The organic phase was separated, concentrated under reduced pressure, and compound (2) was obtained: 86.0 g, yield 96%, purity 98.1%; detection:

[0083] 1 H NMR (400MHz, CDCl3) δ9.49–8.48(m,2H),8.09(s,2H),7.77–7.58(m,2H),4.03(s,6H).

[0084] Example 2 Preparation of compound (2)

[0085] Compound (1), namely 1,4-naphthalenedicarboxylic acid (50 g, 231 mmol) and methanol (350 mL), were added to a 1000 mL round-bottom flask. Concentrated sulfuric acid (47.6 g, 485.7 mmol) was slowly added dropwise with stirring. After the addition was complete, the temperature was raised to 75 °C and the reaction was refluxed for 12 h. After the reaction was completed, the temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a solid crude product. The crude product was dissolved in 400 mL of toluene, washed twice with 100 mL of 10% K2CO3 (mass fraction), and then washed with 150 mL of water. The organic phase was separated and concentrated under reduced pressure to obtain compound (2): 53.0 g, with a yield of 93.8% and a purity of 95%.

[0086] Example 3 Preparation of compound (2)

[0087] Compound (1), namely 1,4-naphthalenedicarboxylic acid (10 g, 46.2 mmol) and methanol (70 mL), were added to a 250 mL round-bottom flask. Concentrated hydrochloric acid (11.5 mL, 138.6 mmol) was slowly added dropwise with stirring. After the addition was complete, the temperature was raised to 75 °C and the reaction was refluxed for 12 h. After the reaction was completed, the temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a solid crude product. The crude product was dissolved in 100 mL of ethyl acetate, washed twice with 50 mL of 10% K2CO3 (mass fraction), and then washed with 50 mL of water. The organic phase was separated and concentrated under reduced pressure to obtain compound (2): 18.3 g, with a yield of 81.1% and a purity of 95.7%.

[0088] Example 4 Preparation of compounds (3) and (4)

[0089]

[0090] Compound (2), namely dimethyl 1,4-naphthalenedicarboxylate (30 g, 122.8 mmol) and THF (120 mL), were added to a 1000 mL round-bottom flask. The mixture was stirred until the solid dissolved, and KOH (11 g, 196.5 mmol) was added. The reaction was carried out at room temperature for 6 h. After the reaction was completed, the reaction solution was cooled to below 0 °C, and water (240 mL) was added. The solution was washed twice with toluene (240 mL), and the liquid was separated. The aqueous phase was slowly added dropwise with 4 mol / L hydrochloric acid (50 mL) at 0 °C. After the addition was completed, the solution was filtered to obtain 26.0 g of off-white solid, namely compound (4), with a yield of 92% and a purity of 96.2%. Detection:

[0091] 1 H NMR (400MHz, DMSO) δ8.93–8.68(m,1H),8.71–8.50(m,1H),8.21–7.97(m,2H),7.75–7.65(m,2H),3.95(s,3H).

[0092] Example 5 Preparation of compounds (6) and (7)

[0093]

[0094] Compound (4), namely 4-methoxycarbonyl-1-naphthoic acid (20 g, 87 mmol), compound (5), namely cyclo(isopropyl)malonic acid (16.3 g, 113 mmol), and dichloromethane (150 mL) were added to a 500 mL round-bottom flask. The temperature was lowered to below 0 °C, and DMAP (6.3 g, 52.2 mmol) and Et3N (26.4 g, 261 mmol) were added with stirring. After the solution became clear, EDCI (33.4 g, 174 mmol) was added. The mixture was stirred at low temperature for 0.5 h, and then the temperature was raised to room temperature for 3 h. The dichloromethane was removed by concentration under reduced pressure. Add toluene (200 mL) and 4 mol / L HCl (100 mL), heat to 65 °C and reflux for 12 h. Separate the phases. Wash the toluene phase with water (200 mL) and then with 5% KHCO3 (200 mL). Concentrate the toluene phase under reduced pressure to obtain a white solid, compound (7): 17.0 g, yield 85%, purity 97.5%. Detection:

[0095] 1 H NMR (400MHz, CDCl3) δ8.88-8.78(m,1H),8.55-8.45(m,1H),8.12(d,J=7.5H z,1H),7.81(d,J=7.5Hz,1H),7.75–7.54(m,2H),4.03(s,3H),2.75(s,3H).

[0096] Example 6 Preparation of compounds (6) and (7)

[0097] Compound (4), namely 4-methoxycarbonyl-1-naphthoic acid (26 g, 113 mmol), compound (5), namely cyclo(isopropyl)malonic acid (24.5 g, 169.5 mmol), and dichloromethane (260 mL) were added to a 500 mL round-bottom flask. The mixture was cooled to below 0 °C, and DMAP (16.4 g, 135.6 mmol) was added with stirring. After the solution became clear, DCC (35.1 g, 169.5 mmol) was added. The mixture was stirred at low temperature for 0.5 h, and then the reaction was allowed to proceed to room temperature for 3 h. The mixture was filtered to remove a large amount of DCC. The reaction solution was washed twice with distilled water (200 mL), and the DCC was evaporated to dryness. Add toluene (200 mL) and 4 mol / L HCl (100 mL), heat to 65 °C and reflux for 12 h. Separate the liquid and wash the toluene phase with water (200 mL). Concentrate the toluene phase under reduced pressure to obtain a yellow solid, namely compound (7): 21.5 g, yield 83.5%, purity 91.7%.

[0098] Example 7 Preparation of 4-acetyl-1-naphthoic acid as shown in formula (II)

[0099]

[0100] Compound (7), namely methyl 4-acetyl-1-naphthoic acid (17 g, 74.5 mmol) and toluene (170 mL), were added to a 250 mL round-bottom flask and stirred to dissolve. Water (170 mL), NaOH (5.9 g, 149 mmol), and TBAB (4.8 g, 14.9 mmol) were added, and the mixture was heated to 65 °C and reacted overnight. The reaction solution was cooled to room temperature, and the liquid was separated. The aqueous phase was washed with toluene (170 mL). Under stirring at room temperature, 4 mol / L HCl (40 mL) was slowly added dropwise until the solid completely precipitated. Stirring was continued for 1 h, and the mixture was filtered and dried to obtain a white solid, namely 4-acetyl-1-naphthoic acid: 14.5 g, yield 91.2%, purity 98.6%; Detection:

[0101] 1 H NMR (400MHz, DMSO) δ8.76(dd,J=7.2,2.3Hz,1H),8.43(dd,J=7.2,2.3Hz,1H),8.07(dd,J=20.6,7.5Hz,2H),7.75–7.60(m,2H),2.72(s,3H).

[0102] In summary, the method for preparing afollana intermediate (Formula II) provided by the present invention has the advantages of using inexpensive and readily available raw materials, simple reaction steps, mild reaction conditions, environmental friendliness, and suitability for industrial production. Compared with the prior art, the afollana intermediate (Formula II) obtained by the method of the present invention has the advantages of high purity and high yield.

[0103] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing 4-acetyl-1-naphthoic acid, comprising: Step (a): Thionyl chloride was added to the reaction solvent of compound (1), and the reaction was carried out under certain temperature conditions to prepare compound (2), as shown in the following equation: in, The reaction solvent is at least one of methanol or ethanol; The addition of thionyl chloride is carried out below 0°C; The specified temperature is 60℃-90℃; The reaction time is from 2 hours to 18 hours; Step (b): Compound (2) reacts with a base in a reaction solvent to obtain compound (3). After post-treatment, compound (3) is hydrolyzed under the action of acid to prepare compound (4). The reaction formula is shown below: in, M is a lithium, sodium, or potassium ion; The reaction solvent is at least one of DMF, toluene, methanol, or benzene. The alkali is at least one selected from KOH, LiOH, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, or potassium carbonate. The acid is at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid; Step (c): Compound (4) and compound (5) react in the presence of a reaction solvent, catalyst, base and condensing agent at a certain temperature to prepare compound (6), as shown in the following reaction formula: in, The catalyst is at least one of DMAP, HOBt, or 4-PPy; The condensing agent is EDCI; The base is triethylamine; Step (d): In the reaction solvent, compound (6) reacts under the conditions of adding acid and a certain temperature to prepare compound (7), as shown in the following equation: in, The acid is at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid; The method further includes: preparing 4-acetyl-1-naphthoic acid by hydrolyzing compound (7).

2. The method of claim 1, wherein in step (c), the reaction solvent is at least one of DCM, dichloroethane, DMSO or DMF.

3. The method of claim 1, wherein in step (d), the reaction solvent is at least one of toluene, xylene, benzene, or ethylbenzene.

4. The method according to claim 1, wherein in step (c), the certain temperature is -10℃ to 30℃.

5. The method according to claim 1, wherein in step (d), the certain temperature is 60℃-90℃.

6. The method of claim 1, in step (c), for every 1.0 mole of compound (4), the amount of compound (5) fed is 1.0-1.5 moles.

7. The method of claim 1, wherein in step (a), the amount of thionyl chloride fed for every 1.0 mole of compound (1) is 1.0-3.5 moles.

Images