Efficient chiral resolution of (±)-cyclohexane-1,2-diamine

Article abstract of DOI:10.3184/174751914X14054315566768

A novel and efficient method has been developed for the chiral resolution and separation from cis-cyclohexane-1,2-diamine of (±)-cyclohexane-1,2- diamine, which reacts with xylaric acid, a substitute for tartaric acid. This method provides (1R,2R)-cyclohexane-1,2-diamine, and (1S,2S)-cyclohexane-1,2- diamine and cis-cyclohexane-1,2-diamine in good yield with high optical purity.

Full text of DOI:10.3184/174751914X14054315566768

490 RESEARCH PAPER
VOL. 38 AUGUST, 490–492
JOURNAL OF CHEMICAL RESEARCH 2014
Efficient chiral resolution of (±)-cyclohexane-1,2-diamine
Chuan-Zhu Gao, Tian-Shuai Wang, Jia Chen, Fan Fei, Ji Chen, Yan Zhang and Bo Yang*
Faculty of Life Science and Technology, Kunming University of Science and Technology (ChengGong Campus), Kunming 650500, Yunnan
Province, P.R. China
A novel and efficient method has been developed for the chiral resolution and separation from cis-cyclohexane-1,2-diamine
of ( )-cyclohexane-1,2-diamine, which reacts with xylaric acid, a substitute for tartaric acid. This method provides (1R,2R)-
cyclohexane-1,2-diamine, and (1S,2S)-cyclohexane-1,2-diamine and cis-cyclohexane-1,2-diamine in good yield with high optical
purity.
Keywords: (±)-cyclohexane-1,2-diamine, chiral resolution, xylaric acid
Optically pure cyclohexane-1,2-diamine (Fig. 1) is a building
block for chiral ligands, which has great interest as a
chemical and pharmaceutical intermediate.1,2 Optically pure
cyclohexane-1,2-diamine has been used as a chiral ligand in
the drug industry. For example, oxaliplatin, which is based
on (1R,2R)-cyclohexane-1,2-diamine, is widely used in the
treatment of malignant tumours.3–5 In addition, it plays an
important role in asymmetric synthesis and is widely used as a
chiral catalyst which can induce epoxidation, cyclopropanation
and hydrolysis of epoxy compounds.6–9 Several methods are
available for the separation of the (±)-cyclohexane-1,2-diamine.
Smith and Raleigh10 reported the preparation of (±)-trans-
cyclohexane-1,2-diamine and more specifically the separation
of trans-cyclohexane-1,2-diamine from stereoisomeric
mixtures of (±)-cyclohexane-1,2-diamine in 52% yield.
However, this method using phosgene has a low yield.10
Larrow et al.11–13 reported a route to (1R,2R)-cyclohexane-1,2-
diamine from racemic (±)-trans-cyclohexane-1,2-diamine by
reaction with L-(+)-tartaric acid. However, the overall yield
was only 60–70%, which restricted large-scale production.
Peng Zhiyong et al.14 reported a similar method to obtain
cyclohexane-1,2-diamine having the three configurations.
He Lin15 described another separation route to optically pure
(1R,2R)-cyclohexane-1,2-diamine using ultrasound where
racemic (±)-trans-cyclohexane-1,2-diamine reacts with L-(+)-
tartaric acid to give a yield of 95%. Galland et al.16 reported a
preparative resolution of (±)-trans-1,2-cyclohexanediamine by
means of preferential crystallisation of its citrate monohydrate.
Schanz et al.17 reported improved resolution methods for (R,R)-
and (S,S)-cyclohexane-1,2-diamine with (R)- and (S)-BINOL.
All these methods require reaction with chiral tartaric acid.
With the market demanding a high yield of optically pure
cyclohexane-1,2-diamine, the improved resolution procedure
with (±)-cyclohexane-1,2-diamine has become the focus of
study.
diamine in good yields. This method makes the best use of
raw materials and most reagents can be recycled. The route is
shown in Scheme 1.
Results and discussion
(2R,4R)-Xylaric acid and (2S,4S)-xylaric acid were prepared
in two steps using L-sorbitol and D-sorbitol, which are cheap
and readily available. First, intermediates L-sorbose and
D-sorbose were obtained from L-sorbitol and D-sorbitol with
yields of 98–100%, which have also been reported recently.18–20
Then, a catalytic oxidation was used to oxidise D-sorbose and
L-sorbose to give (2R,4R)-xylaric acid and (2S,4S)-xylaric acid
in good yields, respectively. The route is shown in Scheme 2.
As shown in Scheme 1, three configurations of cyclohexane-
1,2-diamine have been obtained from a mixture of the
cis- and trans-cyclohexanediamines (50:50) by reaction
with (2R,4R)-xylaric acid and (2S,4S)-xylaric acid in three
steps. First, treatment of the mixture of the cis- and trans-
cyclohexanediamines (50:50) with 0.6 equiv. of (2R,4R)-xylaric
acid in methanol solution at 80 °C for 3 h afforded the salt 2
and a mixture of the cis- and trans-diamines (30/70). Second,
the mixture of the cis- and trans-diamines (30/70) reacts with
0.6 equiv. of (2S,4S)-xylaric acid to give the salt 4 and cis-
cyclohexane-1,2-diamine 5 in good yield, (cis-cyclohexane-
1,2-diamine 5 is a meso compound). Third, the salt 2 and 4
were treated with sodium hydroxide in aqueous solution to
give 6 and 7 respectively in 92% yield, which are based on
the percentage of the different diamines present in the starting
mixture. Chiral resolution coefficients were investigated at
different temperatures and we found the optimum temperature
conditions of T=80 °C, which furnished each enantiomer
in high optical purity, since the higher temperature reduces
the enantiomer-selectivity for cyclohexane-1,2-diamine and
incomplete reaction resulted at a lower temperature.
In conclusion, a novel and efficient chiral resolution method
giving optically pure (1R,2R)-cyclohexane-1,2-diamine and
(1S,2S)-cyclohexane-1,2-diamine and cis-cyclohexane-1,2-
diamine has been achieved in overall 92.9%, 92.2% and 89.6%,
respectively. Moreover, this is a relatively simple procedure,
using easily accessible materials and an easy separation, with
Here, we report a novel and efficient chiral recognition
method by reaction of a mixture of the cis- and trans-
cyclohexane-1,2-diamines (50:50) with chiral xylaric acid
(XA) to give optically pure (1R,2R)-cyclohexane-1,2-diamine,
(1S,2S)-cyclohexane-1,2-diamine and cis-cyclohexane-1,2-
NH2
R
NH2
NH2
NH2
NH2
S
S
R
S
R
NH2
cis-cyclohexane-1,2-diamine
(1R,2R)-cyclohexane-1,2-diamine
(1S,2S)-cyclohexane-1,2-diamine
Fig. 1 Structures of cyclohexane-1,2-diamine.
* Correspondent. E-mail: wtshuaiynn@163.com
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JOURNAL OF CHEMICAL RESEARCH 2014 491
+H3N
R
NH3
+
a
OH
R COO-
-OOC
H2N
NH2
H2N
NH2
NH2
NH2
1
3
H
H
O
O
2
c
b
R R
H2N
6
+H3N
COO-
NH3
+
c
OH
OH
S S
-OOC S
O
S COOH
H
OOC S
S
H2N
NH2
H2N
H
H
H
H
O
O
O
4
5
7
Scheme 1 Reagents and conditions: (a) (2R,4R)-xylaric acid, MeOH, 80 °C, 3 h, 95%; (b) 1.NaOH, pH=9 2. (2S,4S)-xylaric acid, MeOH, 80 °C, 3 h, 93.5%;
(c) 2 M NaOH, pH=9.
