Design and Development of Safe and Selective Deoxofluorinating

Report
DESIGN AND DEVELOPMENT OF
SAFE AND SELECTIVE
DEOXOFLUORINATING REAGENTS
Robyn Biggs
February 17th, 2011
University of Ottawa
13 NATURALLY OCCURRING FLUORINATED
ORGANICS
 Majority
are homologues of fluoroacetic acid
1
10% OF LAUNCHED DRUGS CONTAIN FLUORINE
5-Fluorouracil
Maraviroc
Diflucan
(Fluconazole)
Fluticasone propionate
Lipitor
2
ROLES OF FLUORINE IN MEDICINAL
CHEMISTRY
Can improve:
Metabolic stability
 Binding to target
 Solubility

Thrombin Inhibitor
Burgey, C. S. et al. J. Med. Chem. 2003, 46, 461.
3
OXIDATION OF C-H BONDS BY CYP450S
4
MECHANISM OF OXIDATION BY CYP450S
Active Site
5
DISCOURAGE OXIDATION BY ADDITION OF
ELECTRON WITHDRAWING SUBSTITUENTS
C-H Bond Strength= 99 Kcal/mol
C-F Bond Strength= 117 Kcal/mol
6
FLUORINE SUBSTITUTION EXPLOITED IN
MECHANISM OF ACTION OF 5-FLUOROURACIL
5-Fluorouracil
Inhibits DNA
Replication
7
URACIL CAN BE CONVERTED TO THYMIDINE
TRIPHOSHPATE FOR DNA REPLICATION
8
MECHANISM OF ACTION OF 5-FLUOROURACIL
•No dTMP formed
•No TTP formed
•DNA replication stopped
9
FLUORINATING REAGENTS OVER LAST 130
YEARS
10
REACTIONS WITH ELEMENTAL FLUORINE
Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
11
ELEMENTAL FLUORINE CAN BE VERY
DANGEROUS
High reactivity and toxicity
 Lack of selectivity

12
PERCHLORYL FLUORIDE AS FLUORINATING
AGENT
Gabbard, R. B.; Jensen, E. V. J. Org. Chem. 1958, 23, 1406.
13
PERCHLORYL FLUORIDE IS EXPLOSIVE
Explosion
University of Ottawa, 1982:
Glinski, M. B.; Freed, J. C.; Durst, T. J. Org. Chem. 1987, 52, 2749.
14
MORE STABLE/SELECTIVE ALTERNATIVES
F-F bond strength= 36.6 Kcal/mol
O-F bond strength= 44 Kcal/mol
15
O-F REAGENTS AS SELECTIVE FLUORINATING
AGENTS
Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
16
SAFETY STILL AN ISSUE WITH O-F REAGENTS
Reaction set-up:
1985:
• AcOF explosion
∨
∨
17
Adam, M. J. Chem. Eng. News, 1985, 63, 2.
SAFER ALTERNATIVES TO O-F REAGENTS
O-F Bond Strength= 44 Kcal/mol
N-F Bond Strength= 65 Kcal/mol
NFSI
Selectfluor
18
N-F REAGENTS IN SYNTHESIS
α:β 95:5
Differding, E.; Ofner, H. Synlett, 1991, 187.
Lal, G. S. J. Org. Chem. 1993, 58, 2791.
19
SELECTFLUOR BEST ELECTROPHILIC
REAGENT
Easy to handle (solid)
 Selective
 Stable

Radwan-Olszewska, K.; Palacios, F.; Kafarski, P. J. Org. Chem. 2011, 76, 1170.
20
SELECTIVELY REPLACING AN EXISTING
FUNCTIONAL GROUP WITH FLUORINE
Use nucleophilic reagent
21
FLUORINATING REAGENTS OVER LAST 130
YEARS
22
SF4 WAS FIRST NUCLEOPHILIC FLUORINATING
REAGENT
Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am. Chem. Soc. 1960, 82, 543.
23
MECHANISM OF SF4 REACTION
•HF generated in situ catalyzes
the reaction
24
DANGER OF RUNAWAY REACTION USING SF4
Catalyzes reaction
Rate increases with
production
25
PROBLEMS WITH SF4
Gas
 Highly toxic and corrosive
 Typically requires high temperatures (>100°C)
 Low selectivity

Middleton, W. J. J. Org. Chem. 1975, 40, 574.
26
CONVENIENT SUBSTITUTE FOR SF4
Markovskij (1973)
Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis, 1973, 787.
27
IMPACT WAS NOT REALIZED UNTIL1975
Middleton, W. J. J. Org. Chem. 1975, 40, 574.
28
DAST BECAME POPULAR IN
PHARMACEUTICAL INDUSTRY
Liquid
 Thermally unstable

29
PREPARATION OF DAST

Distillation step is hazardous
30
DAST PRODUCES HF DURING REACTION
•Similar to mechanism of SF4
•HF produced as byproduct
31
DAST USED IN SYNTHESIS OF MARAVIROC

Used in the treatment of HIV


Blocks viral entry into the host immune system cells
DAST used in synthesis of a key fragment
Åhman, J. et al. Org. Process. Res. Dev. 2008, 12, 1104.
32
THREE KEY FRAGMENTS ASSEMBLED TO
MAKE MARAVIROC
33
SYNTHESIS OF TROPANE
FRAGMENT
34
SYNTHESIS OF TROPANE
FRAGMENT
35
DAST STEP OUTSOURCED TO SPECIALIZED
FACILITY
36
COUPLING OF FRAGMENTS
37
COMPLETION OF β-AMINO ESTER FRAGMENT
38
FINAL ASSEMBLY OF MARAVIROC
39
DAST IS THERMALLY UNSTABLE
Recall: DAST step outsourced to specialized fluorination facility
Disproportionation
Detonation
Messina, P. A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42, 137.
40
EXPLOSION REPORTED WHILE DISTILLING
DAST (1979)
Explosion
Cochran, J. Chem. Eng. News, 1979, 57, 43.
41
STABILIZE WITH ENCUMBERING GROUP
AROUND SULFUR
Recall:
Detonation
42
DEOXO-FLUOR IMPROVES STABILITY

Degrades more slowly than DAST

Same decomposition temperature
Lal, G. S. et. al. J. Org. Chem. 1999, 64, 7048.
43
PREVIOUS FLUORINATING REAGENTS HAD
MANY UNDESIRED CHARACTARISTICS
Undesired Characteristics
Difficult to handle
Poor selectivity
Thermally unstable
44
FLUORINATING REAGENTS RECENTLY
DEVELOPED SHOW IMPROVEMENTS
Desired Characteristics
Ease of handling
Selective
Stable
Fluolead
XtalFluor-E
XtalFluor-M
45
FLUOLEAD
Selective deoxofluorinating reagent
 Resistant to aqueous hydrolysis
 Easily handled air stable solid
 Thermally stable

Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199.
46
IMPROVE STABILITY WITH STRONGER BOND
TO SULFUR
Recall:
Detonation
Disproportionation
47
C-S BOND STRONGER THAN N-S BOND
48
DEOXOFLUORINATIONS WITH
FLUOLEAD
49
Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199.
ALTERNATE APPROACH TO IMPROVE STABILITY
Recall:
stronger bond = increased stability
What if?
50
FIRST PREPARATION OF SOLID
DEOXOFLUORINATING REAGENT IN 1977
Markovskij:
• Salts react readily with nucleophiles
• Impact not recognized
Markovskij, L. N.; Pashinnik, V. E.; Saenko, E. P. Zh. Org. Khim. 1977, 13, 1116.
51
DIALKYLAMINODIFLUOROSULFINIUM SALTS
REDISCOVERED IN 2009
2009:
•Researchers at OmegaChem investigated DAST-like salts
XtalFluor-E
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
XtalFluor-M
52
INITIAL PREPARATION OF XTALFLUOR-E SALTS
Markovskij Procedure
53
DIFFERENT POLYMORPH FORMS ON SECOND
CRYSTALLIZATION
Crystallization
Mp 72-76°C
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401
Mp 83-85°C
54
CRYSTALS CAN EXIST IN MORE THAN ONE
PHYSICAL FORM

Have different physical properties

Important in pharmaceuticals
55
CRYSTALS CAN EXIST AS A METASTABLE OR
STABLE FORM

Most stable form desired

Easier to reproduce this form
56
CONTROL POLYMORPHS BY CONTROLLING
CRYSTALLIZATION CONDITIONS
Solvent
 Temperature
 Impurities
 Seeding

57
X-RAY POWDER DIFFRACTION (XRPD) USED
TO IDENTIFY POLYMORPHS
Lin (Counts)
5000
Type II
1000
10
20
30
Type I
2-Theta Scale
58
ALTERNATE PREPARATION AVOIDS HAZARDOUS
DISTILLATION
• Get more stable
polymorph
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
59
APPLICATIONS TO FLUORINATE ALCOHOLS
Pashinnik:
Bezuglov, V. V.; Pashinnik, V. E.; Tovstenko, V. I.; Markovskii, L. N.; Freimanis, Y. A.; Serkov, I. V.
Russ. J. Bioorg. Chem. 1996, 22, 688.
60
FLUORINATION WITH SALTS DOES NOT
PRODUCE HF
No free H-F released
61
REACTION IN CH3CN DID NOT PRODUCE
DESIRED PRODUCTS

