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【结 构 式】 
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【分子编号】25714 【品名】octanal 【CA登记号】124-13-0 |
【 分 子 式 】C8H16O 【 分 子 量 】128.21444 【元素组成】C 74.94% H 12.58% O 12.48% |
合成路线1
该中间体在本合成路线中的序号：(II)Boron enolate obtained from chiral propionyloxazolidinone (I) and dibutylboron triflate (Bu2BOTf) was condensed with n-octanal (II) to produce the syn aldol compound (III), which was protected as the silyl ether (IV) with tert-butyldimethylsilyl triflate. Then, removal of the chiral auxiliary by hydrolysis with lithium peroxide afforded the (2S,3R)-beta-(silyloxy)acid (V). After activation as the mixed anhydride (VII) with 2,4,6-trichlorobenzoyl chloride (VI), esterification with benzyl (S)-2-hydroxy-3-methylbutyrate (VIII) gave diester (IX). Subsequent removal of the silyl group using HF in acetonitrile provided intermediate (X).
| 【1】 Wagner, B.; et al.; Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin. Bioorg Med Chem 1999, 7, 5, 737. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40666 | tert-butyl(dimethyl)silyl trifluoromethanesulfonoperoxoate | C7H15F3O4SSi | 详情 | 详情 | ||
| (I) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 25715 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (IV) | 25716 | (4S)-4-benzyl-3-((2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoyl)-1,3-oxazolidin-2-one | C27H45NO4Si | 详情 | 详情 | |
| (V) | 25717 | (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoic acid | C17H36O3Si | 详情 | 详情 | |
| (VI) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (VII) | 25719 | (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyldecanoic 2,4,6-trichloro-1-benzenecarboxylic anhydride | C24H37Cl3O4Si | 详情 | 详情 | |
| (VIII) | 25720 | benzyl (2S)-2-hydroxy-3-methylbutanoate | C12H16O3 | 详情 | 详情 | |
| (IX) | 25721 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoate | C29H50O5Si | 详情 | 详情 | |
| (X) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of the choral oxazolidinone (I) with octanal (II) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral alcohol (III), which is protected with DHP and PPTS, yielding the tetrahydropyranyl ether (IV). The cleavage of the chiral adjuvant of (IV) by means of LiOH and H2O2 affords the carboxylic acid (V), which is esterified with (2S)-hydroxy-3-methylbutyric acid benzyl ester (VI) by means of trichlorobenzoyl chloride and TEA to provide the adduct (VII). Elimination of the tetrahydropyranyl protecting group of (VII) by means of Ts-OH gives the hydroxyester (VIII), which is condensed with the chiral amino acid (IX) by means of trichlorobenzoyl chloride as before to yield the triester compound (X). Elimination of the Mom protecting group of (X) by means of Tms-Cl and tetrabutylammonium bromide affords the hydroxy compound (XI), which is hydrogenated with H2 over Pd(OH)2 to provide the carboxylic acid (XII). Elimination of the Boc protecting group of (XII) by means of TFA gives the amino acid (XII), which is finally submitted to a macrocyclization by means of DPPA and DIEA in DMF to yield the target hapalosin.
| 【1】 Hermann, C.; et al.; Total synthesis of hapalosin and two ring expanded analogs. Tetrahedron 2000, 56, 43, 8461. |
| 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) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 25715 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (IV) | 50327 | Cyanoethane; Ethyl cyanide; Propionitrile | 107-12-0 | C26H39NO5 | 详情 | 详情 |
| (V) | 50328 | (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoic acid | C16H30O4 | 详情 | 详情 | |
| (VI) | 25720 | benzyl (2S)-2-hydroxy-3-methylbutanoate | C12H16O3 | 详情 | 详情 | |
| (VII) | 50329 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoate | C28H44O6 | 详情 | 详情 | |
| (VIII) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 | |
| (IX) | 50330 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-(methoxymethoxy)-5-phenylpentanoic acid | C19H29NO6 | 详情 | 详情 | |
| (X) | 50331 | benzyl (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-15-isopropyl-7-(methoxymethoxy)-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C42H63NO10 | 详情 | 详情 | |
| (XI) | 50332 | benzyl (6S,7R,11S,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C40H59NO9 | 详情 | 详情 | |
| (XII) | 50333 | (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oic acid | C33H53NO9 | 详情 | 详情 | |
| (XIII) | 50334 | (2S)-2-[((2S,3R)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid | C28H45NO7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The condensation of the chiral oxazolidinone (VIII) with octanal (IX) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral adduct (X), which is treated with benzyl alcohol and BuLi to yield the benzyl ester (XI). The esterification of the OH group of (XI) with the intermediate carboxylic acid (VIII) by means of DCC and DMAP in dichloromethane affords the corresponding ester (XII), whose benzyl ester is hydrogenolyzed with H2 over Pd(OH)2 in ethanol to provide the carboxylic acid (XIII). The esterification of (XIII) with the chiral hydroxyester (XIV) by means of DCC and DMAP as before gives the expected triester (XV), which is treated first with Pd(PPh3)4 and then with TFA (elimination of the allyl, Boc and Tbdms protecting groups) to yield the open-chain precursor (XVI). Finally, this compound is submitted to macrocyclization by means of DPPA and DIEA to afford the target macrocyclic compound.
| 【1】 Ohmori, K.; et al.; Synthetic study on hapalosin, a cyclic depsipeptide possessing multidrug resistance reversing activities. Tetrahedron Lett 1996, 37, 20, 3467. |
| 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) | 50338 | (4S,5R)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IX) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (X) | 50339 | (4S,5R)-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (XI) | 50340 | benzyl (2S,3R)-3-hydroxy-2-methyldecanoate | C18H28O3 | 详情 | 详情 | |
| (XII) | 50337 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoic acid | C23H39NO5Si | 详情 | 详情 | |
| (XIII) | 50341 | benzyl (2S,3R)-3-[((3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoyl)oxy]-2-methyldecanoate | C41H65NO7Si | 详情 | 详情 | |
| (XIV) | 50342 | (2S,3R)-3-[((3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoyl)oxy]-2-methyldecanoic acid | C34H59NO7Si | 详情 | 详情 | |
| (XV) | 37830 | allyl (2S)-2-hydroxy-3-methylbutanoate | C8H14O3 | 详情 | 详情 | |
| (XVI) | 50343 | allyl (6S,7R,11R,12S,15S)-6-benzyl-7-[[tert-butyl(dimethyl)silyl]oxy]-11-heptyl-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C42H71NO9Si | 详情 | 详情 | |
| (XVII) | 50334 | (2S)-2-[((2S,3R)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid | C28H45NO7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(B)The N-protection of 4-(2-aminoethyl)phenol (I) with benzyl chloroformate gives the N-benzyloxycarbonyl derivative (II), which is condensed with 1-methyl-1-(trichloromethyl)ethanol (III) by means of NaOH in acetone yielding the phenoxyisobutyric acid (IV). The deprotection of the amino group of (IV) by hydrogenation over Pd/C affords the ethylamino derivative (V), which is reprotected with 9-fluorenylmethoxycarbonyl protecting group to provide carbamate (VI). The acid group of (VI) is then coupled to a Sasrin polystyrene resin giving the N-protected resin (VII), which is deprotected with piperidine affording resin (VIII) with a free amino group, which is condensed with heptanoic acid (A) by means of DIC and HOBT to give the amide (IX). The reduction of the carbonyl group amide (IX) with BH3/THF yields the heptylamine (X), which is condensed with 4-fluorophenyl isocyanate (XI) to afford the urea (XII). Finally, this compound is treated with trifluoroacetic acid to eliminate the polystyrene resin and isolate the target compound. Alternatively, the heptylamine (X) can also be obtained directly by reductocondensation of the free amino group of the resin (VIII) with heptanal (B) by means of NaBH3CN.
| 【1】 Brown, P.J.; et al.; Generation of secondary alkyl amines on solid support by borane reduction. Application to the parallel synthesis of PPAR ligands. Synthesis 1997, 7, 778. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 | |
| (B) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (A) | 35032 | heptanoic acid | 111-14-8 | C7H14O2 | 详情 | 详情 |
| (I) | 19988 | 4-(2-Aminoethyl)phenol; Tyramine | 51-67-2 | C8H11NO | 详情 | 详情 |
| (II) | 25974 | benzyl 4-hydroxyphenethylcarbamate | C16H17NO3 | 详情 | 详情 | |
| (III) | 25975 | 1,1,1-trichloro-2-methyl-2-propanol | 57-15-8 | C4H7Cl3O | 详情 | 详情 |
| (IV) | 25976 | 2-[4-(2-[[(benzyloxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid | C20H23NO5 | 详情 | 详情 | |
| (V) | 25977 | 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionic acid | C12H17NO3 | 详情 | 详情 | |
| (VI) | 25978 | 2-[4-(2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid | C27H27NO5 | 详情 | 详情 | |
| (VII) | 25978 | 2-[4-(2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid | C27H27NO5 | 详情 | 详情 | |
| (VIII) | 25977 | 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionic acid | C12H17NO3 | 详情 | 详情 | |
| (IX) | 25979 | 2-[4-[2-(heptanoylamino)ethyl]phenoxy]-2-methylpropionic acid | C19H29NO4 | 详情 | 详情 | |
| (X) | 25980 | 2-[4-[2-(heptylamino)ethyl]phenoxy]-2-methylpropionic acid | C19H31NO3 | 详情 | 详情 | |
| (XI) | 17977 | 1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate | 1195-45-5 | C7H4FNO | 详情 | 详情 |
| (XII) | 25981 | 2-(4-[2-[[(4-fluoroanilino)carbonyl](heptyl)amino]ethyl]phenoxy)-2-methylpropionic acid | C26H35FN2O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)The condensation of tert-butyl 4-iodobenzoate (I) with N-(3-butenyl)phthalimide (II) by means of palladium acetate and tri-p-tolylphosphine in TEA at 110 C gives 4-(4-phthalimido-1-butenyl)benzoic acid tert-butyl ester (III), which is hydrogenated with H2 over Pd/C in THF/ethanol yielding the corresponding butyl derivative (IV). The treatment of (IV) with hydrazine in refluxing ethanol affords 4-(4-aminobutyl)benzoic acid tert-butyl ester (V), which is cyclized with 2-sulfanylsuccinic acid (VI) and octanal (VII) in refluxing toluene to provide the thiazolidinone (VIII). The condensation of (VIII) with dibenzylamine (IX) by means of HOBT and EDC in dichloromethane, followed by chromatographic separation of the undesired (2R*,5S*)-isomer, yields the (2S*,5S*)-dibenzylamide (X). Finally, this compound is hydrolyzed with TFA in dichloromethane affording the target benzoic acid.
| 【1】 Willson, T.M.; Holmes, C.P.; Collins, J.L.; Lenhard, J.M. (Glaxo Group Ltd.); PPARgamma ligands. WO 0027832 . |
| 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) | 38028 | tert-butyl 4-iodobenzoate | C11H13IO2 | 详情 | 详情 | |
| (II) | 38029 | 2-(3-butenyl)-1H-isoindole-1,3(2H)-dione | 52898-32-5 | C12H11NO2 | 详情 | 详情 |
| (III) | 38030 | tert-butyl 4-[(E)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-butenyl]benzoate | C23H23NO4 | 详情 | 详情 | |
| (IV) | 38031 | tert-butyl 4-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]benzoate | C23H25NO4 | 详情 | 详情 | |
| (V) | 38032 | tert-butyl 4-(4-aminobutyl)benzoate | C15H23NO2 | 详情 | 详情 | |
| (VI) | 38033 | 2-sulfanylsuccinic acid | 70-49-5 | C4H6O4S | 详情 | 详情 |
| (VII) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (VIII) | 38034 | 2-((2S,5R)-3-[4-[4-(tert-butoxycarbonyl)phenyl]butyl]-2-heptyl-4-oxo-1,3-thiazolidin-5-yl)acetic acid | C27H41NO5S | 详情 | 详情 | |
| (IX) | 12361 | N,N-Dibenzylamine; Dibenzylamine; N-Benzyl(phenyl)methanamine | 103-49-1 | C14H15N | 详情 | 详情 |
| (X) | 38035 | tert-butyl 4-(4-[(2S,5R)-5-[2-(dibenzylamino)-2-oxoethyl]-2-heptyl-4-oxo-1,3-thiazolidin-3-yl]butyl)benzoate | C41H54N2O4S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Synthesis of intermediate (V): The condensation of octanal (II) with the trimethylsilyl ether of the enol form of methyl isobutyrate (I) by means of the chiral oxazaborolidinone catalyst (III) in THF gives 3(S)-hydroxy-2,2-dimethyldecanoic acid methyl ester (IV), which is hydrolyzed with NaOH in methanol/water to yield the acid intermediate (V).
| 【1】 Yokokawa, F.; et al.; Total synthesis of amamistatin A, an antiproliferative linear peptide from an actinomycete. Tetrahedron 2000, 56, 19, 3027. |
| 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) | 42016 | 1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal | 31469-15-5 | C8H18O2Si | 详情 | 详情 |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 42017 | (5R)-5-isopropyl-1-[(4-methylphenyl)sulfonyl]-1,2-azaborolidin-4-one | C13H18BNO3S | 详情 | 详情 | |
| (IV) | 42018 | methyl (3S)-3-hydroxy-2,2-dimethyldecanoate | C13H26O3 | 详情 | 详情 | |
| (V) | 42019 | (3S)-3-hydroxy-2,2-dimethyldecanoic acid | C12H24O3 | 详情 | 详情 |