|
【结 构 式】 
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【分子编号】13162 【品名】2-(Chloromethyl)quinoline; alpha-Chloroquinaldine 【CA登记号】4377-41-7 |
【 分 子 式 】C10H8ClN 【 分 子 量 】177.63296 【元素组成】C 67.62% H 4.54% Cl 19.96% N 7.89% |
合成路线1
该中间体在本合成路线中的序号：(II)By condensation of 1-naphthol (I) with 2-(chloromethyl)quinoline (II) by means of NaH in DMF.
| 【1】 Marshall, L.A.; Wong, A.; Kreft, A.F.; Structure -activity relationships in the quinoline- containing class of inhibitors of 5-lipoxygenase (5-LO) enzyme translocation and activation. Drugs Fut 1994, 19, 3, 255. |
| 【2】 Kreft, A.F.; Failli, A.; Musser, J.H.; et al.; Conversion of a cyclooxygenase (CO) inhibitor into a 5-lipoxygenase (LO) inhibitor - A general route to novel antiinflammatory and antiallergy drugs. Drugs Exp Clin Res 1991, 17, 381-387. |
合成路线2
该中间体在本合成路线中的序号：(A)Alkylation of 3-aminophenol (I) with 2-(chloromethyl)quinoline (A) in a mixture of DMSO and THF employing sodium hydride as the base affords the intermediate amine (II). This amine is reacted with trifluoromethanesulfonic anhydride in toluene employing potassium carbonate as a base to afford ritolukast.
| 【1】 Musser, J.H.; Kubrak, D.M.; Kreft, A.F. (American Home Products Corp.); Quinoline compounds as antiallergy and antithrombotic agents. EP 0232954; GB 2185741; JP 1987190159; US 4675405 . |
| 【2】 Kreft, A.; Musser, J.; Daniel, W.C.; Hand, J.; RITOLUKAST < USAN >. Drugs Fut 1990, 15, 12, 1191. |
| 【3】 Musser, J.H.; Kreft, A.F.; Bender, R.H.W.; Kubrak, D.M.; Carlson, R.P.; Chang, J.; Hand, J.M.; N-[(Arylmethoxy)phenyl] and N-[(arylmethoxy)naphthyl]sulfonamides. Potent orally active leukotriene D4 antagonists of novel structure. J Med Chem 1989, 32, 6, 1176. |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of 2-(chloromethyl)quinoline (I) with 3-nitrophenol (II) by means of Cs2CO3 in refluxing acetone gives the 3-nitrophenyl ether (III), which is reduced with H2 over Raney-Ni in ethanol to afford the 3-aminophenyl ether (IV). Finally this compound is sulfonated with trifluoromethanesulfonic anhydride and Et3N in dichloromethane.
| 【1】 Kreft, A.; Musser, J.; Substituted-[2-quinolynil(bridged)aryl] compounds: modulators of eicosanoid biosynthesis and action. Drugs Fut 1990, 15, 1, 73. |
| 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) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (II) | 18076 | Metanitrophenol; 3-nitrophenol | 554-84-7 | C6H5NO3 | 详情 | 详情 |
| (III) | 43199 | 3-nitrophenyl 2-quinolinylmethyl ether; 2-[(3-nitrophenoxy)methyl]quinoline | C16H12N2O3 | 详情 | 详情 | |
| (IV) | 31234 | 3-(2-quinolinylmethoxy)aniline; 3-(2-quinolinylmethoxy)phenylamine | C16H14N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Alkylation of 5-methoxytetralone (I) with n-butyl iodide in the presence of lithium diisopropylamide (LDA) in dimethoxyethane afforded a mixture of mono- (II) and dialkylated (III) compounds that were separated by column chromatography. Hydrolysis of methoxy group of (III) by treatment with AlBr3 in refluxing benzene yielded phenol (IV), which was converted to ether (VI) by treatment with 2-(chloromethyl)quinoline (V) and K2CO3. The reduction of ketone (VI) with NaBH4 in MeOH provided racemic alcohol (VII). Resolution of racemate (VII) was performed by esterification with (S)-O-methylmandeloyl chloride (VIII), followed by chromatographic separation of the diastereomeric mixture. Then, basic hydrolysis of pure diastereomer (IX) provided the (+)-enantiomer. Alternatively, asymmetric reduction of tetralone (VI) with LiAlH4 in cold THF in the presence of the chiral auxiliary (S)-4-anilino-3-methylamino-1-butanol (X) or (S)-2-amino-3-methyl-1,1-diphenyl-1-butanol (XI) afforded (+)-alcohol (respectively).
