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Novel preparation method of p-aminobenzamidine hydrochloride

A technology of aminobenzamidine hydrochloride and acetamidobenzonitrile, which is applied in the field of preparation of p-aminobenzamidine hydrochloride, can solve the problems of operator's health impact, strong equipment corrosion, low reaction efficiency and the like, and achieves The effect of short reaction time, high product purity and high yield

Inactive Publication Date: 2018-11-06
SICHUAN QINGMU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The biggest disadvantage of this method is that the reaction efficiency is low, the reaction has a violent exothermic phenomenon, the requirements for anhydrous conditions and the concentration of hydrogen chloride are extremely high, and the reaction is extremely corrosive to the equipment, which has an impact on the health of the operators, and the scale-up production is harmful. Security risks

Method used

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  • Novel preparation method of p-aminobenzamidine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Dissolve 1 kg of p-acetamidobenzonitrile in 5 L of dimethyl sulfoxide, add 853 g of sodium amide in batches, stir at room temperature for 30 minutes, then raise the temperature to 80° C. and continue the reaction for 1 hour, monitored by TLC (developing solvent: ethyl acetate / Petroleum ether (60-90°C) = 1 / 1 (V / V)) until p-acetamidobenzonitrile disappears. Cool the reaction solution to 0°C, add concentrated hydrochloric acid dropwise under rapid stirring until the system pH=3-4, stir for 30 minutes, add 5L absolute ethanol to the reaction solution, stir for 1 hour, add the reaction solution to 10L ethyl acetate Stir in the ester for 1 hour at room temperature, filter, and dry the filter cake under reduced pressure at 40°C for 4 hours to obtain 1.27 kg of p-aminobenzonitrile hydrochloride as a white solid with a yield of 97.8% and a purity of 99.6%. 1 H-NMR (DMSO-d 6 ,δ TMS 0): 8.97ppm (2H, s, heavy water exchange disappears), 8.79ppm (2H, s, heavy water exchange disap...

Embodiment 2

[0035] Dissolve 500g of p-acetamidobenzonitrile in 2L of tetrahydrofuran, slowly add 1.56L of sodium bis(trimethylsilyl)amide (2M in THF), stir at room temperature for 30 minutes, then raise the temperature to 80°C and continue the reaction for 2 hours, TLC Monitor (developer: ethyl acetate / petroleum ether (60-90°C) = 1 / 1 (V / V)) until p-acetamidobenzonitrile disappears. Cool the reaction solution to 0°C, add concentrated hydrochloric acid dropwise under rapid stirring until the system pH=3-4, after stirring for 1 hour, add 2L absolute ethanol to the reaction solution, stir for 1 hour, add the reaction solution to 4L ethyl acetate Stir in the ester for 1 h at room temperature, filter, and dry the filter cake under reduced pressure at 40°C for 4 hours to obtain 625.9 g of p-aminobenzonitrile hydrochloride as a white solid with a yield of 96.3% and a purity of 98.2%. The NMR and mass spectrometry identification results are consistent with Example 1.

Embodiment 3

[0037] Dissolve 20g of p-acetamidobenzonitrile in 100mL of toluene, slowly add 17g of sodium amide, stir at room temperature for 30 minutes, then raise the temperature to 80°C and continue the reaction for 4 hours, TLC monitoring (developing solvent: ethyl acetate / petroleum ether (60~ 90°C)=1 / 1(V / V)) until the p-acetamidobenzonitrile disappears. Cool the reaction solution to 0°C, add concentrated hydrochloric acid dropwise under rapid stirring until the system pH=3-4, stir for 1 hour, add 100 mL of absolute ethanol to the reaction solution, stir for 1 hour, add the reaction solution to 160 mL of ethyl acetate Stir in the ester for 1 h at room temperature, filter, and dry the filter cake under reduced pressure at 40°C for 4 hours to obtain 22.8 g of p-aminobenzonitrile hydrochloride as a white solid with a yield of 87.7% and a purity of 98.9%. The NMR and mass spectrometry identification results are consistent with Example 1.

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Abstract

The invention discloses a novel preparation method of p-aminobenzamidine hydrochloride. Particularly, with p-acetaminobenzonitrile as a raw material, the p-aminobenzamidine hydrochloride is prepared through a one-step reaction in an alkaline environment with an ammonia source. By the preparation method, the p-aminobenzamidine hydrochloride is prepared through the one-step chemical reaction; the raw material is cheap and easy to obtain, the operation is simple and controllable, the reaction yield is high, and the product purity is high; and the preparation method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a new method for preparing p-aminobenzamidine hydrochloride. Background technique [0002] P-aminobenzamidine hydrochloride is widely used. It is a ligand of an affinity adsorbent. It can be combined with dextran gel to make a bioseparation material. It can be combined with some specific enzymes and can It can be used as urokinase inhibitor; affinity chromatography ligand; competitive inhibitor of serine protease; as fluorescent probe for active site of serine protease. [0003] In recent years, p-aminobenzamidine hydrochloride has also been reported as a pharmaceutical intermediate, such as an intermediate of dabigatran etexilate. [0004] Dabigatran etexilate original research company Germany Boehringer Ingelheim reported in the patent CN102612517B that the p-aminobenzamidine intermediate is used for the preparation of dabigatran etexilate, and the synthetic route is as follows: [0005] [0006] At present, for the prep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C257/18
CPCC07C257/18
Inventor 李晓迅胡同军李建国王博王颖
Owner SICHUAN QINGMU PHARMA CO LTD
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