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【结 构 式】 
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【分子编号】27115 【品名】4-piperidinone 【CA登记号】40064-34-4 |
【 分 子 式 】C5H9NO 【 分 子 量 】99.1326 【元素组成】C 60.58% H 9.15% N 14.13% O 16.14% |
合成路线1
该中间体在本合成路线中的序号：(II)By condensation of 5-methoxyindole (I) with 4-piperidone (II) in acetic acid at 100 C, followed by neutralization with succinic acid (A).
| 【1】 Dumont, C.; et al. (Aventis Pharma SA); Treating psychic disorders with piperidylindoles. ES 461875; FR 2362628; GB 1556919; JP 53028178; US 4196209 . |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Paton, D.M.; RU-24,969. Drugs Fut 1981, 6, 3, 157. |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 3-(4-fluorophenoxy)propionic acid (I) with 4-piperidone (II) by means of pivaloyl chloride and TEA in refluxing toluene gives the amide (III), which is submitted to oxidation with diacetoxyiodobenzene and KOH in methanol, yielding the hydroxy-dimethoxyketal (IV). The methylation of the OH group of (IV) with Me-I and Ag2O in DMF affords the corresponding methoxy compound (V), which is hydrolyzed with HOAc to provide the methoxypiperidone (VI). The reaction of (VI) with O-benzylhydroxylamine (VII) and pyridine in refluxing toluene gives the oxime (VIII), which is diastereoselectively reduced with BH3 in THF, yielding the cis-isomer (IX). Finally, this amine is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (X) by means of ethyl chloroformate, TEA and HOBt in DMF to afford the target amide.
| 【1】 Cossy, J.; et al.; A short synthesis of cisapride: A gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine. Tetrahedron Lett 2001, 42, 33, 5713. |
| 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) | 39121 | 3-(4-fluorophenoxy)propionic acid | 2967-70-6 | C9H9FO3 | 详情 | 详情 |
| (II) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (III) | 49549 | 1-[3-(4-fluorophenoxy)propanoyl]-4-piperidinone | C14H16FNO3 | 详情 | 详情 | |
| (IV) | 49550 | 3-(4-fluorophenoxy)-1-(3-hydroxy-4,4-dimethoxy-1-piperidinyl)-1-propanone | C16H22FNO5 | 详情 | 详情 | |
| (V) | 49551 | 3-(4-fluorophenoxy)-1-(3,4,4-trimethoxy-1-piperidinyl)-1-propanone | C17H24FNO5 | 详情 | 详情 | |
| (VI) | 49552 | C15H18FNO4 | 详情 | 详情 | ||
| (VII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VIII) | 49553 | 1-[3-(4-fluorophenoxy)propanoyl]-3-methoxy-4-piperidinone O-benzyloxime | C22H25FN2O4 | 详情 | 详情 | |
| (IX) | 49554 | (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine | C15H23FN2O2 | 详情 | 详情 | |
| (X) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 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 title compound was obtained by two related procedures. Reaction of 4-piperidone-HCl (II) with 2-(benzhydryloxy)ethyl chloride (I) in the presence of Na2CO3 and NaI provided the N-alkylated piperidone (III). Horner-Emmons condensation of (III) with triethyl phosphonoacetate (IV) and NaH gave rise to the piperidylidene acetate (V). Then, hydrogenation of the double bond of (V) using Raney Nickel yielded the target compound.
| 【1】 Buzas, A.; Merour, J.-Y.; Ollivier, R. (Laboratoires Meram SA); Benzhydryloxyethylpiperidine derivs., process for their preparation and pharmaceutical compsns., in which they are present. EP 0259227; US 4983614 . |
| 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) | 34744 | 1-[(2-chloroethoxy)(phenyl)methyl]benzene; benzhydryl 2-chloroethyl ether | 32669-06-0 | C15H15ClO | 详情 | 详情 |
| (II) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (III) | 34745 | 1-[2-(benzhydryloxy)ethyl]-4-piperidinone | C20H23NO2 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 34746 | ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinylidene]acetate | C24H29NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The title compound was obtained by two related procedures. Reaction of 4-piperidone-HCl (II) with 2-(benzhydryloxy)ethyl chloride (I) in the presence of Na2CO3 and NaI provided the N-alkylated piperidone (III). Horner-Emmons condensation of (III) with triethyl phosphonoacetate (IV) and NaH gave rise to the piperidylidene acetate (V). Then, hydrogenation of the double bond of (V) using Raney Nickel and hydrolysis yielded the target compound.
