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N-ethylpyridine methylamine mesylate crystal, preparation process thereof and application of N-ethylpyridine methylamine mesylate crystal in preparation of tropicamide

A technology of ethyl picolinium methanesulfonate and ethyl picolinamide, which is applied in the field of pharmaceutical preparation, can solve operational difficulties such as transfer, sub-packaging, storage, transportation, etc., is not suitable for crystallization, N-ethyl picolinate Problems such as low melting point of amines

Pending Publication Date: 2020-04-03
卡博金艾美斯医药(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under the trend that the current national policy has stricter and stricter requirements on raw materials, it is difficult for such low-purity N-ethylpicolylamine to meet the market demand
[0015] The oily N-ethylpicolinylamine has a high viscosity, which makes it difficult to transfer, pack, store, and transport. Moreover, the unpleasant smell that volatile organic amines emit is also extremely unfriendly to the workers in the workshop. In addition, the volatilized amines can easily form smoky urea derivative solids with carbon dioxide in the air, which can easily block the pipeline and cause unnecessary accidents when there is airflow while polluting the product. Purity, low cost, N-ethylpicolylamine that is solidified and easy to operate is very meaningful and necessary;
[0016] The commonly used purification method is crystallization, but N-ethylpicolylamine has a very low melting point and is not suitable for crystallization. Considering that N-ethylpicolylamine itself is a free base, it is solidified to form a salt of this free base with an acid an effective means of purifying and

Method used

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  • N-ethylpyridine methylamine mesylate crystal, preparation process thereof and application of N-ethylpyridine methylamine mesylate crystal in preparation of tropicamide
  • N-ethylpyridine methylamine mesylate crystal, preparation process thereof and application of N-ethylpyridine methylamine mesylate crystal in preparation of tropicamide
  • N-ethylpyridine methylamine mesylate crystal, preparation process thereof and application of N-ethylpyridine methylamine mesylate crystal in preparation of tropicamide

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Experimental program
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Effect test

Embodiment 1

[0045]Preparation of Compound 1: Add 157.8g (1.4mol) of 4-pyridinecarbaldehyde and 2000mL of absolute ethanol to a 5000mL three-neck flask, stir at room temperature to obtain a clear solution, control the temperature in an ice-water bath at 0-10°C, and add 214.6g (1.5mol) dropwise 66% concentration of ethylamine aqueous solution, after dripping, react for 1-2 hours, control in the TLC plate, if the raw material point disappears, the reaction is considered complete, slowly add 58.5g (1.5mol) sodium borohydride in batches, after adding, control React at 10-25°C for 1-2 hours, add 300mL of purified water dropwise, stir overnight at room temperature, and control in TLC. After the reaction is complete, concentrate in vacuo to remove the solvent, add 2000mL of water, extract with 2000mL of dichloromethane, and saturate the organic phase with 1500mL Wash with brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate in vacuo to obtain 192.5 g of dark yellow oil, w...

Embodiment 2

[0048] Preparation of Compound 2: Add 4.03g (0.03mol) of pure N-ethylpicolylamine and 30mL of isopropanol to a 50mL three-neck flask, stir at room temperature to obtain a light yellow clear solution, and slowly add 3.41g (0.036mol) of Methanesulfonic acid was dropped, stirred at room temperature for 1-5 hours, filtered, the filter cake was washed with acetonitrile, and vacuum-dried to obtain 6.32 g of white crystals with a purity of 99.95% and a yield of 92.0%.

Embodiment 3

[0050] Preparation of Compound 2: Add 4.02g (0.03mol) of pure N-ethylpicolinylamine and 30mL of ethyl acetate to a 50mL three-neck flask, stir at room temperature to obtain a light yellow clear solution, slowly add 3.39g (0.036mol) of Methanesulfonic acid, dropwise, stirred at room temperature for 1-5 hours, filtered, the filter cake was washed with acetonitrile, and vacuum-dried to obtain 6.41 g of white crystals with a purity of 99.52% and a yield of 93.3%. The obtained crystals have the following properties: figure 2 Shown XRD pattern, this pattern feature is shown in Table 1.

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Abstract

The invention discloses an N-ethylpyridine methylamine mesylate crystal, a preparation process thereof and the application of the N-ethylpyridine methylamine mesylate crystal in the preparation of tropicamide. Mesylate of N-ethylpyridine methylamine mesylate crystal is prepared from N-ethylpyridine methylamine and methylsulfonic acid, when X-ray powder diffraction is used, and the crystal has diffraction peaks at about 9.49 degrees, 13.16 degrees, 16.18 degrees, 19.10 degrees, 20.54 degrees, 23.24 degrees, 26.96 degrees and 34.63 degrees. The preparation method comprises the following steps ofdissolving the N-ethylpyridine methylamine in an organic solvent, and stirring at room temperature or heating and stirring until a material is completely dissolved; slowly adding acid, and crystallizing; and carrying out heat preservation aging, filtering and drying to obtain the tropicamide key starting material N-ethylpyridine methylamine mesylate crystal. The method is simple to operate and obvious in purification effect, the salt form impurity content and the crystal form impurity content prepared by crystallization are low, the purity is high, and the industrial production is facilitated.

Description

technical field [0001] The invention relates to a mesylate crystal of N-ethylpicolylamine, a preparation process and its application in preparing tropicamide, belonging to the technical field of medicine preparation. [0002] technical background [0003] Tropicamide is an anticholinergic drug and a parasympathetic nerve inhibitor. In the field of ophthalmology, it is the preferred mydriatic drug for fundus examination and diagnosis, and it also has the effect of ciliary muscle anesthesia. It was first synthesized by Roche Company in 1955. In addition to being used alone, it is mostly used as a compound agent clinically. Compared with other mydriatics, tropicamide has many advantages such as rapid mydriasis and short recovery period. [0004] Physicochemical properties of tropic amide: white crystal in powder form, bitter in taste, soluble in ethanol, chloroform and acetone, slightly soluble in water, insoluble in petroleum ether. [0005] At present, the earliest disclosed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/38C07C303/32C07C309/04
CPCC07D213/38C07C309/04C07B2200/13
Inventor 詹祖金王希林
Owner 卡博金艾美斯医药(上海)有限公司