CN102775347A - Improved synthetic method for 4-bromomethyl-1,2-dihydroquinoline-2-one - Google Patents
Improved synthetic method for 4-bromomethyl-1,2-dihydroquinoline-2-one Download PDFInfo
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- CN102775347A CN102775347A CN2011101193262A CN201110119326A CN102775347A CN 102775347 A CN102775347 A CN 102775347A CN 2011101193262 A CN2011101193262 A CN 2011101193262A CN 201110119326 A CN201110119326 A CN 201110119326A CN 102775347 A CN102775347 A CN 102775347A
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Abstract
The invention relates to an improved synthetic method for 4-bromomethyl-1,2-dihydroquinoline-2-one. According to the method, acetoacetanilide is subjected to a bromination reaction in chloroform so as to obtain brominated acetoacet-benzene, and then brominated acetoacet-benzene undergoes cyclization in concentrated sulfuric acid so as to prepare 4-bromomethyl-1,2-dihydroquinoline-2-one; in the bromination reaction, temperature is controlled to be no more than 30 DEG C, a chloroform solution in which bromine is dissolved is slowly added, then stirring is carried out at a temperature of 20 to 30 DEG C for 2 to 3 h after addition of the chloroform solution is finished, and an obtained mixture is slowly heated to a temperature of 60 to 65 DEG C, then is stirred and is insulated for 0.5 to 1 h; in cyclization, the concentrated sulfuric acid is cooled to a temperature of 5 to 10 DEG C through refrigeration, then bromo-acetoacetanilide is added in different batches, feeding temperature is maintained to be lower than 20 DEG C, then the temperature rises up to 25 to 30 DEG after addition of bromo-acetoacetanilide is finished, and an insulation reaction is performed for 2 to 3 h. In the improved synthetic method provided by the invention, reaction temperature of bromination is reduced, loss of chloroform is minimized, product yield is improved, usage amount of the concentrated sulfuric acid in cyclization is reduced, production cost is lowered down and production security is enhanced.
Description
Technical field
The present invention relates to the preparation method of organic cpds, relate in particular to the improvement compound method of cardiovascular important intermediate 4-bromomethyl quinoline-2 (H) ketone with medicament for anti-gastric ulcer of N-substituted benzene oxygen alkanamine class.
Background technology
4-bromomethyl quinoline-2 (H)-ketone, structural formula is by shown in the following formula (I), and outward appearance is an off-white color shape solid, is the important medicine intermediate of synthetic N-phenoxyalkylamine class cardiovascular agent and medicament for anti-gastric ulcer.Like the auspicious crust watt of anti-gastroenteritic ulcer new drug; For promoting stomach skin factor growth type medicine, can accelerate ulcer healing, isolate hydrochloric acid in gastric juice and stomach en-; Thereby the opposing a variety of causes causes stomach mucous membrane is corroded; Reach protection and repair stomach and duodenum purpose, and the gastrointestinal ulceration recurrence rate is low, and chronic gastric ulcer is had obvious effects.Along with the exploitation in succession at home of these medicines, produce listing, bulk drug midbody 4-bromomethyl quinoline-2 (H)-ketone has the very big market space.
The compound method of 4-bromomethyl quinoline-2 (H)-ketone has multiple, presses situation such as raw material sources, cost, preparation process condition, mainly takes alpha.-acetylacetanilide in the prior art, through bromination, and the technology that the cyclization two-step reaction is produced:
But the shortcoming one that above-mentioned route exists is because the temperature of reaction of bromination is high, causes the consumption of solvent chloroform many, and it is low to produce yield, and production cost is high; The 2nd, the consumption that cyclization gets the high vitriol oil of reaction temperature is also bigger, the waste raw materials consumption, and the yield of production is not high, and the total emission volumn of the whole process three wastes is big, has more increased the processing costs of the three wastes, has improved the preparation cost of product.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art; Propose the improvement compound method of a kind of 4-bromomethyl quinoline-2 (H) ketone, reduce the temperature of reaction of bromination, reduce the loss of chloroform; Improve the yield of product; Reduce the usage quantity of the vitriol oil in the cyclization, reduce production costs, improve the security of producing.
Technical scheme of the present invention is: the improvement compound method of a kind of 4-bromomethyl quinoline-2 (H) ketone, get the acetyl bromide phenyl methyl ketone by alpha.-acetylacetanilide bromination reaction in chloroform, and cyclization makes in the vitriol oil then; It is characterized in that: in described bromination reaction; Controlled temperature is no more than 30 ℃ of chloroformic solutions that slowly add the dissolving bromine, adds 20-30 ℃ and stirs 2-3h, slowly is warming up to 60-65 ℃; Stir insulation 0.5-1h.
In preferred embodiment of the present invention, also be included in the described ring-closure reaction, with the vitriol oil with frozen cooling to 5-10 ℃, add the bromo alpha.-acetylacetanilide in batches, keep charge temperature to be lower than 20 ℃, be warming up to 25 ℃-30 ℃ after adding, insulation reaction 2-3h.
In preferred embodiment of the present invention, in the described bromination reaction, alpha.-acetylacetanilide (kg): bromine (kg): chloroform (L)=1: 1: 3-4.
In preferred embodiment of the present invention, in the described ring-closure reaction, the mass ratio of the control bromination acetyl bromide phenyl methyl ketone and the vitriol oil is 1: 4-5.
In preferred embodiment of the present invention, described bromination reaction is cooled to 0-5 ℃ after comprising that also insulation reaction finishes, oven dry, and bromination bullion product gets the acetyl bromide phenyl methyl ketone with 95% ethyl alcohol recrystallization.
In preferred embodiment of the present invention, described bromination bullion product is with in 95% ethyl alcohol recrystallization, and bromination bullion product and 95% alcoholic acid ratio are: acetobromanilide (kg): 95% ethanol (L)=1: 4-5.
In preferred embodiment of the present invention; Described ring-closure reaction also comprises in the frozen water that the reaction solution suction is prepared in advance, keeps temperature to be no more than 40 ℃, stirs 1-1.5h; Centrifugal; Product after centrifugal is washed PH=6-7 with weak caustic solution, oven dry, cyclization bullion product gets 4-bromomethyl quinoline-2 (H) ketone with ethyl alcohol recrystallization.
In preferred embodiment of the present invention, described weak caustic solution is a yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, in the triethylamine a kind of.
In preferred embodiment of the present invention, described cyclization bullion product is with in the ethyl alcohol recrystallization, and the cyclization bullion produces with the alcoholic acid ratio and is: acetobromanilide (kg): ethanol (L)=1: 9-10.
Compared with prior art, beneficial effect of the present invention has been to reduce the temperature of reaction of bromination, has reduced the loss of chloroform; Reduce the usage quantity of the vitriol oil in the ring-closure reaction and the temperature of reaction; Improve the security of producing, improve the total recovery of product, reduced the quantity discharged of the whole process three wastes; Reduce production costs, meet the production requirement of environment-protecting clean.
Embodiment
Below in conjunction with embodiment the present invention is done further elaboration.
Embodiment 1
Bromo-reaction: in reactor, add the chloroform of 126L, add the 50kg alpha.-acetylacetanilide, stir, controlled temperature is no more than 30 ℃ of chloroformic solutions that slowly drip the 24L of dissolving 50kg bromine; Slowly be warming up to 60 ℃ after adding 20-30 ℃ of stirring 2h, drive bromize hydrogen gas in the system away, insulation 0.5h is cooled to 0-5 ℃; Insulation 1h, the centrifugal chloroform solvent of removing, product drench the back water with minimum of chloroform and are washed till neutrality, get bromide bullion product 65kg; 60 ℃ of oven dry, bullion adds the ethyl alcohol recrystallization of 260L, refluxes after the dissolving, lowers the temperature 0-5 ℃; Kept 5-6 hour, centrifuge washing gets purified white plates solid bromo alpha.-acetylacetanilide 56.39kg; Fusing point 130-133 ℃ (decomposition), content 99.12% (high effective liquid chromatography for measuring), yield 78%.
Ring-closure reaction: in the anhydrous response device, add the dense H of 225.56kg
2SO
4, cooling is reduced to 5-10 ℃, adds the refining acetobrom Acetanilide of 56.39kg in five batches, keeps charge temperature to be lower than 20 ℃; Be warming up to 25-30 ℃ after adding, insulation reaction 2h, finish reaction after, in the 1127kg frozen water that the suction of cyclization liquid is prepared in advance; The maintenance temperature is no more than 40 ℃, takes out to add end, stirs 1h, and is centrifugal; Product after centrifugal is washed PH=6-7 with sodium carbonate solution, and 80 ℃ of oven dry get bullion 57.54kg.
The cyclocomplex bullion adds 575.40L reflux in ethanol 1h, cools off 0-5 ℃, centrifugal dry off-white color powdery solid 47.18kg, fusing point 255-258 ℃ (decomposition), content 99.5% (high effective liquid chromatography for measuring), yield 90%.
