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【结 构 式】 
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【分子编号】19490 【品名】3-chloro-1-propanol 【CA登记号】627-30-5 |
【 分 子 式 】C3H7ClO 【 分 子 量 】94.54068 【元素组成】C 38.11% H 7.46% Cl 37.5% O 16.92% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 3-chloropropanol (I) with 2,6-dimethylpiperazine (II) by means of Na2CO3 in refluxing glycol monomethyl ether gives 3-(3,5-dimethyl-1-piperazinyl)propanol (III), which by reaction with refluxing SOCl2 is converted into 3-(3,5-dimethylpiperazinyl)propyl chloride (IV). Finally, this compound is condensed with carbazole (V) by means of NaH in hot DMF; a final treatment with aqueous HCl yields the dihydrochloride.
| 【1】 Harfenist, M.; Jogner, C.T. (Glaxo Wellcome Inc.); Carbazole compounds and medicinal use thereof. DD 147110; EP 0012208; EP 0051321; US 4379160 . |
| 【2】 Blancafort, P.; Hilier, K.; Serradell, M.N.; Castaner, J.; BW-234U. Drugs Fut 1983, 8, 4, 303. |
| 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) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 36062 | 3-[(3R,5S)-3,5-dimethylpiperazinyl]-1-propanol | C9H20N2O | 详情 | 详情 | |
| (IV) | 36063 | (3R,5S)-1-(3-chloropropyl)-3,5-dimethylpiperazine | C9H19ClN2 | 详情 | 详情 | |
| (V) | 36064 | 9H-carbazole | 86-74-8 | C12H9N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The optical resolution of (±)-5'-methoxylaudanosine with (-)-dibenzoyltartaric acid in methanol gives (R)-(-)-5'-methoxylaudanosine (I), which is condensed with 3-chloropropanol (II) by means of NaI and Na2CO3 in refluxing butanone yielding the quinolinium chloride derivative (III). Finally, this compound is esterified with 4(E)-octenedioyl chloride (IV) in hot 1,2-dichloroethane.
| 【1】 Swaringen, R.A. Jr.; El-Sayad, H.A.; Yeowell, D.A.; Savarese, J.J. (General Hospital Corporation; GlaxoSmithKline plc); Bis-dimethoxymethyl(trimethoxybenzyl)isoquinolinium salts, their preparation and pharmaceutical compsns. containing them. EP 0181055; ES 8609260; JP 1986087666; JP 1986087666; US 4761419 . |
| 【2】 Prous, J.; Castaner, J.; MIVACURIUM CHLORIDE < Rec INN; BAN >. Drugs Fut 1989, 14, 7, 632. |
| 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) | 19489 | (1R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline; 4-[[(1R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl]methyl]-2,6-dimethoxyphenyl methyl ether | C22H29NO5 | 详情 | 详情 | |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 19491 | (1R)-2-(3-hydroxypropyl)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolinium chloride | C25H36ClNO6 | 详情 | 详情 | |
| (IV) | 19492 | (E)-4-octenedioyl dichloride | C8H10Cl2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of 3-chloropropanol (I) with 2-methoxypropene (II) by means of PPTS gives the mixed ketal (III), which is condensed with diethyl malonate (IV) by means of sodium ethoxide in hot ethanol, affording the adduct (V). The reduction of (V) with NaH and Red-Al in refluxing toluene provides the allyl alcohol derivative (VI), which is submitted to an asymmetric epoxidation to give the epoxide (VII). The reaction of (VII) with octadecyl bromide (VIII) by means of NaH and tetrabutylammonium iodide (TBAI) yields the corresponding ether (IX), which by reaction with PPTS in HOAc is converted to the tetrahydrofuran-2-methanol derivative (X). Finally, this compound is condensed with POCl3, TEA, choline mesylate (XI) and DMAP in dichloromethane/pyridine to afford the target compound.
