Practical enantioselective synthesis of a 3-aryl-3-trifluoromethyl-2- aminopropanol derivative

Article abstract of DOI:10.1021/op900216v

Development of a large-scale enantioselective synthesis of a lead compound containing a 3-aryl-3-trifluoromethyl-2-aminopropanol core is described. A single isomer of 3,3-disubstituted acrylic acid derivative was prepared via Perkin condensation or Horner

Full text of DOI:10.1021/op900216v

Organic Process Research & Development 2009, 13, 1161–1168
Practical Enantioselective Synthesis of a 3-Aryl-3-trifluoromethyl-2-aminopropanol
Derivative
Asaf Alimardanov,*,† Antonia Nikitenko,† Terrence J. Connolly,‡ Gregg Feigelson,‡ Anita W. Chan,‡ Zhixian Ding,‡
Mousumi Ghosh,‡ Xinxu Shi,‡ Jianxin Ren,‡ Eric Hansen,‡ Roger Farr,‡ Michael MacEwan,‡ Sam Tadayon,§
Dane M. Springer,⊥ Anthony F. Kreft,⊥ Douglas M. Ho,¶ and John R. Potoski†
Wyeth Research, 401 North Middletown Road, Pearl RiVer, New York 10965, U.S.A., Wyeth Research, CN 8000, Princeton,
New Jersey 08543, U.S.A., Wyeth Research, 1025 BouleVard Marcel-Laurin, Saint-Laurent, Quebec H4R 1J6, Canada, and
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544, U.S.A.
Abstract:
to 4,4,4-trifluoromethylbutenoyl derivatives such as 7 with up
to 90% de for electron-rich aromatic derivatives have been
reported (72% de was reported for phenylcuprate).3 The
conjugate addition would then be followed by Evans azidation.
However, the enantiomer of the chiral auxiliary needed for the
introduction of correct stereochemistry at the ꢀ-position would
not be useful for direct R-amination since it would yield the
(2R,3R)-isomer instead of the required (2S,3R). That, in turn,
would necessitate a chiral auxiliary exchange before the
amination and lengthen the synthesis. The indirect approach
through R-bromination followed by nucleophilic substitution
with an azide with inversion of configuration was not desirable.
Apart from safety considerations related to the use of nucleo-
philic sources of azide (sodium azide or tetramethylguanidinium
azide) on large scale, internal reports on related chemistry
highlighted that elimination of HBr under nucleophilic substitu-
tion conditions due to the presence of both ꢀ-CF3- and ꢀ-aryl-
groups was a concern.4 For these reasons Route II (Scheme 2)
was not pursued.
Alternatively, 1 can be accessed from acrylic acid derivative
9 via asymmetric hydrogenation followed by Evans azidation.
Either isomer of 9 can potentially be used, provided a single
isomer is available.
Tetrasubstituted Olefins: Isomerization Studies. For a
successful asymmetric hydrogenation, the E-isomer of the
tetrasubstituted olefin was required. A number of olefins were
therefore prepared starting from trifluoromethyl ketone 2
(Scheme 3).
Development of a large-scale enantioselective synthesis of a lead
compound containing a 3-aryl-3-trifluoromethyl-2-aminopropanol
core is described. A single isomer of 3,3-disubstituted acrylic acid
derivative was prepared via Perkin condensation or Horner-
Wadsworth-Emmons olefination, followed by hydrolysis. The acid
was converted to a chiral acryloxazolidinone derivative. Hydro-
genation of the latter on Pd/C in the presence of MgBr2 proceeded
via a chelation-controlled conformation to yield the desired
isomer with high selectivity. Subsequent Evans azidation,
hydrogenation, reductive cleavage of the chiral auxiliary,
and sulfonylation afforded the target compound as a single
isomer in high overall yield.
Introduction
In a recent Medicinal Chemistry program, a trifluoromethyl-
containing aminoalcohol derivative 1 was identified as a
compound of interest. Early milligram-scale batches of 1 were
prepared via a short synthesis involving Scho¨llkopf olefination1
and hydride reduction, followed by chiral preparative HPLC
separation of a mixture of all four possible isomers. The desired
isomer was obtained in 4% overall yield (Scheme 1). As
kilogram quantities of the target compound were needed for
further studies, a stereoselective and practical synthesis of 1
was required.
Route Selection. The evaluated possible routes to 1 are
shown in Scheme 2. Since alcohol 1 has two adjacent stereo-
centers, asymmetric hydrogenation of an appropriate isomer of
a tetrasubstituted olefin, e.g., a dehydroalanine derivative, would
potentially offer a shorter and more efficient synthesis (Route
I) by setting both stereocenters in one step.
Scho¨llkopf olefination of ketone 2 afforded a single isomer
of olefin 3a or 3b,1 but unfortunately this was the Z-isomer
(confirmed by NOESY). Horner-Wadsworth-Emmons ole-
fination of phosphonates derived from either glycine derivatives5
or hydantoin6 afforded olefins 11 and 12, respectively, both as
2:1 mixtures of isomers. Conversion of ketone 2 to azalactone
13 proceeded stereoselectively,7 but again afforded predomi-
Routes II and III represent the stepwise introduction of
stereocenters. Asymmetric 1,4-addition of organocuprates to
R,ꢀ-unsaturated acyl derivatives containing chiral oxazolidinone
auxiliary has been studied,2 and examples of arylcuprate addition
(3) Yamazaki, T.; Shinohara, N.; Kitazume, T.; Sato, S. J. Fluorine Chem.
1999, 97, 91.
* Corresponding author. E-mail: alimara@wyeth.com.
† Wyeth Research, Discovery Synthetic Chemistry, New York.
‡ Wyeth Research, Chemical Development, New York.
⊥ Wyeth Research, Discovery Medicinal Chemistry, New Jersey.
§ Wyeth Research, Quebec.
(4) Caggiano, T. Wyeth internal report on related substrates.
(5) (a) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487. (b) Su, G.;
Pan, C.; Wang, H.; Zeng, L. Synth. Commun. 2004, 34, 665.
(6) Meanwell, N. A.; Roth, H. R.; Smith, E. C. R.; Wedding, D. L.; Wright,
J. J. K. J. Org. Chem. 1991, 56, 6897.
¶ Princeton University.
(1) Enders, D.; Chen, Z.-X.; Raabe, G. Synthesis 2005, 306.
(2) (a) Han, Y.; Liao, S.; Qui, W.; Cai, C.; Hruby, V. J. Tetrahedron
Lett. 1997, 38, 5135. (b) Liao, S.; Han, Y.; Qui, W.; Bruck, M.; Hruby,
V. J. Tetrahedron Lett. 1996, 37, 7917.
(7) (a) Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L. J. Fluorine
Chem. 2002, 115, 27. (b) Kolycheva, M. T.; Yagupol’skii, Yu., L.;
Zaitsev, L. M.; Gerus, I. J.; Kukhar’, V. P.; Klebanov, B. M. Khim.-
Farm. Zh. 1988, 22, 159.
10.1021/op900216v CCC: $40.75  2009 American Chemical Society
Published on Web 10/27/2009
Vol. 13, No. 6, 2009 / Organic Process Research & Development
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Scheme 1. Medicinal Chemistry synthesis of 1
Scheme 2. Possible routes to 1
nantly the Z-isomer (Z:E ) 94:6) as determined by NOESY of
the solvolyzed derivative 14.
conditions at 450 psig H2 on Rh or Ru catalysts using a variety
of chiral ligands (S,S-MeDuphos, R,R-Et-BPE, Me-f-ketalphos,
R-Binapine, S,S,R,R-Tangphos with Rh(nbd)2BF4, and [RuCl(p-
cymene)C3-TunePhos]Cl). Olefin Z-3a could be hydrogenated
non-enantioselectively on Pd/C in MeOH. Interestingly, when
an E/Z mixture of 3a was subjected to these conditions, we
observed a significant rate difference for the hydrogenation of
the isomers, with the E-isomer remaining virtually unchanged.
Parallel route evaluations using trisubstituted olefins were
showing promising results, so use of tetrasubstituted olefins as
substrates was not evaluated further.
Isomerization of olefins 3, 13, and 14 was then studied under
a variety of conditions. Interestingly, when treated with NaSMe,
NaS-t-Bu, or DABCO in DMF, Z-3a isomerized to afford the
desired E-3a as the major component, but in only 3:1 E:Z ratio.
The t-Bu- analog 3b afforded a 1.5:1 E:Z mixture under the
same conditions. No isomerization was observed on treatment
of 3a with I2 in CHCl3 or NaOEt in EtOH. Attempted
isomerization of azalactone 13 (HBr, AcOH, with or without
(PhCOO)2)8 or ester 14 (DABCO or HBr, AcOH) afforded a
4:1 and a 1:1 Z:E mixtures, respectively.
Trisubstituted Olefin Preparation and Reduction. Perkin
condensation of ketone 2 with Ac2O under conditions reported
for aryl trifluoromethyl ketones (NaOAc, 140 °C)10 afforded a
90:10 E/Z-mixture of acid 9. The selectivity improved to 96:4
at 100 °C. Recrystallization from toluene-heptane afforded a
single isomer of 9 in 85% yield (Scheme 4). Olefin stereo-
chemistry was confirmed by NOESY. This method for selective
preparation of acid 9 was used initially as it employed
inexpensive reagents and could be run easily on >100 g scale.
However, relatively low throughput due to the necessary
aqueous quench of excess Ac2O was considered a drawback
for further scale-up, so an alternative preparation of 9 was
developed.
As an alternative approach, we considered asymmetric
hydrogenation of Z-3a with a possible subsequent chemo-
enzymatic inversion of stereochemistry at the R-position.9
However, in contrast to ꢀ-methyl dehydroalanine ester deriva-
tives described in the literature,9a the ꢀ-trifluoromethyl-contain-
ing Z-3a proved unreactive under asymmetric hydrogenation
(8) (a) Alias, M.; Lopez, M. P.; Cativiela, C. Tetrahedron 2004, 60, 885.
(b) Schmidt, T.; Baumann, W.; Drexler, H.-J.; Arrieta, A.; Heller, D.
Organometallics 2005, 24, 3842.
(9) (a) Roff, G. J.; Lloyd, R. C.; Turner, N. J. J. Am. Chem. Soc. 2004,
126, 4098. (b) Enright, A.; Alexandre, F.-R.; Roff, G.; Fotheringham,
I. G.; Dawson, M. J.; Turner, N. J. Chem. Commun. 2003, 2636. (c)
Alexandre, F.-R.; Pantaleone, D. P.; Taylor, P. P.; Fotheringham, I. G.;
Ager, D. J.; Turner, N. J. Tetrahedron Lett. 2002, 43, 707.
(10) Sevenard, D. V. Tetrahedron Lett. 2003, 44, 7119.
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Scheme 3. Preparation of tetrasubstituted olefins and
LC/MS examination of the reaction mixtures identified that
ketal formation between ketone 2 and ethanol was a side
reaction, albeit ketal formation occurred at a lower rate than
that of the condensation. To avoid the side reaction and have
addition control of the exotherm associated with the reaction,
ketone 2 and triethyl phosphonoacetate were mixed as neat
liquids. Safety testing did not identify any reaction between the
two substrates when mixed neat. The resulting mixture was
added slowly to a mixture of ethanol and K3PO4, followed by
equilibration at room temperature. Addition of water to the
mixture then ensured basic hydrolysis of intermediate ester 15
to afford acid 9, which was isolated as a 98:2 E/Z mixture in
83% yield by filtration after ethanol distillation and acidification.
Asymmetric hydrogenation of olefin 9 was then studied.
Screening of catalysts (Rh and Ru metal sources, Walphos,
TangPhos, and Tunephos ligands) identified Rh(nbd)2BF4 and
Walphos 8-1 as the optimal metal-ligand combination.13
Further evaluation of catalyst loading, hydrogenation pressure,
and temperature showed that the reduction can be done at room
temperature at 45 psig H2 using a 200:1 substrate:catalyst ratio
to afford (S)-16 in quantitative yield as a single enantiomer as
detected by chiral HPLC (Scheme 5).
isomerization resultsa
Acid 16 was converted to the oxazolidinone derivative 10a
by reacting with (S)-benzyloxazolidinone using a standard
protocol.14 It should be noted that conversion of acid 16 to an
alkyl ester followed by enolate generation and treatment with
an N-electrophile (e.g., TrisN3) is expected to produce a
diastereomer opposite to the required one.15 A two-step approach
through R-bromination followed by azidation was not desirable
(Vide supra).
a Reagents
and
conditions:
a)
CNCH2CO2R,
t-BuOK;
b)
CbzNHCH(PO(OMe)2)CO2Me, DBU; c) i) hydantoin, Br2, AcOH; ii) P(OEt)3;
iii) ketone 2, LiOH; d) PhCONHCH2CO2H, AcOH, K2CO3; e) MeOH, NaOAc.
Scheme 4. Selective olefination of ketone 2
Assignment of the Absolute Stereochemistry and a
Second-Generation Route. In order to determine the absolute
configuration of 16, we decided to compare imide 10a with its
diastereomer prepared via a different route. To that end, acid 9
was converted to oxazolidinone derivative 17 in order to
evaluate its hydrogenation products. Literature precedents of
(12) Interestingly, examination of experimental details in various reports
of HWE olefination of phenyl trifluoromethyl ketone in THF or toluene
using NaH as a base might suggest an opposite hold-time/selectivity
relationship.
(13) Walphos
8-1:
(R)-1-[(R)-2-(2′-dicyclohexylphosphinophenyl-
Horner-Wadsworth-Emmons olefination of ketone 2 with
triethyl phosphonoacetate can be run at a higher concentration
to afford ester 15.
)ferrocenyl]ethyldi(bis-(3,5-trifluoromethyl)phenyl)phosphine, available
from Solvias, SL-W008-1; nbd: norbornadiene.
(14) (a) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F.
Tetrahedron 1988, 44, 5525. (b) Cage, J. R.; Evans, D. A. Org. Synth.
1990, 68, 83.
Interestingly, conflicting results are found in the literature
on selectivity of Horner-Wadsworth-Emmons olefination of
aryl trifluoromethyl ketones, with E/Z ratios ranging from 53:
47 to 83:17 reported for the simplest analogue phenyl triflu-
oromethyl ketone using NaH as a base.11 We have observed
that, in the case of olefination of ketone 2 in ethanol using
K3PO4 as a base, an 80:20 E/Z mixture of isomers of 15 forms
after 0.5 h. However, equilibration to a ∼95:5 E/Z mixture takes
place in ethanol over 20 h.12
(15) Anti-diastereomer formation with up to 80% de was reported for a
similar substrate with electron-rich aryl substituent and BnBr as an
electrophile; 62% de and low conversion was reported for N-
electrophile. Tamura, K.; Yamazaki, T.; Kitazume, T.; Kubota, T. J.
Fluorine Chem. 2005, 126, 918.
(16) (a) Sellstedt, J.; Cheal, G.; Noureldin, R.; Chan, A.W.-Y.; Raveen-
dranath, P.; Caggiano, T. J. Production of Pure Chiral Amino Alcohol
Intermediates, Derivatives Thereof, and Uses Thereof. U.S. Patent
Publ. Appl. US 2007/249869, 2007; Chem. Abstr. 2007, 147, 486150.
(b) Prashad, M.; Liu, Y.; Kim, H.-Y.; Repic, O.; Blacklock, T. J.
Tetrahedron: Asymmetry 1999, 10, 3479.
(17) Once again, the (R)-enantiomer of benzyloxazolidinone chiral auxiliary
needed for introduction of (S)-stereocenter at the ꢀ-position that way
would not generate the required diastereomer after R-azidation.
(18) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
(19) In a typical run, 4-5 HPLC area % of 18 was formed, with 2.1%
remaining after crystallization.
(11) (a) Kimura, M.; Yamazaki, T.; Kitazume, T.; Kubota, T. Org. Lett.
2004, 6, 4651. (b) Eguchi, T.; Aoyama, T.; Kakinuma, K. Tetrahedron
Lett. 1992, 38, 5545. (c) Pinna, G. A.; Cignarella, G.; Ruiu, S.; Loriga,
G.; Murineddu, G.; Villa, S.; Grella, G. E.; Cossu, G.; Fratta, W.
Bioorg. Med. Chem. 2003, 11, 4015. (d) Carceller, E.; Merlos, M.;
Giral, M.; Almansa, C.; Bartoli, J.; Garcia-Rafanell, J.; Forn, J. J. Med.
Chem. 1993, 36, 2984. For a reported example of predominant
formation of Z-isomer, see: (e) Ohno, N.; Fukamiya, N.; Okano, M.;
Tagahara, K.; Lee, K.-H. Bioorg. Med. Chem. 1997, 5, 1489.
(20) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem.
Soc. 1990, 112, 4011.
(21) For triisopropylsulfonyl azide stability data, see: Tuma, L. D.
Thermochim. Acta 1994, 243, 161.
