Development of a preparative-scale asymmetric synthesis of (R)-p-tolyl methyl sulfoxide for use in a one-pot synthesis of a drug intermediate containing a trifluoromethyl-substituted alcohol functionality

Article abstract of DOI:10.1021/op700010a

A one-pot process for the synthesis of (S)-1,1,1-trifluoro-4-(5-fluoro-2- methoxy-phenyl)-4-methyl-2-((A)-toluene-4-sulfinyl-methyl)pentan-2-ol (3) is described, which was a key intermediate for the preparation of a class of novel glucocorticoid receptor ligands. The chemistry features the preparative-scale synthesis of (R)-p-tolyl methyl sulfoxide [(R)-pTMSO] from (2R,4S,5R)-4-methyl- 5-phenyl-3-(tolene-4-sulfonyl)oxathiazolidine-2-oxide (5) and the synthesis of 3 from 5 without isolation of (A)-pTMSO during the process.

Full text of DOI:10.1021/op700010a

Organic Process Research & Development 2007, 11, 605−608
Development of a Preparative-Scale Asymmetric Synthesis of (R)-p-Tolyl Methyl
Sulfoxide for Use in a One-Pot Synthesis of a Drug Intermediate Containing a
Trifluoromethyl-Substituted Alcohol Functionality
Zhengxu Han,* Jinhua J. Song, Nathan K. Yee, Yibo Xu, Wenjun Tang, Jonathan T. Reeves, Zhulin Tan, Xiao-jun Wang,
Bruce Lu, Dhileepkumar Krishnamurthy, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc., 900 Old Ridgebury Road,
P.O. Box 368, Ridgefield, Connecticut, 06877, U.S.A.
Abstract:
A one-pot process for the synthesis of (S)-1,1,1-trifluoro-4-(5-
fluoro-2-methoxy-phenyl)-4-methyl-2-((R)-toluene-4-sulfinyl-
methyl)pentan-2-ol (3) is described, which was a key intermedi-
ate for the preparation of a class of novel glucocorticoid receptor
ligands. The chemistry features the preparative-scale synthesis
Figure 1.
of (R)-p-tolyl methyl sulfoxide [(R)-pTMSO] from (2R,4S,5R)-
4-methyl-5-phenyl-3-(tolene-4-sulfonyl)oxathiazolidine-2-ox-
ide (5) and the synthesis of 3 from 5 without isolation of (R)-
pTMSO during the process.
Results and Discussion
Preparation of 3 requires enantiomerically pure (R)-
pTMSO. In the past two decades, chiral sulfoxides have been
widely used as efficient chiral auxiliaries in the synthesis of
enantiopure and biologically active molecules.3-4 Among
different chiral sulfoxides, pTMSO is one of the most widely
employed to incorporate chirality into organic molecules.5-7
However, the lack of an efficient method for the preparation
of pTMSO has limited its application on industrial scales.
Recently, Senanayake et al. reported a versatile chiral
building block 5, from which a variety of sulfoxides could
be prepared in excellent stereoselectivity and yield by
consecutive Grignard additions (Scheme 2).8 We were
interested in extending the scope of this chemistry to the
production of pTMSO on hundred-gram scales.
The synthesis began by preparation of oxathiazolidine-
2-oxide 5 from (1R,2S)-N-tosyl norephedrine (TNE) that is
commercially available in multikilogram quantities.8 Addition
of p-tolyl magnesium bromide to a THF solution of 5
generated the desired intermediate 6 via selective cleavage
of the more reactive S-N bond. Initially, the reaction was
quenched at this stage with NH4Cl aqueous solution, and
intermediate 7 was isolated and used for synthesis of a variety
of p-tolyl-containing chiral sulfoxides. However, slight
epimerization at the sulfur center occurred when this protocol
was used. To avoid this problem and to develop a more
practical procedure, a one-pot process was investigated.
Introduction
Recently, our discovery group disclosed a series of
glucocorticoid receptor ligands of a general structure of (S)-
1, which may be useful in the treatment of various inflam-
matory, autoimmune, and allergic disorders (Figure 1).1 This
class of compounds contains a CF3-substituted stereogenic
quaternary carbon, and very few methods have been reported
for the asymmetric synthesis of this type of structure.2a Our
discovery group has reported that the nucleophilic ring-
opening of chiral epoxide 4 provided a quick access to
compound 1.1 Gram quantities of 4 were prepared from
diastereomerically pure â-hydroxy-â-trifluoromethyl sulfox-
ide adduct 3 (Scheme 1).2b The chiral alcohol center in key
intermediate 3 was installed by diastereoselective addition
of the lithium anion of (R)-p-tolyl methyl sulfoxide [(R)-
pTMSO] to trifluoromethyl ketone 2.
In support of toxicological studies and other drug devel-
opment activities, a large amount of key intermediate 3 was
needed for the synthesis of 4. In this paper, we describe a
preparative-scale synthesis of the key reagent [(R)-pTMSO]
as well as a one-pot process to prepare 3 starting with
norephedrine-derived oxathiazolidine-2-oxide 5 without the
need to use (R)-pTMSO as an isolated intermediate during
the process.
(3) Carreno, M. C. Chem. ReV. 1995, 85, 1717-1760.
(4) Fernandez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651-3705.
(5) Bravo, P.; Frigerio, M.; Resnati, G. J. Org. Chem. 1990, 55, 4216-
4218.
(6) Bravo, P.; Bruche, L.; Farina, A.; Gerus, I. I.; Kolytcheva, M. T.; Kukhar,
V.; Meille, S. V.; Viani, F. J. Chem. Soc., Perkin Trans. 1 1995, 1667-
1671.
* To whom correspondence should be addressed. E-mail: shan@
rdg.boehringer-ingelheim.com.
(1) Lee, T. W.; Proudfoot, J. R.; Thomson, D. S. Bioorg. Med. Chem. Lett.
2006, 16, 654-657.
(2) (a) Pedrosa, R.; Sayalero, S.; Vicente, M.; Maestro, A. J. Org. Chem. 2006,
71, 2177-2180 and references therein. (b) Fujisawa, T.; Takemura, I.; Ukaji,
Y. Tetrahedron Lett. 1990, 31, 5479-5482.
(7) Izzo, I.; Crumbie, R.; Solladie, G.; Hanquet, G. Tetrahedron: Asymmetry
2005, 16, 1503-1511.
(8) Han, Z.; Krishnamurthy, D.; Grover, P. Fang, Q. K.; Su, X.; Wilkinson, H.
S.; Lu, Z.; Magiera, D.; Senanayake, C. H. Tetrahedron 2005, 61, 6386-
6408 and references therein.
10.1021/op700010a CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/17/2007
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Scheme 1. Asymmetric synthesis of epoxide 4 via (R)-pTMSO anion addition to 2
Scheme 2. Asymmetric synthesis of enantiomerically pure (R)-pTMSO
Scheme 3. One-pot process for the synthesis of 3
It was observed that the addition rate of p-tolyl mag-
nesium bromide was crucial for achieving optimum yields.
Fast addition gave a low yield of the desired product due to
the formation of undesired di-p-tolyl sulfoxide. Poor yield
was also seen when the reaction was carried out at higher
temperatures, with formation of other unknown impurities.
An excellent yield was obtained when the reaction was
performed at -65 to -70 °C with p-tolyl magnesium
bromide being added over 2-3 h. Subsequently, MeMgCl
was introduced into the reaction mixture over 30 min, and
the reaction mixture was stirred for 30-60 min and then
was warmed to 0 to -10 °C to complete the reaction.
Standard workup afforded a mixture of the desired chiral
sulfoxide and the cleaved chiral auxiliary (TNE).
Attempts to isolate (R)-pTMSO from the product mixture
via crystallization were not successful. However, thanks to
the large polarity difference between TNE and the target
chiral sulfoxide product, (R)-pTMSO could be readily
isolated by chromatographic purification on silica with a
gradient elution of ethyl acetate/hexanes (from 30:70 to 100:
0). Good separation was obtained when a mass ratio of 1:6
of crude product to silica was used. This one-pot protocol
was very volume efficient and could be performed at a
concentration of 1.2-1.5 M of 5 in THF up to 1-kg scale to
give (R)-pTMSO in greater than 75% isolated yield and
>99% ee.9
desired adducts in a diastereomeric ratio of 2:1. The two
diastereomers were separated by column chromatography on
silica to give 3 in 59% isolated yield and 99% de and the
undesired isomer in approximately 32% yield.
Although the above two-stage route could be used for
preparation of 3 in sufficient amount, this process suffers
from the need to use isolated (R)-pTMSO that was prepared
from 5 via a tedious process. To overcome this limitation
and develop a more efficient process, we envisioned a one-
pot approach from 5 to 3 as shown in Scheme 3. After
Grignard additions, a mixture of (R)-pTMSO and doubly
deprotonated TNE was obtained. It was postulated that,
without isolating the chiral sulfoxide, this crude product
mixture could be used directly for reaction with trifluoro-
methyl ketone 2.
Thus, the reaction for the preparation of (R)-pTMSO was
performed according to the same protocol described above.
At the completion of the reaction, the reaction mixture was
cooled to -65 to -70 °C, and one equivalent of LDA was
added over 15 min. After 30 min, ketone 2, dissolved in
THF, was added dropwise, and the resulting mixture was
stirred for another 30 min. HPLC analysis showed that the
reaction was complete and afforded the desired products in
the same 2:1 diastereomeric ratio.
Attempts to directly isolate product 3 from the crude
product mixture using crystallization were not successful.
TLC analysis showed that TNE was much more polar than
alcohol 3 and that they could be easily separated by
chromatography.10 Thus, the crude product mixture was first
(R)-pTMSO was then treated with LDA at -70 °C in
THF followed by the addition of ketone 2 to furnish the
(9) See the Experimental Section for the chiral HPLC method.
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filtered through a silica pad to remove the auxiliary to afford
alcohol 3 with an improved diastereomeric ratio of 4:1.11
To further enrich the diastereomeric purity, recrystallization
conditions were investigated for 3. A combination of
n-propanol/EtOAc was identified as the optimal solvent
system, and compound 3 was obtained in satisfactory overall
yield (48%) with >99% de after one crystallization.
to -65 to -70 °C, and LDA (25.2 mL, 37.74 mmol, mono-
THF 1.5 M in cyclohexane) was added over 15 min and the
reaction stirred for 20 min. Then a solution of 2 (10.0 g,
35.9 mmol, 1.0 equiv) in THF (25 mL) was added dropwise.
At the completion of the reaction as monitored by TLC
analysis, saturated aqueous NH4Cl (50 mL) and ethyl acetate
(100 mL) were added. The aqueous layer was removed, and
the organic phase was washed once with brine (50 mL). The
organic phase was concentrated, and the residue was
subjected to chromatographic purification eluting with
EtOAc/hexanes (3:7) to afford the desired isomer (9.2 g) in
59.3% yield and >99% de and the undesired isomer (5.1 g)
in 32.7% yield. Major isomer 1H NMR (DMSO-d6) δ 7.35-
7.32 (m, 4 H), 6.98 (dd, 1 H, J ) 10.9, 3.0 Hz), 6.89-6.87
(m, 1 H), 6.80 (dd, 1 H, J ) 9.0, 5.0 Hz), 6.24 (s, 1 H), 3.68
(s, 3 H), 2.84 (d, 1 H, J ) 15.1 Hz), 2.71 (d, 1 H, J ) 14.4
Hz), 2.47 (d, 1 H, J ) 14.3 Hz), 2.38 (s, 3 H), 2.10 (d, 1 H,
J ) 15.1 Hz), 1.51 (s, 3 H), 1.34 (s, 3 H); 13C NMR (DMSO-
d6) δ 157.6, 155.7, 154.4, 142.1, 141.7, 137.6, 137.5, 130.2,
126.2 (q, J ) 287 Hz), 123.9, 114.8, 114.6, 113.5, 113.3,
113.2, 76.0 (q, J ) 26.6 Hz), 61.1, 55.9, 41.7, 37.6, 30.9,
29.3, 21.2; [R]25365 +18.3 (c 0.508 g/100 mL, MeOH); LC-
MS (ES): 433.43 [M + H]+. Minor isomer 1H NMR
(CDCl3) δ 7.27(m, 4H), 7.04-7.01 (m, 1H), 6.90-6.85 (m,
1H), 6.77-6.74 (m, 1H), 3.79 (s, 3H), 2.95-2.71 (m, 3),
2.40 (s, 3H), 2.4-2.36 (m, 1H), 1.57 (s, 3H), 1.42 (s, 3H).
13C NMR (CDCl3) δ 158.3, 155.93, 154.1, 142.2, 140.3,
137.04, 136.9, 130.2, 126.5 (q, J ) 286 Hz), 123.9, 115.5,
115.3, 113.5, 113.3, 112.2, 112.1, 61.0, 55.4, 42.0, 37.7, 31.6,
31.0, 21.4. Chiral HPLC method: column: Super-ODS
column, 4.6 mm × 10 cm, particle size 2 µ; wavelength 220
nm, at 25 °C; mobile phases: A: water with 0.05% TFA,
B: MeCN with 0.05% TFA; gradient conditions are 90% A
to 10% A in 15 min, hold 5 min, back to 90% A, followed
by a 3-min post-run; flow rate: 1 mL/min. rt ) 11.45 min
for minor isomer, rt ) 13.22 min for major isomer.
One-Pot Synthesis of 3 from 5. To a solution of 5 (220
g, 626 mmol) in THF (2000 mL) at -65 to -70 °C was
added p-tolyl magnesium bromide (626 mL, 1.0 M in THF)
over 1.5-2 h. After addition, the reaction mixture was stirred
for 0.5 h, and the reaction was monitored by TLC analysis.
Methyl magnesium chloride (209 mL, 3.0 M in THF) was
added at -55 to -70 °C over 15 min, and the reaction
mixture was warmed up to ∼0 °C. At the completion of the
reaction as monitored by TLC, the reaction mixture was
cooled to -65 to -70 °C, and LDA (438 mL, 1.5 M in
cyclohexane) was added over 15 min. The orange reaction
mixture that formed was stirred for 20 min, and 2 (132 g,
455 mmol, 96% purity) was added dropwise over 30 min.
The reaction mixture was stirred for 0.5 h, and the reaction
was monitored by HPLC analysis. At the completion of the
reaction, saturated aqueous NH4Cl (800 mL) and ethyl acetate
(1000 mL) were added. The aqueous phase was removed,
and the organic phase was washed with brine (800 mL). The
organic solvents were removed, and the residue was diluted
with heptane (100 mL) and EtOAc (20 mL) and loaded onto
a silica pad prepared by slurrying 700 g of silica in heptane.
The pad was flushed with heptane first (500 mL) and then
Conclusion
In conclusion, a scaleable, one-pot process was developed
for the preparation of 3 from diastereomerically pure
oxathiazolidine-2-oxide, 5. The overall process throughput
was greatly improved by obviating the need to use (R)-
pTMSO as an isolated intermediate.
Experimental Section
General Procedures. All reagents were commercially
obtained and used as received unless otherwise noted. All
reactions were performed under an atmosphere of dry
nitrogen. Moisture-sensitive reactions were carried out in
anhydrous solvent either purchased or pretreated with mo-
lecular sieves overnight. Purification of products was per-
formed by flash chromatography on silica gel 60. TLC was
performed on Merck 60F-254 glass plates. HPLC analysis
was performed on an Agilent 1100 instrument. NMR spectra
were measured on a Bruker AM-400 MHz NMR spectrom-
eter.
Synthesis of p-Tolyl Methyl Sulfoxide [(R)-pTMSO].
To a solution of 5 (1.0 kg, 2.84 mol) in anhydrous THF (6-8
L) at -65 to -70 °C was added p-tolyl magnesium bromide
(2.85 L, 1.0 M in THF) over 3-4 h. At the completion of
the reaction as monitored by TLC analysis, methyl magne-
sium chloride (0.95 L, 3.0 M in THF) was added to the
mixture in 30-60 min. The reaction mixture was warmed
to 0 to -10 °C, and the reaction was monitored on TLC. At
the completion of the reaction, saturated NH4Cl aqueous
solution (4-5 L) was added slowly to quench the reaction.
The mixture was diluted by addition of ethyl acetate (5 L)
and warmed to ambient temperature. After removing the
aqueous phase, the organic phase was washed with brine (2
L × 2). Then the organic solvents were evaporated to
dryness, and the residue was subjected to column chroma-
tography eluting with a gradient of EtOAc/heptane (3:7 to
100:0, v/v) to afford TNE (820 g, 94.7%) and the desired
1
sulfoxide (343 g) in 78% yield and 99% ee. H NMR
(CDCl3) δ 2.41 (s, 3H), 2.70 (s, 3H), 7.32-7.34 (m, 2H),
7.35-7.55 (m, 2H). 13C NMR (CDCl3) δ 21.4, 43.9, 123.5,
130.0, 141.5, 142.4. Chiral HPLC method: column: Chiral-
cel OD, 250 mm × 4.6 mm; 220 nm; mobile phase: hexane/
IPA (92:8); flow rate: 1.5 mL/min; rt ) 8.6 min ((R)-
pTMSO); rt ) 9.6 min ((S)-pTMSO).
Synthesis of 3 from (R)-pTMSO and 2. A solution of
(R)-pTMSO (10.0 g, 35.9 mmol) in THF (75 mL) was cooled
(10) When ethyl acetate/hexane (4:6) was used as eluting solvent, the Rf values
are as follows: desired alcohol (major isomer): 0.56; minor isomer: 0.37;
N-tosyl norephedrine: 0.32; sulfoxide: 0.08.
(11) See Experimental Section for details.
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with 15% EtOAc/heptane, and the fractions containing the
major isomer were collected (∼3 L). The solvents were
concentrated and solvent-switched to n-PrOH (131 mL) with
residual EtOAc (solvent weight ratio was n-PrOH/EtOAc )
4.5:1). The mixture was heated to reflux to get a clear
solution and cooled to rt over 1 h. Crystallization occurred
at this temperature, and heptane (26 mL) was added. The
mixture was further cooled to -20 °C and held for 1 h. The
mixture was filtered and rinsed once with 50 mL of cold
n-PrOH (-20 °C). The crystals were air dried followed by
oven drying at 60 °C under vacuum for 15 h to give 3 (98.5
g) in 48% yield, >99% de, and 99.5% chemical purity.
Received for review January 9, 2007.
OP700010A
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