5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde as a key Intermediate

5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde is an important fluorinated pyrrole pharmaceutical intermediate that is highly soluble in organic solvents such as ethanol, chloroform and dichloromethane. In terms of synthesis, this compound is typically prepared from pyrrole; after N-alkylation protection with triisopropylchlorosilane, it reacts with Vilsmeier’s reagent to yield 3-aldehyde-1H-pyrrole, followed by bromination with N-bromosuccinimide, and finally via a Suzuki coupling reaction with 2-fluorophenylboronic acid. The crude product can be purified using toluene, with an overall yield of approximately 35%. The primary application of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde is as a key intermediate in the synthesis of fumaric acid fonorelate, a potassium-competitive acid blocker (P-CAB). This drug is used to treat acid-related conditions such as gastric ulcers, duodenal ulcers and reflux oesophagitis, and can also be combined with antibiotics to eradicate Helicobacter pylori. Furthermore, it can be used in the synthesis of organic fluorescent dyes, photosensitisers and certain pesticide products. It should be stored in a sealed, dry container at room temperature.

Improved Preparation Method of Vonoprazan Fumarate Intermediate

5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde is a key intermediate for the preparation of voroxane fumarate. In the process of preparing this material from 3-cyano-5-(2-fluorophenyl)-1H-pyrrole, excessive reduction reaction is prone to occur to produce final products. During the post-treatment process, these by-products will precipitate as oils, and will remain in the normally precipitated 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde, resulting in a decrease in purity. The structural formulas of the related by-products are as follows: (1) Filter the reaction solution to remove insoluble Raney nickel and other substances, rinse the filter cake with ethyl acetate; (2) Add dropwise to the obtained filtrate Adjust the pH of the sodium hydroxide solution to 7-8 and separate the liquids. The organic phase is washed with sodium bicarbonate solution and sodium chloride solution; (3) The organic phase obtained after washing is adjusted to pH 3.0-3.5 with hydrochloric acid, and then separated again. The obtained organic phase was washed with sodium chloride solution, and then concentrated under reduced pressure; (4) The obtained concentrate was heated to 65～70℃, and then cooled to 45～55℃, continued to stir for 1h, and then cooled to 15～25 ℃, add n-heptane dropwise, after the dropwise addition, cool to 0-10°C, stir and crystallize for 1h, filter and dry to obtain an intermediate.[1]

The refining process yield of the above 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde reaches about 80%, but there are still the following shortcomings: in step (2), the pH of the reaction solution is adjusted to 7-8, and the separation of the by-product is poor, and the purity of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde in the obtained organic phase is low; in step (3), when the pH is adjusted to 3.0-3.5 before concentration, this drug in the reaction solution will be degraded during the concentration process, and the yield and purity are significant Decrease; in step (4), during the addition of n-heptane for crystallization, by-products will be precipitated as oils, encapsulating a large amount of 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde, resulting in a low yield. Therefore, in view of the problems of difficult post-processing, low yield and purity in the preparation process of the intermediate, a preparation method of a high-purity and high-yield vonolax fumarate intermediate  is provided appear particularly important.

A kind of preparation method of fumaric acid vonolasan intermediate, it comprises the following steps: Add compound II, tetrahydrofuran, acetic acid, water and Raney nickel into the hydrogenation kettle, and after stirring evenly, carry out a chemical reaction in a hydrogen atmosphere at a temperature of 20 to 60 °C and a pressure of 0 to 0.6 MPa. After completion, filter, wash and rinse the filter cake with ethyl acetate to obtain a reaction solution; the specific synthesis route is as follows: n-heptane is added dropwise to the organic phase obtained in step (4), and after the dropwise addition is completed, the temperature is lowered to 0-30° C. for stirring and crystallization, filtration, and drying to obtain intermediate 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde. For the present invention, when compound I is prepared from 3-cyano-5-(2-fluorophenyl)-1H-pyrrole, it is generally carried out in a hydrogenation kettle, nitrogen is used to replace the air in the hydrogenation kettle, tetrahydrofuran, acetic acid and water are used as solvents, the hydrogen source is hydrogen, and Raney nickel is used as a catalyst. If the pH of the reaction solution is low before concentration, for example, adding sodium hydroxide aqueous solution dropwise to adjust its pH to 3.0-4.0, during the concentration process, 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde is particularly easily degraded, resulting in a significant decrease in yield and purity. If the pH of the reaction solution is too high before concentration, for example, add sodium hydroxide aqueous solution dropwise to adjust its pH to 7.0-8.0.

References

[1]CN113173876A

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