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【结 构 式】 
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【分子编号】52106 【品名】2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine 【CA登记号】 |
【 分 子 式 】C5H11NO2 【 分 子 量 】117.14788 【元素组成】C 51.26% H 9.46% N 11.96% O 27.31% |
合成路线1
该中间体在本合成路线中的序号：(VII)Catalytic hydrogenation of methyl isobutyrylacetate (I) in the presence of chiral ruthenium catalyst afforded the (S)-hydroxy ester (II). Subsequent alkylation of the lithium enolate of (II) with 3-bromo-2-methyl-1-propene (III) proceeded with diastereoselectivity, yielding (IV). The olefin double bond of (IV) was then hydrogenated over Pd/C to provide the saturated compound (V). After basic hydrolysis of the methyl ester group of (V), the resultant carboxylic acid (VI) was coupled to O-tetrahydropyranylhydroxylamine (VII) to furnish the tetrahydropyranyl-protected hydroxamate (VIII). Conversion of (VIII) into the corresponding mesylate, followed by cyclization under basic conditions, gave rise to the azetidinone (IX). Further azetidinone ring opening under conditions of basic hydrolysis generated the N-hydroxyaminoacid derivative (X). This was converted to the formamide (XI) upon treatment with formic acetic anhydride in pyridine.
| 【1】 Chan, J.H.; Bubacz, D.G.; Andersen, M.W.; McDougald, D.L.; Stanford, J.B.; Andrews, R.C.; Gaul, M.D.; Rabinowitz, M.H.; Musso, D.L.; Cowan, D.J.; Wiethe, R.W. (GlaxoSmithKline plc); Reverse hydroxamate derivs. as metalloprotease inhibitors. EP 1019386; JP 2001513767; WO 9838179 . |
| 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) | 43331 | methyl 4-methyl-3-oxopentanoate | 42558-54-3 | C7H12O3 | 详情 | 详情 |
| (II) | 52102 | methyl (3S)-3-hydroxy-4-methylpentanoate | C7H14O3 | 详情 | 详情 | |
| (III) | 40015 | 3-bromo-2-methyl-1-propene | 1458-98-6 | C4H7Br | 详情 | 详情 |
| (IV) | 52103 | methyl (2R)-2-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-4-pentenoate | C11H20O3 | 详情 | 详情 | |
| (V) | 52104 | methyl (2R,3R)-3-hydroxy-2-isobutyl-4-methylpentanoate | C11H22O3 | 详情 | 详情 | |
| (VI) | 52105 | (2R,3R)-3-hydroxy-2-isobutyl-4-methylpentanoic acid | C10H20O3 | 详情 | 详情 | |
| (VII) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (VIII) | 52107 | (2R,3R)-3-hydroxy-2-isobutyl-4-methyl-N-(tetrahydro-2H-pyran-2-yloxy)pentanamide | C15H29NO4 | 详情 | 详情 | |
| (IX) | 52108 | (3R,4S)-3-isobutyl-4-isopropyl-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone | C15H27NO3 | 详情 | 详情 | |
| (X) | 52109 | (2R,3S)-2-isobutyl-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)amino]pentanoic acid | C15H29NO4 | 详情 | 详情 | |
| (XI) | 52110 | (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutyl-4-methylpentanoic acid | C16H29NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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 |
合成路线3
该中间体在本合成路线中的序号：(XIII)Displacement of the 4-fluoro group of (IX) with thiophenol (X) in the presence of K2CO3 led to the diaryl sulfide (XI). Acid (XII), prepared by alkaline hydrolysis of ester (XI), was then coupled to O-tetrahydropyranyl hydroxylamine (XIII) by means of EDC to furnish (XIV). Finally, acidic cleavage of the tetrahydropyranyl moiety produced the corresponding hydroxamic acid.
| 【1】 Becker, D.P.; Hockerman, S.L.; Barta, T.E.; et al.; Design and synthesis of beta-sulfone and alpha-sulfone hydroxamates as potent and orally active MMP inhibitors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 259. |
| 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) | 56377 | ethyl 4-[(4-fluorophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxylate | C17H20FNO4S | 详情 | 详情 | |
| (X) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (XI) | 56378 | ethyl 4-{[4-(phenylsulfanyl)phenyl]sulfonyl}-1-(2-propynyl)-4-piperidinecarboxylate | C23H25NO4S2 | 详情 | 详情 | |
| (XII) | 56379 | 4-{[4-(phenylsulfanyl)phenyl]sulfonyl}-1-(2-propynyl)-4-piperidinecarboxylic acid | C21H21NO4S2 | 详情 | 详情 | |
| (XIII) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (XIV) | 56380 | 4-{[4-(phenylsulfanyl)phenyl]sulfonyl}-1-(2-propynyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-piperidinecarboxamide | C26H30N2O5S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Acylation of 4-iodoaniline (I) with 3,4-dimethoxybenzenesulfonyl chloride (II), followed by basic methanolysis leads to sulfonamide (III). Heck coupling of aryl iodide (III) with acrylic acid (IV) in the presence of tris(dibenzylideneacetone)dipalladium and tri(o-tolyl)phosphine gives the cinnamic acid derivative (V). This is then coupled to the tetrahydropyranyl-protected hydroxylamine (VI) by means of EDC/HOBt to furnish (VII). The tetrahydropyranyl hydroxamate (VII) is finally deprotected under acidic conditions to produce the title compound.
| 【1】 Bouchain, G.; Leit, S.; Frechette, S.; et al.; Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. J Med Chem 2003, 46, 5, 820. |
| 【2】 Lavoie, R.; Bouchain, G.; Frechette, S.; et al.; Design and synthesis of a novel class of histone deacetylase inhibitors. Bioorg Med Chem Lett 2001, 11, 21, 2847. |
| 【3】 Delorme, D.; Ruel, R.; Lavoie, R.; Thibault, C.; Abou-Khalil, E. (MethylGene Inc.); Inhibitors of histone deacetylase. EP 1233958; JP 2003514904; WO 0138322 . |
| 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) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (II) | 47469 | 3,4-dimethoxybenzenesulfonyl chloride | 23095-31-0 | C8H9ClO4S | 详情 | 详情 |
| (III) | 63287 | N-(4-iodophenyl)-3,4-dimethoxybenzenesulfonamide | C14H14INO4S | 详情 | 详情 | |
| (IV) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (V) | 63288 | (E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-2-propenoic acid | C17H17NO6S | 详情 | 详情 | |
| (VI) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (VII) | 63289 | (E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)-2-propenamide | C22H26N2O7S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)Coupling between N-Boc-4-piperidinol (I) and 4-fluorobenzotrifluoride (II) in the presence of cesium carbonate afforded ether (III). Subsequent acidic cleavage of the Boc protecting group of (III) furnished piperidine (IV) (1). Acylation of piperidine (IV) with 3,4-dimethoxybenzenesulfonyl chloride (V) yielded the corresponding sulfonamide (VI). Regioselective metalation of (VI) by means of tert-butyllithium, followed by quenching with dry carbon dioxide gave rise to the carboxylic acid (VII). This was converted to the corresponding acid chloride (VIII) employing oxalyl chloride, and then condensed with O-tetrahydropyranylhydroxylamine (IX). The resultant tetrahydropyranyl-protected hydroxamate (X) was finally deprotected by treatment with an in situ generated solution of methanolic HCl.
| 【1】 Barta, T.E.; et al.; Selective, orally active MMP inhibitor with an aryl backbone. Bioorg Med Chem Lett 2001, 11, 18, 2481. |
| 【2】 Villamil, C.I.; Becker, D.P.; Bedell, L.J.; Freskos, J.N.; Rao, S.N.; Getman, D.P.; Decrescenzo, G.A.; Mischke, B.V.; Barta, T.E.; McDonald, J.J. (Pharmacia Corp.); Hydroxamic acid derivs. as matrix metalloprotease inhibitors. EP 1177173; WO 0069819 . |
| 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) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (II) | 52131 | 4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene | 402-44-8 | C7H4F4 | 详情 | 详情 |
| (III) | 52132 | tert-butyl 4-[4-(trifluoromethyl)phenoxy]-1-piperidinecarboxylate | C17H22F3NO3 | 详情 | 详情 | |
| (IV) | 52133 | 4-[4-(trifluoromethyl)phenoxy]piperidine; 4-piperidinyl 4-(trifluoromethyl)phenyl ether | C12H14F3NO | 详情 | 详情 | |
| (V) | 47469 | 3,4-dimethoxybenzenesulfonyl chloride | 23095-31-0 | C8H9ClO4S | 详情 | 详情 |
| (VI) | 52134 | 1-[(3,4-dimethoxyphenyl)sulfonyl]-4-piperidinyl 4-(trifluoromethyl)phenyl ether; 1-[(3,4-dimethoxyphenyl)sulfonyl]-4-[4-(trifluoromethyl)phenoxy]piperidine | C20H22F3NO5S | 详情 | 详情 | |
| (VII) | 52135 | 2,3-dimethoxy-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzoic acid | C21H22F3NO7S | 详情 | 详情 | |
| (VIII) | 52136 | 2,3-dimethoxy-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzoyl chloride | C21H21ClF3NO6S | 详情 | 详情 | |
| (IX) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (X) | 52137 | 2,3-dimethoxy-N-(tetrahydro-2H-pyran-2-yloxy)-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzamide | C26H31F3N2O8S | 详情 | 详情 |