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【结 构 式】 
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【分子编号】42542 【品名】2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine 【CA登记号】753-90-2 |
【 分 子 式 】C2H4F3N 【 分 子 量 】99.0557096 【元素组成】C 24.25% H 4.07% F 57.54% N 14.14% |
合成路线1
该中间体在本合成路线中的序号：(XXXII)In an alternative route to intermediate (III), ortho-metalation of 1,2-difluorobenzene (XXIV) with n-hexyllithium in THF followed by sequential addition of ZnCl2, CuCl and then chloroacetyl chloride (XXV) gives 2-chloro-2’,3’-difluoroacetophenone (XXVI). Subsequent condensation of chloroketone (XXVI) with vinylmagnesium bromide followed by cyclization of the resulting chlorohydrin (XXVII) under alkaline conditions yields epoxide (XXVIII). This is then coupled with diethyl acetamidomalonate (XXIX) in the presence of Pd(OAc)2 and 1,2-bis(diphenylphosphino)ethane (dppe) to generate the allyl alcohol adduct (XXX), which after conversion to the corresponding mesylate (XXXI) is reacted with 2,2,2-trifluoroethylamine (XXXII) in dimethylacetamide to furnish the allylic amine (XXXIII). Decarbethoxylation of malonate (XXXIII) by heating with LiCl in moist dimethylacetamide provides the N-acetyl aminoester (XXXIV). Then, cyclization of (XXXIV) by means of trifluoroacetic acid in hot toluene gives the azepinone derivative (XXXV). After acidic hydrolysis of acetamide (XXXV), the resulting racemic amine is resolved utilizing (-)-O,O’-di-p-toluoyl-L-tartaric acid (DTTA) in the presence of a trace amount of 5-nitrosalicylaldehyde to provide the (S)-amine ditoluoyltartrate salt (XXXVI). Finally, liberation of the tartrate salt (XXXVI) with HCl in isopropanol and simultaneous hydrogenation of the azepine double bond in the presence of Pd/BaSO4 provides the trans-perhydroazepinone (III) (2-5). Scheme 3.
| 【2】 Palucki, M., Davies, I., Steinhuebel, D., Rosen, J. (Merck & Co., Inc.). Process for the preparation of caprolactam CGRP antagonist intermediate. WO 2007120589. |
| 【3】 McLaughlin, M., Palucki, M., Marcantonio, K. (Merck & Co., Inc.). Process for the preparation of pyridine heterocycle CGRP antagonist intermediate. WO 2007120590. |
| 【4】 Belyk, K., Rivera, N. (Merck & Co., Inc.). Process for the preparation of CGRP antagonist. WO 2007120591. |
| 【5】 Belyk, K. (Merck & Co., Inc.). CGRP antagonist salt. WO 2007120592. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 65556 | (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine | C14H15F5N2O | 详情 | 详情 | |
| (XXIV) | 65570 | 1,2-Difluorobenzene | 367-11-3 | C6H4F2 | 详情 | 详情 |
| (XXV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XXVI) | 65571 | 2-Chloro-2',3'-difluoroacetophenone | C8H5ClF2O | 详情 | 详情 | |
| (XXVII) | 65572 | C10H9ClF2O | 详情 | 详情 | ||
| (XXVIII) | 65573 | C10H8F2O | 详情 | 详情 | ||
| (XXIX) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (XXX) | 65574 | C19H23F2NO6 | 详情 | 详情 | ||
| (XXXI) | 65575 | C20H25F2NO8S | 详情 | 详情 | ||
| (XXXII) | 42542 | 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine | 753-90-2 | C2H4F3N | 详情 | 详情 |
| (XXXIII) | 65576 | C21H25F5N2O5 | 详情 | 详情 | ||
| (XXXIV) | 65577 | C18H21F5N2O3 | 详情 | 详情 | ||
| (XXXV) | 65578 | C16H15F5N2O2 | 详情 | 详情 | ||
| (XXXVI) | 65579 | C14H13F5N2O.C20H18O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Bromination of 4-bromo-3-methyl anisole derivative (I) by means of NBS and light in CH2Cl2 and (BzO)2 affords derivative (II), which is then treated with protected trifluoroethane derivative (III) in DMF to give (IV). Alternatively, (II) can be converted into (IV) by first treating with 2,2,2-trifluoroethylamine (V) in DMSO followed by N-protection by means of Boc2O in CH2Cl2. Treatment of (IV) with dimethyl itaconate (VII) in the presence of Pd(OAc)2, P(o-tol)3, DIEA and propionitrile yields intermediate (VIII), which is then reduced by hydrogenolysis over Pd/C in EtOAc to afford butanoate (IX). Removal of the Boc protecting group of (IX) by treatment with TFA and anisole provides derivative (X), which is then cyclized by means of tripropylamine in refluxing xylenes to afford benzazepine derivative (XI) in its racemic form. Separation of the two enantiomers of (XI) by chiral HPLC affords (S)-(XII), which is demethylated with BBr3 in CH2Cl2 to yield (XIII). Treatment of N-oxide derivative (XIV) with 3-amino-1-propanol (XV) in tert-amyl alcohol in the presence of NaHCO3 yields derivative (XVI), which is then reacted with phenol derivative (XIII) in a Mitsunobu reaction with PPh3 and DEAD in THF/DMF to give ether derivative (XVII). Reduction of (XVII) with cyclohexene in isopropanol in the presence of Pd/C affords methyl acetate (XVIII), which is finally hydrolyzed by means of aqueous NaOH in dioxane.
| 【1】 Miller, W.H.; Bhatnager, P.K.; Alberts, D.P.; et al.; Discovery of orally active nonpeptide vitronectin receptor antagonists based on a 2-benzazepine gly-asp mimetic. J Med Chem 2000, 43, 1, 22. |
| 【2】 Callahan, J.F.; Cousins, R.D.; Keenan, R.M.; Kwon, C.; Miller, W.H.; Uzinkas, I.N. (SmithKline Beecham plc); Vitronectin receptor antagonists. EP 0957917; WO 9814192 . |
| 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) | 42539 | 4-bromo-3-methylphenyl methyl ether; 1-bromo-4-methoxy-2-methylbenzene | 27060-75-9 | C8H9BrO | 详情 | 详情 |
| (II) | 27552 | 1-bromo-2-(bromomethyl)-4-methoxybenzene | C8H8Br2O | 详情 | 详情 | |
| (III) | 42540 | C7H11F3NNaO2 | 详情 | 详情 | ||
| (IV) | 42541 | tert-butyl 2-bromo-5-methoxybenzyl(2,2,2-trifluoroethyl)carbamate | C15H19BrF3NO3 | 详情 | 详情 | |
| (V) | 42542 | 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine | 753-90-2 | C2H4F3N | 详情 | 详情 |
| (VI) | 42543 | N-(2-bromo-5-methoxybenzyl)-2,2,2-trifluoro-1-ethanamine; N-(2-bromo-5-methoxybenzyl)-N-(2,2,2-trifluoroethyl)amine | C10H11BrF3NO | 详情 | 详情 | |
| (VII) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (VIII) | 42544 | dimethyl 2-[(E)-(2-[[(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino]methyl]-4-methoxyphenyl)methylidene]succinate | C22H28F3NO7 | 详情 | 详情 | |
| (IX) | 42545 | dimethyl 2-(2-[[(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino]methyl]-4-methoxybenzyl)succinate | C22H30F3NO7 | 详情 | 详情 | |
| (X) | 42546 | dimethyl 2-(4-methoxy-2-[[(2,2,2-trifluoroethyl)amino]methyl]benzyl)succinate | C17H22F3NO5 | 详情 | 详情 | |
| (XI) | 42547 | methyl 2-[8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C16H18F3NO4 | 详情 | 详情 | |
| (XII) | 42548 | methyl 2-[(4S)-8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C16H18F3NO4 | 详情 | 详情 | |
| (XIII) | 42549 | methyl 2-[(4S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C15H16F3NO4 | 详情 | 详情 | |
| (XIV) | 34524 | 2-chloro-1-pyridiniumolate | 2402-95-1 | C5H4ClNO | 详情 | 详情 |
| (XV) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XVI) | 34525 | 2-[(3-hydroxypropyl)amino]-1-pyridiniumolate | C8H12N2O2 | 详情 | 详情 | |
| (XVII) | 42550 | 2-[(3-[[(4S)-4-(2-methoxy-2-oxoethyl)-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]oxy]propyl)amino]-1-pyridiniumolate | C23H26F3N3O5 | 详情 | 详情 | |
| (XVIII) | 42551 | methyl 2-[(4S)-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C23H26F3N3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Alkylation of the dilithio derivative of fluorene-9-carboxylic acid (I) with diethyl 4-bromobutylphosphonate (II) affords adduct (III). After conversion of acid (III) to the corresponding acid chloride (IV), condensation with 2,2,2-trifluoroethylamine (V) affords amide (VI). The phosphonate ethyl ester (VI) is cleaved by means of bromotrimethylsilane yielding phosphonic acid (VII), which is further activated as the phosphonic acid chloride (VIII) by using oxalyl chloride in the presence of DMF. Finally, condensation of acid chloride (VIII) with (6-methylpyridin-2-yl)methanol (IX) leads to the target bis-pyridinylmethyl ester.
| 【1】 Magnin, D.R.; Biller, S.A.; Wetterau, J.; Robl, J.A.; Dickson, J.K. Jr.; Prakash, T.; Harrity, T.W.; Lawrence, R.M.; Sun, C.-Q.; Wang, T.; Logan, J.; Fryszman, O.; Connolly, F.; Jolibois, K.; Kunselman, L.; Microsomal triglyceride transfer protein inhibitors: Discovery and synthesis of alkyl phosphonates as potent MTP inhibitors and cholesterol lowering agents. Bioorg Med Chem Lett 2003, 13, 7, 1337. |
| 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) | 47744 | 9H-fluorene-9-carboxylic acid; 9-Fluorenecarboxylic acid; Diphenyleneacetic acid; Fluorene-9-carboxylic acid | 1989-33-9 | C14H10O2 | 详情 | 详情 |
| (II) | 64229 | diethyl 4-bromobutylphosphonate | C8H18BrO3P | 详情 | 详情 | |
| (III) | 64230 | 9-[4-(diethoxyphosphoryl)butyl]-9H-fluorene-9-carboxylic acid | C22H27O5P | 详情 | 详情 | |
| (IV) | 64231 | diethyl 4-[9-(chlorocarbonyl)-9H-fluoren-9-yl]butylphosphonate | C22H26ClO4P | 详情 | 详情 | |
| (V) | 42542 | 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine | 753-90-2 | C2H4F3N | 详情 | 详情 |
| (VI) | 64232 | diethyl 4-(9-{[(2,2,2-trifluoroethyl)amino]carbonyl}-9H-fluoren-9-yl)butylphosphonate | C24H29F3NO4P | 详情 | 详情 | |
| (VII) | 64233 | 4-(9-{[(2,2,2-trifluoroethyl)amino]carbonyl}-9H-fluoren-9-yl)butylphosphonic acid | C20H21F3NO4P | 详情 | 详情 | |
| (VIII) | 64234 | 4-(9-{[(2,2,2-trifluoroethyl)amino]carbonyl}-9H-fluoren-9-yl)butylphosphonic dichloride | C20H19Cl2F3NO2P | 详情 | 详情 | |
| (IX) | 64235 | (6-methyl-2-pyridinyl)methanol | C7H9NO | 详情 | 详情 |