CN102766041A - Method for preparing intermediate of salicylic aldehyde derivatives - Google Patents
Method for preparing intermediate of salicylic aldehyde derivatives Download PDFInfo
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- CN102766041A CN102766041A CN2012102932764A CN201210293276A CN102766041A CN 102766041 A CN102766041 A CN 102766041A CN 2012102932764 A CN2012102932764 A CN 2012102932764A CN 201210293276 A CN201210293276 A CN 201210293276A CN 102766041 A CN102766041 A CN 102766041A
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Abstract
The invention relates to a method for preparing intermediate of salicylic aldehyde derivatives, in particular to a method for preparing 3-tertiary butyl-4-hydroxybenzoic acid. 4-methyl-2-tertiary butyl phenol serves as a starting raw material, is subjected to phenolic hydroxyl group protection and methyl oxidization and is subjected to one-pot reaction without separation and purification to obtain 3-tertiary butyl-4-hydroxybenzoic acid. The preparing method is simple to operate and low in cost.
Description
Technical field
The present invention relates to a kind of salicylaldehyde derivatives intermediates preparation, be specifically related to the benzoic preparation method of a kind of 3-tertiary butyl-4-hydroxy, belong to technical field of organic synthesis.
Background technology
Salicylaldehyde derivatives is important organic synthesis intermediate; This compounds and primary amine synthetic class Schiff alkali; Owing to contain multiple ligating atom; Be prone to generate stable metal complexes with transition metal, nontransition metal and rare earth metal, some title complexs have good anticancer, anti-inflammatory, sterilization, press down biological activity such as mould and the katalysis of oxygen carrier and simulation enzyme preferably, and oneself is applied to key areas such as medicine.
The 5-tertiary butyl-3-formyl radical-4-hydroxy-benzoic acid is a kind of salicylaldehyde derivatives.It is the method for synthetic this compound of starting raw material that document [chemical reagent, 2006,28 (2), 73-74,122] has been reported with 4-methyl-2-tert.-butyl phenol, and reaction formula is following:
Can be found out by above-mentioned reaction formula, be the synthetic 5-tertiary butyl of starting raw material-3-formyl radical-4-hydroxy-benzoic acid with 4-methyl-2-tert.-butyl phenol, and 3-tertiary butyl-4-hydroxy phenylformic acid is its synthetic intermediate product; Because phenolic hydroxyl group is very easily oxidized, so benzoic synthesizing of 3-tertiary butyl-4-hydroxy protected through phenolic hydroxyl group; Reoxidize methyl; Take off three unit processes of blocking group at last, yet that above-mentioned each unit process comprises all is synthetic, separation and purification operations.
Summary of the invention
The objective of the invention is in order to remedy the deficiency of prior art; The intermediate product of a kind of 5-of preparation tertiary butyl-3-formyl radical-4-hydroxy-benzoic acid is provided; Be the benzoic method of 3-tertiary butyl-4-hydroxy, its technology of preparing is simple to operate, mature and reliable; Cost is low, but the also small serial production that can be mass-produced.
To achieve these goals, technical scheme of the present invention is:
With 4-methyl-2-tert.-butyl phenol is starting raw material; Through phenolic hydroxyl group protection and methyl oxidation; Purify without separating, one pot reaction makes the 3-tertiary butyl-4-methoxybenzoic acid, and the 3-tertiary butyl-4-methoxybenzoic acid ehter bond acidolysis again makes 3-tertiary butyl-4-hydroxy phenylformic acid.
The benzoic compound method of 3-tertiary butyl-4-hydroxy of the present invention, available following reaction formula is represented:
4-methyl-2-tert.-butyl phenol 3-the tertiary butyl-4-methoxybenzoic acid 3-tertiary butyl-4-hydroxy phenylformic acid
The benzoic compound method of 3-tertiary butyl-4-hydroxy of the present invention, step is following:
(1) the synthetic 3-tertiary butyl-4-methoxybenzoic acid
With 4-methyl-2-tert.-butyl phenol of 0.1mol, the high boiling organic solvent of 40-60mL and the Pottasium Hydroxide blend of 0.012-0.015mol; Reflux, after 5-6h dripped methylcarbonate 0.1-0.2mol, 1h again refluxed; The adding mass concentration is 15% potassium permanganate solution 180-200mL; Continue to be back to purple and disappear, filtrating uses hcl acidifying, suction filtration to get the 3-tertiary butyl-4-methoxybenzoic acid;
Reaction formula is:
4-methyl-2-tert.-butyl phenol 3-the tertiary butyl-4-methoxybenzoic acid
Said high boiling organic solvent is diglyme or diethyl carbitol, the said 3-tertiary butyl-4-methoxybenzoic acid, and yield representes it is 81-84% with massfraction.
(2) synthetic 3-tertiary butyl-4-hydroxy phenylformic acid
In the 3-of the 0.01mol tertiary butyl-4-methoxybenzoic acid, the adding mass concentration is 40% Hydrogen bromide 25-30mL, reflux 4-5h; Be cooled to room temperature,, add mass concentration and be 35% aqueous sodium hydroxide solution neutralization with the dilution of the water of 30-40mL; Extracted with diethyl ether, organic phase use mass concentration are 10% sodium hydroxide solution washing, use extracted with diethyl ether again; Mix organic phase, revolve steaming, recrystallization gets 3-tertiary butyl-4-hydroxy phenylformic acid;
Reaction formula is:
The 3-tertiary butyl-4-methoxybenzoic acid 3-tertiary butyl-4-hydroxy phenylformic acid
Said 3-tertiary butyl-4-hydroxy phenylformic acid, yield representes it is 85-87% with massfraction.
The technical outstanding characteristics of the present invention are:
(1) by starting raw material synthetic to the compound 3-tertiary butyl-4-methoxybenzoic acid, the protection of phenolic hydroxyl group and methyl oxidation reaction are purified without separating, and one pot reaction makes, and has simplified operation steps, cost reduction, easy realization of industrialization;
(2) one of raw material of relating to of the protection of phenolic hydroxyl group of the present invention methylcarbonate; 1992, this compound was registered as " non-toxic chemicals " in Europe, had been known as in the world " green chemical " at present; This compound is with its stronger chemical property; Noticeable in the Application Areas that methylates, its use makes reaction process environmental protection more, is synthetic close friend's the quality more that provides of derived product.
(3) methyl oxidation becomes carboxyl to adopt inexpensive potassium permanganate oxidant; Because of the aqueous solution of potassium permanganate is alkalescence; Make the protection and the methyl oxidation of phenolic hydroxyl group, purify without separating, one pot reaction becomes possibility, in addition; The structure of phenol methyl ether is not destroyed under the alkaline condition, can obtain the 3-tertiary butyl-4-methoxybenzoic acid of higher yields.
(4) adopting the methoxyl group in the HBr acidolysis phenol is phenolic hydroxyl group, adopts HI acidolysis methoxyl group to compare with routine, and raw materials cost significantly reduces;
(5) the used raw material of reaction process is liquid or solid, is synthesis under normal pressure, has avoided the required autoclave reactor of gas reaction, and reaction safety is easy to operate.
Description of drawings
Fig. 1 is the mass spectrum of the 3-tertiary butyl-4-methoxybenzoic acid;
Fig. 2 is the 1HNMR figure of the 3-tertiary butyl-4-methoxybenzoic acid.
Embodiment
Below in conjunction with accompanying drawing the present invention is further described, but protection scope of the present invention not only is confined to embodiment, the change that this field professional does technical scheme of the present invention all should belong in protection scope of the present invention.
Embodiment 1
(1) the synthetic 3-tertiary butyl-4-methoxybenzoic acid
With 4-methyl-2-tert.-butyl phenol of 0.1mol, the diglyme of 40mL and the Pottasium Hydroxide blend of 0.012mol, reflux is after 5h drips methylcarbonate 0.1mol; 1h again refluxes; The adding mass concentration is 15% potassium permanganate solution 180mL, continues to be back to purple and disappears, and filtrating is used hcl acidifying; Suction filtration gets the 3--tertiary butyl-4-methoxybenzoic acid, and yield representes it is 81% with massfraction;
Mass spectrum by Fig. 1 sintetics can be found out; The main peak of its m/z is 207.1040; The molar mass of the 3-tertiary butyl-4-methoxybenzoic acid is 208.11; 207.1040 molecular ion peak consistent with the molecular ion peak (208.11-1.01=207.10) of the 3-tertiary butyl-4-methoxybenzoic acid, explain that this compound method has obtained target product.
(2) synthetic 3-tertiary butyl-4-hydroxy phenylformic acid
In the 3-of the 0.01mol tertiary butyl-4-methoxybenzoic acid, the adding mass concentration is 40% Hydrogen bromide 25mL, and reflux 4h is cooled to room temperature; With the dilution of the water of 30mL, add mass concentration and be 35% aqueous sodium hydroxide solution neutralization, extracted with diethyl ether; Organic phase use mass concentration is 10% sodium hydroxide solution washing, uses extracted with diethyl ether again, mixes organic phase; Revolve steaming, recrystallization gets 3-tertiary butyl-4-hydroxy phenylformic acid, and yield representes it is 85% with massfraction.
(1) the synthetic 3-tertiary butyl-4-methoxybenzoic acid
With 4-methyl-2-tert.-butyl phenol of 0.1mol, the diethyl carbitol of 50mL and the Pottasium Hydroxide blend of 0.014mol, reflux is after 5.5h drips methylcarbonate 0.15mol; 1h again refluxes; The adding mass concentration is 15% potassium permanganate solution 190mL, continues to be back to purple and disappears, and filtrating is used hcl acidifying; Suction filtration gets the 3-tertiary butyl-4-methoxybenzoic acid, and yield representes it is 83% with massfraction;
By Fig. 2 sintetics
1HNMR figure can find out that chemical shift 1.341ppm is 9 hydrogen on the tertiary butyl, and chemical shift is that 3.879ppm is 3 hydrogen on the methoxyl group, and chemical shift is that 7.054-7.835ppm is 3 hydrogen on the phenyl ring, and chemical shift is that 12.564ppm is 1 hydrogen on the carboxyl,
1HNMR is consistent with the structure of want synthetic product.
(2) synthetic 3-tertiary butyl-4-hydroxy phenylformic acid
In the 3-of the 0.01mol tertiary butyl-4-methoxybenzoic acid, the adding mass concentration is 40% Hydrogen bromide 27mL, and reflux 4.5h is cooled to room temperature; With the dilution of the water of 35mL, add mass concentration and be 35% aqueous sodium hydroxide solution neutralization, extracted with diethyl ether; Organic phase use mass concentration is 10% sodium hydroxide solution washing, uses extracted with diethyl ether again, mixes organic phase; Revolve steaming, recrystallization gets 3-tertiary butyl-4-hydroxy phenylformic acid, and yield representes it is 86% with massfraction;
(1) the synthetic 3-tertiary butyl-4-methoxybenzoic acid
With 4-methyl-2-tert.-butyl phenol of 0.1mol, the diglyme of 60mL and the Pottasium Hydroxide blend of 0.015mol, reflux is after 6h drips methylcarbonate 0.2mol; 1h again refluxes; The adding mass concentration is 15% potassium permanganate solution 200mL, continues to be back to purple and disappears, and filtrating is used hcl acidifying; Suction filtration gets the 3-tertiary butyl-4-methoxybenzoic acid, and yield representes it is 84% with massfraction.
(2) synthetic 3-tertiary butyl-4-hydroxy phenylformic acid
In the 3-of the 0.01mol tertiary butyl-4-methoxybenzoic acid, the adding mass concentration is 40% Hydrogen bromide 30mL, and reflux 5h is cooled to room temperature; With the dilution of the water of 40mL, add mass concentration and be 35% aqueous sodium hydroxide solution neutralization, extracted with diethyl ether; Organic phase use mass concentration is 10% sodium hydroxide solution washing, uses extracted with diethyl ether again, mixes organic phase; Revolve steaming, recrystallization gets 3-tertiary butyl-4-hydroxy phenylformic acid, and yield representes it is 87% with massfraction.
