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【结 构 式】 
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【分子编号】32744 【品名】4-methoxyphenol 【CA登记号】150-76-5 |
【 分 子 式 】C7H8O2 【 分 子 量 】124.13932 【元素组成】C 67.73% H 6.5% O 25.78% |
合成路线1
该中间体在本合成路线中的序号：(B)The reaction of methyl N-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (I) with phenylmagnesium bromide (A) gives methyl 1-methyl-4-phenylpiperidine-3-carboxylate (II), which is reduced with LiAlH4 yielding 1-methyl-3-hydroxymethyl-4-phenylpiperidine (III), which, in turn is resolved into its optical isomers. The alcohol (III) is esterified with methanesulfonyl chloride in pyridine affording 3-(methansulfonyloxymethyl)-1-methyl-4-phenylpiperidine (IV), which is finally condensed with p-methoxyphenol (B) by means of sodium methoxide in refluxing methanol.
| 【1】 Christensen, J.A.; Squires, R.F.; 4-Phenylpiperidine compounds. DE 2404113; FR 2215233; GB 1422263; JP 49101385; JP 58174363; US 3912743 . |
| 【2】 Chatterjee, S.S.; Femoxetine. Drugs Fut 1977, 2, 5, 309. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (B) | 32744 | 4-methoxyphenol | 150-76-5 | C7H8O2 | 详情 | 详情 |
| (I) | 38648 | methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
| (II) | 40118 | methyl (3R,4S)-1-methyl-4-phenyl-3-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (III) | 40119 | [(3R,4S)-1-methyl-4-phenylpiperidinyl]methanol | C13H19NO | 详情 | 详情 | |
| (IV) | 40120 | (3R,4S)-1-methyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-4-phenylpiperidine | C16H25NOS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)By cleavage of the 7-methoxy-9-oxoxanthene-2-carboxylic acid (I) with AlCl3 in xylene to give 7-hydroxy-9-oxoxanthene-2-carboxylic acid (II), which is then esterified with ethanol and anhydrous HCl to the corresponding ethyl ester (III). This product is treated first with ethylene oxide (A) in DMF, and finally hydrolyzed with NaOH in ethanol-water. The condensation of 2-chloro-5-nitrobenzoic acid (IV) with 4-methoxyphenol (V) by means of K2CO3, Cu and Cu2I2 in n-pentanol gives 2-(4-methoxyphenoxy)-5-nitrobenzoic acid (VI), which is cyclized with concentrated H2SO4 to 7-methoxy-2-nitroxanthone (VII). The reduction of the nitro group of (VII) with SnCl2 in concentrated HCl yields 7-methoxy-2-aminoxanthone (VIII). Finally, this product is treated first with NaNO2 - HCl, then with NaCN and finally hydrolyzed with H2SO4 to afford 7-methoxy-9-oxoxanthene-2-carboxylic acid.
| 【1】 Castaner, J.; Blancafort, P.; AH 7725. Drugs Fut 1976, 1, 7, 313. |
| 【2】 Bays, D.E.; Xanthone derivatives.. DE 2058295; FR 2073425; GB 1312620; US 3706768 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (I) | 40469 | 7-methoxy-9-oxo-9H-xanthene-2-carboxylic acid | C15H10O5 | 详情 | 详情 | |
| (II) | 40470 | 7-hydroxy-9-oxo-9H-xanthene-2-carboxylic acid | C14H8O5 | 详情 | 详情 | |
| (III) | 40471 | ethyl 7-hydroxy-9-oxo-9H-xanthene-2-carboxylate | C16H12O5 | 详情 | 详情 | |
| (IV) | 10198 | 4-Chlorophenyl thiocyanate | 3226-37-7 | C7H4ClNS | 详情 | 详情 |
| (V) | 32744 | 4-methoxyphenol | 150-76-5 | C7H8O2 | 详情 | 详情 |
| (VI) | 40466 | 2-(4-methoxyphenoxy)-5-nitrobenzoic acid | C14H11NO6 | 详情 | 详情 | |
| (VII) | 40467 | 2-methoxy-7-nitro-9H-xanthen-9-one | C14H9NO5 | 详情 | 详情 | |
| (VIII) | 40468 | 2-amino-7-methoxy-9H-xanthen-9-one | C14H11NO3 | 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 reaction of 4-methoxyphenol (I) with POCl3 and triethylamine in ethyl ether gives the dichlorophosphate (II), which is condensed with alanine methyl ester (III) by means of triethylamine in dichloromethane yielding the amide (IV). The condensation of (IV) with azidothymidine (V) by means of N-methylimidazole (NMI) in THF affords the 5'-phosphate derivative (VI), which is finally treated with methyl hypobromite (Br2 in methanol).
| 【1】 Uckun, F.M.; Venkatachalam, T.; D'Cruz, O. (Parker Hughes Institute); AZT derivs. exhibiting spermicidal and anti-viral activity. WO 9948902 . |
| 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) | 32744 | 4-methoxyphenol | 150-76-5 | C7H8O2 | 详情 | 详情 |
| (II) | 32741 | Dichlorophosphoric acid 4-methoxyphenyl ester | C7H7Cl2O3P | 详情 | 详情 | |
| (III) | 25315 | methyl 2-aminopropanoate; Alanine, methyl ester | 7625-53-8 | C4H9NO2 | 详情 | 详情 |
| (IV) | 32742 | methyl 2-[[chloro(4-methoxyphenoxy)phosphoryl]amino]propanoate | C11H15ClNO5P | 详情 | 详情 | |
| (V) | 25317 | 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | 101703-35-9 | C10H13N5O4 | 详情 | 详情 |
| (VI) | 32743 | methyl 2-[[([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)(4-methoxyphenoxy)phosphoryl]amino]propanoate | C21H27N6O9P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The reaction of 1,3-dibromopropane (I) with triethyl phosphite (II) at 160 C gives triethyl 3-bromopropylphosphonate (III), which is treated with Tms-Br and water to yield the corresponding phosphonic acid (IV). The reaction of (IV) with PCl3 in refluxing chloroform affords the acyl chloride (V), which is treated with 4-methoxyphenol (VI) and pyridine to provide the expected 4-methoxyphenyl diester (VII). The reaction of (VII) with N,O-bis(tert-butoxycarbonyl)hydroxylamine (VIII) by means of NaH in DMF gives the fully protected hydroxyamino derivative (IX), which by treatment with TFA in dichloromethane yields 3-(hydroxyamino)propylphosphonic acid 4-methoxyphenyl diester (X). Finally, this compound is acylated with Ac-Cl and TEA in ethyl ether to afford the target N-acetylhydroxyamino compound.
