A practical synthesis of highly hindered biphenyl-2-carboxylates via nucleophilic aromatic substitution of tert-butyl 2-methoxybenzoates with aryl grignard reagent

Article abstract of DOI:10.1021/op0001279

The fluorenone derivative (OPC-34165) has potent repairing and protecting activities for peripheral and central nervous system degeneration. A synthesis of the biphenyl-2-carboxylic acid derivative, which is the key intermediate of OPC-34165, is described employing the SNAr reaction of tert-butyl 2-methoxybenzoate with aryl Grignard reagent in refluxing THF-toluene.

Full text of DOI:10.1021/op0001279

Organic Process Research & Development 2001, 5, 535−538
A Practical Synthesis of Highly Hindered Biphenyl-2-carboxylates via
Nucleophilic Aromatic Substitution of tert-Butyl 2-Methoxybenzoates with Aryl
Grignard Reagent
Shinji Aki,* Yoshikazu Haraguchi, Hiroshi Sakikawa, Masashi Ishigami, Takafumi Fujioka, Takuya Furuta, and
Jun-ichi Minamikawa
Synthesis Laboratory, 2nd Tokushima Factory, Otsuka Pharmaceutical Co., Ltd., 224-18, Ebisuno, Hiraishi,
Kawauchi-cho, Tokushima 771-0182, Japan
Abstract:
was selected since the essential carboxylic acid moiety was
contained as the protected form in the starting material, and
an expensive reagent such as Ni or Pd catalyst was not used.
Treating the oxazoline derivative 3a with the aryl Grig-
The fluorenone derivative (OPC-34165) has potent repairing
and protecting activities for peripheral and central nervous
system degeneration. A synthesis of the biphenyl-2-carboxylic
acid derivative, which is the key intermediate of OPC-34165,
5
a,b
nard reagent 4a
gave the corresponding biphenyl com-
is described employing the S
oxybenzoate with aryl Grignard reagent in refluxing THF-
toluene.
N
Ar reaction of tert-butyl 2-meth-
pound 5a in 71% yield. However, the hydrolysis of the
oxazoline ring of 5a gave the corresponding 3-hydroxy-2-
methylpropan-2-yl amide which resisted further hydrolysis.
The drawback of this procedure was the difficulty in
deprotecting an oxazoline moiety to the parent carboxylic
acid. As an alternative procedure, Miyano and co-workers
report that 2,6-dialkyl-substituted phenyl esters serve as
convenient activating groups to carry out ortho-substitutions.
These esters are easily deprotected to the parent carboxylic
acid by transesterification [NaOMe in toluene and 1-methyl-
Introduction
The fluorenone derivative OPC-34165 (1), discovered in
our research institute, has potent repairing and protecting
activities for peripheral and central nervous system degenera-
1
tion. To provide the drug substance for pharmacological and
2
-piperidone (NMP) or HMPA] followed by hydrolysis of
toxicological evaluation, we searched for a suitable process
for the large-scale production of 1. As 1 can be easily derived
from the biphenyl-2-carboxylic acid derivative 2 by the
6
the methyl ester. Hence, we have applied Miyano’s proce-
dure and treated 3b (R ) Me) with 4a to give 5b (R ) Me)
in 92% yield. Unfortunately, 5b (R ) Me) had no reactivities
toward either hydrolytic or the recommended transesterifi-
2
intramolecular Friedel-Crafts cyclization, obtaining steri-
cally congested 2 was the most challenging problem to
overcome. Herein, we disclose an efficient method of
synthesis of 2 by using a nucleophilic aromatic substitution
7
cation conditions, and only a moderate result was obtained
for 2,6-di-tert-butyl-4-methoxyphenyl ester 5b (R ) OMe)
under the oxidative cleavage conditions using ceric am-
N
(S Ar) reaction.
8
monium nitrate (CAN) in giving 54% of 2 (Scheme 1). With
our compound, sterically congested esters to give the desired
biphenyls on S Ar reactions were resistant to deprotection
N
to the parent carboxylic acids.
Next, we investigated alkyl instead of phenyl esters, since
an i-propyl group was shown to be an effective activating
group for the synthesis of congested 1,1′-binaphthyl-2-
9
,10
carboxylate;
however, it was not applicable for the
(
4) Meyers, A. I.; Mihelich, E. D. J. Am. Chem. Soc. 1975, 97, 7383. (b)
Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. Engl. 1976, 15,
270. (c) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837.
5) The synthetic procedure was reported, see: (a) Aki, S.; Haraguchi, Y.;
Tone, H.; Fujioka, T.; Ishigami, M.; Sakikawa, H.; Minamikawa, J.; Nishi,
T.; Tanaka, T.; Watanabe, K. Jpn. Kokai Tokkyo Koho JP11-217348, 1999;
Chem. Abstr. 1999, 131, 129765f. (b) Scammells, P. J.; Baker, S. P.;
Beauglehole, A. R. Bioorg. Med. Chem. 1998, 6, 1517. (c) Hong, F.-T.;
Lee, K.-S.; Tsai, Y.-F.; Liao, C.-C. J. Chin. Chem. Soc. (Taipei) 1998, 45,
Results and Discussion
Although several useful methods of realizing aryl-aryl
(
coupling reaction for the construction of the biphenyl
3
framework are known, we have applied Meyers’ S
N
Ar
reaction to the methoxy group adjacent to the electron-
withdrawing group in aryloxazoline derivatives. This method
4
1.
*
Corresponding author. E-mail: shinaki@fact.otsuka.co.jp.
1) Tanaka, T.; Sakurai, Y.; Fujisawa, N.; Hongoh, O.; Nishi, T. WO95, 1995,
0468; Chem. Abstr., 1995, 122, 239345r.
2) For examples, see: (a) Wassmundt, F. W. J. Org. Chem. 1968, 33, 3322.
b) Suzuki, H.; Enya, T.; Hisamatsu, Y. Synthesis 1997, 1273.
(6) Hattori, T.; Suzuki, T.; Miyano, S. J. Chem. Soc., Chem. Commun. 1991,
1375. (b) Hattori, T.; Suzuki, T.; Hayashizaka, N.; Koike, N.; Miyano, S.
Bull. Chem. Soc. Jpn. 1993, 66, 3034. (c) Hattori, T.; Hayashizaka, N.;
Miyano, S. Synthesis 1995, 41. (d) Hattori, T.; Koike, N.; Miyano, S. J.
Chem. Soc., Perkin Trans. 1 1994, 2273. (e) Hattori, T.; Miyano, S. Yuki
Gosei Kagaku Kyokaishi 1997, 55, 121. (f) Hattori, T.; Koshiishi, E.; Wada,
S.; Koike, N.; Yamabe, O.; Miyano, S. Chirality 1998, 10, 619.
(
(
(
0
(
3) For general reviews, see: (a) Bringman, G.; Walter, R.; Weirich, R. Angew.
Chem., Int. Ed. Engl. 1990, 29, 977. (b) Altenbavh, H.-J. In Organic
Synthesis Highlights; Mulzer, J., Ed.; VCH: Weinheim, 1991; Vol. 1, p
(7) Due to the toxicity, we the authors did not examine the reaction in HMPA.
(8) Pirrung, M. C.; Heathcock, C. H. J. Org. Chem. 1980, 45, 1727.
1
81.
