【结 构 式】 |
【药物名称】Xemilofiban, CS-551, SC-54684A(HCl), SC-54684 【化学名称】3(S)-(4-Amidinophenylaminosuccinylamino)-4-pentynoic acid ethyl ester 【CA登记号】149820-74-6, 156586-91-3 (mono HCl salt), 149193-59-9 (racemate), 149727-64-0 (racemic; trifluoroacetate salt (2:3)) 【 分 子 式 】C18H22N4O4 【 分 子 量 】358.40044 |
【开发单位】Pfizer (Originator) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
The reaction of 4-aminobenzamidine dihydrochloride (I) with succinic anhydride and pyridine in hot DMF gives the succinyl derivative (II), which is activated with isobutyl chloroformate and N-methylmorpholine (NMM) and then coupled to 3(S)-amino-4-pentynoic acid ethyl ester (III) in DMF or DMAc.
【1】 Zablocki, J.A.; Rico, J.G.; Garland, R.B.; et al.; Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists. J Med Chem 1995, 38, 13, 2378-94. |
【2】 Graul, A.; Martel, A.M.; Castaner, J.; Xemilofiban. Drugs Fut 1997, 22, 5, 508. |
【3】 Bovy, P.R.; Rico, J.G.; Rogers, T.E.; Tjoeng, F.S.; Zablocki, J.A. (Pharmacia Corp.); Substd. beta-amino acid derivs. useful as platelet aggregation inhibitors. EP 0542708; EP 0614360; JP 1995500111; US 5239113; WO 9307867 . |
【4】 Process for the preparation of ethyl 3S-[4[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate. US 5536869 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 | |
(I) | 16295 | 4-aminobenzenecarboximidamide hydrochloride; 4-aminobenzamidine | 3858-83-1 | C7H9N3 | 详情 | 详情 |
(II) | 16296 | 4-[4-[amino(imino)methyl]anilino]-4-oxobutyric acid | C11H13N3O3 | 详情 | 详情 | |
(III) | 16297 | ethyl (3S)-3-amino-4-pentynoate | C7H11NO2 | 详情 | 详情 |
合成路线2
The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 1) The reaction of 4-(benzoyloxy)-2-azetidinone (IV) with 2 equivalents of 1-lithio-2-(trimethylsilyl)acetylene (V) gives azetidinone (VI), which is opened with anhydrous HCl in ethanol, yielding racemic 3-amino-5-(trimethylsilyl)-4-pentynoic acid ethyl ester (VII). Resolution of (VII) by means of diastereomeric amide formation with (R)-O-methyl mandelic acid chloride (VIII) and chromatographic separation of the diastereoisomers (MPLC, ether/hexane) affords the amide (IX), which is then N-protected with Boc2O in acetonitrile to give (X). Treatment of (X) with tetramethylguanidine in methanol gives methyl ester (XI), which is finally treated first with TFA and then with HCl in ethanol to afford ethyl ester (III).
【1】 Zablocki, J.A.; Rico, J.G.; Garland, R.B.; et al.; Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists. J Med Chem 1995, 38, 13, 2378-94. |
【2】 Graul, A.; Martel, A.M.; Castaner, J.; Xemilofiban. Drugs Fut 1997, 22, 5, 508. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
17739 | N,N,N',N'-tetramethylguanidine; 1,1,3,3-Tetramethylguanidine | 80-70-6 | C5H13N3 | 详情 | 详情 | |
(III) | 16297 | ethyl (3S)-3-amino-4-pentynoate | C7H11NO2 | 详情 | 详情 | |
(IV) | 16298 | 4-oxo-2-azetanyl benzoate; 4-Benzoyloxy-2-azetidinone | 28562-58-5 | C10H9NO3 | 详情 | 详情 |
(V) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
(VI) | 16300 | 4-[2-(trimethylsilyl)ethynyl]-2-azetanone | C8H13NOSi | 详情 | 详情 | |
(VII) | 16301 | 3-amino-5-(trimethylsilyl)-4-pentynoic acid | C8H15NO2Si | 详情 | 详情 | |
(VIII) | 16302 | (2R)-2-methoxy-2-phenylethanoyl chloride | C9H9ClO2 | 详情 | 详情 | |
(IX) | 16303 | (3S)-3-[[(2R)-2-methoxy-2-phenylethanoyl]amino]-5-(trimethylsilyl)-4-pentynoic acid | C17H23NO4Si | 详情 | 详情 | |
(X) | 16304 | ethyl (3S)-3-[(tert-butoxycarbonyl)[(2R)-2-methoxy-2-phenylethanoyl]amino]-5-(trimethylsilyl)-4-pentynoate | C24H35NO6Si | 详情 | 详情 | |
(XI) | 17740 | ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-pentynoate | C12H19NO4 | 详情 | 详情 |
合成路线3
The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 2) The treatment of (trimethylsilyl)acetylene (XII) with butyllithium and NMM in methyl tert-butyl ether (MTBE), followed by hydrolysis with aqueous HCl, gives 3-(trimethylsilyl)-2-propynal (XIII). Treatment of (XIII) with lithium bis(trimethylsilyl)amide (LiHMDS) and trimethylsilyl chloride at -20 C gives the imine (XIV), which is reacted in situ with lithium tert-butyl acetate followed by hydrolysis with aqueous NH4Cl to afford racemic tert-butyl ester (XV). Treatment of (XV) with refluxing ethanol in the presence of p-toluenesulfonic acid gives the corresponding ethyl ester (VII) (already obtained in the preceding scheme). Desilylation of (VII) with NaOEt/EtOH affords racemic 3-amino-4-pentynoic acid ethyl ester in situ, which is then resolved using R-(-)-mandelic acid in ethyl acetate/MTBE to give mandelic acid salt (XVI). Recrystallization of (XVI) from acetonitrile/MTBE and treatment with gaseous HCl in MTBE affords ethyl ester (III) as the hydrochloride.
【1】 Graul, A.; Martel, A.M.; Castaner, J.; Xemilofiban. Drugs Fut 1997, 22, 5, 508. |
【2】 Process for the preparation of ethyl 3S-[4[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate. US 5536869 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
33800 | 4-morpholinecarbaldehyde | 4394-85-8 | C5H9NO2 | 详情 | 详情 | |
(III) | 16297 | ethyl (3S)-3-amino-4-pentynoate | C7H11NO2 | 详情 | 详情 | |
(VII) | 16301 | 3-amino-5-(trimethylsilyl)-4-pentynoic acid | C8H15NO2Si | 详情 | 详情 | |
(XII) | 23897 | ethynyl(trimethyl)silane;trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
(XIII) | 20043 | 3-(trimethylsilyl)-2-propynal | C6H10OSi | 详情 | 详情 | |
(XIV) | 16307 | trimethyl-N-[(E)-3-(trimethylsilyl)-2-propynylidene]silanamine; N-(trimethylsilyl)-N-[(E)-3-(trimethylsilyl)-2-propynylidene]amine | C9H19NSi2 | 详情 | 详情 | |
(XV) | 16308 | tert-butyl 3-amino-5-(trimethylsilyl)-4-pentynoate | C12H23NO2Si | 详情 | 详情 | |
(XVI) | 16309 | 2(R)-Hydroxy-2-phenylacetic salt with acid 3(S)-amino-4-pentynoic acid ethyl ester | C15H19NO5 | 详情 | 详情 |
合成路线4
A short and efficient synthesis of xemilofiban has been achieved as follows: The reaction of ethyl chloroformate (I) with trimethylsilylacetylene (II) by means of butyllithium gives ethyl 3-(trimethylsilyl)propyonate (III), which is condensed with the lithium salt of ethyl acetate (IV) yielding ethyl 5-(trimethylsilyl)-3-oxo-4-pentynoate (V). The selective reduction of (V) with lyophilized baker's yeast (Saccharomyces cerevisiae, Sigma type II) affords ethyl 3(R)-hydroxy-5-(trimethylsilyl)-4-pentynoate (VI), which by reaction with ammonia (VII), diethyl azodicarboxylate (VIII) and triphenylphosphine, followed by hydrolysis with water gives 3(S)-amino-5-(trimethylsilyl)-4-pentynoate (IX). Finally, this compound is condensed with N-(4-amidinophenyl)succinamic acid (XI) by means of isobutyl chloroformate and N-methylmorpholine (NMM). The intermediate succinamic acid (XI) has been obtained by condensation of 4-aminobenzamidine (XII) with succinic anhydride (XIII) in DMF.
【1】 Cossy, J.; Schmitt, A.; Cinquin, C.; Buisson, D.; Belotti, D.; A very short, efficient and inexpensive synthesis of the prodrug form of SC-54701A a platelet aggregation inhibitor. Bioorg Med Chem Lett 1997, 7, 13, 1699. |
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) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
(II) | 23897 | ethynyl(trimethyl)silane;trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
(III) | 23898 | ethyl 3-(trimethylsilyl)-2-propynoate | 29394-58-9 | C8H14O2Si | 详情 | 详情 |
(IV) | 23899 | lithium 1-ethoxy-1-ethylenolate | C4H7LiO2 | 详情 | 详情 | |
(V) | 23900 | ethyl 3-oxo-5-(trimethylsilyl)-4-pentynoate | C10H16O3Si | 详情 | 详情 | |
(VI) | 23901 | ethyl (3R)-3-hydroxy-5-(trimethylsilyl)-4-pentynoate | C10H18O3Si | 详情 | 详情 | |
(VIII) | 20989 | Diethylazadicarboxylate; Diethyl Azodiformate; Azodiformic Acid Diethyl Ester; Diethyl Azodicarboxylate; Azodicarboxylic Acid Diethyl Ester; Diethyl 1,2-diazenedicarboxylate | 1972-28-7 | C6H10N2O4 | 详情 | 详情 |
(IX) | 23904 | ethyl (3S)-3-amino-5-(trimethylsilyl)-4-pentynoate | C10H19NO2Si | 详情 | 详情 | |
(X) | 16297 | ethyl (3S)-3-amino-4-pentynoate | C7H11NO2 | 详情 | 详情 | |
(XI) | 16296 | 4-[4-[amino(imino)methyl]anilino]-4-oxobutyric acid | C11H13N3O3 | 详情 | 详情 | |
(XII) | 16295 | 4-aminobenzenecarboximidamide hydrochloride; 4-aminobenzamidine | 3858-83-1 | C7H9N3 | 详情 | 详情 |
(XIII) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |