Regio- and diastereoselective ring-opening of (S)-(-)-2-(trifluoromethyl) oxirane with chiral 2,5-disubstituted tetrahydroquinolines in hexafluoro-2-propanol

Article abstract of DOI:10.1039/c004726k

Multi-hundred grams of (S)-1,1,1-trifluoro-3-{(R)-2-[3-(1,1,2,2- tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin- 1(2H)-yl}propan-2-ol, a potent cholesteryl ester transfer protein (CETP) inhibitor, was prepared in quantitative isolated yield (>99%) with excellent chemical (>99% HPLC area%) and optical (>99% de) purities. The cornerstone to these results were achieved by regiospecific and diastereoselective ring-opening of optically pure (S)-(-)-2-(trifluoromethyl)oxirane (>99% ee) with (R)-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]- 1,2,3,4-tetrahydroquinoline (>99% ee) in hexafluoro-2-propanol at 22 °C for 24 h. This reaction did not require a rare earth metal salt (Yb(OTf) ₃) as the catalyst nor a column chromatography for the purification. The excess (S)-(-)-2-(trifluoromethyl)oxirane and the solvent hexafluoro-2-propanol were recovered by distillation from the reaction and reused.

Full text of DOI:10.1039/c004726k

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/greenchem | Green Chemistry
Regio- and diastereoselective ring-opening of
(
S)-(-)-2-(trifluoromethyl)oxirane with chiral 2,5-disubstituted
tetrahydroquinolines in hexafluoro-2-propanol
a
a
a
a
a
a
Xun Li,* Ronald K. Russell, Hongfeng Chen, Yongzheng Zhang, Scott Ballentine, Jan Spink,
a
a
a
b
b
a
Shawn Branum, Fuqiang Liu, Yanping Chen, Thomas Rammeloo, Wim Aelterman, Kirk L. Sorgi and
William V. Murray
a
Received 29th March 2010, Accepted 1st July 2010
DOI: 10.1039/c004726k
Multi-hundred grams of (S)-1,1,1-trifluoro-3-{(R)-2-[3-
1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)-
pure product (R,S)-2 after purification by column chromatogra-
phy, there was a need to find an environmental benign and more
efficient method for scale up preparation of (R,S)-2. Herein, we
report a green chemical process that is suitable for large quantity
production of (R,S)-2.
(
phenyl]-3,4-dihydroquinolin-1(2H)-yl}propan-2-ol,
a
potent cholesteryl ester transfer protein (CETP) inhibitor,
was prepared in quantitative isolated yield (>99%) with
excellent chemical (>99% HPLC area%) and optical
(
>99% de) purities. The cornerstone to these results
Results and discussion
were achieved by regiospecific and diastereoselective
ring-opening of optically pure (S)-(-)-2-(trifluoromethyl)-
oxirane (>99% ee) with (R)-2-[3-(1,1,2,2-tetrafluoroethoxy)-
Among all physical and chemical parameters whose values
determine the quality and yield of the product (R,S)-2 from
the ring-opening of (S)-TFMO with (R)-1, the chemical and
optical purities of both starting (R)-1 and (S)-TFMO have the
phenyl]-5-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-
◦
quinoline (>99% ee) in hexafluoro-2-propanol at 22
C
◦
most impact. Yet, (S)-TFMO with 75% ee (bp 25–32 C) was
for 24 h. This reaction did not require a rare earth
metal salt (Yb(OTf) ) as the catalyst nor a column
chromatography for the purification. The excess (S)-(-)-
-(trifluoromethyl)oxirane and the solvent hexafluoro-2-
the only commercially obtainable source in the early stage of this
project in the beginning of 2006. Although a few stereoselective
3
3
3a
3b
synthetic methods for preparing 96% ee and ≥99% ee (S)-
TFMO were available before 2006, optically pure (S)-TFMO
2
4
propanol were recovered by distillation from the reaction
and reused.
was not commercially available until recently. For the purpose of
scale up, the reproducibility of Yb(OTf) -catalyzed ring-opening
3
1
reaction was examined under the reported conditions, where
(
S)-TFMO with 75% ee was treated with (R)-1 (97% ee) in
Introduction
◦
DCE at 50 C for 48 h, HPLC analysis showed an incomplete
reaction mixture that was composed of 61% of (R,S)-2 and 11%
of (R,R)-2 along with 25% of starting (R)-1 (entry 1 of Table 1).