| 【1】 Buzas, A.; Merour, J.-Y.; Ollivier, R. (Laboratoires Meram SA); Benzhydryloxyethylpiperidine derivs., process for their preparation and pharmaceutical compsns., in which they are present. EP 0259227; US 4983614 . |
| 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) | 34744 | 1-[(2-chloroethoxy)(phenyl)methyl]benzene; benzhydryl 2-chloroethyl ether | 32669-06-0 | C15H15ClO | 详情 | 详情 |
| (II) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (III) | 34745 | 1-[2-(benzhydryloxy)ethyl]-4-piperidinone | C20H23NO2 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 34746 | ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinylidene]acetate | C24H29NO3 | 详情 | 详情 | |
| (VI) | 34748 | ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinyl]acetate | C24H31NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The alkylation of 4-piperidone monohydrate hydrochloride (I) with 5-bromo-2-methyl-2-pentene (II) in the presence of KI and K2CO3 afforded the tertiary amine (III). Subsequent reductive amination using ammonium acetate and sodium cyanoborohydride provided aminopiperidine (IV).
| 【1】 Mase, T.; Mitsuya, M.; Tsuchiya, Y.; et al.; J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors. Bioorg Med Chem 1999, 7, 11, 2555. |
| 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) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (II) | 31462 | 5-bromo-2-methyl-2-pentene | C6H11Br | 详情 | 详情 | |
| (III) | 31464 | 1-(4-methyl-3-pentenyl)-4-piperidinone | C11H19NO | 详情 | 详情 | |
| (IV) | 31463 | 1-(4-methyl-3-pentenyl)-4-piperidinamine; 1-(4-methyl-3-pentenyl)-4-piperidinylamine | C11H22N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XVI)The intermediate 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (VIII) has been obtained by three different ways: 1) The cyclization of 2-hdroxybenzaldehyde (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives ethyl benzofuran-2-carboxylate (III), which is reduced with LiAlH4 in refluxing THF to the carbinol (IV). The reaction of (IV) with acetone cyanohydrin (V), PPh3 and DEAD yields the acetonitrile (VI), which is reduced with H2 over Raney-Ni to afford the ethylamine (VII). Finally, this compound is cyclized with formaldehyde in refluxing water to provide the desired intermediate (VIII). 2) The intermediate ethyl benzofuran-2-carboxylate (III), is hydrolyzed with NaOH to the corresponding free acid (IX), which is decarboxylated with Cu at 240 C in quinoline to yield benzofuran (X). The reaction of (X) with oxirane (XI) by means of n-BuLi in ethyl ether affords 2-(2-benzofuryl)ethanol (XII), which is treated first with MsCl and TEA, and then with NaI in refluxing acetone to provide the 2-(2-iodoethyl)benzofuran (XIII). The reaction of (XIII) with hexamethylenetetramine (HMT) gives the adduct (XIV), which is finally cyclized to the target intermediate (VIII) by means of HCl in refluxing ethanol. 3) The target intermediate (VIII) can also be obtained by cyclization of O-phenylhydroxylamine (XV) with 4-piperidone (XVI) in refluxing isopropanol. Finally, intermediate (VIII) is condensed with 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine (XVII) by means of Na2CO3 and KI in a refluxing organic solvent such as 4-methyl-2-pentanone.
| 【1】 Bischoff, F.P.; Kennis, L.E.J.; Mertens, C.J.; et al.; New 2-substituted 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine having highly active and potent central alpha2-antagonistic activity as potential antidepressants. Bioorg Med Chem Lett 2000, 10, 1, 71. |
| 【2】 Bischoff, F.P.; Kennis, L.E.J.; Love, C.J. (Janssen Pharmaceutica NV); 1,2,3,4-Tetrahydro-benzofuro[3,2-c]pyridine derivs.. EP 1019408; JP 2000505115; WO 9845297 . |
| 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) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 38334 | ethyl 1-benzofuran-2-carboxylate | C11H10O3 | 详情 | 详情 | |
| (IV) | 38335 | 1-benzofuran-2-ylmethanol | C9H8O2 | 详情 | 详情 | |
| (V) | 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 |
| (VI) | 38336 | 2-(1-benzofuran-2-yl)acetonitrile | C10H7NO | 详情 | 详情 | |
| (VII) | 38337 | 2-(1-benzofuran-2-yl)-1-ethanamine; 2-(1-benzofuran-2-yl)ethylamine | C10H11NO | 详情 | 详情 | |
| (VIII) | 38338 | 1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine | C11H11NO | 详情 | 详情 | |
| (IX) | 38339 | Benzofuran-2-carboxylic acid; 1-benzofuran-2-carboxylic acid | 496-41-3 | C9H6O3 | 详情 | 详情 |
| (X) | 38340 | 1-benzofuran | 271-89-6 | C8H6O | 详情 | 详情 |
| (XI) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (XII) | 38341 | 2-(1-benzofuran-2-yl)-1-ethanol | C10H10O2 | 详情 | 详情 | |
| (XIII) | 38342 | 2-(2-iodoethyl)-1-benzofuran | C10H9IO | 详情 | 详情 | |
| (XIV) | 38343 | 1-[2-(1-benzofuran-2-yl)ethyl]-3,5-diaza-1-azoniatricyclo[3.3.1.1(3,7)]decane iodide | C17H22IN3O | 详情 | 详情 | |
| (XV) | 25770 | 1-(aminooxy)benzene; O-phenylhydroxylamine | C6H7NO | 详情 | 详情 | |
| (XVI) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (XVII) | 38344 | 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one | C11H11ClN2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)4-Piperidinone hydrochloride (I) was protected as the tert-butyl carbamate (II) using Boc2O and diisopropyl ethylamine. Condensation of (II) with 2-aminobenzyl alcohol (III) in boiling toluene, followed by reduction with sodium cyanoborohydride gave secondary amine (IV). Subsequent cyclization of (IV) in the presence of triphosgene and diisopropyl ethylamine produced the benzoxazinone (V), from which the Boc group was removed with HCl in EtOAc to yield intermediate (VI).
| 【1】 Freidinger, R.M.; Stauffer, K.; Perlow, D.S.; Sparks, M.A.; Williams, P.D.; Bell, I.M. (Merck & Co., Inc.); Tocolytic oxytocin receptor antagonists. GB 2326410; US 6090805 . |
| 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) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (II) | 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 |
| (III) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (IV) | 18621 | tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate | C17H26N2O3 | 详情 | 详情 | |
| (V) | 18622 | tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate | C18H24N2O4 | 详情 | 详情 | |
| (VI) | 19420 | 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C13H16N2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)Condensation between 2-iodo-5-fluoroaniline (I) and phenylacetylene (II) under catalysis with Pd(PPh3)4, CuI and diethylamine, followed by cyclization catalyzed by CuI and CaCO3 in DMF, affords phenylindole (III), which is then coupled with 4-piperidone (IV) in H3PO4/HOAc to provide tetrahydropyridine derivative (V). Protection of (V) as its benzyloxycarbonyl derivative (VII) by reaction with acid chloride (VI), followed by hydroboration with bis-isopinocampheylborane ((-)-Ipc2BH) and H2O2 in NaOH, provides the secondary alcohol (VIII). Isolation of enantiomer (IX) is then performed by reaction of (VIII) with the acid chloride derived from (1R)-(+)-camphanic acid, separation of diastereoisomers by chromatography and hydrolysis with K2CO3 in MeOH. Treatment of (IX) with diethylaminosulfur trifluoride (DAST) in EtOAc induces a regiospecific and enantioselective rearrangement affording 3-(3-indolyl)-4-fluoropiperidine (X), which is finally converted into the desired compound by deprotection with formic acid and Pd/C.
