A kind of synthetic method of n-benzyl-3-hydroxypiperidine

Abstract

The invention discloses a synthesis method of N-benzyl-3-hydroxypiperidine, and belongs to the technical field of organic synthesis. In the absence of alkaline, and after 3-hydroxypiperidine is protected by halogenated benzyl, hexamethyldisilane is added to continue the reaction to obtain N-benzyl-3-trimethylsiloxidine, and then alcohols solvent or fluorine-containing ionicsalt is added for deprotection to obtain high-purity N-benzyl-3-hydroxypiperidine. According to the synthesis method of N-benzyl-3-hydroxypiperidine, the raw materials and reagents are cheap and easy to obtain, the reactioncondition is mild, continuous operation can be conducted, the product purity reaches up to 99.5% or above, and the method is suitable for enlarged production on a large scale.

Description

Technical field: [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a synthesis method of N-benzyl-3-hydroxypiperidine. Background technique: [0002] 3-Hydroxypiperidine derivatives are widely used in the synthesis of pharmaceutical intermediates, among which N-benzyl-3-hydroxypiperidine is the most important intermediate in the synthesis of benidipine, and only one step of esterification is required Benidipine can be obtained. Benidipine is a second-generation dihydropyridine calcium ion antagonist, which can relax blood vessels, lower blood pressure, and resist angina by blocking L-type calcium channels. In recent years, N-benzyl The market demand for 3-hydroxypiperidine as a pharmaceutical intermediate is rapidly increasing. At present, the synthetic pathways of N-benzyl-3-hydroxypiperidine mainly contain the following four categories: [0003] 1. With 3-hydroxypyridine as raw material, benzyl chloride or benzyl bromi...

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Problems solved by technology

[0003] 1. With 3-hydroxypyridine as raw material, benzyl chloride or benzyl bromide is alkylated into quaternary ammonium salt, and then the pyridine ring is reduced to obtain N-benzyl-3-hydroxypiperidine (CN101817779, CN10130080). In this route, pyridine quaternary The reduction of ammonium salt requires the use of reducing agent metal hydride sodium borohydride or metal catalyst for pressurized hydrogenation. The disadvantage is that the post-treatment operation of sodium borohydride as reducing agent is very dangerous and prone to accidents. The reaction conditions of metal catalyst pressurized hydrogenation are harsh and The cost of the catalyst is relatively high, neither of which is suitable for industrial production

[0004] 2. Using 3-hydroxypyridine as a raw material, first hydrogenate under the action of noble metal catalysts such as rhodium carbon or ruthenium carbon to obtain 3-hydroxypiperidine and then N-benzylation. This route uses noble metals as catalysts, and the cost is relatively high. Moreover, the reaction is carried out at a higher temperature and pressure (60-120°C, 5-10atm), and the raw materials and products have a passivation effect on the catalyst activity. These factors are not conducive to the cost control of the entire process route.

[0005] 3. Using benzyltetrahydrofurfurylamine as raw material, after concentrated hydrochloric acid is formed into a salt, the ring is first opened and the ring is closed in N-benzyl-3-hydroxypiperidine (JP1993-168493), but this method has the following disadvantages : 1) Raw materials are not easy to get, and benzyltetrahydrofurfurylamine must be prepared by reductive amination of tetrahydrofurfurylamine; 2) The conversion rate and selectivity of the reaction are not very good, and the preparation efficiency is low

[0006] 4. Using 3-hydroxypiperidine hydrochloride as raw material, after dissociation of triethylamine and reflux reaction with an equivalent amount of benzyl chloride in toluene, the post-treatment is subjected to high-vacuum, high-temperature and reduced-pressure distillation (125-126°C / 3.5 mmHg) to obtain N-benzyl-3-hydroxypiperidine (US4448964), the conversion of raw materials in this method is not complete, and the by-product benzyl alcohol and oxygen and nitrogen are replaced by benzyl compounds more, and the main by-product oxygen is connected to benzyl The boiling point of the by-product is close to that of the product, and the peak on the GC does not exceed 0.2min. It is difficult to remove by rectification, and the yield is only 56.9%. The purification method requires high temperature and high vacuum, which is not suitable for scale-up production

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