【结 构 式】 |
【分子编号】67732 【品名】(4aR,11aS,12aR,13R)-3-(benzyloxy)-13- (dimethylamino)-10-fluoro-4a,5,7-trihydroxy- 11,11a,12,12a,13,13a-hexahydrotetraceno[2,3-d] isoxazole-4,6(3aH,4aH)-dione 【CA登记号】 |
【 分 子 式 】C28H25FN2O7 【 分 子 量 】520.514 【元素组成】C 64.61% H 4.84% F 3.65% N 5.38% O 21.52% |
合成路线1
该中间体在本合成路线中的序号:(VIII)Lithiationof 5-fluoro-2-methoxybenzoic acid (I) with sec-BuLi in the presence of TMEDA in THF, followed by methylation of the resulting anion with methyliodide, gives 3-fluoro-6-methoxy-2-methylben methyl benzoic acid (II). Chlorination of carboxylic acid (II) with (COCl)2 in the presence of DMF in CH2Cl2 and subsequent reaction of the resulting acid chloride with PhOH by means of Et3N and DMAP in CH2Cl2 provides the corresponding phenyl ester (III). O-Demethylation of ether (III) by means of BBr3 in CH2Cl2 at −78° Cyields the 6-hydroxybenzoate (IV),which is then protected with Boc2O and DMAP in CH2Cl2 to generate the tert-butyl carbonate (V). Treatment of compound (V) with LDA and TMEDA in THF at −78°C, followed by coupling with enone (VI) in THF, produces the tetraceno[2,3-d] isoxazole derivative (VII),which is subsequently deprotected with HF and TFA in acetonitrile to give the octa hydrotetracene derivative (VIII). Reductive cleavage of the isoxazolering of tetracycline (VIII) with H2 over Pd/Cin methanol/dioxane affords the 2-hydroxyamide (IX),which by nitration with HNO3 and H2SO4 affords the 9-nitro-tetracycline derivative (X). Reduction of the nitro group of compound(X) with H2 over Pd/Cin methanol/dioxane gives the corresponding amine(XI).Then, reaction of amine (XI) with bromoacetyl bromide(XII) in the presence of Na2CO3 in DMPU/acetonitrile provides the bromoacetamide(XIII), which is finally condensed with pyrrolidine(XIV). Alternatively,amine(XI) is directly condensed withp yrrolidin-1-ylacetyl chloride(XV) orits hydrochloride salt in DMF.
【1】 Zhou,J.,Xiao,X.-Y.,Plamondon,L.,Hunt,D.K.,Clark,R.B.,Zahler,R.B. (TetraphasePharmaceuticals, Inc.). CA2732883, CN102177134, EP 2323972,EP2682387, JP2011530534, KR2011058800, US2010105671, US2012302527, US2013109657, US8501716,WO 2010017470. |
【2】 Xiao,X.Y.,Hunt,D.K.,Zhou,J. etal.Fluorocyclines.1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: A potent, broad spectrum antibacterial agent. JMed Chem 2012, 55(2):597-605. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(III) | 67727 | phenyl 3-fluoro-6-methoxy-2-methylbenzoate | C15H13FO3 | 详情 | 详情 | |
(V) | 67729 | phenyl 6-((tert-butoxycarbonyl)oxy)-3-fluoro-2-methylbenzoate | C19H19FO5 | 详情 | 详情 | |
(I) | 67725 | 5-fluoro-2-methoxybenzoic acid;2-Methoxy-5-fluorobenzoic acid | 394-04-7 | C8H7FO3 | 详情 | 详情 |
(II) | 67726 | 3-fluoro-6-methoxy-2-methylbenzoic acid | C9H9FO3 | 详情 | 详情 | |
(IV) | 67728 | phenyl 3-fluoro-6-hydroxy-2-methylbenzoate | C14H11FO3 | 详情 | 详情 | |
(VI) | 67730 | (4aR,8aR,9R)-3-(benzyloxy)-4a-((tert- butyldimethylsilyl)oxy)-9-(dimethylamino)-8,8a,9,9a- tetrahydronaphtho[2,3-d]isoxazole-4,5(3aH,4aH)-dione | C26H34N2O5Si | 详情 | 详情 | |
(VII) | 67731 | (4aR,11aS,12aR,13R)-3-(benzyloxy)-4a-((tert- butyldimethylsilyl)oxy)-13-(dimethylamino)-10- fluoro-5-hydroxy-4,6-dioxo- 3a,4,4a,6,11,11a,12,12a,13,13a-decahydrotetraceno [2,3-d]isoxazol-7-yl tert-butyl carbonate | C39H47FN2O9Si | 详情 | 详情 | |
(VIII) | 67732 | (4aR,11aS,12aR,13R)-3-(benzyloxy)-13- (dimethylamino)-10-fluoro-4a,5,7-trihydroxy- 11,11a,12,12a,13,13a-hexahydrotetraceno[2,3-d] isoxazole-4,6(3aH,4aH)-dione | C28H25FN2O7 | 详情 | 详情 | |
(IX) | 67733 | (4R,4aR,5aS,12aR)-4-(dimethylamino)-7-fluoro- 3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2- carboxamide | C21H23FN2O7 | 详情 | 详情 | |
(X) | 67734 | (4R,4aR,5aS,12aR)-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide | C21H22FN3O9 | 详情 | 详情 | |
(XI) | 67735 | (4R,4aR,5aS,12aR)-9-amino-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide | C21H24FN3O7 | 详情 | 详情 | |
(XII) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
(XIII) | 67736 | (4R,4aR,5aS,12aR)-9-(2-bromoacetamido)-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide | C23H25BrFN3O8 | 详情 | 详情 | |
(XIV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
(XV) | 67737 | 2-(pyrrolidin-1-yl)acetyl chloride | C6H10ClNO | 详情 | 详情 |