CN103408491B - 7-chloro-4-oxo-quinoline preparation method - Google Patents
7-chloro-4-oxo-quinoline preparation method Download PDFInfo
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- CN103408491B CN103408491B CN201310368721.3A CN201310368721A CN103408491B CN 103408491 B CN103408491 B CN 103408491B CN 201310368721 A CN201310368721 A CN 201310368721A CN 103408491 B CN103408491 B CN 103408491B
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Abstract
The present invention relates to a kind of pharmaceutical chemicals technique, i.e. 7-chloro-4-oxo-quinoline preparation method.Its step is as follows: (1) decarboxylic reaction.(2) once rough.(3) secondary is rough.(4) refining.(5) dry.Decarboxylic reaction is simple to operate, and production cost is low, and the Toxics such as toluene are saved in decarboxylate aftertreatment, reduces the murder by poisoning of polluting and reducing operator.Product weight yield of the present invention can reach more than 48.4%, higher than former technique by more than 18.3%.Former handicraft product total recovery 28-30%, existing handicraft product is always by rate 48-49%.
Description
technical field
The present invention relates to a kind of pharmaceutical chemicals technique, i.e. 7-chloro-4-oxo-quinoline preparation method.
Background technology
In the prior art, Chinese invention patent document discloses a kind of name and is called " chloro-4-oxo-quinoline (7-chloro-4-oxo-quinoline) of 7-and preparation method thereof and new medical use " application for a patent for invention, patent No. ZL98114407.1, publication date 2000.4.26, content is for " a kind of method preparing the chloro-4-oxo-quinoline of 7-, obtains from 7-chloro-4-hydroxyl-quinoline-3-carboxylic acid high temperature decarboxylation for heat-conducting medium with phenyl ether or whiteruss or white oil.Obtained product Glacial acetic acid, activated carbon are white or off-white color crystal powder finished product through twice recrystallization.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.The shortcoming of its above-mentioned preparation method is: produce 7-chloro-4-oxo-quinoline in order to upper method, decarboxylic reaction complicated operation, cost is high, yield low (yield is no more than 30%), and aftertreatment toluene is raw material, pollutes large.
Summary of the invention
The object of the invention is for above-mentioned deficiency and provide one to improve technique in the past, the 7-chloro-4-oxo-quinoline preparation method design a kind of efficient, low stain, ensuring the quality of products.
Technical solution of the present invention is: 7-chloro-4-oxo-quinoline preparation method, it is characterized in that step is as follows:
(1) decarboxylic reaction: quinolinic acid and cupric oxide (feed ratio is: 7kg quinolinic acid: 0.9-1.3 kg cupric oxide) are dropped in retort, open and stir, open electric heater unit, by heating material to 260-290 DEG C, insulation reaction 50-80 minute, then be cooled to 90-100 DEG C, material is put into material barrel, naturally cool to normal temperature.Quinolinic acid is in the chemical reaction taking cupric oxide as catalyzer, and 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 about 85%, and decarboxylation thing 7-chloro-4-oxo-quinoline content is 61%-63%.Use existing technique, toluene wash operation is saved in decarboxylic reaction aftertreatment, namely reduces raw material consumption, reduces costs, reduce environmental pollution again, avoid the injury to operator.Described quinolinic acid chemical name is: 7-chloro-4-hydroxyl-3-quinolinecarboxylic acid, molecular formula: C
10h
6nO
3cL.
(2) once rough: decarboxylic reaction product to be dropped into once in rough retort, by weight: 1kg decarboxylic reaction product: decarboxylic reaction product 7-chloro-4-oxo-quinoline (is dissolved in pyridine with pyridine by 5-5.5kg pyridine meter, purify after filtering), pyridine is dropped in retort, open after stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 DEG C-90 DEG C, insulation backflow 50-70 minute, with pressurized air by feed liquid after filtration tank pressure in pyridine retort; After treating feed liquid press filtration, carry out underpressure distillation, temperature controls in 50 DEG C-80 DEG C, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness close to siccative, stops underpressure distillation.Once rough object is: purification 7-chloro-4-oxo-quinoline, is removed by impurity, once roughly can carry to more than 93% by 7-chloro-4-oxo-quinoline purity, be avoid the cupric oxide in Glacial acetic acid and decarboxylic reaction thing to react to produce impurity, affect product purity by the object of pyridine.On the other hand, make once rough solvent with pyridine, can yield be improved, former technique crude yield mole about 62%, product 7-chloro-4-oxo-quinoline content about 90%; Existing technique crude yield mole about 85%.When the rough time is less than former technique minimizing more than 30 simultaneously, improves production efficiency, reduce energy consumption.
