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【结 构 式】 
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【药物名称】LY-444711 【化学名称】2(R)-(2-Amino-2-methylpropanamido)-N-[1-[1(R)-(4-methoxyphenyl)-1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-imidazol-4-yl]-5-phenylpentanamide dihydrochloride 【CA登记号】220540-02-3, 220541-10-6 (free base) 【 分 子 式 】C32H44Cl2N6O4 【 分 子 量 】647.65128 |
【开发单位】Lilly (Originator) 【药理作用】ENDOCRINE DRUGS, Pituitary Disorder Therapy, Treatment of Growth Hormone Deficiency, Treatment of Growth Hormone Secretion Disorders, Growth Hormone Secretagogues |
合成路线1
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2
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 |