合成路线:The reaction of the prostaglandin E1 derivative (I) with N,S-dimethylphenylsulfonimide (II) by means of methylmagnesium chloride in THF gives intermediate (III),which is treated with aluminum amalgam in HOAc/water to yield the methylene derivative (IV).Hydroboration of (IV) with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF affords the hydroxymethyl derivative (V),which is treated with methanesulfonyl chloride and TEA in dichloromethane to provide mesylate (VI).Desilylation of compound (VI) with TBAF in THF gives the phenol derivative (VII),which is cyclized by means of NaH in THF yielding the tricyclic prostaglandin derivative (VIII).Alkylation of compound (VIII) with methyl bromoacetate (IX) by means of NaH in glyme affords the 2-hydroxyacetate derivative (X),which is treated first with HOAc/water in order to eliminate the THP protecting groups,and then with KOH in methanol/water to hydrolyze the methyl ester group providing the prostaglandin F1 derivative (XI).Finally,this compound is hydrogenated over Pd/C in ethyl acetate.
参考文献标题:1,2-Disubstd.1,4-dihydro-4-oxoquinoline cpds.
文献作者:Agoh,Y.; Agoh,M.; Tamura,T.; Kuriyama,H.; Soga,M.; Mori,T.(Maruishi Pharmaceutical Co.,Ltd.)
参考来源:EP 1081138; JP 2001064259; JP 2001064261; JP 2001089455; JP 2001089476
合成路线:The reaction of the prostaglandin E1 derivative (I) with N,S-dimethylphenylsulfonimide (II) by means of methylmagnesium chloride in THF gives intermediate (III),which is treated with aluminum amalgam in HOAc/water to yield the methylene derivative (IV).Hydroboration of (IV) with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF affords the hydroxymethyl derivative (V),which is treated with methanesulfonyl chloride and TEA in dichloromethane to provide mesylate (VI).Desilylation of compound (VI) with TBAF in THF gives the phenol derivative (VII),which is cyclized by means of NaH in THF yielding the tricyclic prostaglandin derivative (VIII).Alkylation of compound (VIII) with methyl bromoacetate (IX) by means of NaH in glyme affords the 2-hydroxyacetate derivative (X),which is treated first with HOAc/water in order to eliminate the THP protecting groups,and then with KOH in methanol/water to hydrolyze the methyl ester group providing the prostaglandin F1 derivative (XI).Finally,this compound is hydrogenated over Pd/C in ethyl acetate.
参考文献标题:Methano carbacyclin analogs
文献作者:Aristoff,P.A.(Pharmacia Corp.)
参考来源:US 4349689
合成路线:The reaction of the prostaglandin E1 derivative (I) with N,S-dimethylphenylsulfonimide (II) by means of methylmagnesium chloride in THF gives intermediate (III),which is treated with aluminum amalgam in HOAc/water to yield the methylene derivative (IV).Hydroboration of (IV) with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF affords the hydroxymethyl derivative (V),which is treated with methanesulfonyl chloride and TEA in dichloromethane to provide mesylate (VI).Desilylation of compound (VI) with TBAF in THF gives the phenol derivative (VII),which is cyclized by means of NaH in THF yielding the tricyclic prostaglandin derivative (VIII).Alkylation of compound (VIII) with methyl bromoacetate (IX) by means of NaH in glyme affords the 2-hydroxyacetate derivative (X),which is treated first with HOAc/water in order to eliminate the THP protecting groups,and then with KOH in methanol/water to hydrolyze the methyl ester group providing the prostaglandin F1 derivative (XI).Finally,this compound is hydrogenated over Pd/C in ethyl acetate.
参考文献标题:Carbacyclin analogues
文献作者:Aristoff,P.A.; Kelly,R.C.; Nelson,N.A.(Pharmacia Corp.)
参考来源:CH 648017; CH 655308; FR 2484413; GB 2070596; JP 1990167248; JP 1994145085
合成路线:Reaction of 3-methoxybenzyl alcohol (XXIX) with TBDMS-Cl and imidazole in dichloromethane gives the silyl ether (XXX),which is condensed with allyl bromide (XXXI) by means of BuLi in hexane to yield the 2-allyl derivative (XXXII).Deprotection of (XXXII) by means of TBAF in THF affords the benzyl alcohol (XXXIII),which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide 2-allyl-3-methoxybenzaldehyde (XXXIV).Condensation of compound (XXXIV) with the chiral 1-decyne (XXXV) by means of ethylmagnesium bromide in THF gives the secondary alcohol (XXXVI),which is oxidized with pyridinium chlorochromate (PCC) in dichloromethane yielding ketone (XXXVII).The enantioselective reduction of ketone (XXXVII) by means of trimethylboroxine (TMBO),BH3/Me2S and (R)-(2-pyrrolidinyl)diphenylmethanol in toluene affords the chiral secondary alcohol (XXXVIII) as a single diastereomer.Silylation of alcohol (XXXVIII) with TBDMS-Cl and imidazole yields the corresponding ether (XXXIX),which is submitted to cyclization catalyzed by Co2(CO)8 in refluxing acetonitrile affording the tricyclic ketone (XL).Hydrogenation of the conjugated double bond of (XL) with H2 over Pd/C in ethanol provides the saturated ketone (XLI),which is reduced with NaBH4 in ethanol to give the tricyclic alcohol (XLII).Elimination of the tetrahydropyranyl-protecting group of (XLII) with p-toluensulfonic acid in methanol provides diol (XXV) already described.
