Applications and Synthesis of Deuterium-Labeled...
33
X X Applications and Synthesis of Deuterium-Labeled Compounds Christopher Prier MacMillan Group Meeting February 27, 2014
Transcript of Applications and Synthesis of Deuterium-Labeled...
X
X
Applications and Synthesis ofDeuterium-Labeled Compounds
Christopher Prier
MacMillan Group Meeting
February 27, 2014
X
X
Wiberg, K. B. Chem. Rev. 1955, 55, 713.
Deuterium: A Stable Isotope of Hydrogen
11H21D
1.008 amu2.014 amu
0.015% naturalabundance
■ 1932: Urey, Brickwedde, and Murphy report spectroscopic evidence for heavy hydrogen
■ Urey awarded the Nobel Prize for his discovery in 1934; coins the name "deuterium"
■ Deuterium now broadly employed in organic chemistry, organometallic chemistry, enzymology,spectroscopy, pharmacology, and many other fields
Harold C. Urey
■ 1933: Lewis and MacDonald isolate a pure sample of deuterium oxide (D2O)
X
X
■ KIE is the observation that isotopically substituted molecules react at different rates: kH ≠ kD
Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books: Sausalito, 2006.
The Kinetic Isotope Effecten
ergy
internuclear distance (r)
C H
C Dn = 0
n = 0 µ =m1 • m2
m1 + m2zero-pointenergies
■ Vibrational energy of a bond is dependent on the reduced mass of the two atoms (µ)
µ
k1
2πc=ν
=En (n + 1) hν
µC–H = 0.92
µC–D = 1.71
ΔG‡C–D > ΔG‡C–H
■ Larger activation energy for C–D bond homolysis than for C–H bond homolysis
X
X
■ The distribution of deuterium in an equilibrium is determined by a thermodynamic isotope effect
Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books: Sausalito, 2006.
The Equilibrium Isotope Effect
deuterium prefers the bond with the larger force constant
AH + BD AD + BH
AD
AHBD
BH
ΔZPEC–D > ΔZPEC–H
case 1 case 2
equilibrium favors AD + BH equilibrium favors AH + BD
AD
AHBD
BH
ΔZPEC–D < ΔZPEC–H
X
X
■ Internal standards for mass spectrometry
Applications of Deuterated Compounds
■ Elucidation of biosynthetic pathways
■ Enhance metabolic stability of a drug
■ Total synthesis: alter reaction selectivity
And many more!
■ Study of reaction mechanisms
X
X
■ Internal standards for mass spectrometry
Applications of Deuterated Compounds
■ Elucidation of biosynthetic pathways
■ Enhance metabolic stability of a drug
■ Total synthesis: alter reaction selectivity
And many more!
■ Study of reaction mechanisms
X
X
■ Introduction of deuterium suppresses an undesired pathway via the kinetic isotope effect
Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science 2004, 305, 495.
Deuterium in the Total Synthesis of Norzoanthamine
Me
OTES
Me
H
H
OTBS
OMe
MeO
Me MeOTBS
X X
X = H
X = D
OTES
Me
H
H
OTBS
MeMeO
Me MeOTBS
X X O
OTES
Me
H
H
OTBS
MeMeO
Me MeX
MeX
H H H
Tf2O2,6-di-t-Bu-py
then DBU
norzoanthamine
N
HO
Me H
O H Me
O
Me
HO
Me
O
Meundesired
Me
OMe
MeOTBS
X X
Tf
Me
OMe
MeOTBS
X
TfX
1,5-hydrideshift
66% 30%
81% 9%
X
X
■ Internal standards for mass spectrometry
Applications of Deuterated Compounds
■ Elucidation of biosynthetic pathways
■ Enhance metabolic stability of a drug
■ Total synthesis: alter reaction selectivity
And many more!
■ Study of reaction mechanisms
X
X
■ Deuteration has the potential to impact a drug's stability when metabolism involves cleavage of a C–H bond
Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
Deuterium Effects in Drug Metabolism
■ Potential for a drug to have a longer half-life or reduced/less frequent dosing
■ Improve metabolite profile: prevent formation of toxic metabolites or those that inhibit CYP
Kushner, D. J.; Baker, A.; Dunstall, T. G. Can. J. Physiol. Pharmacol. 1999, 77, 79.Foster, A. B. Trends Pharmacol. Sci. 1984, 5, 524.
Harbeson, S. L.; Tung, R. D. Annu. Rep. Med. Chem. 2011, 46, 403.
C H
cytochrome P450oxidative metabolism
R
RR
C DR
RR
■ Deuteration typically has no effect on biological potency or selectivity
■ To date there are no approved deuterium-enriched pharmaceuticals
C OHR
RR
kH
kD
C OHR
RR
deuteration
X
X
■ Tamoxifen forms adducts with DNA in rats, leading to liver cancer; proposed to proceed via quinone methide
Jarman, M.; Poon, G. K.; Rowlands, M. G.; Grimshaw, R. M.; Horton, M. N.; Potter, G. A.; McCague, R. Carcinogenesis 1995, 16 , 683.
Metabolism and Deuteration of Tamoxifen
ONMe2
Me
OR
MeOH
ONMe2
DD
D
DD
tamoxifen-d5
tamoxifenbreast cancer treament
■ Isotope effect hypothesized
proposed intermediates leading to DNA conjugates
OR
Me
– OH–
+ OH–
■ Reduced genotoxicity observed:
oxidativemetabolism
to reduce extent of DNA alkylation
Phillips, D. H.; Potter, G. A.; Horton, M. N.; Hewer, A.; Crofton-Sleigh, C.; Jarman, M.; Venitt, S. Carcinogenesis 1994, 15 , 1487.
~2-fold reduced adduct formation
X
X
■ Metabolism of efavirenz to a toxic metabolite in rats involves a propargylic oxidation of the cyclopropane
Mutlib, A. E.; Gerson, R. J.; Meunier, P. C.; Haley, P. J.; Chen, H.; Gan, L. S.; Davies, M. H.; Gemzik, B.; Christ, D. D. et al. Toxicol. Appl. Pharmacol. 2000, 169 , 102.
Metabolism of Efavirenz
efavirenz
NH
O
O
F3CCl
NH
O
O
F3CCl
HO
NH
O
O
F3CCl S
HO
NH
O
O
F3CCl
HO3SO HO3SO
HO3SO
reverse transcriptase inhibitorfor the treatment of HIV
metabolite responsible for nephrotoxicity
NH2
O
NH
CO2H
oxidation
NH
O
O
F3CCl S
HO
HO3SO
HN
O
NH
CO2H
OCO2H
glutathione
γ-glutamyltranspeptidase
NH2
propargylicoxidation
X
X
■ Installation of a single deuterium atom at the site of propargylic oxidation reduces toxic metabolite formation
Mutlib, A. E.; Gerson, R. J.; Meunier, P. C.; Haley, P. J.; Chen, H.; Gan, L. S.; Davies, M. H.; Gemzik, B.; Christ, D. D. et al. Toxicol. Appl. Pharmacol. 2000, 169 , 102.
Metabolism of Efavirenz
efavirenz-d1
NH
O
O
F3CCl
NH
O
O
F3CCl
HO
NH
O
O
F3CCl
HO3SO HO3SO
oxidationpropargylicoxidation
D D
concentration of toxicmetabolite in urine
efavirenzefavirenz-d1
28.1 ± 13.0 µg/mL4.0 ± 1.1 µg/mL
efavirenz efavirenz-d1
no. of rats with renal corticalepithelial cell necrosis
severity
0 (unaffected)1 (minimal)2 (mild)3 (moderate)4 (severe)
02422
24310
X
X
■ Telaprevir undergoes epimerization in vivo to its less potent (R)-epimer
Maltais, F.; Jung, Y. C.; Chen, M.; Tanoury, J.; Perni, R. B.; Mani, N.; Laitinen, L.; Huang, H.; Liao, S.; Gao, H. et al. J. Med. Chem. 2009, 52, 7993.
Deuteration of Telaprevir
N
N
HN
ONH
O t-Bu
O
N
O
HN
OHN
OH
Me
telaprevir
■ Hepatitis C protease inhibitor■ Vertex, Johnson & Johnson
N
N
HN
ONH
O t-Bu
O
N
O
HN
OHN
OH
Me
telaprevir (R)-epimer
■ Major metabolite of telaprevir
■ 30-fold lower inhibitory activity
pH ≥ 7
X
X
■ Telaprevir undergoes epimerization in vivo to its less potent (R)-epimer
Maltais, F.; Jung, Y. C.; Chen, M.; Tanoury, J.; Perni, R. B.; Mani, N.; Laitinen, L.; Huang, H.; Liao, S.; Gao, H. et al. J. Med. Chem. 2009, 52, 7993.
Deuteration of Telaprevir
N
N
HN
ONH
O t-Bu
O
N
O
HN
OHN
OH
Me
telaprevir
■ Hepatitis C protease inhibitor■ Vertex, Johnson & Johnson
N
N
HN
ONH
O t-Bu
O
N
O
HN
OHN
OD
telaprevir-d1
■ As efficacious as protio-telaprevirin protease inhibition and viral
Me
replication assays
■ Significantly more resistant toepimerization (kH/kD ≈ 5)
■ ~13% increase in AUC in rats
X
X
Katsnelson, A. Nature Med. 2013, 19 , 656.
Deuterated Drugs in Clinical Trials
CTP-499
■ In Phase II for diabetic nephropathy
N
N N
N
O Me
OMe
D3CDD
OH
■ Phosphodiesterase inhibitor
SD-809
■ In Phase III for treatment of chorea
■ Deuterated analog of the active metaboliteof pentoxifylline
associated with Huntingdon's disease
N
H
OMe
Me
D3CO
D3CO
■ Deuterated analog of tetrabenazine
X
X
Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. Angew. Chem. Int. Ed. 2007, 46, 7744.
Approaches to the Synthesis of Labeled Compounds
"Synthetic Approach"
deuterium-containingstarting material
steps
deuterated target
deuterated target
NH
O
O
F3CCl
D
NH
O
O
F3CCl
D
D
proteo-target molecule
"Exchange Approach"catalyst
deuterium source(D2O, D2, etc.)
NH
O
O
F3CCl
■ Selectivity for various classes of C–H bond? ■ Efficiency in a complex setting?
simple
X
X
■ Deuterated compounds (especially internal standards) ideally possess a narrow isotopic distribution
Atzrodt, J.; Derdau, V. J. Label. Compd. Radiopharm. 2010, 53, 674.
Synthesis of Deuterated Compounds
Natural isotopedistribution
unselectiveH/D exchange
moderatelyselective
H/D exchange
highly selectiveH/D exchange
X
X
■ The source of all deuterium-enriched material is deuterium oxide (D2O)
Paulsen, P. J.; Cooke, W. D. Anal. Chem. 1963, 35, 1560.
Synthesis of Deuterated Reagents
2 Na2O2
– O2
4 NaOD
Cl3C H
O4
4 CDCl3
H3C CH3
Oexcess D2O
LiOD
D3C CD3
O+ 6 HDO
4 HCO2Na+2 D2O +
2 D2Oelectrolysis
2 D2
4 Li0
Δ
4 LiD +AlCl3
LiAlD4 3 LiCl
Kluger, R. J. Org. Chem. 1964, 29, 2045.
Ir
X
X
■ A cationic iridium trihydride complex catalyzes the H/D exchange of arenes, cyclic alkenes
Skaddan, M. B.; Yung, C. M.; Bergman, R. G. Org. Lett. 2004, 6, 11.
Iridium-Catalyzed H/D Exchange
HH
Me3P
Me
Me Me
Me
Me5 mol% Cp*PMe3Ir(H)3OTf
acetone-d6, 75 ºC, 20 h
OH[99]
[99]
[98][99]
R H R D
[88]
[83]
[95]
[95]
[96]
[90]
Me[11]
[32]
[93][94]
N NMe Me
H
Cp*PMe3Ir(H)3+
+
Yung, C. M.; Skaddan, M. B.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126 , 13033.
[98]
TMS[0]
[16]
[98][98]
[27]
[31]
[28][0]
[0]
[0]
X
X
■ Deuterium incorporation
Skaddan, M. B.; Yung, C. M.; Bergman, R. G. Org. Lett. 2004, 6, 11.
Mechanism of Iridium-Catalyzed H/D Exchange
Yung, C. M.; Skaddan, M. B.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126 , 13033.
