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Synthesis method of florfenicol

A technology of fluorine thiamphenicol and a synthesis method, applied in the field of chemical drugs, can solve the problems of long steps, large dosage and the like, and achieves the effects of simple operation, mild conditions and high yield

Active Publication Date: 2011-05-25
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses asymmetric hydroxycyanation and asymmetric induction to construct two chiral centers successively, and the reaction temperature is suitable, and the yield and selectivity are high; Larger dosage

Method used

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  • Synthesis method of florfenicol
  • Synthesis method of florfenicol
  • Synthesis method of florfenicol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 11

[0029] Example 11 Under the protection of nitrogen, (2S,3S)-1-benzhydryl-2-(fluoromethyl)-3-[4-(thysulfonyl)-phenyl] was sequentially added to the dry reaction flask Acridine (II) (3.93 g, 10 mmol), anhydrous dichloromethane (30 mL), DAST (3.0 g, 18 mmol), reacted at room temperature for 12 hours, quenched with 1N NaOH (30 mL), acetic acid Extracted 3 times with ethyl ester, combined, dried, filtered, concentrated, and column chromatographed to give a white solid which is compound (III) (3.80 g, 96%), mp: 166~168°C, optical rotation [α] 25 D = 101.7° (0.52, CHCl 3 ).

[0030] 1 H NMR (CDCl 3 , ppm): δ=2.40-2.47 (m, 2H, NCH), 3.03 (s, 3H, SO 2 CH 3 ), 3.10 (d, J = 6.0 Hz, 1H, ArCHN), 3.96 (s, 1H, PhCHPh), 3.98-4.12 (m, 1H, CH 2 F), 4.25-4.41 (m, 1H, CH 2 F), 7.17-7.50 (m, 10H, ArH), 7.56 (d, J = 8.4Hz, ArH), 7.86 (d, J = 8.4Hz, ArH).

[0031] ESI-MS: (m / z) = 396.1 (M + -+H).

Embodiment 12

[0032] Example 12 Under the protection of nitrogen, (2S,3S)-1-benzhydryl-2-(fluoromethyl)-3-[4-(thysulfonyl)-phenyl] was sequentially added to the dry reaction flask Acridine (II) (3.93 g, 10 mmol), anhydrous dichloromethane (30 mL), BAST (3.97 g, 18 mmol), reacted at room temperature for 12 hours, quenched with 1N NaOH (30 mL), acetic acid Ethyl ester was extracted 3 times, combined, dried, filtered, concentrated, and column chromatographed to obtain a white solid which was compound (III) (3.83 g, 97%), melting point, optical rotation, 1 H NMR and MS are consistent with Example 11.

Embodiment 13

[0033] Example 13 Under the protection of nitrogen, (2S,3S)-1-benzhydryl-2-(fluoromethyl)-3-[4-(thysulfonyl)-phenyl] was sequentially added to the dry reaction flask Acridine (II) (3.93 g, 10 mmol), anhydrous dichloromethane (30 mL), Ishikawa reagent (4.46 g, 20 mmol), sealed tube, reacted at 100°C for 6 hours, cooled to room temperature, washed with 1N NaOH ( 30 mL) to quench the reaction, extracted three times with ethyl acetate, combined, dried, filtered, concentrated, and column chromatographed to obtain a white solid which was compound (III) (2.89 g, 73%), melting point, optical rotation, 1 H NMR and MS are consistent with Example 11.

[0034] Two, (1 R ,2 S )-2-benzhydrylamino-3-fluoro-1-[4-(methylsulfonyl)-phenyl]propanol (IV) preparation

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Abstract

The invention belongs to the technical field of chemical medicaments, in particular to a synthesis method of florfenicol (1). The method comprises the following steps of: 1, performing fluorination on a compound (II) so as to obtain a compound (III); 2, performing ring opening on the compound (III) under the action of p-toluenesulfonic acid so as to obtain a compound (IV); 3, performing palladium-carbon hydrogenation and deprotection on the compound (IV) in an organic solvent under an acid condition so as to obtain a compound (V); and 4, performing dichloro acetylization on the compound (V) in an organic solvent under the action of alkali so as to obtain the florfenicol (1). The method has the advantages that: the design is novel, the condition is mild, the operation is easy and convenient, and industrial production prospect is obtained.

Description

technical field [0001] The invention belongs to the technical field of chemical medicines, and in particular relates to a synthesis method of fluthiamphenicol (I). Background technique [0002] Fluthiamphenicol (I) chemical name is 2,2-dichloro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-[4-(methylsulfonyl)phenyl] Ethyl] acetamide has broad-spectrum antibacterial activity and can be used to treat infections such as Gram-positive bacteria, negative bacteria and Rickettsia, and also has a strong inhibitory effect on drug-resistant bacteria of chloramphenicol and thiamphenicol. And it has less residue in animals, and is safer than chloramphenicol, and has been widely used. Its structural formula is as shown in formula (I): [0003] [0004] (I) [0005] U.S. Patent (US5382673) reports the intermediate of thiamphenicol (1 R ,2 R )-1-p-thiamphenylphenyl-2-amino-1,3-propanediol as the starting material, through oxazoline, isomerization, fluorination, hydrolysis and ring opening ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/14C07C315/04
Inventor 陈芬儿汪忠华李峰
Owner FUDAN UNIV
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