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【结 构 式】 
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【分子编号】18559 【品名】5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine 【CA登记号】1072-98-6 |
【 分 子 式 】C5H5ClN2 【 分 子 量 】128.56088 【元素组成】C 46.71% H 3.92% Cl 27.58% N 21.79% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of pyrazine-2,3-dicarboxylic acid anhydride (I) with 2-amino-5-chloropyridine (II) in refluxing acetonitrile gives 3-(5-chloro-2-pyridyl)carbamoyl pyrazine-2-carboxylic acid (III), which is cyclized by treatment with refluxing SOCl2 affording 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine (IV). The partial reduction of (IV) with KBH4 in dioxane-water yields 6-(5-chloro-2-pyridyl)-7-hydroxy-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one (V), which is finally esterified with 4-methylpiperazine-1-carbonyl chloride (VI) by means of NaH in DMF.
| 【1】 Cotrel, C.; et al. (Aventis Pharma SA); Pyrrolo-[3,4,b]pyrazine derivatives. DE 2300491; GB 1358680; JP 52048687; US 3862149 . |
| 【2】 Castaner, J.; Serradell, M.N.; Zopiclone. Drugs Fut 1979, 4, 1, 59. |
| 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) | 33266 | furo[3,4-b]pyrazine-5,7-dione | C6H2N2O3 | 详情 | 详情 | |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 33267 | 3-[[(5-chloro-2-pyridinyl)amino]carbonyl]-2-pyrazinecarboxylic acid | C11H7ClN4O3 | 详情 | 详情 | |
| (IV) | 33268 | 6-(5-chloro-2-pyridinyl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione | C11H5ClN4O2 | 详情 | 详情 | |
| (V) | 32796 | 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one | C11H7ClN4O2 | 详情 | 详情 | |
| (VI) | 30370 | 4-methyl-1-piperazinecarbonyl chloride | C6H11ClN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)1) 4-Chloro-2'-bromoacetophenone (I) is condensed with 2-amino 5-chloropyridine (II) to give 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (III). 2) The above compound is reacted with formaldehyde and dimethylamine under Mannich conditions affording the 3-dimethylaminomethyl derivative (IV), which is subsequently quaternized with methyl iodide to afford the quaternary iodide (V). 3) Displacement of trimethylamine from salt (V) with cyanide ion leads to formation of the nitrile (VI), which on hydrolysis with hydrochloric acid in acetic acid gives the corresponding acid (VII). 4) In situ conversion of the acid to its acid chloride with phosphorus oxychloride followed by treatment with di-n-propylamine then leads to alpidem.
| 【1】 George, P.; Kaplan, J.-P. (Sanofi-Synthelabo ); Imidazo[1,2-a] pyridine derivs. and their applicat. EP 0050563; US 4382938 . |
| 【2】 Friedmann, J.C.; Morselli, P.L.; Dimsdale, M.; Zivkovic, B.; Alpidem. Drugs Fut 1988, 13, 2, 106. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (2) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (I) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 21851 | 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine | C13H8Cl2N2 | 详情 | 详情 | |
| (IV) | 21852 | [6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dimethylmethanamine; N-[[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]-N,N-dimethylamine | C16H15Cl2N3 | 详情 | 详情 | |
| (V) | 21853 | [6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N,N-trimethylmethanaminium iodide | C17H18Cl2IN3 | 详情 | 详情 | |
| (VI) | 21854 | 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetonitrile | C15H9Cl2N3 | 详情 | 详情 | |
| (VII) | 21855 | 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetic acid | C15H10Cl2N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Synthesis of etoricoxib via dichloropyridine (VIII): a) The bromination of 5-chloro-2-hydroxypyridine (I) with Br2 in acetic acid gives 3-bromo-5-chloro-2-hydroxypyridine (II), which is treated with benzyl bromide and Ag2CO3 in hot benzene to yield benzyl ether (III). Condensation of (III) with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene affords 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (V), which is oxidized with OsO4 and sodium sulfite to furnish sulfone (VI). Treatment of (VI) with TFA provides the 2-hydroxypyridine (VII), which is reacted with POCl3 to yield 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine (VIII). b) Bromination of 2-amino-5-chloropyridine (IX) with Br2 in acetic acid provides 2-amino-3-bromo-5-chloropyridine (X), which is condensed with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene to give 2-amino-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (XI). Oxidation of compound (XI) with OsO4 as before yields sulfone (XII), which is converted into compound (VIII) by treatment first with NaNO2 and HCl and then chlorination with POCl3.
| 【1】 Castañer, R.M.; Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; Etoricoxib. Drugs Fut 2001, 26, 4, 346. |
| 【2】 Friesen, R.W.; Brideau, C.; Chan, C.C.; Charleson, S.; Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier, J.Y.; Girard, Y.; Gordon, R.; Greig, G.M.; Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L.J.; Young, R.N.; 2-Pyridinyl-3-(4-methylsulfonyl)phenylpyridines: Selective and orally active cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1998, 8, 19, 2777. |
| 【3】 Dube, D.; Fortin, R.; Friesen, R.; Wang, Z.; Gauthier, J.Y. (Merck Frosst Canada Inc.); Substd. pyridines as selective cyclooxygenase-2 inhibitors. EP 0912518; JP 1999514008; US 5861419; WO 9803484 . |
| 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) | 25742 | 5-chloro-2-pyridinol | 4214-79-3 | C5H4ClNO | 详情 | 详情 |
| (II) | 25743 | 3-bromo-5-chloro-2-pyridinol | C5H3BrClNO | 详情 | 详情 | |
| (III) | 25744 | benzyl 3-bromo-5-chloro-2-pyridinyl ether; 2-(benzyloxy)-3-bromo-5-chloropyridine | C12H9BrClNO | 详情 | 详情 | |
| (IV) | 18561 | 4-(methylsulfanyl)phenylboronic acid | 98546-51-1 | C7H9BO2S | 详情 | 详情 |
| (V) | 25745 | benzyl 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinyl ether; 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine | C19H16ClNOS | 详情 | 详情 | |
| (VI) | 25746 | 2-(benzyloxy)-5-chloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-[2-(benzyloxy)-5-chloro-3-pyridinyl]phenyl methyl sulfone | C19H16ClNO3S | 详情 | 详情 | |
| (VII) | 25747 | 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinol | C12H10ClNO3S | 详情 | 详情 | |
| (VIII) | 18565 | 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-(2,5-dichloro-3-pyridinyl)phenyl methyl sulfone | C12H9Cl2NO2S | 详情 | 详情 | |
| (IX) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (X) | 18560 | 3-bromo-5-chloro-2-pyridinylamine; 3-bromo-5-chloro-2-pyridinamine | C5H4BrClN2 | 详情 | 详情 | |
| (XI) | 18562 | 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinylamine; 5-chloro-3-[4-(methylsulfanyl)phenyl]-2-pyridinamine | C12H11ClN2S | 详情 | 详情 | |
| (XII) | 18563 | 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinamine; 5-chloro-3-[4-(methylsulfonyl)phenyl]-2-pyridinylamine | C12H11ClN2O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Nitration of 2-amino-5-chloropyridine (I) in hot sulfuric acid afforded (II). Diazotization of amine (II) in the presence of Br2 and HBr produced the bromopyridine (III), and subsequent displacement of the bromide of (III) with cuprous cyanide at 150 C yielded the picolinonitrile (IV). Catalytic hydrogenation of the nitro group of (IV) in the presence of Raney-Ni gave rise to the amino amide (V), which was further hydrolyzed to acid (VI) using conc. HCl. Fischer esterification of acid (VI) with EtOH and H2SO4 furnished the ethyl ester (VII). Acid chloride (IX), prepared from m-phenoxyphenylacetic acid (VIII) and oxalyl chloride, was then condensed with amino ester (VII) to produce amide (X). Finally, cyclization of (X) in the presence of potassium hexamethyldisilazide yielded the title naphthyridinone.
| 【1】 Zhou, Z.-L.; et al.; Synthesis and SAR of 5-,6-,7- and 8-aza analogues of 3-aryl-4-hydroxyquinolin-2(1H)-ones as NMDA/glycine site antagonists. Bioorg Med Chem 2001, 9, 8, 2061. |
| 【2】 Keana, J.F.W.; Cai, S.X.; Martin, V.V.; Zhou, Z.-L.; Navratil, J.M. (Oregon Health Sciences University); Aza and aza (N-oxy) analogs of glycine/NMDA receptor antagonists. EP 0805809; US 5801183; WO 9622990 . |
| 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) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (II) | 52296 | 2-Amino-5-Chloro-3-Nitropyridine | C5H4ClN3O2 | 详情 | 详情 | |
| (III) | 52297 | 2-bromo-5-chloro-3-nitropyridine | C5H2BrClN2O2 | 详情 | 详情 | |
| (IV) | 52298 | 5-chloro-3-nitro-2-pyridinecarbonitrile | C6H2ClN3O2 | 详情 | 详情 | |
| (V) | 52299 | 3-amino-5-chloro-2-pyridinecarboxamide | C6H6ClN3O | 详情 | 详情 | |
| (VI) | 52300 | 3-amino-5-chloro-2-pyridinecarboxylic acid | C6H5ClN2O2 | 详情 | 详情 | |
| (VII) | 52301 | ethyl 3-amino-5-chloro-2-pyridinecarboxylate | C8H9ClN2O2 | 详情 | 详情 | |
| (VIII) | 52302 | 3-Phenoxyphenylacetic acid | 32852-81-6 | C14H12O3 | 详情 | 详情 |
| (IX) | 52303 | 2-[3-(phenyloxy)phenyl]acetyl chloride | C14H11ClO2 | 详情 | 详情 | |
| (X) | 52304 | ethyl 5-chloro-3-({2-[3-(phenyloxy)phenyl]acetyl}amino)-2-pyridinecarboxylate | C22H19ClN2O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Treatment of 2-amino-5-chloropyridine (I) with 2-(1-cyclohexenyl)ethyl isothiocyanate (II) in N,N-dimethylformamide at 90 C produced the target thiourea.
| 【1】 Lind, P.T.; Noreen, R.; Ternansky, R.J.; Morin, J.M. Jr. (Medivir AB); Cpds. and methods for inhibition of HIV and related viruses. WO 9303022 . |
合成路线6
该中间体在本合成路线中的序号：(I)Alternatively, 2-amino-5-chloropyridine (I) was reacted with 1,1'-thiocarbonyldiimidazole (III) in acetonitrile yielding thioimidazolide (IV), which was then condensed with 2-(1-cyclohexenyl)ethylamine (V) in hot DMF.
| 【1】 Maher, D.; Mao, C.; Pendergrass, S.; Venkatachalam, T.K.; Zhu, D.; Tuel-Ahlgren, L.; Uckun, F.M.; N-[2-(1-Cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea and N'-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1. Bioorg Med Chem Lett 1999, 9, 18, 2721. |
| 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) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (IV) | 36903 | C9H7ClN4S | 详情 | 详情 | ||
| (V) | 36902 | 2-(1-cyclohexen-1-yl)ethylamine; 2-(1-cyclohexen-1-yl)-1-ethanamine; 2-(1-Cyclohexenyl)ethylamine | 3399-73-3 | C8H15N | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)2-Amino-5-chloropyridine-3-sulfonamide (II) was obtained by the reaction of 2-amino-5-chloropyridine (I) with chlorosulfonic acid, followed by treatment of the sulfonyl chloride intermediate with aqueous ammonia. Condensation of amino sulfonamide (II) with thiocarbonyldiimidazole (III) produced the imidazolyl pyridothiadiazine (IV). Nucleophilic substitution of the imidazolyl group with 1,2,2-trimethylpropylamine (V) in a sealed vessel at 180 C furnished the corresponding amino pyridothiadiazine.
| 【1】 de Tullio, P.; Quedraogo, R.; Pirotte, B.; et al.; 3-Alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to diazoxide and pinacidil as potassium channel openers acting on vascular smooth muscle cells: Design, synthesis, and pharmacological evaluation. J Med Chem 2000, 43, 8, 1456. |
| 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) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (II) | 46289 | 2-amino-5-chloro-3-pyridinesulfonamide | C5H6ClN3O2S | 详情 | 详情 | |
| (III) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (IV) | 46290 | 7-chloro-3-(1H-imidazol-1-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazine-1,1(4H)-dione | C9H6ClN5O2S | 详情 | 详情 | |
| (V) | 30977 | (2R)-3,3-dimethyl-2-butanamine; (1R)-1,2,2-trimethylpropylamine | C6H15N | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The condensation between 5-chloro-2-nitrobenzoyl chloride (I) and 2-amino-5-chloropyridine (II) produced the corresponding amide (III). Subsequent catalytic hydrogenation of the nitro group of (III) gave aniline (IV). Acid chloride (VI), prepared from N-Boc-isonipecotic acid (V) and oxalyl chloride, was then coupled to aniline (IV) to furnish amide (VII). Further trifluoroacetic acid-promoted cleavage of the Boc protecting group of (VII) yielded piperidine (VIII). Finally, reductive alkylation with acetone in the presence of sodium triacetoxyborohydride gave rise to the target N-isopropyl piperidine.
| 【1】 Kyle, J.A.; et al.; SAR investigations of N-aryl-2-[(piperidin-4-ylcarbonyl)amino]benzamide factor Xa inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 288. |
| 【2】 Aromatic amides. WO 0039118 . |
| 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) | 44133 | 5-chloro-2-nitrobenzoyl chloride | C7H3Cl2NO3 | 详情 | 详情 | |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 44134 | 5-chloro-N-(5-chloro-2-pyridinyl)-2-nitrobenzamide | C12H7Cl2N3O3 | 详情 | 详情 | |
| (IV) | 44135 | 2-amino-5-chloro-N-(5-chloro-2-pyridinyl)benzamide | C12H9Cl2N3O | 详情 | 详情 | |
| (V) | 17404 | 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid; 1-BOC-piperidine-4-carboxylic acid; N-Boc-isonipecotic acid | 84358-13-4 | C11H19NO4 | 详情 | 详情 |
| (VI) | 44136 | tert-butyl 4-(chlorocarbonyl)-1-piperidinecarboxylate | C11H18ClNO3 | 详情 | 详情 | |
| (VII) | 44137 | tert-butyl 4-[(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]anilino)carbonyl]-1-piperidinecarboxylate | C23H26Cl2N4O4 | 详情 | 详情 | |
| (VIII) | 44138 | N-(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]phenyl)-4-piperidinecarboxamide | C18H18Cl2N4O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)Treatment of 3-methoxy-2-nitrobenzoic acid (I) with oxalyl chloride gave the corresponding acid chloride (II), which was then coupled with 2-amino-5-chloropyridine (III) to yield amide (IV). The reduction of the nitro group of (IV) using sodium hydrosulfite afforded aniline (V). Further chlorination of (V) with N-chlorosuccinimide furnished the 5-chloro derivative (VI).
| 【1】 Cheeseman, S.; Chou, Y.-L.; Ye, B.; et al.; Design, synthesis, and biological activity of novel non-amidine factor Xa inhibitors, 4: Optimization of hydrophilic substituents for potency and oral availability. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 128. |
| 【2】 Snider, R.M.; Liang, A.M.; Wu, S.C.; Arnaiz, D.O.; Sacchi, K.L.; Kochanny, M.J.; Phillips, G.B.; Ye, B.; Zhao, Z.; Morrissey, M.M.; Griedel, B.D.; Lee, W.; Sakata, S.T.; Karanjawala, R.E.; Chou, Y.-L.; Shaw, K.J. (Schering AG); Ortho-anthranilamide derivs. as anticoagulants. EP 1040108; JP 2001526283; US 6140351; WO 9932477 . |
| 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) | 25827 | 3-methoxy-2-nitrobenzoic acid | 4920-80-3 | C8H7NO5 | 详情 | 详情 |
| (II) | 25828 | 3-methoxy-2-nitrobenzoyl chloride | C8H6ClNO4 | 详情 | 详情 | |
| (III) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (IV) | 51186 | N-(5-chloro-2-pyridinyl)-3-methoxy-2-nitrobenzamide | C13H10ClN3O4 | 详情 | 详情 | |
| (V) | 51187 | 2-amino-N-(5-chloro-2-pyridinyl)-3-methoxybenzamide | C13H12ClN3O2 | 详情 | 详情 | |
| (VI) | 51188 | C13H11Cl2N3O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(V)2,6-Difluorophenethylamine (II) was prepared by reduction of nitrile (I) with either NaBH4 in the presence of CoCl2 or borane in THF. Reaction of amine (II) with thiocarbonyldiimidazole (III) furnished the thioimidazolide (IV). This was finally condensed with 2-amino-5-chloropyridine (V), yielding the corresponding thiourea.
| 【1】 Lind, P.T.; Noreen, R.; Ternansky, R.J.; Morin, J.M. Jr. (Medivir AB); Cpds. and methods for inhibition of HIV and related viruses. WO 9303022 . |
| 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) | 46429 | 2-(2,6-difluorophenyl)acetonitrile | C8H5F2N | 详情 | 详情 | |
| (II) | 46430 | 2-(2,6-difluorophenyl)-1-ethanamine; 2,6-difluorophenethylamine | C8H9F2N | 详情 | 详情 | |
| (III) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (IV) | 46431 | N-(2,6-difluorophenethyl)-1H-imidazole-1-carbothioamide | C12H11F2N3S | 详情 | 详情 | |
| (V) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)2-(2-Thienyl)ethylamine (I) was protected as the N-Boc derivative (II) with Boc2O in CHCl3. Regioselective halogenation of the thiophene ring of (II) with concomitant Boc group cleavage by means of bromine in cold HOAc yielded the 5-bromothiophene (III). The thioimidazolide (VI) was prepared by reaction of 2-amino-5-chloropyridine (IV) with thiocarbonyl diimidazole (V). Finally, condensation of (VI) with amine (III) in hot DMF furnished the target thiourea.
| 【1】 Uckun, F.M.; Sudbeck, E.A.; Venkatachalam, T.K.; Regiospecific synthesis, X-ray crystal structure and biological activities of 5-bromothiophenethyl thioureas. Tetrahedron Lett 2001, 42, 38, 6629. |
| 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) | 35253 | 2-(2-thienyl)ethylamine; 2-(2-thienyl)-1-ethanamine; 2-Thiophene ethylamine | 30433-91-1 | C6H9NS | 详情 | 详情 |
| (II) | 52887 | tert-butyl 2-(2-thienyl)ethylcarbamate | C11H17NO2S | 详情 | 详情 | |
| (III) | 52888 | 2-(5-bromo-2-thienyl)-1-ethanamine; 2-(5-bromo-2-thienyl)ethylamine | C6H8BrNS | 详情 | 详情 | |
| (IV) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (V) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (VI) | 36903 | C9H7ClN4S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)Coupling of 5-methoxy-2-nitrobenzoic acid (I) with 2-amino-5-chloropyridine (II) by means of POCl3 and pyridine , optionally in acetonitrile solution , yields the corresponding amide (III) , which is then subjected to nitro group reduction to give amine (IV) by either treatment with SnCl2·H2O in refluxing EtOAc or catalytic hydrogenation over sulfided Pt/C in EtOAc or CH2Cl2 . Acylation of aniline (IV) with 4-cyanobenzoyl chloride (V) in the presence of pyridine in CH2Cl2 or THF affords diamide (VI). Finally, nitrile (VI) is converted to amidine by either Pinner reaction with MeOH and HCl in EtOAc and subsequent treatment of the intermediate imino ether with Me2NH in refluxing MeOH , or direct addition of lithium dimethylamide (generated from Me2NH and HexLi) to the cyano group in cold THF .
In an altenative procedure, betrixaban is obtained by coupling of aniline (IV) with the 4-amidinobenzoic acid (VII) in the presence of EDC and a catalytic amount of HCl in DMF or DMA .
| 【1】 Zhu, B.-Y., Wang, L., Goldman, E. et al. (Millennium Pharmaceuticals, Inc.). Benzamides and related inhibitors of factor Xa. EP 1259485, US 6376515, WO 200106442, WO 2001064643. |
| 【2】 Zhang, P., Huang, W., Wang, L. et al. Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl) benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett 2009, 19(8):2179-85. |
| 【3】 Kanter, J.P., Sujino, K., Zuberi, S.S. (Millennium Pharmaceuticals, Inc.).WO 2008057972. |
| 【4】 Pandey, A., Leitao, E.P.T., Rato, J., Song, Z.J. (Millennium Pharmaceuticals, Inc.; Merck & Co., Inc.). Methods of synthesizing factor Xa inhibitors. EP 2513058, US 201131927, WO 201108419. |
| 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) | 68321 | 5-methoxy-2-nitrobenzoic acid;2-Nitro-5-methoxybenzoic acid | C8H7NO5 | 详情 | 详情 | |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 68322 | N-(5-chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide | C13H10ClN3O4 | 详情 | 详情 | |
| (IV) | 68323 | 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide | C13H12ClN3O2 | 详情 | 详情 | |
| (V) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (VI) | 68324 | N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide | C21H15ClN4O3 | 详情 | 详情 | |
| (VII) | 68325 | 4-(N,N-dimethylcarbamimidoyl)benzoic acid hydrochloride | C10H12N2O2.HCl | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XXVII)Aminocyclohexanecarboxylic acid ethyl ester (IV) and some synthetic precursors are prepared as follows. Acylation of 2-amino-5-chloropyridine (XXVII) with either potassium ethyl oxalate (XXVIII) by means of EDC and HOBt in DMF or with methyl oxalyl chloride (XXIX) in the presence of NaHCO3 in THF or CH2Cl2 or Et3N in CH2Cl2 provides the corresponding N-(5-chloro-2-pyridyl)-oxamic acid esters (XXI) and (XXX), respectively. The lithium oxamate (VI) has been prepared by hydrolysis of the methyl ester (XXX) with LiOH in aqueous THF . Coupling of the ehtyl pyridyloxamate (XXI) with the monoprotected diamine (XV) (previously derivatized as the corresponding malate or oxalate salt) in the presence of Et3N in acetonitrile at 65-70 ℃ yields oxamide (XXXI), which is finally deprotected to give intermediate (IV) by removing the N-Boc-protecting group by means of methanesulfonic acid in acetonitrile .
| 【1】 Ohta, T., Komoyira, S., Yoshimo, T. et al. (Daiichi Sankyo Co., Ltd.).Diamine derivatives. CA 2451605, CA 2456841, EP 1405852, EP 1415992, JP 2008143905, US 2005020645, US 2005119486, US 2005245565, US 2008015215, US 2009270446, US 7342014, US 7365205, WO 2003000657, WO 2003000680, WO 2003016302. |
| 【2】 Ohta, T., Komoriya, S., Yoshino, T. et al. (Daiichi Sankyo Co., Ltd.). Diamine derivatives. CA 2511493, EP 1577301, JP 2007070369, JP 2008138011, US 2006252837, US 2009281074, US 7576135, WO 2004058715. |
| 【3】 Schwartz, H.M., Wu, W.-S., Marr, P.W., Jones, J.B. Predicting the enantiomeric selectivity of chymotrypsin. Homologous series of ester substances. J Am Chem Soc 1978, 100(16): 5199-203. |
| 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) | 69423 | (1S,2R,4S)-ethyl 3-amino-4-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)cyclohexanecarboxylate | C16H21ClN4O4 | 详情 | 详情 | |
| (VI) | 69425 | N-(5-chloro-2-pyridyl)oxamic acid lithium salt;lithium 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate | C7H4ClLiN2O3 | 详情 | 详情 | |
| (XV) | 69432 | (1R,3R,4S)-ethyl 4-amino-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate | C14H26N2O4 | 详情 | 详情 | |
| (XXI) | 69438 | ethyl N-(5-chloro-2-pyridyl)oxamate;ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate | C9H9ClN2O3 | 详情 | 详情 | |
| (XXVII) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (XXVIII) | 69444 | potassium 2-ethoxy-2-oxoacetate;potassium ethyl oxalate;Oxalic acid 1-ethyl 2-potassium salt | 1906-57-6 | C4H6KO4 | 详情 | 详情 |
| (XXIX) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (XXX) | 69446 | methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate | C8H7ClN2O3 | 详情 | 详情 | |
| (XXXI) | 69445 | (1R,3S,4R)-ethyl 3-((tert-butoxycarbonyl)amino)-4-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)cyclohexanecarboxylate | C21H29ClN4O6 | 详情 | 详情 |