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【结 构 式】 
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【分子编号】13265 【品名】3-Bromopyridine 【CA登记号】626-55-1 |
【 分 子 式 】C5H4BrN 【 分 子 量 】157.9975 【元素组成】C 38.01% H 2.55% Br 50.57% N 8.87% |
合成路线1
该中间体在本合成路线中的序号：(III)The reaction of 3-bromoanisole (I) with magnesium in THF gives 3-methoxyphenylmagnesium bromide (II), which is condensed with 3-bromopyridine (III) in THF by means of dichlorobis(triphenylphosphine)nickel yielding 3-(3-pyridinyl)anisole (IV). The alkylation of (IV) with propylbromide (A) in acetone at 110 C (under pressure) affords N-propyl-3-(3-methoxyphenyl)pyridinium bromide (V), which is reduced with H2 over Pt in methanol to give 1-propyl-3-(3-methoxyphenyl)piperidine (VI). Finally, this compound is demethylated by treatment with refluxing aqueous 48% HBr. The reduction of (IV) with H2 over Pt in methanol gives 3-(3-methoxyphenyl)piperidine (VII), which is acylated and reduced simultaneously with propionic acid (B) and NaBH4 in refluxing benzene to yield (VI), already obtained.
| 【1】 Arvidsson, F.L.E.; et al.; EP 0030526 . |
| 【2】 Sanchez, D.; Nilsson, J.L.G.; Hacksell, U.; Lindberg, P.; Carlsson, A.; Arvidsson, L.E.; Svensson, U.; Hjorth, S.; Wikstroem, H.; 3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity. J Med Chem 1981, 24, 12, 1475-82. |
| 【3】 Serradell, M.N.; Nohria, V.; Castaner, J.; Blancafort, P.; 3-PPP. Drugs Fut 1983, 8, 1, 27. |
| 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) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (B) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (I) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
| (II) | 35984 | bromo(3-methoxyphenyl)magnesium | 36282-40-3 | C7H7BrMgO | 详情 | 详情 |
| (III) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (IV) | 35985 | 3-(3-methoxyphenyl)pyridine; methyl 3-(3-pyridinyl)phenyl ether | C12H11NO | 详情 | 详情 | |
| (V) | 35986 | 3-(3-methoxyphenyl)-1-propylpyridinium bromide | C15H18BrNO | 详情 | 详情 | |
| (VI) | 35987 | 3-(3-methoxyphenyl)-1-propylpiperidine; methyl 3-(1-propyl-3-piperidinyl)phenyl ether | C15H23NO | 详情 | 详情 | |
| (VII) | 35988 | 3-(3-methoxyphenyl)piperidine; methyl 3-(3-piperidinyl)phenyl ether | C12H17NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)B) Synthesis of intermediate (XIV): Palladium-catalyzed coupling of 1-pentyn-4-ol (VIII) with 3-bromopyridine (IX) afforded the pyridinealkynol (X), which was then subjected to sequential hydrogenation and Swern oxidation followed by reductive amination of the intermediate ketone (XI) with sodium cyanoborohyride to afford the racemic amine (XII). Resolution was achieved through fractional crystallization of the corresponding diastereoisomeric (R)-mandelamides that had been obtained by acylation of the racemic amine with (R)-mandelic acid in DMF in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Acid-catalyzed hydrolysis of the diastereoisomerically pure (R,R)-mandelamide (XII) provided the resolved (R)-alpha-methyl-3-pyridinebutanamine (XIV). C) Synthesis of Ro-24-0238: Stereochemical assignment was based on a single crystal X-ray analysis of the intermediate mandelamide. Reaction of the chiral amine with the activated ester of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid gave Ro 24-0238. Stereochemical assignment was based on a single crystal X-ray analysis of the intermediate mandelamide. Reaction of the chiral amine with the activated ester of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid gave Ro 24-0238.
| 【1】 Vargaftig, B.B.; Benveniste, J.; Lefort, J.; Wal, F.; Chignard, M.; Background and present status of research on platelet-activating factor (PAF-acether). Ann NY Acad Sci 1981, 370, 119-37. |
| 【2】 D'Donnell, M.; Kierstead, R.W.; Guthrie, R.W.; Tilley, J.W.; Ro 24-0238. Drugs Fut 1991, 16, 12, 1103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 13263 | 4-nitrophenyl (2E,4E)-5-(4-methoxyphenyl)-2,4-decadienoate | C23H25NO5 | 详情 | 详情 | |
| (VIII) | 13264 | 4-Pentyn-2-ol | 2117-11-5 | C5H8O | 详情 | 详情 |
| (IX) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (X) | 13266 | 5-(3-Pyridinyl)-4-pentyn-2-ol | C10H11NO | 详情 | 详情 | |
| (XI) | 13267 | 5-(3-Pyridinyl)-2-pentanone | C10H13NO | 详情 | 详情 | |
| (XII) | 13268 | 1-Methyl-4-(3-pyridinyl)butylamine; 5-(3-Pyridinyl)-2-pentanamine | C10H16N2 | 详情 | 详情 | |
| (XIII) | 13269 | (2R)-2-Hydroxy-N-[(1R)-1-methyl-4-(3-pyridinyl)butyl]-2-phenylethanamide | C18H22N2O2 | 详情 | 详情 | |
| (XIV) | 13270 | (1R)-1-Methyl-4-(3-pyridinyl)butylamine; (2R)-5-(3-Pyridinyl)-2-pentanamine | C10H16N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The bromination of 3-ethoxy-2-cyclopenten-1-one (I) with Br2 and triethylamine in chloroform gives the 2-bromo derivative (II), which is condensed with 4-bromothioanisole (III) by means of BuLi in THF yielding 2-bromo-3-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-one (IV). The oxidation of (IV) with Na2WO4 and H2O2 affords the corresponding sulfone (V), which is finally condensed with lithium diisopropyl 3-pyridylboronate (VII) or the corresponding dimethyl ester (VIII) by means of tris(dibenzylideneacetone)dipalladium (III) (Pd2(dba)3) and triphenylphosphine in toluene/propanol/water. The lithium boronates (VII) and (VIII) have been obtained by reaction of 3-bromopyridine (VI) with triisopropyl borate or trimethyl borate and BuLi in ethyl ether.
| 【1】 Chan, C.-C.; Brideau, C.; Black, W.C.; et al.; 2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors. J Med Chem 1999, 42, 7, 1274. |
| 【2】 Black, C.; Hughes, G.; Wang, Z. (Merck Frosst Canada Inc.); Pyridinyl-2-cyclopenten-1-ones as selective cyclooxygenase-2 inhibitors. EP 0900201; JP 2000509032; US 5922742; WO 9740012 . |
| 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) | 25959 | 3-ethoxy-2-cyclopenten-1-one | C7H10O2 | 详情 | 详情 | |
| (II) | 25960 | 2-bromo-3-ethoxy-2-cyclopenten-1-one | C7H9BrO2 | 详情 | 详情 | |
| (III) | 19266 | 4-bromophenyl methyl sulfide; 1-bromo-4-(methylsulfanyl)benzene | 104-95-0 | C7H7BrS | 详情 | 详情 |
| (IV) | 25957 | 2-bromo-3-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-one | C12H11BrOS | 详情 | 详情 | |
| (V) | 25958 | 2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one | C12H11BrO3S | 详情 | 详情 | |
| (VI) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (VII) | 30005 | Triisopropoxy(3-pyridyl)boranuide lithium salt | C14H25BLiNO3 | 详情 | 详情 | |
| (VIII) | 30006 | Trimethoxy(3-pyridyl)boranuide lithium salt | C8H13BLiNO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Condensation of 2-amino-4-iodobenzoic acid (I) with 2-chloronicotinic acid (II) in refluxing EtOH in the presence of HCl yields pyridoquinazoline acid derivative (III), which is then condensed with N,N-dimethylethylenediamine (IV) in CH2Cl2 using BOP as coupling reagent to provide (V). Reaction of 2-bromopyridine (VI) in Et2O with n-BuLi and trimethylborate, followed by treatment with EtOH and HOAc, gives 3-pyridinyl boronic acid (VII), which is finally coupled to (V) in an Na2CO3 solution via a Suzuki coupling catalyzed by Pd(PPh3)4.
