CN1063686A - With the synthetic vesnarinone of active ester method - Google Patents
With the synthetic vesnarinone of active ester method Download PDFInfo
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- CN1063686A CN1063686A CN 92108055 CN92108055A CN1063686A CN 1063686 A CN1063686 A CN 1063686A CN 92108055 CN92108055 CN 92108055 CN 92108055 A CN92108055 A CN 92108055A CN 1063686 A CN1063686 A CN 1063686A
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- vesnarinone
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- active ester
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Abstract
It is synthetic to the present invention relates to medicine.Vesnarinone (Vesnarinone) is a kind of positive inotropic medicament with high selectivity, does not have obvious chronotropic effect and blood vessel function, is the novel cardiac tonic of a class, estimates good.This synthetic active ester method of using is reacted with methlorethamine the amino dihydro-quinolinone of raw material 6-under base catalysis, this intermediate separates or do not separate directly to react with veratrum acid active ester again and obtains vesnarinone, promptly gets salable product through recrystallization.That this method yield height, reaction conditions require is low, be easy to purifying, easy and simple to handle.
Description
The present invention relates to the synthetic method of medicine, particularly use active ester method synthetic drugs vesnarinone.
Vesnarinone (Vesnarinone; chemical name: 3; 4-Dihydro-6-[4-(3; 4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-and quinolinone, 3,4-dihydro-6-[4-(3; 4-dimethoxy benzoyl)-the 1-piperazinyl]-2(1H)-and quinolinone) be a kind of positive inotropic medicament with high selectivity; not having obvious chronotropic effect and blood vessel function, is the novel cardiac tonic of a class, estimates good.Its structural formula is as follows:
At present, the vesnarinone synthetic method of reported in literature has following three kinds:
At Studies on Positive Inotropic Agents I.Synthesis of 3,4-Dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone and Related Compounds(Chem.pharm, bull 32(6): 2100-2110(1984) disclose first kind of synthetic method), its synthetic route is as follows:
This route is at first from the amino dihydro-quinolinone synthetic intermediate of 6-6-piperazine-dihydro-quinolinone, and then with acyl chlorides under low temperature, anhydrous condition, react the product vesnarinone.Two step total recoverys are 44.8%.Owing to adopt acyl chlorides, need make to be reflected under the anhydrous condition and carry out, because of it is active big, side reaction is many again.Final product needs to separate through silica gel column chromatography, can be qualified, and bring difficulty to synthetic work, and yield is also not ideal enough, thereby is difficult to amplify production.
At Piperazinylcarbostyril Compounds(United Ststes Patent 4,415,572(1983)) in second kind of synthetic method disclosed, its synthetic route is as follows:
This route synthetic vesnarinone yield only 46.2%.The used raw material of its reaction is that black false hellebore acyl chlorides and bromine mustargen hydrobromate low-temp reaction under anhydrous condition make, and bromine mustargen toxicity is big, and the yield of synthesis material has only 70%, provide relatively large black false hellebore acylbromide mustargen difficult, and the yield of this reaction is not good enough.
Also disclose the third synthetic method in above-mentioned patent, its synthetic route is as follows:
This route is to be raw material with the veratroyl diethanolamine, and feed ratio is higher than the amino dihydro-quinolinone of 6-, and consumption is big, and the preparation difficulty, because of temperature of reaction higher (165 ℃), easily produces side reaction again, brings difficulty to separation.
Purpose of the present invention provides in order to overcome above-mentioned weak point of the prior art just that a kind of yield height, reaction conditions requirement are low, the method for the synthetic vesnarinone of simplified control.
The objective of the invention is to realize by following measure: with amino dihydro-quinolinone of 6-and methlorethamine is raw material, under base catalysis, react, this intermediate product separates or does not separate, directly react with veratrum acid active ester again, the temperature of reaction is 60～120 ℃, and the time of reaction is 8～72 hours, can obtain vesnarinone, promptly get salable product through recrystallization, synthetic route is as follows:
All can Deng phenyl with electrophilic replacement;
X：Cl、Br、
、OSO
2CH
3。
The catalyzer of building-up reactions can be:
Mineral alkali is as salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide etc.; Or organic bases, as triethylamine, morpholine, pyridine, hexahydropyridine etc.
