|
【结 构 式】 
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【分子编号】32889 【品名】4-chloropyridine 【CA登记号】7379-35-3 |
【 分 子 式 】C5H4ClN 【 分 子 量 】113.5462 【元素组成】C 52.89% H 3.55% Cl 31.22% N 12.34% |
合成路线1
该中间体在本合成路线中的序号：(IV)Compound can be prepared in several different ways: 1) By treatment of pyridine-4-sulfonic acid (I) with NH4OH and ZnCl2 in an autoclave at 160 C. 2) By reduction of 4-nitropyridine (II) with SO2 in hot water or diluted H2SO4. 3) By treatment of pyridine-4-carboxylic acid (III) with NH3 at high temperature using CuO as catalyst. 4) By treatment of 4-chloropyridine (IV) or 3-chloropyridine (V) with KNH2 in liquid NH3. 5) By treatment of 4-iodopyridine (VI) or 3-iodopyridine (VII) with KNH2 in liquid NH3.
| 【1】 Pieterse, M.J.; Den Hertog, H.J.; Rearrangements during aminations of halopyridines, presumably involving a pyridine intermediate. Recl Trav Chim Pays-Bas 1961, 80, 1376-86. |
| 【2】 Suzuki, Y.; Reactions of 4-pyridine- and 4-quinolinesulfonic acids with amines. Yakugaku Zasshi 1961, 81, 1146-50. |
| 【3】 Hayashi, E.; Yamanaka, H.; JP 6115616 . |
| 【4】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Paton, D.M.; 4-Aminopyridine. Drugs Fut 1980, 5, 5, 221. |
| 【5】 Rauch, F.C.; Arzoumanidis, G.G.; DE 2258227 . |
| 【6】 Rauch, F.C.; Arzoumanidis, G.G.; US 3812137 . |
| 【7】 Koenig, C.; et al.; DE 1270563 . |
| 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) | 39036 | 4-pyridinesulfonic acid | C5H5NO3S | 详情 | 详情 | |
| (II) | 39037 | 4-nitropyridine | C5H4N2O2 | 详情 | 详情 | |
| (III) | 25028 | isonicotinic acid | 55-22-1 | C6H5NO2 | 详情 | 详情 |
| (IV) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (V) | 39038 | 3-chloropyridine | 626-60-8 | C5H4ClN | 详情 | 详情 |
| (VI) | 39039 | 4-iodopyridine | C5H4IN | 详情 | 详情 | |
| (VII) | 29108 | 3-iodopyridine | C5H4IN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)1) The esterification of D-penicillamine (I) with trimethylsilyl chloride and DBU in DMF gives the expected ester (II), which is cyclized with 1,2-dibromoethane by means of DBU and DIEA in DMF and protected at the amino group with Fmoc-Cl and NMM to afford 4-(9-fluorenylmethoxycarbonyl)-2,2-dimethylthiomorpholine-3(S)-carboxylic acid (III), which by treatment with O-[tert-butyl(diphenyl)silyl]hydroxylamine (TBDPSO-NH2) and EDC in dichloro-methane yields the silylated carbohydroxamic acid (IV). The removal of the Fmoc group of (IV) with diethylamine in THF affords (V), which is sulfonated with 4-(4-pyridyloxy)phenylsulfonyl chloride (VI) and NMM in dichloroethane to give the protected prinomastat (VII). Finally, this compound is desilylated with concentrated HCl in methanol. The intermediate (VI) is obtained by condensation of 4-chloropyridine (VIII) with phenol (IX) at 150 C to give 4-phenoxypyridine (X), which is then sulfonated with chlorosulfonic acid and treated with oxalyl chloride to afford the desired sulfonyl chloride (VI).
| 【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150. |
| 【2】 Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses. US 5753653 . |
| 【3】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 . |
| 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) | 12567 | (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine | 1113-41-3 | C5H11NO2S | 详情 | 详情 |
| (II) | 32883 | trimethylsilyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate | C8H19NO2SSi | 详情 | 详情 | |
| (III) | 32884 | (3S)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2,2-dimethyl-3-thiomorpholinecarboxylic acid | C22H23NO4S | 详情 | 详情 | |
| (IV) | 32885 | 9H-fluoren-9-ylmethyl (3S)-3-[([[tert-butyl(diphenyl)silyl]oxy]amino)carbonyl]-2,2-dimethyl-4-thiomorpholinecarboxylate | C38H42N2O4SSi | 详情 | 详情 | |
| (V) | 32886 | (3S)-N-[[tert-butyl(diphenyl)silyl]oxy]-2,2-dimethyl-3-thiomorpholinecarboxamide | C23H32N2O2SSi | 详情 | 详情 | |
| (VI) | 32887 | 4-(4-pyridinyloxy)benzenesulfonyl chloride | C11H8ClNO3S | 详情 | 详情 | |
| (VII) | 32888 | (3S)-N-[[tert-butyl(diphenyl)silyl]oxy]-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxamide | C34H39N3O5S2Si | 详情 | 详情 | |
| (VIII) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (IX) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (X) | 32890 | 4-phenoxypyridine; phenyl 4-pyridinyl ether | 4783-86-2 | C11H9NO | 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 reaction of (2S,4R)-1-(tert-butoxycarbonyl)-N-tert-butyl-4-hydroxypiperidine-2-carboxamide (I) with MsCl and TEA gives the mesylate (II), which is treated with tetrabutylammonium bromide in refluxing THF to yield the corresponding 4-bromo derivative (III). The reaction of (III) with potassium thioacetate, followed by hydrolysis with NaOH affords the sodium thiolate (IV), which is condensed with 4-chloropyridine (V) to provide (2S,4R)-1-(tert-butoxycarbonyl)-N-tert-butyl-4-(4-pyridylsulfanyl)piperidine-2-carboxamide (VI). The deprotection of (VI) with TFA or HCl in dioxane gives intermediate (VII), which is condensed with epoxide (VIII) in refluxing ethanol to obtain the expected addition compound (IX). The deprotection of (IX) with TFA or HCl as before yields the amide (X), which is finally condensed with 2-(2,6-dimethylphenoxy)acetic acid (XI) by means of BOP and DIEA to furnish the target diamide.
| 【1】 Anderson, P.C.; Beaulieu, P.L.; Cameron, D.R.; et al.; 2'6'-Dimethylphenoxyacetyl: A new achiral high affinity P3-P2 ligand for peptidomimetic-based HIV protease inhibitors. J Med Chem 2000, 43, 6, 1094. |
| 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) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (II) | 38756 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-piperidinecarboxylate | C18H34N2O4S | 详情 | 详情 | |
| (III) | 38757 | tert-butyl (2S,4S)-4-bromo-2-[(tert-butylamino)carbonyl]-1-piperidinecarboxylate | C15H27BrN2O3 | 详情 | 详情 | |
| (IV) | 38762 | C15H27N2NaO3S | 详情 | 详情 | ||
| (V) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (VI) | 38758 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylsulfanyl)-1-piperidinecarboxylate | C20H31N3O3S | 详情 | 详情 | |
| (VII) | 38759 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylsulfanyl)-2-piperidinecarboxamide | C15H23N3OS | 详情 | 详情 | |
| (VIII) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (IX) | 38760 | tert-butyl (1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylsulfanyl)piperidinyl]-2-hydroxypropylcarbamate | C30H44N4O4S | 详情 | 详情 | |
| (X) | 38761 | (2S,4R)-1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)-4-(4-pyridinylsulfanyl)-2-piperidinecarboxamide | C25H36N4O2S | 详情 | 详情 | |
