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【结 构 式】 
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【分子编号】14130 【品名】5-Bromonicotinoyl chloride 【CA登记号】39620-02-5 |
【 分 子 式 】C6H3BrClNO 【 分 子 量 】220.45266 【元素组成】C 32.69% H 1.37% Br 36.25% Cl 16.08% N 6.35% O 7.26% |
合成路线1
该中间体在本合成路线中的序号：(IX)Protection of the amino group of 2-aminoethanol (I) with di-tert-butyldicarbonate, followed by reaction with phenylchlorocarbonate, gives 2-(tert-butoxycarbonylamino)ethylphenylcarbonate (II), which on reaction in refluxing 1,2,3,4-tetrahydroisoquinoline (III) yields 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-(tert-butoxycarbonylamino)ethyl ester (IV). Compound (IV) is deprotected with HCl in methanol to give 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-aminoethyl ester (V), which is coupled with 3-(N-tert-butoxycarbonyl-N-phenylamino)propanoic acid (VI) in the presence of dicyclohexylcarbodiimide to afford N-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethyl]-3-(N'-tert-butoxycarbonyl-N'-phenylamino)propanamide (VII). Deprotection of (VII) with HCl in methanol gives N-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethyl]-3-(phenylamino)propanamide (VIII), which is acylated with 5-bromonicotinoyl chloride hydrochloride (IX) in the presence of triethylamine to yield 3-bromo-5-[N-phenyl-N-[2-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethylcarbamoyl]ethyl]carbamoyl]pyridine (X). Compound (X) is finally reacted with iodopropane and iodide anion exchanged by nitrate with IRA-410 (NO3-).
| 【1】 Tsushima, S.; Takatani, M.; Nishikawa, K. (Takeda Chemical Industries, Ltd.); Pyridinium nitrate, its production and use. EP 0382380; JP 1990275876; US 4981860 . |
| 【2】 Mealy, N.; Prous, J.; Castaner, J.; TCV-309. Drugs Fut 1993, 18, 8, 721. |
| 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) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (II) | 14123 | 2-[(tert-butoxycarbonyl)amino]ethyl phenyl carbonate | C14H19NO5 | 详情 | 详情 | |
| (III) | 14124 | 1,2,3,4-Tetrahydroisoquinoline | 91-21-4 | C9H11N | 详情 | 详情 |
| (IV) | 14125 | 2-[(tert-butoxycarbonyl)amino]ethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate | C17H24N2O4 | 详情 | 详情 | |
| (V) | 14126 | 2-aminoethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate | C12H16N2O2 | 详情 | 详情 | |
| (VI) | 14127 | 3-[(tert-Butoxycarbonyl)anilino]propionic acid | C14H19NO4 | 详情 | 详情 | |
| (VII) | 14128 | 2-([3-[(tert-butoxycarbonyl)anilino]propanoyl]amino)ethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate | C26H33N3O5 | 详情 | 详情 | |
| (VIII) | 14129 | 2-[(3-anilinopropanoyl)amino]ethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate | C21H25N3O3 | 详情 | 详情 | |
| (IX) | 14130 | 5-Bromonicotinoyl chloride | 39620-02-5 | C6H3BrClNO | 详情 | 详情 |
| (X) | 14131 | 2-[(3-[[(5-bromo-3-pyridinyl)carbonyl]anilino]propanoyl)amino]ethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate | C27H27BrN4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Treatment of 5-bromo-3-pyridinecarboxylic acid (I) with thionyl chloride in 1,2-dichloroethane (DCE) gives acid chloride hydrochloride (II), which is converted to ester (III) on treatment with ethanol in DCE. Claisen condensation of ester (III) with N-vinylpyrrolidinone (IV) in the presence of littium bis(trimethylsilyl)amide followed by refluxing in aqueous hydrochloric acid gives the pyrroline (V). The reduction of pyrroline (V) with sodium borohydride in the presence of the chiral auxiliary N-carbobenzyloxy-L-proline yields the enantiomerically enriched (S)-pyrrolidine (VI) with an e.e. of 30%. This compound is reductively methylated in a mixture of aqueous formaldehyde and formic acid, and the resulting N-methylpyrrolidine (VII) is converted to the di-p-toluoyl-D-tartaric acid salt, and recrystallized from ethanol-ethyl acetate to increase the e.e. to 90%. The free amine (VII) is coupled with trimethylsilyl acetylene (VIII), in the presence of bis(triphenylphosphine)palladium dichloride, cuprous iodide, and triethylamine in THF. The resulting compound (IX) is treated with cesium carbonate in refluxing methanol to remove the trimethylsilyl group, and finally converted to the maleate salt on treatment with maleic acid in methanol.
| 【1】 McCallum, J.S.; Cosford, N.D.P.; McDonald, I.A.; Herbaut, A.; Bleicher, L.S.; A practical and efficient synthesis of the selective neuronal acetylcholine-gated ion channel agonist (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate (SIB-1508Y). J Org Chem 1998, 63, 4, 1109. |
| 【2】 Cosford, N.D.P.; et al.; (S)-(-)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate (SIB-1508Y): A novel anti-parkinsonian agent with selectivity for neuronal nicotinic acetylcholine receptors. J Med Chem 1996, 39, 17, 3225. |
| 【3】 McDonald, I.A.; Whitten, J.P.; Cosford, N.D. (SIBIA Neurosciences, Inc.); Pyridine modulators of acetylcholine receptors. EP 0739342; JP 1997508648; US 5594011; WO 9615123 . |
| 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) | 17913 | 5-Bromonicotinic acid | 20826-04-4 | C6H4BrNO2 | 详情 | 详情 |
| (II) | 14130 | 5-Bromonicotinoyl chloride | 39620-02-5 | C6H3BrClNO | 详情 | 详情 |
| (III) | 17915 | Ethyl 5-bromonicotinate | 20986-40-7 | C8H8BrNO2 | 详情 | 详情 |
| (IV) | 17916 | N-Vinyl-2-Pyrrolidinone; 1-vinyl-2-pyrrolidinone | 88-12-0 | C6H9NO | 详情 | 详情 |
| (V) | 17917 | 3-bromo-5-(3,4-dihydro-2H-pyrrol-5-yl)pyridine | C9H9BrN2 | 详情 | 详情 | |
| (VI) | 17918 | 3-bromo-5-[(2R)pyrrolidinyl]pyridine | C9H11BrN2 | 详情 | 详情 | |
| (VII) | 17919 | 3-bromo-5-[(2R)-1-methylpyrrolidinyl]pyridine | C10H13BrN2 | 详情 | 详情 | |
| (VIII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (IX) | 17921 | 3-[(2R)-1-methylpyrrolidinyl]-5-[2-(trimethylsilyl)ethynyl]pyridine | C15H22N2Si | 详情 | 详情 | |
| (X) | 17922 | 2-methyl-3-butyn-2-ol; 3-Methyl butynol | 115-19-5 | C5H8O | 详情 | 详情 |
| (XI) | 17923 | 2-methyl-4-[5-[(2R)-1-methylpyrrolidinyl]-3-pyridinyl]-3-butyn-2-ol | C15H20N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 5-bromopyridine-3-carboxylic acid (I) with (COCl)2 and CuI in DMF gives the acyl chloride (II), which is reduced with LiAlH(O-tBu)3 in THF to yield the carbaldehyde (III). The allylation of (III) with the organozinc bromide (IV) in THF affords 1-(5-bromo-3-pyridyl)-3-buten-1-ol (V), which is oxidized with DMP in dichloromethane to provide the corresponding ketone (VI). The enantioselective reduction of (VI) with (+)-B-chlorodiisopinocampheyl borane ((+)-DIP-Cl) in ether gives the (R)-enantiomer (VII), which is treated with Ms-Cl and TEA in dichloromethane to yield the mesylate (VIII). The reaction of (VIII) with sodium azide in DMF affords the (S)-azide (IX), which is finally submitted to a reductive cyclization by means of dicyclohexylborane (Cy2BH) in THF to afford the target 3-bromo-5-(2(S)-pyrrolidinyl)pyridine (X) intermediate (see scheme no. 22999801a, intermediate (VI)).
| 【1】 Felpin, F.X.; et al.; Enantioselective reduction of heteroaromatic beta,gamma-unsaturated ketones as an alternative to allylboration of aldehydes. Application: Asymmetric synthesis of SIB-1508Y. Tetrahedron 2002, 58, 37, 7381. |
| 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) | 17913 | 5-Bromonicotinic acid | 20826-04-4 | C6H4BrNO2 | 详情 | 详情 |
| (II) | 14130 | 5-Bromonicotinoyl chloride | 39620-02-5 | C6H3BrClNO | 详情 | 详情 |
| (III) | 57218 | 5-bromonicotinaldehyde | C6H4BrNO | 详情 | 详情 | |
| (IV) | 57219 | allyl(bromo)zinc | C3H5BrZn | 详情 | 详情 | |
| (V) | 57220 | 1-(5-bromo-3-pyridinyl)-3-buten-1-ol | C9H10BrNO | 详情 | 详情 | |
| (VI) | 57221 | 1-(5-bromo-3-pyridinyl)-3-buten-1-one | C9H8BrNO | 详情 | 详情 | |
| (VII) | 57222 | (1R)-1-(5-bromo-3-pyridinyl)-3-buten-1-ol | C9H10BrNO | 详情 | 详情 | |
| (VIII) | 57223 | (1R)-1-(5-bromo-3-pyridinyl)-3-butenyl methanesulfonate | C10H12BrNO3S | 详情 | 详情 | |
| (IX) | 57224 | 3-[(1S)-1-azido-3-butenyl]-5-bromopyridine; (1S)-1-(5-bromo-3-pyridinyl)-3-butenyl azide | C9H9BrN4 | 详情 | 详情 | |
| (X) | 57225 | 3-bromo-5-[(2S)pyrrolidinyl]pyridine | C9H11BrN2 | 详情 | 详情 |