Preparation method of rupatadine fumarate impurity S

A technology for rupatadine fumarate and impurities, which is applied in the field of pharmaceutical synthesis, can solve the problems such as the preparation method of rupatadine fumarate impurity S and the like are not proposed, and achieves low price, good reproducibility, and improved yield Effect

Active Publication Date: 2018-07-20
杭州仟源保灵药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The main purpose of the present invention is to provide a preparation method of rupatadine fumarate impurity S...

Method used

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  • Preparation method of rupatadine fumarate impurity S
  • Preparation method of rupatadine fumarate impurity S
  • Preparation method of rupatadine fumarate impurity S

Examples

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preparation example Construction

[0042] The preparation method includes:

[0043] Substitution reaction: carry out substitution reaction between raw material A and raw material B to obtain a substituted product, raw material A has the structure shown in formula (I), raw material B has the structure shown in formula (II), and the substituted product has the structure shown in formula (III) ,

[0044]

[0045] x 2 is a halogen atom;

[0046] Halogenation reaction: the substitution product is subjected to a halogenation reaction with a halogenation reagent to obtain a halogenation product, which has a structure shown in formula (IV),

[0047] x 1 is a halogen atom; and

[0048] Condensation reaction: react the halogenated product with raw material C to obtain rupatadine fumarate impurity S, raw material C has the structure shown in formula (Ⅴ),

[0049]

[0050] Specifically, the synthetic route is:

[0051]

[0052] Based on the inventor's many years of work experience, the present application ...

Embodiment 1

[0075] (1) Substitution reaction: Add 5-methyl-3-pyridinemethanol hydrobromide (25g, 122.51mmol, 1.00equiv.) in a 1L round bottom flask, then add dichloromethane (500mL) and 5 - Methyl-3-bromomethylpyridine hydrobromide (32.7 g, 122.49 mmol, 1.00 equiv.). The above mixture was cooled to 0-5° C. using an ice bath, and triethylamine (37.1 g, 366.64 mmol, 3.00 equiv.) was added dropwise with stirring. After the dropwise addition was completed, a mixture to be reacted was obtained. It was then warmed to room temperature (25 °C) and stirred for 16 h. The reaction system was distilled under reduced pressure to obtain 73 g of crude product. The above-mentioned concentrate was dispersed in 73mL water (1g / mL), and separated and purified by preparative chromatography. The purification conditions were: the chromatographic column was a C18 filler with a pore size of 20um; the mobile phase was water (0.1% formic acid) / acetonitrile, the volume of acetonitrile Scores range from 0 to 10%, a...

Embodiment 2

[0106] The difference from Example 1 is: in the substitution reaction, the molar ratio of raw material A, raw material B and the first acid-binding agent is 1:2:3. The yield of the substituted product was 15 wt%, and the purity was 97 wt%.

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Abstract

The invention provides a preparation method of a rupatadine fumarate impurity S. The preparation method comprises the following steps: performing a substitution reaction on a raw material A and a rawmaterial B to obtain a substitution product; halogenating the substitution product by a halogenating reagent to obtain a halogenation product; and performing a condensation reaction on the halogenation product and a raw material C to obtain the rupatadine fumarate impurity S. The preparation method has the advantages of wide sources and low prices in the raw materials, increase in the yield of therapamycin fumarate impurity S through a short synthesis route, few side reactions and good reproducibility. A reference substance with excellent quality and high purity can be provided for the qualitative and quantitative analysis of rupatadine fumarate through the preparation and structural identification of the rupabadine fumarate impurity S in order to guide the preparation and the applicationof the rupatadine fumarate. The structure of the rupatadine fumarate impurity S is shown in the description, and X in the structure is a halogen atom.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing rupatadine fumarate impurity S. Background technique [0002] Rupatadine fumarate (Rupatadine fumarate) is a new type of powerful anti-allergic drug developed by Uriach Pharmaceutical Company of Spain. Since it was first listed in Spain in March 2003, it has been listed in many countries and regions one after another. In 2013, my country approved domestic pharmaceutical companies to produce rupatadine fumarate raw materials and preparations. The drug is currently the only anti-allergic drug on the market that has both antihistamine effect and antagonism to the activity of platelet activating factor. It is expected to become a first-line drug for the treatment of allergic rhinitis, pneumonia and skin diseases in the future, and has a broad market prospect. [0003] In the process of drug research, production, supply and clinical use, the purity of the drug mus...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 汤建拓张晖李上挺应梦瑶徐承智虞英民邵婷婷
Owner 杭州仟源保灵药业有限公司
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