Rupatadine fumarate derivative, its preparation method, intermediate and use
A technology of rupatadine fumarate and its derivatives, which is applied in the field of its preparation method and intermediates, and rupatadine fumarate derivatives, and can solve the problem that rupatadine fumarate derivatives cannot be effectively synthesized, Control difficulties and other problems to achieve the effect of low price, cost reduction and excellent quality
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[0039] In another typical embodiment of the present application, a preparation method of the above-mentioned rupatadine fumarate derivative is provided, the preparation method comprising: step S3, reacting compound D with compound E to obtain rupatadine fumarate Phata Derivatives,
[0040] The structural formula of compound D is Wherein X is a halogen atom;
[0041] The structural formula of compound E is
[0042] The reaction scheme of above-mentioned step S3 is as follows:
[0043]
[0044] The preparation method of the above-mentioned rupatadine fumarate derivative (this application is called rupatadine fumarate derivative LP-3) adopts a shorter synthetic route, which can improve the LP-3 of the rupatadine fumarate derivative. -3 yield, while the synthetic route also has the advantages of less side reactions and good reproducibility. On this basis, through the preparation and structural identification of rupatadine fumarate derivative LP-3, a reference substance w...
Embodiment 1
[0063] Add 150ml of water into a 500ml round bottom flask, pass through an inert atmosphere N 2 and maintained, followed by the partial addition of sodium hydroxide (6 g, 150.00 mmol, 1.00 equiv) at 0° C., followed by the addition of 5-methylpyridin-3-ylmethanol hydrobromide (raw material A, 30.6 g, 149.95 mmol, 1.00equiv), and 3-ethoxycarbonyl-acrylic acid (raw material B, 15.66g, 108.66mmol, 1.00equiv), the resulting solution was refluxed in an oil bath at 110°C for 3 days, the solid was filtered while it was hot, and the filtrate was cooled to room temperature , the precipitated solid was collected by filtration, washed with 1x50 ml of ice water and dried by infrared to give 15 g (42%) of compound C 1-(2-carboxy-1-carboxyethyl)-3-hydroxymethyl-5-methylpyridine-1 -onium white solid. Test the substituted products obtained during the synthesis process, see the test results figure 1 .
[0064] The MS spectrum data of the product are:
[0065] LC-MS-PH-JLU-LP-3-1: (ES, m / z):...
Embodiment 2
[0067] Put an inert atmosphere N into a 500ml round bottom flask 2 And hold, add 1-(2-carboxy-1-carboxyethyl)-3-hydroxymethyl-5-methylpyridin-1-ium (3.3g, 13.79mmol, 1.00equiv) and 60ml ethylene glycol dimethyl ether, followed by stirring and dropping phosphorus tribromide (6.6ml, 2.00equiv) at 0°C, the resulting solution was stirred and reacted at room temperature for 5 hours and then directly concentrated in vacuo, the resulting solution was diluted with 30ml ACN, and 5ml was added at 0°C The reaction was quenched with water, and the resulting mixture was concentrated in vacuo. The crude product that obtains adopts Flash-Prep-HPLC to purify, and condition is as follows: chromatographic column is C18 filler; Mobile phase, ACN / water (0.1%NH OH) and acetonitrile; Gradient: 0% ACN rises to 5% ACN in 10min; Detector , UV 254 & 220nm, yielding 12g (crude product) of compound D 1-(2-carboxyethyl)-3-bromomethyl-5-methylpyridin-1-ium. Test the substituted products obtained during t...
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