1
0.1021/op0001279 CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Vol. 5, No. 5, 2001 / Organic Process Research & Development
•
535
Published on Web 06/28/2001

Scheme 1
Table 1. Treatment of tert-butyl 2-methoxybenzoates with
aryl Grignard reagents
yield (%)
entry
3
4
7a
8b
1
2
3
4
5
3d
3d
3e
3e
3f
4a
4b
4a
4b
4a
91 (5d)
96 (2)
97
84
-
85
construction of a simple biphenyl system.11 As our com-
pounds 3 and 4 were sterically congested, we expected that
the carbonyl group of the i-propyl ester moiety might be
resistant to nucleophilic attack of the Grignard reagent 4a,
however, the product from the reaction between the i-propyl
c
26
38
∼0
d
e
91
a
Isolated yield of pure product from 3. b Isolated yield of pure product from
7
. c The major side product was 2′-(2,5-dimethoxy-4,6-dipropylbenzoyl)-2-
ester 3c (X ) CO
2
i-Pr in Scheme 1) and Grignard reagent
methoxybiphenyl (yield <39%; unseparable undetermined impurity was con-
taminated); see: ref 12. The complex mixture was obtained. e The major product
was tri(2-methoxyphenyl)methanol (61% yield).
d
4
a yielded undesired 2′-(2,5-dimethoxy-4,6-dipropylben-
12
zoyl)-2-methoxy-3,5,4′,6′-tetrapropylbiphenyl in 31% yield
and recovered 3c in 42% yield.
After several trials, we found that this problem could be
solved by using a tert-butyl ester. To our knowlege, this is
the first example of the use of an alkyl ester for the
treatment of this compound with 47% aqueous HBr in AcOH
at 50 °C easily furnished the desired biphenyl-2-carboxylic
acid 2 as a colorless solid in 96% yield (Scheme 1 and Table
13
16
construction of a biphenyl system using S
N
Ar methodology.
1
, entry 1). The efficiency of this improved method was
established in a scale-up trial. 3d (4.73 kg) gave the desired
(5.86 kg) after a simple purification (acid/base extraction)
Thus, the reaction of 3d5 with the Grignard reagent 4a (2.0
a,c
1
4
equiv) in refluxing THF-toluene (3:7, at about 88 °C) for
2
2
h gave the biphenyl ester 5d15 in 91% yield. Subsequent
in 94% yield from 3d.
We further investigated the scope and limitation of this
method. The results obtained for some other combinations
of o-methoxybenzoates and aryl Grignard reagents are
summarized in Table 1. (1) The combination of the crowded
3 and the crowded 4 was effective to give the corresponding
highly congested tert-butyl biphenyl-2-carboxylate deriva-
tives, which were readily converted to the parent carboxylic
acids in good yields (entries 1, 5). (2) When the steric crowd
of either reagent 3 or 4 was reduced, the yields of 7 decreased
(
9) Hotta, H.; Suzuki, T.; Miyano, S. Chem. Lett. 1990, 143.
(
N
10) The S Ar reaction of N-alkyl-substituted benzaldimine with aryl Grignard
reagents was reported, see: (a) Shindo, M.; Koga, K.; Tomioka, K. J. Am.
Chem. Soc. 1992, 114, 8732. (b) Flippin, L. A.; Carter, D. S.; Dubree, N.
J. P. Tetrahedron Lett. 1993, 34, 3255. (c) Goubet, D.; Meric, P.; Dormoy,
J.-R.; Moreau, P. J. Org. Chem. 1999, 64, 4516.
(
11) The following result was reported: treating i-propyl 2-methoxybenzoate
with phenylmagnesium bromide gave diphenyl(2-methoxyphenyl)methanol
in 75% yield; see: ref 6a.
12) A similar type of reaction was reported, see: Fuson, R. C.; Speck, S. B. J.
Am. Chem. Soc. 1942, 64, 2446.
13) The required tert-butyl ester 3d was readily prepared by esterification of
the corresponding carboxylic acid with thionyl chloride followed by
treatment with tert-butyl alcohol and potassium carbonate in dichlo-
romethane in 91% yield. For preparation of 3e, the transesterification
technique was more effective, see: (a) Rossi, R. A.; de Rossi, R. H. J.
Org. Chem. 1974, 39, 855. (b) Stanton, M. G.; Gagne, M. R. J. Org. Chem.
