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【结 构 式】 
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【药物名称】NAPAP-PS 【化学名称】4-[2-[2(R)-[N-[1-(4-Amidinobenzyl)-2-oxo-2-(1-piperidinyl)ethyl]carbamoyl]-2-(2-naphthylsulfonamido)ethylsulfanyl]acetamido]-N-[11-(1-O-methyl-2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl)(4--1)(3-O-methyl-2-O-sulfo-alpha-L-idopyranosyluronic acid)(4--1)(2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl)(4--1)(3-O-methyl-2-O-sulfo-beta-D-glucopyranosyluronic acid)(4--1)(2,3,6-tri-O-sulfo-alpha-D-glucopyranos-4-yloxy)]-3,6,9-trioxaundecyl]benzamide 【CA登记号】244606-25-5 (free acid) 【 分 子 式 】C78H96N7Na13O70S13 【 分 子 量 】2967.33912 |
【开发单位】Organon (Originator), Universiteit Leiden (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Heparins, Thrombin Inhibitors |
合成路线1
Condensation of S-(4-monomethoxytrityl)-L-cysteine (I) with 2-naphthalenesulfonyl chloride (II) under Schotten-Baumann conditions afforded sulfonamide (III). Cleavage of the trityl group of (III) by treatment with trifluoroacetic acid and triisopropylsilane gave thiol (IV), which was protected as the thiopyridyl derivative (V) using dithiodipyridine. Coupling of (V) with 4-amidinophenylalanyl piperidine (VI) by means of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide - HCl (EDC), 1-hydroxybenzotriazole (HOBt) and N-ethylmorpholine (NEM) furnished dipeptide (VII). The thiopyridyl group of (VII) was then deprotected by treatment with tributyl phosphine to afford thiol (VIII).
| 【1】 Buijsman, R.C.; van Boeckel, C.A.A.; van der Marel, G.A.; Basten, J.E.M.; van Dinther, T.G.; van Boom, J.H.; Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg Med Chem Lett 1999, 9, 14, 2013. |
| 【2】 Van Boeckel, C.A.A.; Basten, J.E.M.; Dreef-Tromp, C.M.; Buijsman, R.C. (Akzo Nobel N.V.; Universiteit Leiden); Antithrombotic cpds.. WO 9965934 . |
| 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) | 22457 | 2,2'-Dithiodipyridine; 2-(2-pyridinyldisulfanyl)pyridine; 2,2'-Dipyridinyl disulfide | 2127-03-9 | C10H8N2S2 | 详情 | 详情 |
| (I) | 37316 | (2R)-2-amino-3-[[(4-methoxyphenyl)(diphenyl)methyl]sulfanyl]propionic acid | C23H23NO3S | 详情 | 详情 | |
| (II) | 27989 | 2-naphthalenesulfonyl chloride | 93-11-8 | C10H7ClO2S | 详情 | 详情 |
| (III) | 37317 | (2R)-3-[[(4-methoxyphenyl)(diphenyl)methyl]sulfanyl]-2-[(2-naphthylsulfonyl)amino]propionic acid | C33H29NO5S2 | 详情 | 详情 | |
| (IV) | 37318 | (2R)-2-[(2-naphthylsulfonyl)amino]-3-sulfanylpropionic acid | C13H13NO4S2 | 详情 | 详情 | |
| (V) | 37319 | (2R)-2-[(2-naphthylsulfonyl)amino]-3-(2-pyridinyldisulfanyl)propionic acid | C18H16N2O4S3 | 详情 | 详情 | |
| (VI) | 37320 | 4-[2-amino-3-oxo-3-(1-piperidinyl)propyl]benzenecarboximidamide | C15H22N4O | 详情 | 详情 | |
| (VII) | 37321 | (2R)-N-[1-[4-[amino(imino)methyl]benzyl]-2-oxo-2-(1-piperidinyl)ethyl]-2-[(2-naphthylsulfonyl)amino]-3-(2-pyridinyldisulfanyl)propanamide | C33H36N6O4S3 | 详情 | 详情 | |
| (VIII) | 37322 | (2R)-N-[1-[4-[amino(imino)methyl]benzyl]-2-oxo-2-(1-piperidinyl)ethyl]-2-[(2-naphthylsulfonyl)amino]-3-sulfanylpropanamide | C28H33N5O4S2 | 详情 | 详情 |
合成路线2
The known pentasaccharide (IX) was reacted with N-(benzyloxycarbonyl)succinimide (X) yielding carbamate (XI). Sulfation of the free hydroxyl groups of (XI) with triethylamine-sulfur trioxide complex gave the sulfated compound which, after acid cleavage of the formed N-SO3- groups, was converted to the corresponding sodium salt (XII). Hydrogenolysis of the N-benzyloxycarbonyl group then liberated amine (XIII).
| 【1】 Buijsman, R.C.; van Boeckel, C.A.A.; van der Marel, G.A.; Basten, J.E.M.; van Dinther, T.G.; van Boom, J.H.; Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg Med Chem Lett 1999, 9, 14, 2013. |
| 【2】 Van Boeckel, C.A.A.; Basten, J.E.M.; Dreef-Tromp, C.M.; Buijsman, R.C. (Akzo Nobel N.V.; Universiteit Leiden); Antithrombotic cpds.. WO 9965934 . |
合成路线3
Amine (XIII) was coupled with the 4-(iodoacetamido)benzoic acid active ester (XIV) to produce amide (XV).
| 【1】 Buijsman, R.C.; van Boeckel, C.A.A.; van der Marel, G.A.; Basten, J.E.M.; van Dinther, T.G.; van Boom, J.H.; Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg Med Chem Lett 1999, 9, 14, 2013. |
| 【2】 Van Boeckel, C.A.A.; Basten, J.E.M.; Dreef-Tromp, C.M.; Buijsman, R.C. (Akzo Nobel N.V.; Universiteit Leiden); Antithrombotic cpds.. WO 9965934 . |
合成路线4
Displacement of the iodide of (XV) by thiol (VIII) gave rise to the title sulfide derivative.
| 【1】 Buijsman, R.C.; van Boeckel, C.A.A.; van der Marel, G.A.; Basten, J.E.M.; van Dinther, T.G.; van Boom, J.H.; Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg Med Chem Lett 1999, 9, 14, 2013. |
| 【2】 Van Boeckel, C.A.A.; Basten, J.E.M.; Dreef-Tromp, C.M.; Buijsman, R.C. (Akzo Nobel N.V.; Universiteit Leiden); Antithrombotic cpds.. WO 9965934 . |