药物详细合成路线
| Name | Revatropate;UK-112166-04(hydrobromide);UK-112166 | | Chemical Name | 2(S)-(Hydroxymethyl)-4-[(Rs)-methylsulfinyl]-2-phenylbutyric acid quinuclidin-3(R)-yl ester | | CAS | 149926-91-0 | | Related CAS | | | Formula | C19H27NO4S | | Structure |  | | Formula Weight | 365.49534 | | Stage | II 期临床 | | Company | Pfizer (Originator) | | Activity/Mechanism | Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, Muscarinic M3 Antagonists | | Syn. Route | 1 | | Route 1 | | 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. | | |  | | List of intermediates | No. | | methyl 3-hydroxy-5-iodobenzoate | (i) | | methyl 3-(benzyloxy)-5-iodobenzoate | (ii) | | rolipram; 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone | (iii) | | methyl 3-(benzyloxy)-5-[4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-1-pyrrolidinyl]benzoate | (iv) | | methyl 3-[4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-1-pyrrolidinyl]-5-hydroxybenzoate | (v) | | 1-(chloromethyl)-3-methoxybenzene | (vi) | | methyl 3-[4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-1-pyrrolidinyl]-5-[(3-methoxybenzyl)oxy]benzoate | (vii) | | 3-[4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxo-1-pyrrolidinyl]-5-[(3-methoxybenzyl)oxy]benzoic acid | (viii) | | 3-hydroxybenzaldehyde | (ix) | | | Reference 1: martel, a.m.; rabasseda, x.; castaner, j.; revatropate. drugs fut 1997, 22, 2, 135. Reference 2: cross, p.e.; stobie, a. (pfizer inc.); quinuclidine esters process and intermediate for their preparation and pharmaceutical compsns. containing them. ep 0603229; jp 1994510991; jp 1997315970; wo 9306098 . |
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来源:药化网
作者:药化小编
摘要:本文合成路线介绍的是药物中文名瑞伐托酯；英文名Revatropate;UK-112166-04(hydrobromide);UK-112166；CAS[149926-91-0]
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