Preparation method of 4-formyl naphthalene-1-carboxylic acid methyl ester

Abstract

The invention relates to a preparation method of 4-formyl naphthalene-1-carboxylic acid methyl ester, and belongs to the technical field of medicine preparation. In order to solve the technical problems of high raw material cost, pressurized high-risk reaction, large wastewater amount, low yield, more impurities and unsuitability for industrial amplification in the existing preparation method of 4-formyl naphthalene-1-carboxylic acid methyl ester, the invention creatively designs the process, and adopts an intermediate A to generate 4-formyl naphthalene-1-carboxylic acid methyl ester through two times of substitution and one time of hydrolysis; the technical problem is effectively solved, the method has the advantages of being high in yield, good in purity, easy and convenient to operate, low in cost and easy to obtain raw materials, few in generated three wastes and suitable for industrial production, the yield of an intermediate B is 90% or above, the purity reaches 96%, the yield of an intermediate C is 80% or above, the purity can reach 99%, and the HPLC purity of the finally prepared 4-formyl naphthalene-1-carboxylic acid methyl ester is 99% or above. The yield is more than 99%.

Description

Technical Field

[0001] The invention relates to the technical field of medicine preparation, and in particular to a method for preparing methyl 4-formylnaphthalene-1-carboxylate. Background Art

[0002] 4-Formylnaphthalene-1-carboxylic acid methyl ester, CAS number: 62855-40-7, is an important intermediate for the synthesis of Afoxolaner. Afoxolaner, a new generation of oral external anthelmintics for dogs, was developed and produced by Boehringer Ingelheim and approved for marketing in China in August 2017. It is the first oral anthelmintic for dogs in China that kills both ticks and fleas. The chemical structure of 4-Formylnaphthalene-1-carboxylic acid methyl ester is as follows:

[0003]

[0004] In the prior art, the raw material 4-methoxycarbonyl-1-naphthalenemethanol used in the preparation of the product in the document Journal of Medicinal Chemistry, 2002, vol. 45, #26, p. 5755-5775 is expensive and difficult to obtain, resulting in high costs and being unfavorable for large-scale production.

[0005] Patent US201277765 relates to a method for synthesizing the product, using 4-(bromomethyl)-1-naphthoic acid methyl ester as a raw material and oxidizing it through a sodium bicarbonate / dimethyl sulfoxide system. This method has the disadvantages of large amount of wastewater, low yield, and many impurities. At the same time, the raw materials are not easy to obtain.

[0006] The product synthesis method disclosed in patent WO2021 / 127188A uses 4-bromo-1-naphthaldehyde, carbon monoxide and methanol as raw materials, and uses the precious metal DPPF palladium dichloride as a catalyst to produce the product by pressurized reaction. In this route, the raw material 4-bromo-1-naphthaldehyde is relatively expensive, DPPF palladium dichloride is a precious metal, carbon monoxide gas is relatively dangerous, and it is also a pressurized high-risk reaction. Such a synthesis process is not suitable for large-scale production.

[0007] Therefore, it is necessary to develop a new method for preparing methyl 4-formylnaphthalene-1-carboxylate that is more suitable for industrialization, has lower cost and higher purity. Summary of the invention

[0008] Aiming at the technical problems that the preparation method of 4-formylnaphthalene-1-carboxylic acid methyl ester has high raw material cost, high-risk reaction under pressure, large amount of waste water, low yield, many impurities and is not suitable for industrial scale-up, the present invention provides a preparation method of 4-formylnaphthalene-1-carboxylic acid methyl ester, which has the characteristics of high yield, good purity, simple operation, cheap and easy-to-obtain raw materials, less three wastes generated and is suitable for industrial production.

[0009] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0010] The present invention provides a method for preparing methyl 4-formylnaphthalene-1-carboxylate, wherein methyl 4-formylnaphthalene-1-carboxylate is prepared by reacting an intermediate C with hydrochloric acid at a temperature of 10° C. to 20° C.

[0011] Specifically, the intermediate C is reacted in the presence of a reaction solvent and hydrochloric acid at a temperature of 10°C-20°C. After the reaction is complete, the intermediate is layered, washed, and the solvent is removed to obtain methyl 4-formylnaphthalene-1-carboxylate.

[0012] More specifically, the intermediate C is added with hydrochloric acid in a reaction solvent DCM at a temperature of 10°C-20°C, and the pH is controlled to be less than 1.0, and the reaction is carried out for 0.5-1h, and the layers are separated, and the organic layer is washed and concentrated under reduced pressure to obtain 4-formylnaphthalene-1-carboxylic acid methyl ester;

[0013] The molar ratio of the intermediate C to hydrochloric acid is 1:5 to 1:2.0.

