A preparation method of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid

Abstract

The invention discloses a method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid, comprising: using 2-bromo-6-fluorobenzaldehyde as a reaction raw material, difluoromethylating with difluorobromomethyltrimethylsilane in the presence of a base, an iridium catalyst and an additive to obtain 2-bromo-6-(difluoromethoxy)benzaldehyde, and then reacting with ethyl isocyanoacetate under the action of a base and cuprous iodide to close the indole ring to obtain ethyl 4-(difluoromethoxy)-1H-indole-2-carboxylate, and then hydrolyzing the indole ring to obtain the target compound 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. In the present invention, a one-pot method is used to realize the group conversion of halogen atoms to difluoromethoxy, simplify the reaction operation, improve the reaction yield, shorten the reaction steps, the reagents used are low-toxic and easy to obtain, and the use of dangerous reagents such as ethyl azidoacetate is avoided, and the potential safety hazards in the reaction process are effectively avoided, which is suitable for amplified production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical synthesis intermediates, and in particular to a method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. Background Art

[0002] Due to their own atomic properties, fluorinated compounds have ideal lipid solubility and hydrophobicity. In recent years, they have been widely used in the development and assembly of active molecules such as medicines and pesticides, and there is a trend of further improvement. Among them, the biological activity of the difluoromethoxy group has attracted particular attention. It has been introduced into the modification of pesticide active molecules many times, showing excellent pharmacodynamic activity. More importantly, this type of compound has appeared in the molecules of many candidate drugs. It has been reported that indole heterocyclic compounds containing difluoromethoxy groups can be used as key intermediates to synthesize drugs for the treatment of coronavirus, mesothelioma virus and norovirus infections (WO2021252491 A1), and the market application prospects are huge. 4-(Difluoromethoxy)-1H-indole-2-carboxylic acid, as one of the difluoromethoxy indole heterocyclic compounds, also has huge application prospects. Exploring its ideal synthesis route can not only promote the development of this type of compound in the fields of medicine and pesticides, but also further improve the development efficiency of high-efficiency drugs.

[0003] In the prior art, the preparation of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid has not been reported in the literature. The preparation of its similar compound 6-chloro-4-(difluoromethoxy)-1H-indole-2-carboxylic acid can be carried out by the following synthetic route:

[0004]

[0005] This route uses compound A 4-chloro-2-fluorobenzyl ester as a raw material, which is hydrolyzed to obtain compound B 4-chloro-2-hydroxybenzaldehyde, and compound B is difluoromethoxylated with diethyl (bromodifluoromethyl)phosphonate at low temperature to obtain compound C 4-chloro-2-(difluoromethoxy)benzaldehyde, and compound C is then reacted with ethyl azidoacetate to obtain compound D 6-chloro-4-(difluoromethoxy)-1H-indole-2-carboxylic acid ethyl ester, and compound D is then hydrolyzed to obtain the target compound 6-chloro-4-(difluoromethoxy)-1H-indole-2-carboxylic acid (WO2018210988 A1, WO2021252491 A1).

[0006] The above route has certain drawbacks in the process of extensive synthesis of compounds. First, step 2 not only needs to be carried out at -25°C, which is inconvenient, but also has a large room for improvement in the reaction yield, which is only 62%; second, ethyl azidoacetate is used as a ring-closing reagent in step 3, which is an extremely unstable and explosive reagent, and there are great safety hazards in both process production and the preparation of a small amount of compounds in the laboratory; third, the reaction operation of this route is cumbersome and the reaction steps are lengthy, which is not an ideal preparation route for 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. Summary of the invention

[0007] Aiming at the lack of a preparation route of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid in the prior art and the problems of complicated operation, lengthy steps, high potential safety hazard of reagents used, low reaction yield and the like in the preparation route of similar compounds, the present invention provides a preparation method of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid, which has simple operation, short steps, safe and stable reagents and raw materials used, and ideal reaction yield.

[0008] To achieve the above object, the present invention adopts the following technical solution:

[0009] The present invention provides a method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid, and the technical route thereof is shown in the following formula:

[0010]

[0011] The following steps are involved:

[0012] Step 1: dissolve compound 1 in organic solvent 1, add aqueous solution of base 1, stir for 0.5-2h, add catalyst, additive and difluorobromomethyltrimethylsilane under nitrogen protection, heat to 30-150°C and react for 1-24h; obtain compound 2;

[0013] Step 2: Add compound 2 to organic solvent 2, add ethyl isocyanoacetate, cuprous iodide and base 2, and under nitrogen protection, heat to 60-120° C. and react for 5-20 hours to obtain compound 3;

[0014] Step 3: Add compound 3 to organic solvent 3, add water and base 3, react at room temperature for 3 to 24 hours, adjust the pH of the reaction solution to 2 to 3 with acid solution, and obtain the target compound 4.

[0015] Further, the reaction steps can be described as:

[0016] Step a1: dissolving compound 1 in organic solvent 1, controlling the temperature at -5 to 5°C, adding an aqueous solution of alkali, stirring for 0.5 to 2 hours, and then adding a catalyst, an additive and difluorobromomethyltrimethylsilane. After the addition, heating to 30 to 150°C and reacting for 1 to 24 hours; pouring into ice water, extracting the aqueous phase obtained by separation with dichloromethane, combining the organic phases, drying, desolventizing under reduced pressure, and then purifying to obtain compound 2;

[0017] Step a2: Add compound 2 to organic solvent 2, add ethyl isocyanoacetate, cuprous iodide and base 2, and heat to 60-120° C. under nitrogen protection for reaction for 5-20 hours, pour into ice water, extract with dichloromethane, dry, and distill under reduced pressure to obtain compound 3 after purification;

[0018] Step a3: Add compound 3 to organic solvent 3, add water and base 3, react at room temperature for 3 to 24 hours, adjust the pH of the reaction solution to 2 to 3 with acid solution, filter, and obtain the target compound 4.

[0019] Furthermore, in step 1, the organic solvent 1 is selected from one or more of dichloromethane, dichloroethane, chloroform, ethyl acetate, and acetonitrile.

[0020] Furthermore, in step 1, the base 1 is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

[0021] Furthermore, in step 1, the aqueous solution of alkali 1 may be a 20% aqueous solution of alkali 1.

[0022] Furthermore, in step 1, the catalyst is selected from one or more of iridium trichloride and iridium carbonate.

[0023] Furthermore, in step 1, the additive is selected from copper bromide and / or copper chloride.

[0024] Furthermore, in step 1, the molar ratio of the compound 1, the base 1, the catalyst, the additive and difluorobromomethyltrimethylsilane is 1:(2-5):(0.01-0.1):(0.1-0.3):(1-2), preferably 1:5:0.05:0.3:2.

[0025] Furthermore, in step 1, the mass volume ratio of the compound 1 to the organic solvent 1 is 1:5 to 15 g / mL.

[0026] Furthermore, in step 1, the reaction temperature is preferably 80°C.

[0027] Furthermore, in step 1, the reaction time is preferably 8 h.

[0028] Furthermore, in step 2, the organic solvent 2 is selected from one or more of dimethyl sulfoxide, acetonitrile, and N,N-dimethylformamide.

[0029] Furthermore, in step 2, the base 2 is selected from one or more of cesium carbonate, potassium carbonate, and sodium carbonate.

[0030] Furthermore, in step 2, the molar ratio of the compound 2, ethyl isocyanoacetate, cuprous iodide and base 2 is 1:(1-2.5):(0.1-0.25):(1-2.5), preferably 1:1.5:0.15:1.5.

[0031] Furthermore, in step 2, the mass volume ratio of the compound 2 to the organic solvent 2 is 1:5 to 15 g / mL.

[0032] Furthermore, in step 2, the reaction temperature is preferably 90°C.

[0033] Furthermore, in step 2, the reaction time is preferably 12 h.

[0034] Furthermore, in step 3, the base 3 is selected from one or more of potassium hydroxide, sodium hydroxide, aluminum hydroxide, and carbon.

[0035] Furthermore, in step 3, the organic solvent 3 is selected from one or more of tetrahydrofuran, methanol, ethanol, acetonitrile, and N,N-dimethylformamide.

[0036] Furthermore, in step 3, the acid solution is preferably a 5 mol / L hydrochloric acid solution.

[0037] Furthermore, in step 3, the mass volume ratio of the compound 3 to the organic solvent 3 is 1:2-5 g / mL.

[0038] Furthermore, in step 3, the mass volume ratio of the compound 3 to water is 1:1.5-3 g / mL.

[0039] Furthermore, in step 3, the reaction time is preferably 12 h.

[0040] Compared with the prior art, the preparation method of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid in the present invention has the following beneficial effects:

[0041] 1. In the reaction system provided by the present invention, a one-pot method is implemented to directly convert halogen atoms into difluoromethoxy groups, which not only simplifies the reaction operation and improves the reaction yield, but also simplifies the four-step reaction in the prior art into three steps, shortening the reaction steps.

