|
【结 构 式】 
|
【分子编号】15098 【品名】4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine 【CA登记号】2393-23-9 |
【 分 子 式 】C8H11NO 【 分 子 量 】137.18148 【元素组成】C 70.04% H 8.08% N 10.21% O 11.66% |
合成路线1
该中间体在本合成路线中的序号：(I)Compound can be prepared in three different ways all starting from 4-methoxybenzylamine (I) [prepared by methylation of 4-hydroxybenzonitrile (V) with dimethyl sulfate in aqueous NaOH to afford 4-methoxybenzonitrile (VI), which is then hydrogenated with H2 over Raney-Ni in ethanol]: 1) By condensation of 4-methoxybenzylamine (I) with N,N',S-trimethylisothiourea hydroiodide (C) in refluxing ethanol, followed by treatment with H2SO4. 2) By reaction of 4-methoxybenzylamine (I) with diethyl iminocarbonate (A) in water to give diethyl N-(4-methoxybenzyl)iminocarbonate (II), followed by treatment with methylamine in water - ethanol - H2SO4. 3) By reaction of 4-methoxybenzylamine (I) with methyl isothiocyanate (B) in ether to yield N-(4-methoxybenzyl)-N'-methylthiourea (III), which is then methylated with MeI in refluxing methanol affording N-(4-methoxybenzyl)-N',S-dimethylisothiourea (IV). Finally, this compound is treated first with methylamine in refluxing methanol and then with H2SO4.
| 【1】 Maxwell, R.A.; Walton, E. (Glaxo Wellcome Inc.); Substituted guanidine compounds as antifibrillatory agents. US 3949089 . |
| 【2】 Castaner, J.; Blancafort, P.; Meobentine. Drugs Fut 1978, 3, 3, 204. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (A) | 39785 | 1-[ethoxy(imino)methoxy]ethane | C5H11NO2 | 详情 | 详情 | |
| (I) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (II) | 39786 | 1-[[(diethoxymethylene)amino]methyl]-4-methoxybenzene | C13H19NO3 | 详情 | 详情 | |
| (III) | 39788 | N-(4-methoxybenzyl)-N'-methylthiourea | C10H14N2OS | 详情 | 详情 | |
| (IV) | 39789 | 1-methoxy-4-([[(methylimino)(methylsulfanyl)methyl]amino]methyl)benzene | C11H16N2OS | 详情 | 详情 | |
| (V) | 25109 | 4-hydroxybenzonitrile | 767-00-0 | C7H5NO | 详情 | 详情 |
| (VI) | 39790 | 4-methoxybenzonitrile | 874-90-8 | C8H7NO | 详情 | 详情 |
| (C) | 39787 | [[(methylamino)(methylimino)methyl]sulfanyl]methane | C4H10N2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The reaction of daunomycinone (IX) with AlCl3 in dichloromethane gives 4-demethyldaunomycinone (X), which is ketalized with ethylene glycol as before yielding the dioxolane (XI). The selective sulfonation of (XI) with TsCl, DIEA and DMAP in pyridine affords the 4-tosyloxy derivative (XII), which is treated with 4-methoxybenzylamine (XIII) in pyridine providing the secondary benzylamine (XIV). Elimination of the benzyl protecting group of (XIV) with TFA gives 4-amino-4-demethoxydaunomycinone ethylene ketal (XV), which is deaminated by reaction with TFA, NaNO2 and H3PO2 to give 4-demethoxydaunomycinone (XVI). Finally, this compound is submitted to fermentation with Streptomyces peucetius corneus, S. Peucetius caesius, S. Caeruleus, S. Peucetius, S. Coeruleorubidus, and other chemical or radio-induced mutants thereof.
| 【1】 Francalanci, F.; Martinengo, T.; de Bernardinis, S.; Cabri, W. (Pharmacia Corp.); Process for the preparation of 4-demethoxydaunomycinone, the aglycone of 4-demethoxy-daunorubicin. EP 0328399 . |
| 【2】 Mitscher, L.A.; Lednicer, D. (Pharmacia Corp.); Biosynthesis of simplified anthracyclines. US 4471052 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (IX) | 34613 | (2S,4S)-2-acetyl-2,4,5,12-tetrahydroxy-7-methoxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione | C21H16O9 | 详情 | 详情 | |
| (X) | 34614 | (2S,4S)-2-acetyl-2,4,5,7,12-pentahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione | C20H14O9 | 详情 | 详情 | |
| (XI) | 34615 | (2R,4S)-2,4,5,7,12-pentahydroxy-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione | C22H18O10 | 详情 | 详情 | |
| (XII) | 34616 | (8R,10S)-6,8,10,11-tetrahydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-5,7,12-trioxo-5,7,8,9,10,12-hexahydro-1-naphthacenyl 4-methylbenzenesulfonate | C29H24O12S | 详情 | 详情 | |
| (XIII) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (XIV) | 34617 | (2R,4S)-2,4,5,12-tetrahydroxy-7-[(4-methoxybenzyl)amino]-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione | C30H27NO10 | 详情 | 详情 | |
| (XV) | 34618 | (2R,4S)-7-amino-2,4,5,12-tetrahydroxy-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione | C22H19NO9 | 详情 | 详情 | |
| (XVI) | 34610 | (2S,4S)-2-acetyl-2,4,5,12-tetrahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione | C20H14O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The syntheses of the metabolites of grepafloxacin, 7-(2-aminoethylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro quinoline-3-carboxylic acid (III), 7-(2-aminopropylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (V), 7-amino-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid (VIII), 7-(carboxymethylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (XI), 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-7-(3-methylpiperazin-1-yl)-4-o xo-1,4-dihydroquinoline-3-carboxylic acid (XVIII) and 7-amino-1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydroquino line-3-carboxylic acid (XX) have been reported: 1) Compound (III): By condensation of 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid diacetoxyborane ester (I) with 2-(tert-butoxycarbonylamino)ethylamine (II) by heating at 110 C followed by a treatment with HCl in ethanol/water. 2) Compound (V): By condensation of quinolone (I) with 2-(tert-butoxycarbonylamino)ethylamine (IV) by heating at 110 C, followed by hydrolysis with HCl as before. 3) Compound (VIII): The condensation of quinolone (I) with 4-methoxybenzylamine (VII) by heating at 110 C gives 1-cyclopropyl-6-fluoro-7-(4-methoxybenzylamino)-5-methyl-4-oxo-1,4-dihy droquinoline-3-carboxylic acid (VII), which is then debenzylated by treatment with a mixture of trifluoroacetic acid and concentrated sulfuric acid. 4) Compound (XI): The condensation of quinolone (I) with glycine ethyl ester (IX) by heating at 110 C gives 1-cyclopropyl-7-(ethoxycarbonylmethylamino)-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (X), which is then saponified with NaOH in refluxing ethanol.
| 【1】 Otsubo, K.; Kawano, Y.; Ohguro, K.; Uchida, M.; Ohtani, T.; Ohmori, K.; Matsubara, J.; Morita, S.; Synthesis of possible metabolites of 1-cyclopropyl-1,4-dihydro-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (grepafloxacin, OPC-17116). Chem Pharm Bull 1995, 43, 12, 2246. |
| 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) | 15093 | diacetyl (7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinyl)carbonyl borate | C18H16BBrFNO7 | 详情 | 详情 | |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 15095 | 7-[(2-aminoethyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C16H18FN3O3 | 详情 | 详情 | |
| (IV) | 15096 | tert-butyl N-(2-amino-1-methylethyl)carbamate | C8H18N2O2 | 详情 | 详情 | |
| (V) | 15097 | 7-[(2-aminopropyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C17H20FN3O3 | 详情 | 详情 | |
| (VI) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (VII) | 15099 | 1-cyclopropyl-6-fluoro-7-[(4-methoxybenzyl)amino]-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C22H21FN2O4 | 详情 | 详情 | |
| (VIII) | 15100 | 7-amino-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H13FN2O3 | 详情 | 详情 | |
| (IX) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (X) | 15102 | 1-cyclopropyl-7-[(2-ethoxy-2-oxoethyl)amino]-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C18H19FN2O5 | 详情 | 详情 | |
| (XI) | 15103 | 7-[(carboxymethyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C16H15FN2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)5) Compound (XVIII): The esterification of 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid (XII) with SOCl2/methanol gives the corresponding methyl ester (XIII), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide (BPO) in refluxing CCl4 yielding the corresponding bromomethyl derivative (XIV). The reaction of (XIV) with sodium acetate in hot DMF affords the expected acetoxymethyl derivative (XV), which is saponified with K2CO3 in methanol/water to give 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydroquinoline-3-c arboxylic acid (XVI). Finally, this compound is condensed with 2-methylpiperazine (XVII) by heating at 110 C. 6) Compound (XX): The condensation of the hydroxymethylquinolone (XVI) with the benzylamine (VI) as before gives 6-fluoro-5-(hydroxymethyl)-4-(4-methoxybenzylamino)-4-oxo-1,4-dihydroqu inoline-3-carboxylic acid (XIX), which is then debenzylated with trifluoroacetic acid an H2SO4 as before.
