Practical Isolation of the (1R,2R)-Enantiomer from a Racemic cis/trans Mixture of 2-Methyl-1-cyclohexanamine

Article abstract of DOI:10.1021/acs.oprd.7b00263

2-Methyl-1-cyclohexanamine exists in four stereoisomeric forms. Although it is a simple compound, none of the stereoisomers is readily available in its pure form. We herein described a crystallization method identified by a salt screen (diastereomeric salt formation) allowing the isolation of a single trans enantiomer from a readily available commercial source consisting of a mixture of all four stereoisomers.

Full text of DOI:10.1021/acs.oprd.7b00263

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Full Paper
Practical isolation of the (1R,2R)-enantiomer from a
racemic cis/trans mixture of 2-methyl-1-cyclohexanamine
Markus Furegati, and Sandro Nocito
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00263 • Publication Date (Web): 04 Oct 2017
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Practical isolation of the (1R,2R)ꢀenantiomer from a
racemic cis/trans mixture of 2ꢀmethylꢀ1ꢀ
cyclohexanamine
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Markus Furegati,* Sandro Nocito
Synthesis & Technologies Group, Global Discovery Chemistry, Novartis Institutes for
Biomedical Research, Klybeckstrasse 141, 4057 Basel, Switzerland
KEYWORDS
Crystallization, diastereomeric salt formation, salt screen, optical resolution
ABSTRACT
2ꢀMethylꢀ1ꢀcyclohexanamine exists in four stereoisomeric forms. Although it is a simple
compound, none of the stereoisomers is readily available in its pure form. We herein described a
crystallization method identified by a salt screen (diastereomeric salt formation) allowing the
isolation of a single trans enantiomer from a readily available commercial source consisting of a
mixture of all four stereoisomers.
INTRODUCTION
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More than 800 Nꢀsubstituted compounds containing the 2ꢀmethylꢀ1ꢀcyclohexanamine motif with
distinct stereochemistry are described in the literaturea and many more without specification of
the two stereocenters at the cyclohexane ring. We were surprised to find that sourcing of even 10
g of the enantiopure (1R,2R)ꢀ1 turned out to be difficult and reported syntheses thereof rather
cumbersome and lengthy. In order to support our medicinal chemistry programs with this
building block we were looking for an alternative approach. Seven syntheses to racemic or
enantiopure transꢀ2ꢀmethylꢀ1ꢀcyclohexanamine (1) and salts thereof are described in the
literature starting from various precursors (Scheme 1).
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Scheme 1. Literature procedures (aꢀg) for the synthesis of racemic or enantiopure transꢀ2ꢀ
methylꢀ1ꢀcyclohexanamine. See Scheme S1aꢀg in the SI for further details.
a SciFinder substructure search with substitution allowed only at the amine and relative trans stereochemistry revealed 581 compounds (search
date June 30th 2017).
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The hydrogenation of Nꢀ(2ꢀtolyl)acetamide (2) or anthranilic acid (3) gave direct access to
racemic trans substituted cyclohexane cores that were further transformed to 1.1, 2 Hydroboration
of 1ꢀmethylcyclohexꢀ1ꢀene (4) was accomplished nonꢀstereoselectively3, 4 or stereoselectively5, 6
and resulted after amination of the carbonꢀboron bond in the formation of 1; in the latter case
(1S,2S)ꢀ1 HCl was obtained with 99% enantiomeric excess (ee) following a 5 steps sequence in
48% overall yield. Aziridination of cyclohexene (5) and subsequent ring opening led to (1R,2R)ꢀ
1 in 4 more steps.7 The shortest asymmetric synthesis is described as a 4 steps process starting
from racꢀ2ꢀmethylcyclohexanone (6) yielding (1S,2S)ꢀ1 HCl salt in 5.6% and 92% ee.8 6 was
also substrate for an enzymatic approach.9 The syntheses are discussed in more detail in the SI
(Scheme S1).
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RESULTS AND DISCUSSION
Despite the elegance of some of these approaches, we were aiming for a simple and quick
access to (1R,2R)ꢀ1. Chiral amines were often efficiently resolved by diastereomeric salt
formation with an enantiopure acid and liberation of the free amine from the salt.10 Depending on
the selectivity additional crystallizations might be necessary in order to enrich enantiomeric
excess. We found two literature precedents making use of this approach. The first one described
the crystallization of rac 1 with Dꢀcamphorcarboxylic acid from hot EtOH/water. After reꢀ
crystallization from dry ethanol two fractions were obtained of which the major one was reꢀ
crystallized again several times (no yields given). The liberated free amine was assigned as the (–
)ꢀenantiomer.11 In the second one (+)ꢀtartaric acid formed a 1:1 salt with (1S,2S)ꢀ1 (Scheme
S1e).8 This single crystallization from methanol resulted in an increase of the enantiomeric
excess from 70 to 92% with a yield of 28%; in other words, the minor (1R,2R)ꢀenantiomer was
depleted by a factor of 15.1 and the (1S,2S)ꢀenantiomer by 3.6.
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We decided to submit racemic 1 to a salt screen and discovered that the pure racemic transꢀ
isomer was not readily available from commercial sources. On the other hand, an isomeric
mixture of racemic cis/transꢀ1 (between 1:4 and 3:7 for the batches we worked with) was offered
by many vendors.b We used this mixture for the screen, hoping that alongside the resolution,
removal of the undesired cis isomers would also be achieved in parallel. The screen consisted of
300 different resolving agent and solvent combinations. The 20 chiral acids have mostly been
chosen based on widespread utilization, availability and price (Table 1 – see experimental
section). Three of them were mixtures of a set of three similar chiral acids according to the Dutch
resolution.12, 13
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a)
b)
Figure 1. Heat maps of data from the salt screen (resolving agents AꢀT and solvents 1ꢀ15, see
table 1) a) ee of transꢀ1, red: racemic, light green: maximum of 32%ee for G3 and N14 (both
marked with red circles) b) content of transꢀ1, red: same composition as in starting material
b Catalogue price for 1 kg approximately 500 USD.
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(77% trans), green: accumulation, blue: depletion of trans enantiomers, the best result (L2) is
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marked with a red circle. Grey squares resulted in no crystal formation.
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From the screen 44, crystalline salt samples were isolated with yields ranging from 18ꢀ64%. In
order to determine the distribution of the stereoisomers the liberated amines from these salts
were converted into the (S)ꢀMosherꢀamides and analyzed by GC with achiral stationary phase.
Ee values from 0ꢀ44% were found for the cis isomers and 0ꢀ32% for the trans isomers (Figure
1a). Apart from sample L2 the cis/trans ratio was not at all or only slightly affected by the
crystallization (Figure 1b). L2 showed in addition one of the best ee values of the screen, but
only moderate yield: the diastereomeric salt formation with (R)ꢀ(−)ꢀ1,1’ꢀbinaphthylꢀ2,2’ꢀ
phosphoric acid ((R)ꢀ7) in EtOH/water 1:1 resulted in a significant depletion of the cis isomers in
the isolated salt, while the ee of the trans enantiomers was increased to modest 26% (highest ee
achieved was 32%) and a yield of 22%.
A first scaleꢀup with 6 g of 1 (1:4 cis/trans mixture) under those conditions resulted in a
complete removal of the cis isomers after three subsequent crystallizations while the ee of the
trans enantiomers increased to 79% with a yield of 20%. The resolvability S was calculated to be
0.40.c The absolute stereochemistry of the enriched trans enantiomer was determined as (1S,2S)
by comparison of the optical rotation of its HCl salt [α]D21= +16.4 (c=4, MeOH) with the
literature [α]D= −24.66 (c=4, MeOH) for the (1R,2R) enantiomer with an ee >99%.7
Next, the influence of a substoichiometric amount of the chiral acid was investigated. Because
the amine was well soluble in the solvent mixture alone, no achiral strong acid was used to
c The resolvability also known as the Fogassy’s parameter was calculated as the product of the yield divided by the assay of the target isomer in
the starting material (in this case 0.4) and the enantiomeric purity. S equals unity corresponds to complete separation.
