CN1793138A - Process for prepering aspetllinone - Google Patents
Process for prepering aspetllinone Download PDFInfo
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- CN1793138A CN1793138A CN 200510111894 CN200510111894A CN1793138A CN 1793138 A CN1793138 A CN 1793138A CN 200510111894 CN200510111894 CN 200510111894 CN 200510111894 A CN200510111894 A CN 200510111894A CN 1793138 A CN1793138 A CN 1793138A
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Abstract
The invention relates to the manufacture method for ketone selin that includes the following steps: making 4-acetyl nipecotic acid, and acetyl piperidine formyl chloride, and 4-(4-fluorobenzene formacyl) piperidine; making N-ethoxycarbonyl ethyl o-aminobenzoate, 3-(2-ethoxyl)-2, 4(1H, 3H) quinazoline diones, and 2,3-dihydro-5-oxygen-oxazoles(2, 3-sides)quinazoline; making ketone selin. The invention has high yield, and is easy to operate, and no pollution.
Description
Technical field
The present invention relates to the preparation method's of medical material, particularly a kind of ketanserin preparation method.
Background technology
Ketanserin, English name Ketanserin, another name claims Sufrexal again, Kai Tanselin, Ritanserin, Sufrexal, Serefrex is the 5-hydroxytryptamine receptor blocking agent, to 5HT
2The selective retardation of acceptor also has more weak α and H receptor antagonism.Can reduce hyperpietic's Peripheral resistance, more obvious to the decline of renal vascular resistance, and the normal people is not had hypotensive effect.To occlusion vascular disease change person is arranged, can improve the lower extremity blood flow supply.To the Reynolds patient can improve tissue blood perfusion, SkBF is increased.Can reduce right atrial pressure, Ppa pulmonary artery pressure and pulmonary capillary wedge after the intravenous injection presses.Oral absorption is complete rapidly, 0.5-2 hour Plasma Concentration peaking.With plasma protein binding ratio 95%, bioavailability about 50%.At intrahepatic metabolism, t
1/2About 15 hours, food did not influence its absorption.Clinically be mainly used in various hypertension, also be used for congestive heart failure, raynaud's disease and intermittent timpang, recent findings has new purposes on myocardial infarction, inflammatory pain and sexual dysfunction.
Its chemical structure is as follows:
Chemical name is:
3-[2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl]-2，4[1H，3H]-quinazolinedione
Molecular formula C
22H
22FN
3O
3Molecular weight 395.43,227～235 ℃ of molten points.
Present ketanserin preparation technology both domestic and external mainly with the 4-piperidine carboxylic acid be starting raw material through acidylate, the hydrolysis again of chloride, friedel-crafts reaction, salify get intermediate 4-(4-fluorophenyl) piperidine hydrochlorate (a); The 2-cyano-aniline is that starting raw material and isocyanic acid chloroethene ester react cyclization again and get 3-chloroethyl Benzoquinazole diketone (b); The two condensation gets ketanserin (593 pages of Chinese Medicine science and technology of organic drug synthesis method Chen Fener chief editor first roll press) but this technology has following defective:
1, total recovery is low, and the step of the condensation one of ketanserin is in the end gone up yield only 27%; 2, use 2-cyano-aniline and isocyanic acid chloroethene ester in the raw material, this raw material has and is difficult to control in severe toxicity and the preparation process complicated production and causes and buy to be difficult for; 3, in acyl chloride reaction, be solvent, cause very inconvenience and increase three wastes treatment capacity greatly of operation and aftertreatment with the sulfur oxychloride.
Summary of the invention
The technical problem to be solved in the present invention is the defective that overcomes existing technology, and a kind of preparation method of ketanserin is provided, and this method has the yield height, and is easy and simple to handle, free of contamination advantage.
Technical scheme of the present invention comprises the steps:
1, the preparation of 4-ethanoyl piperidine carboxylic acid I:
In the reaction flask, add 4-piperidine carboxylic acid 45-53 gram, acid anhydrides 180-220 restrains, and after reflux 4-9 hour, cooling adds ether 960-1200 gram, and stirring and crystallizing is filtered, and gets white solid, yield 70%.
2, the preparation of 4-ethanoyl piperidine formyl chlorine II:
In the reaction flask, add 4-ethanoyl piperidine carboxylic acid 60-68 gram, toluene 500 grams, sulfur oxychloride 70-87 gram, reflux 9-10 hour, cooling boiled off solvent, added sherwood oil, and agitation and filtration gets solid 70 grams, yield 97%.
3, the preparation of 4-(4-fluoro benzoyl) piperidines III:
In the reaction flask, add 4-ethanoyl piperidine formyl chlorine 65-75 gram, fluorobenzene 200 grams; aluminum chloride 100 grams; stirred temperature rising reflux 4-6 hour, adding concentrated hydrochloric acid 200 grams in the water are poured in cooling into; temperature rising reflux 10-12 hour; cooling, hydro-oxidation sodium transfer PH after alkalescence, use the extracted with diethyl ether layering; be concentrated into dried 40 grams after the drying, yield 70%.
4, the preparation of N-ethoxycarbonyl ethyl o-aminobenzoate IV:
In the reaction flask, add ethyl o-aminobenzoate 100-120 gram, benzene 500-550ml, Vinyl chloroformate 100ml after stirring at room 12-13 hour, filters, filtrate concentrating do 120 grams, yield 76.9%.
5,3-(2-hydroxyethyl)-2,4 (1H, 3H) preparation of quinazoline diones V:
In the reaction flask, add N-ethoxycarbonyl ethyl o-aminobenzoate 110-130 gram, monoethanolamine or halogen ethamine 50-60 gram heat 100-120 ℃ of reaction 4-5 hour, cooling.Add Virahol, agitation and filtration gets 100 gram white solids, yield 97%.
6,2, the preparation of 3-dihydro-5-oxygen-oxazoles (2, the 3-limit) quinazoline VI:
In the reaction flask, add 3-(2-hydroxyethyl)-2,4 (1H, 3H) quinazoline diones 90-100 gram, the oxide compound 100-110 gram of basic metal or alkaline-earth metal, dehydrated alcohol 400-500ml, reflux 5-6 hour, cold filtration, filtrate concentrating are done to such an extent that white solid 84.6 restrains yield 93.5%.
7, the preparation of ketanserin:
In the reaction flask, add 4-(4-fluoro benzoyl) piperidines 40-50 gram, 2,3-dihydro-5-oxygen-oxazoles (2, the 3-limit) quinazoline 50-60 gram, benzene 350-450ml, reflux 8-10 hour cold filtration, filter cake washing, drying.The 4-methyl-2 pentanone recrystallization gets 60 gram products, fusing point: 227-235 ℃.
Reaction expression of the present invention is as follows:
Wherein:
R:C
1-C
4, alkyl, aromatic hydrocarbons
X：OH，F，Cl，Br，I
AB: the oxide compound of alkalies and alkaline earth and carbonate thereof
Synthetic route of the present invention is as follows:
Ketanserin
Since the used technology of the present invention be with the 4-piperidine carboxylic acid be starting raw material through acidylate, chloride, friedel-crafts reaction hydrolysis again get intermediate 4-(4-fluorophenyl) piperidines; Be starting raw material with the anthranilic acid through condensation, cyclization dewater again VI; The two condensation gets ketanserin.This technology has following advantage: 1, total recovery improves, except each step yield compare with former technology slightly improve or close, the final step condensation gets ketanserin yield crude product and reaches 80%, reaches 60% after refining; 2, raw materials used all common being easy to get, and avoided that hypertoxic 2-cyano-aniline and isocyanic acid chloroethene ester are arranged; 3, significantly reduced the consumption of sulfur oxychloride, made that operation is simple; 4, three wastes treatment capacity significantly reduces.
Embodiment
Embodiment 1
In the reaction flask, add 4-piperidine carboxylic acid 51.6 grams, propionic anhydride 200 restrains, and reflux is after 8 hours, and cooling adds ether 1000 grams, and stirring and crystallizing is filtered, and gets white solid 50 grams of 4-propionyl piperidine carboxylic acid I, yield 70%.
In the reaction flask, add the I65.4 gram, toluene 500 grams, sulfur oxychloride 80 grams, reflux 10 hours, cooling boils off solvent, adds sherwood oil, and agitation and filtration gets solid 4-propionyl piperidine formyl chlorine II75 gram, yield 97%.
