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【结 构 式】 
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【分子编号】14338 【品名】potassium 3-ethoxy-3-oxopropanoate 【CA登记号】6148-64-7 |
【 分 子 式 】C5H7KO4 【 分 子 量 】170.20648 【元素组成】C 35.28% H 4.15% K 22.97% O 37.6% |
合成路线1
该中间体在本合成路线中的序号：(XI)A new synthesis of T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with ethyl bromide and K2CO3 in DMSO gives the corresponding ethyl ester (II), which is condensed with tert-butyl cyanoacetate (III) by means of K2CO3, yielding 4-(cyanomethyl)-2,3,5-trifluorobenzoic acid ethyl ester (V) through the intermediate (IV). The cyclopropanation of (V) with 1,2-dibromoethane and benzyltriethylammonium chloride and NaOH in water/dichloromethane affords 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoic acid, which by treatment with H2O2 and NaOH is converted to 4-(1-carbamoylcyclopropyl)-2,3,5-trifluorobenzoic acid (VII). Degradation of amide (VII) with Cl2 and NaOH gives the corresponding 4-aminocyclopropyl derivative (VIII), which is acetylated with acetic anhydride to the acetamide (IX). The reaction of (IX) with SOCl2 yields the acid chloride (X), which is condensed with malonic acid monoethyl ester potassium salt (XI) by means of triethylamine to afford 2-[4-(1-acetamidocyclopropyl)-2,3,5-trifluorobenzoyl]acetic acid ethyl ester (XII). The consecutive reaction of (XII) first with dimethylformamide dimethylacetal (XIII) in acetic acid and then with 2(S)-aminopropanol (XIV) gives the benzoylacrylic intermediate (XV), which, without isolation, is treated with K2CO3 in DMSO at 100 C to afford the ethyl ester of the acetylated T-3761 (XVI). Finally, this compound is deprotected by successive treatment first with ethanolic NaOH and then with hot 6N HCl.
| 【1】 Iino, F.; Momonoi, K.; Hayashi, K.; Todo, Y.; Kuroda, H.; Takagi, H.; Narita, H.; Takata, M.; Practical synthesis of T-3761, (S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. Chem Pharm Bull 1994, 42, 12, 2629. |
| 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) | 14328 | 2,3,4,5-tetrafluorobenzoic acid | 1201-31-6 | C7H2F4O2 | 详情 | 详情 |
| (II) | 14313 | diethyl (2S)-2-[(4-[2-[(6R)-2-(acetamido)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate | C27H35N5O7 | 详情 | 详情 | |
| (III) | 14330 | tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate | 1116-98-9 | C7H11NO2 | 详情 | 详情 |
| (IV) | 14331 | ethyl 4-[2-(tert-butoxy)-1-cyano-2-oxoethyl]-2,3,5-trifluorobenzoate | C16H16F3NO4 | 详情 | 详情 | |
| (V) | 14332 | ethyl 4-(cyanomethyl)-2,3,5-trifluorobenzoate | C11H8F3NO2 | 详情 | 详情 | |
| (VI) | 14333 | ethyl 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoate | C13H10F3NO2 | 详情 | 详情 | |
| (VII) | 14334 | 4-[1-(aminocarbonyl)cyclopropyl]-2,3,5-trifluorobenzoic acid | C11H8F3NO3 | 详情 | 详情 | |
| (VIII) | 14335 | 4-(1-aminocyclopropyl)-2,3,5-trifluorobenzoic acid | C10H8F3NO2 | 详情 | 详情 | |
| (IX) | 14336 | 4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoic acid | C12H10F3NO3 | 详情 | 详情 | |
| (X) | 14337 | 4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl chloride | C12H9ClF3NO2 | 详情 | 详情 | |
| (XI) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (XII) | 14339 | ethyl 3-[4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorophenyl]-3-oxopropanoate | C16H16F3NO4 | 详情 | 详情 | |
| (XIII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XIV) | 14341 | L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol | 2749-11-3 | C3H9NO | 详情 | 详情 |
| (XV) | 14342 | ethyl (E)-2-[4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-[[(1S)-2-hydroxy-1-methylethyl]amino]-2-propenoate | C20H23F3N2O5 | 详情 | 详情 | |
| (XVI) | 14343 | ethyl (3S)-10-[1-(acetamido)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C20H21FN2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)An efficient synthesis of 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XI), a key intermediate in the synthesis of DU-6859a, via an asymmetric microbial reduction has been described: The reaction of N-benzylglycine (I) with tert-butoxycarbonyl anhydride gives N-benzyl-N-(tert-butoxycarbonyl)glycine (II), which is condensed with the potassium salt of ethyl hydrogen malonate (III) by means of carbonyldiimidazole (CDI) in THF yielding 4-[N-benzyl-N-(tert-butoxycarbonyl)amino]-3-oxobutyric acid ethyl ester (IV). The cyclopropanation of (IV) with 1,2-dibromoethane (V) by means of K2CO3 in refluxing acetone affords the cyclopropane derivative (VI), which is cyclized by means of trifluoroacetic acid in dichloromethane to give 5-benzyl-5-azaspiro[2.4]heptane-4,7-dione (VII). The enantioselective microbial reduction of (VII) by means of Phaeocreopsis sp. JCM 1880 in a complex medium containing glucose and polypeptone yields 5-benzyl-7(R)-hydroxy-5-azaspiro[2.4]heptan-4-one (VIII), which by reaction with triphenylphosphine, diethyl azodicarboxylate and diphenylphosphoryl azide (DPPA) followed by reduction with LiAlH4, is converted into 7(S)-amino-5-benzyl-5-azaspiro[2.4]heptane (IX). The protection of (IX) with tert-butoxycarbonyl anhydride as usual gives the protected amine (X), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol affording the desired 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XI).
| 【1】 Yukimoto, Y.; Imura, A.; Satoh, K.; Kanai, K.; Miyadera, A.; An efficient synthesis of a key intermediate of DU-6859a via asymmetric microbial reduction. Chem Pharm Bull 1998, 46, 4, 587. |
| 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) | 27895 | N-(benzylamino)acetic acid; N-Benzylglycine; 2-(benzylamino)acetic acid | 17136-36-6 | C9H11NO2 | 详情 | 详情 |
| (II) | 27846 | 2-[benzyl(tert-butoxycarbonyl)amino]acetic acid | C14H19NO4 | 详情 | 详情 | |
| (III) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (IV) | 27896 | ethyl 4-[benzyl(tert-butoxycarbonyl)amino]-3-oxobutanoate | C18H25NO5 | 详情 | 详情 | |
| (V) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (VI) | 27897 | ethyl 1-[2-[benzyl(tert-butoxycarbonyl)amino]acetyl]cyclopropanecarboxylate | C20H27NO5 | 详情 | 详情 | |
| (VII) | 27898 | 5-benzyl-5-azaspiro[2.4]heptane-4,7-dione | C13H13NO2 | 详情 | 详情 | |
| (VIII) | 27899 | (7R)-5-benzyl-7-hydroxy-5-azaspiro[2.4]heptan-4-one | C13H15NO2 | 详情 | 详情 | |
| (IX) | 27900 | (7S)-5-benzyl-5-azaspiro[2.4]hept-7-ylamine | C13H18N2 | 详情 | 详情 | |
| (X) | 27901 | tert-butyl (7S)-5-benzyl-5-azaspiro[2.4]hept-7-ylcarbamate | C18H26N2O2 | 详情 | 详情 | |
| (XI) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)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4
该中间体在本合成路线中的序号：(XI)The methylation of 2,6-difluorophenol (I) with methyl iodide and K2CO3 in DMF gives 2,6-difluoroanisole (II), which by treatment with butyllithium and CO2 yields 2,4-difluoro-3-methoxybenzoic acid (III). The methylation of (III) with diazomethane in ether affords the methyl ester (IV), which by reaction with BBr3 in dichloromethane results in 2,4-difluoro-3-hydroxybenzoic acid methyl ester (V). The alkylation of (V) with chlorodifluoromethane and K2CO3 in DMF gives 3-(difluoromethoxy)-2,4-difluorobenzoic acid methyl ester (VI), which is treated with sodium azide in DMSO, yielding the azido derivative (VII). The reduction of (VII) with H2 over Pd/C in ethanol affords 3-amino-2,4-difluorobenzoic acid methyl ester (VIII), which is hydrolyzed with NaOH in ethanol, giving the free acid (IX). The reaction of (IX) with NaNO2 and HBr yields 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid (X), which is condensed with the magnesium salt of malonic acid monoethyl ester (XI) by means of CDI in THF, affording the 3-oxopropionate (XII). The reaction of (XII) with dimethylformamide dimethylacetal (XIII) and cyclopropylamine (XIV) by means of acetic anhydride in dichloromethane gives the 3-(cyclopropylamino)acrylate (XV), which is cyclized by means of K2CO3 in hot DMSO, yielding quinolone (XVI). The condensation of (XVI) with the isoindolylboronic acid derivative (XVII) - obtained by reaction of 5-bromo-1(R)-methyl-2-tritylisoindoline (XIX) with triisopropyl borate and butyllithium in THF - by means of bis(triphenylphosphine)palladium(II) chloride as catalyst in refluxing toluene affords the protected compound (XVIII), which is finally deprotected with HCl in ethanol.
