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【结 构 式】 
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【分子编号】31150 【品名】4-methylpyridine 【CA登记号】108-89-4 |
【 分 子 式 】C6H7N 【 分 子 量 】93.12832 【元素组成】C 77.38% H 7.58% N 15.04% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of ethyl acetate (I) with 4-picoline (II) by means of n-butyllithium in THF gives 1-(4-pyridyl)propanone (III), which by reaction with the dimethylacetal of dimethylformamide (IV) in refluxing HMPT is converted into 4-dimethylamino-3-(4-pyridyl)-3-buten-2-one (V). Finally, this compound is cyclized with cyanacetamide (VI) by means of sodium methoxide in refluxing DMF.
| 【1】 Lehser, G.Y.; Philion, R.E.; Page, D.F.; Opalka, C.J. (Sterling Winthrop Inc.); 5-(pyridinyl)-2(1H)-pyridinones, useful as cardiotonic agents and their preparation. DE 3044568; FR 2470124; GB 2065642; NL 8006399 . |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; WIN-47,203. Drugs Fut 1982, 7, 10, 757. |
| 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) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
| (II) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (III) | 32092 | 1-(4-pyridinyl)acetone | C8H9NO | 详情 | 详情 | |
| (IV) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (V) | 32093 | (E)-4-(dimethylamino)-3-(4-pyridinyl)-3-buten-2-one | C11H14N2O | 详情 | 详情 | |
| (VI) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The reaction of 2-(3-benzoylphenyl)propionic acid (I) with SOCl2 or PCl3 gives the corresponding acyl chloride (II), which is then condensed with 4-methylpyridine-2-amine (III) by means of 4-methylpyridine in pyridine.
| 【1】 Vega, A.; Prieto, J.; Moragues, J. (Fordonal SL); Procedimiento para la preparacion de una amida de la 2-amino-4-metylpiridina. BE 0882711; ES 8102556; IT 1130573 . |
| 【2】 Vega Noverola, A.; Prieto Soto, J.; Spickett, R.G.W.; Amide derivs. of 3-benzoyl-phenylalkanoic acids. GB 1436502 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (I) | 24290 | 2-(3-benzoylphenyl)propionic acid | 22071-15-4 | C16H14O3 | 详情 | 详情 |
| (II) | 24291 | 2-(3-benzoylphenyl)propanoyl chloride | C16H13ClO2 | 详情 | 详情 | |
| (III) | 14614 | 2-Amino-4-picoline; 4-Methyl-2-pyridinamine; 4-Methyl-2-pyridinylamine; 2-Amino-4-methylpyridine | 695-34-1 | C6H8N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Synthesis of the intermediate diazepinone (IV) is accomplished by a one-pot synthesis. Condensation of 2-chloro-3-aminopyridine (I) with the anthranilic ester (II) is effected in the presence of potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene yields the corresponding choroacetamide (V). The side chain of AQ-RA 741 is prepared starting from 4-picoline, which is alkylated by reaction with 3-(diethylamino)propylchloride in the presence of n-butyllithium. Hydrogenation of (VIII) using platinum dioxide as a catalyst furnishes the diamine (IX), which is coupled with (V) in the presence of catalytic amounts of sodium iodide in acetone leading to AQ-RA 741 as its free base.