[0014] The intermediate C has the following structural formula:

[0015]

[0016] The intermediate C is prepared by the following method;

[0017] The method comprises dissolving the intermediate B in morpholine, adding lithium hydroxide, reacting for 2-6 hours at a temperature of 55° C.-65° C., cooling the reaction liquid to room temperature, extracting, washing, removing the solvent, and recrystallizing to obtain the intermediate C;

[0018] The intermediate B has the following structural formula:

[0019]

[0020] The molar ratio of the intermediate B to morpholine is 1:1.2 to 1:10.

[0021] The solvent for the recrystallization is acetonitrile.

[0022] The extraction solvent is DCM.

[0023] The preparation method of the intermediate B is to react the intermediate A with NBS in the presence of a solvent and an initiator catalyst at a temperature of 75° C. to 85° C. to obtain the intermediate B;

[0024] Specifically, the intermediate A reacts with NBS in the presence of trifluorotoluene and AIBN at a temperature of 75°C-85°C. After the reaction is complete, the temperature is cooled to room temperature, and the intermediate B is obtained by washing, extraction, washing, and concentration under reduced pressure.

[0025] More specifically, the intermediate A reacts with NBS in the presence of trifluorotoluene solvent and initiator AIBN at 75°C-85°C. After the reaction is complete, the temperature is cooled to room temperature, 25% NaSO3, water and DCM are added for extraction, and then washed and concentrated under reduced pressure to obtain intermediate B.

[0026] The molar ratio of the intermediate A to the initiator is 1:0.1 to 1:1.0.

[0027] The molar ratio of the intermediate A to NBS is 1:1 to 1:2.5.

[0028] The intermediate A has the following structural formula:

[0029]

[0030] Intermediate A can be prepared by methylation reaction of 4-methyl-1-naphthoic acid; the specific preparation method is: 4-methyl-1-naphthoic acid, temperature controlled at 20-25°C, thionyl chloride is added dropwise, the temperature is slowly raised to 50-60°C for reaction after the addition is completed, after the reaction is completed, the reaction liquid is spin-dried, water and ethyl acetate are added for extraction, the water layer is separated, and the organic layer is washed with 20% sodium chloride solution, and the organic phase is evaporated to dry the solvent to obtain intermediate A or prepared by a method in the literature.

[0031] Compared with the prior art, the present invention has the following beneficial technical effects:

[0032] 1. The present invention provides a novel method for preparing methyl 4-formylnaphthalene-1-carboxylate. Through a creative design process, intermediate A is subjected to two substitutions and one hydrolysis to generate afolanine intermediate I, i.e. methyl 4-formylnaphthalene-1-carboxylate; intermediate A is substituted once to obtain intermediate B. The advantage of this step is that NBS is added in batches during the reaction, the temperature is controllable, and the reaction process is also clear. Then, intermediate C is obtained by substitution reaction. The advantage of this step is that intermediate C can obtain a high purity and yield in this step. Then, intermediate C is subjected to hydrolysis to obtain intermediate B. The method is characterized in that 4-formylnaphthalene-1-carboxylic acid methyl ester is prepared by decomposition, and the advantages of this step are fast reaction, high yield and high purity. The technical scheme of the present invention effectively overcomes the technical problems that the existing process for preparing 4-formylnaphthalene-1-carboxylic acid methyl ester generally has high raw material cost, high-risk pressurized reaction, large amount of waste water, low yield, many impurities and is not suitable for industrial scale-up. The method for preparing 4-formylnaphthalene-1-carboxylic acid methyl ester provided by the present invention has the characteristics of high yield, good purity, simple operation, cheap and easy-to-obtain raw materials, less three wastes generated and is suitable for industrial production.

[0033] 2. The preparation method of 4-formylnaphthalene-1-carboxylic acid methyl ester of the present invention has the following characteristics: the yield of intermediate B is more than 90%, and the purity is 96%, the yield of intermediate C is more than 80%, and the purity can reach 99%, and the HPLC purity of the finally obtained 4-formylnaphthalene-1-carboxylic acid methyl ester is more than 99%, and the yield is more than 99%.

[0034] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0035] In the present invention, expressions such as "Compound 1", "Compound represented by Formula 1" and "Formula 1" refer to the same compound. DETAILED DESCRIPTION

[0036] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

[0037] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0038] In the present invention, min means minute; h means hour; g means gram; and ml means milliliter.

[0039] In the present invention, HPLC means high performance liquid chromatography.

[0040] Example 1 Preparation of Intermediate A

[0041] Add 200 ml of methanol and 4-methyl-1-naphthoic acid (16.54 g, 0.088 mol) to a 500 ml reaction bottle at room temperature, control the temperature at 20-25 ° C, add thionyl chloride (19.68 g, 0.165 mol) dropwise, slowly raise the temperature to 50-60 ° C and react for 0.5 h, take a sample and control AF06 < 0.2% in HPLC; spin dry the reaction solution, add 50 ml of water and 100 ml of EA, separate the water layer, add 50 ml of 20% sodium chloride solution to the organic layer for washing, evaporate the organic phase to dry the solvent to obtain intermediate A, 16.8 g, yield 96%, HPLC purity 99%.

[0042] Example 2 Preparation of Intermediate B

[0043] At room temperature, add intermediate A (17.6 g, 0.088 mol), trifluorotoluene 60 g, AIBN 1.0 g (5%) to a 250 ml reaction bottle, control the temperature at 75-85 ° C, add NBS (33.2 g, 0.186 mol) in batches, react at 80-85 ° C for 2 h, take a sample and control the monobrominated intermediate B to be less than 0.5% by HPLC; cool to room temperature, add 25% NaSO3 solution 5 ml to the reaction solution, add water 100 ml, DCM 100 ml, stir and separate, extract the aqueous layer with 50 ml DCM, combine the organic layers, add 20% sodium chloride solution 100 ml for washing, evaporate the organic phase to dry the solvent to obtain intermediate B, 29.0 g, yield 92%, HPLC purity 96%.

[0044] Example 3 Preparation of Intermediate C

[0045] Add intermediate B (37.8 g, 0.079 mol) and 85 g of morpholine to a 500 ml reaction bottle at room temperature, control the temperature at 55-65°C to react for 4 h, and control the intermediate B to be <0.5% in sampling HPLC; cool the reaction to room temperature, add 150 ml of water and 150 ml of DCM, stir to dissolve, separate the layers, extract the aqueous phase once with 50 ml of DCM, combine the organic phases, add 100 ml of water to wash once, wash once with 100 ml of 20% sodium chloride solution, evaporate the solvent, add 50 ml of acetonitrile to recrystallize to obtain intermediate C, 23.4 g, with a yield of 80%.

[0046] Example 44 Preparation of methyl 4-formylnaphthalene-1-carboxylate

[0047] To a 250 ml reaction bottle, add the above intermediate C (14.5 g, 0.0392 mol), DCM72.5 ml, control the temperature at 10-20 ° C, add 6 M hydrochloric acid 30.2 g dropwise, PH <1.0, react for 0.5-1 h, and the intermediate C is controlled to react completely in HNMR; separate the layers, discard the aqueous layer, add 100 ml of water to the organic layer, wash it once, wash it once with 100 ml of 20% sodium chloride solution, and evaporate the solvent to obtain 4-formylnaphthalene-1-carboxylic acid methyl ester product, 8.01 g, yield 95%, purity 99.6%, and very pure by NMR.

[0048] Example 5 Process Optimization

[0049] According to the method in Example 2, the effects of different process parameters on the purity and yield of intermediate B were investigated.

[0050] Table 1 Effect of process parameters on purity and yield of intermediate B

[0051] Example 2-1 2-2 2-3 2-4 2-5 Molar ratio (NBS: intermediate A) 1.0 1.5 2.0 2.5 3.0 Molar ratio (AIBN: intermediate A) 0.1 0.2 0.5 0.8 1.0 temperature 75℃ 75℃ 80℃ 80℃ 85℃ Solvents Trifluorotoluene Toluene DCE Trifluorotoluene Trifluorotoluene Yield / % 15 5 50 93 85 purity / % 40 15 87 97 78

[0052] As can be seen from Table 1, the type of solvent and the equivalent of NBS have a great influence on the reaction results. The most suitable reaction temperature is 75℃-85℃. If the temperature is too low, the reaction is too slow, and if the temperature is too high, impurities are easily generated.

[0053] According to the method in Example 3, the effects of different process parameters on the purity and yield of intermediate C were investigated.

[0054] Table 2 Effect of process parameters on purity and yield of intermediate C

[0055] Example 3-1 3-2 3-3 3-4 3-5 Molar ratio (morpholine: intermediate B) 1.0 1.5 2.0 2.5 3.0 temperature 55℃ 60℃ 60℃ 60℃ 65℃ Solvents Morpholine Morpholine Morpholine Morpholine Morpholine Reaction time / h 12 12 6 6 6 Yield / % 55 75 79 80 80 purity / % 98 99 99 99 99

[0056] As can be seen from Table 2, the equivalent of morpholine has a great influence on the yield and purity of the product, and the temperature only affects the reaction rate. Finally, we chose 2.5 equivalents of morpholine, and the temperature was feasible between 55°C and 65°C.

[0057] According to the method in Example 4, the effects of different process parameters on the purity and yield of methyl 4-formylnaphthalene-1-carboxylate were investigated.

[0058] Table 3 Effect of process parameters on purity and yield of methyl 4-formylnaphthalene-1-carboxylate

[0059] Example 4-1 4-2 4-3 4-4 4-5 Molar ratio (hydrochloric acid: intermediate C) 1 1.5 1.5 1.5 2.0 temperature 10℃ 10℃ 20℃ 20℃ 15℃ Solvents DCM DCM DCE DCM THF Yield / % 80 96 91 80 87 purity / % 94 99.6 98 96 98

[0060] As can be seen from Table 3, the highest yield and purity are achieved when dichloromethane is selected as the solvent, the hydrochloric acid equivalent is 1.5, and the reaction temperature is 10°C. Heating will produce other impurities, and less hydrochloric acid equivalent will lead to incomplete hydrolysis and poor product stability.

[0061] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for preparing methyl 4-formylnaphthalene-1-carboxylate, characterized in that: The method comprises the following steps: reacting the intermediate C with hydrochloric acid at a temperature of 10°C to 20°C to obtain methyl 4-formylnaphthalene-1-carboxylate; The intermediate C has the following structural formula: The intermediate C is prepared by the following method; Dissolve intermediate B in morpholine, add lithium hydroxide, react at 55-65°C for 2-6 hours, then cool the reaction solution to room temperature. After extraction, washing, solvent removal and recrystallization, intermediate C was obtained; The intermediate B has the following structural formula: The preparation method of the intermediate B is that the intermediate A reacts with NBS in the presence of a solvent and an initiator catalyst at a temperature of 75° C. to 85° C. to obtain the intermediate B; The intermediate A has the following structural formula:

2. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to claim 1, characterized in that: The molar ratio of the intermediate C to hydrochloric acid is 1:5 to 1:2.

0.

3. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to claim 1 or 2, characterized in that: The molar ratio of the intermediate B to morpholine is 1:1.2 to 1:

10.

4. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to any one of claims 1 to 3, characterized in that: The molar ratio of the intermediate A to the initiator is 1:0.1 to 1:1.

0.

5. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to any one of claims 1 to 3, characterized in that: The molar ratio of the intermediate A to NBS is 1:1 to 1:2.

5.

6. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to claim 1, characterized in that: The intermediate C is added with hydrochloric acid in a reaction solvent DCM at a temperature of 10°C-20°C, and the pH is controlled to be less than 1.

0. The reaction is carried out for 0.5-1h, and the layers are separated. The organic layer is washed and concentrated under reduced pressure to obtain methyl 4-formylnaphthalene-1-carboxylate.

7. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to claim 1, characterized in that: In the preparation method of the intermediate C, the solvent for recrystallization is acetonitrile.

8. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to claim 1, characterized in that: In the preparation method of the intermediate C, the extraction solvent is DCM.

9. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to claim 1, characterized in that: The preparation method of the intermediate B comprises: reacting the intermediate A with NBS in the presence of a solvent, trifluorotoluene and an initiator, AIBN, at a temperature of 75° C.-85° C., cooling to room temperature after the reaction is complete, adding 25% NaSO3, water and DCM for extraction, washing, and concentrating under reduced pressure to obtain the intermediate B.

10. The method for preparing methyl 4-formylnaphthalene-1-carboxylate according to claim 1, characterized in that: The intermediate A can be prepared by: adding 4-methyl-1-naphthoic acid to a temperature of 20-25° C., dripping thionyl chloride, slowly heating to 50-60° C. after the dripping, and after the reaction is complete, spinning the reaction solution to dryness, adding water and ethyl acetate for extraction, separating the water layer, adding 20% ​​sodium chloride solution to the organic layer for washing, and evaporating the organic phase to dry the solvent to obtain the intermediate A.

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