| 【1】 Castañer, J.; Rabasseda, X.; Graul, A.; T-3811ME. Drugs Fut 1999, 24, 12, 1324. |
| 【2】 Todo, Y.; Hayashi, K.; Takahata, M.; Watanabe, Y.; Narita, H. (Toyama Chemical Co., Ltd.); Quinolonecarboxylic acid derivs. or salts thereof.. EP 0882725; US 6025370; WO 9729102 . |
| 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) | 30619 | 2,6-difluorophenol | 28177-48-2 | C6H4F2O | 详情 | 详情 |
| (II) | 30620 | 2,6-difluorophenyl methyl ether; 1,3-difluoro-2-methoxybenzene | C7H6F2O | 详情 | 详情 | |
| (III) | 30621 | 2,4-difluoro-3-methoxybenzoic acid | 178974-97-5 | C8H6F2O3 | 详情 | 详情 |
| (IV) | 30622 | methyl 2,4-difluoro-3-methoxybenzoate | C9H8F2O3 | 详情 | 详情 | |
| (V) | 30623 | methyl 2,4-difluoro-3-hydroxybenzoate | C8H6F2O3 | 详情 | 详情 | |
| (VI) | 30624 | methyl 3-(difluoromethoxy)-2,4-difluorobenzoate | C9H6F4O3 | 详情 | 详情 | |
| (VII) | 30625 | methyl 4-azido-3-(difluoromethoxy)-2-fluorobenzoate | C9H6F3N3O3 | 详情 | 详情 | |
| (VIII) | 30626 | methyl 4-amino-3-(difluoromethoxy)-2-fluorobenzoate | C9H8F3NO3 | 详情 | 详情 | |
| (IX) | 30627 | 4-amino-3-(difluoromethoxy)-2-fluorobenzoic acid | C8H6F3NO3 | 详情 | 详情 | |
| (X) | 30628 | 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid | C8H4BrF3O3 | 详情 | 详情 | |
| (XI) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (XII) | 30629 | ethyl 3-[4-bromo-3-(difluoromethoxy)-2-fluorophenyl]-3-oxopropanoate | C12H10BrF3O4 | 详情 | 详情 | |
| (XIII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XIV) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XV) | 30630 | ethyl (Z)-2-[4-bromo-3-(difluoromethoxy)-2-fluorobenzoyl]-3-(cyclopropylamino)-2-propenoate | C16H15BrF3NO4 | 详情 | 详情 | |
| (XVI) | 30631 | ethyl 7-bromo-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H14BrF2NO4 | 详情 | 详情 | |
| (XVII) | 30632 | (1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-ylboronic acid | C28H26BNO2 | 详情 | 详情 | |
| (XVIII) | 30633 | ethyl 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C44H38F2N2O4 | 详情 | 详情 | |
| (XIX) | 30634 | (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole | C28H24BrN | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II) (1-3). Ketoester (IV) was prepared by treatment of n-heptanoic acid (III) with 1,1'-carbonyldiimidazole and further condensation with ethyl magnesium malonate (1). Subsequent conjugate addition of (II) to ketoester (IV) using DBU provided adduct (V). Reduction of the nitro group of (V), with concomitant ring closure formed the cyclic imine (VI), which was reduced with NaBH3CN to yield the pyrrolidine (VII) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VIII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VIII) with N,N-dibutyl bromoacetamide (IX) furnished (X). Basic hydrolysis of the ester group of (X) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (XI) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
| 【1】 Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991. |
| 【2】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
| 【3】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIIa) | 35037 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (VIIIb) | 35038 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (Xa),(XI) | 35039 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-hexyl-3-pyrrolidinecarboxylate | C29H46N2O5 | 详情 | 详情 | |
| (Xb) | 35040 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-hexyl-3-pyrrolidinecarboxylate | C29H46N2O5 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35032 | heptanoic acid | 111-14-8 | C7H14O2 | 详情 | 详情 |
| (IV) | 35033 | methyl 3-oxononanoate | C10H18O3 | 详情 | 详情 | |
| (V) | 35034 | methyl 2-[1-(1,3-benzodioxol-5-yl)-2-nitroethyl]-3-oxononanoate | C19H25NO7 | 详情 | 详情 | |
