Preparation method of 5-bromo-2-chlorobenzoic acid
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A technology of chlorobenzoic acid and aminobenzoic acid, which is applied in the preparation of carboxylate, organic compound, and cyanide reaction, etc., can solve the problems of unfavorable industrial production, long reaction time, and high environmental pressure, and achieve effective Benefits of industrial production, short production cycle, high yield and purity
Inactive Publication Date: 2021-12-17
山东诚创蓝海医药科技有限公司
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In this method, when carrying out the chlorination reaction, because phosphorus pentachloride and o-chlorotoluene are solid-liquid two-phase in the early stage of the reaction, ultraviolet light has poor penetration rate to ordinary glass, resulting in longer reaction time, and after the reaction
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[0040] Example 1
[0041] 2-nitrobenzoic acid (50 g, 0.299 mol) were added to dichloromethane (200 mL), stirred, sulfoxide (42.7 g, 0.359 mol), warmed to reflow temperature, reflux for 5 hours, the raw material remaining 1%, stopped the reaction; cooled to 5 ° C, dripping methanol (15 g, 0.469 mol), and the temperature was controlled below 10 ° C, after the dropwise addition, stirred for 30 minutes, 40 ° C under reduced pressure, resulting in light The yellow liquid-shaped 2-nitrophenylmetate (first intermediate) 48.8 g, yield 90%, purity 99.2%.
Example Embodiment
[0042] Example 2
[0043] 2-nitrobenzoic acid (50 g, 0.299 mol) were added to methanol (200 mL), stirred, cooled to 0 ~ 5 ° C, dripping chloride (42.7 g, 0.359 mol), and then added, After 1 hour of temperature of 0 ~ 5 ° C, after the reaction was completed, the temperature was slowly warmed to the reflux temperature, and the reflux reaction was 2 hours, the raw material was left <1%, stopped, concentrated under reduced pressure to obtain a yellow liquid shape 2- Methyl nitrobenzoate (first intermediate) 49.3 g, yield 91%, purity 99.3%.
Example Embodiment
[0044] Example 3
[0045] 2-nitrobenzoic acid (50 g, 0.299 mol) were added to toluene (200 mL), stirred, anhydrous sulfate (20 g), ethanol (22 g, 0.478 mol), warmed to reflow temperature, reflux reaction for 7 hours, The raw material was left <1%, stopped reaction, filtration, and filtrate was concentrated to give crystalline liquid-shaped 2-nitrobenzoate (first intermediate) 51.3 g, yield 87.8%, purity 99.6%.
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Abstract
The invention discloses a preparation method of 5-bromo-2-chlorobenzoic acid, and belongs to the field of medicine synthesis. The preparation method comprises the following steps: (1) carrying out esterification reaction on 2-nitrobenzoic acid and alcohol to obtain a first intermediate; (2) carrying out reduction reaction on the first intermediate and a first reducing agent to obtain a second intermediate; (3) carrying out a halogenation reaction on the second intermediate and a first halogenation reagent, adding a second reducing agent into the reaction system after the halogenation reaction is completed, carrying out a reduction reaction, and then carrying out a hydrolysis reaction with alkali to obtain 5-bromo-2-aminobenzoic acid; and (4) carrying out diazotization reaction on the 5-bromo-2-aminobenzoic acid and a diazotization reagent, and then carrying out halogenation reaction on the 5-bromo-2-aminobenzoic acid and a second halogenation reagent to obtain the 5-bromo-2-chlorobenzoic acid. The preparation method has the advantages of mild reaction conditions, safe and simple operation, short production period, cheap and easily available raw materials and solvents, no explosive or highly toxic products, and facilitation of environmental protection; and the prepared product has high yield and purity, and is beneficial to industrial production.
Description
technical field [0001] The application belongs to the field of drug synthesis, and in particular relates to a preparation method of 5-bromo-2-chlorobenzoic acid. Background technique [0002] 5-Bromo-2-chlorobenzoic acid has an important use in the synthesis of medicines. It is the raw material for the synthesis of hypoglycemic drugs such as Empagliflozin, Dapagliflozin, Soxagliflozin, and Epagliflozin. These drugs are Sodium-glucose cotransporter 2 inhibitors that reduce renal glucose reabsorption and are used in the treatment of patients with type 2 diabetes. [0003] According to literature reports, the synthesis of 5-bromo-2-chlorobenzoic acid mainly contains two methods: [0004] The first method: use toluene as the starting material, react with chlorine gas to obtain o-chlorotoluene, then use potassium permanganate to oxidize the methyl group to obtain o-chlorobenzoic acid, and then carry out bromination reaction with liquid bromine or NBS to obtain 5- Bromo-2-chloro...
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