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【结 构 式】

【药物名称】CP-99994

【化学名称】(+)-(2S,3S)-3-(2-Methoxybenzylamino)-2-phenylpiperidine

【CA登记号】136982-36-0, 136983-42-1 (HCl), 139190-12-8 (mono (R)-alpha-hydroxybenzeneacetate salt), 139241-77-3 (racemic-cis-isomer), 13924

【 分 子 式 】C19H24N2O

【 分 子 量 】296.41593

【开发单位】Pfizer (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, Non-Opioid Analgesics, Tachykinin NK1 Antagonists

合成路线1

Swern oxidation of N,N-dibenzyl-O-(tert-butyldimethylsilyl)serinol (I) afforded the intermediate aldehyde (II), which was condensed with phenylmagnesium bromide to give carbinol (III) as the major diastereoisomer. Displacement of the hydroxyl group of (III) with diphenylphosphoryl azide in the presence of diethyl azodicarboxylate and triphenylphosphine provided azide (IV). This was reduced to the corresponding amine with concomitant desilylation using LiAlH4. Further in situ addition of (Boc)2O produced carbamate (V). The alcohol function of (V) was then oxidized under Swern conditions, and the resulting aldehyde (VI) was condensed with phosphonate (VII) to yield unsaturated ester (VIII). Reduction of (VIII) to the saturated ester (IX) with Mg in MeOH, and further reduction of the ester group employing lithium borohydride gave rise to alcohol (X). After conversion of (X) to mesylate (XI), cyclization in the presence of NaH in THF furnished piperidine (XII). Debenzylation of (XII) afforded primary amine (XIII), which was reductively alkylated with 2-methoxybenzaldehyde (XIV) in the presence of NaCNBH3 to provide (XV). Finally, acid deprotection of the Boc group of (XV) yielded the title compound.

1 Chandrasekhar, S.; Mohanty, P.K.; Stereoselective synthesis of (+)-CP-99,994: A substance P non-peptide antagonist. Tetrahedron Lett 1999, 40, 27, 5071.
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) 31745 (2R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(dibenzylamino)-1-propanol C23H35NO2Si 详情 详情
(II) 31746 (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(dibenzylamino)propanal C23H33NO2Si 详情 详情
(III) 31747 (1R,2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(dibenzylamino)-1-phenyl-1-propanol C29H39NO2Si 详情 详情
(IV) 31748 N-[(1R,2S)-2-azido-1-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-phenylethyl]-N,N-dibenzylamine; (1S,2R)-1-azido-N,N-dibenzyl-3-[[tert-butyl(dimethyl)silyl]oxy]-1-phenyl-2-propanamine C29H38N4OSi 详情 详情
(V) 31749 tert-butyl (1S,2R)-2-(dibenzylamino)-3-hydroxy-1-phenylpropylcarbamate C28H34N2O3 详情 详情
(VI) 31750 tert-butyl (1S,2R)-2-(dibenzylamino)-3-oxo-1-phenylpropylcarbamate C28H32N2O3 详情 详情
(VII) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(VIII) 31751 ethyl (E,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-(dibenzylamino)-5-phenyl-2-pentenoate C32H38N2O4 详情 详情
(IX) 31752 ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-(dibenzylamino)-5-phenylpentanoate C32H40N2O4 详情 详情
(X) 31753 tert-butyl (1S,2S)-2-(dibenzylamino)-5-hydroxy-1-phenylpentylcarbamate C30H38N2O3 详情 详情
(XI) 31754 (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-(dibenzylamino)-5-phenylpentyl methanesulfonate C31H40N2O5S 详情 详情
(XII) 31755 tert-butyl (2S,3S)-3-(dibenzylamino)-2-phenyl-1-piperidinecarboxylate C30H36N2O2 详情 详情
(XIII) 31756 tert-butyl (2S,3S)-3-amino-2-phenyl-1-piperidinecarboxylate C16H24N2O2 详情 详情
(XIV) 12568 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde 135-02-4 C8H8O2 详情 详情
(XV) 31757 tert-butyl (2S,3S)-3-[(2-methoxybenzyl)amino]-2-phenyl-1-piperidinecarboxylate C24H32N2O3 详情 详情

合成路线2

The reaction of 1(R)-phenylethane-1,2-diol (I) with N-hydroxyphthalimide (II) by means of DEAD and PPh3 gives the N-alcoxyphthalimide (III) with(S)-configuration. The hydrazinolysis of (III) with hydrazine hydrate affords the O-alkylhydroxylamine (IV), which is condensed with benzaldehyde (V) to provide the alkylated benzaldoxime (VI). The alkylation of the oxime (VI) with vinyl lithium (VII) in toluene gives the N, O dialkylated hydroxylamine (VIII), which is treated with Zn and AcOH to yield 1(R)-phenylallylamine (IX). The protection of the amine (IX) with Boc2O and NaOH affords the carbamate (X), which is oxidized at the vinyl double bond by means of OsO4 and NaIO4 to provide the acetaldehyde (XI). The reaction of aldehyde (XI) with allylmagnesium bromide (XII) in ethyl ether gives the aminoalcohol (XIII), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (XIV).

1 Yamazaki, N.; et al.; Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue. Tetrahedron Lett 2001, 42, 30, 5029.
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) 56141 (R)-(-)-1-Phenyl-1,2-ethanediol; (R)-(-)-alpha,beta-Dihydroxyethylbenzene; (R)-(-)-Phenyl-1,2-ethanediol; (R)-(-)-Styrene glycol; (-)-Styrene glycol 16355-00-3 C8H10O2 详情 详情
(II) 13505 N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione 524-38-9 C8H5NO3 详情 详情
(III) 56142 2-{[(1S)-2-hydroxy-1-phenylethyl]oxy}-1H-isoindole-1,3(2H)-dione C16H13NO4 详情 详情
(IV) 56143 (2S)-2-(aminooxy)-2-phenyl-1-ethanol C8H11NO2 详情 详情
(V) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VI) 62256 benzaldehyde O-[(1S)-2-hydroxy-1-phenylethyl]oxime C15H15NO2 详情 详情
(VII) 42368 vinyllithium 917-57-7 C2H3Li 详情 详情
(VIII) 62257 (2S)-2-phenyl-2-({[(1R)-1-phenyl-2-propenyl]amino}oxy)-1-ethanol C17H19NO2 详情 详情
(IX) 62258 (1R)-1-phenyl-2-propenylamine; (1R)-1-phenyl-2-propen-1-amine C9H11N 详情 详情
(X) 62259 tert-butyl (1R)-1-phenyl-2-propenylcarbamate C14H19NO2 详情 详情
(XI) 45428 tert-butyl (1S)-2-oxo-1-phenylethylcarbamate C13H17NO3 详情 详情
(XII) 61128   C4H8 详情 详情
(XIII) 62260 tert-butyl (1S)-2-hydroxy-1-phenyl-4-pentenylcarbamate C16H23NO3 详情 详情
(XIV) 62261 tert-butyl (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-4-pentenylcarbamate C22H37NO3Si 详情 详情

合成路线3

). The hydroxylation of the double bond of (XIV) by means of (Sia)2BH and H2O2 affords the pentanol (XV), which is treated with MsCl and TEA to provide the mesylate (XVI). The cyclization of (XVI) by means of t-BuOK in THF gives the piperidine (XVII), which is desilylated by means of TBAF to yield the piperidinol (XVIII). The oxidation of (XVIII) by means of DMP affords the piperidinone (XIX), which is treated with O-methylhydroxylamine and pyridine to provide the O-methyloxime (XX). The reduction of (XX) with BH3/THF gives the cis-disubstituted piperidine (XXI), which is submitted to a reductocondensation with 2-methoxybenzaldehyde (XXII) by means of NaBH3CN in methanol to yield the secondary amine (XXIII). Finally, the carbamate group of (XXIII) is cleaved by means of HCl in methanol to provide the target piperidine derivative

1 Yamazaki, N.; et al.; Enantioselective synthesis of NK-1 receptor antagonists (+)-CP-99,994 and (+)-CP-122,721. Tetrahedron Lett 2002, 43, 44, 7979.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 62261 tert-butyl (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-4-pentenylcarbamate C22H37NO3Si 详情 详情
(XV) 62262 tert-butyl (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-1-phenylpentylcarbamate C22H39NO4Si 详情 详情
(XVI) 62263 (5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-phenylpentyl methanesulfonate C23H41NO6SSi 详情 详情
(XVII) 62264 tert-butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-phenyl-1-piperidinecarboxylate C22H37NO3Si 详情 详情
(XVIII) 62265 tert-butyl (2S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(XIX) 62266 tert-butyl (2S)-3-oxo-2-phenyl-1-piperidinecarboxylate C16H21NO3 详情 详情
(XX) 62267 tert-butyl (2S)-3-(methoxyimino)-2-phenyl-1-piperidinecarboxylate C17H24N2O3 详情 详情
(XXI) 31756 tert-butyl (2S,3S)-3-amino-2-phenyl-1-piperidinecarboxylate C16H24N2O2 详情 详情
(XXII) 12568 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde 135-02-4 C8H8O2 详情 详情
(XXIII) 31757 tert-butyl (2S,3S)-3-[(2-methoxybenzyl)amino]-2-phenyl-1-piperidinecarboxylate C24H32N2O3 详情 详情

合成路线4

The cyclization of (S)-glutamic acid (I) by means of H2SO4 and NaNO2 gives the gamma lactone (II), which is treated with hot SOCl2 to yield the corresponding acyl chloride (III). The reaction of (III) with 4-methoxybenzylamine (IV) affords the expected amide (V), which is submitted to rearrangement in the presence of t-BuOK in THF to provide piperidinedione (VI). The reaction of (VI) with Tbdps-Cl and imidazole gives the silyl ether (VII), which is reduced with NaBH4 in methanol to yield a mixture of regioisomers (VIII). The phenyl migration in (VIII) was easily promoted by reaction with BF3/Et2O through the nonisolated intermediate cis-(IX) to yield (X). The reduction of (X) by means of LiAlH4 in THF affords the N-protected hydroxypiperidine (XI), which is deprotected by hydrogenation with H2 over Pd/C in ethanol to provide the free hydroxypiperidine (XII). The reprotection of (XII) with Boc2O gives the carbamate-protected piperidine (XIII), which is oxidized by means of DMSO, (COCl)2 and DIEA in dichloromethane to yield piperidone (XIV). The reaction of (XIV) with NH2OH and K2CO3 affords the corresponding oxime (XV), which is treated with Ac2O in THF to provide the O-acetyloxime (XVI). The reduction of (XVI) with BH3/Me2S in hot THF gives the expected amine (XVII), which is condensed with 2-methoxybenzaldehyde (XVIII) in THF to yield the imine (XIX). The reduction of (XIX) with NaBH4 in methanol affords the protected benzylamine (XX), which is finally deprotected by means of HCl in methanol to provide CP-99,994.

1 Wei, B.-G.; Huang, P.-Q.; Liu, L.-X.; Ruan, Y.-P.; Asymmetric synthesis of (+)-L-733, 060 and (+)-CP-99, 994 based on a new chiral 3-piperidinol synthon. Org Lett 2003, 5, 11, 1927.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
cis-(IX) 64777 (5S,6S)-5-{[tert-butyl(fluoro)phenylsilyl]oxy}-1-(4-methoxybenzyl)-6-phenyl-2-piperidinone C29H34FNO3Si 详情 详情
(I) 12005 L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid 56-86-0 C5H9NO4 详情 详情
(II) 12006 (R)-(-)-5-Oxo-2-tetrahydrofurancarboxylic acid; (2S)-5-oxotetrahydro-2-furancarboxylic acid 53558-93-3 C5H6O4 详情 详情
(III) 64772 (2S)-5-oxotetrahydro-2-furancarbonyl chloride C5H5ClO3 详情 详情
(IV) 15098 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine 2393-23-9 C8H11NO 详情 详情
(V) 64773 (2S)-N-(4-methoxybenzyl)-5-oxotetrahydro-2-furancarboxamide C13H15NO4 详情 详情
(VI) 64774 (3S)-3-hydroxy-1-(4-methoxybenzyl)-2,6-piperidinedione C13H15NO4 详情 详情
(VII) 64775 (3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-(4-methoxybenzyl)-2,6-piperidinedione C29H33NO4Si 详情 详情
(VIII) 64776 (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-hydroxy-1-(4-methoxybenzyl)-2-piperidinone C29H35NO4Si 详情 详情
(X) 64778 (5S,6S)-5-hydroxy-1-(4-methoxybenzyl)-6-phenyl-2-piperidinone C19H21NO3 详情 详情
(XI) 64779 (2S,3S)-1-(4-methoxybenzyl)-2-phenyl-3-piperidinol C19H23NO2 详情 详情
(XII) 64498 (2S,3S)-2-phenyl-3-piperidinol C11H15NO 详情 详情
(XIII) 64499 tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(XIV) 62266 tert-butyl (2S)-3-oxo-2-phenyl-1-piperidinecarboxylate C16H21NO3 详情 详情
(XV) 64780 tert-butyl (2S)-3-(hydroxyimino)-2-phenyl-1-piperidinecarboxylate C16H22N2O3 详情 详情
(XVI) 64781 tert-butyl (2S)-3-[(acetyloxy)imino]-2-phenyl-1-piperidinecarboxylate C18H24N2O4 详情 详情
(XVII) 31756 tert-butyl (2S,3S)-3-amino-2-phenyl-1-piperidinecarboxylate C16H24N2O2 详情 详情
(XVIII) 12568 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde 135-02-4 C8H8O2 详情 详情
(XIX) 64782 tert-butyl (2S,3S)-3-{[(E)-(2-methoxyphenyl)methylidene]amino}-2-phenyl-1-piperidinecarboxylate C24H30N2O3 详情 详情
(XX) 31757 tert-butyl (2S,3S)-3-[(2-methoxybenzyl)amino]-2-phenyl-1-piperidinecarboxylate C24H32N2O3 详情 详情
Extended Information