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【结 构 式】 
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【分子编号】15147 【品名】Benzylamine; Phenylmethanamine 【CA登记号】100-46-9 |
【 分 子 式 】C7H9N 【 分 子 量 】107.1552 【元素组成】C 78.46% H 8.47% N 13.07% |
合成路线1
该中间体在本合成路线中的序号：(II)A new method for the synthesis of sorbinil has been reported: The condensation of 2,3-dihydro-6-fluoro-4H-1-benzopyran-4-one (I) with methylbenzylamine (II) by means of TiCl4 in benzene gives 2,3-dihydro-6-fluoro-4-(1-phenylethylimino)-4H-1-benzopyran (III), which by reaction with HCN in ethanol is converted to 4-cyano-2,3-dihydro-6-fluoro-4-(1-phenylethylamino)-4H-1-benzopyran (IV). The cyclization of (IV) with chlorosulfonyl isocyanate (V) in methylene chloride affords 2,3-dihydro-6-fluoro-3'-(1-phenylethyl)spiro(4H-1-benzopyran-4,4'-imidazolidine)-2',5'-dione (VI), which is finally treated with 48% HBr in refluxing acetic acid.
| 【1】 Kelbaugh, P.R.; Sarges, R.; Howard, H.R. Jr.; Synthesis of optically active spirohydantoins by asymmetric induction. Hydantoin formation from amino nitriles and chlorosulfonyl isocyanate. J Org Chem 1982, 47, 21, 4081-85. |
| 【2】 Sarges, R. (Pfizer Inc.); Intermediates in the preparation of chiral hydantoins. US 4348526 . |
| 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) | 10056 | 6-Fluoro-2,3-dihydro-4H-chromen-4-one; 6-Fluoro-4-chromanone | 66892-34-0 | C9H7FO2 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 29153 | N-(6-fluoro-2,3-dihydro-4H-chromen-4-ylidene)-1-phenyl-1-ethanamine | C17H16FNO | 详情 | 详情 | |
| (IV) | 29154 | 6-fluoro-4-[(1-phenylethyl)amino]-4-chromanecarbonitrile | C18H17FN2O | 详情 | 详情 | |
| (V) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (VI) | 29155 | (4S)-6-Fluoro-3'-(1-phenylethyl)-3,4-dihydro-2H-spiro[1-benzopyran-4-4'-imidazolidine]-2',5'-dione | C19H17FN2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)This compound has been obtained in two related ways: 1. The reaction of 2-(2-bromoethoxy)anisole (I) with benzylamine (II) by heating at 80 C gives the secondary amine (III), which is condensed with epichlorohydrin (IV) by heating at 60 C to yield the isopropanol derivative (V). The condensation of (V) with 4-hydroxycarbazole (VI) by means of K2CO3 in refluxing dioxane affords the adduct (VII), which is finally debenzylated by hydrogenolysis with H2 over Pd/C in ethanol/water. 2. The condensation of the secondary amine (III) with 4-(2,3-epoxypropoxy)carbazole (VIII) in refluxing ethanol gives the already reported adduct (VII), which is debenzylated as indicated.
| 【1】 Seres, P.; Cselenyak, J.; Nagy, K.; Simig, G.; Gregor, T.; Nagy, P.K.; Greff, Z.; Balazs, L.; Barkoczy, J.; Vereczkey, G.D.; Nemeth, N.; Szabo, T.; Ratkai, Z.; Doman, I. (Egis Pharmaceuticals Ltd.); Process and intermediates for preparing 1-[9'H-carbazol-4'-yloxy]-3-[2''-(2'''-methoxy-phenoxy)ethyl]amino]-propan-2-ol (carvedilol). EP 0918055 . |
| 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) | 51402 | 2-(2-Bromoethoxy)methoxybenzene; 1-Bromo-2-(2-methoxyphenoxy)ethane | 4463-59-6 | C9H11BrO2 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 30528 | N-benzyl-2-(2-methoxyphenoxy)-1-ethanamine; N-benzyl-N-[2-(2-methoxyphenoxy)ethyl]amine | C16H19NO2 | 详情 | 详情 | |
| (IV) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (V) | 51403 | 1-[benzyl[2-(2-methoxyphenoxy)ethyl]amino]-3-chloro-2-propanol | C19H24ClNO3 | 详情 | 详情 | |
| (VI) | 29480 | 4-Hydroxycarbazole; 9H-carbazol-4-ol | 52602-39-8 | C12H9NO | 详情 | 详情 |
| (VII) | 51404 | 1-[benzyl[2-(2-methoxyphenoxy)ethyl]amino]-3-(9H-carbazol-4-yloxy)-2-propanol | C31H32N2O4 | 详情 | 详情 | |
| (VIII) | 40171 | 9H-carbazol-4-yl 2-oxiranylmethyl ether; 4-(2-oxiranylmethoxy)-9H-carbazole | 51997-51-4 | C15H13NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The reaction of 5-acetylsalicylamide (I) with benzyl chloride (II) by means of sodium methoxide in hot DMF gives 4-benzyloxy-3-carbamoylacetophenone (III), which by bromination with Br2 in refluxing CHCl3 is converted into 4-benzyloxy-3-carbamoylphenacyl bromide (IV). The condensation of (IV) with N-(4-phenyl-2-butyl)benzylamine (V) (prepared from benzylamine (VI) and 4-phenyl-2-butanone (VII), p-toluenesulfonic acid and NaBH4 in benzene -methanol) by means of K2CO3 in DMF yields 2-benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide (VIII), which is reduced with NaBH4 in ethanol to afford 2-benzyloxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)-N-benzylamino]ethyl]benzamide (IX). Finally, this compound is debenzylated by hydrogenolysis with H2 over Pd/C in ethanol. The separation into its optical isomers is performed by conventional methods.
| 【1】 Gold, E.H.; Chang, W. (Schering Corp.); A phenylalkylaminoethylsalicylamide, its preparation and pharmaceutical compositions containing it. CA 1151211; DD 150457; EP 0009702; JP 55055147; ZA 7904872 . |
| 【2】 Gold, E.H.; Chang, W. (Schering Biotech Corp.); Diastereoisomers of 5-(1-hydroxy-2-(1-methyl-3-phenylpropylamino)ethyl)salicylamide. US 4173583 . |
| 【3】 Serradell, M.N.; Castaner, J.; Weetman, D.F.; Blancafort, P.; Sch-19,927. Drugs Fut 1982, 7, 11, 815. |
| 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) | 32058 | 5-Acetyl-2-hydroxybenzamide; 5-Acetylsalicylamide | 40187-51-7 | C9H9NO3 | 详情 | 详情 |
| (II) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (III) | 32059 | 4-Benzyloxy-3-carbamoylacetophenone; 5-Acetyl-2-(benzyloxy)benzamide | C16H15NO3 | 详情 | 详情 | |
| (IV) | 32060 | 2-(Benzyloxy)-5-(2-bromoacetyl)benzamide; 4-Benzyloxy-3-carbamoylphenacyl bromide; 2-Benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide | C16H14BrNO3 | 详情 | 详情 | |
| (V) | 30353 | N-benzyl-N-(1-methyl-3-phenylpropyl)amine; N-(4-phenyl-2-butyl)benzylamine; N-benzyl-4-phenyl-2-butanamine | C17H21N | 详情 | 详情 | |
| (VI) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VII) | 32061 | 4-phenyl-2-butanone | 2550-26-7 | C10H12O | 详情 | 详情 |
| (VIII) | 32060 | 2-(Benzyloxy)-5-(2-bromoacetyl)benzamide; 4-Benzyloxy-3-carbamoylphenacyl bromide; 2-Benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide | C16H14BrNO3 | 详情 | 详情 | |
| (IX) | 32063 | 5-[2-[Benzyl(1-methyl-3-phenylpropyl)amino]-1-hydroxyethyl]-2-(benzyloxy)benzamide; 2-Benzyloxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)-N-benzylamino]ethyl]benzamide | C33H36N2O3 | 详情 | 详情 | |
| (X) | 32064 | 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide | 36894-69-6 | C19H24N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(B)4-Benzyloxy-indole-2-carboxylic acid (I) is converted into the corresponding dimethylamide (III), via the corresponding acid chloride (II); the dimethylamide (III) is reduced with LiAlH4 to give 4-benzyloxy-2-dimethylaminomethyl-indole (IV), which is hydrogenated to 4-hydroxy-2-methyl-indole (V). The reaction of (V) with epichlorohydrin (A) in aqueous NaOH gives the crude epoxide which without isolation is treated with isopropylamine (B) in refluxing dioxane.
| 【1】 Seemann, F.; et al.; Synthetic indoles. 10. Chemistry of 4-hydroxy-indoles. Helv Chim Acta 1971, 54, 8, 2411-19. |
| 【2】 Troxler, F.; Hofmann, A.; Verfahren zur Herstellung neuer Indolderivate. AT 316542B; CH 502337 . |
| 【3】 Troxler, F.; Hofmann, A.; Verfahren zur Herstellung neuer Indolderivate. CH 543505 . |
| 【4】 Weetman, D.F.; Castaner, J.; Mepindolol. Drugs Fut 1978, 3, 5, 381. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (B) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (I) | 33536 | 4-(benzyloxy)-1H-indole-2-carboxylic acid | C16H13NO3 | 详情 | 详情 | |
| (II) | 33537 | 4-(benzyloxy)-1H-indole-2-carbonyl chloride | C16H12ClNO2 | 详情 | 详情 | |
| (III) | 33538 | 4-(benzyloxy)-N,N-dimethyl-1H-indole-2-carboxamide | C18H18N2O2 | 详情 | 详情 | |
| (IV) | 33539 | N-[[4-(benzyloxy)-1H-indol-2-yl]methyl]-N,N-dimethylamine; [4-(benzyloxy)-1H-indol-2-yl]-N,N-dimethylmethanamine | C18H20N2O | 详情 | 详情 | |
| (V) | 33540 | 4-Hydroxy-2-methylindole; 2-Methyl-1H-indol-4-ol | 35320-67-3 | C9H9NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(B)The reaction of 4-hydroxy-2-methyl-indole (V) with 1-(N-benzylisopropylamino)-3-chloro-2-propanol (D) by means of NaOH in refluxing aqueous dioxane yields the corresponding benzylamine (X), which is debenzylated by catalytic hydrogenation. The reaction of 4-hydroxy-2-methyl-indole (V) with epichlorohydrin (A) and benzylamine (B) gives 4-(3-benzylamino-2-hydroxypropoxy)-2-methyl-indole (XI), which is debenzylated by hydrogenolysis to 4-(3-amino-2-hydroxypropoxy)-2-methyl-indole (XII). The condensation of (XII) with refluxing acetone (C) affords the corresponding N-isopropylidene derivative (XIII), which is finally hydrogenated with H2 over Pd/C in methanol.
| 【1】 Seemann, F.; et al.; Synthetic indoles. 10. Chemistry of 4-hydroxy-indoles. Helv Chim Acta 1971, 54, 8, 2411-19. |
| 【2】 Troxler, F.; Verfahren zur Herstellung neuer Indolderivate. CH 472404; ES 337457 . |
| 【3】 Troxler, F.; Verfahren zur Herstellung neuer Indolderivate. CH 469002; ES 337458 . |
| 【4】 Troxler, F.; Verfahren zur Herstellung von neuem 4-(2-Hydroxy-3-isopropylaminopropoxy)-2-methylindol und seiner Saureadditionssalze Indolderivate. AT 317199 . |
| 【5】 Weetman, D.F.; Castaner, J.; Mepindolol. Drugs Fut 1978, 3, 5, 381. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (B) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (D) | 33549 | 1-[benzyl(isopropyl)amino]-3-chloro-2-propanol | C13H20ClNO | 详情 | 详情 | |
| (V) | 33540 | 4-Hydroxy-2-methylindole; 2-Methyl-1H-indol-4-ol | 35320-67-3 | C9H9NO | 详情 | 详情 |
| (X) | 33548 | 1-[benzyl(isopropyl)amino]-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol | C22H28N2O2 | 详情 | 详情 | |
| (XI) | 33545 | 1-(benzylamino)-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol | C19H22N2O2 | 详情 | 详情 | |
| (XII) | 33546 | 1-amino-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol | C12H16N2O2 | 详情 | 详情 | |
| (XIII) | 33547 | 1-[(1-methylethylidene)amino]-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol | C15H20N2O2 | 详情 | 详情 | |
| (C) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The condensation of 1,6-dibromohexane (I) with 4-phenyl-1-butanol (II) by means of NaOH under phase transfer catalysis gives 6-(4-phenylbutoxy)hexyl bromide (III), which is condensed with benzylamine (IV) by means of Cs2CO3 in hot DMF to yield the secondary amine (V). The condensation of (V) with methyl alpha-bromo 4-acetylsalicylate (VI) by means of DIEA in refluxing THF affords the tertiary amine (VII), which is submitted to a reductive deuteration by means of deuterated LiAlD4 in THF to provide the trideuterated intermediate (VIII). Finally this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to give rise to the target trideuterated salmeterol.
| 【1】 Molinski, T.F.; Stanley, S.D.; Improved synthesis of 13C,2H3- and 2H3-salmeterol by Cs2CO3-mediated monoalkylation of a primary amine. J Label Compd Radiopharm 2002, 45, 9, 755. |
| 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) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (II) | 27291 | 4-phenyl-1-butanol | 3360-41-6 | C10H14O | 详情 | 详情 |
| (III) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 35836 | methyl 5-(2-bromoacetyl)-2-hydroxybenzoate | C10H9BrO4 | 详情 | 详情 | |
| (VI) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (VII) | 35838 | methyl 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzoate | C33H41NO5 | 详情 | 详情 | |
| (VIII) | 35839 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 | |
| (VIII) | 57250 | 4-(2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)The condensation of 4-phenyl-1-butanol (I) with 1,6-dibromohexane (II) by means of NaH in THF gives the ether (III), which is condensed with benzylamine (IV) by means of NaI and TEA in DMSO to yield the secondary amine (V). The condensation of (V) with 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) in refluxing acetonitrile affords the tertiary amine (VII). The reduction of both carbonyl groups of (VII) by means of NaBH4 in methanol affords the dihydroxy amine (VIII), which is finally debenzylated by means of h2 over Pd/C in the same solvent to provide the target salmeterol. The intermediate 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) has been obtained by Friedel Crafts condensation of 2-hydroxybenzaldehyde (IX) with bromoacetyl chloride (X) by means of AlCl3 in dichloromethane.
| 【1】 Rong, Y.; Ruoho, A.E.; A new synthetic approach to salmeterol. Synth Commun 1999, 29, 12, 2155. |
| 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) | 27291 | 4-phenyl-1-butanol | 3360-41-6 | C10H14O | 详情 | 详情 |
| (II) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (III) | 31479 | 1-[4-[(6-bromohexyl)oxy]butyl]benzene; 6-bromohexyl-4-phenylbutyl ether; 6-Bromohexyloxybutylbenzene | 94749-73-2 | C16H25BrO | 详情 | 详情 |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 35837 | N-benzyl-6-(4-phenylbutoxy)-1-hexanamine; N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine | C23H33NO | 详情 | 详情 | |
| (VI) | 50873 | 5-(2-bromoacetyl)-2-hydroxybenzaldehyde | C9H7BrO3 | 详情 | 详情 | |
| (VII) | 50874 | 5-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]acetyl)-2-hydroxybenzaldehyde | C32H39NO4 | 详情 | 详情 | |
| (VIII) | 35839 | 4-(2-[benzyl[6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl)-2-(hydroxymethyl)phenol | C32H43NO4 | 详情 | 详情 | |
| (IX) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (X) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)A new synthesis of (3R,4S)-1-benzyl-4-phenyl-3-(triethylsilyloxy)azetidin-2-one (XIII), a precursor of the side chain of paclitaxel, has been described: The reaction of ethyl L-tartrate (I) with benzaldehyde and TsOH followed, by reduction with LiAlH4 and AlCl3 gives the monobenzylated tretraol (II), which is submitted to an oxidative cleavage of the alpha-diol bond with NaIO4 to yield the aldehyde (III). Reaction of (III) with benzylamine affords the imine (IV), which is submitted to a Grignard addition of phenylmagnesium bromide in ether providing a 1:9 mixture of aminoalcohols (VI) and (VII) separated by chromatography. Oxidation of the desired major isomer (VII) with CrO3/H2SO4 gives the corresponding acid (VIII), which is then esterified with TMS-Cl in refluxing methanol to the methyl ester (IX). Deprotection of compound (IX) by hydrogenolysis with reluxing HCO2H over Pd/C yields 3(S)-amino-2(R)-hydroxy-3-phenylpropionic acid methyl ester (X), which is silylated at the OH group of with TES-Cl and TEA in ether/THF to afford the silyl ether (XI). Cyclization of (XI) by means of LHMDS in THF provides the beta-lactam (XII), which is finally benzoylated with benzoyl chloride and TEA in the usual way.
| 【1】 Kim, H.-K.; Kim, S.-C.; Synthesis of new Taxol side chain precursor from L-tartaric ester. Bull Korean Chem Soc 2000, 21, 10, 1047. |
| 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) | 16696 | Diethyl L-(+)-Tartrate; diethyl (2S,3S)-2,3-dihydroxybutanedioate | 87-91-2 | C8H14O6 | 详情 | 详情 |
| (II) | 43826 | (2S,3S)-3-(benzyloxy)-1,2,4-butanetriol | C11H16O4 | 详情 | 详情 | |
| (III) | 43827 | (2S)-2-(benzyloxy)-3-hydroxypropanal | C10H12O3 | 详情 | 详情 | |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 43828 | (2R)-3-(benzylimino)-2-(benzyloxy)-1-propanol | C17H19NO2 | 详情 | 详情 | |
| (VI) | 43829 | (2R,3R)-3-(benzylamino)-2-(benzyloxy)-3-phenyl-1-propanol | C23H25NO2 | 详情 | 详情 | |
| (VII) | 43830 | (2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenyl-1-propanol | C23H25NO2 | 详情 | 详情 | |
| (VIII) | 43831 | (2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenylpropionic acid | C23H23NO3 | 详情 | 详情 | |
| (IX) | 43832 | methyl (2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenylpropanoate | C24H25NO3 | 详情 | 详情 | |
| (X) | 43833 | methyl (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoate | C10H13NO3 | 详情 | 详情 | |
| (XI) | 43834 | methyl (2R,3S)-3-amino-3-phenyl-2-[(triethylsilyl)oxy]propanoate | C16H27NO3Si | 详情 | 详情 | |
| (XII) | 10685 | (3R,4S)-4-Phenyl-3-[(triethylsilyl)oxy]-2-azetidinone | C15H23NO2Si | 详情 | 详情 | |
| (XIII) | 10490 | (3R,4S)-1-Benzoyl-4-phenyl-3-[(triethylsilyl)oxy]-2-azetanone | C22H27NO3Si | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(A)The condensation of 2-methoxyphenol (I) with ethylene oxide (II) gives 2-(2-methoxyphenoxy)ethanol (III), which is treated with SOCl2 to yield 2-(2-methoxyphenoxy)ethyl chloride (IV). The reaction of (IV) with benzylamine (A) gives N-[2-(2-methoxyphenoxy)ethyl]benzylamine (V), which is condensed with 2-methyl-5-bromoacetylbenzenesulfonamide (VI) affording N-[2-(2-methoxyphenoxy)ethyl]-N-[(4-methyl-3-aminosulfonylbenzoyl)methyl]benzylamine (VII). The reduction of (VII) with NaBH4 affords the corresponding protected carbinol (VIII), which is finally debenzylated by hydrogenation with H2 over Pd/C.
| 【1】 Arima, H.; Tamazawa, K.; Synthesis of 14C-labeled 5-[1-hydroxy-2-[2-(o-methoxyphenoxy)ethylamino]ethyl]-2-methylbenzenesulfonamide hydochloride (YM-09538). J Label Compd Radiopharm 1983, 20, 7, 803-811. |
| 【2】 Fujikura, T.; et al. (Yamanouchi Pharmaceutical Co., Ltd.); Phenylethanolamine derivatives. DE 2843016; ES 474149; ES 481549; FR 2405931; GB 2006772 . |
| 【3】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Leeson, P.A.; Mealy, N.E.; YM-09,538. Drugs Fut 1981, 6, 7, 425. |
| 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) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (I) | 13182 | Guaiacol; 2-Methoxyphenol | 90-05-1 | C7H8O2 | 详情 | 详情 |
| (II) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (III) | 30526 | 2-(2-methoxyphenoxy)-1-ethanol | C9H12O3 | 详情 | 详情 | |
| (IV) | 30527 | 2-(2-chloroethoxy)phenyl methyl ether; 1-(2-chloroethoxy)-2-methoxybenzene | C9H11ClO2 | 详情 | 详情 | |
| (V) | 30528 | N-benzyl-2-(2-methoxyphenoxy)-1-ethanamine; N-benzyl-N-[2-(2-methoxyphenoxy)ethyl]amine | C16H19NO2 | 详情 | 详情 | |
| (VI) | 30529 | 5-(2-bromoacetyl)-2-methylbenzenesulfonamide | C9H10BrNO3S | 详情 | 详情 | |
| (VII) | 30530 | 5-(2-[benzyl[2-(2-methoxyphenoxy)ethyl]amino]acetyl)-2-methylbenzenesulfonamide | C25H28N2O5S | 详情 | 详情 | |
| (VIII) | 30531 | 5-(2-[benzyl[2-(2-methoxyphenoxy)ethyl]amino]-1-hydroxyethyl)-2-methylbenzenesulfonamide | C25H30N2O5S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)The condensation of 4-fluorobenzaldehyde (I) with ethyl acetoacetate (II) by means of piperidine, followed by a treatment with hot NaOH and esterification with methanol in acid medium, gives 3-(4-fluorophenyl)glutaric acid dimethyl ester (III), which is stereoselectively hydrolyzed with liver esterase in aqueous acetone, yielding the monoester (IV) with a 95% ee. The selective reduction of the ester group of (IV) with LiH and LiBH4 in THF affords the chiral 5-hydroxypentanoic acid (V), which is esterified with dimethyl sulfate in methanol to the corresponding methyl ester (VI). The reaction of (VI) with MsCl and TEA in toluene gives the mesylate (VII), which is cyclized with benzylamine (VIII) and TEA in toluene, affording the chiral piperidone (IX).The reaction of (IX) with dimethyl carbonate (X) and NaH in hot toluene yields the chiral carboxylate (XI), which is reduced at the carboxylate and ketonic groups with LiAlH4 or BH3 in DMSO, providing the chiral piperidine methanol derivative (XII). The reaction of (XII) with MsCl and TEA in toluene yields the mesylate (XIII), which is condensed with the phenol derivative (XIV) by means of NaH in hot DMF, affording the adduct (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.
| 【1】 Yu, M.S.; Lantos, I.; Cacchio, T.; Peng, Z.-Q.; Yu, J.; Asymmetric synthesis of (-)-paroxetine using PLE hydrolysis. Tetrahedron Lett 2000, 41, 30, 5647. |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (III) | 44013 | dimethyl 3-(4-fluorophenyl)pentanedioate | C13H15FO4 | 详情 | 详情 | |
| (IV) | 44014 | (3S)-3-(4-fluorophenyl)-5-methoxy-5-oxopentanoic acid | C12H13FO4 | 详情 | 详情 | |
| (V) | 44015 | lithium (3R)-3-(4-fluorophenyl)-5-hydroxypentanoate | C11H12FLiO3 | 详情 | 详情 | |
| (VI) | 44016 | methyl (3R)-3-(4-fluorophenyl)-5-hydroxypentanoate | C12H15FO3 | 详情 | 详情 | |
| (VII) | 44017 | methyl (3R)-3-(4-fluorophenyl)-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]pentanoate | C15H21FO3S | 详情 | 详情 | |
| (VIII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IX) | 44018 | (4R)-1-benzyl-4-(4-fluorophenyl)-2-piperidinone | C18H18FNO | 详情 | 详情 | |
| (X) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (XI) | 44019 | methyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-2-oxo-3-piperidinecarboxylate | C20H20FNO3 | 详情 | 详情 | |
| (XII) | 44020 | [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol | C19H22FNO | 详情 | 详情 | |
| (XIII) | 44021 | (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)piperidine | C22H28FNOS | 详情 | 详情 | |
| (XIV) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XV) | 44022 | (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether | C26H26FNO3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)The cyclization of 2-butynoic acid methyl ester (I) with 2-(2-chlorobenzylidene)-3-oxobutyric acid ethyl ester (II) and benzylamine (III) in refluxing toluene gives the N-benzylated dihydropyridine (IV), which is debenzylated by reduction with formic acid over Pd/C in refluxing methanol to yield the dihydropyridine (V). The bromination of (V) with C5H5NH+ HBr3- in dichloromethane affords the bromomethyl compound (VI), which is condensed with 2-azidoethanol (VII) by means of NaH in ethyl ether to provide the 2-azidoethoxymethyl compound (VIII). Finally, the azido group of (VIII) is reduced with Zn and HCl in methanol to furnish the desired 2-aminoethoxymethyl compound.
| 【1】 Kim, S.-C.; et al.; Synthesis of amlodipine using aza Diels-Alder reaction. Bull Korean Chem Soc 2002, 23, 1, 143. |
| 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) | 51405 | 2-Butynoic acid methyl ester; Methyl 2-butynoate; Tetrolic acid methyl ester; Methyl tetrolate | 23326-27-4 | C5H6O2 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 51406 | ethyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate | C13H13ClO3 | 详情 | 详情 | |
| (IV) | 51407 | 3-methyl 5-propyl 1-benzyl-4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C26H28ClNO4 | 详情 | 详情 | |
| (V) | 51408 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C18H20ClNO4 | 详情 | 详情 | |
| (VI) | 51409 | 3-ethyl 5-methyl 2-(bromomethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C18H19BrClNO4 | 详情 | 详情 | |
| (VII) | 24111 | 2-azido-1-ethanol | C2H5N3O | 详情 | 详情 | |
| (VIII) | 51410 | 5-methyl 3-propyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C21H25ClN4O5 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(V)The reduction of 6-fluoro-4-oxobenzopyran-2-carboxylic acid (I) with H2 over Pd/C in acetic acid gives 6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxylic acid (II), which is reduced again with bis(2-methylpropyl)aluminum hydride and 1,1'-carbonylbis(1H-imidazole) in THF yielding 6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxaldehyde (III). The reaction of (III) with trimethylsulfoxonium iodide and NaH in DMSO affords 2-oxiranyl-3,4-dihydro-2H-benzopyran (IV), which is condensed with benzylamine (V) in refluxing ethanol to give the benzyl derivative of nebivolol (VI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Van Lommen, G.R.E.; De Bruyn, M.F.L.; Schroven, M.F.J. (Janssen Pharmaceutica NV); Derivatives of 2,2'-iminobisethanol.. AU 8436326; EP 145067; JP 85132977; US 4654362 . |
| 【2】 Prous, J.; Castaner, J.; NEBIVOLOL < Prop INN; USAN >. Drugs Fut 1989, 14, 10, 957. |
| 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) | 19527 | 4-oxo-4H-chromene-2-carboxylic acid | C10H5FO4 | 详情 | 详情 | |
| (II) | 19528 | 6-fluoro-2-chromanecarboxylic acid | C10H9FO3 | 详情 | 详情 | |
| (III) | 19529 | 6-fluoro-2-chromanecarbaldehyde | C10H9FO2 | 详情 | 详情 | |
| (IV) | 19530 | 6-fluoro-2-(2-oxiranyl)chromane | C11H11FO2 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 19532 | 2-[benzyl[2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl]amino]-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-1-ethanol | C29H31F2NO4 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VI)By condensation of 3-(4-acetamido-2-methoxyphenoxy)propyl p-toluenesulfonate with 1-(2-fluorophenyl)piperazine (II). The starting products are obtained as follows: a) The addition of 4-acetamido-2-methoxyphenol (III) to ethyl acrylate (IV) gives ethyl-3-(4-acetamido-2-methoxyphenoxy)propionate (V), which is reduced with LiAlH4 to the corresponding alcohol and tosylated with tosyl chloride to the starting compound (I). b) The condensation of benzylamine (VI) with ethyl bromoacetate (VII) by means of K2CO3 gives N,N-bis(ethoxycarbonyl methyl)benzylamine (VIII), which is reduced with LiAlH4 and treated with SOCl2 to afford N,N-bis(2-chloroethyl)benzylamine (IX). The cyclization of (IX) with 2-fluoroaniline (X) yields 1-benzyl-4-(2-fluorophenyl)piperazine (XI), which is finally debenzylated by hydrogenation with H2 over PdIC to give piperazine (II).
| 【1】 Fukuchi, I.; et al.; Neurochemical study of mafoprazine, a new phenylpiperazine derivative. Jpn Pharmacol 1988, 47, 9, 51. |
| 【2】 Kanno, T.; Gaino, M.; Yamamura, M.; Ishida, R.; Shintomi, K. (Tanabe Seiyaku Co., Ltd.); N-Aryl-N-phenoxy-alkyl-piperazine compounds useful in decreasing intracranial presssure. EP 0034284; JP 156115769; US 4413006 . |
| 【3】 Prous, J.; Castaner, J.; Mafoprazine mesylate. Drugs Fut 1988, 13, 10, 920. |
| 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) | 23114 | 3-[4-(acetamido)-2-methoxyphenoxy]propyl 4-methylbenzenesulfonate | C19H23NO6S | 详情 | 详情 | |
| (II) | 23115 | 1-(2-fluorophenyl)piperazine | 1011-15-0 | C10H13FN2 | 详情 | 详情 |
| (III) | 23116 | N-(4-hydroxy-3-methoxyphenyl)acetamide | C9H11NO3 | 详情 | 详情 | |
| (IV) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (IV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (V) | 23118 | ethyl 3-[4-(acetamido)-2-methoxyphenoxy]propanoate | C14H19NO5 | 详情 | 详情 | |
| (VI) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VIII) | 23121 | ethyl 2-[benzyl(2-ethoxy-2-oxoethyl)amino]acetate | C15H21NO4 | 详情 | 详情 | |
| (IX) | 23122 | N-benzyl-2-chloro-N-(2-chloroethyl)-1-ethanamine; N-Benzylbis(2-chloroethyl)amine | 10429-82-0 | C11H15Cl2N | 详情 | 详情 |
| (X) | 22296 | 2-fluorophenylamine; 2-fluoroaniline | 348-54-9 | C6H6FN | 详情 | 详情 |
| (XI) | 23124 | 1-benzyl-4-(2-fluorophenyl)piperazine | C17H19FN2 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：D 7175 can be obtained in a 5-step synthesis starting from 2,e-dichloropyridine (I). Compound (I) is nitrated with HNO3/H2SO4 yielding 2,6-dichloro-3-nitropyridine (II). Subsequent reaction with ammonia and benzylamine leads to 2-amino-3-nitro-6-benzylaminopyridine (IV), which is hydrogenated using Raney Nickel as catalyst te the corresponding 3-amino derivative (V), which reacts without isolation with ethyl chloroformiate to D-7175.
| 【1】 Bebengurg, W.; Engek, J.; Heese, J.; Thiele, K. (Degussa AG); 2-Amino-3-acylamino-6-benzylaminopyridine derivatives having antiepileptic action. DE 3337593 . |
| 【2】 Molliere, M.; Engel, J.; Emig, P.; D-7175. Drugs Fut 1988, 13, 1, 22. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (II) | 13574 | 2,6-Dichloro-3-nitropyridine | 16013-85-7 | C5H2Cl2N2O2 | 详情 | 详情 |
| (III) | 13575 | 6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine | 27048-04-0 | C5H4ClN3O2 | 详情 | 详情 |
| (IV) | 21572 | N(6)-benzyl-3-nitro-2,6-pyridinediamine | C12H12N4O2 | 详情 | 详情 | |
| (V) | 21573 | 2-amino-6-(benzylamino)-3-pyridinylamine | C12H14N4 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(X)The cyclization of ethyl cyanoacetate (I) with urea (II) in ethanolic NaOEt provided 6-aminouracil (III). Nitrosation of (III) with NaNO2 in aqueous AcOH, followed by reduction of the resulting nitroso compound (IV) using sodium hydrosulfite gave 5,6-diaminouracil, which was purified by conversion to its hydrochloride salt (V). Condensation of this diamine with melted oxalic acid produced tetrahydroxypteridine (VI). Subsequent reaction of (VI) with PCl5 and POCl3 afforded tetrachlorocompound (VII). The reaction of (VII) with pyrrolidine (VIII) in aqueous KHCO3/CHCl3 resulted in a mixture of 2-, 4-, 7- and 4,7-substituted compounds, from which the desired 4-pyrrolidino-2,6,7-trichloropteridine (IX) was isolated by column chromatography. Further treatment of (IX) with benzylamine (X) in dioxan at r.t. provided diamine (XI). Finally, substitution of the third chlorine atom for piperazine (XII) was accomplished in boiling dioxan.
| 【1】 Merz, K.-H.; Marko, D.; Regiert, T.; Reiss, G.; Frank, W.; Eisenbrand, G.; Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth. J Med Chem 1998, 41, 24, 4733. |
| 【2】 Taylor, E.C. Jr.; Sherman, W.R.; Diaminouracil hydrochloride. Org Synth Coll 1957, 37, 15. |
| 【3】 Schopf, C.; Reichert, R.; Zur kenntnis des leukopterins. Liebigs Ann Chem 1941, 548, 82. |
| 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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (III) | 19311 | 6-amino-2,4(1H,3H)-pyrimidinedione | 873-83-6 | C4H5N3O2 | 详情 | 详情 |
| (IV) | 19312 | 6-amino-5-nitroso-2,4(1H,3H)-pyrimidinedione | C4H4N4O3 | 详情 | 详情 | |
| (V) | 19313 | 5,6-diamino-2,4(1H,3H)-pyrimidinedione | 3240-72-0 | C4H6N4O2 | 详情 | 详情 |
| (VI) | 19314 | 2,4,6,7-pteridinetetrol | C6H4N4O4 | 详情 | 详情 | |
| (VII) | 19315 | 2,4,6,7-tetrachloropteridine | C6Cl4N4 | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IX) | 19317 | 2,6,7-trichloro-4-(1-pyrrolidinyl)pteridine | C10H8Cl3N5 | 详情 | 详情 | |
| (X) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XI) | 19319 | N-benzyl-N-[2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinyl]amine; N-benzyl-2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinamine | C17H16Cl2N6 | 详情 | 详情 | |
| (XII) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(V)By cyclocondensation of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and 1-benzyl-3-(acetoacetoxy)pyrrolidine (III) in refluxing isopropanol. The pyrrolidine (III) is obtained as follows: The condensation of 2-hydroxysuccinic acid (IV) with benzylamine (VI), which is reduced with LiAlH4 in dry THF yielding N-benzyl-3-hydroxypyrrolidine (VIII). Finally, this compound is condensed with diketene (VII) by means of sodium acetate at 80 C.
| 【1】 Tamazawa, K.; Takeuchi, M.; Arima, H.; Synthesis of 14C-and 2H-labeled (3S)-1-benzyl-3-py. J Label Compd Radiopharm 1988, 25, 2, 161. |
| 【2】 Kojima, T.; Takenaka, T. (Yamanouchi Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine-3,5-dicarboxylic acid ester de. DE 2904552; US 4220649 . |
| 【3】 Prous, J.; Castaner, J.; YM-09730-5. Drugs Fut 1988, 13, 7, 634. |
| 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) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (III) | 22742 | 2-Oxobutyric acid 1-benzylpyrrolidin-3-yl ester | C15H19NO3 | 详情 | 详情 | |
| (IV) | 22743 | Hydroxysuccinic acid; Malic acid; Hydroxybutanedioic acid | 617-48-1 | C4H6O5 | 详情 | 详情 |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 22745 | 1-Benzyl-3-hydroxypyrrolidine-2,5-dione | C11H11NO3 | 详情 | 详情 | |
| (VII) | 22746 | 1-benzyl-3-pyrrolidinol | C11H15NO | 详情 | 详情 | |
| (VIII) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(V)The reaction of ethyl pentafluorobenzoylacetate (I) with ethyl orthoformate in refluxing acetic anhydride and then with cyclopropylamine (II) in ether gives the aminomethylene derivative (III), which is cyclized by means of NaH in THF yielding ethyl 5,6,7,8-tetrafluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (IV). The reaction of (IV) with benzylamine (V) by means of K2CO3 in refluxing acetonitrile affords the benzylamino derivative (VI), which is deprotected by hydrogenation with H2 over Pd/C in ethanol giving ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (VII). The hydrolysis of (VII) with hot H2SO4 yields the free acid (VIII), which is finally condensed with cis-2,6-dimethylpiperazine (IX) in DMF.
| 【1】 Matsumoto, J.; Miyamoto, T.; Egawa, H.; Nakamura, S. (Dainippon Pharm. Co.; Ltd.); Novel quinoline derivatives and processes for preparation thereof. AU 8664277; EP 0221463; JP 87277362 . |
| 【2】 Prous, J.; Castaner, J.; AT-4140. Drugs Fut 1989, 14, 5, 413. |
| 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) | 20840 | ethyl 3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate | C11H7F5O3 | 详情 | 详情 | |
| (II) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (III) | 20842 | ethyl 2-[(cyclopropylamino)methyl]-3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate | C15H14F5NO3 | 详情 | 详情 | |
| (IV) | 20843 | ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H11F4NO3 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 20845 | ethyl 5-(benzylamino)-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C22H19F3N2O3 | 详情 | 详情 | |
| (VII) | 20846 | ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H13F3N2O3 | 详情 | 详情 | |
| (VIII) | 19819 | 4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid | C17H15NO4S | 详情 | 详情 | |
| (IX) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (S)-(+)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with D-(+)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt.
| 【1】 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 | |
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 25580 | 3-amino-2-methylpropanenitrile | C4H8N2 | 详情 | 详情 | |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 25581 | 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile | C7H11N3 | 详情 | 详情 | |
| (IV) | 25582 | 5-methyl-4-oxo-3-piperidinecarbonitrile | C7H10N2O | 详情 | 详情 | |
| (V) | 25583 | ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate | C10H14N2O3 | 详情 | 详情 | |
| (VI) | 25584 | ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate | C10H16N2O4 | 详情 | 详情 | |
| (VII) | 25585 | ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate | C17H23N3O3 | 详情 | 详情 | |
| (VIII) | 25586 | ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate | C10H14N2O3S | 详情 | 详情 | |
| (IX) | 25587 | 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol | C7H10N2OS | 详情 | 详情 | |
| (X) | 25588 | tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate | C12H18N2O3S | 详情 | 详情 | |
| (XI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (XII) | 25589 | 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether | C10H12N2OS | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (R)-(-)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with L-(-)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt .
| 【1】 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 | |
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 25580 | 3-amino-2-methylpropanenitrile | C4H8N2 | 详情 | 详情 | |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 25581 | 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile | C7H11N3 | 详情 | 详情 | |
| (IV) | 25582 | 5-methyl-4-oxo-3-piperidinecarbonitrile | C7H10N2O | 详情 | 详情 | |
| (V) | 25583 | ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate | C10H14N2O3 | 详情 | 详情 | |
| (VI) | 25584 | ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate | C10H16N2O4 | 详情 | 详情 | |
| (VII) | 25585 | ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate | C17H23N3O3 | 详情 | 详情 | |
| (VIII) | 25586 | ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate | C10H14N2O3S | 详情 | 详情 | |
| (IX) | 25587 | 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol | C7H10N2OS | 详情 | 详情 | |
| (X) | 25588 | tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate | C12H18N2O3S | 详情 | 详情 | |
| (XI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (XII) | 25589 | 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether | C10H12N2OS | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(A)The reaction of 5-chloro-2-hydroxybenzoic acid (I) with 2-methyl-2-propenyl chloride (II) by means of K2CO3 and KI in hot DMF gives 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid 2-methyl-2-propenyl ester (III), which is rearranged by heating at 190 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid 2-methyl-2-propenyl ester (IV). The cyclization of (IV) with refluxing 90% formic acid affords 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (V), which is treated with SOCl2 in DMF and condensed with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI). The acid intermediate (V) can also be obtained by hydrolysis of the ester (III) with NaOH and tetrabutylammonium bisulfate in refluxing water to give 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid (VII), which is rearranged by heating at 170 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid (VIII). Finally, (VIII) is cyclized to acid intermediate (V) by a treatment with aqueous refluxing 2.7N HCl. The intermediate endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI) has been obtained as follows: 2,5-dihydroxytetrahydrofuran (IX) or 2,5-dimethoxytetra-hydrofuran (X) with HCl give butanedialdehyde (XI), which, without isolation, is cyclized with 3-oxoglutaric acid (XII) and methylamine by means of NaOAc and HCl in hot water yielding 8-methyl-8-azabicyclo[3.2.1]octan-3-one (XIII). The reductocondensation of (XIII) with benzylamine by means of NaBH(OAc)3, followed by hydrogenolysis with H2 over Pd/C in basic water gives directly the amine (VI). The intermediate amine (VI) can also be obtained by condensation of bicyclooctanone (XIII) with benzylamine(A) to give the imine (XIV), which is reduced to the benzylamine (XV) with H2 over PtO2 in ethanol. Finally, this compound is debenzylated by hydrogenation over Pd/C in the same solvent yielding amine (VI).
| 【1】 Burks, J.E.; et al.; Development of a manufacturing process for zatosetron maleate. Org Process Res Dev 1997, 1, 3, 198. |
| 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) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (I) | 13895 | 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid | 321-14-2 | C7H5ClO3 | 详情 | 详情 |
| (II) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (III) | 36355 | 2-methyl-2-propenyl 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoate | C15H17ClO3 | 详情 | 详情 | |
| (IV) | 36356 | 2-methyl-2-propenyl 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoate | C15H17ClO3 | 详情 | 详情 | |
| (V) | 13900 | 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C11H11ClO3 | 详情 | 详情 | |
| (VI) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 | |
| (VII) | 36357 | 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoic acid | C11H11ClO3 | 详情 | 详情 | |
| (VIII) | 36358 | 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid | C11H11ClO3 | 详情 | 详情 | |
| (IX) | 36359 | tetrahydro-2,5-furandiol | C4H8O3 | 详情 | 详情 | |
| (X) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (XI) | 36360 | succinaldehyde | C4H6O2 | 详情 | 详情 | |
| (XII) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XIII) | 16443 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one | C8H13NO | 详情 | 详情 | |
| (XIV) | 36361 | N-benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene]amine; N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene](phenyl)methanamine | C15H20N2 | 详情 | 详情 | |
| (XV) | 12413 | N-Benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amine; (1R,5S)-N-Benzyl-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C15H22N2 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(A)The condensation of cyclohexene-epoxide (I) with pyrrolidine (II) gives trans-2-(1-pyrrolidinyl)cyclohexanol (III), which by reaction with NaH and methanesulfonyl chloride, and then with benzylamine is converted into trans-2-(1-pyrrolidinyl)-N-benzylcyclohexylamine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords trans-2-(1-pyrrolidinyl)cyclohexylamine (V), which is formylated with ethyl formate to the corresponding N-formyl-trans-2-(1-pyrrolidinyl)cyclohexylamine (VI). The reduction of (VI) with LiAlH4 in refluxing ether gives trans-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (VII), which is finally condensed with 3,4-dichlorophenylacetic acid (VIII) by means of carbonyl diimidazole (IX) in THF.
| 【1】 Blancafort, P.; Castaner, J.; Serradell, M.N.; U-50488. Drugs Fut 1982, 7, 6, 416. |
| 【2】 Szmuszkovicz, J.; 2-Aminocycloaliphatic amide compounds. DE 2749950; ES 463876; FR 2370723; GB 1569225; JP 53063351; JP 61233654; US 4145435 . |
| 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) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (B) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (IV) | 37038 | N-phenyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]aniline | C16H24N2 | 详情 | 详情 | |
| (V) | 37040 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexylamine; (1R,2R)-2-(1-pyrrolidinyl)cyclohexanamine | C10H20N2 | 详情 | 详情 | |
| (VI) | 37011 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one | C15H20N2O | 详情 | 详情 | |
| (VII) | 31357 | N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine | C11H22N2 | 详情 | 详情 | |
| (VIII) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (IX) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (X) | 37039 | 7-azabicyclo[4.1.0]heptane | C6H11N | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(III)The oxidation of mannitol diacetonide (I) with Pb(OAc)4 in benzene gives the glyceraldehyde acetonide (II), which is reductocondensed with benzylamine (III) by means of H2 over Pd/C in methanol to yield, after acidification with HCl, (S)-3-(benzylamino)propane-1,2-diol (IV). The cyclization of (IV) with benzaldehyde (V) in refluxing toluene affords the chiral oxazolidine (VI), which is treated with tosyl chloride and pyridine to provide the corresponding tosylate (VII). The condensation of (VII) with 4-[2-(cyclopropylmethoxy)ethyl]phenol (VIII) by means of NaH in DMF gives the phenolic ether (IX), which is treated with conc. HCl to open the oxazolidine ring and yield the chiral propanolamine (X). The alkylation of the secondary amino group of (X) with isopropyl iodide (XI) in refluxing ethanol affords the tertiary amine (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the target betaxolol.
| 【1】 Kitteringham, J.; Mitchell, M.B. (GlaxoSmithKline plc); Stereoselective process and chiral intermediates for aryloxydropanolamines. WO 8606368 . |
| 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) | 55678 | (4S)-4-{(1S,2S)-2-[(4S)-1,3-dioxolan-4-yl]-1-methylpropyl}-2,2-dimethyl-1,3-dioxolane | C12H22O4 | 详情 | 详情 | |
| (II) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 详情 | 详情 |
| (III) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IV) | 55679 | (2S)-3-(benzylamino)-1,2-propanediol | C10H15NO2 | 详情 | 详情 | |
| (V) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VI) | 55680 | [(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methanol | C17H19NO2 | 详情 | 详情 | |
| (VII) | 55681 | [(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methyl 4-methylbenzenesulfonate | C24H25NO4S | 详情 | 详情 | |
| (VIII) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 | |
| (IX) | 55682 | (5S)-3-benzyl-5-({4-[2-(cyclopropylmethoxy)ethyl]phenoxy}methyl)-2-phenyl-1,3-oxazolidine; 4-{[(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methoxy}phenethyl cyclopropylmethyl ether | C29H33NO3 | 详情 | 详情 | |
| (X) | 55683 | (2S)-1-(benzylamino)-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C22H29NO3 | 详情 | 详情 | |
| (XI) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (XII) | 55684 | (2S)-1-[benzyl(isopropyl)amino]-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C25H35NO3 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(XXIIIa)The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) can also be obtained as follows: 3) A study of the influence of different substituents in the cis/trans ratio of the cyclopropanation process has been performed. The general method is as follows: the reaction of benzylamine (XXIII) with acetaldehyde and trichloromethyl chloroformate gives the N-benzyl-N-vinylcarbamoyl chloride (XXIV), which by treatment with alcohol yields the N-vinylcarbamate (XXV). The cyclopropanation of (XXV) with fluorodiiodomethane and diethyl zinc as before preferentially affords the cis-N-(2-fluorocyclopropyl)carbamate (XXVI), which is purified by crystallization. The hydrogenolysis of (XXVI) with H2 over Pd/C in acetic acid gives cis-racemic-2-fluorocyclopropylamine (XXVII), which is submitted to optical resolution with L-menthyl chloroformate to afford pure (1R,2S)-isomer (XXII). Finally, this compound is converted into (III) with tert-butoxycarbonyl anhydride as before.
| 【1】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【2】 Kobayashi, Y.; Hashimoto, M.; Tamura, O.; Terashima, S.; Katoh, T.; Hayakawa, I.; Akiba, T.; Nakatani, K.; Kamada, M.; Synthesis and optical resolution of dl-cis-2-fluorocyclopropylamine, the key component of the new generation of quinolonecarboxylic acid, DU-6859. Tetrahedron Lett 1992, 33, 24, 3483-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XXIIIb) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (XXIIIc) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
| (XXIVa) | 15150 | N-benzyl-N-vinylcarbamic chloride | C10H10ClNO | 详情 | 详情 | |
| (XXIVb) | 15151 | N-(1-phenylethyl)-N-vinylcarbamic chloride | C11H12ClNO | 详情 | 详情 | |
| (XXIVc) | 15152 | N-benzhydryl-N-vinylcarbamic chloride | C16H14ClNO | 详情 | 详情 | |
| (XXVa) | 15153 | benzyl N-benzyl-N-vinylcarbamate | C17H17NO2 | 详情 | 详情 | |
| (XXVb) | 15154 | benzyl N-(1-phenylethyl)-N-vinylcarbamate | C18H19NO2 | 详情 | 详情 | |
| (XXVc) | 15155 | benzyl N-benzhydryl-N-vinylcarbamate | C23H21NO2 | 详情 | 详情 | |
| (XXVd) | 15156 | butyl N-benzyl-N-vinylcarbamate | C14H19NO2 | 详情 | 详情 | |
| (XXVe) | 15157 | butyl N-(1-phenylethyl)-N-vinylcarbamate | C14H19NO2 | 详情 | 详情 | |
| (XXVf) | 15158 | butyl N-benzhydryl-N-vinylcarbamate | C20H23NO2 | 详情 | 详情 | |
| (XXVIa) | 15159 | benzyl N-benzyl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C18H18FNO2 | 详情 | 详情 | |
| (XXVIb) | 15160 | benzyl N-[(1R,2S)-2-fluorocyclopropyl]-N-(1-phenylethyl)carbamate | C19H20FNO2 | 详情 | 详情 | |
| (XXVIc) | 15161 | benzyl N-benzhydryl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C24H22FNO2 | 详情 | 详情 | |
| (XXVId) | 15162 | butyl N-benzyl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C15H20FNO2 | 详情 | 详情 | |
| (XXVIe) | 15163 | butyl N-[(1R,2S)-2-fluorocyclopropyl]-N-(1-phenylethyl)carbamate | C16H22FNO2 | 详情 | 详情 | |
| (XXVIf) | 15164 | butyl N-benzhydryl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C21H24FNO2 | 详情 | 详情 | |
| (III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (XXII) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
| (XXVII) | 63957 | rac-(1R*,2S*)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(V)The reaction of labeled 2-hydroxyacetophenone (I) with dimethyl oxalate and NaOMe gives 4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester (II), which is hydrogenated with H2 over Pd/C to yield 3,4-dihydro-2H-1-benzopyran-2(R)-carboxylic acid methyl ester (III). The optical resolution of (III) by chiral chromatography affords the labeled (R)-enantiomer (IV), which is condensed with benzylamine (V) to provide the corresponding amide (VI). The reduction of (VI) by means of NaAlH2(OC2H4OMe)2 gives the labeled chiral amine (VII), which is condensed with the butyl bromide derivative (VIII) to yield the tertiary amine (IX). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C to afford the target labeled Repinotan.
| 【1】 Seidel, D.; et al.; Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6. J Label Compd Radiopharm 2002, 45, 13, 1115. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 | |
| (I) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 62016 | methyl 4-oxo-4H-chromene-2-carboxylate | C11H8O4 | 详情 | 详情 | |
| (III) | 62017 | methyl 2-chromanecarboxylate | C11H12O3 | 详情 | 详情 | |
| (IV) | 62018 | methyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate | C11H12O3 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 62019 | (2R)-N-benzyl-3,4-dihydro-2H-chromene-2-carboxamide | C17H17NO2 | 详情 | 详情 | |
| (VII) | 62020 | N-benzyl-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amine; N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine | C17H19NO | 详情 | 详情 | |
| (VIII) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 | |
| (IX) | 62021 | 2-(4-{benzyl[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C28H30N2O4S | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(IV)The alkylation of 4,4'-dihydroxybiphenyl (I) with ethyl bromoacetate (II) in the presence of sodium methoxide afforded the (biphenylyloxy)acetate (III). Heating of ester (III) with benzylamine (IV) at 85 C produced amide (V), which was subsequently reduced to amine (VI) by means of borane, generated in situ from NaBH4 and BF3. Finally, condensation of the secondary amine (VI) with methyl isocyanate gave rise to the title urea derivative.
| 【1】 Fex, T.; Asp, B.; Stamvik, A.; Carlsson, J.-I.; Billstrom, A. (Pharmacia AB); Novel antitumour cpds. with antimitotic activity. WO 9529155 . |
| 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) | 55986 | 4,4'-Biphenol; 4,4'-Dihydroxybiphenyl; 4,4'-Dihydroxydiphenyl; 4,4'-Diphenol | 92-88-6 | C12H10O2 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 55987 | ethyl 2-[(4'-hydroxy[1,1'-biphenyl]-4-yl)oxy]acetate | C16H16O4 | 详情 | 详情 | |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 55988 | N-benzyl-2-[(4'-hydroxy[1,1'-biphenyl]-4-yl)oxy]acetamide | C21H19NO3 | 详情 | 详情 | |
| (VI) | 55989 | 4'-[2-(benzylamino)ethoxy][1,1'-biphenyl]-4-ol | C21H21NO2 | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(V)Condensation of 1,3-acetonedicarboxylic acid (I) with pyridine-4-carboxaldehyde (II) and subsequent acid decarboxylation produced 1,5-dipyridylpentadienone (III), which was reduced to the saturated ketone (IV) by transfer hydrogenation using formic acid and Pd/C. Condensation of (IV) with benzyl amine (V) in benzene with azeotropical removal of water, followed by reduction of the intermediate imine with NaBH4 gave rise to the secondary amine (VI). Coupling of (VI) with N-Boc-N-methyl-L-4-chlorophenylalanine (VII) in the presence of EDC afforded amide (VIII). After Boc deprotection of (VIII) with trifluoroacetic acid, the resulting amine (IX) was coupled with 3,4,5-trimethoxybenzoylformic acid (X) to furnish the title compound.
| 【1】 Zelle, R.E.; Harding, M.W. (Vertex Pharmaceuticals Inc.); Novel amino acid derivs. with improved multi-drug resistance activity. EP 0797567; JP 1998509151; US 5543423; WO 9615101 . |
| 【2】 Zelle, R.E. (Vertex Pharmaceuticals Inc.); Methods and compsns. for stimulating neurite growth using cpds. with affinity for FKBP2 in combination with neurotrophic factors. WO 9820891 . |
| 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) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 30040 | (1E,4E)-1,5-di(4-pyridinyl)-1,4-pentadien-3-one | C15H12N2O | 详情 | 详情 | |
| (IV) | 30041 | 1,5-di(4-pyridinyl)-3-pentanone | C15H16N2O | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 30042 | N-benzyl-1,5-di(4-pyridinyl)-3-pentanamine; N-benzyl-N-[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]amine | C22H25N3 | 详情 | 详情 | |
| (VII) | 30043 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(4-chlorophenyl)propionic acid | 125324-00-7 | C15H20ClNO4 | 详情 | 详情 |
| (VIII) | 30044 | tert-butyl (1S)-2-(benzyl[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]amino)-1-(4-chlorobenzyl)-2-oxoethyl(methyl)carbamate | C37H43ClN4O3 | 详情 | 详情 | |
| (IX) | 30045 | (2S)-N-benzyl-3-(4-chlorophenyl)-2-(methylamino)-N-[3-(4-pyridinyl)-1-[2-(4-pyridinyl)ethyl]propyl]propanamide | C32H35ClN4O | 详情 | 详情 | |
| (X) | 30046 | 2-oxo-2-(3,4,5-trimethoxyphenyl)acetic acid | C11H12O6 | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).
| 【1】 Hett, R.; et al.; Large-scale synthesis of enantio- and diastereomerically pure (R,R)-formoterol. Org Process Res Dev 1998, 2, 2, 96. |
| 【2】 Hett, R.; Senanayake, C.H.; Fang, K.Q.; Wald, S.A.; Redmon, M.P.; Gao, Y. (Sepracor Inc.); Formoterol process. US 6040344 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 32763 | 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone | C15H12BrNO4 | 详情 | 详情 | |
| (II) | 32764 | (3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C9H10BNO | 详情 | 详情 | |
| (III) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (IV) | 32765 | (1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol | 188690-82-6 | C15H14BrNO4 | 详情 | 详情 |
| (V) | 32766 | (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromo-1-ethanol | C15H16BrNO2 | 详情 | 详情 | |
| (VI) | 32767 | 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenylformamide | C16H16BrNO3 | 详情 | 详情 | |
| (VII) | 32738 | tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate | C34H48N2O6S2 | 详情 | 详情 | |
| (VIII) | 32769 | 5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide | C33H36N2O4 | 详情 | 详情 | |
| (IX) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (X) | 32770 | N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine; N-benzyl-1-(4-methoxyphenyl)-2-propanamine | C17H21NO | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(II)The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture, which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV). The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI), which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF, yielding the chiral bromoethanol derivative (VIII). The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX), which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X). The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI), which is acylated with formic acid to afford the formamide compound (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, providing the target compound.
| 【1】 Wilkinson, H.S.; et al.; Modulation of catalyst reactivity for the chemoselective hydrogenation of functionalized nitroarene: Preparation of a key intermediate in the synthesis of (R,R)-formoterol tartrate. Org Process Res Dev 2000, 4, 6, 567. |
| 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) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 32770 | N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine; N-benzyl-1-(4-methoxyphenyl)-2-propanamine | C17H21NO | 详情 | 详情 | |
| (IV) | 32768 | (2R)-N-benzyl-1-(4-methoxyphenyl)-2-propanamine; N-benzyl-N-[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amine | C17H21NO | 详情 | 详情 | |
| (V) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (VI) | 34898 | (3aR,8aS)-2-methyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C10H12BNO | 详情 | 详情 | |
| (VII) | 32763 | 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone | C15H12BrNO4 | 详情 | 详情 | |
| (VIII) | 32765 | (1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol | 188690-82-6 | C15H14BrNO4 | 详情 | 详情 |
| (IX) | 50312 | (2R)-2-[4-(benzyloxy)-3-nitrophenyl]oxirane; benzyl 2-nitro-4-[(2R)oxiranyl]phenyl ether | C15H13NO4 | 详情 | 详情 | |
| (X) | 50313 | (1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanol | C32H34N2O5 | 详情 | 详情 | |
| (XI) | 50314 | (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-ethanol | C32H36N2O3 | 详情 | 详情 | |
| (XII) | 32769 | 5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide | C33H36N2O4 | 详情 | 详情 |
合成路线29
该中间体在本合成路线中的序号：(III)The anhydrization of pyridine-2,3-dicarboxylic acid (I) with acetic anhydride gives the corresponding anhydride (II), which by treatment with benzylamine (III) is converted into the benzylimide (IV). The hydrogenation of (IV) with H2 over Pd/C yields 8-benzyl-2,8-diazabicyclo[4.3.0]nonane-7,9-dione (V), which is further hydrogenated with LiAlH4, affording (?-cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VI) (1). The optical resolution of (VI) by separation of the cis-(R,R)-isomer as crystalline L-(+)-tartrate and further purification of the cis-(S,S)-isomer (VII) as the D-(-)-tartrate affords enantiomerically pure (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VII). The debenzylation of (VII) by hydrogenolysis with H2 over Pd/C gives (S,S)-2,8-diazabicyclo[4.3.0]nonane (VIII), which is condensed with 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) in basic medium and finally salified with HCl. The 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) has been obtained as follows: The reaction of 2,4,5-trifluoro-3-methoxybenzoyl chloride (X) with malonic acid monoethyl ester monopotassium salt (XI) by means of triethylamine gives 2-(2,4,5-trifluoro-3-methoxybenzoyl)acetic acid ethyl ester (XII), which is condensed with triethyl orthoformate yielding the corresponding ethoxymethylene derivative (XIII). The reaction of (XIII) with cyclopropylamine affords the cyclopropylaminomethylene derivative (XIV), which is finally cyclized to (IX) by means of NaF in DMF.
| 【1】 Martel, A.M.; Leeson, P.A.; Castañer, J.; Bay-12-8039. Drugs Fut 1997, 22, 2, 109. |
| 【2】 Petersen, U.; Bremm, K.-D.; Dalhoff, A.; Endermann, R.; Heilmann, W.; Krebs, A.; Schenke, T.; Synthesis and in vitro activity of BAY 12-8039, a new 8-methoxy-quinolone. 36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18, New Orleans) 1996, Abst. F1.. |
| 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) | 17246 | 2,3-pyridinedicarboxylic acid; Quinolinic Acid | 89-00-9 | C7H5NO4 | 详情 | 详情 |
| (II) | 17247 | furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride | 699-98-9 | C7H3NO3 | 详情 | 详情 |
| (III) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IV) | 17249 | 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione | C14H10N2O2 | 详情 | 详情 | |
| (V) | 17250 | 6-benzyltetrahydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-dione | C14H16N2O2 | 详情 | 详情 | |
| (VI) | 17251 | 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine | C14H20N2 | 详情 | 详情 | |
| (VII) | 17252 | (4aS,7aS)-6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine | C14H20N2 | 详情 | 详情 | |
| (VIII) | 17253 | (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine | C7H14N2 | 详情 | 详情 | |
| (IX) | 12266 | 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 112811-72-0 | C14H11F2NO4 | 详情 | 详情 |
| (X) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
| (XI) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (XII) | 12261 | ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate | C12H11F3O4 | 详情 | 详情 | |
| (XIII) | 12262 | ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C15H15F3O5 | 详情 | 详情 | |
| (XIV) | 12264 | ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C16H16F3NO4 | 详情 | 详情 |
合成路线30
该中间体在本合成路线中的序号：(III)N-Cbz-L-Phenylalaninol (I) was converted to mesylate (II) on treatment with methanesulfonyl chloride and Et3N, and then treated with benzylamine (III) in the presence of NaI to give (IV). Subsequent deprotection of the Cbz group of (IV) with HBr in AcOH afforded diamine (V), which was treated with carbonyl diimidazole to produce the cyclic urea (VI). Finally, condensation with the epoxisulfonamide (VII) in the presence of NaH in DMF provided the target compound.
| 【1】 Salituro, F.G.; Baker, C.T.; Court, J.J.; Deininger, D.D.; Kim, E.E.; Li, B.; Novak, P.M.; Rao, B.G.; Pazhanisamy, S.; Porter, M.D.; Schairer, W.C.; Tung, R.D.; Design and synthesis of novel conformationally restricted HIV protease inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3637. |
| 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) | 16585 | benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate | C17H19NO3 | 详情 | 详情 | |
| (II) | 20158 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropyl methanesulfonate | C18H21NO5S | 详情 | 详情 | |
| (III) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IV) | 20160 | benzyl (1S)-1-benzyl-2-(benzylamino)ethylcarbamate | C24H26N2O2 | 详情 | 详情 | |
| (V) | 20161 | (2S)-N(1)-benzyl-3-phenyl-1,2-propanediamine; N-[(2S)-2-amino-3-phenylpropyl]-N-benzylamine | C16H20N2 | 详情 | 详情 | |
| (VI) | 20162 | (4S)-1,4-dibenzyl-2-imidazolidinone | C17H18N2O | 详情 | 详情 | |
| (VII) | 20163 | N-(cyclopentylmethyl)-4-methoxy-N-[(2R)oxiranylmethyl]benzenesulfonamide | C16H23NO4S | 详情 | 详情 |
合成路线31
该中间体在本合成路线中的序号：(II)Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.
| 【2】 Yazaki, A.; Niino, Y.; Ohshita, Y.; Hirao, Y.; Amano, H.; Hayashi, N.; Kuramoto, Y. (Wakunaga Pharmaceutical Co., Ltd.); Novel pyridonecarboxylic acid derivs. or their salts and antibacterial agent comprising the same as the active ingredient. EP 0911327; EP 0992501; JP 1999322715; JP 2000136191; US 5998436; US 6133284; WO 9711068 . |
| 【1】 Mealy, N.E.; Castaner, J.; ABT-492. Drugs Fut 2002, 27, 11, 1033. |
| 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) | 56640 | 2,3,5,6-Tetrafluoropyridine | 2875-18-5 | C5HF4N | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 56641 | N-benzyl-3,5,6-trifluoro-2-pyridinamine; N-benzyl-N-(3,5,6-trifluoro-2-pyridinyl)amine | C12H9F3N2 | 详情 | 详情 | |
| (IV) | 56642 | 3,5,6-trifluoro-2-pyridinamine; 3,5,6-trifluoro-2-pyridinylamine | C5H3F3N2 | 详情 | 详情 | |
| (V) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (VI) | 56643 | N-(6-amino-3,5-difluoro-2-pyridinyl)-N-(4-methoxybenzyl)amine; 3,5-difluoro-N~2~-(4-methoxybenzyl)-2,6-pyridinediamine | C13H13F2N3O | 详情 | 详情 | |
| (VII) | 11682 | ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate | C14H12ClF3O4 | 详情 | 详情 | |
| (VIII) | 11681 | ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate | 101987-86-4 | C11H8ClF3O3 | 详情 | 详情 |
| (IX) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (X) | 56644 | ethyl 8-chloro-1-{3,5-difluoro-6-[(4-methoxybenzyl)amino]-2-pyridinyl}-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C25H18ClF4N3O4 | 详情 | 详情 | |
| (XI) | 56645 | 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C15H6ClF4N3O3 | 详情 | 详情 | |
| (XII) | 31397 | 3-azetidinol | C3H7NO | 详情 | 详情 |
合成路线32
该中间体在本合成路线中的序号：(XII)Alkylation of the sodium salt of 5-nitroguaiacol (I) with allyl bromide (II) gave the allyl ether (III). The methoxy group of (III) was then displaced by NaOH in hot DMSO to produce 2-(allyloxy)-4-nitrophenol (IV), which was further alkylated with (R)-glycidyl tosylate (V), yielding the chiral oxirane (VI). Claisen rearrangement of the allyl ether function of (VI), followed by intramolecular cyclization between the phenol and epoxide groups in hot mesitylene furnished the benzodioxane derivative (VII). Treatment of (VII) with p-toluenesulfonyl chloride afforded tosylate (VIII). Oxidative cleavage of the allyl group of (VIII) with KMnO4 under phase-transfer conditions gave rise to the carboxylic acid (IX). Catalytic hydrogenation of the nitro group of (IX), followed by lactamization of the resultant aminoacid (X) under acidic conditions produced the dioxinoindolone system (XI). Then, nucleophilic displacement of the tosylate group of (XI) with benzylamine (XII) yielded the desired amine, which was finally converted to the corresponding fumarate salt.
| 【1】 Stack, G.P.; Mewshaw, R.E.; Bravo, B.A.; Kang, Y.H. (Wyeth); Dioxino derivs. and their use as dopamine agonists. EP 0771800; JP 1997249671; US 5756532 . |
| 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) | 56181 | sodium 2-methoxy-5-nitrobenzenolate | C7H6NNaO4 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 56182 | allyl 2-methoxy-5-nitrophenyl ether; 2-(allyloxy)-1-methoxy-4-nitrobenzene | C10H11NO4 | 详情 | 详情 | |
| (IV) | 56183 | 2-(allyloxy)-4-nitrophenol | C9H9NO4 | 详情 | 详情 | |
| (V) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
| (VI) | 56184 | (2R)-2-{[2-(allyloxy)-4-nitrophenoxy]methyl}oxirane; allyl 5-nitro-2-[(2R)oxiranylmethoxy]phenyl ether | C12H13NO5 | 详情 | 详情 | |
| (VII) | 56185 | [(2S)-8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol | C12H13NO5 | 详情 | 详情 | |
| (VIII) | 56186 | [(2R)-8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate | C19H19NO7S | 详情 | 详情 | |
| (IX) | 56187 | 2-[(3R)-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetic acid | C18H17NO9S | 详情 | 详情 | |
| (X) | 56188 | 2-[(3R)-6-amino-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,3-dihydro-1,4-benzodioxin-5-yl]acetic acid | C18H19NO7S | 详情 | 详情 | |
| (XI) | 56189 | [(2R)-8-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate | C18H17NO6S | 详情 | 详情 | |
| (XII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
合成路线33
该中间体在本合成路线中的序号：The chlorosulfonation of 1-methylnaphthalene (I) with chlorosulfonic acid gives 4-methylnaphthalen-1-ylsulfonyl chloride (II), which is nitrated with nitric and sulfuric acids yielding the 8-nitro derivative (III). The reaction of (III) with benzylamine and K2CO3 affords the corresponding sulfonamide (IV), which is cyclized by hydrogenation with formic and Pd/C giving the methylnaphthosultam (VI). The reaction of (VI) with lithium diisopropylamide (LDA) and CO2 yields the carboxymethyl derivative (VII), which is reduced with NaBH4 and BF3 ethearate affording the 2-hydroxyethyl derivative (VIII). Finally, this compound is condensed with 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate (IX) by means of trifluromethanesulfonic anhydride in acetonitrile to provide the desired naphthosultam intermediate (X). Compound (XI) is obtained by condensation of quinuclidine (XI) with chloroacetamide (XII) by means of sodium trilfluoromethanesulfonate in refluxing acetonitrile. Alternatively, 4-methylnaphthalen-1-ylsulfonyl chloride (II) can be condensed with diethylamine giving the corresponding sulfonamide (XIII), which is nitrated with nitric and sulfuric acids yielding the 8-nitro derivative (XIV). Finally, this compound is cyclized to the previously reported naphthosultam (VI) by hydrogenation with H2 or potassium formate over Pd/C.
| 【1】 Miller, R.A.; et al.; A practical an efficient preparation of the releasable naphthosultan side chain of a novel anti -MRSA carbapenem. J Org Chem 2000, 65, 5, 1399. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 30117 | 1-methylnaphthalene | 90-12-0 | C11H10 | 详情 | 详情 |
| (II) | 30118 | 4-methyl-1-naphthalenesulfonyl chloride | C11H9ClO2S | 详情 | 详情 | |
| (III) | 35501 | 4-methyl-8-nitro-1-naphthalenesulfonyl chloride | C11H8ClNO4S | 详情 | 详情 | |
| (IV) | 35500 | N-benzyl-4-methyl-8-nitro-1-naphthalenesulfonamide | C18H16N2O4S | 详情 | 详情 | |
| (V) | 35503 | 2-benzyl-6-methyl-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C18H15NO2S | 详情 | 详情 | |
| (VI) | 30121 | 6-methyl-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C11H9NO2S | 详情 | 详情 | |
| (VII) | 30122 | 2-(1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)acetic acid | C12H9NO4S | 详情 | 详情 | |
| (VIII) | 30123 | 6-(2-hydroxyethyl)-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione | C12H11NO3S | 详情 | 详情 | |
| (IX) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (X) | 35505 | 1-(2-amino-2-oxoethyl)-4-[2-(1,1-dioxo-1,2-dihydro-2H-naphtho[1,8-cd]isothiazol-6-yl)ethyl]-1,4-diazoniabicyclo[2.2.2]octane di(trifluoromethanesulfonate) | C22H26F6N4O9S3 | 详情 | 详情 | |
| (XI) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |
| (XII) | 28964 | 2-chloroacetamide | 79-07-2 | C2H4ClNO | 详情 | 详情 |
| (XIII) | 35502 | 4-methyl-N,N-dipropyl-1-naphthalenesulfonamide | C17H23NO2S | 详情 | 详情 | |
| (XIV) | 35499 | 4-methyl-8-nitro-N,N-dipropyl-1-naphthalenesulfonamide | C17H22N2O4S | 详情 | 详情 |
合成路线34
该中间体在本合成路线中的序号：(II)Reaction of methyl cyanoacetate (I) with benzylamine (II) at 100 C gives N-benzyl cyanoacetamide (III). Subsequent condensation of (III) with 3,4-dihydroxybenzaldehyde (IV) in the presence of NaH provides the title compound.
| 【1】 Gazit, A.; et al.; Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J Med Chem 1991, 34, 6, 1896. |
合成路线35
该中间体在本合成路线中的序号：(XI)Heating p-fluorobenzaldehyde (I) with propionic anhydride (II) in the presence of sodium propionate affords methyl cinnamic acid derivative (III), which is then hydrogenated over Pd/C in EtOH to provide methyl hydrocinnamic acid derivative (IV). Ring closure of (IV) is then performed by heating with polyphosphoric acid to yield methylindanone derivative (V). Condensation of (V) with cyanoacetic acid (VI) by means of ammonium acetate and HOAc in refluxing toluene, followed by treatment with KOH in refluxing EtOH, provides acetic acid derivative (VII), which is then condensed with 3,4,5-trimethoxybenzaldehyde (VIII) by heating with NaOMe in MeOH to give substituted benzylidene derivative (IX). The target product can be finally obtained either by direct condensation of (IX) with benzylamine (XI) by means of DMAP and EDC in DMA or by first conversion of (IX) into the corresponding acetyl chloride by reaction with oxalyl chloride in refluxing THF, followed by coupling with benzylamine (XI) in CH2Cl2. Alternatively, the desired compound can also be obtained by coupling of acetic acid derivative (VII) with benzylamine (XI) by means of DMAP, EDC in DMA to afford N-benzyl acetamide derivative (XII), followed by condensation with 3,4,5-trimethoxybenzaldehyde (VIII) by heating with NaOMe in MeOH.
| 【1】 Sperl, G.; Gross, P.; Brendel, K.; Pamucku, R.; Piazza, G.A. (University of Arizona); Substd. benzylidene indenyl formamides, acetamides and propionamides. WO 9747303 . |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 48870 | (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid | C10H9FO2 | 详情 | 详情 | |
| (IV) | 48871 | 3-(4-fluorophenyl)-2-methylpropionic acid | C10H11FO2 | 详情 | 详情 | |
| (V) | 48872 | 6-Fluoro-2-methylindanone | C10H9FO | 详情 | 详情 | |
| (VI) | 48873 | 2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile | C3H3NO | 详情 | 详情 | |
| (VII) | 48874 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid | C12H11FO2 | 详情 | 详情 | |
| (VIII) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (IX) | 48875 | 2-[5-fluoro-2-methyl-1-[(E)-(3,4,5-trimethoxyphenyl)methylidene]-1H-inden-3-yl]acetic acid | C22H21FO5 | 详情 | 详情 | |
| (X) | 48876 | 2-[5-fluoro-2-methyl-1-[(E)-(3,4,5-trimethoxyphenyl)methylidene]-1H-inden-3-yl]acetyl chloride | C22H20ClFO4 | 详情 | 详情 | |
| (XI) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XII) | 48877 | N-benzyl-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide | C19H18FNO | 详情 | 详情 |
合成路线36
该中间体在本合成路线中的序号：(XI)Ketoester (II) was prepared by condensation of dimethyl carbonate with 5-methoxy-2-tetralone (I) in the presence of NaOMe. The alkylation of (II) with allyl bromide using two equivalents of LDA at -78 C proceeded selectively on the C-3 position to give (III). Further decarbomethoxylation of (III) was carried out with LiCl in moist DMSO at high temperature, and the resulting ketone (IV) was converted to ethylene ketal (V) with ethylene glycol and p-TsOH. Then, hydroboration of (V) with disiamyl borane (VI) in cold THF, followed by oxidation of borane (VII) with H2O2-NaOH furnished the primary alcohol (VIII). After Jones oxidation of alcohol (VIII), the resulting acid (IX) was esterified with MeOH and H2SO4 to give ketoester (X). Subsequent cyclization of (X) with benzylamine (XI) and AcOH in refluxing benzene afforded the intermediate tricyclic enamide (XII), which was sequentially reduced with LiAlH4 to enamine (XIII), and then with NaBH4 in the presence of AcOH to furnish a mixture of cis and trans octahydrobenzo[g]quinolines (XIV). Separation of the major trans isomer by flash chromatography was followed by hydrogenolysis of the benzyl group over Pd/C, yielding the secondary amine (XV), whitch was N-alkylated with propargyl bromide (XVI) in hot DMF to give (XVII).
| 【1】 Tagmatarchis, N.; Thermos, K.; Katerinopoulos, H.E.; N-(Iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: Synthesis and adrenergic and dopaminergic activity studies. J Med Chem 1998, 41, 21, 4165. |
| 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) | 14647 | 5-methoxy-3,4-dihydro-2(1H)-naphthalenone | 32940-15-1 | C11H12O2 | 详情 | 详情 |
| (II) | 20448 | methyl 5-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylate | C13H14O4 | 详情 | 详情 | |
| (III) | 20449 | methyl 3-allyl-5-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylate | C16H18O4 | 详情 | 详情 | |
| (IV) | 20450 | 3-allyl-5-methoxy-3,4-dihydro-2(1H)-naphthalenone | C14H16O2 | 详情 | 详情 | |
| (V) | 20451 | 3'-Allyl-5'-methoxy-1',2',3',4'-tetrahydrospiro[1,3-dioxolan-2,2'-naphthalene] | C16H20O3 | 详情 | 详情 | |
| (VI) | 20452 | bis(1,2-dimethylpropyl)borane | 132509-17-2 | C10H23B | 详情 | 详情 |
| (VII) | 20453 | B-[3-[5'-Methoxy-1',2',3',4'-tetrahydrospiro[1,3-dioxolan-2,2'-naphthalen]-3'-yl]propyl]-B,B-bis(1,2-dimethylpropyl)borane | C26H43BO3 | 详情 | 详情 | |
| (VIII) | 20454 | 3-[5'-Methoxy-1',2',3',4'-tetrahydrospiro[1,3-dioxolan-2,2'-naphthalen]-3'-yl]propan-1-ol | C16H22O4 | 详情 | 详情 | |
| (IX) | 20455 | 3-(8-methoxy-3-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propionic acid | C14H16O4 | 详情 | 详情 | |
| (X) | 20456 | methyl 3-(8-methoxy-3-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanoate | C15H18O4 | 详情 | 详情 | |
| (XI) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XII) | 20458 | 1-benzyl-6-methoxy-3,4,4a,5-tetrahydrobenzo[g]quinolin-2(1H)-one | C21H21NO2 | 详情 | 详情 | |
| (XIII) | 20459 | 1-benzyl-6-methoxy-1,2,3,4,4a,5-hexahydrobenzo[g]quinoline; 1-benzyl-1,2,3,4,4a,5-hexahydrobenzo[g]quinolin-6-yl methyl ether | C21H23NO | 详情 | 详情 | |
| (XIV) | 20460 | 1-benzyl-6-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline; 1-benzyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl methyl ether | C21H25NO | 详情 | 详情 | |
| (XV) | 20461 | (4aS,10aS)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl methyl ether; (4aS,10aS)-6-methoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline | C14H19NO | 详情 | 详情 | |
| (XVI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (XVII) | 20463 | (4aS,10aS)-1-(2-propynyl)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl methyl ether; (4aS,10aS)-6-methoxy-1-(2-propynyl)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline | C17H21NO | 详情 | 详情 |
合成路线37
该中间体在本合成路线中的序号：(VIII)The condensation of 3-(4-morpholinylmethyl)-2H-1-benzopyran-8-ol (VI) with 2(R)-(p-toluenesulfonyloxymethyl)-4-(triphenylmethyl)morpholine (XVI) by means of K2CO3 in DMF gives the protected target compound (XVII), which is finally deprotected with acetic acid and salified with methanesulfonic acid. The intermediates benzopyran (VI) and morpholine (XVI) have been obtained as follows: Benzopyran (VI): The reaction of 8-methoxy-4H-1-benzopyran-3-carboxylic acid (I) with SOCl2 in refluxing toluene gives the acyl chloride (II), which is condensed with morpholine (III) in dioxane yielding the methanone (IV). The reaction of (IV) with BBr3 in dichloromethane affords the 1-(8-hydroxy-2H-1-benzopyran-3-yl)-1-(4-morpholinyl)methanone (V), which is reduced with LiAlH4 in THF giving the desired intermediate benzopyran (VI). Morpholine (XVI): The reaction of benzyl (S)-glycicyl ether (VII) with benzylamine (VIII) gives 1-(benzylamino)-3-(benzyloxy)-2(R)-propanol (IX), which is cyclized with chloroacetyl chloride (X) and triethylamine in dichloromethane yielding the morpholinone (XI). The reduction of (XI) with LiAlH4 in ethyl ether affords the fully protected morpholine (XII), which is debenzylated with H2 over Pd/C in ethanol giving 2(R)-(hydroxyethyl)morpholine (XIII). The reaction of (XIII) with trityl chloride (XIV) and TEA in dichloromethane yields the N-tritylmorpholine (XV), which is finally tosylated with tosyl chloridde and pyridine affording the desired intermediate morpholine (XVI).
| 【1】 Berg, S.; et al.; (R)-(+)-2[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl]morpholine methanesulfonate: A new selective rat 5-hydroxytryptamine1B receptor antagonist. J Med Chem 1998, 41, 11, 1934. |
| 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) | 28621 | 8-methoxy-2H-chromene-3-carboxylic acid | 57543-59-6 | C11H10O4 | 详情 | 详情 |
| (II) | 28622 | 8-methoxy-2H-chromene-3-carbonyl chloride | C11H9ClO3 | 详情 | 详情 | |
| (III) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (IV) | 28623 | (8-methoxy-2H-chromen-3-yl)(4-morpholinyl)methanone | C15H17NO4 | 详情 | 详情 | |
| (V) | 28624 | (8-hydroxy-2H-chromen-3-yl)(4-morpholinyl)methanone | C14H15NO4 | 详情 | 详情 | |
| (VI) | 28625 | 3-(4-morpholinylmethyl)-2H-chromen-8-ol | C14H17NO3 | 详情 | 详情 | |
| (VII) | 22645 | (1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate; Lovastatin | 75330-75-5 | C24H36O5 | 详情 | 详情 |
| (VIII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IX) | 28626 | (2S)-1-(benzylamino)-3-(benzyloxy)-2-propanol | C17H21NO2 | 详情 | 详情 | |
| (X) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XI) | 28627 | (6R)-4-benzyl-6-[(benzyloxy)methyl]-3-morpholinone | C19H21NO3 | 详情 | 详情 | |
| (XII) | 28628 | benzyl [(2R)-4-benzylmorpholinyl]methyl ether | C19H23NO2 | 详情 | 详情 | |
| (XIII) | 12353 | (2R)-1,4-Oxazinan-2-ylmethanol | C5H11NO2 | 详情 | 详情 | |
| (XIV) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (XV) | 28629 | [(2R)-4-tritylmorpholinyl]methanol | C24H25NO2 | 详情 | 详情 | |
| (XVI) | 28631 | [(2R)-4-tritylmorpholinyl]methyl 4-methylbenzenesulfonate | C31H31NO4S | 详情 | 详情 | |
| (XVII) | 28632 | (2R)-2-([[3-(4-morpholinylmethyl)-2H-chromen-8-yl]oxy]methyl)-4-tritylmorpholine | C38H40N2O4 | 详情 | 详情 |
合成路线38
该中间体在本合成路线中的序号：6-Methoxytryptamine (I) was condensed with methyl chloroformate to give carbamate (II), and further alkylation with benzyl bromide yielded the N-benzyl indole (III). Oxidation of the indole ring of (III) with DMSO/HCl gave oxindole (IV). Phase-transfer methylation using iodomethane and benzyltrimethylammonium bromide afforded the racemic methyl derivative (Va-b). Subsequent reduction and cyclization of (Va-b) by means of Red-Al furnished the tricyclic compound (VIa-b), which was resolved with dibenzoyl D-tartaric acid to provide the (3aS)-enantiomer (VII). Conversion of (VII) to the N,N'-dibenzyl analogue (XI) was achieved via quaternization to the ammonium salt (VIII) with iodomethane in Et2O. Ring-opening of (VIII) under basic conditions produced the hydroxy tryptamine (IX), which was again quaternized to (X) with iodomethane and then cyclized with benzylamine to provide directly the dibenzyl compound (XI). Ether cleavage of (XI) with boron tribromide gave the phenolic derivative (XII). This was coupled with 4-isopropylphenyl isocyanate in the presence of a catalytic amount of Na to yield carbamate (XIV). Finally, hydrogenolytic cleavage of the benzyl groups of (XIV) over Pd(OH)2 furnished the title compound.
| 【1】 Yu, Q.-S.; et al.; Total syntheses and anticholinesterase activities of (3aS)-N(8)-norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers and other N(8)-substituted analogues. J Med Chem 1997, 40, 18, 2895-2901. |
| 【2】 Yu, Q.-S.; et al.; Syntheses and anticholinesterase activities of (3aS)-N1,N8-bisnorphenserine, (3aS)-N1,N8-bisnorphysostigmine. Their antipodal isomers and other potential metabolites of phenserine. J Med Chem 1998, 41, 13, 2371-79. |
| 【3】 Holloway, H.W.; Yu, Q.-S.; Greig, N.H.; Utsuki, T.; Brossi, A.; Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease. J Med Chem 1999, 42, 10, 1855. |
| 【4】 Soncrant, T.T.; Brossi, A.; Greig, N.H.; Hausman, M.; Yu, Q.-S. (Axonyx Inc.; National Institutes of Health); Highly selective butyrylcholinesterase inhibitors for the treatment and diagnosis of Alzheimer's disease and dementias. CA 2264750; EP 0949920; WO 9902154 . |
| 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 | |
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (Va) | 36829 | methyl 2-[(3S)-1-benzyl-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]ethylcarbamate | C21H24N2O4 | 详情 | 详情 | |
| (VIa),(VII) | 36830 | (3aS)-8-benzyl-5-methoxy-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole; (3aS)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether | C20H24N2O | 详情 | 详情 | |
| (Vb) | 36837 | methyl 2-[(3R)-1-benzyl-5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]ethylcarbamate | C21H24N2O4 | 详情 | 详情 | |
| (VIb) | 36838 | (3aR)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aR)-8-benzyl-5-methoxy-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole | C20H24N2O | 详情 | 详情 | |
| (I) | 36825 | O-Methylserotonin; 3-(2-Aminoethyl)-5-methoxyindole; 2-(5-Methoxy-1H-indol-3-yl)ethylamine; 2-(5-Methoxy-1H-indol-3-yl)-1-ethanamine; 5-Methoxytryptamine | 608-07-1 | C11H14N2O | 详情 | 详情 |
| (II) | 36826 | methyl 2-(5-methoxy-1H-indol-3-yl)ethylcarbamate | C13H16N2O3 | 详情 | 详情 | |
| (III) | 36827 | methyl 2-(1-benzyl-5-methoxy-1H-indol-3-yl)ethylcarbamate | C20H22N2O3 | 详情 | 详情 | |
| (IV) | 36828 | methyl 2-(1-benzyl-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)ethylcarbamate | C20H22N2O4 | 详情 | 详情 | |
| (VIII) | 36831 | (3aS)-8-benzyl-5-methoxy-1,1,3a-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-1-ium iodide | C21H27IN2O | 详情 | 详情 | |
| (IX) | 36832 | (3S)-1-benzyl-3-[2-(dimethylamino)ethyl]-5-methoxy-3-methyl-2,3-dihydro-1H-indol-2-ol | C21H28N2O2 | 详情 | 详情 | |
| (X) | 36833 | 2-[(3S)-1-benzyl-2-hydroxy-5-methoxy-3-methyl-2,3-dihydro-1H-indol-3-yl]-N,N,N-trimethyl-1-ethanaminium iodide | C22H31IN2O2 | 详情 | 详情 | |
| (XI) | 36834 | (3aS,8aR)-1,8-dibenzyl-5-methoxy-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole; (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether | C26H28N2O | 详情 | 详情 | |
| (XII) | 36835 | (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol | C25H26N2O | 详情 | 详情 | |
| (XIII) | 34537 | 4-isopropylphenyl isocyanate; 1-isocyanato-4-isopropylbenzene | 31027-31-3 | C10H11NO | 详情 | 详情 |
| (XIV) | 36836 | (3aS,8aR)-1,8-dibenzyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl 4-isopropylphenylcarbamate | C35H37N3O2 | 详情 | 详情 |
合成路线39
该中间体在本合成路线中的序号：(IX)Heating p-fluorobenzaldehyde (I) with propionic anhydride (II) in the presence of sodium propionate affords methyl cinnamic acid derivative (III), which is then hydrogenated over Pd/C in EtOH to provide methyl hydrocinnamic acid derivative (IV). Ring closure of (IV) is then performed by heating with polyphosphoric acid to yield methylindanone derivative (V). Condensation of (V) with cyanoacetic acid (VI) by means of ammonium acetate and HOAc in refluxing toluene followed by treatment with KOH in refluxing EtOH provides acetic acid derivative (VII), which is then converted into acetyl chloride compound (VIII) by reaction with oxalyl chloride in refluxing THF. Coupling of (VIII) with benzylamine (IX) in refluxing CH2Cl2 gives indenylacetamide derivative (X), which is finally condensed with 4-pyridinecarboxaldehyde (XI) by means of NaOMe in MeOH to furnish the desired compound.
| 【1】 Piazza, G.; Gross, P.; Brendel, K.; Sperl, G.; Pamukcu, R. (Cell Pathways, Inc.; University of Arizona); N-Benzyl-3-indenylacetamides derivs. for treating neoplasia. EP 1044187; US 5948779; US 6066634; WO 9931065 . |
| 【2】 Mayle, M.J.; Menander, K.B. (Cell Pathways, Inc.); A method for treating patients with acne by administering a cyclic GMP PDE inhibitor. WO 0044372 . |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 48870 | (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid | C10H9FO2 | 详情 | 详情 | |
| (IV) | 48871 | 3-(4-fluorophenyl)-2-methylpropionic acid | C10H11FO2 | 详情 | 详情 | |
| (V) | 48872 | 6-Fluoro-2-methylindanone | C10H9FO | 详情 | 详情 | |
| (VI) | 48873 | 2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile | C3H3NO | 详情 | 详情 | |
| (VII) | 48874 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid | C12H11FO2 | 详情 | 详情 | |
| (VIII) | 48878 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetyl chloride | C12H10ClFO | 详情 | 详情 | |
| (IX) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (X) | 48877 | N-benzyl-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide | C19H18FNO | 详情 | 详情 | |
| (XI) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
合成路线40
该中间体在本合成路线中的序号：(V)Adenine (I) was oxidized with hydrogen peroxide in aqueous acetic acid to give adenine 1-N-oxide (II). Diazotization of (II) with sodium nitrite and acetic acid, followed by hydrolysis of the diazonium salt provided hypoxanthine 1-N-oxide (III). 2,6-Dichloropurine (IV) was then obtained by treatment of (III) with phosphoryl chloride in the presence of triethylamine. Displacement of the 6-chlorine atom of (IV) by benzylamine (V) in boiling n-butanol yielded 6-benzylamino-2-chloropurine (VI), which was subsequently alkylated at the 9-N with isopropyl iodide and NaH to give (VII). Finally, the remaining 2-chloro atom of (VII) was displaced by thiomorpholine (VIII) to furnish the title compound.
| 【1】 Woo, E.-R.; Baek, D.J.; Lee, s.-C.; Hong, C.Y.; Lee, K.-S.; Yang, B.-S.; Cho, J.-H.; Oh, C.-H.; Synthesis and biological activities of C-2, N-9 substituted 6-benzylaminopurine derivatives as cyclin-dependent kinase inhibitor. Arch Pharm 1999, 332, 6, 187. |
| 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) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (II) | 36313 | 6-amino-9H-purin-1-ium-1-olate | C5H5N5O | 详情 | 详情 | |
| (III) | 36314 | 6-hydroxy-9H-purin-1-ium-1-olate | C5H4N4O2 | 详情 | 详情 | |
| (IV) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 36315 | N-benzyl-2-chloro-9H-purin-6-amine; N-benzyl-N-(2-chloro-9H-purin-6-yl)amine | C12H10ClN5 | 详情 | 详情 | |
| (VII) | 36316 | N-benzyl-2-chloro-9-isopropyl-9H-purin-6-amine; N-benzyl-N-(2-chloro-9-isopropyl-9H-purin-6-yl)amine | C15H16ClN5 | 详情 | 详情 | |
| (VIII) | 36317 | thiomorpholine | 123-90-0 | C4H9NS | 详情 | 详情 |
合成路线41
该中间体在本合成路线中的序号：In an alternative method, ring opening of epoxide (I) with benzylamine produced aminoalcohol (III). Subsequent coupling of (III) with chloroacetyl chloride (IV) yielded chloroacetamide (V), which was cyclized to the morpholinone (VI) upon treatment with NaOMe in MeOH. Reduction of the lactam function of (VI) with LiAlH4 gave the N-benzyl morpholine (VII). Finally, the N-benzyl group of (VII) was cleaved by hydrogenolysis using Pearlman's catalyst.
| 【1】 Corral, C.; Lissavetzky, J.; Sánchez-Mateo, C.C.; Darias, V.; Expósito-Orta, M.A.; Martín-Conde, J.A.; Manzanares, I.; Synthesis and preliminary pharmacological evaluation of thiophene analogues of viloxazine as potential antidepressant drugs. Bioorg Med Chem 1999, 7, 7, 1349. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 34727 | 4-ethoxy-3-thienyl 2-oxiranylmethyl ether; 2-[[(4-ethoxy-3-thienyl)oxy]methyl]oxirane | C9H12O3S | 详情 | 详情 | |
| (III) | 34729 | 1-(benzylamino)-3-[(4-ethoxy-3-thienyl)oxy]-2-propanol | C16H21NO3S | 详情 | 详情 | |
| (IV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (V) | 34730 | N-benzyl-2-chloro-N-[3-[(4-ethoxy-3-thienyl)oxy]-2-hydroxypropyl]acetamide | C18H22ClNO4S | 详情 | 详情 | |
| (VI) | 34731 | 4-benzyl-6-[[(4-ethoxy-3-thienyl)oxy]methyl]-3-morpholinone | C18H21NO4S | 详情 | 详情 | |
| (VII) | 34732 | 4-benzyl-2-[[(4-ethoxy-3-thienyl)oxy]methyl]morpholine; 4-[(4-benzyl-2-morpholinyl)methoxy]-3-thienyl ethyl ether | C18H23NO3S | 详情 | 详情 |
合成路线42
该中间体在本合成路线中的序号：(A)Protected 2,4-diaminobutyric acid (I) is coupled with benzylamine (A) in acetonitrile in the presence of DCC and HOBt to yield (II), which is Boc deprotected by means of TFA in CH2Cl2 and loaded onto 2-Cl-trityl-Cl resin to provide (III). Treatment of (III) with piperidine/DMF to remove the Fmoc group, followed by coupling with Fmoc-3,4-difluoro-L-phenylalanine (IV) with HBTU, HOBt in DMF in and DIEA affords (V). The Fmoc group of dipeptide (V) is removed with piperidine/DMF and reaction with (X) in the presence of 4-nitrophenylchloroformate and DIEA in DCM yields (VI). Amine (X) can be obtained by treatment of indole (VII) with bromo derivative (VIII) by means of Cs2CO3 in DMF to yield (IX) followed by reduction of the nitro moiety with FeCl3?H2O, charcoal powder and Me2NNH2 in refluxing MeOH. Finally, Mannich reaction of (VI) with pyrrolidine and formaldehyde in HOAc followed by resin cleavage with TFA in CH2Cl2 furnishes the target molecule.
| 【1】 Derian, C.K.; Andrade-Gordon, P.; Maryanoff, B.E.; et al.; Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. Proceedings of the National Academy of Sciences of the United States of America 1999, 96, 22, 12257. |
| 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) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (I) | 42257 | (2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid | 125238-99-5 | C24H28N2O6 | 详情 | 详情 |
| (II) | 42258 | 9H-fluoren-9-ylmethyl (1S)-1-[(benzylamino)carbonyl]-3-[(tert-butoxycarbonyl)amino]propylcarbamate | C31H35N3O5 | 详情 | 详情 | |
| (III) | 42259 | 9H-fluoren-9-ylmethyl (1S)-3-amino-1-[(benzylamino)carbonyl]propylcarbamate | C26H27N3O3 | 详情 | 详情 | |
| (IV) | 42260 | (2S)-3-(3,4-difluorophenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C24H19F2NO4 | 详情 | 详情 | |
| (V) | 42261 | 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-3-amino-1-[(benzylamino)carbonyl]propyl]amino)-1-(3,4-difluorobenzyl)-2-oxoethylcarbamate | C35H34F2N4O4 | 详情 | 详情 | |
| (VI) | 42262 | (2S)-4-amino-N-benzyl-2-[[(2S)-2-[([[1-(2,6-dichlorobenzyl)-1H-indol-6-yl]amino]carbonyl)amino]-3-(3,4-difluorophenyl)propanoyl]amino]butanamide | C36H34Cl2F2N6O3 | 详情 | 详情 | |
| (VII) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
| (VIII) | 40793 | 2-(bromomethyl)-1,3-dichlorobenzene | 20443-98-5 | C7H5BrCl2 | 详情 | 详情 |
| (IX) | 42263 | 1-(2,6-dichlorobenzyl)-6-nitro-1H-indole | C15H10Cl2N2O2 | 详情 | 详情 | |
| (X) | 42264 | 1-(2,6-dichlorobenzyl)-1H-indol-6-ylamine; 1-(2,6-dichlorobenzyl)-1H-indol-6-amine | C15H12Cl2N2 | 详情 | 详情 |
合成路线43
该中间体在本合成路线中的序号：Alkylation of 4-nitroimidazole (XII) by means of ethyl bromoacetate (XIII) gave ethyl 2-(4-nitro-1-imidazolyl)acetate (XIV). Reduction of (XIV) to the corresponding amine (XV) was effected by catalytic hydrogenation over Pd/C. Coupling of (XV) with dipeptide (XI) gave (XVI), which was hydrolyzed to carboxylic acid (XVII) using LiOH. This was finally coupled with proline amide (XIX), (obtained by treatment of L-proline (XVIII) with benzylamine and CDI), to furnish the title compound.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (XI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (XII) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XIV) | 38800 | ethyl 2-(4-nitro-1H-imidazol-1-yl)acetate | C7H9N3O4 | 详情 | 详情 | |
| (XV) | 38801 | ethyl 2-(4-amino-1H-imidazol-1-yl)acetate | C7H11N3O2 | 详情 | 详情 | |
| (XVI) | 38802 | ethyl 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetate | C27H39N5O6 | 详情 | 详情 | |
| (XVII) | 38803 | 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetic acid | C25H35N5O6 | 详情 | 详情 | |
| (XVIII) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (XIX) | 38804 | (2S)-N-benzyl-2-pyrrolidinecarboxamide | C12H16N2O | 详情 | 详情 |
合成路线44
该中间体在本合成路线中的序号：(S)-Epichlorhydrin (V) was treated with benzylamine to afford aminoalcohol (VI). After protection of the amino group of (VI) as the tert-butyl carbamate (VII) with Boc2O, displacement of the chlorine of (VII) with arylpiperazine (I) furnished (VIII). Deprotection of the N-Boc group of (VIII) by means of trifluoroacetic acid gave (IX). Then, the N-benzyl group of (IX) was removed by transfer hydrogenolysis employing ammonium formate and Pd/C to provide the intermediate amine (IV).
| 【1】 Prouty, C.; Wang, J.; Kuo, G.-H.; Pulito, V.; Murray, W.V.; Cheung, P.; Jolliffe, L.; Varga, S.; Evangelisto, M.; Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines: A novel series of potent and selective alpha1a-adrenergic receptor antagonists. J Med Chem 2000, 43, 11, 2183. |
| 【2】 Murray, W.V.; Kuo, G.-H.; Prouty, C.P. (Ortho-McNeil Pharmaceutical, Inc.); Phthalimido arylpiperazines as alpha 1a receptor antagonists useful in the treatment of benign prostatic hyperplasia. US 6063785; WO 9942445 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 35066 | isopropyl 2-(1-piperazinyl)phenyl ether; 1-(2-isopropoxyphenyl)piperazine | C13H20N2O | 详情 | 详情 | |
| (IV) | 35069 | (2S)-1-amino-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol | C16H27N3O2 | 详情 | 详情 | |
| (V) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (VI) | 35070 | (2S)-1-(benzylamino)-3-chloro-2-propanol | C10H14ClNO | 详情 | 详情 | |
| (VII) | 35071 | tert-butyl benzyl[(2S)-3-chloro-2-hydroxypropyl]carbamate | C15H22ClNO3 | 详情 | 详情 | |
| (VIII) | 35072 | tert-butyl benzyl[(2R)-2-hydroxy-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]propyl]carbamate | C28H41N3O4 | 详情 | 详情 | |
| (IX) | 35073 | (2S)-1-(benzylamino)-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol | C23H33N3O2 | 详情 | 详情 |
合成路线45
该中间体在本合成路线中的序号：(III)Alkylation of 2-amino-3-nitrophenol (I) with 1,2-dichloroethane in 2-butanone afforded the chloroethyl ether (II), which was further condensed with benzylamine (III) to give amine (IV) (1,2). Acylation of (IV) with trifluoroacetic anhydride provided trifluoroacetamide (V). The nitro group of (V) was then reduced by transfer hydrogenation using hydrazine and Pd/C. Cyclization of the resulting phenylenediamine (VI) in refluxing TFA gave rise to benzimidazole (VII). The trifluoroacetamido group of (VII) was finally removed by treatment with K2CO3 in boiling MeOH (1). In a more direct procedure, nitroaniline (IV) was reduced to diamine (VIII) and then cyclized to the title benzimidazole by treatment with TFA.
| 【1】 Brennan, J.A.; Coupet, J.; Mazandarani, H.; Andree, T.H.; Nelson, J.A.; Marquis, K.; Shi, X.; Shah, U.S.; Mewshaw, R.E.; New generation dopaminergic agents 7. heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D2 template. Bioorg Med Chem Lett 1999, 9, 17, 2593. |
| 【2】 Nelson, J.A.; Mewshaw, R.E. (American Home Products Corp.); 4-Aminoalkoxy-1H-benzimidazole derivs., their preparation and their use as dopamine autoreceptor (D2) agonists. EP 0973749; WO 9835945 . |
| 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) | 41985 | 2-amino-3-nitrophenol | 603-85-0 | C6H6N2O3 | 详情 | 详情 |
| (II) | 41986 | 2-(2-chloroethoxy)-6-nitrophenylamine; 2-(2-chloroethoxy)-6-nitroaniline | C8H9ClN2O3 | 详情 | 详情 | |
| (III) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IV) | 41987 | 2-[2-(benzylamino)ethoxy]-6-nitroaniline; N-[2-(2-amino-3-nitrophenoxy)ethyl]-N-benzylamine | C15H17N3O3 | 详情 | 详情 | |
| (V) | 41988 | N-[2-(2-amino-3-nitrophenoxy)ethyl]-N-benzyl-2,2,2-trifluoroacetamide | C17H16F3N3O4 | 详情 | 详情 | |
| (VI) | 41989 | N-benzyl-N-[2-(2,3-diaminophenoxy)ethyl]-2,2,2-trifluoroacetamide | C17H18F3N3O2 | 详情 | 详情 | |
| (VII) | 41990 | N-benzyl-2,2,2-trifluoro-N-(2-[[2-(trifluoromethyl)-1H-benzimidazol-4-yl]oxy]ethyl)acetamide | C19H15F6N3O2 | 详情 | 详情 | |
| (VIII) | 41991 | 2-amino-3-[2-(benzylamino)ethoxy]phenylamine; 3-[2-(benzylamino)ethoxy]-1,2-benzenediamine | C15H19N3O | 详情 | 详情 |
合成路线46
该中间体在本合成路线中的序号：(I)Cyclocondensation of a mixture of benzylamine (I), ethyl propiolate (II) and benzaldehyde (III) in hot AcOH furnished dihydropyridine (IV). Photodimerization of this compound in a MeOH-THF solution gave rise to the cage dimer (V). Finally, reduction of the ester groups of (V) by means of LiAlH4 at low temperature produced the title tetraol compound.
| 【1】 Wiese, M.; Billich, A.; Hilgeroth, A.; Synthesis and biological evaluation of the first N-alkyl cage dimeric 4-aryl-1,4-dihydropyridines as novel nonpeptidic HIV-1 protease inhibitors. J Med Chem 1999, 42, 22, 4729. |
| 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) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (II) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IV) | 40525 | diethyl 1-benzyl-4-phenyl-1,4-dihydro-3,5-pyridinedicarboxylate | C24H25NO4 | 详情 | 详情 | |
| (V) | 40526 | C48H50N2O8 | 详情 | 详情 |
合成路线47
该中间体在本合成路线中的序号：D-Serine (I) was protected as the N-benzyloxycarbonyl derivative (II) by means of benzyl chloroformate in the presence of MgO. Methylation of the alcohol hydroxyl of (II) under Williamson conditions using iodomethane and Ag2O also produced esterification of the carboxyl group to give (III), which was further hydrolyzed to carboxylic acid (IV) with K2CO3 in MeOH-H2O. After activation of (IV) as the mixed anhydride with isobutyl chloroformate, coupling with benzyl amine furnished amide (V). This was alternatively obtained through a related procedure involving coupling of N-Cbz-serine (II) with benzylamine, followed by O-methylation of the resulting hydroxy amide (VI) with iodomethane and Ag2O. Finally, the N-carbobenzoxy protecting group of (V) was removed by catalytic hydrogenolysis in the presence of Pd/C.
| 【1】 Andurkar, S.V.; et al.; Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives. Tetrahedron Asymmetry 1998, 9, 21, 3841. |
| 【2】 Kohn, H.; Andurkar, S.V. (Research Corporation Technologies, Inc.); Anticonvulsant enantiomeric amino acid derivs.. US 6048899; WO 0000463 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 15728 | (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine | 312-84-5 | C3H7NO3 | 详情 | 详情 |
| (II) | 32794 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropionic acid | C11H13NO5 | 详情 | 详情 | |
| (III) | 38794 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxypropanoate | C13H17NO5 | 详情 | 详情 | |
| (IV) | 38795 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxypropionic acid | C12H15NO5 | 详情 | 详情 | |
| (V) | 38796 | benzyl (1R)-2-(benzylamino)-1-(methoxymethyl)-2-oxoethylcarbamate | C19H22N2O4 | 详情 | 详情 | |
| (VI) | 38797 | benzyl (1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxoethylcarbamate | C18H20N2O4 | 详情 | 详情 |
合成路线48
该中间体在本合成路线中的序号：(V)The electrochemical oxidation of 3,4-dihydroxy-2-methoxybenzophenone (I) in the presence of (1-aminocyclopentyl)methanol (II) using tetraethylammonium perchlorate as the supporting electrolyte led to the formation of a transient ortho-quinone (III), which, by intramolecular ring closure with amino alcohol (II), gave rise to the benzoxazinone (IV). Subsequent condensation of (IV) with benzylamine (V) produced the Schiff base (VI). This was finally converted to the title compound by electrochemical reduction.
| 【1】 Largeron, M.; et al.; Synthesis and in vitro evaluation of new-8-amino-1,4-benzoxazine derivatives as neuroprotective antioxidants. J Med Chem 1999, 42, 24, 5043. |
| 【2】 Largeron, M.; Lestage, P.; Fleury, M.B.; Lockhart, B. (ADIR et Cie.); Novel 8-amino-1,4-benzoxazine cpds., preparation method and pharmaceutical compsns. containing them. FR 2779144; WO 9962889 . |
| 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) | 52081 | (3,4-dihydroxy-2-methoxyphenyl)(phenyl)methanone | C14H12O4 | 详情 | 详情 | |
| (II) | 52082 | 1-Amino-1-cyclopentanemethanol; cycloleucinol | 10316-79-7 | C6H13NO | 详情 | 详情 |
| (III) | 52083 | 4-benzoyl-3-methoxybenzo-1,2-quinone | C14H10O4 | 详情 | 详情 | |
| (IV) | 52084 | C19H19NO4 | 详情 | 详情 | ||
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 52085 | C26H26N2O3 | 详情 | 详情 |
合成路线49
该中间体在本合成路线中的序号：Condensation of 5-amino-4,6-dichloropyrimidine (I) with benzylamine afforded diamine (III). Subsequent reaction of (III) with triethyl orthopropionate in the presence of HCl produced imidate (IV), which was cyclized to purine (V) upon heating in diphenyl ether in the presence of p-toluenesulfonic acid. Palladium catalyzed coupling of (IV) with the organozinc derivative generated from Grignard reagent (V) and ZnCl2 produced the corresponding 6-aryl purine (VI). The N-benzyl group of (VI) was then deprotected by hydrogenation in the presence of palladium catalyst and trifluoroacetic acid to furnish (VII). Finally, condensation with dicyclopropylcarbinol (VIII) under Mitsunobu conditions yielded the title compound.
| 【1】 Beck, J.P.; Arvanitis, A.G.; Bakthavatchalam, R.; Wilde, R.G. (DuPont Pharmaceuticals Co.); Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders. EP 0994877; WO 9901454 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
| (II) | 38817 | N(4)-benzyl-6-chloro-4,5-pyrimidinediamine; N-(5-amino-6-chloro-4-pyrimidinyl)-N-benzylamine | C11H11ClN4 | 详情 | 详情 | |
| (III) | 38818 | ethyl N-[4-(benzylamino)-6-chloro-5-pyrimidinyl]propanimidoate | C16H19ClN4O | 详情 | 详情 | |
| (IV) | 38819 | 9-benzyl-6-chloro-8-ethyl-9H-purine | C14H13ClN4 | 详情 | 详情 | |
| (V) | 38820 | bromo[2-chloro-4-(trifluoromethyl)phenyl]magnesium | C7H3BrClF3Mg | 详情 | 详情 | |
| (VI) | 38821 | 9-benzyl-6-[2-chloro-4-(trifluoromethyl)phenyl]-8-ethyl-9H-purine | C21H16ClF3N4 | 详情 | 详情 | |
| (VII) | 38822 | 6-[2-chloro-4-(trifluoromethyl)phenyl]-8-ethyl-9H-purine | C14H10ClF3N4 | 详情 | 详情 | |
| (VIII) | 38823 | dicyclopropylmethanol | 14300-33-5 | C7H12O | 详情 | 详情 |
合成路线50
该中间体在本合成路线中的序号：(IV)The condensation of 2-nitroimidazole (I) with methyl chloroacetate (II) by means of sodium methoxide in methanol - DMF at 150 C gives methyl 2-nitro-1-imidazolylacetate (III), which is then condensed with benzylamine (IV) in methanol.
| 【1】 Castaner, J.; Roberts, P.J.; Benznidazole. Drugs Fut 1977, 2, 9, 568. |
| 【2】 Beaman, A.G.; Duschinsky, R.; Tautz, W.P. (F. Hoffmann-La Roche AG); Novel imidazole derivs. and a process for the manufacture thereof. GB 1138529 . |
| 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) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 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) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
合成路线51
该中间体在本合成路线中的序号：(IX)Treatment of 6-nitroindole (I) with aqueous NaNO2 and HCl affords 3-indazolecarboxaldehyde (II), which is then subjected to reductive amination with pyrrolidine (III) by means of NaBH(OAc)3 in dichloroethane/DMF in the presence of acetic acid to provide compound (IV). Alkylation of (IV) with 2,6-dichlorobenzyl bromide (V) by means of KOH in THF yields compound (VI), whose nitro group is reduced with dimethyl hydrazine (Me2NNH2), FeCl3 and charcoal in refluxing MeOH to furnish aminoindazole intermediate (VII). The synthesis of intermediate (XIII) is performed as follows: Coupling of protected diaminobutyric acid (VIII) with benzylamine (IX) by means of DCC and HOBt in acetonitrile, followed by Fmoc removal after treatment with diethylamine, gives derivative (X), which is then condensed with protected difluorophenylalanine (XI) by means of DIC and HOBt in acetonitrile to afford protected dipeptide (XII). Finally, intermediate (XIII) is obtained by Fmoc removal of (XII) by treatment with ethylamine. The desired product is finally obtained by condensation of intermediates (VII) and (XIII) by means of 4-nitrophenyl chloroformate and DIEA in dichloromethane, followed by Boc removal with TFA in dichloromethane.
| 【1】 Andrade-Gordon, P.; Zhang, H.-C.; Derian, C.K.; et al.; Discovery and optimization of a novel series of thrombin receptor (PAR-1) antagonists: Potent, selective peptide mimetics based on indole and indazole templates. J Med Chem 2001, 44, 7, 1021. |
| 【2】 Zhang, H.-C.; Pandey, A.; Scarborough, R.M.; Maryanoff, B.E. (COR Therapeutics, Inc.; Ortho-McNeil Pharmaceutical, Inc.); Novel indazole peptidomimetics as thrombin receptor antagonists. WO 0100656 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 | |
| (I) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
| (II) | 48891 | 6-nitro-1H-indazole-3-carbaldehyde | C8H5N3O3 | 详情 | 详情 | |
| (III) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IV) | 48892 | 6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole | C12H14N4O2 | 详情 | 详情 | |
| (V) | 40793 | 2-(bromomethyl)-1,3-dichlorobenzene | 20443-98-5 | C7H5BrCl2 | 详情 | 详情 |
| (VI) | 48893 | 1-(2,6-dichlorobenzyl)-6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole | C19H18Cl2N4O2 | 详情 | 详情 | |
| (VII) | 48894 | 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-ylamine; 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-amine | C19H20Cl2N4 | 详情 | 详情 | |
| (VIII) | 42257 | (2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid | 125238-99-5 | C24H28N2O6 | 详情 | 详情 |
| (IX) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (X) | 48895 | tert-butyl (3S)-3-amino-4-(benzylamino)-4-oxobutylcarbamate | C16H25N3O3 | 详情 | 详情 | |
| (XI) | 42260 | (2S)-3-(3,4-difluorophenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C24H19F2NO4 | 详情 | 详情 | |
| (XII) | 48896 | 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-1-[(benzylamino)carbonyl]-3-[(tert-butoxycarbonyl)amino]propyl]amino)-1-(3,4-difluorobenzyl)-2-oxoethylcarbamate | C40H42F2N4O6 | 详情 | 详情 | |
| (XIII) | 48897 | tert-butyl (3S)-3-[[(2S)-2-amino-3-(3,4-difluorophenyl)propanoyl]amino]-4-(benzylamino)-4-oxobutylcarbamate | C25H32F2N4O4 | 详情 | 详情 |
合成路线52
该中间体在本合成路线中的序号：(VII)The intermediate 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide (IX) has been obtained as follows. The esterification of N-(benzyloxycarbonyl)-DL-phenylalanine (I) with methyl iodide and KHCO3 in DMF gives the corresponding methyl ester (II), which is reduced with LiCl and NaBH4 in THF to yield protected DL-phenylalaninol (III). The oxidation of (III) by means of 2,2,6,6-tetramethylpiperdine-1-oxyl free radical (TEMPO), NaBr and NaClO in ethyl acetate/toluene affords protected DL-phenylalaninal (IV), which is condensed with ethyl 2-bromo-2,2-difluoroacetate (V) by means of Zn in THF to provide the 2,2-difluoropentanoic ester (VI). The reaction of ester (VI) with benzylamine (VII) in THF gives the corresponding amide (VIII), which is finally deprotected by means of H2 over Pd/C in methanol/dioxane to yield the target 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide (IX) intermediate.
| 【1】 Kobayashi, F.; Naito, K.; Yoshikawa, T.; Kuwahara, S.; Imada, T.; Komorita, N. (Mitsubishi Pharma Corp.); IgE antibody production inhibitors and autoimmune diseases inhibitors. EP 1062949; US 6528514; WO 9945928 . |
| 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) | 58077 | N-[(benzyloxy)carbonyl]phenylalanine | C17H17NO4 | 详情 | 详情 | |
| (II) | 57836 | methyl 2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanoate | C18H19NO4 | 详情 | 详情 | |
| (III) | 58078 | benzyl 1-benzyl-2-hydroxyethylcarbamate | C17H19NO3 | 详情 | 详情 | |
| (IV) | 48629 | benzyl 1-benzyl-2-oxoethylcarbamate; N-(benzyloxycarbonyl)-L-phenylalaninal | 59830-60-3 | C17H17NO3 | 详情 | 详情 |
| (V) | 40673 | ethyl 2-bromo-2,2-difluoroacetate; Ethylbromodifluoroacetate; 2-bromo-2,2-difluoroacetic acid ethyl ester; bromodifluoroacetic acid ethyl ester | 667-27-6 | C4H5BrF2O2 | 详情 | 详情 |
| (VI) | 57837 | ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-difluoro-5-phenylpentanoate | C21H23F2NO4 | 详情 | 详情 | |
| (VII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VIII) | 57838 | benzyl 1-benzyl-4-(benzylamino)-3,3-difluoro-4-oxobutylcarbamate | C26H26F2N2O3 | 详情 | 详情 | |
| (IX) | 57839 | 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide | C18H20F2N2O | 详情 | 详情 |
合成路线53
该中间体在本合成路线中的序号：(VI)The asymmetric epoxidation of (R)-2-methyl-6-nitro-2H-1-benzopyran-2-carbaldehyde (I) with NaOCl catalyzed by the chiral catalyst Mn(III)-Salen gives the chiral epoxide (II), which is opened by means of NH3 in hot ethanol to yield the amino alcohol (III). The reaction of (III) with diphenylcyanocarbonimidate (IV) by means of TEA in DMF/isopropanol affords the N-cyano-O-phenylisourea (V), which by reaction with benzylamine (VI) in the same solvent provides the N-cyanoguanidine (VII). Finally, the nitro group of this compound is reduced with H2 over Pd/C or NaBH4 in methanol to give the target amino derivative.
| 【1】 Lee, S.; Yoo, S.; Yi, K.Y.; et al.; A novel anti-ischemic ATP-sensitive potassium channel (KATP) opener without vasorelaxation: N-(6-aminobenzopyranyl)-N-benzyl-N'-cyanoguanidine analogue. J Med Chem 2001, 44, 24, 4207. |
| 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) | 51836 | (2S)-2-(dimethoxymethyl)-2-methyl-6-nitro-2H-chromene; methoxy[(2S)-2-methyl-6-nitro-2H-chromen-2-yl]methyl methyl ether | C13H15NO5 | 详情 | 详情 | |
| (II) | 57013 | (1aS,2S,7bS)-2-(dimethoxymethyl)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromene; [(1aS,2S,7bS)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-2-yl](methoxy)methyl methyl ether | C13H15NO6 | 详情 | 详情 | |
| (III) | 51838 | (2S,3S,4R)-4-amino-2-(dimethoxymethyl)-2-methyl-6-nitro-3,4-dihydro-2H-chromen-3-ol | C13H18N2O6 | 详情 | 详情 | |
| (IV) | 25868 | 1-[(cyanoimino)(phenoxy)methoxy]benzene | 107-37-9 | C14H10N2O2 | 详情 | 详情 |
| (V) | 57014 | (2S,3S,4R)-4-{[(cyanoimino)(phenoxy)methyl]amino}-2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromene | C21H22N4O7 | 详情 | 详情 | |
| (VI) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VII) | 51841 | N-benzyl-N''-cyano-N'-[(2S,3S,4R)-2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]guanidine | C22H25N5O6 | 详情 | 详情 |
合成路线54
该中间体在本合成路线中的序号：(II)Condensation of 2,6-dichloropurine (I) with benzylamine (II) in boiling butanol afforded 6-(benzylamino)-2-chloropurine (III), which was subsequently alkylated at the 9-N with isopropyl bromide (IV), yielding purine (V). The 2-chloro group was finally displaced with (R)-2-amino-1-butanol (VI) in a sealed tube at 160 C to provide the title compound.
| 【1】 Wang, S.; et al.; Synthesis and configuration of the cyclin-dependent kinase inhibitor roscovitine and its enantiomer. Tetrahedron Asymmetry 2001, 12, 20, 2891. |
| 【2】 Havlicek, L.; et al.; Cytokinin-derived cyclin-dependent kinase inhibitors: Synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J Med Chem 1997, 40, 4, 408. |
| 【3】 Meijer, L.; Bisagni, E.; Legraverend, M. (CNRS (Centre National de la Recherche Scientifique)); Novel purine derivs. having, in particular, antiproliferative properties, and biological uses thereof. EP 0874847; FR 2741881; JP 2000501408; US 2002049218; US 6316456; WO 9720842 . |
| 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) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 36315 | N-benzyl-2-chloro-9H-purin-6-amine; N-benzyl-N-(2-chloro-9H-purin-6-yl)amine | C12H10ClN5 | 详情 | 详情 | |
| (IV) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (V) | 36316 | N-benzyl-2-chloro-9-isopropyl-9H-purin-6-amine; N-benzyl-N-(2-chloro-9-isopropyl-9H-purin-6-yl)amine | C15H16ClN5 | 详情 | 详情 | |
| (VI) | 48572 | (S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol | 5856-62-2 | C4H11NO | 详情 | 详情 |
合成路线55
该中间体在本合成路线中的序号：(V)4-Chloroanthranilic acid (I) is acylated by butyryl chloride (II) in DMF to produce amide (III). This is then cyclized to the benzoxazinone (IV) upon heating with acetic anhydride. Condensation of (IV) with benzylamine (V) in refluxing chloroform, followed by treatment with NaOH in hot ethyleneglycol, gives rise to the quinazolinone (VI). Subsequent benzylic bromination of (VI) at the propyl side chain produces (VII). The bromide group of (VII) is then displaced with N,N-dimethyl-1,3-propanediamine (VIII) to furnish (IX). Finally, amine (IX) is acylated by 4-bromobenzoyl chloride (X) to afford the corresponding benzamide.
| 【1】 Chabala, J.C.; Morgans, D.J. Jr.; Feng, B.; Finer, J.T.; Bergnes, G.; Smith, W.W. (Cytokinetics, Inc.); Methods and compsns. utilizing quinazolinones. WO 0198278 . |
| 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) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 58445 | 2-(butyrylamino)-4-chlorobenzoic acid | C11H12ClNO3 | 详情 | 详情 | |
| (IV) | 58446 | 7-chloro-2-propyl-4H-3,1-benzoxazin-4-one | C11H10ClNO2 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 58447 | 3-benzyl-7-chloro-2-propyl-4(3H)-quinazolinone | C18H17ClN2O | 详情 | 详情 | |
| (VII) | 58448 | 3-benzyl-2-(1-bromopropyl)-7-chloro-4(3H)-quinazolinone | C18H16BrClN2O | 详情 | 详情 | |
| (VIII) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (IX) | 58449 | 3-benzyl-7-chloro-2-(1-{[3-(dimethylamino)propyl]amino}propyl)-4(3H)-quinazolinone | C23H29ClN4O | 详情 | 详情 | |
| (X) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |
合成路线56
该中间体在本合成路线中的序号：(VI)
| 【1】 Anon. 2009. Novel intermediate compounds and their use in preparation of lacosamide . Anon USA IP.com Journal, 9(4A),35. Publisher: IP.com, Inc, CAN 152: 119915, AN 2009: 642771. |
| 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) | 67180 | 2-amino-3-hydroxypropanoic acid | C3H7NO3 | 详情 | 详情 | |
| (II) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (III) | 67181 | （R）-2-(1,3-dioxoisoindolin-2-yl)-3-hydroxypropanoic acid | C11H9NO5 | 详情 | 详情 | |
| (IV) | 67182 | (R)-methyl 2-(1,3-dioxoisoindolin-2-yl)-3-methoxypropanoate | C13H13NO5 | 详情 | 详情 | |
| (V) | 67183 | (R)-2-(1,3-dioxoisoindolin-2-yl)-3-methoxypropanoic acid | C12H11NO5 | 详情 | 详情 | |
| (VI) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VII) | 67184 | N-benzyl-2-(1,3-dioxoisoindolin-2-yl)-3-methoxypropanamide | C19H18N2O4 | 详情 | 详情 | |
| (VIII) | 67185 | (R)-2-amino-N-benzyl-3-methoxypropanamide | C11H16N2O2 | 详情 | 详情 |
合成路线57
该中间体在本合成路线中的序号：(IV)
| 【1】 Didier B, Alain M, Veronique P, et al. 2009. Novel process for the preparation amino acid derivative lacosamide. PCT Int. Appl. CODEN: PIXXD2 WO 2010052011 A1 20100514 Applicantion: WO 2009EP7962 20091106(UCB Pharma, S A, Belg). |
| 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) | 18341 | ethyl 2,3-dibromopropanoate | 3674-13-3 | C5H8Br2O2 | 详情 | 详情 |
| (II) | 67191 | sodium methanolate | CH3NaO | 详情 | 详情 | |
| (III) | 67192 | 2-bromo-3-methoxypropanoic acid | 65090-78-0 | C4H7BrO3 | 详情 | 详情 |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 67193 | N-benzyl-2-bromo-3-methoxypropanamide | C11H14BrNO2 | 详情 | 详情 | |
| (VI) | 67194 | 2-amino-N-benzyl-3-methoxypropanamide | C11H16N2O2 | 详情 | 详情 | |
| (VII) | 66089 | (2S,3S)-2,3-bis(benzoyloxy)butanedioic acid | 17026-42-5 | C18H14O8 | 详情 | 详情 |
| (VIII) | 67185 | (R)-2-amino-N-benzyl-3-methoxypropanamide | C11H16N2O2 | 详情 | 详情 |
合成路线58
该中间体在本合成路线中的序号：(IV)
| 【1】 Madhra MK, Singh PK, Khanduri CH. 2007. Preparation of tritylated intermediates and their use in preparation of lacosamide in high chiral purity. Indian Pat Appl. CODEN: INXXBQ IN 2007DE02542 A 20090710. Applicant: IN 2007-DE2542 20071204. (Ranbaxy Laboratories Limited, India). |
| 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) | 67180 | 2-amino-3-hydroxypropanoic acid | C3H7NO3 | 详情 | 详情 | |
| (II) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (III) | 67195 | (R)-3-hydroxy-2-(tritylamino)propanoic acid | C22H21NO3 | 详情 | 详情 | |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 67196 | (R)-N-benzyl-3-hydroxy-2-(tritylamino)propanamide | C29H28N2O2 | 详情 | 详情 | |
| (VI) | 67187 | Iodomethane;Methyl iodide | 74-88-4 | CH3I | 详情 | 详情 |
| (VII) | 67197 | (R)-N-benzyl-3-methoxy-2-(tritylamino)propanamide | C30H30N2O2 | 详情 | 详情 | |
| (VIII) | 67185 | (R)-2-amino-N-benzyl-3-methoxypropanamide | C11H16N2O2 | 详情 | 详情 | |
| (IX) | 49701 | Acetic anhydride; Acetyl oxide | 108-24-7 | C4H6O3 | 详情 | 详情 |
合成路线59
该中间体在本合成路线中的序号：(XII)
| 【1】 Morieux P,Stables JP, Kohn H. 2008. Synthesis and anticonvulsant activities of N-benzyl(2R)-2-acetamido-3-oxysubstituted propionamide derivatives. Bioorganic & Medicinal Chemistry, 16(19): 8968～8975. |
| 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) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
| (II) | 67198 | ethanol, sodium salt | C2H6O.Na | 详情 | 详情 | |
| (III) | 67199 | diethoxytriphenylphosphorane | 18509-25-6 | C22H25O2P | 详情 | 详情 |
| (IV) | 67200 | (R)-methyl 2-amino-3-hydroxypropanoate | 24184-43-8 | C4H9NO3 | 详情 | 详情 |
| (V) | 67201 | (R)-ethyl aziridine-2-carboxylate | C5H9NO2 | 详情 | 详情 | |
| (VI) | 67202 | (R)-methyl aziridine-2-carboxylate | 103539-32-8 | C4H7NO2 | 详情 | 详情 |
| (VII) | 67203 | (R)-ethyl 1-acetylaziridine-2-carboxylate | C7H11NO3 | 详情 | 详情 | |
| (VIII) | 67204 | (R)-methyl 1-acetylaziridine-2-carboxylate | C6H9NO3 | 详情 | 详情 | |
| (IX) | 67205 | (R)-ethyl 2-acetamido-3-methoxypropanoate | C8H15NO4 | 详情 | 详情 | |
| (X) | 67206 | (R)-methyl 2-acetamido-3-methoxypropanoate | C7H13NO4 | 详情 | 详情 | |
| (XI) | 67190 | (R)-2-acetamido-3-methoxypropanoic acid | C6H11NO4 | 详情 | 详情 | |
| (XII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XIII) | 67207 | 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride | C10H17ClN4O3 | 详情 | 详情 |
合成路线60
该中间体在本合成路线中的序号：(IV)
| 【1】 Riendner J. 2004. Improved synthesis scheme for lacosamide. Eur Pat Appl. CODEN: EPXXDW EP1642889 A1 20060405 Application: EP 2004-23556 20041002(Schwarz Pharma AG, Germany ). |
| 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) | 67186 | (R)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 67208 | C2H6O4S | 详情 | 详情 | ||
| (III) | 67188 | (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid | 86123-95-7 | C9H17NO5 | 详情 | 详情 |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 67209 | (R)-tert-butyl (1-(benzylamino)-3-methoxy-1-oxopropan-2-yl)carbamate | 880468-89-3 | C16H24N2O4 | 详情 | 详情 |
| (VI) | 67185 | (R)-2-amino-N-benzyl-3-methoxypropanamide | C11H16N2O2 | 详情 | 详情 |
合成路线61
该中间体在本合成路线中的序号：(II)
| 【1】 Madhra MK, Singh PK, Khanduri CH. 2009. Preparation of tritylated intermediates and their use in preparation of lacosamide in high chiral purity. US Pat Appl. CODEN: USXXCO US 2009143472 A1 20090604 Application: US 2008-327124 20081203(Ranbaxy Laborator Limited, India). |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 67197 | (R)-N-benzyl-3-methoxy-2-(tritylamino)propanamide | C30H30N2O2 | 详情 | 详情 | |
| (I) | 67210 | 3-methoxy-2-(tritylamino)propanoic acid | C23H23NO3 | 详情 | 详情 | |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IV) | 67185 | (R)-2-amino-N-benzyl-3-methoxypropanamide | C11H16N2O2 | 详情 | 详情 |