OH
O
OH
H H HN
C 3COOO / O3
H
O
S
S
H
OOC
S
H
COO
S
H
O
R
H
O
H
O
H
O
H
O
H
O
O
H
O
H H HN
C 3COOO / O3
H
O
R
O
R
H
OOC
H
COO
R
O
R
H
O
S
H
H
O
H
H
O
Scheme 2 Reagents and conditions: 1. HNO3, CH3COOOH, 0 °C, 1 h; 2 .ultrasonic instrument, 60 °C, 30 min; 3. excess NaOH, 30 min; 4. HCl/EtOAc, pH=3, 96.5%.
neutralised to pH3 with HCl/EtOAc and the mixture was concentrated
in vacuo to give as white crystals, (2R,4R)-xylaric acid: yield 96.5%;
m.p. 143.2–147.5 °C, ee≥97%. [α]20D =–9.7 (c=4,H2O). IR νmax (KBr/
cm–1) ν=3360, 2959, 2873, 2680, 1710, 1460, 1400, 1374, 1143, 920
875, 718. 1H NMR (500 MHz, D2O): 2.83 (s, 2H, 2OH), 3.62 (s, H, OH),
4.15 (m, H, CHCH(OH)CH), 4.28 (m, 2H, CH(OH)COOH), 11.03 (s,
2H, COOH). MS (ESI+): m/z= 180 [M+, 100], 181 [M+H, 8.2%], 203
[M+Na, 32%].
good yields of products. It could be a useful improvement
to the reported methods for the enatiomeric resolution of
(±)-1,2-cyclohexanediamine and it is suitable for large-scale
production.
Experimental
All reactions were monitored by TLC, melting points were measured
on a YRT-3 temperature apparatus and are uncorrected and optical
(2S,4S)-Xylaric acid: The procedure for preparing (2S,4S)-xylaric
acid was similar to that used for (2R,4R)-xylaric acid. (2S,4S)-Xylaric
acid was obtained in a yield of 93.1%; m.p. 147.3–152.6 °C. ee≥98%
[α]20D =10.1 (c=4,H2O).IR νmax (KBr/cm–1) ν=3360, 2959, 2873, 2680,
1710, 1460, 1400, 1374, 1143, 920 873, 718. 1H NMR (500 MHz, D2O):
2.83 (s, 2H, 2OH), 3.62 (s, H, OH), 4.15 (m, H, CHCH(OH)CH), 4.28
(m, 2H, CH(OH)COOH), 11.03 (s, 2H, COOH). MS(ESI+): m/z=180
[M+, 100], 181 [M+H, 5.6%], 203 [M+Na, 32%].
(1R,2R)-Cyclohexane-1,2-diamine-(2R,4R)-xylaric acid salt (2):
A mixture of the cis- and trans-cyclohexanediamines (50:50) (80 g,
0.7 mol) was dissolved in methanol solution (500 mL), and (2R,4R)-
xylaric acid (72 g, 0.4 mol) in methanol (650 mL) was added with
stirring in one portion. The reaction mixture was stirred at 80 °C for
3 h. Then the precipitate was filtered and washed with methanol to
give a mixture of the cis- and trans-diamines (30/70) in the filtrate and
a residue. The residue was dissolved in methanol solution (500 mL)
and heated at 80 °C for 1 h, then methanol (300 mL) was added. The
mixture was reacted another 1 h. The precipitate was filtered off,
washed with ethanol and recrystallised from ethanol to give salt 2 as
rotations were measured on
a WZZ-1 automatic polarimeter.
Ultrasonic cleaner SK5210LHC was used. IR spectra were recorded
on an Impact 400 FT-IR instrument. Spectral data were recorded on
a Bruker DRX 500 NMR spectrometer and a Finnigan MAT SSQ
710（120–1000) mass spectrometer, respectively. All reagents were
purchased from Aladdin-reagent, China, and used without further
purification. The starting material, the mixture of the cis- and trans-
cyclohexanediamines (50:50), L-sorbitol and D-sorbitol, were
purchased from a local chemical company.
D-sorbose and L-sorbose were obtained by a cheap and easy method
with a yield of 99.6% as recently reported.18–21 HNO3/MeOH and HCl/
MeOH were prepared in our laboratory.
(2R,4R)-Xylaric acid: D-sorbose was dissolved in methanol, and
HNO3/MeOH with density of 2 mol L–1 was added with stirring.
