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【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information