In the reaction flask, adding methyl o-aminobenzoate 100 grams, benzene 500ml, Vinyl chloroformate 100ml, stirring at room was filtered after 12 hours, and filtrate concentrating done to such an extent that N-ethoxycarbonyl methyl o-aminobenzoate IV114 restrains yield 76.9%.
In the reaction flask, add the IV120 gram, chloroethyl amine 70 grams heat 120 ℃ of reactions 5 hours, cooling.Add Virahol, agitation and filtration gets 3-(2-chloroethyl)-2,4 (1H, 3H) quinazoline diones V95 gram white solid, yield 96%.
In the reaction flask, add (2-chloroethyl)-2,4 (1H, 3H) quinazoline diones V95 gram, calcium oxide 100 grams, dehydrated alcohol 500ml, reflux 6 hours, cold filtration, filtrate concentrate to do 1,2,3-dihydro-5-oxygen-oxazoles (2, the 3-limit) quinazoline VI white solid 84.6 grams, yield 93.5%.
In the reaction flask, add (2-chloroethyl)-2,4 (1H, 3H) quinazoline diones V95 gram, salt of wormwood 120 grams, dehydrated alcohol 500ml, reflux 6 hours, cold filtration, filtrate concentrate to do 2,2,3-dihydro-5-oxygen-oxazoles (2, the 3-limit) quinazoline VI white solid 84.6 grams, yield 93.5%.
In the reaction flask, add the III45 gram, VI55 gram, toluene 400ml, 9 hours cold filtrations of reflux, filter cake washing, drying.The 4-methyl-2 pentanone recrystallization gets 58 gram ketanserin products.Fusing point: 227-235 ℃.
Embodiment 2
In the reaction flask, add 4-piperidine carboxylic acid 51.6 grams, aceticanhydride 200 restrains, and reflux is after 8 hours, and cooling adds ether 1000 grams, and stirring and crystallizing is filtered, and gets 4-ethanoyl piperidine carboxylic acid I white solid 48.2 grams, yield 70%.
In the reaction flask, add the I65.4 gram, toluene 500 grams, sulfur oxychloride 80 grams, reflux 10 hours, cooling boils off solvent, adds sherwood oil, and agitation and filtration gets 4-ethanoyl piperidine formyl chlorine II solid 70 grams, yield 97%.
In the reaction flask, add the II70 gram, fluorobenzene 200 grams; aluminum chloride 100 grams stirred temperature rising reflux 6 hours, cooling; pour in the water and add; concentrated hydrochloric acid 200 grams, temperature rising reflux 12 hours, cooling; hydro-oxidation sodium transfers PH after alkalescence; use the extracted with diethyl ether layering, be concentrated into dried 40 gram 4-(4-fluoro benzoyl) piperidines III after the drying, yield 70%.
In the reaction flask, add ethyl o-aminobenzoate 100 grams, benzene 500ml, Vinyl chloroformate 100ml, stirring at room was filtered after 12 hours, filtrate concentrating do 120 gram N-ethoxycarbonyl ethyl o-aminobenzoate IV, yield 76.9%.
In the reaction flask, add the IV120 gram, monoethanolamine 60 grams heat 120 ℃ of reactions 5 hours, cooling.Add Virahol, agitation and filtration gets 100 gram white solid 3-(2-hydroxyethyl)-2,4 (1H, 3H) quinazoline diones V, yields 97%.
In the reaction flask, add the V100 gram, calcium oxide 100 grams, dehydrated alcohol 500ml, reflux 6 hours, cold filtration, filtrate concentrating do 2,3-dihydro-5-oxygen-oxazoles (2, the 3-limit) quinazoline VI white solid 84.6 grams, yield 93.5%.
In the reaction flask, add the III50 gram, VI50 gram, benzene 400ml, 9 hours cold filtrations of reflux, filter cake washing, drying.The 4-methyl-2 pentanone recrystallization gets 60 gram ketanserin products, fusing point: 227-235 ℃.
Embodiment 3
In the reaction flask, add 4-piperidine carboxylic acid 51.6 grams, aceticanhydride 200 restrains, and reflux is after 8 hours, and cooling adds ether 1000 grams, and stirring and crystallizing is filtered, and gets white solid 48 grams of 4-ethanoyl piperidine carboxylic acid I, yield 70%.
