One-pot racemization process of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline: A key intermediate for the antimuscarinic agent solifenacin

Article abstract of DOI:10.1021/op300343q

(S)-(+)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline, which is the key intermediate in preparing the urinary antispasmodic drug solifenacin, was racemized in quantitative yield by a simple one-pot procedure through N-chlorination with trichloroisocyanuric acid, conversion of the N-chloroamine into the imine hydrochloride, and reduction of the imine double bond. The racemized amine was successfully resolved by d-(-)-tartaric acid obtaining (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in 81% yield and with 96.7% ee and, from the crystallization mother liquors, the R enriched form. This was racemized by the same one-pot process and resolved by d-(-)-tartaric acid with the same efficiency. Such an approach to the racemization of 1-phenyl-1,2,3,4- tetrahydroisoquinoline can be industrially useful to recycle the waste R enantiomer resulting from the classical resolution used to obtain the S enantiomer on a large scale.

Full text of DOI:10.1021/op300343q

Communication
pubs.acs.org/OPRD
One-Pot Racemization Process of 1‑Phenyl-1,2,3,4-
tetrahydroisoquinoline: A Key Intermediate for the Antimuscarinic
Agent Solifenacin
Cristiano Bolchi, Marco Pallavicini,* Laura Fumagalli, Valentina Straniero, and Ermanno Valoti
Dipartimento di Scienze Farmaceutiche, Universita
̀
degli Studi di Milano, via Mangiagalli 25, I-20133, Milano, Italia
S
* Supporting Information
patent in 2015.3 On industrial scale, 1 is prepared by (a)
ABSTRACT: (S)-(+)-1-Phenyl-1,2,3,4-tetrahydroisoqui-
noline, which is the key intermediate in preparing the
urinary antispasmodic drug solifenacin, was racemized in
quantitative yield by a simple one-pot procedure through
N-chlorination with trichloroisocyanuric acid, conversion
of the N-chloroamine into the imine hydrochloride, and
reduction of the imine double bond. The racemized amine
was successfully resolved by D-(−)-tartaric acid obtaining
(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in 81% yield
and with 96.7% ee and, from the crystallization mother
liquors, the R enriched form. This was racemized by the
same one-pot process and resolved by D-(−)-tartaric acid
with the same efficiency. Such an approach to the
racemization of 1-phenyl-1,2,3,4-tetrahydroisoquinoline
can be industrially useful to recycle the waste R
enantiomer resulting from the classical resolution used to
obtain the S enantiomer on a large scale.
Bischler−Napieralski cyclization of N-(2-phenylethyl)-
benzamide; (b) reduction of the resulting imine, 1-phenyl-
3,4-dihydroisoquinoline 2, to racemic 1-phenyl-1,2,3,4-tetrahy-
droisoquinoline rac-3; (c) classical resolution of the diastereo-
meric tartrate salts of 3 to give (S)-3; and (d) transformation of
(S)-3 into the carboxylate of (R)-quinuclidin-3-ol 1 by slightly
different procedures (Scheme 1).4,5 As the availability of
Scheme 1. Synthetic route to solifenacin (1)
INTRODUCTION
■
Phenyl-1,2,3,4-tetrahydroisoquinoline is the chiral key sub-
structure of many bioactive compounds.1 One of these is the
(R)-3-quinuclidinyl ester of (S)-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline carboxylic acid, solifenacin (1), a potent and bladder-
selective muscarinic M3 receptor antagonist.2 Its succinate salt,
commercialized as Vesicare, is, along with other antimuscarinics
such as tolterodine, fesoterodine, and darifenacin, one of the
most used urinary antispasmodic drugs for the treatment of
urinary frequency, urinary incontinence, or urgency associated
with overactive bladder (OAB).
