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Preparation method of levofloxacin defluorination impurity

A technology of levofloxacin and defluorination, which is applied in the field of preparation of pharmaceutical impurity standard products, can solve the problems of long steps and high requirements for operators, and achieve the effects of short preparation cycle, high purity and few by-products

Pending Publication Date: 2021-01-05
深圳市祥根生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are five reaction steps in this method, and the steps are relatively long. In the reaction process, various hazardous chemicals such as butyllithium and sodium hydride are used in contact with water, and multiple steps need to control anhydrous operation, which requires high requirements for operators.

Method used

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  • Preparation method of levofloxacin defluorination impurity
  • Preparation method of levofloxacin defluorination impurity
  • Preparation method of levofloxacin defluorination impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: the preparation of levofloxacin defluorination impurity

[0033] Preparation of compound (Ⅲ):

[0034] Add sodium methylthiolate (12.6g, 180 mmol, 6.0 eq) to a solution of levofloxacin (10.83g, 30 mmol, 1.0 eq) dissolved in N,N-dimethylformamide (86 mL), and then at 70°C Stir for 48 h. After the TLC plate showed that the reaction of the raw materials was complete, 200 mL of water was added to the above reaction solution. Finally, the mixture was stirred down to room temperature, and a large amount of off-white solid was precipitated, which was filtered by suction and rinsed with an appropriate amount of water and a small amount of ethanol. The filter cake was collected and dried to obtain 11.11 g of compound (Ⅲ), an off-white solid, with a yield of 95.1%.

[0035] Preparation of levofloxacin defluorinated impurities:

[0036] Add Raney nickel (29 mg, 0.5 mmol, 0.05 eq) to a solution of compound (Ⅲ) (3.89 g, 10 mmol, 1.0 eq) in ethanol (78 mL), and then ...

Embodiment 2

[0046] Embodiment 2: the preparation of levofloxacin defluorination impurity

[0047] Preparation of compound (Ⅲ):

[0048] Sodium methylthiolate (14.7g, 210 mmol, 7.0 eq) was added to levofloxacin (10.83g, 30 mmol, 1.0 eq) dissolved in dimethyl sulfoxide (54 mL), and stirred at 100°C for 48 h. After the TLC plate showed that the reaction of the raw materials was complete, 200 mL of water was added to the above reaction solution. Finally, the mixture was stirred down to room temperature, and a large amount of off-white solid was precipitated. The filter cake was collected by suction filtration and rinsed with an appropriate amount of water and a small amount of ethanol. After drying, 10.52 g of compound (Ⅲ) was obtained as an off-white solid with a yield of 90.0%.

[0049] Preparation of levofloxacin defluorinated impurities:

[0050] Add Raney nickel (59 mg, 1 mmol, 0.1 eq) to a solution of compound (Ⅲ) (3.89 g, 10 mmol, 1.0 eq) in methanol (39 mL), and then wash with N 2 Re...

Embodiment 3

[0051] Embodiment 3: the preparation of levofloxacin defluorination impurity

[0052] Preparation of compound (Ⅲ):

[0053] Add sodium methylthiolate (6.3g, 90 mmol, 3.0 eq) to a solution of levofloxacin (10.83g, 30 mmol, 1.0 eq) in N-methylpyrrolidone (108 mL), then stir at 50°C for 48 h . After the TLC plate showed that the reaction of the raw materials was complete, 150 mL of water was added to the above reaction solution. Finally, the mixture was stirred down to room temperature, and a large amount of off-white solid was precipitated. The filter cake was collected by suction filtration and rinsed with an appropriate amount of water and a small amount of ethanol. After drying, 8.95 g of compound (Ⅲ) was obtained as an off-white solid with a yield of 76.6%.

[0054] Preparation of levofloxacin defluorinated impurities:

[0055] Add Raney nickel (18 mg, 0.3 mmol, 0.03 eq) to a solution of compound (Ⅲ) (3.89 g, 10 mmol, 1.0 eq) in isopropanol (78 mL), and then wash with N ...

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Abstract

The invention provides a preparation method of a levofloxacin defluorination impurity, and belongs to the technical field of preparation of drug impurity standard substances, and the preparation method comprises the following steps: step 1, carrying out substitution reaction on a compound shown in a formula I and sodium methyl mercaptide in a first solvent at a first temperature to obtain a compound shown in a formula III; and 2, carrying out a reduction reaction on the compound represented by the formula III in the presence of hydrogen and a catalyst at a second solvent and a second temperature to obtain the levofloxacin defluorination impurity. According to the method, levofloxacin is used as a raw material, the method has the advantages of being simple to operate, short in preparation period, few in by-product, easy to purify, high in yield and environmentally friendly, and the prepared levofloxacin defluorination impurity is high in purity, meets the requirement of an impurity reference substance, can be used as a levofloxacin defluorination impurity standard substance for qualitative and quantitative research and detection of levofloxacin defluorination impurities.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical impurity standard products, and in particular relates to a preparation method of levofloxacin defluorinated impurities. Background technique [0002] Levofloxacin is a third-generation broad-spectrum fluoroquinolone antibacterial drug developed by Japan's Daiichi Pharmaceutical Company, which has obvious inhibitory effects on most Gram-positive and Gram-negative bacteria. Clinically, it is mainly used for respiratory system infection and genitourinary system infection caused by sensitive bacteria. The chemical name of levofloxacin is (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-[4-methyl-1-piperazinyl]-7-oxo-7 -hydropyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, its structural formula is as follows: [0003] [0004] At present, (2,3,4,5)-tetrafluorobenzoic acid is generally used as raw material in the domestic industrial production of levofloxacin, because the raw mate...

Claims

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Application Information

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IPC IPC(8): C07D498/06G01N1/28
CPCC07D498/06G01N1/28
Inventor 何冬梅李方林彭锦安
Owner 深圳市祥根生物科技有限公司
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