Process development of the PDE4 inhibitor K-34

Article abstract of DOI:10.1021/op100291g

A short and practical synthesis of the PDE4 inhibitor K-34 (1) was developed. This synthesis was achieved in four steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor carboxylic acid assistance. This synthesis also features efficient ketone construction with 4-pyridinylmethyl anion 9 and ester 18, in which overreaction should be prohibited by quick in situ enolate formation. The overall synthesis was carried out under mild conditions and used a simple procedure suitable for large-scale production.

Full text of DOI:10.1021/op100291g

ARTICLE
pubs.acs.org/OPRD
Process Development of the PDE4 Inhibitor K-34
Arata Yanagisawa,†,* Masashi Taga, Toshiyuki Atsumi,† Koichiro Nishimura, Kyoji Ando, Tsuyoshi Taguchi,
Hiroshi Tsumuki, Iwao Chujo, and Shin-ichiro Mohri
Chemical Process Research and Development Laboratories, Kyowa Hakko Kirin Co., Ltd., 1-1-53, Takasu-cho, Sakai-ku, Sakai, Osaka
590-8554, Japan
ABSTRACT: A short and practical synthesis of the PDE4 inhibitor K-34 (1) was developed. This synthesis was achieved in four
steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor
carboxylic acid assistance. This synthesis also features efficient ketone construction with 4-pyridinylmethyl anion 9 and ester 18, in
which overreaction should be prohibited by quick in situ enolate formation. The overall synthesis was carried out under mild
conditions and used a simple procedure suitable for large-scale production.
Scheme 1. Original synthesis
’ INTRODUCTION
Among the c-AMP/c-GMP phosphodiesterases, the type 4
isozyme (PDE4) plays significant roles in regulating the func-
tions of bronchial smooth muscle and inflammatory cells such as
mast cells, neutrophils, eosinophils, T cells, B cells, and macro-
phages.1 K-34 (1) was identified in Kyowa Hakko Kirin as a very
potent and specific PDE4 inhibitor.2 K-34 has been a potential
anti-inflammatory drug candidate for the treatment of asthma or
atopic dermatitis by intratracheal administration or by topical
application, respectively.3 To support further pharmacological
evaluation and clinical trials, development of a practical synthesis
method for the titled compound was required.
K-34 possesses a 3,5-dichloro-4-pyridyl moiety which is one of
the essential structural components for its PDE4 inhibitory
activity. The unique structural feature of this compound is that
the linker between the pyridine unit and the benzene unit is a
ketone, which is different from most of the other PDE4 inhibi-
tors' linkers, which are amides.4 Another unique feature is the
spiro acetal moiety which is rarely seen in pharmaceutical com-
pounds.5 These novel structural features of K-34 therefore
present us with interesting synthetic challenges.
Original Synthesis. The original synthesis used in the med-
icinal chemistry program is shown in Scheme 1.2 Although the
synthesis is very short, it includes significant disadvantages for
large-scale production. It starts with moderate yield acetalization6
of the 3-methoxycatechol 2 followed by a low chemo- and
regioselective Vilsmeier reaction. After separation of isomer 5
by column chromatography, aldehyde 4 is coupled with the
4-pyridinylmethyl anion at -78 °C. Finally, Jones oxidation of
alcohol 7 affords 1 in a total 4% yield. Therefore, we were forced
to establish a practical synthesis of 1, in which both the selective
carbonyl introduction and oxidation-free ketone synthesis could
be achieved.
Although the regioselectivity of electrophilic substitution on
3-methoxycatechol 2 is 6-position favored,7 this is reversed after
acetal formation.8 Our initial attempts for functionalizing acetal
3, such as bromination, also demonstrated that the undesired
ortho-substitution to the methoxy group became favored. More-
over, the spiro acetal was not compatible with harsh reaction
conditions such as Friedel-Crafts reaction. Therefore, we
started new route exploration with 2,3,4-trimethoxybenzoic acid
(8) which already bears the necessary atoms on a benzene ring.
Coupling Partner Selection. With the goal of achieving
oxidation-free direct ketone synthesis, we first examined a model
coupling study between 2,3,4-trimethoxybenzic acid derivative
10 and 4-pyridinylmethyl anion 9 which was formed by LDA
treatment of 6 (Scheme 2).9 Dimethylamide 10a or Weinreb
amide 10b resulted in only recovery of the starting material.