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replace the more expensive chiral resolving agent as often applied by the PopeꢀPeachey
method.10 0.1 mol 1 (3:7 cis/trans mixture, from a different vendor) was crystallized with 0.5
equivalents of (S)ꢀ7 in 250 mL EtOH/water 1:1. A single crystallization resulted in 26% yield
(containing 3% of the cis isomers) and an ee of 39% (GC analysis of the (S)ꢀMosherꢀamides),
resolvability S = 0.26.
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Scheme 2. Diastereomeric salt formation, liberation of the amine and precipitation of the
enantiopure (1R,2R)ꢀ1 as its HCl salt.
The main batch was performed on a 3.75 mol scale with a further reduced amount of the chiral
acid (0.43 equiv.) Six consecutive crystallizations resulted in 73.2 g of the salt in 4.2% yield
(Scheme 2) and an ee of 97.9% (GC analysis of the (S)ꢀMosherꢀamides) and 98.3% (HPLC of
the tosylamide on a chiral stationary phase).d The overall resolvabilty S was calculated being
0.12. The transformation into the HCl salt was achieved by liberating the free amine and
subsequent precipitation with HCl in diethyl ether in 92% yield.
d The latter value was more accurate, because the ee of the (S)ꢀMosher’s chloride used for the derivatization itself was only 99% according to the
vendor and therefore resulted in a slight underestimation of the real ee of the amine
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Figure 2. Assay of the four stereo isomers of 1 in the commercial amine mixture (sm) and after
each crystallization (1ꢀ6) , considering the material loss after each crystallization. Cis isomers
were not detectable from the 2nd crystallization on.
The cis isomers were completely removed after one single crystallization (Figure 2). Therefore,
the initial cis/trans ratio of the starting material is expected to have a minimal influence on the
total number of crystallizations required. When a stoichiometric amount of the resolving acid
was used, three crystallizations were necessary for this, although the initial cis/trans ratio was in
favor for the trans isomer. The resolution of the trans enantiomers was less efficient, the average
depletion factor of the undesired diastereomeric salt was 3.1 and that of the target salt 1.5. In
other words, after each crystallization 30% of the target enantiomer went lost, while the ratio of
the undesired to the desired enantiomer improved by a factor 2.2.
CONCLUSIONS
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The method we described allows the isolation of enantiomerically pure transꢀ2ꢀmethylꢀ1ꢀ
cyclohexanamine (1) from a commercial mixture of racemic cis/trans isomers via diastereomeric
salt formation with 1,1`ꢀbinaphthylꢀ2,2`ꢀphosphoric acid (7), available in both enantiomeric
forms, in environmentally benign water/ethanol solvent. Despite the low overall yield and the six
consecutive crystallizations necessary to exceed an ee of 98%, this route represents in our view
the most practical way to access enantiopure transꢀ1 to date for lab scale. For large scale
however, a process based on a simple racemic process followed by efficient SMB
chromatography (similar to Scheme S1a) or an asymmetric transfer hydrogenation (Scheme S1e)
should be considered.
