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Preparation method of ibuprofen impurity B

An impurity and compound technology, applied in the field of preparation of pharmaceutical impurity standard products, can solve the problems of difficult reaction and cannot be satisfied, and achieve the effects of short preparation period, convenient operation and few by-products

Inactive Publication Date: 2021-03-12
艾希尔(深圳)药物研发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And due to 2-(4-n-butylphenyl)propionic acid due to steric hindrance, the reaction is more difficult
[0008] It can be seen that designing an efficient, directional, and specialized method for synthesizing ibuprofen impurity B, reducing by-product generation, and improving product yield, is the key to the research of the entire preparation process, and the prior art cannot be satisfied

Method used

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  • Preparation method of ibuprofen impurity B
  • Preparation method of ibuprofen impurity B
  • Preparation method of ibuprofen impurity B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the preparation of intermediate formula 2 compound

[0037] Add the compound of formula 1 (1.78 g, 10 mmol, 1.0 eq) into the three-neck flask, Pd(PPh 3 ) 4 (347mg, 0.3mmol, 0.03eq), Cu 2 O (43 mg, 0.3 mmol, 0.03 eq), K 2 CO 3 (2.07 g, 15 mmol, 1.5 eq) and toluene (20 mL), vacuumize, replace with argon 3 times, then stir and heat up to 80°C for 18 hours, TLC monitors 1 reaction is complete, cool down to room temperature, filter with diatomaceous earth , the filtrate was concentrated to remove the solvent, purified by silica gel column chromatography, the elution condition was: petroleum ether: ethyl acetate = 20:1, and 1.92 g of the intermediate compound of formula 2 was obtained, with a yield of 87.3%.

Embodiment 2

[0038] Embodiment 2: the preparation of intermediate formula 3 compound

[0039] Under nitrogen protection, add intermediate 2 compound (1.76g, 8 mmol, 1.0 eq) dissolved in dry tetrahydrofuran (15 mL) into the three-necked flask, then stir and cool to -78°C, slowly add 1.0 M bistrimethyl A tetrahydrofuran solution of lithium silylamide (8.8 mL, 8.8 mmol, 1.1 eq) was added dropwise and continued to stir for 30 minutes, then CH dissolved in dry THF (2 mL) was added dropwise 3 I (0.5 mL, 8 mmol, 1.0eq), continue stirring for 1 hour after the dropwise addition, then return to room temperature and continue stirring for 2 hours, then lower to 0°C, slowly add saturated NH 4 Cl solution (20 mL), then extracted with EA (20 mL×3), the organic phases were combined, washed with saturated brine, separated, and the organic phase was washed with anhydrous Na 2 SO 4 Dry, concentrate to remove the solvent, and purify by silica gel column chromatography, the elution condition is: petroleum et...

Embodiment 3

[0040] Embodiment 3: the preparation of ibuprofen impurity B

[0041] Add intermediate 3 compound (1.64 g, 7 mmol, 1.0 eq) and ethanol (15 mL) into a 100 mL single-necked bottle, and add sodium hydroxide (0.56 g, 14 mmol, 2.0 eq) solution, the reaction was continued for 3 hours after the dropwise addition, and the reaction was completed by TLC monitoring 3, and the pH was adjusted to 3~4 with 1N HCl. Then it was extracted with EA (20 mL×3), the organic phases were combined, washed with saturated brine, separated, and the organic phase was washed with anhydrous Na 2 SO 4 Dry, concentrate to remove the solvent, and purify by silica gel column chromatography. The elution condition is: dichloromethane: methanol: acetic acid = 50:1:0.1 to obtain 1.38 g of ibuprofen impurity B with a yield of 95.5%.

[0042] Molecular formula of ibuprofen impurity B: C 13 h 18 o 2 ;

[0043] Molecular weight of ibuprofen impurity B: 206.28.

[0044] Adopt mass spectrometer to analyze syntheti...

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Abstract

The invention provides a preparation method of an ibuprofen impurity B, and belongs to the technical field of preparation of drug impurity standard substances, and the preparation method comprises thefollowing steps: step 1, carrying out coupling reaction on a compound shown in a formula 1 and ethyl bromoacetate under the action of a catalyst and a first alkali to obtain a compound shown in a formula 2; 2, performing substitution reaction on the compound shown in the formula 2 and methyl iodide under the action of second alkali to obtain a compound shown in a formula 3; and 3, hydrolyzing thecompound shown in the formula 3 under the action of a third alkali to obtain the ibuprofen impurity B. The method has the advantages of simplicity in operation, short preparation period, few byproducts, easiness in purification and high yield, the prepared ibuprofen impurity B has high purity and no obvious impurity point, meets the requirements of impurity reference substances, can be used as anibuprofen impurity B standard substance, is applied to qualitative and quantitative research and detection of the ibuprofen impurity B, and has certain significance for quality control of ibuprofen bulk drugs and related preparations thereof.

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 ibuprofen impurity B. Background technique [0002] Ibuprofen (Ibuprofen, formula I), the chemical name is 2-(4-isobutylphenyl) propionic acid, and the Chinese alias is called "Ba Nufeng". It is a non-steroidal anti-inflammatory drug widely used clinically. Alkanoic acid drugs. Ibuprofen can be used as a substitute for aspirin, and has stronger antipyretic, anti-inflammatory and analgesic effects. It is mainly used for the control of inflammation and pain in diseases such as colds, rheumatism and rheumatoid arthritis, while the side effects are much smaller than aspirin . European Pharmacopoeia, British Pharmacopoeia, American Pharmacopoeia, Pharmacopoeia, and Chinese Pharmacopoeia all record the variety of ibuprofen, and the determination of its related substances is also described in detail. ...

Claims

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Application Information

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IPC IPC(8): C07C51/09C07C57/30C07C67/343C07C69/612
CPCC07C51/09C07C67/343C07C69/612C07C57/30
Inventor 张亮彭锦安李方林
Owner 艾希尔(深圳)药物研发有限公司
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