late-stage fluorination
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Late-Stage Fluorination
Tobias RitterDepartment of Chemistryand Chemical BiologyHarvard University
Positron Emission Tomography
hν
electron
• non-invasive• functional imaging modality • 18F is nuclide of choice
PET-MR MR PET
2
Applications of PET Limited by Chemistry
O2N Cl
NMe3
OHOHO
18F OH
OH
K[18F]F, K2CO3-K222 MeCN, 23 °C, 75% RCY
25 min O2N Cl
18F
H2N Cl
18F N
N
ClO
MeO
NO
[18F]FDG [18F]fluoro-deoxy glucose
• [18F]FDG most common PET tracer• [18F]FDG images glycolysis• applications primarily in oncology
N
N
HNO
MeO
NO
18F
Cl
[18F]IressaNaBH4, Pd/C MeOH, 23 °C, 97% 5 min
iPrOH, 23 °C, 50% 15 min
K222
Seimbille, Phelps, Czernin, Silverman J Label Compd Radiopharm 2005 48 829
18F half-life:110 minutes
O O
N N
O OO O
K
3
F
Late-Stage Fluorination
5
F F F F F
F
late-stage fluorination
• carbon–fluorine bond formation last• advantageous for drug development• required for PET tracer synthesis
conventional synthesis: building block approach (for pharmaceuticals, agrochemicals)
Review: Furuya, Kamlet, Ritter Nature 2011 473 470
18Fluoride Only Practical Fluorine Source for PET
cyclotron
fluoride: 18F ¯ fluorine gas: [18F]F2 = “18F+”
18F18F19F
19F2
receptor
18F19F
5
18F ¯ 18F+
Challenges to Meet:
1. electrophilic fluorination reagent from 18F fluoride
2. late-stage fluorination
18F+
F
6
Fluorination of Palladium Aryl Complexes
NN Cl
F2 BF4
R
F
F
HO
F
H2N
O
F
Me
MeMe
FCl
Me
N
NS
O
O
Pd N
OAc
NO2 B(OH)2
N
NS
O
O
Pd N
NO2
MeCN, 50 °C 30 min
79% 74%
70% 82%
K2CO3 MeOH/C6H6 1:1
23 °C, 2.5 h
76%
Furuya, Kaiser, Ritter Angew Chem Int Ed 2008 47 5993
+
1.2 equiv
N
NS
O
O
Pd N
R
NO2
7
Metal Fluorination; C–F Reductive Elimination
NPdNNS
O
ONF
PdN
NSO2
NF
N
N
Pd
SO2
N
F
C–F reductive
eliminationNN Cl
F 2 BF4
94%
Furuya, Ritter J Am Chem Soc 2008 130 10060 Furuya, Benitez, Tkatchouk, Strom, Tang, Goddard, Ritter J Am Chem Soc 2010 132 3793
BF4
Pd
F
N
NS
NO
O
MeCN 23 °C, 10 min
50 °C, 30 min
PdII, nucleophile, dz2
8
Silver–Catalyzed Late-Stage Fluorination
SnR3R
FR
NHO
MeMe
OHMe
OHMe
AcOMe
MeO
O
O O
O
O
Me
O
MeO
F
OMe
F
O O
BzOOBzO
BzO
BzOOBz
OBzBzO
HH
H
N
N
F
OHF NHBoc
NH
O HN
ONH
O
O
HN Me
MeOMeO
CO2Me
NHBoc
AcO
AcO F
O
O
F
rifamycin, 65%estrol lactoside, 80% taxol, 72%
Leu-enkephalin, 83%F-DOPA, 78%flavanone, 90% quinine, 75%
5 mol% Ag2O 1.0 equiv NaOTf
2.0 equiv NaHCO3
1.5 equiv F-TEDA-PF6 acetone, 65 °C, 3–5 h
Me
OAcO O
HOHO OO
OAcO
O
F
H
Tang, Furuya, Ritter J Am Chem Soc 2010 132 12150 9
An Electrophilic Fluorination Reagent from Fluoride
3 KF . HF . PbF4 3 KF + HF + PbF2 + F2
H F
ML
L L
L
n-2Nu F
18F ¯ 18F+ formal oxidation of fluoride
> 500 °CBrauner Z Anorg Chem 1894 7 1
AgF2
Zweig, Fischer, Lancaster J Org Chem 1980 45 3597
metal [M] in highoxidation state n
ML
L L
L
X
L
nM
L
L L
L
F
L
n+
high-valentmetal fluoride
SN2 reaction
31%
+ AgF
F ¯
Nu
