An improved synthesis of (1R,3S)-3-[(tert-butoxycarbonyl)amino] cyclohexanecarboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2010.04.049

An improved synthesis of (1R,3S)-3-[(tert-butoxycarbonyl)amino] cyclohexanecarboxylic acid from 3-aminobenzoic acid is described utilising milder and more selective conditions. Both a classical salt resolution and an enzymatic approach have been shown to give the desired compound in high selectivity.

Full text of DOI:10.1016/j.tetasy.2010.04.049

Tetrahedron: Asymmetry 21 (2010) 864–866
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An improved synthesis of (1R,3S)-3-[(tert-butoxycarbonyl)amino]
cyclohexanecarboxylic acid
b
a
a
b,
*
Matthew Badland a, , Carol A. Bains , Roger Howard , Daniel Laity , Sandra D. Newman
*
a Pfizer Global Pharmaceutical Sciences, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
b Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved synthesis of (1R,3S)-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid from 3-
aminobenzoic acid is described utilising milder and more selective conditions. Both a classical salt reso-
lution and an enzymatic approach have been shown to give the desired compound in high selectivity.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 April 2010
Accepted 23 April 2010
Available online 27 May 2010
O
1. Introduction
O
Raney Ni
NaOH
H2N
H2N
OH
Asymmetric synthesis has long been at the forefront of organic
chemistry and as such chiral building blocks are indispensable for
the synthesis of biologically active compounds.
Herein we describe an improved synthesis of (1R,3S)-3-amino-
cyclohexancarboxylic acid 5. Several syntheses of this compound
have already been reported,1–5 however, we required a shorter,
scalable route to the title compound.
OH
100bar, 150 ºC,
12h
3:1 cis:trans mixture, 2
1
Boc2O
1,4-Dioxane
O
H
O
H
N
O
N
DCM/ Heptane
OH
O
OH
2. Results and discussion
O
O
The first generation route which was used to prepare racemic
cis-3-[(tert-butoxycarbonyl)amino]cyclohexane carboxylic acid 4
is shown in Scheme 1.
( )
Racemic cis Isomer, 4
5:1 cis:trans mixture, 3
This follows the route described in the literature4 where 3-ami-
nobenzoic acid 1 is hydrogenated over Raney nickel at high
temperature and pressure. The resulting cycloalkane 2 is obtained
as a 3:1 mixture of cis:trans isomers which upgrades to a 5:1 mix-
ture 3 on addition of the BOC group. Recrystallisation from DCM
and n-heptane afforded the racemic cis diastereomer 4.
Scheme 1. Original route used to make racemic cis-3-[(tert-butoxycarbonyl)amino]
cyclohexanecarboxylic acid.
Addition of the BOC group and recrystallisation from DCM/n-
heptane gave exclusively the cis isomer 4. Although the same chiral
amine, namely, (R)-1-phenylethylamine was used for the resolu-
tion, we used an alternative solvent system of ethanol/heptane
which avoided the more hazardous chloroform which had been
used previously.
Asymmetric synthesis of the title compound was also consid-
ered following the work by Corey6 on Oseltamivir (Tamiflu). It
was envisaged that this elegant and high yielding route could be
intercepted at the unsaturated lactam 13 to give the compound
we desired in high yield and enantioselectivity, Scheme 3 below
shows the proposed route.
Whilst this route was able to provide adequate quantities of
racemic cis-3-[(tert-butoxycarbonyl)amino]cyclohexane carboxylic
acid 4 there are some drawbacks. Firstly, the Raney nickel reduc-
tion conditions were unsuitable for the large quantities we re-
quired, and also the ratio of cis:trans isomers is only 3:1.
Thus milder, more selective hydrogenation conditions were
sought. Scheme 2 shows the modified route used, where hydroge-
nation using rhodium on carbon improves the cis:trans isomer ratio
and crucially proceeds at much lower temperature and pressure.
* Corresponding authors. Tel.: +44 01304 642399 (M.B.); +44 01304 644962
(S.D.N.).
E-mail addresses: matthew.badland@pfizer.com (M. Badland), sandra.new-
man@pfizer.com (S.D. Newman).
However, after initial synthetic investigation it was considered
more cost and time effective to prepare the title compound using
the resolution route shown in Scheme 2.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.049

M. Badland et al. / Tetrahedron: Asymmetry 21 (2010) 864–866
865
5% Rh/C,
MeOH:H2O
O
O
O
O
Boc2O,
1,4-Dioxane
H
N
H
N
DCM/heptane
H2N
H2N
O
O
OH
OH
OH
OH
O
O
( )
5:1 cis/trans isomers, 2
1
3
Racemic cis isomer, 4
NH2
i)
ii) salt break
O
H
O
N
OH
O
(1R,3S)-5
Scheme 2. Modified route used to prepare racemic cis-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid.
H
Ph
Ph
+
O
N
H
Tf2N-
NH3
CF3CH2OH
B
I
o-tol
TMSOTf, Et3N, I2
+
OCH2CF3
100%
OCH2CF3
NH2
97%
84%
HN
O
O
O
O
10
6
7
9
8
(Boc)2O, Et3N
99%
I
DBU
96%
O
O
N
CO2H
N
N
N
O
H
O
O
O
O
O
5
O
O
11
13
12
O
Scheme 3. Proposed enantioselective route.
O
3. Enzymatic approach
H
N
O
OH
An alternative resolution approach employing a hydrolase en-
zyme to selectively convert one stereoisomer of racemic ethyl 3-
[(tert-butoxycarbonyl)amino]cyclohexane-carboxylic ester 14 to
enantiomerically enriched cis-(1R,3S)-acid 5 and unreacted cis-
(1S,3R)-ester 15 was envisaged (Scheme 4).
A set of 95 commercially available hydrolases were screened to
identify the one most suitable for kinetic resolution of ester 14
employing a high-throughput screening protocol as described by
Yasbeck et al.7 Four of the hydrolases appeared to exhibit highly
stereoselective hydrolysis. Candida antarctica lipase B (LipozymeÒ
CALB L), Pseudomonas cepacia lipase (Lipase PS ‘Amano’ SD) and
O
O
Hydrolase
Aqueous medium
(1R,3S)-5
H
N
O
OEt
+
O
O
H
N
O
OEt
( )-cis-14
O
(1S,3R)-15
Scheme 4. Enzymatic resolution approach.
Table 1
Reactions were conducted at pH 7.0 (90% 0.1 M potassium phosphate buffer with 10% isopropanol co-solvent), 2 mg/mL substrate, 4 mg/mL enzyme, 30 °C. The reactions were
allowed to proceed for 72 h and then quenched and analysed by hplc
Entry
Enzyme
Conv (%)
(1R,3S) Acid 5 ee (%)
(1S,3R) Ester 15 ee (%)
Ea
1
2
3
4
5
No enzyme
0
50b
43
39
50
Candida antartica Lipase B (LipozymeÒ CALB L)
Pseudomonas cepacia lipase (PS ‘Amano’ SD)
Thermomyces lanuginosus lipase (LipozymeÒ TL 100 L)
Cholesterol esterase from Candida cylindracea (Roche)
96
92
91
97
80
58
198
62
38
>99 (1S,3R)
>99 (1R,3S)
>200
a
Enantiomeric ratio, E, calculated from substrate and product enantiomeric excess by the method of Rakels et al.8
Unidentified hplc peak observed of 5.5% of the total hplc area.
b

866
M. Badland et al. / Tetrahedron: Asymmetry 21 (2010) 864–866
Thermomyces lanuginosus lipase (LipozymeÒ TL 100L) were selec-
tive for the desired cis-(1R,3S)-stereoisomer and cholesterol ester-
ase from Candida cylindracea (Roche) was selective for the
undesired cis-(1S,3R)-stereoisomer, leaving unreacted cis-(1R,3S)-
ester. Enzymatic kinetic resolutions employing the four hydrolases
were repeated in 1 mg-scale microreactions (Table 1). The results
confirmed this enzymatic approach to be viable with cholesterol
esterase from Candida cylindracea exhibiting the highest stereose-
lectivity (Table 1, entry 5, >99% substrate ee and product ee at
50% conversion).
5.3. Purification to give pure cis-isomer 4
At first, 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic
acid 3 (26 g) and dichloromethane (130 mL) were charged to the
reaction vessel giving a clear solution. n-Heptane (130 mL) was
charged slowly at room temperature and the resulting slurry was
granulated for 2–3 h. The mixture was filtered and the cake was
washed with n-heptane (2 ꢀ 20 mL) and dried in vacuum oven at
45 °C for 16 h to afford the title compound as a white solid
(16.2 g, 42% yield). 1H NMR (DMSO-d6) 1–1.3 (m, 5H), 1.3–1.4 (s,
9H), 1.6–1.8 (m, 3H), 1.9–2.0 (m, 1H), 2.1–2.3 (m, 1H), 6.6–6.8 (s,
1H), 11.8–12.1 (s, 1H v broad).
4. Conclusion
A simple, efficient and reliable procedure has been found for the
synthesis of 3-[(tert-butoxycarbonyl)amino]-cyclohexanecarbox-
ylic acid. In addition to the salt resolution using (R)-1-phenylethyl-
amine, a set of four hydrolases have been identified and shown to
resolve the racemic cis-isomer by the stereoselective hydrolysis of
racemic ethyl 3-[(tert-butoxycarbonyl)amino]cyclohexane-carbox-
ylic ester.
5.4. (1R,3S)-3-[(tert-Butoxycarbonyl)amino]cyclohexane-
carboxylic acid. (R)-1-Phenylethylamine salt
Racemic cis 3-[(tert-butoxycarbonyl)amino]cyclohexane carbox-
ylic acid 4 (0.5 g, 2.0 mmol) and ethanol (2.5 mL) were charged to
the reaction vessel and stirred at room temperature until a solution
obtained. (R)-1-Phenylethylamine (0.125 g, 1.0 mmol, 0.5 equiv)
was charged and the resulting precipitate was stirred at 70 °C until
a full solution was obtained which was then allowed cool to ambient
temperature and stirred for 16 h. The product was isolated by filtra-
tion, washed with n-heptane (2 ꢀ 5 mL) and dried under vacuum for
16 h at 45 °C to give the title compound as a white solid (0.186 g, 25%
yield). 1H NMR (DMSO-d6) 1.0–1.2 (m, 4H), 1.2–1.3 (m, 1H), 1.3 (d,
3H), 1.4 (s, 9H), 1.6–1.7 (d, 2H), 1.8 (d, 1H), 1.9 (d, 1H), 2.2 (t, 1H),
4.0 (m, 1H), 6.7 (d, 1H), 7.2 (m, 1H), 7.3 (m, 2H), 7.4 (m, 2H).
5. Experimental
5.1. 3-Aminocyclohexanecarboxylic acid, 2 (5:1 mixture)
At first, 3-aminobenzoic acid 1 (30 g, 0.22 mol), methanol
(570 mL) and water (30 mL) were charged to a suitable-sized
hydrogenation vessel. Rhodium on carbon (5%, Type 20A, 6 g)
was charged and the resulting mixture was hydrogenated at
300 PSi and 70 °C. The hydrogen uptake was monitored and the
reaction was deemed complete after 3 h at which point water
(210 mL) was charged to the reaction slurry to solubilise the prod-
uct. The reaction mixture was filtered through a plug of ArbocelÒ
and the residue was washed with methanol (90 mL). The filtrate
was concentrated to dryness under reduced pressure to leave a
white solid residue. The solid was granulated in MeOH (150 mL)
for 1 h at room temperature before being isolated by filtration
and dried to give the title compound as a white solid (22.6 g, 72%
yield).1H NMR (CDOD3) as sodium salt: 0.9–1.4 (m, 3H), 1.4–1.6
(m, 1H), 1.7–1.9 (m, 3H), 2.0–2.2 (m, 2H), 2.5–2.6 (m, 1H).
5.5. (1R,3S)-3-[(tert-Butoxycarbonyl)amino]cyclohexane
carboxylic acid 5
(1R,3S)-3-[(tert-Butoxycarbonyl)amino]cyclohexane carboxylic
acid. (R)-1-Phenylethylamine salt (45 mg) was suspended in ethyl
acetate (10 mL) and washed with 0.1 M aqueous hydrochloric acid
(2 ꢀ 5 mL). The organic layer was separated, dried over magnesium
sulfate, filtered and evaporated to a white solid which was dried
under vaccum at 50 °C to give 30 mg of the title compound. 1H
NMR (CDCl3) 1.01–1.07 (m, 1H), 1.22–1.41 (m, 2H), 1.45 (s, 9H),
1.84–1.88 (m, 1H), 1.97–2.00 (m, 2H), 2.27–2.31 (m, 1H), 2.40–
2.47 (m, 1H), 4.47 (m, v broad, 1H), 4.44 (m, v broad, 1H), 5.07
(s, v broad, NH). Calcd for C12H22NO4 m/z 244.154883, found m/z
244.1541 and calcd for C12H21NNaO4 266.136828, found m/z
5.2. 3-[(tert-Butoxycarbonyl)amino]cyclohexane carboxylic acid3
At first, 3-aminocyclohexanecarboxylic acid 2 (5:1 mixture,
22.4 g, 0.16 mol), 1,4-dioxane (225 mL) and water (225 mL) were
charged to a 500 mL three-necked flask. Diisopropylethylamine
(82 mL, 0.47 mol, 3.0 equiv) was added to the resulting mixture fol-
lowed by a portionwise addition of di-tert-butyl dicarbonate (39.7 g,
0.18 mol, 1.15 equiv). The reaction mixture was stirred at room tem-
perature for 16 h and then concentrated under reduced pressure to
remove 1,4-dioxane. Dichloromethane (225 mL) was charged to the
residue and the mixture was stirred for 10 min. The organic phase
was removed and the aqueous phase was acidified to pH 3 using
20% w/w citric acid solution. The acidic aqueous layer was extracted
with dichloromethane (2 ꢀ 200 mL). The organic phases were com-
bined, washed with water (100 mL) and dried over MgSO4. Filtration
and concentration to dryness afforded the crude product as a sticky
solid. The residue was granulated in n-heptane (180 mL) for 1 h at
room temperature before being isolated by filtration. The filter cake
was washed with n-heptane (2 ꢀ 40 mL) and dried in vacuum oven
at 45 °C for 16 h to give the title compound as a white solid (26.34 g,
69%). Analysis of the isolated product by 1H NMR confirmed the
presence of the unwanted trans isomer.
266.1362. ½a 2D5
ꢁ
¼ ꢂ46:9 (c 0.10099, MeOH), lit. ½a D25
¼ ꢂ50:5 (c 1,
ꢁ
MeOH).
Acknowledgements
We thank Dr. Simon Mantell and Dr. Andrew Morrell for useful
discussions and Mr. Timothy J. Evans for synthesis of the racemic
intermediate.
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