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Synthesis method of dyclonine hydrochloride

A technique for the synthesis of dyclonine hydrochloride, which is applied in the direction of organic chemistry, can solve the problems of potential safety hazards, harsh storage conditions, and violent reactions, and achieve the effects of increased yield, less waste, and controllable reaction temperature

Pending Publication Date: 2021-12-03
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] This method has been further improved in the route reported by patent CN200810087761.X, mainly using 3-chloropropionyl chloride, which is flammable and reacts violently when it meets water, and the storage conditions are harsh, and there are potential safety hazards

Method used

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  • Synthesis method of dyclonine hydrochloride
  • Synthesis method of dyclonine hydrochloride
  • Synthesis method of dyclonine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1 prepares dyclonine hydrochloride

[0058] (1) Preparation of 4-bromo-β-piperidinylpropiophenone hydrochloride: add 19.9g p-bromoacetophenone, 100ml ethanol, 14.6g piperidine hydrochloride (1.2eq), 8.9 g paraformaldehyde (3.0eq) and 2ml hydrochloric acid, stir and heat up to 60°C for 4 hours, stop heating, cool and crystallize at 0°C for 4 hours, filter with suction, rinse the filter cake with isopropanol, and dry it in vacuum at 60°C , 30.6kg of white solid was obtained, the HPLC purity was 97%, and the yield was 92%.

[0059] (2) Preparation of dyclonine hydrochloride: under nitrogen protection, add 183ml dimethyl sulfoxide, 16.6g 4-bromo-β-piperidinylpropiophenone hydrochloride, 1.9g cuprous iodide to a 500mL three-necked flask (0.2eq), 2.6g trans-4-hydroxy-L-proline (0.4eq), 13.8g potassium carbonate (2.0eq), 3.1g tetrabutylammonium bromide (0.19eq), 33ml acetonitrile, control kettle The inner temperature is 50°C. Quickly add 18.5g of n-butanol (5.0eq...

Embodiment 2

[0061] Embodiment 2 prepares dyclonine hydrochloride

[0062] (1) Preparation of 4-bromo-β-piperidinylpropiophenone hydrochloride: add 19.9g p-bromoacetophenone, 100ml isopropanol, 14.6g piperidine hydrochloride (1.2eq) into a 250mL three-necked flask , 8.9g of paraformaldehyde (3.0eq) and 2ml of hydrochloric acid, stirred and heated to 60°C for 4h, then stopped heating, cooled and crystallized at 0°C for 4h, filtered with suction, rinsed the filter cake with isopropanol, at 60°C After vacuum drying, 27.9kg of white solid was obtained, the HPLC purity was 90%, and the yield was 84%.

[0063] (2) Preparation of dyclonine hydrochloride: the reaction conditions were kept the same as in Example 1 to obtain 12.5 g of white solid powder with a purity of 99.2% and a yield of 77%.

[0064]It can be seen from the above results that in the reaction system of step 2) of this example, the catalyst cuprous iodide is used, and the ligand trans-4-hydroxyl-L-proline is used at the same time,...

Embodiment 3

[0073] Example 3 Structure confirmation (using the sample prepared in Example 1)

[0074] (1) Proton Nuclear Magnetic Resonance (1H-NMR)

[0075] Instrument model: BRUKER AV-400 nuclear magnetic resonance instrument, deuterated chloroform as solvent.

[0076] 1H-NMR (CDCl 3 , 400MHz) δ12.3(s, 1H, H-Cl), 8.0(d, 2H, Ar-H), 6.9(d, 2H, Ar-H), 4.0(t, 2H, CH 2 ), 3.7(t, 2H, CH 2 ), 3.5 (m, 2H, CH 2 ), 3.4 (m, 2H, CH 2 ), 2.7(s, 2H, CH 2 ), 2.2(m, 2H, CH 2 ), 1.9-1.0 (m, 8H, 4×CH 2 ), 1.0 (m, 3H, CH 3 )

[0077] (2) Mass spectrometry (ESI, model: Agilent 1260-6230 TOF LC-MS)

[0078] The molecular weight of dyclonine hydrochloride is 325.9, wherein the molecular weight of the free base is 289.4, the benchmark is M, and molecular ion peaks (M+1) appear in the mass spectrum + It is 290.8, consistent with the corresponding molecular weight of dyclonine hydrochloride free base.

[0079] (3) HPLC purity 99.9%, determined by HPLC area normalization method, namely: chromatograph...

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Abstract

The invention discloses a brand new synthesis method of dyclonine hydrochloride. According to the method, p-bromoacetophenone is taken as a starting material, and dyclonine hydrochloride is produced through Mannich reaction and C-O cross-linking reaction. Compared with the prior art, the method has the advantages of easily available starting materials, controllable reaction temperature, higher purity, shortened time, increased yield and the like, avoids the use of high-toxicity reagents such as acetyl chloride, 3-chloropropionyl chloride and the like, and is more beneficial to drug safety and industrial mass production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing dyclonine hydrochloride. Background technique [0002] Dyclonine hydrochloride (English name Dyclonine hydrochloride); chemical name is 4-butoxy-β-piperidinylpropiophenone hydrochloride, structural formula: [0003] [0004] Dyclonine hydrochloride is a local anesthetic that can block the conduction of various nerve impulses or stimuli, inhibit touch and pain, and has pain-relieving, anti-pruritic and bactericidal effects on the skin. This product was first developed by Sharp&Dohme in the United States in 1932. Until the 21st century, there were few reports about Dyclonine abroad. [0005] In 1993, Indian patent IN172270A reported a route for the synthesis of dyclonine hydrochloride, the synthesis route of which is as follows: [0006] [0007] In this route, the yield of butoxyacetophenone is relatively low (up to 75%), thereby affecting ...

Claims

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Application Information

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IPC IPC(8): C07D295/108
CPCC07D295/108Y02P20/55
Inventor 王亚马振千刘宏远马立金胡丽娜朱琼孙江峰
Owner JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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