A practical synthesis of [(1 S,3 S)-3-aminocyclohexyl]methanol and 2-[(1 S,3 S)-3-aminocyclohexyl]propan-2-ol, useful intermediates for the preparation of novel m PGES-1 inhibitors

Article abstract of DOI:10.1055/s-0031-1289884

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. During the course of studies aimed at the identification of a suitable mPGES-1 inhibitor for clinical development, a need arose for preparing enantiomerically enriched amino alcohols (S,S)-2 and (S,S)-3. Described herein, a concise synthesis of (S,S)-2 and (S,S)-3 has been developed wherein both amino alcohols are derived from a commercially available, low-cost starting material. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289884

LETTER
2959
A Practical Synthesis of [(1S,3S)-3-Aminocyclohexyl]methanol and 2-[(1S,3S)-
3-Aminocyclohexyl]propan-2-ol, Useful Intermediates for the Preparation of
Novel mPGES-1 Inhibitors
P
ractical
S
ynthesis
a
of Enantio
n
merically
E
n
i
r
iched
e
Amino
A
lc
l
ohols P. Walker,*a Steven E. Heasley,a Allison MacInnes,a Tizah Anjeh,b Hwang-Fun Lu,a Yvette M. Fobian,a
Joe T. Collins,a Michael L. Vazquez,a Michael K. Maob
a
Pfizer Worldwide Medicinal Chemistry, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA
Fax +1(860)6860013; E-mail: daniel.p.walker.pfizer@gmail.com
Pfizer Worldwide Pharmaceutical Sciences, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA
b
Received 20 July 2011
While no prior studies on the synthesis of either (S,S)-2 or
Abstract: Microsomal prostaglandin E2 synthase-1 (mPGES-1) is
(S,S)-3 have appeared in the literature, Zhu et al. prepared
a novel therapeutic target for the treatment of inflammation and
the related carboxylic acid (S,S)-4 in six steps from enan-
tiomerically enriched (97% ee) lactone (S,S)-5
pain. During the course of studies aimed at the identification of a
suitable mPGES-1 inhibitor for clinical development, a need arose
for preparing enantiomerically enriched amino alcohols (S,S)-2 and (Scheme 1);3 the latter compound being prepared in four
steps from commercially available material.4 While (S,S)-
(S,S)-3. Described herein, a concise synthesis of (S,S)-2 and (S,S)-3
has been developed wherein both amino alcohols are derived from
a commercially available, low-cost starting material.
4 presumably could be converted into desired (S,S)-2, the
existing synthesis of (S,S)-4 is lengthy, and the starting di-
Key words: carbocycles, heterocycles, anti-inflammatory agents,
enophile is expensive. Based on prior work by Mura-
hashi,5 Zhu et al. attempted to shorten their route via a
chiral resolution, rearrangement
direct SN2 opening of lactone (S,S)-5 with sodium azide.
Unfortunately, partial racemization occurred during the
Inducible microsomal prostaglandin E2 synthase-1 (mPG-
ES-1), the predominate synthase involved in cyclooxyge-
nase-2 (COX-2) mediated PGE2 production, is a novel
therapeutic target of considerable interest in the treatment
of inflammation and pain.1 We have been interested in
preparing substituted benzoxazoles of type 1 as mPGES-1
inhibitors (Figure 1).2 During the course of studies aimed
at the identification of a suitable inhibitor for clinical de-
velopment, a need arose for obtaining hundreds of grams
of enantiomerically enriched amino alcohols (S,S)-2 and
(S,S)-3. Due to the trans-1,3-relationship between the sub-
stituents on (S,S)-2 and (S,S)-3, one of the substituents on
the cyclohexyl ring occupies a presumably thermodynam-
ically unfavorable axial orientation, which could make the
synthesis more challenging.
reaction, presumably due to ring opening via a competing
SN2¢ pathway.3 We detail below a concise synthesis of
(S,S)-2 and (S,S)-3, of which both compounds are derived
from a low cost starting material.
a, b
c, d
H
H
61%
40%
HO
CO2Me
O
O
(S,S)-5
e, b
87%
N3
CO2Me
H2N
CO2H
(S,S)-4
Scheme 1 Zhu’s synthesis of (S,S)-4 based on Trost’s enantiomeri-
cally enriched lactone (S,S)-5. Reagents and conditions: (a) Na2CO3,
MeOH, r.t.; (b) H2, Pd/C, MeOH; (c) TsCl, py, CH2Cl2; (d) NaN3,
DMF, 80 °C; (e) LiOH, THF–MeOH–H2O, 40 °C; acidic workup.
