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【结 构 式】 
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【分子编号】11338 【品名】1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal 【CA登记号】177-11-7 |
【 分 子 式 】C7H13NO2 【 分 子 量 】143.18576 【元素组成】C 58.72% H 9.15% N 9.78% O 22.35% |
合成路线1
该中间体在本合成路线中的序号：(V)The reaction of 2-(7-chloro-1,8-naphthyrin-2-yl)-3-hydroxyisoindolin-1-one (I) with tert-butoxycarbonylmethylenetriphenylphosphorane (II) in refluxing toluene gives 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindolin-1-acetic acid tert-butyl ester (III), which is hydrolyzed with trifluoroacetic acid to the corresponding free acid (IV). Finally, this compound is condensed with 1,4-dioxa-8-azaspiro[4.5]decane (V) by means of diethyl phosphorocyanidate and triethylamine in DMF.
| 【1】 Okada, T.; Mohler, M.; Benzodiazepine receptor: Demonstration in the central nervous system. Science 1977, 198, 849-51. |
| 【2】 Goto, G.; Saji, Y. (Takeda Chemical Industries, Ltd.); Isoindolinone derivs., production and use thereof. EP 0174858; JP 1986069773; JP 1990262578; JP 1992364180; US 4778801 . |
| 【3】 Graul, A.; Prous, J.; Castaner, J.; DN-2327. Drugs Fut 1993, 18, 5, 414. |
| 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) | 11334 | 2-(7-Chloro[1,8]naphthyridin-2-yl)-3-hydroxy-1-isoindolinone | C16H10ClN3O2 | 详情 | 详情 | |
| (II) | 11335 | tert-butyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (tert-Butoxycarbonylmethylene)triphenylphosphorane | 35000-38-5 | C24H25O2P | 详情 | 详情 |
| (III) | 11336 | tert-butyl 2-[2-(7-chloro[1,8]naphthyridin-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetate | C22H20ClN3O3 | 详情 | 详情 | |
| (IV) | 11337 | 2-[2-(7-chloro[1,8]naphthyridin-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetic acid | C18H12ClN3O3 | 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 |
合成路线2
该中间体在本合成路线中的序号：(VII)E-5842 was prepared by reacting (I) with citric acid monohydrate in ethanol. The base (I) can be obtained by two ways: 1) By condensation of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (III) or 8-(4-fluorophenyl)-5-azoniaspiro[4.5]dec-7-ene chloride (IV) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) or 1H-1,2,4-triazole, respectively, in dimethylformamide in the presence of potassium hydrogencarbonate. 2) By dehydration of 1-[4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidyl]butyl]-1H-1,2,4-triazole (VI) in refluxing hydrochloric acid/ethanol. The piperidinol (VI) can be obtained by two procedures: a) By condensation of 4-(4-fluorophenyl)-4-hydroxypiperidine (II) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) in dimethylformamide in the presence of potassium hydrogencarbonate. b) By condensation of 1,4-dioxa-8-azaspiro[4.5]decane (VII) with 1-(4-chlorobutyl)-1H-1,2,4-triazole (V) and hydrolysis of the acetal to give 1-[4-(4-oxo-1-piperidyl)butyl]-1H-1,2,4-triazole (VIII), followed by addition of 4-fluorophenyllithium or 4-fluorophenyl magnesium bromide in ether or tetrahydrofuran to yield (VI).
| 【1】 Merce-Vidal, R.; Frigola-Constansa, J. (Laboratorios del Dr. Esteve, SA); Tetrahydropyridine-(or -4-hydroxypiperidine)alkyla. EP 0721455; FR 2723091; JP 1997503230; US 5731331; WO 9604287 . |
| 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) | 23463 | 4-(4-fluorophenyl)-1-[4-(1H-1,2,4-triazol-1-yl)butyl]-1,2,3,6-tetrahydropyridine | C17H21FN4 | 详情 | 详情 | |
| (II) | 15723 | 4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine | 3888-65-1 | C11H14FNO | 详情 | 详情 |
| (III) | 23465 | 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine | 1978-59-2 | C11H12FN | 详情 | 详情 |
| (IV) | 23466 | 8-(4-fluorophenyl)-5-azoniaspiro[4.5]dec-7-ene | C15H19FN | 详情 | 详情 | |
| (V) | 23467 | 1-(4-chlorobutyl)-1H-1,2,4-triazole | C6H10ClN3 | 详情 | 详情 | |
| (VI) | 23468 | 4-(4-fluorophenyl)-1-[4-(1H-1,2,4-triazol-1-yl)butyl]-4-piperidinol | C17H23FN4O | 详情 | 详情 | |
| (VII) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (VIII) | 23470 | 1-[4-(1H-1,2,4-triazol-1-yl)butyl]-4-piperidinone | C11H18N4O | 详情 | 详情 | |
| (IX) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Acylation of 4-piperidone ethylene ketal (I) with 3-chloro-4-fluorobenzoyl chloride (II) in the presence of Et3N gave amide (III). After ketal hydrolysis of (III) using 80% formic acid and CuSO4, treatment of the resulting N-acyl piperidone (IV) with dimethyloxosulfonium methylide provided epoxide (V). Subsequent ring opening of (V) with HF-pyridine complex afforded the fluoro alcohol (VI), which was converted to tosylate (VII). Then, Gabriel synthesis via the corresponding phthalimide (VIII) produced amine (IX). The pyridine-2-carboxaldehyde (XII) was prepared by reduction of ethyl 6-chloro-5-methylpyridine-2-carboxylate (X) with NaBH4, followed by displacement of the chloro group by ethanolic methylamine in a sealed vessel at 100 C yielding pyridinealcohol (XI), which was further oxidized to the desired aldehyde (XII) using MnO2. The title compound was then obtained by condensation of amine (IX) with aldehyde (XII), followed by reduction of the intermediate imine with KBH4 in MeOH.
| 【1】 Koek, W.; Cosi, C.; Jubault, N.; Funes, P.; Assié, M.-B.; Vacher, B.; Kleven, M.; Bonnaud, B.; Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J Med Chem 1999, 42, 9, 1648. |
| 【2】 Vacher, B.; Bonnaud, B.; Koek, W. (Pierre Fabre Medicament); Pyridin-2-yl-methylamine derivs., method of preparing and application as medicine. EP 0946546; JP 2001504129; US 6020345; WO 9822459 . |
| 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) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (II) | 24370 | 3-chloro-4-fluorobenzoyl chloride | 65055-17-6 | C7H3Cl2FO | 详情 | 详情 |
| (III) | 24371 | (3-chloro-4-fluorophenyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone | C14H15ClFNO3 | 详情 | 详情 | |
| (IV) | 24372 | 1-(3-chloro-4-fluorobenzoyl)-4-piperidinone | C12H11ClFNO2 | 详情 | 详情 | |
| (V) | 24373 | (3-chloro-4-fluorophenyl)(1-oxa-6-azaspiro[2.5]oct-6-yl)methanone | C13H13ClFNO2 | 详情 | 详情 | |
| (VI) | 24374 | (3-chloro-4-fluorophenyl)[4-fluoro-4-(hydroxymethyl)-1-piperidinyl]methanone | C13H14ClF2NO2 | 详情 | 详情 | |
| (VII) | 24375 | [1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl 4-methylbenzenesulfonate | C20H20ClF2NO4S | 详情 | 详情 | |
| (VIII) | 24376 | 2-[[1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl]-1H-isoindole-1,3(2H)-dione | C21H17ClF2N2O3 | 详情 | 详情 | |
| (IX) | 24377 | [4-(aminomethyl)-4-fluoro-1-piperidinyl](3-chloro-4-fluorophenyl)methanone | C13H15ClF2N2O | 详情 | 详情 | |
| (X) | 24378 | ethyl 6-chloro-5-methyl-2-pyridinecarboxylate | C9H10ClNO2 | 详情 | 详情 | |
| (XI) | 24379 | [5-methyl-6-(methylamino)-2-pyridinyl]methanol | C8H12N2O | 详情 | 详情 | |
| (XII) | 24380 | 5-methyl-6-(methylamino)-2-pyridinecarbaldehyde | C8H10N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Acylation of 4-piperidone ethylene ketal (I) with 3-chloro-4-fluorobenzoyl chloride (II) in the presence of Et3N gave amide (III). After ketal hydrolysis of (III) using 80% formic acid and CuSO4, treatment of the resulting N-acyl piperidone (IV) with dimethyloxosulfonium methylide provided epoxide (V). Subsequent ring opening of (V) with HF-pyridine complex afforded the fluoro alcohol (VI), which was converted to tosylate (VII). Then, Gabriel synthesis via the corresponding phthalimide (VIII) produced amine (IX). The title compound was then obtained by condensation of 6-(dimethylamino)pyridine-2-carboxaldehyde (X) with amine (IX), followed by reduction of the intermediate imine with KBH4 in MeOH.
| 【1】 Koek, W.; Cosi, C.; Jubault, N.; Funes, P.; Assié, M.-B.; Vacher, B.; Kleven, M.; Bonnaud, B.; Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J Med Chem 1999, 42, 9, 1648. |
| 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) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (II) | 24370 | 3-chloro-4-fluorobenzoyl chloride | 65055-17-6 | C7H3Cl2FO | 详情 | 详情 |
| (III) | 24371 | (3-chloro-4-fluorophenyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone | C14H15ClFNO3 | 详情 | 详情 | |
| (IV) | 24372 | 1-(3-chloro-4-fluorobenzoyl)-4-piperidinone | C12H11ClFNO2 | 详情 | 详情 | |
| (V) | 24373 | (3-chloro-4-fluorophenyl)(1-oxa-6-azaspiro[2.5]oct-6-yl)methanone | C13H13ClFNO2 | 详情 | 详情 | |
| (VI) | 24374 | (3-chloro-4-fluorophenyl)[4-fluoro-4-(hydroxymethyl)-1-piperidinyl]methanone | C13H14ClF2NO2 | 详情 | 详情 | |
| (VII) | 24735 | tert-Butyl 2-iodoacetate | C6H11IO2 | 详情 | 详情 | |
| (VIII) | 24336 | 5-cyano-5H-dibenzo[b,f]azepine | C15H10N2 | 详情 | 详情 | |
| (IX) | 24337 | 5-cyano-10-nitro-5H-dibenzo[b,f]azepine | C15H9N3O2 | 详情 | 详情 | |
| (X) | 24381 | 6-(dimethylamino)-2-pyridinecarbaldehyde | C8H10N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Acylation of 4-piperidone ethylene ketal (I) with 3-chloro-4-fluorobenzoyl chloride (II) in the presence of Et3N gave amide (III). After ketal hydrolysis of (III) using 80% formic acid and CuSO4, treatment of the resulting N-acyl piperidone (IV) with dimethyloxosulfonium methylide provided epoxide (V). Subsequent ring opening of (V) with HF-pyridine complex afforded the fluoro alcohol (VI), which was converted to tosylate (VII). Then, Gabriel synthesis via the corresponding phthalimide (VIII) produced amine (IX). The title compound was then obtained by condensation of 6-(2-furanyl)pyridine-2-carboxaldehyde (X) with amine (IX), followed by reduction of the intermediate imine with KBH4 in MeOH.
| 【1】 Koek, W.; Cosi, C.; Jubault, N.; Funes, P.; Assié, M.-B.; Vacher, B.; Kleven, M.; Bonnaud, B.; Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J Med Chem 1999, 42, 9, 1648. |
| 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) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (II) | 24370 | 3-chloro-4-fluorobenzoyl chloride | 65055-17-6 | C7H3Cl2FO | 详情 | 详情 |
| (III) | 24371 | (3-chloro-4-fluorophenyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone | C14H15ClFNO3 | 详情 | 详情 | |
| (IV) | 24372 | 1-(3-chloro-4-fluorobenzoyl)-4-piperidinone | C12H11ClFNO2 | 详情 | 详情 | |
| (V) | 24373 | (3-chloro-4-fluorophenyl)(1-oxa-6-azaspiro[2.5]oct-6-yl)methanone | C13H13ClFNO2 | 详情 | 详情 | |
| (VI) | 24374 | (3-chloro-4-fluorophenyl)[4-fluoro-4-(hydroxymethyl)-1-piperidinyl]methanone | C13H14ClF2NO2 | 详情 | 详情 | |
| (VII) | 24375 | [1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl 4-methylbenzenesulfonate | C20H20ClF2NO4S | 详情 | 详情 | |
| (VIII) | 24376 | 2-[[1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl]-1H-isoindole-1,3(2H)-dione | C21H17ClF2N2O3 | 详情 | 详情 | |
| (IX) | 27377 | 2-chloro-N-cyclohexylacetamide | C8H14ClNO | 详情 | 详情 | |
| (X) | 24382 | 6-(2-furyl)-2-pyridinecarbaldehyde | C10H7NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Condensation of ethyl 4-fluorobenzoate (I) with 4-piperidone ethylene ketal (II) afforded the N-arylpiperidine (III). Saponification of the ethyl ester group of (III), followed by acidic hydrolysis of the ethylene ketal function, yielded the benzoic acid derivative (V). Coupling of acid (V) with leucine ethyl ester (VI) using EDC gave amide (VII). Then, reductive amination of piperidone (VII) with the known arylethanolamine (VIII) using NaBH(OAc)3 furnished the aminopiperidine (IX). The ethyl ester group of (IX) was finally hydrolyzed with NaOH to provide the corresponding carboxylic acid.
| 【1】 Hu, B.; et al.; (4-Piperidin-1-yl)phenyl amides: Potent and selective human beta3 agonists. J Med Chem 2001, 44, 9, 1456. |
| 【2】 Taylor, E.C.; Skotnicki, J.S.; A convenient synthesis of 1-aryl-4-piperidones. Synthesis 1981, 606. |
| 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) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
| (II) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (III) | 50886 | ethyl 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzoate | C16H21NO4 | 详情 | 详情 | |
| (IV) | 50887 | 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzoic acid | C14H17NO4 | 详情 | 详情 | |
| (V) | 50888 | 4-(4-oxo-1-piperidinyl)benzoic acid | C12H13NO3 | 详情 | 详情 | |
| (VI) | 50889 | ethyl (2S)-2-amino-4-methylpentanoate | C8H17NO2 | 详情 | 详情 | |
| (VII) | 50890 | ethyl (2S)-4-methyl-2-[[4-(4-oxo-1-piperidinyl)benzoyl]amino]pentanoate | C20H28N2O4 | 详情 | 详情 | |
| (VIII) | 49404 | N-[5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide | C9H14N2O4S | 详情 | 详情 | |
| (IX) | 50891 | ethyl (2S)-2-[(4-[4-[((2R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl)amino]-1-piperidinyl]benzoyl)amino]-4-methylpentanoate | C29H42N4O7S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)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8
该中间体在本合成路线中的序号：(III)Alternatively, hydroxyquinoline (I) is chlorinated in refluxing POCl3 to provide chloroquinoline (II). Substitution of (II) with 4-piperidone ethylene ketal (III) in boiling DMF furnishes the piperidinyl quinoline derivative (IV), which is further hydrolyzed to piperidone (V) under acidic conditions. Addition of cyanide to piperidone (V) gives rise to cyanohydrin (VI), and subsequent dehydration by means of POCl3/pyridine affords the unsaturated nitrile (VII). Finally, partial hydrolysis of nitrile (VII) with HCl in formic acid leads to the target amide compound
| 【1】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 . |
| 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) | 60297 | 8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol | C16H11Cl2NO | 详情 | 详情 | |
| (II) | 60301 | 4-chloro-8-(2,4-dichlorophenyl)-2-methylquinoline | C16H10Cl3N | 详情 | 详情 | |
| (III) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (IV) | 60302 | 8-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylquinoline | C23H22Cl2N2O2 | 详情 | 详情 | |
| (V) | 60303 | 1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-4-piperidinone | C21H18Cl2N2O | 详情 | 详情 | |
| (VI) | 60304 | 1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-4-hydroxy-4-piperidinecarbonitrile | C22H19Cl2N3O | 详情 | 详情 | |
| (VII) | 60305 | 1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-1,2,3,6-tetrahydro-4-pyridinecarbonitrile | C22H17Cl2N3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)4-Piperidone ethylene ketal (V) is acylated with 6-bromonicotinic acid (VI) employing 1,1'-carbonyldiimidazole to yield amide (VII). The bromide group of (VII) is then displaced with CuCN in hot DMF producing nitrile (VIII). Finally, condensation between N-acylpiperidone (VIII) and amidine (IV) in refluxing EtOH leads to the target spiro quinazoline.
| 【1】 Tinker, A.C.; Beaton, H.G.; Boughton-Smith, N.; Cook, T.R.; Cooper, S.L.; Fraser-Rae, L.; Hallam, K.; Hamley, P.; McInally, T.; Nicholls, D.J.; Pimm, A.D.; Wallace, A.V.; 1,2-Dihydro-4-quinazolinamines: Potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo. J Med Chem 2003, 46, 6, 913. |
| 【2】 Hamley, P.R.J.; Pimm, A.D.; Tinker, A.C.; Beaton, H.G.; McInally, T. (AstraZeneca plc); Pharmaceutically active quinazoline cpds.. EP 0858451; JP 1999513679; WO 9714686 . |
| 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) | 63411 | 2-amino-3,6-difluorobenzenecarboximidamide | C7H7F2N3 | 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) | 63412 | 6-bromonicotinic acid | C6H4BrNO2 | 详情 | 详情 | |
| (VII) | 63413 | (6-bromo-3-pyridinyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone | C13H15BrN2O3 | 详情 | 详情 | |
| (VIII) | 63414 | 5-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-2-pyridinecarbonitrile | C14H15N3O3 | 详情 | 详情 |