CN102718718B - Preparation method for 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid - Google Patents
Preparation method for 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid Download PDFInfo
- Publication number
- CN102718718B CN102718718B CN201210174101.1A CN201210174101A CN102718718B CN 102718718 B CN102718718 B CN 102718718B CN 201210174101 A CN201210174101 A CN 201210174101A CN 102718718 B CN102718718 B CN 102718718B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- bromo
- bis
- methyl acetate
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention discloses a preparation method for 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid and belongs to the technical field of chemical synthesis. The preparation method for the 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid comprises the following steps: performing substitution reaction on raw materials (including p-nitrofluorobene and p-hydroxyl methyl phenylacetate) to obtain 2-(4-(4-nitrophenoxyl)phenyl)methyl acetate; brominating the 2-(4-(4-nitrophenoxyl)phenyl)methyl acetate to obtain 2-(3,5-dibromo-4-(4-nitrophenoxyl)phenyl)methyl acetate; reducing to obtain 2-(3,5-dibromo-4-(4-aminophenoxyl)phenyl)methyl acetate; performing amino protection and nitration on the 2-(3,5-dibromo-4-(4-aminophenoxyl)phenyl)methyl acetate to obtain 2-(3,5-dibromo-4-(4-((methoxycarbonyl)amino)-3-nitrophenoxyl)phenyl)methyl acetate; esterifying and reducing to obtain 2-(3,5-dibromo-4-(3,4-aminophenoxyl)phenyl)methyl acetate; and performing ring formation and hydrolysis to obtain the 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid. The preparation method for the 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid has the advantages of simple and readily available raw materials and high yield.
Description
Technical field:
The present invention relates to a kind of 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) preparation method of toluylic acid, belong to chemosynthesis technical field.
Background technology:
The bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) toluylic acid compounds is a kind of novel thryoid receptor aglucon, and it can be used for the treatment of arrhythmia, thyrotoxicosis, subclinical hyperthyroidism and hepatic diseases.Patent WO2007128492A1, WO2009080835A1, CN99815057.6 has reported that this compounds is in the effect in treatment relative disease as a kind of novel thryoid receptor compound.
Synthetic 3 of document WO02062780A2 report, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) method of toluylic acid is with 3, the bromo-4-(4-methoxyphenoxy of 5-bis-) methyl phenylacetate is raw material, by nitrated, amino replacement, the reactions such as Cheng Huan obtain target product, and this reaction scheme is with the starting raw material of complex and expensive comparatively, and the total recovery of three-step reaction is 32%.
Above-mentioned situation based on prior art, applicant makes the present invention.
Summary of the invention:
The present invention aims to provide a kind of simple and easy to get and yield is high 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base by raw material) preparation method of toluylic acid.
The technical scheme that the present invention takes is as follows:
A kind of 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) preparation method of toluylic acid, it is characterized in that, comprise the following steps: take to fluoronitrobenzene and p-hydroxyphenylaceticacid methyl esters is raw material, be substituted reaction and obtain 2-(4-(4-nitrophenoxy) phenyl) methyl acetate, 2-(4-(4-nitrophenoxy) phenyl) methyl acetate obtains 2-(3 through bromo, the bromo-4-of 5-bis-(4-nitrophenoxy) phenyl) methyl acetate, and then obtain 2-(3 through reduction, the bromo-4-of 5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate), 2-(3, the bromo-4-of 5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate) through amido protecting, the nitrated 2-(3 that obtains, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate, through esterification reduction, obtain 2-(3 again, the bromo-4-(3 of 5-bis-, 4-amino-benzene oxygen) phenyl) methyl acetate, then become cyclizing hydrolysis to obtain 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) toluylic acid.
Further arrange and be, comprise the following steps:
(1): compound 2 (2-(4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
Under the existence of salt of wormwood, to 70-80 ℃ of reaction 3-4 hour of fluoronitrobenzene and p-hydroxyphenylaceticacid methyl esters, hydroxyl phenylacetic acid methyl esters and to the amount of substance of fluoronitrobenzene than being 1:1.2-1.5; Amount of substance ratio to fluoronitrobenzene and salt of wormwood is 1:1.5-3, obtains compound 2 alcohol solvent recrystallization;
(2): compound 3 (2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
The compound of preparation 2 and bromine are reacted and obtain compound 3, and the amount of substance ratio of compound 2 and bromine is: 1:8-12, methylene dichloride or chloroform extraction for reaction product;
(3): compound 4 (2-(the bromo-4-of 3,5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
Compound 3 and iron powder are reacted at room temperature and prepare compound 4; The amount of substance ratio of compound 3 and iron powder is 1:4-9;
(4): compound 5 (2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate) synthetic;
Compound 4 and methyl-chloroformate, pyridine reaction are prepared to compound 5, and the amount of substance ratio of compound 4 and methyl-chloroformate is 1:1.2-1.6, and the amount of substance ratio of compound 4 and pyridine is 1:1.5-3;
(5): compound 6 (2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate) synthetic;
The compound 5 of slurry preparation reacts with nitrosonitric acid prepares compound 6, and the amount of substance ratio of compound 5 and nitrosonitric acid is 1:9-12, and 3-5 hour is at room temperature carried out in reaction;
(6): compound 7 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetic acid) synthetic;
The compound of preparation 6 is under reflux conditions hydrolyzed and reacts to obtain compound 7, and temperature of reaction is controlled between 60-90 ℃;
(7): compound 8 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate) synthetic;
Compound 7 and methyl alcohol are reacted under the existence of hydrochloric acid, prepare compound 8, the amount of substance ratio of compound 7 and hydrochloric acid is 1:10-18;
(8): compound 9 (2-(the bromo-4-of 3,5-bis-(3,4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
Compound 8 is reacted with iron powder and prepares compound 9, and the amount of substance ratio of compound 8 and iron powder is 1:4-10, and reaction is carried out in 80～95 ℃, and the reaction times is 6-10 hour;
(9): compound 10 (the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) methyl phenylacetate) synthetic;
By the compound 9 of preparation, in excessive formic acid, back flow reaction 1-3 hour, prepares compound 10;
(10): compound 11 (the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) toluylic acid) synthetic;
Compound 10 and lithium hydroxide are reacted, prepare compound 11, the amount of substance ratio of compound 10 and lithium hydroxide is 1:9-15, reacts for room temperature reaction 10-15 hour.
Further arrange and be, comprise the following steps:
(1): compound 2 (2-(4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
By 40g, 0.28 mol fluoronitrobenzene is dissolved in the DMF of 200ml, then at room temperature add the p-hydroxyphenylaceticacid methyl esters of 38 g, 0.23mol and the salt of wormwood of 90g; Then reaction solution is heated to 75 ℃ and stir 3 hours; Be cooled to room temperature, filtrate imports in the frozen water of 1.2 L, by solid filtering out, and dry obtains crude product, with ethyl alcohol recrystallization, obtains yellow solid 60 g compounds 2;
(2): compound 3 (2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
The 60g compound 2 of step 1 preparation is dissolved in hot 200ml chloroform, adds 8g FeBr
2, then 110 ml bromines and 200 ml chloroformic solutions slowly being joined in solution, backflow is spent the night; Cooling rear reaction solution imports to saturated NaHSO
3in the aqueous solution, then use dichloromethane extraction, extraction liquid water and saturated common salt water washing, and with anhydrous sodium sulfate drying, obtain the compound 3 of 40g white after concentrated, and product is not purified, is directly used in next step reaction;
(3): compound 4 (2-(the bromo-4-of 3,5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
The 40g compound 3 of getting step 2 preparation is dissolved in the acetic acid of 500ml and the water of 60ml, then adds 25g iron powder, under room temperature, reacts 3h; Then reaction solution is poured in the frozen water of 3L and is extracted with ethyl acetate, through filtering and concentrating, obtain 38g compound 4, product is not purified, is directly used in next step reaction;
(4): compound 5 (2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate) synthetic;
