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