Synthetic method for stable isotope labeled thiamphenicol

Abstract

The invention relates to a synthesis method for stable isotope labeled thiamphenicol and belongs to the field of organic synthesis. The synthesis method for stable isotope labeled thiamphenicol is characterized in that p-bromobenzaldehyde and stable isotope labeled dimethylsulfoxide are taken as raw materials, the raw materials are synthesized to obtain stable isotope labeled p-methylthiobenzaldehyde, oxidization is performed to obtain stable isotope labeled 4-methylsulfonyl benzaldehyde, next, condensation is performed on stable isotope labeled 4-methylsulfonyl benzaldehyde and benzhydrylamine to obtain imine, then imine further reacts with ethyl diazoacetate under the action of (R)-VAPOL and triphenyl borate to build an ethylene imine structure fragment, at last, ring opening is performed on ethylene imine under a dichloroacetic acid condition, an ester group is reduced to synthesize stable isotope labeled thiamphenicol. The raw materials required for synthesis and an intermediate are simple and easily accessible, and the target product (stable isotope labeled thiamphenicol) is high in purity and stable isotope abundance, can be used for internal standard substances for veterinary drug residue test in the food safety field and study of the thiamphenicol metabolic mechanism, and has an important practical application value.

Description

technical field

[0001] The invention relates to a synthesis method of stable isotope-labeled thiamphenicol, belonging to the field of organic synthesis. Background technique

[0002] Thiamphenicol is a derivative of chloramphenicol, which is a synthetic broad-spectrum antibiotic of amidoalcohol, and is widely used clinically to prevent and treat infectious diseases in animals. However, due to its toxic and side effects on the blood system, its residues in animal foods may endanger human health. Therefore, many countries and international organizations in the world have stipulated the maximum residue limit of thiamphenicol in animal foods. However, unreasonable application and abuse still exist. The result is drug residues in food. At present, the traditional domestic detection methods use external standard method for determination. Due to the low concentration of the substance to be tested and the The matrix is ​​complex, there are many interfering substances, and the meta...

Examples

Embodiment 1

[0025] Embodiment 1: the synthetic method of deuterium-labeled 4-(methylmercapto) benzaldehyde

[0026]

[0027] In a sealed 25 mL glass tube, add p-bromobenzaldehyde (368 mg, 2 mmoL), cuprous iodide (76 mg, 0.4 mmoL), zinc acetate (364 mg, 4 mmoL), and dry deuterated dimethyl sulfoxide (6.5 mL) . Filled with nitrogen and reacted at 150°C for 12-36h. After the reaction was completed, it was cooled to room temperature, and the catalyst was removed by filtration. The filtrate was extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with water (3×50 mL), washed with saturated sodium chloride solution (3×50 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to obtain a crude product, and then deuterium-labeled 4-(methylmercapto)benzaldehyde (263 mg, 85%) was obtained as a pure product by column chromatography. H NMR (CDCl 3 , 600M) δppm 9.92(s, 1H), 7.77(d, 2H), 7.32(d, 2H); MS ESI+156[M+1].

Embodiment 2

[0028] Embodiment 2: the synthetic method of deuterium-labeled 4-thiamphenicol benzaldehyde

[0029]

[0030] In a 50mL three-necked flask, add a mixed solution of water and n-butanol (10mL, volume ratio 1:1), add 30% hydrogen peroxide (2mL), stir well, add 4-(methylmercapto)benzaldehyde-methyl -D 3 (155mg, 1mmoL), stirred at 0-5°C for 2 hours. Filter, extract the filtrate with ethyl acetate (3×20mL), combine the organic phases, wash with saturated sodium bicarbonate solution (3×20mL), water (3×20mL), and saturated sodium chloride solution (3×20mL) , 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 4-thiamphenicol benzaldehyde (172 mg, 92%). HNMR (CDCl 3 ,600M) δppm 9.88(s,1H), 7.81(d,2H), 7.36(d,2H); MS ESI+188[M+1].

Embodiment 3

[0031] Embodiment 3: The synthetic method of deuterium-labeled N-dianilino-1-(4-thiamphenicol phenyl) methylimine

[0032]

[0033] In a 100mL three-necked flask, add absolute ethanol (50mL), deuterated 4-thiamphenicol benzaldehyde (935mg, 5mmoL), and diphenylmethylamine (920mg, 5mmoL), react at 80°C for 2 hours, and cool to room temperature , the precipitated crystals were collected by filtration, washed with a small amount of cold ethanol, and dried under vacuum at 45° C. to obtain deuterium-labeled N-dianilino-1-(4-thiamphenylphenyl)methylimine (1.67 g, 95%). HNMR (CDCl 3 ,600M) δppm: 8.49(s,1H), 8.02(m,4H), 7.24~7.41(m,10H), 5.67(s,1H); MS ESI+353[M+1].

technical field

[0001] The invention relates to a synthesis method of stable isotope-labeled thiamphenicol, belonging to the field of organic synthesis. Background technique

[0002] Thiamphenicol is a derivative of chloramphenicol, which is a synthetic broad-spectrum antibiotic of amidoalcohol, and is widely used clinically to prevent and treat infectious diseases in animals. However, due to its toxic and side effects on the blood system, its residues in animal foods may endanger human health. Therefore, many countries and international organizations in the world have stipulated the maximum residue limit of thiamphenicol in animal foods. However, unreasonable application and abuse still exist. The result is drug residues in food. At present, the traditional domestic detection methods use external standard method for determination. Due to the low concentration of the substance to be tested and the The matrix is ​​complex, there are many interfering substances, and the meta...

Examples

Embodiment 1

[0025] Embodiment 1: the synthetic method of deuterium-labeled 4-(methylmercapto) benzaldehyde

[0026]

[0027] In a sealed 25 mL glass tube, add p-bromobenzaldehyde (368 mg, 2 mmoL), cuprous iodide (76 mg, 0.4 mmoL), zinc acetate (364 mg, 4 mmoL), and dry deuterated dimethyl sulfoxide (6.5 mL) . Filled with nitrogen and reacted at 150°C for 12-36h. After the reaction was completed, it was cooled to room temperature, and the catalyst was removed by filtration. The filtrate was extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with water (3×50 mL), washed with saturated sodium chloride solution (3×50 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to obtain a crude product, and then deuterium-labeled 4-(methylmercapto)benzaldehyde (263 mg, 85%) was obtained as a pure product by column chromatography. H NMR (CDCl 3 , 600M) δppm 9.92(s, 1H), 7.77(d, 2H), 7.32(d, 2H); MS ESI+156[M+1].

Embodiment 2

[0028] Embodiment 2: the synthetic method of deuterium-labeled 4-thiamphenicol benzaldehyde

[0029]

[0030] In a 50mL three-necked flask, add a mixed solution of water and n-butanol (10mL, volume ratio 1:1), add 30% hydrogen peroxide (2mL), stir well, add 4-(methylmercapto)benzaldehyde-methyl -D 3 (155mg, 1mmoL), stirred at 0-5°C for 2 hours. Filter, extract the filtrate with ethyl acetate (3×20mL), combine the organic phases, wash with saturated sodium bicarbonate solution (3×20mL), water (3×20mL), and saturated sodium chloride solution (3×20mL) , 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 4-thiamphenicol benzaldehyde (172 mg, 92%). HNMR (CDCl 3 ,600M) δppm 9.88(s,1H), 7.81(d,2H), 7.36(d,2H); MS ESI+188[M+1].

Embodiment 3

[0031] Embodiment 3: The synthetic method of deuterium-labeled N-dianilino-1-(4-thiamphenicol phenyl) methylimine

[0032]

[0033] In a 100mL three-necked flask, add absolute ethanol (50mL), deuterated 4-thiamphenicol benzaldehyde (935mg, 5mmoL), and diphenylmethylamine (920mg, 5mmoL), react at 80°C for 2 hours, and cool to room temperature , the precipitated crystals were collected by filtration, washed with a small amount of cold ethanol, and dried under vacuum at 45° C. to obtain deuterium-labeled N-dianilino-1-(4-thiamphenylphenyl)methylimine (1.67 g, 95%). HNMR (CDCl 3 ,600M) δppm: 8.49(s,1H), 8.02(m,4H), 7.24~7.41(m,10H), 5.67(s,1H); MS ESI+353[M+1].

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