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【结 构 式】

【分子编号】15720

【品名】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

【CA登记号】3612-20-2

【 分 子 式 】C12H15NO

【 分 子 量 】189.25724

【元素组成】C 76.16% H 7.99% N 7.4% O 8.45%
与该中间体有关的原料药合成路线共 21 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21

合成路线1

该中间体在本合成路线中的序号：(VI)

Horner-Emmons condensation of 1-benzyl-4-piperidone (VI) with phosphonate (IV) furnished the unsaturated ester (VII). Hydrogenation of (VII) over Pd/C produced double bond reduction and simultaneous N-benzyl group cleavage to afford piperidine (VIII). This was finally alkylated with chloride (I) in the presence of K2CO3 and NaI.

参考文献 中间体
合成目标
【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
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VI) 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
(VII) 34747 ethyl 2-(1-benzyl-4-piperidinylidene)acetate C16H21NO2 详情 详情
(VIII) 28087 4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate C9H17NO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Horner-Emmons condensation of 1-benzyl-4-piperidone (VII) with phosphonate (IV) furnished the unsaturated ester (VIII). Hydrogenation of (VIII) over Pd/C produced double bond reduction and simultaneous N-benzyl group cleavage to afford piperidine (IX). This was finally alkylated with chloride (I) in the presence of K2CO3 and NaI and hydrolyzed to target compound.

参考文献 中间体
合成目标
【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
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VI) 34748 ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinyl]acetate C24H31NO3 详情 详情
(VII) 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
(VIII) 34747 ethyl 2-(1-benzyl-4-piperidinylidene)acetate C16H21NO2 详情 详情
(IX) 28087 4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate C9H17NO2 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 1-benzyl-4-piperidone (I) with aniline (II) and KCN in acetic acid gives the aminonitrile (III), which is treated with H2SO4 at room temperature to yield the carboxamide (IV). The hydrolysis of (IV) with refluxing aqueous HCl affords the carboxylic acid (V), which is esterified with Ms-OH and methanol to provide the methyl ester (VI). Acylation of the NH group of (VI) with propionic anhydride (VII) gives the propionamide (VIII), which is debenzylated with H2 over Pd/C to yield the piperidine (IX). Finally, this compound is condensed with methyl acrylate (XI) in acetonitrile to afford the target compound.

参考文献 中间体
合成目标
【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .
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) 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
(II) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(III) 49674 4-Anilino-1-benzyl-4-cyanopiperidine C19H21N3 详情 详情
(IV) 49675 4-Anilino-1-benzylisonipecotamide C19H23N3O 详情 详情
(V) 33884 4-anilino-1-benzyl-4-piperidinecarboxylic acid C19H22N2O2 详情 详情
(VI) 49676 methyl 4-anilino-1-benzyl-4-piperidinecarboxylate C20H24N2O2 详情 详情
(VII) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(VIII) 49677 methyl 1-benzyl-4-(propionylanilino)-4-piperidinecarboxylate C23H28N2O3 详情 详情
(IX) 15668 methyl 4-(propionylanilino)-4-piperidinecarboxylate C16H22N2O3 详情 详情
(X) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

N-Benzyl-4-piperidone (I) was reacted with a Grignard reagent prepared from 4-fluorobromobenzene (II) to give the carbinol (III). The benzyl group was removed by catalytic hydrogenation and the resulting amine (IV) was alkylated with 3-bromopropionaldehyde ethylene acetal (V) to the alcohol (VI). Ring closure in hydrochloric acid gave the bicyclic endo-alcohol [(±)-VII] along with some of the exo-isomer removed by crystallization. [(±)-VII] was resolved by crystallization with (R,R)-tartaric acid mono-4-chloroanilide (VIII) to give [(+)-VII] of yet unknown absolute configuration. The latter was acylated with propionic anhydride followed by crystallization with hydrogen chloride in ether to furnish the end product.

参考文献 中间体
合成目标
【1】 Sólyom, S.; Abraham, G.; Szölössy, M.; Borsi, J.; Vitális, B.; Karimné Tapfer, M.; Szabóné Bady, E.; Csuzdi, E.; Goldschmidtné Horváth, K.; Máté, G.; Ling, I.; Miklósné Kovács, A. (Gyogyszerkutato Intezet Kft.); New 1-azabicycloalkane derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0556342; JP 1994505706; WO 9207854 .
【2】 Nogradi, M.; GYKI-46903. Drugs Fut 1993, 18, 5, 421.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
((+/-)-VII 15726 (rac)-[(4R*,5S*)-6-(4-fluorophenyl)-1-azabicyclo[3.3.1]non-6-en-4-ol] C14H16FNO 详情 详情
((R,R)-VII) 15727 (2R,3R)-4-(4-chloroanilino)-2,3-dihydroxy-4-oxobutyric acid C10H10ClNO5 详情 详情
((+)-VII) 64680 (4R,5S)-6-(4-fluorophenyl)-1-azabicyclo[3.3.1]non-6-en-4-ol C14H16FNO 详情 详情
(I) 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
(II) 13643 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide 352-13-6 C6H4BrFMg 详情 详情
(III) 15722 1-benzyl-4-(4-fluorophenyl)-4-piperidinol C18H20FNO 详情 详情
(IV) 15723 4-(4-fluorophenyl)-4-piperidinol; 4-(4-Fluorophenyl)-4-hydroxypiperidine 3888-65-1 C11H14FNO 详情 详情
(V) 15724 2-(2-bromoethyl)-1,3-dioxolane 18742-02-4 C5H9BrO2 详情 详情
(VI) 15725 1-[2-(1,3-dioxolan-2-yl)ethyl]-4-(4-fluorophenyl)-4-piperidinol C16H22FNO3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(I)

