Preparation method of 3-hydroxy-4-methoxy-2-nitrobenzoic acid

Abstract

The invention discloses a preparation method of 3-hydroxy-4-methoxy-2-nitrobenzoic acid, and belongs to the field of synthesis of medical intermediates. The preparation method comprises the followingsteps: starting from 3-alkoxy-4-acetoxybenzaldehyde (1), carrying out a nitration reaction process to obtain an intermediate (2), removing acetyl from the intermediate (2) to obtain an intermediate (3), methylating to obtain an intermediate (4), oxidizing the intermediate (4) to obtain an intermediate (5), deprotecting the intermediate (5), and recrystallizing to remove the isomer, thereby obtaining the 3-hydroxy-4-methoxy-2-nitrobenzoic acid (6). The method is simple, convenient and stable to operate, high in yield, environment-friendly, low in production cost and suitable for industrial large-scale production, and products in all steps are easy to separate.

Description

technical field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of 3-hydroxy-4-methoxy-2-nitrobenzoic acid. Background technique

[0002] Certain pyrrolobenzodiazepines (PBD, or pyrrolobenzodiazepines) have the ability to recognize and bind to specific sequences in DNA. The antitumor antibiotic antramycin was discovered in 1965, reference: Leimgruber, et al., J.Am.Chem.Soc., 1965, 87, 5793-5795 and J.Am.Chem.Soc., 1965, 87, 5791-5793.

[0003] Since then, a large number of naturally occurring PBDs have been reported publicly and more than 10 synthetic routes have been developed for various analogs (Thurston, et al., Chem. Rev. 1994, 433-465). A compound with antitumor activity is reported in US4185016, the structural formula is shown in formula I, and its key intermediate is compound II of general formula.

[0004]

[0005] The compound 3-hydroxy-4-methoxy-2-nitrobenzoic acid of the present invention is ...

Examples

Embodiment 1

[0051] The first step: Synthesis of 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester

[0052] A dichloroethane solution of acetyl vanillin (19.4 g, 0.1 mol) was added in batches to fuming nitric acid (80 mL) at -20°C to -10°C, and stirred at 0-5°C. Pour the system into ice water, stir vigorously for half an hour, filter, wash twice with water to obtain the crude product, wash the crude product with cyclohexane, and drain to obtain light yellow solid 4-formyl-2-methoxy-3-nitroacetic acid phenyl , the ratio of isomers detected by HPLC was 11%, and the yield was 80% (including isomers). H-NMR (400MHz, DMSO-d 6):2.40(s,3H),3.87(s,3H),7.75(d,1H,J=8.4Hz),7.94(d,1H,J=8.4Hz),9.90(s,1H).

[0053] The second step: the synthesis of 3,4-dimethoxy-2-nitrobenzoic acid

[0054] 4-Formyl-2-methoxy-3-nitroacetic acid phenyl ester (23.9g, 0.1mol, 1eq) and potassium hydroxide (16.8g, 0.3mol, 3eq) were added in methanol (200mL), at 25 React at -45°C. After confirming the completion of the ...

Embodiment 2

[0058] The first step: Synthesis of 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester

[0059] A dichloromethane solution of acetyl vanillin (0.1 mol) was added to concentrated nitric acid (100 mL) in batches at -20°C to -10°C, and stirred at 0-5°C. The system was poured into ice water, stirred vigorously for half an hour, filtered, washed twice with water to obtain the crude product, which was washed with cyclohexane, and dried to obtain phenyl 4-formyl-2-methoxy-3-nitroacetate. The ratio of isomers detected and analyzed by HPLC was 12%, and the yield was 83% (including isomers). The solid was determined to be phenyl 4-formyl-2-methoxy-3-nitroacetate by TLC detection.

[0060] The second step: the synthesis of 3,4-dimethoxy-2-nitrobenzoic acid

[0061] Add 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester (0.1mol, 1eq) and sodium hydroxide (0.3mol, 3eq) into tetrahydrofuran (200mL) and react at -10-10°C . After confirming the completion of the reaction by pointing the p...

Embodiment 3

[0065] The first step: Synthesis of 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester

[0066] A chloroform solution of acetyl vanillin (0.1 mol) was added in batches to fuming nitric acid (60 mL) at -20°C to -10°C, and stirred at 0-5°C. The system was poured into ice water, stirred vigorously for half an hour, filtered, washed twice with water to obtain the crude product, washed with cyclohexane, and dried to obtain phenyl 4-formyl-2-methoxy-3-nitroacetate, which was analyzed by HPLC The ratio of isomers detected and analyzed was 9%, and the yield was 85% (including isomers).

