Short and efficient process for the synthesis of trans-4- aminocyclohexanecarboxylic acid derivatives

Article abstract of DOI:10.1021/op900195w

This contribution relates to an industrially feasible process for the preparation of isomerically pure trans-4-amino-1-cyclohexanecarboxylic acid derivatives that are useful building blocks in the synthesis of several pharmacologically active compounds su

Full text of DOI:10.1021/op900195w

Organic Process Research & Development 2009, 13, 1141–1144
Short and Efficient Process for the Synthesis of
trans-4-Aminocyclohexanecarboxylic Acid Derivatives
Pankaj S. Patil, Ulhas S. Mahajan, Swapnil P. Sonawane,* and Mukund K. Gurjar
API R & D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjewadi, Pune - 411057, India
Scheme 1
Abstract:
This contribution relates to an industrially feasible process for the
preparation of isomerically pure trans-4-amino-1-cyclohexanecar-
boxylic acid derivatives that are useful building blocks in the
synthesis of several pharmacologically active compounds such as
glimepiride, L-370518.
Introduction
Derivatives of trans-4-amino-1-cyclohexanecarboxylic acid
(1) are known to possess many biological properties. The
antihypertensive activity, particularly the prevention and treat-
ment of coronary, cerebral and renal circulatory diseases is most
pronounced. 4-Amino-1-cyclohexanecarboxylic acid-derived
agents are also useful as neuropeptideYY antagonists,1 thrombin
inhibitors2 and pesticides.3
Ni, Pt/C or Pd/C. However, mixtures of isomers were formed.
Due to presence of the ester functionality, epimerization in favor
of the trans-isomer was reported.9 Moreover, fractional crystal-
lization of the trans-isomer of 4-aminocyclohexanecarboxylic
acid methyl ester from the cis-trans mixture was demonstrated
by Aldrich et al..6
Aldrich et al. observed that, after repeated crystallization and
purification of the isomeric mixture, the trans-isomer was
isolated with a maximum 90% isomeric purity in 18% yield.
In 1988, Toyoshima et al.7 and Shigetaka et al.8 independently
disclosed that the process for partial epimerization of the pure
cis-isomer of 4-cyclopropylcyclohexanecarboxylic acid methyl
ester to the desired trans-isomer could be accomplished by
heating, or in combination with sodium hydride under inert and
anhydrous atmosphere. This method afforded 80% trans product
with 70% isomeric purity. The use of stringent conditions and
high reaction temperature were the limiting factors of this
process. An epimerization process is also described by Masaki
et al.9 using alkali and alkaline earth metals, which provided
an equilibrium mixture (80:20) in favor of the desired trans-
isomer. Recently, Kawanish et al.10 reported an efficient process
for methyl trans-4-aminocyclohexanecarboxylic acid, 8, by
epimerization of the N-sulphonyl or N-benzylidene derivative
of the cis-isomer of 4-amino-1-cyclohexanecarboxylate using
sodium methoxide (Scheme 1, compounds 4 and 6).
A literature study reveals very few approaches for preparing
the stable trans-isomer of 4-amino-1-cyclohexanecarboxylic
acid4a-f some of which are illustrated in Scheme 1. A straight-
forward approach for the trans-isomer was selective aromatic
ring hydrogenation of ethyl 4-hydroxybenzoate with a rhodium
catalyst to give a (83:17) cis-trans mixture of ethyl-4-
hydroxycyclohexylcarboxylate,5 followed by nucleophilic dis-
placement of hydroxyl group with ammonia to give trans-4-
aminobenzoic acid as a major product. To avoid the use of an
expensive rhodium catalyst, hydrogenation was tried with Raney
* Author to whom correspondence may be sent. Fax: +91-20-39821445.
E-mail: Swapnil.Sonawane@emcure.co.in.
(1) Norikazu, O.; Yoshio, O. U.S. Patent 2008161326, 2008.
(2) Cutrona, K. J.; Sanderson, Philip, E. J. Tetrahdron Lett. 1996, 37,
5045–5048.
Results and Discussion
In spite of many strategies being explored towards obtaining
trans-4-amino-1-cyclohexanecarboxylic acid, 8, we hoped to
develop an alternate method which would be amenable for
large-scale production.
(3) Takashi, I.; Akihito, M. U.S. Patent 5,831,118, 1998.
(4) (a) Palaima, A. I. et al., Bulletin of the Academy of Sciences of the
USSR. DiVision of Chemical Science., 1977; Vol. 26, No. 1. (b)
Karpavichyus, K. I.; Kosykhova, L. A.; Pikshilingaite, Yu.-V. K.;
Mikul′′skis, P. P.; Knunyants, I. L. Russ. Chem. Bull. 1987, 36, 1896–
1899. (c) Wright, K.; Sarciaux, M.; de Castries, A.; Wakselman, M.;
Mazaleyrat, J. P.; Toffoletti, A.; Corvaja, C.; Crisma, M.; Peggion,
C.; Formaggio, F.; Toniolo, C. Eur. J. Org. Chem. 2007, 19, 3133–
3144. (d) Ge, P.; Russell, R. A. Tetrahedron 1997, 53, 17469–17476.
(e) Larsen, C. D. J. Am. Chem. Soc. 1938, 60, 2341–2343. (f)
Schneider, W.; Dillmann, R. Chem. Ber. 1963, 96, 2377–2386.
(5) Wayne, T. World Patent WO05/019221, 2005.
(6) Snyder, K. R.; Murray, T. F.; DeLander, G. E.; Aldrich, J. V. J. Med.
Chem. 1993, 36, 1100–1103.
(7) Shigeshi. T.; Yoshiko. S.; Hisashi S.; Koji, T.; Izumi K. K. U.S. Patent
4,816,484, 1989.
(8) Shigetaka, H.; Tsunenori, F.; Kaoru, K. JP 56120636, 1981.
(9) Fujimoto, M. JP 60258141, 1985.
(10) Yasuyuki, K.; Masaaki, U.; Munenori, M. U.S. Patent 7,314,950, 2005.
10.1021/op900195w CCC: $40.75  2009 American Chemical Society
Published on Web 10/14/2009
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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1141

Scheme 2
Scheme 3. Reaction pathway for the synthesis of
trans-4-tert-butoxycarbonylamino-1-cyclohexane carboxylic
acid (16)
In order to achieve a stereoselective approach to trans-4-
aminocyclohexanecarboxylic acid, we aimed at starting with a
readily accessible substrate, which would be easily converted
to the desired trans-compound under mild reaction conditions.
To achieve our goal, we investigated the use of a phthalimido
group as a protecting group for trans-4-amino-1-cyclohexane-
carboxylate. The intention behind the selection of the phthal-
imido group of C4-carbon, (Scheme 2) was based on a thought
that it will try to remain at an equatorial position so that
isomerization can be effectively achieved at the C1 carbon using
a base at the ester functionality as shown in Scheme 2.
This task was executed by constructing a phthalimido ring
onto the amino group of methyl 4-aminocyclohexanecarboxylate
hydrochloride, 10 (cis-trans isomer), in 75% yield.
This was carried out by reacting phthalic anhydride in
toluene under reflux in the presence of triethylamine (Scheme
3). Starting amine hydrochloride, 10, was obtained by aromatic
ring reduction of commercially available methyl 4-aminoben-
zoate hydrochloride, 9, via hydrogenation using Pt/C catalyst.
After having substrate 11 in hand, our ultimate goal was to find
optimized reaction conditions for the critical isomerization
conversion. Keeping in mind that organic nucleophilic base such
as monomethylamine will hydrolyze the phthalimido group of
11, our first attempt was to use a strong, non-nucleophilic
organic base, such as DBU, triethyl amine, Hunig’s base in
various solvents and reaction conditions. Unfortunately, the first
attempt with DBU was unsuccessful; hence, we have not used
other non-nucleophilic organic bases. The results are sum-
marized in Table 1 (entries 1-3).
Our next set of conditions was based on the use of alkoxides
such as sodium methoxide and potassium tert-butoxide. Un-
fortunately when we performed the reaction on substrate 11
using sodium methoxide in methanol at reflux temperature, the
phthalimido ring of 11 was opened, and we ended up with
partially hydrolyzed product 13 as shown in Table 1 (entries
4-6). Having these results in hand, we turned our attention
toward the use of a bulkier base such as potassium tert-butoxide
in isopropanol as solvent for isomerization of methyl 4-phthal-
imidocyclohexanecarboxylate; fortunately, this condition af-
forded trans esterified product with isomerization in 70% yield
with isomeric purity of 99.7% (Table 1, entry 7).
Encouraged by the above result, we studied optimized
reaction conditions for isomerization with respect to solvents
and mole ratio of potassium tert-butoxide. The results are cited
in Table 2 (entries 1-6).
Finally, we could get an optimized reaction condition using
0.5 equiv of potassium tert-butoxide in isopropyl alcohol at 65
°C for the isomerization of methyl 4-phthalimidocyclohexane-
carboxylate (11), which furnished the desired isopropyl trans-
4-phthalimidocyclohexanecarboxylate 12 with trans-esterifica-
Substrate 11 was found to be inert towards methanol, toluene
and THF with DBU under reflux conditions (Table 1, entries
1-3).
Table 1. Study of various bases for isomerizationa
% isolated yield
13
rxn
reaction conditions
12
recovered 11 (%)
cis:trans ratiod
b
b
b
b
1
2
3
4
5
6
7
CH3OH, DBU, 65 °C,8 h
toluene, DBU, 110 °C,8 h
THF, DBU, 66 °C, 8 h
CH3OH, NaOCH3, 65 °C,6 h
toluene, NaOCH3, 80 °C,5 h
THF, NaOCH3, 65 °C,3 h
IPA, KOtBu, 65 °C,4 h
-
-
-
-
78
80
82
-
b
-
-
b
-
-
c
-
-
-
70
quantitative
quantitative
quantitative
-
-
70:30
70:30
70:30
0.30:99.70
c
-
c
-
c
-
a Reactions were carried out on 5 mmol scale using 1.0 equiv of base wrt 11. b No reaction. c Starting material quantity is specified only when it exceeds 30%. d Isomeric
purity was calculated by 1H NMR and HPLC.
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Table 2. Optimization of solvent and molar ratio wrt 11 for isomerizationa
rxn
mol equiv
reaction conditions
yieldb 12 (%)
recovered 11 (%)
cis:trans ratiod
1
2
3
4
5
6
1.0
0.5
0.25
0.5
0.5
0.5
IPA, 25 °C, 24 h
IPA, 65 °C, 3 h
IPA, 65 °C, 8 h
IPA, 65 °C, 8 h
toluene, 65 °C, 8 h
THF, 65 °C, 8 h
NA
70
80
-
-
0.30:99.70
e
40
-
0.30:99.70
c
-
72
60
67
-
-
-
c
-
c
-
a Reactions were carried out on 5 mmol scale using KOtBu. b Isolated yields using column chromatography. c Trace amount of product. d Isomeric purity was calculated by
1H NMR and HPLC. e Unreacted starting material quantity is specified only when it exceeds 30%.
tion in 70-75% yield with 99.7% isomeric purity as shown by
HPLC (Table 2, entry 2).
7.4 kg, 71.7%). An analytical sample was obtained by column
chromatography.
Subsequently, the N-phthalimido group of isopropyl trans-
4-pthalimidocyclohexanecarboxylate (12) was easily deprotected
using hydrazine hydrate with quantitative yield to provide the
pure trans-amino compound (14), which on protection using
BOC anhydride gave N-BOC-isopropyl ester (15) in 97.4%
yield followed by basic hydrolysis to end up with N-BOC-
cyclohexanecarboxylic acid (16) in 88% yield (Scheme 3).
MS(CI): calcd for C8H15NO2 HCl (M + H) m/z: 158.21;
found (M + H) m/z: 158.2; 1H NMR (400 MHz, CDCl3) δ )
1.47-1.65 (m, 5H), 1.79-1.82 (m, 2H), 1.97 (m, 3H),
2.08-2.32 (m, 7H), 3.1 (br s, 1H), 3.2 (br s, 1H), 8.2 (d, 4H).
Anal. for C8H15NO2 HCl. Calcd C, 61.12; H, 9.62; N, 8.91.
Found C, 60.81; H, 9.02; N, 8.94.
Preparation of Methyl 4-Phthalimidocyclohexanecar-
boxylate (11). Methyl 4-aminocyclohexanecarboxylate hydro-
chloride 10 (10 kg, 5.17 mol), toluene (100 L) and phthalic
anhydride (99.5 kg, 6.71 mol) were mixed at room temperature.
Triethylamine (13 kg, 12.92 mol) was added dropwise over a
period of 30 min at room temperature. The reaction mass was
refluxed for 5-6 h by removing water azeotropically using a
Dean-Stark apparatus. After completion of the reaction (moni-
tored by TLC), toluene was distilled below 50 °C under reduced
pressure. DM water (130 L) was added and stirred for 30 min
at ambient temperature, after which methyl 4-phthalimidocyclo-
hexacarboxylate 11 was isolated by filtration (Yield 11.1 kg, 75%).
An analytical sample was obtained by column chromatography.
MS (CI): calcd for C16H17NO4 (M + H) m/z: 288.32; found
Conclusion
Looking at prior articles the process disclosed by us for the
synthesis of trans-4-aminocyclohexanecarboxylic acid is short,
efficient and cost-effective. The overall yield was found to be
68-72% with enhanced isomeric purity. Potassium tert-
butoxide was shown to be a useful base for the isomerization
of methyl-4-phthalimidocyclohexanecarboxylate (11) to desired
trans-isomer in good yields with excellent isomeric purity.
We feel that the process may be commercially feasible.
Experimental Section
All materials were purchased from commercial suppliers.
Unless specified otherwise, all reagents and solvents were used
as supplied by manufacturers. Melting points were determined
by open air capillary with an X-6 melting point apparatus,
Beijing Tech instrument Co Ltd., and are uncorrected. 1H NMR
spectra (400 MHz) and 13CNMR spectra (100 MHz) were
recorded in CDCl3, DMSO-d6, and mass spectra were deter-
mined on API-2000LCMS mass spectrometer, Applied Bio-
sciences. HPLC system was Symmetry C18 (4.6 mm × 250
mm) 5 µ, 1.5 mL/min, 205 nm; mobile phase 1.0 mL
phosphoric acid in 100 mL of water with pH adjusted to 3.0
using triethylamine.
Preparation of Methyl 4-Aminocyclohexanecarboxylate
Hydrochloride (10). Methyl-4-aminobenzoate hydrochloride
9 (10.0 kg, 5.33 mol) and methanol (110 L) were mixed together
in an autoclave under nitrogen atmosphere at room temperature.
Pt/C (100 g, 10% w/w) was added under a nitrogen atmosphere.
The autoclave was heated to 60-65 °C at 7-8 kg/cm2 hydrogen
pressure for 6-8 h until consumption of the starting material
was observed (reaction monitored by TLC analysis). The
reaction mass was removed from the autoclave, and Pt/C was
filtered through a Hyflo bed. The filtered methanol was distilled
under reduced pressure. Dichloromethane (25 L) was added to
the residue; concentration of the mother liquor gave crude
methyl 4-aminocyclohexanecarboxylate hydrochloride (10),
which was then crystallized from ethyl acetate (80 L) (Yield
1
(M + H) m/z: 288.3. Off-white solid, mp: 130-132 °C. H
NMR (400 MHz, CDCl3) δ ) 1.57-1.62 (m, 4H), 1.65 (m,
1H), 2.12 (m, 1H), 2.28-2.33 (m, 4H), 4.12 (m, 1H), 7.68-7.75
(m, 2H), 7.80-7.83 (m, 2H). Anal. for C16H17NO4. Calcd C,
66.89; H, 5.96; N, 4.87. Found C, 66.77; H, 5.93; N, 4.86.
Preparation of Isopropyl trans-4-Phthalimidocyclohex-
anecarboxylate (12). Isopropyl alcohol (100 L) and methyl
4-phthalimidocyclohexanecarboxylate, 11 (10.0 kg, 3.48 mol),
were mixed together, and potassium tert-butoxide (1.954 kg,
1.74 mol) was added to the mixture at ambient temperature.
The reaction mixture was stirred for 2-3 h at 60-65 °C. After
completion of the the reaction (monitored by TLC), the pH was
adjusted to 7 by using acetic acid at room temperature. The
precipitated solid was stirred for 30 min at 10-12 °C; the
resultant precipitated solid was filtered, washed with isopropyl
alcohol (5 L) and dried at 40-45 °C to get pure product. 12
was isolated and then filtered and washed with isopropyl alcohol
(5 L) and dried at 40-45 °C (Yield 7.7 kg, 70.64%). An
analytical sample was obtained by column chromatography. MS
(CI) calcd for C18H21NO4 (M + H) m/z 316.37, found (M +
H) m/z: 316.3. White solid, mp: 120-122 °C. 1H NMR (400
MHz, CDCl3) δ ) 1.22 (d, 6H), 1.65 (m, 2H), 1.75 (m, 2H),
2.11 (m,2H), 2.24 (m,3H), 4.11 (m, 1H), 4.98 (sep,1H), 7.69
(d, 2H), 7.81 (d, 2H). 13C NMR (100 MHz, CDCl3) δ ) 21.76,
28.39, 28.57, 42.17, 49.79, 67.38, 123.03, 131.93, 133.82,
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168.25, 174.84. Anal. for C18H21NO4: Calcd C, 68.55; H, 6.71;
N, 4.44. Found C, 68.27; H, 6.67; N, 4.42.
Preparation of trans-4-tert-Butoxycarbonylamino-1-cy-
clohexanecarboxylic Acid (16). trans-Isopropyl-(4-tert-bu-
toxycarbonylamino)-1-cyclohexanecarboxylate, 15 (10 kg, 3.5
mol), was added to methanol (50 L) at 25-30 °C under constant
stirring. Sodium hydroxide (3.5 kg, 8.75 mol) in DM water (15
L) was added slowly at 25-30 °C with constant stirring. The
reaction mixture was stirred for 11-12 h at 25-30 °C. After
completion of the reaction (monitored by TLC) DM water (90
L) and MDC (50 L) were added; the aqueous layer was
separated and cooled to below 15 °C under constant stirring.
(The MDC layer was discarded.) The pH of the aqueous layer
was adjusted to 5-6 with acetic acid (∼14 L) under constant
stirring at below 15 °C. During the pH adjustment solid material
separated out from the reaction mixture. Precipitated solid was
filtered and dried under vacuum to give white to off-white
trans--N-BOC acid, 15 (yield 7.5 kg, 88%). An analytical
sample was obtained by column chromatography. MS (CI) calcd
for C12H21NO4 (M + H) m/z 243.31, found (M - H) m/z
242.31. Mp: 181-182 °C (Lit.11 182-185 °C). 1H NMR (400
MHz, CDCl3) δ ) 1.13 (m, 2H), 1.47 (s, 9H), 1.57 (m, 2H),
2.01 (m, 4H), 2.26 (t, 1H), 3.41 (br s, 1H), 4.41 (m, 1H), 5.3
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ ) 27.59, 28.35,
32.36, 42.24, 48.87, 76.68, 79.27, 155.15, 181.06. Anal. for
C12H21NO4: Calcd C, 59.24; H, 8.70; N, 5.76. Found C, 59.12;
H, 8.68; N, 5.74.
Preparation of Isopropyl trans-4-Amino-1-cyclohexane-
carboxylate (14). Isopropyl trans-4-phthalimidocyclohexane-
carboxylate, 12 (10 kg, 3.17 mol), was added to a solution of
methanol (60 L) and dichloromethane (25 L) at ambient
temperature. Hydrazine hydrate (11.1 kg, 19.04 mol) in DM
water (50 L) was added dropwise at 25-30 °C under stirring.
The reaction mass was stirred for 12-14 h, and the solid was
filtered off. DM water (20 L) was added to the filtrate; the
dichloromethane layer was separated and concentrated under
reduced pressure to give isopropyl trans-4-amino-1-cyclohex-
anecarboxylate 14 (Yield 5.4 kg, 93.1%). An analytical sample
was obtained by column chromatography. MS (CI) calcd for
C10H19NO2 (M + H) m/z 186.27, found (M + H) m/z: 186.2.
White solid, mp: 89 °C. 1H NMR (400 MHz, CDCl3) δ ) 1.11
(m, 2H), 1.22 (d, 6H), 1.37 (m, 2H), 1.48 (m, 2H), 1.98 (m,
4H), 2.16 (m, 1H), 2.65 (m, 1H), 4.98 (Sep, 1H). 13C NMR
(100 MHz, CDCl3) δ ) 21.50, 27.62, 35.37, 42.50, 49.50,
49.61, 66.92, 175.08. Anal. for C10H19NO2: Calcd C, 64.83; H,
10.34; N, 7.56. Found C, 64.63; H, 10.28; N, 7.53.
Preparation of trans-Isopropyl-(4-tert-butoxycarbonyl-
amino)-1-cyclohexanecarboxylate (15). Isopropyl trans-4-
aminocyclohexanecarboxylate 14 (10 kg, 5.40 mol) was dis-
solved in methanol (80 L), at ambient temperature. Triethylamine
(7 kg, 7.02 mol) was added dropwise at 25-30 °C under
stirring. BOC anhydride (11.78 kg, 5.40 mol) in methanol (20
L) was added at 25-30 °C under stirring at 25-30 °C. Reaction
mass was stirred for 3-4 h. After completion of the reaction
(monitored by TLC) methanol was removed under vacuum
completely. DM water (40 L) was added and extracted with
dichloromethane (2 × 25 L). The combined dichloromethane
layer was dried over sodium sulfate and concentrated under
reduced pressure at 40-45 °C to give a white solid, 15 (Yield
15 kg, 97.4%). An analytical sample was obtained by column
chromatography. MS (CI) calcd for C15H27NO4 (M + H) m/z
286.39, found (M + H)m/z: 286.39. White solid, mp: 86-87
°C. 1H NMR (400 MHz, CDCl3) δ ) 1.13-1.14 (d, 6H), 1.36
(s, 9H), 1.76-1.82 (m, 4H), 2.12 (m, 1H), 3.16 (m, 1H),
4.82-4.88 (sep, 1H), 6.76 (d, 1H). 13C NMR (100 MHz,
CDCl3) δ ) 21.65, 27.27, 27.65, 28.29, 32.38, 42.49, 48.84,
67.25, 78.95, 155.05, 174.84. Anal. for C15H27NO4: Calcd C,
63.13; H, 9.54; N, 4.91. Found C, 63.01; H, 9.51; N, 4.90.
Acknowledgment
We thank Mr. Samit Mehta, our management and the IPM
group of Emcure Pharmaceuticals Ltd. for their generous
support and constant encouragement. Finally, it is a pleasure
to acknowledge the reviewers for their suggestions.
Supporting Information Available
Additional characterization data of compounds 10-12 and
14-16. This material is available free of charge via the Internet
at http://pubs.acs.org.
Received for review July 28, 2009.
OP900195W
(11) Bin, H.; Crider, A. M.; Stables, J. P. Eur. J. Med. Chem. 2001, 36,
265–28.
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