| 【1】 Lohmeyer, M.; Bittman, R.; Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19, 11, 1021. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 41308 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium methanesulfonate | C6H17NO4S | 详情 | 详情 | ||
| (I) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (II) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (III) | 41304 | 1-(3-chloropropoxy)-1-methylethyl methyl ether; 1-chloro-3-(1-methoxy-1-methylethoxy)propane | C7H15ClO2 | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 41309 | diethyl 2-[3-(1-methoxy-1-methylethoxy)propyl]malonate | C14H26O6 | 详情 | 详情 | |
| (VI) | 41305 | 2-[3-(1-methoxy-1-methylethoxy)propyl]-2-propen-1-ol | C10H20O3 | 详情 | 详情 | |
| (VII) | 28797 | 1-bromooctadecane | 112-89-0 | C18H37Br | 详情 | 详情 |
| (VIII) | 41306 | [(2S)-2-[3-(1-methoxy-1-methylethoxy)propyl]oxiranyl]methyl octadecyl ether; (2S)-2-[3-(1-methoxy-1-methylethoxy)propyl]-2-[(octadecyloxy)methyl]oxirane | C28H56O4 | 详情 | 详情 | |
| (IX) | 41307 | [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol | C24H48O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The reaction of tetrahydrofuran-2,2-dimethanol (I) with butyryl chloride (II) and Na2CO3 in dichloromethane gives the dibutyrate (III), which is asymmetrized by means of pancreas lipase type II (PPL) or microbial lipase Mucor javanicus (LMJ) yielding the (R)-monobutyrate (IV). The protection of the OH group of (IV) with Tr-Cl and pyridine in dichloromethane affords the trityl ether (V), which is treated with K2CO3 in methanol to provide the chiral carbinol (VI). The reaction of (VI) with benzyl bromide by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding benzyl ether (VII), which is deprotected with TFA in dichloromethane/water to yield the chiral carbinol (VIII). The reaction of (VIII) with octadecyl bromide (IX) by means of NaH and tetrabutylammonium iodide (TBAI) in refluxing THF gives the corresponding octadecyl ether (X), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to yield the chiral carbinol (XI). Finally, this carbinol is condensed with POCl3, choline tosylate (XII), TEA and pyridine in THF to afford the target compound.
| 【1】 Prasad, K.; et al.; Asymmetrization of tetrahydrofuran-2,2-dimethanol: Synthesis of the enantiomers of SRI 62-834. J Org Chem 1995, 60, 23, 7693. |
| 【2】 Estermann, H.; Houlihan, W.J.; Kapa, P.K.; Underwood, R.L. (Novartis AG; Novartis Deutschland GmbH); Enantiomers of 2-tetrahydrofuran derivs., intermediates therefor and their preparation. EP 0462935; JP 1992270276 . |
| 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) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 47575 | [2-[(butyryloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C14H24O5 | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 47577 | [(2S)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl butyrate | C29H32O4 | 详情 | 详情 | |
| (VI) | 47578 | [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methanol | C25H26O3 | 详情 | 详情 | |
| (VII) | 47579 | benzyl [(2R)-2-[(trityloxy)methyl]tetrahydro-2-furanyl]methyl ether; (2R)-2-[(benzyloxy)methyl]-2-[(trityloxy)methyl]tetrahydrofuran | C32H32O3 | 详情 | 详情 | |
| (VIII) | 47580 | [(2S)-2-[(benzyloxy)methyl]tetrahydro-2-furanyl]methanol | C13H18O3 | 详情 | 详情 | |
| (IX) | 28797 | 1-bromooctadecane | 112-89-0 | C18H37Br | 详情 | 详情 |
| (X) | 47581 | (2R)-2-[(benzyloxy)methyl]-2-[(octadecyloxy)methyl]tetrahydrofuran; benzyl [(2R)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methyl ether | C31H54O3 | 详情 | 详情 | |
| (XI) | 41307 | [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol | C24H48O3 | 详情 | 详情 | |
| (XII) | 41265 | 2-hydroxy-N,N,N-trimethyl-1-ethanaminium 4-methylbenzenesulfonate | C12H21NO4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Alkylation of ethylamine (II) with 3-chloro-1-propanol (I) in a pressure vessel furnished 3-(ethylamino)-1-propanol (III). After protection of the secondary amine group of (III) upon treatment with benzyl chloroformate, the resultant N-(3-hydroxypropyl)carbamate (IV) was activated as the mesylate ester (V) with methanesulfonyl chloride and triethylamine.