| (VI) | 35035 | methyl 3-(1,3-benzodioxol-5-yl)-5-hexyl-3,4-dihydro-2H-pyrrole-4-carboxylate | C19H25NO4 | 详情 | 详情 | |
| (VII) | 35036 | methyl 4-(1,3-benzodioxol-5-yl)-2-hexyl-3-pyrrolidinecarboxylate | C19H27NO4 | 详情 | 详情 | |
| (IX) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with lmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)--3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with cyclopentyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (III) | 51810 | ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51811 | 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H8F2N2OS | 详情 | 详情 | |
| (VI) | 51794 | 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride | 930-28-9 | C5H9Cl | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with malonic acid monoethyl ester potassium salt (III) to yield 4´(2,6-difluorophenyl)-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with cyclopentyl chloride (VII) to provide the target pyrimidinone derivative.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 51820 | 2-(2,6-difluorophenyl)propionic acid | C9H8F2O2 | 详情 | 详情 | |
| (III) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (IV) | 51830 | ethyl 4-(2,6-difluorophenyl)-3-oxopentanoate | C13H14F2O3 | 详情 | 详情 | |
| (V) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VI) | 51831 | 6-[1-(2,6-difluorophenyl)ethyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C12H10F2N2OS | 详情 | 详情 | |
| (VII) | 51794 | 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride | 930-28-9 | C5H9Cl | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with methyl chloride by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (III) | 51810 | ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51811 | 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H8F2N2OS | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with isopropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (III) | 51810 | ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51811 | 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H8F2N2OS | 详情 | 详情 | |
| (VI) | 29984 | 2-chloropropane | 75-29-6 | C3H7Cl | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with butyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (III) | 51810 | ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51811 | 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H8F2N2OS | 详情 | 详情 | |
| (VI) | 51818 | n-Butyl chloride; Butyl chloride; N-Propylcarbinyl chloride; 1-Chlorobutane | 109-69-3 | C4H9Cl | 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 condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with isobutyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (III) | 51810 | ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51811 | 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H8F2N2OS | 详情 | 详情 | |
| (VI) | 13624 | 1-Chloro-2-methylpropane; Isobutyl chloride | 513-36-0 | C4H9Cl | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with lmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with 1-ethylpropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (III) | 51810 | ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51811 | 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H8F2N2OS | 详情 | 详情 | |
| (VI) | 51797 | 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride | 78-86-4 | C4H9Cl | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(II)The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with lmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)--3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with cyclohexyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.
| 【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159. |
| 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) | 51809 | 2,6-Difluorophenylacetic acid | 85068-28-6 | C8H6F2O2 | 详情 | 详情 |
| (II) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (III) | 51810 | ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | C12H12F2O3 | 详情 | 详情 | |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (V) | 51811 | 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H8F2N2OS | 详情 | 详情 | |
| (VI) | 51795 | chlorocyclohexane; Hexahydrochlorobenzene; Cyclohexyl chloride | 542-18-7 | C6H11Cl | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XIb)Deprotonation of 2,2,6-trimethyl-1,3-dioxin-4-one (I) by means of LDA, generated from BuLi and (i-Pr)2NH, in THF, followed by condensation with 1-cyclopentyl-3-(trimethylsilyl)-2-propyn-1-one (II) affords the protected propargylic alcohol (III), which is then desilylated to compound (IV) by treatment with CsF in MeOH . Sonogashira coupling of propargylic alcohol (IV) with 4-bromo-2,6-diethylpyridine (V) in the presence of PdCl2(PPh3)2, CuI and (i-Pr)2NH in DMF at 90 °C provides the pyridylbutynol adduct (VI), which upon catalytic hydrogenation over Pd(OH)2 in EtOH affords the saturated alcohol (VII). Subsequent lactonization of (VII) in the presence of K2CO3 in MeOH gives rise to the perhydropyran-2,4-dione (VIIIa). Finally, racemic keto lactone (VIIIa) is submitted to reductive aldol condensation with 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (IX) in the presence of BH3·Me2NH in MeOH, and resolved by means of chiral HPLC .
In an alternative method, optically pure β-hydroxyacid (X) is activated as the corresponding imidazolide by means of CDI , and optionally, DMAP in MTBE or THF, followed by condensation with magnesium ethyl malonate (XIa) or with potassium ethyl malonate (XIb) in the presence of MgCl2 , to give, after acidic decarboxylation, the keto hydroxy ester (XII). Subsequent lactonization of hydroxy ester (XII) in the presence of K2CO3 in MeOH yields the chiral perhydropyran-2,4-dione derivative (VIIIb). Finally, (R)-keto lactone (VIIIb) , or its dibenzoyl-L-tartrate salt , is submitted to reductive aldol condensation with the triazolopyrimidine aldehyde (IX) in the presence of BH3·pyr in MeOH , THF/MeOH or 2-MeTHF/MTBE .
| 【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725. |
| 【2】 Li, H., Tatlock, J., Linton, A. et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2009, 52(5): 1255-8. |
| 【3】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800. |
| 【4】 Matthews, C.F., Scott, R.W., Tucker, J.L. (Pfizer, Inc.). CN 102336758, EP 1928878, JP 2007056022, US 2009023921, US 7807838, WO 2007023381. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 68336 | racemic 6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)dihydro-2H-pyran-2,4(3H)-dione | C21H29NO3 | 详情 | 详情 | |
| (VIIIb) | 68337 | (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)dihydro-2H-pyran-2,4(3H)-dione | C21H29NO3 | 详情 | 详情 | |
| (XIa) | 68340 | magnesium 3-ethoxy-3-oxopropanoate | C10H14MgO8 | 详情 | 详情 | |
| (XIb) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (I) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (II) | 68330 | 1-cyclopentyl-3-(trimethylsilyl)-2-propyn-1-one | C11H18OSi | 详情 | 详情 | |
| (III) | 68331 | 6-(2-cyclopentyl-2-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one | C18H28O4Si | 详情 | 详情 | |
| (IV) | 68332 | 6-(2-cyclopentyl-2-hydroxybut-3-yn-1-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one | C15H20O4 | 详情 | 详情 | |
| (V) | 68333 | 4-bromo-2,6-diethylpyridine | 877133-54-5 | C9H12BrN | 详情 | 详情 |
| (VI) | 68334 | 6-(2-cyclopentyl-4-(2,6-diethylpyridin-4-yl)-2-hydroxybut-3-yn-1-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one | C24H31NO4 | 详情 | 详情 | |
| (VII) | 68335 | 6-(2-cyclopentyl-4-(2,6-diethylpyridin-4-yl)-2-hydroxybutyl)-2,2-dimethyl-4H-1,3-dioxin-4-one | C24H35NO4 | 详情 | 详情 | |
| (IX) | 68338 | 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde | C8H8N4O | 详情 | 详情 | |
| (X) | 68339 | (R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid | C19H29NO3 | 详情 | 详情 | |
| (XII) | 68341 | (R)-ethyl 5-cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3-oxoheptanoate | C23H35NO4 | 详情 | 详情 |