Method for preparation of justicidin a derivatives of arylnaphthalene lignan structure

Patent metadata

Field	Value
Publication number	US-9650355-B2
Application number	US-201414760400-A
Country	US
Kind code	B2
Filing date	Jan 28, 2014
Priority date	Jan 31, 2013
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The present disclosure relates to a novel method for preparing an arylnaphthalene lignan compound. In synthesis of arylnaphthalene lignan compounds and derivatives according to the present disclosure, a naphthalene backbone may be constructed first and an aryl group may be introduced at the final stage. Through this, various kinds of derivatives that could not be prepared from the existing methods can be synthesized effectively. Further, the synthesis method according to the present disclosure is appropriate for large-scale production.

First claim

The invention claimed is:

1. A method for preparing a precursor of an arylnaphthalene lignan compound using Scheme A:

wherein
each of A and B is independently C1-C8 alkyl or C2-C9 alkylether or A and B are linked via methylene to form a heterocycle;
X is —O, —NR1 or —CH2—;
n is 1 or 2;
R1 is C1-C8 alkyl or C7-C14 arylalkyl; and
M is lithium, potassium or sodium.

2. The method according to claim 1 , wherein the arylnaphthalene lignan compound has a structure of Chemical Formula 6 or 9:

wherein

Y is hydroxyl, sulfonate,
wherein
Ar is

R 2 is hydrogen, C 1 -C 8 alkyl, C 1 -C 4 alkyloxy, C 1 -C 4 alkylether, C 1 -C 4 alkylthiooxy, vinyl, C 3 C 8 alkylvinyl, hydroxyl, nitro (—NO 2 ), fluoro, chloro, cyano, formyl (—CHO), C 2 -C 12 acyl, C 1 -C 5 alkylester or C 7 -C 10 arylester;
R 3 is C 1 -C 10 alkyl, C 6 -C 12 aryl, C 7 -C 10 alkylaryl, C 2 -C 10 arylalkyl, C 1 -C 4 alkylether, C 1 -C 5 alkylester or C 2 -C 12 acyl;
R 4 is hydrogen, C 1 -C 6 alkyl, C 7 -C 12 cyclohexylalkyl, C 7 -C 12 arylalkyl, C 2 -C 6 alkylether, C 2 -C 6 alkylthioether, C 2 -C 6 alkylcyano, C 1 -C 4 alkylalcohol or

R 5 is independently hydrogen, C 1 -C 6 alkyl, C 7 -C 12 cyclohexylalkyl, C 7 -C 12 arylalkyl, C 2 -C 6 alkylether, C 2 -C 6 alkylthioether, C 2 -C 6 alkylcyano, C 1 -C 4 alkylalcohol or

R 6 is hydrogen, C 1 -C 6 alkyl, C 7 -C 10 ) alkylaryl, C 1 -C 4 alkylether, C 1 -C 4 alkylthioether, fluoro or chloro;
o is an integer from 1 to 5; and
p is an integer from 0 to 2, and
Z is O—R 7 ,

 or glycosyl
wherein
R 7 is hydrogen, C 1 -C 8 alkyl, C 2 -C 9 alkylether, C 1 -C 5 alkylester, C 7 -C 10 arylester or

R 8 is C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, nitro (—NO 2 ), cyano (—CN), fluoro, chloro, bromo, iodo or hydrogen;
q is an integer from 0 to 5;
r is an integer from 1 to 4;
R 9 is C 1 -C 8 alkyl or hydrogen;
s is an integer from 1 to 5; and
the glycosyl group is 4-Oβ-D-galactopyranosyl, 4-O-α-L-arabinosyl, 4O-β-D-glucopyranosyl, 4-O-β-D-xylosyl, 6′-O-methyl-4-O-β-D-glucopyranosyl, 6′-O-methyl-4-O-β-D-galactopyranosyl, 4-O-β-D-fucopyranosyl, 6′-O-benzyl-4O-β-D-glucopyranosyl or 6′-0-benzyl-4-O-β-D-galactopyranosyl.

3. The method according to claim 1 , wherein the arylnaphthalene lignan compound is 9-(benzo[d][1,3]dioxol-5-yl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one (justicidin A), t-butyl 9-hydroxy-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(t-butoxycarbonyloxy)-6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl trifluoromethanesulfonate, 9-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl t-butylcarbonate, 9-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one (diphyllin), 9-(3,4-dimethoxyphenyl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one (cilinaphthalide B), t-butyl 9-(3,4-dimethoxyphenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(3,4-dimethoxyphenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 9-(3,5-dimethoxyphenyl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one, t-butyl 9-(3,5-dimethoxyphenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(3,5-dimethoxyphenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 4,6,7-trimethoxy-9-(4-methoxyphenyl)naphtho[2,3-c]furan-1(3H)-one, t-butyl 6,7-dimethoxy-9-(4-methoxyphenyl)-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 4-hydroxy-6,7-dimethoxy-9-(4-methoxyphenyl)naphtho[2,3-c]furan-1(3H)-one, 4,6,7-trimethoxy-9-phenylnaphtho[2,3-c]furan-1(3H)-one, t-butyl 6,7-dimethoxy-1oxo-9-phenyl-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 4-hydroxy-6,7-dimethoxy-9-phenylnaphtho[2,3-c]furan-1(3H)-one, 4,6,7-trimethoxy-9-(4-vinylphenyl)naphtho[2,3-c]furan-1(3H)-one, t-butyl 6,7-dimethoxy-1oxo-9-(4-vinylphenyl)-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 4-hydroxy-6,7-dimethoxy-9-(4-vinylphenyl)naphtho[2,3-c]furan-1(3H)-one, 9-(4-fluorophenyl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one, t-butyl 9-(4-fluorophenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(4-fluorophenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 4-(9-hydroxy-6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl)benzonitrile, t-butyl 9-(4-cyanophenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 4-(9-hydroxy-6,7-dimethoxy-3-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl)benzonitrile, 9-(4-acetylphenyl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one, 9-(4-acetylphenyl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl t-butylcarbonate, 9-(4-acetylphenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, 4,6,7-trimethoxy-9-(thiophen-3-yl)naphtho[2,3-c]furan-1(3H)-one, 4-hydroxy-6,7-dimethoxy-9-(thiophen-3-yl)naphtho[2,3-c]furan-1(3H)-one, 9-(furan-3-yl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1(3H)-one, t-butyl 9-(furan-3-yl)-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl carbonate, 9-(furan-3-yl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one, (E)-4,6,7-trimethoxy-9-styrylnaphtho[2,3-c]furan-1(3H)-one, (E)-4-hydroxy-6,7-dimethoxy-9-styrylnaphtho[2,3-c]furan-1(3H)-one, 5-(1,3-benzodioxol-5-yl)-9-methoxy-furo[3′,4′:6,7]naphtho[2,3-d]-1,3-dioxol-6(8H)-one (justicidin F, taiwanin E methyl ether), t-butyl 9-hydroxy-1oxo-1,3-dihydronaphtho[2,3-d]-1,3-dioxol[2,3-c]furan-4-yl carbonate, 9-(t-butoxycarbonyloxy)-3-oxo-1,3-dihydronaphtho[2,3-d]-1,3-dioxol[2,3-c]furan-4-yl trifluoromethanesulfonate, 9-(benzo[d][1,3]dioxol-5-yl)-1-oxo-1,3-dihydronaphtho[2,3-d]-1,3-dioxol[2,3-c]furan-4-yl t-butylcarbonate, 5-(1,3-benzodioxol-5-yl)-9-hydro-furo[3′,4′:6,7]naphtho[2,3-d]-1,3-dioxol-6(8H)-one (taiwanin E), 4-(benzo[d][1,3]dioxol-5-yl)-6,'7,9-trimethoxynaphtho[2,3-c]furan-1(3H)-one (justicidin C), 9-hydroxy-6,7-dimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl methanesulfonate, 6,7,9-trimethoxy-1oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl methanesulfonate or 9-benzo[1,3]dioxol-5-yl-4,6,7-trimethoxy-2-methyl-2,3-dihydro-benzo[f]isoindol-1-one.

4. The method according to claim 1 , wherein Scheme A comprises:
Michael reaction;
aldol reaction; and
benzannulation.

5. The method according to claim 1 , wherein the base in Scheme A is one or more selected from a group consisting of lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium t-butoxide, potassium t-butoxide, sodium t-butoxide, lithium diisopropylamide, s-butyllithium and t-butyllithium.

6. The method according to claim 1 , wherein, in Scheme A, the α,β-unsaturated carbonyl compound

is used in an amount of 1.0-3.0 equivalents based on the compound of Chemical Formula 1.

7. A method of pr

Assignees

• Korea Inst Sci & Tech

Inventors

• Ham Jungyeob
• Kim Tae Jung
• Kwon Hak Cheol
• Jeong Kyu Hyuk
• Song Jungho
• Chung Bong Chul

Classifications

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D307/88 Primary

  with one oxygen atom directly attached in position 1 or 3 · CPC title

• C07D407/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D493/04

  Ortho-condensed systems · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title