Synthetic method for stable isotope labeled chloramphenicol

Abstract

The invention relates to a synthetic method for stable isotope labeled chloramphenicol and belongs to the field of organic synthesis. The synthetic method for stable isotope labeled chloramphenicol ischaracterized in that a stable isotope labeled bromobenzene derivative is taken as a raw material, the raw material is subjected to para-position nitration, cyan substitution, cyan hydrolysis and reduction, and is further oxidized into carbonyl, a substitution reaction is performed on carbonyl and an aromatic ring to obtain amine which is condensed into imine, imine further reacts with ethyl diazoacetate under the action of (R)-VAPOL and triphenyl borate to build an ethylene imine structure, ring opening is performed on ethylene imine under an acid condition, and at last, an ester group is reduced to obtain stable isotope labeled chloramphenicol. The synthetic method is simple in step and simple and convenient to operate; and the product is high in chemical purity and isotope abundance and can be used for internal standard substances for veterinary drug residue test in the food safety field and study of the chloramphenicol metabolic mechanism.

Description

technical field

[0001] The invention relates to a synthesis method of stable isotope labeled chloramphenicol, which belongs to the field of organic synthesis. Background technique

[0002] Chloramphenicol is a broad-spectrum antibiotic produced by Streptomyces venezuela, which has inhibitory effects on both Gram-positive and Gram-negative bacteria, and has a stronger effect on the latter. Its production price is relatively cheap, so it is widely used in the prevention and treatment of human and animal diseases.

[0003] Although the antibacterial effect of chloramphenicol is very good, its side effects are very large. Chloramphenicol is extremely toxic to the human hematopoietic system, which can reduce white blood cells, especially kill granular white blood cells, affect the maturation of red blood cells, and easily cause regeneration disorders. Sexual anemia can impair vision, cause acute toxic epidermolysis, cause eyelid adhesion and corneal scarring. Moreover, it has a...

Examples

Embodiment 1

[0035] Embodiment 1: the synthetic method of deuterated p-nitrobromobenzene

[0036]

[0037] Add bismuth nitrate (1.6g, 3.6mmoL) and silica gel-loaded sulfuric acid (8g, 24mmoL) into a mortar, grind until a uniform white powder is formed, add deuterated bromobenzene (1.6g, 10mmoL), and continue grinding until deuterated bromobenzene Benzene disappeared, followed by TLC for about 5 minutes. The mixture was extracted with dichloromethane (2×100mL), the combined organic phases were filtered, and the filtrate was washed successively with saturated sodium bicarbonate solution (3×100mL), water (3×100mL), and saturated sodium chloride solution (3× 100mL), adding anhydrous sodium sulfate to dry. The desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain deuterium-labeled p-nitrobromobenzene (1.85 g, 90%). 13 C NMR (100M, CDCl 3 ) δ ppm 146.0, 131.7, 128.1, 124.1, MS ESI+209 [M+1...

Embodiment 2

[0038] Embodiment 2: the synthetic method of deuterated p-nitrobenzonitrile

[0039]

[0040] In a 25mL three-neck flask, add deuterium-labeled p-nitrobromobenzene (1.025g, 10mmoL), ethyl cyanoacetate (3.39g, 30mmoL), palladium acetate (448mg, 2mmoL), DPPE (1.2g, 3mmoL), TMEDA (1.16g, 10mmoL), sodium carbonate (3.18g, 30mmoL) and N,N-dimethylformamide (50mL) were reacted at 130°C for 24 hours under the protection of argon. The reaction mixture was cooled to room temperature, 30 mL of ethyl acetate was added, filtered, and the filtrate was washed with water (2×100 mL) and saturated sodium chloride solution (2×100 mL), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain deuterium-labeled p-nitrobenzonitrile (1.5 g, 90%). 13 C NMR (CDCl 3 , 100MHz) δppm 133.7, 132.9, 128.3, 118.3, 111.4; MS ESI+153 [M+1].

Embodiment 3

[0041] Embodiment 3: the synthetic method of deuterated p-nitrobenzoic acid

[0042]

[0043]In a 100mL three-necked flask, add 4M NaOH aqueous solution (100mL, 0.4moL) and deuterated p-nitrobenzonitrile (3g, 20moL) successively, react at 80°C for 4 hours, pour the reaction solution into 100mL water, and use Extract with ethyl acetate (3×100mL), adjust the pH value of the aqueous phase with dilute hydrochloric acid until the solution becomes turbid, continue to extract with ethyl acetate (3×100mL), combine the organic phases, wash with saturated sodium chloride solution (3×100mL ), dried over anhydrous sodium sulfate, filtered to remove the desiccant, distilled off the solvent under reduced pressure, and the residue was subjected to column chromatography to obtain deuterium-labeled p-nitrobenzoic acid (2.9 g, 85%). 13 C NMR (CDCl 3 , 100MHz) δppm 169.3, 152.2, 135.8, 129.6, 121.8; MS ESI-170 [M-1].

technical field

[0001] The invention relates to a synthesis method of stable isotope labeled chloramphenicol, which belongs to the field of organic synthesis. Background technique

[0002] Chloramphenicol is a broad-spectrum antibiotic produced by Streptomyces venezuela, which has inhibitory effects on both Gram-positive and Gram-negative bacteria, and has a stronger effect on the latter. Its production price is relatively cheap, so it is widely used in the prevention and treatment of human and animal diseases.

[0003] Although the antibacterial effect of chloramphenicol is very good, its side effects are very large. Chloramphenicol is extremely toxic to the human hematopoietic system, which can reduce white blood cells, especially kill granular white blood cells, affect the maturation of red blood cells, and easily cause regeneration disorders. Sexual anemia can impair vision, cause acute toxic epidermolysis, cause eyelid adhesion and corneal scarring. Moreover, it has a...

Examples

Embodiment 1

[0035] Embodiment 1: the synthetic method of deuterated p-nitrobromobenzene

[0036]

[0037] Add bismuth nitrate (1.6g, 3.6mmoL) and silica gel-loaded sulfuric acid (8g, 24mmoL) into a mortar, grind until a uniform white powder is formed, add deuterated bromobenzene (1.6g, 10mmoL), and continue grinding until deuterated bromobenzene Benzene disappeared, followed by TLC for about 5 minutes. The mixture was extracted with dichloromethane (2×100mL), the combined organic phases were filtered, and the filtrate was washed successively with saturated sodium bicarbonate solution (3×100mL), water (3×100mL), and saturated sodium chloride solution (3× 100mL), adding anhydrous sodium sulfate to dry. The desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain deuterium-labeled p-nitrobromobenzene (1.85 g, 90%). 13 C NMR (100M, CDCl 3 ) δ ppm 146.0, 131.7, 128.1, 124.1, MS ESI+209 [M+1...

Embodiment 2

[0038] Embodiment 2: the synthetic method of deuterated p-nitrobenzonitrile

[0039]

[0040] In a 25mL three-neck flask, add deuterium-labeled p-nitrobromobenzene (1.025g, 10mmoL), ethyl cyanoacetate (3.39g, 30mmoL), palladium acetate (448mg, 2mmoL), DPPE (1.2g, 3mmoL), TMEDA (1.16g, 10mmoL), sodium carbonate (3.18g, 30mmoL) and N,N-dimethylformamide (50mL) were reacted at 130°C for 24 hours under the protection of argon. The reaction mixture was cooled to room temperature, 30 mL of ethyl acetate was added, filtered, and the filtrate was washed with water (2×100 mL) and saturated sodium chloride solution (2×100 mL), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain deuterium-labeled p-nitrobenzonitrile (1.5 g, 90%). 13 C NMR (CDCl 3 , 100MHz) δppm 133.7, 132.9, 128.3, 118.3, 111.4; MS ESI+153 [M+1].

Embodiment 3

[0041] Embodiment 3: the synthetic method of deuterated p-nitrobenzoic acid

[0042]

[0043]In a 100mL three-necked flask, add 4M NaOH aqueous solution (100mL, 0.4moL) and deuterated p-nitrobenzonitrile (3g, 20moL) successively, react at 80°C for 4 hours, pour the reaction solution into 100mL water, and use Extract with ethyl acetate (3×100mL), adjust the pH value of the aqueous phase with dilute hydrochloric acid until the solution becomes turbid, continue to extract with ethyl acetate (3×100mL), combine the organic phases, wash with saturated sodium chloride solution (3×100mL ), dried over anhydrous sodium sulfate, filtered to remove the desiccant, distilled off the solvent under reduced pressure, and the residue was subjected to column chromatography to obtain deuterium-labeled p-nitrobenzoic acid (2.9 g, 85%). 13 C NMR (CDCl 3 , 100MHz) δppm 169.3, 152.2, 135.8, 129.6, 121.8; MS ESI-170 [M-1].

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