| 【1】 Mignonac, S.; Guy, A.; De Lamer, V. (Sanofi-Synthelabo); Preparation of polyamine(s), substd. on terminal nitrogen atoms. FR 2714052 . |
| 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) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (II) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
| (III) | 59216 | 3-(ethylamino)-1-propanol | C5H13NO | 详情 | 详情 | |
| (IV) | 59217 | benzyl ethyl(3-hydroxypropyl)carbamate | C13H19NO3 | 详情 | 详情 | |
| (V) | 59218 | 3-[[(benzyloxy)carbonyl](ethyl)amino]propyl methanesulfonate | C14H21NO5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(CXXV)In a further synthetic strategy, an azido precursor of spermidine (CXXX) was used in the reductive amination step. Condensation between 1,3-diaminopropane (CXXIV) and 4-chloro-1-butanol (CXXV) provided the diamino alcohol (CXXVI). Protection of the amino groups of (CXXVI) with di-tert-butyl dicarbonate yielded alcohol (CXXVII), which was converted to mesylate (CXXVIII) by treatment with methanesulfonyl chloride and triethylamine. Subsequent mesylate displacement in (CXXVIII) with NaN3 in DMF furnished the di-Boc-protected azide (CXXIX). The Boc protecting groups of (CXXIX) were then removed by treatment with HCl to give the desired diamino azide (CXXX). Reductive amination of the 3-keto steroid (CXXI) with amine (CXXX) yielded the 3-beta amino steroid (CXXXI). The azido group of (CXXXI) was finally reduced to the title triamino compound by catalytic hydrogenation over Raney-Ni.
| 【1】 Weis, A.L.; et al.; Synthesis of an azido spermidine equivalent. Tetrahedron Lett 1999, 40, 26, 4863. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (CXXIV) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (CXXV) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (CXXI) | 53799 | (1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C27H46O6S | 详情 | 详情 |
| (CXXVI) | 53802 | 3-[(3-aminopropyl)amino]-1-propanol | n/a | C6H16N2O | 详情 | 详情 |
| (CXXVII) | 53803 | tert-butyl 3-[(tert-butoxycarbonyl)amino]propyl(3-hydroxypropyl)carbamate | n/a | C16H32N2O5 | 详情 | 详情 |
| (CXXVIII) | 53804 | 3-((tert-butoxycarbonyl){3-[(tert-butoxycarbonyl)amino]propyl}amino)propyl methanesulfonate | n/a | C17H34N2O7S | 详情 | 详情 |
| (CXXIX) | 53805 | tert-butyl 3-azidopropyl{3-[(tert-butoxycarbonyl)amino]propyl}carbamate | n/a | C16H31N5O4 | 详情 | 详情 |
| (CXXX) | 53806 | N-(3-aminopropyl)-N-(3-azidopropyl)amine; N1-(3-azidopropyl)-1,3-propanediamine | n/a | C6H15N5 | 详情 | 详情 |
| (CXXXII) | 53807 | (1R,4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(3-azidopropyl)amino]propyl}amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C33H61N5O5S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XVII)Alternatively, the intermediate chiral hydroxy sulfoxide (XIX) was prepared by the following procedures. Alkylation of mercaptoimidazole (I) with 3-chloropropanol (XVII) gave thioether (XVIII). This was oxidized with cumene hydroperoxide and titanium tetraisopropoxide in the presence of either D-diethyl tartrate or (R)-mandelic acid as the chiral auxiliaries to provide, after recrystallization from methyl ethyl ketone, the optically pure sulfoxide (XIX). Subsequent treatment with methanesulfonyl chloride and triethylamine gave mesylate (XX), which was finally condensed with the sodium salt of 6-hydroxytetrahydroquinolinone (XXI) in DMSO at 60 C.
