First scale-up synthesis of WAY-262398, a novel, dual-acting SSRI/5HT1a antagonist

Article abstract of DOI:10.1021/op8002085

An alternative synthesis of WAY-262398, 1, a novel, dual-acting SSRI/5-HT_1A antagonist, has been developed. The target compound was initially synthesized as a part of diastereomeric mixture which was separated by chiral preparative HPLC. The ne

Full text of DOI:10.1021/op8002085

Organic Process Research & Development 2009, 13, 91–97
First Scale-Up Synthesis of WAY-262398, a Novel, Dual-Acting SSRI/5HT1a
Antagonist
Antonia Nikitenko,*,† Asaf Alimardanov,† Jay Afragola,† Jean Schmid,† Livia Kristofova,‡ Deborah Evrard,§
Nicole T. Hatzenbuhler,§ Vasilios Marathias,§ Gary Stack,§ Steve Lenicek,§ and John Potoski†
Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl RiVer, New York 10965, U.S.A.,
Chemical DeVelopment, Wyeth Research, 1025 BouleVard Marcel-Laurin, Saint-Laurent, Quebec H4R 1J6, Canada,
and Chemical and Screening Sciences and DiscoVery Neuroscience, Wyeth Research,
CN 8000, Princeton, New Jersey 08543, U.S.A.
Abstract:
acting SSRI/5-HT1a antagonist. Herein is described the first
scale-up synthesis of 1 (WAY-262398).
An alternative synthesis of WAY-262398, 1, a novel, dual-acting
SSRI/5-HT1A antagonist, has been developed. The target
compound was initially synthesized as a part of diastereo-
meric mixture which was separated by chiral preparative
HPLC. The new route was designed around intermediates
suitable for chiral resolution and/or chiral reduction of a
suitable intermediate. Both processes had to be employed
to achieve the target optical purity.
Initial Synthesis of 1, WAY-262398
For the initial SAR studies, 1 was synthesized by the general
approach utilized for this class of molecules.2 Reductive
amination of aminomethylquinolinodioxane 9 with the racemic
aldehyde 8 produced the diastereomeric mixture 10, from which
1 was isolated using chiral preparative HPLC. The absolute
stereochemistry of 1 was assigned on the basis of chiral liquid
crystal NMR analysis of its diastereomer.7 The aldehyde 8 was
synthesized in six steps from commercially available 5-fluor-
oindole 2 (Scheme 1).1,8
Amine 9 was synthesized from chiral quinolinodioxane
derivative 11 (Scheme 2), which had been used as a common
intermediate for several earlier projects,9-13 by conversion into
the azido derivative 12 and subsequent reduction of the azido
group.
Introduction
SSRI/5-HT1A antagonists potentially provide a significant
improvement over SSRIs in the treatment of depression by
addressing a major unmet therapeutic need for a faster-acting
antidepressant agent. There has been a substantial amount of
work reported by our group,1,2 as well as by others,3-5 aimed
at creating a single molecular entity that possesses both 5-HT1A
antagonism and 5-HT reuptake inhibition. Our recent publication
presented the scale-up synthesis of WAY-253752, a potential
dual-acting SSRI/5-HT1A antagonist.6 In preclinical studies, a
related analogue 1, WAY-262398, showed potential as a dual-
* Author for correspondence. E-mail: nikitea@wyeth.com.
† Chemical and Screening Sciences.
An alternative route to the intermediate 6 (Scheme 1), from
fluoroindole aldehyde, 13, has been described up to the ester
15 14,15 and is shown in Scheme 3.
As more material was needed for further investigations, the
preparation of multigram quantities of 1 was addressed.
Although the SAR synthesis did provide access to milligram
quantities of 1, its large-scale synthesis using either racemic
approach to the intermediate 6 would present the major
challenge of separating the diastereomeric mixture 10. It was
highly desirable to develop a chiral approach to the “right-hand”,
‡ Chemical Development.
§ Chemical and Screening Sciences and Discovery Neuroscience.