| 【1】 Yatabe, T.; Kayakiri, H.; Kawai, Y.; Oku, T.; Tanaka, H.; Studies on 5-lipoxygenase inhibitors. II. Discovery, optical resolution and enantioselective synthesis of FR110302, a highly potent non-redox type 5-lipoxygenase inhibitor. Chem Pharm Bull 1998, 46, 10, 1556. |
| 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) | 18568 | 5-methoxy-3,4-dihydro-1(2H)-naphthalenone | 33892-75-0 | C11H12O2 | 详情 | 详情 |
| (II) | 18569 | 2-butyl-5-methoxy-3,4-dihydro-1(2H)-naphthalenone | C15H20O2 | 详情 | 详情 | |
| (III) | 18570 | 2,2-dibutyl-5-methoxy-3,4-dihydro-1(2H)-naphthalenone | C19H28O2 | 详情 | 详情 | |
| (IV) | 18571 | 2,2-dibutyl-5-hydroxy-3,4-dihydro-1(2H)-naphthalenone | C18H26O2 | 详情 | 详情 | |
| (V) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (VI) | 18573 | 2,2-dibutyl-5-(2-quinolinylmethoxy)-3,4-dihydro-1(2H)-naphthalenone | C28H33NO2 | 详情 | 详情 | |
| (VII) | 18574 | 2,2-dibutyl-5-(2-quinolinylmethoxy)-1,2,3,4-tetrahydro-1-naphthalenol | C28H35NO2 | 详情 | 详情 | |
| (VIII) | 18575 | (2S)-2-methoxy-2-phenylethanoyl chloride | C9H9ClO2 | 详情 | 详情 | |
| (IX) | 18576 | 2,2-dibutyl-5-(2-quinolinylmethoxy)-1,2,3,4-tetrahydro-1-naphthalenyl (2S)-2-methoxy-2-phenylethanoate | C37H43NO4 | 详情 | 详情 | |
| (X) | 18577 | (3R)-4-anilino-3-(methylamino)-1-butanol | C11H18N2O | 详情 | 详情 | |
| (XI) | 18578 | 2-amino-1,1-diphenyl-1-pentanol | C17H21NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)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6
该中间体在本合成路线中的序号：(I)The condensation of 2-(chloromethyl)quinoline (I) with hydroquinone monobenzoate (II) by means of K2CO3 in refluxing acetone/DMF gives 4-(2-quinolylmethoxy)phenyl benzoate (III), which is treated with sodium ethoxide in ethanol to yield 4-(2-quinolylmethoxy)phenol (IV). The condensation of (IV) with alpha,alpha'-dichloro-o-xylene (V) by means of NaH in THF affords the benzyl chloride derivative (VI), which is treated with NaCN in toluene/water with a phase-transfer catalyst to provide the benzyl cyanide derivative (VII). Finally, this compound is cyclized with sodium azide in hot DMF to afford the target tetrazole derivative.
| 【1】 Huang, F.-C.; (2-Quinolinylmethoxy)phenyl-containing compounds as leukotriene receptor antagonists: A brief review of structure-activity relationships and the biological profile of RG 12525. Drugs Fut 1991, 16, 12, 1121. |
| 【2】 Huang, F.-C.; et al.; Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 2. Effects of an additional phenyl ring on receptor affinity. J Med Chem 1990, 33, 4, 1194. |
| 【3】 Youssefyeh, R.D.; et al.; Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 1. Initial structure-activity relationships. J Med Chem 1990, 33, 4, 1186. |
| 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) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (II) | 44042 | 4-hydroxyphenyl benzoate | C13H10O3 | 详情 | 详情 | |
| (III) | 44043 | 4-(2-quinolinylmethoxy)phenyl benzoate | C23H17NO3 | 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7
该中间体在本合成路线中的序号：(II)By condensation of 2(S)-(6-hydroxy-2-naphthyl)propionic acid (I) with 2-(chloromethyl)quinoline (II) by means of NaH in DMF.
