A process for the preparation of 4-bromothieno[2,3-c]pyridine-2-carboxylic acid ethyl ester

Abstract

The application discloses a preparation method of 4-bromothieno[2,3-c]pyridine-2-carboxylic acid ethyl ester, which comprises the following steps: 5-bromo-4-iodopyridine-3-thiol and propargyl acid ethyl ester are subjected to a Sonogashira coupling and a ring-closing series reaction under the action of a catalyst and an alkali to obtain 4-bromothieno[2,3-c]pyridine-2-carboxylic acid ethyl ester. The raw material adopted by the method is cheap and easy to obtain, the synthesis method is simple to operate, the reaction condition is mild, the requirement for equipment is low, and the method is suitable for the needs of industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylic acid. Background Technology

[0002] Ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylate is an important organic synthetic intermediate that can be used to synthesize bioactive molecules with antiviral activity, for treating hyperuricemia, or central nervous system diseases. Currently, there are few reported methods for synthesizing this intermediate, and it is difficult to purchase commercially. Therefore, developing a simple and efficient synthetic method to prepare ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylate is of great significance.

[0003] Literature review revealed that the synthesis of ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylate mainly employs the following two methods:

[0004] Method 1: International patents WO2016150255 A1, WO2018172250A1, WO2015131856A1, and WO2023044171A1 report the cyclization reaction of 3,5-dibromoisonic aldehyde with ethyl mercaptohydrate in the presence of cesium carbonate to obtain the target product, ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylate. The raw material 3,5-dibromoisonic aldehyde used in this method is expensive, and ethyl mercaptohydrate has a strong odor and is irritating to the skin, thus it does not meet the requirements for industrial production.

[0005]

[0006] Method 2: Reference "Synthesis of thieno[2,3-c]pyridine derived GRK2 inhibitors"

[0007] The paper "(MonatsheftefuerChemie, 2023, 154(12), 1339-1357)" reported the use of 3,5-dibromoisonitrile and ethyl mercaptophosphate in the presence of potassium carbonate to obtain the target compound 4-bromothiopheno[2,3-c]pyridine-2-carboxylic acid ethyl ester via a cyclization reaction. However, this method also suffers from drawbacks such as expensive raw materials and high toxicity, and therefore does not meet the requirements for large-scale production.

[0008] Summary of the Invention

[0009] To address the shortcomings of the prior art, this invention aims to provide a method for preparing ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylate, which is suitable for industrial production, has inexpensive and readily available raw materials, a simple synthesis method, mild reaction conditions, low equipment requirements, is technically feasible, economically reasonable, and cost-effective.

[0010] The present invention provides a method for preparing ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylate, comprising the following steps:

[0011] Using 5-bromo-4-iodopyridine-3-thiol and ethyl propynate as raw materials, ethyl 4-bromothio[2,3-c]pyridine-2-carboxylic acid was obtained by Sonogashira coupling and cascade closure reaction under the action of catalyst and base.

[0012] The reaction route is shown below:

[0013]

[0014] The catalyst is selected from any one or a combination of at least two of copper catalysts, palladium catalysts, palladium-copper alloy catalysts, nickel catalysts or platinum catalysts, with palladium catalysts being preferred; tetra-triphenylphosphine palladium or bis-triphenylphosphine palladium dichloride are particularly preferred.

[0015] The base is selected from any one of triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, with triethylamine being preferred.

[0016] The reaction is carried out in the presence of a solvent, which is any one of N,N-dimethylformamide, toluene, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, or acetonitrile, preferably N,N-dimethylformamide or toluene.

[0017] The molar ratio of 5-bromo-4-iodopyridine-3-thiol, ethyl propynate, catalyst, and base is 1:1.0-1.5:0.1-0.5:1.0-2.0. For example, 1:1.0:0.1:1.0, 1:1.1:0.2:1.2, 1:1.2:0.3:1.5, 1:1.3:0.4:1.6, or 1:1.5:0.5:2.0, etc.

[0018] The reaction of this invention can be carried out at temperatures ranging from room temperature to the boiling point of the solvent used, such as 10°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or at the boiling point of the solvent, i.e., under reflux. The reaction time is 0.5-48 hours, for example 0.5 hours, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

[0019] Furthermore, the reaction process specifically includes the following steps:

[0020] 5-Bromo-4-iodopyridine-3-thiol was dissolved in N,N-dimethylformamide, and ethyl propynate, palladium catalyst, and base were added sequentially at room temperature. The system was heated overnight under a nitrogen atmosphere. After the reaction was completed by TLC monitoring, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic extract was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a pale yellow solid, which was the product ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid.

[0021] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0022] The present invention provides a method for preparing ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylic acid. The reaction operation is simple, the reaction conditions are mild, the raw materials are inexpensive and readily available, and the equipment requirements are low, making it suitable for the needs of large-scale industrial production. Attached Figure Description

[0023] Figure 1 The 1H NMR spectrum of ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylic acid is shown.

[0024] Figure 2 High-resolution mass spectra of ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylic acid. Detailed Implementation

[0025] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are merely illustrative of the present invention and should not be construed as limiting the invention.

[0026] Example 1:

[0027] The preparation method of ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid is as follows:

[0028]

[0029] 5-Bromo-4-iodopyridine-3-thiol (5.00 g, 15.82 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (60 mL). Bistriphenylphosphine palladium dichloride (1.11 g, 1.582 mmol, 0.1 eq) and triethylamine (2.40 g, 23.74 mmol, 1.5 eq) were added sequentially at room temperature. Ethyl propynate (1.71 g, 17.41 mmol, 1.1 eq) was slowly added dropwise under nitrogen protection. After the addition of the starting materials was complete, the system was heated to 70 °C and reacted overnight. The reaction was stopped when TLC monitoring showed that the reaction had ceased. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL * 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a pale yellow solid product, ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid (3.85 g, yield: 85%). 1 H NMR(400MHz, DMSO-d6)δ9.41-9.29(m,1H),8.71(d,J=0.6Hz,1H),7.99(d,J=0.9Hz,1H),4.41(q,J=7.2Hz,2H),1.38(t,J=7.1Hz,3H).HRMS(ESI)calcd for C 10 H8BrNO2S[M+H + ]:285.9532,found:285.9905.

[0030] Example 2:

[0031] The preparation method of ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid is as follows:

[0032]

[0033] 5-Bromo-4-iodopyridine-3-thiol (5.00 g, 15.82 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (60 mL). Tetraphenylphosphine palladium (1.83 g, 1.582 mmol, 0.1 eq) and triethylamine (2.40 g, 23.74 mmol, 1.5 eq) were added sequentially at room temperature. Ethyl propynate (1.71 g, 17.41 mmol, 1.1 eq) was slowly added dropwise under nitrogen protection. After the addition of the starting materials was complete, the system was heated to 70 °C and reacted overnight. The reaction was stopped when the reaction stopped being monitored by TLC. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL * 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a pale yellow solid product, ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid (3.40 g, yield: 75%). 1 HNMR(400MHz, DMSO-d6)δ9.41-9.29(m,1H),8.71(d,J=0.6Hz,1H),7.99(d,J=0.9Hz,1H),4.41(q,J=7.2Hz,2H),1.38(t,J=7.1Hz,3H).HRMS(ESI)calcd for C 10 H8BrNO2S[M+H + ]:285.9532,found:285.9905.

[0034] Example 3:

[0035] The preparation method of ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid is as follows:

[0036]

[0037] 5-Bromo-4-iodopyridine-3-thiol (5.00 g, 15.82 mmol, 1.0 eq) was dissolved in toluene (60 mL). Bistriphenylphosphine palladium dichloride (1.11 g, 1.582 mmol, 0.1 eq) and triethylamine (2.40 g, 23.74 mmol, 1.5 eq) were added sequentially at room temperature. Ethyl propynate (1.71 g, 17.41 mmol, 1.1 eq) was slowly added dropwise under nitrogen protection. After the addition of the starting materials was complete, the system was heated to 70 °C and reacted overnight. The reaction was stopped when TLC monitoring showed that the reaction had ceased. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL * 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a pale yellow solid product, ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid (3.17 g, yield: 70%). 1 H NMR(400MHz, DMSO-d6)δ9.41-9.29(m,1H),8.71(d,J=0.6Hz,1H),7.99(d,J=0.9Hz,1H),4.41(q,J=7.2Hz,2H),1.38(t,J=7.1Hz,3H).HRMS(ESI)calcd for C 10 H8BrNO2S[M+H + ]:285.9532,found:285.9905.

[0038] Example 4:

[0039] The preparation method of ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid is as follows:

[0040]

[0041] 5-Bromo-4-iodopyridine-3-thiol (5.00 g, 15.82 mmol, 1.0 eq) was dissolved in toluene (60 mL). Tetraphenylphosphine palladium (1.83 g, 1.582 mmol, 0.1 eq) and triethylamine (2.40 g, 23.74 mmol, 1.5 eq) were added sequentially at room temperature. Ethyl propynate (1.71 g, 17.41 mmol, 1.1 eq) was slowly added dropwise under nitrogen protection. After the addition of the starting materials was complete, the system was heated to 70 °C and reacted overnight. The reaction was stopped when the reaction stopped progressing, as monitored by TLC. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL * 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a pale yellow solid product, ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid (2.45 g, yield: 54%). 1 H NMR(400MHz, DMSO-d6)δ9.41-9.29(m,1H),8.71(d,J=0.6Hz,1H),7.99(d,J=0.9Hz,1H),4.41(q,J=7.2Hz,2H),1.38(t,J=7.1Hz,3H).HRMS(ESI)calcd for C 10 H8BrNO2S[M+H + ]:285.9532,found:285.9905.

