4-Nitrophenethylamine hydrochloride is yellow to yellow-green crystalline powder under normal temperature and pressure, with a certain degree of hygroscopicity. 4-Nitrophenethylamine hydrochloride is the hydrochloride of organic amine compounds, with good chemical stability, which can be released under alkaline conditions 4-Nitrophenethylamine, mostly It is used as an intermediate in organic synthesis and medicinal chemistry, mainly applied in the field of medicinal chemistry research and development, for example, it is the key synthetic intermediate of the drug molecule dofetilide. Here we will introduce different synthetic pathways.

Synthesis from β-phenylethylamine

Mirabegron tablet developed by Astellas, Japan, and approved by the U.S. Food and Drug Administration (FDA) on June 28, 2012 and used to treat adult overactive bladder (OAB) Drug. Mirabello is a arylethanolamine beta3 agonist that acts on the bladder to depress urinary smooth muscle beta 3 adrenergic receptors, relaxes the bladder, promotes bladder filling and increases urine storage, effectively reduces the frequency of urination, and improves bladder overactivity. Frequent urination, urgency, and urinary incontinence. Mirabello has broad application prospects in the treatment of overactive bladder due to its specific good safety, efficacy and tolerability. The existing Mirabello synthesis technology mainly has the following two methods: European Patent EP1440969, U.S. Patent No. 7,982,049 for the synthesis of Mirabello is based on D-mandelic acid and 4-Nitrophenethylamine hydrochloride as starting materials, amide condensation, borane reduction, and catalytic hydrogenation reduction. The final condensation with 2-(2-aminothiazol-4-yl)acetic acid produces Mirabelloni. Japanese Patent JP1997285778, U.S. Patent No. 6,346,532 for the synthesis of Mirabello is based on the use of 4-Nitrophenethylamine hydrochloride as a raw material, condensation with (R)-styrene oxide to give amino alcohols, followed by amino protection, nitro reduction, Condensation with 2-(2-aminothiazol-4-yl)acetic acid results in the deprotection of Mirabella. The literature is based on the nitroethylation of phenylethylamine to obtain 4-Nitrophenethylamine hydrochloride, the bromoethylation of p-nitrophenol to obtain p-nitrophenyl bromoethyl ether, and then these two substances are condensed to obtain intermediates. , And then by methylation, hydrogen reduction, methyl sulfonylation products do not Lite.[1]

p-Nitrophenylethylamine hydrochloride is an indispensable important intermediate for the synthesis of miramenerone and dofetilide. The Chinese patent CN201310179528.5, which currently discloses the manufacture of 4-Nitrophenethylamine hydrochloride, is disclosed. The preparation method is that phenylethylamine hydrochloride is slowly added to the mixed acid of concentrated nitric acid and concentrated sulfuric acid at 0° C., then the reaction solution is stirred at this temperature to 1 for complete reaction, warmed to room temperature, and poured into 1.5L. In water, NaOH was adjusted to pH 10 and extracted with ether. [2]The ether phase was extracted with 1M hydrochloric acid. The aqueous phase was spin-dried to give a yellow solid. After recrystallization, a pale yellow solid, 4-nitrophenylethylamine hydrochloride, was obtained. The invention solves a series of problems such as unstable reaction, many by-products and low yield in the preparation process of p-nitrophenylethylamine in the prior art, and needs to protect the amino group of phenylethylamine before the nitrification reaction. After the nitro group is substituted, it is deprotected, ie, the amino group is protected. The electron-withdrawing effect of the acyl group is also helpful for the nitro substitution, and is a method for industrially producing 4-Nitrophenethylamine hydrochloride as a pharmaceutical intermediate.

The synthesis steps are as follows: (1)In a 500L enamel reactor, 120-128 kg of β-phenylethylamine and 145-150 kg of acetic anhydride were added and stirred at 40-50°C for 4-5 h. (2)Add 340-350 kg of 62-64% nitric acid in a 1000-L enamel reactor, stir, add 490-500 kg of 70% sulfuric acid at 30-35°C, and then add the temperature at 25-35°C (1) 2 - Reaction mixture of phenethylamine and acetic anhydride, after completion of the addition, the reaction is stirred at room temperature for 2-3 h and the reaction is completed; (3)The reaction solution was slowly added 30% NaOH alkaline solution to a pH between 6-7, and 295-300 kg of toluene was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated to a viscous consistency. (4)Then add 40% hydrobromic acid 275-280 kilograms, at 102-106 ° C under reflux reaction 2-3h, after the crystallization at 4.8 ° C frozen 4.8-5h, give away the crystal 80-100 kg; (5)In the above-obtained 4-Nitrophenethylamine hydrochloride  crystals, 100-120 kg of a ternary mixed solvent system with a volume ratio of water:ethanol:toluene of 1:6.8-7:2 is added, dissolved by heating, and then frozen and crystallized at ?2° C. for 4.8-5 h. Taking into account the crystal 70-90 kilograms, HPLC detection content of 99.8% or more, a single impurity is less than 0.1%, wherein the isomer 2-nitrophenylethylamine hydrobromide content is less than 0.05%.

Synthesis from β-bromophenylethane

In order to solve the above problems existing in the prior art, the present invention provides a method for preparing a mirabegron intermediate (4-Nitrophenethylamine hydrochloride), wherein the method uses β-bromophenylethane as a starting material, and synthesizes the mirabegron intermediate through two steps of nitration and aminolysis. The method has a simple and efficient process route, mild and easy-to-control reaction conditions, high conversion rate, readily available and low-priced raw materials, and does not use the controlled drug phenylethylamine as a raw material, and is suitable for industrial production. The technical solution of the present invention is: a method for preparing a mirabegron intermediate (4-Nitrophenethylamine hydrochloride), characterized in that it comprises the following steps: At room temperature, add β-bromobenzene ethyl to acetic acid, control the temperature below 30°C and drop concentrated sulfuric acid, then control the temperature at 0-10°C and drop a mixed acid solution of nitric acid and concentrated sulfuric acid, and keep the temperature to react for 2-6 hours after the addition is completed; after the reaction is completed, post-treatment is performed to obtain solid p-nitrophenylethyl bromide; p-nitrophenylethyl bromide is added to a solvent, methanol, and then aqueous ammonia is added, and the mixture is stirred at room temperature overnight; after the reaction is completed, the methanol is concentrated, and dichloromethane and an aqueous sodium hydroxide solution (preferably at a concentration of 10-15%) are added to the remaining concentrated solution, and the solution is allowed to stand for separation, and the organic phase is dried and then hydrochloric acid is added to form a salt, and then 4-Nitrophenethylamine hydrochloride is obtained by post-treatment.[3]

References

[1]ALI CHEMICAL CHANGZHOU - CN107759477, 2018, A

[2]CN104151170A

[3]SHANDONG SIHUAN PHARMACEUTICAL - CN118791389, 2024, A