| 【1】 Kitchen, D.B.; Schow, S.R.; Casscles, W.T. Jr.; Discafani, C.; Trova, M.P.; Lassota, P.; Zhang, N.; Powell, D.W.; Hetero biarylpyridoquinazolinone derivatives as anticancer agents. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 59. |
| 【2】 Trova, M.P.; Zhang, N. (American Cyanamid Co.); Hetero-biaryl-pyridoquinazolinone derivs. as anti-cancer agents. EP 0944628; WO 9823617 . |
| 【3】 Trova, M.P.; Zhang, N. (American Cyanamid Co.); Hetero-biaryl-pyridoquinazolinone derivs. as anti-cancer agents. US 5908840 . |
| 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) | 19964 | 5-Iodoanthranilic acid; 2-amino-5-iodobenzoic acid | 5326-47-6 | C7H6INO2 | 详情 | 详情 |
| (II) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (III) | 42991 | 2-iodo-11-oxo-5,11-dihydro-10lambda(5)-pyrido[2,1-b]quinazoline-6-carboxylic acid | C13H9IN2O3 | 详情 | 详情 | |
| (IV) | 14881 | N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine | 108-00-9 | C4H12N2 | 详情 | 详情 |
| (V) | 42992 | N-[2-(dimethylamino)ethyl]-2-iodo-11-oxo-5,11-dihydro-10lambda(5)-pyrido[2,1-b]quinazoline-6-carboxamide | C17H19IN4O2 | 详情 | 详情 | |
| (VI) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (VII) | 38825 | 3-pyridinylboronic acid | 1692-25-7 | C5H6BNO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Treatment of 4-bromophthalic anhydride (I) in MeOH with NaOMe affords methyl ester (II), which is then treated with diphenylphosphoryl azide ((PhO)2PON3) in toluene, acetone/H2O to yield a mixture of regioisomers from which derivative (III) is obtained by chromatographic separation. Condensation of (III) with 2-chloronicotinic acid (IV) in refluxing EtOH in the presence of HCl yields pyridoquinazoline acid derivative (V), which is then condensed with N,N-dimethylethylenediamine (VI) in CH2Cl2 using BOP as coupling reagent to provide (VII). Reaction of 2-bromopyridine (VIII) in Et2O with n-BuLi and trimethylborate, followed by treatment with EtOH and HOAc, gives 3-pyridinyl boronic acid (IX), which is finally coupled to (VII) in an Na2CO3 solution via a Suzuki coupling catalyzed by Pd(PPh3)4.
| 【1】 Kitchen, D.B.; Schow, S.R.; Casscles, W.T. Jr.; Discafani, C.; Trova, M.P.; Lassota, P.; Zhang, N.; Powell, D.W.; Hetero biarylpyridoquinazolinone derivatives as anticancer agents. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 59. |
| 【2】 Trova, M.P.; Zhang, N. (American Cyanamid Co.); Hetero-biaryl-pyridoquinazolinone derivs. as anti-cancer agents. EP 0944628; WO 9823617 . |
| 【3】 Trova, M.P.; Zhang, N. (American Cyanamid Co.); Hetero-biaryl-pyridoquinazolinone derivs. as anti-cancer agents. US 5908840 . |
| 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) | 43060 | 5-bromo-2-benzofuran-1,3-dione | 86-90-8 | C8H3BrO3 | 详情 | 详情 |
| (II) | 43061 | 5-bromo-2-(methoxycarbonyl)benzoic acid | C9H7BrO4 | 详情 | 详情 | |
| (III) | 43062 | methyl 2-amino-4-bromobenzoate | 135484-83-2 | C8H8BrNO2 | 详情 | 详情 |
| (IV) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (V) | 43063 | 3-bromo-11-oxo-5,11-dihydro-10lambda(5)-pyrido[2,1-b]quinazoline-6-carboxylic acid | C13H9BrN2O3 | 详情 | 详情 | |
| (VI) | 14881 | N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine | 108-00-9 | C4H12N2 | 详情 | 详情 |
| (VII) | 43064 | 3-bromo-N-[2-(dimethylamino)ethyl]-11-oxo-5,11-dihydro-10lambda(5)-pyrido[2,1-b]quinazoline-6-carboxamide | C17H19BrN4O2 | 详情 | 详情 | |
| (VIII) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (IX) | 38825 | 3-pyridinylboronic acid | 1692-25-7 | C5H6BNO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)The condensation between 3-(bromoacetyl)pyridine (I) and either formamide or formamidine acetate produced the intermediate 4-(3-pyridyl)imidazole (II). Alternatively, intermediate (II) was prepared by palladium-catalyzed coupling between 1-trityl-4-iodoimidazole (III) and diethyl(3-pyridyl)borane (IV), followed by acidic deprotection of the resultant 1-trityl-4-(3-pyridyl)imidazole (V). In a further procedure, iodoimidazole (III) was converted to the corresponding Grignard reagent (VI), which was then coupled with 3-bromopyridine (VII) in the presence of ZnCl2 and palladium catalyst, yielding adduct (V). Subsequent acid-catalyzed deprotection gave intermediate (II). Michael addition of crotonaldehyde (VIII) to imidazole (II) furnished the (pyridylimidazolyl)butyraldehyde (IX). Condensation of aldehyde (IX) with the macrocyclic N-amino carbamate (X) produced the intermediate imine (XI), which was reduced to the corresponding amino derivative using sodium cyanoborohydride. The resultant epimeric mixture was separated by chromatography to provide the title (3R)-diastereoisomer. Alternatively, the reductive alkylation of (X) with aldehyde (IX) was carried out in the presence of sodium triacetoxyborohydride.
| 【1】 Su, W.; et al.; The in vitro and in vivo activity of CP-642,959 and its related diastereomers. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1168. |
| 【2】 Kaneko, T.; Su, W.-G.; Wu, Y.-J. (Pfizer Inc.); Carbamate and carbazate ketolide antibiotics. EP 1115732; WO 0017218 . |
| 【3】 Kaneko, T.; McMillen, W.T.; McLaughlin, R.W.; Ripin, D.H.B.; Vanerplas, B.C. (Pfizer Inc.); Synthesis of carbamate ketolide antibiotics. EP 1088828; JP 2001151792 . |
| 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) | 53085 | 2-bromo-1-(3-pyridinyl)-1-ethanone | n/a | C7H6BrNO | 详情 | 详情 |
| (II) | 17164 | 3-(1H-imidazol-4-yl)pyridine | C8H7N3 | 详情 | 详情 | |
| (III) | 32016 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-9-[[(benzyloxy)carbonyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoa | C55H57NO16 | 详情 | 详情 | |
| (IV) | 20086 | 3-(diethylboryl)pyridine | C9H14BN | 详情 | 详情 | |
| (V) | 53086 | 3-(1-trityl-1H-imidazol-4-yl)pyridine | n/a | C27H21N3 | 详情 | 详情 |
| (VI) | 32017 | (2S)-5-amino-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acid | C13H12N2O5 | 详情 | 详情 | |
| (VII) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (VIII) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (IX) | 53087 | 3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butanal | n/a | C12H13N3O | 详情 | 详情 |
| (X) | 45787 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 14-(O-methyloxime) | C32H56N4O10 | 详情 | 详情 | |
| (XI) | 53088 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-({(Z)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylidene}amino)octahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 14-(O-methyloxime) | n/a | C44H67N7O10 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)Chloroacetyl chloride (I) is condensed with bis(trimethylsilyl)acetylene (II) in the presence of AlCl3 to provide 1-chloro-4-(trimethylsilyl)-3-butyn-2-one (III). Cyclization of chloro ketone (III) with thioacetamide (IV) affords the ethynylthiazole derivative (V). Finally, palladium-catalyzed coupling of (V) with 3-bromopyridine (VI) gives rise to the target diarylacetylene.
| 【1】 Cosford, N.D.P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N.D.; Anderson, J.; Bristow, L.; Brodkin, J..; Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M.A.; 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]- pyridine: A potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J Med Chem 2003, 46, 2, 204. |
| 【2】 McDonald, I.A.; Munoz, B.; Vernier, J.-M.; Cosford, N.D.P.; Varney, M.A.; Hess, S.D.; Bleicher, L.S.; Cube, R.V.; Schweiger, E.J. (Merck & Co., Inc.); Heterocyclic cpds. and methods of use thereof. JP 2003508390; WO 0116121 . |
| 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) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (II) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (III) | 63351 | 1-chloro-4-(trimethylsilyl)-3-butyn-2-one | C7H11ClOSi | 详情 | 详情 | |
| (IV) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (V) | 63352 | 2-methyl-4-[2-(trimethylsilyl)ethynyl]-1,3-thiazole | C9H13NSSi | 详情 | 详情 | |
| (VI) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |