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Preparation method of biperiden hydrochloride

A technology for biperiden hydrochloride and intermediates, which is applied in the field of drug synthesis technology, can solve the problems of high internal impurities, pollution, and low yield of hydrochloric acid, and achieve the effects of saving costs and reducing pollution

Active Publication Date: 2019-02-22
ANHUI HEALSTAR PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The present invention is to provide a method for preparing biperiden, which solves the problems of high endotype impurities, low yield and serious pollution in the existing preparation method of biperiden hydrochloride. Easy to obtain, low price, simple operation, mild reaction conditions, and good industrial application value

Method used

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  • Preparation method of biperiden hydrochloride
  • Preparation method of biperiden hydrochloride
  • Preparation method of biperiden hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment one: the preparation of biperiden hydrochloride

[0049] a. Preparation of Intermediate II

[0050] 84g (0.7mol) of 5-ethylene-2-norbornene, 325ml of acetonitrile, 65ml of deionized water, 3.6g of palladium dichloride and 1.8g of copper chloride were added to the autoclave, and the 2 Displacing air, passing O 2, the temperature is maintained at 80-90°C, the pressure is at 15-16 atmospheres, react for 4 hours, GC identifies the reaction end point, the reaction is completed, cooled to room temperature, filtered with diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 65.8g (0.483mol) Colorless oily liquid intermediate II, with a yield of 69.1% and a GC content of 99.1%, was directly used in the next step.

[0051] b. Preparation of Intermediate III

[0052] Glacial acetic acid 480ml, piperidine hydrochloride 60.8g (0.5mol), paraformaldehyde 14.5g (0.5mol), intermediate II 61.3g (0.45mol), heated to 95-98°C under stirring, an...

Embodiment 2

[0059] Embodiment two: the preparation of biperiden hydrochloride

[0060] a. Preparation of Intermediate II

[0061] 59g (0.5mol) of 5-ethylene-2-norbornene, 250ml of DMF, 44ml of deionized water, 2.5g of palladium dichloride and 1.25g of copper chloride were added to the autoclave and heated with N 2 Displacing air, passing O 2 , the temperature is maintained at 85-90°C, the pressure is at 15-17 atmospheres, react for 3h, GC identifies the reaction end point, the reaction is completed, cooled to room temperature, filtered with diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 46g (0.338mol) of The color oily liquid intermediate II, with a yield of 69.7% and a GC content of 99.5%, was directly used in the next step.

[0062] b. Preparation of Intermediate III

[0063] 350ml of glacial acetic acid, 43g (0.35mol) of piperidine hydrochloride, 10.2g (0.35mol) of paraformaldehyde, 43g (0.315mol) of intermediate II, heated to 95-98°C under sti...

Embodiment 3

[0070] Embodiment three: the detection of biperiden hydrochloride

[0071] Instrument: Shimadzu GC-16A gas chromatograph, C-R3A chromatographic processor, poly(dimethyl)-(diphenyl)-(divinyl)siloxane R-50m×0.25mm fused silica glass column ;

[0072] Detector: hydrogen flame ion detector (FID); detection chamber, vaporization chamber temperature: 300°C; carrier gas: N240ml / min; H250ml / min; air 500ml / min; attenuation: 3; injection volume: 2μl; column temperature Follow the table below:

[0073]

[0074] Result: GC content is 99.8%, and the detected impurities are shown in the table below:

[0075]

[0076] The hydrochloric acid prepared by the invention has better quality than periden.

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Abstract

The invention provides a novel biperiden hydrochloride preparation method, belongs to the technical field of drugs and chemical synthesis and achieves the purpose that extravert type biperiden hydrochloride prepared in large scale conforms to latest European pharmacopoeia standards. The novel biperiden hydrochloride preparation method includes that 5-ethylene-2-norbornene is taken as a starting material to prepare key extravert type 5-acetyl norbornene via selective oxidation; the biperiden hydrochloride is prepared via Mannich reaction, extravert type heterogeneous salt-forming reaction, Grignard reaction and salt forming reaction. The novel biperiden hydrochloride preparation method has the advantages of easy obtaining of raw materials, low price, simpleness in operation, moderate reaction conditions and good industrial application value.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis technology, in particular to an organic synthesis method that is simple to operate, conforms to the European Pharmacopoeia 8.7 edition standard, has high yield, and is suitable for large-scale industrial production, and specifically relates to a preparation method of biperiden hydrochloride . Background technique [0002] Parkinson's disease (PD) is a neurodegenerative disease characterized by neurodegeneration of the nigrostriatal pathway. It is the second largest neurodegenerative disease seriously affecting human health. At present, clinically, PD is treated symptomatically, and there is no effective treatment that can restore degenerated neurons. In the treatment of PD, drug therapy is the main method. These drugs are mainly developed based on the key targets or signaling pathways in the pathogenesis of PD, which can relieve the symptoms of PD. The research and development ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/092
CPCC07D295/092
Inventor 徐奎刘丽王亚丽
Owner ANHUI HEALSTAR PHARM CO LTD
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