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【结 构 式】 
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【分子编号】12996 【品名】6-Chloronicotinic acid 【CA登记号】5326-23-8 |
【 分 子 式 】C6H4ClNO2 【 分 子 量 】157.556 【元素组成】C 45.74% H 2.56% Cl 22.5% N 8.89% O 20.31% |
合成路线1
该中间体在本合成路线中的序号：(I)6-Chloronicotinic acid (I) is reacted with thiourea (II) to give 6-mercaptonicotinic acid (III) This is oxidized to the disulfide with iodine or hydrogen peroxide.
| 【1】 Grassetti, D.R.; et al.; The effects of some disulfides and thiols on the carbohydrate metabolism of Ehrlich ascites tumor. J Med Chem 1967, 10, 6, 1170. |
| 【2】 Grassetti, D.R.; CPDS. Drugs Fut 1986, 11, 7, 559. |
合成路线2
该中间体在本合成路线中的序号：(VIII)The condensation of thiophenol (II) with 3-methyl-2-butenyl bromide (I) by means of NaOH in refluxing acetone gives 3-methyl-2-butenyl(phenyl)sulfide (III), which is cyclized by means of P2O5 and H3PO4 in refluxing benzene to yield 4,4-dimethyl-3,4-dihydro-1H-1-benzothiopyran (IV). The acylation of (IV) with acetyl chloride catalyzed by SnCl4 in benzene affords the corresponding 6-acetyl derivative (V), which by dehydration with lithium diisopropylamide and diethyl chlorophosphate in THF is converted into 6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran (VI). Finally, this compound is condensed with ethyl 6-chloropyridine-3-carboxylate (VII) by means of butyllithium in THF. The ester (VII) is obtained by esterification of the corresponding acid (VIII) with ethanol by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP).
| 【1】 Ngo, J.; Leeson, P.A.; Castaner, J.; Tazarotene. Drugs Fut 1997, 22, 3, 249. |
| 【2】 Chandraratna, R.A.S. (Allergan, Inc.); Disubstd. acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity. EP 0284288; JP 88255277; JP 95324085 . |
| 【3】 Chandraratna, R.A.S. (Allergan, Inc.); Disubstd. acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity. US 5089509 . |
| 【4】 Chandraratna, R.A. (Allergan, Inc.); Disubstd. acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity. WO 9611686 . |
| 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) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (II) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (III) | 12991 | 1-[(3-Methyl-2-butenyl)sulfanyl]benzene; 3-Methyl-2-butenyl phenyl sulfide | C11H14S | 详情 | 详情 | |
| (IV) | 12992 | 4,4-Dimethylthiochromane | C11H14S | 详情 | 详情 | |
| (V) | 12993 | 1-(4,4-Dimethyl-3,4-dihydro-2H-thiochromen-6-yl)-1-ethanone | C13H16OS | 详情 | 详情 | |
| (VI) | 12994 | 6-Ethynyl-4,4-dimethylthiochromane | C13H14S | 详情 | 详情 | |
| (VII) | 12995 | ethyl 6-chloronicotinate | 49608-01-7 | C8H8ClNO2 | 详情 | 详情 |
| (VIII) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)Alternatively, reaction of 6-chloronicotinic acid (XIII) with methyllithium-lithium bromide complex gave methyl ketone (XIV). This was brominated by means of dibromobarbituric acid (XV) to produce bromoketone (XVI). Asymmetric reduction of (XVI) with (-)-B-chlorodiisopinocampheylborane provided the (R)-bromohydrin (XVII), which was converted to epoxide (XVIII) with NaOH in aqueous THF. Epoxide (XVIII) opening with 4-nitrophenethylamine (XIX) produced amino alcohol (XX), which by further protection with Boc2O gave carbamate (XXI). Concomitant dechlorination and nitro group reduction in (XXI) by hydrogenation using Raney Nickel as catalyst provided amine (XI). This was finally converted to the target compound by means of sulfonylation and deprotection as above.
| 【1】 Naylor, E.M.; Colandrea, V.J.; Candelore, M.R.; Cascieri, M.A.; Colwell, L.F. Jr; Deng, L.; Feeney, W.P.; Forrest, M.J.; Hom, G.J.; MacIntyre, D.E.; Strader, C.D.; Tota, L.; Wang, P.R.; Wyvratt, M.J.; Fisher, M.H.; Weber, A.E.; 3-Pyridylethanolamines: Potent and selective human beta3 adrenergic receptor agonists. Bioorg Med Chem Lett 1998, 8, 21, 3087. |
| 【2】 Fisher, M.H.; Naylor, E.M.; Ok, D.; Weber, A.E.; Shih, T.; Ok, H. (Merck & Co., Inc.); Substd. sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0757674; JP 1997512275; US 5541197; US 5561142; WO 9529159 . |
| 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) | 26548 | 4-[[(hexylamino)carbonyl]amino]benzenesulfonyl chloride | C13H19ClN2O3S | 详情 | 详情 | |
| (XI) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (XIII) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (XIV) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (XV) | 26556 | 5,5-dibromo-2,4,6(1H,3H,5H)-pyrimidinetrione | 511-67-1 | C4H2Br2N2O3 | 详情 | 详情 |
| (XVI) | 26557 | 2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanone | C7H5BrClNO | 详情 | 详情 | |
| (XVII) | 26558 | (1R)-2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanol | C7H7BrClNO | 详情 | 详情 | |
| (XVIII) | 26559 | 2-chloro-5-[(2R)oxiranyl]pyridine | C7H6ClNO | 详情 | 详情 | |
| (XIX) | 26560 | 4-nitrophenethylamine | 24954-67-4 | C8H10N2O2 | 详情 | 详情 |
| (XX) | 26561 | (1R)-1-(6-chloro-3-pyridinyl)-2-[(4-nitrophenethyl)amino]-1-ethanol | C15H16ClN3O3 | 详情 | 详情 | |
| (XXI) | 26562 | tert-butyl (2R)-2-(6-chloro-3-pyridinyl)-2-hydroxyethyl(4-nitrophenethyl)carbamate | C20H24ClN3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Reaction of 6-chloronicotinic acid (I) with methyllithium lithium bromide complex gives methyl ketone (II), which is treated with dibromobarbituric acid (III) in refluxing THF to afford bromoketone (IV). Asymmetric reduction of (IV) with (-)-DIP-chloride [(-)-B-chlorodiisopinocampheylborane] provides bromohydrin (V), which is converted into epoxide (VI) by treatment with NaOH in THF/H2O. Opening of the epoxide moiety of (VI) with p-nitrophenethylamine hydrochloride (VII) in MeOH in the presence of Et3N followed by N-protection with Boc2O in THF yields ethanolamine (VIII), which is then hydrogenated over Ni-Raney in EtOH/NaOH to furnish dechlorinated aniline (IX). Condensation of (IX) with 1,1-bis(methylsulfanyl)-2-nitroethylene (X) in isopropanol gives compound (XI), which is then subjected to reaction with aniline (XII) in isopropanol to afford nitroethylenediamine (XIII). Finally, the desired product is obtained by Boc removal of (XIII) by treatment with TFA in CH2Cl2.
| 【1】 Wyvratt, M.J.; Cascieri, M.A.; Liu, Y.; Parmee, E.R.; Tota, L.; Brockunier, L.L.; Candelore, M.R.; Fisher, M.H.; Weber, A.E.; Human beta3 adrenergic receptor agonists containing cyanoguanidine and nitroethylenediamide moieties. Bioorg Med Chem Lett 2001, 11, 3, 379. |
| 【2】 Naylor, E.M.; Colandrea, V.J.; Candelore, M.R.; Cascieri, M.A.; Colwell, L.F. Jr; Deng, L.; Feeney, W.P.; Forrest, M.J.; Hom, G.J.; MacIntyre, D.E.; Strader, C.D.; Tota, L.; Wang, P.R.; Wyvratt, M.J.; Fisher, M.H.; Weber, A.E.; 3-Pyridylethanolamines: Potent and selective human beta3 adrenergic receptor agonists. Bioorg Med Chem Lett 1998, 8, 21, 3087. |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (III) | 26556 | 5,5-dibromo-2,4,6(1H,3H,5H)-pyrimidinetrione | 511-67-1 | C4H2Br2N2O3 | 详情 | 详情 |
| (IV) | 26557 | 2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanone | C7H5BrClNO | 详情 | 详情 | |
| (V) | 26558 | (1R)-2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanol | C7H7BrClNO | 详情 | 详情 | |
| (VI) | 26559 | 2-chloro-5-[(2R)oxiranyl]pyridine | C7H6ClNO | 详情 | 详情 | |
| (VII) | 26560 | 4-nitrophenethylamine | 24954-67-4 | C8H10N2O2 | 详情 | 详情 |
| (VIII) | 26562 | tert-butyl (2R)-2-(6-chloro-3-pyridinyl)-2-hydroxyethyl(4-nitrophenethyl)carbamate | C20H24ClN3O5 | 详情 | 详情 | |
| (IX) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (X) | 13853 | Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene | 13623-94-4 | C4H7NO2S2 | 详情 | 详情 |
| (XI) | 48294 | tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl(4-[[(Z)-1-(methylsulfanyl)-2-nitroethenyl]amino]phenethyl)carbamate | C23H30N4O5S | 详情 | 详情 | |
| (XII) | 48295 | 3-aminobenzamide | 3544-24-9 | C7H8N2O | 详情 | 详情 |
| (XIII) | 48296 | tert-butyl 4-([(Z)-1-[3-(aminocarbonyl)anilino]-2-nitroethenyl]amino)phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C29H34N6O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)6-Chloronicotinic acid (I) was converted to the corresponding acid chloride (II) by treatment with oxalyl chloride. Condensation of acid chloride (II) with diethyl malonate in the presence of MgCl2 and Et3N produced the keto diester (III), which was further decarbethoxylated to ketone (IV) upon heating in moist DMSO. Displacement of the chloride group of (III) with 4-piperidone ethylene ketal (V) furnished the piperidinyl pyridine (VI). Knoevenagel condensation of malononitrile with 3-bromobenzaldehyde (VII) using glycine as the catalyst produced the benzylidene malononitrile (VIII). The dipyridyl derivative (IX) was obtained by condensation of ketone (VI) with dinitrile (VIII) in the presence of ammonium acetate. Cyclization of amino nitrile (IX) in hot formamide gave rise to the pyridopyrimidine system (X). Ketone (XI) was then obtained by acid hydrolysis of the ethylene ketal function of (X). Finally, condensation of ketone (XI) with 4-tetrahydropyranyloxyamine (XII) yielded the title oxime.
| 【1】 Zheng, G.Z.; et al.; Pyridopyrimidine analogues as novel adenosine kinase inhibitors. Bioorg Med Chem Lett 2001, 11, 16, 2071. |
| 【2】 Stewart, A.O.; Perner, R.J.; McKie, J.A.; Zheng, G.Z.; Grillot, A.L.; Cowart, M.D.; Bhagwat, S.S.; Lee, C.-H. (Abbott Laboratories Inc.); 5,7-Disubstd.-4-aminopyrido[2,3-d]pyrimidine cpds.. WO 0023444 . |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 49834 | dimethyl 2-[(6-chloro-3-pyridinyl)carbonyl]malonate | C11H10ClNO5 | 详情 | 详情 | |
| (IV) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (V) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (VI) | 49835 | 1-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]-1-ethanone | C14H18N2O3 | 详情 | 详情 | |
| (VII) | 10477 | 3-Bromobenzaldehyde; m-Bromobenzaldehyde | 3132-99-8 | C7H5BrO | 详情 | 详情 |
| (VIII) | 49836 | 2-(3-bromobenzylidene)malononitrile | C10H5BrN2 | 详情 | 详情 | |
| (IX) | 49837 | C24H22BrN5O2 | 详情 | 详情 | ||
| (X) | 49838 | 5-(3-bromophenyl)-7-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]pyrido[2,3-d]pyrimidin-4-amine; 5-(3-bromophenyl)-7-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]pyrido[2,3-d]pyrimidin-4-ylamine | C25H23BrN6O2 | 详情 | 详情 | |
| (XI) | 49839 | 1-[5-[4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-2-pyridinyl]-4-piperidinone | C23H19BrN6O | 详情 | 详情 | |
| (XII) | 49840 | O-tetrahydro-2H-pyran-4-ylhydroxylamine; 4-(aminooxy)tetrahydro-2H-pyran | C5H11NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)6-Chloronicotinic acid (I) was converted to the corresponding N-oxide (II) using trifluoroperacetic acid. Acid (II) was subsequently condensed with 4-fluoroaniline (III) using EEDQ as the coupling reagent to provide the target amide.
| 【1】 Cutshall, N.S.; et al.; Nicotinamide N-oxides as CXCR2 antagonists. Bioorg Med Chem Lett 2001, 11, 14, 1951. |
合成路线7
该中间体在本合成路线中的序号：(I)6-Chloronicotinic acid (I) is converted to the corresponding acid chloride (II) employing either SOCl2 or PCl5/POCl3. Treatment of acid chloride (II) with EtOH and Et3N, followed by reduction of the resultant ethyl ester with LiAlH4, furnishes 6-chloro-3-pyridylmethanol (III). Alcohol (III) is alternatively prepared by NaBH4 reduction of acid chloride (II). Chlorination of (III) by using SOCl2 gives the chloromethyl pyridine (IV), and further chloride displacement with KCN leads to nitrile (V). Substitution of the remaining chloride group of (V) upon heating with pyrrolidine (VI) furnishes the pyrrolidinyl pyridine (VII). Then hydrolysis of the nitrile function of (VII) under acidic conditions provides carboxylic acid (VIII). Bromination of 4-(methylsulfonyl)acetophenone (IX) in the presence of AlCl3 produces the phenacyl bromide (X). Finally, condensation between acid (VIII) and bromo ketone (X) under basic conditions gives rise to the title diaryl furanone
| 【1】 Almansa, C.; Alfon, J.; Cavalcanti, F.L.; Gomez, L.; Miralles, A.; Synthesis and SAR of 4-pyrrolidinylarylheterocycles as COX-2 selective inhibitors. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Almansa Rosales, C.; Gonzalez Gonzalez, C.; Torres Barreda, M.C. (J. Uriach & Cia., SA); Novel heterocyclic cpds. with anti-inflammatory activity. EP 1281709; ES 2166710; WO 0183475 . |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 60372 | (6-chloro-3-pyridinyl)methanol | C6H6ClNO | 详情 | 详情 | |
| (IV) | 60373 | 2-chloro-5-(chloromethyl)pyridine | C6H5Cl2N | 详情 | 详情 | |
| (V) | 60374 | 2-(6-chloro-3-pyridinyl)acetonitrile | C7H5ClN2 | 详情 | 详情 | |
| (VI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VII) | 60375 | 2-[6-(1-pyrrolidinyl)-3-pyridinyl]acetonitrile | C11H13N3 | 详情 | 详情 | |
| (VIII) | 60376 | 2-[6-(1-pyrrolidinyl)-3-pyridinyl]acetic acid | C11H14N2O2 | 详情 | 详情 | |
| (IX) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (X) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 |