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【结 构 式】 
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【药物名称】AP-1903 【化学名称】Bis[1-[2(S)-(3,4,5-Trimethoxypheny)butyryl]piperidine-2(S)-carboxylic acid] ester with 1,2-ethanediylbis[imino(2-oxo-2,1-ethanediyl)oxy-3,1-phenylene[(1R)-3-(3,4-dimethoxyphenyl)propylidene]] ester 【CA登记号】195514-63-7 【 分 子 式 】C78H98N4O20 【 分 子 量 】1411.66556 |
【开发单位】Ariad Pharmaceuticals (Originator) 【药理作用】IMMUNOMODULATING AGENTS, Treatment of Transplant Rejection |
合成路线1
The intermediate alcohol (VIII) was prepared as shown in Scheme 27060901a: Aldol condensation of 3,4-dimethoxybenzaldehyde (I) with 3-hydroxyacetophenone (II) in the presence of KOH provided chalcone (III), which was hydrogenated over Pd/C to yield the corresponding diarylpropanone (IV). Subsequent alkylation of the phenolic hydroxyl group of (IV) with tert-butyl bromoacetate (V) using NaH in DMF gave ether (VI). Then, enantioselective reduction of ketone by means of (+)-beta-chlorodiisopinocampheylborane (VII) at -20 C furnished the (R)-alcohol (VIII).
| 【1】 Yang, W.; Guo, T.; Keenan, T.P.; Laborde, E.; Holt, D.A. (Ariad Pharmaceuticals Inc.); Synthetic derivs. of rapamycin as multimerizing agents for chimeric proteins with immunophilin-derived domains. JP 2000505475; WO 9731898 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (II) | 25331 | 3-hydroxyacetophenone; 1-(3-hydroxyphenyl)-1-ethanone | 121-71-1 | C8H8O2 | 详情 | 详情 |
| (III) | 25332 | (E)-3-(3,4-dimethoxyphenyl)-1-(3-hydroxyphenyl)-2-propen-1-one | C17H16O4 | 详情 | 详情 | |
| (IV) | 25341 | 3-(3,4-dimethoxyphenyl)-1-(3-hydroxyphenyl)-1-propanone | C17H18O4 | 详情 | 详情 | |
| (V) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 25342 | tert-butyl 2-[3-[3-(3,4-dimethoxyphenyl)propanoyl]phenoxy]acetate | C23H28O6 | 详情 | 详情 | |
| (VII) | 25343 | chloro[bis[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | 112246-73-8 | C20H34BCl | 详情 | 详情 |
| (VIII) | 25348 | tert-butyl 2-[3-[(1R)-3-(3,4-dimethoxyphenyl)-1-hydroxypropyl]phenoxy]acetate | C23H30O6 | 详情 | 详情 |
合成路线2
3,4,5-Trimethoxyphenylacetic acid (IX) was alkylated with ethyl iodide in the presence of two equivalents of sodium bis(trimethylsilyl)amide to afford racemic trimethoxyphenylbutyric acid (X). After conversion to the corresponding acid chloride with SOCl2, condensation with (R)-4-benzyl-2-oxazolidinone (XI) in the presence of n-butyllithium gave N-acyloxazolidinone (XII) as a diastereomeric mixture that was separated by column chromatography. The required diastereoisomer was then hydrolyzed with lithium peroxide to provide (S)-2-(3,4,5-trimethoxyphenyl)butyric acid (XIII). Subsequent coupling of (XIII) with methyl (S)-pipecolate (XIV) employing 2-chloro-1-methylpyridinium iodide, followed by ester hydrolysis with LiOH, provided amide (XV). Further DCC-promoted coupling of (XV) to alcohol (VIII) provided (XVI). After acid cleavage of the tert-butyl ester, the resulting carboxylic acid was finally coupled to etylenediamine (XVII) in the presence of 1-benzotriazolyloxy tris(dimethylamino)phosphonium hexafluorophosphate to yield the title compound.
| 【1】 Yang, W.; Guo, T.; Keenan, T.P.; Laborde, E.; Holt, D.A. (Ariad Pharmaceuticals Inc.); Synthetic derivs. of rapamycin as multimerizing agents for chimeric proteins with immunophilin-derived domains. JP 2000505475; WO 9731898 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 25348 | tert-butyl 2-[3-[(1R)-3-(3,4-dimethoxyphenyl)-1-hydroxypropyl]phenoxy]acetate | C23H30O6 | 详情 | 详情 | |
| (IX) | 25349 | 2-(3,4,5-trimethoxyphenyl)acetic acid | 937-52-0 | C11H14O5 | 详情 | 详情 |
| (X) | 25350 | 2-(3,4,5-trimethoxyphenyl)butyric acid | C13H18O5 | 详情 | 详情 | |
| (XI) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (XII) | 25352 | (4R)-4-benzyl-3-[2-(3,4,5-trimethoxyphenyl)butanoyl]-1,3-oxazolidin-2-one | C23H27NO6 | 详情 | 详情 | |
| (XIII) | 25353 | (2S)-2-(3,4,5-trimethoxyphenyl)butyric acid | C13H18O5 | 详情 | 详情 | |
| (XIV) | 25354 | methyl (2S)-2-piperidinecarboxylate | C7H13NO2 | 详情 | 详情 | |
| (XV) | 25355 | (2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]-2-piperidinecarboxylic acid | C19H27NO6 | 详情 | 详情 | |
| (XVI) | 25356 | (1R)-1-[3-[2-(tert-butoxy)-2-oxoethoxy]phenyl]-3-(3,4-dimethoxyphenyl)propyl (2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]-2-piperidinecarboxylate | C42H55NO11 | 详情 | 详情 | |
| (XVII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
合成路线3
In an alternative procedure, the intermediate alcohol (VIII) was coupled with N-Fmoc-(S)-pipecolic acid (XVIII) using DCC and DMAP to give ester (XIX). Subsequent deprotection of the Fmoc group of (XIX) by means of pyrrolidine provided amine (XX). This was further coupled to racemic 2-(3,4,5-trimethoxyphenyl)butyric acid (X), and the resulting diastereomeric mixture of amides (XXI) was separated by column chromatography. Then, TFA-promoted cleavage of the tert-butyl ester from the desired (S,S)-diastereoisomer provided carboxylic acid (XXII), which was finally coupled to ethylenediamine in the same way as before.
| 【1】 Clackson, T.; Yang, W.; Rozamus, L.W.; Hatada, M.; Amara, J.F.; Rollins, C.T.; Stevenson, L.F.; Magari, S.R.; Wood, S.A.; Courage, N.L.; Lu, X.; Cerasoli, F. Jr; Gilman, M.; Holt, D.A.; Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci USA 1998, 95, 18, 10437. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 25348 | tert-butyl 2-[3-[(1R)-3-(3,4-dimethoxyphenyl)-1-hydroxypropyl]phenoxy]acetate | C23H30O6 | 详情 | 详情 | |
| (X) | 25350 | 2-(3,4,5-trimethoxyphenyl)butyric acid | C13H18O5 | 详情 | 详情 | |
| (XVIII) | 25357 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-piperidinecarboxylic acid | C21H21NO4 | 详情 | 详情 | |
| (XIX) | 25358 | 2-[(1R)-1-[3-[2-(tert-butoxy)-2-oxoethoxy]phenyl]-3-(3,4-dimethoxyphenyl)propyl] 1-(9H-fluoren-9-ylmethyl) (2S)-1,2-piperidinedicarboxylate | C44H49NO9 | 详情 | 详情 | |
| (XX) | 25359 | (1R)-1-[3-[2-(tert-butoxy)-2-oxoethoxy]phenyl]-3-(3,4-dimethoxyphenyl)propyl (2S)-2-piperidinecarboxylate | C29H39NO7 | 详情 | 详情 | |
| (XXI) | 25360 | (1R)-1-[3-[2-(tert-butoxy)-2-oxoethoxy]phenyl]-3-(3,4-dimethoxyphenyl)propyl (2S)-1-[2-(3,4,5-trimethoxyphenyl)butanoyl]-2-piperidinecarboxylate | C42H55NO11 | 详情 | 详情 | |
| (XXII) | 25361 | 2-(3-[(1R)-3-(3,4-dimethoxyphenyl)-1-[([(2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]piperidinyl]carbonyl)oxy]propyl]phenoxy)acetic acid | C38H47NO11 | 详情 | 详情 |