H2
Cp*(PMe3)IrIIIH
O
D3C
CD3
Cp*(PMe3)IrIIIHH
H
+ –OTf
acetone-d6
+ –OTf
Cp*(PMe3)IrVH
+ –OTf
DDD
Cp*(PMe3)IrIII+ –OTf
D acetone-d5
Cp*(PMe3)IrVD
H
D
acetone-d6
+ –OTf
proceeds via iterative cycles ofreversible C–H bond activation
iridium(III) monodeuteride
benzene-d1
CD3O
X
X
■ Iridium catalysts promote selective ortho-deuteration via the formation of five-membered metallacycles
Shu, A. Y. L.; Chen, W.; Heys, J. R. J. Organomet. Chem. 1996, 524, 87.
Iridium-Catalyzed Ortho H/D Exchange
t-Bu
O 2 mol% [IrH2(acetone)2(PPh3)2]BF4
Heys, R. J. Chem. Soc., Chem. Commun. 1992, 680.
t-Bu
O
PPh3
IrI
PPh3
L
L
1 atm D2, CH2Cl2, r.t.
+
PPh3
IrIII
PPh3
O
H
t-BuDD
DD
PPh3
IrI
PPh3
L
L
+
DH
D2HD
PPh3
IrIII
PPh3
O
D
t-BuDH
[90]
H/D exchange
directing group: ketone, ester, amide
[0]
[0]
[0]
X
X
■ Palladium-catalyzed ortho-deuteration of arenes bearing weakly coordinating directing groups
Ma, S.; Villa, G.; Thuy-Boun, P. S.; Homs, A.; Yu, J.-Q. Angew. Chem. Int. Ed. 2014, 53, 734.
Ortho-Selective Deuteration of Arenes
PdII
ONa
Oelectrophilic
weakly coordinatedpalladacycle
OH
O
OH
OD
CF3CF3CF3
96% yield
[98]
1) 10 mol% Pd(OAc)21.5 equiv. Na2CO3acetic acid-d4, 120 ºC, 12 h
2) 20 equiv. NaOHH2O/CH2Cl2, 120 ºC, 12 h
D+
cleavage
OH
OD
D
99% yield
[99]
OH
OD
D
88% yield
[93]Me
Me
ibuprofen-d2
SNHC6F5
OD
D
73% yield
[89]
OD
D
62% yield
[86]
N
DD
X
X
■ Palladium-catalyzed ortho-deuteration of arenes bearing weakly coordinating directing groups
Ma, S.; Villa, G.; Thuy-Boun, P. S.; Homs, A.; Yu, J.-Q. Angew. Chem. Int. Ed. 2014, 53, 734.
Ortho-Selective Deuteration of Arenes
PdII
ONa
Oelectrophilic
weakly coordinatedpalladacycle
OH
O
OH
OD
CF3CF3CF3
96% yield
[98]
1) 10 mol% Pd(OAc)21.5 equiv. Na2CO3acetic acid-d4, 120 ºC, 12 h
2) 20 equiv. NaOHH2O/CH2Cl2, 120 ºC, 12 h
D+
cleavage
PdII
N
OCsAr
AcO2
weakly coordinatedpalladacycle
acetic acid-d4
120 ºC, 1 hAr = 4-CF3C6H4
NH
OAr
D
D
88% yield
[94]
PdII
N
AcO2
strongly coordinatedpalladacycle
no reaction
starting materialrecovered
X
X
■ Selective deuteration of vinyl groups is achieved with an iridium catalyst bearing an aliphatic pincer ligand
Zhou, J.; Hartwig, J. F. Angew. Chem. Int. Ed. 2008, 47, 5783.
Vinyl H/D Exchange by an Iridium-Pincer Complex
Ir
Pt-Bu2
Pt-Bu2
HNH2
HR RD
D
D5 mol% iridium catalyst A
AC6D6
Me
Me
Me
D
[97][0]
[0]Si
Me
Me
Me
D
[97][0]
[97]
r.t., 1 min r.t., 1 min
Me
[7]
[7]r.t., 5 min
D
D
[84]
50 ºC, 50 h
r.t., 20 h
D
[92]
Me
D[96]
[97]
D
D
[97]
D
D
r.t., 40 h
[94] D
D[92]
r.t., 3 h
Me
D
D
D
D[0]
[0] [13]
[94]
[44]r.t., 1.5 h
X
X
Zhou, J.; Hartwig, J. F. Angew. Chem. Int. Ed. 2008, 47, 5783.
Vinyl H/D Exchange by an Iridium-Pincer Complex
IrIII
Pt-Bu2
Pt-Bu2
HNH2
H
–NH3
IrI
Pt-Bu2
Pt-Bu2
H IrIII
Pt-Bu2
Pt-Bu2
HC6D5
D
IrI
Pt-Bu2
Pt-Bu2
H
DC6D5
IrIII
Pt-Bu2
Pt-Bu2
DH
C6D5
benzene-d5
IrI
Pt-Bu2
Pt-Bu2
DIrIII
Pt-Bu2
Pt-Bu2
DH
R
IrI
Pt-Bu2
Pt-Bu2
D
H R
IrIII
Pt-Bu2
Pt-Bu2
HD
RD
R
R
H
■ Backbone methineacts as proton shuttle
■ Strong dependenceon sterics; no olefinisomerization
benzene-d6
X
X
■ Selective deuteration of vinyl groups by an iridium catalyst bearing an aliphatic pincer ligand
Zhou, J.; Hartwig, J. F. Angew. Chem. Int. Ed. 2008, 47, 5783.
Vinyl H/D Exchange by an Iridium-Pincer Complex
Ir
Pt-Bu2
Pt-Bu2
HNH2
HR RD
D
D5 mol% iridium catalyst A
AC6D6
O
MeMe
O
tiamulinr.t., 10 min
Me
O
S
NEt2
HO
Me
HD[90]
[7]
O
OHH
MeMeOMe
Me
O
[2]
forskolinr.t., 5 min
HOMeO
Me
D [99]
X
X
■ Ru-catalyzed α-deuteration of amines and alcohols proceeds via a "borrowing hydrogen" mechansim
Takahashi, M.; Oshima, K.; Matsubara, S. Chem. Lett. 2005, 34, 192.
α-Deuteration of Amines and Alcohols
MeOH
90% yield, >99% ee
Ph
[87]
R
NHor
R
OHor
R
OH
D
3.0–5.0 mol% RuCl2(PPh3)2
D2O, 150 ºC, 10 atm100 W microwave
OH
96% yield
[98]OH[97]
90% yield
DR
NH
DD
R' R'
NH2n-C6H13
[94]
HN
68% yield79% yield
[91]
X
X
■ Ru-catalyzed α-deuteration of amines and alcohols proceeds via a "borrowing hydrogen" mechansim
Takahashi, M.; Oshima, K.; Matsubara, S. Chem. Lett. 2005, 34, 192.
α-Deuteration of Amines and Alcohols
R
NDLnRuII
H
D
LnRu0
ClLnRuII
Cl
R
ND2
R
ND2 Cl
R
ND2
R
ND3 Cl
R
NDLnRuII
D
DLnRuII
H
DN
R
R
ND2
DH
R
ND2
H
R
NH2 D2O
D2O
Ru
X
X
■ The Shvo catalyst enables the selective α,β-deuteration of amines using deuterium oxide
Neubert, L.; Michalik, D.; Bähn, S.; Imm, S.; Neumann, H.; Atzrodt, J.; Derdau, V.; Holla, W.; Beller, M. J. Am. Chem. Soc. 2012, 134 , 12239.