(1) Hatzenbuhler, N. T.; Baudy, R.; Evrard, D. A.; Failli, A.; Harrison,
B. L.; Lenichek, S.; Mewshaw, R. E.; Sabb, A.; Shah, U.; Sze, J.;
Zhang, M.; Zhou, D.; Chlenov, M.; Kagan, M.; Golembieski, J.;
Hornby, G.; Lai, M.; Smith, D. L.; Sullivan, K. M.; Schechter, L. E.;
Andree, T. H. J. Med. Chem. 2008, 51, 6980–7004, and references
therein.
(2) Hatzenbuhler, N. T.; Evrard, D. A.; Harrison, B. L.; Huryn, D.;
Inghrim, J.; Kraml, C.; Mattes, J. F.; Mewshaw, R. E.; Zhou, D.;
Hornby, G.; Lin, Q.; Smith, D. L.; Sullivan, K. M.; Schechter, L. E.;
Beyer, C. E.; Andree, T. H. J. Med. Chem. 2006, 49, 4785–4789, and
references therein.
(3) Page, M. E.; Cryan, J. F.; Sullivan, A.; Dalvi, A.; Saucy, B.; Manning,
D. R.; Lucki, I. J. Pharmacol. Exp. Ther. 2002, 302, 1220–1228.
(4) Takeuchi, K.; Kohn, T. J.; Honigschmidt, N. A.; Rocco, V. P.;
Spinazze, P. G.; Koch, D. J.; Nelson, D. L.; Wainscott, D. B.; Ahmad,
L. J.; Shaw, J.; Threlkeld, P. G.; Wong, D. T. Bioorg. Med. Chem.
Lett. 2003, 13, 1903–1905.
(7) See Supporting Information for details.
(8) Hatzenbuhler, N. T.; Evrard, D. A.; Mewshaw, R. E.; Zhou, D.; Shah,
U. S.; Inghrim, J. A.; Lenicek, S. E.; Baudy, R. B.; Butera, J. A.;
Sabb, A. L.; Failli, A. A.; Ramamoorthy, P. S. PCT Int. Appl. WO
2005/012291, 2005; Chem. Abstr. 2005, 142, 219150.
(9) Chan, A. W.-Y.; Curran, T. T.; Iera, S.; Chew, W.; Sellstedt, J. H.;
Vid, G.; Feigelson, G.; Ding, Z. PCT Int. Appl. WO 2002/092602,
2002; Chem. Abstr. 2002, 137, 384846.
(10) Evrard, D. A.; Zhou, D.; Stack, G. P.; Venkatesan, A. M.; Failli, A. A.;
Croce, S. C. U.S. Pat. Appl. Publ. US 2004142926, 2004; Chem Abstr.
2004, 141, 123658.
(11) Stack, G. P.; Webb, M. B.; Evrard, D. A.; Zhou, D. U.S. Pat. Appl.
Publ. US2004138222, 2004; Chem Abstr. 2004, 141, 123637.
(12) Zhou, D.; Stack, G. P. U.S. Pat. Appl. Publ. US2004132714, 2004;
Chem. Abstr. 2004, 141, 89093.
(5) Atkinson, P. J.; Bromidge, S. M.; Duxon, M. S.; Gaster, L. M.; Hadley,
M. S.; Hammond, B.; Johnson, C. N.; Middlemiss, D. N.; North, S. E.;
Price, G. W.; Rami, H. K.; Riley, G. J.; Scott, C. M.; Shaw, T. E.;
Starr, K. R.; Stemp, G.; Thewlis, K. M.; Thomas, D. R.; Thompson,
M.; Vong, A. K. K.; Watson, J. M. Bioorg. Med. Chem. Lett. 2005,
15 (3), 737–741.
(6) Nikitenko, A.; Evrard, D. A.; Sabb, A. L.; Vogel, R. L.; Stack, G.;
Young, M.; Lin, M.; Harrison, B. L.; Potoski, J. R. Org. Process.
Res. DeV. 2008, 12 (1), 76–80.
10.1021/op8002085 CCC: $40.75
Published on Web 12/19/2008
2009 American Chemical Society
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Scheme 1. Initial synthesis of 1, WAY-262398
Scheme 2. Synthesis of compound 9
Scheme 3. Alternative synthesis of the key intermediate 6
fluoroindole, part of the molecule. From this point of view, this
alternate approach, shown in Scheme 3, seemed more suitable,
as it allowed a possibility for chiral hydrogenation of the double
bond in the ester 14, or resolution of the acid 6 in order to get
the key intermediate, chiral acid 16.
