CN102718718A - 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
- CN102718718A CN102718718A CN2012101741011A CN201210174101A CN102718718A CN 102718718 A CN102718718 A CN 102718718A CN 2012101741011 A CN2012101741011 A CN 2012101741011A CN 201210174101 A CN201210174101 A CN 201210174101A CN 102718718 A CN102718718 A CN 102718718A
- Authority
- CN
- China
- Prior art keywords
- compound
- phenyl
- bromo
- reaction
- synthetic
- 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.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 ofly 3, the preparation method of 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid belongs to chemosynthesis technical field.
Background technology:
3,5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid compounds is a kind of novel thryoid receptor aglucon, and it can be used to treat arrhythmia, thyrotoxicosis, subclinical hyperthyroidism and hepatic diseases.Patent WO2007128492A1, WO2009080835A1, CN99815057.6 have reported that this compounds is as a kind of novel effect of thryoid receptor compound in the treatment relative disease.
Synthetic 3 of document WO 02062780A2 report; The method of 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid is with 3, and 5-two bromo-4-(4-methoxyl group phenoxy) methyl phenylacetate is a raw material, through nitrated; The amino replacement; Reactions such as Cheng Huan obtain title 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%.
Based on the above-mentioned situation of prior art, the applicant makes the present invention.
Summary of the invention:
The present invention aim to provide a kind of through raw material be simple and easy to and yield high 3, the preparation method of 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid.
The technical scheme that the present invention takes is following:
A kind of 3, the preparation method of 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid is characterized in that; May further comprise the steps: to be raw material to nitro fluorobenzene and p-hydroxyphenylaceticacid methyl esters, obtain 2-(4-(4-nitrophenoxy) phenyl) methyl acetate through substitution reaction, 2-(4-(4-nitrophenoxy) phenyl) methyl acetate obtains 2-(3 through bromo; 5-two bromo-4-(4-nitrophenoxy) phenyl) methyl acetate, and then the warp reduction obtains 2-(3,5-two bromo-4-(4-amino-benzene oxygen) phenyl) methyl acetate); 2-(3; 5-two bromo-4-(4-amino-benzene oxygen) phenyl), obtains 2-(3 through the esterification reduction again methyl acetate) through amido protecting, nitrated 2-(3,5-two bromo-4-(4-((methoxycarbonyl) the amino)-3-nitro-phenoxy) phenyl) methyl acetate that obtains; 5-two bromo-4-(3; The 4-amino-benzene oxygen) methyl acetate phenyl) becomes cyclizing hydrolysis to obtain 3 then, 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid.
Further setting is, may further comprise the steps:
(1): compound 2 (2-(4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
In the presence of salt of wormwood, to 70-80 ℃ of reaction of nitro fluorobenzene and p-hydroxyphenylaceticacid methyl esters 3-4 hour, the hydroxyl phenylacetic acid methyl esters and to the amount of substance of nitro fluorobenzene than being 1:1.2-1.5; Amount of substance ratio to nitro fluorobenzene and salt of wormwood is 1:1.5-3, obtains compound 2 and uses the alcohol solvent recrystallization;
(2): compound 3 (2-(3,5-two bromo-4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
The compound 2 of preparation reacted with bromine obtain compound 3, the amount of substance ratio of compound 2 and bromine is: 1:8-12, and reaction product is with methylene dichloride or chloroform extraction;
(3): compound 4 (2-(3,5-two bromo-4-(4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
Compound 3 and iron powder are carried out prepared in reaction compound 4 at room temperature; The amount of substance ratio of compound 3 and iron powder is 1:4-9;
(4): compound 5 (2-(3,5-two bromo-4-(4-((methoxycarbonyl) amino) phenoxy) phenyl) methyl acetate) synthetic;
With compound 4 and methyl-chloroformate, pyridine prepared in reaction compound 5, 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-(3,5-two bromo-4-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate) synthetic;
The compound 5 and nitrosonitric acid prepared in reaction compound 6 of slurry preparation, the amount of substance ratio of compound 5 and nitrosonitric acid is 1:9-12, reaction was at room temperature carried out 3-5 hour;
(6): compound 7 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetate) synthetic;
With the preparation compound 6 under refluxad be hydrolyzed react compound 7, 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 in the presence of hydrochloric acid, preparation compound 8, the amount of substance ratio of compound 7 and hydrochloric acid is 1:10-18;
(8): compound 9 (2-(3,5-two bromo-4-(3, the 4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
Compound 8 and iron powder are carried out prepared in reaction compound 9, and the amount of substance ratio of compound 8 and iron powder is 1:4-10, is reflected in 80～95 ℃ and carries out, and the reaction times is 6-10 hour;
(9): compound 10 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) methyl phenylacetate) synthetic;
The compound 9 for preparing in excessive formic acid, back flow reaction 1-3 hour, is prepared compound 10;
(10): compound 11 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid) synthetic;
Compound 10 and Lithium Hydroxide MonoHydrate are reacted, preparation compound 11, the amount of substance ratio of compound 10 and Lithium Hydroxide MonoHydrate is 1:9-15, reacts to be room temperature reaction 10-15 hour.
