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Novel synthesis method of Istaroxime

A synthesis method and the resulting technology are applied in the fields of steroids and organic chemistry, which can solve the problems of large amount of tetrahydrofuran borane complex, high temperature, and increased synthesis input costs, and achieve reduced synthesis costs, simple operation, and effective Conducive to the effect of industrial production

Inactive Publication Date: 2016-05-18
JINAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Novel synthesis method of Istaroxime
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  • Novel synthesis method of Istaroxime

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0075]

[0076] The 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 bottle, 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 about 22 hours, the reaction was complete after TLC detection, and sodium sulfite ice solution was added to the reaction liquid to quench the reaction. After stirring for 5 min, 4 mL of sulfuric acid aqueous solution with a mass fraction of 20% was added, and stirred at room temperature for 12 h. The reaction solution was poured into water, filtered with suction, and the lower precipitate was removed, washed with dichloromethane, and dried to obtain 1.56 g of a white solid, M-02, with a yield of 97%.

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

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

[0080] 1 H-NMR...

Embodiment 2

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

[0148] (i), step (1) uses m-chloroperoxybenzoic acid (m-CPBA) 1.5 times the amount of dehydroepiandrosterone, reacted for 35 hours, and the yield was 79%;

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

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

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

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

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

[0154] (vii), step (7) uses the hydroxylamine hydrochloride of the amount of 1.5 times of substance and the KOH of the amount of 2 times of sub...

Embodiment 3

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

[0162] (i), step (1) uses m-chloroperoxybenzoic acid (m-CPBA) which is 4 times the amount of dehydroepiandrosterone, reacted for 15 hours, and the yield was 86%;

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

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

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

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

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

[0168] (vii), step (7) uses 2.5 times the hydroxylamine hydrochloride of the amount of potassium hydroxide substance to react, and the productive ra...

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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 synthesis method of Istaroxime. Background technique [0002] Istaroxime (chemical name 3-[O-(2-aminoethyl)ketoxime]-(5α)-androst-3,6,17-trione) is a new type of Na + / K + -ATPase and Ca 2+ - Anti-heart failure drug with dual ATPase action. In the early stage, Istaroxime was designed and synthesized by Mauro Gobbini et al. from Sigma-Tau Pharmaceutical Company in Italy, using Cassaine isolated from various plants of the genus Goliath 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 Swiss Debiopharm Pharmaceutical Company 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 begun to carry out follow-up clinical r...

Claims

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Application Information

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