11. Thus, the chiral acid 16 could either be converted to the
amine 18 through the amide 17, followed by alkylation with
the brosylate 11 (Route A, Scheme 4), or to the penultimate
amide 19 Via an acid derivative and the amine 9, followed by
reduction as the last step (Route B, Scheme 4).
The acid 16 could be converted to the corresponding
aldehyde or used directly to provide a wider set of options for
making the final connection with quinaldine dioxane brosylate
(14) Feenstra, R. W.; Stoit, A.; Terpstra, J.; Pras-Ravers, M. L.; McCreary,
A. C.; Van Vliet, B. J.; Hesselink, M. B.; Kruse, C. G.; Van
Scharrenburg, G. J. M. PCT Int. Appl. WO 2006/061376, 2006; Chem.
Abstr. 2006, 145, 62874.
(15) Feenstra, R. W.; Stoit, A.; Terpstra, J.; Pras-Ravers, M. L.; McCreary,
A. C.; Van Vliet, B. J.; Hesselink, M. B.; Kruse, C. G.; Van
Scharrenburg, G. J. M. PCT Int. Appl. WO 2006/061377, 2006; Chem
Abstr. 2006, 145, 62923.
(13) Webb, M. B.; Stack, G. P.; Asselin, M.; Evrard, D. A. PCT Int. Appl.
WO 2004/024733, 2004; Chem. Abstr. 2004, 140, 287397.
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Scheme 4. Possible approaches to scale-up of 1, WAY-262398
Scheme 5. Chiral resolution of the racemic acid 6
Scheme 6. Chiral hydrogenation of acrylic ester 14 and acrylic acid 23
Approaching Optically Active 3-(5-Fluoro-1H-indol-3-yl)-
2-methylpropanoic Acid: Chiral Reduction or Chiral Re-
solution?
The chiral resolution of the racemic acid 6 by crystallization
with various chiral bases was evaluated (Scheme 5). The best
result was achieved using (-)-norephedrine,16 affording of 72:
28 S/R ratio of isomers. Further recrystallization of the salt did
not significantly improve chiral purity.
patent issues. The best catalytic system for the ester 14 was
Rh/R,S-Josiphos,18 and for the acid 23, Rh/R,S-Mandyphos.19
Other parameters, such as solvents, temperature, and pressure,
were screened as well. Early in the course of screening it was
observed that the preferred substrate for chiral reduction was
the acrylic acid 23 rather than the corresponding ester 14 (the
best ratio of 21:22 was 77:23, vs the 92:8 ratio of 16:2021).
In parallel, chiral hydrogenation was addressed by screening
a number of chiral catalysts in reduction of the ester 14, as well
as the acid 23 (Scheme 6). Several catalytic systems for the
asymmetric hydrogenation of R-methyl-ꢀ-aryl-acrylic acids,
with variable enantiomeric excess values (17-92%), have been
reported.17 Our choice of catalysts for screening was based on
two factors: commercial availability, and the lack of potential
(18) (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-bu-
tylphosphine, Solvias SL-J009.
(19) (RR,RR)-2,2′-Bis(R-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis-
[di(3,5-dimethyl-4-methoxyphenyl-phosphino]ferrocene (R)-(S)-NMe2-
P(3,5-Me-4-MeOPh)2-Mandyphos, Solvias SL-M004. The sense of
stereoinduction reported for a similar substrate using the same metal/
ligand combination20 provided further evidence in support of the
assigned absolute stereochemistry.
(20) Briner, P. H.; Fyfe, M. C. T.; Madeley, J. P.; Murray, P. J.; Procter,
M. J.; Spindler, F. PCT Int. Appl. WO 2006/016178, 2006; Chem
Abstr. 2006, 144, 232918.
(16) See Table 1, Salt Screening for the Chiral Resolution of Acid 6,
Supporting Information.
(17) Fox, M. E.; Jackson, M.; Lennon, I. C.; Klosin, J.; Abboud, Kh. A. J.
Org. Chem. 2008, 73, 775–784, and references 21-23 therein.
(21) See Table 2, Conditions for the Chiral Reduction of Ester 14, and
Table 3, Conditions for the Chiral Reduction of Acid 23, Supporting
Information.