| (XI) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Conversion of alcohol (I) into chloro derivative (II) by reaction with PCl3 in DMF, followed by reaction with PCl5/pyridine in CH2Cl2, treatment with iBuOH and acidic treatment with TsOH, provides 7-amino-3-chlorocephalosporanic acid diphenylmethyl ester toluene sulfonic acid salt (III). Separately, O-protection of thiazole derivative (IV) by reaction with TrtCl and tert-BuOK in THF affords trityl protected compound (V), whose ethyl carboxylate group is hydrolyzed by means of KOH in EtOH to furnish carboxylic acid (VI). Chlorination of the thiazol ring of (VI) by means of N-chlorosuccinimide (NCS) in DMF yields chlorothiazole derivative (VII), which is then condensed with 7-amino-3-chlorocephalosporanic acid derivative (III) by means of POCl3 in THF to give acetamido derivative (VIII). Separately, the synthesis of pyridine derivative (XIV) is performed by following these steps: alkylation of chloropyridine (IX) by means of LDA and ethyl formate provides derivative (X), which is then reduced by means of NaBH4 to furnish alcohol (XI). Finally, (XIV) is obtained by first chlorination of (XI) with SOCl2 in DMF to afford chloromethyl derivative (XII), and subsequent condensation of (XII) with N-Boc-ethanethiol (XIII) either by means of Et3N in CH2Cl2 or by means of NaI and DIEA in DMF. Treatment of derivative (VIII) with NaSH in DMF, followed by coupling with chloropyridine derivative (XIV) in DMF, furnishes compound (XV), which is finally converted into the desired product by protecting groups removal with TFA/anisole or TFA/triethylsilane in CH2Cl2, and treatment with MsOH in H2O.
| 【1】 Hecker, S.J.; et al.; Discovery of RWJ-54428 (MC-02,479), a new cephaolosporin active against resistant Gram-positive bacteria. J Antibiot 2000, 53, 11, 1272. |
| 【2】 Glinka, T.W.; et al.; SAR studies of anti-MRSA non-zwitterionic 3-heteroarylthiocephems. J Antibiot 2000, 53, 10, 1045. |
| 【3】 Cho, I.-S.; Hecker, S.; Glinka, T.; Lee, V.J.; Zhang, Z.J. (Microcide Pharmaceuticals, Inc.); Cephalosporin antibiotics. EP 0874854; JP 1999513670; US 6057312; US 6066630; US 6087355; WO 9713772 . |
| 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) | 37977 | benzhydryl (6R,7R)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H24N2O5S | 详情 | 详情 | |
| (II) | 48459 | benzhydryl (6R,7R)-3-chloro-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H23ClN2O4S | 详情 | 详情 | |
| (III) | 48460 | (6R,7R)-2-[(benzhydryloxy)carbonyl]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-aminium 4-methylbenzenesulfonate | C27H25ClN2O6S2 | 详情 | 详情 | |
| (IV) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
| (V) | 48461 | (Z)-ethyl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate；ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetate | C26H23N3O3S | 详情 | 详情 | |
| (VI) | 48462 | 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid；(Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetic acid | 128438-01-7 | C24H19N3O3S | 详情 | 详情 |
| (VII) | 48463 | 2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid | C24H18ClN3O3S | 详情 | 详情 | |
| (VIII) | 48464 | benzhydryl (6R,7R)-7-([2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetyl]amino)-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C44H33Cl2N5O5S2 | 详情 | 详情 | |
| (IX) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (X) | 48465 | ethyl 4-chloro-2-pyridinecarboxylate | C8H8ClNO2 | 详情 | 详情 | |
| (XI) | 48466 | (4-chloro-2-pyridinyl)methanol | C6H6ClNO | 详情 | 详情 | |
| (XII) | 48467 | 4-chloro-2-(chloromethyl)pyridine | C6H5Cl2N | 详情 | 详情 | |
| (XIII) | 33079 | tert-butyl 2-sulfanylethylcarbamate | C7H15NO2S | 详情 | 详情 | |
| (XIV) | 48468 | tert-butyl 2-[[(4-chloro-2-pyridinyl)methyl]sulfanyl]ethylcarbamate | C13H19ClN2O2S | 详情 | 详情 | |
| (XV) | 48469 | benzhydryl (6R,7R)-7-([2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetyl]amino)-3-([2-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-4-pyridinyl]sulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C57H52ClN7O7S4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Condensation of 4-aminophenol (I) with 4-chloropyridine (II) in the presence of potassium tert-butoxide afforded the intermediate diaryl ether (III).
| 【1】 Redman, A.; Paulsen, H.; Lowinger, T.B.; Dumas, J.; Johnson, J.; Wood, J.E.; Scott, W.J.; Khire, U.; Hatoum-Mokdad, H.; Lee, W.; Smith, R.A.; Riedl, B. (Bayer Corp.); Inhibition of raf kinase using substd. heterocyclic ureas. EP 1047418; WO 9932106 . |
合成路线6
该中间体在本合成路线中的序号：(V)Reaction of picolinic acid (I) with hot thionyl chloride in DMF gives 4-chloropyridine-2-carbonyl chloride (II), which is treated with methanol to give ester (III). Subsequent displacement of the methyl ester function with methylamine provides amide (IV). Alternatively, acid chloride (II) is directly converted into amide (IV) by reaction with a cold solution of methylamine. In a different synthetic procedure, amide (IV) can be obtained from 4-chloropyridine (V) via the Menisci reaction using N-methylformamide and hydrogen peroxide in the presence of FeSO4 and H2SO4. Coupling of the amide (IV) with potassium 4-aminophenolate (VI) -obtained by treatment of 4-aminophenol (VII) with potassium tert-butoxide- in hot DMF yields the pyridyloxyaniline (VIII). Aniline (VIII) is finally condensed with either 4-chloro-3-(trifluoromethyl)phenyl isocyanate (IX) in CH2Cl2 or 4-chloro-3-(trifluoromethyl)aniline (X) by means of CDI in CH2Cl2.
| 【1】 Sorbera, L.A.; Castaner, J.; Bozzo, J.; Leeson, P.A.; BAY-43-9006. Drugs Fut 2002, 27, 12, 1141. |
| 【2】 Monahan, M.-K.; Sibley, R.; Natero, R.; Dumas, J.; Bankston, D.; Riedl, B.; A scaleable synthesis of BAY 43-9006: A potent Raf kinase inhibitor for the treatment of cancer. Org Process Res Dev 2002, 6, 6, 777. |
| 【3】 Smith, R.A.; Monahan, M.-K.; Riedl, B.; Scott, W.J.; Khire, U.; Lowinger, T.B.; Natero, R.; Sibley, R.N.; Wood, J.E.; Renick, J.; Dumas, J. (Bayer Corp.); omega-Carboxy aryl substd. diphenyl ureas as p38 kinase inhibitors. WO 0041698 . |
| 【4】 Lowinger, T.B.; Monahan, M.-K.; Dumas, J.; Scott, W.J.; Khire, U.; Wood, J.E.; Renick, J.; Riedl, B.; Smith, R.A.; Natero, R.; Sibley, R.N. (Bayer Corp.); omega-Carboxyaryl substd. diphenyl ureas as raf kinase inhibitors. EP 1140840; WO 0042012 . |
| 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) | 29950 | 2-pyridinecarboxylic acid；picolinic acid;Pyridine-2-carboxylic acid | 98-98-6 | C6H5NO2 | 详情 | 详情 |
| (II) | 49908 | 4-chloropyridine-2-carbonyl chloride hydrochloride;(4-Chloro-2-pyridinecarbonyl Chloride Hydrochloride);4-Chloro-2-pyridinecarbonyl Chloride Hydrochlorid | 51727-15-2 | C6H3Cl2NO.HCl | 详情 | 详情 |
| (III) | 49909 | methyl 4-chloro-2-pyridinecarboxylate | 24484-93-3 | C7H6ClNO2 | 详情 | 详情 |
| (IV) | 49910 | 4-chloro-N-methyl-2-pyridinecarboxamide；4-chloro-N-methylpyridine-2-carboxamide;4-chloro-N-methylpicolinamide;4-Chloro-N-methylpicolinamide;2-(N-Methylcarbamoyl)-4-chloropyridine;4-Chloropyridine-2-carboxylicacid methylamide;N-Methyl-4-chloro-2-pyridinecarboxamide;N-Methyl-4-chloropicolinamide | 220000-87-3 | C7H7ClN2O | 详情 | 详情 |
| (V) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (VI) | 49911 | potassium 4-aminobenzenolate | C6H6KNO | 详情 | 详情 | |
| (VII) | 49912 | 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide | 284462-37-9 | C13H13N3O2 | 详情 | 详情 |
| (VII) | 49912 | 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide | 284462-37-9 | C13H13N3O2 | 详情 | 详情 |
| (VIII) | 37868 | 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene; 4-chloro-3-(trifluoromethyl)phenyl isocyanate | 327-78-6 | C8H3ClF3NO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)The reaction of o-phenylenediamine (IX) with 4-chloropyridine (VIII) gives 2-(4-pyridylamino)aniline (X), which is condensed with 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (I) to give the corresponding pyridinium salt (XI). The reduction of (XI) with NaBH4 yields amino compound (VII). Finally this compound is cyclized with carbon disulfide and KOH
| 【1】 JP 76095096 . |
| 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) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (VII) | 60704 | N-(2-aminophenyl)-N-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)amine; N~1~-(1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4-piperidinyl)-1,2-benzenediamine | C23H30FN3O2 | 详情 | 详情 | |
| (VIII) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (IX) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (X) | 60705 | N-(2-aminophenyl)-N-(4-pyridinyl)amine; N~1~-(4-pyridinyl)-1,2-benzenediamine | C11H11N3 | 详情 | 详情 | |
| (XI) | 60706 | 4-(2-aminoanilino)-1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}pyridinium chloride | C23H25ClFN3O2 | 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 of 4-piperidinylmethanol (I) with 4-chloropyridine (II) gives 1-(4-pyridyl)piperidin-4-ylmethanol (III), which is oxidized with (COCl)2 and TEA in DMSO to yield the carbaldehyde (IV). The reductocondensation of (IV) with N-(tert-butoxycarbonyl)ethylene-1,2-diamine (V) by means of sodium triacetoxyborohydride and acetic acid affords the corresponding adduct as the borane complex (VI), which is acylated with bromoacetyl chloride (VII) and TEA in dichloromethane, providing the bromoacetamide (VIII). The cleavage of the boron complex and the Boc protecting group of (VIII) with TFA and anisole in ethyl ether gives the precursor (IX), which is cyclized to the piperazinone (X) by means of TEA in DMF. Finally, compound (X) is condensed with 6-chloronaphthalene-2-sulfonyl chloride by means of TEA in dichloromethane to yield the target sulfonamide.
| 【1】 Nishida, H.; et al.; Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitor. Chem Pharm Bull 2001, 49, 10, 1237. |
| 【2】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 . |
| 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) | 32954 | 4-piperidinylmethanol | C6H13NO | 详情 | 详情 | |
| (II) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (III) | 45860 | [1-(4-pyridinyl)-4-piperidinyl]methanol | C11H16N2O | 详情 | 详情 | |
| (IV) | 52205 | 1-(4-pyridinyl)-4-piperidinecarbaldehyde | C11H14N2O | 详情 | 详情 | |
| (V) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (VI) | 52206 | C22H37BN4O7 | 详情 | 详情 | ||
| (VII) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VIII) | 52207 | C24H38BBrN4O8 | 详情 | 详情 | ||
| (IX) | 52208 | N-(2-aminoethyl)-2-bromo-N-{[1-(4-pyridinyl)-4-piperidinyl]methyl}acetamide | C15H23BrN4O | 详情 | 详情 | |
| (X) | 52209 | 1-{[1-(4-pyridinyl)-4-piperidinyl]methyl}-2-piperazinone | C15H22N4O | 详情 | 详情 | |
| (XI) | 45865 | 6-chloro-2-naphthalenesulfonyl chloride | C10H6Cl2O2S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Chlorination of picolinic acid (I) with SOCl2 in the presence of DMF at 72 °C gives 4-chloropyridine-2-carbonyl chloride hydrochloride (II), which is then esterified with MeOH to afford the corresponding methyl ester (III). Aminolysis of ester (III) with methylamine in MeOH gives 4-chloro-N-methylpyridine-2-carboxamide (IV) , which can also be prepared by direct amidation of acid chloride (II) with methylamine in THF/MeOH or by Minisci reaction of 4-chloropyridine (V) with N-methylformamide (VI) in the presence of H2SO4, H2O2 and FeSO4·7H2O . Condensation of chloropicolinamide (IV) with 4-amino-3-fluorophenol (VII) –prepared by reduction of 3-fluoro-4-nitrophenol (VIII) by means of H2 and Pd/C in EtOAc– in the presence of t-BuOK in DMAc at 100 °C provides the 4-phenoxypyridine derivative (IX), which is finally coupled with 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (X) in toluene .
| 【1】 Scott, W.J., Joel, R., Ridel, B. et al. (Bayer Healthcare LLC). omega-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors. US 2002042517. |
| 【2】 Dumas, J., Lynch, M., Scott, W.J., Ladouceur, G., Wilhelm, S. (Bayer Pharmaceuticals Corp.). Diaryl ureas with kinase inhibiting activity. CA 2526617, EP 1636585, JP 200751103, US 2007020704, WO 2004113274. |
| 【3】 Dumas, J., Wilhelm, S., Boyer, S., Riedl, B. (Bayer Pharmaceuticals Corp). Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions. EP 1663978, JP 2006528196, US 2005038080, WO 2005009961. |
| 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) | 29950 | 2-pyridinecarboxylic acid；picolinic acid;Pyridine-2-carboxylic acid | 98-98-6 | C6H5NO2 | 详情 | 详情 |
| (II) | 49908 | 4-chloropyridine-2-carbonyl chloride hydrochloride;(4-Chloro-2-pyridinecarbonyl Chloride Hydrochloride);4-Chloro-2-pyridinecarbonyl Chloride Hydrochlorid | 51727-15-2 | C6H3Cl2NO.HCl | 详情 | 详情 |
| (III) | 68688 | methyl 4-chloropicolinate hydrochloride | C7H6ClNO2.HCl | 详情 | 详情 | |
| (IV) | 49910 | 4-chloro-N-methyl-2-pyridinecarboxamide；4-chloro-N-methylpyridine-2-carboxamide;4-chloro-N-methylpicolinamide;4-Chloro-N-methylpicolinamide;2-(N-Methylcarbamoyl)-4-chloropyridine;4-Chloropyridine-2-carboxylicacid methylamide;N-Methyl-4-chloro-2-pyridinecarboxamide;N-Methyl-4-chloropicolinamide | 220000-87-3 | C7H7ClN2O | 详情 | 详情 |
| (V) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (VI) | 68689 | N-methylformamide;Methylformamide;Monomethylformamide;N-Methylformimidic acid;N-Monomethylformamide | 123-39-7 | C2H5NO | 详情 | 详情 |
| (VII) | 68690 | 4-amino-3-fluorophenol;3-Fluoro-4-aminophenol | 399-95-1 | C6H6FNO | 详情 | 详情 |
| (VIII) | 68691 | 3-fluoro-4-nitrophenol;2-Fluoro-4-hydroxy-1-nitrobenzene;4-Nitro-3-fluorophenol | 394-41-2 | C6H4FNO3 | 详情 | 详情 |
| (IX) | 68692 | 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide；4-(4-amino-3- fluorophenoxy)-N-methyl-2-Pyridinecarboxamide;4-(4-Amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide;4-(4-Amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide | 757251-39-1 | C13H12FN3O2 | 详情 | 详情 |
| (X) | 37868 | 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene; 4-chloro-3-(trifluoromethyl)phenyl isocyanate | 327-78-6 | C8H3ClF3NO | 详情 | 详情 |