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【结 构 式】 
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【分子编号】10752 【品名】Nicotinic acid; Niacin 【CA登记号】59-67-6 |
【 分 子 式 】C6H5NO2 【 分 子 量 】123.11124 【元素组成】C 58.54% H 4.09% N 11.38% O 25.99% |
合成路线1
该中间体在本合成路线中的序号：(II)This compound can be obtained by three different ways: 1) By condensation of nicotinoyl chloride (I) with 1,2-diaminopropane (IV) by means of triethylamine in pyridine. 2) By reaction of nicotinic acid (II) with 1,2-diaminopropane (IV) by means of ethyl chloroformate and triethylamine in THF. 3) By heating at 120 C a mixture of methyl nicotinate (III) with 1,2-diaminopropane (IV).
| 【1】 Mori, T.; Takaku, S.; Matsuura, F.; Murakami, Y.; Noda, Y.; Yamazaki, T.; Neichi, T.; Nakakimura, H.; Kataoka, S (Chugai Pharmaceutical Co. Ltd.); Nicotinamide derivative, process dor preparing the same and pharmaceutical composition containing the same. EP 0029602; JP 56075474 . |
| 【2】 Grau, M.; Serradell, M.N.; Castaner, J.; Blancafort, P.; AVS. Drugs Fut 1983, 8, 6, 485. |
合成路线2
该中间体在本合成路线中的序号：(I)This compound has been obtained by two related ways: 1) The reaction of the potassium salt of the nicotinic acid with oxalyl chloride in benzene gives the corresponding anhydride (II), which is condensed with 2-hydroxy-2-phenylacetic acid (III) in dioxane to yield the expected ester (IV). The reaction of (IV) with SOCl2 in dichloromethane affords 2-(nicotinoyloxy)-2-phenylacetyl chloride (V), which is finally esterified with the cyclohexanol (VI) in dichloromethane. 2) By acylation of the 2-hydroxy-2-phenylacetic acid cis-3,3,5-trimethylcyclohexyl ester (VII) with nicotinoyl chloride (VIII) in pyridine.
| 【1】 Verga, A. (Ravizza SpA); New process for preparing cis-3,3,5-trimethylcyclohexyl-D,L-alpha-(3-pyridinecarboxy)-phenylacetate. EP 0157151 . |
| 【2】 Mauri, F. (Gaver SA); Novel spasmolytic cpd. and process for its preparation. BE 0824034; DE 2461909; FR 2256757; JP 1975105670 . |
| 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) | 10752 | Nicotinic acid; Niacin | 59-67-6 | C6H5NO2 | 详情 | 详情 |
| (II) | 35737 | nicotinic anhydride | 16837-38-0 | C12H8N2O3 | 详情 | 详情 |
| (III) | 28161 | 2-hydroxy-2-phenylacetic acid | 611-72-3 | C8H8O3 | 详情 | 详情 |
| (IV) | 35738 | 2-phenyl-2-[(3-pyridinylcarbonyl)oxy]acetic acid | C14H11NO4 | 详情 | 详情 | |
| (V) | 35739 | 2-chloro-2-oxo-1-phenylethyl nicotinate | C14H10ClNO3 | 详情 | 详情 | |
| (VI) | 35740 | (1R,5R)-3,3,5-trimethylcyclohexanol | C9H18O | 详情 | 详情 | |
| (VII) | 35741 | (1R,5R)-3,3,5-trimethylcyclohexyl 2-hydroxy-2-phenylacetate | 456-59-7 | C17H24O3 | 详情 | 详情 |
| (VIII) | 10753 | Nicotinoyl chloride | C6H4ClNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of nicotinic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is condensed with 2-methylpyrazolo[1,5-a]pyridine (III) by heating at 160-80 C or in refluxing dioxane, yielding 2-methyl-3-(3-pyridylcarbonyl)pyrazolo[1,5-a]pyridine (IV). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol at 13 Atm. pressure and 55-8 C.
| 【1】 Hausberg, H.-H.; Koppe, V.; Poetsch, E.; Saiko, O.; Seyfried, C. (Merck Patent GmbH); Indolalkylamines, pharmaceutical compsns. containing them and process for their preparation. EP 0007399 . |
| 【2】 Castaner, J.; Prous, J.; KC-764. Drugs Fut 1991, 16, 2, 108. |
| 【3】 Awano, K.; Segawa, M.; Suzue, S.; Synthesis of 3-substituted pyrazolo[1,5-a]pyridine derivatives with inhibitory activity on platelet aggregation. I. Chem Pharm Bull 1986, 34, 7, 2828-32. |
合成路线4
该中间体在本合成路线中的序号：(I)The esteritication of nicotinic acid (I) with methanol and HCl or H2SO4 yields the corresponding methyl ester (II), which is treated with ethanolamine (A) to afford N-(beta-hydroxyethyl)nicotinamide (III). Finally, this compound is transformed into the nitrate ester by the usual methods.
