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【结 构 式】 
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【分子编号】18473 【品名】(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid 【CA登记号】 |
【 分 子 式 】C20H30N2O5 【 分 子 量 】378.46868 【元素组成】C 63.47% H 7.99% N 7.4% O 21.14% |
合成路线1
该中间体在本合成路线中的序号：(VI)N-Boc-D-(3-phenylpropyl)glycine (I) was esterified to benzyl ester (II), and then, tert-butoxycarbonyl group was cleaved by acidic treatment to give amine (III). This was coupled with N-Boc-2-aminoisobutyric acid (IV) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to afford dipeptide ester (V), from which the benzyl ester group was removed by hydrogenolysis in the presence of Pd/C. The resulting acid (VI) was condensed with 1-(2-nitrophenyl)piperazine (VII) in the presence of EDC and HOBt to produce piperazide (VIII). Subsequent reduction of the nitro group by hydrogenation in the presence of Raney-Ni gave aniline (IX), which was treated with 2-propanesulfonyl chloride (X) to yield sulfonamide (XI). Finally, the tert-butoxycarbonyl protecting group was removed by treatment either with HCl in EtOAc or with trifluoroacetic acid to afford the target compound as the hydrochloride or the trifluoroacetate salt, respectively.
| 【1】 Barakat, K.J.; Cheng, K.; Chan, W.W.; Butler, B.S.; Jacks, T.M.; Schleim, K.D.; Hora, D.F. Jr.; Hickey, G.J.; Smith, R.G.; Patchett, A.A.; Nargund, R.P.; Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues. Bioorg Med Chem Lett 1998, 8, 11, 1431. |
| 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) | 18468 | (2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoic acid | C16H23NO4 | 详情 | 详情 | |
| (II) | 18469 | benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-5-phenylpentanoate | C23H29NO4 | 详情 | 详情 | |
| (III) | 18470 | benzyl (2R)-2-amino-5-phenylpentanoate | C18H21NO2 | 详情 | 详情 | |
| (IV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (V) | 18472 | benzyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C27H36N2O5 | 详情 | 详情 | |
| (VI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (VII) | 18474 | 1-(2-nitrophenyl)piperazine | C10H13N3O2 | 详情 | 详情 | |
| (VIII) | 18475 | tert-butyl 1,1-dimethyl-2-[((1R)-1-[[4-(2-nitrophenyl)-1-piperazinyl]carbonyl]-4-phenylbutyl)amino]-2-oxoethylcarbamate | C30H41N5O6 | 详情 | 详情 | |
| (IX) | 18476 | tert-butyl 2-[((1R)-1-[[4-(2-aminophenyl)-1-piperazinyl]carbonyl]-4-phenylbutyl)amino]-1,1-dimethyl-2-oxoethylcarbamate | C30H43N5O4 | 详情 | 详情 | |
| (X) | 18477 | 2-propanesulfonyl chloride | 10147-37-2 | C3H7ClO2S | 详情 | 详情 |
| (XI) | 18478 | tert-butyl 2-([(1R)-1-[(4-[2-[(isopropylsulfonyl)amino]phenyl]-1-piperazinyl)carbonyl]-4-phenylbutyl]amino)-1,1-dimethyl-2-oxoethylcarbamate | C33H49N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The alkylation of diethyl acetamidomalonate (II) with 1-bromo-3-phenylpropane (I) by means of NaOEt provided the substituted malonate (III), which upon hydrolysis and further decarboxylation gave rise to racemic 2-(acetylamino)-5-phenylpentanoic acid (IVa-b). Kinetic resolution employing Acylase I in the presence of CoCl2 produced a mixture of the (S)-amino acid (V) and the unaltered (R)-amide (VI), which were separated by differential solubility. The desired (R)-amide (VI) was hydrolyzed with aqueous HCl and then treated with EtOH to produce aminoester (VII). Subsequent coupling of (VII) with N-Boc-alpha-aminoisobutyric acid (VIII) employing 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) yielded the protected dipeptide (IX). Basic hydrolysis of the ethyl ester of (IX) afforded the intermediate (X).
