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【结 构 式】 
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【分子编号】21497 【品名】(4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine 【CA登记号】56346-57-7 |
【 分 子 式 】C12H14FNO 【 分 子 量 】207.2477032 【元素组成】C 69.55% H 6.81% F 9.17% N 6.76% O 7.72% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 7-(3-chloropropyl)theophylline (I) with 4-(p-fluorobenzoyl)piperidine (II) gives fluprofylline.
| 【1】 Thiele, K.; Jahn, U.; Geissmann, F.; Zimgibl, L.; Theophylline derivatives. ES 8304981; US 4603204; US 4668786; WO 8700841; ZA 8205123 . |
| 【2】 Thiele, K.; Geissmann, F.; Jahn, U.; Zimgibl, L.; Neue biologisch aktive Theophyllin-Derivate. Arzneim-Forsch Drug Res 1984, 34, 1, 1. |
| 【3】 Jahn, U.; Thiele, K.; Fluprofylline. Drugs Fut 1984, 9, 8, 580. |
| 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) | 34353 | 7-(3-chloropropyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 7-(3-chloropropyl)theophylline | 2770-66-3 | C10H13ClN4O2 | 详情 | 详情 |
| (II) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)By condensation of 4-(4-fluorobenzoyl)piperidine (IX) with 6-(2-bromo ethyl)-7-methyl-2,3-dihydro-5H-thiazolo[2,3-a]pyrimidin-5-one (IV) by means of Na2CO3 in refluxing 4-methyl-2-pentanone. The starting products are obtained as follows: The cyclization of 4-hydroxy-5-(2-hydroxyethyl)-6-methyl-2-mercaptopyrimidine (I) with 1,2-dibromo ethane (II) by means of K2CO3 in hot dimethylacetamide gives 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (II), which by reaction with HBr in refluxing acetic acid is converted to the corresponding 6-(2-bromoethyl) derivative (IV). The Grignard reaction of 4-bromofluorobenzene (V) with N benzyl-4 cyanopiperidine (VI) by means of Mg in dimethoxyethane gives 4-(4-fluorobenzoyl)-N-benzylpiperidine (VII), which is treated with ethyl chlorocarbo-nate in refluxing toluene to afford ethyl 4-(4-fluorobenzoyl)piperidine-1-carboxylate (VIII). Finally, this compound is treated with HBr in refluxing 48% HBr to give (IX).
| 【1】 Kennis, L.; Mertens, J.C. (Janssen Pharmaceutica NV); Bicyclic pyrimidin-5-one derivatives. DD 215553; EP 0070053; US 4443451 . |
| 【2】 Serradell, M.N.; Castaner, J.; Setoperone. Drugs Fut 1985, 10, 1, 40. |
| 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) | 29009 | 5-(2-hydroxyethyl)-6-methyl-2-sulfanyl-4-pyrimidinol | C7H10N2O2S | 详情 | 详情 | |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 29010 | 6-(2-hydroxyethyl)-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one | C9H12N2O2S | 详情 | 详情 | |
| (IV) | 29011 | 6-(2-bromoethyl)-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one | C9H11BrN2OS | 详情 | 详情 | |
| (V) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (VI) | 29013 | 1-benzyl-4-piperidinecarbonitrile | C13H16N2 | 详情 | 详情 | |
| (VII) | 29014 | (1-benzyl-4-piperidinyl)(4-fluorophenyl)methanone | C19H20FNO | 详情 | 详情 | |
| (VIII) | 29015 | ethyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate | C15H18FNO3 | 详情 | 详情 | |
| (IX) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 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 condensation of N-(2-bromoethyl)-2-nitrobenzamide (I) with 4-(4-fluorobenzoyl)piperidine (II) by means of Na2CO3 in refluxing methyl isobutyl ketone gives N-[2-[4-(4-fluorobenzoyl)-2-piperidinyl]ethyl]-2-nitrobenzamide (III), which is reduced with H2 over Pt/C in methanol yielding the corresponding amino derivative (IV). Finally, this compound is cyclized with urea (V) in refluxing xylene.
| 【1】 Janssen, C.G.M.; Lenoir, H.A.C.; Thijssen, J.B.A.; Knaeps, A.G.; Verluyten, W.L.M.; Heykants, J.J.P.; Synthesis of 3H- and 14C-ketanserin. J Label Compd Radiopharm 1988, 25, 7, 783-92. |
| 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) | 21496 | N-(2-bromoethyl)-2-nitrobenzamide | C9H9BrN2O3 | 详情 | 详情 | |
| (II) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (III) | 21498 | N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-nitrobenzamide | C21H22FN3O4 | 详情 | 详情 | |
| (IV) | 21499 | 2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide | C21H24FN3O2 | 详情 | 详情 | |
| (V) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)By condensation of 2,3-dihydro-5H-oxazole[2,3-b]quinazolin-5-one (I) with 4-(4-fluorobenzoyl)piperidine (II) in refuxing toluene.
| 【1】 Signorini, R.; Verga, A. (Ravizza SpA); Process for preparing ketanserine. EP 0098499; IT 1155357 . |
合成路线5
该中间体在本合成路线中的序号：(I)By reaction of 4-(p-fluorobenzoyl)piperidine (I) with 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (II) by means of Na2CO3 in refluxing 4-methyl-2-pentanone. The starting compounds are prepared as follows: 1) The Grignard reaction of N-benzyl-4-cyanopiperidine (III) with p-fluorophenylmagnesium bromide (IV) ethyl ether gives N-benzyl-4-p-fluorobenzoyl)piperidine (V), which by reaction with Na2CO3 and ethyl chloroformate (A) is converted into N-ethoxycarbonyl-4-(p-fluorobenzoyl)piperidine (VI). Finally, this compound is hydrolyzed with 48% HBr to give (I). 2) The reaction of ethyl anthranilate (VII) with ethyl chloroformate (A) in refluxing xylene gives ethyl 2-(ethoxycarbonylamino)benzoate (VIII), which is cyclized with 2-aminoethanol (B) at 170 C to afford 3-(2-hydroxyethyl)-2,4-(1H,3H)-quinazolinedione (IX). Finally, this compound is treated with SOCl2 in refluxing chloroform to afford (II).
| 【1】 Van Der, M.; Keninis, L.; Vandenberk, J.; Van Heertum, A. (Janssen Pharmaceutica NV); Piperidinylalkyl quinazoline compounds, composition and method of use. EP 0013612; JP 55105679; US 4335127 . |
| 【2】 Blancafort, P.; Paton, D.M.; Serradell, M.N.; Castaner, J.; Ketanserin. Drugs Fut 1981, 6, 11, 684. |
| 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 |
| (B) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (I) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (II) | 32277 | 3-(2-chloroethyl)-2,4(1H,3H)-quinazolinedione | 5081-87-8 | C10H9ClN2O2 | 详情 | 详情 |
| (III) | 29013 | 1-benzyl-4-piperidinecarbonitrile | C13H16N2 | 详情 | 详情 | |
| (IV) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (V) | 29014 | (1-benzyl-4-piperidinyl)(4-fluorophenyl)methanone | C19H20FNO | 详情 | 详情 | |
| (VI) | 29015 | ethyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate | C15H18FNO3 | 详情 | 详情 | |
| (VII) | 32278 | ethyl 2-aminobenzoate | 87-25-2 | C9H11NO2 | 详情 | 详情 |
| (VIII) | 32279 | ethyl 2-[(ethoxycarbonyl)amino]benzoate | C12H15NO4 | 详情 | 详情 | |
| (IX) | 32280 | 3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione | C10H10N2O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The condensation of 7-(2-chloroethyl)theophylline (I) with 4-(p-fluorobenzoyl)piperidine (II) gives flufylline.
| 【1】 Thiele, K.; Jahn, U.; Geissmann, F.; Zimgibl, L.; Theophylline derivatives. ES 8304981; US 4603204; US 4668786; WO 8700841; ZA 8205123 . |
| 【2】 Thiele, K.; Geissmann, F.; Jahn, U.; Zimgibl, L.; Neue biologisch aktive Theophyllin-Derivate. Arzneim-Forsch Drug Res 1984, 34, 1, 1. |
| 【3】 Jahn, U.; Thiele, K.; Flufylline. Drugs Fut 1984, 9, 8, 579. |
合成路线7
该中间体在本合成路线中的序号：(IX)2-Pyrrolecarboxylic acid (I) was condensed with ethyl 3-(methylamino)-propionate (II) by means of diethyl phosphorocyanidate to give amide (III). Alkaline hydrolysis of the ethyl ester group of (III) provided carboxylic acid (IV), which was cyclized in 80% polyphosphoric acid at 100 C to afford the pyrroloazepine (V). Subsequent reaction of (V) with 1,4-dichlorobutane (VI) in the presence of K2CO3 yielded the N-(4-chlorobutyl)pyrrole (VII). Treatment of (VII) with hydroxylamine hydrochloride and NaOAc furnished the E-oxime (VIII) as the major isomer. Then, displacement of the chloro atom of (VIII) with 4-(4-fluorobenzoyl)piperidine-HCl (IX) using K2CO3 and NaI yielded the title compound.
| 【1】 Miya, M.; Miyazaki, T.; Inomata, N.; Tatsuoka, T.; Mizuno, A.; Kamei, T.; Takiguchi, C.; Yoshida, M.; Shibata, M.; Synthesis and pharmacological evaluation of pyrroloazepine derivatives as potent antihypertensive agents with antiplatelet aggregation activity. Chem Pharm Bull 1999, 47, 2, 246. |
| 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) | 31796 | Pyrrole-2-carboxylic acid; 1H-pyrrole-2-carboxylic acid | 634-97-9 | C5H5NO2 | 详情 | 详情 |
| (II) | 20771 | ethyl 3-(methylamino)propanoate | C6H13NO2 | 详情 | 详情 | |
| (III) | 31797 | ethyl 3-[methyl(1H-pyrrol-2-ylcarbonyl)amino]propanoate | C11H16N2O3 | 详情 | 详情 | |
| (IV) | 31798 | N-methyl-N-(1H-pyrrol-2-ylcarbonyl)-beta-alanine | C9H12N2O3 | 详情 | 详情 | |
| (V) | 31799 | 7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione | C9H10N2O2 | 详情 | 详情 | |
| (VI) | 31800 | 1,4-dichlorobutane | 110-56-5 | C4H8Cl2 | 详情 | 详情 |
| (VII) | 31801 | 1-(4-chlorobutyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione | C13H17ClN2O2 | 详情 | 详情 | |
| (VIII) | 31802 | 1-(4-chlorobutyl)-7-methyl-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione 4-oxime | C13H18ClN3O2 | 详情 | 详情 | |
| (IX) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)The reduction of 3,5-dimethoxybenzoic acid (I) first with Li in liquid NH3 and methanol, and then with LiAlH4 in THF gives 3,5-dimethoxy-1,4-dihydrobenzyl alcohol (II), which is cyclized with phenylhydrazine (III) in refluxing 4% sulfuric acid yielding 2-(hydroxymethyl)-1,2,3,4-tetrahydrocarbazol-4-one (IV). The reaction of (IV) with tosyl chloride in pyridine affords the corresponding tosylate (V), which is finally condensed with 4-(4-fluorobenzoyl)piperidine (VI) in N-methyl-2-pyrrolidone.
| 【1】 Masaguer, C.F.; Formoso, E.; Raviña, E.; Tristán, H.; Loza, M.I.; Rivas, E.; Fontenla, J.A.; Butyrophenone analogues in the carbazole series: Synthesis and determination of affinities at D2 and 5-HT2A receptors. Bioorg Med Chem Lett 1998, 8, 24, 3571. |
| 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) | 22761 | 3,5-dimethoxybenzoic acid | 1132-21-4 | C9H10O4 | 详情 | 详情 |
| (II) | 25566 | (3,5-dimethoxy-2,5-cyclohexadien-1-yl)methanol | C9H14O3 | 详情 | 详情 | |
| (III) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (IV) | 25567 | 2-(hydroxymethyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one | C13H13NO2 | 详情 | 详情 | |
| (V) | 25568 | (4-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)methyl 4-methylbenzenesulfonate | C20H19NO4S | 详情 | 详情 | |
| (VI) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The condensation of 3,5-dimethoxybenzoic acid (I) with 4-(4-fluorobenzoyl)piperidine (II) by means of DCC and HOBT in DMF gives the piperidide (III), which is reduced with LiAlH4 in THF to yield 1-(3,5-dimethoxybenzyl)-4-(4-fluorobenzoyl)piperidine (IV). The reduction of (IV) with Li in liquid ammonia affords the 1,4-dihydro derivative (V), which is finally cyclized with phenylhydrazine (VI) in refluxing aqueous sulfuric acid to provide the target tetrahydrocarbazolone.
| 【1】 Masaguer, C.F.; Loza, M.I.; Fontenla, J.A.; Brea, J.; Raviña, E.; Tristan, H.; Butyrophenone analogues in the carbazole series as potential atypical antipsychotics: Synthesis and determination of affinities at D2, 5-HT2A, 5-HT2B and 5-HT2C receptors. Eur J Med Chem 2000, 35, 1, 83. |
| 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) | 22761 | 3,5-dimethoxybenzoic acid | 1132-21-4 | C9H10O4 | 详情 | 详情 |
| (II) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (III) | 51415 | (3,5-dimethoxyphenyl)[4-(4-fluorobenzoyl)-1-piperidinyl]methanone | C21H22FNO4 | 详情 | 详情 | |
| (IV) | 51416 | [1-(3,5-dimethoxybenzyl)-4-piperidinyl](4-fluorophenyl)methanone | C21H24FNO3 | 详情 | 详情 | |
| (V) | 51417 | [1-[(3,5-dimethoxy-2,5-cyclohexadien-1-yl)methyl]-4-piperidinyl](4-fluorophenyl)methanone | C21H26FNO3 | 详情 | 详情 | |
| (VI) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)N-protection of the NH group of (I) with Boc2O and NaOH in Et2O yields derivative (II), which is then condensed with compound (III) by means of NaH in DMF to provide (IV). N-deprotection of (IV) by treatment with TFA in CH2Cl2 followed by reductocondensation with N-Boc-4-piperidone (V) in CH2Cl2 in the presence of Na(OAc)3BH affords compound (VI), which is oxidized with NaBO3.4H2O to provide (VII). Boc removal of (VII) by treatment with TFA in CH2Cl2, followed by reaction of the resulting secondary amine with sulfonyl chloride (VIII) in CH2Cl2 in the presence of Et3N, affords propylsulfonamide derivative (IX). Finally, treatment of (IX) with ethyleneglycol (X) in toluene in the presence of HC(OEt)3 and p-TsOH furnishes the target compound.
| 【1】 Boyle, C.D.; Chackalamannil, S.; Chen, L.-Y.; et al.; Benzylidine ketal derivatives as M2 muscarinic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 24, 2727. |
| 【2】 Chackalamannil, S.; Chen, L.-Y.; Boyle, C.D.; et al.; Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 114. |
| 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) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (II) | 45867 | tert-butyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate | C17H22FNO3 | 详情 | 详情 | |
| (III) | 28620 | 1,3-benzodioxole-5-thiol | C7H6O2S | 详情 | 详情 | |
| (IV) | 45868 | tert-butyl 4-[4-(1,3-benzodioxol-5-ylsulfanyl)benzoyl]-1-piperidinecarboxylate | C24H27NO5S | 详情 | 详情 | |
| (V) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (VI) | 45869 | C29H36N2O5S | 详情 | 详情 | ||
| (VII) | 45870 | C29H36N2O7S | 详情 | 详情 | ||
| (VIII) | 45871 | 1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride; | 10147-36-1 | C3H7ClO2S | 详情 | 详情 |
| (IX) | 45872 | C27H34N2O7S2 | 详情 | 详情 | ||
| (X) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)Alkylation of 4-(p-fluorobenzoyl)piperidine (I) with p-fluorophenethyl bromide (II) in hot methyl isobutyl ketone provides the disubstituted piperidine (III). Subsequent keto group reduction in (III) by means of NaBH4 furnishes the title carbinol compound.
| 【1】 Fu, X.; Tan, P.-Z.; Kula, N.S.; Baldessarini, R.; Tamagnan, G.; Innis, R.B.; Baldwin, R.M.; Synthesis, receptor potency, and selectivity of halogenated diphenylpiperidines as serotonin 5-HT2A ligands for PET or SPECT brain imaging. J Med Chem 2002, 45, 11, 2319. |
| 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) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (II) | 17394 | 1-(2-bromoethyl)-4-fluorobenzene | C8H8BrF | 详情 | 详情 | |
| (III) | 64558 | [1-(4-fluorophenethyl)-4-piperidinyl](4-fluorophenyl)methanone | C20H21F2NO | 详情 | 详情 |