Noticeably, the (R,S)-2 produced in this reaction mixture was
(
S)-1,1,1-Trifluoro-3-((R)-2-(3-(1,1,2,2-tetrafluoroethoxy)-
phenyl)-5-(3-(trifluoromethoxy)phenyl)-3,4-dihydroquinolin-
-(2H)-yl)propan-2-ol ((R,S)-2), a potent cholesteryl ester
1
transfer protein (CETP) inhibitor with IC50 = 39 nM
in a CETP SPA assay and IC50 = 0.2 mM in a hu-
6
9.4% de, which was lower than the optical purity of start-
ing (S)-TFMO (75% ee), indicating the epoxide ring-opening
of (S)-TFMO under this Yb(OTf) -catalyzed conditions was
1a,1b
man plasma 3H-CE HDL in vitro assay,
was origi-
3
nally prepared in 29–69% chromatographically isolated yield
not 100% stereoselective. These results contrasted with the
reported ring-opening of (S)-2-(chloromethyl)oxirane (3–5 eq.)
with 1,2,3,4-tetrahydro-1,5-naphthyridine or 2,3,4,5-tetrahydro-
2
via Lewis acid Yb(OTf) -catalyzed epoxide ring-opening
3
of (S)-(-)-2-(trifluoromethyl)oxirane ((S)-TFMO) with (R)-2-
(
3-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)-
1H-pyrido[3,2-b]azepine, where the reactions were carried out
1
◦
phenyl)-1,2,3,4-tetrahydroquinoline ((R)-1, ≥97% ee) in
dichloromethane (DCM) or 1,2-dichloroethane (DCE)
5
under similar conditions (Yb(OTf)
for 3–5 h) but in a pressure tube to afford 53–95% isolated
yields. Furthermore, the treatment of (S)-TFMO (96% ee)
with excess diethylamine (10 eq.) in a sealed tube at 55
afforded a 88% isolated yield of (S)-1-(diethylamino)-3,3,3-
trifluoro-2-propanol with retained optical purity (96% ee).
3
(0.2 eq.) in DCM at 60 C
1b
1a,1c
at
◦
0 C for 48 h. Because a rare earth metal salt (Yb(OTf)
3
) and a
2a
◦
carcinogenic solvent (DCM or DCE) were used in this last step
to afford a low-to-moderate yield of the desired diastereomeric
C
3a
This reaction demonstrated the first example for regiospecifically
a
ring-opening of (S)-TFMO with a secondary amine without
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.,
Welsh & McKean Roads, P. O. Box 776, Spring House, Pennsylvania,
the aid of a Lewis acid as the catalyst. However, sealed-
1
9477, USA. E-mail: xli6@its.jnj.com; Fax: +1 (215) 540-4611;
2a,3a
tube closed-system conditions
are not a first choice for
Tel: +1 (215) 628-7829
scale up production of (R,S)-2 in a regular chemistry lab. In
addition to Yb(OTf) -catalyzed ring-opening, simple epoxides
b
Johnson & Johnson Pharmaceutical Research and Development, a
Division of Janssen Pharmaceutical, API Development, Turnhoutseweg
3
3
0, B-2340, Beerse, Belgium
and 1-substituted-2-(trifluoromethyl)oxirane ethers were treated
1
548 | Green Chem., 2010, 12, 1548–1551
This journal is © The Royal Society of Chemistry 2010

View Online
Table 1 The results of selective ring-opening of (S)-TFMO with (R)-1 or (S)-1 in HFP
(
R)-1
(S)-TFMO
Solvent
(mL or eq.)
