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A method for synthesizing deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride with boc-protected benzylamine

A technology of deuterated dimethylamine hydrochloride and deuterated methylamine hydrochloride, which is applied in the field of organic synthesis and achieves the effects of serious environmental pollution, few by-products and many reaction steps

Active Publication Date: 2022-03-08
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Purpose of the invention: Aiming at various problems faced by the existing synthetic methods of deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride, the present invention provides a brand-new synthesis of deuterated methylamine with Boc-protected benzylamine The method of hydrochloride and deuterated dimethylamine hydrochloride can realize the preparation of deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride with high yield and low cost, and can avoid the generation of multi-substituted by-products

Method used

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  • A method for synthesizing deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride with boc-protected benzylamine
  • A method for synthesizing deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride with boc-protected benzylamine
  • A method for synthesizing deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride with boc-protected benzylamine

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Embodiment 1

[0039] Preparation of deuterated methylamine hydrochloride

[0040]

[0041] Synthesis of Compound 2

[0042] Boc-protected benzylamine (24.12 mmol) (CAS42116-44-9) was added to 25 ml DMF at 0°C under nitrogen protection. Then NaH (60%, 26.54mmol) was added dropwise, and after stirring for 30min, TsOCD dissolved in 5mL DMF was added dropwise 3 (24.12 mmol) (CAS 7575-93-1), then the reaction mixture was heated to room temperature, and after the completion of the reaction was confirmed by thin-layer chromatography analysis, saturated ammonium chloride (40 mL) was added at room temperature to quench the reaction. Extracted with EA (ethyl acetate) and water (3×50ml), combined the organic layers in anhydrous Na 2 SO 4 dried, filtered and concentrated by rotary evaporation to obtain the crude product. Compound 2 (23.15 mmol) was obtained through silica gel column chromatography (EA:PE=1:10) with a yield of 96%; 1 H NMR (400MHz, CDCl 3 ):δ1.47(s,9H,-CH 3 ),4.41(s,2H,-CH 2 ...

Embodiment 2

[0048] Preparation of deuterated dimethylamine hydrochloride

[0049]

[0050] Synthesis of compound 5

[0051] React as in Example 1 to obtain compound 3N-benzyldeuteromethylamine hydrochloride. Add N-benzyldeuteromethylamine hydrochloride (16.10mmol) to 16mL of anhydrous THF under nitrogen protection at -20°C, then add n-butyllithium (16.10mmol) dropwise, stir for 30min, then add 20mL dropwise TsOCD 3 (16.10 mmol) of anhydrous THF solution was reacted for 30 minutes, the reaction mixture was warmed to room temperature and reacted overnight. After completion of the reaction as determined by thin layer chromatography analysis, the reaction was quenched with saturated ammonium chloride (20 mL) at room temperature. Extracted with water and EA (3×30ml), combined organic layers, anhydrous Na 2 SO 4 The crude product was obtained by drying, filtering and rotary evaporation. Silica gel column chromatography (DCM:MeOH20:1) obtained compound 5 (14.68mmol), yield 91%; 1 H NMR...

Embodiment 3

[0063] Embodiment 3 is identical with embodiment 1 preparation method, and difference is:

[0064] Compound 2 was synthesized at -20°C using potassium tert-butoxide and deuteromethyl iodide, and the molar ratio of compound 1 to deuteromethyl iodide was 4:1;

[0065] In the synthesis of compound 3, the reaction molar ratio of compound 2 and HCl is 1:1, and the solvent dimethyl sulfoxide of the HCl solution;

[0066] In the preparation of deuterated methylamine hydrochloride, palladium carbon (0.5% palladium), the reaction temperature is 60°C.

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Abstract

The invention discloses a method for synthesizing deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride with Boc-protected benzylamine, mainly using Boc-protected benzylamine as raw material, and deuterated The methylating reagent reacts to generate deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride. The synthetic method of the present invention can avoid the disadvantage of easily generating trisubstituted and tetrasubstituted methyl by-products in conventional synthetic methods. Therefore, the preparation of deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride by the method of the present invention has the advantages of less by-products and easy purification, and has important guiding value for the research and development of deuterated drugs.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing deuterated methylamine hydrochloride and deuterated dimethylamine hydrochloride by using Boc-protected benzylamine as a raw material. Background technique [0002] Replacing the carbon-hydrogen bond with a carbon-deuterium bond in the molecule can significantly improve the chemical stability of the corresponding site, which has a unique effect on the metabolism and efficacy of the drug. At present, the first case of deuterated drug Austedo has been approved by the FDA in 2017 Since then, more and more companies and researchers have devoted themselves to the research of deuterated drugs. At the same time, the introduction of deuterium atoms into the drugs already on the market can change the properties of the drugs to a minimum, and can be applied as a new drug at the same time. Due to this unique advantage, deuterium generation tec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/04C07C209/62
CPCC07C211/04C07C209/62C07C269/06C07C209/22C07B2200/05C07C211/27C07C271/12Y02P20/55
Inventor 王鹏任翔宇崔梦园徐艳琪刘天广
Owner CHINA PHARM UNIV
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