The solvent of building-up reactions is: methyl alcohol, ethanol, Virahol, propyl carbinol, acetone and other organic solvent and water, water-alcohol solution.
Recrystallization solvent can be: methyl alcohol, ethanol, chloroform, acetone, vinyl acetic monomer, benzylalcohol, glacial acetic acid and their mixed solvent.
The present invention compared with prior art has following advantage:
(1) the active ester method reaction temperature and, reaction conditions requires lowlyer, do not need to react under anhydrous, cold condition, be convenient to grasp;
(2) active ester easily prepares, and can supply in a large number;
(3) products therefrom convenient post-treatment is once made with extra care and is promptly got salable product, without column chromatographic isolation and purification, and simplified control;
(4) this synthesis method is different with raw material according to solvent, can adopt stepwise reaction, and the also available technology for the treatment of different things alike is simple and convenient;
(5) yield height, average yield is 63～65%, the highest yield can reach 75%;
(6) owing to do not need column chromatography for separation, save a large amount of solvents, shorten reaction time.
The present invention is described in further detail below with reference to embodiment:
The amino dihydro-quinolinone 25g of embodiment 1.6-, hydrochloric acid chlorine mustargen 28.6g and water 60ml, reflux stirred 8 hours, added Anhydrous potassium carbonate 24g again, continued stirring reaction 8 hours, the cyclocomplex that cool off, filter, obtains adds 70ml ethanol and veratric acid p-nitrophenol ester 36.5g, Anhydrous potassium carbonate 12g, heating reflux reaction 4 hours filters, with acetone-chloroform recrystallization, vesnarinone 36.2g, m.p.238～239 ℃, faint yellow crystallization.
Embodiment 2. and last method same operation, replacing water with 30% ethanol is solvent, use the vinyl acetic monomer recrystallization, must vesnarinone 36.5g, m.p.238～239 ℃, faint yellow crystallization.
The amino dihydro-quinolinone 25g of embodiment 3.6-, Hydrogen bromide bromine mustargen 49.9g and 80ml methyl alcohol heating reflux reaction 8 hours, cold slightly back adds triethylamine 17.5g, continues reaction 8 hours, add veratric acid m-nitrophenol ester 36.5g and triethylamine 8.8g then, react after 4 hours, cooling is filtered, with vinyl acetic monomer-chloroform recrystallization, vesnarinone 36.8g, m.p.238～239 ℃, faint yellow crystallization.
The amino dihydro-quinolinone 25g of embodiment 4.6-, hydrochloric acid chlorine mustargen 28.6g and the reaction of 70ml alcohol heating reflux 48 hours, cold slightly back adds anhydrous sodium carbonate 18.4g, restir reaction 24 hours adds veratric acid p-nitrophenol ester 36.5g and anhydrous sodium carbonate 9.2g then, continues reflux after 4 hours, cooling, filter,, get vesnarinone 40.2g with ethanol-chloroform recrystallization, m.p.238～239 ℃, faint yellow crystallization.
Embodiment 5. operation replaces hydrochloric acid chlorine mustargen with embodiment 4 with bromine mustargen hydrobromate, and the reaction times can shorten to 16 hours, vesnarinone 42.65g, m.p.238～239 ℃.
Embodiment 6. operation replaces industrial alcohol with embodiment 4 with 70% ethanol, vesnarinone 39.4g, m.p.238～239 ℃, faint yellow crystallization.
Embodiment 7. operation replaces veratric acid m-nitrophenol ester with embodiment 3 with veratric acid p-nitrophenol ester, vesnarinone 36.6g, m.p.238～239 ℃, faint yellow crystallization.
The amino dihydroquinoline keto hydrochloride of embodiment 8.6-31.2g, hydrochloric acid chlorine mustargen 28.6g and ethanol 70ml, reacting by heating also drips 20% sodium hydroxide adjusting pH5.5～6, reacts after 6 hours, and is cold slightly, add veratric acid p-nitrophenol ester 36.5g and anhydrous sodium carbonate 9.2g, continue reaction 4 hours, cooling is filtered, with ethanol-chloroform recrystallization, vesnarinone 34.2g, m.p.238～239 ℃, faint yellow crystallization.
Embodiment 9.6-piperazine dihydro-quinolinone hydrobromate 34.3g, veratric acid m-nitrophenol ester 36.5g and Anhydrous potassium carbonate 31.8g, back flow reaction is 4 hours in ethanol 60ml, cooling, filter, vinyl acetic monomer-benzylalcohol recrystallization gets vesnarinone 40.8g, m.p.238～239 ℃, faint yellow crystallization.
The amino dihydro-quinolinone 25g of embodiment 10.6-, bromine mustargen hydrobromate 49.9g and 50ml propyl carbinol, reacting by heating 8 hours, add anhydrous sodium carbonate 24g, reacted again 8 hours, and added veratric acid p-nitrophenol ester 36.5g and anhydrous sodium carbonate 12g then, ethanol 50ml, react after 4 hours, cold filtration is used the vinyl acetic monomer recrystallization, gets vesnarinone 40.6g, m.p.238～239 ℃, faint yellow crystallization.
Claims (4)
1, with the synthetic vesnarinone (Vesnarinone) of active ester method, its synthesis step is characterised in that: with 6-quinolylamine ketone and methlorethamine is raw material, under base catalysis, react, this intermediate product separates or does not separate, and directly reacts with veratrum acid active ester again, and the temperature of reaction is 60～120 ℃, the time of reaction is 8～72 hours, can obtain vesnarinone, promptly get salable product through recrystallization, synthetic route is as follows:
2, according to claim 1 with the synthetic vesnarinone of active ester method, it is characterized in that R, X are expressed as follows in the structural formula in the synthetic route:
(1) R:
All can Deng phenyl with electrophilic replacement;
（2）X：Cl、Br、
、OSO
2CH
3。
3, according to claim 1 with the synthetic vesnarinone of active ester method, it is characterized in that catalyzer and the solvent in the building-up reactions is:
(1) catalyzer can be:
Mineral alkali, as salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide etc.,
Or organic bases, as triethylamine, morpholine, pyridine, hexahydropyridine etc.;
(2) solvent is: methyl alcohol, ethanol, Virahol, propyl carbinol, acetone and other organic solvent and water, water-alcohol solution.
4, according to claim described 1 with the synthetic vesnarinone of active ester method, it is characterized in that: recrystallization solvent can be methyl alcohol, ethanol, chloroform, acetone, vinyl acetic monomer, benzylalcohol, glacial acetic acid and their mixed solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92108055 CN1063686A (en) | 1992-03-12 | 1992-03-12 | With the synthetic vesnarinone of active ester method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92108055 CN1063686A (en) | 1992-03-12 | 1992-03-12 | With the synthetic vesnarinone of active ester method |
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| Publication Number | Publication Date |
|---|---|
| CN1063686A true CN1063686A (en) | 1992-08-19 |
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|---|---|---|---|
| CN 92108055 Pending CN1063686A (en) | 1992-03-12 | 1992-03-12 | With the synthetic vesnarinone of active ester method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1114597C (en) * | 1998-07-15 | 2003-07-16 | 活跃生物技术有限公司 | Quinoline derivs. |
-
1992
- 1992-03-12 CN CN 92108055 patent/CN1063686A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1114597C (en) * | 1998-07-15 | 2003-07-16 | 活跃生物技术有限公司 | Quinoline derivs. |
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