| 【1】 Reichenberg, A.; et al.; Diaryl ester prodrugs of FR900098 with improved in vivo antimalarial activity. Bioorg Med Chem Lett 2001, 11, 6, 833. |
| 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) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (II) | 15487 | triethyl phosphite | 122-52-1 | C6H15O3P | 详情 | 详情 |
| (III) | 39080 | diethyl 3-bromopropylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (IV) | 39105 | 3-bromopropylphosphonic acid | 1190-09-6 | C3H8BrO3P | 详情 | 详情 |
| (V) | 49412 | 3-bromopropylphosphonic dichloride | C3H6BrCl2OP | 详情 | 详情 | |
| (VI) | 32744 | 4-methoxyphenol | 150-76-5 | C7H8O2 | 详情 | 详情 |
| (VII) | 49413 | bis(4-methoxyphenyl) 3-bromopropylphosphonate | C17H20BrO5P | 详情 | 详情 | |
| (VIII) | 34722 | 2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane | C10H19NO5 | 详情 | 详情 | |
| (IX) | 49414 | 5-(tert-butoxycarbonyl)-1,1-bis(4-methoxyphenoxy)-9,9-dimethyl-1,7-dioxo-6,8-dioxa-5-aza-1lambda(5)-phosphadecane | C27H38NO10P | 详情 | 详情 | |
| (X) | 49415 | bis(4-methoxyphenyl) 3-(hydroxyamino)propylphosphonate | C17H22NO6P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Protection of 4-methoxyphenol (I) with methyl chloroformate in the presence of pyridine affords the carbonate ester (II), which is condensed with dichloromethyl methyl ether and TiCl4 to yield alpha-chloro ether (III). Acidic hydrolysis of (III) with HCl furnishes aldehyde (IV), which is converted into the sodium phenoxide (V) by methanolysis of the carbonate ester (IV). Subsequent alkylation of (V) with p-methoxybenzyl bromide (VI) produces the p-methoxybenzyl ether (VII), which is condensed with 3-morpholinopropionitrile (VIII) employing a catalytic amount of NaOMe to give the morpholino acrylonitrile (IX). After conversion of (IX) to the 3-anilino acrylonitrile (X) upon heating with aniline hydrochloride, condensation with guanidine (XI) produces the diaminopyrimidine (XII). The p-methoxybenzyl group of (XII) is then cleaved by treatment with p-toluenesulfonic acid in MeOH, producing phenol (XIII). The sodium salt generated from phenol (XIII) and NaOEt is then alkylated with ethyl 5-bromopentanoate (XIV) to furnish ether (XV). Finally, alkaline hydrolysis of the ethyl ester group of (XV) leads to the title compound.
| 【1】 Rosowsky, A.; Queener, S.F.; Forsch, R.A.; Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species selectivity. J Med Chem 2002, 45, 1, 233. |
| 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) | 32744 | 4-methoxyphenol | 150-76-5 | C7H8O2 | 详情 | 详情 |
| (II) | 59058 | 4-methoxyphenyl methyl carbonate | C9H10O4 | 详情 | 详情 | |
| (III) | 59059 | 3-[chloro(methoxy)methyl]-4-methoxyphenyl methyl carbonate | C11H13ClO5 | 详情 | 详情 | |
| (IV) | 59060 | 3-formyl-4-methoxyphenyl methyl carbonate | C10H10O5 | 详情 | 详情 | |
| (V) | 59061 | sodium 3-formyl-4-methoxybenzenolate | C8H7NaO3 | 详情 | 详情 | |
| (VI) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (VII) | 59062 | 2-methoxy-5-[(4-methoxybenzyl)oxy]benzaldehyde | C16H16O4 | 详情 | 详情 | |
| (VIII) | 31933 | 3-Morpholinopropionitrile; 3-(4-Morpholinyl)propanenitrile | 4542-47-6 | C7H12N2O | 详情 | 详情 |
| (IX) | 59063 | (Z)-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-3-(4-morpholinyl)-2-propenenitrile | C23H26N2O4 | 详情 | 详情 | |
| (X) | 59064 | (Z)-3-anilino-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2-propenenitrile | C25H24N2O3 | 详情 | 详情 | |
| (XI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (XII) | 59065 | 2-amino-5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-4-pyrimidinylamine; 5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2,4-pyrimidinediamine | C20H22N4O3 | 详情 | 详情 | |
| (XIII) | 59066 | 3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenol | C12H14N4O2 | 详情 | 详情 | |
| (XIV) | 37151 | ethyl 5-bromopentanoate | 14660-52-7 | C7H13BrO2 | 详情 | 详情 |
| (XV) | 59067 | ethyl 5-{3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenoxy}pentanoate | C19H26N4O4 | 详情 | 详情 |