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Synthetic method for stable isotope labeled florfenicol

A stable isotope and florfenicol technology, applied in the direction of isotope introduction of organic compounds, heterocyclic compound isotope introduction, acyclic/carbocyclic compound isotope introduction, etc., can solve the problem of low utilization rate and long route of stable isotope labeling intermediates , low total yield and other problems, to achieve the effect of simple synthesis steps, reduced production costs, and high product yield

Inactive Publication Date: 2018-03-23
山东辉璟生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method has a long route, and stable isotope-labeled intermediates have never been reported in the literature, and the overall yield is low, and the utilization rate of stable isotope-labeled intermediates is not high.

Method used

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  • Synthetic method for stable isotope labeled florfenicol
  • Synthetic method for stable isotope labeled florfenicol
  • Synthetic method for stable isotope labeled florfenicol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: the synthetic method of deuterium-labeled 4-(methylmercapto) benzaldehyde

[0028]

[0029] In a sealed 25 mL glass tube, p-bromobenzaldehyde (184 mg, 1 mmol), cuprous iodide (190 mg, 1 mmol) and dry deuterated dimethyl sulfoxide (5 mL) were added. Filled with nitrogen, reacted at 130°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 (3×20 mL), the organic phases were combined, washed with water (3×20 mL), washed with saturated sodium chloride solution (3×20 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 (143 mg, 92%) 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

[0030] Embodiment 2: the synthetic method of deuterium-labeled 4-thiamphenicol benzaldehyde

[0031]

[0032] In a 50mL three-necked flask, add 0.5M aqueous sodium hydroxide solution, add m-CPBA (380mg, 2.2mmol), 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 (187 mg, 96.2%). H NMR (CDCl 3 ,600M) δppm 9.88(s,1H), 7.81(d,2H), 7.36(d,2H); MS ESI+188[M+1].

Embodiment 3

[0033] Embodiment 3: The synthetic method of deuterium-labeled N-dianilino-1-(4-thiamphenicol phenyl) methylimine

[0034]

[0035] In a 100mL three-necked flask, add absolute ethanol (20mL), 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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Abstract

The invention relates to a synthetic method for stable isotope labeled florfenicol and belongs to the field of organic synthesis. The synthetic method for stable isotope labeled florfenicol 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 toobtain 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, ester group is reduced, a hydroxyl group is fluoridize, and ring opening is performed on ethylene imine under a dichloroacetic acid condition to synthesize stable isotope labeled florfenicol. The raw materials required for synthesis are simple and easily accessible, and the target product (stable isotope labeled florfenicol) 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 florfenicol metabolic mechanism, and has an important practical application value.

Description

technical field [0001] The invention relates to a method for synthesizing stable isotope florfenicol, which belongs to the field of organic synthesis. Background technique [0002] Florfenicol, also known as florfenicol, is a monofluorinated derivative of thiamphenicol. It is a new type of animal-specific chloramphenicol developed by Schering-Plauer in the late 1980s. Spectrum antibiotics. Compared with similar chloramphenicol and thiamphenicol, florfenicol has the advantages of high antibacterial activity and no potential aplastic anemia. play an important role. However, because it still has certain immunotoxicity and embryotoxicity, unreasonable application and abuse will still cause its residues in animal food to endanger human health. Therefore, many countries and international organizations in the world have stipulated the maximum residue limit of florfenicol in animal foods. In my country, the Ministry of Agriculture also issued Announcement No. 2483-8 on December ...

Claims

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Application Information

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IPC IPC(8): C07B59/00C07C317/32C07C315/02C07C315/04C07C319/14C07C323/22C07D203/08C07D203/02
CPCC07B59/001C07B59/002C07B2200/05C07B2200/07C07C315/02C07C315/04C07C319/14C07D203/02C07D203/08C07C317/32C07C323/22
Inventor 董金华梁大伟王玮王朝阳
Owner 山东辉璟生物医药科技有限公司
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