【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% |
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 |