Protected piperidone (I) is condensed with methoxybromobenzene (II) via Grignard reaction by means of Mg and catalytic iodine in refluxing THF, and the resulting alcohol is then dehydrated with refluxing HCl in dioxane to afford compound (III). Hydrogenation of tetrahydropyridine (III) over Pd/C in EtOH yields piperidine derivative (IV), which is then demethylated with aqueous HBr to provide phenol (V). Condensation of (V) with 4-fluorobenzoyl chloride (VI) by means of NaOH in iPrOH/MeOH/H2O furnishes N-benzoylpiperidine derivative (VII), which is converted into the desired product by reaction with ethyl 2-bromo-2-methylpropanoate (VIII) by means of K2CO3 followed by hydrolysis with NaOH in H2O/MeOH/dioxane.

参考文献 中间体
合成目标
【1】 Komoto, T.; et al.; Preparation of new fibrates with piperidine ring and the pharmacological activity. 20th Symp Med Chem (Dec 6 2000, Tokyo) 2000, Abst 2P-06.
【2】 Komoto, T.; et al.; New strong fibrates with piperidine moiety. Chem Pharm Bull 2000, 48, 12, 1978.
【3】 Komoto, T.; Hirota, H.; Sato, S.; Othsuka, M.; Koya, H.; Mizuno, H.; Kuraishi, T. (SSP Co., Ltd.); Arylamide derivs.. EP 0607536; JP 1995053517; US 5411972 .
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) 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
(II) 35983 m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether 2398-37-0 C7H7BrO 详情 详情
(III) 47137 1-benzyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine; 3-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)phenyl methyl ether C19H21NO 详情 详情
(IV) 47138 4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether C12H17NO 详情 详情
(V) 47139 3-(4-piperidinyl)phenol C11H15NO 详情 详情
(VI) 17263 4-fluorobenzoyl chloride 403-43-0 C7H4ClFO 详情 详情
(VII) 47140 (4-fluorophenyl)[4-(3-hydroxyphenyl)-1-piperidinyl]methanone C18H18FNO2 详情 详情
(VIII) 39799 ethyl 2-bromo-2-methylpropanoate 600-00-0 C6H11BrO2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

N-Benzyl-4-hydroxy-4-phenylpiperidine (II) was prepared by addition of phenyllithium to N-benzyl-4-piperidone (I). Carbinol (II) was then converted to acetamide (III) by acid-catalyzed Ritter reaction with acetonitrile. Replacement of the acetamido for an N-Boc group in (III) was effected by acidic hydrolysis of amide (III) to give (IV), followed by treatment with di-tert-butyl dicarbonate. The resultant 1-benzyl-4-(Boc-amino)-4-phenylpiperidine (V) was subjected to catalytic hydrogenolysis in the presence of Pd/C, and the N-debenzylated piperidine (VI) was reprotected as the N-trityl derivative (VII) by treatment with triphenylmethyl chloride and triethylamine. Reduction of the N-Boc group of (VII) by LiAlH4, yielded the N-methyl amine (VIII). After acylation of (VIII) with acetyl chloride to acetamide (IX), its N-trityl group was cleaved by treatment with hot aqueous formic acid to produce the intermediate piperidine (X).

参考文献 中间体
合成目标
【1】 Bichon, D.; Van Broeck, D.; Proietto, V.; Gueule, P.; Emonds-Alt, X. (Sanofi-Synthélabo); Novel N-(3,4-dichlorophenyl-propyl)-piperidine derivs. as selective human NK3-receptor antagonists. EP 0673928; FR 2717477; FR 2717478; FR 2719311; JP 1996048669; US 5741910; US 5942523; US 6124316 .
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) 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
(II) 29470 1-benzyl-4-phenyl-4-piperidinol C18H21NO 详情 详情
(III) 54993 N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide C20H24N2O 详情 详情
(IV) 54994 1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine C18H22N2 详情 详情
(V) 59263 tert-butyl 1-benzyl-4-phenyl-4-piperidinylcarbamate C23H30N2O2 详情 详情
(VI) 54998 tert-butyl 4-phenyl-4-piperidinylcarbamate C16H24N2O2 详情 详情
(VII) 59264 tert-butyl 4-phenyl-1-trityl-4-piperidinylcarbamate C35H38N2O2 详情 详情
(VIII) 59265 N-methyl-4-phenyl-1-trityl-4-piperidinamine; N-methyl-N-(4-phenyl-1-trityl-4-piperidinyl)amine C31H32N2 详情 详情
(IX) 59266 N-methyl-N-(4-phenyl-1-trityl-4-piperidinyl)acetamide C33H34N2O 详情 详情
(X) 59267 N-methyl-N-(4-phenyl-4-piperidinyl)acetamide C14H20N2O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

