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Preparation method of chiral tetrahydroimidazo[1,5-a]piperazine pharmaceutical intermediate

A technology of tetrahydroimidazole and 5-a, applied in the directions of organic chemistry methods, chemical instruments and methods, organic racemization, etc., can solve the problems such as the lack of a synthesis route suitable for scale-up, and achieve the effects of mild reaction conditions and convenient use.

Active Publication Date: 2022-06-14
SHANGHAI TIANYE CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are relatively few synthetic methods reported in the literature, and there is no synthetic route suitable for scale-up. Therefore, it is necessary to study it and develop a suitable preparation method to meet market demand.

Method used

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  • Preparation method of chiral tetrahydroimidazo[1,5-a]piperazine pharmaceutical intermediate
  • Preparation method of chiral tetrahydroimidazo[1,5-a]piperazine pharmaceutical intermediate
  • Preparation method of chiral tetrahydroimidazo[1,5-a]piperazine pharmaceutical intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] First step: synthesis of 2,2,2-trifluoro-N-(3-methyl-pyrazin-2-ylmethyl)-acetamide.

[0027]

[0028] 123.6 g (1.0 mol) of 3-methyl-2-pyrazineethylamine and 1 L of dichloromethane were added to the reaction flask, the temperature was lowered and controlled at -2-2 °C, 231 g (1.1 mol) of trifluoroacetic anhydride was added, and At this temperature, 276.9 g (3.5 mol) of pyridine was added dropwise. After the dropping was completed, the temperature was slowly raised to 20-25° C., and the reaction was carried out for 2 hours. Extract with dichloromethane, combine the organic phases, wash with potassium bicarbonate aqueous solution, and wash with saturated brine. After the organic phase is concentrated, n-heptane is added for slurry filtration to obtain 2,2,2-trifluoro-N-(3-methyl- Pyrazin-2-ylmethyl)-acetamide 200.5 g, yield 91.5%, HPLC: 99.1%. 1 HNMR (400MHz, CDCl 3 )δ: 8.20(m, 2H), 6.31(s, 1H), 4.55-4.46(m, 2H), 2.35(s, 3H).

[0029]

[0030] 123.6g (1.0mol) of 3...

Embodiment 2

[0032] The second step: the synthesis of 8-methyl-3-trifluoromethylimidazo[1,5-a]pyrazine.

[0033]

[0034] 190 g (0.867 mol) of 2,2,2-trifluoro-N-(3-methyl-pyrazin-2-ylmethyl)-acetamide and 950 mL of phosphorus oxychloride were added to the reaction flask, and the temperature was raised to 60- Under 70 ℃, add phosphorus pentoxide 135.4g (0.954mol), be warming up to 80-85 ℃, react for 3-5 hours, TLC detects that the reaction of the raw materials is complete, concentrate under reduced pressure to remove phosphorus oxychloride, cool down to -10 ℃, Add 300 mL of 0°C water dropwise, add 1N aqueous sodium hydroxide solution to adjust pH=7-7.5 under the control of the temperature, add dichloromethane, heat up to 20-25°C, separate layers, extract the aqueous phase with dichloromethane, and combine the organic phases , after concentration, n-heptane was added to make slurry at room temperature, and filtered to obtain 126.4 g of 8-methyl-3-trifluoromethylimidazo[1,5-a]pyrazine, yie...

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Abstract

The invention discloses a preparation method for synthesizing (R)-8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]piperazine The preparation method belongs to the technical field of pharmaceutical intermediates. Taking 3-methyl-2-pyrazineethylamine as raw material to react with trifluoroacetic anhydride under alkaline conditions to obtain 2,2,2-trifluoro-N-(3-methyl-pyrazine-2-ylmethyl base)-acetamide, followed by condensing agent-catalyzed ring closure to give 8-methyl-3-trifluoromethylimidazo[1,5-a]pyrazine, followed by hydrogenation by palladium on carbon to give 8-methyl-3-trifluoromethylimidazo[1,5-a]pyrazine 3‑Trifluoromethyl‑5,6,7,8‑tetrahydroimidazo[1,5‑a]piperazine followed by resolution by D‑DBTA to give (R)‑8‑methyl‑3‑trifluoro Process for the preparation of methyl-5,6,7,8-tetrahydroimidazo[1,5-a]piperazine. The raw materials of this synthesis process are common raw materials in the market, easy to use, and the reaction conditions are relatively mild, and the process verification has been carried out on a 100-gram scale verification.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical intermediates, in particular to a kind of (R)-8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]piperazine preparation method. Background technique [0002] Imidazopiperazine organic compounds widely exist in biologically active natural products, drugs and drug candidates, and can be used as corticotropin-releasing factor and melanocortin receptor, etc. Its derivatives have good bioactivity, It can often be used for the treatment of coronary dilatation, nerve stability and neuropeptide drugs (such as orexin), and peptides synthesized with other amino acids are used for the treatment of diabetes. In addition, its biological activities include antibacterial, antifungal, antitumor and so on. Tetrahydroimidazopiperazine organic compounds are widely used in organic synthesis, especially the synthesis of heterocyclic compounds and biologically active natural products. [0003] (R)-8-M...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07B57/00C07D487/04
CPCC07B57/00C07D487/04C07B2200/07
Inventor 薛峰刘洪强谢楠田贝贝
Owner SHANGHAI TIANYE CHEM