X
O
N
O
N
Z
HN
Y
Our initial API requirements for (S,S)-2 were met via the
synthetic sequence outlined in Scheme 2. Thus, resolution
of Cbz-protected amino alcohol rac-6, which was pur-
chased from a vendor,6 using chiral super critical fluid
chromatography (SFC)7 afforded enantiomerically en-
riched carbamate (S,S)-68 (98% ee). Hydrogenolysis of
the Cbz-group in (S,S)-6 gave rise (98%) to the desired
amine (S,S)-2.9,10 HATU-mediated coupling of amine
(S,S)-2 with carboxylic acid 72 afforded amide (S,S)-8.11
Compound (S,S)-8 was shown to be a potent inhibitor in
our mPGES-1 enzyme assay (Scheme 2). Conversely,
enantiomer (R,R)-812 was 75-fold less active, displaying
only weak activity. The absolute configuration at C(1) and
C(3) on the cyclohexyl ring in (S,S)-8 was unambiguously
n
1
NH2
S
NH2
S
S
S
OH
(S,S)-3
OH
(S,S)-2
Figure 1 General structure of novel mPGES-1 inhibitors (1) and
new synthetic targets (S,S)-2 and (S,S)-3
SYNLETT 2011, No. 20, pp 2959–2962
Advanced online publication: 11.11.2011
x
x
.x
x
.2
0
1
1
DOI: 10.1055/s-0031-1289884; Art ID: S06711ST
© Georg Thieme Verlag Stuttgart · New York

2960
D. P. Walker et al.
LETTER
established as (1S,3S) via X-ray crystallography ly pure amino alcohol (S,S)-2; however, this tactic did not
(Figure 2).13
represent a long-term solution for meeting our API needs.
The high cost of rac-6, coupled with long lead times,
meant sourcing this material was no longer practical;
hence, we sought to develop a practical synthesis of rac-
6, capable of delivering hundreds of grams of API.
The option of purchasing carbamate rac-6 was convenient
as it provided access to gram quantities of enantiomerical-
Cbz
Cbz
HN
HN
Our synthesis of rac-6 commenced from dicarboxylic
acid 9, a low cost, commercially available mixture of cis-
and trans-isomers (Scheme 3).15 The trans-isomer can be
efficiently isolated in high purity using the procedure of
Skita and Rossler.16 Monoesterification of trans-isomer
10 afforded ester 11.17 Under these conditions, no epimer-
ization to the corresponding cis-isomer was seen. Curtius
rearrangement of carboxylic acid 11 and trapping of the
intermediate isocyanate with benzyl alcohol led to the cor-
responding carbamate. Subsequent saponification of the
ester with lithium hydroxide gave rise (72%) to carboxylic
acid 12. Again, under these conditions, no epimerization
to the cis-isomer occurred. It should be mentioned that in
a prior study Hewgill and Jefferies utilized a Schmidt re-
action to convert dicarboxylic acid 10 into the related ami-
no acid rac-4.18 Unfortunately, this procedure utilizes the
highly toxic and potentially explosive hydrazoic acid,
which was seen as a significant drawback to our API
needs.
S
a
b
(S,S)-2
S
98%
OH
OH
rac-6
(S,S)-6 (45%, 98% ee)
O
c
Ar
N
HN
48%
OH
(S,S)-8 (98% ee)
mPGES-1 IC50 = 65 nM (n >100)a
Cl
Cl
N
O
N
O
N
CO2H
Ar =
7
Scheme 2 Reagents and conditions: (a) resolution, SFC, Chiral Pak
AD-H 250 column (EtOH–CO2, 1:3, 40 °C); (b) H2, 10% Pd/C (cat.),
MeOH, 50 psi, 16 h; (c) carboxylic acid 7 (1.0 equiv), amine 2 (1.2 equiv),
HATU (1.2 equiv), i-Pr2NEt (5.0 equiv), DMF, r.t., 16 h. a mPGES-1
enzyme inhibition assay. Numbers indicate IC50 values generated
from 10-point concentration response relationships in duplicate, n va-
lues in parentheses denotes number of iterations. For enzyme assay
conditions, see ref. 14.
Desired alcohol rac-6 was realized in 72% yield via bo-
rane reduction of carboxylic acid 12 (Scheme 3). The
spectral properties of rac-6, prepared according to
Scheme 3, were identical to an authentic sample of rac-6.
Over 100 grams of rac-6 was prepared according to
Scheme 3.
Enantiomerically enriched amino alcohol (S,S)-3 was also
prepared from commercial dicarboxylic acid
9
(Scheme 4). Toward this end, treatment of monoester 11
with methyl magnesium bromide, followed by subsequent
Curtius rearrangement of the carboxylic acid led to tertia-
ry alcohol rac-13. Resolution of rac-13 using SFC afford-
ed enantiomerically enriched alcohol (S,S)-13.19
Hydrogenolysis of the benzyloxycarbonyl group in (S,S)-
13 gave rise (90%) to the desired amino alcohol [(S,S)-
3].9,20 Over 100 grams of rac-13 was prepared via this
synthetic route. HBTU-Mediated coupling of amine (S,S)-
3 with carboxylic acid 142 gave rise to amide (S,S)-15.21
Compound (S,S)-15 was a potent inhibitor of mPGES-1 in
the enzyme assay (Scheme 3); the corresponding enantio-
mer [(R,R)-15] was ca. 50-fold less potent.22
Figure 2 ORTEP diagram of compound (S,S)-8
CO2H
CO2H
CO2H
a
ref. 16
56%
HO2C
HO2C
Cbz
EtO2C
Cbz
9
10
11
The absolute configuration of (S,S)-3 was established
based on the synthesis shown in Scheme 5. Thus, conden-
sation of enantiomerically enriched amine (S,S)-2 with
acetyl acetone afforded dimethylpyrrole 16. Oxidation
(TPAP, NMO) of the alcohol gave the corresponding al-
dehyde. Treatment of the aldehyde with methyl magne-
sium bromide led to secondary alcohol 17. The addition to
the aldehyde was essentially nonselective under these
conditions (dr = 55:45). Oxidation of the alcohol with
TPAP and NMO gave rise (76%) to the corresponding
methyl ketone. Subjection of the ketone to methyl Grig-
HN
HN
b, c
72%
d
72%
HO2C
OH
12
rac-6
Scheme 3 Reagents and conditions: (a) EtOH (1.0 equiv), concd
HCl (cat.), 80 °C, 4 h; (b) DPPA (1.0 equiv), Et3N (1.1 equiv), tolu-
ene, 70 °C, 1 h; BnOH (1.05 equiv), Et3N (1.1 equiv), 80 °C, 5 h; (c)
LiOH·H2O (5.0 equiv), THF–MeOH–H2O (6:3:1), r.t., 5 h; (d)
BH3·THF (2.2 equiv), THF, –5 °C, 4 h.
Synlett 2011, No. 20, 2959–2962 © Thieme Stuttgart · New York

LETTER
Practical Synthesis of Enantiomerically Enriched Amino Alcohols
2961
Cbz
it is highly likely that the absolute configuration at C(1)
and C(3) on the cyclohexyl ring of (S,S)-15 is (1S,3S).
Cbz
HN
HN
S
c
a, b
In summary, we have described a concise racemic synthe-
sis of two amino alcohols, which were resolved by chiral
chromatography to afford enantiomerically enriched
(S,S)-2 and (S,S)-3. Those key intermediates were used for
the preparation of potent mPGES-1 inhibitors. Both amino
alcohols were derived from the same low cost starting ma-
terial. Over 100 grams of (S,S)-2 and (S,S)-3 were pre-
pared utilizing the described chemistry.
11
S
41%
OH
OH
rac-13
(S,S)-13 (45%, 98% ee)
O
e
d
Ar
N
(S,S)-3
HN
90%
63%
OH
Acknowledgment
(S,S)-15 (98% ee)
mPGES-1 enzyme
We thank Jon Bordner and Ivan Samardjiev of Pfizer for generating
x-ray crystallographic data on (S,S)-8. We thank Gina Jerome of
Pfizer for generating mPGES-1 enzyme inhibition data.
IC50 = 15 nM (n = 2)a
Cl
Cl
N
N
Ar =
N
CO2H
O
O
14
References and Notes
Scheme 4 Reagents and conditions: (a) MeMgBr (3.0 M solution in
Et2O, 3.15 equiv), THF, 0 °CÆr.t., 16 h; (b) DPPA (1.0 equiv), Et3N
(1.1 equiv), toluene, 70 °C, 1 h; BnOH (1.05 equiv), Et3N (1.1 equiv),
80 °C, 5 h; (c) resolution, SFC chromatography, Chiral Pak IA 250
column (EtOH–i-PrOH-CO2, 1:1:6, 40 °C); (d) H2, 10% Pd/C,
MeOH, 50 psi, r.t., 18 h; (e) carboxylic acid 14 (1.0 equiv), amine 3
(1) (a) Koeberle, A.; Werz, O. Curr. Med. Chem. 2009, 16,
4274. (b) Samuelsson, B.; Morganstern, R.; Jakobsson, P.-J.
Pharmacol. Rev. 2007, 59, 207.
(2) A full account on the design, synthesis, SAR and in vivo
activity of type-1 compounds will be published elsewhere in
due course.
(3) Hu, Y.; Yu, S.-L.; Yang, Y.-J.; Zhu, J.; Deng, J.-G. Chin. J.
Chem. 2006, 795.
(4) Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991, 1613.
(5) Murahashi, S.-I.; Tanigushi, Y.; Imada, Y.; Tanigawa, Y.
J. Org. Chem. 1989, 54, 3292.
a
(1.2 equiv), HBTU (1.2 equiv), Et3N (1.5 equiv), DMF, r.t., 16 h.
mPGES-1 enzyme inhibition assay. Numbers indicate IC50 values ge-
nerated from 10-point concentration response relationships in dupli-
cate, n values in parentheses denotes number of iterations. For
enzyme assay conditions, see ref. 14.
(6) Our vendor supplied hundreds of grams of rac-4 for ca.
$100/gram with a lead time of 5–7 weeks.
(7) Bhatt, H. S.; Patel, G. F.; Vekariya, N. V.; Jadav, S. K.
J. Pharm. Res. 2009, 2, 1606..
NH2
N
N
S
a
b, c
(8) Analytical data for (S,S)-6: Peak 2; white solid; mp 69–71
°C; [a]25D 0.2 (c = 1.5, MeOH). 1H NMR (500 MHz, MeOH-
d4): d = 7.26–7.40 (m, 5 H), 5.10 (s, 2 H), 3.77–3.85 (m, 1
H), 3.41 (d, J = 6.4 Hz, 2 H), 1.76–1.83 (m, 1 H), 1.64–1.75
(m, 2 H), 1.53–1.64 (m, 4 H), 1.38–1.45 (m, 1 H), 1.14–1.23
(m, 1 H). 13C NMR (125 MHz, MeOH-d4): d = 158.3, 138.6,
129.6, 129.1, 129.0, 67.37, 67.34, 47.67, 36.37, 34.74,
32.37, 29.34, 21.42. LRMS (ESI): m/z = 264 [M + H]+.
(9) Amines 2 and 3 were found to absorb carbon dioxide and
darken with age. We found it more convenient to store these
amines as the corresponding carbamates, 6 and 13, which
were shelf stable for more than a year, and convert them into
2 and 3 on an add-need basis.