参考文献标题:Process for stereoselective synthesis of prostacyclin derivs.
文献作者:Rao,M.S.; Staszewski,J.P.; Guo,L.; Penmasta,R.; Moriarty,R.M.(United Therapeutics Corp.)
参考来源:WO 9921830
合成路线:The reaction of the prostaglandin E1 derivative (I) with N,S-dimethylphenylsulfonimide (II) by means of methylmagnesium chloride in THF gives intermediate (III),which is treated with aluminum amalgam in HOAc/water to yield the methylene derivative (IV).Hydroboration of (IV) with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF affords the hydroxymethyl derivative (V),which is treated with methanesulfonyl chloride and TEA in dichloromethane to provide mesylate (VI).Desilylation of compound (VI) with TBAF in THF gives the phenol derivative (VII),which is cyclized by means of NaH in THF yielding the tricyclic prostaglandin derivative (VIII).Alkylation of compound (VIII) with methyl bromoacetate (IX) by means of NaH in glyme affords the 2-hydroxyacetate derivative (X),which is treated first with HOAc/water in order to eliminate the THP protecting groups,and then with KOH in methanol/water to hydrolyze the methyl ester group providing the prostaglandin F1 derivative (XI).Finally,this compound is hydrogenated over Pd/C in ethyl acetate.
合成路线:The reduction of 2-octyn-1-ol (XII) with bis(2-methoxyethoxy)aluminum hydride in toluene/THF gives 2-octen-1-ol (XIII),which is treated with tert-butyl hydroperoxide,(+)-diethyl L-tartrate and titanium tetraisopropoxide in dichloromethane yielding epoxide (XIV).The latter is reduced with bis(2-ethoxyethoxy)aluminum hydride in toluene/THF,affording the chiral diol (XV).The selective monotosylation of (XV) with TsCl in pyridine provides the primary tosylate (XVI),which is treated with NaI in hot acetone to furnish 1-iodo-3-octanol (XVII).Protection of (XVII) with dihydropyran and pyridine hydrochloride gives the tetrahydropyranyl ether (XVIII),which is condensed with dimethyl methylphosphonate (XIX) by means of BuLi and TEA in THF to yield the phosphonate (XX).Condensation of compound (XX) with 5-methoxy-2,3,3a,4-tetrahydronaphtho[2,3-b]furan-2-one (XXI) by means of BuLi in THF affords the tricyclic adduct (XXII),which is hydrogenated with H2 over Pd/C in ethanol to provide compound (XXIII).Isomerization of (XXIII) with NaOH in refluxing ethanol gives diastereomer (XXIV).The reduction of the carbonyl group of (XXIV) with NaBH4 in methanol,followed by deprotection with HOAc in THF yields compound (XXV).The demethylation of compound (XXV) by means of BuLi and Ph2PH in THF affords the tricyclic phenol (XXVI),which is condensed with 2-chloroacetonitrile (XXVII) by means of K2CO3 in refluxing acetone to provide the precursor (XXVIII).Finally,the cyano group of (XXVIII) is hydrolyzed with KOH in refluxing water.
合成路线:Reaction of 3-methoxybenzyl alcohol (XXIX) with TBDMS-Cl and imidazole in dichloromethane gives the silyl ether (XXX),which is condensed with allyl bromide (XXXI) by means of BuLi in hexane to yield the 2-allyl derivative (XXXII).Deprotection of (XXXII) by means of TBAF in THF affords the benzyl alcohol (XXXIII),which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide 2-allyl-3-methoxybenzaldehyde (XXXIV).Condensation of compound (XXXIV) with the chiral 1-decyne (XXXV) by means of ethylmagnesium bromide in THF gives the secondary alcohol (XXXVI),which is oxidized with pyridinium chlorochromate (PCC) in dichloromethane yielding ketone (XXXVII).The enantioselective reduction of ketone (XXXVII) by means of trimethylboroxine (TMBO),BH3/Me2S and (R)-(2-pyrrolidinyl)diphenylmethanol in toluene affords the chiral secondary alcohol (XXXVIII) as a single diastereomer.Silylation of alcohol (XXXVIII) with TBDMS-Cl and imidazole yields the corresponding ether (XXXIX),which is submitted to cyclization catalyzed by Co2(CO)8 in refluxing acetonitrile affording the tricyclic ketone (XL).Hydrogenation of the conjugated double bond of (XL) with H2 over Pd/C in ethanol provides the saturated ketone (XLI),which is reduced with NaBH4 in ethanol to give the tricyclic alcohol (XLII).Elimination of the tetrahydropyranyl-protecting group of (XLII) with p-toluensulfonic acid in methanol provides diol (XXV) already described.
参考文献标题:UT-15
文献作者:Sorbera,L.A.; Castar,J.; Rabasseda,X.
参考来源:Drugs Fut 2001,26(4),364
产品链接: CAS No. 289480-64-4›› 产品链接: CAS No.81846-19-7››