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A General Strategy for Site-Selective Incorporation of Deuterium and Tritium into Pyridines, Diazines and Pharmaceuticals John Koniarczyk, David Hesk, Alix Overgard, Ian W Davies, and Andrew McNally J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Jan 2018 Downloaded from http://pubs.acs.org on January 29, 2018
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Journal of the American Chemical Society
A General Strategy for Site-Selective Incorporation of Deuterium and Tritium into Pyridines, Diazines and Pharmaceuticals J. Luke Koniarczyk,† David Hesk,§ Alix Overgard,† Ian W. Davies§ and Andrew McNally*† † §
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States. Merck Research Laboratories, Rahway, New Jersey 07065, United States.
Supporting Information Placeholder ABSTRACT: Methods to incorporate deuterium and trit-
ium atoms into organic molecules are valuable for medicinal chemistry. The prevalence of pyridines and diazines in pharmaceuticals means that new ways to label these heterocycles will present opportunities in drug design and facilitate absorption, distribution, metabolism and excretion (ADME) studies. A broadly applicable protocol is presented wherein pyridines, diazines and pharmaceuticals are converted into heterocyclic phosphonium salts and then isotopically labeled. The isotopes are incorporated in high yields and, in general, with exclusive regioselectivity.
Deuteration can Increase Drug Bioavailability and Reduce Toxicity (1)
H 3CO
N
Fe
N
N
H 3CO
SCys
CYP-450 metabolism
H 3CO
O
S
N
N Me
N
H N
Me
S
Mo
S
i-Bu
D 3CO N
H
O
HO
OH
N
HO N
aldehyde oxidase metabolism
N
D
N
D N
Me
N Me
NHMe
O VX-984 (Oncology) – Phase I Clinical Trials
Selective Tritiation of the 4-Position ( ) of Pyridines in Drugs is Unknown (2) Cl
Hydrogen isotopes play vital roles in medicinal chemistry and are used to study the pharmacokinetic and pharmacodynamic (PK/PD) properties of drug compounds.1 Deuterated compounds are used to elucidate metabolic pathways, study reaction mechanisms and as mass spectrometry and nuclear magnetic resonance standards.2,3 Tritium, on the other hand, is often employed as a radiotracer for ADME studies.1 We herein describe a broadly applicable, site-selective method to install hydrogen isotopes into pharmaceuticals with distinct regioselectivity compared to existing protocols. An emerging strategy to improve the PK/PD profile of a therapeutic is to install deuterium at sites subject to oxidative metabolism by cytochrome P450 enzymes (eq 1).4-6 Deutetrabenazine, a treatment for symptoms of Huntington’s disease and the first FDA approved deuterated drug, mitigates metabolism by inclusion of stronger C–D bonds, resulting in a higher dosing efficacy and fewer adverse effects.7 However, metabolism is increasingly found to occur on pyridines and diazines by molybdenum-containing enzymes such as aldehyde oxidases (AOs).8 Deuterated compound VX-948 was developed because of excessive AO metabolism and is currently in phase I clinical trials.4a While AO metabolism of C–H bonds adjacent to the heterocyclic nitrogen is most common, this process can be unpredictable and occur at other positions on the scaffold.
Deutetrabenazine (Huntington's Disease) – FDA Approved H D 3CO
O N
N T via Chirik's Fe-catalyzed HIE reaction
NMe 2
MeO 2S
T
Cl
N
T N
N CO2Et
Loratadine
Me
Etoricoxib
N
Chlorphenamine
Cl
Selective Hydrogen Isotope Installation via Heterocyclic Phosphonium Salts (3) O
H X
R N
Ph
+
1) C–PPh 3 Formation 2) M 2CO 3, R'OD or R'OT
O D/ T R'O
O
P
Ph Ph X
R
D/ T
Azaarene Anion-Equivalent
X
R N
N
For tritium labeling, a metabolically stable site is preferred to prevent the label degrading during ADME studies. For both deuteration and tritiation, it is therefore important to have methods that install hydrogen isotopes at various positions of pyridines and diazines. Methods to label azaarenes include transforming halogentated precursors, metalation-trapping processes and hydrogen isotope exchange (HIE) reactions.9-12 For example, Chirik’s recent Fe-catalyzed process performs multiple C–H to C–D/T exchanges and steric factors control regioselectivity (eq 2).12a Our laboratory described that a range of pyridines and diazines can be regioselectively transformed into phosphonium salts; we envisioned a labeling process using an isotopic form of water or methanol and a metal carbonate (eq 3). A phosphorane is a key postulated intermediate that functions as an azaarene anion equivalent, and a
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Table 1. Deuteration Scope: Azaarenes and Drug-Like Lead Compoundsa,b,c H
Tf 2O; PPh 3; NEt 3 or DBU
X
R
D
K 2CO 3 (1.5 equiv)
X
R
CH 2Cl 2 or EtOAc, –78 ºC to rt
N
N
Heterocyclic Phosphonium Salt
D
X
R
CD 3OD:D 2O 9:1 (0.3 M), rt
N
sequential addition
Azaarene Azaarene Scope
PPh 3
OTf
Deuterated Azaarene
D
D
D
Me
D
S
D
Ph
D
D F
Ph N N
N N
Ph
1a, (84%), 83%
N
1b, (87%), 89%
D
1c, (72%), 74%
D
Me
N
N
N
F
N
1e, (47%), 83%
Me
N
Me
1f, (59%), 84%
D
D
N
D
F 3C
D
Ph
CN
Me
N
N
F
Me
N
1l, (62%), 56%b
1k, (42%), 80%
n-Bu
1m, (83%), 62%
Cl
Cl
N
1o, (85%), 77%
N
MeO
1p, (76%), 92%
1q, (49%),
n-Bu
D
N
Me
1s, (45%), 72%
Small Molecule Fragments
N
N N
2a, (30%, >20:1 r.r.), 88%b
N
Me
N
D
N
D
Et
1t, (83%), 80%c
N
N
1u, (64%), 65%
D
N
N Cl
N
1v, (45%), 60%b 1w, (50%, >20:1 r.r.), 81%
D
Me
O
D
N
D
D
S
Me N
D
1r, (75%), 89%
70%b
MeO
D
N N
Br
N
p-Tol
CN Br
Cl
1n, (81%), 83%
D Me
Ph
1h, (57%), 80%
O
1j, (64%), 91%
D
N
1g, (60%), 87%
O D
Ph
N
O
1i, (73%), 92%
O
1d, (69%), 71%
MeO
Me
N
N
D N
N
N N
2b, (79%, 5.3:1 r.r.), 82%
N Et
2c, (65%), 90%
S
O
Et O
N
N
O
N
N
N
N
N
2d, (61%), 92%
N N
2e, (89%), 78%
a
Isolated yields of single regioisomers (unless stated) shown with yields of phosphonium salts in parentheses. bRun with K2CO3 (1.5 equiv), DMF/D2O (9:1, 0.3 M). cYield calculated by 1H NMR using 1,3,5-trimethoxybenzene as a standard.
fragmentation-trapping event is driven by forming CO2 and Ph3PO.13,14 The process uses commercial reagents, simple experimental protocols and has broad substrate scope, including late-stage labeling. Notably, hydrogen isotopes are selectively installed at the 4-position of pyridines, a different regioselectivity profile from current labeling methods and not reliant on halogenated precursors. Table 1 shows that pyridine and diazine building blocks can be transformed into phosphonium salts and subsequently deuterated by a 9:1 mixture of CD3OD and D2O using potassium carbonate as a nucleophile. The D2O component of the reaction medium solubilizes the carbonate base and increases the rate of deuteration (see the Supporting Information). For pyridines 1a-1p, the deuterium label is incorporated exclusively in the 4position with only traces of C–H products observed by 1 H NMR. A range of monosubstituted as well as 2,3- and 2,5-disubstituted pyridines containing a diverse array of functional groups are effective (1a-1m). For 1l, a 9:1 mixture of DMF/D2O functions effectively as an alternative solvent system, albeit with slower rates (see also 1q, 1v & 2a).15 Pyridines with 3,5-substituents are also deuterated with complete regioselectivity, including halogens in these positions without forming pyridyne inter-
mediates (1n-1p). When the 4-position is blocked, the 2position is deuterated (1q & 1r). Other heterocycles such as azaindoles, pyrazines and pyrimidines also perform well in this protocol (1s-1w). Small molecule fragments, with multiple heterocycles and functional groups, are common as lead compounds in drug discovery programs. These structures are more challenging for selective functionalization because of the additional reactive sites and potential for interference with the phosphonium salt-forming reaction. A set of representative compounds containing benzoxazoles and piperazines are accommodated, and pyridines can be selectively deuterated over 2-amino pyrimidines (2a-2e). Our attention then turned to deuterating pharmaceuticals and other biologically active molecules. Late-stage functionalization is advantageous as deuterated versions of pharmaceutical candidates can be rapidly accessed.16 These compounds are more complex than simple pyridines or lead compounds and can have unfavorable physical properties, particularly poor solubility. Table 2 illustrates that the phosphonium salt formation-deuteration strategy is uniformly effective for azaarene-containing drugs. Nicotine, pyriproxifen, triprolidine, vismodegib and chlorphenamine all installed the isotope at the 4-position of the pyridine with complete regioselectivity (3a-3e). For bisacodyl, the DMF/D2O protocol was used to avoid
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Journal of the American Chemical Society Table 2. Deuteration Scope: Pharmaceuticals and Other Bioactive Moleculesa,b,c H
Drug
OTf
Tf2O; PPh3; NEt3 or DBU
X
N
Deuterated Drug
Heterocyclic Phosphonium Salt
D
X
Drug
CD3OD:D2O 9:1 (0.3 M), rt
N
sequential addition
Bioactive Molecules
D
K2CO3 (1.5 equiv)
X
Drug
CH2Cl2 or EtOAc, –78 ºC to rt
N
Azaarene
PPh3
D
D
O
D N N
Me
O
O
N
N
N
D-Pyriproxyfen (Nylar) 3b, (61%), 66%
N
Cl
D-Vismodegib (Erivedge) 3d, (31%, 7:1 r.r.)b, 73%
D-Triprolidine 3c, (51%), 84% D OAc
Me N
O
Cl
D
D
Me (48% D)
H N
N
p-Tol
O
D-Nicotine 3a, (76%), 79%
O S
Me
F N N
N
Me
N Cl
O
OBn N OAc
Cl
D-Bisacodyl (Dulcolax) 3f, (80%), 84%c
D-Chlorphenamine (Piriton) 3e, (40%), 86%
OBn-D-Cinchonidine 3g, (52%), 89% D
N
O
Cl Me Me
Me
D
MeN
S
N
(80% D)
N
N
H
H
HN N
N
Me
D
D-Loratadine (Claritin) 3k, (88%), 79%, 73%c
D-Etoricoxib (Arcoxia) 3l, (73%), 96%
N Me
N
CO2Et
D-Abiraterone Acetate (Zytiga) 3j, (67%), 62%c
D
Cl
H
AcO
D
D-Quinoxyfen 3i, (84%), 79%
N-Bn D-Varenicline (Chantix) 3h, (58%), 71%c
O
N
Cl
N Bn
D
O
N
N H
D-Imatinib (Gleevec) 3m, (75%, 20:1 r.r.), 92%
a
Isolated yields of single regioisomers (unless stated) shown with yields of phosphonium salts in parentheses. bSalt isolated with 8% of an unknown impurity. cRun with K2CO3 (1.5 equiv), DMF/D2O (9:1, 0.3 M).
methanolysis of the phenolic acetates (3f). Quinoxyfen, as well as protected versions of cinchonidine and varenicline are applicable to the protocol with the isotope installed at the 2-position of the nitrogen heteroaromatic (3g-3i). Abiraterone acetate, a prostate cancer drug, is also effective in this two-step protocol (3j). Chirik’s Fecatalyzed HIE reaction deuterated loratadine at the 2and 3-positions of the pyridine and highlights the distinct, and contra-steric, 4-position selectivity observed using this protocol (3k).12a Etoricoxib and imatinib are challenging substrates due to the bis-heterobiaryl motifs in their structures. For etoricoxib, we observe exclusive reactivity at the 2,5-disubstituted pyridine17 and imatinib is deuterated in a 20:1 ratio at the pyridine 4-position over the 2-amino pyrimidine (3l & 3m). To tritiate pharmaceuticals, we adapted the reaction protocol to accommodate the typical isotope sources used in radiolabeling laboratories. Firstly, stock solutions of tritiated water are available and would represent a convenient means for labeling, provided sufficient radiochemical yields are observed. Secondly, we envi Generation of high-concentration MeOT via hydrogen isotope exchange
Pd/C cat. MeO
H
MeO
T2 (1 Ci), THF, r.t.
T
(4)
sioned a means to generate high-concentration MeOT by a metal-catalyzed HIE between MeOH and T2 gas.18-20 T2 gas is the preferred source due to high isotopic purity and safer handling. In practice, a solution of MeOH in THF is exposed to 1 Ci T2 gas at 0.13 atmospheres with Pd/C as the exchange catalyst (eq 4). After the exchange, the mixture is filtered, rinsed with the respective solvent and added to the phosphonium salt and carbonate. The exchange protocol could be used in other applications that require high activity solutions of MeOT (or THO). We chose a selection of phosphonium derivatives of pharmaceuticals to test these protocols and the radiochemical yields are well within the range required for ADME studies (Table 3). Triprolidine and abiraterone acetate salts are tritiated by MeOT following the HIE protocol and stirring in THF with Cs2CO3 (4c & 4j). Tritiated loratadine (4k) is obtained via this method; a fresh bottle of Cs2CO3 resulted in higher mCi values compared with base stored on the benchtop representing a more effective and reliable protocol, presumably due to lower residual water content. Stock solutions of THO can also be used in both THF and DMF to account for molecules with different solubilites. A tritium analogue of etoricoxib was obtained in good radiochemical yield using both methods (4l). Finally, a 20:1 mixture of imatinib phosphonium salt regioisomers functioned well
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in the MeOT tritiation protocol with the calculated radiochemical yield closely matching an isolated sample of radiopure material (4m). This study shows that pyridinecontaining drugs can be tritiated and the methods are straightforward to apply in radiolabeling laboratories. Table 3. Tritiation of Pharmaceuticalsa T
A
Cs2CO3, MeOT, THF, rt
N
B
Cs2CO3, THO, THF, rt
N
Heterocyclic Phosphonium Salt
C
K2CO3, THO, DMF, rt
Tritiated Drug
Drug
Drug
T
T N T Me
N
N
Cl N
Me H
H
Me
N
T-Loratadine, 4k
AcO
T-Abiraterone Acetate, 4j
T-Triprolidine, 4c A 10.6b Ci mmol-1
CO2Et
A 11.5b Ci mmol-1 A 21.1c Ci mmol-1
A 18.4c Ci mmol-1
B 1.8b,d Ci mmol-1 C 4.6e Ci mmol-1
O Me
MeN
O
N
S
N
Cl
HN
T N Me
N Me
N O
T
c -1 T-Etoricoxib, A 27.5 Ci mmol 4l B 17.6b,d Ci mmol-1
T-Imatinib, 4m
N
N H
A 19.1c Ci mmol-1 (isolated 17.3 Ci mmol-1 at 99.6% radiochemical purity)
a
MeOH HIE protocol: MeOH (10 µL), 6.5 mg Pd/C, 1.0 Ci T2 (0.13 atm). 8.3-29.1 mg of phosphonium salts used in this study. Reported Ci mmol-1 values calculated from the crude Ci mmol-1 corrected for radiochemical purity. See Supporting Information for experimental details. bBenchtop Cs2CO3 used. cFresh bottle of Cs2CO3 used. dUsing 500 mCi THO at 50 Ci/cc. eUsing 150 mCi THO at 50 Ci/cc.
In summary, heterocyclic phosphonium salts are broadly applicable as reagents to install hydrogen isotopes onto azaarenes and pharmaceuticals. The important features of this approach are: orthogonal regioselectivity compared to existing methods, wide substrate scope and simple experimental protocols. We believe that these methods will find applications in drug discovery and radiolabeling groups due to the interest in deuterated therapeutics and the necessity for ADME studies. ASSOCIATED CONTENT Supporting Information. Experimental procedures and spectral data. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION *
[email protected]. Funding Sources
ACKNOWLEDGMENT This work was supported by start-up funds from Colorado State University.
REFERENCES
PPh3
OTf
No competing financial interests have been declared.
(1) (a) Lappin, G.; Temple, S. Radiotracers in Drug Development. CRC Press, Taylor and Francis Group: Boca Raton, FL, 2006. (b) Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson, R. A.; Weidolf, L. Chem. Res. Toxicol. 2012, 25, 532. (c) Marathe, P. H.; Shyu, W. C.; Humphreys, W. G. Curr. Pharm. Des. 2004, 10, 2991. (d) Elmore, C. S. Annu. Rep. Med. Chem. 2009, 44, 515. (e) Lockley, W. J. S.; McEwan, A.; Cooke, R. J. Labelled Comp. Radiopharm. 2012, 55, 235. (f) Voges, R.; Heys, J. R.; Moenius, T. Preparation of Compounds Labelled with Tritium and Carbon-14. John Wiley & Sons, Chichester, 2009. (2) (a) Scheppele, S. E. Chem. Rev. 1972, 72, 511. (b) Cleland, W. W. Arch. Biochem. Biophys. 2005, 433, 2. (3) Busenlehner, L. S.; Armstrong, R. S. Arch. Biochem. Biophys. 2005, 433, 34. (4) (a) Mullard, A. Nat. Rev. Drug Discov. 2016, 15, 219. (b) Gant, T. G. J. Med. Chem. 2013, 57, 3595. (c) Elmore, C. S.; Bragg, R. A. Bioorg. Med. Chem. Lett. 2015, 25, 167. (d) Harbeson, S. L.; Tung, R, D. Annu. Rep. Med. Chem. 2011, 46, 403. (5) Jarman, M.; Poon, G. K.; Rowlands, M. G.; Grimshaw, R. M.; Horton, M. N.; Potter, G. A.; McCague. R. Carcinogenesis 1995, 4, 683. (6) Harbeson, S. L.; Tung, R. D. MedChem. News 2014, 8, 8. (7) Mullard, A. Nat. Rev. Drug Discov. 2017, 16, 305. (8) Xu, Y.; Li, L.; Wang, Y.; Xing, J.; Zhou, L.; Zhong, D.; Luo, X.; Jiang, H.; Chen, K.; Zheng, M.; Deng, P.; Chen, X. J. Med. Chem. 2017, 60, 2973. (9) (a) Alonso, F.; Beletskaya, I. P; Yus, M. Chem. Rev. 2002, 102, 4009. (b) Janni, M.; Peruncheralathan, S. Org. Biomol. Chem. 2016, 14, 3091. (10) (a) Plé, N.; Turck, A.; Couture, K.; Quéguiner, G. J. Org. Chem. 1995, 60, 3781. (b) Pierrat, P.; Gros, P.; Fort, Y. Synlett 2004, 2319. (c) Hawad, H.; Bayh, O.; Hoarau, C.; Trécourt, F.; Quéguiner, G.; Marsais, F. Tetrahedron 2008, 64, 3236. (d) Grainger, R.; Nikmal, A.; Cornella, J.; Larrosa, I. Org. Biomol. Chem. 2012, 10, 3172. (11) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmerman. Angew. Chem. Int. Ed. 2007, 46, 7744. (12) (a) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, P.; Chirik, P. Nature 2016, 529, 195. (b) Crabtree, R.; Felkin, H.; Morris, G. J. Organomet. Chem. 1977, 141, 205. (c) Nilsson, G. N.; Kerr, W. J. J. Labelled Comp. Radiopharm. 2010, 53, 662. (13) (a) Hilton, M. C.; Dolewski, R. D.; McNally, A. J. Am. Chem. Soc. 2016, 138, 13806. (b) Anders, E.; Markus, F. Tet. Lett. 1987, 28, 2675. (c) Haase, M.; Goerls, H.; Anders, E. Synthesis 1998, 195. (14) (a) Shimada, M.; Sugimoto, O.; Sato, A.; Tanji, K. Heterocycles 2011, 83, 837. (b) Nguyen, B. V.; Burton, D. J. J. Fluorine Chem. 2012, 135, 144. (c) Deng, Z.; Lin, J.-H.; Xiao, J.-C. Nat. Commun. 2016, 7:10337. (15) Typical reaction time in 9:1 CD3OD/D2O is 3 hours vs. 15 hours in 9:1 DMF/D2O. Compounds 1l, 1q, 1v, 2a, 3f, 3h, 3j and 3k use the latter protocol. (16) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. Chem. Soc. Rev. 2016, 45, 546. (17) The C–D bonds at the methyl sulfone can be converted back to C–H bonds by stirring with K2CO3 in 9:1 MeOH/H2O. (18) Sajiki, H.; Kurita, T.; Esaki, H.; Aoki, F.; Maegawa, T.; Hirota, K. Org. Lett. 2004, 6, 3521. (19) Morimoto, H.; Williams, P. G. Fusion Sci. Technol. 1992, 21, 246. (20) After submitting this manuscript, MacMillan independently reported a related HIE approach: Loh, Y. Y.; Nagao, K.; Hoover, A. J.; Hesk, D.; Rivera, N. R.; Colletti, S. L.; Davies, I. W.; MacMillan, D. W. C. Science 2017, 358, 1182.
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Journal of the American Chemical Society
Site-Selective Deuteration and Tritiation via Heterocyclic Phosphonium Salts O Me
O
O
S
Me Cl
N Me
N
O S
1) C–P Bond-Formation
Cl
2) M2CO3, D or T Installation
N Me
H
Broad scope
Distinct regioselectivity
N D/ T
Simple protocols
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