late-stage fluorination
TRANSCRIPT
![Page 1: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/1.jpg)
Late-Stage Fluorination
Tobias RitterDepartment of Chemistryand Chemical BiologyHarvard University
![Page 2: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/2.jpg)
Positron Emission Tomography
hν
electron
• non-invasive• functional imaging modality • 18F is nuclide of choice
PET-MR MR PET
2
![Page 3: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/3.jpg)
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
![Page 4: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/4.jpg)
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
![Page 5: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/5.jpg)
18Fluoride Only Practical Fluorine Source for PET
cyclotron
fluoride: 18F ¯ fluorine gas: [18F]F2 = “18F+”
18F18F19F
19F2
receptor
18F19F
5
![Page 6: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/6.jpg)
18F ¯ 18F+
Challenges to Meet:
1. electrophilic fluorination reagent from 18F fluoride
2. late-stage fluorination
18F+
F
6
![Page 7: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/7.jpg)
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
![Page 8: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/8.jpg)
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
![Page 9: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/9.jpg)
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
![Page 10: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/10.jpg)
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
![Page 11: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/11.jpg)
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
![Page 12: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/12.jpg)
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
![Page 13: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/13.jpg)
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
![Page 14: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/14.jpg)
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
![Page 15: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/15.jpg)
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
![Page 16: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/16.jpg)
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%
![Page 17: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/17.jpg)
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
![Page 18: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/18.jpg)
![Page 19: Late-Stage Fluorination](https://reader033.vdocuments.us/reader033/viewer/2022050613/58a566251a28ab20528b5abd/html5/thumbnails/19.jpg)
Purification of PET Tracers
automated synthesis HPLC purification reformulation PET scanner
HPLC chromatogram ICP-MS Pd impurity: 5.3 ppb