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A new synthesis method of istaroxime

A synthesis method and the obtained technology can be applied in the directions of steroids, organic chemistry, etc., and can solve the problems of increased synthesis input cost, high temperature, and large amount of tetrahydrofuran borane complex, and achieve lower synthesis cost, simple operation, and high efficiency. Beneficial to industrial production

Inactive Publication Date: 2017-05-31
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But its disadvantage is that in the process of synthesizing (5α)-androst-3,6,17-trione, because the synthesis temperature is higher than the temperature of method one, the amount of volatile tetrahydrofuran borane complex is relatively large, in addition to increasing The cost of synthesis input also increases the difficulty of purification of (5α)-androsta-3,6,17-trione due to the occurrence of more by-products

Method used

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  • A new synthesis method of istaroxime
  • A new synthesis method of istaroxime
  • A new synthesis method of istaroxime

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] (1) Synthesis of intermediate M-02

[0075]

[0076] Reagents and reaction conditions are: i.m-CPBA, CH 2 Cl 2 ,rt; ii.H 2 SO 4 ,rt.

[0077] Take dehydroepiandrosterone (DHEA, 5mmol) in the reaction flask, add CH 2 Cl 2 After stirring and dissolving, m-chloroperoxybenzoic acid (10 mmol) was added, and the mixture was stirred at room temperature for reaction. After TLC detection, the reaction was complete after about 22 h, and sodium sulfite ice-water solution was added to the reaction solution to quench the reaction. After stirring for 5 min, 4 mL of aqueous sulfuric acid solution with a mass fraction of 20% was added, and the mixture was stirred at room temperature for 12 h. The reaction solution was poured into water, filtered with suction, the lower layer precipitate was removed, washed with dichloromethane, and dried to obtain 1.56 g of a white solid, namely M-02, with a yield of 97%.

[0078] The spectral data of M-02 is:

[0079] ESI-MS: m / z: 323.1[M+H...

Embodiment 2

[0147] The method of this example is the same as that of Example 1, except:

[0148] (i), step (1) uses the m-chloroperoxybenzoic acid (m-CPBA) of 1.5 times the amount of dehydroepiandrosterone substance, reacts 35 hours, and productive rate is 79%;

[0149] (ii), the reaction temperature of step (2) is 0 ℃, and the yield is 93%;

[0150] (iii), step (3) used 20% sulfuric acid 5mL to react for 15 hours, and the yield was 77%;

[0151] (iv), step (4) adopts the nickel chloride hexahydrate of 1 times of the amount of M-04 material and the sodium borohydride of 3 times of the amount of M-04 material to react for 3 hours, and the yield is 68%;

[0152] (v), step (5) drips concentrated hydrochloric acid at the rate of 1 drop / 2s, productive rate is 99%;

[0153] (vi), step (6) uses SOCl that is 1.2 times the mass of M-07 2 Reaction at 65 ° C for 4 hours, the yield is 91%;

[0154] (vii), step (7) uses the hydroxylamine hydrochloride of 1.5 times the amount of material and the KO...

Embodiment 3

[0161] The method of this example is the same as that of Example 1, except:

[0162] (i), step (1) uses the m-chloroperoxybenzoic acid (m-CPBA) of 4 times of the amount of dehydroepiandrosterone substance, reacts 15 hours, and productive rate is 86%;

[0163] (ii), the reaction temperature of step (2) is 20 ℃, and the yield is 78%;

[0164] (iii), step (3) used 2mL of 60% sulfuric acid to react for 4 hours, and the yield was 84%;

[0165] (iv), step (4) adopts the nickel chloride hexahydrate of 2 times of the amount of M-04 material and the sodium borohydride of 7 times of the amount of M-04 material to react for 1 hour, and the yield is 81%;

[0166] (v), step (5) drips concentrated hydrochloric acid at the rate of 3D / s, productive rate is 96%;

[0167] (vi), step (6) uses SOCl that is twice the mass of M-07 2 Reaction at 85 ° C for 3 hours, the yield is 95%;

[0168] (vii), step (7) uses the hydroxylamine hydrochloride of 2.5 times the amount of potassium hydroxide subst...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and discloses a novel synthesis method of Istaroxime. The method comprises the following steps: by using dehydrogenated epiandrosterone as an initial raw material, carrying out epoxidation, ring opening, reduction, oxidation and other reactions to prepare an intermediate M-06; by using ethyl benzoate as an initial raw material, reacting the ethyl benzoate with hydroxylamine hydrochloride to obtain phenyl hydroximic acid, carrying out hydrochlorination and chlorination by using ethanolamine as a raw material to obtain dichloroacetate, and carrying out substitution, hydrolysis and other reactions on the dichloroacetate and the phenyl hydroximic acid to obtain an intermediate M-11; and finally, reacting the M-06 with the M-11 to obtain the end product Istaroxime. According to the method, in the intermediate M-06 synthesis process, the polarity of all the intermediates has great differences from that of the impurities and reaction reagents; and in the intermediate 11 synthesis process, the active spots capable of participating in the chemical reaction in the reaction substrate are simple. Therefore, the method can achieve the requirements without carrying out column chromatography purification, thereby simplifying the synthesis after-treatment process.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a new synthetic method of Istaroxime. Background technique [0002] Istaroxime (chemical name 3-[O-(2-aminoethyl)ketoxime]-(5α)-androsta-3,6,17-trione) is a novel, inhibitory Na + / K + -ATPase and Ca 2+ -Anti-heart failure drug with dual action of ATPase. In the early stage of Istaroxime, it was designed and synthesized by Mauro Gobbini and others of Sigma-Tau Pharmaceutical Company in Italy, using Cassaine isolated from various plants of the genus Gemini as the parent compound, and developed it into a new type of anti-heart failure drug, and obtained a patent . After completing the Phase I clinical trial, in 2006, it signed an agreement with the Swiss pharmaceutical company Debiopharm to jointly develop and promote the drug. Debiopharm has also obtained the license to develop and distribute the drug in most countries and regions around the world, and has started the follo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J41/00
CPCC07J41/0016
Inventor 江仁望梁光平田海妍
Owner JINAN UNIVERSITY