CN102766041B - Method for preparing intermediate of salicylic aldehyde derivatives - Google Patents
Method for preparing intermediate of salicylic aldehyde derivatives Download PDFInfo
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- CN102766041B CN102766041B CN201210293276.4A CN201210293276A CN102766041B CN 102766041 B CN102766041 B CN 102766041B CN 201210293276 A CN201210293276 A CN 201210293276A CN 102766041 B CN102766041 B CN 102766041B
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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 preparation method of salicylaldehyde derivatives intermediate, 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, the class Schiff that this compounds and primary amine synthesize, due to containing multiple ligating atom, easy and transition metal, nontransition metal and rare earth metal generate stable metal complexes, some title complexs have good anticancer, anti-inflammatory, sterilization, press down the katalysis of the biological activity such as mould and oxygen carrier and simulation biological enzyme preferably, and oneself is applied to the key areas such as medicine.
The 5-tertiary butyl-3-formyl radical-4-HBA is a kind of salicylaldehyde derivatives.Document [chemical reagent, 2006,28 (2), 73-74,122] reports with 4-methyl-2-TBP for starting raw material synthesizes the method for this compound, and reaction formula is as follows:
Can be found out by above-mentioned reaction formula; with 4-methyl-2-TBP for the starting raw material synthesis 5-tertiary butyl-3-formyl radical-4-HBA; 3-tertiary butyl-4-hydroxy phenylformic acid is the intermediate product of its synthesis; because phenolic hydroxyl group is very easily oxidized, so the benzoic synthesis of 3-tertiary butyl-4-hydroxy is protected through phenolic hydroxyl group; reoxidize methyl; finally take off blocking group three unit processes, but above-mentioned each unit process comprises synthesis, isolation andpurification operation.
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art; a kind of intermediate product preparing the 5-tertiary butyl-3-formyl radical-4-HBA is provided; the i.e. benzoic method of 3-tertiary butyl-4-hydroxy; its technology of preparing is simple to operate; mature and reliable; cost is low, and can be mass-produced also can small serial production.
To achieve these goals, technical scheme of the present invention is:
With 4-methyl-2-TBP for starting raw material; through phenolic hydroxyl group protection and methyl oxidation; without separating-purifying, one pot reaction obtains the 3-tertiary butyl-4-methoxybenzoic acid, and the 3-tertiary butyl-4-methoxybenzoic acid again ehter bond acidolysis obtains 3-tertiary butyl-4-hydroxy phenylformic acid.
The benzoic synthetic method of 3-tertiary butyl-4-hydroxy of the present invention, available following reaction formula represents:
4-methyl-2-TBP 3-the tertiary butyl-4-methoxybenzoic acid 3-tertiary butyl-4-hydroxy phenylformic acid
The benzoic synthetic method of 3-tertiary butyl-4-hydroxy of the present invention, step is as follows:
(1) the 3-tertiary butyl-4-methoxybenzoic acid is synthesized
By the high boiling organic solvent of the 4-of 0.1mol methyl-2-TBP, 40-60mL and the potassium hydroxide of 0.012-0.015mol blended, reflux, after 5-6h drips methylcarbonate 0.1-0.2mol, reflux 1h again, add the potassium permanganate solution 180-200mL that mass concentration is 15%, continue to be back to purple to disappear, filtrate hcl acidifying, suction filtration obtains the 3-tertiary butyl-4-methoxybenzoic acid;
Reaction formula is:
4-methyl-2-TBP 3-the tertiary butyl-4-methoxybenzoic acid
Described high boiling organic solvent is diglyme or diethyl carbitol, and the described 3-tertiary butyl-4-methoxybenzoic acid, yield represents it is 81-84% with massfraction.
(2) 3-tertiary butyl-4-hydroxy phenylformic acid is synthesized
To in the 3-tertiary butyl-4-methoxybenzoic acid of 0.01mol, add the Hydrogen bromide 25-30mL that mass concentration is 40%, reflux 4-5h, is cooled to room temperature, dilute with the water of 30-40mL, add the aqueous sodium hydroxide solution neutralization that mass concentration is 35%, extracted with diethyl ether, organic phase mass concentration is the sodium hydroxide solution washing of 10%, use extracted with diethyl ether again, mixing organic phase, revolve steaming, recrystallization obtains 3-tertiary butyl-4-hydroxy phenylformic acid;
Reaction formula is:
The 3-tertiary butyl-4-methoxybenzoic acid 3-tertiary butyl-4-hydroxy phenylformic acid
Described 3-tertiary butyl-4-hydroxy phenylformic acid, yield represents it is 85-87% with massfraction.
