A preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

Abstract

The invention provides a method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, and relates to the technical field of organic synthesis. 2-fluoroacetophenone is used as a raw material, and a "one-pot method" is adopted for synthesis. The reaction is relatively mild, the product is easy to handle and purify, the preparation method used is simple, easy to operate, and is a low-cost method suitable for batch preparation.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile. Background Art

[0002] Vonoprazan fumarate (TAK-438) is a second reversible proton pump inhibitor that can inhibit the secretion of potassium ions (K + ) + -K + -ATPase binding action, prematurely terminate the secretion of gastric acid. Vonoprazan fumarate (vonoprazan fumarate) is an indication for peptic esophagitis, Helicobacter infection, duodenal ulcer, esophagitis, gastric ulcer, gastroesophageal reflux disease, peptic ulcer, etc.

[0003] 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile is an important organic synthesis intermediate, with a structural formula as shown in Formula I below. The compounds that can be synthesized include high value-added drugs such as 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine fumarate (Vonoprazan fumarate), which can fill the important needs that are not met in the current digestive system treatment market. Regarding 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, there are currently few synthetic preparation methods reported in the literature, and the steps are numerous and not friendly to the three wastes.

[0004]

[0005] Patent CN112194607A discloses a method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, the steps are as follows: (1) dissolving 2-fluoroacetophenone in tetrahydrofuran, adding tetrabutylammonium tribromide for bromination, concentrating and dissolving in ethyl acetate, washing with water and using in the next step; (2) adding malononitrile to the product of the previous step, stirring with sodium carbonate powder, washing with water, concentrating and recrystallizing with 50% isopropanol solution; (3) dissolving the product of the previous step in ethyl acetate, adding ethyl acetate-hydrogen chloride and stirring at 80° C., concentrating, and slurrying with isopropanol; (4) dissolving the product of (3) in ethanol and transferring it to a hydrogenation kettle, adding diisopropylethylamine, stirring under a hydrogen atmosphere of palladium carbon, filtering, concentrating, adding water for crystallization, and then recrystallizing with 30% ethanol. This patent uses tetrahydrofuran and ethyl acetate as solvents in step (1) and step (2), respectively. The disadvantages are: different solvents are used in the two steps of the preparation process of this method, and post-processing steps such as concentration, water washing, and recrystallization are added in the middle. The process is complicated and inefficient, which is not conducive to large-scale production.

[0006] Patent CN106432191A discloses a method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, the steps are as follows: (1) dissolving 2-fluoroacetophenone in ethyl acetate, adding bromine for bromination, quenching with sodium sulfite solution after the reaction is completed, washing with water and then washing with sodium bicarbonate solution, adding malononitrile to dissolve and then dripping triethylamine, quenching with water after the reaction is completed, adding concentrated hydrochloric acid to adjust the pH, washing the organic layer with saturated brine, and concentrating for the next step; (2) dissolving the product of (1) in ethyl acetate, adding ethyl acetate-hydrogen chloride to 75°C and stirring, concentrating, and then hot beating with 60% acetonitrile, cooling and filtering; (3) dissolving the product of (2) in ethanol and transferring it to a hydrogenation kettle, adding triethylamine, stirring under palladium carbon hydrogen atmosphere, filtering, concentrating and adding water for crystallization. The patent uses expensive ethyl acetate-hydrogen chloride in step (3), which is not economical and environmentally friendly, and is not conducive to large-scale production.

[0007] In view of this, there is an urgent need for a preparation method with simple process, economic and environmental protection, high product purity and high yield. The present application provides a "one-pot" process for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile using 2-fluoroacetophenone as a raw material. The reaction is relatively mild, the process is simple and convenient, and the work efficiency is greatly improved, which is suitable for industrial production. Summary of the invention

[0008] In view of the above problems, the present invention provides a method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile. The method is simple in preparation, green and environmentally friendly, and is conducive to large-scale production.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] The present invention provides a method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, which adopts a "one-pot method" and has the following reaction route:

[0011]

[0012] The following steps are involved:

[0013] (1) 2-fluoroacetophenone (II) is mixed with ethyl acetate and bromine. After the reaction is completed, the mixture is quenched with a sodium sulfite solution and then diethyl phosphite and triethylamine are added until the by-product disappears. After the aqueous phase is separated, an ethyl acetate solution of the intermediate III is obtained;

[0014] (2) adding malononitrile and triethylamine to the ethyl acetate solution of intermediate III obtained in step (1) until the reaction is complete to obtain an ethyl acetate solution of intermediate IV;

[0015] (3) adding palladium carbon, HZSM-5, and acetic acid to the ethyl acetate solution of intermediate IV obtained in step (2), hydrogenating until the reaction is completed, and filtering to obtain an ethyl acetate solution of compound I;

[0016] (4) n-heptane was added dropwise to the ethyl acetate solution of compound I to crystallize, filter, and dry to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I).

[0017] Preferably, in step (1), the reaction temperature is 20-30°C, and the reaction time is 1-5 hours; further preferably, the reaction temperature is 25°C, and the reaction time is 2 hours.

[0018] Preferably, the molar ratio of 2-fluoroacetophenone to bromine in step (1) is 1:1.0-1.4; further preferably, the molar ratio of 2-fluoroacetophenone to bromine in step (1) is 1:1.0-1.2; most preferably, the molar ratio of 2-fluoroacetophenone to bromine is 1:1.1.

[0019] Preferably, in step (1), the volume of 2-fluoroacetophenone and ethyl acetate is 6-10 times, more preferably 6-8 times.

[0020] Preferably, the molar ratio of 2-fluoroacetophenone to diethyl phosphite in step (1) is 1:0.05-0.3; further preferably, the molar ratio of 2-fluoroacetophenone to diethyl phosphite in step (1) is 1:0.1-0.2.

[0021] Preferably, the molar ratio of 2-fluoroacetophenone to triethylamine in step (1) is 1:0.05-0.3; further preferably, the molar ratio of 2-fluoroacetophenone to triethylamine in step (1) is 1:0.1-0.2.

[0022] Preferably, in step (2), the reaction temperature is -10-30°C, and the reaction time is 5-8 hours; further preferably, the reaction temperature is 0-10°C, and the reaction time is 6 hours.

[0023] Preferably, the molar ratio of 2-fluoroacetophenone to triethylamine in step (2) is 1:0.8-1.1; further preferably, the molar ratio of 2-fluoroacetophenone to triethylamine in step (2) is 1:0.85-1.0.

[0024] Preferably, the molar ratio of 2-fluoroacetophenone to malononitrile in step (2) is 1:1.0-1.4; further preferably, the molar ratio of 2-fluoroacetophenone to malononitrile in step (2) is 1:1.0-1.2.

[0025] Preferably, the mass ratio of 2-fluoroacetophenone to Pd / C in step (3) is 1:0.01-0.2. More preferably, the mass ratio of 2-fluoroacetophenone to Pd / C in step (3) is 0.02-0.05.

[0026] Preferably, in step (3), the mass ratio of 2-fluoroacetophenone to HZSM-5 is 1:0.2-0.8. More preferably, in step (3), the mass ratio of 2-fluoroacetophenone to HZSM-5 is 1:0.4-0.6.

[0027] Preferably, the amount of acetic acid used in step (3) is 40-110 mL of acetic acid per 100 g of 2-fluoroacetophenone; further preferably, the amount of acetic acid used in step (3) is 50-100 mL of acetic acid per 100 g of 2-fluoroacetophenone.

[0028] Preferably, the amount of hydrogen used in step (3) is 0.4 MPa-1.0 MPa; further preferably, the amount of hydrogen used in step (3) is 0.5-0.7 MPa.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1) Ethyl acetate is used as the reaction solvent in all three steps of the reaction, which reduces the types of reaction solvents, improves the efficiency of solvent use, and reduces costs;

[0031] 2) The direct ring closure of this reaction shortens the reaction route and improves the reaction efficiency;

[0032] 3) The preparation method provided by the present invention has a relatively mild reaction, and the product is easy to handle and purify, and is suitable for batch preparation. The synthetic route disclosed by the present invention is short, the preparation method used is simple, the raw materials are easily available, and the operation is easy, so it is a low-cost method suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is the HPLC diagram of Formula I in Example 1;

[0034] Figure 2 is the formula I in Example 1 1 H NMR spectra. DETAILED DESCRIPTION

[0035] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0036] Example 1

[0037]

[0038] (1) Synthesis of 2-bromo-2'-fluoroacetophenone (III):

[0039] Add 100 g of 2-fluoroacetophenone and 400 mL of ethyl acetate to a 2L four-necked flask, stir and dissolve, heat to 25°C to dissolve, add dropwise 400 mL of ethyl acetate solution containing 127.2 g of bromine, keep warm at 25°C for 2 h after the addition is complete, and terminate the reaction when the remaining 2-fluoroacetophenone is less than 3% by HPLC; add 0.5 L of 0.5 mol / L sodium sulfite solution to quench, add 15 g of diethyl phosphite and 11 g of triethylamine, stir for 2 hours, wash twice with 200 mL of pure water, and use directly in the next step.

[0040] (2) Synthesis of 2-(2-(2-fluorophenyl)-2-oxoethyl)malononitrile (VI):

[0041] After the reaction in step (1) was completed, 49.97 g of malononitrile was added to the reaction system, and 66.11 g of triethylamine was added dropwise at 5° C. The reaction was kept warm. After the reaction was completed by HPLC, the reaction was quenched with water and ethyl acetate, the liquids were separated, and the organic phase was directly used in the next step.

[0042] (3) Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I):

[0043] After the reaction of step (2) is completed, 50 mL of acetic acid, 40 g of HZSM-5 and 2.5 g of palladium on carbon are added to the reaction system, hydrogen is replaced 3 times, hydrogen is added to 0.6 MPa, and the reaction is carried out at 60-75° C. for 3 hours. After the reaction is completed, the pressure is released and the temperature is lowered to 20-30° C., the catalyst is filtered, and the filtrate is washed with 800 mL of sodium bicarbonate solution until neutral, concentrated to remove ethyl acetate, 200 mL of ethyl acetate is added to the residue, the temperature is raised to 70° C. to dissolve, 800 mL of n-heptane is added dropwise, and after the addition is complete, the temperature is lowered to 20-30° C. for crystallization for 3 hours, filtered, and the solid is dried to obtain 99.5 g of light yellow powder with a purity of 99.48% and a yield of 73.8%.

[0044] Example 2

[0045]

[0046] (1) Synthesis of 2-bromo-2'-fluoroacetophenone (III):

[0047] Add 100 g of 2-fluoroacetophenone and 400 mL of ethyl acetate to a 2L four-necked flask, stir and dissolve, heat to 25°C to dissolve, add dropwise 400 mL of ethyl acetate solution containing 127.2 g of bromine, keep warm at 25°C for 2 h after the addition is complete, and terminate the reaction when the remaining 2-fluoroacetophenone is less than 3% by HPLC; add 0.5 L of 0.5 mol / L sodium sulfite solution to quench, add 15 g of diethyl phosphite and 11 g of triethylamine, stir for 2 hours, wash twice with 200 mL of pure water, and use directly in the next step.

[0048] (2) Synthesis of 2-(2-(2-fluorophenyl)-2-oxoethyl)malononitrile (VI):

[0049] After the reaction in step (1) was completed, 49.97 g of malononitrile was added to the reaction system, and 66.11 g of triethylamine was added dropwise at 5° C. The reaction was kept warm. After the reaction was completed by HPLC, the reaction was quenched with water and ethyl acetate, the liquids were separated, and the organic phase was directly used in the next step.

[0050] (3) Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I):

[0051] After the reaction of step (2) is completed, 100 mL of acetic acid, 80 g of HZSM-5 and 10 g of palladium on carbon are added to the reaction system, hydrogen is replaced 3 times, hydrogen is added to 0.6 MPa, and the reaction is carried out at 60-75° C. for 3 hours. After the reaction is completed, the pressure is released and the temperature is lowered to 20-30° C., the catalyst is filtered, and the filtrate is washed with 800 mL of sodium bicarbonate solution until it is neutral, concentrated to remove ethyl acetate, 200 mL of ethyl acetate is added to the residue, the temperature is raised to 70° C. to dissolve, 800 mL of n-heptane is added dropwise, and after the addition is complete, the temperature is lowered to 20-30° C. for crystallization for 3 hours, filtered, and the solid is dried to obtain 97.3 g of a light yellow powder with a purity of 99.96% and a yield of 72.2%.

[0052] Comparative Example 1:

[0053]

[0054] (1) Synthesis of 2-bromo-2'-fluoroacetophenone (III):

[0055] Add 100 g of 2-fluoroacetophenone and 400 mL of ethyl acetate to a 2L four-necked flask, stir and dissolve, heat to 25°C to dissolve, add dropwise 400 mL of ethyl acetate solution containing 127.2 g of bromine, and keep warm at 25°C for 2 h after the addition is complete. The reaction is terminated when the remaining 2-fluoroacetophenone is <3% by HPLC; add 0.5 L of 0.5 mol / L sodium sulfite solution to quench, wash twice with 200 mL of pure water, and use directly in the next step.

[0056] (2) Synthesis of 2-(2-(2-fluorophenyl)-2-oxoethyl)malononitrile (VI):

[0057] Same as Example 1.

[0058] (3) Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I):

[0059] Same as Example 1.

[0060] 54.3 g of light yellow powder was obtained with a purity of 99.84% and a yield of 43.1%.

[0061] Comparative Example 2

[0062]

[0063] (1) Synthesis of 2-bromo-2'-fluoroacetophenone (III):

[0064] Add 100 g of 2-fluoroacetophenone and 400 mL of ethyl acetate to a 2L four-necked flask, stir and dissolve, heat to 25°C to dissolve, add dropwise 400 mL of ethyl acetate solution containing 127.2 g of bromine, keep warm at 25°C for 2 h after the addition is complete, and terminate the reaction when the remaining 2-fluoroacetophenone is less than 3% by HPLC; add 0.5 L of 0.5 mol / L sodium sulfite solution to quench, add 8 g of diethyl phosphite and 5.9 g of triethylamine, stir for 2 hours, wash twice with 200 mL of pure water, and use directly in the next step.

[0065] (2) Synthesis of 2-(2-(2-fluorophenyl)-2-oxoethyl)malononitrile (VI):

[0066] Same as Example 1.

[0067] (3) Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I):

[0068] Same as Example 1.

[0069] 89.3 g of light yellow powder was obtained with a purity of 99.85% and a yield of 66.26%.

[0070] Comparative Example 3

[0071]

[0072] (1) Synthesis of 2-bromo-2'-fluoroacetophenone (III):

[0073] Add 100 g of 2-fluoroacetophenone and 400 mL of ethyl acetate to a 2L four-necked flask, stir and dissolve, heat to 25°C to dissolve, add dropwise 400 mL of ethyl acetate solution containing 127.2 g of bromine, keep warm at 25°C for 2 h after the addition is complete, and terminate the reaction when the remaining 2-fluoroacetophenone is less than 3% by HPLC; add 0.5 L of 0.5 mol / L sodium sulfite solution to quench, add 15 g of triethyl phosphite and 11 g of triethylamine, stir for 2 hours, wash twice with 200 mL of pure water, and use directly in the next step.

[0074] (2) Synthesis of 2-(2-(2-fluorophenyl)-2-oxoethyl)malononitrile (VI):

[0075] Same as Example 1.

[0076] (3) Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I):

[0077] Same as Example 1.

[0078] 49.3 g of light yellow powder was obtained with a purity of 99.77% and a yield of 39.1%.

[0079] Comparative Example 4

[0080]

[0081] (1) Synthesis of 2-bromo-2'-fluoroacetophenone (III):

[0082] Add 100 g of 2-fluoroacetophenone and 400 mL of ethyl acetate to a 2L four-necked flask, stir and dissolve, heat to 25°C to dissolve, add dropwise 400 mL of ethyl acetate solution containing 127.2 g of bromine, keep warm at 25°C for 2 h after the addition is complete, and terminate the reaction when the remaining 2-fluoroacetophenone is less than 3% by HPLC; add 0.5 L of 0.5 mol / L sodium sulfite solution to quench, add 15 g of diethyl phosphite and 11 g of triethylamine, stir for 2 hours, wash twice with 200 mL of pure water, and use directly in the next step.

[0083] (2) Synthesis of 2-(2-(2-fluorophenyl)-2-oxoethyl)malononitrile (VI):

[0084] Same as Example 1.

[0085] (3) Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I):

[0086] After the reaction of step (2) is completed, 50 mL of acetic acid, 30 g of HZSM-5 and 2 g of palladium on carbon are added to the reaction system, hydrogen is replaced 3 times, hydrogen is added to 0.2 MPa, and the reaction is carried out at 60-75° C. for 3 hours. After the reaction is completed, the pressure is released and the temperature is lowered to 20-30° C., the catalyst is filtered, and the filtrate is washed with 800 mL of sodium bicarbonate solution until it is neutral, concentrated to remove ethyl acetate, 200 mL of ethyl acetate is added to the residue, the temperature is raised to 70° C. to dissolve, 800 mL of n-heptane is added dropwise, and after the addition is complete, the temperature is lowered to 20-30° C. for crystallization for 3 hours, filtered, and the solid is dried to obtain 54.5 g of a light yellow powder with a purity of 43.55% and a yield of 43.22%.

[0087] Comparative Example 5

[0088]

[0089] (1) Synthesis of 2-bromo-2'-fluoroacetophenone (III):

[0090] Add 100 g of 2-fluoroacetophenone and 400 mL of ethyl acetate to a 2L four-necked flask, stir and dissolve, heat to 25°C to dissolve, add dropwise 400 mL of ethyl acetate solution containing 127.2 g of bromine, keep warm at 25°C for 2 h after the addition is complete, and terminate the reaction when the remaining 2-fluoroacetophenone is less than 3% by HPLC; add 0.5 L of 0.5 mol / L sodium sulfite solution to quench, add 15 g of diethyl phosphite and 11 g of triethylamine, stir for 2 hours, wash twice with 200 mL of pure water, and use directly in the next step.

[0091] (2) Synthesis of 2-(2-(2-fluorophenyl)-2-oxoethyl)malononitrile (VI):

[0092] Same as Example 1.

[0093] (3) Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I):

[0094] After the reaction in step (2) was completed, 50 mL of acetic acid and 2.5 g of palladium carbon were added to the reaction system, and the hydrogen was replaced three times. The hydrogen was added to 0.6 MPa, and the reaction was carried out at 60-75°C for 3 hours. There was basically no product when the plate was spotted.

[0095] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, characterized in that: Using the "one-pot method", the reaction route is as follows: The following steps are involved: (1) 2-fluoroacetophenone (II) is mixed with ethyl acetate and bromine, and after the reaction is completed, diethyl phosphite and triethylamine are added until the by-product disappears after quenching with a sodium sulfite solution, and the aqueous phase is separated to obtain an ethyl acetate solution of the intermediate III; the reaction temperature is 20-30° C., and the reaction time is 1-5 hours; the molar ratio of the 2-fluoroacetophenone to diethyl phosphite is 1:0.1-0.2; the molar ratio of the 2-fluoroacetophenone to triethylamine is 1:0.2; (2) adding malononitrile and triethylamine to the ethyl acetate solution of intermediate III obtained in step (1) until the reaction is completed to obtain an ethyl acetate solution of intermediate IV; the reaction temperature is -10-30° C., the reaction time is 5-8 hours; the molar ratio of 2-fluoroacetophenone to triethylamine is 1:0.8-1.1; (3) adding palladium carbon, HZSM-5, and acetic acid to the ethyl acetate solution of intermediate IV obtained in step (2), hydrogenating until the reaction is completed, and filtering to obtain an ethyl acetate solution of compound I; the amount of hydrogen used is 0.4 MPa-1.0 MPa; the mass ratio of 2-fluoroacetophenone to Pd / C is 1:0.025-0.2; the mass ratio of 2-fluoroacetophenone to HZSM-5 is 1:0.4-0.8; (4) n-heptane was added dropwise to the ethyl acetate solution of compound I to crystallize, filter, and dry to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (I).

2. The preparation method according to claim 1, characterized in that: The reaction temperature in step (1) is 25° C. and the reaction time is 2 hours.

3. The preparation method according to claim 1, characterized in that: The molar ratio of 2-fluoroacetophenone to bromine in step (1) is 1:1.0-1.

4.

4. The preparation method according to claim 1, characterized in that: The molar ratio of 2-fluoroacetophenone to bromine in step (1) is 1:1.0-1.

2.

5. The preparation method according to claim 1, characterized in that: The molar ratio of 2-fluoroacetophenone to malononitrile in step (2) is 1:1.0-1.

4.

6. The preparation method according to claim 1, characterized in that: In step (3), the amount of acetic acid used is 40-110 mL per 100 g of 2-fluoroacetophenone.

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