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Scheme 7. Final synthesis of 1, WAY-262398
Disappointingly, no further improvement of the ee was attained
in the course of screening experiments.
with the acid 16 to afford the penultimate amide 19. Several
reducing agents were screened for the final reduction. Incom-
plete conversion was the major problem when LAH and DIBAL
were used. Multiple byproducts were also observed with Red-
Al, LAH-AlCl3, and borane-dimethylsulfide/boron trifluoride
etherate combination. The byproduct presumably formed due
to over-reduction, as judged by LC/MS analysis of the reaction
mixtures. Gratifyingly, it was found that use of excess
BH3-DMS minimized these problems. Reduction of the amide
with borane-dimethylsulfide complex afforded target com-
pound 1 in 62% isolated yield.
Comparing routes A and B in the present form, one
can easily see that route B has fewer problems. In
principle, it is possible to optimize the problematic last
step in the route A to improve the isolation procedure
and, consequently, the isolated yield. However, it still has
a drawback of using an excess of the optically active acid
16. Due to the pressing timelines, further optimization of
route A was not done. The bulk of the material was
processed through route B. Thus, compound 1, WAY-
262398, was synthesized from 5-fluoroindole-2-carbox-
aldehyde 13 in six steps (including enrichment via
crystallization with (-)-norephedrine) with a 41% overall
yield (Scheme 7).
Although neither chiral reduction nor chiral resolution
afforded acceptable optical purity, a combination of both
methods could be utilized in this case. Thus, chiral hydrogena-
tion followed by crystallization in the presence of (-)-
norephedrine afforded 16 in 95% ee.22 This optical purity was
deemed sufficient at this point, since crystallization at later stages
would further increase the ee to the desirable level (Vide infra).
Synthesis of WAY-262398: Final Choice of the Route
Two routes (A and B, Scheme 7) were utilized in parallel
for converting acid 16 to the target compound 1, WAY-262398.
Following Route A, acid 16 was converted to amine 18 through
amide 17. The subsequent alkylation with brosylate 11 required
the use of 1.17 equiv of the amine in order to avoid the
formation of dialkylation byproduct. Separation of the target
compound from the excess of the amine presented a serious
problem, required multiple crystallizations, and resulted in only
28% unoptimized isolated yield of 1.
Route B required conversion of the brosylate 11 in two steps
to the amine 9 (Scheme 2), which was subsequently condensed
(22) For an example of double resolution in a similar class of compounds,
see ref 6.
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Conclusion
In the initial rapid scale-up, chirality often becomes a major
for 30 min. The acrylic acid, 23 (41.5 g, 189 mmol), was
added, and the solution was hydrogenated at 35-50 psi
H2 for 15 h. The resulting solution of the title compound
(84% ee) was concentrated and then dissolved in 350 mL
of hot acetonitrile. A solution of (1R,2S)-(-)-norephedrine
(26.5 g, 175 mmol) in 100 mL of acetonitrile was added.
The mixture was cooled to 0 °C in an ice bath. The
precipitated crystals were filtered, washed with cold
acetonitrile, and air-dried to afford 63 g of the title product
as norephedrine salt (90% ee). The salt was dissolved in
1.2 L of acetonitrile at reflux and allowed to crystallize
overnight at room temperature. The resulting suspension
was cooled to 0 °C, filtered, washed with cold acetonitrile,
and air dried to give 57.4 g of the norephedrine salt of
the target compound, which was taken into a mixture of
ethyl acetate (750 mL) and 2 N HCl (250 mL). The layers
were separated. The aqueous layer was extracted with
ethyl acetate (2 × 100 mL). Combined organic extracts
were washed with brine, dried over MgSO4, and concen-
trated to afford 33.8 g of the title compound 16 (80% yield,
issue and a main factor in choosing the synthetic route. In the
Discovery phase of the presented project, chiral preparative
HPLC purification of the penultimate diastereomers allowed
for the separation, identification, and comparison of the biologi-
cal activity of two close analogues. However, this method was
not feasible for bulk preparation of the target compound. When
developing a scalable approach to the selected compound, both
chiral reduction and resolution were evaluated. Neither method
alone was adequate to achieve the desired outcome. An
approach was developed that combined chiral reduction of the
acrylic acid 23 with the subsequent chiral enrichment of the
resulting chiral acid 16 by its crystallization with an optically
active base, (-)-norephedrine, affording the target compound
in high optical purity.
