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【结 构 式】 
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【分子编号】20687 【品名】(2R,5S)-2,5-dimethylpiperazine 【CA登记号】 |
【 分 子 式 】C6H14N2 【 分 子 量 】114.19064 【元素组成】C 63.11% H 12.36% N 24.53% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The alkylation of trans-2,5-dimethylpiperazine (VIII) with allyl bromide gave rise to a racemic mixture of N-allylpiperazines, which was resolved using (-)-camphoric acid. The desired (2R,5S)-piperazine (IX) was then alkylated with benzhydryl chloride (VII) producing a mixture of the title compound and its benzhydryl epimer (X), which were separated by flash column chromatography.
| 【1】 Evans, S.M.; Lenz, G.R.; Probes of receptor mediated phenomena 19. Synthesis of (+)-4-[(alphaR)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): A highly selective, nonpeptide delta opioid receptor agonist. Chemtracts - Org Chem 1994, 7, 6, 395. |
| 【2】 Calderon, S.N.; et al.; Probes for narcotic receptor mediated phenomena: 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80). J Med Chem 1997, 40, 5, 695. |
| 【3】 Calderon, S.N.; et al.; Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80): A highly selective, nonpeptide delta opioid receptor agonist. J Med Chem 1994, 14, 37, 2125. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 56249 | 4-[chloro(3-methoxyphenyl)methyl]-N,N-diethylbenzamide | C19H22ClNO2 | 详情 | 详情 | |
| (VIII) | 20687 | (2R,5S)-2,5-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (IX) | 20690 | (2R,5S)-1-allyl-2,5-dimethylpiperazine | C9H18N2 | 详情 | 详情 | |
| (X) | 56250 | 4-[(S)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide | C28H39N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Treatment of trans-2,5-dimethylpiperazine (I) with ethyl chloroformate gave racemic ethyl carbamate (II), which was subsequently alkylated with allyl bromide, and then deprotected with ethanolic KOH to yield racemic piperazine (IV). Separation of the desired enantiomer (V) was achieved through recrystallization of the salt with di-p-toluoyl-D-tartaric acid, followed by liberation of the base with NaOH.
| 【1】 Chang, K.-J.; Bishop, M.J.; Bubacz, D.G.; McNutt, R.W. Jr. (Glaxo Wellcome plc); Piperazine cpds. used in therapy. EP 0711289; JP 1997501156; WO 9504051 . |
| 【2】 Chang, K.; Boswell, G.E.; Bubacz, D.G.; Collins, M.A.; Davis, A.O.; McNutt, R.W. (Delta Pharmaceuticals, Inc.); Opioid diarylmethylpiperazines and piperidines. JP 1995503247; US 5658908; US 5681830; WO 9315062 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 20687 | (2R,5S)-2,5-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (II) | 20688 | ethyl (2S,5R)-2,5-dimethyl-1-piperazinecarboxylate | C9H18N2O2 | 详情 | 详情 | |
| (III) | 20689 | ethyl (2S,5R)-4-allyl-2,5-dimethyl-1-piperazinecarboxylate | C12H22N2O2 | 详情 | 详情 | |
| (IV) | 20690 | (2R,5S)-1-allyl-2,5-dimethylpiperazine | C9H18N2 | 详情 | 详情 | |
| (V) | 20690 | (2R,5S)-1-allyl-2,5-dimethylpiperazine | C9H18N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The alkylation of the prochiral trans-2,5-dimethylpiperazine (I) with allyl bromide (II) produced a racemic mixture of N-allyl piperazines. After separation of the (+)-isomer by precipitation with (+)-camphoric acid, the desired (-)-piperazine (III) was isolated from the remaining enriched mixture by crystallization as the di-p-toluoyl-D-tartrate salt.
| 【1】 Maw, G.N. (Pfizer Inc.); Anti-inflammatory piperazinyl-benzyl-tetrazole derivs. and intermediates thereof. EP 0983251; JP 2000513024; WO 9852929 . |
合成路线4
该中间体在本合成路线中的序号：(I),(II)Alkylation of an equimolecular mixture of trans-2,5-dimethylpiperazine dihydrochloride (I) and the free base (II) with benzyl chloride produced the racemic monobenzyl piperazine, which was resolved using (-)-tartaric acid to yield the required (2R,5S)-isomer (III). (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (IV) was protected as the silyl derivative (V) using bis(trimethylsilyl)urea, and subsequently converted to acid chloride (VI) by means of oxalyl chloride. Coupling of acid chloride (VI) with the chiral piperazine (III) afforded amide (VII), which was desilylated in methanolic HCl yielding (VIII). Hydrogenolysis of the N-benzyl group of (VIII) over Pd/C gave piperazine (IX). Finally, coupling of (IX) with 4-cyanobenzoyl chloride (X) furnished the corresponding bisamide.
| 【1】 Anderson, R.C.; Aicher, T.D.; Bebernitz, G.R.; et al.; (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamides are orally active inhibitors of pyruvate dehydrogenase kinase. J Med Chem 1999, 42, 15, 2741. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I),(II) | 20687 | (2R,5S)-2,5-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (III) | 34550 | (2R,5S)-1-benzyl-2,5-dimethylpiperazine | C13H20N2 | 详情 | 详情 | |
| (IV) | 34551 | (2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid | 114715-77-4 | C4H5F3O3 | 详情 | 详情 |
| (V) | 34552 | trimethylsilyl (2R)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoate | C10H21F3O3Si2 | 详情 | 详情 | |
| (VI) | 34553 | (2S)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoyl chloride | C7H12ClF3O2Si | 详情 | 详情 | |
| (VII) | 34554 | (2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]-1-propanone | C20H31F3N2O2Si | 详情 | 详情 | |
| (VIII) | 34555 | (2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-1-propanone | C17H23F3N2O2 | 详情 | 详情 | |
| (IX) | 34556 | (2R)-1-[(2S,5R)-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-1-propanone | C10H17F3N2O2 | 详情 | 详情 | |
| (X) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |