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【结 构 式】 
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【分子编号】29460 【品名】2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether 【CA登记号】 |
【 分 子 式 】C9H17BrO2 【 分 子 量 】237.13678 【元素组成】C 45.59% H 7.23% Br 33.7% O 13.49% |
合成路线1
该中间体在本合成路线中的序号：(IX)The condensation of (3-methoxyphenyl)acetonitrile (VIII) with 3-bromopropyltetrahydropyranyl ether (IX) by means of lithium diisopropylamide in THF gives 2-(3-methoxyphenyl)-5-tetrahydropyranyloxypentanonitrile (X), which is oxidized with chromic anhydride-H2SO4 yielding 4-cyano-3-(3-methoxyphenyl)butyric acid (XI). The hydrolysis of (XI) with KOH in ethanol-water affords 2-(3-methoxyphenyl)glutaric acid (XII), which is anhydrized with refluxing acetic anhydride giving 2-(3-methoxyphenyl)glutaric anhydride (XIII). The reaction of (XIII) with propylamine (C) in refluxing benzene yields 2-(3-methoxyphenyl)-N-propylglutarimide (XIV), which is demethylated with BBr3 in methylene chloride to 2-(3-hydroxyphenyl)-N-propylglutarimide (XV). The benzylation of (XV) with benzyl bromide and K2CO3 in DMF affords 2-(3-benzyloxyphenyl)-N-propylglutarimide (XVI), which is reduced with LiAlH4 in THF giving 3-(3-benzyloxyphenyl)-N-propylpiperidine (XVII). Finally, this compound is debenzylated by hydrogenolysis with H2 over Pd/C in AcOH.
| 【1】 Brands, F.T.L.; Loozen, H.J.J.; An efficient synthesis of 3-arylpiperidines. J R Neth Chem Soc 1981, 100, 9, 333-336. |
| 【2】 Serradell, M.N.; Nohria, V.; Castaner, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (VIII) | 24061 | 3-methoxyphenylacetonitrile; 2-(3-methoxyphenyl)acetonitrile | 19924-43-7 | C9H9NO | 详情 | 详情 |
| (IX) | 29460 | 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether | C9H17BrO2 | 详情 | 详情 | |
| (X) | 35989 | 2-(3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile | C18H25NO3 | 详情 | 详情 | |
| (XI) | 35990 | 4-cyano-4-(3-methoxyphenyl)butyric acid | C12H13NO3 | 详情 | 详情 | |
| (XII) | 35991 | 2-(3-methoxyphenyl)pentanedioic acid | C12H14O5 | 详情 | 详情 | |
| (XIII) | 35992 | 3-(3-methoxyphenyl)dihydro-2H-pyran-2,6(3H)-dione | C12H12O4 | 详情 | 详情 | |
| (XIV) | 35993 | 3-(3-methoxyphenyl)-1-propyl-2,6-piperidinedione | C15H19NO3 | 详情 | 详情 | |
| (XV) | 35994 | 3-(3-hydroxyphenyl)-1-propyl-2,6-piperidinedione | C14H17NO3 | 详情 | 详情 | |
| (XVI) | 35995 | 3-[3-(benzyloxy)phenyl]-1-propyl-2,6-piperidinedione | C21H23NO3 | 详情 | 详情 | |
| (XVII) | 35996 | benzyl 3-(1-propyl-3-piperidinyl)phenyl ether; 3-[3-(benzyloxy)phenyl]-1-propylpiperidine | C21H27NO | 详情 | 详情 | |
| (C) | 23923 | 1-propanamine | 107-10-8 | C3H9N | 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 protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.
| 【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283. |
| 【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 . |
| 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) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (II) | 29460 | 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether | C9H17BrO2 | 详情 | 详情 | |
| (III) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (IV) | 29461 | 2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile | C17H21Cl2NO2 | 详情 | 详情 | |
| (V) | 29132 | ethyl 3-bromopropanoate | 539-74-2 | C5H9BrO2 | 详情 | 详情 |
| (VI) | 29462 | ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate | C22H29Cl2NO4 | 详情 | 详情 | |
| (VII) | 29463 | 5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone | C20H27Cl2NO3 | 详情 | 详情 | |
| (VIII) | 29464 | 3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether | C20H29Cl2NO2 | 详情 | 详情 | |
| (IX) | 29465 | 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (X) | 29466 | 3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (XI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XII) | 29467 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone | C21H23Cl2NO2 | 详情 | 详情 | |
| (XIII) | 29468 | 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 | |
| (XIV) | 29469 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone | C21H22Cl2INO | 详情 | 详情 | |
| (XV) | 28021 | 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine | 40807-61-2 | C11H15NO | 详情 | 详情 |
| (XVI) | 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 |
| (XVII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (XVIII) | 29470 | 1-benzyl-4-phenyl-4-piperidinol | C18H21NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Coupling of ethyl phenylsulfinylfluoro acetate (I) with bromo derivative (II) by means of NaH in DMF yields ethyl hexenoate (III), which is then oxidized by means of Jones reagent in acetone to provide 5-carboxy pentenoate derivative (IV). Alternatively, compound (IV) can be obtained as follows: eduction of gamma-butyrolactone (V) in THF with aluminum diisobutylhydride in toluene affords gamma-butyrolactol (VI), which is treated with ethyl (diethoxyphosphoryl)fluoroacetate (VII) and sodium bis(trimethylsilyl)amide in THF to provide an isomeric mixture of hexenoates (VIII). O-Protection of (VIII) by means of tert-butyldiphenylchlorosilane and imidazole in DMF followed by chromatographic separation of the geometrical isomers furnishes hexenoate (Z)-(IX), which is finally oxidized with Jones reagent in acetone. Conversion of carboxylic acid (IV) into bicycle (±)-(X) is then performed by first reaction with oxalyl chloride in refluxing hexane to form the corresponding acid chloride, followed by treatment with diazomethane in ether and subsequent reaction with cooper(II) bis(N-tert-butylsalicylaldiimidate) in refluxing benzene. Treatment of oxobicycle (±)-(X) with LiHMDS and chlorotrimethylsilane in THF followed by reaction with palladium acetate in acetonitrile gives 6-fluoro-2-oxobicyclo[3.1.0]hex-3-en-6-carboxylate (±)-(XI), from which epoxide (±)-(XII) is obtained by reaction in toluene with tert-butyl hydroxyperoxide (TBHP) and benzyltrimethylammoniumhydroxide (Triton B) in MeOH or EtOH. Epoxide reduction of (±)-(XII) using diphenyl diselenide (PhSe)2 and sodium borohydride in the presence of HOAc in EtOH, or by means of (PhSe)2, N-acetyl-L-cysteine and sodium tetraborate decahydrate in H2O:EtOH, yields hydroxy derivative (±)-(XIII), which is converted into ethylenedithio derivative (±)-(XV) by first protection of the hydroxyl group with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole, followed by thioketalization with 1,2-ethanedithiol (XIV) and boron trifluoride-diethylether complex in CHCl3 (with subsequent TBS group removal during work-up). Oxidation of the hydroxyl group of (±)-(XV) with DMSO and dicyclohexylcarbodiimide (DCC) in the presence of pyridine and TFA gives ketone (±)-(XVI), which is then hydrolyzed with NaOH in EtOH and subjected to reaction with KCN and ammonium carbonate (Bucherer-Bergs conditions) to yield hydantoin (±)-(XVII). Coupling of (±)-(XVII) with (R)-(+)-1-phenylethylamine using EDC-HCl and HOBt followed by chromatographic separation of the two resulting diastereomers furnishes (1R,2S,5R,6S)-(XIX), which is finally converted into the desired product after hydrolysis with H2SO4.
| 【4】 Kumagai, T.; Sakagami, K.; Nakazato, A.; Tomisawa, K. (Taisho Pharmaceutical Co., Ltd.); 6-Fluorobicyclo[3.1.0]hexane derivs.. EP 1110943; JP 2000336071; WO 0012464 . |
| 【1】 Nakazato, A.; et al.; Synthesis, SAR, and biological activities of potent and selective group II mGluR agonists, novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 104. |
| 【2】 Nakazato, A.; et al.; Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylix acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. J Med Chem 2000, 43, 25, 4893. |
| 【3】 Yoshikawa, R.; Kumagai, T.; Suzuki, Y.; Nakazato, A.; Sakagami, K.; Chaki, S.; Okuyama, S.; Synthesis SAR and biological activities of potent and selective group II metabotropic glutamate receptor antagonists, novel 2-amino-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PB-104. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(XIV) | 27313 | 1,2-ethanedithiol | 540-63-6 | C2H6S2 | 详情 | 详情 |
| (rac)-(X) | 49005 | ethyl (rac)-(1S*,5S*,6S*)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO3 | 详情 | 详情 | |
| (rac)-(XI) | 49006 | ethyl (rac)-(1S*,5S*,6S*)-6-fluoro-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate | C9H9FO3 | 详情 | 详情 | |
| (rac)-(XII) | 49007 | ethyl (rac)-(1R*,2S*,4S*,6S*,7S*)-7-fluoro-5-oxo-3-oxatricyclo[4.1.0.0(2,4)]heptane-7-carboxylate | C9H9FO4 | 详情 | 详情 | |
| (rac)-(XIII) | 49008 | ethyl (rac)-(1R*,2R*,5S*,6S*)-6-fluoro-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO4 | 详情 | 详情 | |
| (rac)-(XV) | 49009 | C11H15FO3S2 | 详情 | 详情 | ||
| (rac)-(XVI) | 49010 | C11H13FO3S2 | 详情 | 详情 | ||
| (rac)-(XVII) | 49011 | C11H11FN2O4S2 | 详情 | 详情 | ||
| (VIIIa) | 49014 | ethyl (Z)-2-fluoro-6-hydroxy-2-hexenoate | C8H13FO3 | 详情 | 详情 | |
| (VIIIIb) | 49015 | ethyl (E)-2-fluoro-6-hydroxy-2-hexenoate | C8H13FO3 | 详情 | 详情 | |
| (I) | 49002 | ethyl 2-fluoro-2-(phenylsulfinyl)acetate | C10H11FO3S | 详情 | 详情 | |
| (II) | 29460 | 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether | C9H17BrO2 | 详情 | 详情 | |
| (III) | 49003 | ethyl (Z)-2-fluoro-6-(tetrahydro-2H-pyran-2-yloxy)-2-hexenoate | C13H21FO4 | 详情 | 详情 | |
| (IV) | 49004 | (Z)-6-ethoxy-5-fluoro-6-oxo-4-hexenoic acid | C8H11FO4 | 详情 | 详情 | |
| (V) | 20576 | dihydro-2(3H)-furanone | 96-48-0 | C4H6O2 | 详情 | 详情 |
| (VI) | 49013 | tetrahydro-2-furanol | C4H8O2 | 详情 | 详情 | |
| (VII) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
| (IX) | 49016 | ethyl (Z)-6-[[tert-butyl(diphenyl)silyl]oxy]-2-fluoro-2-hexenoate | C24H31FO3Si | 详情 | 详情 | |
| (XVIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XIX) | 49012 | C19H20FN3O3S2 | 详情 | 详情 |