CN117736132A - Preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde - Google Patents

Abstract

The invention belongs to the field of pharmaceutical and chemical engineering technology, and specifically relates to a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde. The preparation method provided by the invention includes the following steps: mixing an aqueous solution of 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile, a supported nickel catalyst, a polar solvent and a reducing agent; The cyclization reaction is carried out under acidic conditions to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde; the supported nickel catalyst includes a carrier and nickel supported on the pores and surface of the carrier, and the carrier is diatomite , aluminum oxide or silicon oxide. The invention does not require the use of dangerous catalyst Raney nickel and has a high yield of 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde.

Description

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

Technical field

The invention belongs to the technical field of catalysts, and in particular relates to a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde.

Background technique

Vonoprazan fumarate (TAK-438, Vonoprazan fumarate), chemical name is 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3- (Methyl)-N-methylmethylamine fumarate is a new type of oral anti-gastric acid jointly launched by Takeda Pharmaceutical and Otsuka Pharmaceutical. It is used for erosive esophagitis, gastric ulcer, and duodenal ulcer. It was approved for marketing in Japan on December 26, 2014 (trade name: Takecab) for the treatment of acid-related diseases. 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde is an important intermediate for the preparation of vonoprazan fumarate. Chinese patent CN 113651746A discloses a 5-(2-fluorophenyl)- Preparation method of 1H-pyrrole-3-carbaldehyde, in which 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile is used as raw material, Raney nickel is used as catalyst, and a one-step method is used 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde was prepared. However, the yield of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde was low using this method, and the Catalyst Raney Nickel has high chemical activity and is prone to decay under air conditions when dry, which is relatively dangerous.

Contents of the invention

In view of this, the present invention provides a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde. The preparation method provided by the invention does not require the use of dangerous catalyst Raney nickel and 5-(2 -Fluorophenyl)-1H-pyrrole-3-carboxaldehyde has a high yield.

In order to solve the above technical problems, the present invention provides a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde, which includes the following steps:

Mix the aqueous solution of 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile, supported nickel catalyst, polar solvent and reducing agent, and perform a cyclization reaction under acidic conditions to obtain 5 -(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde;

The supported nickel catalyst includes a carrier and nickel supported on the pores and surface of the carrier, and the carrier is diatomite, alumina or silicon oxide.

Preferably, the mass ratio of nickel to carrier is 1:0.5-0.8.

Preferably, the temperature of the cyclization reaction is 20-80°C and the time is 2.8-3.2 hours.

Preferably, the mass ratio of the 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile and the supported nickel catalyst is 1:0.1-0.5.

Preferably, the reducing agent includes one or more of sodium hypophosphite, ammonium hypophosphite and potassium hypophosphite.

Preferably, the molar ratio of the reducing agent and 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile is 1 to 10:1.

Preferably, the acidic condition is adjusted by a pH adjuster, which includes one or more of acetic acid, formic acid, phosphoric acid and benzenesulfonic acid.

Preferably, the dosage ratio of 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile and pH adjuster is 1g:2.5-3mL.

Preferably, the polar solvent includes alcohol solvent and/or water.

Preferably, the mass ratio of the 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile and the volume of the polar solvent is 1g:2-10mL.

The invention provides a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde, which includes the following steps: preparing 2-[2-(2-fluorophenyl)-2-oxoethyl base]malononitrile, a supported nickel catalyst, a polar solvent and a reducing agent are mixed, and a cyclization reaction is performed under acidic conditions to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde; the supported nickel The catalyst includes a carrier and nickel supported on the pores and surface of the carrier, and the carrier is diatomite, alumina or silicon oxide. The present invention does not need to use dangerous catalyst Raney nickel, but uses a supported nickel catalyst to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde through cyclization reaction, and 5-(2-fluorobenzene base)-1H-pyrrole-3-carboxaldehyde has a high yield. In addition, compared with Raney Nickel in the existing technology, with the same amount of NI as the supported nickel catalyst, the supported nickel catalyst will be suspended in the solution, and the carrier will also increase the contact area between the raw material and the catalyst, while Raney Nickel has a higher density It easily sinks to the bottom, has less contact area with raw materials, prolongs the reaction time, increases side reactions, decreases yield, and decreases purity.

Description of drawings

Figure 1 is the hydrogen spectrum of the product in Example 1;

Figure 2 is a liquid chromatogram of the product in Example 1;

Figure 3 is the LCMS spectrum of the product in Example 1.

Detailed ways

The invention provides a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde, which includes the following steps:

Mix the aqueous solution of 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile, supported nickel catalyst, polar solvent and reducing agent, and perform a cyclization reaction under acidic conditions to obtain 5 -(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde;

The supported nickel catalyst includes a carrier and nickel supported on the pores and surface of the carrier, and the carrier is diatomite, alumina or silicon oxide.

In the present invention, the 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile was purchased from Shandong Xuande Pharmaceutical Technology Co., Ltd. In the present invention, the supported nickel catalyst includes a carrier and nickel supported on the pores and surface of the carrier, and the carrier is diatomite, alumina or silica. In the present invention, the mass ratio of the nickel and the carrier is preferably 1:0.5-0.8, and more preferably 1:0.65.

In the present invention, the mass ratio of the 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile and the supported nickel catalyst is preferably 1:0.1~0.5, more preferably 1: 0.3.

In the present invention, the reducing agent preferably includes one or more of sodium hypophosphite, ammonium hypophosphite and potassium hypophosphite, and is more preferably sodium phosphite. In the present invention, the aqueous solution of the reducing agent is preferably obtained by mixing the reducing agent monohydrate and water. The mass ratio of the reducing agent monohydrate and water is preferably 0.75 to 0.85:1, and more preferably 0.8:1. .

In the present invention, the molar ratio of the reducing agent and 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile is preferably 1 to 10:1, more preferably 5 to 6 :1.

In the present invention, the polar solvent preferably includes an alcohol solvent and/or water; the alcohol solvent preferably includes one or more of tert-butyl alcohol, methanol, ethanol and isopropyl alcohol, and more preferably methanol. In the present invention, the acidic condition is adjusted by a pH adjuster. The pH adjuster preferably includes one or more of acetic acid, formic acid, phosphoric acid and benzenesulfonic acid, and more preferably acetic acid.

In the present invention, the volume ratio of the 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile and the polar solvent is preferably 1g:2~10mL, more preferably 1g: 4～8mL. In the present invention, the dosage ratio of 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile and pH adjuster is preferably 1g:2.5~3mL, more preferably 1g: 2.8～2.9mL.

In the present invention, the mixing preferably involves mixing 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile, a polar solvent, and a pH adjuster, and then adding supported nickel in sequence. The aqueous solution of the catalyst and the reducing agent is added dropwise to obtain a reaction liquid.

In the present invention, the dropping speed of the aqueous solution of the reducing agent is 5 to 10 mL/min, and more preferably 7 to 8 mL/min.

In the present invention, the temperature of the cyclization reaction is preferably 20-80°C, more preferably 30-50°C: the time is preferably 2.8-3.2h, more preferably 3h.

In the present invention, after the cyclization reaction, it is preferable that the system obtained by the cyclization reaction is sequentially subjected to first filtration, alcohol washing, and second filtration, and the obtained alcohol phase is extracted with ethyl acetate to obtain the ethyl acetate phase; The obtained ethyl acetate phase was rotary evaporated to dryness to obtain crude product;

After the crude product is redissolved in acetonitrile, crystallization by adding water, crystallization by cooling and third filtration are performed in sequence. The obtained filter cake is washed with acetonitrile aqueous solution and then dried.

In the present invention, the first filtration and the second filtration are not specifically limited, and filtration operations well known in the art can be used. In the present invention, the number of times of alcohol washing is preferably 2 times. In the present invention, the alcohol washing is preferably methanol washing or ethanol washing; the extraction is preferably a mixture of the obtained solid phase, ethyl acetate and water, left to stand and separated into layers, and the ethyl acetate phase is taken. In the present invention, the volume ratio of ethyl acetate and water is preferably 1 to 2:1.

In the present invention, there is no specific limitation on the crystallization by adding water, as long as the product in the acetonitrile aqueous solution can be precipitated; the temperature of the cooling crystallization is preferably 25°C, and the time is preferably 2 hours. In the present invention, the concentration of the acetonitrile aqueous solution is preferably 20 vol%. In the present invention, the drying is not specifically limited, as long as it can remove the solvent remaining in the product.

In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with the examples, but they should not be understood as limiting the protection scope of the present invention.

The technical solutions provided by the present invention will be described in detail below with reference to the examples, but they should not be understood as limiting the protection scope of the present invention.

Example 1

Sodium phosphite aqueous solution: obtained by dissolving 90.7g of sodium hypophosphite monohydrate in 120 mL of water.

Diatomite-supported nickel catalyst: The mass ratio of nickel and diatomite in the diatomite-supported nickel catalyst is 1:0.65.

At 25°C, add 36.5g 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile, 130mL methanol, 105mL acetic acid, and 50mL water into a 1000mL reaction bottle, start stirring, and then After adding 18.0g of diatomite-supported nickel catalyst and adding dropwise (dropping speed is 5 mL/min) the above sodium hypophosphite aqueous solution, the temperature was raised to 50°C to perform a cyclization reaction for 3 hours. After the reaction was completed, filter and wash with methanol twice ( 50mL*2) and filter, add 180mL of ethyl acetate and 130mL of water to the obtained methanol phase, stir, let stand and separate into layers, discard the lower water layer, distill under reduced pressure and spin to dryness. Distilled under reduced pressure to obtain 34.3g of crude product.

Add 34.3g of crude product to 70g of acetonitrile, heat to 55°C to dissolve, then add 140g of water to the resulting solution, and cool to 25°C to crystallize for 2 hours. After crystallization, filter, and wash the filter cake with 50mL of 20vol% acetonitrile aqueous solution. After drying, 28.5 g of yellow solid (5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde) was obtained.

In Example 1, the yield of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde was 85.0%;

After HPLC detection, the purity of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde was 99.74%.

Example 2

Sodium phosphite aqueous solution: Dissolve 58.7g of sodium hypophosphite monohydrate in 70 mL of water.

Add 20.20g 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile, 80mL ethanol, 60mL acetic acid, and 30mL water into the 500mL reaction bottle, start stirring, and add 10g diatomite-type loaded nickel (same as Example 1), add dropwise (dropping speed is 5mL/min) the above sodium hypophosphite aqueous solution, raise the temperature to 55°C and react for 3 hours. After the reaction is completed, filter and wash with ethanol 2 times (50mL*2 ) and filter, add 100 mL of ethyl acetate to the ethanol phase obtained, stir with 70 mL of water, let stand and separate into layers, discard the lower aqueous layer, and distill the upper layer under reduced pressure and spin to dryness to obtain 18.1 g.

Add 18.1g of crude product to 40g of acetonitrile, heat to 55°C to dissolve, then add 80g of water to the solution, cool to 25°C to crystallize for 2 hours, filter, and wash the filter cake with 50mL of 20vol% acetonitrile aqueous solution and dry to obtain 15.7g Yellow solid (5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde).

In Example 2, the yield of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde was 83.2%;

After HPLC detection, the purity of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde was 99.12%.

Example 3

Sodium phosphite aqueous solution: Dissolve 65g of sodium hypophosphite monohydrate in 80mL of water.

Alumina-type supported nickel: The mass ratio of nickel to alumina in alumina-type supported nickel is 1:0.53.

Add 22.20g 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile, 66mL acetic acid, 88mL methanol, and 33mL water into the 500mL reaction bottle, start stirring, and add 11g alumina type supported nickel, add dropwise (dropping speed is 5mL/min) the above sodium hypophosphite aqueous solution, raise the temperature to 60°C for cyclization reaction for 3 hours, after the reaction is completed, filter, wash with methanol twice (50mL*2) and filter, Add 110 mL of ethyl acetate and 77 mL of water to the obtained methanol phase, stir, let stand and separate into layers, discard the lower aqueous layer, and distill the upper layer under reduced pressure and spin to dryness to obtain 20.3 g.

After purification, 18.3 g of dry yellow solid was obtained. The yield was 84.2%, and the purity was 99.45% after HPLC detection.

Example 4

Sodium hypophosphite aqueous solution: 110g of sodium hypophosphite monohydrate, obtained by dissolving in 140 mL of water.

Add 38.3g 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile, 110mL acetic acid, 150mL methanol, and 60mL water into the 1000mL reaction bottle, start stirring, and add 20g of silica-type supported nickel was added dropwise (with a dropping speed of 10mL/min) of the above sodium hypophosphite aqueous solution, and the temperature was raised to 55°C for cyclization reaction for 3 hours. After the reaction was completed, filtered, washed with methanol twice (88mL*2), and filtered. Add 190 mL of ethyl acetate and 130 mL of water to the obtained methanol phase, stir, let stand and separate into layers, discard the lower aqueous layer, and distill the upper layer under reduced pressure and spin to dryness to obtain 32.2g. After purification, 29.0 g of dry yellow solid was obtained. The yield was 81.0%, and the purity was 99.27% after HPLC detection.

Figure 1 is the hydrogen spectrum of the product in Example 1. It can be seen from Figure 1 that the peak position of each hydrogen in the product can correspond to the hydrogen spectrum.

Figure 2 is the liquid chromatogram of the product in Example 1. From Figure 2, it can be seen that the HPLC purity of the product by area normalization method is 99.74%, and the maximum single heterogeneity is 0.26%;

Figure 3 is the LCMS spectrum of the product in Example 1. It can be seen from Figure 3 that the negative ion peak of the product is 187.8, that is, the molecular weight of the product is 189. Combined with the hydrogen spectrum of Figure 1, the structure of the LCMS spectrum of Figure 3 is correct.

Comparative example 1

Add 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile (20.20g), 80mL ethanol, 60mL acetic acid, and 30mL water into a 500mL reaction bottle, start stirring, and stir at 25°C , add 10g of diatomite-type loaded iron, replace hydrogen (use hydrogen to convert the air in the reaction bottle), raise the temperature to 40°C three times, and react for 8 hours. When reacting for 8 hours, it was detected that only 30% of the reaction raw materials were reacted.

Comparative example 2

Add 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile (46.0g), 200mL ethanol, 130mL acetic acid, and 75mL water into a 1000mL reaction bottle, start stirring, and stir at 25°C. , add 30g of Rany-Ni, dropwise add sodium hypophosphite aqueous solution (150g of sodium hypophosphite monohydrate, dissolved in 170mL of water), raise the temperature to 50°C and react for 3 hours. After the reaction is completed, filter, wash with ethanol 2 times (88mL*2) and filter. , separate the liquids, discard the lower aqueous layer, and distill the upper layer under reduced pressure and spin dry to obtain 31.3g. After purification, 28.3 g of dry yellow solid was obtained. The yield was 65.8% and the purity was 98.2%.

Comparative example 3

Add 20.20g 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile and 80mL ethanol into the 500mL reaction bottle, start stirring, and add 2g activated carbon supported palladium catalyst at 25°C. Replace the hydrogen gas (use hydrogen gas to convert the air in the reaction bottle) 3 times, raise the temperature to 40°C and react for 3 hours. After the reaction, filter, wash with ethanol 2 times (50mL*2), filter, separate the liquids, discard the lower water layer, and depressurize the upper layer. Distill and spin dry to obtain 14.1g.

Add 14.1g of crude product to 31g of acetonitrile, raise the temperature to 55°C to dissolve, then add 62g of water, cool to 25°C, crystallize for 2 hours and filter, and rinse the filter cake with 38 mL of 20% acetonitrile. After drying, 12.1 g of yellow solid was obtained. The yield was 64%, and the purity was 98.51% after HPLC detection.

The above are only preferred embodiments of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications can also be made. should be regarded as the protection scope of the present invention.

Claims (10)

1. A method for preparing 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde, which comprises the following steps:

mixing 2- [2- (2-fluorophenyl) -2-oxo-ethyl ] malononitrile, a supported nickel catalyst, a polar solvent and an aqueous solution of a reducing agent, and performing cyclization under acidic conditions to obtain 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde;

the supported nickel catalyst comprises a carrier and nickel supported on the pores and the surface of the carrier, wherein the carrier is diatomite, aluminum oxide or silicon oxide.

2. The preparation method according to claim 1, wherein the mass ratio of nickel to carrier is 1:0.5 to 0.8.

3. The preparation method according to claim 1 or 2, wherein the temperature of the cyclization reaction is 20-80 ℃ and the time is 2.8-3.2 h.

4. The preparation method according to claim 1, wherein the mass ratio of the 2- [2- (2-fluorophenyl) -2-oxoethyl ] malononitrile to the supported nickel catalyst is 1:0.1-0.5.

5. The method of claim 1, wherein the reducing agent comprises one or more of sodium hypophosphite, ammonium hypophosphite and potassium hypophosphite.

6. The process according to claim 1 or 5, wherein the molar ratio of the reducing agent to 2- [2- (2-fluorophenyl) -2-oxoethyl ] malononitrile is 1-10:1.

7. The method of claim 1, wherein the acidic condition is adjusted by a pH adjuster comprising one or more of acetic acid, formic acid, phosphoric acid, and benzenesulfonic acid.

8. The process according to claim 1 or 7, wherein the ratio of the amount of 2- [2- (2-fluorophenyl) -2-oxoethyl ] malononitrile to the pH adjusting agent is 1g: 2.5-3 mL.

9. The method of claim 1, wherein the polar solvent comprises an alcohol solvent and/or water.

10. The process according to claim 1 or 9, wherein the ratio of the mass of 2- [2- (2-fluorophenyl) -2-oxoethyl ] malononitrile to the volume of the polar solvent is 1 g:2-10 mL.