Received: October 29, 2010
Published: January 04, 2011
r
2011 American Chemical Society
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Scheme 2. Ketone synthesis
Scheme 3. Route selectiona
Figure 1.
bromide 19 gave the corresponding acetal in a 30% yield, but
aldehyde 20 did not afford the desired product (Figure 1). In a
similar fashion, both methyl ester 15 and ketone 17 resulted in
low to moderate yield even when using an excess of the sulfonic
acid catalyst. In contrast, benzoic acid 13 exhibited smooth com-
pletion of the acetalization when xylene or chlorobenzene was
used as a reflux solvent. Moreover, the sulfonic acid catalyst
was found to have no effect on the reaction progression.
We investigated this unique high reactivity for acetalization as
well as the non-necessity of the acid catalyst. A small amount of
hemiacetal 23 was isolated and was assumed to be an active
intermediate. However, 23 was not converted to 14 under the
same acetalization condition, which indicated that 23 was just a
byproduct (Figure 1). Thus, we concluded that the neighboring
carboxylic acid moiety acts as an activating group for the phenol
as well as an acid catalyst. Thus, acetal 14 was obtained in 89%
yield with a simple crystallization by cooling the reaction mixture.
Subsequent treatment with methyl iodide and K2CO3 afforded
methyl ester 16 which was then subjected to the above ketone
synthesis method to successfully afford 1 in an 80% yield. The
total yield was dramatically improved, and the oxidation step was
eliminated. We next moved on to optimization of this route
in order to make it possible to carry out multikilogram-scale
production.
Route Optimization. First, replacement of the volatile and
toxic BCl3 was requested in the demethylation step. Other
demethylating reagents, e.g., AlCl3, TMSI, HBr, or thiols, were
less reactive and less selective than BCl3. Only aqueous HI
treatment in acetic acid exhibited the potential to be an alter-
native for BCl3, and was investigated in detail. Monitoring the
reaction progress with HPLC proved that demethylation pro-
ceeds in sequence from the 2-, 3-, then the 4-position (21, 13,
then 22). This reactivity order could be understood with regard
to possible hydrogen bond activation of either oxygen atom by
the neighboring carboxylic acid or phenol. A higher reaction
temperature or longer reaction time yielded considerable full
demethylation product 22. Fortunately, the desired diol 13
was found to precipitate as the reaction proceeded, and this
became an advantage for preventing the overreaction. The
optimal condition is shown in Scheme 4. Simple crystallization
from the reaction mixture by addition of water afforded 13 in a
73% yield. The generated methyliodide was >96% trapped by
In response to the low nucleophilicity of anion 9, more reactive
acid derivatives were examined. Acid chloride 10c gave the
desired ketone 11; however, it also yielded lots of byproduct.
Methyl ester 10d successfully afforded desired ketone 11 in a
satisfactory yield without formation of a double alkylated
byproduct.10 This could be understood by the fact that 3 equiv
of anion 9 was necessary for reaction completion, which implies
the quick in situ formation of enolate 12, which avoids further
reaction of the ketone 11.
Route Selection. Following the above successful ketone
synthesis, we moved on to route selection. It was necessary to
select from three possible routes which were realized in our initial
examination (Scheme 3). BCl3 mediated ortho- and meta-selective
demethylation of 2,3,4-trimethoxyaryl carbonyl compounds such
as 8 was known and was also successfully applied to 10d or 11
(step a) to give diols 13, 15, and 17, respectively.11 The most
critical step was identified as the acetalization step. Especially
when 3-methoxycatechol was substituted at the 6-position, consi-
derable slowing down of the reaction rate was observed. For example,
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Scheme 4. Optimal process synthesis
a combination of a reflux condenser, cold trap, and an alkaline
scrubber.
1 have now been successfully produced in our laboratories using
this procedure.
In the acetalization step, elimination of the generated metha-
nol had become a rate-determining factor in the large-scale syn-
thesis (5 L, 100-g scale). Therefore, the acetalization reagent
was changed to 1-methoxycyclopentene, which generates half
the amount of methanol and also acts as a methanol trapping
reagent. Cyclopentanone was selected as a highly dissolvable
solvent instead of xylene. The reproducibility was good on the
pilot-plant scale.
Because the methyl ester 16 did not exhibit good crystallinity
or a sufficient crystallization yield, other esters were examined.
Next, butyl ester 18 was selected because of its equivalent reac-
tivity to 16 and proper crystallinity, which made it possible to
achieve direct crystallization by adding water to the reaction. In
the final ketone synthesis, LDA was able to be substituted by
LiHMDS, and the overall temperature could be settled at 0 °C.
However, the assay yield was around 70% and therefore was not
satisfactory. The reason was identified to be the relatively rapid
degradation rate of anion 9 at 0 °C (T1/2 = ∼8 h). In order to
minimize the handling time of 9, the procedure was changed to
dropwise addition of LiHMDS into the 0 °C mixture of ester 18
and pyridine 6. The reaction was completed within 0.5 h after the
completion of LiHMDS addition. The in situ enolate formation
was confirmed by a deuterium oxide quenching experiment to
obtain ∼60% deuterated 1 at the methylene position. The yield
was thus dramatically improved and amount of 6 was reduced to
1.3 equiv by this change. Finally, a recrystallization of the crude
mixture from acetone-water afforded pure 1 in a 97% yield.
’ EXPERIMENTAL SECTION
General Information. All reagents and solvents are commer-
cially available (from Tokyo Kasei Kogyo Co., Ltd., Sigma-Aldrich
Co.) and used without further purification. H NMR spectra
1
were obtained on a JEOL JNM-LA300 spectrometer (300 MHz)
or Bruker AVANCE 500 spectrometer (500 MHz). Chemical
shifts (δ) are reported in ppm. Multiplicities are given as: s
(singlet), d (doublet), t (triplet), q (quartet), dd (doublet of
doublets), m (multiplet), br s (broad singlet). Proton-decoupled
13C NMR spectra were obtained on a JEOL JNM-LA300 spec-
trometer (75 MHz) or Bruker AVANCE 500 spectrometer (125
MHz). IR frequencies are given in cm-1 and spectra were obtai-
ned on a Shimadzu FT-IR8700 spectrometer. Mass spectra were
obtained on a JEOL JMS-DX303. Melting points (mp) were
determined on a Mettler FP61. Elemental analysis was perfor-
med on a Perkin Elmer series II CHNS/O analyzer 2400. HPLC
analyses were performed on a Hitachi L-4000 system. GC ana-
lyses were performed on a Shimadzu GC-14A equipped with a
capillary column GL Sciences TC-1.
Route Scouting . Methyl 2,3,4-Trimethylbenzoate (10d). To
a solution of 8 (2.00 g, 9.43 mmol) and DMF (0.87 mL, 11.3 mmol,
1.2 equiv) in CH2Cl2 (10 mL) under N2 was added SOCl2 (0.78
mL, 11.0 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred
at room temperature for 4 h. The acid chloride solution was added
dropwise to a solution of triethylamine (6.6 mL, 47.1 mmol, 5 equiv)
in methanol (20 mL) at 0 °C. The resulting mixture was diluted with
ethyl acetate and washed with aqueous sodium bicarbonate and
brine. The organic layer was dried over sodium sulfate and evapo-
rated to afford 10d (1.93 g, 8.53 mmol, 91% yield) as a colorless oil:
1H NMR (CDCl3) δ 7.61 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz,
1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H); 13CNMR
(CDCl3) δ 166.0, 157.1, 154.7, 142.9, 126.9, 117.8, 106.9, 61.8, 61.0,
56.0, 51.9; IR (film) 2945, 2843, 1724, 1682, 1595, 1495, 1466, 1431,
1412, 1273, 1219, 1188, 1138, 1036, 982, 780, 750, 696 cm-1; MS/
EI m/z 226 [M]þ.
’ CONCLUSION
In summary, a short, practical, and scalable synthesis proce-
dure for the PDE4 inhibitor K-34 (1) was developed. The syn-
thesis was achieved in four steps and with a 58% overall yield. The
unique spiro acetal was created by utilizing assistance from the
neighboring carboxylic acid, that is the sequence of the selective
bis-demethylation and following exceptionally high-yielding ace-
talization. This synthesis also features the efficient ketone
construction with 4-pyridinylmethyl anion 9 and ester 18, in
which excess LiHMDS suppressed over addition to the result-
ing ketone via in situ protection as the corresponding enolate.
Overall, harsh reagents and cryogenic conditions were elimi-
nated, and all intermediates were isolated by direct crystal-
lization from the reaction solutions. Multikilogram quantities of
2-(3,5-Dichloro-4-pyridyl)-1-(2,3,4-trimethoxyphenyl)-
ethanone (11). To a solution of 6 (215 mg, 1.3 mmol, 3 equiv)
in THF (2 mL) under N2 was added LDA (2 mol/L in THF,
0.66 mL, 1.3 mmol, 3 equiv) at -78 °C. The solution was stirred
at this temperature for 30 min, and 10d (100 mg, 0.44 mmol) in
THF (1 mL) was added. The mixture was allowed to warm to
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room temperature over 3 h, poured into aqueous ammonium
chloride, and extracted with ethyl acetate. The organic layer was
washed with brine, dried over magnesium sulfate, and concen-
trated in vacuo. The residue was purified on a silica gel column
chromatography eluting with hexane/ethyl acetate (4/1) to
afford 11 (130 mg, 0.36 mmol, 83% yield) as a white solid: mp
110-112 °C; 1H NMR (CDCl3) δ 8.50 (s, 2H), 7.63 (d, J = 8.9
Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.69 (s, 2H), 4.10 (s, 3H), 3.94
(s, 3H), 3.92 (s, 3H); 13C NMR (CDCl3) δ 192.6, 158.1, 154.4,
147.2, 142.1, 141.6, 133.5, 126.0, 124.4, 107.4, 61.5, 60.9, 56.2,
44.9; IR (KBr) 2950, 1670, 1590, 1470, 1295, 1100 cm-1; MS/EI
m/z 355 [M]þ.
2,3-Dihydroxy-4-methoxybenzoic Acid (13). To a solu-
tion of 2,3,4-trimethoxybenzoic acid (8) (4.25 g, 20 mmol) in
CH2Cl2 (15 mL) under N2 was added BCl3 (1 mol/L in CH2Cl2,
20 mL, 20 mmol, 1.0 equiv) at 0 °C. The mixture was stirred at
room temperature for 1 h, and another portion of BCl3 (1 mol/L
in CH2Cl2, 30 mL, 30 mmol, 1.5 equiv) was added. After stirring
10 h at room temperature, water and ethyl acetate were added.
The mixture was neutralized (pH 8) with 1 mol/L NaOH (40 mL)
and saturated aqueous sodium bicarbonate (10 mL). The sepa-
rated aqueous layer was acidified with 6 mol/L HCl (45 mL) and
extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated in vacuo. The residue was
diluted with methanol (20 mL), heated under reflux for 30 min,
and cooled to 0 °C. The precipitate was filtered, washed with
methanol, and dried to give 13 (2.15 g, 58% yield) as a white
solid. The mother liquor was concentrated in vacuo, and recrys-
tallized from water (33 mL) to afford another crop of 13 (0.92 g,
25% yield) as a white solid.
1213, 1198, 1161, 1096, 1076, 1018, 779, 770, 719 cm-1; MS/
EI m/z 198 [M]þ.
Methyl 7-Methoxyspiro(1,3-benzodioxol-2,10-cyclope-
ntane)-4-carboxylate (16) from 14. To a suspension of 14
(15.0 g, 60 mmol) and K2CO3 (9.9 g 72 mmol, 1.2 equiv) in
DMF (150 mL) under N2 was added methyliodide (4.1 mL, 66
mmol, 1.1 equiv). The mixture was stirred at room temperature
for 1 h, then poured into water and extracted with ethyl acetate.
The organic layer was washed with brine, dried over magnesium
sulfate, and concentrated in vacuo. The residue was dissolved in
methanol-water (5:1, 180 mL) at 40 °C and cooled to 10 °C.
Water (120 mL) was added, and the slurry was aged for 1 h. The
precipitate was filtered, washed with methanol-water (1/1), and
dried to give 16 (15.1 g, 57 mmol, 96% yield) as a white solid: mp
47 °C; 1H NMR (CDCl3) δ 7.40 (d, J = 9.0 Hz, 1H), 6.52 (d, J =
9.0 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 2.28-2.11 (m, 4H),
1.93-1.83 (m, 4H); 13C NMR (CDCl3) δ 165.1, 149.6, 146.7,
135.6, 129.8, 123.5, 106.6, 106.0, 56.4, 51.8, 37.3, 23.4; IR (KBr)
2955, 1713, 1638, 1508, 1433, 1101, 1020, 768 cm-1; MS/EI m/
z 264 [M]þ.
16 from 15. To a solution of cyclopentanone (50.0 g,
0.59 mol) and trimethyl orthoformate (75 mL, 0.71 mol, 1.2
equiv) in methanol (300 mL) was added p-toluenesulfonic acid
monohydrate (0.56 g, 2.9 mmol, 0.5 mol %) at room tempera-
ture. The mixture was stirred at the same temperature for 30 min
and then neutralized with sodium methoxide (28 wt % in metha-
nol, 2.3 g, 1.2 mol, 2 mol %). Hexane and water were added to the
mixture. The organic layer was washed with brine, dried over
magnesium sulfate, and concentrated to give 1,1-dimethoxycy-
clopentane as a pale-yellow oil (47.9 g, 0.37 mol, 62% yield). To a
solution of 15 (1.0 g, 5.04 mmol) and 1,1-dimethoxycyclopen-
tane (2.63 g, 20.2 mmol, 4 equiv) in toluene (50 mL) was added
camphorsulfonic acid (1.17 g, 5.04 mmol, 1 equiv). A dropping
funnel was charged with MS4A (10 g) and installed between the
reaction flask and reflux condenser. The mixture was then heated
under reflux. About every 6 h, 1,1-dimethoxycyclopentane (1.32 g,
10.1 mmol, 2 equiv) and camphorsulfonic acid (0.12 g, 0.50 mmol,
0.1 equiv) were added (eight times). After 50 h, the resultant
mixture was washed with saturated aqueous sodium bicarbonate
and brine, dried over sodium sulfate, and concentrated. The resi-
due was purified on a silica gel column chromatography eluting
with hexane/ethyl acetate (9:1) to afford 16 as a white solid
(0.82 g, 3.10 mmol, 62% yield).
K-34 (1) from 16 using LDA. To a solution of 6 (53 mg,
0.33 mmol, 3 equiv) in THF (1 mL) under N2 was added LDA
(2 mol/L in THF, 0.17 mL, 0.34 mmol, 3 equiv) at -78 °C. The
solution was stirred at this temperature for 50 min, and 10d
(28.7 mg, 0.11 mmol) in THF (1 mL) was added. The mixture
was allowed to warm to room temperature over 3 h, poured into
aqueous ammonium chloride, and extracted with ethyl acetate. The
organic layer was washed with brine, dried over magnesium sulfate,
and concentrated in vacuo. The residue was purified by silica gel
columnchromatography elutingwith hexane/ethyl acetate (5:1) to
afford 1 (34.4 mg, 0.087 mmol, 80% yield) as a white solid.
