Method for preparing 2,3-dihydroxytoluol

Abstract

The invention relates to the field of organic chemical synthesis, and discloses a method for preparing 2,3-dihydroxytoluol serving as a medicinal intermediate. In the method, the 2,3-dihydroxytoluol as the medicinal intermediate is synthesized by using o-cresol as a raw material and by three fine processing steps of esterification, Fries rearrangement and Dakin reactions. The 2,3-dihydroxytoluol is an important fine chemical engineering intermediate, and has the wide applications in medicinal industry; and at present, there are fewer reports on synthetic methods, and the synthetic methods arenot suitable for industrial production. In the method, the total yield of the process is 30 percent. In the method, the raw material is cheap, and the reaction conditions are mild. Thus, a process for synthesizing the 2,3-dihydroxytoluol is developed.

Description

technical field

[0001] The invention relates to the field of organic chemical synthesis, in particular to a preparation method of a pharmaceutical intermediate 2,3-dihydroxytoluene. Background technique

[0002] 2,3-Dihydroxytoluene is widely used as an important pharmaceutical intermediate, such as synthesizing 1) new cephalosporins, penicillins and carbacephems with better antibacterial activity. ( Annett MIKOLASCH, Martina WURSTER, Michael LALK. Novel β-Lactam Antibiotics Synthesized by Amination of Catechols Using Fungal Laccase[J]. Chem. Pharm. Bull., 2008,56(7): 902-907 ); 2) Benzofuran derivatives with a wide range of pharmacological activities, such as anticancer, antibacterial, anti-HIV-1, antitumor, antidepressant and antihypertensive activities. ( Suteera Witayakran, Leslie Gelbaum, Arthur J. Ragauskas. Cascade synthesis of benzofuran derivatives via laccase oxidation–Michael addition[J].Tetrahedron ,2007,63(45):10958-1096 ); 3) Quinoxaline dione derivatives, w...

Examples

Embodiment 1

[0016] (1) Esterification reaction: Add 10.8 g of o-cresol and 1 g of NaHSO to the reaction vessel 4 14.3 g of acetic anhydride was added dropwise with stirring. After the acetic anhydride is dripped, heat to 50-60 °C, and keep the temperature until the end of the reaction. Pour 100 mlH 2 O, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 Extract (30 ml×2), and combine the organic layers. Wash the organic layer with water (30 ml × 2), anhydrous Na 2 SO 4 Dry and filter with suction. The solvent was removed by rotary evaporation to obtain 14.3 g of o-cresol acetate as a colorless transparent liquid with a yield of 95%.

[0017] (2) Fries rearrangement: add 40 ml PhCl, 15 g o-cresol acetate and 20 g AlCl to the reaction vessel 3 , heated to 110~120°C to react. After the reaction, pour the product into 100 ml of water, add 25 ml of concentrated HCl under stirring, and adjust the pH to 3~4. Stand still and filter. The organic layer was s...

Embodiment 2

[0020] (1) Esterification reaction: add 10.8 g o-cresol, 1 g H 2 SO 4 14.3 g of acetic anhydride was added dropwise with stirring. After the acetic anhydride is dripped, heat to 50-60 °C, and keep the temperature until the end of the reaction. Pour 100 mlH 2 O, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 Extract (30 ml×2), and combine the organic layers. Wash the organic layer with water (30 ml × 2), anhydrous Na 2 SO 4 Dry and filter with suction. The solvent was removed by rotary evaporation to obtain 14.3 g of o-cresol acetate as a colorless transparent liquid with a yield of 95%.

[0021] (2) Fries rearrangement: Add 40 ml PhCl, 15 g o-cresol acetate and 20 g AlCl to the reaction vessel 3 , heated to 110~120°C to react. After the reaction, pour the product into 100 ml of water, add 25 ml of concentrated HCl under stirring, and adjust the pH to 3~4. Stand still and filter. The organic layer was separated from the filtrate, th...

Embodiment 3

[0025] 1) Esterification reaction: add 10.8 g o-cresol, 1 g H 3 PO 4 14.3 g of acetic anhydride was added dropwise with stirring. After the acetic anhydride is dripped, heat to 50-60 °C, and keep the temperature until the end of the reaction. Pour 100 mlH 2 O, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 Extract (30 ml×2), and combine the organic layers. Wash the organic layer with water (30 ml × 2), anhydrous Na 2 SO 4 Dry and filter with suction. The solvent was removed by rotary evaporation to obtain 14.3 g of o-cresol acetate as a colorless transparent liquid with a yield of 95%.

