Synthesis method of (R)-2-p-nitrobenzene ethylamine-1-phenethyl alcohol and salt thereof

Abstract

The invention provides a synthesis method of (R)-2-p-nitrobenzene ethylamine-1-phenethyl alcohol and salt thereof, belongs to the technical field of medicine synthesis and solves the problems that in the prior art the cost is high, the product yield is low, the synthesis method is not applicable to large-scale industrial production, and the like. The synthesis method comprises the following steps of: under the action of an oxidant, oxidizing hydroxyl on p-nitrobenzene ethanol into an aldehyde group so as to obtain p-nitrobenzene acetaldehyde; under the action of a reducing agent, carrying out dehydration, condensation and reduction on amino on (R)-2-amino-1-phenethyl alcohol and the aldehyde group on p-nitrobenzene acetaldehyde so as to obtain (R)-2-p-nitrobenzene ethylamine-1-phenethyl alcohol; and mixing a rough product of (R)-2-p-nitrobenzene ethylamine-1-phenethyl alcohol with an acid so as to generate precipitate or stirring till solid (R)-2-p-nitrobenzene ethylamine-1-phenethyl alcohol salt is separated out. The synthesis method of (R)-2-p-nitrobenzene ethylamine-1-phenethyl alcohol and the salt thereof is low cost and high in product yield, and is applicable to large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing a pharmaceutical intermediate, in particular to a method for synthesizing (R)-2-p-nitrophenethylamino-1-phenylethanol and its salt, and belongs to the technical field of drug synthesis. Background technique [0002] According to the Food and Drug Administration, overactive bladder afflicted by symptoms of urge incontinence, urgency, and frequency affects a large number of people, such as about 33 million people in the United States. The use of mirabegron induces relaxation of detrusor smooth muscle storage during the bladder fill-void cycle, thereby promoting increased bladder capacity. And compared with general drugs for the treatment of overactive bladder, mirabegron has the characteristics of simple usage and dosage, and faster onset of drug effects. And (R)-2-p-nitrophenethylamino-1-phenylethanol and its salts are important intermediates for the synthesis of mirabegron. [0003] (R)-2-p-nitrophen...

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Problems solved by technology

[0008] 1) The toxic S-styrene oxide reagent is used in the synthesis method, which has an inhibitory effect on the central nervous system, stimulates and sensitizes the skin, and has positive results in various mutagenic tests, which is unfavorable to operators

[0009] 2) The expensive S-styrene oxide reagent is used in this synthesis method, and column chromatography is required for separation after the reaction, resulting in high cost

[0010] 3) After the reaction is completed, the reaction solution needs to be separated by column chromatography to obtain the pure product, and the yield is low, and the post-processing steps are cumbersome and will generate a lot of three wastes

[0014] 1) In the above synthesis process, toxic toluene was used as a solvent for recrystallization. The borane-tetrahydrofuran reagent used is liquid at room temperature, has a foul smell, is sensitive to humidity, reacts violently with water and releases flammable gases, and can Form explosive peroxides, which are irritating to eyes, respiratory system, and skin, and are harmful to operators and the ecological environment

[0015] 2) 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole, 1,3-dimethyl -2-imidazolinone, tetrahydrofuran, borane-tetrahydrofuran and other reagents, resulting in higher cost of raw materials and post-processing

[0016] 3) The above synthesis method has long reaction steps. After the reaction, the reaction solution needs to be washed with water, pickled, alkali washed, washed with salt water, and recrystallized to obtain the pure product. The yield is low, and the post-processing steps are cumbersome and produce a lot of waste.

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