【结 构 式】 |
【分子编号】10208 【品名】L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone 【CA登记号】14073-97-3 |
【 分 子 式 】C10H18O 【 分 子 量 】154.25232 【元素组成】C 77.87% H 11.76% O 10.37% |
合成路线1
该中间体在本合成路线中的序号:(I)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:(XXXII)A short synthetic strategy utilized the cyclic thioketal (XXXIII), derived from d-menthone (XXXII) and 1,3-propanedithiol, as the chiral template. Stereospecific oxidation of dithiane (XXXIII) employing NaIO4 produced sulfoxide (XXXIV). The carbanion generated from sulfoxide (XXXIV) was stereoselectively alkylated by 5-bromopentanoic acid (XXXV) in the presence of TMEDA to furnish the trans alkylated compound (XXXVI). Finally, acidic hydrolysis of (XXXVI) formed the intermediate mercapto sulfinic acid (XXXVII) which spontaneously cyclized to the desired dithiolane derivative.
【1】 Menon, R.B.; et al.; Stereospecific synthesis of alpha-lipoic acid. Tetrahedron Lett 1987, 28, 44, 5313. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXXII) | 10208 | L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone | 14073-97-3 | C10H18O | 详情 | 详情 |
(XXXIII) | 57961 | (7R,10S)-7-isopropyl-10-methyl-1,5-dithiaspiro[5.5]undecane | C13H24S2 | 详情 | 详情 | |
(XXXIV) | 57962 | (6S,7R,10S)-7-isopropyl-10-methyl-5-thia-1-thioniaspiro[5.5]undecan-1-olate | C13H24OS2 | 详情 | 详情 | |
(XXXV) | 57963 | 5-Bromo-n-valeric acid; 5-Bromopentanoic acid; 5-Bromovaleric acid | 2067-33-6 | C5H9BrO2 | 详情 | 详情 |
(XXXVI) | 57964 | (2R,6S,7R,10S)-2-(4-carboxybutyl)-7-isopropyl-10-methyl-5-thia-1-thioniaspiro[5.5]undecan-1-olate | C18H32O3S2 | 详情 | 详情 | |
(XXXVII) | 57965 | (6R)-6-(hydroxysulfanyl)-8-sulfanyloctanoic acid | C8H16O3S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XV)The optically pure diol intermediate (VIII) can be obtained by several procedures. Aldol condensation of 3-chlorobenzaldehyde (XII) with the lithium enolate of ethyl acetate gives the hydroxy ester (XIII), which is reduced to racemic 1-(3-chlorophenyl)-1,3-propanediol (XIV) by means of LiAlH4 in Et2O. Ketalization of diol (XIV) with (-)-menthone (XV) employing trimethylsilyl triflate and hexamethyldisilazane produces the spiro ketal (XVI) as a diastereomeric mixture, from which the target (S)-diol (VIII) is obtained by fractional crystallization, followed by acidic ketal hydrolysis (1-3). In a different strategy utilizing an enantioselective reduction, 3’-chloroacetophenone (XVII) is condensed with diethyl carbonate by means of t-BuOK in THF to yield the keto ester (XVIII), which is selectively reduced to the (S)-hydroxy ester (XIX) by catalytic hydrogenation over a chiral ruthenium catalyst. After saponification of ester (XIX), the chiral hydroxy acid obtained (XX) is reduced to (VIII) with borane in THF. Similarly, the (S)-hydroxy acid (XX) can be produced by condensation of 3-chlorobenzoyl chloride (XXI) with the lithium enolate of trimethylsilyl acetate, followed by acidic desilylation to yield the keto acid (XXII), which is then reduced to (XX) utilizing (–)-B-chlorodiisopinocamphenylborane (DIP-Cl) in cold CH2Cl2 (1-5). In a further method, 3-chlorocinnamic acid (XXIII) is esterified with H2SO4/EtOH, followed by reduction with DIBAL to provide the cinnamyl alcohol (XXIV), which undergoes Sharpless asymmetric epoxidation to (XXV) with t-butyl hydroperoxide in the presence of (+)-diethyl tartrate. Reductive cleavage of the chiral epoxide obtained (XXV) by means of Red-Al then furnishes the target 1(S)-(3-chlorophenyl)-1,3-propanediol (VIII) (1, 2). Scheme 2.
【1】 Kopcho, J.J., Matelich, M.C., Reddy, K.R., Ugarkar, B.G. (Metabasis Therapeutics, Inc.). Process for preparation of cyclic prodrugs of PMEA and PMPA. JP 2005525422, US 2003225277, WO 2003095665. |
【2】 Erion, M.D., Kopcho, J.J., Matelich, M.C., Reddy, K.R. (Metabasis Therapeutics, Inc.). Novel phosphonic acid based prodrugs of PMEA and its analogues. EP 1532157, US 2003229225, WO 2004037161. |
【3】 Reddy, K.R., Matelich, M.C., Ugarkar, B.G. et al. HepDirect prodrugs of adefovir: Design, synthesis and optimization. 227th ACS Natl Meet (March 28-April 1, Anaheim) 2004, Abst MEDI- 27. |
【4】 Martin, K. (Metabasis Therapeutics, Inc.). Lewis acid mediated synthesis of cyclic esters. CA 2565966, EP 1753762, US 2005282782, WO 2005123729. |
【5】 Erion, M.D., Reddy, K.R., Boyer, S.H. et al. Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phospho(on)ate-based drugs to the liver. J Am Chem Soc 2004, 126(16): 5154-63. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XII) | 13660 | 3-Chlorobenzaldehyde | 587-04-2 | C7H5ClO | 详情 | 详情 |
(XIII) | 65236 | C11H13ClO3 | 详情 | 详情 | ||
(XIV) | 65237 | 1(RS)-(3-chlorophenyl)-1,3-propanediol | C9H11ClO2 | 详情 | 详情 | |
(XV) | 10208 | L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone | 14073-97-3 | C10H18O | 详情 | 详情 |
(XVI) | 65238 | C19H27ClO2 | 详情 | 详情 | ||
(XVII) | 15268 | m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone | 99-02-5 | C8H7ClO | 详情 | 详情 |
(XVIII) | 65239 | ethyl 3-(3-chlorophenyl)-3-oxopropanoate | C11H11ClO3 | 详情 | 详情 | |
(XIX) | 65240 | C11H13ClO3 | 详情 | 详情 | ||
(XX) | 65241 | C9H9ClO3 | 详情 | 详情 | ||
(XXI) | 16687 | 3-chlorobenzoyl chloride | 618-46-2 | C7H4Cl2O | 详情 | 详情 |
(XXII) | 65242 | C9H7ClO3 | 详情 | 详情 | ||
(XXIII) | 65243 | 3-Chlorocinnamic acid | 14473-90-6 | C9H7ClO2 | 详情 | 详情 |
(XXIV) | 65244 | C9H9ClO | 详情 | 详情 | ||
(XXV) | 65245 | C9H9ClO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)
【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 |