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【结 构 式】 
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【分子编号】25691 【品名】3-(4-hydroxyphenyl)propionic acid 【CA登记号】501-97-3 |
【 分 子 式 】C9H10O3 【 分 子 量 】166.1766 【元素组成】C 65.05% H 6.07% O 28.88% |
合成路线1
该中间体在本合成路线中的序号：(I)The esterification of 3-(4-hydroxyphenyl)propionic acid (I) with methanol and H2SO4 gives the corresponding methyl ester (II), which by condensation with epichlorohydrin (III) by means of K2CO3 in refluxing acetone affords methyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate (IV). Finally, the epoxide ring is opened by reaction with isopropylamine (V) in refluxing methanol, and a final treatment with ethereal HCl is performed.
| 【1】 Erhardt, P.W.; Woo, C.M.; Anderson, W.G.; Gorczynski, R.J.; Ultra-short-acting beta-adrenergic receptor blocking agents. 2. (Aryloxy)propanolamines containing esters on the aryl function. J Med Chem 1982, 25, 12, 1408. |
| 【2】 Erhardt, P.W.; Bogman, R.J.; O'Donnell, J.P. (Baxter International Inc.); Method for treatment or prophylaxis of cardiac disorders. EP 0053435; EP 0065542; US 4387103; WO 8201869 . |
| 【3】 Serradell, M.N.; Castaner, J.; Badia, A.; Esmolol Hydrochloride. Drugs Fut 1984, 9, 3, 183. |
| 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) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
| (II) | 30341 | methyl 3-(4-hydroxyphenyl)propanoate; 4-Hydroxyphenylpropionic acid methyl ester; 3-(4-Hydroxyphenyl)propionic acid methyl ester | 5597-50-2 | C10H12O3 | 详情 | 详情 |
| (III) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (IV) | 30342 | methyl 3-[4-(2-oxiranylmethoxy)phenyl]propanoate | 81147-94-6 | C13H16O4 | 详情 | 详情 |
| (V) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Reaction of 3-(4-hydroxyphenyl)propionic acid (I) with the chiral dioxolanylmethyl chloride (II) afforded the corresponding dioxolanylmethyl ester (III). The phenolic hydroxyl group of (III) was then alkylated with (S)-bromohydrin (IV) to produce the intermediate (V).
| 【1】 Iguchi, S.; Kawamura, M.; Miyamoto, T. (Ono Pharmaceutical Co., Ltd.); Novel esters of phenylalkanoic acid. EP 0397031; JP 1991072475; JP 1994073044; US 5013734 . |
| 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) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
| (II) | 45778 | (4S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane | 60456-22-6 | C6H11ClO2 | 详情 | 详情 |
| (III) | 48332 | [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-(4-hydroxyphenyl)propanoate | C15H20O5 | 详情 | 详情 | |
| (IV) | 48333 | (2S)-2-(bromomethyl)oxirane | C3H5BrO | 详情 | 详情 | |
| (V) | 48334 | [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(2S)oxiranylmethoxy]phenyl]propanoate | C18H24O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Coupling of (3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (I) with N-Boc-L-valine (II) using benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) provided amide (III). After deprotection of the Boc group of (III) with trifluoroacetic acid, the resulting valyl amide (IV) was reduced with BH3-Me2S to afford diamine (V). Finally, coupling of (V) with 3-(4-hydroxyphenyl)propionic acid (VI) in the presence of BOP yielded the target compound.
| 【1】 Thomas, J.B.; Fall, M.J.; Cooper, J.B.; Rothman, R.B.; Mascarella, S.W.; Xu, H.; Partilla, J.S.; Dersch, C.M.; McCullough, K.B.; Cantrell, B.E.; Zimmerman, D.M.; Carroll, F.I.; Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine. J Med Chem 1998, 41, 26, 5188. |
| 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) | 16620 | 3-[(3R,4R)-3,4-dimethylhexahydro-4-pyridinyl]phenol | 119193-19-0 | C13H19NO | 详情 | 详情 |
| (II) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (III) | 25688 | tert-butyl (1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidinyl]carbonyl]-2-methylpropylcarbamate | C23H36N2O4 | 详情 | 详情 | |
| (IV) | 25689 | (2S)-2-amino-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidinyl]-3-methyl-1-butanone | C18H28N2O2 | 详情 | 详情 | |
| (V) | 25690 | 3-[(3R,4R)-1-[(2S)-2-amino-3-methylbutyl]-3,4-dimethylpiperidinyl]phenol | C18H30N2O | 详情 | 详情 | |
| (VI) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIX)Azepinone (X) was obtained by cyclization of Boc-L-lysine (IX) in the presence of NaHCO3 and BOP reagent. Subsequent alkylation of the lactam nitrogen of (X) with benzyl bromoacetate (XI) afforded (XII). After Boc deprotection of (XII) with trifluoroacetic acid, coupling with Boc-L-alanine (XIII) gave dipeptide (XIV). This was subjected to a further deprotection and coupling sequence with Boc-L-tryptophan (XV) to give tripeptide (XVI), and then with Boc-L-glutamine (XVII), yielding (XVIII). Acid deprotection of the Boc group of (XVIII), followed by coupling with p-hydroxyphenylpropionic acid (XIX) provided the peptide amide (XX).
| 【1】 Cristau, M.; et al.; Synthesis and biological evaluation of bombesin constrained analogues. J Med Chem 2000, 43, 12, 2356. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 42809 | (2S)-6-amino-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C11H22N2O4 | 详情 | 详情 | |
| (X) | 42810 | L-(-)-N-alpha-Boc-amino-epsilon-caprolactam; tert-butyl (3S)-2-oxoazepanylcarbamate | 76944-95-1 | C11H20N2O3 | 详情 | 详情 |
| (XI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XII) | 42811 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-2-oxoazepanyl]acetate | n/a | C20H28N2O5 | 详情 | 详情 |
| (XIII) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (XIV) | 42812 | benzyl 2-[(3S)-3-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-2-oxoazepanyl]acetate | C23H33N3O6 | 详情 | 详情 | |
| (XV) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (XVI) | 42813 | benzyl 2-[(3S)-3-[((2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl)amino]-2-oxoazepanyl]acetate | C34H43N5O7 | 详情 | 详情 | |
| (XVII) | 31820 | (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13726-85-7 | C10H18N2O5 | 详情 | 详情 |
| (XVIII) | 42814 | benzyl 2-((3S)-3-[[(2S,5S,8S)-8-(3-amino-3-oxopropyl)-5-(1H-indol-3-ylmethyl)-2,12,12-trimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-2-oxoazepanyl)acetate | C39H51N7O9 | 详情 | 详情 | |
| (XIX) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
| (XX) | 42815 | benzyl 2-[(3S)-3-[((2S)-2-[[(2S)-2-[((2S)-5-amino-2-[[3-(4-hydroxyphenyl)propanoyl]amino]-5-oxopentanoyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl)amino]-2-oxoazepanyl]acetate | C43H51N7O9 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Esterification of 3-(4-hydroxyphenyl)propionic acid (I), followed by alkylation of the phenolic hydroxyl, provided methyl 3-(4-benzyloxyphenyl)propionate (II), which was hydrolyzed to the corresponding carboxylic acid (III) by means of LiOH. Coupling of carboxylic acid (III) with the chiral auxiliary (S)-4-benzyl-2-oxazolidinone (IV) gave the oxazolide (V), which was subjected to diastereoselective alkylation with tert-butyl bromoacetate (VI), yielding (VII). Subsequent removal of the chiral auxiliary group of (VII) using lithium hydroperoxide afforded the (R)-acid (VIII). Alkylation of the dianion of acid (VIII) with allyl bromide (IX) and further epimerization in the presence of LDA and Et2AlCl furnished the anti-dialkylated succinate (X). The carboxyl group of (X) was then alkylated using benzyl bromide and DBU to produce the corresponding benzyl ester (XI). Olefin (XI) hydroboration followed by oxidative work-up gave rise to the primary alcohol (XII). This was acylated with 4-nitrophenyl chloroformate (XIII) to provide the activated carbonate (XIV).