997, 62, 8240.
14) The use of THF-toluene as a cosolvent gave better results; the reaction of
d with 4a (3 equiv) in THF gave 82% of 5d after refluxing for 15 h.
(
(
(15) IR (film): 1720 cm-1; 1H NMR (300 MHz, CDCl
): δ ) 0.89-1.08 (m,
3
12H), 1.22 (s, 9H), 1.49-1.78 (m, 8H), 2.49 (t, J ) 8.8 Hz, 2H), 2.52-
2.80 (m, 6H), 3.36 (s, 3H), 3.78 (s, 3H), 6.86 (d, J ) 2.3 Hz, 1H), 6.94 (d,
46 4
J ) 2.3 Hz, 1H), 7.09 (s, 1H); HRMS results: calcd for C31H O , 482.3398;
found 482.3367.
1
(
(16) Green, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic Synthesis,
3
2nd ed.; John Wiley & Sons: New York, 1991; p 245.
536
•
Vol. 5, No. 5, 2001 / Organic Process Research & Development

Scheme 2a
L) and water (47.3 L) and concentrated in vacuo to give the
crude product (9.04 kg) as an oil. HBr (47% aqueous, 11.3
L) was added to the solution of the residual oil containing
1
5
5
d in acetic acid (37.2 L). After stirring for 5.5 h at 50 °C,
the reaction mixture was poured into H O (70.6 L) and
extracted with hexane (2 × 70.6 L). The organic layer was
washed with aqueous NaHCO O (42.4
(2 × 42.4 L) and H
L) and extracted with aqueous KOH (KOH: 1.30 kg in 70.6
L of H O). The aqueous KOH layer was washed with hexane
42.4 L), neutralized with aqueous HCl (concd HCl: 3.1 L
in 10.6 L of H O), and extracted with ethyl acetate (42.4
L). The ethyl acetate layer was washed with brine (42.4 L)
and H O (42.4 L) and concentrated in vacuo to give 2 (5.86
kg, 94% yield from 3d) as a solid: mp 73.4-74.0 °C
2
3
2
2
(
2
2
a
Reagents and conditions: (i) MsOH, 50-60°C, 1.5 h, 93%; (ii) 47% aq.
-
1
1
HBr, AcOH, reflux, 14 h, 93%.
(unrecryst.); IR (KBr) 1698 cm ; H NMR (300 MHz,
CDCl ) δ 0.86-1.15 (m, 12H), 1.50-1.75 (m, 8H), 2.49 (t,
3
significantly (entries 2, 3). (3) When the steric crowding of
both reagent 3 and 4 was relieved, the desired biphenyl
derivative could not be obtained; instead, tri(2-methoxyphe-
nyl)methanol was obtained in 56% yield as a major product
J ) 7.6 Hz, 2H), 2.59 (t, J ) 7.8 Hz, 2H), 2.60-2.82 (m,
4H), 3.35 (s, 3H), 3.79 (s, 3H), 6.87 (d, J ) 2.1 Hz, 1H),
13
6.95 (d, J ) 2.1 Hz, 1H); C NMR (75 MHz, CDCl ) δ 13.8,
3
14.0, 14.1, 14.4, 23.6, 23.9, 24.4, 24.6, 30.2, 31.9, 32.1, 37.4,
60.6, 61.5, 128.8, 129.8, 130.4, 132.1, 132.4, 133.3, 133.9,
135.1, 137.1, 138.0, 153.0, 156.1, 172.2. HRMS results:
(entry 4). The presented method is particularly effective for
the synthesis of sterically congested biphenyl-2-carboxylic
acid derivatives with limited synthesis of less hindered ones.
calcd for C27
,5-Dimethoxy-1,3,6,8-tetrapropyl-9-fluorenone (6). A
solution of 2 (5.85 kg, 13.7 mol) in methanesulfonic acid
46.8 L) was stirred at 50-60 °C for 1.5 h. After completion
38 4
H O , 426.2771; found 426.2743.
