Synthetic approaches to site selective deuterium incorporation in a novel CRTh2 receptor antagonist clinical candidate

Article abstract of DOI:10.1002/jlcr.3174

Selection of acidic or basic reaction conditions, combined with appropriate temperatures, allowed for site selective direct incorporation of deuterium at multiple positions in the 7-azaindole-3-acetic acid CRTh2 receptor antagonist clinical candidate NVP-QAV680. Copyright

Full text of DOI:10.1002/jlcr.3174

Note
Received 1 November 2013,
Accepted 26 November 2013
Published online 23 January 2014 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3174
Synthetic approaches to site selective
deuterium incorporation in a novel CRTh2
receptor antagonist clinical candidate
*
David A. Sandham and Christopher J. Page
Selection of acidic or basic reaction conditions, combined with appropriate temperatures, allowed for site selective direct
incorporation of deuterium at multiple positions in the 7-azaindole-3-acetic acid CRTh2 receptor antagonist clinical
candidate NVP-QAV680.
Keywords: selective deuteration; clinical candidate; CRTh2 antagonist; D2O
Finally, we sought to exploit the reported method for catalytic
Introduction
deuteration of carboxylic esters α- to the carbonyl.5 In our hands,
NVP-QAV680 (Scheme 1, 1) has been recently disclosed as a
stoichiometric triazabicyclo[4.4.0]dec-5-ene was required to
drive complete exchange of 8 to give 9. Basic hydrolysis with
NaOH in THF/MeOH led to some protic exchange; however,
treatment with NaOD in MeOD gave clean conversion to 10, thus
providing a complementary product to those accessible through
direct acid or base promoted deuteration of 1 (Scheme 3).
novel clinical candidate CRTh2 receptor antagonist for the
treatment of allergic diseases.1 During the development of 1,
the requirement arose for preparation of site selectively
deuterated analogues. Deuteration of simple aryl acetic acids
has been reported under both basic and acidic conditions.2–4
Seeking a flexible approach and encouraged by these literature
reports, we elected to explore direct deuteration of the parent
compound. These efforts uncovered some interesting aspects
Conclusion
of selectivity, which are disclosed in the following note.
Choice of appropriate acidic or basic reaction conditions allowed
for site selective direct incorporation of deuterium into the
CRTh2 receptor antagonist NVP-QAV680. In addition, use of the
methyl ester as a deuteration precursor allowed access to an
additional deuterated analogue not directly accessible from the
Results and discussion
We adopted the reported basic thermal conditions2 and
employed K2CO3 as base under microwave irradiation
(Scheme 1). As expected, based on the acidity of the sulfone
moiety, treatment under these conditions gave good conversion
to the CD3SO2 analogue 2. Increasing temperature then led to
additional exchange at the N-1 CH2 group to give 3, although
small amounts of exchange α- to the carboxylic acid were
evident irrespective of whether three or four equivalents of base
were employed. Treatment of 3 under protic basic conditions at
lower temperature afforded 4, albeit with some loss of isotopic
purity at N-1 CD2. Further increase of temperature and base
equivalents then exchanged the C-3 CH2 moiety more efficiently
to provide 5. With prolonged reaction times, C-2 methyl
exchange also became evident, although when additional base
was added to drive this process further, concurrent partial
deuteration on the phenyl sulfone aromatic ring occurred,
providing 6. Application of more forcing conditions was limited
by the maximum working pressure of the microwave reactor.
Next, we explored exposure of 1 to acidic deuteration
conditions recently described for the arylacetic acid diclofenac4
(Scheme 2). As expected, C-3 CH2 exchange occurred, however,
deuteration of the C-2 methyl group was a concurrent process,
affording 7 in excellent isotopic purity.
acid itself. Taken together, these three methods provide
flexible methodology for aliphatic deuteration of this clinical
candidate molecule. The reaction conditions reported herein
are also applicable to analogous CRTh2 antagonists derived
from the 7-azaindole-3-acetic acid scaffold.6
Experimental section
General considerations
Compounds 1 and 8 were prepared as described previously.1 Microwave
reactions were conducted in a Biotage Initiator instrument. LCMS were
recorded using an Agilent 1100 LC system with Waters Xterra MS C18
4.6 × 100 5μM column, eluting for 10 min with gradient of 5–95% MeCN
in water (10 mM ammonium bicarbonate or 0.1% trifluoroacetic acid
Global Discovery Chemistry, Novartis Institutes of Biomedical Research, Horsham
Research Centre, Wimblehurst Road, Horsham RH12 5AB, UK
*Correspondence to: David A. Sandham, Global Discovery Chemistry, Novartis
Institutes of Biomedical Research, Horsham Research Centre, Wimblehurst Road,
Horsham RH12 5AB, UK.
E-mail: david.sandham@novartis.com
J. Label Compd. Radiopharm 2014, 57 175–177
Copyright © 2014 John Wiley & Sons, Ltd.

D. A. Sandham and C. J. Page
Scheme 1. Base promoted deuteration reactions of 1. Reagents and conditions: i) K2CO3, D2O, microwave [K2CO3 equivalents and temperature]; ii) K2CO3 (2 eq), H2O,
100°C microwave. Isotopic incorporation as determined by 1H NMR denoted in italics.
used as buffer). Preparative liquid chromatography was conducted on an and 220 nm, together with ELSD. All 1H NMR spectra were obtained on
ISCO CombiFlash Rf instrument. All final compounds were purified to a Bruker AV400 operating at 400 MHz respectively, at 298 K.
≥95% chemical purity as determined by HPLC with UV detection at 254
2-(2-Methyl-1-(4-((trideuteromethyl)sulfonyl)benzyl)-1H-pyrrolo[2,3-
b]pyridin-3-yl)acetic acid 2
2-(2-Methyl-1-(4-(methylsulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)
acetic acid (30 mg, 0.084 mmol) and K2CO3 (23 mg, 0.166 mmol) were
dissolved in D2O (2 mL) in a microwave vial and irradiated at 100°C for
1 h. The reaction mixture was acidified to pH 5 with AcOH, and the
resultant precipitate collected by filtration, washed with water and dried
in vacuo to afford 2-(2-methyl-1-(4-((trideuteromethyl)sulfonyl)benzyl)-
1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid 2 as a white solid (14 mg, 44%).
>99% CD3SO2- incorporation based on 1H NMR integration. 1H NMR
(DMSO-d6): 2.31 (3H, s), 3.68 (2H, s), 5.63 (2H, s), 7.10 (1H, dd, J = 7.7,4.6),
7.31 (2H, d, J = 8.4), 7.86 (2H, d, J = 8.4), 7.90 (1H, d, J = 7.7), 8.18 (1H, d,
Scheme 2. Acid promoted deuteration of 1. Reagents and conditions: i) DCl-D2O,
J = 4.5), 12.25 (1H, s(br)). [M+H]+ = 362.50.
160°C, microwave. Isotopic incorporation as determined by 1H NMR denoted in italics.
Scheme 3. Base promoted deuteration of 8. Reagents and conditions: i) Triazabicyclo[4.4.0]dec-5-ene, CDCl3, RT; ii) aq NaOD, THF-MeOD, RT. Isotopic incorporation as
determined by 1H NMR denoted in italics.
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D. A. Sandham and C. J. Page
mixture was dilued with water (5 mL) and carefully adjusted to pH 7 with
saturated NaHCO3. The resultant precipitate was washed with water and
dried in vacuo to afford 2,2-dideutero-2-(1-(4-(methylsulfonyl)benzyl)-2-
2-(1-(Dideutero(4-((trideuteromethyl)sulfonyl)phenyl)methyl)-2-methyl-
1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dideuteroacetic acid 3
2-(2-Methyl-1-(4-(methylsulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)
acetic acid (30 mg, 0.084 mmol) and K2CO3 (46.5 mg, 0.336 mmol) were
dissolved in D2O (2 mL) in a microwave vial and irradiated at 150°C for
1 h (four bar pressure). The reaction mixture was acidified to pH 5 with
AcOH, and the resultant precipitate collected by filtration, washed with
water and dried in vacuo to afford 2-(1-(dideutero(4-((trideuteromethyl)
sulfonyl)phenyl)methyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-
dideuteroacetic acid 3, as a white solid (23 mg, 72%). 98% CD3SO2-,
(trideuteromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid
7 (41 mg,
77%) as a white solid; 99% -CD2CO2H, 99% 2-CD3 incorporation based
on 1H NMR integration. 1H NMR 3.17 (3H, s), 5.63 (2H, s), 7.10 (1H, dd,
J = 7.7,4.6), 7.31 (2H, d, J = 8.4), 7.86 (2H, d, J = 8.4), 7.90 (1H, d, J = 7.7),
8.18 (1H, d, J = 4.5), 12.23 (1H, s(br)). [M+H]+ = 366.40.
2,2-Dideutero-2-(2-methyl-1-(4-((trideuteromethyl)sulfonyl)benzyl)-
98% -NCD2- and 10% -CD2CO2H incorporation based on 1H NMR 1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid 10
integration. 1H NMR (DMSO-d6): 2.31 (3H, s), 3.68 (1.8H, s), 7.10 (1H, dd,
Methyl 2-(2-methyl-1-(4-(methylsulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-
J = 7.7,4.6), 7.31 (2H, d, J = 8.4), 7.86 (2H, d, J = 8.4), 7.90 (1H, d, J = 7.7), 8.18
3-yl)acetate
8 (100mg, 0.269 mmol) was added to a solution of
(1H, d, J = 4.5), 12.27 (1H, s(br)). [M+H]+ = 364.50, 366.50.
triazabicyclo[4.4.0]dec-5-ene (75mg, 0.537 mmol) in CDCl3 (0.75mL). The
reaction was stirred at room temperature for 2days then loaded directly
on to a 4g isoluteTM silica column and eluted with 20%-100% EtOAc-
isohexanes gradient to afford 66 mg clear colourless glass. 1H NMR
analysis indicated 79% incorporation of -CD2CO2Me and 78%
incorporation of CD3SO2-. The product was taken into CDCl3 (0.75mL),
triazabicyclo[4.4.0]dec-5-ene (25mg, 0.179mmol) added and the reaction
stirred at room temperature for 3days. The reaction mixture was loaded
directly on to a 4g IsoluteTM silica column and eluted with 20%-100%
EtOAc-isohexanes gradient to afford methyl-2,2-dideutero-2-(2-methyl-1-
(4-((trideuteromethyl)sulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate
9 (47 mg, 46%) as pale yellow glass; 89% -CD2CO2Me and 95% CD3SO2-
incorporation based on 1H NMR integration.. 1H NMR (CD Cl3) 2.34 (3H,
s), 3.03 (0.15H, s), 3.71 (3H, s), 3.75 (0.22H, s), 5.62 (2H, s), 7.12 (1H, dd,
J = 7.7, 4.8), 7.25 (2H, d, J = 8.0), 7.86 (2H, d, J = 8.0), 7.91 (1H, d, J = 7.8),
8.27 (1H, d, J = 4.7).
2-(1-(Dideutero(4-(methylsulfonyl)phenyl)methyl)-2-methyl-1H-pyrrolo
[2,3-b]pyridin-3-yl)acetic acid 4
2-(2-Methyl-1-(4-(trideuteromethylsulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-
3-yl)acetic acid 3 (20 mg, 0.055 mmol) and K2CO3 (15mg, 0.109mmol) were
dissolved in water (1.5 mL) in a microwave vial and irradiated at 100°C for
1 h. The reaction mixture was acidified to pH 5 with AcOH, and the resultant
precipitate collected by filtration, washed with water and dried in vacuo
to afford 2-(1-(dideutero(4-(methylsulfonyl)phenyl)methyl)-2-methyl-
1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid 4 as a white solid (13 mg,
41%); 88% -NCD2- incorporation based on 1H NMR integration. 1H
NMR (DMSO-d6): 2.31 (3H, s), 3.17 (3H, s), 3.68 (2H, s), 5.63 (0.24H, s),
7.10 (1H, dd, J = 7.7,4.6), 7.31 (2H, d, J = 8.4), 7.86 (2H, d, J = 8.4), 7.90
(1H, d, J = 7.7), 8.18 (1H, d, J = 4.5). [M+H]+ = 361.30.
2-(1-(Dideutero(4-((trideuteromethyl)sulfonyl)phenyl)methyl)-2-methyl-
Methyl-2,2-dideutero-2-(2-methyl-1-(4-((trideuteromethyl)sulfonyl)benzyl)-
1H-pyrrolo[2,3-b]pyridin-3-yl)acetate 9 (29 mg, 0.077 mmol) was dissolved in
THF (0.4 mL) and MeOD (0.4 mL) at room temperature. 1M NaOD in D2O
(0.1 mL, 0.1 mmol) was added and the reaction stirred overnight. The solvent
was evaporated, the residue dissolved in water (2 mL) and acidified to pH5
with AcOD. The resultant white solid was collected by filtration, washed with
water and dried in vacuo to afford 2,2-dideutero-2-(2-methyl-1-(4-
((trideuteromethyl)sulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic
acid 10 (22 mg, 75%); 93% CD3SO2- and 96% CD2CO2H incorporation
based on 1H NMR integration. 2.31 (3H, s), 3.17 (0.21H, s), 3.68 (0.08H, s),
5.63 (2H, s), 7.10 (1H, dd, J = 7.7,4.6), 7.31 (2H, d, J = 8.4), 7.86 (2H, d,
J = 8.4), 7.90 (1H, d, J = 7.7), 8.18 (1H, d, J = 4.5), 12.30 (1H, s(br)). [M
+H]+ = 364.40.
1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dideuteroacetic acid 5
2-(2-Methyl-1-(4-(methylsulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)
acetic acid 3 (30 mg, 0.084 mmol) and K2CO3 (34 mg, 0.246 mmol)
were dissolved in D2O (2mL) in a microwave vial and irradiated at 150°C
for 1h (six bar pressure). NMR analysis of the reaction mixture indicated
the presence of 4. Further, K2CO3 (22mg, 0.168mmol) was added and the
solution irradiated at 200°C for 1 h (12 bar pressure). The cloudy solution
was filtered through a plug of glass wool and acidified to pH 4 with AcOD.
The precipitate was collected by filtration, washed with water and dried in
vacuo to afford 2-(1-(dideutero(4-((trideuteromethyl)sulfonyl)phenyl)
methyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dideuteroacetic acid 5
as a white solid (21 mg, 68%); 99% CD3SO2-, 99% -NCD2- and 86% -CD2CO2H
incorporation based on 1H NMR integration. 1H NMR 2.31 (3H, s), 3.68 (0.28H,
s), 7.10 (1H, dd, J =7.7,4.6), 7.31 (2H, d, J =8.4), 7.86 (2H, d, J =8.4), 7.90 (1H, d,
J =7.7), 8.18 (1H, d, J = 4.5), 12.28 (1H, s(br)). [M+H]+ = 366.40.
Conflict of Interest
2-(1-(Dideutero(3-deutero-4-((trideuteromethyl)sulfonyl)phenyl)methyl)-
2-(trideuteromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-
dideuteroacetic acid 6
The author did not report any conflict of interest.
References
2-(2-Methyl-1-(4-(methylsulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic
acid (29 mg, 0.081 mmol) and K2CO3 (68 mg, 0.492 mmol) were dissolved in
D2O (1 mL) in a microwave vial and irradiated at 200°C for 18 h. The dense
slurry was diluted with water (5 mL), filtered through a plug of glass wool
and acidified to pH 4 with AcOH. The precipitate was collected by filtration,
washed with water and dried in vacuo to afford 2-(1-(dideutero(3,5-
dideutero-4-((trideuteromethyl)sulfonyl)phenyl)methyl)-2-(trideuteromethyl)-
1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dideuteroacetic acid as a white solid (20 mg,
63%); 98% CD3SO2-, 98% -NCD2-, 98% -CD2CO2H, 80% 2-CD3, 99% Ar-3-D and
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d, J = 7.7), 8.18 (1H, d, J = 4.5), 12.28 (1H, s(br)). [M+H]+ = 371.40.
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2,2-Dideutero-2-(1-(4-(methylsulfonyl)benzyl)-2-(trideuteromethyl)-
1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid 7
2-(2-Methyl-1-(4-(methylsulfonyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)
acetic acid (50 mg, 0.140 mmol) in 35% DCl (0.8 mL) and D2O (0.1 mL) was
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J. Label Compd. Radiopharm 2014, 57 175–177
Copyright © 2014 John Wiley & Sons, Ltd.
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