A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S) -methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via reductive etherification

Article abstract of DOI:10.1248/cpb.c12-00023

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(25)-pyrrolidinylmethoxy] cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5- dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S) -pyrrolidinylmethoxy] cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4- methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4- triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.

Full text of DOI:10.1248/cpb.c12-00023

882
Regular Article
Chem. Pharm. Bull. 60(7) 882–886 (2012)
Vol. 60, No. 7
A Concise Synthesis of a Very Late Antigen-4 Antagonist trans-4-[1-
[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-
methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid via
Reductive Etherification
Jun Chiba,* Fumihito Muro, Masaki Setoguchi, and Nobuo Machinaga
Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd.; 1–2–58 Hiromachi, Shinagawa-
ku, Tokyo 140–8710, Japan. Received March 8, 2012; accepted April 5, 2012
This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]
cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-
[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]
cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using
(2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycy-
clohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from
commercially available starting material.
Key words 4-hydroxycyclohexanecarboxylic acid; reductive etherification; antagonist
We have discovered a VLA-4 (very late antigen-4, integ- route to 1 than Route A and B. Herein, we describe the new
rin α4β1) antagonist, trans-4-[1-[[2,5-dichloro-4-(1-methyl-3- approach to 1 via the synthesis of ethyl trans-[(4S)-methoxy-
indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)- (2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) based
pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1)1,2) shown on a stereo defined method using reductive etherification.
in Fig. 1. On the basis of its favorable profile,1,2) compound 1
Reductive etherification6–16) of silyl ethers with carbonyl
was advanced into clinical trials for the treatment of asthma.
compounds using triethylsilane as a reductive agent and
Compounds 2a–c are key intermediates for accessing 1. Lewis acids such as trimethylsilyl trifluoromethanesulfonate
Originally, we prepared 2a,b via Route A as shown in Chart (TMSOTf),6,7) trimethyl iodosilane (TMSI),8,9) TrClO4,10)
1, which features Mitsunobu etherification of 3, Rh/Al2O3 BiBr3,11) BiCl3,12) CuOTf,13) InCl3,14) FeCl315,16) as a catalyst, is
catalized high pressured hydrogenation of the benzene ring of a useful transformation reaction in organic synthesis. It is well
4, and the following isomerization of cis-5 to trans-5. On top known that the etherification works well even in case of a sec-
of that, HPLC or flash column chromatography using a large ondary alkoxy silyl ethers with ketone in Chart 2.9,16) At this
amount of silica gel was necessary for separation of trans-5 point, we considered that compound 2b could be efficiently
from a mixture of cis-5 and trans-5. To address the trouble- synthesized by using the etherification reaction. Thus, we en-
some separation, we next established Route B3) in Chart 1, visioned applying it in the synthesis of 2b from silyl ether 10
where we set out tert-butyl trans-4-hydroxycyclohexanecar- and ketone 11 via Route C-1 or aldehyde 12 and silyl ether 13
boxylate (7) as a starting material. At first, the ester 7 was via Route C-2 as shown in Chart 3.
subjected to basic etherification with epichlorohydrin to give
The silyl ether 10a and 10b were prepared from commer-
the ether 8, which was transformed to the amide 9 by utiliza- cially available cis-Z-Hip(OH) (14) as shown in Chart 4. Com-
tion of the sequential 4 steps procedure; nucleophilic addition pound 14 was treated with MeI/NaH to afford the ester 15 in
with vinyl magnesium bromide, amination via a pthalimide, 99% yield. By subjecting to NaBH4 reduction in the presence
and benzoylation. Next, the pyrrolidine ring construction by of MeOH, the ester 15 was transformed to the alcohol 16 in
means of iodine mediated cyclization4,5) and the following 67% yield, which was converted to 10a and 10b by treatment
modification on 4-position substituent of the pyrrolidine suc- with trimethylchlorosilane (TMSCl) or triethylchlorosilane
cessfully provided the amine 2c. However, Route B needed a (TESCl) in the presence of Et3N in 99% and 94%, respec-
total of 13 steps to 2c. In continuation of our work on the syn- tively.
thesis of 1, we have now developed a more concise synthetic
According to the reported procedure,11) we examined Route
Fig. 1. VLA-4 Antagonist 1 and Key Intermediate 2
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: chiba.jun.mv@daiichisankyo.co.jp
© 2012 The Pharmaceutical Society of Japan

July 2012
883
Chart 1. Previously Reported Routes
Chart 2. Reductive Etherification of Carbonyl Compounds
C-1 at first. The trimethylsilyl ether 10a and ketone 11 were
treated 0.1eq BiBr3 and 4eq Et3SiH in CH3CN to afford a
Conclusion
We have developed a concise synthetic route to 2b, a key
trace amount of 17 (Table 1, entry 1). In the case of the trieth- intermediate for VLA-4 antagonist 1, utilizing reductive ether-
ylsilyl ether 10b and the ketone 11, the mixture was obtained ification as a key reaction. The new route, which provides 2b
with inseparable by-products in 42% yield (entry 2). In the in 6 steps with 38% overall yield from commercially available
case of FeCl315,16) as a Lewis acid, the reaction of 10b with 11 cis-Z-Hip(OH) (14) and ethyl trans-4-hydroxy-1-cyclohexane-
afforded only trace amount of 17 (entry 3). On the other hand, carboxylate (13c), represents a promising alternative to the
treatment of 10a with 11 under 0.5eq TMSI and 1.5eq Et3SiH previously reported synthetic procedures to 1.
condition8,9) in dichoromethane (DCM) provided a mixture of
17a and 17b in 46% yield in a ratio of 1:1 (entry 4).
Experimental
Next we examined Route C-2 with a combination of alde-
Optical rotations were measured with a HORIBA SEPA-300
hyde 12 and trans-silyl ether 13a and 13b, which were easily polarimeter. 1H-NMR spectra were recorded on a JEOL
prepared from commercial available 13c. The aldehyde 12 JNM-EX-400 and JNM-ECA500 spectrometer, and chemical
was easily obtained from 16 under Swern oxidation condi- shifts are expressed relative to tetramethylsilane (TMS) at δ
tion without epimerization18) in 93% yield as shown in Chart 0.00ppm. IR spectra were recorded on a HORIBA FT-720
5. The reductive etherification between 12 and 13a using 0.1 spectrometer. Mass spectra were recorded on a SCIEX API-
to 0.5eq TMSI and 1.2eq Et3SiH did not provide 17a (entries 150EX spectrometer (electrospray ionization (ESI)) or a
1 and 2). On the other hand, in the case of a stoichiometric JEOL JMS-HX110 spectrometer (FAB). High resolution-mass
amount of TMSI, the reaction successfully provided 17a as a spectra (HR-MS) spectra were recorded on a JEOL JMS-
single diastereomer in 13% yield (entry 3). Furthermore, we 100LP spectrometer. Elemental analysis was performed using
evaluated other Lewis acids such as BiBr3 and FeCl3. BiBr3 a PerkinElmer CHNS/O 2400II, a Leco CHNS-932, and a
provided 17a in 40% yield (entry 4) and FeCl3 furnished 17a YOKOKAWA analysis IC7000RS. All starting materials and
in 62% yield (entry 5). We additionally investigated a direct synthesis reagents were obtained commercially.
conversion16) of ethyl trans-4-hydroxycyclohexanecarboxylate
(13c) with aldehyde 12, however, resulting in a trace amount dine-2-carboxylate (15)19) To
of 17a. 1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid
Finally, the N-benzyloxycarbonyl group of 17a was removed (14) (5.00g, 18.8mmol) in N,N-dimethylformamide (DMF)
Methyl (2S,4S)-1-Benzyloxycarbonyl-4-methoxypyrroli-
solution of (2S,4S)-
a
°
by hydrogenolysis to give 2b in 100% yield as shown in Chart (50mL) was added 60% oily NaH (1.55g, 38.8mmol) at 0 C
5. Subsequent condensation of 2b with [2,5-dichloro-4-(1- with stirring. After being stirred for 30min, MeI (2.58mL,
methyl-3-indolylcarbonylamino)phenyl]acetic acid (18)1) and 41.4mmol) was added to the reaction mixture at 0 C and al-
°
basic hydrolysis of the ethyl ester group of the resulting amide lowed to reach room temperature for 2d. The reaction mixture
successfully provided 1 in 81% yield from 2b. All of the spec- was poured into 1N HCl solution, and extracted with EtOAc.
