CN108238904A

CN108238904A - The synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid

Info

Publication number: CN108238904A
Application number: CN201710530837.0A
Authority: CN
Inventors: 关艮安
Original assignee: Chiba Longhua Chengdu Petroleum Engineering Technology Consultation Co Ltd
Current assignee: Chiba Longhua Chengdu Petroleum Engineering Technology Consultation Co Ltd; Chengdu Qianye Longhua Petroleum Engineering Technology Consulting Co Ltd
Priority date: 2017-07-03
Filing date: 2017-07-03
Publication date: 2018-07-03
Also published as: AU2018100833A4; GB201713549D0

Abstract

The invention discloses the synthetic methods of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid, include the following steps：4 methyl toluene ether are added in reaction vessel, Klorvess Liquid controls mixing speed, increases solution temperature, and the reaction was continued, adds in lanthanum oxide powder, increases temperature, reaction；Then M Cr solution is added in, increases temperature, controls mixing speed, reaction, temperature is reduced, adds in potassium sulfate solution, solution layering is washed with butyronitrile solution, parachloronitrobenzene solution washs, and is recrystallized in dihexylamine solution, and dehydrating agent dehydration obtains finished product p-methylbenzoic acid.

Description

The synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid

Technical field

The present invention relates to a kind of preparation methods of medicine intermediate, belong to organic synthesis field more particularly to para-amiunomethylbenzoic acid The synthetic method of pharmaceutical intermediate p-methylbenzoic acid.

Background technology

P-methylbenzoic acid mainly for the manufacture of para-amiunomethylbenzoic acid, to formonitrile HCN, Butyltriphenylphosphonium chloride, photosensitive material etc., be used for Organic synthesis intermediate, pesticide industry produce fungicide phosphamide.Existing synthetic method is mostly using concentrated nitric acid oxidation to diformazan Benzene reacts 30h, p-methylbenzoic acid, yield 58% can be made.This synthetic method is reacted due to needing to be done using concentrated nitric acid Object, danger coefficient is higher in building-up process, and to the corrosion-resistant higher of equipment, cost of equipment maintenance is higher, is unfavorable for reducing whole Production cost, and building-up process needs 30 hours or more, and the production time is too long, and ultimate yield is not also high, and only 58% is left It is right, it is therefore necessary to propose a kind of new synthetic method.

Invention content

Technical problems based on background technology, the present invention propose para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid Synthetic method, include the following steps：

A:4- methyl-toluene ether, 1.5L Klorvess Liquids, control mixing speed 230- are added in reaction vessel 260rpm, raising solution temperature is to 30-38 DEG C, the reaction was continued 60-90min, addition lanthanum oxide powder, raising temperature to 40-46 DEG C, react 2-3h；

B:Then M Cr solution is added in, raising temperature controls mixing speed 310-350rpm, instead to 50-55 DEG C 90-130min is answered, reduces temperature to 10-15 DEG C, adds in 1.6L potassium sulfate solutions, solution layering is washed with butyronitrile solution, to chlorine Nitrobenzene solution washs, and is recrystallized in dihexylamine solution, and dehydrating agent dehydration obtains finished product p-methylbenzoic acid.

Preferably, Klorvess Liquid mass fraction is 10-17%.

Preferably, M Cr liquid quality fraction is 40-45%.

Preferably, potassium sulfate solution mass fraction is 15-21%.

Preferably, butyronitrile liquid quality fraction is 45-52%.

Preferably, parachloronitrobenzene liquid quality fraction is 60-65%.

Preferably, dihexylamine liquid quality fraction is 80-87%.

Entire building-up process can be used following net reaction to represent：

Compared to synthetic method disclosed in background technology, para-amiunomethylbenzoic acid pharmaceutical intermediate provided by the invention is to methylbenzene first The synthetic method of acid, does not need to do reactant using concentrated nitric acid, reduces the danger coefficient in building-up process, to the corrosion resistant of equipment Erosion requirement reduces, and reduces cost of equipment maintenance, advantageously reduces whole production cost, building-up process only needs several small When, the production time accelerates, and reaction intermediate link reduces very much, and the reaction time also shortens much, and reaction yield also improves, The present invention provides a kind of new synthetic routes simultaneously, lay a good foundation further to promote reaction yield.

Description of the drawings

Fig. 1 is finished product p-methylbenzoic acid¹³CNMR analysis of spectra.

Fig. 2 is the carbon atom serial number label figure in p-methylbenzoic acid molecule.

Specific embodiment

Embodiment 1：

The synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid, includes the following steps：

A:2mol 4- methyl-toluene ether is added in reaction vessel, the potassium chloride that 1.5L mass fractions are 10% is molten Liquid controls mixing speed 230rpm, and for raising solution temperature to 30 DEG C, the reaction was continued 60min adds in 2mol lanthanum oxide powders, rises High-temperature reacts 2h to 40 DEG C；

B:Then the M Cr solution that 4mol mass fractions are 40% is added in, raising temperature is to 50 DEG C, control stirring Speed 310rpm reacts 90min, reduces temperature to 10 DEG C, adds in the potassium sulfate solution that 1.6L mass fractions are 15%, solution point Layer is washed with the butyronitrile solution that mass fraction is 45%, and the parachloronitrobenzene solution that mass fraction is 60% washs, in quality point For number to be recrystallized in 80% dihexylamine solution, the dehydration of anhydrous magnesium sulfate dehydrating agent obtains finished product p-methylbenzoic acid 239.36g, Yield 88%.

Embodiment 2：

A:2mol 4- methyl-toluene ether is added in reaction vessel, the potassium chloride that 1.5L mass fractions are 16% is molten Liquid controls mixing speed 250rpm, and for raising solution temperature to 37 DEG C, the reaction was continued 85min adds in 2.8mol lanthanum oxide powders, Temperature is increased to 41 DEG C, reacts 2.2h；

B:Then the M Cr solution that 5mol mass fractions are 43% is added in, raising temperature is to 52 DEG C, control stirring Speed 330rpm reacts 120min, reduces temperature to 12 DEG C, adds in the potassium sulfate solution that 1.6L mass fractions are 17%, solution Layering is washed with the butyronitrile solution that mass fraction is 48%, and the parachloronitrobenzene solution that mass fraction is 62% washs, in quality Score is to be recrystallized in 83% dihexylamine solution, and the dehydration of Anhydrous potassium carbonate dehydrating agent obtains finished product p-methylbenzoic acid 247.52g yield 91%.

Embodiment 3：

A:2mol 4- methyl-toluene ether is added in reaction vessel, the potassium chloride that 1.5L mass fractions are 17% is molten Liquid controls mixing speed 260rpm, and for raising solution temperature to 38 DEG C, the reaction was continued 90min adds in 3mol lanthanum oxide powders, rises High-temperature reacts 3h to 46 DEG C；

B:Then the M Cr solution that 6mol mass fractions are 45% is added in, raising temperature is to 55 DEG C, control stirring Speed 350rpm reacts 130min, reduces temperature to 15 DEG C, adds in the potassium sulfate solution that 1.6L mass fractions are 21%, solution Layering is washed with the butyronitrile solution that mass fraction is 52%, and the parachloronitrobenzene solution that mass fraction is 65% washs, in quality Score is to be recrystallized in 87% dihexylamine solution, and the dehydration of anhydrous magnesium sulfate dehydrating agent obtains finished product p-methylbenzoic acid 258.4g, Yield 95%.

Finished product p-methylbenzoic acid¹³CNMR analysis of spectra is as shown in Figure 1.

Carbon atom serial number label figure in p-methylbenzoic acid molecule is as shown in Figure 2.

Concrete operations analytic process is as follows：

Frequency：15.09MHz

Sample and solvent burden ratio：0.130g:0.9ml DMSO-d₆

Table 1¹³C NMR analyze data

It described in above example, is merely preferred embodiments of the present invention, but protection scope of the present invention not office Be limited to this, any one skilled in the art in the technical scope disclosed by the present invention, the technique according to the invention Scheme and its inventive concept are subject to equivalent substitution or change, should be covered by the protection scope of the present invention.

Claims

1. the synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid, which is characterized in that include the following steps：

A:4- methyl-toluene ether is added in reaction vessel, 1.5L Klorvess Liquids control mixing speed 230-260rpm, Solution temperature is increased to 30-38 DEG C, the reaction was continued 60-90min adds in lanthanum oxide powder, and raising temperature is to 40-46 DEG C, reaction 2-3h；

B:Then M Cr solution is added in, raising temperature controls mixing speed 310-350rpm to 50-55 DEG C, reacts 90- 130min reduces temperature to 10-15 DEG C, adds in 1.6L potassium sulfate solutions, and solution layering is washed with butyronitrile solution, to chlorine nitro Benzole soln washs, and is recrystallized in dihexylamine solution, and dehydrating agent dehydration obtains finished product p-methylbenzoic acid.

2. the synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid according to claim 1, which is characterized in that institute The Klorvess Liquid mass fraction stated is 10-17%.

3. the synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid according to claim 1, which is characterized in that institute The M Cr liquid quality fraction stated is 40-45%.

4. the synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid according to claim 1, which is characterized in that institute The potassium sulfate solution mass fraction stated is 15-21%.

5. the synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid according to claim 1, which is characterized in that institute The butyronitrile liquid quality fraction stated is 45-52%.

6. the synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid according to claim 1, which is characterized in that institute The parachloronitrobenzene liquid quality fraction stated is 60-65%.

7. the synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid according to claim 1, which is characterized in that institute The dihexylamine liquid quality fraction stated is 80-87%.

8. the synthetic method of para-amiunomethylbenzoic acid pharmaceutical intermediate p-methylbenzoic acid according to claim 1, which is characterized in that packet Include following steps：

A:2mol 4- methyl-toluene ether is added in reaction vessel, 1.5L mass fractions are 17% Klorvess Liquid, are controlled Mixing speed 260rpm processed, raising solution temperature is to 38 DEG C, the reaction was continued 90min, addition 3mol lanthanum oxide powders, raising temperature To 46 DEG C, 3h is reacted；

B:Then the M Cr solution that 6mol mass fractions are 45% is added in, raising temperature controls mixing speed to 55 DEG C 350rpm reacts 130min, reduces temperature to 15 DEG C, adds in the potassium sulfate solution that 1.6L mass fractions are 21%, and solution is layered, It is washed with the butyronitrile solution that mass fraction is 52%, the parachloronitrobenzene solution that mass fraction is 65% washs, in mass fraction To be recrystallized in 87% dihexylamine solution, the dehydration of anhydrous magnesium sulfate dehydrating agent obtains finished product p-methylbenzoic acid.