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【结 构 式】 
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【分子编号】16432 【品名】tert-Butyl pyrrole-1-carboxylate; tert-Butyl-1H-pyrrole-1-carboxylate; tert-Butyl-1-pyrrolecarboxylate 【CA登记号】5176-27-2 |
【 分 子 式 】C9H13NO2 【 分 子 量 】167.20776 【元素组成】C 64.65% H 7.84% N 8.38% O 19.14% |
合成路线1
该中间体在本合成路线中的序号：(LXVI)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).
| 【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2
该中间体在本合成路线中的序号：(I)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.
| 【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3
该中间体在本合成路线中的序号：(I)Metalation of N-Boc-pyrrole (I) with the lithium amide of tetramethylpiperidine, followed by boronation with triethyl borate and acidic work-up leads to the pyrroleboronic acid (II). Subsequent catalytic hydrogenation over Pt/C provides the racemic pyrrolidineboronic acid (III). Alternatively, protection of pyrrolidine (IV) with Boc2O affords (V). After metalation of N-Boc-pyrrolidine (V) with s-butyllithium, treatment with triethyl borate gives rise to the boronic acid (III). Condensation of the racemic boronic acid (III) with (+)-pinanediol (VI) furnishes the corresponding mixture of diastereoisomeric pinanediol boronates, from which the desired isomer (VII) can be isolated by column chromatography. Further removal of the N-Boc protecting group under acidic conditions yields the pyrrolidineboronic ester (VIII). Coupling of pyrrolidine (VIII) with N-Boc-L-valine (IX) produces amide (X). The N-Boc group is then cleaved with HCl in Et2O to afford the deprotected amine (XI). Finally, removal of the pinanediol moiety by transesterification of the boronic ester (XI) with phenylboronic acid provides the desired boronic dipeptide
| 【1】 Gibson, F.S.; Singh, A.K.; Soumeillant, M.C.; Manchand, P.S.; Humora, M.; Kronenthal, D.R.; A practical synthesis of L-valyl-pyrrolidine-(2R)-boronic acid: Efficient recycling of the costly chiral auxiliary (+)-pinanediol. Org Process Res Dev 2002, 6, 6, 814. |
| 【2】 Coutts, S.J.; Kelly, T.A.; Snow, R.J.; Kennedy, C.A.; Barton, R.W.; Adams, J.; Krolikowski, D.A.; Freeman, D.M.; Campbell, S.J.; Ksiazek, J.F.; Bachovchin, W.W.; Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides. J Med Chem 1996, 39, 10, 2087. |
| 【3】 Wallner, B.P. (Point Therapeutics, Inc.); Cyclic boroproline cpds.. JP 2002517401; WO 9962914 . |
| 【4】 Hoshi, H.; Okumura, J.; Naito, T.; Abe, Y.; Abukari, S. (Bristol-Myers Squibb Co.); Substituted vinyl cephalosporins. DE 3402642; US 4520022 . |
| 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) | 63008 | 1-{[(1,1-dimethylethyl)oxy]carbonyl}-1H-pyrrol-2-ylboronic acid; 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid | C9H14BNO4 | 详情 | 详情 | |
| (III) | 63002 | 1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid | 149682-75-7 | C9H18BNO4 | 详情 | 详情 |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 16439 | tert-butyl 1-pyrrolidinecarboxylate | 86953-79-9 | C9H17NO2 | 详情 | 详情 |
| (VI) | 63005 | (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (+)-Pinanediol | 18680-27-8 | C10H18O2 | 详情 | 详情 |
| (VII) | 63006 | tert-butyl (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]-1-pyrrolidinecarboxylate | C19H32BNO4 | 详情 | 详情 | |
| (VIII) | 63007 | (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidine | 205116-75-2 | C14H24BNO2 | 详情 | 详情 |
| (IX) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (X) | 63011 | tert-butyl (1S)-2-methyl-1-({(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}carbonyl)propylcarbamate | C24H41BN2O5 | 详情 | 详情 | |
| (XI) | 63012 | (2S)-2-amino-3-methyl-1-{(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}-1-butanone | C19H33BN2O3 | 详情 | 详情 |