(1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-one -Drug Synthesis Database

【结构式】

【分子编号】16426

【品名】(1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-one

【CA登记号】

【分子式】C₁₃H₁₅NO₃S

【分子量】265.33304

【元素组成】C 58.85% H 5.7% N 5.28% O 18.09% S 12.09%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：rac-(LX)

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

合成目标

【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	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2

该中间体在本合成路线中的序号：

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

合成目标

【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	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

Extended Information