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa),(VI) | 35759 | (2R)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (IVb) | 35775 | (2S)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (I) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (III) | 35758 | diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate | C18H25NO5 | 详情 | 详情 | |
| (V) | 35760 | (2S)-2-amino-5-phenylpentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 35761 | ethyl (2R)-2-amino-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (IX) | 35762 | ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C22H34N2O5 | 详情 | 详情 | |
| (X) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)4-Methoxyphenylacetic acid (XI) was esterified using EtOH and p-toluenesulfonic acid, and then brominated with NBS to give bromoester (XII). Coupling of (XII) with 4-nitroimidazole (XIII) afforded adduct (XIV), which was alkylated using iodomethane and NaH to yield (XVa-b). Hydrolysis of the ester group of (XVa-b) with LiOH gave the corresponding carboxylic acid, which was converted to acid chloride (XVIa-b) by means of treatment with oxalyl chloride. Reaction of (XVI) with the lithium salt of the chiral oxazolidinone (XVII) provided a diastereomeric mixture of N-acyloxazolidinones, which were separated by silica gel chromatography. Removal of the chiral auxiliary from the desired isomer (XVIII) under basic conditions, followed by treatment with oxalyl chloride provided acid chloride (XIX). Further reaction of (XIX) with pyrrolidine (XX) produced amide (XXI). Reduction of the nitro group of (XXI) using hydrogen and Pd/C generated the aminoimidazole derivative (XXII). This was coupled with the N-Boc-dipeptide (X) affording amide (XXIII). The Boc protecting group of (XXIII) was then cleaved by treatment with trifluoroacetic acid, and the title compound was finally isolated as the dihydrochloride salt.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVa) | 35766 | ethyl (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoate | C15H17N3O5 | 详情 | 详情 | |
| (XVIa) | 35767 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XVIb) | 35768 | (2S)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XVb) | 35769 | ethyl (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoate | C15H17N3O5 | 详情 | 详情 | |
| (X) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (XI) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (XII) | 35763 | ethyl 2-bromo-2-(4-methoxyphenyl)acetate | 77053-56-6 | C11H13BrO3 | 详情 | 详情 |
| (XIII) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XIV) | 35765 | ethyl 2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)acetate | C14H15N3O5 | 详情 | 详情 | |
| (XVII) | 35770 | C10H10LiNO2 | 详情 | 详情 | ||
| (XVIII) | 35771 | (4R,5S)-3-[(2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C23H22N4O6 | 详情 | 详情 | |
| (XIX) | 35767 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)propanoyl chloride | C13H12ClN3O4 | 详情 | 详情 | |
| (XX) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XXI) | 35772 | (2R)-2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)-1-(1-pyrrolidinyl)-1-propanone | C17H20N4O4 | 详情 | 详情 | |
| (XXII) | 35773 | (2R)-2-(4-amino-1H-imidazol-1-yl)-2-(4-methoxyphenyl)-1-(1-pyrrolidinyl)-1-propanone | C17H22N4O2 | 详情 | 详情 | |
| (XXIII) | 35774 | tert-butyl 2-([(1R)-1-[([1-[(1R)-1-(4-methoxyphenyl)-1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-imidazol-4-yl]amino)carbonyl]-4-phenylbutyl]amino)-1,1-dimethyl-2-oxoethylcarbamate | C37H50N6O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Alkylation of diethyl acetamidomalonate (I) with 1-bromo-3-phenylpropane (II) in the presence of NaOEt afforded phenylpropyl malonate (III). Hydrolysis and subsequent decarboxylation of malonate ester (III) yielded racemic 2-(acetylamino)-5-phenylpentanoic acid (IV). Kinetic resolution was achieved by enantioselective hydrolysis of the (S)-acetamide to give amino acid (VI). The desired (R)-enantiomer (V) was then hydrolyzed with HCl and further esterified with HCl-EtOH to provide amino ester (VII). Coupling with N-Boc-alpha-aminoisobutyric acid (VIII) via activation with 2-chloro-4,6-dimethoxy-1,3,5-triazine (IX) furnished dipeptide (X). The ethyl ester group of (X) was then hydrolyzed to acid (XI) using LiOH.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 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) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
| (II) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (III) | 35758 | diethyl 2-(acetamido)-2-(3-phenylpropyl)malonate | C18H25NO5 | 详情 | 详情 | |
| (IV) | 38799 | N-acetyl-5-phenylnorvaline | C13H17NO3 | 详情 | 详情 | |
| (V) | 35759 | (2R)-2-(acetamido)-5-phenylpentanoic acid | C13H17NO3 | 详情 | 详情 | |
| (VI) | 35760 | (2S)-2-amino-5-phenylpentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 35761 | ethyl (2R)-2-amino-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (IX) | 38798 | 2-chloro-4,6-dimethoxy-1,3,5-triazine; 4-chloro-6-methoxy-1,3,5-triazin-2-yl methyl ether | 3140-73-6 | C5H6ClN3O2 | 详情 | 详情 |
| (X) | 35762 | ethyl (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoate | C22H34N2O5 | 详情 | 详情 | |
| (XI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)Alkylation of 4-nitroimidazole (XII) by means of ethyl bromoacetate (XIII) gave ethyl 2-(4-nitro-1-imidazolyl)acetate (XIV). Reduction of (XIV) to the corresponding amine (XV) was effected by catalytic hydrogenation over Pd/C. Coupling of (XV) with dipeptide (XI) gave (XVI), which was hydrolyzed to carboxylic acid (XVII) using LiOH. This was finally coupled with proline amide (XIX), (obtained by treatment of L-proline (XVIII) with benzylamine and CDI), to furnish the title compound.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (XI) | 18473 | (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid | C20H30N2O5 | 详情 | 详情 | |
| (XII) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XIV) | 38800 | ethyl 2-(4-nitro-1H-imidazol-1-yl)acetate | C7H9N3O4 | 详情 | 详情 | |
| (XV) | 38801 | ethyl 2-(4-amino-1H-imidazol-1-yl)acetate | C7H11N3O2 | 详情 | 详情 | |
| (XVI) | 38802 | ethyl 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetate | C27H39N5O6 | 详情 | 详情 | |
| (XVII) | 38803 | 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetic acid | C25H35N5O6 | 详情 | 详情 | |
| (XVIII) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (XIX) | 38804 | (2S)-N-benzyl-2-pyrrolidinecarboxamide | C12H16N2O | 详情 | 详情 |