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【结 构 式】 
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【分子编号】23465 【品名】4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine 【CA登记号】1978-59-2 |
【 分 子 式 】C11H12FN 【 分 子 量 】177.2214232 【元素组成】C 74.55% H 6.82% F 10.72% N 7.9% |
合成路线1
该中间体在本合成路线中的序号：(III)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2
该中间体在本合成路线中的序号：(I)Catalytic hydrogenation of tetrahydropyridine (I) produced piperidine (II). Alkylation of (II) with N-(3-bromopropyl)phthalimide (III) gave (IV). Subsequent hydrazinolysis of the phthalimido group of (IV) yielded amine (V). In a related procedure, piperidine (II) was alkylated with N-Boc-3-bromopropylamine (VI) to give (VII), which was deprotected with HCl in EtOAc to give the diamino precursor (V).
| 【1】 Rittle, K.; et al.; Dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 90. |
| 【2】 Selnick, H.G.; Barrow, J.C.; Nanterment, P.G.; et al.; In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 2000, 43, 14, 2703. |
| 【3】 Selnick, H.G.; Nantermet, P.G.; Barrow, J.C. (Merck & Co., Inc.); alpha1a Adrenergic receptor antagonists. WO 0006565 . |
| 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) | 23465 | 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine | 1978-59-2 | C11H12FN | 详情 | 详情 |
| (II) | 39299 | 4-(4-fluorophenyl)piperidine | 37656-48-7 | C11H14FN | 详情 | 详情 |
| (III) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (IV) | 39300 | 2-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-1H-isoindole-1,3(2H)-dione | C22H23FN2O2 | 详情 | 详情 | |
| (V) | 39302 | 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine | C14H21FN2 | 详情 | 详情 | |
| (VI) | 37752 | tert-butyl 3-bromopropylcarbamate | C8H16BrNO2 | 详情 | 详情 | |
| (VII) | 39301 | tert-butyl 3-[4-(4-fluorophenyl)-1-piperidinyl]propylcarbamate | C19H29FN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)Addition of 4-fluorophenylmagnesium bromide (XIII) to 1-benzyl-4-piperidinone (XII) afforded carbinol (XIV), which was dehydrated to the tetrahydropyridine (XV) by treatment with p-toluenesulfonic acid in refluxing toluene. Hydrogenation of the olefin (XV) with concomitant benzyl group hydrogenolysis gave 4-(4-fluorophenyl)piperidine (XVI) (1). This compound was also obtained by catalytic hydrogenation of the commercially available 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (XVII). Alkylation of piperidine (XVI) with N-(3-bromopropyl)phthalimide (XVIII) provided adduct (XIX), which was subjected to hydrazinolysis in refluxing MeOH to furnish the primary amine (XX). Deprotonation of oxazolidine (IX) with n-butyllithium in THF at -78 C, followed by condensation with p-nitrophenyl chloroformate, gave the p-nitrophenoxycarbonyl derivative (XXI). This was finally coupled with amine (XX) to furnish the title carboxamide.
| 【1】 Tian, D.; Jeon, Y.; Lagu, B.; et al.; De novo design of a novel oxazolidinone analogue as a potent and selective alpha1A adrenergic receptor antagonist with high oral bioavailability. J Med Chem 2000, 43, 15, 2775. |
| 【2】 Broten, T.P.; Nichtberger, S.A.; Siegl, P.K.S. (Merck & Co., Inc.); Combination therapy for the treatment of benign prostatic hyperplasia. WO 9948530 . |
| 【3】 Marzabadi, M.R.; Wong, W.C.; Gluchowski, C.; Tian, D.; Nagarathnam, D.; Lagu, B.; Dhar, T.G.M.; Jeon, Y.T. (Synaptic Pharmaceutical Corp.); Heterocyclic substd. piperidines and uses thereof. EP 0988295; WO 9857940 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 43324 | (4S,5S)-4-(3,4-difluorophenyl)-5-methyl-1,3-oxazolidin-2-one | C10H9F2NO2 | 详情 | 详情 | |
| (XII) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (XIII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XIV) | 15722 | 1-benzyl-4-(4-fluorophenyl)-4-piperidinol | C18H20FNO | 详情 | 详情 | |
| (XV) | 43327 | 1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine | C18H18FN | 详情 | 详情 | |
| (XVI) | 39299 | 4-(4-fluorophenyl)piperidine | 37656-48-7 | C11H14FN | 详情 | 详情 |
| (XVII) | 23465 | 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine | 1978-59-2 | C11H12FN | 详情 | 详情 |
| (XVIII) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (XIX) | 39300 | 2-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-1H-isoindole-1,3(2H)-dione | C22H23FN2O2 | 详情 | 详情 | |
| (XX) | 39302 | 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine | C14H21FN2 | 详情 | 详情 | |
| (XXI) | 43328 | 4-nitrophenyl (4S,5S)-4-(3,4-difluorophenyl)-5-methyl-2-oxo-1,3-oxazolidine-3-carboxylate | C17H12F2N2O6 | 详情 | 详情 |