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【结 构 式】 
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【药物名称】RGD-891 【化学名称】N-Ethyl-N-[4-(4-piperidyl)butyryl]-glycyl-L-aspartyl-L-(3-cyclohexyl)alaninamide 【CA登记号】169512-56-5, 194933-81-8 (monotrifluoroacetate) 【 分 子 式 】C26H45N5O6 【 分 子 量 】523.67845 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
Treatment of N-Boc-beta cyclohexylalanine (I) in THF with Et3N, isobutyl chloroformate (IBCF) and NH3/MeOH, followed by reaction with HCl gas, yields beta-cyclohexyl alaninamide hydrochloride (II). Amino acid (II) is then converted into dipeptide (IV) by first coupling with protected L-aspartic acid (III) by means of isopropyl chloroformate (IPCF) and N-methyl piperidine (A) in CH2Cl2, followed by Boc removal with TFA in CH2Cl2. Condensation of (IV) with Boc-protected N-ethylglycine (V) and successive Boc removal are performed under the same conditions as for the synthesis of (IV) to furnish tripeptide (VI). Then (VI) is coupled to carboxylic acid (VII) by means BOPCl and Et3N in CH2Cl2 to afford intermediate (VIII). Finally the target compound is obtained by debenzylation of (VIII) with H2 over Pd/C in MeOH/AcOH, followed by Boc removal with TFA in CH2Cl2.
| 【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 |
|---|---|---|---|---|---|---|
| (A) | 45848 | 1-methylpiperidine | 626-67-5 | C6H13N | 详情 | 详情 |
| (I) | 23050 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (II) | 45847 | (2S)-2-amino-3-cyclohexylpropanamide | 145232-34-4 | C9H18N2O | 详情 | 详情 |
| (III) | 25219 | (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | 7536-58-5 | C16H21NO6 | 详情 | 详情 |
| (IV) | 45849 | benzyl (3S)-3-amino-4-[[(1R)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]-4-oxobutanoate | C20H29N3O4 | 详情 | 详情 | |
| (V) | 45850 | 2-[(tert-butoxycarbonyl)(ethyl)amino]acetic acid | 149794-10-5 | C9H17NO4 | 详情 | 详情 |
| (VI) | 45851 | benzyl (3S)-4-[[(1R)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]-3-[[2-(ethylamino)acetyl]amino]-4-oxobutanoate | C24H36N4O5 | 详情 | 详情 | |
| (VII) | 45852 | 4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butyric acid | C14H25NO4 | 详情 | 详情 | |
| (VIII) | 45853 | tert-butyl 4-[4-[(2-[[(1S)-1-([[(1R)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]carbonyl)-3-(benzyloxy)-3-oxopropyl]amino]-2-oxoethyl)(ethyl)amino]-4-oxobutyl]-1-piperidinecarboxylate | C38H59N5O8 | 详情 | 详情 |
合成路线2
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 |