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【结 构 式】 
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【药物名称】 【化学名称】N-Benzylsulfonyl-D-arginylglycyl-L-argininal 【CA登记号】186369-21-1 【 分 子 式 】C21H35N9O5S 【 分 子 量 】525.6344 |
【开发单位】Millennium (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors |
合成路线1
Solid-phase synthesis: Reduction of the carboxylic acid moiety of Boc-Arg(NO2)-OH (I) by first treatment with CDI followed by LiAlH4 affords aldehyde (II), which is then condensed with compound (III) in aqueous NaOAc and refluxing EtOH to yield semicarbazone linker (IV). Loading of (IV) onto aminomethyl polystyrene resin provides anchored arginine derivative (V), which is subjected to the following pathway to provide anchored peptide (VI): (i) Boc removal with TFA/CH2Cl2; (ii) incorporation of Boc-Gly-OH (A) by means of coupling agents HOBt, HBTU and DIEA in DMF; (iii) again Boc removal; and finally (iv) coupling of Boc-D-Arg(NO2)-OH (B) with HOBt, HBTU and DIEA in DMF. Deprotection of (VI) with TFA/CH2Cl2 and capping with benzylsulfonyl chloride (VII) and DIEA furnishes anchored derivative (VIII), which is cleaved by means of HOAc, aqueous formaldehyde and HCl in THF and finally hydrogenolyzed over Pd/C. The synthesis can also be performed in an analogous way by substitution of Boc-Arg(NO2)-OH for Boc-Arg(Cbz)2-OH.
| 【1】 Marlowe, C.K.; Sinha, U.; Scarborough, R.M.; Gunn, A.C.; Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: Structures based on the (D)-Arg-Gly-Arg tripeptide sequence. Bioorg Med Chem Lett 2000, 10, 1, 13. |
| 【2】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. US 5721214 . |
| 【3】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. EP 0846125; JP 1999507626; US 5919765; WO 9640743 . |
| 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) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (B) | 39364 | Omega-nitro-Boc-D-arginine | 50913-12-7 | C11H21N5O6 | 详情 | 详情 |
| (I) | 29372 | N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine | C11H21N5O6 | 详情 | 详情 | |
| (II) | 43535 | C11H21N5O5 | 详情 | 详情 | ||
| (III) | 43536 | 4-[[(hydrazinocarbonyl)amino]methyl]cyclohexanecarboxylic acid | C9H17N3O3 | 详情 | 详情 | |
| (IV) | 43537 | C20H36N8O7 | 详情 | 详情 | ||
| (V) | 43538 | C20H37N9O6 | 详情 | 详情 | ||
| (VI) | 43539 | C28H51N15O10 | 详情 | 详情 | ||
| (VII) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (VIII) | 43540 | C30H49N15O10S | 详情 | 详情 |
合成路线2
Solution-phase synthesis: Protection of the side-chain of Boc-Arg-OH (IX) by treatment with Cbz-Cl in aqueous NaHCO3 yields Boc-Arg(Cbz)-OH (X), which is then converted into arginine lactam (XI) by a first treatment with isobutyl chloroformate (i-BuO2CCl) and NMM in THF followed by Boc deprotection with HCl/dioxane. Condensation of N-deprotected lactam (XI) with protected dipeptide (XII) by means of BOP/DIEA in DMF provides the tripeptide lactam (XIII), which is finally reduced with LiAlH4 in THF and hydrogenated over Pd/C for protecting group removal.
| 【1】 Marlowe, C.K.; Sinha, U.; Scarborough, R.M.; Gunn, A.C.; Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: Structures based on the (D)-Arg-Gly-Arg tripeptide sequence. Bioorg Med Chem Lett 2000, 10, 1, 13. |
| 【2】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. EP 0846125; JP 1999507626; US 5919765; WO 9640743 . |
| 【3】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. US 5721214 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 14073 | (2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | 13726-76-6 | C11H22N4O4 | 详情 | 详情 |
| (X) | 14074 | (2S)-5-[(Amino[[(benzyloxy)carbonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C19H28N4O6 | 详情 | 详情 | |
| (XI) | 43542 | benzyl (E)-amino[(3S)-3-amino-2-oxopiperidinyl]methylidenecarbamate | C14H18N4O3 | 详情 | 详情 | |
| (XII) | 43543 | (E,10R)-5-amino-10-[(benzylsulfonyl)amino]-3,11-dioxo-1-phenyl-2-oxa-4,6,12-triaza-4-tetradecen-14-oic acid | C23H29N5O7S | 详情 | 详情 | |
| (XIII) | 43544 | benzyl (E)-amino([(4R)-5-[(2-[[(3S)-1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxopiperidinyl]amino]-2-oxoethyl)amino]-4-[(benzylsulfonyl)amino]-5-oxopentyl]amino)methylidenecarbamate | C37H45N9O9S | 详情 | 详情 |