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【结 构 式】

【分子编号】10216

【品名】(4aS,5R,8S)-8-(2-Hydroxy-1-methylethyl)-5-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone

【CA登记号】

【 分 子 式 】C14H22O2

【 分 子 量 】222.32748

【元素组成】C 75.63% H 9.97% O 14.39%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IX)

Artemisin can be synthesized by several related ways: 1) The reaction of L-menthone (I) with paraformaldehyde and dimethylamine hydrochloride gives the dimethylaminomethyl derivative (II), which is cyclized with ethyl acetoacetate by means of sodium ethoxide and methyl iodide to the octahydronaphthalenone (III) (Indian J Chem 1976, 14B: 901). Epoxidation of (III) with H2O2/NaOH in methanol/water yields the epoxide (IV), which is reduced with LiAlH4 in ether to the diol (V). Selective acetylation of (V) with acetic anhydride in pyridine affords the monoacetoxy compound (VI), which is cyclized by means of lead tetraacetate, catalyzed by irradiation with white light, yielding the furo-decaline (VII). The hydrolysis of the acetoxy group of (VII) followed by oxidation with pyridinium chlorochromate (PCC) gives the ketone (VIII), which is submitted to ring opening with acidic alumina in ethyl acetate/benzene, yielding the unsaturated hydroxy ketone (IX). Hydrogenation of (IX) with H2 over Pd/C in methanol affords the corresponding saturated ketone (X), which by a Grignard methylation with methylmagnesium iodide in ether gives the diol (XI). Selective acetylation of (XI) with acetic anhydride in pyridine gives the monoacetoxy compound (XII), which is dehydrated with POCl3/pyridine to the octahydronaphthalene (XIII). The hydrolysis of (XIII) with KOH in ethanol gives the alcohol (XIV), which is submitted to ozonolysis with O3 in dichloromethane followed by cyclization with p-toluenesulfonic acid, yielding the 2-benzopyran (XVI). The photochemical oxidation of (XVI) with O2 and methylene blue in dichloromethane irradiated with an Na lamp followed by a cyclization catalyzed by p-toluenesulfonic acid affords deoxoartemisinin (XVII), which is finally oxidized with RuCl3 and NaIO4 in acetonitrile/water. 2) The alcohol (XIV) can also be obtained from artemisinic acid (XV) by methylation to the corresponding methyl ester with diazomethane and reduction with LiAlH4-NiCl2 in methanol.

1 Deshpande, V.H.; Bhonsle, J.B.; Pandey, B.; Ravindranathan, T.; New synthetic strategies towards (+)-artemisinin. Tetrahedron Lett 1994, 35, 30, 5489.
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) 10208 L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone 14073-97-3 C10H18O 详情 详情
(II) 10209 (3R,6S)-2-[(Dimethylamino)methyl]-6-isopropyl-3-methylcyclohexanone C13H25NO 详情 详情
(III) 10210 (4aS,5R,8S)-8-Isopropyl-5-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone C14H22O 详情 详情
(IV) 10211 (1aS,4aS,5R,8S,8aS)-8-Isopropyl-5-methylhexahydro-1aH-naphtho[1,8a-b]oxiren-2(3H)-one C14H22O2 详情 详情
(V) 10212 (2S,4aS,5R,8S)-8-Isopropyl-5-methyloctahydro-2,8a(1H)-naphthalenediol C14H26O2 详情 详情
(VI) 10213 (2S,4aS,5R,8S,8aS)-8a-Hydroxy-8-isopropyl-5-methyldecahydro-2-naphthalenyl acetate C16H28O3 详情 详情
(VII) 10214 (3aS,6R,6aS,9S,10aR)-3,6-Dimethyldecahydro-2H-naphtho[8a,1-b]furan-9-yl acetate C16H26O3 详情 详情
(VIII) 10215 (3aS,6R,6aS,10aR)-3,6-Dimethyloctahydro-2H-naphtho[8a,1-b]furan-9(10H)-one C14H22O2 详情 详情
(IX) 10216 (4aS,5R,8S)-8-(2-Hydroxy-1-methylethyl)-5-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone C14H22O2 详情 详情
(X) 10217 (4aS,5R,8R,8aS)-8-(2-Hydroxy-1-methylethyl)-5-methyloctahydro-2(1H)-naphthalenone C14H24O2 详情 详情
(XI) 10218 (4aS,5R,8R,8aS)-8-(2-Hydroxy-1-methylethyl)-2,5-dimethyldecahydro-2-naphthalenol C15H28O2 详情 详情
(XII) 10219 2-[(1R,4R,4aS,8aS)-7-hydroxy-4,7-dimethyldecahydro-1-naphthalenyl]propyl acetate C17H30O3 详情 详情
(XIII) 10220 2-[(1R,4R,4aS,8aS)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]propyl acetate C17H28O2 详情 详情
(XIV) 10221 2-[(1R,4R,4aS,8aS)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]-1-propanol C15H26O 详情 详情
(XV) 10222 2-[(1R,4R,4aS,8aR)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]acrylic acid; Artemisinic acid C15H22O2 详情 详情
(XVI) 10223 4-[(4R,4aS,7R,8S)-4,7-Dimethyl-4,4a,5,6,7,8-hexahydro-3H-isochromen-8-yl]-2-butanone C15H24O2 详情 详情
(XVII) 10224 (1R,4S,5R,8S,9R,12R,13R)-1,5,9-Trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane C15H24O4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IX)