Two or three drops of CH3COOOH (35%) were added. The reaction
mixture was stirred at 0 °C for 1 h. Then the mixture was transferred
to an ultrasonic instrument for 30 min at 60 °C. Excess aqueous
NaOH was added and the mixture stirred another 30 min. Then the
precipitate was filtered and washed with methanol. The residue was
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492 JOURNAL OF CHEMICAL RESEARCH 2014
a white powder (107.9 g), yield 95%; m.p. 273.2–275.6 °C. ee≥99%
[α]20D =12.7 (c=4,H2O). IR νmax (KBr/cm–1) ν=3431, 2983, 2859, 1637,
1584, 1447, 1374, 1295, 1253, 1143, 1005, 873, 718.1H NMR (500 MHz,
D2O): 1.04–1.08 (m, 4H, 2CH2 of DACH), 1.54–1.88 (m, 4H, 2CH2 of
DACH), 2.01–2.25 (d, 2H, 2CH of DACH), 2.80 (s, 2H, 2OH of XA),
3.56 (s, 1H, OH of XA), 4.03 (t, 1H, CH of XA), 4.17 (d, 2H, 2CH of
XA). MS(ESI+): m/z= 294 [M+, 100].
neutralised to pH 9 with 2 M aqueous NaOH. Then the mixture was
extracted with CH2Cl2 (4×50ml) and the combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo to
give the desired diamine 7, yield 92.2% as white to whitish needle
crystals; m.p. 39.6–44.2 °C (lit.21 40–43 °C). ee＞99.2%, [α]20D =24.3
(c=5.1 mol L–1 HCl). IR νmax (KBr/cm–1): ν=3431, 2983, 2859, 1637,
1447, 1374, 1143, 1005, 873.1H NMR (400 MHz, CDCl3): 2.31 (d, 2H,
2CH of DACH), 1.71 (m, 4H, 2CH2 of DACH), 1.05–1.37 (m, 4H, 2CH2
of DACH). MS (ESI+): m/z= 114 [M+, 100].
(1S,2S)-Cyclohexane-1,2-diamine-(2S,4S)-xylaric acid salt (4):
The filtrate from above was neutralised to pH 9 with 2 M aqueous
NaOH. Then the mixture was extracted with CH2Cl2 (4×50 mL) and
the combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo to give the desired diamines 3. The diamines
3 (80 g, 0.7 mol) were dissolved in methanol solution (500 mL) and
(2S, 4S)-xylaric acid (72 g, 0.8 mol) in methanol (650 mL) was added
with stirring in one portion. The reaction mixture was stirred at 80 °C
for 3 h. Then the precipitate was filtered and washed with methanol
to give diamine 5 in the filtrate and a residue. This residue was
recrystallised from ethanol to give salt 4 as a white powder (177.3 g);
yield 93.5%; m.p. 292.2–294.3 °C. ee≥99%. [α]20D =–12.3 (c=4,H2O).
IR νmax (KBr/cm–1): ν=3430, 2983, 2860, 1637, 1583, 1447, 1374, 1295,
1253, 1143, 1004, 875, 719.1H NMR (400 MHz, D2O): 1.03–1.10 (m,
4H, 2CH2 of DACH), 1.50–1.78 (m, 4H, 2CH2 of DACH), 2.27–2.53
(d, 2H, 2CH of DACH), 2.80 (s, 4H, 2OH of 2XA), 3.56 (s, 2H, OH of
2XA), 4.03 (t, 2H, CH of 2XA), 4.17 (d, 4H, 2CH of 2XA). MS (ESI+):
m/z= 472 [M+, 100].
Cis-cyclohexane-1,2-diamine (5): The filtrate which was obtained
from above was neutralised to pH 9 with 2 M aqueous NaOH. Then
the mixture was extracted with CH2Cl2 (4×50 mL) and the combined
organic layers were dried over anhydrous Na2SO4 and concentrated in
vacuo to give the desired diamine 5 as a light yellow clear liquid, yield
89.6%, ee＞98%, IR νmax (KBr/cm–1): ν=3431, 2983, 2859, 1637, 1447,
1374, 1143, 1005, 873.1H NMR (400 MHz, CDCl3): 2.32 (d, 2H, 2CH
of DACH), 1.71 (m, 4H, 2CH2 of DACH), 1.03–1.35 (m, 4H, 2CH2 of
DACH). MS (ESI+): m/z= 114 [M+,80].