| 【1】 Matsugi, M.; et al.; Practical asymmetric oxidation of 3-[1-(2-methylphenyl)imidazol-2-ylthio]propan-1-ol based on a titanium-mandelic acid complex. Tetrahedron Lett 1998, 39, 31, 5591. |
| 【2】 Nishi, T.; Uno, T.; Shu, Y.; Tamura, K.; Okada, M. (Otsuka Pharmaceutical Co., Ltd.); Carbostyril derivs.. EP 0651747; JP 1995033765; US 5541198; WO 9426732 . |
| 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) | 30223 | 1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol | C10H10N2S | 详情 | 详情 | |
| (XVII) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (XVIII) | 30239 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]-1-propanol | C13H16N2OS | 详情 | 详情 | |
| (XIX) | 30240 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-propanol | C13H16N2O2S | 详情 | 详情 | |
| (XX) | 30241 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propyl methanesulfonate | C14H18N2O4S2 | 详情 | 详情 | |
| (XXI) | 30242 | sodium 2-oxo-1,2,3,4-tetrahydro-6-quinolinolate | C9H8NNaO2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Alkylation of 4-fluorothiophenol (I) with 3-chloropropanol (II) in the presence of K2CO3 in DMF provided thioether (III), which was oxidized to sulfone (IV) using Oxone(R). Fluorine displacement in (IV) with phenol and K2CO3 gave phenoxy derivative (V). Subsequent Mitsunobu condensation of (V) with thioacetic acid afforded thioacetate ester (VI), which by further hydrolysis with NaOMe furnished the target thiol.
| 【1】 Freskos, J.N.; Abbas, Z.S.; Decrescenzo, G.A.; Getman, D.P.; Heintz, R.M.; Mischke, B.V.; McDonald, J.J. (Pharmacia Corp.); Thiol sulfone metalloprotease inhibitors. EP 0939628; WO 9803164 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 | |
| (I) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 27076 | 3-[(4-fluorophenyl)sulfanyl]-1-propanol | C9H11FOS | 详情 | 详情 | |
| (IV) | 27077 | 3-[(4-fluorophenyl)sulfonyl]-1-propanol | C9H11FO3S | 详情 | 详情 | |
| (V) | 27078 | 3-[(4-phenoxyphenyl)sulfonyl]-1-propanol | C15H16O4S | 详情 | 详情 | |
| (VI) | 27079 | S-[3-[(4-phenoxyphenyl)sulfonyl]propyl] ethanethioate | C17H18O4S2 | 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 intermediate sulfone alcohol (V) has been obtained by an alternative procedure. 4-Phenoxyphenol (VII) was converted to thiophenol (IX) through the sequence of condensation with N,N-dimethylthiocarbamyl chloride, followed by thermal rearrangement of the resulting O-aryl thiocarbamate (VIII) to the S-aryl thiocarbamate, and then hydrolysis with KOH. Alkylation with 3-chloropropanol (II) provided thioether (X), which was then oxidized to the sulfone (V) with Oxone(R).
| 【1】 Inturrisi, C.E.; Collins, J.J.; Dunkel, I.J.; Portenoy, R.K.; Palmer, L.N.; Lapin, J.; Gupta, S.K.; Weinstein, S.M.; Transdermal fentanyl in children with cancer pain: Feasibility, tolerability, and pharmacokinetic correlates. J Pediatr 1999, 134, 3, 319. |
| 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) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (V) | 27078 | 3-[(4-phenoxyphenyl)sulfonyl]-1-propanol | C15H16O4S | 详情 | 详情 | |
| (VII) | 27080 | 4-Phenoxyphenol | 831-82-3 | C12H10O2 | 详情 | 详情 |
| (VIII) | 27081 | O-(4-phenoxyphenyl) dimethylcarbamothioate | C15H15NO2S | 详情 | 详情 | |
| (IX) | 26254 | 4-phenoxybenzenethiol; 4-phenoxyphenylhydrosulfide | C12H10OS | 详情 | 详情 | |
| (X) | 27082 | 3-[(4-phenoxyphenyl)sulfanyl]-1-propanol | C15H16O2S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Alkylation of 4-fluorothiophenol (I) with 3-chloropropanol (II) in the presence of K2CO3 in DMF provided thioether (III), which was oxidized to sulfone (IV) using Oxone(R). Fluorine displacement in (IV) with thiophenol and K2CO3 gave phenylsulfanyl derivative (V). The hydroxyl group of (V) was converted to mesylate (VI) and then displaced by potassium thioacetate to afford thioacetate ester (VII). Finally, hydrolysis with methanolic NaOMe furnished the target thiol.
| 【1】 Inturrisi, C.E.; Collins, J.J.; Dunkel, I.J.; Portenoy, R.K.; Palmer, L.N.; Lapin, J.; Gupta, S.K.; Weinstein, S.M.; Transdermal fentanyl in children with cancer pain: Feasibility, tolerability, and pharmacokinetic correlates. J Pediatr 1999, 134, 3, 319. |
| 【2】 Freskos, J.N.; Abbas, Z.S.; Decrescenzo, G.A.; Getman, D.P.; Heintz, R.M.; Mischke, B.V.; McDonald, J.J. (Pharmacia Corp.); Thiol sulfone metalloprotease inhibitors. EP 0939628; WO 9803164 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 | |
| (I) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 27076 | 3-[(4-fluorophenyl)sulfanyl]-1-propanol | C9H11FOS | 详情 | 详情 | |
| (IV) | 27077 | 3-[(4-fluorophenyl)sulfonyl]-1-propanol | C9H11FO3S | 详情 | 详情 | |
| (V) | 27078 | 3-[(4-phenoxyphenyl)sulfonyl]-1-propanol | C15H16O4S | 详情 | 详情 | |
| (VI) | 27083 | 3-[[4-(phenylsulfanyl)phenyl]sulfonyl]propyl methanesulfonate | C16H18O5S3 | 详情 | 详情 | |
| (VII) | 27084 | S-(3-[[4-(phenylsulfanyl)phenyl]sulfonyl]propyl) ethanethioate | C17H18O3S3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XI)The condensation of 1-benzyl-4-piperidone (I) with 4-iodoanisole (II) in ethyl ether gives 1-benzyl-4-(2-methoxyphenyl)piperidin-4-ol (III), which is dehydrated by means of p-toluenesulfonic acid in refluxing toluene yielding the tetrahydropyridine (IV). The hydroboration of (IV) with NaBH4 and BF3 ethearate in dimethoxyethane affords trans-1-benzyl-4-(2-methoxyphenyl)piperidin-3-ol (V), which is treated with BBr3 in dichloromethane to give the 4-hydroxyphenyl derivative (VI). The hydrogenolysis of (VI) with H2 over Pd/C in methanol yields trans-4-(2-hydroxyphenyl)piperidin-3-ol (VII), which is treated with tert-butoxycarbonyl anhydride and triethylamine in DMF to afford the carbamate (VIII). The condensation of 3-chloropropyl-(2-methoxyphenyl)ether (IX) (obtained by the NaH promoted condensation of 2-methoxybenzyl chloride (X) and 3-chloropropanol (XI)) with (VIII) by means of K2CO3 in hot 2-butanone gives the expected phenolic ether (XII), which is condensed with 7-(bromomethyl)quinoline (XIII) by means of NaH in DMF yielding the piperidinyl ether (XIV). The selective hydrogenation of (XIV) with NiCl2 and NaBH4 in methanol affords the tetrahydroquinoline derivative (XV), which is finally treated with HCl in methanol to eliminate the carbamate protecting group.
| 【1】 Breu, V.; Guller, R.; Binggeli, A.; et al.; Piperidine-renin inhibitors compounds with improved physicochemical properties. Bioorg Med Chem Lett 1999, 9, 10, 1403. |
| 【2】 Binggeli, A.; Breu, V.; Bur, D.; Fischli, W.; Gueller, R.; Hirth, G.; Maerki, H.-P.; Mueller, M.; Oefner, C.; Stadler, H.; Vieira, E.; Wilhelm, M.; Wostl, W. (F. Hoffmann-La Roche AG); New 4-(oxyalkoxyphenyl)-3-oxy-piperidines for treating heart and kidney insufficiency. EP 0863875; JP 1999500447; WO 9709311 . |
| 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) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 31009 | 1-iodo-4-methoxybenzene; 4-iodophenyl methyl ether | 696-62-8 | C7H7IO | 详情 | 详情 |
| (III) | 31010 | 4-(1-benzyl-4-methyl-4-piperidinyl)phenyl methyl ether; 1-benzyl-4-(4-methoxyphenyl)-4-methylpiperidine | C20H25NO | 详情 | 详情 | |
| (IV) | 31011 | 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)phenyl methyl ether; 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine | C19H21NO | 详情 | 详情 | |
| (V) | 31012 | (3R,4R)-1-benzyl-4-(4-methoxyphenyl)-3-piperidinol | C19H23NO2 | 详情 | 详情 | |
| (VI) | 31013 | (3R,4R)-1-benzyl-4-(4-hydroxyphenyl)-3-piperidinol | C18H21NO2 | 详情 | 详情 | |
| (VII) | 31014 | (3R,4R)-4-(4-hydroxyphenyl)-3-piperidinol | C11H15NO2 | 详情 | 详情 | |
| (VIII) | 31015 | tert-butyl (3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)-1-piperidinecarboxylate | C16H23NO4 | 详情 | 详情 | |
| (IX) | 31016 | 1-[(3-chloropropoxy)methyl]-2-methoxybenzene; 2-[(3-chloropropoxy)methyl]phenyl methyl ether | C11H15ClO2 | 详情 | 详情 | |
| (X) | 31017 | 2-(chloromethyl)phenyl methyl ether; 1-(chloromethyl)-2-methoxybenzene | 7035-02-1 | C8H9ClO | 详情 | 详情 |
| (XI) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (XII) | 31018 | tert-butyl (3R,4R)-3-hydroxy-4-(4-[3-[(2-methoxybenzyl)oxy]propoxy]phenyl)-1-piperidinecarboxylate | C27H37NO6 | 详情 | 详情 | |
| (XIII) | 31019 | 7-(bromomethyl)quinoline | C10H8BrN | 详情 | 详情 | |
| (XIV) | 31020 | tert-butyl (3R,4R)-4-(4-[3-[(2-methoxybenzyl)oxy]propoxy]phenyl)-3-(7-quinolinylmethoxy)-1-piperidinecarboxylate | C37H44N2O6 | 详情 | 详情 | |
| (XV) | 31021 | tert-butyl (3R,4R)-4-(4-[3-[(2-methoxybenzyl)oxy]propoxy]phenyl)-3-(1,2,3,4-tetrahydro-7-quinolinylmethoxy)-1-piperidinecarboxylate | C37H48N2O6 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(B)Acetonitrile derivative (I) is treated with BuLi and alkylated with 3-bromopropanol (A) to yield alcohol (II), which is further alkylated by means of LICKOR (n-BuLi/t-BuOK) and 1-chloro-3-bromopropane (B) to afford (III). Reaction of derivative (III) with secondary amine (VIII) in acetonitrile gives (IV). Amine (VIII) is obtained by trifluoroacetylation of azide (VI) with trifluoroacetic anhydride to yield (VII), which is then N-methylated by means of MeI and hydrolyzed with KOH. Finally, alcohol (IV) reacts with succinimido biotinate (V) in DMSO to provide the desired product.
| 【1】 Teodori, E.; et al.; Synthesis and binding properties of photoactivable biotin-conjugated verapamil derivatives for the study of P-170 glycoprotein. Bioorg Med Chem 1999, 7, 9, 1873. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (B) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (I) | 25857 | 2-(3,4-dimethoxyphenyl)acetonitrile | 93-17-4 | C10H11NO2 | 详情 | 详情 |
| (II) | 42244 | 2-(3,4-dimethoxyphenyl)-5-hydroxypentanenitrile | C13H17NO3 | 详情 | 详情 | |
| (III) | 42245 | 5-chloro-2-(3,4-dimethoxyphenyl)-2-(3-hydroxypropyl)pentanenitrile | C16H22ClNO3 | 详情 | 详情 | |
| (IV) | 42249 | 5-[(2-azidophenethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-(3-hydroxypropyl)pentanenitrile | C25H33N5O3 | 详情 | 详情 | |
| (V) | 42250 | 1-([5-[(3aS,4S,6aR)-3a,4,6a-trimethyl-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoyl]oxy)-2,5-pyrrolidinedione | C17H25N3O5S | 详情 | 详情 | |
| (VI) | 42246 | 2-azidophenethylamine; 2-(2-azidophenyl)-1-ethanamine | C8H10N4 | 详情 | 详情 | |
| (VII) | 42247 | N-(2-azidophenethyl)-2,2,2-trifluoroacetamide | C10H9F3N4O | 详情 | 详情 | |
| (VIII) | 42248 | N-(2-azidophenethyl)-N-methylamine; 2-(2-azidophenyl)-N-methyl-1-ethanamine | C9H12N4 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(II)Alkylation of 4-hydroxy-5-methoxy benzoic acid methyl ester (I) with 3-chloropropyl p-toluene sulfonate (III) by means of K2CO3 and methyl-tricapryl ammonium chloride (Aliquat 128) in refluxing acetone affords compound (III), which is then nitrated by means of HNO3 in HOAc to furnish 2-nitro derivative (IV). Reduction of the nitro moiety of (IV) by means of Fe in H2O/MeOH in the presence of ammonium chloride yields 2-amino compound (V), which is subjected to reaction with refluxing dimethylformamide dimethylacetal (VI) to provide amidine (VII). Condensation of (VII) with acetonitrile by means of n-BuLi in hexane/THF/HOAc gives substituted quinoline-carbonitrile (IX), whose hydroxyl group is replaced by a chlorine by treatment of (IX) with refluxing POCl3 to afford compound (X). Coupling of (X) with 2,4-dichloro-5-methoxyaniline (XI) in 2-ethoxyethanol in the presence of pyridine hydrochloride yields compound (XII), which is finally converted into the desired compound by condensation with 1-methylpiperazine (XII) by means of NaI in refluxing ethylene glycol dimethyl ether.
| 【1】 Boschelli, D.H.; Ye, F.; Wang, Y.D.; Dutia, M.; Johnson, S.L.; Wu, B.; Miller, K.; Powell, D.W.; Yaczko, D.; Young, M.; Tischler, M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.; Weber, J.M.; Boschelli, F.; Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 2001, 44, 23, 3965. |
| 【2】 Boschelli, D.H.; Dutia, M.; Ye, F.; et al.; Inhibition of SRC kinase activity by 4-phenylamino-3-quinolinecarbonitriles Part 2: Optimization of the side chain at C-7. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 145. |
| 【3】 Boschelli, D.H.; Wang, Y.D.; Ye, F.; et al.; Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles. J Med Chem 2001, 44, 5, 822. |
| 【4】 Tsou, H.-R.; Wissner, A.; Johnson, B.D.; Reich, M.F.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); Substituted 3-cyano quinolines. US 6002008 . |
| 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) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 50008 | methyl 4-(3-chloropropoxy)-3-methoxybenzoate | C12H15ClO4 | 详情 | 详情 | |
| (IV) | 50009 | methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate | C12H14ClNO6 | 详情 | 详情 | |
| (V) | 50010 | methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate | C12H16ClNO4 | 详情 | 详情 | |
| (VI) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (VII) | 50011 | methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate | C15H21ClN2O4 | 详情 | 详情 | |
| (VIII) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IX) | 50012 | 7-(3-chloropropoxy)-4-hydroxy-6-methoxy-3-quinolinecarbonitrile | C14H13ClN2O3 | 详情 | 详情 | |
| (X) | 48519 | 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile | C14H12Cl2N2O2 | 详情 | 详情 | |
| (XI) | 50013 | 2,4-dichloro-5-methoxyphenylamine; 2,4-dichloro-5-methoxyaniline | C7H7Cl2NO | 详情 | 详情 | |
| (XII) | 50014 | 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile | C21H18Cl3N3O3 | 详情 | 详情 | |
| (XIII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |