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【结 构 式】 
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【分子编号】12568 【品名】2-Methoxybenzaldehyde; o-Methoxybenzaldehyde 【CA登记号】135-02-4 |
【 分 子 式 】C8H8O2 【 分 子 量 】136.15032 【元素组成】C 70.57% H 5.92% O 23.5% |
合成路线1
该中间体在本合成路线中的序号：(IX)The condensation of acetone (VIII) with 2-methoxybenzaldehyde (IX) by means of NaOH gives 2-methoxybenzalacetone (X), which is reduced with H2 over Raney-Ni in ethanol to yield 4-(2-methoxyphenyl)-2-butanone (XI). The Grignard reaction of (XI) with methylmagnesium iodide in ether affords 1,1-dimethyl-3-(2-methoxyphenyl) propanol (XII), which by reaction with NaCN by means of H2SO4 in acetic acid affords N-[1,1-dimethyl-3-(2-methoxyphenyl)propyl]formamide (XIII). Finally, this compound is hydrolyzed with refluxing 5N NaOH to give (II).
| 【1】 Olsson, O.A.T.; Persson, N.H.A.; Svensson, L.A.; Waldeck, C.B.; Wetterlin, K.J.L.; EP 0004835 . |
| 【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; D-2343. Drugs Fut 1982, 7, 1, 17. |
| 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) | 36422 | 3-(2-methoxyphenyl)-1,1-dimethylpropylamine; 4-(2-methoxyphenyl)-2-methyl-2-butanamine | C12H19NO | 详情 | 详情 | |
| (VIII) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (IX) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (X) | 36418 | (E)-4-(2-methoxyphenyl)-3-buten-2-one | C11H12O2 | 详情 | 详情 | |
| (XI) | 36419 | 4-(2-methoxyphenyl)-2-butanone | C11H14O2 | 详情 | 详情 | |
| (XII) | 36420 | 4-(2-methoxyphenyl)-2-methyl-2-butanol | C12H18O2 | 详情 | 详情 | |
| (XIII) | 36421 | 3-(2-methoxyphenyl)-1,1-dimethylpropylformamide | C13H19NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)This compound is obtained by condensation of 2(S)-(aminomethyl)-1-ethylpyrrolidine (I) with 5-(aminosulfonyl)-2-methoxybenzoyl chloride (II) by means of K2CO3 in acetone. The starting compounds (I) and (II) are obtained as follows: a) The acylation of 2(S)-(hydroxymethyl)pyrrolidine (III) with acetic anhydride in refluxing methanol gives 1-acetyl-2(S)-(hydroxymethyl)pyrrolidine (IV), which by reaction with SOCl2 in CHCl3 is converted into 1-acetyl-2(S)-(chloromethyl)pyrrolidine (V). The reaction of (V) with sodium azide in hot DMF affords the corresponding azide (VI), which is reduced with LiAlH4 in refluxing THF to yield the desired product (I). b) The methylation of 2-hydroxybenzaldehyde (VII) with dimethyl sulfate and K2SO3 in refluxing acetone gives 2-methoxybenzaldehyde (VIII), which is oxidized with KMnO4 in hot aqueous NaOH affording 2-methoxybenzoic acid (IX). The sulfonation of (IX) with hot chlorosulfonic acid yields 5-(chlorosulfonyl)-2-methoxybenzoic acid (X), which is finally treated with 28% aqueous NaOH to give the desired product (II).
| 【1】 Al-Koutayni-Rifai, M.; Jamet, G.; Kerr, R.R.; Jung, L.; Koffel, J.C.; Synthesis of D3-sulpiride and its (R) and (S) isomers. J Label Compd Radiopharm 1989, 27, 7, 811. |
| 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) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (II) | 21346 | 5-(aminosulfonyl)-2-methoxybenzoyl chloride | C8H8ClNO4S | 详情 | 详情 | |
| (III) | 21347 | (2S)pyrrolidinylmethanol | 23356-96-9 | C5H11NO | 详情 | 详情 |
| (IV) | 21348 | 1-[(2S)-2-(hydroxymethyl)pyrrolidinyl]-1-ethanone | C7H13NO2 | 详情 | 详情 | |
| (V) | 21349 | 1-[(2S)-2-(chloromethyl)pyrrolidinyl]-1-ethanone | C7H12ClNO | 详情 | 详情 | |
| (VI) | 21350 | 1-[(2S)-2-(azidomethyl)pyrrolidinyl]-1-ethanone | C7H12N4O | 详情 | 详情 | |
| (VII) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (VIII) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (IX) | 13926 | 2-Methoxybenzoic acid; o-Methoxybenzoic Acid | 579-75-9 | C8H8O3 | 详情 | 详情 |
| (X) | 21354 | 5-(chlorosulfonyl)-2-methoxybenzoic acid | C8H7ClO5S | 详情 | 详情 | |
| (XI) | 21355 | 5-(aminosulfonyl)-2-methoxybenzoic acid; 2-methoxy-5-sulfamoylbenzoic acid | 22117-85-7 | C8H9NO5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)5) The cyclization of D-penicillamine (X) with 2-methoxybenzaldehyde (XI) in ethanol gives (4S)-2-(2-methoxyphenyl)-5,5-dimethylthiazolidine-4-carboxylic acid (XII), which by acetylation with hot acetic anhydride and fractional crystallization yields the chiral (2S,4S)-3-acetyl-2-(2-methoxyphenyl)-5,5-dimethylthiazolidine-4-carboxylic acid (XIII). The esterification of (XIII) with the hydroxyl group of benzothiazinone (I) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) in DMF affords a diastereomeric mixture of esters, which is separated by fractional crystallization giving ester (XIV). Elimination of the chiral auxiliar by treatment with calcium borohydride in THF or sodium borohydride in ethanol (2) gives (R)-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (XV), which is condensed with 3-bromopropanol (XVI) by means of triphenylphosphine and diethyl azodicarboxylate in DMF or THF yielding (R)-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (XVII). Finally, this compound is condensed with the secondary amine (IV) by means of NaI and NaHCO3 as already described, and treated with fumaric acid as before.
| 【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Sesamodil Fumarate. Drugs Fut 1997, 22, 3, 229. |
| 【2】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 . |
| 【3】 Iwao, J.; Iso, T.; Kawashima, Y. (Santen Pharmaceutical Co., Ltd.); Sulfur-containing polycyclic cpds. JP 1988104969 . |
| 【4】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 12567 | (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine | 1113-41-3 | C5H11NO2S | 详情 | 详情 |
| (XI) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (XII) | 12569 | (4S)-2-(2-Methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C13H17NO3S | 详情 | 详情 | |
| (XIII) | 12570 | (2S,4S)-3-Acetyl-2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C15H19NO4S | 详情 | 详情 | |
| (XIV) | 12571 | 4-methoxy-2-[(2R)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]phenyl (2S,4S)-3-acetyl-2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate | C31H32N2O6S2 | 详情 | 详情 | |
| (XV) | 12572 | (2R)-2-(2-Hydroxy-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C16H15NO3S | 详情 | 详情 | |
| (XVI) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (XVII) | 12574 | (2R)-2-[2-(3-Bromopropoxy)-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C19H20BrNO3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：N-(Benzyloxycarbonyl)-6-aminocaproic acid (I) is reacted with 1,8-octanediamine (II) to give amide (III). The protecting group can be removed either by hydrogenolysis or by gaseous HBr affording (IV), which is reduced with borane-methyl sulfide complex to yield N,N'-bis(6-aminohexyl)-1,8-octanediamine (V). Condensation of (V) with 2-methoxybenzaldehyde and subsequent reduction of the intermediate Schiff base gives methoctramine. However, methoctramine can be prepared more conveniently by transforming (IV) to (VI) followed by reduction of amide groups with borane.
| 【1】 Melchiorre, C.; Minarini, A.; Quaglia, W.; Tumiatti, V.; METHOCTRAMINE. Drugs Fut 1989, 14, 7, 628. |
| 【2】 Quaglia, W.; Melchiorre, C.; Cassinelli, A.; Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M2 muscarinic receptors. J Med Chem 1987, 30, 1, 201. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 | |
| (I) | 20964 | 6-[[(benzyloxy)carbonyl]amino]hexanoic acid | 1947-00-8 | C14H19NO4 | 详情 | 详情 |
| (II) | 20965 | 1,8-octanediamine; 8-aminooctylamine | 373-44-4 | C8H20N2 | 详情 | 详情 |
| (III) | 20966 | benzyl 6,17,24-trioxo-26-phenyl-25-oxa-7,16,23-triazahexacos-1-ylcarbamate | C36H54N4O6 | 详情 | 详情 | |
| (IV) | 20967 | 6-amino-N-[8-[(6-aminohexanoyl)amino]octyl]hexanamide | C20H42N4O2 | 详情 | 详情 | |
| (V) | 20968 | N(1),N(8)-bis(6-aminohexyl)-1,8-octanediamine; N-(6-aminohexyl)-N-[8-[(6-aminohexyl)amino]octyl]amine | C20H46N4 | 详情 | 详情 | |
| (VI) | 20969 | 6-[(2-methoxybenzyl)amino]-N-[8-([6-[(2-methoxybenzyl)amino]hexanoyl]amino)octyl]hexanamide | C36H58N4O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIV)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6
该中间体在本合成路线中的序号：(XXII)). 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7
该中间体在本合成路线中的序号：(XVIII)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 |
合成路线8
该中间体在本合成路线中的序号：(III)N-(6-Aminohexyl)cysteamine (I), synthesized according to Wineman et al., is converted to the disulfide (II) by potassium ferricyanide oxidation. The substituent on the terminal nitrogens is introduced by condensation with the aromatic aldehyde (III) and subsequent reduction with NaBH4 of the intermediate Schiff base (IV).
| 【3】 Benfey, B.G.; Melchiorre, C.; Belleau, B.; Yong, M.S.; Molecular properties of the adrenergic alpha receptor. 2. Optimum covalent inhibition by two different prototypes of polyamine disulfides. J Med Chem 1978, 21, 11, 1126-32. |
| 【1】 Benfey, B.G.; Benextramine. Drugs Fut 1981, 6, 12, 751. |
| 【2】 James, J.C.; Wineman, R.J.; Pomponi, A.M.; Gollis, M.H.; Thiolethylation of amines with ethylene disulfide. J Org Chem 1962, 27, 4222-26. |
| 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) | 39011 | 2-[(6-aminohexyl)amino]ethylhydrosulfide; 2-[(6-aminohexyl)amino]-1-ethanethiol | C8H20N2S | 详情 | 详情 | |
| (II) | 39012 | N(1)-[2-([2-[(6-aminohexyl)amino]ethyl]disulfanyl)ethyl]-1,6-hexanediamine; N-(6-aminohexyl)-N-[2-([2-[(6-aminohexyl)amino]ethyl]disulfanyl)ethyl]amine | C16H38N4S2 | 详情 | 详情 | |
| (III) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (IV) | 39013 | 1,24-bis(2-methoxyphenyl)-12,13-dithia-2,9,16,23-tetraazatetracosane-1,24-diol | C32H54N4O4S2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The cyclization of methyl acetoacetate (I), 2-methoxybenzaldehyde (II) and thiourea (III) by means of HCl in refluxing ethanol gives the tetrahydropyrimidine (IV), which is finally cyclized with chloroacetic acid (V) and benzaldehyde (VI) by means of sodium acetate in a refluxing mixture of acetic acid and acetic anhydride.
| 【1】 Kelicen, P.; Ertan, M.; Demirdamar, R.; Krebs, B.; Tozkoparan, B.; Lage, M.; Condensed heterocyclic compounds: Synthesis and antiinflammatory activity of novel thiazolo[3,2-a]pyrimidines. Arch Pharm 1998, 331, 6, 201. |
| 【2】 Assandri, A.; et al.; Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog. Arzneim-Forsch Drug Res 1985, 35, 2, 508. |
| 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) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (II) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (III) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (IV) | 27432 | methyl 4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate | C14H16N2O3S | 详情 | 详情 | |
| (V) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (VI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Reductive condensation of diamine diamide (I) with 2-methoxybenzaldehyde (II) in the presence of NaBH4 provided the corresponding bis(2-methoxybenzyl) derivative (III). Then, Eschweiler-Clarke methylation using formaldehyde and formic acid provided the title compound.
| 【1】 Melchiorre, C.; Andrisano, V.; Bolognesi, M.L.; Budriesi, R.; Cavalli, A.; Cavrini, V.; Rosini, M.; Turmiatti, V.; Recanatini, M.; Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer's disease. J Med Chem 1998, 41, 22, 4186. |
| 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) | 25375 | 6-amino-N-[8-[(6-aminohexanoyl)(methyl)amino]octyl]-N-methylhexanamide | C22H46N4O2 | 详情 | 详情 | |
| (II) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (III) | 25376 | 6-[(2-methoxybenzyl)amino]-N-[8-[[6-[(2-methoxybenzyl)amino]hexanoyl](methyl)amino]octyl]-N-methylhexanamide | C38H62N4O4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Condensation of diamine (I) with 2-methoxybenzaldehyde (II), followed by NaBH4 reduction of the intermediate bis-imine (III) gives rise to the benzylic amine (IV). This is then alkylated with diethyl sulfate, and the resultant N-ethyl amine is finally isolated as the corresponding dioxalate salt.
| 【1】 Tumiatti, V.; Rosini, M.; Bartolini, M.; Cavalli, A.; Marucci, G.; Andrisano, V.; Angeli, P.; Banzi, R.; Minarini, A.; Recanatini, M.; Melchiorre, C.; Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 2. Role of the substituents on the phenyl ring and nitrogen atoms of caproctamine. J Med Chem 2003, 46, 6, 954. |
| 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) | 25375 | 6-amino-N-[8-[(6-aminohexanoyl)(methyl)amino]octyl]-N-methylhexanamide | C22H46N4O2 | 详情 | 详情 | |
| (II) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (III) | 64038 | N-methyl-N-(8-{methyl[6-({[2-(methyloxy)phenyl]methylidene}amino)hexanoyl]amino}octyl)-6-({[2-(methyloxy)phenyl]methylidene}amino)hexanamide | C38H58N4O4 | 详情 | 详情 | |
| (IV) | 25376 | 6-[(2-methoxybenzyl)amino]-N-[8-[[6-[(2-methoxybenzyl)amino]hexanoyl](methyl)amino]octyl]-N-methylhexanamide | C38H62N4O4 | 详情 | 详情 |