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【结 构 式】

【药物名称】Epibatidine, CMI-477(enantiomer), CMI-545(racemate (exo)-isomer), CMI-488

【化学名称】(1R,2R,4S)-2-(6-Chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane
　　　　　　(1R-exo)-2-(6-Chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane

【CA登记号】140111-52-0, 152378-30-8 (enantiomer), 148152-66-3 (racemate (exo)-isomer)

【 分 子 式 】C11H13ClN2

【 分 子 量 】208.69266

【开发单位】US Department of Health & Human Services (Originator), CytoMed (Licensee)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics, Nicotinic Receptor Agonists

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23

合成路线1

The key to the total synthesis of epibatidine is to construct the 7-azabicyclo[2.2.1]heptane system. A number of papers about the syntheses of racemic epibatidine and both of its enantiomers have been published. The different methodologies for the construction of this novel ring system can be classified into four categories. 1) Intramolecular nucleophilic ring closure of 1-amino-4-substituted-cyclohexane derivatives. Broka reported the first total synthesis of (±)-epibatidine in 1993. The preparation of ketoaldehyde (III) was achieved as a single isomer by reaction of enal (II) with 2-(trimethylsilyloxy)-1,3-butadiene. (III) was converted into aminomesylate (IV) in 15 steps, which was heated in CHCl3 to give the mesylate salt of (I) in excellent yield. Starting from 6-chloronicotinaldehyde, epibatidine was obtained via a reaction sequence of 17 steps in an overall yield of 6%. Broka's work confirmed the correctness of the structure proposed by Daly et al.

参考文献 中间体
【1】 Kellar, K.J.; Epibatidine. Its pharmacological actions and utility for studying neuronal nicotinic receptors. Neurotransmissions 1995, 11, 1-5.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【3】 Broka, C.A.; Total synthesis of epibatidine. Tetrahedron Lett 1993, 34, 20, 3251-4.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(III) 16369 (1S,2S)-2-(6-chloro-3-pyridinyl)-4-oxocyclohexanecarbaldehyde C12H12ClNO2 详情 详情
rac-(IV) 16370 (1S,3R,4S)-3-(6-chloro-3-pyridinyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclohexylamine; (1S,3R,4S)-3-(6-chloro-3-pyridinyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclohexanamine C14H21ClN2OS 详情 详情
rac-(I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
(II) 16368 (E)-3-(6-chloro-3-pyridinyl)-2-propenal C8H6ClNO 详情 详情

合成路线2

2) Fletcher and his group also utilized an intramolecular displacement to construct the azabicycloheptane ring system.4-Benzylamino-1,2-epoxycyclohexane (V) was cyclized in N-methyl-pyrrolidone upon heating to yield the exo-alcohol (VI), which was further converted into ketone (VIII). Introduction of the pyridyl group, dehydration and catalytic hydrogenation resulted primarily in the endo-isomer (Xa), which could be epimerized using t-BuOK to afford the more stable exo-isomer (Xb). Fletcher et al. also succeeded in separating the enantiomers of (VII) as their Mosher ester and in establishing the absolute configuration of (I) as (1R,2R,4S).

参考文献 中间体
【1】 Fletcher, S.R.; Baker, R.; Chambers, M.S.; Hobbs, S.C.; Mitchell, P.J.; The synthesis of (+)- and (-)-epibatidine. J Chem Soc Ser Chem Commun 1993, 1216-8.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【3】 Fletcher, S.R.; Baker, R.; Chambers, M.S.; Herbert, R.H.; Hobbs, S.C.; Thomas, S.R.; Verrier, H.M.; Watt, A.P.; Ball, R.G.; Total synthesis and determination of the absolute configuration of epibatidine. J Org Chem 1994, 59, 7, 1771-8.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(VI) 16372 (1R,2S,4S)-7-benzyl-7-azabicyclo[2.2.1]heptan-2-ol C13H17NO 详情 详情
(Xa) 16376 (1R,2S,4S)-2-(6-chloro-3-pyridinyl)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptane C16H21ClN2O2 详情 详情
(Xb) 16377 (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptane C16H21ClN2O2 详情 详情
(rac-I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
(V) 16371 N-benzyl-7-oxabicyclo[4.1.0]heptan-3-amine; N-benzyl-N-(7-oxabicyclo[4.1.0]hept-3-yl)amine C13H17NO 详情 详情
(VII) 16373 (1R,2S,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-ol C11H19NO3 详情 详情
(VIII) 16374 (1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one C11H17NO3 详情 详情
(IX) 16375 (1R,2S,4S)-2-(6-chloro-3-pyridinyl)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-ol C16H21ClN2O3 详情 详情

合成路线3

3) Corey's group published a stereocontrolled route to both enantiomers of epibatidine through HPLC separation of N-(trifluoroacetyl)epibatidine using chiral columns. A Diels-Alder reaction between (Z)-alpha,beta-unsaturated ester (XI) and 1,3-butadiene furnished the cis-4,5-disubstituted cyclohexene (XII), which was converted to the vicinal dibromide (XIII). Upon treatment with t-BuOK, (XIII) underwent intramolecular nucleophilic substitution to give compound (XIV) with the azabicyclo[2.2.1]heptane ring system.

