Process for preparing 4-acyl substituted-2-methylpiperazines

A methylpiperazine and acyl substitution technology is applied in the field of preparation of 4-position-acyl-substituted-2-methylpiperazine compounds, which can solve the problems that monoacylated products cannot be effectively separated and the like, and achieves the elimination of potential safety hazards. , the raw materials are cheap and easy to obtain, the effect of high reaction yield

Active Publication Date: 2006-09-06
深圳市天明医药科技开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] According to conventional acylation methods known in the art, without any regioselectivity, only two different monoacylated products on the 1 and 4 nitrogen atoms and a mixture of diacylated products can be obtained simultaneously, and the two monoacyl Chemicalized products cannot be effectively separated

Method used

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  • Process for preparing 4-acyl substituted-2-methylpiperazines
  • Process for preparing 4-acyl substituted-2-methylpiperazines
  • Process for preparing 4-acyl substituted-2-methylpiperazines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Synthesis of 4-benzoyl-2-methylpiperazine

[0022]

[0023] Benzoic acid (2.5g 0.02mol) and N,N'carbonyldiimidazole (3.3g 0.02mol) were dissolved in dry tetrahydrofuran 50mL and heated to reflux for 3 hours, and (R)-2-methylpiperazine (2.0g0. 02mol), after continuing to reflux for 3 hours, the reaction ended, and the reaction mixture was purified by column chromatography (eluent: ethyl acetate: methanol = 4: 1) to obtain the product 4-benzoyl-2-methylpiperazine 1.6 g, yield 40%. Low resolution mass spectrum (LCMS) M+1, 205.1. h 1 -NMR (300MHz, CD 3 OD): δ7.45 (m, 5H), 4.50 (d, 1H), 3.60 (b, 1H), 3.33-2.60 (m, 5H), 1.16-0.98 (d, 3H).

Embodiment 2

[0025] Synthesis of 4-pivaloyl-2-methylpiperazine

[0026]

[0027] Dissolve pivalic acid (0.02mol) and N,N'carbonyldiimidazole (0.02mol) in 50mL of dry tetrahydrofuran and heat to reflux for 3 hours. After adding (R)-2-methylpiperazine (0.02mol), continue After heating to reflux for 3 hours, the reaction was completed, and the reaction mixture was purified by column chromatography (eluent: ethyl acetate: methanol = 4: 1) to obtain the product 4-pivaloyl-2-methylpiperazine, with a yield of 1.5 g. Yield 40%. Low resolution mass spectrum (LCMS) M+1: 185.1. h 1 -NMR (300MHz, CD 3 OD): 4.32-4.24(m, 2H), 3.00-2.92(m, 2H), 2.76-2.65(m, 2H), 2.59-2.51(m, 1H), 1.26(s, 9H), 1.09(d, 3H).

Embodiment 3

[0029] Synthesis of 4-[4-(1-tert-butoxycarbonylpiperidine)formyl)]-2-methylpiperazine

[0030]

[0031] Add N-tert-butoxycarbonylpiperidine-4-carboxylic acid (3.84g, 0.0166mol) and N,N'carbonyldiimidazole (3.769g, 0.02324mol) into dry tetrahydrofuran (50mL), stir at room temperature until dissolved . At room temperature, (R)-2-methylpiperazine (1.829 g, 0.01826 mol) was added to the reaction solution, stirring was continued at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (ethanol: Ethyl acetate=1:5) to obtain 3.4 g of viscous colorless liquid (3.4 g), yield 65.4%. Low resolution mass spectrum (LCMS) M+1=312.

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Abstract

The invention relates to a method for preparation of selective monoacylated piperazine by N,Ní»-carbonyldiimidazole(CDI) activating carboxyl acid and especially to a method for preparation of 4-acylsubstitution-2-methylpiperazine compound by selectively monoacylating 4-nitrogen atom of 2-methylpiperazine ring.It is characterized in that it prepares carbonyl diimidazolederivant by the reaction of between N,Ní»-carbonyldiimidazole and carboxyl acid, and monoacylated 4-acylsubstitution-2-methylpiperazine compound is obtained by monoacylated condensation reaction between 2-methylpiperazine and the substances of the former step. In relation to the present technology, the said invention selects N,Ní»-carbonyldiimidazole which is cheap and easy for commercial manufacture as effective substitute agent of diethyl aluminium chloride, essentially removes potential safety hazard, avoids the explosive diethyl aluminium chloride, and is of simple operation and high reaction yield rate.

Description

technical field [0001] The invention relates to a method for preparing selective monoacylated piperazine by activating carboxylic acid with N,N' carbonyl diimidazole (CDI), especially selective monoacylation on the 4-position nitrogen atom of 2-methylpiperazine ring A method for preparing a 4-acyl substituted-2-methylpiperazine compound by reaction. Background technique [0002] According to conventional acylation methods known in the art, without any regioselectivity, only two different monoacylated products on the 1 and 4 nitrogen atoms and a mixture of diacylated products can be obtained simultaneously, and the two monoacyl The decomposed products cannot be effectively separated. [0003] Selectively monoacylated 2-methylpiperazines are a class of chemical synthesis intermediates, mainly used in the preparation of medicines, pesticides and dyes. For example, the compound BMS-378806, which is undergoing clinical trials for its HIV-1 inhibitory activity, contains benzoyla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/16
Inventor 李嘉和陈垒胡建兵
Owner 深圳市天明医药科技开发有限公司
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