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【结 构 式】 
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【分子编号】14723 【品名】4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline 【CA登记号】367-24-8 |
【 分 子 式 】C6H5BrFN 【 分 子 量 】190.0148432 【元素组成】C 37.93% H 2.65% Br 42.05% F 10% N 7.37% |
合成路线1
该中间体在本合成路线中的序号：(V)The synthesis of tritium-labeled brifentanil has been described: The hydrogenolysis of 1-benzyl-3-methylpiperidin-4-one (I) with H2 over Pd/C in ethanol gives the free piperidone (II), which is condensed with 1-(2-bromoethyl)-4-ethyl-4,5-dihydro-1H-tetrazol-5-one (III) by means of NaI and Na2CO3 in acetonitrile, yielding the condensation product (IV). The reductocondensation of (IV) with 4-bromo-2-fluoroaniline by means of NaBH3CN and HCl in methanol affords the substituted aniline (VI), which is acylated with 2-methoxyacetyl chloride (VII) and submitted to chromatographic (HPLC) separation to obtain the cis-isomer of bromobrifentanil (VIII). Finally, this compound is submitted to debromination with tritium gas and Pd/C in ethanol to afford [3H]-brifentanil.
| 【1】 Nugent, R.P.; Huang, B.S.; Filer, C.N.; The synthesis of [fluorophenyl-H-3(N)]ocfentanil and [fluorophenyl-H-3(N)]brifentanil. J Label Compd Radiopharm 1995, 36, 11, 1019. |
| 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) | 14714 | 1-Benzyl-3-methyl-4-piperidone; 1-benzyl-3-methyltetrahydro-4(1H)-pyridinone | 34737-89-8 | C13H17NO | 详情 | 详情 |
| (II) | 14720 | 3-methyltetrahydro-4(1H)-pyridinone | C6H11NO | 详情 | 详情 | |
| (III) | 14721 | 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C5H9BrN4O | 详情 | 详情 | |
| (IV) | 14722 | 1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl)ethyl]-3-methyltetrahydro-4(1H)-pyridinone | C11H19N5O2 | 详情 | 详情 | |
| (V) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (VI) | 14724 | 1-[2-[4-(4-bromo-2-fluoroanilino)-3-methylpiperidino]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C17H24BrFN6O | 详情 | 详情 | |
| (VII) | 13429 | 2-Methoxyacetyl chloride; Methoxyacetyl chloride | 38870-89-2 | C3H5ClO2 | 详情 | 详情 |
| (VIII) | 14726 | N-(4-bromo-2-fluorophenyl)-N-[(3R,4S)-1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl)ethyl]-3-methylhexahydro-4-pyridinyl]-2-methoxyacetamide | C20H28BrFN6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Synthesis of intermediate (XVII): Coupling of 4-bromo-2-fluoroaniline (XIV) with pivaloyl chloride (VI) in pyridine affords N-protected substituted aniline (XV), which is then treated with 1-ethoxyvinyltributyltin (XVI) and bis(triphenylphosphine) palladium chloride (PdCl2(PPh3)2) in toluene to provide acetophenone derivative (XVII). Coupling of intermediates (XI) and (XVII): Ethyl benzoate (XI) is treated with NaH and added to a solution of acetophenone (XVII) in refluxing toluene/dioxane to furnish benzopyranone (XVIII), which is finally deprotected with HCl in dioxane to give the desired product.
| 【1】 Akama, T.; et al.; Synthesis of an ethyl 6-amino-3,5-difluorosalicylate derivative by sequential regioselective direct ortho-metalation; a practical synthesis of 4',5-diamino-3',6,8-trifluoroflavone, a potent antitumor agent. Synthesis 1997, 1446. |
| 【2】 Saito, H.; Ishida, H.; Akama, T.; Kimura, U.; Gomi, K.; Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent. J Med Chem 1998, 41, 12, 2056. |
| 【3】 Akama, T.; Ikeda, S.; Ishida, H.; Kimura, U.; Gomi, K.; Saito, H. (Kyowa Hakko Kogyo Co., Ltd.); 5-Aminoflavone derivs., their preparation and their use as antibacterial, anti-estrogenic and/or antitumor agent. EP 0638566; JP 1995109268 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XI) | 46828 | ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)benzoate | C20H27F2NO5 | 详情 | 详情 | |
| (XIV) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (XV) | 46831 | N-(4-bromo-2-fluorophenyl)-2,2-dimethylpropanamide | C11H13BrFNO | 详情 | 详情 | |
| (XVI) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (XVII) | 46832 | N-(4-acetyl-2-fluorophenyl)-2,2-dimethylpropanamide | C13H16FNO2 | 详情 | 详情 | |
| (XVIII) | 46833 | N-(4-[5-[(2,2-dimethylpropanoyl)amino]-6,8-difluoro-7-methyl-4-oxo-4H-chromen-2-yl]-2-fluorophenyl)-2,2-dimethylpropanamide | C26H27F3N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Quinazolinone (III) was prepared by treatment of aminobenzamide (I) with Gold's reagent (II) in refluxing dioxan. Subsequent chlorination using thionyl chloride gave chloroquinazoline (IV). Nucleophilic displacement of the chlorine atom of (IV) with 4-bromo-2-fluoroaniline (V) yielded the anilinoquinazoline (VI). The benzyl group of (VI) was then cleaved with trifluoroacetic acid, and the resulting hydroxyquinazoline (VII) was finally coupled with (hydroxyethyl)triazole (VIII) using DEAD and PPh3 to furnish the title compound.
| 【1】 Thomas, A.P.; Johnstone, C.; Hennequin, L.F.; et al.; Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors. J Med Chem 1999, 42, 26, 5369. |
| 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) | 31528 | 2-amino-4-(benzyloxy)-5-methoxybenzamide | C15H16N2O3 | 详情 | 详情 | |
| (II) | 31529 | N-([[(E)-(dimethylamino)methylidene]amino]methylene)-N-methylmethanaminium | C6H14N3 | 详情 | 详情 | |
| (III) | 31530 | 7-(benzyloxy)-6-methoxy-4(3H)-quinazolinone | C16H14N2O3 | 详情 | 详情 | |
| (IV) | 31531 | benzyl 4-chloro-6-methoxy-7-quinazolinyl ether; 7-(benzyloxy)-4-chloro-6-methoxyquinazoline | C16H13ClN2O2 | 详情 | 详情 | |
| (V) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (VI) | 31532 | 7-(benzyloxy)-N-(4-bromo-2-fluorophenyl)-6-methoxy-4-quinazolinamine; N-[7-(benzyloxy)-6-methoxy-4-quinazolinyl]-N-(4-bromo-2-fluorophenyl)amine | C22H17BrFN3O2 | 详情 | 详情 | |
| (VII) | 31533 | 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinol | C15H11BrFN3O2 | 详情 | 详情 | |
| (VIII) | 31534 | 2-(1H-1,2,3-triazol-1-yl)-1-ethanol | C4H7N3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Condensation of 1,1,1-trifluoro-2,4-pentanedione (I) with 3-bromophenylhydrazine (II) produced an 88:12 mixture of regioisomeric pyrazoles (III) and (IV). Treatment of this mixture with copper cyanide in boiling NMP afforded the corresponding mixture of nitriles, from which the desired major isomer (V) was isolated by flash chromatography. Radical bromination of (V), followed by hydrolysis of the resulting bromomethylpyrazole (VI) with CaCO3 in aqueous dioxan, yielded alcohol (VII). Oxidation of (VII) to carboxylic acid (VIII) was then effected by treatment with sodium periodate in the presence of ruthenium trichloride. After conversion of (VIII) to the corresponding acid chloride (IX) with oxalyl chloride, coupling with 4-bromo-2-fluoroaniline (X) furnished amide (XI). Subsequent Suzuki coupling of (XI) with 2-(methylsulfanyl)phenylboronic acid (XII) gave rise to biphenyl derivative (XIII). The sulfide group of (XIII) was then oxidized to sulfone (XIV) using meta-chloroperbenzoic acid. Finally, catalytic hydrogenation of the cyano group of (XIV) over Pd/C yielded the title primary amine.
| 【1】 Orwat, M.J.; Cacciola, J.; Han, Q.; Fevig, J.M.; Pinto, D.J.P.; Rossi, K.A.; Pruitt, J.R.; Quan, M.L. (DuPont Pharmaceuticals Co.); Nitrogen containing heteroaromatics as factor Xa inhibitors. EP 0946508; WO 9828269 . |
| 【2】 Cacciola, J.; Han, Q.; Pinto, D.J.P.; Pruitt, J.R.; Rossi, K.A.; Fevig, J.M.; Orwat, M.M.; Quan, M.L. (DuPont Pharmaceuticals Co.); Nitrogen containing heteroaromatics as factor Xa inhibitors. US 6020357 . |
| 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) | 46384 | 1,1,1-trifluoro-2,4-pentanedione | C5H5F3O2 | 详情 | 详情 | |
| (II) | 37812 | 1-(3-bromophenyl)hydrazine | 27246-81-7 | C6H7BrN2 | 详情 | 详情 |
| (III) | 46385 | 1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole | C11H8BrF3N2 | 详情 | 详情 | |
| (IV) | 46386 | 1-(3-bromophenyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazole | C11H8BrF3N2 | 详情 | 详情 | |
| (V) | 46387 | 3-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H8F3N3 | 详情 | 详情 | |
| (VI) | 46388 | 3-[5-(bromomethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H7BrF3N3 | 详情 | 详情 | |
| (VII) | 46389 | 3-[5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C12H8F3N3O | 详情 | 详情 | |
| (VIII) | 46390 | 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid | C12H6F3N3O2 | 详情 | 详情 | |
| (IX) | 46391 | 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride | C12H5ClF3N3O | 详情 | 详情 | |
| (X) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (XI) | 46392 | N-(4-bromo-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide | C18H9BrF4N4O | 详情 | 详情 | |
| (XII) | 46393 | 2-(methylsulfanyl)phenylboronic acid | C7H9BO2S | 详情 | 详情 | |
| (XIII) | 46394 | 1-(3-cyanophenyl)-N-[3-fluoro-2'-(methylsulfanyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide | C25H16F4N4OS | 详情 | 详情 | |
| (XIV) | 46395 | 1-(3-cyanophenyl)-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide | C25H16F4N4O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Nucleophilic substitution of the chloroquinazoline (V) with 4-bromo-2-fluoroaniline (VI) in refluxing isopropanol provided the anilino quinazoline (VII). Subsequent cleavage of the benzyl ether group of (VII) by treatment with hot trifluoroacetic acid gave phenol (VIII), which was condensed with tosylate (IV) to furnish the ether adduct (IX). Acid deprotection of the N-Boc group of (IX) gave piperidine (X). Finally, reductive methylation of (X) using formaldehyde and sodium cyanoborohydride yielded the corresponding N-methyl piperidine.
| 【1】 Hennequin, L.F.A.; Stokes, E.S.E.; Thomas, A.P. (AstraZeneca AB; AstraZeneca plc); Quinazoline derivs. as VEGF inhibitors. WO 0132651 . |
| 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) | 49848 | tert-butyl 4-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-piperidinecarboxylate | C18H27NO5S | 详情 | 详情 | |
| (V) | 31531 | benzyl 4-chloro-6-methoxy-7-quinazolinyl ether; 7-(benzyloxy)-4-chloro-6-methoxyquinazoline | C16H13ClN2O2 | 详情 | 详情 | |
| (VI) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (VII) | 31532 | 7-(benzyloxy)-N-(4-bromo-2-fluorophenyl)-6-methoxy-4-quinazolinamine; N-[7-(benzyloxy)-6-methoxy-4-quinazolinyl]-N-(4-bromo-2-fluorophenyl)amine | C22H17BrFN3O2 | 详情 | 详情 | |
| (VIII) | 31533 | 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinol | C15H11BrFN3O2 | 详情 | 详情 | |
| (IX) | 49849 | tert-butyl 4-([[4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinyl]oxy]methyl)-1-piperidinecarboxylate | C26H30BrFN4O4 | 详情 | 详情 | |
| (X) | 49850 | N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(4-piperidinylmethoxy)-4-quinazolinamine; N-(4-bromo-2-fluorophenyl)-N-[6-methoxy-7-(4-piperidinylmethoxy)-4-quinazolinyl]amine | C21H22BrFN4O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)4-Bromo-2-fluoroaniline (I) was protected as the N-Boc derivative (II) upon treatment with di-tert-butyl dicarbonate. Subsequent palladium-catalyzed bromide displacement in (II) with bis-pinacolatodiborane (III) furnished the arylboronate derivative (IV). The (dioxaspirodecyl)pyrimidine (VII) was prepared by coupling between 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (V) and 4-hydroxycyclohexanone ethylene ketal (VI) under Mitsunobu conditions. Subsequent Suzuki coupling of iodopyrrolopyrimidine (VII) with boronate (IV) afforded adduct (VIII). Displacement of the 4-chloro of (VIII) with simultaneous N-Boc group cleavage with ammonium hydroxide in dioxan at 120 C in a sealed vessel furnished the diamino compound (IX).
| 【1】 Wishart, N.; Barlozzari, T.; Arnold, L.D.; et al.; Structure activity relationships for a novel series of pyrrolo[2,3-d]pyrimidine Tie-2 inhibitors. Proc Am Assoc Cancer Res 2002, 43, Abst 4205. |
| 【2】 Hirst, G.C.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D. (BASF AG); Pyrrolopyrimidines as protein kinase inhibitors. EP 1114053; WO 0017203 . |
| 【3】 Hirst, G.C.; Rafferty, P.; Arnold, L.D.; Johnston, D.N.; Calderwood, D.; Munschaufer, R. (BASF AG); Pyrrolopyrimidines as tyrosine kinase inhibitors. WO 0172751 . |
| 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) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (II) | 53560 | tert-butyl 4-bromo-2-fluorophenylcarbamate | n/a | C11H13BrFNO2 | 详情 | 详情 |
| (III) | 53561 | n/a | C12H26B2O4 | 详情 | 详情 | |
| (IV) | 53562 | tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate | n/a | C17H25BFNO4 | 详情 | 详情 |
| (V) | 53563 | 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine | 123148-78-7 | C6H3ClIN3 | 详情 | 详情 |
| (VI) | 53564 | 1,4-dioxaspiro[4.5]decan-8-ol | 22428-87-1 | C8H14O3 | 详情 | 详情 |
| (VI) | 53565 | 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine | n/a | C14H15ClIN3O2 | 详情 | 详情 |
| (VII) | 53566 | tert-butyl 4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylcarbamate | n/a | C25H28ClFN4O4 | 详情 | 详情 |
| (VIII) | 53567 | 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylamine | n/a | C20H22FN5O2 | 详情 | 详情 |