[0042] 2. The reagents used are low-toxic and easily available, avoiding the use of dangerous reagents such as ethyl azidoacetate, effectively avoiding potential safety hazards in the reaction process.

[0043] 3. During the reaction process, there is no ultra-low temperature condition which causes many inconveniences in operation, thus improving the operability of the reaction.

[0044] 4. The entire synthetic route has a high repetition rate and is a potential route for industrial scale-up production, which can provide a reliable reference for the preparation of similar compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is a schematic diagram of the synthesis technology route of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid in the embodiment. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical solution and advantages of the embodiment of the present invention clearer, the technical solution of the embodiment of the present invention will be clearly and completely described in conjunction with the drawings of the embodiment of the present invention. Obviously, the described embodiment is a part of the embodiment of the present invention, not all of the embodiments. Based on the described embodiment of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0047] Example 1

[0048] This embodiment provides a method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid, and its technical route and steps are as follows:

[0049] Step 1

[0050]

[0051] 50 g of compound 1 was added to 500 mL of dichloromethane, and 340 mL of 20% KOH aqueous solution was added at 0° C. The mixture was stirred for 1 h at this temperature. Under nitrogen protection, 3.64 g of iridium trichloride and 10.49 g of copper bromide were added, and then 100 g of difluorobromomethyltrimethylsilane was added dropwise to the system. The temperature was raised to 80° C. and reacted for 8 h. The mixture was poured into 400 mL of ice water, and the liquids were separated. The obtained aqueous phase was extracted with 600 mL of dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was mixed with a sample, and petroleum ether and ethyl acetate (PE:EA=5:1) were used as eluents for column chromatography purification to obtain 53.73 g of compound 2 with a yield of 82.6% and a purity of 97.2%.

[0052] 1 H NMR (600 MHz, CDCl 3)δ10.34(s,1H),7.57(d,J=8.1Hz,1H),7.41(t,J=8.2Hz,1H),7.24(s,1H),6.60(t,J=73.4Hz,1H).

[0053] Step 2

[0054]

[0055] 30g of compound 2 was added to 250mL of dimethyl sulfoxide, 20.11g of ethyl isocyanoacetate, 3.35g of cuprous iodide, and 57.35g of cesium carbonate, and reacted at 90°C for 12h under nitrogen protection. The mixture was rinsed with 200mL of ice water, extracted with 600mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was mixed with a sample, and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA=5:1) as eluents to obtain 25.4g of compound 5, with a yield of 83.02% and a purity of 96.9%.

[0056] 1 H NMR (600 MHz, CDCl 3 )δ8.95(s,1H),7.33(d,J=1.8Hz,1H),7.27(d,J=6.4Hz,2H),6.86(d,J=7.1H z,1H),6.66(t,J=74.1Hz,1H),4.42(q,J=7.1Hz,2H),1.42(t,J=7.1Hz,3H).

[0057] Step 3

[0058]

[0059] 25.45 g of compound 3 was added to 90 mL of THF, 45 mL of water and 6.14 g of lithium hydroxide monohydrate, and the mixture was stirred at room temperature for 12 h. The pH of the reaction solution was adjusted to 3 with 20 mL of 5N hydrochloric acid, and the mixture was filtered. The filter cake was dissolved with 50 mL of ethyl acetate, and the water was removed by distillation under reduced pressure to obtain 20.1 g of compound 4 with a yield of 90.2% and a purity of 98.5%.

[0060] 1 H NMR (600MHz, DMSO) δ13.12(s,1H),12.08(s,1H),7.35(dd,J=41.0,38.8Hz,2H),7.23(dd,J=21.6,13.6Hz,1H),7.05(s,1H),6.84(d,J=7.6Hz,1H).

[0061] In order to further obtain the influence of each reaction condition on the reaction in step 1, Examples 2-9 and Comparative Example 1 used different reaction conditions to explore the influence of each reaction condition on the reaction (Table 1). Except for the variables, the other steps are the same as Example 1.

[0062] Table 1

[0063]

[0064]

[0065] From Table 1, comparing Examples 1, 2, 3 and Example 7, potassium hydroxide has a better promoting effect on the reaction than sodium hydroxide and sodium tert-butoxide, and further, its dosage of 5eq is more suitable; comparing Examples 1 and 4, dichloromethane is better than ethyl acetate as a solvent; comparing Examples 1 and 5, iridium trichloride has a better catalytic effect than iridium carbonate, and further from Comparative Example 1, it can be seen that when there is no catalyst, no product can be obtained, indicating that the catalyst is indispensable in this reaction; from Example 8, it can be seen that the dosage of the catalyst is 0.05eq, which is more suitable; comparing Examples 1 and 6, when copper bromide is used as an additive, the reaction effect is better than copper chloride; from Example 9, it can be seen that the dosage of the additive is 0.3, which is more suitable.

[0066] Example 10

[0067] Step 1

[0068]

[0069] 25 g of compound 1 was added to 250 mL of dichloromethane, and 170 mL of 20% KOH aqueous solution was added at 0° C. The mixture was stirred for 1 h at this temperature. Under nitrogen protection, 1.8 g of iridium trichloride and 3.7 g of copper chloride were added, and then 50 g of difluorobromomethyltrimethylsilane was added dropwise to the system. The temperature was raised to 80° C. and reacted for 8 h. The mixture was poured into 200 mL of ice water and separated. The aqueous phase was extracted with 300 mL of dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was mixed with a sample and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA=5:1) as eluents to obtain 22.46 g of compound 2 with a yield of 70.98% and a purity of 97.7%.

[0070] 1 H NMR (600 MHz, CDCl 3 )δ10.34(s,1H),7.57(d,J=8.1Hz,1H),7.41(t,J=8.2Hz,1H),7.24(s,1H),6.60(t,J=73.4Hz,1H).

[0071] Step 2

[0072]

[0073] 20g of compound 2 was added to 167mL of dimethyl sulfoxide, 8.94g of ethyl isocyanoacetate, 2.23g of cuprous iodide, and 38.23g of cesium carbonate, and reacted at 90°C for 12h under nitrogen protection. The mixture was rinsed with 130mL of ice water, extracted with 400mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was mixed with a sample, and purified by column chromatography using petroleum ether and ethyl acetate (PE:EA=5:1) as eluents to obtain 14.29g of compound 5, with a yield of 69.77% and a purity of 96.5%.

[0074] 1 H NMR (600 MHz, CDCl 3 )δ8.95(s,1H),7.33(d,J=1.8Hz,1H),7.27(d,J=6.4Hz,2H),6.86(d,J=7.1H z,1H),6.66(t,J=74.1Hz,1H),4.42(q,J=7.1Hz,2H),1.42(t,J=7.1Hz,3H).

[0075] Step 3

[0076]

[0077] 14.29 g of compound 3 was added to 50 mL of acetonitrile, 25 mL of water and 3.38 g of lithium hydroxide monohydrate, and the mixture was stirred at room temperature for 12 h. The pH of the reaction solution was adjusted to 3 with 11 mL of 5N hydrochloric acid, and the mixture was filtered. The filter cake was dissolved with 28 mL of ethyl acetate, and the mixture was distilled under reduced pressure to remove the water, thereby obtaining 11.1 g of compound 4 with a yield of 85.6% and a purity of 98.1%.

[0078] 1 H NMR (600MHz, DMSO) δ13.12(s,1H),12.08(s,1H),7.35(dd,J=41.0,38.8Hz,2H),7.23(dd,J=21.6,13.6Hz,1H),7.05(s,1H),6.84(d,J=7.6Hz,1H).

[0079] In order to further obtain the influence of each reaction condition on the reaction in step 2, Examples 10-17 used different reaction conditions to explore the influence of each reaction condition on the reaction (Table 2). Except for the variables, the other steps are the same as Example 1.

[0080] Table 2

[0081]

[0082]

[0083] From Table 2, compared with Examples 1, 10, and 11, the dosage of ethyl isocyanoacetate is more suitable at 1.5 eq; compared with Examples 1, 12, and 13, it can be seen that dimethyl sulfoxide has a better promoting effect on the reaction than acetonitrile and N,N-dimethylformamide; compared with Examples 1, 14, and 15, the reaction effect of cesium carbonate is better than potassium carbonate and sodium carbonate, and it can be seen from Examples 16 and 17 that its dosage is more suitable at 1.5 eq. On this basis, increasing or decreasing its dosage will reduce the reaction yield.

[0084] The above description of the embodiments is to facilitate the understanding and use of the present invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments. Improvements and modifications made by those skilled in the art based on the principles of the present invention without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. A method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid, characterized in that: The synthetic route is shown below: The following steps are involved: Step 1: dissolving compound 1 in organic solvent 1, adding aqueous solution of base 1, stirring for 0.5 to 2 hours, adding catalyst, additive and difluorobromomethyltrimethylsilane under nitrogen protection, heating to 30 to 150° C. and reacting for 1 to 24 hours; obtaining compound 2; the catalyst is selected from iridium trichloride and / or iridium carbonate; the additive is selected from copper bromide and / or copper chloride; Step 2: Add compound 2 to organic solvent 2, add ethyl isocyanoacetate, cuprous iodide and base 2, and under nitrogen protection, heat to 60-120° C. and react for 5-20 hours to obtain compound 3; Step 3: Add compound 3 to organic solvent 3, add water and base 3, react at room temperature for 3 to 24 hours, adjust the pH of the reaction solution to 2 to 3 with acid solution, and obtain the target compound 4.

2. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1, characterized in that: The following steps are involved: Step a1: dissolving compound 1 in organic solvent 1, controlling the temperature at -5 to 5°C, adding an aqueous solution of alkali, stirring for 0.5 to 2 hours, and then adding a catalyst, an additive and difluorobromomethyltrimethylsilane. After the addition, heating to 30 to 150°C for reaction for 1 to 24 hours, pouring into ice water, extracting the aqueous phase obtained by separation with dichloromethane, combining the organic phases, drying, desolventizing under reduced pressure, and purifying to obtain compound 2; Step a2: Compound 2 is added to organic solvent 2, ethyl isocyanoacetate, cuprous iodide and base 2 are added, and the temperature is raised to 60-120° C. under nitrogen protection for reaction for 5-20 hours, poured into ice water, extracted with dichloromethane, dried, and distilled under reduced pressure to obtain compound 3 after purification; Step a3: Add compound 3 to organic solvent 3, add water and base 3, react at room temperature for 3 to 24 hours, adjust the pH of the reaction solution to 2 to 3 with acid solution, filter, and obtain the target compound 4.

3. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1 or 2, characterized in that: The organic solvent 1 is selected from one or more of dichloromethane, dichloroethane, chloroform, ethyl acetate, and acetonitrile; And / or the base 1 is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

4. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1 or 2, characterized in that: In step 1, the aqueous solution of alkali 1 is a 20% aqueous solution of alkali 1.

5. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1 or 2, characterized in that: In step 1, the molar ratio of the compound 1, the base 1, the catalyst, the additive and difluorobromomethyltrimethylsilane is 1:(2-5):(0.01-0.1):(0.1-0.3):(1-2); and / or the mass volume ratio of the compound 1 to the organic solvent 1 is 1:5-15 g / mL; And / or in step 1, the reaction temperature is 80° C. and the reaction time is 8 h.

6. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1 or 2, characterized in that: The organic solvent 2 is selected from one or more of dimethyl sulfoxide, acetonitrile, and N,N-dimethylformamide; And / or the base 2 is selected from one or more of cesium carbonate, potassium carbonate and sodium carbonate.

7. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1 or 2, characterized in that: In step 2, the molar ratio of the compound 2, ethyl isocyanoacetate, cuprous iodide and base 2 is 1:(1-2.5):(0.1-0.25):(1-2.5); and / or the mass volume ratio of the compound 2 to the organic solvent 2 is 1:5-15 g / mL; And / or in step 2, the reaction temperature is 90° C. and the reaction time is 12 h.

8. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1 or 2, characterized in that: The base 3 is selected from one or more of potassium hydroxide, sodium hydroxide and aluminum hydroxide; and / or the organic solvent 3 is selected from one or more of tetrahydrofuran, methanol, ethanol, acetonitrile, and N,N-dimethylformamide; And / or the acid solution is 5 mol / L hydrochloric acid solution.

9. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1 or 2, characterized in that: In step 3, the mass volume ratio of the compound 3 to the organic solvent 3 is 1:2-5 g / mL; and / or the mass volume ratio of the compound 3 to water is 1:1.5-3 g / mL; And / or in step 3, the reaction time is 12 h.

10. The method for preparing 4-(difluoromethoxy)-1H-indole-2-carboxylic acid according to claim 1 or 2, characterized in that: In step 1, the molar ratio of the compound 1, the base 1, the catalyst, the additive and difluorobromomethyltrimethylsilane is 1:5:0.05:0.3:2; And / or in step 2, the molar ratio of compound 2, ethyl isocyanoacetate, cuprous iodide and base 2 is 1:1.5:0.15:1.5.

Images