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【结 构 式】 
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【分子编号】25630 【品名】2-(benzylamino)-1-ethanol 【CA登记号】104-63-2 |
【 分 子 式 】C9H13NO 【 分 子 量 】151.20836 【元素组成】C 71.49% H 8.67% N 9.26% O 10.58% |
合成路线1
该中间体在本合成路线中的序号：(XXVIII)In a further procedure, styrene oxide (XV) was condensed with 2-(benzylamino)ethanol (XXVIII) to give amino diol (XXIX). After chlorination of (XXIX) using SOCl2 and DMAP, dichloro derivative (XXX) was condensed with 2-aminobenzyl alcohol (X) yielding piperazine (XXXI). Cyclization of (XXXI) in hot sulfuric acid afforded the tetracyclic compound (XXXII). The N-benzyl group of (XXXII) was then removed by treatment with butyl chloroformate producing carbamate (XXXIII), which was further hydrolyzed and decarboxylated to (XXXIV) under basic conditions. Finally, methylation of the secondary amine (XXXIV) was performed by reductive alkylation with formaldehyde either in the presence of formic acid under Leuckart-Wallach conditions or by catalytic hydrogenation
| 【1】 Grafe, I.; Ahrens, K.-H.; Morsdorf, J.P.; Kisielowski-Ruppert, L. (Heumann Pharma GmbH); Process for the preparation of 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin and their salts. DE 4305659; EP 0612745 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XV) | 23017 | 2-phenyloxirane | 96-09-3 | C8H8O | 详情 | 详情 |
| (XXVIII) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (XXIX) | 62414 | 2-[benzyl(2-hydroxyethyl)amino]-1-phenyl-1-ethanol | C17H21NO2 | 详情 | 详情 | |
| (XXX) | 62415 | N-benzyl-2-chloro-N-(2-chloroethyl)-2-phenyl-1-ethanamine; N-benzyl-N-(2-chloroethyl)-N-(2-chloro-2-phenylethyl)amine | C17H19Cl2N | 详情 | 详情 | |
| (XXXI) | 62416 | [2-(4-benzyl-2-phenyl-1-piperazinyl)phenyl]methanol | C24H26N2O | 详情 | 详情 | |
| (XXXII) | 62417 | 2-benzyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine | C24H24N2 | 详情 | 详情 | |
| (XXXIII) | 62418 | butyl 3,4,10,14b-tetrahydrodibenzo[c,f]pyrazino[1,2-a]azepine-2(1H)-carboxylate | C22H26N2O2 | 详情 | 详情 | |
| (XXXIV) | 62419 | 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine | C17H18N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)An improved synthesis of the title compound has been developed. Methyl ester (XX) was prepared from the known indazolylbenzoate sodium salt (XIX) by alkylation with iodomethane and K2CO3. Benzylic bromination of (XX) using NBS in the presence of AIBN as the radical initiator furnished the bromomethyl derivative (XXI). The brominated ester (XXI) was cyclized with trifluoromethanesulfonic acid at 100 C to provide the pyrazoloacridone (XXII) along with some phenol analogue (XXIII). Complete cleavage of the methyl ether of (XXII) was then accomplished with HBr in AcOH at 70 C. Further bromination of (XXIII) with elemental bromine in dichloroethane gave the ortho-bromophenol (XXIV). Introduction of the hydroxy group at C-10 was carried out by a two step sequence involving oxidation of (XXIV) to quinone (XXV) with (diacetoxy)iodobenzene, followed by its reduction to the corresponding hydroquinone (XXVI) with tetrabutylammonium triacetoxyborohydride. Condensation of (XXVI) with N-benzylethanolamine (XXVII) yielded the tertiary amine (XXVIII). Further bromine displacement in (XXVIII) with 1,3-propanediamine (XVI) provided (XXIX). The remaining bromine and the N-benzyl protecting groups of (XXIX) were finally subjected to hydrogenolysis in the presence of Pd/C
| 【1】 Mimura, T.; Kato, N.; Sugaya, T.; Ikuta, M.; Kato, S.; Kuge, Y.; Tomioka, S.; Kasai, M.; An efficient synthesis of a new class of DNA intercalating antitumor 7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-ones. Synthesis (Stuttgart) 1999, 6, 947. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (XIX) | 60014 | 2-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methoxybenzoate | C16H12BrN2O3 | 详情 | 详情 | |
| (XX) | 60015 | methyl 2-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methoxybenzoate | C17H15BrN2O3 | 详情 | 详情 | |
| (XXI) | 60016 | methyl 2-[6-bromo-3-(bromomethyl)-1H-indazol-1-yl]-6-methoxybenzoate | C17H14Br2N2O3 | 详情 | 详情 | |
| (XXII) | 60017 | 5-bromo-2-(bromomethyl)-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C16H10Br2N2O2 | 详情 | 详情 | |
| (XXIII) | 60018 | 5-bromo-2-(bromomethyl)-7-hydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H8Br2N2O2 | 详情 | 详情 | |
| (XXIV) | 60019 | 5,8-dibromo-2-(bromomethyl)-7-hydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H7Br3N2O2 | 详情 | 详情 | |
| (XXV) | 60005 | 5,8-dibromo-7-hydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H8Br2N2O2 | 详情 | 详情 | |
| (XXVI) | 60007 | 5,8-dibromo-7,10-dihydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H8Br2N2O3 | 详情 | 详情 | |
| (XXVII) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (XXVIII) | 60020 | 2-{[benzyl(butyl)amino]methyl}-5,8-dibromo-7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C26H23Br2N3O3 | 详情 | 详情 | |
| (XXIX) | 60021 | 5-[(3-aminopropyl)amino]-2-{[benzyl(butyl)amino]methyl}-8-bromo-7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C29H32BrN5O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Condensation of epichlorohydrin (I) with N-benzylethanolamine (II) in the presence of sulfuric acid afforded the (chloromethyl)morpholine (III). Halogen displacement in (III) by potassium phthalimide (IV) provided the substituted phthalimide (V). Further hydrazinolysis of (V) furnished racemic (aminomethyl)morpholine (VI) (1). The desired (S) enantiomer (VII) was obtained by crystallization of (VI) as the dibenzoyl-D-tartaric acid salt, followed by liberation of the base with NaOH. Eschweiler-Clarke reductive methylation of (VII) with formaldehyde and formic acid produced the dimethylamino derivative (VIII). The N-benzyl groupof (VIII) was then cleaved by transfer hydrogenation in the presence of hydrazine and Pd/C yielding chiral morpholine (IX). Finally, coupling of this morpholine (IX) with the difluoroqyuinolone boron chelate (X) provided the title morpholino quinolone.