2
was converted into the desired product 1 as shown in
2
Scheme 2. After Friedel-Crafts cyclization, the resultant
methyl ether of the fluorenone (6) was deprotected to give
(
1
in high yield.
of the reaction, the mixture was poured into water (175.4 L)
at 0 °C and extracted with ethyl acetate (87.7 L). The extract
was combined further with ethyl acetate (58.5 L), washed
Conclusions
We have developed a practical and efficient method for
preparing the highly hindered biphenyl-2-carboxylic acid
derivative 2, which was the key intermediate for the synthesis
of OPC-34165 (1), by taking advantage of aryl-aryl
coupling reaction using tert-butyl o-methoxybenzoate and
an aryl Grignard reagent. Consequently, we have achieved
the large-scale production of 1.
with water (87.7 and 58.5 L), aqueous NaHCO
and H O (58.5 L), and concentrated in vacuo to give 6 (5.20
kg, 93% yield) as a deep orange oil: IR (film) 1698 cm ;
3
(58.5 L),
2
-
1
1
H NMR (300 MHz, CDCl ) δ 0.98 (t, J ) 7.2 Hz, 3H),
3
1.00 (t, J ) 7.2 Hz, 3H), 1.02 (t, J ) 7.1 Hz, 3H), 1.04 (t,
J ) 7.3 Hz, 3H), 1.48-1.78 (m, 8H), 2.61 (t, J ) 7.8 Hz,
2H), 2.65 (t, J ) 7.8 Hz, 2H), 2.94 (t, J ) 7.8 Hz, 2H), 3.01
(
t, J ) 7.6 Hz, 2H), 3.75(s, 3H), 3.82 (s, 3H), 6.82 (s, 1H),
1
3
Experimental Section
3
7.50 (s, 1H); C NMR (75 MHz, CDCl ) δ 14.0, 14.1, 14.2,
1
1
1
4.6, 23.7, 23.8 (×2), 24.1, 27.0, 31.7, 32.6, 32.7, 60.6, 61.7,
NMR spectra were recorded on a Bruker DPX-300
spectrometer (chemical shifts were given in ppm from TMS
as an internal standard in CDCl ). IR spectra were performed
3
on either a Perkin-Elmer FT-IR 1640 or a Nicolet FT-IR
Magna 560 spectrometer. Melting points were measured with
a B u¨ chi 535 and were uncorrected. HPLC was performed
on a Waters LC Module I Plus using a Tosoh TSKgel ODS-
23.0, 130.8, 131.1, 132.2, 135.3, 137.9, 138.9, 139.8, 141.6,
+
43.2, 151.8, 157.4, 194.7; M 408.
2
,5-Dihyroxy-1,3,6,8-tetrapropyl-9-fluorenone (1). A
solution of 6 (5.19 kg, 12.7 mol) and 47% aqueous HBr (15.1
L) in acetic acid (62.3 L) was refluxed for 6 h. HBr (47%
aqueous, 5.2 L) was further added to the reaction mixture
and refluxed for 8 h. After completion of the reaction, the
mixture was poured into a solution of water (186.9 L) and
ethyl acetate (62.3 L) at 10 °C. The aqueous layer was
extracted with ethyl acetate (51.9 and 21.0 L). The extracts
were combined, washed with water (87.7 and 58.5 L), brine
8
1
0T
50/1) phase at 270 nm.
-(3,5-Dipropyl-2-methoxy)phenyl-4,6-dipropyl-5-meth-
oxybenzoic Acid (2). A toluene (33.1 L) solution of
S
column (4.6 × 150 mm) and CH
3 2 3 4
CN/H O/H PO (850/
2
a,b
2
-bromo-4,6-dipropylanisole5 (5.96 kg, 22.0 mol) was
added to a suspension of Mg (534 g, 22.0 mol) and 1,2-
dibromoethane (47 mL) in THF (9.5 L). The mixture was
(3 × 51.9 L), and aqueous NaHCO (2 × 51.9 L). The
3
organic layer was treated with active-C, dried with anhydrous
magnesium sulfate, and concentrated in vacuo to give 1 (4.81
kg, quantitative, HPLC purity: 93%) as a deep red solid.
For purification, 1 (4.79 kg) was treated with acetic anhydride
(3.32 L, 35.2 mol) in pyridine (31.2 L) at room temperature
for 1.3 h to derive the corresponding diacetate (5.12 kg, 86%
yield from 6). The diacetate (5.10 kg) was recrystallized
refluxed for 6 h under N
2
. To this solution was added a
solution of 3d (4.73 kg, 14.7 mol) in toluene (4.7 L), and
the mixture was refluxed for 2 h under N . After completion
5
a,c
2
of the reaction, the mixture was poured into 3% aqueous
HCl (38.1 L) at 3 °C and extracted with ethyl acetate (23.7
L). The combined extracts were washed with brine (2 × 47.3
Vol. 5, No. 5, 2001 / Organic Process Research & Development
•
537

-
1 1
twice from 80% aqueous acetone (38.0 L was used for 1.0
kg of the diacetate) to give 4.42 kg (87% yield) of light
yellow needles.17 After deprotection of the acetyl group by
treating with concentrated HCl (19.7 L) in EtOH (75.0 L)
under reflux for 15 h to give 1 (3.54 kg, 98% yield), the
recrystallization from 65% aqueous EtOH (35.4 L) gave 1
mp 115.8-117.2 °C; IR (KBr) 1677, 3484 cm ; H NMR
(300 MHz, CDCl ) δ 0.91-1.06 (m, 12H), 1.51-1.76 (m,
8H), 2.54 (t, J ) 7.7 Hz, 2H), 2.59 (t, J ) 7.7 Hz, 2H), 2.90
t, J ) 7.7 Hz, 2H), 3.06 (t, J ) 7.7 Hz, 2H), 4.85 (br.s,
H), 4.94 (br.s, 3H), 6.69 (s, 1H), 7.46 (s, 1H); C NMR
3
(
1
13
(75 MHz, CDCl
3
) δ 13.9, 14.0, 14.1, 14.2, 22.7 (×2), 22.9,
(3.10 kg, 88% yield) with high purity (HPLC analysis
2
1
3.9, 25.8, 31.9, 32.5, 33.1, 123.2, 129.6, 129.7, 130.2, 130.8,
31.2, 133.3, 135.3, 136.2, 136.5, 146.9, 151.9, 195.7.
indicated 99.75% purity; t ) 8.7 min.) as deep red prisms:
R
1 1
25 32 3
C H O requires C 78.91, H 8.48. Found C 79.04, H 8.37%.
(
17) Mp 148.0-148.5 °C; IR (KBr): 1705, 1754 cm- ; H NMR (300 MHz,
CDCl ): δ 0.97 (t, J ) 7.3 Hz, 3H), 0.99 (t, J ) 7.3 Hz, 9H), 1.46-1.76
m, 8H), 2.30-3.40 (br. m, 2H), 2.35 (s, 3H), 2.45 (s, 3H), 2.45 (t, J ) 7.7
3
(
1
3
Hz, 4H), 2.97 (t, J ) 7.6 Hz, 2H), 6.91 (s, 1H), 7.20 (s, 1H); C NMR (75
MHz, CDCl
3
): δ 14.0, 14.1 (×2), 14.5, 20.5, 20.9, 22.3, 22.8, 23.1, 23.7,
7.2, 32.4, 32.8, 33.1, 121.5, 130.7, 130.8, 132.5, 134.9, 136.8, 140.2, 140.3,
41.8, 142.0, 142.1, 148.5, 168.7, 169.2, 193.6; M+ 464.
Received for review December 4, 2000.
OP0001279
2
1
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