Embodiment 2
Bromo-reaction: in reactor, add the chloroform of 308L, add the 100kg alpha.-acetylacetanilide, stir, controlled temperature is no more than 30 ℃ of chloroformic solutions that slowly drip the 48L of dissolving 100kg bromine; Slowly be warming up to 60 ℃ after adding 20-30 ℃ of stirring 2h, drive bromize hydrogen gas in the system away, insulation 0.5h is cooled to 0-5 ℃; Insulation 1h, the centrifugal chloroform solvent of removing, product drench the back water with minimum of chloroform and are washed till neutrality, get bromide bullion product 134kg; 60 ℃ of oven dry, bullion adds the 536L ethyl alcohol recrystallization, refluxes after the dissolving, lowers the temperature 0-5 ℃; Kept 5-6 hour, centrifuge washing gets purified white plates solid bromo alpha.-acetylacetanilide 115.7kg; Fusing point 130-133 ℃ (decomposition), content 98.95% (high effective liquid chromatography for measuring), yield 78%.
Ring-closure reaction: in the anhydrous response device, add the dense H2SO4 of 462.8kg, cooling is reduced to 5-10 ℃, adds the refining acetobrom Acetanilide of 115.7kg in five batches, keeps charge temperature to be lower than 20 ℃; Be warming up to 25-30 ℃ after adding, insulation reaction 2h, finish reaction after, in the 2314kg frozen water that the suction of cyclization liquid is prepared in advance; The maintenance temperature is no more than 40 ℃, takes out to add end, stirs 1h, and is centrifugal; Product after centrifugal is washed PH=6-7 with solution of potassium carbonate, and 80 ℃ of oven dry get bullion 116kg.
The cyclocomplex bullion is added the reflux in ethanol 1h of 1160L, cools off 0-5 ℃, centrifugal dry off-white color powdery solid 95.73kg, fusing point 255-258 ℃ (decomposition), content 99.5% (high effective liquid chromatography for measuring), yield 89%.
Embodiment 3
Bromo-reaction: in reactor, add the chloroform of 500L, add the 140kg alpha.-acetylacetanilide, stir, controlled temperature is no more than 30 ℃ of chloroformic solutions that slowly drip the 60L of dissolving 140kg bromine; Slowly be warming up to 65 ℃ after adding 20-30 ℃ of stirring 3h, drive bromize hydrogen gas in the system away, insulation 1h is cooled to 0-5 ℃; Insulation 1h, the centrifugal chloroform solvent of removing, product drench the back water with minimum of chloroform and are washed till neutrality, get bromide bullion product 193kg; 60 ℃ of oven dry, bullion adds the 965L ethyl alcohol recrystallization, refluxes after the dissolving, lowers the temperature 0-5 ℃; Kept 5-6 hour, centrifuge washing gets purified white plates solid bromo alpha.-acetylacetanilide 166kg; Fusing point 130-133 ℃ (decomposition), content 98.95% (high effective liquid chromatography for measuring), yield 82%.
Ring-closure reaction: in the anhydrous response device, add the dense H2S04 of 830kg, cooling is reduced to 5-10 ℃, adds the refining acetobrom Acetanilide of 166kg in five batches, keeps charge temperature to be lower than 20 ℃; Be warming up to 25-30 ℃ after adding, insulation reaction 3h, finish reaction after, in the 3320kg frozen water that the suction of cyclization liquid is prepared in advance; The maintenance temperature is no more than 40 ℃, takes out to add end, stirs 1.5h, and is centrifugal; Product after centrifugal is washed PH=6-7 with sodium hydrogen carbonate solution, and 80 ℃ of oven dry get bullion 172kg.
The cyclocomplex bullion adds the reflux in ethanol 1h of 1720L, cools off 0-5 ℃, centrifugal dry off-white color powdery solid 141.98kg, fusing point 255-258 ℃ (decomposition), content 99.5% (high effective liquid chromatography for measuring), yield 92%.
The above; Be merely embodiment of the present invention; But protection scope of the present invention is not limited thereto; Any those of ordinary skill in the art are in the technical scope that the present invention disclosed, and variation or the replacement that can expect without creative work all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain that claims were limited.
Claims (9)
1. the improvement compound method of a 4-bromomethyl quinoline-2 (H) ketone gets the acetyl bromide phenyl methyl ketone by alpha.-acetylacetanilide bromination reaction in chloroform, and cyclization makes in the vitriol oil then; It is characterized in that: in described bromination reaction, controlled temperature is no more than 30 ℃, slowly adds the chloroformic solution of dissolving bromine; Add 20-30 ℃ and stir 2-3h; Slowly be warming up to 60-65 ℃, stir, insulation 0.5-1h.
2. the improvement compound method of a kind of 4-bromomethyl quinoline-2 according to claim 1 (H) ketone; It is characterized in that: also be included in the described ring-closure reaction; Vitriol oil frozen cooling to 5-10 ℃, is added the bromo alpha.-acetylacetanilide in batches, keep charge temperature to be lower than 20 ℃; Be warming up to 25 ℃-30 ℃ after adding, insulation reaction 2-3h.
3. the improvement compound method of a kind of 4-bromomethyl quinoline-2 according to claim 1 (H) ketone is characterized in that: in the described bromination reaction, and alpha.-acetylacetanilide (kg): bromine (kg): chloroform (L)=1: 1: 3-4.
4. the improvement compound method of a kind of 4-bromomethyl quinoline-2 according to claim 1 and 2 (H) ketone is characterized in that: in the described ring-closure reaction, the mass ratio of the control bromination acetyl bromide phenyl methyl ketone and the vitriol oil is 1: 4-5.
5. the improvement compound method of a kind of 4-bromomethyl quinoline-2 according to claim 1 (H) ketone; It is characterized in that: after described bromination reaction comprises that also insulation reaction finishes; Be cooled to 0-5 ℃, oven dry, bromination bullion product gets the acetyl bromide phenyl methyl ketone with 95% ethyl alcohol recrystallization.
6. the improvement compound method of a kind of 4-bromomethyl quinoline-2 according to claim 5 (H) ketone; It is characterized in that: described bromination bullion product is with in 95% ethyl alcohol recrystallization, and bromination bullion product and 95% alcoholic acid ratio are: acetobromanilide (kg): 95% ethanol (L)=1: 4-5.
7. the improvement compound method of a kind of 4-bromomethyl quinoline-2 according to claim 1 (H) ketone; It is characterized in that: described ring-closure reaction also comprises in the frozen water that the reaction solution suction is prepared in advance, keeps temperature to be no more than 40 ℃, stirs 1-1.5h; Centrifugal; Product after centrifugal is washed PH=6-7 with weak caustic solution, oven dry, cyclization bullion product gets 4-bromomethyl quinoline-2 (H) ketone with ethyl alcohol recrystallization.
8. the improvement compound method of a kind of 4-bromomethyl quinoline-2 according to claim 9 (H) ketone is characterized in that: described weak caustic solution is a yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, in the triethylamine a kind of.
9. the improvement compound method of a kind of 4-bromomethyl quinoline-2 according to claim 8 (H) ketone; It is characterized in that: described cyclization bullion product is with in the ethyl alcohol recrystallization, and the cyclization bullion produces with the alcoholic acid ratio and is: acetobromanilide (kg): ethanol (L)=1: 9-10.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103923003A (en) * | 2014-05-04 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Preparation method of 4-bromomethylquinoline-2(H)-ketone |
| CN112321444A (en) * | 2020-09-17 | 2021-02-05 | 江西邦浦医药化工有限公司 | Synthesis method of 4-bromo-3-oxo-N-phenylbutanamide |
| CN114907260A (en) * | 2022-05-27 | 2022-08-16 | 河南省科学院高新技术研究中心 | Method for preparing 4-bromomethylquinolinone by using ionic liquid |
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| CN101460223A (en) * | 2006-02-24 | 2009-06-17 | 凯利普西斯公司 | Quinolones useful as inducible nitric oxide synthase inhibitors |
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| CN101460223A (en) * | 2006-02-24 | 2009-06-17 | 凯利普西斯公司 | Quinolones useful as inducible nitric oxide synthase inhibitors |
Non-Patent Citations (1)
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| 杨艺虹等: "4-溴甲基-2(H)-喹啉酮的合成研究", 《精细化工中间体》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923003A (en) * | 2014-05-04 | 2014-07-16 | 苏州天马精细化学品股份有限公司 | Preparation method of 4-bromomethylquinoline-2(H)-ketone |
| CN112321444A (en) * | 2020-09-17 | 2021-02-05 | 江西邦浦医药化工有限公司 | Synthesis method of 4-bromo-3-oxo-N-phenylbutanamide |
| CN114907260A (en) * | 2022-05-27 | 2022-08-16 | 河南省科学院高新技术研究中心 | Method for preparing 4-bromomethylquinolinone by using ionic liquid |
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Application publication date: 20121114 |