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【结 构 式】 
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【分子编号】20360 【品名】methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline 【CA登记号】93-61-8 |
【 分 子 式 】C8H9NO 【 分 子 量 】135.1656 【元素组成】C 71.09% H 6.71% N 10.36% O 11.84% |
合成路线1
该中间体在本合成路线中的序号：(V)By cyclocondensation of 3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde (I), isopropyl 3-aminocrotonate (II) and methyl 4-fluoroacetylacetate (III) by heating at 110 C. The starting products are prepared as follows: Aldehyde (I) is obtained by reaction of 1-chloro-4-fluoro-3-(trifluoromethyl)benzene (IV) with N-methyl-N-phenylformamide (V) by means of butyllithium in TNF. Aminocrotonate (II) is obtained by reaction of isopropyl acetoacetate (VI) with dry ammonia in methanol. Finally, the acylation of 2,2-dimethyl-1,3-dioxane-4,6-dione (VII) with fluoroacetyl chloride (VIII) by means of pyridine in dichloromethane gives 5-(fluoroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (IX), which is then treated with refluxing methanol to give 4-fluoroacetylacetate (III).
| 【1】 Baxter, A.J.G.; Dixon, J.; Gould, K.J.; McInally, T.; Tinker, A.C. (Celltech Group plc); Pharmaceutically active dihydropyridines. EP 0125803 . |
| 【2】 Baxter, A.J.G.; Dixon, J.; Gould, K.J.; Tinker, A.C. (Celltech Group plc); Dihydropyridine derivs.. EP 0174131; ES 8800154; ES 8801632; JP 1986065867 . |
| 【3】 Prous, J.; Castaner, J.; FPL-62129XX. Drugs Fut 1989, 14, 2, 121. |
| 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) | 20356 | 3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde | C8H3ClF4O | 详情 | 详情 | |
| (II) | 13331 | isopropyl (E)-3-amino-2-butenoate | 143093-33-8 | C7H13NO2 | 详情 | 详情 |
| (III) | 20358 | methyl 4-fluoro-3-oxobutanoate | C5H7FO3 | 详情 | 详情 | |
| (IV) | 20359 | 1-chloro-4-fluoro-2-(trifluoromethyl)benzene | C7H3ClF4 | 详情 | 详情 | |
| (V) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (VI) | 13332 | isopropyl 3-oxobutanoate; Isopropyl acetoacetate | 542-08-5 | C7H12O3 | 详情 | 详情 |
| (VII) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (VIII) | 20363 | 2-fluoroacetyl chloride | 359-06-8 | C2H2ClFO | 详情 | 详情 |
| (IX) | 20364 | 5-(2-fluoroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione | C8H9FO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)2) The condensation of 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III) with N-methylformanilide (XII) by means of POCl3 in hot dichloromethane gives the carbaldehyde (XIII), which is cyclized with 3-chloro-3-methyl-1-butyne (XIV) by means of ZnCl2 /K2CO3 in hot 2-butanone/DMF, yielding the benzodipyran-carbaldehyde (XV). The enantioselective reaction of (XV) with 2(E)-butene and the chiral borane (+)-(E)-crotyldiisopinocamphenylborane (XVI) affords the single (R, R)-enatiomer (XVII). The selective silylation of (XVII) with TBDMS-Cl as usual gives the monosilyl ether (XVIII), which is cyclized by means of mercuric acetate and NaBH4 in THF, yielding the silylated (10R,11R,12R)-benzotripyran (XIX). The desilylation of (XIX) with tetrabutylammonium fluoride in THF gives the (10R,11S,12R)-benzotripyran (XX) (calanolide B), which is converted into calanolide A by inversion of the C-12 OH-group carried out with a modified Mitsunobu reaction with dimethyl azodicarboxylate (DEAD)/trimethylphosphine/chloroacetic acid in toluene/THF, followed by treatment with NH4OH in methanol.
| 【1】 Tagliaferri, F.; Deshpande, P.P.; Yan, S.; Victory, S.F.; Baker, D.C.; Synthesis of optically active calanoides A and B. J Org Chem 1995, 60, 10, 2964. |
| 【2】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235. |
| 【3】 Tagliaferri, F.; Yan, S.; Deshpande, P.P.; Baker, D.C.; Victory, S.F. (University of Tennessee, Knoxville); Synthesis of optically active calanolides A and B . US 5608085; WO 9626934 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17343 | 2-Butene-cis; (Z)-2-butene | 590-18-1 | C4H8 | 详情 | 详情 | |
| (III) | 22405 | 5,7-dihydroxy-4-propyl-2H-chromen-2-one | C12H12O4 | 详情 | 详情 | |
| (XII) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (XIII) | 22415 | 5,7-dihydroxy-2-oxo-4-propyl-2H-chromene-8-carbaldehyde | C13H12O5 | 详情 | 详情 | |
| (XIV) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (XV) | 22417 | 5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2H,8H-pyrano[2,3-f]chromene-6-carbaldehyde | C18H18O5 | 详情 | 详情 | |
| (XVI) | 22418 | (E)-2-butenyl[bis(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)]borane | C24H41B | 详情 | 详情 | |
| (XVII) | 22419 | 5-hydroxy-6-[(1R,2R)-1-hydroxy-2-methyl-3-butenyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C22H26O5 | 详情 | 详情 | |
| (XVIII) | 22420 | 6-((1R,2R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-3-butenyl)-5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C28H40O5Si | 详情 | 详情 | |
| (XIX) | 22421 | (10R,11R,12R)-12-[[tert-butyl(dimethyl)silyl]oxy]-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C28H40O5Si | 详情 | 详情 | |
| (XX) | 22413 | (10R,11S,12R)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C22H26O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The cyclization of 5-methoxy-1H-indole (I) with hexane-2,6-dione (II) by means of BF3 ethearate in refluxing dioxane gives 6-methoxy-1,4-dimethylcarbazole (III), which is formylated with N-methylformanilide (IV) and POCl3 in hot o-dichlorobenzene yielding the 3-formyl derivative (V). The condensation of (V) with 2-aminoacetaldehyde diethylacetal (VI) by heating at 100 C affords the expected imino derivative (VII), which is cyclized by acid (HCl) hydrolysis of the acetal group and cyclization of the resulting aldehyde by means of NaOH in water to the 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (VIII). The oxidation of (VIII) with m-chloroperbenzoic acid (MCPBA) in acetone gives the correponding N-oxide (IX), which is treated with BBr3 in dichloromethane yielding 9-hydroxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (X). Finally, this compound is treated with 1-bromo-3-methoxy-2-propanone in DMF to afford the desired quaternary salt.
| 【1】 Liu, Q.-R.; et al.; Aust J Chem 1967, 20, 2715. |
| 【2】 Harada, N.; et al.; Synthesis and antitumor activity of quaternary salts of 2-(2'-oxoalkoxy)-9-hydroxyellipticines. Chem Pharm Bull 1997, 45, 1, 134. |
| 【3】 Guthrie, R.W.; et al.; Ellipticine derivatives. J Med Chem 1975, 18, 7, 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) | 25902 | 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole | 1006-94-6 | C9H9NO | 详情 | 详情 |
| (II) | 24848 | acetonyl acetone;1,2-Diacetylethane;a,b-Diacetylethane;2,5-Diketohexane;Diacetonyl;Acetonylacetone;2,5-Dioxohexane;2,5-hexanedione | 110-13-4 | C6H10O2 | 详情 | 详情 |
| (III) | 19938 | 5,8-dimethyl-9H-carbazol-3-yl methyl ether; 6-methoxy-1,4-dimethyl-9H-carbazole | C15H15NO | 详情 | 详情 | |
| (IV) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (V) | 27052 | 6-methoxy-1,4-dimethyl-9H-carbazole-3-carbaldehyde | C16H15NO2 | 详情 | 详情 | |
| (VI) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
| (VII) | 27053 | 1-ethoxy-2-[[(Z)-(6-methoxy-1,4-dimethyl-9H-carbazol-3-yl)methylidene]amino]-1-ethanol | C20H24N2O3 | 详情 | 详情 | |
| (VIII) | 27054 | 9-methoxy-1,4,5,11-tetramethyl-6H-pyrido[4,3-b]carbazole | C20H20N2O | 详情 | 详情 | |
| (IX) | 27055 | 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazol-2-ium-2-olate | C18H16N2O2 | 详情 | 详情 | |
| (X) | 27056 | 9-hydroxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazol-2-ium-2-olate | C17H14N2O2 | 详情 | 详情 | |
| (XI) | 27057 | 1-bromo-3-methoxyacetone | C4H7BrO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)1-Methoxynaphthalene (I) was lithiated with n-butyllithium and subsequently treated with N-methylformanilide (II) to give the 2-naphthaldehyde (III). The Knoevenagel condensation of (III) with the rhodanineacetic acid (IV) in the presence of NaOAc in AcOH provided the target 5-(alkylidene)thiazolidine.
| 【1】 Fresneau, P.; Cussac, M.; Morand, J.M.; Szymonski, B.; Tranqui, D.; Leclerc, G.; Synthesis, activity, and molecular modeling of new 2,4-dioxo-5-(naphthylmethylene)-3-thiazolidineacetic acids and 2-thioxo analogues as potent aldose reductase inhibitors. J Med Chem 1998, 41, 24, 4706. |
| 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) | 21807 | methyl 1-naphthyl ether; 1-methoxynaphthalene | 2216-69-5 | C11H10O | 详情 | 详情 |
| (II) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (III) | 21809 | 1-methoxy-2-naphthaldehyde | C12H10O2 | 详情 | 详情 | |
| (IV) | 21810 | 2-(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetic acid; 3-Carboxmethyl rhadanine; Rhodanine-N-acetic acid | 5718-83-2 | C5H5NO3S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXXIX)In a further method, the acetylide resulting from N,N-dimethyl propargylamine (XXXVIII) and either BuLi or ethylmagnesium chloride was formylated by means of N-methyl formanilide (XXXIX), producing the unstable acetylenic aldehyde (XL), which was immediately subjected to dipolar cycloaddition with sodium azide to furnish 4-(dimethylaminomethyl)-5-formyl-1,2,3-triazole (XLI). The title compound was then obtained by reductive condensation of morpholine (XVIII) with aldehyde (XLI) in the presence of sodium triacetoxyborohydride.
| 【1】 Wang, J.; Crocker, L.; Cai, D. (Merck & Co., Inc.); Polymorphic form of a tachykinin receptor antagonist. WO 0132656 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 18293 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine | 171482-05-6 | C20H18F7NO2 | 详情 | 详情 |
| (XXXVIII) | 53305 | 1-Dimethylamino-2-propyne; N,N-Dimethylpropargylamine | 7223-38-3 | C5H9N | 详情 | 详情 |
| (XXXIX) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (XL) | 53304 | 4-(dimethylamino)-2-butynal | n/a | C6H9NO | 详情 | 详情 |
| (XLI) | 53306 | 5-[(dimethylamino)methyl]-1H-1,2,3-triazole-4-carbaldehyde | n/a | C6H10N4O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXXII)Alkylation of 4’-hydroxy-3’-methoxyacetophenone (XVII) with benzyl bromide by means of K2CO3 in DMF gives benzyl ether (XVIII), which is reacted with fuming HNO3 and concentrated H2SO4 in cold CH2Cl2 to afford 4’-benzyloxy-5’-methoxy-2’-nitroacetophenone (XIX). After reduction of the nitro group of compound (XIX) using iron powder and ammonium formate in refluxing H2O/toluene, the resulting 2-aminoacetophenone derivative (XX) cyclizes with ethyl formate (XXI) in the presence of NaOEt in DME, providing 7-benzyloxy-6-methoxy-4-quinolinol (XXII). Finally, quinolinol (XXII) is treated with trifluoromethanesulfonyl chloride in the presence of DMAP and 2,6-lutidine in cold CH2Cl2 .
| 【1】 Deschamps, N.M., Martin, M.T., Monteith, M.J., Zhou, X. (GlaxoSmithKline Inc.). Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide. US 2010081805, WO 010036831. |
| 【2】 Wilson, J., Zuberi, S., Naganathan, S., Goldman, E., Kanter, J. (Exelixis, Inc.). Methods of preparing quinoline derivatives. WO 2010056960. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIVa) | 22605 | 4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone | 58113-30-7 | C12H15ClO3 | 详情 | 详情 |
| (XXIVb) | 69115 | 1-(4-(3-bromopropoxy)-3-methoxyphenyl)ethanone | C12H15BrO3 | 详情 | 详情 | |
| (XXVa) | 69117 | 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone | C12H14ClNO5 | 详情 | 详情 | |
| (XXVb) | 69116 | 1-(4-(3-bromopropoxy)-5-methoxy-2-nitrophenyl)ethanone | C12H14BrNO5 | 详情 | 详情 | |
| (VI) | 69105 | 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline;4-(3-((4-chloro-6-methoxyquinolin-7-yl)oxy)propyl)morpholine | C17H21ClN2O3 | 详情 | 详情 | |
| (XVII) | 22604 | 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone | 498-02-2 | C9H10O3 | 详情 | 详情 |
| (XXI) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (XXIII) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (XXVI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XXVII) | 69118 | 1-(5-methoxy-4-(3-morpholinopropoxy)-2-nitrophenyl)ethanone | C16H22N2O6 | 详情 | 详情 | |
| (XXVIII) | 56891 | 1,3-propanediol cyclic sulfate;1,3,2-dioxathiane 2,2-dioxide;1,3-Propylene sulfate | 1073-05-8 | C3H6O4S | 详情 | 详情 |
| (XXIX) | 69119 | 4’-(morpholinopropoxy)acetophenone;1-(3-methoxy-4-(3-morpholinopropoxy)phenyl)ethanone | C16H23NO4 | 详情 | 详情 | |
| (XXX) | 69120 | 1-(2-amino-5-methoxy-4-(3-morpholinopropoxy)phenyl)ethanone | C16H24N2O4 | 详情 | 详情 | |
| (XXXI) | 69121 | 6-methoxy-7-(3-morpholinopropoxy)quinolin-4-ol | C17H22N2O4 | 详情 | 详情 | |
| (XXXII) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |