Method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as intermediate of florfenicol

A synthesis method and florfenicol technology are applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., and can solve the problems of difficult industrial production, high waste water treatment costs, and unfavorable control costs, and achieve easy preparation. , The effect of reducing the preparation cost and low cost

Active Publication Date: 2011-01-12
MASTEAM BIO TECH
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Problems solved by technology

The disadvantages of this method are: 1. A large amount of copper sulfate wastewater will be produced during the preparation of copper salt, and the wastewater treatment cost is very high; 2. Although (1R, 2R)-2-amino with high e.e. value can be obtained by chiral resolution -1–(4-(thymphenyl)phenyl)-1,3-propanediol, but in terms of atom economy, 50% of the raw materials are wasted, which is unfavorable for cost control
Jon E. Clark and others in the United States carried out research on this type of reaction in 1991 by using an enzyme-catalyzed method (WO9014434). Later, Wu GZ and others in the United States proposed to use p-thiamphenicyl benzaldehyde as a raw material to asymmetrically synthesize fluorobenzene Nikau's process (WO9414764), but these two methods have the disadvantages of low yield and long process, which are difficult to apply to industrial production

Method used

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  • Method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as intermediate of florfenicol
  • Method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as intermediate of florfenicol
  • Method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as intermediate of florfenicol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1. Synthesis of nitroethanol:

[0038] Add paraformaldehyde (40 g, 1.3 mol), 400 g nitromethane (400.0 g, 6.6 mol), sodium fluoride (2.0 g, 34.4 mmol), and isopropanol (120 ml) to a 1000 ml round bottom flask. , Stirring, reacting at 40 ℃ for about 20 h, filtering to remove sodium fluoride, rotary evaporation to remove excess nitromethane and solvent isopropanol, to obtain a colorless transparent liquid 64.0 g, a yield of 62%. Among them, nitromethane and isopropanol can be recycled and put into the reaction again.

Embodiment 2

[0040] 2. Synthesis of (1R,2R)-2-nitro-1–(4-(methylsulfonyl)phenyl)-1,3-propanediol (IV) by catalyst 1:

[0041] 2.1 Synthesis of chiral catalyst ligand 1:

[0042] Add (1S)-(+)-ketopine acid (4.2 g, 23.0 mmol), 2-aminomethylpyridine (2.6 g, 24.4 mmol), BF to the 250 ml reaction flask 3 ·Et 2 O (0.4 ml), CHCl 3 (150 ml), N 2 Heat and reflux under protection for 4 h. After stopping the reaction, the reaction solution was concentrated under reduced pressure and crystallized in a mixed solvent of n-hexane / dichloromethane (volume ratio 3:1) to obtain 5.0 g of ligand 1 , The yield is 80%. [α] 20 D = + 64.8 (c 1.11, CHCl 3 ).

[0043] 2.2 Synthesis of chiral catalyst 1:

[0044] Add absolute ethanol (200 ml) and the ligand prepared above (4.9 g, 18.0 mmol) to a 1000 ml reaction flask, stir to dissolve and add Cu(OAc) 2 ·H 2 O (3.2 g, 16.3 mmol), and the mixture was stirred for 1 h. The resulting solution was the prepared chiral catalyst solution and was ready for use.

[0045] 2.3 Synt...

Embodiment 3

[0048] 3. Catalyst 2 synthesis (1R,2R)-2-nitro-1–(4-(methylsulfone)phenyl)-1,3-propanediol (IV):

[0049] 3.1 Synthesis catalyst 2:

[0050] Add absolute ethanol (200 ml) to the 1000 ml reaction flask, and the ligand prepared above 1 (4.9 g, 18.0 mmol), stir to dissolve and add Cu(OTf) 2 (5.8 g, 16.3 mmol), the mixture was stirred for 1 h, and the obtained solution was the prepared chiral catalyst solution, ready for use.

[0051] 3.2 Synthesis of catalyst 2 (1R,2R)-2-nitro-1–(4-(methylsulfone)phenyl)-1,3-propanediol (IV):

[0052] The experiment operation is the same Example 2.3 . 11.2 g of the product was obtained, the yield was 25%, and the e.e. value determined by HPLC was 30%.

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Abstract

The invention relates to a method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as an important intermediate of florfenicol, which is chloramphenicol spectrum antibiotic special for animals. The method comprises the following steps of: performing a reaction of methylsulfonyl benzaldehyde and nitro alcohol at 0-40 DEG C in the presence of a chiral catalyst to obtain (1R, 2R)-2-nitro-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol; and reducing the (1R, 2R)-2-nitro-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol through hydrogen to obtain the intermediate. In the invention, the compound (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol with a high e.e. value is obtained by adopting the chiral catalyst, and the compound has the advantages of strong reaction selectivity, high productivity, simple process, low cost, easy preparation of raw materials and low price, is suitable for industrial production, avoids chiral separation frequently used in industry at present and saves the raw materials and the cost. The compound (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol is used for preparing florfenicol and can reduce the preparation cost.

Description

technical field [0001] The invention relates to a synthesis method of (1R,2R)-2-amino-1-(4-(thymphenyl)phenyl)-1,3-propanediol, an important intermediate of veterinary drug florfenicol, belonging to the technical field of organic chemical industry. It also belongs to the technical field of intermediate synthesis of veterinary medicine and medicine. Background technique [0002] The chemical formula of (1R,2R)-2-amino-1–(4-(thysulfonyl)phenyl)-1,3-propanediol is: [0003] . [0004] Florfenicol, also known as D (+)-threo-1-p-thiamphenylphenyl-2-dichloroacetamido-3-fluoropropanol, is produced by American Schering-Plough (Schering - Plow) company Nagab-hushan et al. developed a kind of animal-specific chloramphenicol broad-spectrum antibiotics in the late 1970s; its chemical formula is [0005] . [0006] The antibacterial activity of florfenicol to sensitive bacteria is similar to that of chloramphenicol and thiamphenicol, but it is still sensitive to bacteria resistan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/32C07C315/04
Inventor 彭要武田文敬孙智英
Owner MASTEAM BIO TECH
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