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EXPERIMENTAL SECTION
General. All reagents were purchased and used as received unless otherwise noted. 2ꢀMethylꢀ1ꢀ
cyclohexanamine from TCI, (S)ꢀ(+)ꢀ1,1`ꢀbinaphthylꢀ2,2`ꢀphosphoric acid from A Chemtek Inc.,
(S)ꢀ(+)ꢀαꢀmethoxyꢀαꢀtrifluoromethylphenylacetyl chloride (Mosher’s chloride from Sigma
Aldrich. LCꢀMS method: Acquity HSS T3 1.8 um 2.1 x 50 mm column at 50 °C. Eluent A:
water + 0.05% formic acid + 3.75 mM ammonium acetate; eluent B: acetonitrile + 0.04% formic
acid; gradient: from 2 to 98% B in 1.4 min with a flow rate of 1.2 mL/min, detection at 210ꢀ450
nm. HPLC method:7 Chiralpak ADꢀH (250x4.6 mm, 5 um) column, heptanes/EtOH 70:30,
column temperature r.t., flow rate 1 mL/min, detection at 230 nm, run time 17 min. Purities were
characterized with area% at the wave length declared for the method used. GC method (for
indirect ee determination): Silaren column (30 m x 0.32 mm ID, 0.12 ꢁm film). Temperature
program: 40°C held for 0.3 min, followed by 3.5 °C/min up to 200 °C and 40 °C/min up to 280
°C, at which the temperature was held for 3 min. The hydrogen flow was 2 mL/min, the front
inlet temperature was 220 °C, and the front detection (FID) temperature was 300 °C; split ratio
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1:50. NMR spectra were recorded on a Bruker BioSpin machine. 1H shifts were referenced to
DMSOꢀd6 at 2.49 ppm and CDCl3 at 7.26 ppm. 13C shifts were referenced to DMSOꢀd6 at 39.52
ppm. Optical rotations were measured on a Perkin Elmer 241 Polarimeter.
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Determination of the enantiomeric excess
Mosherꢀamide method: ca 2ꢀ3 mg of the salt were extracted with 1 ml DCM and 0.6 ml sat.
NaHCO3 solution. The DCM phase was filtered through a 2 cm plug of sodium sulfate contained
in a disposable glass pipette into a GC vial. 10 ꢁL diisopropylethylamine and 5 ꢁL (S)ꢀ(+)ꢀαꢀ
methoxyꢀαꢀ(trifluoromethyl)phenylacetyl chloride (Mosher`s chloride) were added and after
standing for 30 min the sample was submitted for GC analysis: tR (cisꢀenantiomer 1) = 43.99
min, tR (cisꢀenantiomer 2) = 44.15 min, tR (1S,2Sꢀenantiomer) = 44.70 min, tR (1R,2Rꢀ
enantiomer) = 45.03 min.
Tosylamide method: to a suspension of 1ꢀHCl (100 mg, 0.67 mmol) in DCM (4 mL) was added
at r.t. triethylamine (0.28 mL, 2.01 mmol) and TsCl (127 mg, 0.67 mmol). The resulting reaction
mixture was stirred for 1 h. The reaction mixture was successively washed with sat. sodium
bicarbonate solution (10 mL), 0.1 N HCl (10 mL), sat. sodium bicarbonate solution (10 mL) and
brine (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in
vacuo at 45°C to yield 186 mg (quant.) of 4ꢀmethylꢀNꢀ(2ꢀmethylcyclohexyl)benzenesulfonamide
(8) as a colorless oil that crystallized after a few minutes at r.t.14 LCꢀMS: tR = 1.17 min (97.7a%);
m/z 268 [M+H]+. HPLC: tR (1R,2Rꢀenantiomer) = 7.55 min, tR (1S,2Sꢀenantiomer) = 10.45 min.7
Salt screen
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300 combinations consisting of 20 chiral acids and 15 solvents or solvent mixtures were applied
(Table 1). The choice of chiral acids and solvents was inspired by the ‘CRC Handbook of
Optical Resolutions via Diastereomeric Salt Formation’.10
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Table 1. Resolving agents and solvents used for the screen (300 combinations).
A
B
C
D
E
F
L
ꢀ(+)ꢀtartaric acid
(–) O,O’ꢀdiacetylꢀ
(+)ꢀO,O’ꢀdibenzoylꢀ
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water
L
ꢀtartaric acid
ꢀtartaric acid
ꢀtartaric acid
EtOH/water 50:50
EtOH/water 96:4
EtOH abs.
MeOH
D
(+)ꢀO,O’ꢀdiꢀ(4ꢀtoluoyl)ꢀ
(R)ꢀ(–)ꢀmandelic acid
(S)ꢀ(–)ꢀmalic acid
D
2ꢀPrOH
G
H
I
Nꢀacetylꢀ
Nꢀacetylꢀ
Nꢀacetylꢀ
L
L
L
ꢀleucine
acetone
ꢀphenylalanine
ꢀvaline
2ꢀbutanone
EtOAc
J
(1S)ꢀ(+)ꢀ10ꢀcamphorsulphonic acid
(1R,3S)ꢀ(+)ꢀcamphoric acid
10 EtOAc + 2.5vol% water
11 acetone/CHCl3 1:1
K
L
M
N
O
(R)ꢀ(ꢀ)ꢀ1,1’ꢀbinaphthylꢀ2,2’ꢀphosphoric acid
12 acetonitrile + 2.5vol% water
13 MeOH/water 2:1
D
ꢀ(–)ꢀquinic acid
(+)ꢀdeoxycholic acid
ꢀpyroglutamic acid
14 EtOAc/EtOH 1:1 + 4vol% water
15 TBME + 1vol% water
L
(1S)ꢀ(+)ꢀ3ꢀbromocamphorꢀ10ꢀsulfonic acid mono
hydrate
P
Q
(+)ꢀ3ꢀbromocamphorꢀ8ꢀsulphonic acid
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PꢀMix, consisting of a 1:1:1 mixture of (S)ꢀ(+)ꢀ
phencyphos hydrate, (R)ꢀ(+)ꢀanicyphos and (R)ꢀ
(+)ꢀchlocyphos
R
S
T
MꢀMix, consisting of a 1:1:1 mixture of (R)ꢀ(–)ꢀ
mandelic acid, (R)ꢀ(–)ꢀ4ꢀmethyl mandelic acid,
(R)ꢀ4ꢀbromo mandelic acid
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TꢀMix, consisting of a 1:1:1 mixture of (+)ꢀO,O’ꢀ
dibenzoylꢀ
D
ꢀtartaric acid, (+)ꢀO,O’ꢀdiꢀ(4ꢀtoluoyl)ꢀ
ꢀ(+)ꢀdianisoylꢀtartaric acid
D
ꢀtartaric acid,
D
For each combination 0.05 mmol racemic cis/trans mixture of 1 and a stoichiometric amount of a
chiral acid were used in a concentration range starting from maximum 250 mM (200 ꢁL) down
to 25 mM (2 mL). 500 ꢁL of a freshly prepared solution (100 mM) of 1 (cis/trans ratio of 23:77)
in MeOH and 625 ꢁL of freshly prepared solutions (80 mM) of the chiral acids in MeOH, DCM
or 1:1 mixture thereof were distributed into 300 2 mL HPLC vials arranged on an aluminum
plate. After removal of the solvent in vacuo at 30°C the 15 different solvents were added and the
vials closed with a screw cap. After heating at 80°C in a drying oven for 1ꢀ2 h (occasional
manual shaking) the vials containing clear solutions were placed on a second, identical plate and
allowed to cool to r.t. To the remaining vials were added solvents in 0.2 to 0.5 mL portions and
the heating and selection steps repeated until the vials were full (1.8 mL). After one day in 39
vials crystals were found that were separated from the mother liquor either by filtration or
decantation followed by drying with paper towel. The crystals were not washed, eventually the
mother liquor was used to transfer the crystals that were further dried in vacuo at 40°C. In a
second round the vials were stored at 4°C for a week and another 5 crystalline salts collected.
The yields were calculated based on the weight assuming a 1:1 stoichiometry and the ee
determined by the Mosherꢀamide method.
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(1R,2R)ꢀ 2ꢀmethylꢀ1ꢀcyclohexylammonium (S)ꢀ(+)ꢀ1,1'ꢀbinaphthylꢀ2,2'ꢀphosphate.
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1st crystallization 2ꢀmethylꢀ1ꢀcyclohexanamine (1) with a cis/trans ratio of 30:70 (493 ml, 3.75
mol) was dissolved in EtOH/water 1:1 (6 L) and loaded into a 10 L triple jacketed reactor
(AMSIꢀGlas) with automated temperature control and equipped with an Unistat 385W
cooling/heating unit, reflux condenser and nitrogen inlet. To the yellow solution (S)ꢀ(+)ꢀ1,1`ꢀ
binaphthylꢀ2,2`ꢀphosphoric acid (7) (561 g, 1.61 mol, 0.43 equiv.) was added. The temperature
raised from 22°C to 50°C, the pale brown suspension was heated to reflux (85°C internal
temperature, jacket temperature was set to 100°C. Further EtOH/water 1:1 (0.5 L) was slowly
added until all solid parts went into solution. The clear pale brown solution was allowed to cool
to 20°C internal temperature over a period of 3 h and stirred for another 2 h at 20°C. The crystals
were filtered off and dryꢀsucked thoroughly (no washing). The solid was dried in vacuo at 50°C
until constant weight was obtained (overnight). 391.5 g (yield: 22.4%) of cropꢀ1 in form of
colorless crystals were obtained. GC analysis of the Mosherꢀamides revealed an ee of 36.9%
(containing 2% of the cis isomers).
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2nd crystallization Cropꢀ1 (391.5 g) was combined with a trial batch (11.9 g) of similar
composition (ee= 38.7%, 3% cisꢀisomers) and suspended in EtOH/water 1:1 (6 L). The pale
brown suspension was heated to reflux (85°C internal temperature, jacket temperature was set to
100°C). Further EtOH/water 1:1 (2 L) was slowly added until all solid parts went into solution.
The clear colorless solution was allowed to cool to 20°C internal temperature over a period of 3
h and stirred for another 2 h at 20°C. The crystals was filtered off and dryꢀsucked thoroughly (no
washing). The solid was dried in vacuo at 50°C until constant weight was obtained (overnight).
268.2 g (yield: 15.4%) of cropꢀ2 as colorless crystals were obtained. GC analysis of the Mosherꢀ
amides revealed an ee of 62.9% (no cis isomers detectable).
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3rd crystallization Cropꢀ2 (268 g) was suspended in EtOH/water 1:1 (6 L + 1.3 L slowly added
when hot). The exact same procedure was applied as described under the 2nd crystallization.
189.7 g (yield: 10.9%) of cropꢀ3 as colorless crystals were obtained. GC analysis of the Mosherꢀ
amides revealed an ee of 82.0%.
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4th crystallization Cropꢀ3 (189.7 g) was suspended in EtOH/water 1:1 (4 L + 1.5 L slowly added
when hot). The exact same procedure was applied as described under the 2nd crystallization.
139.4 g (yield: 8.0%) of cropꢀ4 as colorless crystals were obtained. GC analysis of the Mosherꢀ
amides revealed an ee of 91.9%.
5th crystallization Cropꢀ4 (139.4 g) was suspended in EtOH/water 1:1 (3 L + 1.8 L slowly added
when hot). The exact same procedure was applied as described under the 2nd crystallization
apart from the washing of the product. This time the filtercake was washed twice with ice cold (ꢀ
18°C) ethanol / water 1:1 (2x 300 ml) before drying. 96.7 g (yield: 5.6%) of cropꢀ5 as colorless
crystals were obtained. GC analysis of the Mosherꢀamides revealed an ee of 96%. Due to the
large loss in the washing process the washing liquid was added to the next crystallization.
