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A kind of synthetic method of stable deuterium-labeled melitracen hydrochloride

A technique for the synthesis of melitracen hydrochloride and its synthesis method, which is applied in the field of synthesis of melitracen hydrochloride, achieving the effects of reasonable process design, short route and strong operability

Active Publication Date: 2022-03-18
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

What existing bibliography reports is all the synthetic method of unmarked melitracen hydrochloride, and the method used in the present invention is different; There is no synthetic method of the isotope-labeled melitracen hydrochloride of bibliographical report at present

Method used

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  • A kind of synthetic method of stable deuterium-labeled melitracen hydrochloride
  • A kind of synthetic method of stable deuterium-labeled melitracen hydrochloride
  • A kind of synthetic method of stable deuterium-labeled melitracen hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Such as figure 1 Shown, a kind of synthetic method of the melitracen hydrochloride of stable deuterium label comprises the following steps:

[0031] (1) Take 20.0 g of commercially available 10,10-dimethylanthrone I, add it to a 500 mL round bottom flask, dissolve it with 100 mL of dry ether, add commercially available cyclopropylmagnesium bromide (1M in THF) , After the dropwise addition, react at 35°C for 12 hours; TLC board monitors the complete reaction of the raw materials, process and purify, and obtain 21.2g of intermediate II, MS: 265.2[M+1] + , yield 89.25%;

[0032]

[0033] (2) Dissolve 20.0 g of intermediate II in 80 mL of formic acid, slowly add 48% hydrobromic acid under ice-bath conditions, and then react at 60°C for 8 hours. TLC board monitors that the reaction of the raw materials is complete, process them out, and purify by column chromatography , to obtain 22.0g of intermediate III, the yield is 88.86% (X=Br); 1H NMR (400MHz, CDCl3) of intermedia...

Embodiment 2

[0040] Such as figure 1 Shown, a kind of synthetic method of the melitracen hydrochloride of stable deuterium label comprises the following steps:

[0041] (1) Take 20.0g of commercially available 10,10-dimethylanthrone I, put it into a 500mL round bottom flask, dissolve it with 100mL of dry tetrahydrofuran, add dropwise 130mL of commercially available cyclopropylmagnesium chloride (1M in THF) , after the dropwise addition was completed, the oil bath was reacted at 60 degrees for 6 hours; the TLC board monitored the reaction of the raw materials, quenched the reaction, and purified by column chromatography to obtain 18.0 g of intermediate II, which was a light brown oil with a yield of 75.78%; The structure of II is as follows, MS: 265.2[M+1] + .

[0042]

[0043] (2) Dissolve 10.0 g of intermediate II in 40 mL of acetic acid, slowly add 15 mL of commercially available concentrated hydrochloric acid with a concentration of 36% under ice-bath conditions, and then react at ...

Embodiment 3

[0050] Such as figure 1 Shown, a kind of synthetic method of the melitracen hydrochloride of stable deuterium label comprises the following steps:

[0051] (1) Take 20.0g of commercially available 10,10-dimethylanthrone I, put it into a 500mL round bottom flask, dissolve it with 100mL of dry tetrahydrofuran, add dropwise commercially available cyclopropylmagnesium bromide (1M in THF ) 120mL, after the dropwise addition, put the oil bath at 50 degrees to react for 8 hours; the TLC board monitors the reaction of the raw materials completely, quenches the reaction, and purifies by column chromatography to obtain 19.2g of intermediate II, which is a light brown oil, with a yield of 80.83% ; The structure of intermediate II is as in Example 1, MS: 265.2[M+1] + .

[0052]

[0053] (2) Dissolve 15.0g of intermediate II in 75mL of ethanol, slowly add 15mL of commercially available hydriodic acid with a concentration of 55% under ice bath conditions, and then react at 60°C for 24 ...

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Abstract

The invention discloses a method for synthesizing stable deuterium-labeled melitracen hydrochloride, which belongs to the field of drug stable isotope labeling, and provides a method with reasonable process design, strong operability, high yield, and efficient isotope labeling. The raw material is converted into the labeled target product, which can realize the synthetic method of industrialized production of isotope-labeled melitracen hydrochloride. The present invention uses deuterium 6-labeled methylamine hydrochloride as a starting material, synthesized through four-step reactions, and screens out the optimal preparation steps and reaction conditions through a large number of experiments. The entire process design is reasonable, operable and efficient. The marked raw material is converted into a marked target product, and the marked melitracen hydrochloride prepared by the present invention has a chemical purity of over 98.5% and a marked isotope abundance >98.5%.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing stable deuterium-labeled melitracen hydrochloride. Background technique [0002] Melitracen hydrochloride, also known as melitracene hydrochloride, is an antipsychotic drug whose chemical name is 3-[10,10-dimethyl-9(10H)-anthracene]-N,N-dimethyl propylamine hydrochloride; 3-[10,10-dimethyl-9(10H)-anthracenyl]-N,N-dimethylpropylamine hydrochloride; has strong antipsychotic effect, clinically compared with Chlorprothixene is 4 to 8 times stronger, but its sedative effect is weaker. It also has anti-anxiety and anti-depressant effects. It is suitable for acute and chronic schizophrenia, depression and depressive neurosis. This product is easy to absorb, has a first-pass effect, and is metabolized by the liver and kidney. Tablets are not produced by domestic manufacturers, but have been imported. Capsules are not yet available. The raw material medicine i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C209/00C07C209/08C07C211/31
CPCC07C209/00C07C209/08C07C17/00C07C29/40C07B2200/05C07C2603/24C07C211/31C07C22/04C07C35/40
Inventor 张帅胡永铸刘春樊高骏
Owner TLC NANJING PHARMA RANDD CO LTD
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