(R,S)-2/(R,R)-2/(R)-1
(R,S)-2
◦
Entry
1
(g/% ee)
(eq./% ee)
T/ C
Time/h
48
(HPLC, area%)
(g/%)
b
a
a
1.0/97.0
5.0/75.0
DCE (12 mL)
50
61%/11%/25%
0.62/46.0
Yb(OTf)
5.0/75.0
5.0/75.0
3
(0.25 eq.)
2
3
1.0/97.0
1.0/97.0
DCE (12 mL)
DCE/HFP
40
40
24
48
0%/0%/97%
50%/7%/40%
0/0
N/I
b
(
5 mL/5 eq.)
4
5
6
7
8
9
1
1
1
1.0/97.0
1.0/97.0
1.0/97.0
0.5/99.0
30/99.0
1.0/99.7
255.3/99.5
0.2/99.8
(S)-1 0.2/99.7
5.0/75.0
2.3/75.0
5.0/75.0
2.0/96.0
3.6/75.0
3.0/99.2
3.0/99.2
8.5/75.0
8.5/75.0
HFP (23 eq.)
HFP (23 eq.)
IPA (12 mL)
40
40
40
40
40
22
22
22
22
6
87.7%/11.6%/0.67%
77%/11%/9%
0%/0%/96%
0.96/78.0
N/I
N/I
N/I
b
24–48
24
48
19
24
24
48
48
b
b
H
2
O (0.2 mL)
0%/0%/99%
HFP (14 eq.)
HFP (9.3 eq.)
HFP (10 eq.)
HFP (11.5 eq.)
HFP (11.5 eq.)
83.6%/12.4%/4%
99.7%/0.0%/0.3%
99.2%/0.0%/0.2%
88.0%/12.0%/0.0%
(S,S)-2/(S,R)-2/(S)-1
29.5/80.0 (99.5% de)
1.27/103 (99.5% de)
294.5/99.3 (99.5% de)
c
d
0
1
2
b
N/I
N/I
b
8
8.0%/12.0%/0.0%
(S,S)-4/(S,R)-4/(S)-3
2.6%/7.4%/0.0%
e
1
3
(S)-3 223.5/85.0
2.5/99.2
HFP (9.0 eq.)
50
19
(S,S)-4 162.3/61.0
(>98% de)
9
a
b
c
d
Isolated yield after chromatography. The reaction mixture was not purified. The compound contained traces of solvent residue HFP. Isolated
e
without chromatographic purification. The isolated yield from crystallization.
with secondary aromatic amines in 1,1,1,3,3,3-hexafluoro-2-
propanol (HFP, bp 58.2 C) without the need for a Lewis
purity (75% de for (R,S)-2) the same as starting (S)-TFMO
(entry 4 of Table 1 and Scheme 1). When the amount of (S)-
TFMO was reduced to 2.3 eq., an incomplete reaction was
observed with 9% of unreacted (R)-1 (entry 5 of Table 1); the
diastereomeric excess of (R,S)-2 was still unchanged at 75%
de. Attempts for ring-opening in other solvents, such as IPA
or water, were studied and neither (R,S)-2 nor (R,R)-2 was
observed in either reaction by HPLC analyses after 24–48 h
◦
acid to afford moderate-to-high yields of the corresponding
5a,5b
cyclic amino alcohols (68–92%)
dole derivatives (65–98%), respectively.
reaction of 1-substituted 2-(trifluoromethyl)oxirane ethers with
and 3-trifluoromethyl in-
5c,5d
Interestingly, the
1
9
4
,2,3,4-tetrahydroquinoline in HFP resulted in high yields (90–
8%) of 2-substituted 3-(trifluoromethyl)-1,2,5,6-tetrahydro-
H-pyrrolo[3,2,1-ij]quinolin-1-ols. However, regiospecific and
5c
◦
at 40 C (entries 6 and 7 of Table 1). In contrast, a scale up
diastereoselective ring-opening of (S)-TFMO with (R)-1 in HFP
have not yet been communicated. In order to investigate the role
of HFP in this reaction, a control experiment was conducted
reaction using a 30 g input of (R)-1 with conditions (S)-TFMO
(75% ee; 3.6 eq.) and HFP (14 eq.) at 40 C for 19 h resulted in
◦
an 80% of (R,S)-2 after chromatography with excellent optical
purity, which demonstrated the scalable reproducibility of this
HFP-assisted ring-opening of (S)-TFMO (entry 8 of Table 1).