Selective α,β-Deuteration of Amines
Ph
Ph O
Ph
PhH
RuPh
PhO
Ph
PhH
CO COCOOC
Shvo catalyst
Δ
Ru
PhPh
O
Ph Ph
OCOC X
dehydrogenatedmonomer
+
hydrogenatedmonomer
RuH
PhPh
OHPh Ph
OCOC
N Me
3
5 mol% Shvo catalyst
D2O, 150 ºC, 24 hN Me
3[80] [0] [0]
[92] [0] [0]
N Me
[0]
[0][91]
[95][95][97]
[0]NMe
2
[92][88] [0]
[0]
[0]
N Me
3
[80] [0]
Me
[0]
[69]
[0]
Mechanism of Amine α,β-Deuteration by the Shvo Catalyst
RuN
PhPh
OPh Ph
OCOC
R R
R'H
Ru
PhPh
O
Ph Ph
OCOC X
Ru
PhPh
OHPh Ph
OCOC R'
NRR
R2NR'
R2NR'Ru
H
PhPh
OHPh Ph
OCOC
RuD
PhPh
ODPh Ph
OCOCR2N
R'
Ru
PhPh
ODPh Ph
OCOC R'
NRR
D
RuN
PhPh
OPh Ph
OCOC
R R
R'D
D
R2NR'
D
D
2 R''OD2 R''OH
Shvo catalystdehydrogenated
monomer
X
X
Neubert, L.; Michalik, D.; Bähn, S.; Imm, S.; Neumann, H.; Atzrodt, J.; Derdau, V.; Holla, W.; Beller, M. J. Am. Chem. Soc. 2012, 134 , 12239.
α,β-Deuteration of Complex Amine-Containing Molecules
O
NH
sunitinib, 67% yield
N
Me
Me
HNMe
Me
NH
F
O
[90]
[95] [95][92]
[0]
[0]
[0][0]
[0]
[0]
Pfizer, tyrosine kinase inhibitor
HNN
F
[0][0]
[90][90]
[93] [90][3]
Conditions: 10 mol% Shvo catalyst, i-PrOD-d8 or t-BuOD, toluene, microwave heating, 150 ºC
HN O
OMe
NH2
Cl
N
Me
Me
metoclopramide, 83% yield
[96][97] [95]
[65][0]
[0]
[0]
antiemetic
F
N
OH
OOMe
Me[0]
[0] [50]
[20]
[92] [70][0]
[12]
[0][0]
[0]
[0]
[0]74% yield 71% yield
X
X
Neubert, L.; Michalik, D.; Bähn, S.; Imm, S.; Neumann, H.; Atzrodt, J.; Derdau, V.; Holla, W.; Beller, M. J. Am. Chem. Soc. 2012, 134 , 12239.
Me
X
X
■ Palladium-based catalyst systems preferentially deuterate aliphatic C–H bonds; platinum catalyst systems
Sajiki, H.; Aoki, F.; Esaki, H.; Maegawa, T.; Hirota, K. Org. Lett. 2004, 6, 1485.
Heterogeneous Metal Catalysis for H/D Exchange
PhCO2Na
10% Pd/CH2, D2O
r.t., 24 hPh
CO2Na
[0]
[89]
[0]
[0]
[0]
■ Selectivity for benzylic H/D exchange can be obtained under less forcing conditions
show selectivity for deuteration of aryl C–H bonds
Sajiki, H.; Ito, N.; Esaki, H.; Maesawa, T.; Maegawa, T.; Hirota, K. Tetrahedron Lett. 2005, 46, 6995.
Me
Me
MeONa
OMe
Me
MeONa
O
10% Pd/CH2, D2O
160 ºC, 24 h[29]
99% yield[92]
[99]
[97]
[97]
[99]
Me
Me
MeONa
O
10% Pd/CH2, D2O
160 ºC, 24 h[97]
99% yield[96]
[97]
[97]
[97]
[96]
5% Pt/CH2, D2O
160 ºC, 24 h91% yield
Me
Me
MeONa
O[96]
[40][54]
[94]
[91]
[56]
X
X
■ Methods developed for deuteration are often also applicable to the installation of tritium (31H, T)
Skaddan, M. B.; Yung, C. M.; Bergman, R. G. Org. Lett. 2004, 6, 11.
Tritium-Labeling of Organic Molecules
N
F
NH
N
OOMe
OMe[Ir(cod)(dppe)]BF4
T2 N
F
NH
N
OOMe
OMeT
single regioisomer
Shu, A. Y. L.; Saunders, D.; Levinson, S. H.; Landvatter, S. W.; Mahoney, A.; Senderoff, S. G.; Mack, J. F.; Heys, J. R. J. Labelled Cpd. Radiopharm. 1999, 42, 797.
warfarin
OH
O
Me
O
[Cp*(PMe3)Ir(Me)(CH2Cl2)][BARF]
T2, 25 ºC, 1 hOH
O
Me
O
T
T
8.37 mCi [T]warfarin
