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【结 构 式】 
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【分子编号】18663 【品名】o-aminophenol; 2-aminophenol 【CA登记号】95-55-6 |
【 分 子 式 】C6H7NO 【 分 子 量 】109.12772 【元素组成】C 66.04% H 6.47% N 12.84% O 14.66% |
合成路线1
该中间体在本合成路线中的序号：(VI)Ortho lithiation of sulfonamide (I) with n-butyllithium, followed by carbonation with CO2 afforded benzoic acid (II). Subsequent cyclization with PPA with concomitant elimination of the N-tert-butyl group provided the saccharin analogue (III). Alkylation of the sodium salt of (III) with 1,4-dibromobutane (IV) in DMF yielded bromide (V). The reductive alkylation of 2-aminophenol (VI) with 1-tert-butoxycarbonyl-4-piperidone (VII) in the presence of sodium tri(acetoxy)borohydride provided the aminopiperidine (VIII), which was cyclized with triphosgene to afford benzoxazolone (IX). Then, removal of the N-Boc protecting group provided piperidine (X), which was finally alkylated with bromide (V) in the presence of Et3N in DMF at 80 C to furnish the title compound.
| 【1】 Nerenberg, J.B.; Erb, J.M.; Thompson, W.J.; Lee, H.Y.; Guare, J.P.; Munson, P.M.; Bergman, J.M.; Huff, J.R.; Broten, T.P.; Chang, R.S.; Chen, T.B..; O'Malley, S.; Schorn, T.W.; Scott, A.L.; Design and synthesis of N-alkylated saccharins as selective alpha1-a adrenergic receptor antagonists. Bioorg Med Chem Lett 1998, 8, 18, 2467. |
| 【2】 Lombardino, J.G.; Preparation of substituted 1,2-benzoisothiazolin-3-one 3 1,1-dioxides (o-benzoic sulfimides). J Org Chem 1971, 36, 13, 1843. |
| 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) | 18658 | N-(tert-butyl)-4-chlorobenzenesulfonamide | C10H14ClNO2S | 详情 | 详情 | |
| (II) | 18659 | 2-[(tert-butylamino)sulfonyl]-5-chlorobenzoic acid | C11H14ClNO4S | 详情 | 详情 | |
| (III) | 18660 | 5-chloro-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C7H4ClNO3S | 详情 | 详情 | |
| (IV) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (V) | 18400 | 2-(4-bromobutyl)-5-chloro-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H11BrClNO3S | 详情 | 详情 | |
| (VI) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (VII) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (VIII) | 18665 | tert-butyl 4-(2-hydroxyanilino)-1-piperidinecarboxylate | C16H24N2O3 | 详情 | 详情 | |
| (IX) | 18666 | tert-butyl 4-[2-oxo-1,3-benzoxazol-3(2H)-yl]-1-piperidinecarboxylate | C17H22N2O4 | 详情 | 详情 | |
| (X) | 18667 | 3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one | C12H14N2O2 | 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 cyclization of 2-aminophenol (I) with ethyl 2,3-dibromopropionate (II) produced benzoxazine (III), which was converted to the corresponding formamide (IV) upon refluxing with formic acid. Reduction of (IV) with borane in THF gave rise to the N-methyl benzoxazine (V). Further treatment of (V) with ethanolic ammonia afforded amide (VI), which was dehydrated to nitrile (VII) by means of POCl3 in pyridine. Subsequent addition of MeOH to the nitrile group of (VII), followed by reaction with ethylenediamine yielded the target imidazoline.
| 【1】 Buttler, R.C.M.; et al.; Synthesis of 2-(2-imidazolinyl) substituted 2,3-dihydro-4H-1,4-benzothiazine and 3,4-dihydro-2H-1,4-benzoxazines. J Heterocycl Chem 1985, 22, 1, 177. |
| 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) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (II) | 18341 | ethyl 2,3-dibromopropanoate | 3674-13-3 | C5H8Br2O2 | 详情 | 详情 |
| (III) | 34706 | ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate | C11H13NO3 | 详情 | 详情 | |
| (IV) | 34707 | ethyl 4-formyl-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate | C12H13NO4 | 详情 | 详情 | |
| (V) | 34708 | ethyl 4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate | C12H15NO3 | 详情 | 详情 | |
| (VI) | 34709 | 4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide | C10H12N2O2 | 详情 | 详情 | |
| (VII) | 34710 | 4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-carbonitrile | C10H10N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Coupling of 2-tetrahydrofuroic acid (VI) with ortho-aminophenol (VII) by means of PyBOP gave the corresponding ortho-hydroxyanilide (VIII), which was cyclized to the benzoxazole (IX) in the presence of DEAD and triphenylphosphine. The lithium derivative of (IX) was acylated with methyl chloroformate to produce the carboxylate ester (X). Acid (XI), generated by basic hydrolysis of ester (X), was then coupled with amino ester (V) to afford amide (XII). The tert-butyl ester group of (XII) was finally cleaved to the title carboxylic acid by treatment with trifluoroacetic acid.
| 【1】 Yang, G.X.; Hagmann, W.K.; Doherty, G.; Chang, L.L.; Delaszlo, S.E. (Merck & Co., Inc.); Heterocycle amides as cell adhesion inhibitors. WO 0112183 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 52095 | tert-butyl (2S)-2-amino-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C21H27NO4 | 详情 | 详情 | |
| (VI) | 52096 | Tetrahydrofuran-2-carboxylic Acid; 2-Tetrahydrofuroic acid | 16874-33-2 | C5H8O3 | 详情 | 详情 |
| (VII) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (VIII) | 52097 | N-(2-hydroxyphenyl)tetrahydro-2-furancarboxamide | C11H13NO3 | 详情 | 详情 | |
| (IX) | 52098 | 2-tetrahydro-2-furanyl-1,3-benzoxazole | C11H11NO2 | 详情 | 详情 | |
| (X) | 52099 | methyl 2-(1,3-benzoxazol-2-yl)tetrahydro-2-furancarboxylate | C13H13NO4 | 详情 | 详情 | |
| (XI) | 52100 | 2-(1,3-benzoxazol-2-yl)tetrahydro-2-furancarboxylic acid | C12H11NO4 | 详情 | 详情 | |
| (XII) | 52101 | tert-butyl (2S)-2-([[2-(1,3-benzoxazol-2-yl)tetrahydro-2-furanyl]carbonyl]amino)-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C33H36N2O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)N-Cbz-L-Valinal cyanohydrin (I) is converted into imidate (II) and then condensed with 2-aminophenol (III) to afford benzoxazole (IV). Removal of the N-Cbz group of (IV) with H2 and Pd/C provides amine (V), which is then coupled to N-Cbz-valyl proline (VI), yielding the dipeptide amide (VII). After hydrogenolysis of the N-Cbz protecting group of (VII), the free amine (VIII) is coupled to the acid fragment (IX) by means of EDC/pyridine to furnish (X).
| 【1】 Sato, F.; Inoue, Y.; Omodani, T.; Imano, K.; Okazaki, H.; Takemura, T.; Komiya, M.; Design and synthesis of peptide-based carboxylic acid-containing transition-state inhibitors of human neutrophil elastase. Bioorg Med Chem Lett 2002, 12, 4, 551. |
| 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) | 62768 | benzyl (1S)-1-[cyano(hydroxy)methyl]-2-methylpropylcarbamate | C14H18N2O3 | 详情 | 详情 | |
| (II) | 62769 | ethyl (3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-methylpentanimidoate | C16H24N2O4 | 详情 | 详情 | |
| (III) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (IV) | 62770 | benzyl (1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropylcarbamate | C20H22N2O4 | 详情 | 详情 | |
| (V) | 62771 | (2S)-2-amino-1-(1,3-benzoxazol-2-yl)-3-methyl-1-butanol | C12H16N2O2 | 详情 | 详情 | |
| (VI) | 22787 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid | C18H24N2O5 | 详情 | 详情 | |
| (VII) | 62772 | benzyl (1S)-1-({(2S)-2-[({(1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropylcarbamate | C30H38N4O6 | 详情 | 详情 | |
| (VIII) | 55792 | (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide | C22H32N4O4 | 详情 | 详情 | |
| (IX) | 62773 | 2-({4-[2-(tert-butoxy)-2-oxoethoxy]benzoyl}amino)acetic acid | C15H19NO6 | 详情 | 详情 | |
| (X) | 62774 | tert-butyl 2-(4-{[(2-{[(1S)-1-({(2S)-2-[({(1S)-1-[1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropyl]amino}-2-oxoethyl)amino]carbonyl}phenoxy)acetate | C37H49N5O9 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Acetylation of o-aminophenol (I) gives o-hydroxy acetanilide (II), which is then protected as the benzyl ether (III) with benzyl bromide and K2CO3. Treatment of acetamide (III) with P2S5 affords the corresponding thioamide (IV), and subsequent S-methylation of (IV) gives rise to the thioimidate (V). Cyclization of thioimidate (V) with 4-biphenylcarboxylic acid hydrazide (VI) in hot DMF leads to the triazole derivative (VII). After benzyl group hydrogenolysis in (VII), the resultant phenol (VIII) is alkylated with 1,6-dibromohexane (IX) to produce the bromohexyl ether (X). Finally, condensation of bromide (X) with N-methylpiperazine (XI) furnishes the title compound.
| 【1】 Kakefuda, A.; et al.; Synthesis and pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human vasopressin V1A receptor. J Med Chem 2002, 45, 12, 2589. |
| 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) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (II) | 56976 | 2-Acetamidophenol; 2-Hydroxyacetanilide; o-Acetamidophenol; o-Hydroxyacetanilide | 614-80-2 | C8H9NO2 | 详情 | 详情 |
| (III) | 56977 | N-[2-(benzyloxy)phenyl]acetamide | C15H15NO2 | 详情 | 详情 | |
| (IV) | 56978 | N-[2-(benzyloxy)phenyl]ethanethioamide | C15H15NOS | 详情 | 详情 | |
| (V) | 56979 | methyl N-[2-(benzyloxy)phenyl]ethanimidothioate | C16H17NOS | 详情 | 详情 | |
| (VI) | 56980 | 4-Biphenylcarboxylic acid hydrazide; 4-Phenylbenzhydrazide | 18622-23-6 | C13H12N2O | 详情 | 详情 |
| (VII) | 56981 | benzyl 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenyl ether; 4-[2-(benzyloxy)phenyl]-3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazole | C28H23N3O | 详情 | 详情 | |
| (VIII) | 56982 | 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenol | C21H17N3O | 详情 | 详情 | |
| (IX) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (X) | 56983 | 3-[1,1'-biphenyl]-4-yl-4-{2-[(6-bromohexyl)oxy]phenyl}-5-methyl-4H-1,2,4-triazole; 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenyl 6-bromohexyl ether | C27H28BrN3O | 详情 | 详情 | |
| (XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Treatment of beta-alanine (I) with phthalic anhydride (II) in refluxing toluene provides phthalimidopropionic acid (III), which upon cyclocondensation with 2-aminophenol (IV) in hot polyphosphoric acid provides the benzoxazole derivative (V). Hydrazinolysis of phthalimide (V) affords the primary amine (VI), which is finally condensed with pyrazole-1-carboxamidine hydrochloride (VII) in DMF to produce the target guanidine compound.
| 【1】 López-Tudanca, P.; Labeaga, L.; Innerárity, A.; Alonso-Cires, L.; Tapia, I.; Mosquera, R.; Orjales, A.; Synthesis and pharmacological characterization of a new benzoxazole derivative as a potent 5-HT3 receptor agonist. Bioorg Med Chem 2003, 11, 13, 2709. |
| 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) | 17022 | beta-Alanine; 3-aminopropionic acid | 107-95-9 | C3H7NO2 | 详情 | 详情 |
| (II) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (III) | 53389 | 3-Phthalimidopropionic acid; Phthalyl-beta-alanine | 3339-73-9 | C11H9NO4 | 详情 | 详情 |
| (IV) | 18663 | o-aminophenol; 2-aminophenol | 95-55-6 | C6H7NO | 详情 | 详情 |
| (V) | 64846 | 2-[2-(1,3-benzoxazol-2-yl)ethyl]-1H-isoindole-1,3(2H)-dione | C17H12N2O3 | 详情 | 详情 | |
| (VI) | 64847 | 2-(1,3-benzoxazol-2-yl)-1-ethanamine; 2-(1,3-benzoxazol-2-yl)ethylamine | C9H10N2O | 详情 | 详情 | |
| (VII) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |