CN103408491A - Chloroxoquinoline preparation method - Google Patents
Chloroxoquinoline preparation method Download PDFInfo
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- CN103408491A CN103408491A CN2013103687213A CN201310368721A CN103408491A CN 103408491 A CN103408491 A CN 103408491A CN 2013103687213 A CN2013103687213 A CN 2013103687213A CN 201310368721 A CN201310368721 A CN 201310368721A CN 103408491 A CN103408491 A CN 103408491A
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Abstract
The invention relates to a chemical drug process, i.e., a chloroxoquinoline preparation method. The chloroxoquinoline preparation method comprises the following steps: (1), decarboxylic reaction, (2), primary roughing, (3), secondary roughening, (4), refining, and (5), drying. According to the chloroxoquinoline preparation method disclosed by the invention, the decarboxylic reaction is simple to operate, the production cost is low, toxic substances including methyl benzene and the like are avoided during aftertreatment of the decarboxylic products, the pollution is lowered and harms to operation personnel are reduced. Moreover, the weight yield of the product can reach 48.4% or more, which is higher than that of the original process by 18.3% or more. Besides, the total yield of the product in the original process is 28%-30%, and the total yield of the product in the existing process is 48%-49%.
Description
Technical field
The present invention relates to a kind of pharmaceutical chemicals technique, i.e. the 7-chloro-4-oxo-quinoline preparation method.
Background technology
In the prior art, the Chinese invention patent document discloses a kind of name and has been called " chloro-4-oxo-quinoline of 7-(7-chloro-4-oxo-quinoline) and preparation method thereof and new medical use " application for a patent for invention, patent No. ZL98114407.1, open day 2000.4.26, content is for " method of the chloro-4-oxo-quinoline of a kind of 7-of preparation be take phenyl ether or whiteruss or white oil and is heat-conducting medium, makes from 7-chloro-4-hydroxyl-quinoline-3-carboxylic acid high temperature decarboxylation.Prepared product is white in color or off-white color crystal powder finished product through twice recrystallization with Glacial acetic acid, activated carbon.The chloro-4-oxo-quinoline of 7-is for the preparation of anticancer drugs.The 7-chloro-4-oxo-quinoline national drug standards number are: WS
1-(X-050)-2006Z.Its above-mentioned preparation method's shortcoming is: in order to upper method, produce 7-chloro-4-oxo-quinoline, and the decarboxylic reaction complicated operation, cost is high, yield low (yield is no more than 30%), aftertreatment toluene is raw material, pollutes large.
Summary of the invention
The objective of the invention is provides a kind of improvement technique in the past for above-mentioned deficiency, designs a kind of efficient, low 7-chloro-4-oxo-quinoline preparation method who pollutes, ensures the quality of products.
Technical solution of the present invention is: the 7-chloro-4-oxo-quinoline preparation method is characterized in that step is as follows:
(1) decarboxylic reaction: (feed ratio is: the 7kg quinolinic acid: 0.9-1.3 cupric oxide kg) drop in retort by quinolinic acid and cupric oxide, open and stir, open electric heater unit, by heating material to 260-290 ℃, insulation reaction 50-80 minute, then be cooled to 90-100 ℃, material is put into to material barrel, naturally cool to normal temperature.Quinolinic acid take cupric oxide in the chemical reaction of catalyzer, and the decarboxylic reaction transformation efficiency is high.Former technique decarboxylic reaction molar product yield is 71%, and decarboxylation thing 7-chloro-4-oxo-quinoline content is 47%-53%: by existing technique, decarboxylic reaction molar product yield is 85% left and right, and decarboxylation thing 7-chloro-4-oxo-quinoline content is 61%-63%.Use existing technique, the toluene wash operation is saved in the decarboxylic reaction aftertreatment, namely reduces raw material consumption, reduces costs, and environmental contamination reduction, avoid the injury to operator again.Described quinolinic acid chemical name is: 7-chloro-4-hydroxyl-3-quinolinecarboxylic acid, molecular formula: C
10H
6NO
3CL.
(2) once rough: that the decarboxylic reaction product is dropped into once in rough retort, by weight: 1kg decarboxylic reaction product: 5-5.5kg pyridine meter (is dissolved in decarboxylic reaction product 7-chloro-4-oxo-quinoline in pyridine with pyridine, after filtering, purify), pyridine is dropped in retort, after opening stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 ℃-90 ℃, insulation backflow 50-70 minute, with pressurized air by feed liquid after filtration tank pressure to the pyridine retort; After treating the feed liquid press filtration, carry out underpressure distillation, temperature is controlled in 50 ℃-80 ℃, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness near siccative, stops underpressure distillation.Once rough purpose is: the purification 7-chloro-4-oxo-quinoline, impurity is removed, and once rough 7-chloro-4-oxo-quinoline purity can being carried to more than 93%, be to avoid Glacial acetic acid to react generation impurity with the cupric oxide in the decarboxylic reaction thing by the purpose of pyridine, affects product purity.On the other hand, make once rough solvent with pyridine, can improve yield, former technique is rough yield mole 62% left and right once, product 7-chloro-4-oxo-quinoline content 90% left and right; Existing technique is rough yield mole 85% left and right once.The rough time reduces more than 30 hour than former technique simultaneously, has improved production efficiency, has reduced energy consumption.
(3) secondary is rough: to the acetum 300-350L and the gac 3-3.5kg that add 60% concentration in the pyridine retort, by heating material to 80 in retort ℃-85 ℃, insulation backflow 50-70 minute, then material is compressed in the secondary crystal tank with pressurized air, open freezing ethylene glycol terminal valve, temperature of charge in crystallizer is down to 0 ℃-5 ℃, insulation 10-11 hour; Then use whizzer filtering for crystallizing liquid, after filtering end, crystallisate is taken out and weighs.Secondary is rough can be purified to 7-chloro-4-oxo-quinoline more than 97.5%, and than high 5% left and right of former technique 7-chloro-4-oxo-quinoline purity, the production time, than the rough time decreased of former technique 26 hours, has been improved production efficiency.
(4) refining: that the rough centrifugal thing of secondary is dropped in treatment tank, press feed ratio: 1kg secondary raw product: 4-4.1kg60% concentration acetum, drop into acetum and 3kg gac, reflux, keep 80 ℃-85 ℃ of temperature, 1 hour, with the pressure filtration of titanium rod strainer, filtrate was depressed in the refining crystallization tank, then be cooled to 0 ℃-5 ℃, insulation crystallization 10-11 hour, filter with whizzer, and rinse crystallisate by purified water, when filtrate pH value reaches after 6, stop washing, crystallization is dried, crystallization is taken out and weighed.More than 98.5%, the quality product indices all reaches criterion of acceptability through refining 7-chloro-4-oxo-quinoline purity, compares with former technique, and the Glacial acetic acid consumption reduces 40%, refining time decreased 26 hours.
(5) dry: will make with extra care material after centrifugal and pack in the stainless steel pallet, thickness 2.7-3.3cm, then put into Hotaircirculatingoven, temperature is controlled in 105 ℃ ± 3 ℃ scopes, dry 11-11.5 hour, stop drying, and temperature in baking oven is down to 30-35 ℃, open baking oven, material metage is packed.
Preferred version is: the 7-chloro-4-oxo-quinoline preparation method is characterized in that step is as follows:
(1) decarboxylic reaction: 70kg quinolinic acid and 10kg cupric oxide are dropped in retort, open and stir, open electric heater unit, by heating material to 270 ℃, insulation reaction 1 hour, then be cooled to 100 ℃, material is put into to material barrel, naturally cool to normal temperature, after weighing, carry out once rough;
(2) once rough: that the decarboxylic reaction product is dropped into once in rough retort, by weight: 1kg decarboxylic reaction product: 5kg pyridine meter, pyridine is dropped in retort, after opening stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 ℃-90 ℃, after insulation refluxed 1 hour, with pressurized air by feed liquid after filtration tank pressure to the pyridine retort; After treating the feed liquid press filtration, carry out underpressure distillation, temperature is controlled in 50 ℃-80 ℃, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness near siccative, stops underpressure distillation;
(3) secondary is rough: add 300L in the pyridine retort, the acetum of 60% concentration and 3kg gac, by heating material to 80 in tank ℃-85 ℃, insulation refluxed 1 hour, then material is compressed in the secondary crystal tank with pressurized air, open freezing ethylene glycol terminal valve, temperature of charge in tank is down to 0 ℃-5 ℃, be incubated 10 hours.Then use whizzer filtering for crystallizing liquid, after filtering end, crystallisate is taken out and weighs;
(4) refining: that the rough centrifugal thing of secondary is dropped in treatment tank, press feed ratio: 1kg secondary raw product: 4kg, 60% concentration acetum, drop into acetum and 3kg gac, reflux, kept 80 ℃ of temperature-85 ℃, 1 hour, with the pressure filtration of titanium rod strainer, filtrate is depressed in the refining crystallization tank, then be cooled to 0 ℃-5 ℃, insulation crystallization 10 hours, filter with whizzer, and rinse crystallisate by purified water, when filtrate pH value reaches after 6, stop washing, crystallization is dried, crystallization is taken out and weighed, send drying process;
(5) dry: will make with extra care material after centrifugal and pack in the stainless steel pallet, the about 3cm of thickness, then put into Hotaircirculatingoven, temperature is controlled in 105 ℃ ± 3 ℃ scopes, dry 11 hours, stops drying, when temperature in baking oven is down to 35 ℃, open baking oven, material metage is packed.After testing, contain C
9H
6CLNO 99.5%.In such scheme, kg unit is not limited to this, can zoom in or out in proportion as required.
Advantage of the present invention is: decarboxylic reaction is simple to operate, and production cost is low, and the Toxics such as toluene are saved in the decarboxylate aftertreatment, reduces pollution and reduces the murder by poisoning to operator.Product weight yield of the present invention can reach more than 48.4%, higher more than 18.3% than former technique.Former handicraft product total recovery 28-30%, existing handicraft product total recovery 48-49%.Press dry product and calculate, after testing, contain C
9H
6CLNO 99-99.5%, improved product purity.
Below in conjunction with embodiment, embodiments of the present invention are described in further detail.
Embodiment
Embodiment
The 7-chloro-4-oxo-quinoline preparation method, its step is as follows:
1, decarboxylic reaction: 70kg quinolinic acid and 10kg cupric oxide are dropped in retort, open and stir, open electric heater unit, by heating material to 270 ℃ left and right, insulation reaction 1 hour, then be cooled to 100 ℃, and material is put into to material barrel, naturally cool to normal temperature, after weighing, carry out once rough.(the about 70.37kg of decarboxylic reaction product).
2, once rough: that the decarboxylic reaction product is dropped into once in rough tank, by weight: 1kg decarboxylic reaction product: 5kg pyridine meter, pyridine is dropped in retort, after opening stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 ℃-90 ℃, after insulation refluxed 1 hour, with pressurized air by feed liquid after filtration tank pressure to the pyridine retort.After treating the feed liquid press filtration, carry out underpressure distillation, temperature is controlled in 50 ℃-80 ℃, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness near siccative, stops underpressure distillation.
3, secondary is rough: add 300L acetum (60% concentration) in the pyridine retort, and 3kg gac, by heating material to 80 in tank ℃-85 ℃, insulation refluxed 1 hour, then material is compressed in the secondary crystal tank with pressurized air, open freezing ethylene glycol terminal valve, temperature of charge in tank is down to 0 ℃-5 ℃, be incubated 10 hours.Then use whizzer filtering for crystallizing liquid, after filtering end, crystallisate is taken out and weighs.(approximately obtaining wet stock 44.3kg).