| 【1】 Rowley, M.; et al.; 3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT2A receptor antagonists. J Med Chem 2001, 44, 10, 1603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 50178 | 7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride | C9H11ClO3 | 详情 | 详情 | ||
| (I) | 50173 | 5-fluoro-2-iodoaniline; 5-fluoro-2-iodophenylamine | C6H5FIN | 详情 | 详情 | |
| (II) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |
| (III) | 50174 | 6-fluoro-2-phenyl-1H-indole | C14H10FN | 详情 | 详情 | |
| (IV) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (V) | 50175 | 6-fluoro-2-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole | C19H17FN2 | 详情 | 详情 | |
| (VI) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 50176 | benzyl 4-[2-(1,2,3,5-cyclohexatetraen-1-yl)-6-fluoro-1H-indol-3-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate | C27H21FN2O2 | 详情 | 详情 | |
| (VIII) | 50177 | benzyl 4-(6-fluoro-2-phenyl-1H-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate | C27H25FN2O3 | 详情 | 详情 | |
| (IX) | 50179 | benzyl (3S,4S)-4-(6-fluoro-2-phenyl-1H-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate | C27H25FN2O3 | 详情 | 详情 | |
| (X) | 50180 | benzyl (3R,4R)-4-fluoro-3-(6-fluoro-2-phenyl-1H-indol-3-yl)-1-piperidinecarboxylate | C27H24F2N2O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Protection of 4-piperidone (I) with trityl chloride and TEA gives 1-tritylpiperidin-4-one (II), which is condensed with ethyl 2-oxoacetate (III) by means of pyrrolidine in refluxing benzene to yield 3-(ethoxycarbonylmethylene)-1-tritylpiperidin-4-one (IV). The deprotection and simultaneous reduction of compound (IV) with NaBH4 in methanol affords the 4-hydroxypiperidine derivative (V), which is condensed with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone (VI) by means of K2CO3 in DMF to provide the adduct (VII). Reaction of the OH group of (VII) with CBr4 and PPh3 in dichloromethane gives the 4-bromopiperidine derivative (VIII), which by reaction with potassium thioacetate (IX) in ethanol provides the 4-(acetylthio)piperidine derivative (X). Selective hydrolysis of compound (X) with HCl in ethanol yields the 4-sulfanylpiperidine derivative (XI), which is finally submitted to a new hydrolysis with HCl in acetic acid.
| 【1】 Castaner, J.; Mealy, N.E.; Doggrell, S.A.; CS-747 and R-99224. Drugs Fut 2001, 21, 9, 835. |
| 【2】 Asai, F.; Sugidachi, A.; Ikeda, T.; Koike, H.; Inoue, T.; Takata, K.; Iwamura, R.; Kita, J.; Yoneda, K. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Cyclic amine derivs.. EP 0934928; JP 1998120649; US 6087379; WO 9808811 . |
| 【3】 Shibakawa, N.; Iwabuchi, H.; Sugidachi, A.; Ikeda, T.; Iwamura, R.; Kuroki, Y.; Inoue, T.; Asai, F. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Cyclic amino cpds.. EP 1063230; WO 9943648 . |
| 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) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (II) | 48590 | 1-trityl-4-piperidinone | C24H23NO | 详情 | 详情 | |
| (III) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
| (IV) | 48592 | ethyl 2-(4-oxo-1-trityl-3-piperidinylidene)acetate | C28H27NO3 | 详情 | 详情 | |
| (V) | 48593 | ethyl 2-(4-hydroxy-3-piperidinylidene)acetate | C9H15NO3 | 详情 | 详情 | |
| (VI) | 48584 | 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone | 204205-33-4 | C11H10BrFO | 详情 | 详情 |
| (VII) | 48594 | ethyl 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-hydroxy-3-piperidinylidene]acetate | C20H24FNO4 | 详情 | 详情 | |
| (VIII) | 48595 | ethyl 2-[4-bromo-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-piperidinylidene]acetate | C20H23BrFNO3 | 详情 | 详情 | |
| (IX) | 17190 | potassium ethanethioate | 10387-40-3 | C2H3KOS | 详情 | 详情 |
| (X) | 48596 | ethyl 2-[4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-piperidinylidene]acetate | C22H26FNO4S | 详情 | 详情 | |
| (XI) | 48597 | ethyl 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanyl-3-piperidinylidene]acetate | C20H24FNO3S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VI)Condensation of substituted aniline (I) with acrylic acid (II) in toluene affords bicyclic derivative (III), whose carbonyl is reduced by means of Red-Al in toluene to yield compound (IV). Conversion of (IV) into bicyclic hydrazine (V) is then performed by treatment with NaNO2 and HOAc followed by reduction of the resulting diazo derivative with LiAlH4 in THF. Derivative (V) is then subjected to a Fisher indole cyclization process by reaction with ketone (VI) and HCl in iPrOH to provide compound (VII), which is then regioselectively reduced with NaCNBH3 in TFA to give tetracyclic indoline (VIII). N-Protection of (VIII) with Boc2O and NaOH affords Boc protected derivative (IX), which is then selectively brominated by means of NBS in DMF to yield bromo derivative (X). Finally, the desired compound is obtained by a Suzuki cross-coupling reaction between (X) and boronic acid (XI) catalyzed by Pd(PPh3)4, followed by Boc removal with TFA in CH2Cl2.