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Scheme 5. Asymmetric hydrogenation and conversion to acyloxazolidinone
hydrogenationofsimilarolefinsindicatethat,duetodipole-dipole
interactions of the carbonyl groups, the hydrogenation of 17
would proceed through conformation A (Figure 1), yielding
predominantly (S,R)-diastereomer 10b.16,17
This result presented a more practical alternative to asym-
metric hydrogenation. Therefore, a second-generation route
eliminating the need for the chiral ligand was used further. The
procedure used for large-scale preparation of 10a from acid 9
involved conversion to acryloxazolidinone derivative 17 by
treating the mixture of 9, (S)-benzyloxazolidinone, LiCl, and
pivaloyl chloride with triethylamine at -20 °C,18 followed by
crystallization from heptane or IPA/water. Olefin 17 was then
hydrogenated at 60-65 psig H2 and 45-50 °C in THF in the
presence of 1.2 equiv of MgBr2 and Pd/C catalyst, followed
by crystallization from IPA-water to afford 10a typically in
70-76% yield and >98% de. It should be noted that an aqueous
wash to remove MgBr2 was necessary before the solvent switch
to IPA. When a direct solvent replacement from THF to IPA
via atmospheric pressure distillation was attempted, significant
decomposition of 10a occurred, generating impurity 18 and its
derivative resulting from further loss of HBr (m/z ) 369). In
addition, prolonged reaction times led to increased formation
of impurity 19 (Figure 2; structure assignments based on LC/
MS data). Formation of this impurity is presumed to have
occurred via MgBr2-promoted oxazolidinone ring-opening of
10a (or 17 followed by olefin hydrogenation) followed by
decarboxylation to generate 18, followed by further reduction
to generate 19.19
We reasoned that in the presence of a Lewis acid hydroge-
nation on Pd/C would proceed via chelation-controlled confor-
mation B, resulting in reversal of the sense of stereoinduction
and formation of the (S,S)-diastereomer 10a predominantly.
Correlation of spectral properties with imide 10a produced from
acid 16 would then allow us to assign its stereochemistry. We
were also hopeful that a choice of an appropriate Lewis acid
might yield a selectivity high enough to allow the preparation
of diastereomer 10a from olefin 17 directly, thus using the same
chiral auxiliary to set both stereocenters and avoiding the need
for the expensive chiral hydrogenation catalyst.
Gratifyingly, both assumptions proved to be true. Hydro-
genation of olefin 17 at room temperature and 450 psig H2 in
the absence of a Lewis acid resulted in the formation of a 71:
29 mixture of isomers 10b and 10a. The sense of stereoinduc-
tion was reversed when LiCl was added. Correlation of spectral
data for the diastereomers allowed assignment of absolute
stereochemistry of acid 16 as (S) to be confirmed. More
importantly, hydrogenation was highly selective in the presence
of MgBr2, producing a 95:5 mixture of 10a and 10b, albeit
initially with 79% conversion. Further optimization studies
demonstrated that full conversion could be achieved in 4 h at
50 °C at useful H2 pressures (50-65 psig). Use of dry catalyst
(<3% water) was important for achieving high selectivity (up
to 96.5:3.5).
Completion of Synthesis. The oxazolidinone derivative 10a
was converted to azide 20 via enolization and reaction with
triisopropylsulfonyl azide (TrisN3).20,21 The reaction could be
run at -40 °C, with only a minor selectivity loss compared to
typical lower-temperature conditions, and afforded intermediate
Figure 1. Hydrogenation of olefin 17.
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oxazolidinone byproduct. In addition, sulfonylation of 21 was
found to be slow and was accompanied by the formation of
∼15% of an impurity resulting from intramolecular attack of
the amine on the oxazolidinone moiety. For those reasons imide
21 was first converted to aminoalcohol 22 which was isolated
as its hydrochloride salt. It should be noted that direct conversion
of crude azide 20 to aminoalcohol 22 was also possible, but it
resulted in an inferior impurity profile and required extensive
purification at the expense of the yield.
Figure 2. Proposed structures for impurities generated during
hydrogenation of 17 in the presence of MgBr2.
During the reduction of 21 to 22, two impurities were
identified, the structures of which were proposed on the basis
of LC/MS data (Figure 3). Significant levels of the des-fluoro
impurity 23 were formed when the substrate was added to a
solution of lithium borohydride while attempting to increase
the reaction throughput. Changing the order of addition easily
controlled the level of 23 generated, and it was not detected in
isolated 22. Controlling the formation of 24 and limiting the
amount of it in 22 proved more challenging and critical.
Compound 24 reacted with the sulfonyl chloride used in the
last step and generated a persistent impurity 25 that was difficult
to purge from the API. Further experiments identified that the
level of 24 in 22 had to be controlled at <1.0 HPLC area % in
order to control the level of 25 below 0.5% in the API. To
minimize the formation of 24, the temperature was maintained
between -10 and 0 °C during the addition of LiBH4. Using
these conditions, the level of 24 generated in-process was
controlled at 2-3%. Filtration of the slurry of 22 at 35-40 °C
assisted in controlling the level of 24 in 22 to the desired level.
Aminoalcohol 22 was then treated with 5-chlorothiophene-
2-sulfonyl chloride to afford sulfonamide 1. Use of N-methyl-
morpholine as the base and catalytic amounts of 4-dimethy-
laminopyridine (DMAP) in dichloromethane at 0-10 °C was
found to be optimal, as it minimized the amount of O-
Figure 3. Proposed structures for impurities generated during
LiBH4 reduction of 21, and fate of 24 in API.
azide 20 with high selectivity (93:7 dr at -40 °C; 97:3 dr at
-78 °C). Evidently, the directing effect of the oxazolidinone
chiral auxiliary overrides any directing effect of the ꢀ-substitu-
ent. The use of other N-electrophiles (RO2CNdNCO2R, R )
t-Bu, i-Pr, Bn) resulted in significantly lower diastereomer ratios
even at -78 °C. The crude azide 20 was used without isolation.
Hydrogenation after a solvent switch afforded amine 21, which
was crystallized as a hydrochloride salt of high purity and as a
∼98.5:1.5 mixture of diastereomers.