(3) secondary is rough: in pyridine retort, add 60% concentration acetum 300-350L and gac 3-3.5kg, by heating material to 80 in retort DEG C-85 DEG C, insulation backflow 50-70 minute, then material pressurized air is compressed in secondary crystal tank, open freezing ethylene glycol terminal valve, temperature of charge in crystallizer is down to 0 DEG C-5 DEG C, insulation 10-11 hour; Then use whizzer filtering for crystallizing liquid, filter after terminating, crystallisate is taken out and weighs.Secondary is rough can purify to more than 97.5% by 7-chloro-4-oxo-quinoline, higher by about 5% than former technique 7-chloro-4-oxo-quinoline purity, when the production time is less than the rough time decreased of former technique 26, improves production efficiency.
(4) refining: rough for secondary centrifugal thing is dropped in treatment tank, by feed ratio: 1kg bis-raw products: 4-4.1kg60% concentration acetum, drop into acetum and 3kg gac, reflux, keep temperature 80 DEG C-85 DEG C, 1 hour, with the pressure filtration of titanium rod strainer, filtrate was depressed in refining crystallization tank, then 0 DEG C-5 DEG C are cooled to, insulation crystallization 10-11 hour, filters with whizzer, and rinses crystallisate by purified water, when filtrate pH value reaches after 6, stop washing, crystallization is dried, crystallization is taken out and weighs.Can reach more than 98.5% through refining 7-chloro-4-oxo-quinoline purity, quality product indices all reaches criterion of acceptability, and compared with former technique, Glacial acetic acid consumption reduces 40%, and Refining times reduces 26 hours.
(5) dry: by refining centrifugal after material load in stainless steel pallet, thickness 2.7-3.3cm, then Hotaircirculatingoven is put into, temperature controls within the scope of 105 DEG C ± 3 DEG C, dry 11-11.5 hour, stops dry, oven temperature is down to 30-35 DEG C, open baking oven, material metage is packed.
Preferred version is: 7-chloro-4-oxo-quinoline preparation method, it is characterized in that step is as follows:
(1) decarboxylic reaction: 70kg quinolinic acid and 10kg cupric oxide are dropped in retort, opens and stir, open electric heater unit, by heating material to 270 DEG C, insulation reaction 1 hour, is then cooled to 100 DEG C, material is put into material barrel, naturally cools to normal temperature, carry out once rough after weighing;
(2) once rough: decarboxylic reaction product to be dropped into once in rough retort, by weight: 1kg decarboxylic reaction product: 5kg pyridine meter, pyridine is dropped in retort, open after stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 DEG C-90 DEG C, insulation backflow after 1 hour, with pressurized air by feed liquid after filtration tank pressure in pyridine retort; After treating feed liquid press filtration, carry out underpressure distillation, temperature controls in 50 DEG C-80 DEG C, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness close to siccative, stops underpressure distillation;
(3) secondary is rough: in pyridine retort, add 300L, the acetum of 60% concentration and 3kg gac, by heating material to 80 in tank DEG C-85 DEG C, insulation backflow 1 hour, then material pressurized air is compressed in secondary crystal tank, open freezing ethylene glycol terminal valve, temperature of charge in tank is down to 0 DEG C-5 DEG C, be incubated 10 hours.Then use whizzer filtering for crystallizing liquid, filter after terminating, crystallisate is taken out and weighs;
(4) refining: rough for secondary centrifugal thing is dropped in treatment tank, by feed ratio: 1kg bis-raw product: 4kg, 60% concentration acetum, drop into acetum and 3kg gac, reflux, keep temperature 80 DEG C-85 DEG C, 1 hour, with the strainer pressure filtration of titanium rod, filtrate is depressed in refining crystallization tank, then be cooled to 0 DEG C-5 DEG C, insulation crystallization 10 hours, filters 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 weighs, send drying process;
(5) dry: by refining centrifugal after material load in stainless steel pallet, thickness is about 3cm, then puts into Hotaircirculatingoven, temperature controls within the scope of 105 DEG C ± 3 DEG C, dry 11 hours, stops dry, when oven temperature being down to 35 DEG C, open baking oven, material metage is packed.After testing, containing C
9h
6cLNO 99.5%.In such scheme, kg unit is not limited thereto, and can scale up or reduce 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 decarboxylate aftertreatment, reduces the murder by poisoning of polluting and reducing operator.Product weight yield of the present invention can reach more than 48.4%, higher than former technique by more than 18.3%.Former handicraft product total recovery 28-30%, existing handicraft product total recovery 48-49%.Calculate, after testing, containing C by dry product
9h
6cLNO 99-99.5%, improves product purity.
Below in conjunction with embodiment, embodiments of the present invention are described in further detail.
Embodiment
Embodiment
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 about heating material to 270 DEG C, insulation reaction 1 hour, is then cooled to 100 DEG C, material is put into material barrel, naturally cool to normal temperature, carry out once rough after weighing.(decarboxylic reaction product is about 70.37kg).
2, once rough: decarboxylic reaction product to be dropped into once in rough tank, by weight: 1kg decarboxylic reaction product: 5kg pyridine meter, pyridine is dropped in retort, open after stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 DEG C-90 DEG C, insulation backflow after 1 hour, with pressurized air by feed liquid after filtration tank pressure in pyridine retort.After treating feed liquid press filtration, carry out underpressure distillation, temperature controls in 50 DEG C-80 DEG C, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness close to siccative, stops underpressure distillation.
3, secondary is rough: in pyridine retort, add 300L acetum (60% concentration), and 3kg gac, by heating material to 80 in tank DEG C-85 DEG C, insulation backflow 1 hour, then material pressurized air is compressed in secondary crystal tank, open freezing ethylene glycol terminal valve, temperature of charge in tank is down to 0 DEG C-5 DEG C, be incubated 10 hours.Then use whizzer filtering for crystallizing liquid, filter after terminating, crystallisate is taken out and weighs.(about obtaining wet stock 44.3kg).
4, refining: rough for secondary centrifugal thing is dropped in treatment tank, by feed ratio: 1kg bis-raw products: 4kg acetum (60% concentration), drop into acetum, and 3kg gac, reflux, keeps temperature 80 DEG C-85 DEG C 1 hour, with the pressure filtration of titanium rod strainer, filtrate is depressed in refining crystallization tank, then be cooled to 0 DEG C-5 DEG C, insulation crystallization 10 hours, filters 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 weighs, send drying process.(about obtaining wet stock 39.6kg).
5, dry: by refining centrifugal after material load in stainless steel pallet, thickness is about 3cm, then puts into Hotaircirculatingoven, temperature controls within the scope of 105 DEG C ± 3 DEG C, dry 11 hours, stops dry, when oven temperature being down to 35 DEG C, open baking oven, material metage is packed.(about obtaining product 30.5kg).After testing, containing C
9h
6cLNO 99.5%.
