| (11) | EP 2 981 260 B1 |
(12) | EUROPEAN PATENT SPECIFICATION |
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(54) | NOVEL ANALOGUES OF EPICATECHIN AND RELATED POLYPHENOLS NEUARTIGE EPICATECHIN-ANALOGA UND ZUGEHÖRIGE POLYPHENOLE NOUVEAUX ANALOGUES D'ÉPICATÉCHINE ET POLYPHÉNOLS ASSOCIÉS |
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Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
OBJECT OF THE INVENTION
SUMMARY OF THE INVENTION
1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;
1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;
1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;
1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;
1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;
1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;
1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;
1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;
1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;
1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;
1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;
1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;
1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;
1021 Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;
1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;
1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;
1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;
1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;
1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;
1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;
1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;
1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;
1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;
1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;
1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;
1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and
1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
comprising the steps of:
1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;
1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;
1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;
1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;
1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;
1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;
1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;
1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;
1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;
1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;
1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;
1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;
1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;
1021 Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;
1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;
1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;
1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;
1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;
1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;
1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;
1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;
1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;
1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;
1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;
1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;
1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and
1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol.
DETAILED DESCRIPTION OF EXAMPLES
A is independently deuterium, hydrogen, alkyl, F, Cl
B is independently A or hydroxyl; OR11, NR11R12
R1 to R10 are independently hydrogen; deuterium, NH2, F, Cl, hydroxyl, alkoxy, lower acyclic or cyclic alkyl, lower acyclic or cyclic acyl, -CO-OR11, -OCO-OR11, -CO-NR11R12, -COR11,-CR11R12, -O-CO-R11, -CR11R12, -O-CO-NR11R12, OCONHCHR11R12, -OCR11R12, -O-CO-R11R12, -CO-aminoacid; or -CO-hydroxyacid; which may be optionally substituted with lower alkyl, acyl, alkoxy, OR11, NR11R12, COOR11, CONR11R12, OCOR11R12, OCONR11R12, OSO3R11, OSO2NR11R12, NR11SO2NR12, NR11SO3R12;
When any two adjacent R1 to R6 are either OH or NHR11, these may be additionally be joined together by a CR11R12, -(C=O)n, -CO(CH2)n-,-C=S, C=NR12 or -OSO3-; wherein n=1 to 2.
A is independently deuterium, hydrogen, alkyl, F, Cl;
B is independently A or hydroxyl; OR11, NR11R12;
R1 to R7 and R9 are independently; H, D, NH2, F, Cl, hydroxyl, -CO-OR11, -CO-NR11R12, OCONHCHR11R12, -COR11, -CR11R12, -O-CO-R11, -CR11R12, -O-CO-NR11-R12, -OCR11R12,-O-CO-R11R12;
R11 and R12 are independently hydrogen, OH, halo, C1-6 alkyl, aryl, alkaryl , arylalkyl, substituted alkyl, which may be straight, branched chain or cyclic, C1-6 alkoxy which may be straight, branched chain or cyclic, COOR13, CH2COOR13, C(R13)2OCOR13, C(R13)2OCOOR13, C(R13)2OCON(R13)2, C(R13)2N(R13)COOR13 or haloalkyl, aryl, substituted aryl, or R11 and R12 taken together with the atoms to which they may attach to form a 5- to 7-member ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is optionally substituted with further substituents
or A and R6 may form an oxime;
R13 is independently hydrogen, lower straight or branched alkyl, substituted or unsubstituted aryl or benzyl, when two R13 groups are present on the same atom, they can be joined to form a 3 to 6 membered ring;
Where substitution at C2 and C3 of pyran ring is always cis (+) or cis (-) or mixture of two. In other words, absolute configuration at C2 and C3 of pyran ring may either have RR or SS stereochemistry or a racemic mixture of RR and SS.
Compounds of the present invention:
1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;
1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;
1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;
1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;
1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;
1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;
1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;
1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;
1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;
1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;
1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;
1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;
1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;
1021 Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;
1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;
1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;
1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;
1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;
1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;
1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;
1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;
1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;
1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;
1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;
1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;
1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and
1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol.
SPR No | Structure | Chemical name | Molecular Formula | Mol. Weight |
1001 |
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(R,E)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman- 3 -one oxime | C15H13NO6 | 303.07 |
1002 |
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Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol | C15H14O4 | 258.09 |
1003 |
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Cis (±) 2-(3,4-dihydroxyphenyl)chroma n-3,7-diol | C15H14O5 | 274.08 |
1004 |
|
Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol | C15H14O4 | 258.09 |
1005 |
|
Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol | C15H14O4 | 258.27 |
1006 |
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Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol | C15H14O4 | 258.27 |
1007 |
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Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol | C15H14O4 | 258.27 |
1008 |
|
Cis (±) 2-(4-hydroxyphenyl)chroman-3,5,7-triol | C15H14O5 | 274.27 |
1009 |
|
(2R,3S)-2-(3,4-dihydroxyphenyl)-3-methylchroman-3,5,7-triol | C17H18NO7 | 348.11 |
1010 |
|
(2R,3R)-2-(2,3-dihydroxyphenyl)-3-fluorochroman-5,7-diol | C15H13FO5 | 292.07 |
1011 |
|
Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol | C15H14O3 | 242.09 |
1012 |
|
Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol | C15H14O3 | 242.09 |
1013 |
|
Cis (±) 2-(3,4-dihydroxyphenyl)chroma n-3,5-diol | C15H14O5 | 274.08 |
1014 |
|
Cis (±) 2-(3-hydroxyphenyl)chroman-3,5,7-triol | C15H14O5 | 274.08 |
1015 |
|
Cis (±) 2-phenylchroman-3,5,7-triol | C15H14O4 | 258.1 |
1016 |
|
Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol | C16H16O4 | 272.1 |
1017 |
|
Cis (±) 2-(4-methoxyphenyl)chroman -3,7-diol | C16H16O4 | 272.1 |
1018 |
|
Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol | C16H16O4 | 272.1 |
1019 |
|
Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman -3-ol | C17H18O4 | 286.12 |
1020 |
|
Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl) chromane | C18H20O4 | 300.14 |
1021 |
|
Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate | C17H16O5 | 300.1 |
1022 |
|
Cis (±)3-(3,7-dihydroxychroman-2-yl)phenyl acetate | C17H16O5 | 300.1 |
1023 |
|
Cis (±) 3-hydroxy-2-(4-hydroxyphenyl)chroman-7-yl acetate | C17H16O5 | 300.1 |
1024 |
|
Cis (±)3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate | C19H18O6 | 342.11 |
1025 |
|
Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate | C21H20O7 | 384.12 |
1026 |
|
2-(3-methoxy-4-methylphenyl)chromane-3,7-diol | C17H18O4 | 286.12 |
1027 |
|
2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol | C16H16O4 | 272.10 |
1028 |
|
2-(4-fluoro-3-methoxyphenyl)chroman e-3,7-diol | C16H15FO4 | 290.10 |
1029 |
|
2-(4-fluoro-3-hydroxyphenyl)chromane -3,7-diol | C15H13FO4 | 276.08 |
1030 |
|
2-(3-hydroxyphenyl)-3-propoxychroman-7-ol | C18H20O4 | 300.14 |
1031 |
|
Cis (±) 2-(3,4-dihydroxy-2-methylphenyl)chroman-3,5,7-triol | C16H16O6 | 304.29 |
1032 |
|
Cis (±) 2-(2-fluoro-3,4-dihydroxyphenyl)chroma n-3,5,7-triol | C15H13FO6 | 308.07 |
1033 |
|
Cis (±) 2-(2-fluoro-4,5-dihydroxyphenyl)chroma ne-3,5,7-triol | C15H13FO6 | 308.07 |
1034 |
|
Cis (±) 2-(3-fluoro-4-hydroxyphenyl)chromane -3,5,7-triol | C15H13FO5 | 292.07 |
1035 |
|
Cis(±) (2-(3,4-dihydroxy-5-methylphenyl)chromane-3,5,7-triol | C16H16O6 | 304.09 |
1036 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)chroma ne-4,4-d2-3,5,7-triol | C15H12D2O6 | 292.09 |
1037 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)chroma ne-2-d-3,5,7-triol | C15H13DO6 | 291.09 |
1038 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)chroma ne-2,4-d2-3,5,7-triol | C15H12D2O6 | 292.09 |
1039 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isobutyl carbonate | C20H22O8 | 390.13 |
1040 |
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tert-butyl (2-hydroxy-5-(2R,3R)-3,5,7-trihydroxychroman-2yl)phenyl)carbonate | ||
1041 |
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3-((((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)carbonyl)-1-methylpyridin-1-ium | C22H20INO7+ | 537.03 |
1042 |
|
2-hydroxy-5-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenyl neopentyl carbonate | C21H24O8 | 404.15 |
1043 |
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2-hydroxy-4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenyl octanoate | C23H28O7 | 416.18 |
1044 |
|
4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene bis(isopropylcarbamate) | C23H28N2O8 | 460.18 |
1045 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl neopentyl carbonate | C21H24O8 | 404.15 |
1046 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isopropylcarbamate | C19H21NO7 | 375.13 |
1047 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl dimethylcarbamate | C18H19NO7 | 361.12 |
1048 |
|
dibenzyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) | C31H26O10 | 558.15 |
1049 |
|
dimethyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) | C19H18O10 | 406.09 |
1050 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diisobutyl bis(carbonate) | C25H30O10 | 490.18 |
1051 |
|
4-((2R,3R)-5,7-bis((benzylcarbamoyl)ox y)-3-hydroxychroman-2-yl)-1,2-phenylene bis(benzylcarbamate) | C47H42N4O10 | 822.29 |
1052 |
|
dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl )oxy)-3-hydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) | C47H38O14 | 826.23 |
1053 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl ethyl carbonate | C18H18O8 | 362.10 |
1054 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diisobutyl bis(carbonate) | C25H30O10 | 490.18 |
1055 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isopropyl carbonate | C19H20O8 | 376.12 |
1056 |
|
methyl ((((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)carbonyl)glycinat e | C19H19NO9 | 405.11 |
1057 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diethyl bis(carbonate) | C21H22O10 | 434.12 |
1058 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl dimethyl bis(carbonate) | C19H18O10 | 406.09 |
1059 |
|
4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene bis(benzylcarbamate) | C31H28N2O 8 | 556.18 |
1060 |
|
dibenzyl (4-((2R,3R)-3-hydroxy-5,7-bis((isobutoxycarbonyl)o xy)chroman-2-yl)-1,2-phenylene) bis(carbonate) | C41H42O14 | 758.26 |
1061 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl heptanoate | C22H26O7 | 402.17 |
1062 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl) -3,5-dihydroxychroman-7-yl heptanoate | C22H26O7 | 402.17 |
1063 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diheptanoate | C29H38O8 | 514.26 |
1064 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl octanoate | C23H28O7 | 416.18 |
1065 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl octanoate | C23H28O7 | 416.18 |
1066 |
|
dibenzyl (4-((2R,3R)-3-hydroxy-5,7-bis((methoxycarbonyl)ox y)chroman-2-yl)-1,2-phenylene) bis(carbonate) | C35H30O14 | 674.16 |
1067 |
|
(2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane | C20H24O4 | 328.17 |
1068 |
|
(2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol | C19H22O4 | 314.15 |
1069 |
|
(2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol | C16H16O4 | 272.10 |
1070 |
|
(2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman -3-ol | C17H18O4 | 286.12 |
1071 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl nicotinate | C21H17NO7 | 395.10 |
1072 |
|
dineopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) | C27H34O10 | 518.22 |
1073 |
|
tert-butyl ((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl) carbonate | C20H22O8 | 390.13 |
1074 |
|
(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl (R)-3-hydroxybutanoate | C19H20O8 | 376.12 |
1075 |
|
diisopropyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) | C23H26O10 | 462.15 |
1076 |
|
dineopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) | C27H34O10 | 518.22 |
Step 1: Hydroxyl groups of an acetophenone of Formula 1 is optionally protected with a protecting agent in presence of a base and a solvent;
The protecting agent is preferably a benzylating agent such as benzyl bromide in presence of suitable base such as potassium carbonate in presence of suitable solvent such as dimethylformamide or acetone at ambient temperature may be converted to a compound having protected hydroxyl group. The protected compound is further converted to chalcone of formula [3] in presence of suitable base such as NaOH, KOH, or piperidine in presence of suitable solvents as such MeOH, EtOH, THF at an ambient temperature;
Step 2: Chalcone of formula [3] may be converted into compound [4] in presence of suitable base such as NaOH, in presence of suitable epoxidizing agent such as hydrogen peroxide and in presence of suitable solvent such as MEOH or EtOH.
Step 3: Compound of formula [4] may be treated with a protecting agent to protect the hydroxyl group(s) if any, preferably with a benzylating agent such as benzyl bromide in presence of suitable base such as potassium carbonate in presence of suitable solvent such as dimethylformamide or acetone at ambient temperature may be converted to a compound [5] having protected hydroxyl group;
Step 4: Compound [5] may be converted to mixture of compound [6] and [7] in presence of chiral/achiral reducing agents such as lithium aluminum hydride/deutride in solvents such as THF or ether at a temperature ranging from ambient to reflux.
Step 5: Compounds [6] and [7] may be converted to compound [8] and [9] on deprotection. 4H-chromene and 2H-chromene compounds obtained in step 4 when subjected to hydrogenation in presence of palladium on carbon in presence of hydrogen atmosphere or palladium hydroxide at a temperature ranging from ambient to 60°C is converted to polyphenol analogues.
Step 1: Chalcone 3 which may be synthesized as described in synthetic scheme 1, on treatment with a reducing reagent such as NaBH4 may be converted to 10 in presence of a suitable solvent such as EtOH or MeOH at temperature ranging from ambient to reflux.
Step 2: Compound 10 may be converted to compound of general formula 11 in presence of suitable reagents such as OsO4, with or without chiral co-catalysts such as AD-mix-α or AD-mix-β in presence of suitable solvent such as THF at a temperature ranging from ambient to reflux.
Step 3: Compound 11 may be converted to 12 when treated with suitable reducing agents such as NaCNBH3 in presence of suitable solvents as AcOH or THF at ambient temperature.
Step 4: Compound 12 may be converted to compound 13 in presence of suitable oxidizing agents such as dess-martin periodinane in presence of suitable solvents such as THF or DCM.
Step 5: Compound [13] may be converted to compound 8 in presence of suitable reducing agents such as 1-selectride at a temperature ranging from -78°C to room temperature in presence of suitable solvents such as THF.
Salts and Isomers and counter ions
Composition containing the novel entities
EXAMPLES
Reference EXAMPLE 1: Synthesis of (R,E)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-one oxime [1001]
Step 1: Synthesis of Tetrabenzylated Catechin [20] from catechin [19]
Step 2: Synthesis of [21] from tetrabenzylated catechin [20]
Step 3: Synthesis of [22] from [21]
Step 4: Synthesis of 1001 from [22]
Reference EXAMPLE 2: Synthesis of (2R,3R)-2-(2,3-dihydroxyphenyl)-3-fluorochroman-5,7-diol [1010]
Step 1: Synthesis of [1010] from catechin [19]
Reference EXAMPLE 3: Synthesis of (2R,3S)-2-(3,4-dihydroxyphenyl)-3-aminochroman-5,7-diol [1009]
Step 1: Synthesis of [23(A+B)] from [21]
Step 2: Synthesis of 1009 from [23A]
Example 4: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol [1004]
Step 1: Synthesis of 1-(4-benzyloxy)-2-hydroxyphenyl)ethanone from 1-(2,4-dihydroxyphenyl)ethanone.
Step 2: Synthesis of [27] from 1-(4-benzyloxy)-2-hydroxyphenyl) ethanone and [26].
Step 3: Synthesis of [28] from [27].
Step 4: Synthesis of [29] from [28].
Step 5: Synthesis of [30] and [31] from [29].
Step 6: Synthesis of [1004] from [30] and [31].
EXAMPLE 5: Synthesis of Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol [1003] was carried out by procedure as described for [1004] with [25] and 3,4-bis(benzyloxy)benzaldehyde as starting material.
EXAMPLE 6: Synthesis of Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol [1007] was carried out by procedure as described for [1004] with [25] and 3-(benzyloxy)benzaldehyde as starting material.
EXAMPLE 7: Synthesis of Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol
Step 1: Synthesis of (E)-3-(3,4-bis-(benzyloxy)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one [35]:
Step 2: Synthesis of 2-(3,4-bis(benzyloxy)phenyl)-3-hydroxy-4H-chromen-4-one (36):
Step 3: Synthesis of 3-(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-4H-chromen-4-one [37]:
Step 4: Synthesis of compound [38] and [39]
Step 5: Synthesis of 1002
EXAMPLE 8: Synthesis of Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol [1011] was carried out by procedure as described for 1002 with [33] and 3-(benzyloxy)benzaldehyde as starting material.
EXAMPLE 9: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol [1012] was carried out by procedure as described for 1002 with [33] and 4-(benzyloxy)benzaldehyde as starting material.
EXAMPLE 10: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol [1006]
Step 1: Synthesis of 1-(2-(benzyloxy)-6-hydroxyphenyl)-ethanone [41]
Step 2: Synthesis of (E)-1-(2-(benzyloxy)-6-hydroxyphenyl)-3-(4-(benzyloxy)-phenyl)-prop-2-en-1-one (43):
Step 3: Synthesis of 5-(benzyloxy)-2-(4-(benzyloxy)-phenyl)-3-hydroxy-4H-chromen-4-one (44):
Step 4: Synthesis of 3,5-bis-(benzyloxy)-2-(4-(benzyloxy)-phenyl)-4H-chromen-4-one (46):
Step 5: Synthesis of compound 62 (A) + 62 (B) from [61]
Step 6: Synthesis of 2-(4-hydroxyphenyl)-chroman-3,5-diol (1006):
EXAMPLE 11: Synthesis of Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol [1005] was carried out by procedure as described for 1006 with [41] and 3-(benzyloxy)benzaldehyde as starting material.
EXAMPLE 12: Synthesis of Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol [1013] was carried out by procedure as described for 1006 with [41] and 3,4-bis(benzyloxy)benzaldehyde as starting material.
EXAMPLE 14: Synthesis of 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol [1028] and 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol [1029] was carried out by procedure as described for 1004 with [25] and 4-fluoro-3-methoxybenzaldehyde as starting material. [1028] ESIMS: 290[M++1] [1029] ESIMS: 276[M++1]
EXAMPLE 15: Synthesis of Cis (±) 2-(3-methoxyphenyl)chroman-3,7-diol, Cis (±) 2-(3-hydroxyphenyl)-7-methoxychroman-3-ol, Cis(±)7-methoxy-2-(3-methoxyphenyl) chroman-3-ol [1017, 1018 and 1019]
Step 1: Synthesis of [1017], [1018] and [1019] from [1007]
EXAMPLE 16: Synthesis of Cis (±)3-(3,7-dihydroxychroman-2-yl)phenyl acetate [1022], Cis (±) 3-hydroxy-2-(4-hydroxyphenyl)chroman-7-yl acetate [1023] and Cis (±)3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate [1024]
Step 1: Synthesis of [1022], [1023] and [1024] from [1007]
EXAMPLE 17: Synthesis of 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol [1030]
Step 1: Synthesis of [48] from [1007]
Step 2: Synthesis of [49] from [48]
Step 3: Synthesis of [1030] from [49]
Reference EXAMPLE 18: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3,5,7-triol [1008]
Step 1: Synthesis of 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-ethanone:
Step2: Synthesis of (E)-3-(4-(benzyloxy)phenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-prop-2-en-1-one:
Step 3: Synthesis of 5,7-bis(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-hydroxy-4H-chromen-4-One:
Step 4: Synthesis of 3,5,7-tris(benzyloxy)-2-(4-(benzyloxy)phenyl)-4H-chromen-4-one:
Step 5: Synthesis of compound 55(A) + 55(B):
Step 6: Synthesis of 1011 from 55(A) and 55(B)
Reference EXAMPLE 19: Synthesis of Cis (±) 2-(3-hydroxyphenyl)chroman-3,5,7-triol [1014] was carried out by procedure as described for 1008 with [51] and 3-(benzyloxy)benzaldehyde as starting material.
Reference EXAMPLE 20: Synthesis of Cis (±) 2-phenylchroman-3,5,7-triol [1015] was carried out by procedure as described for 1008 with [51] and benzaldehyde as starting material.
Reference EXAMPLE 21: Synthesis of Cis (±) 2-(3,4-dihydroxy-2-methylphenyl)chroman-3,5,7-triol [1035]
Step 1: Synthesis of 51 from 50
Step 2: Synthesis of [53] from [51] and [56].
Step 3: Synthesis of [58] from [57].
Step 4: Synthesis of [59] from [58].
Step 5: Synthesis of [60] and [61] from [59].
Step 6: Synthesis of 1031 from [60] and [61].
Reference EXAMPLE 22: Synthesis of Cis (±) 2-(2-fluoro-3,4-dihydroxyphenyl)chroman-3,5,7-triol [1032] was carried out by procedure as described for 1031 with [51] and 3,4-bis(benzyloxy)-2-fluorobenzaldehyde as starting material. ESIMS: 309[M++1]
Reference EXAMPLE 23: Synthesis of Cis (±) 2-(2-fluoro-4,5-dihydroxyphenyl)chromane-3,5,7-triol [1033] was carried out by procedure as described for 1031 with [51] and 4,5-bis(benzyloxy)-2-fluorobenzaldehyde as starting material. ESIMS: 309[M++1]
Reference EXAMPLE 24: Synthesis of Cis (±) 2-(3-fluoro-4-hydroxyphenyl)chromane-3,5,7-triol
Step 1: Synthesis of [63] from [51] and [62].
Step 2: Synthesis of [64] from [63].
Step 3: Synthesis of [65] from [64].
Step 4: Synthesis of [66] from [65]
Step 5: Synthesis of [67] from [66]
Step 6: Synthesis of [68] from [67]
Step 7: Synthesis of [1034] from [68]
Reference EXAMPLE 25: Synthesis of Cis(±) (2-(3,4-dihydroxy-5-methylphenyl)chromane-3,5,7-triol [1035] was carried out by procedure as described for 1031 with [51] and 3,4-bis(benzyloxy)-5-methylbenzaldehyde as starting material. ESIMS: 305[M++1]
Reference EXAMPLE 26: Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-4,4-d2-3,5,7-triol [1036]
Step 1: Synthesis of [84 and 85] from [86]
Step 2: Synthesis of [1036] from [71]
Step 3: [1038] from [70]
Reference EXAMPLE 27 Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-2-d-3,5,7-triol [1037]
Step 1: Synthesis of [73 and 74] from [72]
Step 2: Synthesis of [1037] from [73]
Reference Example 28:- Synthesis of dibenzyl (4-(3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) [1048]
Reference Example 29:- Synthesis of 4-(3,5,7-trihydroxychroman-2-yl)-1,2-phenylene bis(benzylcarbamate) [1059]
Reference Example 30:- Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isopropylcarbamate [1046]
Step 1: Synthesis of tetrabenzylated racemic epicatechin [76] form racemic epicatechin [75]
Step 2: Synthesis of [77] from [76]
Step 3: synthesis of [1046] from [77]
Reference Example 31:- Synthesis of dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl)oxy)-3-hydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) [1052]
Reference Example 32:- Synthesis of dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl)oxy)-3-hydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) [1066]
Step 1: synthesis of [1066] from [1048]
Step 2: Synthesis of [1058] from [1066]
Reference Example 33: Synthesis of [1061], [1062] and [1063]
Step 1: Synthesis of [78], [79] and [80] from [1048]
Step 2:
Synthesis of [1061], [1062] and [1063] was carried out as described for [1058] from [78], [79] and [80].
Example 34: Testing of compounds for their AMPK activation potential:
Compound | %pAMPK(at 10nm) |
1002 | 108 |
1004 | 114 |
1005 | 102 |
1006 | 103 |
1007 | 113 |
1008 | 103 |
1009 | 101 |
1015 | 119 |
1017 | 110 |
1018 | 100 |
1019 | 101 |
1026 | 101 |
1027 | 94 |
1028 | 101 |
1029 | 93 |
1030 | 94 |
1032 | 104 |
1031 | 101 |
1033 | 107 |
1034 | 107 |
1035 | 102 |
1036 | 105 |
1037 | 110 |
1041 | 88 |
1042 | 95 |
1043 | 98 |
1044 | 96 |
1045 | 105 |
1046 | 101 |
1047 | 100 |
1048 | 103 |
1049 | 105 |
1050 | 91 |
1051 | 85 |
1052 | 103 |
1053 | 94 |
1054 | 91 |
1055 | 105 |
1056 | 112 |
1058 | 117 |
1059 | 144 |
1060 | 110 |
1064 | 110 |
1066 | 139 |
1068 | 90 |
1069 | 110 |
1070 | 126 |
1071 | 102 |
1072 | 99 |
1073 | 109 |
1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;
1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;
1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;
1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;
1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;
1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;
1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;
1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;
1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;
1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;
1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;
1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;
1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;
1021 Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;
1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;
1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;
1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;
1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;
1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;
1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;
1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;
1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;
1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;
1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;
1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;
1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and
1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol; comprising the steps of:
i. protecting the hydroxyl groups of an acetophenone of Formula 1, wherein X is methyl, with a protecting agent in the presence of a base and a solvent;
ii. reacting compound of Formula 1 obtained from step (i) with a compound of formula 2 in the presence of a base and a solvent to obtain a chalcone of formula 3;
iii. converting the chalcone of formula 3 to a compound 4 in the presence of an epoxidizing agent or a base;
iv. optionally protecting hydroxyl group(s) of the compound obtained in step (iii);
v. reducing the compounds of step (iii) or step (iv) in the presence of a chiral/achiral reducing agent to obtain a mixture of 4H-chromene and 2H-chromene compounds of formula 6 and 7; and
hydrogenating 4H-chromene and 2H-chromene compounds obtained in step (v) to obtain the compound of Formula (I).
i. protecting hydroxyl groups of a flavan-3-ol of formula 12 with a protecting agent;
ii. treating the protected flavan-3-ol of step (i) with an oxidizing agent to obtain a compound of formula 13;
iii. functionalising the oxo group of compound 13 to obtain a compound of formula 14; and
iv. deprotecting the compound obtained in step (iii) to obtain the compound of Formula (I).
i. optionally protecting hydroxyl groups of a flavan-3-ol of formula 15 with a protecting agent;
ii. functionalising the protected/unprotected hydroxyl group of the compound of formula 15 to obtain compound of formula 16; and
deprotecting the compound obtained in step (ii) of formula 16 to obtain the compound of Formula (I).
i. treating a chalcone of formula 3 with a reducing agent in presence of a solvent at a temperature ranging from ambient to reflux to obtain a compound of formula 10;
ii. converting the compound of formula 10 to compound of formula 11 in the presence of a hydroxylating agent with or without chiral co-catalysts and a suitable solvent at a temperature ranging from ambient to reflux;
iii. functionalizing the hydroxyl group of compound of formula 11 with a suitable reagent in the presence of a suitable solvent to obtain a compound of formula 12;
iv. treating the compound of formula 12 with an oxidizing agent to obtain a compound of formula 13; and
iii. reducing the compound of formula 13 from step iv in the presence of a chiral reducing agent at a temperature ranging from -78°C to room temperature in presence of suitable solvents to obtain the compound of Formula (I).
1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;
1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;
1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;
1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;
1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;
1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;
1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;
1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;
1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;
1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;
1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;
1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;
1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;
1021 Cis (±) 7-hydroxy-2-(4-hydroxyphcnyl)chroman-3-yl acctatc;
1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;
1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;
1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;
1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;
1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;
1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;
1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;
1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;
1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;
1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;
1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;
1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and
1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol.
1002 cis-(±)-3-Hydroxychroman-2-yl)benzol-1,2-diol;
1003 cis-(±)-2-(3,4-Dihydroxyphenyl)chroman-3,7-diol;
1004 cis-(±)-2-(4-Hydroxyphenyl)chroman-3,7-diol;
1005 cis-(±)-2-(3-Hydroxyphenyl)chroman-3,5-diol;
1006 cis-(±)-2-(4-Hydroxyphenyl)chroman-3,5-diol;
1007 cis-(±)-2-(3-Hydroxyphenyl)chroman-3,7-diol;
1011 cis-(±)-2-(3-Hydroxyphenyl)chroman-3-ol;
1012 cis-(±)-2-(4-Hydroxyphenyl)chroman-3-ol,
1013 cis-(±)-2-(3,4-Dihydroxyphenyl)chroman-3,5-diol;
1016 cis-(±)-2-(4-Hydroxyphenyl)-3-methoxychroman-7-ol;
1017 cis-(±)-2-(4-Methoxyphenyl)chroman-3,7-diol;
1018 cis-(±)-2-(4-Hydroxyphenyl)-7-methoxychroman-3-ol;
1019 cis-(±)-7-Methoxy-2-(4-methoxyphenyl)chroman-3-ol;
1020 cis-(±)-3,7-Dimethoxy-2-(4-methoxyphenyl)chroman;
1021 cis-(±)-7-Hydroxy-2-(4-hydroxyphenyl)chroman-3-ylacetat;
1022 cis-(±)-3-(3,7-Dihydroxychroman-2-yl)phenylacetat;
1023 cis-(±)-3-Hydroxy-2-(3-hydroxyphenyl)chroman-7-ylacetat;
1024 cis-(±)-3-(7-Acetoxy-3-hydroxychroman-2-yl)phenylacetat;
1025 cis-(±)-2-(4-Acetoxyphenyl)chroman-3,7-diyldiacetat;
1026 2-(3-Methoxy-4-methylphenyl)chroman-3,7-diol;
1027 2-(3-Hydroxy-4-methylphenyl)chroman-3,7-diol;
1028 2-(4-Fluor-3-methoxyphenyl)chroman-3,7-diol;
1029 2-(4-Fluor-3-hydroxyphenyl)chroman-3,7-diol;
1030 2-(3-Hydroxyphenyl)-3-propoxychroman-7-ol;
1067 (2R,3R)-7-Methoxy-2-(3-methoxyphenyl)-3-propoxychroman;
1068 (2R,3R)-2-(3-Methoxyphenyl)-3-propoxychroman-7-ol;
1069 (2R,3R)-2-(3-Hydroxy-4-methylphenyl)chroman-3,7-diol; und
1070 (2R,3R)-7-Methoxy-2-(4-methoxyphenyl)chroman-3-ol;
das die folgenden Schritte umfasst:
i. Schützen der Hydroxylgruppen eines Acetophenons der Formel 1, wobei X Methyl ist, mit einem Schutzmittel in Gegenwart einer Base und eines Lösungsmittels;
ii. Reagieren der Verbindung der Formel 1, die von Schritt (i) erhalten wurde, mit einer Verbindung der Formel 2 in Gegenwart einer Base und eines Lösungsmittels, um ein Chalkon der Formel 3 zu erhalten;
iii. Umwandeln des Chalkons der Formel 3 in eine Verbindung 4 in Gegenwart eines Epoxidierungsmittels oder einer Base;
iv. optionales Schützen von Hydroxylgruppe(n) der Verbindung, die im Schritt (iii) erhalten wurde;
v. Reduzieren der Verbindungen von Schritt (iii) oder Schritt (iv) in Gegenwart eines chiralen/achiralen Reduktionsmittels, um eine Mischung aus 4H-Chromen- und 2H-Chromenverbindungen der Formel 6 und 7 zu erhalten; und
Hydrieren der 4H-Chromen- und 2H-Chromenverbindungen, die im Schritt (v) erhalten wurden, um die Verbindung der Formel (I) zu erhalten.
i. Schützen von Hydroxylgruppen eines Flavan-3-ols der Formel 12 mit einem Schutzmittel;
ii. Behandeln des geschützten Flavan-3-ols von Schritt (i) mit einem Oxidationsmittel, um eine Verbindung der Formel 13 zu erhalten;
iii. Funktionalisieren der Oxogruppe der Verbindung 13, um eine Verbindung der Formel 14 zu erhalten; und
iv. Entschützen der Verbindung, die im Schritt (iii) erhalten wurde, um die Verbindung der Formel (I) zur erhalten.
i. optionales Schützen von Hydroxylgruppen eines Flavan-3-ols der Formel 15 mit einem Schutzmittel;
ii. Funktionalisieren der geschützten/ungeschützten Hydroxylgruppe der Verbindung der Formel 15, um die Verbindung der Formel 16 zu erhalten; und
Entschützen der Verbindung, die im Schritt (ii) erhalten wurde, der Formel 16, um die Verbindung der Formel (I) zur erhalten.
i. Behandeln eines Chalkons der Formel 3 mit einem Reduktionsmittel in Gegenwart eines Lösungsmittels bei einer Temperatur im Bereich von Umgebungs- bis Rückflusstemperatur, um eine Verbindung der Formel 10 zu erhalten;
ii. Umwandeln der Verbindung der Formel 10 in die Verbindung der Formel 11 in Gegenwart eines Hydroxylierungsmittels mit oder ohne chirale Cokatalysatoren und eines geeigneten Lösungsmittels bei einer Temperatur im Bereich von Umgebungs- bis Rückflusstemperatur;
iii. Funktionalisieren der Hydroxylgruppe der Verbindung der Formel 11 mit einem geeigneten Reagenz in Gegenwart eines geeigneten Lösungsmittels, um eine Verbindung der Formel 12 erhalten;
iv. Behandeln der Verbindung der Formel 12 mit einem Oxidationsmittel, um eine Verbindung der Formel 13 zu erhalten; und
iii. Reduzieren der Verbindung der Formel 13 von Schritt iv in Gegenwart eines chiralen Reduktionsmittels bei einer Temperatur im Bereich von -78 °C bis Raumtemperatur in Gegenwart von geeigneten Lösungsmitteln, um die Verbindung der Formel (I) zur erhalten.
1002 cis-(±)-3-Hydroxychroman-2-yl)benzol-1,2-diol;
1003 cis-(±)-2-(3,4-Dihydroxyphenyl)chroman-3,7-diol;
1004 cis-(±)-2-(4-Hydroxyphenyl)chroman-3,7-diol;
1005 cis-(±)-2-(3-Hydroxyphenyl)chroman-3,5-diol;
1006 cis-(±)-2-(4-Hydroxyphenyl)chroman-3,5-diol;
1007 cis-(±)-2-(3-Hydroxyphenyl)chroman-3,7-diol;
1011 cis-(±)-2-(3-Hydroxyphenyl)chroman-3-ol;
1012 cis-(±)-2-(4-Hydroxyphenyl)chroman-3-ol,
1013 cis-(±)-2-(3,4-Dihydroxyphenyl)chroman-3,5-diol;
1016 cis-(±)-2-(4-Hydroxyphenyl)-3-methoxychroman-7-ol;
1017 cis-(±)-2-(4-Methoxyphenyl)chroman-3,7-diol;
1018 cis-(±)-2-(4-Hydroxyphenyl)-7-methoxychroman-3-ol;
1019 cis-(±)-7-Methoxy-2-(4-methoxyphenyl)chroman-3-ol;
1020 cis-(±)-3,7-Dimethoxy-2-(4-methoxyphenyl)chroman;
1021 cis-(±)-7-Hydroxy-2-(4-hydroxyphenyl)chroman-3-ylacetat;
1022 cis-(±)-3-(3,7-Dihydroxychroman-2-yl)phenylacetat;
1023 cis-(±)-3-Hydroxy-2-(3-hydroxyphenyl)chroman-7-ylacetat;
1024 cis-(±)-3-(7-Acetoxy-3-hydroxychroman-2-yl)phenylacetat;
1025 cis-(±)-2-(4-Acetoxyphenyl)chroman-3,7-diyldiacetat;
1026 2-(3-Methoxy-4-methylphenyl)chroman-3,7-diol;
1027 2-(3-Hydroxy-4-methylphenyl)chroman-3,7-diol;
1028 2-(4-Fluor-3-methoxyphenyl)chroman-3,7-diol;
1029 2-(4-Fluor-3-hydroxyphenyl)chroman-3,7-diol;
1030 2-(3-Hydroxyphenyl)-3-propoxychroman-7-ol;
1067 (2R,3R)-7-Methoxy-2-(3-methoxyphenyl)-3-propoxychroman;
1068 (2R,3R)-2-(3-Methoxyphenyl)-3-propoxychroman-7-ol;
1069 (2R,3R)-2-(3-Hydroxy-4-methylphenyl)chroman-3,7-diol; und
1070 (2R,3R)-7-Methoxy-2-(4-methoxyphenyl)chroman-3-ol.
1002 le cis-(±)-3-hydroxychroman-2-yl)benzène-1,2-diol ;
1003 le cis-(±)-2-(3,4-dihydroxyphényl)chromane-3,7-diol ;
1004 le cis-(±)-2-(4-hydroxyphényl)chromane-3,7-diol ;
1005 le cis-(±)-2-(3-hydroxyphényl)chromane-3,5-diol ;
1006 le cis-(±)-2-(4-hydroxyphényl)chromane-3,5-diol ;
1007 le cis-(±)-2-(3-hydroxyphényl)chromane-3,7-diol ;
1011 le cis-(±)-2-(3-hydroxyphényl)chroman-3-ol ;
1012 le cis-(±)-2-(4-hydroxyphényl)chroman-3-ol ;
1013 le cis-(±)-2-(3,4-dihydroxyphényl)chromane-3,5-diol ;
1016 le cis-(±)-2-(4-hydroxyphényl)-3-méthoxychroman-7-ol ;
1017 le cis-(±)-2-(4-méthoxyphényl)chromane-3,7-diol ;
1018 le cis-(±)-2-(4-hydroxyphényl)-7-méthoxychroman-3-ol ;
1019 le cis-(±)-7-méthoxy-2-(4-méthoxyphényl)chroman-3-ol ;
1020 le cis-(±)-3,7-diméthoxy-2-(4-méthoxyphényl)chromane ;
1021 l'acétate de cis-(±)-7-hydroxy-2-(4-hydroxyphényl)chroman-3-yle ;
1022 l'acétate de cis-(±)-3-(3,7-dihydroxychroman-2-yl)phényle ;
1023 l'acétate de cis-(±)-3-hydroxy-2-(3-hydroxyphényl)chroman-7-yle ;
1024 l'acétate de cis-(±)-3-(7-acétoxy-3-hydroxychroman-2-yl)phényle ;
1025 le diacétate de cis-(±)-2-(4-acétoxyphényl)chroman-3,7-diyle ;
1026 le 2-(3-méthoxy-4-méthylphényl)chromane-3,7-diol ;
1027 le 2-(3-hydroxy-4-méthylphényl)chromane-3,7-diol ;
1028 le 2-(4-fluoro-3-méthoxyphényl)chromane-3,7-diol ;
1029 le 2-(4-fluoro-3-hydroxyphényl)chromane-3,7-diol ;
1030 le 2-(3-hydroxyphényl)-3-propoxychroman-7-ol ;
1067 le (2R,3R)-7-méthoxy-2-(3-méthoxyphényl)-3-propoxychromane ;
1068 le (2R,3R)-2-(3-méthoxyphényl)-3-propoxychroman-7-ol ;
1069 le (2R,3R)-2-(3-hydroxy-4-méthylphényl)chromane-3,7-diol ; et
1070 le (2R,3R)-7-méthoxy-2-(4-méthoxyphényl)chroman-3-ol ;
comprenant les étapes consistant à :
i. protéger les groupements hydroxyle d'une acétophénone de formule 1, où X est méthyle, par un agent protecteur en présence d'une base et d'un solvant ;
ii. réagir le composé de formule 1 obtenu dans l'étape (i) avec un composé de formule 2 en présence d'une base et d'un solvant, afin d'obtenir une chalcone de formule 3 ;
iii. convertir la chalcone de formule 3 en un composé 4 en présence d'un agent d'époxydation ou d'une base ;
iv. éventuellement, protéger le ou les groupements hydroxyle du composé obtenu dans l'étape (iii) ;
v. réduire les composés de l'étape (iii) ou de l'étape (iv) en présence d'un agent réducteur chiral/achiral, afin d'obtenir un mélange de composés de 4H-chromène et de 2H-chromène de formule 6 et 7 ; et
hydrogéner les composés de 4H-chromène et de 2H-chromène obtenus dans l'étape (v) afin d'obtenir le composé de Formule (I).
i. protéger les groupements hydroxyle d'un flavan-3-ol de formule 12 par un agent protecteur ;
ii. traiter le flavan-3-ol protégé de l'étape (i) par un agent oxydant, afin d'obtenir un composé de formule 13 ;
iii. fonctionnaliser le groupement oxo du composé 13, afin d'obtenir un composé de formule 14 ; et
iv. déprotéger le composé obtenu dans l'étape (iii), afin d'obtenir le composé de Formule (I).
i. éventuellement, protéger les groupements hydroxyle d'un flavan-3-ol de formule 15 par un agent protecteur ;
ii. fonctionnaliser le groupement hydroxyle protégé/non protégé du composé de formule 15, afin d'obtenir un composé de formule 16 ; et
déprotéger le composé obtenu dans l'étape (ii) de formule 16, afin d'obtenir le composé de Formule (I).
i. traiter une chalcone de formule 3 par un agent réducteur en présence d'un solvant à une température allant de la température ambiante au reflux, afin d'obtenir un composé de formule 10 ;
ii. convertir le composé de formule 10 en composé de formule 11 en présence d'un agent d'hydroxylation avec ou sans co-catalyseurs chiraux et d'un solvant convenable, à une température allant de la température ambiante au reflux ;
iii. fonctionnaliser le groupement hydroxyle du composé de formule 11 par un réactif convenable en présence d'un solvant convenable, afin d'obtenir un composé de formule 12 ;
iv. traiter le composé de formule 12 par un agent oxydant, afin d'obtenir un composé de formule 13 ; et
iii. réduire le composé de formule 13 de l'étape (iv) en présence d'un agent réducteur chiral à une température allant de -78°C à la température ambiante, en présence de solvants convenables, afin d'obtenir le composé de Formule (I).
1002 le cis-(±)-3-hydroxychroman-2-yl)benzène-1,2-diol ;
1003 le cis-(±)-2-(3,4-dihydroxyphényl)chromane-3,7-diol ;
1004 le cis-(±)-2-(4-hydroxyphényl)chromane-3,7-diol ;
1005 le cis-(±)-2-(3-hydroxyphényl)chromane-3,5-diol ;
1006 le cis-(±)-2-(4-hydroxyphényl)chromane-3,5-diol ;
1007 le cis-(±)-2-(3-hydroxyphényl)chromane-3,7-diol ;
1011 le cis-(±)-2-(3-hydroxyphényl)chroman-3-ol ;
1012 le cis-(±)-2-(4-hydroxyphényl)chroman-3-ol ;
1013 le cis-(±)-2-(3,4-dihydroxyphényl)chromane-3,5-diol ;
1016 le cis-(±)-2-(4-hydroxyphényl)-3-méthoxychroman-7-ol ;
1017 le cis-(±)-2-(4-méthoxyphényl)chromane-3,7-diol ;
1018 le cis-(±)-2-(4-hydroxyphényl)-7-méthoxychroman-3-ol ;
1019 le cis-(±)-7-méthoxy-2-(4-méthoxyphényl)chroman-3-ol ;
1020 le cis-(±)-3,7-diméthoxy-2-(4-méthoxyphényl)chromane ;
1021 l'acétate de cis-(±)-7-hydroxy-2-(4-hydroxyphényl)chroman-3-yle ;
1022 l'acétate de cis-(±)-3-(3,7-dihydroxychroman-2-yl)phényle ;
1023 l'acétate de cis-(±)-3-hydroxy-2-(3-hydroxyphényl)chroman-7-yle ;
1024 l'acétate de cis-(±)-3-(7-acétoxy-3-hydroxychroman-2-yl)phényle ;
1025 le diacétate de cis-(±)-2-(4-acétoxyphényl)chroman-3,7-diyle ;
1026 le 2-(3-méthoxy-4-méthylphényl)chromane-3,7-diol ;
1027 le 2-(3-hydroxy-4-méthylphényl)chromane-3,7-diol ;
1028 le 2-(4-fluoro-3-méthoxyphényl)chromane-3,7-diol ;
1029 le 2-(4-fluoro-3-hydroxyphényl)chromane-3,7-diol ;
1030 le 2-(3-hydroxyphényl)-3-propoxychroman-7-ol ;
1067 le (2R,3R)-7-méthoxy-2-(3-méthoxyphényl)-3-propoxychromane ;
1068 le (2R,3R)-2-(3-méthoxyphényl)-3-propoxychroman-7-ol ;
1069 le (2R,3R)-2-(3-hydroxy-4-méthylphényl)chromane-3,7-diol ; et
1070 le (2R,3R)-7-méthoxy-2-(4-méthoxyphényl)chroman-3-ol.
REFERENCES CITED IN THE DESCRIPTION
Patent documents cited in the description