10
High-Valent Palladium Fluoride Complex
N
Pd
N N
N NNNB
N
N N
MeOTf2
2
OTfF
Pd
N N
N NNNB
N
N N
N
N
N
N
NB
NPd
N
N
N
N
N
Pd
N N
N NNNB
N
N N
MeOTf2
2
LUMO;only lobe on F
exposed
1 equiv KF 3 equiv 18-cr-6
MeCN, 50 °C, 5 min 90%
1. Pd(OAc)2, MeOH, 23 °C 2. KB(pz)4, THF, 23 °C
94%, 2 steps
1. PhI(4-CN-py)2OTf2, MeCN, 23 °C 2. 4-picoline, MeCN, 23 °C
83%, 2 steps
11
OTfF
Pd
N N
N NNNB
N
N N
N
NN
S OO
Pd
MeO
OiPr
Oxidative Fluorine Transfer
N
NN
S OO
Pd
MeO
F OiPr
N
OiPr
F
MeCN 85 °C, 10 min
+
80%
PdII, nucleophile, dz2
PdIV –F, electrophile, σ*Pd–F
PdIV –F
PdII
+
12Brandt, Lee, Boursalian, Ritter Chem. Sci. 2014, 5, 169
Late-Stage Fluorination with 18F Fluoride
N
Pd
N N
N NNNB
N
N N
MeOTf2
2
18F 18-cr-6, KHCO3
acetone 23°C, 10 min N
NS
O
O
OMe
Pd N
[Pd]
18F–Pd(IV)
acetone 85°C, 10 min
18F–Pd(IV)
acetone 85°C, 10 min
33 ± 7% RCY (n=7) 2 steps, from 18F
10 ± 2% RCY (n=7) 2 steps, from 18F
Lee, Kamlet, Powers, Neumann, Boursalian, Furuya, Choi, Hooker, Ritter Science 2011 334 639
[Pd]
Me
H
H H
O Me O
18FHH
H
O
NDAMS
O
O
OMOM[Pd]
O
NDAMS
O
O
OMOM18F
OTf18F
Pd
N N
N NNNB
N
N N
13
Biodistribution of Paroxetine
14
HN
FH
O O
O
Paxil
HN
18FH
O O
O
22 ± 4% RCY > 13 Ci / μmol
> 10 mCi prepared
OTf18F
Pd
N N
N NNNB
N
N N[18F]Paxil
Kamlet, Neumann, Lee, Carlin, Moseley, Stephenson, Hooker, Ritter PLoS ONE 2013 8 e59187
A Practical Fluorination Reagent: PhenoFluor®
FR
F
S
F
H
OF
Br
F
MeO
F
H2N
NBn
F
N
OAcN
F
O
OH
F
O Me
O
OMe
F
H
H H
N
F
Cl
MeO
F
OEt
O
N
F
N
F
95% 86% 88%
50% 90% 84%
75% 91%82%
88% 75%
95% 90%
Tang, Wang, Ritter J Am Chem Soc 2011 133 11482
N N
iPr
iPr iPr
iPrH
N N
iPr
iPr iPr
iPrCl
N N
iPr
iPr iPr
iPrF F
3 equiv CsF toluene, 80–110 °C, 3–20 h
OHR
Cl
N N
iPr
iPr iPr
iPrF F
1.2 equiv KOtBu 1.2 equiv Cl3C–CCl3 THF, 23 °C, 24 h 81%
4.0 equiv CsF MeCN, 60 °C, 24 h 87%
15
Practical 18F Fluorination
18
Oxfluor, K18F 130 °C, 20 min
RCC
heteroarenes
basic and protic functional groups
N
CN
18F
ROH
R
18F
N
N18F NS18F
HO
HO
OMe
O
HN
NO2
18F
NN
18F
OH
NMe
MeN
O
O
N
18F
MeO
H
H
72%% 96%
28% 86%
80%
67%
AcknowledgementsCurrent Group Members Collaborators
Funding
Beyzavi,, Hassan Hooker, Jacob Harvard AcceleratorBoursalian, Gregory Brady, Thomas Harvard Catalyst
D’Amato, Erica Mahmood, Umar NIH-NIGMS RO1Evans, Helen NIH-NIBIB RO1
Fujimoto, Teppei NSF-CareerGarber, Jeff Air Force
Harald Locke Sloan FoundationGoldberg, Nat Beckman Foundation
Ham, Won Seok Smith FamilyHoover, Andrew Mass Life Science CenterIvashkin, Pavel ACS PRF
Lee, Heejun SciFluorLi, Jiakun Merck & Co.
Mazzotti, Anthony Eli Lilly and CompanyMandal, Debashis AstraZeneca
Neumann, Constanze AmgenShi, Hang Bayer
Strebl, Martin BASFXu, Jess Sanofi Aventis
Zhao, Chen PfizerUCBUCB
Purification of PET Tracers
automated synthesis HPLC purification reformulation PET scanner
HPLC chromatogram ICP-MS Pd impurity: 5.3 ppb
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