The 38g compound 4 of step 3 preparation is dissolved in 200 ml methylene dichloride, add again 15g pyridine, the methyl-chloroformate of 12g is dissolved in the methylene dichloride of 50ml, then at 0 ℃, be added drop-wise in reaction solution, room temperature reaction, after 2 hours, is poured into reaction solution in frozen water, then use dichloromethane extraction, filter and be dried and concentrated obtain compound 5, product is not purified, is directly used in next step reaction;
(5): compound 6 (2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate) synthetic;
The compound 5 of the 40g of step 4 preparation is dissolved in the acetic acid of 1800 ml, then drips the nitrosonitric acid of 38ml, room temperature reaction is after 3 hours, reaction solution is poured in the frozen water of 4L, filtration obtains the compound 6 of 44g, and product is not purified, is directly used in next step reaction;
(6): compound 7 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetic acid) synthetic;
By step 5 preparation 44g compound 6 be dissolved in the methyl alcohol of 2.5L, then the NaOH aqueous solution that adds the massfraction 15% of 850ml, after back flow reaction 3 hours, be cooled to room temperature, with dilute hydrochloric acid, neutralize, then be extracted with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, the concentrated 38g compound 7 that obtains, product is not purified, is directly used in next step reaction;
(7): compound 8 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate) synthetic;
The 38g compound 7 obtaining of step 6 preparation is dissolved in the methyl alcohol of 2.5 L, then adds 35 ml concentrated hydrochloric acids, back flow reaction 3 hours, is cooled to room temperature, filters and obtains yellow solid product 24g compound 8, and product is not purified, is directly used in next step reaction;
(8): compound 9 (2-(the bromo-4-of 3,5-bis-(3,4-amino-benzene oxygen) phenyl) methyl acetate) synthetic.
By obtaining in acetic acid that 24g compound 8 is dissolved in 1000ml of step 7 preparation, then add 15g iron powder, at 90～95 ℃, react 7 hours, underpressure distillation recovery of acetic acid, residuum is poured in frozen water, is extracted with ethyl acetate product, the dry concentrated 23g compound 9 that obtains, product is not purified, is directly used in next step reaction;
(9): compound 10 (the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) methyl phenylacetate) synthetic;
By step 8 preparation 23g compound 9 crude products be dissolved in the formic acid of 300ml, refluxes 2 hours, then except desolventizing, then residuum is soluble in water, be extracted with ethyl acetate, concentrate, obtain 23g white solid compound 10;
(10): compound 11 (the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) toluylic acid) synthetic;
The 23g compound 10 of step 9 preparation is dissolved in the tetrahydrofuran (THF) of 200ml, then add 22g lithium hydroxide aqueous solution, room temperature reaction spends the night, except desolventizing, with the hydrochloric acid of 2N, regulate pH=2, filtration obtains yellow solid, then this thick product recrystallization in ethanol is obtained to 20g white solid compound 11.
The chemical equation the present invention relates to is as follows:
Beneficial effect of the present invention is as follows:
It is raw material that the present invention be take to fluoronitrobenzene and p-hydroxyphenylaceticacid methyl esters, by 10 step reaction preparations 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) toluylic acid, syntheti c route of the present invention, selected reagent is all raw material simple and easy to get, and the productive rate of every step reaction is all higher, most of intermediate product is without carrying out purification operations, can directly carry out next step reaction, from nitration reaction, start the synthetic final product 11 that obtains, although through 6 step reactions, but total recovery can reach 55% left and right, the total recovery of whole 11 step reactions has also reached 20%, and this route also can obtain multiple useful reaction intermediate.
Below in conjunction with the drawings and specific embodiments, the invention will be further described.
Accompanying drawing explanation:
Fig. 1 be product 11 of the present invention (
1h NMR, 400M, solvent MeOD) nuclear magnetic resonance map.
Embodiment:
Embodiment 1: compound 2 (2-(4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic.
1 pair of fluoronitrobenzene of the compound of 40g, 0.28 mol is dissolved in the DMF of 200ml, then at room temperature adds the p-hydroxyphenylaceticacid methyl esters of 38 g, 0.23mol and the salt of wormwood of 90g.Then reaction solution is heated to 75 ℃ and stir 3 hours.Be cooled to room temperature, filtrate imports in the frozen water of 1.2 L, by solid filtering out, and dry obtains crude product, with ethyl alcohol recrystallization, obtains yellow solid 60 g(2), productive rate 91%.
Embodiment 2: compound 3 (2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate) synthetic.
