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【结 构 式】 
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【分子编号】16230 【品名】resorcylic acid; 3,5-dihydroxybenzoic acid 【CA登记号】99-10-5 |
【 分 子 式 】C7H6O4 【 分 子 量 】154.12224 【元素组成】C 54.55% H 3.92% O 41.52% |
合成路线1
该中间体在本合成路线中的序号：(I)3,5-Dihydroxybenzoic acid (I) was carboxylated under CO2-pressure in aqueous KOH solution. Acidification in situ directly precipitated 2,6-dihydroxyterephthalic acid (II), which was per-ethylated with diethyl sulfate in acetone to afford diethyl 2,6-diethoxyterephthalate (III). The sterically more hindered 1-ester group of di-ester (III) underwent Lossen rearrangement upon treatment with hydroxylamine sulfate in polyphosphoric acid. The resulting ethyl 4-amino-3,5-diethoxybenzoate (IV) was condensed with 2,5-dimethoxytetrahydrofuran in hexane under acetic acid catalysis and water removal yielding ethyl 3,5-diethoxy-4-(pyrrol-1-yl)benzoate (V), which was reduced with diisobutylaluminum hydride in toluene. The intermediate benzyl alcohol was oxidized in situ with activated manganese(IV) oxide to yield 3,5-diethoxy-4-(pyrrol-1-yl)benzaldehyde (VI). The following steps achieved the construction of the 2,4-diaminopyrimidine moiety of the title drug and reflect well established methodology. The benzaldehyde (VI) was condensed with 3-morpholinopropionitrile under potassium tert-butylate catalysis in N,N-dimethylformamide. The crude acrylonitrile intermediate was treated with aniline hydrochloride in 2-propanol in order to provide a better leaving group for the final cyclization, which was carried out by heating with an excess of guanidine in methyl sulfoxide.
| 【1】 Stockel, K.; Kompis, I.; Then, R.L.; Stephan-Guldner, M.; Hartman, P.G.; Epiroprim. Drugs Fut 1994, 19, 5, 446. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 | |
| (I) | 16230 | resorcylic acid; 3,5-dihydroxybenzoic acid | 99-10-5 | C7H6O4 | 详情 | 详情 |
| (II) | 16231 | 2,6-dihydroxyterephthalic acid | C8H6O6 | 详情 | 详情 | |
| (III) | 16232 | diethyl 2,6-diethoxyterephthalate | C16H22O6 | 详情 | 详情 | |
| (IV) | 16233 | ethyl 4-amino-3,5-diethoxybenzoate | C13H19NO4 | 详情 | 详情 | |
| (V) | 16234 | ethyl 3,5-diethoxy-4-(1H-pyrrol-1-yl)benzoate | C17H21NO4 | 详情 | 详情 | |
| (VI) | 16235 | 3,5-diethoxy-4-(1H-pyrrol-1-yl)benzaldehyde | C15H17NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 3,5-dihydroxybenzoic acid (I) with Bn-Br, K2CO3 and 18-crown-6 in refluxing acetone gives 3,5-bis(benzyloxy)benzoic acid (II), which is reduced with LiAlH4 in ethyl ether to yield the corresponding benzyl alcohol (III). The reaction of (III) with PBr3 in ethyl ether/pyridine affords the benzyl bromide (IV), which is treated with triisopropyl phosphite (V) at 140-150 C to provide the phosphonate (VI). The condensation of (VI) with 4-benzyloxybenzaldehyde (VII) by means of NaOMe in DMF gives (E)-3,4',5-tris(benzyloxy)stilbene (VIII), which is finally debenzylated by treatment with BBr3 in dichloromethane. Alternatively, the synthesis of the target product can be performed by first condensation of 3,5-dimethoxybenzoyl chloride (IX) with 4-acetoxystyrene (X) by means of palladium(II) acetate and Et3N in p-xylene to yield (E)-4-acetoxy-3',5'-dimethoxystilbene (XI), whose acetoxy group is subjected to saponification either with NaOMe or with K2CO3 in THF/H2O/MeOH and whose methoxy groups are cleaved by means of BBr3 in CH2Cl2.
| 【1】 Meredith, E.; Andrus, M. (Brigham Young University); Synthesis of resveratrol. WO 0160774 . |
| 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) | 16230 | resorcylic acid; 3,5-dihydroxybenzoic acid | 99-10-5 | C7H6O4 | 详情 | 详情 |
| (II) | 25157 | 3,5-bis(benzyloxy)benzoic acid | 28917-43-3 | C21H18O4 | 详情 | 详情 |
| (III) | 50091 | [3,5-bis(benzyloxy)phenyl]methanol | C21H20O3 | 详情 | 详情 | |
| (IV) | 50092 | 1,3-bis(benzyloxy)-5-(bromomethyl)benzene; benzyl 3-(benzyloxy)-5-(bromomethyl)phenyl ether | C21H19BrO2 | 详情 | 详情 | |
| (V) | 32162 | Triisopropyl phosphite | 116-17-6 | C9H21O3P | 详情 | 详情 |
| (VI) | 50093 | diisopropyl 3,5-bis(benzyloxy)benzylphosphonate | C27H33O5P | 详情 | 详情 | |
| (VII) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (VIII) | 50094 | benzyl 3-(benzyloxy)-5-[(E)-2-[4-(benzyloxy)phenyl]ethenyl]phenyl ether; 1,3-bis(benzyloxy)-5-[(E)-2-[4-(benzyloxy)phenyl]ethenyl]benzene | C35H30O3 | 详情 | 详情 | |
| (IX) | 50095 | 3,5-Dimethoxybenzoyl chloride | 17213-57-9 | C9H9ClO3 | 详情 | 详情 |
| (X) | 27297 | 4-vinylphenyl acetate | 2628-16-2 | C10H10O2 | 详情 | 详情 |
| (XI) | 50096 | 4-[(E)-2-(3,5-dimethoxyphenyl)ethenyl]phenyl acetate | C18H18O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)The condensation of 1,3-diamino-2-propanol (XIII) with carbon disulfide produced 5-hydroxytetrahydropyrimidine-2-thione (XIV). Alkylation of thione (XIV) with iodomethane gave the cyclic S-methylisothiourea (XV), which was further protected as the N-Boc derivative (XVI). 3-Amino-5-hydroxybenzoic acid (XVIII) was prepared from 3,5-dihydroxybenzoic acid (XVII) by treatment with ammonia and ammonium chloride. Coupling of thioether (XVI) with amino acid (XVIII) in hot DMA furnished the guanidine adduct (XIX). This was then condensed with the intermediate (XII) via activation as the mixed anhydride with isobutyl chloroformate, producing amide (XX). Acid cleavage of the Boc group of (XX) gave (XXI). The ethyl ester of (XXI) was then hydrolyzed using NaOH in aqueous dioxan. The title compound was finally isolated as the hydrochloride salt after lyophilization from an HCl solution.
| 【2】 Ruminski, P.G.; Rogers, T.E. (Pharmacia Corp.); Meta-azacyclic amino benzoic acid cpds. and derivs. thereof being integrin antagonists. EP 1060164; WO 9944994 . |
| 【3】 Gordon, G.B.; Ruminski, P.G.; Nickols, G.A.; Westlin, W.F.; Rogers, T.E.; Cunningham, J. (Pharmacia Corp.); Use of integrin antagonist and a chemotherapeutic agent in the treatment of neoplasia. WO 0051686 . |
| 【1】 Ruminski, P.G.; Clare, M.; Collins, P.W.; Desai, B.N.; Lindmark, R.J.; Rico, J.G.; Rogers, T.E.; Russell, M.A. (Pharmacia Corp.); Meta-guanidine, urea, thiourea or azacyclic amino benzoic acid derivs. as integrin antagonists. EP 0850221; JP 1999510814; US 6013651; WO 9708145 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 47974 | ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C13H16Cl2N2O4 | 详情 | 详情 | |
| (XIII) | 47975 | 1,3-diamino-2-propanol | 616-29-5 | C3H10N2O | 详情 | 详情 |
| (XIV) | 47976 | 5-hydroxytetrahydro-2(1H)-pyrimidinethione | C4H8N2OS | 详情 | 详情 | |
| (XV) | 47977 | 2-(methylsulfanyl)-1,4,5,6-tetrahydro-5-pyrimidinol | C5H10N2OS | 详情 | 详情 | |
| (XVI) | 47978 | tert-butyl 5-hydroxy-2-(methylsulfanyl)-5,6-dihydro-1(4H)-pyrimidinecarboxylate | C10H18N2O3S | 详情 | 详情 | |
| (XVII) | 16230 | resorcylic acid; 3,5-dihydroxybenzoic acid | 99-10-5 | C7H6O4 | 详情 | 详情 |
| (XVIII) | 47979 | 3-amino-5-hydroxybenzoic acid | C7H7NO3 | 详情 | 详情 | |
| (XIX) | 47980 | 3-[[1-(tert-butoxycarbonyl)-5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl]amino]-5-hydroxybenzoic acid | C16H21N3O6 | 详情 | 详情 | |
| (XX) | 47981 | tert-butyl 2-(3-[[(2-[[(1S)-1-(3,5-dichloro-2-hydroxyphenyl)-3-ethoxy-3-oxopropyl]amino]-2-oxoethyl)amino]carbonyl]-5-hydroxyanilino)-5-hydroxy-5,6-dihydro-1(4H)-pyrimidinecarboxylate | C29H35Cl2N5O9 | 详情 | 详情 | |
| (XXI) | 47982 | ethyl (3S)-3-(3,5-dichloro-2-hydroxyphenyl)-3-[[2-([3-hydroxy-5-[(5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl)amino]benzoyl]amino)acetyl]amino]propanoate | C24H27Cl2N5O7 | 详情 | 详情 |