Preparation method of varenicline tartrate crystal form

Abstract

The invention relates to a preparation method of two anhydrous crystal forms A and B of varenicline tartrate, and belongs to the technical field of medicinal chemistry. The preparation method comprises the steps of dissolving varenicline in a solvent I, adding a solvent II after complete dissolution to obtain a varenicline solution, and heating the varenicline solution to 40 DEG C or above; dissolving L-tartaric acid in the solvent I, and after L-tartaric acid is completely dissolved, adding the solvent II to obtain an L-tartaric acid solution; dropwise adding the L-tartaric acid solution into the varenicline solution, and carrying out heat preservation and stirring after dropwise adding is completed; and filtering, washing with the solvent II, and drying to obtain the varenicline tartrate with the crystal form A. The method adopted by the invention is easy to operate, low in product solvent residue, good in appearance color, high in crystal form purity and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of two anhydrous crystal forms A and B of varenicline tartrate. Background technique [0002] Varenicline is a non-nicotine drug and a highly selective neuronal nicotinic acetylcholine receptor partial agonist, which can highly selectively bind to the neuronal nicotinic acetylcholine receptor α4β2 subtype. Its smoking cessation effect is considered to be combined with nicotinic receptor subtypes, stimulates N receptors, produces moderate and mild nicotine-like effects, stimulates the release of a small amount of dopamine, alleviates the craving for nicotine and withdrawal syndrome of smokers, and regulates smokers The craving for nicotine and the reduction of withdrawal symptoms; at the same time, it blocks the combination of nicotine and acetylcholine α4β2 receptors, eliminates the stimulating effect of nicotine on dopaminergic neurons in the m...

AI Technical Summary

Problems solved by technology

According to the requirements of ICH Q3C for solvent residues in pharmaceuticals, methanol ≤ 3000ppm, ethanol ≤ 5000ppm, and acetone ≤ 5000ppm. Therefore, if a single methanol, ethanol or acetone is used as a solvent to prepare A crystal form or B crystal form, the solvent residue may exceed the standard. Does not meet quality requirements for pharmaceuticals

The reason for this phenomenon may be that a single methanol, ethanol or acetone will form intermolecular hydrogen bonds with the product, and the solvent is bound and difficult to be dried

In the process of preparing crystal form A or form B with this patented method, it was also found that the temperature, order of addition and time of adding L-tartaric acid and varenicline into salt would all affect the crystal form, and if the control is not good, it is easy to form AB mixed crystal

A single ether or ester solvent is used to prepare crystal form A or B, and the solvent residue can meet the requirements of ICHQ3C, but the solubility of varenicline and L-tartaric acid is relatively low, and a larger amount of solvent is required; acetonitrile belongs to Second-class solvents, ICH Q3C limit requirements are ≤410ppm, experiments have confirmed that it is difficult to dry to a lower level, and there is a possibility of exceeding the standard

[0013] Considering the potential excess of solvent residue and the amount of solvent, there are certain limitations in the preparation of crystal form A or form B in patent CN100370987, and only the feasibility of the preparation method is considered, but the practicability of the preparation method in production is not considered.

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