Furthermore, the treatment of a small (1 g) or a large (255 g)
amount of optically pure (R)-1 (>99.5% ee) with (S)-TFMO
(99.2% ee) in HFP at room temperature for 24 h afforded
quantitative isolated yields of the desired (R,S)-2 with retained
optical purity (99.5% de) without chromatographic purification
(entries 9 and 10 of Table 1).
in DCE by treating (S)-TFMO with (R)-1 without Yb(OTf)
3
at
◦
40 C for 24 h, which gave no reaction (entry 2 of Table 1). When
Yb(OTf) was replaced with five equivalents of HFP in DCE,
3
the formation of a diastereomeric mixture of (R,S)-2 and (R,R)-
2
was observed along with 40% of unreacted starting (R)-1 after
4
8 h (HPLC analysis). This result demonstrated the usefulness
of HFP to selectively open (S)-TFMO with (R)-1 (entry 3 of
Table 1 and Scheme 1).
The above incomplete reaction was advanced to near 100%
conversion when DCE was replaced by HFP (23 eq.) as the
solvent, which achieved a diastereomeric mixture of (R,S)-
The scope of this HFP-assisted selective opening of (S)-
TFMO was extended to prepare diastereomeric mixture pairs
of (R,S)-2/(R,R)-2 and (S,S)-2/(S,R)-2 for qualitative controls
on (R,S)-2 production. The resulting diastereomeric pairs,
2/(R,R)-2 (87.7%/11.6%; HPLC area%) that retained an optical
Scheme 1
This journal is © The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 1548–1551 | 1549

View Online
Scheme 2
Scheme 3
R,S)-2/(R,R)-2 or (S,S)-2/(S,R)-2, were prepared in quanti-
(
system at UVmax = 210, 240, and 280 nm, using a Agilent
Zorbax SB–C18 column (4.6 mm ID ¥ 250 mm, 3.5 micron)
tative yield using (S)-enriched TFMO (75% ee) with optically
pure (R)-1 (99.8% ee) or (S)-1 (99.7%% ee), respectively (entries
◦
-1
at 35 C with flow rate of 1.0 mL min and run time of
1
1 and 12 of Table 1 and Scheme 2). Moreover, this HFP-assisted
method was also successfully used in the scale up production of
S,S)-4 (Scheme 3), another known potent CETP compound, in
20 min. Solvents: A H O + 0.05% TFA, B CH CN; Gradient:
2
3
B 10%/0 min, B 50%/6 min, B 90%/12 min, B 50%/18 min, B
10%/20 min. The diastereomeric excess of (S,S)-4/(S,R)-4 were
determined with an Agilent Series 1100 system at UVmax = 210,
254, and 280 nm, using a Chiralcel OD column (4.6 mm ID ¥
(
6
1
1% isolated yield with high chemical and optical purities (entry
6
3 of Table 1).
◦
-1
In summary, an efficient synthetic method has been developed
150 mm, 10 micron) at 35 C with flow rate of 1.0 mL min
for the preparation of multi-hundred gram quantities of potent
CETP inhibitor (R,S)-2 in a quantitative isolated yield with
excellent chemical (>99% HPLC area%) and optical (>99%
de) purities, by regiospecific and diastereoselective ring-opening
of (S)-TFMO (99.2% ee) using optically pure R-1 (99.5% ee)
and run time of 30.0 min. Solvents: A hexane, B EtOH, and
C MeOH; Gradient: isocratic with 2% of EtOH and 2% of
MeOH. While The chemical purity of (S,S)-4 was determined
with an Agilent Series 1100 system at UVmax = 310 (220–
400 nm), using a Waters Sunfire C18 column (0.3 mm ID ¥
◦
◦
-1
in HFP at 22 C for 24 h. Excess reagent (S)-TFMO and the
150 mm, 3.5 micron) at 45 C with flow rate of 0.6 mL min and
run time of 40 min. Solvents: A H O + 0.1% formic acid + 0.01%
TFA, B CH CN + 0.1% formic acid + 0.01% TFA; Gradient:
solvent HFP were easily recycled after distillation. This process
does not require special equipment nor conditions and generates
a minimal amount of chemical waste, which provided a green
process for scale-up production of (R,S)-2 as well as (S,S)-4.
2
3
B 25%/0 min, B 25%/3 min, B 95%/30 min, B 95%/35 min,
B 25%/35.1 min, B 25%/40 min. All reactions were conducted
in a 4-neck round bottom flask equipped with a thermocouple
controller, a mechanical stirrer, a pressure-equalization dropping
funnel, a cooling condenser, and a nitrogen inlet/outlet adapter.
Experimental
Starting materials, reagents, and solvents were obtained from
commercial suppliers and were used without further purifi-
cation. H-NMR spectra were recorded at 300 MHz on a
Bruker Avance-300 instrument. Mass spectra were recorded on
an Agilent Series 180 LC/MS instrument (positive/negative
modes). The diastereomeric excess of (R,S)-2/(R,R)-2 and
A general procedure for the preparation of (S)-1,1,1-trifluoro-3-
1
{(R)-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoro-
methoxy)phenyl]-3,4-dihydroqui-nolin-1-(2H)-yl}propan-2-ol
(R,S)-2)
(
(
S,S)-2/(S,R)-2 were determined with an Agilent Series 1100
A 2 L 4-neck round bottom flask equipped with a thermocouple,
a mechanic stirrer, a dry ice-cooled condenser, and a nitrogen
inlet/outlet adapter was charged with (R)-1 (255.3 g, 0.487 mol),
1,1,1,3,3,3-hexafluoro-2-propanol (511 mL, 4.866 mol), and
cold 3,3,3-trifluoro-1,2-epoxypropane (165 g, 1.473 mol) from
system at UVmax = 210, 254, using a Chiralcel OJ column
(
of 0.5 mL min and run time of 50.0 min. Solvents: A heptane,
B IPA; Gradient: isocratic with 10% IPA. While the chemical
purity of (R,S)-2 was determined with an Agilent Series 1100
◦
4.6 mm ID ¥ 250 mm, 10 micron) at 20 C with a flow rate
-
1
◦
4 C freezer. The flask was wrapped with aluminium foil and
1
550 | Green Chem., 2010, 12, 1548–1551
This journal is © The Royal Society of Chemistry 2010

View Online
◦
the mixture was stirred at 20–30 C for 24 h. The progress of
W. V. Murray, B. P. Damiano and M. A. Connelly, J. Med. Chem.,
009, 52, 1768–1772; (c) T. Rano, G.-H. Kuo, E. Sieber-McMaster,
2
the reaction was monitored by HPLC and LC-MS. The solvent
◦
K. T. Demarest, P. Pelton and A. Wang, U.S. Patent, US 2007265304
HFP was recovered in vacuo at 40 C to afford an oil, which was
A1, 2007.
dissolved in EtOH (500 mL; 200 proof), polish filtered through
a M-sintered glass filtration funnel, and concentrated in vacuo at
0 C. The resulting material was dissolved in EtOH (500 mL;
00 proof) and concentrated again in vacuo at 50 C, dried at
0 C under high vacuum (<6 mmHg) for 24 h to afford the
desired (R,S)-2 (294.45 g, 99.3% yield; 99.4% HPLC area% with
9.5% de) as a very viscous golden oil. (Found: C, 54.4; H, 3.65;
requires C, 54.28; H, 3.55; N,
.34; F, 31.8.%; Ash < 0.1). [a]D -125.5 , (C 1.0 in CHCl
Si): 7.38 (d, J = 7.6 Hz, 1 H), 7.33 (d, J =
.5 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.20–7.10 (m, 5 H), 7.04
s, 1 H), 6.73 (d, J = 8.3 Hz, 1 H), 6.67 (d, J = 7.3 Hz, 1 H), 5.89
tt, J = 53.0, 2.8 Hz, 1 H), 4.90 (t, J = 4.5 Hz, 1 H), 4.45–4.36
m, 1 H), 3.91 (d, J = 15.6 Hz, 1 H), 3.30 (dd, J = 15.6, 9.7 Hz, 1
2 (a) G. H. C. Woo, A. B. Beeler and J. K. Snyder, Tetrahedron, 2007,
63, 5649–5665; (b) M. Beaton and D. Gani, Tetrahedron Lett., 1998,
39, 8549–8552; (c) C. Fu, A. Linden and H. Heimgartner, Helv. Chim.
Acta, 2001, 84, 3319–3334; (d) J. Picione, S. J. Mahmood, A. Gill,
M. Hilliard and M. M. Hossain, Tetrahedron Lett., 1998, 39, 2681–
2684; (e) A. E. Vougioukas and H. B. Kagan, Tetrahedron Lett., 1987,
◦
5
2
5
◦
◦
2
8, 6065–6068; (f) S. Ishida, S. Suzuki, T. Hayano, H. Furuno and J.
Inanaga, J. Alloys Compd., 2006, 408–412, 441–443.
9
3
(a) P. V. Ramachandran, B. Gong and H. C. Brown, J. Org. Chem.,
1
N, 2.33; F, 31.4%. C27
2
H
21
F
10NO
3
2
995, 60, 41–46; (b) C. Von dem Bussche-Huennefeld, C. Cescato and
2
◦
). d
H
D. Seebach, Chem. Ber., 1992, 125, 2795–2802; (c) P. V. Ramachandran
and K. J. Padiya, J. Fluorine Chem., 2007, 128, 1255–1259; (d) E. T.
McBee and T. M. Burton, J. Am. Chem. Soc., 1952, 74, 3022–3023.
(S)-TFMO with 75% ee was purchased from TCI America, Inc before
2006. Sigma-Aldrich added (S)-TFMO with 96% ee to the market in
2006 while Tyger Scientific, Inc. supplied (S)-TFMO with >99% ee in
3
(300 MHz; CDCl
3
; Me
4
7
4
5
(
(
(
2
007.
(a) U. Das, B. Crousse, V. Kesavan, D. Bonnet-Delpon and J.-P. B e´ gu e´ ,
J. Org. Chem., 2000, 65, 6749–67518; (b) V. Kesavan, D. Bonnet-
Delpon and J.-P. B e´ gu e´ , Tetrahedron Lett., 2000, 41, 2895–2898; (c) I.
Rodrigues, D. Bonnet-Delpon and J.-P. B e´ gu e´ , J. Org. Chem., 2001, 66,
H), 2.51 (d, J = 4.5 Hz, 1 H), 2.47–2.31 (m, 2 H), 2.18–2.09 (m,
H), 2.00–1.91 (m, 1 H).). LC-MS m/z 598 [MH ] (100), 1216
+
1
+
[2M + Na] (36).
2
098–2103; (d) J. Iskra, D. Bonnet-Delpon and J.-P. B e´ gu e´ , Eur. J. Org.
Chem., 2002, 3402–3410.
6
(a) K. L. Sorgi, F. Liu, Y. Chen, H. Chen, M. N. Patel, X. Li, A. Wang,
S. A. Ballentine, D. A. Beauchamp, J.-M. T. J. L. Rammeloo and
T. J. Vanhoegaerden, International Patent, WO 2008141077 A1, 2008;
(b) A. Wang, C. P. Prouty, P. D. Pelton, M. Yang, K. T. Demarest,
W. V. Murray and G.-H. Kuo, Bioorg. Med. Chem. Lett., 2010, 20,
1432–1435.
References
1
(a) T. A. Rano, E. Sieber-McMaster, P. D. Pelton, M. Yang, K. T.
Demarest and G.-H. Kuo, Bioorg. Med. Chem. Lett., 2009, 19, 2456–
460; (b) G.-H. Kuo, T. Rano, P. Pelton, K. T. Demarest, A. C. Gibbs,
2
This journal is © The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 1548–1551 | 1551