Possible Ritter-type reaction
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
62
RITTER-TYPE REACTION IN CH3CN
Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045.
63
SOLVENT CHANGE PROVIDED PRODUCT
•Fluoride product produced very
slowly
•All of starting material consumed
within 5 minutes
64
MECHANISM OF DEOXOFLUORINATION WITH
XTALFLUORS
Recall:
65
FLUORIDE STARVATION LED TO SIDE
PRODUCTS
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401
66
FLUORIDE STARVATION LED TO SIDE
PRODUCTS
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
67
FLUORIDE STARVATION LED TO SIDE
PRODUCTS
68
MECHANISM OF DAST
Recall:
69
USE OF 3HFNEt3 as Additive

Serves as source of HF




Anhydrous
Inexpensive
Less corrosive than HF
Does not etch borosilicate glassware at <150°C
70
ORDER OF ADDITION IS IMPORTANT
71
HIGH CONCENTRATION OF ALCOHOL LEADS TO
ETHER SIDE PRODUCT
Want to minimize concentration
of alcohol
72
LOW CONCENTRATION OF FLUORIDE
CONTRIBUTES TO FORMATION OF SULFINATE
73
HIGH CONCENTRATION OF FLUORIDE WITH
RESPECT TO ALCOHOL FOR BEST RESULTS
74
COULD HF REACT WITH THE SALT AND FORM
A DIFFERENT SPECIES?

Could the following be occurring?
Unlikely because:
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
75
19F
NMR SUGGESTS DAST NOT FORMED IN
SITU
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
76
USE OF NON-NULCEOPHILIC BASE AS
ADDITIVE?
Recall:
77
USE OF NON-NULCEOPHILIC BASE AS
ADDITIVE?
78
ORDER OF ADDITION IS IMPORTANT
79
SUBSTRATE SCOPE FOR REACTIONS OF
ALCOHOLS WITH XTALFLUOR-E
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
80
SUBSTRATE SCOPE FOR REACTIONS OF
ALCOHOLS WITH XTALFLUOR-M
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
81
GEMINAL DIFLUORINATIONS OF CARBONYLS
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
82
NO GENERAL TRENDS OBSERVED

Need to optimize conditions for each substrate
Reagent Choice:
Additive Choice:
83
SUMMARY OF REACTIONS WITH SALTS
Right salt, additive, temperature
 Rapid reactions
 High yielding
 Increased selectivity

84
HOW SAFE ARE THESE REAGENTS?

Differential Scanning Calorimetry (DSC)
85
BROAD CURVES CORRESPOND TO GRADUAL
RELEASE OF ENERGY
86
SHARP CURVES CORRESPONDS TO SUDDEN
RELEASE OF ENERGY
87
Less D
Energy
Released
UponHigher
Decomposition
DSC
ATA FOR
R
Temperature
EAGENTS
Decomposition
of XtalFluor Salts
For
XtalFluor Salts
Ereleased
Tmax=155°C
=1641 J/g
Deoxo-Fluor
DAST
Xtalfluor-E
Xtalfluor-M
Ereleased
Tmax=205°C
=1260 J/g
Ereleased
Tmax=158°C
=1031 J/g
Ereleased=
T773
max=243°C
J/g
Couturier, M. et. al. Org. Lett. 2009, 11, 5050.
Couturier, M. et. al. J. Org. Chem. 2010, 75, 3401.
88
FLUORINATED ORGANIC COMPOUNDS
IMPORTANT IN MEDICINAL CHEMISTRY
Can increase:



Metabolic stability
Binding to target
Solubility
Maraviroc
5-Fluorouracil
89
MANY FLUORINATING REAGENTS CAN BE
DANGEROUS/DIFFICULT TO USE

Two types of fluorination


Electrophilic
Nucleophilic
90
INCREASE IN X-F BOND STRENGTH
CONTRIBUTES TO STABILITY OF ELECTROPHILIC
REAGENTS
F-F bond strength= 36.6 Kcal/mol
O-F bond strength= 44 Kcal/mol
N-F Bond Strength= 65 Kcal/mol
91
INCREASE IN Y-SFN BOND STRENGTH
CONTRIBUTES TO THERMAL STABILITY OF
NUCLEOPHILIC REAGENTS
92
SELECTIVE FLUORINATION OF ALCOHOLS AND
CARBONYLS WHEN USE XTALFLUOR SALTS
WITH AN ADDITIVE

Ease of handling (solid)
or
or
or
93
XTALFLUOR REAGENTS DEVELOPED AS
SAFEST NUCLEOPHILIC FLUORINATING
REAGENTS TO DATE
• Higher decomposition
temperature than DAST
and Deoxo-Fluor
• Less energy released
upon decomposition
94
ACKNOWLEDGEMENTS

Dr. W. Ogilvie




Natasha Gulati
Dan Carter-Ramirez
Lyanne Betit
Anthony Pianosi
95
96
97
X-RAY POWDER DIFFRACTION (XRPD)
98
STEREOSELECTIVE DEOXOFLUOROARYLSULFINYLATION
Proposed Mechanism:
99
FLUORIDE STARVATION LED TO SIDE
PRODUCTS
100

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