troscopic data of 1 were completely identical with those we The combined extracts were washed with brine. After hav-
had previously reported.1,3)
ing been dried over Na2SO4, the extracts were concentrated

884
Vol. 60, No. 7
Chart 3. Retrosynthetic Strategies
Chart 4
Table 1. Results of Reductive Etherification between 10 and 11 via Route C-1
Entry
Substrate
Reagents and conditions
Yield
Ratio (cis/trans)
1
2
3
4
10a
10b
10b
10a
BiBr3 (0.1eq)/Et3SiH (4.0eq)/CH3CN
BiBr3 (0.1eq)/Et3SiH (4.0eq)/CH3CN
FeCl3 (0.1eq)/Et3SiH (1.2eq)/CH3CN
TMSI (0.5eq)/Et3SiH (1.5eq)/DCM
Trace
42%a)
Trace
46%
Nd
Nd
Nd
1/1b)
a) Determined by 1H-NMR. b) Determined by HPLC.17)
Chart 5
under reduced pressure. The resulting residue was purified with brine. After being dried over Na2SO4, the extracts were
by chromatography using Merck silica gel 60 (particle size concentrated under reduced pressure. The residue was purified
70–230 mesh) eluting with 33% EtOAc/n-hexane to give 15 by flash chromatography using a Biotage SNAP KP-Sil 50g
1
(5.49g, 99%) as a colorless oil. H-NMR (CDCl3, 400MHz) δ: eluted with 10–80% EtOAc/n-hexane to give 16 (1.96g, 67%)
1
2.21–2.37 (2H, m), 3.26 (3H, s), 3.54–3.76 (5H, m), 3.93–3.96 as a colorless oil. H-NMR (CDCl3, 400MHz) δ: 1.75–1.88
(1H, m), 4.41–4.51 (1H, m), 5.06–5.21 (2H, m), 7.27–7.38 (5H, (2H, m), 2.17–2.25 (1H, m), 3.27–3.35 (3H, m), 3.52–3.70 (2H,
m); 13C-NMR (CDCl3, 100MHz) δ: 34.6, 51.6, 52.2, 56.5, 57.5, m), 2.72–3.94 (3H, m), 4.05–4.15 (1H, m), 5.10–5.18 (2H, m),
67.0, 77.9, 127.9, 128.0, 128.4, 136.6, 154.4, 172.2; ESI-MS 7.27–7.40 (5H, m); 13C-NMR (CDCl3, 125MHz) δ: 34.1, 52.2,
m/z: 294 (M++1).
56.7, 60.0, 66.7, 67.3, 78.7, 128.0, 128.1, 128.5, 136.4, 156.6;
(2S,4S)-1-Benzyloxycarbonyl-4-methoxy-2-pyrrolidinyl- ESI-MS m/z: 266 (M++1).
methanol (16) To a stirred suspension of methyl (2S,4S)-
(2S,4S)-1-Benzyloxycarbonyl-4-methoxypyrrolidine-
1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxylate (15) 2-carboxyaldehyde (12) To a stirred solution of oxalyl
(3.22g, 11.0mmol) and NaBH4 (0.830g, 22.0mmol) in toluene chloride (1.37mL, 16.2mmol) in DCM (50mL) was added
°
(100mL) was added MeOH (5.35mL, 131.7mmol) at room dimethyl sulfoxide (DMSO) (2.14mL, 30.2mmol) at −60 C.
temperature. After stirring 4h, the reaction mixture was After stirring for 30min, (2S,4S)-1-benzyloxycarbonyl-
°
heated at 50 C for 18h. After cooling down to room tem- 4-methoxy-2-pyrrolidinylmethanol (16) (2.01g, 7.55mmol)
perature, the reaction mixture was poured into water and in DCM (30mL) was dropwised to the reaction mixture.
