Synthesis method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline

Abstract

The invention discloses a synthesis method of 7-benzyloxy-6-methoxyl-4-hydroxyquinoline, which is characterized by comprising the following step of: under the action of proton acid, performing nitro reduction reaction and cyclization reaction for a compound C and a reducing agent to obtain a compound D, namely 7-benzyloxy-6-methoxyl-4-hydroxyquinoline. The synthesis method has the advantages of simple operation, mild reaction condition, high safety, high reactions conversion rate and selectivity, low cost and good environmental-protection property and conforms to the green chemistry standard of atom economy. By adopting post-processing methods, such as filtering, crystallizing and the like, the synthesis method is simple, convenient and feasible, and is suitable for both small-scale preparation in a laboratory and large-scale industrialized production.

Description

technical field

[0001] The invention relates to a synthesis method of a pharmaceutical intermediate, in particular to a synthesis method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline. Background technique

[0002] 7-benzyloxy-6-methoxy-4-hydroxyquinoline (compound D), has the following structure:

[0003]

[0004] Wherein, Bn is benzyl.

[0005] The compound is a quinoline compound, which is a commonly used intermediate in the field of pharmaceutical synthesis, and is especially widely used in the preparation of antimalarial drugs, antitumor drugs, anti-inflammatory and analgesic drugs, and the like.

[0006] At present, the synthesis method of the compound D (US6809097B1) needs to adopt high-temperature heating to close the ring and separate the product through silica gel column. This method has the characteristics of high cost, complicated operation, large solvent requirement and high risk, and is not suitable for industrial production; The synthesis method of compound ...

Examples

Embodiment 1

[0049] Example 1 Preparation of 4-benzyloxy-5-methoxy-2-nitroacetophenone (compound B)

[0050] Compound A (67 g, 0.25 mol) was dissolved in dichloromethane (450 ml), cooled to -5°C with stirring. After 65% nitric acid (24 g, 0.25 mol, 17 ml) was dissolved in acetic acid (250 ml), it was added dropwise to the acetic anhydride solution of compound A, stirred at 0-5° C. for 20 hours, and LCMS detected that the reaction was complete.

[0051] After concentrating under reduced pressure to remove dichloromethane, the reaction solution was poured into stirred ice water, the precipitated solid was filtered, washed with water and beaten with absolute ethanol, and the solid was filtered and dried to obtain compound B, 62.8 g, yield 81%, liquid chromatography The detection purity is 96%.

Embodiment 2

[0052]Example 2 Preparation of 4-benzyloxy-5-methoxy-2-nitroacetophenone (compound B)

[0053] Compound A (67 g, 0.25 mol) was dissolved in acetic anhydride (450 ml), cooled to -5°C with stirring. After 65% nitric acid (44.9 g, 0.46 mol, 32 ml) was dissolved in acetic acid (450 ml), it was added dropwise to the acetic anhydride solution of compound A, stirred at 0-5° C. for 18 hours, and the reaction was detected by LCMS to be complete.

[0054] The reaction solution was poured into stirred ice water, and the precipitated solid was filtered, washed with water, slurried with absolute ethanol, and the solid was filtered and dried to obtain Compound B, 64.4 g, with a yield of 83% and a purity of 98% by liquid chromatography.

Embodiment 3

[0055] Example 3 Preparation of 4-benzyloxy-5-methoxy-2-nitroacetophenone (compound B)

[0056] Compound A (67 g, 0.25 mol) was dissolved in acetic anhydride (450 ml), cooled to -5°C with stirring. After 65% nitric acid (44.9 g, 0.46 mol, 32 ml) was dissolved in 96% sulfuric acid (240 ml), it was added dropwise in the acetic anhydride solution of compound A, stirred at 0-5° C. for 18 hours, and LCMS detected that the reaction was complete.

[0057] The reaction solution was poured into stirred ice water, the precipitated solid was filtered, washed with water, beaten with anhydrous 95% ethanol, and the solid was filtered and dried to obtain compound B, 66.0 g, yield 85%, purity 96% by liquid chromatography.

technical field

[0001] The invention relates to a synthesis method of a pharmaceutical intermediate, in particular to a synthesis method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline. Background technique

[0002] 7-benzyloxy-6-methoxy-4-hydroxyquinoline (compound D), has the following structure:

[0003]

[0004] Wherein, Bn is benzyl.

[0005] The compound is a quinoline compound, which is a commonly used intermediate in the field of pharmaceutical synthesis, and is especially widely used in the preparation of antimalarial drugs, antitumor drugs, anti-inflammatory and analgesic drugs, and the like.

[0006] At present, the synthesis method of the compound D (US6809097B1) needs to adopt high-temperature heating to close the ring and separate the product through silica gel column. This method has the characteristics of high cost, complicated operation, large solvent requirement and high risk, and is not suitable for industrial production; The synthesis method of compound ...

Examples

Embodiment 1

[0049] Example 1 Preparation of 4-benzyloxy-5-methoxy-2-nitroacetophenone (compound B)

[0050] Compound A (67 g, 0.25 mol) was dissolved in dichloromethane (450 ml), cooled to -5°C with stirring. After 65% nitric acid (24 g, 0.25 mol, 17 ml) was dissolved in acetic acid (250 ml), it was added dropwise to the acetic anhydride solution of compound A, stirred at 0-5° C. for 20 hours, and LCMS detected that the reaction was complete.

[0051] After concentrating under reduced pressure to remove dichloromethane, the reaction solution was poured into stirred ice water, the precipitated solid was filtered, washed with water and beaten with absolute ethanol, and the solid was filtered and dried to obtain compound B, 62.8 g, yield 81%, liquid chromatography The detection purity is 96%.

Embodiment 2

[0052]Example 2 Preparation of 4-benzyloxy-5-methoxy-2-nitroacetophenone (compound B)

[0053] Compound A (67 g, 0.25 mol) was dissolved in acetic anhydride (450 ml), cooled to -5°C with stirring. After 65% nitric acid (44.9 g, 0.46 mol, 32 ml) was dissolved in acetic acid (450 ml), it was added dropwise to the acetic anhydride solution of compound A, stirred at 0-5° C. for 18 hours, and the reaction was detected by LCMS to be complete.

[0054] The reaction solution was poured into stirred ice water, and the precipitated solid was filtered, washed with water, slurried with absolute ethanol, and the solid was filtered and dried to obtain Compound B, 64.4 g, with a yield of 83% and a purity of 98% by liquid chromatography.

Embodiment 3

[0055] Example 3 Preparation of 4-benzyloxy-5-methoxy-2-nitroacetophenone (compound B)

[0056] Compound A (67 g, 0.25 mol) was dissolved in acetic anhydride (450 ml), cooled to -5°C with stirring. After 65% nitric acid (44.9 g, 0.46 mol, 32 ml) was dissolved in 96% sulfuric acid (240 ml), it was added dropwise in the acetic anhydride solution of compound A, stirred at 0-5° C. for 18 hours, and LCMS detected that the reaction was complete.

[0057] The reaction solution was poured into stirred ice water, the precipitated solid was filtered, washed with water, beaten with anhydrous 95% ethanol, and the solid was filtered and dried to obtain compound B, 66.0 g, yield 85%, purity 96% by liquid chromatography.

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