Experimental Section
General Methods. NMR spectra of the intermediates
were recorded on a Bruker 300 NMR spectrometer. HPLC
analysis of the intermediates and reaction monitoring was
performed on an Agilent 1100 liquid chromatograph
equipped with a Phenomenex Prodigy ODS3 4.6 mm ×
50 mm column. Standard method: 90:10 to 10:90 gradient
of water/acetonitrile containing 0.02% TFA over 8 min,
flow rate 1 mL/min. Chiral HPLC analysis was performed
on Agilent 1100 liquid chromatograph equipped with a
Whelk O1 RR 4.6 mm × 250 mm column. Mobile phase
composition: 60% heptane containing 0.02% TFA, 40%
isopropyl alcohol, flow rate 1 mL/min.
1
95% ee). Mp 81-83 °C. MS 220.1 (M - H). H NMR
(300 MHz, DMSO-d6, δ): 12.03 (s, 1H), 10.92 (s, 1H),
7.32 (dd, 1H, J1 ) 8.9 Hz, J2 ) 4.7 Hz), 7.26 (dd, 1H, J1
) 10.1 Hz, J2 ) 2.6 Hz), 7.19 (d, 1H, J ) 2.4 Hz), 6.90
(dt, 1H, J1 ) 9.5 Hz, J2 ) 2.6 Hz), 2.97 (dd, 1H, J1 )
13.7 Hz, J2 ) 6.7 Hz), 2.76-2.64 (m, 2H), 1.085 (d, 3H,
J ) 6.7 Hz).
(S)-3-(5-Fluoro-1H-indol-3-yl)-2-methylpropanamide (17).
To a solution of (S)-3-(5-fluoro-1H-indol-3-yl)-2-methylpro-
panoic acid, 16 (30 g, 135.6 mmol) and HOBt (22.67 g,
containing 11.12 wt % water, 149.17 mmol, 1.1 equiv) in THF
(350 mL) was added a suspension of N-(3-dimethylaminopro-
pyl)-N′-ethylcarbodiimide hydrochloride (31.2 g, 172.7 mmol,
1.2 equiv) in THF (200 mL). The mixture was stirred at room
temperature for 18 h (HPLC monitored) and then added to conc.
ammonia solution (800 mL) at 7-8 °C. Residual heavy oil was
dissolved in 100 mL of conc. ammonia and added to the
mixture. The resultant mixture was stirred for 1 h and allowed
to warm up to 12 °C. THF was distilled off in Vacuo. The
residual aqueous phase was extracted with MTBE (250 + 100
mL). The combined MTBE solution was washed with 2 N HCl
(3 × 150 mL) and brine (150 mL), dried over MgSO4, and
concentrated to afford 25.83 g of the title product, 17, as a white
solid (87% yield). 1H NMR (300 MHz, CDCl3, δ): 8.06 (s, 1
H), 7.30-7.19 (m, 2 H), 7.08 (s, 1 H), 6.94 (dt, 1 H, J ) 9, 2.5
Hz), 5.25 (br s, 2 H), 3.07 (dd, 1 H, J ) 14.5, 8 Hz), 2.82 (dd,
1 H, J ) 14.5, 6 Hz), 2.72-2.59 (m, 1 H), 1.26 (d, 3 H, J )
7 Hz).
(S)-3-(5-Fluoro-1H-indol-3-yl)-2-methylpropan-1-
amine (18). To a solution of (S)-3-(5-fluoro-1H-indol-3-yl)-2-
methylpropanamide 17 (25.83 g, 117.4 mmol) in THF (130
mL), LiAlH4 (235 mL of 1 M THF solution, 235 mmol, 2
equiv) was added at 10-20 °C. The mixture was heated to 65
°C, stirred for 1 h, and cooled to 5 °C. Saturated Rochelle salt
solution (73 mL) was added. The precipitated solids were
filtered off and washed with 2 × 100 mL of MTBE. The
combined organic fraction was concentrated and chased with
THF (100 mL; to remove residual moisture) to afford 23.2 g
(2E)-3-(5-Fluoro-1H-indol-3-yl)-2-methylacrylic Acid (23).