Claims (3)
1. a 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, opens and stir, open electric heater unit, by heating material to 260-290 DEG C, insulation reaction 50-80 minute, is then cooled to 90-100 DEG C, material is put into material barrel, naturally cools to normal temperature;
(2) once rough: decarboxylic reaction product to be dropped into once in rough retort, by weight: 1kg decarboxylic reaction product: 5-5.5kg pyridine meter, pyridine is dropped in retort, open after stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 DEG C-90 DEG C, insulation backflow 50-70 minute, with pressurized air by feed liquid after filtration tank pressure in pyridine retort; After treating feed liquid press filtration, carry out underpressure distillation, temperature controls in 50 DEG C-80 DEG C, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness close to siccative, stops underpressure distillation;
(3) secondary is rough: in pyridine retort, add 60% concentration acetum 300-350L and gac 3-3.5kg, by heating material to 80 in retort DEG C-85 DEG C, insulation backflow 50-70 minute, then material pressurized air is compressed in secondary crystal tank, open freezing ethylene glycol terminal valve, temperature of charge in crystallizer is down to 0 DEG C-5 DEG C, insulation 10-11 hour; Then use whizzer filtering for crystallizing liquid, filter after terminating, crystallisate is taken out and weighs;
(4) refining: rough for secondary centrifugal thing is dropped in treatment tank, by feed ratio: 1kg bis-raw products: 4-4.1kg60% concentration acetum, drop into acetum and 3-3.5kg gac, reflux, keep temperature 80 DEG C-85 DEG C, 1 hour, with the pressure filtration of titanium rod strainer, filtrate was depressed in refining crystallization tank, then 0 DEG C-5 DEG C are cooled to, insulation crystallization 10-11 hour, filters with whizzer, and rinses crystallisate by purified water, when filtrate pH value reaches after 6, stop washing, crystallization is dried, crystallization is taken out and weighs;
(5) dry: by refining centrifugal after material load in stainless steel pallet, thickness 2.7-3.3cm, then Hotaircirculatingoven is put into, temperature controls within the scope of 105 DEG C ± 3 DEG C, dry 11-11.5 hour, stops dry, oven temperature is down to 30-35 DEG C, open baking oven, material metage is packed.
2., according to 7-chloro-4-oxo-quinoline preparation method according to 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, opens and stir, open electric heater unit, by heating material to 270 DEG C, insulation reaction 1 hour, is then cooled to 100 DEG C, material is put into material barrel, naturally cools to normal temperature, carry out once rough after weighing;
(2) once rough: decarboxylic reaction product to be dropped into once in rough retort, by weight: 1kg decarboxylic reaction product: 5kg pyridine meter, pyridine is dropped in retort, open after stirring, open once rough tank reflux cooling device, open heater valve, by heating material to 80 DEG C-90 DEG C, insulation backflow after 1 hour, with pressurized air by feed liquid after filtration tank pressure in pyridine retort; After treating feed liquid press filtration, carry out underpressure distillation, temperature controls in 50 DEG C-80 DEG C, and vacuum degree control, in 0.05-0.08Mpa, when material in tank is concentrated into thickness close to siccative, stops underpressure distillation;
(3) secondary is rough: in pyridine retort, add 300L, the acetum of 60% concentration and 3kg gac, by heating material to 80 in tank DEG C-85 DEG C, insulation backflow 1 hour, then material pressurized air is compressed in secondary crystal tank, open freezing ethylene glycol terminal valve, temperature of charge in tank is down to 0 DEG C-5 DEG C, be incubated 10 hours; Then use whizzer filtering for crystallizing liquid, filter after terminating, crystallisate is taken out and weighs;
(4) refining: rough for secondary centrifugal thing is dropped in treatment tank, by feed ratio: 1kg bis-raw product: 4kg, 60% concentration acetum, drop into acetum and 3kg gac, reflux, keep temperature 80 DEG C-85 DEG C, 1 hour, with the strainer pressure filtration of titanium rod, filtrate is depressed in refining crystallization tank, then be cooled to 0 DEG C-5 DEG C, insulation crystallization 10 hours, filters 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 weighs, send drying process;
(5) dry: by refining centrifugal after material load in stainless steel pallet, thickness 3cm, then puts into Hotaircirculatingoven, temperature controls within the scope of 105 DEG C ± 3 DEG C, dry 11 hours, stops dry, when oven temperature being down to 35 DEG C, open baking oven, material metage is packed.
3., according to 7-chloro-4-oxo-quinoline preparation method according to claim 1, it is characterized in that quinolinic acid and cupric oxide feed ratio are: 7kg quinolinic acid: 0.9-1.3 kg cupric oxide.
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| 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 |
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| JPS59205380A (en) * | 1983-04-05 | 1984-11-20 | Mitsubishi Paper Mills Ltd | Production of pyrazolo(1,5-a)pyrazine derivative |
| WO2008072257A2 (en) * | 2006-12-12 | 2008-06-19 | Ind-Swift Laboratories Limited | Process for the preparation of indole derivatives |
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| 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 |
Non-Patent Citations (1)
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| Copper-Catalyzed Protodecarboxylation of Aromatic Carboxylic;Lukas J. Gooßen等;《Adv. Synth. Catal》;20071231;第349卷;2241-2246 * |
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