Synthesis of a capillarisin sulfur-analogue possessing aldose reductase inhibitory activity by selective isopropylation

Article abstract of DOI:10.1248/cpb.53.1088

We describe the synthesis of 2-[(4-hydroxyphenyl)thio]-7-isopropoxy-5,6- dimethoxy-4H-chromen-4-one 2 from 3,4,5-trimethoxyphenol 6 via the key intermediate, 3-iodo-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 3. An important feature of this synthetic scheme involves selective alkylation, which can be achieved by two different routes. One route involves the selective isopropylation of a triacetate derivative 4 under basic conditions. The second route employs the selective demethylation of a trimethoxy derivative 5 under acidic conditions followed by isopropylation. The product of these alternative routes, compound 3, is then converted to a capillarisin sulfur analogue 2 in a one-pot reaction via the imidazolyl intermediate 22.

Full text of DOI:10.1248/cpb.53.1088

1088
Chem. Pharm. Bull. 53(9) 1088—1091 (2005)
Vol. 53, No. 9
Synthesis of a Capillarisin Sulfur-Analogue Possessing Aldose Reductase
Inhibitory Activity by Selective Isopropylation
Yasushi IGARASHI, ,a Hiroaki KUMAZAWA,a Toshihoro OHSHIMA,a Hisanori SATOMI,a
*
c
Susumu TERABAYASHI,a Shuichi TAKEDA,a Masaki ABURADA,a,b and Ken-ichi MIYAMOTO
a Research Division, Tsumura & Co.; 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300–1192, Japan: b Faculty of
c
Pharmacy, Musashino University; 1–1–20 Shinmachi, Nishitokyo, Tokyo 202–8585, Japan: and Department of Hospital
Pharmacy, School of Medicine, Kanazawa University; Kanazawa 920–8641, Japan.
Received February 9, 2005; accepted June 12, 2005
We describe the synthesis of 2-[(4-hydroxyphenyl)thio]-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2
from 3,4,5-trimethoxyphenol 6 via the key intermediate, 3-iodo-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one
3. An important feature of this synthetic scheme involves selective alkylation, which can be achieved by two dif-
ferent routes. One route involves the selective isopropylation of a triacetate derivative 4 under basic conditions.
The second route employs the selective demethylation of a trimethoxy derivative 5 under acidic conditions fol-
lowed by isopropylation. The product of these alternative routes, compound 3, is then converted to a capillarisin
sulfur analogue 2 in a one-pot reaction via the imidazolyl intermediate 22.
Key words capillarisin; selective isopropylation; substitution reaction; aldose reductase inhibitor; 3,4,5-trimethoxyphenol
Capillarisin 1,1) a bioactive constituent of Artemisiae Cap- tion10) of 8 using iodine afforded 3-iodochromone 9 in 84%
illaris Herba, is an antioxidant,2) as well as a choleretic3) and yield (Chart 2).
antitumor agent4) and an inhibitor of aldose reductase (AR).5)
To obtain the desired compounds, 14 or 15, demethylation
We have synthesized a number of capillarisin analogues and of compound 9 was carried out under various conditions
tested their ability to inhibit AR.6) Among them, the sulfur (Table 1). Demethylation proceeded in the order of the posi-
analogue 2, which was prepared from capillarisin 1 by a tion 5, 6 and 7 using Lewis acids (runs 1—4). Interestingly,
semi-synthetic method (Chart 1), showed excellent in vitro the reaction of 9 with sulfuric acid (run 5) occurred selec-
activity with an IC50 of 3ꢀ10ꢁ8 mol/l against rat lens AR.
Therefore compound 2 is an excellent lead structure for an
AR inhibitor. 6-Demethoxycapillarisin has been synthesized
by two groups,7,8) but total synthesis of 1 has not been re-
ported. During the development of a drug to treat diabetic
complications, we devised a synthetic route to the sulfur ana-
logue 2 from a commercially available compound.
A key feature of this synthesis is the selective construction
of the A-ring substituted with trialkoxy groups and introduc-
tion of the phenylthio group into the 2-position in its struc-
ture. The retrosynthetic analysis of 2 is outlined in Fig. 1.
A substitution reaction using 3-iodochromone 3 with 4-hy-
droxybenzenethiol affords 2. To selectively arrange the 7-iso-
propoxy-5,6-dimethoxy groups on the A-ring of 3, two syn-
thetic routes were investigated. The first route involves the
selective isopropylation using a triacetate derivative 4 (route
a), and the second route involves selective demethylation of
the trimethoxy derivative 5 (route b). Compounds 4 and 5
can be prepared from 3,4,5-trimethoxyphenol 6. In this
paper, we describe the total synthesis of the novel capillarisin
derivative 2 by these two methods.
Fig. 1. Retrosynthetic Analysis of 2
Chart 2. Synthesis of 9
Table 1. Demethylation of 9
Synthesis of 3 via 4 (Route a) The starting material 7, is
commercially available or can easily be prepared from 3,4,5-
trimethoxyphenol 6.9) Condensation of 7 with N,N-dimethyl-
formamide dimethyl acetal gave 8 in 91% yield. Cyclyza-
Run Reagent
Solv.
Temp.
rt.
ꢁ78 °C 10 min
rt.
100 °C
80 °C
Reflux
Time
20 h
Products (Yield)
1
2
3
4
5
6
BCl3
BCl3
CH2Cl2
CH2Cl2
10 (82%), 11 (18%)
10 (90%)
10 (46%), 11 (21%)
12 (94%)
13 (96%)
10 (100%)
TiCl4 Tol., CH2Cl2
20 h
6 h
2 h
AlCl3
H2SO4
LiI
Tol.
Dioxane
20 h
Chart 1. Conversion of Capillarisin 1 to Sulfur-Analogue 2
∗ To whom correspondence should be addressed. e-mail: igarashi_yasushi@mail.tsumura.co.jp
© 2005 Pharmaceutical Society of Japan

September 2005
1089
Chart 3. Isopropylation of 12
Chart 6. One-Pot Conversion of 3 to 2
in 5 steps (route a). Thus we planned an alternative route in-
volving the selective demethylation at the 7-position via in-
termediate 5, possessing a carbonyl function at the 8-posi-
tion.
Friedel–Crafts reaction of 3,4,5-trimethoxyphenol 6 using
acetic anhydride and aluminum chloride in nitromethane af-
forded the diacetyl derivative 18 in 74% yield. Condensation
of 18 with N,N-dimethylformamide dimethyl acetal (1 eq)
followed by treatment with iodine gave 5. Demethylation of 5
using titanium tetrachloride as Lewis acid proceeded selec-
tively to afford the 5,7-dihydroxy-6-methoxy derivative 20 as
expected. The acetyl group of 20 was then removed by reac-
tion with trifluoromethanesulfonic acid12) to afford 14 in 89%
yield. Isopropylation at the 7-position followed by methyla-
tion at the 5-position of 14 gave compound 3 in 62% yield
(Chart 5).
Chart 4. Synthesis of Key Intermediate 3 via 4
Preparation of 2 from 3 The conversion of 3 to 2 is out-
lined in Chart 6. A direct substitution reaction of the 3-iodo-
derivative 3 with 4-hydroxybenzenethiol gave only the re-
duced product 21 in 88% yield. It was reported that 3-
iodochromone reacted with imidazole to give 2-(1-imida-
zolyl)chromone.13) Treatment of 3 with imidazole in the pres-
ence of potassium carbonate in DMF gave the imidazolyl de-
rivative 22, which without isolation then underwent a substi-
Chart 5. Alternative Synthetic Method of Key Intermediate 3
tively at the 6-position to afford 13 in 96% yield. Addition- tution reaction with 4-hydroxybenzenethiol to give 2 in 86%
ally, compound 10 was exclusively obtained after treatment yield. These two steps could proceed either in a one-pot reac-
with lithium iodide (run 6). However, the desired com- tion or step-by-step.
pounds, 14 and 15, could not be obtained by this method.
We then tried selective isopropylation at the 7-position Conclusion
using the trihydroxy derivative 12 under various conditions
We have developed two synthetic routes for the prepara-
(base; K2CO3, Cs2CO3 or Li2CO3: solvent; DMF, MEK, ace- tion of the key intermediate 3 in the synthesis of a capillar-
tone or EtOH). However, the yield (maximum 43%) of de- isin-analogue 2. Both reaction schemes use readily available
sired compound 16 was unsatisfactory (Chart 3). Presumably starting reagents. One route employs the selective isopropy-
the reactivity of the 7-hydroxy group was equal to that of the lation of 4, whereas the second route involves the selective
6-hydroxy group, and the substrate 12 is unstable under basic demethylation of 5. Compound 2 was prepared from 3 in a
conditions.
one-pot reaction via the imidazoyl derivative 22.
We judged that direct isopropylation of 12 is difficult, and
therefore adopted a selective alkylation methodology using
methyl gallate.11) Compound 12 was converted to the triac-
etate 4 in 83% yield, and then reacted with 2-iodopropane in
the presence of potassium carbonate. As expected, the 7-ace-
toxy group para to the carbonyl group reacted selectively to
give the desired compound 17 in 86% yield. Hydrolysis of 17
followed by methylation afforded the key intermediate 3 in
86% yield (Chart 4).
Experimental
Melting points were measured by the use of a Yanaco micro melting point
apparatus and are uncorrected. H-NMR spectra were recorded on a JEOL
1
FX-200 (200 MHz) using tetramethylsilane as an internal standard. Infrared
spectra were recorded using a Hitachi 270-30 spectrophotometer. Mass spec-
tra were recorded on a JEOL DX-300 spectrometer. Elemental analyses were
performed on a Heraus CHN-O-Rapid.
(E)-3-(Dimethylamino)-6ꢀ-hydroxy-2ꢀ,3ꢀ,4ꢀ-trimethoxyacrylophenone
(8) A mixture of 6ꢂ-hydroxy-2ꢂ,3ꢂ,4ꢂ-trimethoxyacetophenone (607 mg,
2.69 mmol) and N,N-dimethylformamide dimethyl acetal (0.534 ml,
4.03 mmol) was stirred at 100 °C for 2 h. The reaction mixture was purified
Synthesis of 3 via 5 (Route b) Since selective demethy-
lation of 9 failed (Table 1), conversion of 9 to 3 was achieved by flash chromatography on silica gel (hexane/EtOAcꢃ1/1) to give the title

1090
Vol. 53, No. 9
compound (691.1 mg, 91%). Recrystallization from EtOAc–hexane afforded
perature for 1 h, extracted with EtOAc, dried over Na2SO4 and concentrated.
The residue was purified by flash chromatography on silica gel
yellow crystals: mp 113—114 °C. 1H-NMR (CDCl3) d: 2.96 (3H, br s), 3.18
(3H, br s), 3.81 (3H, s), 3.86 (3H, s), 3.87 (3H, s), 6.25 (1H, s), 6.33 (1H, d, (hexane/EtOAcꢃ6/1) to give the title compound (3.35 g, 74%). Recrystal-
Jꢃ12.4 Hz), 7.95 (1H, d, Jꢃ12.4 Hz), 14.84 (1H, s). IR (KBr) cmꢁ1: 1616, lization from hexane afforded colorless crystals: mp 85—86 °C. 1H-NMR
1528. EI-MS m/z: 281 (Mꢄ). Anal. Calcd for C14H19NO5: C, 59.78; H, 6.81; (CDCl3) d: 2.59 (6H, s), 3.79 (3H, s), 4.00 (6H, s), 13.31 (1H, s). EI-MS
N, 4.98. Found: C, 59.71; H, 6.96; N, 5.09.
3-Iodo-5,6,7-trimethoxy-4H-chromen-4-one (9)
m/z: 268 (Mꢄ). Anal. Calcd for C13H16O6: C, 58.20; H, 6.01. Found: C,
58.18; H, 6.04.
A mixture of 8
(1.897 g, 6.75 mmol) and iodine (3.40 g, 13.4 mmol) in toluene (19 ml) was
stirred at room temperature for 1.5 h. The reaction mixture was quenched
(E)-3ꢀ-Acetyl-3-(dimethylamino)-2ꢀ-hydroxy-4ꢀ,5ꢀ,6ꢀ-trimethoxyacry-
lophenone (19) A mixture of 18 (3.33 g, 12.4 mmol) and N,N-dimethylfor-
with Na2S2O3 aq and extracted with EtOAc. The organic phase was dried mamide dimethyl acetal (1.65 ml, 12.4 mmol) in DMF (3.3 ml) was stirred at
over Na2SO4, concentrated and then recrystallized from EtOAc–hexane to
give the title compound (1.871 g, 77%). The filtrate of the recrystallization
was purified by flash chromatography on silica gel (CH2Cl2/EtOAcꢃ10/1) to
100 °C for 6 h. The reaction mixture was purified by flash chromatography
on silica gel (hexane/EtOAcꢃ1/4) to give the title compound (2.70 g, 67%).
Recrystallization from EtOAc–hexane afforded yellow crystals: mp 113—
1
1
give the title compound (177 mg, 7%): mp 183—184 °C. H-NMR (CDCl3)
114 °C. H-NMR (CDCl3) d: 2.60 (3H, s), 2.91 (3H, s), 3.12 (3H, s), 3.81
d: 3.90 (3H, s), 3.95 (3H, s), 3.97 (3H, s), 6.68 (1H, s), 8.13 (1H, s). IR (3H, s), 3.94 (3H, s), 3.97 (3H, s), 5.78 (1H, br d, Jꢃ12.4 Hz), 7.65 (1H,
(KBr) cmꢁ1: 1628, 1612. EI-MS m/z : 362 (Mꢄ). Anal. Calcd for C12H11IO5: br s), 13.96 (1H, br s). EI-MS m/z: 323 (Mꢄ). Anal. Calcd for C16H21NO6: C,
C, 39.80; H, 3.06. Found: C, 39.95; H, 3.19.
59.43; H, 6.55; N, 4.33. Found: C, 59.21; H, 6.53; N, 4.31.
5,6,7-Trihydroxy-3-iodo-4H-chromen-4-one (12) To a suspension of 9
(497.9 mg, 1.38 mmol) in toluene (10 ml) was added AlCl3 (915 mg,
6.88 mmol) at room temperature. The mixture was then heated and stirred at
100 °C for 6 h. After cooling, the reaction mixture was poured into 3 N-HCl,
and stirred at room temperature for 1 h. The reaction mixture was extracted
with EtOAc, dried over Na2SO4 and concentrated. The residue was washed
with CH2Cl2 to give the title compound (415.6 mg, 94%): mp 227—229 °C.
1H-NMR (DMSO-d6) d: 6.50 (1H, s), 8.65 (1H, s), 12.11 (1H, s). IR (KBr)
8-Acetyl-3-iodo-5,6,7-trimethoxy-4H-chromen-4-one (5) A mixture
of 19 (1.23 g, 3.81 mmol) and iodine (1.94 g, 7.62 mmol) in CH2Cl2 (12 ml)
was stirred at room temperature for 2 h. The reaction mixture was quenched
with Na2S2O3 aq and extracted with EtOAc. The organic phase was dried
over Na2SO4, concentrated, and purified by flash chromatography on silica
gel (hexane/EtOAcꢃ8/3) to give the title compound (1.27 g, 83%). Recrys-
tallization from EtOAc–hexane afforded colorless crystals: mp 139—140 °C.
1H-NMR (CDCl3) d: 2.56 (3H, s), 3.93 (3H, s), 3.99 (3H, s), 4.05 (3H, s),
cmꢁ1: 3472, 3420, 1650, 1612. EI-MS m/z: 320 (Mꢄ). Anal. Calcd for 8.11 (1H, s). EI-MS m/z: 404 (Mꢄ). Anal. Calcd for C14H13IO6: C, 41.61; H,
C9H5IO5: C, 33.78; H, 1.57. Found: C, 33.75; H, 1.72.
3.24. Found: C, 41.35; H, 3.16.
5,6,7-Triacetoxy-3-iodo-4H-chromen-4-one (4) To a solution of 12
8-Acetyl-5,7-dihydroxy-3-iodo-6-methoxy-4H-chromen-4-one
(20)
(1.02 g, 3.19 mmol) in pyridine (5 ml) was added acetic anhydride (1.51 ml, To a solution of 5 (100 mg, 0.248 mmol) in toluene (2 ml) was added TiCl4
15.95 mmol), and the mixture was stirred at room temperature for 4 h. The
reaction mixture was poured into 3 N-HCl, and the resulting solid was fil-
tered, washed with H2O, and dried in vacuo to give the title compound
(1.18 g, 83%). Recrystallization from EtOAc–hexane afforded colorless
(0.74 ml, 1 M solution in toluene) at room temperature, and the mixture was
then stirred at 100 °C for 1 h. After cooling, the reaction mixture was poured
into 3 N-HCl and stirred at 80 °C for 0.5 h. The reaction mixture was ex-
tracted with EtOAc, dried over Na2SO4 and concentrated. The residue was
purified by flash chromatography on silica gel (CH2Cl2/EtOAcꢃ30/1) to
1
crystals: mp 200—202 °C. H-NMR (CDCl3) d: 2.33 (3H, s), 2.34 (3H, s),
2.45 (3H, s), 7.40 (1H, s), 8.21 (1H, s). IR (KBr) cmꢁ1: 1774, 1646, 1626.
give the title compound (68 mg, 73%). Recrystallization from EtOAc af-
EI-MS m/z: 446 (Mꢄ). HR-EI-MS m/z: 445.9482 (Calcd for C15H11IO8: forded colorless crystals: mp 224—226 °C. H-NMR (CDCl3) d: 2.76 (3H,
1
445.9499).
s), 3.93 (3H, s), 8.31 (1H, s), 13.26 (1H, s), 14.54 (1H, s). EI-MS m/z: 376
5,6-Diacetoxy-3-iodo-7-isopropoxy-4H-chromen-4-one (17)
A
mix- (Mꢄ). Anal. Calcd for C12H9IO6: C, 38.32; H, 2.41. Found: C, 38.11; H,
ture of 4 (928 mg, 2.08 mmol), 2-iodopropane (0.416 ml, 4.16 mmol), and
K2CO3 (861 mg, 6.24 mmol) in DMF (4.6 ml) was stirred at 40 °C for 6 h.
H2O was added to the mixture, and the mixture was extracted with EtOAc,
dried over Na2SO4 and concentrated. The residue was purified by flash chro-
matography on silica gel (hexane/EtOAcꢃ2/1) to give the title compound
2.47.
5,7-Dihydroxy-3-iodo-6-methoxy-4H-chromen-4-one (14) To a solu-
tion of 20 (222 mg, 0.59 mmol) in 1,2-dichloroethane (4 ml) was added tri-
fluoromethanesulfonic acid (0.2 ml) and H2O (0.2 ml) at room temperature.
The mixture was then refluxed for 20 h. The reaction mixture was extracted
(795.5 mg, 86%). Recrystallization from EtOAc–hexane afforded colorless with CH2Cl2, dried over Na2SO4 and concentrated. The residue was purified
by flash chromatography on silica gel (CH2Cl2/EtOAcꢃ30/1) to give the title
crystals: mp 138—139 °C. 1H-NMR (CDCl3) d: 1.39 (6H, d, Jꢃ6.1 Hz),
2.32 (3H, s), 2.44 (3H, s), 4.64 (1H, septet, Jꢃ6.1 Hz), 6.79 (1H, s), 8.14 compound (174.8 mg, 89%). Recrystallization from EtOAc–hexane afforded
(1H, s). IR (KBr) cmꢁ1: 1762, 1626. EI-MS m/z: 446 (Mꢄ). Anal. Calcd for colorless crystals: mp 175—176 °C. 1H-NMR (CDCl3) d: 4.03 (3H, s), 6.52
C16H15IO7: C, 43.07; H, 3.39. Found: C, 43.08; H, 3.51.
3-Iodo-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one (3) 1) To a
solution of 17 (793.8 mg, 1.78 mmol) in acetone (8 ml) was added 6 N-HCl,
(1H, s), 6.57 (1H, s), 8.14 (1H, s), 12.45 (1H, s). EI-MS m/z: 334 (Mꢄ).
Anal. Calcd for C10H7IO5: C, 35.95; H, 2.11. Found: C, 35.91; H, 2.03.
2-[(4-Hydroxyphenyl)thio]-7-isopropoxy-5,6-dimethoxy-4H-chromen-
and the mixture was stirred at 70 °C for 5 h. After adding H2O the mixture 4-one (2) A mixture of 3 (225.2 mg, 0.578 mmol), imidazole (79 mg,
was extracted with EtOAc, dried over Na2SO4 and concentrated to give 5,6-
hydroxy-3-iodo-7-isopropoxy-4H-chromen-4-one (554 mg, 86%). Recrystal-
lization from EtOAc–hexane afforded colorless crystals: mp 151—152 °C.
1H-NMR (CDCl3) d: 1.45 (6H, d, Jꢃ6.1 Hz), 4.70 (1H, septet, Jꢃ6.1 Hz),
5.43 (1H, s), 6.50 (1H, s), 8.17 (1H, s), 11.96 (1H, s). IR (KBr) cmꢁ1: 3508,
1.16 mmol) and K2CO3 (798 mg, 5.78 mmol) in DMF (2.3 ml) was stirred at
80 °C for 2 h. After cooling, a solution of 4-hydroxybenzenethiol (146 mg,
1.16 mmol) in acetone (1 ml) was added to the reaction mix, and the mixture
was stirred at room temperature for 2 h. The reaction mixture was poured
into 3 N-HCl, extracted with CH2Cl2, dried over Na2SO4 and concentrated.
1660, 1596. EI-MS m/z: 362 (Mꢄ). Anal. Calcd for C12H11IO5: C, 39.80; H, The residue was purified by flash chromatography on silica gel (CH2Cl2/ace-
3.06. Found: C, 39.97; H, 3.24.
2) A mixture of the above compound (554 mg, 1.53 mmol), K2CO3
(1.47 g, 10.68 mmol) and iodomethane (0.665 ml, 10.68 mmol) in DMF
toneꢃ10/1) to give the title compound (193 mg, 86%). Recrystallization
from EtOH afforded colorless crystals: mp 213—215 °C. H-NMR (CDCl3)
d: 1.45 (6H, d, Jꢃ6.1 Hz), 3.86 (3H, s), 3.92 (3H, s), 4.65 (1H, septet,
1
(8 ml) was stirred at 40 °C for 5 h. After adding H2O the mixture was ex- Jꢃ6.1 Hz), 5.64 (1H, s), 6.70 (1H, s), 6.85 (2H, d, Jꢃ8.8 Hz), 7.36 (2H, d,
tracted with EtOAc, dried over Na2SO4 and concentrated. The residue was
Jꢃ8.8 Hz), 9.82 (1H, s). IR (KBr) cmꢁ1: 3230, 1612, 1578. EI-MS m/z: 388
purified by flash chromatography on silica gel (hexane/EtOAcꢃ4/1) to give (Mꢄ), 373, 331.
the title compound (597.8 mg, 100%). Recrystallization from EtOAc–hexane
1
afforded colorless crystals: mp 99—100 °C. H-NMR (CDCl3) d: 1.45 (6H, Reference and Notes
d, Jꢃ6.1 Hz), 3.87 (3H, s), 3.96 (3H, s), 4.65 (1H, septet, Jꢃ6.1Hz), 6.65
(1H, s), 8.11 (1H, s). IR (KBr) cmꢁ1: 1638, 1608, 1478. EI-MS m/z: 390
(Mꢄ). Anal. Calcd for C14H15IO5: C, 43.10; H, 3.88. Found: C, 43.06; H,
3.82.
1) Komiya T., Tsukui M., Oshio H., Chem. Pharm. Bull., 23, 1387—
1388 (1975).
2) Chu C., Tseng T., Hwang J., Chou F., Wang C., Toxicology, 73, 263—
268 (1999).
2,6-Diacethyl-3,4,5-trimethoxyphenol (18) To a solution of 3,4,5-
trimethoxyphenol (3.21 g, 16.96 mmol) and acetic anhydride (6.41 ml,
67.84 mmol) in nitromethane (31 ml) was added AlCl3 (6.77 g, 50.88 mmol)
at 0 °C. The mixture was then stirred at room temperature for 20 h. 3 N-HCl
was added to the reaction mixture, and the mixture was stirred at room tem-
3) Nakata K., Sakaguchi H., Wakan Iyaku Gakkaishi, 1, 222—229
(1984).
4) Xu Q., Mori H., Sakamoto O., Koda A., Nishioka I., Ogawa Y.,
Hosaka K., Wakan Iyaku Gakkaishi, 6, 1—7 (1989).
5) Yamaguchi T., Sato S., Chin M., Ageta T., Nakajima K., Mitsuhashi

September 2005
H., Wakan Iyaku Gakkaishi, 5, 374—375 (1988).
6) Igarashi Y., Yamaguchi T., Ogawa Y., Tomita M., Hayashi H., Sato T.,
Hosaka K., WO 9209594 (1992).
1091
3,4,5-trimethoxyphenol and acetic anhydride using zinc choride in ni-
tromethane followed by hydrolysis using sodium hydrogencarbonate to
give 7 in 91% yield.
7) Takeno H., Hashimoto M., J. Chem. Soc., Chem. Commun., 1981, 10) Gammil R. B., Synthesis, 1979, 901—903 (1979).
474—475 (1981).
11) Zhu J., Chastanet J., Beugelmans R., Synth. Commun., 26, 2479—2486
8) Okutani T., Kawakita K., Aki O., Morita K., Heterocycles, 6, 1581—
1586 (1977).
(1996).
12) Keumi T., Morita T., Ozawa Y., Kitajima H., Bull. Chem. Soc. Jpn., 62,
9) Although the acetophenone 7 was a commercially available material, it
599—601 (1989).
was synthesized by the following method. Friedel–Crafts reaction of 13) Sugita Y., Yokoe I., Heterocycles, 43, 2503—2511 (1996).