Deuterated methyl telmisartan as well as preparation method and application thereof
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A technology of telmisartan and deuterated methyl, applied in the field of deuterated methyl telmisartan and its preparation, can solve the problems of limited use, high price, etc. Well-designed effects
Inactive Publication Date: 2018-07-27
QINZHOU UNIV
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In addition, deuterium is still the best internal standard. For a long time, the deuterium internal standard used in my country has been dependent on imports. Due to its extremely high price, it has severely limited the wide use of this type of standard in China.
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preparation example Construction
[0052] A kind of preparation method that deuterium replaces misartan, it comprises the following steps:
[0053] 1): Dissolving 3-methyl-4-nitrobenzoic acid in ethanol, adding thionyl chloride dropwise, heating under reflux to obtain compound (2);
[0054]
[0055] 2): dissolving compound (2) in a solvent, and hydrogenating palladium carbon to obtain compound (3);
[0056]
[0057] 3): dissolving compound (3) in dichloromethane, adding an alkaline antacid, and adding n-butyryl chloride dropwise at 0°C for acylating reaction to obtain compound (4);
[0058]
[0059] 4): At 0°C, add concentrated sulfuric acid to compound (4), add fuming nitric acid or concentrated nitric acid dropwise, and react to obtain compound (5);
[0060]
[0061] 5): dissolving compound (5) in an acidic solvent, adding a reducing agent, and reducing ring closure to obtain compound (6);
[0062]
[0063] 6): dissolving compound (6) in a solvent, adding a base, and then adding 4-bromobenzyl...
Embodiment 1
[0089] The preparation of compound (2):
[0090]
[0091] Add 3-methyl-4-nitrobenzoic acid (18.1g, 100mmol) into a 500mL dry three-necked flask, add 200mL of absolute ethanol, then ice-bath to 0°C, slowly add 10mL of thionyl chloride dropwise into the three-necked flask, keep the temperature in the three-necked flask not exceeding 10°C, after the dropwise addition, the reaction temperature gradually rises from 0°C to 80°C, and the tail gas is absorbed with aqueous sodium hydroxide solution, and the reaction is completed for 2 hours. Remove methanol and remaining thionyl chloride, obtain white solid 20.1g compound (2),
[0092] yield: 96.1%, LCMS[M+H]=210.
[0093] The preparation of compound (3):
[0094]
[0095] Compound (2) (10.45g, 50mmol) was added to a 150mL single-necked bottle filled with 60mL of EtOH, 1.0g of 10% anhydrous Pd / C was added, and it was reacted overnight at room temperature under a hydrogen atmosphere. TLC monitored that the reaction was basically c...
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Abstract
The invention belongs to the field of organic and pharmaceutical synthesis, and discloses deuterated methyl telmisartan as well as a preparation method and application thereof. The method adopts 3-methyl-4-nitrobenzoic acid as a raw material, adopts deuterated iodomethane as a deuterated raw material and synthesizes deuterated telmisartan-d3 by virtue of eleven-step reaction. The preparation method is simple in operation, saves a deuterated reagent, is low in cost and easy to purify. After being rapidly purified by preparation chromatography, a pure product is obtained. A deuterated telmisartan standard product prepared according to the invention is high in purity and stable in chemical performance; and the preparation of the standard product can be conveniently analyzed. The preparation method can be used for producing and analyzing a deuterated internal standard substance used when the deuterated telmisartan is detected; and a medicinal composition can be prepared, i.e, the medicinalcomposition can be used for angiotensin II receptor antagonist to lower the blood pressure and can lower the blood pressure of patients with high cardiovascular disease risk and diabetic patients.
Description
technical field [0001] The invention relates to the technical field of medicine, in particular to the technical field of organic drug synthesis, in particular to a deuterated methyl telmisartan and a preparation method, composition and application thereof. Background technique [0002] Telmisartan, as an angiotensin (AT1) II receptor antagonist, is a new type of antihypertensive drug. The compound was developed by Boehringer Ingethiem in Germany, and it was first launched in the United States in March 1999, and in Germany in the same year. Non-peptide angiotensin II receptor antagonists can selectively and irreversibly block ATI receptors without affecting other receptor systems. For mild to moderate high blood pressure. Telmisartan is a new type of antihypertensive drug and a specific angiotensin II receptor (ATI type) antagonist for the treatment of essential hypertension. The alternative angiotensin II receptor binds with high affinity to the ATI receptor subtype (the ...
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