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【结 构 式】 
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【分子编号】13161 【品名】Quinaldine; 2-Methylquinoline 【CA登记号】91-63-4 |
【 分 子 式 】C10H9N 【 分 子 量 】143.1882 【元素组成】C 83.88% H 6.34% N 9.78% |
合成路线1
该中间体在本合成路线中的序号：(I)A synthesis of RG-12525 has been published: The reaction of 2-methylquinoline (I) with chlorine gas gives 2-(chloromethyl)quinoline (II), which is condensed with an excess of hydroquinone (III) yielding 4-(quinolin-2-ylmethoxy)phenol (IV). The reaction of (IV) with an excess of alpha,alpha'-dichloro-o-xylene (V) affords the monoaddition compound (VI), which is treated with sodium cyanide giving the phenylacetonitrile derivative (VII). Finally, this compound is submitted to cyclization with sodium azide.
| 【1】 Bridge, A.W.; et al.; The process development of RG 12525 (2-'{[4-(tetrazol-5-ylmethylphenyl)-methoxy]phenoxymethyl}quinoline). Org Process Res Dev 2001, 5, 1, 9. |
| 【2】 O'Brien, M.; Sledeski, A.W.; Truesdale, L.K.; Approaches to p-hydroxyphenoxymethylquinolines which avoid intermediate chloromethylquinolines for the synthesis of the LTD4 antagonist, RG 12525. Tetrahedron Lett 1997, 38, 4, 509. |
| 【3】 Huang, F.-C.; Galemmo Jr., R.A.; Campbell, H.F. (Aventis Pharma SA); Quinoline derivs. as antagonists of leukotriene D4, compsns. containing the same and processes for their preparation. EP 0348155; EP 0784052; US 4920131 . |
| 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) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (II) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (III) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (IV) | 13164 | 4-(2-Quinolinylmethoxy)phenol | C16H13NO2 | 详情 | 详情 | |
| (V) | 13165 | 1,2-Bis(chloromethyl)benzene | 612-12-4 | C8H8Cl2 | 详情 | 详情 |
| (VI) | 13166 | 2-(Chloromethyl)benzyl 4-(2-quinolinylmethoxy)phenyl ether; 2-[(4-[[2-(Chloromethyl)benzyl]oxy]phenoxy)methyl]quinoline | C24H20ClNO2 | 详情 | 详情 | |
| (VII) | 13167 | 2-(2-[[4-(2-Quinolinylmethoxy)phenoxy]methyl]phenyl)acetonitrile | C25H20N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Synthesis of intermediate 4-(2-quinolinylmethoxy)phenol (V): The oxidation of 2-methylquinoline with urea and H2O2 in dichloromethane gives the N-oxide (II), which is treated with TsCl and K2CO3 in acetonitrile to yield the tosylate (III). Finally this compound is condensed with an excess of hydroquinone by means of NaOH in methanol/acetonitrile to afford the target intermediate (V).
| 【1】 Sledeski, A.W.; et al.; A convergent synthesis of an LTD4 antagonist, RG12525. Tetrahedron Lett 1997, 38, 7, 1129. |
| 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) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (II) | 43890 | 2-methyl-1-quinoliniumolate | C10H9NO | 详情 | 详情 | |
| (III) | 43891 | 2-quinolinylmethyl 4-methylbenzenesulfonate | C17H15NO3S | 详情 | 详情 | |
| (IV) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (V) | 13164 | 4-(2-Quinolinylmethoxy)phenol | C16H13NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)[14C]-Saquinavir: The cyclization of [ring-14C]-aniline (I) with crotonic aldehyde (II) by means of HCl and acetic anhydride gives labeled 2-methylquinoline (III), which is brominated with Br2 in acetic acid yielding the tribromo derivative (IV). The hydrolysis of (IV) with hot sulfuric acid afforded labeled quinoline-2-carboxylic acid (V), which is finally condensed with Ro-32-0445 (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC) in THF.
| 【1】 Wiltshire, H.R.; et al.; The synthesis of labelled forms of saquinavir. J Label Compd Radiopharm 1998, 41, 12, 1103. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (I) | 22516 | aniline; phenylamine | C6H7N | 详情 | 详情 | |
| (II) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (III) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (III) | 22518 | 2-methylquinoline | C10H9N | 详情 | 详情 | |
| (IV) | 22519 | 2-(tribromomethyl)quinoline | C10H6Br3N | 详情 | 详情 | |
| (IV) | 22526 | 2-(tribromomethyl)quinoline | 613-53-6 | C10H6Br3N | 详情 | 详情 |
| (V) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (V) | 22520 | 2-quinolinecarboxylic acid | C10H7NO2 | 详情 | 详情 | |
| (VI) | 22521 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Pentadeuterated saquinavir: The nitration of hexadeuterobenzene (VII) with HNO3/H2SO4 gives pentadeuteronitrobenzene (VIII), which is hydrogenated with deuterium/Pt in D1-methanol yielding heptadeuteroaniline (IX). The cyclization of (IX) with crotonic aldehyde (II) by means of DCI/D2O and acetic anhydride as before affords hexadeuterated quinoline (X), which is brominated with Br2 as before giving the tribromo derivative (XI). The hydrolysis of (XI) with sulfuric acid as before yields the acid (XII), which is finally condensed with Ro-32-0445 (VI) as before.
| 【1】 Wiltshire, H.R.; et al.; The synthesis of labelled forms of saquinavir. J Label Compd Radiopharm 1998, 41, 12, 1103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (VI) | 22521 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (VII) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (VII) | 63831 | benzene | C6H6 | 详情 | 详情 | |
| (VIII) | 22523 | 1-nitrobenzene | 28250-14-8 | C6H5NO2 | 详情 | 详情 |
| (VIII) | 63832 | 1-nitrobenzene | C6H5NO2 | 详情 | 详情 | |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IX) | 63833 | aniline; phenylamine | C6H7N | 详情 | 详情 | |
| (X) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (X) | 63834 | 2-methylquinoline | C10H9N | 详情 | 详情 | |
| (XI) | 22526 | 2-(tribromomethyl)quinoline | 613-53-6 | C10H6Br3N | 详情 | 详情 |
| (XI) | 63835 | 2-(tribromomethyl)quinoline | C10H6Br3N | 详情 | 详情 | |
| (XII) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XII) | 63836 | 2-quinolinecarboxylic acid | C10H7NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)Tetradeuterated saquinavir: The cyclization of heptadeuteroaniline (IX) with crotonic aldehyde (II) by means of HCl and acetic anhydride as before gives the tetradeuteroquinoline (XIII), which is brominated as described yielding the tribromo derivative (XIV). The hydrolysis of (XIV) with sulfuric acid affords tetradeuterated acid (XV), which is finally condensed with Ro-32-0445 (VI) as indicated.
| 【1】 Wiltshire, H.R.; et al.; The synthesis of labelled forms of saquinavir. J Label Compd Radiopharm 1998, 41, 12, 1103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (VI) | 22521 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IX) | 63833 | aniline; phenylamine | C6H7N | 详情 | 详情 | |
| (XIII) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (XIII) | 63834 | 2-methylquinoline | C10H9N | 详情 | 详情 | |
| (XIV) | 22526 | 2-(tribromomethyl)quinoline | 613-53-6 | C10H6Br3N | 详情 | 详情 |
| (XV) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XV) | 63836 | 2-quinolinecarboxylic acid | C10H7NO2 | 详情 | 详情 | |
| (XVI) | 63835 | 2-(tribromomethyl)quinoline | C10H6Br3N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXIV)5)[15N,13C,2H]-Saquinavir: The nitration of [13C6]-benzene (XXI) with [15N]-nitric acid gives the corresponding nitrobenzene (XXII), which is reduced with Sn/HCl to the aniline (XXIII). The cyclization of (XXIII) with crotonic aldehyde (II) by means of ClD/D2O and acetic ahydride yields the tetradeuterated quinoline (XXIV), which is brominated as before givig the tribromo derivative (XXV). The hydrolysis of (XXV) with sulfuric acid as usual affords the [15N,13C6,2H3]-labeled quinoline-2-carboxylic acid (XXVI), which is finally condensed with Ro-32-0445 (VI) by means of HOBT and CDI as indicated.
| 【1】 Wiltshire, H.R.; et al.; The synthesis of labelled forms of saquinavir. J Label Compd Radiopharm 1998, 41, 12, 1103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (VI) | 22521 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (XI) | 22526 | 2-(tribromomethyl)quinoline | 613-53-6 | C10H6Br3N | 详情 | 详情 |
| (XI) | 45225 | 2-(tribromomethyl)quinoline | C10H6Br3N | 详情 | 详情 | |
| (XII) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XII) | 45226 | 2-quinolinecarboxylic acid | C10H7NO2 | 详情 | 详情 | |
| (XXI) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (XXI) | 22536 | benzene | C6H6 | 详情 | 详情 | |
| (XXII) | 22523 | 1-nitrobenzene | 28250-14-8 | C6H5NO2 | 详情 | 详情 |
| (XXII) | 22537 | 1-nitrobenzene | C6H5NO2 | 详情 | 详情 | |
| (XXIII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (XXIII) | 22538 | phenylamine; aniline | C6H7N | 详情 | 详情 | |
| (XXIV) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (XXIV) | 45224 | 2-methylquinoline | C10H9N | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)The intermediate acetophenone (III) was prepared from 5-chlorosalicylic acid (I) by O-acetylation with acetic anhydride and a catalytic amount of sulfuric acid, followed by Fries rearrangement of the resulting acetate (II) on heating with aluminum chloride. Condensation of 2-methylquinoline (IV) with an excess of 1,3-benzene dicarboxaldehyde (V) in a refluxing mixture of acetic anhydride and xylene provided aldehyde (VI), which was then condensed with acetophenone (III) by treatment with KOH in a mixture of ethanol and tetrahydrofuran to give chalcone (VII). Finally, oxidative ring closure by refluxing with selenium dioxide in dioxan yielded the desired flavone.
| 【1】 Zwaagstra, M. E.; et al.; Synthesis and structure-activity relationships of carboxyflavones as structurally rigid CysLT1 (LTD4) receptor antagonists. J Med Chem 1998, 41, 9, 1428. |
| 【2】 Zwaagstra, M.E.; et al.; Synthesis and structure - activity relationships of carboxylated chalcones: A novel series of CysLT1 (LTD4) receptor antagonists. J Med Chem 1997, 40, 7, 1075. |
| 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) | 13895 | 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid | 321-14-2 | C7H5ClO3 | 详情 | 详情 |
| (II) | 18865 | 2-(acetoxy)-5-chlorobenzoic acid | C9H7ClO4 | 详情 | 详情 | |
| (III) | 18866 | 3-acetyl-5-chloro-2-hydroxybenzoic acid | C9H7ClO4 | 详情 | 详情 | |
| (IV) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (V) | 18868 | isophthalaldehyde | 626-19-7 | C8H6O2 | 详情 | 详情 |
| (VI) | 18869 | 3-[(E)-2-(2-quinolinyl)ethenyl]benzaldehyde | C18H13NO | 详情 | 详情 | |
| (VII) | 18870 | 5-chloro-2-hydroxy-3-((E)-3-[3-[(E)-2-(2-quinolinyl)ethenyl]phenyl]-2-propenoyl)benzoic acid | C27H18ClNO4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Benzylic bromination of 2-methylquinoline (I) by means of N-bromosuccinimide afforded 2-(bromomethyl)quinoline (II). Dimerization of (II) using ethylenediamine gave the corresponding bis(quinolylmethyl)ethylenediamine, which was finally converted to the tetrahydrochloride salt.
| 【1】 Mikata, Y.; et al.; Effect of the linking position of a side chain in bis (quinolymethyl)ethylenediamine as a DNA binding agent. Chem Pharm Bull 2000, 48, 4, 477. |