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【结 构 式】 
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【分子编号】17426 【品名】N-methoxy-N-methylacetamide 【CA登记号】78191-00-1 |
【 分 子 式 】C4H9NO2 【 分 子 量 】103.121 【元素组成】C 46.59% H 8.8% N 13.58% O 31.03% |
合成路线1
该中间体在本合成路线中的序号：(XII)1NK-104 in its open and lactone forms has been synthesized by several different ways: 1) Lactone form: The reaction of 1(R),7,7-trimethylbicyclo[2.2.1]heptan-2-one (I) with 1-naphthylmagnesium bromide (II) gives the tertiary alcohol (III), which by reaction with SOCl2 and then with NaHCO3 yields 2-(1-naphthyl)-1(R),7,7-trimethylbicyclo[2.2.1]heptene (IV). Hydroboration of (IV) with BH3 followed by oxidation with H2O2 affords 4(S),7,7-trimethyl-3exo-(1-naphthyl)bicyclo[2.2.1]heptan-2exo-ol (V), which is submitted to transesterification with methyl acetoacetate (VI) and dimethyl-aminopyridine (DMAP) to give the corresponding ester (VII). The condensation of (VII) with N-methoxy-N-methyl-3-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-2(E)-propenamide (VIII) by means of NaH yields the corresponding chiral 3,5-dioxoheptenoic acid ester (IX), which is selectively reduced first with diisobutylaluminum hy-dride acid (DIBAL) and then with diethylmethoxyborane and sodium borohydride affording the 3(R),5(S)-dihydroxyheptenoic ester (X). Finally, this compound is saponified with NaOH and treated with acetic acid/sodium acetate. The intermediate amide (VIII) is obtained by condensation of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde (XI) with N-methoxy-N-methylacetamide (XII) by means of butyllithium to the hydroxy propionamide (XIII), which is then dehydrated with methanesulfonyl chloride and triethylamine in the usual way).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Guntor, B.; Kaiyama, T.; Arai, K.; Minami, T.; Suzuki, M.; Kobara, Y.; Sakota, R. (Nissan Chemical Industry, Ltd.; Sagami Chemical Research Center); Optically active ß,*-diketo acid esters and their reduced forms. JP 1994025092 . |
| 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) | 17415 | (1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one | 464-49-3 | C10H16O | 详情 | 详情 |
| (II) | 17416 | bromo(1-naphthyl)magnesium | C10H7BrMg | 详情 | 详情 | |
| (III) | 17417 | (1R,2S,4R)-1,7,7-trimethyl-2-(1-naphthyl)bicyclo[2.2.1]heptan-2-ol | C20H24O | 详情 | 详情 | |
| (IV) | 17418 | 1-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]naphthalene | C20H22 | 详情 | 详情 | |
| (V) | 17419 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]heptan-2-ol | C20H24O | 详情 | 详情 | |
| (VI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VII) | 17421 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl 3-oxobutanoate | C24H28O3 | 详情 | 详情 | |
| (VIII) | 17422 | (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-N-methoxy-N-methyl-2-propenamide | C23H21FN2O2 | 详情 | 详情 | |
| (IX) | 17423 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dioxo-6-heptenoate | C45H42FNO4 | 详情 | 详情 | |
| (X) | 17424 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate | C45H46FNO4 | 详情 | 详情 | |
| (XI) | 17425 | 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde | 121660-37-5 | C19H14FNO | 详情 | 详情 |
| (XII) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (XIII) | 17427 | 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3-hydroxy-N-methoxy-N-methylpropanamide | C23H23FN2O3 | 详情 | 详情 | |
| (XLVI) | 64696 | (4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one | C25H22FNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with morpholine-4-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.
| 【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669. |
| 【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 . |
| 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) | 51550 | 3-Bromo-4-fluorobenzaldehyde | 77771-02-9 | C7H4BrFO | 详情 | 详情 |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 53185 | 4-(3-bromo-4-fluorobenzyl)morpholine | n/a | C11H13BrFNO | 详情 | 详情 |
| (IV) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (V) | 53186 | 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone | n/a | C13H16FNO2 | 详情 | 详情 |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 53187 | ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate | n/a | C16H20FNO4 | 详情 | 详情 |
| (VIII) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (IX) | 53188 | ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate | n/a | C19H24FNO5 | 详情 | 详情 |
| (X) | 35977 | 4-morpholinylamine; 4-morpholinamine | 4319-49-7 | C4H10N2O | 详情 | 详情 |
| (XI) | 53191 | ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-(4-morpholinylamino)-2-propenoate | n/a | C21H28FN3O5 | 详情 | 详情 |
| (XII) | 53192 | ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C21H27N3O5 | 详情 | 详情 |
| (XIII) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 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 reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with piperazine-1-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.
| 【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669. |
| 【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 . |
| 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) | 51550 | 3-Bromo-4-fluorobenzaldehyde | 77771-02-9 | C7H4BrFO | 详情 | 详情 |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 53185 | 4-(3-bromo-4-fluorobenzyl)morpholine | n/a | C11H13BrFNO | 详情 | 详情 |
| (IV) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (V) | 53186 | 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone | n/a | C13H16FNO2 | 详情 | 详情 |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 53187 | ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate | n/a | C16H20FNO4 | 详情 | 详情 |
| (VIII) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (IX) | 53188 | ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate | n/a | C19H24FNO5 | 详情 | 详情 |
| (X) | 40655 | 4-Methyl-1-piperazinamine; 1-Amino-4-methylpiperazine; 4-Methyl-1-piperazinylamine | 6928-85-4 | C5H13N3 | 详情 | 详情 |
| (XI) | 53189 | ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-[(4-methyl-1-piperazinyl)amino]-2-propenoate | n/a | C22H31FN4O4 | 详情 | 详情 |
| (XII) | 53190 | ethyl 1-(4-methyl-1-piperazinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C22H30N4O4 | 详情 | 详情 |
| (XIII) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXII)Reaction of 2-acetyl-4-methylpyridine (XVI) with (trimethylsilyl)trifluoromethane (XVII) in the presence of NaOAc in DMSO produces the silylated tertiary alcohol (XVIII), which is further desilylated to alcohol (XIX) by treatment with k2CO3 in MeOH. Treatment of alcohol (XIX) with MsCl and NaH in THF, followed by substitution of the resultant mesylate (XX) with Me3Al in cyclohexane/hexane provides 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine (XXI). Metalation of pyridine (XXI) with LDA (prepared from n-hexyllithium and didiisopropylamine in hexane) in THF, followed by condensation with Weinreb amide (XXII) at –15 °C, and subsequent quenching with H2SO4 in toluene leads to ketone (XXIII). Cyclization of crude ketone (XXIII) with thiourea (XXIV) in the presence of NBS in toluene/EtOH gives the hydrobromide salt 2-aminothiazole (XXV), which is finally converted to the free base intermediate (X) using pyridine in THF . Alternatively, intermediate (XXI) can be obtained by lithiation of 2,4-lutidine (XXVI) with BuLi in methyltetrahydrofuran at –30 °C, followed by condensation with diethyl carbonate (XXVII) in the same solvent, and subsequent dialkylation with MeI to produce the 2-pyridylisobutyrate (XXVIII). Finally, ethyl ester (XXVIII) is hydrolyzed with NaOH in EtOH at 78 °C, and the obtained sodium carboxylate (XXIX) subsequently fluorinated by using SF4 and HF .
| 【1】 Erb, B., Gallou, I.S., kleinbeck, F.k. (Novartis AG). Synthesis of 2-carboxamide cycloamino urea derivatives. US 2013331579; kR 2014009432; EP 2681192; JP 2014511387; CN 103402982; WO 2012117071. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 67537 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine | C13H14F3N3S | 详情 | 详情 | |
| (XVI) | 67540 | 2-acetyl-4-methylpyridine；1-(4-Methylpyridin-2-yl)ethanone | 59576-26-0 | C8H9NO | 详情 | 详情 |
| (XVII) | 67541 | trimethyl(trifluoromethyl)silane | C4H9F3Si | 详情 | 详情 | |
| (XVIII) | 67542 | 4-methyl-2-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propan-2-yl)pyridine | C12H18F3NOSi | 详情 | 详情 | |
| (XIX) | 67543 | 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol | C9H10F3NO | 详情 | 详情 | |
| (XX) | 67544 | 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-yl methanesulfonate | C10H12F3NO3S | 详情 | 详情 | |
| (XXI) | 67545 | 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine | C10H12F3N | 详情 | 详情 | |
| (XXII) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (XXIII) | 67546 | 1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)propan-2-one | C12H14F3NO | 详情 | 详情 | |
| (XXIV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (XXV) | 67547 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine hydrobromide | C13H14F3N3S.HBr | 详情 | 详情 | |
| (XXVI) | 67548 | 2,4-lutidine | 108-47-4 | C7H9N | 详情 | 详情 |
| (XXVII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (XXVIII) | 67549 | ethyl 2-methyl-2-(4-methylpyridin-2-yl)propanoate | C12H17NO2 | 详情 | 详情 | |
| (XXIX) | 67550 | sodium 2-methyl-2-(4-methylpyridin-2-yl)propanoate | C10H12NaNO2 | 详情 | 详情 |