[0067] The second step: the synthesis of 3,4-dimethoxy-2-nitrobenzoic acid

[0068] Add 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester (0.1mol, 1eq) and lithium hydroxide (0.3mol, 3eq) into dioxane (200mL), at 10-25°C The next reaction. After confirming the completion of the reaction by pointing the plate, add iodomethane (0.11mol, 1.1eq) to the above solution, and stir the reaction solution at...

technical field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of 3-hydroxy-4-methoxy-2-nitrobenzoic acid. Background technique

[0002] Certain pyrrolobenzodiazepines (PBD, or pyrrolobenzodiazepines) have the ability to recognize and bind to specific sequences in DNA. The antitumor antibiotic antramycin was discovered in 1965, reference: Leimgruber, et al., J.Am.Chem.Soc., 1965, 87, 5793-5795 and J.Am.Chem.Soc., 1965, 87, 5791-5793.

[0003] Since then, a large number of naturally occurring PBDs have been reported publicly and more than 10 synthetic routes have been developed for various analogs (Thurston, et al., Chem. Rev. 1994, 433-465). A compound with antitumor activity is reported in US4185016, the structural formula is shown in formula I, and its key intermediate is compound II of general formula.

[0004]

[0005] The compound 3-hydroxy-4-methoxy-2-nitrobenzoic acid of the present invention is ...

Examples

Embodiment 1

[0051] The first step: Synthesis of 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester

[0052] A dichloroethane solution of acetyl vanillin (19.4 g, 0.1 mol) was added in batches to fuming nitric acid (80 mL) at -20°C to -10°C, and stirred at 0-5°C. Pour the system into ice water, stir vigorously for half an hour, filter, wash twice with water to obtain the crude product, wash the crude product with cyclohexane, and drain to obtain light yellow solid 4-formyl-2-methoxy-3-nitroacetic acid phenyl , the ratio of isomers detected by HPLC was 11%, and the yield was 80% (including isomers). H-NMR (400MHz, DMSO-d 6):2.40(s,3H),3.87(s,3H),7.75(d,1H,J=8.4Hz),7.94(d,1H,J=8.4Hz),9.90(s,1H).

[0053] The second step: the synthesis of 3,4-dimethoxy-2-nitrobenzoic acid

[0054] 4-Formyl-2-methoxy-3-nitroacetic acid phenyl ester (23.9g, 0.1mol, 1eq) and potassium hydroxide (16.8g, 0.3mol, 3eq) were added in methanol (200mL), at 25 React at -45°C. After confirming the completion of the ...

Embodiment 2

[0058] The first step: Synthesis of 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester

[0059] A dichloromethane solution of acetyl vanillin (0.1 mol) was added to concentrated nitric acid (100 mL) in batches at -20°C to -10°C, and stirred at 0-5°C. The system was poured into ice water, stirred vigorously for half an hour, filtered, washed twice with water to obtain the crude product, which was washed with cyclohexane, and dried to obtain phenyl 4-formyl-2-methoxy-3-nitroacetate. The ratio of isomers detected and analyzed by HPLC was 12%, and the yield was 83% (including isomers). The solid was determined to be phenyl 4-formyl-2-methoxy-3-nitroacetate by TLC detection.

[0060] The second step: the synthesis of 3,4-dimethoxy-2-nitrobenzoic acid

[0061] Add 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester (0.1mol, 1eq) and sodium hydroxide (0.3mol, 3eq) into tetrahydrofuran (200mL) and react at -10-10°C . After confirming the completion of the reaction by pointing the p...

Embodiment 3

[0065] The first step: Synthesis of 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester

[0066] A chloroform solution of acetyl vanillin (0.1 mol) was added in batches to fuming nitric acid (60 mL) at -20°C to -10°C, and stirred at 0-5°C. The system was poured into ice water, stirred vigorously for half an hour, filtered, washed twice with water to obtain the crude product, washed with cyclohexane, and dried to obtain phenyl 4-formyl-2-methoxy-3-nitroacetate, which was analyzed by HPLC The ratio of isomers detected and analyzed was 9%, and the yield was 85% (including isomers).

[0067] The second step: the synthesis of 3,4-dimethoxy-2-nitrobenzoic acid

[0068] Add 4-formyl-2-methoxy-3-nitroacetic acid phenyl ester (0.1mol, 1eq) and lithium hydroxide (0.3mol, 3eq) into dioxane (200mL), at 10-25°C The next reaction. After confirming the completion of the reaction by pointing the plate, add iodomethane (0.11mol, 1.1eq) to the above solution, and stir the reaction solution at...

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