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【结 构 式】

【药物名称】GW-4459

【化学名称】Nalpha-[3(S)-(N-Formyl-N-hydroxyamino)-2(R)-isobutylhexanoyl]-Nomega'-nitro-N1-(2-thiazolyl)-L-argininamide

【CA登记号】260270-56-2

【 分 子 式 】C20H34N8O6S

【 分 子 量 】514.60798

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Antiarthritic Drugs, Oncolytic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Matrix Metalloproteinase Inhibitors, TNF-alpha-Converting Enzyme (TACE) Inhibitors

合成路线1

Hydrogenation of methyl butyrylacetate (I) in the presence of the chiral catalyst [RuCl2(BINAP)]2.Et3N furnished the (R)-hydroxyester (II). Alkylation of (II) with 3-bromo-2-methyl-1-propene (III) in the presence of lithium diisopropylamide gave the isobutenyl derivative (IV), which was further hydrogenated to (V) in the presence of Pd/C. After basic hydrolysis of the methyl ester of (V), the resulting carboxylic acid (VI) was coupled with 2-tetrahydropyranyloxyamine by means of EDC to provide the tetrahydropyranyl-protected hydroxamic acid (VII). Mesylation of the free hydroxyl group of (VII) to give (VIII), followed by its cyclization in the presence of potassium carbonate, gave rise to the azetidinone (IX). Opening of the lactam ring of (IX) with NaOH afforded the protected hydroxyamino acid (X). Then, formylation of the amino group with formic acetic anhydride in pyridine provided intermediate (XI).

1 Wiethe, R.W.; Andrews, R.C.; Rabinowitz, M.H.; Musso, D.L.; Chan, J.H.; McDougald, D.L.; Gaul, M.D.; Cowan, D.J.; Stanford, J.B.; Babacz, D.G.; Andersen, M.W. (Glaxo Group Ltd.); Formamide cpds. as therapeutic agents. US 6191150; WO 0012466 .
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) 44115 methyl 3-oxohexanoate 30414-54-1 C7H12O3 详情 详情
(II) 44116 methyl (3R)-3-hydroxyhexanoate C7H14O3 详情 详情
(III) 40015 3-bromo-2-methyl-1-propene 1458-98-6 C4H7Br 详情 详情
(IV) 44117 methyl (2R)-2-[(1R)-1-hydroxybutyl]-4-methyl-4-pentenoate C11H20O3 详情 详情
(V) 44118 methyl (2R,3R)-3-hydroxy-2-isobutylhexanoate C11H22O3 详情 详情
(VI) 44119 (2R,3R)-3-hydroxy-2-isobutylhexanoic acid C10H20O3 详情 详情
(VII) 44120 (2R,3R)-3-hydroxy-2-isobutyl-N-(tetrahydro-2H-pyran-2-yloxy)hexanamide C15H29NO4 详情 详情
(VIII) 44121 (1R,2R)-4-methyl-1-propyl-2-[[(tetrahydro-2H-pyran-2-yloxy)amino]carbonyl]pentyl methanesulfonate C16H31NO6S 详情 详情
(IX) 44122 (3R,4S)-3-isobutyl-4-propyl-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone C15H27NO3 详情 详情
(X) 44123 (2R,3S)-2-isobutyl-3-[(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid C15H29NO4 详情 详情
(XI) 44124 (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid C16H29NO5 详情 详情

合成路线2

Coupling of N(alpha)-Boc-N(G)-nitro-L-arginine (XII) with 2-aminothiazole (XIII) gave amide (XIV). After cleavage of the Boc group of (XIV) with HCl, the resulting amine (XV) was coupled with the intermediate carboxylic acid (XI) using diethyl cyanophosphonate to afford adduct (XVI). The terahydropyranyl group of (XVI) was finally deprotected by treatment with aqueous acetic acid.

1 Wiethe, R.W.; Andrews, R.C.; Rabinowitz, M.H.; Musso, D.L.; Chan, J.H.; McDougald, D.L.; Gaul, M.D.; Cowan, D.J.; Stanford, J.B.; Babacz, D.G.; Andersen, M.W. (Glaxo Group Ltd.); Formamide cpds. as therapeutic agents. US 6191150; WO 0012466 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 29372 N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine C11H21N5O6 详情 详情
(XIII) 19795 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine 96-50-4 C3H4N2S 详情 详情
(XIV) 44125   C14H23N7O5S 详情 详情
(XV) 44126   C9H15N7O3S 详情 详情
(XVI) 44124 (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid C16H29NO5 详情 详情
(XVII) 44127   C25H42N8O7S 详情 详情

合成路线3

The alkylation of 3(R)-hydroxyhexanoic acid methyl ester (I) with isobutyl bromide (II) and LDA in THF gives 3(R)-hydroxy-2(R)-isobutylhexanoic acid methyl ester (III), which is hydrolyzed with LiOH in THF/MeOH/water to yield the corresponding lithium salt (IV). The condensation of (IV) with O-tetrahydropyranyl-hydroxylamine (V) by means of DCC in ethyl acetate affords the protected hydroxamic acid (VI), which is treated with Ms-Cl and pyridine to provide the mesylate (VII). The cyclization of (VII) by means of K2CO3 in refluxing acetone gives the chiral azetidinone (VIII), which is opened by means of NaOH in dioxane/water, yielding the carboxylic acid (IX). The formylation of the NH group of (IX) with acetic formic anhydride and pyridine in dichloromethane affords the intermediate (X). The condensation of the N-protected nitro arginine (XI) with 2-aminothiazole (XII) by means of EDC in DMF gives the argininamide (XIII), which is deprotected by means of HCl in dioxane to yield the intermediate (XIV). Condensation of (XIV) with (X) by means of diethyl phosphorylcyanide (DEPC) and NMM in DMF gives the protected dipeptide (XV), which is treated with AcOH in warm water to yield the target dipeptide.

1 Rabinowitz, M.H.; Andrews, R.C.; Becherer, J.D.; et al.; Design of selective and soluble inhibitors of tumor necrosis factor-alpha converting enzyme (TACE). J Med Chem 2001, 44, 24, 4252.
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) 44116 methyl (3R)-3-hydroxyhexanoate C7H14O3 详情 详情
(II) 24599 1-bromo-2-methylpropane 78-77-3 C4H9Br 详情 详情
(III) 44118 methyl (2R,3R)-3-hydroxy-2-isobutylhexanoate C11H22O3 详情 详情
(IV) 62871   C10H19LiO3 详情 详情
(V) 52106 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine C5H11NO2 详情 详情
(VI) 44120 (2R,3R)-3-hydroxy-2-isobutyl-N-(tetrahydro-2H-pyran-2-yloxy)hexanamide C15H29NO4 详情 详情
(VII) 44121 (1R,2R)-4-methyl-1-propyl-2-[[(tetrahydro-2H-pyran-2-yloxy)amino]carbonyl]pentyl methanesulfonate C16H31NO6S 详情 详情
(VIII) 44122 (3R,4S)-3-isobutyl-4-propyl-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone C15H27NO3 详情 详情
(IX) 44123 (2R,3S)-2-isobutyl-3-[(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid C15H29NO4 详情 详情
(X) 44124 (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid C16H29NO5 详情 详情
(XI) 29372 N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine C11H21N5O6 详情 详情
(XII) 19795 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine 96-50-4 C3H4N2S 详情 详情
(XIII) 44125   C14H23N7O5S 详情 详情
(XIV) 44126   C9H15N7O3S 详情 详情
(XV) 44127   C25H42N8O7S 详情 详情
Extended Information