参考文献 中间体
【1】 Corey, E.J.; Loh, T.E.; Achyutha-Rao, S.; Daley, D.C.; Sarshar, S.; Stereocontrolled total synthesis of (+)- and (-)-epibatidine. J Org Chem 1993, 58, 5600-2.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(XII) 16379 methyl (1R,6S)-6-(6-chloro-3-pyridinyl)-3-cyclohexene-1-carboxylate C13H14ClNO2 详情 详情
rac-(XIII) 16380 N-[(1R,2R,4S,5S)-4,5-dibromo-2-(6-chloro-3-pyridinyl)cyclohexyl]-2,2,2-trifluoroacetamide C13H12Br2ClF3N2O 详情 详情
rac-(XIV) 16381 1-[(1R,2S,4R,5R)-2-bromo-5-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-7-yl]-2,2,2-trifluoro-1-ethanone C12H14BrClN2 详情 详情
(rac-I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
(XI) 16378 methyl (Z)-3-(6-chloro-3-pyridinyl)-2-propenoate C9H8ClNO2 详情 详情

合成路线4

4) Szantay et al. reported a practical route to epibatidine by using commonly available starting materials under convenient reaction conditions. The alpha,beta-unsaturated ketone (XV) was synthesized by Wittig reaction of 6-chloronicotinaldehyde and the appropriate phosphorane. Ring closure took place by treatment of compound (XV) with KF/Al2O3. Reduction of the keto group followed by mesylation and subsequent reduction of the nitro group afforded amine (XVII). Upon boiling in toluene, (XVII) was immediately transformed into the undesired endo-isomer of epibatidine (XVIII). Taking advantage of Fletcher's endo- to exo-epimerization, (XVIII) was converted into racemic epibatidine in moderate yield. The advantage of this route is that no protection and consequently no deprotection steps are involved. But the combined yield in the last two steps is only 30%.

参考文献 中间体
【1】 Fletcher, S.R.; Baker, R.; Chambers, M.S.; Hobbs, S.C.; Mitchell, P.J.; The synthesis of (+)- and (-)-epibatidine. J Chem Soc Ser Chem Commun 1993, 1216-8.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【3】 Szántay, C.; Kardos-Balogh, Z.; Moldvai, I.; Szántay, C. Jr.; Major-Temesváry, E.; Blaskó, G.; A practical route to epibatidine. Tetrahedron Lett 1994, 35, 19, 3171-4.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(XVI) 16383 (3S,4R)-3-(6-chloro-3-pyridinyl)-4-nitrocyclohexanone C11H11ClN2O3 详情 详情
rac-(XVII) 16384 (1R,2S,4R)-2-(6-chloro-3-pyridinyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclohexanamine; (1R,2S,4R)-2-(6-chloro-3-pyridinyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclohexylamine C14H21ClN2OS 详情 详情
(rac-I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
rac-(XVIII) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
(XV) 16382 (E)-1-(6-chloro-3-pyridinyl)-6-nitro-1-hexen-3-one C11H11ClN2O3 详情 详情

合成路线5

5) Later on, Szantay's group modified the above described procedure based on a polarity reversal approach (8). Compound (XVI) was thus converted to the ring closure precursor (XIX) in 7 steps. Base-catalyzed ring closure of (XIX) afforded racemic epibatidine.

参考文献 中间体
【1】 Szántay, C.; Kardos-Balogh, Z.; Moldvai, I.; Szántay, C. Jr.; Major-Temesvary, E.; Blasko,G.; A practical enantioselective synthesis of epibatidine. Tetrahedron 1996, 52, 11053-62.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac-XVI) 16383 (3S,4R)-3-(6-chloro-3-pyridinyl)-4-nitrocyclohexanone C11H11ClN2O3 详情 详情
(rac-I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
rac-(XIX) 16386 N-[(1S,2R,4S)-4-amino-2-(6-chloro-3-pyridinyl)cyclohexyl]-4-methyl-N-[(4-methylphenyl)sulfonyl]benzenesulfonamide C25H28ClN3O4S2 详情 详情

合成路线6

6) Nakai et al. used 3-lithio pyridine as a nucleophile to attack ketone (XX), yielding the tertiary alcohol (XXI) stereoselectively. Reductive elimination of the hydroxyl group followed by oxidation and acid hydrolysis gave N-oxide (XXII), which was treated with POCl3 to produce (I) and (XXIII) in low yields.

参考文献 中间体
【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【2】 Senokuchi, K.; Nakai, H.; Kawamura, M.; et al.; Synthesis and biological evaluation of (±)-epibatidine and the congeners. Synlett 1994, 343-4.
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) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
(XX) 16387 (1R,4S)-7-acetyl-7-azabicyclo[2.2.1]heptan-2-one C8H11NO2 详情 详情
(XXI) 16388 1-[(1R,2S,4S)-2-hydroxy-2-(3-pyridinyl)-7-azabicyclo[2.2.1]hept-7-yl]-1-ethanone C13H16N2O2 详情 详情
(XXII) 16389 3-[(1R,2R,4S)-7-azabicyclo[2.2.1]hept-2-yl]-1-pyridiniumolate C11H14N2O 详情 详情
(XXIII) 16390 (1R,2R,4S)-2-(2-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane C11H13ClN2 详情 详情

合成路线7

7) Sestanj and his coworkers succeeded in synthesizing epibatidine by a conjugate addition intramolecular displacement strategy.Conjugate addition of higher order cyanocuprate (XXIV) to alpha,beta-unsaturated ketone (XXV) obtained the ketone (XXVI), which was converted to (XXVII) in 60% overall yield. Under Mitsunobu conditions with DEAD and PPh3 as reagents, only the beta-amino-tosylate cyclized to give the epibatidine ring system.

参考文献 中间体
【1】 Sestanj, K.; Melenski, E.; Jirkovsky, I.; Synthesis of epibatidine. Tetrahedron Lett 1994, 35, 5417-20.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac-I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
(rac-XVIII) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
rac-(XXVI) 16393 (3S,4S)-3-(6-methoxy-3-pyridinyl)-4-[(trimethylsilyl)methyl]cyclohexanone C16H25NO2Si 详情 详情
rac-(XXVII) 16394 N-[(3R,4S)-4-hydroxy-3-(6-methoxy-3-pyridinyl)cyclohexyl]-4-methylbenzenesulfonamide C19H24N2O4S 详情 详情
rac-(XXVIII) 16395 (1R,2R,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane; methyl 5-[(1R,2R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridinyl ether C19H22N2O3S 详情 详情
(XXIV) 16391 (6-Methoxypyridin-3-yl)(2-thienyl)copper dilithium cyanide complex C10H9CuNOS 详情 详情
(XXV) 16392 4-[(trimethylsilyl)methyl]-2-cyclohexen-1-one C10H18OSi 详情 详情

合成路线8

8) Ko and his coworkers employed the [4+2] addition reaction of 1-(2-chloro-5-pyridyl)cyclohexa-2,4-diene (XXIX) with singlet oxygen to form the bicyclic peroxide (XXX) as the key step. (XXX) was converted to azidomesylate (XXXI) in 42% overall yield. Based on Broka's epibatidine synthesis, (±)-(I) was obtained through reduction and intramolecular displacement.

参考文献 中间体
【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【2】 Ko, S.Y.; Lerpiniere, J.; Linney, I.D.; Wrigglesworth, R.; The total synthesis of epibatidine. J Chem Soc Ser Chem Commun 1994, 1775-6.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac-I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
rac-(XXX) 16397 2-chloro-5-[(1S,4R,5S)-2,3-dioxabicyclo[2.2.2]oct-5-yl]pyridine C11H12ClNO2 详情 详情
rac-(XXXI) 16398 5-((2S,5S)-5-azido-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclohexyl)-2-chloropyridine; (1S,4S)-3-(6-chloro-3-pyridinyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclohexyl azide C14H19ClN4OS 详情 详情
(XXIX) 16396 2-chloro-5-(2,4-cyclohexadien-1-yl)pyridine C11H10ClN 详情 详情

合成路线9

9) The first asymmetric synthesis of (-)-epibatidine was disclosed by Trost and Cook through a Pd-catalyzed desymmetrization of cis-dibenzoyloxy-2-cyclohexene (XXXII) and a Pd-catalyzed cross-coupling reaction. Dibenzoate (XXXII) was reacted with trimethylsilylazide in the presence of a Pd catalyst with chiral phosphine ligands to give ent-(XXXIII) in excellent yield and e.e. (XXXIII) was converted to vinyl bromide (XXXIV), which was coupled with the stable organostannane (XXXV) through a Pd(0)-catalyzed reaction to give enone (XXXVI). Reduction of the double bond and carbonyl, O-mesylation of the resulting amido alcohol and finally heating of the crude amino mesylate in acetonitrile produced (-)-epibatidine.

参考文献 中间体
【1】 Trost, B.M.; Cook, G.R.; An asymmetric synthesis of (-)-epibatidine. Tetrahedron Lett 1996, 37, 7485-8.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac-I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
rac-(XXXII) 16399 (1S,4R)-4-(benzoyloxy)-2-cyclohexen-1-yl benzoate C20H18O4 详情 详情
(XXXIII) 16400 (1S,4R)-4-azido-2-cyclohexen-1-yl benzoate C13H13N3O2 详情 详情
(XXXIV) 16401 (4R)-2-bromo-4-[[(2,2-dimethylpropanoyl)oxy]amino]-2-cyclohexen-1-one C11H16BrNO3 详情 详情
(XXXV) 16402 2-chloro-5-(tributylstannyl)pyridine C17H30ClNSn 详情 详情
(XXXVI) 16403 (4R)-2-(6-chloro-3-pyridinyl)-4-[[(2,2-dimethylpropanoyl)oxy]amino]-2-cyclohexen-1-one C16H19ClN2O3 详情 详情

合成路线10

10) Albertini et al. reported a formal synthesis of epibatidine utilizing the enantiopure cyclohexanone (XXXVIII) as a convenient starting material which was easily available from D-(-)quinic acid (XXXVII). An important step in this synthesis was the regioselective intramolecular nucleophilic ring opening of the vicinal diol cyclic sulfate (XXXIX). When (XXXIX) was subjected to hydrogenation, the azido group was converted into an amino group and an internal displacement took place spontaneously to form the inner salt (XL). Three standard manipulations furnished the optically pure ketone (VIII), which had already been converted to epibatidine as described by Fletcher and coworkers.

参考文献 中间体
【1】 Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G.P.; Zanirato, V.; Enantioselective approach to 7-azabicyclo[2.2.1]heptane ring systems using D-(-)-quinic acid as the chiral educt: Application to the formal synthesis of (+)-epibatidine. Tetrahedron Lett 1997, 38, 4, 681-4.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IXL) 16406 (3aR,5S,7aS)-5-azidohexahydro-1,3,2lambda(6)-benzodioxathiole-2,2-dione C6H9N3O4S 详情 详情
(VIII) 16374 (1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one C11H17NO3 详情 详情
(XXXVII) 11524 D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid 77-95-2 C7H12O6 详情 详情
(XXXVIII) 16405 (3aR,7aS)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-one C9H14O3 详情 详情
(XL) 16407 (1R,2R,4S)-2-(sulfonatooxy)-7-azoniabicyclo[2.2.1]heptane C6H11NO4S 详情 详情

合成路线11

11) Hassner and Belostotskii reported a simple synthesis of 7-alkyl-7-azabicyclo[2.2.1]heptanes. The starting aminoalcohols which were easily available from the monoethylene ketal of 1,4-cyclohexanedione (XLI) were treated with triphenylphosphine-carbon tetrachloride, leading to 7-alkyl-7-azabicyclo[2.2.1]heptanes (XLIII) in good yields. Recently, Davis et al. described the microbial hydroxylations of (XLIII) using the fungi Beauveria bassiana, Rhizopus nigricans, Aspergillus ochraceus and Rhizopus arrhizus as the primary organisms. Though the enantioselectivity was not high enough, these results demonstrated the potential of microbiological oxygenations to deliver enantioselective reactions.

参考文献 中间体
【1】 Hassner, A.; Belostotskii, A.M.; A simple method of preparation of 7-alkyl-7-azabicyclo[2.2.1]heptanes. Tetrahedron Lett 1995, 36, 1709-12.
【2】 Davis, C.R.; Johnson, R.A.; Cialdella, J.I.; Liggett, W.F.; Mizsak, S.A.; Marshall, V.P.; Microbiological oxygenation of bridgehead azabicycloalkanes. J Org Chem 1997, 62, 7, 2244-51.
【3】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(XLII) 16409 (1R,4R)-4-(methylamino)-2-cyclohexen-1-ol C7H13NO 详情 详情
rac-(XLIII) 16410 7-methyl-7-azabicyclo[2.2.1]heptane C7H13N 详情 详情
(XLI) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(XLIV) 16411 (1R,2S,4S)-7-methyl-7-azabicyclo[2.2.1]heptan-2-ol C7H13NO 详情 详情

合成路线12

12) Reaction of N-substituted-pyrrole derivatives with activated dienophiles. Retrosynthetic analysis revealed that the [4+2] cycloaddition reaction between pyrrole and dienophiles should be a general method for the synthesis of the 7-azanorborane ring system. Unfortunately, pyrrole is not a good diene for the Diels-Alder reactions. Pyrrole and its derivatives readily undergo Michael addition upon treatment with dienophiles, and the resulting 7-aza[2.2.1]bicycloheptenes are thermodynamically unstable. In order to stablize the resultant products and accelerate the cycloaddition reaction, N-protected pyrroles with a decreased aromaticity of the pyrrole ring are usually used as diene components and acetylene equivalents are used as dienophiles. In 1993 Shen et al. first reported a 4-step synthesis of racemic epibatidine. A Diels-Alder reaction of N-carbomethoxypyrrole (XLV) and phenylsulfonyl(6-chloro-3-pyridyl)acetylene (XLVI) afforded the adduct (XLVII) in 70% yield. Desulfonation and concomitant reduction of conjugated double bond with sodium amalgam resulted in a mixture of 1:2 ratio of exo-(XLVIII) to endo-(XLVIII).

参考文献 中间体
【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【2】 Chen, Z.; Trudell, M.L.; Chemistry of 7-azabicyclo[2.2.1]hepta-2,5-dienes, 7-azabicyclo[2.2.1]hept-2-enes, and 7-azabicyclo[2.2.1]hepatanes. Chem Rev 1996, 96, 1179-93.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(XLVII) 16414 methyl (1R,4S)-2-(6-chloro-3-pyridinyl)-3-(phenylsulfonyl)-7-azabicyclo[2.2.1]hepta-2,5-diene-7-carboxylate C19H15ClN2O4S 详情 详情
rac-(XLVIII) 16415 methyl (1R,4R)-5-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate C13H13ClN2O2 详情 详情
(IL) 16416 methyl (1R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C13H15ClN2O2 详情 详情
(XLV) 16412 N-Methyl pyrrolecarboxylate; methyl 1H-pyrrole-1-carboxylate 4277-63-8 C6H7NO2 详情 详情
(XLVI) 16413 2-(6-chloro-3-pyridinyl)ethynyl phenyl sulfone; 2-chloro-5-[2-(phenylsulfonyl)ethynyl]pyridine C13H8ClNO2S 详情 详情

合成路线13

13) Later on Carroll and Kotian modified Shen's route by replacement of N-carbomethoxypyrrole with N-(t-carbobutoxy)pyrrole in order to avoid the drastic reaction condition in the deprotection step. However, there was the problem of competing retro Diels-Alder reaction of the cycloadduct (L) and dechlorination. Therefore, the selective reduction of the least substituted double bond of (L) was carried out first. Desulfonation and simultaneous reduction of (LI) with amalgam obtained a 1:2 mixture of exo-(LII) and endo-(LII) analogous to Shen's report. The endo-isomer was epimerized to the exo-isomer in 46% yield using Fletcher's procedure. Finally, deprotection of the BOC group under mild conditions produced (I) in nearly quantitative yield.

参考文献 中间体
【1】 Kotian, P.L.; Carrol, F.I.; Synthesis of (+) and (-) epibatidine. Synth Commun 1995, 25, 63-71.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(L) 16417 tert-butyl (1R,4S)-2-(6-chloro-3-pyridinyl)-3-(phenylsulfonyl)-7-azabicyclo[2.2.1]hepta-2,5-diene-7-carboxylate C22H21ClN2O4S 详情 详情
rac-(LI) 16418 tert-butyl (1R,4S)-2-(6-chloro-3-pyridinyl)-3-(phenylsulfonyl)-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate C22H23ClN2O4S 详情 详情
rac-(LII) 16419 tert-butyl (1R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C16H21ClN2O2 详情 详情

合成路线14

14) It is noteworthy that Regan et al. described a very concise synthesis of racemic epibatidine. The key step was a reductive Pd-catalyzed Heck-type coupling of the known starting materials olefin (LVI) and 2-chloro-5-iodopyridine (LVII). The desired exo-isomer (LVIII) was formed stereoselectively.

参考文献 中间体
【1】 Clayton, S.C.; Regan, A.C.; A total synthesis of (±)-epibatidine. Tetrahedron Lett 1993, 34, 7493-6.
【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(LIV) 16420 methyl (1S,4R)-2-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hepta-2,5-diene-7-carboxylate C15H15NO4S 详情 详情
rac-(LV) 16421 methyl (1S,4R)-2-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate C15H17NO4S 详情 详情
rac-(LVI) 16422 methyl (1R,4S)-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate C8H11NO2 详情 详情
rac-(LVII) 16424 methyl (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C13H15ClN2O2 详情 详情
(LVII) 16423 2-chloro-5-iodopyridine C5H3ClIN 详情 详情

合成路线15

15) Natsume's approach to epibatidine was to construct the basic skeleton of (I) by condensation of N-protected 7-azabicyclo[2.2.1]heptan-2-one with 5-lithio-2-chloropyridine, which was similar to Fletcher's synthesis. However, the azabicycloheptanone (LX) was derived from the Diels-Alder adduct (LIX) of 1-(p-toluenesulfonyl)pyrrole and dimethyl acetylenedicarboxylate through a standard sequence of reactions. Reaction of (LX) with 5-lithio-2-methoxypyridine gave (LXI), which was dehydrated to (LXII) with Burgess reagent. Catalytic hydrogenation of (LXII) over palladium-on-charcoal in 2-propanol/water (12:1) containing 1% HCl afforded (LXIII) and (LXIV) in 22% and 72% yields, respectively. Treatment of (LXIV) with POCl3/DMF obtained (LXV) in 70% yield.

参考文献 中间体
【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【2】 Okabe, K.; Natsume, M.; Total synthesis of a frog poison, (±)-epibatidine, a potent non-opioid analgesic. Chem Pharm Bull 1994, 42, 7, 1432-6.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac(LXIV) 16395 (1R,2R,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane; methyl 5-[(1R,2R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridinyl ether C19H22N2O3S 详情 详情
rac-(LIX) 16425 dimethyl (1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene-2,3-dicarboxylate C17H19NO6S 详情 详情
rac-(LX) 16426 (1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-one C13H15NO3S 详情 详情
rac-(LXI) 16427 (1R,2S,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-ol C19H22N2O4S 详情 详情
rac-(LXII) 16428 methyl 5-[(1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-en-2-yl]-2-pyridinyl ether; (1R,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene C19H20N2O3S 详情 详情
rac-(LXIII) 16429 (1R,2S,4S)-2-(6-methoxy-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane; methyl 5-[(1R,2S,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridinyl ether C19H22N2O3S 详情 详情
rac-(LXV) 16431 (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane C18H19ClN2O2S 详情 详情

合成路线16

16) A similar approach was described by Zhang and Trudell in a recent report: The known 7-azabicyclo[2.2.1]heptan-2-one (VIII) was conveniently synthesized by the [4+2] cycloaddition of methyl 3-bromopropynoate (LXVII) and N-BOC-pyrrole (LXVI). They modified Fletcher's synthesis rendering it more stereoselective and suitable for the preparation of (I) on a large scale. The tertiary alcohol (IX) was successfully deoxygenated by a radical reaction via its methyl oxalyl ester with Bu3SnH in the presence of AIBN. This afforded the deoxygenated product stereoselectively as the endo-isomer (Xa).

参考文献 中间体
【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【2】 Zhang, C.; Trudell, M.L..; A short and efficient total synthesis of (±)-epibatidine. J Org Chem 1996, 61, 20, 7189-91.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac-I) 16385 (+)-Epibatidine hydrochloride; (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane 140111-52-0 C11H13ClN2 详情 详情
rac-(LXVIII) 16434 7-(tert-butyl) 2-methyl (1S,4R)-3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate C13H16BrNO4 详情 详情
rac-(VIII) 16435 tert-butyl (1R,4S)-2-oxo-7-azabicyclo[2.2.1]heptane-7-carboxylate C11H17NO3 详情 详情
rac-(IX) 16436 tert-butyl (1R,2S,4S)-2-(6-chloro-3-pyridinyl)-2-hydroxy-7-azabicyclo[2.2.1]heptane-7-carboxylate C16H21ClN2O3 详情 详情
rac-(Xa) 16437 tert-butyl (1R,2S,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C16H21ClN2O2 详情 详情
rac-(Xb) 16438 tert-butyl (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C16H21ClN2O2 详情 详情
(LXVI) 16432 tert-Butyl pyrrole-1-carboxylate; tert-Butyl-1H-pyrrole-1-carboxylate; tert-Butyl-1-pyrrolecarboxylate 5176-27-2 C9H13NO2 详情 详情
(LXVII) 16433 methyl 3-bromo-2-propynoate C4H3BrO2 详情 详情

合成路线17

17) Pandey et al. reported an efficient synthesis of epibatidine via [3+2] cycloaddition of nonstabilized azomethine ylide and substituted 6-chloro-3-vinylpyridine. The precursor (LXX) was obtained in 73% yield from N-BOC pyrrolidine (LXIX) by standard manipulations. The [3+2] cycloaddition between (LXX) and alpha,beta-unsaturated ester (LXXI) furnished cycloadduct (LXXII) stereoselectively. Decarboxylation followed by reductive N-debenzylation converted (LXXII) into (I) in 78% overall yield.

