合成路线:A new partial synthesis for taxol has been reported:The cyclization of N-(4-methoxyphenyl)benzylideneimine (I) with acetoxyacetyl chloride (II) by means of triethylamine in dichloromethane gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (III),which is treated with ceric ammonium nitrate in acetonitrile to afford cis-3-acetoxy-4-phenylazetidin-2-one (IV).Hydrolysis of (IV) with KOH in THF-water yields cis-3-hydroxy-4-phenylazetidin-2-one (V),which is submitted to optical resolution giving the (3R,4S)-isomer (VI).The reaction of (VI) with ethyl vinyl ether (VII) by means of methanesulfonic acid in THF affords (3R,4S)-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (VIII),which is benzoylated with benzoyl chloride (IX) and butyllithium in hexane to give (X).Opening of the azetidine ring of (X) with KOH in THF-water gives (2R,3S)-3-(benzamido)-2-(1-ethoxyethoxy)propanoic acid (XI),which is cyclized with potassium tert-butoxide and methanesulfonyl chloride to (4S,5R)-5-(1-ethoxyethoxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-6-one (XII).Finally,this compound is condensed with 7-O-(triethylsilyl)baccatin III (XIV) [prepared from 10-deacetylbaccatin III (XIII) by successive reaction with triethylsilyl chloride and acetyl chloride] by means of dimethylaminopyridine (DMAP) in pyridine.
参考文献标题:Method for preparation of taxol using an oxazinone
文献作者:Holton,R.A.(University of Florida)
参考来源:US 5015744
合成路线:Two new syntheses of taxol have been described:1) The oxidative cleavage of 10-deacetyltaxol-7-xyloside (I) with sodium periodate in methanol - chloroform gives 10-deacetyltaxol (II),which is then acetylated with acetic anhydride and pyridine.2) By deacetylation of 2'-acetyltaxol (III) by means of dimethylamine in aqueous methanol.
参考文献标题:Process for the preparation of taxol and 10-deacetyltaxol
文献作者:Rao,K.V.(University of Florida)
参考来源:US 5200534
合成路线:A new synthesis of paclitaxel has been reported: The cyclization of the 4-methoxyphenylimine of benzaldehyde (I) with acetoxyacetyl chloride (II) by means of triethylamine gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (III),which is treated with ceric ammonium nitrate to afford cis-3-acetoxy-4-phenylazetidin-2-one (IV).The hydrolysis of (IV) with KOH in THF/water affords the corresponding hydroxy compound (V),which is submitted to optical resolution by crystallization of the 2-methoxy-2-[2-(trifluoromethyl)phenyl]acetic esters.The (3R,4S)-regioisomer (VI) is protected with ethyl vinyl ether,giving the 1-ethoxyethyl derivative (VII),which is benzoylated with benzoyl chloride and butyllithium to afford (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (VIII).The condensation of (VIII) with baccatin III (IX) by means of dimethylaminopyridine (DMAP) in pyridine yields the protected paclitaxel derivative (X),which is finally deprotected with HCl in ethanol/water.
参考文献标题:Method for preparation of taxol
文献作者:Holton,R.A.(University of Florida)
参考来源:EP 0400971; US 5336785
合成路线:1) The reaction of the known ketoketal (I) with N-phenyltrifluoromethanesulfonimide and KHMDS in THF gives the enol triflate (II),which is condensed with VIBuSn using tetrakis(triphenylphosphine)palladium(0) as catalyst in THF,yielding the diene (III).The reaction of (III) with 9-BBN in THF affords the alcohol (IV) and,after protection with TBDMS-Cl in dichloromethane,the silyl ether (V),which is oxidized with CrO3 and DMP in dichloromethane to the enone (VI).The stereoselective reduction of (VI) with BH3/THF catalyzed with the chiral borane (VII) yields the alcohol (VIII),which is protected with TBDMS-Cl as before to give (IX).Selective deprotection of (IX) affords the primary alcohol (X),which is oxidized with oxalyl chloride in DMSO to the aldehyde (XI).The condensation of (XI) with the vinyl iodide (XII) catalyzed by NiCl2 and CrCl2 gives the allyl alcohol (XIII),which is oxidized with oxalyl chloride as before to the enone (XIV).The oxidation of (XIV) with 3-phenyl-2-(phenylsulfonyl)oxaziridine and KHMDS yields the hydroxy ketone (XV),which is further oxidized with oxalyl chloride as before to afford the unsaturated dione (XVI).The Diels-Alder condensation between (XVI) and the diene (XVII) gives compound (XVIII) or (XIX),depending on the reaction conditions.The oxidation of the primary alcohol of (XIX) with oxalyl chloride as usual yields the aldehyde (XX),which by elimination of the ketal group in acidic medium affords the tetraketonic aldehyde (XXI).
合成路线:The intramolecular pinacolic cyclization of (XXI) by means of SmI2 yields the compound (XXII) with the basic ABC subskeleton of paclitaxel.Selective acetylation and silylation of (XXII) with acetic anhydride/pyridine and TBDMS-Cl gives the trihydroxy compound (XXIII),which is oxidized with oxalyl chloride as usual to the trione (XXIV).Selective reduction of (XXIV) with Zn(BH4)2 yields the dihydroxydione (XXV),which is selectively benzoylated and,after benzyl protection of the remaining hydroxy groups,affords the protected dione (XXVI).Selective reduction of (XXVI) with L-selectride followed by oxidation of the sulfanyl group to sulfinyl and its elimination by heating gives a methylene double bond,which is oxidized in situ with MCPBA and OsO4 to the vicinal triol (XXVII).The cyclization of (XXVII) according to Tetrahedron Lett 1991,47: 9823 affords the hydroxy ketone (XXVIII) with the basic skeleton of paclitaxel.Acetylation of (XXVIII) with acetic anhydride/pyridine followed by selective elimination of the TBDMS group affords the secondary alcohol (XXIX).The attachment of the propenoyl side-chain of paclitaxel to (XXIX) according to J Amer Chem Soc 1988,110: 5917 gives the protected paclitaxel derivative (XXX),which is finally deprotected by hydrogenolysis with H2 over Pd/C.
合成路线:2) The silylation of the hydroxyketal (XXXI) with TBDMS-Tf in dichloromethane gives the corresponding silyl ether (XXXII),which is treated sequentially with borane in THF,with H2O2 and tetrapropylammonium perruthenate catalyst to afford ketone (XXXIII).The reaction of (XXXIII) with KHMDS and TFNP in anhydrous THF yields the enol triflate (XXXIV),which by addition of CO catalyzed by triphenylphosphine and Pd(OAc)2 in methanol is converted to the methyl ester (XXXV).The reduction of (XXXV) with DIBAL in hexane gives the alcohol derivative (XXXVI),which by OsO4 oxidation in acetone/water gives the triol (XXXVII).The dehydration of (XXXVII) by previous silylation with TMS-Cl and reaction with trifluoromethanesulfonic anhydride in dichloromethane affords the oxetane derivative (XXXVIII),which is submitted to deketalization with CLTS to yield the ketone (XXXIX).The dehydrogenation of (XXXIX) by reaction with lithium diisopropylamide TMS-Cl and Pd(OAc)2 in THF gives the enone (XL),which is silylated with TBDMS-Cl in DMF to the fully silylated enone (XLI).The enolization of (XLI) with butyllithium and TMS-Cl followed by ozonolysis with O3 in dichloromethane yields the dialdehyde (XLII),which is submitted to a selective ketalization of the less hindered aldehyde group,affording the monoketal (XLIII).The addition of the lithium dithiane derivative (XLIV) to (XLIII) followed by a Swern oxidation of the intermediate alcohol gives the ketone (XLV),which is deketalized in acidic medium to yield the keto aldehyde (XLVI).The addition of the vinyllithium compound (XLVII) to (XLVI) gives the Diels-Alder precursor (XLVIII),which is submitted to cyclization by heating to afford the polycyclic compound (II) with the basic skeleton of paclitaxel.
合成路线:The stereoselective reduction of the lesshindered ketonic group of (II) followed by benzoylation yields the polycyclic ketone (L),which is submitted to an allylic oxidation to afford the unsaturated dione (LI).The sequential selective reduction of the less hindered ketone with a bulky borohydride gives an alpha-alcohol,which is then benzylated with benzyl chloride and finally treated with H2 and Raney Nickel to eliminate the dithiane group and afford the polycyclic ketone (LII).The regioselective Franklin Davis hydroxylation of (LII) followed by desilylation with TBAF and peracetylation with acetic anhydride yields the triacetoxy ketone (LIII),which is debenzylated by hydrogenation with H2 over Pd/C to the secondary alcohol (LIV).The attachment of the propenoyl side-chain of paclitaxel to (LIV) according to J Amer Chem Soc 1988,110: 5917 gives the protected paclitaxel derivative (LV),which is submitted to a selective deacetylation to the paclitaxel precursor (LVI).Finally,this compound is deprotected to paclitaxel.
参考文献标题:Total synthesis of taxol
文献作者:Danishefsky,S.J.; Bornmann,W.G.; Queneau,Y.; Magee,T.V.; Krol,W.J.(Sloan-Kettering Institute)
参考来源:US 5416225
合成路线:Three partial syntheses of Taxol are described starting from Taxol analogues such as Taxol C or Taxol B (cephalomannine):1) The reaction of Taxol C (I) with triethylsilyl chloride (TES-Cl) in pyridine gives the bis(triethylsilyl) derivative (II),which by reduction with zirconocene chloride hydride [bis(cyclopentadienyl)zirconium chloride hydride] in dry THF yields compound (III).The hydrolytic cleavage of (III) with simultaneous desilylation by means of HCl in ethanol affords [2aR-[2aalpha,4beta,4abeta,6beta,9alpha(2R,3S),11beta,12alpha,12aalpha,12balpha]]-6,12b-diacetoxy-9-(3-amino-2-hydroxy-3-phenylpropionyloxy)-1 2-benzoyloxy-4,11-dihydroxy-4a,8,13,13-tetramethyl-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxet-5-one (IV) with a free amino group,which is benzoylated with benzoyl chloride (V) and pyridine to Taxol.
合成路线:2) The silylation of Taxol B (VI) with triethylsilyl chloride as before gives the bis(triethylsilyl) compound (VII),which by reduction with zirconocene chloride hydride as described yields compound (VIII).Finally,the hydrolytic cleavage of (VIII) with simultaneous desilylation with HCl in ethanol affords the previously reported compound (IV) with its free amino group easily benzoylated to Taxol.3) The ozonolysis of the silylated Taxol B (VII) with O3 in methanol gives compound (IX),which is reduced with zirconocene as before yielding the 2-oxopropylideneimine (X).Finally,the hydrolytic cleavage of (X) with simultaneous desilylation with HCl in ethanol affords the previously reported compound (IX) with its free amino group easiely benzoylated to Taxol.
合成路线:Several partial syntheses of docetaxel have been described:The selective hydrolysis of Taxol A (I,R = Ph),Taxol B (I,R = C(Me)=CHMe) or Taxol C (I,R = C5H11) with NaHCO3 in THF/water gives the corresponding 10-deacetyl derivatives (II),which by selective silylation with triethylsilyl chloride in pyridine are converted into the 10-deacetyl-2',7-bis(triethylsilyl) compounds (III).The reaction of compounds (III) with zirconocene chloride hydride [bis(cyclopentadienyl)zirconium chloride hydride] in THF afford the corresponding imino derivatives (IV),which,without isolation are hydrolyzed and desilylated by a treatment with concentrated aqueous HCl in ethanol giving 10-deacetyltaxolamine (V).Finally,this compound is acylated at the amino group by a treatment by di-tert-butyl dicarbonate and NaHCO3 in ethyl acetate/water.
参考文献标题:Preparation of Taxol and docetaxel through primary amines
文献作者:Young,T.H.(Hauser,Inc.)
参考来源:EP 0852581; WO 9623780
合成路线:A partial synthesis of Taxol starting from deacetyl Baccatin III (XI) has been developed:The starting compounds,the acid (I) and the silylated Baccatin III (II) have been obtained as follows:a) The reaction of 3(S)-amino-2(R)-hydroxy-3-phenylpropionic acid ethyl ester (VIII) with benzyloxycarbonyl chloride and Na2CO3 in ethyl or tert-butyl ether/water gives 3(S)-(benzyloxycarbonylamino)-2(R)-hydroxy-3-phenylpropionic acid ethyl ester (IX),which is condensed with benzyloxymethyl chloride by means of BuLi in THF yielding the fully protected ester (X).The hydrolysis of (X) with LiOH in ethanol/water affords the desired acid (I).b) The silylation of (deacetyl Baccatin III) (XI) with triethylsilyl chloride in pyridine gives the monosilylated deacetyl Baccatin III (XII),which is then acetylated with acetyl chloride in pyridine or BuLi in THF to afford the desired silylated Baccatin III (II).
合成路线:The benzoylation of (IV) with benzoyl chloride (V) and triethylamine in ethyl acetate affords the fully protected Taxol derivative (VI),which is desillylated with HF in acetonitrile giving the partially protected Taxol derivative (VII).Finally,this compound is fully deprotected by hydrogenation with H2 over Pd/C in isopropanal at 40 atm to give taxol.
参考文献标题:Paclitaxel synthesis from precursor compounds and methods of producing the same
文献作者:Sisti,N.J.; Swindell,C.S.; Chander,M.C.(NaPro BioTherapeutics,Inc.)
参考来源:US 5675025
产品链接: CAS No. 33069-62-4››