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【结 构 式】 
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【分子编号】17247 【品名】furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride 【CA登记号】699-98-9 |
【 分 子 式 】C7H3NO3 【 分 子 量 】149.10576 【元素组成】C 56.39% H 2.03% N 9.39% O 32.19% |
合成路线1
该中间体在本合成路线中的序号：(II)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2
该中间体在本合成路线中的序号：(I)Addition of 4-tolylmagnesium bromide (II) to 2,3-pyridinedicarboxylic acid anhydride (I) afforded ketoacid (III). Subsequent condensation of (III) with diethyl bromomalonate (VII) in the presence of Et3N, followed by DBU-promoted cyclization produced the pyridine lactone (VI). In an alternative procedure, acid (III) was converted to acid chloride (IV) using SOCl2, and then condensed with diethyl hydroxymalonate (V) in the presence of NaH to give (VI). The tertiary alcohol group of (VI) was then dehydrated with HCl in AcOH to give (VIII). Acid chloride (IX), prepared by treatment of (VIII) with SOCl2, was coupled with 3,5-bis(trifluoromethyl)benzylamine (X) to furnish amide (XI). The tetrahydropyranyl-protected aminoalcohol (XIII) was obtained by reduction of nitrile (XII) with LiAlH4. Reaction of (XIII) with lactone (XI), followed by treatment with DBU, produced the 1,7-naphthyridine system (XIV). Acid-catalyzed deprotection of the tetrahydropyranyl group yielded alcohol (XV).
| 【1】 Tanaka, T.; Kawada, M.; Ishichi, Y.; Kamo, I.; Ishimaru, T.; Fujishima, A.; Ikeura, Y.; Natsugari, H.; Doi, T.; Kasahara, F.; Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists: Synthesis, antagonistic activity, and effects on bladder functions. J Med Chem 1999, 42, 19, 3982. |
| 【2】 Natsugari, H.; Ishimaru, T.; Doi, T.; Ikeura, Y.; Kimura, C. (Takeda Chemical Industries, Ltd.); Cyclic cpds., their production and use as tachykinin receptor antagonists. CA 2172421; EP 0733632; JP 1997263585; JP 1997263587; US 5786352 . |
| 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) | 17247 | furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride | 699-98-9 | C7H3NO3 | 详情 | 详情 |
| (II) | 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 |
| (III) | 35643 | 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid | C14H11NO3 | 详情 | 详情 | |
| (IV) | 35644 | 3-(4-methylbenzoyl)-2-pyridinecarbonyl chloride | C14H10ClNO2 | 详情 | 详情 | |
| (V) | 35645 | diethyl tartronate | C7H12O5 | 详情 | 详情 | |
| (VI) | 35646 | diethyl 5-hydroxy-5-(4-methylphenyl)-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridine-6,6-dicarboxylate | C21H21NO7 | 详情 | 详情 | |
| (VII) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (VIII) | 35648 | 5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxylic acid | C16H11NO4 | 详情 | 详情 | |
| (IX) | 35649 | 5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carbonyl chloride | C16H10ClNO3 | 详情 | 详情 | |
| (X) | 35650 | [3,5-bis(trifluoromethyl)phenyl]methanamine; 3,5-bis(trifluoromethyl)benzylamine | 85068-29-7 | C9H7F6N | 详情 | 详情 |
| (XI) | 35651 | N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamide | C25H16F6N2O3 | 详情 | 详情 | |
| (XII) | 35652 | (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C10H17NO2 | 详情 | 详情 | |
| (XIII) | 35653 | (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butylamine; (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C10H21NO2 | 详情 | 详情 | |
| (XIV) | 35654 | N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-7-[(3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide | C35H35F6N3O4 | 详情 | 详情 | |
| (XV) | 35655 | N-[3,5-bis(trifluoromethyl)benzyl]-7-[(3R)-4-hydroxy-3-methylbutyl]-5-(4-methylphenyl)-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide | C30H27F6N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Addition of the organozinc reagent (II) to the cyclic anhydride (I) produced keto acid (III). After activation of the carboxyl group of (III) with carbonyl diimidazole, condensation with the lithium enolate of tert-butyl acetate furnished keto ester (IV). This was subsequently cyclized to the cyclopentapyridine system (V) upon treatment with silica in CHCl3. Addition of 2,2-difluoro-1,3-benzodioxol-5-ylmagnesium bromide (VI) to the keto group of (V) gave carbinol (VII). After hydroxyl group acetylation, hydrogenation of the olefin and simultaneous hydrogenolysis of the O-benzyl groups of (VII) over Pd/C yielded (VIII). Further epimerization of the carboxylate group of (VIII) in the presence of potassium tert-butoxide afforded isomer (IX). After conversion of (IX) to the aryl triflate (X), palladium-catalyzed coupling of (X) with allylic alcohol (XI) produced (XII).
| 【1】 Hayama, T.; Ohtake, N.; Niiyama, K.; et al.; New cyclopentenopyridine derivatives. A potent, orally active, selective endothelin ETA receptor antagonist. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-78. |
| 【2】 Nishikibe, M.; Hayama, T.; Otake, N. (Banyu Pharmaceutical Co., Ltd.); Substd. 5-(2,2-difluoro-1,3-benzodioxol-5-yl) cyclopentenopyridine deriv.. EP 1049691; WO 9937639 . |
| 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) | 17247 | furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride | 699-98-9 | C7H3NO3 | 详情 | 详情 |
| (II) | 27599 | [2-(benzyloxy)-4-methoxyphenyl](chloro)zinc | C14H13ClO2Zn | 详情 | 详情 | |
| (III) | 43947 | 2-[2-(benzyloxy)-4-methoxybenzoyl]nicotinic acid | C21H17NO5 | 详情 | 详情 | |
| (IV) | 43948 | tert-butyl 3-[2-[2-(benzyloxy)-4-methoxybenzoyl]-3-pyridinyl]-3-oxopropanoate | C27H27NO6 | 详情 | 详情 | |
| (V) | 43949 | tert-butyl 7-[2-(benzyloxy)-4-methoxyphenyl]-5-oxo-5H-cyclopenta[b]pyridine-6-carboxylate | C27H25NO5 | 详情 | 详情 | |
| (VI) | 43950 | bromo(2,2-difluoro-1,3-benzodioxol-5-yl)magnesium | C7H3BrF2MgO2 | 详情 | 详情 | |
| (VII) | 43951 | tert-butyl 7-[2-(benzyloxy)-4-methoxyphenyl]-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-hydroxy-5H-cyclopenta[b]pyridine-6-carboxylate | C34H29F2NO7 | 详情 | 详情 | |
| (VIII) | 43952 | tert-butyl (5S,6S,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(2-hydroxy-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C27H25F2NO6 | 详情 | 详情 | |
| (IX) | 43953 | tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(2-hydroxy-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C27H25F2NO6 | 详情 | 详情 | |
| (X) | 43954 | tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(4-methoxy-2-[[(trifluoromethyl)sulfonyl]oxy]phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C28H24F5NO8S | 详情 | 详情 | |
| (XI) | 43956 | 2-methyl-2-propen-1-ol | 513-42-8 | C4H8O | 详情 | 详情 |
| (XII) | 43955 | tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-[2-(3-hydroxy-2-methylpropyl)-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C31H33F2NO6 | 详情 | 详情 |