合成路线:The reaction of the benzocycloheptanone (I) with dimethylcarbonate in the presence of NaOMe gave the beta-ketoester (II).The benzocycloheptene-8-carboxylic acid (III) was prepared by NaBH4 reduction of (II) in CH2Cl2/MeOH and subsequent dehydration by mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF and alkaline hydrolysis.On the other hand,the aniline (VII) was obtained by reductive aminations of 4-nitrobenzylamine (IV) successively with tetrahydropyran-4-one (V) and formalin in 1,2-dichloroethane using NaBH(OAc)3,followed by Fe reduction in AcOH or hydrogenation in EtOH of the resulting nitrobenzylamine (VI).The carboxylic acid (III) was reacted with oxalyl chloride in CH2Cl2/cat.DMF to afford the acid chloride,which was condensed with the aniline (VII) in THF/Et3N to give the anilide derivative (VIII).Compound (VIII) was treated with iodomethane in DMF to provide the quaternary ammonium iodide,which was converted to TAK-779 using ion exchange resin (Cl-).
合成路线:Coupling of the carboxylic acid (III) with the O-protected 4-aminobenzylalcohol (IX) as above and subsequent deprotection of the tert-butyldimethylsilyl (TBDMS) group with 6N HCl in acetone gave the benzylalcohol (X),which was reacted with thionyl chloride in chloroform/cat.pyridine to provide the benzylchloride (XI).Treatment of (XI) with the tertiary amine (XII) in DMF yielded TAK-779.
参考文献标题:Pharmaceutical composition for antagonizing CCR5 comprising anilide derivative
文献作者:Kuroshima,K.; Kanzaki,N.; Nishimura,O.; Shiraishi,M.; Sawada,H.; Baba,M.; Aramaki,Y.(Takeda Chemical Industries,Ltd.)
参考来源:JP 2000128782; JP 2000128842; US 6096780; WO 9932100
合成路线:The reaction of the benzocycloheptanone (I) with dimethylcarbonate in the presence of NaOMe gave the beta-ketoester (II).The benzocycloheptene-8-carboxylic acid (III) was prepared by NaBH4 reduction of (II) in CH2Cl2/MeOH and subsequent dehydration by mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF and alkaline hydrolysis.On the other hand,the aniline (VII) was obtained by reductive aminations of 4-nitrobenzylamine (IV) successively with tetrahydropyran-4-one (V) and formalin in 1,2-dichloroethane using NaBH(OAc)3,followed by Fe reduction in AcOH or hydrogenation in EtOH of the resulting nitrobenzylamine (VI).The carboxylic acid (III) was reacted with oxalyl chloride in CH2Cl2/cat.DMF to afford the acid chloride,which was condensed with the aniline (VII) in THF/Et3N to give the anilide derivative (VIII).Compound (VIII) was treated with iodomethane in DMF to provide the quaternary ammonium iodide,which was converted to TAK-779 using ion exchange resin (Cl-).
合成路线:Coupling of the carboxylic acid (III) with the O-protected 4-aminobenzylalcohol (IX) as above and subsequent deprotection of the tert-butyldimethylsilyl (TBDMS) group with 6N HCl in acetone gave the benzylalcohol (X),which was reacted with thionyl chloride in chloroform/cat.pyridine to provide the benzylchloride (XI).Treatment of (XI) with the tertiary amine (XII) in DMF yielded TAK-779.
参考文献标题:TAK-779,a small molecule CCR5 antagonist: Design,synthesis,and in vitro activity of anilide derivatives
文献作者:Shiraishi,M.; Seto,M.; Aramaki,Y.; et al.
