Revatropate, UK-112166-04(hydrobromide), UK-112166
瑞伐托酯Chemical Name: 2(S)-(Hydroxymethyl)-4-[(Rs)-methylsulfinyl]-2-phenylbutyric acid quinuclidin-3(R)-yl ester
CAS No. 149926-91-0
项目整合开发状态: Phase II
项目研究机构: Pfizer (Originator)
合成路线:The alkylation of 2-phenylacetic acid (I) with 2-chloroethyl(methyl)sulfide (II) by means of lithium diisopropylamide (LDA) in THF gives 4-(methylsulfanyl)-2-phenylbutyric acid (III),which is esterified with methanol/H2SO4 yielding the methyl ester (IV).The transesterification of (IV) with quinuclidin-3(R)-ol (V) by means of NaH in refluxing toluene affords the 3(R)-quinuclidinyl ester (VI),which is hydroxymethylated with paraformaldehyde and NaH in DMF giving 2(RS)-(hydroxymethyl)-4-(methylsulfanyl)-2-phenylbutyric acid 3(R)-quinuclidinyl ester (VII) as a diastereomeric mixture.Chromatographic separation of (VII) over SiO2 using CHCl3/methanol/NH4OH as a gradient elution yields the 2(S)-hydroxymethyl isomer (VIII),which is oxidized with trifluoroperacetic acid in trifluoroacetic acid affording the corresponding sulfinyl derivative (IX) as a new diastereomeric mixture.Finally,this mixture is resolved by HPLC over Kromasil C-8 SiO2 using as eluant water/acetonitrile containing 1% trifluoroacetic acid.
📌 参考资料/链接：
参考文献标题:Quinuclidine esters process and intermediate for their preparation and pharmaceutical compsns.containing them
文献作者:Cross,P.E.; Stobie,A.(Pfizer Inc.)
参考来源:EP 0603229; JP 1994510991; JP 1997315970; WO 9306098
📄 详细内容
合成路线:The alkylation of 2-phenylacetic acid (I) with 2-chloroethyl(methyl)sulfide (II) by means of lithium diisopropylamide (LDA) in THF gives 4-(methylsulfanyl)-2-phenylbutyric acid (III),which is esterified with methanol/H2SO4 yielding the methyl ester (IV).The transesterification of (IV) with quinuclidin-3(R)-ol (V) by means of NaH in refluxing toluene affords the 3(R)-quinuclidinyl ester (VI),which is hydroxymethylated with paraformaldehyde and NaH in DMF giving 2(RS)-(hydroxymethyl)-4-(methylsulfanyl)-2-phenylbutyric acid 3(R)-quinuclidinyl ester (VII) as a diastereomeric mixture.Chromatographic separation of (VII) over SiO2 using CHCl3/methanol/NH4OH as a gradient elution yields the 2(S)-hydroxymethyl isomer (VIII),which is oxidized with trifluoroperacetic acid in trifluoroacetic acid affording the corresponding sulfinyl derivative (IX) as a new diastereomeric mixture.Finally,this mixture is resolved by HPLC over Kromasil C-8 SiO2 using as eluant water/acetonitrile containing 1% trifluoroacetic acid.
参考文献标题:Revatropate
文献作者:Martel,A.M.; Rabasseda,X.; Castar,J.
参考来源:Drugs Fut 1997,22(2),135
产品链接: CAS No. 149926-91-0››