| 【1】 Eberlein, W.; Engel, W.; Trummlitz, G.; Mihm, G.; Mayer, N.; Doods, H. (Dr. Karl Thomae GmbH); Condensed diazepinones, process for their preparation and medicines containing them. AU 8824122; DE 3735895; EP 0312895; JP 1989230580; US 5175158 . |
| 【2】 Eberlein, W.; Doods, H.; Wetzel, B.; AQ-RA-741. Drugs Fut 1990, 15, 8, 786. |
| 【3】 LaMontagne, M.P.; et al.; Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics. J Med Chem 1989, 32, 8, 1728-32. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (I) | 11160 | 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine | 6298-19-7 | C5H5ClN2 | 详情 | 详情 |
| (II) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
| (III) | 11162 | 2-Amino-N-(2-chloro-3-pyridinyl)benzamide | C12H10ClN3O | 详情 | 详情 | |
| (IV) | 11163 | 5,11-Dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one | C12H9N3O | 详情 | 详情 | |
| (V) | 11164 | 11-(2-Chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one | C14H10ClN3O2 | 详情 | 详情 | |
| (VI) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 31151 | N-(3-chloropropyl)-N,N-diethylamine; 3-chloro-N,N-diethyl-1-propanamine | C7H16ClN | 详情 | 详情 | |
| (VIII) | 31152 | N,N-diethyl-N-[4-(4-pyridinyl)butyl]amine; N,N-diethyl-4-(4-pyridinyl)-1-butanamine | C13H22N2 | 详情 | 详情 | |
| (IX) | 31153 | N,N-diethyl-N-[4-(4-piperidinyl)butyl]amine; N,N-diethyl-4-(4-piperidinyl)-1-butanamine | C13H28N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVII)In a different strategy, the lithium derivative of 4-picoline (XVII) was alkylated with 2-(3-bromopropoxy)tetrahydropyran (XVIII) to afford (XIX). Acidic hydrolysis of the tetrahydropyranyl protecting group furnished 4-(4-pyridinyl)butanol (XX). Alternatively, lithiation of 4-picoline (XVII), followed by alkylation with 1-bromo-3-chloropropane (XXI) gave rise to 4-(4-pyridinyl)butyl chloride (XXII).
| 【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. US 5312923; WO 9316994 . |
| 【2】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. WO 9316995 . |
| 【3】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L.; Grabowski, E.E.; A practical synthesis of fibrinogen receptor antagonist MK-383 - Selective functionalization of (S)-tyrosine. Tetrahedron 1993, 49, 26, 5767. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (XVIII) | 42252 | 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran | C8H15BrO2 | 详情 | 详情 | |
| (XIX) | 59549 | 4-(4-pyridinyl)butyl tetrahydro-2H-pyran-2-yl ether; 4-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]pyridine | C14H21NO2 | 详情 | 详情 | |
| (XX) | 59550 | 4-(4-pyridinyl)-1-butanol | C9H13NO | 详情 | 详情 | |
| (XXI) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (XXII) | 59551 | 4-(4-chlorobutyl)pyridine | C9H12ClN | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The lithium derivative of 4-picoline (I) was acylated with ethyl 4-fluorobenzoate (II) to afford ketone (III). Condensation of (III) with dimethylformamide dimethylacetal provided enaminone (IV) which was subsequently cyclized with hydroxylamine to give the diaryl isoxazole (V). Isoxazole ring opening in (V) under basic conditions led to keto nitrile (VI). Chlorination of (VI) by means of POCl3, followed by reaction with hydrazine, furnished the amino pyrazole (VII). The diazonium salt (VIII) prepared from amino pyrazole (VII) was then added to the phosphorane aldehyde (IX) to generate the pyrazolotriazine (X). Hydrogenation of the triazine ring of (X) employing NaBH3CN produced the tetrahydro pyrazolotriazine (XI). This was finally acylated by phenylglyoxylic acid (XII) to yield the target alpha-oxo amide.
| 【1】 Kawai, Y.; Yamazaki, H.; Tanaka, H.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolitriazines with interleukin-1 and tumour necrosis factor inhibitory activity. EP 0686156; JP 1996507056; WO 9419350 . |
| 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) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (II) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
| (III) | 45005 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
| (IV) | 55996 | (Z)-3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridinyl)-2-propen-1-one | C16H15FN2O | 详情 | 详情 | |
| (V) | 55997 | 4-[5-(4-fluorophenyl)-4-isoxazolyl]pyridine | C14H9FN2O | 详情 | 详情 | |
| (VI) | 55998 | 3-(4-fluorophenyl)-3-oxo-2-(4-pyridinyl)propanenitrile | C14H9FN2O | 详情 | 详情 | |
| (VII) | 55999 | 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-ylamine; 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine | C14H11FN4 | 详情 | 详情 | |
| (VIII) | 56000 | 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-diazonium | C14H9FN5 | 详情 | 详情 | |
| (IX) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (X) | 56001 | 7-(4-fluorophenyl)-8-(4-pyridinyl)pyrazolo[5,1-c][1,2,4]triazine | C16H10FN5 | 详情 | 详情 | |
| (XI) | 56002 | 7-(4-fluorophenyl)-8-(4-pyridinyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine | C16H14FN5 | 详情 | 详情 | |
| (XII) | 55589 | Benzoylformic acid; Phenylglyoxylic acid | 611-73-4 | C8H6O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)Wittig reaction between 2-nitrobenzyltriphenylphosphonium bromide (I) and pyridine-4-carboxaldehyde (II) provided the olefin adduct (IIIa-b) as a mixture of geometric isomers. After, nitro group reduction employing SnCl2, the desired E-isomer (VII), was isolated from the reaction mixture by fractional crystallization. In an alternative approach to intermediate (VII), condensation between 2-nitrobenzaldehyde (IV) and 4-picoline (V) in refluxing acetic anhydride furnished the E-olefin (VI), which was subsequently reduced with SnCl2 to the desired aniline (VII). Acylation of amine (VII) with 4-methoxybenzenesulfonyl chloride (VIII) in pyridine gave sulfonamide (IX). Subsequent oxidation of the pyridine ring to the corresponding N-oxide (X) was accomplished by treatment with peracetic acid at 70 C. The sulfonamide N was finally acetylated in boiling acetic anhydride.
| 【1】 Matsuura, A.; Matsuda, M. (Nippon Shinyaku Co., Ltd.); Aminostilbazole derivs. and medicine. EP 0754682; WO 9527699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 58544 | 9-amino-3-ethyl-3,7-dihydro-6H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazin-6-one | C10H10N6O | 详情 | 详情 | |
| (IIIb),(VI) | 58555 | 4-[(E)-2-(2-nitrophenyl)ethenyl]pyridine | C13H10N2O2 | 详情 | 详情 | |
| (I) | 58553 | (2-nitrobenzyl)(triphenyl)phosphonium bromide | C25H21BrNO2P | 详情 | 详情 | |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (IV) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 58556 | 2-[(E)-2-(4-pyridinyl)ethenyl]aniline; 2-[(E)-2-(4-pyridinyl)ethenyl]phenylamine | C13H12N2 | 详情 | 详情 | |
| (VIII) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IX) | 58557 | 4-methoxy-N-{2-[(E)-2-(4-pyridinyl)ethenyl]phenyl}benzenesulfonamide | C20H18N2O3S | 详情 | 详情 | |
| (X) | 58558 | 4-[(E)-2-(2-{[(4-methoxyphenyl)sulfonyl]amino}phenyl)ethenyl]-1-pyridiniumolate | C20H18N2O4S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Condensation of phthalic anhydride (I) with 4-methylpyridine (II) and heating with NH2-NH2 hydrate yields phthalazine (III) which is converted into chloro derivative (IV) by directly heating in presence of POCl3 or alternatively by heating a solution of (IV) in CH3CN with HCl/dioxane and POCl3. Phthalazine (III) is added to a melt formed by 4-chloroaniline (V), P2O5 and Et3N.HCl to afford the desired product. Alternatively the final product is obtained by heating (V) with (IV) in EtOH or 1-butanol.
| 【1】 DE 1061788; GB 871753 . |
| 【2】 Altmann, K.-H.; Mett, H.; Wood, J.; Stover, D.R.; Frei, J.; Bold, G.; Traxler, P. (Novartis AG); Phthalazines with angiogenesis inhibiting activity. EP 0970070; WO 9835958 . |
| 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) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (II) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (III) | 41366 | 4-(4-pyridinylmethyl)-1,2-dihydro-1-phthalazinol | C14H13N3O | 详情 | 详情 | |
| (IV) | 41367 | 1-chloro-4-(4-pyridinylmethyl)phthalazine | C14H10ClN3 | 详情 | 详情 | |
| (V) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)The reaction of 3,5-dihydroxybenzoic acid (I) with N,O-dimethylhydroxylamine (II) by means of EDC and NMM in dichloromethane gives the N,O-dimethylbenzamide (III), which is alkylated with butyl bromide (IV) and K2CO3 in hot DMF to yield the dibutoxybenzamide (V). The condensation of (V) with 4-methylpyridine (VI) by means of LDA in THF affords 1-(2,4-dibutoxyphenyl)-2-(4-pyridyl)ethanone (VII), which is oxidized with SeO2 in hot acetic acid to provide the dione (VIII). Finally, this compound is cyclized with 4-chlorobenzaldehyde (IX) and ammonium acetate in refluxing acetic acid to furnish the target imidazole.
| 【1】 Chang, L.L.; et al.; Substituted imidazoles as gluagon receptor antagonists. Bioorg Med Chem Lett 2001, 11, 18, 2549. |
| 【2】 de Laszlo, S.; O'Keefe, S.; Li, B.; MacCoss, M.; Rolando, A.; mantlo, N.; Koch, G.; Cascieri, M.A.; Hagmann, W.K.; Chang, L.L.; Pang, M.; Sidler, K.L.; Selective, non-peptide antagonists for the glucagon receptor: Substituted imidazoles. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 237. |
| 【3】 Chang, L.L. (Merck & Co., Inc.); Triaryl substd. imidazoles as glucagon antagonists. EP 0959886; JP 2000514088; US 5880139; WO 9822109 . |
| 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) | 48820 | 2,4-Dihydroxybenzenecarboxylic acid; 2,4-Dihydroxybenzoic acid; beta-Resorcylic acid; Resorcinol-4-carboxylic acid | 89-86-1 | C7H6O4 | 详情 | 详情 |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 48821 | 2,4-dihydroxy-N-methoxy-N-methylbenzamide | C9H11NO4 | 详情 | 详情 | |
| (IV) | 28721 | 1-bromobutane | 109-65-9 | C4H9Br | 详情 | 详情 |
| (V) | 48822 | 2,4-dibutoxy-N-methoxy-N-methylbenzamide | C17H27NO4 | 详情 | 详情 | |
| (VI) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 48823 | 1-(2,4-dibutoxyphenyl)-2-(4-pyridinyl)-1-ethanone | C21H27NO3 | 详情 | 详情 | |
| (VIII) | 48824 | 1-(2,4-dibutoxyphenyl)-2-(4-pyridinyl)-1,2-ethanedione | C21H25NO4 | 详情 | 详情 | |
| (IX) | 29029 | 4-chlorobenzaldehyde | 104-88-1 | C7H5ClO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VI)Acylation of the lithium derivative of 4-picoline (VI) with the Weinreb amide of 4-fluorobenzoic acid (V) yielded ketone (VII). The sodium enolate of (VII) was then alkylated with chloro ketone (IV) to afford diketone (VIII). The Paal-Knorr cyclization of diketone (VIII) in the presence of ammonium acetate in boiling HOAc led to pyrrole (IX). Finally, reduction of the benzyloxycarbonyl group of (IX) by means of LiAlH4 furnished the target N-methyl piperidine.
| 【1】 De Laszlo, S.E.; Mantlo, N.B.; Ponticello, G.S.; Selnick, H.G.; Liverton, N.J. (Merck & Co., Inc.); 2-Substd. aryl pyrroles, compsns. containing such cpds. and methods of use. EP 0863757; JP 1999510510; US 5792778; WO 9705877 . |
| 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) | 56084 | benzyl 4-(2-chloroacetyl)-1-piperidinecarboxylate | C15H18ClNO3 | 详情 | 详情 | |
| (V) | 29514 | 4-fluoro-N-methoxy-N-methylbenzamide | C9H10FNO2 | 详情 | 详情 | |
| (VI) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 45005 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
| (VIII) | 56085 | benzyl 4-[4-(4-fluorophenyl)-4-oxo-3-(4-pyridinyl)butanoyl]-1-piperidinecarboxylate | C28H27FN2O4 | 详情 | 详情 | |
| (IX) | 56086 | benzyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrrol-2-yl]-1-piperidinecarboxylate | C28H26FN3O2 | 详情 | 详情 |