60g compound 2 is dissolved in hot 200ml chloroform, adds 8g FeBr
2, then 110 ml bromines and 200 ml chloroformic solutions slowly being joined in solution, backflow is spent the night.Cooling rear reaction solution imports to saturated NaHSO
3in the aqueous solution, then use dichloromethane extraction, extraction liquid water and saturated common salt water washing, and with anhydrous sodium sulfate drying, obtain the compound (3) of 40g white after concentrated, and product is not further purified, and is directly used in next step reaction.
Embodiment 3: compound 4 (2-(the bromo-4-of 3,5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate) synthetic.
Get the 40 g crude products 3 that embodiment 2 obtains and be dissolved in the acetic acid of 500ml and the water of 60ml, then add 25g iron powder, under room temperature, react 3h.Then reaction solution is poured in the frozen water of 3L and is extracted with ethyl acetate, through filtering and concentrating, obtain 38g compound (4), be directly used in next step reaction.
Embodiment 4: compound 5 (2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate) synthetic.
38g compound 4 is dissolved in 200 ml methylene dichloride, add again 15g pyridine, the methyl-chloroformate of 12g is dissolved in the methylene dichloride of 50ml, then at 0 ℃, be added drop-wise in reaction solution, room temperature reaction, after 2 hours, is poured into reaction solution in frozen water, then use dichloromethane extraction, filter and be dried and concentrated obtain compound (5), this product is not purified, is directly used in next step reaction.
Embodiment 5: compound 6 (2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate) synthetic.
The compound of 40g 5 is dissolved in the acetic acid of 1800 ml, then drips the nitrosonitric acid of 38ml, room temperature reaction is after 3 hours, and reaction solution is poured in the frozen water of 4L, filters the compound (6) that obtains 44g, and product is not purified, is directly used in next step reaction.
Embodiment 6: compound 7 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetic acid) synthetic.
The 44g compound 6 that embodiment 5 is obtained is dissolved in the methyl alcohol of 2.5L, then the NaOH aqueous solution that adds the massfraction 15% of 850ml, after back flow reaction 3 hours, be cooled to room temperature, with dilute hydrochloric acid, neutralize, then be extracted with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, the concentrated 38g compound (7) that obtains, product is not purified, is directly used in next step reaction.
Embodiment 7: compound 8 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate) synthetic.
The 38g compound 7 that embodiment 6 is obtained is dissolved in the methyl alcohol of 2.5 L, then adds 35 ml concentrated hydrochloric acids, and back flow reaction 3 hours, is cooled to room temperature, filters and obtains yellow solid product 24g compound (8), and productive rate is 60%.Product is not purified, is directly used in next step reaction.
Embodiment 8: compound 9 (2-(the bromo-4-of 3,5-bis-(3,4-amino-benzene oxygen) phenyl) methyl acetate) synthetic.
Embodiment 7 is obtained in acetic acid that 24g compound 8 is dissolved in 1000ml, then add 15g iron powder, at 90～95 ℃, react 7 hours, underpressure distillation recovery of acetic acid, residuum is poured in frozen water, is extracted with ethyl acetate product, the dry concentrated 23g compound (9) that obtains, product is not purified, is directly used in next step reaction.
Embodiment 9: compound 10 (the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) methyl phenylacetate) synthetic.
23g compound 9 crude products that embodiment 8 is obtained are dissolved in the formic acid of 300ml, reflux 2 hours, and then except desolventizing, then residuum is soluble in water, be extracted with ethyl acetate, concentrated, obtain 23g white solid compound 10.
Embodiment 10: compound 11 (the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) toluylic acid) synthetic.
23g compound 10 is dissolved in the tetrahydrofuran (THF) of 200ml, then add 22g lithium hydroxide aqueous solution, room temperature reaction spends the night, except desolventizing, with the hydrochloric acid of 2N, regulate pH=2, filter and obtain yellow solid, then this thick product recrystallization in ethanol is obtained to white solid product, 20g compound 11, productive rate 90%.
1H?NMR(MeOD,?400M)?
δ?3.79?(s,?2H),?7.18?(d,?2H,?
J?=?6.8?Hz),?7.27?(s,?1H),?7.72?(s,?1H),?7.77?(d,?1H,?
J?=?8.8?Hz),?8.80?(s,?1H)。
Claims (2)
1. one kind 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) preparation method of toluylic acid, is characterized in that, comprises the following steps:
(1): 2-(4-(4-nitrophenoxy) phenyl) methyl acetate synthetic;
Under the existence of salt of wormwood, to 70-80 ℃ of reaction 3-4 hour of fluoronitrobenzene and p-hydroxyphenylaceticacid methyl esters, p-hydroxyphenylaceticacid methyl esters and to the amount of substance of fluoronitrobenzene than being 1:1.2-1.5; Amount of substance ratio to fluoronitrobenzene and salt of wormwood is 1:1.5-3, obtains 2-(4-(4-nitrophenoxy) phenyl) methyl acetate alcohol solvent recrystallization;
(2): 2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate synthetic;
2-(4-(4-nitrophenoxy) phenyl) methyl acetate of preparation and bromine are reacted and obtain 2-(3, the bromo-4-of 5-bis-(4-nitrophenoxy) phenyl) methyl acetate, the amount of substance ratio of 2-(4-(4-nitrophenoxy) phenyl) methyl acetate and bromine is 1:8-12, methylene dichloride or chloroform extraction for reaction product;
(3): 2-(the bromo-4-of 3,5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate synthetic;
2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate and iron powder are reacted to preparation 2-(the bromo-4-of 3,5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate at room temperature; The amount of substance ratio of 2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate and iron powder is 1:4-9;
(4): 2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate synthetic;
By 2-(3, the bromo-4-of 5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate and methyl-chloroformate, pyridine reaction preparation 2-(3, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate, 2-(3, the bromo-4-of 5-bis-(4-amino-benzene oxygen) phenyl) the amount of substance ratio of methyl acetate and methyl-chloroformate is 1:1.2-1.6, the amount of substance ratio of 2-(the bromo-4-of 3,5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate and pyridine is 1:1.5-3;
(5): 2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate synthetic;
By the 2-(3 of preparation, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate reacts preparation 2-(3 with nitrosonitric acid, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate, 2-(3, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) the amount of substance ratio of methyl acetate and nitrosonitric acid is 1:9-12, and 3-5 hour is at room temperature carried out in reaction;
(6): 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetic acid synthetic;
By the 2-(3 of preparation, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate is under reflux conditions hydrolyzed and reacts to obtain 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetic acid, temperature of reaction is controlled between 60-90 ℃;
(7): 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate synthetic;
By 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetic acid and methyl alcohol react under the existence of hydrochloric acid, preparation 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate, the amount of substance ratio of 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetic acid and hydrochloric acid is 1:10-18;
(8): 2-(the bromo-4-of 3,5-bis-(3,4-diamino phenoxy) phenyl) methyl acetate synthetic;
By 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate reacts preparation 2-(3 with iron powder, the bromo-4-(3 of 5-bis-, 4-diamino phenoxy) phenyl) methyl acetate, 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) amount of substance of methyl acetate and iron powder ratio is 1:4-10, and reaction is carried out in 80～95 ℃, and the reaction times is 6-10 hour;
(9): the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) methyl phenylacetate is synthetic;
By 2-(the bromo-4-of 3,5-bis-(3, the 4-diamino phenoxy) phenyl) methyl acetate of preparation, in excessive formic acid, back flow reaction 1-3 hour, prepares the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) methyl phenylacetate;
(10): the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) toluylic acid is synthetic;
By 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) methyl phenylacetate and lithium hydroxide react, preparation 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) toluylic acid, 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) the amount of substance ratio of methyl phenylacetate and lithium hydroxide is 1:9-15, reacts for room temperature reaction 10-15 hour.
2. according to one kind 3 of claim 1, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) preparation method of toluylic acid, is characterized in that, comprises the following steps:
(1): 2-(4-(4-nitrophenoxy) phenyl) methyl acetate synthetic;
By 40g, 0.28 mol fluoronitrobenzene is dissolved in the DMF of 200ml, then at room temperature add the p-hydroxyphenylaceticacid methyl esters of 38 g, 0.23mol and the salt of wormwood of 90g; Then reaction solution is heated to 75 ℃ and stir 3 hours; Be cooled to room temperature, filtrate imports in the frozen water of 1.2 L, by solid filtering out, and dry obtains crude product, with ethyl alcohol recrystallization, obtains yellow solid 60 g 2-(4-(4-nitrophenoxy) phenyl) methyl acetate;
(2): 2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate synthetic;
60g 2-(4-(4-nitrophenoxy) phenyl) methyl acetate of step 1 preparation is dissolved in hot 200ml chloroform, adds 8g FeBr
2, then 110 ml bromines and 200 ml chloroformic solutions slowly being joined in solution, backflow is spent the night; Cooling rear reaction solution imports to saturated NaHSO
3in the aqueous solution, then use dichloromethane extraction, extraction liquid water and saturated common salt water washing, and with anhydrous sodium sulfate drying, obtain 2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate of 40g white after concentrated, product is not purified, is directly used in next step reaction;
(3): 2-(the bromo-4-of 3,5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate synthetic;
40g 2-(the bromo-4-of 3,5-bis-(4-nitrophenoxy) phenyl) methyl acetate of getting step 2 preparation is dissolved in the acetic acid of 500ml and the water of 60ml, then adds 25g iron powder, under room temperature, reacts 3h; Then reaction solution is poured in the frozen water of 3L and is extracted with ethyl acetate, through filtering and concentrating, obtain 38g 2-(the bromo-4-of 3,5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate, product is not purified, is directly used in next step reaction;
(4): 2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate synthetic;
By the 38g 2-(3 of step 3 preparation, the bromo-4-of 5-bis-(4-amino-benzene oxygen) phenyl) methyl acetate is dissolved in 200 ml methylene dichloride, add again 15g pyridine, the methyl-chloroformate of 12g is dissolved in the methylene dichloride of 50ml, then at 0 ℃, be added drop-wise in reaction solution, after room temperature reaction 2 hours, reaction solution is poured in frozen water, then use dichloromethane extraction, filter and be dried the concentrated 2-(3 that obtains, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate, product is not purified, is directly used in next step reaction;
(5): 2-(the bromo-4-of 3,5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate synthetic;
By the 40g 2-(3 of step 4 preparation, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino) phenoxy group) phenyl) methyl acetate is dissolved in the acetic acid of 1800 ml, then drip the nitrosonitric acid of 38ml, after room temperature reaction 3 hours, reaction solution is poured in the frozen water of 4L, filtration obtains the 2-(3 of 44g, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate, product is not purified, is directly used in next step reaction;
(6): 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetic acid synthetic;
By the 44g 2-(3 of step 5 preparation, the bromo-4-of 5-bis-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate is dissolved in the methyl alcohol of 2.5L, then the NaOH aqueous solution that adds the massfraction 15% of 850ml, after back flow reaction 3 hours, be cooled to room temperature, with dilute hydrochloric acid, neutralize, then be extracted with ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated 2-(4-(4-amino-3-nitro-phenoxy)-3, the 5-dibromo phenyl) acetic acid that obtains 38g, product is not purified, is directly used in next step reaction;
(7): 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate synthetic;
By the 38g 2-(4-(4-amino-3-nitro-phenoxy)-3 of step 6 preparation, 5-dibromo phenyl) acetic acid is dissolved in the methyl alcohol of 2.5 L, then add 35 ml concentrated hydrochloric acids, back flow reaction 3 hours, be cooled to room temperature, filter 2-(4-(4-amino-3-nitro-phenoxy)-3, the 5-dibromo phenyl) methyl acetate that obtains yellow solid product 24g, product is not purified, is directly used in next step reaction;
(8): 2-(the bromo-4-of 3,5-bis-(3,4-diamino phenoxy) phenyl) methyl acetate synthetic;
Step 7 preparation obtained to 24g 2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate is dissolved in the acetic acid of 1000ml, then adds 15g iron powder, reacts 7 hours at 90～95 ℃, underpressure distillation recovery of acetic acid, residuum is poured in frozen water, is extracted with ethyl acetate product, the dry concentrated 23g 2-(3 that obtains, the bromo-4-(3 of 5-bis-, 4-diamino phenoxy) phenyl) methyl acetate, product is not purified, is directly used in next step reaction;
(9): the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) methyl phenylacetate is synthetic;
By the 23g 2-(3 of step 8 preparation, the bromo-4-(3 of 5-bis-, 4-diamino phenoxy) phenyl) methyl acetate crude product is dissolved in the formic acid of 300ml, reflux 2 hours, then except desolventizing, then residuum is soluble in water, be extracted with ethyl acetate, concentrated, obtain 23g white solid 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) methyl phenylacetate;
(10): the bromo-4-(5-benzoglyoxaline of 3,5-bis-oxygen base) toluylic acid is synthetic;
By the 23g 3 of step 9 preparation, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) methyl phenylacetate is dissolved in the tetrahydrofuran (THF) of 200ml, then add 22g lithium hydroxide aqueous solution, room temperature reaction spends the night, except desolventizing, with the hydrochloric acid of 2N, regulate pH=2, filter and obtain yellow solid, then this thick product recrystallization in ethanol is obtained to 20g white solid 3, the bromo-4-(5-benzoglyoxaline of 5-bis-oxygen base) toluylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210174101.1A CN102718718B (en) | 2012-05-31 | 2012-05-31 | Preparation method for 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210174101.1A CN102718718B (en) | 2012-05-31 | 2012-05-31 | Preparation method for 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102718718A CN102718718A (en) | 2012-10-10 |
| CN102718718B true CN102718718B (en) | 2014-09-24 |
Family
ID=46944619
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210174101.1A Expired - Fee Related CN102718718B (en) | 2012-05-31 | 2012-05-31 | Preparation method for 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102718718B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9828442D0 (en) * | 1998-12-24 | 1999-02-17 | Karobio Ab | Novel thyroid receptor ligands and method II |
| US7144909B2 (en) * | 2001-02-08 | 2006-12-05 | Karo Bio Ab | Phenoxy substituted benzocondensed heteroaryl derivatives as thyroid receptor ligands |
| GB0608724D0 (en) * | 2006-05-03 | 2006-06-14 | Karobio Ab | Novel Pharmaceutical Compositions |
-
2012
- 2012-05-31 CN CN201210174101.1A patent/CN102718718B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102718718A (en) | 2012-10-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103570633B (en) | The preparation method of Gefitinib | |
| CN104860872A (en) | Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method | |
| CN105646285B (en) | One kind dimension Lactel sieve intermediate and its preparation method and application | |
| CN102417486B (en) | Method for synthesizing valsartan | |
| WO2023174449A1 (en) | Method for preparing n-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide | |
| CN102304090A (en) | Method for preparing 5-substituted thiophenyl-benzimidazol-2-N-methoxycarbonyl compound | |
| CN103214421B (en) | The industrialized preparing process of 2-sulfydryl-1-Methylimidazole | |
| CN103319366B (en) | Lacosamide synthesis technology | |
| CN102718718B (en) | Preparation method for 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid | |
| CN102030707A (en) | Method for preparing Blonanserin intermediate | |
| CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
| CN102690211B (en) | The preparation method of tolvaptan intermediate | |
| CN104974057A (en) | Preparation method and important intermediate of bromfenac sodium | |
| CN102964225A (en) | Preparation method of 2, 3-dichloroanisole | |
| CN102276522A (en) | Method for preparing roflumilast and intermediate of roflumilast | |
| CN105198838A (en) | Preparation method of repaglinide | |
| CN104276979B (en) | The preparation method of agomelatine intermediate body | |
| CN103044356A (en) | New method for synthesizing levocetirizine and key intermediate thereof | |
| CN102976958A (en) | Preparation method of 4-methoxy-beta-phenylethylamine | |
| CN106748725B (en) | preparation method of 4-chloro-2-fluoro-phenylpropionic acid | |
| CN104211652A (en) | Method for preparing plerixafor | |
| CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate | |
| CN103288806A (en) | Synthesis method of troxacitabine | |
| CN100546973C (en) | The preparation method of 3-(N-methyl-N-penta amino) propionic salt hydrochlorate | |
| CN105777582B (en) | A kind of method for preparing cancer therapy drug Vorinostat |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140924 Termination date: 20170531 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |