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【结 构 式】

【分子编号】16621

【品名】(3R,4R)-1-[(2S)-2-benzyl-3-methoxy-3-oxopropyl]-4-(3-hydroxyphenyl)-3,4-dimethylhexahydropyridinium chloride

【CA登记号】

【 分 子 式 】C24H32ClNO3

【 分 子 量 】417.97572

【元素组成】C 68.97% H 7.72% Cl 8.48% N 3.35% O 11.48%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

LY246736 dihydrate is prepared in 12 steps from 1,3-dimethyl-4-piperidone (I) in 6.2% yield as depicted in Scheme 20754901a. Piperidinol (II) can be prepared from (I) using standard methodology. Selective elimination to tetrahydropyridine (IV) is accomplished by the cis-thermal elimination of an ethyl carbonate (III) at 190 C in refluxing Decalin(R). This maintains the stereochemistry at C-3, following resolution of carbonate (III) with di-p-toluoyl-D-tartaric acid ((+)-DDTA), and also enables the trans-stereochemistry of the methyl groups to be established in the next step. Alkylation of the metalloenamine with dimethyl sulfate at -50 C proceeds both regio- and stereospecifically, giving the trans-3,4-dimethyl-gamma-alkylation product (V). Reduction of the enamine with NaBH4 and N,O-didealkylation with phenyl chloroformate followed by HBr/AcOH gives the chiral 3,4-dimethyl-4-arylpiperidine (VII). The benzyl group of the N-substituent is introduced via a nonselective benzylation of the Michael adduct dianion at -20 C followed by a highly efficient crystallization of the (3R,4R,alphaS)-hydrochloride (VIII) from methanol. The undesired diastereomer can be epimerized (LDA, H2O) and recycled to afford additional (VIII). Hydrolysis of the ester with NaOH, DCC coupling of the glycine ester, and hydrolysis of the ester with NaOH in ethanol/water completes the synthesis. The crystalline dihydrate (X) is isolated directly from the saponification reaction mixture upon neutralization with hydrochloric acid (overall yield 6.2% with one recycle of (3R,4R,alphaR)-isomer of (VIII).

1 Copley-Merriman, C.R.; Maki, J.; Barnett, C.J.; Synthesis of picenadol via metalloenamine alkylation methodology. J Org Chem 1989, 54, 4795-800.
2 Robey, R.L.; Evans, D.A.; Zimmerman, D.M.; Mitch, C.H.; Thomas, R.C.; Application of metalated enamines to alkaloid synthesis. An expedient approach to the synthesis of morphine-based analgesics. J Am Chem Soc 1980, 102, 5955-6.
3 Werner, J.A.; Cerbone, L.R.; Selective "cis-dehydration" of 3-methyl-4-piperidinols via thermal elimination of carbonates and its application in synthesis. 203rd ACS Natl Meet (April 5-10, San Francisco) 1992, Abst ORGN 409.
4 Prather, D.E.; Werner, J.A.; Wad, J.A.; Frank, S.A. (Eli Lilly and Company); Trisubstd.-piperidinyl-N-alkylcarboxylates as opioid antagonists. EP 0984004 .
5 Pohland, R.C.; Franklin, R.B.; Cantrell, B.E.; Means, J.R.; Leander, J.D.; Parli, C.J.; Francis, P.C.; Zimmerman, D.M.; Gidda, J.S.; Werner, J.A.; LY246736 Dihydrate. Drugs Fut 1994, 19, 12, 1078.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
63423 3-bromophenyl isopropyl ether; 1-bromo-3-isopropoxybenzene C9H11BrO 详情 详情
(I) 16614 1,3-dimethyltetrahydro-4(1H)-pyridinone; 1,3-Dimethyl-4-piperidone 4629-80-5 C7H13NO 详情 详情
(II) 16615 (3S,4R)-4-(3-isopropoxyphenyl)-1,3-dimethylhexahydro-4-pyridinol C16H25NO2 详情 详情
(III) 16616 ethyl (3S,4R)-4-(3-isopropoxyphenyl)-1,3-dimethylhexahydro-4-pyridinyl carbonate C19H29NO4 详情 详情
(IV) 16617 (3R)-4-(3-isopropoxyphenyl)-1,3-dimethyl-1,2,3,6-tetrahydropyridine; 3-[(3R)-1,3-dimethyl-1,2,3,6-tetrahydro-4-pyridinyl]phenyl isopropyl ether C16H23NO 详情 详情
(V) 16618 (3R,4R)-4-(3-isopropoxyphenyl)-1,3,4-trimethylhexahydropyridine; isopropyl 3-[(3R,4R)-1,3,4-trimethylhexahydro-4-pyridinyl]phenyl ether C17H27NO 详情 详情
(VI) 16618 (3R,4R)-4-(3-isopropoxyphenyl)-1,3,4-trimethylhexahydropyridine; isopropyl 3-[(3R,4R)-1,3,4-trimethylhexahydro-4-pyridinyl]phenyl ether C17H27NO 详情 详情
(VII) 16620 3-[(3R,4R)-3,4-dimethylhexahydro-4-pyridinyl]phenol 119193-19-0 C13H19NO 详情 详情
(VIII) 16621 (3R,4R)-1-[(2S)-2-benzyl-3-methoxy-3-oxopropyl]-4-(3-hydroxyphenyl)-3,4-dimethylhexahydropyridinium chloride C24H32ClNO3 详情 详情
(IX) 16622 (2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyltetrahydro-1(2H)-pyridiniumyl]propanoate hydrate C23H29NO3.H2O 详情 详情