| 【1】 Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351. |
| 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) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
| (II) | 53167 | methyl 3-[4-(benzyloxy)phenyl]propanoate | n/a | C17H18O3 | 详情 | 详情 |
| (III) | 53168 | 3-[4-(benzyloxy)phenyl]propanoic acid | 50463-48-4 | C16H16O3 | 详情 | 详情 |
| (IV) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (V) | 53169 | (4S)-4-benzyl-3-{3-[4-(benzyloxy)phenyl]propanoyl}-1,3-oxazolidin-2-one | n/a | C26H25NO4 | 详情 | 详情 |
| (VI) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VII) | 53170 | tert-butyl (3R)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[4-(benzyloxy)benzyl]-4-oxobutanoate | n/a | C32H35NO6 | 详情 | 详情 |
| (VIII) | 53171 | (2R)-2-[4-(benzyloxy)benzyl]-4-(tert-butoxy)-4-oxobutanoic acid | n/a | C22H26O5 | 详情 | 详情 |
| (IX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (X) | 53172 | (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(tert-butoxycarbonyl)-5-hexenoic acid | n/a | C25H30O5 | 详情 | 详情 |
| (XI) | 53173 | 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-[4-(benzyloxy)benzyl]butanedioate | n/a | C32H36O5 | 详情 | 详情 |
| (XII) | 53174 | 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-hydroxypropyl)butanedioate | n/a | C32H38O6 | 详情 | 详情 |
| (XIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIV) | 53175 | 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate | n/a | C39H41NO10 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)4-Hydroxybenzaldehyde (I) was acetylated using Ac2O in pyridine. The resultant 4-(acetyloxy)benzaldehyde (II) was then subjected to a Wadsworth-Emmons condensation with trimethyl phosphonoacetate to afford methyl 4-(acetyloxy)cinnamate (III). After catalytic double bond hydrogenation, the resultant saturated ester (IV) was reduced by LiAlH4 to furnish 3-(4-hydroxyphenyl)-1-propanol (V) –alternatively (V) can be obtained by reduction with LiAlH4 of the propionic acid derivative (VI) (isolated from Asplenium onopteris)-. Methylation of the phenolic hydroxyl group of (V) with iodomethane and K2CO3 in acetone gave the methyl ether (VII). Then, oxidation of alcohol (VII) to 3-(4-methoxyphenyl)propanal (VIII) was accomplished by means of pyridinium chlorochromate.
| 【1】 Gonzalez, A.G.; et al.; Synthesis and antiproliferative activity of a new compound containing an alpha-methylene-gamma-lactone group. J Med Chem 2002, 45, 12, 2358. |
| 【2】 Bermejo Barrera, J.; Hernandez Silva, M.; Alvarez de Mon, M.; Pivel Ranieri, J.P. (CSIC (Consejo Superior de Investigaciones Cientificas)); Derivs. of p-hydroxy phenyl propionic acid as antiproliferative agents. ES 2160093; WO 0172733 . |
| 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) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 56432 | 4-Acetoxybenzaldehyde; p-Acetoxybenzaldehyde; p-Formylphenyl acetate | 878-00-2 | C9H8O3 | 详情 | 详情 |
| (III) | 56433 | methyl (E)-3-[4-(acetyloxy)phenyl]-2-propenoate | C12H12O4 | 详情 | 详情 | |
| (IV) | 56434 | methyl 3-[4-(acetyloxy)phenyl]propanoate | C12H14O4 | 详情 | 详情 | |
| (V) | 56435 | 3-(4-Hydroxyphenyl)-1-propanol | C9H12O2 | 详情 | 详情 | |
| (VI) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
| (VII) | 56436 | 3-(p-Methoxyphenyl)propanol; 3-(4-Methoxyphenyl)propanol | 5406-18-8 | C10H14O2 | 详情 | 详情 |
| (VIII) | 56437 | 3-(4-methoxyphenyl)propanal | C10H12O2 | 详情 | 详情 |