 

1 Deshpande VH, Bhonsle JB, Pandey B, et al. 1994. New synthesis strategies towards(+) -artemisinin. Tetrahedron Lett, 35(30):5489~5492.
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) 10208 L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone 14073-97-3 C10H18O 详情 详情
(II) 10209 (3R,6S)-2-[(Dimethylamino)methyl]-6-isopropyl-3-methylcyclohexanone C13H25NO 详情 详情
(III) 10210 (4aS,5R,8S)-8-Isopropyl-5-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone C14H22O 详情 详情
(IV) 10211 (1aS,4aS,5R,8S,8aS)-8-Isopropyl-5-methylhexahydro-1aH-naphtho[1,8a-b]oxiren-2(3H)-one C14H22O2 详情 详情
(V) 10212 (2S,4aS,5R,8S)-8-Isopropyl-5-methyloctahydro-2,8a(1H)-naphthalenediol C14H26O2 详情 详情
(VI) 10213 (2S,4aS,5R,8S,8aS)-8a-Hydroxy-8-isopropyl-5-methyldecahydro-2-naphthalenyl acetate C16H28O3 详情 详情
(VII) 67030 (3aS,6R,6aS,9S,10aR)-3,6-Dimethyldecahydro-2H-naphtho[8a,1-b]furan-9-ol   C14H24O2 详情 详情
(VIII) 10215 (3aS,6R,6aS,10aR)-3,6-Dimethyloctahydro-2H-naphtho[8a,1-b]furan-9(10H)-one C14H22O2 详情 详情
(IX) 10216 (4aS,5R,8S)-8-(2-Hydroxy-1-methylethyl)-5-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone C14H22O2 详情 详情
(X) 10217 (4aS,5R,8R,8aS)-8-(2-Hydroxy-1-methylethyl)-5-methyloctahydro-2(1H)-naphthalenone C14H24O2 详情 详情
(XI) 10218 (4aS,5R,8R,8aS)-8-(2-Hydroxy-1-methylethyl)-2,5-dimethyldecahydro-2-naphthalenol C15H28O2 详情 详情
(XII) 10219 2-[(1R,4R,4aS,8aS)-7-hydroxy-4,7-dimethyldecahydro-1-naphthalenyl]propyl acetate C17H30O3 详情 详情
(XIII) 10220 2-[(1R,4R,4aS,8aS)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]propyl acetate C17H28O2 详情 详情
(XIV) 10221 2-[(1R,4R,4aS,8aS)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydro-1-naphthalenyl]-1-propanol C15H26O 详情 详情
(XV) 67031 3-((4S,4aR,7S,8R)-4,7-dimethyl-4,4a,5,6,7,8-hexahydro-3H-isochromen-8-yl)propanoic acid   C14H22O3 详情 详情
(XVI) 10224 (1R,4S,5R,8S,9R,12R,13R)-1,5,9-Trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane C15H24O4 详情 详情
Extended Information