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【结 构 式】 
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【分子编号】14588 【品名】Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate 【CA登记号】383-63-1 |
【 分 子 式 】C4H5F3O2 【 分 子 量 】142.0777096 【元素组成】C 33.82% H 3.55% F 40.12% O 22.52% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of 1,3-dibromobenzene (I) with trimethylsilyl chloride (II) by means of Mg in ethyl ether gives 3-(trimethylsilyl)bromobenzene (III), which is then condensed with ethyl trifluoroacetate (IV) by means of butyllithium in ethyl ether - hexane.
| 【1】 Schirlin, D.; Collard, J.-N.; Hornsperger, J.-M. (Merrell Pharmaceuticals, Inc.); Novel acetylcholinesterase inhibitors. EP 0403713; EP 0409676; JP 1991038591; US 5693668 . |
| 【2】 Prous, J.; Graul, A.; Castaner, J.; Subreum. Drugs Fut 1994, 19, 9, 845. |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 4-methylacetophenone (I) with ethyl trifluoroacetate (II) by means of NaOMe in refluxing methanol gives 4,4,4-trifluoro-1-(4-methylphenyl)butane-1,3-dione, which is cyclized with 4-hydrazinophenylsulfonamide (III) in refluxing ethanol.
| 【1】 Penning, T.D.; Talley, J.J.; Bertenshaw, S.R.; et al.; Synthesis and biological evaluation of the 1, 5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib). J Med Chem 1997, 40, 9, 1347. |
| 【2】 Graul, A.; Martel, A.M.; Castañer, J.; Celecoxib. Drugs Fut 1997, 22, 7, 711. |
| 【3】 Talley, J.J.; Penning, T.D.; Collins, P.W.; Rogier, D.J. Jr.; Malecha, J.W.; Miyashiro, J.M.; Bertenshaw, S.R.; Khanna, I.K.; Granets, M.J.; Rogers, R.S.; Carter, J.S.; Docter, S.H.; Yu, S.S. (Pharmacia Corp.); Substd. pyrazolyl benzenesulfonamides for the treatment of inflammation. EP 0731795; EP 0922697; EP 0924201; JP 1997506350; JP 2000109466; US 5521207; WO 9515316 . |
| 【4】 Zhi, B.; Newaz, M.; Talley, J.J.; Bertenshaw, S. (Pharmacia Corp.); Method of preparing 3-haloalkyl-1H-pyrazoles. WO 9637476 . |
| 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) | 17145 | 1-(4-methylphenyl)-1-ethanone; p-methylacetophenone; 4-methylacetophenone; 4-methylphenylethanone | 122-00-9 | C9H10O | 详情 | 详情 |
| (II) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (III) | 17147 | 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione; 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione | 720-94-5 | C11H9F3O2 | 详情 | 详情 |
| (IV) | 17148 | 4-Hydrazinobenzenesulfonamide; 4-Sulfonamidophenylhydrazine | 4392-54-5 | C6H9N3O2S | 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 acylation of 4-methoxyaniline (I) with pivaloyl chloride (II) and TEA in CH2Cl2 gives the anilide (III), which is condensed with ethyl trifluoroacetate (IV) by means of n-BuLi in THF yielding the trifluoroacetyl derivative (V). The hydrolysis of the amido group of (V) with 6N HCl in refluxing DMF affords the 2-aminoacetophenone (VI), which is condensed with cyclopropylacetylene (VII) by means of n-BuLi in THF to give the tertiary alcohol (VIII). Finally, this compound is cyclized with phosgene and DIPEA in toluene yielding the racemic form of target compound.
| 【1】 Ko, S.S.; Patel, M.; Cordova, B.C.; Klabe, R.M.; Srivastava, A.S.; Markwalder, J.A.; McHugh, R.J. Jr.; Seitz, S.P.; Trainor, G.L.; Erickson-Vittanen, S.; Synthesis and evaluation of analogs of efavirenz (Sustiva(TM)) as HIV-1 reverse transcriptase inhibitors. Bioorg Med Chem Lett 1999, 9, 19, 2805. |
| 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) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (II) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (III) | 40412 | N-(4-methoxyphenyl)-2,2-dimethylpropanamide | C12H17NO2 | 详情 | 详情 | |
| (IV) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (V) | 40413 | N-[4-methoxy-2-(2,2,2-trifluoroacetyl)phenyl]-2,2-dimethylpropanamide | C14H16F3NO3 | 详情 | 详情 | |
| (VI) | 40414 | 1-(2-amino-5-methoxyphenyl)-2,2,2-trifluoro-1-ethanone | C9H8F3NO2 | 详情 | 详情 | |
| (VII) | 16575 | 1-ethynylcyclopropane; cyclopropyl acetylene | 6746-94-7 | C5H6 | 详情 | 详情 |
| (VIII) | 40415 | 2-(2-amino-5-methoxyphenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol | C14H14F3NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)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 |
合成路线5
该中间体在本合成路线中的序号：(V)Reaction of 3-(tetrahydropyranyloxy)benzaldehyde (I) with acetonitrile (II) in the presence of t-BuOK in THF gives the b-hydroxypropionitrile (III), which by reduction with LiAlH4 in THF/Et2O yields the primary amine (IV). N-Protection of amine (IV) with ethyl trifluoroacetate (V) in THF affords the carbamate (VI), whose secondary hydroxyl group is oxidized with MnO2 in CH2Cl2 to yield the ketone (VII). Enantioselective reduction of ketone (VII) with (–)-DIP-Cl and DIEA in THF provides the (R)-alcohol (VIII), which is O-alkylated at its phenolic hydroxyl group with cyclohexylmethyl bromide (IX) and K2CO3 in DMF to give ether (X). Finally, compound (X) is N-deprotected by means of K2CO3 in MeOH/H2O and treated with HCl in i-PrOH .
| 【1】 Scott, I.L., Kuksa, V.A. Orme, M.W., Little, T., gall, A., Hong, f. (Acucela, Inc.). Alkoxy compounds for disease treatment. CN 103553945, EP 2091955, JP 2011512321, US 2009326074, US 7982071, US 2012122938, US 2012214852, US 2013197096, US 8829244, WO 2009045479. |
| 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) | 67832 | 3-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde | C12H14O3 | 详情 | 详情 | |
| (II) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (III) | 67833 | 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propanenitrile | C14H17NO3 | 详情 | 详情 | |
| (IV) | 67834 | 3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propan-1-ol | C14H21NO3 | 详情 | 详情 | |
| (V) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (VI) | 67835 | 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)acetamide | C16H20F3NO4 | 详情 | 详情 | |
| (VII) | 67836 | 2,2,2-trifluoro-N-(3-oxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)acetamide | C16H18F3NO4 | 详情 | 详情 | |
| (VIII) | 67837 | (R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-hydroxyphenyl)propyl)acetamide | C11H12F3NO3 | 详情 | 详情 | |
| (IX) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (X) | 67838 | (R)-N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide | C18H24F3NO3 | 详情 | 详情 |