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Rupatadine fumarate intermediate and preparation method of rupatadine fumarate
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A technology for rupatadine fumarate and an intermediate, which is applied in the field of chemical synthesis, can solve the problems of complicated post-processing, difficult to remove by-products, harsh reaction conditions, etc. Moderate effect
Pending Publication Date: 2022-03-04
CHONGQING HUAPONT PHARMA
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[0006] The disadvantage of this method is that lithium aluminum tetrahydrogen is used in the reaction, the reaction temperature is below -70~-75°C, the risk is high, and the reaction conditions are harsh, so it is not suitable for industrial production
[0009] The disadvantage of this method is that the yield of the bromination reaction is low, and there are multiple substitutions in the bromination process, it is difficult to separate, column chromatography purification is required, the yield is low, the post-treatment is complicated, and it is not suitable for industrial production
[0012] The disadvantage of this method is that: the acylation reaction uses DCC, the by-product DCU is difficult to remove, and the reduction uses POCl 3 , will generate a large amount of colloidal substances, cannot be stirred, have many by-products, complex post-processing, low yield, and are not suitable for commercial production
[0013] In summary, there are technical problems such as many by-products, low yield, and complex post-processing in the existing synthetic average for preparing rupatadine fumarate or its intermediates
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example 1
[0074] Example 1 Compound V Preparation
[0075] Under nitrogen protection, add the compound of formula (VI) (2.5g, 0.02mol, 1.0eq) into a 100ml reaction flask, add 50ml of acetonitrile, start stirring, heat up to reflux, add NCS (3.2g, 0.024mol, 1.2eq), AIBN (0.33g, 0.002mol, 0.1eq), reacted for 6h, TLC (developing solvent, methanol:dichloromethane=1:2, add 2 drops of ammonia) to monitor the disappearance of the compound of formula (Ⅵ), concentrated the acetonitrile under reduced pressure, added 20ml of toluene was stirred for 30min, filtered, and the filtrate was collected, and 60ml of n-hexane was added dropwise with stirring at room temperature. After the dropwise addition was completed, the temperature was lowered to 0-10°C and stirred for 60min, filtered, and dried to obtain the compound of formula (Ⅴ) (2.8g), with a yield of 88.9% , HPLC purity 86.05%, see figure 1 . MS-ESI(m / z): 157.1[M+H] + ,See Image 6 .
example 2
[0076] Preparation of Example 2 Compound V
[0077] Under nitrogen protection, add the compound of formula (VI) (2.5g, 0.02mol, 1.0eq) into a 100ml reaction flask, add 50ml of acetonitrile, start stirring, heat up to reflux, add NCS (4.0g, 0.03mol, 1.5eq), AIBN (0.33g, 0.002mol, 0.1eq), reacted for 6h, TLC monitored the disappearance of the compound of formula (VI), concentrated the acetonitrile under reduced pressure, added 20ml of toluene, stirred for 30min, filtered, collected the filtrate, added dropwise 60ml of n-hexane while stirring at room temperature, After the dropwise addition was completed, the temperature was lowered to 0-10°C and stirred for 60 minutes, filtered and dried to obtain the compound of formula (Ⅴ) (2.6g), with a yield of 82.5% and an HPLC purity of 67.05%, see figure 2 .
example 3
[0078] Preparation of Example 3 Compound V
[0079] Under nitrogen protection, add the compound of formula (VI) (2.5g, 0.02mol, 1.0eq) into a 100ml reaction flask, add 50ml of acetonitrile, start stirring, heat up to reflux, add NCS (2.67g, 0.02mol, 1.0eq), AIBN (0.33g, 0.002mol, 0.1eq), reacted for 6h, TLC monitored that the compound of formula (VI) was not completely reacted.
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a rupatadine fumarate intermediate and a preparation method of rupatadine fumarate. The method comprises the following steps: (1) reacting a compound shown in a formula VI with a halogenating reagent to obtain a rupatadine fumarate intermediate shown in a formula V; (2) adding the intermediate of formula V and a compound of formula IV into an acid-binding agent for reaction to obtain a compound of formula III; (3) reacting the compound in the formula III with a reducing agent to obtain a compound in a formula II; and (4) reacting the compound shown in the formula II with fumaric acid to obtain rupatadine fumarate. According to the preparation method, 3, 5-dimethylpyridine-N-oxide is used for carrying out bromination or chlorination, and compared with bromination or chlorination carried out by using 3, 5-dimethylpyridine, the purity and the yield of a halogenated product are higher. Moreover, after the compound shown in the formula V reacts with the compound shown in the formula IV, column chromatography is not needed, the compound shown in the formula III is obtained through solvent refining, post-treatment operation is simple, and industrial production is facilitated.
Description
technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a rupatadine fumarate intermediate and a preparation method of rupatadine fumarate. Background technique [0002] Rupatadine Fumarate (Rupatadine Fumarate), the chemical name is 8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidinylidene]-6, 11-Dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate, an antihistamine and platelet activating factor (PAF) dual-action antihistamine developed by Spain Uriach Company Allergymedicine, indicated for seasonal and perennial allergic rhinitis. The chemical structural formula of rupatadine fumarate is as follows: [0003] [0004] In Synthetic Communications, 38(1), 122-127; 2008, a method for preparing rupatadine fumarate is mentioned, specifically: [0005] [0006] The disadvantage of this method is that lithium aluminum tetrahydrogen is used in the reaction, the reaction temperature is below -70--75°C...
Claims
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