S
57%
72%
H
OH
OH
HO
16
17
(S,S)-2
dr = 55:45
NH2
e
b, c, d
20%
(S,S)-15
mPGES-1 enzyme
IC50 = 9.3 nM (n = 4)
69%
HO
(S,S)-3
Scheme 5 Reagents and conditions: (a) acetyl acetone (1.1 equiv),
AcOH (cat.), toluene, reflux, Dean–Stark, 2 h; (b) TPAP (cat.), NMO
(1.5 equiv), 4 Å mol. sieves, CH2Cl2, 2 h; (c) MeMgBr (3.0 M soln in
Et2O, 1.2 equiv), Et2O, 0 °C, 30 min; (d) NH2OH·HCl (20 equiv),
Et3N (10 equiv), i-PrOH–H2O (2.5 mL, 4:1), reflux, 6 h; NaOH (4.0
equiv), 0 °C, 16 h; (e) carboxylic acid 14 (1.0 equiv), amine (S,S)-3
(1.2 equiv), HBTU (1.2 equiv), Et3N (1.5 equiv), DMF, r.t., 16 h.
(10) Analytical data for (S,S)-2: 1H NMR (400 MHz, MeOH-d4):
d = 3.43 (d, J = 6.7 Hz, 2 H), 3.02–3.09 (m, 1 H), 1.79–1.90
(m, 1 H), 1.49–1.70 (m, 7 H), 1.19–1.30 (m, 1 H). 13C NMR
(100 MHz, MeOH-d4): d = 66.54, 47.42, 35.99, 35.42, 33.33,
28.87, 20.83. LRMS (ESI): m/z = 130.1 [M + H]+.
(11) Analytical data for (S,S)-8: 98% ee (analytical chiral HPLC);
[a]25D –6.4 (c = 1.8, MeOH). 1H NMR (400 MHz, MeOH-
d4): d = 7.78 (br d, J = 7.4 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H),
7.23 (d, J = 1.96 Hz, 1 H), 7.02 (dd, J = 8.2, 1.95 Hz, 1 H),
4.26–4.32 (m, 2 H), 3.96–4.03 (m, 1 H), 3.43 (d, J = 6.6 Hz,
2 H), 3.20 (td, J = 13.3, 3.1 Hz, 2 H), 2.57 (tt, J = 11.3, 3.9
Hz, 1 H), 1.72–1.91 (m, 5 H), 1.63–1.72 (m, 2 H), 1.53–1.62
(m, 4 H), 1.37–1.46 (m, 1 H), 1.17–1.26 (m, 1 H). 13C NMR
(100 MHz, MeOH-d4): d = 175.3, 163.2, 147.4, 144.2, 129.4,
120.5, 115.3, 109.5, 65.81, 45.16, 44.80, 44.70, 42.11,
42.06, 35.24, 33.03, 30.79, 28.04, 27.93, 20.17. LRMS
(ESI): m/z = 392 [M + H]+.
nard afforded the tertiary alcohol in 83% yield. Subse-
quent hydrolysis of the dimethyl pyrrole gave amine
(S,S)-3 in low yield. Coupling (S,S)-3 with carboxylic acid
14 afforded (S,S)-15. Using chiral SFC conditions similar
to above, (S,S)-15, prepared according to Scheme 5, co-
eluted with (S,S)-15 prepared according to Scheme 4. In
addition, the biological activity of (S,S)-15, prepared ac-
cording to Scheme 5, was identical to the activity of (S,S)-
15 prepared according to Scheme 4. Based on these data,
Synlett 2011, No. 20, 2959–2962 © Thieme Stuttgart · New York

2962
D. P. Walker et al.
LETTER
(12) Compound (R,R)-8 (98% ee) was prepared using similar
conditions to that described for the preparation of (S,S)-8
except (R,R)-6 (98% ee) was used in place of (S,S)-6.
(13) Data for compound (S,S)-8 (crystals from MeCN) were
collected on a Bruker APEX diffractometer at Pfizer Groton
laboratories, and all crystallographic calculations were
facilitated by the SHELXIL system:
J = 12.9 Hz, 1 H), 1.58–1.64 (m, 1 H), 1.47–1.58 (m, 2 H),
1.43 (tt, J = 13.2, 3.4 Hz, 1 H), 1.27 (td, J = 13.2, 3.5 Hz,
1 H), 1.11 (s, 3 H), 1.10 (s, 3 H), 1.02 (qd, J = 12.3, 3.8 Hz,
1 H). 13C NMR (125 MHz, MeOH-d4): d = 158.4, 138.6,
129.6, 129.1, 129.0, 73.24, 67.37, 43.92, 32.65, 31.35,
28.19, 27.03, 26.93, 25.41, 22.09. LRMS (ESI): m/z = 313.9
[M + Na]+.
C20H26N3O3Cl·MeCN·H2O; FW = 450.96; monoclinic;
space group P2 (1); unit cell dimensions: a = 5.0339 (3) Å,
b = 12.3675 (5) Å, c = 18.4354 (9) Å; volume = 1145.14 (10)
Å3; Z = 2; Dcalcd = 1.308 Mg/m3; absorption coefficient =
1.772 mm–1; F(000) = 480; GOF on F2 = 1.029; final R
indices [I >2s(I)]: R1 = 0.0393, wR2 = 0.1026.
(20) Analytical data for (S,S)-3: clear oil. 1H NMR (400 MHz,
DMSO-d6): d = 3.80–4.25 (br s, 2 H), 3.24–3.28 (m, 1 H),
1.65–1.76 (m, 2 H), 1.48–1.61 (m, 3 H), 1.40–1.48 (m, 1 H),
1.34 (tt, J = 13.7, 3.9 Hz, 1 H), 1.18 (td, J = 12.9, 3.5 Hz,
1 H), 1.00 (s, 6 H), 0.89 (qd, J = 12.1, 3.5 Hz, 1 H). LRMS
(ESI): m/z = 158.1 [M + H]+.
(14) Wang, J.; Limburg, D.; Carter, J.; Mbalaviele, G.; Gierse, J.;
Vazquez, M. Bioorg. Med. Chem. Lett. 2010, 1604.
(15) Dicarboxylic acid 7 is sold as a mixture of cis- and trans-
isomers (cis/trans = ca. 3:1), and is available in bulk
quantities from various vendors for $0.60/gram;
alternatively, it can be efficiently prepared via catalytic
hydrogenation of isophthalic acid, see: Freifelder, M.;
Dunnigan, D. A.; Baker, E. J. J. Org. Chem. 1966, 31, 3438.
(16) Skita, A.; Rossler, R. Chem. Ber. 1939, 72, 265.
(17) Hart, R. W.; Gibson, R. E. J. Med. Chem. 1975, 18, 323.
(18) Hewgill, F. R.; Jefferies, P. R. J. Chem. Soc. 1955, 2767.
(19) Analytical data for (S,S)-13: clear oil; Peak 2 (98% ee);
[a]25D –10 (c = 1.0, MeOH). 1H NMR (500 MHz, MeOH-d4):
d = 7.26–7.38 (m, 5 H), 6.92 (br d, J = 6.59 Hz, 1 H), 5.07
(ABq, JAB = 15.0 Hz, DnAB = 12.0 Hz, 2 H), 3.92–3.98 (m,
1 H), 1.91–1.97 (m, 1 H), 1.82 (d, J = 12.7 Hz, 1 H), 1.74 (d,
(21) Analytical data for (S,S)-15: white solid; 98% ee (analytical
chiral HPLC). 1H NMR (400 MHz, DMSO-d6): d = 7.57 (br
d, J = 7.69 Hz, 1 H), 7.39 (s, 1 H), 7.29 (s, 1 H), 4.11–4.15
(m, 2 H), 3.99–4.03 (m, 1 H), 3.92 (s, 1 H), 3.09–3.15 (m, 2
H), 2.53–2.57 (m, 1 H), 2.34 (s, 3 H), 1.71–1.79 (m, 4 H),
1.54–1.64 (m, 3 H), 1.46–1.53 (m, 3 H), 1.26–1.34 (m, 1 H),
1.08–1.15 (m, 1 H), 1.02 (s, 3 H), 1.01 (s, 3 H), 0.87–0.95
(m, 1 H). 13C NMR (125 MHz, DMSO-d6): d = 173.1, 162.4,
147.3, 142.5, 128.1, 126.9, 115.4, 110.8, 70.46, 44.97,
44.08, 42.00, 40.69, 30.89, 29.64, 27.86, 27.76, 27.21,
26.81, 26.49, 20.52, 19.83. LRMS (ESI): m/z = 434 [M +
H]+.
(22) Compound (R,R)-15 (98% ee) was prepared using similar
conditions to that described for the preparation of (S,S)-15
except (R,R)-13 (98% ee) was used in place of (S,S)-13.
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