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【结 构 式】 
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【分子编号】17590 【品名】2-methylpyridine; 2-picoline 【CA登记号】109-06-8 |
【 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：(IV)A new method for the synthesis of encainide has been reported: The acylation of methyl anthranilate (I) with 4-anisoyl chloride (II) by means of NaOH in methylene chloride gives methyl N-(p-anisoyl)anthranilate (III), which is condensed with 2-picoline (IV) by means of n-butyllithium in THF yielding 2-(2-pyridylacetyl)-p-anisanilide (V). Finally, this compound is reduced with H2 over Pt/C then with Pd/C, treated with formaldehyde and reduced again with H2 over Pt/C.
| 【1】 Madding, G.D. (Bristol-Myers Squibb Co.); Process for production of encainide. JP 58105963; NL 8204775; US 4394507 . |
| 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) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
| (II) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (III) | 29100 | methyl 2-[(4-methoxybenzoyl)amino]benzoate | C16H15NO4 | 详情 | 详情 | |
| (IV) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
| (V) | 29101 | 4-methoxy-N-[2-[2-(2-pyridinyl)acetyl]phenyl]benzamide | C21H18N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of 2-methylpyridine (I) with 2-nitrobenzaldehyde (II) in acetic anhydride gives 2-(2-nitrostyryl)pyridine (III), which is quaternized with methyl iodide in refluxing acetone yielding 2-(2-nitrostyryl)-1-methylpyridinium iodide (IV) . The reduction of (IV) with H2 over PtO2 in ethanol affords 2-(2-aminophenethyl)-1-methylpiperidine (V), which is then acylated with 4-methoxybenzoyl chloride (A) in pyridine.
| 【1】 Dykstra, S.J.; Minielli, J.L.; Substituted piperidines and a process for the preparation thereof. BE 0779951; CA 961038; CH 578529; DE 2210154; FR 2128584; GB 1346261; NL 161443C; NL 7202614 . |
| 【2】 Kendrick, W.D.; Ferguson, H.C.; acid and quimidine analogs. 2-(o-Acylaminophenethyl)piperidines. J Med Chem 1973, 16, 9, 1015. |
| 【3】 Castaner, J.; MJ 9067. Drugs Fut 1977, 2, 3, 176. |
| 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) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (I) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
| (II) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (III) | 40197 | 2-[(E)-2-(2-nitrophenyl)ethenyl]pyridine | C13H10N2O2 | 详情 | 详情 | |
| (IV) | 40198 | 1-methyl-2-[(E)-2-(2-nitrophenyl)ethenyl]pyridinium iodide | C14H13IN2O2 | 详情 | 详情 | |
| (V) | 40199 | 2-[2-(1-methyl-2-piperidinyl)ethyl]phenylamine; 2-[2-(1-methyl-2-piperidinyl)ethyl]aniline | C14H22N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Addition of lithium bis(trimethylsilyl)amide to a cooled solution of benzaldehyde (I), followed by treatment with the lithiated anion of 2-picoline (II), gave rise to the silylated amino intermediate (III), which, upon acidic quenching, yielded the racemic alpha-phenyl-2-pyridineethanamine (IV). Resolution of amine (IV) with S-(+)-mandelic acid in EtOAc provided the target (S)-amine mandelate salt (V). Liberation of the free amine with NaOH and subsequent treatment with HCl in EtOAc furnished the corresponding dihydrochloride
| 【1】 Murray, R.J.; Mathisen, D.; Balestra, M. (Celltech Group plc); (S)-Alpha-phenyl-2-pyridineethanamine (S)-malate and its use as a medicament. EP 0691957; EP 0691958; JP 1996508292; JP 1996508475; WO 9422831; WO 9422832 . |
| 【2】 Griffith, R.C.; Murray, R.J.; Balestra, M. (Celltech Group plc); Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders. EP 0633879; JP 2000319259; WO 9320052 . |
| 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) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
| (III) | 60500 | N-[1-phenyl-2-(2-pyridinyl)ethyl]-N,N-bis(trimethylsilyl)amine; trimethyl-N-[1-phenyl-2-(2-pyridinyl)ethyl]-N-(trimethylsilyl)silanamine | C19H30N2Si2 | 详情 | 详情 | |
| (IV) | 60501 | 1-phenyl-2-(2-pyridinyl)-1-ethanamine; 1-phenyl-2-(2-pyridinyl)ethylamine | C13H14N2 | 详情 | 详情 | |
| (V) | 60502 | C21H22N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)AMD473 is prepared by a modified Dhara synthesis: The procedure is similar to that described for the preparation of the platinum(II) precursor of the other mixed amine platinum drug currently in development, JM216. In the first step, potassium amminetrichloroplatinate (II) is reacted with 2-picoline in the presence of iodide at ambient temperature. The direction of substitution in platinum(II) complexes is controlled by the trans effect of the different ligands. Since in [PtCl3(NH3)] the trans effect for Cl > NH3, one of the trans pair of chloride ligands is initially substituted by iodide. Iodide has a much greater trans effect than chloride or ammine ligands and directs further substitution trans to itself. Binding of 2-picoline results in precipitation of the desired isomer [PtCl(I)(NH3)(2-picoline)]. In the second step, the iodide ligand is removed by reaction with silver ions in water at ambient temperature and treatment of the resulting aqua platinum complexes with chloride yields [PtCl2(NH3)(2-picoline)]. This occurs with retention of stereochemistry at platinum, so yielding the pure cis isomer. This complex may be recrystallized from dilute hydrochloric acid.
| 【1】 Dhara, S.C.; A rapid method for the synthesis of cis-[Pt(NH3)2Cl2]. Indian J Chem 1970, 8, 193-4. |
| 【2】 Wyer, S.B.; Vollano, J.F.; Higgins, J.D.; Bossard, G.E.; Giandomenico, C.M.; Murrer, B.A.; Abrams, M.J.; Rheinheimer, M.I.; III. Carboxylation of kinetically inert platinum(IV) hydroxy complexes. An entrée into orally active platinum(IV) antitumor agents. Inorg Chem 1995, 34, 1015-21. |
| 【3】 Kelland, L. R.; Barnard, C.D.J.; AMD473. Drugs Fut 1998, 23, 10, 1062-1065. |
| 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) | 17589 | Ammonia trichloro platinum(II) complex potassium salt | H3Cl3KNPt | 详情 | 详情 | |
| (II) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
| (III) | 17591 | Ammonia 2-methylpyridine chloro iodo platinum complex | C6H10ClIN2Pt | 详情 | 详情 | |
| (IV) | 17592 | Acqua ammoia 2-methylpyridine chloro platinum cationic complex | C6H11ClN2OPt | 详情 | 详情 | |
| (V) | 17593 | Diacqua ammonia 2-methylpyridine platinum dicationic complex | C6H12N2O2Pt | 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 condensation of 2-methylpyridine (I) with 2,3-dichlorobenzonitrile (II) by means of BuLi and diisopropylamine in THF gives the vinyl derivative (III), which is cyclized by heating at 200 C.
| 【1】 Mettey, Y.; Vierfond, J.-M.; Benzo[c]quinoliziums: A new family of inhibitors for protein kinase CK II. Bioorg Med Chem Lett 1997, 7, 8, 961. |
| 【2】 Becq, F.; Mettey, Y.; Vierfond, J.-M.; Verrier, B.; Gola, M. (CNRS (Centre National de la Recherche Scientifique)); CFTR channel activator cpds. and pharmaceutical compsns. containing same. EP 0937044; WO 9805642 . |
合成路线6
该中间体在本合成路线中的序号：(XXIII)The reaction of adipic acid monomethyl ester (XIII) with SOCl2 gives the acyl chloride (XIV), which is brominated with NBS in carbon tetrachloride to yield 5-bromo-5-(chloroformyl)pentanoic acid methyl ester (XV). The reaction of (XV) with phenol (XVI) by means of DIEA in ethyl ether affords the mixed diester (XVII), which is reduced with tri-tert-butoxylithiumaluminum hydride in THF to provide 5-bromo-5-formylpentanoic acid methyl ester (XVIII). The cyclization of (XVIII) with chiral ethanone (XIX) by means of DIEA in hot dioxane gives the methyl ester (XX) of the target compound, which is finally hydrolyzed with NaOH in ethanol/water to obtain the target acid . The intermediate chiral ethanone (XIX) has been obtained as follows: The reaction of the chiral alcohol (VIII) with 4-hydroxybenzoic acid methyl ester (XXI) under Mitsunobu conditions (DEAD, PPh3) gives the chiral ether (XXII), which is then condensed with 2-methylpyridine (XXIII) by means of LiHMDS in THF to yield the target ethanone.
| 【1】 Sawada, K.; Tanaka, H.; Watanabe, S.; Kuroda, A.; Okada, S. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of indolizine derivs.. WO 9507279 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 49223 | (1R)-1-(4-isobutylphenyl)-1-butanol | C14H22O | 详情 | 详情 | |
| (XIII) | 49227 | 6-methoxy-6-oxohexanoic acid | C7H12O4 | 详情 | 详情 | |
| (XIV) | 49228 | methyl 6-chloro-6-oxohexanoate | C7H11ClO3 | 详情 | 详情 | |
| (XV) | 49229 | methyl 5-bromo-6-chloro-6-oxohexanoate | C7H10BrClO3 | 详情 | 详情 | |
| (XVI) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (XVII) | 49230 | 6-methyl 1-phenyl 2-bromohexanedioate | C13H15BrO4 | 详情 | 详情 | |
| (XVIII) | 49231 | methyl 5-bromo-6-oxohexanoate | C7H11BrO3 | 详情 | 详情 | |
| (XIX) | 49232 | 1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]phenyl)-2-(2-pyridinyl)-1-ethanone | C27H31NO2 | 详情 | 详情 | |
| (XX) | 49233 | methyl 4-[1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoyl)-3-indolizinyl]butanoate | C34H39NO4 | 详情 | 详情 | |
| (XXI) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XXII) | 49234 | methyl 4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoate | C22H28O3 | 详情 | 详情 | |
| (XXIII) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The intermediate 4-(4-methoxyphenyl)-2-methylpyridine (IV) was obtained by two different procedures. Acylation of 2-picoline (I) with ethyl chloroformate, followed by addition of the Grignard reagent (II), prepared from 4-bromoanisole and magnesium, furnished the 4-aryl dihydropyridine (III). Aromatization of (III) by heating at 200 C with sulfur in decahydronaphthalene produced the phenylpyridine (IV). In an alternative method, 2-methylpyridine (I) was converted to the N-aminopyridinium salt (V) by reaction with hydroxylamine-O-sulfonic acid. This was then condensed with dehydroacetic acid (VI) under acidic conditions to produce the bipyridinium derivative (VII), which was isolated as the tetrafluoroborate salt. Alternatively, addition of 4-methoxyphenylmagnesium bromide (II) to (VII) yielded the phenyl bipyridinone (VIII), which upon elimination of the dimethylpyridone moiety in refluxing DMF generated the intermediate phenyl pyridine (IV). Methyl ether cleavage of (IV) in refluxing HBr afforded phenol (IX). This was then alkylated with 3-chloro-3-methylbutyne (X) to yield the aryl propargyl ether (XI) ,which was subjected to a Claisen rearrangement in hot ortho-dichlorobenzene to produce chromene (XII).
| 【1】 Manley, P.W. (Novartis AG; Novartis Deutschland GmbH); 2,2-Dialkyl- and 2,2-dialkyl-3, 4-dihydro-3-hydroxy-2H-1-benzopyrans, their use as pharmaceuticals. EP 0623129; WO 9412493 . |
| 【2】 Manley, P.W. (Novartis AG); 2,2-Dialkyl- and 2,2-dialkyl-3, 4-dihydro-3-hydroxy-2H-1-benzopyrans. US 5574049 . |
| 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) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
| (II) | 37674 | Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide | 352-13-6 | C7H7BrMgO | 详情 | 详情 |
| (III) | 50053 | ethyl 4-(4-methoxyphenyl)-2-methyl-1(4H)-pyridinecarboxylate | C16H19NO3 | 详情 | 详情 | |
| (IV) | 50055 | 4-(4-methoxyphenyl)-2-methylpyridine; methyl 4-(2-methyl-4-pyridinyl)phenyl ether | C13H13NO | 详情 | 详情 | |
| (V) | 50051 | 1-amino-2-methylpyridinium hydrogen sulfate | C6H10N2O4S | 详情 | 详情 | |
| (VI) | 43660 | 3-acetyl-6-methyl-2H-pyran-2,4(3H)-dione | 520-45-6 | C8H8O4 | 详情 | 详情 |
| (VII) | 50052 | C13H15BF4N2O | 详情 | 详情 | ||
| (VIII) | 50054 | C20H22N2O2 | 详情 | 详情 | ||
| (IX) | 50056 | 4-(2-methyl-4-pyridinyl)phenol | C12H11NO | 详情 | 详情 | |
| (X) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (XI) | 50057 | 1,1-dimethyl-2-propynyl 4-(2-methyl-4-pyridinyl)phenyl ether; 4-[4-[(1,1-dimethyl-2-propynyl)oxy]phenyl]-2-methylpyridine | C17H17NO | 详情 | 详情 | |
| (XII) | 50058 | 4-(2,2-dimethyl-2H-chromen-6-yl)-2-methylpyridine | C17H17NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The condensation of 2-methylpyridine (I) with 2,6-dichlorobenzonitrile (II) by means of BuLi and diisopropylamine in THF gives the vinyl derivative (III), which is cyclized by heating at 200 C.
| 【1】 Mettey, Y.; Vierfond, J.-M.; Benzo[c]quinoliziums: A new family of inhibitors for protein kinase CK II. Bioorg Med Chem Lett 1997, 7, 8, 961. |
| 【2】 Becq, F.; Mettey, Y.; Vierfond, J.-M.; Verrier, B.; Gola, M. (CNRS (Centre National de la Recherche Scientifique)); CFTR channel activator cpds. and pharmaceutical compsns. containing same. EP 0937044; WO 9805642 . |
合成路线9
该中间体在本合成路线中的序号：(III)Reaction of piperonyloyl chloride (I) with N,O-dimethylhydroxylamine gives rise to the Weinreb amide (II). This is then condensed with the lithium anion of 2-picoline (III) to produce ketone (IV). Nitrosation of (IV) with NaNO2/HCl leads to keto oxime (V). Subsequent cyclization of (V) with p-formylbenzonitrile (VI) in the presence of ammonium acetate in AcOH affords the N-hydroxy imidazole (VII), which is further reduced to the triaryl imidazole (VIII) by means of triethyl phosphite in DMF. The cyano group of (VIII) is then hydrolyzed under acidic conditions to provide carboxylic acid (IX). After activation of (IX) as the corresponding acid chloride (X), treatment with ammonium hydroxide in THF yields the target carboxamide (1,2).
| 【1】 Callahan, J.F.; Burgess, J.L.; Fornwald, J.A.; Gaster, L.M.; Harling, J.D.; Harrington, F.P.; Heer, J.; Kwon, C.; Lehr, R.; Mathur, A.; Olson, B.A.; Weinstock, J.; Laping, N.J.; Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J Med Chem 2002, 45, 5, 999. |
| 【2】 Callahan, J.F.; Burgess, J.L. (GlaxoSmithKline Inc.); Triarylimidazoles. EP 1169317; JP 2002541253; US 6465493; WO 0061576 . |
| 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) | 28821 | 1,3-benzodioxole-5-carbonyl chloride | 20850-43-5 | C8H5ClO3 | 详情 | 详情 |
| (II) | 64530 | N-methoxy-N-methyl-1,3-benzodioxole-5-carboxamide | C10H11NO4 | 详情 | 详情 | |
| (III) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |
| (IV) | 64531 | 1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)-1-ethanone | C14H11NO3 | 详情 | 详情 | |
| (V) | 64532 | 1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)-1,2-ethanedione 2-oxime | C14H10N2O4 | 详情 | 详情 | |
| (VI) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (VII) | 64533 | 4-[4-(1,3-benzodioxol-5-yl)-1-hydroxy-5-(2-pyridinyl)-1H-imidazol-2-yl]benzonitrile | C22H14N4O3 | 详情 | 详情 | |
| (VIII) | 64534 | 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzonitrile | C22H14N4O2 | 详情 | 详情 | |
| (IX) | 64535 | 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzoic acid | C22H15N3O4 | 详情 | 详情 | |
| (X) | 64536 | 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzoyl chloride | C22H14ClN3O3 | 详情 | 详情 |