6th crystallization Cropꢀ5 (96.7 g) and the washing liquid (0.7 L) were suspended in EtOH/water
1:1 (1.8 L + 1.8 L slowly added when hot). The exact same procedure was applied as described
under the 2nd crystallization. 73.2 g (yield: 4.2%) of cropꢀ6 as olorless crystals were obtained.
GC analysis of the Mosherꢀamides revealed an ee of 97.9%. 1H NMR (600 MHz, DMSOꢀd6) δ
8.05 (dd, J = 18.5, 8.5 Hz, 4H), 7.88 (s, 3H), 7.51 – 7.39 (m, 4H), 7.31 (ddd, J = 8.1, 6.6, 1.3 Hz,
2H), 7.22 (d, J = 8.5 Hz, 2H), 2.45 (td, J = 10.8, 3.8 Hz, 1H), 1.83 (dt, J = 13.3, 3.4 Hz, 1H),
1.57 (dq, J = 12.7, 2.9 Hz, 1H), 1.52 – 1.43 (m, 2H), 1.32 – 1.22 (m, 1H), 1.21 – 1.05 (m, 2H),
1.00 (dddd, J = 15.6, 12.3, 8.2, 3.6 Hz, 1H), 0.86 – 0.82 (m, 1H), 0.84 (d, J = 6.5 Hz, 3H).
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(1R,2R)ꢀ2ꢀmethylꢀ1ꢀcyclohexanamine hydrochloride ((−)ꢀ(1R,2R)ꢀ1ꢀHCl). Cropꢀ6 (72 g, 156
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mmol) was suspended in TBME (500 ml) and ice water (500 ml). Sodium hydroxide solution 1
in water (187 ml, 187 mmol) was added within 5 minutes. The resulting biphasic mixture was
stirred for 5 min at room temperature. After phase separation, the aqueous layer was washed four
times with TBME (4 x 300 ml). During this procedure, phosphoric acid sodium salt precipitated
that was filtered off (glass fritt, good filtration). The organic phase was washed twice with brine
(2 x 300 ml) and dried over sodium sulfate, filtered and concentrated in vacuo at 40°C/180 mbar
to a volume of ca 500 ml, the clear solution became slightly turbid after standing at r.t. and was
filtered through a hard paper filter.
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To this clear and colorless solution was added under argon and vigorous stirring a solution of
hydrochloric acid 1M in diethyl ether (156 ml, 156 mmol) dropwise within 30 minutes until pH 1
(25 ml of HCl solution were left). A white suspension was formed that was stirred for another
hour at room temperature. The product was filtered off and the solid was washed three times
with diethyl ether. The solid was dried in vacuo at 45°C until constant weight was obtained. 21.4
g (−)ꢀ(1R,2R)ꢀ1ꢀHCl (92% yield) as white crystals were obtained. The overall yield of the
resolution was 3.9% based on the racemic isomeric mixture of 2ꢀmethylꢀ1ꢀcyclohexanamine that
allowed a maximum theoretical yield of 35% (½ of the 70% trans isomers). ee= 98.3%
(tosylamide method). 1HꢀNMR (400 MHz, DMSOꢀd6) δ 8.03 (s, 3H), 2.58 (td, J = 10.6, 4.0 Hz,
1H), 2.01 – 1.92 (m, 1H), 1.73 – 1.62 (m, 2H), 1.62 – 1.53 (m, 1H), 1.53 – 1.38 (m, 1H), 1.31 –
1.06 (m, 3H), 1.06 – 0.96 (m, 1H), 0.94 (d, J = 6.5 Hz, 3H). Optical rotation: [α]D22 –24.7 (c=4.0,
MeOH) confirmed the correct enantiomer.7
ASSOCIATED CONTENT
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Supporting Information. A pdf summarizing the current literature approaches toward 1.
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AUTHOR INFORMATION
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* To whom correspondence should be addressed. Tel: +41 61 6964576. Eꢀmail:
markus.furegati@novartis.com.
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ACKNOWLEDGMENT
The authors would like to thank Caroline Radoch for analytical support.
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