Further setting is, may further comprise the steps:
(1): compound 2 (2-(4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
With 40g, 0.28 mol the nitro fluorobenzene is dissolved among the DMF of 200ml, at room temperature add the p-hydroxyphenylaceticacid methyl esters of 38 g, 0.23mol and the salt of wormwood of 90g then; Then reaction solution is heated to 75 ℃ and stirred 3 hours; Be cooled to room temperature, filtrating imports in the frozen water of 1.2 L, solid filtering is come out, and drying obtains crude product, obtains yellow solid 60 g compounds 2 with ethyl alcohol recrystallization;
(2): compound 3 (2-(3,5-two bromo-4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
The 60g compound 2 of step 1 preparation is dissolved in the 200ml chloroform of heat, adds 8g FeBr
2, then 110 ml bromines and 200 ml chloroformic solutions slowly being joined in the solution, backflow is spent the night; Cooling afterreaction liquid imports to saturated NaHSO
3In the aqueous solution, use dichloromethane extraction then, extraction liquid water and saturated common salt water washing, and use anhydrous sodium sulfate drying, and obtaining the compound 3 of 40g white after concentrating, product is not purified, directly is used for next step reaction;
(3): compound 4 (2-(3,5-two bromo-4-(4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
The 40g compound 3 of getting step 2 preparation is dissolved in the water of acetate and 60ml of 500ml, adds the 25g iron powder then, reacts 3h under the room temperature; Then reaction solution is poured in the frozen water of 3L and uses ethyl acetate extraction, obtain 38g compound 4 through filtering and concentrating, product is not purified, directly is used for next step reaction;
(4): compound 5 (2-(3,5-two bromo-4-(4-((methoxycarbonyl) amino) phenoxy) phenyl) methyl acetate) synthetic;
The 38g compound 4 of step 3 preparation is dissolved in the 200 ml methylene dichloride, adds the 15g pyridine again, the methyl-chloroformate of 12g is dissolved in the methylene dichloride of 50ml; Under 0 ℃, be added drop-wise in the reaction solution then, room temperature reaction was poured into reaction solution in the frozen water after 2 hours; Use dichloromethane extraction then; Filter also dry concentrating and obtain compound 5, product is not purified, directly is used for next step reaction;
(5): compound 6 (2-(3,5-two bromo-4-(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, drips the nitrosonitric acid of 38ml then, 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, directly is used for next step reaction;
(6): compound 7 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetate) synthetic;
With step 5 preparation 44g compound 6 be dissolved in the methyl alcohol of 2.5L, add the NaOH aqueous solution of the massfraction 15% of 850ml then, back flow reaction is after 3 hours; Be cooled to room temperature,, use ethyl acetate extraction then with the Hydrogen chloride neutralization; The saturated common salt water washing, anhydrous sodium sulfate drying concentrates and obtains 38g compound 7; Product is not purified, directly is used for next step reaction;
(7): compound 8 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate) synthetic;
The 38g compound 7 that obtains of step 6 preparation is dissolved in the methyl alcohol of 2.5 L, adds 35 ml concentrated hydrochloric acids then, back flow reaction 3 hours is cooled to room temperature, filters and obtains yellow solid product 24g compound 8, and product is not purified, directly is used for next step reaction;
(8): compound 9 (2-(3,5-two bromo-4-(3, the 4-amino-benzene oxygen) phenyl) methyl acetate) synthetic.
With step 7 preparation obtain add the 15g iron powder then in the acetate that 24g compound 8 is dissolved in 1000ml, 90～95 ℃ of reactions 7 hours down; Acetic acid is reclaimed in underpressure distillation; Residuum is poured in the frozen water, uses the ethyl acetate extraction product, dry concentrating obtains 23g compound 9; Product is not purified, directly is used for next step reaction;
(9): compound 10 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) methyl phenylacetate) synthetic;
With step 8 preparation 23g compound 9 crude products be dissolved in the formic acid of 300ml, refluxed 2 hours, remove then and desolvate, again that residuum is soluble in water, use ethyl acetate extraction, concentrated, obtain 23g white solid compound 10;
(10): compound 11 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid) synthetic;
The 23g compound 10 of step 9 preparation is dissolved in the THF of 200ml; Add the 22g lithium hydroxide aqueous solution then; Room temperature reaction spends the night, and removes and desolvates, and regulates pH=2 with the hydrochloric acid of 2N; Filtration obtains yellow solid, should obtain 20g white solid compound 11 by thick product recrystallization in ethanol then.
The reaction formula that the present invention relates to is following:
Beneficial effect of the present invention is following:
The present invention is to be raw material to nitro fluorobenzene and p-hydroxyphenylaceticacid methyl esters, through 10 step prepared in reaction 3,5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid; Preparation route of the present invention, the reagent of being selected for use all be simple and easy to raw material, and the productive rate of per step reaction is all higher; Most of intermediate product need not to carry out purification operations, can directly carry out next step reaction, begins the synthetic final product 11 that obtains from nitration reaction; Though through the reaction of 6 steps; But total recovery can reach about 55%, and the total recovery of whole 11 steps reactions has also reached 20%, and this route also can obtain multiple useful reaction intermediate.
Below in conjunction with accompanying drawing and embodiment the present invention is described further.
Description of drawings:
Fig. 1 for 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 nitro fluorobenzene of compound of 40g, 0.28 mol is dissolved among the DMF of 200ml, at room temperature adds the p-hydroxyphenylaceticacid methyl esters of 38 g, 0.23mol and the salt of wormwood of 90g then.Then reaction solution is heated to 75 ℃ and stirred 3 hours.Be cooled to room temperature, filtrating imports in the frozen water of 1.2 L, solid filtering is come out, and drying obtains crude product, obtains yellow solid 60 g (2), productive rate 91% with ethyl alcohol recrystallization.
Embodiment 2: compound 3 (2-(3,5-two bromo-4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic.
60g compound 2 is dissolved in the 200ml chloroform of heat, adds 8g FeBr
2, then 110 ml bromines and 200 ml chloroformic solutions slowly being joined in the solution, backflow is spent the night.Cooling afterreaction liquid imports to saturated NaHSO
3In the aqueous solution, use dichloromethane extraction then, extraction liquid water and saturated common salt water washing, and use anhydrous sodium sulfate drying, and obtaining the compound (3) of 40g white after concentrating, product is not further purified, and directly is used for next step reaction.
Embodiment 3: compound 4 (2-(3,5-two bromo-4-(4-amino-benzene oxygen) phenyl) methyl acetate) synthetic.
Get in the water of acetate and 60ml that 40 g crude products 3 that embodiment 2 obtains are dissolved in 500ml, add the 25g iron powder then, react 3h under the room temperature.Then reaction solution is poured in the frozen water of 3L and uses ethyl acetate extraction, obtain 38g compound (4), directly be used for next step reaction through filtering and concentrating.
Embodiment 4: compound 5 (2-(3,5-two bromo-4-(4-((methoxycarbonyl) amino) phenoxy) phenyl) methyl acetate) synthetic.
38g compound 4 is dissolved in the 200 ml methylene dichloride, adds the 15g pyridine again, the methyl-chloroformate of 12g is dissolved in the methylene dichloride of 50ml; Under 0 ℃, be added drop-wise in the reaction solution then, room temperature reaction was poured into reaction solution in the frozen water after 2 hours; Use dichloromethane extraction then; Filter also dry concentrating and obtain compound (5), this product is not purified, directly is used for next step reaction.
Embodiment 5: compound 6 (2-(3,5-two bromo-4-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate) synthetic.
The compound 5 of 40g is dissolved in the acetic acid of 1800 ml, drips the nitrosonitric acid of 38ml then, 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, directly is used for next step reaction.
Embodiment 6: compound 7 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetate) synthetic.
The 44g compound 6 that embodiment 5 is obtained is dissolved in the methyl alcohol of 2.5L, adds the NaOH aqueous solution of the massfraction 15% of 850ml then, and back flow reaction is after 3 hours; Be cooled to room temperature,, use ethyl acetate extraction then with the Hydrogen chloride neutralization; The saturated common salt water washing, anhydrous sodium sulfate drying concentrates and obtains 38g compound (7); Product is not purified, directly is used for 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, adds 35 ml concentrated hydrochloric acids then, 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, directly is used for next step reaction.
Embodiment 8: compound 9 (2-(3,5-two bromo-4-(3, the 4-amino-benzene oxygen) phenyl) methyl acetate) synthetic.
Embodiment 7 is obtained adding the 15g iron powder then in the acetate that 24g compound 8 is dissolved in 1000ml, 90～95 ℃ of reactions 7 hours down; Acetic acid is reclaimed in underpressure distillation; Residuum is poured in the frozen water, uses the ethyl acetate extraction product, dry concentrating obtains 23g compound (9); Product is not purified, directly is used for next step reaction.
Embodiment 9: compound 10 (3,5-two bromo-4-(5-benzoglyoxaline 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, remove then and desolvate, and are again that residuum is soluble in water, use ethyl acetate extraction, concentrate, and obtain 23g white solid compound 10.
Embodiment 10: compound 11 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid) synthetic.
23g compound 10 is dissolved in the THF of 200ml, adds the 22g lithium hydroxide aqueous solution then, room temperature reaction spends the night; Remove and desolvate; Hydrochloric acid with 2N is regulated pH=2, filters and obtains yellow solid, should obtain white solid product by thick product recrystallization in ethanol then; 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 (3)
1. one kind 3, the preparation method of 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid is characterized in that; May further comprise the steps: to be raw material to nitro fluorobenzene and p-hydroxyphenylaceticacid methyl esters, obtain 2-(4-(4-nitrophenoxy) phenyl) methyl acetate through substitution reaction, 2-(4-(4-nitrophenoxy) phenyl) methyl acetate obtains 2-(3 through bromo; 5-two bromo-4-(4-nitrophenoxy) phenyl) methyl acetate, and then the warp reduction obtains 2-(3,5-two bromo-4-(4-amino-benzene oxygen) phenyl) methyl acetate); 2-(3; 5-two bromo-4-(4-amino-benzene oxygen) phenyl), obtains 2-(3 through the esterification reduction again methyl acetate) through amido protecting, nitrated 2-(3,5-two bromo-4-(4-((methoxycarbonyl) the amino)-3-nitro-phenoxy) phenyl) methyl acetate that obtains; 5-two bromo-4-(3; The 4-amino-benzene oxygen) methyl acetate phenyl) becomes cyclizing hydrolysis to obtain 3 then, 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid.
2. according to claim 1 a kind of 3, the preparation method of 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid is characterized in that, may further comprise the steps:
(1): compound 2 (2-(4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
In the presence of salt of wormwood, to 70-80 ℃ of reaction of nitro fluorobenzene and p-hydroxyphenylaceticacid methyl esters 3-4 hour, the hydroxyl phenylacetic acid methyl esters and to the amount of substance of nitro fluorobenzene than being 1:1.2-1.5; Amount of substance ratio to nitro fluorobenzene and salt of wormwood is 1:1.5-3, obtains compound 2 and uses the alcohol solvent recrystallization;
(2): compound 3 (2-(3,5-two bromo-4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
The compound 2 of preparation reacted with bromine obtain compound 3, the amount of substance ratio of compound 2 and bromine is: 1:8-12, and reaction product is with methylene dichloride or chloroform extraction;
(3): compound 4 (2-(3,5-two bromo-4-(4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
Compound 3 and iron powder are carried out prepared in reaction compound 4 at room temperature; The amount of substance ratio of compound 3 and iron powder is 1:4-9;
(4): compound 5 (2-(3,5-two bromo-4-(4-((methoxycarbonyl) amino) phenoxy) phenyl) methyl acetate) synthetic;
With compound 4 and methyl-chloroformate, pyridine prepared in reaction compound 5, 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-(3,5-two bromo-4-(4-((methoxycarbonyl) amino)-3-nitro-phenoxy) phenyl) methyl acetate) synthetic;
The compound 5 and nitrosonitric acid prepared in reaction compound 6 of slurry preparation, the amount of substance ratio of compound 5 and nitrosonitric acid is 1:9-12, reaction was at room temperature carried out 3-5 hour;
(6): compound 7 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetate) synthetic;
With the preparation compound 6 under refluxad be hydrolyzed react compound 7, 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 in the presence of hydrochloric acid, preparation compound 8, the amount of substance ratio of compound 7 and hydrochloric acid is 1:10-18;
(8): compound 9 (2-(3,5-two bromo-4-(3, the 4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
Compound 8 and iron powder are carried out prepared in reaction compound 9, and the amount of substance ratio of compound 8 and iron powder is 1:4-10, is reflected in 80～95 ℃ and carries out, and the reaction times is 6-10 hour;
(9): compound 10 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) methyl phenylacetate) synthetic;
The compound 9 for preparing in excessive formic acid, back flow reaction 1-3 hour, is prepared compound 10;
(10): compound 11 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid) synthetic;
Compound 10 and Lithium Hydroxide MonoHydrate are reacted, preparation compound 11, the amount of substance ratio of compound 10 and Lithium Hydroxide MonoHydrate is 1:9-15, reacts to be room temperature reaction 10-15 hour.
3. according to claim 1 a kind of 3, the preparation method of 5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid is characterized in that, may further comprise the steps:
(1): compound 2 (2-(4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
With 40g, 0.28 mol the nitro fluorobenzene is dissolved among the DMF of 200ml, at room temperature add the p-hydroxyphenylaceticacid methyl esters of 38 g, 0.23mol and the salt of wormwood of 90g then; Then reaction solution is heated to 75 ℃ and stirred 3 hours; Be cooled to room temperature, filtrating imports in the frozen water of 1.2 L, solid filtering is come out, and drying obtains crude product, obtains yellow solid 60 g compounds 2 with ethyl alcohol recrystallization;
(2): compound 3 (2-(3,5-two bromo-4-(4-nitrophenoxy) phenyl) methyl acetate) synthetic;
The 60g compound 2 of step 1 preparation is dissolved in the 200ml chloroform of heat, adds 8g FeBr
2, then 110 ml bromines and 200 ml chloroformic solutions slowly being joined in the solution, backflow is spent the night; Cooling afterreaction liquid imports to saturated NaHSO
3In the aqueous solution, use dichloromethane extraction then, extraction liquid water and saturated common salt water washing, and use anhydrous sodium sulfate drying, and obtaining the compound 3 of 40g white after concentrating, product is not purified, directly is used for next step reaction;
(3): compound 4 (2-(3,5-two bromo-4-(4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
The 40g compound 3 of getting step 2 preparation is dissolved in the water of acetate and 60ml of 500ml, adds the 25g iron powder then, reacts 3h under the room temperature; Then reaction solution is poured in the frozen water of 3L and uses ethyl acetate extraction, obtain 38g compound 4 through filtering and concentrating, product is not purified, directly is used for next step reaction;
(4): compound 5 (2-(3,5-two bromo-4-(4-((methoxycarbonyl) amino) phenoxy) phenyl) methyl acetate) synthetic;
The 38g compound 4 of step 3 preparation is dissolved in the 200 ml methylene dichloride, adds the 15g pyridine again, the methyl-chloroformate of 12g is dissolved in the methylene dichloride of 50ml; Under 0 ℃, be added drop-wise in the reaction solution then, room temperature reaction was poured into reaction solution in the frozen water after 2 hours; Use dichloromethane extraction then; Filter also dry concentrating and obtain compound 5, product is not purified, directly is used for next step reaction;
(5): compound 6 (2-(3,5-two bromo-4-(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, drips the nitrosonitric acid of 38ml then, 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, directly is used for next step reaction;
(6): compound 7 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) acetate) synthetic;
With step 5 preparation 44g compound 6 be dissolved in the methyl alcohol of 2.5L, add the NaOH aqueous solution of the massfraction 15% of 850ml then, back flow reaction is after 3 hours; Be cooled to room temperature,, use ethyl acetate extraction then with the Hydrogen chloride neutralization; The saturated common salt water washing, anhydrous sodium sulfate drying concentrates and obtains 38g compound 7; Product is not purified, directly is used for next step reaction;
(7): compound 8 (2-(4-(4-amino-3-nitro-phenoxy)-3,5-dibromo phenyl) methyl acetate) synthetic;
The 38g compound 7 that obtains of step 6 preparation is dissolved in the methyl alcohol of 2.5 L, adds 35 ml concentrated hydrochloric acids then, back flow reaction 3 hours is cooled to room temperature, filters and obtains yellow solid product 24g compound 8, and product is not purified, directly is used for next step reaction;
(8): compound 9 (2-(3,5-two bromo-4-(3, the 4-amino-benzene oxygen) phenyl) methyl acetate) synthetic;
With step 7 preparation obtain add the 15g iron powder then in the acetate that 24g compound 8 is dissolved in 1000ml, 90～95 ℃ of reactions 7 hours down; Acetic acid is reclaimed in underpressure distillation; Residuum is poured in the frozen water, uses the ethyl acetate extraction product, dry concentrating obtains 23g compound 9; Product is not purified, directly is used for next step reaction;
(9): compound 10 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) methyl phenylacetate) synthetic;
With step 8 preparation 23g compound 9 crude products be dissolved in the formic acid of 300ml, refluxed 2 hours, remove then and desolvate, again that residuum is soluble in water, use ethyl acetate extraction, concentrated, obtain 23g white solid compound 10;
(10): compound 11 (3,5-two bromo-4-(5-benzoglyoxaline oxygen base) toluylic acid) synthetic;
The 23g compound 10 of step 9 preparation is dissolved in the THF of 200ml; Add the 22g lithium hydroxide aqueous solution then; Room temperature reaction spends the night, and removes and desolvates, and regulates pH=2 with the hydrochloric acid of 2N; Filtration obtains yellow solid, should obtain 20g white solid compound 11 by thick product recrystallization in ethanol then.
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 true CN102718718A (en) | 2012-10-10 |
| CN102718718B 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) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1337953A (en) * | 1998-12-24 | 2002-02-27 | 卡罗生物股份公司 | New thryoid receptor ligands and process II |
| WO2002062780A2 (en) * | 2001-02-08 | 2002-08-15 | Karo Bio Ab | Phenoxy substituted benzocondensed heteroaryl derivatives as thyroid receptor ligands |
| WO2007128492A1 (en) * | 2006-05-03 | 2007-11-15 | Karo Bio Ab | Novel pharmaceutical compositions |
-
2012
- 2012-05-31 CN CN201210174101.1A patent/CN102718718B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1337953A (en) * | 1998-12-24 | 2002-02-27 | 卡罗生物股份公司 | New thryoid receptor ligands and process II |
| WO2002062780A2 (en) * | 2001-02-08 | 2002-08-15 | Karo Bio Ab | Phenoxy substituted benzocondensed heteroaryl derivatives as thyroid receptor ligands |
| WO2007128492A1 (en) * | 2006-05-03 | 2007-11-15 | Karo Bio Ab | Novel pharmaceutical compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102718718B (en) | 2014-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108689968B (en) | Two compounds, preparation method thereof and application thereof in synthesis of brivaracetam | |
| CN102584893B (en) | Preparation method for glufosinate | |
| CN103570696B (en) | A kind of preparation method of Axitinib intermediate and preparing the application in Axitinib | |
| CN101570550B (en) | Method for synthesizing chiral ferrocene diphosphine ligand | |
| CN102557977A (en) | Synthesis intermediate of erlotinib and preparation method thereof | |
| CN103570633B (en) | The preparation method of Gefitinib | |
| CN101891649A (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN108947861A (en) | The synthetic method of C14H10Cl2NNaO2 | |
| CN104610164B (en) | 2 (base of 2 normal-butyl, 4 hydroxyl, 6 methylpyrimidine 5) N, the preparation method of N dimethyl acetamides | |
| CN102911128A (en) | Synthetic method of valsartan | |
| CN107098822A (en) | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 | |
| CN101020628A (en) | Preparation method of 2, 4-difluoro-3-hydroxybenzoic acid | |
| CN102304090A (en) | Method for preparing 5-substituted thiophenyl-benzimidazol-2-N-methoxycarbonyl compound | |
| CN103467445B (en) | Preparation method of alogliptin benzoate | |
| CN103319366B (en) | Lacosamide synthesis technology | |
| CN102030707A (en) | Method for preparing Blonanserin intermediate | |
| CN102746235A (en) | Improved method for preparing imidafenacin | |
| CN102718718B (en) | Preparation method for 3,5-dibromo-4-(5-benzimidazole oxygen group)phenylacetic acid | |
| CN104974057A (en) | Preparation method and important intermediate of bromfenac sodium | |
| CN109988108A (en) | A kind of rich preparation method for Buddhist nun of card | |
| CN102964225A (en) | Preparation method of 2, 3-dichloroanisole | |
| CN102690211B (en) | The preparation method of tolvaptan intermediate | |
| CN109574830B (en) | Rosuvastatin calcium intermediate, and preparation method and application thereof | |
| CN106748725B (en) | preparation method of 4-chloro-2-fluoro-phenylpropionic acid | |
| CN102976958A (en) | Preparation method of 4-methoxy-beta-phenylethylamine |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140924 Termination date: 20170531 |