Benzhydryl piperazine compound containing straight-chain olefin and preparation method of benzhydryl piperazine compound

A technology of benzhydrylpiperazine and straight-chain olefins, which is applied in the field of medicine, can solve the problems of unreported synthesis of new benzhydrylpiperazine compounds, and achieve mild conditions, high reaction yield, and easy operation Effect

Pending Publication Date: 2021-12-07
凯美克(上海)医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Since in the prior art, the synthesis of new benzhydryl piperazine compounds containing linear olefins has not been reported, it is very necessary to study its synthetic route

Method used

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  • Benzhydryl piperazine compound containing straight-chain olefin and preparation method of benzhydryl piperazine compound
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  • Benzhydryl piperazine compound containing straight-chain olefin and preparation method of benzhydryl piperazine compound

Examples

Experimental program
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preparation example Construction

[0076] The above-mentioned preparation method of a benzhydryl piperazine compound containing linear olefins specifically comprises the following steps:

[0077] Step 1: Dissolve compound SM1 in the first solvent, add compound SM2 and alkali, and reflux the system until the reaction is complete. After the reaction is completed, the system temperature is cooled to room temperature, filtered, spin-dried, and purified to obtain compound A;

[0078] Step 2: Dissolve the compound A in the second solvent, add 1-alkenylhexylboronic acid, base, catalyst, and ligand in sequence, reflux reaction under nitrogen protection until the reaction is complete, and spin the system to dry to obtain the target compound.

[0079] In the above step 1, the first solvent is selected from at least one of acetonitrile, dichloroethane, tetrahydrofuran, and 1,2-dioxane; the base is selected from potassium carbonate, sodium carbonate, potassium acetate, At least one of sodium acetate and N,N-diisopropylethy...

Embodiment 1

[0098] Below, with R 1 selected from hydrogen; R 2 selected from hydrogen; R 3 selected from -CH 2 OAc; as an example, to illustrate the preparation method of the above-mentioned benzhydrinyl piperazine compound containing linear olefin in the embodiment of the present invention.

[0099] Step 1: Synthesis of Compound B1

[0100]

[0101] Compound SM1 (20g, 61.34mmol, 1eq) was dissolved in acetonitrile (150mL), compound SM2 (15.85g, 61.36mmol, 1eq) and potassium carbonate (17g, 123.0mmol, 2eq) were added, and the system was refluxed for 4 hours. After the reaction was completed, the system was cooled to room temperature and then filtered. After the solvent was spin-dried, silica gel column chromatography gave 27.51 g of a white solid, namely compound B1, with a yield of 87.4% and a purity of 98.1%.

[0102] The structural characterization data of compound B1 are as follows:

[0103] [M+H] + =503.16

[0104] 1 H-NMR (300MHz, CDCl 3 )δ7.79(m,1H),7.48(m,3H),7.28(m,3H)...

Embodiment 2-11 and comparative example 1-5

[0120] The steps of Examples 2-11 and Comparative Examples 1-5 are the same as the above-mentioned Example 1, only part of the process conditions of Step 2 are changed. In order to make the results more intuitive and clear, Examples 2-11 and Comparative Examples 1-5 adopt the form of a list to describe the present invention in detail.

[0121] The influence of table 1 reaction conditions on intermediate compound B2 yield

[0122]

[0123] From Table 1, the reaction can obtain a relatively ideal reaction yield in a high-boiling solvent. As shown in the above-mentioned examples 1-4, the preferred solvent is toluene, dimethyl sulfoxide, N,N-dimethylformamide, For 1,2-dioxane, when the low boiling point solvent as shown in Comparative Example 4 is used for reaction, the reaction yield decreases significantly. Due to the partial deboronation of 1-alkenylhexylboronic acid in the reaction, when its amount is greater than 1eq of the theoretical value, the reaction yield is ideal, ...

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Abstract

The embodiment of the invention discloses a benzhydryl piperazine compound containing straight-chain olefin and a preparation method of the benzhydryl piperazine compound. The benzhydryl piperazine compound is expected to directly act on a focus or be used as a molecular building block to participate in new drug research and development. According to the preparation method of the new benzhydryl piperazine compound containing straight-chain olefin, 1-bromo-2-(bromo(phenyl)methyl)benzene is taken as a raw material, and a target compound is obtained through two-step reaction of nucleophilic substitution and carbon-carbon coupling. In the carbon-carbon coupling reaction, a catalytic system consisting of Pd2(dba)3 and 1,3-bis(dicyclohexylphosphino)propane is preferably selected to catalyze the reaction, the reaction activity is remarkably improved, the reaction is realized at high yield, particularly, a NiCl2(PCy3)2 and tricyclohexylphosphine catalytic system is adopted to carry out the reaction, the reaction result is relatively ideal, and a reference is provided for catalyzing the carbon-carbon coupling of the compound by a nickel catalyst. The whole preparation route is stable in reaction, mild in used condition, simple and convenient to operate and high in reaction yield.

Description

technical field [0001] The embodiment of the present invention relates to the field of medical technology, in particular to a benzhydryl piperazine compound containing linear olefins and a preparation method thereof. Background technique [0002] Diphenylmethylpiperazines can be used as antihistamines and opioid analgesics to treat or alleviate diseases such as dermatitis, dizziness, stroke, diabetes and moderate pain (US20090176792A1); this type of compound can also be used as a key intermediate Synthesize drugs that regulate calcium channel activity, anticancer drugs, targeted treatment of congenital migraine, angina pectoris, epilepsy, hypertension, and some arrhythmia, obesity and other diseases (WO2007071035A1, WO2004032874A2, US2009124620A1, WO2013103973A1, Acs Chemical Biology, 2013,8(7):1590-1599.), is a class of heterocyclic compounds with wide application and great potential. However, with the in-depth application of this type of compound in the field of medicine,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/04
CPCC07D241/04
Inventor 郦荣浩王治国罗春艳
Owner 凯美克(上海)医药科技有限公司
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