The condensation of 1-benzylpiperidin-4-one (I) with 4-acetamidoacetophenone (II) by means of lithium diisopropylamide in HMPA/THF gives the piperidinol (III), which is dehydrated by reaction first with SOCl2 and then with NaOH yielding a mixture of compounds (IV) and (V) with exo and endo double bonds. This mixture is hydrogenated with H2 over PtO2 in ethanol/toluene to afford the saturated piperidine derivative (VI), which is treated with HCl in refluxing ethanol to cleave the acetamido substituent giving (VII) with a free amino group. Finally, this compound is condensed with 4-chloro-5-methylpyrimidine (VIII) by means of HCl in refluxing ethanol/CHCl3.

参考文献 中间体
合成目标
【1】 Kimura, T.; Kuroki, Y.; Fujiwara, H.; Anpeiji, S. (Ube Industries, Ltd.); Pyrimidine cpd.. EP 0664291; WO 9407890 .
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) 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
(II) 26414 N-(4-acetylphenyl)acetamide 2719-21-3 C10H11NO2 详情 详情
(III) 26415 N-[4-[2-(1-benzyl-4-hydroxy-4-piperidinyl)acetyl]phenyl]acetamide C22H26N2O3 详情 详情
(IV) 26416 N-[4-[2-(1-benzyl-4-piperidinylidene)acetyl]phenyl]acetamide C22H24N2O2 详情 详情
(V) 26417 N-[4-[2-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)acetyl]phenyl]acetamide C22H24N2O2 详情 详情
(VI) 26418 N-[4-[2-(1-benzyl-4-piperidinyl)acetyl]phenyl]acetamide C22H26N2O2 详情 详情
(VII) 26419 1-(4-aminophenyl)-2-(1-benzyl-4-piperidinyl)-1-ethanone C20H24N2O 详情 详情
(VIII) 26420 4-chloro-5-methylpyrimidine C5H5ClN2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(V)

In an alternative procedure, lithiation of 4-(benzyloxy)-1-bromobenzene (IV), followed by addition of 1-benzyl-4-piperidone (V), gave piperidinol (VI). Subsequent treatment of (VI) with HCl produced dehydration of the tertiary alcohol and benzyl ether cleavage to give (VII). Double bond reduction and hydrogenolysis of the N-benzyl group of (VII) with H2 over Pd/C gave 4-(4-hydroxyphenyl)piperidine (VIII). This was finally alkylated with tosylate (II) to yield the title compound.

参考文献 中间体
合成目标
【1】 Guzikowski, A.P.; Acosta-Burruel, M.; Tamiz, A.P.; et al.; Synthesis of N-substituted 4-(4-hydroxyphenyl)piperidines, 4-(4-hydroxybenzyl)piperidines, and (±)-3-(4-hydroxyphenyl)pyrrolidines: Selective antagonists at the 1A/2B NMDA receptor subtype. J Med Chem 2000, 43, 5, 984.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 43154 4-phenylbutyl 4-methylbenzenesulfonate C17H20O3S 详情 详情
(IV) 43156 1-(benzyloxy)-4-bromobenzene; benzyl 4-bromophenyl ether 6793-92-6 C13H11BrO 详情 详情
(V) 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
(VI) 43157 1-benzyl-4-[4-(benzyloxy)phenyl]-4-piperidinol C25H27NO2 详情 详情
(VII) 43158 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)phenol C18H19NO 详情 详情
(VIII) 43159 4-(4-piperidinyl)phenol C11H15NO 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

Condensation of N-benzyl-4-piperidinone (I) with phenethylamine (II) produced the corresponding imine (III), which was subsequently reduced to amine (IV) using NaBH4. Schweiler-Clarke methylation of the secondary amine (IV) in the presence of formaldehyde and formic acid gave (V). The N-benzyl protecting group of (V) was then removed by catalytic hydrogenation, yielding piperidine (VI). This was finally coupled with 3,5-dimethyl-4-propionamidobenzoic acid (VII) by means of diethyl cyanophosphate to produce the target compound, which was isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Fujioka, T.; Teramoto, S.; Tanaka, M.; Shimizu, H.; Tabusa, F.; Tominaga, M. (Otsuka Pharmaceutical Co., Ltd.); Peripheral vasodilating agent containing N-acylated 4-amino piperidine derivs. as active ingredients. EP 0650476; JP 1994340627; US 5656642; US 5760058; US 6136826; WO 9422826 .
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) 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
(II) 18333 Phenethylamine; 2-Phenyl-1-ethanamine 64-04-0 C8H11N 详情 详情
(III) 55870 N-(1-benzyl-4-piperidinylidene)-N-phenethylamine; N-(1-benzyl-4-piperidinylidene)-2-phenyl-1-ethanamine C20H24N2 详情 详情
(IV) 55871 N-(1-benzyl-4-piperidinyl)-N-phenethylamine; 1-benzyl-N-phenethyl-4-piperidinamine C20H26N2 详情 详情
(V) 55872 N-(1-benzyl-4-piperidinyl)-N-methyl-N-phenethylamine; 1-benzyl-N-methyl-N-phenethyl-4-piperidinamine C21H28N2 详情 详情
(VI) 55873 N-methyl-N-phenethyl-N-(4-piperidinyl)amine; N-methyl-N-phenethyl-4-piperidinamine C14H22N2 详情 详情
(VII) 55874 3,5-dimethyl-4-(propionylamino)benzoic acid C12H15NO3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(III)

The Grignard reagent (II), prepared form 4-methylbenzyl chloride (I), was condensed to N-benzyl-4-piperidone (III) in cold THF to provide the 4-hydroxy-4-benzylpiperidine (IV). Catalytic hydrogenolysis of the N-benzyl group of (IV) over Pd/C gave piperidine (V), which was then alkylated with 2-(4-benzyloxyphenoxy)ethyl bromide (VI) in refluxing acetonitrile to afford (VII). The O-benzyl group of (VII) was finally cleaved by hydrogenolysis in the presence of Pd(OH)2 to furnish the target compound.

参考文献 中间体
合成目标
【1】 Zhou, Z.-L.; et al.; Synthesis and SAR of 4-benzyl-4-hydroxy-N-(hydroxy. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, 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) 22166 1-(chloromethyl)-4-methylbenzene 104-82-5 C8H9Cl 详情 详情
(II) 22167 chloro(4-methylbenzyl)magnesium C8H9ClMg 详情 详情
(III) 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
(IV) 22169 1-benzyl-4-(4-methylbenzyl)-4-piperidinol C20H25NO 详情 详情
(V) 22170 4-(4-methylbenzyl)-4-piperidinol C13H19NO 详情 详情
(VI) 22171 1-(benzyloxy)-4-(2-bromoethoxy)benzene; benzyl 4-(2-bromoethoxy)phenyl ether C15H15BrO2 详情 详情
(VII) 22172 1-[2-[4-(benzyloxy)phenoxy]ethyl]-4-(4-methylbenzyl)-4-piperidinol C28H33NO3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(I)

The title compound is prepared by two related methods. N-Benzyl-4-piperidone (I) is condensed with KCN and MeNH2.HCl to produce amino nitrile (II). Partial hydrolysis of nitrile (II) with H2SO4 furnishes amide (III). Condensation of the amino amide (III) with triethyl orthoformate gives rise to the spiro imidazolinone (IV). Catalytic hydrogenation of the imidazoline double bond of (IV) and simultaneous N-benzyl group hydrogenolysis gives rise to 1-methyl-1,3,8-triazaspiro[4,5]decan-4-one (V). This is finally alkylated with 4'-fluoro-4-chlorobutyrophenone (VI) to yield the desired compound (1,2).

参考文献 中间体
合成目标
【1】 Metwally, K.A.; Dukat, M.; Egan, C.T.; Smith, C.; Dupre, A.; Gauthier, C.B.; Herrick-Davis, K.; Teitler, M.; Glennon, R.A.; Spiperone: Influence of spiro ring substituents on 5-HT2A serotonin receptor binding. J Med Chem 1998, 41, 25, 5084.
【2】 Janssen, P.A.J. (Janssen Pharmaceutica NV); 2,4,8-Triaza-spiro(4,5)dec-2-enes. US 3155669 .
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) 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
(II) 64576 1-benzyl-4-(methylamino)-4-piperidinecarbonitrile C14H19N3 详情 详情
(III) 22019 1-benzyl-4-(methylamino)-4-piperidinecarboxamide 1024-11-9 C14H21N3O 详情 详情
(IV) 64577 8-benzyl-1-methyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one C15H19N3O 详情 详情
(V) 64578 1-methyl-1,3,8-triazaspiro[4.5]decan-4-one C8H15N3O 详情 详情
(VI) 35864 4-chloro-1-(4-fluorophenyl)-1-butanone 3874-54-2 C10H10ClFO 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

Similarly, the condensation of N-benzyl-4-piperidone (I) with KCN in the presence of NH4Cl provides amino nitrile (II), which is further hydrolyzed to amide (III) with 95% H2SO4. Cyclization of amino amide (III) with formamide under acidic conditions yields the spiro imidazolinone (IV), which is further reduced to imidazolidinone (V) employing NaBH4 in hot MeOH. Debenzylation of (V) with H2 and Pd/C provides 1,3,8-triazaspiro[4,5]decan-4-one (VI). Then, alkylation of (VI) with 4'-fluoro-4-chlorobutyrophenone (VII) by means of K2CO3 and catalytic KI in methyl isobutyl ketone furnishes (VIII). The imidazolidinone ring of (VIII) is finally methylated with iodomethane and KOH to produce the title compound (2).

参考文献 中间体
合成目标
【1】 Metwally, K.A.; Dukat, M.; Egan, C.T.; Smith, C.; Dupre, A.; Gauthier, C.B.; Herrick-Davis, K.; Teitler, M.; Glennon, R.A.; Spiperone: Influence of spiro ring substituents on 5-HT2A serotonin receptor binding. J Med Chem 1998, 41, 25, 5084.
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) 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
(II) 64579 4-amino-1-benzyl-4-piperidinecarbonitrile C13H17N3 详情 详情
(III) 64580 4-amino-1-benzyl-4-piperidinecarboxamide C13H19N3O 详情 详情
(IV) 64581 8-benzyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one C14H17N3O 详情 详情
(V) 64582 8-benzyl-1,3,8-triazaspiro[4.5]decan-4-one C14H19N3O 详情 详情
(VI) 64583 1,3,8-triazaspiro[4.5]decan-4-one C7H13N3O 详情 详情
(VII) 35864 4-chloro-1-(4-fluorophenyl)-1-butanone 3874-54-2 C10H10ClFO 详情 详情
(VIII) 64584 8-[4-(4-fluorophenyl)-4-oxobutyl]-1,3,8-triazaspiro[4.5]decan-4-one C17H22FN3O2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XVI)

The protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.

参考文献 中间体
合成目标
【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283.
【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 .
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) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 29460 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether C9H17BrO2 详情 详情
(III) 26935 2-(3,4-dichlorophenyl)acetonitrile 3218-49-3 C8H5Cl2N 详情 详情
(IV) 29461 2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile C17H21Cl2NO2 详情 详情
(V) 29132 ethyl 3-bromopropanoate 539-74-2 C5H9BrO2 详情 详情
(VI) 29462 ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate C22H29Cl2NO4 详情 详情
(VII) 29463 5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone C20H27Cl2NO3 详情 详情
(VIII) 29464 3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether C20H29Cl2NO2 详情 详情
(IX) 29465 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol C14H19Cl2NO 详情 详情
(X) 29466 3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol C14H19Cl2NO 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 29467 [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone C21H23Cl2NO2 详情 详情
(XIII) 29468 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate C22H25Cl2NO4S 详情 详情
(XIV) 29469 [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone C21H22Cl2INO 详情 详情
(XV) 28021 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine 40807-61-2 C11H15NO 详情 详情
(XVI) 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
(XVII) 24014 Phenyllithium 591-51-5 C6H5Li 详情 详情
(XVIII) 29470 1-benzyl-4-phenyl-4-piperidinol C18H21NO 详情 详情

合成路线14

该中间体在本合成路线中的序号：(I)

The condensation of 1-benzyl-4-piperidone (I) with 4-iodoanisole (II) in ethyl ether gives 1-benzyl-4-(2-methoxyphenyl)piperidin-4-ol (III), which is dehydrated by means of p-toluenesulfonic acid in refluxing toluene yielding the tetrahydropyridine (IV). The hydroboration of (IV) with NaBH4 and BF3 ethearate in dimethoxyethane affords trans-1-benzyl-4-(2-methoxyphenyl)piperidin-3-ol (V), which is treated with BBr3 in dichloromethane to give the 4-hydroxyphenyl derivative (VI). The hydrogenolysis of (VI) with H2 over Pd/C in methanol yields trans-4-(2-hydroxyphenyl)piperidin-3-ol (VII), which is treated with tert-butoxycarbonyl anhydride and triethylamine in DMF to afford the carbamate (VIII). The condensation of 3-chloropropyl-(2-methoxyphenyl)ether (IX) (obtained by the NaH promoted condensation of 2-methoxybenzyl chloride (X) and 3-chloropropanol (XI)) with (VIII) by means of K2CO3 in hot 2-butanone gives the expected phenolic ether (XII), which is condensed with 7-(bromomethyl)quinoline (XIII) by means of NaH in DMF yielding the piperidinyl ether (XIV). The selective hydrogenation of (XIV) with NiCl2 and NaBH4 in methanol affords the tetrahydroquinoline derivative (XV), which is finally treated with HCl in methanol to eliminate the carbamate protecting group.

参考文献 中间体
合成目标
【1】 Breu, V.; Guller, R.; Binggeli, A.; et al.; Piperidine-renin inhibitors compounds with improved physicochemical properties. Bioorg Med Chem Lett 1999, 9, 10, 1403.
【2】 Binggeli, A.; Breu, V.; Bur, D.; Fischli, W.; Gueller, R.; Hirth, G.; Maerki, H.-P.; Mueller, M.; Oefner, C.; Stadler, H.; Vieira, E.; Wilhelm, M.; Wostl, W. (F. Hoffmann-La Roche AG); New 4-(oxyalkoxyphenyl)-3-oxy-piperidines for treating heart and kidney insufficiency. EP 0863875; JP 1999500447; WO 9709311 .
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) 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
(II) 31009 1-iodo-4-methoxybenzene; 4-iodophenyl methyl ether 696-62-8 C7H7IO 详情 详情
(III) 31010 4-(1-benzyl-4-methyl-4-piperidinyl)phenyl methyl ether; 1-benzyl-4-(4-methoxyphenyl)-4-methylpiperidine C20H25NO 详情 详情
(IV) 31011 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)phenyl methyl ether; 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine C19H21NO 详情 详情
(V) 31012 (3R,4R)-1-benzyl-4-(4-methoxyphenyl)-3-piperidinol C19H23NO2 详情 详情
(VI) 31013 (3R,4R)-1-benzyl-4-(4-hydroxyphenyl)-3-piperidinol C18H21NO2 详情 详情
(VII) 31014 (3R,4R)-4-(4-hydroxyphenyl)-3-piperidinol C11H15NO2 详情 详情
(VIII) 31015 tert-butyl (3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)-1-piperidinecarboxylate C16H23NO4 详情 详情
(IX) 31016 1-[(3-chloropropoxy)methyl]-2-methoxybenzene; 2-[(3-chloropropoxy)methyl]phenyl methyl ether C11H15ClO2 详情 详情
(X) 31017 2-(chloromethyl)phenyl methyl ether; 1-(chloromethyl)-2-methoxybenzene 7035-02-1 C8H9ClO 详情 详情
(XI) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(XII) 31018 tert-butyl (3R,4R)-3-hydroxy-4-(4-[3-[(2-methoxybenzyl)oxy]propoxy]phenyl)-1-piperidinecarboxylate C27H37NO6 详情 详情
(XIII) 31019 7-(bromomethyl)quinoline C10H8BrN 详情 详情
(XIV) 31020 tert-butyl (3R,4R)-4-(4-[3-[(2-methoxybenzyl)oxy]propoxy]phenyl)-3-(7-quinolinylmethoxy)-1-piperidinecarboxylate C37H44N2O6 详情 详情
(XV) 31021 tert-butyl (3R,4R)-4-(4-[3-[(2-methoxybenzyl)oxy]propoxy]phenyl)-3-(1,2,3,4-tetrahydro-7-quinolinylmethoxy)-1-piperidinecarboxylate C37H48N2O6 详情 详情

合成路线15

该中间体在本合成路线中的序号：(I)

Horner-Emmons reaction of 1-benzyl-4-piperidone (I) with diethyl cyanomethylphosphonate (II) in the presence of K2CO3 provided the piperidinilydeneacetonitrile (III). Reduction of the double bond of (III) with magnesium in MeOH yielded the saturated nitrile (IV), which was further reduced to amine (V) using LiAlH4. Treatment of 6-phenyl-3-pyridazinone (VI) with POCl3 gave the chloropyridazine (VII). This was coupled with diamine (V) in the presence of ammonium chloride in refluxing butanol to furnish the title pyridazinamine, which was finally converted to the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Rival, Y.M.; Bourguignon, J.-J.; Contreras, J.-M.; Chayer, S.; Wermuth, C.G.; Aminopyridazines as acetylcholinesterase inhibitors. J Med Chem 1999, 42, 4, 730.
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) 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
(II) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(III) 31448 2-(1-benzyl-4-piperidinylidene)acetonitrile C14H16N2 详情 详情
(IV) 31449 2-(1-benzyl-4-piperidinyl)acetonitrile C14H18N2 详情 详情
(V) 17606 2-(1-benzyl-4-piperidinyl)-1-ethanamine; 2-(1-benzyl-4-piperidinyl)ethylamine C14H22N2 详情 详情
(VI) 31450 6-phenyl-3(2H)-pyridazinone C10H8N2O 详情 详情
(VII) 31451 3-chloro-6-phenylpyridazine C10H7ClN2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The condensation of the protected 3,5-difluoroaniline (I) with 1-benzyl-4-piperidone (II) by means of BuLi in THF gives 4-(1-benzyl-4-hydroxypiperidin-4-yl)-3,5-difluoroaniline (III), which is dehydrated with refluxing conc. HCl to yield the tetrahydropyridine (IV). The reaction of (IV) with benzyl chloroformate in acetone/water affords the carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) by means of BuLi in THF to provide the oxazolidinone (VII). The condensation of (VII) with isoxazol-3-ol (VIII) by means of PPh3 and DIAD in THF gives the expected ether adduct (IX), which is debenzylated by reaction with 1-chloroethyl chloroformate in dichloromethane, yielding the free tetrahydropyridine derivative (X). The condensation of (X) with (S)-2,3-O-isopropylideneglyceric acid (XI) by means of DEC or DCC and TEA in dichloromethane affords the corresponding acyl tetrahydropyridine (XII), which is finally deprotected with HCl in THF to provide the target dihydroxy compound.

参考文献 中间体
合成目标
【1】 Gravestock, M.B. (AstraZeneca plc); Oxazolidinone derivs., process for their preparation and pharmaceutical compsns. containing them. EP 1082323; JP 2002517498; WO 9964417 .
【2】 Gravestock, M.B.; Warren, K.E.H.; Ennis, D.S.; Currie, A.C.; Ainge, D. (AstraZeneca AB; AstraZeneca plc); Chemical processes and intermedies. WO 0140236 .
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) 59481 1-(3,5-difluorophenyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine C12H19F2NSi2 详情 详情
(II) 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
(III) 59482 4-(4-amino-2,6-difluorophenyl)-1-benzyl-4-piperidinol C18H20F2N2O 详情 详情
(IV) 59483 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenylamine; 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluoroaniline C18H18F2N2 详情 详情
(V) 59484 benzyl 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenylcarbamate C26H24F2N2O2 详情 详情
(VI) 17017 (2S)oxiranylmethyl butyrate C7H12O3 详情 详情
(VII) 59485 (5R)-3-[4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C22H22F2N2O3 详情 详情
(VIII) 59486 3-isoxazolol C3H3NO2 详情 详情
(IX) 59487 (5R)-3-[4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl]-5-[(3-isoxazolyloxy)methyl]-1,3-oxazolidin-2-one C25H23F2N3O4 详情 详情
(X) 59488 (5R)-3-[3,5-difluoro-4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-5-[(3-isoxazolyloxy)methyl]-1,3-oxazolidin-2-one C18H17F2N3O4 详情 详情
(XI) 59489 (4S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid C6H10O4 详情 详情
(XII) 59490 (5R)-3-[4-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl]-5-[(3-isoxazolyloxy)methyl]-1,3-oxazolidin-2-one C24H25F2N3O7 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XII)

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.