A suspension of 5-fluoroindole-3-carbaldehyde (13, 135.5
g, 0.83 mol) and (carbethoxyethylidene)triphenyl-
phosphorane (Wittig reagent, 465 g of 97% purity, 1.28
mol, 1.5 equiv) in absolute ethanol was stirred at ambient
temperature for 3 days. To the reaction were added 5 N
NaOH (465 mL) and water (310 mL), and the mixture
was heated to reflux for 1.5 h. The reaction mixture was
poured onto water (2.9 L), and the triphenylphosphine
oxide byproduct was extracted with diethyl ether (2 ×
1.25 L). The ethereal layers were back extracted with 1.0
N NaOH (2 × 500 mL), and the combined aqueous layers
were extracted with methylene chloride (1 L). The aqueous
layer was then treated with 6 N HCl (500 mL). A solid
precipitate was formed and isolated by filtration. The solid
was washed with water (1 L) and dissolved in ethyl acetate
(1.5 L). The organic solution was washed with brine and
dried over MgSO4. The solvent was removed, and the solid
was dried in Vacuo to give 23, 162.0 g (89%). Mp
1
207-210 °C. MS 218.1 (M - H). H NMR (300 MHz,
DMSO-d6, δ): 12.10 (s, 1H), 11.84 (s, 1H), 7.85-7.81
(m, 2H), 7.49-7.42 (m, 2H), 7.03 (dt, 1H J1 ) 9.3 Hz, J2
) 2.5 Hz), 2.06 (d, 3H, J ) 1.0 Hz).
(2S)-3-(5-Fluoro-1H-indol-3-yl)-2-methylpropanoic Acid
(16). The ligand (Mandyphos SL-M004-1 by Solvias,
1.99 g) and bis(norbornadiene)Rh(I)BF4 (788 mg) were
dissolved in nonaqueous methanol under N2, and the
resulting orange solution was stirred at room temperature
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of the title product as an off-white solid (96% yield). 1H NMR
(300 MHz, CDCl3, δ): 8.37 (s, 1H), 7.29-7.18 (m, 2H), 7.01
(s, 1H), 6.91 (dt, 1H, J ) 9, 2.5 Hz), 2.81-2.68 (m, 2H),
2.61-2.47 (m, 2H), 2.01 (br s, 2H), 1.96-1.80 (m, 1H), 0.95
(d, 3H, J ) 7 Hz).
organic layer was dried over MgSO4 and concentrated to afford
32.0 g of the title compound as oil (72% yield). MS 231.1 (M
+ H). H NMR (300 MHz, CDCl3, δ): 8.31 (d, 1H, J ) 8.7
Hz), 7.55 (d, 1H, J ) 8.7 Hz), 7.28 (d, 1H, J ) 8.7 Hz), 7.24
(d, 1H, J ) 8.7 Hz), 4.39 (dd, 1H, J1 ) 11.4 Hz, J2 ) 2.4 Hz),
4.34-4.25 (m, 1H), 4.12 (dd, 1H, J1 ) 11.4 Hz, J2 ) 7.2 Hz),
3.18-3.03 (m, 2H), 2.71 (s, 3H).
1
(2S)-3-(5-Fluoro-1H-indol-3-yl)-2-methylpropyl]{[(2S)-8-
methyl-2,3-dihydro[1,4]dioxino- [2,3-f]quinolin-2-yl]methyl}-
amine (1) (Route A). A mixture of (2R)-quinaldine dioxane
brosylate 11 (43.14 g, 95.87 mmol), (S)-3-(5-fluoro-1H-indol-
3-yl)-2-methylpropan-1-amine, 18 (23.2 g, 112.62 mmol, 1.17
equiv), 4-dimethylaminopyridine (11.7 g, 95.87 mmol, 1 equiv),
and DMSO (300 mL) was stirred at 90 °C for 3 h (HPLC
monitored), then cooled to room temperature, and poured into
600 mL of saturated NaHCO3 solution. The resultant mixture
was stirred at room temperature for 20 min. The precipitated
heavy oil was separated from aqueous suspension by decanta-
tion, washed with water (100 mL + 50 mL), and dissolved in
500 mL of EtOAc. The EtOAc solution was washed with
NaHCO3 solution (200 mL), dried over Na2SO4, and concen-
trated to afford 26.73 g of heavy oil.
