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【结 构 式】 
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【分子编号】39563 【品名】nitromethane 【CA登记号】75-52-5 |
【 分 子 式 】CH3NO2 【 分 子 量 】61.04036 【元素组成】C 19.68% H 4.95% N 22.95% O 52.42% |
合成路线1
该中间体在本合成路线中的序号：(II)The enantioselective condensation of 4-(tert-butyldimethylsilyloxy)benzaldehyde (I) with nitromethane (II), catalyzed by the chiral Zn ligand complex (III) in THF gives the (R)-2-nitroethanol derivative (IV), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminoethanol derivative (V). The condensation of (V) with carboxylic acid (VI) by means of 2,2-dimethylpropanoyl chloride and DIEA in THF affords the corresponding amide (VII), which is reduced with LiAlH4 in Et2O to yield the protected hydroxyamine (VIII). Finally, this compound is desilylated by means of HCl and KF in MeOH to furnish the target tetrahydroxyamine derivative.
| 【1】 Ito, H.; Bremeyer, N.; Trost, B.M.; Yeh, V.S.C.; Effect of ligand structure on the zinc-catalyzed Henry reaction. Asymmetric syntheses of (-)-denopamine and (-)-arbutamine. Org Lett 2002, 4, 16, 2621. |
| 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) | 57897 | 4-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde | C13H20O2Si | 详情 | 详情 | |
| (II) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (III) | 57893 | C64H60O3Zn2 | 详情 | 详情 | ||
| (IV) | 57898 | (1R)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-nitro-1-ethanol | C14H23NO4Si | 详情 | 详情 | |
| (V) | 57899 | (1R)-2-amino-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanol | C14H25NO2Si | 详情 | 详情 | |
| (VI) | 24049 | 2-(3,4-dimethoxyphenyl)acetic acid | 93-40-3 | C10H12O4 | 详情 | 详情 |
| (VII) | 57900 | N-[(2R)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-hydroxyethyl]-2-(3,4-dimethoxyphenyl)acetamide | C24H35NO5Si | 详情 | 详情 | |
| (VIII) | 57901 | (1R)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C24H37NO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：The bromination of 3,4-dihydro-1H-2-benzopyran (VII) with Br2 gives the 1-bromo derivative (VIII), which, without isolation, is treated with hot HBr yielding 2-(2-bromoethyl)benzaldehyde (IX). The condensation of (IX) with nitromethane in acidic medium affords the nitrostyrene (X), which is cyclized with treatment with FeCl3 and acetyl chloride giving 4-(2-bromoethyl)-3-chloroindolin-2-one (XI). The dechlorination of (XI) with NaH2PO2 over Pd/C yields 4-(2-bromoethyl)indolin-2-one (XII), which is finally condensed with dipropylamine (II).
| 【1】 Hayler, J.D.; et al.; Development of large-scale syntheses or ropinirole in the pursuit of a manufacturing process. Org Process Res Dev 1998, 2, 1, 3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (VII) | 34866 | 3,4-dihydro-1H-isochromene | 493-05-0 | C9H10O | 详情 | 详情 |
| (VIII) | 34867 | 1-bromo-3,4-dihydro-1H-isochromene | C9H9BrO | 详情 | 详情 | |
| (IX) | 34868 | 2-(2-bromoethyl)benzaldehyde | C9H9BrO | 详情 | 详情 | |
| (X) | 34869 | 1-(2-bromoethyl)-2-[(E)-2-nitroethenyl]benzene | C10H10BrNO2 | 详情 | 详情 | |
| (XI) | 34870 | 4-(2-bromoethyl)-3-chloro-1,3-dihydro-2H-indol-2-one | C10H9BrClNO | 详情 | 详情 | |
| (XII) | 34871 | 4-(2-bromoethyl)-1,3-dihydro-2H-indol-2-one | C10H10BrNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：The reaction of 3,4-dihydro-1H-2-benzopyran (VII) with benzoyl chloride and ZnCl2 gives benzoic acid 2-[2-(chloromethyl)phenyl]ethyl ester (XIII), which is condensed with hexamethylenetetramine (XIV) yielding the amminium salt (XV). The hydrolysis of (XV) affords 2-(2-benzoyloxyethyl) benzaldehyde (XVI), which is condensed with nitromethane as before to give the nitrostyrene (XVII). The cyclization of (XVII) with FeCl3 and acetyl chloride as before yields 4-(2-benzoyloxyethyl)-3-chloroindolin-2-one (XVIII), which is dechlorinated with hydrazine and Pd/C to the indolinone (XIX). The hydrolysis of (XIX) with NaOH affords 4-(2-hydroxyethyl)indolin-2-one (XX), which is acylated with TsCl giving the tosylate (XXI). Finally, this compound is condensed with dipropylamine (II).
