|
【结 构 式】 
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【分子编号】37690 【品名】4-fluorophenylamine; 4-fluoroaniline 【CA登记号】371-40-4 |
【 分 子 式 】C6H6FN 【 分 子 量 】111.1187832 【元素组成】C 64.85% H 5.44% F 17.1% N 12.61% |
合成路线1
该中间体在本合成路线中的序号：(X)a) Condensation of the phenolic compound (I) with 7-benzyloxy-6-methoxyquinolinyl triflate (II) in refluxing 2,6-lutidine affords the quinolinyl ether (III), which is O-debenzylated by transfer hydrogenation with 1,4-cyclohexadiene and Pd/C in EtOH at 65 °C, producing the 7-hydroxyquinoline derivative (IV). Finally, the hydroxyquinoline (IV) is alkylated with N-(3-chloropropyl)morpholine hydrochloride (V) by means of K2CO3 in DMF at 90 °C .
b) Direct coupling of the phenol derivative (I) with 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (VI) in the presence of Pd(OAc)2, 2-(di-tert-butylphosphino)-1,1’-binaphthyl (DTBPB) and K3PO4 in anisole at 110 °C or NMP/toluene at 95 °C .
c) Acylation of the quinolinyloxyaniline intermediate (VII) with 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride (VIII) by means of K2CO3 in THF/H2O .
| 【1】 Bannen, L.C., Chan, D.S.-M., Chen, J. (Exelixis, Inc.). c-Met modulators and methods of use. EP 1673085, EP 2210607, EP 2213661, JP 2007506777, JP 2010235631, JP 2010235632, WO 2005030140. |
| 【2】 Deschamps, N.M., Martin, M.T., Monteith, M.J., Zhou, X. (GlaxoSmithKline Inc.). Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide. US 2010081805, WO 010036831. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (I) | 69100 | N-(3-fluoro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | C17H14F2N2O3 | 详情 | 详情 | |
| (VIII) | 69107 | 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride | C11H9ClFNO2 | 详情 | 详情 | |
| (IX) | 69108 | cyclopropane-1,1-dicarboxylic acid | C5H6O4 | 详情 | 详情 | |
| (X) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (XI) | 69109 | 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid | C11H10FNO3 | 详情 | 详情 | |
| (XII) | 17013 | 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene | 369-34-6 | C6H3F2NO2 | 详情 | 详情 |
| (XIII) | 67754 | 1-benzyloxy-2-fluoro-4-nitrobenzene;1-(benzyloxy)-2-fluoro-4-nitrobenzene | C13H10FNO3 | 详情 | 详情 | |
| (XIV) | 67755 | 4-benzyloxy-3-fluoroaniline | C13H12FNO | 详情 | 详情 | |
| (XV) | 69110 | N-(4-(benzyloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | C24H20F2N2O3 | 详情 | 详情 | |
| (XVI) | 69111 | 4-amino-2-fluorophenol;2-Fluoro-4-aminophenol | 399-96-2 | C6H6FNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Condensation of 2,4-dichoro-5-fluoroacetophenone (I) with diethyicarbonate (II) in the presence of sodium hydride gives ethyl 2,4-dichloro-5-fluorobenzoylacetate (III). The condensation of (III) with triethylorthoformate in reftuxing acetic anhydride yields ethyl 2-(2,4-dichloro-5-fluornbenzoyl)-3-ethoxyacrylate (IV), which is treated with p-fluoroaniline in methylene chloride to yield ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(p-fluoroanilino)acrylate (V). Cyclization of (V) with sodium hydride in tetrahydrofuran followed by hydrolysis yields 7-chloro-1-(p-fluorophenyl)-8 fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (VI). Condensation of (VI) with N-methylpiperazine in 1-methyl-2-pyrrolidinone followed by treatment with hydrochloric acid yields A-56619.
| 【1】 Clairbone, A.K.; Pihuleac, E.; Nordeen, C.; Fernandes, P.B.; Pernet, A.; Chu, D.T.W.; O'Donell, T.J.; A-56619 and A-56620: Synthesis and antibacterial activities of the novel aryl-fluoro-quinolones and their analogs. 24th Intersci Conf Antimicrob Agents Chemother (Oct 8-10, Washington, D.C) 1984, Abs 72. |
| 【2】 Granneman, G.R.; Chu, D.T.W.; Fernandes, P.B.; Abbott-56619. Drugs Fut 1985, 10, 7, 543. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 | |
| 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 | |
| (I) | 24574 | 1-(2,4-dichloro-5-fluorophenyl)-1-ethanone | 704-10-9 | C8H5Cl2FO | 详情 | 详情 |
| (II) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (III) | 22096 | ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate | C11H9Cl2FO3 | 详情 | 详情 | |
| (IV) | 22098 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate | C14H13Cl2FO4 | 详情 | 详情 | |
| (V) | 24578 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-(4-fluoroanilino)-2-propenoate | C18H13Cl2F2NO3 | 详情 | 详情 | |
| (VI) | 24579 | 7-chloro-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C16H8ClF2NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The silylation of butane-2,3-dione(I) with TMSCl and TEA in hot DMF gives the silylated enol (II), which is cyclized with dimethyl acetylenedicarboxylate (III) in refluxing toluene to yield 4,5-bis(trimethylsilyloxy)-3,6-dihydrophthalic acid dimethyl ester (IV). The condensation of (IV) with 4-fluoroaniline (V), with simultaneous aromatization in refluxing acetic acid affords 4,5-bis(4-fluorophenylamino)phthalic acid dimethyl ester (VI), which is hydrolyzed with LiOH in methanol and anhydrized with acetic anhydride in toluene giving the corresponding phthalic anhydride (VII). Finally this compound is treated with ammonium formate at 140-50 C to furnish the target phthalimide.
| 【1】 Traxler, P.; Lydon, N.; Recent advances in protein tyrosine kinase inhibitors. Drugs Fut 1995, 20, 12, 1261. |
| 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) | 37053 | biacetyl | 431-03-8 | C4H6O2 | 详情 | 详情 |
| (II) | 41193 | 2,2,7,7-tetramethyl-4,5-dimethylene-3,6-dioxa-2,7-disilaoctane; 1-methylene-2-[(trimethylsilyl)oxy]-2-propenyl trimethylsilyl ether | C10H22O2Si2 | 详情 | 详情 | |
| (III) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (IV) | 41194 | dimethyl 4,5-bis[(trimethylsilyl)oxy]-1,4-cyclohexadiene-1,2-dicarboxylate | C16H28O6Si2 | 详情 | 详情 | |
| (V) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (VI) | 41197 | dimethyl 4,5-bis(4-fluoroanilino)phthalate | C22H18F2N2O4 | 详情 | 详情 | |
| (VII) | 41198 | 5,6-bis(4-fluoroanilino)-2-benzofuran-1,3-dione | C20H12F2N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.
| 【1】 Vaccaro, W.D.; Sher, R.; Davis, H.R. Jr.; 2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 phenyl ring. Bioorg Med Chem 1998, 6, 9, 1429. |
| 【2】 Rosenblum, S.B.; Dugar, S.; Burnett, D.A.; Clader, J.W.; McKittrick, B.A. (Schering Corp.); Hydroxy-substd. azetidinone cpds. useful as hypocholesterolemic agents. EP 0720599; JP 1996509989; US 5631365; WO 9508532 . |
| 【3】 Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Ezetimibe. Drugs Fut 2000, 25, 7, 679. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| trans-(XVI) | 20652 | (rac)-methyl 3-[(2S*,3R*)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoate | C26H24FNO4 | 详情 | 详情 | |
| trans-(XVII) | 20653 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propionic acid | C25H22FNO4 | 详情 | 详情 | |
| trans-(XVIII) | 20654 | 3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propanoyl chloride | C25H21ClFNO3 | 详情 | 详情 | |
| (II) | 37689 | N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-4-fluoroaniline; N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-N-(4-fluorophenyl)amine | C20H16FNO | 详情 | 详情 | |
| (XI) | 20657 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-azetidinone | C31H27F2NO3 | 详情 | 详情 | |
| (XII) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (XIII) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (XIV) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (XV) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
| (XIX) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XX) | 20656 | (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone | C31H25F2NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 13C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 13C-labeled SCH-58235.
| 【1】 Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm 2002, 45, 2, 145. |
| 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) | 53476 | 1-(4-fluorophenyl)-5-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,5-pentanedione | n/a | C20H18FNO4 | 详情 | 详情 |
| (II) | 53477 | (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one | n/a | C20H20FNO4 | 详情 | 详情 |
| (III) | 53478 | n/a | C13H10FNO | 详情 | 详情 | |
| (III) | 53481 | 4-{[(4-fluorophenyl)imino]methyl}phenol | 3382-63-6 | C13H10FNO | 详情 | 详情 |
| (IV) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (V) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (V) | 53479 | n/a | C7H6O2 | 详情 | 详情 | |
| (VI) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (VI) | 53480 | n/a | C37H40F2N2O7SSi | 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 enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 14C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 14C-labeled SCH-58235.
| 【1】 Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm 2002, 45, 2, 145. |
| 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) | 53476 | 1-(4-fluorophenyl)-5-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,5-pentanedione | n/a | C20H18FNO4 | 详情 | 详情 |
| (II) | 53477 | (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one | n/a | C20H20FNO4 | 详情 | 详情 |
| (III) | 53481 | 4-{[(4-fluorophenyl)imino]methyl}phenol | 3382-63-6 | C13H10FNO | 详情 | 详情 |
| (III) | 53484 | n/a | C13H10FNO | 详情 | 详情 | |
| (IV) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (V) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (V) | 53483 | 4-hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VI) | 53482 | (1S,4R,5S)-5-(4-fluoroanilino)-1-(4-fluorophenyl)-4-{[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]carbonyl}-5-{4-[(trimethylsilyl)oxy]phenyl}pentyl methanesulfonate | n/a | C37H40F2N2O7SSi | 详情 | 详情 |
| (VI) | 53485 | n/a | C37H40F2N2O7SSi | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XI)Chlorination of 5,6-dimethyl-2,4-dihydroxypyrimidine (VIII) using phosphorus oxychloride in the presence of N,N-dimethylaniline provided dichloropyrimidine (IX). The 4-chloro group of (IX) was then selectively displaced with tetrahydroisoquinoline (IV) to afford adduct (X). The title compound was then obtained by condensation of the 2-chloropyrimidine (X) with 4-fluoroaniline (XI), followed by conversion to the corresponding hydrochloride salt
| 【1】 Lee, J.W.; Chae, J.S.; Kim, C.S.; Kim, J.K.; Lim, D.S.; Shon, M.K.; Choi, Y.S.; Lee, S.H. (Yuhan Corp.); Novel pyrimidine derivs. and processes for the preparation thereof. EP 0775120; JP 1997509188; US 5750531; WO 9605177 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 54971 | 1-methyl-1,2,3,4-tetrahydroisoquinoline | C10H13N | 详情 | 详情 | |
| (VIII) | 54974 | 2,4-Dihydroxy-5,6-dimethylpyrimidine; 5,6-Dimethyl-2,4-pyrimidinediol; 5,6-Dimethyluracil | 26305-13-5 | C6H8N2O2 | 详情 | 详情 |
| (IX) | 54975 | 2,4-dichloro-5,6-dimethylpyrimidine | C6H6Cl2N2 | 详情 | 详情 | |
| (X) | 54976 | 2-(2-chloro-5,6-dimethyl-4-pyrimidinyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline | C16H18ClN3 | 详情 | 详情 | |
| (XI) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XI)In an alternative procedure, 4-fluoroaniline (XI) was condensed with cyanamide under acidic conditions to afford the fluorophenyl guanidine (XII). Cyclization of guanidine (XII) with ethyl 2-methylacetoacetate (XIII) in hot DMF produced pyrimidine (XIV). After chlorination of (XIV) with POCl3, the resultant chloropyrimidine (XV) was condensed with tetrahydroisoquinoline (IV) in the presence of either KOAc or Et3N to furnish the title diaminopyrimidine.
| 【1】 Lee, Y.N.; Hong, Y.W.; Kim, H.B. (Yuhan Corp.); Process for preparation of pyrmidine derivs.. US 5990311; WO 9742186 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 54971 | 1-methyl-1,2,3,4-tetrahydroisoquinoline | C10H13N | 详情 | 详情 | |
| (XI) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (XII) | 54977 | N-(4-fluorophenyl)guanidine | C7H8FN3 | 详情 | 详情 | |
| (XIII) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (XIV) | 54978 | 2-(4-fluoroanilino)-5,6-dimethyl-4-pyrimidinol | C12H12FN3O | 详情 | 详情 | |
| (XV) | 54979 | N-(4-chloro-5,6-dimethyl-2-pyrimidinyl)-N-(4-fluorophenyl)amine; 4-chloro-N-(4-fluorophenyl)-5,6-dimethyl-2-pyrimidinamine | C12H11ClFN3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Condensation between 1-phenyl-1,4-pentanedione (I) and 4-fluoroaniline (II) under Paal-Knorr reaction conditions provides the pyrrole derivative (III). This is then subjected to Mannich reaction with thiomorpholine (IV) and formaldehyde to furnish the target thiomorpholimomethyl pyrrole.
| 【1】 Biava, M.; Porretta, G.C.; Deidda, D.; Pompei, R.; Tafi, A.; Manetti, F.; Importance of the thiomorpholine introduction in new pyrrole derivatives as antimycobacterial agents analogues of BM 212. Bioorg Med Chem 2003, 11, 4, 515. |
合成路线10
该中间体在本合成路线中的序号：(IV)The condensation of 2-chloropyridine (I) with ethyl trifluoroacetate (II) by means of LDA in THF gives 2-chloro-3-(trifluoroacetyl)pyridine (III), which is condensed with 4-fluoroaniline (IV) by means of refluxing aqueous acetic acid to yield the diarylamine (V). The cyclization of (V) by means of concentrated H2SO4 affords 7-fluoro-5-hydroxy-5-(trifluoromethyl)-5,10-dihydro-benzo[b]-1,8-naphthyridine (VI), which is dehydrated in THF to give 7-fluoro-5-(trifluoromethyl)benzo[b]-1,8-naphthyridine (VII). The condensation of (VII) with cyclopropylmethanol (VIII) by means of anhydrous HCl in dichloromethane yields the 5-(cyclopropylmethoxy)-7-fluoro-5-(trifluoromethyl)-5,10-dihydro-benzo[b]-1,8-naphthyridine (IX), which is oxidated by means of MCPBA in dichloromethane to afford the N-oxide (X) (1, 2). Finally, this racemic compound is submitted to chiral HPLC to obtain the target enantiomer (1).
| 【1】 Novel 5,10-dihydrobenzo[B][1,8]napthyridine N-oxides as non-nucleoside reverse transcriptase inhibitors of HIV-1 with high potency against clinically relevant mutants variants. 226th ACS Natl Meet (Sept 7 2003, New York) 2003, Abst MEDI 129. |
| 【2】 Patel, M.; Rodgers, J.D.; Wang, H.; Johnson, B.L. (Bristol-Myers Squibb Co.); Tricyclic cpds. useful as HIV reverse transcriptase inhibitors. JP 2003512375; US 6593337; WO 0129037 . |
| 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) | 17503 | 2-chloropyridine | 109-09-1 | C5H4ClN | 详情 | 详情 |
| (II) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (III) | 64759 | 1-(2-chloro-3-pyridinyl)-2,2,2-trifluoro-1-ethanone | C7H3ClF3NO | 详情 | 详情 | |
| (IV) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (V) | 64760 | 2,2,2-trifluoro-1-[2-(4-fluoroanilino)-3-pyridinyl]-1-ethanone | C13H8F4N2O | 详情 | 详情 | |
| (VI) | 64761 | 7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b][1,8]naphthyridin-5-ol | C13H8F4N2O | 详情 | 详情 | |
| (VII) | 64762 | 7-fluoro-5-(trifluoromethyl)benzo[b][1,8]naphthyridine | C13H6F4N2 | 详情 | 详情 | |
| (VIII) | 64763 | cyclopropylmethanol | C4H8O | 详情 | 详情 | |
| (IX) | 64764 | 5-(cyclopropylmethoxy)-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine; cyclopropylmethyl 7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b][1,8]naphthyridin-5-yl ether | C17H14F4N2O | 详情 | 详情 | |
| (X) | 64765 | 5-(cyclopropylmethoxy)-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b][1,8]naphthyridin-1-ium-1-olate | C17H14F4N2O2 | 详情 | 详情 |