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【结 构 式】 
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【分子编号】28106 【品名】methyl 4-oxo-3-piperidinecarboxylate 【CA登记号】56026-52-9 |
【 分 子 式 】C7H11NO3 【 分 子 量 】157.16928 【元素组成】C 53.49% H 7.05% N 8.91% O 30.54% |
合成路线1
该中间体在本合成路线中的序号：(I)Alkylation of methyl 4-oxo-3-piperidinecarboxylate (I) with ethyl bromoacetate provided piperidineacetate (II). Subsequent decarbomethoxylation of (II) using LiCl in boiling DMF produced piperidone (III). On the other hand, coupling between 4-aminobenzonitrile (IV) and N-Boc-glycine (V) via activation with carbonyldiimidazole gave amide (V). The Boc group of (V) was then deprotected with HCl in EtOAc to yield 2-amino-N-(4-cyanophenyl)acetamide (VI). Reductive condensation of amine (VI) with piperidone (III) employing NaBH(OAc)3 furnished adduct (VII), which was further reductocondensed with chloroacetaldehyde to give chloroethyl amine (VIII). Cyclization of (VIII) in the presence of NaH generated piperazinone (IX). Finally, addition of hydroxylamine to the cyano group of (IX) provided the corresponding hydroxyamidine.
| 【1】 Suzuki, K.; Tsukamoto, S.; Yanagisawa, I.; Matsumoto, Y.; Ichihara, M.; Akamatsu, S.; Kaku, S.; Kawasaki, T.; Novel orally active GPIIb/IIIa antagonists: Synthesis and structure-activity relationship studies of oxopiperazine derivatives. Symp Med Chem 1999, Abst 1P-02. |
| 【2】 Matsumoto, Y.; Akamatsu, S.; Ichihara, M.; Kawasaki, T.; Kaku, S.; Yanagisawa, I. (Merck Patent GmbH; Yamanouchi Pharmaceutical Co., Ltd.); Substd. amidinobenzene derivs. and medicinal compsns. thereof. EP 0905129; US 6057324; WO 9745413 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 | |
| (I) | 28106 | methyl 4-oxo-3-piperidinecarboxylate | 56026-52-9 | C7H11NO3 | 详情 | 详情 |
| (II) | 37983 | methyl 1-(2-ethoxy-2-oxoethyl)-4-oxo-3-piperidinecarboxylate | C11H17NO5 | 详情 | 详情 | |
| (III) | 37984 | ethyl 2-(4-oxo-1-piperidinyl)acetate | C9H15NO3 | 详情 | 详情 | |
| (IV) | 15361 | 4-Aminobenzonitrile | 873-74-5 | C7H6N2 | 详情 | 详情 |
| (V) | 37985 | tert-butyl 2-(4-cyanoanilino)-2-oxoethylcarbamate | C14H17N3O3 | 详情 | 详情 | |
| (VI) | 37986 | 2-amino-N-(4-cyanophenyl)acetamide | C9H9N3O | 详情 | 详情 | |
| (VII) | 37988 | ethyl 2-(4-[[2-(4-cyanoanilino)-2-oxoethyl]amino]-1-piperidinyl)acetate | C18H24N4O3 | 详情 | 详情 | |
| (VIII) | 37987 | ethyl 2-(4-[(2-chloroethyl)[2-(4-cyanoanilino)-2-oxoethyl]amino]-1-piperidinyl)acetate | C20H27ClN4O3 | 详情 | 详情 | |
| (IX) | 37989 | ethyl 2-[4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidinyl]acetate | C20H26N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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 |