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Synthesis method of N-hydroxy tropisetron

A technology of hydroxytropane and a synthetic method, applied in the field of drug synthesis, can solve problems such as unreported, and achieve the effects of strong operability, reasonable process design and high yield

Active Publication Date: 2020-07-03
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The synthetic method of N-hydroxytropisetron provided by the invention has not yet been reported

Method used

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  • Synthesis method of N-hydroxy tropisetron
  • Synthesis method of N-hydroxy tropisetron
  • Synthesis method of N-hydroxy tropisetron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The synthetic method of N-hydroxytropisetron comprises the following steps:

[0055] (1) Synthesis of Intermediate II

[0056] The reaction process is:

[0057]

[0058] Get 20 grams of benzyl 2-nitrophenylacetate and dissolve it in 400 milliliters of dioxane, add 5.01 grams of tetrabutylammonium bisulfate, 20.38 grams of potassium carbonate and 6.64 grams of paraformaldehyde, then heat the mixture to 100°C for reaction 4 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was partially concentrated and purified by column chromatography to obtain 15.65 g of an oily substance, namely Intermediate II, with a yield of 74.9%.

[0059] (2) Synthesis of Intermediate III

[0060]

[0061] The reaction process is:

[0062] Dissolve 15 grams of intermediate II in 600 milliliters of tetrahydrofuran, add 40.16 grams of anhydrous stannous chloride and 77.86 grams of anhydrous potassium acetate, use mechanical stirring, reac...

Embodiment 2

[0080] The synthetic method of N-hydroxytropisetron comprises the following steps:

[0081] (1) Synthesis of Intermediate IIa

[0082] The reaction process is:

[0083]

[0084] Get 20 grams of tert-butyl 2-nitrophenylacetate and dissolve in 120 milliliters of toluene, add 1.56 grams of tetrabutylammonium iodide, 8.94 grams of sodium carbonate and 9 milliliters of 37% aqueous formaldehyde solution, then the mixture is heated to 115 ° C to react 8 Hour. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried and concentrated over anhydrous sodium sulfate, and purified by column chromatography to obtain 6.40 g of an oily substance, namely intermediate IIa, with a yield of 60.9%.

[0085] (2) Synthesis of Intermediate IIIa

[0086]

[0087] The reaction process is:

[0088] Dissolve 6.4 grams of intermediate IIa in 128 milliliters of ethyl acetate, add 3.6 grams of reduce...

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Abstract

The invention discloses a synthetic method of tropisetron oxide, namely N-hydroxy tropisetron, belonging to the field of drug synthesis. According to the invention, 2-nitrophenyl acetate is used as araw material, and six reactions are successively conducted to synthesize the tropisetron oxide, namely N-hydroxy tropisetron; optimal preparation steps and reaction conditions are screened out througha large number of experiments; and the purity of the prepared target product can reach 99% or above, and the prepared target product does not contain tropisetron serving as a crude drug, can be usedfor research on pharmacokinetics, crude drug impurity identification and the like, and has important application value in impurity identification of tropisetron, research on metabolic mechanism of tropisetron and research design of novel drugs of tropisetron.

Description

technical field [0001] The invention belongs to medicine synthesis technology, in particular to a synthesis method of tropisetron oxide N-hydroxytropisetron. Background technique [0002] Anticancer drugs or radiotherapy can stimulate the chromaffin cells of the small intestinal mucosa to release serotonin (5-HT), induce the gag reflex, and cause nausea and vomiting. Tropisetron is a highly efficient and selective 5-HT3 receptor antagonist, which is a highly selective inhibitor of 5-HT3 receptors in peripheral neurons and central nervous system, and can selectively inhibit this reflex. Excitation of presynaptic 5-HT3 receptors in perineurons and may have a direct effect on the postvagal post-afferents of 5-HT3 receptor transmission in the central nervous system. This dual action blocks the chemical transmission of neurotransmitters during the gag reflex, and thus has a therapeutic effect on emesis induced by chemotherapy and radiotherapy. Clinical studies have shown that t...

Claims

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Application Information

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IPC IPC(8): C07D451/12
CPCC07D451/12Y02P20/55
Inventor 李砚涛李海峰张池徐一鸣
Owner TLC NANJING PHARMA RANDD CO LTD
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