extracted with EtOAc. The combined extract was washed The reaction mixture was stirred for 1h, and then DIPEA

July 2012
885
1
Table 2. Results of Reductive Etherification between 12 and 13 via
Route C-2
A yellow oil (yield, 97%). H-NMR (CDCl3, 400MHz) δ:
0.13 (9H, s), 1.08–1.53 (7H, m), 1.83–2.05 (4H, m), 2.13–2.26
(1H, m), 3.51–3.62 (1H, m), 4.11 (2H, q, J=7.3Hz); 13C-NMR
(CDCl3, 100MHz) δ: 14.2, 27.3, 34.7, 42.2, 60.0, 70.2, 175.6.
trans Ethyl 4-Triethylsilanyloxycyclohenexanecarboxyl-
ate (13b) The compound 13b was prepared according to the
procedure of 10a.
1
A yellow oil (yield, 100%). H-NMR (CDCl3, 400MHz) δ:
0.52–0.58 (6H, m), 0.89–0.92 (9H, m), 1.21 (3H, t, J=7.0Hz),
1.24–1.56 (4H, m), 1.82–1.99 (4H, m), 2.12–2.22 (1H, m),
3.56–3.46 (1H, m), 4.07 (2H, q, J=7.2Hz); 13C-NMR (CDCl3,
100MHz) δ: 4.8, 6.8, 14.2, 27.4, 35.0, 42.3, 60.2, 70.3, 175.8.
trans-4-[1-Benzyloxycarbonyl-(4S)-methoxy-(2S)-
pyrrolidinylmethoxy]cyclohexanecarboxilic Acid Ethyl Es-
ter (17a). Typical Procedure of the Reductive Etherification
To a stirred solution of (2S,4S)-1-benzyloxycarbonyl-4-me-
thoxypyrrolidine-2-carboxyaldehyde (12) (263mg, 1.00mmol)
and trans-4-triethylsilyloxycycholhexanecarboxilic acid ethyl
ester (344mg, 1.20mmol) in CH3CN (10mL) were added tri-
ethylsilane (195µL, 1.20mmol) and FeCl3 (8.1mg, 50µmol) at
room temperature under an atmosphere of nitrogen. After 20h
of stirring, the reaction mixture was poured into sat.NaHCO3
Entry
1
Substrate Reagents and conditions
Yield
13a
13a
13a
13b
13b
13c
TMSI (0.1eq)/Et3SiH
(1.2eq)/DCM
Complex mixture
2
3
4
5
6
TMSI (0.5eq)/Et3SiH
(1.2eq)/DCM
Complex mixture
TMSI (1.0eq)/Et3SiH
(1.0eq)/DCM
13%
40%
62%
Trace
BiBr3 (0.1eq)/Et3SiH
(4.0eq)/CH3CN
FeCl3 (0.1eq)/Et3SiH
(1.2eq)/CH3CN
FeCl3 (0.1eq)/Et3SiH
(1.2eq)/CH3CN
(8.42mL, 60.4mmol) was dropwised and stirred for 1h. The solution and extracted with EtOAc. The combined extracts
reaction mixture was poured into sat.NH4Cl solution and ex- were washed with brine. After being dried over Na2SO4, the
tracted with DCM. The combined extracts were washed with extracts were concentrated in vacuo. The residue was purified
ice water and brine. After they were dried over Na2SO4, the by thin layer chromatography Merck TLC Plate Silica gel 60
extracts were concentrated in vacuo. The residue was purified [EtOAc/n-hexane=1/1 (v/v)] to give 17a (261mg, 62%) as a
1
by flash chromatography using a Biotage SNAP KP-Sil 100g colorless oil. H-NMR (CDCl3) δ: 1.17–1.50 (7H, m), 1.91–2.27
eluted with 10–80% EtOAc/n-hexane to give 12 (1.86g, 93%) (8H, m), 3.30 (3H, s), 3.36–4.08 (6H, m), 4.09–4.14 (2H, m),
1
as a colorless oil. H-NMR (CDCl3, 400MHz) δ: 2.03–2.19 5.03–5.23 (2H, m), 7.28–7.46 (5H, m); 13C-NMR (CDCl3,
(1H, m), 2.32–2.45 (1H, m), 3.21 and 3.23 (total 3H, each s, 125MHz) δ: 13.9, 26.7, 30.8, 31.1, 32.0, 42.1, 51.9, 56.2, 56.4,
amide isomers), 3.46–3.55 (1H, m), 3.68 and 3.75 (total 1H, 59.9, 66.5, 78.7, 127.6, 127.7, 128.2, 136.7, 154.6, 175.3; MS
each d, J=11.0, 12.8Hz respectively, amide isomers), 3.93 (1H, (ESI), m/z 420 (M++1); ESI-MS (HR) m/z: 420.2386 (Calcd for
t, J=2.8Hz), 4.19 and 4.27 (total 1H, each d, J=10.1, 9.6Hz C23H34NO6: 420.2386); [α]D25 −30.1 (c=0.52, CHCl3).