合成路线2

该中间体在本合成路线中的序号: (X)

 

1 Buehler JD. 2007. Process for preparing alvimopan and their compositions containing opioid antagonists. WO 2007047935(Adolor Corp., USA).
2 Copley-Merriman CR, Maki J, Barnett CJ. 1989. Synthesis of picenadol via metalloenamine alkylation methodology. J Org Chem, 54(4): 795~800.
3 Frank SA, Prather DE, Ward JA, et al. 1995. Preparation of 3,4,4-trisubtituted piperidinyl N-alkylcarboxylates and intermediates, useful as opioid antagonists. EP 657428(Eli Lilly and Co., USA)
4 Robey RL, Evans DA, Zimmerman DM, et al. 1980. Application of metalated enamines to alkaloid synthesis. An expedient approach to the synthesis of morphine-based analgesics. J Am Chem Soc, 102(5): 955~956
5 Werner JA, Cerbone LR, Frank SA, et al. 1996. Synthesis of trans-3,4-dimethyl-(3-hydroxyphenyl)piperidine opioid antagonists: application of the cis-thermal elimination of carbonates to alkaloid synthesis. J Org Chem, 61(2):587~597
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 16621 (3R,4R)-1-[(2S)-2-benzyl-3-methoxy-3-oxopropyl]-4-(3-hydroxyphenyl)-3,4-dimethylhexahydropyridinium chloride C24H32ClNO3 详情 详情
(I) 16614 1,3-dimethyltetrahydro-4(1H)-pyridinone; 1,3-Dimethyl-4-piperidone 4629-80-5 C7H13NO 详情 详情
(II) 66993 (3-isopropoxyphenyl)lithium   C9H11LiO 详情 详情
(III) 16615 (3S,4R)-4-(3-isopropoxyphenyl)-1,3-dimethylhexahydro-4-pyridinol C16H25NO2 详情 详情
(IV) 16616 ethyl (3S,4R)-4-(3-isopropoxyphenyl)-1,3-dimethylhexahydro-4-pyridinyl carbonate C19H29NO4 详情 详情
(V) 16617 (3R)-4-(3-isopropoxyphenyl)-1,3-dimethyl-1,2,3,6-tetrahydropyridine; 3-[(3R)-1,3-dimethyl-1,2,3,6-tetrahydro-4-pyridinyl]phenyl isopropyl ether C16H23NO 详情 详情
(VI) 67021     C17H25NO 详情 详情
(VII) 16618 (3R,4R)-4-(3-isopropoxyphenyl)-1,3,4-trimethylhexahydropyridine; isopropyl 3-[(3R,4R)-1,3,4-trimethylhexahydro-4-pyridinyl]phenyl ether C17H27NO 详情 详情
(VIII) 16620 3-[(3R,4R)-3,4-dimethylhexahydro-4-pyridinyl]phenol 119193-19-0 C13H19NO 详情 详情
(IX) 67022 methyl 3-((3S,4S)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanoate   C17H25NO3 详情 详情
(XI) 67023 (2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyltetrahydro-1(2H)-pyridiniumyl]propanoate   C23H29NO3 详情 详情
(XII) 67024 tert-butyl 2-(2-benzyl-3-(4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanamido)acetate   C29H40N2O4 详情 详情
(XIII) 67025 2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanamido)acetic acid   C25H32N2O4 详情 详情
Extended Information