The conversion of amine 21 to the target 1 through
sulfonylation followed by reductive removal of the auxiliary
would require chromatographic purification to remove the
Scheme 6. Large-scale synthesis of 1
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sulfonylation byproduct. Addition of N-methylpiperazine to the
reaction mixture, when the reaction was deemed complete,
scavenged residual 4-dimethylaminopyridinium-(5-chlo-
rothiophene)-2-sulfonyl chloride, which otherwise tended to
survive the acidic workup and react with the product. The crude
product isolated from the reaction mixture was dissolved in IPA,
polish-filtered, and precipitated by addition of water. Following
this sequence, the target compound was isolated as a single
stereoisomer as detected by chiral HPLC, in seven steps and
28% overall yield starting from ketone 2. The absolute con-
figuration of 1 was confirmed by single crystal X-ray analysis
(see Supporting Information for details).
isomer 2: 4.79 min; isomer 3 (isomer of interest): 5.54 min;
isomer 4: 7.51 min.
(E)-3-(3,5-Difluorophenyl)-4,4,4-trifluorobut-2-enoic acid
(9). Method A. A mixture of 1-(3,5-difluorophenyl)-2,2,2-
trifluoroethanone 2 (114.59 g, 0.545 mol), NaOAc (89.48 g,
1.091 mol, 2 equiv), and acetic anhydride (773 mL, 8.18 mol,
15 equiv) was stirred at 100 °C for 5 h. The reaction mixture
was cooled to 4 °C, and 1.375 L of water was added over 30
min at 4-12 °C. The mixture was allowed to warm up to room
temperature and stirred for 2 h (completion of hydrolysis was
monitored by HPLC). MTBE (1 L) was added, followed by
1.145 L of water. Phases were separated. The aqueous phase
was extracted with 2 × 0.5 L of MTBE. The combined organic
fractions were concentrated in vacuum. Toluene was added, and
the mixture was concentrated in vacuum. Crude product, 138.83
g, was obtained as a yellow solid (96:4 mixture of E/Z isomers
based on 1H and 19F NMR). The solids were dissolved in 2.7
L of 4:1 heptane-toluene mixture at 70 °C. The solution was
allowed to cool to room temperature and then stirred at 2-4
°C for 6 h. Precipitated solids were filtered, washed with 3 ×
150 mL of heptane, and dried in vacuum at room temperature
for 24 h to afford 117.5 g of the title product as a white solid
Conclusions
A practical enantioselective approach to a 3-aryl-3-triflu-
oromethyl-2-aminopropanol and its derivatives has been de-
veloped. The described method relies on a Lewis acid-mediated
hydrogenation followed by Evans azidation. It is amenable to
scale-up and was the basis for two campaigns that produced
kilogram quantities of API. Although the approach relies on
the stoichiometric use of a chiral auxiliary, it utilizes the
auxiliary to set both stereocenters of the target compound and
avoids the use of an expensive chiral ligand.
1
(85% yield; single isomer as judged by H, 19F NMR, and
HPLC; >99.9% pure by HPLC). Mp: 129-130 °C. 1H NMR
(300 MHz, CDCl3) δ 6.95-6.78 (m, 3 H), 6.64 (br. q, J ) 1.2
Hz, 1 H). 19F NMR (282 MHz, CDCl3) δ -68.18 (s, 3 F),
-109.14 (s, 2 F). 13C NMR (75 MHz, CDCl3) δ 168, 162.63
(dd, J ) 250, 12 Hz), 142.51 (q, J ) 31 Hz), 133.01 (dd, J )
10, 10 Hz), 124.44 (q, J ) 5.4 Hz), 121.71 (q, J ) 274 Hz),
112.03 (dd, J ) 19, 8 Hz), 105.31 (dd, J ) 25, 25 Hz). HRMS
(for M - H): calcd: 251.0137; found: 251.0135.
Method B. A solution of 2 (11.5 kg, 54.74 mol) in triethyl
phosphonoacetate (12.3 kg, 54.86 mol) was added to a mixture
of K3PO4 (29.1 kg, 137.09 mol, 2.5 equiv) and anhydrous
ethanol (40.2 kg) over 1 h at e30 °C After the addition the
temperature was adjusted to 23-28 °C, and the mixture was
stirred for 20 h. Water (80.5 kg) was added to the mixture.
Ethanol was distilled off at atmospheric pressure (pot temper-
ature 95-96 °C). The batch was cooled to 12 °C, and 6 N HCl
solution (46 L) was added over 45 min. The temperature was
adjusted to 20-25 °C, and the mixture was stirred for 1.5 h.
The solids were filtered. The cake was washed with water (11.5
kg). The wet cake was reslurried in water (115 kg) at 50 °C
for 30 min. The slurry was filtered. The cake was washed with
water (2 × 11.5 kg) and dried in vacuum at 40-50 °C to afford
12.7 kg of the title product (92% yield; 90.6% strength, 83%
yield adjusted to strength).
(S)-3-(3,5-Difluorophenyl)-4,4,4-trifluorobutanoic acid (16).
Rh(nbd)2BF4 (0.501 g, 0.00134 mol, 0.005 equiv) and Walphos
8-1 (1.262 g, 0.00134 mol, 0.005 equiv) were placed in a 2.5-L
Parr bottle. MeOH (1 L; deoxygenated by purging with N2)
was added. The mixture was kept at room temperature for 30
min to allow solids to dissolve. Acid 9 (67.37 g, 0.267 mol)
was added. The resultant solution was hydrogenated in a Parr
shaker at 45 psig H2 at room temperature for 23 h. Solvent
was distilled off in vacuum to afford 69.17 g of the title product
as a gray solid (99.3% pure by HPLC). A single enantiomer
was observed by chiral HPLC. The product was used without
This method is complementary to the one relying on a
hydrogenation directed by a chiral auxiliary in the absence of
a Lewis acid, followed by enolate trapment with an electrophilic
nitrogen.16a The latter method would produce a different
diastereomer of the product when the same enantiomer of the
chiral auxiliary is used. The combination of both methods
potentially allows for selective, highly practical, and industrially
applicable routes to any isomer of 3,3-disubstituted 2-amino-
propanol or 3,3-disubstituted alanine derivative by starting from
a single isomer of a 3,3-disubstituted acrylic acid and choosing
an appropriate chiral auxiliary. This approach is an alternative
to the one relying on asymmetric conjugate addition of
organocuprates to acryloxazolidinone derivatives followed by
Evans azidation (Route II, Scheme 2). The described synthesis
also demonstrates a case where the developed methodology
offered an advantage over the conjugate addition approach.
Experimental Section
General. HPLC analysis of the intermediates and reaction
monitoring was carried out on an Agilent 1100 liquid chro-
matograph equipped with a Phenomenex Prodigy ODS3 4.6
mm × 50 mm column. LC/MS data were obtained on an
Agilent 1100 LC system with an Agilent 1100 LC/MS detector
equipped with a 4.6 mm × 50 mm Chromolith SpeedROD
column.
Chiral HPLC conditions for 16: column type: Chiralpak
AS-H 250 mm × 4.6 mm; mobile phase: 98% heptane/TFA/
2% isopropanol isocratic; flow rate: 1.0 mL/min; column
temperature: room temperature; injection solvent: methanol;
wavelength: 254 nm; retention times: enantiomer 1: 10.0 min;
enantiomer 2: 11.3 min. Chiral HPLC conditions for 1: column
type: Chiralcel AD 250 mm × 4.6 mm; mobile phase:15%
isopropanol in hexane isocratic; flow rate: 1.0 mL/min; column
temperature: room temperature; injection solvent: ethanol;
wavelength: 254 nm; Retention times: isomer 1: 4.66 min;
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1
further purification. Mp: 73-75 °C. H NMR (300 MHz,
MHz, CDCl3) δ 7.38-7.27 (m, 3 H), 7.21-7.14 (m, 2 H), 6.94
(app. d, J ) 6 Hz, 2 H), 6.85-6.75 (m, 1 H), 4.63-4.53 (m,
1 H), 4.18 (d, J ) 5 Hz, 2 H), 4.17-4.03 (m, 1 H), 3.67 (dd,
J ) 18.5, 9.5 Hz, 1 H), 3.56 (dd, J ) 18.5, 4.5 Hz, 1 H), 3.26
CDCl3) δ 6.92-6.76 (m, 3H), 3.94-3.78 (m, 1 H), 3.08 (dd,
J ) 17, 4.6 Hz, 1H), 2.89 (dd, J ) 17, 10 Hz, 1H). 19F NMR
(282 MHz, CDCl3) δ -70.72 (s, 3 F), -108.94 (s, 2 F). MS
(m/z, negative ESI, for M - H): 253. [R]25 +28 (c ) 1,
(dd, J ) 13, 3.5 Hz, 1 H), 2.74 (dd, J ) 13, 9.5 Hz, 1 H). 19
F
D
MeOH).
NMR (282 MHz, CDCl3) δ -70.17 (s, 3 F), -109.14 (s, 2 F).
MS (m/z, positive ESI, for M + H): 414. [R]25D +96.2 (c ) 1,
MeOH).
(S, E)-4-Benzyl-3-(3-(3,5-difluorophenyl)-4,4,4-trifluorobut-
2-enoyl)oxazolidin-2-one (17). Acid 9 (11 kg, 43.63 mol), (S)-
(-)-4-benzyl-2-oxazolidinone (8.5 kg, 47.97 mol, 1.1 equiv)
and LiCl (3.7 kg, 87.28 mol, 2 equiv) were added to THF (95.7
kg) cooled to -15 °C. The temperature was adjusted to 20 °C,
the mixture was stirred for 30 min and then cooled to -21 °C.
Trimethyl acetyl chloride (13.1 kg, 108.54 mol, 2.5 equiv) was
added over 30 min at -21 °C. Triethylamine (11.5 kg, 113.64
mol, 2.6 equiv) was added over 4.5 h at -22 to -20 °C. The
mixture was stirred at -23 °C for 30 min. The reaction
completion was confirmed by HPLC (no residual acid 9 was
detected). The mixture was warmed to 15 °C over 30 min. A
12.5% ammonium chloride solution (37.7 kg) was added over
10 min. Phases were separated. The aqueous phase was
extracted with THF (53.6 kg). The combined THF solutions
were distilled at atmospheric pressure to a final volume of 35
L. Isopropanol (80.1 kg) was added. The mixture was concen-
trated by atmospheric pressure distillation to a volume of 55 L.
An in-process GC showed the presence of 3.2% residual THF.
Water (55 kg) was added over ∼30 min at 60-70 °C. The
resulting slurry was cooled to 0 °C over 75 min and stirred for
30 min. The slurry was filtered and washed with water (2 ×
44 kg). The solid was dried on the filter for 19 h and then in a
vacuum oven at 43-48 °C to afford 16.68 kg of the title product
Method B. To a solution of acid 16 (1.06 g, 4.2 mmol) in
toluene (15 mL), oxalyl chloride (0.63 g, 0.445 mL, 5 mmol,
1.2 equiv; 98% pure) was added at room temperature, followed
by DMF (0.01 mL). The mixture was stirred at room temper-
ature for 1 h. NMR of an aliquot indicated consumption of the
acid and acid chloride formation. Solvent and excess oxalyl
chloride were distilled off in vacuum. The residue was dissolved
in THF (12 mL).
In a separate flask, i-PrMgCl (4 mmol, 2 mL of 2 M THF
solution) was added to a solution of (S)-(-)-4-benzyl-2-
oxazolidinone (0.675 g, 3.81 mmol) in THF (12 mL) at -30
°C. The mixture was stirred at -30 °C for 1.5 h, then a THF
solution of acid chloride prepared as described above was added
over 15 min. The reaction mixture was allowed to warm up to
room temperature and was stirred for 18 h. Water (10 mL) was
added. THF was distilled off in vacuum. MTBE and sodium
citrate solution were added. Phases were separated, and the
aqueous phase was extracted with MTBE. The combined
organic fractions were washed with NaHCO3 solution and then
brine, and were dried over MgSO4, filtered through a pad of
silica gel, and concentrated to afford 1.6 g of crude product.
Recrystallization from MTBE-heptane afforded 1.3 g of the
title product as a white solid (75% yield based on acid 16).
(S)-3-((2S,3R)-2-Amino-3-(3,5-difluorophenyl)-4,4,4-tri-
fluorobutanoyl)-4-benzyloxazolidin-2-one hydrochloride (21).
To a solution of 10a (5.18 kg, 12.53 mol) in THF (11.2 kg)
was added KHMDS (20% THF solution, 13.5 kg, 13.54 mol,
1.08 equiv) at -48 to -42 °C over 75 min. The solution was
stirred at -49 °C for 30 min. A solution of 2,4,6-triisopropy-
lbenzensulfonyl azide (3.77 kg, 12.18 mol, 0.97 equiv) in
toluene (8.8 kg) was added over 75 min at -49 to -40 °C.
The mixture was held at -46 °C for 30 min. A solution of
acetic acid (3.4 kg, 56.6 mol, 4.5 equiv) in water (3.4 kg) was
added over 5 min. The temperature was adjusted to 20 °C, and
the mixture was stirred for 20 min. Heptanes (8.65 kg) were
added. Phases were separated. The organic phase was heated
to 34 °C, washed at that temperature with 28 kg of 0.5 M K3PO4
solution, 2 × 28 kg of 0.25 M K3PO4 solution, 31.6 kg of 20%
NaCl solution, and concentrated in vacuum to a volume of ∼26
L. Solvent exchange to ethanol was performed by adding 41.1
kg of ethanol and concentrating in vacuum to a volume of 25
L. (Residual solvents: toluene, 2.7%; heptane, not detected.)
The concentrated solution was filtered and split into two equal
portions for hydrogenation.
1
(93% yield; 96.6% HPLC strength). H NMR (300 MHz,
CDCl3) δ 7.48 (q, J ) 1.5 Hz, 1 H), 7.36-7.23 (m, 3H),
7.15-7.1 (m, 2 H), 6.94-6.85 (m, 3 H), 4.64-4.54 (m, 1 H),
4.28-4.16 (m, 2 H), 3.18 (dd, J ) 13.5, 3 Hz, 1 H), 2.67 (dd,
J ) 13.5, 9.5 Hz, 1 H). 19F NMR (282 MHz, CDCl3) δ -67.68
(s, 3 F), -108.91 (s, 2 F). MS (m/z, positive ESI, for M + H):
412.
(S)-4-Benzyl-3-((S)-3-(3,5-difluorophenyl)-4,4,4-trifluo-
robutanoyl)oxazolidin-2-one (10a). Method A. MgBr2 (0.58
kg, 3.15 mol, 1.2 equiv), 10% Pd/C (0.109 kg, anhydrous) and
17 (1.08 kg, 2.63 mol) were charged to a pressure reactor. The
reactor was sealed, and THF (19.1 kg) was added. The reactor
contents were stirred, and hydrogen was introduced into the
reactor at a pressure of 60-65 psig. The reaction mixture was
stirred at 45-50 °C while maintaining hydrogen pressure at
50-65 psig for 4 h. The hydrogen was vented, and the reactor
was flushed with nitrogen. The reaction mixture was filtered
through a sparkler filter that was precoated with Celite (0.6 kg),
and the cake was rinsed with MTBE (9.7 kg). The combined
filtrate was washed three times with a brine solution (∼1 kg
NaCl + 5.5 kg water for each wash), and the organic layer
was concentrated to 8-10 L in vacuum (25-30 °C batch
temperature). Isopropyl alcohol (6 L) was added, and the
mixture was concentrated at 70 °C to a volume of about 4 L.
Water (4 L) was added, and the slurry was cooled to 25 °C.
The solid was filtered and dried in vacuum at 60 °C to afford
0.825 kg of the title product (76% yield; 94.2% pure by HPLC;
single largest impurity: 2.1%). Mp: 127-128 °C. 1H NMR (300
Half of the solution was acidified with 6 N hydrogen chloride
(2.2 kg). A hydrogenation reactor was charged with 10% Pd/C
(50% wet, 0.258 kg). The acidified solution described above
was added, chasing with 7.4 kg of ethanol. The mixture was
hydrogenated at 50 psig H2 at 24-28 °C for 5 h. Methanol
(4.97 kg) was added. The mixture was filtered through Celite
Vol. 13, No. 6, 2009 / Organic Process Research & Development
•
1167

(0.65 kg). The Celite pad was washed with methanol (3.0 kg),
and the wash was combined with the filtrate. The hydrogenation
was repeated with the second half of the solution of intermediate
20.
(0.116 kg, 0.95 mol, 0.05 equiv) and 22 (5.57 kg, 19.09 mol),
N-methylmorpholine (4.12 kg, 40.73 mol, 2.1 equiv) was added
over ∼15 min at 0-3 °C, chasing with dichloromethane (5.6
kg). A solution of 5-chlorothiophene-2-sulfonyl chloride (4.39
kg, 20.22 mol, 1.06 eqiuv) in dichloromethane (4.9 kg) was
added over 30 min at 1-4 °C. The mixture was stirred at 6 °C
for ∼21 h. The completion of conversion was monitored by
HPLC (<4% of 22 remaining). N-Methylpiperazine (0.172 kg,
1.48 mol) was added at 0-6 °C. A solution of concentrated
hydrochloric acid (1.9 kg) and water (28 kg) was added,
maintaining the temperature at 25-30 °C. Phases were sepa-
rated. The organic layer was washed at 25-30 °C with a
solution of concentrated hydrochloric acid (1.9 kg) and water
(28 kg), then water (28 kg), and was then concentrated at
atmospheric pressure to a volume of 38-40 L. Heptane (30.7
kg) was added over 55 min at 33-39 °C. The mixture was
cooled to 2 °C and stirred for 1 h. The solids were filtered,
washed with a heptane-dichloromethane mixture (15.3 kg/7.4
kg), and dried in vacuum.
The solutions containing hydrogenation products were
combined and distilled in vacuum to a volume of 25 L. Heptanes
(13.8 kg) were added over 30 min. The mixture was stirred at
22 °C for 30 min then at -9 °C for 15 min. The resulting slurry
was filtered, washed with a mixture of heptanes/ethanol (6.9
kg/2.02 kg) and dried on the filter under a stream of nitrogen
to afford 3.65 kg of the title product as a white solid (63%
yield; 99.5% HPLC strength). Mp: 151-153 °C. 1H NMR (300
MHz, CD3OD) δ 7.37-7.04 (m, 8 H), 5.9 (d, J ) 9 Hz, 1 H),
4.52 (p, J ) 9 Hz, 1 H), 4.4-4.3 (m, 1 H), 4.21 (dd, J ) 9, 2
Hz, 1 H), 3.9 (dd, J ) 9, 7.5 Hz, 1 H), 3.23 (dd, J ) 13.5, 3
Hz, 1 H), 2.85 (dd, J ) 13.5, 9 Hz, 1 H).19F NMR (282 MHz,
CD3OD) δ -65.79 (s, 3 F), -109.23 (s, 2 F). MS (m/z, positive
ESI, for M + H): 429.
(2S,3R)-2-Amino-3-(3,5-difluorophenyl)-4,4,4-trifluorobu-
tan-1-ol hydrochloride (22). To a solution of 21 (11 kg, 23.67
mol) in THF (59.6 kg), LiBH4 (5% solution in THF, 24.1 kg,
55.33 mol, 2.3 equiv) was added at -7 to -10 °C over 2 h.
The mixture was warmed up to 21 °C and stirred for 15 min.
HPLC analysis confirmed the completion of conversion (1%
of 21 remaining). The mixture was cooled to 9 °C. Methanol
(15.1 kg) was added over 30 min at <25 °C. 37% HCl solution
(22.9 kg) was added over 30 min at <25 °C. The mixture was
cooled to 10 °C, and water (56.1 kg) was added over 10 min.
The mixture was allowed to warm to 17 °C and stirred for 30
min. HPLC analysis confirmed decomposition of borane
complexes (<2.5% of borane complex remaining). The mixture
was concentrated in vacuum at 25-30 °C to a volume of 66
L, diluted with water (56.1 kg) and washed with dichlo-
romethane (2 × 74.4 kg). Toluene (68.1 kg) was added. A 50%
NaOH solution (26.7 kg) was added over 75 min at 7-18 °C.
Phases were separated. The aqueous phase was extracted with
toluene (68.1 kg). The combined toluene solution was washed
with water (2 × 45 kg).
The crude product was dissolved in isopropanol (24.7 kg)
at 21 °C. The solution was filtered and heated to 42 °C. Water
(23.7 kg) was added at 40-45 °C. The mixture was cooled to
∼21 °C over 30 min, then to 10 °C over 50 min. Water (55.2
kg) was added. The solids were filtered, washed with a cold
isopropanol - water mixture (3.1 kg/35.5 kg), dried in vacuum
at 50-55 °C and micronized (to 90% particle size <10 µm) to
afford 7.4 kg of the title product (94% yield). Mp 125-126
°C. HPLC purity: 99.98%. Chiral purity: >99.9% as detected
by chiral HPLC. 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J )
4 Hz, 1 H), 6.94 (d, J ) 4 Hz, 1 H), 6.88-6.78 (m, 3 H), 5.25
(d, J ) 8 Hz, 1 H), 3.96-3.64 (m, 3 H), 3.3 (ddd, J ) 11, 4.6,
3.8 Hz, 1 H), 1.74 (t, J ) 4.6 Hz, 1 H). 19F NMR (282 MHz,
CDCl3) δ -63.91 (s, 3 F), -108.07 (s, 2 F). Anal. Calc. for
C14H11ClF5NO3S2: C 38.58%, H 2.54%, N 3.21%; found: C
38.69%, H 2.7%, N 3.16%. HRMS (for M + H) calcd:
435.98618; found: 435.98728. [R]25 +33.6 (c ) 1, MeOH).
D
HCl (6 N solution in IPA, 8.5 kg) was added over 30 min.
The solution was concentrated in vacuum to a volume of 88 L.
The resultant suspension was heated to 70 °C, stirred for 1 h,
cooled to 35 °C over 2 h, and filtered. The filter cake was
washed with CH2Cl2 (20 kg) and toluene (19 kg), and dried in
vacuum at 50-55 °C to afford 5.59 kg of the title product as
a white solid (81% yield; 98.8% pure by HPLC). Mp: 231-233
Acknowledgment
We thank M. Young, E. Muszynska, Dr. M. Lin, Pearl River
Kilogram laboratory Team, the Process Safety Group, and
Analytical and Quality Science for their support on the program.
Supporting Information Available
1
Single crystal X-ray data and ORTEP diagram for compound
1; experimental and spectral data for compounds 3a, 3b, 11-14.
This material is available free of charge via the Internet at
http://pubs.acs.org.
°C. H NMR (300 MHz, CD3OD) δ 7.15-7.05 (m, 3 H),
4.14-3.96 (m, 2 H), 3.64 (dd, J ) 12, 2 Hz, 1 H), 3.25 (dd, J
) 12, 3.5 Hz, 1 H). 19F NMR (282 MHz, CD3OD) δ -67.62
(s, 3 F), -110.9 (s, 2 F). MS (m/z, positive ESI, for M + H):
256. [R]25 +40.4 (c ) 1, MeOH).
D
5-Chloro-N-((2S,3R)-3-(3,5-difluorophenyl)-4,4,4-trifluoro-
1-hydroxybutan-2-yl)thiophene-2-sulfonamide (1). To a mix-
ture of dichloromethane (59.4 kg), 4-dimethylaminopyridine
Received for review August 14, 2009.
OP900216V
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Vol. 13, No. 6, 2009 / Organic Process Research & Development