2-(3,5-Dichloro-4-pyridyl)-1-(2,3-dihydroxy-4-methyl-
phenyl)ethanone (17). To a solution of 11 (1.84 g, 5.17 mmol)
in CH2Cl2 (30 mL) under N2 was added BCl3 (1 mol/L in
CH2Cl2, 10.4 mL, 10.4 mmol, 2 equiv) at 0 °C. The mixture was
stirred at room temperature for 12 h, and another portion of BCl3
(1 mol/L in CH2Cl2, 5.2 mL, 5.2 mmol, 1 equiv) was added. The
mixture was stirred again at room temperature for 12 h, and
then diluted with ethyl acetate and washed with aqueous sodium
7-Methoxyspiro(1,3-benzodioxol-2,10-cyclopentane)-
4-carboxylic Acid (14). To a solution of cyclopentanone (841
g, 10.0 mol) and p-toluenesulfonic acid monohydrate (9.5 g,
50 mmol, 0.5 mol %) in methanol (2.5 L) was added trimethyl
orthoformate (1.15 L, 10.5 mol, 1.05 equiv) at 5 °C. The mixture
was stirred at the same temperature for 30 min and then
neutralized with sodium methoxide (28 wt % in methanol, 38.6
g, 0.20 mol, 2 mol %). Xylene (4.0 L) and water (2.0 L) were
added to the mixture, and then the organic layer was separated to
give 1,1-dimethoxycyclopentane as a xylene solution (5.7 L, net
1209 g, 1.64 mol/L, 9.29 mol, 93% yield). To the xylene
solution of 1,1-dimethoxycyclopentane (3.32 L, net 707 g,
5.43 mol, 10 equiv) was added 13 (100 g, 543 mmol). The
reaction mixture was heated at 130 °C for 17 h, continuously
removing methanol and methyl formate by Dean-Stark
apparatus. Then the resultant mixture was slowly cooled to
5 °C over 2 h. The precipitate was collected by filtration and
washed with toluene and then dried to give 14 (120.8 g, 483 mmol,
89%) as a white solid.
Methyl 2,3-Dihydroxy-4-methoxybenzoate (15). To a
solution of 10d (8.80 g, 38.9 mmol) in CH2Cl2 (20 mL) under
N2 was added BCl3 (1 mol/L in CH2Cl2, 98 mL, 98 mmol, 2.5
equiv) at 0 °C. The mixture was stirred at room temperature for
1 h, then diluted with ethyl acetate and washed with water.
The separated organic layer was dried over magnesium sulfate
and evaporated. The residue was recrystallized from methanol
(6 mL) to afford 15 (5.44 g, 27.4 mmol, 71% yield) as a white
solid: mp 93 °C; 1H NMR (CDCl3) δ 10.84 (s, 1H), 7.41 (d,
J = 9.0 Hz, 1H), 6.50 (d, J = 9.0 Hz, 1H), 5.49 (br s, 1H), 3.95
(s, 3H), 3.93 (s, 3H); 13C NMR (CDCl3) δ 170.4, 151.5,
149.3, 133.3, 121.3, 106.7, 102.9, 56.2, 52.1; IR (KBr) 3450,
3373, 2955, 1670, 1628, 1508, 1479, 1440, 1364, 1292, 1261,
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bicarbonate and brine. The separated organic layer was dried
over magnesium sulfate and evaporated. The residue was recrys-
tallized from hexane/ethyl acetate to afford 17 (1.57 g, 4.78
mmol, 93% yield) as a white solid: mp 190-192 °C; 1H NMR
(CDCl3) δ 11.90 (s, 1H), 8.54 (s, 2H), 7.51 (d, J = 9.1 Hz, 1H),
6.62 (d, J = 9.1 Hz, 1H), 5.59 (br s, 1H), 4.68 (s, 2H), 4.00 (s,
3H); IR (KBr) 3400, 3100, 1635, 1505, 1310, 1260 cm-1; MS/EI
m/z 327 [M]þ.
K-34 (1) from 17. A solution of 17 (92 mg, 0.28 mmol),
1,1-dimethoxycyclopentane (0.40 mL, 0.29 mmol, 1 equiv), and cam-
phorsulfonic acid (65 mg, 0.28 mmol, 1 equiv) in toluene (4.6 mL)
was heated under reflux for 8 h. 1,1-Dimethoxycyclopentane
(0.40 mL, 0.29 mmol, 1 equiv) was added every hour (seven
times) until reaction stopped. The resultant mixture was washed
with saturated aqueous sodium bicarbonate and brine, dried over
sodium sulfate, and concentrated. The residue was purified by
silica gel column chromatography eluting with hexane/ethyl
acetate (9:1) to afford 1 as a pale-yellow solid (21 mg, 0.053
mmol, 19% yield).
3,4-Dimethoxy-2-hydroxybenzoic Acid (21): white solid:
mp 164 °C; 1H NMR (CDCl3) δ 7.90 (d, J = 9.9 Hz, 1H), 6.55
(d, J= 9.9 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H); IR (KBr) 2943, 2548,
1651, 1605, 1504, 1460, 1275, 1103 cm-1; MS/EI m/z 198 [M]þ.
8-Hydroxy-7-methoxyspiro[4H-4-oxo-1,3-benzodioxin-
2,10-cyclopentane] (23):. white solid: mp 117 °C; 1H NMR
(CDCl3) δ 7.56 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 5.45
(br s, 1H), 3.98 (s, 3H), 2.22-2.17 (m, 4H), 1.89-1.81 (m, 4H),
3.92 (s, 3H); IR (KBr) 3419, 2934, 1726, 1620, 1508, 1323, 1194,
1119, 1076 cm-1; MS/EI m/z 250 [M]þ.
Optimal Process Route . 2,3-Dihydroxy-4-methoxyben-
zoic Acid (13). To a solution of 2,3,4-trimethoxybenzoic acid
(8) (300.0 g, 1.41 mol) in acetic acid (1.8 L) under N2 was added
57% HI (750 mL, 5.69 mol, 4.0 equiv) at 20 °C. The mixture was
gradually heated to 80 °C over 6 h and stirred at the same tempe-
rature for 7 h. Generated methyl iodide was trapped by a sequen-
tially connected Dean-Stark apparatus, a dry-ice-cooled trap,
and a NaOH (5 mol/L) bubbling trap. The resulting mixture was
cooled to 20 °C and partially neutralized (pH 1.5) by NaOH
(5 mol/L, 600 mL). The precipitate was collected by filtration,
washed with water (1.8 L), and dried to give 13 (191.0 g, 1.04 mol,
73.4% yield) as a white solid: mp 234 °C; 1H NMR (DMSO-d6)
δ 7.29 (d, J = 8.9 Hz, 1H), 6.57 (d, J = 8.9 Hz, 1H), 3.81 (s, 3H);
13C NMR (DMSO-d6) δ 172.4, 152.8, 150.7, 133.8, 120.8, 106.7,
103.4, 55.9; IR (KBr) 3350, 2818, 1655, 1618, 1508, 1283, 1090,
772 cm-1; MS/EI m/z 184 [M]þ.
precipitate was collected by filtration, washed with cold toluene
(0.4 L), and dried to give 14 (166.2 g, 0.66 mol, 88.6% yield) as a
white solid: mp 215 °C; 1H NMR (CDCl3) δ 7.47 (d, J = 9.1 Hz,
1H), 6.56 (d, J = 9.1 Hz, 1H), 3.96 (s, 3H), 2.26-2.12 (m, 4H),
1.92-1.86 (m, 4H); 13C NMR (CDCl3) δ 169.6, 150.2, 147.4,
135.6, 130.1, 124.3, 106.4, 105.7, 56.5, 37.4, 23.4; IR (KBr) 2990,
1678, 1639, 1452, 1286, 1111, 766 cm-1; MS/EI m/z 250 [M]þ.
Butyl 7-Methoxyspiro(1,3-benzodioxol-2,10-cyclopen-
tane)-4-carboxylate (18). To a solution of 14 (50.0g, 0.20mol)
in DMF (500 mL) under N2 were added K2CO3 (27.6 g,0.20 mol,
1.0 equiv) and butyliodide (25.0 mL, 0.22 mol, 1.1 equiv). The
mixture was stirred at 50 °C for 5 h then cooled to 20 °C. Water
(500 mL) was added, and the mixture was cooled and stirred
for 1 h at 5 °C. The precipitate was filtered, washed with water
(500 mL), and dried to give 18 (58.5 g, 0.19 mol, 95.5% yield) as
a white solid: mp 51 °C; 1H NMR (CDCl3) δ 7.39 (d, J = 9.1 Hz,
1H), 6.51 (d, J = 9.1 Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 3.93 (s,
3H), 2.25-2.10 (m, 4H), 1.92-1.81 (m, 4H), 1.72 (tt, J = 6.5,
8.0 Hz, 2H), 1.48 (tq, J = 8.0, 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz,
3H); 13C NMR (CDCl3) δ 164.6, 149.6, 146.5, 135.6, 129.5,
123.4, 107.0, 105.9, 64.3, 56.3, 37.2, 30.7, 23.3, 19.2, 13.7; IR
(KBr) 2955, 1701, 1639, 1450, 1339, 1285, 1215, 1138, 1107 cm-1
;
MS/EI m/z 306 [M]þ.
2-(3,5-Dichloro-4-pyridyl)-1-(7-methoxyspiro[1,3-ben-
zodioxol-2,10-cyclopentane]-4-yl)ethanone (K-34, 1). To
a solution of 18 (4.50 kg, 14.7 mol) and 3,5-dichloro-4-methyl-
pyridine 6 (3.10 kg, 19.1 mol, 1.3 equiv) in THF (45 L) under N2
was added dropwise LiHMDS (1.05 mol/L in THF, 42.0 L, 44.1
mol, 3.0 equiv) at 0 °C over 30 min. The mixture was stirred at
0 °C for 1 h and then quenched with aqueous ammonium
chloride (60 L). The organic layer was separated, washed with
brine, and concentrated in vacuo. The residue was diluted with
acetone (36 L) and concentrated again. The residue was dissol-
ved in acetone (45 L) at 50 °C, and active carbon (225 g) was
added with acetone (2 L). After 30 min of agitation, the active
carbon was filtered off and washed with hot acetone (13.5 L)
at the same temperature. The filtrate was diluted with water
(67.5 L) and cooled to 10 °C. The formed precipitate was fil-
tered, washed with acetone/water (1:1, 20 L), and dried to afford
1 (5.40 kg, 13.7 mol, 93.2% yield) as a white solid: mp 149 °C; 1H
NMR (CDCl3) δ 8.50 (s, 2H), 7.47 (d, J = 9.1 Hz, 1H), 6.61 (d,
J = 9.1 Hz, 1H), 4.59 (s, 2H), 3.97 (s, 3H), 2.27-2.22 (m, 4H),
1.93-1.88 (m, 4H); 13C NMR (CDCl3) δ 189.3, 149.3, 147.5,
147.2, 141.2, 135.4, 133.5, 129.9, 122.3, 113.4, 107.0, 56.5, 44.0,
37.4, 23.4; IR (KBr) 2968, 1685, 1635, 1505, 1310, 1260 cm-1
;
7-Methoxyspiro(1,3-benzodioxol-2,10-cyclopentane)-
4-carboxylic Acid (14). To a solution of cyclopentanone
(1262 g, 15.0 mol) and p-toluenesulfonic acid monohydrate
(14.3 g, 75 mmol, 0.5 mol %) in methanol (1262 mL) was added
trimethyl orthoformate (1723 mL, 15.8 mol, 1.05 equiv) at 5 °C.
The mixture was stirred at the same temperature for 30 min, then
slowly heated to 130 °C over 4 h, and stirred at the same tempe-
rature for 22 h under nitrogen gas flow (50-100 mL/min). The
resultant mixture was concentrated and distilled (70 °C/70-
75 mmHg) to give 1-methoxycyclopentene (926 g, 7.5 mol, 50%
yield) as colorless oil. A suspension of 13 (138.0 g, 0.75 mol) and
1-methoxycyclopentene (926 g, 7.5 mol, 10 equiv) in cyclopen-
tanone (828 mL) was heated 120 °C for 6 h under N2 flow. The
reaction mixture was cooled to 70 °C, and volatile components
were removed (∼1.6 L) under reduced pressure (70-75 mmHg).
The residue was diluted with toluene (1.6 L), and the resulting
slurry was heated at 90 °C for 1 h and then cooled to 0 °C. The
MS/EI m/z 393 [M]þ; Anal. Calcd for C19H17Cl2NO4: C,
57.88; H, 4.35; N, 3.55. Found: C, 58.05; H, 4.32; N, 3.52.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: arata.yanagisawa@kyowa-kirin.co.jp
Present Addresses
†Current address: Medicinal Chemistry Research Laboratories,
Fuji Research Park, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun,
Shizuoka 411-8731, Japan.
’ ACKNOWLEDGMENT
We thank Drs. Masaji Kasai and Koji Suzuki at former Sakai
Research Laboratories of Kyowa Hakko Kogyo, and Dr. Yoshisuke
Nakasato at Medicinal Chemistry Research Laboratories for helpful
discussions.
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Organic Process Research & Development
ARTICLE
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