The oil was dissolved in 280 mL of i-PrOH. HCl (70 mL
of 2 N solution in Et2O) was added dropwise (exothermic). The
resultant suspension was stirred at room temperature for 1 h.
The solids were filtered and washed with i-PrOH (40 mL). The
filtered salt was added to a stirred mixture of CH2Cl2 (300 mL)
and saturated NaHCO3 solution (300 mL). The mixture was
stirred at room temperature for 1 h. Phases were separated.
Aqueous phase was extracted with CH2Cl2 (100 mL). The
combined organic fractions were concentrated to afford 20.76
g of the crude title product as an oil (52% crude yield). The oil
was dissolved in acetonitrile (24 mL). The solution was stirred
at room temperature for 18 h. The precipitated solid was filtered,
washed with acetonitrile to afford 11.3 g of the title product, 1,
as an off-white solid (28% yield).
(2S)-2-(Azidomethyl)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-
f]quinoline (12). A solution of (2R)-quinaldine dioxane brosy-
late (11) (90.06 g, 0.2 mol) and sodium azide (52.66 g, 4.0
equiv, 0.81 mol) in DMF (700 mL) was stirred at 60 °C for
2.5 h. The reaction was poured onto ice water (2 L) and allowed
to precipitate. The solid was isolated by filtration and dried in
Vacuo overnight at ambient temperature to give the target
compound 12, 49.3 g (96%). Mp 98-100 °C. MS 257.1 (M +
H). 1H NMR (300 MHz, DMSO-d6, δ): 8.23 (d, 1H, J ) 8.8
Hz), 7.49-7.32 (m, 3H), 4.67-4.59 (m, 1H), 4.44 (dd, 1H, J1
) 11.5 Hz, J2 ) 2.4 Hz), 4.14 (dd, 1H, J1 ) 11.5 Hz, J2 ) 6.9
Hz), 3.78-3.63 (m, 2H), 2.61 (s, 3H).
[(2S)- 8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methylamine (9). A solution of azide 12 (49.3 g, 0.19 mol)
and triphenylphosphine (63.08 g, 1.25 equiv, 0.24 mol) in THF
(1 L) and water (10 mL) was stirred at room temperature for 2
days. The reaction was concentrated, acidified, and extracted
with diethyl ether (2 × 1 L). The ethereal layer was concentrated
and treated with 1 N NaOH (250 mL) for 6 h. This basic
solution was acidified with 6 N HCl (50 mL) and extracted
with diethyl ether (2 × 1 L) and methylene chloride (1 × 1 L).
The organic layers were back extracted with water (250 mL).
The combined aqueous layers were basified with 5 N NaOH
(75 mL) and extracted with methylene chloride (2 × 1 L). The
(2S)-3-(5-Fluoro-1H-indol-3-yl)-2-methyl-N-{[(2S)-8-methyl-
2,3-dihydro[1,4]dioxino- [2,3-f]quinolin-2-yl]methyl}propa-
namide (19). To a solution of the acid, 16 (28 g, 126.6 mmol),
and hydroxybenzotriazole (23.8 g, 176 mmol) in 380 mL of
THF cooled to 10-12 °C was added diisopropylcarbodiimide,
and the resulting mixture was stirred at room temperature for
15 h. Amine 9 (35 g, 152 mmol) was dissolved in 150 mL of
THF and added to the reaction mixture (the temperature
increased to 30 °C). The resulting solution was stirred at room
temperature and monitored by HPLC, which indicated complete
conversion to the target compound in 1 h. The reaction mixture
was poured into 1.5 L of water with vigorous stirring. The
mixture was stirred for 1 h. The formed precipitate was filtered
and washed with water. The wet filtercake was suspended in
400 mL of methanol, stirred for 10 min, filtered, washed with
methanol, and dried in Vacuo at 50 °C to give 51 g of the target
compound, 19 (93% yield). MS 434.3 (M + H). 1H NMR (300
MHz, DMSO-d6, δ): 10.86 (s, 1H), 8.21 (d, 1H, J ) 8.8 Hz),
8.17 (t, 1H, J ) 5.8 Hz), 7.42 (d, 1H, J ) 9.1 Hz), 7.35-7.28
(m, 3H), 7.25 (dd, 1H, J1 ) 8.9 Hz, J2 ) 4.7 Hz), 7.16 (d, 1H,
J ) 2.4 Hz), 6.85 (dt, 1H, J1 ) 9.2 Hz, J2 ) 2.4 Hz), 4.32-4.23
(m, 2H), 3.97 (dd, 1H, J1 ) 11.5 Hz, J2 ) 6.8 Hz), 3.49-3.37
(m, 2H), 2.93 (dd, 1H, J1 ) 13.0 Hz, J2 ) 6.2 Hz), 2.71-2.61
(m, 2H), 2.60 (s, 3H), 1.04 (d, 3H, J ) 6.5 Hz).
(2S)-3-(5-Fluoro-1H-indol-3-yl)-2-methylpropyl]{[(2S)-8-
methyl-2,3-dihydro[1,4]dioxino- [2,3-f]quinolin-2-yl]methyl}-
amine (1) (Route B). A 2 M solution of borane/dimethyl-
sulfide complex in THF (1180 mL, 2360 mmol) was
cooled to 10-15 °C, and the amide 19 (34 g, 78.5 mmol)
was added in one portion. The resulting suspension was
allowed to warm up to room temperature, at which point
the solids dissolved (orange solution). After stirring the
reaction mixture at room temperature for 18 h, HPLC
analysis indicated 98.4% conversion to the target com-
pound. The reaction was poured into a vigorously stirred
mixture of ice, 200 mL of conc. HCl, and 1 L of methanol.
The resulting solution was concentrated on a rotovap (bath
temperature kept below 45 °C). The residue was parti-
tioned between methylene chloride (1.5 L) and aqueous
sodium bicarbonate (1 L). The organic layer was separated,
washed with brine, dried over Na2SO4, and concentrated
to afford 38.7 g of crude product. The crude product was
crystallized from acetonitrile (50 mL) to afford 20.5 g of
the title compound as off-white crystals (62% yield, 99%
ee). Mp 120-122 °C. [R]D -30.9 (1% solution in
1
methanol, 25 °C). MS 420.2 (M + H). H NMR (300
MHz, DMSO-d6, δ): 10.87 (s, 1H), 8.27 (d, 1H, J ) 8.7
Hz), 7.42 (d, 1H, J ) 9.1 Hz), 7.35-7.29 (m, 3H), 7.25
(dd, 1H, J1 ) 10.1 Hz, J2 ) 2.6 Hz), 7.17 (d, 1H, J ) 2.2
Hz), 6.88 (dt, 1H, J1 ) 9.3 Hz, J2 ) 2.5 Hz), 4.46 (dd,
1H, J1 ) 11.4 Hz, J2 ) 2.2 Hz), 4.42-4.35 (m, 1H), 4.10
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(dd, 1H, J1 ) 11.4 Hz, J2 ) 7.3 Hz), 2.96-2.75 (m, 3H),
2.60 (s, 3H), 2.60-2.40 (m, 3H), 2.01 (s, 1H), 1.97-1.85
(m, 1H), 0.88 (d, 3H, J ) 6.8 Hz). 13C NMR (300 MHz,
DMSO-d6, δ): 156.50 (d, J ) 231.3 Hz), 156.25, 143.16,
137.99, 135.34, 132.76, 128.50, 127.81 (d, J ) 10.2 Hz),
125.05, 121.21, 120.98, 120.71, 118.08, 113.26 (d, J )
5.1 Hz), 112.04 (d, J ) 9.5 Hz), 108.65 (d, J ) 26.1 Hz),
102.99 (d, J ) 23.2 Hz), 73.04, 66.21, 55.68, 49.39, 34.04,
29.71, 24.48, 18.23.
from Drs. Jerauld Skotnicki and Boyd Harrison in preparing
this manuscript.
Supporting Information Available
Conditions screening tables for the chiral reduction of acid
23 and ester 14, and salt screening tables for the resolution of
acid 6; details for determination of the absolute stereochemistry
of the acid 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment
We greatly appreciate analytical support provided by Joseph
Ashcroft, Mairead Young, and Elwira Muszynska, and help
Received for review August 26, 2008.
OP8002085
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