| 【1】 Sakurai, N.; Sano, M.; Hirayama, F.; Kuroda, T.; Uemori, S.; Moriguchi, A.; Yamamoto, K.; Ikeda, Y.; Kawakita, T.; Synthesis and structure-activity relationships of 7-(2-aminoalkyl)morpholinoquinolones as anti-Helicobacter pylori agents. Bioorg Med Chem Lett 1998, 8, 16, 2185. |
| 【2】 Uemori, S.; Hirayama, F.; Moriguchi, A.; Sano, M.; Yokoyama, Y.; Ikeda, Y.; Miyoshi, M.; Sakurai, N.; Yamamoto, K.; Kawakita, T.; Synthesis and anti-Helicobacter pylori activity of Y-34867, a new 7-morpholinoquinolone. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-85. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (II) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (III) | 13396 | 4-Benzyl-2-(chloromethyl)morpholine | C12H16ClNO | 详情 | 详情 | |
| (IV) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (V) | 13398 | 2-[(4-Benzyl-2-morpholinyl)methyl]-1H-isoindole-1,3(2H)-dione | C20H20N2O3 | 详情 | 详情 | |
| (VI) | 13399 | (4-Benzyl-2-morpholinyl)methylamine; (4-Benzyl-2-morpholinyl)methanamine | C12H18N2O | 详情 | 详情 | |
| (VII) | 25362 | 1,4,8,11-Tetraazacyclotetradecane | 295-37-4 | C10H24N4 | 详情 | 详情 |
| (VIII) | 25633 | N-[[(2S)-4-benzylmorpholinyl]methyl]-N,N-dimethylamine | C14H22N2O | 详情 | 详情 | |
| (IX) | 25634 | N,N-dimethyl-N-[(2R)morpholinylmethyl]amine | C7H16N2O | 详情 | 详情 | |
| (X) | 25635 | 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid diacetoxyboron complex | C18H16BF2NO8 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXVII)In an alternative route to morpholine (XVIII), bromination of 1,3-bis(trifluoromethyl)benzene (XX) by means of 1,3-dibromo-5,5-dimethylhydantoin (XXI) yielded bromide (XXII). The Grignard reagent prepared from aryl bromide (XXII) was acylated with acetic anhydride at -15 C to produce acetophenone (XXIII). Enantioselective reduction of ketone (XXIII) with ruthenium(II) chloride in the presence of (1S,2R)-cis-1-amino-2-indanol furnished the (R)-alcohol (XXIV). N-Benzyl ethanolamine (XXV) was condensed with glyoxylic acid (XXVI) to give the hydroxy oxazinone (XXVII). This was coupled with the chiral alcohol (XXIV) using trifluoroacetic anhydride and boron trifluoride etherate to afford the target (R,R)-adduct (XXVIII) as the main diastereoisomer. Addition of 4-fluorophenylmagnesium bromide (XXIX) to the lactam function of (XXVIII), followed by catalytic hydrogenation of the intermediate (XXX), provided the required disubstituted morpholine (XVIII).
| 【1】 Wang, J.; Crocker, L.; Cai, D. (Merck & Co., Inc.); Polymorphic form of a tachykinin receptor antagonist. WO 0132656 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 18293 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine | 171482-05-6 | C20H18F7NO2 | 详情 | 详情 |
| (XX) | 53293 | 1,3-Bis(trifluoromethyl)benzene; 1,3-Di(trifluoromethyl)benzene; alpha,alpha,alpha,alpha',alpha',alpha'-Hexafluoro-m-xylene; m-Xylene hexafluoride | 402-31-3 | C8H4F6 | 详情 | 详情 |
| (XXI) | 31277 | 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione | 77-48-5 | C5H6Br2N2O2 | 详情 | 详情 |
| (XXII) | 53294 | 1,3-Bis(trifluoromethyl)-5-bromobenzene; 1-Bromo-3,5-bis(trifluoromethyl)benzene; 3,5-Bis(trifluoromethyl)bromobenzene | 328-70-1 | C8H3BrF6 | 详情 | 详情 |
| (XXIII) | 40778 | 1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanone | 30071-93-3 | C10H6F6O | 详情 | 详情 |
| (XXIV) | 53295 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanol | n/a | C10H8F6O | 详情 | 详情 |
| (XXV) | 53296 | 4-benzyl-2-hydroxy-3-morpholinone | 287930-73-8 | C11H13NO3 | 详情 | 详情 |
| (XXVI) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXVII) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (XXVIII) | 53297 | (2R)-4-benzyl-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-morpholinone | n/a | C21H19F6NO3 | 详情 | 详情 |
| (XXIX) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XXX) | 53298 | (2R)-4-benzyl-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)-3-morpholinol | n/a | C27H24F7NO3 | 详情 | 详情 |