| 【1】 Masayoshi, S.; Solubilizing agents. V. Pyridinecarboxamides. Yakugaku Zasshi 1960, 80, 1706-12. |
| 【2】 Thorpe, P.J.; Castaner, J.; SG-75. Drugs Fut 1979, 4, 2, 134. |
| 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) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (I) | 10752 | Nicotinic acid; Niacin | 59-67-6 | C6H5NO2 | 详情 | 详情 |
| (II) | 13980 | methyl nicotinate; Nicotinic acid, methyl ester | 93-60-7 | C7H7NO2 | 详情 | 详情 |
| (III) | 13982 | N-(2-Hydroxyethyl)nicotinamide | C8H10N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III), which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine. The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide, followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1). The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII). Nitration of (VIII) with KNO3 in H2SO4 gave (IX), which was reduced to the diamino derivative (X) using stannous chloride. Finally, regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.
| 【2】 Pascal, Y.; Jacobelli, H.; Calvet, A.; Payne, A.; Dahl, S.G. (Institut de Recherche Jouveinal); Diazepino-indoles as phosphodiesterase IV inhibitors. EP 0828742; US 5972927; WO 9736905 . |
| 【1】 Burnouf, C.; Auclair, E.; Avenel, N.; et al.; Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[]1,4]diazepino[6,7,1-]indoles: Discovery of potent, selective phosphodiesterase type 4 inhibitors. J Med Chem 2000, 43, 25, 4850. |
| 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) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (II) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (III) | 47455 | 2,3-dihydro-1H-indol-7-yl(phenyl)methanone | C15H13NO | 详情 | 详情 | |
| (IV) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (V) | 47456 | 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N2O | 详情 | 详情 | |
| (VI) | 47457 | 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime | C17H13N3O2 | 详情 | 详情 | |
| (VII) | 47458 | 3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (VIII) | 47459 | (3R)-3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (IX) | 47460 | (3R)-3-amino-9-nitro-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N4O3 | 详情 | 详情 | |
| (X) | 47461 | (3R)-3,9-diamino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H16N4O | 详情 | 详情 | |
| (XI) | 10752 | Nicotinic acid; Niacin | 59-67-6 | C6H5NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)Acylation of phenethylamine (III) with acid chloride (II), prepared from phthalimidopropionic acid (I) and SOCl2, gave amide (IV). Subsequent Bischler-Napieralski cyclization of amide (IV) in the presence of POCl3 and P2O5 produced the corresponding dihydroisoquinoline, which was isolated as the hydrochloride salt (V). Catalytic hydrogenation of (V) using PtO2 afforded the tetrahydroisoquinoline (VI). After protection of (VI) as the N-Boc derivative (VII), the primary amine (VIII) was liberated by phthaloyl group hydrazinolysis. Coupling of amine (VIII) with nicotinic acid (IX) employing EDC and HOBt yielded the nicotinamide compound (X). Subsequent acidic cleavage of the Boc protecting group of (X) provided amine (XI), which was finally acylated with 4-butylbenzenesulfonyl chloride (XII) in the presence of resin-bound piperidine to furnish the target sulfonamide.
| 【1】 Barn, D.R.; et al.; Parallel synthesis and biological activity of a new class of high affinity and selective delta-opioid ligand. Bioorg Med Chem 2001, 9, 10, 2609. |
| 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) | 53389 | 3-Phthalimidopropionic acid; Phthalyl-beta-alanine | 3339-73-9 | C11H9NO4 | 详情 | 详情 |
| (II) | 53390 | 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride | n/a | C11H8ClNO3 | 详情 | 详情 |
| (III) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (IV) | 53391 | 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-phenethylpropanamide | n/a | C19H18N2O3 | 详情 | 详情 |
| (V) | 53392 | 2-[2-(3,4-dihydro-1-isoquinolinyl)ethyl]-1H-isoindole-1,3(2H)-dione | n/a | C19H16N2O2 | 详情 | 详情 |
| (VI) | 53393 | 2-[2-(1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]-1H-isoindole-1,3(2H)-dione | n/a | C19H18N2O2 | 详情 | 详情 |
| (VII) | 53394 | tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | n/a | C24H26N2O4 | 详情 | 详情 |
| (VIII) | 53395 | tert-butyl 1-(2-aminoethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate | n/a | C16H24N2O2 | 详情 | 详情 |
| (IX) | 10752 | Nicotinic acid; Niacin | 59-67-6 | C6H5NO2 | 详情 | 详情 |
| (X) | 53396 | tert-butyl 1-{2-[(3-pyridinylcarbonyl)amino]ethyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate | n/a | C22H27N3O3 | 详情 | 详情 |
| (XI) | 53397 | N-[2-(1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]nicotinamide | n/a | C17H19N3O | 详情 | 详情 |
| (XII) | 53398 | 4-n-Butylbenzenesulphonyl chloride | 54997-92-1 | C10H13ClO2S | 详情 | 详情 |