合成路线:3) The cyclization of the previously described trans-4-(methanesulfonyloxy)-1-(3-pyridylmethyl)-L-prolinemethyl ester (XXI) with NaOH in acetonitrile gives the expected lactone (XXVIII),which by methanolysis with K2CO3 in methanol yields cis-4-hydroxy-1-(3-pyridylmethyl)-L-proline methyl ester (XXIX).The acylation of (XXIX) with 4-nitrophenylsulfonyl chloride (XXX) and triethylamine in dichloromethane affords the corresponding cis-sulfonyloxyproline derivative (XXXI),which is treated with the sodium salt of 4-chlorophenylsulfonamide (XXXII) in DMSO to give trans-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)-L-proline methyl ester (XXV) already obtained.The reduction of (XXV) with NaBH4 in THF yields the corresponding hydroxymethyl derivative (XXXIII),which is oxidized with SO3/pyridine to the previously described aldehyde (XXVI).4) The condensation of the previously described cis-4-hydroxyproline derivative (XXIX) with N-(4-chlorophenylsulfonyl)carbamic acid methyl ester (XXXIV) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives (2S,4R)-trans-4-[4-chloro-N-(methoxycarbonyl)phenylsulfonamido]-1-(3-pyridylmethyl)pyrrolidine-2-carboxylic acid methyl ester (XXXV),which is reduced with NaBH4 to the trans-hydroxymethyl derivative (XXXIII),already described.
参考文献标题:Novel pyrrolidine derivs
文献作者:Kamijo,T.; Hokari,H.; Hirata,K.; Yanagi,T.; Oda,Y.(Kissei Pharmaceutical Co.,Ltd.)
参考来源:JP 1996012670
合成路线:3) The cyclization of the previously described trans-4-(methanesulfonyloxy)-1-(3-pyridylmethyl)-L-prolinemethyl ester (XXI) with NaOH in acetonitrile gives the expected lactone (XXVIII),which by methanolysis with K2CO3 in methanol yields cis-4-hydroxy-1-(3-pyridylmethyl)-L-proline methyl ester (XXIX).The acylation of (XXIX) with 4-nitrophenylsulfonyl chloride (XXX) and triethylamine in dichloromethane affords the corresponding cis-sulfonyloxyproline derivative (XXXI),which is treated with the sodium salt of 4-chlorophenylsulfonamide (XXXII) in DMSO to give trans-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)-L-proline methyl ester (XXV) already obtained.The reduction of (XXV) with NaBH4 in THF yields the corresponding hydroxymethyl derivative (XXXIII),which is oxidized with SO3/pyridine to the previously described aldehyde (XXVI).4) The condensation of the previously described cis-4-hydroxyproline derivative (XXIX) with N-(4-chlorophenylsulfonyl)carbamic acid methyl ester (XXXIV) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives (2S,4R)-trans-4-[4-chloro-N-(methoxycarbonyl)phenylsulfonamido]-1-(3-pyridylmethyl)pyrrolidine-2-carboxylic acid methyl ester (XXXV),which is reduced with NaBH4 to the trans-hydroxymethyl derivative (XXXIII),already described.
参考文献标题:Manufacturing method of (5Z)-6-[(2S,4R)-4-(4-chlorophenylsulfonylamino)-1-(3-pyridylmethyl)-2-pyrrolidinyl-5-hexenoic acid and its intermediates
文献作者:Kamijo,T.; Hokari,H.; Hirata,K.; Yanagi,T.; Oda,Y.(Kissei Pharmaceutical Co.,Ltd.)
参考来源:JP 1995291966
合成路线:2) The esterification of trans-4-hydroxy-L-proline (XVI) with SOCl2 and methanol gives the methyl ester (XVII),which is condensed with 3-(methanesulfonyloxymethyl)pyridine (XVIII),obtained by treatment of 3-(hydroxymethyl)pyridine (XIX) with methanesulfonyl chloride,by means of triethylamine yielding trans-N-(3-pyridylmethyl)-4-hydroxy-L-proline methyl ester (XX).The treatment of (XX) with methanesulfonyl chloride affords the corresponding mesylate (XXI),which by reaction with LiCl in hot polyethylene glycol gives cis-4-chloro-N-(3-pyridylmethyl)-L-proline methyl ester (XXII).The reaction of (XXII) with sodium azide in DMSO yields the trans-4-azido derivative (XXIII),which is reduced with triphenylphosphine in hot ethyl acetate to the corresponding trans-4-amino compound (XXIV).The treatment of (XXIV) with 4-chlorophenylsulfonyl chloride (VIII) and triethylamine in ethyl acetate affords the sulfonamide (XXV),which is reduced with diisobutylaluminum hydride in toluene/dichloromethane giving (2S,4R)-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidine-2-carbaldehyde (XXVI).Finally,this compound is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium chloride (XXVII) and potassium tert-butoxide in THF.
参考文献标题:Process for producing pyrrolidine deriv.and salt thereof
文献作者:Kagara,K.; Goto,S.; Yonishi,S.; Ikushima,M.; Baba,Y.; Horiai,H.(Fujisawa Pharmaceutical Co.,Ltd.)