4, refining: that the rough centrifugal thing of secondary is dropped in treatment tank, press feed ratio: 1kg secondary raw product: 4kg acetum (60% concentration), drop into acetum, and 3kg gac, reflux, kept 80 ℃-85 ℃ of temperature 1 hour, with the pressure filtration of titanium rod strainer, filtrate is depressed in the refining crystallization tank, then be cooled to 0 ℃-5 ℃, insulation crystallization 10 hours, filter with whizzer, and rinse crystallisate by purified water, when filtrate pH value reaches after 6, stop washing, crystallization is dried, crystallization is taken out and weighed, send drying process.(approximately obtaining wet stock 39.6kg).
5, dry: will make with extra care material after centrifugal and pack in the stainless steel pallet, the about 3cm of thickness, then put into Hotaircirculatingoven, temperature is controlled in 105 ℃ ± 3 ℃ scopes, dry 11 hours, stops drying, when temperature in baking oven is down to 35 ℃, open baking oven, material metage is packed.(approximately obtaining product 30.5kg).After testing, contain C
9H
6CLNO 99.5%.
Claims (3)
1. 7-chloro-4-oxo-quinoline preparation method is characterized in that step is as follows:
(1) decarboxylic reaction: quinolinic acid and cupric oxide are dropped in retort, open and stir, open electric heater unit, to 260-290 ℃, insulation reaction 50-80 minute, then be cooled to 90-100 ℃ by heating material, material is put into to material barrel, naturally cool to normal temperature;
(2) once rough: that the decarboxylic reaction product is dropped into once in rough retort, by weight: 1kg decarboxylic reaction product: 5-5.5kg pyridine meter, pyridine is dropped in retort, after opening stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 ℃-90 ℃, insulation backflow 50-70 minute, with pressurized air by feed liquid after filtration tank pressure to the pyridine retort; After treating the feed liquid press filtration, carry out underpressure distillation, temperature is controlled in 50 ℃-80 ℃, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness near siccative, stops underpressure distillation;
(3) secondary is rough: to the acetum 300-350L and the gac 3-3.5kg that add 60% concentration in the pyridine retort, by heating material to 80 in retort ℃-85 ℃, insulation backflow 50-70 minute, then material is compressed in the secondary crystal tank with pressurized air, open freezing ethylene glycol terminal valve, temperature of charge in crystallizer is down to 0 ℃-5 ℃, insulation 10-11 hour; Then use whizzer filtering for crystallizing liquid, after filtering end, crystallisate is taken out and weighs;
(4) refining: that the rough centrifugal thing of secondary is dropped in treatment tank, press feed ratio: 1kg secondary raw product: 4-4.1kg60% concentration acetum, drop into acetum and 3-3.5kg gac, reflux, keep 80 ℃-85 ℃ of temperature, 1 hour, with the pressure filtration of titanium rod strainer, filtrate was depressed in the refining crystallization tank, then be cooled to 0 ℃-5 ℃, insulation crystallization 10-11 hour, filter with whizzer, and rinse crystallisate by purified water, when filtrate pH value reaches after 6, stop washing, crystallization is dried, crystallization is taken out and weighed;
(5) dry: will make with extra care material after centrifugal and pack in the stainless steel pallet, thickness 2.7-3.3cm, then put into Hotaircirculatingoven, temperature is controlled in 105 ℃ ± 3 ℃ scopes, dry 11-11.5 hour, stop drying, and temperature in baking oven is down to 30-35 ℃, open baking oven, material metage is packed.
2. according to 7-chloro-4-oxo-quinoline preparation method claimed in claim 1, it is characterized in that step is as follows:
(1) decarboxylic reaction: 70kg quinolinic acid and 10kg cupric oxide are dropped in retort, open and stir, open electric heater unit, by heating material to 270 ℃, insulation reaction 1 hour, then be cooled to 100 ℃, material is put into to material barrel, naturally cool to normal temperature, after weighing, carry out once rough;
(2) once rough: that the decarboxylic reaction product is dropped into once in rough retort, by weight: 1kg decarboxylic reaction product: 5kg pyridine meter, pyridine is dropped in retort, after opening stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 ℃-90 ℃, after insulation refluxed 1 hour, with pressurized air by feed liquid after filtration tank pressure to the pyridine retort; After treating the feed liquid press filtration, carry out underpressure distillation, temperature is controlled in 50 ℃-80 ℃, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness near siccative, stops underpressure distillation;
(3) secondary is rough: add 300L in the pyridine retort, the acetum of 60% concentration and 3kg gac, by heating material to 80 in tank ℃-85 ℃, insulation refluxed 1 hour, then material is compressed in the secondary crystal tank with pressurized air, open freezing ethylene glycol terminal valve, temperature of charge in tank is down to 0 ℃-5 ℃, be incubated 10 hours; Then use whizzer filtering for crystallizing liquid, after filtering end, crystallisate is taken out and weighs;
(4) refining: that the rough centrifugal thing of secondary is dropped in treatment tank, press feed ratio: 1kg secondary raw product: 4kg, 60% concentration acetum, drop into acetum and 3kg gac, reflux, kept 80 ℃ of temperature-85 ℃, 1 hour, with the pressure filtration of titanium rod strainer, filtrate is depressed in the refining crystallization tank, then be cooled to 0 ℃-5 ℃, insulation crystallization 10 hours, filter with whizzer, and rinse crystallisate by purified water, when filtrate pH value reaches after 6, stop washing, crystallization is dried, crystallization is taken out and weighed, send drying process;
(5) dry: will make with extra care material after centrifugal and pack in the stainless steel pallet, the about 3cm of thickness, then put into Hotaircirculatingoven, temperature is controlled in 105 ℃ ± 3 ℃ scopes, dry 11 hours, stops drying, when temperature in baking oven is down to 35 ℃, open baking oven, material metage is packed.
3. according to 7-chloro-4-oxo-quinoline preparation method claimed in claim 1, it is characterized in that quinolinic acid and cupric oxide feed ratio are: the 7kg quinolinic acid: 0.9-1.3 cupric oxide kg.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59205380A (en) * | 1983-04-05 | 1984-11-20 | Mitsubishi Paper Mills Ltd | Production of pyrazolo(1,5-a)pyrazine derivative |
| CN1251364A (en) * | 1998-10-21 | 2000-04-26 | 中外合资通化茂祥制药有限公司 | 7-chloro-4-oxo-quinoline and its preparation method and novel use as medicine |
| WO2008072257A2 (en) * | 2006-12-12 | 2008-06-19 | Ind-Swift Laboratories Limited | Process for the preparation of indole derivatives |
-
2013
- 2013-08-22 CN CN201310368721.3A patent/CN103408491B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59205380A (en) * | 1983-04-05 | 1984-11-20 | Mitsubishi Paper Mills Ltd | Production of pyrazolo(1,5-a)pyrazine derivative |
| CN1251364A (en) * | 1998-10-21 | 2000-04-26 | 中外合资通化茂祥制药有限公司 | 7-chloro-4-oxo-quinoline and its preparation method and novel use as medicine |
| WO2008072257A2 (en) * | 2006-12-12 | 2008-06-19 | Ind-Swift Laboratories Limited | Process for the preparation of indole derivatives |
Non-Patent Citations (1)
| Title |
|---|
| LUKAS J. GOOßEN等: "Copper-Catalyzed Protodecarboxylation of Aromatic Carboxylic", 《ADV. SYNTH. CATAL》, vol. 349, 31 December 2007 (2007-12-31), pages 2241 - 2246 * |
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