参考来源:39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999,San Francisco) 1999,Abst F911
合成路线:Suzuki coupling of 3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (I) with 4-methylphenylboronic acid (II) by means of palladium tetrakis(triphenylphosphine) gave (III).Subsequent refluxing of (III) with dimethyl carbonate in the presence of NaOMe afforded ketoester (IV).This was reduced with NaBH4 to give hydroxy ester (V),which was then dehydrated and hydrolyzed to the unsaturated acid (VI) with HCl in diglyme at 100 C.Alternatively,ketone (III) was carboxylated under CO2 atmosphere in the presence of either potassium carbonate or potassium tert-butoxide.The resulting ketoacid (VII) was reduced to hydroxyacid (VIII) with NaBH4,and then dehydrated to (VI) using 80% formic acid at 100 C.Carboxylic acid (VI) was then converted to the corresponding acid chloride (IX) by means of oxalyl chloride in CH2Cl2.
合成路线:The reaction of the benzocycloheptanone (I) with dimethylcarbonate in the presence of NaOMe gave the beta-ketoester (II).The benzocycloheptene-8-carboxylic acid (III) was prepared by NaBH4 reduction of (II) in CH2Cl2/MeOH and subsequent dehydration by mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF and alkaline hydrolysis.On the other hand,the aniline (VII) was obtained by reductive aminations of 4-nitrobenzylamine (IV) successively with tetrahydropyran-4-one (V) and formalin in 1,2-dichloroethane using NaBH(OAc)3,followed by Fe reduction in AcOH or hydrogenation in EtOH of the resulting nitrobenzylamine (VI).The carboxylic acid (III) was reacted with oxalyl chloride in CH2Cl2/cat.DMF to afford the acid chloride,which was condensed with the aniline (VII) in THF/Et3N to give the anilide derivative (VIII).Compound (VIII) was treated with iodomethane in DMF to provide the quaternary ammonium iodide,which was converted to TAK-779 using ion exchange resin (Cl-).
合成路线:Coupling of the carboxylic acid (III) with the O-protected 4-aminobenzylalcohol (IX) as above and subsequent deprotection of the tert-butyldimethylsilyl (TBDMS) group with 6N HCl in acetone gave the benzylalcohol (X),which was reacted with thionyl chloride in chloroform/cat.pyridine to provide the benzylchloride (XI).Treatment of (XI) with the tertiary amine (XII) in DMF yielded TAK-779.
参考文献标题:Discovery of small molecule CCR5 antagonists
文献作者:Shiraishi,M.; Aramaki,Y.; Seto,M.; et al.
参考来源:19th Symp Med Chem and 8th Annu Meet Div Med Chem Jpn (Nov 17-19,Tokyo) 1999,Abst 2P-06
合成路线:The reaction of the benzocycloheptanone (I) with dimethylcarbonate in the presence of NaOMe gave the beta-ketoester (II).The benzocycloheptene-8-carboxylic acid (III) was prepared by NaBH4 reduction of (II) in CH2Cl2/MeOH and subsequent dehydration by mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF and alkaline hydrolysis.On the other hand,the aniline (VII) was obtained by reductive aminations of 4-nitrobenzylamine (IV) successively with tetrahydropyran-4-one (V) and formalin in 1,2-dichloroethane using NaBH(OAc)3,followed by Fe reduction in AcOH or hydrogenation in EtOH of the resulting nitrobenzylamine (VI).The carboxylic acid (III) was reacted with oxalyl chloride in CH2Cl2/cat.DMF to afford the acid chloride,which was condensed with the aniline (VII) in THF/Et3N to give the anilide derivative (VIII).Compound (VIII) was treated with iodomethane in DMF to provide the quaternary ammonium iodide,which was converted to TAK-779 using ion exchange resin (Cl-).
合成路线:Coupling of the carboxylic acid (III) with the O-protected 4-aminobenzylalcohol (IX) as above and subsequent deprotection of the tert-butyldimethylsilyl (TBDMS) group with 6N HCl in acetone gave the benzylalcohol (X),which was reacted with thionyl chloride in chloroform/cat.pyridine to provide the benzylchloride (XI).Treatment of (XI) with the tertiary amine (XII) in DMF yielded TAK-779.
参考文献标题:TAK-779
文献作者:Kanzaki,N.; Shiraishi,M.; Fujino,M.; Nishimura,O.; Baba,M.; Lizawa,Y.
参考来源:Drugs Fut 2000,25(3),252
合成路线:The reaction of the benzocycloheptanone (I) with dimethylcarbonate in the presence of NaOMe gave the beta-ketoester (II).The benzocycloheptene-8-carboxylic acid (III) was prepared by NaBH4 reduction of (II) in CH2Cl2/MeOH and subsequent dehydration by mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF and alkaline hydrolysis.On the other hand,the aniline (VII) was obtained by reductive aminations of 4-nitrobenzylamine (IV) successively with tetrahydropyran-4-one (V) and formalin in 1,2-dichloroethane using NaBH(OAc)3,followed by Fe reduction in AcOH or hydrogenation in EtOH of the resulting nitrobenzylamine (VI).The carboxylic acid (III) was reacted with oxalyl chloride in CH2Cl2/cat.DMF to afford the acid chloride,which was condensed with the aniline (VII) in THF/Et3N to give the anilide derivative (VIII).Compound (VIII) was treated with iodomethane in DMF to provide the quaternary ammonium iodide,which was converted to TAK-779 using ion exchange resin (Cl-).
合成路线:Coupling of the carboxylic acid (III) with the O-protected 4-aminobenzylalcohol (IX) as above and subsequent deprotection of the tert-butyldimethylsilyl (TBDMS) group with 6N HCl in acetone gave the benzylalcohol (X),which was reacted with thionyl chloride in chloroform/cat.pyridine to provide the benzylchloride (XI).Treatment of (XI) with the tertiary amine (XII) in DMF yielded TAK-779.
参考文献标题:Discovery of novel,potent,and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety
文献作者:Shiraishi,M.; Aramaki,Y.; Seto,M.; Imoto,H.; Nishikawa,Y.; Kanzaki,N.; Okamoto,M.; Sawada,H.; Nishimura,O.; Baba,M.; Fujino,M.
参考来源:J Med Chem 2000,43(10),2049
合成路线:A new large-scaleable synthesis of TAK-779 has been developed: The reduction of 4'-methylbiphenyl-4-carbonitrile (I) with sodium bis(2-methoxyethoxy)aluminum hydride (SBMEA) in THF gives the corresponding aldehyde (II),which is submitted to a Wittig condensation with the phosphonium bromide (III) by means of NaOMe in methanol to yield the pentenoic acid derivative (IV).Reduction of the double bond of (IV) with H2 over Pd/C in THF,followed by cyclization with hot PPA affords the benzocycloheptanone (V),which is treated with refluxing dimethyl carbonate and NaOMe to provide the beta-ketoester (VI).The reduction of (VI) with NaBH4 in THF gives the hydroxyester (VII),which is dehydrated with Ms-Cl and DBU and hydrolyzed with NaOH to yield 8-(4-methylphenyl)benzocyclohept-1-ene-2-carboxylic acid (VIII).Condensation of (VIII) with 4-aminobenzyl alcohol (IX) by means of (COCl)2 and TEA in THF affords the corresponding amide (X),which is treated with SOCl2 in THF to provide the chloromethyl derivative (XI).Finally,this compound is condensed with 4-(dimethylamino)tetrahydropyran (XII) in hot DMF to furnish the target ammonium salt.The tertiary amine (XII) has been obtained by reductive condensation of tetrahydropyran-4-one (XIII) with dimethylamine by means of H2 over Pd/C in THF.
参考文献标题:Development of a new synthetic route of a non-peptide CCR5 antagonist,TAK-779,for large-scale preparation
文献作者:Ikemoto,T.; Hashimoto,H.; Kaarasaki,T.; Tomimatsu,K.; Ito,T.; Nishiguchi,A.; Wakimasu,M.; Mitsudera,H.
参考来源:Org Process Res Dev 2000,4(6),520
产品链接: CAS No. 229005-80-5››