| 【1】 Kreft, A.F.; Failli, A.; Musser, J.H.; et al.; Conversion of a cyclooxygenase (CO) inhibitor into a 5-lipoxygenase (LO) inhibitor - A general route to novel antiinflammatory and antiallergy drugs. Drugs Exp Clin Res 1991, 17, 381-387. |
| 【2】 Kreft, A.; Musser, J.; Substituted-[2-Quinolinyl(Bridged)Aryl] compounds: Modulators of eicosanoid biosynthesis and action. Drugs Fut 1990, 15, 1, 73. |
| 【3】 Marshall, L.A.; Wong, A.; Kreft, A.F.; Structure -activity relationships in the quinoline- containing class of inhibitors of 5-lipoxygenase (5-LO) enzyme translocation and activation. Drugs Fut 1994, 19, 3, 255. |
合成路线8
该中间体在本合成路线中的序号：(II)Alkylation of the disodium salt of the known optically active hydroxyacid (I) with 2-chloromethylquinoline (II) in DMF afforded Wy-50,295 free acid (III). This was reacted with tromethamine in aqueous ethanol to afford the salt (IV).
| 【1】 Kreft, A.F.; Musser, J.H.; Bicksler, J.J.; Giberson, J.W.; Kubrak, D.M. (American Home Products Corp.); 2-Aryl substituted heterocyclic compounds as antiallergic and antiinflammatory agents. AU 8819209; EP 0301813; GB 2207428; US 5208344 . |
| 【2】 Riegl, J.; Maddox, M.L.; Harrison, I.T.; Determination of the absolute configurations of (+)-2-(6-methoxy-2-naphthyl)propionic acid. J Med Chem 1974, 17, 377. |
| 【3】 Kreft, A.; Musser, J.; Marshall, L.; Grimes, D.; Wy-50,295 TROMETHAMINE. Drugs Fut 1990, 15, 8, 805. |
合成路线9
该中间体在本合成路线中的序号：(II)By condensation of 2-(2-fluoro-4'-hydroxybiphenyl-4-yl)acetic acid (I) with 2-(chloromethyl)quinoline (II) by means of NaH in DMF.
| 【1】 Marshall, L.A.; Wong, A.; Kreft, A.F.; Structure -activity relationships in the quinoline- containing class of inhibitors of 5-lipoxygenase (5-LO) enzyme translocation and activation. Drugs Fut 1994, 19, 3, 255. |
| 【2】 Kreft, A.F.; Failli, A.; Musser, J.H.; et al.; Conversion of a cyclooxygenase (CO) inhibitor into a 5-lipoxygenase (LO) inhibitor - A general route to novel antiinflammatory and antiallergy drugs. Drugs Exp Clin Res 1991, 17, 381-387. |
合成路线10
该中间体在本合成路线中的序号：The racemic mixture containing the (R)-enantiomer BAY X 1005 (IV) can be prepared according to the following scheme: 4-Hydroxyphenylacetic acid methyl ester (I) is coupled with 2-chloromethylquinoline and potassium carbonate in DMF. The resulting product (II) is alkylated with cyclopentylbromide and sodium hydride in DMF to give product (III). Final saponification is undertaken with sodium hydroxide in methanol leading to the racemic carboxylic acid (IV).
| 【1】 Muller-Peddinghaus, R.; Raddatz, S.; BAY X 1005. Drugs Fut 1995, 20, 10, 996. |
| 【2】 Mohrs, K.; Raddatz, S.; Perzborn, E.; Fruchtmann, R.; Kohlsdorfer, C.; Müller-Peddinghaus, R.; Theisen, P. (Bayer AG); Substd. 4-(quinoline-2-yl-methoxy)phenyl-acetic acid derivs. AU 8935270; DE 3900261; EP 0344519; JP 1990019359; JP 1998053577; US 4970215 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10972 | 1-Bromocyclopentane; Cyclopentyl bromide | 137-43-9 | C5H9Br | 详情 | 详情 | |
| 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 | |
| (I) | 15822 | Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate | 14199-15-6 | C9H10O3 | 详情 | 详情 |
| (II) | 15823 | methyl 2-[4-(2-quinolinylmethoxy)phenyl]acetate | C19H17NO3 | 详情 | 详情 | |
| (III) | 15824 | methyl 2-cyclopentyl-2-[4-(2-quinolinylmethoxy)phenyl]acetate | C24H25NO3 | 详情 | 详情 | |
| (IV) | 15825 | 2-cyclopentyl-2-[4-(2-quinolinylmethoxy)phenyl]acetic acid | C23H23NO3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(III)By condensation of 4-(2-quinolinylmethoxy)benzaldeyde (I) with 2-hydroxy-5(1H-tetrazol-5-yl)acetophenone (II) by means of KOH in ethanol/water. The intermediates (I) and (II) have been obtained as follows: Benzaldehyde (I): By condensation of 2-(chloromethyl)quinoline (III) with 4-hydroxybenzaldehyde (IV) by means of K2CO3 in hot DMF. Acetophenone (II): The acetylation of 4-hydroxybenzonitrile (V) with acetic anhydride/sulfuric acid and AlCl3 gives 5-cyano-2-hydroxyacetophenone (VI), which is then cyclized with sodium azide and ammonium chloride in hot DMF.
| 【1】 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) | 25883 | 4-(2-quinolinylmethoxy)benzaldehyde | C17H13NO2 | 详情 | 详情 | |
| (II) | 25884 | 1-[2-hydroxy-5-(1H-1,2,3,4-tetraazol-5-yl)phenyl]-1-ethanone | C9H8N4O2 | 详情 | 详情 | |
| (III) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (IV) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (V) | 25109 | 4-hydroxybenzonitrile | 767-00-0 | C7H5NO | 详情 | 详情 |
| (VI) | 12857 | 3-Acetyl-4-hydroxybenzonitrile | C9H7NO2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)Esterification of 4,4-bis(4-hydroxyphenyl)pentanoic acid (I) was performed in a refluxing methanolic solution, using sulfuric acid as the catalyst. The resulting methyl ester (II) was alkylated on both phenolic groups with 2-(chloromethyl)quinoline hydrochloride (III) in the presence of potassium carbonate to afford IV. Hydrolysis of this ester (IV) with NaOH in a refluxing mixture of dioxane-methanol yielded acid (V), which was then converted into the sodium salt on treatment with one equivalent of NaOH in dioxane-methanol.
| 【1】 Brooks, C.D.W.; Bhatia, P.; Kolasa, T.; Stewart, A.O.; Gunn, D.E.; Craig, R.A. (Abbott Laboratories Inc.); Symmetrical bis-heteroarylmethoxyphenylalkyl carboxylates as inhibitors of leukotriene biosynthesis. EP 0862557; US 5795900; WO 9712867 . |
| 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) | 22391 | 4,4-bis(4-hydroxyphenyl)pentanoic acid | 126-00-1 | C17H18O4 | 详情 | 详情 |
| (II) | 22392 | methyl 4,4-bis(4-hydroxyphenyl)pentanoate | C18H20O4 | 详情 | 详情 | |
| (III) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (IV) | 22394 | methyl 4,4-bis[4-(2-quinolinylmethoxy)phenyl]pentanoate | C38H34N2O4 | 详情 | 详情 | |
| (V) | 22395 | 4,4-bis[4-(2-quinolinylmethoxy)phenyl]pentanoic acid | C37H32N2O4 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(V)The reaction of phenol (I) with 4-oxopentanoic acid (II) by means of H2SO4 gives 4,4-bis(4-hydroxyphenyl)pentanoic acid (III), which is esterified with MeOH and H2SO4 to yield the methyl pentanoate (IV). The condensation of (IV) with 2-(chloromethyl)quinoline (V) by means of K2CO3 in DMF affords the adduct (VI), which is finally hydrolyzed with NaOH in methanol/dioxane to provide the target sodium salt. Alternatively, the intermediate methyl pentanoate (IV) can also be obtained by direct condensation of phenol (I) with methyl 4-oxopentanoate (VII) by means of H2SO4 as before.
| 【1】 Gunn, D.E.; Bhatia, P.; Kolasa, T.; et al.; Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis. J Med Chem 2000, 43, 17, 3322. |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 36170 | 4-oxopentanoic acid | 123-76-2 | C5H8O3 | 详情 | 详情 |
| (III) | 22391 | 4,4-bis(4-hydroxyphenyl)pentanoic acid | 126-00-1 | C17H18O4 | 详情 | 详情 |
| (IV) | 22392 | methyl 4,4-bis(4-hydroxyphenyl)pentanoate | C18H20O4 | 详情 | 详情 | |
| (V) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (VI) | 22394 | methyl 4,4-bis[4-(2-quinolinylmethoxy)phenyl]pentanoate | C38H34N2O4 | 详情 | 详情 | |
| (VII) | 50960 | Methyl levulinate | C6H10O3 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(II)Condensation of 4-hydroxyphenylethanol (I) with 2-(chloromethyl)quinoline (II) in ethanolic KOH provided ether (III). The free hydroxyl group of (III) was then converted to the corresponding mesylate (IV) by treatment with methanesulfonyl chloride and Et3N. Alkylation of 11-(4-piperidinylidene)-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-methanol (V) with mesylate (IV) in the presence of NaHCO3 gave adduct (VI). The primary alcohol of (VI) was oxidized to aldehyde (VII) using MnO2 in CH2Cl2. Finally, aldehyde (VII) was further oxidized to the title methyl ester by means of MnO2 in the presence of sodium cyanate in HOAc-MeOH.
| 【1】 Janssens, F.E.; Leenaerts, J.E.; Sommen, F.M.; Surleraux, D.L.N.G. (Janssen Pharmaceutica NV); Fused imidazole derivs. as multidrug resistance modulators. EP 0888352; JP 2000505477; US 6218381; WO 9734897 . |
| 【2】 Snoeck, H.J.M. (Janssen Pharmaceutica NV); Fused imidazole derivs. for improving oral bioavailability of pharmaceutical agents. WO 9913871 . |
| 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) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
| (II) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (III) | 47356 | 2-[4-(2-quinolinylmethoxy)phenyl]-1-ethanol | C18H17NO2 | 详情 | 详情 | |
| (IV) | 47357 | 4-(2-quinolinylmethoxy)phenethyl methanesulfonate | C19H19NO4S | 详情 | 详情 | |
| (V) | 47358 | [11-(4-piperidinylidene)-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepin-3-yl]methanol | C18H21N3O | 详情 | 详情 | |
| (VI) | 47359 | (11-[1-[4-(2-quinolinylmethoxy)phenethyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepin-3-yl)methanol | C36H36N4O2 | 详情 | 详情 | |
| (VII) | 47360 | 11-[1-[4-(2-quinolinylmethoxy)phenethyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-carbaldehyde | C36H34N4O2 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(I)The alkylation of N-formylpiperazine (II) with 2-(chloromethyl)quinoline (I) produced the disubstituted piperazine (III). The formyl group of (III) was then cleaved by means of H2SO4 in boiling EtOH, yielding quinolylmethylpiperazine (IV). Subsequent alkylation of (IV) with 1-bromo-3-chloropropane (V) afforded the chloropropyl derivative (VI). This was finally condensed with 7-hydroxybenzothiazinone (VII) in the presence of K2CO3 and a phase-transfer catalyst to furnish the title compound.
| 【1】 Tohma, T.; Onogi, K.; Zang, M.; Timmerman, H.; Wada, Y.; Tamura, M. (Kowa Co., Ltd.); Diamine derivs. and pharmaceutical containing the same. EP 0957100; WO 9902520 . |
| 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) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (II) | 23801 | 1-piperazinecarbaldehyde; N-Formylpiperazine | 7755-92-2 | C5H10N2O | 详情 | 详情 |
| (III) | 41113 | 4-(2-quinolinylmethyl)-1-piperazinecarbaldehyde | C15H17N3O | 详情 | 详情 | |
| (IV) | 41114 | 2-(1-piperazinylmethyl)quinoline | C14H17N3 | 详情 | 详情 | |
| (V) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (VI) | 41115 | 2-[[4-(3-chloropropyl)-1-piperazinyl]methyl]quinoline | C17H22ClN3 | 详情 | 详情 | |
| (VII) | 28290 | 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one | C8H7NO2S | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(IV)Ether cleavage of 4-(4-methoxyphenylsulfanyl)benzoic acid (I) with pyridine hydrochloride at 220 C provided phenol derivative (II). Subsequent esterification of (II) with methanol and sulfuric acid gave methyl ester (III). The quinolylmethyl ether (V) was then prepared by alkylation of (III) with 2-(chloromethyl)quinoline (IV) in the presence of K2CO3 and KI. Finally, the methyl ester group of (V) was hydrolyzed employing a hydroalcoholic solution of KOH.
| 【1】 Bucharova, V.; Jrickova, H.; Brunova B.; Kuchar, M.; Jandera, A.; Panajotova V.; Kmonicek, V. (Research Institute of Pharmacy and Biochemistry (VUFB)); Derivs. of hydroxyphenylsulfanylbenzoic and hydroxyphenylsulfanylarylacetic acids. WO 9967208 . |
| 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) | 42102 | 4-[(4-methoxyphenyl)sulfanyl]benzoic acid | C14H12O3S | 详情 | 详情 | |
| (II) | 42103 | 4-[(4-hydroxyphenyl)sulfanyl]benzoic acid | C13H10O3S | 详情 | 详情 | |
| (III) | 42104 | methyl 4-[(4-hydroxyphenyl)sulfanyl]benzoate | C14H12O3S | 详情 | 详情 | |
| (IV) | 13162 | 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine | 4377-41-7 | C10H8ClN | 详情 | 详情 |
| (V) | 42105 | methyl 4-[[4-(2-quinolinylmethoxy)phenyl]sulfanyl]benzoate | C24H19NO3S | 详情 | 详情 |