| 【1】 Hayler, J.D.; et al.; Development of large-scale syntheses or ropinirole in the pursuit of a manufacturing process. Org Process Res Dev 1998, 2, 1, 3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (VII) | 34866 | 3,4-dihydro-1H-isochromene | 493-05-0 | C9H10O | 详情 | 详情 |
| (XIII) | 34872 | 2-(chloromethyl)phenethyl benzoate | C16H15ClO2 | 详情 | 详情 | |
| (XIV) | 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 |
| (XV) | 34874 | 1-[2-[2-(benzoyloxy)ethyl]benzyl]-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane chloride | C22H27ClN4O2 | 详情 | 详情 | |
| (XVI) | 34875 | 2-formylphenethyl benzoate | C16H14O3 | 详情 | 详情 | |
| (XVII) | 34876 | 2-[(E)-2-nitroethenyl]phenethyl benzoate | C17H15NO4 | 详情 | 详情 | |
| (XVIII) | 34877 | 2-(3-chloro-2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate | C17H14ClNO3 | 详情 | 详情 | |
| (XIX) | 34878 | 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate | C17H15NO3 | 详情 | 详情 | |
| (XX) | 34879 | 4-(2-Hydroxyethyl)indolin-2-one | 139122-19-3 | C10H11NO2 | 详情 | 详情 |
| (XXI) | 34880 | 4-heptanol | 589-55-9 | C7H16O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The reaction of the commercially available (1S-cis)-2-cyclopentan-1,4-diol 4-acetate (I) with methyl pyrocarbonate and DMAP in THF gives the carbonate ester (II), which by reaction with nitromethane (III), triisopropyl phosphite and a Pd catalyst, yields (1R-cis)-1-acetoxy-4-(nitromethyl)-2-cyclopentene (IV). The hydrolysis of (IV) by means of Ts-OH in methanol affords the corresponding alcohol (V), which by treatment with O3, NaOMe and NaBH4 in methanol provides (1R-cis)-4-(hydroxymethyl)-2-cyclopenten-1-ol (VI). The selective monotritylation of the primary OH group of (VI) with trityl chloride (VII) in pyridine gives the trityl ether (VIII), which is condensed with 2-amino-6-chloropurine (IX) by means of Pd(PPh3)4 in THF to yield the adduct (X). The destritylation of (X) with HOAc/water affords the hydroxymethyl compound (XI), which is finally dechlorinated by hydrolysis with hot HCl or NaOH to provide the target (-)-carbovir. Alternatively, the dechlorination of (XI) can be performed by reaction of (XI) with liquid ammonia at 75-80 C in a Parr bomb to give the diaminopurine (XII), which is finally submitted to an enzymatic deamination with adenosine deaminase (from calf intestinal mucosa).
| 【1】 Vince, R.; Peterson, M.L.; Lackey, J.W.; Mook, R.A. Jr.; Partridge, J.J. (GlaxoSmithKline plc); Synthesis of purine substd. cyclopentene derivs.. US 5126452 . |
| 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) | 45407 | (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol | 60410-16-4 | C7H10O3 | 详情 | 详情 |
| (II) | 55528 | (1R,4S)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl acetate | C9H12O5 | 详情 | 详情 | |
| (III) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (IV) | 55529 | (1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl acetate | C8H11NO4 | 详情 | 详情 | |
| (V) | 55530 | (1R,4S)-4-(nitromethyl)-2-cyclopenten-1-ol | C6H9NO3 | 详情 | 详情 | |
| (VI) | 45405 | (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VII) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (VIII) | 55531 | (1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-ol | C25H24O2 | 详情 | 详情 | |
| (IX) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (X) | 55532 | 6-chloro-9-{(1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-9H-purin-2-amine; 6-chloro-9-{(1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-9H-purin-2-ylamine | C30H26ClN5O | 详情 | 详情 | |
| (XI) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XII) | 55533 | [(1S,4R)-4-(2,6-diamino-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H14N6O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The enantioselective condensation of 3,4-bis(tert-butyldimethylsilyloxy)benzaldehyde (I) with nitromethane (II), catalyzed by the chiral Zn ligand complex (III) in THF gives the (R)-2-nitroethanol derivative (IV), which is reduced with H2 over Pd/C in methanol to yield the 2-aminoethanol derivative (V). The condensation of (V) with 4-[4-(tert-butyldimethylsilyloxy)phenyl]butyric acid (VI) by means of diphenyl chlorophosphate and DIEA in dichloromethane affords the corresponding amide (VII), which is reduced by conventional methods to the protected hydroxyamine (VIII). Finally, this compound is desilylated as usual to furnish the target tetrahydroxyamine derivative.
| 【1】 Ito, H.; Bremeyer, N.; Trost, B.M.; Yeh, V.S.C.; Effect of ligand structure on the zinc-catalyzed Henry reaction. Asymmetric syntheses of (-)-denopamine and (-)-arbutamine. Org Lett 2002, 4, 16, 2621. |
| 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) | 55602 | 3,4-bis{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde | C19H34O3Si2 | 详情 | 详情 | |
| (II) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (III) | 57893 | C64H60O3Zn2 | 详情 | 详情 | ||
| (IV) | 55605 | (1R)-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-nitro-1-ethanol | C20H37NO5Si2 | 详情 | 详情 | |
| (V) | 55606 | (1R)-2-amino-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanol | C20H39NO3Si2 | 详情 | 详情 | |
| (VI) | 57894 | 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)butanoic acid | C16H26O3Si | 详情 | 详情 | |
| (VII) | 57895 | N-[(2R)-2-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-hydroxyethyl]-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)butanamide | C36H63NO5Si3 | 详情 | 详情 | |
| (VIII) | 57896 | (1R)-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)butyl]amino}-1-ethanol | C36H65NO4Si3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：The acetylation of 3,5-dimethylaniline (I) with acetic anhydride gives the acetamide (II), which is treated with chlorosulfonic acid yielding the benzenesulfonyl chloride (III). The reduction of (III) with Na2SO3 and NaHCO3 in water affords the sulfinic acid (IV), which by reaction with sodium methoxide in methanol gives the corresponding sodium salt (V). The reaction of (V) with nitromethane and sodium methoxide yields the sulfonylnitromethane (VI), which is deacetylated with hot 2N NaOH affording 3,5-dimethyl-4-(nitromethylsulfonyl)aniline (VII). Finally, this compound is treated with thiophosgene in acetone to provide the target isothiocyanate.
| 【1】 Rodriguez, L.; Miller, D.D.; Kador, P.F.; Saab, N.H.; Donkor, I.O.; Phenylsulfonylnitromethasanes as potent irreversible inhibitors of aldose reductase. Eur J Med Chem 1999, 34, 9, 745. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 29008 | Chlorosulfonic acid | 7790-94-5 | HClO3S | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (I) | 18431 | 3,5-dimethylaniline; 3,5-dimethylphenylamine | 108-69-0 | C8H11N | 详情 | 详情 |
| (II) | 31521 | N-(3,5-dimethylphenyl)acetamide | C10H13NO | 详情 | 详情 | |
| (III) | 31596 | 4-(acetamido)-2,6-dimethylbenzenesulfonyl chloride | C10H12ClNO3S | 详情 | 详情 | |
| (IV) | 31597 | N-[4-(dioxo-lambda(6)-sulfanyl)-3,5-dimethylphenyl]acetamide | C10H13NO3S | 详情 | 详情 | |
| (V) | 31598 | [[4-(acetamido)-2,6-dimethylphenyl]sulfonyl]sodium | C10H12NNaO3S | 详情 | 详情 | |
| (VI) | 31599 | N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]acetamide | C11H14N2O5S | 详情 | 详情 | |
| (VII) | 31600 | 3,5-dimethyl-4-[(nitromethyl)sulfonyl]aniline; 3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenylamine | C9H12N2O4S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)The intermediate mixed anhydride (V) has been obtained as follows: the condensation of 2-nitroimidazole (I) with methyl 2-bromoacetate (II) by means of NaOMe in methanol gives 2-(2-nitro-1H-imidazol-1-yl)acetic acid methyl ester (III), which is hydrolyzed with NaOH to yield the corresponding acid (IV). Finally, this compound is condensed with isobutyl chloroformate by means of NMM in THF to afford the desired mixed anhydride intermediate (V). The condensation of 2,2,2-trifluoroacetaldehyde ethyl hemiacetal (VI) with nitromethane (VII) by means of K2CO3 gives 1,1,1-trifluoro-3-nitro-2-propanol (VIII), which is reduced with H2 over RaNi in ethanol to yield 3-amino-1,1,1-trifluoro-2-propanol (IX). Finally, this compound is condensed with the mixed anhydride intermediate (V) by means of NMM in THF to afford the target amide.
| 【1】 Tracy, M.; Kelson, A.B.; Workman, P.; Lewis, A.D.; Aboagye, E.O. (Cancer Research UK; SRI International); Fluorinated 2-nitroimidazole analogs for detecting hypoxic tumor cells. EP 0775117; JP 1998506104; US 5721265; WO 9604249 . |
| 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) | 10145 | 2-Nitro-1H-imidazole; 2-Nitroimidazole | 527-73-1 | C3H3N3O2 | 详情 | 详情 |
| (II) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (III) | 10258 | methyl 2-(2-nitro-1H-imidazol-1-yl)acetate; Methyl 2-nitro-1-imidazoleacetate | 22813-31-6 | C6H7N3O4 | 详情 | 详情 |
| (IV) | 56733 | 2-(2-nitro-1H-imidazol-1-yl)acetic acid | C5H5N3O4 | 详情 | 详情 | |
| (V) | 56734 | C10H13N3O6 | 详情 | 详情 | ||
| (VI) | 26582 | 1-ethoxy-2,2,2-trifluoro-1-ethanol | 433-27-2 | C4H7F3O2 | 详情 | 详情 |
| (VII) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (VIII) | 56735 | 1,1,1-trifluoro-3-nitro-2-propanol | C3H4F3NO3 | 详情 | 详情 | |
| (IX) | 56736 | 3-amino-1,1,1-trifluoro-2-propanol | 431-38-9 | C3H6F3NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：Condensation of piperonal (I) with nitromethane in the presence of ammonium acetate in AcOH provided nitrostyrene (II). Ketoester (IV) was prepared by carbethoxylation of 4'-propoxyacetophenone (III) with diethyl carbonate. Subsequent conjugate addition of ketoester (IV) to nitrostyrene (II) using DBU provided adduct (V). Hydrogenation of the nitro group of (V) over Raney Nickel, with concomitant ring closure formed the cyclic imine (VI), and further reduction of (VI) with NaBH3CN yielded the corresponding pyrrolidine as a diastereomeric mixture. Chromatographic separation removed the cis,cis isomer, affording a mixture of trans,trans and cis,trans pyrrolidines (VIIa, VIIb). 2,6-Diethylbromoacetanilide (IX) was prepared by acylation of 2,6-diethylaniline (VIII) with bromoacetyl bromide. N-Alkylation of the mixture of pyrrolidines (VIIa, VIIb) with bromoacetanilide (IX) furnished (Xa, Xb).
| 【1】 Sorensen, B.K.; Tasker, A.S.; von Geldern, T.W.; et al.; Pyrrolide-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ETB selectivity. J Med Chem 1999, 42, 18, 3668. |
| 【2】 Tasker, A.S.; Boyd, S.A.; Sorensen, B.K.; Winn, M.; Jae, H.-S.; Von Geldern, T.W.; Henry, K.J. (Abbott Laboratories Inc.); 4-(Benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivs. as endothelin antagonists. EP 0888340; JP 2000504727; WO 9730046 . |
| 【3】 Tasker, A.S.; Henry, K.J.; Boyd, S.A.; Von Geldern, T.W.; Sorensen, B.K.; Jae, H.-S.; Winn, M. (Abbott Laboratories Inc.); Pyrrolidine carboxylic acid derivs. as endothelin antagonists. EP 0991620; WO 9857933 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 | |
| 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIa) | 35056 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C23H27NO5 | 详情 | 详情 | |
| (VIIb) | 35057 | ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C23H27NO5 | 详情 | 详情 | |
| (Xa) | 35060 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C35H42N2O6 | 详情 | 详情 | |
| (Xb),(XI) | 35061 | ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C35H42N2O6 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35052 | 1-(4-propoxyphenyl)-1-ethanone | C11H14O2 | 详情 | 详情 | |
| (IV) | 35053 | ethyl 3-oxo-3-(4-propoxyphenyl)propanoate | C14H18O4 | 详情 | 详情 | |
| (V) | 35054 | ethyl 3-(1,3-benzodioxol-5-yl)-4-nitro-2-(4-propoxybenzoyl)butanoate | C23H25NO8 | 详情 | 详情 | |
| (VI) | 35055 | ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-propoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate | C23H25NO5 | 详情 | 详情 | |
| (VIII) | 35058 | 2,6-diethylphenylamine; 2,6-diethylaniline | 579-66-8 | C10H15N | 详情 | 详情 |
| (IX) | 35059 | 2-bromo-N-(2,6-diethylphenyl)acetamide | C12H16BrNO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II). Subsequent conjugate addition of (II) to ketoester (III) using DBU provided adduct (IV). Reduction of the nitro group of (IV), with concomitant ring closure and olefinic double bond hydrogenation formed the cyclic imine (V), which was reduced with NaBH3CN to yield the pyrrolidine (VI) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VII) with N,N-dibutyl bromoacetamide (VIII) furnished (IX). Basic hydrolysis of the ester group of (IX) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (X) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
| 【1】 Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991. |
| 【2】 Dive, V.; Toma, F.; Yiotakis, A. (Commissariat a l'Energie Atomique); Derivs. of peptides usable as inhibitors of bacterial collagenases. US 5500414 . |
| 【3】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
| 【4】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIa) | 35045 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate | C18H25NO4 | 详情 | 详情 | |
| (VIIb) | 35046 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate | C18H25NO4 | 详情 | 详情 | |
| (IXa) | 35047 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-pentyl-3-pyrrolidinecarboxylate | C28H44N2O5 | 详情 | 详情 | |
| (IXb),(X) | 35048 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-pentyl-3-pyrrolidinecarboxylate | C28H44N2O5 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35041 | methyl (E)-3-oxo-6-octenoate | C9H14O3 | 详情 | 详情 | |
| (IV) | 35042 | methyl (E)-2-[1-(1,3-benzodioxol-5-yl)-2-nitroethyl]-3-oxo-6-octenoate | C18H21NO7 | 详情 | 详情 | |
| (V) | 35043 | methyl 3-(1,3-benzodioxol-5-yl)-5-pentyl-3,4-dihydro-2H-pyrrole-4-carboxylate | C18H23NO4 | 详情 | 详情 | |
| (VI) | 35044 | methyl 4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate | C18H25NO4 | 详情 | 详情 | |
| (VIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II) (1-3). Ketoester (IV) was prepared by treatment of n-heptanoic acid (III) with 1,1'-carbonyldiimidazole and further condensation with ethyl magnesium malonate (1). Subsequent conjugate addition of (II) to ketoester (IV) using DBU provided adduct (V). Reduction of the nitro group of (V), with concomitant ring closure formed the cyclic imine (VI), which was reduced with NaBH3CN to yield the pyrrolidine (VII) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VIII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VIII) with N,N-dibutyl bromoacetamide (IX) furnished (X). Basic hydrolysis of the ester group of (X) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (XI) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
| 【1】 Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991. |
| 【2】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
| 【3】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIIa) | 35037 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (VIIIb) | 35038 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (Xa),(XI) | 35039 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-hexyl-3-pyrrolidinecarboxylate | C29H46N2O5 | 详情 | 详情 | |
| (Xb) | 35040 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-hexyl-3-pyrrolidinecarboxylate | C29H46N2O5 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35032 | heptanoic acid | 111-14-8 | C7H14O2 | 详情 | 详情 |
| (IV) | 35033 | methyl 3-oxononanoate | C10H18O3 | 详情 | 详情 | |
| (V) | 35034 | methyl 2-[1-(1,3-benzodioxol-5-yl)-2-nitroethyl]-3-oxononanoate | C19H25NO7 | 详情 | 详情 | |
| (VI) | 35035 | methyl 3-(1,3-benzodioxol-5-yl)-5-hexyl-3,4-dihydro-2H-pyrrole-4-carboxylate | C19H25NO4 | 详情 | 详情 | |
| (VII) | 35036 | methyl 4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (IX) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II). Subsequent conjugate addition of (II) to ketoester (III) using DBU provided adduct (IV). Reduction of the nitro group of (IV), with concomitant ring closure formed the cyclic imine (V), which was reduced with NaBH3CN to yield the pyrrolidine (VI) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VII) with N,N-dibutyl bromoacetamide (VIII) furnished (IX). Basic hydrolysis of the ester group of (IX) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (X) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
| 【1】 Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991. |
| 【2】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
| 【3】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIa) | 35028 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate | C20H27NO4 | 详情 | 详情 | |
| (VIIb) | 35029 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate | C20H27NO4 | 详情 | 详情 | |
| (IXa) | 35030 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate | C30H46N2O5 | 详情 | 详情 | |
| (IXb),(X) | 35031 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate | C30H46N2O5 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35024 | methyl 3-(4-methylcyclohexyl)-3-oxopropanoate | C11H18O3 | 详情 | 详情 | |
| (IV) | 35025 | methyl 3-(1,3-benzodioxol-5-yl)-2-[(4-methylcyclohexyl)carbonyl]-4-nitrobutanoate | C20H25NO7 | 详情 | 详情 | |
| (V) | 35026 | methyl 3-(1,3-benzodioxol-5-yl)-5-(4-methylcyclohexyl)-3,4-dihydro-2H-pyrrole-4-carboxylate | C20H25NO4 | 详情 | 详情 | |
| (VI) | 35027 | methyl 4-(1,3-benzodioxol-5-yl)-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate | C20H27NO4 | 详情 | 详情 | |
| (VIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(B)The starting phenylethylamine (I) is prepared by condensation of N-formyl-5-bromo-3,4-methylenedioxyphenylethylamine (VIII) with N-carbobenzoxy-3-methoxy-4-hydroxyphenylethylamine (IX) through an Ullman condensation catalysed by CuO, followed by elimination of the formyl group with HCl in methanol. Compound (VIII) is prepared as follows: 3,4-dihydroxy-5-bromobenzaldehyde (X) is methylenated with methylene bromide (A) and CuO in DMF giving 3,4-methylenedioxy-5-bromobenzaldehyde (XI), which is condensed with nitromethane (B) in acetic acid containing ammonium acetate affording 3,4-methylenedioxy-5-bromo-beta-nitrostyrene (XII). The reduction of (XII) under Clemensen conditions yields 3,4-methylenedioxy-5-bromophenylethylamine (XIII), which is finally formylated with formic acid in decalin. Compound (IX) is prepared as follows: 3-methoxy-4-hydroxy-beta-nitrostyrene (XIV) is treated with ethyl chloroformate (C) in pyridine yielding the corresponding ethoxycarbonyl derivative (XV), which is reduced under Clemensen conditions to 3-methoxy-4-ethoxycarbonyloxyphenylethylamine (XVI). Finally, this compound is treated first with benzyloxycarbonyl chloride and then with aqueous NaHCO3.
| 【1】 Tomita, M.; et al.; Synthesis of di-cepharanthine. Tetrahedron Lett 1967, 1201-06. |
| 【2】 Serradell, M.N.; Blancafort, P.; Mealy, N.; Castañer, J.; Cepharanthine. Drugs Fut 1979, 4, 7, 481. |
| 【3】 Kondo, H.; et al.; US 2206407 . |
| 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) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (B) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (I) | 39554 | benzyl 4-[[6-(2-aminoethyl)-1,3-benzodioxol-4-yl]oxy]-3-methoxyphenethylcarbamate | C26H28N2O6 | 详情 | 详情 | |
| (VIII) | 39566 | 2-(7-bromo-1,3-benzodioxol-5-yl)ethylformamide | C10H10BrNO3 | 详情 | 详情 | |
| (IX) | 39570 | benzyl 3-hydroxy-4-methoxyphenethylcarbamate | C17H19NO4 | 详情 | 详情 | |
| (X) | 39561 | 3-bromo-4,5-dihydroxybenzaldehyde | 16414-34-9 | C7H5BrO3 | 详情 | 详情 |
| (XI) | 39562 | 7-bromo-1,3-benzodioxole-5-carbaldehyde | C8H5BrO3 | 详情 | 详情 | |
| (XII) | 39564 | 4-bromo-6-[(E)-2-nitroethenyl]-1,3-benzodioxole | C9H6BrNO4 | 详情 | 详情 | |
| (XIII) | 39565 | 2-(7-bromo-1,3-benzodioxol-5-yl)ethylamine; 2-(7-bromo-1,3-benzodioxol-5-yl)-1-ethanamine | C9H10BrNO2 | 详情 | 详情 | |
| (XIV) | 39567 | 2-methoxy-5-[(E)-2-nitroethenyl]phenol | C9H9NO4 | 详情 | 详情 | |
| (XV) | 39568 | ethyl 2-methoxy-5-[(E)-2-nitroethenyl]phenyl carbonate | C12H13NO6 | 详情 | 详情 | |
| (XVI) | 39569 | 5-(2-aminoethyl)-2-methoxyphenyl ethyl carbonate | C12H17NO4 | 详情 | 详情 | |
| (C) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VIII)The reaction of 3-fluoro-4-methylbenzoic acid (I) with malonic acid monoethyl ester potassium salt (II) by means of CDI and MgCl2 in THF gives 3-(3-fluoro-4-methylphenyl)-3-oxopropionic acid ethyl ester (III), which can alternatively be obtained by condensation of 3'-fluoro-4'-methylacetophenone (IV) with diethyl carbonate (V) by means of NaH in THF. The condensation of ketoester (III) with 5-(2-nitrovinyl)-2,3-dihydrobenzofuran (VI) (obtained by condensation of 2,3-dihydrobenzofuran-5-carbaldehyde (VII) with nitromethane (VIII) by means of NH4OAc in hot acetic acid) yields the adduct (IX), which is reductively cyclized by hydrogenation with H2 over Raney-Ni in acetic acid, followed by a treatment with TFA to afford the pyrrolidine (X) as a mixture of isomers. The isomerization of (X) with DBU in refluxing toluene provides (rac)-(trans,trans)-pyrrolidine derivative (XI), which is hydrolyzed with NaOH and protected with Boc2O to give the racemic carboxylic acid (XII), which is suitable for optical resolution. The optical resolution of (XII) is performed with (R)-(+)-alpha-methylbenzylamine and the resulting chiral acid is esterified with HCl and ethanol, yielding the (R,R,S)-esterified precursor (XIII). The condensation of (XIII) with 2-bromo-N,N-dibutylacetamide (XIV) by means of DIEA in acetonitrile affords the chiral pyrrolidine-carboxylate (XV), which is finally hydrolyzed with NaOH to provide the target carboxylic acid.
| 【1】 Jae, H.-S.; et al.; Pyrrolidine-3-carboxylic acids as endothelin antagonists.5. Highly selective potent, and orally active ETA antagonists. J Med Chem 2001, 44, 23, 3978. |
| 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) | 52193 | 3-Fluoro-p-toluic acid; 3-Fluoro-4-methylbenzoic acid | 350-28-7 | C8H7FO2 | 详情 | 详情 |
| (II) | 52194 | ethyl propionate | C5H10O2 | 详情 | 详情 | |
| (III) | 52195 | ethyl 3-(3-fluoro-4-methylphenyl)-3-oxopropanoate | C12H13FO3 | 详情 | 详情 | |
| (IV) | 52196 | 1-(3-fluoro-4-methylphenyl)-1-ethanone | C9H9FO | 详情 | 详情 | |
| (V) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VI) | 52197 | 5-[(E)-2-nitroethenyl]-2,3-dihydro-1-benzofuran | C10H9NO3 | 详情 | 详情 | |
| (VII) | 52198 | 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde | C9H8O2 | 详情 | 详情 | |
| (VIII) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (IX) | 52199 | methyl 3-(2,3-dihydro-1-benzofuran-5-yl)-2-(3-fluoro-4-methylbenzoyl)-4-nitrobutanoate | C21H20FNO6 | 详情 | 详情 | |
| (X) | 52200 | methyl 4-(2,3-dihydro-1-benzofuran-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate | C21H22FNO3 | 详情 | 详情 | |
| (XI) | 52201 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate | C20H20FNO4 | 详情 | 详情 | |
| (XII) | 52202 | (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylic acid | C24H26FNO6 | 详情 | 详情 | |
| (XIII) | 52203 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate | C21H22FNO4 | 详情 | 详情 | |
| (XIV) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XV) | 52204 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate | C31H41FN2O5 | 详情 | 详情 |