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【结 构 式】 
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【分子编号】41712 【品名】(E)-3-phenyl-2-propenal 【CA登记号】14371-10-9 |
【 分 子 式 】C9H8O 【 分 子 量 】132.16192 【元素组成】C 81.79% H 6.1% O 12.11% |
合成路线1
该中间体在本合成路线中的序号：(IV)A new asymmetric synthesis of orlistat has been described: Reaction of the chiral aminoindanol (I) with octanoyl chloride (II) in pyridine gives the chiral ester (III), which is condensed with cinnamaldehyde (IV) by means of TiCl4, DIEA and Bu2BOTf in dichloromethane yielding, after chromatographic purification, the anti-aldol adduct (V). Hydrolysis of the chiral auxiliary of (V) with lithium hydroperoxide affords the beta-hydroxy acid (VI), which is protected as the 1,3-dioxan-4-one (VIII) by reaction with pivalaldehyde (VII), TMS-OTf and isopropoxytrimethylsilane (TMS-O-i-Pr). Ozonolysis of (VIII) with O3 in dichloromethane yields the aldehyde (IX), which is condensed with 1-nitrododecane (X) by means of TBAF in DMF to provide the nitroaldol (XI). The dehydration of (XI) with DCC and CuCl in hot acetonitrile gives the nitroalkene (XII), which is reduced with Zn/HOAc to oxime (XIII). Oxidative hydrolysis of (XIII) with ceric ammonium nitrate (CAN) and HNO3 yields diketone (XIV), which is hydrolyzed with HCl in THF providing the beta-hydroxy acid (XV). Esterification of (XV) with benzyl iodide and CsCO3 gives the benzyl ester (XVI), which is estereoselectively reduced with Me4NB(OAc)3H in HOAc/acetonitrile yielding the chiral anti-1,3-diol (XVII). The selective protection of (XVII) with TIPS-OTf and 2,6-lutidine affords the monosilylated ester (XVIII), which is treated with H2 over Pd(OH)2 in ethyl acetate/methanol to furnish the free beta-hydroxy acid (XIX). Cyclization of acid (XIX) by means of PhSO2Cl in pyridine affords the beta-lactone (XX), which is desilylated with TBAF and HOAc in THF giving lactone (XXI). Finally, lactone (XXI) is esterified under Mitsunobu conditions with N-formyl-L-leucine (XXII) by means of DIAD and PPh3 in THF.
| 【1】 Ghosh, A.K.; Fidanze, S.; Asymmetric synthesis of (-)-tetrahydrolipstatin: An anti-aldol-based strategy. Org Lett 2000, 2, 16, 2405. |
| 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) | 41710 | N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-4-methylbenzenesulfonamide | C16H17NO3S | 详情 | 详情 | |
| (II) | 11091 | Octanoic acid | 124-07-2 | C8H16O2 | 详情 | 详情 |
| (III) | 41711 | (1S,2R)-1-[[(4-methylphenyl)sulfonyl]amino]-2,3-dihydro-1H-inden-2-yl octanoate | C24H31NO4S | 详情 | 详情 | |
| (IV) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
| (V) | 41713 | (1S,2R)-1-[[(4-methylphenyl)sulfonyl]amino]-2,3-dihydro-1H-inden-2-yl (2S,3S,4E)-2-hexyl-3-hydroxy-5-phenyl-4-pentenoate | C33H39NO5S | 详情 | 详情 | |
| (VI) | 41714 | (2S,3S,4E)-2-hexyl-3-hydroxy-5-phenyl-4-pentenoic acid | C17H24O3 | 详情 | 详情 | |
| (VII) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VIII) | 41715 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-one | C22H32O3 | 详情 | 详情 | |
| (IX) | 41716 | (2S,4R,5S)-2-(tert-butyl)-5-hexyl-6-oxo-1,3-dioxane-4-carbaldehyde | C15H26O4 | 详情 | 详情 | |
| (X) | 41717 | 1-nitroundecane | C11H23NO2 | 详情 | 详情 | |
| (XI) | 41718 | (2S,5S,6R)-2-(tert-butyl)-5-hexyl-6-(1-hydroxy-2-nitrododecyl)-1,3-dioxan-4-one | C26H49NO6 | 详情 | 详情 | |
| (XII) | 41719 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[(E)-2-nitro-1-dodecenyl]-1,3-dioxan-4-one | C26H47NO5 | 详情 | 详情 | |
| (XIII) | 41720 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[2-(hydroxyimino)dodecyl]-1,3-dioxan-4-one | C26H49NO4 | 详情 | 详情 | |
| (XIV) | 41721 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-(2-oxododecyl)-1,3-dioxan-4-one | C26H48O4 | 详情 | 详情 | |
| (XV) | 41722 | (2S,3S)-2-hexyl-3-hydroxy-5-oxopentadecanoic acid | C21H40O4 | 详情 | 详情 | |
| (XVI) | 41723 | benzyl (2S,3S)-2-hexyl-3-hydroxy-5-oxopentadecanoate | C28H46O4 | 详情 | 详情 | |
| (XVII) | 41724 | benzyl (2S,3S,5R)-2-hexyl-3,5-dihydroxypentadecanoate | C28H48O4 | 详情 | 详情 | |
| (XVIII) | 41725 | benzyl (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(triisopropylsilyl)oxy]pentadecanoate | C37H68O4Si | 详情 | 详情 | |
| (XIX) | 41726 | (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(triisopropylsilyl)oxy]pentadecanoic acid | C30H62O4Si | 详情 | 详情 | |
| (XX) | 41727 | (3S,4S)-3-hexyl-4-[(2R)-2-[(triisopropylsilyl)oxy]dodecyl]-2-oxetanone | C30H60O3Si | 详情 | 详情 | |
| (XXI) | 41728 | (3S,4S)-3-hexyl-4-[(2R)-2-hydroxydodecyl]-2-oxetanone | C21H40O3 | 详情 | 详情 | |
| (XXII) | 11081 | N-Formyl-L-leucine; (2S)-2-(Formylamino)-4-methylpentanoic acid | 6113-61-7 | C7H13NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A new practical synthesis of FK-453, suitable for large scale manufacture is described: Bromination of cinnamic aldehyde (I) with Br2 in HOAc gives the dibromoderivative (II), which is treated with NaHSO3 and triethylamine yielding alpha-bromocinnamic aldehyde (III). The reaction of (III) with triethyl orthoformate affords the corresponding acetal (IV), which is treated with KOH in hot ethanol to give the acetylenic acetal (V). Acidic hydrolysis of the acetal (V) with sulfuric acid in refluxing water affords phenylpropargyl aldehyde (VI), which by a Horner-Emmons condensation with the phosphonate (VII) by means of KOH in DMSO gives 5-phenylpent-2(E)-en-4-ynoic acid ethyl ester (VIII). The 1,3-dipolar cycloaddition of (VIII) with 1-aminopyridinium iodide (IX) by means of KOH and K2CO3 in the same solvent yields 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (X), which is hydrolyzed with NaOH in hot methanol affording the corresponding free acid (XI). Reaction of (XI) with SOCl2 and DMF gives the activated acyl chloride (XII), which is condensed with the silylated chiral piperidineethanol (XIII) [obtained by silylation of the chiral piperidineethanol (XIV) with N,N'-bis(trimethylsilyl)urea (BSU)] by means of Et3N and DMAP in CH2Cl2, yielding the silylated target compound (XV). Finally, this compound is desilylated by means of K2CO3 in methanol.
| 【1】 Morinaga, Y.; Zanka, A.; Uematsu, R.; Yamazaki, H.; Yasuda, H.; Process development of a novel-xanthine adenosine A1 receptor antagonist. Org Process Res Dev 1999, 3, 6, 389. |
| 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) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
| (II) | 41735 | 2,3-dibromo-3-phenylpropanal | C9H8Br2O | 详情 | 详情 | |
| (III) | 41736 | (Z)-2-bromo-3-phenyl-2-propenal | 5443-49-2 | C9H7BrO | 详情 | 详情 |
| (IV) | 41737 | (Z)-2-bromo-1-ethoxy-3-phenyl-2-propenyl ethyl ether; 1-[(Z)-2-bromo-3,3-diethoxy-1-propenyl]benzene | C13H17BrO2 | 详情 | 详情 | |
| (V) | 41738 | 1-(3,3-diethoxy-1-propynyl)benzene; 1-ethoxy-3-phenyl-2-propynyl ethyl ether | 6142-95-6 | C13H16O2 | 详情 | 详情 |
| (VI) | 41739 | 3-phenyl-2-propynal | 2579-22-8 | C9H6O | 详情 | 详情 |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 41740 | ethyl (E)-5-phenyl-2-penten-4-ynoate | C13H12O2 | 详情 | 详情 | |
| (IX) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
| (X) | 13273 | methyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C17H14N2O2 | 详情 | 详情 | |
| (XI) | 13274 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid | C16H12N2O2 | 详情 | 详情 | |
| (XII) | 13275 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride | C16H11ClN2O | 详情 | 详情 | |
| (XIII) | 41741 | (2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidine; 2-[(2R)piperidinyl]ethyl trimethylsilyl ether | C10H23NOSi | 详情 | 详情 | |
| (XIV) | 13276 | 2-[(2R)Piperidinyl]-1-ethanol | C7H15NO | 详情 | 详情 | |
| (XV) | 41742 | (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1-((2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidinyl)-2-propen-1-one | C26H33N3O2Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The synthesis of the intermediate (S,S)-3-(Fmoc-amino)-2-methyl-5-phenyl-4-pentenoic acid (XI) has been performed as follows: The Horner-Wadsworth-Emmons condensation of cinnamaldehyde (I) with phosphonate (II) by means of NaH in THF gives (E,E)-5-phenyl-2,4-pentadienoic acid ethyl ester (III), which is condensed with (S)-N-benzyl-N-(alpha-methylbenzyl)amine (IV) by means of BuLi in THF to yield the chiral adduct (V). The reaction of (V) with LDA affords the corresponding lithium enolate, which is methylated with methyl iodide in THF to afford the enantioselectively methylated compound (VI). The hydrogenation of (VI) with H2 over Pd(OH)2 in methanol/water/HOAc provides (S,S)-3-amino-2-methyl-5-phenylpentanoic acid methyl ester (VII), which is treated with Boc2O and NaHCO3 in dioxane/water to give the N-protected ester (VIII). The reaction of (VIII) with NBS in CCl4, followed by treatment with DBU at 60 C, yields the pentenoic ester derivative (IX), which is treated first with LiOH and then with TFA to provide (S,S)-3-amino-2-methyl-5-phenyl-4-pentanoic acid (X). Finally, this compound is N-protected by reaction with Fmoc-Cl and K2CO3 in dioxane/water to furnish the target pentenoic acid intermediate (XI).
| 【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696. |
| 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) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
| (II) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (III) | 52431 | methyl 5-phenyl-2,4-pentadienoate | C12H12O2 | 详情 | 详情 | |
| (IV) | 38470 | (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine | 38235-77-7 | C15H17N | 详情 | 详情 |
| (V) | 52432 | methyl 5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate | C27H29NO2 | 详情 | 详情 | |
| (VI) | 52433 | methyl 2-methyl-5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate | C28H31NO2 | 详情 | 详情 | |
| (VII) | 52434 | methyl 3-amino-2-methyl-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 52435 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenylpentanoate | C18H27NO4 | 详情 | 详情 | |
| (IX) | 52436 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (X) | 52437 | 3-amino-2-methyl-5-phenyl-4-pentenoic acid | C12H15NO2 | 详情 | 详情 | |
| (XI) | 52438 | 3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid | C27H25NO4 | 详情 | 详情 |