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A technology for ticagrelor and intermediates, which is applied in the field of preparation of ticagrelor intermediates, can solve the problems of difficult purification of products and low yield of sulfur-alkylation, and achieve easy purification of products, few by-products, The effect of cheap and easy-to-obtain raw materials
Inactive Publication Date: 2017-03-15
QINGDAO YUNTIAN BIOTECH
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[0013] The purpose of the present invention is to overcome the difficulties in the preparation of the existing ticagrelor intermediate 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine, the difficulty in purification of the product, and the partic...
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Embodiment 1
[0033] In a 500ml flask, add 200ml 30% acetic acid aqueous solution, then add 41g (200mmol) of 2-nitro-1,3-diethyl malonate, 19.5g (240mmol) of sodium thiocyanate and 24.8g (400mmol) of ammonium acetate ) into the flask, kept stirring at 25°C for 5 hours, TLC monitored the completion of the reaction, poured the reaction solution into ice water, adjusted the pH to 8 with sodium bicarbonate, filtered, washed the filter cake with water three times, and dried in vacuo to obtain the compound shown in formula II 45.7g, yield 97.1%.
Embodiment 2
[0035]In the 500ml flask, add 200ml 20% acetic acid aqueous solution, then 2-nitro-1,3-diethyl malonate 41.0g (200mmol), sodium thiocyanate 19.5g (240mmol) and ammonium acetate 22.4g ( 360mmol) was added in the flask, kept stirring at 20°C for 5 hours, TLC monitored the completion of the reaction, poured the reaction solution into ice water, adjusted the pH to 8 with sodium bicarbonate, filtered, washed the filter cake with water three times, and dried in vacuo to obtain the compound shown in formula II Compound 46.0g, yield 97.7%.
Embodiment 3
[0037] In a 500ml flask, add 220ml 30% acetic acid aqueous solution, then add 41g (200mmol) of 2-nitro-1,3-diethyl malonate, 22.7g (280mmol) of sodium thiocyanate and 18.6g (300mmol) of ammonium acetate ) into the flask, heat up and keep stirring at 40°C for 4.5 hours, TLC monitors the completion of the reaction, pours the reaction solution into ice water, adjusts the pH to 8 with sodium bicarbonate, filters, washes the filter cake with water three times, and vacuum-dries to obtain formula II Compound 45.7g, yield 97.2%.
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Abstract
The invention discloses a preparation method for a cagrelor intermediate. The preparation method comprises the following steps; step 1, reacting 2-nitro-1,3-malonic acid diester with sodium sulfocyanate and ammonium acetate in an aqueous solution of acetic acid so as to obtain a compound as shown in a formula II which is described in the specification; step 2, subjecting the compound as shown in the formula II to reflux in ethanol under the action of sodium alkoxide so as to obtain a compound as shown in a formula III which is described in the specification; step 3, subjecting the compound as shown in the formula III and 1-bromopropane to a contact reaction in 1,4-dioxane in the presence of alkali under the catalysis of zinc chloride; and step 4, subjecting a product of the step 3 and a chlorination reagent to a chlorination reaction in acetonitrile so as to obtain the ticagrelor intermediate 4,6-dichloro-5-nitro-2-(propylthio)pyridine. The preparation method provided by the invention has the advantages of few by-products, easy purification and high yield of the ticagrelor intermediate, usage of cheap and easily available raw materials and suitable for industrial production.
Description
technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method of a ticagrelor intermediate. Background technique [0002] Ticagrelor, the chemical name is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5 -(Propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2- Diol, which is the first reversible binding oral P2Y12 adenosine diphosphate receptor antagonist, has obvious inhibitory effect on ADP-induced platelet aggregation, and can effectively improve the symptoms of patients with acute coronary heart disease. The compound was developed by AstraZeneca and approved for marketing in the European Union and the United States in 2010 and 2011 respectively. In addition, the imported tablet has also been approved by the China Food and Drug Administration (SFDA) to be marketed in my country. The specific structural formula of ticagrelor is as follows. [0003] [0...
Claims
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