| 【1】 Robichaud, A.J.; Chen, W.; McClung, C.; et al.; Synthesis and biological evaluation of novel, selective 5-HT2C receptor agonists for the treatment of obesity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 105. |
| 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) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (II) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (III) | 48910 | 2,3,4,5-Tetrahydro-1,5-benzothiazepin-4-one | C9H9NOS | 详情 | 详情 | |
| (IV) | 22617 | 2,3,4,5-tetrahydro-1,5-benzothiazepine | C9H11NS | 详情 | 详情 | |
| (V) | 48146 | 3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine | C9H12N2S | 详情 | 详情 | |
| (VI) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (VII) | 48147 | 6,7,9,10,11,12-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H16N2S | 详情 | 详情 | |
| (VIII) | 48150 | (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H18N2S | 详情 | 详情 | |
| (IX) | 48149 | tert-butyl (8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate | C19H26N2O2S | 详情 | 详情 | |
| (X) | 48911 | tert-butyl (8aS,12aR)-2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate | C19H25BrN2O2S | 详情 | 详情 | |
| (XI) | 48912 | 2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid | 68716-47-2 | C6H5BCl2O2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)The condensation of 3-ethylphenol (I) with 4-piperidone (II) by means of gaseous HCl in acetic acid gives 5-ethyl-2-(1,2,3,6-tetrahydropyridin-4-yl)phenol (III), which is treated with acetic anhydride in pyridine to yield the diacetyl derivative (IV). The selective hydrolysis of the O-acetyl group of (IV) by means of K2CO3 in methanol affords the phenol derivative (V), which is hydrogenated with H2 over Pd/C in methanol to provide the acetyl piperidine (VI). The alkylation of the phenolic group of (VI) with ethyl iodide and Cs2CO3 in refluxing acetone gives 1-acetyl-4-(2-ethoxy-4-ethylphenyl)piperidine (VII), which is deacetylated by means of NaOH in refluxing methanol to yield 4-(2-ethoxy-4-ethylphenyl)piperidine (VIII). The alkylation of the piperidine (VIII) with N-(4-bromobutyl)phthalimide (IX) by means of Cs2CO3 in refluxing acetone affords the adduct (X), which is cleaved with hydrazine in hot methanol to provide 1-(4-aminobutyl)-4-(2-ethoxy-4-ethylphenyl)piperidine (XI). Finally, this amine is condensed with 4-(4-chlorobenzamido)benzoic acid (XII) by means of EDC, HOBT and TEA in DMF to give the target diamide. The intermediate 4-(4-chlorobenzamido)benzoic acid (XII) is obtained as follows: The condensation of 4-aminobenzoic acid ethyl ester (XIV) with 4-chlorobenzoyl chloride (XIII) by means of TEA and DMAP gives 4-(4-chlorobenzamido)benzoic acid ethyl ester (XV), which is finally hydrolyzed with NaOH to afford the target benzoic acid intermediate (XII).
| 【1】 Grand-Perret, T.A.R.; Issandou, M. (GlaxoSmithKline plc); Binding competition of SREBP-cleavage activating protein (SCAP) antagonists. WO 0106261 . |
| 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) | 53495 | 3-Ethyl phenol; m-Ethyl phenol | 620-17-7 | C8H10O | 详情 | 详情 |
| (II) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (III) | 53496 | 5-ethyl-2-(1,2,3,6-tetrahydro-4-pyridinyl)phenol | n/a | C13H17NO | 详情 | 详情 |
| (IV) | 53497 | 2-(1-acetyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-ethylphenyl acetate | n/a | C17H21NO3 | 详情 | 详情 |
| (V) | 53498 | 1-[4-(4-ethyl-2-hydroxyphenyl)-3,6-dihydro-1(2H)-pyridinyl]-1-ethanone | n/a | C15H19NO2 | 详情 | 详情 |
| (VI) | 53499 | 1-[4-(4-ethyl-2-hydroxyphenyl)-1-piperidinyl]-1-ethanone | n/a | C15H21NO2 | 详情 | 详情 |
| (VII) | 53500 | 1-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]-1-ethanone | n/a | C17H25NO2 | 详情 | 详情 |
| (VIII) | 53501 | 4-(2-ethoxy-4-ethylphenyl)piperidine; ethyl 5-ethyl-2-(4-piperidinyl)phenyl ether | n/a | C15H23NO | 详情 | 详情 |
| (IX) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (X) | 53502 | 2-{4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]butyl}-1H-isoindole-1,3(2H)-dione | n/a | C27H34N2O3 | 详情 | 详情 |
| (XI) | 53503 | 4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]-1-butanamine; 4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]butylamine | n/a | C19H32N2O | 详情 | 详情 |
| (XII) | 53504 | 4-[(4-chlorobenzoyl)amino]benzoic acid | n/a | C14H10ClNO3 | 详情 | 详情 |
| (XIII) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (XIV) | 16498 | Benzocaine; ethyl 4-aminobenzoate | 94-09-7 | C9H11NO2 | 详情 | 详情 |
| (XV) | 53505 | Ethyl 4-(4-chlorobenzamido)benzoate | n/a | C16H14ClNO3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(IX)The reaction of the chiral benzyl alcohol (I) with 4-chlorobenzenesulfonyl chloride (II) and DABCO in toluene gives the sulfonate (III), which is condensed with the monoprotected piperazine (IV) by means of K2CO3 in hot toluene/acetonitrile to yield the adduct (V). The deprotection of (V) by means of hot aqueous HCl affords the piperazine derivative (VI), which is condensed with the acyl piperidine (VII) --obtained by condensation of 4,6-dimethylpyrimidine-5-carboxylic acid (VIII) with 4-piperidone (IX) --by means of acetone cyanohydrin or NaCN/AcOH to provide the cyano adduct (X). Finally, this compound is treated with AlMe3 and Me-MgCl in THF/toluene to yield the target compound.
| 【1】 Gala, D.; Leong, W.; Jones, A.D.; Shi, X.; Chen, M.; D'sa, B.A.; Zhu, M.; Xiao, T.; Tang, S.; Goodman, A.J.; Nielsen, C.M.; Lee, G.M.; Gamboa, J.A. (Schering Corp.); Synthesis of piperidine and piperazine cpds. as CCR5 antagonists. WO 0384950 . |
| 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) | 64951 | (1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]-1-ethanol | C10H11F3O2 | 详情 | 详情 | |
| (II) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (III) | 64952 | (1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl 4-chlorobenzenesulfonate | C16H14ClF3O4S | 详情 | 详情 | |
| (IV) | 50647 | benzyl (3R)-3-methyl-1-piperazinecarboxylate | C13H18N2O2 | 详情 | 详情 | |
| (V) | 64953 | benzyl (3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methyl-1-piperazinecarboxylate | C23H27F3N2O3 | 详情 | 详情 | |
| (VI) | 64946 | 2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}piperazine; methyl 2-(2-methyl-1-piperazinyl)-2-[4-(trifluoromethyl)phenyl]ethyl ether | C15H21F3N2O | 详情 | 详情 | |
| (VII) | 64954 | 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-piperidinone | C12H15N3O2 | 详情 | 详情 | |
| (VIII) | 64955 | 4,6-dimethyl-5-pyrimidinecarboxylic acid | C7H8N2O2 | 详情 | 详情 | |
| (IX) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (X) | 64956 | 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-((3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methylpiperazinyl)-4-piperidinecarbonitrile | C28H35F3N6O2 | 详情 | 详情 |