[0042] Example 5:

[0043] The preparation method of ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid is as follows:

[0044]

[0045] 5-Bromo-4-iodopyridine-3-thiol (5.00 g, 15.82 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (60 mL). Bistriphenylphosphine palladium dichloride (1.11 g, 1.582 mmol, 0.1 eq) and N,N-diisopropylethylamine (3.07 g, 23.74 mmol, 1.5 eq) were added sequentially at room temperature. Ethyl propargylate (1.71 g, 17.41 mmol, 1.1 eq) was slowly added dropwise under nitrogen protection. After the addition of the starting materials was complete, the system was heated to 70 °C and reacted overnight. The reaction was stopped when TLC monitoring showed that the reaction no longer proceeded. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL * 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a pale yellow solid product, ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid (3.71 g, yield: 81.9%). 1 H NMR(400MHz, DMSO-d6)δ9.41-9.29(m,1H),8.71(d,J=0.6Hz,1H),7.99(d,J=0.9Hz,1H),4.41(q,J=7.2Hz,2H),1.38(t,J=7.1Hz,3H).HRMS(ESI)calcd forC 10 H8BrNO2S[M+H + ]:285.9532,found:285.9905.

[0046] Example 6:

[0047] The preparation method of ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid is as follows:

[0048]

[0049] 5-Bromo-4-iodopyridine-3-thiol (5.00 g, 15.82 mmol, 1.0 eq) was dissolved in acetonitrile (60 mL). Bistriphenylphosphine palladium dichloride (1.11 g, 1.582 mmol, 0.1 eq) and triethylamine (2.40 g, 23.74 mmol, 1.5 eq) were added sequentially at room temperature. Ethyl propynate (1.71 g, 17.41 mmol, 1.1 eq) was slowly added dropwise under nitrogen protection. After the addition of the starting materials was complete, the system was heated to 70 °C and reacted overnight. The reaction was stopped when TLC monitoring showed that the reaction no longer proceeded. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL * 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a pale yellow solid product, ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylate (2.04 g, yield: 45%). 1 H NMR(400MHz, DMSO-d6)δ9.41-9.29(m,1H),8.71(d,J=0.6Hz,1H),7.99(d,J=0.9Hz,1H),4.41(q,J=7.2Hz,2H),1.38(t,J=7.1Hz,3H).HRMS(ESI)calcd for C 10 H8BrNO2S[M+H + ]:285.9532,found:285.9905.

[0050] Example 7:

[0051] The preparation method of ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid is as follows:

[0052]

[0053] 5-Bromo-4-iodopyridine-3-thiol (5.00 g, 15.82 mmol, 1.0 eq) was dissolved in 1,4-dioxane (60 mL). Bistriphenylphosphine palladium dichloride (1.11 g, 1.582 mmol, 0.1 eq) and triethylamine (2.40 g, 23.74 mmol, 1.5 eq) were added sequentially at room temperature. Ethyl propynate (1.71 g, 17.41 mmol, 1.1 eq) was slowly added dropwise under nitrogen protection. After the addition of the starting materials was complete, the system was heated to 70 °C and reacted overnight. The reaction was stopped when TLC monitoring showed that the reaction had ceased. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL * 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give a pale yellow solid product, ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylate (2.17 g, yield: 47.9%). 1 H NMR(400MHz, DMSO-d6)δ9.41-9.29(m,1H),8.71(d,J=0.6Hz,1H),7.99(d,J=0.9Hz,1H),4.41(q,J=7.2Hz,2H),1.38(t,J=7.1Hz,3H).HRMS(ESI)calcd for C 10 H8BrNO2S[M+H + ]:285.9532,found:285.9905.

[0054] This invention illustrates the preparation method of ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylate through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily depend on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials for the product of this invention, selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

Claims

1. A method for preparing ethyl 4-bromothiopheno[2,3-c]pyridine-2-carboxylate, characterized in that: Using 5-bromo-4-iodopyridine-3-thiol and ethyl propargyl ester as raw materials, 4-bromothiophene[2,3-c]pyridine-2-carboxylic acid ethyl ester was obtained by Sonogashira coupling and cascade closure reaction under the action of catalyst and base. The reaction route is shown below: ； The catalyst is tetratetraphenylphosphine palladium or bis(triphenylphosphine)palladium dichloride; The base is triethylamine; The reaction is carried out in the presence of a solvent, namely N,N-dimethylformamide or toluene.

2. The preparation method according to claim 1, characterized in that: The molar ratio of 5-bromo-4-iodopyridine-3-thiol, ethyl propynate, catalyst, and base is 1:1.0-1.5:0.1-0.5:1.0-2.

0.

3. The preparation method according to claim 1 or 2, characterized in that... Includes the following steps: 5-Bromo-4-iodopyridine-3-thiol was dissolved in a solvent, and ethyl propynate, palladium catalyst, and base were added sequentially at room temperature. The system was heated under a nitrogen atmosphere. After the reaction was completed by TLC monitoring, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic extract was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a pale yellow solid, which was the product ethyl 4-bromothieno[2,3-c]pyridine-2-carboxylic acid.

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