Feature outstanding in the technology of the present invention is:
(1) by the synthesis of starting raw material to the compound 3-tertiary butyl-4-methoxybenzoic acid, the protection of phenolic hydroxyl group and methyl oxidation reaction, without separating-purifying, one pot reaction obtains, and simplifies operation steps, and cost reduces, and easily realizes industrialization;
(2) one of raw material of relating to of the protection of phenolic hydroxyl group of the present invention methylcarbonate; 1992; this compound is registered as in Europe " non-toxic chemical "; now be known as in the world " green chemical "; this compound is with its stronger chemical property; noticeable in the Application Areas that methylates, its use makes reaction process environmental protection more, and the synthesis for derived product provides more friendly quality.
(3) methyl oxidation becomes carboxyl to have employed inexpensive potassium permanganate oxidant; the aqueous solution because of potassium permanganate is alkalescence; make protection and the methyl oxidation of phenolic hydroxyl group; possibility is become without separating-purifying, one pot reaction; in addition; under alkaline condition, the structure of phenol methyl ether is not destroyed, and can obtain the 3-tertiary butyl-4-methoxybenzoic acid of higher yields.
(4) adopt the methoxyl group in HBr acidolysis phenol to be phenolic hydroxyl group, compared with adopting HI acidolysis methoxyl group with routine, raw materials cost significantly reduces;
(5) raw material that reaction process is used is liquid or solid, is synthesis under normal pressure, avoids the autoclave reactor needed for gas reaction, and reaction safety is easy to operate.
Accompanying drawing explanation
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 invention will be further described, but protection scope of the present invention is not only confined to embodiment, the change that this field professional does technical solution of the present invention, all should belong in protection scope of the present invention.
Embodiment 1
(1) the 3-tertiary butyl-4-methoxybenzoic acid is synthesized
By the diglyme of the 4-of 0.1mol methyl-2-TBP, 40mL and the potassium hydroxide of 0.012mol blended, reflux, after 5h drips methylcarbonate 0.1mol, reflux 1h again, add the potassium permanganate solution 180mL that mass concentration is 15%, continue to be back to purple and disappear, filtrate hcl acidifying, suction filtration obtains the 3--tertiary butyl-4-methoxybenzoic acid, and yield represents it is 81% with massfraction;
Can be found out by the mass spectrum of Fig. 1 sintetics, the main peak of its m/z is 207.1040, the molar mass of the 3-tertiary butyl-4-methoxybenzoic acid is 208.11, the molecular ion peak of 207.1040 is consistent with the molecular ion peak (208.11-1.01=207.10) of the 3-tertiary butyl-4-methoxybenzoic acid, illustrates that this synthetic method obtains target product.
(2) 3-tertiary butyl-4-hydroxy phenylformic acid is synthesized
To in the 3-tertiary butyl-4-methoxybenzoic acid of 0.01mol, add the Hydrogen bromide 25mL that mass concentration is 40%, reflux 4h, be cooled to room temperature, dilute with the water of 30mL, add the aqueous sodium hydroxide solution neutralization that mass concentration is 35%, extracted with diethyl ether, organic phase mass concentration is the sodium hydroxide solution washing of 10%, use extracted with diethyl ether again, mixing organic phase, revolves steaming, recrystallization obtains 3-tertiary butyl-4-hydroxy phenylformic acid, and yield represents it is 85% with massfraction.
Embodiment 2
(1) the 3-tertiary butyl-4-methoxybenzoic acid is synthesized
By the diethyl carbitol of the 4-of 0.1mol methyl-2-TBP, 50mL and the potassium hydroxide of 0.014mol blended, reflux, after 5.5h drips methylcarbonate 0.15mol, reflux 1h again, add the potassium permanganate solution 190mL that mass concentration is 15%, continue to be back to purple and disappear, filtrate hcl acidifying, suction filtration obtains the 3-tertiary butyl-4-methoxybenzoic acid, and yield represents it is 83% with massfraction;
By Fig. 2 sintetics
1hNMR figure can find out, chemical shift 1.341ppm is 9 hydrogen on the tertiary butyl, chemical shift 3 hydrogen that to be 3.879ppm be on methoxyl group, chemical shift 3 hydrogen that to be 7.054-7.835ppm be on phenyl ring, chemical shift 1 hydrogen that to be 12.564ppm be on carboxyl,
1hNMR is consistent with the structure of the product that will synthesize.
(2) 3-tertiary butyl-4-hydroxy phenylformic acid is synthesized
To in the 3-tertiary butyl-4-methoxybenzoic acid of 0.01mol, add the Hydrogen bromide 27mL that mass concentration is 40%, reflux 4.5h, be cooled to room temperature, dilute with the water of 35mL, add the aqueous sodium hydroxide solution neutralization that mass concentration is 35%, extracted with diethyl ether, organic phase mass concentration is the sodium hydroxide solution washing of 10%, use extracted with diethyl ether again, mixing organic phase, revolves steaming, recrystallization obtains 3-tertiary butyl-4-hydroxy phenylformic acid, and yield represents it is 86% with massfraction;
Embodiment 3
(1) the 3-tertiary butyl-4-methoxybenzoic acid is synthesized
By the diglyme of the 4-of 0.1mol methyl-2-TBP, 60mL and the potassium hydroxide of 0.015mol blended, reflux, after 6h drips methylcarbonate 0.2mol, reflux 1h again, add the potassium permanganate solution 200mL that mass concentration is 15%, continue to be back to purple and disappear, filtrate hcl acidifying, suction filtration obtains the 3-tertiary butyl-4-methoxybenzoic acid, and yield represents it is 84% with massfraction.
(2) 3-tertiary butyl-4-hydroxy phenylformic acid is synthesized
To in the 3-tertiary butyl-4-methoxybenzoic acid of 0.01mol, add the Hydrogen bromide 30mL that mass concentration is 40%, reflux 5h, be cooled to room temperature, dilute with the water of 40mL, add the aqueous sodium hydroxide solution neutralization that mass concentration is 35%, extracted with diethyl ether, organic phase mass concentration is the sodium hydroxide solution washing of 10%, use extracted with diethyl ether again, mixing organic phase, revolves steaming, recrystallization obtains 3-tertiary butyl-4-hydroxy phenylformic acid, and yield represents it is 87% with massfraction.
Claims (1)
1. a preparation method for salicylaldehyde derivatives intermediate, is characterized in that, is realized by following steps:
(1) the 3-tertiary butyl-4-methoxybenzoic acid is synthesized
By the high boiling organic solvent of the 4-of 0.1mol methyl-2-TBP, 40-60mL and the potassium hydroxide of 0.012-0.015mol blended, reflux, after 5-6h drips methylcarbonate 0.1-0.2mol, reflux 1h again, add the potassium permanganate solution 180-200mL that mass concentration is 15%, continue to be back to purple to disappear, filtrate hcl acidifying, suction filtration obtains the 3-tertiary butyl-4-methoxybenzoic acid; The 3-tertiary butyl-4-methoxybenzoic acid yield represents it is 81-84% with massfraction;
Described high boiling organic solvent is diglyme or diethyl carbitol;
Reaction formula is:
(2) 3-tertiary butyl-4-hydroxy phenylformic acid is synthesized
To in the 3-tertiary butyl-4-methoxybenzoic acid of 0.01mol, add the Hydrogen bromide 25-30mL that mass concentration is 40%, reflux 4-5h, is cooled to room temperature, dilute with the water of 30-40mL, add the aqueous sodium hydroxide solution neutralization that mass concentration is 35%, extracted with diethyl ether, organic phase mass concentration is the sodium hydroxide solution washing of 10%, use extracted with diethyl ether again, mixing organic phase, revolve steaming, recrystallization obtains 3-tertiary butyl-4-hydroxy phenylformic acid; 3-tertiary butyl-4-hydroxy phenylformic acid, yield represents it is 85-87% with massfraction;
Reaction formula is:
。
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