Preparation method of (S)-1, 2, 3, 4-tetrahydro-1-naphthoic acid

Abstract

The invention discloses a preparation method of (S)-1, 2, 3, 4-tetrahydro-1-naphthoic acid, which avoids a product degradation reaction and a racemization reaction in a high-temperature process when an ethyl acetate solvent is distilled, avoids the use of a class II solvent n-hexane, and eliminates potential safety hazards in production. According to the obtained product (S)-1, 2, 3, 4-tetrahydro-1-naphthoic acid, the content of the enantiomer (R)-1, 2, 3, 4-tetrahydro-1-naphthoic acid is 0.05% or below, the chemical purity is 99.5% or above, and no n-hexane solvent is left.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an antiemetic drug, a key intermediate (S)-1,2,3,4-tetrahydro-1-naphthoic acid of palonosetron hydrochloride. Background technique [0002] Palonosetron hydrochloride was developed by Helsinn Healthcare SA in Switzerland. It is a 5-HT3 receptor antagonist for the treatment of acute nausea and vomiting caused by chemotherapy drugs. Medications for nausea and vomiting. It was approved by the FDA in July 2003, and is now listed in many countries such as the United States, Japan, and China. [0003] (S)-1,2,3,4-tetrahydro-1-naphthoic acid (formula I) and (R)-1,2,3,4-tetrahydro-1-naphthoic acid (formula II) are a pair Enantiomers, the two compounds can be obtained by chemical resolution from 1,2,3,4-tetrahydro-1-naphthoic acid (formula III). Among them, (S)-1,2,3,4-tetrahydro-1-naphthoic acid (formula I) is a key intermediate for the...

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Problems solved by technology

In this method, when analyzing (S)-1,2,3,4-tetrahydro-1-naphthoic acid*quinine salt, extract and wash the salt with hydrochloric acid and ethyl acetate, remove quinine by layering, and obtain (S )-1,2,3,4-tetrahydro-1-naphthoic acid ethyl acetate solution, the product obtained during the concentration process is a thick liquid, and the last part of the remaining ethyl acetate wrapped is difficult to evaporate to dryness, for this reason It needs to be under high vacuum and raise the temperature to more than 90 degrees to distill this part of residual ethyl acetate, otherwise it will lead to the next step of n-hexane recrystallization and cannot precipitate solid crystals; when industrialized scale-up production, this The time of this high-temperature distillation state needs to last for more than 5 hours; this will first cause the racemization reaction of (S)-1,2,3,4-tetrahydro-1-naphthoic acid, resulting in a decrease in the optical purity of the product; in addition, with With the prolongation of the high temperature time, the color of the product will obviously turn yellow, and new degraded impurities will be produced, which will affect the chemical purity of the product; moreover, n-hexane is a second-class solvent, which has certain toxicity and is also flammable and explosive. The use of n-hexane to crystallize products will have a negative impact on production safety. Not only that, there will be unavoidable residual n-hexane in the final product, which will affect product quality

In short, the products obtained through the above literature methods have flaws in quality, which is not the best choice for the pharmaceutical industry that prioritizes quality; according to the literature methods, there are potential safety hazards in industrial production

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