-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4-[4-[3-[4(R)-Methyl-2,5-dioxo-3-phenylimidazolidin-1-yl]propoxy]phenylsulfonyl]tetrahydro-2H-pyran-4-carbohydroxamic acid

【CA登记号】

【分子式】C₂₅H₂₉N₃O₈S

【分子量】531.58918

【开发单位】Pfizer (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, MMP-13 (Collagenase 3) Inhibitors

合成路线1 合成路线2

合成路线1

Tetrahydropyran-4-carboxylic acid tert-butyl ester (I) is treated with 4-fluorophenyl disulfide (II) in the presence of LDA to produce sulfide (III), which is further oxidized to the corresponding sulfone (IV) utilizing m-chloroperbenzoic acid. Displacement of the aryl fluoride (IV) with the sodium alkoxide of 3-(dibenzylamino)-1-propanol (V) affords the amino ether (VI). Debenzylation of (VI) by hydrogenation in the presence of Pd(OH)2/C gives the primary amine (VII). This is coupled with N-Boc-D-alanine (VIII) employing EDC to provide amide (IX). Cyclization of (IX) in the presence of DMAP, NMM and Boc2O leads to the N-protected hydantoin (X). The N-Boc group of (X) is then selectively removed by HCl in dioxane to furnish (XI).

参考文献中间体

【1】 Becker, D.P.; Villamil, C.; Barta, T.E.; et al.; Design and synthesis of potent and selective 4,4-disubstituted alpha-sulphones hydroxamates as MMP inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 309.

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)	58908	tert-butyl tetrahydro-2H-pyran-4-carboxylate		C₁₀H₁₈O₃	详情	详情
(II)	52287	bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene		C₁₂H₈F₂S₂	详情	详情
(III)	58809	allyl 3-({(tert-butoxycarbonyl)[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate		C₃₃H₅₀N₄O₈Si	详情	详情
(IV)	58910	tert-butyl 4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate		C₁₆H₂₁FO₅S	详情	详情
(V)	58911	3-(Dibenzylamino)-1-propanol		C₁₇H₂₁NO	详情	详情
(VI)	58912	tert-butyl 4-({4-[3-(dibenzylamino)propoxy]phenyl}sulfonyl)tetrahydro-2H-pyran-4-carboxylate		C₃₃H₄₁NO₆S	详情	详情
(VII)	58913	tert-butyl 4-{[4-(3-aminopropoxy)phenyl]sulfonyl}tetrahydro-2H-pyran-4-carboxylate		C₁₉H₂₉NO₆S	详情	详情
(VIII)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(IX)	58914	tert-butyl 4-({4-[3-({(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl}amino)propoxy]phenyl}sulfonyl)tetrahydro-2H-pyran-4-carboxylate		C₂₇H₄₂N₂O₉S	详情	详情
(X)	58915	tert-butyl (5R)-3-[3-(4-{[4-(tert-butoxycarbonyl)tetrahydro-2H-pyran-4-yl]sulfonyl}phenoxy)propyl]-5-methyl-2,4-dioxo-1-imidazolidinecarboxylate		C₂₈H₄₀N₂O₁₀S	详情	详情
(XI)	58916	tert-butyl 4-[(4-{3-[(4R)-4-methyl-2,5-dioxoimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate		C₂₃H₃₂N₂O₈S	详情	详情

合成路线2

N-Arylation of hydantoin (XI) with phenylboronic acid in the presence of cupric acetate gives rise to the N-phenyl hydantoin (XII). Subsequent hydrolysis of the tert-butyl ester with trifluoroacetic acid in CH2Cl2 affords acid (XIII). This is then coupled with O-(tetrahydropyranyl)-hydroxylamine, yielding the tetrahydropyranyl-protected hydroxamic acid (XIV). Finally, removal of the tetrahydropyranyl protecting group of (XIV) under acidic conditions provides the title compound.

参考文献中间体

【1】 Becker, D.P.; Villamil, C.; Barta, T.E.; et al.; Design and synthesis of potent and selective 4,4-disubstituted alpha-sulphones hydroxamates as MMP inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 309.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	58916	tert-butyl 4-[(4-{3-[(4R)-4-methyl-2,5-dioxoimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate	C₂₃H₃₂N₂O₈S	详情	详情
(XII)	58917	tert-butyl 4-[(4-{3-[(4R)-4-methyl-2,5-dioxo-3-phenylimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate	C₂₉H₃₆N₂O₈S	详情	详情
(XIII)	58918	4-[(4-{3-[(4R)-4-methyl-2,5-dioxo-3-phenylimidazolidinyl]propoxy}phenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid	C₂₅H₂₈N₂O₈S	详情	详情
(XIV)	58919	4-[(4-{3-[(4R)-4-methyl-2,5-dioxo-3-phenylimidazolidinyl]propoxy}phenyl)sulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-4-carboxamide	C₃₀H₃₇N₃O₉S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)