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【结 构 式】 
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【分子编号】45854 【品名】2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid 【CA登记号】51052-78-9 |
【 分 子 式 】C7H13NO2 【 分 子 量 】143.18576 【元素组成】C 58.72% H 9.15% N 9.78% O 22.35% |
合成路线1
该中间体在本合成路线中的序号：(II)4-Pyridineacetic acid (I) was hydrogenated to the corresponding piperidine (II) in the presence of PtO2. After protection of (II) as the N-Boc derivative (III), reduction of its carboxylate group with borane in THF provided alcohol (IV). Subsequent Swern oxidation of alcohol (IV) furnished aldehyde (V). This was then subjected to a Wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (VI), which was further hydrogenated to (VII) in the presence of Pd/C. After saponification of the methyl ester function of (VII), the resultant carboxylic acid was reduced to alcohol (VIII) by means of borane in THF. Conversion of alcohol (VIII) into the alkyl bromide (IX) was accomplished by treatment with carbon tetrabromide and triphenylphosphine. Then, alkylation of the phenolic hydroxyl of N-Cbz-L-tyrosine (X) with bromide (IX) in the presence of NaH in DMF afforded adduct (XI).
| 【1】 Egbertson, M.S.; Laswell, W.L.; Hartman, G.D.; Duggan, M.E.; Halczenko, W. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. EP 0478363; EP 0743302; JP 1992288051; US 5292756 . |
| 【2】 Egbertson, M.S.; Hartman, G.D.; Halczenko, W.; Laswell, W.L.; Duggan, M.E. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. WO 9319046 . |
| 【3】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537. |
| 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) | 17883 | 2-(4-pyridinyl)acetic acid | 28356-58-3 | C7H7NO2 | 详情 | 详情 |
| (II) | 45854 | 2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid | 51052-78-9 | C7H13NO2 | 详情 | 详情 |
| (III) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (IV) | 43453 | tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate | C12H23NO3 | 详情 | 详情 | |
| (V) | 59541 | tert-butyl 4-(2-oxoethyl)-1-piperidinecarboxylate | C12H21NO3 | 详情 | 详情 | |
| (VI) | 45855 | tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate | C15H25NO4 | 详情 | 详情 | |
| (VII) | 45856 | tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 59542 | tert-butyl 4-(4-hydroxybutyl)-1-piperidinecarboxylate | C14H27NO3 | 详情 | 详情 | |
| (IX) | 59543 | tert-butyl 4-(4-bromobutyl)-1-piperidinecarboxylate | C14H26BrNO2 | 详情 | 详情 | |
| (X) | 39328 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid | C17H17NO5 | 详情 | 详情 | |
| (XI) | 59544 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid | C31H42N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Intermediate (VII) can be obtained by following two different pathways: 1. Hydrogenation of 4-pyridine acetic acid (IX) over PtO2 in AcOH affords piperidinyl derivative (X), which is then protected with Boc2O and NaOH in THF to yield (XI). Reduction of the CO2H group of (XI) with BH3.THF in THF gives alcohol (XII), which is then subjected to Swern oxidation with oxalyl chloride and DMSO in CH2Cl2, followed by reaction with Wittig reagent (XIII) and N-methyl morpholine (NMM), to provide crotonate (XIV). Hydrogenation of (XIV) over Pd/C in MeOH furnishes methyl butyrate (XV), which is finally hydrolyzed with NaOH in MeOH. 2. Alternatively, intermediate (VII) can be obtained by reaction of diethyl malonate (XVI) with 4-vinylpyridine and NaH in EtOH to afford derivative (XVIII), which is hydrolyzed and decarboxylated with HCl/H2O and then hydrogenated over PtO2 to provide piperidine derivative (XIX). Finally, (XIX) is protected by reaction with Boc2O and NaOH in THF.
| 【1】 Molino, B.F.; Klein, S.I.; Czekaj, M.; et al.; Design of a new class of orally active fibrinogen receptor antagonists. J Med Chem 1998, 41, 14, 2492. |
| 【2】 Klein, S.I.; Molino, B.F. (Aventis Pharma SA); Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides. EP 0812205; JP 1997507213; US 5866685; WO 9510295 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 45852 | 4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butyric acid | C14H25NO4 | 详情 | 详情 | |
| (IX) | 17883 | 2-(4-pyridinyl)acetic acid | 28356-58-3 | C7H7NO2 | 详情 | 详情 |
| (X) | 45854 | 2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid | 51052-78-9 | C7H13NO2 | 详情 | 详情 |
| (XI) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (XII) | 43453 | tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate | C12H23NO3 | 详情 | 详情 | |
| (XIII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XIV) | 45855 | tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate | C15H25NO4 | 详情 | 详情 | |
| (XV) | 45856 | tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate | C15H27NO4 | 详情 | 详情 | |
| (XVI) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XVII) | 45857 | 4-vinylpyridine | C7H7N | 详情 | 详情 | |
| (XVIII) | 45858 | diethyl 2-[2-(4-pyridinyl)ethyl]malonate | C14H19NO4 | 详情 | 详情 | |
| (XIX) | 45859 | 4-(4-piperidinyl)butyric acid | C9H17NO2 | 详情 | 详情 |