The increasing interest, by both academic and industrial
research groups, in new synthetic strategies for the preparation
of these anticholinergics is justified by the continued growth of
the urinary incontinence market and by the approach of the
expiry date of the patents, which will allow their manufacture as
generics by several companies. In particular, 1 will come off
enantiomerically pure 3 is crucial for the whole process,
innovative approaches to the enantiomers of this intermediate
are actively pursued to avoid patent protections and, in their
turn, be patented. Obviously, the asymmetric reduction of the
prochiral imine 2, the immediate synthetic precursor of 3, can
be regarded as a first-choice alternative option; examples of
asymmetric reduction have been described,6−8 but also
asymmetric Pictet−Spengler condensations and enantioselec-
tive 1-arylations have been investigated.9,10 It is widely accepted
that asymmetric catalysis in industrial processes can provide
superior performances in the synthesis of pharmaceutical
intermediates relative to racemate resolutions, penalized by
the waste of the undesired enantiomer. However, such a
drawback can be overcome by associating a practical
racemization method with an efficient resolution. A dynamic
kinetic resolution occurred when the in situ racemization of 6,7-
dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline promoted
by an iridium catalyst was combined with the enzyme catalyzed
resolution of the amine.11 In the case of 1, the combination of
Chart 1. Structure of the muscarinic antagonist solifenacin
(1)
Received: November 30, 2012
Published: February 7, 2013
© 2013 American Chemical Society
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resolution with racemization would be not only competitive in
the crowded scenario of patented and not patented processes
but also applicable without restriction because the resolution of
rac-3 with tartrate is efficient and well documented since the
1920s.5 That is why we focused on the racemization of 3, and
here we report a new simple and efficient one-pot procedure to
accomplish it.
exploited to accomplish the racemization (Scheme 2). Indeed,
restoration of the C(2)C(3) double bond in one enantiomer
of the cis-piperidine 6 and conversion of the aminomethyl
group of one enantiomer of 4 into nitrile were successful, and
the unsaturated products could be easily racemized by
hydrogenation of C(2)C(3) and, after treatment with a
base, of CN, respectively.12,13 Analogously, we required that the
restoration of the C(1)C(2) double bond in (S)- or (R)-3
and the successive achiral saturation be easy, quantitative, and
possibly accomplished without isolating intermediates. On
these conditions, such a strategy would be advantageous in
comparison to the claimed racemizations of (R)-3 that are
effected, in moderate yield, by treatment with KOH in DMSO
at high temperature for several hours16 or, in higher yields, by
two separate steps, namely by transformation into an amide and
successive heating of the isolated amide in concentrated
mineral acid mixtures.17 On the other hand, many examples
for the conversion of 1,2,3,4-tetrahydroisoquinolines into 3,4-
dihydroisoquinolines are reported in literature, but their
applicability on a large scale is limited by the use of hazardous
and/or costly reagents or severe conditions, by modest yields,
or by the need to isolate intermediates.18
RESULTS AND DISCUSSION
■
Suggestions on how to racemize 3 came from our recent studies
on pregabalin [(S)-4] and on moxifloxacin (5),12,13 two drugs
also near to becoming generics. Like solifenacin, pregabalin and
moxifloxacin are industrially prepared or preparable by
diastereomeric resolution, respectively, of 3-amino-5-methyl-
hexanoic acid (rac-4) with (+)-mandelic acid and of the
intermediate N-benzylimide of cis-piperidine-2,3-dicarboxylic
acid (rac-cis-6) with (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-
gulonic acid (Scheme 2).14,15 Two other close and more
Scheme 2. Analogies between the syntheses of pregabalin,
moxifloxacin, and solifenacin and the proposed racemization
routes
On the basis of the results of our recent studies on the N-
chlorination and dehydrochlorination of various sub-
strates,12,13,19 we decided to follow the same approach to
convert 3 into 2. To the best of our knowledge, the only
example of conversion of 3 into 2 by N-chlorination and
dehydrochlorination was effected in high yield but under
conditions (t-BuOCl, KO2, 18-crown-6-ether, diethyl ether)
quite inappropriate for industrial applications.20 In contrast,
trichloroisocyanuric acid (TCCA) and sodium dichloroisocya-
nurate (NaDCC) are inexpensive, stable, and safe and we had
already successfully exploited their N-chlorinating properties on
amides, amino acids, and amino imides according to simple
protocols assuring quantitative yields in a short time and with
very simple reaction workup.12,13,19,21 In particular, TCCA
seemed appropriate for our target, which was a one-pot
procedure to convert chirally pure 3 into the racemate through
the N-chloroamine 7 and the imine 2 intermediates and thus
required, first of all, neat and quantitative N-chlorination of the
substrate and quantitative separation of the dechlorinated
chlorinating agent, that is isocyanuric acid. In fact, only upon
these two conditions, the successive dehydrochlorination of 7
to imine 2 and reduction to racemic 3 would be directly feasible
without extractions and purifications. This notwithstanding,
before developing a one-pot process, we studied the single steps
starting from (S)-3, the enantiomer available to us (Scheme 3).
In particular, we carefully characterized the intermediates with
particular focus on 7, which is described as not isolable due to
its instability and its tendency to rapidly convert to the imine
2.20
Treatment of (S)-3 with a slight excess of TCCA, that is little
more than a 0.33 molar portion (0.37 mol TCCA/1 mol (S)-
3), in DCM22 at 5 °C for 90 min gave (S)-7 as an oil, which
was isolated in quantitative yield by simple filtration of the
reaction mixture at −15 °C and concentration of the filtrate. At
room temperature, the N-chloroamine rapidly solidifies and is
indefinitely stable if stored at low temperatures (−15 °C),
whereas it transforms into the imine hydrochloride 2·HCl in
the course of several days at room temperature or
instantaneously at 60 °C. Such a conversion is observable in
the DSC trace of (S)-7, where an exothermic event occurs at 60
°C and is followed by an endothermic transformation at 228
interesting analogies relate rac-3 to rac-4 and rac-cis-6: (a) they
are prepared by hydrogenation of unsaturated precursors; (b)
the multiple bond of these unsaturated precursors directly
involves the stereogenic carbons of the hydrogenation products
(3 and 6) or is vicinal to the stereocenter and can promote its
racemization under mild conditions before the conversion into
the hydrogenated derivative (4). Therefore, in all three cases,
the conversion back to the unsaturated precursor can be
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caused the precipitation of rac-3, which was isolated as a unitary
product by filtration.
Scheme 3. Three-step and one-pot racemization of (S)-3
The overall yield of the one-pot procedure, scaled up to a
multigram scale, was 92%. According to a recently reported
method,23 we then verified the resolvability of the racemate
obtained from (S)-3 by tartaric acid and, in sequence, the
resolvability of the racemate obtained from the R enriched
amine recovered from the mother liquors of the first resolution.
In detail, the racemized amine was resolved with D-(−)-tartaric
acid with 0.78 experimental resolution efficiency, calculated by
multiplying the yield of the precipitated tartrate of (S)-3 (81%)
and the enantiomeric excess of liberated (S)-3 (96.74%). The R
enriched amine (63.28% ee), recovered from the crystallization
mother liquors, was racemized in 89% yield by the same one-
pot procedure previously used to racemize the S enantiomer
and the subsequent resolution with D-(−)-tartaric acid
accomplished with 0.77 efficiency (79% yield, 97.43% ee).
The two amounts of resolved (S)-3, having 96.74% and
97.43% ee respectively, were brought together to be recrystal-
lized in order to increase the enantiomeric excess. The success
and the optimization of such a practice is greatly improved by
the knowledge of the enantiomeric system nature, that is
existence, number, and location of eutectics both in the binary
melting point diagram and in the ternary solubility diagram.
According to procedures previously accomplished for other
enantiomer systems,24 we performed IR and DSC analyses and
solubility measurements to determine the racemate type
formed by 3. The IR spectra of (S)-3 and of rac-3 were
different, and the final melting temperature of (S)-3, 91 °C, was
lower than that of rac-3, 103 °C. These data indicated that 3
forms a racemic compound. The nature of the racemic
compound was confirmed by DSC analyses of rac-3, (S)-3,
and a number of their mixtures, which allowed us to construct
the binary phase diagram for mole fractions of (S)-3 ranging
from 0.5 to 1 (Figure 1). The DSC melting profiles of
°C, that is the melting point of 2·HCl. This coincidence and the
fact that no mass loss is associated with the exothermic event, as
shown by the TGA curve, indicate that 7 undergoes
dehydrochlorination and salification by the formed hydrogen
chloride. The transformation of the solid chloroamine into
imine hydrochloride, which is slowly progressive at room
1
temperature, is confirmed and monitored by the H NMR
spectra registered for samples drawn immediately after isolation
and in the subsequent days. The same transformation takes
place in solution: we observed that the DCM solution of (S)-7,
filtered at −15 °C to remove isocyanuric acid and excess
TCCA, stirred at room temperature overnight and then
concentrated, furnished 2·HCl as a sole product.
The subsequent step, that is the dehydrochlorination, was
easily and quantitatively effected as suggested by the above-
described behaviour of the chloroamine in solution, namely by
dissolving (S)-7 in dichloromethane, storing the solution at
room temperature overnight, and concentrating it. The
resulting white solid was confirmed to be 2·HCl by comparison
1
of the analytical data (mp and H and 13C NMR spectra) with
literature. Alternatively, (S)-7 was dissolved in methanol and
treated with stoichiometric KOH, and after 1 h, 2 (free imine)
was isolated by filtering off KCl and concentrating the filtrate.
To convert 2·HCl into the racemic tetrahydroisoquinoline
rac-3, a solution of the former in methanol was treated with
sodium borohydride. After 3 h, methanol was evaporated and
the residue was poured into water and dichloromethane: rac-3
was recovered in 95% yield as a white solid by concentration of
the organic phase. The reaction product had no optical
rotation, and HPLC analysis on a chiral stationary phase
confirmed that it was a racemate. No other peaks except those
of the two enantiomers of 3 were observed in the chromato-
Figure 1. Binary melting-point phase diagram for 1-phenyl-1,2,3,4-
tetrahydroisoquinoline (3). The solid curve represents the values
calculated on the basis of the Prigogine−Defay and the Schroder−van
̈
Laar equations.
1
gram. H and 13C NMR spectra were identical with those in
literature.
After ascertaining that the three reactions, N-chlorination,
dehydrochlorination, and imine reduction, were quantitative,
we developed a one-pot procedure to transform (S)-3 into rac-
3 (Scheme 3). The N-chlorination was accomplished as
described above, that is with 0.37 mol of TCCA per 1 mol of
(S)-3. After the precipitated isocyanuric acid was removed, a
methanol solution of KOH, equimolar to the starting substrate,
was added. Again, the formed precipitate, KCl, was removed
and the reaction solution was concentrated. The residue was
taken up into methanol, and sodium borohydride, 1.5 mol per 1
mol of starting (S)-3, was added. Successive addition of water
differently proportioned rac-3/(S)-3 mixtures were character-
ized by the presence of two peaks, the former, between 85 and
86 °C, representing the fusion of the eutectic E+, and the latter,
representing the fusion of the excess of the racemic compound
or (S)-enantiomer over the eutectic composition at temper-
atures that increase with such an excess. As can be seen in
Figure 1, the experimental values fit well with the theoretical
ones (solid curves), calculated on the basis of the melting point
of (S)-3 and of its heat of fusion (125.9 J/g) by the Schroder−
̈
van Laar equation25 and of the melting point of rac-3 and of its
heat of fusion (146.2 J/g) by the Prigogine−Defay equation.26
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The two curves intersect at the 0.889 molar fraction of (S)-3.
Such a theoretical value of the E+ composition is consistent
with the experimental observation that, unique among the DSC
curves recorded for the nine differently proportioned (S)-3/rac-
3 mixtures, a sample with a 0.89 mol fraction of (S)-3 shows
only one sharp melting peak at 89.1 °C. The solubility
measurements were made for (S)-3, rac-3, the eutectic mixture
E+ (89/11 (S)-3/(R)-3), and two enantiomeric mixtures close
to E+ (80/20 and 95/5) in the 86/14 (v/v) methanol/water
mixture at 23 °C.21 The data, listed in Table 1 and plotted in a
Table 1. Compositions (weight percentages) of saturated
solutions of rac-3, (S)-3, and S enriched 3 in aqueous
methanol at 23 °C
% 86/14
MeOH/H2O
solute
% (+)-(S)-3 % (−)-(R)-3
(S)-3
6.74
7.53
9.02
5.39
2.31
0
93.26
92.07
89.87
93.26
95.38
95/5 (S)3/(R)-3
89/11 (S)3/(R)-3
80/20 (S)3/(R)-3
rac-3
0.40
1.11
1.35
2.31
ternary diagram (Figure 2), show that E+ has the highest
solubility (92.5 mg/mL, 10.1% w/w). These findings imply
that, since (S)-3 liberated from the two precipitated
diastereomeric tartrates has an S enantiomer content sensibly
higher than 89%, namely ∼98.5% (97% ee), its recrystallization
under equilibrium conditions can maximize the enantiomeric
excess with minimal yield decrease. Indeed, (S)-3 crystallized in
80.6% yield and with 99.04% ee using a slight excess (28%) of
the 86/14 (v/v) methanol/water mixture22 over the volume
necessary to solubilise E+, calculated on the basis of the
solubility of E+ at 23 °C and of the E+ content (14%) of starting
97% enantiomerically pure (S)-3. The 19.4% loss of amine was
consistent with the fact that just the eutectic fraction (14%) was
retained in the mother liquors. Chiral HPLC analysis confirmed
that unprecipitated amine had a composition nearly identical to
that of E+, that is 89.55% of (S)-3 and 10.45% of (R)-3.
Figure 2. Solubility diagram for 1-phenyl-1,2,3,4-tetrahydroisoquino-
line (3) in 86/14 (v/v) methanol/water at 23 °C. The concentrations
of the components are expressed as weight percentages and are listed
in Table 1. The magnified upper part of the diagram shows the
solubility curve and the location of the two eutectics [E+: 9.02%
(+)-(S)-3, 1.11% (−)-(R)-3, 89.87% solvent mixture; E−: 9.02%
(−)-(R)-3, 1.11% (+)-(S)-3, 89.87% solvent mixture].
CONCLUSIONS
■
In summary, we have developed an efficient one-pot procedure,
which racemizes 1-phenyl-1,2,3,4-tetrahydroisoquinoline via N-
chlorination, dehydrochlorination, and imine reduction by
using mild reaction conditions and safe and cheap reagents. As
the S enantiomer of 1-phenyl-1,2,3,4-tetrahydroisoquinoline,
which is the key intermediate in the industrial synthesis of
antispasmodic drug solifenacin, is prepared by classical
resolution of the racemate, such a simple procedure might be
profitably applied on a large scale to racemize and to recycle the
undesired R enantiomer. To demonstrate that the racemic
substrate maintains suitable quality for resolution through this
one-pot process, two successful resolutions of previously
racemized 1-phenyl-1,2,3,4-tetrahydroisoquinoline were accom-
plished in sequence with tartaric acid.
ALPHA-P Bruker spectrometer. The melting points were
determined by DSC analysis and correspond to the peak
maximum, while the final melting temperatures were utilized to
construct the binary phase diagram of 3. The DSC curves were
recorded and integrated with the aid of a TA Instruments DSC
2010 apparatus. The enantiomer mixtures of 3 were prepared
by mixing the solid racemate with the solid (S)-enantiomer.
The TGA curves were recorded with the aid of a TA
Instruments TGA Q50 apparatus. Optical rotations were
determined in a 1 dm cell with a 1 mL capacity using a
Perkin-Elmer 241 polarimeter. HPLC analyses of 3 were
performed after conversion into the corresponding acetamide
using a Kromasil AmyCoat column (250 mm × 4.6 mm i.d.).
Synthesis of (S)-N-Chloro-1-phenyl-1,2,3,4-tetrahy-
droisoquinoline [(S)-7]. TCCA (0.408 g, 1.75 mmol) was
added to a solution of (S)-3 (1 g, 4.78 mmol) in DCM (10
mL) at 3 °C. The mixture was stirred at 5 °C for 90 min and
then cooled to −15 °C and filtered to remove precipitated
isocyanuric acid. The filtrate was concentrated at room
temperature under vacuum to give (S)-7 in quantitative yield
EXPERIMENTAL SECTION
■
1H NMR spectra were recorded on a Varian Gemini 300
operating at 300 MHz and 13C NMR at 75 MHz. Chemical
shifts are reported in ppm relative to residual solvent (CHCl3
or DMSO) as an internal standard. ESI-MS analyses were
acquired using a Thermo Finnigan TSQ Quantum Mass
Spectrometer. IR spectra were recorded with an FT-IR
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1
as a white solid: H NMR (300 MHz, CDCl3) δ 3.05 (dt, J1 =
Resolutions of Racemized 3. rac-3 (9 g), obtained from
the above one-pot racemization of (S)-3, was resolved with D-
(−)-tartaric acid according to the procedure described in ref 22.
The precipitated salt was decomposed to give (S)-3 (3.61 g,
80% yield) with 96.74% ee, while (R)-3 (5.30 g, 63.28% ee) was
isolated from the mother liquors. The R enriched amine was
one-pot racemized, obtaining rac-3 (4.69 g, 89%), which was
resolved with D-(−)-tartaric acid again. The resolution provided
(S)-3 (1.85 g, 79% yield) with 97.43% ee and (R)-3 (2.78 g,
62.22% ee).
Recrystallization of (S)-3 Obtained by Resolution. The
two amounts (3.61 and 1.85 g) of (S)-3, resulting from the
resolutions, were brought together and recrystallized from 86/
14 v/v MeOH/H2O (11.1 mL). The precipitate was isolated by
filtration at 23 °C, obtaining 4.40 g of (S)-3 (80.6%) with
99.04% ee. The amine recovered from the mother liquors
showed a 79.10% ee.
4.1 Hz, J2 = 16.5 Hz, 1 H), 3.28−3.39 (m, 1 H), 3.51 (ddd, J1 =
4.1 Hz, J2 = 9.6 Hz, J3 = 11.0 Hz, 1 H), 3.80 (ddd, J1 = 4.1 Hz,
J2 = 5.5 Hz, J3 = 9.6 Hz, 1 H), 5.14 (s, 1 H), 6.72 (d, J = 8.0
Hz,1 H), 7.1 (dt, J1 = 2.5 Hz, J2 = 6.3 Hz, 1 H), 7.18−7.22 (m,
2 H), 7.33−7.42 (m, 5 H). 13C NMR(75 MHz, CDCl3) δ
29.76, 58.21, 76.51, 126.39, 127.14, 128.27, 128.48, 128.57,
128.76, 128.94, 129.84, 133.01, 136.99, 142.49. MS (ESI) m/z
calcd for C15H15ClN (MH+ + 2) 246.09 and (MH+) 244.09, for
C15H16N (MH+ − Cl+ + H+) 210.13, for C15H14N (MH+ −
HCl) 208.11: found 246.10, 244.10 (base peak), 210.15, and
208.12.
Synthesis of 1-Phenyl-3,4-dihydroisoquinoline HCl
[2·HCl]. A solution of (S)-7 (1 g, 4.10 mmol) in DCM (8
mL) was stirred at room temperature overnight. After
evaporating the solvent, 2·HCl was obtained in quantitative
1
yield as a white solid: Mp 228.8 °C; H NMR (300 MHz,
DMSO-d6) δ 3.21 (t, J = 7.7 Hz, 2H), 3.96 (t, J = 7.7 Hz, 2 H),
7.39 (d, J = 7.7 Hz, 1 H), 7.50 (pseudo t, 1H), 7.60 (d, J = 7.4
Hz, 1 H), 7.65−7.81 (m, 6H). 13C NMR (75 MHz, DMSO-d6)
δ 25.32, 41.75, 126.31, 128.57, 129.46, 129.55, 130.38, 131.52,
133.67, 134.35, 137.19, 140.23, 173.52. Alternatively, (S)-7 was
dissolved in methanol and treated with a stoichiometric 1 M
methanol solution of KOH, and after 1 h, 2 (free imine) was
isolated in quantitative yield by filtering off KCl and
concentrating the filtrate.
ASSOCIATED CONTENT
* Supporting Information
NMR, IR, and MS spectra; DSC and TGA traces; HPLC
chromatograms. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: marco.pallavicini@unimi.it.
Notes
■
Synthesis of rac-1-Phenyl-1,2,3,4-tetrahydroisoquino-
line [rac-3]. Sodium borohydride (0.233 g, 6.15 mmol) was
added to a solution of 2·HCl (1 g, 4.10 mmol) in methanol (10
mL). After the reaction mixutre stirred at room temperature for
3 h, it was concentrated under vacuum, and DCM (20 mL) and
water (10 mL) were added to the resulting residue. The layers
were separated, and the organic phase was dried over Na2SO4,
filtered, and evaporated to give rac-3 (0.815 g, 95%) as a white
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Italian Ministry of University and Research for
financial support and Prochifar srl (Milano, Italy) for kindly
providing free samples of both rac- and (S)-1-phenyl-1,2,3,4-
tetrahydroisoquinoline.
20
1
solid: Mp = 98.9 °C;[α]D ∼0 (c 1, CHCl3); H NMR (300
MHz, CDCl3) δ 1.99 (s, 1H), 2.79−2.90 (m, 1H), 2.99−3.15
(m, 2 H), 3.24−3.32 (m, 1H), 5.12 (s, 1H), 6.76 (d, J = 7.6 Hz,
1H), 7.02−7.08 (m, 1H), 7.12−7.17 (m, 2H), 7.24−7.36 (m,
5H). 13C (75 MHz, CDCl3) δ 30.07, 42.56, 62.40, 125.91,
126.53, 127.66, 128.39, 129.69, 129.27, 129.32, 135.72, 138.57,
145.17. Chiral HPLC analysis of the corresponding acetamide
(Amycoat, Kromasil, el. N-hexane/2-propanol 9/1, 0.8 mL/
min, λ 220 nm) proved complete racemization, showing only
two peaks of identical area, the first-eluted acetamide of (R)-3
(tR ≈ 13 min) and the second-eluted acetamide of (S)-3 (tR ≈
16 min).
REFERENCES
■
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S.; Watts, V. J.; Nichols, D. E.; Mailman, R. B. J. Med. Chem. 1994, 37,
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TCCA (4.08 g, 17.5 mmol) was added to a solution of (S)-3
(10 g, 47.8 mmol) in DCM (100 mL) at 3 °C. The mixture was
stirred at 5 °C for 90 min and then cooled to −15 °C and
filtered to remove isocyanuric acid. A methanol solution of
KOH (1 M, 48 mL) was added to the filtrate, and the mixture
was stirred at room temperature for 1 h. Precipitated KCl was
removed by filtration, and the clear filtrate was concentrated to
remove dichloromethane. The residue was diluted with
methanol (50 mL), and NaBH4 (2.7 g, 7.17 mmol) was slowly
added. After the reaction mixture stirred at room temperature
for 3 h, it was poured into cool water (200 mL) and stirred for
10 min.The resulting solid was collected, washed with water,
and oven-dried at 60 °C for 30 min to give rac-3 (9.16 g, 92%)
as a white solid that was analytically identical to rac-3 obtained
by the three-step procedure.
̌
̌ ̌ ̌
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