[0026] (2) Fries rearrangement: add 40 ml PhCl, 15 g o-cresol acetate and 20 g AlCl to the reaction vessel 3 , heated to 110~120°C to react. After the reaction, pour the product into 100 ml of water, add 25 ml of concentrated HCl under stirring, and adjust the pH to 3~4. Stand still and filter. The organic layer was separated from the filtrate, ...

technical field

[0001] The invention relates to the field of organic chemical synthesis, in particular to a preparation method of a pharmaceutical intermediate 2,3-dihydroxytoluene. Background technique

[0002] 2,3-Dihydroxytoluene is widely used as an important pharmaceutical intermediate, such as synthesizing 1) new cephalosporins, penicillins and carbacephems with better antibacterial activity. ( Annett MIKOLASCH, Martina WURSTER, Michael LALK. Novel β-Lactam Antibiotics Synthesized by Amination of Catechols Using Fungal Laccase[J]. Chem. Pharm. Bull., 2008,56(7): 902-907 ); 2) Benzofuran derivatives with a wide range of pharmacological activities, such as anticancer, antibacterial, anti-HIV-1, antitumor, antidepressant and antihypertensive activities. ( Suteera Witayakran, Leslie Gelbaum, Arthur J. Ragauskas. Cascade synthesis of benzofuran derivatives via laccase oxidation–Michael addition[J].Tetrahedron ,2007,63(45):10958-1096 ); 3) Quinoxaline dione derivatives, w...

Examples

Embodiment 1

[0016] (1) Esterification reaction: Add 10.8 g of o-cresol and 1 g of NaHSO to the reaction vessel 4 14.3 g of acetic anhydride was added dropwise with stirring. After the acetic anhydride is dripped, heat to 50-60 °C, and keep the temperature until the end of the reaction. Pour 100 mlH 2 O, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 Extract (30 ml×2), and combine the organic layers. Wash the organic layer with water (30 ml × 2), anhydrous Na 2 SO 4 Dry and filter with suction. The solvent was removed by rotary evaporation to obtain 14.3 g of o-cresol acetate as a colorless transparent liquid with a yield of 95%.

[0017] (2) Fries rearrangement: add 40 ml PhCl, 15 g o-cresol acetate and 20 g AlCl to the reaction vessel 3 , heated to 110~120°C to react. After the reaction, pour the product into 100 ml of water, add 25 ml of concentrated HCl under stirring, and adjust the pH to 3~4. Stand still and filter. The organic layer was s...

Embodiment 2

[0020] (1) Esterification reaction: add 10.8 g o-cresol, 1 g H 2 SO 4 14.3 g of acetic anhydride was added dropwise with stirring. After the acetic anhydride is dripped, heat to 50-60 °C, and keep the temperature until the end of the reaction. Pour 100 mlH 2 O, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 Extract (30 ml×2), and combine the organic layers. Wash the organic layer with water (30 ml × 2), anhydrous Na 2 SO 4 Dry and filter with suction. The solvent was removed by rotary evaporation to obtain 14.3 g of o-cresol acetate as a colorless transparent liquid with a yield of 95%.

[0021] (2) Fries rearrangement: Add 40 ml PhCl, 15 g o-cresol acetate and 20 g AlCl to the reaction vessel 3 , heated to 110~120°C to react. After the reaction, pour the product into 100 ml of water, add 25 ml of concentrated HCl under stirring, and adjust the pH to 3~4. Stand still and filter. The organic layer was separated from the filtrate, th...

Embodiment 3

[0025] 1) Esterification reaction: add 10.8 g o-cresol, 1 g H 3 PO 4 14.3 g of acetic anhydride was added dropwise with stirring. After the acetic anhydride is dripped, heat to 50-60 °C, and keep the temperature until the end of the reaction. Pour 100 mlH 2 O, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 Extract (30 ml×2), and combine the organic layers. Wash the organic layer with water (30 ml × 2), anhydrous Na 2 SO 4 Dry and filter with suction. The solvent was removed by rotary evaporation to obtain 14.3 g of o-cresol acetate as a colorless transparent liquid with a yield of 95%.

[0026] (2) Fries rearrangement: add 40 ml PhCl, 15 g o-cresol acetate and 20 g AlCl to the reaction vessel 3 , heated to 110~120°C to react. After the reaction, pour the product into 100 ml of water, add 25 ml of concentrated HCl under stirring, and adjust the pH to 3~4. Stand still and filter. The organic layer was separated from the filtrate, ...