(1R,2R)-Cyclohexane-1,2-diamine (6): (1R,2R)-Cyclohexane-1,2-
diamine-(2R,4R)-xylaric acid salt (2) as obtained above was
neutralised to pH 9 with 2 M aqueous NaOH. Then the mixture was
extracted with CH2Cl2 (4×50 mL) and the combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo to give
the desired diamine 6, yield 92.9%, as white needle crystals; m.p.
41–45 °C (lit.21 43–45 °C). ee＞99.5%, [α]20D =–24.5 (c=5, 1 mol L–1
HCl). IR νmax (KBr/cm–1): ν=3431, 2983, 2859, 1637, 1447, 1374, 1143,
1005, 873. 1H NMR (400 MHz, CDCl3): 2.32 (d, 2H, 2CH of DACH),
1.70 (m, 4H, 2CH2 of DACH), 1.05–1.35 (m, 4H, 2CH2 of DACH). MS
(ESI+):m/z= 114 [M+, 100].
The project was supported by the National Natural Science
Foundation of China (21361014, 21302074, 21062009), Doctoral
Programme of the Ministry of Education (20125314120007)
and Yunnan Province Natural Science Foundation of China
(KKSY201226108).
Received 6 May 2014; accepted 3 July 2014
Paper 1402633 doi: 10.3184/174751914X14054315566768
Published online: 12 August 2014
References
1
2
3
4
S. IIhan, J. Chem. Res., 2009, 33, 766.
I. Alfonso, Org. Synth., 2013, 5, 51.
C.Z. Gao, G. Xu and S.H. Gou, Bioorg. Med. Chem. Lett., 2011, 21, 6386.
C.Z. Gao, S.H. Gou, L. Fang and J. Zhao, Bioorg. Med. Chem. Lett., 2011,
21, 1763.
5
6
7
8
C.Z. Gao, S.H. Gou and G. Xu, Chem. Pharm. Bull., 2011, 59, 851.
M. Keiji, O. Takashi and K. Taichi, Chem. Commun., 2007, 15, 1487.
D.F. Giorgio, I. Gennadiy and W. Michael, Chem. Soc. Rev., 2011, 40, 1722.
D.Y.-K. Chen, R.H. Pouwer and J.-A. Richard, Chem. Soc. Rev., 2012, 41,
4631.
9
M. Tokunaga, J.F. Larrow, F. Kakiuchi and E.N. Jacobsen, Science, 1997,
277, 936.
10 A.I. Smith and N.C. Raleigh, PCT Int. Appl., US3167587.
11 J.F. Larrow and E.N. Jacobsen, J. Org. Chem., 1994, 59, 1939.
12 J.F. Larrow and E.N. Jacobsen, Org. Synth., 2004, 10, 96.
13 J.F. Larrow and P.F. Quigley. Comprehensive Chirality, 2012, 9, 129.
14 Z.Y. Peng. K. Zhang and J.L. Ge, PCT Int. Appl., CN102329241A.
15 L. He. Shang Dong Hua Gong, 2010, 39, 5.
16 A. Galland, V. Dupray, A. Lafontaine, B. Berton, M. Sanselme, H. Atmani
and G. Coquerel. Tetrahedron: Asymmetry, 2010, 21, 2212.
17 H.J. Schanz, M.A. Linseis and D.G. Gilheany, Tetrahedron: Asymmetry,
2003, 14, 2763.
18 E. Dag, M. Svein, S. Yngve, Carbohydrate. Res., 2007, 342, 1992.
19 G. Pushpakiran, Y. Akihide, M. Kenji, R. Devendar, A. Kazuya, S.F.
Jenkinson, G.W.J. Fleet, I. Ken, Tetrahedron. Lett., 2010, 51, 895.
20 H.M. Liaw, R.L. Kowzic, J.M. Eddington, Y.Q. Yang, PCT Int. Appl.,
US6387654.
(1S,2S)-Cyclohexane-1,2-diamine (7): (1R,2R)-Cyclohexane-1,2-
diamine-(2S,4S)-xylaric acid salt (4) as obtained above was
21 D. Paolo, P. Paola and R. Stefano, J. Org. Chem., 2001, 66, 4930.
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