2-[(3aR,5S,7S,7aS)-7-hydroxy-7-(2-methoxyphenyl)octahydro-1H-isoindol-5-yl]acetonitrile -Drug Synthesis Database

【结构式】

【分子编号】19722

【品名】2-[(3aR,5S,7S,7aS)-7-hydroxy-7-(2-methoxyphenyl)octahydro-1H-isoindol-5-yl]acetonitrile

【CA登记号】

【分子式】C₁₇H₂₂N₂O₂

【分子量】286.37396

【元素组成】C 71.3% H 7.74% N 9.78% O 11.17%

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：(XXVI)

The Diels-Alder cyclization of 1-acetoxy-1,3-butadiene (XIV) with maleimide (XV) in toluene at 80 C gives racemic (3aRS,4RS,7aSR)-4-acetoxy-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione (XVI), which is reduced with LiAlH4 in THF to the racemic alcohol (XVII). Optical resolution of (XVII) with Di-p-toluoyl-L-tartaric acid in THF/ethanol/ /water yields the (3aS,4S,7aR)-isomer (XVIII), which is N-protected with tert-butoxycarbonyl anhydride to the protected compound (XIX). The Oppenauer oxidation of (XIX) catalized by aluminum isopropoxide affords the unsaturated ketone (XX), which is condensed with cyanacetic acid (XXI) by means of NaOH in toluene/water to afford the substituted cyanacetic derivative (XXII). The decarboxylation of (XXII) catalized by Cu2O in refluxing acetonitrile gives the suitably substituted ketone (XXIII), which is submitted to a Grignard condensation with 2-methoxy-phenylmagnesium bromide (XXIV) in THF yielding the alcohol (XXV) as a single isomer. The deprotection of (XXV) with HCl in THF affords compound (XXVI) with a free NH group, which is finally acylated with 2(S)-(2-methoxyphenyl)propionic acid (II) by means of SOCl2 and K2CO3 to obtain RPR-111905.

参考文献中间体

合成目标

【1】 Mutti, S.; et al.; Practical enantiospecific synthesis of RPR 111905: A novel non-peptide substance P antagonist. Tetrahedron Lett 1996, 37, 48, 8743.
【2】 Achard, D.; Peyronel, J.-F.; Tabart, M. (Aventis Pharma SA); Perhydroisoindole derivs. as antagonists of substance P. FR 2727411; JP 1998509970; US 5739351; WO 9616939 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	19710	(1E)-1,3-butadienyl acetate	1515-76-0	C₆H₈O₂	详情	详情
(XV)	19711	1H-pyrrole-2,5-dione	541-59-3	C₄H₃NO₂	详情	详情
(XVI)	19712	(3aR,4S,7aR)-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl acetate		C₁₀H₁₁NO₄	详情	详情
(XVII)	19713	(3aS,4S,7aR)-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol		C₈H₁₃NO	详情	详情
(XIX)	19715	tert-butyl (3aS,4S,7aR)-4-hydroxy-1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate		C₁₃H₂₃NO₃	详情	详情
(XX)	19716	tert-butyl (3aS,7aR)-4-oxo-1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate		C₁₃H₁₉NO₃	详情	详情
(XXII)	19718	(2S)-2-[(3aR,5R,7aS)-2-(tert-butoxycarbonyl)-7-oxooctahydro-1H-isoindol-5-yl]-2-cyanoethanoic acid		C₁₆H₂₂N₂O₅	详情	详情
(XXIII)	19719	tert-butyl (3aS,6S,7aR)-6-(cyanomethyl)-4-oxooctahydro-2H-isoindole-2-carboxylate		C₁₅H₂₂N₂O₃	详情	详情
(XXV)	19721	tert-butyl (3aS,4S,6S,7aR)-6-(cyanomethyl)-4-hydroxy-4-(2-methoxyphenyl)octahydro-2H-isoindole-2-carboxylate		C₂₂H₃₀N₂O₄	详情	详情
(XXVI)	19722	2-[(3aR,5S,7S,7aS)-7-hydroxy-7-(2-methoxyphenyl)octahydro-1H-isoindol-5-yl]acetonitrile		C₁₇H₂₂N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The Friedel Crafts condensation of thioanisole (I) with isobutyryl chloride (II) by means of AlCl3 gives the propiophenone (III), which is alpha hydroxylated by means of Aliquant 336 and NaOH yielding the alpha hydroxy ketone (IV). The oxidation of the methylsulfanyl group of (IV) with magnesium monoperoxyphthalate (MMPP) affords the corresponding sulfone (V), which is finally cyclized with 2-(3,4-difluorophenoxy)acetic acid (VI) by means of 1-cyclohexyl-3-[2-(4-morpholinyl)ethyl]carbodiimide metho-p-toluenesulfonate (CMC), DMAP and DBU to furnish the target furanone.

参考文献中间体

合成目标

【1】 Brideau, C.; Li, C.-S.; Chan, C.C.; Black, W.C.; et al.; A new structural variation on the methanesulfonylphenyl class of selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1999, 9, 22, 3181.
【2】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 .

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)	19722	2-[(3aR,5S,7S,7aS)-7-hydroxy-7-(2-methoxyphenyl)octahydro-1H-isoindol-5-yl]acetonitrile		C₁₇H₂₂N₂O₂	详情	详情
(II)	14932	isobutyryl chloride; 2-methylpropanoyl chloride	79-30-1	C₄H₇ClO	详情	详情
(III)	36573	2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone		C₁₁H₁₄OS	详情	详情
(IV)	36574	2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone		C₁₁H₁₄O₂S	详情	详情
(V)	36575	2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-propanone		C₁₁H₁₄O₄S	详情	详情
(VI)	18826	2-(3,4-difluorophenoxy)acetic acid		C₈H₆F₂O₃	详情	详情

Extended Information