参考文献 中间体
【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【2】 Pandey, G.; Bagul, T.D.; Lakshmaiah, G.; An expeditious synthesis of epibatidine and analogues. Tetrahedron Lett 1994, 35, 7439-42.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(LXXII) 16442 2-[(1S,2S,3R,4R)-7-benzyl-3-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-2-yl]ethyl formate C21H23ClN2O2 详情 详情
(LXIX) 16439 tert-butyl 1-pyrrolidinecarboxylate 86953-79-9 C9H17NO2 详情 详情
(LXX) 16440 1-benzyl-2,5-bis(trimethylsilyl)pyrrolidine C17H31NSi2 详情 详情
(LXXI) 16441 ethyl (E)-3-(6-chloro-3-pyridinyl)-2-propenoate C10H10ClNO2 详情 详情

合成路线18

18) Ring contraction of the tropinone skeleton via a Favorskii rearrangement. Bai et al. utilized the readily available tropinone (LXXIII) as a starting material. Compound (LXXIV), which could be obtained from (LXXIII) in one step, was brominated with cupric bromide to give the monobromide (LXXV). Without separation of the two isomers, both isomers (LXXV) underwent Favorskii rearrangement to yield the expected ester (LXXVI). The key intermediate (LXXVII) was then obtained by selenation of (LXXVI) followed by selenoxide elimination. A palladium-catalyzed Heck-type coupling of (LXXVII) and 2-chloro-5-iodopyridine (LVII) furnished the exo-isomer (LXXVIII) stereoselectively in 56% yield. Conversion of (LXXVIII) to (I) was achieved by radical decarboxylation of the corresponding thiohydroxamic ester followed by cleavage of the carbamate with iodotrimethyl silane.

参考文献 中间体
【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【2】 Xu, R.; Chu, G.; Bai, D.; Total synthesis of (±)-epibatidine. Tetrahedron Lett 1996, 37, 1463-6.
【3】 Bai, D.; Xu, R.; Chu, G.; Zhu, X.; Synthesis of (±)-epibatidine and its analogues. J Org Chem 1996, 61, 4600-6.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(LXXXIII) 16443 (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one C8H13NO 详情 详情
rac-(LXXIV) 16444 ethyl (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate 32499-64-2 C10H15NO3 详情 详情
rac-(LXXV) 16445 ethyl (1R,5S)-2-bromo-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate C10H14BrNO3 详情 详情
rac-(LXXVI) 16446 ethyl (1R,2S,4S)-2-[(formyloxy)methyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate C11H17NO4 详情 详情
rac-(LXXVII) 16447 7-ethyl 2-methyl (1S,4R)-7-azabicyclo[2.2.1]hept-2-ene-2,7-dicarboxylate C11H15NO4 详情 详情
rac-(LXXVIII) 16448 ethyl (1R,2R,3S,4S)-2-(6-chloro-3-pyridinyl)-3-[(formyloxy)methyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate C16H19ClN2O4 详情 详情

合成路线19

19) Intramolecular cyclization of substituted proline derivatives. Rapoport et al. developed an asymmetric methodology which had potential for the enantiospecific synthesis of (+)- and (-)-epibatidine. The triflate (LXXIX) was readily synthesized from levulinic acid in 3 straightforward steps. Alkylation of S-thiolactam (LXXX) prepared from L-glutamic acid with triflate (LXXIX), followed by sulfide contraction provided the carbamate (LXXXI). (LXXXI) was then converted into keto acid (LXXXII). (LXXXII) was decarboxylated and the resulting iminium ions were subjected to intramolecular cyclization to give a mixture of trans-2,3-disubstituted-7-azabicyclo[2.2.1]heptanes (LXXXIII) and (LXXXIV). This mixture was selectively converted into (+)- and (-)-N-BOC-7-azabicyclo[2.2.1]heptane-2-ones (VIII), which are versatile intermediates for the enantiospecific synthesis of (+)- and (-)-epibatidine.

参考文献 中间体
【1】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210.
【2】 Hernández, A.; Marcos, M.; Rapoport, H.; Synthesis of (+)- and (-)-N-BOC-7-azabicyclo[2.2.1]heptan-2-ones, versatile intermediates for the enantiospecific synthesis of (+)- and (-)-epibatidine and analogues. J Org Chem 1995, 60, 2638-91.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
((-)-VIII) 16435 tert-butyl (1R,4S)-2-oxo-7-azabicyclo[2.2.1]heptane-7-carboxylate C11H17NO3 详情 详情
(LXIV) 16454 [(1R,2R,3R,4S)-7-benzyl-3-(2-oxoethyl)-7-azabicyclo[2.2.1]hept-2-yl]methyl formate C17H21NO3 详情 详情
(LXXIX) 16449 methyl 3-(2-methyl-1,3-dioxolan-2-yl)-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate C9H13F3O7S 详情 详情
(LXXX) 16450 2-[(2S)-1-benzyl-5-thioxotetrahydro-1H-pyrrol-2-yl]-1,1-dimethylethyl formate C16H21NO2S 详情 详情
(LXXXI) 16451 methyl 2-[(5S)-1-benzyl-5-[2-(formyloxy)-2-methylpropyl]tetrahydro-2H-pyrrol-2-ylidene]-3-(2-methyl-1,3-dioxolan-2-yl)propanoate C24H33NO6 详情 详情
(LXXXII) 16452 methyl (2S)-2-[(2R,5R)-1-benzyl-5-(formyloxy)tetrahydro-1H-pyrrol-2-yl]-4-oxopentanoate C18H23NO5 详情 详情
(LXXXIII) 16453 [(1R,2S,3S,4S)-7-benzyl-3-(2-oxoethyl)-7-azabicyclo[2.2.1]hept-2-yl]methyl formate C17H21NO3 详情 详情

合成路线20

20) A total synthesis of epibatidine has been reported: The cyclization of 1-(tert-butoxycarbonyl)pyrrole (I) with tosylacetylene (II) by means of H2 over Pd/C in acetonitrile gives the bicyclic compound (III), which is condensed with 5-bromo-2-methoxypyridine (IV) by means of BuLi in THF yielding the 2exo-(6-methoxy-3-pyridyl) derivative (V). The detosylation of (V) by means of Na(Hg) in methanol/THF affords intermediate (VI), which is treated with POCl3 in DMF to effect the conversion of the methoxypyridine into the desired chloropyridine derivative (VII), with simultaneous elimination of the tert-butoxycarbonyl protecting group and N-formylation. Finally, this formyl group is eliminated with HCl in hot THF.

参考文献 中间体
【1】 Giblin, G.M.P.; Jones, C.D.; Simpkins, N.S.; The total synthesis of the analgesic alkaloid epibatidine. J Chem Soc - Perkins Trans I 1998, 22, 3689.
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) 16432 tert-Butyl pyrrole-1-carboxylate; tert-Butyl-1H-pyrrole-1-carboxylate; tert-Butyl-1-pyrrolecarboxylate 5176-27-2 C9H13NO2 详情 详情
(II) 29860 ethynyl 4-methylphenyl sulfone; ethynyl(4-methylphenyl)dioxo-lambda(6)-sulfane 13894-21-8 C9H8O2S 详情 详情
(III) 29861 tert-butyl (1S,4R)-2-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate C18H23NO4S 详情 详情
(IV) 29862 5-bromo-2-methoxypyridine; 5-bromo-2-pyridinyl methyl ether 13472-85-0 C6H6BrNO 详情 详情
(V) 29863 tert-butyl (1R,2R,3S,4S)-2-(6-methoxy-3-pyridinyl)-3-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate C24H30N2O5S 详情 详情
(VI) 29864 tert-butyl (1R,2R,4S)-2-(6-methoxy-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C17H24N2O3 详情 详情
(VII) 29865 (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carbaldehyde C12H13ClN2O 详情 详情

合成路线21

21) A new synthesis of epibatidine has been reported: The reaction of 2-tosyl-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylic acid tert-butyl ester (I) with tributyltin hydride (II) by means of azobis(isobutyronitrile) (AIBN) in benzene gives the tin derivative (III), which by treatment with tetrabutylammonium fluoride in THF provides 7-azabicyclo[2.2.1]hept-2-ene-7-carboxylic acid tert-butyl ester (IV). The condensation of (IV) with 5-iodopyridine-2-amine (V) by means of palladium acetate/tetrabutylammonium chloride/potassium formate in hot DMF yields exo-2-(6-amino-3-pyridyl)-7-azabicyclo[2.2.1]heptane-7-carbo-xylic acid tert-butyl ester (VI), which is finally submitted to diazotization with NaNO2/HCl and treated with CuCl.

参考文献 中间体
【1】 Abraham, P.; Brieaddy, L.E.; Carroll, F.I.; Lee, J.R.; Liang, F.; New synthesis of 7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-2-ene. A key intermediate in the synthesis of epibatidine and analogs. Tetrahedron Lett 1998, 39, 30, 5321.
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) 29861 tert-butyl (1S,4R)-2-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate C18H23NO4S 详情 详情
(II) 29870 butyl(dipentyl)stannane C14H32Sn 详情 详情
(III) 29866 tert-butyl (1R,4S)-2-[butyl(dipentyl)stannyl]-3-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate C32H55NO4SSn 详情 详情
(IV) 29867 tert-butyl (1R,4S)-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate C11H17NO2 详情 详情
(V) 29868 5-iodo-2-pyridinamine; 5-iodo-2-pyridinylamine C5H5IN2 详情 详情
(VI) 29869 tert-butyl (1R,2R,4S)-2-(6-amino-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate C16H23N3O2 详情 详情

合成路线22

The synthesis of (-)-7-tosyl-7-azabicyclo[2.2.1]heptan-2-one, a key chiral intermediate for the asymmetric synthesis of (-)-epibatidine has been described: The reaction of (+)-camphorsultam (I) first with triphosgene and DIEA, and then with NH2OH gives the (+)-hydroxamic acid (II), which is oxidized with tetraethylammonium periodate in CH2Cl2 to yield the acylnitroso compound (III). The asymmetric hetero Diels-Alder cycloaddition of (III) with 2-(tert-butyldimethylsilyloxy)-1,3-cyclohexadiene (IV) affords the (1S,4R)-cycloadduct (V), which is cleaved with Mo(CO)6 providing the (+)-6-amino-2-cyclohexenone (VI) as s single diastereomer. Reduction of the carbonyl group of (VI) with NaBH4 and CeCl3 in methanol gives a 9:1 mixture of cis:trans-diastereomers, from which the major (+)-cis-diastereomer (VII) is isolated by chromatography. Elimination of the chiral auxiliary with KOH in MeOH gives the chiral (-)-oxazolidinone (VIII), which is tosylated with TsCl and NaH in THF yielding the (-)-N-tosyloxazolidinone (IX). Bromination of (IX) with Br2 in DME affords a 80:20 mixture of diastereomeric bromohydrins, from which the desired (-)-diastereo-mer (X) is isolated by column chromatography. Reductive debromination of (X) with Bu3SnH and AIBN in hot toluene followed by hydrolysis of the oxazolidinone ring by treatment with LiOH in MeOH, yields the (+)-aminocyclohexanediol (XI). The cyclization of (XI) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF affords the chiral (-)-7-azabicyclo[2.2.1]heptanol (XII) which is finally oxidized with oxalyl chloride and TEA in DMSO to provide the target chiral intermediate (-)-7-tosyl-7-azabicyclo[2.2.1]heptan-2-one.

参考文献 中间体
【1】 Berrien, J.F.; Cabanal Duvillard, I.; Ghosez, L.; Husson, H.P.; Royer, J.; A formal asymmetric synthesis of (-)-epibatidine using a highly diastereoselective hetero Diels-Alder reaction. Tetrahedron 2000, 56, 23, 3763.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16426 (1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-one C13H15NO3S 详情 详情
(I) 10609 (1R,5S,7S)-10,10-Dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C10H17NO2S 详情 详情
(II) 41743 (1S,5S,7R)-N-hydroxy-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-4-carboxamide C11H18N2O4S 详情 详情
(III) 41744 (1S,5S,7R)-10,10-dimethyl-N,3,3-trioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-4-carboxamide C11H16N2O4S 详情 详情
(IV) 41745 tert-butyl(1,5-cyclohexadien-1-yloxy)dimethylsilane; tert-butyl(dimethyl)silyl 1,5-cyclohexadien-1-yl ether C12H22OSi 详情 详情
(V) 41746 (1S,5S,7R)-4-[((1S,4R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)carbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C23H38N2O5SSi 详情 详情
(VI) 41747 (1S,5S,7R)-10,10-dimethyl-3,3-dioxo-N-[(1R)-2-oxo-3-cyclohexen-1-yl]-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-4-carboxamide C17H24N2O4S 详情 详情
(VII) 41748 (1S,5S,7R)-N-[(1R,2S)-2-hydroxy-3-cyclohexen-1-yl]-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-4-carboxamide C17H26N2O4S 详情 详情
(VIII) 41749 (3aR,7aS)-3a,4,5,7a-tetrahydro-1,3-benzoxazol-2(3H)-one C7H9NO2 详情 详情
(IX) 41750 (3aR,7aS)-3-[(4-methylphenyl)sulfonyl]-3a,4,5,7a-tetrahydro-1,3-benzoxazol-2(3H)-one C14H15NO4S 详情 详情
(X) 41751 (3aR,6R,7S,7aR)-7-bromo-6-hydroxy-3-[(4-methylphenyl)sulfonyl]hexahydro-1,3-benzoxazol-2(3H)-one C14H16BrNO5S 详情 详情
(XI) 41752 N-[(1R,2S,4R)-2,4-dihydroxycyclohexyl]-4-methylbenzenesulfonamide C13H19NO4S 详情 详情
(XII) 41753 (1S,2S,4R)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-ol C13H17NO3S 详情 详情

合成路线23

A new total synthesis of racemic epibatidine has been reported: The benzoylation of trans-4-aminocyclohexanol (I) with benzoyl chloride gives the benzamide (II), which is treated with methanesulfonyl chloride and triethylamine to yield the mesylate (III). Cyclization of (III) by means of potassium tert-butoxide in DMF/benzene affords the 7-azanorbornane (IV), which by microbial hydroxylation using the fungus Beauveria bassiana gives stereoselectively the endo-2-hydroxy-7-azanorbornane (V). Oxidation of (V) with TPAP and NMO in dichloromethane yields the ketone (VI), which is condensed with 2-chloro-5-iodopyridine (VII) by means of butyllithium in THF affording exclusively the endo-alcohol (VIII). Reaction of (VIII) with methoxalyl chloride (IX) and DMAP/2,6-lutidine in dichloromethane gives the mixed oxalate (IX), which is reduced with tributyltin hydride and AIBN to yield exclusively the endo-isomer (XI). Isomerization of (XI) by means of potassium tert-butoxide in refluxing tert-butanol affords the exo-isomer (XII), which is finally debenzoylated by treatment with 6N HCl at 100 C.

参考文献 中间体
【1】 Olivo, H.F.; Hemenway, M.S.; Total synthesis of (±)-epibatidine using a biocatalytic approach. J Org Chem 1999, 64, 24, 8968.
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) 19581 trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情
(II) 41754 N-(4-hydroxycyclohexyl)benzamide C13H17NO2 详情 详情
(III) 41755 4-(benzoylamino)cyclohexyl methanesulfonate C14H19NO4S 详情 详情
(IV) 41756 7-azabicyclo[2.2.1]hept-7-yl(phenyl)methanone C13H15NO 详情 详情
(V) 41757 [(1S,2R,4R)-2-hydroxy-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone C13H15NO2 详情 详情
(VI) 41758 (1S,4R)-7-benzoyl-7-azabicyclo[2.2.1]heptan-2-one C13H13NO2 详情 详情
(VII) 16423 2-chloro-5-iodopyridine C5H3ClIN 详情 详情
(VIII) 41759 [(1S,2S,4R)-2-(6-chloro-3-pyridinyl)-2-hydroxy-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone C18H17ClN2O2 详情 详情
(IX) 26971 2-methoxy-2-oxoacetyl chloride 5781-53-3 C3H3ClO3 详情 详情
(X) 41760 (1S,2S,4R)-7-benzoyl-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-2-yl 2-methoxy-2-oxoacetate C21H19ClN2O5 详情 详情
(XI) 41761 [(1S,2S,4R)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone C18H17ClN2O 详情 详情
(XII) 41762 [(1S,2R,4R)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone C18H17ClN2O 详情 详情
Extended Information