In the reaction flask, add the I65.4 gram, toluene 500 grams, sulfur oxychloride 80 grams, reflux 10 hours, cooling boils off solvent, adds sherwood oil, and agitation and filtration gets 4-ethanoyl piperidine formyl chlorine II solid 70 grams, yield 97%
In the reaction flask, add the II70 gram, fluorobenzene 200 grams; aluminum chloride 100 grams stirred temperature rising reflux 6 hours, cooling; pour in the water and add; concentrated hydrochloric acid 200 grams, temperature rising reflux 12 hours, cooling; hydro-oxidation sodium transfers PH after alkalescence; use the extracted with diethyl ether layering, be concentrated into dried 40 gram 4-(4-fluoro benzoyl) piperidines III after the drying, yield 70%
In the reaction flask, add ethyl o-aminobenzoate 100 grams, benzene 500ml, Vinyl chloroformate 100ml, stirring at room was filtered after 12 hours, filtrate concentrating do 120 gram N-ethoxycarbonyl ethyl o-aminobenzoate IV, yield 76.9%.
In the reaction flask, add the IV120 gram, monoethanolamine 70 grams heat 120 ℃ of reactions 5 hours, cooling.Add Virahol, agitation and filtration gets 3-(2-chloroethyl)-2,4 (1H, 3H) quinazoline diones V93 gram white solid, yield 96%.
In the reaction flask, add (2-chloroethyl)-2,4 (1H, 3H) quinazoline diones V95 gram, lime carbonate 150 grams, dehydrated alcohol 500ml, reflux 6 hours, cold filtration, filtrate concentrate to do 1,2,3-dihydro-5-oxygen-oxazoles (2, the 3-limit) quinazoline VI white solid 84.6 grams, yield 93.5%.
In the reaction flask, add the III50 gram, VI50 gram, benzene 400ml, 9 hours cold filtrations of reflux, filter cake washing, drying.The 4-methyl-2 pentanone recrystallization gets 60 gram ketanserin products, fusing point: 227-235 ℃.
Claims (8)
1. the preparation method of a ketanserin is characterized in that comprising the steps:
(1) preparation of 4-ethanoyl piperidine carboxylic acid I:
In the reaction flask, add 4-piperidine carboxylic acid 45-53 gram, acid anhydrides 180-220 gram, after reflux 4-9 hour, cooling adds ether 960-1200 gram, and crystallization filters;
(2) preparation of 4-ethanoyl piperidine formyl chlorine II:
Add 4-ethanoyl piperidine carboxylic acid 60-68 gram, toluene 500 grams, sulfur oxychloride 70-87 gram, reflux 9-10 hour, cooling boiled off solvent, added sherwood oil, agitation and filtration;
(3) preparation of 4-(4-fluoro benzoyl) piperidines III:
Add 4-ethanoyl piperidine formyl chlorine 65-75 and restrain, fluorobenzene 200 grams, aluminum chloride 100 grams stirred temperature rising reflux 4-6 hour, and adding concentrated hydrochloric acid 200 grams in the water are poured in cooling into, and temperature rising reflux 10-12 hour, cooling transferred PH to the alkaline extraction layering, and is dry concentrated;
Add ethyl o-aminobenzoate 100-120 gram, benzene 500-550ml, Vinyl chloroformate 100ml, after stirring at room 12-13 hour, filtering and concentrating;
(4) preparation of N-ethoxycarbonyl ethyl o-aminobenzoate IV:
Add ethyl o-aminobenzoate 100-120 gram, benzene 500-550ml, Vinyl chloroformate 100ml, after stirring at room 12-13 hour, filtering and concentrating;
(5) 3-(2-hydroxyethyl)-2,4 (1H, 3H) preparation of quinazoline diones V:
Add N-ethoxycarbonyl ethyl o-aminobenzoate 110-130 gram, monoethanolamine or halogen ethamine 50-60 gram heat 100-120 ℃ of reaction 4-5 hour, and cooling adds Virahol, agitation and filtration;
The preparation of (6) 2,3-dihydro-5-oxygen-oxazoles (2, the 3-limit) quinazoline VI:
Adding 3-(2-hydroxyethyl)-2,4 (1H, 3H) quinazoline diones 90-100 gram, the oxide compound 100-110 gram of basic metal or alkaline-earth metal, dehydrated alcohol 400-500ml, reflux 5-6 hour, cold filtration concentrated;
(7) preparation of ketanserin:
Add 4-(4-fluoro benzoyl) piperidines 40-50 gram, 2,3-dihydro-5-oxygen-oxazoles (2, the 3-limit) quinazoline 50-60 gram, benzene 350-450ml, reflux 8-10 hour, cold filtration, dry recrystallization.
2. the preparation method of a kind of ketanserin as claimed in claim 1, the acid anhydrides that it is characterized in that described step (1) is propionic anhydride or aceticanhydride.
3. the preparation method of a kind of ketanserin as claimed in claim 1 is characterized in that described step (3) adds 4-ethanoyl piperidine formyl chlorine 70 grams, fluorobenzene 200 grams; aluminum chloride 100 grams stirred temperature rising reflux 6 hours, cooling; pour into and add concentrated hydrochloric acid 200 grams, temperature rising reflux 12 hours in the water.
4. the preparation method of a kind of ketanserin as claimed in claim 1 is characterized in that described step (5) halogen ethamine is chloroethyl amine.
5. the preparation method of a kind of ketanserin as claimed in claim 1, the oxide compound that it is characterized in that described step (6) basic metal or alkaline-earth metal is lime carbonate or calcium oxide.
6. the preparation method of a kind of ketanserin as claimed in claim 1 is characterized in that step (6) adds (2-chloroethyl)-2,4 (1H, 3H) quinazoline diones 95 grams, lime carbonate 150 grams, dehydrated alcohol 500ml, reflux 6 hours.
7. the preparation method of a kind of ketanserin as claimed in claim 1 is characterized in that described step (6) adds 3-(2-hydroxyethyl)-2,4 (1H, 3H) quinazoline diones 100 grams, calcium oxide 100 grams, dehydrated alcohol 500ml, reflux 6 hours.
8. the preparation method of a kind of ketanserin as claimed in claim 1 is characterized in that step (6) adds (2-chloroethyl)-2,4 (1H, 3H) quinazoline diones 95 grams, calcium oxide 100 grams, dehydrated alcohol 500ml, reflux 6 hours.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288762A (en) * | 2013-05-16 | 2013-09-11 | 苏州摩尔医药有限公司 | Preparation method of ketanserin intermediate 3-chloroethyl-2,4(1H,3H) quinazolinedione |
| CN104003929A (en) * | 2014-04-30 | 2014-08-27 | 上海应用技术学院 | Method for synthesis of alpha,alpha-diphenyl-4-piperidine methanol |
| CN108329319A (en) * | 2018-01-18 | 2018-07-27 | 新乡医学院 | A kind of 1,4- naphthoquinone derivatives and its synthetic method and medical usage |
| CN112142760A (en) * | 2020-10-20 | 2020-12-29 | 江苏法安德医药科技有限公司 | Ketanserin intermediate and preparation method of ketanserin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1155357B (en) * | 1982-07-06 | 1987-01-28 | Ravizza Spa | KENTANSERINE PREPARATION PROCESS |
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2005
- 2005-12-23 CN CN 200510111894 patent/CN1793138B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288762A (en) * | 2013-05-16 | 2013-09-11 | 苏州摩尔医药有限公司 | Preparation method of ketanserin intermediate 3-chloroethyl-2,4(1H,3H) quinazolinedione |
| CN103288762B (en) * | 2013-05-16 | 2015-11-18 | 苏州摩尔医药有限公司 | Ketanserin intermediate 3-chloroethyl-2,4(1H, 3H) preparation method of quinazoline diones |
| CN104003929A (en) * | 2014-04-30 | 2014-08-27 | 上海应用技术学院 | Method for synthesis of alpha,alpha-diphenyl-4-piperidine methanol |
| CN104003929B (en) * | 2014-04-30 | 2016-07-20 | 上海应用技术学院 | A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols |
| CN108329319A (en) * | 2018-01-18 | 2018-07-27 | 新乡医学院 | A kind of 1,4- naphthoquinone derivatives and its synthetic method and medical usage |
| CN112142760A (en) * | 2020-10-20 | 2020-12-29 | 江苏法安德医药科技有限公司 | Ketanserin intermediate and preparation method of ketanserin |
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| CN1793138B (en) | 2010-05-12 |
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