|
【结 构 式】 
|
【分子编号】35032 【品名】heptanoic acid 【CA登记号】111-14-8 |
【 分 子 式 】C7H14O2 【 分 子 量 】130.18696 【元素组成】C 64.58% H 10.84% O 24.58% |
合成路线1
该中间体在本合成路线中的序号：(A)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2
该中间体在本合成路线中的序号：(III)Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II) (1-3). Ketoester (IV) was prepared by treatment of n-heptanoic acid (III) with 1,1'-carbonyldiimidazole and further condensation with ethyl magnesium malonate (1). Subsequent conjugate addition of (II) to ketoester (IV) using DBU provided adduct (V). Reduction of the nitro group of (V), with concomitant ring closure formed the cyclic imine (VI), which was reduced with NaBH3CN to yield the pyrrolidine (VII) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VIII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VIII) with N,N-dibutyl bromoacetamide (IX) furnished (X). Basic hydrolysis of the ester group of (X) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (XI) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
| 【1】 Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991. |
| 【2】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
| 【3】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIIa) | 35037 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (VIIIb) | 35038 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (Xa),(XI) | 35039 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-hexyl-3-pyrrolidinecarboxylate | C29H46N2O5 | 详情 | 详情 | |
| (Xb) | 35040 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-hexyl-3-pyrrolidinecarboxylate | C29H46N2O5 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35032 | heptanoic acid | 111-14-8 | C7H14O2 | 详情 | 详情 |
| (IV) | 35033 | methyl 3-oxononanoate | C10H18O3 | 详情 | 详情 | |
| (V) | 35034 | methyl 2-[1-(1,3-benzodioxol-5-yl)-2-nitroethyl]-3-oxononanoate | C19H25NO7 | 详情 | 详情 | |
| (VI) | 35035 | methyl 3-(1,3-benzodioxol-5-yl)-5-hexyl-3,4-dihydro-2H-pyrrole-4-carboxylate | C19H25NO4 | 详情 | 详情 | |
| (VII) | 35036 | methyl 4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (IX) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：4-Bromothiophenol (I) was alkylated with tert-butyl bromoisobutyrate (II) to give the bromoester (III). Heck reaction of (III) with vinylphthalimide (IV) produced adduct (V), which was hydrogenated in the presence of Wilkinson's catalyst to yield the arylethyl phthalimide (VI). Following phthalimide deprotection with hydrazine, the resulting primary amine (VII) was coupled with heptanoic acid using diisopropyl carbodiimide and hydroxybenzotriazole affording amide (VIII). Borane reduction of (VIII) furnished the secondary amine (IX), which was condensed with 2,4-difluorophenyl isocyanate (X) to give urea (XI). Finally, trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (IX) provided the title carboxylic acid.
| 【1】 Brown, P.J.; Winegar, D.A.; Plunket, K.D.; et al.; A ureido thiosobutyric acid (GW9578) is a subtype selective PPARalpha agonist with potent lipid lowering activity. J Med Chem 1999, 42, 19, 3785. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 35032 | heptanoic acid | 111-14-8 | C7H14O2 | 详情 | 详情 | |
| (I) | 29626 | 4-bromophenylhydrosulfide; 4-bromobenzenethiol | 106-53-6 | C6H5BrS | 详情 | 详情 |
| (II) | 34947 | tert-butyl 2-bromo-2-methylpropanoate | 23877-12-5 | C8H15BrO2 | 详情 | 详情 |
| (III) | 34948 | tert-butyl 2-[(4-bromophenyl)sulfanyl]-2-methylpropanoate | C14H19BrO2S | 详情 | 详情 | |
| (IV) | 32749 | 2-vinyl-1H-isoindole-1,3(2H)-dione | 3485-84-5 | C10H7NO2 | 详情 | 详情 |
| (V) | 34949 | tert-butyl 2-([4-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]phenyl]sulfanyl)-2-methylpropanoate | C24H25NO4S | 详情 | 详情 | |
| (VI) | 34950 | tert-butyl 2-([4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]phenyl]sulfanyl)-2-methylpropanoate | C24H27NO4S | 详情 | 详情 | |
| (VII) | 34951 | tert-butyl 2-[[4-(2-aminoethyl)phenyl]sulfanyl]-2-methylpropanoate | C16H25NO2S | 详情 | 详情 | |
| (VIII) | 34952 | tert-butyl 2-([4-[2-(heptanoylamino)ethyl]phenyl]sulfanyl)-2-methylpropanoate | C23H37NO3S | 详情 | 详情 | |
| (IX) | 34953 | tert-butyl 2-([4-[2-(heptylamino)ethyl]phenyl]sulfanyl)-2-methylpropanoate | C23H39NO2S | 详情 | 详情 | |
| (X) | 23255 | 2,4-difluorophenyl isocyanate; 2,4-difluoro-1-isocyanatobenzene | 59025-55-7 | C7H3F2NO | 详情 | 详情 |
| (XI) | 34954 | tert-butyl 2-[(4-[2-[[(2,4-difluoroanilino)carbonyl](heptyl)amino]ethyl]phenyl)sulfanyl]-2-methylpropanoate | C30H42F2N2O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The reaction of heptanoic acid (I) with H3PO3, PCl3 and benzenesulfonic acid at 65 C, followed by a treatment in refluxing water gives the target diphosphonic acid.