Claims (4)
1. a salicylaldehyde derivatives intermediates preparation is characterized in that, is realized by following steps:
(1) the synthetic 3-tertiary butyl-4-methoxybenzoic acid
With 4-methyl-2-tert.-butyl phenol of 0.1mol, the high boiling organic solvent of 40-60mL and the Pottasium Hydroxide blend of 0.012-0.015mol; Reflux, after 5-6h dripped methylcarbonate 0.1-0.2mol, 1h again refluxed; The adding mass concentration is 15% potassium permanganate solution 180-200mL; Continue to be back to purple and disappear, filtrating uses hcl acidifying, suction filtration to get the 3-tertiary butyl-4-methoxybenzoic acid;
Reaction formula is:
(2) synthetic 3-tertiary butyl-4-hydroxy phenylformic acid
In the 3-of the 0.01mol tertiary butyl-4-methoxybenzoic acid, the adding mass concentration is 40% Hydrogen bromide 25-30mL, reflux 4-5h; Be cooled to room temperature,, add mass concentration and be 35% aqueous sodium hydroxide solution neutralization with the dilution of the water of 30-40mL; Extracted with diethyl ether, organic phase use mass concentration are 10% sodium hydroxide solution washing, use extracted with diethyl ether again; Mix organic phase, revolve steaming, recrystallization gets 3-tertiary butyl-4-hydroxy phenylformic acid;
Reaction formula is:
2. a kind of salicylaldehyde derivatives intermediates preparation as claimed in claim 1 is characterized in that the high boiling organic solvent in the said step (1) is diglyme or diethyl carbitol.
3. a kind of salicylaldehyde derivatives intermediates preparation as claimed in claim 1 is characterized in that, the 3-tertiary butyl-4-methoxybenzoic acid in the said step (1), and yield representes it is 81-84% with massfraction.
4. a kind of salicylaldehyde derivatives intermediates preparation as claimed in claim 1 is characterized in that, the 3-tertiary butyl-4-hydroxy phenylformic acid in the said step (2), and yield representes it is 85-87% with massfraction.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905136A (en) * | 2017-02-08 | 2017-06-30 | 泰力特医药（湖北）有限公司 | A kind of preparation method of 2 (4 (2-hydroxybenzoyl)) benzoic acid |
| WO2018028508A1 (en) * | 2016-08-08 | 2018-02-15 | 罗楹 | Method for preparing hydronidone |
| WO2018028506A1 (en) * | 2016-08-08 | 2018-02-15 | 罗楹 | Method for preparing hydronidone |
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| WO2006001835A2 (en) * | 2003-12-30 | 2006-01-05 | The Regents Of The University Of California | Aromatic triamide-lanthanide complexes |
| WO2007144379A1 (en) * | 2006-06-13 | 2007-12-21 | Medivir Ab | Bicyclic compounds useful as cathepsin s inbhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006001835A2 (en) * | 2003-12-30 | 2006-01-05 | The Regents Of The University Of California | Aromatic triamide-lanthanide complexes |
| WO2007144379A1 (en) * | 2006-06-13 | 2007-12-21 | Medivir Ab | Bicyclic compounds useful as cathepsin s inbhibitors |
Non-Patent Citations (2)
| Title |
|---|
| 《化学试剂》 20061231 张雅然等 "两种新型水杨醛衍生物的合成及表征" 73-74，122 1-4 第28卷, 第2期 * |
| 张雅然等: ""两种新型水杨醛衍生物的合成及表征"", 《化学试剂》 * |
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| WO2018028508A1 (en) * | 2016-08-08 | 2018-02-15 | 罗楹 | Method for preparing hydronidone |
| WO2018028506A1 (en) * | 2016-08-08 | 2018-02-15 | 罗楹 | Method for preparing hydronidone |
| CN107698498A (en) * | 2016-08-08 | 2018-02-16 | 罗楹 | A kind of preparation method of oxycodone |
| CN107698499A (en) * | 2016-08-08 | 2018-02-16 | 罗楹 | A kind of preparation method of oxycodone |
| CN109563039A (en) * | 2016-08-08 | 2019-04-02 | 天津睿瀛生物科技有限公司 | A kind of preparation method of oxycodone |
| CN109641841A (en) * | 2016-08-08 | 2019-04-16 | 天津睿瀛生物科技有限公司 | A kind of preparation method of oxycodone |
| JP2019524811A (en) * | 2016-08-08 | 2019-09-05 | ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド | Method for producing hydronidone |
| JP2019525946A (en) * | 2016-08-08 | 2019-09-12 | ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド | Method for producing hydronidone |
| CN106905136A (en) * | 2017-02-08 | 2017-06-30 | 泰力特医药（湖北）有限公司 | A kind of preparation method of 2 (4 (2-hydroxybenzoyl)) benzoic acid |
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