参考来源:WO 9401400
合成路线:3) The cyclization of the previously described trans-4-(methanesulfonyloxy)-1-(3-pyridylmethyl)-L-prolinemethyl ester (XXI) with NaOH in acetonitrile gives the expected lactone (XXVIII),which by methanolysis with K2CO3 in methanol yields cis-4-hydroxy-1-(3-pyridylmethyl)-L-proline methyl ester (XXIX).The acylation of (XXIX) with 4-nitrophenylsulfonyl chloride (XXX) and triethylamine in dichloromethane affords the corresponding cis-sulfonyloxyproline derivative (XXXI),which is treated with the sodium salt of 4-chlorophenylsulfonamide (XXXII) in DMSO to give trans-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)-L-proline methyl ester (XXV) already obtained.The reduction of (XXV) with NaBH4 in THF yields the corresponding hydroxymethyl derivative (XXXIII),which is oxidized with SO3/pyridine to the previously described aldehyde (XXVI).4) The condensation of the previously described cis-4-hydroxyproline derivative (XXIX) with N-(4-chlorophenylsulfonyl)carbamic acid methyl ester (XXXIV) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives (2S,4R)-trans-4-[4-chloro-N-(methoxycarbonyl)phenylsulfonamido]-1-(3-pyridylmethyl)pyrrolidine-2-carboxylic acid methyl ester (XXXV),which is reduced with NaBH4 to the trans-hydroxymethyl derivative (XXXIII),already described.
参考文献标题:Novel pyrrolidine derivs
文献作者:Kamijo,T.; Hokari,H.; Hirata,K.; Yanagi,T.; Oda,Y.(Kissei Pharmaceutical Co.,Ltd.)
参考来源:JP 1995291965
合成路线:1) The mesylation of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (I) with mesyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (II),which is treated with sodium benzoate in DMSO yielding the (2S,4S)-benzoate (III).The hydrolysis of (III) with K2CO3 in methanol affords (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (IV),which is mesylated with mesyl chloride and triethylamine as before giving the mesylate (V).The reaction of (V) with sodium azide in DMSO yields the corresponding (2S,4R)-azide (VI),which is reduced with H2 over Pd/C in methanol affording (2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid methyl ester (VII).The acylation of (VII) with 4-chlorobenzenesulfonyl chloride (VIII) and triethylamine in dichloromethane gives the corresponding amide (IX),which is reduced with diisobutylaluminum hydride (DIBAL) in toluene/THF yielding the aldehyde (X).The Wittig condensation of aldehyde (X) with (4-carboxybutyl)triphenylphosphonium bromide (XI) by means of lithium bis(trimethylsilyl)amide (LBSA) in HMPT affords 6-[1-(tert-butoxycarbonyl)-4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid (XII),which is esterified and deprotected with methanol/HCl to give 6-[4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XIII).The condensation of (XIII) with 3-(chloromethyl)pyridine (XIV) and triethylamine in refluxing THF yields 6-[4(R)-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XV),which is finally hydrolyzed with NaOH in methanol/water.
合成路线:2) The esterification of trans-4-hydroxy-L-proline (XVI) with SOCl2 and methanol gives the methyl ester (XVII),which is condensed with 3-(methanesulfonyloxymethyl)pyridine (XVIII),obtained by treatment of 3-(hydroxymethyl)pyridine (XIX) with methanesulfonyl chloride,by means of triethylamine yielding trans-N-(3-pyridylmethyl)-4-hydroxy-L-proline methyl ester (XX).The treatment of (XX) with methanesulfonyl chloride affords the corresponding mesylate (XXI),which by reaction with LiCl in hot polyethylene glycol gives cis-4-chloro-N-(3-pyridylmethyl)-L-proline methyl ester (XXII).The reaction of (XXII) with sodium azide in DMSO yields the trans-4-azido derivative (XXIII),which is reduced with triphenylphosphine in hot ethyl acetate to the corresponding trans-4-amino compound (XXIV).The treatment of (XXIV) with 4-chlorophenylsulfonyl chloride (VIII) and triethylamine in ethyl acetate affords the sulfonamide (XXV),which is reduced with diisobutylaluminum hydride in toluene/dichloromethane giving (2S,4R)-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidine-2-carbaldehyde (XXVI).Finally,this compound is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium chloride (XXVII) and potassium tert-butoxide in THF.
合成路线:3) The cyclization of the previously described trans-4-(methanesulfonyloxy)-1-(3-pyridylmethyl)-L-prolinemethyl ester (XXI) with NaOH in acetonitrile gives the expected lactone (XXVIII),which by methanolysis with K2CO3 in methanol yields cis-4-hydroxy-1-(3-pyridylmethyl)-L-proline methyl ester (XXIX).The acylation of (XXIX) with 4-nitrophenylsulfonyl chloride (XXX) and triethylamine in dichloromethane affords the corresponding cis-sulfonyloxyproline derivative (XXXI),which is treated with the sodium salt of 4-chlorophenylsulfonamide (XXXII) in DMSO to give trans-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)-L-proline methyl ester (XXV) already obtained.The reduction of (XXV) with NaBH4 in THF yields the corresponding hydroxymethyl derivative (XXXIII),which is oxidized with SO3/pyridine to the previously described aldehyde (XXVI).4) The condensation of the previously described cis-4-hydroxyproline derivative (XXIX) with N-(4-chlorophenylsulfonyl)carbamic acid methyl ester (XXXIV) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives (2S,4R)-trans-4-[4-chloro-N-(methoxycarbonyl)phenylsulfonamido]-1-(3-pyridylmethyl)pyrrolidine-2-carboxylic acid methyl ester (XXXV),which is reduced with NaBH4 to the trans-hydroxymethyl derivative (XXXIII),already described.
参考文献标题:KDI-792
文献作者:Graul,A.; Castar,J.
参考来源:Drugs Fut 1996,21(12),1224
产品链接: CAS No. 130047-30-2››