°
respectively, amide isomers), 5.14–5.21 (2H, m), 7.29–7.41 (5H,
m), 9.52 and 9.60 (total 1H, each s, amide isomers); ESI-MS, hexanecarboxilic Acid Ethyl Ester (2b)
m/z: 264 (M++1).
sion of trans-4-[1-benzyloxycarbonyl-(4S)-methoxy-(2S)-
trans-4-[(4S)-Methoxy-(2S)-pyrrolidinylmethoxy]cyclo-
A
suspen-
(2S,4S)-1-Benzyloxycarbonyl-4-methoxy-2-trimethylsil- pyrrolidinylmethoxy]cyclohexanecarboxilic acid ethyl ester
yloxymethylpyrrolidine (10a) To a solution of (2S,4S)- (17a) (675mg, 1.61mmol) and 10% Pd(OH)2/C (135mg) in
1-Benzyloxycarbonyl-4-methoxy-2-pyrrolidinylmethanol (16) MeOH (15mL) was stirred at room temperature under 1atom
(1.48g, 5.58mmol) and Et3N (0.93mL, 6.67mmol) in ether hydrogen atmosphere for 15h. After removing the catalyst
(20mL) was added TMSCl (0.85mL, 6.70mmol) at room tem- by filtration, the filtrate was concentrated in vacuo to give
1
perature with stirring. After being stirred for 15h, the reaction 2b (459mg, 100%) as a pale brown oily. H-NMR (CDCl3)
was filtered to remove unsolved material and the mother liquid δ: 1–1.32 (5H, m), 1.41–1.52 (2H, m), 1.70–1.75 (1H, m),
was concentrated under reduced pressure. The resulting resi- 1.99–2.28 (6H, m), 3.12–3.34 (6H, m), 3.55–3.65 (3H, m),
due was purified by chromatography using Merck silica gel 60 3.98–4.02 (1H, m), 4.11 (2H, q, J=7.1Hz); 13C-NMR (CDCl3,
(particle size 70–230 mesh) eluting with 33% EtOAc/n-hexane 125MHz) δ: 14.2, 27.0, 31.1, 34.1, 42.4, 50.0, 56.6, 58.3, 60.2,
1
to give 10a (1.86g, 99%) as a colorless oil. H-NMR (CDCl3, 63.1, 69.2, 71.9, 79.1, 80.4, 175.6; MS (ESI), m/z 286 (M+); EI-
400MHz) δ: 0.04 and 0.11 (total 9H, each s), 1.98–2.03 MS (HR) m/z: 286.2012 (Calcd for C15H28NO4: 286.2018); [α]D25
°
(1H, m), 2.21–2.24 (1H, m), 3.30 (3H, s), 3.37–3.97 (6H, m), −11.7 (c=1.05, CHCl3).
5.08–5.19 (2H, m), 7.28–7.38 (5H, m).
(2S,4S)-1-Benzyloxycarbonyl-4-methoxy-2-triethylsilyl-
oxymethylpyrrolidine (10b) The compound 10b was pre-
pared according to the procedure of 10a.
References and Notes
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A colorless oil (yield, 94%). H-NMR (CDCl3, 400MHz)
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