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【结 构 式】 
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【分子编号】22460 【品名】4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine 【CA登记号】 |
【 分 子 式 】C13H13NO 【 分 子 量 】199.25236 【元素组成】C 78.36% H 6.58% N 7.03% O 8.03% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of p-benzyloxyaniline (I) with 1-chloro-2-hydroxy-3-methoxypropane (II) in ethanol, followed by cyclization ot the resulting amino alcohol (III) with ethyl carbonate (A) in toluene in the presence of CH3ONa and debenzylation affords a phenolic 2-oxazolidinone (V), which is alkylated with m-cyanobenzyl bromide (VI) to give cimoxatone.
| 【1】 Ancher, J.F.; Bourgery, G.; Dostert, P.; Douzon, C.; Guerret, P.; Lacour, A.; Laglois, M.; Nouvelles oxazolidinones, oxazolidinethiones et pyrrilidinones, leur procédé de préparation et leur application en thérapeutique. FR 2428032; JP 55051064; JP 56167666 . |
| 【2】 Ancher, J.F.; Cimoxatone. Drugs Fut 1984, 9, 6, 412. |
| 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) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (I) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (III) | 34215 | 1-[4-(benzyloxy)anilino]-3-methoxy-2-propanol | C17H21NO3 | 详情 | 详情 | |
| (IV) | 28690 | (5R)-3-[4-(benzyloxy)phenyl]-5-(methoxymethyl)-1,3-oxazolidin-2-one | C18H19NO4 | 详情 | 详情 | |
| (V) | 28682 | (5R)-3-(4-hydroxyphenyl)-5-(methoxymethyl)-1,3-oxazolidin-2-one | C11H13NO4 | 详情 | 详情 | |
| (VI) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)2) Synthesis of Oxazolidinone (II): 2a) The reaction of 4-benzyloxyaniline (IX) with 1,4-dioxaspiro[4.5]decan-2(S)-ylmethyl methanesulfonate (X) by means of TEA at 140 C gives 3-(4-benzyloxyphenylamino)propane-1,2(R)-diol (XI), which is cyclized with diethyl carbonate and sodium methoxide in refluxing toluene, yielding 3-(4-benzyloxyphenyl)-5(R)-(hydroxymethyl)oxazolidin-2-one (XII). The methylation of (XII) with dimethyl sulfate, NaOH and tetrabutylammonium bisulfate in hot toluene/water affords the corresponding methoxymethyl derivative (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol/dichloromethane to give oxazolidinone (II). 2b) The methylation of 4(S)-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (XIV) with dimethyl sulfate and NaOH gives 4(S)-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane (XV), which is hydrolyzed with hot aqueous HCl to 3-methoxypropane-1,2(R)-diol (XVI). The cyclization of (XVI) with diethyl carbonate by means of NaH affords 4(S)-(methoxymethyl)-1,3-dioxolan-2-one (XVII) (2, 5). The condensation of (XVII) with N-(4-benzyloxyphenyl)carbamic acid methyl ester (XVIII) (obtained by reaction of 4-benzyloxyaniline (IX) with methyl chloroformate) by means of K2CO3 at 160 C provides the protected oxazolidinone (XIII), which is finally debenzylated as before to give oxazolidinone (II).
| 【1】 Castaner, J.; Sorbera, L.A.; Rabasseda, X.; Befloxatone. Drugs Fut 1999, 24, 10, 1057. |
| 【2】 Koenig, J.-J.; Schoofs, A.; Jarreau, F.-X.; Rovei, V. (Laboratoires Delalande); 3-Aryl oxazolidinones, process for their preparation and their therapeutical use. EP 0424243; EP 0424244; EP 0428421; JP 1992502333; JP 1992502334; JP 1992502335; US 5036090; US 5036091; US 5171747; US 5196543; WO 9105775 . |
| 【3】 Jarreau, F.-X.; Koenig, J.-J.; Rovei, V. (Laboratoires Delalande); 3-Aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. EP 0511031; FR 2675504; JP 1993112542; US 5264443 . |
| 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) | 28682 | (5R)-3-(4-hydroxyphenyl)-5-(methoxymethyl)-1,3-oxazolidin-2-one | C11H13NO4 | 详情 | 详情 | |
| (IX) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (X) | 28688 | (2R)-1,4-dioxaspiro[4.5]dec-2-ylmethyl methanesulfonate | C10H18O5S | 详情 | 详情 | |
| (XI) | 28689 | (2R)-3-[4-(benzyloxy)anilino]-1,2-propanediol | C16H19NO3 | 详情 | 详情 | |
| (XII) | 28695 | (5R)-3-[4-(benzyloxy)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C17H17NO4 | 详情 | 详情 | |
| (XIII) | 28690 | (5R)-3-[4-(benzyloxy)phenyl]-5-(methoxymethyl)-1,3-oxazolidin-2-one | C18H19NO4 | 详情 | 详情 | |
| (XIV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (XV) | 28691 | (4S)-4-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane | C7H14O3 | 详情 | 详情 | |
| (XVI) | 28692 | (2R)-3-methoxy-1,2-propanediol | C4H10O3 | 详情 | 详情 | |
| (XVII) | 28693 | (4S)-4-(methoxymethyl)-1,3-dioxolan-2-one | C5H8O4 | 详情 | 详情 | |
| (XVIII) | 28694 | methyl 4-(benzyloxy)phenylcarbamate | C15H15NO3 | 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 acylation of 4-benzyloxyaniline (I) with trifluoroacetyl chloride and triethylamine in dichloromethane gives the corresponding amide (II), which is treated with resin-supported triphenylphosphine and CCl4 to yield the iminochloride (III). The cyclization of (III) with sodium azide in hot acetic acid affords the tetrazole (IV), which is debenzylated with H2 over Pd/C in ethanol/THF, giving the phenol (V). The reaction of (V) with hexamethylenetetramine (HMT) in hot trifluoroacetic acid yields the benzaldehyde (VI), which by methylation with methyl iodide/K2CO3 in acetone affords 2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]benzaldehyde (VII). Finally, this compound is reductocondensed with (2S,3S)-2-phenylpiperidin-3-amine (VIII) by means of sodium triacetoxyborohydride/acetic acid in dichloromethane. The chiral (2S,3S)-2-phenylpiperidin-3-amine (VIII) has been obtained as follows: The condensation of 2-chloro-3-nitropyridine (IX) with phenylboronic acid (X) by means of palladium tetrakis(triphenylphosphine) and Na2CO3 in dimethoxyethane gives 3-nitro-2-phenylpyridine (XI), which is hydrogenated with H2 over Pd/C in ethanol/HCl, yielding (?-cis-2-phenylpiperidin-3-amine (XII). Finally, this compound is submitted to optical resolution by means of di-p-toluoyl-L-tartaric acid in ethanol/water.
| 【1】 Congreve, M.; Chung, K.M.L.; Armour, D.R.; et al.; Tetrazole NK1 receptor antagonists: The identifica. Bioorg Med Chem Lett 1996, 6, 9, 1015. |
| 【2】 Silvestre, J.S.; Castañer, J.; Sorbera, L.A.; GR-205171. Drugs Fut 1999, 24, 3, 254. |
| 【3】 Armour, D.R.; Evans, B.; Giblin, G.M.P.; Hann, M.M.; Hubbard, T.; Lewell, X.; Middlemiss, D.; Naylor, A.; Pegg, N.A.; Vinader, M.V.; Watson, S.P. (Glaxo Wellcome plc); 3-(5-Tetrazolyl-benzyl)amino-piperidine derivs. an. EP 0720609; JP 1999106341; US 5703240; US 5843966; WO 9508549 . |
| 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) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 22461 | N-[4-(benzyloxy)phenyl]-2,2,2-trifluoroacetamide | C15H12F3NO2 | 详情 | 详情 | |
| (III) | 22462 | N-[4-(benzyloxy)phenyl]-2,2,2-trifluoroethanimidoyl chloride | C15H11ClF3NO | 详情 | 详情 | |
| (IV) | 22463 | 1-[4-(benzyloxy)phenyl]-5-(trifluoromethyl)-1H-1,2,3,4-tetraazole; benzyl 4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl ether | C15H11F3N4O | 详情 | 详情 | |
| (V) | 22464 | 4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenol | C8H5F3N4O | 详情 | 详情 | |
| (VI) | 22465 | 2-hydroxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde | C9H5F3N4O2 | 详情 | 详情 | |
| (VII) | 22466 | 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde | C10H7F3N4O2 | 详情 | 详情 | |
| (VIII) | 22467 | (2S,3S)-2-phenylpiperidinylamine; (2S,3S)-2-phenyl-3-piperidinamine | C11H16N2 | 详情 | 详情 | |
| (IX) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (IX) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (XI) | 22470 | 3-nitro-2-phenylpyridine | C11H8N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Alkylation of 4-hydroxybenzaldehyde (I) with chloro derivative (II) by means of K2CO3 in DMF at reflux affords benzaldehyde derivative (III), which is reduced with NaBH4 in MeOH to provide the benzylic alcohol (IV) --alternatively, alcohol (IV) can be obtained by reaction of 4-hydroxybenzyl alcohol (V) with chloro derivative (II) by means of NaOH and benzyltriethylammonium bromide in toluene--. Alcohol (V) is treated with HCl in THF and then chlorinated with SOCl2 to furnish hydrochloride salt (VI), which is condensed with the indole derivative (VII) – produced by condensation of the bromo ketone (VIII) and 4-benzyloxyaniline hydrochloride (IX) either refluxing by with DMF or with Et3N in refluxing DMF – by means of NaH in DMF to give the N-alkylated indole (X). Finally, the O-benzyl protecting groups of (X) are removed by transfer hydrogenolysis using cyclohexadiene and Pd/C.
| 【1】 Miller, C.P.; Collini, M.D.; Tran, B.D.; et al.; Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J Med Chem 2001, 44, 11, 1654. |
| 【2】 Vid, G.; Potoski, J.R.; Raveendranath, P.; Zeldis, J.; Ren, J. (American Home Products Corp.); Novel aryloxy-alkyl-dialkylamines. EP 1025077; WO 9919293 . |
| 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) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 22918 | 1-(2-chloroethyl)azepane | C8H16ClN | 详情 | 详情 | |
| (III) | 60165 | 4-[2-(1-azepanyl)ethoxy]benzaldehyde | C15H21NO2 | 详情 | 详情 | |
| (IV) | 60166 | {4-[2-(1-azepanyl)ethoxy]phenyl}methanol | C15H23NO2 | 详情 | 详情 | |
| (V) | 29474 | 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol | 623-05-2 | C7H8O2 | 详情 | 详情 |
| (VI) | 60167 | 1-{2-[4-(chloromethyl)phenoxy]ethyl}azepane; 2-(1-azepanyl)ethyl 4-(chloromethyl)phenyl ether | C15H22ClNO | 详情 | 详情 | |
| (VII) | 38490 | 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; benzyl 4-[5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl ether | C29H25NO2 | 详情 | 详情 | |
| (VIII) | 38489 | 4-Benzyloxy-alpha-bromopropiophenone; 1-[4-(benzyloxy)phenyl]-2-bromo-1-propanone; alpha-Bromo-4-benzyloxy propiophenone | 54081-45-9 | C16H15BrO2 | 详情 | 详情 |
| (IX) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (X) | 38495 | 1-[4-[2-(1-azepanyl)ethoxy]benzyl]-5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; 4-[1-[4-[2-(1-azepanyl)ethoxy]benzyl]-5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl benzyl ether | C44H46N2O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Condensation between p-benzyloxyaniline (VI) and bromo ketone (VII) in refluxing DMF produced the indole derivative (VIII). Alkylation of (VIII) with chloride (V) in the presence of NaH gave the N-alkylated indole (IX). The O-benzyl protecting groups of (IX) were then removed by transfer hydrogenolysis using cyclohexadiene and Pd/C.
| 【1】 Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Pipendoxifene. Drugs Fut 2002, 27, 10, 942. |
| 【2】 Vid, G.; Potoski, J.R.; Raveendranath, P.; Zeldis, J.; Ren, J. (American Home Products Corp.); Novel aryloxy-alkyl-dialkylamines. EP 1025077; WO 9919293 . |
| 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) | 46522 | 1-[2-[4-(chloromethyl)phenoxy]ethyl]piperidine; 4-(chloromethyl)phenyl 2-(1-piperidinyl)ethyl ether | C14H20ClNO | 详情 | 详情 | |
| (VI) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (VII) | 38489 | 4-Benzyloxy-alpha-bromopropiophenone; 1-[4-(benzyloxy)phenyl]-2-bromo-1-propanone; alpha-Bromo-4-benzyloxy propiophenone | 54081-45-9 | C16H15BrO2 | 详情 | 详情 |
| (VIII) | 38490 | 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; benzyl 4-[5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl ether | C29H25NO2 | 详情 | 详情 | |
| (IX) | 46523 | 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indole; benzyl 4-(5-(benzyloxy)-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indol-2-yl)phenyl ether | C43H44N2O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The intermediate 2-[4-(chloromethyl)phenoxy]acetic acid ethyl ester (IV) has been obtained as follows: The reaction of 4-hydroxybenzyl alcohol (I) with ethyl 2-bromoacetate (II) by means of K2CO3 gives the phenoxyacetate (III), which is then treated with SOCl2 in THF to obtain the desired intermediate (IV). The cyclization of 4-(benzyloxy)aniline (V) with 2-bromo-1-[4-(benzyloxy)phenyl]-1-propanone (VI) by means of TEA in DMF gives 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole (VII), which is alkylated with the intermediate (IV) by means of NaH in DMF to yield the adduct (VIII). The reduction of the ester group of (VIII) with LiAlH4 in THF affords the 2-hydroxyethoxy compound (IX), which is treated with CBr4 and PPh3 in THF to provide the 2-bromoethoxy compound (X). The reaction of (X) with piperidine in THF gives the piperidinoethoxy compound (XI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol/THF to afford the target indole derivative.
| 【1】 Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Pipendoxifene. Drugs Fut 2002, 27, 10, 942. |
| 【2】 Miller, C.P.; Collini, M.D.; Tran, B.D.; et al.; Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J Med Chem 2001, 44, 11, 1654. |
| 【3】 Miller, C.P.; Tran, B.D.; Collini, M.D. (American Home Products Corp.); Estrogenic agents. EP 0802183; JP 1998036346; US 5998402 . |
| 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) | 29474 | 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol | 623-05-2 | C7H8O2 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 51988 | ethyl 2-[4-(hydroxymethyl)phenoxy]acetate | C11H14O4 | 详情 | 详情 | |
| (IV) | 38491 | ethyl 2-[4-(chloromethyl)phenoxy]acetate | C11H13ClO3 | 详情 | 详情 | |
| (V) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (VI) | 38489 | 4-Benzyloxy-alpha-bromopropiophenone; 1-[4-(benzyloxy)phenyl]-2-bromo-1-propanone; alpha-Bromo-4-benzyloxy propiophenone | 54081-45-9 | C16H15BrO2 | 详情 | 详情 |
| (VII) | 38490 | 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; benzyl 4-[5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl ether | C29H25NO2 | 详情 | 详情 | |
| (VIII) | 38492 | ethyl 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]acetate | C40H37NO5 | 详情 | 详情 | |
| (IX) | 38493 | 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]-1-ethanol | C38H35NO4 | 详情 | 详情 | |
| (X) | 38494 | benzyl 4-[5-(benzyloxy)-1-[4-(2-bromoethoxy)benzyl]-3-methyl-1H-indol-2-yl]phenyl ether; 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-1-[4-(2-bromoethoxy)benzyl]-3-methyl-1H-indole | C38H34BrNO3 | 详情 | 详情 | |
| (XI) | 46523 | 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indole; benzyl 4-(5-(benzyloxy)-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indol-2-yl)phenyl ether | C43H44N2O3 | 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 reductocondensation of 4-benzyloxyaniline (I) with 1-(tert-butoxycarbonyl)piperidin-4-one (II) by means of NaBH(OAc)2 in dichloromethane gives N-(4-benzyloxyphenyl)-N-[1-(tert-butoxycarbonyl)piperidin-4-yl]amine (III), which is alkylated with 3-methyl-2-butenyl bromide (IV) by means of DIEA in THF yielding the tertiary amine (V). The deprotection of (V) with TFA in dichloromethane affords the piperidine (VI), which is condensed with N-(tert-butoxycarbonyl)-L-leucine (VII) by means of HBTU and DIEA in DMF to provide the intermediate (VIII). Finally, (VIII) is deprotected with TFA in dichloromethane.
| 【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic properties. J Med Chem 1999, 42, 20, 4239. |
| 【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 . |
| 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) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 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) | 38230 | tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate | C23H30N2O3 | 详情 | 详情 | |
| (IV) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (V) | 38231 | tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate | C28H38N2O3 | 详情 | 详情 | |
| (VI) | 38232 | N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine | C23H30N2O | 详情 | 详情 | |
| (VII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VIII) | 38233 | tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]carbonyl)-3-methylbutylcarbamate | C34H49N3O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)The reaction of N-(tert-butoxycarbonyl)-L-leucine (I) with N,O-dimethylhydroxylamine and HBTU in DMF gives the corresponding methoxyamide (II), which is reduced with LiAlH4 in ethyl ether yielding the aldehyde (III). The reductocondensation of (III) with the piperidine (IV) by means of sodium triacetoxyborohydride in dichloromethane affords the protected adduct (V), which is finally deprotected with TFA in dichloromethane. The intermediate piperidine (IV) has been obtained as follows: The reductocondensation of the piperidinone (VI) with 4-(benzyloxy)aniline (VII) by means of sodium triacetoxyborohydride in dichloromethane gives the secondary amine (VIII), which is alkylated with 3-methyl-2-butenyl bromide (IX) and DIPEA in THF yielding the protected piperidine (IX). Finally, this compound is deprotected with TFA in dichloromethane to afford the target intermediate (IV).
| 【1】 Siebers, K.M.; Hu, L.-Y.; Rafferty, M.F.; et al.; Neuronal N-type calcium channel blocker: Structure-activity relationship of a series of (S)-2-amino-1(4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl)-4-methyl-pentan-1-one analogs. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 259. |
| 【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 . |
| 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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 38232 | N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine | C23H30N2O | 详情 | 详情 | |
| (V) | 40394 | tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]methyl)-3-methylbutylcarbamate | C34H51N3O3 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (VIII) | 38230 | tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate | C23H30N2O3 | 详情 | 详情 | |
| (IX) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (X) | 38231 | tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate | C28H38N2O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Reductive condensation of N-Boc-4-piperidone (I) with 4-(benzyloxy)aniline (II) in the presence of NaBH(OAc)3 produced the secondary amine (III), which was further alkylated with 4-bromo-2-methyl-2-butene (IV) to afford the tertiary amine (V). Subsequent acid cleavage of the Boc protecting group of (V) furnished the intermediate piperidine (VI).
| 【1】 Ryder, T.R.; Rafferty, M.F.; Hu, L.-Y. (Pfizer Inc.); Heterocyclic substd. aniline calcium channel blockers. US 6251919; WO 9943658 . |
| 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) | 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 |
| (II) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (III) | 38230 | tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate | C23H30N2O3 | 详情 | 详情 | |
| (IV) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (V) | 38231 | tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate | C28H38N2O3 | 详情 | 详情 | |
| (VI) | 38232 | N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine | C23H30N2O | 详情 | 详情 |