|
【结 构 式】 
|
【分子编号】16374 【品名】(1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one 【CA登记号】 |
【 分 子 式 】C11H17NO3 【 分 子 量 】211.26092 【元素组成】C 62.54% H 8.11% N 6.63% O 22.72% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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).
| 【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2
该中间体在本合成路线中的序号：(VIII)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.
| 【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3
该中间体在本合成路线中的序号：(IX)Solid-phase peptide synthesis started with N-Boc-L-leucine linked to a PAM resin (VII). Deprotection of the Boc group was effected by treatment with trifluoroacetic acid in CH2Cl2 to give leucine-resin (VIII). Sequential couplings with the respective protected amino acids were mediated by DCC and HOBt, and trifluoroacetic acid in CH2Cl2 was used for deprotection of the Boc groups. The following protected amino acids were sequentially coupled: N-Boc-L-proline (IX), N-Boc-L-isoleucine (XI), N-Boc-L-proline (IX), N-Boc-L-glutamic acid omega-benzyl ester (XIV), N-Boc-L-phenylalanine (XVI) and N-Boc-L-aspartic acid omega-cyclohexyl ester (XVIII) to afford the peptide resins (X), (XII), (XIII), (XV), (XVII) and (XIX), respectively.
| 【1】 DiMaio, J. (National Research Council of Canada); Thrombin inhibitors based on the amino acid sequence of hirudin. JP 1999502203; WO 9629347 . |
| 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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VIII) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
| (IX) | 16374 | (1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one | C11H17NO3 | 详情 | 详情 | |
| (IX) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (X) | 37334 | (2S)-4-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoic acid | 52899-07-7 | C11H20N2O3 | 详情 | 详情 |
| (XI) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (XII) | 37335 | (2S)-2-[([(2S)-1-[(2S,3S)-2-amino-3-methylpentanoyl]pyrrolidinyl]carbonyl)amino]-4-methylpentanoic acid | C17H31N3O4 | 详情 | 详情 | |
| (XIII) | 37336 | (2S)-4-methyl-2-([[(2S)-1-((2S,3S)-3-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoyl)pyrrolidinyl]carbonyl]amino)pentanoic acid | C22H38N4O5 | 详情 | 详情 | |
| (XIV) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (XV) | 37337 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-amino-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C34H51N5O8 | 详情 | 详情 | |
| (XVI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XVII) | 37338 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C43H60N6O9 | 详情 | 详情 | |
| (XVIII) | 37339 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(cyclohexyloxy)-4-oxobutyric acid | 73821-95-1 | C15H25NO6 | 详情 | 详情 |
| (XIX) | 37340 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[((2S)-2-[[(2S)-2-amino-4-(cyclohexyloxy)-4-oxobutanoyl]amino]-3-phenylpropanoyl)amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C53H75N7O12 | 详情 | 详情 |