参考文献 中间体
合成目标
【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

合成路线18

该中间体在本合成路线中的序号：(I)

Horner-Emmons reaction of 1-benzyl-4-piperidone (I) with triethyl 4-phosphonocrotonate (II) afforded the (piperidinylidene)butenoate (III). Catalytic hydrogenation of the double bond of (III) with concomitant N-debenzylation yielded the piperidinylbutanoate (IV). After reprotection as the N-benzyl derivative (V), reduction of the ester function of (V) using LiAlH4 gave alcohol (VI), which was further converted to mesylate (VII). Displacement of the mesylate group of (VII) with diethylamine produced diamine (VIII). The N-benzyl group of (VIII) was then deprotected by transfer hydrogenation to furnish piperidine (IX). The chloroacetyl derivative (XI) was prepared by acylation of iminodibenzyl (X) with chloroacetyl chloride. Chloride (XI) was finally condensed with piperidine (IX) in the presence of Na2CO3 and NaI to afford the title compound.

参考文献 中间体
合成目标
【1】 Maiorana, S.; Colibretti, M.L.; Terni, P.; Imbimbo, B.P.; Mandelli, G.R.; Lamperti, G.; Synthesis of new cardioselective M2 muscarinic receptor antagonists. Chem Pharm Bull 2000, 48, 11, 1611.
【2】 Imbimbo, B.P.; Mandelli, G.R.; Terni, P.M.L.; Maiorana, S. (Mediolanum Farmaceutici); Selective M2 muscarinic receptor antagonists having 5H-dibenz[b,f]azepine structure. WO 0102386 .
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) 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
(II) 22705 ethyl (E)-4-(diethoxyphosphoryl)-2-butenoate C10H19O5P 详情 详情
(III) 48038 ethyl (E)-4-(1-benzyl-4-piperidinylidene)-2-butenoate C18H23NO2 详情 详情
(IV) 48039 ethyl 4-(4-piperidinyl)butanoate C11H21NO2 详情 详情
(V) 48040 ethyl 4-(1-benzyl-4-piperidinyl)butanoate C18H27NO2 详情 详情
(VI) 48041 4-(1-benzyl-4-piperidinyl)-1-butanol C16H25NO 详情 详情
(VII) 48042 4-(1-benzyl-4-piperidinyl)butyl methanesulfonate C17H27NO3S 详情 详情
(VIII) 48043 4-(1-benzyl-4-piperidinyl)-N,N-diethyl-1-butanamine; N-[4-(1-benzyl-4-piperidinyl)butyl]-N,N-diethylamine C20H34N2 详情 详情
(IX) 31153 N,N-diethyl-N-[4-(4-piperidinyl)butyl]amine; N,N-diethyl-4-(4-piperidinyl)-1-butanamine C13H28N2 详情 详情
(X) 47619 Iminostilbene; 5H-dibenzo[b,f]azepine 256-96-2 C14H11N 详情 详情
(XI) 48044 2-chloro-1-(5H-dibenzo[b,f]azepin-5-yl)-1-ethanone C16H12ClNO 详情 详情

合成路线19

该中间体在本合成路线中的序号：(VIII)

The aliphatic amino group of 4-aminophenethylamine (VI) was regioselectively protected as the N-Boc derivative (VII) using Boc2O. Subsequent reductive alkylation of aniline (VII) with N-benzyl-4-piperidone (VIII) afforded the anilinopiperidine (IX). The N-benzyl group of (IX) was then removed by transfer hydrogenolysis, and the resulting piperidine (X) was condensed with octyl isocyanate (XI), yielding the corresponding urea (XII). After acidic cleavage of the N-Boc protecting group of (XII), the primary amine (XIII) was condensed with the intermediate epoxide (V) to produce the amino alcohol (XIV). Final desilylation of (XIV) gave rise to the title compound.

参考文献 中间体
合成目标
【1】 Solvibile, W.R.; et al.; Potent, selective agonists of the human beta3-adrenergic receptor. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 35.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 52064 tert-butyl[4-[(2S)oxiranylmethoxy]phenoxy]diphenylsilane; tert-butyl(diphenyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether C25H28O3Si 详情 详情
(VI) 18961 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine 13472-00-9 C8H12N2 详情 详情
(VII) 18966 tert-butyl 4-aminophenethylcarbamate C13H20N2O2 详情 详情
(VIII) 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
(IX) 52065 tert-butyl 4-[(1-benzyl-4-piperidinyl)amino]phenethylcarbamate C25H35N3O2 详情 详情
(X) 52066 tert-butyl 4-(4-piperidinylamino)phenethylcarbamate C18H29N3O2 详情 详情
(XI) 52067 1-isocyanatooctane; octyl isocyanate C9H17NO 详情 详情
(XII) 52068 tert-butyl 4-([1-[(octylamino)carbonyl]-4-piperidinyl]amino)phenethylcarbamate C27H46N4O3 详情 详情
(XIII) 52069 4-[4-(2-aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide C22H38N4O 详情 详情
(XIV) 52070 4-[4-(2-[[(2S)-3-(4-[[tert-butyl(diphenyl)silyl]oxy]phenoxy)-2-hydroxypropyl]amino]ethyl)anilino]-N-octyl-1-piperidinecarboxamide C47H66N4O4Si 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XI)

4-Aminophenethylamine (IX) was selectively protected at the aliphatic amino group by means of Boc2O to afford (X). Reductive alkylation of aniline (X) with N-benzyl-4-piperidone (XI) in the presence of NaBH(OAc)3 furnished the secondary amine (XII). Subsequent N-benzyl group cleavage in (XI) by transfer hydrogenolysis gave rise to diamine (XIII), which was further converted to urea (XV) by coupling with isocyanate (XIV). The N-Boc group of (XV) was then cleaved by means of formic acid, yielding amine (XVI). The title compound was then obtained by condensation of amine (XVI) with epoxide (VIII), followed by removal of the N-Boc and silyl protecting groups.

参考文献 中间体
合成目标
【1】 Mulvey, R.; Ashwell, M.A.; Solvibile, W.R. Jr.; Han, S.; Tillet, J.; Largis, E.; 4-Aminopiperidine ureas as potent selective agonists of the human beta3-adrenergic receptor. Bioorg Med Chem Lett 2001, 11, 24, 3123.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 59665 tert-butyl 2-{[tert-butyl(diphenyl)silyl]oxy}-5-[(2S)oxiranylmethoxy]phenyl(methylsulfonyl)carbamate C31H39NO7SSi 详情 详情
(IX) 18961 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine 13472-00-9 C8H12N2 详情 详情
(X) 18966 tert-butyl 4-aminophenethylcarbamate C13H20N2O2 详情 详情
(XI) 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
(XII) 52065 tert-butyl 4-[(1-benzyl-4-piperidinyl)amino]phenethylcarbamate C25H35N3O2 详情 详情
(XIII) 52066 tert-butyl 4-(4-piperidinylamino)phenethylcarbamate C18H29N3O2 详情 详情
(XIV) 59666 1,4-difluoro-2-(isocyanatomethyl)benzene; 2,5-difluorobenzyl isocyanate C8H5F2NO 详情 详情
(XV) 59667 tert-butyl 4-[(1-{[(2,5-difluorobenzyl)amino]carbonyl}-4-piperidinyl)amino]phenethylcarbamate C26H34F2N4O3 详情 详情
(XVI) 59668 4-[4-(2-aminoethyl)anilino]-N-(2,5-difluorobenzyl)-1-piperidinecarboxamide C21H26F2N4O 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

The cyclization of (3R)-N-Boc-3-cyclohexyl-D-serine (I) with 1-benzylpiperidin-4-one (II), benzyl isonitrile (III) and butylamine (IV) in refluxing methanol gives the piperidine derivative (V), whose Boc group is removed by treatment with TFA in dichloromethane, yielding compound (VI). The cyclization of (VI) by means of AcOH in hot toluene affords the spiro[piperazine-2,4'-piperidine] derivative (VII), which is hydrogenated in methanol over palladium hydroxide on carbon to cleave the benzyl protecting group and provide the unprotected spiro derivative (VIII). Finally, this compound is reductocondensed with 4-(4-formylphenoxy)benzoic acid (IX) by means of sodium triacetoxyborohydride in DMF/AcOH to give the target spiro[piperazine-2,4'-piperidine] derivative.

参考文献 中间体
合成目标
【1】 Shibayama, S.; Hamano, S.; Takaoka, Y.; Habashita, H. (Ono Pharmaceutical Co., Ltd.); Triazaspiro[5.5]undecane derivs. and drugs containing the same as the active ingredient. EP 1378510; WO 0274770 .
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) 64663 (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexyl-3-hydroxypropanoic acid C14H25NO5 详情 详情
(II) 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
(III) 16730 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate 3173-56-6 C8H7NO 详情 详情
(IV) 39041 butylamine; 1-butanamine 109-73-9 C4H11N 详情 详情
(V) 64664 tert-butyl (1R)-2-[{1-benzyl-4-[(benzylamino)carbonyl]-4-piperidinyl}(butyl)amino]-1-[(R)-cyclohexyl(hydroxy)methyl]-2-oxoethylcarbamate C38H56N4O5 详情 详情
(VI) 64665 4-[[(2R,3R)-2-amino-3-cyclohexyl-3-hydroxypropanoyl](butyl)amino]-N,1-dibenzyl-4-piperidinecarboxamide C33H48N4O3 详情 详情
(VII) 64666 (3R)-9-benzyl-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione C26H39N3O3 详情 详情
(VIII) 64667 (3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione C19H33N3O3 详情 详情
(IX) 64668 4-(4-formylphenoxy)benzoic acid C14H10O4 详情 详情
Extended Information