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【结 构 式】 
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【分子编号】28103 【品名】(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid 【CA登记号】 |
【 分 子 式 】C19H28N2O6 【 分 子 量 】380.4412 【元素组成】C 59.99% H 7.42% N 7.36% O 25.23% |
合成路线1
该中间体在本合成路线中的序号：(VI)The intermediate dipeptide (VI) was prepared by two similar ways. Treatment of N-Boc-O-benzyl-D-serine (I) with MeI and K2CO3 produced the methyl ester (II). Subsequent deprotection of the Boc group of (II) with trifluoroacetic acid gave aminoester (III), which was coupled with N-Boc-alpha-methylalanine (IV) using EDC and HOBt yielding (V). Hydrolysis of the resulting dipeptide ester (V) then provided intermediate (VI). In an alternative procedure, N-Boc-alpha-methyl alanine (IV) was activated as the N-hydroxysuccinimidyl ester (VII), which was condensed with O-benzyl-D-serine (VIII) to produce dipeptide (VI).
| 【1】 Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.; Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 276. |
| 【2】 Carpino, P.A.; Jardine, D.P.A.; Lefker, B.A.; Ragan, J.A. (Pfizer Inc.); Growth-hormone secretagogues. EP 0869968; JP 1999501945; WO 9724369 . |
| 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) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (II) | 28100 | methyl (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoate | C16H23NO5 | 详情 | 详情 | |
| (III) | 28101 | methyl (2R)-2-amino-3-(benzyloxy)propanoate | C11H15NO3 | 详情 | 详情 | |
| (IV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (V) | 28102 | methyl (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoate | C20H30N2O6 | 详情 | 详情 | |
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (VII) | 28104 | tert-butyl 2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1,1-dimethyl-2-oxoethylcarbamate | C13H20N2O6 | 详情 | 详情 | |
| (VIII) | 28105 | (2R)-2-amino-3-(benzyloxy)propionic acid | C10H13NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Methyl 4-oxopiperidine-3-carboxylate (IX) was protected as the tert-butyl carbamate (X) with Boc2O. This was alkylated with benzyl bromide in the presence of NaH to provide the racemic benzyl derivative (XI). Subsequent cyclization of (XI) with methylhydrazine produced the pyrazolopyridine (XII), which was deprotected with trifluoroacetic acid. The resulting amine (XIII) was then coupled with dipeptide (VI) using EDC and HOBt to afford the diastereomeric amides (XIV). After chromatographic isolation of the (R,R)-diastereoisomer, acid deprotection of the Boc group furnished the title compound.
| 【1】 Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.; Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 276. |
| 【2】 Carpino, P.A.; Jardine, D.P.A.; Lefker, B.A.; Ragan, J.A. (Pfizer Inc.); Growth-hormone secretagogues. EP 0869968; JP 1999501945; WO 9724369 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 | |
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (IX) | 28106 | methyl 4-oxo-3-piperidinecarboxylate | 56026-52-9 | C7H11NO3 | 详情 | 详情 |
| (X) | 28107 | 1-(tert-butyl) 3-methyl 4-oxo-1,3-piperidinedicarboxylate | C12H19NO5 | 详情 | 详情 | |
| (XI) | 28108 | 1-(tert-butyl) 3-methyl 3-benzyl-4-oxo-1,3-piperidinedicarboxylate | C19H25NO5 | 详情 | 详情 | |
| (XII) | 28109 | tert-butyl 3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate | C19H25N3O3 | 详情 | 详情 | |
| (XIII) | 28110 | 3a-benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one | C14H17N3O | 详情 | 详情 | |
| (XIV) | 28111 | tert-butyl 2-([(1R)-2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-1-[(benzyloxy)methyl]-2-oxoethyl]amino)-1,1-dimethyl-2-oxoethylcarbamate | C33H43N5O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Treatment of N-Boc-D-serine benzyl ether (I) with methyl iodide and NaHCO3 provided methyl ester (II). Subsequent acid cleavage of the Boc group of (II) gave aminoester (III), which was coupled with N-Boc-alpha-aminoisobutyric acid (IV) to afford dipeptide (V). The methyl ester group of (V) was then hydrolyzed to acid (VI) 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) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (II) | 28100 | methyl (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoate | C16H23NO5 | 详情 | 详情 | |
| (III) | 28101 | methyl (2R)-2-amino-3-(benzyloxy)propanoate | C11H15NO3 | 详情 | 详情 | |
| (IV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (V) | 28102 | methyl (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoate | C20H30N2O6 | 详情 | 详情 | |
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)4-Methoxyphenylacetic acid (VII) was esterified with EtOH and p-toluenesulfonic acid. The resulting ethyl ester (VIII) was brominated by means of N-bromosuccinimide to produce bromoester (IX), which was condensed with 4-nitroimidazole (X) yielding (XI). Reduction of the nitro group of (XI) by catalytic hydrogenation over Pd/C gave amine (XII). This was coupled with acid (VI) by means of EDC and HOBt to afford amide (XIII). Then, hydrolysis of the methyl ester of (XIII) with LiOH gave rise to carboxylic acid (XIV). Finally, coupling of (XIV) with 4-methylpiperidine (XV) generated 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 |
|---|---|---|---|---|---|---|
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 38805 | methyl 2-(4-methoxyphenyl)acetate | 23786-14-3 | C10H12O3 | 详情 | 详情 |
| (IX) | 38806 | methyl 2-bromo-2-(4-methoxyphenyl)acetate | C10H11BrO3 | 详情 | 详情 | |
| (X) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XI) | 38807 | methyl 2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)acetate | C13H13N3O5 | 详情 | 详情 | |
| (XII) | 38808 | methyl 2-(4-amino-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetate | C13H15N3O3 | 详情 | 详情 | |
| (XIII) | 38809 | methyl 2-(4-[[(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoyl]amino]-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetate | C32H41N5O8 | 详情 | 详情 | |
| (XIV) | 38810 | 2-(4-[[(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoyl]amino]-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetic acid | C31H39N5O8 | 详情 | 详情 | |
| (XV) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |