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药物详细合成路线

Name Artemisine;Artemisinin;Qinghaosu;Artesin;Cotexin
Chemical Name (3R,5aS,6R,8aS,9R,12S,12aR)-Octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one
CAS 63968-64-9
Related CAS
Formula C15H22O5
Structure
Formula Weight 282.33959
Stage 上市-1986
Company Walter Reed Army Institute (Originator)
Activity/Mechanism ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases
Syn. Route 5
Route 1
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.
List of intermediates No.
(2s)-2-amino-1-(1h-indol-3-yl)-3,3-dimethyl-1-butanone (i)
1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2s,3r)-2-allyl-3-isobutylbutanedioate (ii)
tert-butyl (2s)-2-[(1r)-1-([[(1s)-1-(1h-indol-3-ylcarbonyl)-2,2-dimethylpropyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate (iii)
(2s)-2-[(1r)-1-([[(1s)-1-(1h-indol-3-ylcarbonyl)-2,2-dimethylpropyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid (iv)
(aminooxy)(tert-butyl)dimethylsilane; o-[tert-butyl(dimethyl)silyl]hydroxylamine (v)
(4s)-4-benzyl-1,3-oxazolidine-2,5-dione (vi)
(2s)-2-amino-1-(1h-indol-3-yl)-3-phenyl-1-propanone (vii)
tert-butyl (2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-(1h-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate (viii)
(2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-(1h-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid (ix)
4-(tert-butyl) 1-(2,3,4,5,6-pentafluorophenyl) (2r,3s)-2-isobutyl-3-(4-pentenyl)butanedioate (x)
tert-butyl (2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-(1h-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-6-heptenoate (xi)
(2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-(1h-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-6-heptenoic acid (xii)
1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2s,3r)-2-hydroxy-3-isobutylbutanedioate (xiii)
tert-butyl (2s,3r)-2-hydroxy-3-([[(1s)-1-(1h-indol-3-ylcarbonyl)-2,2-dimethylpropyl]amino]carbonyl)-5-methylhexanoate (xiv)
(2s,3r)-2-hydroxy-3-([[(1s)-1-(1h-indol-3-ylcarbonyl)-2,2-dimethylpropyl]amino]carbonyl)-5-methylhexanoic acid (xv)
tert-butyl (1s)-1-benzyl-2-oxo-2-phenylethylcarbamate (xvi)
(2s)-2-amino-1,3-diphenyl-1-propanone hydrochloride (xvii)
Reference 1:
    deshpande, v.h.; bhonsle, j.b.; pandey, b.; ravindranathan, t.; new synthetic strategies towards (+)-artemisinin. tetrahedron lett 1994, 35, 30, 5489.

Route 2
3) the cyclization of (r)-(+)-citronellal (xviii) with znbr2 followed by reaction with diborane and h2o2 gives the diol (xi), which is selectively benzylated with benzyl chloride and nah to the monobenzyl ether (xx). the oxidation of (xx) with the jones reagent yields the cyclohexanone (xxi), which is condensed with 3-(trimethylsilyl)-3-buten-2-one (xxii) by means of lithium diisopropylamide to the dione (xxiii). the cyclization of (xxiii) by means of ba(oh)2 and oxalic acid affords the benzylated octahydronaphthalenone (xxiv), which by reduction with nabh4 followed by reoxidation with the jones reagent gives the decalinone (xxv). the grignard methylation of (xxv) with methylmagnesium iodide yields the tertiary alcohol (xxvi), which is dehydrated with p-toluenesulfonic acid to the octahydronaphthalene (xxvii). the debenzylation of (xxvii) with sodamide, followed by oxidation with the jones reagent and methylation with diazomethane affords the ester (xxviii), which is ozonolyzed with o3 to the formyl ketone (xxix). selective protection of the ketone group with propane-1,3-dithiol (xxx) and p-toluenesulfonic acid gives the substituted 1,3-dithiane (xxxi), which is treated with methyl orthoformate and p-toluenesulfonic acid to yield the methoxymethylene derivative (xxxii). the elimination of the dithiane group with hgcl2 in aqueous acetonitrile affords the ketoester (xxxiii), which is submitted to a photochemical oxidation using rose bengal as catalyst in methanol, giving the peroxide (xxxiv). finally, this compound is cyclized by means of hclo4 and oso4.4) the benzylated octahydronaphthalenone (xxiv) can also be obtained by benzylation of the ketone (viii) with benzyl bromide by means of nah in dmf.
List of intermediates No.
tert-butyl (2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-(1h-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate (vii)
tert-butyl (2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-oxo-2-phenylethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate (xviii)
(2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-oxo-2-phenylethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid (xix)
methyl (2s)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate (xx)
1h-pyrrole (xxi)
tert-butyl (1s)-1-benzyl-2-oxo-2-(1h-pyrrol-2-yl)ethylcarbamate (xxii)
(2s)-2-amino-3-phenyl-1-(1h-pyrrol-2-yl)-1-propanone hydrochloride (xxiii)
tert-butyl (2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-oxo-2-(1h-pyrrol-2-yl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate (xxiv)
(2s)-2-[(1r)-1-([[(1s)-1-benzyl-2-oxo-2-(1h-pyrrol-2-yl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid (xxv)
2-thienyllithium (xxvi)
tert-butyl 1-benzyl-2-oxo-2-(2-thienyl)ethylcarbamate (xxvii)
2-amino-3-phenyl-1-(2-thienyl)-1-propanone hydrochloride (xxviii)
tert-butyl (2s)-2-[(1r)-1-([[1-benzyl-2-oxo-2-(2-thienyl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate (xxix)
(2s)-2-[(1r)-1-([[1-benzyl-2-oxo-2-(2-thienyl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid (xxxi)
1,3-oxazol-2-yllithium (xxxii)
tert-butyl 1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethylcarbamate (xxxiii)
2-amino-1-(1,3-oxazol-2-yl)-3-phenyl-1-propanone hydrochloride (xxiv)
(2r)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propionic acid (xxx)
Reference 1:
    deshpande, v.h.; bhonsle, j.b.; pandey, b.; ravindranathan, t.; new synthetic strategies towards (+)-artemisinin. tetrahedron lett 1994, 35, 30, 5489.

Route 3
a synthesis of trideuterated artemisin has been published:the methylation of the ketal acid (i) with lithium diisopropylamide and cd3i in thf gives the methylated intermediate (ii), which is then submitted to an oxidative cyclization with ozone in dichloromethane. the key intermediate (i) had already been obtained as an intermediate of a previously published total synthesis of artemisin (avery, m.a. et al. j amer chem soc 1992, 114: 974).
List of intermediates No.
tert-butyl (2s)-2-[(1r)-1-([[1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate (i)
(2s)-2-[(1r)-1-([[1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid (ii)
Reference 1:
    bonk, j.d.; avery, m.a.; mehrotra, s.; deuterated antimalarials: synthesis of trideutero-artemisinin, dihydroartemisinin, and arteether. j label compd radiopharm 1996, 38, 8, 249.

Route 4
a synthesis of [14c]-labeled artemisin has been reported:the methylation of the ketal acid (i) with lithium diisopropylamide and [14c]-mei in thf gives the methylated intermediate (ii), which is then submitted to an oxidative cyclization with ozone in dichloromethane. the key intermediate (i) had already been obtained as an intermediate of a previously published total synthesis of artemisin (avery, m.a. et al. j amer chem soc 1992, 114: 974).
List of intermediates No.
tert-butyl (2s)-2-[(1r)-1-([[1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate (i)
(2s)-2-[(1r)-1-([[1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid (ii)
1-(2,3,4-trimethoxyphenyl)-1-ethanone (ii)
Reference 1:
    avery, m.a.; bonk, j.d.; bupp, j.; radiolabeled antimalarials: synthesis of c-14-artemisinin. j label compd radiopharm 1996, 38, 3, 263.

Route 5
the (+)-isolimonene (i) was submitted to a regioselective hydroboration with dicyclohexylborane to give the alcohol (ii), which was oxidized with cro3 to the corresponding carboxylic acid (iii). the iodolactonization of (iii) by means of ki, i2 and nahco3 yielded a separable, diastereomeric mixture of iodolactones (iv) + (v). the suitable isomer (iv) was condensed with methyl vinyl ketone (vi) by means of tris(trimethylsilyl)silane and aibn in refluxing toluene to afford the alkylated lactone (vii) as an inseparable diastereomeric mixture. the ketonic group of (vii) was treated with ethanedithiol (viii) and bf3/et2o in dichloromethane to provide a separable mixture of thioketal lactones (ix)+(x). the suitable isomer (x) was hydrolyzed with naoh in refluxing methanol to give the hydroxyacid (xi), which was treated with diazomethane to yield the corresponding methyl ester (xii). the oxidation of the oh group of (xii) by means of pcc affords the ketoester (xiii), which is submitted to a wittig condensation with methoxymethyltriphenylphosphonium chloride (xiv) by means of khmds in thf/hmpa to provide the methoxymethylene derivative (xv). the cleavage of the dithioketal group of (xv) by means of hgcl2 and caco3 in acetonitrile regenerates the keto group giving compound (xvi), which is finally transformed into the target (+)-artemisinin by photooxidation with o2 in methanol in the presence of rose bengal, followed by a treatment with 70 % hclo4.
List of intermediates No.
tert-butyl 1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethylcarbamate (xvi)
ethyl 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoate (viii)
(2s,3e)-3-penten-2-ol (vi)
2-ethoxy-3-[4-[2-(10h-phenoxazin-10-yl)ethoxy]phenyl]propionic acid (xiv)
Reference 1:
    yadav, j.s.; et al.; stereoselective total synthesis of (+)-artemisinin. tetrahedron lett 2003, 44, 2, 387.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名青蒿素;英文名Artemisine;Artemisinin;Qinghaosu;Artesin;Cotexin;CAS[63968-64-9]

 
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