| 【1】 Otsubo, K.; Kawano, Y.; Ohguro, K.; Uchida, M.; Ohtani, T.; Ohmori, K.; Matsubara, J.; Morita, S.; Synthesis of possible metabolites of 1-cyclopropyl-1,4-dihydro-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (grepafloxacin, OPC-17116). Chem Pharm Bull 1995, 43, 12, 2246. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (XII) | 15104 | 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H11BrFNO3 | 详情 | 详情 | |
| (XIII) | 15105 | methyl 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H13BrFNO3 | 详情 | 详情 | |
| (XIV) | 15106 | methyl 7-bromo-5-(bromomethyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H12Br2FNO3 | 详情 | 详情 | |
| (XV) | 15107 | methyl 5-[(acetoxy)methyl]-7-bromo-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C17H15BrFNO5 | 详情 | 详情 | |
| (XVI) | 15108 | 7-bromo-1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H11BrFNO4 | 详情 | 详情 | |
| (XVII) | 12267 | 2-Methylpiperazine | 109-07-9 | C5H12N2 | 详情 | 详情 |
| (XVIII) | 15110 | 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-7-(3-methylpiperazino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C19H22FN3O4 | 详情 | 详情 | |
| (XIX) | 15111 | 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-7-[(4-methoxybenzyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C22H21FN2O5 | 详情 | 详情 | |
| (XX) | 15112 | 7-amino-1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C14H13FN2O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The cyclization of (S)-glutamic acid (I) by means of H2SO4 and NaNO2 gives the gamma lactone (II), which is treated with hot SOCl2 to yield the corresponding acyl chloride (III). The reaction of (III) with 4-methoxybenzylamine (IV) affords the expected amide (V), which is submitted to rearrangement in the presence of t-BuOK in THF to provide piperidinedione (VI). The reaction of (VI) with Tbdps-Cl and imidazole gives the silyl ether (VII), which is reduced with NaBH4 in methanol to yield a mixture of regioisomers (VIII). The phenyl migration in (VIII) was easily promoted by reaction with BF3/Et2O through the nonisolated intermediate cis-(IX) to yield (X). The reduction of (X) by means of LiAlH4 in THF affords the N-protected hydroxypiperidine (XI), which is deprotected by hydrogenation with H2 over Pd/C in ethanol to provide the free hydroxypiperidine (XII). The reprotection of (XII) with Boc2O gives the carbamate-protected piperidine (XIII), which is oxidized by means of DMSO, (COCl)2 and DIEA in dichloromethane to yield piperidone (XIV). The reaction of (XIV) with NH2OH and K2CO3 affords the corresponding oxime (XV), which is treated with Ac2O in THF to provide the O-acetyloxime (XVI). The reduction of (XVI) with BH3/Me2S in hot THF gives the expected amine (XVII), which is condensed with 2-methoxybenzaldehyde (XVIII) in THF to yield the imine (XIX). The reduction of (XIX) with NaBH4 in methanol affords the protected benzylamine (XX), which is finally deprotected by means of HCl in methanol to provide CP-99,994.
| 【1】 Wei, B.-G.; Huang, P.-Q.; Liu, L.-X.; Ruan, Y.-P.; Asymmetric synthesis of (+)-L-733, 060 and (+)-CP-99, 994 based on a new chiral 3-piperidinol synthon. Org Lett 2003, 5, 11, 1927. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| cis-(IX) | 64777 | (5S,6S)-5-{[tert-butyl(fluoro)phenylsilyl]oxy}-1-(4-methoxybenzyl)-6-phenyl-2-piperidinone | C29H34FNO3Si | 详情 | 详情 | |
| (I) | 12005 | L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid | 56-86-0 | C5H9NO4 | 详情 | 详情 |
| (II) | 12006 | (R)-(-)-5-Oxo-2-tetrahydrofurancarboxylic acid; (2S)-5-oxotetrahydro-2-furancarboxylic acid | 53558-93-3 | C5H6O4 | 详情 | 详情 |
| (III) | 64772 | (2S)-5-oxotetrahydro-2-furancarbonyl chloride | C5H5ClO3 | 详情 | 详情 | |
| (IV) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (V) | 64773 | (2S)-N-(4-methoxybenzyl)-5-oxotetrahydro-2-furancarboxamide | C13H15NO4 | 详情 | 详情 | |
| (VI) | 64774 | (3S)-3-hydroxy-1-(4-methoxybenzyl)-2,6-piperidinedione | C13H15NO4 | 详情 | 详情 | |
| (VII) | 64775 | (3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-(4-methoxybenzyl)-2,6-piperidinedione | C29H33NO4Si | 详情 | 详情 | |
| (VIII) | 64776 | (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-hydroxy-1-(4-methoxybenzyl)-2-piperidinone | C29H35NO4Si | 详情 | 详情 | |
| (X) | 64778 | (5S,6S)-5-hydroxy-1-(4-methoxybenzyl)-6-phenyl-2-piperidinone | C19H21NO3 | 详情 | 详情 | |
| (XI) | 64779 | (2S,3S)-1-(4-methoxybenzyl)-2-phenyl-3-piperidinol | C19H23NO2 | 详情 | 详情 | |
| (XII) | 64498 | (2S,3S)-2-phenyl-3-piperidinol | C11H15NO | 详情 | 详情 | |
| (XIII) | 64499 | tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (XIV) | 62266 | tert-butyl (2S)-3-oxo-2-phenyl-1-piperidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (XV) | 64780 | tert-butyl (2S)-3-(hydroxyimino)-2-phenyl-1-piperidinecarboxylate | C16H22N2O3 | 详情 | 详情 | |
| (XVI) | 64781 | tert-butyl (2S)-3-[(acetyloxy)imino]-2-phenyl-1-piperidinecarboxylate | C18H24N2O4 | 详情 | 详情 | |
| (XVII) | 31756 | tert-butyl (2S,3S)-3-amino-2-phenyl-1-piperidinecarboxylate | C16H24N2O2 | 详情 | 详情 | |
| (XVIII) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (XIX) | 64782 | tert-butyl (2S,3S)-3-{[(E)-(2-methoxyphenyl)methylidene]amino}-2-phenyl-1-piperidinecarboxylate | C24H30N2O3 | 详情 | 详情 | |
| (XX) | 31757 | tert-butyl (2S,3S)-3-[(2-methoxybenzyl)amino]-2-phenyl-1-piperidinecarboxylate | C24H32N2O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Pyrimidopyrimidine tetraone (I) was converted to the disodium salt (II), which was then treated with PCl5 in refluxing POCl3 to provide the tetrachloro pyrimidopyrimidine (III). Displacement of the more reactive 4- and 8-chlorine atoms of (III) by 4-methoxybenzylamine (IV) in THF at room temperature gave the 4,8-di(4-methoxybenzylamino) derivative (V). Finally, the remainig chlorine atoms of (V) were displaced by diethanolamine (VI) at 110 C, yielding the title compound.
| 【1】 Barlow, H.C.; et al.; Resistance-modifying agents. Part 7: 2,6-Disubstituted-4,8-dibenzylaminopyrimido[5,4-d]pyrimidines that inhibit nucleoside transport in the presence of alpha1-acid glycoprotein (AGP). Bioorg Med Chem Lett 2000, 10, 6, 585. |
| 【2】 Calvert, A.H.; Griffin, R.J.; Curtin, N.J.; Golding, B.T.; Newell, D.R. (University of Newcastle upon Tyne); Pyrimidopyrimidine cpds.. WO 9843974 . |
| 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) | 41123 | 1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8(3H,7H)-tetrone | 6713-54-8 | C6H4N4O4 | 详情 | 详情 |
| (II) | 41124 | disodium 2,6-dioxo-1,2,6,7-tetrahydropyrimido[5,4-d]pyrimidine-4,8-diolate | C6H2N4Na2O4 | 详情 | 详情 | |
| (III) | 36173 | 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine | C6Cl4N4 | 详情 | 详情 | |
| (IV) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (V) | 41125 | 2,6-dichloro-N(4),N(8)-bis(4-methoxybenzyl)pyrimido[5,4-d]pyrimidine-4,8-diamine; N-[2,6-dichloro-8-[(4-methoxybenzyl)amino]pyrimido[5,4-d]pyrimidin-4-yl]-N-(4-methoxybenzyl)amine | C22H20Cl2N6O2 | 详情 | 详情 | |
| (VI) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(X)The triarylcarbinol intermediate (IV) is obtained by two different ways: 1. The reaction of 2-chloro-4-methoxypyridine-3-carboxylic acid (I) with (COCl)2 in dichloromethane gives the acyl chloride (II), which is condensed with 2-methylsulfanylpyrimidin-4-yl lithium salt (III) in THF to yield the triarylcarbinol (IV). 2. The reaction of the lithium salt (III) with 0.4 equiv. of diethyl carbonate (V) in THF gives the symmetric ketone (VI), which is then condensed with the 2-chloro-4-methoxypyridin-3-yl lithium salt (VII) in THF to yield the desired triarylcarbinol intermediate (IV). The cyclization of the triarylcarbinol intermediate (IV) by means of Tes-H and TEA in 1,2-dichloroethane at 100 C gives the desired core structure (VIII), which is oxidized at its sulfanyl groups with MCPBA in chloroform to yield the sulfinyl derivative (IX). The reaction of (IX) with 4-methoxybenzylamine (X) at 85 ?C affords the protected diamine (XI). The demethylation of (XI) by means of EtS-Na in hot DMF provides the pyridinol (XII), which is finally N-deprotected by means of triflic acid to yield the target variolin B (1).
| 【1】 Morris, J.C.; Anderson, R.J.; Total synthesis of variolin B. Tetrahedron Lett 2001, 42, 49, 8697. |
| 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) | 55708 | 2-chloro-4-methoxynicotinic acid | C7H6ClNO3 | 详情 | 详情 | |
| (II) | 55709 | 2-chloro-4-methoxynicotinoyl chloride | C7H5Cl2NO2 | 详情 | 详情 | |
| (III) | 55710 | [2-(methylsulfanyl)-4-pyrimidinyl]lithium | C5H5LiN2S | 详情 | 详情 | |
| (IV) | 55711 | (2-chloro-4-methoxy-3-pyridinyl){bis[2-(methylsulfanyl)-4-pyrimidinyl]}methanol | C17H16ClN5O2S2 | 详情 | 详情 | |
| (V) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (VI) | 55712 | bis[2-(methylsulfanyl)-4-pyrimidinyl]methanone | C11H10N4OS2 | 详情 | 详情 | |
| (VII) | 55713 | (2-chloro-4-methoxy-3-pyridinyl)lithium | C6H5ClLiNO | 详情 | 详情 | |
| (VIII) | 55714 | 4-methoxy-9-(methylsulfanyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine; methyl 9-(methylsulfanyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-yl ether | C17H15N5OS2 | 详情 | 详情 | |
| (IX) | 55715 | 4-[4-methoxy-9-(methylsulfinyl)pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-5-yl]-2-pyrimidinyl methyl sulfoxide; 4-methoxy-9-(methylsulfinyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine | C17H15N5O3S2 | 详情 | 详情 | |
| (X) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (XI) | 55716 | N-(4-methoxybenzyl)-N-(4-{4-methoxy-9-[(4-methoxybenzyl)amino]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-5-yl}-2-pyrimidinyl)amine; 4-methoxy-N-(4-methoxybenzyl)-5-{2-[(4-methoxybenzyl)amino]-4-pyrimidinyl}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-9-amine | C31H29N7O3 | 详情 | 详情 | |
| (XII) | 55717 | 9-[(4-methoxybenzyl)amino]-5-{2-[(4-methoxybenzyl)amino]-4-pyrimidinyl}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol | C30H27N7O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.
| 【2】 Yazaki, A.; Niino, Y.; Ohshita, Y.; Hirao, Y.; Amano, H.; Hayashi, N.; Kuramoto, Y. (Wakunaga Pharmaceutical Co., Ltd.); Novel pyridonecarboxylic acid derivs. or their salts and antibacterial agent comprising the same as the active ingredient. EP 0911327; EP 0992501; JP 1999322715; JP 2000136191; US 5998436; US 6133284; WO 9711068 . |
| 【1】 Mealy, N.E.; Castaner, J.; ABT-492. Drugs Fut 2002, 27, 11, 1033. |
| 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) | 56640 | 2,3,5,6-Tetrafluoropyridine | 2875-18-5 | C5HF4N | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 56641 | N-benzyl-3,5,6-trifluoro-2-pyridinamine; N-benzyl-N-(3,5,6-trifluoro-2-pyridinyl)amine | C12H9F3N2 | 详情 | 详情 | |
| (IV) | 56642 | 3,5,6-trifluoro-2-pyridinamine; 3,5,6-trifluoro-2-pyridinylamine | C5H3F3N2 | 详情 | 详情 | |
| (V) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (VI) | 56643 | N-(6-amino-3,5-difluoro-2-pyridinyl)-N-(4-methoxybenzyl)amine; 3,5-difluoro-N~2~-(4-methoxybenzyl)-2,6-pyridinediamine | C13H13F2N3O | 详情 | 详情 | |
| (VII) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
| (VIII) | 11681 | ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate | 101987-86-4 | C11H8ClF3O3 | 详情 | 详情 |
| (IX) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (X) | 56644 | ethyl 8-chloro-1-{3,5-difluoro-6-[(4-methoxybenzyl)amino]-2-pyridinyl}-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C25H18ClF4N3O4 | 详情 | 详情 | |
| (XI) | 56645 | 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C15H6ClF4N3O3 | 详情 | 详情 | |
| (XII) | 31397 | 3-azetidinol | C3H7NO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The condensation of 2,6-dichloropurine (I) with 4-methoxybenzylamine (II) in butanol at 120 C gives 2-chloro-6-(4-methoxybenzylamino)purine (II), which is treated with isopropyl iodide (IV) and NaH in DMF yielding 2-chloro-9-isopropyl-6-(4-methoxybenzylamino)purine (V). Finally, this compound is condensed with diethanolamine (VI) in DMSO at 160 C.
| 【1】 Schow, S.R.; et al.; Synthesis and activity of 2,6,9-trisubstituted purines. Bioorg Med Chem Lett 1997, 7, 21, 2697. |
| 【2】 Lum, R.T.; Blum, C.L.; Mackman, R.; Wick, M.M.; Schow, S.R. (CV Therapeutics, Inc.); Purine inhibitors of cyclin dependent kinase 2 and IkappaB-alpha. EP 1021186; US 5866702; WO 9805335 . |
| 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) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (II) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (III) | 38022 | N-(2-chloro-9H-purin-6-yl)-N-(4-methoxybenzyl)amine; 2-chloro-N-(4-methoxybenzyl)-9H-purin-6-amine | C13H12ClN5O | 详情 | 详情 | |
| (IV) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (V) | 38023 | 2-chloro-9-isopropyl-N-(4-methoxybenzyl)-9H-purin-6-amine; N-(2-chloro-9-isopropyl-9H-purin-6-yl)-N-(4-methoxybenzyl)amine | C16H18ClN5O | 详情 | 详情 | |
| (VI) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The condensation between methyl (R)-5-hydroxy-3-methylpentanoate (I) and 4-methoxybenzylamine (II) afforded amide (III). Swern oxidation of the alcohol function led to the corresponding aldehyde, which spontaneously evolved to the cyclic hemiaminal form (IV). Dehydration of (IV) to the tetrahydropyridinone (V) was accomplished by either heating in toluene, or by treatment with phosphoric acid in refluxing dimethyl carbonate. The bicyclic derivative (VI) was then obtained by addition of dichlorocarbene, generated from either ethyl trichloroacetate or chloroform and a base, to tetrahydropyridinone (V). Mono-dehalogenation of dichloro compound (VI) employing zinc dust and ethylenediamine provided a mixture of diastereomeric mono-chloro derivatives (VIIa-b) . After acid-promoted cleavage of the p-methoxybenzyl group, the major isomer (VIII) was isolated by selective crystallization from the reaction mixture. Alternatively, dichloro compound (VI) was first subjected to acidic p-methoxybenzyl group cleavage yielding (IX). Then, radical dehalogenation with triphenyltin hydride and AIBN produced a mixture of mono-chloro compounds, which were separated by column chromatography. Lactam (VIII) was converted to imidate (X) upon treatment with trimethyloxonium tetrafluoroborate. Optionally, the analogous ethyl imidate (XI) was prepared by a similar procedure. Treatment of imidates (X) or (XI) with either ammonia or ammonium acetate furnished the target amidine, which was finally isolated as the corresponding hydrochloride salt.
| 【1】 Kobayashi, K.; Taniguchi, N.; Naka, M. (Ono Pharmaceutical Co., Ltd.); Condensed piperidine derivs. used as a nitrogen monoxide synthase inhibitors. EP 0870763; JP 1999171866; US 6110930; US 6228866 . |
| 【2】 Hashimoto, S.; Kusuda, S.; Kuwabe, S. (Ono Pharmaceutical Co., Ltd.); Process for the preparation of intermediate cpds. of drugs. EP 1188749; WO 0078722 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 58739 | (1S,5S,6R,7S)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one | C15H18ClNO2 | 详情 | 详情 | |
| (VIIa) | 58740 | (1S,5S,6R,7R)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one | C15H18ClNO2 | 详情 | 详情 | |
| (I) | 57410 | methyl (3R)-5-hydroxy-3-methylpentanoate | C7H14O3 | 详情 | 详情 | |
| (II) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (III) | 57411 | (3R)-5-hydroxy-N-(4-methoxybenzyl)-3-methylpentanamide | C14H21NO3 | 详情 | 详情 | |
| (IV) | 58412 | N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-N-(3-pyridinyl)amine; N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-3-pyridinamine | C20H28N2O2Si | 详情 | 详情 | |
| (V) | 57406 | (4S)-1-(4-methoxybenzyl)-4-methyl-3,4-dihydro-2(1H)-pyridinone | C14H17NO2 | 详情 | 详情 | |
| (VI) | 57407 | (1S,5S,6R)-7,7-dichloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one | C15H17Cl2NO2 | 详情 | 详情 | |
| (VIII) | 57408 | (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one | C7H10ClNO | 详情 | 详情 | |
| (IX) | 58738 | (1S,5S,6R)-7,7-dichloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one | C7H9Cl2NO | 详情 | 详情 | |
| (X) | 57415 | (1S,5S,6R,7R)-7-chloro-3-methoxy-5-methyl-2-azabicyclo[4.1.0]hept-2-ene; (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-yl methyl ether | C8H12ClNO | 详情 | 详情 | |
| (XI) | 58741 | (1S,5S,6R,7R)-7-chloro-3-ethoxy-5-methyl-2-azabicyclo[4.1.0]hept-2-ene; (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-yl ethyl ether | C9H14ClNO | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VII)Reaction of N-acetyl-L-tyrosine (I) with tert-butyldimethylsilyl chloride and N-methylmorpholine (NMM), followed by phosphitylation with dibenzyldiisopropylamine phosphoramidite produced the intermediate phosphite ester (II), which was oxidized to phosphate (III) using tert-butyl hydroperoxide. Subsequent coupling of (III) with protected glutamic acid (IV) in the presence of DCC and HOBt afforded dipeptide (V). Deprotection of the allyl ester of (V) by means of Pd(PPh3)4 and pyrrolidine provided acid (VI). After conversion of (VI) to the corresponding mixed anhydride with isobutyl chloroformate, condensation with 4-methoxybenzyl amine (VII) yielded amide (VIII). Finally, the benzyl ester groups were eliminated by catalytic hydrogenation over Pd/C (1).
| 【1】 Llinas-Brunet, M.; et al.; Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain. J Med Chem 1999, 42, 4, 722. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40669 | C17H22NO2P | 详情 | 详情 | |||
| (I) | 26159 | N-Acetyl-L-tyrosine; (2S)-2-(acetamido)-3-(4-hydroxyphenyl)propionic acid | 537-55-3 | C11H13NO4 | 详情 | 详情 |
| (II) | 26160 | tert-butyl(dimethyl)silyl (2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphino]oxy]phenyl)propanoate | C31H40NO6PSi | 详情 | 详情 | |
| (III) | 26161 | (2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphoryl]oxy]phenyl)propionic acid | C25H26NO7P | 详情 | 详情 | |
| (IV) | 26162 | 1-allyl 5-benzyl (2S)-2-aminopentanedioate | C15H19NO4 | 详情 | 详情 | |
| (V) | 26163 | 1-allyl 5-benzyl (2S)-2-[[(2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphoryl]oxy]phenyl)propanoyl]amino]pentanedioate | C40H43N2O10P | 详情 | 详情 | |
| (VI) | 26164 | (2S)-2-[[(2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphoryl]oxy]phenyl)propanoyl]amino]-5-(benzyloxy)-5-oxopentanoic acid | C37H39N2O10P | 详情 | 详情 | |
| (VII) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (VIII) | 26165 | benzyl (4S)-4-[[(2S)-2-(acetamido)-3-(4-[[bis(benzyloxy)phosphoryl]oxy]phenyl)propanoyl]amino]-5-[(4-methoxybenzyl)amino]-5-oxopentanoate | C45H48N3O10P | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XII)The intermediate benzylamine derivative (XIII) was prepared by chlorination of 4-methoxybenzylamine (XII) employing either chlorine in HOAc or sulfuryl chloride. The 9-chloro group of (XI) was finally displaced with amine (XII) by heating at 170 C in a pressure tube to furnish the target 6,9-disubstituted tricyclic compound.
| 【1】 Kim, S.; Wang, Y.; Yu, G.; Macor, J.; Chung, H.-J.; Humora, M.; Katipally, K. (Bristol-Myers Squibb Co.); Fused pyridopyridazine inhibitors of cGMP phosphodiesterase. EP 1165521; JP 2002540102; US 6316438; WO 0056719 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 58548 | 1-(9-chloro-3-ethyl-3H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazin-6-yl)-N-methyl-1H-imidazole-4-carboxamide | C15H13ClN8O | 详情 | 详情 | |
| (XII) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (XIII) | 51978 | (3-chloro-4-methoxyphenyl)methanamine; 3-chloro-4-methoxybenzylamine | C8H10ClNO | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(IV)The alkylation of 6-chloro-2-fluoropurine (I) with isopropanol (II) under Mitsunobu conditions gives 6-chloro-2-fluoro-9-isopropylpurine (III), which is regioselectively alkylated at the 6 position with 4-methoxybenzylamine (IV) to yield 2-fluoro-9-isopropyl-N6-(4-methoxybenzyl)adenine (V). Finally, the 2-fluoro position of (V) is aminated with perhydroazepine (VI) in n-butanol at high temperature in a sealed tube to afford the target trisubstituted purine.
| 【1】 Verdugo, D.E.; et al.; Discovery of estrogen sulfotransferase inhibitors from a purine library screen. J Med Chem 2001, 44, 17, 2683. |
| 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) | 51672 | 6-chloro-2-fluoro-9H-purine | C5H2ClFN4 | 详情 | 详情 | |
| (II) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (III) | 51673 | 6-chloro-2-fluoro-9-isopropyl-9H-purine | C8H8ClFN4 | 详情 | 详情 | |
| (IV) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (V) | 51674 | N-(2-fluoro-9-isopropyl-9H-purin-6-yl)-N-(4-methoxybenzyl)amine; 2-fluoro-9-isopropyl-N-(4-methoxybenzyl)-9H-purin-6-amine | C16H18FN5O | 详情 | 详情 | |
| (VI) | 18672 | azepane | 111-49-9 | C6H13N | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(III)Radical bromination of 2,6-dibromo-4-methoxytoluene (I) affords the benzylic bromide (II), which is subsequently condensed with p-methoxybenzylamine (III) to produce the bis-benzyl amine derivative (IV). Coupling of amine (IV) with 2,6-dichlorophenyl isocyanate (V) furnishes urea (VI). Intramolecular cyclization of (VI) in the presence of K2CO3 and CuI leads to quinazolinone (VII). The p-methoxybenzyl protecting group is then removed by refluxing in trifluoroacetic acid to provide (VIII). Transmetalation of 2-chloro-4-fluoro-1-iodobenzene (IX) with isopropylmagnesium chloride, followed by condensation with trimethyl borate results in the boronic acid (X). Then, Suzuki coupling of (X) with aryl bromide (VIII) furnishes (XI). The methyl ether group of (XI) is cleaved by means of BBr3 to yield phenol (XII), which is further converted into triflate (XIII) upon treatment with either N-phenyl trifluoromethanesulfonimide or with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide.
| 【1】 Stelmach, J.E.; Liu, L.; Patel, S.B.; Pivnichny, J.V.; Scapin, G.; Singh, S.; Hop, C.E.C.A.; Wang, Z.; Strauss, J.R.; Cameron, P.M.; Nichols, E.A.; O'Keefe, S.J.; O'Neill, E.A.; Schmatz, D.M.; Schwartz, C.D.; Thompson, C.M.; Zaller, D.M.; Doherty, J.B.; Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg Med Chem Lett 2003, 13, 2, 277. |
| 【2】 Doherty, J.B.; Rupprecht, K.M.; Goulet, J.L.; Chen, M.-H.; Bao, J.; Liu, L.; Miao, S.; Hunt, J.A.; Hong, X.; Stelmach, J.E.; Ruzek, R.D.; Wisnoski, D.D.; Natarajan, S.R. (Merck & Co., Inc.); (Halo-benzo carbonyl)heterocyclic fused phenyl p38 kinase inhibiting agents. EP 1345603; WO 0258695 . |
| 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) | 63179 | 3,5-dibromo-4-methylphenyl methyl ether; 1,3-dibromo-5-methoxy-2-methylbenzene | C8H8Br2O | 详情 | 详情 | |
| (II) | 63180 | 1,3-dibromo-2-(bromomethyl)-5-methoxybenzene; 3,5-dibromo-4-(bromomethyl)phenyl methyl ether | C8H7Br3O | 详情 | 详情 | |
| (III) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (IV) | 63181 | N-(2,6-dibromo-4-methoxybenzyl)(4-methoxyphenyl)methanamine; N-(2,6-dibromo-4-methoxybenzyl)-N-(4-methoxybenzyl)amine | C16H17Br2NO2 | 详情 | 详情 | |
| (V) | 63182 | 2,6-dichlorophenyl isocyanate; 1,3-dichloro-2-isocyanatobenzene | C7H3Cl2NO | 详情 | 详情 | |
| (VI) | 63183 | N-(2,6-dibromo-4-methoxybenzyl)-N'-(2,6-dichlorophenyl)-N-(4-methoxybenzyl)urea | C23H20Br2Cl2N2O3 | 详情 | 详情 | |
| (VII) | 63184 | 5-bromo-1-(2,6-dichlorophenyl)-7-methoxy-3-(4-methoxybenzyl)-3,4-dihydro-2(1H)-quinazolinone | C23H19BrCl2N2O3 | 详情 | 详情 | |
| (VIII) | 63185 | 5-bromo-1-(2,6-dichlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone | C15H11BrCl2N2O2 | 详情 | 详情 | |
| (IX) | 63186 | 2-chloro-4-fluoro-1-iodobenzene | C6H3ClFI | 详情 | 详情 | |
| (X) | 63187 | 2-chloro-4-fluorophenylboronic acid | C6H5BClFO2 | 详情 | 详情 | |
| (XI) | 63188 | 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone | C21H14Cl3FN2O2 | 详情 | 详情 | |
| (XII) | 63189 | 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxy-3,4-dihydro-2(1H)-quinazolinone | C20H12Cl3FN2O2 | 详情 | 详情 | |
| (XIII) | 63190 | 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydro-7-quinazolinyl trifluoromethanesulfonate | C21H11Cl3F4N2O4S | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(IV)Iodination of 3-(trifluoromethyl)-2-pyridinol (I) with NIS in acetonitrile/DMF at 80 °C gives 5-iodo-3-(trifluoromethyl)-2-pyridinol (II), which is treated with POCl3 in DMF at 110 °C under microwave to yield 2-chloro-5-iodo-3-(trifluoromethyl)pyridine (III). Condensation of iodide (III) with 4-methoxybenzylamine (IV) in the presence of Pd2dba3, xantphos and t-BuONa in refluxing toluene or using Pd(OAc)2, BINAP, Et3N and Cs2CO3 in toluene under microwave provides secondary amine (V), which is reacted with Zn(CN)2 in the presence of Pd2dba3 and dppf in DMF at 130 °C to obtain nitrile (VI). N-Deprotection of compound (VI) by means of TFA in CH2Cl2 affords 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (VII), which is condensed with thiophosgene (VIII) in CHCl3/H2O to yield 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (IX). Finally, isothiocyanate (IX) is submitted to cyclocondensation with nitrile (X) in DMF at 80 °C under microwave, followed by treatment with HCl in refluxing MeOH .
Synthesis of intermediate (X): Condensation of 2,4-difluorobenzoyl chloride (XI) with methylamine (XII) in THF produces 2,4-difluoro-N-methylbenzamide (XIII), which is condensed with 4-methoxybenzylamine (IV) in acetonitrile (1, 3, 4) or DMSO at 190 °C under microwave (2) to give the secondary amine (XIV). N-Deprotection of compound (XIV) by means of TFA in CH2Cl2 provides 4-amino-2-fluoro-N-methylbenzamide (XV), which is finally condensed with cyclobutanone (XVI) and NaCN in AcOH at 80 °C . Alternatively, amino nitrile (X) is obtained by direct condensation of fluoride (XIII) with 1-aminocyclobutanecarbonitrile (XVII) (prepared by Strecker reaction of cyclobutanone (XVI) with NaCN, NH4Cl and NH3 in the presence of MgSO4) .
| 【1】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 8802689; EP 2004181; US 2011003839; WO 2007126765; EP 2656842; EP 2656841; EP 2368550; JP 2009531439. |
| 【2】 Ouerfelli, O., Dilhas, A., Yang, G., Zhao, H. (Sloan-Kettering Institute for Cancer Research). Synthesis of thiohydantoins. US 2013225821; US 8461343; WO 2008119015. |
| 【3】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 2013072511. |
| 【4】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 2013072511. |
| 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) | 67484 | 3-(trifluoromethyl)pyridin-2-ol | C6H4F3NO | 详情 | 详情 | |
| (II) | 67485 | 5-iodo-3-(trifluoromethyl)pyridin-2-ol | C6H3F3INO | 详情 | 详情 | |
| (III) | 67486 | 2-chloro-5-iodo-3-(trifluoromethyl)pyridine | C6H2ClF3IN | 详情 | 详情 | |
| (IV) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (V) | 67487 | 6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine | C14H12ClF3N2O | 详情 | 详情 | |
| (VI) | 67488 | 5-((4-methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile | C15H12F3N3O | 详情 | 详情 | |
| (VII) | 67489 | 5-amino-3-(trifluoromethyl)picolinonitrile | C7H4F3N3 | 详情 | 详情 | |
| (VIII) | 67490 | Thiophosgene;Thiocarbonyl chloride | 463-71-8 | CCl2S | 详情 | 详情 |
| (IX) | 67491 | 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile | C8H2F3N3S | 详情 | 详情 | |
| (X) | 67492 | 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide | C13H14FN3O | 详情 | 详情 | |
| (XI) | 67493 | 2,4-difluorobenzoyl chloride | 72482-64-5 | C7H3ClF2O | 详情 | 详情 |
| (XII) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (XIII) | 67494 | 2,4-difluoro-N-methylbenzamide | C8H7F2NO | 详情 | 详情 | |
| (XIV) | 67495 | 2-fluoro-4-((4-methoxybenzyl)amino)-N-methylbenzamide | C16H17FN2O2 | 详情 | 详情 | |
| (XV) | 67496 | 4-amino-2-fluoro-N-methylbenzamide | C8H9FN2O | 详情 | 详情 | |
| (XVI) | 26374 | cyclobutanone | 1191-95-3 | C4H6O | 详情 | 详情 |
| (XVII) | 67497 | 1-aminocyclobutanecarbonitrile | C5H8N2 | 详情 | 详情 |